WO2018214814A1 - 氨基亚甲基环己烷1,3-二酮化合物的用途 - Google Patents

氨基亚甲基环己烷1,3-二酮化合物的用途 Download PDF

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WO2018214814A1
WO2018214814A1 PCT/CN2018/087452 CN2018087452W WO2018214814A1 WO 2018214814 A1 WO2018214814 A1 WO 2018214814A1 CN 2018087452 W CN2018087452 W CN 2018087452W WO 2018214814 A1 WO2018214814 A1 WO 2018214814A1
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cancer
substituted
autophagy
unsubstituted
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PCT/CN2018/087452
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French (fr)
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罗成
乐立艳
万伟
张元元
蒋华良
陈凯先
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苏州偶领生物医药有限公司
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Priority to CN201880033796.7A priority Critical patent/CN111108083B/zh
Priority to US16/614,521 priority patent/US11529321B2/en
Publication of WO2018214814A1 publication Critical patent/WO2018214814A1/zh

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Definitions

  • the present invention relates to the field of biomedicine, and in particular to a class of aminomethylenecyclohexane 1,3-dione compounds or salts thereof for the preparation of a medicament for treating diseases associated with autophagy, particularly mammalian ATG8 homologous proteins. the use of.
  • Autophagy is a pathway of intracellular degradation. It is a process of transporting damaged or loss-of-function proteins and organelles into lysosomes, and digesting and degrading them. In biological evolution, autophagy is a conserved process, from yeast to plant cells to mammals.
  • small molecule modulators targeting autophagy are mainly limited to mTOR and lysosomal modulators, and studies on small molecule modulators of autophagy-related proteins such as ATG4 and ULK1 are still in the early stages of development.
  • the most important autophagy-related proteins, ATG8 and its mammalian homologous family proteins LC3, GABARAP and GATE-16 subfamily regulators have not been reported.
  • the LC3 family has LC3A, LC3B, LC3C
  • the GABARAP family has GABARAPL and GABARAPL1
  • the GATE-16 family has GABARAPL2.
  • LC3B is undoubtedly the most studied one, and it is considered to be a marker of autophagy. There have been no reports on modulators of LC3B, and the development of modulators of LC3B is urgent for the treatment of related diseases.
  • a compound that regulates autophagy and a marketed drug is applied to various cancers, cardiovascular diseases, autoimmune diseases, neurodegenerative diseases, hypertension, bone tissue cells and bone diseases, Crohn Disease, acute kidney injury, cerebral ischemia, retinal disease, bronchial asthma, Vici syndrome, and various infectious diseases will have broad prospects.
  • a first aspect of the present invention provides the use of a compound of the following formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with other drugs, for the preparation of a medicament for modulating autophagy and treating diseases associated with autophagy :
  • R 3 , R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxy, amino, halogen, cyano, nitro, carboxy, formyl, amide, ester, C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, C 3-7 cycloalkyl, and 3-7 Metacyclic heterocyclic group;
  • the halogen is selected from the group consisting of F, Cl, Br, I; preferably from F, Cl, Br;
  • substitution means that said group is substituted by one or more substituents selected from the group consisting of: hydroxy, amino (-NH 2 ), cyano, halogen, nitro, trifluoromethyl, carboxyl, ester , formyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 yuan heteroaryl;
  • n is selected from 0, 1, 2 and 3, preferably 1 or 2.
  • the C 5-10 aryl or 5-10 membered heteroaryl group is preferably selected from the group consisting of the loss of one hydrogen atom by the following ring:
  • the C 3-7 cycloalkyl or 3-7 membered heterocyclic group is preferably selected from the group consisting of the loss of one hydrogen atom by the following ring:
  • the compound of formula (I) is selected from the group consisting of:
  • the agent that modulates autophagy is a modulator of a mammalian ATG8 homologous protein, particularly LC3B.
  • the agent that modulates autophagy is a drug that treats diseases associated with autophagy, particularly mammalian ATG8 homologous proteins, particularly LC3B.
  • a method for regulating the activity of a mammalian ATG8 homologous protein especially LC3B
  • the above compound or a salt thereof is used alone or in combination with other drugs to modulate LC3B and a mammalian ATG8 homologous protein Interaction with other proteins in the body.
  • the method can be carried out in vivo or in vitro.
  • a method of modulating autophagy of a cell comprising the step of administering the above compound or a salt thereof, alone or in combination with other drugs.
  • a method of treating a disease associated with autophagy in particular a mammalian ATG8 homologous protein (especially LC3B), the method comprising, alone or in combination with other drugs, a patient in need of such treatment
  • the step of administering the above compound or a salt thereof in combination comprising, alone or in combination with other drugs, a patient in need of such treatment.
  • the mammalian ATG8 homologous proteins include the LC3, GABARAP and GATE-16 subfamily proteins.
  • the LC3 family has LC3A, LC3B and LC3C
  • the GABARAP family has GABARAPL and GABARAPL1
  • the GATE-16 family has GABARAPL2.
  • the diseases associated with autophagy include: tumors, such as liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colorectal cancer, gastric cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate Cancer, leukemia, lymphoma, myeloma, etc.; cardiovascular disease; autoimmune disease; neurodegenerative disease; hypertension; bone tissue cells and bone diseases; Crohn's disease; acute kidney injury; cerebral ischemia; Retinal diseases; bronchial asthma; Vici syndrome; and infectious diseases such as AIDS.
  • tumors such as liver cancer, lung cancer, pancreatic cancer, breast cancer, cervical cancer, endometrial cancer, colorectal cancer, gastric cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, prostate Cancer, leukemia, lymphoma, myeloma, etc.
  • cardiovascular disease autoimmune disease
  • neurodegenerative disease hypertension
  • bone tissue cells and bone diseases Crohn's
  • the other drug may be a marketed drug, including, but not limited to, ibrutinib, imatinib, gemcitabine, erlotinib, pemetrexed disodium, AZD3759 and lenalidomide.
  • Figure 1 shows the effect of LC3B on autophagy in cells.
  • Figure 2 shows the effect of Compound 38 on autophagy in cells.
  • Figure 3 shows the effect of Compound 38 in combination with some of the marketed drugs on the proliferation of some tumor cells.
  • the invention establishes a high-throughput screening platform based on fluorescence polarization by designing FITC-labeled peptide and GST fusion protein expressing LC3B, and high-throughput screening of compound library, and found a class of aminomethylenecyclohexane 1,3-
  • the diketone compound or a salt thereof can be used as a modulator for targeting a mammalian ATG8 homologous protein (especially LC3B).
  • immunostaining, immunofluorescence staining and fluorescence microscopy of the LC3-I/LC3-II protein confirmed that the above compound or its salt has the ability to regulate autophagy, and thus can be used to regulate autophagy and treat related diseases.
  • Embodiments of the present invention will be described in detail below.
  • C 1-6 alkyl refers to "C 1-6 alkyl” and "C 1-6 hydroxyalkyl”, “C 1-6 haloalkyl”, “C 1-6 alkoxy”"C1-6alkyl” moiety.
  • the drug which modulates autophagy and treats diseases associated with autophagy may be a pharmaceutical composition.
  • “Pharmaceutical composition” means a composition suitable for administration to a patient.
  • the composition may contain only a compound of the invention or a mixture containing a compound of the invention, or a salt, solvate, prodrug, isomer or tautomer of the compound of the invention, or may contain one or A compound of the invention in combination with a plurality of pharmaceutically acceptable carriers or adjuvants.
  • "Patient” includes both human and non-human animals.
  • the pharmaceutical composition may be in various forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be present in a suitable solid or liquid carrier or diluent and suitable for use. In the sterilizing device for injection or drip.
  • the unit dosage of the formulation formulation comprises from 0.05 to 200 mg of the compound of formula (I), preferably from 0.1 mg to 100 mg of the compound of formula (I) per unit dosage of the formulation.
  • the compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, by routes of administration to the mouth, nose, skin, lungs, or the gastrointestinal tract. Most preferably oral.
  • the most preferred daily dose is from 0.01 to 200 mg/kg body weight, taken once, or from 0.01 to 100 mg/kg body weight in divided doses.
  • the optimal dosage for the individual should be based on the particular treatment. Usually starting with a small dose, gradually increase the dose until the most suitable dose is found.
  • Halogen (or halo) means fluoro, chloro, bromo or iodo.
  • C 1-6 alkyl group means a straight or branched alkyl group having 1 to 6 carbon atoms, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Branched means that an alkyl group of one or more carbon atoms such as a methyl group, an ethyl group or a propyl group is bonded to a linear alkyl group.
  • Preferred C 1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl groups and the like.
  • C1-6 haloalkyl means a C1-6 alkyl group as defined above which contains one or more substituents of a halogen atom.
  • Preferred C 1-6 haloalkyl groups include, but are not limited to, trifluoromethyl.
  • C 1-6 hydroxyalkyl means that one or more hydroxy groups are contained in the C 1-6 alkyl group as defined above.
  • Preferred C1-6 hydroxyalkyl groups include, but are not limited to, hydroxymethyl and 2-hydroxyethyl.
  • C1-6 alkoxy means a C1-6 alkyl-O- group bonded to the parent moiety through oxygen, wherein the C1-6 alkyl group is as defined above.
  • Preferred C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • C 6-10 aryl means an aromatic monocyclic or polycyclic ring system containing from 6 to 10 carbon atoms.
  • Preferred C6-10 aryl groups include, but are not limited to, phenyl and naphthyl.
  • C 3-7 cycloalkyl refers to a non-aromatic saturated monocyclic or polycyclic group having from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms in the ring.
  • Preferred monocyclic C3-7 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • 5-10 membered heteroaryl means an aromatic monocyclic or polycyclic group having 5 to 10 ring atoms, and the 5-10 membered heteroaryl group includes 1 to N, O and S selected from 4 heteroatoms. Preferred 5-10 membered heteroaryl groups contain 5 to 6 ring atoms. The nitrogen atom of the 5-10 membered heteroaryl group can be optionally oxidized to the corresponding N-oxide.
  • Preferred C5-10 heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridone, oxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl , thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, pyridazinyl, oxindole Mercapto, imidazo[1,2-a]pyridyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, fluorenyl, azaindole, benzimidazolyl , benzothienyl, quinolyl, imidazolyl, thienopyridyl, quinazolin
  • the "3-7 membered heterocyclic group” means a non-aromatic monocyclic or polycyclic group having 3 to 7 ring atoms, preferably 3 to 6 ring atoms, preferably 5 to 6 ring atoms, wherein The 3-10 membered heterocyclic group contains 1 to 4 hetero atoms selected from N, O and S.
  • the nitrogen or sulfur atom of the 3-10 membered heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S-dioxide.
  • oxide refers to the corresponding N-oxide, S-oxide or S-dioxide.
  • Preferred monocyclic 3-7 membered heterocycloalkyl groups include, but are not limited to, piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1, 4-dioxaalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam (such as pyrrolidone), lactone groups having 3 to 7 ring atoms, and oxides thereof.
  • Ester group means that a hydrogen atom is removed from an ester formed by esterification of an aliphatic or aromatic carboxylic acid having 1 to 20 carbon atoms with a primary, secondary or tertiary alcohol having 1 to 20 carbon atoms. The group obtained.
  • Preferred ester groups include, but are not limited to, methyl ester groups, ethyl ester groups, isopropyl ester groups, tert-butyl ester groups, phenyl ester groups.
  • “Amido” means an amide obtained by the amidation reaction of an aliphatic or aromatic carboxylic acid having 1 to 20 carbon atoms with a primary or secondary amine having 1 to 20 carbon atoms to obtain a hydrogen atom. Group.
  • unsubstituted or substituted means that a particular group is unsubstituted or substituted with one or more substituents.
  • Substituents include, without limitation, hydrogen, hydroxy, amino, cyano, nitro, carboxy, halo, C1-6 alkyl, C1-6 haloalkyl or C1-6 hydroxyalkyl. Two adjacent substituents may be joined to form a C6-10 aryl group, a 5-10 membered heteroaryl group, a C3-10 cycloalkyl group or a 3-10 membered heterocycloalkyl group.
  • Substitutions on the C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl group, etc. include any of the groups Substitution of the ring portion.
  • the compounds of the invention may form metal chelates with one or more metal ions.
  • Metal ions include, but are not limited to, copper, iron, magnesium, calcium, zinc, nickel, platinum, and the like. It should be noted that the compounds of the invention include all metal chelates.
  • pharmaceutically acceptable salt refers to a substance that is suitable for use in humans and/or animals without excessive adverse side effects (eg, toxicity, irritation, and allergies), ie, having a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts include inorganic and organic salts which may be obtained during the final isolation and purification of the compounds of the invention or by reaction of the free acid or base function with a suitable base or acid.
  • Acids suitable for salt formation include, but are not limited to, mineral acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as capric acid, ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid.
  • Bases suitable for forming salts include, but are not limited to, inorganic bases such as sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, lithium hydroxide, calcium acetate, calcium chloride or magnesium chloride, and the like, and organic bases such as aminoethanol and the like.
  • an effective amount means that the amount of the compound of the invention contained in the administered composition is sufficient to modulate (e.g., inhibit or agonize, etc.) a mammalian ATG8 homolog.
  • the compounds of the present invention can be prepared by various methods similar to those known in the art, and the following examples of the preparation of the compounds are exemplary schemes for the preparation of the compounds of the present invention.
  • Mass spectrometry was recorded by liquid chromatography-mass spectrometry (LC-MS, Agilent 6120B single quadrupole liquid chromatography-mass spectrometer).
  • 1 H nuclear magnetic resonance spectroscopy (NMR) was recorded on a Bruker AMX-400 NMR spectrometer and recorded in deuterated dimethyl sulfoxide (DMSO-d6) with reference to the deuterated solvent peak.
  • the unit of chemical shift ⁇ is ppm
  • the unit of coupling constant (J or J) is Hertz (Hz, Hertz)
  • the coupling split peak in NMR spectrum is expressed as: wide single peak (brs), single peak (s), double Peak (d), doublet (dd), triplet (t), quartet (q) and multiplet (m).
  • the compound 5-phenylcyclohexane-1,3-dione (5.0 g, 26.6 mmol) was dissolved in chloroform (25 mL), and N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added. (5 mL), the above mixture was reacted at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was concentrated, and the concentrate was crystallized from 10% ethyl acetate (EA) / petroleum ether (PE). The precipitate was filtered, and the residue was dried to give the title compound 4.81 g, yield 74%.
  • EA ethyl acetate
  • PE petroleum ether
  • the purified LC3B protein was expressed by constructing prokaryotic expression system, and a preliminary screening and verification platform was established by fluorescence polarization experiment. The activity of the synthesized small compound library was determined.
  • Recombinant protein GST-LC3B (final concentration 180 nM, SEQ ID NO: 1) and N-terminal FITC-labeled peptide (SEQ ID NO: 2, final concentration 18 nM) were placed in FP buffer (50 mM HEPES pH 7.5, 0.1 mg/mL BSA). In 1 mM DTT), a compound serially diluted with FP buffer was added thereto, and then the above mixture was incubated at 25 ° C in the dark. Monitoring the fluorescence polarization values (PerkinElmer Envision, emission wavelength 480 nm; light absorption wavelength 535nm), and IC 50 values calculated using GraphPad Prism 6.0 program.
  • test results are shown in Table 1, in which the IC 50 value of the compound indicates the method: 100 ⁇ M ⁇ IC 50 ⁇ 1 mM is considered to be less active for LC3B (+); compound 15 ⁇ M ⁇ IC 50 ⁇ 100 ⁇ M is considered to be moderately active for LC3B (++); 3 ⁇ M ⁇ IC 50 ⁇ 15 ⁇ M is considered to be highly active for LC3B (+++); IC 50 ⁇ 3 ⁇ M is considered to have high activity (++++) for LC3B.
  • Example 5 Modulation of autophagy by a compound or a salt thereof
  • Hela cells were seeded into 6-well plates, cultured overnight, treated with a concentration of compound for 12 h, and then starved for 24 hours in serum-free medium.
  • the medium was aspirated, washed once with PBS, and lysed by SDS-PAGE with 2 x loading buffer.
  • the sample was boiled at 99 ° C for 10 minutes, and after separation by SDS-PAGE, LC3-I/LC3-II detection was performed using LC3B antibody (Novus), and the results are shown in Fig. 2A.
  • LC3-II accumulates as the compound treatment time increases.
  • HeLa cells were seeded on glass coverslips in 6-well plates, cultured until the cells were in good condition, treated with a certain concentration of compound for 12 hours, and then starved for 24 hours in serum-free medium.
  • the cells were pre-cooled for 10 minutes, then punched with 0.2% Triton X-100 and allowed to stand at room temperature for 10 minutes. Then, the cells were blocked with PBS containing 2.5% BSA and then incubated with a 4 degree anti-LC3B primary antibody overnight, after which the primary antibody was recognized with a fluorescent secondary antibody and the nuclei were stained with DAPI and photographed under a microscope.
  • the test results are shown in Figure 2B.
  • the cell autophagosomes accumulated after treatment with Compound 38, and the higher the concentration, the more accumulated.
  • Example 6 Inhibition of proliferation of different types of tumor cells by using a compound or a salt thereof in combination with a partially marketed drug
  • Tumor cell lines large B lymphoma cells (DB, Toledo, Pfeiffer, SU-DHL6, WSU-DLCL2, OCI-Ly19, SU-DHL2, SU-DHL8), mantle cell lymphoma cell lines (REC-1, Z- 138, Jeko-1, Maver-1), pancreatic cancer cell lines (AsPC-1, BxPC-3, MIAPaCa-2, Panc-3.014, CaPan-1, Panc-1), colon cancer cell line HCT116, non-small cells Lung cancer cell lines (PC9, HCC827, NCI-H1975) and multiple myeloma cell lines (H929, KMS26, RPMI-8226).
  • Listed drugs used in combination Ibrutinib, imatinib, gemcitabine, erlotinib, pemetrexed disodium, AZD3759 and lenalidomide.

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Abstract

氨基亚甲基环己烷1,3-二酮化合物的用途，具体涉及下式(I)所示化合物或其药学上可接受的盐单独或者与其他药物联合在制备调节细胞自噬及治疗细胞自噬，特别是哺乳动物ATG8同源蛋白，相关的疾病的药物中的用途。

Description

氨基亚甲基环己烷1,3-二酮化合物的用途 技术领域
本发明涉及生物医药领域，具体涉及一类氨基亚甲基环己烷1,3-二酮化合物或其盐在制备治疗与细胞自噬，特别是哺乳动物ATG8同源蛋白，相关的疾病的药物的用途。
背景技术
细胞自噬是一种细胞内降解的通路，是将细胞内受损或失去功能的蛋白质以及细胞器运输至溶酶体，并进行消化和降解的过程。在生物进化中，细胞自噬是一种保守的过程，从酵母到植物细胞再到哺乳动物，都存在这样的过程。
现有的研究表明，细胞自噬在维持生理功能如饥饿时提供营养、清除细胞内容物、抗原呈递等方面起着重要的作用，并在癌症、心血管疾病、自身免疫性疾病、神经退行性疾病、高血压、骨组织细胞及骨类疾病、克罗恩氏病、急性肾损伤、脑缺血、视网膜疾病、支气管哮喘、Vici综合征以及各类感染性疾病等扮演着重要的角色。
细胞自噬在肿瘤的发生发展中起到双刃剑的作用：在肿瘤发生早期，自噬缺陷会增加基因组的不稳定性，促进癌变过程；肿瘤快速生长和转移阶段，自噬可以抵抗应激条件抑制失巢凋亡，维持肿瘤细胞生存。虽然自噬与肿瘤之间的关系在肿瘤发生发展的不同阶段不同，针对进展晚期以及化疗耐药的癌症，细胞自噬调节剂的开发将有重大的价值。
目前共有30余项关于调节自噬的药物临床试验，例如单独使用羟氯喹、氯喹或与其他抗肿瘤药物联用评价细胞自噬的抑制对难治性、复发性为主的实体瘤的治疗效果，相关结果可在clinicaltrial.gov官网查询。不过，由于缺乏明确的分子靶标，抗溶酶体抑制剂的副作用以及化学空间改造的方向不明会严重限制该类细胞自噬抑制剂的进一步发展。
目前靶向细胞自噬的小分子调节剂主要限于mTOR和溶酶体调节剂，针对细胞自噬相关蛋白，如ATG4和ULK1的小分子调控剂的研究依然处于开发的早期。而最重要的细胞自噬相关蛋白，ATG8及其哺乳动物同源家族蛋白LC3,GABARAP和GATE-16子家族的调控剂均未有任何报道。在人体内，LC3家族有LC3A,LC3B,LC3C,GABARAP家族有GABARAPL和GABARAPL1,GATE-16家族有GABARAPL2。在ATG8的哺乳动物同源蛋白中，LC3B无疑是研究得最为深入的一个，它被认为是细胞自噬的标志物。目前尚未有任何针对LC3B的调控剂的报道，开发LC3B的调控剂对于治疗相关疾病的来说十分迫切。
同时，将调控细胞自噬的化合物与已上市药物的组合物应用于各种癌症、心血管疾病、 自身免疫性疾病、神经退行性疾病、高血压、骨组织细胞及骨类疾病、克罗恩氏病、急性肾损伤、脑缺血、视网膜疾病、支气管哮喘、Vici综合征以及各类感染性疾病将有广阔的前景。
发明内容
本发明的第一方面提供了下式(I)所示化合物或其药学上可接受的盐单独或者与其他药物联合在制备调节细胞自噬及治疗与细胞自噬相关的疾病的药物中的用途：
Figure PCTCN2018087452-appb-000001
其中：
R 1和R 2各自独立选自：氢，羟基，氨基，氰基，甲酰基，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C(＝O)R a，SO 2R a，取代或未取代的-(CH 2) m-C 5-10芳基或5-10元杂芳基，取代或未取代的-(CH 2) m-C 3-7环烷基或3-7元杂环基；所述R a选自氢，羟基，C 1-6烷基，C 1-6卤代烷基，取代或未取代的C 1-6羟基烷基，取代或未取代的氨基，取代或未取代苯基，取代或未取代的五至六元杂芳基；
R 3、R 4、R 5和R 6各自独立选自：氢，羟基，氨基，卤素，氰基，硝基，羧基，甲酰基，酰胺基，酯基，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，取代或未取代的C 6-10芳基，取代或未取代的5-10元杂芳基，C 3-7环烷基，和3-7元杂环基；
所述卤素选自F，Cl，Br，I；优选自F，Cl，Br；
所述取代表示所述基团被一个或多个取代基取代，所述取代基选自：羟基，氨基(-NH 2)，氰基，卤素，硝基，三氟甲基，羧基，酯基，甲酰基，C 1-6烷基，C 1-6卤代烷基，C 1-6羟基烷基，C 1-6烷氧基，3-10元杂环基，C 6-10芳基，和5-10元杂芳基；
m选自0、1、2和3，优选为1或2。
在一个优选的实施方式中，所述C 5-10芳基或5-10元杂芳基优选选自由下列环失去一个氢原子形成的基团：
Figure PCTCN2018087452-appb-000002
所述C 3-7环烷基或3-7元杂环基优选选自由下列环失去一个氢原子形成的基团：
Figure PCTCN2018087452-appb-000003
在一个优选的实施方式中，所述通式(I)的化合物选自下述化合物：
Figure PCTCN2018087452-appb-000004
Figure PCTCN2018087452-appb-000005
Figure PCTCN2018087452-appb-000006
在一个具体实施方式中，所述调节细胞自噬的药物是哺乳动物ATG8同源蛋白(尤其是LC3B)的调节剂。
在一个具体实施方式中，所述调节细胞自噬的药物是治疗与细胞自噬，特别是哺乳动物ATG8同源蛋白(尤其是LC3B)相关的疾病的药物。
本发明的第二方面，提供了一种调控哺乳动物ATG8同源蛋白(尤其是LC3B)活性的方法，其中，用上述化合物或其盐单独或者与其他药物联合调控LC3B及哺乳动物ATG8同源蛋白与体内其他蛋白的相互作用。所述方法可以在体内或体外进行。
本发明的第三方面，提供了调节细胞自噬的方法，所述方法包括单独或者与其他药物联合施用上述化合物或其盐的步骤。
本发明的第四方面，提供了治疗与细胞自噬，特别是哺乳动物ATG8同源蛋白(尤其是LC3B)，相关的疾病的方法，所述方法包括像需要该治疗的患者单独或者与其他药物联合施用上述化合物或其盐的步骤。
所述哺乳动物ATG8同源蛋白包括LC3，GABARAP和GATE-16子家族蛋白。在人体内，LC3家族有LC3A,LC3B和LC3C，GABARAP家族有GABARAPL和GABARAPL1，GATE-16家族有GABARAPL2。
优选地，所述与细胞自噬相关的疾病包括：肿瘤，例如肝癌、肺癌、胰腺癌、乳腺癌、***、子宫内膜癌、大肠癌、胃癌、肺癌、鼻咽癌、卵巢癌、***癌、白血病、淋巴瘤、骨髓瘤等；心血管疾病；自身免疫性疾病；神经退行性疾病；高血压；骨组织细胞及骨类疾病；克罗恩氏病；急性肾损伤；脑缺血；视网膜疾病；支气管哮喘；Vici综合征；以及感染性疾病，例如艾滋病等。
所述其他药物可以是已上市药物，非限制性地包括：依鲁替尼，伊马替尼，吉西他滨，厄洛替尼，培美曲塞二钠，AZD3759和来那度胺等。
附图说明
图1显示了LC3B在细胞自噬中的作用。
图2显示了化合物38对细胞自噬的影响。
图3显示了化合物38与部分已上市药物联用对部分肿瘤细胞增殖的影响。
具体实施方式
本发明通过设计FITC标记肽、表达LC3B的GST融合蛋白建立了基于荧光偏振的高通量筛选平台，对化合物库进行高通量筛选，发现了一类氨基亚甲基环己烷1,3-二酮化合物或其盐可以作为靶向哺乳动物ATG8同源蛋白(尤其是LC3B)的调控剂。此外，通过LC3-I/LC3-II蛋白的免疫印迹、免疫荧光染色和荧光显微镜拍照验证了上述化合物或其盐具有调控细胞自噬的能力，从而可以用于调节细胞自噬及治疗相关疾病。以下将详细描述本发明的实施例。
本发明使用的术语具有其在本技术领域的一般含义，在有抵触的情况下，适用本申请中的定义。化学名称、通用名称和化学结构可以互换使用以描述相同的结构。无论术语是单独使用还是与其他术语组合使用，这些定义都适用。因此，“C 1-6烷基”的定义适用于“C 1-6烷基”以及“C 1-6羟基烷基”、“C 1-6卤代烷基”、“C 1-6烷氧基”等的“C1-6烷基”部分。
本发明中，调节细胞自噬及治疗与细胞自噬相关的疾病的药物可以是药物组合物。“药物组合物”是指适合于患者用药的组合物。所述组合物可以只含有本发明化合物或含有本发明化合物的混合物，或含有本发明化合物的盐、溶剂合物、前体药物、异构体或互变异构体，或含有与一种或多种药学上可接受的载体或辅料合用的本发明化合物。“患者”包括人类和非人类的动物。所述药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中以及适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位剂量中包含0.05-200mg通式(I)化合物，优选地，制剂配方的单位剂量中包含0.1mg-100mg通式(I)化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径。最优选为口服。最佳优选日剂量为0.01-200mg/kg体重，一次性服用，或0.01-100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
“卤素”(或卤代基)是指氟、氯、溴或碘。
“C 1-6烷基”是指含有1至6个碳原子的直链或支链烷基，优选为1至4个碳原子的直链或支链烷基。支链是指一个或多个碳原子的烷基如甲基、乙基或丙基等与直链烷基连接。优选的C 1-6烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基等。
“C 1-6卤代烷基”是指如上定义的C1-6烷基中含有一个或多个卤素原子取代基。优选 的C 1-6卤代烷基包括但不限于三氟甲基。
“C 1-6羟基烷基”是指如上定义的C1-6烷基中含有一个或多个羟基。优选的C1-6羟基烷基包括但不限于羟甲基和2-羟乙基。
“C 1-6烷氧基”是指C 1-6烷基-O-基团，通过氧与母体部分键接，其中C 1-6烷基如上所述。优选的C 1-6烷氧基包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基和正丁氧基。
“C 6-10芳基”是指含有6至10个碳原子的芳族单环或多环***。优选的C6-10芳基包括但不限于苯基和萘基。
“C 3-7环烷基”是指环上含有3至7个碳原子，优选3至6个碳原子的非芳族饱和单环或多环基团。优选的单环C3-7环烷基包括但不限于环丙基、环戊基、环己基、环庚基等。
“5-10元杂芳基”是指含有5至10个环原子的芳族单环或多环基团，所述5-10元杂芳基包含选自N、O和S中的1至4个杂原子。优选的5-10元杂芳基含有5至6个环原子。5-10元杂芳基的氮原子可以任选地被氧化成相应的N-氧化物。优选的C5-10杂芳基包括但不限于吡啶基、吡嗪基、呋喃基、噻吩基、嘧啶基、吡啶酮、噁唑基、异噻唑基、噁唑基、噁二唑基、噻唑基、噻二唑基、吡唑基、呋咕基(furazanyl)、吡咯基、***基、1,2,4-噻二唑基、哒嗪基、喹喔啉基、酞嗪基、羟吲哚基、咪唑并[1,2-a]吡啶基、咪唑并[2,1-b]噻唑基、苯并呋咕基(benzofurazanyl)、吲哚基、氮杂吲哚基、苯并咪唑基、苯并噻吩基、喹啉基、咪唑基、噻吩并吡啶基、喹唑啉基、噻吩并嘧啶基、吡咯并吡啶基、咪唑并吡啶、异喹啉基、苯并吖嗪基、1,2,4-三嗪基、苯并噻唑基其氧化物等。术语“5-10元杂芳基”也指部分饱和的5-10元杂芳基，例如四氢异喹啉基，四氢喹啉基等。
“3-7元杂环基”是指含有3至7个环原子，优选3至6个环原子，优选5至6个环原子的非芳族单环或多环基团，其中，所述3-10元杂环基包含选自N、O和S中的1至4个杂原子。所述3-10元杂环基的氮或硫原子可以任选地氧化成相应的N-氧化物、S-氧化物或S-二氧化物。因此本发明中术语“氧化物”是指相应的N-氧化物、S-氧化物或S-二氧化物。“3-7元杂环基”还包括环上相同碳原子上的两个可用氢原子同时被单一的基团＝O取代(即形成羰基)，这样的＝O基团在本发明中可以称为“氧代”。优选的单环3-7元杂环烷基包括但不限于哌啶基、氧杂环丁烷基、吡咯基、哌嗪基、吗啉基、硫代吗啉基、噻唑烷基、1,4-二噁烷基、四氢呋喃基、四氢噻吩基、内酰胺基(如吡咯烷酮基)、具有3至7个环原子的内酯基及其氧化物。
“酯基”是指由具有1-20个碳原子的脂肪族或芳香族羧酸与具有1－20个碳原子的伯、仲或叔醇经酯化反应形成的酯中除去一个氢原子而获得的基团。优选的酯基包括但不限于甲酯基，乙酯基，异丙酯基，叔丁酯基，苯酯基。
“酰胺基”是指由具有1-20个碳原子的脂肪族或芳香族羧酸与具有1－20个碳原子的伯或仲胺经酰胺化反应组成的酰胺中除去一个氢原子而获得的基团。
术语“未取代或取代”表示特定基团未被取代或被一个或多个取代基取代。取代基包括，不局限于，氢，羟基，氨基，氰基，硝基，羧基，卤素，C1-6烷基，C1-6卤代烷基或C1-6羟基烷基。二个相邻取代基可以连接形成C6-10芳基，5-10元杂芳基，C3-10环烷基或3-10元杂环烷基。C6-10芳基，5-10元杂芳基，C3-10环烷基，3-10元杂环烷基，3-7元杂环烯基等基团上的取代包括在基团的任何环部分的取代。
为方便起见，在本发明中仅示例了每种化合物的一种异构体。应当注意，本发明的化合物包括所有的立体异构体。
本发明的化合物可以与一种或多种金属离子形成金属螯合物。金属离子包括但不限于铜，铁，镁，钙，锌，镍和铂等。应当注意，本发明的化合物包括所有的金属螯合物。
术语“药学上可接受的盐”是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和***反应)，即有合理的效益/风险比的物质。药学上可接受的盐包括无机盐和有机盐，它们可以在本发明化合物的最终分离和纯化期间获得，或者通过游离酸或碱官能团与合适的碱或酸反应成盐。适合形成盐的酸包括但不限于：无机酸如盐酸、磷酸或硫酸，或有机酸如枸橼酸、抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、富马酸、乙醇酸、琥珀酸、丙酸、乙酸或甲磺酸等。适合形成盐的碱包括但不限于：无机碱如碳酸钠、氢氧化钠、碳酸钾、氢氧化钾、氢氧化锂、醋酸钙、氯化钙或氯化镁等，有机碱如氨基乙醇等。
术语“有效量”是指施用的组合物中所含的本发明化合物的量足以调节(例如抑制或激动等)哺乳动物ATG8同源物。
本发明化合物可以通过本领域中类似已知的各种方法制备，下述制备化合物的实施例为制备本发明化合物的示例性方案。
实施例
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围，且本发明不限于这些实施例。本领域的技术人员将容易理解的是，可使用以下制备方法的条件和过程的已知变型来制备这些化合物。本发明中用到的起始反应物未经特别说明，均为商业购买。
一般合成方法：
除非另有说明，否则所有反应均在惰性气体(如氩气或氮气)环境下进行，使用的市售试剂和无水溶剂无需进行进一步处理。
质谱用液相色谱-质谱联用仪(LC-MS，安捷伦6120B型单四级杆液相色谱-质谱联用仪)记录。 1H核磁共振谱(NMR)用BrukerAMX-400型核磁共振仪记录，在氘代二甲亚砜(DMSO-d6)中记录并以氘代溶剂峰为参考标准。化学位移δ的单位为ppm，耦合常数(J 或J)的单位为赫兹(Hz，Hertz)，核磁谱中耦合裂分峰表示为：宽单峰(brs)、单峰(s)、二重峰(d)、双二重峰(dd)、三重峰(t)、四重峰(q)和多重峰(m)。
实施例1：化合物2-((二甲基氨基)亚甲基)-5-苯基环己烷-1,3-二酮的合成(化合物1)的合成
Figure PCTCN2018087452-appb-000007
将化合物5-苯基环己烷-1,3-二酮(5.0g,26.6mmol)溶于氯仿(25mL)中，加入N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)(5mL)，上述混合物于室温下反应1小时。反应完毕，反应液浓缩，浓缩物用10％乙酸乙酯(EA)/石油醚(PE)匀浆析出沉淀，过滤，将滤渣干燥即得目标化合物4.81g，产率74％。化合物1： 1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.32(d,J＝4.3Hz,4H),7.25–7.17(m,1H),3.43(s,3H),3.32–3.24(m,1H),3.09(s,3H),2.70–2.61(m,2H),2.53–2.51(m,1H),2.49–2.46(m,1H)；MS:244.2[M+1]。
实施例2：化合物5-苯基-2-((苯基氨基)亚甲基)环己烷-1,3-二酮(化合物11)的合成
Figure PCTCN2018087452-appb-000008
将化合物2-((二甲基氨基)亚甲基)-5-苯基环己烷-1,3-二酮(200mg，0.82mmol)(化合物1)、苯胺(60mg，0.65mmol)和醋酸(0.5mL)溶解于10mL乙醇中，回流反应1小时。冷却至室温，浓缩得粗品，经柱层析分离得到目标化合物150mg，产率79％。化合物11： 1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),7.49-7.41(m,4H),7.35-7.28(m,5H),7.25-7.22(m,1H),3.46-3.40(m,1H),2.95-2.70(m,4H)；MS:292.1[M+1]。
实施例3：使用相应的取代1，3-环己二酮和相应的氨基化合物，化合物2-10和12-61可以通过以上的合成方法制备。
实施例4化合物或其盐靶向LC3B的分子水平实验
通过构建原核表达***来表达纯化LC3B蛋白，利用荧光偏振实验建立了初步的筛选验证平台，对合成的小化合物库进行活性测定。
重组蛋白GST-LC3B(终浓度180nM,SEQ ID NO:1)和N末端FITC标记肽(SEQ ID NO:2，终浓度18nM)置于FP缓冲液(50mM HEPES pH7.5，0.1mg/mL BSA，1mM DTT)中，向其中加入使用FP缓冲液连续梯度稀释的化合物，然后将上述混合物于25℃下在 避光孵育。监测荧光偏振值(PerkinElmer Envision，发射光波长480nm；吸收光波长535nm)，并用GraphPad Prism 6.0程序计算IC 50值。
测试结果如表1所示，其中化合物的IC 50值表示方法：100μM<IC 50≤1mM被认为对LC3B的活性较低(+)；化合物15μM<IC 50≤100μM被认为是对LC3B的活性中等(++)；3μM<IC 50≤15μM被认为对LC3B活性较高(+++)；IC 50≤3μM被认为对LC3B具有高活性(++++)。
表1 化合物对LC3B调节的活性数据
Figure PCTCN2018087452-appb-000009
实施例5：化合物或其盐对细胞自噬的调节作用
LC3-I/LC3-II蛋白的免疫印迹检测
将Hela细胞接种至6孔板中，培养过夜，加入一定浓度化合物处理12h，之后换无血清的培养基饥饿处理24小时。吸除培养基，用PBS洗一遍，加入SDS-PAGE用2×上样缓冲液裂解细胞。样品在99℃煮沸10分钟，经SDS-PAGE分离后，使用LC3B抗体(Novus)进行LC3-I/LC3-II检测，检测结果如图2A所示。
由图2A可以看出，LC3-II随化合物处理时间延长而出现累积。
免疫荧光染色和荧光显微镜拍照
将Hela细胞接种至6孔板中的玻璃盖玻片上，培养至细胞状态良好，加入一定浓度化合物处理12小时，之后换无血清的培养基饥饿处理24小时。细胞先预冷10分钟后用0.2％的Triton X-100打孔处理，室温放置10分钟。然后用含2.5％BSA的PBS封闭处理后放置4度抗LC3B一抗孵育过夜，后用荧光二抗识别一抗并用DAPI对细胞核进行染色，置于显微镜下拍照。检测结果如图2B所示。
由图2B可以看出，相对对照组，化合物38处理后细胞自噬体出现累积，且浓度越 高，累积越多。
实施例6：化合物或其盐与部分上市药物联合使用对不同类型肿瘤细胞增殖的抑制作用
肿瘤细胞株：大B淋巴瘤细胞(DB、Toledo、Pfeiffer、SU-DHL6、WSU-DLCL2、OCI-Ly19、SU-DHL2、SU-DHL8)，套细胞淋巴瘤细胞株(REC-1、Z-138、Jeko-1、Maver-1)，胰腺癌细胞株(AsPC-1、BxPC-3、MIAPaCa-2、Panc-3.014、CaPan-1、Panc-1)，结肠癌细胞株HCT116，非小细胞肺癌细胞株(PC9、HCC827、NCI-H1975)和多发性骨髓瘤细胞株(H929、KMS26、RPMI-8226)。
联合使用的上市药物：依鲁替尼，伊马替尼，吉西他滨，厄洛替尼，培美曲塞二钠，AZD3759和来那度胺。
实验方法：采用含10％FBS的完全培养基，细胞计数后，以每孔～10000个/100μL接种于96孔板中，同时给予上市药物和化合物38处理，药物按1:3的浓度梯度稀释，化合物38的浓度点设置为100μM,50μM,30μM三组。通过Cell Titer-Glo法检测给药72小时后细胞增殖的变化。以细胞存活率为纵坐标，药物浓度为橫坐标做图。结果见图3。
细胞存活率(％)计算方法为：存活率(％)＝(给药孔OD-空白孔OD)/(对照孔OD-空白孔OD)×100。
检测结果如表2所示，其中：“++++“表示30μM联用效果很明显；“+++”表示50μM联用效果明显；“++”表示100μM联用效果明显；“+”表示100μM联用效果不明显。
表2 化合物38与已上市药物联用对各种肿瘤细胞增殖的影响
Figure PCTCN2018087452-appb-000010
Figure PCTCN2018087452-appb-000011

Claims (10)

  1. 通式(I)所示化合物或其药学上可接受的盐单独或者与其他药物联合在制备调节细胞自噬及治疗细胞自噬相关疾病的药物中的用途：
    Figure PCTCN2018087452-appb-100001
    其中：
    R 1和R 2各自独立选自：氢，羟基，氨基，氰基，甲酰基，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，C(＝O)R a，SO 2R a，取代或未取代的-(CH 2) m-C 6-10芳基或5-10元杂芳基，取代或未取代的-(CH 2) m-C 3-7环烷基或3-7元杂环基；所述R a选自氢，羟基，C 1-6烷基，C 1-6卤代烷基，取代或未取代的C 1-6羟基烷基，取代或未取代的氨基，取代或未取代的苯基，取代或未取代的五至六元杂芳基；
    R 3、R 4、R 5和R 6各自独立选自：氢，羟基，氨基，卤素，氰基，硝基，羧基，甲酰基，酰胺基，酯基，C 1-6烷基，C 1-6卤代烷基，C 1-6烷氧基，取代或未取代的C 6-10芳基，取代或未取代的5-10元杂芳基，C 3-7环烷基，和3-7元杂环基，
    或者R 3和R 5和/或R 4和R 6连接形成C 6-10芳基或5-10元杂芳基；
    所述卤素选自F，Cl，Br，I；优选选自F，Cl，Br；
    所述取代表示所述基团被一个或多个取代基取代，所述取代基选自：羟基，氨基，氰基，卤素，硝基，三氟甲基，羧基，酯基，甲酰基，C 1-6烷基，C1-6卤代烷基、C1-6羟基烷基、C 1-6烷氧基，3-10元杂环基，C 6-10芳基和5-10元杂芳基；
    m选自0、1、2和3，优选为1或2。
  2. 根据权利要求1所述的用途，其中，所述C 6-10芳基或5-10元杂芳基选自由下列环失去一个氢原子形成的基团：
    Figure PCTCN2018087452-appb-100002
    Figure PCTCN2018087452-appb-100003
    和/或
    所述C 3-7环烷基或3-7元杂环基选自由下列环失去一个氢原子形成的基团：
    Figure PCTCN2018087452-appb-100004
  3. 根据权利要求1或2所述的用途，其中，所述通式(I)的化合物选自下述化合物：
    Figure PCTCN2018087452-appb-100005
    Figure PCTCN2018087452-appb-100006
    Figure PCTCN2018087452-appb-100007
  4. 根据权利要求1-3中任一项所述的用途，其中，所述调节细胞自噬的药物是哺乳动物ATG8同源蛋白(尤其是LC3B)的调节剂。
  5. 根据权利要求1-4中任一项所述的用途，其中，所述调节细胞自噬的药物是治疗与细胞自噬，特别是哺乳动物ATG8同源蛋白(尤其是LC3B)相关的疾病的药物。
  6. 根据权利要求5所述的用途，其中，所述与细胞自噬，特别是哺乳动物ATG8同源蛋白(尤其是LC3B)相关的疾病包括：肿瘤，心血管疾病，自身免疫性疾病，神经退行性疾病，高血压，骨组织细胞及骨类疾病，克罗恩氏病，急性肾损伤，脑缺血，视网膜疾病，支气管哮喘，Vici综合征，以及感染性疾病。
  7. 根据权利要求6所述的用途，其中，所述肿瘤选自肝癌、肺癌、胰腺癌、乳腺癌、***、子宫内膜癌、大肠癌、胃癌、肺癌、鼻咽癌、卵巢癌、***癌、白血病、淋巴瘤、骨髓瘤。
  8. 根据权利要求1-7中任一项所述的用途，其中，所述其他药物是已上市药物，选自：依鲁替尼，伊马替尼，吉西他滨，厄洛替尼，培美曲塞二钠，AZD3759和来那度胺。
  9. 根据权利要求4-6中任一项所述的用途，其中，所述哺乳动物ATG8同源蛋白包括LC3，GABARAP和GATE-16子家族蛋白。
  10. 根据权利要求9所述的用途，其中，
    LC3家族蛋白包括LC3A,LC3B和LC3C蛋白；
    GABARAP家族蛋白包括GABARAPL和GABARAPL1蛋白；
    GATE-16家族蛋白包括GABARAPL2蛋白。
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