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

• US 4,654,331 A
• Filed: 08/23/1984
• Issued: 03/31/1987
• 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): CLARKE, VERA
• Application Number:
  US06/643,575
• Time in Patent Office: 950 Days
• Field of Search: 260/239.1, 260/245.3, 260/245.2 R, 260/245.2 T, 544/21, 544/25, 544/26, 544/27, 544/28, 544/22, 514/195, 514/161, 514/202, 514/203, 514/204, 514/206, 514/207, 514/263, 514/314, 514/333, 514/415, 514/467, 514/120, 514/461, 514/397, 549/229, 540/225, 540/226, 540/227, 540/228, 540/221, 540/304, 540/314, 540/347
• US Class Current: 514/120
• 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-C₁ -C₆ -alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of a carboxylic acid selected from the group consisting of (+)-α

-(fluoromethyl)histidine hydrochloride;

(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-5-indanyloxy)acetic acid;

3-fluoro-D-alanine-2-deuterium labeled;

10,11-dihydro-5-(1-methyl-4-piperidinylidine)-5H-dibenzo (a,d)cycloheptene-3-carboxylic acid hydrochloride;

N-formimidoyl thienamycin monohydrate;

(Z)-7(R)-[(2-amino-2-carboxyethyl-thio]-2-(S)-[(2,2-dimethylcyclopropyl) carbonyl]amino-2-heptenoic acid;

N-[(S)-1-(carboxyl)-3-phenylpropyl]-L-alanyl-L-proline maleate;

N² -[1-(S)-carboxy-3-phenyl-propyl]-L-lysyl-L-proline;

N-[1(S)-carboxy-3-phenylpropyl]-L-alanine-L-proline;

dihydroxyphosphine carboxylic acid oxide;

moxalactam;

somatostatin;

thienamycin;

cefmetazole;

cefmenoxime;

7β

-[D-(31 )-α

-(4(5)-carboxyimidazole5(4)-carboxamidophenylacetamido]-3-(4-.beta.-sulfoethylpyridinium)-methyl-3-cephem-4-carboxylic acid;

7-[D-α

-[3-(2'"'"'-amino-sulfonylanilino-4-hydroxy-5-pyrimidinyl)ureido]-p-hydrophenylacetamido]-3-[1-methytetrazo-5-yl)thiomethyl]-ceph-3-em carboxylic acid;

ceforanide;

ceftizoxime;

ceftazidime;

cefotetan;

cefsulodin;

7-[D(-)-α

-(4-hydroxy-6-methylpyridine-3-carboxyamido)-α

-(4-hydroxyphenyl-acetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid;

cefatriaxon;

cefaperazone;

7β

-(D-2-amino-2-carboxyethylthio)-acetamido-7α

methoxy-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxyic acid;

cefotaxime;

cephalexin;

furosemide;

ibuprofen;

aspirin;

sodium levothyroxine;

fenoprofen;

7-theophyllineacetic acid;

tolmetin;

clofibric acid;

cefaclor;

pirprofen;

isoxepac;

benoxaprofen;

suprofen;

diclofenac sodium;

corprofen;

flurbiprofen; and

naprosyn.

2. A pharmaceutical composition containing an effective amount of the compund of claim 1 in a pharmaceutically acceptable carrier.