USOO5807847A United States Patent (19) 11 Patent Number: 5,807,847 Thatcher et al. (45) Date of Patent: Sep. 15, 1998 54 NITRATE ESTERS Bennett, B.M., McDonald, B.J., Nigam, R., and Simon, W.C., “Biotransformation of organic nitrates and vascular 75 Inventors: Gregory R. J. Thatcher; Brian M. Smooth muscle cell function', Trends in Pharmacol. Sci. 15: Bennett, both of Kingston, Canada 245–249 (1994). Cameron, D.R., Borrajo, A.M.P., Bennett, B.M., and 73 Assignee: Queen's University at Kingston, Thatcher, G.R.J., “Organic nitrates, thionitrates, peroxyni Kingston, Canada trites, and nitric oxide: a molecular orbital study of RXNO es RXONO (X=O.S) rearrangement, a reaction of potential 21 Appl. No.: 658,145 biological significance”, Can. J. Chem. 73: 1627-1638 22 Filed: Jun. 4, 1996 (1995). Chong, S., and Fung, H.-L., “Biochemical and pharmaco 51) Int. Cl. ...................... C07C 38/102; CO7C 203/04; logical interactions between nitroglycerin and thiols. Effects A61K 31/255; A61K 31/66; A61K 31/39; of thiol Structure on nitric oxide generation and tolerance A61K 31/21; CO7F 9/40; CO7D 327/04 reversal”, Biochem. Pharm. 42: 1433–1439 (1991). 52 U.S. Cl. .............................. 514/129; 514/23: 514/24; 514/439; 514/517; 514/509; 536/18.7; 536/55; Feelisch, M., “Biotransformation to nitric oxide of organic 549/40; 558/175; 558/480; 558/484; 558/485; nitrates in comparison to other nitrovasodilators”, Eur: Heart 560/309 J., 14: 123–132 (1993). 58 Field of Search ..................................... 514/129, 439, Fung, H-L., "Nitrate therapy: is there an optimal Substance 514/509, 517; 549/40; 558/175, 480, 484, and formulation'Eur: Heart J., 12:9-12 (1991). 485; 560/309 Kojda, G., Feelisch, M., and Noack, E., "Sulfhydryl-con taining nitrate esters: a new class of nitric oxide donors', 56) References Cited Cardiovasc. Drug Rev. 13:275-288 (1995). U.S. PATENT DOCUMENTS Yang, K., Artz, J.D., Lock, J., Sanchez, C., Bennett, B.M., Fraser, A.B., and Thatcher, G.R.J., “Synthesis of novel 4,801,596 1/1989 Simon et al. organic nitrate esters: guanylate cyclase activation and tissue 4,863,949 9/1989 Simon et al. relaxation”, J. Chem. Soc., Perkin Trans. 1, 1073–1075 5,049,694 9/1991 Bron et al. 5,284,872 2/1994 Sandrock et al. (1996). 5,428,061 6/1995 Sandrock et al. Yeates, R.A., “Possible mechanisms of activation of Soluble guanylate cyclase by organic nitrates', Arzneim-Forsch./ FOREIGN PATENT DOCUMENTS Drug Res. 42(II): 1314-1317 (1992). 764461 8/1967 Canada. Yeates, R.A. Lauren, H., and Leitold, M., “The reaction 792246 8/1968 Canada. between organic nitrates and Sulfhydryl compounds’, Mol. 2075988 8/1991 Canada. 2158368 9/1994 Canada. Pharm. 28: 555–559 (1985). 362575 4/1995 European Pat. Off.. Zanzinger, J., Feelisch, M., and Bassenge, E., “Novel 451760 9/1995 European Pat. Off.. organic nitrates are potent dilators of large coronary arteries 51-125750 11/1976 Japan. with reduced development of tolerance during long-term 01-304353 12/1989 Japan. infusion in dogs: role of the sulfhydryl moiety”, J. Cardio 1-304353 12/1989 Japan. vas. Pharm., 23: 772–778 (1994). WO94/06428 3/1994 WIPO. 9500477 1/1995 WIPO. Primary Examiner Michael G. Ambrose OTHER PUBLICATIONS Attorney, Agent, or Firm-Richard J. Hicks; Carol Database CAPLUS on STN, Chemical Abstracts Service, Miernicki Steeg (Columbus, Ohio), Acc. No. 1990:430989, JP 01–304353 57 ABSTRACT (Sumitomo Chemical), abstract, 1990. Database CAPLUS on STN, Chemical Abstracts Service, Aliphatic Nitrate esters having a Sulfur or phosphorus atom (Columbus, Ohio), Acc. No. 1977:166380, JP 51–125750 B or Y to a nitrate group having efficacy as vasodilators are (Misato et al.), abstract, 1990. described. Preferred nitrate esters may be synthesized by Artz, J.D., Yang, K., Lock, J., Sanchez, C., Bennett, B.M., nitration of a 3-bromo-1,2-propanediol, and Subsequent and Thatcher, G.R.J., “Reactivity of thionitrate ester: puta reaction to yield the desired mono, di or tetra nitrate ester. tive intermediates in nitrovasodilator activity”, Chem. Com mun. 927–928 (1996). 7 Claims, No Drawings 5,807,847 1 NITRATE ESTERS FIELD OF INVENTION This invention relates to novel aliphatic nitrate esters and use thereof as nitro Vasodilators. More particularly this invention relates to nitrate esters bearing a Sulfur or phos phorus atom B or Y to a nitrate group which have therapeutic utility as vasodilators and nitric oxide pro-drugs and/or Substitutes for nitroglycerin in therapy. 1O where X is CHO, NMe, S, SM, POHM, POM, SH, SR, P(O)(OR)(OR), P(O)(OR)(OM), P(O)(OR)(R), P(O) BACKGROUND OF INVENTION (OM)R., SOM, S(O)Rs, S(O).R., S(O)ORs or S(O) OR; Glyceryl trinitrate (GTN) or nitroglycerin has been used Y is zero, SR, SR, SSR, SOM, SOM, PO HM, as a vasodilator in the treatment of angina pectoris for over 15 POM, P(O)(ORs)(OM), or P(O)(OR)OR; a hundred years, and is now believed to exert its therapeutic Rs, Re, Rs, Ro, Ro are the same or different alkyls effect through in-vivo release of nitric oxide (NO), which containing 1-12 carbon atoms or C or C connections to itself has been identified as Endothelium Derived Relaxing R-R in cyclic derivatives, Factor (EDRF). Other organic nitrates, such as isosorbide Riis C-C alkyl or acyl, dinitrate, have also been identified as effective and clinically R and R are the Same or different and Selected from H, important vasodilators. Unfortunately, the use of GTN is not ONO, C-C alkyl optionally bearing 1-3 nitrate groups, without its disadvantages, a principal of which is the toler and acyl groups (-C(O)Ro); ance effect which builds up quite rapidly over a relatively Short period of time and markedly reduces the efficacy of R and R are the same or different and selected from H, GTN as a vasodilator. C-C alkyl and chains, which may include one O, linking 25 R and R to form pentosyl, hexosyl, cyclopentyl or cyco A Substantial body of evidence Supports the hypothesis hexyl rings, which rings optionally bear hydroxyl Substitu that the vasodilatory activity of organic nitrates is largely the ents, and result of activation of guanylate cyclase (Gcase) leading to M is H, Na', K", NH," or NH,R,L, where n is 0–3. vascular Smooth muscle relaxation. GTN must undergo By another aspect of this invention there is provided a biotransformation in Vivo and it is proposed that tolerance pharmaceutical composition comprising an effective amount development may be associated with this need for biotrans of an aliphatic nitrate ester having the formula formation; the exact mechanism of which remains unre Solved. Proposed Sulfhydryl-dependent pathways include enzymic and non-enzymic biotransformation by a thiol. Indeed, the non-enzymic interaction of GTN with a limited 35 range of thiols Such as cysteine, N-acetylcysteine and thiosalicylic acid leads to activation of Gcase with an ECso in the Submillimolar range in vitro. Regardless of the exact mechanism of biotransformation of GTN in vivo, it is postulated herein that if Sulfur-containing functionalities are 40 incorporated into the Structure of nitrate esters, Such mol ecules have the potential to activate Gcase and release NO where X is CH, O, NH, NMe, S, SOM, PO HM, POM, without reliance on GTN biotransformation pathways. SH, SR, P(O)(OR)(OR), P(O)(OR)(OM), P(O)(OR) Based upon bioassay data it is postulated that phosphorus (R), P(O)(OM)R., SOM, S(O)Rs, S(O).R., S(O)ORs or containing functionalities So incorporated might have simi 45 S(O)OR; lar potential. Thus, there is a need for Synthetic aliphatic Y is zero, SR, SR, SSR, SOM, SOM, PO HM, nitrate esters containing Sulfur or phosphorus functionalities POM, or P(O)(OR)(OM), P(O)(OR)OR; that may Substitute for nitroglycerin as therapeutic agents. Rs, R. Rs, Ro, Rio are the same or different alkyls containing 1-12 carbon atoms or C or C connections to R. OBJECT OF INVENTION 50 or R in cyclic derivatives, R7 is C-C alkyl or acyl; It is an object of the present invention to provide novel R and R are the same or different and Selected from H, aliphatic nitrate esters bearing a Sulfur or phosphorus atom ONO, C-C alkyl optionally bearing 1-3 nitrate groups, B or Y to a nitrate group. and acyl groups (-C(O)Ro); Another object of the present invention is to provide 55 R and R are the same or different and selected from H, methods for making the novel S or P-containing nitrate C-C alkyl and chains, which may include one O, linking eSterS. R and R to form pentosyl, hexosyl, cyclopentyl or cyco hexyl rings, which rings optionally bear hydroxyl Substitu Yet another object of the present invention is to provide ents, and novel pro-drugs for use as vasodilators. 60 M is H, Na', K", NH," or Nh,R, where n is 0–3. BRIEF DESCRIPTION OF INVENTION in admixture with a physiologically acceptable carrier therefore. By one aspect of this invention there is provided aliphatic By yet another aspect of this invention there is provided nitrate esters containing at least one nitrate group, in which 65 a method for effecting tissue relaxation in a patient in need a S or Patom is situated B or Y to a nitrate group, having the thereof comprising administering to Said patient an effective general formula; amount of an aliphatic nitrate ester having the formula: 5,807,847 S-S (1) ONO ONO ONO ONO2 SR (2) ONO where X is CH, O, NH, NMe, S, SOM, POHM, POM, 1O ONO SH, SR, P(O)(OR)(OR), P(O)(OR)(OM), P(O)(OR) (R), P(O)(OM)R., SOM, S(O)Rs, S(O).R., S(O)ORs or where R is SOM S(O)OR; and M is Na" or K" Y is zero, SR, SR, SSR, SOM, SOM, POHM, O (3) POM, P(O)(OR)(OM), or P(O)(OR)OR; 15 \ Rs, Re, Rs, Ro, Ro are the same or different alkyls SO containing 1-12 carbon atoms or C or C connections to R.