Controlled release N-substituted pyrrolidone esters and process for the use thereof

• US 5,206,386 A
• Filed: 03/20/1991
• Issued: 04/27/1993
• Est. Priority Date: 03/20/1991
• Status: Expired due to Fees

• Current Assignee: ISP Investments, Inc. (Ashland Global Holdings, Inc.)
• Original Assignee: ISP Investments, Inc. (Ashland Global Holdings, Inc.)
• Inventors: Narayanan, Kolazi S., Taylor, Paul D.
• Primary Examiner(s): Springer, David B.
• Application Number:
  US07/675,367
• Time in Patent Office: 769 Days
• Field of Search: 548/551, 548/413, 514/91, 514/424
• US Class Current: 548/551
• CPC Class Codes: C07D 207/27 with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

Abstract

N-substituted cyclic lactam esters are made from biologically active organic acids and N-haloalkyl substituted cyclic lactam, preferably N-chloromethyl pyrrolidone. Such esters provide slow release of the organic acids in situ through slow hydrolysis of the ester to release the organic acid and the N-alkyl substituted cyclic lactam. The esters are useable for delivering a large variety of biologically active organic acids in slow release fashion to target organisms and promote effective long term therapeutic treatment. In particular, an ester made from acetyl salicyclic acid and chloromethyl pyrrolidone provides a vehicle for dermal penetration and slow release of aspirin for long term treatment.

Claims

1. A controlled release N-alkylene substituted cyclic lactam ester of a biologically active organic acid as represented by Formula I:

##STR12## where n=1 to 3, m=3, and R is ester moiety of a biologically active medicinal carboxylic acid or amino carboxylic acid, the ester group being hydrolyzabel in vivo to release the biologically active carboxylic acid substance, where R is derived from a carboxylic acid from the group consisting of aspirin(acetyl salicyclic acid), 2,4 dichlorophenoxy acetic acid, 3,6, dichloro 2- methyoxybenzoic acid, endothall, alpha and beta naphthoic acids, N-phenylphthalamic acid, acrylic acid, glycine, alphaamino butyric acid, phosphonomethyl glycine, amiben, indobufen, idoprofen, indomethacin, and ibuprofen.

2. The ester of claim 1 where R is acetyl salicylate.

4. A method for controllably releasing a biological active organic acid in situ comprising:

providing the N-alkylene substituted cyclic lactam ester of the biologically active organic acid of claim 1;

contacting the ester with aqueous body fluids, and,

hydrolyzing the ester in vivo to release the biologically active organic acid from the N-alkyl substituted cyclic lactam, the rate of acid deposition controlled by the rate of hydrolysis.

3. A controlled release N-alkylene substituted pyrrolidone ester of a biologically active acid as represented by Formula II:

##STR13## where R'"'"', R", and R'"'"'"are lower alkyl alkoxy, cycloalkyl, aralkyl or H, at least one of R'"'"', R" or '"'"'" being H;

n=1 or 2 and where R is an organic moiety of a biologically active medicinal carboxylic acid or amino carboxylic acid, the ester hydrolyzable in vivo to release the biologically active carboxylic acid substance, where R is derived from a carboxylic acid from the group consisting of aspirin(acetyl salicyclic acid), 2,4 dichlorophenoxy acetic acid, 3,6 dichloro 2-methoxybenzoic acid, endothall, alpha and beta naphthoic acids, N-phenylphthalamic acid, acrylic acid, glycine, alpha-amino butyric acid, phosphonomethyl glycine, amiben, indobufen, idoprofen, indomethacin, and ibuprofen.