Note: Descriptions are shown in the official language in which they were submitted.
W092/06085 2 0 919 ~ 9 PCT/GB91/~1663
PHENYLPYRIDINOL DERIVATIVES
AS MEDICAMENTS
The present invention relates to pyridinol
derivatives, 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-dependent protein Xinase (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, lusitropic,
anti-allergic or anti-inflammatory activities. They are
likely to be useful in the treatment of cardiovascular
diseases such as congestive heart-failure, cancer,
psoriasis, atherosclerosis, thrombosis, chronic reversible
lung disease such as asthma and bronchitis, allergic
disease such as allergic asthma, allergic rhinitis and
urticaria or gut motility disorders such as irritable
bowel syndrome.
Accordingly the present invention provides compounds
of the formula (1) :
Ar
~ N (1)
R 0
or pharmaceutically acceptable salts thereof, wherein :
W092/06085 2 0 91~ 8 9 PCT/GB91/01663
RO is OH or a bioprecursàr thereof,
Rl is 5-tetrazolyl or a bioprecursor thereof, and
Ar is phenyl substituted by one to three groups independently
selected from C1_6alkyl, C2_6alkenyl, C1_6alkoxy,
C3_6alkenyloxy, C3_6cycloalkyl, C3_6cycloalkoxy,
C1_6alkylthio, phenyl, phenylthio, benzyloxy,
C1_6polyfluoroalkyl, C1_6polyfluoroalkoxy, halo, NR2, or
NHCOR wherein R is H or Cl_6alkyl, or -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 C1_6alkyl, C2_6alkenyl or C1_6alkoxy yroups can be
independently substituted by OH, C1_6alkoxy,
C3_6cycloalkyl, NR2, CO2R or CONR2; with the proviso
that Ar is not phenyl monosubstituted by 2-C1_6alkoxy.
Bioprecursors of the group RO are derivatives thereof
which are convertible in vivo into the group RO.
A suitable bioprecursor of the group RO is oR2 wherein
R2 is C1_4alkyl, arylCl_4alkyl (for example phenylCl_4-
alkyl such as benzyl), Cl_4alkanoyl (for example acetyl),
arylC1_4alkanoyl (for example phenyl C1_4alkanoyl such as
benzoyl), arylsulphonyl (for example optionally substituted
phenylsulphonyl or toluenesulphonyl) or Cl_4alkylsulphonyl
(for example methylsulphonyl).
Suitably R0 is hydroxy or o~2, preferably hydroxy.
A suitable bioprecursor of Rl is a N-protected
tetrazolyl group. Suitable N-protecting groups include
pivalolyoxymethyl, propionyloxymethyl and
pivaloyloxycarbonyloxymethyl.
WO92/06085 2 0 919 8 9 PCT/GB91/01663
By the term alkyl is meant both straight- and branched-
chain alkyl.
By the term C1_6 polyfluoroalkyl is meant a C1_6alkyl
group having at least one hydrogen replaced with fluoro eg.
CF3, or CF2CF2H.
Suitably Ar is phenyl mono-substituted by a group as
hereinbefore defined, for example in the 2,3, or 4
positions by C1_6alkyl, C3_6alkenyloxy,
C1_6alkylthio, phenyl, phenylthio, benzyloxy, CF3, halo
or NHCOR, or in the 3, or 4-positions with C1_6alkoxy.
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_5alkoxy,
C3 6cycloalkoxy, halo, -X(CH2)nY- or C1_6alkoxy
C1_6 alkoxy.
Suitably Ar is phenyl trisubstituted by any groups 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, C1_6alkoxy or halo.
Examples of Cl_6alkoxy include methoxy, ethoxy,
propoxy, butoxy, or pentyloxy.
Examples of C1_6alkyl include methyl, ethyl,
propyl, butyl, isobutyl or pentyl.
Examples of halo include fluoro, chloro, bromo or
iodo, preferably chloro or bromo.
Particular compounds of this invention include :
W O 92/06085 2 0 91~ ~ 9 P ~ /GB91/01663
6~ thoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(3-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(3-benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2tlH)-one,
6-(3-bromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
lS
6-(3-trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(3-ethylphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(4-isobutylphenyl)pyridin-2(lH)-one,
6-(4-biphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(4-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-
2(lH)-one,
W092/06085 2 ~ 91~ 8 ~ PCT/GB91/01663
6-(3,4-methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-
one,
6-(3,4-dichlorophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
s
6-(3,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(3,5-dibromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(2,4-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
.
6-(2,5-dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(2,3,4-trichlorophenyl)-3-(S-tetrazolyl)pyridin-2(lH)-
one,
6-[6-(1,2,3,4-tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-
2(lH)-one,
6-(3-chlorophenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3-phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
3,4-dimethoxyphenyl-3-(5-tetrazolyl)pyridin-2(lH)-one,
W ~ 9~/06085 2 ~ 919 8 9 P ~ /GB91/01663
6-(3-methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-
one,
6-(3-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(3,4-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-
one,
6-(2,3-di-n-propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-
one,
6-(3-cyclopentyloxy-4-methoxyphenyl)-3-(S-tetrazolyl)-
pyridin-2(lH)-one
6-(3-ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(3,5-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(2-butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(3-allyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one,
6-(4-methoxy-2-pentyloxyphenyl)-~-(5-tetrazolyl)pyridin-
2(lH)-one
6-(3-iso-butoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-
2(lH)-one,
6-(2-bromo-3,5-diethoxyphenyl-3-(5-tetrazolyl)pyridin-
2(lH)-one,
W092/0608~ 2 0 919 ~ 9 PCT/GB91/01663
6-(5-bromo-4-methoxy-2-pentyloxphenyl)-3-(5-tetrazolyl)-
pyridin-2( lH) -one,
6-(2-allyl-4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)-
pyridin-2(lH)-one,
6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)pyridi
n-2(lH)-one,
6-(4-methoxy-3-propoxyphenyl)-3-[5-(1-pivaloyloxymethyl)-
tetrazolyl)pyridin-2(lH)-one,
:
6-(4-methoxy-3-propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-
tetrazolyl]pyridin-2(lH)-one,
6-[3-ethoxy-5-(2-methoxyethoxy)phenyl]-3-(5-tetrazolyl)-
pyridin-2(lH)-one,
6-[3-(2,2-dimethylpropyloxy)-4-methoxyphenyl~-3-(5-
tetrazolyl)pyridin-2(lH)-one,
6-(3-ethoxy-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-
one,
2S 6-(3-propionamidophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one,
6-(4-methoxy-3-propylphenyl)-3-(5-tetrazolyl)pyridir.-2(lH)-
one,
6-(3-bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-
one,
6-(3-phenyl-4-methoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-
one,
W092/06085 2 0 919 8 9 PCT/GB91/01663
6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]-3-(5-tetrazolyl)-
pyridin-2(lH)-one,
6-[3-(E-1-propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-
pyridin-2(lH)-one,
6-(3-bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-
pyridin-2-(lH)-one,
6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-
2(lH)-one,
6-(3-bromo-4-N,N-dimethylaminophenyl)-3-(5-tetrazolyl)-
pyridin-2(lH)-one,
6-(3-acetamido-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-
pyridin-2(lH)-one,
6-[3-methoxymethyl-4-methoxy-5-(E-l-propenyl)phenyl]-3-(5-
tetrazolyl)pyridin-2(lH)-one,
6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-1-propenyl)-
phenyl]-3-(5-tetrazolyl)pyridin-2-(lH)-one, and
6-(3-cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2(lH)-one
and pharmaceutically acceptable salt-; thereof.
This invention covers all tautcmeric, geometric and
optical isomeric forms of compounds of formula (1). In
WO9~/06085 2 0 919 8 9 PCT/GB91t01663
particular when R0 is hydroxy the compound can exist in
its keto tautomeric form :
Rl/$~/Ar = Rl/~Ar
OH O
Compounds of the formula (l) can form
pharmaceutically acceptable base addition salts with metal
ions, such as alkali metals for example sodium or
potassium, or with an ammonium ion.
In order to use a compound of the formula (l) or a
pharmaceutically acceptable salt thereof for the treatment
of humans and other mammals it is normally formulated in
accordance 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
orally, sublingually, parenterally, transdermally,
rectally, via inhalation or via buccal administration.
Compounds of formula (l) and their pharmaceutically
acceptable,salts which are active when given orally or via
buccal administration can be formulated appropriately in
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 example, ethanol, glycerine
or water with a flavouring or colouring agent. Where the
W O 92/06085 2 0 919 8 9 PC~r/GB91/01663
-- 10 --
composition is in the form of a tablet, any pharmaceutical
carrier routinely used for preparing solid formulations
may be used. Examples of such carriers include starch,
celluloses, lactose, sucrose and magnesium stearate.
Where the composition is in the 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
considered, for example aqueous gums, celluloses,
silicates or oils and 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
or non-aqueous carrier optionally containing a parenterally
acceptable oil or solubilising agent, for example
polyethylene glycol, polyvinylpyrrolidone, lecithin,
2-pyrrolidone, cyclodextrin, arachis oil, or sesame oil.
A typical suppository formulation comprises a
compound of formula (1) or a pharmaceutically acceptable
salt thereof which is active when administered in this
way, with a binding andtor lubricating agent, $or 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 plaster, patch or membrane.
Typical compositions for inhalation are in the form of
a solution, suspension or emulsion that may be administered
W092/06085 2 ~ 919 ~ 9 ; PCT/GB91/01663
in the form of an aerosol using a conventional propellant
such as dichlorodifluoromethane or trichlorofluoromethane,
or are in the form of a powder for insufflation.
Preferably the composition is in unit dosage form,
for 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
0.005 mg/Kg to 15 mg/Kg, and each dosage unit for
parenteral administration contains suitably from 0.001
mg/Kg to 10 mg/Kg, of a compound of formula (1) or a
pharmaceutically acceptable salt thereof calculated as the
free acid.
The daily dosage regimen for oral administration is
suitably about 0.001 mg/Kg 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 administration is suitably about 0.001 mg/Kg to
40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a
compound of the formula (1) or a pharmaceutically accept-
able salt thereof calculated as the free acid. The
active ingredient may be administered as required for
example from 1 - 8 times a day or by infusion. The
compositions of the invention are agonists of a cA-PrK and
are of use in combatting 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 by inhalation dosages are controlled by a
valve, are administered as required and for an adult are
conveniently in the range 0.1 - 5.0 mg of a compound of
the formula (1) or a pharmaceutically acceptable salt
thereof.
W O 92/06085 2 0 919 g 9 PC~r/GB91/01663
- 12 -
The compounds of this invention may be
co-administered with other pharmaceutically active
compounds, 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 composition.
Examples of compounds which may be included in
pharmaceutical compositions with the compounds of the
formula (1) are bronchodilators such as sympathomimetic
amines for example isoprenaline, isoetharine, sulbutamol,
phenylephrine and ephedrine or xanthine derivatives for
example theophylline and aminophylline, anti-allergic
agents for example disodium cromoglycate, histamine
H1-antagonists, drugs used in the treatment of cancer
lS such as those which inhibit the synthesis of or inactivate
DNA, for example 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 another aspect the present invention provides a
process for the preparation of compounds of the formula (1)
or pharmaceutically acceptable salts thereof, which
process comprises reacting a compound of the formula (2) :
~ Ar ~2)
NC
OH
W092/06085 ~ U Yl ~ ~ PCT/GB9i/01663
- 13 -
wherein Ar is as hereinbefore defined with an azide salt,
and optionally thereafter :
forming a bioprecursor of R0 and/or
o forming a pharmaceutically acceptable salt.
A compound of the formula (2) is suitably reacted
with an azide salt such as ammonium, sodium, potassium or
aluminium azide in an organic solvent such as
dimethylformamide, dimethylsulphoxide, N-methyl-
pyrrolidone or tetrahydrofuran at an elevated temperature
e.g. 40 - 200C, preferably at the reflux temperature of
- the reaction mixture.
A compound of the formula (1) wherein ~ is OH can
be converted to the corresponding compound where R0 is
oR2 by reaction with R2L wherein R2 is as
hereinbefore defined and L is a leaving group such as
halo e.g. bromo, chloro, iodo.
A compound of the formula (1) can be converted to a
N-protected tetrazolyl derivative by reaction with a
suitable N-protecting agent in standard manner, for
example with a pivalolyoxymethyl halide.
A compound of the formula (2) can suitably be
prepared by reacting a compound of the formula (3) :
ArCOCH = CHLl (3)
wherein Ar is as hereinbefore defined and Ll is a
displaceable group,
with a compound of the formula (4) :
W092/0608; 2 ~ 9 1~ ~ 9 PCT/GB91/01663
- 14 -
H2NCOCH2CN (4)
Suitably Ll in a compound of the formula (3) is
hydroxy or a derivative thereof for example Ll is
protected hydroxy such as silyloxy, an acid residue (for
example Cl_6alkanoyloxy) or an ether residue (for
example methoxy or ethoxy). Alternatively Ll is a
secondary amino group, for example di-Cl_6alkylamino
such as dimethylamino or a cyclic amino group such as
lo piperidino, pyrrolidino or morpholino. Preferably
is hydroxy or dimethylamino.
Suitably an alkali metal (e.g. sodium) salt of a
compound of the formula (3) wherein Ll is hydroxy is
treated with a compound of the formula (4) under mildly
alkaline aqueous conditions, for example in water in the
presence of piperidine and glacial acetic acid, at an
elevated temperature e.g. 30 - 200C, preferably at the
reflux temperature of the reaction mixture.
Alternatively a compound of the formula (3) wherein
Ll is a secondary amino group, for example
dimethylamino, is treated with a compound of the formula
(4) in a suitable solvent such as dimethylformamide, a
Cl_4alkanol or pyridine at an elevated temperature e.g.
30 - 200C, preferably at the reflux temperature of the
reaction mixture optionally in the presence of a base such
as pyridine or an alkali metal alkoxide, e.g. sodium
methoxide.
Compounds of the formula (3) wherein Ll is hydroxy
can suitably be prepared by reaction under basic
conditions of a compound o~ the formula (S) :
ArCOCH3 (5)
W092/0608~ ,5 ' PCT/GB91/01663
2091989
- 15 -
wherein Ar is as hereinbefore defined,
with a compound of the formula HCOL2 wherein L2 is a
leaving group.
Suitably L2 is ethoxy or methoxy. Conveniently a
solution of a compound of the formula (5) and a compound of
the formula HCOL2 in a suitable organic solvent such as
diethyl ether is treated with a suitable base such as an
alkali metal alkoxide, e.g. sodium methoxide at ambient
temperature. The resulting reaction mixture is
preferably extracted with water and the aqueous extract
which contains the alkali metal salt of a compound of the
formula (3) wherein L1 is hydroxy is then treated with a
compound of the formula (4) as hereinbefore described.
Compounds of the formula (5) are known or can be prepared
by methods known in the art.
Compounds of the formula (3) wherein L1 is a
secondary amino group (e.g. dimethylamino) can suitably be
prepared by reacting a compound of the formula (5) with a
compound of the formula HC(oR3)2Ll wherein R3 is
C1_4alkyl and L1 is a secondary amino group (for
example HC(oR3)2Ll is N,N-dimethylformamide dimethyl or
diethyl acetal), or with a compound of the formula HCL13 where
Ll is a secondary amino group (for example HCL13 is
trisdimethylaminomethane).
Alternatively a compound of formula (2) can be
prepared by demethylation of a compound of formula (6) :
W092/06085 2 0 919 8 9 PCT/GB91/01663
- 16 -
~ Ar (6)
NC
OMe
wherein Ar is as hereinbefore defined.
Suitable demethylating agents include sodium iodide
and chlorotrimethylsilane in an organic solvent such as
acetonitrile, or a halohydrocarbon eg. dichloromethane or
chloroform at elevated (eg. 30-80C) or ambient
temperature or sodium thiomethoxide in an organic solvent
such as dimethylformamide at an elevated temperature, for
example 40-120C.
The Ar group in compounds of the formula (2j, (5) or
(6), preferably (5) or (6) may be appropriately
functionalised by methods of aromatic substitution 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 C1_6alkoxy) by reaction with 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 nitroniumtetrafluoroborate. Such
a group can be readily hydrogenated to an amino group
which if desired can be converted to a NHCOR group by
reaction with LCOR wherein L is a leaving group and R is
as hereinbefore defined. Suitable examples of the reagent
LCOR include acid halides (L is halo eg. chloro or bromo)
or acid anhydrides (L is OCOR).
W092/06085 2 0 919 ~ 9 PCT/GB91/01663
- 17 -
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 an allyloxy derivative which
on heating undergoes a Claisen rearrangement to form an
ortho allyl hydroxy derivative. 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 an E-l-propenyl group by
reaction with a strong base, such as sodium methoxide.
This can occur during the conversion of a compound of
formula (5) to a compound of formula (2) as hereinbefore
described if such a base is used. An E-l-propenyl group
can be cleaved to a formyl group by reaction with an
lS oxidising agent such as N-methylmorpholine-N-oxide in the
presence of a catalyst such as osmium tetroxide to form a
l,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 functionalised, for example it can be 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 reagent such as (R40)2P(o)CH2Co2R4 or
Ph3P=CHCO2R4 wherein R4 is Cl_4alkyl to form a
CH=CHCo2R4 group which can be optionally hydrolysed to
a -CH=CHCO2H group. A -CH=CHCo2R4 group can be
converted to a -CH=CHCONR2 group by reaction with an
amine HNR2 or a chemical equivalent thereof wherein R 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 then
W092/06085 2 0 919 ~ 9 ` PCT/GB9l/01663
- 18 -
be reacted with an amine HNR2 or a chemical equivalent
thereof. An example of a chemical equivalent is ammonium
hydoxide which will form a CH=CHCONH2 group.
A compound of formula (6) is suitably prepared by
reacting a compound of formula (2) wherein Ar is as
hereinbefore defined with an O-methylating agent such as
dimethylformamide dimethylacetal in dimethylformamide or
trimethylphosphite at an elevated temperature (eg.
40-120C).
Pharmaceutically acceptable base addition salts of the
compounds of the formula (1) may be prepared by standard
methods, for example` by reacting a solution of the
compound of the formula (1) with a solution of the base.
The following biological test methods, data and
Examples serve to illustrate this invention.
Cvclic-AM~ Protein Kinase (cA-PrK) Aqonist Activitv
Type II cA-PrK was prepared from the cardiac muscle
of a cow. The supernatant from a muscle homogenate
(3 mls of 10 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
activity by incubating the enzyme at 30C for 5 minutes
with [ -32P]-adenosine triphosphate and a suitable
peptide substrate such as malantide (Malencik et al.,
1983, Anal. Biochem., 132, 34-40). The reaction was
W092/0608; 2 0 919 ~ ~ PCT/GB91/01663
-- 19 --
terminated by the addition of hydrochloric acid and the
[32P]-phosphopeptide quantified by spotting the reaction
mixture onto phosphocellulose papers, The concentration
of compound required to give 10% phosphotrans~erase
S activation is given as the EClo (~M). The compounds of
Examples 1 to 26 had EC1o values in the range 10 -
130 ~M.
Inhibition of Platelet Aqqreqation
Human platelet-rich-plasma was separated from freshly
drawn blood (in acid/citrate/dextrose) and treated with
100 ~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 1.5x108
cells/ml. Aliquots of this suspension were pre-incubated
with compounds for 5 minutes at 37C, then challenged with
1.0 yM U46619. The extent of 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 2, 4, 5, 11-13, 15, 19-23, and
25-26 had IC50 values in the range 0.8-300 ~M.
Anti-proliferative activitY
Compounds under test were dissolved in dimethyl-
sulphoxide and diluted 1:10,000 with DMEM (Dulbecco's
Modified Eagle's Medium) containing 10% fetal bovine serum
to give 12.5, 25, 50 and 100 ~M concentrations used in the
assay. Indicator cells consisting of 3 human colorectal
cells lines (SW-620, NRK-52 and HT-29) were plated at a
cell density of 1000 cells in 0.1 ml of DMEM
media in 96 well plates. Cells were incubated for 4 days
at 37C and 10% CO2 atmosphere. On day 5, tetrazolium
W 092/0608~ 2 ~ ~19 g 9 PCT/GB91/01663
- 20 -
reagent (50 llg MTT/250 111 total medium volume) was added
for 16 - 20 hours. Insoluble formazan was dissolved in
150 ~l of dimethylsulphoxide and absorbance
was measured using a microculture plate reader at 560 nm
interfaced with an IBM computer. Cell line growth and
inhibition were expressed in terms of mean absorbance unit
of triplicate samples following subtraction of mean
background absorbance. IC50 values (concentration that
show 50g~ growth inhibition) were determined from the dose
10 response curves. (Cancer Res., 48, 589-601, 1988). In
the cell line SW-620 the compound of Example 23 had an
IC50 value in the range 56 - 90 ~IM. In the cell line
NRK-52 the compound of Example 23 had an IC50 value in
the range 46 - 48 ~M. In the cell line HT-29 the
15 compound of Example 23 had an IC50 value in the range of
55 - 66 ~ .
Inhibition of S~ontaneous Contraction in Guinea-Piq 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. Inhibitory responses were
calculated as % maximum inhibition 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 contrac:tion is
given as the EC50 (~M). The compounds of Examples 5,
15-17 and 23 had EC50 values in the range 2 - 25 ~5.
W092/0608~ 2 0 919 8 9 PCT/GB91/01663
- 21 -
sronchodilatation - In vitro (Tracheal spiral)
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 spontaneousl~ and concentrations of test compounds
added in a cumulative fashion. The concentration of
compound which caused 50% inhibition of
the spontaneously developed tension is given as the
IC50(~M)-
The compounds of Examples 5 and 23 had IC50 values
of ll and 6.5 ~M respectively.
Measurement of cardiac muscle relaxation time in rabbitventricle
Papillary muscles from the right ventricle of female
Albino New Zealand rabbits were mounted in standard organ
baths containing oxygenated Krebs solution. One end of
the muscle was connected to an isometric transducer which
allowed recording of contractile force and its first
derivative on chart recorders. Test compounds were added
to the bath in a cumulative manner. Relaxation time was
calculated as the time taken from peak tension to the end
of the contraction. At concentrations of 30-l00 ~M,
compounds of Examples 12 and 23 caused a 10-20% decrease
in the relaxation time indicating a lusitropic effect of
use in the treatment of cardiovascular diseases such as
congestive heart failure.
WO 92/0608~ 19 8 9 PCI`/GB91/01663
-- 22 --
ExamPle 1
6-(3-Methoxyphenyl)-3-(5-tetrazolyl)pyridin- 2 ( lH ) -one
a) 3'-Methoxyacetophenone (15g) and dimethylformamide
dimethylacetal (16ml) were heated together at 120C in
dimethylformamide (8Oml) for 6 hours, the deep red
solution was diluted with ethyl acetate (400ml), washed
with water (5xlOOml), dried (MgS04) and solvent removed
at reduced pressure. The oil obtained was dissolved in
dimethylformamide (80ml), cyanoacetamide (10.08g) and
sodium methoxide (10.8g) added and the mixture heated at
130C for 35 minutes. The deep red solution was poured
into 5% aqueous acetic acid (400ml), the precipitated
product collected by filtration and washed with water,
ethanol and diethyl ether. Recrystallisation from
n-butanol gave 3-cyano-6-(3-methoxyphenyl)pyridin-
2(lH)-one (15.14g) m.p. 251C as a colourless solid.
b) 3-Cyano-6-(3-methoxyphenyl~pyridin-2(lH)-one (lg)
sodium azide (0.39g) and ammonium chloride (0.32g) were
heated together in N-methylpyrrolidin-2-one (lOml) at
140C for 2hours. The reaction mixture was poured into 10%
aqueous acetic acid (150ml), the precipitated solid
collected by filtration, washed with water and
recrystallised from n-butanol to give the title compound
(0.93g) m.p. 298C (decomp). lH NMR ~(DMSO-d6)
3.87(s,3H), 6.92(d,1H), 7.13(m,1H), 7.41-7.50(m,3H) and
8.48(d,lH).
~ ExamPle 2
6-(3-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
W O 92/06085 2 ~ 919 8 ~ P ~ /GB91/01663
- 23 -
(a) 3'-Hydroxyacetophenone (13.6g), iodopropane (10.7ml)
and potassium carbonate (13.8g) were heated together in
dimethylformamide (80ml) at 90C for 20hrs. The reaction
mixture was diluted with ethyl acetate (400ml), washed
with 2N sodium hydroxide (2xlOOml) and water (4xlOOml),
dried (MgS04), filtered and solvent removed at reduced
pressure to give 3'-propoxyacetophenone (16.46g) as an
oil. 1H NMR ~(DMSO-d6) 0.99(t,3H), 1.66-1.83(m,2H),
2.58((s,3H), 3.98(t,3H), 7.19(dd,1H) and 7.39-7.57(m,3H).
The following compounds were similarly prepared from
the appropriate phenol and alkyl iodide.
3'-Butoxyacetophenone:- oil, yield 90%, lH NMR
15 ~(DMSO-d6) 0.94(t,3H), 1.37-1.52(m,2H), 1.66-1.77(m,2H),
2.57(s,3H), 4.02(t,2H), 7.19(dd,1H) and 7.39-7.55(m,3H).
3'-Benzyloxyacetophenone:- oil, yield 89%, lH NMR
20 ~tCDC13) 2-57(s,3H), 5.09(s,2H), 7.17(dd,lH) and
7.29-7.56(m,8H).
4'-Methoxy-3'-propoxyacetophenone from 3'~hydroxy-4'-
methoxyacetophenone:- (A. Brossi et al J. Org. Chem.,
25 1967, 32, 1269) :- oil, yield 71%, lH NMR ~(CDC13)
1.05(t,3H), 1.87(m,2H), 2.56(s,3H), 3.93(s,1H),
4.04((t,2H), 6.88(d,1H), 7.52(d,1H), and 7.57(dd,1H).
3',5'-Dipropoxyacetophenone:- oil, yield 58%, 1H
30 NMR ~(DMSO-d6) 0.98(t,6H) 1.66-1.80(m,4H), 2.55(s,3H),
3.96(t,4H), 6.73(t,lH) and 7.04(d,2H).
3',5'-Diethoxyacetophenone:- oil, yield 64%, 1H NMR
~(DMSO-d6) 1.42(t,6H), 2.56(s,3H), 4.05(q,4H),
35 6.64(t,1H) and 7.07(d,2H).
W092/06085 2 0 91 9 8 g PCT/GB91/01663
2',5'-Dipropoxyacetophenone:- oil, yield 64%, lH
NMR ~(DMSO-d6) 0.96(t,3H), 1.04(t,3H), 1.62-1.84(m,4H),
2.S5(s,3H), 3.88(t,2H), 3.99(t,2H) and 7.03-7.11(m,3H).
3',4'-Dipropoxyacetophenone:- yield 95%, lH NMR
~(CDCl3) 1.00-l.l9(m,6H), 1.78-2.02(m,4H), 2.55(s,3H),
3.98-4.17(m,4H), 6.87(d,1H), 7.52(s,lH) and 7.54(d,lH).
3'-Allyloxyacetophenone:- oil, yield 71%, lH
NMR~(CDCl3) 2.58(s,3H), 4.57(d,2H), 5.27-5.47(m,2H),
5.96-6.15(m,1H), 7.12(dd,1H), 7.31(t,1H) and
7.49-7.55(m,2H).
4'-Methoxy-2'-pentyloxyacetophone:-From
4'-methoxy-2'hydroxyacetophenone and iodopentane, yield
92%, lH NMR ~(DMS0-d6)0.86(t.3H), 1.20-1.47(m,4H),
1.74-1.85(m,2H), 2.49(s,3H), 3.82(s,3H), 4.09(t,2H),
6.56-6.62(m,2H) and 7.66(d,lH).
3'-iso-Butoxy-4'-methoxyacetophenone:-From
4'-methoxy-3'-hydroxyacetophenone and iso-butyl bromide
using acetone as solvent, yield 68~. lH NMR
~(DMSO-d6) O.99(d,6H), 1.96-2.15(m,1H), 2.53(s,3H),
3.78(d,lH), 3.86(s,3H), 7.06(d,lH), 7.42(d,lH) and
7.62(dd,1H).
3'-Allyloxy-4'-methoxyacetophenone:-From
4'-methoxy-3'-hydroxyacetophenone and allyl bromide, yield
67%, lH NMR ~(CDCl3) 2.55(s,3H), 3.95(s,3H),
4.63-4.68(m,2H), 5.29-5.47(m,lH), 6.02-6.18(m,lH),
6.90(d,1H),7.53(d,1H) and 7.60(dd,1H).
3'-(2,2,-dimethylpropyloxy)-4'-methoxyacetophenone:-Fr
m 4'-methoxy-3'-hydroxyacetophenone and 1-bromo-2,2-
dimethylpropane, yield 76~, lH NMR ~(CDCl3)
W O 92/06085 2 O 9 19 ~ ~ PC~r/GB91/01663
- 25 -
1.07(s,9H), 2.56(s,3H), 3.69(s,2H), 6.88(d,1H) and
7.50-7.58(m,2H).
3'-ethoxy-4'-methoxyacetophenone:-from
3'-hydroxy-4'-methoxyacetophenone and iodoethane using
acetone as solvent, yield 83%, lH NMR ~(CDC13)
1.49(t,3H),2.57(s,3H),3.94(s,3H),4.17(q,2H),6.8g(d,1H),7.53
-7.60(m,2H).
3'-Allyl-4'-methoxyacetophenone:-from
3'-allyl-4'-hydroxyacetophenone, yield 87% as an oil.
lH NMR ~(CDCl3)2.55(s,3H),3.40(d,2H),3.89(s,3H),
5.02-5.10(m,2H), 5.90-6.04(m,lH),6.88(d,lH),7.77(d,lH) and
7.85(dd,lH).
(b) From 3'-propoxyacetophenone (9g), 3-cyano-6-(3-
propoxyphenyl)pyridin-2(1H)-one (3.49g) m.p. 240-241C
after recrystallisation from ethanol, was prepared
according to the method of Example l(a).
(c) From 3-cyano-6-(3-propoxyphenyl)pyridin-2(lH)-one
(lg), the title compound (0.61g) m.p. 270-271C after
recrystallisation from n-butanol, was prepared according
to the method of Example l(b).
Exam~le 3
6-(3-Butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) 3'-Butoxyacetophenone (17.3g) and dimethylformamide
dimethylacetal (11.9g) were boiled together in
dimethylformamide (9Oml) for 15 hours. The deep red
solution was cooled to room temperature, cyanoacetamide
(8.3g) and sodium methoxide (10.3g) added and the mixture
boiled for a further 3 hours. The reaction mixture was
W092/0608~ 2 ~ 9 ~. 9 8 9 PCT/GB91/01663
- 26 -
poured into 10% aqueous acetic acid (300ml) the
precipitated product separated by filtration, washed with
water and recrystallised from n-butanol to give
3-cyano-6-(3-butoxyphenyl)pyridin-2(lH)-one (10.66g) m.p.
201-202C.
(b) From 3-cyano-6-(3-butoxyphenyl)pyridin-2(1H)-one
(2.15g), the title compound (o.55g) m.p. 259-260C after
recrystallisation from n-butanol, was prepared according
to the method of Example l(b).
Example 4
6-(3-Benzyloxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3'-benzyloxyphenylacetophenone (20.2g),
3-cyano-6-(3-benzyloxyphenyl)pyridin-2(lH)-one (2.6g)
m.p.202-203C after recrystallisation from ethanol, was
prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-benzyloxyphenyl)pyridin-2(lH)-one
(lg), the title compound (0.35g) m.p.276C (decomp) after
recrystallisation from dimethylformamide was prepared
according to the method of Example l(b). lH NMR
~(DMSO-d6) 5.23(s,2H), 6.91(d,1H), 7.16-7.20(m,1H),
7.31-7.54(m,8H), 8.47(d,1H) and 12.67(br s,lH).
Example 5
6-(3-Bromophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) From 3'-bromoacetophenone ~13.2g), 3-cyano-6-(3-
35 bromophenyl)pyridin-2(1H)-one (21.8g) m.p. 309C (decomp)
after recrystallisation from n-butanol, was prepared
W092/06085 2 0 919 ~ 9 PCT/G~91/01663
- 27 -
according to the method of Example l(a). lH NMR
~(DMSO-d6) 6.89(br s,lH), 7.48(t,1H), 7.75(d,1H),
7.83(d,lH), 8.06(s,lH), 8.21(d,lH) and 12.75(br s,lH).
(b) From 3-cyano-6-(3-bromophenyl)pyridin-2(lH)-one
(1.37g), the title compound (0.39g) m.p. 285-286C after
recrystallisation from dimethylformamide, was prepared
according to the method of Example l(b).
ExamPle 6
6-(3-Trifluoromethyl)-3-(5-tetrazolyl)pyridin-2(IH)-one
(a) From 3'-trifluoromethylacetophenone (9.4g), 3-cyano-
6-(3-trifluoromethylphenyl)pyridin-2~lH)-one (11.38g)
m.p.255-256C after recrystallisation from ethanol, was
prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-trifluoromethylphenyl)pyridin-
2(lH)-one (1.06g), the title compound (0.93g)
m.p.274-275C after recrystallisation from n-butanol, was
prepared according to the method of Example l(b).
ExamPle 7
6-(3-Ethylphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) From 3'-ethylacetophenone (7.4g), 3-cyano-6-(3-
ethylphenyl)pyridin-2(lH)-one (3.97g~ m.p.241-242C after
recrystallisation from n-butanol, was prepared according
to the method of Example 3(a).
(b) From 3-cyano-6-(3-ethylphenyl)pyridin-2(1H)-one
(0.89g), the title compound (0.37g) m.p.278-279C after
W092/0608~ 2 0 9 i 9 8 9 PCT/GB91/01663
- 28 -
recrystallisation from n-butanol, was prepared according
to the method of Example l(b).
Exam~le 8
6-(4-Butoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
ta) From 4'-butoxyacetophenone (5.6g), 3-cyano-6-(4-
o butoxyphenyl)pyridin-2(lH)-one (1.12g) m.p. 245C after
recrystallisation from ethanol, was prepared according to
the method of Example l(a).
(b) A mixture of 3-cyano-6-(4-butoxyphenyl)pyridin-
2(lH)-one (0.3g), sodium azide (0.098g), ammonium chloride
(0.08g) and lithium chloride (0.064g) were heated in
dimethylformamide (15ml) at 120C for 72 hours. Solvent
was removed at reduced pressure, the product precipitated
by the addition of 10% aqueous acetic acid (40ml) and
separated by filtration. The solid was dissolved in 5%
potassium hydrogen carbonate and insoluble material
- separated by filtration. The filtrate was acidified with
conc. hydrochloric acid, the precipitated product
collected by filtration and recrystallised from ethanol to
give the title compound (0.05g) m.p.289-292C.
Example 9
6-(4-iso~utylphenyl)pyridin-2(lH)-one
(a) From 4'-isobutylacetophenone (8.8g); 3-cyano-6-(4-
isobutylphenyl)pyridin-2(lH)-one (6.0g) m.p. 264C after
recrystallisation from ethanol, was prepared according to
the method of Example 3(a).
W092/0608~ PCT/GB91/01663
- 29 -
(b) From 3-cyano-6-(4-isobutylphenyl)pyridin-2(1H)-one
(2.52g), the title compound (1.54g) m.p. 275C (decomp)
after recrystallisation from dimethylformamide, was
prepared according to the method of Example l(b) but using
dimethylformamide instead of N-methylpyrrolidin-2-one as
solvent. lH NMR ~(DMSO-d6) 0.89(d,6H), 1.81-1.96
(m,lH), 2.51(m,2H), 6.87(d,lH), 7.33(d,2H), 7.78(d,2H),
8.46(d,1H) and 12.63(br s,lH).
ExamPl 10
6-(4-Biphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
15 (a) From 4-acetylbiphenyl (19.6g), 6-(4-biphenyl)-3-
cyanopyridin-2(lH3-one (14.01g) m.p. 312-316C after
recrystallisation from n-butanol, was prepared according
to the method of Example l(a).
20 (b) From 6-(4-biphenyl)-3-cyanopyridin-2(1H)-one (1.36g),
the title compound (0.84g) m.p. 305C (decomp) after
recrystallisation from dimethylformamide, was prepared
according to the method of Example l(b). 1H NMR
~(DMSO-d6) 7.00(d,lH), 7.41-7.S4(m,3H), 7.77(d,2H),
25 7.85(d,2H), 7.98(d,2H) and 8.50(d,lH).
ExamPle 11
6-(4-Propoxy,phenyl)-3-(S-tetrazolyl)pyridin-2(1H)-one
(a) From 4'-propoxyacetophenone (15.4g) (E. Eckhart and
J. Varga, Maqvar. Kem. FolYoirat 1961, 67, 509, Chem
Abs. 1962, S6, 15557e),
35 3-cyano-6-(4-propoxyphenyl)pyridin-2(lH)-one (1.8g) m.p.
262-265C after recrystallisation from dimethylformamide,
W092/06085 2 0 919 8 9 PCT/GB91/01663
- 30 -
was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(4-propoxyphenyl)pyridin-2(lH)-one
(lg), the title compound (0.85g) m.p. 292C (decomp) after
recrystallisation from dimethylformamide, was prepared
according to the method of Example l(b). lH NMR
~(DMSO-d6) 0.99(tr3H), 1.63-1.84(m,2H), 4.02(t,2H),
6.81(d,lH), 7.07(d,2H), 7.82(d,2H~ and 8.45(d,lH).
Exam~le 12
6-(4-Methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)pyridin-
2(lH)-one
(a) From 4'-methoxy-3'-propoxyacetophenone (12g), 3-cyano-
6-(4-methoxy-3-propoxyphenyl)pyridin-2(lH)-one (14.03g)
m.p. 24~.C after recrystallisation from ethanol, was
prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(4-methoxy-3-propoxyphenyl)pyridin-
2(lH)-one (3.12g), the title compound (1.69g) m.p.
289-290C after recrystallisation from n-butanol, was
prepared according to the method of Example l(b).
ExamPle 13
6-(3,4-Methylenedioxyphenyl)-3-(5-tetrazolyl)pyridin-
2(lH)-one
(a) From 3',4'-(methylenedioxy)acetophenone (16.4g),
3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-2(lH)-one
(10.2g) m.p. ~320C after recrystallisation from dimethyl-
formamide, was prepared according to the method of Example
35 3(a). lH NMR ~(DMSO-d6) 6.13(s,2H), 6.72(d,1H),
7.06(d,1H), 7.36-7.42(m,2H), 8.13(d,1H) and 12.58(br s,lH).
W092/0608; 2 0 919 8 9 PCT/GB91/01663
- 31 -
(b) From 3-cyano-6-(3,4-methylenedioxyphenyl)pyridin-
2(lH)-one (0.96g), the title compound (O.lg) m.p. >325C
after recrystallisation from ethanol, was prepared
according to the method of Example l(b) but using
dimethylformamide instead of N-methylpyrrolidinone as
solvent. lH-NMR ~(DMSO-d6) 6.14(s,2H), 6.83(d,1H),
7.08(d,lH),7.37-7.46(m,2H), 8.43(d,lH), 12.S5(br s,lH) and
13.28(br s,lH).
Ex,~mPle 14
6-(3,4-Dichlorophenyl)-3-(5-tetrazolyl)pyridi~-2(lH)-one
15 (a) From 3',4'-dichloroacetophenone (18.9g),
3-cyano-6-(3,4-dichlorophenyl~pyridin-2(lH)-one (1.94g)
m.p. >330C after recrystallisation from dimethyl-
formamide, was prepared according to the method of Example
l(a). lH NMR ~(DMSO-d6) 6.97(br d,lH), 7.76-7.87
20 (m,2H), 8.15(s,1H) and 8.23(d,1H).
(b) From 3-cyano-6-(3,4-dichlorophenyl)pyridin-2(lH)-one
(1.06g), the title compound (0.54g) m.p.295C (decomp)
after recrystallisation from dimethylformamide, was
prepared according to the method of Example l(b) but
using dimethylformamide instead of N-methylpyrrolidinone
as solvent. lH NMR ~(DMSO-d6) 7.02(d,1H) 7.76-7.89
(m,2H), 8.17(s,lH) and 8.48(s,lH).
ExamPle 15
6-(3,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
(a) From 3',5'-dipropoxyacetophenone (11.82g), 3-cyano-6-
(3,5-dipropoxyphenyl)pyridin-2(lH)-one (7.lg) m.p.
W092/0608~ 2 0 9 ~ 9 8 9 PCT/GB91/01663
209-210C after recrystallisation from ethanol, was
prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-dipropoxyphenyl)pyridin-2(lH)-one
(1.25g), the title compound (1.31g) m.p.224-225C after
recrystallisation from n-butanol, was prepared according
to the method of Example l(b).
Example 16
6-(3,5-Diethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) From 3',5'-diethoxyacetophenone (4.16g), 3-cyano-6-
(3,5-diethoxyphenyl)pyridin-2(1H)-one (l.Og) m.p.259-261C
after recrystallisation from n-butanol, was prepared
according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-diethoxyphenyl)pyridin-2(lH)-one
(0.82g), the title compound (0,57g) m.p. 282-283C after
recrystallisation from n-butanol, was prepared according
to the method of Example l(b).
Example 17
6-(3,5-Dibromophenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one
(a) From 3',5'-dibromoacetophenone (M. Tashiro, S Mataka,
H. Nakamura and K Nakayama, J. Chem. Soc. Perkin Trans I.,
1988, 179) (l.llg), 3-cyano-6-(3,5-dibromophenyl)pyridin-
2(lH)-one (0.73g) m.p. >300C after recrystallisation from
n-butanol, was prepared according to the method of Example
3(a). 1H NMR ~(DMSO-d6) 7.00(br d,lH), 8.02(s,1H),
8.09(s,2H) and 8.23(d,lH).
W O 92/0608~ 2 0 g 19 8 9 P ~ /GB91/01663
- 33 -
(b) From 3-cyano-6-(3,5-dibromophenyl)pyridin-2(lH)-one
(o.s3g), the title compound (0.15g) m.p. 295-296C
(decomp) after recrystallisation from n-butanol was
prepared according to the method of Example l(a). lH NMR
S ~(DMSO-d6) 7.10(br d,lH), 8.02(s,1H), 8.13(s,2H) and
8.47(d,lH).
Example 18
10 6-(2,4-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(IH)-one
(a) From 2',4'-dipropoxyacetophenone (17.9g) (P.
Chabrier, H. Najer, R. Giudicelli and E. Joannie-Voisinet,
15 8ull. Soc. Chim. France, l9S8, 1488.), 3-cyano-6-(2,4-
dipropoxyphenyl)pyridin-2(1H)-one (1.69g) m.p. 148C after
recrystallisation from ethanol, was prepared according to
the method of Example 3(a).
20 (b) From 3-cyano-6-(2,4-dipropoxyphenyl)pyridin-2(1H)-one
(lg), the title compound (0.60g) m.p. 205C after
recrystallisation twice from ethanol, was prepared
according to the method of Example l(b).
Exam~le 19
6-(2,5-Dipropoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-one
30 (a) From 2',5'-dipropoxyphenylacetophenone (11.8g),
3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(lH)-one (14.36g)
m.p. 160-162C after recrystallisation from ethanol, was
prepared according to the method of Example 3(a). 1H NMR
~(DMS0-d6) 0.92(t,3H), 0.97(t,3H), 1.61-1.76(m,4H),
3S 3.92(t,4H), 6.54(d,lH), 7.01-7.06(m,3H), 8.18(d,1H).
W092/06085 2 0 ~19 ~ 9 PCT/GB9l/01663
- 34 -
(b) From 3-cyano-6-(2,5-dipropoxyphenyl)pyridin-2(lH)-one
(2.5g), the title compound (0.81g) m.p.188-189C after
recrystallisation from ethanol, was prepared according to
the method of Example l(b).
ExamPle 20
6-(2,3,4-Trichlorophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) 2',3',4'-Trichloroacetophenone (22.15g) and
dimethylformamide (12.5g3 were boiled in dimethylformamide
(lOOml) for 3 hours. The solution was diluted with ethyl
acetate (500ml), washed with water (6xlOOml), dried
(MgS04), filtered and solvent removed at reduced
pressure. The residue was triturated with diethyl ether to
give 3-N,N-dimethylamino-1-(2,3,4-trichlorophenyl)prop-
2-ene-1-one (17.5g). lH NMR ~(DMSO-d6) 2.8~(s,3H)
3.08(br s,3H), 5.17(d,1H), 7.1(very br,lH), 7.30(br d,lH)
and 7.65(d,1H).
(b) A solution of 3-N,N-dimethylamino-1-(2,3,4-
trichlorophenyl)prop-2-ene-1-one (9.8g) and cyanoacetamide
(3.18g) in dimethylformamide (35ml) was boiled for 48
hours. The reaction mixture was poured into 10% aqueous
acetic acid (lOOml), the precipitated product separated by
filtration and recrystallised from ethanol to give
3-cyano-6-(2,3,4-trichlorophenyl)pyridin-2(1H)-one
(4.4g). 1H NMR ~(DMSO-d6) 6.52(d,lH),7.58(d,lH),
7.79(d,1H), 8.24(d,1H) and 12.95(br s,lH).
(c) From 3-cyano-6-(2,3,4-trichlorophenyl)pyridin-
2(1H)-one (1.2g), the title compound (1.21g) m.p.>300C
after recrystallisation from dimethylformamide/water, was
prepared according to the method of Example l(a). lH NMR
~(DMSO-d6) 6.63(d,lH), 7.61(d,lH), 7.83(d,lH),
W092/0608~ 2 0 919 ~ 9 PCT/GB91/01663
- 35 -
8.51(d,1H) and 12.98(br s,lH).
EXamD1e 2 1
6-[6-(1,2,3,4-Tetrahydronaphthyl)]-3-(5-tetrazolyl)pyridin-
2(lH)-one
(a) From 6-acetyltetralin (4.23g), 3-cyano-6-[6-(1,2,3,4-
tetrahydronaphthyl)]pyridin-2(lH)-one (1.27g) m.p.
245-246OC after recrystallisation from n-butanol, was
prepared according to the method of Example 3(a). lH NMR
~(DMSO-d6) 1.75(m,4H), 2.77(m,4H), 6.71(d,lH), 7.19
(d,lH), 7.50(d,1H), 7.53(s,1H) and 8.15(d,1H).
(b) From 3-cyano-6-[6-(1,2,3,4-tetrahydronaphthyl)pyridin-
2(lH)-one (lg), the title compound (0.55g) m.p. 284-285C
after recrystallisation from dimethylformamide/water,was
prepared according to the method of Example l(b).
Exam~le 22
6-(3-Chlorophenyl)-3-(5-tetrazolyl~pyridin-2(lH)-one
(a) From 3'-chloroacetophenone (15.46g), 6-(3-chloro-
phenyl)-3-cyanopyridin-2(lH)-one (17.12g) m.p. 304-305C
after recrystallisation from n-butanol, was prepared
according to the method of Example 3(a).
(b) From 6-(3-chlorophenyl)pyridin-2(1H)-one (1.2g), the
title compound (l.Olg) m.p. 301-302C (decomp) after
recrystallisation from n-butanol, was prepared according
to the method of Example l(b). lH NMR ~(DMSO-d6)
6.94(d,1H), 7.48-7.62(m,2H), 7.81(d,1~), 7.96(s,1H),
8.48(d,lH) and 12.77(br s,lH)
W092/0608; 2 0 9 ~ 9 8 9 PCT/GB91/01663
- 36 -
Example 23
6-(3-Phenylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) 3'-Phenylthioacetophenone (2.05g) (L. Victor, Brit.
Pat. 1,519,354) and dimethylformamide dimethylacetal
(1.19g) were heated together in dimethylformamide (lOml)
at 100C for 18 hours. The reaction mixture was diluted
with ethyl acetate (50ml) washed with water (6x30ml),
dried (MgS04) filtered and solvent removed at reduced
pressure. The residue was column chromatographed (silica
gel, dichloromethane-5% ethanol/dichloromethane eluant) to
give 3-N,N-dimethylamino-1-(3-phenylthiophenyl)-
prop-2-ene-1-one (1.72g) as a yellow oil.
(b) A mixture of 3-N,N-dimethylamino-1-~3-phenylthio-
phenyl)prop-2-ene-1-one (1.72g), sodium methoxide (0.76g)
and cyanoacetamide (0.59g) were boiled together in
dimethylformamide (lOml) for 1 hour. The reaction mixture
was poured into 10% aqueous acetic acid (lOOml), the
precipitated product separated by filtration and
recrystallised from ethanol to give 3-cyano-6-(3-
phenylthiophenyl)pyridin-2(lH)-one (l.Og) m.p. 262-264C.
(c) From 3-cyano-6-(3-phenylthiophenyl)pyridin-2(1H)-one
(0.79g), the title compound (0.77g) m.p.265-266C after
recrystallisation from n-butanol, was prepared according
to the method of Example l(b).
Exam~le 24
3,4-Dimethoxyphenyl-3-(S-tetrazolyl)pyridin-2(lH)-one
(a) From 3',4'-Dimethoxyacetophenone (18g), 3-cyano-6-
W092/0608~ 2 0 ~ ~ PCT/GB91/01663
- 37 -
(3,4-dimethoxyphenyl)pyridin-2(1H)-one (9.86g) m.p.
269-270C after recrystallisation from ethanol, was
prepared according to the method of Example l(a).
(b) From 3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(lH)-one
(1.02g), the title compound (0.02g) m.p. 293-295C after
recrystallisation from dimethylformamide, was prepared
accordlng to the method of Example l(b).
Example 25
6-(3-Methylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
15 (a) From 3'-methylthioacetophenone (4.64g), 3-cyano-6-
(3-methylthiophenyl)pyridin-2(lH)-one (4.3g) m.p.234-238C
after recrystallisation from ethanol, was prepared
according to the method of Example 3(a).
(b) From 3-cyano-6-(3-methylthiophenyl)pyridin-2tlH)-one
(lg), the title compound (0.85g) m.p.274-2760C (decomp)
after recrystallisation from n-butanol, was prepared
according to the method of Example l(b). 1H NMR
~(DMSO-d6) 2.58(s,3H), 6.91(d,1H), 7.39-7.63(m,3H),
25 7.68(s,1H) and 8.47(d,1H).
Example 26
6-(3-Butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) Copper-(I)-n-butylmercaptide (R. Adams,
W. Reijschneider and A. Ferretti, Org, Syn. Coll. Vol., V,
plO7) (3.34g) and 3-cyano-6-(3-bromophenyl)pyridin-
2(lH)-one (2.61g) were heated together in a mixture of
quinoline (lOml) and pyridine (3ml) at 160C for 4 hours.
W O 92/0608~ 2 0 ~ 9 P ~ /GB91/01663
- 38 -
The reaction mixture was poured onto conc. hydrochloric
acid (30ml) and ice (lOOg) and the precipitated material
collected by filtration. The residue was column
chromatographed (silica gel,
dichloromethane-dichloromethane/2% ethanol) to give
3-cyano-6-(3-butylthiophenyl)pyridin-2(lH)-one (0.35g)
m.p. 191-193C after recrystallisation from ethanol.
(b) From 3-cyano-6-(3-butylthiophenyl)pyridin-2(lH)-one
(0.23g), the title compound (O.llg) m.p.237-238C after
recrystallisation from n-butanol, was prepared according
to the method of Example l(b).
Example 27
6-(3,4-Di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(1H)-
one
(a) From 3',4'-di-propoxyacetophenone (3.6g)
3-cyano-6-(3,4-dipropoxyphenyl)pyridin-2(1H)-one (3.21g)
m.p. 249C after recrystallisation from ethanol, was
prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,4-di-propoxyphenyl)-
pyridin-2(lH)-one (l.OOg) the title compound m.p. 280C
(decomp) after recrystallisation from n-butanol,was
prepared according to the method of Example l(b). lH NMR
~d6-DMSO) 0.97-1.05(m,6H), 1.71-1.81(m,4H), 4.01(t,2H),
4.03(t,2H), 6.88(d,lH), 7.09(d,lH),
7.43(d,1H), 7.46(s,1Hj and 8.44(d,1H) and 12.61(br.s,1H).
Example 28
6-(2,3-di-Propoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-
one
W O 92/0608~ 2 0 919 ~ ~ P ~ /GB91/01663
- 39 -
(a) From 2,3-dihydroxybenzaldehyde (20g), 2,3-di-propoxy
benzaldehyde (18.6g) isolated as an oil was prepared
according to the method of Example 2(a). lH-NMR
~(CDCl3) 1.04(t,3H), l.O9(t,3H), 1.74-1.96(m,4H),
3.97(t,2H), 4.15(t,3H), 7.03-7.16(m,2H), 7.39(dd,lH) and
10.47(s,lH)
(~) To a solution of 2,3-di-propoxybenzaldehyde (18.6g)
in tetrahydrofuran at -78C methyl lithium (61ml, l.SM in
diethyl ether) was added over 10 minutes. The reaction
mixture was stirred at -78C for two hours and at room
temperature for 16 hours. After quenching with water the
organic phase was separated, dried (MgS04) and solvent
removed to give 1-(2,3-di-propoxyphenyl)-1-hydroxyethane
(20g) as an oil. lH-NMR ~(CDCl3) 1.04(t,3H),
1.06(t,3H), 1.72-1.93(m,4H), 3.89tt,2H), 3.99(t,2H),
5.15(m,lH), 6.80(m,lH) and 6.95-7.04(m,2H).
(c) To an ice cooled solution of 1-(2,3-di-propoxy-
phenyl)-1-hydroxyethane (20g) in dichloromethane (250ml)
powdered 4A molecular sieves (23g), N-methylmorpholine-
N-oxide (14.9g) and tetrapropylammonium perruthenate (lg).
The mixture was stirred for one hour with ice cooling and
at room temperature overnight. After filtration through
Hyflo solvent was removed at reduced pressure to give
2',3'-di-propoxyacetophenone (18.3g). lH-NMR ~(CDCl3)
1.03(t,3H), 1.08(t,3H), 1.72-1.96(m,4H), 2.63(s,3H),
3.96(t,2H), 4.01(t,2H) and 6.99-7.19(m,3H).
(d) From 2',3'-dipropoxyacetophenone (lOg),
3-cyano-6-(2,3-di-propoxyphenyl)pyridin-2(1H)-one (1.87g)
m.p. 195-198C was prepared according to the method of
Example 3(a), omitting sodium methoxide. 1H-NMR
(d6-DMSO) 0.81(t,3H), l.Ol(t,3H), 1.51(m,2H),
1.76(m,2H), 3.84(t,2H), 3.99(t,2H), 6.43(d,lH),
6.97(d,1H), 7.10- 7.27(m,2H) and 8.17(d,1H).
W092/0608~ 2 0 919 ~ ~ PCT/GB91/01663
- 40 -
(e) From 3-cyano-6-(2,3-di-propoxyphenyl)pyridin-
2(1H~-one (lg), the title compound (0.47g) m.p. 186-187C
after recrystallisation from aqueous ethanol was prepared
according to the method of Example l(b).
Exam~le 2g
6-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(5-tetrazolyl)-
pyridin-2(lH)-one
(a) A mixture of 3'-hydroxy-4'-methoxyacetophenone
(20.8g), potassium carbonate (24.15g), cyclopentyl bromide
(22.35g) and potassium iodide (3.32g) were combined in
acetone (250ml) and boiled for 24 hours. Dimethylformamide
'5 (25ml) was added and boiling continued for a further 24
hours. The reaction mixture was cooled to room
temperature, filtered and solvent removed at reduced
pressure. The residue was dissolved in diethyl ether
(200ml) washed with 2N sodium hydroxide (3x50ml) and water,
dried and solvent removed at reduced pressure to give
3'cyclopentyloxy, 4'-methoxyacetophenone as an oil that
solidified on standing m.p. 59-60C.
(b) From 3'-cyclopentyloxy-4'-methoxyacetophenone
(11~25g), 3-cyano-6-(3-cyclopentyloxy-4-methoxyphenyl)-
pyridin-2(1H~-one (4.07g) m.p.259-260C after digestion
with acetonitrile was prepared according to the method of
Example 3(a) omitting sodium methoxide.
(c) From 3-cyano-6-(3-cyclopentyloxyphenyl-4-
methoxyphenyl)pyridin-2(1H)-one (0.8g), the title compound
(0.6g) m.p. 286-287C (decomp) after recrystallisation
from dimethylformamide was prepared according to the
method of Example l(b). lH-NMR ~(d6-DMSO)
W O 92/06085 2 ~ g g PC~r/GB91/01663
- 41 -
1.54-2.02(m,8H), 3.83(s,3H), 5.00(m,lH), 6.87(d,lH),
7.10(d,1H), 7.43(s,1H), 7.46(d,1H) and 8.44(d,1H).
Example 30
6-(3-Ethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) A mixture of 3-hydroxyacetophenone (6.8g) and
tris(dimethylamino)methane (14.5g) were heated together in
dimethylformamide (30ml) at 80C for 4 hours. The reaction
mixture was cooled to room temperature cyanoacetamide
(8.4g) added and the mixture boiled for 8 hours. After
cooling to room temperature the mixture was poured into
10% aqueous acetic acid (200ml), filtered and the residue
washed with water and ethanol to give 3-cyano-6-(3-
hydroxyphenyl)pyridin-2(lH)-one. lH-NMR ~(d6-DMSO)
6.64(br.d,1H), 6.95(dd,1H), 7.12(s,1H), 7.20(d,1H),
7.32(t,1H), 8.15(d,1H), 9.87(s,1H) and 12.70(b,.s,1H).
(b) To a suspension of sodium hydride (lg, 50% in oil) in
dimethylformamide (15ml) 3-cyano-6-(3-hydroxy-
phenyl)pyridin-2(lH)-one (2.12g) was added in portions
over 30 minutes. When gas evolution had ceased
iodoethane (1.56g) was added and the mixture stirred
overnight. The mixture was diluted with ethyl acetate
(lOOml), washed with 2N hydrochloric acid (2x30ml) and
with water (4x50ml), dried (MgS04) and solvent removed
at reduced pressure. The residue was recrystallised from
n-butanol to give 3-cyano-6-(3-ethoxyphenyl)pyridin-
2(lH)-one (0.68g). 1H-NMR ~(d6-DMSO) 1.35(t,3H),
4.12(q,2H), 6.80(d,1H), 7.08(d,1H), 7.31-7.47(m,3H) and
8.18(d,lH).
(5) From 3-cyano-6-(3-ethoxyphenyl)pyridin-2(1H)-one
(0.5g), the title compound (0.44g) m.p.279C (decomp)
W092/06085 PCT/GB9t/01663
2091~8~
- 42 -
after recrystallisation from n-butanol, was prepared
according to the method of Example l(b). lH-NMR
~(d6-DMSO) 1.36(t,3H), 4.14(q,2H), 6.90(d,lH), 7.10(m,lH),
7.34-7.48(m,3H) and 8.47(d,lH).
Exam~le 31
6-(3,5-Dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) From 3',5'-dimethoxyacetophenone (4.1g),
3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(lH)-one (2.4lg)
m.p. 297C after recrystallisation from ethanol, was
prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3,5-dimethoxyphenyl)pyridin-2(lH)-one
(1.4g), the title compound (1.36g) m.p. 338C (decomp)
after recrystallisation from acetonitrile/dimethyl-
formamide was prepared according to the method of Example
l(b). lH NMR ~(d6-DMSO) 3.86(s,6H), 6.66(m,1H),
6.95(d,1H), 7.02(m,2H), 8.47(d,1H) and 12.66(br.s,1H).
ExamPle 32
6-(2-Butylthiophenyl)-3-(5-tetrazolyl)pyridin-2(lH)-one
(a) From 2'-bromoacetophenone (19.9g), 6-(2-bromophenyl)-
3-cyanopyridin-2(1H)-one (11.4g) m.p. 245-246C after
recrystallisation from ethanol,was prepared according to
the method of Example l(a).
(b) From 6-(2-bromophenyl)-3-cyanopyridin-2(lH)-one
(2.6lg), 6-(2-butylthiophenyl)-3-cyanopyridin-2(lH)-one
(0.83g) m.p.163-165C after recrystallisation from
W092/06085 2 ~ 919 8 ~ PCT/GB91/01663
- 43 -
ethanol, was prepared according to the method of Example
26(a).
(c) From 6-(2-butylthiophenyl)-3-cyanopyridin-2(lH)-one
(0.71g), the title compound (0.53g) m.p.l81-182C after
recrystallisation from ethanol, was prepared according to
the method of Example l(b).
Example 33
6-(3-Allyloxyphenyl)-3-(5-tetrazolyl)p~ridin-2(1H)-one
~a) From 3'-allyloxyacetophenone (15.07g),
6-(3-allyloxyphenyl)-3-cyanopyridin-2(lH)-one (14.7g) was
prepared according to the method of Example 3(a). lH NMR
o(d6-DMSO) 4.67(d,2H), 5.26-5.46(m,2H), 5.98-6.20(m,1H),
6.80(d,1H), 7.13(m,1H), 7.33(m,3H) and 8.20(d,1H).
(b) From 6-(3-allyloxyphenyl)-3-cyanopyridin-2(1H)-one
(lg), the title compound (0.34g) m.p.260C (decomp) after
recrystallisation from n-butanol, was prepared according
to the method of Example l(b). lH NMR O(d6-DMSO)
4.72(m,2H), 5.28-5.52(m,2H), 6.04-6.20(m,1H), 6.94(d,1H),
7.14(m,lH), 7.48(m,3H) and 8.47(d,lH).
ExamPle 34
6-(4-Methoxy-2-pQntyloxyphenyl)-3-~5-tetrazolyl)pyridin-
2(1H)-one
(a) From 4'-methoxy-2'-pentyloxyacetophenone (11.8g), 3-
cyano-6-(4-methoxy-2-pentyloxyphenyl)pyridin-2(lH)-one
(3.4g) m.p. 143-144C after recrystallisation from ethanol,
was prepared according to the method of Example 3(a).
W092/0608~ 2 Q 9 ~ PCT/GB91/~1663
- 44 -
~b) From 3-cyano-6-(4 methoxy-2-pentyloxyphenyl)pyridin-
2(lH)-one ~1.25g), the title compound (0.65g) m.p. 193-
194C after recrystallisation from ethanol was prepared
according to the method of Example l(b).
~xamPle 35
6-~3-i~o-Butoxy-4-metho~yphenyl)-3-(5-tetrazolyl)pyridin-
2(1~)-one
(a) From 3'-iso-butoxy-4'-methoxyacetophenone (7.6g), 3-
cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-2(lH)-one
(6.02g) m.p.234-235C after recrystallisation from ethanol,
was prepared according to the method of Example 3(a).
(b) From 3-cyano-6-(3-iso-butoxy-4-methoxyphenyl)pyridin-
2(lH)-one (1.19g), the title compound (1.2g) m.p. 296-297C
(decomp) after recrystallisation from ethanol, was prepared
according to the method of Example l(b). lH NMR ~(DMSO-d6)
l.Ol(d,6H), 2.02-2.16(m,lH), 3.85(s,3H3, 3.89(d,2H),
6.89(d,lH), 7.12(d,lH), 7.41-7.50(m,2H) and 8.47(d,lH).
ExamPle 36
6-(2-Bromo-3,5-diethoxyphenyl)-3-(5-tetrazolyl)py~idin-
2(1~)-one
(a) To an ice cooled solution of 3',5'-diethoxyacetophenone
(10.4g) in dimethylformamide (50ml) N-bromosuccinimide
(9.79g) was added in portions over 1 hour. The mixture was
stirred at 0C for 3 hours and stood at room temperature
for 48 hours. After diluting with ethyl acetate (200ml) the
mixture was washed with water (5xlOOml), dried (MgS04) and
solvent removed at reduced pressure to give 2'-bromo-3',5'-
diethoxyacetophenone (12.53g) as an oil.lH NMR ~(CDC13)1.41(t,3H), 1.50(t,3H), 2.60(s,3H), 4.00(q,2H), 4.10(q,2H),
6.45(d,lH) and 6.50(d,lH).
WO 92/0608~ 2 0 919 8 9 . PCr/GBgl/01663
-- 45 --
(b) From 2'-bromo-3',5'-diethoxyacetophenone (4.31g), 3-
cyano-6- (2-bromo-3,5-diethoxyphenyl)pyridin-2(lH)-one
(0.75g) m.p. 234-235C after recrystallisation from
5 ethanol, was prepared according to the method of Example
3(a)-
(c) From 3-cyano-6-(2-bromo-3,5-diethoxyphenyl)pyridin-
2(lH)-one (0.6g), the title compound m.p. 276C after
10 recrystallisation from ethanol was prepared according to
the method of Example l(b).
Example 37
6-(5-Bromo-4-methoxy-2-pentyloxyphenyl)-3-(5-tetrazolyl)-
pyridin-2(1EE)-one
(a) A mixture of 3-cyano-6-(4-methoxy-2-pentyloxyphenyl)-
pyridin-2(lH)-one (1.71g), silver carbonate (1.92g) and
20 iodomethane in chloroform (30ml) were stirred in the dark
for 48 hours. After filtration (celite pad) solvent was
removed at reduced pressure and the residue column
chromatographed (silica gel, 40%hexane/dichloromehane
eluant) to give 3-cyano-2-methoxy-6-(4-methoxy-2-
25 pentyloxyphenyl)pyridine (1.45g) m.p.76-78C.
(b) To a cooled (ice bath) solution of 3-cyano-2-methoxy-6-
(4-methoxy-~-pentyloxyphenyl)pyridine (1.3g) in
dimethylformamide (lOml) N-bromosuccinimide (0.71g) was
30 added in portions over 30 minutes. The solution was stirred
at room temperature overnight diluted with ethyl acetate
(SOml) and washed with water (5x50ml). The organic phase
was dried (MgS04) solvent removed at reduced pressure and
the residue recrystallised from ethanol to give 3-cyano-2-
35 methoxy-6-(5-bromo-4-methoxy-2-pentyloxyphenyl)pyridine
(l.lg) m.p. 136-l37C.
W092/06085 2 ~ 91~ ~ 3 PCT/GB91/01663
- 46 -
(c) 3-Cyano-2-methoxy-6-(2-bromo-4-methoxy-2-
pentyloxyphenyl)pyridine (lg) and sodium iodide (1.50g)
(dried a~ 70C in vacuo for 4 hours) were dissolved in
acetonitrile (lOml) and chlorotrimethylsilane (1.08g)
added. The reaction mixture was stirred in the dark for 2
hours, diluted with ethyl acetate (SOml) washed with water
~2x50ml), with 5% aqueous sodium metabisulphite (30ml) and
water (50ml). The organic phase was dried (MgS04) solvent
removed at reduced pressure and the residue recrystallised
from ethanol to give 3-cyano-6-(5-bromo-4-methoxy-2-
pentyloxyphenyl)pyridin-2(lH)-one (0.55g) m.p.188-190C.
(d) From 3-cyano-6-(5-bromo-4-methoxy-2-
pentyloxyphenyl)pyridin-2(lH)-one (0.5g), the title
compound (0.38g) m.p.246-248C after recrystallisation from
ethanol, was prepared according to the method of Example
l(b).
Example 38
6-(2-Allyl 4-m~thoxy-3-propoxyphenyl)-3-(5-tQtrazolyl)-
pyridin-2(1~)-one
(a) A mixture of 3'-allyloxy-4'-methoxyacetophenone (7.76g)
and diethylaniline (5.96g) was degassed with nitrogen for
15 minutes and heated at 215C for 90 minutes. After
cooling to room temperature the reaction mixture was
dissolved in ethyl acetate (lOOml) and washed with 2N
hydrochloric acid (3xlOOml). The organic phase was dried
~MgS04) and solvent removed at reduced pressure to give
after recrystallisation from ethanol/water 2'-allyl-3'-
hydroxy-4'-methoxyacetophenone (S.lg) m.p.~1-83C.
(b) 2'-Allyl-3'-hydroxy-4'-methoxyacetophenone (5.0g),
potassium carbonate (3.3g) and iodopropane were heated
together in a mixture of dimethylformamide (20ml) and
butanone (30ml) for 48 hours~ The mixture was filtered and
W092/060~5 2 0 919 ~ 9 PCT/GB91/01663
- 47 -
solvent removed from the filtrate at reduced pressure to
give a residue which was dissolved in ethyl acetate (lOOml)
and washed with water (5x50ml). The organic phase was dried
(MgS04) and solvent removed at reduced pressure to give 2'-
allyl-4'-methoxy-3'-propoxyacetophenone (5.0g) as an oil.
1H NMR ~5DMSO-d6) 0.98(t,3H), 1.62-1.80(m,2H), 2.48(s,3H),
3.62-3.69(m,2H), 3.79(t,2H), 3.85(s,3H), 4.82-4.91(m,2H),
5.78-5.93(m,lH), 6.99(d,lH and 7.63(d,lH).
10 (c) From 2'-allyl-4'-methoxy-3'-propoxyacetophenone (4.96g)
3-cyano-6-(2-allyl-4-methoxy-3-propoxyphenyl)pyridin-2(lH)-
one (1.15g) m.p. 170-171C after recrystallisation from
ethanol was prepared according to the method of Example
3(a) with, however, the omission of sodium methoxide.
16
(d) From 3-cyano-6-(2-allyl-4-methoxy-3-
propoxyphenyl)pyridin-2(lH)-one (0.49g), the title compound
(0.24g) m.p. 210-211C after recrystallisation from ethanol
was prepared according to the method of Example l(b).
ExamPle 39
~-t3-(E-l-propenyl)-4-methoxyphenyl]-3-(5-tetrazolyl)
pyridin-2(1R)-one
(a) From 3-allyl-4-methoxyacetophenone (7.6g), 3-cyano-6-
[3-(E-1-propenyl)-4-methoxyphenyl]pyridin-2(lH)-one (4g)
after recrystallisation from n-butanol, was prepared
according to the method of Example 3(a). 1H NMR ~(DMSO-d
30 1.88(d,3H), 3.87(s,3H), 6.40-6.67(m,3H), 6.~8(d,lH),
7.10(d,lH), 7.72(dd,lH), 7.93(d,lH) and 8.14(d,lH).
(b) From 3-cyano-6-[3-(E-1-propenyl)-4-
methoxyphenyl]pyridin-2(1H)-one (2.13g), the title compound
35 (0.8g) m.p. 291-29~C (decomp) after recrystallisation from
dimethylformamide was prepared according to the method of
Example l(b). lH NMR ~(DMSO-d6) 1.89(d,3H), 3.88(s,3H),
W092/06085 2 0 919 ~ 3 PCT/GB91/01663
- 48 -
6.42-6.71(m,3H), 6.90(d,lH), 7.12(d,lH), 7.76(dd,lH),
7.97(d,lH) and 8.44(d,lH).
,
ExamPle 40
6-(4-~ethoxy-3-propoxyphsnyl)-3-~S-~l-pi~aloyloxymHthyl)-
tetrazolyl)pyridin-2(1~)-one and 6-(4-~ethoxy-3-
propoxyphenyl)-3-[5-(2-pivaloyloxymethyl)-
tetrazolyl~pyridin-2(1~)-one
A mixture of 4-methoxy-3-propoxyphenyl)-3-(5-
tetrazolyl)pyridin-2(lH)-one (1.64g), pivaloyloxymethyl
chloride (0.75g), sodium hydrogen carbonate (420mg) and
sodium iodide (50mg) were heated in dimethylformamide (5ml)
at 70C for 24 hours. The mixture was diluted with ethyl
acetate (SOml) and washed with water 6 x SOml). The organic
phase was dried (MgS04) filtered and solvent removed at
reduced pressure. The residue was column chromatographed
(silica gel, 70% hexane/ethyl acetate - 30% hexane/ethyl
acetate eluant to give:- a) 6-(4-methoxy-3-propoxyphenyl)-
3-[5-(1-pivaloyloxymethyl)tetrazolyl]pyridin-2(lH)-one
(0.26g) m.p. 169-170C after recrystallisation from ethanol
and b) 6-(4-methoxy-3-propoxyphenyl)-3-[5-~2-
pivaloyloxymethyl)tetrazolyl]pyridin-2(lH)-one (0.35g)
m.p.195-196C after recrystallisation from ethanol.
Example 41
6-~3-Ethoxy-5-(2-methoxyethoxy)phenyl]-3-(S-tetrazolyl)-
pyridin-2(1~)-one
a) 3',5'-Dihydroxyacetophenone (15.2g), potassium carbonate
(7.59g) and iodoethane (17.16g) were combined and heated at
reflux for 15 hours. Additional potassium carbonate (2.76g)
and iodoethane (6.2g) were added and heating was continued
for a further 10 hours. The reaction mixture was filtered,
solvent removed at reduced pressure, the residue dissolved
W092/0608S 2 ~ 919 ~ 9 ;; PCT/~B91/0166~
_ ~9 _
in ethyl acetate (lOOml) and extracted with 2N sodium
hydroxide (3x50ml). The combined basic extracts were washed
with ethyl acetate (2xSOml), acidified with 2N hydrochloric
acid and extracted with dichloromethane (3xlOOml). The
combined dichloromethane extracts were washed with water
(2x50ml), dried (MgS04), filtered and solvent removed at
reduced pressure. The residue was column chromatographed
(silica gel, dichloromethane eluant) to give 3'-ethoxy-5'-
hydroxyacetophenone (4.83g) m.p. 96-98C.
b) To a suspension of sodium hydride (0.92g, 60% in oil
washed with hexane) in dimethylformamide (lOml), 3'-ethoxy-
5'-hydroxyacetophenone (3.24g) was added in portions over
10 minutes. When gas e~olution had ceased chloroethylmethyl
ether (1.9g) and sodium iodide (50mg) were added and the
mixture heated to 90C for 18 hours and stirred at room
temperature for 24 hours. The mixture was diluted with
ethyl acetate (lOOml), washed with 2N sodium hydroxide
(3x50ml) and water (3x50ml). The organic phase was dried
~MgS04), filtered and solvent removed at reduced pressure
to give 3'-ethoxy-S'-(2-methoxyethoxy)acetophenone (4.03g)
as an oil. lH NMR ~(CDCl3) 1.42(t,3H), 2.56(s,3H),
3.46(s,3H), 3.74-3.78(m,2H), 4.05(q,2H), 4.13-4.17(m,2H),
6.68(m,lH) and 7.10(m,2H).
^5
c) From 3'-ethoxy-5'-t2-methoxyethoxy)acetophenone, 3-
cyano-6-[3-ethoxy-5-~2-methoxyethoxy)phenyl~pyridin-2~lH)-
one (l.lg) m.p.199C after recrystallisation from ethanol,
was prepared according to the method of Example 3(a).
d) From 3-cyano-6-[3-ethoxy-5-(2-
methoxyethoxy)phenyl]pyridin-2(lH)-one (0.94g), the title
compound (0.6g) m.p.205-206C after recrystallisation from
ethanol, was prepared according to the method of Example
l(b).
W092/0608~ 2 0 919 8 ~ PCT/GB91tO1663
- 50 -
xamPle 42
6-t3-(2,2-Dimethylpropyloxy)-4-methoxyphenyl)-3-(5-
tetrazolyl)pyridin-2(1~)-one
a) From 3'-(2,2-dimethylpropyloxy)-4'-methoxyacetophenone
~9.Og), 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4-
methoxyphenyl]pyridin-2(lH)-one (3.46g) was prepared
according to the method of Example 3(a). lH NMR ~(DMSO d6)
1.02(s,9H), 3.74(s,2H), 3.85(s,3H), 6.79(d,lH), 7.09(d,lH~,
7.42(s,lH), 7.43(d,lH) and 8.14(d,lH).
b) From 3-cyano-6-[3-(2,2-dimethylpropyloxy)-4-
methoxyphenyl]pyridin-2(lH)-one (1.2Sg), the title compound
(1.28g) m.p. >300C after recrystallisation from n-butanol,
was prepared according to the method of Example l(b). lH
NMR ~(DMSO-d6) 1.04(s,9H), 3.77(s,2H), 3.86(s,3H),
6.90(d,lH), 7.10(d,lH), 7.45(m,2H) and 8.44(d,lH).
ExamPle 43
6-(3-Ethoxy-4-methoxyphenyl)-3-(S-tetrazolyl)pyridin-2(1~)-
one
a) From 3'-ethoxy-4'-methoxyacetophenone (2.91g), 3-cyano-
6-(3-ethoxy-4-methoxyphenyl)pyridin-2(lH)-one (2.02g)
m.p.273C after recrystallisation from ethanol was prepared
according to the method of Example l(a).
b) From 3-cyano-6-(3-ethoxy-4-methoxyphenyl)pyridin-2(lH)-
one (l.Og), the title compound (l.Q6g) m.p.299C (decomp)
after recrystallisation from n-butanol, was prepared
according to the method of Example l(b). lH NMR ~(DMSO-d6)
1.37(t,3H), 3.84(s,3H), 4.15(q,2H), 6.92(d,lH), 7.10(d,lH),
7.41-7.50(m,2H) and 8.43(d,lH).
W092/0608~ 2 0 919 8 ~ PCT/GB91/01663
ExamPle 44
6-(3-~ropionamidophenyl)-3-(5-tetrazolyl)pyridin-2(1~-one
a) To a stirred suspension of sodium methoxide (4.32g) in
diethyl ether (50ml) a mixture of 3'-
propionamidoacetophenone (5.73g) and ethyl formate (4.44g)
in tetrahydrofuran (lOOml) was added over 30 minutes. After
stirring overnight the mixture was filtered and the residue
washed with diethyl ether. The residue was dissolved in
water (50ml), the pH adjusted to 9.0 with glacial acetic
acid and cyanoacetamide (4.2g) added. The solution obtained
was boiled overnight cooled to room temperature and
adjusted to pH 5 with glacial acetic acid (US Patent
4,278,681). The precipitated material was collected by
filtration, washed thoroughly (4x50ml) with ethanol and
recrystallised from dimethylformamide/water to give 3-
cyano-6-(3-propionamidophenyl)pyridin-2(lH)-one (0.4g) m.p.
328-330C
b) From 3-cyano-Ç-(3-propionamidophenyl)pyridin-2(lH)-one
(0.3g) the title compound (0.2g) m.p.291-293C (decomp)
after recrystallisation from dimethylformamide/water, was
prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) l.ll(t,3H), 2.37(q,2H), 6.75(d,lH), 7.46(m,2H),
7.69(m,lH), 8.09(m,lH~ and 8.50(d,lH).
Example 45
6-(4-Methoxy-3-propylphenyl)-3-~5-tetrazolyl)pyridin-2(1~)-
one (SB 20525))
(a) A solution of 3'-allyl-4'-methoxyacetophenone t20g) in
ethanol ~250ml) containing 10% palladium on charcoal (2g)
was treated with hydrogen at 50 p.s.i until the calculated
volume of hydrogen had been taken up. The mixture was
filtered (celite pad) and solvent removed at reduced
W092/06085 2 ~ 919 8 ~ PCT/GB91/01663
- 52 -
pressure. The residue was dissolved in dichloromethane
(lOOml) and manganese dioxide (60g) added. The mixture was
stirred at room temperature for 48 hours, filtered (celite
pad) and solvent removed at reduced pressure to give 4'-
methoxy-3'-propylacetophenone (15.16g) as an oil. lH NMR
~(CDCl3) 0.95(t,3H), 1.52-1.79(m,2H), 2.55(s,3H),
2.61(t,2H), 3.88(s,3H), 6.86(d,lH), 7.77(d,lH) and
7.82(dd,lH).
10 (b) From 4'-methoxy-3'-propylacetophenone (5.77g), 3-cyano-
6-(4-methoxy-3-propylphenyl)pyridin-2(lH)-one (4.43g) m.p.
239C after recrystallisation from butanol, was prepared
according to the method of Example 3(a).
15 (c) From 3-cyano-6-(4-methoxy-3-propylphenyl)pyridin-2(lH)-
one (4.02g), the title compound (3.64g) m.p.293-294C
(decomp) after recrystallisation from ethanol, was prepared
according to the method of Example l(b). lH NMR ~(DMSO-d6)
0.93(t,3H), 1.51-1.71(m,2H), 2.59(t,2H), 3.87(s,3H),
6.83~d,1H), 7.10(d,1H), 7.68-7.74(m,2H) and 8.46(d,1H).
ExamPle 46
6-(3-Bromo-4-methoxyphenyl)-3-(5-tetrazolyl)pyri~in-2(1~)-
one (SB 204617~
(a) From 3'-bromo-4'-methoxyacetophenone (K.W.Rosenmund et.
al. Chem. Ber., 1922, 90, 1957) (2.29g), 3-cyano-6-(3-
bromo-4-methoxyphenyl)pyridin-2(lH)-one (1.42g) m.p. 284-
286C after recrystallisation from ethanol, was preparedaccording to the method of Example 3(a).
(b) From 3-cyano-6-(3-bromo-4-methoxyphenyl)pyridin-2(lH)-
one (1.22g), the title compound (1.28g) m.p. 292-293C
(decomp) after recrystallisation from dimethylformamide,
was prepared according to the method of Example l(b). 1H
W092/06085 2 0 919 ~ 9 P~T/GB91/01663
- 53 -
NMR ~(DMSO-d6) 3.94(s,3H), 6.90(d,lH), 7.27(d,lH),
7.90(dd,lH), 8.14(d,lH) and 8.45(d,lH).
Example 47
6-(3-phenyl-4-methoxyphQnyl)-3-(5~tetrazolyl)pyridin-2(1R)-
one ~S8 204649)
(a) To a suspension of
tetrakis(triphenylphosphine)palladium (O) (O.Sg) in aoueous
sodium hydrogen carbonate (5.04g in 60ml water), solutions
of phenylboronic acid (2.65g) in dimethoxyethane (lOOml)
and 3'-bromo-4'-methoxyacetophenone (4.58g) in
dimethoxyethane (llOml) were added. The mixture was stirred
under reflux for 3 hours cooled to room temperature and
solvent removed at reduced pressure. The residue was
partitioned between chloroform (200ml) and water (200ml),
the organic phase separated dried (MgS04) and solvent
removed at reduced pressure. The residue was recrystallised
from ethanol to give 4'-methoxy-3'-phenylacetophenone
(2.87g) m.p. 92-93C.
(b) From 4'-methoxy-3'-phenylacetophenone (3.3g), 3-cyano-
6-(3-phenyl-4-methoxyphenyl)pyridin-2(lH)-one (2.37g) m.p.
288-291C after recrystallisation from propan-2-ol, was
prepared according to the method of Example 3(a).
(c) From 3-cyano-6-[(3-phenyl)-4-methoxyphenyl]pyridin-
2(lH)-one (0.9lg), the title compound (0.70g) m.p. 289-
291C after recrystallisation from
dimethylformamide/ethanol, was prepared according to the
method of Example l(b). lH NMR ~(DMSO-d6) 3.86(s,3H),
6.92(d,lH), 7.28(d,lH), 7.33-7.48(m,3H), 7.62(d,2H), 7.81-
7.89(m,2H~, 8.45(d,lH), 11.96(br.s,lH) and 12.71(br.s,lH)
W092/06085 2 0 919 ~ 9 PCT/GB91/01663
- 54 -
! Example 48
6-[4-~ethoxy-3,5-di~E-1-propenyl)phenyl]-3-~-tetrazolyl)-
pyridin-2(lE)-one (SB 204788)
(~) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl-
4'-allyloxyacetophenone (20.7g) isolated as an oil, was
prepared according to the method of Example 2~a) using
acetone as solvent. lH NMR ~(CDCl3) 2.55(s,3H), 3.44(d,2H),
4.61~m,2H), 5.04-5.46~m,4H), 5.94-6.10(m,2H), 6.86(d,lH),
7.78d,lH) and 7.83(dd,lH).
(b) From 3'-allyl-4'-allyloxyacetophenone (20.5g), 3',5'-
diallyl-4'-hydroxyacetophenone (16.3g) m.p. 83-84C was
prepared according to the method of Example 38(a).
(c) From 3',5'-diallyl-4'-hydroxyacetophenone (16g), 3',5'-
diallyl-4'-methoxyacetophenone (17g) isolated as an oil,
was prepared according to the method of Example 2(a). 1H
NMR ~(CDC13) 2.55(s,3H), 3.46(d,4H), 3.77(s,3H), 5.05-
5.14(m,4H), 5.91-6.07(m,2H) and 7.69(s,2H).
(d) From 3',5'-diallyl-4'-methoxyacetophenone (8.5g), 3-
cyano-6-[4-methoxy-3,5-di(E-1-propenyl)phenyl]pyridin-
2(lH)-one (6.1g) m.p. 248-250C after trituration with hot
ethanol, was prepared according to the method of Example
3(a).
(e) From 3-cyano-6-[4-methoxy-3,5-di(E-l-
propenyl)phenyl]pyridin-2(lH)-one (0.46g), the title
compound (0.27g) m.p. 285-287C (decomp) after
recrystallisation from dimethylformamide/water, was
prepared according to the method of Example l(b). lH NMR
~(DMSO-d6) 1.92(d,6H), 3.68(s,3H), 6.49-6.68(m,4H),
7.00(d,lH), 7.89(s,2H) and 8.45(d,lH).
W O 92/06085 2 0 9 ~ ~ ~ 9 P ~ /GB91/01663
- 55 -
ExamPle 49
6-[3-(E-l-Propenyl)-4-propoxyphenyl]-3-(5-tetrazolyl)-
pyridin-2(1H)-o~e. (SB 201433)
(a) From 3'-allyl-4'-hydroxyacetophenone ~5.28g), 3'-allyl-
4'-propoxyacetophenone (6.06g) isolated as an oil was
prepared according to the method of Example 2(a). lH NMR
~(CDCl3) 1.07(t,3H), 1.66-1.92(m,2H), 2.5S(s,3H),
10 3.41(d,2H), 3.99(t,2H), 5.04-5.12(m,2H), 5.90-6.06(m,lH),
6.86(d,lH), 7.77(d,lH) and 7.83(dd,lH).
(b) From 3'-allyl-4'-propoxyacetophenone (5.7g), 3-cyano-6-
[3-(E-1-propenyl)-4-propoxyphenyl]pyridin-2(lH)-one (2.57g)
15 m.p. 240-244C after recrystallisation from butanol, was
prepared according to the method of Example 3(a).
(c) From 3-cyano-6-[3-(E-1-propenyl)-4-
propoxyphenyl]pyridin-2(lH)-one (1.18g), the title compound
20 (0.7g) m.p.290-292C (decomp) after recrystallisation from
butanol, was prepared according to the method of Example
l(b). lH NMR ~(DMSO-d6) 1.02(t,3H), 1.73-1.86(m,2H),
l.90(d,3H), 4.04(t,2H), 6.48-6.61(dq,lH), 6.65(d,lH),
6.89(d,lH), 7.11(d,lH), 7.70(dd,1~:), 7.97(d,lH) and
25 8.43(d,lH).
Example 50
6-(3-Bromo-4-methoxy-5-propylphenyl)-3-(5-tetrazolyl)-
30 pyridin-2(1H)-one. ~273/2534)
(a) From 4'-methoxy-3'-propylacetophenone (7.6g), 3'-bromo-
4'-methoxy-5'-propylacetophenone (4.8g) isolated as an oil
after column chromatography (silica gel, 50%
hexane/dichloromethane eluant) was prepared according to
the method of Example 36(a). lH NMR ~(CDCl3) 0.98(t,3H),
W092/06085 2 0 91~ 8 9 PCT/GB91/01663
- 56 -
1.'7-1.73(m,2H), 2.56(s,3H), 2.67(t,2H), 3.87(s,3H),
7.74(d,lH) and 7.98(d,lH).
(b) From 3'-bromo-4'-methoxy-5'-propylacetophenone (3.4g),
6-(3-bromo-4-methoxy-5-propylphenyl)-3-cyanopyridin-2(lH)-
one (1.2g) after recrystallisation from ethanol, was
prepared according to the method of Example 3~a). lH NMR
~(DMSO-d6) 0.94(t,3H), 1.57-1.67(m,2H), 2.65(t,2H),
3.79(s,3H), 6.38(br.d,lH), 7.74(d,lH), 7.97(d,lH) and
8.18(d,lH).
(c) From 6-(3-bromo-4-methoxy-5-propylphenyl)-3-
cyanopyridin-2(lH)-one (0.39g), the title compound (0.17g)
m.p. 2~6-287 (decomp) after recrystallisation from ethanol,
was prepared according to the method of Example l(a). lH
NMR S(DMSO-d6) 0.96(t,3H), 1.61-1.70(m,2H), 2.67(t,2H),
3.81(s,3H), 6.94(d,lH), 7.76(d,lH), 7.99(d,lH) and
8.45(d,lH).
Example 51
6-(2-Butylthio-3,5-diethoxyphenyl)-3-(5-tetrazolyl)pyridin-
2(1R)-one
25 (a) From 2'-bromo-3',5'-diethoxyacetophenone (2.53g), 2'-
butylthio-3',5'-diethoxyacetophenone ~1.96g) after column
chromatography (silica gel, hexane/dichloromethane 4:1
eluant) was prepared according to the method of Example
26(a). lH NMR ~(CDCl3) 0.87(t,3H), 1.25-1.65(m,10H),
30 2.59(s,3H), 2.76(t,2H), 4.02(q,2H), 4.08(q,2H), 6.33(d,1H)
and 6.46(d,1H).
(b) From 2'-butylthio-3',5'-diethoxyacetophenone (1.95g),
3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)pyridin-2(1H)-one
(0.13g) after recrystallisation from ethanol, was prepared
according to the method of Example 3(a). lH NM~ ~(DMSO-d6)
W092/06085 2 0 919 8 9 PCT/GB91/01663
0.71(t,3H), 1.18-1.43(m,10H), 2.66(t,2H), 4.03-4.18(m,4H),
6.27(d,lH), 6.59(d,lH), 6.71(d,lH) and 8.15(d,lH).
(c) From 3-cyano-6-(2-butylthio-3,5-diethoxyphenyl)-3-(5-
tetrazolyl~pyridin-2(lH)-one (0.12g), the title compound
(0.08g) m.p. 138-140C after recrystallisation ~rom
ethanol, was prepared according to the method of Example
l(a). lH NMR ~(DMSO-d6) 0.76(t,3H), 1.18-1.43(m,10H),
2.64(t,2H), 4.05-4.19(m,4H), 6.40(d,lH), 6.62(d,lH),
6.70(d,1H), 8.48(d,1H) and 12.67(br.s,1H).
Example 52
6-~3-Bromo-4-~,N-dimethylam;nophQnyl)-3-(5-tetrazolyl1-
pyridin-2(1~)-one ~SB 204789)
(a) From 4'-N,N-dimethylaminoacetophenone (4.9g), 3'-bromo-
4'-N,N-dimethylaminoacetophenone (7.0g) was prepared
according to the method of Example 36(a). lH NMR ~(CDCl3)
2.53(s,3H), 2.91(s,6H), 7.03(d,lH), 7.83(dd,lH) and
8.13(d,lH).
(b) From 3'-bromo-4'-N,N-dimethylaminoacetophenone (2.42g),
3-cyano-6-(3-bromo-4-N,N-dimethylaminophenyl)pyridin-2(lH)-
one (2.63g) was prepared according to the method of Example3(a). lH NMR ~(DMSO-d6) 2.82(s,6H), 6.82(d,1H), 7.22(d,1H),
7.79(dd,lH), 8.08(d,lH), 8.15(d,lH) and 12.67(br.slH).
; (c) From 3-cyano-6-(3-bromo-4-N,N-
dimethylaminophenyl)pyridin-2(lH)-one (0.8g), the title
compound (0.57g) m.p.275-277C was prepared according to
the method of Example l(b).
W O 92/06085 2 0 919 8 9 PC~r/GB91/01663
- 58 -
Exau~ple 53
6-~3-Acctamido-4-methoxy-5-propylphenyl) -3-(5-
tetrazolyl)pyridin-2(1~)-ono (SB 20~790)
(a) From 3'-allyl-4'-hydroxyacetophenone (17.6g), 3'-allyl-
4'-benzyloxyacetophenone (23~lg) isolated as an oil was
prepared according to the method of Example 2(a) using
acetone as solvent. lH NMR ~(CDCl3) 2.55(s,3H), 3.47(d,2H),
5.04-5.11(m,4H), 5.16(s,2H), 5.93-6.09(m,lH), 6.93(d,lH),
7.25-7.41(m,5H), 7.81(s,lH) and 7.82(d,lH).
(b) From 3'-allyl-4'-benzyloxyacetophenone (23g), 6-[4-
benzyloxy-3-(E-l-propenyl)phenyl]-3-cyanopyridin-2(lH)-one
(11.2g) m.p. 255-257C after recrystallisation from
dimethylformamide/water, was prepared according to the
method of Example 3(a).
(c) A solution of 6-~4-benzyloxy-3-(E-l-propenyl)phenyl~-3-
cyanopyridin-2(lH)-one (6.8g) in dimethylformamide ~20ml)
containing dimethylformamide dimethyl acetal (4.76g) was
heated at 120C for 6 hours. The mixture was diluted with
ethyl acetate (200ml), washed with water (6 x lOOml), dried
(MgSO4) and solvent removed at reduced pressure. The
residue was column chromatographed (silica gel,
hexane/dichloromethane 1:1 eluant) to give 6-[4-benzyloxy-
3-(E-l-propenyl)phenyl]-3-cyano-2-methoxypyridine (6g) m.p.
124-125C after recrystallisation from ethanol.
(d) A suspension of 6-[4-benzyloxy-3-(E-l-propenyl)phenyl]-
3-cyano-2-methoxypyridine (1.78g) in ethanol (250ml)
containing 10~ palladium/charcoal (0.2g) was hydrogenated
at 50 p.s.i until the calculated quantity of hydrogen had
been absorbed. The mixture was filtered (celite pad) and
solvent removed at reduced pressure. The residue was column
chromatographed (silica gel, hexaneldichloromethane 1:1 -
2% ethanol/dichloromethane eluant) to give 3-cyano-6-(4-
W092/06085 2 ~ 919 8 9 PCT/GB91/01663
_ 59 _
hydroxy-3-propylphenyl)-2-methoxypyridine ~l.Og). 1H NMR
~(CDCl3) l.Ol(t,3H), 1.65-1.74(m,2H), 2.66(t,2H),
4.15(s,3H) 5.19(s,1H), 6.86(d,1H), 7.35(d,1H) and 7.81-
7.87(m,3H).
(e) To a stirred suspension of 6-(4-hydroxy-3-
propylphenyl)-3-cyano-2-methoxypyridine (1.88g) in
sulpholane ~3ml) a solution of nitronium tetrafluoroborate
in sulpholane (0.5M, 16ml) was added over 5 minutes with
ice cooling. The solution obtained was stirred for 5 hours,
additional nitronium tetrafluoroborate (0.5M in sulpholane,
2ml) added and stirring continued for a further 3 hours.
The solution was diluted with diethyl ether ~lOOml) washed
with water (8 x lOOml), dried (MgS04) and solvent removed
at reduced pressure. The residue was recrystallised from
ethanol to give 3-cyano-6-(4-hydroxy-3-nitro-5-
propylphenyl)-2-methoxypyridine (1.75g) m.p. 160-162C.
(f) From 3-cyano-6-(4-hydroxy-3-nitro-5-propylphenyl)-2-
methoxypyridine (1.57g), 3-cyano-6-(4-methoxy-3-nitro-5-
propylphenyl)-2-methoxypyridine (1.53g) m.p. 150-152C was
prepared according to the method of Example 2(a) using
acetone/dimethylformamide (1:1) as reaction solvent. 1H NMR
~(CDCl3) 1.03(t,3H), 1.67-1.81(m,2H), 2.77(t,2H),
3.95(s,3H), 4.17(s,3H), 7.42(d,lH), 7.96(d,lH), 8.07(d,lH)
and 8.35(d,lH).
(g) A suspension of 3-cyano-6-(4-methoxy-3-nitro-5-
propylphenyl)-2-methoxypyridine (1.4g) in ethanol (lOOml)
containing 10% palladium/charcoal (200mg) was treated with
hydrogen at 50 p.s.i until hydrogen uptake was complete.
The mixture was filtered (celite pad) and solvent removed
from the filtrate at reduced pressure. The residue was
dissolved in dichloromethane (lOml) containing
triethylamine (l.Olg) added followed by the addition of
acetic anhydride (0.61g) over 5 minutes. The reaction
mixture was stirred for 15 hours, diluted with
W092/06085 2 ~ 919-8 9 PCT/GB91/01663
- 60 -
dichloromethane (lOOml) and washed with 2N hydrochloric
acid (2 x 50ml) and with water (50ml). After drying
(MgS04), sol~ent was removed at reduced pressure to give
after recrystallisation from ethanol 6-(3-acetamido-4-
methoxy-5-propylphenyl-3-cyano-2-methoxypyridine (1.04g)
m.p.174-175C.
(h) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-cyano-
2-methoxypyridine (0.7g), 6-(3-acetamido-4-methoxy-5-
propylphenyl)-3-cyanopyridin-2(lH)-one (0.48g) m.p.247-
249C was prepared according to the method of Example
37(c). 1H NMR ~(CDCl3) 1.02(t,3H), 1.68-1.83(m,2H),
2.27(s,3H), 2.78(t,2H), 3.83(s,3H), 6.65(d,1H), 7.49(d,1H),
7.80(br.s,lH), 7.90(d,lH) and 8.62(d,lH).
~5
(i) From 6-(3-acetamido-4-methoxy-5-propylphenyl)-3-
cyanopyridin-2(lH)-one (0.4g), the title compound (0.25g)
m.p. 239-241C after recrystallisation from ethanol, was
prepared according to the method of Example l(b)
ExamPle 54
6-[3-N~thoxymethyl-4-methoxy-5-~E-1-propenyl)phenyl~-3-(5-
tetrazolyl)pyridin-2(1~)-on~ (273/2588)
(a) From 3-cyano-6-[4-methoxy-3,5-di(E-1-
propenyl)phenyl]pyridin-2(lH)-one (4.59g), 3-cyano-6-[4-
methoxy-3,5-di(E-1-propenyl)phenyl]-2-methoxypyridine
(4.lg) m.p. 145C was prepared according to the method of
Example 5~(c). lH NMR ~(DMSO-d6) 1.93(d,6H), 3.67(s,3H),
4.11(s,3H), 6.42-6.56(m,2H), 6.66(d,2H), 7.87(d,lH),
8.15(s,2H) and 8.30(d,lH).
(b) To an ice cooled suspension of 3-cyano-6-[4-methoxy-
3,5-di(E-1-propenyl)phenyl~-2-methoxypyridine (1.6g) in
acetone/water (9:1, lOOml) N-methylmorpoline-N-oxide
(0.63g) and osmium te~roxide (2.5% w/w solution in tert-
W O 92/06085 2 0 919 8 9 P ~ /GB91/01663
- 61 -
butanol, 0.4ml) were added. The mixture was stirred with
ice cooling for 1 hour and at room temperature for 1 hour.
Additional N-methylmorpholine-N-oxide (O.lg) was added and
stirring continued for an additional 1 hour. The solution
was quenched with 5% sodium metabisulphite (5ml) and
solvent removed at reduced pressure. The residue was
dissolved in ethyl acetate (200ml), washed with water (2 x
lOOml)), dried (MgS04) and solvent removed at reduced
pressure. Column chromatography (silica gel,
dichloromethane-5% ethanol/dichloromethane eluant) gave 3-
cyano-6-[3-[1-(1,2-dihydroxypropyl)]-4-methoxy-5-(E-1-
propenyl)phenyl]-2-methoxypyridine (0.99g). lH NMR ~(CDCl3)
1.171d,3H), 1.97(d,3H), 2.5(br.s,1H), 2.98(br.s,1H),
3.82(s,3H), 3.94-4.05(m,lH), 4.16(s,3H), 4.77(d,lH), 6.30-
6.42(m,lH~, 6.66(d,lH), 7.41(d,lH), 7.90(d,lH), 7.93(d,lH)and 8.08(d,lH).
(c) To a solution of 3-cyano-6-[3-[1-(1,2-
dihydroxypropyl)]-4-methoxy-5-(E-1-propenyl)phenyl]-2-
methoxypyridine (0.99g) in tetrahydrofuran(20ml) a solutionof sodium metaperiodate (0.64g) in water (3ml) was added.
The mixture was stirred for 2 hours, additional sodium
metaperiodate (O.lg) in water (2ml) added and stirring
continued for a further 2 hours. The mixture was filtered,
diluted with ethyl acetate (lOOml), washed with water (2 x
50ml), dried (MgS04) and solvent removed at reduced
pressure. The residue was column chromatographed (silica
gel, dichloromethane- 5% ethanol/dichloromethane eluant) to
give 3-cyano-6-[3-formyl-4-methoxy-5-(E-l-propenyl)phenyl]-
2-methoxypyridine (0.7g) m.p. 174C. 1H NMR ~(CDCl3)
2.00(d,3H), 3.93(s,3H), 4.18(s,3H), 6.38-6.53(m,lH),
6.69(d,lH), 7.47(d,lH), 7.94(d,lH), 8.33(d,lH), 8.41(d,lH)
and 10.44(lH).
35 (d) A solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-l-
propenyl)phenyl]-2-methoxypyridine (0.65g) in ethanol
(lOml) was treated with sodium borohydride (lOOmg) in
W092/06085 2 0 919 8 9 PCT/GB91/01663
port ons over 30 minutes. The solution was stirred for a
further 2 hours, solvent removed at reduced pressure, the
residue dissolved in ethyl acetate (lOOml), washed with
water (2 x 50ml) , dried (MgS04) and solvent removed at
reduced pressure. The residue was dissolved in dimethyl
sulphoxide ~5ml), potassium hydroxide (0.56g, crushed
pellets) added, followed by iodomethane (0.6g) and the
mixture stirred for 30 minutes. After diluting with ethyl
acetate (lOOml) the reaction mixture was washed with water
10 (6 x 50ml), dried (MgS04) and solvent removed at reduced
pressure. The residue was column chromatographed (silica
gel, 40% hexane/dichloromethane - dichloromethane) to give
3-cyano-6-~3-methoxymethyl-4-methoxy-5-(E-1-
propenyl)phenyl]-2-methoxypyridine (0.54g) m.p. 81-82C. 1H
NMR ~(CDC13) 1.96(d,3H), 3.47(s,3H), 3.79(s,3H),
4.17(s,3H), 4.56(s,2H), 6.306.42(m,lH), 6.70(d,lH),
7.42(d,lH), 7.88(d,lH), 7.92(d,lH) and 8.10(d,lH).
(e) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1-
propenyl)phenyl]-2-methoxypyridine (0.54g), 3-cyano-6-[3-
methoxymethyl-4-methoxy-5-(E-1-propenyl)phenyl]pyridin-
2(lH)-one (0.33g) m.p.188-190C after column chromatography
(silica gel, dichloromethane - 2~5% ethanolldichloromethane
eluant), was prepared according ~o the method of Example
37(c). lH NMR ~(CDCl3) l.99(d,3H~, 3.49(s,3H), 3.81(s,3H),
4.60(s,2H), 6.46-6.70~m,3H), 7.72(d,1H), 7.85(d,1H),
7.91(d,lH) and 12.89(br.s,lH).
(f) From 3-cyano-6-[3-methoxymethyl-4-methoxy-5-(E-1-
propenyl)phenyl]pyridin-2(lH)-one (0.3g) the title compound
(0.22g) m.p. 245-246~C after recrystallisation from
ethanol, was prepared according to the method of Example
l(b). 1H NMR ~(DMSO-d6) 1.92(d,3H), 3.61(s,3H), 3.83(s,3H),
4.81(s,2H), 6.26-6.44(m,lH), 6.68(d,lH), 6.88(d,lH)
7.73(d,lH), 8.04(d,lH), 8.75(d,lH)
W092/06085 2 0 9 1~ ~ 9 PCT/GB91/01663
- 63 -
Example 55
6-13-(E-2-Carbamoylethenyl)-4-methoxy-5-~E-1-
prop~nyl)phenyl]-3-~5-tetrazolyl)pyridin-2-(lH)-ona
5 (273/2602)
(a) Triethylphosphonoacetate (0.9g) was added dropwise to a
suspension of sodium hydride (0.18g, 50% in oil) in
tetrahydrofuran (lOml). When gas evolution had ceased a
solution of 3-cyano-6-[3-formyl-4-methoxy-5-(E-1-
propenyl)phenyl]-2-methoxypyridine in tetrahydrofuran
(lOml)was added and the mixture stirred for 4 hours.
Ethanol (lOml) and 2N sodium hydroxide (lOml) were added
and the mixture boiled for 2 hours. Solvent was removed at
reduced pressure, the residue dissolved in water and
acidified with 2N hydrochloric acid. The precipitate was
collected by filtration to give 3-cyano-6-[3-(E-2-
carboxylatoethenyl)-4-methoxy-5-(E-1-prope~yl)phenyl]-2-
methoxypyridine (0.9g). lH NMR ~(CDCl3) 1.94(d,3H),
3.73(s,3H), 4.14(s,3H), 6.50-6.62(m,lH), 6.69(d,lH), 6.7
8(d,lH), 7.82(lH), 7.99(d,lH) and 8.33-8.42(m,3H).
(b) Oxalyl chloride (0.76g) was added over 5 minutes to an
ice cooled suspension of 3-cyano-6-[3-(E-2-
carboxylatoethenyl)-4-methoxy-5-(E-l-propenyl)phenyl]-2-
methoxypyridine in dichloromethane (20ml) containing
dimethylformamide (O.lml). When gas evolution had ceased (4
hours) solvent was removed at reduced pressure and the
residue redissolved in dichloromethane (20ml). To the ice
cooled solution ammonium hydroxide (lOml, SG 0.88) was
added and the solution stirred at 0C for 30 minutes and at
room temperature for 30minutes. The precipitated solid was
collected by filtration and recrystallised twice from
ethanol to give 3-cyano-6-~3-(E-2-carbamoylethenyl~-4-
methoxy-5-(E-1-propenyl)phenyl]pyridin-2(lH)-one (0.4g)
m.p. 245-246C. lH NMR ~(DMSO-d6) 1.94(d,3H), 3.72(s,3H),
4.14(s,3H), 6.49-6.62(m,lH), 6.66(d,lH), 6.80~d,lH),
W O 92/06085 2 ~ ~19 ~ 9 PC~r/GB91/01663
- 64 -
7.19(br.s,lH), 7.62(br.s,lH), 7.62(d,lH), 7.89(d,lH),
8.27(d,lH), 8.29(d,lH) and 8.34(d,lH).
(c) From 3-cyano-6-[3-(E-2-carbamoylethenyl)-4-methoxy-5-
(E-l-propenyl)phenyl]-2-methoxypyridine (0.35g), 3-cyano-6-
[3-(E-2-carbamoylethenyl)-4-methoxy-5-(E-l-
propenyl)phenyl]pyridin-2(lH)-one (0.2g) m.p. >300C after
recrystallisation from dimethylformamide/ethanol/water, was
prepared according to the method of Example 37(c). lH NMR
~(DMSO-d6) I.93(d,3H), 3.71(s,3H), 6.51-6.71(m,2H),
6.91(br.d,lH), 7.21(br.s,lH), 7.61(d,lH), 7.62(br.s,lH),
7.93(s,lH), 7.99(s,lH), 8.20(d,lH) and 12.78(br.s,lH).
(d) From 3-cyano-6-[3-(E-2-car~amoylethenyl)-4-methoxy-5-
(E-l-propenyl)phenyl]pyridin-2(lH)-one (0.16g), the title
compound (0.08g) m.p.292-294C (decomp) after
recrystallisation from dimethylformamide/ethanol/water, was
prepared according to the method of Example ltb) lH NMR
~(DMSO-d6) 1.94(d,3H), 3.73(s,3H), 6.55-6.72(m,2H),
6.83(d,lH), 7.00(d,lH), 7.23(br.s,lH), 7.62(d,lH),
7.66(br.s,lH), 7.99(d,lH) and 8.48(d,lH).
ExamPl~ 56
6-(3-Cyclopropylmethyloxy-4-methoxyphenyl)pyridin-2~1H)-one
(a) From 3'-hydroxy-4'-methoxyacetophenone (3.32g), 3'-
cyclopropylmethyloxy-4'-methoxyacetophenone (4.34g) was
prepared according to the method of Example 2(a). lH NMR
~(CDCl3) 0.34-0.40(m,2H), 0.63-0.70(m,2H), 1.28-1.43m,lH),
2.56(s,3H), 3.91(d,2H), 3.95(s,3H), 6.89(d,1H), 7.50(d,1H)
and 7.56(dd,lH).
(b) From 3'-cyclopropylmethyloxy-4'-methoxyacetophenone
(3.55g), 3-cyano-6-(3-cyclopropylmethyloxy-4-
me~hoxyphenyl)pyridin-2(lH)-one (1.30g) m.p. 241-242C
W092/06085 2 0 9 1 9 8 9 PCT/GB91/01663
after recrystallisation from butanol was prepared according
to the method of Example 3(a).
(c) From 3~cyano-6-(3-cyclopropylmethyloxy-4-
methoxyphenyl)pyridin-2(lH)-one (0.89g), the title compound
(0.67g) m.p. 296-297C (decomp) after recrystallisation
from butanol, was prepared according to the method of
Example l(b). lH NMR ~(DMSO-d6) 0.32-0.38(m,2H), 0.57-
0.66(m,2H), 1.22-1.37(m,1H), 3.85(s,1H), 3.94(d,2H),
6.88(d,1H), 7.10(d,1H), 7.39-7.48(m,2H), 8.43(d,1H) and
12.56(br.s,lH).
ExamPle 57
6-~2-methoxy-4-propoxyphenyll-3-(5-tetrazolyl)pyridin-
2~1H)-one
(a) From 2'-4'-dihydroxyacetophenone (50g), 2'-hydroxy-4'-
propoxyacetophenone (6g) was prepared according to the
method of Example 2(a), using bromopropane (40g) and
acetone as solvent. lH NMR ~(DMSO-d6) 0.93((t,3H), 1.61-
1.72(m,2H), 2.38(s,3H), 3.75(t,2H), 5.61(dd,lH), 5.80(d,lH)
and 7.40(d,lH).
(b) From 2'-hydroxy-4'-propoxyacetophenone (6g), 2'-
methoxy-4'-propyloxyacetophenone (5.18g) was prepared
according to the method of Example 2(a). lH NMR ~(CDCl3)
1.05(t,3H), 1.74-l.91(m,2H), 2.57(s,3H), 3.89(s,3H),
3.97(t,2H), 6.46-6.53(m,2H) and 7.80(d,lH).)
(c) From 2'-methoxy-4'-propoxyacetcphenone (5g), 3-cyano-6-
(2-methoxy-4-propoxyphenyl)pyridin-2(lH)-one (0.38g)
m.p.l86-188C after trituration with diethyl ether was
prepared according to the method of Example 3(a). lH NMR
~(DMSO-d6) O.99(t,3H), 1.72-1.81(m,2H), 3.82(s,3H),
4.02(s,2H), 6.47(d,lH), 6.61-6.67(m,2H), 7.39(d,lH) and
8.11(d lH).
W092/06085 2 0 91~ ~ 9 PCT/GB9t/01663
- 66 -
(d) From 3-cyano-6-(2-methoxy-4-propoxyphenyl)pyridin-
2(lH)-one (0.36g), the title compound (0.04g) m.p. >300~C
after recry~_allisation from ethanol and trituration with
diethyl ether, was prepared according to the method of
Example l(b). lH NMR ~(DMSO-d6 at 370K) l.OO(t,3H), 1.69-
1.82(m,2H), 3.83(s,3H), 4.02~t,2H), 6.61-6.66tm,2H),
6.98(unresolved,lH), 7.55(unresolved,lH) and
8.44(unresolved,lH).
Example X
Pharmaceutical compositions for oral administration are
prepared by combining the following :
% w/w
6-(3-methoxyphenyl)-3-
(5-tetrazolyl)pyridin-2(1H)-one 0.5 3.0 7.14
2% w/w Soya lecithin in soya
bean oil 90.4588.284.41
- Hydrogenated vegetable
25 shortening and beeswax 9.058.8 8.45
The formulations are then filled into individual soft
gelatin capsules.
Examvle Y
A pharmaceutical composition for parenteral
administration is prepared by dissolving the title
compound of Example 23 (0.02 g) in polyethylene glycol 300
(25 ml) with heating. This solution is then diluted with
water for injections Ph. Eur. (to lOO ml). The solution
is then sterilised by filtration through a 0.22 micron
membrane filter and sealed in sterile containers.
