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WO2017173973A1 - 氮杂色胺酮衍生物作为ido1和/或tdo抑制剂的用途 - Google Patents

氮杂色胺酮衍生物作为ido1和/或tdo抑制剂的用途 Download PDF

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WO2017173973A1
WO2017173973A1 PCT/CN2017/079371 CN2017079371W WO2017173973A1 WO 2017173973 A1 WO2017173973 A1 WO 2017173973A1 CN 2017079371 W CN2017079371 W CN 2017079371W WO 2017173973 A1 WO2017173973 A1 WO 2017173973A1
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Prior art keywords
pyrimido
indole
oxopyrido
compound
pyrido
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PCT/CN2017/079371
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English (en)
French (fr)
Inventor
孟祥豹
陈宇
李中军
卢东渤
张美琪
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北京大学
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Priority to EP17778637.3A priority Critical patent/EP3421472B1/en
Priority to US16/090,486 priority patent/US10669273B2/en
Priority to AU2017247282A priority patent/AU2017247282B2/en
Publication of WO2017173973A1 publication Critical patent/WO2017173973A1/zh

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • the present application relates to, but is not limited to, the field of medicinal chemistry, and more particularly to the use of a azine derivative as a inhibitor of tryptophan along the kynuric acid pathway key enzymes - IDO1 and / or TDO, the treatment has Diseases characterized by IDO1 and/or TDO-mediated pathology of tryptophan metabolism, including but not limited to tumors, autoimmune diseases, infectious diseases, Alzheimer's disease, depression, anxiety.
  • tryptophan As an essential amino acid in the human body, tryptophan can only be taken through diet, and the content in the body is small. The concentration of tryptophan in adult plasma is about 40-80 ⁇ M, and about 95% of tryptophan is metabolized by the kynuric acid pathway. Armstrong, MD and Stave, U. Metabolism. 1973, 22, 561–569.]. Metabolites of this pathway have immunosuppressive effects and play a key role in the immune escape of tumors. The earliest discovered tryptophan metabolism enzyme was tryptophan-2,3-dioxygenase (TDO) [Kotake, Y.; Masayama, IZ Physiol. Chem.
  • TDO tryptophan-2,3-dioxygenase
  • IDO1 or TDO can oxidatively cleave the 2,3-double bond of the indole ring in tryptophan with the help of molecular oxygen, thereby producing N-formyl kynuric acid (NFK), which is further oxidized to form a canine.
  • NFK N-formyl kynuric acid
  • Metabolites such as uric acid, picolinic acid and quinolinic acid (Scheme 1).
  • Indoleamine-2,3-dioxygenase 1 (IDO1, EC 1.13.11.52) is the first enzyme that catalyzes the metabolism of tryptophan along the kynuric acid pathway in mammals, and is also the rate-limiting enzyme, which is tumor immunity.
  • IDO1 Indoleamine-2,3-dioxygenase 1
  • One of the causes of tolerance and is associated with poor prognosis in cancer patients [Platten, M.; Wick, W.; Van den Eynde, BJ Cancer Res. 2012, 72, 5435-5440].
  • IDO1 is highly expressed in a variety of tumor tissues, resulting in local tryptophan depletion, inducing T cells to arrest in G1 phase, thereby inhibiting T cell proliferation; and IDO-dependent tryptophan degradation leads to kynurenine levels Enhancement also induces oxygen free radicals to mediate T cell apoptosis; and enhances local regulatory T cell (Treg)-mediated immunosuppression when antigen-presenting cells such as macrophages and dendritic cells overexpress IDO To promote the body's peripheral immune tolerance to tumor-specific antigens.
  • Treg local regulatory T cell
  • IDO1 inhibitors can Enhance the role of tumor therapeutic vaccines, therapeutic monoclonal antibodies, chemotherapy and radiation therapy [Godin-Ethier, J.; Hanafi, L.-A.; Piccirillo, CA; Lapointe, R. Clin. Cancer Res. 2011, 17, 6985-6991].
  • IDO1 enhances regulatory T cell-mediated immunosuppression at the site of infection, prompting the body to develop immune tolerance to pathogenic microorganisms, which is closely related to the resistance of antibacterial and antiviral drugs.
  • IDO1 is closely related to the pathogenesis of various diseases, including autoimmune diseases, Alzheimer's disease, depression, anxiety, cataracts and the like. Therefore, IDO1 inhibitors have attracted more and more attention as potential drugs.
  • Tryptophan-2,3-dioxygenase is another important enzyme regulating the metabolism of tryptophan along the kynuric acid pathway.
  • TDO Tryptophan-2,3-dioxygenase
  • Platten et al. demonstrated that TDO is highly expressed in human glioma cells. Inhibition or knockout of TDO by drugs can block the release of kynuric acid in dogs. Conversely, knocking out IDO1 does not affect the concentration of kynuric acid in dogs, suggesting that TDO is one of the key enzymes for the metabolism of tryptophan in these cells [CAOpitz, UMLitzenburger, F .Sahm, M. Ott, I. Tritschler, S. Trump, T.
  • Van den Eynde et al. found that 20 cell lines expressed only TDO, 17 cell lines only expressed IDO1, and 16 cell lines expressed both TDO and IDO1 (malignant glioma, Mesothelioma, head and neck cancer, pancreatic cancer, non-small cell lung cancer, malignant sarcoma, bladder cancer, gallbladder cancer, etc.).
  • IDO1 inhibitors are effective against 32% of tumor cell lines
  • TDO inhibitors are effective against 35% of tumor cell lines
  • IDO1 and TDO dual inhibitors are effective against 51% of tumor cell lines.
  • dual inhibitors of IDO1 and TDO will further enhance the effectiveness of tumor immunotherapy [L. Pilotte, P. Larrieu, V. Stroobant, D. Colau, E. Dolusic, R. Frederick, E. De Plaen, C U.S. U.S.
  • the tryptamine is an quinazoline alkaloid and is present in blue plants such as horse blue and indigo. Studies have shown that such compounds have antibacterial, antiviral, anti-inflammatory, anti-parasitic and anti-tumor effects.
  • Valliante et al. synthesized a series of tryptamine and azine derivatives and found that these compounds contribute to the production of TNF- ⁇ , and some compounds can produce effects at a concentration of 5 ⁇ M or lower (US Patent No.: US8193185B2) ).
  • the patent does not address IDO1 and TDO targets, and the results of the study also indicate that the introduction of nitrogen atoms in the benzene ring is not directly related to the activity, and the concentration of 8-nitro-1-azamine is not as high as 20 ⁇ M. Shows activity.
  • the present inventors have surprisingly discovered a azine derivative having significant indole-2,3-dioxygenase 1 and/or tryptophan-2,3-dioxygenation Enzyme inhibiting activity.
  • Embodiments of the invention provide the use of a azine derivative as a guanamine-2,3-dioxygenase 1 and/or tryptophan-2,3-dioxygenase inhibitor.
  • Embodiments of the invention provide a novel azine derivative.
  • Embodiments of the present invention provide a method of preparing the above novel nitroamine ketone derivatives.
  • Embodiments of the invention provide pharmaceutical compositions comprising the novel nitroamine ketone derivatives described above.
  • an embodiment of the present invention provides a azine derivative as guanamine-2,3-dioxygenase 1 and/or tryptophan-2,3-dual addition
  • an oxygenase inhibitor such as the formula (I), or a geometric isomer, tautomer, isotope label thereof, hydration , solvate, metabolite, pharmaceutically acceptable salt or prodrug:
  • One of A and B is N and the other is CR 3 ;
  • E is N or -CR 6 ;
  • R 1 to R 7 are each independently selected from hydrogen, unsubstituted C1-C4 alkane or substituted C1-C4 alkane, unsubstituted C1-C4 alkoxy or substituted C1-C4 alkoxy, halogen, Nitro, cyano, methylsulfonyl or hydroxy;
  • R 8 and R 9 are each independently selected from hydrogen or an unsubstituted C1-C4 alkane group.
  • the substituted C1-C4 alkane group means that the hydrogen at any position on the carbon chain is substituted with an optional group: halogen, hydroxy, amino, or -N(R 10 )(R 11 ), here, R 10 and R 11 are each independently selected from hydrogen or an unsubstituted C1-C4 alkane group; for example, trifluoromethyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl, or 3-(dimethyl A propyl group, or a nitrogen-containing 4 to 7 membered heterocyclic ring (for example, tetrahydropyrrole, piperidine, morpholine, piperazine, homopiperazine, etc.) formed by R 10 and R 11 and its linkage with N.
  • R 10 and R 11 are each independently selected from hydrogen or an unsubstituted C1-C4 alkane group; for example, trifluoromethyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl,
  • a azine derivative according to an embodiment of the invention as an IDO1 and/or TDO inhibitor, wherein the unsubstituted C1-C4 alkoxy group is selected from the group consisting of methoxy groups Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • the substituted C1-C4 alkoxy group means that hydrogen at any position on the carbon chain is substituted with an optional group: halogen, hydroxy, amino, or -N(R 10 )(R 11 ), here, R 10 and R 11 are each independently selected from hydrogen or an unsubstituted C1-C4 alkane group; for example, trifluoromethoxy, 2-hydroxyethoxy, 2-(dimethylamino)ethoxy, or -(Dimethylamino)propoxy.
  • the use of the azine derivative of the present invention as an IDO1 and/or TDO inhibitor wherein the unsubstituted C2-C4 olefin group is selected from the group consisting of vinyl and olefin A propyl group, a 1-butenyl group, a 2-butenyl group or the like.
  • the substituted C2-C4 olefin group means that hydrogen at any position on the carbon chain is substituted with an optional group: halogen, or hydroxy.
  • the use of the azine derivative of the present invention as an IDO1 and/or TDO inhibitor wherein the unsubstituted C2-C4 alkyne group is selected from the group consisting of ethynyl groups, Alkynyl, butynyl and the like.
  • the substituted C2-C4 alkyne group means that the hydrogen at any position on the carbon chain is substituted with an optional group: a halogen, or a hydroxyl group.
  • a azine derivative of the invention as an IDO1 and/or TDO inhibitor, wherein the halogen is fluorine, chlorine, bromine, or iodine.
  • an embodiment of the present invention provides a nitrogen serotonin derivative as an IDO1 and/or TDO inhibitor, the derivative being represented by the general formula (I), Wherein G is O; A is N, and B is -CH, or B is N and A is -CH.
  • an embodiment of the present invention provides a nitrogen serotonin derivative as an IDO1 and/or TDO inhibitor, the derivative being represented by the general formula (I), Wherein G is O; A is N, and B is -CH, or B is N and A is -CH; and E is N.
  • IDO1 and/or TDO inhibitor the derivative being represented by the general formula (I), Wherein G is O; A is N, and B is -CH, or B is N and A is -CH; and E is N.
  • an embodiment of the present invention provides a nitrogen serotonin derivative as an IDO1 and/or TDO inhibitor, the derivative being represented by the general formula (I), Wherein G is O; A is N, and B is -CH, or B is N and A is -CH;
  • E is -CR 6 ;
  • R 1 , R 2 , R 4 to R 7 are each independently selected from hydrogen, unsubstituted C1-C4 alkane or substituted C1-C4 alkane, unsubstituted C1-C4 alkoxy or substituted C1-C4 Alkoxy, halogen, nitro, cyano, methylsulfonyl or hydroxy.
  • an embodiment of the present invention provides a nitrogen serotonin derivative as an IDO1 and/or TDO inhibitor, the derivative being represented by the general formula (I), Wherein G is O; A is N, and B is -CH, or B is N and A is -CH;
  • E is -CR 6 ;
  • R 1 and R 2 are hydrogen, and R 4 to R 7 are each independently selected from hydrogen, unsubstituted C1-C4 alkane or substituted C1-C4 alkane, unsubstituted C1-C4 alkoxy or substituted C1. -C4 alkoxy, halogen, nitro, cyano, methylsulfonyl or hydroxy.
  • an embodiment of the present invention provides a nitrogen serotonin derivative as an IDO1 and/or TDO inhibitor, the derivative being represented by the general formula (I), Wherein G is O; A is N, and B is -CH, or B is N and A is -CH;
  • E is -CR 6 ;
  • R 1 and R 2 are hydrogen, and R 4 to R 7 are each independently selected from hydrogen, methyl, trifluoromethoxy, methoxy, fluoro, chloro, bromo, nitro, cyano, methylsulfonyl or hydroxy .
  • E is -CR 6 ;
  • R 1 , R 2 , R 4 to R 7 are each independently selected from hydrogen, unsubstituted C1-C4 alkane or substituted C1-C4 alkane, unsubstituted C1-C4 alkoxy or substituted C1-C4 Alkoxy, halogen, nitro, cyano, methylsulfonyl or hydroxy.
  • E is -CR 6 ;
  • R 1 and R 2 are hydrogen, and R 4 to R 7 are each independently selected from hydrogen, unsubstituted C1-C4 alkane or substituted C1-C4 alkane, unsubstituted C1-C4 alkoxy or substituted C1. -C4 alkoxy, halogen, nitro, cyano, methylsulfonyl or hydroxy.
  • E is -CR 6 ;
  • R 1 and R 2 are hydrogen, and R 4 to R 7 are each independently selected from hydrogen, methyl, trifluoromethoxy, methoxy, fluoro, chloro, bromo, nitro, cyano, methylsulfonyl or hydroxy .
  • an embodiment of the invention provides the use of a compound of the above formula (I) selected from the group consisting of:
  • Embodiments of the invention provide for the use of a compound of formula (I) for the treatment of a disease having pathological features of IDO1 and/or TDO-mediated tryptophan metabolism, including but not limited to tumors, infectious diseases, and self Immune disease, Alzheimer's disease, depression, anxiety.
  • the reference dose for each administration of the human is 0.1-20 mg/kg body weight, and the method of administration is oral or injection.
  • an embodiment of the invention provides a novel azine derivative which is an IDO1 and/or TDO inhibitor, as shown in formula (II), or a geometric isomer thereof, a tautomer thereof , isotopic labels, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:
  • One of A and B is N and the other is CR 3 ;
  • E is N or -CR 6 ;
  • R 1 to R 7 are each independently selected from hydrogen, unsubstituted C1-C4 alkane or substituted C1-C4 alkane, unsubstituted C1-C4 alkoxy or substituted C1-C4 alkoxy, halogen, Nitro, cyano, methylsulfonyl or hydroxy;
  • R 8 and R 9 are each independently selected from hydrogen or an unsubstituted C1-C4 alkane group.
  • a novel azine derivative of the present invention is provided by the formula (II), wherein A is N and B is -CH, or B Is N and A is -CH.
  • a novel azine derivative of the present invention is provided by the formula (II), wherein A is N and B is -CH, or B Is N and A is -CH; and E is N.
  • a novel azine derivative of the present invention is provided by the formula (II), wherein A is N and B is -CH, or B Is N and A is -CH;
  • E is -CR 6 ;
  • R 1 , R 2 , R 4 to R 7 are each independently selected from hydrogen, unsubstituted C1-C4 alkane or substituted C1-C4 alkane, unsubstituted C1-C4 alkoxy or substituted C1-C4 Alkoxy, halogen, nitro, cyano, methylsulfonyl or hydroxy.
  • a novel azine derivative of the present invention is provided by the formula (II), wherein A is N and B is -CH, or B Is N and A is -CH;
  • E is -CR 6 ;
  • R 1 and R 2 are hydrogen, and R 4 to R 7 are each independently selected from hydrogen, unsubstituted C1-C4 alkane or substituted C1-C4 alkane, unsubstituted C1-C4 alkoxy or substituted C1. -C4 alkoxy, halogen, nitro, cyano, methylsulfonyl or hydroxy.
  • a novel azine derivative of the present invention is provided by the formula (I), wherein A is N and B is -CH, or B Is N and A is -CH;
  • E is -CR 6 ;
  • R 1 and R 2 are hydrogen, and R 4 to R 7 are each independently selected from hydrogen, methyl, trifluoromethoxy, methoxy, fluoro, chloro, bromo, nitro, cyano, methylsulfonyl or hydroxy ;
  • R 8 and R 9 are each independently selected from hydrogen or an unsubstituted C1-C4 alkane group.
  • an embodiment of the invention provides a novel azine derivative which is selected from the group consisting of:
  • an embodiment of the present invention provides a method of preparing a azine derivative of the formula (II), comprising the steps of:
  • the compound of the formula (III) is reacted with a compound of the formula (IV) to give a compound of the formula (II'), which is further reacted with a compound of the formula (V) to give a compound of the formula (II).
  • the method for preparing the azine derivative of the formula (II) provided by the embodiment of the present invention can be specifically referred to the following method:
  • the isatin derivative IV (0.9 mmol) and 1,8-diazabicycloundec-7-ene (abbreviated as DBU, 2.0 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for ten minutes to obtain a solution.
  • DBU 1,8-diazabicycloundec-7-ene
  • 2-Aminonicotinic acid analog III (1 mmol), N-methylmorpholine (1.8 mmol), and HBTU (1.0 mmol) were dissolved in DMF (3 mL) to give solution (2).
  • an embodiment of the invention provides a pharmaceutical composition comprising the novel tryptamine analog described above.
  • the pharmaceutical composition comprises a pharmacologically effective amount of a compound of formula (II) and a pharmaceutically acceptable adjuvant.
  • excipients are known to those skilled in the art, for example, physiological saline, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, modified starch, cellulose, modified cellulose, sodium glycolate , calcium hydrogen phosphate, magnesium stearate, talc, colloidal silica, and the like.
  • these compositions may further comprise: stabilizers, wetting agents, emulsifiers, sweeteners, flavoring agents, buffers and the like.
  • the pharmaceutical composition comprising the above tryptamine analog provided by the embodiment of the present invention can be formulated into a solid or liquid form for oral administration, such as a tablet, a pill, an oral solution, etc., as needed; In the form of a sterile solution, suspension or emulsion for parenteral administration, a spray or the like.
  • the embodiment of the present invention Compared with the compound (5a, 5b, 5c, 5i) of the Yangqing research group of Fudan University (see Table 1 below), the embodiment of the present invention introduces a nitrogen atom into a specific position of the tryptophan structure, and obtains a new derivative to the enzyme.
  • the inhibitory activity of IDO1 has an unexpected increase, up to a factor of more than 100.
  • the compounds of the embodiments of the present invention also have significant inhibitory activity against TDO.
  • the methylene chloride, methanol, N,N-dimethylformamide, and the like used in the reaction are all commercially available analytical reagents and are dried and re-steamed according to literature methods; other reagents and raw materials are domestically analyzed or chemically pure. Reagents.
  • the melting point was measured by XT5B or X-4 type precision micro melting point meter (temperature control type) (Beijing Fukai Instrument Co., Ltd.), and the temperature was not corrected.
  • Nuclear magnetic resonance spectroscopy 1 H NMR, 13 C NMR was measured by a Bruker NMR system 400 MHz superconducting nuclear magnetic resonance spectrometer, and TMS was an internal standard.
  • N,N-dimethyl-2-aminooxyethylamine hydrochloride was used instead of hydroxylamine hydrochloride, and CY-1-4 was used in place of CY-1-1.
  • the preparation method was the same as that of CY-1-12 of Example 12.
  • the product was a yellow solid with a yield of 32%.
  • the compound N,N-dimethyl-2-aminooxyethylamine hydrochloride was used instead of hydroxylamine hydrochloride, and CY-1-2 was used instead of CY-1-1.
  • the preparation method was the same as that of CY-1-12 of Example 12.
  • the product was a yellow solid with a yield of 43%.
  • the compound N,N-dimethyl-2-aminooxypropylamine hydrochloride was used instead of hydroxylamine hydrochloride, and CY-1-5 was used in place of CY-1-1 in the same manner as in the CY-1-12 of Example 12.
  • the product was a yellow solid with a yield of 49%.
  • the compound O-allylhydroxylamine was used instead of hydroxylamine hydrochloride, and CY-1-4 was used instead of CY-1-1.
  • the preparation method was the same as that of CY-1-12 of Example 12.
  • the product was a pale yellow solid with a yield of 32%.
  • N,N-dimethylthiosemicarbazide was used instead of hydroxylamine hydrochloride, and CY-1-6 was used instead of CY-1-1.
  • the preparation method was the same as that of CY-1-12 of Example 12.
  • the product was a red solid with a yield of 52%.
  • 1 H NMR 400 MHz, CD 3 COOD
  • IDO-1 can cleave ruthenium of tryptophan to form N-formylated kynuric acid.
  • Reference to the literature (Eddy W.Yue, et al. J. Med. Chem. 2009, 52, 7364-7367), 20 nM IDO-1, 2 mM D-tryptophan was added to 50 mM potassium phosphate buffer at room temperature. , 20 mM ascorbic acid, 3.5 ⁇ M methyl blue and 0.2 mg/mL antioxidant enzyme. Due to the formation of N-formylated kynuric acid, the reaction rate was recorded by the increasing absorbance of the solution at 321 nm. IC 50 values were calculated using Prism GraphPad software. The compound INCB024360 developed by Incyte Pharmaceutical Company of the United States was used as a positive control drug. The experimental results are as follows:
  • TDO can cleave ruthenium of tryptophan to form N-formylated kynuric acid.
  • Reference method (Eddy W. Yue, et al. J. Med. Chem. 2009, 52, 7364-7367) was used to sequentially add a detection buffer containing 50 nM TDO, 10 ⁇ M inhibitor, 200 ⁇ M tryptophan or the like at room temperature. Due to the formation of N-formylated kynuric acid, the reaction rate was recorded by the increasing absorbance of the solution at 321 nm. IC 50 values were calculated using Prism GraphPad software. The experimental results of the enzyme inhibition rate at a concentration of 10 ⁇ M of the compound are as follows:
  • the degree of decrease in kynuric concentration in venous blood of rats can reflect the inhibitory activity of the compound on IDO1 in vivo.
  • Three male rats weighing approximately 300 g were randomly assigned to each group, and the compounds CY-1-4, CY-1-10, CY-1-17 fumarate, CY-1-26 hydrochloride And CY-1-32 and other intragastric administration of 50mg/Kg, at the 0, 0.5, 1, 2, 4, 8, 12, 24 hours, eight time points, blood from the eye of the rat 120-150 microliters After centrifugation at 3000 rpm for 10 min, the supernatant was taken to obtain serum.
  • the concentration of kynuric acid in the serum at different time points was determined by a kynuric acid ELISA test kit. The average value of kynuric acid concentration in three rats was taken from each group.
  • test compounds exhibited varying degrees of activity in reducing uric acid concentration in dogs, with a decreasing ratio of 18-56%.
  • mice After 11 days of continuous intraperitoneal injection of tumor-bearing mice, the animals were euthanized, the subcutaneous tumors were dissected, weighed, photographed, and the animals were dissected for gross observation.
  • the tumor weight of the animals in the drug-administered group was significantly lower than that in the negative control group, the tumor inhibition rate of cyclophosphamide was 29.9%, and the tumor inhibition rate of CY-1-17 (20 mg/kg) was 51.8%.
  • the mice were dissected for gross observation and no obvious tumor metastases were seen.
  • CY-1-26 hydrochloride inhibits melanoma experiment in mice
  • the in vivo efficacy of the test compound was tested with C57BL/6J mice bearing melanoma B16, administered intragastrically with 20 mg/kg, and 1-MT was a positive control (200 mg/kg), both once daily. On the day of the first dose, the relevant indicators were observed, measured and recorded. At the end of the experiment, the tumor-bearing mice were sacrificed and the tumor pieces were dissected and weighed.
  • the tumor-bearing mice were administered by continuous intragastric administration for 10 days.
  • the body weight of the animals in the drug-administered group was slightly slower than that of the negative control group.
  • the animals were in good condition and no obvious side effects were observed.
  • the animals were euthanized, the subcutaneous tumors were dissected, weighed, and the animals were dissected for gross observation.
  • the tumor weight of the animals in the drug-administered group was lower than that in the negative control group, the tumor inhibition rate of 1-MT was 26.3%, and the tumor inhibition rate of CY-1-26 was 33.0%.
  • the in vivo efficacy of the test compound was tested in three groups (6 in each group) of C57BL/6J mice bearing melanoma B16, and CY-1-26 hydrochloride was intragastrically administered at 20 mg/kg (suspended in 0.5% carboxymethyl fiber).
  • An aqueous sodium solution), 1-MT was a positive control (200 mg/kg, suspended in 0.5% aqueous sodium carboxymethylcellulose solution), and the blank control was a 0.5% aqueous solution of sodium carboxymethylcellulose, both once daily.
  • the day began to observe, measure and record the relevant indicators, the tumor-bearing mice were sacrificed at the end of the experiment, and the tumor pieces were dissected and weighed.
  • the tumor-bearing mice were administered by continuous intragastric administration for 14 days.
  • the body weight of the animals in the drug-administered group was slightly slower than that of the negative control group.
  • the animals were in good condition and no obvious side effects were observed.
  • the animals Fourteen days after the administration, the animals were euthanized, the subcutaneous tumors were dissected, weighed, and the animals were dissected for gross observation.
  • the tumor weight of the animals in the drug-administered group was lower than that in the negative control group, and the tumor inhibition rate of CY-1-26 hydrochloride was 46.0%, which was significantly better than 1-MT.
  • the embodiment of the present invention introduces a nitrogen atom into a specific position of the tryptophan structure, and the obtained new derivative has an unexpected improvement effect on the enzyme IDO1 inhibitory activity and exhibits a strong inhibitory activity against TDO.
  • the azine derivative of the present application has an inhibitory effect of tryptophan along the key enzyme of kynuric acid metabolism, IDO1 and/or TDO, and can be used as a pathological feature of tryptophan metabolism mediated by IDO1 and/or TDO.
  • Medicines including but not limited to tumors, autoimmune diseases, infectious diseases, Alzheimer's disease, depression, anxiety).

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Abstract

本文公开了氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示。该通式(I)所示的化合物对吲哚胺-2,3-双加氧酶1(IDO1)和/或色氨酸-2,3-双加氧酶(TDO)具有抑制作用，可用于治疗具有IDO1和/或TDO介导的色氨酸代谢的病理学特征的疾病，包括但不限于肿瘤、自身免疫性疾病、感染性疾病、阿尔茨海默病、抑郁症、焦虑症。

Description

氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途 技术领域
本申请涉及但不限于，药物化学领域，更具体地说涉及一种氮杂色胺酮衍生物作为色氨酸沿犬尿酸途径代谢关键酶—IDO1和/或TDO的抑制剂的用途，治疗具有IDO1和/或TDO介导的色氨酸代谢的病理学特征的疾病，包括但不限于肿瘤、自身免疫性疾病、感染性疾病、阿尔茨海默病、抑郁症、焦虑症。
背景
色氨酸作为人体内的必需氨基酸，只能通过饮食摄取，体内含量较少，成人血浆中的色氨酸浓度约为40-80μM，约95％的色氨酸是通过犬尿酸途径代谢的[Armstrong,M.D.and Stave,U.Metabolism.1973,22,561–569.]。该途径的代谢产物具有免疫抑制作用，在肿瘤的免疫逃逸过程中起着关键作用。最早发现的色氨酸代谢酶为色氨酸-2,3-双加氧酶(TDO)[Kotake,Y.；Masayama,I.Z.Physiol.Chem.1936,243,237-244.]，后来又发现了吲哚胺-2,3-双加氧酶1(IDO1)[Higuchi,K.；Hayaishi,O.1967,Arch.Biochem.Biophys.120,397–403]。这两个酶都可以使色氨酸及其它含吲哚的内源性物质沿犬尿酸途径代谢，并且都是该代谢过程的限速酶。在体内、外，IDO1或TDO可以在分子氧的协助下，将色氨酸中吲哚环的2,3-双键氧化断裂，进而生成N-甲酰基犬尿酸(NFK)，进一步氧化生成犬尿酸、吡啶甲酸和喹啉酸等代谢产物(路线1)。
Figure PCTCN2017079371-appb-000001
路线1色氨酸沿犬尿酸代谢途径
吲哚胺-2,3-双加氧酶1(简称IDO1,EC 1.13.11.52)是哺乳动物体内催化色氨酸沿犬尿酸途径代谢的第一个酶，而且也是限速酶，是肿瘤免疫耐受的原因之一，并且与肿瘤患者预后不良有关[Platten,M.；Wick,W.；Van den Eynde,B.J.Cancer Res.2012,72,5435-5440]。IDO1在多种肿瘤组织中有较高的表达，导致局部的色氨酸耗竭，诱导T细胞停滞于G1期，从而抑制T细胞增殖；而且IDO依赖性的色氨酸降解导致犬尿氨酸水平的提高，也诱导氧自由基介导T细胞凋亡；还有当抗原呈递细胞，如巨噬细胞、树突状细胞高表达IDO时，加强局部调节性T细胞(Treg)介导的免疫抑制，促使机体对肿瘤特异性抗原的外周免疫耐受。体内、外的研究表明，IDO1抑制剂可以 增强肿瘤治疗性疫苗、治疗性单克隆抗体、化疗和放疗的作用[Godin-Ethier,J.；Hanafi,L.-A.；Piccirillo,C.A.；Lapointe,R.Clin.Cancer Res.2011,17,6985-6991]。
IDO1加强感染部位调节性T细胞介导的免疫抑制，促使机体对病原微生物产生免疫耐受，这与抗菌、抗病毒药物的耐药性产生密切相关。此外，IDO1还与多种疾病的发病机制密切相关，已被证实的有自身免疫性疾病、阿尔茨海默病、抑郁症、焦虑症、白内障等。因此IDO1抑制剂作为极具潜力的药物已引起越来越多的关注。
色氨酸-2,3-双加氧酶(TDO)作为另一个调节色氨酸沿犬尿酸途径代谢的重要酶，近年来其作为抑制剂成为研究热点。Platten等人证实TDO在人胶质瘤细胞中高表达。通过药物抑制或敲除TDO可以阻碍犬尿酸的释放，相反，敲除IDO1并不影响犬尿酸的浓度，这说明TDO是这些细胞代谢色氨酸的关键酶之一[C.A.Opitz,U.M.Litzenburger,F.Sahm,M.Ott,I.Tritschler,S.Trump,T.Schumacher,L.Jestaedt,D.Schrenk,M.Weller,M.Jugold,G.J.Guillemin,C.L.Miller,C.Lutz,B.Radlwimmer,I.Lehmann,A.von Deimling,W.Wick,M.Platten,Nature.2011,478,197–203.]。在对104个人肿瘤细胞株的评价研究中，Van den Eynde等人发现有20个细胞株只表达TDO，17个细胞株只表达IDO1，16个细胞株同时表达TDO和IDO1(恶性胶质瘤、间皮瘤、头颈癌、胰腺癌、非小细胞肺癌、恶性肉瘤、膀胱癌、胆囊癌等)。也就是说，IDO1抑制剂对32％的肿瘤细胞株有效，TDO抑制剂对35％的肿瘤细胞株有效，而IDO1与TDO双重抑制剂则可以对51％的肿瘤细胞株有效。理论上，IDO1与TDO双重抑制剂将会进一步提高肿瘤免疫治疗的有效性[L.Pilotte,P.Larrieu,V.Stroobant,D.Colau,E.Dolusic,R.Frederick,E.De Plaen,C.Uyttenhove,J.Wouters,B.Masereel,B.J.Van den Eynde,Proc.Natl.Acad.Sci.USA 2012,109,2497 2502.]。
色胺酮为吲哚喹唑啉类生物碱，存在于马蓝、菘蓝等产蓝植物中。研究表明此类化合物具有抗菌、抗病毒、抗炎、抗寄生虫以及抗肿瘤的作用。复旦大学杨青等人合成了一系列色胺酮衍生物，并且测试了其对IDO1的抑制活性。其中，氟取代的色胺酮衍生物(结构如下)具有很好的活性，对重组 人源IDO-1的IC50值为0.534μM，可以促进T细胞的增殖，表面等离子体共振(SPR)实验证明该化合物可与IDO1直接结合，KD值为46.8μM[Yang,S.；Li,X.；Hu,F.；Li,Y.；Yang,Y.；Yan,J.；Kuang,C.；Yang,Q.J.Med.Chem.2013,56,8321-8231]。杨青等人还在色胺酮3位引入氨甲基取代基，发现抑制IDO1的活性没有显著变化(WO 2015070766)。
Figure PCTCN2017079371-appb-000002
Valliante等人合成了一系列色胺酮和氮杂色胺酮衍生物，发现此类化合物有助于TNF-α的生成，部分化合物在5μM或更低浓度即可产生效果(美国专利号：US8193185B2)。但是该专利未涉及IDO1及TDO靶点，而且其研究结果也表明，苯环中氮原子的引入与活性没有直接关系，其中8-硝基-1-氮杂色胺酮浓度高达20μM时仍未表现出活性。
发明概述
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
本发明人令人惊奇地发现了一种氮杂色胺酮衍生物，其具有显著的吲哚胺-2,3-双加氧酶1和/或色氨酸-2,3-双加氧酶抑制活性。
本发明实施方案提供氮杂色胺酮衍生物作为吲哚胺-2,3-双加氧酶1和/或色氨酸-2,3-双加氧酶抑制剂的用途。
本发明实施方案提供一种新型氮杂色胺酮衍生物。
本发明实施方案提供一种制备上述新型氮杂色胺酮衍生物的方法。
本发明实施方案提供包含上述新型氮杂色胺酮衍生物的药用组合物。
具体地说，第一方面，本发明实施方案提供了一种氮杂色胺酮衍生物作为吲哚胺-2,3-双加氧酶1和/或色氨酸-2,3-双加氧酶抑制剂的用途，所述的衍生物如通式(I)所示，或其几何异构体、互变异构体、同位素标记物、水合 物、溶剂化物、代谢产物、药学上可接受的盐或前药：
Figure PCTCN2017079371-appb-000003
这里，式(I)中
A和B其中一个为N，而另一个为C-R3；
E为N或-C-R6；
G为O或N-Y-Z，其中，Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、羧甲基(-CH2C(＝O)OH)、磺酰基(-S(＝O)2OH)、或磷酰基(-P(＝O)(OH)2)；或者，Y为-N(H)-，而Z为氢、-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；
R1至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基；
R8和R9各自独立地选自氢、或者未取代的C1-C4烷烃基。
在本发明的实施方案中，本发明实施方案提供的氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，其中，所述未取代的C1-C4烷烃基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。所述取代的C1-C4烷烃基是指其碳链上任意位置的氢被任选的下列基团所取代：卤素、羟基、氨基、或-N(R10)(R11)，这里，R10和R11各自独立地选自氢、或者未取代的C1-C4烷烃基；例如三氟甲基、2-羟基乙基、2-(二甲基氨基)乙基、或3-(二甲基氨基)丙基、或R10与R11及其连接N一起形成的含氮4～7元杂环(例如四氢吡咯、哌啶、吗啉、哌嗪、高哌嗪等)。
在本发明的实施方案中，本发明实施方案提供的氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，其中，所述未取代的C1-C4烷氧基选自甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。所述 取代的C1-C4烷氧基是指其碳链上任意位置的氢被任选的下列基团所取代：卤素、羟基、氨基、或-N(R10)(R11)，这里，R10和R11各自独立地选自氢、或者未取代的C1-C4烷烃基；例如三氟甲氧基、2-羟基乙氧基、2-(二甲基氨基)乙氧基、或3-(二甲基氨基)丙氧基。
在本发明的实施方案中，本发明实施方案提供的氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，其中，所述未取代的C2-C4烯烃基选自乙烯基、烯丙基、1-丁烯基、2-丁烯基等。所述取代的C2-C4烯烃基是指其碳链上任意位置的氢被任选的下列基团所取代：卤素、或羟基。
在本发明的实施方案中，本发明实施方案提供的氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，其中，所述未取代的C2-C4炔烃基选自乙炔基、丙炔基、丁炔基等。所述取代的C2-C4炔烃基是指其碳链上任意位置的氢被任选的下列基团所取代：卤素、或羟基。
在本发明的实施方案中，本发明实施方案提供的氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，其中，所述卤素为氟、氯、溴、或碘。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为O；A为N、而B为-CH，或者B为N、而A为-CH。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为O；A为N、而B为-CH，或者B为N、而A为-CH；而且，E为N。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为O；A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1、R2、R4至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为O；A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1和R2为氢，R4至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为O；A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1和R2为氢，R4至R7各自独立地选自氢、甲基、三氟甲氧基、甲氧基、氟、氯、溴、硝基、氰基、甲砜基或羟基。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为N-Y-Z，其中，Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、羧甲基(-CH2C(＝O)OH)、磺酰基(-S(＝O)2OH)、或磷酰基(-P(＝O)(OH)2)；或者，Y为-N(H)-，而Z为氢、-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；A为N、而B为-CH，或者B为N、而A为-CH。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为N-Y-Z，其中，Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、羧甲基(-CH2C(＝O)OH)、磺酰基(-S(＝O)2OH)、或磷酰基(-P(＝O)(OH)2)；或者，Y为-N(H)-，而Z为氢、-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；A为N、而B 为-CH，或者B为N、而A为-CH；而且，E为N。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为N-Y-Z，其中，Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、羧甲基(-CH2C(＝O)OH)、磺酰基(-S(＝O)2OH)、或磷酰基(-P(＝O)(OH)2)；或者，Y为-N(H)-，而Z为氢、-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1、R2、R4至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为N-Y-Z，其中，Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、羧甲基(-CH2C(＝O)OH)、磺酰基(-S(＝O)2OH)、或磷酰基(-P(＝O)(OH)2)；或者，Y为-N(H)-，而Z为氢、-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1和R2为氢，R4至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基。
在本发明的一种实施方案中，本发明实施方案提供的一种氮杂色胺酮衍生物作为IDO1和/或TDO抑制剂的用途，所述的衍生物如通式(I)所示，其中，G为N-Y-Z，其中，Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取 代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、羧甲基(-CH2C(＝O)OH)、磺酰基(-S(＝O)2OH)、或磷酰基(-P(＝O)(OH)2)；或者，Y为-N(H)-，而Z为氢、-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1和R2为氢，R4至R7各自独立地选自氢、甲基、三氟甲氧基、甲氧基、氟、氯、溴、硝基、氰基、甲砜基或羟基。
在本发明的实施方案中，本发明实施方案提供的一种上述通式(I)化合物的用途，其选自下列化合物：
吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-1)；
9-氟吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-2)；
9-(三氟甲氧基)吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-3)；
9-硝基吡啶[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-4)；
9-氯吡啶并[2',3'；4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-5)；
9-甲氧基吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-6)；
9-甲基吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-7)；
吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-8)；
9-甲氧基吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-9)；
9-氯吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-10)；
9-氟吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮(化合物CY-1-11)；
11-(羟基亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-12)；
9-氯-11-(肟基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-13)；
11-(羟基亚氨基)-9-甲基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化 合物CY-1-14)；
11-(羟基亚氨基)-9-甲氧基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-15)；
11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-16)；
11-((2-(二甲基氨基)乙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-17)；
9-氯11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(1H)-酮(化合物CY-1-18)；
11-((2-(二甲基氨基)乙氧基)亚氨基)-9-氟吡啶[2'，3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-19)；
9-氯11-((3-(二甲基氨基)丙基)亚氨基)吡啶并[2'，3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-20)；
11-(2-羟基乙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-21)；
N,N-二甲基-2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)肼硫代甲酰胺(化合物CY-1-22)；
2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒(化合物CY-1-23)；
(((9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)氨基)氧基)磺酸(化合物CY-1-24)；
11-(甲氧基亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-25)；
11-(乙氧基亚氨基)-9-硝基吡啶[2',3:4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-26)；
11-((烯丙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-27)；
11-((羧基氧亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-28)；
2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚11(5H)-亚基)肼硫代甲酰胺(化合物CY-1-29)；
2-(9-甲氧基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)-N，N-二甲基肼硫代甲酰胺(化合物CY-1-30)；
吡啶并[2,3-D]吡啶并[3'，4':4,5]吡咯并[1,2-a]嘧啶-5,11-二酮(化合物CY-1-31)；
2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒(化合物LDB-1-1)；
2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺化合物(LDB-1-2)；
2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒(化合物LDB-1-3)；
2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺(化合物LDB-1-4)；
2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒(化合物LDB-1-5)；和
2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺(化合物LDB-1-6)。
本发明实施方案提供了式(I)化合物在治疗具有IDO1和/或TDO介导的色氨酸代谢的病理学特征的疾病中的应用，这样的疾病包括但不限于肿瘤、感染性疾病、自身免疫性疾病、阿尔茨海默病、抑郁症、焦虑症。人每次用药的参考剂量为0.1-20mg/kg体重，使用方法为口服或注射。
第二方面，本发明实施方案提供了一种作为IDO1和/或TDO抑制剂的新型氮杂色胺酮衍生物，如式(II)所示，或其几何异构体、互变异构体、同位素标记物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
Figure PCTCN2017079371-appb-000004
这里，式(II)中
A和B其中一个为N，而另一个为C-R3；
E为N或-C-R6；
Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、或羧甲基(-CH2C(＝O)OH)、磺酰基(-S(＝O)2OH)、或磷酰基(-P(＝O)(OH)2)；或者，Y为-N(H)-，而Z为氢，-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；
R1至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基；
R8和R9各自独立地选自氢、或者未取代的C1-C4烷烃基。
在本发明的一种实施方案中，本发明实施方案提供的一种新型氮杂色胺酮衍生物，如通式(II)所示，其中，A为N、而B为-CH，或者B为N、而A为-CH。
在本发明的一种实施方案中，本发明实施方案提供的一种新型氮杂色胺酮衍生物，如通式(II)所示，其中，A为N、而B为-CH，或者B为N、而A为-CH；而且，E为N。
在本发明的一种实施方案中，本发明实施方案提供的一种新型氮杂色胺酮衍生物，如通式(II)所示，其中，A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1、R2、R4至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的 C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基。
在本发明的一种实施方案中，本发明实施方案提供的一种新型氮杂色胺酮衍生物，如通式(II)所示，其中，A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1和R2为氢，R4至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基。
在本发明的一种实施方案中，本发明实施方案提供的一种新型氮杂色胺酮衍生物，如通式(I)所示，其中，A为N、而B为-CH，或者B为N、而A为-CH；
而且，E为-C-R6；
R1和R2为氢，R4至R7各自独立地选自氢、甲基、三氟甲氧基、甲氧基、氟、氯、溴、硝基、氰基、甲砜基或羟基；
Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、或羧甲基(-CH2C(＝O)OH)、磺酰基(-S(＝O)2OH)、或磷酰基(-P(＝O)(OH)2)；或者，Y为-N(H)-，而Z为氢、-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；
R8和R9各自独立地选自氢、或者未取代的C1-C4烷烃基。
在本发明的实施方案中，本发明实施方案提供的一种新型氮杂色胺酮衍生物，其选自下列化合物：
11-(羟基亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-12)；
9-氯-11-(肟基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-13)；
11-(羟基亚氨基)-9-甲基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化 合物CY-1-14)；
11-(羟基亚氨基)-9-甲氧基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-15)；
11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-16)；
11-((2-(二甲基氨基)乙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-17)；
9-氯11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(1H)-酮(化合物CY-1-18)；
11-((2-(二甲基氨基)乙氧基)亚氨基)-9-氟吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-19)；
9-氯11-((3-(二甲基氨基)丙基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-20)；
11-(2-羟基乙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-21)；
N,N-二甲基-2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)肼硫代甲酰胺(化合物CY-1-22)；
2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒(化合物CY-1-23)；
(((9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)氨基)氧基)磺酸(化合物CY-1-24)；
11-(甲氧基亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-25)；
11-(乙氧基亚氨基)-9-硝基吡啶[2',3:4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-26)；
11-((烯丙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-27)；
11-((羧基氧亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-28)；
2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺(化合物CY-1-29)；
2-(9-甲氧基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)-N，N-二甲基肼硫代甲酰胺(化合物CY-1-30)；
吡啶并[2,3-D]吡啶并[3'，4'：4,5]吡咯并[1,2-a]嘧啶-5,11-二酮(化合物CY-1-31)；
2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒(化合物LDB-1-1)；
2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺化合物(LDB-1-2)；
2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒(化合物LDB-1-3)；
2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺(化合物LDB-1-4)；
2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒(化合物LDB-1-5)；和
2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺(化合物LDB-1-6)。
第三方面，本发明实施方案提供了一种制备如通式(II)所示的氮杂色胺酮类似物的方法，包括如下步骤：
式(III)化合物与式(IV)化合物反应，得到式(II’)化合物，式(II’)化合物进一步再与式(V)化合物反应，得到式(II)化合物
Figure PCTCN2017079371-appb-000005
这里，式(III)、(IV)、(V)、(II’)化合物中涉及的取代基A、B、E、Y、Z以及R1、R2、R4、R5和R7的定义与其在前述如式(II)化合物中的定义相同。
本发明实施方案提供的制备如通式(II)所示氮杂色胺酮类似物的方法，具体说可以参照下述方法：
将靛红衍生物IV(0.9mmol)和1,8-二氮杂二环十一碳-7-烯(英文简称DBU,2.0mmol)溶于DMF(3mL)中，室温搅拌十分钟，得溶液(1)。将2-氨基烟酸类似物III(1mmol)、N-甲基吗啡啉(1.8mmol)、HBTU(1.0mmol)溶于DMF中(3mL)，得溶液(2)。将溶液(1)滴加入溶液(2)中，室温搅拌20h，TLC监测，待反应完全，蒸干溶剂，柱层析分离(二氯甲烷—甲醇混合溶剂洗脱)得到式(II’)化合物，为固体。
将上述反应得到的固体与含氨基的化合物V或其盐酸盐(1mmol)溶于甲醇中(10mL)，加热回流过夜，待反应完全，浓缩后析出固体可得通式II化合物；或蒸干溶剂，柱层析分离(二氯甲烷—甲醇混合洗脱溶剂)得到产品。
第四方面，本发明实施方案提供了一种包含上述新型色胺酮类似物的药用组合物。该药用组合物包括药理学上有效量的式(II)化合物和药学上可接受的辅料。对于本领域技术人员而言，这些辅料都是已知的，例如，生理盐水，明胶，阿拉伯树胶，乳糖，微晶纤维素，淀粉，改性淀粉，纤维素，改性纤维素，羟乙酸钠，磷酸氢钙，硬脂酸镁，滑石，胶体二氧化硅等。此外，这些组合物还可进一步地包含：稳定剂，润湿剂，乳化剂，甜味剂，香味剂，缓冲剂等。
本发明实施方案提供的包含上述色胺酮类似物的药用组合物，根据需要，能够配制成用于口服给药的固体或液体形式，如片剂、丸剂、口服液等；用 于非肠道给药的无菌溶液、悬浮液或乳液形式，喷雾剂等。
与复旦大学杨青课题组的化合物(5a、5b、5c、5i)相比较(见下表1)，本发明实施方案将氮原子引入色胺酮结构的特定位置，得到的新衍生物对酶IDO1的抑制活性具有出人意料的提高作用，最高可超过100倍。而且本发明实施方案中的化合物还对TDO具有显著的抑制活性。
Figure PCTCN2017079371-appb-000006
表1.IDO-1的抑制活性(IC50,μM)对比
Figure PCTCN2017079371-appb-000007
注：++++＝0.001-0.10μM；+++＝0.10-1.0μM；++＝1.1-10μM；+>10μM.
详细描述
以下通过实施例来示例性说明本发明的实施方案，对于本领域的普通技术人员而言，在本发明实施方案的教导下，根据现有技术，对本发明实施方案进行的改进，仍属于本发明实施方案的保护范围内。
反应过程中使用的二氯甲烷、甲醇、N,N-二甲基甲酰胺、等溶剂均为市售分析纯试剂并按文献方法干燥重蒸处理；其它试剂和原料为国产分析纯或化学纯试剂。
熔点用XT5B或X-4型精密显微熔点仪(控温型)测定(北京福凯仪器有限公司)，温度未校正。核磁共振氢谱(1H NMR,13C NMR)用Bruker NMR system400MHz超导核磁共振谱仪测定，TMS为内标。
实施例1
化合物CY-1-1：吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000008
将靛红(0.9mmol)和DBU(2mmol)溶于DMF中(3ml)，室温搅拌十分钟。将2-氨基烟酸(1mmol)、N-甲基吗啡啉(1.8mmol)、HBTU(1mmol)溶于DMF中(3ml)，将反应好的靛红与DBU的溶液滴加入该溶液中，室温搅拌20h，TLC监测，待反应完全，蒸干溶剂，柱层析分离(二氯甲烷：甲醇＝80:1)得到橙黄色固体，产率59％。1H NMR(400MHz,DMSO-d6)δ9.08(dd,J＝4.6,2.0Hz,1H),8.71(dd,J＝7.9,2.0Hz,1H),8.45(d,J＝8.0Hz,1H),7.90(t,J＝7.9,4.4Hz,2H),7.75(dd,J＝7.9,4.6Hz,1H),7.51(t,J＝7.6,0.7Hz,1H)。13C NMR(101MHz,DMSO-d6)δ182.28,158.08,157.20,156.11,147.63,145.70,137.90,136.30,127.23,124.92,124.70,122.14,119.17,116.89。
实施例2
化合物CY-1-2：9-氟吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000009
采用5-氟靛红代替靛红，制备方法同实施例1的CY-1-1。产物为黄色固体，产率51％。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.69(d,J＝6.4Hz,1H),8.44(d,J＝4.7Hz,1H),7.83(d,J＝4.5Hz,1H),7.75(d,J＝7.5Hz,2H)。13C NMR(101MHz,DMSO-d6)δ181.85,160.13,158.53,157.46,156.72,142.41,136.83,125.34,124.62,124.34,119.54,119.23,112.48,112.18。
实施例3
化合物CY-1-3：9-(三氟甲氧基)吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000010
采用5-三氟甲氧基靛红代替靛红，制备方法同实施例1的CY-1-1。产物为淡黄色固体，产率29％。1H NMR(400MHz,DMSO-d6)δ9.09(d,J＝3.7Hz,1H),8.71(d,J＝7.7Hz,1H),8.54(d,J＝8.7Hz,1H),7.97(s,1H),7.92(d,J＝8.7Hz,1H),7.77(dd,J＝7.7,4.6Hz,1H)。13C NMR(101MHz,DMSO-d6)δ181.56,158.48,157.55,156.84,148.22,146.96,144.61,136.89,130.69,125.40,124.39,121.75,119.46,119.19,119.06,118.38。
实施例4
化合物CY-1-4：9-硝基吡啶[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000011
采用5-硝基靛红代替靛红，制备方法同实施例1的CY-1-1。产物为棕色固体，产率42％。1H NMR(400MHz,DMSO-d6)δ9.12(d,J＝3.9Hz,1H),8.75(d,J＝8.0Hz,2H),8.69-8.55(m,2H),7.88-7.70(m,1H)。
实施例5
化合物CY-1-5：9-氯吡啶并[2',3'；4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000012
采用5-氯靛红代替靛红，制备方法同实施例1的CY-1-1。产物为橙黄色固体，产率37％。1H NMR(400MHz,DMSO-d6)δ9.09(dd,J＝4.6,2.0Hz,1H),8.72(dd,J＝7.9,2.0Hz,1H),8.44(d,J＝8.6Hz,1H),8.02(d,J＝2.2Hz,1H),7.95(dd,J＝8.6,2.3Hz,1H),7.82-7.70(m,1H)。13C NMR(101MHz,DMSO-d6)δ181.11,157.96,157.11,156.28,147.50,144.11,136.98,136.36,131.56,124.86, 124.51,123.89,119.02,118.46。
实施例6
化合物CY-1-6：9-甲氧基吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000013
采用5-甲氧基靛红代替靛红，制备方法同实施例1的CY-1-1。产物为黄色固体，产率61％。1H NMR(400MHz,DMSO-d6)δ9.06(dd,J＝4.6,2.0Hz,1H),8.69(dd,J＝7.9,1.9Hz,1H),8.43-8.28(m,1H),7.74(dd,J＝7.9,4.6Hz,1H),7.43(dd,J＝7.2,2.6Hz,2H),3.88(s,3H)。13C NMR(101MHz,DMSO-d6)δ182.17,158.21,157.63,157.16,155.94,147.93,139.60,136.15,124.65,123.79,123.31,119.27,118.10,108.76,56.07。
实施例7
化合物CY-1-7：9-甲基吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000014
采用5-甲基靛红代替靛红，制备方法同实施例1的CY-1-1。产物为黄色固体，产率32％。1H NMR(400MHz,DMSO-d6)δ9.06(d,J＝4.2Hz,1H),8.68(d,J＝7.8Hz,1H),8.29(d,J＝8.1Hz,1H),7.73(dd,J＝7.9,4.2Hz,2H),7.68(d,J＝8.1Hz,1H),2.41(s,3H)。
实施例8
化合物CY-1-8：吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000015
采用3-氨基异烟酸代替2-氨基烟酸，制备方法同实施例1的CY-1-1。黄色固体，产率43％。1H NMR(400MHz,CD3COOD)δ9.74(s,1H),9.01(d,J＝15.9Hz,2H),8.55(d,J＝8.0Hz,1H),8.00(d,J＝7.4Hz,1H),7.91(t,J＝7.6Hz,1H),7.57(t,J＝7.5Hz,1H)。13C NMR(101MHz,CD3COOD)δ184.26,156.83,151.80,148.25,148.12,146.82,142.87,142.20,139.53,132.11,129.29,128.30,123.65,120.90。
实施例9
化合物CY-1-9：9-甲氧基吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000016
采用3-氨基异烟酸代替2-氨基烟酸，5-甲氧基靛红代替靛红，制备方法同实施例1的CY-1-1。产物为黄色固体，产率33％。1H NMR(400MHz,CD3COOD)δ10.06-9.45(m,1H),9.16-8.73(m,2H),8.39(t,J＝21.2Hz,1H),7.72-7.25(m,2H)。13C NMR(101MHz,CD3COOD)δ182.06,161.25,154.76,150.46,150.06,146.16,144.42,140.05,137.18,126.85,126.32,122.96,120.36,110.90,55.62。
实施例10
化合物CY-1-10：9-氯吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000017
采用3-氨基异烟酸代替2-氨基烟酸，5-氯靛红代替靛红，制备方法同实施例1的CY-1-1。产物为黄色固体，产率63％。1H NMR(400MHz,CD3COOD)δ9.51(s,1H),8.82(d,J＝6.0Hz,1H),8.76(d,J＝6.0Hz,1H),8.29(d,J＝8.6Hz,1H),7.72(s,1H),7.69-7.52(m,1H)。13C NMR(101MHz,CD3COOD)δ181.09,155.04,149.60,146.28,144.69,144.09,140.44,140.08,137.57,137.19, 126.88,126.37,122.90,119.78。
实施例11
化合物CY-1-11：9-氟吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮
Figure PCTCN2017079371-appb-000018
采用3-氨基异烟酸代替2-氨基烟酸，5-氟靛红代替靛红，制备方法同实施例1的CY-1-1。产物为黄色固体，产率67％。1H NMR(400MHz,CD3COOD)δ9.68(s,1H),8.97(dd,J＝19.7,6.1Hz,2H),8.54(dd,J＝8.8,3.7Hz,1H),7.60(dd,J＝6.2,2.5Hz,1H),7.54(td,J＝8.6,2.6Hz,1H)。13C NMR(101MHz,CD3COOD)δ182.67,156.28,151.28,147.40,146.11,143.84,141.71,139.01,128.71,128.39,127.75,124.91,124.83,122.34,122.26,115.34。
实施例12
化合物CY-1-12：11-(羟基亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000019
将化合物CY-1-1(1mmol)与盐酸羟胺(1mmol)溶于甲醇中(10mL)，加入吡啶(1mmol)，加热回流过夜，待反应完全，蒸干溶剂，柱层析分离(二氯甲烷：甲醇＝80:1)得到橙黄色固体，产率69％。1H NMR(400MHz,DMSO-d6)δ14.01(s,1H),9.02(m,1H),8.71(d,J＝7.8Hz,1H),8.45(d,J＝8.0Hz,1H),8.35(d,J＝7.6Hz,1H),7.71-7.60(m,2H),7.47(t,J＝7.6Hz,1H)。13C NMR(101MHz,DMSO-d6)δ159.07,157.11,155.34,152.31,144.70,139.30,137.46,132.60,127.75,127.54,123.31,119.19,117.90,116.60。
实施例13
化合物CY-1-13：9-氯-11-(肟基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)- 酮
Figure PCTCN2017079371-appb-000020
采用化合物CY-1-5代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率56％。1H NMR(400MHz,DMSO-d6)δ14.16(s,1H),9.03(s,1H),8.63(d,J＝7.7Hz,1H),8.37(t,J＝8.0Hz,H),8.32(s,1H),7.79-7.48(m,2H)。13C NMR(101MHz,DMSO-d6)δ159.17,157.63,156.32,151.44,143.93,137.99,136.47,132.11,131.24,126.98,123.36,120.64,118.03,117.35。
实施例14
化合物CY-1-14：11-(羟基亚氨基)-9-甲基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000021
采用化合物CY-1-7代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率71％。1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),8.99(s,1H),8.61(d,J＝7.6Hz,1H),8.30(d,J＝8.0Hz,1H),8.15(s,1H),7.61(d,J＝4.8Hz,1H),7.41(d,J＝7.9Hz,1H),2.38(s,4H)。13C NMR(101MHz,DMSO-d6)δ159.03,157.59,156.13,151.80,144.68,137.23,136.89,136.33,132.84,128.06,123.13,119.21,117.57,116.24,21.04。
实施例15
化合物CY-1-15：11-(羟基亚氨基)-9-甲氧基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000022
采用化合物CY-1-6代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率48％。1H NMR(400MHz,DMSO-d6)δ13.92(s,1H),9.52-8.78(m,1H),8.61(d,J＝7.8Hz,1H),8.33(d,J＝8.8Hz,1H),7.84(s,1H),7.60(dd,J＝7.7,4.6Hz,1H),7.17(d,J＝8.7Hz,1H),3.82(s,3H)。13C NMR(101MHz,DMSO-d6)δ158.73,158.24,157.62,156.05,151.66,144.65,136.36,132.99,123.07,120.15,117.62,117.56,117.48,112.81,55.99。
实施例16
化合物CY-1-16：11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000023
采用化合物N,N-二甲基-2-氨氧基乙胺盐酸盐代替盐酸羟胺，制备方法同实施例12的CY-1-12。产物为黄色固体。1H NMR(400MHz,DMSO-d6)δ9.19-8.92(m,1H),8.83-8.60(m,1H),8.45(m,1H),8.28(d,J＝7.6Hz,1H),7.59(m,3H),4.78-4.48(m,2H),2.97-2.66(m,2H),2.33(s,6H)。13C NMR(101MHz,DMSO-d6)δ159.21,157.63,156.27,151.01,144.78,140.08,136.60,133.43,128.28,127.21,123.56,118.82,117.78,116.62,75.05,57.54,45.78。
实施例17
化合物CY-1-17：11-((2-(二甲基氨基)乙氧基)亚氨基)-9-硝基吡啶[2',3'：4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000024
采用化合物N,N-二甲基-2-氨氧基乙胺盐酸盐代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率32％。1H NMR(400MHz,CDCl3)δ9.12(s,1H),9.09-9.04(m,1H),8.83-8.65(m,2H), 8.59-8.41(m,1H),7.55(dd,J＝7.3,4.9Hz,1H),4.79(t,J＝5.5Hz,2H),2.98(t,J＝10.9,10.0Hz,2H),2.36(s,6H)。
实施例18
化合物CY-1-18：9-氯11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3'：4,5]嘧啶并[1,2-a]吲哚-5(1H)-酮
Figure PCTCN2017079371-appb-000025
采用化合物N,N-二甲基-2-氨氧基乙胺盐酸盐代替盐酸羟胺，CY-1-5代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率41％。1H NMR(400MHz,CDCl3)δ9.03(s,1H),8.70(s,1H),8.58-8.46(m,1H),8.26(s,1H),7.59-7.43(m,2H),4.65(m,2H),2.89(s,2H),2.31(s,6H)。13C NMR(101MHz,CDCl3)δ158.93,157.47,156.12,150.59,143.27,137.66,136.38,132.73,132.52,128.09,123.01,119.98,117.87,117.36,57.90,45.77,29.80。
实施例19
化合物CY-1-19：11-((2-(二甲基氨基)乙氧基)亚氨基)-9-氟吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000026
采用化合物N,N-二甲基-2-氨氧基乙胺盐酸盐代替盐酸羟胺，CY-1-2代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率43％。1H NMR(400MHz,DMSO-d6)δ9.06-8.98(m,1H),8.71-8.59(m,1H),8.52-8.36(m,1H),8.15(dd,J＝8.2,2.5Hz,1H),7.76–7.63(m,2H),7.55(ddd,J＝27.5,9.1,2.6Hz,1H),4.92(s,2H),3.66(s,2H),2.93(s,6H)。13C NMR(101MHz,DMSO-d6)δ159.04,156.49,150.83,136.85,124.62,123.90,120.31,120.01,119.20,118.66,118.16,117.88,115.56,108.50,71.81,55.72,43.10。
实施例20
化合物CY-1-20：9-氯11-((3-(二甲基氨基)丙基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000027
采用化合物N,N-二甲基-2-氨氧基丙胺盐酸盐代替盐酸羟胺，CY-1-5代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率49％。1H NMR(400MHz,DMSO-d6)δ9.11-8.92(m,1H),8.60(dd,J＝7.9,1.7Hz,1H),8.35(d,J＝8.6Hz,1H),8.11(d,J＝1.7Hz,1H),7.72(dd,J＝8.6,2.1Hz,1H),7.65(dd,J＝7.8,4.6Hz,1H),4.66(t,J＝5.9Hz,2H),3.32-3.19(m,3H),2.80(s,6H)。13C NMR(101MHz,DMSO-d6)δ158.41,156.85,156.04,150.09,143.62,138.01,136.10,132.73,130.96,127.02,123.36,119.63,117.58,117.16,74.61,53.63,42.35,24.24。
实施例21
化合物CY-1-21：11-(2-羟基乙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000028
采用化合物2-氨氧基乙醇代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为淡黄色固体，产率48％。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.89(s,1H),8.72-8.41(m,3H),7.66(s,1H),4.99(m,1H),4.65(s,2H),3.88(s,2H)。13C NMR(101MHz,DMSO-d6)δ159.29,157.29,156.73,150.96,145.79,143.81,143.47,136.71,129.26,124.04,122.71,119.41,117.67,117.12,80.33,60.05。
实施例22
化合物CY-1-22：N,N-二甲基-2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)肼硫代甲酰胺
Figure PCTCN2017079371-appb-000029
采用化合物N,N-二甲基氨基硫脲代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为紫色固体，产率39％。1H NMR(400MHz,DMSO-d6)δ10.14-8.71(m,2H),8.27(m,3H),7.48(m,1H),3.06(m,6H)。
实施例23
化合物CY-1-23：2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒
Figure PCTCN2017079371-appb-000030
采用化合物氨基胍代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为橙色固体，产率21％。1H NMR(400MHz,CD3COOD)δ9.31(d,J＝7.9Hz,1H),9.02(d,J＝5.7Hz,1H),8.72(d,J＝1.7Hz,1H),8.59(s,1H),8.52(d,J＝8.9Hz,1H),8.44-8.34(m,1H),8.01(d,J＝1.7Hz,1H)。
实施例24
化合物CY-1-24：(((9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)氨基)氧基)磺酸
Figure PCTCN2017079371-appb-000031
采用化合物氨基磺酸代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为白色固体，产率47％。1H NMR(400MHz,DMSO-d6)δ14.43(s,1H),9.03(dd,J＝4.4,1.7Hz,1H),8.99(d,J＝2.3Hz,1H),8.70-8.61(m,2H),8.56(dd,J＝8.9,2.4Hz,1H),7.66(dd,J＝7.9,4.6Hz,1H)。13C NMR(101MHz,DMSO-d6)δ159.44,157.55,156.62,151.63,145.77,143.55,143.36,136.69,128.47,123.66,122.19,119.53,117.43,117.05。
实施例25
化合物CY-1-25：11-(甲氧基亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000032
采用化合物O-甲羟基胺代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为淡黄色固体，产率28％。1H NMR(400MHz,DMSO-d6)δ9.03(dd,J＝4.4,1.8Hz,1H),8.82(s,1H),8.66(dd,J＝7.8,1.6Hz,1H),8.63-8.54(m,2H),7.67(dd,J＝7.9,4.6Hz,1H),4.42(s,3H)。
实施例26
化合物CY-1-26：11-(乙氧基亚氨基)-9-硝基吡啶[2',3:4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000033
采用化合物O-乙基羟胺代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为淡黄色固体，产率57％。1H NMR(400MHz,DMSO-d6)δ9.07-9.02(m,1H),8.85(s,1H),8.67(t,J＝7.0Hz,1H),8.65(m,2H),7.68(dd,J＝7.8,4.6Hz,1H),4.68(q,J＝7.0Hz,2H),1.50(t,J＝7.1Hz,3H)。13C NMR(101MHz,DMSO-d6)δ159.22,157.30,156.68,150.99,145.79, 143.92,143.31,136.70,129.23,123.92,122.39,119.31,117.60,117.17,74.28,14.65。
实施例27
化合物CY-1-27：11-((烯丙氧基)亚氨基)-9-硝基吡啶[2',3'：4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000034
采用化合物O-烯丙基羟胺代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为淡黄色固体，产率32％。1H NMR(400MHz,DMSO-d6)δ9.08-9.03(m,1H),8.90(d,J＝1.9Hz,1H),8.74-8.59(m,3H),7.69(dd,J＝7.8,4.6Hz,1H),6.22(m,1H),5.55(d,J＝17.2Hz,1H),5.44(d,J＝10.7Hz,1H),5.18(d,J＝5.6Hz,2H)。13C NMR(101MHz,DMSO-d6)δ159.34,157.27,156.77,151.03,145.85,144.18,143.96,136.47,133.64,129.20,123.99,122.44,120.07,119.54,117.67,117.04,78.70。
实施例28
化合物CY-1-28：11-((羧基甲氧亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮
Figure PCTCN2017079371-appb-000035
采用3-氨氧基乙酸代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为白色固体，产率33％。1H NMR(400MHz,DMSO-d6)δ9.11-8.92(m,2H),8.63(m,3H),7.74-7.62(m,1H),3.79(s,2H)。13C NMR(101MHz,DMSO-d6)δ170.31,169.20,159.29,157.45,156.73,150.82,145.84,144.76,144.54,144.30,144.27,136.76,129.83,129.69,124.11,123.13,119.30,117.89,117.29,73.79。
实施例29
化合物CY-1-29：2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺
Figure PCTCN2017079371-appb-000036
采用氨基硫脲代替盐酸羟胺，CY-1-4代替CY-1-1，制备方法同实施例12的CY-1-12。产物为红色固体，产率29％。1H NMR(400MHz,DMSO-d6)δ9.19-8.98(m,1H),8.84-8.64(m,2H),8.63-8.47(m,2H),7.89-7.65(m,1H),4.56(m,1H)。
实施例30
化合物CY-1-30：2-(9-甲氧基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚11(5H)-亚基)-N，N-二甲基肼硫代甲酰胺
Figure PCTCN2017079371-appb-000037
采用N，N-二甲基氨基硫脲代替盐酸羟胺，CY-1-6代替CY-1-1，制备方法同实施例12的CY-1-12。产物为红色固体，产率52％。1H NMR(400MHz,CD3COOD)δ9.22(t,J＝10.8Hz,1H),8.99–8.72(m,1H),8.21–8.03(m,1H),7.99–7.74(m,1H),7.26(m,1H),7.16–6.83(m,1H),4.00–2.95(m,9H)。
实施例31
化合物CY-1-31：吡啶并[2,3-D]吡啶并[3',4':4,5]吡咯并[1,2-a]嘧啶-5,11-二酮
Figure PCTCN2017079371-appb-000038
用5-氮杂靛红替换靛红，制备方法同实施例1的CY-1-1，产物为黄色固体，产率41％。HR-ESI-MS:C13H6N4O2理论值：251.05032[M+H]+,实测值：251.04989[M+H]+。
实施例32
化合物LDB-1-1：2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒
Figure PCTCN2017079371-appb-000039
采用氨基胍代替盐酸羟胺，CY-1-5代替CY-1-1，制备方法同实施例12的CY-1-12。产物为橙黄色固体，产率43％。HR-ESI-MS:C15H10ClN7O理论值：340.10[M+H]+，实测值：340.10[M+H]+。
实施例33
化合物LDB-1-2：2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺
Figure PCTCN2017079371-appb-000040
采用氨基硫脲代替盐酸羟胺，CY-1-5代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率65％。1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),9.30(s,1H),9.07(s,2H),8.73(s,1H),8.39(s,1H),8.23(s,1H),7.73(s,1H),7.70(s,1H)。
实施例34
化合物LDB-1-3：2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒
Figure PCTCN2017079371-appb-000041
采用氨基胍代替盐酸羟胺，CY-1-3代替CY-1-1，制备方法同实施例12的CY-1-12。产物为橙黄色固体，产率：49％。HR-ESI-MS:C16H10F3N7O2理论值：390.10[M+H]+,实测值：390.10[M+H]+。
实施例35
化合物LDB-1-4：2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺
Figure PCTCN2017079371-appb-000042
采用氨基硫脲代替盐酸羟胺，CY-1-3代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率56％。1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),9.33(s,1H),9.15–9.04(m,2H),8.74(dd,J＝7.9,2.2Hz,1H),8.46(d,J＝8.8Hz,1H),8.16(s,1H),7.74(dd,J＝7.7,4.9Hz,1H),7.64(d,J＝8.9Hz,1H)。13C NMR(101MHz,DMSO)δ114.07,117.39,117.74,123.67,123.85,125.39,129.35,136.30,137.56,146.54,148.03,156.03,156.26,158.14,178.89。
实施例36
化合物LDB-1-5：2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒
Figure PCTCN2017079371-appb-000043
采用氨基胍代替盐酸羟胺，CY-1-10代替CY-1-1，制备方法同实施例12的CY-1-12。产物为橙色固体，产率52％。1H NMR(400MHz,DMSO-d6)δ12.84(s,1H),9.73(s,1H),9.34(s,1H),8.85(d,J＝5.0Hz,1H),8.60(s,2H),8.34(d,J＝8.6Hz,1H),8.25(s,1H),8.16(d,J＝4.9Hz,1H),7.72(d,J＝8.6Hz,1H)。13C NMR(101MHz,DMSO)δ117.95,118.84,121.70,124.73,127.09,131.34,131.51,134.54,138.00,140.56,146.18,148.43,151.37,155.71,156.76。
实施例37
化合物LDB-1-6：2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺
Figure PCTCN2017079371-appb-000044
采用氨基硫脲代替盐酸羟胺，CY-1-10代替CY-1-1，制备方法同实施例12的CY-1-12。产物为黄色固体，产率47％。1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),9.26(s,1H),9.10(d,J＝2.4Hz,1H),8.99(s,1H),8.82(d,J＝4.8Hz,1H),8.27(d,J＝8.5Hz,1H),8.12(s,2H),7.59(d,J＝8.5Hz,1H)。13C NMR(101MHz,DMSO)δ117.80,118.99,120.96,125.20,126.76,128.62,130.46,131.38,137.20,140.46,146.46,148.14,150.19,156.67,178.72。
生物活性试验实施例
吲哚胺-2,3-双加氧酶1抑制活性
实验方法：IDO-1可以将色氨酸的吲哚环氧化断裂生成N-甲酰化犬尿酸。参照文献(Eddy W.Yue,et al.J.Med.Chem.2009,52,7364-7367)方法，室温条件下向50mM磷酸钾缓冲液中依次加入20nM IDO-1,2mM D-色氨酸，20mM抗坏血酸，3.5μM甲基蓝和0.2mg/mL抗氧化酶。由于生成N-甲酰化犬尿酸，反应速率通过溶液在321nm不断升高的吸收度来记录。运用Prism GraphPad软件计算IC50值。美国Incyte制药公司开发的化合物INCB024360作为阳性对照药，实验结果如下：
表2.化合物对IDO-1的抑制活性(IC50,μM)
Figure PCTCN2017079371-appb-000045
注：++++＝0.001—0.10μM；+++＝0.11—1.0μM；++＝1.1—10μM.
色氨酸-2,3-双加氧酶抑制活性
实验方法：TDO可以将色氨酸的吲哚环氧化断裂生成N-甲酰化犬尿酸。参照文献(Eddy W.Yue,et al.J.Med.Chem.2009,52,7364-7367)方法，室温条件下依次加入含有50nM TDO的检测缓冲液，10μM抑制剂，200μM色氨酸等。由于生成N-甲酰化犬尿酸，反应速率通过溶液在321nm不断升高的吸收度来记录。运用Prism GraphPad软件计算IC50值。化合物10μM浓度下的酶抑制率实验结果如下：
表3.化合物在10μM对TDO的抑制率活性
Figure PCTCN2017079371-appb-000046
注：-表示尚未进行测试。
降低大鼠静脉血中犬尿酸含量实验
大鼠静脉血中犬尿酸浓度的下降程度可以反映出化合物在体内对IDO1的抑制活性。每组随机分配3只体重约为300克的雄性大鼠，将化合物CY-1-4、CY-1-10、CY-1-17的富马酸盐、CY-1-26的盐酸盐和CY-1-32等一次性灌胃给药50mg/Kg，在0,0.5,1,2,4,8,12,24小时八个时间点，从大鼠眼眶取血120-150微升，3000rpm离心10min，取上清得到血清。通过犬尿酸ELISA检测试剂盒测定不同时间点血清中犬尿酸的浓度。每组均取三只大鼠体内犬尿酸浓度的平均值。
结果显示，测试化合物表现出不同程度的降低犬尿酸浓度的活性，下降比例为18-56％。
体内抗肿瘤实验：
CY-1-17的富马酸盐抑制小鼠体内路易斯肺癌实验
用荷路易斯肺癌的C57BL/6J小鼠测试化合物的体内药效，采用腹腔注射 给药途径(20mg/Kg)，环磷酰胺(20mg/Kg)为阳性对照。于首次给药当天开始观察、测量并记录相关指标，实验终点时处死荷瘤小鼠，并解剖分离瘤块称重。荷瘤小鼠连续腹腔注射给药11天，给药组动物体重较阴性对照组体重增长略缓慢，动物状态良好，未见明显的毒副反应。荷瘤小鼠连续腹腔注射给药11天后，将动物安乐死，解剖皮下肿瘤，称重、拍照，并解剖动物进行大体观察。给药组动物肿瘤重量明显低于阴性对照组，环磷酰胺的抑瘤率为29.9％，CY-1-17(20mg/kg)的抑瘤率为51.8％。解剖小鼠进行大体观察,未见明显的肿瘤转移灶。
CY-1-26盐酸盐抑制小鼠体内黑色素瘤实验
(1)实验方法
用荷黑色素瘤B16的C57BL/6J小鼠测试化合物的体内药效，灌胃给药20mg/kg，1-MT为阳性对照(200mg/kg)，均为每日一次剂量。于首次给药当天开始观察、测量并记录相关指标，实验终点时处死荷瘤小鼠，并解剖分离瘤块称重。
(2)对荷瘤小鼠体重的影响
荷瘤小鼠连续灌胃给药10天，给药组动物体重较阴性对照组体重增长略缓慢，动物状态良好，未见明显的毒副反应。
(3)对荷瘤小鼠肿瘤生长的影响
给药10天后，将动物安乐死，解剖皮下肿瘤，称重、并解剖动物进行大体观察。给药组动物肿瘤重量均低于阴性对照组，1-MT的抑瘤率为26.3％，CY-1-26的抑瘤率为33.0％。
CY-1-26盐酸盐抑制小鼠体内黑色素瘤实验的重复验证
(1)实验方法
用三组(每组6只)荷黑色素瘤B16的C57BL/6J小鼠测试化合物的体内药效，CY-1-26盐酸盐灌胃给药20mg/kg(悬浮于0.5％羧甲基纤维素钠水溶液)，1-MT为阳性对照(200mg/kg，悬浮于0.5％羧甲基纤维素钠水溶液)，空白对照为0.5％羧甲基纤维素钠水溶液，均为每日一次剂量。于首次给药当 天开始观察、测量并记录相关指标，实验终点时处死荷瘤小鼠，并解剖分离瘤块称重。
(2)对荷瘤小鼠体重的影响
荷瘤小鼠连续灌胃给药14天，给药组动物体重较阴性对照组体重增长略缓慢，动物状态良好，未见明显的毒副反应。
(3)对荷瘤小鼠肿瘤生长的影响
给药14天后，将动物安乐死，解剖皮下肿瘤，称重、并解剖动物进行大体观察。给药组动物肿瘤重量均低于阴性对照组，CY-1-26盐酸盐的抑瘤率为46.0％，显著优于1-MT。
综上所述，本发明实施方案将氮原子引入色胺酮结构的特定位置，得到的新衍生物对酶IDO1抑制活性具有出人意料的提高作用，并显示出对TDO的强烈抑制活性。
以上仅为本申请实施例的原则的示例，并非用于限定本申请的保护范围，因此，凡在本申请的精神和原则之内所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。
工业实用性
本申请的氮杂色胺酮衍生物具有色氨酸沿犬尿酸途径代谢关键酶—IDO1和/或TDO的抑制作用，能用作由IDO1和/或TDO介导的色氨酸代谢病理学特征的疾病(包括但不限于肿瘤、自身免疫性疾病、感染性疾病、阿尔茨海默病、抑郁症、焦虑症)的药品。

Claims (10)

  1. 氮杂色胺酮衍生物作为吲哚胺-2,3-双加氧酶1和/或色氨酸-2,3-双加氧酶抑制剂的用途，所述的衍生物如通式(I)所示，或其几何异构体、互变异构体、同位素标记物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
    Figure PCTCN2017079371-appb-100001
    这里，式(I)中
    A和B其中一个为N，而另一个为C-R3；
    E为N或-C-R6；
    G为O或N-Y-Z，其中，Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、或羧甲基-CH2C(＝O)OH、磺酰基-S(＝O)2OH、或磷酰基-P(＝O)(OH)2；或者，Y为-N(H)-，而Z为氢、-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；
    R1至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基；
    R8和R9各自独立地选自氢、或者未取代的C1-C4烷烃基。
  2. 如权利要求1所述的用途，其中，所述的衍生物，G为O；A为N、而B为-CH，或者B为N、而A为-CH。
  3. 如权利要求1所述的用途，其中，所述的衍生物，G为O；A为N、而B为-CH，或者B为N、而A为-CH；
    而且，E为-C-R6；
    R1、R2、R4至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基。
  4. 如权利要求1所述的用途，其中，所述的衍生物选自下列化合物：
    吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-氟吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-(三氟甲氧基)吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-硝基吡啶[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-氯吡啶并[2',3'；4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-甲氧基吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-甲基吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-甲氧基吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-氯吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    9-氟吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮；
    11-(羟基亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    9-氯-11-(肟基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(羟基亚氨基)-9-甲基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(羟基亚氨基)-9-甲氧基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-((2-(二甲基氨基)乙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    9-氯11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(1H)-酮；
    11-((2-(二甲基氨基)乙氧基)亚氨基)-9-氟吡啶[2',3':4,5]嘧啶并[1,2-a] 吲哚-5(11H)-酮；
    9-氯11-((3-(二甲基氨基)丙基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(2-羟基乙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    N,N-二甲基-2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)肼硫代甲酰胺；
    2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒；
    (((9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)氨基)氧基)磺酸；
    11-(甲氧基亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(乙氧基亚氨基)-9-硝基吡啶[2',3:4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮(化合物CY-1-26)；
    11-((烯丙氧基)亚氨基)-9-硝基吡啶[2',3'：4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(羧基氧亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺；
    2-(9-甲氧基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)-N，N-二甲基肼硫代甲酰胺；
    吡啶并[2,3-D]吡啶并[3',4':4,5]吡咯并[1,2-a]嘧啶-5,11-二酮；
    2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒；
    2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺化合物；
    2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒；
    2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺；
    2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒；和
    2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺。
  5. 如权利要求1所述的用途，是指在治疗具有IDO1和/或TDO介导的色氨酸代谢的病理学特征的疾病中的应用，所述疾病包括但不限于肿瘤、感染性疾病、自身免疫性疾病、阿尔茨海默病、抑郁症、焦虑症。
  6. 一种氮杂色胺酮衍生物，如式(II)所示，或其几何异构体、互变异构体、同位素标记物、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：
    Figure PCTCN2017079371-appb-100002
    这里，式(II)中
    A和B其中一个为N，而另一个为C-R3；
    E为N或-C-R6；
    Y为-O-，而Z为氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C2-C4烯烃基或取代的C2-C4烯烃基、未取代的C2-C4炔烃基或取代的C2-C4炔烃基、或羧甲基-CH2C(＝O)OH、磺酰基-S(＝O)2OH、或磷酰基-P(＝O)(OH)2；或者，Y为-N(H)-，而Z为氢，-C(＝S)-N(R8)(R9)、或-C(＝O)-N(R8)(R9)、或-C(＝N)-N(R8)(R9)；
    R1至R7各自独立地选自氢、未取代的C1-C4烷烃基或取代的C1-C4烷烃基、未取代的C1-C4烷氧基或取代的C1-C4烷氧基、卤素、硝基、氰基、甲砜基或羟基；
    R8和R9各自独立地选自氢、或者未取代的C1-C4烷烃基。
  7. 如权利要求6所述的衍生物，其中，A为N、而B为-CH，或者B为N、而A为-CH。
  8. 如权利要求6所述的衍生物，选自下列化合物：
    11-(羟基亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    9-氯-11-(肟基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(羟基亚氨基)-9-甲基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(羟基亚氨基)-9-甲氧基吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-((2-(二甲基氨基)乙氧基)亚氨基)-9-硝基吡啶[2',3'：4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    9-氯11-((2-(二甲基氨基)乙氧基)亚氨基)吡啶并[2',3'：4,5]嘧啶并[1,2-a]吲哚-5(1H)-酮；
    11-((2-(二甲基氨基)乙氧基)亚氨基)-9-氟吡啶[2'，3'：4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    9-氯11-((3-(二甲基氨基)丙基)亚氨基)吡啶并[2'，3'：4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(2-羟基乙氧基)亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    N,N-二甲基-2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)肼硫代甲酰胺；
    2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼甲脒；
    (((9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)氨基)氧基)磺酸；
    11-(甲氧基亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-(乙氧基亚氨基)-9-硝基吡啶[2',3:4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-((烯丙氧基)亚氨基)-9-硝基吡啶[2',3'：4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    11-((羧基氧亚氨基)-9-硝基吡啶[2',3':4,5]嘧啶并[1,2-a]吲哚-5(11H)-酮；
    2-(9-硝基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚-11(5H)-亚基)肼硫代甲酰胺；
    2-(9-甲氧基-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-a]吲哚-11(5H)-亚基)-N，N-二甲基肼硫代甲酰胺；
    吡啶并[2,3-D]吡啶并[3',4':4,5]吡咯并[1,2-a]嘧啶-5,11-二酮；
    2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚11(5H)-亚基)肼甲脒；
    2-(9-氯-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚11(5H)-亚基)肼硫代甲酰胺化合物；
    2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚11(5H)-亚基)肼甲脒；
    2-(9-(三氟甲氧基)-5-氧代吡啶并[2',3':4,5]嘧啶并[1,2-α]吲哚11(5H)-亚基)肼硫代甲酰胺；
    2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚11(5H)-亚基)肼甲脒；和
    2-(9-氯-5-氧代吡啶并[3',4':4,5]嘧啶并[1,2-α]吲哚11(5H)-亚基)肼硫代甲酰胺。
  9. 一种制备如权利要求6所述的衍生物的方法，包括如下步骤：
    式(III)化合物与式(IV)化合物反应，得到式(II’)化合物，式(II’)化合物进一步再与式(V)化合物反应，得到式(II)化合物
    Figure PCTCN2017079371-appb-100003
    其中，式(III)、(IV)、(V)、(II’)化合物中涉及的取代基A、B、E、Y、Z以及R1、R2、R4、R5和R7的定义如式(II)化合物。
  10. 包含权利要求6-8中任一项所述衍生物的药物组合物。
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CN115710276B (zh) * 2022-11-21 2024-04-05 贵州大学 一类7-脂肪胺取代色胺酮衍生物、其制备方法及应用

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