WO2018223969A1 - N-苄基色胺酮类衍生物作为色氨酸双加氧酶(tdo)抑制剂的用途 - Google Patents

N-苄基色胺酮类衍生物作为色氨酸双加氧酶(tdo)抑制剂的用途 Download PDF

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WO2018223969A1
WO2018223969A1 PCT/CN2018/089989 CN2018089989W WO2018223969A1 WO 2018223969 A1 WO2018223969 A1 WO 2018223969A1 CN 2018089989 W CN2018089989 W CN 2018089989W WO 2018223969 A1 WO2018223969 A1 WO 2018223969A1
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substituted
unsubstituted
group
tdo
alkyl
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PCT/CN2018/089989
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French (fr)
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杨青
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复旦大学
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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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and particularly relates to the use of an N-benzyltryptamine derivative as a TDO inhibitor.
  • TDO (or TDO 2, EC.1.13.11.11) is a heme-containing multimeric dioxygenase present in cells, composed of four heme-containing identical subunits, first discovered in rabbits in 1936.
  • the liver is mainly distributed in the liver of mammals and is stimulated to be expressed in other parts such as the skin, placenta and brain. Exogenous tryptophan, kynurenine (Kyn) and glucocorticoids induce the expression of the endogenous TDO2 gene.
  • the human TDO coding gene (Tdo or Tdo2) is located on chromosome 4 (4q32.1) and has a full length of about 16 kb. It contains 12 exons and 11 introns.
  • TDO eukaryotic and prokaryotic TDO have high catalytic activity for L-Trp and low catalytic activity for D-Trp.
  • TDO and IDO1 catalyze the same biochemical pathway, the substrate specificity of the two is different.
  • TDO specifically catalyzes L-tryptophan and its specific derivatives.
  • IDO1 can catalyze a series of substrates, L-tryptophan, D- Tryptophan, serotonin and the like.
  • TDO is very low, but TDO is highly similar to IDO1 in its active fraction containing heme.
  • TDO is associated with tumor immune escape, and the activity of TDO is enhanced, resulting in a significant increase in the content of tryptophan metabolites such as kynurenine, thereby increasing the level of regulatory T cells in the body and subsequently producing immune tolerance.
  • Amino acid can bind and activate aromatic hydrocarbon receptors, increasing tumor cell survival rate to help tumor cells to escape immune.
  • TDO and IDO1 play similar roles in tryptophan metabolism, there are few studies on the use of TDO inhibitors in oncology. Until 2011, studies have shown the relationship between TDO and glioma. Experimental data indicate that in glioma cells. In the line, the expression level of TDO was significantly up-regulated. The knockdown of IDO1 and IDO2 expression by genetic engineering did not affect the metabolism level of tryptophan in the cells, while knockdown of TDO expression reduced the kynurenine pathway product canine urine. The amount of amino acid produced can be used to confirm the importance of TDO in the tryptophan metabolism of glioma. The study clarified the role of TDO in oncology and used TDO as a disease target.
  • TDO enzymes are also associated with TDO enzymes.
  • TDO is overexpressed in most tumor cell lines, such as bladder cancer, liver cancer, melanoma, lung cancer, colon cancer, myeloma, leukemia and pancreatic cancer.
  • tumor cells TDO-catalyzed tryptophan catabolism is the material basis for immunosuppressive responses. This mechanism promotes the survival, growth, differentiation and metastasis of malignant cells.
  • IDO1 and IDO2 have little effect on mediating tryptophan metabolism.
  • TDO inhibitors are potential drugs for the treatment of diseases associated with abnormal expression or activation of TDO.
  • TDO TDO inhibitors for the treatment of TDO alone (such as liver cancer, glioma, mental disorders) or IDO1, TDO to participate in the mediation of human major diseases (multiple cancers) , Alzheimer's disease, etc.) to provide new drug targets and ideas.
  • N-benzyltryptamine derivative represented by the following formula A1, or a pharmaceutically acceptable salt thereof, which has the following structural formula:
  • R 1 is selected from the group consisting of hydrogen, fluorine, -(substituted or unsubstituted C1-C6 alkyl)-substituted or unsubstituted 5-12 membered heterocyclic group; wherein said heterocyclic ring
  • the base includes 1-3 heteroatoms selected from the group consisting of N, O or S;
  • R 2 is selected from the group consisting of H, Cl, Br, substituted or unsubstituted C1-C4 alkyl, -NR 3 R 4 , or -(substituted or unsubstituted C1-C6 alkyl)-NR 3 R 4 ;
  • the R 3 and R 4 are each independently selected from the group consisting of H, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2- a C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group;
  • R 3 , R 4 together with an adjacent nitrogen atom constitute a substituted or unsubstituted 5-12 membered heterocyclic group, wherein the 5-12 membered heterocyclic group has 1-2 nitrogen atoms, and 0 - 2 heteroatoms selected from the group consisting of O, S;
  • substitution means that one or more hydrogen atoms on the group (preferably a hydrogen atom on a nitrogen atom) are substituted with a substituent selected from the group consisting of a C1-C4 alkyl group, a C1-C4 haloalkyl group, and an amine group protection.
  • Base preferably tert-butoxycarbonyl), halogen, phenyl;
  • It is characterized by being used for the preparation of a pharmaceutical composition or preparation for inhibiting TDO activity.
  • the heterocyclic group is a saturated heterocyclic group, a partially unsaturated heterocyclic group or an all unsaturated heterocyclic group (aryl group).
  • R 1 when R 2 is H, Cl, Br, substituted or unsubstituted C1-C4 alkyl, R 1 is -(substituted or unsubstituted C1-C6 alkyl)-substituted or not Substituted 5-12 membered heterocyclyl, and when R 1 is hydrogen or fluoro, R 2 is -(substituted or unsubstituted C1-C6 alkyl)-NR 3 R 4 .
  • the 5-12 membered heterocyclic group is selected from the group consisting of substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted four Pyrazine, substituted or unsubstituted pyrrole, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted triazole, substituted or unsubstituted imidazole, substituted or unsubstituted thiazole, substituted or unsubstituted Oxazole, substituted or unsubstituted pyrazole, substituted or unsubstituted isothiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted thiadiazole, substituted or not
  • the 5-12 membered heterocyclic group is a substituent formed by a ring selected from the group consisting of:
  • the R 2 is selected from the group consisting of:
  • the derivative is a compound selected from the group consisting of:
  • the pharmaceutical composition or formulation is for inhibiting the activity of tryptophan dioxygenase (TDO).
  • TDO tryptophan dioxygenase
  • 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 useful for inhibiting the activity of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan dioxygenase (TDO).
  • IDO1 indoleamine 2,3-dioxygenase 1
  • TDO tryptophan dioxygenase
  • the TDO is a human TDO.
  • the pharmaceutical composition is also used to treat a disease associated with TDO.
  • the "TDO-associated disease” includes a disease mediated by TDO alone, or a disease in which IDO1 and TDO are involved together.
  • the disease characterized by pathological features of the tryptophan metabolism disorder of the TDO-related disease is selected from the group consisting of liver cancer, glioma, and the like, which are not expressed by IDO1, and mental disorders.
  • a TDO inhibitor comprising the N-benzyltryptamine derivative represented by Formula A1 of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof.
  • an N-benzyltryptamine derivative represented by the following formula A1, or a pharmaceutically acceptable salt thereof:
  • the R 1 is selected from the group consisting of hydrogen, fluorine, a -substituted or unsubstituted (C1-C6 alkyl)-substituted or unsubstituted 5-12 membered heterocyclic group; wherein the heterocyclic group includes 1-3 heteroatoms selected from the group consisting of N, O or S;
  • R 2 is selected from the group consisting of H, Cl, Br, substituted or unsubstituted C1-C4 alkyl, -NR 3 R 4 , or -(substituted or unsubstituted C1-C6 alkyl)-NR 3 R 4 ;
  • the R 3 and R 4 are each independently selected from the group consisting of H, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C2-C4 alkenyl group, a substituted or unsubstituted C2- a C4 alkynyl group, a substituted or unsubstituted C3-C6 cycloalkyl group;
  • R 3 , R 4 together with an adjacent nitrogen atom constitute a substituted or unsubstituted 5-12 membered heterocyclic group, wherein the 5-12 membered heterocyclic group has 1-2 nitrogen atoms, and 0 - 2 heteroatoms selected from the group consisting of O, S;
  • substitution means that one or more hydrogen atoms on the group (preferably a hydrogen atom on a nitrogen atom) are substituted with a substituent selected from the group consisting of a C1-C4 alkyl group, a C1-C4 haloalkyl group, and an amine group protection.
  • Base preferably tert-butoxycarbonyl), halogen, phenyl;
  • R 2 is selected from the group consisting of H, Cl, Br, C1-C4 alkyl
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, amino protecting group (preferably tert-butoxycarbonyl), halogen ;
  • R 1 is hydrogen or fluorine
  • the R 2 is -NR 3 R 4 or -(C1-C6 alkyl)-NR 3 R 4 ; or when R 2 is H, Cl, Br, C1 -C4 alkyl, said R 1 is -(C1-C6 alkyl)-substituted or unsubstituted 5-12 membered heterocyclic group;
  • At least one of R 1 and R 2 is
  • the 5-12 membered heterocyclic group is selected from the group consisting of substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyridazine, substituted or unsubstituted four Pyrazine, substituted or unsubstituted pyrrole, substituted or unsubstituted thiophene, substituted or unsubstituted furan, substituted or unsubstituted triazole, substituted or unsubstituted imidazole, substituted or unsubstituted thiazole, substituted or unsubstituted Oxazole, substituted or unsubstituted pyrazole, substituted or unsubstituted isothiazole, substituted or unsubstituted isoxazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted thiadiazole, substituted or not
  • the 5-12 membered heterocyclic group is a substituent formed by a ring selected from the group consisting of:
  • the compound of formula A1 is selected from the group consisting of
  • a fourth aspect of the invention there is provided a method of preparing a compound according to the third aspect of the invention, comprising the steps of:
  • each group is as defined in the third aspect of the invention.
  • a pharmaceutical composition comprising (i) an N-benzyltryptamine derivative according to the third aspect of the invention, or a pharmaceutically acceptable thereof And a (ii) pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for treating a disease associated with IDO1, IDO2 or TDO activity or expression.
  • the IDO1, IDO2 or TDO is a person IDO1, IDO2 or TDO.
  • a compound according to the third aspect of the invention for the preparation of a pharmaceutical composition or formulation for inhibiting the activity of a target protein, wherein said target protein is selected from the group consisting of: TDO, IDO1, IDO2, or a combination thereof.
  • a tryptamine derivative or a pharmaceutically acceptable salt thereof, which has the structural formula represented by the following formula A1:
  • R 1 is F or
  • R 2 is selected from the group consisting of H, Cl, Br, C1-C4 alkyl, And one of R 1 and R 2 is
  • substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, amino protecting group (preferably tert-butoxycarbonyl), halogen ;
  • It is characterized by being used for the preparation of a pharmaceutical composition or preparation for inhibiting IDO2 activity.
  • substituted means that one or more hydrogen atoms on a group are substituted with a substituent selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy group, halogen, hydroxyl group, carboxyl group (-COOH), C 1 -C 10 aldehyde group, C 2 -C 10 acyl group, C 2 -C 10 ester group, amino group, phenyl group;
  • the phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 10 alkyl, cyano, OH, nitro, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, amino.
  • C 1 -C 6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Base, tert-butyl, or the like.
  • 5-12 membered heterocyclyl refers to a saturated or unsaturated (including aromatic) ring system having from 5 to 12 members having one or more heteroatoms selected from O, S, N or P.
  • the group such as pyridyl, thienyl, piperidinyl, or the like, is preferably a 5- to 9-membered heterocyclic group.
  • halogen refers to F, Cl, Br and I.
  • the terms "containing”, “comprising” or “including” mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms “consisting mainly of” and “consisting of” are encompassed by the term “included.”
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation, and allergic reaction), that is, a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted. Substituted or halogenated C2-C6 acyl, unsubstituted or halogenated C1-C6 alkyl-hydroxy.
  • each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • the tryptamine is an quinazoline alkaloid whose chemical name is ⁇ [2,1-b]quinazoline-6,12-dione. Tryptamine is a yellow needle crystal which is mainly found in blue plants such as horse blue, indigo and indigo. Alternatively, it may be extracted from a fermentation broth of microorganisms.
  • N-benzyltryptamine derivatives used in the present application can be prepared or extracted by methods known in the art.
  • a compound of the invention As used herein, “a compound of the invention”, “tryptamine of the invention and derivatives thereof”, or “compound of formula A1” are used interchangeably and refer to a compound of formula A1, 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 TDO, but also has a certain inhibitory effect on IDO1.
  • IDO1 inhibitors have TDO inhibition, for example, the inhibitor L-1-MT known in the art is a single IDO1 inhibitor.
  • 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 present invention provides a composition for inhibiting tryptophan dioxygenase.
  • 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 tryptophan dioxygenase 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.
  • the compound of the formula A1 of the present invention can also inhibit IDO1, and thus can be used as an IDO1/TDO dual target inhibitor.
  • the present invention also provides a novel structure of a TDO inhibitor having both IDO1, IDO2 and TDO inhibitory activity, and a method for preparing the same, which can be used for comprehensively blocking tryptophan metabolism in dogs and urine. Amino acid pathway.
  • Some of the compounds can be synthesized by referring to existing methods, for example, the method described in Chinese Patent No. 201310560572.0.
  • the synthesis route uses 4-nitrobenzyl chloride as a starting material, and reacts with sodium azide to prepare 4-nitrobenzyl azide 1; and then with phenylacetylene catalyzed by cuprous iodide and sodium ascorbate 1,3 - Dipolar ring addition reaction to prepare triazole 2; after reduction of the nitro group in 2 with iron powder, react with trichloroacetaldehyde and hydroxylamine hydrochloride to form ⁇ 4; 4 under the action of sulfuric acid, the ring is prepared to contain three Azole 5 of azole. Finally, triazole-containing ruthenium 5 is condensed with a perylene anhydride derivative containing a methyl group, a bromine or a chlorine group to form three kinds of tryptophan derivatives (3d, 3e, 3f).
  • Triazole-containing hydrazine 5 (304 mg, 1 mmol), 5-methyl erythroic anhydride (177 mg, 1 mmol), triethylamine (505 mg, 5 mmol), toluene (2.5 mL) were added to the reaction flask in turn, and then The temperature was raised to 110 ° C, and the reaction was stirred under reflux for 4 h. TLC showed that after the reaction was completed, triethylamine and toluene were removed by evaporation in vacuo, and recrystallized from anhydrous ethanol to give a yellow-green solid 3d 315 mg, yield 75.1%.
  • Triazole-containing hydrazine 5 (304 mg, 1 mmol), 5-bromoindole anhydride (197 mg, 1 mmol), triethylamine (505 mg, 5 mmol), toluene (2.5 mL) were added to the reaction flask, followed by heating. The reaction was stirred at 110 ° C for 4 h under reflux. After TLC detection showed that the reaction was completed, triethylamine and toluene were removed by evaporation in vacuo, and recrystallized from anhydrous ethanol to give a yellow-green solid 3e 343 mg (yield 70.8%).
  • IDO1, IDO2 and TDO Nucleotide sequences of IDO1, IDO2 and TDO have been disclosed, and the active IDO1, IDO2 and TDO in the examples are human-derived IDO1, IDO2 and TDO, which can be prepared by conventional molecular cloning means.
  • the IC 50 test of IDO1 can be carried out by referring to the methods described in the art, such as the method described in Chinese Patent No. 201310560572.0.
  • IDO2 inhibitors including the compound of the present invention, L-1-MT and D-1-MT each having a concentration of 10 ⁇ M were mixed, and the mixture was added to IDO2 at 37 ° C for 5 min, and reacted at 37 ° C for 30 min.
  • the inhibition rate of the compound of the present invention against IDO2 was significantly higher than that of L-1-MT and D-1-MT.
  • the preliminary screening results of the compounds of this example provide the basis for data validation for subsequent IC50 values, Ki value determinations, and inhibition type determinations.
  • 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 HEK293 cell line 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 Mix incubate for 20 min at room temperature, add to the cell culture medium to be transfected uniformly, and incubate for 4-6 hours at 37 ° C, 5% CO 2 incubator, then change to DMEM medium containing 10% serum, and culture for 12 h.
  • the cells were seeded at a density of 2.5 ⁇ 10 4 cells/well in a 96-well plate, and cultured in an incubator at 37° C., 95% humidity, and 5% CO 2 for 12 hours to add different concentrations of the test compound (including the compound of the present invention, L-1-MT and INCB023460), and supplemented with cell culture medium to a total volume of 200 ⁇ L per well.
  • the experimental groups were pcDNA3.1(+)-hTDO transfection group (experimental group), pcDNA3.1(+) transfection group (empty plasmid control group) and untransfected group (blank control group), and each group had three complexes. hole. In inhibition vs. inhibitor concentration plotted IC 50 value calculated using the modified Karber method. The experimental results are shown in Table 1.
  • NI is non-inhibitory and ND is undetected.
  • the IDO2 inhibitor INCB023460 in clinical trials has poor IDO2 and TDO inhibitory activity, especially TDO inhibitory activity, and is a single inhibitor of IDO1.
  • the compound of the present application has good IDO1 inhibitory activity and TDO inhibitory activity, and thus can be used as a dual inhibitor of IDO1/TDO.
  • the IDO1 inhibitory activity of this type of parent compound is basically superior to the TDO inhibitory activity, such as 1e and 1f, but the TDO inhibitory activity of 1c is superior to the IDO1 inhibitory activity.

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Abstract

本发明提供了一种N-苄基色胺酮作为TDO抑制剂的用途，具体地，本发明提供了一种N-苄基色胺酮类衍生物，或其药学上可接受的盐的用途，所述衍生物具有如下式1所示的结构通式，其中各基团的定义如说明书中所述。本发明的化合物具有优良的TDO抑制活性，可以作为TDO抑制剂用于制备治疗与TDO活性或表达量相关的疾病。

Description

N-苄基色胺酮类衍生物作为色氨酸双加氧酶(TDO)抑制剂的用途 技术领域
本发明属于药物化学技术领域，具体涉及一种N-苄基色胺酮衍生物作为TDO抑制剂的用途。
背景技术
哺乳动物体内催化必需氨基酸L-色氨酸(L-tryptophan,L-Trp)循犬尿氨酸途径(kynurenine pathway,KP)分解代谢的首个限速酶有三个，即色氨酸双加氧酶(tryptophan 2,3-dioxygenase,TDO)、吲哚胺2,3-双加氧酶1(indoleamine2,3-dioxygenase 1,IDO1)以及吲哚胺2,3-双加氧酶2(indoleamine 2,3-dioxygenase 2,IDO2)。
TDO(or TDO 2,EC.1.13.11.11)是存在于细胞内的含血红素的多聚体双加氧酶，由四个含血红素的相同亚基组成,于1936年首次被发现于兔肝脏中，主要分布在哺乳动物的肝脏，经过刺激后在其他部位如皮肤、胎盘和脑中也有表达。外源的色氨酸、犬尿氨酸(kynurenine,Kyn)以及糖皮质激素可诱导内源TDO2基因的表达。人TDO的编码基因(Tdo or Tdo2)位于4号染色体上(4q32.1)，全长约16kb，包含12个外显子和11个内含子，其单体蛋白产物分子量约46.7kDa，由406个氨基酸构成。真核和原核TDO都对L-Trp具有高的催化活性，而对D-Trp的催化活性很低。尽管TDO和IDO1催化相同的生化反应途径，二者的底物特异性不同，TDO特异性催化L色氨酸及其特定衍生物，IDO1可以催化一系列底物，L-色氨酸，D-色氨酸，5-羟色胺等等。
TDO与IDO1序列相似性很低，但是TDO与IDO1其含亚铁血红素的活性部位高度相似。近年研究发现TDO与肿瘤免疫逃逸有关，TDO活性的增强，造成犬尿氨酸等色氨酸代谢产物的含量显著上升，进而提高体内调节性T细胞的水平并随之产生免疫耐受，犬尿氨酸可以结合并激活芳香烃受体，增加肿瘤细胞存活率来帮助肿瘤细胞进行免疫逃逸。
尽管TDO与IDO1在色氨酸代谢中作用相似，TDO抑制剂在肿瘤医学中的应用研究却寥寥无几，直到2011年有研究表明TDO与胶质瘤的关系，实验数据表明，在胶质瘤细胞系中，TDO的表达量明显上调，通过基因工程的手段敲减IDO1和IDO2的表达并不影响细胞中色氨酸的代谢水平，而敲减TDO的表达会降低犬尿氨酸途径产物犬尿氨酸的生成量，由此可以确认TDO在胶质瘤的色氨酸代谢中的重要意义。该研究明确了TDO在肿瘤医学中的地位，将TDO作为一个疾病靶点。另有实验报道一些重大脑科疾病如阿尔茨海默症、精神分裂症等也与TDO酶相关。研究发现TDO会在精神分裂症患者的神经元、脑部血管以及星形胶质细胞内表达，而抑制犬尿氨酸途径可有效治疗躁郁症、阿尔兹海默症等多种认知疾病。另有实验报道一些重大脑科疾病如阿尔茨海默症、精神分裂症等也与TDO酶相关。
有研究表明，TDO在大多数肿瘤细胞系中都有过度表达，例如膀胱癌、肝癌、黑色素瘤、肺癌、结肠癌、骨髓瘤、白血病及胰腺癌等。在肿瘤细胞内，TDO催化的色氨酸分解代谢是免疫抑制反应的物质基础。这种机制可促进恶性细胞的存活、生长、分化及转移。例如膀胱癌(bladder carcinoma)，肝癌(hepatocarcinoma)以及黑色素瘤(melanoma)等等。在一些组成型表达TDO的肿瘤细胞系中，IDO1和IDO2几乎没有介导色氨酸代谢的作用。TDO在肿瘤调节中的重要作用已经被研究人员采用P815肿瘤模型清晰地证明，并且已经证明抑制TDO可有效控制肿瘤的生长。这样的发现为TDO抑制剂在肿瘤疾病治疗上的可能应用提供了科学依据。因此，TDO抑制剂是潜在的治疗与TDO异常表达或活化相关的疾病的药物。
综上所述，本领域迫切需要开发新型的TDO抑制剂，从而为治疗TDO单独介导(如肝癌，胶质瘤，精神紊乱)或IDO1、TDO共同参与介导的人类重大疾病(多种癌症、阿尔茨海默病等)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N-苄基色胺酮类衍生物在TDO抑制方面的用途。
本发明的第一方面，提供了一种如下式A1所示的N-苄基色胺酮衍生物，或其药学上可接受的盐的用途，所述衍生物的结构通式如下：
Figure PCTCN2018089989-appb-000001
其中：所述R 1选自下组：氢、氟、-(取代或未取代的C1-C6的烷基)-取代或未取代的5-12元杂环基；其中，所述的杂环基包括1-3个选自下组的杂原子：N、O或S；
R 2选自下组：H、Cl、Br、取代或未取代的C1-C4烷基、-NR 3R 4、或-(取代或未取代的C1-C6的烷基)-NR 3R 4；
所述的R 3、R 4各自独立地选自下组：H、取代的或未取代的C1-C4烷基、取代的或未取代的C2-C4烯基、取代的或未取代的C2-C4炔基、取代的或未取代的C3-C6环烷基；
或R 3、R 4与相邻的氮原子共同构成取代或未取代的5-12元杂环基，其中，所述的5-12元杂环基上具有1-2个氮原子，和0-2个选自下组的杂原子：O、S；
所述的取代指基团上的一个或多个氢原子(优选为氮原子上的氢原子)被选自下组的取代基取代：C1-C4烷基、C1-C4卤代烷基、胺基保护基(优选叔丁氧羰基)、卤素、苯基；
其特征在于，用于制备抑制TDO活性的药物组合物或制剂。
在另一优选例中，所述的杂环基为饱和杂环基、部分不饱和杂环基或全部不饱和杂 环基(芳香基)。
在另一优选例中，当R 2为H、Cl、Br、取代或未取代的C1-C4烷基时，R 1为-(取代或未取代的C1-C6的烷基)-取代或未取代的5-12元杂环基，且当R 1为氢或氟时，R 2为-(取代或未取代的C1-C6的烷基)-NR 3R 4。
在另一优选例中，所述的5-12元杂环基选自下组：取代或未取代的吡啶、取代或未取代的嘧啶、取代或未取代的哒嗪、取代或未取代的四嗪、取代或未取代的吡咯、取代或未取代的噻吩，取代或未取代的呋喃，取代或未取代的三氮唑、取代或未取代的咪唑、取代或未取代的噻唑、取代或未取代的噁唑、取代或未取代的吡唑、取代或未取代的异噻唑、取代或未取代的异噁唑、取代或未取代的噁二唑、取代或未取代的噻二唑、取代或未取代的吲哚、取代或未取代的吲唑、取代或未取代的喹啉、取代或未取代的异喹啉、取代或未取代的苯并呋喃、取代或未取代的苯并噻吩、取代或未取代的苯并咪唑、取代或未取代的苯并噁唑、取代或未取代的苯并噻唑、取代或未取代的苯并异噻唑、取代或未取代的苯并异噁唑、取代或未取代的苯并三氮唑、取代或未取代的吗啉、取代或未取代的二氢哌啶、取代或未取代的硫代吗啉、取代或未取代的哌啶、取代或未取代的哌嗪，取代或未取代的四氢吡喃、取代或未取代的二氢吡喃、取代或未取代的吡咯啉、取代或未取代的四氢噻吩、取代或未取代的四氢呋喃、取代或未取代的氧杂环丁烷、取代或未取代的硫杂环丁烷、取代或未取代的氮杂环丁烷。
在另一优选例中，所述的5-12元杂环基是选自下组的环所形成的取代基：
Figure PCTCN2018089989-appb-000002
在另一优选例中，所述的R 2选自下组：
Figure PCTCN2018089989-appb-000003
Figure PCTCN2018089989-appb-000004
在另一优选例中，所述衍生物为选自下组的化合物：
Figure PCTCN2018089989-appb-000005
在另一优选例中，所述的药物组合物或制剂用于抑制色氨酸双加氧酶(TDO)的活性。
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抑制吲哚胺2,3-双加氧酶1(IDO1)和色氨酸双加氧酶(TDO)的活性。
在另一优选例中，所述的TDO为人源TDO。
在另一优选例中，所述的药物组合物还用于治疗与TDO相关的疾病。
在另一优选例中，所述的“与TDO相关的疾病”包括由TDO单独介导的疾病，或IDO1、TDO共同参与介导的疾病。
在另一优选例中，所述的与TDO相关的疾病的色氨酸代谢紊乱的病理学特征的疾病选自下组：肝癌、胶质瘤等IDO1不表达的肿瘤，精神紊乱。
本发明的第二方面，提供了一种TDO抑制剂，包含如本发明第一方面的式A1所示的N-苄基色胺酮类衍生物，或其药学上可接受的盐。
本发明的第三方面，提供了一种如下式A1所示的N-苄基色胺酮类衍生物，或其药学上可接受的盐：
Figure PCTCN2018089989-appb-000006
式中，
所述R 1选自下组：氢、氟、-取代或未取代的(C1-C6的烷基)-取代或未取代的5-12元杂环基；其中，所述的杂环基包括1-3个选自下组的杂原子：N、O或S；
R 2选自下组：H、Cl、Br、取代或未取代的C1-C4烷基、-NR 3R 4、或-(取代或未取 代的C1-C6的烷基)-NR 3R 4；
所述的R 3、R 4各自独立地选自下组：H、取代的或未取代的C1-C4烷基、取代的或未取代的C2-C4烯基、取代的或未取代的C2-C4炔基、取代的或未取代的C3-C6环烷基；
或R 3、R 4与相邻的氮原子共同构成取代或未取代的5-12元杂环基，其中，所述的5-12元杂环基上具有1-2个氮原子，和0-2个选自下组的杂原子：O、S；
所述的取代指基团上的一个或多个氢原子(优选为氮原子上的氢原子)被选自下组的取代基取代：C1-C4烷基、C1-C4卤代烷基、胺基保护基(优选叔丁氧羰基)、卤素、苯基；
R 2选自下组：H、Cl、Br、C1-C4烷基；
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：C1-C4烷基、C1-C4卤代烷基、胺基保护基(优选叔丁氧羰基)、卤素；
且当R 1为氢或氟时，所述的R 2为-NR 3R 4、或-(C1-C6的烷基)-NR 3R 4；或当R 2为H、Cl、Br、C1-C4烷基时，所述的R 1为-(C1-C6的烷基)-取代或未取代的5-12元杂环基；
且当R 2为H时，R 1不为
Figure PCTCN2018089989-appb-000007
在另一优选例中，R 1和R 2中至少一个为
Figure PCTCN2018089989-appb-000008
在另一优选例中，所述的5-12元杂环基选自下组：取代或未取代的吡啶、取代或未取代的嘧啶、取代或未取代的哒嗪、取代或未取代的四嗪、取代或未取代的吡咯、取代或未取代的噻吩，取代或未取代的呋喃，取代或未取代的三氮唑、取代或未取代的咪唑、取代或未取代的噻唑、取代或未取代的噁唑、取代或未取代的吡唑、取代或未取代的异噻唑、取代或未取代的异噁唑、取代或未取代的噁二唑、取代或未取代的噻二唑、取代或未取代的吲哚、取代或未取代的吲唑、取代或未取代的喹啉、取代或未取代的异喹啉、取代或未取代的苯并呋喃、取代或未取代的苯并噻吩、取代或未取代的苯并咪唑、取代或未取代的苯并噁唑、取代或未取代的苯并噻唑、取代或未取代的苯并异噻唑、取代或未取代的苯并异噁唑、取代或未取代的苯并三氮唑、取代或未取代的吗啉、取代或未取代的二氢哌啶、取代或未取代的硫代吗啉、取代或未取代的哌啶、取代或未取代的哌嗪，取代或未取代的四氢吡喃、取代或未取代的二氢吡喃、取代或未取代的吡咯啉、取代或未取代的四氢噻吩、取代或未取代的四氢呋喃、取代或未取代的氧杂环丁烷、取代或未取代的硫杂环丁烷、取代或未取代的氮杂环丁烷。
在另一优选例中，所述的5-12元杂环基是选自下组的环所形成的取代基：
Figure PCTCN2018089989-appb-000009
在另一优选例中，所述的式A1化合物选自下组：
Figure PCTCN2018089989-appb-000010
本发明的第四方面，提供了一种如本发明第三方面所述的化合物的制备方法，其特征在于，包括步骤：
Figure PCTCN2018089989-appb-000011
式III化合物与式II化合物反应，生成式A1化合物；
各式中，各基团的定义如本发明第三方面所述。
本发明的第四方面，提供了一种药物组合物，所述的药物组合物包含(i)如本发明第三方面所述的N-苄基色胺酮类衍生物，或其药学上可接受的盐；以及(ii)药学上可接受的载体。
在另一优选例中，所述的药物组合物用于治疗与IDO1，IDO2或TDO活性或表达量相关的疾病。
在另一优选例中，所述的IDO1，IDO2或TDO为人IDO1，IDO2或TDO。
本发明的第五方面，提供了一种如本发明第三方面所述的化合物的用途，用于制备抑制靶蛋白的活性的药物组合物或制剂，其中所述的靶蛋白选自下组：TDO、IDO1、IDO2、或其组合。
本发明的第六方面，提供了一种色胺酮类衍生物，或其药学上可接受的盐的用途，所述衍生物具有如下式A1所示的结构通式：
Figure PCTCN2018089989-appb-000012
式中，
R 1为F或
Figure PCTCN2018089989-appb-000013
R 2选自下组：H、Cl、Br、C1-C4烷基、
Figure PCTCN2018089989-appb-000014
且R 1和R 2中之一为
Figure PCTCN2018089989-appb-000015
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：C1-C4烷基、C1-C4卤代烷基、胺基保护基(优选叔丁氧羰基)、卤素；
其特征在于，用于制备抑制IDO2活性的药物组合物或制剂。
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。
具体实施方式
本发明人经过长期而深入的研究，意外地发现，具有如式1所示结构的一类N-苄基色胺酮类衍生物具有相当优异的TDO抑制活性，因此可作为IDO/TDO双重抑制剂使用，具有很好的应用前景。基于上述发现，发明人完成了本发明。
术语
除非特别说明，在本文中，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C 1～C 10烷基、C 3～C 10环烷基、C 1～C 10烷氧基、卤素、羟基、羧基(-COOH)、C 1～C 10醛基、C 2～C 10酰基、C 2～C 10酯基、氨基、苯基；所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基，所述取代基选自：卤素、C 1-C 10烷基、氰基、OH、硝基、C 3～C 10环烷基、C 1～C 10烷氧基、氨基。
术语“C 1～C 6烷基”指具有1～6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“5-12元杂环基”指具有5-12元的环系上具有一个或多个选自O、S、N或P的杂原子的饱和或非饱和(包括芳香性)环系取代基，如吡啶基、噻吩基、哌啶基，或类似基团，优选为5-9元的杂环基。
术语“卤素”指F、Cl、Br和I。
本发明中，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含 有”中。
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6酰基、未取代或卤代的C1-C6烷基-羟基。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
N-苄基色胺酮类衍生物
色胺酮为吲哚喹唑啉类生物碱，其化学名称为吲哚[2,1-b]喹唑啉-6,12-二酮。色胺酮是一种黄色针状结晶，主要存在于马蓝、蓼蓝、菘蓝等产蓝植物中。另外，也可以从微生物的发酵液中提取。
本申请中所使用的N-苄基色胺酮类衍生物均可采用本领域已知方法进行制备或提取。
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A1化合物”可互换使用，指式A1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 PCTCN2018089989-appb-000016
式中，各基团的定义如上所述。
本发明化合物不仅对TDO具有抑制作用，对IDO1也有一定的抑制作用。但需知，并非所有的IDO1抑制剂均具有TDO抑制作用，例如本领域中已知的抑制剂L-1-MT即为单一的IDO1抑制剂。
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。
组合物和施用方法
本发明提供了一种用于抑制色氨酸双加氧酶的组合物。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，本发明的色氨酸双加氧酶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A1化合物对TDO具有较好的抑制效果。
(b)本发明的式A1化合物对IDO1也能起到抑制作用，因此可以作为IDO1/TDO双靶点抑制剂。
(c)本发明还提供了一类结构新颖的TDO抑制剂及其制备方法，所述的TDO抑制剂同时具有IDO1、IDO2和TDO抑制活性，因此可以用于全面阻断色氨酸代谢犬尿氨酸途径。
(d)提供了一种治疗与TDO相关的疾病的新方法。
(e)提供了一种治疗由IDO1和TDO介导的色氨酸代谢异常疾病的新方法。
(f)提供了一种治疗由IDO2介导的色氨酸代谢异常疾病的新方法。
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。
部分化合物可以参照现有方法合成，例如中国专利201310560572.0中所述的方法。
N-苄基色胺酮类衍生物的合成：
Figure PCTCN2018089989-appb-000017
反应过程：
本合成路线以4-硝基苄氯为起始原料，与叠氮钠反应制备4-硝基苄基叠氮1；再与苯乙炔在碘化亚铜和抗坏血酸钠的催化下发生1，3-偶极环加成反应制备三氮唑2；用铁粉将2中的硝基还原为氨基后，与三氯乙醛、盐酸羟胺反应生成肟4；4在硫酸作用下关环制备含三氮唑的吲哚醌5。最后，将含三氮唑的吲哚醌5分别与含有甲基、溴、氯取代的靛红酸酐衍生物缩合生成三种色胺酮衍生物(3d、3e、3f)。
1、三氮唑的吲哚醌
合成路线：
Figure PCTCN2018089989-appb-000018
反应步骤：
1)1-叠氮甲基-4-硝基苯1的制备
将4-硝基苄氯(162mg,1mmol)、叠氮钠(78mg,1.2mmol)、二甲亚砜(2mL)依次加入到反应瓶中，铝箔纸避光，室温反应1h，TLC检测显示反应完成后，向反应体系内加入水，用乙酸乙酯萃取，有机相水洗，无水硫酸钠干燥，真空旋转蒸发除去乙酸乙酯，即得淡黄棕色液体1，直接用于下一步反应。
2)1-(4-硝基苯基)-4-苯基-1H-1,2,3-三氮唑2的制备
将对硝基苄基叠氮(178mg,1mmol)，抗坏血酸钠(79mg,0.4mmol)、碘化亚铜(38mg,0.2mmol)、乙腈(3mL)、水(0.3mL)和苯乙炔(204mg,2mmol)依次加入反应瓶中，氮气保护，常温搅拌反应过夜，TLC检测显示反应完成后，将反应液倒入水中，用乙酸乙酯萃取，饱和食盐水洗至中性，有机相用无水硫酸钠干燥，真空旋转蒸发除去乙酸乙酯，硅胶柱层析分离，得淡黄色晶体2 224mg，收率80％。
表征数据如下：
1HNMR(400MHz,CDCl 3):δ＝8.24(d,2H),7.83(d,2H),7.75(s,1H),7.44(m,4H),7.35(m,1H),5.71(s,2H)
3)4-((4-苯基-1H-苯基-1H-1,2,3-三氮唑-1-基)甲基)苯胺3的制备
向反应瓶中加入还原铁粉(448mg,8mmol)、氯化铵(350mg,6.54mmol)、水(7mL)，将反应液加热到100℃，活化铁粉1h，然后降温至80℃，缓慢分批加入上步产物(280mg,1mmol)，反应5h，TLC检测显示反应完后,冷却至室温。加入固体碳酸钠调PH＝8-9，加20ml乙酸乙酯搅拌0.5h，然后硅藻土过滤，滤液用乙酸乙酯萃取，饱和食盐水洗至中性，有机相用无水硫酸钠干燥，真空旋转蒸发除去乙酸乙酯，即得黄色固体3 228mg，收率91％。
表征数据如下：
1HNMR(400MHz,CDCl 3):δ＝7.79(d,2H),7.60(s,1H),7.39(t,2H),7.30(t,1H),7.13(d,2H),6.68(d,2H),5.44(s,2H)
4)(4-苯基-1H-1,2,3-三氮唑-1-亚甲基)肟4的制备
向反应瓶中加入水合三氯乙醛(165mg,1mmol)、无水硫酸钠(141mg,1mmol)、水(2.2mL)，在搅拌下加入上步产物(250mg,1mmol)，然后加入5％盐酸溶液(0.7mL)，再加入盐酸羟胺(209mg,3mmol)、水(0.95mL)，然后升温至100℃，反应3h，TLC检测显示反应完成后，将反应液冷至室温，抽滤；滤饼依次用10％的盐酸溶液洗涤、水洗涤，所得固体真空干燥，得淡黄色固体4 161mg，收率50％。
5)(4-苯基-1H-1,2,3-三氮唑-1-亚甲基)吲哚醌5的制备
将浓硫酸(2.5mL)加入反应瓶中，搅拌下分批加入上步产物(320mg,1mmol)，至全部溶解，然后升温至65℃，反应5h，TLC检测显示原料反应完全后，将反应液倒入冷水中，析出黄色固体，抽滤，滤饼用水洗涤，所得固体真空干燥，得橙黄色固体5 289mg，收率95％。
表征数据如下：
1HNMR(400MHz,CDCl 3):δ＝7.97(s,1H),7.80(d,3H),7.73(s,1H),7.61(s,1H),7.55(d,1H),7.50(d,2H),6.93(d,1H),5.55(s,2H)
2、靛红酸酐的合成
合成路线：
Figure PCTCN2018089989-appb-000019
反应步骤：
1)5-甲基靛红酸酐6的合成
向反应瓶中加入冰乙酸(1mL)、浓硫酸(0.05mL)，在搅拌下分批加入5-甲基吲哚醌(161mg,1mmol)，然后开始滴加乙酸酐(0.2mL)与30％过氧化氢(0.23mL)的混合液，反应液加热至70℃，反应4h，TLC检测显示原料反应完全后，将反应液冷却，抽滤，滤饼依次用水洗涤，5％碳酸氢钠溶液洗涤，水洗涤，所得固体真空干燥，得橙黄色固体6135mg，收率76.3％。
2)5-溴靛红酸酐7的合成
向反应瓶中加入冰乙酸(1mL)、浓硫酸(0.05mL)，在搅拌下分批加入5-溴吲哚醌(226mg,1mmol)，然后开始滴加乙酸酐(0.2mL)与30％过氧化氢(0.23mL)的混合液，反应液加热至70℃，反应4h，TLC检测显示原料反应完全后，将反应液冷却，抽滤，滤饼依次用水洗涤，5％碳酸氢钠溶液洗涤，水洗涤，所得固体真空干燥，得浅黄色固体7194mg，收率80.1％。
3)5-氯靛红酸酐8的合成
向反应瓶中加入冰乙酸(1mL)、浓硫酸(0.05mL)，在搅拌下分批加入5-氯吲哚醌(181mg，1mmol)，然后开始滴加乙酸酐(0.2mL)与30％过氧化氢(0.23mL)的混合液，反应液加热至70℃，反应4h，TLC检测显示原料反应完全后，将反应液冷却，抽滤，滤饼依次用水洗涤，5％碳酸氢钠溶液洗涤，水洗涤，所得固体真空干燥，得浅黄色固体8135mg，收率68.2％。
3、N-苄基色胺酮类衍生物3d-3f的合成
合成路线：
Figure PCTCN2018089989-appb-000020
反应步骤：
1)8-(4-苯基-1H-1,2,3-三氮唑-1-亚甲基)-2-甲基色胺酮3d的合成
在反应瓶中依次加入含三氮唑的吲哚醌5(304mg,1mmol)、5-甲基靛红酸酐(177mg,1mmol)、三乙胺(505mg,5mmol)、甲苯(2.5mL)，然后升温至110℃，回流搅拌反应4h，TLC检测显示反应完成后,真空旋转蒸发除去三乙胺、甲苯，用无水乙醇重结晶，得黄绿色固体3d 315mg，收率75.1％。
表征数据如下：
1HNMR(400MHz,CDCl 3):δ＝8.66(d,1H),8.23(s,1H),7.91(d,1H),7.84(t,3H)7.76(t,2H),7.67(d,1H),7.42(t,2H),7.34(t,1H),5.68(s,2H),2.56(s,3H)
2)8-(4-苯基-1H-1,2,3-三氮唑-1-亚甲基)-2-溴色胺酮3e的合成
在反应瓶中依次加入含三氮唑的吲哚醌5(304mg,1mmol)、5-溴靛红酸酐(197mg,1mmol)、三乙胺(505mg,5mmol)、甲苯(2.5mL)，然后升温至110℃，回流搅拌反应4h，TLC检测显示反应完成后,真空旋转蒸发除去三乙胺、甲苯，用无水乙醇重结晶，最后即得黄绿色固体3e 343mg，收率70.8％。
表征数据如下：
1HNMR(400MHz,CDCl 3):δ＝8.61(d,1H),8.27(s,1H),8.01(d,1H),7.81(t,3H)7.78(t,2H),7.54(d,1H),7.47(t,2H),7.31(t,1H),5.69(s,2H)
3)8-(4-苯基-1H-1,2,3-三氮唑-1-亚甲基)-2-氯色胺酮3f的合成
在25mL反应瓶中依次加入含三氮唑的吲哚醌5(304mg,1mmol)、5-氯靛红酸酐(242mg,1mmol)、三乙胺(505mg,5mmol)、甲苯(2.5mL)，然后升温至110℃，回流搅拌反应4h，TLC检测显示反应完成后,真空旋转蒸发除去三乙胺、甲苯，用无水乙醇重结晶，最后即得黄绿色固体3f 340mg，收率77.3％。
表征数据如下：
1HNMR(400MHz,CDCl 3):δ＝8.61(d,1H),8.25(s,1H),7.92(d,1H),7.83(t,3H)7.76(t,2H),7.63(d,1H),7.45(t,2H),7.33(t,1H),5.65(s,2H)
活性实施例
通用材料
IDO1、IDO2和TDO的核苷酸序列均已公开，实施例中的活性IDO1、IDO2和TDO为来源于人的IDO1、IDO2和TDO，可通过常规分子克隆手段进行制备。
IDO1的IC 50测试可参考本领域现有方法，如中国专利201310560572.0中所述的方法进行。
实施例1
IDO2半数有效抑制浓度IC 50(酶水平)的测定
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。
在pH为7.5的条件下，本发明化合物对IDO2的抑制率均显著高于L-1-MT和D-1-MT。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
IDO2抑制剂的抑制类型及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。
实施例3
IDO2半数有效抑制浓度IC 50(细胞)的测定
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％CO 2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％CO 2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2.5×10 4细胞/孔的密度接种于96孔板中，37℃、湿度95％、5％CO 2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IC 50值。
实施例4 TDO半数有效抑制浓度IC 50(酶水平)的测定
500μL的标准检测体系中，将50mmol/L磷酸钾缓冲液(pH 7.0)、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-色氨酸以及待测hTDO抑制剂混合，混合液于37℃水浴5min后向上述混合液中加入hTDO,37℃反应30min，酶促反应结束后加入100μL 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。以抑制率对抑制剂浓度作图，利用改良寇氏法计算IC 50值，实验结果如表1所示。
实施例5 TDO半数有效抑制浓度IC 50(细胞)的测定
HEK293细胞株用含有10％胎牛血清的DMEM高糖培养基于37℃、5％CO 2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％CO 2培养箱培育4～6小时后换成含10％血清的DMEM培养基，培养12h后将细胞以2.5×10 4细胞/孔的密度接种于96孔板中，37℃、湿度95％、5％CO 2的培养箱中培养12h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INCB023460)，并用细胞培养基补齐至每孔总体积200μL，孵育5h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(+)-hTDO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IC 50值。实验结果如表1所示。
利用上述实施例1-5的方法，对实施例1-5制备的化合物的IDO1、IDO2以及TDO抑制活性进行测定，并用目前体内、外实验中通用的IDO抑制剂1-甲基色氨酸(1-MT，市售)作为对照物，测定结果如表1所示。
表1 上述实施例中合成的N-苄基色胺酮衍生物(A1)的IDO1，IDO2和TDO抑制活性
Figure PCTCN2018089989-appb-000021
注：NI是无抑制活性，ND是未检测。
从上述结果中可以看出，处于临床试验的IDO1抑制剂INCB023460的IDO2和TDO抑制活性较差，尤以TDO抑制活性为差，是IDO1单一抑制剂。本申请化合物具有良好的IDO1抑制活性和TDO抑制活性，因此可以作为IDO1/TDO双重抑制剂使用。从IC 50值看，这一类母核化合物的IDO1抑制活性基本均优于TDO抑制活性，例如1e和1f，但1c的TDO抑制活性优于IDO1抑制活性。
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 (7)

  1. 一种如下式A1所示的N-苄基色胺酮衍生物，或其药学上可接受的盐的用途，所述衍生物的结构通式如下：
    Figure PCTCN2018089989-appb-100001
    其中：所述R 1选自下组：氢、氟、-(取代或未取代的C1-C6的烷基)-取代或未取代的5-12元杂环基；其中，所述的杂环基包括1-3个选自下组的杂原子：N、O或S；
    R 2选自下组：H、Cl、Br、取代或未取代的C1-C4烷基、-NR 3R 4、或-(取代或未取代的C1-C6的烷基)-NR 3R 4；
    所述的R 3、R 4各自独立地选自下组：H、取代的或未取代的C1-C4烷基、取代的或未取代的C2-C4烯基、取代的或未取代的C2-C4炔基、取代的或未取代的C3-C6环烷基；
    或R 3、R 4与相邻的氮原子共同构成取代或未取代的5-12元杂环基，其中，所述的5-12元杂环基上具有1-2个氮原子，和0-2个选自下组的杂原子：O、S；
    所述的取代指基团上的一个或多个氢原子(优选为氮原子上的氢原子)被选自下组的取代基取代：C1-C4烷基、C1-C4卤代烷基、胺基保护基(优选叔丁氧羰基)、卤素、苯基；
    其特征在于，用于制备抑制TDO活性的药物组合物或制剂。
  2. 如权利要求1所述的用途，其特征在于，所述的5-12元杂环基选自下组：取代或未取代的吡啶、取代或未取代的嘧啶、取代或未取代的哒嗪、取代或未取代的四嗪、取代或未取代的吡咯、取代或未取代的噻吩，取代或未取代的呋喃，取代或未取代的三氮唑、取代或未取代的咪唑、取代或未取代的噻唑、取代或未取代的噁唑、取代或未取代的吡唑、取代或未取代的异噻唑、取代或未取代的异噁唑、取代或未取代的噁二唑、取代或未取代的噻二唑、取代或未取代的吲哚、取代或未取代的吲唑、取代或未取代的喹啉、取代或未取代的异喹啉、取代或未取代的苯并呋喃、取代或未取代的苯并噻吩、取代或未取代的苯并咪唑、取代或未取代的苯并噁唑、取代或未取代的苯并噻唑、取代或未取代的苯并异噻唑、取代或未取代的苯并异噁唑、取代或未取代的苯并三氮唑、取代或未取代的吗啉、取代或未取代的二氢哌啶、取代或未取代的硫代吗啉、取代或未取代的哌啶、取代或未取代的哌嗪，取代或未取代的四氢吡喃、取代或未取代的二氢吡喃、取代或未取代的吡咯啉、取代或未取代的四氢噻吩、取代或未取代的四氢呋喃、取代或未取代的氧杂环丁烷、取代或未取代的硫杂环丁烷、取代或未取代的氮杂环丁烷。
  3. 如权利要求1所述的用途，其特征在于，所述的5-12元杂环基是选自下组的环所形成的取代基：
    Figure PCTCN2018089989-appb-100002
  4. 如权利要求1所述的用途，其特征在于，所述衍生物为选自下组的化合物：
    Figure PCTCN2018089989-appb-100003
  5. 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用于抑制色氨酸双加氧酶(TDO)的活性。
  6. 如权利要求1所述的用途，其特征在于，所述的药物组合物还用于治疗与TDO相关的疾病。
  7. 一种TDO抑制剂，其特征在于，包含如权利要求1的式1所示的N-苄基色胺酮类衍生物，或其药学上可接受的盐。
PCT/CN2018/089989 2017-06-05 2018-06-05 N-苄基色胺酮类衍生物作为色氨酸双加氧酶(tdo)抑制剂的用途 WO2018223969A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020088614A1 (zh) * 2018-11-02 2020-05-07 苏州如鹰生物医药有限公司 色胺酮衍生物治疗神经系统疾病的用途

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110183454B (zh) * 2019-06-20 2022-01-07 同济大学 一种含1,2,3-三氮唑的色胺酮及其制备方法和应用
CN110294740A (zh) * 2019-06-20 2019-10-01 同济大学 一种n-苄基氨基酸水溶性色胺酮及其制备方法和应用
CN110283192B (zh) * 2019-07-18 2021-08-06 同济大学 一种含硼酸的色胺酮衍生物的制备方法及应用
CN115124531A (zh) * 2022-08-09 2022-09-30 贵州大学 一类4-氮杂色胺酮芳香硫醚衍生物、制备方法及应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532144A (zh) * 2012-01-20 2012-07-04 辽宁思百得医药科技有限公司 一种新型吲哚胺-2，3-双加氧酶抑制剂及其制备方法和用途
CN103570727A (zh) * 2013-11-12 2014-02-12 复旦大学 一种n-苄基色胺酮衍生物及其制备方法和应用
CN103570726A (zh) * 2013-07-15 2014-02-12 上海天慈生物谷生物工程有限公司 N-烷基色胺酮衍生物及其制备方法和应用
WO2017034420A1 (en) * 2015-08-27 2017-03-02 Auckland Uniservices Limited Inhibitors of tryptophan dioxygenases (ido1 and tdo) and their use in therapy
WO2017173973A1 (zh) * 2016-04-05 2017-10-12 北京大学 氮杂色胺酮衍生物作为ido1和/或tdo抑制剂的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532144A (zh) * 2012-01-20 2012-07-04 辽宁思百得医药科技有限公司 一种新型吲哚胺-2，3-双加氧酶抑制剂及其制备方法和用途
CN103570726A (zh) * 2013-07-15 2014-02-12 上海天慈生物谷生物工程有限公司 N-烷基色胺酮衍生物及其制备方法和应用
CN103570727A (zh) * 2013-11-12 2014-02-12 复旦大学 一种n-苄基色胺酮衍生物及其制备方法和应用
WO2017034420A1 (en) * 2015-08-27 2017-03-02 Auckland Uniservices Limited Inhibitors of tryptophan dioxygenases (ido1 and tdo) and their use in therapy
WO2017173973A1 (zh) * 2016-04-05 2017-10-12 北京大学 氮杂色胺酮衍生物作为ido1和/或tdo抑制剂的用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020088614A1 (zh) * 2018-11-02 2020-05-07 苏州如鹰生物医药有限公司 色胺酮衍生物治疗神经系统疾病的用途

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