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Thi Na to Da Un Dari Matutulottuk THI NA TO DAUS009844599B2 UN DARIMATUTULOTTUK (12 ) United States Patent ( 10 ) Patent No. : US 9 ,844 , 599 B2 Satyam (45 ) Date of Patent: Dec . 19, 2017 ( 54 ) NITRIC OXIDE RELEASING PRODUGS OF C07C 201/ 04 (2013 . 01 ) ; C07C 203 / 04 THERAPEUTIC AGENTS ( 2013 .01 ) ; C07C 227/ 18 (2013 . 01 ) ; C07C 229 /42 ( 2013 .01 ) (71 ) Applicant : Apparao Satyam , Mumbai ( IN ) (58 ) Field of Classification Search CPC . .. C07C 201 /00 ; C07C 203 /00 ; C07C 201 /04 ; (72 ) Inventor: Apparao Satyam , Mumbai ( IN ) A61K 31 /21 ; A61K 4 /4817 ; A61K 31 /60 ( * ) Notice : Subject to any disclaimer , the term of this USPC .. 514 / 161, 162 , 165 , 166 , 509 patent is extended or adjusted under 35 See application file for complete search history . U . S . C . 154 ( b ) by 0 days. (56 ) References Cited ( 21 ) Appl. No. : 14 / 761, 887 U . S . PATENT DOCUMENTS ( 22 ) PCT Filed : Jan . 17 , 2014 6 ,610 ,676 B18 /2003 Del Soldato ( 86 ) PCT No. : PCT / IN2014 /000033 6 ,613 ,784 B1 9 /2003 Benedini et al. $ 371 ( c) ( 1 ), (Continued ) ( 2 ) Date : Jul. 17 , 2015 FOREIGN PATENT DOCUMENTS (87 ) PCT Pub . No .: WO2014 /111957 CN 1966484 A 5 /2007 CN 101053662 A 10 / 2007 PCT Pub . Date : Jul. 24 , 2014 (Continued ) (65 ) Prior Publication Data OTHER PUBLICATIONS US 2015/ 0328323 A1 Nov . 19, 2015 International Search Report for PCT Application No . PCT/ IN2014 / ( 30 ) Foreign Application Priority Data 000033 , dated Jun . 5 , 2014 , 3 pages . Jan . 21 , 2013 ( IN ) .. .. .. .. .. 181/ MUM / 2013 (Continued ) (51 ) Int. CI. Primary Examiner — Janet L Coppins A61K 31/ 21 ( 2006 . 01 ) ( 74) Attorney , Agent, or Firm — Sreenivasarao Vepachedu A61K 31 /60 ( 2006 .01 ) C07D 201 / 04 ( 2006 .01 ) ( 57 ) ABSTRACT A61K 47 / 48 ( 2006 .01 ) C07C 229 /42 ( 2006 . 01 ) The present invention relates to nitric oxide releasing pro C07C 201 / 04 ( 2006 .01 ) drugs of known drugs or therapeutic agents wherein the drug C07C 227 / 18 ( 2006 .01 ) or therapeutic agents contain at least one carboxylic acid A61K 31 /216 ( 2006 .01 ) group . The invention also relates to processes for the prepa ( Continued ) ration of these nitric oxide releasing prodrugs, to pharma (52 ) U . S . CI. ceutical compositions containing them and to methods of CPC . .. A61K 47 /481 (2013 .01 ) ; A61K 31/ 21 using these produgs. ( 2013 . 01) ; A61K 31/ 216 ( 2013 . 01) ; A6IK 31/ 60 ( 2013 .01 ) ; A61K 31/ 621 ( 2013 .01 ) ; 6 Claims, 12 Drawing Sheets 1A ) Plasmasalicylatewg/ml) S.EM,n3) (Mean Time ( h ) + Aspirin ( 30 mg/ kg p . o . ) + - D1 -R1 (44 . 83 mg /kg p . o . + 1 -D1 - R2 ( 47 . 16 mg/ kg p . o . ) - | -D1 -R3 (49 . 49 mg /kg p . o . IB ) 125 91. 13 1 12. 2 89 .78 10 . 2 73 . 54 4 . 9 T 53 . 00 15 . 6 AUG(pgWM) (MeantS.EM,n=3) $ Aspirin(30 mg P7097 /kg p (.o44 .) .83 mg P7244 /kg p(.49o. ). 49 maig P7245 p.(o47 .) . 16mging p.o .) Oral absorption profile of aspirin and its prodrugs I- DI- R1 ( i. e ., P7097) , 1- D1 - R2 ( i. e ., P7244 ) and I- DI- R3 (i . e. , P7245 ) in SD Rats ; A ) Line graph ; B ) Bar graph , US 9 ,844 ,599 B2 Page 2 (51 ) Int . Cl. Kubes, Paul & Wallace , John L ., Nitric Oxide as a Mediator of A61K 31 /621 ( 2006 .01 ) Gastrointestinal Mucosal Injury ? — Say it ain 't so ; Mediators of C07C 203 /04 ( 2006 . 01 ) Inflammation , 1995 ; 4 : 397 -405 . Kulkarni, S . K . , Jain , N . K . , Singh , A . , Nitric Oxidxe -releasing NSAIDs : A new dimension in nonsteroidal antiinflammatory drugs ; ( 56 ) References Cited Drugs of the Future 2001; 26 ( 5 ) : 485 . ( Abstract only ) . U . S . PATENT DOCUMENTS J . E . Keeble and P . K . Moore , Pharmacology and potential therapeu tic applications of nitric oxide - releasing non - steroidal anti- inflam 7 , 199 ,154 B2 * 4 / 2007 Berthelette . .. C07C 317 / 46 matory and related nitric oxide -donating drugs . British Journal of 514 / 509 Pharmacology , 2002 ; 137 ( 3 ) : 295 -310 . (Article first published 7 ,220 , 749 B2 5 / 2007 Letts et al . online : Feb . 2 , 2009 ) ( Abstract only ) . 7 , 524 , 836 B2 4 / 2009 Del Soldato Muscara M . N ., Wallace J . L . ; Nitric Oxide, V . Therapeutic potential 2006 /0058363 A1 3 / 2006 Wang et al. of nitric oxide donors and inhibitors , American Journal of Physi 2008 /0293781 AL 11/ 2008 Gasco et al . ology , Gastrointestinal and liver physiology , 1999 ; 39 : G1313 - 1316 . 2011/ 0263526 A1 * 10 /2011 Satyam .. .. .. C07C 203/ 04 Berguad et al . , Nitric Oxide -Releasing Drugs A Novel Class of 514 /50 Effective and Safe Therapeutic Agents, Ann . N . Y . Acad . Sci ., 962 : 360 - 371, 2002 . (Abstract only ) . FOREIGN PATENT DOCUMENTS S Fiorucci , P Del Soldato , NO -aspirin : mechanism of action and gastrointestinal safety , Dig Liver Dis 2003 ; 35 ( suppl. 2 ) , 9 - 19 . EP 0722434 B1 7 /1996 EP 1219306 A1 7 / 2002 ( Abstract only ) . WO 9530641 AL 11 / 1995 Lirk , P ., Hoffmann , G ., and Rieder , J . , Inducible nitric oxide WO 9716405 A1 5 / 1997 synthase time for reappraisal , Curr . Drug Targets Inflamm . WO 9809948 A2 3 / 1998 Allergy , 2002 ; 1 : 89 - 108 . ( Abstract only ) . WO 9821193 A1 5 / 1998 Ian L Megson , David J Webb , Nitric oxide donor drugs: current WO 9858910 Al 12 / 1998 status and future trends, Expert Opin . Investing . Drugs, 2002 ; 11 ( 5 ) : WO 2001010814 A1 2 / 2001 587 -601 . ( Abstract only ) . WO 2003084550 AL 10 / 2003 Press reports on naproxcinod and NCX4016 , www .nicox . com ; WO 2003094923 AL 11 / 2003 2014 . WO 2004004648 A2 1 / 2004 Nemmani, Kumar V . S . et al ., NO -NSAIDs : Gastric -sparing nitric WO 2004020384 A1 3 / 2004 oxide releasable prodrugs of non -steroidal anti - inflammatory drugs , WO 2004035042 A1 4 /2004 Bioorganic & Medicinal Chemistry Letters 19 (2009 ) , 5297 - 5301. WO 2004105754 Al 12 / 2004 WO 2005011646 A2 2 /2005 Pathan , A . R . , et al. , Oral bioavailability , efficacy and gastric WO 2005030224 A1 4 / 2005 tolerability of P2026 , a novel nitric oxide - releasing diclofenac in WO 2005070868 A1 8 / 2005 rat , Inflammopharmacology , 2010 , 18 ( 4 ) , 157 - 168 . ( Abstract only ) . WO 2007054451 A1 5 / 2007 O . A . al - Swayeh et al. , A comparison of the anti - inflammatory and WO 2007088123 A2 8 / 2007 anti -nociceptive activity of nitroaspirin and aspirin , British Journal WO 2007099548 A1 9 / 2007 of Pharmacology (2000 ) 129 , 343 - 350 . WO 2008095809 AL 8 / 2008 Lanas , Angel, Role of nitric oxide in the gastrointestinal tract , WO 2009000592 A1 12 / 2008 Arthritis Research & Therapy 2008 , 10 (Suppl 2 ) : S4 , Oct. 17 , 2008 . Dermot Cox et al , Effect of enteric coating on antiplatet activity of low - dose aspirin in healthy volunteers , Stroke 2006 ; 37 ( 8 ) : 2153 - 8 . OTHER PUBLICATIONS Patrignani, Paola et al. , Selective Cumulative Inhibition of Platelet Hyo -Kyung Han and Gordon L . Amidon , Targeted Prodrug Design Thromboxane Production by Low - dose Aspirin in Healthy Subjects , to Optimize Drug Delivery , AAPS PharmSci 2000 , 2 ( 1 ) , Mar . 21, American Society for Clinical Investigations 69 , Jun . 1982 , 1366 2000 . 1372 . Symposium on “ New Anti - inflammatory agents : NO - NSAIDs and Esser , Ronald et al. , Preclinical pharmacology of lumiracoxib : a COX - 2 inhibitors ” part of the 11th international conference on novel selective inhibitor of cyclooxygenase - 2 , Br. J . Pharmacol. “ Advances in prostaglandin and leukotrine research : Basic science 2006 , 144 , 538 -550 . ( Abstract only ) . and new clinical applications” held in Florence ( Italy ) , Jun . 4 - 8 , Gund , Machindra et al ., Gastric -sparing nitric oxide releasable 2000 . ' true ' prodrugs of aspirin and naproxen , Bioorganic & Medicinal Menlo Bolla et al. , Therapeutic Potential of Nitrate Esters of Chemistry Letters 24 ( 2014 ) , 5587 -5592 . Commonly Used Drugs , Curr. Topics Med . Chem . 2005 ; 5 : 707 720 . ( Abstract only ) . * cited by examiner U . S . Patent Dec . 19 , 2017 Sheet 1 of 12 US 9 ,844 , 599 B2 S Plasmasalicylate(ng/ml) À (MeanS.EM,n=3) Time ( h ) + Aspirin (30 mg/ kg p . o .) • 1- D1 - R1 (44 .83 mg/ kg p . o . ) 1 -D1 -R2 (47 . 16 mg/ kg p . o .) + 1- D1- R3 (49 . 49 mg/ kg p . o . ) IB ) 91 . 13 $ 12 .2 89 .78 10 . 2 73 . 54 + 4 . 9 53 . 56 $ 15 . 6 AUC(ug*h/mi) (MeanS.EM,n=3) ñ ñ Aspirin(30 mg P7097 /kg p.( 44o . ). 83 mgP7244 /kg p.( o49 . ). 49 mg P7245 /kg p. (o47. ) . 16mg /kg p. o. ) Figure 1 . Oral absorption profile of aspirin and its prodrugs I- D1 - R1 ( i. e ., P7097) , I -D1 - R2 ( i. e ., P7244 ) and I -D1 - R3 ( i . e . , P7245 ) in SD Rats ; A ) Line graph ; B ) Bar graph . U . S . Patent Dec . 19 , 2017 Sheet 2 of 12 US 9 ,844 , 599 B2 2A ) Plasmasalicylate(ug/ml) (Mean-S.EM,n=3) - Time ( h ) + Aspirin ( 30 mg/ kg p . o . ) * 1 -D1 - R1 ( 44 .82 mg/ kg p . o . ) 2B ) 500 436 . 8 £ 26 . 2 397 . 6 # 28 . 0 AUC(ug*h/ml)(MeanS.EM,n=3) Aspirin( 30 mg /kg po )I -DI -R1 (44 . 82 mg /kg p. o. ) Figure 2 . Oral Absorption profile of aspirin and its prodrug I -D1 - R1 in Wistar Rats ; A ) Line graph ; B ) Bar graph . U . S . Patent Dec . 19, 2017 Sheet 3 of 12 US 9 ,844 , 599 B2 3A ) Plasmanaproxen(ug/ml) (Mean+SEM,n=3) Ø ? o Time ( h ) ta + Naproxen ( 10 mg/ kg ) * 1 -D2 - R1 (13 .87 mg/ kg ) * 1- D2 - R3 ( 15 .07 mg /kg ) + 1- D2 - R2 ( 14 .47 mg/ kg ) * 1- D2 - R4 ( 15 .69 mg/ kg ) 3B ) 272 . 6 £ 8 . 5 3007 * * 1207. 8 18 . 2 S.EM,n=3) 182 .7 8 . 1 178 . 6 + 8 . 1 177 . 4 4 . 1 AUC(ug*h/ml) 100 (Mean filmNaproxen(10 mg /kg ) P7135(14 . 47 mg /kg ) P7133(13 . 87 mg /kg ) P7134(15 .
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