U.S. patent number 3,622,615 [Application Number 04/773,973] was granted by the patent office on 1971-11-23 for n -(p-tolylsulfonyl)-l-arginine esters.
This patent grant is currently assigned to Parke, Davis & Company. Invention is credited to Richard E. Maxwell, Ernest D. Nicolaides.
United States Patent |
3,622,615 |
Nicolaides , et al. |
November 23, 1971 |
N -(p-tolylsulfonyl)-L-arginine esters
Abstract
Pharmaceutical compositions containing as an active ingredient
an N.sup.2 -(p-tolylsulfonyl)-L-arginine ester or a salt thereof,
methods for the use of the N.sup.2 -(p-tolylsulfonyl)-L-arginine
esters and salts thereof as agents that potentiate the action of
urokinase in lysing blood clots; and the isopropyl, sec-butyl, and
2-isopropoxyethyl esters of N.sup.2 -(p-tolylsulfonyl)-L-arginine
and salts thereof and their production by reacting N.sup.2
-(p-tolylsulfonyl)-L-arginine with 2-propanol, 2-butanol, and
2-isopropoxyethanol, respectively, in the presence of a strong
acid.
Inventors: |
Nicolaides; Ernest D. (Ann
Arbor, MI), Maxwell; Richard E. (Ann Arbor, MI) |
Assignee: |
Parke, Davis & Company
(Detroit, MI)
|
Family
ID: |
25099870 |
Appl.
No.: |
04/773,973 |
Filed: |
November 6, 1968 |
Current U.S.
Class: |
560/13 |
Current CPC
Class: |
C07C
311/19 (20130101) |
Current International
Class: |
A61K
38/43 (20060101); C07c 143/78 () |
Field of
Search: |
;260/470 |
Other References
Von Margrit Gemperli et al., Helv. Chim. Acta, (48), pp. 939-945,
(1965). .
Curragh et al., Bioch. J., 93 (1), pp. 163-171 (1964)..
|
Primary Examiner: Gotts; Lewis
Assistant Examiner: Gleiman; Edward Jay
Claims
We claim:
1. A member of the class consisting of N.sup.2
-(p-tolylsulfonyl)-L-arginine esters having the formula
##SPC5##
and pharmaceutically-acceptable acid-addition salts thereof; where
R.sub.2 is a member of the class consisting of isopropyl,
sec-butyl, and 2-isopropoxyethyl.
2. N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl ester.
3. N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl ester,
monohydrochloride.
4. N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl ester,
mono-p-toluenesulfonate.
5. N.sup.2 -(p-tolylsulfonyl)-L-arginine, sec-butyl ester,
mono-p-toluenesulfonate.
6. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-isopropoxyethyl ester,
mono-p-toluenesulfonate.
Description
SUMMARY AND DETAILED DESCRIPTION
The present invention relates to amino acid ester compounds. More
particularly, the invention relates to pharmaceutical compositions
containing as an active ingredient an N.sup.2
-(p-tolysulfonyl)-L-arginine ester compound having the formula
##SPC1##
Or a pharmaceutically acceptable acid-addition salt thereof; to
methods for the use of the foregoing compounds as agents that
potentiate the action of urokinase in lysing blood clots; to new
N.sup.2 -(p-tolylsulfonyl)-L-arginine esters having the formula
##SPC2##
And acid-addition salts thereof; and to a method for the production
of the esters having formula II and their salts; where R.sub.1 is
alkyl of not more than ten carbon atoms, allyl, cycloalkyl of from
four to eight carbon atoms, mono- or di-alkoxyalkyl of not more
than 10 carbon atoms, or phenoxy-alkyl of not more than 10 carbon
atoms; and R.sub.2 is isopropyl, sec-butyl, or
2-isopropoxyethyl.
The term "pharmaceutically acceptable acid-addition salt" as used
herein includes any acid-addition salt that is not substantially
more toxic than an equal weight of the N.sup.2
-(p-tolylsulfonyl)-L-arginine ester compound from which it is
derived when measured in the same mammalian host using the same
vehicle and method of administration. Some examples of such salts
are the salts formed with a mineral acid, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, and
phosphate salts, as well as salts formed with various organic
acids, such as the acetate, benzoate, maleate, succinate, citrate,
benzenesulfonate, and p-toluenesulfonate salts. The preferred
pharmaceutically acceptable acid-addition salts are the mineral
acid salts and the p-toluenesulfonate salt.
In accordance with the invention, pharmaceutical compositions are
produced by formulating an N.sup.2 -(p-tolylsulfonyl)-L-arginine
ester compound having formula I above or a pharmaceutically
acceptable acid-addition salt thereof, either alone or in
combination with urokinase, in a form suitable for intravenous
administration. Such a form can be prepared, for example, by
dissolving the N.sup.2 -(p-tolysulfonyl)-L-arginine ester compound
or a salt thereof together with a preparation of human urokinase
that is pharmaceutically acceptable for intravenous use in an
aqueous medium, buffered at pH 7.0-7.5, and filtering the resulting
solution under sterile conditions. The sterile solution can be used
directly, or preferably, can be divided into uniform portions, for
example 30 ml. amounts, which are placed into ampuls, lyophilized,
and the ampuls sealed. The individual compositions obtained in this
way can then be stored in the sealed ampuls until required for use,
at which time they are redissolved in a sufficient quantity of
sterile water or saline to give a desired concentration of the
active ingredients. It is to be understood that the compositions
encompassed by the scope of the present invention include both the
buffered aqueous solutions and the solid mixtures obtained from
them by lyophilization.
Another example of a composition envisioned by the present
invention is a therapeutic package in which separate ampuls of the
N.sup.2 -(p-tolylsulfonyl)-L-arginine ester compound or a salt
thereof and urokinase, prepared as described above by lyophilizing
separate sterile buffered aqueous solutions of the individual
components, are provided in a single container. The advantage of
such a package is that, after the contents of each ampul are
reconstituted for use by dissolution in sterile water or saline,
the separate solutions can be caused to flow together for infusion
into a selected human patient's bloodstream in such a way that the
ratio of the active components can be varied according to the
observed response of the patient.
The concentrations of the N.sup.2 -(p-tolylsulfonyl)-L-arginine
ester compound or a pharmaceutically acceptable salt thereof and
the urokinase in the foregoing compositions can be varied within
wide limits. The preferred concentration range of the N.sup.2
-(p-tolylsulfonyl)-L-arginine ester or a salt thereof is 0.005
g./ml. to 0.05 g./ml., while that of the urokinase is 2,500 to
10,000 Ploug units/ml. These concentrations are such that following
intravenous administration of a convenient volume, for example, 60
ml. of the sterile buffered aqueous solutions or of the
reconstituted lyophilized solutions, there is obtained in the
patient's total plasma volume of about 3 liters a concentration of
from 0.00025 M to 0.0015 M of the N.sup.2
-(p-tolylsulfonyl)-L-arginine ester or a salt thereof and of from
50 to 200 Ploug units/ml. of urokinase.
The N.sup.2 -(p-tolylsulfonyl)-L-arginine esters and acid-addition
salts thereof, which are used as an active ingredient in the
foregoing compositions, are prepared by esterifying N.sup.2
-(p-tolylsulfonyl)-L-arginine, for example, by reaction with an
alcohol, R.sub.1 -OH, where R.sub.1 is as defined earlier, in the
presence of a strong acid, as described in greater detail
hereinafter.
The methods of the invention are for the purpose of lysing blood
clots and comprise contacting the blood clot with, in combination,
a pharmaceutically acceptable preparation of human urokinase and an
N.sup.2 -(p-tolylsulfonyl-L-arginine ester having formula I or a
pharmaceutically acceptable acid-addition salt thereof. For the
lysis of blood clots in human patients, the urokinase and the
N.sup.2 -(p-tolylsulfonyl)-L-arginine ester or salt thereof, in
combination, are administered intravenously. The amount of each of
these agents administered at any given time naturally varies with
an individual patient's response to the treatment. In general,
however, a sufficient amount of each is administered to give in the
patient's total plasma volume of about 3 liters the concentrations
stated above, namely, 0.00025-0.0015 M of the N.sup.2
-(p-tolylsulfonyl)-L-arginine ester or salt thereof and 50-200
Ploug units/ml. of urokinase. For those patients in whom such
concentrations evoke an inadequate response, the therapeutic
package composition described above can advantageously be employed,
since it permits the separate solutions of urokinase and the
N.sup.2 -(p-tolylsulfonyl)-L-arginine ester or salt thereof to be
administered to the patient simultaneously in such a way that the
infusion rate and final concentration of each can be varied over a
wide range according to the patient's observed response.
The occurrence of intravascular blood clots is today one of the
most serious problems of medical science and a major cause of
death, especially in Western civilizations. Frequently, the blood
clots form in locations from which they cannot be removed by
surgery and, when once formed, are not affected by anticoagulants.
For these reasons, much effort has been devoted in recent times
toward finding agents that might be effective in dissolving blood
clots.
Agents that have been studied include naturally occurring enzymes,
and one of the most promising of these is human urokinase, because
it is both effective and lacking in antigenicity and other serious
side effects. (For reports of studies carried out with urokinase,
see the following: The Journal of Laboratory and Clinical Medicine,
Vol. 65, pages 713-731, May, 1965 and The New England Journal of
Medicine, Vol. 277, pages 116 1-1167 and 1168-1173, Nov. 30, 1967.)
The use of urokinase for this purpose, however, also suffers from a
number of disadvantages. Since it must be laboriously isolated and
purified from human urine, it is in short supply and very
expensive. When it is added to human plasma, its ability to bring
about lysis of a blood clot disappears very quickly, thus requiring
uneconomically large amounts for therapy.
In accord with the present invention, it has been found that the
N.sup.2 -(p-tolylsulfonyl)-L-arginine ester compounds of formula I
and pharmaceutically acceptable acid-addition salts thereof
strikingly potentiate the action of urokinase in lysing blood
clots, so that significantly smaller amounts of this enzyme can be
employed and the cost of such therapy made more reasonable. This
potentiating effect of the N.sup.2 -(p-tolylsulfonyl)-L-arginine
esters can be demonstrated and quantitatively determined in a
standardized clot lysis test carried out as described in the
following.
Blood clots are formed in glass vials by treating 80 percent human
plasma containing trace amounts either of polystyrene particles or
of .sup.125 I-labeled human fibrinogen with thrombin and calcium
ions. In separate vials, lysing fluids are prepared as follows.
Urokinase alone or urokinase in combination with a test compound is
added to 80percent human plasma so that the concentration of
urokinase is 70 Ploug units/ml. and that of the test compound, when
present, is 0.0005 M. To the fluids are next added a buffer
solution, for example, Tris acetate, to give a pH of 7.4 and 0.1 M
sodium chloride for approximate physiological ionic strength, and
the resulting fluids are incubated at 37.degree. C. for varying
periods. Following the measured preincubation period, the lysing
fluids are added over the previously formed clots for an 18-hour
lysis period. To prevent bacterial growth during this period
penicillin and streptomycin are added. At the end of the 18-hour
period, the amount of lysis of the clots is quantitatively
determined by analyzing the supernatant lysing fluids for the
release of polystyrene particles of .sup.125 I from the clots.
The results obtained in the foregoing test procedure for two
representative compounds of the compositions of the present
invention are summarized in the following table. In the table, the
active components of the lysing fluids are identified as
follows:
UK = urokinase
A= N.sup.2 -(p-tolylsulfonyl)-L-arginine, methyl ester
B= N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl ester
##SPC3##
Further in accord with the present invention, N.sup.2
-(-p-tolylsulfonyl)-L-arginine esters having the formula
##SPC4##
II
which are preferred compounds of the invention because of their
high degree of activity in potentiating the blood clot-lysing
action of urokinase, are produced by reacting N.sup.2
-(p-tolylsulfonyl)-L-arginine with an alcohol compound having the
formula
R.sub.2 -OH
III
in the presence of a strong acid; where R.sub.2 has the same
meaning as previously given. Strong acids that may be used include
hydrochloric, hydrobromic, sulfuric, nitric, phosphoric,
methanesulfonic, benzenesulfonic, and p-toluenesulfonic acids. The
reaction may be carried out in an excess of the alcohol reactant or
in a nonreactive solvent medium. Suitable solvents include aromatic
hydrocarbons, such as benzene, toluene, and xylene; chlorinated
hydrocarbons, such as methylene chloride, chloroform, and
tetrachloroethane; and ethers, such as dioxane, tetrahydrofuran,
and 1,2-dimethoxyethane; as well as mixtures of these. A preferred
solvent is benzene, and when this or other water-immiscible solvent
is used, best results are obtained when the water that is formed in
the reaction is removed by means of a water separator. It is most
convenient to carry out the reaction at the reflux temperature of
the reaction mixture, although other temperatures, ranging from
about 0.degree. to about 150.degree. C. may also be used. The
duration of the reaction is not critical and may be varied widely,
depending somewhat on the alcohol reactant and temperature
employed. At the preferred reflux temperature, the reaction is
normally complete after a period of from one to about 20 hours.
Although equivalent amounts of reactants may be used, it is
preferable to use a moderate to large excess of the alcohol
reactant. The strong acid should be present in the reaction mixture
in an amount at least equivalent to the amount of N.sup.2
-(p-tolylsulfonyl)-L-arginine used. At the conclusion of the
reaction, the ester product may be isolated directly as the
acid-addition salt formed in the reaction, or by adjustment of the
pH, as the free base. The free base ester can then be converted
into other acid-addition salt forms by reaction with a selected
acid preferably in a suitable nonreactive solvent medium.
The invention is illustrated by the following examples.
EXAMPLE 1
N.sup.2 -(p-tolysulfonyl)-L-arginine, isopropyl ester,
mono-hydrochloride, hemihydrate (125 g.) and solid human urokinase
equivalent to 30.times.10.sup.6 Plough units are together dissolved
in 6 liters of 0.1 M aqueous phosphate buffer, pH 7.4. The
resulting solution is sterile-filtered, and the filtrate is divided
into 30-ml. aliquots, which are placed into glass ampuls and
lyophilized, and the ampuls are sealed. Prior to use, the ampuls
are broken open, and the contents of each are redissolved in 30 ml.
of sterile water or saline to give solutions suitable for
intravenous administration.
EXAMPLE 2
This example describes the preparation of a composition comprising
a therapeutic package consisting of separate ampuls of N.sup.2
-(p-tolylsulfonyl)-L-arginine ester compound and urokinase.
N.sup.2 -(p-tolylsulfonyl)-L-arginine, sec-butyl ester,
monohydrochloride (125 g.) is dissolved in 6 liters of 0.1 M
aqueous phosphate buffer, pH 7.4, and the solution is
sterile-filtered. The filtrate is then divided into 30-ml. aliquot
portions in glass ampules, the aliquots in each ampul are
lyophilized, and the ampuls are sealed. A separate solution is
prepared by dissolving solid urokinase equivalent to
30.times.10.sup.6 Ploug units in 6 liters of 0.1 M aqueous
phosphate buffer, and this solution is sterile-filtered. The
filtrate is divided into 30-ml. aliquots, which are lyophilized in
glass ampuls and the ampuls are sealed. The individual ampuls are
then packaged in pairs, one ampul containing the lyophilized
N.sup.2 -(p-tolylsulfonyl)-L-arginine, sec-butyl ester,
monohydrochloride composition and one containing the lyophilized
urokinase composition per package. Prior to use, the contents of
each ampul in the package are reconstituted in 30 ml. of sterile
water or saline, and the separate solutions are caused to flow
together in a common tubing for intravenous administration.
In the foregoing procedure, with the substitution of 125 g. of
N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl ester,
monohydrochloride, hemihydrate for the N.sup.2
-(p-tolylsulfonyl)-L-arginine, sec-butyl ester, monohydrochloride,
there is obtained a therapeutic package composition containing
separate ampuls of N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl
ester and urokinase.
EXAMPLE 3
N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-isopropoxyethyl ester,
mono-p-toluenesulfonate (176 g.) and solid urokinase equivalent to
60.times.10.sup.6 Ploug units are together dissolved in 6 liters of
0.1 M aqueous phosphate buffer, pH 7.4, and the resulting solution
is sterile-filtered. The filtrate is divided into 30-ml. aliquot
portions, which are lyophilized in glass ampuls, and the ampuls are
sealed. Prior to use, the contents of each ampul are reconstituted
in 30 ml. of sterile water or saline to give solutions for
intravenous administration.
EXAMPLE 4
N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl ester,
mono-p-toluenesulfonate (65.1 g.) and solid urokinase equivalent to
20.times.10.sup.6 Ploug units are together dissolved in 6 liters of
0.1 M aqueous phosphate buffer, pH 7.4, and the solution is
sterile-filtered. The filtrate is divided into 30-ml. aliquots in
glass ampuls the aliquots are lyophilized, and the ampuls are
sealed. Prior to use, the contents of each ampul are reconstituted
in 30 ml. of sterile water or saline to give solutions for
intravenous administration.
EXAMPLE 5
N.sup.2 -(p-tolysulfonyl)-L-argine, ethyl ester, monohydrochloride
(200 g.) and solid urokinase equivalent to 40.times.10.sup.6 Ploug
units are together dissolved in 6 liters of 0.1 M aqueous phosphate
buffer, pH 7.4, and the solution is sterile-filtered. The filtrate
is divided into 30-ml. aliquots in glass ampuls, the aliquots are
lyophilized, and the ampuls are sealed. Prior to use, the contents
of each ampul are reconstituted in 30 ml. of sterile water or
saline to give solutions for intravenous administration.
By utilizing the foregoing procedure, similar compositions are
obtained by substituting the amounts of each of the N.sup.2
-(p-tolylsulfonyl)-L-arginine ester salts designated below for the
N.sup.2 -(p-tolylsulfonyl)-L-arginine, ethyl ester,
monohydrochloride:
a. N.sup.2 -(p-tolylsulfonyl)-L-arginine, propyl ester,
monohydrochloride, 125 g.
b. N.sup.2 -(p-tolylsulfonyl)-L-arginine, butyl ester,
monohydrochloride, 125 g.
c. N.sup.2 -(p-tolylsulfonyl)-L-arginine,
2-ethoxy-1-(ethoxy-methyl)ethyl ester, monohydrochloride, 125
g.
d. N.sup.2 -(p-tolylsulfonyl)-L-arginine, cyclopentyl ester,
hemisulfate, 125 g.
e. N.sup.2 -(p-tolylsulfonyl)-L-arginine, cyclohexyl ester,
monohydrochloride, 125 g.
f. N.sup.2 -(p-tolylsulfonyl)-L-arginine, cycloheptyl ester,
monohydrochloride, 125 g.
g. N.sup.2 -(p-tolylsulfonyl)-L-arginine, allyl ester,
monohydrochloride, 200 g.
h. N.sup.2 -(p-tolylsulfonyl)-L-arginine, isobutyl ester,
mono-p-toluenesulfonate, 125 g.
i. N.sup.2 -(p-tolylsulfonyl)-L-arginine, pentyl ester,
mono-p-toluenesulfonate, 125 g.
j. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 1,2-dimethylpropyl ester,
mono-p-toluenesulfonate, 125 g.
k. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-methylbutyl ester,
mono-p-toluenesulfonate, 125 g.
l. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 1-ethylpropyl ester,
mono-p-toluenesulfonate, 125 g.
m. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-ethoxyethyl ester,
mono-p-toluenesulfonate, 125 g.
n. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-butoxyethyl ester,
mono-p-toluenesulfonate, 100 g.
o. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-phenoxyethyl ester,
mono-p-toluenesulfonate, 100 g.
p. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-methoxyethyl ester,
mono-p-toluenesulfonate, 125 g.
q. N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopentyl ester,
mono-p-toluenesulfonate, 125 g.
r. N.sup.2 -(p-tolylsulfonyl)-L-arginine, hexyl ester,
mono-p-toluenesulfonate, 125 g.
s. N.sup.2 -(p-tolylsulfonyl)-L-arginine, octyl ester,
mono-p-toluenesulfonate, 100 g.
EXAMPLE 6
Dry hydrogen chloride is bubbled into a suspension of 23 g. of
N.sup.2 -(p-tolylsulfonyl)-L-arginine in 250 ml. of 2-propanol
until a clear solution is obtained. The solution is heated under
reflux for 1 hour, kept at room temperature for 16 hours, and then
evaporated under reduced pressure to give a solid residue of
N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl ester,
monohydrochloride; m.p. 75.degree. -85.degree. C.
The free base ester is obtained by making alkaline an aqueous
solution of the hydrochloride salt with aqueous sodium hydroxide,
extracting the alkaline mixture with methylene dichloride, and
drying and evaporating the methylene dichloride extract.
Utilizing the foregoing procedure, the following N.sup.2
-(p-tolylsulfonyl)-L-arginine ester compounds, which are used as
active components of two of the compositions described in example 5
above, are obtained from the reaction of the indicated amounts of
N.sup.2 -(p-tolylsulfonyl)-L-arginine and the designated
alcohol:
a. N.sup.2 -(p-tolylsulfonyl)-L-arginine, butyl ester,
monohydrochloride, m.p. 138.degree. -142.degree. C., following
crystallization from 1-butanol-ether; from 2.0 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine and 50 ml. of 1-butanol.
b. N.sup.2 -(p-tolylsulfonyl)-L-arginine,
2-ethoxy--(ethoxy-methyl)ethyl ester, monohydrochloride, obtained
as an oil from 5.0 g. of N.sup.2 -(p-tolylsulfonyl)-L-arginine and
30 ml. of 1,3-diethoxy-2-propanol.
EXAMPLE 7
A mixture consisting of 3.8 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 15 ml. of 2-butanol, 5.7 g. of
p-toluenesulfonic acid, and 50 ml. of benzene is heated under
reflux under a water separator for 12 hours. Upon cooling, the
resulting solution is diluted with excess ether, and the solid
N.sup.2 -(p-tolylsulfonyl)-L-arginine, sec-butyl ester,
mono-p-toluenesulfonate that precipitates is isolated and dried;
m.p. 119.degree. -122.degree. C., following crystallization from
methanol-ether.
EXAMPLE 8
A mixture consisting of 11.5 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 90 ml. of 2-propanol, 17.1 g. of
p-toluenesulfonic acid, and 50 ml. of benzene is heated under
reflux under a water separator for 24 hours. Upon cooling, the
resulting solution is diluted with excess ether, and the solid
N.sup.2 -(p-tolylsulfonyl)-L-arginine, isopropyl ester,
mono-p-toluenesulfonate that precipitates is isolated by
filtration; m.p. 90.degree. -94.degree. C., following
crystallization from ethanol-ether.
Utilizing the foregoing procedure, the following N.sup.2
-(p-tolylsulfonyl)-L-arginine ester salt compounds, which are used
as active components of the compositions described in example 5
above, are obtained from the reactions indicated below:
a. N.sup.2 -(p-tolylsulfonyl)-L-arginine, isobutyl ester,
mono-p-toluenesulfonate, m.p. 98.degree. -101.degree. C.
(ethanol-ether); from the reaction of 3.8 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 50 ml. of 2-methyl-1-propanol, and
5.7 g. of p-toluenesulfonic acid in 45 ml. of benzene for 6 hours
under reflux.
b. N.sup.2 -(p-tolylsulfonyl)-L-arginine, pentyl ester,
mono-p-toluenesulfonate, m.p. 102.degree. -104.degree. C.
(methanol-ether); from the reaction of 3.8 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 80 ml. of 1-pentanol, and 5.7 g. of
p-toluenesulfonic acid in 50 ml. of benzene for 18 hours under
reflux.
c. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 1,2-dimethylpropyl ester,
mono-p-toluenesulfonate, m.p. 105.degree. -108.degree. C.
(ethanol-ether); from the reaction of 3.8 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 70 ml. of 3-methyl-2-butanol, and
5.7 g. of p-toluenesulfonic acid in 45 ml. of benzene for 6 hours
under reflux.
d. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-methylbutyl ester,
mono-p-toluenesulfonate, m.p. 98.degree. -101.degree. C.
(methanol-ether); from the reaction of 3.8 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 50 ml. of 2-methyl-1-butanol, and
5.7 g. of p-toluenesulfonic acid in 45 ml. of benzene for 6 hours
under reflux.
e. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 1-ethylpropyl ester,
mono-p-toluenesulfonate, m.p. 119.degree. -123.degree. C.
(methanol-ether); from the reaction of 3.8 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 80 ml. of 3-pentanol, and 5.7 g. of
p-toluenesulfonic acid in 30 ml. of benzene for 18 hours under
reflux.
EXAMPLE 9
A mixture consisting of 3.8 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 80 ml. of 2-isopropoxyethanol, 5.7
g. of p-toluenesulfonic acid, and 45 ml. of benzene is heated under
reflux under a water separator for 18 hours. Upon cooling, the
resulting solution is diluted with excess ether, and the solid
N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-isopropoxyethyl ester,
mono-p-toluenesulfonate that precipitates is isolated by
filtration; m.p. 107.degree. -109.degree. C., following
crystallization from ethanol-ether.
In a similar manner, the following N.sup.2
-(p-tolylsulfonyl)-L-arginine ester salt compounds, which are used
as active components of the compositions described in example 5
above, are obtained from the reactions indicated below:
a. N.sup.2 -(p-Tolylsulfonyl)-L-arginine, 2-ethoxyethyl ester,
mono-p-toluenesulfonate, m.p. 96.degree.-98.degree. C.; from the
reaction of 5.0 g. of N.sup.2 -(p-tolylsulfonyl)-L-arginine, 25 ml.
of 2-ethoxyethanol, and 4.0 g. of p-toluenesulfonic acid in 100 ml.
of benzene for 10 hours under reflux.
b. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-butoxyethyl ester,
mono-p-toluenesulfonate, m.p. 166.degree.-117.degree. C.; from the
reaction of 5.0 g. of N.sup.2 -(p-tolylsulfonyl)-L-arginine, 25 ml.
of 2-butoxyethanol, and 4.0 g. of p-toluenesulfonic acid in 100 ml.
of benzene for 10 hours under reflux.
c. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-methoxyethyl ester,
mono-p-toluenesulfonate, m.p. 60.degree. -75.degree. C.; from the
reaction of 3.8 g. of N.sup.2 -(p-tolylsulfonyl)-L-arginine, 60 ml.
of 2-methoxyethanol, and 5.7 g. of p-toluenesulfonic acid in 45 ml.
of benzene for 6 hours under reflux.
d. N.sup.2 -(p-tolylsulfonyl)-L-arginine, 2-phenoxyethyl ester,
mono-p-toluenesulfonate, m.p. 155.degree. -156.degree. C.; from the
reaction of 5.0 g. of N.sup.2 -(p-tolylsulfonyl)-L-arginine, 25 ml.
of 2-phenoxyethanol, and 4.0 g. of p-toluenesulfonic acid in 100
ml. of benzene for 10 hours under reflux.
e. N.sup.2 (p-Tolylsulfonyl)-L-arginine, isopentyl ester,
mono-p-toluenesulfonate, m.p. 97.degree. -100.degree. C.; from the
reaction of 3.8 g. of N.sup.2 -(p-tolylsulfonyl)-L-arginine, 70 ml.
of 3-methyl-1-butanol, and 5.7 g. of p-toluenesulfonic acid in 45
ml. of benzene for 6 hours under reflux.
f. N.sup.2 -(p-tolylsulfonyl)-L-arginine, hexyl ester,
mono-p-toluenesulfonate, m.p. 107.5.degree. -1085.degree. C.; from
the reaction of 5.0 g. of N.sup.2 -(p-tolylsulfonyl)-L-arginine, 20
ml. of 1-hexanol, and 4.0 g. of p-toluenesulfonic acid in 100 ml.
of benzene for 10 hours under reflux.
g. N.sup.2 -(p-tolysulfonyl)-L-argine, octyl ester,
mono-p-toluenesulfonate, m.p. 92.degree. -93.degree. C.; from the
reaction of 5.0 g. of N.sup.2 -(p-tolysulfonyl)-L-arginine, 25 ml.
of 1-octanol, and 4.0 g. of p-toluenesulfonic acid in 100 ml. of
benzene for 10 hours under reflux.
Additional N.sup.2 -(p-tolylsulfonyl)-L-arginine ester salt
compounds that are used as active components of the compositions
described in example 5 above are prepared as follows:
1. A mixture consisting of 7.6 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 0.75 ml. of 96 percent sulfuric
acid, and 60 ml. of cyclopentanol is heated under reflux for 18
hours and then evaporated under reduced pressure to give N.sup.2
-(p-tolylsulfonyl)-L-arginine, cyclopentyl ester, hemisulfate; m.p.
76.degree. -90.degree. C.
2. A mixture consisting of 7.6 g. of N.sup.2 50 ml. of
cycloheptanol, 20 ml. of 37 percent hydrochloric acid, and 50 ml.
of benzene is heated under reflux under a water separator for 18
hours and then evaporated under reduced pressure to give N.sup.2
-(p-tolylsulfonyl)-L-arginine, cycloheptyl ester,
monohydrochloride; m.p. 75.degree. -85.degree. C.
3. A mixture consisting of 7.6 g. of N.sup.2
-(p-tolylsulfonyl)-L-arginine, 100 ml. of allyl alcohol, 15 ml. of
37 percent hydrochloric acid, and 50 ml. of benzene is heated under
reflux under a water separator for 18 hours and then evaporated
under reduced pressure to give N.sup.2
-(p-tolylsulfonyl)-L-arginine, allyl ester, monohydrochloride; m.p.
121.degree. -123.degree. C., following crystallization from
methanol-ether .
* * * * *