Note: Descriptions are shown in the official language in which they were submitted.
108~ 4
Background of the~Invention
The present invention relates to novel aliphatic
sulfamates. The sulfamates may be represented by the formula:
Y~n
CH2S2NRlR2
wherein n is an integer from 0-8 and X and Y are hydrogen; -
provided that when n is 1, X and Y are hydrogen, lower alkyl
having 1-3 carbon atoms, aryl such as phenyl or arylal~yl
such as benzyl, phenethyl and the like; and Rl and R2 are -
hydrogen, alkyl having 1-7 carbon atoms, aryl, arylalkyl
such as benzyl, phenethyl, phenylpropyl and the like, cycloalkyl -~
such as cyclopentyl, cyclohexyl and the like, or Rl and R2
together with the N-atom to which they are attached form a
saturated heterocyclic ring. Preferred among these compounds
are those compounds wherein Rl and R2 are hydrogen.
j The novel aliphatic sulfamates of the present invention
I
are prepared by reacting an alkanediol with a sulfamoyl halide
in a suitable solvent in the presence of a strong base.
Suitable alkanediols which may be employed include 1,2~
ethanediol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol,
l,lQ-decanediol and the like. As the halide reactant, sulfamoyl --
chloride and N,N-di or mono substituted sulfamoyl halides
may be employed. Bases such as sodium hydride, sodium amide,
sodium hydroxide, pyridine and tributyltin are examples of -
suitable strong bases. Examples of solvents which may be ~ ;
employed include 1,2-dimethoxyethane, ether, tetrahydrofuran, - -
diglyme and p-dioxane. The reaction with the sulfamoyl halide ~
. .
- -2- ~ ~
~ ~.
.. . . . .
108;~194
may be carried out at room temperature, but it is preferred
to carry out the reaction at a temperature between 0-10C.
~ The sulfamate is obtained from the reaction mixture by
techniques known to those skilled in the art.
The present invention also relates to an alternative
process for the preparation of aliphatic primary sulfamates.
The sulfamates which can be prepared by said alternative process
may be represented by- the formula:
:~ IH20SO2NH2 I' .
~CXY~n : :
CH2 OS02NH2
wherein n, X and Y are as defined above. .
. The aliphati.c primary sulfamates of the present
invention are prepared in accordance with said alternative
process- by reacting an alkanediol with a substituted sulfamoyl :~
hali.de such as a substituted sulfamoyl chloride, for example, in
a suitable solvent in the presence of a strong base. Suitable
alkanediols which may be employed include 1,2-ethanediol,
1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, l,10-decane-
diol and the like. As the~halide reactant, a substituted
sulfamoyl halide is employed wherein the substituent is a
protecting group which can be readily removed under acid
conditions. Suitable groups which. may be employed include groups
such. as t-butyl, benzyl, ~-alkyl benzyl wherein the alkyl group
has 1-3 carbon atoms, allyl and l-alkyl-allyl wherein the alkyl
group has 1-3 carbon atoms. The substituent on the sulfamoyl
halide reactant is removed by treating the compound obtained
from the reaction mixture with a strong acid. Acids such as
trich.loroacetic acid, trifluoroacetic acid, methanesulfonic
-3-
' ~ . . , ' ~ ' ~ :
1~8~1~4
acid, conc. sulfuric acid and conc. hydrochloric acid, for
example, may be employed. The preparation of unsubstituted
sulfamoyl halides involves steps ~hich are inherently hazardous.
The use of a substituted sulfamoyl halide in place of an
unsubstituted sulfamoyl halide avoids the hazards associated
with the preparation of sulfamoyl halides. Substituted sulfamoyl
halides are prepared by reacting an appropriate amine such as,
for example, t-butylamine or benzylamine, with a sulfuryl
halide in a suitable solvent, such as acetonitrile, for example.
Bases such as sodium hydride, potassium t-butoxide, potassium
hydride, tributyltin, sodium amide and sodium are examples of
bases which may be employed for the initial reaction. Suitable
solvents for the reaction include toluene, benzene, xylene,
ether, tetrahydrofuran, diglyme, 1,2-dimethoxyethane and p-
dioxane.
The reaction with the substituted sulfamoyl halide
may be carried out at room temperature, but it is preferred
to carry out the reaction at a temperature between room
temperature and about 60C. The removal of the protecting
group is preferably carried out at room temperature in an
inert atmosphere such as nitrogen, for example. The product
is obtained from the reaction mixture by techniques known to
those skilled in the art.
The novel aliphatic sulfamates are useful in the
control of fertility in male animals. The compounds are
capable of interfering with sperm as they sojourn in the
epidimdymis and thus result in what is known as functional
sterility, i.e. the gametes remain morphologically normal
and show motility but normal fertilization is not achieved.
Generally dosage levels of from about 5-200 mg./kg. are
effective in inducing functional sterility. The preferred
-4-
., -:
`~ 108Z194
. :
dosage range is from about 1~-150 mg./kg, In addition to
causing functional sterility of epididymal sperm, the novel
sulfamates have antiandrogenic properties as manifested by -
inhibition of the size of the ventral prostate.
The general procedure followed to determine the
activity of compounds which inhibit male fertility by
altering the functional capacity of epididymal sperm is as
-' follows: ~,
A two week dosing period (i.e., the approximate
period required for sperm transport through the epididymis)
enables separation of those drugs which affect epididymal
sperm maturation and/or function from the antispermatogenic
agents which have a longer delay in the onset of sterility.
Each individual test involves 5 male rats (250-300 g.) caged
together in air conditioned animal quarters and maintained
on laboratory chow and tap water ad libitum. The compound
to be tested is dissolved or suspended in appropriate
~- vehicles (usually methylcellulose~ and administered dailyusually i.g.~ for 14 consecutive days. Control animals
' 20 receive the vehicle only. At the end of the 14th day of
treatment each male is individually caged with a proestrus - -
female. Vaginal smears are checked the following morning for
evidence of positive mating, and those males failing to mate
are recohabited with proestrus females the following night.
Males are sacrificed and autopsied the day after cohabitation
for a gross examination of testes, epididymides, and accessory
sex organs. Tissue samples of these organs are preserved for
histological processing if observation yields a possible
effect. Females Cregardless of sperm presence in the vaginal
washingsl are autopsied 14 days after cohabitation to examine
for pregnancy-. ~;~
--5--
.. .
~.
.
- ' ' . ' ,,' ': '' " ' " "' . . ' ' ,
.
lOBZ194
The inability of females to produce a viable embryo
following a successful mating wïth treated males (two weeks
of medication~ is used as a measure of functional infertility.
The number of males mating of those cohabited gives a gross
indication of the drug's effect on libido. The size of the
accessory sex organs provides an indication of the effect on
androgen production. Microscopic analysis of epididymal
sperm provides information on sperm quality ~motility and
morphology~ and quantity.
lQ The following examples describe the invention in
greater particularity and are intended to be a way of
illustrating and not limiting the invention.
EXAMPLE 1
1,2-Bis-O-sulfamyl-1,2-ethanediol
A 57~ oil dispersion of sodium hydride (8.45 g.; ~-
a. 2~ mol.l is added to a solution of ethylene glycol
~3.1 g.; 0.05 mol.l in 1,2-dimethoxyethane (100 ml.). The
resulting suspension is stirred at room temperature for two
hours and then cooled to +4C. Sulfamoyl chloride (20.79 g.;
0.18 mol.l is dissolved in 1,2-dimethoxyethane (400 ml.l and
added dropwise to the solution with stirring. The reaction
mixture is stirred at +4C for an additional 24 hours. A
precipitate forms which is filtered off and the filtrate is
concentrated. The residue is partitioned between heptane and
methanol, and the methanol solution is concentrated to a
syrup which crystallizes from ethyl acetate to yield 6.1 g. ~ ~ -
(58%~ of 1,2-bis-O-sulfamyl-1,2-ethanediol, m.p. 96.5-99C.
When in the above procedure 1,5-pentanediol is employed in
place of ethylene glycol, 1,5-bis-O-sulfamyl-1,5-pentanediol
is obtained.
-6-
-
.. . . .. .. , . . . . :
: , , .,, - . . . ,: . . .
10~32194
EXAMPLE 2
1,10-Bis-O-sulfamyl-l, la.-decaned;ol
A 57% oil dispersion of sodium hydride (8.45 g.; 0.20
mol.l is added to a solution of l,10-decanediol (8.71 g.; 0.05
mol.~ in 1,2-dimethoxyethane ClOO ml.~. The resulting solution
is stirred at room temperature for two hours and then cooled to
+4C. Sulfamoyl chloride ~20.79 g.; 0.18 mol.~ is dissolved
in 1,2-dimethoxyethane ~400 ml.) and added dropwise to the
solution with stirring. The reaction mixture is stirred at
+4C for an additional 48 hours. A precipitate forms which is
filtered off and the filtrate is concentrated. The residue
is partitioned between heptane and methanol and the methanol
solution is concentrated to a syrup which crystallizes from
ethyl acetate to yield 6.0 g. (36%~ of l,10-bis-O-sulfamyl-
l,10-decanediol, m.p. 129-131C.
When în the above procedure 1,6-hexanediol is employed
` in place of l,10-decanediol, 1,6-bis-O-sulfamyl-1,6-hexanediol
is obtained.
EXAMPLE 3
1,4-Bis-O-sulfamyl-1,4-butanediol
A 57% oil dispersion of sodium hydride (8.45 g.;
a. 20 mol.l is added to a solution of 1.4-butanediol (4.5 g.;
~ 0.05 mol.~ in 1,2-dimethoxyethane (100 ml.~. The resulting
; solution is stirred at room temperature for two hours and
then cooled to +4C. Sulfamoyl chloride (20.79 g.; 0.18
mol.~ is dissolved in 1,2-dimethoxyethane (400 ml.) and
added dropwise to the solution with stirring. The reaction
mixture is stirred at +4C for an additional 48 hours. A
precipitate forms which is filtered off and the filtrate is
concentrated. The residue is partitioned between heptane and
methanol and the methanol solution is concentrated to a
-7-
~82~9d~
syrup which crystallizes from ethyl alcohol to yield 5.5 g.
~47%~ of 1,4-bis-O-sulfamy1-1,4-butanediol, m.p. 126-129C.
When in the above procedure 1,7-heptanediol is
employed in place of 1,4-butanediol, 1,7-bis-O-sulfamyl-
1,7-heptanediol is obtained.
EXAMPLE 4
1,3-Bis-O-sulfamyl-1,3-propanediol
A 57% oil dispersion of sodium hydride (25.4 g.;
a.60 mol.l is added to a solution of 1,3-propanediol (11.41 g.;
Q.15 mol.~ in 1,2-dimethoxyethane (100 ml.~. The resulting
solution is stirred at room temperature for two hours and
then cooled to ~4C. Sulfamoyl chloride (62.37 g.; 0.54
mol.~ is dissolved in 1,2-dimethoxyethane (400 ml.~ and added
dropwise to the solution with stirring. The reaction mixture
is stirred at +4C for an additional 24 hours. A precipitate
` forms which is filtered off and the filtrate is concentrated.
^ ,
The residue is partitioned between heptane and methanol and
the methanol solution is concentrated to a syrup. The residue ~
is washed with heptane and chromatographed through SilicAR, - -
CC-7 using 50% acetone-chloroform as the eluent. The
fractions are collected and upon removal of the solvent
1,3-bis-O-sulfamyl-1,3-propanediol is obtained as a crystalline
residue, m.p. 85-87.5C.
When in the above procedure 1,8-octanediol and 1,9-
nonanediol are employed in place of 1,3-propanediol, 1,8-
bis-O-sulfamyl-1,8-octanediol and l,9-bis-O-sulfamyl 1,9-
nonanediol respectively are obtained.
EXAMPLE 5
2-Methyl-2-propyl-1,3-bis-O-sulfamyl-
1,3-propanediol
To a solution of 10 g. ~0.076 mol.) of 2-methyl-
.. . . -:
2-propyl-1,3-propanediol in 20Q ml. of dimethoxyethane is
added 12.7 g. (0.3 mol.l of 57~ sodium hydride followed by
an additîonal 400 ml. of dimethoxyethane. After stirring
overnight the suspension is cooled to 4C and a solution of
31.2 g. (-0.27 mol.~ of sulfamoyl chloride in 600 ml. of
dimethoxyethane is added dropwise. The resulting suspension
is stirred overnight at room temperature. The mixture is
then filtered, the filtrate is concentrated and the residue
washed with heptane. The residue is then chromatographed
through SilicAR, CC-7 and eluted with 25~ acetone-chloroform.
The solid obtained after removal of the solvent is
crystallized from a mixture of ethyl acetate-hexane-methylene
chloride to afford 2-methyl-2-propyl-1,3-bis-O-sulfamyl-1,3-
propanediol, m.p. 92-94C.
When in the above procedure 2-ethyl-2-propyl-1,3-
propanediol, 2,2-dimethyl-1,3-propanediol and 2-methyl-1,3-
propanediol are employed instead of 2-methyl-2-propyl-1,3-
propanediol, 2-ethyl-2-propyl-1,3-bis-O-sulfamyl-1,3-
propanediol, 2,2-dimethyl-1,3-bis-O-sulfamyl-1,3-propanediol
and 2-methyl-1,3-bis-O-sulfamyl-1,3-propanediol, respectively,
are obtained.
B AMPLE 6
2,2-Diphenyl-1,3-bis-O-sulfamyl-1,3-propanediol
To a solution of 17.3 g. (0.076 mol.) of 2,2-
diphenyl-1,3-propanediol in 200 ml. of dimethoxyethane is
added 12.7 g. ~0.3 mol.l of 57% sodium hydride followed by
an additional 400 ml. of dimethoxyethane. After stirring
overnight the suspension is cooled to 4C. A solution of
31.2 g. (0.27 mol.l of sulfamoyl chloride in 600 ml. of
dimethoxyethane is then added dropwise. The suspension is
stirred overnight at room temperature. After filtering the
108~9~
mixture the filtrate is concentrated and the residue washed
with heptane. Chromatography on SilicA~R, CC-7, followed by
crystallization affords 2,2-diphenyl-1,3-bis-O-sulfamyl-1,3-
propanediol.
When in the above procedure 2,2-dibenzyl-1,3-
propanediol and 2,2-dicyclohexyl-1,3-propanediol are
employed in place of 2,2-diphenyl-1,3-propanediol, 2,2-
dibenzyl-1,3-bis-O-sulfamyl-1,3-propanediol and 2,2-
dicyclohexyl-1,3-bis-O-sulfamyl-1,3-propanediol are obtained.
EXAMPLE 7
1,2-Bis-O-(N,N-dimethylsulfamyl~-l, `
2-ethanediol
A 57~ oil dispersion of sodium hydride (8.45 g.;
0.20 mol.l is added to a solution of ethylene glycol
(3.1 g.; 0.05 mol.~ in 1,2-dimethoxyethane (100 ml.). The
resulting suspension is stirred at room temperature for two
hours and then cooled to +4C. N,N-dimethylsulfamoyl
chloride, 25.8 g. ~0.18 mol.l, is dissolved in 1,2-dimethoxy-
, ethane ~400 ml.) and added dropwise to the solution with -~
stirring. The reaction mixture is stirred at +4C for an -
additional 24 hours. A precipitate forms which is filtered
off and the filtrate is concentrated. The residue is
- partitioned between heptane and methanol, and the methanol
solution is concentrated to a syrup which crystallizes from
ethyl acetate to yield 1,2-bis-O-~N,N-dimethylsulfamyl)-l, :
2-ethanediol.
When in the above procedure N,N-diphenylsulfamoyl
chloride and N-ethylsulfamoyl chloride are employed in place
of sulfamoyl chloride, 1,2-bis-O-(N,N-diphenylsulfamyl)-
1,2-ethanediol and 1,2-bis-O-(N-ethylsulfamyl)-1,2-ethanediol -~
are obtained.
"' ' ' '' `
--10-- , .
: :'
-,
108Zl9~
When in the above procedure N-cyclohexylsulfamoyl
chloride, N,N-cyclopentylsulfamoyl chloride, N,N-dibenzyl-
sulfamoyl chloride and l-piperidylsulfonyl chloride are
employed ïn place of sulfamoyl chloride, 1,2-bis-O-(N-
cyclohexysulfamyl~-1,2-ethanediol, 1,2-bis-O-(N,N-dicyclopentyl-
sulfamyl~-1,2-ethanediol, 1,2-bls-O-(N,N-dibenzylsulfamyl~-1,2-
ethaned;ol and 1,2-bis-~1-piperidylsulfonyl)-1,2-ethanediol
are obtained.
EXAMPLE 8
1,2-Bis--O--sulfamyl-1,2-ethanediol
Ethylene glycol ~21.7 ml., 0.385 mol.) is added
dropwise during 15 mins. to a suspension of sodium hydride
C37 g. 50% m.o., 0.77 mol.~ in toluene (450 ml.) at room
temperature. The suspension is stirred for 15 mins., then
i warmed slowly to 45-50C and stirred at that temperature for
,
2.5 hrs. The reaction mixture is then cooled to 20C and a
solution of t- butyl-sulfamoyl chloride ~132 g., 0.77 mol.)
in toluene ~131 ml.~ is added dropwise at 20-35C during
1.25 hrs. Heavy foaming occurs during the addition, and
cooling is required to maintain the temperature at 20-35C. -
The resulting tan colored viscous suspension is stirred for
2.5 hrs. at 20C, then for 1.5 hrs. at 45-50C and then for
16 hrs. without further heating. The gelatinous solid
which forms is collected by filtration, washed with toluene,
and extracted twice with hot chloroform (600 ml., 300 ml.).
The solids which remain are then suspended in water (500 ml.)
and extracted with chloroform until no solid remains. The
chloroform extracts are combined and evaporated. The resulting
solid is crystallized from chloroform/heptane to afford
72.26 g. ~56.4%~ of 1,2-b -O-~N-t-buty-lsulfamyl~-l, 2-
--11--
... . .
' , ,
1082~94
ethanediol, m.p. 119-121~ The crystalline compound
(llQ g., 0.33 mol.l is added to CF3CO2H C330 ml ) with
stirring at 25 under N2. The resulting clear solution is
stirred at room temperature for 20 hrs. The solid is
; collected by filtration, w-ashed wïth CHC13 (2 x 50 ml.l and
; dried _ vacuo at 50-55 to afford the crude product
C61.1 g. 84~T The crude material (61.1 g.~ is dissolved
in acetone C185 ml.~ at reflux temperature and treated
with charcoal C1.2 g.). The charcoal suspension is
refluxed for 5 mins. and then filtered through Supercel.
The colorless filtrate is treated with CHC13 (185 ml.),
cooled and stirred at 0-5 for 1 hr. The solid which
settles out is collected by filtration and dried in vacuo
--
at 50-55 to afford 54.0 g. (75.5~1 of 1,2-bls-O-sulfamyl-
1,2-ethanediol, m.p. 98.5-101.
EXAMPLE 9
l,10-Bis-O-sulfamyl-l,10-decanediol -~
l,10-Bis-O-sulfamyl-l,10-decanediol is prepared in
the s-ame manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in
Example 8 except that l,10-decanediol (67 g., 0.385 mol.) ~-
is employed as the alkanediol.
When in the above procedure 1,6-hexanediol is
employed in place of l,10-decanediol, 1,6-bis-O-sulfamyl-
1,6-hexanediol is obtained.
EXAMPLE lQ
1,4-Bis-O-sulfamyl-1,4-butanediol
..... ...... .
1,4-Bis-O-sulfamyl-1,4-butanediol is prepared in
the same manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in
Example 8 except that 1,4-butanediol (34.6 g., 0.385 mol.)
~ 30 is employed as the alkanediol.
- -12-
.
- . :.:, .... . .
,, . ,:- ,: :: , - . '."' ' ,~ , . .
- , , ~ , : :
.. . .. . . . ..
1082194
When in the above procedure 1,7-heptanediol is
employed in place of 1,4-butanediol, 1.7-bls-O-sulfamyl-
1,7-heptanediol is obtained.
EXAMPLE 11
1 7 3-sis-o-sulfamyl-l~3-propanediol
1,3-Bis-O-sulfamyl-1,3-propanediol is prepared in
the same manner as 1,2-bis-O-sulfamyl-1,2-ethanediol in
Example 8 except that 1,3-propanediol (29.~ g., 0.385 mol.)
is employed as the alkanediol.
When in the above procedure 1,8-octanediol and
l,9-nonanediol are employed in place of 1,3-propanediol,
1,8-bis-O-sulfamyl-1,8-octanediol and l,9-bis-O-sulfamyl-
l,9-nonanediol, respectively, are o~tained.
EXAMPLE 12
2-Methyl-2-propyl-1,3-bis-O-sulfamyl-1,3-propanediol
2-Methyl-2-propyl-1,3-bis-O-sulfamyl-1,3-propanediol
is prepared in the same manner as 1,2-b -O-sulfamyl-
1,2-ethanediol in Example 8 except that 2-methyl-2-propyl-
1,3-propanediol (50.8 g., 0.385 mol.) is employed as the
alkanediol.
When in the above procedure 2-ethyl-2-propyl-1,3-
propanediol, 2,2-dimethyl-1,3-propanediol and 2-methyl-1,3-
~ propanediol are employed instead of 2-methyl-2-propyl-1,3-
- propanediol, 2-ethyl-2-propyl-1,3-b -O-sulfamyl-1,3-
- propanediol, 2,2-dimethyl-1,3-bis-O-sulfamyl-1,3-propanediol
and 2-methyl-1,3-bis-O-sulfamyl-1,3-propanediol, respectively,
are obtained.
EXAMPLE 13
2,2-Diphenyl-1,3-bis-0-sulfamyl-1,3-propanediol
2,2-Diphenyl-1,3-bis-O-sulfamyl-1,3-propanediol
is prepared in an identical manner as the sulfamate reported
-13-
': ' ; :. -
1082194
in Example 8 except for the use of 2,2-diphenyl-1,3-
propanediol (87.7 g., 0.385 mol.) as the alkanediol.
When in the above procedure 2,2--dibenzyl-1,3-
propanediol and 2,2-dicyclohexyl-1,3-propanediol are
employed in place of 2,2-diphenyl--1,3-propanediol, 2,2-
dibenzyl-1,3-bis--O-sulfamyl-1,3-propanediol and 2,2-
dïcyclohexyl-1,3-bis-o-sulfamyl-1,3-propanediol are obtained.
EXAMPLE 14
Preparation of t-butyl-sulfamoyl chloride
t-Butylamine (65.7 g., 0.90 mol.~ is added during
1 hr. at 20-30C to a stirred solution of sulfuryl chloride
(240 ml., 3 mol.~ in acetonitrile ~450 ml.~. A vigorous
evolution of hydrogen chloride takes place and the amine
hydrochloride settles out of solution. The mixture is
refluxed for 24 hrs. and additional sulfuryl chloride
::
(240 ml.) is added. After stirring and refluxing the mixture ~ -
for 40 hrs., a more complete solution forms. The solution is
concentrated in vacuo to a viscous oil which is distilled
under reduced pressure. A main fraction is collected at
89--94C, 0.3-0.5 mm., 100.1 g., 64.896 yield. On standing,
transparent, needle-like crystals of t-butyl-sulfamoyl
chloride form, m.p. 23-3~C.
'~
--14--
- .
" . . . . . . . .
'' : ', '' , , ~ , .
