CN109836356B - Aryl methyl ether derivative and application thereof - Google Patents
Aryl methyl ether derivative and application thereof Download PDFInfo
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- CN109836356B CN109836356B CN201711193892.1A CN201711193892A CN109836356B CN 109836356 B CN109836356 B CN 109836356B CN 201711193892 A CN201711193892 A CN 201711193892A CN 109836356 B CN109836356 B CN 109836356B
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Abstract
The invention relates to a compound for regulating or inhibiting the enzymatic activity of indoleamine 2, 3-dioxygenase 1(IDO-1), in particular to an arylmethyl ether derivative and application thereof. The invention provides an aromatic methyl ether derivative for regulating or inhibiting the enzymatic activity of indoleamine 2, 3-dioxygenase (IDO), a pharmaceutical composition containing the aromatic methyl ether derivative and application of the aromatic methyl ether derivative in treating cancer, virus infection, depression, organ transplant rejection or autoimmune diseases.
Description
Technical Field
The invention relates to a compound for regulating or inhibiting the enzymatic activity of indoleamine 2, 3-dioxygenase 1(IDO-1), in particular to an arylmethyl ether derivative and application thereof.
Background
Indoleamine-2, 3-dioxygenase (IDO) is a heme-containing enzyme that is the first enzyme in the mammalian tryptophan metabolic pathway and is the rate-limiting enzyme. IDO catalyzes the conversion of the essential amino acid tryptophan to N-formylkynurenine and is responsible for the clearance of tryptophan in humans. IDO degrades tryptophan to create a tryptophan-deficient microenvironment in vivo, thereby causing various diseases closely related to tryptophan deficiency, such as cancer, viral infection, depression, organ transplant rejection or autoimmune diseases. Therefore, the search for efficient inhibitors based on IDO targets has become a research focus for drug development in recent years.
Incyte CN200980134351 and CN200680024326 patents report compounds with inhibitory activity to IDO1 enzyme, and the compounds enter clinical three-stage and two-stage researches respectively. Compounds with IDO-1 inhibitory activity reported in the Newlink Genetics CN10354757 patent have also entered clinical phase II studies. However, no medicine is available in the market at the present stage, and the disease related to the IDO enzyme still lacks related treatment medicines and treatment schemes. .
Disclosure of Invention
The invention aims to provide an aryl methyl ether derivative and application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
an arylmethyl ether derivative characterized by: the aryl methyl ether derivative is a compound shown as a formula I:
in the formula
W is selected from CH2O or NH;
x is selected from CH2O or NH;
m is selected from N or C;
R1selected from H, COOH, CONHR10、CONHSO2R10、COOR10、C1-C12Alkyl radical, C2-C12Alkenyl, unsubstituted or substituted by 1 to 5R11Substituted of the following groups: aryl, heteroaryl；
R2、R3、R4And R5Selected from H, C1-C12Alkyl, halo C1-C12Alkyl radical, C2-C12Alkenyl, halo C3-C12Alkenyl, unsubstituted or substituted by 1 to 5R11Substituted of the following groups: aryl, heteroaryl;
R6selected from H, halogen, nitro, cyano, C1-C12Alkyl radical, C3-C12Cycloalkyl radical, C3-C12Heterocycloalkyl, halogeno C1-C12Alkyl radical, C1-C12Alkoxy, halo C1-C12Alkoxy radical, C1-C12Alkoxy radical C1-C12Alkyl, halo C1-C12Alkoxy radical C1-C12Alkyl radical, C2-C12Alkenyl radical, C3-C12Cycloalkenyl, halo C2-C12Alkenyl radical, C2-C12Alkynyl, halo C2-C12Alkynyl, unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C12Alkyl, heteroaryl C1-C12Alkyl, aryl C1-C12Alkoxy, heteroaryl C1-C12Alkoxy, aryloxy or heteroaryloxy;
R7and R8Each of which may be the same or different is selected from H, C1-C12Alkyl radical, C3-C12Cycloalkyl radical, C3-C12Heterocycloalkyl, halogeno C1-C12Alkyl radical, C1-C12Alkoxy radical C1-C12Alkyl, halo C1-C12Alkoxy radical C1-C12Alkyl radical, C2-C12Alkenyl radical, C3-C12Cycloalkenyl, halo C2-C12Alkenyl radical, C2-C12Alkynyl, halo C2-C12Alkynyl, unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C12Alkyl, heteroaryl C1-C12An alkyl group;
R9selected from H, C1-C12Alkyl radical, C3-C12Cycloalkyl radical, C3-C12Heterocycloalkyl, halogeno C1-C12Alkyl radical, C1-C12Alkoxy, halo C1-C12Alkoxy radical, C1-C12Alkoxy radical C1-C12Alkyl, halo C1-C12Alkoxy radical C1-C12Alkyl radical, C2-C12Alkenyl radical, C3-C12Cycloalkenyl, halo C2-C12Alkenyl radical, C2-C12Alkynyl, halo C2-C12Alkynyl, unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C12Alkyl, heteroaryl C1-C12An alkyl group;
R10is selected from C1-C12Alkyl radical, C3-C12Cycloalkyl, halo C1-C12Alkyl, halo C3-C12Cycloalkyl, unsubstituted or substituted by 1 to 5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C12Alkyl, heteroaryl C1-C12An alkyl group;
R11selected from H, halogen, nitro, cyano, C1-C10Alkyl, halo C1-C10Alkyl radical, C1-C10Alkoxy, halo C1-C10Alkoxy radical, C1-C10Alkylthio radical, C1-C10Alkylcarbonyl group, C1-C10Alkoxycarbonyl group, C2-C10Alkenyl, halo C2-C10Alkenyl radical, C3-C10Alkenyloxy, halogeno C3-C10Alkenyloxy radical, C2-C10Alkynyl, halo C2-C10Alkynyl, C3-C10Alkynyloxy, halo C3-C10Alkynyloxy, halo C1-C10Alkylthio, halo C1-C10Alkylcarbonyl group, C1-C10Alkylamino, halogeno C1-C10Alkylamino radical, C2-C10Dialkylamino radical, C1-C10Alkylcarbonylamino, halo C1-C10Alkylcarbonylamino, C1-C10Alkylaminocarbonyl or halogeno C1-C10An alkylaminocarbonyl group;
or, stereoisomers, tautomers, or salts thereof of the compounds of formula I.
Preferably in said formula I:
w is selected from NH;
x is selected from CH2Or NH;
m is selected from C or N;
R1selected from COOH, CONHR10、CONHSO2R10、COOR10Unsubstituted or substituted by 1 to 5R11Substituted of the following groups: aryl, heteroaryl;
R2is selected from H;
R3、R4and R5Selected from H, C1-C6Alkyl, halo C1-C6Alkyl radical, C2-C6Alkenyl, halo C2-C6Alkenyl, unsubstituted or substituted by 1 to 5R11Substituted of the following groups: aryl, heteroaryl;
R6selected from H, halogen, nitro, cyano, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Heterocycloalkyl, halogeno C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkoxy radical, C1-C6Alkoxy radical C1-C6Alkyl, halo C1-C6Alkoxy radical C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C6Cycloalkenyl, halo C2-C6Alkenyl radical, C2-C6Alkynyl, halo C2-C6Alkynyl, unsubstituted orBy 1-5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C6Alkyl, heteroaryl C1-C6Alkyl, aryl C1-C6Alkoxy, heteroaryl C1-C6Alkoxy, aryloxy or heteroaryloxy;
R7and R8Each of which may be the same or different is selected from H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Heterocycloalkyl, halogeno C1-C6Alkyl radical, C1-C6Alkoxy radical C1-C6Alkyl, halo C1-C6Alkoxy radical C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C6Cycloalkenyl, halo C2-C6Alkenyl radical, C2-C6Alkynyl, halo C2-C6Alkynyl, unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C6Alkyl, heteroaryl C1-C6An alkyl group;
R9selected from H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Heterocycloalkyl, halogeno C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkoxy radical, C1-C6Alkoxy radical C1-C6Alkyl, halo C1-C6Alkoxy radical C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C6Cycloalkenyl, halo C2-C6Alkenyl radical, C2-C6Alkynyl, halo C2-C6Alkynyl, unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl;
R10is selected from C1-C6Alkyl radical, C3-C6Cycloalkyl, halo C1-C6Alkyl, halo C3-C6Cycloalkyl, unsubstituted or substituted by 1 to 5R11Substituted byThe following groups: aryl, heteroaryl, aryl C1-C6Alkyl, heteroaryl C1-C6An alkyl group;
R11selected from H, halogen, nitro, cyano, C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C6Alkylcarbonyl group, C1-C6Alkoxycarbonyl group, C2-C6Alkenyl, halo C2-C6Alkenyl radical, C3-C6Alkenyloxy, halogeno C3-C6Alkenyloxy radical, C2-C6Alkynyl, halo C2-C6Alkynyl, C3-C6Alkynyloxy, halo C3-C6Alkynyloxy, halo C1-C6Alkylthio, halo C1-C6Alkylcarbonyl group, C1-C6Alkylamino, halogeno C1-C6Alkylamino radical, C2-C6Dialkylamino radical, C1-C6Alkylcarbonylamino, halo C1-C6Alkylcarbonylamino, C1-C6Alkylaminocarbonyl or halogeno C1-C6An alkylaminocarbonyl group;
or, stereoisomers, tautomers, or salts thereof of the compounds of formula I.
Further preferred is that in formula I:
w is selected from NH;
x is selected from CH2Or NH;
m is selected from C;
R1selected from COOH, CONHR10、CONHSO2R10、COOR10、
R2Is selected fromH；
R3、R4And R5Selected from H, C1-C2Alkyl, halo C1-C2Alkyl radical, C2-C4Alkenyl, halo C2-C4Alkenyl, unsubstituted or substituted by 1 to 5R11Substituted of the following groups: phenyl, pyridyl;
R6selected from H, halogen, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Heterocycloalkyl radical, C1-C6Alkoxy radical, C1-C6Alkoxy radical C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C6Cycloalkenyl radical, C2-C6Alkynyl, unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C6Alkyl, heteroaryl C1-C3Alkyl, aryl C1-C3Alkoxy, heteroaryl C1-C3Alkoxy, aryloxy or heteroaryloxy;
R7and R8Each of which may be the same or different is selected from H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Heterocycloalkyl radical, C1-C6Alkoxy radical C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C6Cycloalkenyl radical, C2-C6Alkynyl, unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C3Alkyl, heteroaryl C1-C3An alkyl group;
R9selected from H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Heterocycloalkyl, halogeno C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkoxy radical, C1-C6Alkoxy radical C1-C6Alkyl, halo C1-C6Alkoxy radical C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C6Cycloalkenyl, halo C2-C6Alkenyl radical, C2-C6Alkynyl, halo C2-C6Alkynyl, unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C3Alkyl, heteroaryl C1-C3An alkyl group;
R10is selected from C1-C3Alkyl radical, C3-C6Cycloalkyl, halo C1-C3Alkyl, halo C3-C6Cycloalkyl, unsubstituted or substituted by 1 to 5R11Substituted of the following groups: aryl, heteroaryl, aryl C1-C3Alkyl, heteroaryl C1-C3An alkyl group;
R11selected from H, halogen, nitro, cyano, C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy, halo C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C6Alkylcarbonyl group, C1-C6Alkoxycarbonyl group, C2-C6Alkenyl, halo C2-C6Alkenyl radical, C3-C6Alkenyloxy, halogeno C3-C6Alkenyloxy radical, C2-C6Alkynyl, halo C2-C6Alkynyl, C3-C6Alkynyloxy, halo C3-C6Alkynyloxy, halo C1-C6Alkylthio, halo C1-C6Alkylcarbonyl group, C1-C6Alkylamino, halogeno C1-C6Alkylamino radical, C2-C6Dialkylamino radical, C1-C6Alkylcarbonylamino, halo C1-C6Alkylcarbonylamino, C1-C6Alkylaminocarbonyl or halogeno C1-C6An alkylaminocarbonyl group;
or, stereoisomers, tautomers, or salts thereof of the compounds of formula I.
Still further preferred is that in said formula I:
w is selected from NH;
x is selected from CH2Or NH;
m is selected from C;
R1selected from COOH,
CONHSO2CH3、CONHSO2CF3Or COOCH2CH3；
R2Is selected from H;
R3、R4and R5Selected from H, CH3、CH2CH3Or CF3；
R6Selected from H or halogen;
R7and R8Each of which may be the same or different, is selected from H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
R9selected from phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2, 4-dimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2, 4-difluorophenyl, 2-fluoro-4-methylphenyl, 2-fluoro-4-chlorophenyl, 3-trifluoromethyl-4-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl or 5-methylisoxazolyl;
R9selected from unsubstituted or substituted by 1-5R11Substituted of the following groups: aryl, heteroaryl;
R11selected from H, halogen, nitro, cyano, C1-C3Alkyl, halo C1-C3Alkyl radical, C1-C3Alkoxy, halo C1-C3Alkoxy radical, C1-C3Alkylthio radical, C1-C3Alkylcarbonyl group, C1-C3Alkoxycarbonyl group, C2-C3Alkenyl, halo C2-C3Alkenyl radical, C3-C6Alkenyloxy, halogenGeneration C3-C6Alkenyloxy radical, C2-C3Alkynyl, halo C2-C3Alkynyl, C3-C6Alkynyloxy, halo C3-C6Alkynyloxy, halo C1-C3Alkylthio, halo C1-C3Alkylcarbonyl group, C1-C3Alkylamino, halogeno C1-C3Alkylamino radical, C2-C3Dialkylamino radical, C1-C3Alkylcarbonylamino, halo C1-C3Alkylcarbonylamino, C1-C3Alkylaminocarbonyl or halogeno C1-C3An alkylaminocarbonyl group;
or stereoisomers, tautomers and salts thereof of the compounds of formula I.
More preferably in said formula I:
w is selected from NH;
x is selected from CH2Or NH;
m is selected from C;
R1selected from COOH,
Or COOCH2CH3；
R2And R4Is selected from H;
R3and R5Is selected from H or CH3；
R6Is selected from H;
R7and R8The same or different are respectively selected from n-butyl, isobutyl or cyclohexyl;
R9selected from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2, 4-dimethyl, 2, 4-difluorophenyl, 2-fluoro-4-methylphenyl, 3-trifluoromethyl-4-chlorophenyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-fluorophenyl or 5-methylisoxazolyl;
or stereoisomers, tautomers and salts thereof of the compounds of formula I.
In the above compounds, stereoisomers, including R-and S-isomers and mixtures thereof in any proportion, may be formed due to the carbon linkage of different substituents.
The salts of the compounds of formula I are in the form of acids or salts which are basic or acidic and which form no toxicity. The compounds having a basic or acidic property which are carboxylic acids may form usable salts with alkali metals or alkaline earth metals. The salt with related acid radical can be hydrochloride, hydrobromide, sulfate, hydrosulfate, methanesulfonate, p-toluenesulfonate, fumarate, citric acid, acetate, lactate and other commonly used salt-forming acid radical salts, and the salt with related alkali metal and alkaline earth metal can be sodium salt, potassium salt, calcium salt, zinc salt and other commonly used salt-alkali base salts.
In the definitions of the compounds of the general formula I given above, the terms used are generally defined as follows:
halogen: refers to fluorine, chlorine, bromine or iodine.
Alkyl groups: straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
Cycloalkyl groups: substituted or unsubstituted heteroatom-containing cyclic alkyl groups, such as cyclopropyl, cyclopentyl, or cyclohexyl. Substituents such as methyl, halogen, and the like.
Heterocycloalkyl group: substituted or unsubstituted cyclic alkyl groups containing 1 or more heteroatoms of N, O, S, for example tetrahydrofuranyl, cyclopentylpiperidinyl. Substituents such as methyl, halogen, and the like.
Halogenated alkyl groups: straight-chain or branched alkyl groups in which the hydrogen atoms may be partially or completely substituted with halogen atoms, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and the like.
Alkoxy groups: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages.
Haloalkoxy groups: straight-chain or branched alkoxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms. For example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy and the like.
Alkoxyalkyl groups: the alkoxy group is attached to the structure via an alkyl group. Such as-CH2OCH3，-CH2OCH2CH3。
Haloalkoxyalkyl groups: the hydrogen atoms on the alkyl group of the alkoxyalkyl group may be partially or fully substituted with halogen atoms. Such as-CH2OCH2CH2Cl。
Alkylthio group: straight or branched chain alkyl groups attached to the structure via a sulfur atom.
Haloalkylthio: straight-chain or branched alkylthio groups in which the hydrogen atoms may be partially or wholly replaced by halogen atoms. For example, chloromethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio and the like.
Alkylamino group: straight or branched chain alkyl, linked to the structure via a nitrogen atom.
Haloalkylamino group: straight-chain or branched alkylamino groups in which the hydrogen atoms may be partially or fully substituted by halogen atoms.
Alkenyl: straight-chain or branched alkenes, for example ethenyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl and hexenyl isomers. Alkenyl also includes polyenes such as 1, 2-allenyl and 2, 4-hexadienyl.
Halogenated alkenyl groups: straight-chain or branched alkenes in which the hydrogen atoms may be partially or completely replaced by halogen atoms.
Alkynyl: straight-chain or branched alkynes, for example ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. Alkynyl also includes groups consisting of multiple triple bonds, such as 2, 5-hexadiynyl.
Halogenated alkynyl group: straight-chain or branched alkynes, in which the hydrogen atoms may be partially or completely replaced by halogen atoms.
Alkenyloxy: linear or branched alkenes linked to the structure via oxygen atoms.
Haloalkenyloxy: straight-chain or branched alkenyloxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms.
Alkynyloxy: straight or branched alkynes, linked to the structure via oxygen atom bonds.
Haloalkynyloxy: straight-chain or branched alkynyloxy, in which the hydrogen atoms may be partially or completely substituted by halogen atoms.
An alkylcarbonyl group: the linear or branched alkyl group is linked to the structure via a carbonyl group (-CO-), such as acetyl.
Halogenated alkylcarbonyl group: straight-chain or branched alkylcarbonyl whose hydrogen atoms on the alkyl group may be partially or fully substituted by halogen atoms, such as trifluoroacetyl.
Alkoxycarbonyl group: the alkoxy group is attached to the structure via a carbonyl group. Such as-COOCH3，-COOCH2CH3。
Halogenated alkoxycarbonyl group: the hydrogen atoms of the alkyl group of the alkoxycarbonyl group may be partially or wholly replaced by halogen atoms, e.g. -COOCH2CF3，-COOCH2CH2Cl, and the like.
Alkylcarbonylamino group: such as-NHCOCH3，-NHCOC(CH3)3。
Alkyl amino carbonyl: such as-C (═ O) NHCH3，-C(＝O)N(CH3)2。
Aryl groups and aryl moieties in arylalkyl, aryloxy, arylalkoxy, arylamino, and the like include phenyl, naphthyl, and the like.
Heteroaryl is a five or six membered ring containing 1 or more heteroatoms N, O, S. Such as furyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, and the like.
Heteroaryl as well as heteroaryl moieties in heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, etc., refer to five or six membered rings containing 1 or more N, O, S heteroatoms. Such as furyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, benzoxazolyl, indolyl, and the like.
The following tables respectively list some specific substituents of each substituent in formula I, but they are not limited to these substituents, and other substituents in formula I are as described above.
Wherein W is a specific substituent CH2O or NH;
x is CH as a specific substituent2O or NH;
m is C or N;
R2、R3、R4and R5The specific substituents may be the same or different and are selected from H, CH3、CH2CH3、CH2CH2CH3、CF3。
Tables 1 to 4 respectively show R in the general formula I6、R1、R7(R8)、R9The moiety (c) is not limited to these substituents.
TABLE 1 is R6Substituent group
TABLE 2R1Substituent group
Table 3 is R7(R8) Substituent group
TABLE 4R9Substituent group
The compounds of the present invention can be illustrated by the specific compounds of formula I listed in tables 5.1-5.15, but are not intended to limit the present invention.
In the compounds of the general formula I in the following tables
W is NH;
x is NH;
m is C;
R2is H;
R4is H;
R 6is H;
R9is 1-5R11In the case of substituted aryl radicals, the substituents R1、R3、R5、R7、R8And R11Are different substituents, see tables 5.1-5.15, the corresponding compounds are represented by the general formula II
See tables 5.1-5.15.
Table 5.1:
table 5.2:
table 5.3:
table 5.4:
table 5.5:
table 5.6:
table 5.7:
table 5.8:
table 5.9:
table 5.10:
table 5.11:
table 512:
table 5.13:
table 5.14:
table 5.15:
the compounds of formula I of the present invention can be prepared according to the following method:
in the preparation method, a commercial halogenated aromatic compound 1 and a substituted amino compound 2 react under the action of alkali to generate a substituted amino nitroaromatic compound 3. The compound 3 is directly reduced or halogenated hydrolyzed to obtain an arylcarbinol compound 4.
The compound 4 reacts with the halide 5 to obtain an arylmethyl ether compound 6, and the compound 6 is subjected to reduction of the nitro group to obtain a compound 7 of which the amino group is reduced by the reducing agent. The compound 7 reacts with isocyanate or with chloroformate compound 8 to produce the compound of formula I.
In the general formula I, R1The different selection modes are as follows:
1) the hydrolysis of the ester compound to produce the carboxylic acid compound is:
2) the carboxylic acid compound and the sulfonamide compound are condensed to obtain the sulfonamide acyl compound:
3) the cyano compound reacts with the azide to obtain the tetrazole compound:
wherein, in each reaction:
l is selected from halogen, selected from fluorine, chlorine, bromine and iodine; the other groups are as defined above.
The base is selected from potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide or sodium tert-butoxide, etc.
The reaction of the cyano compound with the azide compound is carried out in a suitable solvent, which may be selected from tetrahydrofuran, acetonitrile, toluene, xylene, benzene, N-dimethylformamide, dimethylsulfoxide, acetone, or butanone, for example.
The reaction temperature may be between room temperature and the boiling temperature of the solvent, and is generally from 20 to 100 ℃.
The reaction time is from 30 minutes to 20 hours, usually from 1 to 10 hours.
The application of the arylmethyl ether derivative, and the application of the compound shown in the formula I, and the stereoisomer, the tautomer or the salt thereof in the preparation of regulating and inhibiting IDO-1 enzyme activity.
The compound shown in the formula I, and the stereoisomer, the tautomer or the salt thereof can be applied to the preparation of medicines for treating cancers, virus infection, depression, organ transplant rejection or autoimmune diseases.
The compound of formula I, and stereoisomers, tautomers or salts thereof, can be administered prior to, concurrently with, or subsequent to administration as an effective amount of an antiviral agent, chemotherapeutic agent, immunosuppressive agent, radiation, anti-tumor vaccine, antiviral vaccine, cytokine therapy, and/or tyrosine kinase inhibitor.
The compound shown in the formula I, and the stereoisomer, the tautomer or the salt thereof can be used as an active ingredient of an antitumor drug, can be used alone, and can also be combined with other antitumor drugs for use. The combined treatment process of the invention comprises the use of at least one compound of the invention and its active derivatives together with one or more other anti-neoplastic agents to increase the overall therapeutic effect. The dosage and administration time of the combination should be determined according to the most reasonable therapeutic effect obtained under different conditions.
The cancer is selected from colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer or gastric cancer.
A pharmaceutical composition is prepared by mixing active ingredient (one or more of the compounds shown above, and its stereoisomer, tautomer or pharmaceutically acceptable salt) with pharmaceutically acceptable carrier or diluent, wherein the content of active ingredient is 10-70%.
The invention also comprises a preparation component prepared by using the compound shown in the formula I and the stereoisomer, tautomer or salt thereof as active ingredients and the preparation of the preparation component. The preparation method comprises the following steps: dissolving the compound covered by the present invention in a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipid, various cyclodextrins, fatty acids, fatty acid esters, phospholipids or a combination thereof to prepare a preparation solution; adding physiological saline to obtain 1-20% carbohydrate. The organic solvent includes polyethylene glycol (PEG), ethanol, propylene glycol or a combination of these solvents.
The contemplated pharmaceutical combinations include an effective dose of the compound of formula I. An "effective amount" as used herein refers to the amount of the compound required to produce a therapeutic effect in the subject being treated. The effective dose or dosages may be varied by the experiential person according to the recommendations of the individual case. For example, the types of tumors to be treated are different, and the use of drugs is different; the dosage can be changed if the composition is used together with other treatment methods such as other anti-tumor medicaments. Can be made into any available dosage form.
The compounds included in the compounds represented by formula I, and stereoisomers, tautomers or salts thereof in the present invention are generally easily soluble in organic solvents, water-soluble solvents, and mixed solvents of organic solvents and water-soluble solvents with water. The water-soluble solvent is preferably alcohol, polyethylene glycol, N-methyl-2-pyrrolinone, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, acetonitrile, or a combination thereof. The alcohol is preferably methanol, ethanol, isopropanol, glycerol or ethylene glycol. The compounds of the present invention can be formulated by mixing with conventional formulation carriers. Dissolving the compound in water-soluble organic solvent, aprotic solvent, water-soluble lipid, cyclodextrin, fatty acid, phospholipid or their mixture to obtain medicinal solution; adding physiological saline to obtain 1-20% carbohydrate, such as glucose water solution. The thus-prepared preparation is stable and useful for animals and clinics.
The product medicine prepared by using the compound shown in the formula I, and the stereoisomer, the tautomer or the salt thereof as the active ingredients can be administrated by oral or parenteral routes, and also can be administrated by a medicine pump transplanted in vivo and other methods, wherein the parenteral route administration refers to subcutaneous intradermal, intramuscular, intravenous, intraarterial, intraatrial, intrasynovial, intrasternal, intrathecal, wound site, intracranial injection or instillation technology and the like. The technical personnel mix the components by a conventional method to finally obtain the required medicament form. Can be made into tablet, capsule, emulsion, powder, intravenous injection, infusion solution, lyophilized powder, dripping pill, emulsion suspension, aqueous suspension, water solution, colloid, colloidal solution, sustained release preparation, nanometer preparation, or other dosage forms for animal or clinical use.
Detailed Description
The following description of the embodiments is provided to assist in a comprehensive understanding of the invention as defined by the claims and their equivalents, and not as a limitation of the invention.
Example 1:
10.0 g of 3-nitro-4-chloroacetophenone and 100mL of diisobutylamine were added to a 250mL flask, and the mixture was heated to 100 ℃ to react for 20 hours. After TLC monitoring reaction, decompression desolventizing of reaction liquid, dissolving of residue with ethyl acetate 300mL, washing with water 100mL × 3, drying of organic phase with anhydrous sodium sulfate for 12 hours, decompression desolventizing, and column chromatography of residue (eluent is ethyl acetate and petroleum ether (boiling range 60-90 deg.C), volume ratio is 1:6) to obtain compound 4- (diisobutylamino) -3-nitrophenyl ethanone, and yellow solid is 11.3 g.
Example 2:
in a 500mL flask were added 10.0 g of 4- (diisobutylamino) -3-nitrophenylethanone and 150mL of methanol, and 10.0 g of sodium borohydride solid was added in portions with stirring. After the addition, the mixture is stirred at room temperature, and after the TLC monitoring reaction is finished, 200mL of saturated ammonium chloride solution is added dropwise under the condition of stirring and controlling the temperature to be 20-30 ℃. After dropping, 300mL of ethyl acetate is used for extraction, 100mL of water is used for washing, the organic phase is dried for 12 hours by anhydrous sodium sulfate, decompression and desolventization are carried out, and the residue is purified by column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) with the volume ratio of 1:5) to obtain the compound 1- (4- (diisobutylamine) -3-nitrophenyl) -1-ethanol, and 7.3 g of yellow viscous liquid.
1H NMR(400MHz,CDCl3)δ7.72(d,J＝2.2Hz,1H),7.41(dd,J＝8.7,2.2Hz,1H),7.12(d,J＝8.7Hz,1H),4.86(q,J＝6.4Hz,1H),2.92(d,J＝7.2Hz,4H),1.91(dt,J＝13.5,6.8Hz,2H),1.50(d,J＝6.5Hz,3H),0.84(d,J＝6.6Hz,12H).
Example 3:
a250 mL flask is added with 3.0 g of compound (1- (4- (diisobutylamino) -3-nitrophenyl) -1-ethanol and 60mL of DMF, 0.5 g of sodium hydride (60%) is added in portions under stirring at room temperature, after the addition is finished, the mixture is stirred at room temperature for 0.5 hour, 1.8 g of ethyl bromoacetate is added dropwise, after TLC monitoring reaction is finished, the mixture is poured into 200mL of water, extracted by 150mL of ethyl acetate, washed by 50mL of water multiplied by 3, an organic phase is dried for 12 hours by anhydrous sodium sulfate, desolventized under reduced pressure, and subjected to column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) and the volume ratio is 1:6) to be purified to obtain 1.9 g of compound 2- ((1- (4- (diisobutylamino) -3-nitrophenyl) -1-ethoxy) ethyl acetate and yellow viscous liquid.
Example 4:
a250 mL flask is added with compound (2- ((1- (4- (diisobutylamino) -3-nitrophenyl) -1-ethoxy) ethyl acetate 1.9 g, ammonium chloride 1.3 g, zinc powder 1.6 g, ethanol 100mL, water 20mL, stirred for reaction at room temperature for 2 hours, after TLC monitoring reaction is finished, filtration is carried out, filtrate is decompressed and desolventized, and residue column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) with volume ratio of 1:10) is carried out to obtain compound 2- ((1- (4- (diisobutylamino) -3-aminophenyl) -1-ethoxy) ethyl acetate, and light yellow viscous liquid is 0.6 g.
Example 5:
in a 100mL flask was charged 0.6 g of ethyl 2- ((1- (4- (diisobutylamino) -3-aminophenyl) -1-ethoxy) acetate, 0.3 g of 2, 4-difluoroisocyanate, and 30mL of tetrahydrofuran, and the mixture was stirred at room temperature for 8 hours, after the completion of the reaction was monitored by TLC, desolventization under reduced pressure was carried out, and the residue was purified by column chromatography (eluent composed of ethyl acetate and petroleum ether (boiling range: 60-90 ℃ C.) in a volume ratio of 1:5) to give ethyl 2- (1- (3- (3- (2, 4-difluorophenyl) ureido) -4- (diisobutylamino) phenyl) ethoxy) acetate (Compound B14) as a white solid, 0.3 g.
1H NMR (600MHz, internal standard TMS, solvent CDCl3)δ(ppm):8.34(s,1H),8.10(d,J＝1.9Hz,1H),8.02(d,J＝5.9Hz,1H),7.17(d,J＝8.2Hz,1H),7.03(dd,J＝8.2,1.9Hz,1H),6.85-6.88(m,2H),6.38(s,1H),4.53(q,J＝6.4Hz,1H),4.20-4.22(m,2H),4.02(d,J＝16.5Hz,1H),3.90(d,J＝16.4Hz,1H),2.58(d,J＝7.2Hz,4H),1.70-1.73(m,2H),1.52(d,J＝6.5Hz,3H),1.31–1.27(m,3H),0.91(d,J＝6.6Hz,12H).
Example 6:
a100 mL flask was charged with 0.3 g of ethyl 2- (1- (3- (3- (2, 4-difluorophenyl) ureido) -4- (diisobutylamino) phenyl) ethoxy) acetate, 50mL of ethanol, and 3.0 g of sodium hydroxide. Stirred at room temperature for 12 hours. After the completion of the reaction monitored by TLC, the reaction was removed under reduced pressure, the residue was dissolved in 300mL of ethyl acetate and 100mL of water, adjusted to pH 3 with concentrated hydrochloric acid, extracted, the organic phase was dried over anhydrous sodium sulfate for 12 hours, removed under reduced pressure, and subjected to column chromatography (eluent: ethyl acetate and petroleum ether (boiling range 60-90 ℃), volume ratio: 1:2) to obtain compound 2- (1- (3- (3- (2, 4-difluorophenyl) ureido) -4- (diisobutylamino) phenyl) ethoxy) acetic acid (compound E14) as a white solid, 0.10 g.
1H NMR (600MHz, internal standard TMS, solvent CDCl3)δ(ppm):8.36(s,1H),8.11(d,J＝1.9Hz,1H),8.03(d,J＝5.9Hz,1H),7.19(d,J＝8.2Hz,1H),7.05(dd,J＝8.2,1.9Hz,1H),6.87-6.91(m,2H),6.39(s,1H),4.55(q,J＝6.4Hz,1H),4.05(d,J＝16.5Hz,1H),3.91(d,J＝16.4Hz,1H),2.59(d,J＝7.2Hz,4H),1.71-1.75(m,2H),1.55(d,J＝6.5Hz,3H),0.90(d,J＝6.6Hz,12H).
In the manner described above, other compounds, isomers or salts of formula I can be obtained by simply replacing the reactants.
Example 7
Compound X1 was prepared as follows:
compound X1
1H-NMR (300MHz, internal standard TMS, solvent DMSO-d6)δ(ppm):0.83(t,J＝6.9Hz,6H),
1.18-1.26(m,8H),2.49(s,3H),2.74-2.76(m,4H),2.99(s,3H),4.06(s,2H),6.15-6.18(m,1H),6.93(d,J＝8.4Hz,1H).7.01-7.04(m,2H),7.32-7.35(m,2H),7.66(s,1H),9.26(s,1H),12.46(s,1H)。
Application example
Test method and results of enzyme inhibition rate of IDO1 on Hela cells:
collecting human cervical cancer cell Hela (purchased from cell bank of Chinese academy of sciences) growing to logarithmic growth phase, counting after conventional digestion, and adjusting concentration to 1 × 10 with RPMI1640 complete medium (American Corning, containing 10% FBS)7One/ml, inoculated into 96-well plates at 100ul per well, and incubated for 24 hr.
Preparing a stimulation solution: after being subpackaged according to the instructions, the human recombinant IFN-gamma (Shanghai Biotech) is adjusted to the concentration 2 times of the final concentration by using RPMI1640 complete culture medium, namely 100 ng/ml;
a test object is prepared, the compound prepared in the embodiment is dissolved by DMSO, and then the test object is diluted to 2 times of the detection concentration by RPMI1640 complete culture medium;
discarding culture solution in the 96-well plate for culturing Hela cells, and adding 100ul of stimulating solution and 100ul of test substance into each well to serve as an experimental group; simultaneously, an interferon growth control group is arranged, and each group has three multiple holes; the experimental group and the control group were incubated for 48 hr.
Sucking culture medium in 96-well plate at 180ul, adding trichloroacetic acid at 45ul (30%, W/V), at 8000rpm/min, and centrifuging for 5 min; the supernatant was added with an equal volume of fresh 4-dimethylaminobenzaldehyde (2%, W/V), and after sufficient shaking, the mixture was detected by an enzyme-linked immunosorbent assay at 480nm (see Table 6).
The test results are given in table 6 below:
the data in table 6 show that the series of compounds have excellent IDO1 inhibitory activity and can be used alone or in combination with other related antiviral agents, chemotherapeutic agents, immunosuppressive agents, radiation, antitumor vaccines, antiviral vaccines, cytokine therapy and/or tyrosine kinase inhibitors to treat diseases associated with the IDO enzyme.
In addition, other compounds, isomers or salts of formula I obtained according to the above preparation process also have corresponding IDO1 inhibitory activity and can be used alone or in combination with other related antiviral agents, chemotherapeutic agents, immunosuppressive agents, radiation, anti-tumor vaccines, antiviral vaccines, cytokine therapy and/or tyrosine kinase inhibitors for treating IDO enzyme-related diseases.
Claims (6)
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1379765A (en) * | 1999-10-15 | 2002-11-13 | 弗·哈夫曼-拉罗切有限公司 | Benzodiazepine derivatives usable as parental metabolic glutamate receptor antagonist |
| CN105209443A (en) * | 2013-03-15 | 2015-12-30 | 百时美施贵宝公司 | Inhibitors of indoleamine 2,3-dioxygenase (IDO) |
| CN105324362A (en) * | 2013-03-15 | 2016-02-10 | 百时美施贵宝公司 | Ido inhibitors |
| WO2016161269A1 (en) * | 2015-04-03 | 2016-10-06 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer |
| WO2017139414A1 (en) * | 2016-02-09 | 2017-08-17 | Inventisbio Inc. | Inhibitor of indoleamine-2,3-dioxygenase (ido) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1379765A (en) * | 1999-10-15 | 2002-11-13 | 弗·哈夫曼-拉罗切有限公司 | Benzodiazepine derivatives usable as parental metabolic glutamate receptor antagonist |
| CN105209443A (en) * | 2013-03-15 | 2015-12-30 | 百时美施贵宝公司 | Inhibitors of indoleamine 2,3-dioxygenase (IDO) |
| CN105324362A (en) * | 2013-03-15 | 2016-02-10 | 百时美施贵宝公司 | Ido inhibitors |
| WO2016161269A1 (en) * | 2015-04-03 | 2016-10-06 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer |
| WO2017139414A1 (en) * | 2016-02-09 | 2017-08-17 | Inventisbio Inc. | Inhibitor of indoleamine-2,3-dioxygenase (ido) |
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