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United States Patent (10) Patent No.: US 7,524,836 B2 Del Soldato (45) Date of Patent: Apr

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United States Patent (10) Patent No.: US 7,524,836 B2 Del Soldato (45) Date of Patent: Apr USOO7524836B2 (12) United States Patent (10) Patent No.: US 7,524,836 B2 Del Soldato (45) Date of Patent: Apr. 28, 2009 (54) NITROOXYDERIVATIVESTEROIDAL JP 58-045724 3, 1983 COMPOUNDS JP 5-39.261 2, 1992 JP 4-273892 9, 1992 (75) Inventor: Piero Del Soldato, Milan (IT) WO 98.15568 4f1998 OTHER PUBLICATIONS (73) Assignee: Nicox S.A., Paris (FR) English language abstract of JP 58-045724. (*) Notice: Subject to any disclaimer, the term of this English language abstract of JP4-273892. patent is extended or adjusted under 35 English language abstract of DE 19634793. U.S.C. 154(b) by 173 days. K. B. Schwarz, “Oxidative Sress During Viral Infection: A Review”. Free Radical Biology & Medicine, vol. 21, No. 5, 1996, pp. 641-649. Goodman & Gillman, “The Pharmacological Basis of Therapeutics'. (21) Appl. No.: 11/643,887 9" Edition, 1996, McGraw-Hill Health preffsions Division, pp. 1-1. 1459–1465 and 1474. (22) Filed: Dec. 22, 2006 Martindale, The Extraphamacopeia,30" Edition, 1993, pp. 712-723. O O Nenseter et al., “Paracetamol inhibits Copper Ion-Induced, AZO Com (65) Prior Publication Data pound-Initialed, and Mononuclear Cell-Mediated Oxidative Modifi US 2007/O142342 A1 June 21, 2007 cation of LDL', Arterioscierosis, Thombosis, and Vascular Biology, s vol. 15, No. 9, Sep. 1995, pp. 1338-1344. O O Baylis et al. “Chronic Blockade of Nitric Oxide Synthesis in the Rat Related U.S. Application Data Produces Syntemic Hypertension and Glomemerular Damage'. J. (62) Division of application No. 1 1/028, 198, filed on Jan. 4, Clin. Investigation, vol.90, 1992, pp. 279-281. 2005, now Pat. No. 7,186,708, which is a division of International Search Report, Nov. 21, 2000. application No. 09/926,327, filed on Oct. 15, 2001, E.ederqvist Ny'She ... Biochen. E. OfSE7O. 1053, 1994 now Pat. No. 6,909,007. Bonn et al., Cardiovasc. Drug Rev. 16(3), 195-211, 1998. (51) Int. Cl McCance & Huetherm "Pathophysiology: The Biologic Basic for we Disease in Adults and Children.” Third Edition, Mosby, 1998, pp. A6 IK3I/56 (2006.01) 48-54, 71-77 and 1025. C07J 5/00 (2006.01) (52) U.S. Cl. ........................ 514/182, 514/169,552/557 Primary Examiner Barbara P Badio (58) Field of Classification Search ................. 552/557 (74) Attorney, Agent, or Firm-Arent Fox, L.L.P. 514/169, 182 See application file for complete search history. (57) ABSTRACT (56) References Cited Steroidal compounds or their salts having general formulas (I) and (II) wherein: S is an integer equal to 1 or 2, preferably U.S. PATENT DOCUMENTS s=2; b0=0 or 1: A R , wherein R is the steroidal drug 3,702.335 A 11, 1972 Lafill radical, C and C are two bivalent radicals. The precursors of 3,963,707 A 6/1976 Högberg et al. the radicals B and B are such as to meet the pharmacological 4,913,852 A 4, 1990 Millioni et al. tests reported in the description. 4.956,384. A 9/1990 Chiesi et al. A-(B) to C N (O) (I) 5,318,987. A 6/1994 Weithmann et al. EO s 5,508,275 A 4, 1996 Weithmann et al. 5,707,984. A 1/1998 Tjoeng et al. 5,837,698 A 11/1998 Tjoeng et al. (II) A-C1-B FOREIGN PATENT DOCUMENTS o DE 19634.793 3, 1998 EP O 549 318 A2 6, 1993 EP O 562 497 A1 9, 1993 EP O 578 494 A1 1, 1994 7 Claims, No Drawings US 7,524,836 B2 1. 2 NITROOXYDERVATIVE STEROIDAL This happenss for example with steroids. COMPOUNDS Drug research is directed to find new molecules having an improved therapeutic index (efficacy/toxicity ratio) or a lower This is a divisional of U.S. patent application Ser. No. risk/benefit ratio, also for pathological conditions as those 11/028,198, filed Jan. 4, 2005, now U.S. Pat. No. 7,186,708, above mentioned, wherein the therapeutic index of a great issued Mar. 6, 2007, which is a divisional of U.S. patent number of drugs results lowered. In fact in the above men application Ser. No. 09/926,327, filed Oct. 15, 2001, now tioned conditions of oxidative stress and/or endothelial dys U.S. Pat. No. 6,909,007, issued Jun. 21, 2005, which claims functions, many drugs show a lower activity and/or higher priority benefit to MI99A0000751, filed Apr. 13, 1999. The toxicity. disclosures of all applications is hereby incorporated by ref 10 It is well known that steroids represent a first choice phar erence in their entirety. macological intervention in the therapy of inflammatory dis The present invention relates to novel steroidal compounds eases. This class of drugs, among which can be mentioned for for systemic use and non systemic use, and their composi example hydrocortisone, cortisone, prednisone, predniso tions, to be used in the conditions of oxidative stress and/or lone, fludrocortisone, desoxycorticosterone, metilpredniso endothelial dysfuntions. Specifically it relates to compounds 15 lone, triamcinolone, paramethasone, betamethasone, dexam with a steroidal structure having antiinflammatory, immun ethasone, triamcinolone acetonide, fluocinolone acetonide, odepressive and angiostatic activity (the so called antiinflam beclomethasone, acetoxypregnelone, etc., elicits remarkable matory steroids), or gastrointestinal activity. pharmaco-toxicological effects on different organs, and for The compounds according to the present invention result this reason both their clinical use and its interruption cause a therapeutically useful in the treatment of morbid conditions series of side effects, some of which very serious. See for wherein the steroidal products are generally used with greater example Goodman & Gilman, “The pharmaceutical Basis of benefit, in terms both of a better tolerability and/or efficacy. Therapeutics' 9" ed., pages 1459-1465, 1996. By oxidative stress it is meant the generation of free radi Among said toxic effects can be mentioned those affecting cals on radicalic compounds, which causes injury both of the the bone tissue leading to an altered cellular metabolism and cell and of that of the Surrounding tissue (Pathophysiology: 25 an high osteoporosis incidence; those affecting the cardiovas the biological basis for disease in adults and children, cular system, generating an hypertensive response; those McCance & Huether 1998 pages 48-54). affecting the gastrointestinal apparatus giving gastric dam By endothelial dysfunctions are meant those relating to the ageS. Vasal endotheliun. The damage of the Vasal endothelium is See for example Martindale “The extrapharmacopoeia, known as one of those important events that can bring about 30 30" ed., pages 712-723, 1993. a series of pathological processes affecting various organs To the class of steroidal drugs belong also biliary acids, that and body apparatuses, as described hereinafter (Pathophysi have been used in the therapy of hepatic disorders and in ology: The biological basis for disease in adults and children, biliary colics. Ursodesoxycholic acid is also used in some McCance & Huether 1998 page 1025). hepatic dysfunctions (hepatic cirrhosis of biliary origin, etc.). As known, the oxidative stress and/or the endothelial dys 35 Their tolerability is strongly worsened in the presence of functions are associated to various pathologies as reported gastrointestinal complications (chronic hepatic damage, pep hereinafter. The oxidative stress can also be caused by toxic tic ulcer, intestinal inflammation, etc.). Also in the case of ity of a great variety of drugs, which significantly affects their biliary acids the oxidative stress remarkably affects drug per performances. formance: both the efficacy and the tolerability of chenode Said pathological events are of a chronic, debilitating char 40 oxycholic,and ursodesoxycholic acids are significantly acter and are very ofthen typical of the elderly. As already reduced. In particular the unwanted effects on liver are found said, in said pathological conditions the drugs used show a exalted. Among the steroidal compounds can be mentioned remarkably worsened performance. also estrogens for the treatment of dislipidaemias, hormonal Examples of pathological situations caused by the oxida troubles, female apparatus tumours treatment can be men tive stress and/or by the endothelial dysfunctions, or present 45 tioned. Also said steroids show side effects as above men in elderly, are the following: tioned, in particular at the hepatic level. For the cardiovascular system: myocardial and vascular According to the above mentioned prior artit seems almost ischaemia in general, hypertension, stroke, arterioscle impossible to separate therapeutic activity from side effects, rosis, etc. see Goodman et al, above mentioned, at p. 1474. For the connective tissue: rheumatoid arthritis and Con 50 The steroidal compounds are completely different from the nected inflammatory diseases, etc. antiinflammatory non steroidal compounds from the chemi For the pulmonary system: asthma and connected inflam cal, pharmacological and biochemical point of view, since the matory diseases, etc. pharmaco-toxicological mechanism of action of nonsteroidal For the gastrointestinal system: ulcerative and non ulcer antiinflammatory products is based on the inhibition of one or ative dyspepsias, intestinal inflammatory diseases, etc. 55 more of the cyclooxygenases (COX), while steroids do not For the central nervous system: Alzheimer disease, etc. influence COX and have more complex pharmaco-toxico For the urogenital system: impotence, incontinence. logical mechanisms of action not yet fully cleared. For the cutaneous system: eczema, neurodermatitis, acne. Indeed it is well known that these two groups of drugs are The infective diseases in general (ref: Schwarz-KB, Brady classified in different classes in the pharmacopoeias. “Oxidative stress during viral infection: A review Free 60 The need was felt to have available steroids showing an radical Biol. Med. 21/5, 641-649 1996). improved therapeutic performance, i.e. endowed both of a Further the ageing process can be considered as a true lower toxicity and/or higher efficacy, so that they could be pathologic condition (ref.
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