CN108558760A - A kind of aromatic amides and its preparation method and application - Google Patents
A kind of aromatic amides and its preparation method and application Download PDFInfo
- Publication number
- CN108558760A CN108558760A CN201810529542.6A CN201810529542A CN108558760A CN 108558760 A CN108558760 A CN 108558760A CN 201810529542 A CN201810529542 A CN 201810529542A CN 108558760 A CN108558760 A CN 108558760A
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- aromatic amides
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000008430 aromatic amides Chemical class 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 239000003098 androgen Substances 0.000 claims abstract description 33
- 201000010099 disease Diseases 0.000 claims abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 13
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 13
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 8
- 201000004384 Alopecia Diseases 0.000 claims abstract description 8
- 206010000496 acne Diseases 0.000 claims abstract description 8
- 231100000360 alopecia Toxicity 0.000 claims abstract description 8
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 7
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims abstract description 6
- 201000001531 bladder carcinoma Diseases 0.000 claims abstract description 6
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 73
- 150000003839 salts Chemical class 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 19
- -1 cyano, nitro, amino Chemical group 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 230000024053 secondary metabolic process Effects 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 239000000651 prodrug Substances 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 6
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 150000001263 acyl chlorides Chemical group 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
- 230000036571 hydration Effects 0.000 claims 1
- 238000006703 hydration reaction Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 20
- 102100032187 Androgen receptor Human genes 0.000 abstract description 19
- 108010080146 androgen receptors Proteins 0.000 abstract description 19
- 238000011282 treatment Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 11
- 230000000593 degrading effect Effects 0.000 abstract description 3
- 108010038795 estrogen receptors Proteins 0.000 abstract description 3
- 102100038595 Estrogen receptor Human genes 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 50
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Substances [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 29
- 238000001819 mass spectrum Methods 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
- 238000001228 spectrum Methods 0.000 description 25
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- 239000012071 phase Substances 0.000 description 21
- 229910052786 argon Inorganic materials 0.000 description 20
- 239000007789 gas Substances 0.000 description 20
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 19
- 238000005191 phase separation Methods 0.000 description 19
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 19
- 229940080818 propionamide Drugs 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- 150000001721 carbon Chemical group 0.000 description 17
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
- 239000002994 raw material Substances 0.000 description 15
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 10
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000002280 anti-androgenic effect Effects 0.000 description 8
- 239000000051 antiandrogen Substances 0.000 description 8
- 229960002074 flutamide Drugs 0.000 description 8
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- 229960003473 androstanolone Drugs 0.000 description 7
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 7
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 5
- 229960000997 bicalutamide Drugs 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 210000002307 prostate Anatomy 0.000 description 5
- 229960003604 testosterone Drugs 0.000 description 5
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 5
- PYXNITNKYBLBMW-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole Chemical class FC(F)(F)C1=CC=NN1 PYXNITNKYBLBMW-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 4
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
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- 206010028980 Neoplasm Diseases 0.000 description 3
- 230000001548 androgenic effect Effects 0.000 description 3
- 229940030486 androgens Drugs 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
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- 238000009472 formulation Methods 0.000 description 3
- RYPKRALMXUUNKS-UHFFFAOYSA-N hex-2-ene Chemical compound CCCC=CC RYPKRALMXUUNKS-UHFFFAOYSA-N 0.000 description 3
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- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 235000015424 sodium Nutrition 0.000 description 3
- 230000003637 steroidlike Effects 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CZKLEJHVLCMVQR-UHFFFAOYSA-N 4-fluorobenzoyl chloride Chemical class FC1=CC=C(C(Cl)=O)C=C1 CZKLEJHVLCMVQR-UHFFFAOYSA-N 0.000 description 2
- ACSFOIGNUQUIGE-AIPUTVCKSA-N 5beta-dihydrocortisol Chemical compound C1C(=O)CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CC[C@@H]21 ACSFOIGNUQUIGE-AIPUTVCKSA-N 0.000 description 2
- 206010069921 Anti-androgen withdrawal syndrome Diseases 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
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- 229920002472 Starch Polymers 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
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- 239000012267 brine Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
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- 239000000890 drug combination Substances 0.000 description 2
- 238000009261 endocrine therapy Methods 0.000 description 2
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- 102000015694 estrogen receptors Human genes 0.000 description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
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- OGTLYUDOIVBATN-UHFFFAOYSA-N 1-bromopyrazole Chemical class BrN1C=CC=N1 OGTLYUDOIVBATN-UHFFFAOYSA-N 0.000 description 1
- RGEJKWOVQAWKGQ-UHFFFAOYSA-N 1-chloropyrazole Chemical class ClN1C=CC=N1 RGEJKWOVQAWKGQ-UHFFFAOYSA-N 0.000 description 1
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical class CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 1
- DBSMXZFYDNXILM-UHFFFAOYSA-N 1-methylpyrazole-3-carboxamide Chemical class CN1C=CC(C(N)=O)=N1 DBSMXZFYDNXILM-UHFFFAOYSA-N 0.000 description 1
- IBXNCJKFFQIKKY-UHFFFAOYSA-N 1-pentyne Chemical compound CCCC#C IBXNCJKFFQIKKY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to the application of aromatic amides and preparation method thereof shown in general formula I, the pharmaceutical composition containing the general formula I compounds represented and pharmaceutical preparation and the general formula I compounds represented in terms of the drug for preparing treatment and androgen relevant disease, R in general formula1、R2、R3、R4、R5、R6, the definition of X, Y, Q and n it is identical as in specification.The general formula I compounds represented can be combined with androgen receptor, had and resisted androgen and estrogen receptor activity of degrading.The compound can be individually or as composition for treating the various and relevant disease of androgen, such as prostate cancer, hyperplasia of prostate, breast cancer, carcinoma of urinary bladder, moreover it can be used to the treatment of the diseases such as acne, crinosity, alopecia.
Description
Technical field
The present invention relates to the application of a kind of aromatic amides and preparation method thereof as well as drug, the chemical combination
Object has the function of resistance androgen and androgen receptor of degrading, and can be used for prostate cancer, hyperplasia of prostate, breast cancer, wing
Guang cancer, acne, crinosity, alopecia etc. and the relevant disease treatment of androgen.
Background technology
Androgen receptor belongs to nuclear receptor family, is the receptor of the nuclear factor induced by ligand.Androgen receptor is
A kind of important cyclin, it is played an important role by endogenous androgens in a series of physiology course,
It develops and safeguards including male secondary sex characters, include the quality of muscle and bone, male's hair, the growth of prostate, sperm hair
It educates.Endogenous steroidal androgens are referred to as male sex hormone, including testosterone and dihydrotestosterone（DHT）.Testosterone is in male's blood
The main steroidal androgens found in clear, it is mainly by testicular secretion.In many peripheral tissues, such as prostate and skin,
Testosterone can be converted into the stronger androgen dihydrotestosterone of activity by 5α-reductase（DHT）.
Many diseases are related with androgen levels.With advancing age, internal androgen levels can be gradually reduced male,
Decline along with muscle reduction, osteoporosis, sexual function etc..On the contrary, androgen levels are excessively high in vivo can also cause some diseases,
Such as prostate cancer, hyperplasia of prostate, acne, crinosity, alopecia and the relevant disease of androgen.
Prostate cancer is hormonal dependent, thus the endocrine therapy of prostate cancer be use at most, be most ripe, and
Most effective means.Early in nineteen forty-one, Huggins and Hodges are found that operation castration, as operation cuts away bilateral testes to disappear
Except testosterone source and estrogen can delay the progress of metastatic prostate cancer, and confirm that prostate cancer removes androgen for the first time
The reactivity removed.But clinical research shows that the content of androgen in blood can be reduced by cutting away testis merely, but can not be big
The content for reducing androgen in prostata tissue of amplitude, because being in the presence of using the steroidal of acth secretion in prostata tissue
The enzyme system of Material synthesis androgen, and it is the stronger androgen dihydrotestosterone of activity that can convert androgenic testosterone.Therefore, even if
Castration therapy is taken, for prostate cancer, the treatment of antiandrogen drug is also necessary.
Androgen and androgen receptor on prostatic cell are blocked using antiandrogen drug (androgen antagonist) is competitive
The combination of body is the standard treatments of current treatment prostate cancer.Common Nonsteroic androgen acceptor antagonist has Flutamide
（Flutamide）, Bicalutamide（Bicalutumide）With the miscellaneous Shandong amine of grace（Enzalutamide, trade name：Xtandi）.
Flutamide（Flutamide）It is first generation Nonsteroic androgen acceptor antagonist（Endocrinology 1972,
91, 427–437；Biochemical Society Transactions 1979,7,565-569；Journal of
Steroid Biochemistry 1975,6,815-819）, 2 monohydroxy Flutamide of metabolite is its chief active shape
Formula can be combined in target tissue with androgen receptor, and dihydro cortisol is blocked to be combined with androgen receptor, inhibit target tissue intake
Cortisol, to play anti-androgenic effect.Because dose is larger, long-term use can cause gynecomasty, with tumour
And tenderness, and have nausea,vomiting,diarrhea, occur dermoreaction once in a while, it is denaturalized methemoglobinemia anaemia, leucocyte and blood platelet
It reduces.In addition, Flutamide is also easy to produce antiandrogen withdrawal syndrome in the treatment, a few patients have the problems such as hepatotoxicity wind agitation.
Bicalutamide（Bicalutumide）It is second generation Nonsteroic androgen acceptor antagonist（The Journal of
Endocrinology 1987,113, R7-R9；Urologic Clinics of North America 1991,18,
99–110）.This drug is a racemization isomers, and active constituent is laevoisomer.Bicalutamide, which removes, has antiandrogen
Effect is outer, and curative effect is higher than Flutamide, and side effect reduces 70%.It is similar with Flutamide, it can be in target tissue and androgen receptor
In conjunction with blocking dihydro cortisol is combined with androgen receptor, and target tissue is inhibited to absorb cortisol, is made to play antiandrogen
With.The disadvantage is that after certain middle position phase (general 18~24 months), nearly all patient finally can develop into hormone and support
Refractory prostate cancer.In addition, Bicalutamide also generates the problems such as antiandrogen withdrawal syndrome in the treatment.
The miscellaneous Shandong amine of grace（Enzalutamide, trade name：Xtandi）, it is third generation Nonsteroic androgen acceptor antagonist
（Archives of Pharmacal Research 2015,38 (11): 2076–82）, U.S. FDA should in approval in 2012
Medicine lists.It is stronger androgen receptor antagonist, new drug is added for endocrine therapy.The disadvantage is that it is expensive, and
Also Hormone refractory prostate cancer can be developed into.In addition, the miscellaneous Shandong amine of grace finds the side effect that patient can be caused to twitch in the treatment,
Therefore its application is subject to certain restrictions.
Therefore, the novel antiandrogen drug more safer and more effective than existing drug is developed in treatment and androgen relevant disease
Research in have important value and status.
Invention content
It is an object of the invention to find a kind of novel safely and effectively antiandrogen drug.
The present inventor is in depth studied to achieve the goals above, as a result, it has been found that：Fragrance with specific structure
Amides compound is more pacified with resistance androgenic activity and with degradable androgen receptor effect, compared with existing drug
It is complete effective, it has thus completed the present invention.
That is, the present invention provides aromatic amides or its pharmaceutically acceptable salt shown in following general formula I（Below also
Referred to as the compounds of this invention）, it is more safer and more effective than existing drug new there is resistance androgenic activity and with can drop
A kind of compound for solving androgen receptor effect can be used for treating and the relevant disease of androgen, such as prostate cancer, prostate increasing
Life, breast cancer, carcinoma of urinary bladder, acne, crinosity, alopecia etc..
Wherein R1And R2It is each independently hydrogen atom, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base,
Cyano, nitro, halogen or amino, the C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl and C3-6Naphthenic base optionally by
1 or more halogen atom substitution；
R3And R4It is each independently hydrogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl or C3-6Cycloalkanes
Base；
R5And R6It is each independently hydrogen atom, halogen, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkanes
Base, cyano, nitro, amino, C1-6Alkyl-carbonyl, hydroxyl C1-6Alkyl, C1-6Alkyl-NH-C (=O)-or aryl, the C1-6Alkane
Base, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base and aryl are optionally by selected from C1-6Alkyl, halogen, cyano, nitre
1 or more substituent group substitution in base；
X is carbon atom or nitrogen-atoms；With
Y and Q is each independently carbon atom, nitrogen-atoms, oxygen atom or sulphur atom；N is 2 or 3.
In the preferred embodiment of the present invention, R1And R2It is each independently hydrogen atom, optionally by 1 or more halogen
The C of plain atom substitution1-6Alkyl, cyano, nitro, halogen or amino, more preferable R1And R2Be each independently hydrogen atom, cyano,
Nitro, halogen or the C replaced by 1~3 halogen atom1-4Alkyl, wherein the C replaced by 1~3 halogen atom1-4Alkane
Base is preferably the C replaced by 1~3 fluorine atom1-4Alkyl, the methyl more preferably replaced by 1~3 fluorine atom, particularly preferably
It is trifluoromethyl.
In the preferred embodiment of the present invention, R3And R4It is each independently hydrogen atom, hydroxyl or C1-6Alkyl, it is more excellent
Select R3And R4It is each independently hydrogen atom, hydroxyl or C1-4Alkyl, particularly preferred R3And R4It is each independently hydroxyl or first
Base.
In the preferred embodiment of the present invention, R5And R6It is each independently hydrogen atom, halogen, optionally by 1 or more
Halogen atom substitution C1-6Alkyl, cyano, nitro, C1-4Alkyl-carbonyl, hydroxyl C1-4Alkyl, C1-4Alkyl-NH-C (=O)-or
Aryl；
It is preferred that R5And R6It is each independently hydrogen atom, halogen, the C replaced by 1~3 halogen atom1-4Alkyl, cyano, nitre
Base, C1-4Alkyl-carbonyl, 1- hydroxyethyls, N- methylcarbamoyls or aryl.It is wherein described to be replaced by 1~3 halogen atom
C1-4Alkyl is preferably the C replaced by 1~3 fluorine atom1-4Alkyl, the methyl more preferably replaced by 1~3 fluorine atom,
Particularly preferably trifluoromethyl, the C1-4Alkyl-carbonyl is preferably acetyl group.
In the preferred embodiment of the present invention, Y and Q are each independently carbon atom or nitrogen-atoms；It is preferred that Y and Q are
Carbon atom or nitrogen-atoms.
In the preferred embodiment of the present invention, aromatic amides of the invention have to be tied shown in following general formula II
Structure：
Wherein, R1、R2、R3、R4、R5、R6It is identical as above-mentioned definition respectively with the meaning of X.
In the preferred embodiment of the present invention, aromatic amides of the invention have shown in following general formula III
Structure：
Wherein, R1、R2、R3、R4、R5、R6It is identical as above-mentioned definition respectively with the meaning of X.
Have chiral atom in above-mentioned general formula I, II and III molecule, in the present invention the compounds of this invention can be raceme,
It is left-handed（R configurations）And/or dextrorotation（S configurations）.Therefore, the invention also includes aromatic amides shown in general formula I or its medicines
The stereoisomer of acceptable salt on, i.e. the left-handed of them, dextrorotation and/or raceme.
In the preferred embodiment of the present invention, general formula I compounds represented of the present invention are preferably following aromatic amides
Close object and its pharmaceutically acceptable salt：
。
The invention also includes aromatic amides, its pharmaceutically acceptable salt or its alloisomerisms shown in general formula I
The hydrate of body, internal level-one and/or secondary metabolism object and prodrug.
As the example of internal level-one metabolin, such as can enumerate：
Level-one metabolin in aromatic amides body shown in general formula I
Level-one metabolin in aromatic amides body shown in general formula I
Level-one metabolin in aromatic amides body shown in general formula I
Level-one metabolin in aromatic amides body shown in general formula I.
As the example of internal secondary metabolism object, such as can enumerate：
Add the example of secondary metabolism object as internal level-one, such as can enumerate：
。
As the example of prodrug, such as can enumerate：
。
It is a further object to provide the preparation methods of aromatic amides shown in the general formula I, special
Sign is, includes the following steps：Compound IV and compound V（It can be directly commercially available or respectively by document Tetrahedron
1979,2337-2343 and Tetrahedron 1979,2345-2352 methods synthesize）Be obtained by the reaction compound VI, then with it is folded
Nitrogen compound, such as Sodium azide（NaN3）Reaction is converted into compound VII.Compound VII is compound by catalytic hydrogen reduction
VIII.Compound VIII and compound IX are in EDCI（[1- ethyls -3- (3- dimethylamino-propyls) carbodiimide]（1-Ethyl-
3-(3-dimethylaminopropyl)carbodiimide））With HOBt (hydroxybenzotriazoles
（Hydroxybenzotriazole）) in the presence of（When IX is acid）Or under alkaline condition（When IX is acyl chlorides）Reaction generates knot
Target compound shown in structure general formula I, chemical equation are as follows：
。
The preparation of corresponding chipal compounds can be first commercially available or prepares optically pure initial compounds X or XV（By document
Tetrahedron 1979,2337-2343, Tetrahedron 1979,2345-2352 methods synthesize）, then press following institute
State route synthesising target compound, such as the target compound of synthesis S configurations（XIV）：
For another example the target compound of R configurations is synthesized（XIX）：
Wherein R shown in chemical equation1、R2、R5、R6, X, Y, Q and n definition and general formula I described in R1、R2、R5、R6、
X, Y, Q are identical with the definition of n.
Some general formulas I compounds represented according to the present invention（Wherein R3For methyl, R4For hydroxyl）It also can be by following road
Line synthesizes：The peroxide such as compound XX and Peracetic acid, trifluoro peracetic acid, hydrogen peroxide, benzoyl hydroperoxide（As oxidation
Agent）Reaction is converted into epoxide XXI, then with azido compound, such as Sodium azide（NaN3）Reaction is converted into compound
XXII.Then compound XXII is compound XXIII by catalytic hydrogen reduction.Compound XXIII and compound IX in EDCI and
Under HOBt is existing（When IX is acid）Or under alkaline condition（When IX is acyl chlorides）Reaction generates compound XXIV.
Wherein R shown in chemical equation1、R2、R5、R6, X, Y, Q and n define it is identical as in above-mentioned general formula I.
Wherein, "" indicate that compound IX is（Acid）Or（Acyl chlorides）.
It is also another object of the present invention to provide aromatic amides shown in the general formula I or its is pharmaceutically acceptable
Salt preparing the application in terms for the treatment of or preventing with the drug of the relevant disease of androgen.
A further object of the present invention is to provide the method for the treatment of or prevention and the relevant disease of androgen, including has given
The general formula I compounds represented or its pharmaceutically acceptable salt of this mammalian therapeutic needed or prevention effective dose.
In the preferred embodiment of the present invention, the described and relevant disease of androgen includes prostate cancer, prostate increasing
Life, breast cancer, carcinoma of urinary bladder, acne, crinosity, alopecia etc..
In the present invention, term " halogen " refers to fluorine, chlorine, bromine or iodine.
In the present invention, " C1-6Alkyl " refers to the straight chain of carbon atom number 1~6 or the sturated aliphatic hydrocarbon base of branch, example
Such as, as specific group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, amyl, isoamyl can be enumerated
Base, hexyl etc..Wherein it is preferably the C that carbon atom number is 1~41-4The C that alkyl, more preferably carbon atom number are 1~31-3Alkane
Base.
In the present invention, " C2-6Alkenyl " refers to the straight chain or branch of carbon atom number 2~6 with unsaturated double-bond
The aliphatic alkyl of shape, such as vinyl, 1- acrylic, 2- acrylic, 2- methyl-1-propylenes base, 2- methyl -2- can be enumerated
Acrylic, 2- butene-1s-base, 3- butene-1s-base, 2- amylene -1- bases, 3- amylene -1- bases, 4- amylene -1- bases, 5- hexenes -1-
Base, 4- hexene -1- bases, 3- hexene -1- bases, 2- hexene -1- bases etc..Wherein it is preferably the C that carbon atom number is 2~42-4Alkenyl,
The C that more preferably carbon atom number is 2~32-3Alkenyl.
In the present invention, " C2-6Alkynyl " refers to the straight chain or branch of the carbon atom number 2~6 with unsaturated three keys
The aliphatic alkyl of shape, such as acetenyl, 1- propine -1- bases, 2- propine -1- bases, 2- butine -1- bases, 3- butine-can be enumerated
1- bases, valerylene -1- bases, 3- pentyne -1- bases, 4- pentyne -1- bases, 5- hexin -1- bases, 4- hexin -1- bases, 3- hexin -1- bases
With 2- hexin -1- bases etc..Wherein it is preferably the C that carbon atom number is 2~42-4Alkynyl, more preferably carbon atom number are 2~3
C2-3Alkynyl.
In the present invention, " C3-6Naphthenic base " refers to the cyclic aliphatic hydrocarbon group of carbon atom number 3~6, for example, as tool
The group of body can enumerate cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl etc..
In the present invention, " C1-6Alkoxy " refers to being bonded with " C defined above1-6The oxygroup of alkyl ", such as can enumerate：
Methoxyl group, ethyoxyl, 1- propoxyl group, 2- propoxyl group, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc..
In the present invention, " C1-6Alkyl-carbonyl " refers to " C defined above1-6Alkyl " and carbonyl（-C(=O)）It is bonded
Group, for example,：Acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, pivaloyl group etc..
In the present invention, " hydroxyl C1-6Alkyl " refers to " C defined above1-6Group made of alkyl " is optionally substituted by a hydroxyl group,
For example,：1- hydroxyethyls (), 2- hydroxyethyls, 1- hydroxypropyls, 2- hydroxypropyls, 3- hydroxyls third
Base, 1- hydroxybutyls, 2- hydroxybutyls, 3- hydroxybutyls, 4- hydroxybutyls etc..
It should be noted that in above-mentioned definition, such as " C1" etc. " C " indicate that carbon atom, subsidiary thereafter digital representation carbon are former
Subnumber.For example, " C1-6" indicate that carbon atom number 1 arrives the range of carbon atom number 6.
In the present invention, statement is " optionally by 1 or more group（Substituent group）Substitution " refers to optionally being substituted
One or more identical or different groups of the arbitrary position of group（Substituent group）Substitution.For example, " C1-6Alkyl is optionally
Replaced by 1 or more halogen atom " refer to C1-6Alkyl can not be substituted, or can be in C1-6The arbitrary of alkyl can quilt
Substituted position is replaced with one or more halogen atoms.
In the present invention, in the ring on the right side of general formula "" indicate that the ring is unsaturation ring.
In the present invention, term " aryl ", which refers to the 5-10 members of unsubstituted or substituted base substitution, has the list of armaticity
Ring or bicyclic ring system carbon ring group or containing selected from N, O and S heteroatomic monocycle or bicyclic heterocycle radical group, wherein bicyclic ring system
One ring can be hydrogenated；Including such as phenyl, naphthalene, ihydro naphthyl, tetralyl, pyridyl group, pyridazinyl, pyrimidine
Base, pyrazinyl, furyl, imidazole radicals, pyranose, pyrazolyl, oxazolyl, isoxazolyls, thiazolyl, isothiazolyl, thienyl,
Purine radicals, benzofuranyl, benzothienyl, diazine, isobenzo-thienyl, isobenzofuran-base, indyl, iso-indoles
Base, quinolyl, isoquinolyl etc.；The substituent group be selected from hydrogen atom, alkyl, halogen, trifluoromethyl, cyano, nitro, etc. bases
Group.
In the present invention, described " pharmaceutically acceptable salt " refers to pharmaceutically nontoxic acid and general formula I institutes of the present invention
The alkaline part for the compound shown reacts the salt to be formed, including such as hydrochloride, acetate, hydrobromate, sulfate, hydrogen sulfate
It is salt, carbonate, bicarbonate, sulphite, phosphate, hydrophosphate, oxalates, malonate, valerate, borate, right
Toluene fulfonate, mesylate, tartrate, benzoate, lactate, citrate, maleate, fumarate, apple
Hydrochlorate, salicylate, mandelate, succinate, gluconate, Lactobionate etc..This salt can pass through this field skill
It is prepared by method well known to art personnel.
It is demonstrated experimentally that general formula I compounds represented of the present invention can be combined with androgen receptor, have significant resistance male
Hormone and estrogen receptor activity of degrading.The compound can be individually or as composition for treating various and androgen
Relevant disease, including such as prostate cancer, hyperplasia of prostate, breast cancer, carcinoma of urinary bladder, moreover it can be used to acne, crinosity, alopecia etc.
The treatment of disease.
Therefore, the present invention also provides the drugs containing the general formula I compounds represented or its pharmaceutically acceptable salt
Composition, and containing the general formula I compounds represented or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier
Pharmaceutical preparation.
The pharmaceutically acceptable carrier may include the pharmaceutical carrier of this field routine, for example, diluent, filler,
Adhesive, disintegrant, lubricant, solvent, solubilizer etc.；Including but not limited to for example starch, Icing Sugar, calcium phosphate, magnesium stearate,
Talcum powder, dextrin, cellulose and its derivates, microcrystalline cellulose, polyethylene glycol, physiological saline, glucose solution etc..
Pharmaceutical composition of the present invention and pharmaceutical preparation can also include various other common additives, such as preservative,
Emulsifier, suspending agent, corrigent etc..
Pharmaceutical composition of the present invention can be prepared into pharmaceutically acceptable any dosage form appropriate, including but not limited to example
Such as tablet, capsule, pill, granular preparation, syrup, injection, solution, suspension.
General formula I compounds represented of the present invention or its pharmaceutically acceptable salt can be applied to by any effective way
Mammal, such as people, the approach includes in oral, intravenous, peritonaeum, intramuscular, it is local, transdermal, through eye, intranasal, suction
Enter, be subcutaneous, is intramuscular, mouth containing, sublingual, rectum etc..They can be administered alone, or with other active components administering drug combinations.This
The effective quantity of invention compound of Formula I or its pharmaceutically acceptable salt can be by those skilled in the art such as attending physician
It is determined by using conventional method.In the effective quantity for determining the compounds of this invention, many factors should be considered by attending physician,
Including but not limited to；The particular compound to be given；With the drug combination of other medicaments；The type of mammal, size, year
Age and general health；The severity of disease；The reaction of individual patient；Administering mode；The biology profit for the preparation being administered
With rate characteristic；Selected dosage；The use of other concomitant drugs；And the situation etc. of other correlations.Usual dosage is
10-1000 milligrams.
Specific implementation mode
The present invention is further specifically described with embodiment, it is clear that described embodiment is only the one of the present invention below
Part, rather than all.These embodiments are only used for the illustration present invention, should not be construed as the limit to the scope of the present invention
System.Based on the embodiment of the present invention, those skilled in the art obtained under the premise of not making the creative labor it is all its
Its technical solution, shall fall within the protection scope of the present invention.
In embodiment, abbreviation THF represents tetrahydrofuran, DMSO-d6Represent deuterated dimethyl sulfoxide, DMSO represents dimethyl
Sulfoxide, HPLC represent high performance liquid chromatography, EDCI represents [1- ethyls -3-（3- dimethylamino-propyls）Carbodiimide]（1-
Ethyl-3-(3-dimethylaminopropyl)carbodiimide）, DIPEA represent（N, N- diisopropylethylamine）（N,N-
Diisopropylethylamine）, HOBT represent（Hydroxybenzotriazole）（Hydroxybenzotriazole）, DMF represent two
Methylformamide.
1H NMR, which are measured, uses Bruker AVANCE II 400MHz Nuclear Magnetic Resonance, and wherein behalf is unimodal, bs or brs generations
Table width unimodal, d represent doublet, m represents multiplet, and Ar is aryl.Mass spectroscopy Bruker amaZon SL mass spectrographs.It is high
Resolution Mass Spectrometry, which measures, uses Waters Acquity HPLC+Xeno G2-S TOF Mass.High-pressure liquid chromatography is used
SHIMADZU CBM-20A.Thin-layer chromatography, which measures, uses Silica gel 60F254 Plates (Merck).
I. compound prepares embodiment
Embodiment 1
（S) -5- acetyl group-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxos third
Base）- 1H- pyrazole-3-carboxamides (C18H16F3N5O4) preparation
The first step is reacted
Thionyl chloride（2.4 milliliters, 33.6 mMs）It is added dropwise to（R）The bromo- 2- hydroxyls -2- methylpropanoic acids of -3-（5.11
Gram, 28 mMs）In the solution of 30 milliliters of THF, the control of the temperature of dropwise addition is at 0-12 DEG C, 10 minutes used times.By the mixed of gained
Object is closed to stir under the same conditions 2 hours.Interior temperature is adjusted to -5 DEG C or so, and triethylamine is slowly added to the mixture of reaction
（Et3N）（5.0 milliliters, 36.4 mmol, 1.3eq）, interior temperature is less than 12 DEG C during charging.It is stirred in identical reaction condition
20 minutes.4-cyano-3- trifluoromethyl-anilines are then added dropwise thereto（4.0 grams, 21 mMs）In 40 mL THF
Solution, by gained mixture in 50 DEG C stir two hours.Reaction solution is cooled to 20 ± 5 DEG C, and water is then added（15 millis
It rises, 2.9 volumes）And toluene（20 milliliters, 4.0 volumes）, liquid separation after of short duration stirring, organic phase is washed with water（15 milliliters, 2.9 bodies
Product）, 5 ± 0.5 volumes are concentrated by vacuum distillation after organic phase is merged（6.4 weight）, temperature is kept in distillation process
Less than 50 DEG C.Toluene is added in concentrate（31 milliliters, 6 volumes）, it is diluted to 5 ± 0.5 volumes（6.4 weight）, by temperature tune
It whole to 2.5 ± 2.5 DEG C, stirs one hour at such a temperature, crystal seed is added（0.018 gram, 0.005 weight）, continue stirring one
Hour, filtering, filter cake is washed twice with toluene（8.5 milliliters every time, 1.7 volume every time）.Then by the batch of material in vacuum drying chamber
It is dry, obtain 5.8 grams（R）The bromo- N- of -3- (4- cyano -3- trifluoromethyl-phenyls) -2- hydroxy-2-methyl propionamides.Yield
59%, HPLC（Mobile phase is water and second cyanogen）Purity 99% (220nm), 99% (254nm), optics HPLC purity 99%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ10.52 (s, 1H, NH), 8.55(d, J=1.6Hz,
1H, ArH), 8.31(dd, J=8.2Hz, J=1.6Hz, 1H, ArH), 8.11(d, J=8.2Hz, 1H, ArH),
6.40(s, 1H, OH), 3.84(d, J=10.4Hz, 1H, CH), 3.60(d, J=10.4Hz, 1H, CH), 1.50
(s, 3H, CH3)。
Mass spectrum：(ESI, Positive): 351.9[M+H]+。
Second step reacts
It is added in 250mL round-bottomed flasks（R）The bromo- N- of -3- (4- cyano -3- trifluoromethyl-phenyls) -2- hydroxy-2-methyls third
Amide (2.00 grams, 5.696 mMs), the anhydrous DMSO of 40mL add Sodium azide as solvent（sodium azide）
(1.84 grams, 0.02848 mole), then reaction solution are stirred at room temperature under protection of argon gas 3 days.
Thin-layered chromatography（Solvent is hexane：Ethyl acetate=2:1）Determine reaction after the completion of, be added ethyl acetate and
Water, two phase separations, organic phase is washed with brine, magnesium sulfate is dry, filter, exchange of solvent is methanol, head product (S) -3- nitrine
Base-N- (4- cyano -3- trifluoromethyl-phenyls) -2- hydroxy-2-methyl propionamides are directly used in react in next step.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, CDCl3) δ9.00(bs, 1H, NH), 8.08(s, 1H, ArH),
7.95(d, J=8.4 Hz, 1H, ArH), 7.81(d, J=8.4 Hz, 1H, ArH), 3.92 (d, J=12.4Hz,
1H, CH), 3.50 (d, J=12.4Hz, 1H, CH), 2.96 (s, 1H, OH), 1.54 (s, 3H, CH3)。
Mass spectrum：(ESI, Negative): 312.18 [M-H]-; (ESI, Positive): 314.03 [M+H]+。
Three-step reaction
By (S) -3- azidos-N- (4- cyano -3- trifluoromethyl-phenyls) -2- hydroxy-2-methyl propionamides（1.78 gram,
5.696 mMs) methanol（30mL）Solution palladium carbon catalytic hydrogenation（30 psi）, react 3-4 hours.
After the completion of thin-layered chromatography determines reaction, diatomite filtering drains, obtains yellow/light brown powder substance, does
It is dry, obtain (S) -3- amino-N-（4- cyano -3- trifluoromethyl-phenyls）1.57 grams of -2- hydroxy-2-methyls propionamide, yield are about
96%。
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, CDCl3) δ9.01(bs, 1H, NH), 8.10(s, 1H, ArH),
7.98(d, J=8.6Hz, 1H, ArH), 7.79(d, J=8.6Hz, 1H, ArH), 5.10(m, 2H, NH2), 4.12
(d, J=12.4Hz, 1H, CH), 3.75 (d, J=12.4Hz, 1H, CH), 3.02(s, 1H, OH), 1.51 (s,
3H, CH3)。
Mass spectrum： (ESI, Positive):288.09 [M+H]+。
Four-step reaction
5- acetyl group -1H- pyrazoles -3- carboxylic acids (0.13 gram, 0.8355 mM), 2.0mL are added in 100mL round-bottomed flasks
Anhydrous DMF adds EDCI (0.16 gram, 1.0444 mMs) as solvent, and DIPEA (0.18 gram, 1.3926 mmoles
You) and HOBT (32 milligrams, 0.2098 mM), gained mixture is stirred 20 minutes.By another raw material (S) -3- ammonia
Base-N-（4- cyano -3- trifluoromethyl-phenyls）(0.20 gram, the 0.6963 mM) dissolving of -2- hydroxy-2-methyls propionamide
In 5.0mL anhydrous DMFs, it is added in said mixture, then reaction solution is stirred at room temperature 3 days under protection of argon gas.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=9:1）, purify, obtain faint yellow powder substance
0.14 gram, yield is about 50%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H, pyrazoles-NH), 10.53 (s, 1H,
NH), 8.50(s, 1H, ArH), 8.35(br s, 1H, NH), 8.26(d, J=8.8Hz, 1H, ArH), 8.09(d,
J=8.8Hz, 1H, ArH), 7.37 (s, 1H, pyrazoles-H), 6.20 (s, 1H, OH), 3.62-3.58 (m, 2H,
CH2), 1.99(s, 3H, CH3), 1.38(s, 3H, CH3)。
Mass spectrum：(ESI, Negative): 422.16 [M-H]-。
Embodiment 2
N-(S)-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）-5-（1- hydroxyls
Base ethyl）The preparation of -1H- pyrazole-3-carboxamides
It is added in 100mL round-bottomed flasks（S) -5- acetyl group-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）-2-
Hydroxy-2-methyl -3- oxopropyls）- 1H- pyrazole-3-carboxamides (0.10 gram, 0.2362 mM), 5 mL absolute ethyl alcohols are made
For solvent, sodium borohydride is slowly added into this reaction solution（Sodium borohydride, 22 milligrams, 0.5905mmol）And second
The suspension of alcohol, then reaction solution under protection of argon gas, in room temperature, be stirred overnight.
After the completion of thin-layered chromatography determines reaction, 0.5mL water and 1mL 0.5M HCl is added, is evaporated under reduced pressure after of short duration stirring
It is concentrated to dryness, then adds methylene chloride（20mL）Dissolving, organic phase NaHCO3Aqueous solution, salt water washing, magnesium sulfate drying, mistake
It filters, drain to obtain oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=9:1）, purify, obtain yellowish
76 milligrams of the non-substance of toner, yield is about 76%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H, pyrazoles-NH), 10.52 (s, 1H,
NH), 8.49(s, 1H, ArH), 8.33(br s, 1H, NH), 8.25(d, J=8.8Hz, 1H, ArH), 8.09(d,
J=8.8Hz, 1H, ArH), 7.31 (s, 1H, pyrazoles-H), 6.20 (s, 1H, OH), 4.68-4.62 (m, 1H,
CH), 3.64-3.58(m, 3H, OH+CH2), 1.51(s, 3H, CH3), 1.38(s, 3H, CH3)。
Mass spectrum： (ESI, negative) m/z 424.10 [M-H]-。
Embodiment 3
(S)-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）- 5- trifluoros
Methyl-1 H- pyrazole-3-carboxamides (C17H13F6N5O3) preparation
5- Trifluoromethyl-1 H pyrazoles -3- carboxylic acids (0.23 gram, 1.253 mMs), 2.3mL are added in 100mL round-bottomed flasks
Anhydrous DMF adds EDCI (0.24 gram, 1.567 mMs), DIPEA (0.27 gram, 2.089 mMs) as solvent
With HOBT (48 milligrams, 0.3133 mM), stir 20 minutes.Another raw material (S) -3- amino-N- is added（4- cyano -3-
Trifluoromethyl-phenyl）- 2- hydroxy-2-methyls propionamide (0.30 gram, 1.044 mMs) is molten in 6.0mL anhydrous DMFs
Then liquid reaction solution is stirred at room temperature under protection of argon gas 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=9:1）, purify, obtain faint yellow powder substance
0.23 gram, yield is about 50%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H, pyrazoles-NH), 10.50 (s, 1H,
NH), 8.58(s, 1H, NH), 8.48(s, 1H, ArH), 8.26(d, J=8.0Hz, 1H, ArH), 8.09(d, J=
8.0Hz, 1H, ArH), 7.36 (s, 1H, pyrazoles-H), 6.12 (s, 1H, OH), 3.67-3.45 (m, 2H, CH2),
1.39(s, 3H, CH3)。
Mass spectrum：(ESI, Negative): 448.00 [M-H]-。
Embodiment 4
(S) the chloro- N- of -5-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）-
1H- pyrazole-3-carboxamides（C16H13ClF3N5O3）Preparation
The chloro- 1H- pyrazoles -3- carboxylic acids of 5- (0.122 gram, 0.8355 mM) are added in 100mL round-bottomed flasks, 1.5mL is anhydrous
DMF adds EDCI (0.16 gram, 1.0444 mMs) as solvent, DIPEA (0.24mL, 1.3926 mMs) and
HOBT (32 milligrams, 0.2089 mM) is stirred 20 minutes.Another raw material (S) -3- amino-N- is added（4- cyano -3- three
Methyl fluoride-phenyl）- 2- hydroxy-2-methyls propionamide (0.20 gram, 0.6963 mM) is molten in 4.0mL anhydrous DMFs
Then under protection of argon gas by reaction solution liquid is stirred at room temperature 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=9:1）, purify, obtain faint yellow powder substance
0.15 gram, yield is about 51.0%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ13.79(s, 1H, NH), 10.50(s, 1H, NH),
8.50(s, 1H, ArH), 8.44(bs, 1H, NH), 8.25(d, J=8.2Hz, 1H, ArH), 8.10(d, J=
8.2Hz, 1H, ArH), 6.93 (s, 1H, pyrazoles-H), 6.11 (s, 1H, OH), 3.66-3.61 (m, 1H, CH2),
3.54-3.50(m, 1H, CH2), 1.38(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 414.25 [M-H]-。
Embodiment 5
(S) the bromo- N- of -5-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）-
1H- pyrazole-3-carboxamides (C16H13BrF3N5O3) preparation
The bromo- 1H- pyrazoles -3- carboxylic acids of 5- (0.16 gram, 0.8355 mM) are added in 100mL round-bottomed flasks, 1.5mL is anhydrous
DMF adds EDCI (0.16 gram, 1.0444 mMs) as solvent, DIPEA (0.24mL, 1.3926 mMs) and
HOBT (32 milligrams, 0.2089 mM) is stirred 20 minutes.Another raw material (S) -3- amino-N- is added（4- cyano -3- three
Methyl fluoride-phenyl）- 2- hydroxy-2-methyls propionamide (0.20 gram, 0.6963 mM) is molten in 4.0mL anhydrous DMFs
Then under protection of argon gas by reaction solution liquid is stirred at room temperature 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=9:1）, purify, obtain faint yellow powder substance
0.176 gram, yield is about 55.0%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ13.82(s, 1H, NH), 10.49(s, 1H, NH),
8.51(m, 2H), 8.27(d, J=8.2Hz, 1H, ArH), 8.08(d, J=8.2Hz, 1H, ArH), 7.38(s,
1H, pyrazoles-H), 6.13 (s, 1H, OH), 3.65-3.50 (m, 2H, CH2), 1.39(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 457.97 [M-H]-。
Embodiment 6
(S)-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）- 5- nitros-
1H- pyrazole-3-carboxamides (C16H13F3N6O5) preparation
In 100mL round-bottomed flasks be added 5- nitro -1H- pyrazoles -3- carboxylic acids (0.13 gram, 0.8355 mM), 1.5mL without
Water DMF adds EDCI (0.16 gram, 1.0444 mMs), DIPEA (0.24mL, 1.3926 mMs) as solvent
With HOBT (32 milligrams, 0.2089 mM), stir 20 minutes.Another raw material (S) -3- amino-N- is added（4- cyano -3-
Trifluoromethyl-phenyl）- 2- hydroxy-2-methyls propionamide (0.20 gram, 0.6963 mM) is in 4.0mL anhydrous DMFs
Then under protection of argon gas by reaction solution solution is stirred at room temperature 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=9:1）, purify, obtain yellow powder substance
0.14 gram, yield is about 48.0%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ14.62(s, 1H, NH), 10.54(s, 1H, NH),
8.59(s, 1H, NH), 8.50(s, 1H, ArH), 8.27(d, J=8.8Hz, 1H, ArH), 8.09(d, J=
8.8Hz, 1H, ArH), 7.41 (s, 1H, pyrazoles-H), 6.22 (s, 1H, OH), 3.70-3.51 (m, 2H, CH2),
1.39(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 425.03 [M-H]-。
Embodiment 7
(S) -5- cyano-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）-
1H- pyrazole-3-carboxamides (C17H13F3N6O3) preparation
5- cyano -1H- pyrazoles -3- carboxylic acids (0.115 gram, 0.8355 mM), 1.5mL are added in 100mL round-bottomed flasks
Anhydrous DMF adds EDCI (0.16 gram, 1.0444 mMs), DIPEA (0.24mL, 1.3926 mmoles as solvent
You) and HOBT (32 milligrams, 0.2089 mM), it stirs 20 minutes.Another raw material (S) -3- amino-N- is added（4- cyanogen
Base -3- trifluoromethyl-phenyls）- 2- hydroxy-2-methyls propionamide (0.20 gram, 0.6963 mM) is in 4.0mL anhydrous DMFs
In solution then under protection of argon gas by reaction solution be stirred at room temperature 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=95:5）, purify, obtain faint yellow powder substance
0.15 gram is obtained, yield is about 54.0%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ14.53(s, 1H, NH), 10.52(s, 1H, NH),
8.58(s, 1H, NH), 8.49(s, 1H, ArH), 8.26(d, J=8.4Hz, 1H, ArH), 8.09(d, J=
8.4Hz, 1H, ArH), 7.39 (s, 1H, pyrazoles-H), 6.19 (s, 1H, OH), 3.68-3.52 (m, 2H, CH2),
1.38(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 405.05 [M-H]-。
Embodiment 8
(S)-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）-5-（4- fluorine
Phenyl）- 1H- pyrazole-3-carboxamides (C22H17F4N5O3) preparation
5- (4- fluoro-phenyls) -1H- pyrazoles -3- carboxylic acids (0.17 gram, 0.8355 mM) are added in 100mL round-bottomed flasks,
1.7mL anhydrous DMFs add EDCI (0.16 gram, 1.0444 mMs) as solvent, and DIPEA (0.24mL, 1.3926
MM) and HOBT (32 milligrams, 0.2089 mM), it stirs 20 minutes.Another raw material (S) -3- amino-N- is added（4-
Cyano -3- trifluoromethyl-phenyls）- 2- hydroxy-2-methyls propionamide (0.20 gram, 0.6963 mM) is anhydrous in 4.0mL
Then under protection of argon gas by reaction solution solution in DMF is stirred at room temperature 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=95:5）, purify, obtain faint yellow powder substance
0.17 gram is obtained, yield is about 50.0%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ14.20(s, 1H, NH), 10.51(s, 1H, NH),
8.52-8.50(m, 2H), 8.25(d, J=8.8Hz, 1H, ArH), 8.09(d, J=8.8Hz, 1H, ArH), 7.65-
7.57 (m, 2H, ArH), 7.36 (s, 1H, pyrazoles-H), 7.16-7.06 (m, 2H, ArH), 6.15 (s, 1H,
OH), 3.66-3.53(m, 2H, CH2), 1.38(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 474.08 [M-H]-。
Embodiment 9
(S)-N-（3-（The chloro- 4- cvano-phenyls of 3-）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）- 5- trifluoromethyls-
1H- pyrazole-3-carboxamides (C16H13ClF3N5O3) preparation
The first step is reacted
Thionyl chloride（2.38 milliliters, 32.787 mMs）It is added dropwise to（R）The bromo- 2- hydroxy-2-methyls propionic acid of -3-
（5.00 grams, 27.322 mMs）In the solution of 30 milliliters of THF, the control of the temperature of dropwise addition is at 0-12 DEG C, 10 minutes used times.It will
The mixture of gained stirs 2 hours under the same conditions.Interior temperature is adjusted to -5 DEG C or so, and three are slowly added to the mixture of reaction
Ethylamine（4.95 milliliters, 35.52 mmol, 1.3eq）, interior temperature is less than 12 DEG C during charging.It is stirred in identical reaction condition
It mixes 20 minutes.3-chloro- 4-cyano-phenyl amines are then added dropwise thereto（3.96 grams, 25.96 mMs）In 40 mL THF
Solution, by gained mixture in 50 DEG C stir two hours.Silica gel column chromatography detaches（Mobile phase is hexane:Ethyl acetate=
2:1）, purify, vacuum drying chamber drying obtains 7.30 grams（R）The bromo- N- of -3-（The chloro- 4- cvano-phenyls of 3-）- 2- hydroxyl -2- first
Base propionamide.Yield 88.6%, HPLC purity 99% (220nm), 99% (254nm).
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ10.22 (s, 1H, NH), 8.13(d, J=2.0Hz,
1H, ArH), 7.88(dd, J=8.2Hz, J=2.0Hz, 1H, ArH), 7.80(d, J=8.2Hz, 1H, ArH),
6.20(s, 1H, OH), 3.94(d, J=10.4Hz, 1H, CH), 3.72(d, J=10.4Hz, 1H, CH), 1.48
(s, 3H, CH3)。
Mass spectrum：(ESI, Positive):351.99 [M+H]+。
Second step reacts
It is added in 250mL round-bottomed flasks（R）The bromo- N- of -3-（The chloro- 4- cvano-phenyls of 3-）- 2- hydroxy-2-methyl propionamides
(2.00 grams, 6.278 mMs) are added the anhydrous DMSO of 40mL as solvent, add Sodium azide（sodium azide）
(2.05 grams, 0.03149 mole), then under protection of argon gas by reaction solution, are stirred overnight in 80 DEG C.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, two phase separations wash organic phase with salt
It washs, magnesium sulfate is dry, filter, exchange of solvent is methanol, head product (S) -3- azidos-N-（The chloro- 4- cvano-phenyls of 3-）-
2- hydroxy-2-methyl propionamides are directly used in react in next step.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ8.95(bs, 1H, NH), 8.03(s, 1H, ArH),
7.86(d, J=8.4 Hz, 1H, ArH), 7.74(d, J=8.4 Hz, 1H, ArH), 3.91(d, J=12.4 Hz,
1H, CH), 3.49(d, J=12.4 Hz, 1H, CH), 2.95(s, 1H, OH), 1.56(s, 3H, CH3)。
Mass spectrum：(ESI, Negative): 278.42[M-H]-; (ESI, Positive): 280.03[M+H]+。
Three-step reaction
By (S) -3- azidos-N-（The chloro- 4- cvano-phenyls of 3-）- 2- hydroxy-2-methyls propionamide (1.68 grams, 5.9739 millis
Mole) methanol (30mL) solution palladium carbon catalytic hydrogenation（30 psi）, react 3-4 hours.
After the completion of thin-layered chromatography determines reaction, diatomite filtering drains, obtains yellow/light brown powdered (S) -3-
Amino-N-（The chloro- 4- cvano-phenyls of 3-）1.47 grams of -2- hydroxy-2-methyls propionamide, yield is about 97%.
Mass spectrum： (ESI, Positive):254.03 [M+H]+。
Four-step reaction
5- Trifluoromethyl-1 H- pyrazoles -3- carboxylic acids (0.256 gram, 1.4191 mMs) are added in 100mL round-bottomed flasks,
2.6mL anhydrous DMFs add EDCI (0.275 gram, 1.7748 mMs) as solvent, and DIPEA (0.41mL, 2.365
MM) and HOBT (54 milligrams, 0.3548 mM), it stirs 20 minutes.Another raw material (S) -3- amino-N- is added（3-
Chloro- 4- cvano-phenyls）- 2- hydroxy-2-methyls propionamide (0.30 gram, 1.1826 mMs) is in 6.0mL anhydrous DMFs
Then under protection of argon gas by reaction solution solution is stirred at room temperature 3 days.
Thin-layered chromatography（Solvent is dichloromethane:Methanol=9:1）Determine reaction after the completion of, be added ethyl acetate and
Water, two phase separations, organic phase is drained, oily mater is obtained.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=
9:1）, purify, obtain 0.30 gram of faint yellow powder substance, yield is about 61.0%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ14.40(s, 1H, NH), 10.42(s, 1H, NH),
8.49(s, 1H, NH), 8.11(d, J=1.6Hz, 1H, ArH), 7.86(d, J=8.8Hz, J=1.6Hz, 1H,
), ArH 7.81 (d, J=8.8Hz, 1H, ArH), 7.34 (s, 1H, pyrazoles-H), 6.10 (s, 1H, OH), 3.65-
3.51(m, 2H, CH2), 1.42(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 414.03 [M-H]-。
Embodiment 10
(S)-N-（3-（6- cyano -5- trifluoromethylpyridin -3- bases）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）-5-
Trifluoromethyl-1 H- pyrazole-3-carboxamides (C16H12F6N6O3) preparation
The first step is reacted
Thionyl chloride（2.39 milliliters, 32.79 mMs）It is added dropwise to（R）- 3-bromo- 2- hydroxy-2-methyls propionic acid
（5.00 grams, 27.322 mMs）In the solution of 30 milliliters of THF, the control of the temperature of dropwise addition is at 0-12 DEG C, 10 minutes used times.It will
The mixture of gained stirs 2 hours under the same conditions.Interior temperature is adjusted to -5 DEG C or so, and three are slowly added to the mixture of reaction
Ethylamine（4.95 milliliters, 35.52 mmol, 1.3eq）, interior temperature is less than 12 DEG C during charging.It is stirred in identical reaction condition
It mixes 20 minutes.5- amino -3- trifluoromethyl -2- cyanopyridines are then added thereto（4.86 grams, 25.97 mMs）40
Gained mixture is stirred two hours by the solution in mL THF in 50 DEG C.Reaction solution is cooled to 20 ± 5 DEG C, is then added
Water（15 milliliters, 2.9 volumes）And ethyl acetate（20 milliliters, 4.0 volumes）, liquid separation after of short duration stirring, organic phase is washed with water（15
Milliliter, 2.9 volumes）Once, it is concentrated to dryness by vacuum distillation after organic phase being merged.Residue is detached with silica gel column chromatography
（Mobile phase is hexane:Ethyl acetate=2:1）, purify, vacuum drying chamber drying obtains 7.77 grams（R）The bromo- N- of -3-（6- cyanogen
Base -5- trifluoromethylpyridin -3- bases）- 2- hydroxy-2-methyl propionamides.Yield 85%, HPLC purity 99% (220nm),
99%(254nm)。
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ10.82(s, 1H, NH), 9.41(d, J=2.0Hz,
1H, ArH), 8.90(d, J=2.0Hz, 1H, ArH), 6.51(s, 1H, OH), 3.84(d, J=10.4Hz, 1H,
CH), 3.61(d, J=10.4Hz, 1H, CH), 1.50(s, 3H, CH3)。
Mass spectrum：(ESI, Positive):351.9915 [M+H]+。
Second step reacts
It is added in 250mL round-bottomed flasks（R）The bromo- N- of -3-（6- cyano -5- trifluoromethylpyridin -3- bases）- 2- hydroxyls -2-
Methyl propanamide (2.00 grams, 5.680 mMs) is added the anhydrous DMSO of 40mL as solvent, adds Sodium azide（sodium
azide）(1.85 grams, 0.0288 mole), then reaction solution under protection of argon gas, in 80 DEG C stir 14 hours.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added and carries out two-phase separation, by organic phase salt
Water washing, magnesium sulfate are dry, filter, exchange of solvent is methanol, head product（S）- 3- azidos-N-（6- cyano -5- fluoroforms
Base-pyridin-3-yl）- 2- hydroxy-2-methyl propionamides are directly used in react in next step.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, CDCl3) δ9.18(bs, 1H, NH), 8.92(s, 1H, ArH),
8.55(s, 1H, ArH), 3.94(d, J=12.4Hz, 1H, CH), 3.52(d, J=12.4Hz, 1H, CH), 2.97
(s, 1H, OH), 1.55 (s, 3H, CH3)。
Mass spectrum：(ESI, Negative): 313.16[M-H]-; (ESI, Positive): 315.04[M+H]+。
Three-step reaction
It will（S）- 3- azidos-N-（6- cyano -5- trifluoromethylpyridin -3- bases）- 2- hydroxy-2-methyls propionamide (1.78
Gram, 5.6607 mMs) methanol (30mL) solution palladium carbon catalytic hydrogenation（30 psi）, react 3-4 hours.
After the completion of thin-layered chromatography determines reaction, diatomite filtering is drained, dry, obtains yellow/light brown powdered
（S）- 3- amino-N-（6- cyano -5- trifluoromethylpyridin -3- bases）1.55 grams of -2- hydroxy-2-methyls propionamide, yield is about
It is 95%.
Mass spectrum： (ESI, Positive):289.09 [M+H]+。
Four-step reaction
5- Trifluoromethyl-1 H- pyrazoles -3- carboxylic acids (0.225 gram, 1.2490 mMs) are added in 100mL round-bottomed flasks, add
Enter 2.3mL anhydrous DMFs as solvent, adds EDCI (0.24 gram, 1.5612 mMs), DIPEA (0.26mL,
2.0817 mMs) and HOBT (48 milligrams, 0.3123 mM), it stirs 20 minutes.Another raw material is added（S）- 3- ammonia
Base-N-（6- cyano -5- trifluoromethylpyridin -3- bases）- 2- hydroxy-2-methyls propionamide (0.30 gram, 1.0408 mmoles
You) then under protection of argon gas by reaction solution the solution in 6.0mL anhydrous DMFs is stirred at room temperature 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=7:1）, purify, obtain faint yellow powder substance
0.28 gram, yield is about 60.0%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ14.42(s, 1H, NH), 10.73(s, 1H, NH),
9.32 (s, 1H, ArH), 8.82 (s, 1H, ArH), 8.60 (s, 1H, NH), 7.39 (s, 1H, pyrazoles-H),
6.41(s, 1H, OH), 3.69-3.55(m, 2H, CH2), 1.39(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 449.05 [M-H]-。
Embodiment 11
(S)-N-（3-（6- Cyano-pyridin -3- bases）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）- 5- trifluoromethyls-
1H- pyrazole-3-carboxamides (C15H13F3N6O3) preparation
The first step is reacted
Thionyl chloride（2.39 milliliters, 32.79 mMs）It is added dropwise to（R）- 3-bromo- 2- hydroxy-2-methyls propionic acid
（5.00 grams, 27.322 mMs）In the solution of 30 milliliters of THF, the control of the temperature of dropwise addition is at 0-12 DEG C, 10 minutes used times.It will
The mixture of gained stirs 2 hours under the same conditions.Interior temperature is adjusted to -5 DEG C or so, and Et3N is slowly added to reaction mixture
（4.95 milliliters, 35.52 mmol, 1.3eq）, interior temperature is less than 12 DEG C during charging.20 points are stirred in identical reaction condition
Clock.5- amino -2- cyanopyridines are then added dropwise thereto（3.09 grams, 25.96 mMs）It is molten in 40 mL THF
Gained mixture is stirred two hours by liquid in 50 DEG C.Reaction solution is cooled to 20 ± 5 DEG C, and water is then added（15 milliliters, 2.9
Volume）And ethyl acetate（20 milliliters, 4.0 volumes）, liquid separation after of short duration stirring, organic phase is washed with water（15 milliliters, 2.9 volumes）
Once, it is concentrated to dryness by vacuum distillation after organic phase being merged.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol
= 19:1）, purify, vacuum drying chamber drying obtains 6.64 grams（R）The bromo- N- of -3-（6- Cyano-pyridin -3- bases）- 2- hydroxyls-
2- methyl propanamides.Yield 85%, HPLC purity 99% (220nm), 99% (254nm).
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ 10.42(s, 1H, NH), 9.12(d, J=2.4Hz,
1H, ArH), 8.44(dd, J=8.8Hz, J=2.4Hz, 1H, ArH), 8.00(d, J=8.8Hz, 1H, ArH),
6.40(s, 1H, OH), 3.83(d, J=10.4Hz, 1H, CH), 3.59(d, J=10.4Hz, 1H, CH), 1.49
(s, 3H, CH3)。
Mass spectrum：(ESI, Positive): 284.0042 [M+H]+。
Second step reacts
It is added in 250mL round-bottomed flasks（R）The bromo- N- of -3-（6- Cyano-pyridin -3- bases）- 2- hydroxy-2-methyl propionamides
(2.00 grams, 7.0395 mMs), the anhydrous DMSO of 40mL add Sodium azide as solvent（sodium azide）(2.29
Gram, 0.035198 mole), then under protection of argon gas by reaction solution, it is stirred overnight in 80 DEG C.
After the completion of thin-layered chromatography determines reaction, it is added ethyl acetate and water, two phase separations, organic phase is washed with brine,
Magnesium sulfate is dry, filter, exchange of solvent is methanol, head product（S）- 3- azidos-N-（6- Cyano-pyridin -3- bases）- 2- hydroxyls
Base -2- methyl propanamides are directly used in react in next step.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, CDCl3) δ8.98(bs, 1H, NH), 8.77(d, J=2.0Hz,1H,
ArH), 8.45(dd, J=8.6Hz, 1H, ArH), 7.79(d, J=8.6Hz, 1H, ArH), 3.93(d, J=
12.4Hz, 1H, CH), 3.51(d, J=12.4Hz, 1H, CH), 2.98(s, 1H, OH), 1.55 (s, 3H,
CH3)。
Mass spectrum：(ESI, Negative): 245.17[M-H]-; (ESI, Positive): 247.05[M+H]+。
Three-step reaction
It will（S）- 3- azidos-N-（6- Cyano-pyridin -3- bases）- 2- hydroxy-2-methyl propionamides（1.73 grams, 7.0262 millis
Mole）Methanol (30mL) solution palladium carbon catalytic hydrogenation（30 psi）, react 3-4 hours.
After the completion of thin-layered chromatography determines reaction, diatomite filtering drains, yellow/light brown powdered is obtained after dry
（S）- 3- amino-N-（6- Cyano-pyridin -3- bases）1.47 grams of -2- hydroxy-2-methyls propionamide, yield is about 95%.
Mass spectrum： (ESI, Positive):221.09 [M+H]+。
Four-step reaction
5- Trifluoromethyl-1 H- pyrazoles -3- carboxylic acids (0.294 gram, 1.6347 mMs) are added in 100mL round-bottomed flasks, add
Enter 3.0mL anhydrous DMFs as solvent, adds EDCI (0.32 gram, 2.0433 mMs), and DIPEA (0.48mL, 2.7244
MM) and HOBT (63 milligrams, 0.4087 mM), it stirs 20 minutes.Another raw material is added（S）- 3- amino-N-（6-
Cyano-pyridin -3- bases）- 2- hydroxy-2-methyls propionamide (0.30 gram, 1.622 mMs) is in 6.0mL anhydrous DMFs
Then under protection of argon gas by reaction solution solution is stirred at room temperature 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Methanol=7:1）, purify, drying obtains faint yellow powder
0.21 gram of shape target compound, yield is about 41.0%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ14.45(s, 1H, NH), 10.54(s, 1H, NH),
9.31(d, J=2.4Hz, 1H, ArH), 8.50-8.47(m, 2H), 8.05(d, J=8.8Hz, 1H, ArH), 7.36
(s, 1H, pyrazoles-H), 6.13 (s, 1H, OH), 3.68-3.49 (m, 2H, CH2), 1.39(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 381.02 [M-H]-。
Embodiment 12
(S)-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）- 4- fluorobenzene
Formamide (C19H15F4N3O3) preparation
Raw material (S) -3- amino-N- is added in 100mL round-bottomed flasks（4- cyano -3- trifluoromethyl-phenyls）- 2- hydroxyls -2-
Methyl propanamide (0.22 gram, 0.7659 mM), anhydrous THF 10mL are down to 0 DEG C as solvent, argon gas protection, temperature,
4- fluorobenzoyl chlorides (0.14mL, 1.1489 mMs, 1.5equ) are added, stir 10 minutes, then triethylamine is added dropwise
（Et3N, 0.32mL, 2.2977 mM, 3equ), temperature is warmed to room temperature, stirring, reaction time 5-6 hour.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.Silica gel column chromatography detaches（Mobile phase is dichloromethane:Ethyl acetate=19:1）, purify, it is white to obtain class for drying
0.16 gram of color powdered target compound, yield is about 50%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ10.52(s, 1H, NH), 8.50-8.48(m, 2H,
NH+ArH), 8.25(d, J=8.2Hz, 1H, ArH), 8.09(d, J=8.2Hz, 1H, ArH), 7.91-7.87(m,
2H, ArH), 7.30-7.26(m, 2H, ArH), 6.19(s, 1H, OH), 3.66-3.54(m, 2H, CH2), 1.38
(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 408.06 [M-H]-。
Embodiment 13
(S)-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）-4-（Trifluoro
Methyl）Benzamide (C20H15F6N3O3) preparation
Raw material (S) -3- amino-N- is added in 100mL round-bottomed flasks（4- cyano -3- trifluoromethyl-phenyls）- 2- hydroxyls -2-
Anhydrous THF 10mL are added as solvent in methyl propanamide (0.25 gram, 0.8704 mM), and argon gas is protected, and temperature is down to 0
DEG C, 4- is added（Trifluoromethyl）Chlorobenzoyl chloride (0.55mL, 1.0444 mMs, 1.2 equivalents) is stirred 10 minutes, then is dripped
Add triethylamine（Et3N, 0.24mL, 1.7408 mM, 2.0 equivalents), temperature is warmed to room temperature, stirring, reaction time 5-6
Hour.
After the completion of thin-layered chromatography determines reaction, water is added to terminate reaction, ethyl acetate and water is added, two phase separations will have
Machine is mutually drained, and oily mater is obtained.It is detached with silica gel column chromatography（Mobile phase is dichloromethane:Ethyl acetate=9:1）,
Purifying, drying, obtains 0.29 gram of off-white color powdered target compound, yield is about 72%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ10.54(s, 1H, NH), 8.52-8.48(m, 2H,
NH+ArH), 8.26(d, J=8.4Hz, 1H, ArH), 8.14(d, J=8.4Hz, 1H, ArH), 8.01-7.97(m,
2H, ArH), 7.54-7.50(m, 2H, ArH), 6.21(s, 1H, OH), 3.70-3.58(m, 2H, CH2), 1.39
(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 458.02 [M-H]-。
Embodiment 14
(S)-N1-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）- N4- first
Base-terephthalamide (C21H19F3N4O4) preparation
N- methyl-terephthalic acid (TPA) monoamides is added in 100mL round-bottomed flasks（N-Methyl-terephthalamic
acid）(0.21 gram, 1.0444 mMs), and EDCI (0.20 gram, 1.3055 mMs), HOBT (40 milligrams, 0.2611
MM), DIPEA (0.30mL, 1.7401 mMs), and 2.0mL anhydrous DMFs are added as solvent, it stirs 20 minutes.It will
Another raw material (S) -3- amino-N-（4- cyano -3- trifluoromethyl-phenyls）- 2- hydroxy-2-methyls propionamide (0.25 gram,
0.8704 mM) solution in 5.0mL anhydrous DMFs is added thereto, then under protection of argon gas by reaction solution, in room temperature
Stirring 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.It is detached with silica gel column chromatography（Mobile phase is dichloromethane:Ethyl acetate=9:1）, purify, drying obtains
0.18 gram of off-white color powdered target compound, yield is about 46%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ10.49(s, 1H, NH), 8.48-8.45(m, 2H,
NH+ArH), 8.21(d, J=8.4Hz, 1H, ArH), 8.06(d, J=8.4Hz, 1H, ArH), 7.87-7.83(m,
2H, ArH), 7.31-7.24(m, 2H, ArH), 6.17(s, 1H, OH), 3.64-3.51(m, 2H, CH2), 1.37
(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 447.09 [M-H]-。
Embodiment 15
(S) -4- acetyl group-N-（3-（4- cyano -3- trifluoromethyl-phenyls）Amino）- 2- hydroxy-2-methyl -3- oxos third
Base）Fluoro- benzamide (the C of -3-21H17F4N3O4) preparation
4- acetyl group -- the fluoro- benzoic acid of 3- (0.19 gram, 1.0444 mMs), EDCI are added in 100mL round-bottomed flasks
(0.20 gram, 1.055 mMs), HOBT (40 milligrams, 0.2611 mM), DIPEA (0.30mL, 1.7401 mmoles
You), and 2.0mL anhydrous DMFs are added as solvent, it stirs 20 minutes.Another raw material (S) -3- amino-N- is added thereto（4-
Cyano -3- trifluoromethyl-phenyls）- 2- hydroxy-2-methyls propionamide (0.25 gram, 0.8704 mM) is dissolved in 5.0mL
Then under protection of argon gas by reaction solution solution in anhydrous DMF is stirred at room temperature 3 days.
After the completion of thin-layered chromatography determines reaction, ethyl acetate and water is added, organic phase is drained, obtained by two phase separations
Oily mater.It is detached with silica gel column chromatography（Mobile phase is dichloromethane:Ethyl acetate=9:1）, purify, drying obtains
0.18 gram of faint yellow powdered target compound, yield is about 46%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ10.53(s, 1H, NH), 8.51-8.47(m, 2H,
NH+ArH), 8.27(d, J=8.6Hz, 1H, ArH), 8.10(d, J=8.6Hz, 1H, ArH), 8.01-7.96(m,
2H, ArH), 7.42(d, J=2.0Hz, 1H, ArH), 6.22(s, 1H, OH), 3.71-3.59(m, 2H, CH2),
1.41(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 450.07 [M-H]-。
Embodiment 16
(S)-N-（3-（6- cyano -5- trifluoromethylpyridin -3- bases）Amino）- 2- hydroxy-2-methyl -3- oxopropyls）-4-
Fluorobenzamide (C18H14F4N4O3) preparation
Raw material (S) -3- amino-N- is added in 100mL round-bottomed flasks（6- cyano -5- trifluoromethylpyridin -3- bases）- 2- hydroxyls
Base -2- methyl propanamides (0.20 gram, 0.6939 mM), and anhydrous THF 10mL are added as solvent, argon gas protection, temperature
Degree is down to 0 DEG C, and 4- fluorobenzoyl chlorides (0.10mL, 1.3878 mMs, 1.2 equivalents) are added, and stirs 10 minutes, then be added dropwise
Triethylamine（Et3N, 0.19mL, 1.3878 mM, 2.0 equivalents), temperature is warmed to room temperature, and stirring, the reaction time, 5-6 was small
When.
After the completion of thin-layered chromatography determines reaction, water is added to terminate reaction, ethyl acetate and water is added, two phase separations will have
Machine is mutually drained, and oily mater is obtained.It is detached with silica gel column chromatography（Mobile phase is dichloromethane:Methanol=95:5）, pure
Change, drying obtains 0.21 gram of off-white color powdered target compound, yield is about 75%.
Nuclear magnetic resoance spectrum：1H NMR (400 MHz, DMSO-d6) δ10.52(s, 1H, NH), 9.31(s, 1H, ArH),
8.80(s, 1H, ArH), 8.50-8.48(m, 1H, NH), 7.91-7.86(m, 2H, ArH), 7.31-7.26(m,
2H, ArH), 6.19(s, 1H, OH), 3.67-3.53(m, 2H, CH2), 1.38(s, 3H, CH3)。
Mass spectrum： (ESI, Negative) m/z 409.05 [M-H]-。
II. formulation preparation example
Example of formulations A：The preparation of injection
(1) preparation forms:
3 compound 25g of embodiment
Polyoxyethylene sorbitan monoleate 20g
Mannitol 10g
Water for injection is to 5000ml
(2) preparation method:
3 compound of embodiment, polyoxyethylene sorbitan monoleate and mannitol are added in 4000 m1 waters for injection by composition, stirred
After dissolving, add to the full amount of water for injection 5000m1, continues to stir, by 0.22um miillpore filters carry out aseptic filtration, filtrate with
Every 5m1 sterile filling (specification 20mg/ branch) in 5ml ampullas seals, sterilizing.
Example of formulations B：The preparation of tablet
（One）Composition
Prescription 2-1 compound of Formula I tablet formulations（Every 1000 dosages）
Prescription 2-2 compound of Formula I tablet formulations（Every 1000 dosages）
Prescription 2-3 compound of Formula I tablet formulations（Every 1000 dosages）
（Two）Preparation process
In 3 tablet formulation ratio of embodiment, embodiment 3, lactose and microcrystalline cellulose are pressed 200:100:40 ratios are micronized, and are pressed
Microcrystalline cellulose, pregelatinized starch, superfine silica gel powder and the sodium carboxymethyl starch of 80 mesh sieve was added after mixing in prescription ratio,
It is appropriate that 0.3%HPMC solution is added, softwood processed, the sieve granulation of 18 mesh, 60 DEG C of dryings（Granule moisture level is controlled 3% or so）, add
Entered the magnesium stearate and particle mixing of 80 mesh sieve, 16 mesh sieves, tabletting, packaging.
III. bioactivity detects
Reagent and instrument and equipment：With radiolabeled dihydrotestosterone（DHT-d3）With unlabelled dihydrotestosterone（DHT）Purchase
In Sigma-Aldrich（St. Louis, MO）.Scintillation solution (scintillation solution) is purchased from Perkin
Elmer Life Sciences （Boston, MA).Hydroxyapatite (HAP) suspension is purchased from Bio-Rad Laboratories
（Hercules, CA).Buffer solution（Contain 10 mM Tris, 1.5 mM EDETATE SODIUMs, 0.25 M sucrose, 10 mM molybdenums
Sour sodium, and then pH is adjusted to 7.4 to 1 mM PMSF）.Hydroxyapatite（HAP）Washing lotion（Contain 50 mM Tris and 1 mM
KH2PO4Then pH is adjusted to 7.4）.
In the present invention, aromatic amides bioactivity shown in general formula I detects by the following method.It will prepare real
It applies some obtained the compounds of this invention of example and control compound is dissolved in DMSO, be configured to certain density mother liquor, with
DMSO is diluted to several concentration gradients, then is diluted each concentration with buffer solution（10-1NM to 104NM), 4 DEG C of ice
Case preserves until using.Androgen receptor (is prepared in the prostate of male SD rat, male Sprague-Dawley rat
200-250 grams) and with radiolabeled dihydrotestosterone（DHT-d3,84 Ci/mmol）It is added in buffer solution, mixes equal
It is even, it is configured to reaction solution, each compound concentration gradient dilution is added separately in reaction solution, is mixed evenly, 4 DEG C are incubated 15
Hour, so that compound and dihydrotestosterone is fully reacted with androgen receptor, hydroxyapatite (HAP) suspension be added, is mixed evenly,
4 DEG C are incubated 10 minutes, centrifugation, discard the supernatant containing free dihydrotestosterone.The dihydrotestosterone combined with androgen receptor is logical
It crosses and is adsorbed on hydroxyapatite and is retained in precipitation particle, combine to reaching separation and radiolabeled match with unbonded
The purpose of body.Scintillation solution (scintillation solution) is added into precipitation, is mixed evenly, WALLACE
MicroBeta Trilux liquid scintillation instruments（Perkin Elmer）Carry out radioactive intensity detection.According to each concentration ladder detected
The radioactive intensity numerical value of degree carries out data processing, obtains IC50And KiValue.Specific bioactivity（Androgen receptor ligand
Competitive radioligand result）It see the table below：
Biological activity determination in upper table the result shows that, with positive controls（Bicalutamide and the miscellaneous Shandong amine of grace）Compare,
The compounds of this invention can be combined more strongly with androgen receptor, had and more strongly resisted estrogen receptor activity.Therefore, it is possible to
More safer than existing drug, effective, novel aromatic amides antiandrogen drug is developed into, and related to androgen treating
There is important value and status in the research of disease.
The compounds of this invention can be individually or as composition for treating the various and relevant disease of androgen, such as forefront
Gland cancer, hyperplasia of prostate, breast cancer, carcinoma of urinary bladder, moreover it can be used to the treatment of the diseases such as acne, crinosity, alopecia.
Example the above is only the implementation of the present invention is not intended to limit the scope of the present invention, every to utilize this specification
Equivalent structure or equivalent flow shift made by content is applied directly or indirectly in other relevant technical fields, similarly
It is included within the scope of the invention.
Claims (14)
1. aromatic amides or its pharmaceutically acceptable salt shown in the following general formula I：
Wherein R1And R2It is each independently hydrogen atom, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base,
Cyano, nitro, halogen or amino, the C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl and C3-6Naphthenic base optionally by
1 or more halogen atom substitution；
R3And R4It is each independently hydrogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl or C3-6Cycloalkanes
Base；
R5And R6It is each independently hydrogen atom, halogen, cyano, nitro, amino, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6
Alkynyl, C3-6Naphthenic base, C1-6Alkyl-carbonyl, hydroxyl C1-6Alkyl, C1-6Alkyl-NH-C (=O)-or aryl, the C1-6Alkyl,
C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-6Naphthenic base and aryl are optionally by selected from C1-6In alkyl, halogen, cyano, nitro
1 or more substituent group substitution；
X is carbon atom or nitrogen-atoms；With
Y and Q is each independently carbon atom, nitrogen-atoms, oxygen atom or sulphur atom；N is 2 or 3.
2. aromatic amides according to claim 1 or its pharmaceutically acceptable salt, wherein R1And R2Respectively solely
It is on the spot hydrogen atom, cyano, nitro, halogen or the C optionally replaced by 1~3 halogen atom1-4Alkyl.
3. aromatic amides according to claim 1 or 2 or its pharmaceutically acceptable salt, wherein R3And R4Respectively
It independently is hydrogen atom, hydroxyl or C1-4Alkyl.
4. aromatic amides according to any one of claim 1-3 or its pharmaceutically acceptable salt, wherein R5
And R6It is each independently hydrogen atom, halogen, the C optionally replaced by 1~3 halogen atom1-4Alkyl, cyano, nitro, C1-4Alkane
Base carbonyl, 1- hydroxyethyls, N- methylcarbamoyls or aryl.
5. the aromatic amides according to any one of claim 1-4 or its pharmaceutically acceptable salt, wherein institute
Aromatic amides are stated with structure shown in following general formula II：
Wherein, R1、R2、R3、R4、R5、R6It is identical as the definition in any one of claim 1-4 respectively with the definition of X.
6. the aromatic amides according to any one of claim 1-4 or its pharmaceutically acceptable salt, wherein institute
Aromatic amides are stated with structure shown in following general formula III：
Wherein, R1、R2、R3、R4、R5、R6It is identical as the definition in any one of claim 1-4 respectively with the definition of X.
7. the aromatic amides according to any one of claim 1-6 or its pharmaceutically acceptable salt, to disappear
Revolve object, laevoisomer and/or dextroisomer.
8. aromatic amides according to claim 1 or its pharmaceutically acceptable salt, wherein the aromatic amides
Compound is selected from following compounds：
。
9. the hydration of the aromatic amides or its pharmaceutically acceptable salt according to any one of claim 1-8
Object, prodrug or internal level-one and/or secondary metabolism object.
10. the preparation method of aromatic amides described in claim 1, includes the following steps：Make compound IV and chemical combination
Object V reactions, obtain compound VI, so that gained compound VI is reacted with azido compound and are converted into compound VII；By chemical combination
Object VII catalytic hydrogen reductions, and obtain compound VIII；
When compound IX is acid, keep compound VIII and compound IX sub- in 1- ethyls -3- (3- dimethylamino-propyls) carbon two
It is reacted in the presence of amine and hydroxybenzotriazole, when compound IX is acyl chlorides, makes compound VIII and compound IX in alkalinity
Under the conditions of react, generate target compound shown in general formula I,
R shown in above-mentioned reaction equation1、R2、R3、R4、R5、R6, X, Y, Q and n definition and claim 1 in R1、R2、R3、
R4、R5、R6, X, Y, Q it is identical with the definition of n.
11. pharmaceutical composition, containing described in any one of claim 1-8 aromatic amides or its is pharmaceutically acceptable
Salt or claim 9 described in hydrate, prodrug or internal level-one and/or secondary metabolism object.
12. pharmaceutical preparation, described in any one of acceptable carrier or diluent and claim 1-8 in pharmaceutics
Hydrate, prodrug or internal level-one described in aromatic amides or its pharmaceutically acceptable salt or claim 9 and/
Or secondary metabolism object.
13. the aromatic amides or its pharmaceutically acceptable salt described in any one of claim 1-8 or claim 9
Hydrate, prodrug or the internal level-one and/or secondary metabolism object is relevant with androgen for preventing or treating in preparation
Purposes in terms of the drug of disease.
14. purposes according to claim 13, wherein it is described with the relevant disease of androgen be prostate cancer, hyperplasia of prostate,
Breast cancer, carcinoma of urinary bladder, acne, crinosity or alopecia.
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| CN109593061A (en) * | 2018-12-03 | 2019-04-09 | 昆明积大制药股份有限公司 | Androgen receptor antagonists, preparation method and its application |
| CN110179821A (en) * | 2019-05-17 | 2019-08-30 | 嘉兴市爵拓科技有限公司 | The composition and method and its application for promoting hair growth and/or color development to thicken |
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|---|---|---|---|---|
| WO1998022432A1 (en) * | 1996-11-18 | 1998-05-28 | Yamanouchi Pharmaceutical Co., Ltd. | Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same |
| WO2011035143A2 (en) * | 2009-09-17 | 2011-03-24 | The Regents Of The University Of Michigan | Methods and compositions for inhibiting rho-mediated diseases and conditions |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998022432A1 (en) * | 1996-11-18 | 1998-05-28 | Yamanouchi Pharmaceutical Co., Ltd. | Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same |
| WO2011035143A2 (en) * | 2009-09-17 | 2011-03-24 | The Regents Of The University Of Michigan | Methods and compositions for inhibiting rho-mediated diseases and conditions |
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| CN109593061A (en) * | 2018-12-03 | 2019-04-09 | 昆明积大制药股份有限公司 | Androgen receptor antagonists, preparation method and its application |
| CN109593061B (en) * | 2018-12-03 | 2021-09-14 | 昆明积大制药股份有限公司 | Androgen receptor antagonist, preparation method and application thereof |
| CN110179821A (en) * | 2019-05-17 | 2019-08-30 | 嘉兴市爵拓科技有限公司 | The composition and method and its application for promoting hair growth and/or color development to thicken |
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