CN106256830A - A kind of deuterated IDO inhibitor and its production and use - Google Patents
A kind of deuterated IDO inhibitor and its production and use Download PDFInfo
- Publication number
- CN106256830A CN106256830A CN201610436352.0A CN201610436352A CN106256830A CN 106256830 A CN106256830 A CN 106256830A CN 201610436352 A CN201610436352 A CN 201610436352A CN 106256830 A CN106256830 A CN 106256830A
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- CN
- China
- Prior art keywords
- compound
- deuterated
- pharmaceutically acceptable
- dried
- hydrate
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
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- 230000015572 biosynthetic process Effects 0.000 claims abstract description 45
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000013078 crystal Substances 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 208000002177 Cataract Diseases 0.000 claims abstract description 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 4
- 201000011510 cancer Diseases 0.000 claims abstract description 4
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 3
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 3
- 210000000056 organ Anatomy 0.000 claims abstract description 3
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- 239000003814 drug Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
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- 239000000126 substance Substances 0.000 claims description 4
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 33
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 15
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 12
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-LIDOUZCJSA-N ethanol-d6 Chemical compound [2H]OC([2H])([2H])C([2H])([2H])[2H] LFQSCWFLJHTTHZ-LIDOUZCJSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000012279 sodium borohydride Substances 0.000 description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 7
- 229910052796 boron Inorganic materials 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 6
- 239000002024 ethyl acetate extract Substances 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- YGACXVRLDHEXKY-WXRXAMBDSA-N O[C@H](C[C@H]1c2c(cccc2F)-c2cncn12)[C@H]1CC[C@H](O)CC1 Chemical compound O[C@H](C[C@H]1c2c(cccc2F)-c2cncn12)[C@H]1CC[C@H](O)CC1 YGACXVRLDHEXKY-WXRXAMBDSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
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- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 4
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- BSQFJBYJUQJNMZ-UHFFFAOYSA-N 4-bromo-1-tritylimidazole Chemical class C1=NC(Br)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BSQFJBYJUQJNMZ-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
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- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 4
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
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- HWWVAHCWJLGKLW-UHFFFAOYSA-N n,n-dimethylhydroxylamine;hydron;chloride Chemical compound Cl.CN(C)O HWWVAHCWJLGKLW-UHFFFAOYSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
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- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
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- 229960001008 heparin sodium Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
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- 230000001590 oxidative effect Effects 0.000 description 1
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- 239000000575 pesticide Substances 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical compound OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 1
- ZADWXFSZEAPBJS-UHFFFAOYSA-N racemic N-methyl tryptophan Natural products C1=CC=C2N(C)C=C(CC(N)C(O)=O)C2=C1 ZADWXFSZEAPBJS-UHFFFAOYSA-N 0.000 description 1
- 239000012354 sodium borodeuteride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 239000011593 sulfur Substances 0.000 description 1
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of deuterated IDO inhibitor and its production and use, it is provided that compound shown in formula I or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate.Compound prepared by the present invention or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate, can be as IDO inhibitor, can be used for the treatment of IDO relevant disease, especially cancer, viral infection, depression, neurodegenerative diseases, wound, age-related cataract, organ transplant rejection and autoimmune disease.
Description
Technical field
The present invention relates to a kind of IDO inhibitor and its production and use.
Background technology
Indoleamine 2,3-pair adds oxidase (indoleamine2,3-dioxygenase, IDO) is uniquely to urge beyond liver
Change tryptophan along the catabolic rate-limiting enzyme of kynurenine pathway.IDO can reach by reducing the concentration of tryptophan in microenvironment
The effect of suppression pathogenic microorganism propagation；IDO is the most closely related with nervous system disease, and it can reduce the level of 5-hydroxy tryptamine and lead
Cause depression, it is possible to cause quinolinic acid in brain etc. to have the accumulation of neurovirulent metabolite；IDO suppression T cell immunity and
Antineoplastic immune, induction Maternal-placental immune toler ance and graft immunologic tolerance all play important metabolic immunoregulation effect.
It is closely related, therefore that IDO has been found to multiple mankind's major diseases such as Ahl tribulus sea silent sickness, cataract, cancer
IDO inhibitor as important medicine by increasingly extensive concern.
NLG919 is a kind of novel IDO inhibitor, has been enter into clinical experimental stage at present.But, its drug effect and medicine generation
Kinetic property, be still significantly improved space.
Summary of the invention
It is an object of the invention to provide a kind of IDO inhibitor and its production and use.
Compound as follows or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate:
R1-R21It is respectively selected from H or D；
And, R1-R21In at least one is D.
Further, R1And R2It is H or simultaneously for D simultaneously.
Further, R3-R6It is H or simultaneously for D simultaneously.
Further, R8And R9It is H or simultaneously for D simultaneously.
Further, R12-R21It is H or simultaneously for D simultaneously.
Further, R1And R2It is H or simultaneously for D simultaneously；And, R3-R6It is H or simultaneously for D simultaneously；And, R7For H or D；
And, R8And R9It is H or simultaneously for D simultaneously；And, R10For H or D；And, R11For H or D；And, R12-R21It is H or simultaneously for D simultaneously；
And, R1-R21In at least one is D.
Further, R1And R2It is D simultaneously；And, R3-R21In at least one is D.
Further, R1And R2It is H simultaneously；And, R3-R6It is D simultaneously；And, R7-R21In at least one is D.
Further, R1-R6It is D simultaneously；And, R7-R21In at least one is D.
Further, R1-R6It is H simultaneously；And, R7-R11In at least one is D.
Further, R1-R7It is H simultaneously；And, R8-R11In at least one is D.
Further, R7Or/and R10For D.
Further, described compound is one of following compound:
Present invention also offers one and prepare above-claimed cpd or its crystal formation, pharmaceutically acceptable salt, hydrate or molten
The method of agent compound, comprises the following steps:
With the compound shown in formula II as raw material, obtain compound shown in formula I through carbonyl reduction.
Further, described preparation method is, is dissolved in solvent by the compound shown in formula II, adds carbonyl reduction reagent
Carry out reduction reaction, isolated and purified obtain compound shown in formula I.
Further, described solvent selected from methanol.
Further, described carbonyl reduction reagent is selected from NaBH4Or NaBD4。
Further, the temperature of described reduction reaction is 0 DEG C.
Present invention also offers described compound or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate exist
Preparation purposes in treatment with IDO relevant disease medicine.
Further, described compound or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate are that IDO presses down
Preparation.
Further, described IDO relevant disease includes cancer, viral infection, depression, neurodegenerative diseases, wound
Wound, age-related cataract, organ transplant rejection, autoimmune disease.
Present invention also offers a kind of pharmaceutical composition, it is with described compound or its crystal formation, pharmaceutically acceptable
Salt, hydrate or solvate are active component, add pharmaceutically acceptable adjuvant or/and the system that is prepared from of complementary composition
Agent.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, adjuvant, and/or the salt formed is usual
In chemistry or physically with constitute certain pharmaceutical dosage form other becomes split-phase compatibility, and physiologically mutually compatible with receptor.
Term " salt " and " pharmaceutically useful salt " are by compound or its stereoisomer, with inorganic and/or organic bronsted lowry acids and bases bronsted lowry
The acid formed and/or basic salt, also include amphion salt (inner salt), also include quaternary ammonium salt, such as alkylammonium salt.These salt
Can be to directly obtain in purification being finally separating of compound.Can also be by by compound, or its stereoisomer,
It is obtained by mixing with a number of acid or alkali suitably (such as equivalent).These salt may form precipitation in the solution
And collect with filter method, or reclaim after the solvent evaporates and obtain, or it is prepared to react postlyophilization in aqueous medium.This
Salt described in bright can be the hydrochlorate of compound, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphorus
Hydrochlorate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleate, tartaric acid
Salt or trifluoroacetate.
Result of the test shows, the compound of the present invention has significant inhibitory action to IDO, and effect is with NLG919 the most very
To more excellent.Further pharmacokinetic trial also shows, compared with NLG919, the compounds of this invention is in drug effect the most even more
In the case of height, also there is more preferable pharmacokinetic property, there is wide market prospect.
Obviously, according to the foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area, without departing from
Under the present invention above-mentioned basic fundamental thought premise, it is also possible to make the amendment of other various ways, replace or change.
The detailed description of the invention of form by the following examples, remakes the most specifically the foregoing of the present invention
Bright.But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to below example.All above-mentioned interior based on the present invention
Hold the technology realized and belong to the scope of the present invention.
Detailed description of the invention
In following embodiment, the source of agents useful for same is as follows:
Kingsoft, Chengdu chemical reagent company limited: hexahydrobenzoid acid, thionyl chloride, dichloromethane, dimethyl azanol hydrochloride,
Triethylamine, methyl-magnesium-bromide, ammonium chloride, imidazoles, sodium acetate, acetic acid, bromine, sodium sulfate, triphenylchloromethane, oxolane,
2-formylphenylboronic acid, four triphenyl phosphorus palladiums, sodium carbonate, DMF, Sodium ethylate, methanol, sodium borohydride.
Chengdu Ke Long chemical reagent factory: heavy water, palladium charcoal, deuterated methanol, boron deuterate sodium, potassium carbonate.
The deuterated formylphenylboronic acid of Chengdu Ruizhi Chemical Research Co., Ltd.: 2-, 3,4,5,6-tetra-deuterated-2-formoxyl deuteriums
For phenylboric acid, the deuterated formoxyl of 2--deuterated phenylboric acid.
The synthesis of embodiment 1 1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethanol (compound 10)
(1) synthesis of acetyl cyclohexane (intermediate 3)
In the single port bottle of 100ml, add cyclohexanecarboxylic acid (5g, 39mmol) and dichloromethane (20ml), stir under room temperature
Under instill thionyl chloride (5.67ml, 78mmol) lentamente, react 5h, concentrated solvent.By dimethyl azanol hydrochloride (4.5g,
47mmol) mixed liquor of dichloromethane (10ml) and triethylamine (13ml, 96mmol) instills wherein lentamente, stirs under room temperature
3h, filters off solid, instills 1N hydrochloric acid and remove the triethylamine of excess in liquid, and ethyl acetate extracts, and merges organic layer, with anhydrous
Sodium sulfate is dried, and is spin-dried for solvent and obtains crude product 2 (5.3g).Crude Compound 2 (5g, 29mmol), tetrahydrochysene is added in there-necked flask
Furan (15ml), temperature controls, at 0 DEG C, to add under nitrogen protection, is slowly added to methyl-magnesium-bromide (10ml, 29mmol), 0
Stir 2h at DEG C, add ammonium chloride cancellation methyl-magnesium-bromide, add dichloromethane extraction, merge organic layer and use anhydrous sodium sulfate
It is dried, is spin-dried for dichloromethane and obtains compound 3 (4.2g, yield 85%).
(2) 2, the synthesis of 4,5-tribromoimidazoles (intermediate 5)
Imidazoles (29.24g, 0.43mol), sodium acetate (317.34g, 3.87mol) and acetic acid is added in there-necked flask
(150ml), the bromine (65ml, 1.28mol) being dissolved in acetic acid (100ml) is at room temperature slowly dropped into by constant voltage separatory funnel,
Controlling temperature and be less than 40 DEG C, be stirred at room temperature 3h, reactant liquor is poured in the water of 1.5L, separates out solid, sucking filtration, washes with water
Solid, dries and obtains compound 5 (120g, yield 92%), mass spectrum: 305 (M+H+)。
(3) synthesis of 4-bromine imidazoles (intermediate 6)
In single port bottle add 2,4,5-tribromoimidazoles (49g, 161mmol), sodium sulfite (101.5g, 806mmol) and
Water (500ml), stirs 6h at 110 DEG C, adds ethyl acetate extraction, merges organic layer and be dried with anhydrous sodium sulfate, being spin-dried for
Ethyl acetate obtains compound 6 (20.5g, yield 89%), mass spectrum: 148 (M+H+)。
(4) synthesis of 4-bromo-1-trityl-1H-imidazoles (intermediate 7)
4-bromine imidazoles (30g, 205mmol), dichloromethane: oxolane=1:1, and triphenyl chlorine is added in single port bottle
Methane (62g, 226mmol), is stirred at room temperature lower addition triethylamine (29ml), continues stirring 1h, adds water and 1N hydrochloric acid,
Add dichloromethane extraction, merge organic layer and be dried with anhydrous sodium sulfate, be spin-dried for dichloromethane and obtain compound 7 (61g, receipts
Rate 72%).
(5) synthesis of 2-(1-trityl-1H-imidazoles-4-) benzaldehyde (intermediate 8)
Addition 4-bromo-1-trityl-1H-imidazoles (1.5g, 3.9mmol) in single port bottle, sodium carbonate (1.2g,
11.7mmol), 2-formylphenylboronic acid (864mg, 5.8mmol) and DMF (10ml), water (2ml), make reaction system be full of nitrogen
Gas, adds tetrakis triphenylphosphine palladium (242mg, 0.195mmol), under nitrogen protection, 90 DEG C of stirring 16h, adds water, acetic acid second
Ester extracts, and merges organic layer and is also dried with anhydrous sodium sulfate, concentrated solvent, with silica gel cross column purification obtain compound 8 (930mg,
Yield 58%).
(6) synthesis of 1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethyl ketone (intermediate 9)
2-(1-trityl-1H-imidazoles-4-) benzaldehyde (400mg, 0.97mmol), acetyl group is added in there-necked flask
Hexamethylene (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by Sodium ethylate (85mg,
Ethanol solution 1.25mmol) at room temperature adds, and is stirred at room temperature 3h, is spin-dried for solvent, adds saturated ammonium chloride
(10ml), it is extracted with ethyl acetate, merges organic layer and be dried with anhydrous sodium sulfate, be spin-dried for solvent, add acetic acid (1ml) and second
Alcohol (5ml), stirs 3h at 90 DEG C, is cooled to room temperature, adds saturated sodium carbonate regulation PH=10, is extracted with ethyl acetate, closes
And organic layer being dried with anhydrous sodium sulfate, concentrated solvent, cross column purification with silica gel and obtain compound 9 (210mg, yield
77%), mass spectrum: 281 (M+H+)。
(7) synthesis of cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethanol (compound 10)
In single port bottle add 1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethyl ketone (140mg,
0.5mmol) with methanol (3ml), at 0 DEG C, add sodium borohydride (57mg, 1.5mmol), stir 1h, be spin-dried for solvent, add 2N
Hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent, crossing column purification with silica gel
Obtain compound 10 (105mg, yield 73%, LCMS purity 99.0%),1H NMR(DMSO-d6, 400MHz): δ (ppm) 1.10-
1.37(m,6H),1.66-1.80(m,5H),2.05(m,2H),2.15(m,1H),3.72(m,1H),5.36-5.46(m,1H),
7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 7.80
(s,1H)；Mass spectrum: 283 (M+H+)。
Embodiment 2 1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethanol (compound 15
(D1) synthesis)
(1) synthesis of the deuterated-1H-imidazoles of the bromo-1,2,5-of 4-tri-(intermediate 11)
Under room temperature, palladium carbon (2g, 10%Pd) stirs one hour in hydrogen, then will be dissolved in pure heavy water (50g,
4-bromine imidazoles (10g, 69mmol) 2.5mol) adds, and after dehydrogenation gas, stirs 1h at 100 DEG C, and reacting liquid filtering removes and urges
Agent, is spin-dried for solvent and obtains compound 11 (9.2g, yield 91%), mass spectrum: 151 (M+H+)。
(2) 4-bromo-1-trityl-2,5, the synthesis of-two deuterated-1H-imidazoles (intermediate 12)
Bromo-1,2, the 5-tri-deuterated-1H-imidazoles (30g, 205mmol) of 4-, dichloromethane: tetrahydrochysene furan is added in single port bottle
Mutter=1:1, and triphenylchloromethane (62g, 226mmol), is stirred at room temperature lower addition triethylamine (29ml), continues stirring
1h, adds water and 1N hydrochloric acid, adds dichloromethane extraction, merges organic layer and be dried with anhydrous sodium sulfate, being spin-dried for dichloromethane
Alkane obtains compound 12 (61g, yield 72%).
(3) synthesis of 2-(1-trityl-2,5-bis-deuterated-1H-imidazoles-4-) benzaldehyde (intermediate 13)
4-bromo-1-trityl-2,5 ,-two deuterated-1H-imidazoles (1.5g, 3.9mmol), carbonic acid is added in single port bottle
Sodium (1.2g, 11.7mmol), 2-formylphenylboronic acid (864mg, 5.8mmol) and DMF (10ml), water (2ml), make reaction system
It is full of nitrogen, adds tetrakis triphenylphosphine palladium (242mg, 0.195mmol), under nitrogen protection, 90 DEG C of stirring 16h, add water,
Ethyl acetate extracts, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent, crossing column purification with silica gel and obtain compound 13
(930mg, yield 58%).
(4) conjunction of 1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethyl ketone (intermediate 14)
Become
In there-necked flask add 2-(1-trityl-2,5-bis-deuterated-1H-imidazoles-4-) benzaldehyde (400mg,
0.97mmol), acetyl cyclohexane (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by ethanol
The ethanol solution of sodium (85mg, 1.25mmol) at room temperature adds, and is stirred at room temperature 3h, is spin-dried for solvent, adds saturated chlorination
Ammonium (10ml), is extracted with ethyl acetate, and merges organic layer and is also dried with anhydrous sodium sulfate, is spin-dried for solvent, add acetic acid (1ml) and
Ethanol (5ml), stirs 3h at 90 DEG C, is cooled to room temperature, adds saturated sodium carbonate regulation PH=10, is extracted with ethyl acetate,
Merge organic layer and be dried with anhydrous sodium sulfate, concentrated solvent, crossing column purification with silica gel and obtain compound 14 (210mg, yield
77%), mass spectrum: 283 (M+H+)。
(5) conjunction of 1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethanol (compound 15)
Become
1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethyl ketone is added in single port bottle
(140mg, 0.5mmol) and methanol (3ml), add sodium borohydride (57mg, 1.5mmol) at 0 DEG C, stir 1h, be spin-dried for solvent,
Add 2N hydrochloric acid (3ml), be extracted with ethyl acetate, merge organic layer and be dried with anhydrous sodium sulfate, concentrated solvent, using silica gel mistake
Column purification obtains compound 15 (105mg, yield 78%, LCMS purity 99.4%),1H NMR(DMSO-d6, 400MHz): δ
(ppm)1.10-1.37(m,6H),1.66-1.80(m,5H),2.05(m,2H),2.15(m,1H),3.72(m,1H),5.36-
5.46 (m, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz)；Matter
Spectrum:
285(M+H+)。
The embodiment 3 1-deuterated-2-of cyclohexyl-1-(5H-imidazo [5,1-a] iso-indoles-5-) ethanol (compound 16
(D5) synthesis)
In single port bottle add 1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethyl ketone (140mg,
0.5mmol) with deuterated methanol (5ml), at 0 DEG C, add boron deuterate sodium (57mg, 1.5mmol), stir 24h under room temperature, be spin-dried for
Solvent, adds 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent, uses
Silica gel is crossed column purification and is obtained compound 16 (105mg, yield 69%, LCMS purity 99.3%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz),7.80(s,1H)；Mass spectrum: 284 (M+H+)。
The embodiment 4 1-deuterated-2-of cyclohexyl-1-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethanol
(compound 17 (D15))
1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethyl ketone is added in single port bottle
(140mg, 0.5mmol) and deuterated methanol (5ml), add boron deuterate sodium (57mg, 1.5mmol) at 0 DEG C, stir under room temperature
24h, is spin-dried for solvent, adds 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate, concentrates
Solvent, crosses column purification with silica gel and obtains compound 17 (105mg, yield 78%, LCMS purity 99.7%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz)；Mass spectrum: 286
(M+H+)。
The embodiment 5 1-deuterated-2-of cyclohexyl-1-(5H-imidazo [5,1-a]-8,9,10,11-tetra-deuterated iso-indoles-
5-) ethanol (compound 20 (D25))
(1) synthesis of 2-(1-trityl-1H-imidazoles-4-)-3,4,5,6-tetra-deuterated benzaldehydes (intermediate 18)
Addition 4-bromo-1-trityl-1H-imidazoles (1.5g, 3.9mmol) in single port bottle, sodium carbonate (1.2g,
11.7mmol), 3,4,5,6-tetra-deuterated adjacent formylphenylboronic acid (864mg, 5.8mmol) and DMF (10ml), water (2ml), make anti-
Answer system to be full of nitrogen, add tetrakis triphenylphosphine palladium (242mg, 0.195mmol), under nitrogen protection, 90 DEG C of stirring 16h,
Adding water, ethyl acetate extracts, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent, crossing column purification with silica gel and obtain
Compound 18 (930mg, yield 58%).
(2) 1-cyclohexyl-2-(the deuterated iso-indoles-5-of 5H-imidazo [5,1-a] 8,9,10,11-tetra-) ethyl ketone (intermediate
19) synthesis
In there-necked flask add 2-(1-trityl-1H-imidazoles-4-)-3,4,5,6-tetra-deuterated benzaldehydes (400mg,
0.97mmol), acetyl cyclohexane (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by ethanol
The ethanol solution of sodium (85mg, 1.25mmol) at room temperature adds, and is stirred at room temperature 3h, is spin-dried for solvent, adds saturated chlorination
Ammonium (10ml), is extracted with ethyl acetate, and merges organic layer and is also dried with anhydrous sodium sulfate, is spin-dried for solvent, add acetic acid (1ml) and
Ethanol (5ml), stirs 3h at 90 DEG C, is cooled to room temperature, adds saturated sodium carbonate regulation PH=10, is extracted with ethyl acetate,
Merge organic layer and be dried with anhydrous sodium sulfate, concentrated solvent, crossing column purification with silica gel and obtain compound 19 (210mg, yield
77%), mass spectrum: 285 (M+H+)。
(3) synthesis of cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethanol (compound 20)
1-cyclohexyl-2-(the deuterated iso-indoles-5-of 5H-imidazo [5,1-a] 8,9,10,11-tetra-) is added in single port bottle
Ethyl ketone (140mg, 0.5mmol) and deuterated methanol (5ml), add boron deuterate sodium (57mg, 1.5mmol) at 0 DEG C, stir under room temperature
Mix 24h, be spin-dried for solvent, add 2N hydrochloric acid (3ml), be extracted with ethyl acetate, merge organic layer and be dried with anhydrous sodium sulfate, dense
Contracting solvent, crosses column purification with silica gel and obtains compound 20 (105mg, yield 72%, LCMS purity 99.5%),1H NMR(DMSO-
d6, 400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 3.72 (m, 1H), 5.36-
5.46(m,1H),7.16(s,1H),7.80(s,1H)；Mass spectrum: 288 (M+H+)。
Embodiment 6 1-(the deuterated cyclohexyl of 1-)-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethanol (compound 24
(D6) synthesis)
(1) synthesis of the deuterated hexamethylene of acetyl group 1-(intermediate 22)
In the single port bottle of 100ml, add cyclohexanecarboxylic acid (5g, 39mmol) and dichloromethane (20ml), stir under room temperature
Under instill thionyl chloride (5.67ml, 78mmol) lentamente, react 5h, concentrated solvent.By dimethyl azanol hydrochloride (4.5g,
47mmol) mixed liquor of dichloromethane (10ml) and triethylamine (13ml, 96mmol) instills wherein lentamente, stirs under room temperature
3h, filters off solid, instills 1N hydrochloric acid and remove the triethylamine of excess in liquid, and ethyl acetate extracts, and merges organic layer, with anhydrous
Sodium sulfate is dried, and is spin-dried for solvent and obtains crude product 2 (5.3g).Crude product 2 (4g, 23mmol), potassium carbonate is added in there-necked flask
Stirring 48h at (9.5g, 69mmol) and 80 DEG C of heavy water (5ml), ethyl acetate extracts, and merges organic layer anhydrous sodium sulfate and is dried,
It is spin-dried for solvent and obtains crude product 23 (5g), there-necked flask adds crude Compound 23 (5g, 29mmol), oxolane (15ml), temperature
Degree controls, at 0 DEG C, to add under nitrogen protection, is slowly added to methyl-magnesium-bromide (10ml, 29mmol), stirs 2h, add at 0 DEG C
Enter ammonium chloride cancellation methyl-magnesium-bromide, add dichloromethane extraction, merge organic layer and be dried with anhydrous sodium sulfate, being spin-dried for dichloro
Methane obtains compound 22 (4.2g, yield 85%)
(2) synthesis of 1-(the deuterated cyclohexyl of 1-)-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethyl ketone (intermediate 23)
2-(1-trityl-1H-imidazoles-4-) benzaldehyde (400mg, 0.97mmol), acetyl group is added in there-necked flask
The deuterated hexamethylene of 1-(122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by Sodium ethylate (85mg,
Ethanol solution 1.25mmol) at room temperature adds, and is stirred at room temperature 3h, is spin-dried for solvent, adds saturated ammonium chloride (10ml),
It is extracted with ethyl acetate, merges organic layer and be dried with anhydrous sodium sulfate, be spin-dried for solvent, add acetic acid (1ml) and ethanol
(5ml), at 90 DEG C, stir 3h, be cooled to room temperature, add saturated sodium carbonate regulation PH=10, be extracted with ethyl acetate, merge
Organic layer is also dried with anhydrous sodium sulfate, concentrated solvent, crosses column purification with silica gel and obtains compound 23 (210mg, yield 77%),
Mass spectrum: 282 (M+H+)。
(3) synthesis of 1-(the deuterated cyclohexyl of 1-)-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethanol (compound 24)
1-(the deuterated cyclohexyl of 1-)-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethyl ketone is added in single port bottle
(140mg, 0.5mmol) and methanol (3ml), add sodium borohydride (57mg, 1.5mmol) at 0 DEG C, stir 1h, be spin-dried for solvent,
Add 2N hydrochloric acid (3ml), be extracted with ethyl acetate, merge organic layer and be dried with anhydrous sodium sulfate, concentrated solvent, using silica gel mistake
Column purification obtains compound 24 (105mg, yield 72%, LCMS purity 99.6%),1H NMR(DMSO-d6, 400MHz): δ
(ppm)1.10-1.37(m,6H),1.66-1.80(m,4H),2.05(m,2H),2.15(m,1H),3.72(m,1H),5.36-
5.46 (m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz),7.80(s,1H)；Mass spectrum: 284 (M+H+)。
Embodiment 7 1-(the deuterated cyclohexyl of the 1-) deuterated-2-of-1-(5H-imidazo [5,1-a] iso-indoles-5-) ethanol (is changed
Compound 25 (D56))
1-(the deuterated cyclohexyl of 1-)-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethyl ketone is added in single port bottle
(140mg, 0.5mmol) and deuterated methanol (5ml), add boron deuterate sodium (57mg, 1.5mmol) at 0 DEG C, stir under room temperature
24h, is spin-dried for solvent, adds 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate, concentrates
Solvent, crosses column purification with silica gel and obtains compound 25 (105mg, yield 78%, LCMS purity 99.1%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 4H), 2.05 (m, 2H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz),7.80(s,1H)；Mass spectrum: 285 (M+H+)。
Embodiment 8 1-(the deuterated cyclohexyl of 1-)-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethanol
(compound 27 (D16))
(1) 1-(the deuterated cyclohexyl of 1-)-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethyl ketone is (middle
Body 26) synthesis
In there-necked flask add 2-(1-trityl-2,5-bis-deuterated-1H-imidazoles-4-) benzaldehyde (400mg,
0.97mmol), the deuterated hexamethylene of acetyl group 1-(122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection,
The ethanol solution of Sodium ethylate (85mg, 1.25mmol) is at room temperature added, is stirred at room temperature 3h, be spin-dried for solvent, add full
With ammonium chloride (10ml), it is extracted with ethyl acetate, merges organic layer and be dried with anhydrous sodium sulfate, be spin-dried for solvent, add acetic acid
(1ml) with ethanol (5ml), at 90 DEG C, stir 3h, be cooled to room temperature, add saturated sodium carbonate regulation PH=10, use acetic acid second
Ester extracts, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent, crossing column purification with silica gel and obtain compound 26
(210mg, yield 77%), mass spectrum: 284 (M+H+)。
(2) 1-(the deuterated cyclohexyl of 1-)-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethanol (chemical combination
Thing 27) synthesis
In single port bottle add 1-(the deuterated cyclohexyl of 1-)-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-
5-) ethyl ketone (140mg, 0.5mmol) and methanol (3ml), adds sodium borohydride (57mg, 1.5mmol) at 0 DEG C, stirs 1h, rotation
Dry solvent, adds 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent,
Cross column purification with silica gel and obtain compound 27 (105mg, yield 68%, LCMS purity 99.9%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 4H), 2.05 (m, 2H), 2.15 (m, 1H), 3.72 (m,
1H), 5.36-5.46 (m, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz)；Mass spectrum: 286 (M+H+)。
Embodiment 9 1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-)-2,2-two deuterated ethanol (compound
29(D4))
(1) 1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-)-2, the deuterated ethyl ketone of 2-bis-(intermediate 28)
Synthesis
In there-necked flask add 1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethyl ketone (140mg,
0.5mmol), potassium carbonate (207mg, 1.5mmol) and heavy water (5ml), stir 48h, be extracted with ethyl acetate, anhydrous sulfur at 80 DEG C
Acid sodium is dried, and is spin-dried for solvent and obtains compound 28 (130mg, yield 92%), mass spectrum: 283 (M+H+)。
(2) 1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-)-2, the deuterated ethanol of 2-bis-(compound 29)
Synthesis
1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-) the deuterated ethyl ketone of-2,2-two is added in single port bottle
(140mg, 0.5mmol) and methanol (3ml), add sodium borohydride (57mg, 1.5mmol) at 0 DEG C, stir 1h, be spin-dried for solvent,
Add 2N hydrochloric acid (3ml), be extracted with ethyl acetate, merge organic layer and be dried with anhydrous sodium sulfate, concentrated solvent, using silica gel mistake
Column purification obtains compound 29 (105mg, yield 71%, LCMS purity 99.7%),1H NMR(DMSO-d6, 400MHz): δ
(ppm)1.10-1.37(m,6H),1.66-1.80(m,5H),2.15(m,1H),3.72(m,1H),5.36-5.46(m,1H),
7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 7.80
(s,1H)；Mass spectrum: 285 (M+H+)。
The embodiment 10 1-deuterated-2-of cyclohexyl-1-(5H-imidazo [5,1-a] iso-indoles-5-) the deuterated ethanol of-2,2-two
(compound 30 (D45))
1-cyclohexyl-2-(5H-imidazo [5,1-a] iso-indoles-5-)-2, the deuterated ethyl ketone of 2-bis-is added in single port bottle
(140mg, 0.5mmol) and deuterated methanol (5ml), add boron deuterate sodium (57mg, 1.5mmol) at 0 DEG C, stir under room temperature
24h, is spin-dried for solvent, adds 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate, concentrates
Solvent, crosses column purification with silica gel and obtains compound 30 (105mg, yield 80%, LCMS purity 99.2%),1H NMR(DMSO-
D6,400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 3.72 (m, 1H), 5.36-5.46 (m, 1H),
7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 7.80
(s,1H)；Mass spectrum: 285 (M+H+)。
Embodiment 11 1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-)-2,2-two is deuterated
Ethanol (compound 32 (D14))
(1) 1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-)-2,2 two deuterated ethyl ketones (in
Mesosome 31) synthesis
1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-) ethyl ketone is added in there-necked flask
(140mg, 0.5mmol), potassium carbonate (207mg, 1.5mmol) and heavy water (5ml), stir 48h, extract by ethyl acetate at 80 DEG C
Taking, anhydrous sodium sulfate is dried, and is spin-dried for solvent and obtains compound 31 (130mg, yield 92%), mass spectrum: 285 (M+H+)。
(2) 1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-)-2,2 two deuterated ethanol (are changed
Compound 32) synthesis
1-cyclohexyl-2-(5H-7,8-bis-deuterated imidazo [5,1-a] iso-indoles-5-)-2,2-two is added in single port bottle
Deuterated ethyl ketone (140mg, 0.5mmol) and methanol (3ml), add sodium borohydride (57mg, 1.5mmol) at 0 DEG C, stirs 1h, rotation
Dry solvent, adds 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent, uses
Silica gel is crossed column purification and is obtained compound 32 (105mg, yield 75%, LCMS purity 99.4%),1H NMR(DMSO-d6, 400MHz): δ
(ppm)1.10-1.37(m,6H),1.66-1.80(m,5H),2.15(m,1H),3.72(m,1H),5.36-5.46(m,1H),7.25
(m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz)；Mass spectrum: 287 (M+H+)。
Embodiment 12 1-(the deuterated cyclohexyl of the 1-) deuterated-2-of-1-(5H-imidazo [5,1-a] iso-indoles-5-)-2,2-two
Deuterated ethanol (compound 34 (D456))
(1) 1-(the deuterated cyclohexyl of 1-)-2-(5H-imidazo [5,1-a] iso-indoles-5-)-2, the deuterated ethyl ketone of 2-bis-is (middle
Body 33) synthesis
1-(the deuterated cyclohexyl of 1-)-2-(5H-imidazo [5,1-a] iso-indoles-5-) ethyl ketone is added in there-necked flask
(140mg, 0.5mmol), potassium carbonate (207mg, 1.5mmol) and heavy water (5ml), stir 48h, extract by ethyl acetate at 80 DEG C
Taking, anhydrous sodium sulfate is dried, and is spin-dried for solvent and obtains compound 33 (130mg, yield 92%), mass spectrum: 284 (M+H+)。
(2) 1-(the deuterated cyclohexyl of the 1-) deuterated-2-of-1-(5H-imidazo [5,1-a] iso-indoles-5-) the deuterated second of-2,2-two
Alcohol (compound 34)
1-(the deuterated cyclohexyl of 1-)-2-(5H-imidazo [5,1-a] iso-indoles-5-)-2,2-bis-deuterium is added in single port bottle
For ethyl ketone (140mg, 0.5mmol) and deuterated methanol (5ml), at 0 DEG C, add boron deuterate sodium (57mg, 1.5mmol), under room temperature
Stirring 24h, is spin-dried for solvent, adds 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate,
Concentrated solvent, crosses column purification with silica gel and obtains compound 34 (105mg, yield 70%, LCMS purity 99.8%),1H NMR
(DMSO-d6, 400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 4H), 3.72 (m, 1H), 5.36-5.46
(m, 1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=
7.6Hz),7.80(s,1H)；Mass spectrum: 287 (M+H+)。
Embodiment 13 1-cyclohexyl-2-(5H-imidazo [5,1-a]-6-deuterated iso-indoles-5-) ethanol (compound 37 (D3))
(1) synthesis of 2-(1-trityl-1H-imidazoles-4-) deuterated benzaldehyde (intermediate 35)
Addition 4-bromo-1-trityl-1H-imidazoles (1.5g, 3.9mmol) in single port bottle, sodium carbonate (1.2g,
11.7mmol), the deuterated phenylboric acid of the deuterated formoxyl of 2-(864mg, 5.8mmol) and DMF (10ml), water (2ml), make reaction system
It is full of nitrogen, adds tetrakis triphenylphosphine palladium (242mg, 0.195mmol), under nitrogen protection, 90 DEG C of stirring 16h, add
Water, ethyl acetate extracts, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent, crossing column purification with silica gel and obtain chemical combination
Thing 35 (930mg, yield 58%), mass spectrum: 415 (M+H+)。
(2) synthesis of 1-cyclohexyl-2-(5H-imidazo [5,1-a]-6-deuterated iso-indoles-5-) ethyl ketone (intermediate 36)
2-(1-trityl-1H-imidazoles-4-) deuterated benzaldehyde (400mg, 0.97mmol), 1-is added in there-necked flask
Acetyl cyclohexane (122mg, 0.97mmol) and anhydrous tetrahydro furan (5ml), under nitrogen protection, by Sodium ethylate (85mg,
Ethanol solution 1.25mmol) at room temperature adds, and is stirred at room temperature 3h, is spin-dried for solvent, adds saturated ammonium chloride (10ml),
It is extracted with ethyl acetate, merges organic layer and be dried with anhydrous sodium sulfate, be spin-dried for solvent, add acetic acid (1ml) and ethanol
(5ml), at 90 DEG C, stir 3h, be cooled to room temperature, add saturated sodium carbonate regulation PH=10, be extracted with ethyl acetate, merge
Organic layer is also dried with anhydrous sodium sulfate, concentrated solvent, crosses column purification with silica gel and obtains compound 36 (210mg, yield 77%),
Mass spectrum: 283 (M+H+)。
(3) synthesis of 1-cyclohexyl-2-(5H-imidazo [5,1-a]-6-deuterated iso-indoles-5-) ethanol (compound 37)
1-cyclohexyl-2-(5H-imidazo [5,1-a]-6-deuterated iso-indoles-5-) ethyl ketone is added in there-necked flask
(140mg, 0.5mmol), methanol (5ml), at 0 DEG C, add sodium borohydride (57mg, 1.5mmol), under room temperature, stir 24h, rotation
Dry solvent, adds 2N hydrochloric acid (3ml), is extracted with ethyl acetate, and merges organic layer and is dried with anhydrous sodium sulfate, concentrated solvent,
Cross column purification with silica gel and obtain compound 37 (105mg, yield 82%, LCMS purity 99.3%),1H NMR(DMSO-d6,
400MHz): δ (ppm) 1.10-1.37 (m, 6H), 1.66-1.80 (m, 5H), 2.05 (m, 2H), 2.15 (m, 1H), 3.72 (m,
1H), 7.16 (s, 1H), 7.25 (m, 1H), 7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz),
7.80(s,1H)；Mass spectrum: 284 (M+H+)。
The embodiment 14 1-deuterated-2-of cyclohexyl-1-(5H-imidazo [5,1-a]-6-deuterated iso-indoles-5-) ethanol (is changed
Compound 3 (D35) 8)
In there-necked flask add 1-cyclohexyl-2-(5H-imidazo [5,1-a]-6-deuterated iso-indoles-5-) ethyl ketone (140mg,
0.5mmol), methanol (5ml), at 0 DEG C, add sodium borohydride (57mg, 1.5mmol), stir 24h under room temperature, be spin-dried for solvent, add
Enter 2N hydrochloric acid (3ml), be extracted with ethyl acetate, merge organic layer and be dried with anhydrous sodium sulfate, concentrated solvent, crossing post with silica gel
Purification obtains compound 37 (105mg, yield 79%, LCMS purity 99.2%),1H NMR(DMSO-d6, 400MHz): δ (ppm)
1.10-1.37(m,6H),1.66-1.80(m,5H),2.05(m,2H),3.72(m,1H),7.16(s,1H),7.25(m,1H),
7.34 (m, 1H), 7.43 (d, 1H, J=7.6Hz), 7.54 (d, 1H, J=7.6Hz), 7.80 (s, 1H)；Mass spectrum: 284 (M+H+)。
The test of pesticide effectiveness of embodiment 15 the compounds of this invention
The test of IDO inhibiting compound is carried out: the IC of each compound by IDO enzyme test50By at PH=6.5
In 50mM kaliumphosphate buffer, the activity to IDO is tested.Mankind's IDO albumen of 70nM purification, 200 μMs of L-Trps,
20mM Ascorbate, 20 μMs of methylene blue, 0.1%DMSO.Inhibitor first dilutes in the DMSO of 100mM, then the phosphorus at 50mM
Diluting in acid potassium, last solubility joins in reactant liquor between 1mM to 5nM, with enzyme preculture 5 minutes at 25 DEG C.Reaction
Add L-Trp reach 200 μMs then at 60 DEG C cultivate 30min N-formoxyl kynurenin is hydrolyzed to kynurenin.Instead
Should be centrifuged under 3400g 5 minutes and remove protein precipitation, the supernatant is anti-to dimethylamine benzaldehyde with 2% (w/v) in acetic acid
Should.10min is cultivated in reaction at 25 DEG C, reads 480nm in spectrophotometer.Control sample with there is no IDO inhibitor, or
There is no IDO enzyme, or used as control group with reference to inhibitor 1-methyl tryptophan (200 μMs) and menadione (1.2 μMs)
In to it needs to be determined that the IC of each compound50Nonlinear regression parameter is set.Nonlinear regression and IC50It is to pass through
GraphPad Prism 4 software determines.Result is as shown in table 1 below.
Table 1
The medicine generation test of embodiment 16 the compounds of this invention
(1) pharmacokinetic parameter of compound 10,16,37,38
Compound 10 after gavage gives 25mg/kg compound 10,16,37,38 respectively in detection SD rat plasma, 16,37,
The concentration of 38 is also drawn Drug-time curve and is calculated the pharmacokinetic parameter of this medicine.
Experiment uses healthy male SD rat, body weight 180-220g, animal center tested by the medicine of Shanghai provide, and uses
Credit number SYXK (river) 2011-178.Feeding environment room temperature controls at 16-26 DEG C.Relative humidity 40-70%, artificial lighting,
12 hours light and shades alternately, raise to the north of the feedstuff of capital Hu Kang Experimental Animal Center particular formulation, freely drink water.Animal subject is in reality
Test and carry out adaptability raising in experiment place day the last week.
Laboratory animal carries out euthanasia process according to SOP after sample collecting terminates.
Laboratory animal packet and dosage regimen:
According to experiment purpose and the requirement of experimental design, gavage gives 25mg/kg compound 10,16,37,38 respectively, is administered
Volume is 25ml/kg, and administration concentration is 1mg/kg.SD rat 16, male, it is randomly divided into 4 groups, often group 4, gavage is given respectively
Give tested compound.Fasting 12h before test, freely drinks water, the unified feed of 2h after administration.Unified feed after being administered 2h.
Weigh the desired amount of test sample in 10ml import centrifuge tube (BD), add while stirring after high temperature sterilize
0.5%HPMC (hydroxymethyl cellulose) aqueous solution, to desired concn, is formulated as suspensoid, mixing before being administered.In be administered after 0.25,
Within 0.5,1.0,2.0,3.0,4.0,6.0,8.0 and 24 hour, gather sample.Blood 0.3ml is taken through rat eye rear vein beard.Blood sample
Process with heparin sodium anticoagulant, separated plasma (lucifuge) about 200 μ L after 3500rpm is centrifuged 10 minutes in 4 DEG C of centrifuges.Freezing guarantor
It is stored in-80 DEG C of refrigerators to be detected.
Pharmacokinetic parameter DAS2.1 software is analyzed, and selects non-compartment model to calculate pharmacokinetic parameters.Use
Each time point blood drug level meansigma methods calculates.Reach peak concentration CmaxWith peak time TmaxFor measured value；Below Drug-time curve
Long-pending AUC0-tValue: use trapezoidal method to calculate；AUC0-∞=AUC0-t+Ct/ke, CtThe blood medicine that can record time point for last is dense
Degree, keFor elimination rate constant；Eliminate half-life t1/2=0.693/ke.Result is as shown in table 2 below.
PK data during table 2 rat oral gavage 25mg/kg
| Compound | Cmax(ng/ml) | AUC0-t(ng*h/ml) | AUC0-∞(ng*h/ml) | T1/2(h) |
| 10 | 6512 | 7954 | 8063 | 1.2 |
| 16 | 6353 | 13657 | 14543 | 1.9 |
| 37 | 6406 | 9651 | 10075 | 1.8 |
| 38 | 6309 | 14142 | 15895 | 2.6 |
(2) compound 10,16,37,38 metabolism in rat plasma
Rat plasma sample in above-mentioned pharmacokinetic studies is temporally put equal-volume respectively merge, it is thus achieved that each time
Point (0h, 9h and 48h) merges plasma sample.Take merging blood plasma 100 μ L, add 300 μ L acetonitriles, eddy current 1min, be centrifuged
(14000rpm) 5min, takes 40 DEG C of nitrogen streams of whole supernatant and dries up, and adds 100 μ L acetonitrile/water (1:1, v/v) and dissolves, centrifugal
5min (14000rpm), takes 7.0 μ L and carries out UPLC-UV/Q-TOFMS analysis.Record the content of each metabolite.Result such as table 3 below
Shown in.
Table 3 rat plasma metabolite
| Compound | Former medicine | Isomerization metabolite | Oxidative metabolites | Dehydrogenation metabolite |
| 10 | 52 | 15.8 | 2.5 | 27.5 |
| 16 | 71.1 | 9.8 | 2.6 | 16.5 |
| 37 | 63 | 10.2 | 2.1 | 24.7 |
| 38 | 81.4 | 2.7 | 2.8 | 13.1 |
Result of the test shows, the compound of the present invention has significant inhibitory action to IDO, and effect is with NLG919 the most very
To more excellent.Further pharmacokinetic trial also shows, compared with NLG919, the compounds of this invention is in drug effect the most even more
In the case of height, also there is more preferable pharmacokinetic property, there is wide market prospect.
Claims (10)
- Compound the most as follows or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate:R1-R21It is respectively selected from H or D；And, R1-R21In at least one is D.
- Compound the most according to claim 1 or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate, its It is characterised by:R1And R2It is H or simultaneously for D simultaneously；And, R3-R6It is H or simultaneously for D simultaneously；And, R7For H or D；And, R8And R9It is H or simultaneously for D simultaneously；And, R10For H or D；And, R11For H or D；And, R12-R21It is H simultaneously；And, R1-R21In at least one is D.
- Compound the most according to claim 1 and 2 or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate, It is characterized in that:R1And R2It is D simultaneously, and R3-R21In at least one is D；Or, R1-R6It is H simultaneously, and R7-R11In at least one is D；Or, R1And R2It is H simultaneously, and R3-R6It is D, R simultaneously7-R21In at least one is D；Or, R1-R7It is H simultaneously, and R8-R11In at least one is D.
- 4. according to the compound described in any one of claim 1-3 or its crystal formation, pharmaceutically acceptable salt, hydrate or solvent Compound, it is characterised in that: R7Or/and R10For D.
- Compound the most according to claim 1 or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate, its It is characterised by: described compound is one of following compound:
- 6. prepare compound described in any one of claim 1-5 or its crystal formation, pharmaceutically acceptable salt, hydrate or molten for one kind The method of agent compound, comprises the following steps:With the compound shown in formula II as raw material, obtain compound shown in formula I through carbonyl reduction.
- 7. compound described in any one of claim 1-5 or its crystal formation, pharmaceutically acceptable salt, hydrate or solvate In preparation purposes in treatment with IDO relevant disease medicine.
- Purposes the most according to claim 7, it is characterised in that: described compound or its crystal formation, pharmaceutically acceptable Salt, hydrate or solvate are IDO inhibitor.
- 9. according to the purposes described in claim 7 or 8, it is characterised in that: described IDO relevant disease includes that cancer, virus are sexy Dye, depression, neurodegenerative diseases, wound, age-related cataract, organ transplant rejection, autoimmunity Disease.
- 10. a pharmaceutical composition, it is characterised in that: it is with the compound described in claim 1-5 any one or its crystalline substance Type, pharmaceutically acceptable salt, hydrate or solvate are active component, add pharmaceutically acceptable adjuvant or/and assist The preparation that property composition is prepared from.
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| CN109384791A (en) * | 2017-08-09 | 2019-02-26 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of imidazo isoindoles derivative free alkali |
| WO2019042451A1 (en) * | 2017-09-01 | 2019-03-07 | 南京药捷安康生物科技有限公司 | Deuterated indoleamine 2,3-dioxygenase inhibitor and application thereof |
| CN115215803A (en) * | 2022-09-19 | 2022-10-21 | 苏州美诺医药科技有限公司 | Preparation method of 4-halogenated-1- (difluoromethyl) -1H-imidazole |
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| CN105037371A (en) * | 2015-06-30 | 2015-11-11 | 西华大学 | Deuterated indoleamine-2,3-dioxygenase inhibitor |
| CN109384791A (en) * | 2017-08-09 | 2019-02-26 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of imidazo isoindoles derivative free alkali |
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| CN115215803A (en) * | 2022-09-19 | 2022-10-21 | 苏州美诺医药科技有限公司 | Preparation method of 4-halogenated-1- (difluoromethyl) -1H-imidazole |
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