• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    METHOD FOR OBTAINING DERIVATIVES OF INDOLINONE total formula I CH3 0- (CH2) n- $ Om-K where R is aryl. With -substituted or mono- or disubstituted With -C-alkyl, hydroxyloM, With -C-alkoxyl imii with halogen atoms, moreover, the substituents may be the same or different and the phenyl rings may additionally be substituted with an amino group, a hydroxyl group or a C -Cj alkanoylamino group, an aryl, three or four C -C-artkyl groups each, phenyl substituted with phenyl, halophenyl or cycloalkyl, C-C-aralkyl, pentamethylphenyl, pyridyl or chi neol; m 1 or 2; Claim 2, 3, 4, 5 or 6, characterized in that a compound of the general formula II. , 0- (CH2) n-SOm-R where Kip has the indicated values, and t 0 or 1, is subjected to oxidation. JV with
    公开号:SU1107759A3
    申请号:SU813349304
    申请日:1981-11-03
    公开日:1984-08-07
    发明作者:Мюллер Эрих；Никль Йозеф；РОХ Йозеф；Нарр Бертхольд；Хаарманн Вальтер；Максимилиан Вейзенбергер Йоганнес
    申请人:Др.Карл Томэ Гмбх (Фирма)；
    IPC主号:
    专利说明:

    eleven
    This invention relates to the production of new indoliion derivatives with antithrombotic effect, which can be used in medicine,
    The literature widely describes the reaction of thioether oxidation of hydrogen peroxide in glacial acetic acid to form sulfoxides or LIJ sulfones.
    The purpose of the invention is to obtain new compounds with valuable pharmacological properties.
    The goal is achieved by the fact that according to the method for producing indolinone derivatives of general formula I
    0 - ((5H2) n-Ofn-S
    where R is aryl C / -C-unsubstituted or
    mono- or disubstituted with C-C-alkyl by hydroxyl, -alkoxy or halogen atoms, and the substituents may be the same or different and the phenyl rings may additionally be replaced by an amino group, a hydroxyl group or a C-C-alkanylamino group, -y-aryl, substituted by three or four C-C-alkyl groups each, phenyl, substituted by phenyl, halophenyl or cycloalkyl C -Cj, aralkyl of p.-methylphenyl, pyridyl or quinolyl; m 1 or 2, p 2, 3.4, 5 or 6, the compound of General formula II
    OHS
    0 - ((H2) n- $ Om-R
    - have the specified value of 0 or 1, is subjected to oxidation.
    For the preparation of compounds I, where the oxidation is carried out by the equivalent of an oxidizing agent — hydrogen peroxide in glacial acetic or formic acid.
    To prepare compound I, where the oxidation is carried out with one, two or more equivalents of the y oxidized oxidant.
    7759. 2
    Example 1. 3,3-dimethyl-5-h (4-cyclohexylphenyl-sulfinyl) -6-current si-indolinone-2.
    5.46 g (0.0129 mol) of 3,3-dimethyl2 (4-cyclohexyl-phenyl-mercapto) butoxy-indolinone-2 is suspended in 40 ml of glacial acetic acid and 1.16 ml (1.05x0) are added with stirring , 0129 mol) o hydrogen peroxide (397.4 mg / ml) dissolved in 12 ml of glacial acetic acid. After 5 minutes, complete dissolution occurs, after 85 minutes the reaction at room temperature is complete. The resulting solution 5 is poured into ethyl acetate and extracted with a 20% soda solution until alkaline. The aqueous phase is separated, the organic phase is dried over magnesium sulphate and the solvent is distilled off. 0s0 tatok recrystallized from cyclohexane with the addition of a small amount of ethyl acetate.
    M.p. 125-12bS, yield 4.67 g (82.4% of theory).
    5 Example 2. 3,3-dimethyl-5-4 (4-cyclohexylphenylsulfonyl) -butoxy-indolinone-2.
    0.439 g (0.001 mol) of 3,3-dimethyl5-4- (4-cyclohexylphenylsulfinyl) Q butoxy-indolinone-2 is dissolved in 5 ml of formic acid and 0.086 ml (2.5x0.001 mol) of hydrogen peroxide ( 397.4 mg / ml). After 2.5 hours, ethyl acetate is added, neutralized with 20% soda solution, and the ethyl acetate phase is dried over magnesium sulfate. The residue after evaporation is recrystallized from cyclohexane with the addition of a small amount of ethyl acetate.
     M.p. 153-156C, yield 0.419 g (92% of theory).
    Analogously to Examples 1 and 2, the following compounds were prepared.
    3,3-dimethyl-5- 4- (3,5-dibromo-4-amino-phenyl-sulfinyl) -butoxyJ-indolinone-2.
    Melting point 118.5-119.5 ° C, yield 64.9% of theory.
    3, 3-dimethyl-5- 4- (3,5-dibromo-4 amino-phenylsulfonyl) -butoxy-indolinone-2.
    Melting point 188-139C, yield 68.2% of theory.
    3,3-dimethyl-5- 4- (3-methyl-4-bromo-5-phenylsulfinyl) -butoxy-indolinone-2,
    Melting point 121-123-C, yield 64% of theory. 3 3,3-dimethyl-5-C4- (3-methyl-4-bromophenylsulf6nyl) -butoxy5-indolinone Melting point 1A2-14A ° C, yield 78% of theory. 3,3-dimethyl-5- 4- (2-fluoro-4-biphenylyl-sulfinyl) -butoxy-indolino 2. Melting point 143-145 ° C, yield 85% of theory. 3,3-dimethyl-5- 4- (2-fluoro-4-biphenylyl-sulfonyl) -butoxy-3-indolinone-2. Melting point 163-164 ° C, yield 77% of theory. 3,3-dimesh1-5- {4- (4-tert-butylphenyl-sulfinyl) -butoxy} -indolinone-2. Melting point 156-158 ° C, yield 87% of theory. 3,3-dimethyl-5-4- (4-tert-butylphenylsulfonyl) -butoxy-indolinone Melting point 189-191 ° C, yield 77% of theory. 3,3-dimethyl-5- 4- (3,4-dimethoxyphenylsulfinyl) -butoxy-indolinone Melting point 146-148 0, yield 85% of theory. 3, 3-dimethyl-5- 4- (3,4-dimethoxyphenylsulfonyl) -butoxy} -indolinone Melting point 155-156 ° C, yield 81% of theory. 3,3-dimethyl-5- 4- (6,7-dimethoxynaphthyl- (2) -sulfinyl) -butoxy -indo linon-2. Melting point 181-182 ° C, yield 84% of theory. 3, 3-dimethyl-5- 4- (6 j | D7-dimethoxacinaftsht- (2) -sulfonyl) -butoxy -indo linon-2. Melting point 203-205 ° C, 68% yield of theory. 3, 3-dimethyl-5- 4- (4-acetamino-phenylsulfinyl) -butoxy} -indolinone Cm colorless substance, which is purified by chromatography on a column of silica gel using an ethyl acetate / methylene chloride / ethanol mixture (4.5: 4.5 :one). Rr: 0.2 (silica gel plate with phosphor; ethyl acetate solvent: methylene chloride: ethanol 4.5: 4.5: 1), 76% of theory. 3,3-dimethyl-5- 4- (4-acetaminophenylsulfonyl) -butoxy-indolinone-2. Melting point 183-184 ° C, yield 84% of theory. 3, 3-dimethyl-5- 4- (2-pyridylsulfinyl) -butoxy-indolinone-2. 9- The orange resin is purified by chromatography on a silica gel-containing column using a mixture of ethyl ester of acetic acid and methylene chloride (1: 1). Melting point 137-138 ° C, 80% of theory. 3, 3-dimethyl-5- 4- (2-shiridshl sulfonyl) -butoxy-j-indolinone-2. Melting point 89-90C, yield 78% of theory. 3, 3-dimethyl-5- 4- (2-quinolylsulchoyl) -butoxy 3 -indolinone-2. The gummy crude product is purified by chromatography on a silica gel column using a mixture of ethyl acetate and methylene chloride (1: 1). Melting point 1b4-1b5 ° C (from ethyl acetate), yield 67% of theory. 3,3-dimethyl-5- 4- (4-methoxy-phenylsulfmyl) -butoxy-indolinone-2. Melting point 91-92 ° C, yield 82% of theory. 3, 3-dimethyl-5-4- (4-methoxy-fensh1sulfonyl) -butoxy-indolinone-2. The melting point is 149-150 ° C, and the yield code is 96% of theory. 3,3-dimethyl-5- 4- (6-methoxy-naphthyl (2) -sulfinyl) -butoxy-indolinone-2. Melting point 201-202 ° C, yield 93% of theory. ; 3, 3-dimethyl-5-C4- (6-methoxy-naphthyl (2) -sulphonyl) -butoxy-β-indolinone-2. Melting point 169-170 ° C, yield 90% of theory. 3,3-dImetsh-5-4- (3,5-di-tert-butyl-4-hydroxy-phenylsulfinyl) -butoxy indolinone-2. Melting point 118-120 ° C, yield 87% of theory. 3,3-dimethyl-5- 4- (3,5-di-tert-butyl-4-hydroxy-phenylsulfonyl) -butoxy indolinone-2. Melting point 87-89 ° C, yield 93% of theory. 3,3-dimesh-1-5-1 4- (naphthyl- (2) -sulphinyl) -butoxy3-indolinone-2. Melting point 111-113 0, yield 72% of theory. 3, 3-dimethyl-5- 4- (naphthyl- (2) -sulfonyl) -butoxy1-INDOLINON-2. Melting point 126-127 ° C, yield 186% of theory. I 3,3-dimethyl-5- 4- (4-chlorophenylsulfinyl) -butoxy 3 -indolinone-2. Melting point 128-130 s, yield 91% of theory.
    3,3-dimest-5-4 (4-chlorophenyl sulfonyl) -butoxy} -indolinone-2.
    Melting point 128-129 ° C, yield 88% of theory.
    3,3-dimethyl-5- {- (4-bromopheni51sul
    FINAL) -butoxy -INDOLINON-2.
    Melting point 144-146 ° C. yield 89% of theory.
    3,3-dimethyl-5-4- (4-bromofequylsulfonyl) -butoxyJ-indolon-2.
    Melting point 148-149 ° C, yield 79% of theory.
    3,3-dimethyl-5- 4- (4-fluorophenylsulfinyl) butoxy-indolinone-2.
    Melting point 79-81 ° C, yield 91 of the theory.
    3,3-dimethyl-5- 4- (4-fluorophenylsulfonyl) -butoxy-indolinone-2.
    Melting point 124-125 ° C, yield 81% of theory.
    3,3-dimethyl-5- 4- (2,5-dichlorophenylsulfonic) -butoxy-indolinone-2.
    Melting point 77-79 ° C, yield 88% of theory.
    3,. Methyl-5- 4- (2,5-dichlorophenyl sulfonyl) -butoxy-indolinone-2.
    Melting point: 122-123 ° C, yield 81% of theory.
    3, 3-di etsh-5-4- (4-methylphenylsulfinyl) butoxy-indolinone-2.
    Melting point 125-126 ° C, yield 78% of theory.
    3,3-dimethyl-5- 4- (4-methylsulfonium butoxy-indolinone-2.
    Melting point 141-142C, yield 74% of theory.
    3,3-dimethyl-5- 5- (4-cyclohexylphenylsulfinyl) -pentoxy-indolinone Melting point 131-133 ° C, yield 95% of theory.
    3,3-dimethyl-5- 3- (4-cyclohexylphenylsulfinyl) -propoxy-indolinone Colorless resin. Value, 2 (silica gel luminescent plates; solvent - a mixture of ethyl acetate a and methylene chloride in the ratio 1: 1), the use of 81% of theory.
    3, 3-dimethyl-5- .5- (3,4-dichlorophenyl sulfinyl) -pentoxy-nindolinone-2.
    The melting point is 125-127 ° C, 64% of the theory is input.
    3, 3-dimethyl-5- 3- (3,4-dichlorophenylsulfinyl) -propoxy-indolinone-2.
    Melting point 131-13J C, yield 95% of theory.
    3,3 dimethyl-5- 2- (3,4-dichlorophenyl sulfinyl) -ethoxy iidolinone-2.
    Melting point 150-151 ° C, yield 80% of theories.
    3,3-dimethyl-5- 2- (4-piclohexnylphenylsulfinyl) -ethoxy-indolinone-2
    Melting point 141-143 ° C, yield 69% of theory.
    3, 3-dimethyl-5- 4- (2,4,6-trimethylphenyl-sulfinyl) -butoxy-indolinone Melting point 96-97 ° C, yield 95% of theory.
    3, 3-dimethyl-5- 4- (2,4,6-trimethylphenyl-sulfonyl) -butoxy} -indolinone Melting point 80-82 ° C, yield 83% of theory.
    3,3-dimethyl-5- 4- (2-methoxyphenylsulfinyl) -butoxy-indolinone-2.
    Melting point 109-11 ° C., 84% yield of theory.
    3, 3-dimethyl-5-4- (2-meToxyphenylsulfonyl) -butoxy-indolinone-2.
    A resinous substance with a Rr value: 0.4 (silica gel luminescent plates; the solvent is a mixture of ethylene chloride and ethanol in a ratio of 9: 1) yield 79% of theory.
    3, 3-dimethyl-5- 4- (2-methyl-4-tert-butylphenylsulfinyl) -butoxy-indolinone-2.
    Melting point 90-93 ° C, yield 91% of theory.
    3, 3-dimethyl-5- 4- (2,3,4,5,6-pentamethylphenylsulfinyl) -butoxy-indlinon-2.
    Melting point 173-175 ° C, yield 52% of theory.
    3, 3-dimethyl-5- (4-benzylsulfinyl) butoxy-indolinone-2.
    Melting point: 122-123 ° C, yield 32% of theory.
    3, 3-dimethyl-5- (4-benzylsulfonylbutoxy) -and 1dolinon-2.
    Melting point 127-128 ° C, yield 80% of theory.
    3, 3-dimethyl-5- 4- (3,4-dichlorophenylsulfinyl) -butoxy-indolinone-2.
    Melting point 124-125 ° C, yield 73% of theory.
    3,3-dimethyl-5- (4-phenylsulfinylbutoxy) -indolinone-2.
    Oil Rt- value: 0.35 Silica gel; eluent - a mixture of chloroform and ethnol 9: 1), yield 85% of theory.
    As already mentioned, the compounds obtained by the general formula I, with good oral resorption, have valuable pharmacological properties, in particular, an antithrombotic effect. have a delayed effect on phosphodiesterase and on tumor metastasis. The following compounds were examined for biological properties: A - Z.Z-dimethyl-3-C-phenylsulfinyl butoxy) -indolinone-2; B - 3,3-dimethyl-5- 4- (3, A-dichlorophenylsulfinyl) -butoxy-indolinone-2; in - ZlZ-dimethyl-5- 4- (4-cyclohexylphenylmercapto) -butoxy7-iMdoliHOH-2J G - 3,3-dimethyl-5- 4- (2-fluoro-4-biphenylylsulftsyn) -butoxy3-indon-linone-2; D - 3,3-dimethyl-5- 4- (3,4-dimethoxy phenylsulfinyl) -butoxy j-indoli non-2; E - 3,3-dimethyl-5- 4- (6,7-dimethoxy naphthyl- (2) -sulfonyl-butoxy indolinone-2; 3,3-dimethyl-3-4- (3,5-di-tert-butyl) 4-hydroxy-phenylsulfinyl) butoxy-indolinone-2; 3, 3-dimethyl-5- 4- (3,5-di-tert-butyl-4-hydroxy-phenyl-sulfonyl) butoxy D-indolinone-2; 3, H-dimethyl-5- 4- (4-methoxyphenyl sulfinyl) -butoxy-indolinone-2 3,3-dimethyl-5-4-tert-butylphenyl-sulfinyl) -butoxy-indolinone-2; 3,3-dimethyl-5- 4- (6,7-dimethoxy naphthyl- (2) -sulfinyl3-butoxy indolinone-2; 3,3-dimethyl-5-4- (3,5-DICHLOR-4oxy-phenyl-phenyl mercapto) -butoxy} indolinon-2; 3, 3-dimethyl-5-4- (3,5-dibromo-4-amino-phenyl-sulfinl) -butoxy indolinone-2; 3,3-gdimethyl-5-4- (naphthyl - (2) sulfinyl) -butoxy-indolinone-2 3, 3-dimethyl-5-4- (4-chlorophenylsulfinyl) -butoxy-indolinone-2; 3,3-dimethyl-5-5- (4-cyclohexyl Phenylsulfinyl) -pentoxy} -indo linon-2} 3,3-dimethyl-5 4- (4-tert-butylphenyl-sulphonyl) -butoxy 3-y-dolinone-2; T - 3, 3-dimethyl-5 - 4- (4-cyclohexyl phenylsulfinyl) -butoxy -indo linon-2 compared with the known compounds Yen. m Y and F 2: Y - 5- (4-phenylsulfonyl-butoxy) oxindole; f 5- (4-phenylsulfinyl-butoxy) oxindole. 11 9 Definition, prolonged bleeding time. The human body, as well as warm-blooded animals, have a specific mechanism that protects it from blood poisoning in the event of injury. This system consists of platelets, which with their adhesive properties must quickly clog the damaged vessels and cause this primary hemostasis. Along with this purely cellular hemostasis, the body also has a blood clotting system. With this system, protein bodies are brought into effective form, which liquid plasma fibrinogen converts into a fibrinous clot. The primary hemostasis system, which mainly consists of platelets, and the coagulation system complement one another and protect the body from blood loss. In some diseases, even with an intact system of blood vessels, disruption of the coagulation process, as well as flocculation of platelets, can occur. The weakening of the blood coagulation system due to coumarin or heparin is known and can be easily established using known blood clotting tests, which, by means of drugs, show an extension of the plasma recovery time, thrombin time, etc.). Since in the event of injury, rapid bleeding occurs with the help of platelets, then in the presence of experimental injury, the function of platelets can be easily determined with the help of. measure bleeding time. A normal bleeding time in a person is about 1-3 minutes under condition if there are a sufficient number of normally functioning platelets. With a normal number of platelets, prolonged blood flow, the flow indicates a violation of the function of platelets. This is observed, for example, in certain congenital disorders of platelet functions. If medications tend to prevent the propensity for spontaneous adhesion of platelets with the consequences of vascular occlusion in the arterial system, then with good platelet therapy, the bleeding time when exposed to the substance should be increased. Thus, with a substance acting on the platelets, a prolongation of the bleeding time is expected, and since the surgeon's plasma bristle is not affected, the normal blood coagulability time is not affected. To determine the time of hemorrhage, sleep mice are given to the study of oral matter with an oral dose of 1b mg / k. After 1 hour, about 0.5 mm is cut off from the tip of the tail. Protruding blood is carefully removed every 30 seconds with filter paper. The number of drops collected in this way gives the measure for the bleeding time (5 animals per experience). In tab. 1 shows the numerical data, denoted 1 percent extension relative to the control. -Table of extending blood flow time Compound%, after 1 h. Suggested B Known Y 9. Phosphodiesterase Inhibition. Cyclic A-denosin-3; 5-monophosphate from phosphodiesterase from various sources, also from platelets, is hydrolyzed to adenosine-myophosphate. This hydrolysis is inhibited depending on the concentration of phosphodiesterase inhibitors. Method. As a phosphodisterase, a 10,000-fold S-supernatant of human platelets is used, which have been frozen in distilled water and thawed again. 0.3 ml of a mixture consisting of 0.1 mol / l of trioxy-aminomethane (4), 3 mmol / l of magnesium chloride, 1 mmol / l of adenosine phosphate, 1 μmol / l of the H-cycle. A-denosin-3, 5mrnophosphate (special activity about 10 MV / μmol), phosphodisterase, as well as from the test substance, respectively, of the water under control, are incubated for 15 min at. Incubation by adding 0.5 ml of zinc sulfate (0.266 mol / l) and 0.5 ml of barium hydroxide (0.226 mol / l) is stopped, the precipitate is separated by centrifugation and the unreacted H-cycle activity remaining in the supernatant is determined. Adenosine-3, 5-monophosphate. When comparing the initial substance with respect to the control, the concentration required for the 50% inhibitory effect (ICjj) of the corresponding substance is calculated. The results of the experiments are given in table. 2. Table2, Proposed A
    groups of 5 mice were not observed. Toxic side effects (observation time 14 days).
    The results of the experiments are given in table 5. 3
    Table 3
    Substance
    Toxicity
    From the comparison table. 1 and 2, it follows that the compounds obtained have clear advantages over the known ones.
    Acute toxicity. When oral, giving pi 250 mg / kg, respectively, I000 mg / kg of the test substance
    A 250 mg / kg in oral dacha (About up to 5 animals.
    died)
    B 1000 mg / kg during oral dacha (O from 5 animals died)
    B, D, D, E, G 3, and K
    nwtrr. 1000 mg / kg with oral
    J1.M, p. And f. P. G
    „„ „Cottage (.0 from 6 animals
    P, R, C, T
    died)
    Based on their pharmacological properties, new compounds of general form I are suitable for the prevention of thromboembolic diseases, such as myocardial infarction, cerebral infarction (transient ischaemic attacks, Amaurosis fup, ax), and also for the prevention of arteriosclerosis and metastasis. In combination with other active substances, new compounds can be prepared in conventional pharmacological preparations, for example, in pills, tablets, suppositories or suspensions. A single dose is 50-100 mg 2-3 times a day, and a daily dose is 100-300 mg.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING INDOLINONE DERIVATIVES of General Formula I
    CH S & Om ~ R
    About n
    H where R is aryl C ^ -. C ^ 0 unsubstituted or mono- or disubstituted by C ^ -C ^ -alkyl, hydroxyl, C and -C 3 -alkoxyl or halogen atoms, wherein the substituents may be the same or different and phenyl nuclei can be additionally substituted by an amino group, a hydroxyl group or a C ^ -C ^ alkanoylamino group, C 6 -C 1o- aryl substituted with three or four C 1 -C ^ -alkyl groups each, phenyl substituted by phenyl, halogenphenyl or cycloalkyl C -C 7 , Su-C. ^ - aralkyl, pentamethylphenyl, pyridyl or quinolyl; w = 1 or 2;
    η = 2, 3, 4, 5 or 6, characterized in that the compound of the general formula II l
    0- (CH 2 ) p -aO t '-H where R and η have the indicated meanings. And t' = 0 or 1, they undergo oxidation.
    SU < m 1107759
    1 1107759 2
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    同族专利:
    公开号 | 公开日
    PT73969A|1981-12-01|
    CH652120A5|1985-10-31|
    IL64252A|1985-02-28|
    NL8105100A|1982-06-01|
    FI75806C|1988-08-08|
    ES8304081A1|1983-02-16|
    KR880002227B1|1988-10-20|
    NO156167C|1987-08-05|
    PL134525B1|1985-08-31|
    US4629733A|1986-12-16|
    FI75806B|1988-04-29|
    IL64252D0|1982-02-28|
    LU83744A1|1983-04-13|
    KR830007554A|1983-10-21|
    ES8206470A1|1982-08-16|
    NZ198941A|1984-10-19|
    ES507015A0|1982-08-16|
    JPS57114569A|1982-07-16|
    GR81330B|1984-12-11|
    ES511834A0|1983-02-16|
    NO813821L|1982-05-13|
    PT73969B|1983-11-23|
    IT1171624B|1987-06-10|
    YU266681A|1983-10-31|
    SE452156B|1987-11-16|
    ATA478981A|1984-02-15|
    FR2493841B1|1984-03-30|
    IE52107B1|1987-06-24|
    AU7739081A|1982-05-20|
    BE891103A|1982-05-12|
    GB2098595A|1982-11-24|
    FR2493841A1|1982-05-14|
    NO156167B|1987-04-27|
    DK154138C|1989-04-17|
    DK496781A|1982-05-13|
    AT375923B|1984-09-25|
    HU183680B|1984-05-28|
    GB2098595B|1984-09-05|
    ZA817787B|1983-07-27|
    DK154138B|1988-10-17|
    YU41995B|1988-04-30|
    DD201889A5|1983-08-17|
    IE812640L|1982-05-12|
    AU547929B2|1985-11-14|
    IT8149602D0|1981-10-30|
    PL233774A1|1982-12-20|
    FI813561L|1982-05-13|
    SE8106704L|1982-05-13|
    CA1183848A|1985-03-12|
    引用文献:
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    US5204344A|1989-08-22|1993-04-20|Merck Frosst Canada, Inc.|indoles as inhibitors of the biosynthesis of leukotrienes|
    GB9008605D0|1990-04-17|1990-06-13|Smith Kline French Lab|Process|
    US5308850A|1991-09-30|1994-05-03|Merck Frosst Canada, Inc.|indoles as inhibitors of leukotriene biosynthesis|
    US5389650A|1991-09-30|1995-02-14|Merck Frosst Canada, Inc.|indoles as inhibitors of leukotriene biosynthesis|
    US5190968A|1991-09-30|1993-03-02|Merck Frosst Canada, Inc.| indoles as inhibitors of leukotriene biosynthesis|
    US5290798A|1991-09-30|1994-03-01|Merck Frosst Canada, Inc.|indoles as inhibitors of leukotriene biosynthesis|
    US5374635A|1993-03-29|1994-12-20|Merck Frosst Canada, Inc.|Furo[3,2-b]pyridines and thieno[3,2-b]pyridines as inhibitors of leukotriene biosynthesis|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3042632|1980-11-12|
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