Substituted hydrazino derivatives of benzisothiazole-1,1-dioxides

Compounds which have the general formula ##STR1## and those which can be obtained from them with a Vilsmeier type reagent and have the formula ##STR2## as well as salts thereof, are useful as anti-inflammatory agents.

SUMMARY OF THE INVENTION 
This invention relates to new compounds, and acid addition salts thereof, 
which have the general formula 
##STR3## 
wherein R.sub.1 and R.sub.2 each is lower alkyl or together with the 
nitrogen form a 5- or 6- membered heterocycle, 
X is hydrogen, halogen, lower alkyl lower alkoxy or nitro; and 
Y is hydrogen, lower alkoxy or halogen. 
It also relates to compounds which can be obtained from them with a 
Vilsmeier type reagent, such as that obtained from phosphorus oxychloride 
and a formamide having the formula 
##STR4## 
The compounds thus derived have the general formula 
##STR5## 
wherein X, Y, R.sub.1 and R.sub.2 have the same meaning as above, and 
R.sub.3 and R.sub.4 have the same meaning as R.sub.1 and R.sub.2. 
DETAILED DESCRIPTION 
The lower alkyl groups represented by the symbols are straight or branched 
chain aliphatic hydrocarbon radicals having up to 7 carbon atoms, for 
example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and 
the like. The C.sub.1 -C.sub.4 and especially the C.sub.1 -C.sub.3 groups 
are preferred. 
The lower alkylene radicals are straight or branched chain groups of the 
same type having 2 to 7 carbons, with those having up to 4 carbons being 
preferred. 
The lower alkoxy groups are also similar groups having up to 7 carbons like 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, etc. 
The C.sub.1 -C.sub.4 and especially C.sub.1 -C.sub.3 groups are similarly 
preferred. 
The halogens are the four common halogens, chlorine and bromine being 
preferred in that order. 
When Y is other than hydrogen, X is the same as Y. 
The amino groups 
##STR6## 
in the compounds of both formula I and formula II, wherein 
R.sub.1,R.sub.2,R.sub.3 and R.sub.4 each represents lower alkyl, include 
di-lower alkylamino groups like dimethylamino, diethylamino, 
methylethylamino, dipropylamino, dibutylamino and the like (preferably, 
but not necessarily, R.sub.1 is the same as R.sub.2 and R.sub.3 is the 
same as R.sub.4 in a given compound). R.sub.1 and R.sub.2 and/or R.sub.3 
and R.sub.4 can also join with its nitrogen to form one of the 5- or 
6-membered heterocyclic radicals pyrrolidino, morpholino, thiamorpholino, 
piperidino or N-lower alkyl piperazino, e.g., N-methylpiperazino. 
The preferred compounds of both formula I and formula II are those wherein 
X and Y are both hydrogen and R.sub.1, R.sub.2, R.sub.3 and R.sub.4 each 
is lower alkyl, preferably methyl or ethyl, especially the first. The 
lower alkylene group preferably has 2 to 6 carbons, especially 2 to 4 and 
most especially 3 carbons. 
The products of formula I are produced by reacting a 
3-halo-1,2-benzisothiazole, 1,1-dioxide having the formula 
##STR7## 
wherein Z is halogen, preferably chlorine or bromine, especially the 
first, 
with an aminoalkylhydrazine having the formula 
##STR8## 
in an inert organic solvent like tetrahydrofuran, dioxane, 
dimethylformamide, benzene, toluene or the like, at an elevated 
temperature, preferably about reflux temperature. 
The compounds of formula II are then derived from the product of this 
reaction by treating the compound of formula I with a formamide having the 
formula 
##STR9## 
and phosphorus oxychloride, forming a Vilsmeier type reagent in situ. This 
reaction occurs most conveniently at a temperature in the range of about 
10.degree. to 60.degree. C., preferably about room temperature or slightly 
below. 
The starting materials of formula III are produced from saccharin or 
substituted saccharins which have the formula 
##STR10## 
by reaction with thionyl chloride in an inert organic solvent like dioxane 
in the presence of dimethylformamide catalyst. 
The compounds of formula I and formula II form salts which are also part of 
this invention. The salts include acid-addition salts, particularly the 
non-toxic, physiologically acceptable members. The bases of formula I and 
formula II form salts by reaction with an equivalent or more of a variety 
of inorganic and organic acids providing acid addition salts including, 
for example, hydrohalides (especially hydrochloride and hydrobromide), 
sulfate, nitrate, phosphate, oxalate, tartrate, maleate, citrate, acetate, 
ascorbate, succinate, benzenesulfonate, methanesulfonate, 
cyclohexanesulfamate and toluenesulfonate. The acid addition salts 
frequently provide a convenient means for isolating the product, e.g., by 
forming and precipitating the salt (which is not necessarily nontoxic) in 
an appropriate medium in which the salt is insoluble, then after 
separation of the salt, neutralizing with a base such as barium hydroxide 
or sodium hydroxide, to obtain the free base. Other salts can then be 
formed from the free base by reaction with an equivalent or more of acid. 
The new compounds of both formula I and formula II have anti-inflammatory 
properties and are useful as anti-inflammatory agents, for example, to 
reduce local inflammatory conditions such as those of an edematous nature 
or resulting from proliferation of connective tissue in various mammalian 
species such as rats, dogs and the like when given orally or parenterally 
in dosages of about 5 to 150 mg/kg/day, preferably 10 to 75 mg/kg/day, in 
single or 2 to 4 divided doses, as indicated by the Mouse Active Arthus or 
Delayed Hypersensitivity Skin Reaction tests. The active substance may be 
utilized in compositions such as tablets, capsules, solutions or 
suspensions containing up to about 500 mg per unit of dosage of a compound 
or mixture of compounds of formula I or physiologically acceptable acid 
addition salt thereof. They may be compounded in conventional manner with 
a physiologically acceptable vehicle or carrier, excipient, binder, 
preservative, stabilizer, flavor, etc. as called for by accepted 
pharmaceutical practice.

The following examples are illustrative of the invention. They are 
representative of and serve as models for the preparation of other members 
of the class which can be synthesized by replacing each of the reactants 
with the suitably substituted analog. 
EXAMPLE 1 
3-[1-[3-(Dimethylamino)propyl]hydrazino]-1,2-benzisothiazole, 1,1-dioxide, 
hydrochloride 
(a) 100 g (545 mM) of benzisothiazole 1,1-dioxide, 100 ml. of thionyl 
chloride, 4 ml. of dimethylformamide (catalyst), 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 refluxed overnight. 
The reaction mixture is evaporated to dryness and the residue 
recrystallized from toluene to obtain 73.4 g. of 3-chloro-1, 
2-benzisothiazole-1,1-dioxide, m.p. 140.degree.-145.degree.. 
(b) 30.0 g (148 mM) of 3-chloro-1,2-benzisothiazole-1,1-dioxide is 
dissolved in 200 ml. of dry tetrahydrofuran and then added dropwise over 
15 minutes to 17.4 g (148 mM) of dimethylaminopropyl hydrazine in 1.1 of 
tetrahydrofuran. The resulting mixture is refluxed for 30 minutes. After 
cooling to room temperature, the yellow solid is filtered off, dissolved 
in 200 ml. of water, filtered, washed with chloroform, and made basic with 
10% sodium hydroxide. The resulting precipitate is filtered off, washed 
with water, and recrystallized from a mixture of 150 ml. of ethanol and 
100 ml. of water to obtain 17.5 g of free base, m.p. 
179.degree.-180.degree.. 
The free base (4.5 g.) is dissolved in 800 ml. of hot dioxane and the 
hydrochloride salt is precipitated by the addition of HCl/dioxane. The 
white solid 3-[1-[3-(dimethylamino)- 
propyl]hydrazine]-1,2-benzisothiazole, 1,1-dioxide, hydrochloride is 
collected on a filter, washed with dioxane, and dried at 80.degree. under 
vacuum; yield 9.7 g, m.p. 265.degree.-267.degree.. 
EXAMPLE 2 
3-[2-[(Dimethylamino)methylene]-1-[3-dimethylaminopropyl]-hydrazino]-1,2-be 
nzisothiazole, 1,1-dioxide 
3.25 ml. (35.5 mM) of phosphorus oxychloride is added to a solution of 10.0 
g (35.5 mM) of 3-[1-[3-(dimethyl- 
amino)propyl]hydrazino]-1,2-benzisothiazole, 1,1-dioxide in 100 ml. of 
dimethylformamide and stirred in a flask cooled by a water bath. After 
stirring for 2 hours, the solvent is evaporated and the residue taken up 
in water which is made basic with 10% sodium hydroxide, then extracted 
with chloroform. The chloroform extract is washed with water, dried 
(Na.sub.2 SO.sub.4), and evaporated. The residue, 3-[2-[(dimethyl- 
amino)methylene]-1-[3-dimethylamino)propyl]hydrazino]-1,2-benzothiazole, 
1,1-dioxide is recrystallized twice from methanol/water; yield 6.4 g, m.p. 
119.degree.-121.degree.. 
The hydrochloride is formed as in Example 1. 
The following additional compounds having the substituents in the table are 
produced according to the procedures of Example 1 by substituting for the 
3-chloro-1,2-benzisothiazole-1,1-dioxide the compound of formula III 
having the X and Y substituents in the table and substituting for the 
dimethylaminopropyl hydrazine the hydrazine of formula IV having the 
substituents in the table: 
__________________________________________________________________________ 
##STR11## 
##STR12## 
##STR13## 
Example 
X Y lower alkylene 
##STR14## 
__________________________________________________________________________ 
3 6-Cl H (CH.sub.2).sub.4 
##STR15## 
4 6-Br H (CH.sub.2).sub.3 
##STR16## 
5 6-Br H (CH.sub.2).sub.3 
##STR17## 
6 6-Cl 7-Cl (CH.sub.2).sub.3 
##STR18## 
7 8-Cl 5-Cl (CH.sub.2).sub.2 
##STR19## 
8 H H (CH.sub.2).sub.6 
##STR20## 
9 6-CH.sub.3 
H (CH.sub.2).sub.2 
##STR21## 
10 6-OCH.sub.3 
7-OCH.sub.3 
(CH.sub.2).sub.2 
##STR22## 
11 6-OCH.sub.3 
7-OCH.sub.3 
(CH.sub.2).sub.2 
##STR23## 
12 7-NO.sub.2 
H (CH.sub.2).sub.3 
##STR24## 
13 H H (CH.sub.2).sub.3 
##STR25## 
14 6-Cl H (CH.sub.2).sub.4 
##STR26## 
15 H H (CH.sub.2).sub.5 
##STR27## 
16 6-OC.sub.2 H.sub.5 
7-OC.sub.2 H.sub.5 
(CH.sub.2).sub.4 
##STR28## 
17 7-OCH.sub.3 
8-OCH.sub.3 
(CH.sub.2).sub.2 
##STR29## 
18 H H (CH.sub.2).sub.3 
##STR30## 
19 6-Cl H (CH.sub.2).sub.2 
##STR31## 
__________________________________________________________________________ 
By treating the product of Examples 3 to 19, respectively, according to the 
procedure of Example 2, substituting for the dimethyl formamide the 
formamide having the 
##STR32## 
in the table the following products of formula II are obtained: 
__________________________________________________________________________ 
##STR33## 
Example 
X Y lower alkylene 
##STR34## 
##STR35## 
__________________________________________________________________________ 
20 6-Cl H (CH.sub.2).sub.4 
##STR36## 
##STR37## 
21 6-Br H (CH.sub.2).sub.3 
##STR38## 
##STR39## 
22 6-Br H (CH.sub.2).sub.3 
##STR40## 
##STR41## 
23 6-Cl 7-Cl (CH.sub.2).sub.3 
##STR42## 
##STR43## 
24 8-Cl 5-Cl (CH.sub.2).sub.2 
##STR44## 
##STR45## 
25 H H (CH.sub.2).sub.6 
##STR46## 
##STR47## 
26 6-CH.sub.3 
H (CH.sub.2).sub.2 
##STR48## 
##STR49## 
27 6-OCH.sub.3 
7-OCH.sub.3 
(CH.sub.2).sub.2 
##STR50## 
##STR51## 
28 6-OCH.sub.3 
7-OCH.sub.3 
(CH.sub.2).sub.2 
##STR52## 
##STR53## 
29 7-NO.sub.2 
H (CH.sub.2 ).sub.3 
##STR54## 
##STR55## 
30 H H (CH.sub.2).sub.3 
##STR56## 
##STR57## 
31 6-Cl H (CH.sub.2).sub.4 
##STR58## 
##STR59## 
32 H H (CH.sub.2).sub.5 
##STR60## 
##STR61## 
33 6-OC.sub.2 H.sub.5 
7-OC.sub.2 H.sub.5 
(CH.sub.2).sub.4 
##STR62## 
##STR63## 
34 7-OCH.sub.3 
8-OCH.sub.3 
(CH.sub.2).sub.2 
##STR64## 
##STR65## 
35 H H (CH.sub.2).sub.3 
##STR66## 
##STR67## 
36 6-Cl H (CH.sub.2).sub.2 
##STR68## 
##STR69## 
__________________________________________________________________________