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(12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub US 20110263526A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0263526 A1 SATYAM (43) Pub. Date: Oct. 27, 2011 (54) NITRICOXIDE RELEASING PRODRUGS OF CD7C 69/96 (2006.01) THERAPEUTICAGENTS C07C 319/22 (2006.01) CD7C 68/02 (2006.01) (75) Inventor: Apparao SATYAM, Mumbai (IN) A6IP 29/00 (2006.01) A6IP 9/00 (2006.01) (73) Assignee: PIRAMAL LIFE SCIENCES A6IP37/08 (2006.01) LIMITED, Mumbai (IN) A6IP35/00 (2006.01) A6IP 25/24 2006.O1 (21) Appl. No.: 13/092.245 A6IP 25/08 308: A6IP3L/04 2006.O1 (22) Filed: Apr. 22, 2011 A6IP3L/2 308: Related U.S. Application Data 39t. O 308: (60) Provisional application No. 61/327,175, filed on Apr. A6IP3/10 (2006.01) 23, 2010. A6IPL/04 (2006.01) A6IP39/06 (2006.01) Publication Classification A6IP3/02 (2006.01) (51) Int. Cl. A6IP 9/06 (2006.01) A 6LX 3L/7072 (2006.01) 39t. W 308: A6 IK3I/58 (2006.01) A6IP II/08 (2006.015 A6 IK3I/55 (2006.01) A63/62 (2006.015 A6 IK 3/495 (2006.01) A6 IK 3/4439 (2006.01) (52) U.S. Cl. ........... 514/50: 514/166; 514/172: 514/217; A6 IK 3L/455 (2006.01) 514/255.04: 514/338; 514/356; 514/412; A6 IK 3/403 (2006.01) 514/420; 514/423: 514/510,536/28.53:540/67; A6 IK 3/404 (2006.01) 540/591; 544/396; 546/273.7: 546/318: 548/452: A6 IK 3/40 (2006.01) 548/500: 548/537; 549/464; 558/275 A6 IK3I/265 (2006.01) C7H 9/06 (2006.01) (57) ABSTRACT CO7I 71/00 (2006.01) CO7D 22.3/26 (2006.01) The present invention relates to nitric oxide releasing pro C07D 295/14 (2006.01) drugs of known drugs or therapeutic agents which are repre CO7D 40/12 (2006.01) sented herein as compounds of formula (I) wherein the drugs CO7D 213/80 (2006.01) or therapeutic agents contain one or more functional groups C07D 209/52 (2006.01) independently selected from a carboxylic acid, an amino, a CO7D 209/26 (2006.01) hydroxyl and a sulfhydryl group. The invention also relates to C07D 207/34 (2006.01) processes for the preparation of the nitric oxide releasing CO7D 49.3/04 (2006.01) prodrugs (the compounds of formula (I)), to pharmaceutical C07C32.3/56 (2006.01) compositions containing them and to methods of using the A6IP 25/8 (2006.01) prodrugs. Patent Application Publication Oct. 27, 2011 US 2011/0263526 A1 Figure 1 Oxyhemoglobin in blood Oxyhemoglobin in blood Oral bacteria Blood deoxyhemoglobin (by Bacterial Nitrate reductase) Protons in Stomach/tissues Xanthine Oxidase in tissues Xanthine Oxidase in tissues Cytochromes in liver/tissues Different pathways for oxidation and reduction of nitrate, nitrite and NO in the human body US 2011/0263526 A1 Oct. 27, 2011 NITRC OXDE RELEASING PRODRUGS OF used drugs to relieve pain, symptoms of arthritis and soft THERAPEUTICAGENTS tissue inflammation. Most patients with rheumatoid arthritis receive NSAIDs as first-line treatment which is continued for INCORPORATION BY REFERENCE prolonged periods. Although, NSAIDs provide anti-inflam 0001. This application is a non-provisional application matory and analgesic effects, they also have adverse effects and claims benefit under 35 U.S.C. 119(e) of Ser. No. 61/327, on the upper gastrointestinal (GI) tract. The occurrence of GI 175, filed on 23 Apr. 2010. toxicity appears to be strictly correlated to the mechanism of 0002 Any foregoing applications and all documents cited action of these drugs, namely the inhibition of the enzyme therein or during their prosecution (“application cited docu cyclooxygenase. In fact, inhibition of platelet cyclooxyge ments') and all documents cited or referenced in the applica nase, which causes prolonged bleeding time, and inhibition of tion cited documents, and all documents cited or referenced cyclooxygenase in gastrointestinal mucosa, which results in a herein (“herein cited documents'), and all documents cited or decreased synthesis of cytoprotective gastric prostaglandins, referenced in herein cited documents, together with any represent the major cause of serious gastrointestinal toxicity manufacturer's instructions, descriptions, product specifica (Symposium on “New Anti-inflammatory agents: tions, and product sheets for any products mentioned herein NO-NSAIDs and COX-2 inhibitors' part of the 11" interna or in any document incorporated by reference herein, are tional conference on Advances in prostaglandin and leukot hereby incorporated herein by reference, and may be rine research: Basic science and new clinical applications' employed in the practice of the invention. held in Florence (Italy), Jun. 4-8, 2000). This problem has 0003 Citation or identification of any document in this been solved by derivatisation of carboxylic acid group of application is not an admission that such document is avail able as prior art to the present invention. NSAIDs into its ester and amide derivatives. 0007 Another common approach to minimize adverse FIELD OF THE INVENTION effects of the known drugs or therapeutic agents consists of attaching a carrier group to the therapeutic agents to alter their 0004. The present invention relates to nitric oxide releas physicochemical properties and then Subsequent enzymatic ing prodrugs of known drugs or therapeutic agents which are represented herein as compounds of formula (I) wherein the or non-enzymatic mechanism to release the active drug mol drugs or therapeutic agents contain one or more functional ecule (therapeutic agent). The therapeutic agent is linked groups independently selected from the group consisting of a through a covalent linkage with specialized non-toxic protec carboxylic acid, an amino, a hydroxyl or a sulfhydryl group. tive groups or carriers or promoieties in a transient manner to The invention also relates to processes for the preparation of alter or eliminate undesirable properties associated with the the nitric oxide releasing prodrugs (the compounds of for parent drug to produce a carrier-linked prodrug. mula (I)), to pharmaceutical compositions containing them 0008 Indeed, a more recent strategy for devising a gastric and to methods of using the prodrugs. The present invention sparing NSAID involves chemically coupling a nitric oxide also relates to a bio-cleavable linker of formula (IA) capable (NO) releasing moiety to the parent NSAID. Nitric oxide is of forming a covalent linkage with a drug or a therapeutic one of the most important mediators of mucosal defense, agent (designated herein as D) containing one or more func influencing Such factors as mucus secretion, mucosal blood tional groups independently selected from a carboxylic acid, flow, ulcer repair and the activity of a variety of mucosal an amino, a hydroxyl or a sulfhydryl group and also processes immunocytes (Med Inflammation, 1995; 4: 397-405). Com for their synthesis. pounds that release nitric oxide in Small amounts over a prolonged period of time may also be very useful for the BACKGROUND OF THE INVENTION prevention of gastrointestinal injury associated with shock 0005. Many drugs (therapeutic agents) have undesirable and with the use of drugs that have ulcerogenic effects (Mus properties, for instance, low oral drug absorption, toxicity, cara M. N.; Wallace J. L. American Journal of Physiology, poor patient compliance etc., that may become pharmaco Gastrointestinal and liver physiology, 1999; 39:G 1313 logical, pharmaceutical, or pharmacokinetic barriers in clini 1316). Nitric oxide has been reported to play a critical role in cal drug application. Among the various approaches to mini maintaining the integrity of the gastroduodenal mucosa and mize the undesirable drug properties, while retaining the exerts many of the same effects as endogenous prostaglandins desirable therapeutic activity, the chemical approach using (Drugs Fut 2001; 26(5): 485). drug derivatisation offers perhaps the highest flexibility and 0009. Several mechanisms are considered to understand has been demonstrated as an important means of improving the protective effect of nitric oxide in the stomach including drug efficacy (Hyo-Kyung Hanand Gordon L. Amidon AAPS vasodilation of local mucosal blood vessels, inhibition of PharmSci. 2000; 2 (1), 48-58.). leukocyte adhesion and inhibition of caspase enzyme activity. 0006. The conventional approach that is adapted to mini The inactivation of caspase(s) appears to be an important mize the toxic side effects associated with the therapeutic factor in the GI tolerance of nitric oxide releasing NSAIDs agents has been to derivatise one or more functional groups (NO-NSAIDs). Caspases are a family of cysteine proteases present in the therapeutic agent or the drug molecule. The that resemble interleukin-113 (IL-113) converting enzyme derivatives are then assessed for their therapeutic efficacy as (ICE). These enzymes fall into two broad groups, i.e. caspase well as toxicity. The carboxylic acid group is often present as 1-like (including caspase-1, -4 and -5) and caspase-3-like an active functional group for derivatisation in several thera enzymes. Caspase-1 is primarily involved in cytokine release, peutic agents. Non-steroidal anti-inflammatory drugs cleaving pro-IL-1B to produce IL-1B. The ability of a range of (NSAIDs) represent the best characterized class of drugs for NO-NSAIDs to inhibit cytokine formation and caspase-1 therapeutic agents containing a carboxylic acid group as an (ICE) activity, thereby reducing the formation of pro-inflam active functional group. NSAIDs are also the most commonly matory IL-1B provides a possible explanation for the reduced US 2011/0263526 A1 Oct. 27, 2011 gastric damaging effect of these compounds (J. E. Keeble and oxide, the strategy of linking NO-releasing moieties has been P. K. Moore, British Journal of Pharmacology, 2002; 137: extended to a wide array of therapeutic agents selected from 295-310). cardiovascular drugs, for instance, Angiotensin converting 0010. In recent years, several NO-releasing non-steroidal enzyme (ACE) inhibitors, calcium antagonists and beta anti-inflammatory drugs (NO-NSAIDs) have been synthe blockers, antitumor agents, antihistamines, glucocorticoids, sized by an ester linkage formed through coupling of a NO etc.
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