BR112019015278A2

BR112019015278A2 - compostos

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Info

Publication number: BR112019015278A2
Authority: BR; Brazil
Prior art keywords: mmol; group; alkyl; methyl; pharmaceutically acceptable
Prior art date: 2017-01-25

Application number

BR112019015278A

Other languages

English (en)

Portuguese (pt)

Inventor

Zhao Baowei

Ren Feng

Xing Weiqiang

Ding Xiao

Zhan Yang

Sang Yingxia

Original Assignee

Glaxosmithkline Ip Dev Ltd

Priority date

2017-01-25

Filing date

2018-01-23

Publication date

2020-04-14

2018-01-23 Application filed by Glaxosmithkline Ip Dev Ltd filed Critical Glaxosmithkline Ip Dev Ltd

2020-04-14 Publication of BR112019015278A2 publication Critical patent/BR112019015278A2/pt

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 254
238000011282 treatment Methods 0.000 claims abstract description 77
238000000034 method Methods 0.000 claims abstract description 46
206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 31
208000024827 Alzheimer disease Diseases 0.000 claims abstract description 26
-1 cyano, hydroxyl Chemical group 0.000 claims description 320
150000003839 salts Chemical class 0.000 claims description 128
125000001424 substituent group Chemical group 0.000 claims description 116
125000000623 heterocyclic group Chemical group 0.000 claims description 111
125000005843 halogen group Chemical group 0.000 claims description 88
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 85
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 76
208000018737 Parkinson disease Diseases 0.000 claims description 72
229910052757 nitrogen Inorganic materials 0.000 claims description 64
125000004433 nitrogen atom Chemical group N* 0.000 claims description 54
125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 46
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 38
125000000217 alkyl group Chemical group 0.000 claims description 37
230000035772 mutation Effects 0.000 claims description 34
229910052760 oxygen Inorganic materials 0.000 claims description 31
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
229910052739 hydrogen Inorganic materials 0.000 claims description 27
239000000546 pharmaceutical excipient Substances 0.000 claims description 27
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
239000003814 drug Substances 0.000 claims description 24
125000003545 alkoxy group Chemical group 0.000 claims description 23
239000008194 pharmaceutical composition Substances 0.000 claims description 23
CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 20
125000004093 cyano group Chemical group *C#N 0.000 claims description 17
238000004519 manufacturing process Methods 0.000 claims description 17
125000000753 cycloalkyl group Chemical group 0.000 claims description 11
229940079593 drug Drugs 0.000 claims description 9
125000005842 heteroatom Chemical group 0.000 claims description 9
108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 claims description 8
208000015122 neurodegenerative disease Diseases 0.000 claims description 8
125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 7
125000004122 cyclic group Chemical group 0.000 claims description 7
230000004770 neurodegeneration Effects 0.000 claims description 7
125000004438 haloalkoxy group Chemical group 0.000 claims description 6
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
125000001153 fluoro group Chemical group F* 0.000 claims description 3
102100032693 Leucine-rich repeat serine/threonine-protein kinase 2 Human genes 0.000 claims description 2
238000002560 therapeutic procedure Methods 0.000 claims description 2
239000000203 mixture Substances 0.000 abstract description 250
108091000080 Phosphotransferase Proteins 0.000 abstract description 25
102000020233 phosphotransferase Human genes 0.000 abstract description 25
230000000694 effects Effects 0.000 abstract description 17
238000002360 preparation method Methods 0.000 abstract description 9
230000008569 process Effects 0.000 abstract description 5
102000001253 Protein Kinase Human genes 0.000 abstract description 4
108060006633 protein kinase Proteins 0.000 abstract description 3
230000006806 disease prevention Effects 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 584
235000019439 ethyl acetate Nutrition 0.000 description 286
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 245
229910001868 water Inorganic materials 0.000 description 232
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 219
239000000243 solution Substances 0.000 description 205
239000007787 solid Substances 0.000 description 186
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 179
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239000011541 reaction mixture Substances 0.000 description 123
238000006243 chemical reaction Methods 0.000 description 121
239000012071 phase Substances 0.000 description 121
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 115
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 110
238000005481 NMR spectroscopy Methods 0.000 description 107
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 99
239000000047 product Substances 0.000 description 97
239000012267 brine Substances 0.000 description 92
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 92
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 89
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208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 62
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125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 54
239000012043 crude product Substances 0.000 description 52
201000010099 disease Diseases 0.000 description 52
238000004440 column chromatography Methods 0.000 description 47
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238000004587 chromatography analysis Methods 0.000 description 40
229910000404 tripotassium phosphate Inorganic materials 0.000 description 40
235000019798 tripotassium phosphate Nutrition 0.000 description 40
239000000706 filtrate Substances 0.000 description 39
239000003921 oil Substances 0.000 description 37
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
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ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
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229910017906 NH3H2O Inorganic materials 0.000 description 31
KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 30
DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 30
239000002904 solvent Substances 0.000 description 30
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
229910052938 sodium sulfate Inorganic materials 0.000 description 29
235000011152 sodium sulphate Nutrition 0.000 description 29
239000007832 Na2SO4 Substances 0.000 description 28
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
239000001301 oxygen Substances 0.000 description 28
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 27
239000000725 suspension Substances 0.000 description 26
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
238000004809 thin layer chromatography Methods 0.000 description 23
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
238000000746 purification Methods 0.000 description 21
238000010898 silica gel chromatography Methods 0.000 description 21
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 20
239000012074 organic phase Substances 0.000 description 19
PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 18
102200092160 rs34637584 Human genes 0.000 description 18
KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 17
241000896938 Dikwa Species 0.000 description 16
229940124786 LRRK2 inhibitor Drugs 0.000 description 16
125000004432 carbon atom Chemical group C* 0.000 description 15
239000000460 chlorine Substances 0.000 description 15
KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 15
IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 15
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
239000002253 acid Substances 0.000 description 14
125000004429 atom Chemical group 0.000 description 14
239000012230 colorless oil Substances 0.000 description 14
JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 14
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
239000003153 chemical reaction reagent Substances 0.000 description 13
239000000543 intermediate Substances 0.000 description 13
125000003566 oxetanyl group Chemical group 0.000 description 13
125000003386 piperidinyl group Chemical group 0.000 description 13
239000002585 base Substances 0.000 description 12
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
210000004027 cell Anatomy 0.000 description 11
238000003818 flash chromatography Methods 0.000 description 11
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 11
125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 11
TVTOCLWXRZCKIL-UHFFFAOYSA-N tert-butyl 4-(5-methyl-1H-indazol-6-yl)piperidine-1-carboxylate Chemical compound CC1=CC2=C(NN=C2)C=C1C1CCN(CC1)C(=O)OC(C)(C)C TVTOCLWXRZCKIL-UHFFFAOYSA-N 0.000 description 11
239000003112 inhibitor Substances 0.000 description 10
230000002265 prevention Effects 0.000 description 10
QFKPIRBSLXURDL-YUMQZZPRSA-N (1S,4S)-5-(6-iodo-2-methylpyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane Chemical compound IC1=CC(=NC(=N1)C)N1[C@@H]2CO[C@H](C1)C2 QFKPIRBSLXURDL-YUMQZZPRSA-N 0.000 description 9
208000035475 disorder Diseases 0.000 description 9
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JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
PEJMENKOZJMEMK-RNFRBKRXSA-N (1R,4R)-5-(6-iodo-2-methoxypyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane Chemical compound IC1=CC(=NC(=N1)OC)N1[C@H]2CO[C@@H](C1)C2 PEJMENKOZJMEMK-RNFRBKRXSA-N 0.000 description 8
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
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CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
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VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical compound CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 description 8
238000004296 chiral HPLC Methods 0.000 description 8
230000006870 function Effects 0.000 description 8
239000002808 molecular sieve Substances 0.000 description 8
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
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RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 8
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IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 7
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125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 7
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206010028980 Neoplasm Diseases 0.000 description 6
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