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21-Substituted Pregnane Derivatives

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21-Substituted Pregnane Derivatives Europaisches Patentamt J European Patent Office CO Publication number: 0 452 914 A2 Office europeen des brevets EUROPEAN PATENT APPLICATION © Application number: 91106170.3 © int. CIA C07J 41/00, C07J 71/00, A61K 31/57, A61K 31/58 0 Date of filing: 17.04.91 ® Priority: 23.04.90 JP 107255/90 2606-6, Akabane, Ichikai-machi Haga-gun, Tochigi(JP) © Date of publication of application: Inventor: Shigeru, Moriwaki 23.10.91 Bulletin 91/43 2990-2, lshii-cho Utsunomiya-shi, Tochigi-ken(JP) ® Designated Contracting States: Inventor: Hirota, Osamu CH DE FR GB IT LI NL 2606-6, Akabane Ichikai-machi, Haga-gun, Tochigi-ken(JP) © Applicant: KAO CORPORATION Inventor: Tsuchiya, Shuichi 1-14-10, Nihonbashikayaba-cho 2-11-10, Izumigaoka Chuo-ku Tokyo(JP) Utsunomiya-shi, Tochigi-ken(JP) Inventor: Hase, Tadashi @ Inventor: Hori, Kimihiko 2606-6, Akabane Ichikai-machi 1348-2, Esoshima-cho, Utsunomiya-shi Haga-gun, Tochigi-ken(JP) Tochigi-ken(JP) Inventor: Suzuki, Yasuto 4594, Ichigana, Ichikai-machi © Representative: Wachtershauser, Giinter, Dr. Haga-gun, Tochigi(JP) Tal29 Inventor: Morioka, Tomoki W-8000 Munchen 2(DE) © 21 -Substituted pregnane derivatives. © A 21 -substituted steroid compound is disclosed. The compound has a structure of formula (I), CM < CD <M in (I) Q_ UJ wherein R1 is a hydrogen atom, a lower alkyl, lower alkenyl, lower alkoxy, or phenyl group, R2 is a hydroxyl Rank Xerox (UK) Business Services EP 0 452 914 A2 group or an acyloxy group having 1-6 carbon atoms, R3 is a hydrogen atom or a lower alky I group, or R2 and R3 may together form a lower alkylidenedioxy group, X1 and X2 may be the same or different and individually represents a hydrogen atom or a halogen atom, Y1 and Y2 may be the same or different and individually represents a methylene group or a sulfur atom, Z is a sulfur atom or an imino group, the wave line means that the configuration of R3 may be of either a or 0, and dotted line between the 1 and 2 position means that the bond may be the double bond. It has excellent anti-inflammatory, anti-allergic and anti-asthma activities with little side effects, and is useful for the prevention, cure, and treatment of on inflammation, allergic diseases, rheumatism, and the like. EP 0 452 914 A2 BACKGROUND OF THE INVENTION Field of the Invention: 5 The present invention relates to novel steroid compounds. Description of the Background Art: Steroid compounds are very important drug which are essential for the treatment and the cure of skin to diseases and allergic diseases such as bronchial asthma, and rheumatism, etc. They are widely applicable to all allergic and inflammatory diseases, including, for example, contact dermatitis, atopic dermatitis, seborrheic dermatitis, eczema nummulare, lichen simplex chronicus Vidal, housewive's eczema, prurigo, drug eruption, toxicodermia, psoriasis, pustulosis palmaris et plantaris, lichen planus, lichen nitidus, pityriasis rubra pilaris, pityriasis rosea Gibert, erythema-group, erythroderma, discoid lupus erythematosus, 75 pemphigus, pemphigoid, Duhring dermatitis herpetiformis, alopecia areata, vitiligo vulgaris, sarcoidosis, keloid, hypertrophic scar, hypoadrenalism, rheumatism, bronchial asthma, ulcerous intestinitis, allergic rhinitis, conjunctivitis, and the like. Many of the patients to whom these steroid compounds are to be administered are those suffering from intractable inflammation, allergic diseases, or rheumatism, requiring the treatment in wide and various parts 20 of the body extending over a long period of time. In spite of doctor's efforts in designing and advising the manner in which the steroid drugs are administered, e.g. encapsulation, so as to prevent the side effects of the drug, the problem of side effects remains still to be solved. Such side effects include, for example, localized ones, e.g. dermal atrophy, steroid acne, steroid rosacea, depigmentation, etc., as well as those systemic, extending over the whole body of the patient, e.g. cushingoid signs, infant hypoevolutism, 25 infectious diseases, osteoporosis, etc. in the internal medicine. Steroid compounds substituted by acylthio groups derived from thiol carboxylic acid are reported to decrease the risks of the side effects (Japanese Patent Application Laid-open (kokai) Nos. 79399/1980, 26899/1983, 48999/1985, 36273/1976, etc.). These compounds, however, are not always satisfactory in their rather weak pharmacological activity and insufficient effects in reducing the side effects. 30 Development of a steroid compound is therefore awaited which possesses pharmacological activity strong enough to permit fast cure of the intractable inflammation, allergic diseases, or rheumatism without side effects. SUMMARY OF THE INVENTION 35 In view of this situation, the present inventors have undertaken extensive studies and found that a steroid compound of formula (I) hereinafter in which the 21 position of the steroid structure is substituted by acylthio or amide group derived from N-acylamino acid exhibited an excellent pharmacological activity against inflammation, allergic diseases, or rheumatism, and the like without minimal side effects. This 40 finding has led to the completion of the present invention. Accordingly, an object of the present invention is to provide a 21 -substituted steroid compound of formula (I), 45 50 55 EP 0 452 914 A2 10 75 (I) 20 wherein R1 is a hydrogen atom, a lower alkyl, lower alkoxy, or phenyl group, R2 is a hydroxyl group or an acyloxy group having 1-6 carbon atoms, R3 is a hydrogen atom or a lower alkyl group, or R2 and R3 may together form a lower alkylidenedioxy group, X1 and X2 may be the same or different and individually represents a hydrogen atom or a halogen atom, Y1 and Y2 may be the same or different and individually 25 represents a methylene group or a sulfur atom, Z is a sulfur atom or an imino group, the wave line means that the configuration of R3 may be of either a or /3, and dotted line between the 1 and 2 position mearns that the bond may be the double bond. Another object of the present invention is to provide a pharmaceutical composition for curing inflamma- tion (especially external application), allergic diseases (e.g. bronchial asthema, allergic rhinitis, etc.), or 30 rheumatism, or for an eye drop comprising an effective amount of the above steroid compound and a pharmaceutically acceptable carrier. Other and further objects, features and advantages of this invention will appear more fully from the following description. 35 BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 and 2 are graphs showing the eosinophiles infiltration inhibitory effect, which is an indicator of the anti-allergic activities, of the steroid compound of the present invention obtained from the experiment using guinea pigs. 40 Figure 3 is a graph showing the interleukin-1 production inhibitory effect, which is an indicator of the anti-rheumatism activities, of the steroid compound of the present invention obtained from the experiment using guinea pigs. DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 45 Examples of lower alkyl groups which are represented by R1 and R2 in formula (I) include linear or branched alkyl groups having 1-5 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or amyl groups. A lower alkoxy group which is represented by R1 may be a linear or branched alkoxy groups having 1-5 carbon atoms, e.g. methoxy, ethoxy, n-propyloxy, 2-propyloxy, n-butyloxy, t-butyloxy, or so pentyloxy group. As examples of an acyloxy group having 1-6 carbon atoms, which is represented by R2, e.g. formyloxy, acetoxy, propionyloxy, butanoyloxy, pentanoyloxy, and hexanoyloxy groups are given. Isopropylidenedioxy group, 3-pentylidenedioxy group, and the like may be the lower alkylidenedioxy groups which can be formed together by R2 and R3. Chlorine, florine, bromine, and iodine are typical examples of the halogen atom represented by X1 and X2. 55 21 -Substituted steroid compounds of formula (I) of the present invention can be prepared, for example, by reacting 21-mercapto (or amino) steroid of formula (II) and an N-acylamino acid of formula (111) in the presence of a suitable condensing agent according to the following reaction scheme. EP 0 452 914 A2 2H Y>Ts\ HO NHCOR1 (1) 10 75 (I) 20 wherein Ft1, Ft2, R3, X1, X2, Y1, Y2, and Z have the same meanings as defined previously for formula (I). 21-Mercapto steroid of formula (II) can be prepared by a known method, e.g. the method described in Japanese Patent Publication (kokoku) Nos. 40470/1974, 42080/1982, Japanese Patent Application Laid-open (kokai) Nos. 215695/1988, 303994/1988, and the like. 21-Amino steroid of formula (II) can be prepared by a known method, e.g. the method described in 25 U.S.P. 3,020,275 and the like. The reaction for the preparation of compound (I) may be carried out using 1-10 moles of N-acylamino acid of formula (III) per one mole of 21-mercapto (or amino) steroid of formula (II) in the presence of 1-10 moles of condensing agent and, optionally, a basic catalyst, in a solvent at a temperature of -10 C to ° 100° C, preferably 10 to 50 C. 30 As a condensing agent, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide with N-hydrox- ysuccinimide, N,N'-dicyclohexylcarbodiimide with 1 -hydroxybenzotriazol or the like can be used. Examples of the basic catalyst are 4-pyrrodinopyridine, dimethylaminopyridine, pyridine, triethylamine, and the like. Any solvent, e.g. methylene chloride, ethyl acetate, N,N-dimethylformamide, or the like may be used so far as it is inert to the reaction. 35 The 21 -substituted steroid compounds of formula (I) prepared in this manner can be separated from the reaction mixture and purified by a known method, e.g. column chromatography, recrystallization, and the like. The 21 -substituted steroid compounds of formula (I) thus prepared exhibits an excellent pharmacologi- cal activity against inflammation, allergic diseases, or rheumatism, and the like without minimal side effects, 40 and effective as an active component of pharmaceutical compositions for curing inflammation, allergic diseases, or rheumatism, or for an eye drop.
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