• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention concerns a series of phenoxyacetic acid ethers (and pharmaceutically acceptable salts thereof) of the formula I in which R1 is H or F, R2 and R3 are H or alkyl, Z is CH2OH or a group -CO.R4 in which R4 is OH, NH2 or alkoxy. The invention also includes pharmaceutical compositions for use in treating obesity and related conditions and provides processes for the manufacture of the ethers.
    公开号:SU1632370A3
    申请号:SU864027877
    申请日:1986-07-29
    公开日:1991-02-28
    发明作者:Рой Холловей Брайан；Хоув Ральф；Сингх Рао Балбир；Стриблинг Дональд
    申请人:Империал Кемикал Индастриз Плс (Фирма)；
    IPC主号:
    专利说明:

    The invention is related to a process for the preparation of new acetic acid derivatives of the formula
    R OH
    . O-oaijCuaijNHCHjCH - VocHjZ,
    where R is hydrogen or fluorine;
    Z is a COR group,
    where R, q - C. | -C j-olkoxyl or hydroxyl.
    The invention also encompasses the pharmacologically acceptable salts of these compounds, which are obtained in the form of a racemate or optically active antipodes.
    The proposed compounds can be used as an active principle in pharmaceutical formulations for treatment and other related matters.

    x
    ten
    15
    31632370
    The purpose of the invention is to obtain new derivatives in the range of phenoxyacetic acid, which have the ability to stimulate metabolism.
    Example 1. A mixture of M-benzyl-N-. (2-p-hydroxyphenoxyethyl-2-hydroxy-3-phenoxypropshgamine (4.0 g), methyl bromoacetate (1.56 g), anhydrous potassium carbonate (1.7 g) and potassium iodide (0.05 g ) stirred under reflux in dry acetone (50 ml) for 24 hours. The reaction mixture was cooled, the solids were removed by filtration, and the solvent was evaporated. The residue methyl 2-p-2-m-benzyl- (2-hydroxy 3 α-phenoxypropyl) -amino ethoxyTphenoxyacetate is dissolved in Me -Anol (90 ml) and acetic acid (30 ml). The resulting solution was subjected to 20% pure hydrogenation in the presence of 10% by weight. Coal catalysis The papladium-coated coating (0.4 g) at a pressure of about 20 bar and 60 ° C for 48 hours. The mixture is cooled, solid particles are removed by filtration, and the solvent is evaporated. The residual oil is dissolved in methanol and treated with a solution of ether saturated with hydrogen chloride. 30 The precipitated solids are twice crystallized from methanol to obtain methyl 2-p- | 2 - {(2-hydroxy-3-phenoxy-propyl) amino Dethoxy-phenoxy, ethe hydrochloride, 0.22 g, t. square 170 ° C.
    The original product was obtained as follows.
    A. A mixed mixture of 2-p-hydroxy-phenoxy-ethylamine (4.0 g) and benz35
    B.M.be 13NL-2-p-hydroxyphenoxyethylaminingyl chloride (3.5 g) is shaken with a solution of 1N. caustic soda (20 ml) and dichloromethane
    (20 ml). The organic layer is separated and washed with water (10 ml), dried-yug (M.gSO) and the solvent is evaporated to obtain H-benyl-2-p-hydroxyphenoxyethnlamine as an oil.
    C. A mixture of Mn-° nzil-2 p-hydroxyphenoxylamine (2.5 g) and 1,2-epoxy-3-phenoxypropane (1.54 g) in propan-2-ol (50 ml) is heated under reflux.
    within 72 hours. The solvent is removed by evaporation to obtain M-benzyl-H- (2-p-hydroxyphenoxy-ethyl) -2-hydroxy-3-phenoxypropylamine D as an oil, which was practically
    as indicated by thin layer chromatography (TCL) (silica and 5% methanol plates in dichloromethane were used as eluent and used without purification).
    Example 2. A mixture of methyl 2-p- (2- Ј (2-hydroxy-3-phenoxypropyl) amino-ethoxy) phenoxy-acetate, (0.92 g) (-1) -di-n-toluene-tartaric acid the monohydrate (0.991 g) in methanol (15 ml) is evaporated by boiling to obtain a final volume of 5 ml. Methyl acetate (.10 ml) is added and the mixture is concentrated to a volume of 5 ml. This treatment is repeated several times. The mixture is then left for 18 hours at ambient temperature. The solids that are formed are collected and recrystallized from meta45.
    aldehyde (5.0 g) in methanol (50 ml) 40 Nola and methclacetate to give (-) -methyl-2-P- (2- (2-hydroxy-3-phenoxy-propyl) -amino-Zeroxn) phenoxyacetate (- ) -di-p-toluentartrate / (0.337 g), b.p. 146-148 ° C; OD -80,3 ° (, 97; methanol).
    (-) - Methyl-2-p- (2 2-hydroxy-3-phenoxypropano) amino 3-ethoxy) phenoxy-acetic acid (-) - di-p-toluene tartrate (0.33 g) is divided into 5 all .%/about. sodium carbonate solution (0 ml) and dichloromethane (10 ml). The organic layer is separated, dried (Mp, S04), and the solvent is evaporated. Solid
    cooled with ice and sodium borohydride (2.0 g) added in portions over more than one hour. After stirring for 18 hours, the solvent is evaporated. The residue was partitioned between 2M hydrochloric acid (200 ml) and ethyl acetate (100 ml). The acid layer is separated, potassium carbonate is added and then it is extracted with ethyl acetate. Ex-, tracts are dried () and evaporated-50; The residual oil is dissolved in ethyl acetate and the dry hydrogen chloride is passed through the solution until solid particles precipitate. The precipitate is collected and recrystallized from methanol and ethyl acetate to give N-benzyl-U.-p-hydroxyphenoxy-ethylamine hydrochloride, 2.3 g, m.p. 182-184.
    55
    residue (0.148 g), so pl. 114-116 ° C, (chloromethane. Dissolved in methyl acetate.
    Dry hydrogen chloride is passed through the solution until the formation of a solid precipitate is stopped. Sediment with clean
    B.M.be 13NL-2-p-hydroxyphenoxyethylaminingyl chloride (3.5 g) is shaken with a solution of 1N. caustic soda (20 ml) and dichloromethane
    (20 ml). The organic layer is separated and washed with water (10 ml), dried-yug (M.gSO) and the solvent is evaporated to obtain H-benyl-2-p-hydroxyphenoxyethnlamine as an oil.
    C. A mixture of Mn-° nzil-2 p-hydroxyphenoxylamine (2.5 g) and 1,2-epoxy 3-phenoxypropane (1.54 g) in propan-2-ol (50 ml) is heated under reflux.
    within 72 hours. The solvent is removed by evaporation to obtain M-benzyl-H- (2-p-hydroxyphenoxy-ethyl) 2-hydroxy-3-phenoxypropylamine D as an oil, which was practically
    as indicated by thin layer chromatography (TCL) (silica and 5% methanol plates in dichloromethane were used as eluent and used without purification).
    Example 2. A mixture of methyl 2-p- (2- Ј (2-hydroxy-3-phenoxypropyl) amino-ethoxy) phenoxy-acetate, (0.92 g) (-1) -di-n-toluene-tartaric acid the monohydrate (0.991 g) in methanol (15 ml) is evaporated by boiling to obtain a final volume of 5 ml. Methyl acetate (.10 ml) is added and the mixture is concentrated to a volume of 5 ml. This treatment is repeated several times. The mixture is then left for 18 hours at ambient temperature. The solid particles that were formed were collected and recrystallized from methanol and methclacetate to give (-) - merate and crystallized from methanol metnanetat, to give (-) - m "tnl-2- - (2-Ј (2-hydroxy-3-phenoxykinyl ) minH | -ethoxy) phenoxyacetate chlorohydrate (0.092 g), m.p. 156-157 ° C, 5 21, 1 °, (01.0; methane).
    PRI me R 3. A mixture of N-benyl-M- (2-p-hydroxyphenoxyethyl) -3-o-phyrenoxy-2-gndrokeipropilamin (5,4 r) ,, Q methyl bromoacetate (2.0 g) anhydrous potassium carbonate (1.79) and iodine kai (0.05 g) are stirred under phlegmon in dry acetone (80 mi) for 24 hours. The reaction mixture is cooled, 15 solids are removed by filtration, and the solvent is evaporated. The residue was dissolved in dichloromethane (40 ml) and washed successively with 10% w / v. a solution of sodium bicarbonate 20 (20 ml) and water (20 ml), then dried (Mp, SO.), and the solvent removed by evaporation. The resulting oil (6.18 g) is purified by chromatography on silica-25 me, subjected to elution using 1% v / v methanol in dichloromethane and get 2-p- (2- -benzyl- (3-o-fluorophenoxy-2 -hydroxypropyl) - aminosP ethoxy) phenoxyacetate in the form of a colorless oil. The oil is dissolved in methanol (100 ml) and mixed with charcoal (1 g) for an hour. The charcoal is removed by filtration, and the filtrate is hydrogenated in the presence of benzyl chloride (0.71 g) and 10 wt.% By weight of catalyst (palladium on carbon) for 2 hours at atmospheric pressure. The catalyst is removed by filtration and the solvent is evaporated from the filtrate. The residual solid is crystallized twice from a mixture of methanol and anhydrous ether to obtain methyl 2-p- (2- (3-0-4,
    fluorophenoxy-2-hydroxypropyl) amino
    ethoxy) -phenoxyacetate hydrochloride (0.55 g), so pl. 120-122 ° C.
    The original product is obtained as follows, „
    A mixture of S benzyl-2-p-hydroxyfenox-ethylamine hydrochloride (5.6 g), 1,2-epoxy-3-o-fluorophenoxypropane (3.6 g) and anhydrous potassium carbonate (2.7 g) is heated for 24 h under reflux in propan-2-ol (100 ml). The reaction mixture is cooled, the solids are removed by filtration, and the solvent is evaporated from the filtrate.
    The residual oil is purified by chromatography on silica, and is subjected to elution at IIOMOI UI 1% V / V
    methanol in dichloromethyl to obtain M-bin: CL-G. - (2-p-gi, t.roxgphenoxyethne) - 3-o-fluoro-refx-xn-2-g; foxypropylamine as a colorless oil;
    And p N me R 4, a Mixture of methyl-p- (2-oxipro-irox. And) phenoxyacetate (15.3 g) and 2-hydroxy-3-phenoxypropylamnn. (10.75 g) in dry toluene (250 ml) is mixed under reflux for 18 hours in an aerootropic water distillation apparatus, the solvent is evaporated, and the residual oil is dissolved in methanol (150 ml). This solution was added to a previously reconstituted suspension of Adams catalyst (0.25 g) in methanol (100 ml) and then the mixture was subjected to hydrogenation at atmospheric pressure for 6 hours. The catalyst was removed by filtration and the concentrate was concentrated in vacuo. The residual oil is purified by chromatography on silica using 1% w / v. methanol in dichloromethane as solvent for elution. The obtained solid was recrystallized with igmptylacetate to obtain methyl 2-p .- (2-Ј (2-hydroxy-3-phenox-propyl) -aminylЛ igupoxy) - phenoxyacetate (2.88 g), t, pl. 115-116 ° Co
    The mixture of the bottom stereo-dimensional forms is divided as follows.
    )
    (i) the aforementioned 50; 50 mixture of the above compound (2.8 g) is dissolved in methanol (20 ml) and then a solution of anhydrous acetic acid (0.65 g) in methanol (20 ml) is added. The solvent is removed by evaporation, and the residue is recrystallized from methanol to obtain one diastereisomeric form as the oxalate at 191-192 ° C. This salt is divided between 10 M sodium hydroxide (0.5 ml), brine (20 ml) and dichloromethane (40 ml), the organic layer is dried (Mp, 50d) and the solvent is removed by evaporation. The residue is crystallized from methyl acetate to obtain the diastereon isomeric form A as a free base (0.53 g) with a melting point of 103.5-105.5 ° C.
    (ii) Uterine solutions from the recrystallization stage of the oxalate salt of the compound from methanol in (i)
    evaporated. The residual solid was then fractionally crystallized from methyl acetate to produce another oxalate salt with a mp. 125-. This salt is converted into the free base form as described in example (i). The resulting residual solid was twice crystallized from a mixture of methanol and methyl acetate to obtain the free base form of the compound as a mixture of two diastereomers A and B (0.15 g), m.p. 116-117CC, microanalytically pure and containing approximately 25% of diastereoisomer A and 75% of diastereoisomer B (based on measurements of the nuclear magnetic resonance spectrum at a frequency of 400 MHz of two duplicates of duplicates at 3.11 delta).
    Example 5. Using the method described in Example 1, but using n-benyl (2-M-hydroxyphenoxyethyl) -2-hydroxy-3-phenoxypropylamine (1.6 g), methyl bromoacetate (0.58 g), anhydrous potassium carbonate (0.6 g) and potassium iodide (0.05 g) in acetone (80 ml) and with an intermediate release of methyl 2-t- (2-1t1-benzyl- (2-hydroxy-3-phenoxypropyl) -amino ethoxy) ) phenoxyacetate (1.1 g), methyl 2-t- (2-Ј (2-hydroxy-3-phenoxypropyl) amino ethoxy) phenoxy acetate hydrochloride (0.35 g) is obtained, m.p. 164-167 ° C.
    The original product is obtained as follows.
    A mixture of resorcinol (88 g), 1,2 dibromoethane (180 g) and caustic potash
    (44.8 g) stirred for 24 h
    ether (. ml) .. The extracts are sequentially washed with water (50 t-s) and brine (50 ml) and then dried. The dry ethereal solution is treated with a solution of ether, saturated with hydrogen chloride. The precipitated solid is twice crystallized from methanol / ethyl acetate to obtain N-ben, sil-2- (t-hydroxynphenoxy) ethnylnhydlorochloride (19.2 g) with m.p. . 148-149 ° C. With a mixture of M-benzl-2- (t-hydroxyphenoxy) ethnlamine hydrochloride (2.79 g), 1,2-epoxy-3-phenoxypropane (1.5 g)
    J5 and anhydrous potassium carbonate (2.0 g) are heated by reflux in propan-2-ol-. within 18 hours. The reaction mixture is cooled, and the solvent is evaporated to obtain M-methyl-K- (2-t-gndroxy20 phenoxyegap) -2-hydroxy-3-phenoxy-polypropylene in the form of an oil which was practically pure, as shown thin layer chromatography (silica plates used
    25 5% methanol in dichloroethane (as solvent for elution).
    Example 6 Suspension of methyl.-P- (2- (2-hydroxy-3-phenoxynpropyl) amine Zethoxy) phenoxyacetate hydrochloride 30 Read (0.015 g) in 2M hydrochloric acid (1 ml) is heated for 30 minutes at 95-100 ° C, the resulting pure the solution is cooled to ambient temperature to obtain
    2 $ 2-p-2 (2- (2-hydroxy-3-phenoxy propyl) amino ethoxy) phenoxyacetic acid g and hydrochloride (0.011 g), mp = 180-182 ° C,
    Example 7: A mixture of methyl 2-p- (2 under reflux in methanol (600 ml). -Ј (2-hydroxy-3-phenoxypropyl)) The mixture was cooled. The residual solid was removed by filtration, and the filtrate was evaporated to give 3- (2-Bromoethoxy) phenol as an oil that was practically pure, as indicated by thin layer chromatography (using silica plates and 10% by volume of the volume of methacol in dichloromethane as a solvent for elution).
    B. A mixture of 3- (2-bromoethoxy) phenol (40 g) and benylamine (39.2 g) is stirred under reflux in ethanol (800 ml) for 18 hours. The reaction mixture is cooled and the solvent is evaporated. The residual oil is washed with 2M hydrochloric acid (100 ml). Basement with solid potassium carbonate and extract
    ethoxy) phenoxyacetate hydrochloride (0.507 g) and sodium hydroxide (100 mg) in methanol (5 ml) and water (15 ml) are heated for 18 hours at 95-100 ° C.
    g5 Methanol is removed by distillation and the pF value of the {residual layer is adjusted to 6 by means of 2N hydrochloric acid. Oil precipitated, which slowly solidified.
    50 The solid was crystallized from water to obtain 2-p- (2- Ј 2-hydroxy-3-phenoxypropyl) amchg - tox) phenoxy acetic acid, melting point 186
    188 ° C.
    PRI me R 8, a Mixture of N-benz L-I- (2-p-hydroxyphenoxyethyl) -2-gndroxy-3-pheno-ipylphenolamide (3.22 g), t-butyl bromoacetate (1.6 g), Pcspl- potassium carbonate (1.13 g) and iodide as a solid. The substance was crystallized from water to obtain 2-p- (2- Ј 2-hydroxy-3-phenoxypropyl) ammonium-toxn) - phenoxy-acetic acid, melting point-186 -
    188 ° C.
    PRI me R 8, a Mixture of N-benz L-I- (2-p-hydroxyphenoxyethyl) -2-gndroxy-3-pheno-ipylphenolamide (3.22 g), t-butyl bromoacetate (1.6 g), Pcspl- potassium carbonate (1.13 g) and ka10 iodide
    15
    20
    25
    lx (0.02 g) is stirred under reflux in dry acetone (150 ml) for 72 h. The reaction mixture is cooled.
    Example 9. Sodium hydride (30 mg, 60 wt.% / By weight dispersion in mineral oil) is added to a solution of p- (2- (2-hydro: and-3-phenoxypropyl) amno-ethoxy) phenol (240 mg) in dime - tilformamide (10 m) at 0-10 ° C in an argon atmosphere. The resulting suspension is stirred for about 15 minutes until a clear solution is obtained. After that, methyl bromoacetate (0.8 ml) is added and the mixture is stirred for 18 hours under argon atmosphere. It is poured into water (50 ml) and extracted with dichloromethane (3 × x 20 ml). The extracts were washed successively with water (2x20 ml) and brine (20 ml), then they were dried (MflSO), and the solvent was evaporated.
    The residue is dissolved in methidacetate and cyxoi; hydrogen chloride is passed through the solution to stop the formation of a solid precipitate. The solid is collected and washed with methyl acetate to obtain methyl 2-p- (hydroxy-3-phenoxypropanol) amino ethoxy) phenoxyacetate hydrochloride (0.12 g), which is essentially identical to that obtained in example 1.
    Compounds according to pred. by the method they are able to regulate heat transfer in warm-blooded animals, and therefore can be used in the treatment of obesity. These compounds exhibit selective activity on Lj receptors, which are responsible for the heat-generating effect. But they are not active in relation to J5, - and receptors, thereby reducing side effects to a minimum.
    Experiments include the assessment of activity (-receptors by measuring the effect of table blood pressure, the response is determined. At a cumulative dose of the compound. A decrease in blood pressure indicates the activity of the -receptor. After the last dose of an experimental compound, 50 doses of ioprenaline (which has maximum lowering effect on blood pressure)
    163247010
    The rats (280-360 g) are lightly anesthetized with halothane and open up to the trachea in the neck and cannulae are inserted using a rigid 2.5 mm polyethylene tube,
    The spinal cord is destroyed by inserting a pointed stainless steel rod 1.5 mm in diameter (covered with nylon with the exception of 10 mm, upper end) through the eye socket and its wire along the spinal cord, the rod there and remained during the experiment.
    The rats breathed oxygen in the room air,
    Ventilation of animals in this way maintained an adequate equilibrium of blood gases and oxygen for 2-3 hours.
    A cannula was inserted into both carotid arteries. One was connected to the blood pressure sensor with a needle and a tube (inner diameter 0.5 mm; maximum length 10 cm), the other cannula with a short tube (inner diameter 0.5 mm, 1, 5-2 cm) connected with a needle and a syringe with a capacity of 1 ml, filled with heparnis
    SALT WERE BEEN TAKEN FOR THE DOGS FROM THIS
    removing the syringe from the needle, allowing the needle to fill with blood and remove a 50 ml capillary before inserting the syringe into place.
    ten
    At the beginning of the experiment, both catheters were filled with approximately 0.2 Mp of heparized salt. The compound was administered subcutaneously at a dose of 0.05 ml / 100 g of weight. A response to a cumulative dose is obtained by increasing the dose of the drug at a 10-minute interval.
    After obtaining the maximum reaction with the test compound, one large dose of isoprenaline (50 mg / kg) was given,
    Counting results.
    At least 3 animals were used for each experiment.
    Number of strokes irritated and blood pressure.
    50 mg / kg of isoprenaline causes the maximum, associated with ty-receptor, an increase in the number of heartbeats and a decrease in diastolic blood pressure. All results can be expressed as a percentage of the maximum isoprenaline,
    Test results Measurement of the number of heart beats of blood pressure in rats.
    35 ®
    5-50
    five
    At the beginning of the experiment, both catheters were filled with approximately 0.2 Mp of heparized salt. The compound was administered subcutaneously at a dose of 0.05 ml / 100 g of weight. A response to a cumulative dose is obtained by increasing the dose of the drug at a 10-minute interval.
    After obtaining the maximum reaction with the test compound, one large dose of isoprenaline (50 mg / kg) was given,
    Counting results.
    At least 3 animals were used for each experiment.
    Number of strokes irritated and blood pressure.
    50 mg / kg of isoprenaline causes the maximum, associated with ty-receptor, an increase in the number of heartbeats and a decrease in diastolic blood pressure. All results can be expressed as a percentage of the maximum isoprenaline,
    The amounts obtained were measured to determine the peak change in the number of heartbeats and diastolic blood pressure caused by successive doses of the compound and isoprenaline to represent:
    1) cumulative change in the number of heartbeats and diastolic blood pressure, i.e. deviations from the main;
    2) the grocent response to isoprenaline obtained from each animal;
    3) the percentage change from the main.
    (1) and (3) indicate the partial agonist or opposing properties of the test compounds; if the increase in the number of heartbeats and the decrease in blood pressure caused by isoprenaline is significantly lower than the expected changes, then the test compound can act as a reaction.
    2) is used to calculate the ED50 of each compound on the number of heartbeats (caused by / 3) and diastolic KROYAN pressure (caused by ftp.
    The resulting EDSO value is used to calculate the potency of each compound to the two receptors relative to eoprenaline and to determine the degree of dilution, i.e. specificity of each compound for fit and Psg of adrenoceptors.
    The effect on the number of heartbeats (L) and lyastolic blood pressure (A2) in rats with a destroyed spinal cord is given in the table.
    As can be seen from the table, the known compound has a significant effect on the fit receptors even with minimal doses, while the compounds of the proposed method do not affect
     62-receptor activity even at high doses.
    With regard to toxicity data, the compounds of the invention are classified as little toxic.
    F. formula
    The method of obtaining phenoxyacetic acid derivatives of the general formula
    R OH
    (oshgnsnnglngsngsn2b- {3-osn, g,
    where R is hydrogen or fluorine;
    Z is a COR4 group, where Kf is C-C alkoxy or hydroxyl, or their pharmacologically acceptable salts in the form of a racemate or an optically active isomer, characterized by
    so that the connection is common
    TO
    HE
    -OSNgSNS2ZHI2SNGO - @ - OH
    where R is hydrogen or fluorine;
    A - hydrogen or benzyl, reacts with methyl (butyl) -bromoacetate, followed by deprotection, in the case when A is benzyl, by catalytic hydrogenation, and, if necessary, de-esterifying the resulting product and isolating the desired product as a free acid, Aarmatologists - a scientifically acceptable salt in the form of a racemate or an optically active isomer.
    Known compound (6P 140243)
    0.05
    Blood pressure drop at 0.001 (partial agonist)
    权利要求:
    Claims (2)
    [1]
    Claim
    A method of obtaining derivatives of phenoxyacetic acid of the General formula where R is hydrogen or fluorine;
    20 Ζ - group C0R 4 , where - € <-0 $ alkoxyl or hydroxyl, or their pharmacologically acceptable salts in the form of a racemate or optically active isomer, characterized in that the compound of the general formula
    30 R A OH <^> - OCH 2 CHCH NSN g g g of CH-θ-OH wherein R - is hydrogen or fluoro;
    35 A is hydrogen or benzyl, is reacted with methyl (butyl) bromoacetate, followed by deprotection, in the case when A is benzyl, by catalytic
    40 hydrogenation, and if necessary, deesterification of the obtained product and isolation of the target product in the form of a free acid, a pharmacologically acceptable salt in the form of a racemate45 or an optically active isomer.
    Connection but to examples The number of moats of the heart ud- Diastolic blood pressure (pp 1 0.18No impact at 5 mg / kg ё 0.1834,4 8 0.27No exposure at 10 mg / kg
    5 0.40 Small exposure at 10 mg / kg
    [2]
    2 0.1 No exposure at 10 mg / kg Famousconnection (br * 140243) 0.05 Lowering blood pressure at 0.001 (partial agonist)
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    PT83085B|1989-01-30|
    US4772631A|1988-09-20|
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    法律状态:
    优先权:
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