WO2018068665A1 - Inhibiteur de protéine de microtubules - Google Patents

Inhibiteur de protéine de microtubules Download PDF

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Publication number
WO2018068665A1
WO2018068665A1 PCT/CN2017/104307 CN2017104307W WO2018068665A1 WO 2018068665 A1 WO2018068665 A1 WO 2018068665A1 CN 2017104307 W CN2017104307 W CN 2017104307W WO 2018068665 A1 WO2018068665 A1 WO 2018068665A1
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Prior art keywords
propenylene
group
compound
piperazine
tert
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PCT/CN2017/104307
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English (en)
Chinese (zh)
Inventor
唐田
彭江华
吴婧
冯贻东
杨经安
佘琴
冯汉林
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深圳海王医药科技研究院有限公司
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Publication of WO2018068665A1 publication Critical patent/WO2018068665A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to the field of medicine, and in particular to a novel series of compounds as tubulin inhibitors and uses thereof.
  • the invention also relates to intermediate compounds for the preparation of said compounds.
  • the invention further relates to a pharmaceutical composition comprising the compound.
  • microtubule inhibitors drugs acting on microtubules
  • the current clinical drugs are affected by the following unfavorable problems: poor water solubility, unfavorable allergic reactions, serious toxic side effects and acquired drug resistance, resulting in reduced efficacy, complicated chemical structure and difficulty in synthesis.
  • the scarcity of sources limits their further use. Therefore, there is an urgent need to find new types of tubulin inhibitors, especially small molecule inhibitors with simple structures.
  • Microtubules are important components of eukaryotic cells and important targets for antitumor drugs. Microtubules are the main components of the cytoskeleton. They are composed of ⁇ -tubulin and ⁇ -tubulin heterodimer and have the characteristics of hollow tubular structure. In addition, there is a gamma tubulin, which is not a component of microtubules but participates in the assembly of microtubules.
  • Microtubules have the dynamic properties of polymerization and depolymerization, and play an important role in cell morphology, cell division, signal transduction and material transport. Microtubules polymerize into spindles in the early stage of cell division, and the spindle in the mitosis pulls the chromosomes into the two poles and moves into the two daughter cells to complete cell proliferation. Since microtubules play an extremely important role in cell division, they have become one of the important targets for antitumor drug research. Tubulin inhibitors acting on microtubule systems have also become an effective class of antitumor drugs.
  • tubulin inhibitors There are two classification methods for tubulin inhibitors. One is divided into two types according to the different mechanism of action: 1 tubulin depolymerization inhibitor that inhibits tubulin polymerization; 2 tubulin polymerization agent that promotes tubulin polymerization. Another classification method is divided into three categories according to the different sites of tubulin inhibitor and tubulin: 1 tubulin inhibitor acting on the colchicine site; 2 microactin acting on the vinblastine site Tubulin inhibitor; 3 tubulin inhibitor acting on the paclitaxel site.
  • the colchicine site is conducive to the study of small molecule anti-tumor inhibitors due to the small volume of its own binding cavity.
  • Chinese patent application CN 1684955 relates to a compound for the treatment of cancer and fungal infections, dehydrophenyl phenyl pinabulin (formula II), which is a cell cycle inhibitor, as a tumor growth inhibitor or Fungal inhibitors.
  • Chinese patent application CN1934101A relates to the use of the above compounds for reducing vascular proliferation and vascular density, acting on tumor blood vessels, but plinabulin alone has a weaker inhibitory effect on tumors and a greater interference with the immune system.
  • the properties, key functional residues and potential binding sites of each sub-region are determined; starting from the common group in the inhibitor structure, the consensus is gradually expanded.
  • the nature of the group thus assuming a structural template for the inhibitor.
  • the three-dimensional pharmacophore model of the inhibitor and some structural factors affecting the activity were proposed.
  • the design, synthesis, structural modification and in vitro activity studies of novel microtubule inhibitors were carried out.
  • Another object of the present invention is to provide an intermediate for the preparation of the above compounds.
  • the invention also provides a pharmaceutical composition comprising the above-described tubulin inhibitor.
  • tubulin inhibitor having the structure of formula (I):
  • n independently represents an integer of 0 to 5, with the proviso that n ⁇ 5, and A represents a mono- or poly-substituted group selected from H, C 1 -C 20 alkyl, C 1 -C 20 hydrocarbyl, C 1- C 20 acylamino group, C 1 -C 20 acyloxy group, C 1 -C 20 alkanoyl group, C 1 -C 20 alkoxycarbonyl group, C 1 -C 20 alkoxy group, C 1 -C 20 alkylamino group, C 1 -C 20 alkylcarboxyamino, aroyl, aralkyl, carboxyl, cyano, halogen, hydroxy, nitro and methylthienyl.
  • n independently represents an integer of 0 to 2, with the proviso that n ⁇ 2, and A represents a mono- or poly-substituted group selected from the group consisting of H, vinyl, and A.
  • Base trifluoromethoxy, methoxy, cyano, halogen and benzoyl.
  • Representative compounds of the invention include:
  • the synthetic route 1 of the present invention is as follows:
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant for the treatment of various cancers, infections, inflammations and conventional proliferation Sexual disease, or treatment of other diseases characterized by the appearance of rapidly proliferating cells such as psoriasis and other skin diseases.
  • the therapeutically effective amount means that the amount of the compound of formula (I) contained in the pharmaceutical composition is sufficient to produce a clinically desired therapeutic effect, e.g., the tumor size of the patient is reduced to a clinically acceptable range.
  • the compounds or pharmaceutical compositions of the invention are used to treat sarcomas, carcinomas and/or leukemias.
  • exemplary conditions in which the compound or composition can be used alone or as part of a therapeutic regimen include fibrosarcoma, mucinous sarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma , lymphatic endothelial sarcoma, synovial tumor, mesothelioma, Ewing's tumor, leiomyomas, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, sweat gland Cancer, sebaceous gland cancer, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma,
  • the compounds or compositions of the invention are used to treat conditions such as cancer of the breast, prostate, kidney, bladder, or colon tissue.
  • the compounds or pharmaceutical compositions of the invention are used to treat proliferative or neoplastic diseases occurring in adipose tissue, such as adipocyte tumors, namely lipomas, fibroids, lipoblastoma, fat Symptomatic, brown lipoma (hibemomas), hemangiomas and/or liposarcoma.
  • adipocyte tumors namely lipomas, fibroids, lipoblastoma, fat Symptomatic, brown lipoma (hibemomas), hemangiomas and/or liposarcoma.
  • compositions and compounds can also be used to control infectious agents and parasites (e.g., bacteria, trypanosomes, fungi, etc.).
  • infectious agents and parasites e.g., bacteria, trypanosomes, fungi, etc.
  • the pharmaceutical composition of the present invention can be administered by intravenous, intradermal, intramuscular, subcutaneous, oral or inhalation, and the pharmaceutical composition can be used as a gastrointestinal preparation such as a tablet, a capsule or a pill. Alternatively, it may be a parenteral preparation such as an injection or a topical preparation.
  • the invention provides a method of treating an anti-tumor and related disease, the method comprising administering to a patient having cancer or a related condition a therapeutically effective amount of a compound of the formula (I).
  • the invention also provides a method of modulating microtubule polymerization in a patient, the method comprising administering a therapeutically effective amount of at least one compound of the invention or a pharmaceutically acceptable prodrug, salt, hydrate, solvate, crystalline form thereof Or diastereomers.
  • the compounds of the present invention can be used in combination with chemotherapeutic agents for the treatment of tumors, and experiments have shown that the compounds of the present invention can increase the tumor suppressing effect when combined with a chemotherapeutic agent, while reducing the toxicity of the chemotherapeutic agent.
  • the most preferred compound is compound (9), and the chemotherapeutic agent can be a conventional chemotherapeutic agent generally used for treating tumors.
  • compound (9) is used in combination with docetaxel to obtain a very good therapeutic effect. .
  • the compound of the invention can bind to tubulin, can inhibit the growth and proliferation of cancer cells, has almost no influence on the corresponding white blood cells and granulocytes, and has less interference with immune system function when fighting tumor proliferation, and greatly improves anti-tumor drugs.
  • the drawbacks of clinical use Such compounds are also useful in the treatment of other conditions associated with hyperproliferation.
  • Figure 1 shows the tumor growth inhibition effect of the compound of the present invention
  • Figure 2 shows the antitumor effect and safety test results of compound (9).
  • A Inhibition of tumor growth inhibition in nude mice
  • B Effect of compound on tumor weight in nude mice
  • C Compound (9) and continuous administration of docetaxel for SD The effect of murine neutrophil count
  • Figure 3 is a graph showing the effect of the compounds of the invention on neutrophil counts in rats.
  • the structural modification of the compound of the present invention is based on the natural product Phenylahistin as a lead compound.
  • the corresponding structural transformation is carried out in combination with the reported structure-activity relationship. According to the principle of olefin insertion, a double bond is inserted between the piperazine and the benzene ring.
  • the piperazine diene and the benzene ring are directly connected, and different substituents are introduced to the benzene ring, it may be A compound having similar activity or more activity is obtained; and a double olefin bond is further inserted between the piperazine ring and the pyrazole to make the compound more stable and not easily deteriorated at normal temperature, so that the compound of the present invention has better stability and safety. high.
  • TLC was carried out on a silica gel GF254 high efficiency plate (Yantai Zhifu Silica Gel Development Test Plant).
  • the optical rotation measurement was carried out on a WZZ-1S optical rotation measuring instrument (Shanghai Precision Scientific Instrument Co., Ltd.).
  • step 1
  • the intermediate B was prepared in the same manner as in Steps 1 and 2, and the same as Steps 1 and 2 in Example 1.
  • the preparation of other intermediates and final products is shown in the following table:
  • HTRF kinEASE TK kit was used to detect the inhibitory activity of 11 compounds on Lyn ⁇ , AKT2, KDR, IKK- ⁇ , c-RAF enzyme, and the test compound was diluted from 10 ⁇ L to 0.1 ⁇ M to control the DMSO concentration. 1%, each concentration is a duplicate well.
  • HT-1080CAKi-1 human fibrosarcoma cells AGS human gastric adenocarcinoma cells, A375 human skin melanoma cells, Fadu human pharyngeal squamous carcinoma cells, NCI-H1975 human lung adenocarcinoma cells, SK-ES-1 human osteosarcoma cells, MDA- MB-231 human breast cancer cells and MIAPaCa-2 human pancreatic cancer cells were all derived from ATCC.
  • the cells were digested from the cell culture plate using trypsin, and the cell density was measured after resuspending in the medium.
  • McCoys'5A medium is used to culture SK-ES-1 cells (INVITROGEN)
  • Luminescent cell viability assay kit (promega#G7572)
  • the cell culture plate to which the compound was added was returned to the incubator and incubated for 72 hours under humidified conditions of 37 ° C, 5% CO 2 .
  • the luminescent cell viability assay kit (promega #G7572), the substrate lyophilized powder and the buffer were mixed, added to a 96-well plate at a dose of 30 ul/well, and placed at room temperature for 30 minutes before the experiment to equilibrate.
  • the time to read the board is set to 0.5 seconds per hole.
  • the above compounds had a strong inhibitory effect on each of the tumor cell lines examined, and compared with the reference drug [(-)phenyl Astrastin] (commercially available), the compound in this example inhibited the tumor with a high intensity.
  • the concentration of the compound in the present embodiment to inhibit the tumor is significantly lower than the concentration of the inhibitory enzyme, so it can be inferred that the compound of the present embodiment inhibits tumor proliferation.
  • it has a strong inhibitory effect on other enzyme activities or intracellular molecules that have not been investigated, and may affect various intracellular and extracellular targets to exert strong synergistic inhibition to varying degrees. Tumor effect.
  • MES-SA human uterine sarcoma cells (derived from ATCC) were cultured in low concentrations of doxorubicin for a long time to maintain sufficient cell viability and induce the expression of p-glycoprotein. After 10 months of culture, the expression results were induced by WB detection. After successful induction, after one week of culture without doxorubicin medium, the cell concentration was adjusted, and the tumor cells were inoculated into the armpit of nude mice, and the transplanted tumors were proliferated to a certain volume and then treated with different drugs. The doses of different doses of different drugs were used to explore the doses that did not affect the body weight gain of the animals, which was the dose to be treated for the transplanted tumor animals (Fig. 1).
  • Tumor inhibition rate (%) (1 - treatment group tumor weight / control tumor weight) * 100%, according to Figure 1, the tumor inhibition rate of docetaxel is close to 80%, and higher than compound 9, compound 11 , Compound 15, Compound 18.
  • the nude mice inoculated with tumor cells were given blank vehicle, docetaxel, compound 9 and docetaxel and compound 9 in combination, and the tumor volume was measured at different time points after drug administration and the tumor volume change process was detected. At the same time, the change in body weight of nude mice was examined to evaluate the antitumor effect and the degree of toxicity of the drug. In addition, in normal SD rats, blood neutrophil counts were measured before and after the administration according to the above administration and grouping methods to evaluate the degree of influence of the drug on neutrophil counts.
  • the multi-dose was given different drugs to inhibit the degree of tumor xenografting in nude mice, and the equivalent dose of each drug was explored, and different drugs were given to rats by the inter-species dose conversion. That is, the effect of the drug on neutrophil count in rats was examined under the dose of the same pharmacodynamic dose to the rats.
  • Human umbilical vein endothelial cells (HuVEC from Cambrex) were used in this study to evaluate compounds 9, 11, 15, 18 and tert-butylphenyl by staining ⁇ -tubulin with colchicine and paclitaxel. The effect of ustin on tubulin.
  • the compounds according to the invention may be combined with a physiologically acceptable carrier or vehicle to provide a pharmaceutical composition, such as a lyophilized powder in the form of a tablet or capsule containing various fillers and binders.
  • a pharmaceutical composition such as a lyophilized powder in the form of a tablet or capsule containing various fillers and binders.
  • the compounds can be co-administered with other agents, and co-administration should mean at least two agents are used in the patient to provide the beneficial effects of the combination of the two agents.
  • the medicament can be used simultaneously or sequentially in a certain period of time.
  • the effective dosage of the compound in the composition can be determined extensively by one skilled in the art.
  • the compounds of the invention may be used alone or in combination with one or more additional agents.
  • Combination therapies contemplated by the present invention include, for example, the use of the compounds of the invention and additional agents in a single pharmaceutical formulation, as well as the use of the compounds of the invention and additional agents in separate pharmaceutical formulations.
  • the compounds of the invention may be administered to a dairy animal, preferably a human, alone or in combination with a pharmaceutically acceptable carrier or diluent, optionally together with known adjuvants such as microcrystalline cellulose, in a pharmaceutical composition according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected compound can be administered, for example, in the form of a tablet or capsule or as an aqueous solution or suspension.
  • usual carriers are usually added including lactose and corn starch, and lubricants such as magnesium stearate.
  • diluents which may be employed include lactose and anhydrous corn starch, and when an aqueous suspension for oral use is required, the active ingredient is mixed with emulsifying and suspending agents. If desired, some sweeteners and/or flavoring agents may be added.
  • the total concentration of solutes should be controlled to make the formulation isotonic.
  • the active compound, the disintegrant and the filler of the present invention are sieved in a ratio of 60-100 mesh, uniformly mixed, and the soft material is prepared by using 2 to 20% of povidone K30 in ethanol solution, and granulating through 20 to 50 mesh. Dry at 40 ⁇ 90°C, the moisture content of the granules is controlled within 3%. After the whole granules, add appropriate amount of lubricant, mix well, and compress.
  • the pharmaceutical composition of the above embodiment can also be prepared by weighing the compound 9, 18, the filler and the disintegrant in a 50-fold prescription amount through a 60- and 80-mesh sieve, and mixing uniformly, using 2 to 20 % povidone K30 50% ethanol solution soft material, 30 mesh sieve granulation, 60 ° C drying, particle moisture control within 3%, 20 mesh sieve granules, add appropriate amount of lubricant, mix evenly, tablet, That is the product.
  • the obtained compound 9 was subjected to stability investigation (10-day accelerated test), and the moisture, purity, maximum single and total impurities, and 0 days of the compound were observed at 40 ° C, 60 ° C, humidity of 75%, 92.5%, and light conditions. The data were compared and the results showed that the obtained compound was stable. However, the degradation of (-) phenyl azanthine was obvious at 60 °C, indicating that high temperature has an effect on the stability of (-) phenyl axidine.

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  • Organic Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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Abstract

L'invention concerne un nouvel inhibiteur de protéine de microtubules et ses applications, ledit inhibiteur de protéine de microtubules étant une série de composés à base de squelettes hétérocycliques substitués, ayant pour cible les sites de liaison de colchicine de tubuline. La structure est représentée par la formule (1) ci-dessous, dans laquelle pour la formule (A), n représente indépendamment un nombre entier compris entre 0 et 5, la condition étant que n ≤ 5, A représente des groupes mono- ou poly- substitués, lesdits groupes étant choisis parmi H, un groupe amide C 1 -C 20 , un groupe acyloxy C 1 -C 20 , un groupe alcanoyle C 1 -C 20 , un groupe alcoxycarbonyle C 1 -C 20 , un groupe alcoxy C 1 -C 20 , un groupe alkylamino C 1 -C 20 , un groupe alkyle amino carbonyle groupe C 1 -C 20 , un groupe aroyle, un groupe aralcanoyle, un groupe carboxyle, un groupe cyano, un groupe halogène, un groupe hydroxyle, un groupe nitro et un groupe méthylthiényle.
PCT/CN2017/104307 2016-10-11 2017-09-29 Inhibiteur de protéine de microtubules WO2018068665A1 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2022012329A1 (fr) * 2020-07-14 2022-01-20 深圳海王医药科技研究院有限公司 Utilisation d'un composé ayant un effet synergique dans le traitement des tumeurs

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CN106565685B (zh) * 2016-10-11 2019-03-01 深圳海王医药科技研究院有限公司 微管蛋白抑制剂
CN109580801B (zh) * 2018-06-26 2021-09-07 深圳海王医药科技研究院有限公司 一种检测微管蛋白抑制剂及相关杂质的高效液相色谱法
CN109030642B (zh) * 2018-06-26 2021-03-09 深圳海王医药科技研究院有限公司 一种脱氢苯基阿夕斯丁类似物及其异构体的测定方法

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CN1684955A (zh) * 2002-08-02 2005-10-19 尼瑞斯药品公司 脱氢苯基阿夕斯丁及其类似物以及脱氢苯基阿夕斯丁及其类似物的合成
WO2007035841A1 (fr) * 2005-09-21 2007-03-29 Nereus Pharmaceuticals, Inc. Analogues de deshydrophenylahistines et utilisation therapeutique de ceux-ci
CN106565685A (zh) * 2016-10-11 2017-04-19 深圳海王医药科技研究院有限公司 微管蛋白抑制剂

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BRPI0417354A (pt) * 2003-12-03 2007-03-13 Cytopia Res Pty Ltd compostos inibidores de tubulina, composições e seus usos
WO2012035436A1 (fr) * 2010-09-15 2012-03-22 Tokyo University Of Pharmacy And Life Sciences Analogues de promédicaments à base de plinabuline et utilisations thérapeutiques associées

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CN1684955A (zh) * 2002-08-02 2005-10-19 尼瑞斯药品公司 脱氢苯基阿夕斯丁及其类似物以及脱氢苯基阿夕斯丁及其类似物的合成
WO2007035841A1 (fr) * 2005-09-21 2007-03-29 Nereus Pharmaceuticals, Inc. Analogues de deshydrophenylahistines et utilisation therapeutique de ceux-ci
CN106565685A (zh) * 2016-10-11 2017-04-19 深圳海王医药科技研究院有限公司 微管蛋白抑制剂

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022012329A1 (fr) * 2020-07-14 2022-01-20 深圳海王医药科技研究院有限公司 Utilisation d'un composé ayant un effet synergique dans le traitement des tumeurs

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