Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
oo~
: This invention relates to certain new heterocyclic
compounds and in particular to certain novel 1,2-benzisoxa-
- zole derivatives which have been found to possess valuable
pharmacological activity and/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:-
.~. R
~',,' ~
. J~ ~
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, preferably
~ chlorine or bromine Cl 4 alkyl, preferably methyl, Cl-C4 2
; alkoxy, preferably methoxy, nitro, and trifluoromethyl, and R
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 ,
. 30
.,
:
. ' ~
10~'ZOO~
where R3 is Cl 4 alkyl; except that when R represents a
hydrogen atom R is not hydrogen.
Compounds in which R2 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-,
i ethyl-, n-propyl-, iso-propyl-, _-butyl, s-butyl- or _-butyl-.
; The term "carboxymethyl" as used herein means, of course,
the group -CH CO H.
A preferred cl~ss 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 Rl
- represents a halogen substituent, particularly a para halo-
substituent.
A presently preferred compound of the invention is
; ~-methyl-3-p-chlorophenyl-1,2-benzisoxazol-7-yl acetic acid.
- 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.
-. ~
~ II
HO. ~ ¦
- wherein R is hydroxy or halogen (preferably 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
'. '
-- 3 --
10~'~00~;
either or both of X and Y represent a group which is convertible
to the desired group R or R , respectively, the said group
X and/or Y is converted to the group R and/or R 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 ~nown 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 ~
O III
!hydroxylamine
lor a hydrazine
C ~ IV
- 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
lO~ZOO~
choosing appropriate reaction conditions) convertible to the
class of benzoxazoles described in Belgian Patent Specification
No. 799,7g~ or ~nited States Patent No. 3,912,748. 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.
In the case where the compound of formula VI in which
R4 is hydroxy is cyclised to the benzisoxazole, the con-
figuration of the intermedlate :~
I C ~ VI
I R
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 -
. ,
104'~0()~;
.
x ~Cl r
.
the Q group should be anti- to the hydroxyl group.
In a further aspect of this invention there is
provided a process for preparing a 5- or 6- substituted
benzoxazole of formula
- 10 N -~- ~ R2
~ 1~
R
- wherein Rl repres~nts 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
is one of the following: hydrogen, Cl 4 alkyl, carboxy Cl 4
alkyl, cyano Cl 4 alkyl, -CH(R3)-COOH, -CH2-CooR3, and
-CH(R )-CooR3, where R3 is Cl 4 alkyl; except that when Rl
represents a hydrogen atom R~ is not hydrogen, which process
comprises cylising, under acidic conditions an oxime or
hydrazone of formula
O~ ~ R
: `
- 6 -
: '' - .
~042006
` where Q is hydroxyl or an amino group.
When R4 is halogen, heating with an alkali such as
potassium hydroxi~e produces the benzisoxazole, which
` in all cases has the formu~ia :
X ~
~ VII
. ~ ' ` ~ ,~
Y
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 :
~,', ' ~\~
. I~J
Q - N = C
o \~
~` 4 /
; 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
: 30
-: may be halogenated using conventional halogenating agents
-: ~ such as chlorine, sulphuryl chloride, bromine, or N-bromo-
succinnimide, preferably in the presence of a suitable
-- 7 --
:'`
~0~ )6
solvent such as carbon tetrachloride, and thereafter a cyano
group substituted from the halogen atom. Hydrolysis of the
nitrile produces the corresponding carboxylic acid which may
if desired be esterified. Alternatively, the halogen atom
- can be replaced by a carboxylic acid group via an organo-
metallic compound such as a Grignard reagent. This procedure
is fully described in Standard reference books, for example
for the Grignard reaction, see page ll 72 of the ~erck Index,
VIIIth Edition, published 1968. Acids or esters 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
'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 -
.
~042~0~
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 bringing 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 ~R ) COOH it is necessary to hydrolyse a group
- of formula -CH (R ) CN.
- Alternatively, the above class of acids can be pre-
pared from derivatives of formula I where R2 is a Cl 4
~: haloalkyl group using the Grignard reaction. After reaction
. 20 with magnesium and treatment with carbon dioxide a compound
- of formula I is formed in which R 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
., `~
~',` ~ .
.` .. ~ CHR CO2H
. 30
wherein Rl is as defined previously and the -CHR CO2H group
is at the 5-, 6-, or 7- position of the benzisoxazole nucleus
_ g _
: 10~Z00~
and R5 represents hydrogen or Cl 4 alkyl, which comprises
hydrolysing a compound of formula:
.'''' lJ
:' ' ~
~ 5
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:
-,: ' -C~
~OMgX
where Xl is a halogen atom.
The novel compounds of the present invention in which
- R2 is a carboxy or esterified carboxy 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 association 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
-- 1 0 --
:' -
20Q~;
diluted by a carrier, or enclosed or encapsulated by a carrier
in the form of 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,
sorbitol, mannitol, starch, gum acacia, calcium phosphate,
liquid paraffin, 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.
-
~ Z~6
In addition to the active ingredient of formula I, the
compositions of the present invention may also 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 cou_se, be formulated in delayed or sustained release :;
form in a manner well known in the art. -`
Compounds of formula I in which R 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 is also useful
for the treatment of diseases in which excessive amounts of
prostaglandins are released. ~
~'':' :' ~ .
- 12 -
. ,
.
00~
The following examples will further illustrate the
present invention.
Example 1
4'-Chloro-5-ethyl-2-hydroxybenzophenone
Aluminium 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
lost. The remaining material was separated and the aqueous
fraction extracted twiae with chloroform (200ml.), and the
; combined organic layers evaporated to a dark oil which was
distilled in vacuo giving two main fractions: s (17.4g)
150-160C @ 0.3mm~g, C (110.8g) 160-168C ~ 0.3mmHg.
Both remained liquid on cooling.
Microanalysis : C15H13C1O2 requires 69.1%C, 5.0%H, 13.6%Cl;
found 69.0%C, 5.0%H, 13.9%Cl
Example 2
; 5-Ethyl-2-(4-chlorophenyl)benzoxazole
To a solution of hydrazine (0.7g) and water (0.36ml)
was added a solution of 4'-chloro-5-ethyl-2-hydroxybenzophenone
(2.6g) in ethanol (4ml). The solution was refluxed for 1.5
hours then evaporated to dryness to give the crude hydrazone
22.5
as an oil. ~ 1.6245. A portion of this oil (0.27g)
was added to a solution of 90% sulphuric acid (1.25ml) and
sodium nitrite (O.lg) with cooling and stirring at a tempera-
ture below 15C. There was effervescence and stirring was
- 30 continued below 15C until this subsided (r_30 mins). The
mixture was added to ice/ammonium hydroxide and extracted with
chloroform. T.L.C. showed that 5-ethyl-~-(4-chlorophenyl)
~ benzoxazole had been produced.
;'
- 13 -
~,09~ 00~;
ample 3
(a) 2-(p-Chlorophenyl)-5-ethyl benzoxazole
, .
Polyphosphoric acid (wt. per mil. 2.1 g) (495g), was
warmed to 85C on the steam bath and 4'-chloro-5-ethyl-2-
hydroxybenzophenone oxime (25g, 0.09 mole) added in portions
with stirring (temperature rose to 102C). The reaction was
stirred on a steam bath for 30 minutes. The mixture was
poured into water (500ml) and stirred and cooled for 30
minutes. The solid was filtered (and some larger lumps of
solid broken up) and washed with water (200 ml). The solid
was dried to give 24g. of crude product. This was
recrystallised, with carbon treatment, from ethanol (250ml) ; -~
to give a white solid (17.14g, 74%) m.p. 111C, which was
the title compound.
GLC purity 99%. Material checked by NMR, GLC and T.L.C.
Similarly prepared and characterised by NMR and T. L. C. were
.
~- (b) 2-(_-fluorophenyl)-5-ethyl benzoxazole;
~ (c) 2-(2,4-dichlorophenyl)-5-ethyl benzoxazole; and
!,: (d) 2-(p-chlorophenyl)-6-ethyl benzoxazole
- 20 Example 4
(a) 2-p-Chlorophenyl-5t~-bromoethyl benzoxazole
The oxazole of Example 3 (a) (200g, 0.776 mole) was
stirred in carbon tetrachloride (2400ml), N-bromosuccinimide
(152g, 0.854 mole) was added and the stirred mixture brought
to the boil. The U.V. lamp (Hanovia type MPC, 125 watts,
mounted outside the pyrex reaction vessel) was switched on.
The progress of the reaction was monitored by gas chromato-
graphy and by this criterion was complete in six hours. The
solution was allowed to cool overnight and then filtered to
remove succinimide and the filtrate evaporated almost to
dryness and then stirred with n-hexane (0.5-1 litre), filtered
washed with hexane (1/4 to 1/2 litre) and dried at 40~C/high
- 14 -
' '~' `
: ' .
,. . . . . . . . . .
104200~
:
vacuum to give the ~-bromo compound (240.2g, 92%) m.p. 110-
- 112C (softening slightly at 107C) NMR was in accordance
with the expected structure.
Similarly prepared and characterised by NMR were :
(b) 2-(_-fluorophenyl)-5-~-bromoethyl benzoxazole;
(c) 2-(2,4-dichlorophenyl)5-~-bromoethyl benzoxazole;
and
(d) 2-(p-chlorophenyl)-6-~-bromoethyl benzoxazole
Example 5
(a) 2-(2-p-chlorophenyl-5-benzoxazolyl)propionitrile
The ~-bromo compound of Example 4(a) (166.4g, 0.49
mole) was stirred in dimethyl formamide (1584 ml, containing
0.32~ H2O dried by distillation over anhydrous K2CO3) until
; it dissolved, then treated with powdered fused sodium iodide
; (7.4g, 0.049 mole) and partially powdered sodium cyanide
(24.44g, 0.49 mole) with cooling to maintain the temperature
at 15 - 20C. The solution was left overnight and then - -
- evaporated almost to dryness, treated with water, filtered,
washed with water (approximately 5-7 litres) until the
washings gave only a faint trubidity with AgNO3 solution.
Drying at 50C/high vacuum was then carried out to give the
title compound in high yield (m.p. 142C).
Similarly prepared were :
(b) 2-(2-_-fluorophenyl-5-benzoxazolyl)propionitrile;
(c) 2-[2-(2,4-dichlorophenyl)-5-benzoxazolyl]pro-
pionitrile; and
(d) 2-(2-_-chlorophenyl-6-benzoxazolyl) propionitrile.
Example 6
- (a) 2-(2-P-Chlorophenyl-5-benzoxazolyl) propionic acid
The nitrile of Example 6 (a) (139.lg, 0.49 mole) was
stirred and heated to 80 + 5C in concentrated hydrochloric
- 15 -
.
- ~ .. .,j .
10~Z0~6
acid (1390ml). The mixture (which became a solution) was
stirred and heated at this temperature for two hours. It
was then poured into water (approximately 7 litres) and the
mixture cooled in ice to approximately 10C. The initial ~-
precipitate which formed was filtered and washed with water, ~ -
then dried to constant weight at 45C/high vacuum. The ,~-
product was the title compound in crude form (m.p. 165-171C).
After recrystallisation from butyl acetate there was obtained
pure 2-(2-p-chlorophenyl-5-benzoxazolyl)propionic acid (m.p.
190C). Similarly prepared ~rom the nitriles of Examples - ;
46(b) and (c) were :
(b) 2-(2-_-fluorophenyl-5-benzoxazolyl)propionic
acid (m.p. 163C);
(c) 2-[2-(2,4-dichlorophenyl)-5-benzoxazolyl] pro- ,~
pionic acid (m.p. 152C); and
(d) 2-(2-_-chlorophenyl-6-benzoxazolyl)propionic
acid (m.p. 196C).
' ~
~ 20 ~
~- .
",, ~.:
. .
... .
;' .' :
::
;~ :
: .
: ' .. i.,
,: ::
- 16 -
,
