Note: Descriptions are shown in the official language in which they were submitted.
9( 1~
This invention relates to certain new heterocyclic
compo~nds a~d in particular to certain novel 1,2-benzisoxa-
zole derivatives which ~ve ~een found to possess valuable
pharmacological activity a~d/or are useful as intermediates
for preparing such active compounds and to a process by
which such compounds may be prepared. The invention also
includes pharmaceutical compositions containing said
pharmacologically active compounds and a method of treating
animals including humans comprising administering thereto
an effective dose of said compounds or compositions.
According to the present invention there are provided
novel 1,2-benzisoxazole derivatives of the formula:-
N
R
wherein Rl represents one or more substituents which are at20
any one or more of the available positions in the benzene
ring and which are selected from one or more of the
. following atoms or groups: hydrogen, halogen, preferably
chlorine or bromine Cl 4 alkyl, preferably methyl, Cl-C4
alkoxy, preferably methoxy, nitro, and trifluoromethyl, and R2
is a substituent at the 5-, 6-, or 7- position of the 1,2-
benzisoxazole nucleus and is one of the following: Hydrogen,
Cl 4 alkyl, preferably methyl, carboxy Cl 4 alkyl, preferably
carboxymethyl, cyano Cl 4 alkyl, preferably cyanomethyl or
. l-cyanoethyl, -CH(R )- COOH, -CH2.COOR , and -CH(R )-COOR ,
~ ~ s"~
: - 2 -
.,
~. . . .
` ~04;~9Q4
; where R3 is Cl 4 alkyl; except that when Rl represents a
hydrogen ~tom R2 is not hydrogen.
- Compounds in which R is halo Cl 4 alkyl are useful
as intermediates.
The terms Cl_4 alkyl and Cl_4 alkoxy" as used here-
; in mean a straight or branched chain alkyl or alkoxy group
containing from 1 to 4 carbon atoms, that is methyl-,
ethyl-, n-propyl-, iso-propyl-, n-butyl, s-butyl- or t-butyl-.
. .
The term "carboxymethyl" as used herein means, of course,
the group -CH2CO2H.
A preferred class of compounds of formula I are those
in which R2 represents a carboxymethyl group or a group of
formula -CH(R )COOH. In this preferred class there exists
a still further preferred class, namely those in which R
represents a halogen substituent, particularly a para halo-
substituent.
A presently preferred compound of the invention is
~-methyl-3-~-chlorophenyl-1,2-benzisoxazol-7-yl acetic acidO
The present invention also provides a process for
preparing the novel 1,2-benzisoxazole derivatives of the
` invention which process comprises cyclising a compound of
the following formula.
X
.. ~. ~
~ II
HO.
R
. ~ Y
- wherein R4 is hydroxy or halogen tpreferably chloro or bromo
; and especially the latter), X and Y are respectively Rl and
R2 as hereinbefore defined or, independently, either or both
of X and Y represent a group which is convertible to the
; desired groups R or R2, respectively, and thereafter when
: ,
i ~0~2gQ~
either or both of X and Y represent a group which is convertible
t~ the desired group Rl or R2, respectively, the said group
- X and~or Y is converted to the group Rl and/or R2 in
conventional manner.
Alternatively, an obvious chemical equivalent of the
oxime such as a hydrazone can be used in the ring-closure
reaction.
- Conveniently a precursor of the oxime of formula II, ~'
or the hydrazone, is the corresponding benzophenone derivative,
which may be synthesised by methods well known in the art.
The benzophenone may be reacted with hydroxylamine to produce
` the oxime, or reacted with a suitable hydrazine to yield the
hydrazone.
; This reaction can be represented by the following
reaction scheme:
: '.` X
~, ~C~
\=/ 11 ~
R4 Y III
hydroxylamine
or a hydrazine
, . X ~
Y IV
R4
Q
where Q is a hydroxyl or amino group. The above conversion,
when X is not hydrogen, is novel and is thus provided in
a further aspect of the invention. Similarly, when X is not
hydrogen, the intermediates of formula IV are novel. The
intermediates of formula IV where R is hydroxyl are particu-
larly valuable since, as well as being convertible to benzis-
~; oxazoles according to the invention, they are also (by
:
- 4 -
~42g~4
choosing appropriate reaction conditions) convertible to the
cl~ss of benzoxazoles described in Belgian Patent Specification
-` No. 7~,7~0 or ~nited States Patent No. 3,912,74S. The
appropriate reaction conditions to use when it is desired that
a benzoxazole rather than a benzisoxazole should be prepared
are well-known see, for example, Chapter 6, of Heterocyclic
- Compounds", Volume 5, edited by Elderfield and published
in 1957 by John Wiley. Briefly, to obtain the benzoxazole,
acidic conditions (e.g. using polyphosphoric acid) should be
used to effect a Beckmann rearrangement, whereas if it is
desired to obtain a benzisoxazole basic conditions (e.g.
using Na2CO3 in triglyme) should be employed.
In the case where R4 is hydroxy, acylation of the
appropriate oxime stereoisomer followed by heating, if
necessary, effects the cyclisation, although it is possible
to ring-close the oxime direct.
The hydrogen atom from the R4 hydroxyl group can be
replaced by a group IA metal, such as sodium, a group IIA
metal or ammonium ion.
` 20 In the case where the compound of formula VI in which
` ` R4 is hydroxy is cyclised to the benzisoxazole, the con-
figuration of the intermediate :-
. .
X ~ ~ ~ VI
Q
should be such that the Q group is anti- to the phenolic
` hydroxyl group. When R4 is halo, the Q group should be
syn thereto.
.. ..
When it is desired to prepare a benzoxazole from the
intermediate of formula:
-- 5 --
~04Z9Q4
I OH
the Q group should be anti- to the hydroxyl group. ~,.
In a fuxther aspect of this invention there is
provided a process for preparing a 5- or 6- substituted
benzoxazole of formula
~ O ~ R2
R
wherein Rl represents one or more substituents which are at
any one or more of the available positions in the benzene
. ring and which are selected from one or more of the following
atoms or groups; hydrogen, halogen, Cl 4 alkyl, Cl_4 alkoxy,
nitro, and trifluoromethyl, and R2 is a substituent at the
5-, 6-, or 7~ position of the 1,2-benzisoxazole nucleus and
~ 20 is one of the following: hydrogen, Cl 4 alkyl, carboxy Cl 4
alkyl, cyano Cl 4 alkyl, -CH(R )-COOH, -CH2-COOR , and--
; : -CH(R3)-CooR3, where R3 is Cl 4 alkyl; except that when Rl
represents a hydrogen atom R2 is not hydrogen, which process
~ comprises cylising, under acidic conditions an oxime or
hydrazone of formula
.
~ R ~ Q~ O~ R
30
;~ `
~4~
where ~ is hydroxyl or an amino group.
When R4 is haloyen, heating with an alkali such as
- potassium hydroxide produces the benzisoxazole, which
~ in all cases has the formula :
X~
,',-
~ ~ ~ VII
i~ - O
wherein X and Y are as previously defined.
. Thus, in general terms, the present invention provides
a process for preparing a compound of formula I which com-
prises the ring-closure under basic conditions of a compound
of formula :
' ~
~J
Q - N = C
; R Y
where X and Y are as previously defined, Q is a hydroxyl,
amino, acyloxy (preferably a group of formula -o-C-R3, where
R3 is Cl 4 alkyl) or sulphonyloxy radical, and R4 is halogen
or a group of formula -OM where M is hydrogen, ammonium or
a group IA or IIA metal, followed, if necessary, by the
conversion of X and/or Y to the desired Rl and/or R2 groups
by conventional means.
For example, when Y represents alkyl, the alkyl group
may be halogenated using conventional halogenating agents
. such as chlorine, sulphuryl chloride, bromine, or N-bromo-
succinnimide, preferably in the presence of a suitable
i~zg~4
solvent such as carbon tetrachloride, and thereafter a cyano
group substituted ~rom the halogen atom. Hydrolysis of the
nitrile produces the corresponding carboxylic acid which may
if desired be esteri~ied. Alternatively, the halogen atom
can be replaced by a carboxylic acid gro~lp vla an organo-
metallic compound such as a Grignard reagent. This procedure
is fully described in Standard re~erence books, for example
for the Grignard reaction, see page 11 72 of the ~erck Index,
VIIIth Edition, published 1968. Acids or est~rs Formula I
may be alkylated at the ~-carbon atom using an alkyl halide
such as methyl or ethyl iodide. An ester of formula I may
also be converted to the hydroxamic acid derivative by reaction
with hydroxylamine.
An acid of formula I may be salified by treatment with
an appropriate base such as ammonium, alkylammonium, aralkyl-
ammonium, alumium, alkali metal or alkaline earth metal
hydroxide and of course a salt of formula I may readily be
converted to the free acid by treatment with an acid such as
hydrochloric or sulphuric acid. The salts, e.g. the sodium
salt, are pharmaceutically active. An acid of formula I or
a salt thereof may be converted to an ester by treatment with
an appropriate alcohol or by treatment with a halide of the
appropriate ester moiety or a salt of that halide if the
~ ester moiety contains a basic nitrogen atom. An ester of
; formula I may, of course, be hydrolysed to the corresponding
acid of formula I by treatment with a suitable hydrolytic
agent such as an inorganic base or acid. An acid of formula I
or an ester thereof may also be converted to an amide of
formula I by reaction with ammonia or an appropriate primary
or secondary amine.
It will be understood that the above described specific
cyclisation procedure is not the only method of synthesising
`:
8 --
~(34~904
the novel compounds of this invention; any obvious chemical
equivalent cyclisation reaction may be employed, that is
' ~ any reaction, or sequence of reactions, which is capable
of bringin~ a nitrogen atom and/or an oxygen atom into the
desired relationship with the benzophenone derivative so as
to produce a compound of formula VII.
- As mentioned above, the acids of formula I, i.e. those
compounds in which R2 is carboxymethyl or -CH(R3) COOH are
preferred compounds of the invention. These acids can be
prepared by hydrolysis of the corresponding nitriles of
formula VII where Y is cyano Cl 4 alkyl. Clearly, when it is
desired to prepare the acid in which R2 is carboxymethyl,
cyanomethyl is the group which needs to be hydrolysed.
Similarly, when it is desired to produce an acid group of
formula -CH(R3)COOH it is necessary to hydrolyse a group
; of formula -CH(R3)CN.
Alternatively, the above class of acids can be pre-
pared from derivatives of formula I where R is a Cl 4
` haloalkyl group using the Grignard reaction. After reaction
with magnesium and treatment with carbon dioxide a compound
of formula I is formed in which R2 represents the group
-C-OMgXl where Xl is a halogen atom. This group can then be
converted to a carboxylic acid group simply by hydrolysis.
Thus, according to yet a further feature of the
invention there is provided a method of preparing an acid
of formula : Rl
O ~ CHR5C02H
wherein Rl is as defined previously and the -CHR5Co2H group
is at the 5-, 6-, or 7- position of the benzisoxazole nucleus
'
_ g _
~ 29Q4
and R represents hy~rogen or Cl 4 alkyl, which comprises
hydrolysing a compound of formula:
. Rl
','' ~
CHR Z
where the group -CHR5Z is at the 5-, 6- or 7- position of
the benzisoxazole nucleus and Z represents a nitrile, ester,
carboxylate or hydroxamic acid group, or a group of formula:
, ~0
~ OMgX
where Xl is a halogen atom.
The novel compounds of the present invention in which
R is a carboxy or esterified caEboxy moiety have been found
to possess anti-inflammatory activity and in some cases other
pharmacological activity, whilst the other novel compounds of
formula I are useful as intermediates in the synthesis of
` the aforementioned pharmacologically active compounds. The
pharmacological activity has been demonstrated in tests
, , carried out in animals, usually at doses of from 0_1 to
500 mg./Kg. In the treatment of humans, the dose administered
` may be for example, between 0.1 and 25 mg./kg. but, of course,
doses outside this range may be used at the discretion of
the physician treating the patient. The pharmacologically
active compounds of formula I may be administered by the
enteral or parenteral routes and for this purpose they will
normally be formulated into pharmaceutical compositions
comprising the active ingredient in associat~on with at
least one pharmaceutically acceptable carrier therefor. Such
compositions form a part of this invention and will normally
consist of the active ingredient mixed with a carrier, or
::
-- 10 --
1~2~Q4
diluted by a carrier, or enclosed or encapsulated by a carrier
in the for~ o~ a capsule, sachet, cachet or other container.
The carrier may be a solid, semi-solid or liquid material
which serves as a vehicle, excipient, coating agent, or
medium for the active ingredient. Some examples of the
carriers which may be used are lactose, dextrose, sucrose,
sor~itol, mannitol, starch, gum acacia, calcium phosphate,
liquid p~ra~fin, cocoa butter, oil of theobroma, alginates,
tragacanth, gelatin, methyl cellulose, polyoxyethylene
sorbitan monolaurate, methyl - or propyl - hydroxybenzoate,
ethyl cellulose acetate phthalate, low viscosity acetyl
cellulose acetate, paraffin wax, mineral wax, vegetable wax,
vegetable gum, silicone rubbers such as liquid polydimethyl-
siloxane rubber, plasticised or unplasticised polyvinyl
- chloride, plasticised polyethylene terephthalate, modified
collagen, cross-linked hydrophilic polyether gel, cross-
linked polyvinyl alcohol or cross-linked partially hydrolysed
polyvinyl acetate.
Advantageously the compositions of the invention are
formulated in a dosage unit form containing from 1 to 1000 mg.
(preferably 25 to 500 mg.) of the active ingredient. Examples
of suitable dosage unit forms are tablets, hard or soft
gelatin capsules, microcapsules and suppositories as well
as drug dispensing systems comprising the active ingredient
contained in a flexible, imperforate polymeric material
through which the drug may be released slowly by diffusion.
More generally, the term "dosage unit form" as used herein
means a physically discrete unit containing the active
ingredient, generally in admixture with and/or enclosed
by a pharmaceutical carrier, the quantity of active ingredient
being such that one or more units are normally required for
a single therapeutic administration.
- ~ .
~4;~
~ a~tion to the active ingredient of formula I, the
compositions of the present invention may al50 contain one or
- more pharmacologically active ingredients, for example,
acetylsalicyclic acid and salts thereof, caffeine, codeine
phosphate, phenylbutazone, paracetamol, dextropropoxyphene
and indomethacin.
The compositions of the present invention will of
course be adapted to the particular route of administration.
. ~ Thus, for oral administration, tablets, pills, capsules,
solutions or suspensions may be used; ~or parenteral
administration, sterile injection solutions or suspensions
may be used; for rectal administration, suppositories may be
used; and for topical administration, creams, lotions or
ointments may be used. Any of the foregoing compositions
may, of course, be formulated in delayed or sustained release
form in a manner well known in the art.
Compounds of formula I in which R2 is a Cl 4 alkyl
group, preferably ethyl, and in which Rl is a hydrogen or hal-
ogen are also useful in the treatment of immediate hypersensi-
tivity diseases including asthma, and in the alleviation of
status asthmaticus. This class of compounds i5 also useful
for the treatment of diseases in which excessive amounts of
prostaglandins are released.
The following-examples will further illustrate
the invention. No examples of the formation of acids via
the Grignard route are given. However, those skilled in
the art will appreciate that the halo-alkyl intermediates
described hereinafter can be converted to the corresponding
acids by this method, if so desired.
- 12 -
~0912~
~.
Example 1
5-Methyl-3-~4-chl~rophenyl~-1,2-benzisoxazole
2-~lydroxy-5-methyl-41-chlorobenzophenone (13.5 g,
0.055 moles) was stirred with a solution of potassium hydroxide
(44 g.) in water (150 ml.) and then hydroxylamine hydrochloride
~17.4 g, 0.25 mole) was added with ice cooling. After stirring
over~ight at room temperature 100 ml. of water was added and
the mixture was acidified with 5N-hydrochloric acid to give
an off-white precipitate which was filtered, washed and
dried (14.7 g.). Recrystallisation of the product from
benzene gave the oxime (7 g.) m.p. 163C. (This is the stereo
isomer in which the oxime -OH group and the _-chlorophenyl
group are in the syn positions relative to each other, and is
therefore the correct isomer for the next stage.)
The above oxime (5 g, 0.019 mole) was heated on the
steam bath with acetic anhydride (10 ml.) until it all
dissolved and then for 5 minutes longer. The solution was
evaporated in vacuo to a clear oil which crystallised
to give a white solid on cooling. This was heated under
nitrogen at 290-300C. for 5 minutes and acetic acid distilled
over. The product was distilled in vacuo to give 5-methyl-3-
(4-chlorophenyl)-1,2-benzisoxazole (2.4 g.), b.p. 154-
158C/0.2 mm. After purification by preparative t. 1. c. an
off-white solid; m.p. 95C. was obtained. This compound was
also prepared by boiling 2-bromo-5-methyl-41-chlorobenzophanone
oxime with alcoholic potassium hydroxide solution.
Example 2
5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole
. _ . . . _
N-Bromosuccinimide (26 g.) was added to a cold solution
of 5-methyl-3-(4-chlorophenyl)-1,2-benzisoxazole (35 g.) in
carbon tetrachloride (250 ml.). Benzoyl peroxide (500 mg.)
was added and the mixture was heated under reflux for 3 hours
- 13 -
.
~OglZ9~4
in the pxesence of U.V. light. The solid residue was filtered
off, and the ~iltrate was evaporated to give 5-bromoethyl-3-
(4-chlorophenyl)-1,2-benzisoxazole (m.p. 142C.).
Example 3
3-(4-Chlorophenyl?-1,2-benzisoxazol-5-ylacetonitrile
A mixture of 5-bromomethyl-3-(4-chlorophenyl)-1,2-
benzisoxazole (45 g.~ and sodium cyanide (7.4 g.) in dry
: dimethylformamide (800 ml.) was hea~ed on a steam bath for3 hours. The mixture was filtered and the filtrate was
evaporated to dryness, to give 3-(4-chlorophenyl)-1,2-
benzisoxazol-5-ylacetonitrile (m.p. 118C.).
; .
- Exam~le 4
:
3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl acetic acid
A solution of the above nitrile (11 g.) in concentrated
hydrochloric acid (100 ml.) was heated on a steam bath for
1 hour. The solution was then allowed to cool, evaporated
; to dryness and the product dissolved in chloroform. The
chloroform solution was repeatedly extracted with sodium
bicarbonate solution. The combined extracts were acidified
to give 3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl acetic acid,
(m.p. 189C.).
Example 5
Ethyl 3-(4-chlorophenyl-1,2-benzisoxazol-5-yl ace_ate
A solution of 3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl
acetic acid (20 g.) in ethanol (200 ml.) was heated under
reflux for 6 hours, during which time dry hydrogen chloride
gas was passed through the solution. The solution was
evaporated to dryness, the residue treated with sodium bi-
carbonate solution and the product extracted with ether. The
extract, after drying (Na2SO4) and evaporation, gave ethyl
3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl acetate.
- 14 -
~ .. ..
~29
Example 6
Ethyl 2-~3-(4-chloropheny1)-1,2-benzisoxazol-5-yll propionate
A solution of ethyl 3- (4-chlorophenyl)-1,2-benzisoxazol-
5-yl acetate (39 g.) in ether (200 ml.) was added to a stirred
solution of sodamide (from 3.2 g. sodium) in liquid ammonia
(500 ml.). This mixture was stirred for 15 minutes, then
a solution of methyl iodide (~.5 ml.) in ether ~10 ml.) was
added rapidly. When the reaction mixture became colourless
the reaction was stopped by the addition of excess ammonium
- 10 chloride. ~he mixture was evaporated to dryness and the
residue was e~tracted with ether. The ethereal solution was
evaporated to dryness to yield ethyl 2- E3- (4-chlorophenyl)-
1,2-benzisoxazol-5-yl] propionate.
Example 7
2-[3-(4-Chlorophenyl?-1,2-benzisoxazol-5-yl] propionic ac d
A solution of ethyl 2-[3-(4-chlorophenyl)-1,2-benzisoxa-
zol-5-yl] propionate (15 g.) in concentrated hydrochloric acid
(150 ml.) was heated on a steam bath for 6 hours. The solution
was cooled and the crystals which formed were filtered off
and recrystallised to yield 2-[3-(4-chlorophenyl)-1,2-
benzisoxazol-5-yl] propionic acid, (m.p. 137-9C.). ~he
following compounds were prepared using methods analogous
i to those described above:-
6-Methyl-3-(4-chlorophenyl)-1,2-benzisoxazole.
7-Methy~3-(2,~dichlorophenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-bromophenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-methylphenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-methoxyphenyl)-1,2-benzisoxazole,
5-Methyl-3-(4-nitrophenyl)-1,2-benzisoxazole~
5-Methyl-3-(4-trifluoromethylphenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-bromophenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-methylphenyl)-1,2-benzisoxazole.
-- 15 --
~LID4;~:9~
6-Methyl-3-(4-methoxyphenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-nitrophenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-trifluoromethyl)-1,2-benzisoxazole~
Also the following acetic and propionic acids and
their esters and corresponding nitriles:-
3-Phenyl-1,2-benzisoxazol-5-ylacetic acid.
3~ Bromophenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Methylphenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Methoxyphenyl)-1,2-benzisoxazol~5-ylacetic acid.
3-(4-Nitrophenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Trifluoromethylphenyl)-1,2-benzisoxazol-5-
ylacetic acid.
2-[3-(4-Bromophenyl)-1,2-benzisoxazol-5-yl] propionic
acid.
2-[3-(4-Methylphenyl)-1,2-benzisoxazol-5-yl] propionic
acid.
2-[3-(4-methoxyphenyl)-1,2-benzisoxazol-5-yl] propionic
acid.
2-[3-(4-Nitrophenyl)-1,2-benzisoxazol-5-yl] propionic
acid.
2-[3-(4-Trifluoromethylphenyl)-1,2-benzisoxazol-5-
yl]-propionic acid.
2-[3-phenyl-1,2-benzisoxazol-5-yl] propionic acid.
3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl acetic acid.
2-[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl] propionic
acid.
2-[3-phenyl-1,2-benzisoxazol-6-yl] propionic acid.
2-[3-(4-chlorophenyl)-1,2-benzisoxazol-7-yl] propionic
acid.
3-(2,4-dichlorophenyl)-1,2-benzisoxazol-7-yl acetic
acid.
3-(2,4-dichlorophenyl)-1,2-benzisoxazol-7-yl propionic
acid.
- 16 -
,r'' ~ .
~ '
~4Z904
Confirmation of the correct structures of the above-named
compounds was obtained by t.l.c. evidence.
Example 8
5-sromoethyl-3-(4-chlorophenyl)-1,2-benzisoxazole
3-(4-Chlorophenyl)-5-methyl-1,2-benzisoxazole (12.2 g.)
and N-bromosuccinimide (9.6g.)were mixed in carbon tetrachloride
(200ml~) and heated under reflux in the presence oE UV light.
(Hanovia medi~ pressure lamp 125 watts, emitting at 254,
265, 297, 313, 366 mp). On cooling, the mixture was filtered
and the filtrate evaporated to dryness. The resulting solid
was recrystallised from 33% toluene/60-80 petrol ether (150
ml.) to give the title compound as a white crystalline solid
(10.0g.) m.p. 142C.
Microanalysis: C14HgBrClNO re~uires 52.1%C, 2.8%H, 4.3%N,
11.0%Cl, 24.8%Br
found 51.9%C, 3.0%H, 4.6%N,
10.7%Cl, 24.7%Br
Example 9
3-(4-Chloxophenyl)-1!2-benzisoxazol-5-ylacetonitrile
5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole
~6.5 g.), sodium cyanide (l.lg) and dry sodium iodide (0.3g)
were stirred together in dry dimethylformamide (50ml) for
20 hours at ambient temperature. The mixture was poured into
water (500ml.), stirred for one hour and the brown solid
filtered off, washed and dried (5.lg). ~his was recrystallised,
with charcoaling, from 50% toluene/60-80 petrol ether (lOOml.)
to give the title compound as an off-white solid (3.4g)
m.p. 118C.
Microanalysis : C15HgClN2O requires 67.0%C, 3.4%H, 10.4%N,
13.2%Cl.
found 67.2%C, 3.6%H, 10.2%N,
13.5%Cl
- 17 -
9~4
E mple 10
3-(4-Chlorophenyl)--1,2-benzisoxazol-~ tic acid
3-(4-Chlorophenyl-1,2-benzisoxazol-5-ylacetonitrile
(4.7g) was mixed with concentrated hydrochloric acid (40ml.)
and glacial acetic acid (20ml.) and heated at 80C. for three
hours. The mixture was poured into water (300ml.) and the
residue filtered off and washed with water. This solid was
stirred with 5~ aqueous sodium carbonate solution ~200ml.)
and the solution was then filtered. The filtrate was acidified
with 2N-hydrochloric acid giving a white precipitate which
was filtered, washed and dried to give the title compound
(4.2g) m.p. 189C.
Microanalysis : C15HloClNO3 requires 62.6%C, 3.5%H, 4.9~N,
12.3~Cl
found 62.5%C, 3.7%H, 5.0~N,
12.6~Cl
Example 11
4'-Chloro-5-ethyl-2-hydroxybenzophenone
Aluminum chloride (267g) was added in portions over
30 minutes to a stirred solution of 4-ethylphenol (122.lg.)
and 4-chloro-benzoyl chloride -~140ml.) in dry 1,1,2,2-tetra-
chloroethane (800ml.~. The mixture was heated at 105C.
for 22 hours with stirring, and on cooling a mixture of
ice (600g) and concentrated hydrochloric acid was added
slowly. A vigorous reaction occurred and some material was
lo~t. The remaining material was separated and the aqueous
fraction extracted twice with chloroform (200ml.), and the
combined organic layers evaporated to a dark oil which was
distilled in vacuo giving two main ~ractions: B (17.4g)
150-160C ~ 0.3mmHg, C (110.8g) 160-168C 0 0.3mmHg. Both
remained liquid on cooling.
- 18 -
: ~ ,: ,
~4Z9(~
icroanalysis : C15H13C1O2 requires 69.1%C, 5.0%H, 13.6%C1;
found 69.0%C, 5.0%H, 13.9%Cl
Example 12
4'-Chloro-5-ethyl-2-hydroxybenzophenone-oxime
, . .
4'-Chloro-5-ethyl-2-hydroxybenzophenone (65.2g) and
potassium hydroxide (170g) in water (700ml) and ethanol
(150ml.) were treated with hydroxylamine hydrochloride
(70.0g), with cooling, ana the resulting mixture was stirred
for 18 hours at ambient temperature. Dissolution occurred
during this time. The solution was acidified with 5N-
hydrochloric acid and then extracted with~ether (3x200ml.).
The combined ether solutions were washed with 10% aqueous
sodium carbonate solution (2x200~1) and evaporated to dryness
to give an off-white solid. This solid was recrystallised
from 40% benzene/60-80 petrol ether to give a white crystal-
line solid ~29.9g), second crop (14.5g.) m.p. 117C.
Microanalysis : C15H14ClNO2 requires 65.3%C, 5.1%H, 5.1~N,
12.9%C1;
found 65.3~C, 4.9%H, 5.1%N,
12.9%C1
(Stereoisomer as in Example 1)
Example 13
3-(4-Chlorophenyl)5-ethyl-1,2-benzlsoxazole
4'-Chloro-5-ethyl-2-hydroxybenzophenone-oxime (22.0g)
was dissolved in hot acetic anhydride (45ml) and immediately
cooled, causing the oxime mono-acetate to crystallise. This
was filtered and dried (19.7g) m.p. 105C. The oxime mono-
acetate (19.0g) and sodium carbonate (13.3g) were heated
together in triglyme, under reflux, for 30 minutes. On
cooling, the mixture was poured into water (1.01.) this was
extracted with ether (3x250ml). The combined ether extracts
were washed with water (3x250ml) and evaporated to dryness to
19
9~4
give a yellow oil which crystallised at room t~mperature
(16.4g). A sample (3.0g) of this solid was recrystallised
from methanol/water to give a white solid (1.5g) m.p. 42-45C.
Microanaly5is : C15H12ClNO requires 69.9%C, 4.7%H, s.4%
13.8%Cl;
found 69.6%C, 4.8~H, 5.4%N,
13.8%Cl
Example 14
5~ Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole
3-(4-Chlorophenyl)-5-ethyl-1,2-benzisoxazoIe (12.3g)
was brominated similarly to Example 8, to give the title
compound (11.3g), m.p. 111-6C.
MiCroanalysis: C15HllBrClNO requires 53.5%C, 3.3%H, 4.2%N,
10.5%Cl, 23.7%Br;
found 53.6%C, 3.5%H, 4.0%N,
10.3%Cl, 24.0%Br.
Example 15
2-[3-_4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-propionitrile
5-(1-Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole
(9.Og) was treated with sodium cyanide in a similar manner to
Example 9 to give the title compound as a viscous yellow
oil (6.4g).
Example 16
2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-propionic acid
2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-
propionitrile (6~4g) was hydrolysed similarly -to Example 10
to give an off-white solid (5.lg). This was recrystallised
from toluene with charcoaling to give the title compound
(3.9g) m.p. 137-9C.
Example 17
4'-Chloro-4-ethyl-2-hydroxybenzophenone
.
3-Ethylphenol (122.lg) was reacted with 4 chlorobenzoyl
-- ~0 --
-
-
~4Z9~)~
chloride (140ml) similarly to Example 11, giving two main
fractions on distillation A (141.8g) 155-160C @ 0.09 mmHg;
B (15.3g.) 150~170C ~ 0.09 mmHg. Both ~ractions contained
about 80% o~ the title compound~ plus 20% of the isomer.
4'-Chloro-2-ethyl-4-hydroxybenzophenone, and the mixture used
in Example 18.
Example 18
4'-Chloro-4-ethyl-2-hydroxybenzophenone-oxime
4'-Chloro-4-ethyl-2-hydroxybenzophenone (130.4g) was
treated withhydroxylamine hydrochloride (140g) similarly to
Example 12, to give the title compound, one isomer only
(81.2g), m.p. 159-161C.
Microanalysis C15H14ClNO2 requires 65.3%C, 5.1%H, 5.1%N,
12.9%Cl;
~ound 65.6%C, 5.1%H, 5.4%N,
12.8~Cl.
Stereoisomer as in Example 1.
Example 19
3-(4-Chlorophenyl)-6-ethyl-1,2-benzisoxazole
4'-Chloro-4-ethyl-2-hydroxybenzophenone (44.0g) was
treated with acetic anhydride similarly to Example 13, to
give the oxime-monoacetate (42.7g). This was immediately
converted to the title compound as in Example 13 (34.7g).
8.9g of this was recrystallised ~rom methanol/water to
give a white crystalline solid (6.5g), m.p. 78-9C.
Microanalysis : C15H12ClNO requires 69.9%C, 4.7%H, 5.4%N,
13.8%Cl;
found 69.6~C, 4.7%H, 5.2%N,
13.8%Cl.
Example 20
6-(1-Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole
_
3-(4-Chlorophenyl)-6-ethyl-1,2-benzisoxazole (25.8g) was
- 21 -
~4Z9~4
brominated similarly to Exa~ple 8 to give the title compound
(22.2g), which was used without further purification.
Example 21
2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-propionitrile
.. _ .. .. . . _ . _ .
6-(1-Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole
(16.8g) was treated with sodium cyanide in a similar manner to
Example 9 to give the title compound as an off-white solid
(lO.Og), which was used without further purification.
Example 22
2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-propionic acid
2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-pro-
pionitrile (lO.Og) was hydrolysed similarly to Example 10 to
give the title compound as a white solid (1.8g), m.p. 176-9C.
Microanalysis : C16H12ClNO3 requires 63.7%C, 4.0%H, 4.6%N,
11.8~Cl;
found 63.4%C, 4.1~H, 4.6%N,
11.5~Cl.
Example 23
4-Ethyl-4'-fluoro-2-hydroxybenzophenone
3-Ethylphenol (24.4g) and 4-fluorobenzoyl chlaride
(34.9g) was reacted together as in Example 11 giving three
main fractions: B (11.4g) 126-129C ~ 0.07 mmHg; C (7.9g),
129-132C ~ 0.06 mmHg; D (5.9g), 132-150C @ 0.06 mmHg,
all containing ^- 80~ of the required isomer. B (4.0g) was
separated by preparative thin layer chromatography to give
the title compound (2.6g), m.p. 44-48C.
Example 24
4-Ethyl-4'-fluoro-2-hydroxybenzophenone-oxime
4-Ethyl-4'-fluoro-2-hydroxybenzophenone (21.0g, 80%
pure) was treated with hydroxylamine hydrochloride (24.0g)
similarly to Example 12, to give, after recrys-tallisation
from benzene, the title compound as a white crystalline solid
~ - 22 -
1~4Z9a~
(10.7g) m.p. 130-2C.
Microanalysis : C15H14FN02 requires 69.5~C, 5.4%H, 5.4~N,
7.3%F;
found 69.2~C, 5.5%H, 5.2~N,
7.2%F
Example 25
6-Ethyl-3-(4-fluorophenyl)-1,2-benzisoxazole
4-Ethyl-4'-fluoro-2-hydroxybenzophenone-oxime t9.6g)
was treated with acetic anhydride similarly to Example 13 to
give the oxime mono-acetate (7.5g). This was immediately
converted to the title compound as in Example 19 t5.7g).
Example 26
6-~1-Bromoethyl)-3-t4-fluorophenyl)-1,2-benzisoxazole
6-Ethyl-3-t4-fluorophenyl)-1,2-benzisoxazole t3.5g)
was brominated similar to Example 8 to give the title
compound t4-1g), which was used without further purification.
Example 27
2-[3-t4-Fluo~Ee~heny ~ -6-yl]-propionitrile
6-tl-Bromoethyl)-3-t4-fluorophenyl)-1,2-benzisoxazole
(4.1g) was treated with sodium cyanide in a similar manner to
Example 9 to give the title compound as a brown solid t3.Bg)
which was used without further purification.
Example 28
. . .
2-[3-t4-Fluorophenyl)-1,2-benzisoxazol-6-yl]-propionlc acid
2-[3-t4-Fluorophenyl)-1,2-benzisoxazol-6-yl]-propionitrile
t3.8g) was hydrolysed similarly to Example 10 to give the
title compound as an off-white solid tO.45g) m.p. 151-4C.
Example 29
. . _
3-t4-chlorophenyl)-5-methyl-l~2-benzisoxazole
. _ .. . . _ .
4'-Chloro-2-hydroxy-4-methylbenzophenone-oxime tO.2g)
and anhydrous sodium carbonate tO~2g) were heated together
~ - 22a -
, . .
l~Z9~4
under reflux in triglyome (5ml) for 30 minutes. On cooling,
the mixture was poured into water ~50ml`.) and filtered. On
standing a solid separated from the filtrate and was filtered,
washed, dried and examined by NMR. The NMR spectrum was
consistent with the preparation of the title compound (~ 30~).
T . L .C. also confirmed the presence of the benzisoxazole.
Example 30
2-Hydroxy-3-methyl-4'-chlorobenzophenone
Chlorobenzene (78.79g, 71.6ml; 0.7mole), AlC13
10 ~ (14g, 0.105mo1e) were mixed, stirred and treated with a
solution of 2-hydroxy-3-methylbenzoic acid chloride (12g,
0.07mole) ln chlorobenzene (20ml.). The mixture was stirred
and heated at 100C overnight. The cooled mixture was added
to conc. HCl (lOml) and ice, extraction with ether, and ether
washed with saturated sodium bicarbonate solution, dried
(Na2SO4), filtered and the filtrate distilled, to give (after
removal of the ether), a main fraction 2-hydroxy-3-methyl-4'-
chlorobenzophenone, b.p. 148-152C/0.5mm (8.13g), which
solidified to yellow microplates, m.p. 55-58C.
Found : C.68.23; H.4.71; Cl.14.61. C14HllClO2
Requires : C.68.16; H.4.49; Cl.14.37%.
Example 31
2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime
The ketone of Example 30 (7.5g, 0.03mole) in ethanol
(18ml) was added with stirring to a solution of (85%)
potassium hydroxide (20.74g, 0.3mole) in water (85ml) at
10C, this colloidal solution was treated with solid hydroxyl-
amine hydrochloride (8.54g, 0.12 mole) and stirred overnight.
The solution was acidified with 5NHCl to give a solid, which
was filtered, washed with water and stirred for 45 minutes,
with 5~ Na2CO3 solution (30.5ml), to remove unwanted oxime
~ - 22b -
:: .
~0429~4
stereoisomer, filtered, washed with 5% Na2C03 solution
(lOOml) and then with water until free of alkali. The dried
solid had m.p. 175-177C. Recrystallisation from 54% benzene-
light petroleum (b.p. 60-80C) mixture gave the oxime, m.p.
178C ("bonded isomer") 5.45g.
Foun~: C.64.25; H.4.79; C1.13.41; N.5.3% C14H12Cl C02
Requires: C.64.25; H.4.6; Cl.13.55; N.5.35
Example 32
2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime acetate
Acetic anhydride (12ml) was warmed to 60C and treated
with the oxime of Example 31 (5.25g. 0.02mole). The stirred
mixture was warmed to 80C. to dissolve the oxime and the
solution was then immediately cooled in an ice bath. The
precipitated solid was filtered off, washed with light
petroleum (b.p. 40-60) to give the acetate, 4.8g, m.p. 154-
156C
Found: C.63.18; H.4.86; Cl.11.5; N.4.77. C16H14ClN03
Requires C.63.26; H.4.64; C1.11.67; N.4.6%
Example 33
3-p-Chlorophen ~ -1,2-benzisoxazole
The oxime acetate of Example 32 (4.36g, 0.014mole) was
refluxed with sodium carbonate (3.3g; 0.031mole) in triethylene
glycol dimethyl ether (44ml) for 35 minutes. The mixture
was poured into water (200ml), cooled in ice filtered and
washed neutral with water. After drying the benzisoxazole
(3.4g) had m.p. 88-90C and m.p. 97-99 on recrystallisation
from EtOH.
Found: C.68.87; H.4.37; Cl.14.82; N.5.83. C14HloClNO
Requires: C.68.99; H.4.14; C1.14.55; N.5.75
3n
- 22c -
~0~3Q4
1 Example 34
3-p-Chlorophenyl-7-bromomethyl-1,2-benzisoxazole
The above benzisoxazole of Example 33 (28.9g, O.lmole) with N-
bromosuccimide (19.59g, O.llmole) was refluxed in carbon tetrachloride-
(309ml) under illumination from an ultra-violet lamp (Hanovia type MPC)
with stirring for three hours. The mixture was cooled and the so~d
was
succinimide /filtered off and washed with-CC14. The-~filtrate-was =~ -
evaporated to dryness and the product recrystallised from light pet'roleum
(b.p. 60-80)-CC14 to give the bromo-methyl compound (26.59g) m.p. 117-120 C.
(;containing a little 7 methyL starting material ).
Found : Br. 25.68; Cl. 10.75; No 4.24; C14~ BrClN0
Requires: Br. 24.77j Cl. 10.99; N. 4.34%
Example 35
3-p-Chlorophenyl-1,2-benzisoxazol-7-yl-acetic acid
_
The bromomethyl compound of Example 34 (20g, 0.062mole) was stirred5
at room temperature in dimethyl formamide (190ml.) with sodium cyanide (3.03g
0.062 mole ) and sodium iodide (0.93g, 0.0062 mole) for 22 hours. The
solution was evaporated to dryness to yie'ld a solid which was treated with
water/ ground up~ filtered and washed with water until the filtrate was free
of halidoions. The dried crude nitrile (21.45g) had m.p. 110-125C, NMR
showed that it contained 50% of the required product. The crude nitrile
~20.67g, Ca 0.04 mole ) was refluxed for four hours in conc.HCl.(207ml)
and acetic acid (103 ml.). The mixture was poured into water (21.) to
give a solid which was extracted with sodium carbonate solution, this was
extracted with ether and the sodium carbonate solution was acidified to give
the acetic acid which was recrystallised from 50% ethanol to give the acetic
acid (2.76g), m.p. 198-200 C.
Found : C. 62.84; H. 3.56; Cl. 12.55; N. 5.07; C15HloClN03
Requires:C. 62.62; H. 3.5; Cl. 12.32; N. 4.87%
Example 36
~-Methyl-3-p-chlorophenyl-1,2-benzisoxazol-7-yl-acetic acid
n-Butyl lithium (31ml, 46m Mole of 1.5M) was cooled to -30cunder
nitrogen with stirring and treated with a solution of diisopropylamine (6.25
. 23.
,
' '- '1'1-
~4
1 ml. 4.65g., 4~m Mole) in tetrahydrofuran (38ml) keeping the temperature at-30 to -50 C. A solution of the acetic acid of Example 35 (4.5g,15.64m Mole
in THF (38ml) and hexamethylphosphoramide (38ml) was added dropwise to the
Bu ~i solution and the solution stirred at -30 to ~40C for 1.5 hours. -It -
was then transferred to a solution of methyliodide (150ml) which was stirred
and had been cooled to 5 ~C. in an ice bath. The mixture was stirred in the
melting ice bath for 1.5 hours~ acidified with a litt-le conc.HCl, evaporated
to small bulk and treated with water (500ml). The mixture was extracted with
chloroform which was dried (Na2~04) and evaporated to leave the a methyl
acetic acid as a mixture with its methyl ester. This was refluxed with conc.
HCl (60ml) and acetic acid (30ml) for four hours, diluted with water, extrac-
ted with chloroform, which was dried (Na2S04)~ evaporated to leave a gum
which was purified on preparative thin layer chromotography to give the ~-
methyl acetic acid (0.85g), m.p. 136-138 C.
Found : C.6~88; H.4.27; Cl.11.46; N.4.65; C16H12ClN3
Requires: C.63.69; H.4~1; Cl.11.75; N.4.64%
Example 37
2-Hydroxy-3-ethylbenzophenone
. ~
This compound (44.67g) was prepared from benzene (172g.,2.2 mole)
and 2-hydroxy-3-ethyl benzoic acid chloride (63.15g,0.34 mole)~ using the
same conditi~ns as in Example 30. The h.p. of the compound was 123-126C./
0.14mm~ bD 1.6081,~ max.(film) 1630cm 1.
Example 38
2-Hydroxy-3-ethylbenzophenone oxime
Using the conditions of Example 31, the ketone of Example 37
(45.34g,0.2mole) and hydroxylamine hydrochloride (56g~0.8 mole) gave
the oxime (43.82g), m.p. 146-148C, ~ max.(Nujol),3340,1650,1608~1600 cm
Example 39
2-Hydroxy-3-ethylbenzophenone oxime acetate
. . .
The oxime of Example 38 (39.76g, 0.185 mole) (using the conditions
of Example 32 above, followed by evaporation of the acetic a~hydride and
~2~
washing the product with light petroleum (b.p. 40-60)),
gave the acetate (40.45g), m.p. 63-65C, ~ max. (Nujol)
1770 cm 1.
- Example 40
3-Phenyl-7-ethyl-1,2-benzisoxazole
Using the conditions of Example 33, the acetate of
Example 39 (39.34g, 0.145 mole) wi~h sodium carbonate (31.86g,
0.3mole) in triethyleneglycol dimethyl ether (425ml) gave
3-phenyl-7-ethyl-1,2-benzisoxazole (27.32g) b.p. 129-130C/
0.3mm, nD 1.6045, ~max. (film) 1625, 1608. NMR ~ 1.42(3H)
3.05 (2H), ~ 7.0-7.3 (8H)
Example 41
3-Phenyl-7 ~bromoethyl-1,2-benzisoxazole
The 7-ethyl compound of Example 40 (2.23g, lOm Mole~
in carbon tetrachloride (30ml) with N-bromosuccinimide
(1.96g, llm Mole) and a trace of benzoyl peroxide or ~-azo-
isobutyronitrile was stirred and refluxed while being
illuminated with ultra violet light for 2 hours. The cooled
solution was filtered and the carbon tetrachloride evaporated
orf to leave the ~-bromoethyl compound (3.18g) as an oil
n23 1.6280. ~ max (film) 780, ll90cm 1 NMR S 1.22 (3H),
5.62 ~lH), ~ 7.0-8.0 (8H).
Example 42
3-Phenyl-1,2-benzisoxazol-7-yl
The ~-bromoethyl compound of Example 41, (18.6g,
61.55 m Mole) in dimethyl formamide (19Oml) with sodium
cyanide (3.02g, 61.55 m Mole) and sodium iodide (0.92g, 6.15m
Mole) was stirred at room temperature for 22 hours. The
solution was evaporated to small bulk, the residue treated with
~ 30 water (200ml), extracted with chloxoform (4x200ml), the CHC13
- was washed with saturated sodium chloride solution and dried
- 25 -
:
(Na2S04), filtered and evaporated to give the crude ~-cyano-
ethyl nitrile (25g) nD 1.5838, ~max. (film) 750cm
The crude nitrile (25g) was stirred and refluxed in acetic
acid (125ml) and conc. HCl (250ml) for four hours. The
mixture was poured into water (2500ml), extracted with CHC13,
which was then extracted with sodium bicarbonate solution.
` The latter was acidified to yield an oil which was extracted
with chloroform, dried (Na2SO4), filtered and evaporated to
leave 3-phenyl-1,2-benzisoxazol-7-yl acetic acid (5.94g)
as an oil, n2D1 1.5830. ~max Ifilm) 2620, 1710, 750, 700 cm 1,
NMR ~ 1.71 (3H), 4.42 (lH), 7.12-8.25 (8H), 9.95 (lH). Mass
spectrum Parent ion m/e 267, others at 223 (loss of CO2),
222 (loss of CO2H), 208 (loss of CH3CO~), 195 (loss of
CH3C.CO2H).
In the following examples of pharmaceutical compositions
of the present invention, the term "medicament" is used to
indicate the compound ~-methyl-3-_-chlorophenyl-1,2-benz-
isoxazol-7-yl acetic acid. That compound may, of course, be
replaced by any other active compound of formula I and the
amount of medicament may be increased or decreased depending
~n the degree of activity of the medicament used.
Example 43
Tablets each containing lOOmg of medicament are made
as follows:-
..
. . .
- 26 -
Medicament 1~ 4 lOOmg
Potato starch 38mg
Lactose 25mg
- Ethyl cellulose (as 20~ solution in industrial
alcohol) 2mg
.- Alginic acid 7mg
Magnesium stearate lmg
Talc 2mg
Total 175mg
The medicament, starch and lactose are passed through
1~
a No. 44 mesh B.S.S. sieve and mixed thoroughly. The
solution of ethyl cellulose is mixed with the resultant powders
which are then passed through a No. 12 mesh B.S.S. sieve.
The granules produced are dried at 50-60C. and then passed
through a No. 16 mesh B.S.S. sieve. The alginic acid,
magnesium stearate and talc, previously passed through a
No. 60 mesh B.S.S. sieve, are added to the granules, mixed
and compressed in a tabletting machine to yield tables each
weighing 175 mg.
Exam~le 44
` 20
Capsules each containing 200 mg of medicament are
, . ~ .
made as follows:-
Medicament 200 mg
Lactose 48 mg
Magnesium stearate 2 mg
The medicament, lactose and magnesium stearate are
` passed through a No. 44 mesh B.S.S. sieve and filled into
hard gelatine capsules in 250 mg quantities.
Example 45
Injection solutions each containing 100 mg of30
medicament per 5 ml solution are made as follows:-
- 27 -
.
,
Medicament 100 mg
Sodium hydroxide (10~ solution) q.s.
Water for injection to 5 ml
The medicament is suspended in the water and the
sodium hydroxide solution added drop by drop with stirring
until the medicament is in solution. The pH of the
solution is adjusted to between 8.0 and 8.5, the solution is
sterilised by filtration through a bacteria-proof filter and
filled into previously sterilised glass ampoules which are
then hermetically sealed under aseptic conditions.
Example 46
Suppositories each containing 250 mg of medicament are
; made as follows:-
Medicament 250 mg
Theobroma Oil to 2000 mg
The medicament is passed through a No. 60 mesh B.S.S.
sieve and suspended in the theobroma oil previously melted
using the minimum of heat necessary. The mixture is then
poured into a suppository mould of nominal 2 g capacity and
allowed to cool.
,.;
,;~ ,,
'.
' '
. .
.:
`
: ',
. ~
- 28 -
