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    • 专利摘要:
    Substituted hydantoins with formula <CHEM> wherein Z is hydrogen or alkyl and Z<1> and Z<2> represent the usual prostaglandin chains, having pharmacological properties related to those of prostaglandins and are useful in medicine, for example in the treatment of thrombosis.
    公开号:SU1005658A3
    申请号:SU782663656
    申请日:1978-09-05
    公开日:1983-03-15
    发明作者:Виттакер Норман；Гордон Колдвелл Альберт
    申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
    IPC主号:
    专利说明:

    selected from hydrogen and IU.  thyl, y is carbonyl, methylene, substituted hydroxy, or methylene, substituted hydroxy, and alkyl 2 Y — covalent bond or linear or branched alkylene, optionally substituted on carbon adjacent to Y, one, or two groups, from which to be with. } -C-alkyl or. the p-cyclic radical U is hydrogen, hydroxy, C-C is cyclic phenyl, benzyl, phenoxy or benzyl oxy, and phenyl, benzyl, fe, noxy and benzyloxy can be substituted on the benzene ring with phenyl or benzyloxy,.  or is a bond. CH2, or -CH ,. : y, u taken together, ybrazut S. -C-cycloalkyl or bicycloalkyl substituted by a hydroxy group, which preferably contains three carbon atoms separating it from the hydantoin ring, provided that either a) X or X is or includes an oxa group, or one of X, X and X is or includes a thiagroup, or X, X and X meanings other than defined in a, then at least one of Y and Y is or includes a cyclic radical, defined as above, or other than unsubstituted C-C -cycloalkyl or unsubstituted .  C4 C 0-yocycloalkyl, or Y, Y, Y, taken together to form an oxo-substituted bicycloalkyl group} or Y includes a benzene ring, a substituted benzyloxy group whose cyclic radical, means a monovalent radical obtained due to ytpraty of a ring hydrogen atom from a monocyclic or polycyclic a compound having bt 3 up to 12 ring atoms selected among carbon, oxygen or sulfur, and this compound may be saturated or unsaturated and may be additionally substituted by one or more alkyl s groups, but excluding phenyl, the compound of formula 2. where one of Y and Y means Z-NG-CO, where G is hydrogen, carboxyl or its reactive derivative, provided that at least one of G and Y or one of G and Y means;, hydrogen; 2 have the above. | meaning cyclization with the release of pure product, mainly in an acidic medium, for example in hydrochloric acid, in the presence of potassium cyanate, in an environment of alcohol, such as ethanol.  The hydantoins of formula () are valuable from the point of view of the pharmacological properties of the compound, since they are associated with the properties of natural prostaglandins.  Thus, for example, hydantoins mimic; and counteract the biologic effects of members of the prostaglandin (PG) A, B, C, E, and F series. For example, it was found that the hydantoins of formula (I) mimic the anti-aggregation effect of PGE on blood platelets and prevent the reduction caused by PGE2 or PGF, smooth muscle derived from the stomach of a rat, the colon of a chicken rectal rat and the guinea-pig trachea.  As was observed, antagonistic properties, as opposed to imitating (their properties, manifest when using large doses of hydantoins, pharmacological files, by which they mean relative activities - imitating or antagonizing (compared to natural prostaglandins), depend on the specific hydantoin in question.  Hook as properties of hydantoins of the formula (1).  close to the properties of prostaglandin, these hydantoins are applicable in the pharmacological determination and differentiation of the biological activities of natural prostaglandins and their receptors.  Hydantoins of formula (I) are also valuable as therapeutic agents.  In particular, hydantoins, which have a strong antiaggregation effect on blood platelets, are necessary when it is necessary to inhibit platelet aggregation or reduce the adhesive capacity of platelets, they can be used to treat or prevent blood clots in mammals, including humans.  For example, these compounds are useful in the treatment and prevention of myocardial infarction, in the treatment or prevention of thrombosis, in promoting the open condition of transplanted vessels after surgery, and in the treatment of atherosclerosis and such complications. conditions such as atherosclerosis, coagulation of blood due to lipemia and other clinical conditions, the main etiology of which is associated with lipid imbalance or hyperlipidemia.  These compounds can be used as additives to blood and other fluids used in external artificial blood circulation systems and in perfusion of isolated parts of the body.  The most valuable inhibitors of platelet aggregation are compounds of formula (1), in which Z is hydrogen, Z is carboxyalkyl, in which the alkylene moiety contains from 3 to 9% carbon, and Z is the group - (. OH. y. In y, y, Y is a bond or branched alkylene containing a quarter carbon atom adjacent to a carbon substituted by hydroxyl, a.  KM is as defined for formula (. one).  In this group of compounds, the most active compounds are those in which 4x Z is carboxyhexyl, and Y is cycloalkyl containing from ij to 7 carbon atoms.  Hydantoins of the formula (G also cause relaxation of vascular smooth muscle in the same way as members. Prostaglandin A and E.  Those compounds that relax vascular smooth muscle can cause vasodilation and therefore have antihypertensive properties and are useful for reducing blood pressure in mammals, including humans, and can be used either separately, because in combination with fb-adrenoceptor blocking an agent or other antihypertensive agent for treating all types of hypertension, including primary, malignant, and secondary hypertension.  .  The compounds of formula (1) also mimic the action of PGE, which consists in suppressing histamine caused by bronchospasm.  The compound of formula (I), which differs in this property, can be used in the treatment and prevention of bronchial asthma and bronchitis to relieve b &amp; onchospasm.  Hydantoins of formula (I) that inhibit gastric secretion. Pentagastrin-induced acids and reducing the formation of gastric lesions caused by aspirin in rats are useful in reducing excess gastric secretion.  or the prevention of avascular formations in the gastrointestinal tract and accelerating the healing of ulcers already present in the gastrointestinal tract, if such ulcers occur spontaneously or as part of a pleriglandular adenomas6 syndrome.  Intravenous administration of hydantoins of formula (I) to dogs causes an increase in urine volume, which indicates the potential use of such compounds 8 as diuretic agents used in the treatment of edema, for example, associated with human (), hepatic or renal failure in humans or other mammals.  Hydantoins of formula (I), which mimic the action of RBE and smooth muscle of the uterus, can be used as drugs against pregnancy, in particular, as a fruit-bearing agent.  In addition, the compounds of formula (I) can be used in the treatment of proliferative skin diseases, for example, diseases associated with excessive division of cells in the epidermis or skin, which may be accompanied by incomplete differentiation of cells {psoriasis, superficial dermatitis, non-specific dermatitis, dermatitis caused by primary contact, allergic contact dermatitis, cell carcinomas of the skin, lamellar ichthyosis, epidermal hyperdislocal kepekeratosis.  sunburn caused by benign lesions, benign keratosis, rashes and seborrheic dermatitis in humans and superficial dermatitis and scab in domestic animals, it is desirable to administer the compounds to treat these diseases, applied to the surface of the affected area of the skin, and you can also enter subcutaneously or intramuscularly directly affected areas of skin or around the tissue.  Compositions for injection should usually contain from 0.1 to 0.5 weight. about. % active ingredient.  The amount of a compound of formula CO required to achieve the desired biological effect depends on a number of factors / for example, on the particular compound chosen, the intended use, the type of administration and the patient.  Presumably, the daily dosage is in the range of 1 µg - 20 mg per 1 kg of weight.  For example, an intravenous dose of 5 µg - 1 mg / kg.  Such a dose is usually administered at a rate of 0.01-50 µg / kg per minute.  Fluids for infusion suitable for this purpose may contain from 0.001 to 100, for example, 0.01 to 10 µg / ml.  A single dose may contain from 10 µg to 100 mg of a compound of formula C), for example, ampoules for injection may contain from 0.01 to 1 mg, and a single dose for oral administration in the form of tablets or capsules may contain 0.1-50, for example from 2 to 20 mg.  When using a compound of the formula c) to inhibit platelet aggregation, it is usually adjusted to 1 μg -10 mg, for example, 10 µg-1 mg per liter of liquid in the corresponding fluid, either in the patient’s blood or in the infusion fluid.  The above doses relate to acids, amides, esters, alcohols and tetrazoles of formula (I). If salt is used, its amount should be taken as calculated for the corresponding anion.  For the treatment and prophylaxis of the conditions mentioned above, hydantoin compounds can be used in pure form, but it is desirable to use them in the form of pharmaceutical compositions.  The carrier must be compatible with the other ingredients of the composition and must not adversely affect the patient.  The carrier may be solid or liquid and is preferably mixed with.  hydantoin compound in the form of a unit dose, for example in a tablet, which may contain from 0.05 to 95% by weight of the hydantoin compound.  As mentioned above, the compositions of the present invention may also contain other pharmacological active substances.  Hydantoin compounds can be administered in compositions either in the form of acids or their salts, or their esters. Compositions can be prepared according to any of the methods known in pharmacology.  Compositions are prepared for oral, rectal, parenteral administration (the method of administration in each particular case depends on the nature and severity of the disease.  subject to treatment and from a particular hydantoin compound).  Compositions for oral administration may be in the form of discrete dosages, such as capsules, cachets, lozenges or tablets, each containing a specific amount of hydantoin compound, in the form of powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; in the form of oil-in-water emulsions, or in the form of water-in-oil liquid emulsions.  Such compositions can be prepared according to any of the methods known in pharmacology, however, all methods include the step of mixing the hydantoin compound with a carrier containing one (or more) additional ingredients.  The positions are primed, mixing the hydantoin compound evenly and thoroughly with a liquid or finely divided solid carrier or both, and then, if necessary, decorating the resulting product in the desired form.  For example, tablets can be made by pressing or melting a hydantoin compound powder or granule, not necessarily with one or more additional ingredients.  The compaction of the tablets can be carried out in a suitable mold, with the hydantoin compound (powder or granules) being optionally mixed with a bond, lubricant, inert diluent, surface active or dispersing agent (agents.  Tablets from the melt can be obtained by melting in a suitable device a powdered hydantoin compound moistened with an inert liquid diluent. Oral (cake) pellets contain the hydantoin compound in a flavor filler, usually in sugar, acacia or tragaeauth; lozenges contain hydantoin compound in an inert base, for example gelatin and glycerin, or in sugar and acacia.  Compositions for -an external application to the skin are preferably made in the form of ointments, creams, lotions, gel pastes, pulverizing liquids, aerosols or oils.  Carriers suitable for use are,.  with petrolatum, lanolin, polyethylene glycols, lirts, and combinations thereof.  The active ingredient is usually present in a concentration of 0.1-15% w / v of the composition, for example 0.52.  Compositions for parenteral administration may be in the form of sterile aqueous preparations of hydantoic compounds, and these preparations are preferably isotonic with the blood of the intended patient.  Such drugs are preferably administered intravenously; they can also be injected subcutaneously intramuscularly.  These preparations are common, but by mixing a hydantoin compound with water, sterilize the product and make it isotonic with blood.  Compositions suitable for rectal administration are usually prepared in the form of suppositories containing a single dose of a substance.  BUT.  Diethyl 2-aminononanedioate.  | Diethylamine amide (1b, 7 g) and ethyl-7-bromoheptanoate (16.6 g) were diluted in ethanolic ethylate, prepared from 1, 51 g of sodium, 30 ml of absolutized ethanol, and the mixture was boiled with p. reflux for 27 hours  The cooled solution is poured into ice water, the product is extracted with ether, and the dried extract is evaporated.  as a result, crude diethyl acetamido (6-ethoxycarbonylhex100 yl) malonate is obtained in the form of a pale yellow asla, 2.2 (3N, singlet, -COCH),, 17 (6H, multiplet, 3x-OCH-CH3).  Thus, the amide is obtained under reflux with concentrated hydrochloric acid for 5 1/2 hours, the cooled solution is washed with ether and water.  the layer is decolorized with activated charcoal and evaporated to dryness in a vacuum.  The remaining colorless glassy product is dissolved in a minimum amount of absolute ethanol and added dropwise with stirring to a cooled (-10 ° C) mixture of absolute ethanol (125 ml) of thionyl chloride (g).  The resulting solution was left at room temperature for 1 hour, then refluxed for 1 1/2 hours, cooled, and poured into a mixture of ice-water, adjusted to pH 9 with aqueous sodium hydroxide.  The resulting mixture is extracted with ether, and the dried extracts are concentrated and dispersed. , resulting in a 2-aminononanedioate (55% yield as a colorless oil, t. Kip, 11-115C at 0.020, 03 mm Hg. Art.  AT.  Diethyl-2 Oi4, C-dimethyl-3-oko-phenylpentyl) amino nonanoate.  To 5.18 g of 2-aminononanedioate, A, α-dimethyl-5-phenylpect-1-yon-3-one (3.95 g) is added dropwise with cooling and the resulting mixture is kept at room temperature for 21 hours, resulting in diethyl-2- fC, -dimethyl-3-. oxo-5-phenylpentyl) amino-Znanedioate.  WITH.  Diethyl 2- (3-hydroxy-4, -dimethyl-5-phenylpentyl) amino nonandioate. The previous crude ketone (5.1 g) was dissolved in absolute ethanol (70 ml) and the resulting solution was stirred in an ice bath for a gradual addition sodium borohydride (38.0 mg).  The resulting solution was stirred in an ice bath for another 10 minutes, and then kept at room temperature for 5 hours, most of the alcohol evaporated, then water was added and the resulting solution was acidified to pH 6.  The insoluble oil is extracted with ether, and the ethereal solution is dried and evaporated, resulting in a diethyl 2- (3-hydroxy -, - dime10-methyl-5-phenylpentyl) amino nonandioate being obtained as a pale yellow oil, which is used without further purification, output .  D.  5 (6-Ethoxycarboyl-hexyl) -1- (3-hydroxy-, Dimethyl-5-phenylpentyl) hydantoin and co-acidic.  A solution of the above alcohol (8.45 g in 37.6 ml of ethanol) and 2n.  hydrochloric acid (18.8 ml) was stirred and cooled on ice, while simultaneously adding a solution of potassium cyanate (3.05 g) in water (5.6 ml) dropwise.  The mixture was kept at room temperature for 18 hours, then the alcohol was evaporated, water was added and the insoluble oil was extracted with ether.  The dried ether solution is evaporated to a viscous oil, which is heated on a steam bath, resulting in 6 hours after which 5 - (6-ethoxy-carbonylhexyl) -1 - (3-hydroxy-4, -dimethyl-5-phenylpentyl) is obtained - Antoin hydride in the form of a viscous pale yellow oil.  This ester is added to cm C. 2 n.  sodium hydroxide (25 ml) and water (60 ml) and the resulting cloudy solution was left at room temperature for 2 hours.  The resulting solution was washed with ether and the clear, alkaline solution was acidified with 2N.  hydrochloric acid, and the precipitated oil is extracted with ether.  After evaporation and drying of the ethereal solution, a viscous oil is obtained (6.8. g) which chromatographic on a column of silica gel.  whereby 5 (6-carboxyhexyl) -1 - (3-hydroxy-, -dimethyl-5.5 f €; nylpentyl) hydantoin is obtained in the form of a colorless, viscous, oil, which solidifies (i.e. square  ), the precipitation of the mixture of diastereomers with t. square . Pysle non-single recrystallization from a mixture of ethyl acetate and ethyl ether (t. Kip, 60-8os) receive one of diastereomers in the form of a mat „pl.  TZB-TZU S.  laziness x needles.  Similarly to the above, 1a) diethyl-2- (3-oxo-3-) -tetrahydropyranyl (propyl) amine nonbondioate 2a) diethyl-2- (3-oxo-trans-methyl-clog exylpropyl) amino-nonon nitioate 8 Za) diethyl 2- (3-oxo-3) 1-adamantyl ylpropyl) amino) nonandioate, ka} diethyl-2- (3-oxo-3-) 2-thienyl (propyl) amine nonandioate, 5a) diethyl- 2- (3-oxo-3) cyclopent-3-enyl (propyl) amino nonandioate, 6a) diethyl-2-t (Hop6opaH) -2-one-3-yl (methyl) amino-3-nonanedioate 7a) diethyl-2- (3 -oxo-3-) 3,3-dimethylcy clobutyl (propyl) amino-nonandioate.  Za) diethyl-2- (3-oxo-3-) 2,2,3,3-tetramethylcyclopropyl (propyl) amiHoJnonanedioate, 9a) diethyl-2- (3 oxo-3-) 1-methylcyclohexyl (propyl) amino -nonandioate , 10a) diethyl-2- (3-oxo-3-trans- | -methylcyclohexylpropyl) amino} -non-4-endioate.  Pa-) ethyl-2- (3-oxo-3-phenylpropyl) amino} -4- (ethoxycarbonyl) methylthiohexane.  12a) ethyl 2- (3-oxo-3-cyclohexylpropyl) amino} -5-ethoxycarbonylmethylthiopentanoate, 13a).  ethyl 2- (3-oxo-3 cyclohexylpropyl) amino-6-ethoxycarbonylmethylthiohex-4-anoate, 1ta) ethyl-2- (3-oxo-3-cyclohexylpropyl) amino-ethoxycarbonylmethylthiohex-E-anoate, 15a) ethyl 2- (3-oxo-3-cyclohexylpropyl) amino-3- (3-ethoxycarbonylpropylthio) propionate,.  1b) ethyl-2- (3-oxooctylamino) 3 (Zethoxycarbonylpropylthio / propionate, 1,7a) ethyl 2- (3-oxo-3-cyclopentylpropyl) amino 3 (t-ethoxycarbonylbutylthio) propionate, 1 Over) diethyl-2- ( Z-oxo-3 -) - benzyloxyphenyl (propyl) aminos nonandioate, 19a).  ethyl 2- (3-oxo-3 cyclohexylpropyl) aminoD-5- (2-ethoxycarbonylethylthio) pentanoate ,.  which are converted to: 1b) diethyl-2-C (3 hydroxy-3-) -tetrahydropyranyl (propyl) amino-nonanedioate, 2b) diethyl-2- (3Hydroxy-3-trans-meth1-lcy clohexylpropyl) amine-nonanoioate, 3b) diethyl 2- (3-hydroxy-3-) 1-adamantyl (propyl) amiHOJnonanedioate, b) diethyl-2- (3-hydroxy-3-) 2-thienyl (propyl) amino nonandioate, 5b) diethyl-2 - (3-g. idroxy-3-) cyclopent-3-enyl (propyl) amino nonandioate, 1310 6b) diethyl-2- (norboran-2-hydroxy-3 ylmethyl) amino 3-n-nandioate, 7b) diethyl-2- (3-hydroxy-. 3-) 3 | 3-dimethylcyclobutyl (propyl) -aMMHoJ-HO nandioate, 8b) diethyl-2- (3-hydroxy-3-) 1, 2,3,3, -tetramethylcyclopropyl (propyl) -amino-3-nano-dandioate, 9b) diethyl- 2- (3-hydroxy-3-) 1-methylcyclohexyl (propyl) amino nonane; 1Ob) diethyl 2- (3-hydroxy-3-trans-α-methylcyclohexyl (propyl) amino-non-4-edeoate, lib) ethyl-2- (3-hydroxy-3 cyclohexylpropyl) amino-5-ethoxycarbonylmethylthiopentanoate, 13b) ethyl 2- (3-hydroxy-3 Cyclohexylpropyl) amine-6-ethoxycarbonyl methylthiohex-4-anoate, 1tb) ethyl-2- (3-hydroxy-3-Cyclohexylpropyl) amino-6-ethoxycarbonylmethylthiohex-E-anoate, 15b) ethyl 2-f (3H-HYDROXY-3-Cyclohexylpropyl) amino-3- (3-ethoxycarbyl-nylpropylthio) propionate, 16b) ethyl-2- (3-hydroxyoctyl | 1o) -3- (3-ethoxy; arbonylpropylthio-propionate ,) ethyl-2-L (3-hydroxy-3-cyclo-pentilpropyl) amino-3- (-electric icarbonylbutylthio) propionate, i3b) diethyl 2- (3-HYDROXY-3 -) - benzyloxyphenyl (propyl) amino nonaneioate, 19b) ethyl-2-E (3-hydroxy-3 cyclohexylpropyl) amino 3-5 (2-ethoxycarbonyl ethylthio) pentanoate, from which the following hydantoins are obtained, which, where indicated, are separated to obtain individual diastere isomers, with the indicated characteristics:.  .  .  (1c) 5- (6-carboxyhexyl) -1- (3-hydroxy-3-) | -tetrahydropyranyl- (propyl) hydantoin, tob-tob c, yt-yuz c, 25% yield; 2c) 5- (6-carboxyhexyl) -1- (3-hyA roxy-3-trans-methylcyclohexylpropyl) hydantoia, 87-89C, 99-10l C.  you move 65%; 3c) A- (6-carbrhexhexyl) -1- (3-hydroxy-3-) 1-adamantyl (propyl) hydantoin, 155-157 ° C, yield kk% i kc).  5- (6-carbox; Ihexyl) -1 - (3-hydroxy-3-) 2-thienyl (propyl) hydantoin, 78-80 ° C, v out (d 58% o 5s) 5 - ((- carsoxyhexyl) - - (3- i hydroxy-3-) cyclopent-3-enyl (proyl) hydantoin, ib-vU C, yield 50% J 6c) 5-6-carboxyhexyl) -1- (2hydroxynorboran-3-ylmethyl) hydantoi, 103 -107 C, yield 7c) 5- (7-carboxyhexyl) -1- (3-hydroxy-3-) 3,3 dimethylcyclobutyl (propyl) hydantoin, JISZ C, 10809 C, yield 73% 8c) 5- (6-carboxyhexyl) -1- (3-Hydroxy-3-) 2,2,3,3-tetramethylcyclo (propyl) hydantoin, 93-95 C, 135.  37C, yield 9c) 3- (carboxyhexyl) -2- (3hydroxy-3-) 1-methylcyclohexyl (proyl) hydantoin, 100g102C, 131-U2 C, yield 57%, 10s) 5- (6-carboxyhex-2-enyl ) -1 (3-hydroxy-3-trans-β-methylcyclohexylpropyl) hydantoin, 63-65 C, 879 C, yield 60%; 11c) 5- (6-carboxymethylthiobuyl) -1- (3-hydroxy-3-0enylpropyl) hydantoin, 101-102, yield 28%, 1 2c) 5 (3-carboxymethylthiopropyl) 1 - (3-hydroxy-3- Cyclohexylpropyl) hydantoin, 93-96 C, yield, 13c) 5- (-carboxymethylthiobut-2-enyl) -1g. (3-hydroxy-3-cyclohexyl (propyl) hydantoin, 117-118 ,, 116-117 ,, yield kk%, Gyu) 5- (-carboxymethylthiobut-2E-enyl) -1- (3-cyclohexyl-3-hydroxycypropyl ) hydanthin exit. 5 B%.  Found,%: C 5b ,, H 7.3, N7.3.  WiOffS С 56, V-, Н 7,3i Calculated, N 7,3.  (G () 2.67 (2I, t, SNCH,), 3.05 (2H, S, SCH,) 3.20 (2H, bd, CH), C, 19 (1H, t, COCHN), 5 , 7 (2H, m), 5.93 (2H, b SOHt), 9.7 bs, H). .  Also, l5c) 5- (3-carboxypropylthiomethyl) -1 - (3-hydroxy-3-cyclohexylpropyl) hydantoin, 131-133 C, 108-POS, 25% yield, 16c) 5- (3-carboxypropylthiomethyl) -1 - (Z-hydroxyoctyl) hydantoin, two diastereoisomers, t. pl, kk-kJ C, 57-60 0, yield 35% -, 17c) 5 - (- carboxybutylthiomethyl) (3-hydroxy-3-cyclopentylpropyl) -hydanthrine, 80-82 C, 91-93C, yield 30%.
    18c) 5- (6-car6oxyhexyl) -1- (if-benzyloxyphenylpropyl) hydantoin, yO / fC, 1 30-130,.
    1 9c) (-K rboxyethylthio) propyl -1- (3 hydroxy-3-cyclohexyl propyl hydration, 100.5-102 ,, 9637, yield 48.
    Example 1. Inhibition of platelet aggregation.
    Platelet aggregation is recorded in 1 ml of fresh human plasma rich in platelets (PRP) using a Bern agregometer.
    The compound to be tested is added to the plasma at the desired concentration, and the resulting mixture is incubated for 1 minute, after which the platelet aggregation is stimulated by the addition of adenosine diphosphate (LDF to a concentration of 5 μM.
    The anti-aggregation effect is evaluated for a specific compound by measuring the percentage inhibition of platelet aggregation in the presence of this compound.
    Each of the prostaglandins EI and 5 - (L-carboxymethylthiobutyl) -1 - (3-qi ohexyl-3-hydroxypropyl) hydantoin was thus tested and it was found that the corresponding hydanthrin was 20 times stronger than PGF.
    Example2. The manufacture of tablets containing 5- (-carboxymethyl tibutyl) -1 - (3-cyclohexyl-3-hydroxycipol) hydantoin (compound) in the following ratio of ingredients, mg
    Compound 5.0 Lactose B „P. 82
    Starch B, P „10
    Povidone In „R.S. 2.0
    Magnesium Stearate 1.0
    Mix together the compound, lactose and starch. A solution of povidone in distilled water is used to granulate the powders. Dry the granules, add magnesium stearate and compress tablets 100 mg.
    PRI me R 3 Production of capsules containing the compound according to example 2 in the following ratio of ingredients, mg:
    Connection 10
    Lactose79
    Starch10
    Magnesium Stearate 1
    Mix powders in a powder mixer, fill hard gelatin capsules (100 mg per capsule)
    Example. Preparation of the solution for injection containing the compound according to example 2,
    Compound, µg 100 Water for Injection, ml. Up to 100 Dissolve the compound in Water for Injection. The solution obtained is sterilized, filtered through a membrane filter with a pore size of 0.22 µm, the filtrate is collected in sterile receivers. Under aseptic conditions, the solution is filled with 1 ml sterile glass ampoules per ampoule, sealed, the glass is melted (compound content 1 µg / ml) .
    PRI me R, 5. Preparation of injection solution containing the compound according to example 2, Compound, mg 1 Ethyl alcohol, mg 10 Propylene glycol, mg30
    Water for injection, Mldo 100
    Dissolve the compound in ethyl alcohol, add propylene glycol and dilute to volume with water for injection. Sterilize the solution, filter it through a membrane filter with a pore size of 0.22 μm, collect the filtrate in a sterile vessel. Under aseptic conditions, fill the solution with sterile glass ampoules of 10 ml per vial. Cover with sterile rubber stoppers and seal with aluminum caps (compound content 10 µg / ml)
    权利要求:
    Claims (3)
    [1]
    Invention Formula
    Method for preparing hydanthine derivatives of general formula t
    ABOUT
    2Z-N 1
     about
    where Z is hydrogen or alkyl,
    one of Z and Z is represented by a group
    -X-X-X -X
    where X is methylene, X is -cis-or trans-CH-CH, or, where each of Q is independently selected from hydrogen and C-C-alkyl, 17 is a covalent bond or a linear or branched alkylene, X is chosen from carboxyl, carbamoyl, hydroxymethylene and alkoxycarbonyl, one among any of the methyleno O L. X, X and X groups can be replaced by ox or tiagroup, provided that at least one carbon atom is separated by any oxa or tiagroup from any —CH — CH or —CO — group or from nitrogen in the hydantoin ring, the other of Z and Z is em group YY-Y -Y where Y means -CR-iCH, in which each of R is independently selected from one another among hydrogen and methyl; U-carbonyl, methylene, substituted hydroxy, or methylene, substituted hydroxy and C |-C alkyl, Y is a covalent bond or linear or branched alkylene, optionally substituted on carbon adjacent to one or two groups, each of which may be C. keel, or C, -C cyclic radical; hydrogen, a hydroxy group, a cyclic radical, phenyl, benzyl, phenoxy or benzyloxy, and phenyl, benzyl, phenoxy-., or benzyloxy can be substituted on the benzene ring by phenyl or benzyl oxy, or Y means or, y bond, and Y, when taken together, C, -C-cycloalkyl or Ci-C-bicycloalkyl is substituted by an oxy group, which preferably contains 3 carbon atoms, which separate it from. hydantoin ring, under the condition that either a) X or X is or includes an oxa group, or one of X, X and X is or includes a thiagroup; or b) if the values of X, X and X are different than those defined in a, then at least one of Y and Y is or includes a cyclic radical, defined as above, or other than unsubstituted (pCycloalkyl, or unsubstituted. bicycloalkyl ) or Y, Y, Y, taken together are -C-C ob100 uazuyut hydroxy-substituted bicycloalkylene group, or Y vklyumaet benzene ring substituted benziloksigrupoy, wherein the cyclic radical oznaaet monovalent radical derived due to the loss odoroda ring atom of a monocyclic compound or poitsiklicheskogo Having t 3 to 12 ring atoms selected from carbon, oxygen or ery, and this compound may be saturated or unsaturated and may be further substituted with one or more alkyl groups. however, excluding phenyl, which is similar in that the combination of the formula I is - z where one of the Y and Y means Z-NG-CO, where G is hydrogen, carboxyl or its reactive derivative, provided that at least one of G and Y or one among G and Y is hydrogen; have the above meanings, cyclized to isolate the desired product.
    [2]
    2. The method according to claim 1, wherein the cyclization is carried out in an acidic medium.
    [3]
    3. Method according to paragraphs. 1 or 2, m.p. that the cyclization is carried out in the presence of hydrochloric acid,. Method according to any one of claims. 1-3, characterized in that the cyclization is carried out in the presence of potassium cyanate; 5. The method according to any one of claims 1 to 1, wherein the cyclization is carried out in an alcohol medium such as ethanol. Priority on the grounds:, I - -., - 05.09.77 X - methylene; X is cisily trans-CH CH- or., In which each Q is independently one from the other, is chosen among hydrogen and: alkyl, X is a covalent bond or linear or branched C-C-alkylene, X is chosen among carboxyl, carbamoyl, oxymethylene and alkoxycarbonyl, and one of the methylene groups
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    同族专利:
    公开号 | 公开日
    AT372681B|1983-11-10|
    IE781794L|1979-03-05|
    EP0001238A1|1979-04-04|
    AU3955678A|1980-03-13|
    CA1150250A|1983-07-19|
    FI782717A|1979-03-06|
    EP0001238B1|1984-07-04|
    ATA641378A|1983-03-15|
    JPS5463083A|1979-05-21|
    IE48747B1|1985-05-15|
    AU527959B2|1983-03-31|
    DK391678A|1979-03-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2138225A1|1971-07-30|1973-02-08|Diamalt Ag|HYDANTOIN DERIVATIVES|
    CA1176261A|1976-06-03|1984-10-16|Albert G. Caldwell|Hydantoin derivatives|GB1599740A|1978-05-31|1981-10-07|Wellcome Found|Hydantoin derivatives|
    EP0007180B1|1978-06-15|1983-03-30|Beecham Group Plc|Prostaglandin analogue triazole derivatives, processes for their preparation and a pharmaceutical composition containing them|
    EP0006352A1|1978-06-15|1980-01-09|Beecham Group Plc|Hydantoins and thiohydantoins, process for their preparation and pharmaceutical compositions containing them|
    AU4778279A|1978-06-15|1979-12-20|Beecham Group Limited|Prostaglandin analogues|
    IL57504D0|1978-06-15|1979-10-31|Beecham Group Ltd|Prostagandin analogues,their preparation and pharmaceutical compositions containing|
    IL59065D0|1979-01-18|1980-05-30|Beecham Group Ltd|Hydantoin derivatives,their preparation pharmaceutical compositons containing them|
    EP0023083A1|1979-06-27|1981-01-28|Beecham Group Plc|Oxodiazole derivatives, processes for their production and pharmaceutical composition containing them|
    CA1268107A|1984-07-19|1990-04-24|Alfred Fuller Leatherman|Thermoset bonding agent for non-distortionjoiningof self-supporting thermoset component parts|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB37054/77A|GB1603407A|1977-09-05|1977-09-05|Hydantoin derivatives|
    GB5009277|1977-12-01|
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