Anti-inflammatory agents and antiasthmatic agents

N-(1,3-dithiolan-2-ylidene)-4-alkylanilines are useful as anti-inflammatory agents, as analgesic agents and as antiasthmatic agents. The compounds involved can be prepared by the reaction of an appropriate 4-alkylaniline with a methyl(1,3-dithiolan-2-ylidene)sulfonium salt or with carbon disulfide and ethylene dibromide in the presence of a base.

N-(1,3-dithiolan-2-ylidene)aniline and some closely related compounds have 
been described in the literature for various purposes but there has been 
no indication of pharmacological activity. U.S. Pat. No. 4,131,683 
describes 1,3-dithiolan-2-ylideneamino substituted phenylactic acids and 
describes their utility for a number of purposes, including their use as 
anti-inflammatory agents. It has now been found, surprisingly, that the 
carboxylic acid function is not necessary for anti-inflammatory activity 
in such compounds and simple alkylphenyl compounds are active 
anti-inflammatory agents. Such compounds are also useful as antiasthmatic 
agents and analgesic agents. 
Thus, the present invention is directed to methods of treatment using 
certain N-(1,3-dithiolan-2-ylidene)anilines which have the following 
structural formula 
##STR1## 
wherein R is a straight or branched-chain alkyl of 1-10 carbon atoms or 
cycloalkyl of 5-7 carbon atoms; and the pharmaceutically acceptable acid 
addition salts of those compounds. 
Examples of the alkyl groups referred to above are propyl, isopropyl, 
butyl, isobutyl, hexyl, octyl, and decyl. The examples of the cycloalkyl 
groups are cyclopentyl, cyclohexyl and cycloheptyl. 
The pharmaceutically acceptable acid addition salts are equivalent to the 
aforesaid amines for the purposes of this invention. Illustrative of such 
salts are salts with inorganic acids such as, for example, hydrochloric, 
hydrobromic, sulfuric, phosphoric and like acids; with organic carboxylic 
acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, 
malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, 
hydroxymaleic and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 
4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 
2-phenoxybenzoic, 2-acetoxybenzoic, mandelic and like acids; and with 
organic sulfonic acids such as methanesulfonic acid and 4-toluenesulfonic 
acid. 
With regard to the methods of treatment of the present invention, the 
compounds as described in the structural formula above are useful as 
antiasthmatic agents and analgesic agents. Those compounds wherein R is 
alkyl of 3-10 carbon atoms are particularly preferred for use as 
anti-inflammatory agents. The compounds wherein R is alkyl of 6-10 carbon 
atoms are further especially preferred as anti-inflammatory agents. As 
anti-inflammatory agents, the above compounds are useful in the treatment 
of painful inflammation conditions such as rheumatoid arthritis or 
osteoarthritis or also dental, post-operative and trauma-induced pain. The 
compounds are also useful in the treatment of dysmenorrhea. 
As examples of compounds useful in the present invention are the following: 
N-(1,3-dithiolan-2-ylidene)-4-pentylaniline. 
N-(1,3-dithiolan-2-ylidene)-4-heptylaniline. 
N-(1,3-dithiolan-2-ylidene)-4-decylaniline. 
N-(1,3-dithiolan-2-ylidene)-4-isobutylaniline. 
N-(1,3-dithiolan-2-ylidene)-4-(1-methylpropyl)aniline. 
N-(1,3-dithiolan-2-ylidene)-4-(2-methylhexyl)aniline. 
4-Cyclopentyl-N-(1,3-dithiolan-2-ylidene)aniline. 
4-Cycloheptyl-N-(1,3-dithiolan-2-ylidene)aniline. 
The compounds used in the present invention are conveniently obtained by 
the reaction of methyl(1,3-dithiolan-2-ylidene)sulfonium iodide with a 
4-alkylaniline of the formula 
##STR2## 
wherein R is defined as above. The reaction is carried out at room 
temperature in the presence of a tertiary amine such as triethylamine and 
using an inert solvent such as dimethylformamide. 
Alternatively, the alkylaniline referred to above can be reacted with 
carbon disulfide and an alkali metal base such as potassium carbonate to 
give the corresponding alkali metal dithiocarbamate which is then reacted 
with ethylene dibromide to give the desired dithiolane. Actually, the 
dithiocarbamate is not isolated from the reaction mixture but it is simply 
further reacted with the ethylene dibromide. The entire reaction is 
carried out in an inert solvent such as dimethylformamide. 
The procedure described above will ordinarily give the product as the free 
base and this can be converted to the corresponding salt by standard 
procedures. 
The activity of the compounds as anti-inflammatory agents was determined by 
the following procedure. Groups of male Sprague-Dawley rats were starved 
overnight before dosing with the test compounds. One (1) hour after 
dosing, 0.05 ml of 1% carrageenan was injected into the left-hind paw and 
swelling was measured three (3) hours later. Animals were then autopsied 
and the stomaches were examined for the presence of ulcers. The compounds 
above wherein R is alkyl of 3-10 carbon atoms were found to be active in 
this test and, surprisingly, the animals showed little or no stomach 
ulceration. 
Anti-inflammatory activity was further demonstrated by the adjuvant 
arthritis test in the rat. Arthritis was induced by injection of 
heat-killed Mycobacterium turberculosis into the tail of Sprague-Dawley 
rats. When the disease had fully developed fifteen (15) days later, the 
animals were weighed, the hind-paw volumes determined and dosing 
commenced. After eight (8) daily doses of test compound, the measurements 
were repeated and the changes in the parameters over the dosing period 
were recorded. The procedure involved is a demonstration of 
anti-inflammatory activity on prolonged dosing and those compounds wherein 
R is alkyl of 6-10 carbon atoms are particularly active in this test. 
Analgesic activity for the present compounds was demonstrated by the acetic 
acid writhing test. The method was a modification of the procedure of 
Whittle [Brit. J. Pharmacol., 22, 246 (1964)]. Groups of 5 to 10 mice were 
administered one or more doses of test compound by the route desired 
(except intraperitoneal). At a selected time thereafter, acetic acid (0.4 
ml of a 0.25% v/v solution) was administered intraperitoneally to the 
mice. Starting 5 minutes later, the animals were observed for a period of 
15 minutes for the appearance of abdominal writhing and the number of 
squirms for each mouse was counted. Analgesia was considered significant 
in those mice which did not squirm during the 15 minute observation 
period. To determine the ED.sub.50, 4 or more doses were tested in groups 
of 10 mice. The compounds of the present invention were active when tested 
by the above procedure. 
Utility of the present compounds as antiasthmatic agents was demonstrated 
by their inhibition of SRS biosynthesis. Specifically, rat peritoneal 
cells were incubated at 37.degree. C. in Hanks' balanced-salt solution 
containing indomethacin (1/.mu./ml) and various concentrations of test 
compounds for thirty (30) minutes before adding calcium ionophore. After a 
further fifteen (15) minutes of incubation, the reaction was stopped, and 
the SRS was extracted and bioassayed. The indomethacin was present during 
the incubation to block formation of prostaglandins which could interfere 
with the bioassay. When tested by the above procedure, all of the 
compounds of the present invention were found to be active. 
The anti-inflammatory, analgesic and antiasthmatic agents of this invention 
can be administered by any means that produces contact of the active agent 
with the agent's site of action in the body of a mammal. They can be 
administered by any conventional means available for use in conjunction 
with pharmaceuticals, either as individual therapeutic agents or in a 
combination of therapeutic agents. They can be administered alone, but are 
generally administered with a pharmaceutical carrier selected on the basis 
of the chosen route of administration and standard pharmaceutical 
practice. 
The compositions used may be in the form of tablets, capsules, dragees, 
gelules, granules, suppositories, injectable solutions or suspensions, 
pomades, creams, gels and aerosol prepartions formed in the usual fashion. 
Examples of suitable excipients are talc, gum arabic, lactose, starch, 
magnesium stearate, cacao butter, aqueous and non-aqueous vehicles, fatty 
bodies of animal or vegetable origin, paraffinic derivatives, glycols, 
diverse wetting agents, dispersants and emulsifiers and preservatives. 
The novel methods of the invention for treating inflammation, pain and 
asthma in mammals comprise administering to warm-blooded animals an 
effective amount of at least one compound of the invention. The dosage 
administered will, of course, vary depending upon known factors such as 
the pharmacodynamic characteristics of the particular agent, and its mode 
and route of administration; age, health and weight of the recipient; 
nature and extent of the symptoms, kind of concurrent treatment, frequency 
of treatment, and the effect desired. Usually, for anti-inflammatory 
purposes, a daily dosage of active ingredient can be about 0.5 to 500 
milligrams and preferably 5 to 100 milligrams per kilogram of body weight 
per day in the adult by the oral route. The active ingredient can be given 
in a single daily dose, in divided doses 2 to 4 times a day, or in 
sustained release form to obtain the desired results. 
The compositions of specific illustrative dosage units for pharmaceutical 
formulations which may be employed in practicing the present invention are 
given below. Standard procedures are used in the preparation of the 
individual formulations. Similar formulations can also be prepared using 
appropriate quantities of the active ingredients or other active 
ingredients. 
______________________________________ 
Amount 
______________________________________ 
Capsule 
(a) N--(1,3-dithiolan-2-ylidene)-4- 
100 mg 
hexylaniline dihydrogen sulfate 
(b) microcrystalline cellulose 
30 mg 
(c) magnesium stearate 2 mg 
Tablet 
(a) N--(1,3-dithiolan-2-ylidene)-4- 
100 mg 
hexylaniline dihydrogen sulfate 
(b) microcrystalline cellulose 
30 mg 
(c) starch glycolate sodium 
4 mg 
(d) polyvinylpyrrolidone 5 mg 
(e) magnesium stearate 2 mg 
Suppository 
(a) N--(1,3-dithiolan-2-ylidene)-4- 
50 mg 
hexylaniline dihydrogen sulfate 
(b) Polyethylene glycol 1000 
1350 mg 
(c) Polyethylene glycol 4000 
450 mg 
______________________________________ 
The polyethylene glycols are melted and mixed, the active ingredient is 
then suspended and the resultant mixture is then molded to give 
appropriate dosage units. 
The following examples are set forth to illustrate the preparation of 
compounds employed in the present invention but should not be construed as 
limiting it in any way.

EXAMPLE 1 
A solution was prepared from 2.83 g of 4-hexylaniline and 100 ml of 
dimethylformamide and 4 g of triethylamine was added. Then, all at once, 
4.9 g of methyl(1,3-dithiolan-2-ylidene)sulfonium iodide was added. This 
dissolved slowly to give a pale-yellow solution which was allowed to stir 
at room temperature under argon for 1 hour. It was then poured into an 
equal volume of water and extracted 3 times with diethyl ether. The 
combined ether extracts were washed with 0.2 N hydrochloric acid until 
thin-layer chromatography showed that residual 4-hexylaniline had been 
removed. The ether solution was then washed once with aqueous saturated 
sodium bicarbonate solution, 3 times with water, and once with saturated 
aqueous sodium chloride solution and then dried over anhydrous magnesium 
sulfate. The solution was then filtered and the solvent was evaporated 
under reduced pressure. Methylene chloride was added to the residue and 
evaporation was repeated to leave a crude yellow oil. The product thus 
obtained was N-(1,3-dithiolan-2-ylidene)-4-hexylaniline and it has the 
following structural formula 
##STR3## 
EXAMPLE 2 
The crude product obtained in Example 1 was dissolved in 200 ml of 
anhydrous diethyl ether and a solution of 1.57 g of concentrated sulfuric 
acid in 100 ml of anhydrous diethyl ether was added dropwise at room 
temperature. A white precipitate formed immediately and, after the 
addition was complete, the mixture was cooled to -20.degree. C. and 
filtered cold, and the separated solid was washed with cold diethyl ether. 
The solid was air dried and recrystallized from hot acetone to give 
N-(1,3-dithiolan-2-ylidene)-4-hexylaniline dihydrogen sulfate as shiny 
white platelets melting at about 145.degree.-146.degree. C. 
EXAMPLE 3 
If the procecure of Example 1 was repeated using 
methyl(1,3-dithiolan-2-ylidene)sulfonium iodide and the appropriate 
4-substituted aniline, the following compounds were obtained: 
4-Cyclohexyl-N-(1,3-dithiolan-2-ylidene)aniline melting at about 
138.5.degree.-139.5.degree. C. after recrystallization from a mixture of 
toluene and hexane. 
4-(t-Butyl)-N-(1,3-dithiolan-2-ylidene)aniline melting at about 
73.5.degree.-74.5.degree. C. after recrystallization from hexane. 
EXAMPLE 4 
The procedure of Example 1 was repeated using 
methyl(1,3-dithiolan-2-ylidene)sulfonium iodide and the appropriate 
4-alkyl substituted aniline. The product obtained in this was was then 
reacted with sulfuric acid as described in Example 2, to give the 
following compounds: 
N-(1,3-Dithiolan-2-ylidene)-4-methylaniline dihydrogen sulfate melting at 
about 203.5.degree.-204.5.degree. C. after recrystallization from acetic 
acid. 
N-(1,3-Dithiolan-2-ylidene)-4-propylaniline dihydrogen sulfate melting at 
about 156.degree.-157.5.degree. C. after recrystallization from acetone. 
EXAMPLE 5 
Methyl(1,3-dithiolan-2-ylidene)sulfonium iodide was reacted with the 
appropriate 4-alkyl substituted aniline according to the procedure 
described in Example 1. The crude product obtained was purified by 
chromatography on silica gel using ethyl acetate/hexane and the product 
thus obtained was reacted with sulfuric acid according to the method 
described in Example 2 to give the following compounds: 
N-(1,3-dithiolan-2-ylidene)-4-ethylaniline dihydrogen sulfate melting at 
about 174.5.degree.-175.5.degree. C. after recrystallization from a 
mixture of acetone and methanol. 
N-(1,3-dithiolan-2-ylidene)-4-isopropylaniline dihydrogen sulfate melting 
at about 96.5.degree.-98.5.degree. C. after recrystallization from 
acetone. 
N-(1,3-dithiolan-2-ylidene)-4-octylaniline dihydrogen sulfate melting at 
about 139.5.degree.-180.degree. C. after recrystallization from acetone. 
4-Butyl-N-(1,3-dithiolan-2-ylidene)aniline, salt with 4-toluenesulfonic 
acid, melting at about 93.degree.-95.degree. C. after recrystallization 
from a mixture of chloroform and ether. In this case, 4-toluenesulfonic 
acid was used in place of sulfuric acid in the preparation of the salt. 
EXAMPLE 6 
A solution of 1.77 g of 4-hexylaniline in 20 ml of dried dimethylformamide 
containing 2.76 g of potassium carbonate was prepared and 0.84 g of carbon 
disulfide was added. The mixtue was allowed to stir at room temperature 
and its first became yellow and then yellow-orange. After about 1 hour, a 
solution of 2.26 g of 1,2-dibromoethane in 5 ml of dimethylformamide was 
added dropwise to the stirred solution. After this addition, the color of 
the solution began changing to light yellow and a fine precipitate began 
to form. After 2 hours at room temperature, an additional 0.84 g of carbon 
disulfide was added all at once and the mixture was stirred for an 
additional 3 hours. Then, 2.26 g of 1,2-dibromoethane was added and the 
mixture was stirred for an additional 20 hours. The reaction mixture was 
poured into water and the resultant aqueous mixture was extracted 3 times 
with diethyl ether. The combined ether extracts were washed with 0.2 N 
hydrochloric acid, water, and aqueous saturated sodium chloride solution 
and then dried over magnesium sulfate. The solvent was then evaporated, 
methylene chloride was added, and the solvent was again evaporated to 
leave and orangish oil which was crude 
N-(1,3-dithiolan-2-ylidene)-4-hexylaniline. 
The crude product obtained above was dissolved in 150 ml of anhydrous 
diethyl ether and to the resultant yellowish solution was added dropwise 
1.0 g of sulfuric acid in 75 ml of diethyl ether. A solid began to 
precipitate immediately. When the addition was completed, the resultant 
mixture was placed in a freezer for 1 hour. The precipitate was then 
separated by filtration, washed well with diethyl ether, and dried under 
reduced pressure. The off-white solid obtained was recrystallized by 
dissolving it in 375 ml of hot acetone, filtering the solution through a 
coarse fritted funnel, concentrating it to about 200 ml, and then cooling. 
After crystallization had occurred at room temperature, the mixture was 
then placed in a freezer to complete crystallization. The solid was then 
separated by filtration, washed with cold acetone and dried to give 
N-(1,3-dithiolan-2-ylidene)-4-hexylaniline dihydrogen sulfate as white 
platelets. 
EXAMPLE 7 
A solution was prepared from 13.6 g of 1,3-dithiolane-2-thione 
(ethylenetrithiocarbonate) in 25 ml of reagent nitromethane and 14.2 g of 
methyl iodide was added dropwise at room temperature with stirring under 
an atmosphere of nitrogen. The reaction mixture was wrapped with foil for 
protection from light and stirring was continued for 16 hours. The 
crystals that formed were separated by filtration, washed with dry benzene 
and dried in vacuo to give methyl(1,3-dithiolan-2-ylidene)sulfonium iodide 
as brown crystals melting at about 80.degree.-83.degree. C.