Note: Descriptions are shown in the official language in which they were submitted.
wo 93/1~107 pcr/GBs2/o2lls
-` 2112~003
PHENOL DERIVATIVES AS AGONISTS OF A CYCLI~ AMP DEPENDENT PROTEIN KINhSE
The present invention relates to phenol derivatives,
s processes for their preparation, intermediates in their
preparation, their use as medicaments and to pharmaceutical
compositions comprising them.
The compounds of this invention are agonists of a cyclic AMP-
o dependent protein kinase (cA-PrK) (see J. Biol. Chem., 1989,
264, 8443 - 8446) and are of use in combatting such
conditions where such agonism is thought to be beneficial.
They are likely to have anti-proliferative, anti-aggregatory,
cholesterol-lowering,~smooth muscle relaxant, positive
lusitropic, anti-allergic or anti-inflammatory activi_ies.
They are likely to be useful in the treatment of
; cardiovascular diseases where there is a component of
diastolic failure, cancer, psoriasis, atheroschlerosis,
thrombosis, re-stenosis, chronic reversible lung disease such
0; as asthma and bronchitis, allergic disease such as allergir
asthma, allergic rhinltis and urticaria or gut motility
dlsorders such~as~lrrltable bowel syndrome.
Accordingly the present invention p~ovides compounds of the
2;5~ fo~rmula ~
R
; or pharmaceutically acceptable salts thereof, wherein :
RO is OH or a bioprecursor thereof,
R1 is AOC02H, P(Z)~OH)(OR2], S02H, S03H or 5-tetrazolyl or a
bioprecursor thereof,
~::
WO93/10107 PCT/GB92~02119
2 1~0 ~ ~ 2
A0 is CH2, CHF, CF2 CR3(oR4), CO or C~oR5)(oR6),
R2 is phenyl, C3_5cycloalkyl, C3_5cycloalkylC1_4alkyl, or
s C1_galkyl optionally substituted by C1_4alkoxy,
,
R3 is H, methyl or ethyl,
~;~ R4 is H or C1_3alkyl,
1 0
; ~ R5 and R6 are each C1_3alkyl or together form a 1,2-~; ethanediyl g.oup or 1,3-propanediyl group,
Z is O or S, and
;~ Ar is phenyl optionally substituted by one to three groups
independently~selected from C1_6alkyl, C2_6alkenyl,
1_6alkoxy, C3 6alkenyloxy, C3_6cycloalkyl,
: C3_6cycloalkoxy,:Cl_6alkylthio, phenyl, phenylthio,
~ benzyloxy, ~1 6polyfluoroalkyl, C1_6polyfluoroalkoxy,
halo, N(R7)2 or NHCoR7 wherein R7 is H or Cl_6alkyl, or
~h~ : -X(CH2)nY- attached to adjacent carbon atoms of the
phenyl ring wherein X and Y are independently CH2 or O
and n is 1 to 3, wherein said Cl_6alkyl, C2_6alkenyl or
~ :Cl_6alkoxy groups can be independently substituted by OH,
C1_6alkoxy, C3_6cycloalkyl, N(R7)2, Co2R7 or CoN~R7)2.
Bioprecursors of the groups R0 and R1 are derivatives thereof
which are convertible in vivo into the groups R0 and Rl.
A suitablT bioprecursor of the group R0 is oR8 wherein R8 is
alkanoyl (for example acetyl), arylC1_~alkanoyl (for
: example phenyl C1_4alkanoyl such as benzoyl)~ arylsulphonyl
`~ ; (for example optionally substituted phenylsulphonyl or
toluenesulphonyl) or C1_4alkylsulphonyl
(for example methylsulphonyl).
When R1 is A0C02H a suitable bioprecursor is A0CO2R9 wherein
R9 is an ester-forming group.
,~
',~
WO93/10107 2 12 4 0 0 3 PCT/GB92/02119
_ 3 -
When Rl is P(Z)(OH)(OR2~ a suitable bioprecursor is
P~Z)(OR2)2 wherein Z and R2 are as hereinbefore defined or
P(Z)(OR2~(OR10) wherein R10 is an O-protecting group.
s Suitable O-protecting groups include pivaloyloxymethyl,
propionyloxymethyl and pivalolyloxycarbonyloxymethyl.
When R1 is 5-~etrazolyl, a suitable biopricursor is a
N-protected derivati~e thereof. Suitable N-protecting groups
0 include pivalolyloxymethyl, propionyloxymethyl and
pivalolyloxycarbonyloxymethyl.
Alternatively bioprecursors of the groups R0 and R1 are those
formed when R1 and R0 are linked together to form a cyclic
structure such that Rl-R0 is A1CO2 or A20CH20, in which :
i ^
A~1~is CH2, CHF, CF2,~CR3(oR4), CO or C(oR5)~oR6),
A2 is p~Z)oR2 or~CR3;(CO2R9), and
R2 to R6, R9 and Z are as hereinbefore defined.
i i ~
Suitably R0 is hydroxy or oR8, preferably hydroxy.
Z5~ ~Suit~ably Rl is A0CO~H~or A0Co2R9.
Suitably R1 is P(Z)~OH)(OR2) or P(Z)(OR2)2.
Suitably ~1 is~SO2H, SO3H or 5-tetrazolyl.
Suitably R1 and R0 are linked together such that R1-R0 is
~ A1CO2.
h~ Suitably R1 and R0 are linked together such that R1-R0 is
is A20CH20.
By the term alkyl is meant both straight- and branched- chain
alkyl
;
WO93/10107 PCTfGB92/02119
4 - ~
2i~Q03
By the term C1_6polyfluoroalkyl is meant a C1_6alkyl group
having at least one hydrogen replaced with fluoro, e.g. CF3
or CF2CF2H.
s Suitably R2 is methyl, ethyl, propyl, butyl, pentyl, hexyl,
2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl
or cyclopropylmethyl.
Suitably R3 is H, methyl or ethyl, preferably H or methyl.
Suitably R4 is H, methyl, ethyl or propyl, preferably H or
methyl.
Suitably R5 and R6 are independently methyl, ethyl or propyl,
preferably together they form a 1,2-ethanediyl group.
Preferably Z is 0.
~ Suitably R9 is Cl_4alkyl optionally subs~ituted by hydroxy,
;~i?~ 20~e.g. 2-hydroxyethyl~or arylCl_4alkyl (for example
phènylC1_4alkyl such as benzyl).
Suitably Ar is phenyl optionally mono-substituted by a group
as~hereinbefore de~fined, for example in the 2,3, or 4
2s ~posltions by C1_6alkyl, Cl_6alkoxy, C3_6alkenyloxy,
Cl~_6alkylthio,~ phenyl~, phenylthio, benzyloxy, CF3, halo or
NHCoR7.
Suitably Ar is phenyl di-substituted by any groups as
hereinbefore defined, for example in the 3,4-,3,5-,2,3-,2,4-
or 2,5-, positions by groups independently selected from
C2_6alkenyl, C1_6alkoxy, C3_6cycloalkoxy, halo, -X(CH2)nY- or
Cl_6alkoxyC1_6 alkoxy.
; 35~ Suitably Ar is phenyl trisubstituted by any ~roups as
hereinbefore defined, for example in the 2,3,4-, 2,3,5-, or
3,4,5-positions by groups independently selected from
C2_6alkenyl, Cl_6alkoxy or halo.
W093/10107 21 2 4 0 0 3 PCI/GB92/OZ119
- 5 -
Examples of Cl_6alkoxy include methoxy, ethoxy, propoxy,
butoxy, or pentyloxy.
Examples of Cl_6alkyl include methyl, ethyl, propyl, butyl,
s isobutyl or pentyl.
Examples of halo include fluoro, chloro, bromo or iodo.
Parti~ular compounds of this invention include :
2-(5-tetrazolyl)-5-(2,3-dipropoxyphenyl)phenol, or
ethyl 2-hydroxy-4-~2,3-dipropoxyphenyl)phenyl phosphonate,
lS and pharmaceutically acceptable salts thereof.
;~ This in~ention covers all tautomeri , geometric and optical
isomeric forms of compounds of formula ~l).
Compounds of the formula ~l) can form pharmaceutically
acceptable base addition salts with me~al ions, such as
alkali metals for example sodium or potassium, or with an
ammonium ion.
,
~25 In order to use a compound of the formu}a (l) or a
pharma~eutlcally acceptable salt thereof for the treatment of
humans~and other mammals it is normally formulated in
arcordance with standard pharmaceutical practice as a
pharmaceutical composition.
Compounds;of formula (l) and their pharmaceutically
acceptable salts may be administered in standard manner for
the treatment of the indicated diseases, for example srally,
sublingually, parenterally, transdermally, rectally, via
inhalation or via buccal administration.
~ .
Compounds of formula (l) and their pharmaceutically
accep~able salts which are acti~e when given orally or via
buccal administration can be formulated appropriately in
WO93/10107 PCT/GB92/02119
~2~03 - 6 -
dosage forms such as liquids, syrups, tablets, capsules and -
lozenges. An oral liquid formulation will generally consist ;
of a suspension or solution of the compound or salt in a
liquid carrier for exampIe, ethanol, glycerine or water with
s a flavouring or colouring agent. Where the composition is
in the form of a tablet, any pharmaceutical carrier routinely
used for preparin~ solid formulations may be used. Examples
of such carriers include starch, celluloses, lactose, sucrose
and magnesium stearate. Where the composition is in the
O form of a capsule, any routine encapsulation is suitable, for
example using the aforementioned carriers in a hard gelatin
capsule shell. Where the composition is in the form of a soft
gelatin shell capsule, any pharmaceutical carrier routinely
used for preparing dispersions or suspensions may be
lS considered, for example aqueous gums, celluloses, silicates
or oiIs an~ are incorporated in a soft gelatin capsule shell.
; Typical parenteral compositions consist of a solution or
suspension of the~compound or salt in a sterile aqueous
2~0 ~or non-aqueous carrier optionally containing a parenterally
accept~able oil or solubilising agent, for example
; polyethylene glycoL, polyvinylpyrrolidone, lecithin,
2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil.
. ~.
Zs~ ~A typical suppository formulation comprises a compound of
formula (l) or a pharmaceutlcally acceptable salt thereof
which is acti~e when administered in this way, with a binding
and/or lubricat~ing~agent, for example polymeric glycols,
gelatins, cocoa-butter or other low melting vegetable waxes
or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional
aqueous or non-aqueous vehicle, for example a cream,
ointment, lotion or paste or are in the form of a medicated
35- ~plaster, patch or membrane.
Typical compositions for inhalation are in the form of a
solution, suspension or emulsion that may be administered in
the form of an aerosol using a conventional propellant such
WO93/10107 2 12 4 O ~ 3 PCT/GB92/02119
.
-- 7 --
as dichlorodifluoromethane or trichlorofluoromethane, or are
in the form of a powder for insufflation.
Preferably the composition is in unit dosage form, for
s example a tablet, capsule or metered aerosol dose, so that
the patient may administer to himself a single dose.
Each dosage unit for oral administration contains suitably
from 0.001 mg~Kg to 30 mg/Kg, and preferably from O.OOS mg/Kg
0 to 15 mg/Kg, and each dosage unit for parenteral
administration contains suitably from 0.001 mgtKg to 10
mg/Kg, of a compound of formula (1) or a pharmaceutically
acceptable salt thereof calculated as the free acid.
S The daily dosage regimen for oral administration is suitably
about 0.001 mg/Xg to 120 mg/Kg, of a compound of formula ~1)
or~a pharmaceutically acceptable salt thereof calculated as
the free acid. The daily dosage regimen for parenteral
adm~nistration is~suitably about 0.001 mg/Kg to 40 mg/Kg, for
example about 0.005 mg/~g to 10 mg/Kg, of 2 compound of the
formula ~1) or a pharmaceutically acceptable salt thereof
calculated as the free acid. The active ingredient may be
administered as required for example from 1 - 8 times ~ day
or by infusion. The compositions of the invention are
agonists of a cA-PrK and are of use in co~batting such
:
-~ conditions where such agonism is thought to be beneficial.
Such conditions can be treated by administration orally,
sublingually topically, rectally, parenterally or by
inhalation. For administration ~y inhalation dosages are
controlled by a valve, are administered as required and for
~n~adult are conveniently in the range 0.1 - 5.0 mg of a
compound of the formula (1) or a pharmaceutically acceptable
~; salt thereof.
`
3s The compounds of this invention may be co-administered with
other pharmaceutically active compsunds, for example in
;~ combination, concurrently or sequentially. Conveniently the
compounds of this invention and the other active compound or
compounds are formulated in a single pharmaceutical
W093/tO107 PCT/~B92/02119
~ ~ ~ e ~ 0 3 8
composition. Examples of compounds which may be included in
pharmaceutical compositions with the compounds of the formula
(l) are bronchodilators such as sympathomimetic amines for ;
example isoprenaline, isoetharine, sulbutamol, phenylephrine
S and ephedrine or xanthine derivatives for example
theophylline and aminophylline, anti-allergic''"agents for ::
example disodium cromoglycate, histamine Hl-antagonists,
drugs used in the treatment of cancer such as those which
inhibit the synthesis of or inactivate DNA, for example
: lO methotrexate, fluoracil, cisplatin, actinomycin D, anti-
: atherschlerotic agents for example cholesterol lowering drugs
such as HMGCoA reductase inhibitors, bile acid sequestrants,
drugs for the treatment of psoriasis, for example retinoids,
: anthralin, anti-inflammatories for example cortiscosteroids,
non-steroid anti-inflammatories such as aspirin,
:; antithrombotics for example dipyridamole, or fibrinolytic
agents. ~ ~
In~anothèr~ aspect~the present invention provides a process
20~:for the preparation~of compounds of the formula (l) or
pharmaceutically acceptable salts thereof, which process ':
: comprises : :
a) fo~ compounds~wherein Rl is AOC02H or AOC02R9 and :
25 ` ~ ~
AO is CR3 (oR4) ~ ~:
réactlng in the presence of a strong base a compound of the
:: :formula ~2) :
:~; 30
: ' : ~f
~'~:; ~ 11 (2)
3s wherein Rll is methyl and Al is as hereinbe~ore defined,
'~ ~
:
2124003
WO93/10107 PCT/GB92/02119
_ 9 _
with a compound of the formula (3) :
R3CoCO2R9 l3)
wherein R3 and R9 are as hereinbefore defined~to form a
compound of the formula (4) :
~Ar
ll
R'2~. (4)
OR
wherein R12 is C:R3 (OH) C02R9 and R3, R9, Rll, and Ar are as
hereinbefore defined and 'chereafter optionally reacting with
15 a: Cl_3alkylating agent ~o form the corresponding compound
wherein R12 is C~3 ~OCl_3alkyl) CO;~R9,
is CO,
reacting in the presence of a strong base a compound of
; 20 the formula ~2) as hereinbefore defined with a compound of
the ormula (5) :
R9o2c~o2R
2s: wherein ~9 is as hereinbefore defined to form a compound of
~ _ the formula (4) wherein R12 is COCO2R9 and R9, R11 and Ar are
: ~ as hereinbefore defined,
A0 is CH (OH~,
: 30 reacting a compound of the formula (4) wherein R12 is COC02R9
~: and R9, R11, and Ar are as hereinbefore defined with a
reducing agent to form the corresponding compound wherein R12
ls CH (OH) CO2R9,
iv) A0 is CH2,
W093/10107 PCT~GB92/02119
2124003 - lO- `
reacting a compound of the formula (4) wherein R12 is COC02H
or COCO~R9 and R9, Rll, and Ar are as hereinbefore defined
with a suitable reducing agent to form the corresponding
compound wherein R12 is CH2C02H,
v) AO is C~oR5t~oR6), --~
reacting a compound of the formula (4) wherein R12 is COC02R9
and R9, Rll, and Ar are as hereinbefore defined with a
C1_3alcohol, 1,2-ethanediol or 1,3-propanediol to form the
corresponding compound wherein R12 is C(oR5)(aR6)Co2~9,
vi) AO is CF2,
reacting a compound of the formula (4) wherein R12 is COC02R9
and R9, R11, and Ar are as hereinbefore defined with a
S fluorinating agent to form the corresponding compound wherein
Rll is CF2C02R9, or
:~
~ii) AO is C~F,
; ~ reactlng a compound of the formula (4) wherein R12 is
CH(OH)C02R9 and~R9,~Rl1, and Ar are as hereinbefore defined
with a fluorinating agent to form the corresponding compound
wherein R12 is CHEC02R9,
and thereafter optionally :
2s
: ~ converting the group OR11 into OH
~ ~ con~erting the group AOC02R9 into AQCO~H; or
: ~ bi for compounds wherein Rl is CH2C02H,
converting a compound of the formula ~6) :
: il I
R ~ (6)
, ,
~ 35 C~H
W093/10107 2 12 ~ O 0 3 PCT/GB92~02119
wherein ~13 is acetyl and Ar is as hereinbefore defined into
the corresponding compound wherein R13 is CH2C02H; or
s c) for compounds wherein Rl is CH(oR4)Co2H reacting a
compound of the formula (4~ wherein R12 is -C.~(OH)CN with a
Cl_3alkylating agent and/or converting the group CN into
C02H, and optionally converting the group ORll into OH; or
lo d) for compounds wherein Rl is P(O)~OH)(OR2),
hydrolysing a compound of the formula (5) wherein R13 is
P(O)(OR2)2 and R2, and Ar are as hereinbefore defined; or
: e) for compounds wherein Rl is P(S)(OH)(OR2), converting
a compound of the formula (6) wherein R13 is P(o)(N~R14)(oR2)
and R14 is phenyl or Cl_4alkyl and Ar is as hereinbefore
: defined into the corresponding compound wherein R13 is
P~S)(OH)(OR2); or
~ ~ .
f~ for compounds:where Rl is S03H,
reacting in the presen~e of a strong base a compound of the
formula (2) as hereinbefore defined with sulphuryl chloride
:: or a chemical equivalent thereof and optionally converting
the group ORll into OH; or
~- : 2:5
:~ ~ g)~ for compounds wherein Rl is S02H,
reacting in the presence of a strong base a compound of the
formula (2) as hereinbefore defined with sulphur dioxide and
optionally converting the group ORll into OH; or
h~ for compounds wherein Rl is 5-tetrazolyl, reacting a
compound of the formula (4) wherein R12 is cyano and Rll is
as hereinbefore defined or benzenesulphonyl, or a compound of
he formula (6) wherein R12 is cyano with an azide salt and
thereafter if necessary converting the group ORll into OH; or
i) for compounds wherein Rl is as defined for compounds
of the formula (1) reacting in the presence of a palladium
catalyst a compound of the formula (7):
W~93/10107 PCT/GB92/02119
- 12 -
2 ~ 0 3
Rb~g ,
Ra
wherein Rb is a group Rl as hereinbefore defined or a
precursor thereof and Ra is R0 or ORll as hereinbefore
defined and Ll is a leaving ~roup with a compound of the
formula (8~:
ArBSO~2 ~8)
or a chemical equivalent thereof wherein Ar is as
hereinbefore defined and then, if necessary, con~erting a
~: : lS precursor of Rl into Rl and/or converting the group ORll into
;~ OH~
and optionally thereafter :
20: forming a ~ioprecursor of R~ and/or Rl
forming a pharmaceutically acceptable salt.
Sui~ably a compound of the formula (2) is reacted with ~
2s strong base such as lithium diisopropylamide, or a Cl_~alkyl
lithium or aryl lithium such as mesityl lith~um in an organic
solvent such as tetrahydrofuran, diethylether or
dimethoxyethane with cooling (-100 - 0C) to form the anion
thereof. The strong base may be formed in situ, for example
by the addition of a Cl_4alkyl lithium e.g. methyllithium
followed by a ca~alytic quantity of diisopropylamine.
The anion of a compound of the formula (2) is suitably
reacted wi~h, a compound of the formula (3) or a compound of
: 35 the formula (5) in an organic sol~ent such as
WO93/10107 ~ 1 2 ~ O 0 3 PCT/~B~2/02119
- 13 -
tetrahydrofuran, diethylether or dimethoxyethane with cooling
~-100 to 0C) to form a compound of the formula (4) wherein
~12 is CR3(0H)C02~9 or COCO2R9 respectively. A suitable
compound of the formula (3) is ethylpyruvate, or ethyl
s glyoxylate or a chemical equivalent thereof and a suitable
compound of the formula (5) is diethyloxalate-.
A compound of the formula (4~ wherein R1~ is CR3~0H)Co2R9 is
suitably reacted with a Cl_3alkylating agent such as
0 iodomethane, iodopropane or dimethylsulphate in the presence
of a base such as sodium hydride or potassium hydroxide in' an
organic solvent such~as dimethylformamide or
dimethylsulphoxide at elevated (e.g. 30 - 80C) or preferably
ambient temperature to form the corresponding compound
wherein R12 is CR3(OC1_~alkyl)CO2R9. When potassium
hydroxide is used as base the CO2R9 group may be directly
converted to carboxy.
A compound of the~formula (4) wherein R12 is COCO2R9 is
20 ~suitably reacted wlth a reducing agent such as sodium
borohydride, or diisobutylaluminium hydride in an organic
solvent such as dichloromethane, a C1_4alcohol e.g. ethanol,
or acetic acid or mixtures thereof at ambient or elevated
temperature (e.g. 30 - 80C), or with cooling (e.g. 0 - 5C)
~to~form~the corresponding compound wherein R12 is
C~( ~)CO2R9. ; ~ ~
A compound of the formula ~4) wherein R12 is COCO2H or
COCO2R9 is suitably reacted with a reducing agent such as a
zinc amalgam in hydrochloric acid in the absence of a solvent
or in a solvent such as ethanol, acetic acid or dioxan and
hydrogen chloride gas at am~ient or elevated temperature
(e.g. 40-100C) to form the corresponding compound wherein
R12 is CH2CO2H. Under these reaction conditions the CO2R9
group is con~erted to carboxy.
A compound of the formula ~4~ wherein R12 is COCO2R9 is
- suitably reacted with a C1_3alcohol, 1,2-ethanediol or 1,3-
propanediol in the presence of an acid catalyst such as
~ ::
W093/10107 PCT/GB92/02119
2 l2 40 ~3 - 14 - "`"`
paratoluenesulphonic acid, concentrated sulphuric acid or
anhydrous hydrogen chloride, at ambient or elevated
temperature to form the corresponding compound wherein R12 is
c (oR5) (oR6) C02R9.
s
A compound of the formula (4) wherein R12 is COCO2R9 or
CHOHCO2R9 is suitably reacted with a fluorinating agent such
as diethylaminosulphur trifluoride in an organic solvent such
as a halohydrocarbon or an ether such as glyme, or THF at
lo am~ient or elevated temperature (e.g. 30-6QC) to orm the
corresponding compound where R12 is CF2C02R9 or CHFCO2R9
respectively.
A compound of the formula (4) wherein OR11 is methoxy can
1S suitably be converted to the corresponding compound wherein
ORll is hydroxy by reaction with sodium iodide and
chlorotrimethylsilane in an organic solvent such as
acetonitrile~ or~a~hal~ohydrocarbon e.g. dichloromethane or
chloroform at elevated~(e.g. 30 - 80C) or preferably ambient
20 ~temperature. This method ~s particularly suitable for
preparing compounds of the formula (1) wherein R1 is AOCO2~9
since the ester-forming~group R9 is not hydrolysed under the
reacti~on conditions.~ Another method utilises sodium
thiomethoxidè in an ~orqanic sol~ent such as dimethylformamide
~at~an ele*ated temperature for example 40 - 120C. The more
forcing; conditions of this method are suitable for preparing
compounds~of formula~ ~1) wherein R1 is AOC02H.
A;compound of the~formula ~4) wherein R12 is AOCO2R9 can
suitably be converted to the corresponding compound wherein
R12 is AOCO2H by reaction w~th an aqueous base such as sodium
or potassium hydroxide at ambient or elevated temperature
e.g. 40 - 120). This method is particularly suitable for
preparing compounds of the formula (1) wherein R0 is methoxy
since the OR11 group is not hydrolysed. Another hydrolysis
method utilises aqueous acid such as concentrated
; hydrochloric acid at an elevated temperature (e.g. 40 -
120C) which provides directly compounds of 'he formula ~1)
wherein R0 is hydroxy and R1 is AOCO2H.
WO93/10107 2 12 4 O 0 3 PCT/GB92/02119
- 15 -
Suitably a compound of the formula (6) wherein Rl3 is acetyl
is converted to the corresponding compound where Rl3 is
CH2CO2H by reaction with sulphur and morpholine
s at ele~ated temperature (e.g. 50 - 200C), followed by
hydrolysis with an aqueous base such as sodium hydroxide at
elevated temperature, preferably at the reflux temperature of
the reaction mixture.
:
0 Suitably a compound of formula ~4) where Rl2 is -CH(OH)CN is
reacted with a Cl 3alkylating agent as hereinbefore descrlbed
followed by reaction with aqueous mineral acid such as
hydrochloric acid at ambient or elevated temperature
preferably at reflux in order to prepare the corresponding
compound where Rl2 is CH(OCl_3alkyl) CO2H. The alkylation
can be omitted if the corresponding compound where Rl2 is
CH(OH)CO2H is desired. During the hydroly~is of the CN group
the OR11 group may~be~converted to hydroxy. If not and if
deslred thl~ group~can be converted to hydroxy as
hereinbefore described.
A compound of the formula (4) wherein Rl2 is -CH(OH)CN can be
prepared by reacting the corresponding compound wherein Rl2
is -CHO with a source of cyanide such as potassium cyanide in
25~ the presence of an~acid such as hydrochloric acid preferably
at~ambient temperature.
A compound of the formula (4) or (6) where Rl2 or Rl3 is CHO
is suitably prepared by reacting the corresponding compound
wherein Rl2 or R13 is cyano with a suitable reducing agent
such as diisobuty}aluminium hydride followed by aqueous
acidic work-up.
, ~ ~
Suitably a compound of the formula (6) wherein Rl3 is
P(O)(OR2)2 is hydrolysed by reaction with an aqueous base
such as sodium hydroxide optionally in a cosolvent such as a
Cl_4alcohol at an elevated temperature (e.g. 40-100C),
~;; préferably at the reflux temperature of the reaction mixture.
:::
:- ~
WO93/10107 PCT/GB92/02119
21240-03 - 16 - " ~
Suitably a compound of the formula (6) wherein R13 is
P~o)(MHR14)(oR2) is con~erted to the corresponding compound
wherein R9 is P(S)~OH)(OR2) by reaction with a strong base
such as sodium hydride in an organic solvent such as
dimethoxyethane at ambient or elevated ~emperature, ~ç.g~ 40
- 100C) followed by reaction with car~sn dis~lphide.
Suitably the anion of a compound of the formula (2) prepared
as hereinbefore described is reacted with sulphuryl chloride :
0 or a chemical equivalent thereof or with sulphur dioxide in
an organic solvent such as tetrahydrofuran with cooling (-'
100 - 0C) ~o form after aqueous work-up a compound of the
formula ~4) wherein R12 is ~03H or SO2H respectively and OR
is methoxy which if desired can be converted to the
corresponding compound wherein OR11 is hydroxy as
hereinbefore described.
A~compound of the formula ~4) wherein R12 is cyano or a
compound of the formula (6) wherein R13 is cyano is suitably
~ 20 reacted with an azide salt such as ammonium, sodium or
:~ ~ aluminium azide in an organic solvent such as
diethylformamide, dimethylsulphoxide, N-methylpyrrolidone or
tetrahydrofuran at an ele~ated temperature e~g. 40-200C,
:: ~ preferably at 100-150C to form the corresponding
; 2s 5-tetrazolyl compound. Preferably in a compound of the
f~ormula ~4) OR11 is benzenesulphonyl which can be introduced
: : in standard manner, for example by reacting the corresponding
hydroxy compound with benzenesulphonyl chloride in the
presence of a base such as triethylamine. This group can be
; 30 remo~ed in standard manner, for example by reaction with a
base such as sodium hydroxide.
Suitably a compound of the formula ~7) is reacted with a
ompound of the formula (8) in the pre~ence of 1-50 mole %,
~ 35 preferably 2-10 mole %, of a palladium catalyst and a base
: such as triethylamine, sodium bicarbonat~, or aqueous sodium
carbonate and optionally lithium chloride ~n an organic
;~ ~ sol~ent such as dimethylformamide, dimethoxyethane
acetonitrile, toluene, tetrahydrofuran, ethanol, or mixtures
WO93/l0107 2 1 2 4 0 0 ~ PCT/GB92/02119
- 17 -
thereof, at elevated temperature, ~e.g. 30-150C), preferably
at the reflux temperature of the mixture. Suitably kl is
halo for e~ample iodo, bromo or chloro or a
trifluoromethanesulphonate. Subsequently the OR11 group can
s be converted to hydroxy as hereinbefore described for
compounds of formula (4). Examples of palladium catalysts
that can be used include:
tetrakis(triphenylphosphine)palladium (Pd[PPh314),
0 bis(triphenylphosphine)palladium dichloride (Pd~PPh3~2C12),
[1,4-bis-(diphenylphosphine)~utane~palladium dichloride
(Pd(dppb)C12),
[1,3-bis-(diphenylphosphine)propanelpalladium dichloride
(Pd(dppp)Cl2)~
~1,2-bis-(diphenylphosphine)ethanelpalladium dichloride
(Pd(dppe)C12),
bis~tri-o-tolylphosphine)palladium diacetate or dichloride
Pd(totp);(OAc)2~or Pd~totp)C12), or
bis(d phenylphosphine)ferrocinopalladium diacetate or
dichl~oride (Pd[dppf](OAc)2 or Pd~dppflC12).
By a chemical equivalent of a compound of the formula (8) is
meant a~reagent that~can couple the Ar group onto the pyridyl
ring of a compound of the formula (7). For example aryl
25~stannanes can be used, such as ArSnMe3 which can suitably be
prepared by reacting a suitab}e aryl halide (such as ArBr or
ArI)~ with a~base~such~as t-butyl lithium followed by reaction
with~a trimethyl tin halide (e.g. Me3SnCl). Alternatively
the~aryl halide can be reacted with Me3SnSnMe3 in the
presence of a palladi~m catalyst as hereinbefore described to
prepare a suitable aryl stannane.
When Rb is a group Rl as hereinbefore defined reaction of a
compound of the formula (7) with a compound of the formula
(8) results directly in compounds of the formula (1).
,,
An example of a precursor for R1 is when Rb is hydrogen. In
this situation reaction of a compound of the formula (7) with
a compound of the formula (8) or a chemical equivalent
WO93f10107 PCT/GB92/02119
~ 1 2 ~ 0 03 - 18 ~
thereof results in a compound of the formula (2) or a
compound of the formula (6) wherein Rl3 is hydrogen. Such
compounds can then be converted into a compound of the
formula (l) as herein described.
Other precursors for R~ include CN, CHO or COMe. Reaction of
a compound of the formula (7) wherein Rb represents such a
precursor with a ~ompound of the formula (8) or a chemical
equivalent thereof results in a compound of the formula (4)
0 or a compound of the formula (6) wherein Rl2 or Rl3 is CN,
CHO or COMe. Such compounds can be con~erted to compounds of
the formula (l) as herein described.
If desired a compound of the formula (l) wherein Rl is A0CO2H
lS can be converted to the corresponding compound wherein Rl is
A0C02R9 by reaction with a compound R9OH wherein R9 is as
hereinbefore defined.
' A compound of the formula (lj wherein R0 is OH can be
convert,ed to the corresponding compound where R0 is oR8 by
reactlon with R8L2~wherein R8 is as hereinbefore defined and
; L2 is a leaving~group such as halo e.g. bromo, chloro, iodo.
If~desired a compound~of the formula (l) wherein Rl is
25~;P~Z~ (OR2)(0H) can~be converted to the corresponding compound
wherein~Rl is P(Zj~(OR2)(ORl0)~by reaction with a suitable
O-protecting agent in stsndard manner. For example the
compound can be reacted with a pivalolyloxymethyl halide.
30~ A compound of the formula (l) wherein Rl is 5-tetrazole can
be ~reacted with a suitable N-protecting agent in standard
manner, for example with à pivalolyloxymethyl halide.
. ~
A compound of the formula (l) wherein Rl-R0 is AlCO2 is
35 suitably prepared by heating a compound of the formula (l)
wherein Rl is AlCO2H and R0 is OH with a dehydrating agent
such as acetic anhydride, at an elevated temperature (e.g. 40
200C), preferably at the reflux temperature of the
reaction mixture.
WO 93~10107 2 1 2 4 0 0 3 PCT/GB92/02119
-- 19 --
A compound of the formula (1) wherein R1-R0 is A20CH20 is
suitably prepared by reacting a compound of the formula (1)
wherein R1 is A2OH and R0 is OH with a dihalomethane such as
diiodo- or dibromomethane in the presence of silver carbonate
in an organic solvent such as dimethylformamide at an
elevated temperature (e.g. 40 - 120C~.
A compound of the formula (2) is suitably prepared by
reacting a compound of the formula (6) wherein R13 is
hydrogen with an O-methylating agent such as
dimethylformamide dimethylacetal in dimethylformamide or
trimethylphosphite at an elevated temperature (e.g. 40 -
120C) or with iodomethane and silver carbonate in toluene or
chloroform. This method can also be used for converting
compounds of the formula (6) into corresponding compounds of
the formula (4) and compounds of formula (7) wherein Ra is
hydroxy into corresponding compounds wherein Ra is OR11.
:
A ~compound of the formula (6) wherein R13 is acetyl can also
be prepared by reacting a compound of the formula ~6) wherein
R13 is cyano with methyl lithium followed by aqueous acidic
work up with for example hydrochloric acid.
A compound of the form~la (6) wherein R13 is hydrogen can be
prepared by reacting a compound of the formula ~6) wherein
R13 is cyano wi~h orthophosphoric acid at an elevated
temperature, e.g. 50 - 200C.
A compound of ~ormula (4) wherein R12 is cyano is suitably
prepared by reactlng the anion of a compound of formula ~2)
wherein Ar and Rll are as hereinbefore defined with
dimethylformamide with cooling (e.g. -80 to 10C), followed
by ambient temperature and aqueous work-up. The resulting
compound of formula (4) wherein R12 is carboxaldehyde is
treated with hydroxylamine hydrochloride and sodium acetate
in a suitable solvent such as ethanol or methanol at ele~ated
temperature, e.g. 40-100~C, preferably at the reflux
temperature of the reaction mixture followed by dehydrating
,
WOg3/10107 PCT/GB92/02119
212~00~
the product o~tained for example by heating with acetic
anhydride.
A compound of the formula (6) wherein R13 is cyano or acetyl
and Ar is as hereinbefore defined can be suitably prepared by
reaction of a compound of formula (4) wherein ~12 is cyano or
acetyl and R11 and Ar are as hereinbefore defined with a
demethylating agent such as sodium
iodide/chlorotrimethylsilane in the absence of solvent or in
o an organic solvent such as acetonitrile or chloroform at an
elevated temperature (e.g. 40 to 100C) or at ambient
temperature.
A compound of the formula (6) wherein R13 is P~O)~OR2~2 can
lS be prepared by treating a compound of the formula 12) wherein
R11 is P~O)~OR2)2 with a strong base such as lithium
diisopropylamide~in a~ organic solvent such as
tetrahydrofuran with cooling (e.g. -100-0C).
20~ ~ A~compound of the~formula ~2) wherein R11 is P~O)~OR2)2 is
sui~ably prepared~by treating a compound of the formula ~6)
wherein R~3 is hydrogen with a compound of the formula (9):
3P~(o)(oRz)2 (9)
2s ' ~ ~
' wherein~L3 is a lea~ing group and R2 is as hereinbefore
defined with a base such as diisopropylethylamine.
Suitably L3 is halo, for example chloro or bromo.
30~
A compound of form~ula, (2), wherein R11 is P(O?~OR2)2 can a~lso
be prepared by treating a compound of the formula (6) wherein
R13 is hydrogen with a compound of the formula (10):
~P(O)(OR2~2 (10)
wherein R2 i5 as hereinbefore defined in the presence of an
amine base such as triethylamine, and carbon tetrachloride.
: ~
2124003
WO93/10107 PCT/~92/02119
....
- 21 -
Alternatively, a compound of the formula t6~ wherein R13 is
P(O)(OR2)2 is suitably prepared by treating a compound of the
formula (6) wherein R13 is hydrogen with a compound of the
formula (9) in the presence of a strong base such as lithium
s diisopropylamide in an organic sol~ent such as
tetrahydrofuran with cooling (e.g. -100-0C) without
isolation of the intermediate compound of the formula (2)
wherein R11 is P(O)(OR2)2
A compound of formula (6) wherein R13 is hydrogen is suitably
prepared by demethylating a compound of formula (2) as
hereinbefore defined. Suitably a compound of formula ~2) is
treated with boron tribromide in an organic solvent such as
dichloromethane or toluene with cooling (e.g. -80 to 10C)
followed by ambient temperature and aqueous work-up. Or a
compound of formula (2)~is treated with sodium iodide and
chlorotrimethylsilane~at ambient or elevated temperature
e.g. 40-80-C) canveniently ambient temperature in a solvent
such~as acetonitrile or dichloromethane.
A compound of the formula (6) wherein R13 is P(o)(NHR14)~oR2)
can~be prepared~by~reaction of a compound of the formula (6)
wherein ~13 is P(O)~tOH)(OR2) with carbon tetrachloride,
triphenylpAosphine and aniline or a Cl_4alkylamine in an
,25~ organi~c solvent such ~as~pyridine at ambient temperature or
'with cooling (e.g~ 10 to 5C). Alternatively a compound of
the~formula 16)~where R13 is P(O)~OH)(OR2) can be reacted
with~dimethylformamide,~and oxalyl chloride in an organic
solvent such as a~halo hydrocarbon e.g. dichloromethane at
ambient temperature, followed by reaction with aniline or a
C1_4alkylamine preferably with cooling (-10 to 5C).
Compounds of the formula (7) are known or can be prepared
from a compound of the formula (11):
~ , ,
:~ ~
: ~ :::
WO93/10107 PCT/GB92/02119
- 22 -
2~124003
~ ~11)
s wherein Ra and Ll are as hereinbefore defined using similar
methods to those described for preparing compounds of the
formula (l).
Thus, a compound of the formula (7) wherein Rb is P(o)~OR2)~
0 can be prepared by reacting a compound of the formula ~ll)
wherein Ra is OH with a compound of the formula (9) or ~l0)
:~ in similar manner to the reaction of a compound of the
f~rmula (6~ wherein Rl~ is hydrogen with a compound of the
formula (9) or (l0). If desired th~ group Ra can then be
; IS con~erted to OMe.
Similarly, a compound~ of the formula (ll) where R~ is OMe can
be treated in the presence of a stxong base with a compound
:: of~the formula (3), a compound of the formula ~5), sulphuryl
20 : chloride, sulphur dioxide or dimethylformamide to prepare a
compou~d of:the formula (7).wherein Rb is CR3~oR4)Co2R9,
GOCO2R9, SO3H, SO2H,~or C~O respectively in simllar manner to
the corresponding reaction with a compound of the formula (2)
; ; as hereinbefore described. Particularly suitable as a strong
2S base is li~hium tetramethyl piperidide.
A.compound of the formula (8) is suita~ly prepared by
~; reacting the organolithium or Grignard reagent, formed from a
~ ~ compound of the formula (12):
:~: 30
Ar-L~ ~12)
:~ wherein ~4 is bromo or iodo and Ar is as hereinbefore defined
with a tri-Cl_4alkylborate such as trimethyl, tri-isopropyl
WO93/10107 2 1 2 4 O 0 3 PCT/GBg2/02llg
. - 23 -
or tri-n-butyl borate in an organic solvent such as diethyl
ether or tetrahydrofuran with cooling ~e.g. - 80-l0C).
The Ar group in compounds of the formula (2), (4), (6) or
(12) preferably (2) or (4) may be appropriately
functionalised by methods of aromatic substi~ution known in
the art. For example, a bromo group may be introduced into a
suitably substituted phenyl ring ~eg. disubstituted in the 2-
and 4-positions by electron-donating groups such as
0 Cl_6alkoxy) by reaction wi~h a brominating agent such as
N-bromosuccinimide or bromine in a solvent such as
dimethylformamide. Alternatively a nitro group can be
introduced into a phenyl ring by reaction with a suitable
nitrating agent, such as nitronium tetrafluoroborate. Such a
s group can be readily hydrogenated to an amino group whicn if
desired can be converted to a NHCoR7 group by reaction with
LCoR7 wherein 1 is a lea~ing gro~lp and R7 is as hereinbefore
:~ deflned. Suitable examples of the reagent LCOR include acid
hàlides (L is halo eg. c~loro or bromo) or acid anhydrides ~L
is oCoR7).
Other suitable functionalisations include the introduction of
~ an allyl group ortho to a hydroxy substituent on a phenyl
:~ ring by reaction:with an allyl halide, eg. bromide, to form
2s :an allyloxy derivative which on heating undergoes a Claisen
. rearrangement to form an ortho allyl hydroxy deriYative. The
; hydroxy group can-in turn be functionalised, eg. by reaction.
with a Cl_6alkyl halide to form a Cl_6alkoxy group. If
desired, an allyl group can be converted to a~ E-l-propenyl
group by reaction with a strong base, such as sodium
methoxide. An E-l!-propenyl group can be cleaved to a formyl
group by reaction with an oxidising agent such as
N-me~hylmorpholine-N-oxide in the presence of a catalyst such
: as osmium tetroxide to form a 1, 2,dihydroxypropyl group which
on reaction with an oxidising agent such as sodium periodate
forms the formyl group. Alternatively the E-l-propenyl group
: can be converted directly to a formyl group by reaction with
a mixture of osmium tetroxide and sodium periodate or by
reaction with ozone. A formyl group can in turn be further
WO93/10107 PCT/GB92/02119
,~ ~ .
2121~3 - 24 -
functionalised, for example it can ~e converted to a
hydroxymethyl group by reaction with a suitable reducing
agent such as sodium borohydride, the hydroxymethyl group
then being reacted further, eg. with a Cl_6alkyl halide to
form a Cl_6alkoxymethyl group. Alternatively a formyl group
can be reacted with a suitable Horner Wittig or Wittig ;
rea~ent such as ~Rl50)2P(Q)CH2C02Rl5 or Ph3P=CHCO2Rl5 wherein
Rl5 is Cl_4alkyl to form a CH=CHCO2RlS group which can be
optionally hydrolysed to a -CH=CHCO2H group. A -CH=CHCo2Rl5
group can be converted to a -CH=CHCONtR7)2 group by reaction
with an amine HNtR7)2 or a chemical equivalent thereof
wherein R7 is as hereinbefore defined. Alternatively a
-CH=CHCO2H group can be converted to an acid halide, eg. the
acid chloride by reaction with oxalyl chloride, which can
lS then be reacted with an amine HN(R7)2 or a chemical
equivalent thereof. An example of a chemical equivalent is
ammonium hydroxide which will form a CH=CHCONH2 group.
Pharmaceutically~acceptable base addition salts of the ;~
compounds of the formula~(l) may be prepared by standard
methods, for example~by~reacting a solution of the compound
of the formula ~l) with a solution of the base.
The following biological test methods, data and Exampies
;serve~to illustrate this invention.
Cycl~c~AMP Pro~n ~18~sc (ca-Pr~) A4Oniat Acti~ty
Type II cA-PrK was prepared from the cardiac muscle of a cow.
The~supernatant from a muscle homogenate ~3 mls of l0 mM
potassium phosphate, 1 mM EDTA per g tissue) was applied to a
column of DEAE-cellulose equilibrated with the homogenisation
buffer and the type II cA-PrK was eluted with homogenisation
buffer containing 350 mM sodium chloride (Rannels et al.,
1983, Methods Enzymol., 99, 55-62).
Type II cA-PrK was assayed for phosphotransferase acti~ity by
incu~ating the enzyme at 30C for 5 minutes with
32P]-adenosine triphospha~e and a suitable peptide
;
,
WO93/10107 2 12 4 0 0 3 PCT/GB92/02119
. . .
- 25 -
substrate such as malantide (Malencik et al., 1983, Anal.
Biochem., 132, 34-4~). The reaction was terminated by the
addition of hydrochloric acid and the [32P]-phosphopeptide
quantified by spotting the reaction mixture onto
s phosphocellulose papers. The concentration of compound
required to give 10% phosphotransferase activ-ation is given
as the EClo (~M). The compounds of Examples l and 2 had EClo
values of 2.6 and l.0 ~M respectively.
Iahibition of ~lat~let A4gregation
~;~ Human platelet-rich-plasma was separated from freshly drawn
~; blood (in acid/citrateidextrose) and treated with l00 ~M
acetylsalicylic acid for 15 minutes at 37C. A washed
platelet suspension was then prepared in a Hepes-isotonic
saline buffer after a single centrifugation step and adjusted
to a concentration of l.5xl08 cells/ml. Aliquots of this
suspension were pre-incubated with compounds for 5 minutes at
37C, then challenged with l.0 ~M U46619. The extent of
20~aggregation after 2 minutes were expressed as a percentage of
control and results~obtained are expressed as an IC50
concentration to cause 50% inhibition of platelet
aggregation, ~M). The compounds of Examples 1 and 2 had ICso
values~of 20 and 38 ~M respectively.
~ ~
IDhibition of Spontan~ou~ CQntraction i~ GuinQa-Pig Colon
Segments of isolated guinea-pig colon ~2 cm) were suspended
under 2 g tension in standard organ baths containing Krebs
solution. The tissues were connected at the free end to
~; ~ isometric transducers which allow recording and display of
developed tension on chart recorders. On-line computer
capture and analysis was used to quantify the effects of test
compounds on spontaneous contractions. Inhi~itory responses
3s were calculated as %;maximum inhi~ition of spontaneous
contraction distance over 3 consecutive pre and post dose 2
minute readings. The concentration of compound which caused
50% inhibition of the spontaneous contraction is given as the
EC50 ~1~1
WO 93/10107 PCT/GB92/02119
2124003 26 - `"`'
Bro~chodilatation - In ~itro
Spiral strips of guinea-pig trachea were suspended in
standard organ baths containing Krebs solution. The tissues
were connected at the free end to isometric transducers which
allow recording and display of developed tension on chart
recorders. Tension was allowed to develop spontaneously and
concentrations of test compounds added in a cumulative
fashion. The concentrat~ion of compound which caused 50%
inhibition of the spontaneously developed tension is given as
;~ the IC50(~M).
Measurement o~ cardiac mu~cl~ r~laxation time in rabbit
ventricl~
Papillary muscles from the right ventricle of female Albino
New~Zealand rabbits~are~mounted in standard organ baths
containing oxygenated Krebs solution. One end of the muscle
;20~ ~Ls c~onnected to an isometr1c transducer which allowed
recording of contractile force and its first derivative on
chart recorders.;;Test compounds are added to the bath in a
cumulative manner. ReIaxation time is calculated as the time
taken from peak;tension to the end of the contraction.
2s~ Compounds~ which cause a decrease in the relaxation time
indicate a positive lusitropic effect of use in the treatment
of cardiovascular~diseases where there is a component of
diastolic fai~ure~such as congestive heart failure, angina,
hypertension and cardiomyopathy.
,.. ~ ~- :~ :
:. ~
WO93/10107 2 1 2 4 ~ 0 3 PCT/GB92/02119
- 27 -
Exa~ple 1
2-~5-Tetrazolyl)-5-~2,3-di-n-propo~ypha~yl)ph~ol
(a) From l,2-di-n-propoxybenzene ~13.8g~, 2,3-di-n-
propoxyphenylboronic acid (13g~ was prepared according to the
method of W. J. Thompson and J. Gaudino J. OrgO Chem. 1984,
4g, ~237.
(b) To methyl 2,4-dihydroxybenzoate (5.95g) and 4-N,N-
dimethylaminopyridine ~8.65g) in dichloromethane at -50C,
trifluoromethanesulphonic anhydride (lO.Og) was added over
5mins. The mixture was warmed to room temperature stirred ~or
l hour, treated with 2N hydrochloric acid and the organic
phase separated, dried ~MgS04) and solvent removed at
reduced pressure. The residue was column chromatographed
silica gel, diethyl ether/petroleum ether eluant) to give
methyl 2-hydroxy-4-trifluoromethanesulphonyloxy benzoate
(S.Og) lH NMR~ (CDCl3) 3.99(s,3H), 7.25~d<lH1, 7.44(dd,lH)
and 8.23(d,1H).
(c3 From methyl 2-hydroxy-4-trifluoromethanesulphonyloxy
benzoate ~8.7g) and 2,3-di-n-propoxyphenylboronic acid (7.4g)
an;d using the method of A. Huth, I. Beetz and I. Schumann,
;Te~trahedron, 1989, 45, 667~, methyl 2-hydroxy-4-(2~3-di-n-
p~ropoxyphenyl)benzoate (4.6g) was prepared. lH NMR (CDCl3)
; 0O82(t,3H), l.08(t,3H3, l.48-l.59(m,2H), l.8l-l.95(m,2H),
3.70(t,2H), 3.96(s,3H), 3.98(t,2H), 6.93(d,2H), 7.07-
7.17(m,3H), 7.83(d,1H) and 10.76(s,1H).
3~
. . .
(d~ Methyl 2-hydroxy-4-(2,3-di-n-propoxyphenyl)benzoate
(2.2g) in ethanol (15ml) and dioxane (30ml) was treated with
sodium borohydride llg) and stirred at room temperature for
48 hours. Sol~ent was removed at reduced pressure and the
residue column chromatographed Isilica gel, dichloromethane
eluant) to gi~e 2-hydroxy-4-12,3-di-n-propoxyphenyl)benzyl
alcohol (1.7g). The benzyl alcohol was oxidised according to
~; the method of S. V. Ley et al J. C. S. Chem. Comm., l987,
162~ to give 2-hydroxy-4-(2,3-di-n-propoxyphenyl)-
:
W093/10107 PCT/GB9~/021l9
212~003 - 28 -
benzaldehyde (0.7~g). lH NMR (CDCl3~ 0.82~t,3H), 1.08(t,3H),
1.41-1.62(m,2H), 1.84-1.95(m,2H), 3.72(t,2H), 3.99~t,2H),
6.91-6.96(m,2H), 7.09(t,lH), 7.18(s,lH), 7.26(dd,lH~,
9.92(s~1H) and 11.06(s,1H)~
..
(e) A solution of 2-hydroxy-4-(2,3-di-n-propoxyphenyl)-
benzaldehyde ~0.78g) in ethanol (15ml) and saturated aqueous
sodium acetate (8ml) containing hydroxylamine hydrochloride
~0.23g) was stirred for 16 hours. Solvent was removed at
reduced pressure acetic anhydride added and the mixture
: boiled for 4 hours. Solvent was removed at reduced pressure,
the residue dissolved in diethyl ether (50ml) and washed with
water ~2 x 50ml~. The organic layer was dried (MgS04) and
solvent removed at reduced pressure to give 2-hydroxy-4-(2,3-
di-n-propoxyphenyl)benzonitrile (0.8g). IR ~nujol mull)
2,230cm-1.
(f) A mixture of 2-hydroxy-4-~2,3-di-n-propoxyphenyl~-
benzonitrile (0.8g), sodium azide (0.38g) and ammonium
chloride (0.35g) in N-methylpyrrolidinone (20ml) was heated
at 130C for 3 hours. The reaction mixture was absorbed onto
silica gel and column chromatographed (silica gel, diethyl
:ether then diethyl ether/methanol 85/lS eluant). Appropriate
fractions were combined, solvent removed at reduced pressure
~and the~residue triturated with water to give the title
compound ~0.26g) m.p. 187-189C.
xampl~ 2
~: .
~ 30 Ethyl 2-hydroxy-4-~2,3-di-~-propo~yp~Q~yl)phæ~yl phosph4nate
, .
~a~ From 3-bromsphenol (1.73g) and 2,3-di-n-propoxyphenyl-
~;: boronic acid (2.38g), 3-(2,3-di-n-propoxyphenyl)phenol m.p.
78-80C after column chromatography (silica gel, diethyl
ether/petroleum ether 1:9 eluant) was prepared according to
the method of Example l(c).
(b) From 3-(2,3-di-n-propoxyphenyl)phenol (l.Og), di2thyl
3-(2,3-di-n-propoxyphenyl) phenyl phosphate ~1.2g) was
W093/10107 PCT/GB92/02119
- 29 -
prepared according to the method of G. W. Kenner and N. R.
Williams J. Chem. Soc. 1955, 522.
(c) Diethyl 3-(2,3-di-n-propoxyphenyl)phenyl phosphate
s (1.2g) was rearranged to diethyl 2-hydroxy-4-(2,3-di-n-
propoxyphenyl)phenyl phosphonate according to the method of
L. S. Melvin Tet. Letters, 1981, 22, 3375 and subsequently
hydrolysed to the title compound, isolated as an oil, by
boiling with SN aqueous sodium hydroxide (lOml). lH NMR
lo ~DMSO-d6) 0.75(t,3H), 1.05(t,3H), 1.20~6H), 1.43-1.53(m,2H),
1.54-1.83(m,2H), 3.72(t,2H, 3.86-3.92(m,4H), 4.03(t,2H),
6.88-7.66(m,5H) and 7.46~dd,1~).
~ampl~ 3
1 5
Pharmaceutical compositions for oral administration are
prepared by comhining the following :
2-~(5-tetrazolyl)-5-
(2~,~3-dipropoxyphenyl)phenol 0.5 3.0 7.14
2% w/w Soya lecithin in~soya
25~ bean oi1 90.4588.2 84.41
Hydrogenated vegetable
shortening and beeswax 9.05 8.B 8.45
30 ~The formulations~are then filled into individual soft gelatin
capsules.
mple 4
3s A pharmaceutical composition for parenteral administration is
prepared by dissolving ethyl 2-hydroxy-4-(2,3-
dipropox~phenyl~phenyl phosphonate ~0.02 g) in polyethylene
glycol 300 ~25 ml) with heating. This solution is then
diluted with water for injections Ph. Eur. ~to 100 ml). The
~ .~
WO 93~10107 PCI~/GB92~02119
~.
2~2~ 003 - `
solution is ~hen sterilised by filtration through a ~ . 22
micron membrane filter and sealed in sterile containers~
:: :
,
: ~ ~
~: :
: ~: : :: ::
~, ,
~: :
:: ~: ::
,' ~`
: :: :
~ ~:
: :
~ .
