BENZISOTHIAZOLE-1,1-DIOXIDES

BENZISOTHIAZOLE-1,1-DIOXYDES

English Abstract

Abstract
Compounds having the formula
<IMG>
wherein R1 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro, R2 is hydrogen, halogen or lower alkoxy,
and A is -Q-COOR1, wherein Q is lower alkylene or cyclo-
lower alkyl and R is hydrogen or lower alkyl, or A is
-(CH2)n-R3 wherein R3 is imidazol-4-yl or indol-3-yl
and n is 1,2,3 or 4, are useful as anti-inflammatory
agents.

Claims

QA143/154
The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:-
1. A process for preparing compounds having
the formula
<IMG>
wherein R1 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro; R2 is hydrogen, halogen or lower
alkoxy, with the proviso that if R2 is other than
hydrogen, R1 and R2 are the same; A is (i)-Q-COOR,
wherein Q is lower alkylene or cyclo-lower alkyl,
and R is hydrogen or lower alkyl, or (ii)-(CH2)n-R3,
wherein R3 is
<IMG> ,
wherein R4 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro, or
<IMG> ;
and n is 1,2,3 or 4, and pharmaceutically acceptable
salts thereof, which comprises, when A is to be -Q-COOR,
reacting a compound of the formula

QA143/154
<IMG>
wherein Z is halogen, and R1 and R2 are defined as
hereinabove, with an aminoalkanoic acid ester having
the formula
H2N-Q-COOR
wherein Q and R are defined as hereinabove; and
optionally, converting the resulting ester to the
free acid by hydrolysis; and when A is to be
-(CH2)n-R3, reacting a compound of the formula
<IMG>
wherein Z is halogen and R1 and R2 are defined as
hereinabove, with a primary amine having the formula
H2N-(CH2)n-R3
wherein R3 and n are defined as hereinabove.
2. A process for preparing compounds having the
formula
<IMG>
wherein R is hydrogen or lower alkyl; Q is lower
alkylene or cyclo-lower alkyl; R1 is hydrogen, halogen,

QA143/154
17
lower alkyl, lower alkoxy or nitro; R2 is hydrogen,
halogen or lower alkoxy, with the proviso -that if R2
is other than hydrogen, R1 and R2 are the same; and
pharmaceutically acceptable salts thereof, which
comprises reacting a compound of the formula
<IMG>
wherein Z is halogen and R1 and R2 are defined as
hereinabove, with an aminoalkanoic acid ester having
the formula
H2N-Q-COOR
wherein Q and R are defined as hereinabove, and
optionally, converting the resulting ester to the
free acid by hydrolysis.
3. A process for preparing compounds having
the formula
<IMG>
wherein R1 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro; R2 is hydrogen, halogen or lower
alkoxy, with the proviso that if R2 is other than
hydrogen, R1 and R2 are the same; R3 is (i)

QA143/154
18
<IMG>
wherein R4 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro, or
(ii)
; n is 1,2,3 or 4; and
<IMG>
pharmaceutically acceptable salts thereof, which
comprises reacting a compound of the formula
<IMG>
wherein Z is halogen and R1 and R2 are defined as
hereinabove, with a primary amine having the formula
H2N-(CH2)n-R3
wherein R3 and n are defined as hereinabove.
4. A process as in claim 2 wherein R1 and R2
are both hydrogen.
5. A process as in claim 2 wherein R1 and R2
are both hydrogen; R is hydrogen or lower alkyl; and
Q is lower alkylene.
6. A process as in claim 2 wherein R1 and R2
are hydrogen, Q is lower alkylene and R is ethyl.

QA143/15A
19
7. A process as in claim 2 wherein R is ethyl
and Q is (CH2)3 and R1 and R2 are hydrogen.
8. A process as in claim 2 wherein R is ethyl
and Q is CH2 and R1 and R2 are hydrogen.
9. A process as in claim 2 wherein R is hydrogen
and Q is CH2 and R1 and R2 are hydrogen.
10. A process as in claim 2 wherein R is
hydrogen and Q is (CH2)3 and R1 and R2 are hydrogen.
11. A process as in claim 2 wherein R2 is
hydrogen.
12. A process in accordance with claim 3 wherein
R3 is
<IMG>
13. A process in accordance with claim 3 wherein
R3 is
<IMG>
14. The process in accordance with claim 3
wherein Rl and R2 are hydrogen, n is two and R3 is
<IMG>
and R4 is hydrogen.
15. The process in accordance with claim 3
wherein R1 and R2 is hydrogen, n is two and R3 is

QA143/154
<IMG>
16. A compound of the formula
<IMG>
wherein R1 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro; R2 is hydrogen, halogen or lower
alkoxy, with the proviso that if R2 is other than
hydrogen, R1 and R2 are the same; A is (i)-Q-COOR,
wherein Q is lower alkylene or cyclo-lower alkyl, and
R is hydrogen or lower alkyl, or (ii)-(CH2)n-R3,
wherein R3 is
<IMG>
wherein R4 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro, or
<IMG>
and n is 1,2,3 or 4, and pharmaceutically acceptable
salts thereof when prepared by the process of claim 1.

QA143/154
17. A compound of the formula
<IMG>
wherein R is hydrogen or lower alkyl; Q is lower
alkylene or cyclo-lower alkyl; R1 is hydrogen,
halogen, lower alkyl, lower alkoxy or nitro; R2
is hydrogen, lower alkoxy or halogen with the proviso
that if R2 is other than hydrogen, R1 and R2 are
the same; and pharmaceutically acceptable salts
thereof when prepared by the process of claim 2.
18. A compound having the formula
<IMG>
wherein R1 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro and R2 is hydrogen, halogen or lower
alkoxy, with the proviso that if R2 is other than
hydrogen, R1 and R2 are the same; R3 is (i)
<IMG>
wherein R4 is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro or (ii) ; n is 1,2,3 or 4,
<IMG>

QA143/154
22
and pharmaceutically acceptable salts thereof when
prepared by the process of claim 3.
19. A compound as in claim 17 wherein R1 and R2
are both hydrogen when prepared by the process of claim
4.
20. A compound as in claim 17 wherein R1 and R2
are both hydrogen; R is hydrogen or lower alkyl; and
Q is lower alkylene when prepared by the process of
claim 5.
21. A compound as in claim 17 wherein R1 and R2
are hydrogen, Q is lower alkylene and R is ethyl when
prepared by the process of claim 6.
22. A compound as in claim 17 wherein R is ethyl
and Q is (CH2)3, R1 and R2 are hydrogen when prepared
by the process of claim 7.
23. A compound as in claim 17 wherein R is ethyl
and Q is CH2; R1 and R2 are hydrogen when prepared
by the process of claim 8.
24. A compound as in claim 17 wherein R is
hydrogen and Q is CH2, R1 and R2 are hydrogen when
prepared by the process of claim 9.
25. A compound as in claim 17 wherein R is
hydrogen and Q is (CH2)3, R1 and R2 are hydrogen when
prepared by the process of claim 10.
26. A compound as in claim 17 wherein R2 is
hydrogen when prepared by the process of claim 11.
27. A compound in accordance with claim 18
wherein R3 is
<IMG>
when prepared by the process of claim 12.

QA143/154
23
28. A compound in accordance with claim 18
wherein R3 is
<IMG>
when prepared by the process of claim 13.
29. The compound in accordance with claim 18
having the name N-[2-(1H-indol-3-yl)ethyl]-1,2-
benzisothiazol-3-amine, 1,1-dioxide when prepared
by the process of claim 14.
30. The compound in accordance with claim 11
having the name N-[2-(1H-imidazol-4-yl)ethyl]-1,2-
benzisothiazol-3-amine, 1,1-dioxide and its hydro-
chloride salt when prepared by the process of claim
15 .

Description

Qal43/154
Benzoisothiaxole-.l,l-Dioxides
Compounds having the formula
NH-A
~S/
R2 / 2
and the pharmaceutically acceptable salts thereof,
have antiinflammatory activity. In formula I, and
throughout the specification, the symbols are as
defined below.
Rl is hydrogen, halogen, lower alkyl, lower
alkoxy or nitro and R2 is hydrogen, halogen or lower
alkoxy, with the proviso that if R2 is other than
hydrog~n, Rl and R2 are the same;
A is (i)~Q-COOR, wherein Q is lower alkylene
or cyclo-lower alkyl, and R is hydrogen or lower
alkyl, or ~ii)-(CH2)n-R3, wherein
R3 is H
~ R4, wherein R4 is
hydrogen, halogen, lower alkyl, lower alkoxy or nitro,
or
~N ~
NH; and n is 1,2,3 or 4(2 and 3 are preferred).

5~:~
QAl43/154
The lower alkyl groups represented by the symbols
are straight or branched chain al:iphatic hydrocarbon
radicals having up to 7 carbon atoms~ for example,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-
butyl and the like. The lower alkylene radicals are
straight and branched chain radicals of the same type.
The Cl-C4 and especially the Cl-C3 groups are pre-
ferred.
The lower alkoxy groups are also similar groups
having up to 7 carbons like methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, t-butoxy, etc~ The
Cl-C4 and especially Cl-C3 groups are similarly
preferred.
The cycloalkyl groups are the 3 to 7 carbon ali-
cyclics cyclopropyl, cyclobutyl, cyclohexyl and cyclo-
heptyl, the cyclopentyl and cyclohexyl (especially
cyclohexyl) groups being preferred.
The halogens are the four common halogens, chlorine
and bromine being preferred in that order.
The products of formula I wherein ~ is -Q-COOR
are produced by reacting a 3-halo-1,2-benzisothiazole,
l,l-dioxide having the formula
(II) R Z
~o\ r ~ N
R S~2
wherein Z is halogen, preferably chlorine or bromine,
especially chlorine, with an aminoalkanoic acid ester
having the formula
(III)
H N-Q-COOR
wherein R is lower alkyl

~753~
QA143/154
in an inert organic solvent like dioxane, benzene, di-
methyIformamide~ dimethoxyethane, or the like in the
optional presence oE a basic acid acceptor, e.g.,
potassium carbonate, sodium carbona~e, a trialkylamine
like triethylamine or pyridine, or the like, pre-
ferably at an elevated temperature, e.g., at reflux
temperature.
The resulting ester can then be converted to the
free acid (R=H) by a conventional technique such as
hydrolysis with dilute hydrochloric acid.
The compounds of formula I wherein A is -(CH2)n-
R3 can be prepared by reacting a 3-halo-1,2-benzisothia-
zole, l,l-dioxide having the formula
II z
1~ ~ ~ N
2
wherein Z is halogen (chloride being the most preferred)
with a primary amine having the formula
IV
2 ( 2)n 3
The reaction can be run in an organic solvent, e.g.,
dioxane, benzene, dimethylformamide, dimethoxyethane
or the like.

7533
QA143/154
The s-tartin~ materials of forrnula IIIand IV are
known in -the art. Some of the skartiny materials
are commercially availahle and all of thern are
readily obtainable via conventional synthetic
routes.
The 3-halo-1,2-benzisothiazole, 1,1-
dioxides of formula II are also known in the
art; see, for example, United States patent
3,225,056, i.ssued December 12, 1965. They can
be prepared from the corresponding saccharin com-
pound having the formula
IV
o
15 ~1 ~o\
by reaction with thionyl chloride in an inert organic
solvent, prefera~ly with a catalytic amount of dimeth~lformamide.
The pharmaceutically acceptahle salts
of the compounds of formula I can be prepared
from the corresponding free base using procedures
well known in the art. Acid-addition salts
are specifically contemplated, e.g., the
hydrohalides (particularly the hydrochloride
and hydrobromide), sulfate, nitrate, phosphate,
tartrate, maleate, fumarate, citrate,
succinate, methanesulfonate, benzenesulfonate,
toluenesulfonate and the like.

i3~
Q~143/154
The compounds of forrnula I, and the
pharmaceutically acceptable salts thereof, can
be used to treat inflamma-tion in mammals. Joint
tenderness and stiffness (in conditions such
as rheumatoid arthritis) can be reduced by
these compounds.
The compounds of this invention can be
formulated for use as antiinflammatory agents
according to accepted pharmaceutical practice
in oral dosage forms such as tahlets, capsules,
elixirs or powders, or in an in~ectable form
in a sterile aqueous vehicle. The compounds
of this invention can be administered in
amounts of lO0 milligrams per kilogram of
animal body weight per day to 2 grams per
kilogram of animal body weight per day,
preferably lO0 milligrams per kilogram of
animal body weight per day to l gram per
kilogram of animal body weight per day.
The following examples are specific
embodiments of this invention.

7~33
QA143/154
Example 1
4 ~(1,1-Dioxo-1,2-benzl othiazol~3-yl)arnino]butanoic acid,
ethyl ester
a) 100 g. (545 mM) of henzisothiazole 1,1-
dioxidel 100 ml. thionyl chloride, 4 ml. of dimethyl-
formamidel and 400 ml of dioxane are refluxed overnight.
Thionyl chloride (50 ml.) and dimethylformamide (1 ml.)
are added to the reaction mixture which is again re~
fluxed overnight. l'he reaction mixture is evaporated
to dryness and the residue recrystallized from toluene
to obtain 73.4 g. of 3-chloro-1,2-benzisothiazole-1,
l-dioxide, m.p. 140-145 .
b) 4 07 ml (29.2mM) of triethylamine is added
to 5.0 g. (29.2mM) of ethyl 4-aminobutyrate hydro-
chloride, suspended in 75 ml of dioxane. Afterstirring for 5 minutes, 5.88 g. (29.2 mM) of 3-chloro-
1l2-benzisothiazole lll-dioxide is added and the mi~ture
is refluxed for one hour. The solvent is evaporated
in vacuo and the residue is taken up in chloroform,
washed with water, and evaporated to dryness. The
residual 4-[(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]-
butanoic acid, ethyl ester is recrystallized from 40
ml. of methanol/water, yield 3.72 g., m.p. 125-127 .
Example 2
2-[(1,1-Dioxo-1,2-benzisothiazol-3-yl)amino]acetic
acid, ethyl ester
15.0 g. (74.4 mM) of 3-chloro-1,2-benzisothiazole
l,l-dioxide (prepared as in Example 1) 10.4 g. (74O4 mM)
of glycine ethyl ester, hydrochloride and 20.4 ml.
(148.8 mM) of triethylamine are refluxed in 250 ml of
dioxane for 2 hours. The dioxane is evaporated and the

~L75~3
QA143/154
residue lS taken up in chloroform which is washed with
water (2 x) and ev~porated. The residue 2-[(1,1-
dioxo-1,2-benzisothiazol-3-yl)amino~ace~ic acid, ethyl
ester is recrystallized once from 150 ml of methanol/
water (1:1) and once frorn 200 ml. of water to give 2-
~(l,l-dioxo-1,2-benzisothiazol-3-yl)amino]acetic acid,
ethyl ester as yellow needles, yield 14.35 g., m.p.
166-167 .
~
2-[(1,1-Dioxo-1,2~benzisothiazol-3-yl)amino]acetic acid
8.8 g. (32.8 mM) of 2-[((1,1-dioxo-1,2-benzisothia-
zol-3-yl)amino)acetic acid, ethyl ester ~prepared as
in Example 2) is refluxed in 100 ml of lX hydrochloric
acid for 3 hours. After standing overnight at room
temperature, the product crystallizes as white plates
and is filtered out, washed with water and recrystallized
from 150 ml water to yield 6.4 g. of 2-[(1,1-dioxo-1,
2-benzisothiazol~3-yl)amino]acetic acid: m.p. 259-
260 . 3 g. of this product is added to an aqueous
sodium hydroxide solution containing one equivalent
of base and warmed to obtain a homogenous solution.
The sodium salt is ob~ained by lyophilization of the
resulting solution.
2S
Example 4
4-[(1,1-Dioxo-1,2-benzisothiazol-3-yl)amino]butanoic
acid
5.68 g. (28.1 mM) of 3-chloro-1,2-benzisothiazole,
l,l-dioxide (prepared as in ExampLe 1) 4.8 g. (28.1 mM
of ethyl-4-aminobutyrate hydrochloride and 7.84 ml.

53~
QA143/154
(56.2 mM) of triethylamine are refluxed in 100 ml. of
dioxane for one hour. The solvent is evaporated and
the residue refluxed in 1~ hydrochloric acid for 2 . 5
hours. The product crystallizes out overniyht at
room temperature. The product, 4-[(1,1-dioxo-1,2-
benzisothiazol-3 yl)amino]butanoic acid is iltered
out, washed with water, and recrystallized from 150
ml. water, yield 4.2 g., m.p. 200-202 .
Example 5
4-[(5-Chloro-1 t l-dioxo-l, 2-benzisothiaæole-3-yl)amino]
cyclohexanecarboxylic acid ethyl ester
By substituting 4-aminocyclohexane carboxylic
acid ethyl ester for the ethyl-4-aminobutyrate hydro-
chloride in the procedure of Example 1, and 3.5-di-
chloro-1,2-benzisothiazole, l,l-dioxide for the 3-
chloro-1,2-benzisothiazole, l,l-dioxide, 4-[(5-chloro-1,
l-dioxo-1,2-benzisothiazol-3-yl)amino]cyclohexane-
carboxylic acid, ethyl ester is obtained.
The following additional esters are produced
by the proceudre of Example 1 by replacing the 3-chloro-
1,2-benzisothiazole, l,l-dioxide, with its X and/or
Y substituted analog and/or replacing the ethyl 4-
aminobutyrate with the analogous aminoalkanoic acid
lower alkyl ester. The acids are obtained by hydro-
lyzing the ester as in Example 3.
HN Q-- COOR
~ ~ /N
~ ~ 2

l7~i3;~
0~143/1~4
I~.x~m~)lc~ X '~ Q R
6 6-Cl H -(CH2)4- C3H7
1 6-Br H -(C~2)3- C4 9
8 6-Br H -(CH2)3- H
9 6-Cl 7-Cl -(CH2)3- 2 5
8-Cl 5-Cl -(CH2)2- 2 5
ll H H -(CH2)6- 7 15
12 6-CH3 H -(CH2)2- H
13 6-OCH3 7-OCH3 -CH2- C2H5
14 6-OCH3 7-OCH3 -CH2~ H
6-N02 H -(CH2)2- C2H5
16 H H ~ 'C2H5
17 6-Cl H ~ -C2H5
18 H H ~ - H
19 6-OC2H5 7-oc2H5-(CH2)5 2 5
7-OCH3 8-OCH3-(CH2)2 C2H5
21 5-F H -(CH2)3- -CH3

3~
QA143/154
~.
E mple 22
N-[2~ dol-3-yl)ethyl]-L,2-~enzisothiazol-3-
amine, l,l-dioxide
.
Tryptamine hydrochlorlde (10.46 g) is
converted to its free base using chloroform and aqueous
sodium hydroxide. The free base and 8.0 g. of
3-chloro-1,2-benzisothiazole, l,l-dioxide are
refluxed in 100 ml. of dioxane for 30 minutes
and then stirred for about 16 hours at room
temperature. A precipitate (tryptamine
hydrochloride) is filtered off.
The dioxane filtrate is evaporated and
the solid residue is washed as a slurry with
10% hydrochloric acid, water and 5% sodium
hydroxide, collected on a filter and washed
with water. The filter cake is dissolved ina mixture of
5 ml. of dimethylformamide-100 ml. of ethanol
and crystallized out by adding 100 ml. of
water. The material is dissolved in a hot solu
tion of2 ml dimethylformamide-300 ml ethanol
and 50 ml of water, stirred with 2 g of
charcoal for 5 minutes and filtered through
diatomaceous earth. After adding 300 ml
of water to the filtrate, the product crystallizes
~5 out, is filtered off, washed with water and
dried at 70C, ln _cuo, yielding 4.25 g of the
title compound, melting point 203-205C.

~17$33 QA143/154
Il
r~ixample 23
N-[2~1H-Imlda ~ h 1 _
3-amine, l,1-dioxide and the hydrochloride salt
thereof
-
Histamine dihydrochloride (7.31 g.) is
exactly neutralized by dissolution in 79.4 ml. of lN
sodium hydroxide. The water is evaporated
under vacuum and the residue is stirred in
25 ml~ of dimethylformamide. 3-Chloro-1,2~
~enzisothiazole, l,1-dioxide (8.~ g), in lnn ml
of dioxane is added dropwi.se over a period of
10 minute~s at room temperature. The reaction
mixture is stirred for ln minutes and then
filtered. The solvent is removed from the
filtrate, in vacuo, and the residue is taken up
in a mixture of henzene, water and triethylamine.
After shaking for 4 hours M-[2-(lH-imidazol-4-
yl)ethyl]-1,2-benzisothiazol-3-amine, 1,1-
dioxide is filtered from the two liquid phases,
washed in a funnel with water and dried at
60C (lmm of Hg) for 4 hours, ~ielding 3.2 g
of the free base product, melting point
n-l40c .
The above free hase is dissolved in ethanolic
hydrogen chloride and the hydrochloride salt
is precipitated out by the addition of ether.
The hydrochloride salt is filtered off and
dried at 80C (lmm of Hg) for 4 hours to ~ield
1.3 g of N~[2-(lH-imidazol-4-yl)ethyl]-1,2-
benzisothiazol-3 amine, l,l-dioxide, hydro-
chloride (1:1), melting point 222-224C.

L75~
QA143/154
The oriyinal filter cake is taken up in a
mixture of benzene, water and triethylamine and
shaken for 4 hours. N-[2-lH~Imi.dazol-4-yl)ethyl]-
1,2-benzisothiazol-3-arnine, l,l-dioxide is filtered
S from the two liquid phages, washed in the funnel
with water and dried at 60 C (lmm of Hg) for 4
hours to yield 5.8 g of the free base product,
melting point 143-145 C~
_amples 24-31
Following the procedure of Example 22, but
substituting the compound listed in column I for the
free base of tryptamine hydrochloride and the
compound lis-ted in column II for 3-chloro-1,2-
benzisothiazole,l,l-dioxide, yields the compound
listed in column III.

~33
(,~A143/154
13
,~ ,_ ,_
5 ,i ~
~ O ~ I ~ r-i
1~1 ~~) N i O ~i I ~ C~
rl O ~ O I 'E;i
~r) ~rl O S ~ N ~J N O
Hi 1-~ N
H ~ rl (U
0 ~c~ r ~i
~i ~ ri
æ ~ l
'~ o H o~ i ~ ~ -i T , i Z I ~i
~o ~ , ~ I ri L ~ 1 ~ r~ b Ni
ri ~ ~ I ` O
I -~ ) I ~ a) I o a) r1 .~ ~r~
n I l i ~ ~ j ~ p ~i ~ I o
x I Ln ~ z I Lr ~ z I L~
N
N X
ri ~ri~ a
,t ~ ,~ r ~ O ,
o ~
h r-l ~ r-l~i ri ~ r~ r-i r-i
H
',~ Ll ~01 Lin rl Lin ~ rO~ .
i P ~ a) h fNd h ~ O ~ O a~
O I ~ Orl O aJ ~ o ~ ,1
C~ ~ N 0~ T 0~ ~ c
. al , ~ ~ .
' ' ~ R ~c ~ ,1~ ,~ ~L ~ ~c
Ln
l~
H ~ ri
, ~ ~ e
, 3 3. ~ ~
~ ~ q
Ln ~ Ln
~r Ln ~ I` oo
N t~ L~

~7533
QA143/154
14
~ ~,
H
~A u ~
l U H I ~ 1 N 0 I ~1
-1 N ~ r l ~ ~ --1 0
~
~ ~ rl ~a
15 '
z;l ~ æl ~ zl ~i
~ I
2 0 ,, 'I , ~, 4,
H
H ~ N
~ O
~! rl 5~ ~! ';i
'Y ~ . Y ~ ~ y ~ ,~
~A, ,~
.
a~ o ~1
~ ^. ~