• 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 present invention relates to quinoline derivatives of the formula <CHEM> wherein Z is an amino group or a halogen atom, <CHEM> in which R1 is a hydrogen atom, a lower alkyl or haloalkyl group, R2 is a hydrogen atom or a lower alkyl group, R3 is a lower alkyl or haloalkyl group, R4 is a hydrogen atom or a lower alkyl group, R5 and R6 are the same or different and each represents a hydrogen atom or a lower alkyl group, or R5 and R6, together with the nitrogen atom to which they are attached, form a heterocyclic ring, and n is 0 or 1, with the proviso that when Z is an amino group R is (B); and esters thereof and salts thereof and processes for preparation thereof. These compounds show excellent antbacterial activity and are useful antibacterial agents.
    公开号:SU1582986A3
    申请号:SU884355430
    申请日:1988-03-28
    公开日:1990-07-30
    发明作者:Мацумото Юн-Ити；Миямото Теруюки；Егава Хироси；Накамура Синити
    申请人:Дайниппон Фармасьютикал Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a method for producing new quinoline derivatives having high bactericidal activity.
    The aim of the invention is a method for producing new quinoline derivatives that exhibit higher activity against gram-positive and gram-negative bacteria compared with known structural analogues.
    Example 1 (reference).
    1-Cyclopropyl-5,6,7,8-tetrafluoro--1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
    1.1 A mixture of pentafluorobenzoyl acetic acid ethyl ester (25 g), ethyl formate (20 g) and acetic anhydride (23 g) was boiled for 2 hours. Reac. The mixture is evaporated under reduced pressure to dryness. The residue is dissolved in diethyl ether and introduced into
    reaction with cyclopropylamine (5.1 g) i to obtain 2-penta-ftsrbenzoyl-3-cyclopropylamino-acrylic acid ethyl ester (28 g), mp, 89 ° C,
    1.2. The compound obtained above (28 g) is dissolved in dry tetrahydrofuran and reacted at room temperature with 60% hydride.
    fluoro-1,4 dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 255-256 ° C;
    d) 7- (cis-3-trifluoroacetylamino-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    e) 7- (trans-3-amino 4-fluoromethyl-3-methyl-1-pyrrolidinyl) -1-cyclopro
     sodium (3.85 g) to give 1-cyclopropyl-5,6,7,8 tetra 1-cyclopropyl-5,6,78 ethyl, JQ-5,6,8-trifluoro-1,4-dihydro-4-oxo to obtain ethyl, 4-dihydro-4-oxoquinolin-3-cc side acid (18.4 g), so pl. 170171 ° C.
     1.3. Compound j obtained above (10 g) is hydrolyzed by boiling it in i for 30 min in a mixture of glacial acetic acid (60 ml), water (500 ml) and concentrated sulfuric acid (7 ml) to give 1-cyclopropyl- JQ 5.697, 8-tetrafluoro-1,4 - dihydro-4-oxy-quinoline-3-carboxylic acid (857g mp. 181-182 ° С.
    Example 2 (reference). 7- (3-Amino-3-methyl-I-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-di-hydro-4-hydroxyquinoline-3-carboxylic acid.
    A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.8 g), 3-amino-3-methylpyrrolidine (0 , 8 g) and acetonitrile (35 ml) are stirred for 30 minutes at 50 ° C. The precipitated crystals are separated by filtration and washed with water, dissolved in 10% aqueous ammonia, treated with activated carbon and concentrated under reduced pressure. The precipitated crystals are filtered, washed with water and dried to give 7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl 5,6,8-trifluoro--1,4-dihydro-4-oxoquinoline 3-carbo - new acid (0.81 g), mp, 280 - 282 ° С.
    thirty
    quinoline-3-carboxylic acid, so pl. 300 ° C;
    (f) 7- (cis-3-aminomethyl-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    g) 7- (trans-3-aminomethyl-4-methyl--1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4 dihydro-4-oxoquinoline-3-carboxylic acid;
    (B) 7 -, (trans-3-aminomethyl-4-ethyl-1-β-pyrrolidinyl) -1-cyclopropyl-5,6,8-TRIFTO-1, 4-DIHYDRO-4-OXOHINOLIN-3-carboxylic acid;
    i) 7- (cis-3-acetylaminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;
    j) 7 (cis-3-trifluoroacetyl ethylaminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-5, 6,8-difluoro-1,4-dihydro-1-oxoquinoline-3-carboxylic acid
    Example 4. 5-amino-7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinolin-3 - carboxylic acid and its salts,
    4.1. A mixture of 7- (3-amino-3 methyl-1-β-pyrrolidinyl) -1-cyclopropyl-5,6,8-40-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.14 d) and an aqueous ammonia solution (100 ml) is heated at 100 ° C for 48 hours in a sealed tube. The reaction mixture is evaporated to dryness under reduced pressure and water is added to the residue. The precipitated crystals are filtered and washed with acetonitrile. The crystals are then suspended in water (30 ml) and dissolved by adding a 10% aqueous solution of acetic acid. The resulting solution is treated with activated carbon and the addition of 10% aqueous ammonia (the pH of the solution is adjusted to
    35
    45
    Example 3 {reference).
    Using the procedure of Example 2, the following compounds are obtained:
    a) 7- (3-amino-3-ethyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    4.1. A mixture of 7- (3-amino-3 methyl-1-β-pyrrolidinyl) -1-cyclopropyl-5,6,8-40-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.14 d) and an aqueous ammonia solution (100 ml) is heated at 100 ° C for 48 hours in a sealed tube. The reaction mixture is evaporated to dryness under reduced pressure and water is added to the residue .. The precipitated crystals are filtered and washed with acetonitrile. The crystals are then suspended in water (30 ml) and dissolved by adding a 10% aqueous solution of acetic acid. The resulting solution is treated with activated carbon and the addition of 10% aqueous ammonia (the pH of the solution is adjusted to
    50
    b) 7- (trans-3-methoxycarbonylamino-4-ethyl-1-pyrrolidinyl) -1-cyclopro-55 I ° Precipitated crystals of the filter-5,6 „8-trifluoro-1,4-dihydro-4-oxo - quin olin-3-ap ar lateral acid;
    c) 7- (trans-3-amino-4-methyl-1 rolidinyl) -1-cyclopropyl-5 „6,8-tritration, washed with water, then with ethanol and dried. 5-amino-7- (3-amino-3-methyl-1-pyrrolidinyl) -1 -1 cyclopropyl-6,8-difluoro-1,4-dihydrO is obtained
    Q
    0
    quinoline-3-carboxylic acid, so pl. 300 ° C;
    (f) 7- (cis-3-aminomethyl-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;
    g) 7- (trans-3-aminomethyl-4-methyl--1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4 dihydro-4-oxoquinoline-3-carboxylic acid;
    (B) 7 -, (trans-3-aminomethyl-4-ethyl-1-β-pyrrolidinyl) -1-cyclopropyl-5,6,8-TRIFTO-1, 4-DIHYDRO-4-OXOHINOLIN-3-carboxylic acid;
    i) 7- (cis-3-acetylaminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ;
    j) 7 (cis-3-trifluoroacetyl ethylaminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-5, 6,8-difluoro-1,4-dihydro-1-oxoquinoline-3-carboxylic acid
    Example 4. 5-amino-7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinolin-3 - carboxylic acid and its salts,
    4.1. A mixture of 7- (3-amino-3 methyl-1-β-pyrrolidinyl) -1-cyclopropyl-5,6,8-0-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.14 d) and an aqueous ammonia solution (100 ml) is heated at 100 ° C for 48 hours in a sealed tube. The reaction mixture is evaporated to dryness under reduced pressure and water is added to the residue. The precipitated crystals are filtered and washed with acetonitrile. The crystals are then suspended in water (30 ml) and dissolved by adding a 10% aqueous solution of acetic acid. The resulting solution is treated with activated carbon and the addition of 10% aqueous ammonia (the pH of the solution is adjusted to
    five
    five
    0
    I ° Precipitated crystals filtered
    It is washed, washed with water, then with ethanol and dried. 5-amino-7- (3-amino-3-methyl-1-pyrrolidinyl) -1 -1 cyclopropyl-6,8-difluoro-1,4-dihydrO is obtained
    -4-oxoquinoline-3-carboxylic acid (480 mg), so pl. 271-273 ° С (with decomposition).
    4.2. The resulting compound (200 mg) is dissolved in 20% hydrochloric acid (5 ml) and the resulting solution is concentrated to dryness under reduced pressure. Ethanol was added to the residue and the resulting crystals were filtered. Recrystallization from a mixture of water - ethanol gives 5-amino-7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-ca hydrochloride. - sohinolin-3-carboxylic acid
    (145 mg), mp, 293-297 ° C (with decomposition).
    4.3. Salt in the usual way
    with acetic acid (mp. 272-274 ° C, with decomposition) and salt with methanesulfonic acid (mp. 300 ° C).
    Example 5. 5-amino-7- (3-amino-3-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro 4-oxoquinolin-3- carboxylic acid.
    According to the procedure of Example 4, using 7- (3-amino-3-ethyl-1-pyrrolidinyl) -1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic an acid (1.19 g) for reacting ammonia in ethanol at 48 hours,
    100 ° C for
    the title compound is obtained (580 mg), mp. 205-206 ° C.
    Example 6. 5-Amino-7- (trans-3-amino-4-e-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxoquinoline 3-carboxylic acid.
    6.1. 7- (trans-3 Methoxycarbonylamino-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-5, 6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1, 36 g) according to the method of example 4 is subjected to interaction with ammonia in dimethylforma2Q with hydrochloric acid, after which the addition of concentrated aqueous ammonia is made slightly alkaline. The mixture is concentrated under reduced pressure and the precipitated crystals are filtered, washed with water and dried. Recrystallization from dimethylformamide gives 5-amino-1-cyclopropyl-7- (cis-3-amino-4-fluoromethyl-1-pyrrolidinyl) -6,8-difluoro-1, 4-dihydro-4-oxoquinoline-3- carboxylic acid (310 mg), so pl. 248-249 ° C
    40
    amide at 130 ° C for 12 hours in a sealed tube to obtain 5-amino-Gp and m-8. The following compounds were obtained by the method of 1-meter 4: a) 5-amino-7- (trans-3-amino -4-fluoro .-,, o45 methyl-3-methyl-1-pyrrolidinyl) -1-cyc-1-cyclopropyl-7- (trans-3-methoxycar-0. ,,
    , lopropil-o, o-dyltor-1.4-DIHIDRO-4-OKbonylamino-4-e-1-pyrrolidinyl) - m Mi
    -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (620 mg), mp,
    231-232 ° C
    50 methyl-1-pyrrolidinyl) -1-cyclopropylsoquinoline-3-carboxylic acid, m.p. 299-301 ° C;
    B) 5-amino-7- (cis-3-aminomethyl-4f
    6.2. A mixture of the carboxylic acid obtained above (600 mg), a 20% aqueous solution of potassium hydroxide (2 ml) and methanol (4 ml) was boiled for 10 hours, then concentrated under reduced pressure. The residue is diluted with water and the pH is adjusted to 8 with acetic acid. After cooling, the precipitated crystals are filtered, 55
    -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 221-223 ° C (hydrochloride, mp 268-271 ° C (with decomposition);
    c) 5-amino-7- (trans-3-aminomethyl-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, so pl. 223-225 ° C;
    0
    therefore washed with water and ethanol and after drying, 5-amino-1-cycloprolyl-7- (trans-3-amino-4-ethyl-1-pyrrolidinyl) -6,8-difluoro -1,4-dihydro- 4-oxoquinoline-3-carboxylic acid (490 mg), so pl. 195 - 196 ° C.
    Example 7. 5-amino-7- (cis-3-amino-4-fluoromethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3 - carboxylic acid.
    7.1. According to the method of example 4 7- (cis-3-trifluoroacetamido-4-fluoromethyl-15-pyrrolidinyl) -cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.49 g) is used in the reaction with ammonia in acetonitrile at 60 ° C for 48 hours in a sealed tube to obtain 5-amino-7- - (cis-3-trifluoroacetylamino-4-fluoromethyl-1 -pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-DIHIDRO-4-OXOHINOLIN-3-carboxylic acid (520 mg).
    5 7.2. A mixture of the carboxylic acid obtained above (500 mg) and 10% aqueous sodium hydroxide (5 ml) is boiled in a boiling water bath. The resulting mixture is acidified with 10% aqueous acetic acid, followed by addition of concentrated aqueous ammonia, slightly alkaline. The mixture is concentrated under reduced pressure and the precipitated crystals are filtered, washed with water and dried. By recrystallization from dimethylformamide, 5-amino-1-cyclopropyl-7- (cis-3-amino-4-fluoromethyl-1-pyrrolidinyl) -6,8-difluoro-1, 4-dihydro-4-oxoquinoline-3-car is obtained - boom acid (310 mg), so pl. 248-249 ° C
    0
        m Mi
    Sohinolin-3-carboxylic acid, so pl. 299-301 ° C;
    B) 5-amino-7- (cis-3-aminomethyl-4
    -6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 221-223 ° C (hydrochloride, mp 268-271 ° C (with decomposition);
    c) 5-amino-7- (trans-3-aminomethyl-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6, 8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, so pl. 223-225 ° C;
    715
    d) 5-amino-7- (trans-3-aminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4 dihydro-4-oxoha nolin-3-carboxylic acid m.p. 121-122 ° C, in the form of hydrochloride so pl. 183-184 ° C;
    e) 5-amino-7- (cis-3-acetylaminome tyl-4-ethyl-1-pyrrolidinyl) 1-cyclopropyl-6,8-difluoro-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrolyzed as described in Example 7.2, 5 amino-7- (cis-3-aminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-DIGIDRO-4-OXOHSR is obtained -ULY-3-carboxylic acid, so pl. 220 - 222 ° С (with decomposition);
    f) 5-amino-7- (cis-3-trifluoroacetylethylaminomethyl-4 ethyl-1-pyrrolidinyl -1-cyclopropyl-b, 8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, t mp 145-146 ° C;
    According to the procedure of Example 7.2, 5-amino-7- (cis-3 ethylaminomethyl-4-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-7- 3-carboxylic acid, so pl. 171-172 ° C.
    In tab. Figure 1 shows the compounds of formula I obtained in Examples 4-8.


    The chemotherapeutic effect of the compounds obtained by the proposed method is illustrated by examples 9-11.
    ;,
    The following compounds were used: Compound 1 - 5-amino-7- (3 amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro 4-oxoquinoline 3-carboxylic acid.
    Compound 2 - 5-amino-7- (3-amino-3-ethyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinolin-3- carboxylic acid.
    Compound 3 - 5-amino-7- (trans-3-amino-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-ox-co-quinoline- 3-carboxylic acid.
    Compound 4 - 5-amino-7- (cis-3-aminomethyl-4-methyl-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3 hydrochloride -carboxylic acid.
    Compound A - 5-amino-1-ethyl-6,8-difluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid slot
    soon
    C2H5
    Compound B - 1-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride
    soon
    HC1-HN
    Example 9. In vitro bactericidal action is illustrated in Table. 2, listed in Table. 2 values correspond to the minimum inhibitory concentration (MIC) (in terms of free base). The minimum inhibitory concentration was determined by the method of double dilution of agar (using Mueller-Hinton agar). One loop of the test organism culture grown during the day in Mueller-Hinton broth was applied to the drug-containing layers in 10 ml of agar in Petri dishes. The bacterial inoculum contains about 10 colonizing units. Bacterial growth was observed after 20 h incubation at 37 ° C. MIC is defined as the lowest concentration of drug that prevents visible growth of bacteria.
    As can be seen from the data table. 2, compounds 1-4 show a very high bactericidal activity against gram-positive and gram-negative bacteria, a better in vitro effect against gram-positive and gram-negative bacteria compared with compound A.
    Example 10. The effect of in vitro against common infections in mice (Table 3).
    Each compound is dissolved in de-ionized water. Each solution is administered orally to mice infected with the test organism under the conditions listed below and, based on the analysis of the samples, calculate the value of the average effective dose (ED $ o).
    It is resulted in tab. 3 digits correspond to 3 / 7fo (mg / kg) in terms of free base.
    Experimental conditions.
    Mice - male individuals (ddy-S) weighing about 20 g.
    Infection.
    Staphylococcus aureus 50774. Immunosuppression of 5 x 10 cells per mouse suspended in saline.
    Streptococcus pyogenes A65. Intraperitoneally infecting 3 x 10 cells per mouse suspended in heart brain broth for infusion.
    Pseudoraonas aeruginosa 12. Intraperitoneally infecting 5 x 10 3 cells per mouse suspended in tryptosoic broth with 4% mucin.
    Medication twice: immediately after infection and after 6 hours,
    Observations for 14 days for Staphylococcus aureus 50774 and for 7 days for other organisms.
    As can be seen from the table. 3, compound 1 has a stronger therapeutic effect on common infections, challenges
    Gram-positive and gram-negative bacteria are compared with compounds A and B.
    Example 11 (acute toxicity).
    Male mice (ddy) are orally administered solutions containing each compound of the proposed method in different concentrations, in a dosage of 0.1 ml per 10 g of body weight. After 7 days, the number of dead mice is counted and, in accordance with the method of Heyrens-Kerber, the value of the average lethal dose (LD5 &amp; mg / kg) is calculated (see Table 4).
    As can be seen from the above results, compounds 1, 2, 3 (obtained by the proposed method) show low toxicity when administered orally.
    Studies have shown that the proposed compounds have a strong therapeutic effect on experimental (mental infections caused by gram
    positive and gram negative. bacteria have low toxicity, as well as good adsorbability and metabolic resistance, low cytotoxicity, and when administered parenterally, cause low local irritation.
    权利要求:
    Claims (1)
    [1]
    Thus, the compounds obtained by the proposed method are applicable as bactericidal agents for oral administration or administration by injection, the claims, the method of obtaining quinoline derivative of the general formula
    A-NHO
    F
    20
    i
    25
    where a is hydrogen;
    R, is a group of the formula
    Cs
    thirty
    R4HN- (CH2) n
     J
    five
    0
    where R2 is lower alkyl or haloalkyl;
    R3 is hydrogen or lower alkyl;
    R is hydrogen or lower alkyl;
    n 0 or 1,
    or a pharmaceutically acceptable ester thereof, or pharmaceutically acceptable salts of said derivative or ester thereof, characterized in that it is a compound of formula
    X o
    45
    where X is halogen;
    Y is hydrogen or lower alkyl;
    R - has the indicated values, is reacted with ammonia, followed, if necessary, by hydrolysis of the ester to carboxylic acid, to release the desired product in free form or as a pharmaceutically acceptable salt.
    X 0
    1582986
    by N F
    A-NHO COOY A - 1Sh, F -COOY
    --R,
     2 Ta
    OH3 NHZ
    C2H5 JIX W2
    HA
    C2HS
    CH3OCO: NH
    FCH2 "
    CFgCONH
    Nft
    FCH2
    CH3
    ™ 2
    CH3,
    n
    N
    Mr.
    TH
    jm2CH2 С И5ч
    J-
    SNC
    2L2
    C2H5
    KСН3СОШ1СНГ
    Oy
     2 Table
    100
    48
    EtOH
    100
    48
    DMF
    130
    12
    CH3CN
    60
    48
    H00
    100
    48
    H20
    100
    48
    H20
    100
    48
    H20
    100
    48
    H20
    100
    48
    13
    Compound
    1 2 3
    1582986
    14 Continued table. I
    Table 3
    DD mg / kg
    2000 2000 2000
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    NO871727D0|1987-04-24|
    SU1588281A3|1990-08-23|
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    FI871788A0|1987-04-23|
    AU7190987A|1987-10-29|
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    法律状态:
    优先权:
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    JP9754386|1986-04-25|
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