• 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:
    Novel series of 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones of the Formula <IMAGE> (XII) wherein R1 is halogen, lower alkyl, lower alkoxy, trifluoromethyl; R2 is hydrogen, halogen, lower alkyl, lower alkoxy; R3 is hydrogen, halogen, lower alkyl, lower alkoxy; and R4 is hydrogen or lower alkyl. The compounds are therapeutically useful as inhibitors of blood platelet aggregation and/or as cardiotonic agents.
    公开号:SU1560056A3
    申请号:SU874203391
    申请日:1987-09-25
    公开日:1990-04-23
    发明作者:А.Минвел Николас；Дж.Райт Джон
    申请人:Бристоль - Мейерз Компани (Фирма)；
    IPC主号:
    专利说明:

    ) -KH-C (0) -CH-CH2-C6HB1R2R3-opTO-N02
    where P f -R is as indicated, followed by cyclization of the resulting compound and isolation of the target compound in free form or in the form of a pharmaceutically acceptable salt. The novel compounds are semi-invented relates to a method for preparing heterocyclic compounds, which are intermediate products of phosphodiesterase inhibitors, an antiaggregant of platelets and cardiotonic agents,
    The aim of the invention is a method of obtaining new derivatives of 2H-nmiducts in the preparation of 2H-imidazo 4,5-b quinolin-2-ones derivatives used for the treatment and prevention of diseases where platelet and thrombosis are observed. 3 tab.
    SP
    Od
    ate
    about
    , 5-b} quinolin-2-ones with valuable pharmacological properties.
    Example 1. The preparation of compounds of formula (III).
    A solution of nitrohydantoin (8 mmol) of formula (II) in dimethylformamide (60 ml) is hydrogenated over 10% palladium
    sn
    31560056
    it on charcoal (0.4 g) at 219 kg / cm. After the hydrogen uptake ceased, the mixture was filtered through infusor earth and 5 the solvent was evaporated under reduced pressure. The residual substance consists of aminogidantoin Lormula (III A), which can be used to prepare compounds of formula 10 (I) without further purification. If necessary, the residual substance can be further purified using conventional methods: trituration or crystallization from an appropriate solvent. 15
    The compounds of Formula (III A) given in Table. 1, is obtained in accordance with this method from the corresponding nitrohydantoin of formula (II) .20
    The compound from example 1.3 is ground to powder with diethyl ether, yield 90%, so pl. 308-310 ° C (decomp.) An NMR spectrum shows a partial dimethylformamide solvate.
    Calculated,%: C 59.58; H 6.21 ;, N, 19.17.
    С 1 (, Н14ЫеОг-0,2СзН., ИО
    Found,%: C 59.30; H 6.17.3Q
    N 18.75.
    Example 2. Preparation of 1,3,9, 9a-tetrahydro-2H-imidazo4,5-bzquinoline-2-one compounds of formula (I).
    A mixture of aminogidantoin Lormula (III A), in which a and b are hydrogen (16 mmol) and p-toluenesulfonic acid monohydrate (0.25 g) in methanol (180 ml) is heated to temperature. refluxing under an inert atmosphere (e.g. argon) for 1.25 hours. The solvent is removed under reduced pressure. The crude tetrahydroquinoline of formula (II B). . The residue is purified by crystallization or trituration from solvents such as methanol, ether and the like. If necessary, the acid addition salts of tetrahydroquinoline of formula (I) can be prepared by acidifying the residual substance in an appropriate solvent.
    The compounds of formula (I) obtained in Example 2 are listed in Table. 2
    Acidification of the residue with methanolic hydrogen chloride and precipitation with diethyl ether gives
    50
    yield of 62% of hydrates of un-hLORG idrate of 8-methyl-1, 3.979a-tetrahydro-2H-imidazo 4,5-bSquinolin-2-one, m.p. 220-225 ° C (decomp.).
    Calculated,%: C 53.36; H 5.33; N 16.97; HjO 4.00.
    C HC1-0,55N20
    Found,%: C 53.03; H 5.44; N 16.74; HgO 3.49.
    NMR (DMSO-dg): 2.29 (3, singlet), 2.78 (3, triplet, F 15 Hz), 3.30 (1, double doublet, F 15 Hz, F 8 Hz), 4.92 (1, double doublet, F - 15 Hz, F 8 Hz), 7.15-7.60 (3, multiplet), 9.20 (1, wide singlet), 9.80 (2, wide singlet).
    Example 3. 7,8-Drmethyl-1, 3, 9,9a-tetrahydro-2H-imidazo 4, nolin-2-one
    H3S


    0
    A mixture of 5-X6-amino-2,3-dimethylphenyl) methyl -2,4-imidazolyl-dione (2.52 g, 10 mmol), p-toluenesulfonic acid (0.25 g) and methanol (50 ml) is heated in reverse reflux under argon for 1 hour. The mixture is then cooled, the gray solid is filtered off and dissolved in 10% hydrogen chloride in methanol with heating. Addition of ether gives the previously described 7,8-dimethyl-1,3,9,9a-tetrahydro-2H-imidazo A, 5-b quinolin-2-one (example 2-; 7) as hydrochloride (1, 68 g, 87%), so pl. above 230 ° C.
    Calculated,%: C 57.26; H 5.61; N 16.70.
    CflHfЈlЈ HCl.
    Found,%: C 56.92; H 5.48; N 16.44.
    NMR (DMSO-d): delta, 2.20 (ZN, singlet, SI 3), 2.27 (ZN, singlet, CH3)., 2.80 (1H, triplet, F 14 Hz, benzyl H), 3 , 34 (1H, double doublet, F 14 Hz, F 8 Guy, benzyl N), 4.84 (1H, double doublet, F -, F 8 Hz, SP; CO), 7.18 (1H, doublet , F 9 Hz, aromatic H), 7.31 (1H, doublet, F 8 Hz, aromatic H) and 9.22 (2H, singlet, NH).
    Example 4. 1,3,9,9a Tetrahydro-1,8-dimethyl-2H-imzzazo 4,5-х hinot-lin-2-one
    sn
    Prepared according to example 2 of 1-metip-5- (2-amino-6-methylphenyl) methyl -2,4-imidazolidine, so pl. 340-345 ° C (decomp.)
    Calculated% J C 57.27; H 5.61; N 16.70.
    CflHf3N30-HCl.
    Found,%: C 57.47; H 5.55; N 16.64.
    The compounds of this invention are intermediates in the preparation of 2H-imidazo derivatives (4,5-b quinoline-2-ones).
    The compounds of formula (XII) or their pharmaceutically acceptable salts, as well as the compounds of formula (I), have pharmacological properties that make them useful as inhibitors of cosblodiesterase, blood platelet antiaggregators and / or cardiotonic agents.
    The pharmacological properties of the compounds of this invention may be demonstrated by routine biological tests in vitro and in vivo.
    Inhibition of in vitro platelet aggregation.
    The various test compounds were dissolved in dimethyl sulfoxide (DMSO) so that 5 µl added to platelet-rich plasma would give the required test concentration. Control experiments were carried out with the carrier and compared with aggregation experiments induced in a rich

    ten
    15
    )


    600566
    platelets of the serpentine containing various concentrations of TEST-E aimnine connections. Dose response curves for dose v were obtained. The effective concentration values () were calculated. In this experiment, EC, U for cypiridolol, Hcrrxnb3veM - clinics of the antithrombogenic agent, is more than 512 µg / l compared to ADP and 45 µg / ml compared to collagen.
    In tab. 3 shows the results for "various compounds of Formula (I)
    - Inhibition of platelet aggregation after oral administration.
    Aggregation is carried out by injection on plasma platelet-rich plasma samples obtained from rats given doses of the test compound or vehicle. So, in all cases, the activity is determined 2 hours after the medicine is prescribed - orally in various doses of the feed through the probe, in the form of a suspension in 0.9% of water plus a few drops of TBIT 20. The activity of the medicine is expressed as ED5 the dose required to inhibit the induced aggregation by 50%, calculated from the results obtained in groups of 10 animals treated with different doses of the test compound compared to the individual control groups,
    In this experience, the value of dnpi20
    25
    thirty
    35
    0
    100 mg / kg and anagreil 4.9 mg / kg. The results are given in: abl. 3 for various compounds of Lormul (XII) and tl).
    Inhibitory cyclic adenosine monophosphate (AMP) Phosphodiesterase.
    Tritiated cAMP is incubated with phosphodiesterase (PDE) enzyme, obtained from human platelets, which converts a portion of cAMP to 5 AMP in culture tubes. This reaction is terminated by immersing the tubes in a boiling water bath, after which they are placed on ice, and an aliquot of snake venom is added to each tube. With erte incubation, this reaction transforms 5 AMP into adenosine. An ion exchange resin is added to bind the remaining cAMP. The tubes are centrifuged to precipitate: the resins, and a portion of the transparent top-floating layer, which contains radioactive adenosine, is calculated in
    0
    five
    liquid scintillation counter. The inhibition activity of cAMP fossbodiesterase of the test agent is determined by preincubating the XRD enzyme preparation with the test agent. Dose response values are obtained, and the activity of the test agent is given as the molar concentration (M) of the test agent, which inhibits 50% of the activity of RDE (IC,). In this experiment, the IC value of milrinone, a known inotropic agent, is mol. The results are given in Table. 3 for various compounds of formulas (XII) and (I).
    The compounds of formula (XII) are classified as low toxic.
    Thus, the compounds of the present invention, which have anti-detrophic properties and phosphodiesterase inhibitory properties, are useful in the prevention or treatment of diseases in which platelet and thrombosis occur.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining the derivatives of 1,3, 9,9a-tetrahydro-2H-imidazo 4, nolin-2-one common bourmula
    (ABOUT
    45
    40
    i-
    where R, is halogen, lower alkyl, lower alkoxy or trifluoromethyl; every hydrogen, halogen,
    lower alkyl or lower alkoxy;
    R 4 is hydrogen or lower alkyl, or their pharmaceutically acceptable salts, characterized in that the substituted hydantoin of the total Lormu-O
    (Ii)
    where R - R have the indicated meanings, is subjected to reduction to obtain a compound of the formula
    (Iii)
    where R., - RJ have the indicated meanings, followed by cyclization of the obtained compound of formula (III) and isolation of the target compound in free form or in the form of a pharmaceutically acceptable salt.
    Priority featured:
    04/25/85 for R1 - halogen, lower alkyl, lower alkoxy; R and R are each hydrogen, halogen, niolet algyl, lower alkoxy; R is hydrogen or lower alk.
    02.26.86 when R, is triLoromethyl; R and R3 are each hydrogen, halogen, lower alkyl or nizpy alkoxy; P 4 - hydrogen or lower alkokgi.
    Tablia I
    类似技术:
    公开号 | 公开日 | 专利标题
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    引用文献:
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    US3932407A|1973-11-19|1976-01-13|Bristol-Myers Company|Optionally substituted 1,2,3,5-tetrahydroimidezo-quinazolin-2-ones and 6-1,2,3,4-tetrahydropyimidoquinazolin-2-ones|US4775674A|1986-05-23|1988-10-04|Bristol-Myers Company|Imidazoquinolinylether derivatives useful as phosphodiesterase and blood aggregation inhibitors|
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    US4803210A|1987-05-29|1989-02-07|Merrell Dow Pharmaceuticals Inc.|Cardiotonic tricyclic oxazolones|
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    US4943573A|1989-11-01|1990-07-24|Bristol-Myers Squibb Company|Imidazo[4,5-b]quinolinyloxyalkanoic acid amides with enhanced water solubility|
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    WO2008121333A1|2007-03-30|2008-10-09|Cytokinetics, Incorporated|Certain chemical entities, compositions and methods|
    CA2849213A1|2011-07-13|2013-01-17|Cytokinetics, Inc.|Combination of riluzole and ck-2017357 for treating als|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US72686985A| true| 1985-04-25|1985-04-25|
    US06/832,212|US4668686A|1985-04-25|1986-02-26|Imidazoquinoline antithrombrogenic cardiotonic agents|
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