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Publication numberUS3412131 A
Publication typeGrant
Publication dateNov 19, 1968
Filing dateAug 2, 1966
Priority dateAug 2, 1966
Publication numberUS 3412131 A, US 3412131A, US-A-3412131, US3412131 A, US3412131A
InventorsJoseph V Swintosky
Original AssigneeSmith Kline French Lab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Alkyl carbonates of salicylic acid
US 3412131 A
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Description  (OCR text may contain errors)

United States Patent 3,412,131 ALKYL CARBONATES 0F SALICYLIC ACID Joseph V. Swintosky, Perkiomenville, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. FiledAug. 2, 1966, Ser. No. 569,591 3 Claims. (Cl. 260-463) This invention relates to new organic compounds having valuable pharmacodynamic properties. More specifically this invention relates to alkyl carbonates of salicylic acid having the following structural formula:

Formula 1 t -COH wherein R is an alkyl group. The term alkyl is here and elsewhere employed to designate a straight or branched group containing from four to eight carbon atoms. Most advantageously the lower alkyl group will contain from four to six carbon atoms.

The preferred and most advantageous compounds of this invention are the n-butyl-o-carboxyphenylcarbonate and the corresponding n-hexyl-o-carboxyphenylcarbonate.

The compounds of this invention are particularly useful as analgetics. The novel compounds of this invention are as potent analgetics as aspirin and they are absorbed rapidly giving blood concentrations equivalent to those of aspirin. However, these compounds are particularly advantageous analgetics because they do not cause the gastrointestinal disturbances which is observed following the administration of aspirin. The compounds of this invention demonstrate a marked decrease in the incidence and severity of gastrointestinal irritation and ulceration. The novel alkyl carbonates of this invention are therefore eflFective analgetic agents demonstrating minimal side effects.

The closest compound reported in the literature is the ethyl carbonate of salicylic acid, n-ethyl-o-carboxyphenylcarbonate. This compound is disclosed in Beilstein, vol. 10, page 69. Gastric irritation studies were conducted to compare the above noted prior art compound, aspirin and the novel butyl and hexyl carbonates of salicylic acid as disclosed above in Formula 1. The following standard procedure was employed. Rats were orally given equal molar doses of suspensions of the compounds in 1% methyl cellulose. The rats were sacrificed after two hours and the stomachs were removed, opened and macroscopically examined for gastric hemorrhage. Results of these gastric irritation studies disclosed that at the same equal molar doses at which aspirin and the known ethyl carbonate derivative produced 100% incidence of hemorrhage in the rats only a 30% was noted with the novel butyl carbonate and a 50% incidence with the novel hexyl carbonate compounds of this invention. These studies show that the gastric irritation liabilities of the compounds of this invention are markedly less than those of aspirin and the closest prior art compound.

The novel salicylic acid carbonates of this invention 3,412,131 Patented Nov. 19, 1968 are prepared according to the following synthetic procedure in which R is given above.

This general procedure employed to prepare the novel salicylic acid carbonates of this invention utilizes readily available starting materials. By way of example, the salicylic acid is treated with the proper alkyl chloroformate in the presence of an acid scavenger, such as, for example, N,N-dimethylaniline or trie'thylamine, to yield the desired product. The reaction may be carried out in any suitable organic solvent, such as, for example, benzene, toluene, carbon tetrachloride, chloroform or methylene chloride.

The desired chloroformate starting materials may also be prepared by treating the appropriate alkanol with phosgene according to' standard methods known to the art, as for example, Slimowicz et al., J .A.C.S., 71, 1044 (1949).

The novel carbonates as represented by the above Formula 1 are advantageously employed in combination with either a liquid or solid nontoxic pharmaceutical carrier. A wide variety of pharmaceutical forms useful for oral ingestion may be employed. l kdvantageously the preparation may take the form of tablets, capsules, powders, troches or lozenges. When a solid form is employed the pharmaceutical carrier may be, for example, lactose, magnesium stearate, starch, gums such as acacia, terra alba, stearic acid, sorliitol, mannitol, "ethyl cellulose or gelatin. The amount of solid carrier will vary widely but preferably is from about 25 mg. to about 1 gm. If a liquid carrier is used the preparation; can be in the form of a soft gelatin capsule, placed him ampule or in a liquid suspension.

The pharmaceutical forms comprising the above compounds of Formula 1 are administered in dosage units preferably orally to obtain the beneficial analgetic effects with a low order of gastric irritation.

The following examples will further serve to describe this invention. These examples are not limiting but are illustrative of compounds of this invention and the procedures for their preparation.

EXAMPLE 1 To a cooled solution of 101 g. of salicylic acid and 185 ml. of N,N-dimethylaniline in'520 ml. of dry benzene is added 100 g. of n-butyl chlo'roformate with stirring. The mixture is stirred for approximately 15 minutes and extracted with dilute hydrochloric acid. The organic layer is separated and the solvent removed. The residual product is dissolved in warm carbon tetrachloride and treated with charcoal. The product is then crystallized from a carbon tetrachloridehexane mixture to yield n-butyl-ocarboxyphenylcarbonate having a melting point of 77.5- 79.5 C.

EXAMPLE 2 To a solution of g. of salicylic acid in 475 ml. of

r,enzenmisfadded=155.:mlhof N,N-dimethylaniline and the--=-- What is claimed -is:- solution is cooled. To the cooled solution 100 g. of n-hexyl 1. A compound of the formula: chloroformate is slowly added with stirring. The reaction mixture is then extracted with dilute hydrochloric ll acid and thegproduct is crystallized from carbon tetra- OH chloride-hexane to yield n-hexyl o-carboxyphenylcarbonate having a melting point of 78-79 c. F

EXAMPLE 3 wherein R is an alkyl group comprising from four to Employing the general procedures outlined in Examples Eight Carbon atoms- 1 and 2 above equivalent amounts of tarting 2. COIIIPOHHd Of claim 1 wherein R represents material, similar transformations give the following ren-butyl and Sald comPolmd is Y YP Y 91$: 4 ,i a a A., carbonate.

"(13) sfg iif "mteri h 'n g t 'l "hloi-bfo f Land 3. The compound of 01311 11 1 wherein R represents salicylic acid. Product: n-octyl-o carboxyphenylcarbonate. 15 Y cbmpolmdvkls i f fi p fi y (B) Starting material: n-amylchloroformate and salin t -1 cylic acid Product: n-amyl-o-carboxyphenylcarbonateI a A iq iii 159 t i1 C) Starting material isobutyl chloroformate and CHARLES pA p m salicylic acid. Product: 1sobutyl-o-carboxyphenylcarbon- 1 I ate.

L. c. MAR'UZOQ mm) Examiner;

Non-Patent Citations
Reference
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4851426 *Feb 12, 1986Jul 25, 1989Teva Pharmaceutical Industries, Ltd.Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids and pharmaceutical compositions thereof
Classifications
U.S. Classification558/273
International ClassificationC07C69/86, C07C69/96
Cooperative ClassificationC07C69/96
European ClassificationC07C69/96, C07C69/86
Legal Events
DateCodeEventDescription
Jun 21, 1982ASAssignment
Owner name: SMITHKLINE BECKMAN CORPORATION
Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769
Effective date: 19820304
Owner name: SMITHKLINE BECKMAN CORPORATION, PENNSYLVANIA