Title of Invention

A STEROIDAL COMPOUND

Abstract

The present invention relates to steroidal compounds or their salts having general formulas (I) and (II) wherein; s is an integer equal to 1 or 2, preferably s=2;bO=O or 1; A=R-, wherein R is the steroidal drug radical, C and C1 are two bivalent radials. The precursors of the radicals Band B1 are such as to the pharmacological tests reported in the description; A -(B) bO -C- N ( 0) s ( I ) A-C1-B1 (II) I N (0) s

Full Text

PHARMACEUTICAL COMPOUNDS" • ****• The present invention relates to novel steroidal compounds for systemic use and non systemic use, and their compositions, to be used in the conditions of oxidative stress and/or endothelial dysfuntions. Specifically it relates to compounds with a steroidal structure having antiinflammatory, immunodepressive and angiostatic activity (the so called antiinflammatory steroids), or gastrointestinal activity. The compounds according to the present invention result therapeutically useful in the treatment of morbid conditions wherein the steroidal products are generally used with greater benefit, in terms both of a better tolerability and/or efficacy. By oxidative stress it is meant the generation of free radicals or. radicalic compounds, which causes injury both of the cell and of that of the surrounding tissue (Pathophysiology: the biological basis for disease in adults and children, McCance & Huether 1998 pages 48-54). By endothelial dysfunctions are meant those relating to the vasal endothelium. The damage of the vasal endothelium is known as one of those important events that can bring about a series of pathological processes affecting various organs and body apparatuses, as described hereinafter (Pathophysiology: The biological basis for disease in adults and children, McCance & Huether 1998 page 1025). As known, the oxidative stress and/or the endothelial dysfunctions are associated to various pathologies as reported hereinafter. The oxidative stress can also be caused by toxicity of a great variety of drugs, which significantly affects their performances. Said pathological events are of a chronic, debilitating character and are very of then typical of the elderly. As already said, in said pathological conditions the drugs used show a remarkably worsened performance. Examples of pathological situations caused by the oxidative stress and/or by the endothelial dysfunctions, or present in elderly, are the following: For the cardiovascular system: myocardial and vascular ischaemia in general, hypertension, stroke, arterioscle- ■« -. rosis, etc. For the, connective tissue: rheumatoid arthritis and connected inflammatory diseases, etc. For the pulmonary system: asthroa and connected inflammatory diseases, etc. For the gastrointestinal system: ulcerative and non ulcerative dyspepsias, intestinal inflammatory diseases, etc. For the central nervous system: Alzheimer disease, etc. For the urogenital system: impotence, incontinence. For the cutaneous system: eczema, neurodermatitis, acne. The infective diseases in general (ref.: Schwarz-KB, Brady "Oxidative stress during viral infection: A review" Free radical Biol. Med. 21/5,.641-649 1996). Further the ageing process can be considered as a true pathologic condition (ref. Pathophysiology: the biological basis for disease in adults and children, pages 71-77). The known drugs when administered to patients having pathologies associated to oxidative stress emd/or endothelial dysfunctions, show a lower efficacy and/or higher toxicity. This happenss for example with steroids. Drug research is directed to find new molecules having ajn improved therapeutic index (efficacy/toxicity ratio) or a lower risk/benefit ratio, also for pathological conditions as those above mentioned, wherein the therapeutic index of a great number of drugs results lowered. In fact in the above mentioned conditions o'f oxidative stress and/or endothelial dysfunctions, many drugs show a lower activity and/or higher toxicity. It is well known that steroids represent a first choice pharmacological intervention in the therapy of inflammatory diseases. This class of drugs, among which can be mentioned for example hydrocortisone, cortisone, prednisone, prednisolone, fludrocortisone, desoxycorticosterone, metilprednisolone. triamcinolone, paramethasone, betamethasone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, beclomethasone, acetoxypregnelone, etc. , elicits remarkable pharmaco-toxicological effects on different organs, and for this reason both their clinical use and its interruption cause a series of side effects, some of which very serious. See for example Goodman & Gilman, "The pharmaceutical Basis of Therapeutics" 9th ed. , pages 1459-1465, 1996. Among said toxic effects can be mentioned those affecting the bone tissue leading to esi altered cellular metabolism and an high osteoporosis . incidence; those affecting the cardiovascular system, generating an hypertensive response; those affecting the gastrointestinal apparatus giving gastric damages. See for example Martindale "The extrapharmacopoeia", 30th ed., pages 712-723, 1993. To the class of steroidal drugs belong also biliary acids, that, have been used in the therapy of hepatic disorders and in biliary coli-cs. Ursodesoxycholic acid is also used in some hepatic dysfunctions (hepatic cirrhosis of biliary origin, etc.). Their tolerability is strongly worsened in the presence of gastrointestinal complications (chronic hepatic damage, peptic ulcer, intestinal inflammation, etc.). Also in the case of biliary acids the oxidative stress remarkably affects drug performance: both the efficacy and the tolerability of chenodeoxycholic and ursodesoxycholic acids are significantly reduced. In particular the unwanted effects on liver are found exalted. Among the steroidal compounds can be mentioned also estrogens for the treatment of dislipidaemiaS/ hormonal troubles, female apparatus tiomours treatment can be mentioned. Also said steroids show side effects as above mentioned, in particular at the hepatic level. According to the above mentioned prior art it seems almost impossible to separate therapeutic activity from side effects, see Goodman et al, above mentioned, at p. 1474. The steroidal compounds are completely different from the antiinflammatory non steroidal compounds from the chemical, pharmacological and biochemical point of view, since the pharmaco-toxicological mechanism of action of nonsteroidal antiinflammatory products is based on the inhibition of one or more of the cyclooxygenases (COX), while steroids do not influence COX and have more complex pharmaco-toxicological *-• - mechanisms of action not yet fully cleared. Indeed "it is well known that these two groups of drugs are classified in different classes in the pharmacopoeias. The need was felt to have available steroids showing an improved therapeutic performance, i.e. endowed both of a lower toxicity and/or higher efficacy, so that they could be administered to patients in morbid conditions of oxidative stress and/or endothelial dysfunctions, without showing the drawbacks of the drugs of the prior art. It has been now surprisingly and unexpectedly found that the aforementioned technical problems shown in the administration of steroidal drugs to patients affected by oxidative stress and/or endothelial dysfiinctions, or to the elderly in general, are solved by a new class of drugs as described hereinafter. An object of the invention are steroidal compounds or their salts having the following general formulas (I) and (II): A—(B)t,o—C-N{0)s (I) wherein: s = is an integer equal to 1 or 2, preferably s = 2; bO = 0 or 1; A = R—T1-, wherein R is the steroidal drug radical as defined hereunder, B = -Tg—X2—TBI- wherein Tg and Tgj are equal or different; • T3= (CO) when the reactive function in the precursor steroid is -OH; T3 = X when the reactive function in the precursor steroid is -COOH; X = 0, S, Nr1C R1c is H or a linear or branched alkyl having from 1 to 5 carbon atoms, or a free valence; TQT = (CO)tx or (X)txx, wherein tx and txx have the value of 0 or 1; with the proviso that tx = 1 when txx = 0, tx = 0 when txx = 1; X is as above defined; X2 is a bivalent bridging bond as defined hereunder; C is the bivalent radical -Tc-Y- wherein Tc = (CO) when tx = 0, Tc = X when txx = 0, X being as above defined; Y is: wherein: nIX is an integer between 0 and 3, preferably 1; nllX is an integer between 1 and 3, preferably 1; Rtxx' RTIx' TRIIx' RTIIx' equal to or different from each other are H or a linear or branched C3_-C4 alkyl; preferably RTIX, RTIX, RTIX, RTIX, are H. Y3 is a saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen atom, preferably one or two nitrogen atoms, said ring having 5 or 6 atoms • or Y is YQ, selected from the following: an alkylenoxy group R'O wherein R' is linear or branched when possible C1-C20, preferably having from 1 to 6 carbon atoms, most preferably 2-4 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylenic ring one or more carbon atoms can be substituted with heteroatoms, the ring I can have "side chains of R' type, R' being as above defined; or wherein R1f,= K, CH3 and nf is an integer from 1 to 6; preferably from 1 to 4; preferably Y = -Y0 = R'O- wherein R' is as above defined; preferably R' is a C1-C6 alkylene; ^ci- (CO) when the reactive function of the precursor steroid is -OH, Tc- = X when the reactive function of the precursor steroid is -COOH, X being as above defined; Tc3:= (CO)-r or (X)-(X)tii, wherein tl and tII have the 0 or 1 value; with the proviso that tl = 1 when tII = 0; tl = 0II when tII = 1; X is as above defined; Y' is as Y above defined, but with three free valences instead of two, preferably it is selected from the following: a -R'O- group wherein R' is linear or branched I C-C20, preferably having from 1 to 6 carbon atoms, most preferably 2 - 4, or a saturated, optionally substituted, ring having from 5 to 7 carbon atoms; or II wherein n3 is an integer from 0 to 3 and n3' is an integer from 1 to 3; wherein n3 and n3' have the above mentioned meaning; wherein one hydrogen atom on one of the carbon atoms is substituted by a free valence; wherein nf' is an integer from 1 to 6 preferably from 1 to 4; wherein one hydrogen atom on one of the *" - carbon atoms is substituted by a free valence; wherein one hydrogen atom on one of the carbon atoms is substituted by a free valence; wherein 14 = H, CH3 and nf is an integer from 1 to 6; preferably from 1 to 4; wherein one. hydrogen atom in position 3: there may be CO, -O-CH2-CH2-CI, OH; in position 3-4: there may be a double bond; in position 4-5: there may be a double bond; in position 5-6: there may be a double bond; in position 5-10: there may be a double bond; in position 6: there may be CI, F, CH3, -CHO; in position 7: there may be CI, OH; in position 9: thre may be CI, F; in position 11: there may be OH, CO, CI, CH3; in position 15: there may be CH3, OH, =CH2: in position 17: there may be OH, CH3, OCO(0)^2(CH2)vaCH3 , C=CH or wherein ua is an integer equal to 0 or 1, va is an integer from 0 to 4; in position" 16-17: there may be the following groups: R and R' , equal to or different from each other, can be hydrogen or linear or branched alkyls from 1 to 4 carbon atoms, preferably R -,R' = CH3; R" is -(CO-L)t.-(L)t2-(Xot)tl- wherein t, tl and t2 are integers equal to or different from each other, equal to 0 or 1, with the proviso that when t = 0 t2 = 1 and when t = 1 t2 = 0, and that t and tl, or t2 and tl, cannot contemporaneously be equal to 0 when A does not contain -OH groups; the bivalent bridging group L is selected from: (CR4R5)na(0)nb(CR4%)n'a(CO)j,,i5(0)n-b(CO)n-/b(CR4R5)n-a wherein na, n'a, and n' 'a, equal to or different from eacn other, are integers from 0 to 6, preferably 1-3; nb, n'b, n'b and n''b, equal to or different from each other, are integers equal to 0 or 1; R4, R5, equal to or different from each other, are selected from H, linear or branched alkyl from 1 to 5 carbon atoms, preferably from 1 to 3; XQ^ is X as above defined, but R^^^ is a linear or branched alkyl from 1 to 10 carbon atoms, or equal to X2'^ wherein X2"^ is equal *~ - to.OH, CH3, CI, N(-CH2-CH3)2, SCHjF, SH, or wherein test 4 is the following: it is an analytical determination carried out by adding portions of methanol solutions of the,,precursor of 3 or B1 at a 10-4 M concentration, to a methcinol solution of DPPH (2,2-diphenyl-l-picryl hydrazyl - free radical); after having maintained the solution at room temperature away from light for 30 minutes, it is read the absorbance at the wave length of 517 nm of the test solution ctnd of a solution containing only DPPH in the same amount as in the test solution; and then the inhibition induced by the precursor towards radical production by DPPH is calculated as a percentage by means of the following formula: (1 - As/Ac)X100 wherein A3 and Ac are respectively the absorbance values of the solution containing the test compound + DPPH and that of the solution containing only DPPH; the acceptance criterium of the compounds according to this test is the following: test 4 is met by B or B;j_ precursor compounds if the inhibition percentage as above defined is higher than or equal to 50%; wherein test 5 is the following: it is an analytical ^^ -determination carried out by adding aliquots of 10-4 M methanol sdlutions of the precursor of B or 3i_ or of C = -Tc-Y- H, having the free valence saturated as above indicated, to a solution formed by admixing a 2 mM solution of desoxyribose in water with 100 mM of phosphate buffer and 1 mM of the salt FeII (NH4 ) 2 ( SO4 ) 2 ; after having therrrostatted the solution at 37oC for one hour, aliquots of aqueous solutions of trichloroacetic acid 2.8% and of thiobarbituric acid 0.5 M are added, in the order, heating is effected at 100oC for 15 minutes asid the absorbance of the tested solutions is then read at 532 nm; the inhibition induced by the precursor of B or B1 or C = -T^-Y-H with respect to radical production by Fe12 is calculated as a percentage by means of the following forrmila: (1 - As/Ac)X100 wherein A3 and Ac are respectively the absorbance values of the solution containing the tested compound and the iron salt and that of the solution containing only the iron salt/ the compound meets test 5 when the inhibition percentage as above defined of the precursor of B or B-. or C = -Tc-Y-H, having the free valence saturated as above indicated, is higher than or equal to 50%; provided that in the compounds of formula (I) are excluded the drugs with A = R- , wherein R is as above defined, when bQ = 0 and C = -TC-YQ- wherein the free valence of Y0 is saturated as indicated above, s = 1 or 2. Preferably the B or 31 precursor compound (precursor of w — the X2 or X2- radical in formulas (I) and (II) respectively) which meets"" test 4, is selected from the following classes of compounds: Aminoacids, selected from the following: L-carnosine (formula CI); anserine (CXI) , selenocysteine (CIII), selenomethionine (CIV), penicillamine (CV), N-acetyl-penicillamine (CVI), cysteine (CVII), N-acetylcysteine (CVIII), glutathione (CIX) or its esters, preferably ethyl (formula DI), ferulic acid (DII), gentisic acid (Dili), citric acid (DIV), caffeic acid (DV), hydrocaffeic acid (DVT) , p-coiomaric acid (DVTI), vanillic acid (DVIII), chlorogenic acid (DIX), kynurenic acid (DX) , syringic acid (DXI): Aromatic ajid heterocyclic mono- cind polyalcohols, selected from the following: nordihydroguaiaretic acid (EI), quercetin (EII), catechin (EIII), kaempferol (EIV), sulphurethyne (EV), ascorbic acid (EVT), isoascorbic acid (EVII), hydroquinone (EVTII), gossypol (EIX), reductic acid (EX), methoxyhydroquinone (EXI), hydroxyhydroquinone (EXII), propyl gallate (EXIII), saccharose (EXIV), vitamin E (EXV), vitamin A (EXVT), 8-quinolol (EXVII), 3-tert-butyl-4-hydroxyanisole {EXVIII) , 3-hydroxyf lavone (EXIX), 3,5-tert-butyl-p-hydroxytoluene (EXX), p-tert-butyl phenol (EXXI), timolol (EXXII), xibomol (EXXIII), 3,5-di-ter-butyl-4-hydroxybenzyl-thioglycolate (EXXIV), 4' -hydroxybutyranilide (EXXV) , guaiacol (EXXVT) , tocol (EXXVII), isoeugenol (EXXVIII), eugenol (EXXIX), pipe-ronyl alcohol (EXXX), allopurinol (EXXXI), conyferyl alcohol (EXXXII), 4-hydroxyphenetyl alcohol (EXXXIII), p-coumaric alcohol (EXXXIV), curcumin (EXXXV): aromatic and heterocyclic amines, selected from the following: N, N' -diphenyl-p-phenylenediamine (MI)> ethoxyquin (Mil), thionine (Mill) , hydroxyurea (MIV) : Compoiinds containing at least a free acid function, selected from the following: 3,3' -thiodipropionic acid (NI), fumaric acid (Nil), dihydroxyinaleic acid (NIII), thioctic acid (NIV) , edetic acid (NV) , bilirubin (NVI), 3 / 4 -methylendioxycinnamic acid (NVTI), piperonylic acid (NVIII): The above mentioned substances precursors of B or B1 are prepared according to the known methods in the prior art, described, for example, in "The Merck Index, 12a Ed. (1995), herein incorporated by reference. When available, the corresponding isomers and optical isomers can be used. Preferably the precursor compound of B or of B1 (precursor of the X2 or X2a radical in formulas (I) and (II) respectively) which meets test 5, is selected from the following compounds: Aminoacids: aspartic acid (PI), histidine (PII), mono and polyalcohols or thiols: 2-thiouracil (QI)/ 2-mercaptoethanol (QII), esperidine (QUI), secalcif erol (QIV), 1-a-OH vitamin D2 (QV) , f localcitriol (QVT), 22-oxacalcitriol (QVTI) , the vitamin D3 derivative esterif ied with the vitamin A radical (QVIII), the formula (QIX) compoiind, 24,28-methylene-lor-hydroxyvitamin D2 (QX) the compound derived from la,25-dihydroxyvitamin D2 (QXI), 2-mercaptoimidazol (QXII) The precursor compounds of B or B1 of the above mentioned groups P, Q and R are prepared according to the known methods in the .prior art ajid described for example in "The Merck Index", 12a Ed. (1996), herein incorporated by reference. The vitamin D3 derivative with retinoic acid (QVIII) is prepared as described in JP 93039261 (ref, C.A. 119 117617); the formula (QIX) compound according to EP 562497; 24,28- methylene-la-hydroxtvitamin D2 (QX) according to E? 5734S4; the derivative corapound of dehydroxyvitamin D2 (QXI) according to EP 549,318. The precursors of B or B2 which meet test 4, are preferred- The tests carried out to identify the precursors of B or Bi are in detail the following: Test 4 is a colorimetric test which affords to establish whether nhe precursors of B or B1 inhibit the production of radicals from DPPH (2,2-diphenyl-l-picryl-hydra2yl) (M.S. Nenseter et Al. , Atheroscler. Thromb. 15, 1338-1344, 1S95). 100 μM solutions in methanol of the tested substances are prepared, and an aliquot of each of said solutions is added to a DPPH solution in methanol 0.1 M. After having stored the solutions at room temperature away from, light for 30 minutes, their absorbances are read at the wave length of 517 nm, together with that of the corresponding DPPK solution at the same concentration. The absorbance decrease with respect to that of the solution of DPPH at the same concentration of the test solutions is determined. The effectiveness of the tested compound in inhibiting formation of radicals by DPPH is expressed by the following fonuula: (1 - A3/Ac)X100 wherein As and Ac are respectively the absorbance values of the solution containing the test compound together with DPPH and of the solution containing only DPPK; the compounds precursor of B or B1 meet test 4 when the inhibition percentage of radical production from DP?H, expressed as a percentage according to the above equation, is higher than or equal co 50% at the indicated concentration (10-4 M) . If the precursors of B or B1 do not meet test 4, test 5 is carried out. Test 5 is a colorimetric test wherein 0.1 ml aliquots of 10-4 M methanolic solutions of the tested products are added to test tubes containing a solution formed by 0.2 ml of 2 mM desoxyribose, 0.4 ml of phosphate buffer pK 7.4 100 mM and 0.1 ml of 1 mM Fe--(NH4)2(SO4)2 in 2mM KCl. The test tubes are then maintained at 37oC for one hour. Then in each test tube 0.5 ml of a 2.8% solution in trichloroacetic acid water and 0.5 ml of an aqueous 0.1 M solution of thiobarbituric acid are added, in the order. A reference blank is formed by adding to a test tube containing only the above described aqueous solution of reactants 0.1 ml of methanol. The test tubes are closed and heated in an oil bath at 100oC for 15 minutes. A pink coloration is developed the intensity of which is proportional to the quantity of desoxyribose undergone to radical oxidative degradation. The solutions are cooled at room temperature and their absorbances are read at 532 nm against the blank. The inhibition induced by the precursor of B or BT or C = -Tc,-Y-H in comparison with the radical production by FeII is determined by means of the following formula: (1 - As/Ac)X100 wherein A3 and A4 are respectively the absorbance values of the solution containing the tested compound + the iron salt and that of the solution containing only the iron salt, the compound meets test 5 when the inhibition percentage of radical production as above defined from the precursor of B or B-^ or C = -T^-y-H is higher than or equal to 50%. Y3 in formula (III) is preferably selected from the following: The most preferred of Y"^ is Y12 (pyridyl) substituted in positions 2 and 6, The bonds can find also in asymmetric posi-tion, for example Y12 (pyridyl) can be substituted also in position 2 and 3; Yl (pyrazol) may be 3,5-disubstituted. The. compounds according to the present invention of formula (I) and (II) can be transformed into the corresponding salts. For example one way to form salts is the following: when in the molecule one nitrogen atom sufficiently basic to be salified, in organic solvent such as for example acetonitrile, tetrahydrof uran, ' is present, it is reacted with an equimolecular amount of the corresponding organic or inorganic acid. Preferably in the formula of the invention compounds Y or Y' of formula (III) is present. Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of inorganic acids are: nitric, hydrochloric, sulphoric, phosphoric acids- In the steroid precursors preferably R" = -CO-CH2OK, -CH(CH3)-CH2-CH2-COOH, Among the steroid precursors those having the hydroxyl function in position 3 or in position 11, or having in R" an hydroxyl or carboxylic function in terminal position, are preferred. The steroid precursors of A which can be mentioned and which are preferred, are those listed hereinunder, obtainable •^ - Lccording to the processes known in the art. As precursors and respective processes, those for example described in The Merck Index, ed. 12 of 1996, herein incorporated by reference, can be mentioned. The precursors (according to the Merck nomenclature) are the following, wherein H2, H, R, R', R' have the meaning mentioned in the compounds listed herein: Budesonide, Hydrocortisone, Alclome-thasone, Algestone, Beclomethasone, Betamethasone, Chloro- prednisone, Clot)etasol, cloiDetasone, uxocortoione, L,iopreano±; Cortisone , Corticosterone, Deflazacort, Desonide, Desoxi-methasone, Dexamethasone, Diflorasone Diflucortolone, Diflu-prednate, Fluazacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortyn Butyl, Fluocortolone, Fluorometholone, Fluperolone Acetate, Flu -prednidene Acetate, Fluprednisolone, Flurandrenolide, Formo-cortal, Halcinonide, Halobetasol Propionate, Halomethasone, Halopredone Acetate, Hydrocortamate, Loteprednol Etabonate, Medrysone, Meprednisone, Methylprednisolone, Momethasone Furcate , Paramethasone, Prednicarbate, Prednisolone, Prednisolone 25-Diethylaminoacetate, Prednisolone Sodium Phosphate, Prednisone, Prednival, Prednylidene, Rimexolone, Triamcinolone, Triamcinolone Acetonide, 21-Acetoxypregnenolone, Cortivazol, Am-cinonide, Fluticasone Propionate, Mazipredone, Tixocortol, Triamcinolone Hexacetonide, Ursodesoxycholic acid, Chenodeoxycholic acid, Mitatrienediol, Moxestrol, Ethynylestra- diol, Estradiol, Mestranol. J* Unexpectedly the invention products of the formulas (I) and (II), in conditions of oxidative stress, have an improved therapeutic index compared with the precursor steroids. For illustrative purposes the ' above mentioned tests are referred to the following compounds (see the tables attached to the description): Test 4 (test for the precursor of B and B1, ref- Table III) N-acetylcysteine inhibits of 100% radical production from DPPH, therefore it meets test 4 and it can be used as precursor of B or B1- 4 -thiazolidincarboxylic acid does not inhibit radical production from DPPH, therefore it does not meet test 4: it cam be used as precursor of B or B;^ ^^ ^^ meets test 5. Test 5 (test for the precursor of B and B1 or of C= -Tc-Y-H, ref. Table IV) 4-thiazolidincarboxylic acid meets test 5 since the inhibition is of 100%. Therefore the compound can be used as precursor of B or B1 in formula (I). The compounds of the invention can be used in the same therapeutic indications of the precursor drug with the above mentioned advantages. The compounds of formula (I) or (II) are prepared by synthesis methods mentioned hereinunder. The choice of the reactions for each method depends on the reactive group present in the steroid molecule, in the precursor compound of B or B1, which can be, as above mentioned/ bivalent or monovalent, and in the precursor compound of C. The reactions are carried out with well known methods in the prior art, which allow to obtain bonds among the steroid, the precursor compound of B or B1 and the precursor compound of C as above defined. When the reactive function of the steroid (for example -COOK, -OH) is involved in a covalent bond,- for example of ester, amide, ether type, said function can be restored with the well known methods in the prior art. Some synthesis schemes for obtaining the compounds of the invention are reported hereinafter: A) Synthesis of the compounds of formula (I). 1. Synthesis of the compound obtained by reaction between the steroid and the compound precursor of B. la. When the steroid contains a carboxylic function (general formula: R-COOH) and the functional group of the precursor compound of B which binds itself to the carboxylic function has the formula XZ, X being as above defined and Z = H, the effected reactions depend, on the nature of the second reactive group present in the precursor compound of B. la.i When the second reactive group present in the precursor compound of B is a carboxylic group, the synthesis general scheme expects the initial formation of the acyl halide of the R-COHal steroid (Hal = CI, Br) and the subsequent reaction with the HX group of the precursor compound of B: RCOOK RCOHal + H-X-X2-COOH ^ R-T3-X2-COOH (lA.l) X2, TB being as above defined. When in the two reaction compounds other functional groups COOH and/or HZ are present, they must be protected before the reaction according to the methods known in the prior art; for example as described in the publication by Th. W. Greene: 'Protective groups in organic synthesis", Harward University Press, 1980. The RCOHal acylhalide is prepared according to the known methods in the prior art, for example by thionyl or oxalyl chloride, PIII or Pv halides in inert solvents under the reaction conditions, such as for example toluene, chloroform, DMF, etc. Specifically, when the HX group of the precursor compound of B is NH2, or OH or SH, the steroid of formula R-COOH is first converted into the corresponding acyl halide RCOHal, as above mentioned, and then reacted with the HX group of the precursor compound of B in the presence of an organic base, such as triethylamine, pyridine, etc. using an inert solvent in the reaction conditions such as toluene, tetrahydrofuran, etc. at a temperature in the range 0oC- 25oC. Alternatively to the previous synthesis, the steroid of formula R-COOH can be treated with an agent activating the carboxyl group selected from N,N' -carbonyldiimidazol (CDI), N-hydroxybenzotriazol and dicyclohexylcarbodiimide in solvent such as for example DMF, TKF, chloroform etc. at a temperature in the range -5oC - 50oC and the obtained coinmpound reacted in situ with the reactive function of the precursor compound of B for obtaining the compound of formula (lA.l). la. 2 When the precursor compound of 3 contains two functional groups XZ, equal to or different from each other, X being as above defined and Z = H, the steroid having formula R-COOK is first treated with an agent activating the carboxyl group, as above described in la-1, and then with the precursor compound of B, after having protected one of the two reactive HX groups, for example with acetyl or tert-butyloxycarbonyl, restoring the initial function at the synthesis end. The scheme is the following: wherein X, TgT X2 are as above defined and G is a protective group of the HX function. 2. Nitroxyderivative synthesis. 2a. 1 When the compound obtained at the end of the previous step •la. has formula (lA.l), the acid can be converted into the corresponding sodic salt and one can then follow the known prior art methods for preparing the final compound, for example according to one of the following synthesis schemes: wherein T3, X2, TB1, TC are as above defined; R4 is selected from CI, Br, Y is as above defined, Z- is the Y radical free from the oxygen atom, R3 is CI, Er, Iodine, OK. If R3 = OH the compound of formula (lA.lb) is subje-cted to halogenation, for example with PBr3, PCI5, SOCI2, PPh3 ^ ±2, and then reacted with AgN03 in organic solvent such as acetonitrile, tetrahydrofuran. If R3 is CI, Br, Iodine, the compound of formula (lA.lb) is directly react ed with AgN03 as above mentioned. wherein R5 = OH or NHR^^^, R^c/ % ^^^ the other symbols being as above defined. When X^ is a linear C4 alkyl, the corresponding acid R-T^-X-7-COOK is reacted with triphenylphosphine in the presence of an halogenating agent such as CBr4 or N-bro-mosuccinimide in tetrahydrof uran obtaining the compound (lA.lc) wher;ein R3 = Br, 2a. 2 When the compound obtained at the end cf the previous step la. has formula (IA.2), the corresponding nitroxyderiva-tive is obtained by treating an halogen-carboxylic acid of formula Kal-X-_-COOH, X- being as above defined, first with an agent activating the carboxyl group as described in lA.l, and then with the compound of formula (IA.2), obtaining an halogen derivative, which is isolated and then dissolved in organic solvent, (ref. paragraph 2a.1), and treated with silver nitrate. The global reaction scheme is the following: wherein T3, X2, TBI, Tc, Y are as above defined. Alternatively, the halide Hal-X^-COCl can be used, wherein , Hal is preferably bromine, which is let react with the compound of formula (lA.2). lb. When the reactive function of the steroid is -OH (general formula: R-OH) , the two functional groups present on the precursor compound of B can be the following: lb. 1 A carboxylic group, which reacts with the steroid OH function, and a HX group, the latter reactive group of the precursor compound of B being equal to or different from the steroid functional group. The formula of the precursor compound of B is of the K-X-X2-COOH type, wherein X and X2 are as above defined. The H-X- function of the precursor compound of B is protected according to the known prior art' methods and the carboxyl is reacted, as above mentioned, according to the following scheme: At the end of the reaction the HX function of the precursor compound of B is restored. lb. 2 When the precursor compound of B contains two carboxylic groups, it is treated with an equimolar amount of an agent activating the carboxyl group under the conditions previously described in la.l, and then reacted with the reactive OH function of the steroid molecule. Possible other reactive functions of KX type present in the two • compounds must be carefully protected as previously mentioned- Lastly a compound of formula R-T3-X2-COOH (IB.2 ) is obtained. 2b. Nitroxyderivative synthesis. 2b. 1 To obtain the final nitroxyderivative starting from the compound of formula R-TQ-X2-X-H (IB.l), obtained at the end of the synthesis described in Ib.l, the (IB.l) compound is reacted with an halogenacid of formula Hal-X-, - COCK which has been treated as previously described in paragraph la.l, or with the corresponding halogenacid chloride, the resulting compound is dissolved in organic solvent, for example acetonitrile or tetrahydrofuran and reacted with silver nitrate. 2b. 2 To obtain the final nitroxyderivative starting from the compound of formula R-T3-X2-COOH (IE.2), obtained at the end of the ,synthesis described in lb, 2, the acid is transfcrrned into the corresponding sodic salt, it is reacted with a R2 -X- - R3 compound , previous ly def ined in the reaction A. scheme of paragraph 2a.1, obtaining according to the same process therein mentioned the final nitroxyderivative. Alternatively, when X- is a linear C2 alkyl, the acid (IB. 2) is reacted with triphenyl-phosphine in the presence of an halogenating agent such as CBr4 or N-bromosuccinimide in tetrahydrofuran and the resulting compound dissolved in organic solvent for example ' acetonitrile, tetrahydrofuran, is reacted with silver nitrate. 2b.3 Alternatively to the synthesis process according to Ib.l and 2b. 1, it is possible to react in a first step the KX-function of the precursor compound of B HX-X2-COOH with the acyl chloride of an halogenacid of formula Hal-X2-CO-Cl, wherein Hal is preferably Br, and subsequently the carboxvlic function of the so obtained compound, with the steroid of formula R-OH. In the third and last step the -Hal group is substituted with -ONO2 according to the process described in 2b.1. The reaction scheme is the following: In the previous scheme the nitration can alternatively be carried out on the acid compound of formula (2B.3). In the above mentioned processes the steroid reaction with the precursor of B for the compounds of formula (I) is not carried out when bQ = 0, and in the reaction with the precursor compound of C the steroid with its reactive function is directly used. B) Synthesis of compounds of formula (II). la. When the steroid reactive function is a carboxylic group and the precursor compound of B1 contains only one functional reactive group of formula XH, X being as above defined, the steroid is initially converted into the corresponding acyl-halide (RCOCl)/ or treated with an agent activating the carboxyl group as described in la.l, and then reacted with the HX function of an halogen-acid compound, said function being equal to or different from that present on the precursor compound of B1, said wherein X' is Y' as above defined without the oxygen atom through which the -NO2 group is linked, X and Hal are as above def ined. The compound (IIA.l) can be obtained with the known method of the prior art. For example when X = NH, it can be obtained from the corresponding hydroxy-aminoacid, by protecting- the aminic group by the corresponding tert-butyl-oxycarbonyl derivative and t reins forming the hydroxyl function into halogen group as described for the compound halogenation (lA.lb) in 2a.1. The free carboxylic function of the compound resulting from the reaction with the steroid molecule is reacted with the function present in the molecule of the precursor of B1 as previously illustrated in la.l for the reaction between the steroid of formula R-COOH and the precursor compound of B. In the final step the halogen atom (Hal) present on the radical X1 is substituted with an ONO2 group by adding AgNO3 to an organic solution of the compound. The reaction scheme is the following, exemplified starting from the RCOCl halide: lb. When the steroid reactive function is a OH group and the precursor compound of B- contains a reactive group of general fonaula XH, HX wherein X is as above defined, being equal to or different from OE, the synthesis is carried out starting from an halogendiacid compound of formula X11 being as above defined, said compound being prepared from the corresponding hydroxy-diacid as described for the halogenation of the compound (lA.lb) in 2a. 1- The halogendiacid compound is treated with an equimolar amount of an agent activating the carboxyl group, under the conditions previously described in la.l., and then it is reacted with ,the reactive function of the steroid molecule. In the subsequent step the second carboxylic function is treated with an activating agent, as previously made for the first, and reacted with the precursor compound of B1 according to the following scheme: The halogen atom is then substituted with the ONO2 group as above mentioned. 3. Synthesis of the nitroso (s=l) derivatives of formula (I). 3a. 1 The compound of formula (lA.lb) wherein R3 = OH is reacted with sodium nitrite in a solvent formed of a mixture of water with tetrahydrofuran in the presence of hydrochloric acid. The reaction is widely illustrated in the prior art. The general scheme is the following: 3a. 2 If the compound obtained at the end of step A has formula (IA.2) the corresponding nitroso derivative is obtained by treating an hydroxyacid of formula KO-Xr-COOH, X- being as above defined, first with an agent activating the carboxyl group, as described in la.l, then with 1A.2 and the resulting product with sodium nitrite as described in 3a. 1. 3b-1* To obtain the nitroso derivative starting from the compound of formula R-T3-X2'XH (IB.l) obtained at the end of the synthesis described in Ib.l, the compound (IB.l) is reacted with an hydroxyacid as described in 3a. 2. 3b-2 To obtain the nitroso derivative from the compound of formula R-T3-X2-COOH (IB. 2) obtained at the end of the synthesis described in lb. 2, the acid is transformed into the sodic salt and reacted with a compound Hal-X-1-OH, as previously described, and the obtained alcohol is treated as described in 3a.1. 4) Synthesis of the nitroso derivatives of formula (II) 4a-1 When the sceroid reactive function is a carboxylic group (general formula R-COOH) and the precursor compound of B-contains only one functional reactive group of formula XK, X being as above defined, R-COOH is initially converted into the corrsponding acyl-halide or treated with an agent activating the carboxyl group as described in la,l, and then reacted with the HX function of an hydroxy-acid compound, said function being equal to or different from that present on the precursor compound of B-_, said hydroxy-acid having the formula: wherein X- ' is Y' as above defined without the oxygen atom through which the -NO group is linked, X is as above defined. The free carboxylic function of the compound resulting from the reaction with the steroid molecule is reacted with the function present in the molecule of the precursor compound of B, as previously illustrated in la.l for the reaction between the R-COOK acid and the precursor compound of E. In the final step the alcohol is transformed into the nitroso-derivative as described in I 4b. When the reactive steroid function is a OH group and the precursor compound of B1 contains a reactive group of general formula XK, HX in which X is as above defined being equal to or different from OH, the synthesis is carried out starting from an hydroxydiacid compound of formula X1, being as above defined, said hydroxydiacid compound is treated with gn equimolar amount of an agent activating the carboxyl group, under the conditions previously described in la. 1. , and then it is reacted with the steroid reactive function. In the subsequent step the second carboxylic function is treated with an activating agent, as previously made for the first one, and reacted with the precursor compound of B1 according to the The obtained compound is reacted as described in 3a. 1. The compounds object of the present invention are formulated in the corresponding pharmaceutical compositions for parenteral, oral and topic use according to the well knov/n methods in the art, together with the usual excipients; see for example the volume "Remington's Pharmaceutical Sciences 15a Ed. " The amount on molar basis of the active principle in these formulations is the same, or lower, in comparison with that used of the corresponding precursor drug. The daily administrable doses are those of precursor drugs, or in the case lower. The daily doses can be found in the publications of the field, such as for example in "Physi-cian's Desk reference". The following examples have the purpose to illustrate the invention and are not to be considered as limitative of the same, EXAMPLE 1 Preparation of 3- [ 4-[ (3r, 5S , 7;3 ) - 3 , 7-dihydroxycolan-24-oiloxy]-3-methoxyphenyl ]-2-propenoic acid 4-nitroxybutyl ester 1 wherein the precursor steroid is ursodesoxycholic acid of formula (XL), the precursor of B is ferulic acid of formula (DID: acid 4-bromobutyl ester To a solution of 3 - (4 -hydroxy- 3 -methoxyphenyl) - 2 -propenoic acid (10 g, 51,5 mmoles) in THF (400 ml) triphenylphosphine (2.7 g, 10.3 xnmoles) and carbon tetrabromide (34.16 g, 10.3 mmoles) are added and the solution is left at room temperature, Under magnetic stirring, for 48 hours. The solid is filtered and then evaporated at reduced pressure. The obtained crude product is purified by chromatogrphy on silica gel eluting with n-hexane/ethyl acetate 7/3. S g of 3-(4-hydroxy-3-methoxyphenyl) -2-propenoic acid 4-bromobutyl ester are obtained. M.p. = 86-89oC. b) Synthesis of the 3'[4-[ ( Sa, 5/3,7^ )-3 , 7-dihydroxycolan-24-oiloxy] -3-methoxyphenyl]-2-propenoic acid 4-bromobutyl ester To a solution of ( 2a, 5/3, 7j3 ) - 3 , 7-dehydroxycolan- 24 -oic acid (2.9 g, 7.38 mmoles) dissolved in chloroform (25 ml) and di-methylacetamide (25 ml) , 3 - ( 4 -hydroxy- 3 -methoxyphenyl) - 2 -propenoic acid 4-bromobutyi ester (2.73 g, 8.28 mmoles) is added under stirring. To the solution cooled at 0C, kept under stirring, N/N'-dicyclohexylcarbodiimide (2 g, 9.7 mmoles) and 4-dimethylamino pyridine (100 mg, 0.81 mmoles) are added. After 1 hour the mixture is heated to room temperature, after 24 hours; the precipitate is filtered, the solvent is evaporated at reduced pressure. The residue is treated with ethyl acetate (150 ml) and "washed with water (3X 100 ml). After the organic phase is anhydrif ied with sodium sulphate the solvent is evaporated- The obtained crude product is purified by chromatography on silica gel column eluting with n-hexane/ethyl acetate 1/9. 2.5 g of 3-[ 4-[ ( 3α,5β ,7β)-3, 7-dihydroxycolan-24-oiloxy] - 3-methoxyphenyl-2-propenoic acid 4-bromobutyl ester are obtained . c) Synthesis of ' the 3 - [ 4 - [ (3, 5β,7β) • 3 ,7 -dihydroxycolan- 24 -oiloxy]-3-raethoxyphenyl] "2-propenoic acid 4-nitroxybutyl ester To a solution of 3-[4-[ ( 3or,5β, 7β) - 3 , 7-dehydroxycolan-24-oildxy] - 3 -methoxyphenyi] -2-propenaic acid 4-bromobutyl ester (2.3 g, 3,27 mmoles) in acetonitrile (20 ml) and tetrahydrofu-ran (5 ml) silver nitrate (0.84 g, 4.94 mmoles) is added under stirring and the mixture is heated to 80oC under magnetic stirring for 5 hours, vrnen the reaction is over the precipitate is filtered aind the solvent is evaporated. The obtained crude product is purified by chromatography on silica gel column eluting with methylene chloride/ethyl acetate 3/7. 1.5 g of 3-[4- [ (3a,55 ,7/3) -3 ,7-dehydrcxycolan-24-oiloxy] - 3-methoxyphenyl ] -2-propencic acid 4-nitroxybutyl ester are obtained. Total yield 32%. wherein the precursor steroid is chenodeoxycholic acid of formula (XLI) and the B precursor is ferulic acid of formula (DID The compound is prepared following the procedure reported in Example 1. Total yield 28%. Elementary analysis Calculated C 66.55% H 8.08% N 2.04% Found C 66.64% H 8.13% N 1.94% EXAMPLE 3 A solution of 4-broinobutyric acid (5.1 g, 30.6 mmoles) and 1,1'-carbonyldiimidazol (5.61 g, 34.6 irmoles)) in chlorofonn (50 ml) is left at room temperature under stirring for 1 hour. To the reaction mixture N-acetyl cysteine (5 g, 30.6 mmoles) dissolved in N,N-dimethylformamide (5 ml) and sodium ethylate (50 mg) is added under stirring. After 24 hours the solution is washed with HCl 1% and brine, the organic phase is anhydrified with sodium sulphate and evaporated at reduced pressure. The obtained crude product is purified by chromatography on silica gel colum, eluting with ethyl acetate/chloroform7/3 . N-acetyl-S- (4-bromobutyroyl)cysteine is obtained. b) Synthesis of (11β)-ll,17-Dihydroxy-21[N-acetyl-S-(4-bromobu- tyroyl) cysteinyloxy ] - pregn -1,4- diene -3,20- dione To a solution of N- acetyl - S - (4 -bromobutyroyl) cysteine (2.7 g, 8 .64 inmoles) and (11/3) -11,17, 21-trihydroxypregn-l,4-diene-3,20-dione (3.2 g, 8.86 mmoles) in tetrahydrofuran (100 ml) cooled at , 0°C and kept under stirring, N,N' -dicyclohexylcarbodiimide (l.S g, 9.2mmoles) and 4-dimethylam-nopyridine (100 mg, 0.8 mmoles) are added. After 1 hour the mixture is heated to room temperature, after 24 hours the precipitate is filtered/ the solvent is evaporated at reduced pressure. The residue is created with ethyl acetate (150 ml) and washed with water {3X 100 ml). After having anhydrified the organic phase with sodium sulphate the solvent is evaporated. The obtained crude product is purified by chromatography on silica gel column eluting with chloroform/ethyl acetate 3/7. 0.94 g of (11/3)-11,17-dehydroxy-21[N-acetyl-S- (4-bromobutyroyl)cysteinyloxy] -pregn-l,4-diene-3,20-dione are obtained. c) Synthesis of (11/3) -11,17-Dihydroxy-21[N-acetyl-S-(4-nitroxybucyroyl )cysteinyloxy] -pregn-1, 4-diene-3 , 20-dione To a solution of (11/3)-11,17-dehydroxy-21[N-acetyl-S-( 4-bromobutyroyl)cysteinyloxy]-pregn-1, 4-diene-3/20-dione (0.8 g, 1.28*inmoles) in acetonitrile (10 ml) and tetrahydrofuran (5 ml) silver nitrate (0,4 g, 2.35 mmoli) is added under stirring and the mixture is heated to 80°C under magnetic stirring for 20 hours. At the end of the reaction the precipitate is filtered and the solvent is evaporated. The obtained crude product is purified by chromatography on silica gel column eluting with methylene chloride/ethylacetate 3/7. (11/3)-11,17-dehydroxy-21[N-acetyl-S- (4-nitroxybutyroyl)cysteinyloxy] -pregn-1,4-diene- 3,20-dione is obtained. Total yield 12%. Elementary analysis Calculated C 55.59% H 6.33% N 4.40% S 5,04% Found C 56.63% H 6.38% N 4.36% S 5.01% EXAMPLE 4 Preparation of (11/3) -ll,17-Dihydroxy-21[N-acetyl-S- (4-nitro- wherein the precursor steroid is hydrocortisone of formula (XLIII) and the precursor of B is N-acetyl cysteine of formula (CVIII) The compound is prepared according to the procedure reported in Example 3, Total yield 15%. Elementary analysis Calculated C 56.37% H 6,78% N 4.39% S 5.02% Found C 56.39% H 6.81% N 4.31% S 4.93% EXAMPLE 5 Preparation of (11/3,16a) -9-Fluoro-11,17-dihydroxy-21 [N-acetyl- S - {4 -nitroxybutyroyl) cysteinyloxy ] -16 -methylpregn-1,4 -diene - wherein the precursor steroid is desamethasone of formula (X-LIV) and the precursor of B is N-acetyl cysteine of formula (CVIII) The compound is prepared according to the procedure reported in Example 3. Total yield 17%, Elementary analysis Calculated C 55.68% H 6,18% N 4.19% S 4.79% The animals (Long Evans rats, average weight 350-450 g) are divided in groups as herein beicv described. The group receiving L-NAME is treated for 4 weeks with said compound dissolved at the concentration of 400 mg/litre in drinking water. The following groups. (No. 10 animals for group) are constituted: A) Control groups: 1o group: treatment: only carrier (physiologic solution), 2o group: treatment: carrier -r L-NAME, B) Groups treated with the drug: 3o group: treatment: carrier + drug, 4o group: treatment: carrier -f- drug + L-NAME. The drugs screened in the test are hydrocortisone, desamethasone, prednisolone, chenodeoxycholic acid, ursodesoxycholic acid and the corresponding derivatives according to the present invention. In those groups of rats treated, respectively, with hydrocortisone, desamethasone, prednisolone and thereof corresponding compounds according to the present invention, the blood-pressure is determined- In those groups of rats treated, respectively, with ursodesoxycholic acid and chenodeoxycholic acid and thereof corresponding compounds according to the present invention, GPT is determined. Each drug is administered by intraperitoneal route once a day for 4 weeks. At the end of the four weeks access to water is prevented and after 24 hours the animals are sacrificed. Four hourS' after the last administration the blood- Test 4: inhibition of the radical production from DPPH of some substances used to prepare the precursors of B or Bl The method is based or. a colorimetric test in which DPPH (2,2-diphenyl-l-picryl-hydrazyl) is used as the compound-forming radicals (M.S. Nenseter et Al. , Atheroscler. Thrcmb. 15, 1338-1344, 1995). Solutions in methanol of the tested substances at a final concentration lOQ pK are initially prepared. 0.1 ml of each of these solutions are added to aliquots of 1 ml of a methanol solution C.l M of D?PH and then the final volume is brought to 1.5 ml. Afcer having stored the solutions at room temperature away from light for 30 minutes, the absorbance at the wave length of 517 nm is read. It is determined the absorbance decrease with respect to the absorbance of a solution containing che same concentration of DPPH. The efficacy of the test compound to inhibit the production of radicals; otherwise said antiradical activity, is expressed by the following formula: (1 - A3/Ac)X100 wherein As and Ac are, respectively, the absorbance values of the solution containing the test compound together + DPPH and * of the solution containing only DPPH. The compound to be used as precursor of B or B1 according to the present invention meets test 4 if it inhibits radical production from DPPH in a percent equal to or higher than 50%. In Table III are reported the results obtained in said test with the following compounds: N- acetylcysteine, cysteine, ferulic acid, (L) -carnosine, gentisic acid, 4-thiazolidin carboxylic acid and 2-oxc-4-thiazolidincarboxylic acid. Table III shows t-he following: N-acetylcysteine, cysteine, ferulic acid, (L)-carnosine, gentisic acid meet rest 4 since they inhibit the production of radicals induced by DPPH ro an extent higher than 50%. Therefore they can be used as precursors of the B compound in the synthesis of che ccnpc-m-ds according to the present invention. 4-thia2olidin carboxylic acid and the 2-oxo-4-thia2olidin carboxylic acid do not meet test 4 since they do not inhibit solution containing the nested compound + the iron salt and that of the solution containing only the iron salt. The results are reported in Table IV, which shows that both acids meet test 5 since they inhibit radical production from FeII in a percentage higher than 50%. Therefore both 4-thiazolidin carboxylic acid and 2-oxo-4-thia2olidin carboxylic acid can be used as precursors of B, B1 or C = -T1-Y-H for obtaining compounds of the present invention, EXAMPLE F4 Example Fl was repeated with three groups of rats (each group of of ten animals) , one control group not receiving L-NMIE and two groups receiving L-NAMZ, and i.p. administered as it follows : a. control group (not receiving L-NAME) : the carrier (physiologic solution), b. 1st group receiving L-NAME (group b - comparative ) administered at the same time with 25 mg/Kg . (0.064 mmoles/Kg) of dexamethasone + 10.4 mg/Kg (0.064 mmoles/Kg) of N-acetylcysteine in the same above carrier, c. 2nd group receiving L-NAME (group c) administered with 4 2.5 mg/Kg (0.064 mmoles/Kg) of the dexamethasone derivative according to the invention (ref, ex. 5) in the same above carrier. In this experiment vascular tolerability, i.e. the rise in blood pressure (vascular damage) was determined in the animals of groups b and c and expressed as percentages to that of the control group a, assumed to be 100 %'. The results are reported in Table V and show that the mixture administered to group b (comparative) induced in the animals an higher blood pressure increase than the compound of the invention (group c). EXAMPLE F5 Example. Fl was repeated with three groups of rats (each group of of ten animals), one control group not receiving L-NAME and two groups receiving L-NAME, and i.p. administered as it follows : a, control group (not receiving L-NAMS) : the carrier an higher GPT increase than the compound of the invention (group e) . Table V Table VI CLAIMS 1. Steroidal compounds or their salts having the following general formulas (I) and (II): A—(B)b0-C-N(O)3 (I) wherein: s = is an integer equal to 1 or 2, preferably s = 2; bO = 0 or 1; an alkylenoxy group R'O wherein R' is linear or when possible branched C2_-C20/ preferably having from 1 to 6 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylenic ring one or more carbon atoms can be substituted by heteroatoxnS/ the ring can have side chains of R' type, R' being as above defined; or wherein n3 is an integer from 0 to 3 and n3' is an integer from 1 to 3; wherein n3 and n3' have the above mentioned meaning wherein nf is an integer from 1 to 6 preferably from wherein R1f = K, CH3 and nf is an integer from 1 to 6; preferably from 1 to 4; preferably Y = -YQ = R'O- wherein R' is as above defined; preferably R' is a C1-C6 alkyl; wherein: wherein TCI- and TCII are equal or different, TCI= (CO) when the reactive function of the precursor steroid is -OH; TCI = X when the reactive function of the precursor steroid is -COOH, X being as above defined; TCII (CO)TI or (X)tII, wherein tI and tII have the 0 or 1 value; with the proviso that tl = 1 when tII = 0; tl = 0 when tII = 1; X is as above defined; Y' is as Y above defined, but with three free valences instead of two, preferably selected from the following: a -R'O- group wherein R' is C3-20 linear or I branched, preferably having from 1 to 6 carbon atoms, or a saturated ring having from 5 to 7 carbon atoms, optionally substituted; or wherein n3 and n3' have the above mentioned meaning; wherein one hydrogen atom on one of the carbon atoms is substituted by a free valence; wherein nf' is an integer from 1 to 6 preferably from 1 to 4; wherein one hydrogen atom on one of the carbon atoms is substituted by a free valence; wherein one hydrogen atom on one of the carbon atoms is substituted by a free valence; wherein R1f = H, CH3 and nf is an integer from 1 to 6; preferably from 1 to 4; wherein one hydrogen atom on one of the carbon atoms is substituted by a free valence; free bond indicated in C1 formula; or y' = Y0 as defined in (I) but with three free valences instead of 2; // wherein X22 is a monovalent radical, . T311 = (CO) when tl = 0, TBII = X when tII = 0, X being as above defined; X2, bivalent radical is such that the corresponding B precursor: -T3—X2—TBI- meets test 4 or test 5, precursor in which the T3 and TBI free valences are each saturated with OZ, with Z or with -ZI-N-ZII, 2I I and Z-I- being equal or different and have the Z values as above defined, depending on whether Tg and/or TBI = CO or X, in connection with the values of t, t', tx and txx; the C precursor when bO = 0 is of -Tc-Y-H type wherein the Tc free valence is saturated with OZ, Z, or with -Z-c-N-ZcII, ZI emd ZII being as above I defined, meets test 5; X2^ monovalent radical, such that the corresponding precursor of B "T3T;—X25 meets test 4 or test 5, precursor wherein the Tgr; free valence is saturated with OZ or with Z or with -Z--N-Z--, Z" and Z"^ I being equal or different and having the Z values as above defined, depending on whether T-BII = CO or X, in connection with the tI and tII values; A = R— has the following structure: wherein in substitution of the hydrogens of the CH groups or of the two hydrogens of the CH2 groups mentioned in the general formula, the following substituents can be present: in position 1-2: there may be a double bond; in position 2-3: there may be the following substituent: in position 2: there may be CI, Br; jm^ - in position 3: there may be CO, -O-CH2-CH2-Cl, OH; in position 3-4: there may be a double bond; in position 4-5: there may be a double bond; in position 5-6: there may be a double bond; in position 5-10: there may be a double bond; in position 6: there may be CI, F, CH3, -CHO; in position 7: there may be CI, OH; in position 9: thre may be Cl, F; solutions of the precursor of B or B^ at a 10" M concentration, to a methanol solution of DPPH (2,2-diphe-nyl-1-picryl hydrazyl - free radical); after having maintained the solution at room temperature away from light for 30 minutes, it is read the absorbance at the wave length of 517 nm of the test solution and of a solution containing only DPPH in the same amount as in the test solution; and then the inhibition induced by the precursor towards radical production by DPPH is calculated as a percentage by means of the following formula: (1 - As/Ac)X100 wherein As and Ac are respectively the absorbance values of the solution containing the test compound + DPPH and that of the solution containing only DPPH; test 4 is met by B or B1 precursor compounds if the % inhibition as above defined is higher thsm or equal to 50%; wherein test 5 is an analytical determination carried out by adding aliquots of 10-4 M methanol solutions of the precursor of B or B1 or of C = -Tc-Y-H, having the free valence saturated as above indicated, to a solution formed by admixing a 2 mM solution of desoxyribose in water with 100 mM of phosphate buffer and 1 mM of the salt Fe-"(NH4)2{304)2; after having thermostatted the solution at 37oC for one hour, aliquots of aqueous solutions of trichloroacetic'acid 2,8% cind of thiobarbituric acid 0.5 M are added, in the order, heating is effected at 100oC for 15 minutes and the absorbance of the tested solutions is then read at 532 nm; the inhibition induced by the precursor of B or B1 or C = -Tc-Y-H with respect to radical production by Fe-II is calculated as a percentage by means of the following formula: (1 - As/Ac)X100 wherein Ag and Ac are respectively the absorbance values of the solution containing the tested compound and the iron salt and that of the solution containing only the iron salt, the compound meets test 5 when the inhibition percentage as above defined of the precursor of B or B2 or C = -Tc-Y-H is higher than or equal to 50%; provided that in the compounds of formula (I) are excluded the drugs with A = R- when b0 = 0 and C = -Tc-Y0 wherein the free valence of Y0 is saturated as indicated above, s = 1 or 2. Compounds according to claim 1, wherein the precursor compound of B or B1 which meets test 4, is selected in the following classes: Aminoacids, selected from the following: L-camosine (formula CI), anserine (CII), selenocysteine (CIII), selenomethionine (CIV) , penicillamine (CV) , N - acetyl-penicillamine (CVT) , cysteine (CVII) , N-acetyl-, cysteine (CVIII), glutathione (CIX) or its esters, preferably ethyl or isopropyl ester: hydroxyacids, selected from the following: gallic acid (formula DI) , ferulic acid (DII), gentisic acid (Dili), citric acid (DIV), caffeic acid (DV), hydro caffeic acid (DVI), p-coumaric acid (DVII), vanillic acid (DVIII), chlorogenic acid (DIX), kynurenic acid Aromatic and heterocyclic mono- and polyalcohols, selected from the following: nordihydroguaiaretic acid {EI)„ quercetin (EII), catechin (EIII) , ka- empferol (EIV), sulphurethyne. (EV) , ascorbic acid (E- VI), isoascorbic acid (EVTI), hydroguinone {EVTII), gossypol (EIX), reductic acid (EX), methoxy- hydroquinone (EXI), hydroxyhydroquinone (EXII), pro pyl gallate (EXIII), saccl:iarose (EXIV), vitamin E (EXV), vitamin A (EXVI), 8-quinolol (EXVII), 3- tert-butyl-4-hydroxyanisole (EXVIII), 3-hydroxyf lavo- ne (EXIX), 3,5-tert-butyl-p-hydroxytoluene (EXX), p- tert-butyl phenol (EXXI), timolol (EXXII), xibornol (EXXIII) , 3,5-di-ter-butyl-4-hydroxybenzyl-thio- glycolate (EXXIV), 4'-hydroxybutyranilide (EXXV), guaiacol (EXXVI), tocol (EXXVII), isoeugenol (EX-XVIII), eugenol (EXXIX), piperonyl alcohol (EXXX), allopurinol (EXXXI), conyferyl alcohol (EXXXII), 4-hydroxyphenetyl alcohol (EXXXIII), p-coumaric alcohol (EXXXIV) , curcimin (EXXXV) : aromatic and heterocyclic amines, selected from the following: N, N' -diphenyl-p-phenylenediamine (MI) , ethoxyquin (Mil), thionine (Mill), hydroxyurea (M- Compounds containing at least a free acid function, selected from the following: 3,3'-thiodipropionic acid (NI), fumaric acid (Nil), dihydroxymaleic acid (NIII), thioctic acid (NTv) , edetic acid (NV) , bilirubin (NVI) , 3 ,4-methylendioxycinnamic acid (NVI-I) , piperonylic acid (NVTII) : Compoimds according to claim 1 wherein the precursor compound of B or B1 meeting test 5 is selected from the following: Acninoacids: aspartic acid (PI), histidine (PII), 5-hydroxy-tryptophan (PIII), 4- thiazolidincarboxylic acid (PIV) , 2-oxo-4-thiazolidincarboxylic acid (PV) mono and polyalcohols or thiols: 2-thiouracil (QI), 2-mercaptoethanol (QII) , esperidine (QUI) , secalcif erol (QIV) , 1-ar-OH vitamin D2 (QV) , flocalcitriol (QVI), 22-oxacalcitriol (QVII), the vitamin D3 derivative esterified with the vitamin A radical (QVTII), the formula (QIX) compound, 24,28- methylene - lar-hydroxyvitamin D2 (QX) the compound derived from lor, 25-dehydroxyvitamin D2 (QXI), 2-mer- captoimidazol (QXII) 4. Compounds according to claiias 1-2 wherein the precursors of B and B1, are those meeting test 4. 5. Compounds according to claims 1 - 4 wherein Y3 in formula ("III) is selected from the following: » substituted, in positions 2 and 6. 7. Compounds according to claims 1-6 wherein in the precursor steroids R" = -CO-CH2OH, -CH(CH3)-CH2-CH2-COOH, 8. Compounds according to claims 1-7 wherein in the precursor steroids the hydroxyl function is in position 3 and/or in position 11, and/or having in R" an hydroxyl or carboxylic function in terminal position. 9. Compounds according to claims 1-8, wherein the'precursor steroids are selected from the following: Budesonide, Hydrocortisone, Alclomethasone, Algestone, Beclomethasone, Betamethasone, Chloroprednisone, Clobeta-sol, Clobetasone, Clocortolone, Cloprednol, Cortisone, Corticosterone, Def lazacort, Desonide, Desoximethasone, Dexamethasone, Diflorasone Dif lucortolone, Dif luprednate, Fluazacort, Flucloronide, Flumethasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortyn Butyl, Fluocortolone, Fluorometholone, Fluperolone Acetate, Flu-prednidene Acetate, Fluprednisolone, Flurandrenolide, For-mocortal, Halcinonide, Halobetasol Propionate, Halomethasone, Halopredone Acetate, Hydrocortamate, Loteprednol Etabonate, Medrysone, Meprednisone, Methylpre-dnisolone, Momethasone Furcate, Paramethasone, Prednicar-bate, Prednisolone, Prednisolone 25-Diethylaminoacetate, Prednisolone Sodium Phosphate, Prednisone, Prednival, Prednylidene, Rimexolone, Triamcinolone, Triamcinolone Acetonide, 21-Acetoxypregnenolone, Cortivazol, Amcinonide, Fluticasone Propionate, Mazipredone, Tixocortol, Triamcinolone Hexacetonide, Ursodesoxycholic acid, Chenodeoxycholic acid, Mitatrienediol, Moxestrol, Ethynylestradiol, Estradiol, Mestranol. 10. Compounds or salts, or their compositions " according to claims 1-9 for use as a medicament; provided that in the compounds of formula (I) are excluded the drugs with A = R- when bo = 0 and C = -TE-Y0- wherein the free valence of Y0 is saturated as indicated above, and s - 1. or 2. 11. Use of the compounds or salts, or their compositions according to claims 1-9 for the preparation of drugs for the therapeutic stress oxidative use; in the compounds of formula (I) when bo = 0 and C = -T-C-Y0 wherein the free valence of YQ is saturated as indicated above, s = 1 or 2, the drug can be A = R-, 12. Pharmaceutical formulations containing as active principle -•^ -the compounds or their salts of claims 1-S, 13. A compound substantially as herein described and exemplified. 14. Pharmaceutical formulations substantially as herein described and exemplified. Dated this 8 day of October 2001

Documents:

in-pct-2001-1382-che-abstract.pdf

in-pct-2001-1382-che-claims duplicate.pdf

in-pct-2001-1382-che-claims original.pdf

in-pct-2001-1382-che-correspondence others.pdf

in-pct-2001-1382-che-correspondence po.pdf

in-pct-2001-1382-che-description complete duplicate.pdf

in-pct-2001-1382-che-description complete original.pdf

in-pct-2001-1382-che-form 1.pdf

in-pct-2001-1382-che-form 26.pdf

in-pct-2001-1382-che-form 3.pdf

in-pct-2001-1382-che-form 5.pdf

in-pct-2001-1382-che-other documents.pdf

in-pct-2001-1382-che-pct.pdf