WO2017114260A1 - 色胺酮及其衍生物在制备hIDO2抑制剂中的用途 - Google Patents

色胺酮及其衍生物在制备hIDO2抑制剂中的用途 Download PDF

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WO2017114260A1
WO2017114260A1 PCT/CN2016/111318 CN2016111318W WO2017114260A1 WO 2017114260 A1 WO2017114260 A1 WO 2017114260A1 CN 2016111318 W CN2016111318 W CN 2016111318W WO 2017114260 A1 WO2017114260 A1 WO 2017114260A1
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ido2
compound
indoleamine
dioxygenase
ido1
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French (fr)
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匡春香
杨春
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苏州康正生物医药有限公司
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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
    • A61K31/395—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • the present invention relates to the field of medicinal chemistry, and more particularly to compounds of formula I and their use in inhibiting guanamine 2,3-dioxygenase 2.
  • IDO1 Indoleamine 2,3-dioxygenase 1
  • IDO1 is the first rate-limiting enzyme in mammals that catalyzes the metabolism of tryptophan along the kynurenine pathway. Studies have shown that IDO1 is highly expressed in a variety of tumor tissues, can inhibit lymphocyte proliferation by reducing tryptophan concentration in the tumor microenvironment, and plays an important role in tumor immune escape. Therefore, it is currently considered that the high expression of IDO1 is One of the important factors leading to the body's immune tolerance to tumors.
  • IDO2 is located downstream of the IDO1 gene.
  • the sequence of IDO2 is structurally highly similar to the sequence of IDO1. It is located on chromosome 8 of humans and mice and is highly expressed in the kidney, reproductive system, and liver of mice. Studies have found that IDO2 is also expressed in cancer tissues of gastric cancer, colon cancer, pancreatic cancer, and kidney cancer.
  • IDO2 can also catalyze the degradation of tryptophan.
  • IDO1 in tumor immune tolerance has been recognized, and in gene expression, signal transduction, diseases for pathological features with IDO1-mediated tryptophan metabolism pathways (including cancer, AIDS, The treatment of Alzheimer's disease, depression, cataract and other major diseases has become a research hotspot. At present, there are relatively few studies on the biological characteristics, function and immune tolerance of IDO2. It is urgent to develop high-efficiency and selective inhibition of IDO2 inhibitors, so as to mediate IDO2 alone or IDO1 and IDO2. Leading human major diseases provide new drug targets and ideas.
  • IDO2 indoleamine 2,3-dioxygenase 2
  • a compound of formula I for the manufacture of a pharmaceutical combination for inhibiting the activity of indoleamine 2,3-dioxygenase 2 (IDO2) Or preparation,
  • R1, R2, R3 and R4 are each independently selected from the group: H, CH 3, halomethyl, F, Cl, Br, and -NO 2.
  • said R1, R2, R3 and R4 are the same or different.
  • At least two of said R1, R2, R3 and R4 are H.
  • said R1, R2 and R4 are both H.
  • said R1, R2 and R3 are both H.
  • both R2 and R4 are H.
  • At least one of R2 and R3 is halogen, methyl, or -NO 2 .
  • the R2 and R3 is a halogen, methyl, or -NO 2, and the other is H.
  • said R2 and R3 is halogen or -NO 2, and the other is H.
  • said one of R2 and R3 is -NO 2, and the other is H.
  • the compound of formula I is selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of Compound 1, Compound 4.
  • the compound of formula I is selected from the group consisting of Compound 2, Compound 3, and Compound 8.
  • the indoleamine 2,3-dioxygenase 2 is human indoleamine 2,3-dioxygenase 2.
  • the pharmaceutical composition or formulation is also useful for inhibiting the activity of indoleamine 2,3-dioxygenase 1 (IDO1).
  • IDO1 indoleamine 2,3-dioxygenase 1
  • the pharmaceutical composition or formulation is also used to prevent or treat a disease associated with IDO2.
  • the "IDO2-related disease” includes a disease mediated by IDO2 alone, or a disease in which IDO1 and IDO2 are involved together.
  • the disease comprises a disease of abnormal tryptophan metabolism.
  • the disease is selected from the group consisting of tumorigenesis, tumor immune tolerance, cancer, AIDS, Alzheimer's disease, depression, and cataract.
  • the cancer is selected from the group consisting of liver cancer, lung cancer, cervical cancer, breast cancer, melanoma, pancreatic cancer, colon cancer, kidney cancer, prostate cancer, and the like.
  • the pharmaceutical composition contains from 0.001 to 99% by weight, preferably from 0.1 to 90% by weight, more preferably from 1 to 80% by weight, of a compound of formula I or a pharmaceutically acceptable salt thereof, by composition Total weight.
  • the pharmaceutical composition is in the form of an oral dosage form or an injectable dosage form.
  • the oral dosage form comprises a tablet, a capsule, a film, a granule, etc., and further comprises a sustained release or non-release type.
  • the pharmaceutical composition may also contain other pharmaceutically active ingredients.
  • the other pharmaceutically active ingredient comprises a compound, an antibody, a nucleic acid molecule, an anti-tumor immune cell, or a combination thereof.
  • the compound comprises a chemotherapeutic agent for treating a tumor, such as cisplatin or paclitaxel.
  • the antibody comprises an anti-tumor antibody, such as an antibody against Her2, an antibody against VEGF2, or a combination thereof.
  • the anti-tumor immune cells comprise CAR-T cells.
  • the indoleamine 2,3-dioxygenase 2 is in a free state or is expressed in a cell.
  • step (a) a compound of formula I, or a pharmaceutically acceptable salt thereof, is added to the cell culture system to render it with indoleamine 2,3-dioxygenase 2 Make contact.
  • the cell is a normal cell or a tumor cell.
  • the cell is a mammalian cell.
  • the cell is a human cell.
  • a method of inhibiting indoleamine 2,3-dioxygenase 2 or treating a disease associated with IDO2 comprising: (i) administering to a subject in need thereof A compound of the formula I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof.
  • the subject comprises a human and a non-human mammal.
  • Figure 1 shows the inhibition of IDO2 activity by the compounds of the invention.
  • the inventors have extensively and intensively studied, and for the first time, unexpectedly discovered that a compound of the formula I, such as the compound of formula I, can significantly inhibit the activity of IDO2.
  • a compound of the formula I can significantly inhibit the activity of IDO2.
  • the compound of formula I has a good inhibitory effect on IDO2, and its inhibitory effect is superior to that of IDO2 inhibitor 1-MT (1-methylchroman) which is common in vitro and in vivo.
  • Acid and the compounds of formula I are all reversible inhibitors.
  • the compounds of formula I of the present invention are useful for the treatment or prevention of major human diseases, including cancer, which are mediated by IDO2 alone or that are co-involved by IDO1 and IDO2. On the basis of this, the present invention has been completed.
  • a compound of the invention As used herein, "a compound of the invention”, “tryptamine of the invention and derivatives thereof”, or “compound of formula I” are used interchangeably and refer to a compound of formula I, or a racemate thereof, or a different A construct, or a pharmaceutically acceptable salt thereof. It should be understood that the term also includes mixtures of the above components.
  • each group is as defined above.
  • the compound of the present invention not only has an inhibitory effect on IDO2, but also has a certain inhibitory effect on IDO1.
  • pharmaceutically acceptable salts of the compounds of formula I are also included in the invention.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention which is formed with an acid or a base and which is suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the tryptamine is a known compound, and the compound of the formula I of the present invention can be produced by a method well known to those skilled in the art in the prior art, and the reaction parameters of the respective steps are not particularly limited.
  • IDO1 Indoleamine 2,3-dioxygenase 1
  • IDO1 is the first rate-limiting enzyme in mammals that catalyzes the metabolism of tryptophan along the kynurenine pathway. Studies have shown that IDO1 is highly expressed in a variety of tumor tissues, can inhibit the proliferation of lymphocytes by reducing the concentration of tryptophan in the tumor microenvironment, and plays an important role in tumor immune escape.
  • guanamine 2,3-dioxygenase 2 ie indoleamine 2,3-dioxygenase 2 (IDO2), an enzyme found in 2007 that resembles IDO1 in coding gene sequence, molecular structure and biological activity.
  • IDO2 is located downstream of the IDO1 gene, and at the amino acid level, human IDO1 and IDO2 are approximately 43% identical.
  • IDO2 also has an expression characteristic different from that of IDO1, which is mainly expressed in renal tubules, liver and sperm, but both IDO1 and IDO2 are expressed by antigen-presenting dendritic cells.
  • IDO1 and IDO2 have different expression patterns and different kinetic characteristics, therefore, IDO2 may have a function different from IDO1.
  • IDO2 is expressed in cancer tissues of gastric cancer, colon cancer, pancreatic cancer, and kidney cancer.
  • Sorensen's research and Munn et al. were mixed with IDO1-positive dendritic cells and T lymphocytes using IDO1, IDO2 specific inhibitor D-1-methyltryptophan (D-1MT), L-1-methyltryptophan (L-1-MT) treated cells and found that T cells proliferated, indicating that inhibition of IDO1 or IDO2 activity promoted lymphocyte proliferation. effect.
  • D-1MT D-1-methyltryptophan
  • L-1-MT L-1-methyltryptophan
  • IDO2 knockout mice have reduced pathogenic autoimmune antibodies and antibody-secreting cells, and arthritic symptoms are alleviated, while IDO1 knockout mice This phenomenon does not indicate that IDO2 is an important mediator of autoantibody production and inflammation.
  • the inventors have found that different compounds have different types of inhibition for IDO2 and/or IDO1.
  • the types of suppression mainly include: competitive, anti-competitive, non-competitive, and hybrid competition.
  • the present invention provides a composition for inhibiting indoleamine 2,3-dioxygenase 2.
  • compositions include, but are not limited to, pharmaceutical compositions, food compositions, dietary supplements, beverage compositions, and the like.
  • the pharmaceutical composition can be directly used for the treatment of diseases, for example, for the treatment of anti-tumor.
  • other therapeutic agents such as antitumor drugs and the like can also be used at the same time.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a safe and effective amount of a compound of the invention together with a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier or excipient include, but are not limited to, saline, buffer, dextrose, water, glycerol, ethanol, powders, and combinations thereof.
  • the pharmaceutical preparation should be matched to the mode of administration.
  • the composition of the present invention can be prepared into an injection form, for example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under sterile conditions.
  • the pharmaceutical combination of the invention may also be formulated as a powder for nebulization.
  • the amount of active ingredient administered is a therapeutically effective amount, for example from about 1 microgram per kilogram body weight to about 5 milligrams per kilogram body weight per day.
  • the indoleamine 2,3-dioxygenase 2 inhibitors of the invention may also be used with other therapeutic agents.
  • composition of the present invention can be administered to a subject (e.g., human and non-human mammal) by a conventional means.
  • a subject e.g., human and non-human mammal
  • Representative modes of administration include, but are not limited to, oral, injection, nebulization, and the like.
  • a safe and effective amount of the medicament is administered to the mammal, wherein the safe and effective amount is usually at least about 10 micrograms per kilogram of body weight, and in most cases no more than about 8 milligrams per kilogram of body weight, preferably The dose is from about 10 micrograms per kilogram of body weight to about 1 milligram per kilogram of body weight.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • IDO1 and IDO2 The nucleotide sequences of IDO1 and IDO2 have been disclosed, and the active IDO1 and IDO2 in the examples are sources. Human IDO1 and IDO2 can be prepared by conventional molecular cloning means.
  • the inhibitor to be tested includes the IDO inhibitors L-1-MT and D-1-MT (L-1-methyltryptophan, D-1-methyltryptophan, which are commonly used in experiments in vitro and in vivo. All are commercially available), and the compounds of the invention selected from the group consisting of:
  • the tryptamine and its derivatives of the present invention are all reversible inhibitors of IDO2, wherein compound 8 is an anti-competitive inhibitor, and the Ki value of inhibiting IDO2 is 0.97 ⁇ M, reaching nanomolar level (0.97). ⁇ M, ie 970 nM), is only 0.23% of L-1-MT. In addition, compound 8 also has a strong inhibitory effect on IDO1, with a Ki value of 0.054, which is only 0.16% of L-1-MT.
  • the Ki values of Compound 2 and Compound 3 were 3.51 and 5.62 ⁇ M, respectively, and both were less than 10 ⁇ M; even the compound 4 having a relatively poor inhibitory effect had a Ki value of only 1/4 of that of L-1-MT. Therefore, the compound of the present invention has an excellent inhibitory effect on IDO2. Furthermore, the compounds of the invention have an inhibitory effect on IDO1 or IDO2 and thus have a better therapeutic potential for IDO1 or IDO2-mediated tumor immune escape.
  • In vitro level (enzyme level): In the 500 ⁇ L detection system described in Example 1, 30 mM substrate L-tryptophan and inhibitors of different concentration gradients (including the compounds of the invention, L-1-MT and D-) were added. 1-MT), the control group was not added with an inhibitor, and the other treatments were the same as in Example 1. After the reaction, the absorbance was measured at 492 nm using a microplate reader. In inhibition vs. inhibitor concentration plotted IC 50 value calculated using the modified Karber method.
  • U87MG cell line (ATCC No.: HTB-14) was cultured in a DMEM high glucose medium containing 10% fetal bovine serum at 37 ° C in a 5% CO 2 incubator. The cells were pipetted and evenly passaged in a 6-well plate, and transfected when the cells were grown to 80% to 90% confluence.
  • Lipofectamine 2000 with a slight modification: aspirate serum-containing medium and wash the cells twice with PBS, and add 1500 ⁇ L of serum-free medium to each well. Plasmids and liposomes were added to EP tubes pre-filled with 125 ⁇ L Opti-MEM medium in a ratio of 1:2 (2.5 ng plasmid per well and 5 ⁇ L liposome) and gently mixed.
  • both The mixture was incubated for 20 min at room temperature, and then uniformly added to the cell culture medium to be transfected, and cultured at 37 ° C in a 5% CO 2 incubator for 6 hours.
  • the cells were adhered to DMEM medium containing 10% serum and cultured for 18 h.
  • the cells were seeded at a density of 2.5 ⁇ 10 4 cells/well in a 96-well plate, cultured in an incubator at 37° C., 95% humidity, and 5% CO 2 for 6 hours to adhere to the cells, and the test compounds with different concentration gradients were added.
  • L-1-MT and D-1-MT including the compound of the present invention, L-1-MT and D-1-MT
  • a cell culture medium containing L-tryptophan final concentration 200 ⁇ M, filter sterilization
  • 140 ⁇ L of the supernatant was taken to another 96-well plate, 10 ⁇ L of 30% (w/v) trichloroacetic acid was added, heated at 65 ° C for 15 min, and centrifuged at 13 800 ⁇ g for 5 min.
  • the tryptamine and its derivatives of the present invention are effective inhibitors of IDO2, and have a good inhibitory effect on IDO1.
  • IC 50 values of cellular enzyme levels and levels of compound 8 was significantly lower than common inhibitors L-1-MT and D-1-MT, which suppress IDO2
  • the activities were 185-fold and 334-fold, respectively, of L-1-MT and D-1-MT inhibitory activities (at the cell level IC 50 value).
  • IC 50 values were 1.87,7.68,8.26 ⁇ M (less than 10 M), respectively, IC 50 values enzyme level L-1-MT of 1 / 30,1 / 8 1, 7 indicates that the inhibitory activities of the above three compounds on hIDO2 at the enzyme level are about 30-fold, 8-fold and 7-fold, respectively, of L-1-MT.
  • the compounds of the present invention have excellent IDO2 inhibitory effects at both the enzyme level and the cell level.

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Abstract

本发明提供了吲哚胺2,3-双加氧酶2的抑制剂及其应用。具体地，提供了本发明式I化合物或其药学上可接受的盐，所述化合物具有优异的抑制吲哚胺2,3-双加氧酶2活性和抗肿瘤效果。本发明还提供了含有所述化合物的药物组合物以及在抑制吲哚胺2,3-双加氧酶方面的应用。

Description

色胺酮及其衍生物在制备hIDO2抑制剂中的用途 技术领域
本发明涉及药物化学领域，更具体地涉及式I化合物和其在抑制吲哚胺2,3-双加氧酶2方面的应用。
背景技术
吲哚胺2，3-双加氧酶1(indoleamine2,3-dioxygenase1,IDO1)是哺乳动物中催化色氨酸沿着犬尿氨酸途径(kynurenine pathway)代谢的第一个限速酶。研究表明IDO1在多种肿瘤组织中有高表达，可以通过降低肿瘤微环境中色氨酸浓度来抑制淋巴细胞的增殖，在肿瘤免疫逃逸中起到重要作用，因此,目前认为IDO1的高表达是导致机体对肿瘤产生免疫耐受的重要因素之一。
Ball等在2007年发现了一种在编码基因序列、分子结构及生物活性上与IDO1都十分相似的酶，并命名为INDOL1(indoleamine 2,3-dioxygenase-like protein)，即现在的吲哚胺2，3-双加氧酶2(indoleamine2,3-dioxygenase2,IDO2)。IDO2位于IDO1基因的下游，在结构上IDO2的序列和IDO1的序列高度相似，位于人和小鼠的第八号染色体上，在小鼠的肾脏，生殖系统，肝脏中高表达。有研究发现在胃癌、结肠癌、胰腺癌、肾癌的癌组织中也有IDO2的表达。多项研究表明尽管活性比IDO1低，且不起主导作用，但IDO2也能催化色氨酸的降解。研究表明，IDO2与IDO1关系密切，两者可能共同作用参与肿瘤发生、肿瘤免疫耐受、炎症反应等重大疾病或生理活动，因此IDO2有望成为继IDO1之后治疗人类重大疾病的有效药物靶标。
IDO1在肿瘤的免疫耐受中的重要作用已被人们所承认，并且在基因表达、信号转导、用于具有IDO1介导的色氨酸代谢途径的病理学特征的疾病(包括癌症、艾滋病、阿尔茨海默病、抑郁症、白内障等重大疾病)的治疗等方面成为研究热点。目前关于IDO2的生物学特征、功能与免疫耐受的研究还相对较少，本领域迫切需要开发高效的、选择性抑制IDO2的抑制剂，从而为治疗IDO2单独介导或IDO1、IDO2共同参与介导的人类重大疾病提供新的药物靶标和思路。
发明内容
本发明的目的在于提供一种抑制吲哚胺2，3-双加氧酶2(IDO2)活性的化合物及其应用。
在本发明的第一方面，提供了一种式I化合物，或其药学上可接受的盐的用途，用于制备抑制吲哚胺2,3-双加氧酶2(IDO2)活性的药物组合物或制剂，
Figure PCTCN2016111318-appb-000001
其中，
R1、R2、R3和R4各自独立地选自下组：H、CH3、卤代甲基、F、Cl、Br、和-NO2。
在另一优选例中，所述的R1、R2、R3和R4是相同或者不同的。
在另一优选例中，所述的R1、R2、R3和R4中至少有两个为H。
在另一优选例中，所述的R1、R2和R4都为H。
在另一优选例中，所述的R1、R2和R3都为H。
在另一优选例中，所述的R2和R4都为H。
在另一优选例中，所述的R2和R3中至少一个为卤素、甲基、或-NO2。
在另一优选例中，所述的R2和R3中一个为卤素、甲基、或-NO2，而另一个为H。
在另一优选例中，所述的R2和R3中一个为卤素或-NO2，而另一个为H。
在另一优选例中，所述的R2和R3中一个为-NO2，而另一个为H。
在另一优选例中，所述的式I化合物选自下组：
Figure PCTCN2016111318-appb-000002
Figure PCTCN2016111318-appb-000003
在另一优选例中，所述的式I化合物选自下组：化合物1、化合物4。
在另一优选例中，所述的式I化合物选自下组：化合物2、化合物3、和化合物8。
在另一优选例中，所述的吲哚胺2,3-双加氧酶2为人的吲哚胺2,3-双加氧酶2。
在另一优选例中，所述的药物组合物或制剂还用于抑制吲哚胺2,3-双加氧酶1(IDO1)的活性。
在另一优选例中，所述的药物组合物或制剂还用于预防或治疗与IDO2相关的疾病。
在另一优选例中，所述的“与IDO2相关的疾病”包括由IDO2单独介导的疾病，或IDO1、IDO2共同参与介导的疾病。
在另一优选例中，所述的疾病包括色氨酸代谢异常疾病。
在另一优选例中，所述的疾病选自下组：肿瘤发生、肿瘤免疫耐受、癌症、艾滋病、阿尔茨海默病、抑郁症、和白内障。
在另一优选例中，所述的癌症选自下组：肝癌、肺癌、宫颈癌、乳腺癌、黑色素瘤，胰腺癌，结肠癌，肾癌，前列腺癌等。
在另一优选例中，所述药物组合物中含有0.001-99wt％，较佳地0.1-90wt％，更佳地1-80wt％的式I化合物或其药学上可接受的盐，按组合物的总重量计。
在另一优选例中，所述的药物组合物的剂型为口服剂型、或注射剂型。
在另一优选例中，所述口服剂型包括片剂、胶囊剂、膜剂、颗粒剂等，还包括缓释型或非缓释型剂型。
在另一优选例中，所述的药物组合物还可含有其他药物活性成分。
在另一优选例中，所述的其他药物活性成分包括化合物、抗体、核酸分子、抗肿瘤的免疫细胞、或其组合。
在另一优选例中，所述的化合物包括治疗肿瘤的化疗药，如顺铂、紫杉醇。
在另一优选例中，所述的抗体包括抗肿瘤的抗体，如抗Her2的抗体、抗VEGF2的抗体、或其组合。
在另一优选例中，所述的抗肿瘤的免疫细胞包括CAR-T细胞。
在本发明的第二方面，提供了一种体外非治疗性的抑制吲哚胺2,3-双加氧酶2活性的方法，包括步骤：
(a)将吲哚胺2,3-双加氧酶2与本发明第一方面所述的式I化合物、或其药学上可接受的盐进行接触，从而抑制吲哚胺2,3-双加氧酶2的活性。
在另一优选例中，所述的吲哚胺2,3-双加氧酶2为游离状态，或表达于细胞中。
在另一优选例中，在步骤(a)中，将式I化合物、或其药学上可接受的盐添加到细胞培养体系中，从而使其与吲哚胺2,3-双加氧酶2进行接触。
在另一优选例中，所述的细胞为正常细胞或肿瘤细胞。
在另一优选例中，所述的细胞为哺乳动物细胞。
在另一优选例中，所述的细胞为人细胞。
在本发明的第三方面，提供了一种抑制吲哚胺2,3-双加氧酶2或治疗与IDO2相关的疾病的方法，所述的方法包括：(i)给需要的对象施用本发明第一方面所述的式I化合物体、或其药学上可接受的盐。
在另一优选例中，所述的对象包括人和非人哺乳动物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了本发明化合物对IDO2活性的抑制情况。
具体实施方式
本发明人经过广泛而深入地研究，首次意外地发现了一类结构如式I所示化合物可以显著地抑制IDO2的活性。实验表明，所述的式I化合物对IDO2有较好的抑制效果，其抑制效果优于体内外实验通用的IDO2抑制剂1-MT(1-甲基色氨 酸)，并且所述式I化合物均为可逆抑制剂。本发明的式I化合物可用于治疗或预防由IDO2单独介导的或IDO1、IDO2共同参与介导的包括癌症在内的人类重大疾病。在此基础上，完成了本发明。
术语
如本文所用，“本发明化合物”、“本发明的色胺酮及其衍生物”、或“式I化合物”可互换使用，指式I所示的化合物、或其消旋体、对应异构体、或其药学上可接受的盐。应理解，该术语还包括上述组分的混合物。
Figure PCTCN2016111318-appb-000004
式中，各基团的定义如上所述。
本发明化合物不仅对IDO2具有抑制作用，对IDO1也有一定的抑制作用。
在本发明中，还包括式I化合物的药学上可接受的盐。术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
色胺酮为已知化合物，本发明的式I化合物可采用现有技术中本领域技术人员熟知的方法进行制备，对各个步骤的反应参数没有特别限制。
吲哚胺2，3-双加氧酶
吲哚胺2，3-双加氧酶1(indoleamine2,3-dioxygenase1,IDO1)是哺乳动物中催化色氨酸沿着犬尿氨酸途径(kynurenine pathway)代谢的第一个限速酶。研究表明IDO1在多种肿瘤组织中有高表达，可以通过降低肿瘤微环境中色氨酸浓度来抑制淋巴细胞的增殖，在肿瘤免疫逃逸中起到重要作用。
如本文所用，“吲哚胺2，3-双加氧酶2”，即indoleamine2,3-dioxygenase2 (IDO2)，是2007年发现的一种在编码基因序列、分子结构及生物活性上与IDO1相似的酶。IDO2位于IDO1基因的下游，在氨基酸水平上，人IDO1和IDO2约有43％的同一性。此外，IDO2还具有不同于IDO1的表达特性，IDO2主要在肾小管，肝脏和精子中表达，但IDO1和IDO2均通过抗原呈递树突状细胞进行表达。研究表明，IDO1和IDO2具有不同的表达模式和不同的动力学特性，因此，IDO2可能具有不同于IDO1的功能。有研究发现在胃癌、结肠癌、胰腺癌、肾癌的癌组织中有IDO2的表达。
Sorensen的研究以及Munn等用IDO1阳性的树突状细胞和T淋巴细胞混合培养，用IDO1、IDO2特异性抑制剂D-1-甲基色氨酸(dextro-1-methyltryptophan，D-1MT)、L-1-甲基色氨酸(levo-1-methyltryptophan，L-1-MT)处理细胞后发现T细胞都有增殖的表现，说明抑制了IDO1或IDO2的活性后对淋巴细胞的增殖有促进作用。而Hou等研究发现，在用黑色素瘤研究中，用IDO2的特异性抑制剂D-1-MT和环磷酰胺连用有明显的缩小肿瘤的效果，比IDO1的特异性抑制剂L-1-MT的效果明显。而且在D-1-MT组生存率也得到明显的延长。研究结果表明抑制IDO2比抑制IDO1在延缓肿瘤生长、减小肿瘤方面更有效果，推测其在免疫耐受中也起到重要作用。
Merlo等研究发现与野生型类风湿性关节炎小鼠相比，IDO2基因敲除的小鼠体内致病性自免疫抗体及抗体分泌细胞减少，关节炎症状减轻，而IDO1基因敲除的小鼠则无此现象，表明IDO2是自体抗体产生及炎症发生的重要介导分子。
抑制类型
本发明人研究发现，不同化合物对于IDO2和/或IDO1的抑制类型是不同。在本发明中，抑制类型主要包括：竞争性、反竞争、非竞争、和混合型竞争。
组合物和施用方法
本发明提供了一种用于抑制吲哚胺2,3-双加氧酶2的组合物。所述的组合物包括(但并不限于)：药物组合物、食品组合物、膳食补充剂、饮料组合物等。
在本发明中，所述的药物组合物可直接用于疾病治疗，例如，用于抗肿瘤方面的治疗。在使用本发明药物制剂时，还可同时使用其他治疗剂，如抗肿瘤的药物等。
本发明还提供了一种药物组合物，它含有安全有效量的本发明化合物以及药学上可接受的载体或赋形剂。这类载体包括(但并不限于)：盐水、缓冲液、葡萄糖、水、甘油、乙醇、粉剂、及其组合。药物制剂应与给药方式相匹配。
以药物组合物为例，本发明的组合物可以被制成针剂形式，例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。诸如片剂和胶囊之类的药物组合物，可通过常规方法进行制备。药物组合物如针剂、溶液、片剂和胶囊宜在无菌条件下制造。本发明的药物组合也可以被制成粉剂用于雾化吸入。活性成分的给药量是治疗有效量，例如每天约1微克/千克体重-约5毫克/千克体重。此外，本发明的吲哚胺2,3-双加氧酶2抑制剂还可与其他治疗剂一起使用。
对于本发明的药物组合物，可通过常规的方式施用于所需的对象(如人和非人哺乳动物)。代表性的施用方式包括(但并不限于)：口服、注射、雾化吸入等。
使用药物组合物时，是将安全有效量的药物施用于哺乳动物，其中该安全有效量通常至少约10微克/千克体重，而且在大多数情况下不超过约8毫克/千克体重，较佳地该剂量是约10微克/千克体重-约1毫克/千克体重。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
(a)本发明的式I化合物对IDO2具有较好的抑制效果。
(b)本发明的式I化合物对对IDO1也能起到抑制作用。
(c)本发明的式I化合物对于IDO1或IDO2介导的肿瘤免疫逃逸具有更好的治疗潜能。
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。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
通用材料
IDO1和IDO2的核苷酸序列均已公开，实施例中的活性IDO1和IDO2为来源 于人的IDO1和IDO2，可通过常规分子克隆手段进行制备。
实施例中，待测抑制剂包括目前体内外实验通用的IDO抑制剂L-1-MT和D-1-MT(L-1-甲基色氨酸，D-1-甲基色氨酸，均为市售)，以及选自下组的本发明化合物：
Figure PCTCN2016111318-appb-000005
实施例1
酶水平IDO2抑制剂的初步筛选
500μL的标准检测体系中，将50mmol/L磷酸钾缓冲液(pH 7.5)、200μg/mL过氧化氢酶、40mmol/L抗坏血酸、20μmol/L亚甲基蓝、适宜浓度的底物L-色氨酸(0-40mM)以及终浓度均为10μM的待测IDO2抑制剂(包括本发明化合物、L-1-MT和D-1-MT)混合，混合液于37℃水浴5min后向上述混合液中加入IDO2，37℃反应30min，酶促反应结束后加入200μL 30％(w/v)三氯乙酸终止反应，然后在65℃水浴锅中加热15min，使反应产物完成从N-甲酰犬尿氨酸到犬尿氨酸的转化。138000×g离心10min，吸取上清100μL与等体积的2‰(w/v)对二甲氨基苯甲醛的乙酸溶液充分混匀，犬尿氨酸可与该溶液反应并使混合液变为黄色，使用酶标仪在492nm处检测其吸光度。
初筛结果如图1所示，本发明9个化合物对IDO2的抑制率均显著高于L-1-MT和D-1-MT(抑制率均小于8％)。其中，化合物8对IDO2的抑制效果最好， 抑制率63％；其余化合物对IDO2抑制率为18％-47％。本实施例化合物初筛结果为后续IC50值、Ki值测定以及抑制类型判定提供了数据验证的基础。
实施例2
本发明化合物抑制类型及Ki值测定
在实施例1所述的500μL检测体系中，分别加入不同浓度(20、30、40mM或20、25、35mM)的底物L-色氨酸，并在每一个底物浓度下，加入不同浓度梯度的待测抑制剂(包括本发明化合物、L-1-MT和D-1-MT)，对照组不加抑制剂，混合液于37℃水浴5min后加入10μL IDO2(约1μM)，37℃反应30min，酶促反应结束后加入200μL 30％(w/v)三氯乙酸终止反应，然后在65℃水浴锅中加热15min，使反应产物完成从N-甲酰犬尿氨酸到犬尿氨酸的转化。138000×g离心10min，吸取上清100μL与等体积的2‰(w/v)对二甲氨基苯甲醛的乙酸溶液充分混匀，犬尿氨酸可与该溶液反应并使混合液变为黄色，使用酶标仪在492nm处检测其吸光度。以Dixon作图法(1/v～[i])判定抑制剂类型；以[S]/v～[i]作图，可以得到抑制剂的Ki值。
类似方法测定待测抑制剂对IDO1的抑制类型及Ki值。
结果如下表所示：本发明的色胺酮及其衍生物均为IDO2的可逆抑制剂，其中，化合物8为反竞争性抑制剂，抑制IDO2的Ki值为0.97μM，达到纳摩尔水平(0.97μM，即970nM)，仅为L-1-MT的0.23％，此外，化合物8对IDO1也有很强的抑制作用，Ki值为0.054，仅为L-1-MT的0.16％。化合物2和化合物3的Ki值分别为3.51、5.62μM，均小于10μM；即使是抑制效果相对较差的化合物4的Ki值也仅为L-1-MT的1/4。因此，本发明的化合物对IDO2具有极好的抑制效果。此外，本发明的化合物对IDO1或IDO2都能起到抑制作用，因而对于IDO1或IDO2介导的肿瘤免疫逃逸具有更好的治疗潜能。
Figure PCTCN2016111318-appb-000006
Figure PCTCN2016111318-appb-000007
注：ND：没有测出；—：没有测过。
实施例3
本发明化合物半数有效抑制浓度IC50值的测定
分别测定体外水平和细胞水平下本发明化合物抑制IDO1和IDO2的IC50值。
体外水平(酶水平)：在实施例1所述的500μL检测体系中，加入30mM的底物L-色氨酸及不同浓度梯度的抑制剂(包括本发明化合物、L-1-MT和D-1-MT)，对照组不加抑制剂，其他处理与实施例1相同，反应结束后使用酶标仪在492nm处检测吸光度。以抑制率对抑制剂浓度作图，利用改良寇氏法计算IC50值。
细胞水平：U87MG细胞株(ATCC No.:HTB-14)，采用含有10％胎牛血清的DMEM高糖培养基于37℃、5％CO2培养箱中培养。将细胞吹打均匀传代于6孔板里，待细胞生长至80％～90％融合时进行转染。按照Lipofectamine 2000的说明书进行操作，并稍作改良：吸弃含血清培养基并用PBS洗涤细胞2次，每孔加入1500μL无血清培养基。质粒和脂质体以1:2(每孔2.5ng质粒和5μL脂质体)的比例分别加入到预装有125μL Opti-MEM培养基的EP管中并轻轻混匀，5min后将两者混合，室温孵育20min后分别逐滴均匀的加到待转染细胞培养液中，37℃、5％CO2培养箱培育6小时细胞贴壁后换成含10％血清的DMEM培养基，培养18h后将细胞以2.5×104细胞/孔的密度接种于96孔板中，37℃、湿度95％、5％CO2的培养箱中培养6h待细胞贴壁，加入不同浓度梯度的待测化合物(包括本发明化合物、L-1-MT和D-1-MT)，并用含L-色氨酸(终浓度200μM，过滤除菌)的细胞培养基补齐至每孔总体积200μL，孵育24h后，取140μL上清到另一96孔板中，加入10μL 30％(w/v)三氯乙酸，65℃加热15min，13 800×g离心5min。取100μL上清与等体积2‰(w/v)对-二氨基苯甲醛的冰乙酸溶液混合，充分混匀后采用酶标仪在492nm检测吸光值。实验分组为pcDNA3.1(+)-IDO2转染组(实验组)、pcDNA3.1(+)转染组(空质粒对照组)和未转染组(空白对照组)，每组有三个复孔。以抑制率对抑制剂浓度作图，利用改良寇氏法计算 IC50值
结果如下表所示，本发明的色胺酮及其衍生物均为IDO2的有效抑制剂，同时对IDO1也有较好的抑制效果。其中，化合物8对于IDO1和IDO2均有极好的抑制效果，化合物8的酶水平和细胞水平的IC50值均显著低于通用抑制剂L-1-MT和D-1-MT，其IDO2抑制活性分别为L-1-MT和D-1-MT抑制活性的185倍和334倍(以细胞水平IC50值为例)。化合物8、化合物2、化合物3的酶水平的IC50值分别为1.87、7.68、8.26μM(均小于10μM)，分别为L-1-MT的酶水平IC50值的1/30、1/8、1/7，表明上述三种化合物在酶水平对hIDO2的抑制活性分别是L-1-MT的约30倍、8倍和7倍。综上，本发明化合物在酶水平和细胞水平均有极好的IDO2抑制效果。
Figure PCTCN2016111318-appb-000008
注：ND：没有测出；—：没有测过。
本发明中所有数据均为3次独立实验(每次实验同一化合物设定3个重复)的均值。每组实验数据经公式计算相对标准偏差RSD(相对偏差/平均值)均小于1.5％，表明我们的数据重复性、再现性较好。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献 被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I化合物，或其药学上可接受的盐的用途，其特征在于，用于制备抑制吲哚胺2,3-双加氧酶2(IDO2)活性的药物组合物或制剂，
    Figure PCTCN2016111318-appb-100001
    其中，
    R1、R2、R3和R4各自独立地选自下组：H、CH3、卤代甲基、F、Cl、Br、和-NO2。
  2. 如权利要求1所述的用途，其特征在于，所述的R1、R2和R4都为H。
  3. 如权利要求1所述的用途，其特征在于，所述的R2和R3中一个为卤素、甲基、或-NO2，而另一个为H。
  4. 如权利要求1所述的用途，其特征在于，所述的式I化合物选自下组：
    Figure PCTCN2016111318-appb-100002
  5. 如权利要求1所述的用途，其特征在于，所述的吲哚胺2,3-双加氧酶2为人的吲哚胺2,3-双加氧酶2。
  6. 如权利要求1所述的用途，其特征在于，所述的药物组合物或制剂还用于抑制吲哚胺2,3-双加氧酶1(IDO1)的活性。
  7. 如权利要求1所述的用途，其特征在于，所述的药物组合物或制剂还用于预防或治疗与IDO2相关的疾病。
  8. 如权利要求1所述的用途，其特征在于，所述药物组合物中含有0.001-99wt％，较佳地0.1-90wt％，更佳地1-80wt％的式I化合物或其药学上可接受的盐，按组合物的总重量计。
  9. 如权利要求1所述的用途，其特征在于，所述的药物组合物还可含有其他药物活性成分。
  10. 一种体外非治疗性的抑制吲哚胺2,3-双加氧酶2活性的方法，其特征在于，包括步骤：
    (a)将吲哚胺2,3-双加氧酶2与权利要求1所述的式I化合物、或其药学上可接受的盐进行接触，从而抑制吲哚胺2,3-双加氧酶2的活性。
PCT/CN2016/111318 2015-12-30 2016-12-21 色胺酮及其衍生物在制备hIDO2抑制剂中的用途 WO2017114260A1 (zh)

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