US2608506A - Arylsulfamyl benzoic acids - Google Patents

Description

Patented Aug. 26, 1952 ARYLSULFAMYL BENZOIC ACIDS James M. Sprague, Drexel Hill, and Charles S. Miller, Prospect Park, Pa., assignors to Sharp & Dohme, Incorporated, Philadelphia, Pa., a

corporation of Maryland Application August 20, 1949, Serial No. 111,583

4 Claims. (01. 167-55) No Drawing.

This inventionrelates to sulfamylbenzoic acids which are effective as adjuvants for use in conjunction with the administration of penicillin to provide an increase in the blood plasma penicillin concentration with a given dose of penicillin,

thereby making possible very high penicillin blood levels, or permitting the use of smaller quantities of penicillin for providing a given blood level,

or permitting the less frequent administration of penicillin'while maintaining a penicillin blood level adequate for bactericidal or bacteriostatic purposes. This invention also relates to the preparation of various dosage forms in which one or more of the new compounds are incorporated for administration by various routes.

Penicillin today is a well established therapeutic agent used in the treatment of bacterial, in particular, coccus infections. For internal use, it is commonly administered intravenously, or intramuscularly, or orally. When high blood levels are required intravenous administration or administration by continuous venoclysis, is

used. r

The major cause of the difficulties involved in attempting to maintain adequate or high penicillin blood levels follows from the fact that substantially all of the penicillin in the blood is removed in a single circulation through the kidneys.

Penicillin appears to be almost quantitatively excreted from the blood by the epithelial cells of the tubules, at least within plasma concentra tions which have been explored, with the result that its rate of excretion from the blood stream is approximately five times that of materials which are excreted by glomerular filtration alone, the tubular excretion accounting for about 80 (81)% and the glomeruli about 20 (19)%.

Various proposals have been made to overcome the difliculties due to the rapid elimination of penicillin, such as the administration'of it in suspension in an oleagenous material, the mixture being administered by intramuscular injection. While this proposal is effectivein prolonging the time interval between injections, its disadvantage is that the penicillin is still excreted almost quantitatively when the blood passes through the renal system, and therefore does not permit the maintenance of high blood levels nor does it permit the use of smaller quantities of penicillin to obtain a given blood level.

The second proposal which has been made to provide for the reduction in the rate of excretion of penicillin has been to use, in conjunction with it, a material which, like penicillin, is selectively 2 excreted by the tubules. By having the ratio of the added agent to the penicillin sufliciently large, this concept provides for a substantial reduction, in the rate of excretion of penicillin by the tubules and thus slows down its removal to a substantial extent. Various agents including diodrast and hippuric acid, or derivatives or precursors thereof, havebeen proposed or used for this purpose. Such agents do not, however, seem to afford a solution to the problem of value except in extreme cases, because as the reduction in the rate of penicillin excretion is a, reflection of the degree of overloading of thetubules with materials which they function to, remove from the blood, it is necessary to maintain a very high concentration of the agent in the blood stream to afford a. favorable partition ratio between the agent and the penicillin, and, in addition, because the agents are themselves rapidly removed from the blood stream, it is necessary to administer them in large quantities to maintain the neces sary high plasma concentrations; This presents an additional problem since in order to maintain the high concentration of theseagents theymust be administered intravenously as they are not well absorbed from the gastroq-intestinal tract.

The present invention is based upon the discovery that removal .of penicillin from the blood stream by the kidney tubules can be effectively blocked by the adjuvants of this invention, having the general formula? The sulfamylbenzoic acids ofthe'invention are relatively non-toxic, they are soluble in blood plasma and operate, when carried by the blood stream'into contact'withthe tubules, to prevent their normal action in removing penicillin from the blood streamfr. The'adjuvants themselves are not excreted to any substantial extent by the tu-,

. injection by this route impractical.

bules, and the available evidence indicates that on coming into contact with the epithelial cells of the tubules, they operate to block their action by interference with the normal functioning of the epithelial cells and do not inhibit the excretion of the penicillin by competing with it within the tubular functional capacity. Thus, the adjuvants are effective in eliminating or very radically reducing tubular excretion of penicillin in plasma concentrations around 10 mg. per 100 cc., which is about the threshhold value for agents such as p-aminohippuric acid or diodrast which inhibit tubular penicillin excretion by competition for the available tubular excretion capacity. The highly effective adjuvants of this invention will reduce the excretion of penicillin by the tubules, at a blood plasma concentration of about 10 mg. per 100 cc. to almost zero, so that the actual elimination of penicillin from the blood stream becomes substantially that resulting from glomerular filtration, that is, aboutone-fifth. the normal rate (ignoring plasma binding) The adjuvants are also eliminated by the glomeruli.

The adjuvants may be administered orally or,

when dissolved in an aqueous solution, they may be administered intravenously or intramuscularly. This last method has not yet proven desirable for single injection of the material, because in general, administration of more than 2 cc; per

singleinjection intramuscularly is inadvisable,

and the quantities of adjuvant desirable to use, i. e-., 4 to 16 grams per day, are such. as to make However, the sulfamylbenzoic. acids or their salts are well adapted for continuous intramuscular or subcutaneous clysis.

In general, oral administration of the adjuvants at the rate of 4 to 16 grams per day is adequate to suppress the rate of penicillin excretion to an extent such that the blood level with a given dose of penicillin administered orally or intramuscularly in aqueous solution will be increased to as much. as four times the level. obtained without the use of the adjuvant, and will permit either the use of a very muchsmaller quantity of penicillin: to provide a given blood level, for example, permitting the penicillin doses to be about one-fourth of those commonly used, or permitting the provision of penicillin blood levels several times as great. as thosefobtainable with the administration of. penicillin by the routes ordinarily used today.

The adjuvants of the invention or a suitable salt of any one of them may be administered in admixture with the penicillin, or separately therefrom. In any event, whether the adjuvant is administered in admixture with or separately from the penicillin, the quantity used should be such as to provide a concentration in the blood stream of adjuvant adequate to block substantially the excretory mechanism of the tubules. Maximum effect will be obtained with blood plasma concentrations of about 5 to 15 mg. per

100 cc., obtainable at dosage levels of about 4,

to 16 grams per day'orallyand somewhat less than this intravenously.

The adjuvants maybe prepared in any convenient dosage form, either alone or admixed with penicillin, such as in a compresed tablet, a dry filled capsule, or a soft elastic capsule. It is to be understood, of course, that other ingredients such as binders, diluents, excipients, antacid substances, or'other inert or therapeutically active compounds may be incorporated into, any selected. dosage form. alongwith the adju vant or adjuvant plus penicillin, provided the added ingredient does not destroy the activity of either the adjuvant or penicillin; Similarly, the adjuvant and, if desired, the penicillin, may be dispersed in an oleagenous base either alone or along with other suitable substances and filled into soft elastic capsules or an aqueous solution may be prepared and filled into ampuls. Other suitable dosage forms will be readily apparent to those skilled inthe art, and it is not the purpose of this discussion to limit the mode of packag- The new sulfamylbenzoic acid compounds of;

r the invention are advantageously inade by react-- ing para-carboxybenzenesulfonyl halide with nitroaniline, preferably in the presence of an excess, e. g., a 2-3 molar excess, of the nitroaniline, and advantageously in the presence of an inert solvent, such as acetone; followed, if desired, by reduction of the resulting para-'(nitrophenylsulfamyl) -benzoic acid to the corresponding amine. The adjuvants of this invention may also be obtained by (I) reacting para-carboxybena zene-sulfonyl halide with phenylenediamine di-- hydrochloride, preferably in the presence of. a solvent, such as acetone, and in the presence of aqueous alkali, e. g, an aqueous: solution of so dium hydroxide, or (2) by reacting paraetoluene sulfonyl halide with nitroaniline in an inert solvent, such as pyridineand oxidizing the para (nitrophenylsulfamyl) -toluene thus. obtained to para-(nitro-phenylsulfamyl) benzoic acid, and, if desired, reducing the nitro tor the: amino group.

The ortho-sulfamylb'enzoic acid. derivatives may be prepared. by reacting saccharin with. the nitroor amino-phenyl halide, and treating. the product thllS. formed, with. an alkali metal also-- holate. 1

. The meta-sulfamyl' benzoic'acid derivative may be prepared by reacting meta-sulfo-benzoyldichloride with an alcohol, e. g., methanol, adding the product thus formed to the nitroor amine phenylhalide, preferably dissolved. in a solvent,

. thereby obtaining. alkyl. meta-nitroror amino.

phenylsulfamyl) -.b'enzoate. The ester is uneasy-- drolyzed to the corresponding benzoic acid d'e' obtained by any one of the abovermethods may be alkylated by'knownmethods,suchias by'reacting the arylsulfamylbenzo-ic acidwith. an alkyl halide.

The preparation of" the compoundsof the invention is illustrated by, but not restricted to, the following examples:

Para (meta--aminophenylsitlfamyly benzoi'c acid-To a solution of 27.6 g. (0.2.mole) of m.- nitroaniline in l0 0icc..drypyridine', ll-.8; g; (10% excess) of p-toluene-sulfonyl' chloride was added in portions withstirring; 'Considerableheat was evolved, andwhen this had. subsided. the flask' was warmed on'a hot plate for about one-half hour. The reaction mixture wascooled andthen poured into approximately 500cc. dilute: hydro chloricv acid with stirring), Anr oil; separated which solidified onrfurther 'stirring,.yielding. 5719i g., quantitative yield, of para-(meta-aminophenylsulfamyD-toluene, melting at 134-5.

A suspension was prepared from 85 cc. of water, 27.4 g- (0.094 mole) para-(meta-nitrophenylsulfamyD-toluene and 37.7 g. (0.127 mole) of sodium dichromate dihydrate. 93.5 g. of concentrated sulfuric acid was added dropwise with stirring over a half-hour period. The temperature was raised to 100 and maintained at 100- 115 for one hour. After cooling, the mixture was diluted with 250 cc. of water and the mixture filtered. The solid residue was treated with excess aqueous sodium bicarbonate solution and the insoluble material filtered, yielding 18.83 g. of the para-(meta-nitrophenylsulfamyl) -toluene starting material, melting at 1334. The bicarbonate filtrate was treated with charcoal and 6 coal and reprecipltated by neutralizing the solution with sodium hydroxide. 11.92 grams (61% yield) of theproductwas obtained, which, upon recrystallization from 50% alcohol, yielded 8.36

grams of. para (meta aminophenylsulfamyl) Table a j ticiitii I Toxicity Adluvam lnfll V Adminis Coadminisin Dogs 1 a tered tered Dose" CIYSS, without with Ins/kg Adjnvan-t Adjuvant msm-Oooon ]& 30.0 25.0 3.03 1. 22 o 1 NH,

1 In all experiments, the calculated dose of penicillin was 10,000 units initially followed immediately by a venoclysis of penicillin at a rate of 125 units per minute. l

2 Initial dose given at the time the constant intravenous infusion (venoclysis) of the adjuvant was begun. The initial dose was administered intravenously unless otherwise noted.

3 Expressed as a multiple of the amount that was calculated as being filtered at the glomerulus, uncorrected for plasma protein binding of penicillin. ,(Control phase of experiment.)

4 Same as 3, but following the coadministration of the adjuvant. i

5 0=not toxic to dogs in the dosage administered in these experiments.

the soluble material precipitated by acidification with dilute hydrochloric acid, yielding 4.32 g. of para-(meta nitrophenylsulfamyl) -benzoic acid, melting at 235 with decomposition. Similar resuits were obtained when p-(m-nitrophenylsulfamyl) -toluene was oxidized in alkaline permanganate.

To a solution of 33.1 g. (0.24 mole) of m-nitroaniline in 150 cc. of acetone 17.7 g. (0.08 mole) of p-carboxybenzenesulfonyl chloride was added, in portions with stirring. When solution was complete the acetone was evaporated on a steambath. The residue was treated with excess aqueous sodium bicarbonate solution and the insoluble residue filtered off. The filtrate was treated with charcoal and the product precipitated with dilute hydrochloric acid, yielding 21.7 g. of p-(mnitrophenylsulfamyl) -benzoic acid. A sample was purified further by recrystallization from 50 alcohol. Melting point 245-6" with decomposition.

21.5 grams (0.0667 mole) of the thus obtained nitro compound was suspended in 150 ml. of water, and sodium hydroxide solution added dropwise until the compound went into solution. The solution was weakly basic. Haney-nickel catalyst was added to the solution and hydrogenation at room temperature was begun. Since there was no appreciable drop in pressure at the end of six hours, the catalyst was filtered off and 4.5 gramsof 10% palladium-charcoal catalyst was added. Hydrogenation was continued until the pressure drop was 17 pounds (calculated pressure drop 17.2 pounds). The catalyst was filtered ed. The filtrate was neutralized with hydrochloric acid, precipitating 17.22 grams of the crude product. The precipitate was dissolved in dilute hydrochloric acid, treated with char- It will be seen from the above table that the adjuv'ants of this invention are safe, effective and reliable for the purpose described.

The invention is further illustrated by, but not restricted'to, the following various dosage forms of different compositions for administration by various routes.

Emample a.-Compressed tablet.10,000 grams of lactose and 100,000 grams of the adjuvant, para- (meta-aminophenylsulfamyl) -benzoic acid, are uniformly mixed and wetted with suflicient water to permit its ready granulation. 2,000 grams of dried cornstarch, 500 grams of karaya gum powder, 2,500 grams of talc, and 1,000 grams of calcium stearate are intimately mixed and then mixed together uniformly with the 110,000 grams of the mixture of the granulated adjuvant and lactose. The final mixture is then tableted (using 5 inch die standard curvature punches) yielding 200,000 tablets of 0.58 gram each, and each containing 0.5 gram of the adjuvant.

By replacing the quantity of the adjuvant in the above example by the same quantity of any other selected adjuvant embraced within the scope of the general formula above, tablets of the same individual weight and same content of any of the other adjuvants are obtained.

Measured amounts of the composition of Example a containing any selected adjuvant, or merely the adjuvant alone, can be filled into hard gelatin, telescopic capsules, each holding 0.5 gram of adjuvant.

Alternately, the selected adjuvant may be homogeneously dispersed in an equal quantity of corn oil, and the composition encapsulated in known manner in soft, elastic, sheet gelatin, hermetically sealed capsules each containing one gram of the adjuvant-oi1composltion 1 Example b.'-Ampul.-10' kilos of the adjuvant, para- (meta-aminophenylsulfamyl) -benzoic acid, are suspended infvery nearly 50 liters of distilled water and 1368.6"grams of sodium hydroxide are added to help in the dissolution of the adjuvant. 390 grams of monopotassium phosphate are added and distilled water added to make the volume of solution up to 50 liters (pH is about 7.4) The solution is then' filled int ampuls for 5 cc. liquid content each, which are then flame-sealed and autoclaved at pounds pressure for minutes.

Example c.--C'ompressed tablet containing penz'cz'ZZin.'l0,000 grams of lactose are mixed with 100,000 grams of the adjuvant, para-(metaaminophenyls'ulfamyl)-benzoic acid, and granulated as in Example-a. 3375 grams of sodium penicillin (1630 units per mg), 2625 grams dried cornstarch, 500 grams karaya gum powder, 2500 grams talc andlOGO grams calcium stearate are mixed together in an; atmosphere controlled at 10% relative humidity 'at 21 C., and then under the same conditions-mixed with the granulation of the adiuvant and the lactose and tableted with the same die as in Example 12 yielding 200,000 tablets weighing 0.6- gram and each containing 0.5 gram of adjuvantand 25,000 units penicillin (plus 10% excess). 7

Any other selected adjuvant'may replace the adjuvant of Example 2) in equal amount to obtain tablets of the same weight and same content of' anyof the other adjuvants.

Eivample cl.-Dry filled capsule with penicillin-Underatmosphere controlled as in- Example c, 25 kilos of the adjuvant, para-(metaaminophenylsulfamyl) -benzoic acid, 850 grams of crystalline penicillin sodium (as used above), and 150 grams of dried cornstarch are intimately and uniiorm y mixed, and the mixture filled into capsules, .yielding, 50,000; capsules, each holding 0.52 gram of mixture-containing 0.5 gram of adjuvant and 25,000 units-penicillin (plus. 10% excess).

'Ezcample e. '-Soyt-.elasiic capsule for penicillin-,Uhderhtmospher controlled as in Example c, 1.69 kilos of the same crystalline penicillin sodium are homogeneously dispersed in 48.31 kilos of corn oil and 50 kilosof' the adjuvant, para- (meta-aminophenylsulfamyl)-benzoic acid, similarly dispersed in theoi-l, and the resulting composition encapsulated in known manner in'soft, elastic, sheet gelatin, hermetically sealed capsules, yielding 100,000 capsules, each holding one gram'net of the composition and containing 0.5 grain of, adjuvant with 25,000 units penicillin (plus 10% excess).' I

Example f. Flctme-sealecl ampul filled with pc'niciZZin.l2.5 kilos of the adjuvant, para- (meta-aminophenylsulfamyl)-benzo-ic acid, are stirred into very nearly liters of sterile, pyro-- gen-free, distilled water and 1710.75-grams of sodiumhyd'roxide are added to aid in the dissolution oi-theadjuvant. Then 350 grams of moncpotassiiun. phosphate are added and, under atmosphereconditions, as in Example 0, 169 grams of the same crystalline. penicillin sodium are added and stirrcdinto solution and sufficient Water added to bring the-total volume of solution to 30 lite'rs. 112cc. of -this.solution are then filled into each of the required number of 20 cc. total volume ampul-vials. The contents of the vials are then quickly frozen by rotating them in a bathof 'riethyl Cellosolve chilled With Dry Ice;to +10. C and; desiccated under high vacuum for' i lfi hoursibythe method and apparatus as in United Statesl 'atent No. 2,353,985 and rubher stoppers inserted neck of eachof; the

containers while the vacuum is still being main-,

units penicillin (plus the 10% excess) and 25% of the adjuvant.

Example o.-Ampul oil suspension with penicillin.3 kilos of USP white wax are mixed into 35.127 kilos of purified peanut oil heated sufficiently to melt and permit homogeneous dispersion of the white wax. While this mixture is still sufiiciently liquid, and under atmosphere conditions as in Example 0, 10 kilos of the adjuvant,

para-(meta-aminophenylsulfamyl) -benzoic acid,

and 1873 grams 0:" calcium penicillin (734 units/mg.) are added and the mixture stirred to homogeneity. Each cc. of the resulting oil suspension contains 25,000 units of penicillin (plus 10% excess) and 0.2 gram of adjuvant. It is put up in flame-seal ampuls containing suitable volume of the suspension which is as stable as the ordinary penicillin in peanut oil preparation.

While each of the preceding Examples a through 9 contains its respective specific adj uvant, each of them may be prepared with any other suitable, effective adjuvant, for example, any other adjuvant embraced by the general formula above.

In addition, in those compositions containing penicillin, it is advisable, in accordance with customary practice, to include an excess of the penicillin, for example, a ten per cent excess over the label-claimed quantity in accordance with present practice. An excess of penicillin introduces no difficulty save its cost. The penicillin used may be any of the forms available for use, such as the calcium, sodium, potassium, procaine, and the hire salts of amorphous or crystalline penicillin.

The quantity per dose of adjuvant and penicillin will depend upon the blood leveland duration of action required for the particular condition encountered in each case. An advantageous ratio of adjuvant to penicillin per tablet or capsule is about one-half gram of the selectedadjuvant to 25,000 to 200,000 units of penicillin.

The compositions of the invention may also include an antacid material such as aluminum hydroxide, magnesium trisilicate, trisodium citrate, calcium carbonate, magnesium oxide, or other antacid substances suitable for administration for the purpose of neutralizing gastric acidity. The amount of antacid material. is limited only to that Whichis desirable to use in connection with penicillin or Which can be physically incor-- porated in a tablet'or capsule of suitable size for administration. V I

As to binders and lubricants used in making the tablets, such materials as lactose, corn starch, gum karays, talc, calcium stearate, gelatin, ethyl cellulose, mineral oil, propylene glycol, glycerin, and the like, may be included in pro-portions commonly used in preparing tablets of this nature.

If. the compositions are produced in the'form of suspensions or solutions in an oleaginous material, there are available various substances which may be used for this purpose. Corn oil or other'suitable oil is used with advantage.

9 We claim: 1. A sulfamylbenzoic acid which is a member of the group consisting of compounds having the general formula:

Q-NB-S 02-0-0 0 0H and their salts, wherein X is a member of the group consisting of the nitro and an amino radical.

2. Para-(meta aminophenylsulfamyl) -benzoic acid.

3. A composition suitable for use in conjunction with the administration of penicillin, comprising an adjuvant which is a member of the group consisting of compounds having the general formula and their salts, wherein X is a member of the group consisting of the nitro and an amino radical.

4. A composition suitable for therapeutic use, comprising penicillin and an adjuvant which is a. member of the group consisting of compounds having the general formula:

and their salts, wherein X is a member of the group consisting of the nitro and an amino radical, the quantity of adjuvant and penicillin in the composition being in the ratio of 0.5 gram of adjuvant to from 25,000 to 200,090 units of penicillin.

JAMES M. SPRAGUE. CHARLES S. MILLER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Reid, Prolongation of Penicillin Activity with Penicillinaise-Inhibitng Compounds," Proc. Soc. Exptl. Biol. and Med., November 1946, pages 438- 443.

Soo-I-Ioo, Activity of Penicillin Combined with Other Anti-Streptococcal Agents, Archives Biochemistry, September 1944, pages 99-106.

Meads, Caronamide and Penicillin, J. Am.

Med. Assoc, November 20, 1948, pages 874-877.

Pratt et al., Antibiotics, Lippincott Co., 1949, pages 112-116. (Book in Division 43.)

Micewicz-Chemical Abstracts, vol. 22, page 41111 (1928).

Ruggli et al.-Chemica1 Abstracts, vol. 35, column 5473-5474 (1941).

ArntzenChemical Abstracts, Vol. 38, column 61 (1944).

Gilman et a1.-J. Am. Chem. Soc., vol. 69, pages 1537-1538 (1947).

Claims (1)

1. 3. A COMPOSITION SUITABLE FOR USE IN CONJUNCTION WITH THE ADMINISTRATION OF PENICILLIN, COMPRISING AN ADJUVANT WHICH IS A MEMBER OF THE GROUPS CONSISTING OF COMPOUNDS HAVING THE GENERAL FORMULA