• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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    • 专利摘要:
    Use of non-peptidic nk1 antagonists in a certain dose for the treatment of cancer. Use of the non-peptide antagonist of the nk1 receptor, preferably aprepitant, for the treatment of cancer in determined doses. The present invention further describes pharmaceutical compositions comprising said agents, alone or in combination with at least one other active ingredient, for the treatment of cancer. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2541870A1
    申请号:ES201331923
    申请日:2013-12-27
    公开日:2015-07-27
    发明作者:Manuel Vicente Salinas Martín
    申请人:Servicio Andaluz de Salud；
    IPC主号:
    专利说明:

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    760735. Similarly, other non-peptide antagonist compounds of NK1 and SP receptors such as: Vofopitant or GR-205171 (Pfizer), Ezlopitant or CJ 11974 (Pfizer), CP-122721 (Pfizer), L- can be used. 758298 (MSD), L-741671, L-742694, CP-99994, Lanepitant or LY-303870, T-2328, LY-686017. Compounds are preferred: Aprepitant or MK 869 or L-754030 (MSD), Vestipitant or GW597599 (GSK) and Casopitant or GW679769 (GSK).
    Therefore, in another preferred embodiment, the NK1 receptor non-peptide antagonist is selected from the list consisting of: Aprepitant, Vestipitant, Casopitant, Vofopitant, Ezlopitant, Lanepitant, LY-686017, L-733,060, L-732,138, L- 703.606, WIN 62.577, CP122721, TAK-637, R673, CP-100263, WIN 51708, CP-96345, L-760735, CP-122721, L758298, L-741671, L-742694, CP-99994, T-2328, or any of its combinations. In a more specific embodiment, antagonists selected from: Aprepitant, Vestipitant, Casopitant, Vofopitant, Ezlopitant and Lanepitant, or any combination thereof are especially preferred. Even more preferably, the non-peptide antagonist of the NK1 receptor is Aprepitan.
    In another preferred embodiment of this aspect of the invention, the cancer is selected from the list comprising: gastric carcinoma, colon carcinoma, pancreas carcinoma, breast carcinoma, ovarian carcinoma, endometrial carcinoma, choriocarcinoma, cervical carcinoma uterine, lung carcinoma, thyroid carcinoma, bladder carcinoma, prostate carcinoma, glial tumors of the central nervous system, sarcomas, melanomas, embryonic cancers and hematological cancers. In another more preferred embodiment, the cancer is affected by the peritumoral environment. In another more preferred embodiment, the cancer that is present with alteration of the peritumoral environment shows an increase in the synthesis of the markers selected from the list consisting of: NF-kB, EGF, VEGF, TNF-α, TGF-α, TGF- β 1, TGF-β 2, TGF-β 3, SPARC, MMP-3; MMP-7, MMP-9, MMP11, MMP-13, MMP-14 and / or combinations thereof.
    In another preferred embodiment, the mammal is human. Even more preferably, the cells of the tumors treated for the purpose of the invention overexpress the markers NF-kB, EGF, VEGF, TNF-α, TGF-α, TGF-β 1, TGF-β 2, TGF-β 3, SPARC, MMP-3; MMP-7, MMP-9, MMP-11, MMP-13, MMP-14 and / or any combination thereof.
    A second aspect of the invention relates to the use of a combined preparation comprising a non-peptide NK1 receptor antagonist in a given dose of the
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    preferred, cancer is affected by peritumoral environment. In another more preferred embodiment, the cancer that is affected by the alteration of the peritumoral environment shows an increase in the synthesis of the following markers selected from the list comprising: NF-kB, EGF, VEGF, TNF-α, TGF-α, TGF- β 1, TGF-β 2, TGF-β 3, SPARC, MMP-3; MMP-7, MMP-9, MMP-11, MMP-13, MMP-14 and / or combinations thereof.
    In another preferred embodiment, the mammal is human. Even more preferably, the cells of the tumors treated for the purpose of the invention overexpress the markers NF-kB, EGF, VEGF, TNF-α, TGF-α, TGF-β 1, TGF-β 2, TGF-β 3, SPARC, MMP-3; MMP-7, MMP-9, MMP-11, MMP-13, MMP-14 and / or any combination thereof.
    A third aspect of the invention relates to a composition, hereinafter composition of the invention, which comprises a non-peptide NK1 receptor antagonist a given dose of the invention. In a preferred embodiment, the NK1 receptor non-peptide antagonist is selected from the list consisting of: Aprepitant, Vestipitant, Casopitant, Vofopitant, Ezlopitant, Lanepitant, LY-686017, L-733,060, L-732,138, L-703,606, WIN 62,577, CP-122721, TAK-637, R673, CP-100263, WIN 51708, CP-96345, L-760735, CP-122721, L-758298, L-741671, L-742694, CP-99994, T-2328 , or any of its combinations. In a more specific embodiment, antagonists selected from: Aprepitant, Vestipitant, Casopitant, Vofopitant, Ezlopitant and Lanepitant, or any combination thereof are especially preferred. Even more preferably, the non-peptide antagonist of the NK1 receptor is Aprepitan.
    In another preferred embodiment of this aspect of the invention, the composition of the invention is a pharmaceutical composition. More preferably, the composition may further comprise a pharmaceutically acceptable carrier and / or excipients. Even more preferably, it additionally comprises at least one other active ingredient (active ingredient B). Preferably, the active ingredient B is selected from the list consisting of: Chlorambucil, Melphalan, Aldesleukin, 6-Mercaptopurine, 5-Fluoruracil, Ara-c, Bexarotene, Bleomycin, Capecitabine, Carboplatin, Cisplatin, Docetaxel, Doxorubicin, Epirrubinacin, Fluirubicin , Irinotecan Methotrexate, Mitoxantrone Oxaliplatin, Paclitaxel, Rituximab, Vinblastine, Etoposide, Teniposide, Vincristine, Vinorelbine, Imatinib, Erlotinib, Cetuximab Trastuzumab, or any combination thereof.
    In another preferred embodiment it refers to the use of a pharmaceutical composition comprising a non-peptide NK1 receptor antagonist in the preparation of a
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    Pharmaceutically acceptable can be selected for their ability to improve patient acceptance. Suitable pharmaceutically acceptable excipients include the following types of excipients, not excluding others known in the state of the art: diluents, fillers, binders, disintegrants, lubricants, glidants, granulation agents, coating agents, moisturizing agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavorings, flavor masking agents, coloring agents, anti-cake agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents. The person skilled in the art will appreciate that certain pharmaceutically acceptable excipients can perform more than one function and can perform alternative functions depending on the amount of excipient that is present in the formulation and what other ingredients are present in the formulation. The specialists have the knowledge and skill in the art that allows them to select suitable pharmaceutically acceptable excipients in the appropriate amounts for use in the invention. In addition, there are several resources available to those skilled in the art that describe pharmaceutically acceptable excipients and may be useful in the selection of suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
    The dosage of the active ingredient, in the present invention, of the NK1 receptor non-peptide antagonist, will be selected depending on the desired therapeutic effect, the route of administration and the duration of treatment. The dose of administration and the frequency will depend on the size, age and general health conditions of the individual, taking into account the possibility of side effects. Administration will also depend on the simultaneous treatment with other drugs and the tolerance of each individual to the drug administered. Persons skilled in the art may establish the appropriate dose using standard procedures. It is understood that the dose should be the effective amount of the active ingredient, peritumoral environment modulating agent, preferably non-peptide NK1 antagonist, in the sense that the treatment has at least the same or better effect than the current therapies in these patients.
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    measured and the mice were evaluated for their health status and weight daily. The mice were randomized in nine groups when the tumors reached a volume of 75 mm3. One of the groups was treated with 200 µl of placebo (control group) and the remaining eight groups with doses of 10 (group 1), 20 (group 2), 30 (group 3), 40 (group 4), 50
    5 (group 5), 60 (group 6), 70 (group 7) and 80 (group 8) mg per kilogram of weight and day of the NK1 Aprepitant receptor antagonist. Three animals were treated for each group, for 28 days. All mice were sacrificed at the end of the experiment. Table 1 shows the size of the tumor (in cubic millimeters ± standard deviation) at 7, 14, 21 and 28 days of treatment, respectively with each of the doses used.
    10 Table 1. Tumor size of tumors caused in an in vivo mouse model. Mean tumor volume in control mice (untreated) or in mice after treatment with the NK1 receptor non-peptide antagonist (Aprepitant).
    Lung carcinoma cell line reference HCC-44. 7 days14 days21 days28 days
    Control 230 ± 6270 ± 5310 ± 6340 ± 8
    Group 1 (10 mg / kg / day) 210 ± 2190 ± 4165 ± 6135 ± 3
    Group 2 (20 mg / Kg / day) 205 ± 8170 ± 3145 ± 4110 ± 4
    Group 3 (30 mg / Kg / day) 185 ± 4150 ± 6135 ± 5105 ± 2
    Group 4 (40 mg / Kg / day) 155 ± 5130 ± 4120 ± 495 ± 4
    Group 5 (50 mg / Kg / day) 130 ± 4115 ± 7105 ± 685 ± 6
    Group 6 (60 mg / kg / day) 110 ± 395 ± 880 ± 765 ± 4
    Group 7 (70 mg / Kg / day) 95 ± 480 ± 665 ± 840 ± 7
    Group 8 (80 mg / Kg / day) 70 ± 455 ± 740 ± 625 ± 5
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    Example 2. Treatment with non-peptide antagonists of NK1 receptors at doses between 10 and 80 mg per kilogram of weight and day reduces the size of cancerous tumors of glial line (eg, astrocytomas) of the system
    20 central nervous in mammals.
    To verify that the administration of non-NK1 receptor antagonists at doses between 10 and 80 mg per kilogram of weight and day reduces, the size of the glial line tumors of the nervous system in mammals, cells were implanted
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    Table 3. Tumor size of tumors caused in an in vivo mouse model. Mean tumor volume in control mice (untreated) or in mice after treatment with the NK1 receptor non-peptide antagonist (Aprepitant).
    Fibrosarcoma cell line reference HT-1080. 7 days14 days21 days28 days
    Control 255 ± 5270 ± 3310 ± 4340 ± 7
    Group 1 (10 mg / kg / day) 220 ± 4205 ± 4195 ± 6170 ± 6
    Group 2 (20 mg / Kg / day) 195 ± 5180 ± 5165 ± 7150 ± 7
    Group 3 (30 mg / Kg / day) 175 ± 5155 ± 6135 ± 5140 ± 4
    Group 4 (40 mg / Kg / day) 160 ± 4150 ± 3120 ± 5110 ± 6
    Group 5 (50 mg / Kg / day) 145 ± 5135 ± 7100 ± 3100 ± 7
    Group 6 (60 mg / kg / day) 135 ± 7120 ± 690 ± 885 ± 4
    Group 7 (70 mg / Kg / day) 120 ± 8100 ± 485 ± 680 ± 7
    Group 8 (80 mg / Kg / day) 100 ± 490 ± 870 ± 865 ± 9
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    Example 4. Treatment with non-peptide antagonists of NK1 receptors at doses between 10 and 80 mg per kilogram of weight and day reduces the size of cancerous tumors of hematological lineage (leukemia / lymphomas) in
    10 mammals
    To verify that the administration of non-NK1 receptor antagonists at doses between 10 and 80 mg per kilogram of weight and day, reduces the size of glial line tumors of the nervous system in mammals, cells were implanted
    15 tumors in mice and subsequently treated with non-peptide NK1 receptor antagonists.
    Immunocompromised female mice of 5-6 weeks of age were used, under the same conditions as explained in Example 1. They were injected with 2 x 107 tumor cells 20, corresponding to hematological strain tumor (Human lymphoma; reference BC-1 ; supplied by DSMZ) in 200 µl of PBS via subcutaneous. Tumor size was measured and mice were evaluated for their health status and weight daily. The mice were randomized in nine groups when the tumors reached a volume of 75 mm3. One of the groups was treated with 200 µl of placebo (control group) and the remaining eight 25 groups with doses of 10 (group 1), 20 (group 2), 30 (group 3), 40 (group 4), 50
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    measured and the mice were evaluated for their health status and weight daily. The mice were randomized in nine groups when the tumors reached a volume of 75 mm3. One of the groups was treated with 200 µl of placebo (control group) and the remaining eight groups with doses of 10 (group 1), 20 (group 2), 30 (group 3), 40 (group 4), 50
    5 (group 5), 60 (group 6), 70 (group 7) and 80 (group 8) mg per kilogram of weight and day of the NK1 Aprepitant receptor antagonist. Three animals were treated for each group, for 28 days. All mice were sacrificed at the end of the experiment. Table 5 shows the size of the tumor (in cubic millimeters ± standard deviation) at 7, 14, 21 and 28 days of treatment, respectively with each of the doses used.
    10
    Table 5. Tumor size of tumors caused in an in vivo mouse model. Mean tumor volume in control mice (untreated) or in mice after treatment with the NK1 receptor non-peptide antagonist (Aprepitant).
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    Melanoma cell line reference MEL-HO. 7 days14 days21 days28 days
    Control 250 ± 6230 ± 6205 ± 7340 ± 7
    Group 1 (10 mg / kg / day) 235 ± 3215 ± 4190 ± 4170 ± 6
    Group 2 (20 mg / Kg / day) 210 ± 6200 ± 5175 ± 5150 ± 7
    Group 3 (30 mg / Kg / day) 195 ± 7185 ± 6160 ± 6140 ± 4
    Group 4 (40 mg / Kg / day) 175 ± 8160 ± 8140 ± 4110 ± 6
    Group 5 (50 mg / Kg / day) 160 ± 5150 ± 4125 ± 5100 ± 7
    Group 6 (60 mg / kg / day) 145 ± 6135 ± 5115 ± 685 ± 4
    Group 7 (70 mg / Kg / day) 125 ± 4105 ± 690 ± 480 ± 7
    Group 8 (80 mg / Kg / day) 100 ± 695 ± 765 ± 765 ± 9
    Example 6. Treatment with non-peptide antagonists of NK1 receptors at doses between 10 and 80 mg per kilogram of weight per day reduces the size of 20 cancerous tumors of an embryonic nature (eg neuroblastoma) in mammals.
    To verify that the administration of non-NK1 receptor antagonists at doses between 10 and 80 mg per kilogram of weight per day, reduces the size of the 25 tumors of the glial line of the nervous system in mammals, cells were implanted
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    Table 7. Tumor size of tumors caused in an in vivo mouse model. Mean tumor volume in control mice (untreated) or in mice after treatment with the NK1 receptor non-peptide antagonist (Aprepitant).
    Human lung carcinoma cell line reference HCC-44. 7 days14 days
    Control. Cisplatin only. 105 ± 470 ± 7
    Group 1. Cisplatin + Aprepitant 1 mg / Kg / day 85 ± 655 ± 6
    Group 2. Cisplatin + Aprepitant 3 mg / Kg / day 70 ± 745 ± 7
    Group 3. Cisplatin + Aprepitant 5 mg / Kg / day 60 ± 830 ± 4
    Group 4. Cisplatin + Aprepitant 6 mg / Kg / day 55 ± 425 ± 6
    Group 5. Cisplatin + Aprepitant 7 mg / Kg / day 40 ± 310 ± 3
    Group 6. Cisplatin + Aprepitant 8 mg / Kg / day 35 ± 75 ± 2
    Group 7. Cisplatin + Aprepitant 9 mg / Kg / day 20 ± 60 ± 0
    Group 8. Cisplatin + Aprepitant 10 mg / Kg / day 10 ± 80 ± 0
    5
    Example 8. Treatment with non-peptide antagonists of NK1 receptors at doses between 1 and 10 mg per kilogram of weight and day, in combination with another antitumor drug reduces the size of cancerous tumors of glial strain.
    10 of the nervous system (gliomas) in mammals.
    To verify that the administration of non-NK1 receptor antagonists at doses between 1 and 10 mg per kilogram of weight and day, in combination with other antitumor agents reduces the size of the glial line tumors (gliomas) of the system
    In nervous animals in mammals, tumor cells were implanted in mice and subsequently treated with chemotherapy alone and in combination with non-peptide NK1 receptor antagonists.
    Immunocompromised female mice of 5-6 weeks of age were used in the
    20 same conditions as explained in example 1. They were injected with 2 x 107 tumor cells, corresponding to tumor of the glial race of the nervous system (human glioma; reference GAMG; supplied by DSMZ) in 200 µl of PBS via subcutaneous route. Tumor size was measured and mice were evaluated for their health status and weight daily. Mice were randomized in nine groups when tumors
    25 reached a volume of 75 mm3. One of the groups was treated with two simple doses of Cisplatin, 8mg per kilogram of weight, on days 1 and 7 of the experiment (control group).
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    权利要求:
    Claims (1)
    [1]
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    ES201331923A|ES2541870B1|2013-12-27|2013-12-27|Use of NK1 non-peptide antagonists in a given dose for cancer treatment|ES201331923A| ES2541870B1|2013-12-27|2013-12-27|Use of NK1 non-peptide antagonists in a given dose for cancer treatment|
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