US 9,809,557 B2
Prodrugs of non-steroid anti-inflammatory agents (NSAIDS)
Claus Selch Larsen, Lejre (DK); Susan Weng Larsen, Rødvore (DK); Mette Agergaard Thing, Copenhagen (DK); Jesper Langgaard Kristensen, Copenhagen (DK); Henrik Jensen, Roskilde (DK); and Jesper Østergaard, Farum (DK)
Appl. No. 14/355,010
Filed by Claus Selch Larsen, Lejre (DK)
PCT Filed Oct. 31, 2012, PCT No. PCT/DK2012/050400
§ 371(c)(1), (2) Date Apr. 29, 2014,
PCT Pub. No. WO2013/064153, PCT Pub. Date May 10, 2013.
Claims priority of application No. 2011 70591 (DK), filed on Oct. 31, 2011.
Prior Publication US 2014/0315960 A1, Oct. 23, 2014
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/44 (2006.01); C07D 235/06 (2006.01); A61K 47/48 (2006.01); C07C 219/10 (2006.01); C07C 219/32 (2006.01); C07C 229/42 (2006.01); C07D 487/04 (2006.01); C07D 233/61 (2006.01); C07D 235/16 (2006.01); C07D 235/18 (2006.01); C07D 213/55 (2006.01)
CPC C07D 235/06 (2013.01) [A61K 47/48023 (2013.01); A61K 47/48061 (2013.01); C07C 219/10 (2013.01); C07C 219/32 (2013.01); C07C 229/42 (2013.01); C07D 213/55 (2013.01); C07D 233/61 (2013.01); C07D 235/16 (2013.01); C07D 235/18 (2013.01); C07D 487/04 (2013.01)] 20 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Drawing
wherein:
R1 represents an immobility promoting unit (IPU) with a molecular weight lower than 1000 g/mol and a pKa of between 4 and 7.6 at 37° C., wherein the IPU is selected from the group consisting of:

OG Complex Work Unit Drawing
wherein R3 is attached on any ring carbon or any nitrogen of the IPU and R3 is straight or branched C1-8 alkyl or alkoxyalkyl, with the proviso that when R3 is attached on a nitrogen atom R3 is not —CH2
R4 and R5 are each independently hydrogen, straight or branched C1-8 alkyl, alkoxyalkyl or phenyl, or when R1 is a phenylamino or benzimidazolyl moiety as set forth above, R4 may be R3, or when R1 is an imidazolyl moiety as set forth above, R5 may be R3;
—O—(C═O)—R2 represents an acyloxy residue of a carboxylic acid group of;
and
x is 1;
salts, solvates or hydrates thereof,
wherein the aqueous solubility of the compound is pH dependent, such that the aqueous solubility at a pH between 2 to 6 pH units lower than a pH of a physiological fluid having a pH of from 6 to 8 is at least 100 times higher than its aqueous solubility at the pH of the physiological fluid.