Note: Descriptions are shown in the official language in which they were submitted.
1~39~7~;~J
This application is a divisional of S.N. 275,337 filed 1 April, 1977, and
is directed to the preparation of intermediates of formula (V~ and the inter-
mediates so produced whereas the parent application is directed to the prepara-
tion of compounds of formula (I) and the compounds 90 produced.
The present invention relates to novel amino chromanols, to their
preparatlon and to anti-hypertensively effectlve co~lpositions containing them.
Belgian Patent No. 829611 discloses a group of hypotensive agents of the
formula (0):
o A4 6
and acid addition salts thereof wherein Al is a hydrogen atom or a
Cl 9 hydrocarbon group optically substituted by a hydroxyl or
Cl 6 alkoxyl group; A2 is a hydrogen atom or Cl 6 alkyl group or
NAlA2 is a 3 - 8 membered heterocyclic group optionally substituted
by one or two methyl groups; A3 is a hydrogen or halogen atom or a
Cl_6 alkyl, C2_6 alkenyl, Cl_6 alkoxyl, C2_6 alkenoxyl, Cl_6
allcylthio, hydroxyl, amino, Cl 6 alkylamino, Cl 6 dialkylamino,
nitro, trifluoromethyl, C2 7 acylamino, Cl 6 alkoxysulphonylamino,
carboxyl, nitrile or XOA7, xSA7, XS02A7, XNHA7, XNA7COA8, XNA7S02A8
or XNA7CC2A8 group wherein X is an allcylene group of 1 - 4
carbon atoms, A7 is an alkyl group of 1 - 4 carbon atoms and
A8 is an alkyl group of 1 - 4 carbon atoms, and A4 is
a hydrogen or halogen atom or A3 together with A~ forms
a -CH = CH - CH = CH-, -NH - CH = CH-, -CH2-CH2-CH2-CH2~
,
g ~6~-
or ~CH2-CH2-CH2-CO- system; A5 is a hydrogen atom or a
Cl 6 alkyl or phenyl group; and A6 is a hydrogen atom
or a Cl ~ alkyl or phenyl group.
It has now been discovered that a distinct group
o~ amino chromanols have use~ul anti-hypertensi~e act~vity.
Aocordingly the pre~ent lnvention pro~ides compounds
of the formula (I):
NR R
1 2 OH
~ 3 (I)
where~n Rl i9 a hydrogen atom or an alkyl group of up
to 4 osrbon atoms optionally substltuted by a chlorine
or bromine atom or by a hydroxyl group or by an alkoxyl
~roupo~ up to 4 carbon atoms or by a~ ac~loxy Kro~p of
up to 4 carbon atoms and R~ is a hydrogen atom or a~
slkyl group of up to 4 carbon atom~ or Rl is ~oined to
~ sothat together wlth the n~trogen atom to which they
are attached they form a 5-, 6- or 7- membered hetero-
alicycl~c ring which ls optionally ~ub~tituted by methyl;
Y is a group CO.R3,.C02R3, SO.R3. S02.R3, 3 2 3
C~O~)R3, C(R3)NOH, C(R3)NNH2, CONH2, CO.NR~R5, SO.NR4R5
or S02NR4R5 where R3 and R4 are independently a hydrocarbon
grou~ of up to 8 carbon atoms or such a group inertly
substituted by a ehlorine or bromine atom or by a hydroxyl
"
, .
. '`` '~ l~9t7t~
group ~r by an alkoxyl group o~ 1 ~ 4 car~on atoms or
b~ an acyloxy group of up to 4 carbon atoms or by 3
fluorine atoms attached to the same carbon atom and ~5
is a hydrogen atom or an alkyl group of up to 4 carbon
atoms; and salts thereof and O-acyl deri~atiYes thereo~
wherein t~e O-acyl mo~ety contalns up to lB carbon a~oms.
Su~tably Y i~ a COr~ C02R~, SO.~3v S02R~, SO.OR3,
S02.OR3, CO.NR~R5, SO.NR4R5 or S0~N~4R5 ~roup
Suitably Y is a CH(OH)R3, C(R3)NOH or C(R3)~NH2 group-
Suitably groups Rl i~clude the hydrogen atom and
the ~ethyl, ethyl, isopropyl, t-butyl, ~-hydroxyethyl~
~-a~etoxyeth~ methoxyethyl, ~-chloropropyl and the
like.
Suitable groups R2 include the methyl, ethyl, iso-
propyl and t-butyl groups and hydrogen~
Suitable cyclic groups NRl ~ include groups o~ the
~ub-~rmula (a):
R~ (a)
wherein Z is a bond joining the two oarbon atoms or is
a CH2, CH2.CH2, CH2.CH~.CH2, CH:CH9 O, S or NCH3 group;
R6 is a hydrogen atom or a methyl group and ~ is a
hydrogen atom or a methyl group,
.,
- 4 -
,
,
.~ :
1139'7~5
Particularly suitable groups NRl ~ include NHCH~t
NH(C~2)3Cl, N(CH3)2, NH.CH~CH3~, NH.C(CH3)3 and those
of the sub-~ormula (b):
~1 .
~ N ~ (b)
wherei~ zl i~ a bond ~o~n~ng the two carbon atoms or
2 ~ ~H2-C~2-~ -CH2-C~2-~H2- or -CH:CH_ gruup
or an oxygen atom.
The pre~erred groups NRlR2 are the piperid~no ~nd
pyrollid~o groups.
Preferred compounds o~ the formula ~ clude
those of the ~ormulae (II) and (III):
~J (II)
Y ~1
Y~'~
and salts and O-acyl derivati~es thereof wherein Y is
as defined in relation to formula (I)-.
., ,
. ~
39 7 ~ 5
,
Su~tably Y is a CO.R3, C02R3, SO-R~ S02-R3~
SO.OR3. S2.~, CO.NR4R5, s~.NR4Rs or $2NR4R5 group
where R3~ R4 and R5 are as defined in relation to formula (I).
Suitably Y is a CH(OH)R3, C(R3)NOH or C(R3)NNH2
group where R3 is as ~efined in relation to formula (I).
Particularly suitable values for Y in the compounds
~f ~ormulae (I) - (III) are the CO.R3, C02R3 or CO.NR4~5
groups, especially the C02R3 group.
Further particularly suitable ~alues for Y in the
compound.s of the ~ormulae (I~ re the S02.R3,
S2R3 and S2NR4R~ groups-
Another particularly suitable value ~or Y in the
compound~ o~ the formulae (I) - tI~ the C~I(OH)R3
group.
Pre~erred values for R3 in relation to a compound
of the formulae (I~ are the methyl and ethyl
groups.
A preferred O-acyl deri~ati~e of the compounds o~
the formulae (I~ - (III) is the O-acety~ derivative.
Most suitably the O-acyl deri~atives o~ the compounds
of the ~ormulae (I) - (III~ are those wherein the acyl
mo~ety is of the ~ormula -CO.Rl where Rl is an n-alkyl
group of 1 - 6 carbon atoms optionally substituted
by a phe~yl group.
., 3
3~7~
Most suitably ln the compounds of the formulae (I) -
~III) the group Y is attached to the 6- or 7- position
of the chroman nucleus.
One preferred position of attachment of the
group Y in the compounds of th~ ~ormulae (I) - (I~I)
ls the 6- position of the chroman nuc~eus~
Favoured value~ for Y include the ~-CH(OH)R3,
6-Co2R 5, 6-C(R3 )NOH, CO. R3, 6-Co.NH2 a~d 6-C~R~ 2
group~ more sultably where ~3 is a methyl or ethyl group
a~d especially where R~; is a methyl group.
Acid addition salts of the amino compounds of
fo~mulae (I) - (III) may be made with acids in conventional
manner. Suitable salt-~orming acids lnclude hydroohloric,
hydrobromic, s~lphuric, phosphoric, methanesulphonlc,
p-toluenesulphonic, acetic, propionic, succlnic, cltric,
tartaric~ m~ndellc, lactic, gluconic a~d other
pharmaceutically acceptable organic or inorganic acids.
The compounds of the ~nvention exist in opt~o~ally
acti~e form~. Those ~killed in the c~emical art will
realise that racemic mixtures of amino compounds can
often ~e separated into pure optical isomers using
such techniques as fractional crystallisation using optically
acti~e acids and the like.
-- 7 --
~ 3~ 5
_ Partlcularly suitable compou~ds of thi~ ~n~ention
include 6-ac~yl-3,4-dihydro~2,2-dimethyl-trans-4-
piperidino-2H-benzo[b3pyran-3-ol, 6-acetyl-3,4-dihydro-
2,2-dimethyl-trans-4~pyrrolidino~2H-benzoCb]pyran~3-ol,
6-carbomethoxy-3,4-dihydro-2,2-dimethyl-tran.s-4 piperidino-
2H-ben~o[b3pyran-3-ol, 6-carbomethoxy-3,4-dihydro-2,2-
dimethyl-trans-4-pyrrolidino-2H benzoCb]pyran-3-ol,
l-~trans-2l2-dimethyl-3-hydroxy-4-piper:Ldinochroman-6-yl]-
ethanone oxime, l-[trans-2,2-dimethyl~3-hydroxy-4
pyrrol~dinochroman-6-yl3-ethanone oxime~ 6-carboxamido-
3,4-dihydro-2,2-dimethyl-trans-4-piperid~no-2~-benzo~b~-
pyran-3-ol, and 6-carboxamido-3 ~ 4-dihydro-2, 2-dimethyl-
trang-4-pyrrolidino-2H-benzo[b3pyr~n-3-ol and their
pharmaceutically acceptable sal~s and O~acyl deri~ati~es
such as thelr O-acetyl deri~atives.
.. .. ~ . __ _~_ ._.. .. _ .. ... _ .
The most suitable group of compounds according to the
invention and to which the claims relate in broadest aspect are of
the formula (I)
NR ~
~ 1 2 OH
N3 (I)
--8--
'7t;~
~~ wherein Rl is a hydrogen atom or an alkyl group of up to 4 carbon
atoms or an alkyl of up to 4 carbon atoms su~stituted b~ a chlorine
or bromine atom or by a hydroxyl group or by an alkoxyl group of up
to 4 carbon atoms and R~ is a hydrogen atom or an alkyl group of
up to 4 carbon atoms or Rl is joined to R2 so that together they
form a C4-6 alkylene grou~ or said group substituted by methyl;
3, 2R3, SO.R3, S02R3, SO.OR3, S02.0R , CH(OH)R
C(R3)NOH, C(R3)NNH;~, CO.NH2, CO.NR4R5, SO.NR4n5 or SO;~NR,~R5where
R3 and R4 are independently a hydrocarhon group of up to 4 car~on
atoms or such hydrocar~on group inertly substituted by a chl~rine
or bromineatom or by a hydroxyl group or by an alkoxyl group of 1-4
carbon atoms or by 3 fluorine atoms attached to the same carbon atom
and R5 is a hydrogen atom or an alkyl group of up to 4 carbon atoms;
and pharmaceutically acceptable salts thereof and O-acyl derivatives
thereoE wherein the O-acyl moiety conta~ns up to 8 carbon a~-om~.
A further aspect of thi~ invention provides
pharmaceutical composition~ ~ultable for the treatment
of hypertension. Such compositions may be suitable for
parenteral or oral administration, but in general,
oral compositions are preferred because of convenience
of administration. Frequently, it is advantageous to
administer compounds of the invention together with an
adrenergic ~ blocking agent.
-8a-
~ ;,~
~ ~ .
.:
11~39~7~5
The compositions of this invention are preferably
in the form o~ unit dosage forms such as tablets or
capsules. Suoh unit dosage forms will usually contain
from O.S to 100 mg, for example, 2 to 5~ mg, and will
usu~lly be administered from 1 to 6 times a day so that
the daily dose ~o~ a 70 kg human is ~rom 2 to 150 mg,
for example, 10 to 100 mg.
The composit~ons of this in~ention may be formulated
~n conven~anal manner, for.example, in a manner sim~lar
to that used for.known anti-hypertensive sgents such as
-methyldopa, propranalol, guanethidine and ~he like.
In conventional manner, the compos~tlons o~ thls
in~ention may contain further actiYe agen~s such as
additional anti-hypertensi~e agents, diuretics and the
like,
The compounds of formula (I) may be prepared by
the reaction o~ an amine o~ the formula NHRlR2 with an
epoxide o~ the ~ormula (IV):
,~
Y ~ H3 (IV)
wherein Y ls as defined in relation to formula (I).
, . .
~;3~3~
~ ,. ,
The r~action of the amine and epoxide may be carried
out at any non-extrems low, medium or high temperature
(for example, -10C to 200C) but in general ambient
or slightly ele~ated temperatures are most suitable t~or
example, 12C to 100C). The reaction i~ normally
carried out in the presence of a sol~ent ~uch as alkanolic
or ketonic solvent (~or example, methanol, ethanol,
propanol9 acetone or methylethylketone).
. It has bee~ found that the reaction frequently
1~ proceed~ smoothly and suf~iciently if the reaction is
carried out in wa~med or refl~ing ethanol.
The above reaction has been found to give a trans
product substantially free ~rom the cis-i~omer.
The oximes and hydrazines of ~ormula (I) may also
be prepared ~rom the corresponding ketone by reaction
~th hydroxylamine or hydrazine in conventional manner,
for example in an alkanolic sol~ent such as metha~ol
or ethanol at a non-extreme temp~rature, for example
any convenient temperature ~rom 0C to 100C such as
the re~lux temperature of the solution.
Tho~e co~pounds of the for~ula (I) wherein Y is a
CH~OH)R3 group may also be prepared by the reduction of
the corresponding compound of the formula ~I) wherei~ Y
is a CO.R3 group under conventional conditions, for
exa~ple in an alkanolic solvent such as aqueous methanol
or ethanol at a non-extreme temperature, for example
0C to 50C, using a conventional reducing agent such
as sodium borohydride, lithium aluminium hydride, hydrogen
in the presence of a transition metal catalyst or the
like reaction.
-- 10 --
A
,
. ' '` .
~ 7 ~
The use~ul inter~ediate3 of the formula (I~) may
be prepared by proces~es analogous to tho~e described
in Belgian ~atent No. 829611.
A ~uitable method o~ preparing the compounds is
as follows:
Cl-c(cH3)2-c--cH
C CU
H3
" .
Heat in Diethylaniline
CH3
¦ B ~
NBS/DMSO/
. '
.3~'7~
-
Br
Br
~3
NBS/DMSO/
H20
H20/Acetorle
OH
yl
~3
¦ KOH/~ther
~IV)
In the preceding scheme yl is an inert group within
Y. Chemically reactive groups within Y such as oxime,
hydrazlneor alkanolic groups, may be prepared from
corresponding ketones as previously outlined.
The reaction conditions for the con~ersions shown
in the ~cheme are`con~entional and will be understood
by the skilled man from the available literature such
as Belgian Patent No. 829611.
~ ~ , ,
- 12 -
- -:
lL~39'7t~5
,,
Other groups Y may be prepared from analogous moieties in
known manner, for example a nitrile may be hydrolysed to yield
a carboxamido group. The nitrile would of course have the
formula (V)
NR R
1 2 OH
C~ ~cc~3 (V)
wherein Rl and R2 are as defined for formula (I).
The O-acyl derivatives of the compounds of formula (I) may
be prepared by conventional methods of acylation such as by
reaction with an acid anhydride, acid halide or the like.
The following Examples illustrate the invent.ion:
- 13 -
~,
.3~ 6t.
EXAMPLE 1
~ -4-piperidino-
and
(b) 6-Acetyl-3,4-dihydro-2,2-dimethyl-trans-4-isopropyl-
rides
p-Hydroxyacetophenone (3~.66 g), sodium hydroxide
pellets (14.80 g), 40~ benzyltrimethy7~mmonium hydroxide
in methanol (51.75 g) and ~-methyl-3-chlorobutyne (61.25 g)
were stirred in water (225 ml) and d~chloromethane (225 ml)
for 4 days at room temperature~ After separa-tion o~
the layers~ the aqueous layer wa~ extracted twice w~th
chloroform, and the combined organic phase evaporated
leaving a viscous l~quid which was taken up i~ ether and
washed three t~mes with 10% sodium hydroxide solutlon
and once with water before drying over sodium sulphate.
Remov~l o~ dryin~ agent an~ sol~ent, and distillation
at 1,0 mm Hg gaYe an oil (55.31 g) ~hich was dissolved
in N,N-diethylaniline (275 ml) and heated at 210-220C
~or 8 hours under nitrogen. The ma~or part of the
solvent was distilled off, and treatment of an ethereal
solution of the residue with anhydrous ethereal hydrogen
chloride precipitated the remainder, leaving an oil
after sol~ent evaporation which was distilled giving
~ ~ ~ ~ (40002 g),
b.p. 100-102/0,2 mm Hg.
- 14 -
.
~ ~l3~ ~6t:~
.~ .
Addition to this ~hromene (39.07 g) dlssolved in
dimQthyl sulphoxide ~390 ml) containing water (7.00 ml),
o~ N-bromosuccinimlde ~69.00 g) with ~igorou~ stirring
and cooling, followed by dilutlonwith water and extraction
via ethyl acetate gave ~
thyl-211-b~nzo Ib ]D~-ran-4-ol as pale pink
crystals (44.65 g) of m.p. 109-113C from ethyl acetate.
The bromohydrin (~9.35 g) was vigorously ~tirred in
dry ether (3.9 litres) containing potassium hydroxide
pellets (39.00 g) for 4 days at room temperature.
Filtration and evaporation followed by recrystallisatio~
from 60-80 petroleum ether yielded ~ POXy-
~ as cream
coloure~ crystals (22.00 g) m.p. 75-76C.
This epoxide (10.00 g) and piperidine (3.5 ml)
were re~l~ed in ethanol (100 ml) for 24 haurs. Remo~al
of sol~ent, addition of ether, washing with water before
dryingJ followed by filtration and treatment of the ethereal
solution with ethereal hydrogen chloride, gave a
precipitate wh~ch was collected and washed with dry ether
leaving ~-acetyl-3,4-dihydro-2,2-dimethyl-trans-4-
p~peridino-2H-benzo~b 3pyran ~-ol hydrochloride as a
white solid (12.33 g) m.p. 234-236C.
Similarly prepared from the epoxide was 6-acetyl-
3,4-dihydro-2,2-dimethyl-trans-4-isoprop~lamino 2H-
benzo~b]pyran=3-ol hydrochloride as a white solid of
. .
m.p. 250-253C.
-- 15 --
~' 1 1 3~ 7 ~ 5
EXAMPLE 2
6-Acetyl-~,4-dihydro-2,2-dimethyl-trans-~-piperidino-
2H-benzo~b~pyran-3-ol (~.00 g), hydroxylamine h~dro-
chloride (0.8~ g) and sodium hydroxicle pellets (0.50 g)
were refluxed in methano7 (150 ml) for 50 hours. After
cooling the olvent was eYaporated and the residue
taken up in ether and washed with water until the washings
were neutral, leaving a white solid ~2095 g) which wa~
chromatographed on ~ilica gel (100 g) using a gradient
elution technique with ethyl acetate-60~80 petroleum
ether. A~ter elutio~ of starting material, the anti-
epimer was obtained ~ 1.37 g), pure by thin layer
chromatographic and nmr analysis.
The oxime (0.77 g) dissol~ed in 'sodium dry'
ether (20 ml) was treated with methane sulphonic acid
(0~16 ml). A preciiitate farmed which was c~llected
(0.9~ g) and recry~tallised from ethanol-ether giving
1-~trans-2,2-dimethyl-3-hydroxy-4-piperidino-
chro an-6-yl]-ethanone oxime methane sul,phonate as a
white solid (0.70 g) m.p. 208.5-210C.
Similarly prepared was l-~trans-2,2-dimethyl-3-
-- ;:; .,_ . . r
hydrox~-4-isopro ylamino-chroman-6-yl~-ethanone oxime
~ of m.p. 215.5-217C.
- 16 -
-
.
6-Acetyl-~,4-dihydro-2,-dimethyl-trans-4-piperidino-
2H-ben20~b~pyran-3-ol (l.OO g) was dissolved in
methanol (10 ml) and water (2 ml) and treated with sodium
borohydride (O.10 g) with stirring at room temperature
during ~ minutes. A~ter.a~ additional 2 hours stirring,
the reaction mixture was diluted with water (100 ml),
Extraction using diethyl ether ga~e l-hydroxy-l-ttrans-
__
~=S~]_
e~hane (1.00 g) which was dissolved in dry ether and
treated with ethereal hydrogen chloride giving the
hydrochloride salt (0.90 ~) m.p. 179 - 181C as a white
powder from e~hanol-ether,
Similarly prepared was l-hy~rD}y-l-[t~ 2,2-
h ~ m.p. 203C.
. . .
-
3 7~i
EXAMPLE 4
pyrrolidino-2H-benzv~b~p~ran-~-ol methane sul~honate
To a stirred suspension of methyl P-hydroxy-
benzoate ~50.~ g), ~nhydrous potassium carbonate (60.8 g)
and potassiu~ iodlde (3.0 g) in acetone (500 ml) under
nitrogen, was added 3-met~yl-3-chlorobutyne (85.4 g)
in acetone (100 ml). The suspension w~s stirred and
heated to reflux temperature for a further 42 hours
10 before coollng and filtering. Remo~al o~ solvent gave
a gum which was taken up in diethyl ether and ~ashed
three times with lN sodium hydroxida solution, and once
with water before drying o~er sodium sulphate. Removal of
dr~in~ agent and solvent gave a ~um (74.~6 g) which wa~
15 shown by nmr to be a mixture of the propargyl ether and
dimethylchromene.
Cyclisation was completed by heating this mixture
(74.00 g) in o-dichlorobenzene ~150 ml) for 3.5 hours.
Removal of solven~ and distillation at 0.15 mm Hg gave
20 the analytical sample ~60.45 g) boiling at 114-120
having a nmr spectrwm in accord with that reported ~or
6-carbomethoxy-2,2-dimethyl-chromene by K. Shima,
S. ~isada and I. Inagaki, Yakugaku ~ass. 91 1124 ~1971).
.
. .
s
Addition to this chro~ene (60.40 g) dissolved in
dlmethyl sulpho~ide ~250 ml) containing water (10 ml)
o~ N-~romosuccinimide (99.00 g) with vigorous stirring
and cooling, followed by dilution with water and
extraction via ethyl acetate, and recrystallisation
from 60-80 petroleum ether gave 6-car
~=~" ~
(63.02 g) m.p. 88-90C. The bromohydr~n
(36.00 g) was ~igorously stirred in dry ether (2.5 litres)
contai~ing potass~um hydroxide pellets (36.00 g) for
3.75 days at room temperature. Filtration and evaporation
~ollowed by recrystallisation ~rom 60-80 petroleum ether
yielded ~-carbomethoxy-trans-3,4-epoxy-3,4-dihydro- _ -
dimethyl-2~-benzo~b~pyran as white needles of m.p. 51-5~C
(19.55 ~).
Thl~ epoxide (19.55 g) and pyrrolidine (8.35 ml)
were refluxed in ethanol (35Q ml) ~or 22 hours~ Removal
of solve~t ~ave a crude solid (2~3~ g) part of which
tl5.27 g) was dissolved in ethanol (80 ml) and treated
with methane sulphonic acid (3.40 ml). Addition of
ether (200 ml) gave crystalline material which was
recrystallised from ethanol-diethyl ether as white
needles being ~ -
trans-4-pyrrolidino-2H-benzo[b]pyran-~-ol me~hane
sulphonate (16.30 g) of m.p. 138-140C,
, .. - 19 --
3~ S
~ -4-piperid~no-
2H-benzo~b]pyran-3-ol
and
6-Carbamoyl-3,4-dihydro-2 9 2-dimethyl-tra~s~ sopropyl-
To trans-4-piperidino-3,4-dihydro-2,2-dimethyl-6-
cyano-2H-benzo~b3pyran-3-ol hydrochloride (0.70 g~
stirred in t-butanol (10 ml) was added finely powdered
potassium hydroxide (1.5 g). The mixture was refluxed
for 50 minutes and after cooling poured into brine (25 ml)
and the ~olut~on extracted with ohloroform (3 x 10 ml).
The combined extrac~s were dried, and removal o~ drylng
agent and ~olvent gave a pale yellow solid (0.32 g)
of m~p, 229-230C. Some of this solid ~Q.25 g) dissolved
in ethanol and treated with methanesulphonic acid ~0.06 ml)
~nd ether. A gum ~ormed which solidi~ied after decanting
off ~ol~ent and addi~g dry ether. Three recrystallisations
from ethanol-ether gave
methyl-trans-4-piperidino-2H-benzo~bJpyran-3-ol methane
sul~honate (0.22 g) a white solid of m.p~ 229-230C.
Similarly prepared from trans-~-isopropylamino-3,4-
dihydro-2,~-dimethyl-6-cyano-2H-benzo[bJpyran-3-ol
hydrochloride (0.70 g) gave ~ -
2,2-dimethyl-trans-4-isopro~ylamino-2H-benzo[b]pyran-3-ol
methane sulPhonate (0.27 g) as a white solid o~ m.p.
176-177G from e~hanol-ether.
- 20 -
.
,
$XAMPLE 6
a~L~
The following results were obta~ned a~ter oral
administration in DOCA-salt treated hypertensive rats
Emethod o~ I.M. Cl~xto~, M~G. Palfreyman, R.H. Poyser
and R.L. Whitin~ 5D~ D~ L~ æ~a~Y~
~7, 179 (1976)] or spontaneously hyperten~ive rats ~SHR)
at the ~ollowing doses:
,, , . . .. , . , ,
Compound of T~me Pos+% Change in % Change in
Example No. Dose (hrs.~Pressure Heart Rate
~ ., _ , .., . _
l (a) l - 58 ~ 58
at lOOm~/k~ 2 - 47 + 17
~ - 49 ~ 25
24 - 24 + l~
48 - 14 -~ l .
__ . . ,, .
2 l - 33 ~ 27
at OOm~/~g 2 - 31 ~ 24
4 - 37 + 31
... Z~ - 7 _ .,
- 21 -
~ 976~
,
__ _ . Time Post % Change in ~e~rt ~ate
___ _ . _
4 1 - 27 I 10
5a (0 mg/kg 2 - 23 + 5
24 ~ 3 - 10
_ 1 - 21 ~ . .
at 1 Omg/kg 6 ~ 20 -
3 1 + 3
15at lOOm~/kg 2 - 32 ~ 3
6 - 18 + 4
______________ 24 _ _ S _ - 9 _
The compounds tested did not have a high level of
acute toxicity, ~or example oral LD50 values greater
than 200 mg/kg are to be expected.
- 22 -
~'`' ~ '
~ ;3L~
~XAM
Th~ intermediate cyano compounds o~ Example 5
may be prepared as follows:
4-Cyanophenol (19.6 g), sodium hydroxide pellets (9.9 g),
3-chloro-3-methylbut-1-yne ~40.83 g~ and ben~yltrimethyl
ammonium hydroxide (34.5 g, 40% ln metharlol) wera stirred
in methylene chloride (150 ml) and water ~150 ml) at
room temperature ~or 4 days. A~tèr separation of the
layers, the aqueous layer was extracted twice with chloroform.
The com~ined organic extracts were e~aporated and the
residue taken up in ether and washed with water and
2N sodium hydroxide solution before drying over anhydrous
sodium sulphate. Removal o~ solvent and drying agent
gave an oil (15.72 ~). Di~tillation a~ 0.5 mm ~g gave
the analytlcal material as the fraction boiling at
96-102C (10.13 g)~
Cyclisation o~ the 3-(p-cyanophenoxy)-3-methybut-1-
yne (9.77 g) was accompllqhed by heating in diethylaniline
at 210-220C under nitrogen. Purification by disti.llation,
and extraction with dilute hydrochl~ric acid gave 2~L_-
dimethyl-6-c~ano-?H-benzo~b ~ as a colourless oil (6.84 g),
which slowly crystallised on standing, having a nmr
spectrum showir.g signals at Sl.46, 6.25 (d, J = 10),
5.67 (d, J = 10), 6.74 (d, J = 8), 7.18 (d, J = 2),
7'34 (q' J = 8,2)
-- ~3 --
.i
,
\
To a stirred cooled solution of 2,2-dimethyl-6-
cyano-2H-benzo[b]pyran (6.56 g) in dimethyl sulphoxide (65 ml)
and water ~1.30 ml) was added ~reshly crystallised
N-bromosuccinimide (12.63 g) in one portlon. Dilution
with water a~ter stirring for an add:itional 1 hour, and
isolation via ethyl acetate gave t ~n _ - ~
~ ~ano-2H-benzo~ as
a white crystalline solid (10.54 g), a small portion of
w~ich recrystallised ~rom 60-80 petroleum ether had
m.p. 12~-12805C~
This bromohydrin (5.63 g) was s-tirred with
sodium hydroxide (0.80 g) in dioxan (75 ml) and water (18 ml)
at room temperature for 3 hours. 'Work up by dilu~ion
and extraction with ethyl acetate gave ~L~ ~3E~L ~
S~S~. ~J-
~y~ t4.35 g) as a colourless oil having signals at
~1.26 and 1.54 (-CH3), 3.80 (d, J = 4, ~-4), 3.40 (d,
J = 4, H-3), 6.77 (d, J - 8, H-8), 7,43 (q9 J = 8,2
4.7) and 7.58 (d, J = 2, H-5) in its nmr spectrum.
Treatment of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6- ~Qn~-
2E-benzo[b~pyran (2.09 g) with piperidine (0.86 g) in
re~luxing ethanol (60 ml) for 24 hours followed by
evaporation of sol~ent gave a yellow oil which was dissolved
in the minimum quantity of ethanol and treated with
ethereal hydrogen chloride to give cry~tals of trans-
-4-piperidino-~l4-dih~dro-2~2-dimethyl-6-cyano-2H-
benzo[b~yran-3-ol h~drochloride on standing (2.06 g)
o~ m.p. 253-257C.
- 24 -
.
:
'
.
,:
Similarly prepared from the epoxide was trans-4-
ano-,2H-
ben~o~b]pyran-3-ol hydrochlor~de m.p. 251C~
- 25 -
