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Патент USA US2404737

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Patented July 23, 1946 ’
2,404,737
UNITED STATES PATENT OFFICE
2,404,737
SULPHANILYLSULPHANILADHDE
DERIVATIVES‘ ‘
‘
Maurice L. Moore, Detroit, Mich., assignor a
Sharp & Dohme, Incorporated, Philadelphia,
Pa., a corporation of Maryland
No Drawing. Application July 5, 1943,
Serial No. 493,578
20 ‘Claims.
(Cl.260-239..6)
'
1
2
This invention relates to N4-carboxyacyl-sul
of the radical T is ‘different from the radical M;
and E, G, and ‘R1 are. each separately selected
phanilylsulphanilamidothiazoles, in which the
carboxyacyl group is the radica1 remaining when ‘
from hydrogen and alkyl, aralkyl and aryl rad
the hydroxyl group is removed from only one of
icals; and R2 and R3 may be separately hydrogen
as well as an alkyl radical, saturatedlor unsatu
the two or more carboxyl ‘groups of a polycar
rated, for example, methyl, ethyl, propyl, butyl,
amyl, allyl, hexyl, heptyl, octyl and the like, or
boxylic acid, and the invention covers such prod
ucts containing the remaining 'carboxyl group
decyl, dodecyl, hexadecyl and the like, as well as
anaralkyl radical as benzy1 and the like, as well
or groups'unaltered as well as with the hydrogen
in any of such remaining carboxyl groups replaced
by a carboxylate-forming element or radical.
The new products of this invention are in gen
eral therapeutically useful in varying degrees and
applications, for example, in treating ailments of
theintestinal tract.‘
,
The products of this invention may be repre
sented by the general formula
10 as an aryl radical as phenyl, (unsubstituted as
well, as substituted, for example, having nitro,
amino, alkyl, carboxyl, sulphonic ‘acid, hydroxy,
alkoxy with the alkyl saturated or unsaturated
and straight or branched chain, phenyl, halogen
15 such as chlorine, and the like substituentaas well
as the naphthyl and diphenylradicals, eachsim
ilarly unsubstituted as well as substituted, and a‘
(...C00...),,...T
nitrogen-containing radical as nitro and amino
(unsubstituted and substituted as ‘acyl- and
20 alkyl—), and an oxygenated radical, for example,
hydroxy,
m
in which M is selected from hydrogen and mono
valent and polyvalent radicals capable of com‘
bining with a carboxyl radical to form arcar
boxylate, such as the alkali metals sodium, potas
sium, lithium and the like, the alkaline earths
alkoxy such .as methoxy, ethoxy,
propoxy, and carbalkoxy such as carbmethoxy,
carboxyL- and halo-alkyl as chlorethyl and the
like, and halogen, for example, chlorine and
2
bromine,
,
I
In this speci?cation and its appending claims,
the term “carboxylates” relates to the products
as calcium, magnesium, barium and the like, an
resulting when the acid formiof the products of
timony, copper, gold, iron, bismuth and man
the invention (that is, the form in which the
ganese and the like, an alkyl radical, a nitrogen 30 carboxyl groups of thecompounds have not been
base as ammonium and corresponding radicals
neutralized) is converted to the carboxylate form
of alkyl amines and alkanolamines and the like;
by replacement of the hydrogen of the free car
and R is the residue of a polycarboxylic acid,
boxyl group or groups thereof by a mono-valent
aliphatic, aromatic, as well as heterocyclic,
metal or group, or by one of the valences of a
stripped of its carboxyl groups; and T is selected 35 poly-valent metal as illustrated at column 1, lines
from hydrogen and the M-monovalent radicals
23-32 above.
,
i
and free valences 0f the M-polyvalent radicals not
The carboxyacyl group (remaining group when
satis?ed by the single carboxyl group shown di
the hydroxy group is removed from only one of
rectly linked to M; and n is selected from zero
the at least two carboxyl groups of a polycar
and any whole number up to four, whereby the 40 boxylic acid) may be derived from any desirable
grouping (- - - COO - -
‘)n - - - T represents the
carboxyl and the carboxylate groups over two
from any polycarboxylic acid having more than
two carboxyl groups, and m is a small number se
polycarboxylic acid, for example, aliphatic, aro
matic, and heterocyclic, such asthe aliphatic
polycarboxylic acids as‘ the saturated aliphatic
polycarboxylic acids such as the dicarboxylic acids,
lected from the'class consisting of (A) one, in 45 oxalic and malonic acids and their methylene
those compounds embraced herein in which all of
non-substituted homologues, succinic, glutaric,
the carboxyl groups in the carboxyacyl radical
adipic, pimelic, suberic, azelaic and sebacic ‘acids
satisfy all of the valences of any polyvalent rad
and‘the like, and derivatives thereof exempli?ed
icals represented by M and T, and (B) a small
by malonic acid and its homologues, in any of
number equal to the valences of M, in those com w which at least one of-the hydrogens of at least
pounds embraced herein and selected from those
one of ‘the available chain methylene groups is ‘re
(a) in which n is zero, (12) in which each 00
placed by any desirable substituent, for example,
currence of the radical T is selected from hy
alkylisaturated as well as unsaturated) , hydroxy,
drogen and any of the monovalent radicals repre
amino, carboxyl, and the like.- O-fsrichderiva
sented by T, and (0,)‘ in which each occurrence 55 tives, the saturated-alkyl-substituted-methylene
2,404,737
4
3
type is shown by the monoalkyl examples as
ample, the dicarboxypyrazines, such as antipella
inethyl-malonic, ethyl-malonic, butyl-malonic,
pyrotartaric (methyl-succinic) and ethyl-succinic
acids, and the saturated-dialkyls by dimethyl
pyrazine and 2,6-dicar-boxyDyrazine, as well as the
gric acid (2,3-dicarboxypyrazine), 2,5-dicarboxy-.
malonicrand diethyl-malonic acids, and the un
derivatives thereof substituted on the nucleus, for '
5 example, those alkyl-substituted on the nucleus,
saturated-alkyl by allyl-malonic acid. The hy
droxy-substituted-methylene type is exempli?ed
by tartronic (hydroxy-malonic) and malic (hy
nuclear-monoalkyl derivatives, as 2,3-dicarboxy
é-methyl-pyrazine, and the nuclear-dialkyl deriv
droxy-succinia'in the three isomeric forms) acids
atives as 2,3edicarboxy-5,6-dimethyl-pyrazine, as
as the homologs of antipellagric acid such as the
and the polyhydroxy-substituted by the dihydroxy 10 Well as 2-carboxy-3-methylu5-carboxy-?-methyl
pyrazine, and also dicarboxypyridazines such as
type shown by tartaric (dihydroxy-succinic) acid
é,5-dicarboxypyridazine as well as the derivatives‘
and the tetrahydroxy example in talomucic acid.
The amino~substituted-methylene type is demon
thereof substituted on the nucleus, such as those
strated by aspartic (aminosuccinic) and glutamic » alkyl substituted on the nucleus as 4.5-dicarboxy
acids. The mixed-substituted-methylene type is 15 3,6-dimethyl-pyridazine, and also the dicarboxy
pyrimidines such as e,5-dicarboxypyrimidine and
4,6-dicarboxy-pyrimidine. Also included are the
thiazole polycarboxylic acids such as the dicar
boxythiazoles, as well as the derivatives thereof
type.
Unsaturated aliphatic dicarboxylic acids from 20 substituted on the nucleus, such as 2-methyl-4,5
shown by citramalic (2-hydroxy-2-methyl-bu
tanedioic) and citric acids, the latter serving also
to point out the carboxylic-substituted-methylene
which the carboxyacyl radical is derived corre
spond to any of the above mentioned saturated
examples having at least four carbon atoms and
dicarboxythiazole.
these N4-carboxyacylsulphanilylsulphanilamid
othiazoles by heating the desired polycarboxylic
further particularized by maleic and citraconic
(methylmaleic) acids and their respective iso
mers, ,fumaric and mesaconic (methyl-fumaric)
acids.
'
,
i
acid, its anhydride,» or an ester, such as an ‘alkyl
ester, or a monohalide, such as the monochloride
or a monochloride of the ester, or acid chloride
'
Other aliphatic polycarboxylic acids from
which the carboxyacyl radical may be derived are
the tribasic, saturated as Well as unsaturated,
acids exempli?ed respectively by tricarballylic
'
The invention also includes the preparation of
36
such as the di-acid chloride, thereof with, for
example, any desired sulphanilylsulphathiazole,
either merely together or in an inert reaction me
dium such as an inert solvent, and as in'the lat
ter case'separating the desired end product or,
and aconitic acids and derivatives thereof as
as in the'case of the use of the ester or the acid
those in which anyof the methylene or chain hy~
chloride, liberating the end product by hydrolysis,
drogens is replaced by any desirable substituent
(as pointed out in relation to the dicarboxylic 35 and in any case, where necessary, subjecting it
to puri?cation as by recrystallization. Thus, for
acids) illustrated by citric acid.
example, with the aliphatic dicarboxylic acids
" The aromatic=>'(aryl) polycarboxylic acids from
which ,the-carboxyacyl radical may be derived
having less than four carbon atoms in the chain.
the alkyl diester vof the dicarboxylic acid is re
may be anaryl dicarboxylic acid or .aryl tricar
boxylic acid as trimellitic acid as, well as‘pne V40 acted with the sulphamlylsulphathiazole selected. With the aliphatic acids having four and ?ve car
containing up to six carboxyl groups, as mellitic
acid, and > those having replaceable hydrogen
bon atoms in the chain and with the aromatic
polycarboxylic acids ‘having two carboxyl groups '
atoms may or may not have other substituents on
the aromatic nucleus. Those having no substit- ,. orthoto each other, the desired anhydride is
uents on the aromatic nucleus are illustratedjby '“ taken as the starting material, While with the ali
the aryl dicarboxylic. acids, such as the isomeric
phatic acids having. over ?ve carbon atoms in the
phthalic acids, phthalic (ortho), isophthalic
(meta) and terephthalic (para). In those ‘having
other substituents on the nucleus, such substit“
uents may be illustrated by alkyl (mono- and di-),
alkoxy, hydroxy, halo,'nitro and other common
groups, for example, xylidic (or uvitic, 5-methyl—
chain
vwith the‘ aromatic acids ‘having no
carboxyl group in ortho position to another car
boxyl group, the free acid may be heated directly
with the selected .sulphanilylsulphathiazole. If
desired,- the monohalide of the est-er of any
of the acids may be used as the starting material.
1,-3-dicarboxylicbenzene), cumidic (dimethyl
The invention may be illustrated by, but not
phthalic), hemipic' (dimethoxy-phthalic), and
restricted to, the following:
coccinic (hydroXy-methyl-phthalic) acids, While 55
ExampZc.—-N4-succinyl -N1 -4- (2 ethiazolyl
the above speci?cally named aromatic acids illus
sulphamyl) ephenylsulphanilamide '
trate the mononuclear or phenyl-polycarboxylic
acid type, these aromatic polycarboxylic acids in
25.5 grams vof sulphathiazole was dissolved by
clude also those of the polynuclear type such as
warming in 200 cc. of dry pyridine. To this was
the naphthyl polycarboxylic acids as naphthalic 60 added, in portions with stirring, 34.0 grams of
(naphthalene-1,8-dicarboxylic acid), naphtha
p-acetylamino-benzene sulphonyl chloride. The
lene-1,2-dicarboxylic acid, naphthalene-2,3-di
reaction mixture after standing overnight was
carboxylic
acid,
50
naphthalene-1,4-dicarb0xylic
poured into a mixtureof crushed ice and hydro
chloric acid. vThe resulting precipitated solid was
The-heterocyclic polycarboxylic acids from which 65 collected on a ?lter-and'washed with water. The
the carboxyacyl radical may be derived may be
crude acetyl derivative,
'
'‘
acid and naphthalene-1,5-dicarboxy1ic acid.
any desirable heterocyclic polycarboxylic acid, for
example, the pyridine polycarboxylic acids as the
dicarboxypyridines such as quinolinic acid (2.3
dicarboxypyridine), lutidinic acid (2,5i-dicar 70
'
.
r
I
011,0 ONHGSOzNHOSOzNHC
‘
1
t
-
"
1!
\
on
/
N
..
. boxypyridine), 2,5r-dicarboxypyridine, cinchome
ronic, acid; t('3,4'-dicarboxypyridine), dipicolinic
thus obtained'was heated in a mixture of 400 cc.
of 6N hydrochloric acid and 50 cc. of ethyl alcohol.
acid (2,6-dicarboxypyridine), and dinicotinic acid
After about 30 minutes heating, the‘ deep red
(3,5-dicarboxypyridine) , also the diazine polycar
boxylio acids as the dicarboxydiazines, for ex 75 solution. which. resulted was decolorized with’
.
2,404,737
5
6
charcoal, cooled slightly, and the solid sulphanilyl
thiazole with a substantial excess of ethyloxalate
on a, hot plate at around 130-150” C. for about
two hours with occasional stirring and then wash
ing the reaction mixture with dilute hydrochloric
acid and water and directly or after intermediate
sulphathiazole,
puri?cation, for example, ‘by recrystallizations
such as from dilute alcohol, placing the reaction
precipitated by adding 200 cc. of concentrated
product in approximately 150 cc. of a 2.5% solu
ammonia, melted at 168° C. 11.82 grams of this
tion of sodium hydroxide and heating on the hot
intermediate was suspended in 100 cc. of dry
dioxan, heated to re?ux, and 8.0 grams of suc 10 plate for around a half hour at 95-100” 0., and
then decolorizing the solution with charcoal and
cinic anhydride added with stirring. The reac
making it slightly acid by the addition of con
tion mixture was re?uxed further for 20 minutes,
centrated hydrochloric acid, there results N4
during which period, all of the material went
oxalyl-sulphanilylsulphathiazole. By replacing
into solutionand a solid subsequently started
crystallizing out. The cooled reaction mixture 15 the ethyl oxalate by ethyl malonate, there results
N4-malonyl-N1—4- (2-thiazolylsulphamyl) —phenyl
was ?ltered and washed with dilute hydrochloric
sulphanilamide.
The corresponding carboxyacylsulphanilylsul
acid, yielding 12.18 grams of N4-succinyl-N1-‘l
(2.-thiazolylsulphamyl) -phenylsulphanilamide,
S—CH
I
II
110 o 0 011201120 ONHOSOZNHOsOENHQ
\ /o11
phathiazoles from the transform succinic acid
20 derivatives may be obtained by replacing the
ethyl oxalate or malonate in the immediately pre
ceding procedure by an equivalent quantity of a
monochloride-ester of such succinic acid deriva
tive or unsaturated isomer and with little or no
N
which crystallized from a water-dioxan mixture
as needles decomposing at 233° C.
‘By replacing the succinic anhydride in this 25 heating, for example, with the equivalent quan
tity of the moncchloride of the ethyl'ester of, for
example by the equivalent quantity of the possible
example, fumaric or mesaconic acid.
These compounds and those from the amino
inner anhydrides of other succinic acid deriva
tives, such as pyrotartaric, ethylsuccinic, maleic
and hydroxy-substituted derivatives of succinic
and citraconic acid anhydrides and the like or by
glutaric anhydride, or by phthalic, cumidic or 30 acid are exempli?ed by: Nt-malylsulphanilyh
sulphathiazole,
N4 - aspartylsulphanilylsulpha
hemipic anhydride, or the anhydride of diphenic
thiazole,
N4-citramalylsulphanilylsulphathiazole,
acid or of naphthalic acid, corresponding N4
N4- tartarylsulphanilylsulphathiazole, N4- fum
carboxyacylsulphanilylsulphathiazoles are ob
tained, for example:
‘
35
N4; pyrotartaryl-N1- 4 -(2 - thiazolylsulphamyl) -
phenylsulphanilamide,
N4-ethylsuccinyl - N1‘- 4 -(2-thiazolylsulphamyl) phenylsulphanilamide,
'
‘
N4-maleyl-N1- 4 -(2-thiazolylsulphamyl) éphenyl
sulphanilamide,
40 nitylsulphanilylsulphathiazole,
phanilylsulphathiazole,
‘
‘
N4-glutary1-N1—4- (2-thiazolylsulphamyl) -phenyl
sulphanilamide,
‘
Né- phthalyl - N1- 4 -(2 - thiazolylsulphamyD
- phenylsulphanilamide,
N4-cumidyl-N1-4- (Z-thiazolylsulphamyl) -pheny1
sulphanilamide,
N4-hemipyl-N1-4— (2-thiazoly1sulphamy1) —pheny1_
sulphanilamide,
'
By heating separate 10 gram portions of sul
45 phanilylsulphathiazole separately with an equi-‘
molecular weight of adipic acid, pimelic acid,
suberic acid, azelaic acid and sebacic acid, at
around 130-150° C. for at least twenty minutes
and then treating the respective reaction mix
50 tures separately with a suitable quantity, for ex
ample, 60 cc. of 10% sodium carbonate solution,‘
N4- diphenoyl - N1- 4 -(2 - thiazolylsulphamyl) phenylsulphanilamide, and
‘
?ltering off the insoluble, undesired ‘by-Products,
and neutralizing the ?ltrate with dilute hydro
chloric acid, there results the corresponding:
'
N4-naphthaloyl - N1- 4 -(2 - thiazolylsulphamyl) phenylsulphanilamide.
‘
N4 - mellitylsul
N4-coccinylsulphanilyl
sulphathiazole and N4-(4-hydroxy-3-carboxyl
benzoyl) -sulphanilylsulphathiazoleQ
N4- citraconyl - N1- 4 -( 2 - thiazolylsulphamyl) phenylsulphanilamide, ‘
arylsulphanilylsulphathiazole and N4-mesaconyl
sulphanilylsulphathiazole.
Similarly, there is obtained N4-citrylsulphanil
ylsulphathiazole, N4-glutamylsulphanilylsulpha
thiazole, N4-talomucylsulphanilylsulphathiazole,
N4-tricarballylsulphanilylsulphathiazole, N4-aco—
65
Similarly, by separately replacing the succinic
N4-adipyl-N1-4-(2 - thiazolylsulphamyl) -phenyl- '
sulphanilamide, N4-pimelyl-N1-4 - (2-thiazolylsul
phamyl) -phenylsulphanilamide, N4-suberyl-N1-4
‘anhydride by the equivalent quantity of ‘2,3
(2 - thiazolylsulphamyl) - phenylsulphanilamide,
dicarboxy-pyrazine anhydride, and the anhydride
N4-_azelay1-N1-4- (2- thiazolylsulphamyll -phenyl
of 2,3-dicarboxy-5,6-dimethyl-pyrazine andxof
2,3-dicarboxy-S-methyl-pyrazine, there results 60 sulphanilamide, and N4-sebacy1-N1-4-(Z-thiazol
ylsulphamyl)-phenylsulphanilamide.
the corresponding: N4- (B-carboxy-pyrazinoyl) N1- 4 -( 2 - thiazolylsulphamyl) -phenylsulphanil
amide, N4-(3-carboxy-5,6—dimethyl-pyrazinoy1) N1- 4 -(2 - thiazolylsulphamyl) — phenylsulphanil- ,
amide, and N4-(3-carboXy-5-methyl-pyrazinoyl) - ‘
'
By heating sulphanilylsulphathiazole with ap
proximately a 15% excess over an equimolecular
65
portion of respectively lutidinic acid, dinicotinic
acid, and 'dipicolinic acid, in intimate mixture to
a fusion temperature around between 160-190° C.
in a sand bath for about between an hour and
amide. Likewise, with the corresponding stoi
an hour and a half with occasional manual stir
chiometric equivalent of respectively quinolinic
ring, then cooling the melt and taking it up in
acid anhydride, cinchomeronic acid anhydride
and of 2-methyl-4,5-carboxythiazole anhydride,‘ 70 dilute alkali, around 5%, and precipitating with
a slight excess of hydrogen chloride, and then
there results: N4-quinolinoyl-sulphanilylsulpha—
?ltering off the precipitate and treating it with
thiazole, cinchomeronoyl- and (2,-rnethyl-5
cool sodium bicarbonate solution and ?ltering oil“
carboxythiazole-4-carboxylyl) -N1-4-(2-thiazolyl
the ‘soluble residue, and then making this ?ltrate
sulphamyl) -phenylsulphanilamide.
.
slightly acid with hydrogen chloride, there result
By heating 5 grams of sulphanilylsulpha
N1- 4 —(2 - thiazolylsulphamyl) - phenylsulphanil
2,404,737
the iollowine ‘corresponding products, which may
be further puri?ed by, forexample, reprecipita
therein Within the scope of the depending claims
tion: N4-lutidinoyl-Nl-4- (‘Z-thiazolylsulphamyl) -
as limited by the state'of the art.
tions, extensions or substitutions may be made
‘ "
'
phenylsulphanilamide, N4-dinicotinoyl-N1-4-(2
What is claimed is:
thiazolylsulphamyl)ephenylsulphanilamide, and 5
1. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl
N‘l-dipicolinoyl - N1 - 4 -(2 - thiazolylsulphamyl) -
phenylsulphanilamide.
By adding an equimolecular stoichiometric
equivalent of sulphanilylsulphathiazole in small
~
;
r
_
sulphamyl) -phenyl] -sulphanilamides having the
general formula
V.
(...Q00..,),,...T
'
‘
S_.-C-';[?;iv
portions over a forty minute period to a solution
of a given amount of the di-acid chloride of 4,6
dicarboxypyrimidine in a suitable quantity of a
solvent such as dioxan (for example, .006 mol of
N_-
my
and the carboxylates thereof, in which R is the
residue of a polycarboxylicra'cid stripped of'its
carboxyl groups; nris selected from zero and any
whole number less than five; E, G and R1 are
each separately and independently a 'memb'er‘of
each reactant in about 50 cc. of solvent) and per
mitting the mixture to stand at room temperature
for about at least ten minutes after the addition
is completed, and then pouring the mixture into
the class consisting of hydrogen and alkyl, aral
a suitable quantity (approximately 100 cc.) of
kyl and aryl radicals; and the thiazole ring‘ to
dilute sodium bicarbonate solution, ?ltering. o?
the insoluble portion after the effervescence dis 20 gether with R2 and R3 attachedto that ring rep
resent a member of the 'class consisting of thi
continues, then clarifying the ?ltrate with char
azole radicals.
'
'
l
coal and after the removal of the latter making
2. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl the ?ltrate acid with hydrogen chloride and chill
‘ sulphamyl) -phenyll-sulphanilamides, in which .
ing it, there results N4-(6-carboxy-pyrimidine-4
carboxylyl) -sulphanilylsulphathiazole.
’
25
The carboxylate form of any of the compounds
of the invention may be prepared, for example,
“Z-thiazolylsulphamyl” represents a thiazolyl nu
cleus linked through its carbon atom in the 2-po
sition to the sulphonamido nitrogen and having
by adding to a small amount of water an excess
its carbon atoms in the four and five positions
of the compound over its solubility in water and
linked to one another by a double bond,
dissolving the excess by stirring in a su?icient 30
'
3. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl ‘
quantity of, for example, anhydrous sodium car
sulphamyl) -phenyl'] -sulphanilamides, in ' which
bonate. The solution is preferably ?ltered and
from the ?ltrate the highly soluble sodium salt
“2-thiazolylsulphamyl” represents . a thiazolyl
nucleus linked through its carbon atom in the ,
can be isolated, for example, by adding an equal
Z-position to, ' the sulphonamido nitrogen ‘and
volume of alcohol and pouring the resulting so 35 having its carbon atoms in the four and ?ve po
sitions linked to one ‘another by a double bond,
lution into about 10 volumes of acetone. ‘The
in which the carboxyacyl group is ‘aliphatic.
‘
substance thrown out of solution is permitted to
4. N4 - carboxyacyl - N1 .- [4 .- (2.- thiazolyl settle and the supernatant liquid withdrawn and
sulphamyl) -phenyll-sulphanilamides,r in’ which
the residue preferably treated several times with
fresh acetone. After decanting the acetone from 40 “Z-thiazolylsdlphamyl” represents a: thiazolyl
nucleus linked through its carbon atom in‘ the
the last treatment, the resulting desired sodium
2-position to the sulphonamido nitrogen and
salt may be dried preferably under vacuum.
having its carbon atoms in the-four and '?ve po
Other metal carboxylate salts of the com
sitions linked to one another by a double bond,
pounds such as the copper, gold, iron and bismuth
salts and the like may be obtained by reacting 45 in which the carboxyacyl group is aromatic.
5. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl the alkali metal salts, preferably in aqueous solu
sulphamyl) -phenyl] -sulphanilamides, in- ‘which
tion, with a suitable soluble salt of the metal,
“2-thiazolylsulphamyl‘»’ represents a thiazolyl
the carboxylate salt of which is desired. The de
nucleus linked through its carbon atom in the
sired carboxylate salt is obtained by resulting
double decomposition.
'
50 2-position to the sulphonamido nitrogen. and
having its carbon atoms in the four and ?ve, po
The compounds of the invention, applicable in
sitions linked to one another by a double bond;
treating ailments of the intestinal tract, exhibit
in which the carboxyacyl group is heterocyclic.
such activity by the introduction to the various
6. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl nuclear portions of the individual compound; of
sulphamyl)-phenyl]-sulphanilamides, in which
substituents, the introduction of which into the
"2-thiazolylsulphamyl” represents a thiazolyl
basic nucleus leaves the compound substantially
nucleus linked through its carbon atom in the
non-toxic so that it would cause no permanent‘
2-position to the sulphonamido nitrogen and
injury to the subject when administered in the
having its carbon atoms in the four and ?ve po
necessary therapeutic dosage. The metallic ele
ment in the compounds used as in preparations 60 sitions linked to one another by a double bond,
and in which the carboxyacyl group is saturated
for treating intestinal ailments are such that
aliphatic.
'
their inclusion in the compound introduces simi
7. N4 - carboxyacyl - N1 .- [4 - (2 ,-'thia_zolyl larly no unduly toxic characteristics. Thus, for
example, as withv N4-succinylsulphanilylsulpha—
multaneously high blood level.»
sulphamyl)-phenyll-sulphanilamides, in which
05 “2-thiazolylsulphamyl” represents a thiazolyl
nucleus linked through its carbon atom in the
thiazole, it is possible to build up a high con
.centration in the intestinal tract Without a- si
‘
2-position to the sulphonamido nitrogen and
having its carbon atoms in the four and ?vepo-v
The'various compounds, used in the treatment
of intestinal ailments are administered orally,
sitions linked to one another by a double bond,
either in the form of tablets, capsules or powders 70 and in which the carboxyacyl group is saturated
aliphatic and is free of substituents on the meth
of the solid material, or as solutions of any suit
able concentration thereof.
'
lyene carbons of its chain.
'
‘
While the compounds constituting the inven
8. N't- carboxyacyl - Nl - [4 - (2 - thiazolyl tion have been described by reference to certain
sulphamyl) -phenyllesulphanilamides, in which
speci?c embodiments thereof, other modi?ca 76 "2-thiazolylsulphamyl”r represents a thiazolyl
2,404,737
10
in which the carboxyacyl group is ‘derived from
a mononuclear aryl dicarboxylic acid having its
nucleus linked through its carbon atom in the
2-position to the sulphonamido nitrogen and
carboxy groups in ortho position to one another.
having its carbon atoms in the four and ?ve po
sitions linked to one another by a double bond,
and in which the carboxyacyl group is aliphatic
and has four carbon atoms in its carbon chain.
15. N4 - carboxyacyl-N1-[4-(2-thiazolylsulph
‘amyl) -phenyl]-sulphanilamides, in which “2
9. N4 - carboxyacyl - N1 — [4 - (2 ‘- thiazolyl -
thiazolylsulphamyl” represents a thiazolyl nu
cleus linked through its carbon atom in the 2
sulphamyl)-phenyl]-su1phanilamides, in which
“2-thiazolylsu1phamyl” represents a thiazolyl
ing its carbon atoms in the four and ?ve posi
position to the sulphonamido nitrogen and hav
nucleus linked through its carbon atom in the 10 tions linked to one another by a double bond,
and in which the carboxyacyl group is-derived
2-position to the sulphonamido nitrogen and
from a mononuclear aryl dicarboxylic acid hav
having its carbon‘ atoms in the four and ?ve po
ing ‘its aryl radical free of substituents on the
sitions linked to one another by a double bond,
remaining nuclear carbons.
and in which the carboxyacyl group is saturated
16. N4 - phthalyl - N1 - [4-(2-thiazolylsulph
aliphatic and has four carbon atoms in its car
amyl) ~pheny1l-su1phanilamide in which the 2
bon chain.
‘ i
thiazolylsulphamyl group is the radical
10. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl -
sulphamyl)-phenyl]-sulphanilamides, in which
“Z-thiazolylsulphamyl” represents a thiazolyl
nucleus linked through its carbon atom in the 20
2-position to the sulphonamido nitrogen and
having its carbon atoms in the four and ?ve po
17. N“1 - carboxyacyl - N1-[4-(2-thiazoly1sulph
sitions linked to ‘one another by a double bond,
amyl)-phenyl]-sulphanilamides, in which “2-.
and in which the carboxyacyl group is saturated
thiazolylsulphamyl” represents a thiazolyl nu
aliphatic and has four carbon atoms in its car 25 cleus linked through its carbon atom in the 2- ‘
bon chain and is free of substituents on the
position to the sulphonamido nitrogen and hav
methylene carbons of its chain.
.
ing its carbon atoms in the four and ?ve posi
11. N4-succinyl-N1- [4- (Z-thiazolylsulphamyl) tions linked to one another by a double bond, and
phenyll-sulphanilamide, in which the 2-thia
in which the carboxyacyl group is derived from a
30 dicarboxypyridine.
zolylsulphamyl group is the radical
,
18. N4 - carboXyacyl-N1-[4-(Z-thiazolylsulph
i'—‘ W‘
~—S_OzNH-C
C—H
amyl) -phenyl]-sulphanilamides, in which “2
thiazolylsulphamyl” represents a thiazolyl nu
cleus linked through its carbon atom in the 2
N
position to the sulphonamido nitrogen and hav
ing ‘its carbon atoms in the four and ?ve posi
12. N4 - carboXyacyl-N1-[4-(2-thiazolylsulph
amyl)-pheny1]-sulphanilamides, in which “2—
tions linked to one another by a double bond, and
in which the carboxyacyl group is derived from a
thiazolylsulphamy ” represents a thiazolyl nu
cleus linked through its carbon atom in the 2
position to the sulphonamido nitrogen and hav~>
ing its carbon atoms in the four and ?ve positions
linked to one another by a double bond, and in
which the carboxyacyl group is derived from an
aryl dicarboxylic acid.
13. N4 _ carboxyacy1-N1-[4-(2-thiazolylsulph
amyl) -phenyll-sulphanilamides, in which "2
thiazolylsulphamyl” represents a thiazolyl nu
cleus linked through its carbon atom in the 2
position to the sulphonamido nitrogen and hav
ing its carbon atoms in the four and ?ve posi
tions linked to one another by a double bond,
and in which the carboxyacyl group is derived
from a mononuclear aryl dicarboxylic acid.
14. N4 - carboxyacyl-Nl-[4-(2-thiazolylsulph
Mv
dicarboxypyridine having its carboxy groups in
ortho position to one another.
.
19. N4 - carboXyacyl-N1-[44(2-thiazoly1su1ph
amyl)-phenyl]-sulphani1amides, in which “2
thiazolylsulphamyl” represents a thiaz'olyl nu
cleus linked through its carbon atoms in the 2
position to the sulphonamido nitrogen and hav
ing its carbon atoms in the four and ?ve posi
tions linked to one another by a double bond,
and in which the carboxyacyl group is derived
from a dicarboxypyridine free of substituents on
the remaining nuclear atoms.
'
20. N4 _ quinolinyl - N1-[4-(2-thiazo1y1su1ph
amyl) -phenyll-sulphanilamide, in which the 2
thiazolylsulphamyl group is the radical
amyl)-pheny1]-sulphanilamides, in which
thiazolylsulphamyl” represents a thiazolyl nu
cleus linked through its carbon atom in the 2
position to the sulphonamido nitrogen and hav
ing its carbon atoms in the four and ?ve posi
tions linked to one another by a double bond, and
' MAURICE L. MOORE.
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