• 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:
    Indole derivatives characterized by having a 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid nucleus bearing a substituent in position 1 and 4. The nucleus may be optionally substituted at positions 5, 6, 7 and 8. The derivatives are useful anti-inflammatory and analgesic agents and methods for their preparation and use are also disclosed.
    公开号:SU1531856A3
    申请号:SU874202082
    申请日:1987-02-27
    公开日:1989-12-23
    发明作者:Ховард Кац Алан；Александр Демерсон Кристофер；Джордж Хамбер Лесли
    申请人:Американ Хоум Продактс Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    one
    (21) 4202082 / 7.3-04
    (22) 02.27.87
    (31) 838510
    (32) 03/11/86
    (33) US
    (46) 12/23/89. Bup. Number 47
    (71) American Home Products Corporation (US)
    (72) Alan Howard Katz, Christopher Alexander Demerson and Leslie George Humber (SA)
    (53) 547.814.07 (088.8)
    (56) Patent SICHA No. 3939178,
    cl. 260-3..28, published 1976.
    Demerson S.A. et al. Activities of prodolic acid and related 1,3,4,9- -tetrahydropyrano 3,4-b indole-1 -alkonic Acids - Jour, of Medicinal Chem., 1975, v. 18, No. 2, p. 189.
    (54) METHOD FOR OBTAINING MEASURED 1,3,4,9-TETRAGALROPYRANO 3,4-S3 INDPL-1-ACETIC ACIDS OR THEIR PHARMACEUTICALLY ACCEPTABLE DILC
    (57) The invention relates to heterocyclic substances and, in particular, the preparation of substituted 1,3,4,9-tetrahydropyrano 3, 4-b indole-1-acetic acids or their pharmaceutically acceptable salts of the total f-ly
    .
    CH-CHj-0-CR, -CH {-C (ObQH CHRj CR -CHj
    where R is —C, —C — alkyl; R,
     3 and
    or rj +
    Rj -SI-CH-CH-CH- (included in
    the composition of the benzene ring), R and RJ - And, C1, C, -C-alkyl, has anti-inflammatory and analgesic properties that can be used in medicine. The purpose of the invention is the creation of new, more active substances of the specified class. Synthesis is carried out by condensation of the corresponding isatin with the ester of enolate of CMM CR -aiy-Cn-CW-fy-Cn in the presence of lithiumsisopropylamine at a temperature from -78 ° P to room temperature in an organic rasporitel. The resulting compound is reduced without isolation using lithium aluminum hydride, followed by treatment with 3-methoxy-2-C, -C-alkeneic acid methyl ester and hydrolysis of the resulting ester. The desired product in the form of a base or salt has a higher activity without the appearance of side effects. 3 tab.
    (L
    ate
    with
    00
    ate
    ABOUT)
    This invention relates to a process for the preparation of novel compounds substituted with 1, 3,4, 9-tetrahydropyrano, 4-bJ-indol-1-yl cyclic acids or their pharmaceutically acceptable salts, which have anti-inflammatory properties.
    and analgesic effect and can be used in medicine.
    The purpose of the invention is to obtain a new pass: 1 water 1, 3,4, 9-tetragilum-3,4-b of indol, possess higher
    cm
    Coy anti-inflammatory and analgesic activity.
    Example 1. 1-Ethyl-1,3,4,9- -tetrahydro-; (Phenylmethyl) -pyrano-3, 4-b indole-1-acetic acid (isomer A).
    Step 1. Preparation of methyl 3-phenylpropanoic acid ester.
    A mixture of 118.2 g (778 mmol) of 3-phenylpropionic acid, 5.9 g of sulfuric acid and 100 ml of methanol is refluxed for 8 hours. Thin layer chromatography shows no starting material. The reaction mass is evaporated in vacuo. The residue is dissolved in 200 ml of sulfuric ether, washed with sodium bicarbonate (100 ml), sugate over magnesium sulfate, filtered and concentrated to give 124, A g (96.3%) of the ester as a tan oil.
    Zh-spectrum (undiluted), cm: 3020, 2940, 1730.
    Step 2. Preparation of - (Phenylmethyl) -1H-indole-ethanol.
    To a solution of lithium diisopropylamine in tetrahydrofuran / cyclohexane (2.2 mol, 13fi, 4 ml, 300 mmol) cooled to -78 ° C, under a nitrogen atmosphere, is added a solution of 44.6 g (272 mmol) of methyl ester 3-phenyl- propionic acid (prepared in stage 1) in 150 ml of dry tetrahydrofuran. The mixture is stirred for 30 minutes. A solution of 20.0 g (138 mmol) and zatin in 300 ml of tetrahydrofuran is added dropwise, and the mixture is kept at room temperature without cooling for 3 hours. The mixture is quenched with 500 ml of saturated ammonium chloride solution and the layers are separated. The aqueous layer is washed ether (2 x 150 ml). The combined organic extracts are dried over magnesium sulphate, filtered and concentrated to give 71.8 g of a brown oil. The methyl ester of 3-phenylpropionic acid (95 ° C, 1.5 mm) was removed by distillation, and the residue (50.6 g) was dissolved in 300m of dry tetrahydrofuran and meticulously added to the lithium aluminum hydride cooled to O О. (18.56 g, 489 mmol in 225 ml of tetrahydrofuran. The mixture spontaneously heats up to room temperature and then it is kept at reflux for 3 hours. The mixture is cooled,
    0
    0
    five
    -one
    ice bath and 250 ml of water are slowly added. Salt is filtered off and washed with sulfuric ether (three times, 400 ml). The organic layer is separated from the filtrate and dried over magnesium sulfate, filtered and concentrated to give 35.5 g of a red-brown oil. This material is purified by chromium ttographically on sipikegel, using a mixture of 30% ethyl acetate and hexane as eluate. The result is tryptophol in the form of a brown oil (16.02 g, 46.9%). H NMR Spectrum
    5 (in CAClj): J 8.08 (singlet, 1 H); 7.65 (doublet, 1H, J 7.5 Hz); 7.36 (doublet, 1 H, J 7.5 Hz); 7.18 (multiplet, 7H); 7.01 (doublet, 1H, J 2.0 Hz); 3.84 (doublet, 2H ,, 0 Hz);
    0 3.43 (double triplet, 1H ,, 5 Hz); 3.10 (doublet, 2H, J 8.0 Hz), 1.79 (singlet, 1H).
    IR spectrum (undiluted), cm 3420, 3020.
    5 Stage 3. Preparation of 1-ethyl-1,3,4,9-tetra hydro-4- - (phenylmethyl) -pyrano- (3,4-bnidol-1-acetic acid) methyl ester.
    A solution of 15.97 g (63.6 mmol) A - (phenylmethyl) -1H-indol-ethanol (from stage 2}, 9.95 g (76 MMOjfb) methyl propionyl acetate and 1.60 g paratoluenesulfonic acid in 500 ml of benzene, and water is collected in
    5 receiver Lina and Stark. The reaction mixture is cooled to room temperature and washed with 200 ml of 5% aqueous sodium bicarbonate solution, 200 ml of water, dried over magnesium sulfate, filtered and concentrated to give 21.37 g of crude product. The diastereoisomers are chromatographed over silica gel using 13% ethyl acetate as the eluting solvent, the rest being g-hexane. Isomer L (above Rf, 2.26 g, 9.8%) and isomer B (below Rf 2.23 g, 9.8%) are obtained as yellow oils.
    0 P1zomer A. H-NMR (SLS1z): & 9.17 (singlet, 1H); 7.42-7.00 (multi-pin, 9H); 3.80 (m, 2H); 3.72 (singlet, ZN); 3.20 (m, 2H); 3.01 (doublet, 1H, L 17 Hz);
    5 2.80 (dugshet, 1H, J 17 Hz); 2.85 (multiplet, W) 2.05 (quartet, 2H, L 7.5 Hz); 0.90 (triplet, 3N, J 7.5 Hz).
    515318566
    IR (KBr) cm-: 3420, 1725. H-NMR spectrum (SDTS) 5 8.70
    Isomer B. N-NMR (SDS1) 8.88 (singlet, 1H); 7.43-7.03 (multiplet
    (singlet, 1H) j 7.38-7.00 (multiplet, 9H) 3.87 (doublet, 2H, 7 2.5 Hz) -,
    9H), 3.84 (multiplet, 2H); 3.70
    (singlet, ZN) 3.04 (doublet, 1H, 3 17.5 PO; 2.78 (doublet, 1H, 3 17.5 Hz); 3.15 (multiplet, 2H), 2.82 (multiplet, 1H ); 2.20 (quartet, 2H), J 7.5 Hz); 0.82 (triplet, 3N, J 7.5 Hz).
    IR spectrum (KBG) 3440, 1725.
    Step 4. Preparation of 1-ethyl-1,3,4, - G9-tetrahydro-4- (phenylmethyl) -pyrano-3, 4-bJindole-1-acetic acid.
    3.0 g (8.25 mmol) of isomer A of methyl 1-ethyl-4- (phenylmethyl) 3, 23 (multiplet, 2H) is dissolved in 100 ml of ethanol; 2.97 (luplet, 2H, 3 3.0 Hz); 2.85 (m, 1H); 2.04 (multiplet, 2H); 0.93 (triplet, 3N, 3 7.5 Hz). IR spectrum (KVg) cm-: 3380; 1740. 0 Found,% carbon 75.96; hydrogen 6.43i nitrogen 3.99.
    C ,,,
    Calculated,%: carbon 75.62; hydrogen 6.63; nitrogen 4.01.
    15 Preparation of sodium salt of 1-ethyl-1,3-4,9-tetrahydro-4- (phenylmethyl) -pyrano-3,4-b-indole-1-acetic acid (isomer A).
    To a stirred solution of 0.965 g
    -1, 3,4,9-tetrahydropyrano 3,4, -h in-20 (2.76 mmol) of 1-ethyl-1,3,4,9-tetradol-1-cyctic acid (from step 3) and added 100 ml of 10% aqueous sodium hydroxide are added. The mixture was heated under reflux for 2 hours and then concentrated to a cloudy aqueous solution. Concentrated hydrochloric acid is added until an acidic medium is obtained. It is then washed with ether (twice with 100 ml), and the combined ether extracts are dried over magnesium sulfate, filtered and concentrated to obtain 2.8 g of an off-white foam. The resulting material is subjected to recrystallization from benzene petroleum ether, obtaining 2.30 g (80%) of pure acid as a white solid with a melting point of 144 - 146 ° C.
    hydro-4- (phenylmethyl) -pyrano 3,4-b) - indole-1-acetic acid in 50 ml of methanol was added aqueous caustic soda (2.6 ml of 1N solution). pH adjusted to
    25 to 7.75 the introduction of portions of 1-ethyl-1, 3,4,9-tetrahydro-4- (phenylmethyl) -pyrano p, 4-bj indol-1-acetic acid. The resulting solution is evaporated to dryness and then dissolved in benzene and two times 3Q dy are evaporated. The residue is dissolved in ethyl acetate (8 ml), stirred and 30 ml of petroleum ether are added slowly with a boiling point of 30-60 ° C. The precipitate is stirred for 1 h, filtered, washed with petroleum ether and dried to give 1.0 (98%) of the salt as a white solid with a melting point of 18035.
    190 C (with decomposition).
    NM (ZhSO-d j): Proton, TypeChim. shift (s)
    CH-s0,84 (triplet, L 8 Hz)
    CHi2.0 (2g J 8 Hz)
    ZS11, CH2.2-3.9 (multiplet)
    3 2 7 9 aromatic. 6.7-7.2 (multiplet)
    Calculated,%: carbon 71,14; hydrogen 5.97; nitrogen 3.77.
    Found,%: carbon 70.41, hydrogen 6.03: nitrogen 3.64.
    In a similar way, the compounds shown in Table 2 are obtained one.
    Compounds of the general formula have been tested for anti-inflammatory activity.
    The beneficial anti-inflammatory activity of pyranindoleacetic acid derivatives of the general formula was established by standard pharmacology3, 23 (multiplet, 2H); 2.97 (luplet, 2H, 3 3.0 Hz); 2.85 (m, 1H); 2.04 (multiplet, 2H); 0.93 (triplet, 3N, 3 7.5 Hz). IR spectrum (KVg) cm-: 3380; 1740. Found,%: carbon 75.96; hydrogen 6.43i nitrogen 3.99.
    C ,,,
    Calculated,%: carbon 75.62; hydrogen 6.63; nitrogen 4.01.
    Preparation of sodium salt of 1-ethyl-1,3-4,9-tetrahydro-4- (phenylmethyl) -pyrano-3,4-b-indole-1-acetic acid (isomer A).
    To a stirred solution of 0.965 g
    (2.76 mmol) 1-ethyl-1,3,4,9-tetra20 (2.76 mmol) 1-ethyl-1,3,4,9-tetrahydro-4- (phenylmethyl) pyrano 3,4- b) - indole-1-acetic acid in 50 ml of methanol was added aqueous sodium hydroxide (2.6 ml of 1N solution). pH adjusted to
    25 to 7.75 the introduction of portions of 1-ethyl-1, 3,4,9-tetrahydro-4- (phenylmethyl) -pyrano p, 4-bj indol-1-acetic acid. The resulting solution is evaporated to dryness and then dissolved in benzene and two times 3Q dy are evaporated. The residue is dissolved in ethyl acetate (8 ml), stirred and 30 ml of petroleum ether are added slowly with a boiling point of 30-60 ° C. The precipitate is stirred for 1 h, filtered, washed with petroleum ether and dried to give 1.0 (98%) of the salt as a white solid with a melting point of 18035.
    for example, in the so-called prevention of stimulated edema.
    The purpose of the test in rats is 0 to determine the ability of the tested drugs to have a strong anti-inflammatory effect. This test is a primary test for anti-inflammatory drugs.
    Individuals. Experiments were performed on male Dawley rats (weighing 180 - 200 g). The animals had free access to water, but they were deprived of pipo 18 hours before the experiment.
    five
    A full Lanenda stimulator was prepared by suspension of 5 mg of killed and dried Mycobacterium butyricum (Dif-c) in 1 ml of mineral oil. The test compounds were dissolved or suspended in distilled water with 0.5% Tween 80, as determined by their solubility. For the initial screening, all drugs were injected into the stomach with a probe at a dosage of 25 mg / kg, orally in a volume of 0.5 ml / 100 g of animal weight, using a group of 10 animals.
    The test method.
    The technique is as described by Wax. A group of rats was injected intradermally into the left hind paw with 0.1 ml of Freund's full stimulator. The test compound or vehicle was administered immediately before the introduction of the stimulator, 24 and 48 hours after the stimulator (days 0, 1, and 2). The volume of the injected paw was measured before the injection of the stimulator and 24 hours after the last administration of the drug (day 3), using a Buchs Electronics pulpometer. The difference in hind paw volume on day zero and on day 3 corresponds to the volume of edema. Etodolac (25 mg / kg, orally) was administered as a positive regulator.
    Presentation of the results.
    The average volume of edema (expressed in ml EM) was calculated for each group, and the percentage of drug-related protection was determined:
    % protection
    (c - t) -100
    where c is the average volume of edema in carriers of treated animals (0.5% Tween 80 in distilled water) of the control group;
    t is the average volume of edema in animals treated with the drug. Analgesic activity. Additional tests have been carried out to determine the scope of the proposed compounds. Jitching is referred to: Drug effects on pain caused by phenylbenzoquinone in mice.
    The purpose of the test in mice is to determine the ability of the tested drugs to suppress
    nociceptive (pain) reaction caused by chemical irritant. Such a test is a primary test of peripheral and central action analgesics.
    Individuals. The experiments were carried out on white mice-males (weighing 15-25 g). The animals were locked up 18h before the test,
    Q but they had free access to water.
    The drugs were dissolved or suspended, as determined by their solubility, in distilled water with 0.5% Tween 80. The drugs were introduced through a stomach tube in a volume of 5 ml / kg. , P / 1I of the initial screening, all drugs were administered orally at a dose of 25 mg / kg. The studies were conducted on a group of 10 singular.
    0 Methodology experiment. A modification of the Sigmund method was applied.
    Groups of five Mhuiieii were injected with a test compound or vehicle. After (SO min intraperitoneal animals5 but 0.3 ml / 20 g of animal weight was injected with a 0.02% solution of phenylbenzoquinone (PBO; 2-phenyl-1,4-benzoquinone), and they were placed in separate observation boxes. Each Miijiun was counted
    0 number of convulsions or abdominal involuntary contractions over the next 15 minutes. The experiment was repeated with another group of five mice, and the average number of convulsions was calculated for M1L1 pg in a group of 10 Mbmiefi.
    Presentation of the results. We compared the group of animals that were injected with the animals with animals, com. the role of the group, which was introduced media, and calculated the percentage of protection caused by the drug:
    five
    (с - t) 100 /, tak1cytes
    0
    five
    where c is the average number of convulsions in
    control group; t is the average number of convulsions in
    experiment group. An additional test to determine the field of application of the proposed compounds has the name: Rendell-Selitto test in rats.
    The goal of the experiment is to determine the efficacy of central and peripheral drugs and the suppression of peaKiniH rats on oii rn) inflammation of inflammatory papm. Individuals. Ex915
    Periments were performed on Dawley rats (weighing 180–200 g). Animals were locked at night before the administration of the drug.
    A complete Freund stimulator (FCA) was prepared, suspending 5 mg of dry killed Mycobacterium Butyriaem (Difco) in 1 ml of mineral oil. The test compounds were dissolved or suspended in distilled water with 0.5% Tween 80. Drugs were injected into the stomach through a tube in a volume of 0.5 ml / 100 g animal, using groups of ten animals.
    The technique. The group included 10 animals. The technique is similar to that described by Rendel and Selitto. The apparatus that is used to create pressure on the paw (bolemer for rat legs, Hugo Basile, Comeri, Italy) has been modified in accordance with the development of Gifelo.
    A device is a device that generates a force that varies at a constant speed. The force is constantly recorded by the carriage, the motor (along the linear scale, and measured in grams. The inflammatory reaction was caused in the rats in the rear left leg by intradermal injection of 0.1 ml Freund's stimulator. The test compound and vehicle were injected 24 hours after the injection stimulator, 1 h later, the pain threshold for the inflamed paw was determined in the treated group and in the control group of animals.
    Data presentation and activity criteria.
    Each animal that had a score 1.5 times higher than the average for the control group was considered to be sensitive to treatment (the analgesic property manifests itself). In each group, the number of animals for which the effect of the analgesic was found was determined.
    Then, KDj (the dose that causes the analgesic effect in 50% of the animals) was determined at at least three dosages, CJIedy using this method of Litchfield and Wilcoxon.
    As a result of the tests described, using the compounds of the general formula as therapeutic preparations, the following data were obtained, which are presented in Table. 2
    185610
    Test data of known compounds are presented in table. 3
    The percentage of inhibition shown by the pyranoindoles was obtained at doses of 100 mg / kg% inhibition of the inventive compounds of the invention at lower doses of 25 mg / kg and below. Therefore, as can be seen from
    1Q data table. 3, the compounds of the general formula exhibit a significantly higher activity compared with the known compounds.
    No side effects when
    The use of compounds of the general formula was established during standard acute toxicity experiments carried out in accordance with the Turner method and by prolonged administration.
    2Q of these drugs are warm-blooded animals.
    When compounds of the general formula are used as analgesics or anti-inflammatory drugs for treating warm-blooded animals, these
    the compounds are administered orally as individual substances or in dosage forms, for example, in the form of capsules or tablets, together with pharmaceutically acceptable excipients 30
    35
    40
    45
    50
    55
    such as starch, milk sugar, etc., or these compounds are administered orally in the form of a solution in an acceptable carrier such as vegetable oil or water. The proposed compounds may be administered orally in the form of a long-term release dosage, or applied to the skin in the form of ointments or patches. They are suitable for use in the form of candles.
    The dosages of the compounds according to the general formula depend on the nature of the specific compound and the form of treatment. Moreover, they depend on the particular patient. Typically, these compounds are administered in an amount that is effective and at the same time does not have any undesirable side effects. Typically, these effective anti-inflammatory and analgesic concentration levels are achieved within the therapeutic range from 1.0 µg to 300 µg / kg per day, with a range of 1.0-100 µg / kg-day being preferred. The preferred range of anti-respiratory doses is limited to 1-20 mg / kg intradermally. Pre ; pochtnte. This range of benzine; P1Va1O | Cich Lot is within 1–4 mg / kg intradermally.
    权利要求:
    Claims (1)
    [1]
    The compounds may be administered in combination with non-steroidal anti-inflammatory drugs, such as acetaminophen, ibuprophin and aspirin, and / or narcotic analgesics, such as codeine, oxycodone and morphine, together with conventional doses of caffeine. When used with other drugs, the dosage of the compounds is changed accordingly. The compounds also have an anti-fever effect. Invention Formula
    The method of obtaining substituted 1,3,4,9-tetrahydropyrano (3,4-b) -indo-1-acetic acids of the general formula
    Liao
    Yats RS
    I RI CH-COOH
    n
    R and R J together ob-ZO
    - lower C, -C-alkyl; hydrogen or
    razryt group-CH-CH-CH-CH-, part of the benzene core;
    hydrogen or halogen, -alkyl, 35
    pharmaceutically acceptable, equivalent to, still isotin formulas
      40
    RS N
    H
    where they have the indicated meanings, they are condensed with an enolate or carboxylic acid ester of the formula
    i,
    SN-C-OCHN
    where R2 and R5 have the indicated meanings, in the presence of lithium diisopropylamine at a temperature of from (-78) ° C to room temperature in the medium of an organic solvent, the resulting compound of the formula
    -Kz
    L;
    BUT
    sh
    CH-CO CHZ
    he
    the specified values restore hydro
    reed, such as LiAlH, obtained tryptophol formula
    where they have the indicated meanings, they are reacted with methyl 3-methoxy-2-alkeneic acid methyl ester of the formula
    ABOUT
    D
    RI-YNC-OCH
    OSSN
    where R is as defined, the resulting methyl ester of the formula
    / Yaz R, SnLv,
    Ooo
     VCH.-COOCH i
    50 where R, R5 have the indicated meanings, is subjected to hydrolysis and the desired product is isolated in free form or in the form of a pharmaceutically acceptable salt.
     31531856 l-i
    Table 1
    Substituted 1,3,4,9-tetrahydropyrano 3,4-b indole-acetic acid
    Table 2
    Substituted 1,3,4,9-tetrahydroggarano 3,4-b-indole-1-acetic acid
     R.
    Rs n
    I RI CH-i-COOH
    rl
    37
    10 o
    (3.2) 37
    (7.8)
    55
    32
    36
    46
    thirty
    (3)
    44
    15
    52
    34
    40
    47
    ABOUT
    2
    40
    ten
    22
    eleven
    26
    ABOUT
    14
    34
    ABOUT
    42 15 73 31
    (1.9)
    nineteen
    86
    (18)
    15
    (1.8)
    21
    (7)
    eleven
    (9.5)
    2
    21
    25
    (5.5)
    eleven
    (3.2)
    (3.3)
    eleven
    eleven
    (4.7)
    (1.4)
    ABOUT
    (3.1)
    ten
    24
    ABOUT
    (3.2)
    26
    ABOUT
    a o
    24 (1.4) 13 8 °
    10 °
    you go
    The numbers indicate the percentage of inhibition at 25 mg / kg or DBO, mg / kg, if taken in parentheses, and - tested at doses of 10 mg / kg; b - tested at 5 mg / kg; c - ispgani at 50 mg / kg.
    (0,003) (0,5)
    (0.04)
    ° b
    (one)
    (0.012)
    (0.8) (1.6)
    (0.25)
    Dose 100 mg / kg.
    R, CH-COOH
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    KR940009788B1|1994-10-17|
    FI870627A0|1987-02-13|
    DK103987A|1987-09-12|
    KR870008890A|1987-10-21|
    FI85857C|1992-06-10|
    CS107487A2|1990-11-14|
    DK169338B1|1994-10-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
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    US4824961A|1987-08-27|1989-04-25|American Home Products Corporation|Production of substituted 1,3,4,9-tetrahydropyranoindole-1-acetic acids|
    US4897493A|1987-08-27|1990-01-30|American Home Products Corporation|Production of substituted 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acids|
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    US4925955A|1989-02-28|1990-05-15|American Home Products Corporation|Resolution of -1-ethyl-1,3,4,9-tetrahydro-4- pyrano[3,4-B]indole-1-acetic acid using brucine|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/838,510|US4670462A|1986-03-11|1986-03-11|Substituted 1,3,4,9-tetrahydropyranoindole-1-acetic acids|LTRP1022A| LT2623B|1986-03-11|1993-09-21|CHANGED 1,3,4,9-TETRAHIDROPIRANINDOL-1-ACTO RUGSCIU OR ITS PHARMACEUTICAL ACCEPTABLE SALTS|
    LV931160A| LV5622A3|1986-03-11|1993-10-19|Substitution for the replacement of substituted 1,3,4,9-tetrahydropyranoindol-1-yl-ethicabs or their pharmaceutically acceptable islands|
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