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Патент USA US3041341

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3,941,331
ice
United States
Patented June 26, 1962
2
1
from 5 to 9 nuclear atoms, according to the process
'
disclosed by Marshall 'et al., J. Org. Chem. 23, 9,27, 1958,
the said N-amino compound having the formula
3,041,331
N-ALKANOYLBENZENESULFDNYL-N'-(CYCLIC
.
AMINO) UREA DERIVATIVE
John B. Wright, _Kalamazoo Township, Kalamazoo
County, Micln, assignor to The Upjohn Company,
’ /\
H2N~¢N
.
. Kalamazoo, Mich., a corporation of Delaware
No Drawing. Filed Sept. 12,1960, Ser. No. 55,151
5 Claims. (Cl. 260—239)
Z, wherein —N
.
Z
V
has the value noted above.
_ The starting alkanoyl‘benzenesulfonylurethanes can be
The present invention relates to novel N-(alkanoyl 10 prepared by reacting anv alkanoylibenzenesulfonamide
having the formula:
‘benzenesulfonyD-N’-(cyclicamino)ureas and more spe
ci?cally relates to novel N-(alkanoylbenzenesulfonyl)
(Ii
N'-(cyclicamino)urea free bases and pharmacologically
R-C
_ acceptable acid addition salts thereof, and to oral anti
diabetic compositions containing said novel compounds
by the formula:
-
v
'
'-
F
'
15
as active ingredients.
'
The novel N - (alkanoylbenzenesulfonyl) - N’ - (cyclic
amino) ureas of the present invention can be represented
‘
wherein R has the value noted above, with ethyl chloro
carbonate in the presence of an alkali-metal carbonate,
using the process disclosed by Marshall et al., supra.
'
20
The alkanoylbenzenesul-fonamides can be prepared by
the process disclosed by Bur-tonet al., J. Chem.. Soc.
1949,. 178.
Alternatively, the alkanoylbenzenesulfon
amides can be prepared by reacting an aminoalkanophe
25
none having the formula:
.
'
wherein R represents alkyl of 1 to 4Vcarbon atoms, in
"clusive, i.e., methyl, ethyl, propyl, isopropyl, butyl, iso
butyl, and the like.
30
wherein R has the value noted above, with nitrous acid
(produced in situ, e.g., by means of an alkali metal ni
represents a saturated heterocyclic amino radical having
from 5 to 9 ring atoms, inclusive, wherein Z represents
trite, such as sodium nitrite, and an acid such as hy
a- saturated bivalent radical, e.g., polymethylene, oxa 35 drochloric acid); adding to the diazotized mixture a
polymethylene, thiapolymethylene, and azapolymethyl
30% solution of sulfur dioxide in ‘acetic acid to which
ene.
The term “saturated heterocyclic amino radical”
has been added an aqueous solution of a cupric salt
ash is employed herein includes unsubstituted saturated
heterocyclic amino radicals, as well'as thepmono- and
such as cupric chloride, to produce the corresponding
alkanoylbenzenesulfonyl chloride; and then reacting the
v.polyalkyl-substituted saturated heterocyclic amino, radi
40 alkanoylbenzenesulfonyl chloride with ammonia to ob
cals wherein alkyl is of 1 to 4 carbon atoms, inclusive.
tain the desired alkanoylbenzenesulfonamide.
' y
Representative saturated heterocyclic amino radicals ‘with
The starting N-amino saturated heterocyclic‘ amino
in the scope of the present invention include, e.g., piper
compounds can be prepared utilizing the process of Zim
mer et al., J. Amer. Chem. Soc.,77, 790, 1955, which
idino, morpholino, thiamorpholino, piperazino, py-rrol
idino, hexamethyleneirnino, heptamethyleneimino, octa
. involves nitrosating a saturated heterocyclic amino com
pound having the formula
methyleneimino, homomorpholino, Z-methylhexamethyl
eneimino, 2,2-dibutylhexamethyleneimino, 3,6-dimethyl
hexamethyleneimino, Z-ethylmorp‘holino, Z-ethyl-S-meth
ylmorpholino, 3,3-dimethylmorpholino, 3-methylthiamor
pholino, 2,3,5 ,6 - tetramethylthiamorpholino,
2,3,6 - tri
50
methylthiarnorpholino, 4 - butylpiperazino, 4 - isopropyl- '
has the value noted above, with nitrous. acid (produced
piperazino, 2,2,4,5,5~pentamethylpiperazino, 2,5-diiso
butylpiperazino, 2,4,5-trimethylpiperazino, Z-methylpiper
in situ as disclosed above) and reducing the resulting
N-nitroso saturated heterocyclic amino compound with
idino, 3-methylpiperidino, V4-met-hylpiperidino, 2-butyl
lithium ‘aluminum ‘hydride.
Other (reducing agents, e,g., ’
piperidino, 2 - propylpiperidino, 4 - isopropylpiperidino, 55 .a mixture of zinc and acetic acid, can also be employed
3,4-diethylpiperidino, 2-sec—butylpyrrolidino, 2,2-dimethyl
pyrrolidino, Z-ethylpyrrolidino, 2,4-dimethylpyrrolidino,
Z-isopropylpyrrolidino, hexahydIo-3-isopropylpyrimidino,‘
and the like.
, ~
to reduce the N-nitroso compound. Since nitrosation
of piperazine, unsubstituted in'the 1 and 4 positions, can
occur on both nitrogen atoms, it is generally desirable
to utilize l-benzylpiperazine as a starting compound and
The novel compounds of the present invention are 60 to ‘debenzylate the resulting N- (alkanoylbenzenesul- ,
fonyl)-N’-(4Jbenzylpiperazino)urea with hydrogen, in
the presence of a palladium catalyst according to the
sugar content in mammals, especially humans, to a safe
process disclosed in U.S. .Patent 2,415,786. The reduc- '
level and at dosages of the order disclosed below. In
ti-on of the N-nitroso compound with lithium aluminum
addition, the novel compounds are useful in animal feeds
and animal feed supplements as set forth in U.S. Patent 65 hydride is highly exothermic in many instances. Accord
ingly, it is good practice to bring the reactants together
2,941,884. The novel compounds are also useful as
orally active antidiabetic agents useful for lowering blood
wetting, emulsifying, and waterproo?ng agents in the
gradually, such as by gradual addition of a solution of
paper and leather industry.
N - (alkanoylbenzenesulfonyl)-N'-(cyclicamino)
the N-nitroso compound in an inert solvent to the reaction
mixture containing the lithium aluminum hydride.
'
ureas of the present invention can be prepared by re
acting an alkanoylbenzenesulfonylurethane with an N
70 present invention can be prepared from the N-(alkanoyl
The
amino saturated heterocyclic amino compound having
Pharmacologically acceptable acid addition salts of the
benzenesulfonyl) -N’-'(cyclicamino)urea rfree bases by
3,041,331
conventional methods. For example, the free base can
be dissolved in an aqueous solution of the appropriate
acid and the salt can ‘be isolated by evaporation of the
solution. rAlternatively, the'free base dissolved in an
there was obtained 1-nitrosohexamethyleneimine as a
yellow oil boiling at 136-138” C./34 mm.
(E) l-aminohexamethyleneimiue: To a mixture of
15.18 g. ‘of lithium aluminum hydride and 400 ml. of an
hydrous other was added'about 10% of a solution of
51.27 g. of 1-nitrosohexamethyleneimine in 100
of
anhydrous ether. The mixture was re?uxed until the re
action'started. The remainder of the solution was added
organic solvent such as methanol, ethanol, ethyl acetate,
ether, and the like, can be treated with the appropriate
acid and according to the'natuire of the solvent employed
the desired salt will separate spontaneously or can be
precipitated by the addition of a solvent in which the
at such a rate as to maintain gentle re?ux. Re?uxing was
salt is insoluble. Suitable ‘acids include hydrochloric,‘ 10 continued for 2 hours more, followed by the successive
sulfuric, hydrobromic, phosphoric, tartaric, acetic, citric,
addition of 16 ml. of water, 12 ml. of 20% aqueous so
succinic, maleic, benzoic, salicylic, and the like.
dium hydroxide’solution, and 756 ml. of water. The in
The following examples are illustrative of the products
of the present invention, ‘but are not to 'be construed
as limiting.
7
Example 1.—N-(4-Acetylbenzenesulfonyl) -N'
Hexamez‘hyleniminourea
organic precipitate was removed by ?ltration and washed
with ether. The ?ltrate and ether washes were dried
15 and the ether was removed by evaporation. Upon dis
tillation of the residue there was obtained 25.46 g. (56%)
of l-aminohexamethyleneimine as a colorless liquid boil
ing at 94-_96°- C./55
(A) 4~acetylbenzenesulfonyl chloride: To 13.52 g. (0.1 20 In the same manner as shown in Parts D and E, the
following N~amino saturated heterocyclic amines were
mole) of p-aminoacetophenone (Beilstein’s Handbuch der
prepared 'by_ substituting the corresponding secondary
Organischen Chemie, 4th edition, vol. 14, p. 46) was
heterocyclic
amine having the formula
added 100 ml. .of acetic acid and 34 ml. of concentrated x
hydrochloric acid. The resulting suspension was'cooled
to about 0° C. and to this was added dropwise ‘a solution 25
or 7.59 g. of sodium nitrite in 12 ml. of water. The
shown above, for hexamethyleneimine: l-aminopiperi
' slightly turbid yellow solution was stirred for 1/2 hourat
about 0‘_’ C. and then 80 ml. ofa 30% sulfur dioxide so
lution in acetic acid, to which had been'added a solution
dine, 1-amino-4-methylpiperazine, l-‘amino-lé-dimethyl
hexamethyleneimine, 1 - amino42,2-dibutylhexamethylene—
imine, 1damino-4-methylhexamethyleneimine,
l-amino
containing 4 g. of cupric chloride dihydrate dissolved in 30 heptamethyleneimine, _1 - aminooctamethyleneimine, 4 7 ml. of water, was ‘added. The mixture was allowed to
warm to about 25° C., poured into .ice water, ?ltered,
and the ?lter cake was'washed with Water. The ‘resulting
4-acety-lbenzenesulfonyl chloride melted at 87—89° C.
(B)._4-acetylbenzenesulfonamide: ' The
4-acetylben
-zenesu1fonyl chloride of Part A was added to ‘70 ml. of
,aminomorpholine, 4-amino-2-ethylmorpholine, 4-amino
3,5 - dimethylmorpholine,
4 - *aminohomomorpholine,
4*aminothiamorpholine, 4-amino-2,3,5-trimethylthiamor
pholine, 4-amino-2,6-dimethylthiamorpholine, l-aminoe2
35 butylpipeiidine, rl-ramino - 5 - ethyl-Z-methylpipe?dine,
1 - amino - 4 - isopropylpi-peridine,
concentrated ammonium hydroxide solution, whereupon
l~aminopyrrolidine,
1 - amino-Z-butyl-5-methylpyrrolidine,
1—amino-2,5-diiso
an exothermic reaction occurred. After standing for
'propylpyrrolidine, 1-amino-4-butylpiperazine, Lamina-4
about .12 hours the mixture was ?ltered, washed with
isopropylpiperazine, and 1-amino-2,4,5-trimethylpipera
water, and the recovered solid was recrystallized from 40 zine.
'
ethanol.
The product, 4 - acetylbenzenesulfonamide,_
weighed 10.92 g. and melted at 176-178° C.
- @(C) 4-Jacetylbenzenesulfonylurethane:
To . a
stirred
mixture of 199 g. (0.1 mole) of 4~acetylbenzenesulfonam
ide, 36.0 g. of ?nely ground anhydrous potassium car
bonate, and 120 ml. of acetone was added 14.26 'g. (0.132
mole) of ethyl chlorocarbonate. The reaction mixture
(F) N - (4dacetylbenzenesulfonyl)-N'-hexamethylene
iminourea ?r'ee base: A mixture of 11.4 g. of l-aminohex
~arnetzhyleneimine and 25.5 g. of 4-acetylbenzenesulfonyl~
urethane was heated at 130° C. (oil bath temperature)
45 for 2 hours. Theresulting ethanol and unreacted amine
were removed at 1100 mm. pressure for 1 hour and at 20
for Zhours while keeping the oil bath at 130° ,C.
was stirred at re?ux'temp'erature for 2.5 hours, cooled,
‘The residue was cooled and recrystallized from methyl
and 20 m1. of acetone was added. The resulting solid
‘ethyl ketone, giving N-(4-acetylbenzenesulfonyl)-N'-hex
was recovered by ?ltration, pressed dry, and stirred with 50 'amethyleneiminourea free base.
'
500
of water for liminutes. The mixture was ?l
(G) N - (4aacetylbenzenesulfonyl) -N'-hexamethylene
tered, and the clear ?ltrate was acidi?ed with 30 ml. of
iminourea hydrochloridezr N-(4-acetylbenzenesulfonyl)
concentrated hydrochloric acid, with cooling. The re
'N'-hex=amethyleneiminourea free base was dissolved in
sulting precipitate was recovered by ?ltration, Washed
‘ether and gaseous hydrogen chloride was added thereto to
with water, and air dried. There was thus obtained 16.49 55 produce N-(4-acetylbenzenesulfonyl)-N’-hexamethylene
_. g.) (61%): of 4Aacetylbenzenesulfonylurethane which
iminourea hydrochloride.
melted at 128-130“ C. An analytical sample prepared
Example 2.——N-(4-Pr0pi0nylbenzenesulfonyl)-N'- v
by recrystallization from benzene melted at 128.5
130.5° C.
>
Analysis.—¢Calcd. for CHI-113N055: C, 48.70; H, 4.83;
N, 5.16; S, 11.82. ‘Found: C, 48.56; H, 5.02; N, 5.11; S,
.
Piperidinourea
'
11.91.
(D) »1-nitrosohexamethyleneimine: A solution of 89.5
g. of hexamethyleneimine, 75 ml. of concentrated hydro
chloric acid, and 26 ml. of water was heated‘ to 70° C.
on a steam bath. The solution was made acidic by add
ing 5 ml. of 2 N hydrochloric acid. While maintaining
>60 "
'
'
_ (A) 4-propionylbenzenesulfonylurethane: In the same
'manner as shown in Example 1, Farts A, B, and C, 4-pro
>pionylbenzenesulfonylurethane was prepared by using
p—aminopropiophenone. (Beilstein’s Handbuch der Organ
ischen Chemie, 4th edition, vol. 14, p. .59) ' instead of
p-aminoacetophenone.
_
'
(B) N-(4-propionylbenzenesulfonyl) - N’ - piperidino
urea free base: In the same manner 'as shown in Example
the reaction mixture at 70-75" C., a solution of 67 g. of
1, Part F, N-(4-propionylbenzenesulfonyl)JN'-piperidino
sodium nitrite in 95
of water was added with stirring
urea free base was prepared by using 4-pr0pi0nylbenzene
over a period of 1 hour. The mixture was then stirred 70 sulfonyluret-hane and l-arninopiperidine instead of 4-acet
‘at 70° C. for 2 hours, and then cooled. Theupper oily
Vylbenzenesulfonylurethane and 1~aminohexamethylene
layer was separated and the ‘aqueous layer was then ex
tracted with ether. The combined ether extract and oil
(C) N - (4-propionylbenzenesulfonyl)-N'-pipetidino
was dried over anhydrous magnesium sulfate and con
‘urea citrate: In the same manner 'as shown in Example
centrated to dryness. Upon distillation of the residue 75 vl, Part G, N-(4-propionylbenzenesulfonyl)-N'—piperidino
imine'.
"
.
3,041,331 '
6
5
urea citrate was prepared by using N-(4-propionylben
methyleneiminourea free base'was prepared by using 1
zenesulfonyl)-N’-piperidinourea free base and citric acid
aminooctamethyleneirnine instead of l-aminohexamethyl
instead of 'N-(4-acetylbenzenesulfonyl)-N’-hexamethyl
eneimine.
eneiminourea free base ‘and hydrogen chloride.
‘
(B) N - (4 - acetylbenzenesulfonyl) - N’ - octarnethyl
eneiminourea hydrochloride: In the same manner as
Example 3.---N -- (4 - butylrylbenzenesulfonyl) _ N’ - (4
shown in Example 1, Part G, N-(4-acety1benzenesul
fonyl)-N’-octamethyleneiminourea hydrochloride was
M ethylpiperazino) area
prepared by using N-(4-acetylbenzenesulfony1)-N’-octa
(A) 4-butyrylbendenesulfonylurethane: In the same
manner as shown in Example 1, Parts A, B, and C, 4-bu
tyrylbenzenesulfonylurethane was prepared by using p
methyleneiminourea free base instead‘of N-(4-acety1ben
Zenesulfonyl)-N’-hexamethyleneiminourea free base.
amino-butyrophenone (Beilstein’s Handbuch der Organ
ischen Chemie, 4th edition, vol. 14, p. 65) instead of p
Example 7.—-N - (4‘- Propionylbenzenesulfonyl) - N’
(B) N - (4 - butyrylbenzenesulfonyl) - N’ - (4 - methyl
(A) N - (4 - propionyl-benzenesulfonyl) - N’ - mor
Morpholino‘urea
aminoacetophenone.
piperazino)urea free base: In the same manner as shown 15 pholinourea free base: In the same manner as shown in
in Example 1, Part F, N-(4-butyrylbenzenesulfonyl)-N’
Example 1, Part F, N-(4-propionylbenzenesulfonyl)-N’
(4-methylpiperazino)urea free base was prepared by using
morpholiuourea free base was prepared by using 4-pro
4-butyry1benzenesulfonylurethane and 1~amino-4-methy1
pionylbenzenesulfonylurethane and 4-aminomorpholine
piperazine instead of 4-acetylbenzenesulfonylurethane and
instead of 4-acetylbenzenesulfonylurethane and l-amin-o
l-aminohexamethyleneimine.
hexamethyleneirnine.
'
(B) N - (4 _- propionylbenzenesulfonyl) - N’ - mor
(C) N - (4 - butyrylbenzenesulfonyl) - N’ - (4 -methyl
piperazino)urea sulfate: In the same manner as shown
pholinourea maleate: In the same manner as shown in
in Example 1, Part G, N-(4-butyrylbenzenesulfonyl)-N’
(4-methylpiperazino)urea sulfate was prepared by using
xample 1, Part G, N-(4-propionylbenzenesulfonyl)-N'
morpholinourea maleate was prepared by using N-(4-pro
25 pionlybenzenesulfonyl)-N’-morpholinourea free base and
N - (4 - butyrylbenzenesulfonyl) - N’ - (4 - methylpiper
maleic acid instead of N-(4-acetylbenzenesulfonyl)-N'
hexamethyleneiminourea free base and hydrogen chloride.
azino)urea free base and sulfuric acid instead of N-(4
acetylbenzenesulfonyl)
- N’ - hexamethyleneiminourea,
free base and hydrogen chloride.
Example 8.—-—N - (4 - Propitmylbenzenesulfonyl) - N’ -
(Z-Ethylmorpholino) Urea Free, Base
Heptamethyleneiminourea
In the same manner as shown in Example 1, Part F, N
(4 - propionylbenzenesulfonyl) - N’ - ‘(2 - ethylmorpho
(A) 4-isobutyrylbenzenesulfonylurethane: In the same
lino)u’rea free base was prepared by using 4-pr0pionyl
manner as shown in Example 1, Parts A, B, and C, 4~iso
benzenesulfonylurethane and 4-amino-2-ethylrno1'pholine
butyrylbenzenesulfonylurethane was prepared by using p
aminoisobutyrophenone instead of p-aminoacetophenone. 35 instead of 4-acetylbenzenesulfonylurethane and l-amino
Example 4 .——N- (4-Is0butyry lbenzenesulfonyl ) -N'
(B) N - (4 -isobutyrylbenzesu1fonyl) - N’ - hepta
hexamethyleneimine.
methyleneiminourea free base: In the same manner as
shown in Example 1, Part F, N-(4-isobutyrylbenzenesul
morpholinourea
fonyl)-N'-heptamethyleneiminourea ‘free base was pre
pared by using 4-isobutyrylbenzenesulfonylurethane and
.l-aminoheptamethyleneimine instead of 4-acetylbenzene
'
Example 9.-—N '- (Butyrylbenzenesulfoayl) -VN’ - Homo
40
(A) v N - (4 - butyrylbenzenesulfonyl) ->N' ,- homomor
pholinourea freebase: In the same (manner as shown in
Example 1, Part-F, N-(4-butyrylbenzene'sulfonyl)-N’
sulfonylurethane and 1-aminohexamethyleneimine.
as shown in Example 1, Part G, N-(4-isobutyrylbenzene
homomorpholinourea free base Was prepared by using 4
butyrylbenzenesulfonylurethane and 4-aminohom0mor
pholine instead of 4-acetylbenzenesulfonylurethane and
sulfonyl) - N’ - heptamethyleneiminourea hydrochloride 45
1"-aminohexamethyleneirnine.
was prepared by using N-(4-isobutyrylbenzenesulfonyl)
N’-heptamethyleneiminourea free base instead of N-(4
pholinourea hydrobromide: In the same manner as shown
(C) N - (4 - isobutyrylbenzenesulfonyl) - N’ - hepta
methyleneiminourea hydrochloride: In the same manner
(B) N - (4 - butyrylbenzenesulfonyl) - N’ g- homomor
in Example 1, Part G, N-(4-butyrylbenzenesulfonyl)-N’
homomorpholinourea hydrobromide was» prepared by
acetylbenzenesulfonyl ) -N'-hexamethyleneiminourea ' free
base.
‘Example 5.-—N - (4 - Propz'onylbenzenesulfonyl) - N’ -(3,
50 using N -(4 - butyrylbenzenesulfonyl) - N’ - homomor
pholinourea free base and hydrogen bromide, instead of
d-Dimethylhexam ethyleneimino) area
N - (4 ,- acethylbenzenesulfonyl) - N’ - hexamethylene
iminourea free base and hydrogen chloride.
(A) N - (4 - propionylbenzenesulfonyl) - N’ - (3,6-di
methylhexamethy1eneimino)urea free base: In the same
manner as shown in Example 1, Part F, N-(4-propionyl 55
Example 10.—N - (3 - Isobutyrylbenzenesulfonyl) - N’
Thiamorpholinourea
'
benzenesul-fonyl) '- N’ - (3,6 - dimethylhexamethylene
imino)urea free base-was prepared by using 4-propionyl
benzenesulfonylurethane and 1-amino-3,6-dimethylhexa
methyleneimine instead of 4-acetylbenzenesulfonylure
thane and l-aminohexamethyleneimine.
(A) N - (3 - isobutyrylbenzenesulfonyl) - N’ - thia-'
morpholinourea free base: In the same manner as shown
in Example 1, Part F, N-(3-isobutyrylbenzenesulfonyl)
60 N’-thiamorpholinourea free base was prepared by using
3-isobutyrylbenzenesulfonylurethane
. '(B) N - (4 - propionylbenzenesulfonyl) - N’ - (3,6 - di
and
4-aminothia
methylhexamethyleneimino)urea tartrate: In the same
morpholine instead of 4-acetylbenzenesulfonylurethane
manner as shown in Example 1, Part G, N-(4-propionyl
and 1-aminohexamethyleneimine.
,
(B) N - (3 - isobutyrylbenzenesulfonyl) - N’ - thia
benzenesulfonyl) --N’ - (3,6 - dimethylhexamethylene
imino)urea tartrate was prepared by using N-(4-propionyl 65 morpholinourea phosphate: In the same manner as shown ,
in Example 1, Part G, N-(3-isobutyrylbenzenesulfonyl)
N’-thiamorpholinourea phosphate was prepared by using
imin0)urea free base and tartaric acid instead of N-(4
N - (3 - isobutyrylbenzenesulfonyl) - N’ ? thiamorpho
acetylbenzenesulfonyl)-N'-hexamethyleneiminourea free
linourea free base and phosphoric acid instead of N-(4
base and hydrogen chloride.
vbenzenesulfonyl) - N’ - (3,6 - dimethylhexamethylene
Example 6.—N - (4 - Acetylbenzenesulfonyl) - N’ - 0cm‘
methyleneiminourea
(A) N - (4 - acetylbenzenesnlfonyl) - N’ - octamethyl
70
acetylbenzenesulfonyl) - N’ - hexamethyleneiminourea
and hydrogen chloride.
Example 11.—-N-(4-Acetylbenzenesulfonyl)-N'-(2,3,5
Trimethylthiamorpholino) Urea Free Base
.eneiminourea free base: In the same manner as shown in
, Example 1, Part F, N-(4-acetylbenzenesulfonyl)-N’-octa 75 ,In the same manner as shown in Example 1, Part F,
3,0a1,331
Exaiizp le 1 7.-'—N- (4-Valerylbenzenesulfonyl) -N'
Hexamethyleneiminourea
(A) 4-valerylbenzenesulfonylurethane: In the same
N - (4 -,acetylbenzenesulfonyl) - N’ - (2,3,5 -' trimethyl
thiamorpholino)urea free base was prepared by using 4
amino-2,3,S-trirnethylthiamorpholine instead of’ l-arnino
rhexarnethyleneimin'e.
, ,
'
.
'
y
manner as shown in Example 1, Parts A, B, and C, 4
valerylbenzenesulfonylurethane was preparedtby using p
arninovalerophenone (Sugirnoto et al., J. Pharm. Soc.
Japan 71, 1161, 1951; CA. 46,5011, 1952) instead of
Butylpiperidino)Ureu Free Base
,7" In the. same manner as? shown-J in Example 1, Part F,
p-arninoacetoplienone.
- (4 - propionylbenzenesulfonyl)‘- N’ -' (2 - butylpiper
_
(B) N - (4 - valerylbenzenesulfonyl) - N’ - hexa
idino)urear free base was prepared by using \4-propionyl
benzenesulfonylurethane , and l-arhino-Z-butylpiperidine 10 methyleneirninourea free base: In the same manner as
shown in Example 1, Part F, N-(4-valerylbenzenesulfon
instead of 4-acetylbenzenesulfonylurethane and l-amino
yl)-N’-hexamethyleneiminourea free base was prepared
hexarnethyleneirnine.
by using 4-valerylbenzenesulfonylurethane instead of 4
acetylbenzenesulfonylurethane.
ButyZ-S-Methylpyrrolidiuo) Urea Free Base
15
(C) N - (4 - valerylbenzenesulfonyl) - N’ - hexa
In the same manner as, shown in Example 1, Part F, r rnethyleneiminourea hydrochloride: In the same manner
as shown in Example 1, Part G, N-(4-valerylbenzenesul
methylpyr'rolidinwurea free base was prepared by using
fonyl)-N'-hexamethyleneiminourea hydrochloride was
3~propionylbenzenesulfonylurethane and l-amino-Z-butyl
prepared by using7 N-(4-valerylbenzenesulfonyl)-N'-hexa
S-methylpyrrolidine instead of 4-acetylbenzenesulfonyl 20 rnethyleneiminourea free base instead of N-(4-acetylben
urethane and l-aminohexarnethyleneimine.
"zenesulfonyD-N’-hexamethyleneirninourea free base.
As indicated hereinbefore the compounds of the present
Example 14.—N- (Z-Butyrylbenzenesulfonyl) -
‘N - (3 - propionylbenzenesulfonyl) - N’ - (2 - butyl - 5
invention are useful for the treatment of diabetes peroral
ly and for this purpose the active compounds are asso
N’-Pyrr0lidinourea
(A) N - (2 - butyrylbenzenesulfonyl) - N’ - pyrroli
25
dinourea free base: In the same manner as shown in Ex
ciated with a’ pharmaceutically acceptable carrier.
_
ample '1, Part F, N-(Z-butyrylbenzenesulfonyl)-N’-pyr
‘lrolidinourea free base was prepared by using Z-butyryl
methyleneimine.
_
r
30 suspensions and solutions (depending on concentration
desired), and ?avored oil suspensions and solutions where
in edible oils such as corn oil, cottonseed oil, coconut oil,
s
(B) N - (2 - butyrylbenzenesulfonyl) - N’ - pyrroli
,dinourea salicylate: In the same manner as shown in
:peanut oil, sesame oil, or mixtures ‘of these, and the like
Example 1, Part G, N-(Z-butyrylbenzenesulfonyl)-N'- V
'pyrrolidinourea' salicylate was prepared by using N-(2
butyrylbenzenesulfonyl)-N’-pyrrolidinourea free base and
salicylic acid instead of N-(4-acetylbenzenesulfonyl)-N'~
hexamethyleneiminourea free base and hydrogen chloride.
Example 15.,—N-(2-Pr0pi0nylbe‘nzenesulfonyl -N'
'
can be employed.
,
35'
For preparing compositions such as tablets and other
compressed formulations the composition can include
any compatible and edible tableting material used in
pharmaceutical practice such as corn starch, lactose, di-_
basic'calcium phosphate, stearic acid, magnesium stearate,
40 talc, methyl cellulose, and the like.
(4-Butylpiperazino) Ure'a Free Base
'
' . Similarly, the compounds of‘ the present invention can
be mixed with suitable adjuvants for the preparation of
resorbable hard gelatin or soft capsules utilizing conven
In the same manner as shown in Example 1, Part F,
N - (2 ~ propionylbenzenesulfonyl) - N’ - (4 - butylpiper- i
tional pharmaceutical practices.
The following illustrative compositions are within the
.azino)urea free base was prepared by using 2-propionyl
benzenesulfonylurethane and 1-aruino-4-butylpiperazine
scope of the present invention:
instead of .4-acetylbenzenesulfonylurethane and I-amino
hexamethyleneimine.
( 1) ~ HARD GELATIN CAPSULES
Example ' 16.—’N- (3-Prop‘i0nylbenzenesulfonyl) -N’
'
Solid
forms include capsules, tablets, powders, pills, and the
like, and liquid forms include suitably ?avored aqueous
benzenesulfonylurethane and l-aminopyrrolidine instead
of 4-acetylbenzenesulfonylurethane and l-aminohexa
For such oral administration'the active compounds can
1be administered in liquid or solid dosage form.
10,000 two-piece hard gelatin capsules for oral use,
each containing 200 milligrams of N-(4-acetylbenzenesul
Piperazz'nourea
(A) 1sarnino-4-benzylpiperazine: In the same manner
.as shown in Examplel, Parts D and E, 1-arnino-4-benzyl
piperazine- was ‘prepared by using 4-benzylpiperazine
(US. Patent 2,415,785) instead of hexarnethyleneimine.
(B)"N - (3 - propionylbenze'nesulfonyl) -,N"- (4
benzylpiperazino)urea free base: In the same manner as
50 , fonyl)¢N’-hexamethyleneiminourea free base are prepared
from‘ the following amounts and types of materials:
3
_
V
‘
Gm.
N - (4 - acetylbenzenesulfonyl) ,- N’ - hexamethyl
eneiminourea free base _______ __' _________ __
55
shown in Example 1, ‘Part F, 7N-(3-propionylbenzenesul
2000
.Corn starch,
_
‘
1616
Mineral oil, U.S.P. ________ _; ______________ __ 129.6
fonyl)-N’-(4-benzylpiperazino)urea free base was pre
,Magnesiurn stea/rate, powder _______________ __
pared by using 3-propionylbenzenesulfonylurethane and
1~amino-4-benzylpiperazine instead of 4-acetylbenzrene
sulfonylurethane and l-aminohexamethyleneimine.
Talc, 'U.S.P.
the rest of the ingredients and then capsulated.
azinourea free base: In the‘ same manner as shown in
N’-piperazinourea free base was prepared by debenzylat 65
ing N - (3 - propionylbenzenesulfonyl) - N’ - (4 - benzyl
’
(2) SOFT ELASTIC CAPSULES
» VOné-piece soft elastic capsules for oral use, each con- ’
'piperazino)urea free base with hydrogen in the presence
raining ‘100 milligrams of N-(4-acetylbenzenesulfonyl)
‘
*(D) N - (3’ - propionylbenzenesulfonyl)' - N’ - piper
ample 1, Part G, N-(3-propionylbenzenesulfonyl)-N'
162
The ?nely powdered N-(4-acetylben2enesulfonyl)-N'
-U.S.~Patent 2,415,786, N-(3-propionylbenzenesulfonyl)
iazinourea tar'trate: In the same‘ manner as shown in Ex
1,62
hexamethyleneimino free base is mixed thoroughly with
(C) N - (3 - propionylbenzenesulfonyl) - N’ - piper
' ‘ of p‘alladium-on-charcoal catalyst.
__'
70
N'-hexamethyleneiminourea free base are prepared in the
usual manner by ?rst dispersing the active ingredient in
sui?cient corn oil to render the material capsulatable. .
piperazinourea' tartrate was prepared by using N-(3-pro
7(3) OIL SUSPENSION
pionylbenzenesulfonyl)-N'-piperazinourea free ‘base and
tartaric acid instead of N-(4-acetylbenzenesu1fonyl)-N’
An oil suspension for oral use; containing in‘each 5
‘hexamethyleneirninourea tlree base and hydrogen chloride. 75 milliliters 500 milligrams of N-(4-acetylbenzenesu1fonyl)
3,041,331
1 10
N'-hexamethyleneiminourea free base is prepared from the
following types and amounts of materials:
sweetening agent
gm
I claim:
1. A compound selected from the group consisting of
(1) N-alkanoylbenzenesulfonyl - N’ - (cyclicamino)urea
3.5
free bases having the formula:
N - (4 - acetylbenzenesulfonyl) -N'-hexamethy1ene
0
iminourea free base _________________ .._gm__ 1000
Preservative
am
20
. Antioxidant
Flavoring
_
gm
1
ml
25
Aluminum monostearate-corn oil gel to make 10,000 ml.
II
R-C
0
II
Z
10 wherein R is alkyl of 1 to 4 carbon atoms, inclusive, and
(4) TABLET
10,000 oral tablets each containing 250 milligrams of
A
—N
Z
V
N-(4 - pripionylbenzenesulfonyl)-N’-piperidinourea free
is- saturated heterocyclic amino selected from the group 0
base are prepared from the following types and amounts
15 consisting of unsubstituted and mono- and polyalkyl sub
of materials:
stituted piperidino, morpholino, thiamorpholino, piper
-
azino, pyrrolidino, hexamethyleneimino, heptamethyl
eneimino, octamethyleneimino, and homomorpholino,
Gm.
N - (4 - propionylbenzenesulfonyl)-N'-piperidino
urea free base
2500
wherein each alkyl is of 1 to 4 carbon atoms, and (2)
Dicalcium phosphate _______________________ __ 3050
Methylcellulose, U.S.P. (15 cps.) ____________ __
Talc, bolted
'
Calcium stearate, fine powder ________________ __
pharmacologically acceptable acid addition salts thereof.
65 20
2. A compound having the formula:
450
35
‘1?
R-C
The ingredients are mixed in a conventional manner
and compressed into tablets, each containing 250 mg. 25
of active ingredient.
‘(5) SYRUP
A
2
\./
@somnonnnr
wherein R is alkyl of 1 to 4 carbon atoms, inclusive, and
A sugar-free syrup for oral use containing in each 5
-—N
milliliters 250 milligrams of N-(4-butyrylbenzenesul
fonyl)-N'-(4-methylpiperazino)urea sulfate is prepared 30
from the following types and amounts of materials:
piperazino)urea sulfate ______________ "gm..Methylparaben U.S.P. _________________ __gm__
Sorbic acid
'
gm-..
Sweetening agent
2111
Flavoring
ml _
Glycerin
Deionized water to make 10,000 ml.
ml‘
3. A compound having the formula:
I
N - (4 - butyrylbenzenesulfonyl)-N’ - (4 ~ methyl
Z is piperidino
it
13-0
500
3 35
3
wherein R is an alkyl of 1 to 4 carbon atoms, inclusive,
and
18
3
1500
—N
Z is pyrrolidlno
4.0
vA dose of 1 teaspoonful (5 ml.) to 1 tablespoonful (15
ml.) will give the patent 250 to 750 mg. of N-(4»butyryl
benzenesulfonyl)-N’-(4-methylpiperazino)urea sulfate.
The dosage of the novel compounds of the present in
4. A compound having the formula:
0
ll
0
. R—C
'
vention for the treatment of diabetes depends on the age, 45
weight, and condition of the patient being treated. Gen
erally speaking for adult oral administration the pre
ferred unit dosage is 100 to 500 mg. of active compound
with a suitable pharmaceutical diluent and/ or lubricant.
One or two unit dosages are given one to four times a 50
day. A total daily dose of from 100 to 1500 mg. given
singly but preferably in divided doses, embraces the effec
II
.
/\
SOzNHONH-N
z
V
wherein R is alkyl of 1 to 4 carbon atoms, inclusive, and
-N
Z is morpholino
5. A compound having the formula:
tive range for the treatment of diabetes.
In addition to the foregoing principal active ingredients,
the present compositions can also include, as supple 55
mentary active ingredients, other blood sugar lowering
compounds, such as tolbutamide, chlorpropamide and
phenformin. Such supplementary active ingredients can
be included in these compositions in amounts approxi
mately equal to or less than the concentrations employed
where such materials are the sole active ingredients.
wherein R is alkyl of 1 to 4 carbon atoms, inclusive, and
-N
Z is hexamethyleneimino
Nov references cited.
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