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    • 专利摘要:
    A compound according to formula (I) is provided, where X and Y can be identical or different and represent O, NH or S; R 1, R 2, R 8, R 4, R 5, R 6, R 7, R 8, R 9 and R 10 can be the same or different and represent H, halogen, CN, NO 2, (C 1- 4) alkyl, (C 1-4) haloalkyl, (C 2-4) alkenyl, OH, O (C 1-4) alkyl, O (C 1-4) haloalkyl, N (RA) RB , C (O) N (RA) RB, C (O) RA, CO 2 RA, CHO, C 2-4 -alkenyl substituted with CN, C 2-4 -alkenyl substituted with COOH, C 2-4 -alkenyl substituted CHO or C 2-4 alkenyl substituted with OH; R A and R B can be the same or different and both represent H, (C 1-4) -alkyl, (C 1-4) -haloalkyl or (C2-4) -alkenyl; A 1, A 2, A 3 and A 4 can be the same or different and are CH or N, with the proviso that A 1 and A 2 cannot both be N and that R 5 and R 10 are absent when A 3 and A 4 are N; or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    公开号:CH715452B1
    申请号:CH00244/20
    申请日:2017-08-29
    公开日:2021-05-14
    发明作者:Techasakul Supanna；Makarasen Arthit；Reuk-Ngam Nanthawan；Khlaychan Panita；Kuno Mayuso；Hannongbua Supa
    申请人:Chulabhorn Found；Kasetsart Univ；Srinakharinwirot Univ；
    IPC主号:
    专利说明:

    Field of invention
    This invention relates to derivatives of quinoline and naphthyridine, and a pharmaceutical composition containing these derivatives.
    State of the art
    Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be effective against the human immunodeficiency virus type 1 (HIV-1). First generation NNRTIs, i.e. efavirenz (EFV) and nevirapine (NVP), are common components of first-line and highly active antiretroviral therapy (ARV) for HIV-1 patients. EFV and NVP both have long-term efficacy, generally good tolerability and low pill exposure. However, clinical use of EFV and NVP may be limited due to their relatively low genetic barrier to resistance, cross-resistance between them, and some tolerability issues. In this regard, various strategies have been developed to identify next-generation drugs with activities against NNRTI-resistant viruses. One such strategy, such as computational chemistry using molecular docking, led to the identification of etravirine (ETR; TMC125) as a diarylpyrimidine NNRTI with activity against a wide range of wild-type and first-generation NNRTI-resistant HIV-1 viruses. The same strategy was used to characterize TMC278 (rilpivirine) as the second NNRTI of the diarylpyrimidine family. Meanwhile, TMC278 is a potential clinical candidate currently being investigated in treatment-naive patients (Azijn H, Tiny I, Vingerhoets J et al., TMC278, NNRTI (Next Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), Active against Wild-Type and NNRTI- Resistant HIV-1, Antimicrobial Agents and Chemotherapy, 2010; 54 (2): 718-727, doi: 10.1128 / AAC.00986-09).
    It has recently been reported that in HIV-1 infected patients after initiation of highly active antiretroviral therapy, precancerous lesions recede. NNRTIs, like EFVs, could be mediators of regression due to their cytotoxicity to tumor cells. In addition, a possible mechanism involved in this effect is the activation of cannabinoid receptors such as CB1 and CB2, which mediate tumor toxicity. EFV has selective cytotoxic effects on several tumor cell lines, but not on primary fibroblasts. These cytotoxic effects are associated with CB1 expression. In addition, EFV promotes the phosphorylation of the tumor suppressor protein p53, as shown in previous studies that reported that EFV is a potential anti-tumor and cytostatic agent (Hecht M et al., Cyctotoxic effect of efavirenz is selective against cancer cells and associated with cannabinoid system , AIDS, August 24, 2013; 27 (13): 2031-40. Doi: 10.1097 / QAD.ObO 13e3283625444).
    It is expected that cancer prevention and therapy in HIV-1 infected patients will play an important role in the future. NNRTIs, particularly EFV and NVP, are cytotoxic to cancer cells in vitro. However, there are few studies of other NNRTIs. Therefore, the current work tested all clinically used NNRTIs and their in vitro toxic concentrations are compared with the drug concentrations in patients in order to predict possible anti-cancer effects in vivo. The in vitro EC50 values of the active ingredients used in BxPC-3 pancreatic cancer cells are 31.5 µmol / l EFV and 24.4 µmol / l TMC278. Among the NNRTIs, EFV and TMC278 have the highest cytotoxic potential against pancreatic cancer cells at low concentrations. In particular, the NNRTIs studied are toxic to cancer cells in a wide range of toxic concentrations. The toxicity of NNRTIs against cancer cells promotes the idea of using these drugs in HIV-1 infected patients to prevent or even treat cancer (Hecht M, Erber S, Harrer T et al. Efavirenz Has the Highest Anti-Porliferative Effect of Non - Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells. Menendez-Arias L, ed. PLoS ONE. 2015; 10 (6); e0130277. Doi: 10.1371 j ournal.pone.0130277).
    Summary of the invention
    In the present invention new derivatives of quinoline and naphthyridine are presented which are useful for the treatment of diseases, particularly HIV infection and cancer.
    The compounds of the present invention have the following formula: whereinX and Y can be identical or different and represent O, NH or S;R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 can be the same or different and represent H, halogen, CN, NO2, (C1-4) -alkyl, (C1-4) -haloalkyl, ( C2.4) -alkenyl, OH, O (C1.4) -alkyl, O (C1.4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO, C2.4-alkenyl substituted with CN, C2.4-alkenyl substituted with COOH, C2.4-alkenyl substituted with CHO or C2. 4-alkenyl substituted with OH;R <A> and R <B> can be identical or different and both can represent H, (C1.4) -alkyl, (C1.4) -haloalkyl, or (C2.4) -alkenyl;A1, A2, A3 and A4 can be the same or different and are CH or N, but A1 and A2 cannot both be N, and R5 and R10 are absent when A3 and A4 areN;or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    Particular compounds of the present invention are those of formula (I), whereinX and Y can be identical or different and represent O, NH or S;R1, R2, R3, R4 and R5 can be the same or different and represent H, halogen, CN, NO2, (C1.4) -alkyl, (C1.4) -haloalkyl, (C2.4) -alkenyl, OH, O (C1.4) -Alkyl, O (C1.4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO, C2.4-alkenyl substituted with CN, C2.4-alkenyl substituted with COOH, C2.4-alkenyl substituted with CHO or C2.4-alkenyl substituted with OH;R6, R7, R8, R9 and R10 can be the same or different and stand for H, CN, NO2, (C1.4) -haloalkyl, (C2.4) -alkenyl, OH, O (C1.4) -alkyl, O ( C1.4,) - haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO, C2.4-alkenyl substituted with CN, C2.4-alkenyl substituted with COOH, C2.4-alkenyl substituted with CHO or C2.4-alkenyl substituted with OH;R <A> and R <B> can be identical or different and represent H, (C1.4) -alkyl, (C1.4) -haloalkyl or (C2.4) -alkenyl;A1, A2, A3 and A4 can be the same or different and represent CH or N with the proviso that A1 and A2 cannot both be N. R5 and R10 are absent when A3 and A4 are N;or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    Particular compounds of the present invention are those of formula (I), whereinX and Y can be identical or different and represent O, NH or S;R1, R2, R3, R4, R5, R6, R7, R8 and R9 can be the same or different and represent H, halogen, CN, NO2, (C1.4) -alkyl, (C1.4) -haloalkyl, (C2. 4) -Alkenyl, OH, O (C1.4) -alkyl, O (C1.4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R < B>, C (O) R <A>, CO2R <A>, CHO, C2-4-alkenyl substituted with CN, with C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted with CHO, or C2- 4-alkenyl substituted with OH;R <A> and R <B> can be identical or different and represent H, (C1.4) -alkyl, (C1-4) -haloalkyl or (C2-4) -alkenyl;A1, A2 and A3 can be the same or different and are CH or N, with the proviso that A1 and A2 cannot both be N and that R5 is absent when A3 isN;A4 stands for N;or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    Particular compounds of the present invention also include those of the formula (I), whereinX and Y can be the same or different and are O, NH, or S, with the proviso that X and Y cannot both be NH or X and Y cannot both be O;R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 can be the same or different and represent H, halogen, CN, NO2, (C1-4) -alkyl, (C1-4) -haloalkyl, ( C2.4) -alkenyl, OH, O (C1.4) -alkyl, O (C1.4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO, C2.4-alkenyl substituted with CN, C2.4-alkenyl substituted with COOH, C2.4-alkenyl substituted with CHO or C2. 4-alkenyl substituted with OH;R <A> and R <B> can be identical or different and both can represent H, (C1.4) -alkyl, (C1.4) -haloalkyl or (C2.4) -alkenyl;A1, A2, A3 and A4 can be the same or different and are CH or N, with the proviso that A1 and A2 cannot both be N and that R5 and R10 are absent when A3 and A4 are N;or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    Particular compounds of the present invention are those of the formula (I), whereX and Y can be identical or different and represent O, NH or S;R] ,, R2, R4, R5, R6, R7, R8, R9 and R10 can be the same or different and represent H, halogen, CN, NO2, (C1-4) -alkyl, (C1-4) -haloalkyl, ( C2-4) -alkenyl, OH, O (C1-4) -alkyl, O (C1-4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO, C2-4-alkenyl substituted with CN, C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted with CHO or C2- 4-alkenyl substituted with OH;R3 is CN;R <A> and R <B> can be identical or different and represent H, (C1-4) -alkyl, (C1-4) -haloalkyl or (C2-4) -alkenyl;A1, A2, A3 and A4 can be the same or different and are CH or N, with the proviso that A1 and A2 cannot both be N and that R5 and R10 are absent when both A3 and A4 are N;or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    Particular compounds of the present invention also include those of the formula (I), whereinX and Y can be identical or different and represent O, NH or S;R1, R2, R4, R5, R6, R7, R8, R9 and R10 can be the same or different and represent H, halogen, CN, NO2; (C1-4) -Alkyl, (C1-4) -haloalkyl, (C2-4) -alkenyl, OH, O (C1-4) -haloalkyl, N (R <A>) R <B>, C (O ) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO, C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted with CHO, or C2- 4-alkenyl substituted with OH;R3 is CHO;R <A> and R <B> can be identical or different and represent H, (C1-4) -alkyl, (C1-4) -haloalkyl or (C2-4) -alkenyl;A1, A2, A3 and A4 can be the same or different and are CH or N, with the proviso that A1 and A2 cannot both be N and R5 and that R10 is absent when A3 and A4 areN;or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    Most of the specific compounds of the invention are exemplified herein.
    In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients or diluents.
    Part of the disclosure is the compound according to the present invention for use in therapy.
    Part of the disclosure is to provide the compound according to the present invention for use in the treatment or prevention of HIV infection.
    Part of the disclosure is to provide the compound according to the present invention for use in combination with other antiretroviral agents for the treatment or prevention of HIV infection.
    Part of the disclosure is to provide the compound according to the present invention for use in the treatment or prevention of cancer.
    Part of the disclosure is to provide the compound according to the present invention for use in combination with radiation and / or one or more other chemotherapeutic agents for the treatment or prevention of cancer.
    Part of the disclosure is directed to the use of a compound according to the present invention in the manufacture of a medicament for treating or preventing HIV infection.
    Part of the disclosure is directed to the use of a compound according to the present invention in the manufacture of a medicament for the treatment or prevention of cancer.
    Part of the disclosure is directed to the use of a compound according to the present invention and other antiretroviral agents in the manufacture of a medicament for treating or preventing HIV infection.
    Part of the disclosure is directed to the use of a compound according to the present invention and one or more other chemotherapeutic agents in the manufacture of a medicament for the treatment of cancer.
    Part of the disclosure is directed to a combination of a compound according to the present invention and one or more other antiretroviral agents for use in the manufacture of a medicament for treating or preventing HIV infection.
    Part of the disclosure is directed to a combination of a compound according to the present invention and one or more other chemotherapeutic agents for use in the manufacture of a medicament for the treatment or prevention of cancer.
    Part of the disclosure is the provision of a method for treating or preventing HIV infection, comprising administering to a patient an HIV-inhibiting dose of a compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present invention Invention.
    Part of the disclosure is to provide a method for treating or preventing cancer, comprising administering to a patient an anti-cancer dose of a compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present invention.
    Part of the disclosure is the provision of a method for the treatment or prevention of HIV infection, comprising the administration of an HIV-inhibiting dose of a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of the present invention in combination with a or more other antiretroviral agents.
    Part of the disclosure is to provide a method of treating or preventing cancer comprising administering to a patient an anti-cancer dose of a compound according to the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a compound of the present invention , in combination with radiation and / or one or more other chemotherapeutic agents.
    DETAILED DESCRIPTION
    Viruses resistant to first generation NVP and EFV carry one or more mutations in their reverse transcriptase (RT) genes. These mutations immediately give the two active ingredients a high level of resistance and cross-resistance. Such mutations were found to be close to the binding site of NNRTIs and the joining domain of HIV RT. They can lead to a loss of drug affinity without impairing viral fitness (Ghosn J, Chaix ML and Delaugerre C. Aids Rev. 2009 11 (3): 165-173). NVP, EFV and TMC278 bind to the same binding site at different efficiencies in the inhibition of HIV-1 RT. NVP has a lower IC50 than EFV and TMC278. No significant difference is observed in the IC50 values of EFV and TMC278.
    After comparing their effectiveness in inhibiting HIV-1 RT, TMC278 was found to be more effective than EFV because the former has greater structural flexibility than the latter in forming complexes at the binding site. In addition, EFV shows decreased HIV-1 RT mutations (Domaoal RA and Demeter LM. Int. J. Biochem. Cell. Biol. 2004 36 (9): 1735-1751).
    The inventor has created a new structure of NNRTIs based on the analyzed molecular properties of the NNRTIs NVP, EFV and TMC278 of the first and second generation.
    The novel compounds of the present invention are generated by a hybrid pharmacophore approach based on the structure of EFV and TMC278. In the docking model in which the low energy forms of EFV and TMC278 templates are superimposed in the NNRTI binding sites, most of the fragments in the EFV and TMC278 structures can be effectively superimposed.
    Given the overlap between EFV and TMC278, the C = 0 group of EFV overlaps with the TMC278 core structure while the side chain of EFV overlaps that of TMC278. Computational chemistry using molecular docking is used to find alternatives or potential HIV-1 RT inhibitors. The novel compounds of the present invention can be developed into medicines for HIV and cancer treatments. Both side chains of TMC278 are built into the structure of the new compound. The estimated binding free energy obtained by the Auto Dock method is determined to study potential NNRTIs. The estimated free energy of binding of quinoline, 1,6-naphthyridine, and 1,7-naphthylridine obtained by the Auto Dock method is lower than that of TMC278. Substituent groups at positions 2 and 4 of quinoline, 1,6-naphthyridine and 1,7-naphthylridine are then determined to create new compounds in the docking process.
    In the present invention, a number of EFV-TMC278 hybrids, characterized by 2,4-substituted quinoline (1), 2,4-substituted 1,6-naphthyridine (2) and 2,4-substituted 1, 7-naphtyridine (3), synthesized. These new compounds show excellent biological activity against HIV infection and cancer proliferation.
    Examples of the compounds according to the invention are listed in Tables 1-24. These examples are provided to enable those skilled in the art to clearly understand and practice the present invention. They are not to be construed as limiting the scope of the invention, but merely as an illustration and representation.
    The compounds in the tables below are shown with generalized substituents; however, the nature of the R groups will vary to give the different compounds contemplated in this invention.
    Table 1
    [0037]
    1-01 HH CHO HH -12.16 -11.95 92 1-02 CH3 H CHO H CH3 -13.05 -12.87 120 1-03 HH COOH HH -11.65 -11.33 65 1-04 CH3 H COOH H CH3 -12.56 -12.28 101 1- 05 HH COCH3 HH -12.83 -12.44 68 1-06 CH3 H COCH3 H CH3 -13.77 -13.45 99 1-07 HH COOCH3 HH -12.55 -11.95 44 1-08 CH3 H COOCH3 H CH3 -13.50 -12.83 53 1-09 HH CN HH -12.59 -12.24 135 1-10 CH3 H CN H CH3 -13.48 -13.28 123 1-11 HF CN HH -12.83 -12.27 86 1-12 HF CN FH -12.79 -12.08 71 1-13 H CH3 H CH3 H -11.97 -11.23 18 1-14 Br H CHO H Br -13.97 -13.67 117 1-15 HH OH HH -11.57 -11.12 12 1-16 H OH H OH H -10.98 -10.48 32
    Table 2
    [0038]
    2-01 HH CHO HH -11.83 -11.63 73 2-02 CH3 H CHO H CH3 -12.93 -12.7 122 2-03 HH COOH HH -11.33 -11.07 57 2-04 CH3 H COOH H CH3 -12.47 -12.12 104 2- 05 HH COCH3 HH -12.56 -12.2 64 2-06 CH3 H COCH3 H CH3 -13.63 -13.23 110 2-07 HH COOCH3 HH -12.22 -11.68 55 2-08 CH3 H COOCH3 H CH3 -13.34 -12.64 76 2-09 HH CN HH -12.29 -11.97 135 2-10 CH3 H CN H CH3 -13.38 -13.18 131 2-11 HF CN HH -12.65 -12.24 103 2-12 HF CN FH -12.77 -12.19 72 2-13 H CH3 H CH3 H -12.05 -11.46 29 2-14 Br H CHO H Br -13.77 -13.48 125 2-15 HH OH HH -11.48 -11.02 27 2-16 H OH H OH H -11.45 -11.16 5
    Table 3
    [0039]
    3-01 HH CHO HH -11.90 -11.67 76 3-02 CH3 H CHO H CH3 -12.22 -11.75 21 3-03 HH COOH HH -11.38 -11.03 49 3-04 CH3 H COOH H CH3 -11.73 -10.76 10 3- 05 HH COCH3 HH -12.45 -12.06 64 3-06 CH3 H COCH3 H CH3 -12.50 -11.53 8 3-07 HH COOCH3 HH -12.27 -11.68 38 3-08 CH3 H COOCH3 H CH3 -12.19 -11.49 7 3-09 HH CN HH -12.13 -11.74 110 3-10 CH3 H CN H CH3 -12.49 -12.10 7 3-11 HF CN HH -12.44 -11.98 86 3-12 HF CN FH -11.93 -11.44 11 3-13 H CH3 H CH3 H -12.51 -12.05 85 3-14 Br H CHO H Br -12.21 -11.74 39 3-15 HH OH HH -11.55 -11.08 16 3-16 H OH H OH H -11.47 -10.77 30
    Table 4
    [0040]
    4-01 HH CHO HH -12.11 -11.96 97 4-02 CH3 H CHO H CH3 -13.21 -12.99 118 4-03 HH COOH HH -11.61 -11.40 87 4-04 CH3 H COOH H CH3 -12.74 -12.45 111 4- 05 HH COCH3 HH -12.81 -12.47 74 4-06 CH3 H COCH3 H CH3 -13.90 -13.48 100 4-07 HH COOCH3 HH -12.55 -12.10 61 4-08 CH3 H COOCH3 H CH3 -13.64 -12.99 78 4-09 HH CN HH -12.55 -12.38 126 4-10 CH3 H CN H CH3 -13.65 -13.48 131 4-11 HF CN HH -12.90 -12.59 87 4-12 HF CN FH -12.93 -12.46 50 4-13 H CH3 H CH3 H -12.19 -11.76 42 4-14 Br H CHO H Br -14.05 -13.81 119 4-15 HH OH HH -11.30 -11.18 83 4-16 H OH H OH H -11.26 -10.90 42
    Table 5
    [0041]
    5-01 HH CHO HH -11.87 -11.68 55 5-02 CH3 H CHO H CH3 -12.76 -12.54 117 5-03 HH COOH HH -11.41 -10.93 50 5-04 CH3 H COOH H CH3 -12.26 -12.03 99 5- 05 HH COCH3 HH -12.58 -12.22 55 5-06 CH3 H COCH3 H CH3 -13.45 -13.04 93 5-07 HH COOCH3 HH -12.29 -11.61 33 5-08 CH3 H COOCH3 H CH3 -13.23 -12.53 72 5-09 HH CN HH -12.30 -12.00 133 5-10 CH3 H CN H CH3 -13.22 -13.03 127 5-11 HF CN HH -12.63 -12.16 60 5-12 HF CN FH -12.61 -12.06 22 5-13 H CH3 H CH3 H -11.93 -11.51 41 5-14 Br H CHO H Br -13.65 -13.37 124 5-15 HH OH HH -11.61 -11.23 21 5-16 H OH H OH H -11.29 -10.80 13
    Table 6
    [0042]
    6-01 HH CHO HH -11.63 -11.32 125 6-02 CH3 H CHO H CH3 -12.22 -11.80 74 6-03 HH COOH HH -11.14 -10.61 96 6-04 CH3 H COOH H CH3 -11.66 -11.26 42 6- 05 HH COCH3 HH -12.27 -11.65 101 6-06 CH3 H COCH3 H CH3 -12.62 -11.95 36 6-07 HH COOCH3 HH -12.13 -11.24 71 6-08 CH3 H COOCH3 H CH3 -12.43 -12.09 22 6-09 HH CN HH -12.03 -11.74 125 6-10 CH3 H CN H CH3 -12.73 -12.34 95 6-11 HF CN HH -12.54 -12.01 76 6-12 HF CN FH -12.15 -11.35 70 6-13 H CH3 H CH3 H -12.01 -11.04 52 6-14 Br H CHO H Br -12.22 -11.91 104 6-15 HH OH HH -11.64 -11.24 10 6-16 H OH H OH H -11.17 -10.96 4
    Table 7
    [0043]
    7-01 HH CHO HH -11.78 -11.45 110 7-02 CH3 H CHO H CH3 -12.81 -12.40 117 7-03 HH COOH HH -11.17 -10.84 17 7-04 CH3 H COOH H CH3 -12.13 -11.52 100 7- 05 HH COCH3 HH -12.31 -11.72 72 7-06 CH3 H COCH3 H CH3 -13.35 -12.68 106 7-07 HH COOCH3 HH -12.05 -11.40 64 7-08 CH3 H COOCH3 H CH3 -13.16 -12.40 83 7-09 HH CN HH -12.11 -11.81 96 7-10 CH3 H CN H CH3 -13.06 -12.65 127 7-11 HF CN HH -12.56 -12.08 94 7-12 HF CN FH -12.69 -12.09 104 7-13 H CH3 H CH3 H -12.59 -12.00 79 7-14 Br H CHO H Br -13.77 -13.30 119 7-15 HH OH HH -11.56 -11.05 29 7-16 H OH H OH H -11.32 -10.97 11
    Table 8
    [0044]
    8-01 HH CHO HH -11.69 -11.41 40 8-02 CH3 H CHO H CH3 -12.56 -12.09 116 8-03 HH COOH HH -11.35 -10.96 22 8-04 CH3 H COOH H CH3 -11.91 -11.28 97 8- 05 HH COCH3 HH -12.04 -11.59 18 8-06 CH3 H COCH3 H CH3 -13.12 -12.46 92 8-07 HH COOCH3 HH -11.84 -11.11 47 8-08 CH3 H COOCH3 H CH3 -12.86 -12.01 86 8-09 HH CN HH -11.98 -11.66 111 8-10 CH3 H CN H CH3 -12.90 -12.53 115 8-11 HF CN HH -12.25 -11.77 73 8-12 HF CN FH -12.21 -11.69 93 8-13 H CH3 H CH3 H -12.35 -11.75 72 8-14 Br H CHO H Br -13.51 -13.06 106 8-15 HH OH HH -11.78 -11.43 34 8-16 H OH H OH H -11.60 -11.19 12
    Table 9
    [0045]
    9-01 HH CHO HH -11.72 -11.53 123 9-02 CH3 H CHO H CH3 -12.49 -12.11 136 9-03 HH COOH HH -11.24 -10.74 103 9-04 CH3 H COOH H CH3 -11.91 -11.42 115 9- 05 HH COCH3 HH -12.38 -11.93 102 9-06 CH3 H COCH3 H CH3 -13.08 -12.51 113 9-07 HH COOCH3 HH -12.21 -11.48 68 9-08 CH3 H COOCH3 H CH3 -12.92 -12.52 33 9-09 HH CN HH -12.09 -11.89 124 9-10 CH3 H CN H CH3 -12.93 -12.62 137 9-11 HF CN HH -12.57 -12.18 116 9-12 HF CN FH -12.71 -12.26 100 9-13 H CH3 H CH3 H -12.16 -11.46 66 9-14 Br H CHO H Br -13.36 -12.99 139 9-15 HH OH HH -11.42 -11.11 30 9-16 H OH H OH H -11.29 -10.61 30
    Table 10
    [0046]
    10-01 HH CHO HH -11.75 -11.46 75 10-02 CH3 H CHO H CH3 -12.64 -12.43 109 10-03 HH COOH HH -11.28 -10.85 59 10-04 CH3 H COOH H CH3 -12.14 -11.83 93 10- 05 HH COCH3 HH -12.45 -11.99 58 10-06 CH3 H COCH3 H CH3 -13.33 -12.99 85 10-07 HH COOCH3 HH -12.13 -11.57 35 10-08 CH3 H COOCH3 H CH3 -13.08 -12.55 55 10-09 HH CN HH -12.18 -11.81 132 10-10 CH3 H CN H CH3 -13.08 -12.89 126 10-11 HF CN HH -12.45 -11.84 70 10-12 HF CN FH -12.46 -11.67 49 10-13 H CH3 H CH3 H -11.69 -11.13 21 10-14 Br H CHO H Br -13.55 -13.29 103 10-15 HH OH HH -11.13 -10.90 12 10-16 H OH H OH H -10.65 -10.37 21
    Table 11
    [0047]
    11-01 HH CHO HH -11.52 -11.25 78 11-02 CH3 H CHO H CH3 -12.60 -12.30 122 11-03 HH COOH HH -11.01 -10.72 58 11-04 CH3 H COOH H CH3 -12.11 -11.75 101 11- 05 HH COCH3 HH -12.20 -11.79 55 11-06 CH3 H COCH3 H CH3 -13.31 -12.84 101 11-07 HH COOCH3 HH -11.95 -11.28 46 11-08 CH3 H COOCH3 H CH3 -13.03 -12.34 85 11-09 HH CN HH -11.95 -11.62 127 11-10 CH3 H CN H CH3 -13.05 -12.78 130 11-11 HF CN HH -12.32 -11.84 109 11-12 HF CN FH -12.43 -11.91 58 11-13 H CH3 H CH3 H -11.73 -11.15 34 11-14 Br H CHO H Br -13.43 -13.08 123 11-15 HH OH HH -11.18 -10.73 25 11-16 H OH H OH H -11.11 -10.65 19
    Table 12
    [0048]
    12-01 HH CHO HH -11.44 -10.99 81 12-02 CH3 H CHO H CH3 -11.92 -11.30 10 12-03 HH COOH HH -10.91 -10.39 43 12-04 CH3 H COOH H CH3 -11.79 -10.78 15 12- 05 HH COCH3 HH -12.08 -11.16 61 12-06 CH3 H COCH3 H CH3 -11.97 -11.01 33 12-07 HH COOCH3 HH -11.83 -11.06 36 12-08 CH3 H COOCH3 H CH3 -12.21 -10.79 9 12-09 HH CN HH -11.78 -11.31 103 12-10 CH3 H CN H CH3 -12.26 -11.32 18 12-11 HF CN HH -12.09 -11.49 66 12-12 HF CN FH -11.68 -11.41 11 12-13 H CH3 H CH3 H -12.38 -11.77 81 12-14 Br H CHO H Br -12.29 -11.52 21 12-15 HH OH HH -11.18 -10.75 28 12-16 H OH H OH H -11.58 -10.80 31
    Table 13
    [0049]
    13-01 HH CHO HH -11.73 -11.44 102 13-02 CH3 H CHO H CH3 -12.82 -12.56 125 13-03 HH COOH HH -11.23 -10.89 79 13-04 CH3 H COOH H CH3 -12.34 -12.01 115 13- 05 HH COCH3 HH -12.41 -12.06 80 13-06 CH3 H COCH3 H CH3 -13.47 -13.09 105 13-07 HH COOCH3 HH -12.17 -11.67 49 13-08 CH3 H COOCH3 H CH3 -13.25 -12.62 79 13-09 HH CN HH -12.16 -11.93 116 13-10 CH3 H CN H CH3 -13.26 -13.01 125 13-11 HF CN HH -12.51 -12.18 88 13-12 HF CN FH -12.57 -12.20 43 13-13 H CH3 H CH3 H -11.87 -11.31 50 13-14 Br H CHO H Br -13.67 -13.39 100 13-15 HH OH HH -10.98 -10.63 28 13-16 H OH H OH H -11.00 -10.46 36
    Table 14
    [0050]
    14-01 HH CHO HH -11.53 -11.15 59 14-02 CH3 H CHO H CH3 -12.39 -12.18 119 14-03 HH COOH HH -11.06 -10.59 53 14-04 CH3 H COOH H CH3 -11.91 -11.60 100 14- 05 HH COCH3 HH -12.16 -11.76 55 14-06 CH3 H COCH3 H CH3 -13.13 -12.65 93 14-07 HH COOCH3 HH -11.85 -11.27 33 14-08 CH3 H COOCH3 H CH3 -12.87 -12.17 53 14-09 HH CN HH -11.97 -11.68 65 14-10 CH3 H CN H CH3 -12.87 -12.64 126 14-11 HF CN HH -12.27 -11.80 35 14-12 HF CN FH -12.20 -11.54 25 14-13 H CH3 H CH3 H -11.52 -11.21 25 14-14 Br H CHO H Br -13.30 -12.96 117 14-15 HH OH HH -11.28 -11.28 1 14-16 H OH H OH H -10.86 -10.68 10
    Table 15
    [0051]
    15-01 HH CHO HH -11.75 -11.46 75 15-02 CH3 H CHO H CH3 -12.64 -12.43 109 15-03 HH COOH HH -11.28 -10.85 59 15-04 CH3 H COOH H CH3 -12.14 -11.83 93 15- 05 HH COCH3 HH -12.45 -11.99 58 15-06 CH3 H COCH3 H CH3 -13.33 -12.99 85 15-07 HH COOCH3 HH -12.13 -11.57 35 15-08 CH3 H COOCH3 H CH3 -13.08 -12.55 55 15-09 HH CN HH -12.18 -11.81 132 15-10 CH3 H CN H CH3 -13.08 -12.89 126 15-11 HF CN HH -12.45 -11.84 70 15-12 HF CN FH -12.46 -11.67 49 15-13 H CH3 H CH3 H -11.69 -11.13 21 15-14 Br H CHO H Br -13.55 -13.29 103 15-15 HH OH HH -11.13 -10.90 12 15-16 H OH H OH H -10.65 -10.37 21
    Table 16
    [0052]
    16-01 HH CHO HH -11.38 -11.04 89 16-02 CH3 H CHO H CH3 -12.41 -11.95 123 16-03 HH COOH HH -10.94 -10.50 3 16-04 CH3 H COOH H CH3 -11.72 -11.07 107 16- 05 HH COCH3 HH -11.92 -11.37 71 16-06 CH3 H COCH3 H CH3 -12.99 -12.34 97 16-07 HH COOCH3 HH -11.77 -10.95 59 16-08 CH3 H COOCH3 H CH3 -12.89 -12.03 87 16-09 HH CN HH -11.82 -11.45 103 16-10 CH3 H CN H CH3 -12.71 -12.28 121 16-11 HF CN HH -12.02 -11.34 82 16-12 HF CN FH -12.01 -11.49 78 16-13 H CH3 H CH3 H -12.27 -11.65 64 16-14 Br H CHO H Br -13.40 -12.87 113 16-15 HH OH HH -11.24 -10.88 30 16-16 H OH H OH H -11.14 -10.85 11
    Table 17
    [0053]
    17-01 HH CHO HH -11.42 -11.13 48 17-02 CH3 H CHO H CH3 -12.18 -11.73 108 17-03 HH COOH HH -11.00 -10.69 27 17-04 CH3 H COOH H CH3 -11.59 -10.86 99 17- 05 HH COCH3 HH -11.78 -11.14 26 17-06 CH3 H COCH3 H CH3 -12.74 -12.13 97 17-07 HH COOCH3 HH -11.48 -10.75 54 17-08 CH3 H COOCH3 H CH3 -12.57 -11.75 77 17-09 HH CN HH -11.62 -11.42 108 17-10 CH3 H CN H CH3 -12.55 -12.16 111 17-11 HF CN HH -12.05 -11.45 67 17-12 HF CN FH -11.92 -11.34 78 17-13 H CH3 H CH3 H -12.06 -11.48 65 17-14 Br H CHO H Br -13.08 -12.66 107 17-15 HH OH HH -11.45 -10.98 39 17-16 H OH H OH H -11.27 -10.86 17
    Table 18
    [0054]
    18-01 HH CHO HH -11.35 -11.02 115 18-02 CH3 H CHO H CH3 -12.15 -11.82 130 18-03 HH COOH HH -10.94 -10.35 81 18-04 CH3 H COOH H CH3 -11.48 -10.96 111 18- 05 HH COCH3 HH -12.12 -11.39 101 18-06 CH3 H COCH3 H CH3 -12.67 -12.15 116 18-07 HH COOCH3 HH -11.84 -10.99 68 18-08 CH3 H COOCH3 H CH3 -12.52 -11.80 84 18-09 HH CN HH -11.85 -11.46 116 18-10 CH3 H CN H CH3 -12.51 -12.26 137 18-11 HF CN HH -12.31 -11.75 103 18-12 HF CN FH -12.35 -11.84 87 18-13 H CH3 H CH3 H -12.02 -10.96 62 18-14 Br H CHO H Br -12.91 -12.47 127 18-15 HH OH HH -11.13 -10.69 33 18-16 H OH H OH H -11.26 -10.52 29
    Table 19
    [0055]
    19-01 HH CHO HH -11.98 -11.77 82 19-02 CH3 H CHO H CH3 -12.71 -12.55 125 19-03 HH COOH HH -11.54 -11.17 53 19-04 CH3 H COOH H CH3 -12.21 -11.92 101 19- 05 HH COCH3 HH -12.47 -12.12 65 19-06 CH3 H COCH3 H CH3 -13.43 -13.09 93 19-07 HH COOCH3 HH -12.14 -11.45 22 19-08 CH3 H COOCH3 H CH3 -13.18 -12.54 61 19-09 HH CN HH -12.36 -12.13 136 19-10 CH3 H CN H CH3 -13.13 -12.96 126 19-11 HF CN HH -12.47 -12.14 91 19-12 HF CN FH -12.41 -11.89 77 19-13 H CH3 H CH3 H -11.71 -11.05 54 19-14 Br H CHO H Br -13.57 -13.39 114 19-15 HH OH HH -11.08 -10.89 80 19-16 H OH H OH H -11.12 -10.86 65
    Table 20
    [0056]
    20-01 HH CHO HH -11.92 -11.72 86 20-02 CH3 H CHO H CH3 -12.57 -12.37 113 20-03 HH COOH HH -11.50 -11.34 47 20-04 CH3 H COOH H CH3 -12.11 -11.72 107 20- 05 HH COCH3 HH -12.36 -12.09 84 20-06 CH3 H COCH3 H CH3 -13.28 -12.89 119 20-07 HH COOCH3 HH -11.91 -11.29 41 20-08 CH3 H COOCH3 H CH3 -12.94 -12.26 80 20-09 HH CN HH -12.14 -11.96 121 20-10 CH3 H CN H CH3 -13.02 -12.80 125 20-11 HF CN HH -12.41 -12.11 101 20-12 HF CN FH -12.40 -11.97 82 20-13 H CH3 H CH3 H -11.56 -11.11 36 20-14 Br H CHO H Br -13.41 -13.15 128 20-15 HH OH HH -11.09 -10.93 95 20-16 H OH H OH H -11.40 -10.99 69
    Table 21
    [0057]
    21-01 HH CHO HH -11.45 -11.14 89 21-02 CH3 H CHO H CH3 -11.81 -11.36 19 21-03 HH COOH HH -10.92 -10.60 53 21-04 CH3 H COOH H CH3 -11.43 -10.72 34 21- 05 HH COCH3 HH -12.06 -11.59 59 21-06 CH3 H COCH3 H CH3 -12.26 -11.49 17 21-07 HH COOCH3 HH -11.91 -11.31 39 21-08 CH3 H COOCH3 H CH3 -12.09 -10.77 11 21-09 HH CN HH -11.81 -11.47 117 21-10 CH3 H CN H CH3 -12.12 -11.36 21 21-11 HF CN HH -12.02 -11.54 86 21-12 HF CN FH -11.33 -10.99 16 21-13 H CH3 H CH3 H -12.29 -11.88 80 21-14 Br H CHO H Br -12.19 -11.61 42 21-15 HH OH HH -11.14 -10.83 9 21-16 H OH H OH H -10.98 -10.59 8
    Table 22
    [0058]
    22-01 HH CHO HH -11.83 -11.62 74 22-02 CH3 H CHO H CH3 -12.77 -12.61 112 22-03 HH COOH HH -11.35 -11.07 79 22-04 CH3 H COOH H CH3 -12.30 -12.07 101 22- 05 HH COCH3 HH -12.54 -12.19 55 22-06 CH3 H COCH3 H CH3 -13.49 -13.13 81 22-07 HH COOCH3 HH -12.29 -11.68 40 22-08 CH3 H COOCH3 H CH3 -13.23 -12.75 55 22-09 HH CN HH -12.26 -11.94 136 22-10 CH3 H CN H CH3 -13.21 -13.03 125 22-11 HF CN HH -12.53 -11.95 73 22-12 HF CN FH -12.40 -11.75 61 22-13 H CH3 H CH3 H -11.73 -11.36 28 22-14 Br H CHO H Br -13.63 -13.44 117 22-15 HH OH HH -11.16 -10.91 14 22-16 H OH H OH H -10.90 -10.44 6
    Table 23
    [0059]
    23-01 HH CHO HH -11.55 -11.40 75 23-02 CH3 H CHO H CH3 -12.63 -12.41 116 23-03 HH COOH HH -11.02 -10.80 62 23-04 CH3 H COOH H CH3 -12.14 -11.88 107 23- 05 HH COCH3 HH -12.24 -11.94 70 23-06 CH3 H COCH3 H CH3 -13.32 -12.96 97 23-07 HH COOCH3 HH -11.99 -11.27 40 23-08 CH3 H COOCH3 H CH3 -13.09 -12.49 89 23-09 HH CN HH -11.98 -11.66 124 23-10 CH3 H CN H CH3 -13.06 -12.85 126 23-11 HF CN HH -12.33 -11.96 116 23-12 HF CN FH -12.45 -11.78 83 23-13 H CH3 H CH3 H -11.65 -11.08 30 23-14 Br H CHO H Br -13.47 -13.16 106 23-15 HH OH HH -10.99 -10.59 23 23-16 H OH H OH H -11.02 -10.40 30
    Table 24
    [0060]
    24-01 HH CHO HH -11.48 -11.21 78 24-02 CH3 H CHO H CH3 -12.32 -11.67 19 24-03 HH COOH HH -10.96 -10.69 68 24-04 CH3 H COOH H CH3 -11.59 -10.89 5 24- 05 HH COCH3 HH -12.05 -11.62 71 24-06 CH3 H COCH3 H CH3 -12.65 -11.98 11 24-07 HH COOCH3 HH -11.91 -11.29 31 24-08 CH3 H COOCH3 H CH3 -11.94 -10.91 7 24-09 HH CN HH -11.85 -11.40 12 24-10 CH3 H CN H CH3 -12.84 -11.81 17 24-11 HF CN HH -12.05 -11.58 74 24-12 HF CN FH -11.43 -10.62 49 24-13 H CH3 H CH3 H -12.23 -11.87 85 24-14 Br H CHO H Br -12.24 -11.99 9 24-15 HH OH HH -11.11 -10.75 11 24-16 H OH H OH H -10.93 -10.68 11 BE is the estimated binding free energy. ABE is the mean binding energy. NOC is the number of shapes in this cluster.
    The compounds of the present invention can be synthesized by various methods. The starting materials and reagents used in the synthesis are available from commercial suppliers or can be prepared by known methods. The following synthesis reaction scheme as Scheme 1 is merely an illustration of a method for synthesizing a compound of the present invention. The preparation of the compounds of the following examples is not intended to limit the scope of the invention. Various modifications to the synthesis reaction scheme are intended to be included within the scope of the present invention.
    The precursors and intermediates of the synthesis reaction scheme can be isolated and purified by conventional techniques such as filtration, distillation, crystallization, and chromatography. Similarly, characterization of these materials can be performed using conventional means including physical constants and spectral data.
    Unless stated otherwise, the reaction described here is preferably carried out under an inert atmosphere at atmospheric pressure in a reaction temperature range from about 50 ° C to about 150 ° C, preferably from about 80 ° C to about 120 ° C most preferably and conveniently at about 120 ° C. The reaction conditions are exemplary.
    In general, the nomenclature used in the description is based on ChambridgeSoft ™ v. 12.0 for creating the IUPAC systematic nomenclature. If there is a discrepancy between a structure shown and its name, the structure shown should be given more weight.
    In the meantime, 4 - ((2 - ((4-cyanophenyl) amino) quinolin-4-yl) oxy) -3,5-dimethylbenzonitrile in 30% yield by coupling 2,4-dichloroquinoline with 4-hydroxy-3,5-dimethylbenzonitrile. The final compound is obtained from the nucleophilic substitution reaction of 4 - ((2-chloroquinolin-4-yl) oxy) -3,5-dimethylbenzonitrile with 4-aminobenzonitrile (Scheme 1).
    Process for the preparation of 4 - ((2 - ((4-Cyanophenyl) amino) quinolin-4-yl) oxy) -3,5-dimethylbenzonitrile.
    Example 1: Synthesis of 4 - ((2-chloroquinolin-4-yl) oxy) -3,5-dimethylbenzonitrile 4-hydroxy-3,5-dimethylbenzonitrile (247 mg) and cesium carbonate (100 mg) were made into one Solution of 2,4-dichloroquinoline (300 mg) given in redistilled DMF (15 ml). The mixture was stirred at 80 ° C. under the protection of argon. After the reaction, thin layer chromatography was carried out until it was completed. H2O with ice (50 ml) was added and the aqueous solution extracted with EtOAc (3 × 15 ml). The combined organic layer was washed with saturated saline (20 ml), dried over anhydrous Na2SO4, and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 10% EtOAc / hexane to obtain the target compound (280 mg; 59% yield).
    Example 2: Synthesis of 4 - ((2 - ((4-Cyanophenyl) amino) quinolin-4-yl) oxy) -3,5-dimethylbenzonitrile
    Pd (OAc) 2 (5 mg) and PhDavePhos (8.6 mg) were added to a solution of 4 - ((2-chloroquinolin-4-yl) oxy) -3,5-dimethylbenzonitrile (70 mg) and 4-aminobenzonitrile (35 mg) in redistilled DMF (5 ml) was added. The mixture was stirred at 120 ° C. under the protection of argon. After the reaction, thin layer chromatography was carried out until it was completed. H2O with ice (50 ml) was added and the aqueous solution extracted with EtOAc (3 × 15 ml). The combined organic layer was washed with saturated saline (20 ml), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography using 15% EtOAc / hexane to give the target compounds (45 mg; 51% yield).
    The pharmaceutical compositions of the present invention comprise a compound based on the invention and one or more pharmaceutically acceptable carriers, excipients or diluents. Other therapeutic substances are optional. Pharmaceutical compositions containing a compound according to the invention as an active ingredient can be in any form which is suitable for the intended method of administration. When used orally, tablets, troches, coated tablets, aqueous or oil suspensions, dispersible powders or granulates, emulsions, hard or soft capsules, syrups or elixirs can be produced. Compositions intended for oral use can be prepared by any conventional method for preparing pharmaceutical compositions which may contain one or more substances, such as antioxidants, sweeteners, flavorings, colors and preservatives, to provide a palatable preparation. Tablets containing an active ingredient in the mixture with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets are possible. These auxiliaries can be inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; Granulating and disintegrating agents such as corn starch or alginic acid; Binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or coated by conventional methods such as microencapsulation in order to delay disintegration and absorption in the gastrointestinal tract and thereby achieve a sustained effect over a long period of time.
    The drug intended for oral use can also be offered as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as pregelatinized starch, calcium phosphate or kaolin; or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
    Aqueous and oil-containing suspensions according to the invention contain the active ingredients in the mixture with auxiliaries which are suitable for the preparation of aqueous suspensions. Such adjuvants include a suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersants or wetting agents such as naturally occurring phosphatide (e.g. lecithin), a condensation product of alkylene oxide with a fatty acid (e.g. polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain of aliphatic alcohol (e.g. heptadecaethyleneoxycetanol) and a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol anhydride (e.g. polyoxyethylene sorbitan monooleate).
    The aqueous suspension can also contain one or more preservatives (ethyl or n-propyl p-hydroxybenzoate), colorants, flavorings and sweeteners (such as sucrose, sucralose or saccharin).
    Oil suspensions can be formulated by suspending the active ingredient in vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in mineral oil such as liquid paraffin. The oral suspensions can contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavors can be added to provide a palatable oral preparation. These compositions can be preserved with the addition of an antioxidant such as ascorbic acid and butylated hydroxytoluene (BHT).
    The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated by methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fatty oils can be used as a solvent or suspending medium. Any mild fatty oil, including synthetic mono- or diglycerides, can be used for this purpose. Fatty acids such as oleic acid can also be used in the manufacture of injectables.
    The pharmaceutical compositions of the invention can be injected parenterally. In particular, they can be injected intravenously, intraperitoneally, intrathecally, intraventricularly, intracranially, intramuscularly or subcutaneously. They can also be given via infusion techniques. They are used in the form of a sterile aqueous solution, which may contain other substances such as salts or glucose, to make the solution isotonic with blood. The aqueous solutions should, if necessary, be suitably buffered. The preparation of suitable parenteral formulations under sterile conditions is easily accomplished by standard pharmaceutical techniques.
    Dispersible powders and granules according to the invention, which are suitable for the preparation of an aqueous suspension with the addition of water, provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Additional substances such as sweeteners, flavorings and colorings can also be present.
    A combination of the compound of the invention and other ARV agents for treating or preventing HIV infection is also provided.
    For the purpose, other ARV drugs / agents or anti-HIV agents can be selected from nucleoside and nucleotide reverse transcription inhibitors (NRTIs), NNRTIs, protease inhibitors (Pls), maturation inhibitors (Mls) and any of their combinations. The term "nucleosides and NRTIs" used in the pre-determined study refers to the nucleosides, nucleotides, and their analogs that inhibit the activity of HIV-1 RT, thereby causing the conversion of HIV-1 viral genomic RNA into HIV-1 proviral DNA is catalyzed.
    NRTIs that can be used in combination with the present invention include zidovudine; Didanosine; Stavudine; Lamivudine; Abacavir; Adefovir; Lobucavir; Entecavir; Apricitabine; Emtricitabine; Zalcitabine; Dexelvucitabine; Alovudine; Amdoxovir; Elvucitabine; AVX754; BCH-189; Phosphazide; Racivir; SP 1093V; Stampidin; BCH-10652, p-L-FD4 (also called -L-D4C and called P-L-2 ', 3'-Dicleoxy-5-fluorocytiden); DAPD, the purine nucleoside (-) - P-D-2,6-diamino-purinedioxolane; Lodenosine (FddA), 9- (2,3-dideoxy-2-fluoro-D-threopentofiranosyl) adenine; and any combination thereof.
    NRTIs that can be used in the pharmaceutical composition of the present invention can include tenofovir, adefovir, emtricitabine, lamivudine, zidovudine, or any combination thereof.
    NNRTIs that can be used in combination with the present invention can include nevirapine, rilpivirine, delaviridine, efavirenz, and ETR. Other NNRTIs include PNU-142721, fiiropyridine-thiopyrimide; Capravirine (S-1153 or AG-1 549; 5- (3,5-dichlorophenyl) -thio-4-isopropyl-1- (4-pyridyl) methyl-1H-imidazol-2-ylmethyl carbonate); Emivirin [MKC-442; (1- (Ethoxymemyl) -5- (1-methylethyl) -6- (phenylmethyl) - (2,4 (1H, 3H) -pyrimid-inedione)]; (+) - calanolide A (NSC-67545 1 ) and B, coumarin derivatives; DAPY (TMC120; 4- {4- [4 - ((E) -2-cyano-vinyl) -2,6-dimethyl-phenylamino] -pyrimidin-2-ylamino-] - benzonitrile ); BILR-355 BS (12-ethyl-8- [2- (1-hydroxy-quinolin-4-yloxy) -ethyl] -5-methyl-1, 1,12-dihydro-5H-1, 5, 10 , 12-tetraaza-dibenzo [a, e] cycloocten-6-one; and PHI-236 (7-bromo-3- [2- (2,5-dimethoxyphenyl) -ethyl] -3,4-dihydro-IH- pyrido [1,2-a] [-1,3,5] triazine-2-thione) and PHI-443 (TMC-278, 1- (5-bromo-pyridin-2-yl) -3- (2- thiophen-2-yl-ethyl) thiourea).
    Pls that can be used in the pharmaceutical composition of the present invention may include saquinavir; Ritonavir; Nelfinavir; Amprenavir; Lopinavir, indinavir; Nelfinavir; Atazanavir; Lasinavir; Palinavir; Tipranavir; Fosamprenavir; Darunavir; TMC114; DMP450, a cyclic urea; BMS-2322623, BMS-232623; GS3333; KNI-413; KNI-272; LG-71350; CGP-61755; PD 173606; PD 177298; PD 178390; PD 178392; U-140690; ABT-378; and AG-1549, an imidazole carbamate. Additional PIs include N-cycloalkylglycines, α-hydroxyarylbutanamides; α-Hydroxy-γ - [[(carbocyclic or heterocyclic substituted) amino) carbonyl] alkanamide derivatives; γ-hydroxy-2- (fluoroalkylaminocarbonyl) -1-piperazine pentanamides; Dihydropyrone derivatives and α- and β-amino acid hydroxyethylaminosulfonamides; and N-amino acid substituted L-lysine derivatives.
    ARV agents can be used in the form of salts or esters derived from inorganic or organic acids.
    A combination of the compound of the invention and other chemotherapeutic agents for treating or preventing HIV infection is also provided.
    Other chemotherapeutic agents such as vinca alkaloids, agents that interfere with microtubule formation (e.g., colchicine and its derivatives), anti-angiogenic agents, therapeutic antibodies, EGFR targeting agents, tyrosine kinase targeting agents (e.g., tyrosine kinase inhibitors), transition metal complexes, proteasome inhibitors , Antimetabolites (e.g. nucleoside analogs), alkylating agents, platinum-based agents, anthracycline antibiotics, topoisomerase inhibitors, macrolides, therapeutic antibodies, retinoids (e.g. all-trans retino acids or a derivative thereof), geldanamycin or a derivative thereof (e.g. 17 -AAG) and other standard chemotherapeutic agents.
    Other chemotherapeutic agents may include adriamycin, colchicine, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, mitoxantrone, fluorouracil, carboplatin, carmopine (BCNU), carmopine (BCNU) and their derivatives, phenesterol, taxanes and derivatives thereof (e.g. paclitaxel and derivatives thereof, taxotere and derivatives thereof), toptecan, vinblastine, vincristine, tamoxifen, piposulfan, nab-5404, nab-5800, nab-5801, irinotecan, HKP, ortataxel , Gemcitabine, Herceptin®, Vinorelbine, Doxil®, Capecitabine, Alimta®, Avastin®, Velcade®, Tarceva®, Neulasta®, Lapatinib, Sorafenib, derivatives thereof, chemotherapeutic agents known in the art, and the like.
    Other chemotherapeutic agents may include an antineoplastic agent such as Carboplatin, Navelbin® (Vinorelbine), Anthracycline (Doxil®), Lapatinib (GW57016), Herceptin®, Gemcitabine (Gemzar®), Capecitabine (Xeloda®), Alimta®, Cisplatin, 5-fluorouracil, epirubicin, cyclophosphamide, Avastin ® and Velcade ®.
    Other chemotherapeutic agents can include antagonists such as EGFR, ErbB2 (also known as Herb), ErbB3, ErbB4, and TNF, which are involved in tumor growth.
    These chemotherapeutic agents apply to chemotherapeutic agents or their derivatives or analogs.
    Table 25 shows some examples of representative compounds evaluated which have inhibitory effects on HIV infection and cancer proliferation. Their inhibitory results are given in Tables 26-27 for reference. They are not to be regarded as limiting the scope of protection of the invention, but merely as representations and representations.
    In vitro HIV-1 Reverse Transcriptase (HIV-1 RT) Kit Assay
    The HIV RT inhibition assay was performed using an RT assay kit (Roche) according to the protocol of the kit. Briefly, the reaction mixture consisted of template / primer complex, 2 / -deoxynucleotide-5 / -triphosphates (dNTPs) and RT enzyme in the lysis buffer with or without inhibitors. After incubation at 37 ° C. for 1 hour, the reaction mixture was transferred to a microtiter plate (MTP) coated with streptavidin. Biotin-labeled dNTPs were incorporated into the template due to the activity of the RT bound to steptavidin. The unbound dNTPs were washed with washing buffer and antidigoxigenin peroxidase (anti-DIG-POD) was added to the MTP. The digoxigenin-labeled dNTPs built into the template were bound to the anti-DIG-POD antibody. The unbound anti-DIG-POD was washed and the peroxide substrate (ABST) was added to the MTP. A colored reaction product was generated during cleavage of the substrate catalyzed by a peroxide enzyme. The absorbance of the sample was determined at OD 405 nM using a microtiter plate ELISA reader.
    The resulting color intensity was directly proportional to the actual RT activity. The percent inhibitory activity of the RT inhibitors was calculated by comparison with that of the sample without inhibitor.
    The HIV-1 RT inhibitory activity of compounds 1-8 in Table 25 was tentatively assessed by their percentage inhibition of HIV-RT activity in the HIV-1 RT kit compared to those of NVP, EFV and Rilpivirine was determined. The results are shown in Table 26.
    Table 26 Inhibitory activity of compounds 1-8, nevirapine, efavirenz, rilpivrine against HIV-1 RT
    1 42.08 2 43.37 3 39.62 4 62.23 5 40.31 6 47.16 7 39.71 8 27.61 nevirapine 55.58 efavirenz 96.20 rilpivirine 96.48
    Cytotoxic activity
    The cell lines were sown in a 96-well microplate (Costar No. 3599, USA) with 100 μl / well and a density of 5 × 10 3 × 10 4 cells / well. Background control wells contained the same volume of total culture medium. The microplate was incubated for 24 hours at 37 ° C., 5% CO 2 and 95% atmospheric humidity (Shellab, USA). Samples at various concentrations were added to the microplate, which was incubated for an additional 48 hours. Cell viability was determined by staining with the MTT assay [3 (4,5-dimethylthiazol-2-yl) -2-5-diphenyltetrazolium bromide (Sigma-Aldrich, St. Louis, MO, USA)]. The reagent was dissolved in 5 mg / ml phosphate buffered saline and filtered to sterilize and remove the small amount of insoluble residue present in some lots of MTT. MTT solution (10 µl / 100 µl medium) was added to all wells of each well array and the plates were incubated for 2-4 hours at 37 ° C, 5% CO2, and 95% humidity. Dimethyl sulfoxide (Merck, Germany) (100 µl) was then added to dissolve the resulting formazan using ultrasound.
    The plates were read on a microplate reader (Molecular Devices, CA, USA). OD was measured at a test wavelength of 550 nm and a reference wavelength of 650 nm.
    XTT arrangement (3 '- [1 - [(phenylamino) carbonyl] -3,4-tetrazolium] bis (4-methoxy-6-nitro) benzenesulfonic acid hydrate) for suspension cells was carried out in acute lymphoblastic leukemia (MOLT- 3). The plates were incubated for 4 h after the addition of 50 μL of a mixture containing 1 mg / ml sample (5 ml) and 0.383 mg / ml phenazine methosulfate (100 μl).
    The absorbance of the orange formazan compound formed was measured at wavelengths of 492 and 690 nm. The IC50 values were determined in the same way as the drug and sample concentrations at 50% inhibition of cell growth.
    The cytotoxic activity of the compounds 1-8 shown in Table 25 was evaluated in advance by determining their cytotoxic activities against hepatocarcinoma, acute lymphoblastic leukemia, cholangiocarcinoma and lung carcinoma. Their cytotoxic activities were then compared with those of etoposide and doxorubicin hydrochloride. The results are shown in Table 27.
    Table 27 in vitro cytotoxic activity of the compounds tested against human cancer cell lines <2>
    [0100] 1 21.55 ± 5.23 2.62 ± 0.30 4.7 ± 0.30 6.37 ± 0.56 2 25.95 ± 2.40 4.63 ± 0.62 11.58 ± 0.77 20.13 ± 1.20 3 41.63 ± 6.80 8.76 ± 0.75 ≥ 50 ≥ 50 4 36.53 ± 4.65 4.98 ± 0.43 49.5 ± 0.7 42.44 ± 0.48 5 38.67 ± 2.87 ≥ 50 35.02 ± 4.65 23.28 ± 2.40 6 ≥ 50 19.04 ± 6.02 ≥ 50 ≥ 50 7> 50 ≥ 50 ≥ 50 ≥ 50 8 39.96 ± 0.26 5.12 ± 0.41 8.31 ± 0.33 5.09 ± 0.81 Etoposide 21.14 ± 0.70 0.048 ± 0.007 N / A NA Doxorubicin Hydrochloride 0.23 ± 0.02 N / A 0.89 ± 0.04 0.19 ± 0.01 <a> HepG2 (hepatocarcinoma), MOLT-3 (acute lymphoblastic leukemia), HuCCA-1 (cholangiocarcinoma ), A549 (lung cancer) <b> Results are expressed as the mean ± standard error of perceptual inhibition for all cell lines. Doxorubicin and etoposide were used as positive controls. The experiments were carried out in triplicate.
    Docking protocol
    The docking studies were carried out with Auto Dock 4.2 as described by Olson et al. (Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS and Olson AJ. J. Comput. Chem. 2009 16: 2785-91).
    权利要求:
    Claims (6)
    [1]
    1. Compound according to formula (I): whereinX and Y can be identical or different and represent O, NH or S;R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 can be the same or different and represent H, halogen, CN, NO2, (C1-4) -alkyl, (C1-4) -haloalkyl, ( C2-4) -alkenyl, OH, O (C1-4) -alkyl, O (C1-4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO, C2-4-alkenyl, substituted with CN, C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted CHO or C2- 4-alkenyl substituted with OH;R <A> and R <B> can be identical or different and both represent H, (C1-4) -alkyl, (C1-4) -haloalkyl or (C2-4) -alkenyl;A1, A2, A3 and A4 can be the same or different and are CH or N, with the proviso that A1 and A2 cannot both be N, and R5 and R10 are absent when A3 and A4 areN;or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    [2]
    2. A compound according to claim 1, whereinX and Y are different and represent O, NH or S;R1, R2, R3, R4 and R5 can be the same or different and represent H, halogen, CN, NO2, (C1-4) -alkyl, (C1-4) -haloalkyl, (C2-4) -alkenyl, OH, O (C1-4) -Alkyl, O (C1-4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO, C2-4-alkenyl substituted with CN, C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted with CHO or C2-4-alkenyl substituted with OH;R6, R7, R8, R9 and R10 can be the same or different and stand for H, CN, NO2, (C1-4) -haloalkyl, (C2-4) -alkenyl, OH, O (C1-4) -alkyl, O ( C1-4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B>, C (O) R <A>, CO2R <A>, CHO , C2-4-alkenyl substituted with CN, C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted with CHO or C2.4-alkenyl substituted with OH;R <A> and R <B> can be identical or different and represent H, (C1-4) -alkyl, (C1-4) -haloalkyl or (C2-4) -alkenyl;A1 and A2 are different and represent CH and N,A3 and A4 may be the same or different and represent CH or N, where R5 and R10 are absent when A3 and A4 areN;or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    [3]
    3. A compound according to claim 1, whereinX and Y are different and represent O, NH or S;R1, R2, R4, R5, R6, R7, R9 and R10 can be the same or different and represent H, halogen, CN, NO2, (C1-4) -alkyl, (C1-4) -haloalkyl, (C2-4) -Alkenyl, OH, O (C1-4) -alkyl, O (C1-4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B> , C (O) R <A>, CO2R <A>, CHO, C2-4-alkenyl substituted with CN, C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted with CHO or C2-4-alkenyl substituted with OH;R3 is CN,R8 is CHO or C2-alkenyl, substituted with CN,R <A> and R <B> can be identical or different and represent H, (C1-4) -alkyl, (C1-4) -haloalkyl or (C2-4) -alkenyl;A1 and A2 are different and represent CH or N,A3 and A4 can be the same or different and represent CH or N, where R5 and R10 are absent when A3 and A4 are N,or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    [4]
    4. A compound according to claim 1, whereinX and Y are different and represent O, NH or S; R1, R2, R4, R5, R6, R7, R9 and R10 can be the same or different and represent H, halogen, CN, NO2, (C1-4) -alkyl, (C1-4) -haloalkyl, (C2-4) -Alkenyl, OH, O (C1-4) -alkyl, O (C1-4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B> , C (O) R <A>, CO2R <A>, CHO, C2-4-alkenyl substituted with CN, C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted with CHO or C2-4-alkenyl substituted with OH;R3 is CN,R8 is CHO,R <A> and R <B> can be identical or different and represent H, (C1-4) -alkyl, (C1-4) -haloalkyl or (C2-4) -alkenyl;A1 is N,A2 is CH,A3 is N, where R5 is missing,A4 is C, where R10 is present,or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    [5]
    5. A compound according to claim 1, whereinX and Y are different and represent O, NH or S;R1, R2, R4, R5, R6, R7, R9 and R10 can be the same or different and represent H, halogen, CN, NO2, (C1-4) -alkyl, (C1-4) -haloalkyl, (C2-4) -Alkenyl, OH, O (C1-4) -alkyl, O (C1-4) -haloalkyl, N (R <A>) R <B>, C (O) N (R <A>) R <B> , C (O) R <A>, CO2R <A>, CHO, C2-4-alkenyl substituted with CN, C2-4-alkenyl substituted with COOH, C2-4-alkenyl substituted with CHO or C2-4-alkenyl substituted with OH;R3 is CNR8 is CHO,R <A> and R <B> can be identical or different and represent H, (C1-4) -alkyl,(C1-4) haloalkyl or (C2-4) alkenyl;A1 is CH,A2 is N,A3 is N, where R5 is missing,A4 is C, where R10 is present,or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a mixture comprising stereoisomers thereof.
    [6]
    6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in an HIV or cancer inhibiting proportion, and one or more pharmaceutically acceptable carriers, excipients or diluents.
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    同族专利:
    公开号 | 公开日
    EP3676252A4|2021-03-31|
    JP6965432B2|2021-11-10|
    US10889566B2|2021-01-12|
    JP2020536844A|2020-12-17|
    EP3676252A1|2020-07-08|
    US20200223820A1|2020-07-16|
    WO2019045655A1|2019-03-07|
    CN111032629A|2020-04-17|
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    法律状态:
    优先权:
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    PCT/TH2017/000066|WO2019045655A1|2017-08-29|2017-08-29|Derivatives and composition of quinoline and naphthyridine|
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