Патент USA US3422208

United States Patent 0 "ice
3,422,201
Patented Jan. 14, 1969
1
2
3,422,201
e.g., phosgene, phosphorous pentachloride, phosphorus
pentabromide, phosphorus trichloride, phosphorus tribro
wherein R1 and R are as de?ned above and an acid halide,
BENZENESULFONYLCARBODIIMIDES AS
ANTI-DIABETIC AGENTS
mide, thionyl chloride, and the like, the acid chloride be
Adnan A. R. Sayigh, North Haven, and Henri Ulrich,
Northford, Conn., and John B. Wright, Kalamazoo
Township, Kalamazoo County, Mich., assignors to The
Upjohn Company, Kalamazoo, Mich., a corporation of
ing preferred. The two reactants are mixed, preferably in
the presence of an inert solvent, under substantially an
hydrous conditions, in the presence or absence of an acid
Delaware
acceptor, and at a temperature in the range from about
No Drawing. Original application Jan. 2, 1964, Ser. No.
0° to about 60° 0., preferably from about 15° to about
335,414. Divided and this application Oct. 3, 1966,
50°‘ C. Thereafter the reaction mixture is heated at a
10
Ser. No. 583,994
temperature in the range from about 75° to about 200° C.,
US. Cl. 424—321
2 Claims
preferably from about 75° to about 150° C.
Int. Cl. A61k 25/00
' In carrying out the preparation, it is not essential that
the initial reaction mixture or the subsequent ?rst-stage or
ABSTRACT OF THE DISCLOSURE
15
free of all moisture. For example, access of the reaction
mixture to the moisture normally present in the atmos
Oral anti-diabetic compositions containing about 15 to
500 milligrams of a benzenesulfonylcarbodi-imide to
phere will not cause a substantial decrease in the amount
gether with a pharmaceutically acceptable carrier.
of sulfonylcarbodiimide ultimately produced. It is de
sirable, however, to use reactants, reaction solvents, and
reaction vessels which are substantially free of water. For
example, it is desirable that no more than 0.01 mole of
water per mole of acid halide be present in a reaction
mixture. Preferably, less water should be present. The
This application is a division of US. Ser. No. 335,414
?led on Jan. 2, 1964.
The present invention relates to novel unit dosage com
positions containing sulfonylcarbodiimides.
The sulfonylcarbodiimides contemplated by the present
second-stage reaction mixtures be maintained completely
25 presence of more water will decrease the yield of the de
sired sulfonylcarbodiimide by reacting with the sulfonyl
invention possess the formula:
carbodiimide. The reaction as noted above can be carried
out in the presence or absence of an acid acceptor. In the
event that an acid acceptor is employed, it is preferable to
wherein R1 represents alkyl of one to six carbon atoms, in 30 utilize a tertiary amine acid acceptor, e.g., triethylamine.
Practically any quantity of acid acceptor can be added
clusive, e.g., methyl, ethyl, propyl, butyl, isobutyl, pentyl,
hexyl, and the like, and
without adversely affecting the yield but, preferbly, it is
wherein X and X1 represent hydrogen, alkyl of one to
advisable to employ one mole or less per mole of liberated
acid.
35
Although the presence of a reaction solvent is not es
sential, particularly if the thiourea of Formula II is. a
liquid at the ?rst-stage reaction temperature, it is usually
four carbon atoms, inclusive, e.g., methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, and the like, alkoxy of one to
advantageous to dissolve or suspend the sulfonylthiourea
reactant in an inert solvent, and then to add a solution of
four carbon atoms, inclusive, e.g., methoxy, ethoxy, pro 40 acid halide in the same or similarly inert solvent. Alterna
poxy, isopropoxy, butoxy, and the like, halogen, e.g.,
tively, a solvent can be used to dissolve or disperse the
chloro, bromo, ?uoro, and the like, and alkanoyl of two
thiourea, and the desired amount of acid halide can then
to four carbon atoms, inclusive, e.g., acetyl, propionyl,
be added in gaseous form. Suitable solvents are aromatic
butyryl, and the like. X and X1 can be alike or different.
hydrocarbons, e.g., benzene, toluene, xylene; aliphatic hy
R represents alkyl of one to six carbon atoms, inclusive, 45 drocarbons, e.g., hexane, heptane, octane, mineral oil;
e.g., methyl, ethyl, propyl, isopropyl, isobutyl, butyl,
cycloalkanes, e.g., cyclohexane, tetrahydronaphthalene,
500 milligrams of a benzenesulfonyl carbodiimide to
hexyl, and the like, cycloalkyl of ?ve to eight carbon
Decalin; chlorinated hydrocarbons, e.g., chlorobenzene,
ethylene dichloride and carbon tetrachloride; dialkyl
ethers. of ethylene glycol and diethylene glycol, e.g., the
atoms, inclusive, e.g., cyclopentyl, cyclohexyl, cyclohep
50 dimethyl ethers; dialkyl sulfoxides, e.g.,‘dimethyl sulfox
tyl, cyclooctyl, and the like, and
ide, and the like. Especially preferred as reaction solvents
are the normally ?uid aromatic hydrocarbons and chlori
nated hydrocarbons. Important criteria in the choice of a
n
z
k)
——N
which represents a saturated heterocyclic amino selected
from the group ‘consisting of unsubstituted and mono 55 reaction solvent are that the solvent be a liquid over the
entire desired reaction temperature range and that the
and polyalkyl substituted piperidino and hexamethylene
solvent not react with the acid halide or with the desired
imino wherein each alkyl is of one to four carbon atoms,
sulfonylcarbodiimide. In general, solvents should be
inclusive. Representative saturated heterocyclic amino
radicals include, e.g., piperidino, hexamethyleneimino, 2
avoided which contain active hydrogen atoms as deter
mined by the Zerewitinoff procedure [1. Amer. Chem.
methylpiperidino, 3-methylpiperidino, 4-1nethylpiperidino,
2-butylpiperidino, 2-propylpiperidino, 4-isoproylpiperi
Soc. 49, 3181 (1927)]. The amount of solvent to be used
is not critical, it being desirable, however, that a reason
ably ‘?uid reaction mixture be maintained to facilitate con
tact between the acid halide and the sulfonylthiourea.
dino, 3,4-diethyliperidino, and the like.
The sulfonylcarbodiimides can be prepared by a novel
two-stage reaction of substantially equal molecular
amounts of a sulfonylthiourea of the formula:
65
It is preferred to react substantially equal molecular
amounts of the acid halide and thiourea. Lesser or greater
amounts of acid halide will result in smaller yield of the
desired sulfonylcarbodiimide. When lesser amounts of
3
2,422,201
acid halide are used, some of the sulfonylthiourea remains
unreacted.
The time required for completion of the ?rst and sec
ond stages of the reaction vary according to the nature of
the sulfonylthiourea reactant. Satisfactory results are usu
ally obtained by a slow mixing of acid halide and the
thiourea, for example, during about 20 to about 120 min
4
at temperatures between 25-28" C., the reaction mixture
was re?uxed for 40 minutes with nitrogen passing through
the reaction mixture. Evaporation of the chlorobenzene
gave 6.6 g. of crude product which upon distillation under
reduced pressure produced (40.2 percent) of N-(4-methyl
benzenesulfonyl)-N’-ethylcarbodiimide, B.P. 147-15 1° C.
(0.25 mm).
Analysis.—Calcd. for CNHIZNQOZS: C, 53.55; H, 5.39;
N, 12.49; S, 14.30. Found: C, 53.56; H, 5.26; N, 12.62;
S, 14.42.
utes within the relatively low ?rst-stage temperature range.
Although the ?rst-stage reaction usually proceeds to com
pletion rapidly, it is desirable to maintain the reaction
mixture within the ?rst-stage temperature range for about
5 minutes to about 6 hours before starting the second
stage of the reaction. The second stage usually requires
heating within the higher temperature range for about 1
In the same manner as shown above, N-(4-ethylbenzene
sulfonyl) - N’ - ethylcarbodiimide, N - (3 - propiylbenzene
sulfonyl)-N’-ethylcarbodiimide, and N-(4-butylbenzene
sulfonyl)-N’-ethylcarbodiimide are prepared by substitut
to 6 hours.
15 ing N-(4-ethylbenzenesu-lfonyl)-N’-ethylthiourea, N-(3
propylbenzenesulfonyl)-N’-ethylthiourea, and N-(4-butyl
The second stage can also, if desired, be conducted in
benzenesulfonyl)-N’-ethylthiourea, respectively, for N-(4
the presence of an inert gas, for example, passing nitrogen
methylbenzenesulfonyl) -N’-ethylthiourea.
or helium through the reaction mixture in order to re
move undesired reaction products.
‘EXAMPLE 3
The isolation of a sufonylcarbodiimide from a second 20
stage reaction mixture can be carried out by conventional
N- (benzenesulfonyl ) -N’-butylcarbodiimide
techniques, for example, by evaporation of the reaction
To 10.88 g. (0.04 mole) of N-benzenesulfonyl-N’-butyl
solvent and distillation of the residue at reduced pressure.
Alternatively, the sulfonylcarbodiimide can be isolated
thiourea in 20 ml. of chlorobenzene was added 3.9 g.
(0.04 mole) of phosgene in 40 ml. of dry chlorobenzene
from said residue by chromatography. If the sulfonyl 25 dropwise
with stirring and cooling over a period of 11
carbodiimide is normally a solid, it can be isolated and
minutes at 3 ° C. After stirring for 70 minutes at tempera
puri?ed by crystallization from a suitable solvent or pair
tures between 25~28° C., the reaction mixture was re?uxed
of solvents.
The starting sulfonylthiourewsv can be prepared accord
for 80 minutes at 130-132° C. while nitrogen was passed
through for the ?rst 30 minutes. A small amount of solid
ing to the procedures outlined in Chem. Rev., 50, 1-46, 30 material was removed by ?ltration and evaporation of the
1952, and Ber., 83, 551, 1950. For example, the starting
solvent afforded 8.9 g. of crude product. Distillation under
sulfonylthioureas can be prepared by reacting sulfonamides
reduced pressure produced 3.8 g. (40 percent) of N-ben
zenesulfonyl-N’-butylcarbodiimide, B.P. 151-155“ C.
in aqueous sodium hydroxide with a substituted isothio
cyanate.
‘
mm).
The following preparations are illustrative of the 35 (0.1
Analysis.—Calcd. for C11H14N2O2S: C, 55.45; H, 5.92;
preparation of sulfonylcarbodiimides.
N, 11.75. Found: C, 55.51; H, 5.89; N, 11.70.
EXAMPLE 1
In the same manner as shown above, N-benzenesulfonyl
N’-cyclopentylcarbodiimide, N-benzenesulfonyl-N’-cyclo
N-benzenesulfonyl-N’-ethylcarbodiimide
hexylcarbodiimide, N - benzenesulfonyl - N’ — cycloheptyl
To 9.76 g. (0.04 mole) of N-benzenesulfonyl-N’-ethyl 40 carbodiimide, and N-benzenesulfonyl-N’-cyclooctylcarbo
thiourea in 60 ml. of dry chlorobenzene was added 4 g.
diimide are prepared by substituting N-benzenesulfonyl
(0.04 mole) of phosgene in 40 ml. of dry chlorobenzene
N’-cyclopentylthiourea, N-benzenesulfonyl-N’-cyclohexyl
dropwise with cooling and stirring over a period of 14
thiourea, N-benzenesulfonyl-N’-cycloheptylthiourea and
minutes at 5° C. After stirring for 90 minutes at 25° C.,
N-benzenesulfonyl-N’-cyclooctylthiourea, respectively, for
the reaction was heated at 132° C. for 50 minutes while 45 N-benzenesulfonyl-N’-butylthiourea.
nitrogen was passed through the reaction mixture. A small
EXAMPLE 4
amount of solid material was removed by ?ltration and
upon evaporation of the chlorobenzene 7.8 g. of crude
N- (4-methylbenzenesulfonyl) -N’-butylcarbodiimide
product was obtained. Distillation under reduced pressure
produced 4 g. (47.6 percent) of N-benzenesulfonyl-N’ 50
To 13.44 g. (0.047 mole) of N~(4-methylbenzenesul
ethylcarbodiimide, B.P. 139~144° C. (0.2 mm.).
fonyl)-N’-butylthiourea in 94 ml. of dry chlorobenzene
Analysis.—Calcd. for C9H10N2O2S: C, 51.41; H, 4.79;
was added 4.7 g. (0.047 mole) of phosgene in 40 ml. of
N, 13.32. Found: C, 51.37; H, 4.80; N, 13.11.
dry chlorobenzene dropwise with stirring and ice cooling
In the same manner as shown above, N-benzenesulfonyl
over a period of 11 minutes at 4° C. After stirring for 10
N’-methylcarbodiimide, N - benzenesulfonyl - N’ - propyl
carbodiimide, N - benzenesulfonyl - N’ - isopropylcarbodi
55 minutes at about 40° C., nitrogen was passed through the
imide, N-benzenesulfonyl-N’-isobutylcarbodiimide, N-ben
minutes at 130-132° C. Evaporation of the chlorobenzene
gave 12.3 g. of crude product. Distillation under reduced
reaction mixture and the mixture was re?uxed for 70
zenesulfonyl-N'-pentylcarbodiimide, N - benzenesulfonyl
pressure produced 5.6 g. (47.3 percent) of N-(4-methyl
benzenesulfonyl)-N’-butylcarbodiimide, B.P. 159—162° C.
N’ ~ isopentylcarbodiimide, and N - benzenesulfonyl ' N’
hexylcarbodiimide are prepared by substituting N-benzene
sulfonyl-N’-methylthiourea, N-benzenesulfonyl-N’-propyl
(0.2 mm).
Analysis.—Calcd. for C12H16N2O2S: C, 57.12; H, 6.38;
N, 11.10; S, 12.70. Found: C, 56.36; H, 6.36; N, 11.05;
thiourea, N-benZenesulfonyl-N’-isopropylthiourea, N-ben
zenesulfonyl~N'-isobutylthiourea, N — benzenesulfonyl-N'
pentylthiourea, N - benzenesulfonyl-N’-isopentylthiourea,
and N-benzenesulfonyl-N’-hexylthiourea, respectively, for
N-benzenesulfonyl-N’-ethylthiourea.
EXAMPLE 2
N-(4-rnethylbenzenesulfonyl)-N’-ethylcarbodiimide
To 7.74 g. (0.03 mole) of N-(4-methylbenzenesul
fonyl)-N'-ethylthiourea in 50 ml. of dry chlorobenzene
S, 13.17.
65
In the same manner as shown above, N-(4-methyl
benzenesulfonyl) - N’ - cyclopentylcarbodiirnide,
N - (4
methylbenzenesulfonyl)-N’-cyclohexylcarbodiimide, N~(4
methylbenzenesulfonyl)-N’ - cycloheptylcarbodiimide, N~
(4-methylbenzenesulfonyl) -N’-cyclooctylcarbodiimide, N
70 (4-ethylbenzenesulfonyl)-N’ - cyclohexylcarbodiimide, N
(4-propylbenzenesulfonyl) - N’ - cycloheptylcarbodiimide,
and N- ( 3-butylbenzenesulfonyl) -N’-cyclooctylcarb odiim
ide are prepared by substituting N-(4-methylbenzenesul
was added 3 g. (0.03 mole) of phosgene in 30 ml. of dry
chlorobenzene dropwise with stirring and cooling over a
fonyl)-N’-cyclopentylthiourea, N - (4 - methylbenzenesul
period of 11 minutes at 3—4° C. After stirring for one hour 75 fonyl)-N’-cyclohexylthiourea, N - (4 - methylbenzenesul
3,422,201
6
pared by substituting N-(4-chlorobenzenesulfonyl-N’s
5
fonyl)-N'-cycloheptylthiourea, N - (4 - methylbenzenesul
fonyl)-N’-cyclooctylthiourea, N - (4 - ethylbenzenesulfo
propylthiourea for N-benzenesulfonyl-N’-ethylthiourea.
Similarly,
N-(4-chlorobenzenesulfonyl) -N'-cycloheptylcarbo
diimide,
nyl) -N’-cyclohexylthiourea, N- (4-propylbenzenesulfonyl ) -
N’-cycloheptylthiourea, and N-(3-butylbenzenesulfonyl)
N’-cyclooctylthiourea, respectively, for N-(4-methyl
benzenesulfonyl ) -N’-buty1thiourea.
N- (4-bromobenzenesulfony-l) -N’-cycloheptylcarbo
diimide,
EXAMPLE 5
N-(4-chlorobenzenesulfonyl) -N’-butylcarbodiimide,
N- (4-methylbenzenesulfonyl ) -N'-butylcarbodiimide
To 11.54 g. (0.04 mole) of N-(4-methylbenzenesul
fonyl)-N’-butylthiourea suspended in 120 ml. of carbon
10
N- (4-chlorobenzenesulfonyl) -N’-methy1carbodiimide,
N~ (4-bromobenzenesulfonyl ) -N'-butylcarbodiimide,
N-(3-chlorobenzenesulfonyl)-N’-butylcarbodiimide,
N- (4-chlorobenzensulfonyl ) -N’-hexamethyleneimino
tetrachloride was added 8.32 g. (0.04 mole) of phos
phorus pentachloride. On heating at 35° C. evolution of
carbodiimide, and
‘
N-(4-chlorobenzenesulfonyl)-N’-piperidinocarbodiimide
hydrogen chloride was observed and the phosphorus
15
are prepared by substituting
pentachloride was consumed within 15 minutes (tem
N- ( 4-chlorob enzenesulfonyl) -N’-cycloheptylthiourea,
perature 35-47“ C.). The reaction mixture was re?uxed
N- (4-bromob enzenesulfonyl ) -N'-cycloheptylthiourea,
N- ( 4-chlorob enzenesulfonyl ) -N'-butylthioure a,
at 77—78° C. for ?ve hours and on evaporation of the
solvent and distillation under reduced pressure produced
N-(4-chlorobenzenesulfonyl) -N’-methylthi0urea,
7.7 g. (75.5 percent) of N-(4-methylbenzenesulfonyl)
N’-butylcarbodiimide, B.P. 185—186° C. (1.3 mm.).
N- (4-brornobenzenesulfonyl) -N’-'butylthiourea,
N- ( 3 -chlorobenzenesulfonyl) -N’#bu tylthiourea,
N- (4-chlorobenzenesulfonyl) -N’-hex amethyleneimino
thiourea, and
In the same manner as shown above,
N- (3,4-dimethylbenzene-sulfonyl) -N'-butylcarbodiimide,
N-(3-chloro-4-methylbenzenesulfonyl) TN’ - propylcar
bodiimide,
N-(3-ethyl-4-ethoxybenzenesulfonyl)-N' - propylcarbodi
N-(4-chlorobenzenesu1fonyl)-N’ - piperidinothiourea, re
25
imide, and
spectively, for N-benzenesulfonyl-N'-ethylthiourea in
Example 1.
EXAMPLE 9
N - (3 - chloro - 4 - methoxybenzenesulfonyl) - N’ - piper
idinocarbodiimide are prepared by substituting N-(3,4
dimethylbenzenesulfonyl ) -N'-butylthiourea,
N-( 3-chloro-4-rnethylbenzenesulfonyl) -N’-propyl
thiourea,
-
N-(4-methoxybenzenesulfonyl ) -N’-cyclohexylcarbo
30
diimide
In the same manner as shown in Example 1, N-(4¢
-
N-(3-ethyl-4—eth-oxybenzenesulfonyl)-N-1-propylthiourea,,
methoxybenzenesulfonyl)-N’-cyclohexylcarbodiimide was
prepared by substituting N-(4-methoxybenzenesulfonyl)
and N-(3-chloro-4-methoxybenzenesulfonyl)-N’ - piper
idinothiourea for N-(4-methylbenzenesulfonyl)-N’ 35 N'-cyclohexylthiourea for N-benzenesulfonyl-N’-ethyl
butylthiourea.
thiourea.
EXAMPLE 6
_
N- (4-methylb enzenesulfonyl ) -N’-buty1carbodiimide
To 11.54 g. (0.04 mole) of N-(4-methylbenesulfonyl)
N'-butylthiourea in 90 ml. of dry chlorobenzene was
added 4.76 g. (0.04 mole) of thionyl chloride dropwise
with coOling and stirring over a period of 3 minutes at
5-8" C. After stirring for 100 minutes at 25° C., the re
action mixture was re?uxed for 90 minutes at 132—133° 45
C. Evaporation of the chlorobenzene and distillation
under ‘reduced pressure produced 1.2 g. (11.9 percent)
of N-(4-methylbenzenesulfonyl)-N' - butylcarbodiimide,
B.P. 157—166° C. (0.3 mm).
EXAMPLE 7
imide are prepared by substituting
N- ( 3-methoxybenzenesulfonyl ) -N’-propylthiourea,
N- (4-ethoxybenzenesulfonyl) -N'-butylthiourea,
N- ( 3,4-dimethoxybenzenesulfonyl ) -N’-pentylthiourea,
carbodiimide
N~(4-propoxybenzenesulfony1) -N’-isobutylthiourea,
In the same manner as shown in Example 1, N-(4
N~ ( 4-methoxybenzenesulfonyl) -N’-hexamethyleneimino
thiourea,
N-(4-butoxybenzenesu1fonyl)-N’-ethylthiourea, and
methylbenzenesulfonyl) - N’ - hexamethyleneiminocar
bodiimide was prepared by substituting N-(4-methyl
benzenesulfonyl) - N’ - hexamethylene - iminothiourea
for N - benzenesulfonyl - N’ - ethylthiourea.
Similiarly, N -
(4 - methylbenzenessulfonyl)
N—(4-prop0xybenzenesulfonyl) -N'-isobutylcarbodiimide,
N— (4-methoxybenzenesulfonyl ) -N’-hexamethyleneim
inocarbodiimide,
N- (4-butoxybenzenesulfony1) -N’-ethylcarbodiimide, and
N- (4-methoxyb enzenesulfonyl ) -N’-piperidinocarbodi
(4-rnethoxybenzenesulfonyl) -N'-butylthiourea,
50 NN- (4-methoxybenzenesulfonyl) -N’-methylthiourea,
N- (4-methylbenzenesulfonyl) -N'-hexamethyleneimino
’
Similarly,
N- (4-methoxybenzenesulfonyl) -N’-butylcarbodiirnide,
N-(4-methoxybenzenesulfonyl ) -N'-methylcarbodiimide,
N- ( 3-methoxybenzenesulfonyl) -N’-propylcarbodiimide,
N- ( 4-ethoxybenzenesulfonyl) -N’-butylcarbodiim.ide,
N~ ( 3,4-dimethoxybenzenesulfonyl) -N'-pentylcarbodi
imide,
N-(4-methoxybenzenesulfonyl) -N'-piperidinothiourea,
- N'
respectively, for N-benzenesulfonyl-N'-ethylthiourea in
piperidinocarbodiimide, N - (4-methylbenzenesulfonyl)
N’ - (4 - methylpiperidino) carbodiimide, and N-(4
Example 1.
methylbenzenesulfonyl) - N’ - (4,4-di-methylpiperidino)
carbodiirnide are prepared by substituting
N-(4-methylbenzenesulfonyl) - N’ - piperidinothiourea,
N-(4amethylbenzenesulfonyl) -N'- (4-methylpiperidino)
thiourea and N-(4-methylbenzenesulfonyl)-N’
(4,4-dimethylpiperidion)thiourea, respectively, for N
benzenesulfonyl-N’-ethylthiourea in Example 1.
'
EXAMPLE 10
N- (4-acetylbenzenesulfonyl) -N’-cyc1ohexylcarbodiimide In the same manner as shown in Example 1, N-(4
acetylbenzenesulfonyl)~N’-cyclohexylcarbodiimide was
prepared by substituting N-(4-acetylbenzenesulfonyl)-N'
cyclohexylthiourea for N-benzenesulfonyl - N’ - ethyl
70
EXAMPLE 8
-N- (4-chlorobenzenesulfonyl ) -N'-p ropylcarbodiimide
In the same manner as shown in Example 1', N-(4
chlorobenzenesulfonyl)-N’-propylcarbodiirnide was pre 75
thiourea.
Similarly,
N-(4-acetylbenzenesulfonyl) -N’-hexamethyleneimino
carbodiimide,
N- (4-propionylbenzenesu1fonyl) -N'-piperidinocarbodi
imide,
I
7
3,422,201
N- ( 3-butyrylbenzenesulfonyl ) -N'-propylcarbodiimide,
N- (4-acetylbenzenesulfonyl ) -N’-butylcarbodiimide,
N-(4-acetylbenzenesulfonyl) -N’-methylcarbodiimide,
8
blood sugar disorders of animals. The blood sugar reduc
ing activities of compounds such as N-(4-methylbenzene
and N- (4-acetylbenzenesulfonyl) -N'-cyclooctyl
sulfonyl) —N'-butylurea, N- (4-chlorobenzenesulfonyl) -N'
propylurea, N-(4-aminobenzenesulfonyl) -N’-butylurea are
well known. Particularly contemplated are sulfonylcar
carbodiimide are prepared by substituting
bodiimides having the formula:
N-(4-acetylbenzenesulfonyl) -N'-cycloheptylcarbodiimide
N- (4aacetylbenzenesulfonyl) -N'-hexamethyleneimino
thiourea,
N- (4-propionylbenzenesulfonyl) -N'-piperidinothiourea,
N- (3 -butyrylbenzenesulfonyl) -N'-propylthiourea,
N-(4-acetylbenzenesulfonyl) -N'-butylthioure a,
N- ( 4-acetylbenzenesulfonyl) -N'-methylthiourea,
N- (4-acetylbenzenesulfony1) -N’-cycloheptylthiourea, and
10
respectively, for N-benzenesulfonyl-N'-ethylthiourea in
15
X1
(III)
wherein X and X1 have the values represented above and
R2 represents alkyl of two to six carbon atoms, inclusive,
e.g., ethyl, propyl, isopropyl, isobutyl, butyl, hexyl, and
N-(4-acetylbenzenesulfonyl) -N'-cyclooctylthiourea,
Example 1.
EXAMPLE 11
the like, cycloalkyl of ?ve to eight carbon atoms, inclusive,
e.g., cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and
the like, and
m
K.)
N-methylsulfonyl-N'-n-propylcarbodiimide
To 12.7 g. (0.065 mole) of N-rnethylsulfonyl-N'-n 20
propylthiourea in 87 ml. of dry chlorobenzene was added
which represents a saturated heterocyclic amino selected
6.5 g. (0.065 mole) of phosgene in 40 ml. of dry chloro
from the group consisting of unsubstituted and mono- and
benzene with cooling and stirring over a period of 17
polyalkyl substituted piperidino and hexamethyleneimino
minutes at 34° C. After stirring for 30 minutes While
wherein each alkyl is of one to four carbon atoms, in
the temperature was allowed to come to 20° C., the re 25 clusive, also possess such desirable properties. Representa
action mixture was re?uxed for 30 minutes at 130° C.
tive saturated heterocyclic amino radicals include, e.g. pi
with nitrogen passing through the reaction mixture to re
peridino, hexamethyleneimino, 2-methylpiperidino, 3
move traces of phosgene. Evaporation of the chloro
methylpiperidino, 4-methylpiperidino, Z-butylpiperidino,
benzene afforded 11 g. of crude product which was dis
2-propylpiperidino, 4-isopropylpiperidino, 3,4-diethylpi
tilled under reduced pressure to afford 7.7 g. (73.3%)
peridino, and the like. For the treatment of diabetes, these
of N—methylsulfonyl-N'-n-propylcarbodiimide, B.P. 93°
compounds are useful perorally and for this purpose the
C. (0.25 mm.).
active compounds are used alone or admixed with a phar
maceutically acceptable carrier.
Analysis.—Calcd. for C5H10N2O2S: C, 37.02; H, 6.21;
N, 17.26. Found: C, 37.58; H, 6.30; N, 17.37.
In the same manner as shown above, N-ethylsulfonyl
N'-methylcarbodiimide, N-propylsulfonyl-N'-propylcar
For such oral administration, the active compounds can
35 be administered in liquid or solid dosage forms. Solid
forms include capsules, tablets, powders, granules, pills,
bodiimide, N-butylsulfonyl-N’-butylcarbodiimide, -N-pen—
tylsuzlfonyl-N'ethylcarbodiimide, N-hexytlsulfonyl-N’-hex_
soluble elastic capsules or suitably sealed hard gelatin or
methylcellulose capsules, and the like. Liquid forms in
ylcarbodiimide are prepared by substituting N-et-hylsul
clude nonaqueous dispersions such as in glycols (propyl
40
fonyl-N'-methylthiourea, N-propylsulfonyl-N’~propylthio
ene glycol, lower molecular weight polyethylene glycols,
urea, N-butylsulfonyl-N’-butylthiourea, N-pentylsulfonyl
etc.) and edible oils, mixtures of these, and the like, and
N'-ethylthiourea and N-hexylsulfonyl-N'-hexylthiourea
for N-methylsulfonyl-N’-n-propylthiourea.
EXAMPLE 12
oil suspensions and solutions in edible oils such as corn
oil, cottonseed oil, coconut oil, peanut oil, sesame oil, or
mixtures of these, and the like. Dispersions in other non
45
toxic pharmaceutically acceptable liquid vehicles such as
glycerol, sorbitol, and the like, or combinations of these
liquid vehicles can also be employed. Suitable ?avors, pre
servatives, dispersing agents and stabilizers can also be
N-methylsu1fonyl-N'-n-butylcarbodiimide
To 10.5 g. (0.05 mole) of N-methylsulfonyl-N’-n-butyl
thiourea in 65 ml. of dry chlorobenzene was added 5 g.
added.
(0.05 mole) of phosgene in 40 ml. of dry chlorobenzene 50
For preparing compositions such as tablets and other
compressed formulations, the compositions can include
any compatible and edible tableting material used in phar
maceutical practice such as corn starch, lactose, dicalcium
with stirring over a period of 17 minutes at 5° C. After
stirring for one hour at a temperature of about 25° C.,
the reaction mixture was re?uxed at 130° C. for 30 min
utes with nitrogen passing through to remove unreacted
phosphate, stearic acid, magnesium stearate, talc, methyl
phosgene. Evaporation of the chlorobenzene afforded 9.6 55 cellulose, as well as natural and synthetic gums, and the
like.
g. of crude product which upon distillation under reduced
pressure gave 7 g. (79.5%) of N-methylsulfonyl-N'-n~
Similarly, the compositions of the present invention can
butylcarbodiimide, B.P. 103—105° C. (0.3 mm.).
be mixed with suitable adjuvan-ts for the preparation of
resorbable hard or soft gelatin or methylcellulose capsules
Analysis.—Calcd. for C6H12N2O2S: C, 40.89; H, 6.86;
N, 15.90. Found: C, 41.17; H, 6.77; N, 16.12.
In the same manner as shown above, N-methylsulfonyl
N'-cyclopentylcarbodiirnide, N-ethylsulfonyl-N’-cyclohep
tylcarbodiimide, N-propylsulfonyl-N'-piperidinocarbodi
imide, N-butylsulfonyl-N'-hexamethyleneiminocarbodiim
60
utilizing conventional pharmaceutical practices. To im
prove blood level, surfactants such as polysorbate 80 and
dioctyl sodium sulfo-succinate can be added. The hard
capsules are advantageously hermetically sealed against
leakage and moisture from the air.
ide and N-hexy1sulfonyl-N’-(4,4-dimethylpiperidino)car 65
The optimum dosage of the compositions of the present
bodiimide are prepared by substituting N-methylsulfonyl
invention for the treatment of diabetes depends on the
N'-cyclopentylthiourea, N-ethylsulfonyl-N'-cycloheptyl
thiourea, N-propylsulfonyl-N'-piperidinothiourea, N-bu
tylsulfonyl-N'-hexamethyleneiminothiourea and N-hexyl—
age, weight, and condition of the patient being treated.
Generally speaking, the preferred unit dosage is 15 to 500
mg. of active compound, usually admixed with a pharma
sulfonyl-N'-(4,4-dimethylpiperidino)thiourea for N-meth 70 ceutical diluent. One or two unit dosages are given one to
ylsulfonyl-N'-n-butylthiourea.
four times a day. A total daily dose of from 60 to 4000
The sulfonylcarbodiimides are valuable medicaments
and, more particularly, are suitable as the active ingredi
ent in blood sugar reducing compositions, more particu
mg. given in a single dose, or preferably in divided doses,
embraces the effective range of the treatment of diabetes.
The following compositions are within the scope of the
larly, in unit dosage compositions for the treatment of 75 present invention.
3,422,201
10
25 mg. polysorbate 80 were prepared from the following
amounts and types of materials:
Gm.
No. 12 screen and the resulting granules compressed into
tablets containing 100 mg. of the active material per tablet.
In the same manner, 10,000 tablets of N-(4-methylbcn
zenesulfonyl)-N'-butylcarbodiimide were prepared, con
taining 500 mg. of active ingredient per tablet, by sub
stituting 5000 g. of N-(4-methylbenzenesulfonyl)-N’
N-(4-rnethylbenzenesulfonyl)-N’-butylcarbodiirnide 5000
butylcarbodiimide for N - (bromobenzenesulfonyl)-N'
(1) Hard capsules.—10,000 two-piece hard methylcel
lulose capsules for oral use, each containing 500 mg. of
N'-(4-methylbenzenesulfonyl)-N'-butylcarbodiimide and
Polysorbate 80 ____________________________ __
cycloheptylcarbodiimicle.
250
Also, 10,000 tablets of N-(4-chlorobenzenesulfonyl)
Corn starch ______________________________ __ 1616
Mineral oil, U.S.P. ________________________ __ 129.6 10 N'-pr0pylcarbodiimide were prepared, containing 200 mg.
of active ingredient per tablet, by substituting 2000 g. of
Magnesium stearate, powder ________________ __ 162
N - (4-chlorobenzenesulfonyl)-N'-propylcarbodiimide for
_Talc, U.S.P. ______________________________ __ 162
N - (4 - bromobenzenesulfonyl) - N’-cycloheptylcarbodi
The N- (4-methylbenzenesulfonyl) -N'-butylcarbodiim—
imide.
ide was mixed thoroughly with the rest of the ingredients
15
and then capsulated.
In the same manner 10,000 two-piece hard gelatin cap
(5) Soft elastic capsules.—One-piece soft elastic cap
sules for oral use, each containing 500 mg. of N-(4
methylbenzenesulfonyl)-N'-butylcarbodiimide liquid were
prepared directly without prior dilution.
N’-cycloheptylcarbodiimide were prepared by substituting
Similarly, one-piece soft elastic capsules containing 150
1000 g. of N-(4-methylbenzenesulfonyl)-N’-cycloheptyl
mg. of N-(4-methylbenzenesulfonyl)-N'-cycloheptylcar
carbodiimide for N-(4-methylbenzenesulfonyl)-N'-butyl 20 bodiimide
or 100 mg. of N-(4-methylbenzenesulfonyl)
carbodiimide.
N’-hexamethyleneiminocarbodiimide
were prepared.
(2) Soft elastic capsules.-—One-piece soft elastic cap
sules containing 100 mg. of N-(4-methylbenzenesulfonyl)
sules for oral use, each containing 35 mg. of N-(4-bromo
benzenesulfonyl)-N'—cycloh§eptylcarbodiimide were pre
pared according to accepted pharmaceutical practice .by
(6) Drop dosage form-A liquid concentrate for oral
use, each ml. containing 100 mg. of N-(4-bromobenzene
25 sulfonyl)-N'-cycloheptylcarbodiimide was prepared from
the following materials:
?rst dispersing the active material in su?icien-t polyethylene
glycol 400 to render the material capsulatable.
Saccharin sodium ______________________ __gm__
1
Similarly, one-piece soft elastic capsules each contain
Cyclamate sodium ______________________ __gm__ 10
ing 60 mg. of N-(chlorobenzenesulfonyl)-N’-propylcar
N - (4 - bromobenzenesulfonyl) - N'-cycloheptylcar
30
bodiimide were prepared.
bodiimide _______________________________ __ 100
(3) Oil suspension.—An oil suspension for oral use,
Oil of peppermint ______________________ __ml__ 2.5
each 5 ml. containing 250 mg. of N-(4-methoxybenzene
Polyethylene glycol 400 to make 1000 ml.
lsulfonyl)-N’-butylcarbodiimide, was prepared from the
following types and amounts of materials:
In the same manner, a liquid concentrate containing
35 500 mg. of N-(4-methylbenesulfonyl)-N'-butylcarbodi
Saccharin sodium ______________________ __gm__
10
imide in each ml. was prepared by substituting 500 g. of
Cyclamate sodium (sodium
cyclohexylsulfamate)
________________ __gm__
N-(4-methylbenzenesulfonyl)-N'-butylcarbodiimide for N
( 4-b romob enzenesulfonyl) -N’-cycloheptylcarbodiimide.
2.5
N-(4-methoxybenzenesulfonyl)
N'-butylcarbodiimide _________________ __gm__ 500 40
Benzoic acid, powder ___________________ __gm__
10
Methylparaben ________________________ __gm__
Butylated hydroxyanisole _______________ __gm__
10
1
25
Oil of orange _________________________ __ml__
Also, a liquid concentrate containing 200 mg. of N-(4
chlorobenzenesulfonyl) - N’ - propylcarbodiimide in each
ml. was prepared by substituting 200 g. of N-(4-chloro~
benzenesulfonyl)-N'-propylcarbodiimide for N-(4-bromo
benzenesulfonyl) -N'-cycloheptylcarbodiimide.
We claim:
Aluminum monostearate-corn oil gel to make 10,000 m1. 45
1. An oral composition effective for the treatment of
In the same manner, an oil suspension containing 100
diabetes containing as an active ingredient from about 15
mg. of N - (4 - methylbenzenesulfonyl)-N'-cyclohexylcar
mg. to about 500 mg. of a sulfonylcarbodiirnide having
bodiimide in each 5 ml. of suspension was prepared by
the following formula:
'
substituting 200 g. of N-(4-methylbenzenesulfonyl)—N’
cyclohexylcarbodiimide for N — (4 - methoxybenzenesul 50
fonyl) -N’-butylcarbodiimide.
Similarly, an oil suspension containing 100 mg. of N-(4
chlorobenzenesulfonyl) - N’ - cycloheptylcarbodiimide
in
each 5 ml. of suspension was prepared by substituting N
(4 - chlorobenzenesulfonyl)-N’-cycloheptyl-carbodiimide 55
for N-(4-methoxybenzenesulfonyl)-N'-butylcarbodiimide.
wherein X and X1 are selected from the group consisting
of hydrogen, alkyl of one to four carbon atoms, inclusive,
alkoxy of one to four carbon atoms, inclusive, halogen,
and alkanoyl of two to four carbon atoms, inclusive, R2 is
(4) Tablet.—10,000 oral tablets each containing 100
mg. of N - (4 - bromobenzenesulfonyl)-N’-cycloheptylcar 60 selected frm the group consisting of alkyl of two to six
carbon atoms, inclusive, cycloalkyl of ?ve to eight carbon
bodiimide were prepared from the following types and
amounts of materials:
atoms, inclusive, and
Gm.
Adult dose is one or two teaspoonfuls (5-10 ml.), one
to three times a day.
N - (4 - bromobenzenesulfonyl)-N'-cycloheptylcar
bodiimide
______________________________ __
1000
65
Dicalcium phosphate _______________________ __ 3050
Starch ___________________________________ __
65
Talc, bolted ______________________________ __
450
Calcium stearate, ?ne powder ________________ __
35
which is selected from the group consisting of unsubsti
70 tuted and mono- and polyalkyl substituted piperidino and
hexamethyleneimino wherein each alkyl is of one to four
The ?nely powdered N - (4 - bromobenzenesulfonyl)-N’
cycloheptylcarbodiimide, dicalcium phosphate, starch,
carbon ‘atoms, inclusive, and a diluent amount of a
pharmaceutically acceptable carrier.
talc and calcium stearate were mixed well and slugged.
2. An oral composition according to claim 1 containing
The slugs were forced through a No. 8 screen and the
granules slugged again. These were forced through a 75 as an active ingredient from about 15 mg. to about 500
11
3,422,201
12
mg. of N - (4 - methylbenzenesulfonyl)-N'-buty1carbodi-
2,968,158
1/1961
Ruschig et a1 ________ __ 167-65
imide and a diluent amount of a pharmaceutically accept-
3,063,903
11/ 1962
Wright ____________ __ 167-65
able carrier.
References Cited
UNITED STATES PATENTS
2,907,697
2,964,560
10/1959
12/1960
Haack et a1 _________ __ 167-65
Haack et a1 _________ __ 167-65
ALBERT T. MEYERS, Primary Examiner.
5
I. GOLDBERG, Assistant Examiner.
U.S. Cl. X.R.
424-244, 267
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent No. 3,422,201
January 14, 1969
Adnan A. R. Sayigh et al.
It is certified that error appears in the above identified
patent and that said Letters Patent are hereby corrected as
shown below:
Column 1, lines 32 to 35, the formula should appear as shown below:
X1
same column 1, lines 47 and 48, cancel "500 milligrams of a benzenesulfonyl
carbodiamide to-hexyl, and the like" and insert -— , hexyl --; line 61,
"4-isoproylpiperidino" should read —— 4-isopropylpiperidino —-; line 62,
"3,4-diethyliperidino" should read -— 3,4-diethylpiperidino ——.
Column 5,
line 33, "—Nl-" should read —— -N’— —-; line 60, "benzenessulfonyl“ should
read -- benzenesulfonyl ——.
Column 9, line 3, "N/—" should read -- N- --;
line 29, "N- (chloro“ should read —- N- (4-chloro ——.
Column 10, line 7,
"N- (bromo" should read -— N- (4—bromo --; line 31, "100" should read -- 100 gm‘
-—; line 60, "R2" should read -— R2 --,- line 61, "frm" should read -— from ——.
Column ll, line 7, "2,907,697" should read —- 2,907,692 ——.
Signed and sealed this 7th day of April 1970.
(SEAL)
Attest:
EDWARD M.FLETCHER,JR.
WILLIAM E. SCHUYEER, JR.
Attesting Officer
Commissioner of Patents