U.S. patent number 3,705,185 [Application Number 04/816,038] was granted by the patent office on 1972-12-05 for n-aroyl sulfonamides.
This patent grant is currently assigned to Minnesota Mining and Manufacturing Company. Invention is credited to Alvin C. Conway, George G. I. Moore.
United States Patent |
3,705,185 |
Moore , et al. |
December 5, 1972 |
N-AROYL SULFONAMIDES
Abstract
N-Aroylperfluoroalkanesulfonamides wherein the perfluoroalkane
group is methyl or ethyl and the aryl group is phenyl, naphthyl,
pyridyl, thienyl, furyl, or pyrazinyl, optionally substituted, and
their pharmaceutically acceptable salts, are active anticonvulsant
agents. Processes for the preparation of these compounds are
described.
Inventors: |
Moore; George G. I. (White Bear
Lake, MN), Conway; Alvin C. (North St. Paul, MN) |
Assignee: |
Minnesota Mining and Manufacturing
Company (St. Paul, MN)
|
Family
ID: |
25219537 |
Appl.
No.: |
04/816,038 |
Filed: |
April 14, 1969 |
Current U.S.
Class: |
558/413; 549/72;
544/406; 546/288; 546/293; 546/316; 549/68; 549/487; 546/286;
546/287; 546/289; 546/309; 546/323; 564/96 |
Current CPC
Class: |
C07C
317/46 (20130101) |
Current International
Class: |
C07c 143/74 () |
Field of
Search: |
;260/556F,465D |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
2732398 |
January 1956 |
Brice et al. |
2915554 |
December 1959 |
Ahlbrecht et al. |
|
Primary Examiner: Jiles; Henry R.
Assistant Examiner: Winters; S. D.
Claims
WHAT IS CLAIMED IS:
1. A compound of the group consisting of acidic compounds of the
formula
wherein n is zero, one or two, Y is selected independently from the
group consisting of lower alkyl, lower haloalkyl, lower alkoxy,
phenyl, halogen, nitro and cyano but Y may not occupy a position
ortho to the carbonyl group except when Y is fluorine or when Ar is
phenyl, n is two and Y is chlorine, and not more than one chlorine
atom may occupy the ortho position, Ar is phenyl or naphthyl and
R.sub.f is perfluoroalkyl of one or two carbon atoms; and
pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 wherein R.sub.f is
trifluoromethyl and Ar is phenyl.
3. The compound sodium
N-(2,4-dichlorobenzoyl)trifluoromethanesulfonamide according to
claim 1.
4. The compound N-(3-chlorobenzoyl)trifluoromethanesulfonamide
according to claim 1.
5. The compound N-(4-chlorobenzoyl)trifluoromethanesulfonamide
according to claim 1.
6. The compound N-(3-bromobenzoyl)trifluoromethanesulfonamide
according to claim 1.
7. The compound N-(2-fluorobenzoyl)trifluoromethanesulfonamide
according to claim 1.
8. The compound N-(3-nitrobenzoyl)trifluoromethanesulfonamide
according to claim 1.
9. The compound
N-(3-trifluoromethylbenzoyl)trifluoromethane-sulfonamide according
to claim 1.
10. The compound N-(3-fluorobenzoyl)trifluoromethanesulfonamide
according to claim 1.
11. The compound N-(4-nitrobenzoyl)trifluoromethanesulfonamide
according to claim 1.
12. The compound N-(4-fluorobenzoyl)trifluoromethanesulfonamide
according to claim 1.
13. The compound N-(4-cyanobenzoyl)trifluoromethanesulfonamide
according to claim 1.
14. The compound N-(p-biphenylcarbonyl)trifluoromethanesulfonamide
according to claim 1.
15. The compound N-(3,4-dichlorobenzoyl)trifluoromethanesulfonamide
according to claim 1.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to N-substituted perfluoroalkanesulfonamides
and to compounds having anticonvulsant activity.
2. Prior Art
N-Substituted sulfonamides and N-substituted
perfluoroalkanesulfonamides wherein the fluoroalkane chain is four
to 12 carbon atoms are known to the art. U.S. Pat. No. 2,995,542
described compounds in which the nitrogen atom of the
fluoroalkanesulfonamido group is substituted by a carbonyl carbon.
However, the compounds described there are fluorocarbon
acrylic-type sulfonamides. No prior disclosure of
N-aroylperfluoroalkanesulfonamides or their physiological activity
is known.
SUMMARY OF THE INVENTION
This invention relates to certain N-aroyl-substituted
fluoroalkanesulfonamides, in which the aryl radical is selected
from the group consisting on phenyl, naphthyl, pyridyl, thienyl,
furyl and pyrazinyl, which may be substituted. The fluoroalkane
group must contain one or two carbon atoms. Pharmaceutically
acceptable salts of the compounds are also within the scope of the
invention. Compositions containing the compounds of the invention
and processes for their reparation are described. These compounds
are active anticonvulsive agents .
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to compounds of the formula
wherein n is zero, one or two, Y is selected independently from the
group consisting of lower alkyl, lower haloalkyl, lower alkoxy,
phenyl, halogen, nitro, and cyano but Y may not occupy a position
ortho to the carbonyl group except when Y is fluorine, or when Ar
is phenyl, n is 2 and Y is chlorine and not more than one chlorine
atom is in the ortho position; Ar is phenyl, naphthyl, pyridyl,
thienyl, furyl or pyrazinyl and R.sub.f is perfluoroalkyl of one or
two carbon atoms; and pharmaceutically acceptable salts
thereof.
The term "lower" when applied herein to alkyl, haloalkyl, alkoxy
and alkylsulfonyl substituents signifies the presence of one to
four carbon atoms; substituents having one carbon atom are
preferred, because starting materials for such compounds are
generally more readily available.
R.sub.f is preferably trifluoromethyl, since the compounds
containing this group have generally been somewhat more active as
anticonvulsant agents. Compounds wherein R.sub.f contains as many
as four carbon atoms are inactive.
When the substituent Y occupies a position ortho to the carbonyl
group of Formula I it has been observed that substituents other
than fluorine generally result in reduced activity in the compounds
of the present invention. No completely satisfactory theoretical
explanation for this observation is known, although the steric bulk
of the substituent is probably involved. However, one exception to
this observation is the case of compounds having two chlorine atoms
occupying positions on the aromatic ring, although both chlorine
atoms may not be ortho.
The amido nitrogen of the compounds of Formula I bears a hydrogen
which is relatively acidic. It may be replaced by metal ions by
neutralization e.g., with a base or a salt of a weak acid to form
salts of the compound. Suitable metal ions which may be utilized
are preferably those which are pharmaceutically acceptable, for
example sodium and potassium, when the compounds of the invention
are to be used as anticonvulsants. Other pharmaceutically
acceptable cations, which are well known to the art, may also be
included in salts of the compounds of the invention.
The compounds of the invention are prepared conveniently by the
reaction of an aroyl halide with a perfluoroalkanesulfonamide or
its salt as shown in the following equation:
In this equation Y, n, Ar and R.sub.f are as defined above, M is
hydrogen or a metal ion and X is halogen, preferably chlorine,
since the aroyl chlorides are generally more conveniently
available.
The aroyl halides or their precursor acids and the
perfluoroalkanesulfonamides and their salts used to prepare the
compounds of this invention are known to the art, or are readily
prepared by methods known to the art. Thus, the
perfluoroalkanesulfonamides can be prepared as described in U. S.
Pat. No. 2,732,398; aroyl halides are readily prepared by treating
aromatic acids or anhydride with thionyl chloride.
Aroyl anhydrides may be used in place of aroyl halides, although
they are generally not preferred.
It is preferred that the reaction be run in the presence of base,
although base is not essential, and a non-reactive solvent is
preferred. Conveniently, this solvent is acetone, but other
solvents including alkyl ketones, esters, mono- and diglyme,
benzene, alkanes, chlorinated hydrocarbons and the like can be
used. It is preferred that these solvents dissolve most of the
reactants to facilitate homogeneous reaction. Bases which are
suitable include salts of weak acids such as sodium acetate and
sodium carbonate and organic tertiary amines such as triethylamine
and N,N-dimethylaniline. The reaction is preferably run under
anhydrous conditions, and when very reactive acyl halides are used,
under an atmosphere of a relatively inert gas such as nitrogen.
Other equivalent procedures to obtain dry conditions are apparent
to those skilled in the art.
The reaction between the aroyl halide and the
perfluoroalkanesulfonamide is generally quite rapid at room
temperature, although stirring is continued for up to several hours
in order to insure completion of the reaction. Refluxing and/or
extended reaction periods may be useful to obtain reaction of
relatively unreactive pairs of reactants.
These reactions may also be run in high pressure reactors, without
solvent.
An alternative route to some of the compounds of this invention is
available. This consists of the reaction of an amide, or its salt,
with a perfluoroalkanesulfonyl halide, as shown in the following
equation
In the equation above Y, n, Ar, R.sub.f, M and X are as defined
previously hereinabove. However, this route is presently believed
to be less desirable. Other routes such as the reaction of ketenes
with perfluoroalkanesulfonamides are possible routes to the
compounds of the invention.
For general use as anticonvulsants, the compounds of the present
invention are preferably administered orally. For oral
administration they are preferably administered as salts of
pharmaceutically acceptable cations, as are well known to the art,
and particularly as sodium salts. The compounds of the present
invention are active as anticonvulsants, although it will be
appreciated that some are more active than others.
The compounds of the invention are especially advantageous because
the duration of their effect is quite long, often exceeding 48
hours. This permits longer intervals between doses, with no
reduction in effectiveness. Alternatively, the repeated
administration of lower, acutely subeffective dosages has been
demonstrated to result in ultimate complete effectiveness. Thus
subeffective dosages have a cumulative effect.
The specific does amounts of the compounds of Formula I which are
to be administered will depend on several factors including the
weight of the warm-blooded animal recipient and the route of
administration employed. Generally, the compounds of this invention
are effective in doses of 0.1 to 20 milligrams per kilogram daily.
The amounts can be given in single or multiple doses, as
required.
The compounds of Formula I or their pharmaceutically acceptable
salts can be suitably formulated in physiologically acceptable
solutions and carriers to make tablets, syrups, isotonic solutions,
injectable solutions, suppositories and other dosage forms.
In order to examine the efficacy of the compounds of the present
invention in the prevention or reduction in severity of convulsive
seizures, they were tested by two methods, electro-shock and
chemically-induced shock. More specifically, antagonism of corneal
supramaximal electroshock and 1,5 -pentamethylene-tetrazole-induced
seizures was used as the test methods.
The supramaximal electroshock technique is described in detail by
Toman, et al., Journal of Neurophysiology 9:231, (1946).
In order to obtain a correlation of the effectiveness of the
protection with the lethal hazard, the dose (ED.sub.50) that
protects 50 percent of the animals at the time of peak anti-shock
effect is calculated, and is compared to the median lethal dose,
LD.sub.50. A therapeutic index (T.I. = LD.sub.50 /ED.sub.50) is
calculated. Several of the preferred compounds of the invention
have been found to have a therapeutic index greater than 5.
The production of 1,5-pentamethylenetetrazole-induced seizures is
described in detail by Everett and Richards, Journal of
Pharmacology and Experimental Therapeutics 81, 402 (1944).
The preferred anticonvulsant compounds of the present invention
include
N-(2-fluorobenzoyl)trifluoromethanesulfonamide
N-benzoyltrifluoromethanesulfonamide
N-(3-nitrobenzoyl)trifluoromethanesulfonamide
N-(3-trifluoromethylbenzoyl)trifluoromethanesulfonamide
N-(3-chlorobenzoyl)trifluoromethanesulfonamide
N-(3-fluorobenzoyl)trifluoromethanesulfonamide
N-(4-nitrobenzoyl)trifluoromethanesulfonamide
N-(2,4-dichlorobenzoyl)trifluoromethanesulfonamide
N-(4-chlorobenzoyl)trifluoromethanesulfonamide
N-(3-bromobenzoyl)trifluoromethanesulfonamide
N-(4-fluorobenzoyl)trifluoromethanesulfonamide
N-(3,4-dichlorobenzoyl)trifluoromethanesulfonamide
and the sodium salts of the above compounds. The preparation and
use of these compounds for their anticonvulsant action appears to
be the presently best known means for practicing the invention.
Certain compounds of this invention also show activity as
insecticides, antimicrobial agents, diuretics, herbicides and plant
growth modifiers. The herbicidal and plant growth modifying
activity was determined using screening tests against experimental
plantings. The compounds of this invention are useful as chemical
intermediates.
The activity of these compounds is theorized to be the result of
inhibition of the enzyme carbonic anhydrase. This theory is
supported by positive results in a standard in vitro assay. Thus
some of the compounds of the invention can be expected to be useful
in a similar fashion to known carbonic anhydrase inhibitors, for
example as diuretics, anti-glaucoma agents and in the facilitation
of acclimatization to higher altitudes. Certain plant growth
modifiers are known to be effective inhibitors of plant carbonic
anhydrase.
In order to further illustrate the invention the following
non-limiting examples are provided. Melting points are
uncorrected.
EXAMPLE 1
N-Acylfluoroalkanesulfonamides: General Procedure, according to
Equation I.
A mixture of fluoroalkanesulfonamide (0.1 mole), sodium carbonate
(0.2 mole) and acetone (about 200 ml.) is stirred one or more hours
under a nitrogen atmosphere. The co-reactant acid chloride (0.1
mole), diluted with a small amount of acetone, is added during one
or more hours. A mild exotherm is sometimes observed. The reaction
mixture is stirred under nitrogen for one or more hours, the
mixture is filtered and the acetone is removed in vacuo. The
product is a sodium salt, usually solid but sometimes a sticky gum.
Dissolution in water, treatment with decolorizing charcoal and
filtration may be used to partially purify the product. The product
is reisolated by evaporation as the sodium salt, or acidification
of the filtrate may be used to obtain the product compound of
Formula I. Some of these compounds of Formula I have an appreciable
water solubility. Recrystallization of compounds is usually carried
out from trichloroethylene, or mixtures of aromatic and aliphatic
hydro-carbons such as benzene-hexane. Sublimation may also be used
as a purification technique. Sodium salts of the compounds are
successfully recrystallized from nitromethane.
EXAMPLE 2
Trifluoromethanesulfonamide (9.1 g., 0.06 mole), sodium carbonate
(12.9 g., 0.12 mole) and acetone (250 ml.) are stirred for four
hours. 4-Cyanobenzoyl chloride (10.1 g., 0.061 mole) is added and
the solution is stirred overnight. The solution is filtered and the
acetone is evaporated in vacuo. Water is added to dissolve the
crude product and the solution is filtered, then acidified to
precipitate the product. The suspension is extracted with
dichloromethane, the extracts are dried over magnesium sulfate,
filtered, and the solvent is removed in vacuo. The product is
purified by sublimation at 130.degree. C./0.03 mm. to yield a white
solid, N-4-(cyanobenzoyl)trifluoromethanesulfonamide, m.p.
148.degree.-150.degree. C.
analysis % C % H % N calculated for C.sub.9 H.sub.5 F.sub.3 N.sub.2
O.sub.3 S: 38.8 1.8 10.1 Found: 38.9 1.8 10.2
The following compounds are prepared from trifluoromethane -- or
trifluoroethane sulfonamide and appropriately substituted aroyl
halides, according to the procedure of Example 1.
Example Melting point No. Compound (in .degree.C.) 3
N-benzoyltrifluoromethane- sulfonamide 112.5-114.5 4
N-(2-fluorobenzoyl)trifluoro- methanesulfonamide 62-64 5
N-(3-nitrobenzoyl)trifluoro- methanesulfonamide 145-152 6
N-(3-trifluoromethylbenzoyl)- trifluoromethanesulfonamide 148-149.5
7 N-(3-bromobenzoyl)trifluoro- methanesulfonamide 134-135 8
N-(3-chlorobenzoyl)trifluoro- methanesulfonamide 118-119.5 9
N-(3-fluorobenzoyl)trifluoro- methanesulfonamide 129.5-131 10
N-(4-nitrobenzoyl)trifluoro- methanesulfonamide 140-145 11
N-(4-chlorobenzoyl)trifluoro- methanesulfonamide 156.5-158 12
N-(4-fluorobenzoyl)trifluoro- methanesulfonamide 148-150 13
N-(3,4-dichlorobenzoyl)- trifluoromethanesulfonamide 167-168.5 14
Sodium N-(2,4-dichloro- benzoyl)trifluoromethane- sulfonamide
218-220 d. 15 N-(2-naphthoyl)trifluoro- methanesulfonamide 149-151
16 N-(p-biphenylcarbonyl)- trifluoromethanesulfonamide 176-178 17
N-(4-methoxybenzoyl)- trifluoromethanesulfonamide 112-114 18
N-(3-methylbenzoyl)- trifluoromethanesulfonamide 134-136 19
N-benzoylperfluoroethane- sulfonamide 115-117.5 20*
Triethylammonium N-(4-nitro- benzoyl)- trifluoromethanesulfonamide
101.5-105 21 Sodium N-(3-nicotinyl)- trifluoromethanesulfonamide
361-364 d. 22 N-(2-thenoyl)- trifluoromethanesulfonamide 128-130 23
N-(2-furoyl)- trifluoromethanesulfonamide 130-131.5 24 Sodium
N-pyrazinecarbonyl- trifluoromethanesulfonamide 366-367
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