Note: Descriptions are shown in the official language in which they were submitted.
~0475~l)
-- 2 --
36555/73
This invention relates to new compounds, processes for their
production and processes using them.
According to our invention we provide compounds of formula I,
OXO ~ E
in which E represents a carboxylic acid, a carbohydroxamic acid
or a lH-tetrazol-5-yl group, or a derivative thereof, and
X represents an alkylene chain which is optionally substituted
by a hydroxy group,
and pharmaceutically acceptable derivatives thereof.
According to our invention we also provide a process for the
production of a compound of fornula I, or a pharmaceutically
acceptable derivative thereof, which oomprises,
(a) reacting a compound of formLla II,
Hal Hal Hal ~Hal
zO E ~ OXO ~ E
in which E and X are as defined above, and
Hal represents a halogen atom,
with a sulphur nucleophile, or
Cb) reac~ing a compound of fornLla r~ or V,
- 2 -
~0~75iO
o o
E ~ OXO ~ E IV
0 0 o O
E ~ OXO ~ Z EV
in which E and X are as defined above, and
Z represents hydrogen or an alkali metal cation,
with phosphorus pentasulphide, boron sulphide or silieon
disulphide,
and i desired or necessary converting the compound of
fo~mula I to a pha~maceutically acceptable derivative thereof or
vice versa.
Process (a) may be carried out in a solvent which is inert
under the reaction c~nditions, for example benzene. The reaction
is preferably carried out at a temperature of from about O to
20 100Co When the group X represents an alkylene chain substituted
by a hydroxy group it may be desirable to protect the hydroxy group,
for example by formylation, before the reaction and to remove the
protecting group after the reaction. The sulphur nu d eophile
may be, for exampIe a bisulphide ion, an alkali metal bisulphide
in an alkanol, hydrogen sulphide and hydrochloric acid in an alkanol
1047S~(J
-- 4 --
thiourea, a thiosulphate, an alkali metal xanthate in petroleum ether
or a compound of formula III,
RCOSH j III
S in which R represents an alkyl te.g. C 1 to 6), or an aryl (e.g.
a phenyl) group.
Process (b) may be carried out in a solvent which is inert under
the reaction conditions, e.g. benzene or chloroforn. The reaction is
conveniently carried out at an elevated temperature, e.g. the re1ux
temperature of the reaction mLxture.
The compounds of folmula I may be isolated from reaction
mixtures containing them using conventional techniques known
E~! se-
The compounds of fo~mula II, and protected derivatives
thereof, may be made by reaction of a compound of formula IV or
V, or a protected derivative thereof, with a thionyl halide.
It is usual not to isolate the compound of formula II, but
to convert it directly to the compound of formula I.
The compounds of formulae IV and V are known compounds or may
be made from known compounds using conventional techniques.
Pharmaceutically acceptable derivatives of the compounds of
formula I include pharmaceutically acceptable salts, and whero E
is a -COOH group, esters and amides thereof. Suitable salts
include water soluble salts~ for example ammonium, alkali metal
(eOgO sodium and potassium) and alkaline earth metal (e.g. calcium
-- 4 --
1~4'~510
and magnesium) salts and salts with suitable organic bases, e~g.
salts with lower (C 1 to 6) alkyl amines, eOg. methylamine or
ethylamine, with hydroxy substituted C 1 to 6 alkylamines, or
with simple nocyclic nitrogen heterocyclic compounds, e,g~
piperid me and morpholineO Suitable esters include C 1 to 10,
and preferably C 1 to 6, alkyl esters, and C 1 to 6 alkyl amino-
C 1 to 6 alkyl esters, e.g. the diethylaminoethyl ester, and the
acid addition salts thereof.
The pharmaceutically acceptable derivatives of the compound
of formula I may be made and interconverted by conventional
techniques known ~ se.
The compounds of formulae I and IV, and pharmaceutically
acceptable deri~atives thereof, are useful because they possess
pharmacological activity in animals; in particular they are useful
because they inhibit the release and/or action of phaTmacological
mediators which result from the in vivo combination of certain
types of antibody and specific antigen, e.g. the combination of
reaginic antibody with specific antigen~ (See Example 15 of
British Patent Specification No 1,230,087).
In man, both subjective and objective changes which result
from the inhalation of specific antigen by sensitised subjects
are inhibited by pTior administration of the new compounds.
Thus the new compounds are indicated for use in the treatment
of asthma, e~g. allergic asthmaO The new compounds are also
indicated for use in the treatment of so-called 'intrinsic' asthma
~04'75i'~
-- 6 --
(in which no sensitivity to extrinsic antigen can be demonstrated).
The new compounds may also be of value in the treatment of other
conditions in which antigen-antibody reactions are responsible for
disease, for example, allergic rhinitis; certain eye conditions,
S e.g. trachoma; urticaria; and gastrointestinal allergy, especially
in children, eOgO milk allergy.
For the above mentioned uses the dosage administered will,
of course, vary with the com~ound employed, the mode of
administration and the treatment desired~ However, in general
satisfactory results are obtained when the compounds are
adminîstered at a dosage of from 0.1 to 50 mg per kg of animal
body weight in the test set out in Example 15 of British Patent
Specification No 1,230,087. For man the total daily dosage
is in the range of from about 1 mg to 3,5C0 mg which may be
adm m istered in divided doses from 1 to 6 times a day or in
sustained release fonm. Thus dosage forms suitable for
administration (by inhalation or oesophageally) comprise from
about 0.17 mg to 600 mg of the compound admixed with a solid
or liquid pharmaceutically acceptable diluent or carrierO
According to our invention we also provide a pharmaceutical
composition co~prising (preferably a minor proportion of) a
compound of formula I, or a pharmaceutically acceptable
derivative thereo~, in combination with a pharmaceutically
acceptable adjuvant, diluent or carrier~ Examples of suitable
adjuvants, diluents or carrier are:- for tablets and dragées;
- 6 -
10~'7SiO
lactose, starch, talc or stearic acid; for capsules, tartaric
acid or lactose; for suppositories, natural or hardened oils
or waxes; for inhalation compositions, coarse lactose. For use
in inhalation compositions, the compound of formLla I, or the
pharmaceutically acceptable derivative thereof, preferably has a
mass median diameter of from 0.01 to 10 microns. The compositions
may also contain suitable preserving, stabilising and wetting
agents, solubilisers, sweetening and colouring agents and
flavourings. The compositions may, if desired, be formLlated in
sustained release form.
According to the invention there is also provided a process
for the production of a pharmaceutically acceptable salt of a
compound of formula I, which comprises treating a compound of
foTmula Ix,
1S s oxo_ J L G
in which X is as defined above, and
G is a group E, or another salt thereof, or when E in the
compound of formula I is a carboxylic acid group, G may be a
carboxylic ester group, a nitrile group, an acid halide group
or an amide group,
with a compound containing an available pharmaceutically
acceptable cation and capable of converting the group G to a
ln47510
p~larmaceutically acceptable salt of an E gTOUp.
Com~ounds capable of converting the group G to a
p]larmaceutically acceptable salt of E include compounds, e.g.
bases and ion exchange resins, containing pharmaceutically
acceptable cations, e.g. sodium, potassium, calcium, ammonium
and appropriate nitrogen containing organic cations. In general
we prefer to form the pharmaceutically acceptable salt by treating
the free acid of formula I with an appropriate base, e.g. with an
alkaline-earth or alkali metal hydroxide, carbonate or bicarbonate
in aqueous solution, or by treating another salt of a compound of
foxmula I with an appropriate salt by a metathetical process. When
a strongly basic compound is used care should be taken, e.g. by
keeping the temperature sufficiently low, to ensure that the
compound of formula I is not hydrolysed or otherwise degraded.
The pharmaceutically acceptable salt may be recovered from the
reaction mixture by, for example, solvent precipitation and/or
removal of the solvent by evaporation, e.g. by freeze drying.
According to a further feature of our invention we provide
a process for the production of a compound of foTmula rv, which
comprises hydrolysis; or alkylation followed by hydrolysis or
oxidation followed by hydrolysis, of a compound of formula I,
or a derivative thereof.
When simple hydrolysis is used the reaction may be carried
out in the presence of a heavy metal compound, e.g. a compound
of group Ib, IIb or IIIb of the Periodic Table as catalyst.
ln~slo
- 9 -
Suitable compounds include mercury, thallium and silver compounds,
eOg. mercury (11) acetate or chloride, thallium (111)
trifluoroacetate, and silver oxide. The reaction may be carried
out in the presence of water and an organic solvent system such
as acetone-acetic acid, alkanols, tetrahydrofuran/methanol, or
tetrahydrofuran. Alternatively the hydrolysis may be carried
out in the presence of an acid, e.g. sulphuric acid, hydrochloric
acid, trifluoroacetic acid, P-toluenesulphonic acid or a Lewis
acid such as boron trifluoride, preferably in the presence of a
polar solvent such as dimethylsulphoxide.
When the reaction involves alkylation followed by hydrolysis
the reaction may be effected by (i) an alkyl halide or sulphonate
(e.g. methyl iodide) in a moist solvent, e.g. acetone, (ii) an
alkylfluorosulphonate and water in sulphur dioxide, or tiii) a
trialkyl oxonium fluoroborate followed by aqueous sodium hydroxide.
When the reaction involves oxidation followed by hydrolysis
the reactlon may involve l-chlorobenzotriazole in methylene chloride
followed by hydrolysis with sodium hydroxide, chlora~ine-T in water
or an aqueous alkanol, ceric amnonium nitrate in aqueous
acetonitrile, or N-halosuccinimide opti ally in conjunctian
with silver nitrate in aqueous acetonitrile.
It is preferred that X should contain from 2 to 10 and more
preferably from 3 to 7 carbon atoms, eOg. a group -GH2CHoHCH2-, and
that the -OX0- group should link the 5,5' positions on the benzopyran
Z5 nuclei~
_ g _
- 1047S~0
The invention is found to be particularly useful in
providing a process for the preparation of a compound of formula
VII,
O O
HOOC_ ~ J ; ~ COOH
in which X represents an alkylene chain which is optionally
substituted by a hydroxy group, or a pharmaceutically acceptable
salt, ester or amide thereof, which comprises, hydrolysis: or
alkylation followed by hydrolysis; or oxidation followed by
hydrolysis, of a compound of formula Vl,
~ ~ + OXO ~ ~ COOH
in which X is as defined above; or a corresponding salt, e~ter
or amide thereof.
, .. .
.
1~47S10
The invention is illustrated but in no way limited by
the following Examples.
Example 1
D thyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzopyran
-2-carboxylate)
Diethyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-thioxo-4H
-l-benzopyran-2-carboxylate) (41 mgs, 0.074 m mole) in lOml Analar
acetone + 4 drops water was mixed with an excess of mercury (11)
acetate (302 mgs, 0.95 m mole) in 6ml glacial acetic acid. A red
colour was immediately observed and the resulting mixture was
stirred at room temperature for 5 minutes and then warmed for
2 minutes on a hot plate. The colour had by this time faded to
orange. The reaction mixture was filtered through a diatomaceous
earth (kieselguhr) filter aid known by the trade mark 'Hiflo-
supercel' and the residue washed thoroughly with acetone. The
filtrate was poured into water and extracted three times with
dichloromethane. The combined organic layers were shaken with
aqueous sodium bicarbonate solution, washed with water, dried
(anhydrous sodium sulphate) and concentrated affording a solid/gum
mixture. This crude product was recrystallised from ethanol
affording 6 mgs of solid product, mp 172-180, whose rf value on
TLC, using ethyl acetate as eluent, was identical to that of an
authentic sample of diethyl 5,5'-(2-hydroxy-trimethylene)bis
(4-oxo-4H-l-benzopyran-2-carboxylate).
Example 2
Diethyl 5,5'-(2-Hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzopyran-
2-carboxylate)
-- 10 --
104'~51V
A mixture of 25 mgs (00045 mmole of diethyl 5,5'-t2-
hydroxy-trimethylenedioxy)bis~4-thioxo-4H-l-benzopyran-2-carboxylate)
and 3 drops methyl iodide in 10 ml analar acetone containing 4 drops
of water was stirred in the dark at room temperature for 2 days.
Concentration of the reaction mixture afforded a light brown solid
which was recrystallised from aqueous ethanol to yield an off-yellow
solid, mp 178-180Co
The ir spectru~ and tlc rf value ~ethyl acetate as eluent) of this
solid were identical to that of an authentic sample of diethyl
5,5'-~2-hydroxy-trimethylenedioxy)bis~4-oxo-4H-l-benzopyran-2-
carboxylate)O
Exampls 3
Diethyl 5,5'-t2-Hydroxytrimethylenedioxn bist4-thioxo-4H-l-benzopyran-
2-carboxylate~
ta) Diethyl 5,5'-(2-Formyl~ytrimethylenedioxy)bis(4-thioxo-4H-l-
benzopyran-2-carboxylate)
A stirred mixture of 2.0g (3.62 mmole) of diethyl 5,5'-~2-
fo~myloxytrimethylenedioxy)bis~4-oxo-4H-l-benzopyran-2-carboxylate)
in lS ml thionyl chloride was refluxed for 18 hoursO The orange
zO solution was evaporated to dryness and the glassy residue dissolved
in benzeneO This solution was treated with 2 ml (28.2 le) of
thioacetic acid and the resulting mixture refluxed for 4 hours.
Evaporation of the solution afforded a green gum which was crystallised
from ethanol affording 1.37 g of a green solid, mp 137-140o
m4 7sio
- 12 -
Cb) Diethyl 5,5'-(2-Hydroxytrimethylenedioxy)bist4-thioxo-4H-l-
benzopyran-2-carboxylate)
A stirred m~xture of 005g (0086 mmole) of diethyl 5,5'-(2-
formyloxytrimethylenedioxy)bis(4-thioxo-4H-l-benzopyran-2-carboxylate)
S in 15 ml ethanol containing 3 drops of concentrated hydrochloric acid
was refluxed for 5 hours and then left stirring overnight at room
temperatureO The reaction mixture was diluted with chloroform and
washed twice with waterO The organic layer was ~ried (anhydrous
sodium sulphate) and concentrated affording a dark green solid,
0046g, mp 150-155.
The diethyl ester may be hydrolysed to the correspo.nding
dicarboxylic acid 5,5'-(2-Hydroxytrimethylenedioxy)bis(4-thioxo-4H-
l-benzopyran-2-carboxylic acid).
- 12 -
ln47si(~
Example 4
Diethyl 5,5'(2-hydroxytrimethylenedioxy)bis(4-oxo-4H-l-benzo-
E~-an-2-carboxylate)
A mixture of diethyl 5,5'(2-hydroxytrimethylenedioxy)
bis(4-thioxo-4H-l-benzopyran-2-carboxylate) (27mg, 0.05 m mole)
in acetonitrile (lOml) was added with stirring to a solution of
N-chlorosuccinimide (27 mg, 0.2 m mole) and silver nitrate
(38.3mg, 0.225 m mole) in 80% aqueous acetonitrile (lOml) at 25.
The mixture was heated to 50 stirred at that temperature for
2 hours and then treated with saturated aqueous sodium sulphite,
aqueous sodium bicarbonate and brine. Dichloromethane was adde~
and mixture filtered through a diatomaceous earth (kieselguhr)
filter aid known by the trade mark 'Celite'. The aqueous layer
was extracted with dichloromethane and the combined organic layers
dried and concentrated affording a solid which was recrystallised
from aqueous ethanol to yield an off-yellow solid m.p., 174-180C
whose RF value on thin layer chromatography using ethyl acetate
as eluent was identical to that of an authentic sample of the
title compound.
