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Publication numberUS3622615 A
Publication typeGrant
Publication dateNov 23, 1971
Filing dateNov 6, 1968
Priority dateNov 6, 1968
Publication numberUS 3622615 A, US 3622615A, US-A-3622615, US3622615 A, US3622615A
InventorsErnest D Nicolaides, Richard E Maxwell
Original AssigneeParke Davis & Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
N{11 -(p-tolylsulfonyl)-L-arginine esters
US 3622615 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent Inventors Appl. No.

Filed Patented Assignee N -(P-TOLYLSULFONYL)-L-ARGIN1NE ESTERS 6 Claims, No Drawings US. Cl 260/470, 424/309 Int. Cl C07c 143/78 Field of Search 260/470 References Cited OTHER REFERENCES Von Margrit Gemperli et aL, Helv. Chim. Acta, (48), pp.

Curragh et al., Bioch. 1., 93(1), pp. 163-171 (1964).

ABSTRACT: Pharmaceutical compositions containing as an active ingredient an N -(p-tolylsulfonyl)-L-arginine ester or a salt thereof, methods for the use of the N -(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 -(p-tolylsulfonyl)-L-arginine and salts thereof and their production by reacting N -(p-tolylsulfonyl)-L-arginine with 2-propanol. 2- butanol, and 2-isopropoxyethanol. respectively, in the presence of a strong acid.

N -(P-TOLYLSULFONYL)-L-ARGININE ESTERS 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*-( p-tolysulfonyl)-L-arginine ester compound having the formula B TE-S O r-Q- C H:

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*-(p-tolylsulfonyl)-L-arginine esters having the formula and acid-addition salts thereof; and to a method for the production of the esters having formula II and their salts; where R is alkyl of not more than ten carbon atoms, allyl, cycloalkyl of from four to eight carbon atoms, monoor di-alkoxyalkyl of not more than 10 carbon atoms, or phenoxy-alkyl of not more than 10 carbon atoms; and R 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 -(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. 0

In accordance with the invention, pharmaceutical compositions are produced by formulating an N -(p-tolylsulfonyb-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 -(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 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 -(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 patients 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 -(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 -(p-tolylsulfonyl)-L-arginine ester or a salt thereof is 0.005 g./m1. 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 patients total plasma volume of about 3 liters a concentration of from 0.00025 M to 0.0015 M of the N -(p-tolylsulfonyl)-L- arginine ester or a salt thereof and of from 50 to 200 Ploug units/ml. of urokinase.

The N"(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 -(ptolylsulfonyl)-L-arginine, for example, by reaction with an alcohol, R,-0n, where R 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 -(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 -(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 patients response to the treatment. In general, however, a sufficient amount of each is administered to give in the patients total plasma volume of about 3 liters the concentrations stated above, namely, 0.00025-0.0015 M of the N -(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 (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 patients 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 1161-1167 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-(p-tolylsulfonyl)-L-arginine ester compounds of formula l 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-(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 l'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 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 l8-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 '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 -(p-tolylsulfonyl)-L-arginine, methyl ester B=N'*'-(p-tolylsulfonyl)-L-arginine, isopropyl ester POTENTIATION OF UROKINASE LYSIS OF OLO'IS Lysls of clot, percent, by-

Lysing fluid preincu'oatlon time, minutes UK UK+A UK+B Further in accord with the present invention, N p-tolylsulfonyl )-L-arginine esters having the formula JUHW CH.

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 -(p-tolyb sulfonyl)-Larginine with an alcohol compound having the formula in the presence of a strong acid; where R, 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 l,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 to about 150 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 -(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 -(p-tolysulfonyl)-L-arginine, isopropyl ester, monohydrochloride, hemihydrate g.) and solid human urokinase equivalent to 30 l0 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 -(p-tolylsulfonyl)-L-arginine ester compound and urokinase.

N -(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 sterilefiltered. 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 30x10 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 -(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-(p-tolylsulfonyl)-L-arginine, isopropyl ester, monohydrochloride, hemihydrate for the N-(p-tolylsulfonyl)- L-arginine, sec-butyl ester, monohydrochloride, there is obtained a therapeutic package composition containing separate ampuls of N-(p-tolylsulfonyl)-L-arginine, isopropyl ester and urokinase.

EXAMPLE 3 NHp-tolylsulfonyl)-L-arginine, 2-isopropoxyethyl ester, mono-p-toluenesulfonate (176 g.) and solid urokinase equivalent to 60Xl0 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 -(p-tolylsulfonyl)-L-arginine, isopropyl ester, mono-ptoluenesulfonate (65.1 g.) and solid urokinase equivalent to 20X Ploug units are together dissolved in 6 liters of 0.1 M aqueous phosphate buffer, pH 7.4, and the solution is sterilefiltered. 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 -(p-tolysulfonyl)-L-argine, ethyl ester, monohydrochloride (200 g.) and solid urokinase equivalent to 40X 10 Ploug units are together dissolved in 6 liters of 0.1 M aqueous phosphate buffer, pH 7.4, and the solution is sterilefiltered. 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 -(ptolylsulfonyl)-L-arginine ester salts designated below for the N p-tolylsulfonyl )-L-arginine, ethyl ester, monohydrochloride:

a. N"-(p-tolylsulfonyl)-L-arginine, propyl ester, monohydrochloride, 125 g.

b. N p-tolylsulfonyl )-L-arginine, butyl ester,

monohydrochloride, 125 g.

c. N -(p-tolylsulfonyl)-L-arginine, 2-ethoxy-l-(ethoxymethyl)ethyl ester, monohydrochloride, l25 g.

monohydrochloride, 200 g.

h. N -(p-tolylsulfonyl)-L-arginine, isobutyl ester, mono-ptoluenesulfonate, 125 g.

i. N-(p-tolylsulfonyl)-L-arginine, pentyl ester, mono-ptoluenesulfonate, 125 g.

j. N -(p-tolylsulfonyl)-L-arginine, l,2-dimethylpropyl ester, mono-p-toluenesulfonate, l25 g.

k. N-(p-tolylsulfonyl)-L-arginine, Z-methylbutyl ester, mono-p-toluenesulfonate, 125 g.

l. N-( p-tolylsulfonyl )-L-arginine, l-ethylpropyl ester,

mono-p-toluenesulfonate, 125 g.

m. N -(p-tolylsulfonyl)-L-arginine, 2-ethoxyethyl ester, mono-p-toluenesulfonate, 125 g.

n. N -(p-tolylsulfonyl)-L-arginine, 2-butoxyethyl ester, mono-p-toluenesulfonate, I00 g.

o. N -(p-tolylsulfonyl)-L-arginine, Z-phenoxyethyl ester, mono-p-toluenesulfonate, g.

p. N -(p-tolylsulfonyl)-L-arginine, 2-methoxyethyl ester, mono-p-toluenesulfonate, g.

q. N -(p-tolylsulfonyl)-L-a.rginine, isopentyl ester, mono-ptoluenesulfonate, 125 g.

r. N' -(p-tolylsulfonyl)-L-arginine, hexyl ester, mono-ptoluenesulfonate, 125 g.

s. N -(p-tolylsulfonyl)-L-arginine, octyl ester, mono-ptoluenesulfonate, 100 g.

EXAMPLE 6 Dry hydrogen chloride is bubbled into a suspension of 23 g. of N +(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 -(p-tolylsulfonyl)-L-arginine, isopropyl ester, monohydrochloride; m.p. 7585 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 -(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 -(p-tolylsulfonyl)-L-arginine and the designated alcohol:

a. N -(p-tolylsulfonyl)-L-arginine, butyl ester, monohydrochloride, m.p. 138 -l42 C., following crystallization from l-butanol-ether; from 2.0 g. of N -(p-tolylsulfonyh- L-arginine and 50 ml. of l-butanol.

b. N -(p-tolylsulfonyl)-L-arginine, 2-ethoxy--(ethoxymethyl)ethyl ester, monohydrochloride, obtained as an oil from 5.0 g. of N -(p-tolylsulfonyl)-L-arginine and 30 ml. of l ,3-diethoxy-2-propanol.

EXAMPLE 7 A mixture consisting of 3.8 g. of N -(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 -(p-tolylsulfonyl)-L- arginine, sec-butyl ester, mono-p-toluenesulfonate that precipitates is,isolated and dried; m.p. 1 19 -l22 C., following crystallization from methanol-ether.

EXAMPLE 8 A mixture consisting of 11.5 g. of N -(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 -(p-tolylsulfonyh-L- arginine, isopropyl ester, mono-p-toluenesulfonate that precipitates is isolated by filtration; m.p. 9094 C., following crystallization from ethanol-ether.

Utilizing the foregoing procedure, the following N -(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 -(p-tolylsulfonyl)-L-arginine, isobutyl ester, mono-ptoluenesulfonate, m.p. 98-l0l C. (ethanol-ether); from the reaction of 3.8 g. of N -(p-tolylsulfonyl)-L-arginine, 50 ml. of 2-methyl-l-propanol, and 5.7 g. of p-toluenesulfonic acid in 45 ml. of benzene for 6 hours under reflux.

b. N -(p-tolylsulfonyl)-L-arginine, pentyl ester, mono-ptoluenesulfonate, m.p. l02-l04 C. (methanol-ether); from the reaction of 3.8 g. of N*-(p-tolylsulfonyl)-L-argininc, 80 ml.

of l-pentanol, and 5.7 g. of p-toluenesulfonic acid in 50 m1. of benzene for 18 hours under reflux.

c. N'-( p-tolylsulfonyl)-L-arginine, 1,2-dimethylpropyl ester, mono-p-toluenesulfonate, m.p. l05-l08 C. (ethanol-ether); from the reaction of 3.8 g. of N-(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-(p-tolylsulfonyl)-L-arginine, 2-methylbutyl ester, mono-p-toluenesulfonate, m.p. 98- 1 1 C. (methanol-ether); from the reaction of 3.8 g. of N*-(p-tolylsulfonyl)-L-arginine, 50 ml. of 2-methyl-l-butanol, and 5.7 g. of p-toluenesulfonic acid in 45 ml. of benzene for 6 hours under reflux.

e. N'-(p-tolylsulfonyl)-L-arginine, l-ethylpropyl ester, mono-p-toluenesulfonate, m.p. l l9-l23 C. (methanolether); from the reaction of 3.8 g. of N -(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 -(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 -(p-tolylsulfonyl)-L-arginine, Z-isopropoxyethyl ester, mono-ptoluenesulfonate that precipitates is isolated by filtration; m.p. l07- l 09 C., following crystallization from ethanol-ether.

in a similar manner, the following N*-(p-tolylsulfonyl)-L-arginine ester salt compounds, which are used as active components of the compositions described in example above, are obtained from the reactions indicated below:

a. N-(p-Tolylsulfonyl)-L-arginine, 2-ethoxyethyl ester, mono-p-toluenesulfonate, m.p. 96-98 C.; from the reaction of 5.0 g. of N-(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 -(p-tolylsulfonyl)-L-arginine, 2-butoxyethyl ester, mono-p-toluenesulfonate, m.p. l66-1l7 C.; from the reaction of 5.0 g. of N*-(p-tolylsulfonyl)-L-arginine, ml. of 2- butoxyethanol, and 4.0 g. of p-toluenesulfonic acid in 100 ml. of benzene for 10 hours under reflux.

c. N -(p-tolylsulfonyl)-L-arginine, Z-methoxyethyl ester, mono-p-toluenesulfonate, m.p. 60-75 C.; from the reaction of 3.8 g. of N -(ptoly1sulfonyl)-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"'-(p-tolylsulfonyl)-L-arginine, 2-phenoxyethyl ester, mono-p-toluenesulfonate, m.p. l55l56 C.; from the reaction of 5.0 g. of N(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(p-Tolylsulfonyl)-L-arginine, isopentyl ester, mono-ptoluenesulfonate, m.p. 97100 C.; from the reaction of 3.8 g. of N-(p-tolylsulfonyl)-L-arginine, 70 ml. of 3-methyl-l-butanol, and 5.7 g. of p-toluenesulfonic acid in 45 ml. of benzene for 6 hours under reflux.

f. N-(p-tolylsulfonyl)-L-arginine, hexyl ester, mono-ptoluenesulfonate. m.p. l07.5-l085 C.; from the reaction of 5.0 g. of N-(p-tolylsulfonyl)-L-arginine, 20 ml. of l-hexanol, and 4.0 g. of p-toluenesulfonic acid in lOO ml. of benzene for 10 hours under reflux.

g. N-(p-tolysulfonyl)-L-argine, octyl ester, mono-ptoluenesulfonate, m.p. 92-93 C.; from the reaction of 5.0 g. of N-(p-tolysulfonyl)-Larginine, 25 ml. of l-octanol, and 4.0 g. of p-toluenesulfonic acid in ml. of benzene for l0 hours under reflux.

Additional N-(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:

I. A mixture consisting of 7.6 g. of N'-(p-tolylsulfonyI)-L- arginine, 0.75 ml. of 96 percent sulfuric acid, and 60 ml. of

cyclopentanol is heated under reflux for l8 hours and then evaporated under reduced pressure to give N -(p-tolylsulfonyl)-L-arginine, cyclopentyl ester, hemisulfate; m.p. 76-90 C 2. A mixture consisting of 7.6 g. of N'SO 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- (p-tolylsulfonyl)-L-arginine, cycloheptyl ester, monohydrochloride; m.p. 75-85 C.

3. A mixture consisting of 7.6 g. of N-(p-tolylsulfonyl)-L- arginine, 100 ml. of allyl alcohol, l5 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 -(p-tolylsulfonyl)-L-arginine, allyl ester, monohydrochloride; m.p. l2 l-l 2 3 C., following crystallization from methanol-ether.

We claim:

1. A member of the class consisting of N--(p-tolylsulfonyl)- L-arginine esters having the formula ester,

Non-Patent Citations
Reference
1 *Curragh et al., Bioch. J., 93 (1), pp. 163 171 (1964).
2 *Von Margrit Gemperli et al., Helv. Chim. Acta, (48), pp. 939 945, (1965).
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Classifications
U.S. Classification560/13
International ClassificationA61K38/43
Cooperative ClassificationC07C311/19
European ClassificationA61K38/43