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(12) Patent Application Publication (10) Pub. No.: US 2009/0306412 A1 Wallace Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0306412 A1 Wallace Et Al US 200903 06412A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0306412 A1 Wallace et al. (43) Pub. Date: Dec. 10, 2009 (54) 4-HYDROXYTHIOBENZAMIDE (86). PCT No.: PCT/CA07/O1273 DERVATIVES OF DRUGS S371 (c)(1), (75) Inventors: John L. Wallace, Hamilton (CA); (2), (4) Date: Jun. 24, 2009 Giuseppe Cirino, Naples (IT): O O Vincenzo Santagada, Cosenza Related U.S. Application Data (IT): Giuseppe Caliendo, Napoli (60) Provisional application No. 60/887,188, filed on Jan. (IT) 30, 2007, provisional application No. 60/807,639, filed on Jul.18, 2006. Correspondence Address: BENNETT JONES LLP Publication Classification CFO MS ROSEANN CALDWELL (51) Int. Cl. NSERS HALL EAST, 8ss - ND C07D 309/30 (2006.01) CALGARY,9 ABT2P 4K7 (CA) (52) U.S. Cl. ........................................................ 549/292 (57) ABSTRACT (73) Assignee: ANTIBETHERAPEUTICS INC., Hamilton, ON (CA) Derivatives of drugs are provided, said derivatives compris ing the H2S-releasing moiety 4-hydroxythiobenzamide that (21) Appl. No.: 12/374,273 is either covalently linked to the drug or forms a salt with the drug. The compounds of the present invention exhibit (22) PCT Filed: Jul.18, 2007 enhanced activity or reduced side effects or both. Patent Application Publication Dec. 10, 2009 Sheet 1 of 22 US 2009/0306412 A1 FIGURE 4 3 2 Healthy Vehicle Mesalamine 4-HTB Compound Mesalamine XXV -- 4-H TEB Colitis Patent Application Publication Dec. 10, 2009 Sheet 2 of 22 US 2009/0306412 A1 FIGURE 2 15 1 O Healthy Vehicle Mesaarine 4-HTB Cornpound Mesaarine XXV s 4-HB Coitis Patent Application Publication Dec. 10, 2009 Sheet 3 of 22 US 2009/0306412 A1 FIGURE 3 Vehicle MeSalamine 4 S Compound XXVII Alone Glibencamide Patent Application Publication Dec. 10, 2009 Sheet 4 of 22 US 2009/0306412 A1 FIGURE 4 Wehicle Mesalamine Compound XXVI 4. Patent Application Publication Dec. 10, 2009 Sheet 5 of 22 US 2009/0306412 A1 FIGURE 5 7.5 50 2.5- ..) Vehicle Aspirin Comp XXVI Glibenc se Aspirin Comp XXV se Aspirin Patent Application Publication Dec. 10, 2009 Sheet 6 of 22 US 2009/0306412 A1 FIGURE 6 its Buffer I Homogenate Homogenate - PAG 7S i. 9. 50 s R, 25 O Weice Cysteine arE compound XXV Patent Application Publication Dec. 10, 2009 Sheet 7 of 22 US 2009/0306412 A1 FIGURE 7a nom Vehicle r 10 - Trimebutine maleate -A Compound ill 0.4 0.8 12 1.6 Distending Volume (mL) Patent Application Publication Dec. 10, 2009 Sheet 8 of 22 US 2009/0306412 A1 FIGURE 7b -Om Vehicle O' Thiocarbamoylbenzoate 4. O 3 5 2 s C O T-T--- 0.4 0.8 1.2 1.6 Distending Volume (mL) Patent Application Publication Dec. 10, 2009 Sheet 9 of 22 US 2009/0306412 A1 FIGURE 8 10.0 ha O i 7.5 O S.is 5.0 9 st 2.5 (D O.O Vehicle Diclofenac CmpdXVIf TBZ Diclofenac Patent Application Publication Dec. 10, 2009 Sheet 10 of 22 US 2009/0306412 A1 FIGURE 9 Vehicle Diclofenac Cmpd XVI TBZ Diclofenac te BZ Patent Application Publication Dec. 10, 2009 Sheet 11 of 22 US 2009/0306412 A1 FIGURE 10 Patent Application Publication Dec. 10, 2009 Sheet 12 of 22 US 2009/0306412 A1 FIGURE 11 4O O Patent Application Publication Dec. 10, 2009 Sheet 13 of 22 US 2009/0306412 A1 FIGURE 12 2 O k Vehicle Vehicle Diclofenac TBZ Cmpd XVI -m-m-m-mamma-HT Zymosan Patent Application Publication Dec. 10, 2009 Sheet 14 of 22 US 2009/0306412 A1 FIGURE 13 Vehicle Vehicle Diclofenac TBZ Cmpd XVI Zymosan Patent Application Publication Dec. 10, 2009 Sheet 15 of 22 US 2009/0306412 A1 FIGURE 14 -o-Vehicle - O- Diclofenac (1 mg/kg) -- Diclofenac (3 mg/kg) - O-Diclofenac (10 mg/kg) -- Cmpd XVI (4.1 mg/kg) Y M O1 8O 0.6 1 2 3 4. 5 Hours. After Carrageenan Patent Application Publication Dec. 10, 2009 Sheet 16 of 22 US 2009/0306412 A1 FIGURE 15 2 O 1 5 10 + Zymosan Patent Application Publication Dec. 10, 2009 Sheet 17 of 22 US 2009/0306412 A1 FIGURE 16 S kE C X X s O ECis 9 E2. S. O E k-E s ea s s No1 C E 9. - to and d CD O C O O - - - - - - - cs CD .9E O) D O O O O O O O O CN N re ta (u/bu) SIseulu AS euexoduou Patent Application Publication Dec. 10, 2009 Sheet 18 of 22 US 2009/0306412 A1 FIGURE 17 18 15 12 69 3 O Vehicle Diclofenac Cmpd XVI Naproxen TBZ Patent Application Publication Dec. 10, 2009 Sheet 19 of 22 US 2009/0306412 A1 FIGURE 18 15 p30.001 9 - 10 E Ea 9 () 9 vehicle Naproxen CmpdXX Patent Application Publication Dec. 10, 2009 Sheet 20 of 22 US 2009/0306412 A1 FIGURE 19 100 5 - 75 . 5O 50 D E ca, E. 25 s O TBZ Cmpd XVII TBZ Cmpd XVI s-as-ite-ser Buffer Homogenate Patent Application Publication Dec. 10, 2009 Sheet 21 of 22 US 2009/0306412 A1 FIGURE 20 OVehicle Simvastatin to Compound ... : : 8 45 5 3 5 nya, , , 10 Concentration of Drug (uM) Patent Application Publication Dec. 10, 2009 Sheet 22 of 22 US 2009/0306412 A1 FIGURE 21 OVehicle 8O 6O 40 2O 3 10 30 100 Concentration of Drug (M) US 2009/03 06412 A1 Dec. 10, 2009 4-HYDROXYTHOBENZAMIDE 0007. It is believed that the production of endogenous HS DERVATIVES OF DRUGS is altered in many diseases. Furthermore, the levels of HS may be effected by currently used drugs. For example, ace tylsalic acid and non-steroidal anti-inflammatory drugs 0001. This application is filed as a Continuation-in-Part of (NSAIDs) have been shown to have an inhibitory effect on the PCT/CA2006/000484, filed Mar. 31, 2006, which claims pri CSE-HS pathway in gastrointestinal mucosa (Fiorucci, S. et ority to PCT/CA2005/000819, filed May 27, 2005. This al). This effect may contribute to gastric mucosal injury application is further a Continuation-in-Part of U.S. patent induced by these drugs. Thus, pharmacological modulation application Ser. No. 1 1/759,154, which is a Continuation-in of HS levels could be of potential therapeutic value. Part of PCT/CA2006/000484, and which claims priority to 0008. It is also thought that HS may have a role in car U.S. provisional patent application No. 60/804,067, filed Jun. diovascular pathology and, as such, its level should be exam 6, 2006. This application further claims priority to U.S. pro ined in patients with various risk factors of atherosclerosis visional patent applications Nos. 60/807,639, filed Jul. 18. Such as arterial hypertension, hyperlipidemia, diabetes mel 2006, and 60/887,188, filed Jan. 30, 2007. litus, etc. Given that HS is quenched by reactive oxygen species (ROS) (Whiteman, M. et al., The novel neuromodu FIELD OF INVENTION lator hydrogen Sulfide: an endogenous peroxynitrate scav 0002 The present invention relates to hydrogen sulfide enger?, J. Neurochem. 2004: 90: 765-768), and considering (HS) releasing derivatives of drugs having improved activity the important role of oxidative stress in many diseases such as and/or reduced side effects. In particular, the present inven atherosclerosis, arterial hypertension, Alzheimer's disease, tion relates to drug derivatives comprising the HS-releasing etc., it is thought that excessive ROS production may cause moiety 4-hydroxythiobenzamide either covalently linked to a HS deficiency. drug or forming a salt with the drug. 0009 Beta-blockers, which used for angina, hypertension and cardiac arrhythmia treatment, show respiratory side BACKGROUND OF THE INVENTION effects such as dyspnoea, bronchoconstriction, etc., and therefore may cause problems in patients affected by asthma, 0003) Nitric oxide (NO) and carbon monoxide (CO) syn bronchitis, and the like. Therefore, beta-blockers further thesized from L-arginine by NO synthase and from heme by worsen respiratory diseases Such as asthma. Hence, in asth heme oxygenase, respectively, are the well-known neu matic patients doses of said drugs must be used reduced in rotransmitters and are also involved in the regulation of vas order not to jeopardize even more the respiratory functional cular tone. Recent studies suggest that hydrogen Sulfide (H2S) ity. Thus the efficacy of the beta-blockers is reduced. is the third gaseous mediator in mammals. HS is synthesized 0010 Antithrombotics, such as for example dipyridamole, from L-cysteine by either cystathionine beta-synthase (CBS) aspirin, etc., used for the prophylaxis of thrombotic phenom or cystathionine gamma-lyase (CSE), both using pyridoxal ena, have a number of side effects Such as stomach pain, 5'-phosphate (vitamin B) as a cofactor. nausea and other gastrointestinal tract complications. In 0004. It is believed that HS stimulates ATP-sensitive patients affected by pathologies connected to oxidative stress, potassium channels (K) in the vascular Smooth muscle the therapeutic action or the tolerability of these drugs, as in cells, neurons, cardiomyocytes and pancreatic beta-cells. In the case of aspirin, is greatly reduced. addition, H2S may react with reactive oxygen and/or nitrogen 0011 Bronchodilators, for example, salbutamol, etc., are species limiting their toxic effects but also attenuating their used in the treatment of asthma and bronchitis and drugs physiological functions, like nitric oxide does. active on the cholinergic system are used in pathologies Such 0005 Recent studies have shown that HS is involved in as urinary incontinence. Their administration can produce the regulation of vascular tone, myocardial contractility, neu side effects affecting the patient's cardiovascular system, rotransmission, and insulin secretion. HS deficiency was causing problems both to cardiopathic and to hypertensive observed in various animal models of arterial and pulmonary patients.
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