Note: Descriptions are shown in the official language in which they were submitted.
~)6~ 7
This invention relates-to 2-cyclopropanecar~oxamido- -
5-halothiazole which is useful as anti-inflammatory agents.
The co~pounds, 2-cyclopropanecarboxamido-5-halothiazole,
have the following structural formula.
X ~ ~ N~_g_cH = ~2
in which X is chloro, bromo, iodo or fluoro.
These compounds are known as herbicides as evidenced
10 by Chem. Abst. Vol. 69 106540r 1968 or by French Patent
1,499,577 of October 27, 1967 to May & Baker Ltd. and may be
~ prepared according to those teachings or to teaching of the
; following example.
Example
2-cyclo~ropanecarboxamido-5 bro ~hiazole
Br ~IH --CH2
10.4 g (10.10 m) cyclopropanecarboxylic acid chloride
was added to a stirred mixture of 16 ml (10.20 m) piperdine
20 100 ml ethylenedichloride, and 25.9 g (0.10 m) 2-amino-5-
~romothiozole hydrobromide over a period of 5 minutes with ice
bath cooling to keep the temperature under 20C. After
standing for 15 minutes, the mixture was diluted with a 100 ml ;
H2O to give a solid a~nd 2 liquid phases. This mixture was
diluted with 100 ml n-pentane and solid filtered off, washed
with ld~ ml water, and n-pentane to yield 16.5 g solid after
drying in vacuo of the desired product.
: . ,
` m.p. 211-218C. ~ ~
. ~ .. . .
- In a similar manner the chloro, iodo and fluoro
derivatives may readily he prepared employing the appropriate
reactants. -
- 2 -
; ,.~ `' '
',^?~
~6 0 7
The product of the example will hereinafter be
called Compound Number 1. The corresponding chloro compound
will hereinafter be called Compound Number 2.
Anti-Inflammatory Screenin~
The compounds of the present invention have
S pharmaceutical activity especially as anti-inflammatory
agents. Anti-inflammatory activity is demonstrated by a
test which involves the diminution of experimental edema
induced in the hind paw of the rat by ~he injection of
carrageenin.
Carrageenin injected into the foot o the rat
produces an edematous condition which simulates part of the
inflammatory process. Non-steroidal anti-inflammatory
compounds inhibit the formation of this edema.
'~
Methods and Procedures
The procedure used for measuring the inhibitio~
of carrageenin-induced edema is a standard procadure well
known in the pharmaceutical art and is as follows:
~ Male rats (Long Evans Strain) weighing between
: 130-200 grams are used in this assay. Five rats eaeh are
used in the treatment groups and in the known standard
` 20 control; whereas ten rats are used in the control edema
; group. Unless otherwise indicated, phenylbutazone is
administered orally at 100 mg/kg to the standard control
group. The edema control group is administered the vehicle
; which consists of 0.25% methylcellulose solution. All of
the rats are fasted for at least 15 hours prior to ~he test.
Water is available ad ~ibit~m. All of the experimental
i . .
- 3 -
.
.
lL06~ 7
drugs are given orally and are dissolved or suspended in
0.2570 methylcellulose solution. One hour after administra-
tion of the test compound, .05 ml of a l~/o sterile solution
of carrageenin is inJected into the plantar tissues o~ the
left hind paw of each rat. Three hours after carrageenin
administration, the paw volumes of in~ected paws are then
measured by means of a water displacemen~ apparatus. The
apparatus used is a modification of tha~ described by
Adamkiewicz et al~, Canadian Jou~nal of Biochemistry and
P~ysiology, 33 332~ 1955~ The a~ount of edema is calcu-
lated and the percent reduction of edema from control values
is determined. The mean volume of edema, based on 50 de-
terminat~ons, is 1. 25 cc with a standard deviation of 0.226 cc.
A reduction in edema greater than 25~/o of the control value
is considered significant. Based on 46 determinations,
~ phenylbutazone produced a mean inhibition of edema of 43.8%
`; with a standard deviation of 13.4%.
`~ ~e have found that the compounds of this invention
produce a significant inhibition of i~duced edema in rats
- 20 at a dose rate of 200 mg/kg.
Table I shows the reduction in edema in the hind
paw of the rat according to ~he above-described test pro-
`; cedure, at 200 mg/kg unless otherwise indicated.
:`~
TABLE I
Percent Reduction in Edema at 200 mg/kg
Compound Percent Reduction
Number o~ Induced Ed~
1 51
; 2 50
~` '
. - , : ,. ~ . .. .. .
:`
~ ~86 ~ ~
The compounds of the present invention, either
alone or in the form of pharmaceutical composition may be
administered to an animal subject in any of a number of
~orms and via any of several routes. Thus, the compounds
or compositions thereof may be orally administered in the
form of tablets, pills, capsules, or in the form of a sus-
pension. The compounds may also be administered parenterally
in ~he form of an injectable solution or suspension. The
compounds or compositions thereof may also be administered
topically, in the form of an ointment or rec ally, in the
form of a suppository.
When orally administering the compounds or compo-
sitions, use can be made of a tablet, pill or capsule
consisting entirely of the desired compound, although
ordinarily9 a composition comprîsing an effective amount
of the compound and varying amounts of one or more physio-
logically inert materials such as carriers, vehicles, binders
and the like will be used. Additionally, the compounds may
be orally administered in the form of a suspension thereof
in a suitable vehicle such as a syrup.
When parenterally administering the compounds or
compositions, use ma~ be made of a parenteral solution or
suspension of the compound in a suitable solvent or suspension
medium.
The compounds of the present invention may also
be administered rectally in the for~ of a suppository com-
prising an effective amount of the desired compound and a
suitable vehicle such as petroleum jelly.
- 5 -
.
:
~06S~
Finally, the compounds of the present invention
may be applied topically in the form of an ointment, salve,
cream or lotion comprising an effective amount of the de-
sired compound and a suitable vehicle such as petroleum
jelly, etc.
., .
,
.. . . .
- 6 -
"'', '
.
.. , . . . . . . . , . ., .. . - --
~ . . . .
.. . . . . . . . .
