• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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  • 优先权
    • 专利摘要:
    Cyclodextrin clathrates of carbacyclin analogs of general Formula I <IMAGE> (I) wherein R1 is hydrogen, alkyl or alkenyl of up to 10 carbon atoms, A is a -CH2CH2-, trans-CH=CH-, or -C 3BOND C- group, W is a free or functionally modified hydroxymethylene group or a free or functionally modified <IMAGE> wherein the OH-group can be in the alpha - or beta -position, D is <IMAGE> alkylene, or unsaturated alkylene each of which can optionally be substituted by fluorine atoms, m is 1, 2 or 3, E is a direct bond, a -C 3BOND C- group, or -CR4=CR5- group, wherein R4 is hydrogen or an alkyl group of 1-5 carbon atoms, and R5 is hydrogen or an alkyl group of 1-5 carbon atoms, and R5 is hydrogen, halogen, or an alkyl group of 1-5 carbon atoms, R2 is alkyl or alkenyl of up to 10 carbon atoms, cycloalkyl of 3-10 carbon atoms or an optionally substituted aryl group of 6-10 carbon atoms, or a heterocyclic group, and R3 is a free or functionally modified hydroxy group, n is 1, 2, 3, 4 or 5, and X is -CH2- or oxygen as valuable crystalline pharmaceuticals.
    公开号:SU1632371A3
    申请号:SU874203626
    申请日:1987-11-05
    公开日:1991-02-28
    发明作者:Скубалла Вернер；Форбрюгген Хельмут；Даль Хельмут；Штюрцебехер Клаус-Штеффен；ТИРАУХ Карл-Хайнц
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:


    Ow
    The invention approaches to methods for producing a fj-cyclodextrin clathrate of a carfacilim analogue of the general formula (I)
    Yu
    15
    where R {- C-C alkyl; R4 is hydroxy; A - trans-CH CH- or-C C-gru
    na; U - free oxymethylene
    Group; D - branched C2-alkyleno-
    wa group; E - group
    X - SNG-group or oxygen: p "1.3 with valuable pharmacological properties. The purpose of the invention is to obtain a new carbacyclin analogue, which has advantages when administered orally.
    Example 1. 560 mg of p-Cyclodextrin is dissolved in A ml of water at 80 ° C. cooled to 60ffC and this solution is added dropwise to a solution heated to 60 ° C 18. mg (5E) - (16R, 5) -16-methyl- 18,18, 19,19-tetrahydro-6a-carboprostaglandin-1g in 0.3 ml of ethanol. Stir for 4 hours at 60 ° C, 1 hour at and 16 hours at 25 ° C. The precipitated solid is filtered off with suction, washed with 20 ml of a mixture of water and ethanol (1: O, and dried for 8 hours at O, 1 Torr, and 25 C over phosphorus pentoxide. 340 mg of free-flowing A-cyclodextrin clathrate crystals of the indicated carbocycpine analog is obtained .
    The content of carbacyclic enalogue in the clathrate is determined by high pressure liquid chromatography and is 4.231.
    PRI mme R 2.; g (5E) - (16 3) -13 14-Didehydro-16., 20-dimethyl-3-oxa - 18,18,19,19-tetrahydro-6a-carbaprostaglandin -1 together with 30.3 g ft-cyclodextrin in 214 ml of water is stirred for 48 hours at 25 C.
    The solid is filtered off with suction and washed with 15 ml of a mixture of water and ethanol (1: 1) and dried for 24 hours at O, Torr and 25 ° C over phosphorus pentoxide. Get 22,45 g of free-flowing crystals of the ft-cyclodextrin clathrate of the specified analogue of carbacyclin.
    The content of the carbacyclin analogue in the clathrate is determined by titration and is 3.5%.
    Example 3. 41.75 g / 5-cyclodextrin is dissolved in 298 ml of water at 80 ° C. A solution of 1.5 g of (5E) - (168) -13,14-didehydro-1a, 1b-cygomo-16 is added dropwise , 20-dimethyl-3-oxa-18,18, 19,19-tetradehydro-ba-carbaprostaglandandine in 24 ml of ethanol for 15 minutes. Stir for 4 hours at 6 ° C, then leave to cool overnight with stirring. The precipitated solid is filtered off with suction and washed with 50 ml of a mixture of water and ethanol (1: 1) and dried for 24 hours at 0.1 Torr and 25 ° C over phosphorus pectoxide. 38 g of free flowing β-cyclodextrin clathrate crystals of the indicated carbacyclin analog are obtained. The content of the carbacyclin analogue in the clathrate is determined by titration and is 3.3%.
    PRI me R 4. 0.5 g (5E) - (16 S) - 13,14-Didehydro-16, 20-dimethyl-18 "-18, 19,19-tetradehydro-6a-carbaprostag-andine- instead of 15 g of A-cyclodextrin in 100 ml of water, they are mixed for 5Q hours at 25 C. The solid matter is sucked off and washed with about 10 ml of a mixture of water with ethanol (1: 1) and dried for 24 hours at O, 1 Torr 15 ° C over phosphorus pentoxide. 11 g of free-flowing crystals / 3-cyclodextrin clathrate of the indicated carbacycling analogue are obtained.
    The content of the carbaccleate clathrate analogue is determined by titration of 3.6%.
    .
    Example 5. 57.75 g-Cyclodextrin at 45 ° C is dissolved in 1.53 liters of water, a solution of 7.633 g of (5E) - (16X5) -16-methyl- 18.18 is added dropwise to this solution over 30 minutes while stirring. , 19,19-tetradehydro-6a-carbaprostaglandin - in 45 ml of ethanol and additionally washed with 5 ml of ethanol. Cool for 1 h to 25 ° C, stir for 2 h at this temperature and 3 h in an ice bath. Crnstallizat
    5163
    sucked off and washed with ice-cold water, acetone and again with water.
    Dry in vacuum until crystallization begins at ambient temperature and ambient humidity — absorb water from the air again and the weight can be set to a constant. Get G 56.01 g (93.9%) free flowing
    crystallized, which contains 6% water and has a content of biologically active substance determined by titration of 12.8%.
    Supat in vacuum over phosphorus pentoxide and get 52.7 g of free-flowing, HYGROSCOPIC crystallisate, which has a content of biologically active substance determined by titration of 13.6%.
    Example 6. 3.877 g (5E) - (13,14-didehydro-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-tert 11.7 ml of 1N sodium hydroxide solution was washed with butyl ester, the impurities were extracted with diethyl ether and diluted with water to a solution of 660 ml. Added to 24.52 g of B-cyclodextrin and heated with stirring at 26 ° C up to within 30 minutes, 11.7 ml of 1N hydrochloric acid is added to this solution and stirred for 90 minutes, heated to 55 ° C, cooled for 1 hour to 25 ° C, and stirred for 1 hour with this perature and 2.5 hours in an ice bath. The crystallized ice is sucked off, washed with ice water and dried as in Example 4.
    This gives 22.53 g (89.2%) of free-flowing crystallisate, which contains 7.2% of water and has a content of biologically active substance determined by titration of 13.36%. 21.0 g of a free-flowing, hygroscopic crystallisate is obtained, which has a content of an active substance determined by titration of 14.3%.
    Example. g of p-cycldextrin at 50 ° C is dissolved. In 205 ml of water, a solution of 1.456 (5E) - (16S) - 13,14-didehydro-1a, 1b-digrammo- 16.20-dimethyl-18,18,19,19-tetradehydro-6a carbaprostaglandin-12 in 6 ml of ethanol and additionally washed with 1.2 ml
    one
    ethanol. Cool for 1 h to 23 ° C, stir for 2 h at this temperature and 18 h in an ice bath. Suck off the crystallite, rinse with ice-cold water and dry with cor according to Example 4.
    14.155 g (95.8%) of free flowing crystalline is obtained, which contains 7.6% of water and definitely has a titration of biologically active substance 9.9%. Get 13,1 v free-flowing, hygroscopic crystallized, which is determined by titration of the content of biologically active substances 10.7
    Example (5E) - (16S) -13, t4, 18,18,19,19-Hexadehydro-16,20-dimethyl-6a-carbaprostaglandin-12-J-cyclo dextrin clathrate analogously to Example 1 of (5E) - ( 16S) -13, U, 18,18,19, 19-hexadehydro-16,20-dimethyl-6a-car ba-prostaglandin-12 and ft-cyclodextrin clathrate.
    By selecting suitable amounts of water and cyclodextrin, one can obtain clichrates of stoichiometric composition with reproducible content of biologically active substance. The clathrates obtained according to this invention are valuable pharmacological agents. Kapatrata can be used in an anhydrous, hygroscopic form or in a water-containing, slightly hygroscopic form.
    The new Zacyclin car clathrates according to the formula 1 are in the stoichiometrical carbacycline: y-cyclodextrin-1: 2 ratio (3).
    The dose of the compound is 1-1500 µg / kg / day if it is administered to humans. The single dose for a pharmaceutically acceptable carrier is 0.01-100 mg. The clathrates of this isoretenia act as reducing blood pressure in the bronchodilator. They are further suitable for suppressing platelet aggregations. They act cytoprotectively on the stomach. heart, liver, kidney and on the pancreas. Therefore, the new cyclodextrin clathrates of formula 1 are valuable pharmaceutical biologically active substances. In addition, with a similar spectrum of action, when compared with the corresponding prostaglandins, they have greater specificity and are not available. Order 553 Circulation 249 Subscription
    VCNPI Gosul.tskh-: nekhchyogo.komiteta izoreoreteni m-and discoveries at the State Committee on Science and Technology of the USSR MZP35, Moscow, Zh-35, 4/5 Raushsk nab.
    Prokzvodstvoins -:. YTELSKNY PLANT Patent, Uzhgorod, st. Gagarin, 101
    权利要求:
    Claims (1)
    [1]
    ίχο
    A method of obtaining a jB-cyclodextrin clathrate, an analogue of carbacycin 1 line of the general formula I; o (en g ) l -s-he x
    I sn, ι *. SI I : Y 'VViW-DE-fi, b where - C (-C 2 -alkyl;
    .Rf is a hydroxy group;
    A is trans-CH = CH- or —C = C-group;
    W is a free oxymethylene group;
    D is a branched C - alkylene group;
    E is a group —C = C˜;
    X is a CHg group or oxygen;
    η = 1,3, characterized in that the sodium cog ^> analog of carbocycline of the general formula I, where R f , Rg, A, W, D, E, X and η have the indicated meanings,. obtained by saponification of an alkyl ester - an analogue of carbacycline of the general formula I with sodium hydroxide is introduced into interaction with an aqueous solution of β-cyclodextrin in a molar ratio of the original analogue of carbacycline of the general formula I: ^ -cyclodextrin = 1: (2-3) in a pharmacologically safe alcohol at 2560 ° C.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3608088A|DE3608088C2|1986-03-07|1986-03-07|Pharmaceutical preparations containing cyclodextrin clathrates of carbacyclin derivatives|
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