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Nitrate Esters of Corticoid Compounds And Europäisches Patentamt *EP000929565B1* (19) European Patent Office Office européen des brevets (11) EP 0 929 565 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07J 41/00, A61K 31/57 of the grant of the patent: 29.05.2002 Bulletin 2002/22 (86) International application number: PCT/EP97/05426 (21) Application number: 97910409.8 (87) International publication number: (22) Date of filing: 02.10.1997 WO 98/15568 (16.04.1998 Gazette 1998/15) (54) NITRATE ESTERS OF CORTICOID COMPOUNDS AND PHARMACEUTICAL APPLICATIONS THEREOF NITRATESTER VON CORTICOID VERBINDUNGEN UND DIE THERAPEUTISCHE VERWENDUNGEN DAVON ESTERS DE NITRATES DE COMPOSES CORTICOIDES ET APPLICATIONS PHARMACEUTIQUES ASSOCIEES (84) Designated Contracting States: • BAYUNOVA V I ET AL: "SYNTHESIS AND AT BE CH DE DK ES FI FR GB GR IE IT LI NL PT BIOLOGICAL ACTIVITY OF ALKYL SE SUCCINATES OF PREDNISOLONE" Designated Extension States: PHARMACEUTICAL CHEMISTRY JOURNAL, LT RO SI vol. 14, no. 12, 1981, pages 878-880, XP002035558 (30) Priority: 04.10.1996 IT MI962048 • HAYASHI H ET AL: "1,4:3,6-DIANHYDROHEXITOL NITRATE (43) Date of publication of application: DERIVATIVES. II. 1) SYNTHESIS AND 21.07.1999 Bulletin 1999/29 ANTIANGINAL ACTIVITY OF ARYL- OR ARYLCARBONYLPIPERAZINE DERIVATIVES (73) Proprietor: NICOX S.A. 2)" CHEMICAL AND PHARMACEUTICAL 75116 Paris (FR) BULLETIN, vol. 41, no. 6, June 1993, pages 1100-1110, XP000611905 (72) Inventor: DEL SOLDATO, Piero • HODOSAN F ET AL: "Nitrate esters of steroid I-20052 Monza (IT) hormones and related compounds. Preparation and biological properties" ARZNEIMITTEL (74) Representative: Sama, Daniele, Dr. FORSCHUNG. DRUG RESEARCH., vol. 19, no. 4, Sama Patents, 1969, AULENDORF DE, pages 684-685, Via G.B. Morgagni, 2 XP002061312 20129 Milano (IT) • TEUTSCH G ET AL: "Design of ligands for the glucocorticoid and progestin receptors" (56) References cited: BIOCHEM. SOC. TRANS., vol. 19, no. 4, 1991, WO-A-97/34871 WO-A-97/40836 pages 901-908, XP002061313 WO-A-97/41144 DE-A- 1 643 034 • CHEMICAL ABSTRACTS, vol. 099, no. 11, 12 DE-A- 2 222 491 FR-A- 1 561 908 September 1983 Columbus, Ohio, US; abstract FR-A- 2 274 309 GB-A- 1 544 512 no. 088460, LI Z ET AL: "Synthesis of US-A- 2 990 401 US-A- 3 183 252 5-pregnene-3.beta.,17.alpha.-diol-20-one US-A- 3 494 941 3-acetate 17.alpha.-carboxylic acid esters, and studies on their structure-activity relations" XP002061315 & YAOXUE XUEBAO (YHHPAL,05134870);83; VOL.18 (2); PP.119-24, BEIJING MED. COLL.;DEP. PHARM.; BEIJING; PEOP. REP. CHINA (CN), Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 929 565 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 0 929 565 B1 • CHEMICAL ABSTRACTS, vol. 097, no. 11, 13 • CHEMICAL ABSTRACTS, vol. 070, no. 15, 14 September 1982 Columbus, Ohio, US; abstract April 1969 Columbus, Ohio, US; abstract no. no. 092623, LI Z ET AL: "Synthesis of 068654, BROWNFIELD R B: "Antiphlogistic 3.beta.-hydroxypregn-5-en-20-one A and B ring pregnane derivatives" XP002061317 & ZA 6 704 derivatives and studies on their 880 - (AMERICAN CYANAMID CO.) 18 January structure-activity relationships" XP002061316 & 1968 YAOXUE XUEBAO (YHHPAL,05134870);82; VOL.17 (4); PP.265-74, BEIJING MED. Remarks: COLL.;DEP. PHARM.; BEIJING; PEOP. REP. The file contains technical information submitted CHINA (CN), after the application was filed and not included in this • M. HELLER ET AL: "16-Hydroxylated Steroids. specification XXII. The Preparation of the 16-Methyl Ether of Triamcinolone" JOURNAL OF ORGANIC CHEMISTRY., vol. 27, no. 1, 18 January 1962, EASTON US, pages 328-331, XP002061314 2 EP 0 929 565 B1 Description [0001] The present invention relates to preparation of new corticoid compounds. [0002] In particular it relates to steroid-structured compounds having anti-inflammatory, immunodepressive and an- 5 giostatic activities (the so-called steroid anti-inflammatory drugs). [0003] The compounds according to the present invention are therapeutically useful in the treatment of pathologic conditions where generally corticosteroid (corticoids) preparations are used, but with increased benefits. [0004] This represents an unexpected advantage over the known corticoids products. In fact, by taking into account the various defined therapeutic uses of a specific product, it is always possible, with the new products of the present 10 invention, to find a better combination of results with respect to the known corticoids. Contrary to any expectation the products of the present invention are characterised by the fact that they show an improved therapeutic profile: high activity combined with low side-effects. [0005] Corticoids are well known as a first-choice pharmacological measure in the treatment of inflammatory disease. Drugs in this category - which include, for example, hydrocortisone, cortisone, prednisolone, prednisone, fludrocorti- 15 sone, desoxycorticosterone, methylprednisolone, triamcinolone, paramethasone, betametasone, dexamethasone, tri- amcinolone acetonide, fluocinolone acetonide, beclomethasone, acetoxypregnelone, etc. - have marked pharmaco- toxicological effects on various organs. Because of this, the clinical use and discontinued use thereof cause a series of side effects some of which are very severe. See for example Goodman & Gilman: "The Pharmaceutical Basis of Therapeutics", 9th Ed., pages 1459-1465, 1996. 20 [0006] These toxic effects include: - those on bone which lead to changed cell metabolism and a high frequency of osteoporosis; - those on the cardiovascular system which cause hypertensive reactions; - those on the gastrointestinal tract which cause gastric damage. 25 See for instance Martindale: "The Extrapharmacopoeia", 30th Ed., pages 712-723, 1993. [0007] According to the above mentioned art it appears to be almost impossible for therapeutic activities to be sep- arated from side effects, see Goodman et al., as mentioned above, at page 1474. [0008] Known in the art are non-steroid anti-inflammatory drugs either with or without acidic ending, see patents WO 30 94/04484, WO 94/l2463, WO 95/09831, WO 95/30641 for non-acidic ending and the patents therein mentioned for those with acidic ending. [0009] DE-A-2222491 (1) discloses pregnane derivatives having at position 21 the group -CH2-O-NO2. [0010] Said compounds are said to be endowed of antiinflammatory, antiallergic and cardiotropic activity. The single compounds are vasodilators. 35 [0011] US-A-3494941 (2) discloses steroid derivatives from estrane-3-ol or estr-4-en-3-one useful as vasodilators in the treatment of heart conditions, such as coronary insufficiency and angina pectoris. Said compounds have at position 17 an ether linker attached to a nitrate radical. Nitrate groups can be also at positions 3 and 16 of the steroid ring. [0012] Arzneimittel Forschung, vol. 19, n. 4, 1969, pp. 584-685 (3) discloses 3- and 17- nitrate ester of androstane derivatives, 3, a 17-dinitrate derivative of androstene, 17- nitrate esters of testosterone derivatives and 21-nitrate esters 40 derivatives of desoxicortisone, cortisone and prednisone. In the paper it is stated that desoxicorticosterone nitrate promotes protein anabolism in different organs. [0013] WO-A-97/34871 (4) discloses (i) compounds comprising a steroid, a β-agonist, an anticholinergic, a mast cell stabilizer or a PDE (phosphodiesterase) inhibitor to which is directly or indirectly linked at least one NO or NO2 group or a group which stimulates the endogenous production of NO or EDRF (endothelium-derived relaxing factor) in vivo, 45 said group linked through sites such as oxygen, sulfur, carbon and nitrogen; (ii) compositions comprising a therapeu- tically effective amount of a steroid, a β-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor, optionally substituted with at least one NO or NO2 moiety or a group which stimulates endogenous production of NO or EDRF in vivo, in combination with a compound that donates, transfers, or releases nitric oxide and/or a compound that stim- ulates endogenous production of NO or EDRF in vivo. 50 [0014] WO-A-97/40836, published after the priority date if the present Aplication, discloses steroid nitrate ester de- rivatives bearing at least one nitroxy group at position 11 of the steroid ring. According to this patent a further nitroxy or, optionally, a nitroxyalkanoyl group can be found at position 21, 17,16. [0015] WO-A-97/41144, published after the priority date of the present Application, discloses novel steroid nitrite and nitrate ester derivatives, useful as antiinflammatory drugs, defined by the formula A-B-C, wherein A is a residue of a 55 steroidal hormone containing hydroxyl groups, B is a spacer containing a maximum of 12 carbon atoms, said spacer linked to A through the hydroxyl moiety and to C through an amino or a hydroxyl group via an amide, ester, carbamate or carbonate linkage; C is an organic nitrite or nitrate compound. [0016] USA-3183253 discloses of 16-nitratoalkyl-pregnanes wherein the alkyl group is linked to the pregnane back- 3 EP 0 929 565 B1 bone by a carbon-carbon bond. The compounds are said to be vasodilators. [0017] However, it should be noted that steroid compounds are completely different from non-steroid compounds chemically, pharmacologically and biochemically as the pharmaco-toxicological mechanism of action of non-steroid products is based on inhibition of one or more cyclo-oxygenases (COX), while steroid products have nothing to share 5 with COX and have more complex pharmaco-toxicological mechanisms of action which have not yet been fully ex- plained. [0018] It is well known that these two groups of compounds are listed in completely separate categories in interna- tional pharmacopoeias.
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