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

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• 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

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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, triamcinolone 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 separated 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 therapeutically 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 stimulates 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 derivatives 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-

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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 international pharmacopoeias. [0019] The applicant has surprisingly and unexpectedly found corticosteroids (corticoids) which are very effective, 10 even superior to those in the known art, and have, at the same time, a higher tolerance than the known corticoids as unexpectedly they do not cause the above side effects, or when they do, these are lower. [0020] An object of the present invention are corticosteroids and their use as anti-inflammatory, immunosuppressive and angiostatic agents having the general formula:

15 B-X1-NO2

or their esters or salts, where: B has the following structure: 20

35 where, in place of the hydrogens H in the CH group or two hydrogens H2 in the CH2 group shown in the general formula, there may be the following substituents:

at position 1-2: there may be a double bond; at position 2-3: there may be the following substituent: 40

at position 2: there may be Cl, Br; 55 at position 3: there may be CO, -O-CH2-CH2-Cl, OH; at oosition 4-5: there may be a double bond; at position 5-6: there may be a double bond; at position 6: there may be Cl, F, CH3, -CHO;

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at position 7: there may be Cl; at position 9: there may be Cl, F; at position 11: there may be OH, CO, Cl; at position 16, there may be CH3, OH, =CH2; 5 at position 17: there may be OH, CH3, OCO(O)ua(CH2)va CH3, or

15 where ua is an integer equal to 0 or 1, va is an integer from 0 to 4; at positions 16-17: there may be the following groups

R and R' are equal or different one from the other and may be hydrogen or linear or branched alkyls having from 1 to 30 4 carbon atoms, preferably R = R' = CH3; when at position 9 there is F, at position 11 there is OH, at positions 1-2 and at positions 4-5 there are two double bonds, at positions 3 and 20 two groups CO, at positions 16 and 17 there cannot be the group:

B being a corticosteroid residue; R" is -(CO-L)t-(X)t1- 45 where t and t1 are integers both equal to 1, t1 being also 0; the bivalent bridging group L is selected from:

(CR4R5)na(O)nb(CR4R5)n'a(CO)n'b(O)n''b(CO)n'''b(CR4R5)n''a 50 where na, n'a and n''a are equal or different one from.the other and are integers from 0 to 6, preferably from 1 to 3; nb, nb', n''b and n'''b are equal or different one from the other and are integers equal to 0 or R4 and R5 are equal or different one from the other and are chosen from H, linear or branched alkyl having from 1 to 5 carbon atoms, preferably from 1 to 3; 55 X is equal to X0 = 0, NH, NR1C where R1C is a linear or branched alkyl having from 1 to 10 C atoms; X1 is a bivalent connecting bridge chosen from:

- YO

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where Y is a linear or whenever possible branched C1-C20 alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms; - Y1 selected from

where n3 is an integer from 0 to 3; 15

25 -

where nf' is an integer from 1 to 6, preferably from 2 to 4; -

where R1f= H, CH3 and nf is an integer from 1 to 6, preferably from 2 to 4. 40 [0021] The compounds which can be mentioned, and which are those preferred, are the ones listed below where B can be obtained according to the known processes of the art. [0022] For example, the precursors and related processes described for example in The Merck Index, 12th Ed. of 1996, herein incorporated by reference, can be mentioned as precursors and related processes. The precursors (according to the Merck nomenclature) include the following, where H2, H, R, R', R'' have the meaning as defined in the 45 compounds listed below: budesonide, hydrocortisone, alclometasone, alge-stone, beclomethasone, betamethasone, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, corticosterone, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortyn butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, formocortal, halcinonide, halobetasol propionate, halometa- 50 sone, halopredone acetate, hydrocortamate, loteprednol etabonate, medrysone, meprednisone, methylprednisolone, mometasone furoate, parametasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, triamcinolone, 21-acetoxypregnenolone, cortivazol, amcinonide, fluticasone proprionate, mazipredone, tixocortol, triamcinolone hexacetonide. [0023] The X1 connecting bridges as above defined are obtainable by using the methods known in the art as indicated 55 above or by modifing the known methods by introducing X1 bridges when these are different from the connecting bridges described in the listed patents, using processes known in the art. Generally the connection between B and X1 is, as seen, of an ester or amide type (NH or NR1C, as defined in X). Any well known synthetic route for forming these bonds can be used to form this connection.

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[0024] In the case of esters, the most direct synthethic route includes: reaction of acyl chlorides B-CO-Cl in halogen alcohols of the HO-Ya-Cl, HO-Ya-Br, HO-Ya-I-type, where Ya is equal to Y or Y1 without the oxygen atom, in test conditions which are part of the known art. [0025] The reaction products of formula B-CO-O-Y-Cl(Br,I) can also be obtained by reacting the sodium or potassium 5 salts of salts acids B-CO-OH with dihalogen derivatives of the general formula YaCl2,YaBra or YaI2, ClYaBr, ClYaI, BrYaI. [0026] The reaction products are converted into the final products by reacting with AgNO3 in acetonitrile according to what is known in the literature. [0027] The general scheme is as follows:

10 B-CO-Cl+HO-Ya-Br → B-CO-O-Ya-Br+AgNO3 → B-X1NO2

where X1 = YaO. [0028] The general scheme may also be as follows: 15

B-CO-ONa+Br2Ya → B-CO-O-Ya-Br+AgNO3 → B-X1NO2

where X1 = YaO. 20 [0029] In this case of amide, the synthetic sequence includes reaction of the same acyl chlorides BCOCl with ami- noalcohols of the general formula NH2-Ya-OH, NHR1C-Ya-OH to give amides of the general formula:

B-CO-NH-Ya-OH

25 and

B-CO-NR1C-Ya-OH

30 according to known methods. [0030] Reaction of these amides with halogenating agents such as, for example PCl5, PBr3, SOCl2, etc., gives the halogen derivatives of the general formula:

35 B-CO-NH-Ya-Br(Cl)

and

40 B-CO-NR1C-Ya-Br(Cl).

[0031] The latter give the final products BX1NO2 by reacting with AgNO3 in acetonitrile according to methods known in the literature. 45 [0032] The sequence may be represented as:

where YaO is X1. 55 [0033] An alternative route to ester formation is reaction of the sodium or potassium salts of the acids with the nitric esters of halogen alcohols of the general formula:

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NO2-O-Ya-Cl(Br,I)

to directly give the products of the invention. 5 [0034] The reaction scheme is as follows:

B-CO-ONa+Br-Ya-ONO2 → B-CO-O-Ya-ONO2

10 where YaO is X1. [0035] Other synthetic routes similar to those described above include those in which the dihalogen derivative Br2Ya is reacted with enolates. The reaction products are then converted by reacting with AgNO3 in acetonitrile according to the above reaction. The general scheme is shown for an -OH in group B, of the type -CH2-OH, =CH-OH, is as follows:

20 [0036] The processes to obtain these X1 connecting groups are described in patent application WO95/30641 herein incorporated by reference. [0037] As said above the compounds of the invention of formula B-X1-NO2 or their pharmaceutical compositions, are used for the treatment of diseases in which the well known corticoids products are employed. [0038] In particular, it can be specifically mentioned the use in respiratory disorders, e.g. antiasthmatic, the use as 25 antiarthritic, antipruritic, antipsoriatic, antieczematic; the use in vascular disorders, e.g. as angiostatic, the use in im- munology disorders, e.g. as immunosoppressive. [0039] The compounds, or their compositions, of the present invention can-be administered for example by oral, rectal (intestinal disorders), parenteral route or by local (dermal, topical, transdermal, ocular, inhalatory, etc.) application. 30 [0040] The following examples are given only for illustrative purpose as an explanation but not as a limitation of the present invention.

EXAMPLE 1

35 CHEMICAL SYNTHESIS: preparation of hydrocortisone nitroderivative (HCN)

[0041]

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EXAMPLE 1A

Preparation of hydrocortisone (4-chloro)butanoate

5 [0042]

[0043] 4 portions of 4-chlorobutanoylchloride (0.32 ml x 4) and triethylamine (0.3 g x 4) were added in 24 hours to a solution of hydrocortisone (1 g) in CHCl3 dried over P2O5, and stirred for 3 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure. The crude residue 20 was ground with hexane and CH2Cl2 to give a white solid with a 53% yield by weight, which had a melting point (m. p.) of 155°C. [0044] The product was characterised by mass spectometry: M+493. 1 H NMR (300 MHz CDCl3) : 0.95 (3H,s,CH3), 1.45 (3H, s, CH3), 2.12 (2H, t, CH2 in 2), 2.6(2H, t, CH2COO), 3.65 (2H, t, CH2Cl), 4.45 (1H, m, CHOH), 4.35 and 5.05 (2H, 2d, COCH2O), 5.70 (1H, s, olefin H). 25 Preparation of hydrocortisone (4-nitroxy)butanoate

[0045] AgNO3 (0.2 g) was added to a solution of hydrocortisone-4-chlorobutanoate prepared as above (0.23 g) in acetonitrile (70 ml) and refluxed for 16 hours. The solution was deprived of the solvent at reduced pressure and chro- 30 matographed on silica gel using a solution of ethyl acetate and CH2Cl2 (3:7) as an eluant. [0046] Cortisone 4-nitroxybutanoate was recovered from the head fractions. 1 [0047] The product was characterised by H NMR (300 MHz CDCL3): 0,95 (3H, s, CH3), 1.45 (3H, s, CH3), 2.12 (2H, t, CH2 in 2), 2.6 (2H, t, CH2COO), 4.45 (1H, m, CHOH), 4.45 (2H, t, CH2O-NO2), 4.35 and 5.05 (2H, 2d, COCH2O), 5.68 (1H, s, olefin H). 35 EXAMPLE 1B

[0048] The product from Example 1A was also prepared using another synthetic route.

40 Preparation of hydrocortisone 4-bromobutanoate

[0049]

[0050] Five portions of 4-bromobutanoylchloride (0.35 ml x 5) and potassium carbonate (0.4 g x 5) were added in 55 24 hours to a solution of hydrocortisone (1 g) in CHCl3 dried over P2O5 and stirred for 5 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure.

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Preparation of hydrocortisone 4-nitroxybutanoate (HCN)

[0051] AgNO3 (0.2 g) was added to a solution of hydrocortisone 4-bromobutanoate prepared as above (0.23 g) in acetonitrile (70 ml) and stirred for 48 hours at room temperature. 5 [0052] The solution was deprived of the solvent at reduced pressure and chromatographed on silica gel using a solution of ethyl acetate and CH2Cl2 (3:7) as an eluant. [0053] Cortisone 4-nitroxybutanoate was recovered from the head fractions and characterised by mass spectometry: M+ 493. The spectrum was the same as that shown in Example 1A.

10 EXAMPLE 2

Evaluation of safety and activity

[0054] The products were administered in a 2%-by-weight carboxymethyl cellulose suspension during in vivo tests, 15 while a 0.1%-by-weight dimethylsulphoxide suspension was used for in vitro studies. [0055] The test groups always included 8 samples (except when differently stated in the examples) for adequate statistical evaluation, to be carried out when necessary according to common statistical procedures.

EXAMPLES 2A 20 Acute toxicity study

[0056] The acute toxicity of the product from Example 1A was roughly evaluated by orally administering a single dose of substance to a group of 10 mice of the Swiss strain. 25 [0057] Death incidence and appearance of toxic symptoms were observed during a period of 14 days after the compound administration. [0058] The animals showed no sign of apparent toxicity even after administration of a 50 mg/kg dose.

EXAMPLE 2B 30 Study of antiarthritic activity

[0059] Adjuvant arthritis was induced in male rats of Lewis strain, weighing 170 ± 15 g-by intracaudal injection of 0.6 mg of Mycobacterium butyricum (Difco) suspended in 0.1 ml of mineral oil. The animals were treated with a vehicle 35 made up of an intraperitoneal (i.p.) 2%-by-weight suspension of carboxymethyl cellulose in water, with intraperitoneal hydrocortisone of HCN (a suspension as described above) at doses of 5 mg/kg or doses of 10 mg/kg, starting from the first day after mycobacterium inoculation. [0060] Arthritis development was assessed 21 days later. To the arthritic lesions an arbitrary score was assigned according to the following scale: 40 - hind limbs: 0 to 7 for each (0 for no lesions and 7 for most severe lesions); - forelimbs: 0 to 4.5 for each (0 for no lesions and 4.5 for most severe lesions); - tail: 0 to 5 (0 for no lesions and 5 for most severe lesions); - ears: 0 to 2 for each (0 for no lesions and 2 for most severe lesions); 45 - nose and eyes: 0 to 1 ofr each (0 for no lesions and 1 for most severe lesions).

[0061] The results were expressed as a percentage of inhibition compared to the value obtained in the control group (animals treated withe the vehicle alone). [0062] The result are shown in Table 1. 50 TABLE 1 - STUDY OF ANTIARTHRITIC ACTIVITY OF COMPOUND HCN VERSUS HYDROCORTISONE IN RATS COMPOUND DOSE (mg/kg) ANTIARTHRITIC ACTIVITY (%) 55 HYDROCORTISONE 5 40 HYDROCORTISONE 10 55

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TABLE 1 - (continued) STUDY OF ANTIARTHRITIC ACTIVITY OF COMPOUND HCN VERSUS HYDROCORTISONE IN RATS COMPOUND DOSE (mg/kg) ANTIARTHRITIC ACTIVITY (%) 5 HCN 5 45 HCN 10 62

[0063] As shown by the results in Table 1, the test products were capable of similarly inhibiting development of the 10 arthritic process caused by mycobacterium. However, being the tolerability of HCN much higher than that of hydrocortisone (see ex 2C below), the results in terms of activity are much better in the case of HCN (see for comparison 40% of antiarthritic activity obtained with 5 mg/kg hydrocortisone with respect to 62% obtained with 10 mg/kg HCN).

EXAMPLE 2C 15 Study of gastric tolerability (safety)

[0064] Male Sprague-Dawley rats fasted for 24 hours were treated with 5 to 10 mg/kg of intraperitoneal hydrocortisone or HCN. 20 [0065] Twenty-four hours later the animals were sacrified, the stomach was removed and tissue was grossly exam- ined for the presence of lesions as described by Del Soldato et al.: "The influence of fasting and cimetidine on the relationship between ulcerogenic and anti-inflammatory properties of cimetidine", Br.J.Pharmacol. 67, 33-37, 1979. The degree of severity of the disease was evaluated according to common methods and expressed as arbitrary values. The results are shown in Table 2. 25 TABLE 2 - STUDY OF GASTRIC TOLERABILITY OF COMPOUND HCN VERSUS HYDROCORTISONE IN RATS COMPOUND DOSE (mg/kg) GASTRIC TOLERABILITY 30 HYDROCORTISONE 5 2.0 HYDROCORTISONE 10 3.5 HCN 5 0.5*

35 HCN 10 1.2* Data are expressed as arbitrary values according to the following scale: 0 = absent; 1 = mild lesions; 2 = moderate lesions; 3 = punctiform ulcers; 4 = severe and numerous ulcers. * P < 0.05 (where P is probability) compared to corresponding value in group treated with hydrocortisone.

[0066] As shown in Table 2, the rats treated with hydrocortisone exhibited a marked disease in the gastrointestinal 40 tract, varying in severity from mucosal erosion to ulcer involving the muscle layer, wall adhesions, ascites, peritonitis. In the other groups treated with the vehicle alone or HCN, the damage was much lower or even absent.

EXAMPLE 2D

45 Study of nitroxysynthetase activity

[0067] The nitroxy-sinthetase inhibiting activity induced by lipopolysaccharide (LPS) was determined in rat neu- trophils and stomach after administration of one of the test compounds and compared with that obtained after treatment with the suspending vehicle only. Wistar rats fasted for 24 hours before treatment received one of the test compounds 50 intraperitoneally (10 mg/kg) or LPS intravenously (caudal vein) (5 mg/kg). Four hours later the animals were sacrificed. Blood for neutrophil isolation and stomach were removed. [0068] Enzymatic activity was determined according to the method described by Assreuy et al.: "Feedback inhibition of nitric oxide synthase activity by nitric oxide", Br.J.Pharmacol. 108, 833-7, 1993. The results are shown in Table 3.

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TABLE 3 - STUDY OF NITROXYSYNTHETASE ACTIVITY IN COMPOUND HCN VERSUS HYDROCORTISONE IN RATS a 5 COMPOUND DOSE (mg/kg/i.p.) NITROXYSYNTHETASE ACTIVITY VEHICLE - 100 HYDROCORTISONE 10 55* HCN 10 62* 10 a per cent inhibition compared to group treated with vehicle alone * p < 0.05 compared to corresponding value in group treated with vehicle.

[0069] As shown by Table 3, both test products proved to be very effective in inhibiting nitroxysynthetase compared to the group treated with the vehicle alone. 15 EXAMPLE 2E

Study of bone toxicitv

20 [0070] Bone tissues (parietal bone from rat foetus) grown in vitro according to the method described by Doherty et al. ("The effect of glucocorticoids on osteoblast function. The effect of corticosterone on osteoblast, expression of beta- I integrins", Journal of Bone and Joint Surgery, Series A77/3, 396-404, 1995) was used. Hydrocortisone or HCN or the vehicle were incubated at concentrations of 100 nmol. [0071] Ninety six hours later calcium content and bone dry weight were measured. 25 [0072] The results are shown in Table 4.

TABLE 4 - EFFECT OF HCN AND HYDROCORTISONE ON BONE GROWTH IN RATS

30 TREATMENT (nmol) Calcium DRY TISSUE WEIGHT ∆°% ∆°% VEHICLE - 310 160 HXDROCORTISONE 10 70* 95* 35 HCN 10 287 149

° Compared to initial value (incubation time zero) * P < 0.05 compared to values obtained in control group (vehicle)

40 [0073] As shown in Table 4, a significant increase in tissue dry weight and increased calcium were observed after incubation with the vehicle or HCN. After incubation with hydrocortisone, the calcium content decreased and the bone dry weight did not increase. This shows that this treatment with hydrocortisone adversely affected bone growth.

EXAMPLE 2F

45 Study of some cardiovascular parameters

[0074] The effect of the test products on some cardiovascular parameters was studied in conscious Long Evans rats (350 to 450 g) which were appropriately monitored, as described by Gardiner et al.: "Influence of dexamethasone on

50 the regional haemodynamic responses to lipopolysaccharide in conscious rats: effect of the non-selective endothelin antagonist: SB 209670", Br.J. Pharmacology 117, 49P, 1996. The animals were treated with the vehicle (physiologic saline solution, 0,9% sodium chloride, s.c.) subcutaneous hydrocortisone or HCN (10 mg/kg). Heart rate and blood pressure were recorded 4 hours after treatment. [0075] Table 5 shows the data obtained as per-cent variation from control values.

12 EP 0 929 565 B1

TABLE 5 - STUDY OF COMPOUND HCN VERSUS HYDROCORTISONE IN SOME CARDIOVASCULAR PARAMETERS IN RATS 5 COMPOUND DOSE (mg/kg) HEART RATEa BLOOD PRESSURE b (%) VEHICLE - 100 160 HYDROCORTISONE 10 89* 115* 10 HCN 10 98 103

* P < 0.05 compared to group treated with vehicle a per-cent change compared to value recorded in group treated with vehicle alone (324±7 beats per minute) b per-cent change compared to value recorded in group treated with vehicle alone (101±2 mm Hg) 15 [0076] The results in Table5 show that the product of the invention HCN does not affect the cardiovascular parameters measured. On the contrary, hydrocortisone used in the known art shows significant pressure as well as cardiac changes.

EXAMPLE 2G 20 Study of angiostatic activity in rats

[0077] Male Wistar rats weighing 180 to 200 g were used according to the procedure described by Andrade et al.: "Quantitative in vivo studies on angiogenesis in a rat sponge model", Brit. J. Exp. Pathol. 68, 755-766, 1987. The 25 neovascularisation was evaluated in relation to blood flow by implanting a small sponge in the subcutaneous tissue for 14 days and determining 133Xe clearance. Briefly, an amount of 133Xe equal to 10µl was injected into the sponge using a small polyethylene cannula. The residual radioactivity from implantation using a gamma ray detector and the 133Xe clearance for 6 minutes was measured as a percentage of the initial value. The validity of this method for measuring neovascularisation was recently demonstrated by HU et al.: "Correlation of 133Xe clearance, blood flow and 30 histology in the rat sponge model for angionenesis. Further studies with angiogenic modifiers", Lab. Invest. 72, 601-610, 1995. [0078] The test compounds were administered by the subcutaneous route at a dose of 10 mg/kg from day 1 to day 13 after implantation. 133Xe was measured at day 14 from subcutaneous implantation, the animals were then sacrificed and the weights of thymus and spleen were recorded. 35 [0079] Table 6 shows the data obtained regarding the effect of the test products on neovascularisation and on the weight of spleen and thymus.

TABLE 6 - EFFECT OF HCN AND HYDROCORTISONE ON 133Xe CLEARANCE AND WEIGHT OF SPLEEN AND THYMUS 40 AT DAY 14 TREATMENT 133Xe(%) SPLEEN (mg) THYMUS (mg) VEHICLE 42 663±25 313±28

45 HYDROCORTISONE 33 642±32 185±17* HCN 22* 673±38 297±31

* P < 0.05 compared to values obtained in control group (vehicle)

50 [0080] As evident, HCN proved to be capable of exerting a marked angiostatic effect without changing the weight of spleen or thymus, differently from the reference product. [0081] As it is clear from the whole of the data shown in Tables 1 to 6, the pharmacodynamic activity - anti-arthritic, immunosuppressive and antiangiogenic activities - and tolerability of the nitroderivative are superior than those of the corticoid from the known art.

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EXAMPLE 3

[0082]

5 Dexamethasone 21-(4-bromobutyrate) [II] Dexamethasone [I] 3.5 g 8.9 mmol 4-Bromobutyryl chloride 4.06 ml 35 mmol Potassium carbonate 4.9 g 35 mmol 10 Tetrahydrofuran 70ml

[0083] The solution of compound I in tetrahydrofuran is portionwise treated with 4-bromobutyryl chloride (0.81 ml x 5) and potassium carbonate (0.98 g x 5) during 7 hours. The mixture is stirred overnight, the solvent is evaporated under vacuum and the residue is treated with ethyl ether and water. The organic layer is separated, washed with water 15 and dried with anhydrous sodium sulfate. After evaporation of the solvent, the residue is purified by silica gel flash column chromatography eluting with t.butyl methyl ether - hexane 1-1 to give:

- less polar compound 1.0 g; - derivative II 1.5 g (m.p. 184-187 °C; yield 31%) 20 TLC: t.butyl methyl ether-hexane 2-1.

Dexamethasone 21-(4-nitrooxybutyrate) [III] (compound DXN)

25 Compound II 1.5 g 2.7 mmol Silver nitrate 2.4 g 14.1 mmol Acetonitrile 250 ml

[0084] The mixture of compound II and silver nitrate in acetonitrile is refluxed for 7 hours. After filtration of inorganic 30 salts, the solvent is evaporated under vacuum and the residue is treated with ethyl ether. The organic layer is twice washed with water, dried with anhydrous sodium sulfate and evaporated under vacuum. The residue is poured into ethyl ether and filtered to give 1.27 g of pure compound III as a white solid (m.p. 183-185° C; yield 90%) TLC: t.butyl methyl ether-hexane 2-1. The following forms are enclosed: 35 - synthetic scheme; - NCX 1005 batch 1; - NCX 1005/1 analysis.

14 EP 0 929 565 B1

EXAMPLE 4 55 Study of the activity on leucocyte accumulation

[0085] Male Swiss albino mice (27-33 g) maintained on a standard chow pellet diet and tap water ad libitum were

15 EP 0 929 565 B1

used. The experiment was done as previously described by Perretti et al. (Perretti M., Solito E., Parente L., "Evidence that endogenous interleukin-1 is involved in neutrophil migration in acute experimental inflammation in rats and mice", Agents Actions, 35,71,1992). Animals were pretreated with zymosan (1mg/0.5ml) i.p. at time 0. Two hours later DEX- AMETHASONE (1 mg/kg)(Ex3-I), DXN (Ex3-III)(1mg/kg) or phosphate buffered saline (PBS) was given intravenously. 5 The animals were sacrificed at 4 and 24h the lavage fluids were collected and differential cell counts were performed following staining in Turk's. [0086] Table 7 reports results obtained on the inhibitory effect of the tested compounds on zymosan-induced leucocyte migration in mice. As can be observed the nitroderivative steroid is much more active than dexamethasone.

10 TABLE 7- Inhibition of neutrophil and monocyte recruitement bY DEXAMETHASONE and DXN (1mg/kg) given 2h i.v. after zymosan (1mg/0.5ml) i.p. treatment PMNx106/mouse % reduction mono-m0 x106/ %reduction 15 (time 4h) mouse (time 24h) vehicle 10.1±1.0 ...... 8.8±1.3 ...... DXN 4.5±0.3 55.4 4.5±0.6 48.8 20 DEXAMETHASONE 6.4±0.4 36.6 6.3±0.2 28.4

EXAMPLE 5

Study of the anti-proliferative activity in human airway smooth muscle cells 25 [0087] Human airway smooth muscle cells were cultured by standard explant methods. Tissues were collected into sterile pots containing PBS and penicillin and streptomycin. Under sterile tissue culture conditions, tissues were cut into small pieces (approximately 1 mg weight) and placed into standard medium containing 20% fetal calf serum (FCS) for several days (medium changed every 2-4 days). 3H-thymidine was measured in the DNA fraction of cells cultured 30 into 48 well plates. Cells were cultured to confluence in the medium containing 10% FCS. Cells were deprived of serum for 24h before the addition of 10% FCS, together with different concentration of steroids. After 24h, 3H-thymidine was added to the cells for 4h. Cells were washed with phosphate buffered saline and ethanol. The DNA was extracted with sodium hydroxide solution and the 'H material counted by scintillation. The data represent observations made in trip- licate wells from smooth muscle cultured from one healthy lung donor. Table 8 reports results obtained on the inhibitory 35 effect of the tested compounds on human airway smooth cell proliferation. As can be observed the nitroderivative steroid is much more active than dexamethasone.

TABLE 8- Inhibition of human airway smooth cell mitogenesis by different concentrations of DEXAMETHASONE and DXN 40 Treatment Concentration 3H-thymidine (logM) (CPMx1000) DEXAMETHASONE -5 14.1 -7 15.0 45 DXN -5 10.8 -7 12.6

CONCLUSIONS 50 [0088] As can be observed from results reported above, both activity and safety of the new nitroderivatives are better than those owned by the precursor steroids.

55 Claims

1. Compounds of the general formula:

16 EP 0 929 565 B1

B-X1-NO2

or their esters or salts, where: 5 B has the following structure:

where, in place of the hydrogens H in the CH group or two hydrogens H2 in the CH2 group shown in the general formula, there may be the following substituents:

at position 1-2: there may be a double bond; 25 at position 2-3: there may be the following substituent:

40 at position 2: there may be Cl, Br; at position 3: there may be CO, -O-CH2-CH2-Cl, OH, at position 4-5: there may be a double bond; at position 5-6: there may be a double bond; at position 6: there may be Cl, F, CH3, -CHO; 45 at position 7: there may be Cl; at position 9; there may be Cl, F; at position 11: there may be OH, CO, Cl; at position 16: there may be CH3, OH, =CH2 at position 17: there may be OH, CH3, OCO(O)ua(CH2)vaCH3, or 50

where ua is an integer equal to 0 or 1 va is an integer from 0 to 4;

17 EP 0 929 565 B1

at position 16-17: there may be the following groups

R and R' are equal or different one from the other and may be hydrogen or linear or branched alkyls having from 1 to 4 carbon atoms, preferably R = R' = CH3 15 when at position 9 there is F, at position 11 there is OH, at positions 1-2 and at positions 4-5 there are two double bonds, at positions 3 and 20 two groups CO, at positions 16 and 17 there cannot be the group:

B being a corticosteroid residue; R'' is -(CO-L)t-(X)t1- where t and t1 are integers both equal to 1, t1 being also 0; 30 the bivalent bridging L is chosen from:

(CR4R5)na(O)nb(CR4R5)n'a(CO)n'b(O)n''b(CO)n'''b(CR4R5)n''a

35 where na, n'a, and n''a are equal or different one from the other and are integers from 0 to 5, preferably from 1 to 3, nb, n'b, n''b and n'''b are equal or different one from the other and are integers equal to 0 or 1; R4 and R5 are equal or different one from the other and are chosen from E, linear or branched alkyl having from 1. to 5 carbon atoms, preferably from 1 to 3; X is equal to X0 where X0 = O, NH, NR1C where R1C is a linear or branched alkyl having from 1 to 10 C atoms; 40 X1 is a bivalent connecting bridge chosen from:

- YO where Y is a linear or whenever possible branched C1-C20 alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms; 45 - Y1, chosen from

55 where n, is an integer from 0 to 3;

18 EP 0 929 565 B1

where nf' is an integer from 1 to 6, preferably from 2 to 4;

where R1f =H,CH3and nf is an integer from 1 to 6, prepreferably from 2 to 4; wherein the connection between B and X1 is of ester or amide type

30 2. Compounds according to claim 1, in which B include the following, where H2, H, R, R', R'' are as defined in the compounds listed below: budesonide, hydrocortisone, alclometasone, algestone, beclomethasone, betamethasone, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, corticosterone, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortyn butyl, fluocortolone, fluorometholone, 35 fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, loteprednol etabonate, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, triamcinolone, 21-acetoxypregnenolone, cortivazol, amcinonide, fluticasone propionate, mazipredone, tixocortol, triam- 40 cinolone hexacetonide, where R" is as defined in Claim 1.

3. Compounds or compositions according to Claim 1 to be used as medicaments.

4. Use of the compounds or compositions in Claim 2 for the preparation of medicaments such as corticoids. 45 5. Use of the compounds or compositions according to Claim 4 for the preparation of medicaments such as antiarthritic.

6. Use of the compounds or composition according to Claim 4 for the preparation of medicaments such as immun- 50 odepressives.

7. Use of the compounds or compositions according to Claim 4 for the preparation of medicaments such as angi- ostatics.

55 8. Use of the compounds or compositions according to Claim 4 for the preparation of medicaments such as antiasth- matics.

9. Use of the compounds or compositions according to Claim 4 for the preparation of medicaments for dermatological

19 EP 0 929 565 B1

disorders.

10. Use of the compounds or compositions according to Claim 4 for the preparation of medicaments for ocular disorders. 5 11. Use of the compounds or compositions according to Claim 4 for the preparation of medicaments for intestinal disorders.

12. Pharmaceutical compositions comprising as the active ingredients the compounds of claims 1 or 2. 10

Patentansprüche

1. Verbindungen der allgemeinen Formel: 15

B-X1-NO2

oder ihre Ester oder Salze, in welchen 20 B die folgende Struktur hat:

wobei, an der Stelle der Wasserstoffe H in der CH-Gruppe oder zweier Wasserstoffe H2 in der CH2-Gruppe, die 35 in der allgemeinen Formel gezeigt sind, die folgenden Substituenten auftreten können:

an Position 1-2: dort kann eine Doppelbindung auftreten; an Position 2-3: dort kan der folgende Substituent sein:

50 an Position 2: Dort kan Cl, Br sein; an Position 3: dort kann CO, -O-CH2-CH2-Cl, OH sein, an Position 4-5: dort kann eine Doppelbindung sein; an Position 5-6: dort kan eine Doppelbindung sein; an Position 6: dort kann Cl, F, CH3, -CHO sein; 55 an Position 7: dort kann Cl sein; an Position 9: dort kann Cl, F sein; an Position 11: dort kan OH, CO, Cl sein; an Position 16: dort kann CH3, OH, =CH2 sein

20 EP 0 929 565 B1

an Position 17: dort kann OH, CH3, OCO(O)ua(CH2)vaCH3, oder

sein, wobei ua ein Integer ist, der gleich 0 oder 1 ist, va ein Integer von 0 bis 4 ist; 10 an Position 16-17: dort können die folgenden Gruppen sein:

20 R und R' sind gleich oder unterschiedlich voneinander und können Wasserstoff oder lineare oder verzweigte Alkyle sein, die 1 bis 4 Kohlenstoffatome haben, vorzugsweise R=R'=CH3 wenn an Position 9 ein F ist, ist an Position 11 ein OH, an Positionen 1-2 und an Positionen 4-5 sind zwei Dop- pelbindungen, an Positionen 3 und 20 zwei CO-Gruppen, an Positionen 16-17 darf nicht die folgende Gruppe sein: 25

35 wobei B ein Corticosteroid-Rest ist; R" ist -(CO-L)t-(X)t1- wobei t und t1 Integers sind, die beide gleich 1 sind, t 1 auch 0 ist; die bivalente Brücke L ausgewählt ist aus:

40 (CR4R5)na(O)nb(CR4R5)n'a(CO)n'b(O)n''b(CO)n'''b(CR4R5)n''a

wobei na, n'a und n"a gleich oder unterschiedlich zueinander sind und Integers von 0 bis 6, vorzugsweise von 1 bis 3, nb, n'b, n"b und n"'b gleich oder unterschiedlich zueinander sind und Integers 0 oder 1 sind; R4 und R5 sind 45 gleich oder unterschiedlich zueinander und sind ausgewählt aus H, linearen oder verzweigten Alkylen, die 1 bis 5 Kohlenstoffatome haben, vorzugsweise 1 bis 3; X ist gleich X0, wobei X0=O, NH, NR1c, wobei R1c ein lineares oder verzweigtes Alkyl ist, das 1 bis 10 Kohlenstoffatome hat; X1 ist eine bivalente Verbindungsbrücke ausgewählt aus: YO 50 wobei Y linear ist oder, wo möglich, verzweigtes C1 -C20-Alkylen, vorzugsweise mit 2 bis 5 Kohlenstoffatomen, oder ein optional substituiertes Cycloalkylen mit 5 bis 7 Kohlenstoffatomen; Y1 ist ausgewählt aus

21 EP 0 929 565 B1

wobei n, ein Integer zwischen 0 und 3 ist; 10

wobei nf' in Integer von 1 bis 6 ist, vorzugsweise von 2 bis 4;

wobei R1f=H, CH3 und nf ein Integer von 1 bis 6 ist, vorzugsweise von 2 bis 4; wobei die Verbindung zwischen B und X1 ein Ester oder Amid-Typ ist.

40 2. Verbindungen nach Anspruch 1, in welchen B umfasst die folgenden, wo H2, H, R, R', R" definiert sind als die im folgenden aufgelisteten Verbindungen: Budesonid, Hydrocortison, Alclometason, Algeston, Beclomethason, Beta- methason, Chloroprednison, Clobetasol, Clobetason, Clocortolon, Cloprednol, Cortison, Corticosteron, Deflaza- cort, Desonid, Desoximetason, Dexamethason, Diflorason, Diflucortolon, Difluprednat, Fluazacort, Flucloronid, Flumethason, Flunisolid, Fluocinolonazetonid, Fluocinonid, Fluocortyn-Butyl, Fluocortolon, Fluorometholon, Flu- 45 perolon-Acetat, Flupredniden-Acetat, Fluprednisolon, Flurandrenolid, Formocortal, Fhalcinonid, Halobetasol-Pro- pionat, Halometason, Halopredon-Acetat, Hydrocortamat, Loteprednol-Etabonat, Medryson, Meprednison, Me- thylprednisolon, Mometason-Furoat, Paramethason, Prednicarbat, Prednisolon, Prednisolon-25-Diethylaminoa- cetat, Prednisolon-Natriumphosphat, Prednison, Prednival, Prednilyden, Rimexolon, Triamcinolon, 21-Ace- toxypregnenolon, Cortivazol, Amcinonid, Fluticason-Propionat, Mazipredon, Tixocortol, Triamcinolon-Hexaceto- 50 nid, wobei R" wie in Anspruch 1 definiert ist.

3. Verbindungen oder Zusammensetzungen nach Anspruch 1, die als Medikamente verwendet werden.

4. Verwendung von Verbindungen und Zusammensetzungen nach Anspruch 2 für die Zubereitung von Medikamenten 55 wie Corticoide.

5. Verwendung von Verbindungen und Zusammensetzungen anch Anspruch 4 für die Zubereitung von Medikamenten wie Antiarthritika.

22 EP 0 929 565 B1

6. Verwendung von Verbindungen und Zusammensetzungen nach Anspruch 4 für die Zubereitung von Medikamenten wie Immun-suppressiva.

7. Verwendung von Verbindungen und Zusammensetzungen nach Anspruch 4 für die Zubereitung von Medikamenten 5 wie Angiostatika.

8. Verwendung von Verbindungen und Zusammensetzungen nach Anspruch 4 für die Zubereitung von Medikamenten wie Antiasthmatika.

10 9. Verwendung von Verbindungen und Zusammensetzungen nach Anspruch 4 für die Zubereitung von Medikamenten für Hauterkrankungen.

10. Verwendung von Verbindungen und Zusammensetzungen nach Anspruch 4 für die Zubereitung von Medikamenten für Augenerkrankungen. 15 11. Verwendung von Verbindungen und Zusammensetzungen nach Anspruch 4 für die Zubereitung von Medikamenten für Erkrankungen des Darmes.

12. Pharmazeutische Zusammensetzungen enthaltend als aktive Bestandteile die Verbindungen aus den Ansprüchen 20 1 oder 2.

Revendications

25 1. Composés de formule générale :

B-X1-NO2

30 ou leurs esters ou sels, où B a la structure suivante :

dans laquelle, au lieu des hydrogènes H dans le groupe CH ou de deux hydrogènes H2 dans le groupe CH2 montré dans la formule générale, il peut y avoir les substituants suivants :

sur la position 1-2, il peut y avoir une double liaison ; 50 sur la position 2-3, il peut y avoir le substituant suivant :

23 EP 0 929 565 B1

sur la position 2, il peut y avoir Cl, Br ; sur la position 3, il peut y avoir CO,-O-CH2-CH2-Cl, OH ; 15 sur la position 4-5, il peut y avoir une double liaison ; sur la position 5-6, il peut y avoir une double liaison ; sur la position 6, il peut y avoir Cl, F, CH3,-CHO ; sur la position 7, il peut y avoir Cl ; sur la position 9, il peut y avoir Cl, F ; 20 sur la position 11, il peut y avoir OH, CO, Cl ; sur la position 16, il peut y avoir CH3, OH, =CH2 ; sur la position 17, il peut y avoir OH, CH3, OCO(O)ua(CH2)vaCH3 ;

ou 25

où ua est un entier égal à 0 ou 1, va est un entier de0à4;surlaposition 16-17, il peut y avoir les groupes suivants : 35

45 R et R' sont identiques ou différents l'un de l'autre et peuvent être un atome d'hydrogène ou un groupe alkyle à chaîne droite ou ramifiée ayant de 1 à 4 atomes de carbone, de préférence R = R'= CH3, quand on a F en position 9, OH en position 11, deux doubles liaisons en positions 1-2 et 4-5, deux groupes CO en positions 3 et 20, on ne peut avoir en positions 16 et 17 le groupe : 50

24 EP 0 929 565 B1

B étant un résidu de corticostéroïde ; R" est -(CO-L)t-(X)t1- où t et t1 sont tous les deux égaux à 1, t1 valant aussi 0 ; le groupe pontant bivalent L est choisi parmi : 5

(CR4R5)na(O)nb(CR4R5)n'a(CO)n'b(O)n''b(CO)n'''b(CR4R5)n''a

où na, n'a et n"a sont identiques ou différents les uns des autres et sont des entiers de 0 à 6, de préférence 10 de 1 à 3, nb, n'b, n"b et n"'b sont identiques ou différents les uns des autres et sont des entiers égaux à 0 ou 1 ; R4 et R5 sont identiques ou différents l'un de l'autre et sont choisis parmi H et les groupes alkyle à chaîne droite ou ramifiée ayant de 1 à 5 atomes de carbone, de préférence de 1 à 3 atomes de carbone ; X est égal à Xo où Xo = O, NH, NR1c, où R1c est un groupe alkyle à chaîne droite ou ramifiée ayant de 1 à 10 atomes de carbone, X1 est un pont de liaison divalent choisi parmi 15 YO où Y est un radical alkylène en C1 àC20, à chaîne droite ou chaque fois que possible à chaîne ramifiée, ayant de préférence de2à5atomes de carbone, ou encore un radical cycloalkylène éventuellement substitué et ayant de 5 à 7 atomes de carbone ; Y1, choisi parmi 20

où n3 est un entier de 0 à 3 ; 30

45 où nf' est un entier de 1 à 6 et de préférence de 2 à 4 ;

55 où R1f est H, CH3, et nf est un entier de 1 à 6, de préférence de 2 à 4, où la liaison entre B et X1 est du type ester ou amide.

2. Composés selon la revendication 1, dans lesquels B comprend les composés suivants, dans lesquels H2,H,R,

25 EP 0 929 565 B1

R', R" sont tels que définis dans les composés ci-dessous : budégnoside, hydrocortisone, alclométasone, algestone, baclométhasone, bétaméthasone, chloroprednisone, clobétasol, clobétasone, clocortclone, cloprednol, cortisone, corticostérone, déflazacort, désonide, desoximéthasone, dexaméthasone, diflorasone, diflucortolone, difluprednate, fluazacort, flucloronide, flumétasone, flunisolide, acétonide de fluocinolone, fluocinonide, fluocortyn- 5 butyl, fluocortolone, fluorométholone, acétate de flupérolone, acétate de fluprednidène, fluprednisolone, fluran- drénolide, formocortal, halciconide, propionate de halobétasol, halométasone, acétate d'haloprédone, hydrocortamate, étabonate de lotéprednol, médrysone, méprednisone, méthylprednisolone, furoate de mométasone, pa- raméthasone, prednicarbate, prednisolone, 2 5-diéthylaminoacétate de prednisolone, phosphate de prednisolo- nesodium, prednisone, prednival, prednylidène, rimexolone, triamcinolone, 21-acétoxypregnénolone, cortivazol, 10 amcinonide, propionate de fluticasone, maziprédone, tixocortol, hexacétonide de triamcinolone, où R" est tel que défini dans la revendication 1.

3. Composés ou compositions selon la revendication 1, pour utilisation en tant que médicaments.

15 4. Utilisation des composés ou compositions selon la revendication 2, pour préparer des médicaments tels que les corticoïdes.

5. Utilisation des composés ou compositions selon la revendication 4 pour préparer des médicaments tels que des antiarthritiques. 20 6. Utilisation des composés ou compositions selon la revendication 4 pour préparer des médicaments tels que des immunodépresseurs.

7. Utilisation des composés ou compositions selon la revendication 4 pour préparer des médicaments tels que des 25 angiostatiques

8. Utilisation des composés ou compositions selon la revendication 4 pour préparer des médicaments tels que des antiasthmatiques.

30 9. Utilisation des composés ou compositions selon la revendication 4 pour préparer des médicaments pour les trou- bles dermatologiques.

10. Utilisation des composés ou compositions selon la revendication 4 pour préparer des médicaments pour les trou- bles oculaires. 35 11. Utilisation des composés ou compositions selon la revendication 4 pour préparer des médicaments pour les trou- bles intestinaux.

12. Compositions pharmaceutiques comprenant en tant que principes actifs les composés selon les revendications 1 40 ou 2.