Oral absorption enhancement of carboxylic acid pharmaceuticals using (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester group

• US 4,479,947 A
• Filed: 06/07/1982
• Issued: 10/30/1984
• Est. Priority Date: 07/13/1981
• Status: Expired due to Term

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Christensen, Burton G.
• Primary Examiner(s): Trousof, Natalie
• Assistant Examiner(s): Clarke, Vera C.
• Application Number:
  US06/385,199
• Time in Patent Office: 876 Days
• Field of Search: 260/239.1, 260/245.2 R, 260/245.2 T, 260/245.4, 544/21, 544/29, 548/196, 548/194, 548/344, 548/494, 548/500, 548/531, 548/532, 548/533, 548/535, 424/246, 424/271, 424/270, 424/278, 424/232, 424/203, 549/229, 546/189
• US Class Current: 514/99
• CPC Class Codes: C07D 317/40 Vinylene carbonate; Substituted vinylene carbonates
• CPC Class Codes: C07D 499/88 Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
• CPC Class Codes: C07D 501/00 Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• CPC Class Codes: C07F 7/0812 comprising a heterocyclic ring
• CPC Class Codes: C07F 9/65515 the oxygen atom being part of a five-membered ring

Abstract

The (5-R-2-oxo-1,3-dioxolen-4-yl)methyl moiety: ##STR1## wherein R is loweralkyl of 1-6 carbon atoms, especially methyl or t-butyl; when utilized as an ester on a pharmaceutical having a carboxylic acid functionality, enhances oral absorption of the pharmaceutical. This effect is applicable to a broad range of pharmaceutically active substances, including antibiotics, and antihypertensives as well as other classes of therapeutic agents.

Claims

1. The (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of a carboxylic acid wherein alkyl has 1-6 carbon atoms and wherein said carboxylic acid is cefoxitin, methyldopa, 3β

-[2-methoxyimino-2-(2-amino-1,3-thiazolol-4-yl)acetamido]monobactamic acid, 2-ethylthio)-6β

-(1R-hydroxyethyl)-penem-3-carboxylic acid or fosfomycin.

2. The compound of claim 1 wherein the carboxylic acid is cefoxitin.

3. The compound of claim 1 wherein the carboxylic acid is methyldopa.

4. The compound of claim 1 wherein the carboxylic acid is 3β

-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]monobactamic acid.

5. The compound of claim 1 wherein the carboxylic acid is 2-(ethylthio)-6β

-(1R-hydroxyethyl)penem-3-carboxylic acid.

6. The compound of claim 1 wherein the carboxylic acid is fosfomycin.

9. A pharmaceutical composition containing an effective amount of the compound of any one of claims 1 through 8 in a pharmaceutically acceptable carrier.

10. The compound of claim 1 wherein said alkyl is other than methyl.

11. The compound of claim 1 wherein said alkyl is t-butyl.

7. The compound 4-t-butyl-1,3-dioxol-2-one-5-ylmethyl(S)-3-hydroxy-α

-methyltyrosinate(2R,3R)hydrogentartrate, and in hemihydrate form.

8. The compound 4-methyl-1,3-dioxol-2-one-5-ylmethyl(S)-3-hydroxy-α

-methyltyrosinate(2R,3R)hydrogentartrate, and in hemihydrate form.