JP6267112B2 - ピルビン酸キナーゼアクチベーターの使用方法 - Google Patents

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Publication number

JP6267112B2

JP6267112B2 JP2014509459A JP2014509459A JP6267112B2 JP 6267112 B2 JP6267112 B2 JP 6267112B2 JP 2014509459 A JP2014509459 A JP 2014509459A JP 2014509459 A JP2014509459 A JP 2014509459A JP 6267112 B2 JP6267112 B2 JP 6267112B2

Authority

JP

Japan

Prior art keywords

compound

phenyl

carbonyl

sulfonamide

nmr

Prior art date

2011-05-03

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.)

Expired - Fee Related

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• 229940126295 pyruvate kinase activator Drugs 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 436
• 239000000203 mixture Substances 0.000 claims description 133
• -1 carbocycle Chemical group 0.000 claims description 104
• 150000003839 salts Chemical class 0.000 claims description 60
• 125000000217 alkyl group Chemical group 0.000 claims description 50
• 125000003118 aryl group Chemical group 0.000 claims description 31
• 229910052799 carbon Inorganic materials 0.000 claims description 28
• 210000003743 erythrocyte Anatomy 0.000 claims description 24
• 125000000623 heterocyclic group Chemical group 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
• 239000003937 drug carrier Substances 0.000 claims description 21
• 125000005843 halogen group Chemical group 0.000 claims description 21
• 150000001721 carbon Chemical group 0.000 claims description 19
• 210000004369 blood Anatomy 0.000 claims description 18
• 239000008280 blood Substances 0.000 claims description 18
• 125000001188 haloalkyl group Chemical group 0.000 claims description 17
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 239000001257 hydrogen Substances 0.000 claims description 16
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 208000007475 hemolytic anemia Diseases 0.000 claims description 10
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
• XOHUEYCVLUUEJJ-UHFFFAOYSA-I 2,3-Diphosphoglycerate Chemical compound [O-]P(=O)([O-])OC(C(=O)[O-])COP([O-])([O-])=O XOHUEYCVLUUEJJ-UHFFFAOYSA-I 0.000 claims description 6
• 108700014121 Pyruvate Kinase Deficiency of Red Cells Proteins 0.000 claims description 6
• 125000002252 acyl group Chemical group 0.000 claims description 6
• 125000000304 alkynyl group Chemical group 0.000 claims description 6
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• 125000002837 carbocyclic group Chemical group 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 150000002431 hydrogen Chemical class 0.000 claims description 4
• 238000000338 in vitro Methods 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 3
• 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 3
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 3
• RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 3
• 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 claims description 3
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 3
• 208000007056 sickle cell anemia Diseases 0.000 claims description 3
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 3
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 3
• 208000030760 Anaemia of chronic disease Diseases 0.000 claims description 2
• 208000008601 Polycythemia Diseases 0.000 claims description 2
• 208000002903 Thalassemia Diseases 0.000 claims description 2
• 208000022400 anemia due to chronic disease Diseases 0.000 claims description 2
• 208000009601 hereditary spherocytosis Diseases 0.000 claims description 2
• 208000011580 syndromic disease Diseases 0.000 claims description 2
• 208000004622 abetalipoproteinemia Diseases 0.000 claims 1
• 238000005481 NMR spectroscopy Methods 0.000 description 244
• 238000004128 high performance liquid chromatography Methods 0.000 description 243
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
• 239000000243 solution Substances 0.000 description 101
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 91
• 230000002829 reductive effect Effects 0.000 description 73
• 230000015572 biosynthetic process Effects 0.000 description 72
• 238000003786 synthesis reaction Methods 0.000 description 71
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
• 239000011541 reaction mixture Substances 0.000 description 65
• 238000006243 chemical reaction Methods 0.000 description 62
• 238000000034 method Methods 0.000 description 60
• 239000011734 sodium Substances 0.000 description 53
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
• 239000000047 product Substances 0.000 description 50
• 239000000543 intermediate Substances 0.000 description 48
• 235000019439 ethyl acetate Nutrition 0.000 description 46
• 239000000741 silica gel Substances 0.000 description 46
• 229910002027 silica gel Inorganic materials 0.000 description 46
• 238000004440 column chromatography Methods 0.000 description 45
• 235000002639 sodium chloride Nutrition 0.000 description 42
• 150000001412 amines Chemical class 0.000 description 40
• 239000012044 organic layer Substances 0.000 description 36
• 238000003756 stirring Methods 0.000 description 36
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 35
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 30
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
• 239000012299 nitrogen atmosphere Substances 0.000 description 27
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
• 239000008194 pharmaceutical composition Substances 0.000 description 25
• 102000004190 Enzymes Human genes 0.000 description 24
• 108090000790 Enzymes Proteins 0.000 description 24
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
• 238000002360 preparation method Methods 0.000 description 24
• 239000002253 acid Substances 0.000 description 23
• 239000012043 crude product Substances 0.000 description 23
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
• 238000003556 assay Methods 0.000 description 21
• 239000002904 solvent Substances 0.000 description 21
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 20
• 208000035475 disorder Diseases 0.000 description 19
• 230000000694 effects Effects 0.000 description 18
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
• 210000004027 cell Anatomy 0.000 description 16
• 239000007787 solid Substances 0.000 description 16
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
• 230000035772 mutation Effects 0.000 description 15
• 239000012267 brine Substances 0.000 description 14
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
• 125000005842 heteroatom Chemical group 0.000 description 13
• 238000007792 addition Methods 0.000 description 12
• 208000024891 symptom Diseases 0.000 description 12
• 150000001299 aldehydes Chemical class 0.000 description 11
• 125000002619 bicyclic group Chemical group 0.000 description 11
• 125000004432 carbon atom Chemical group C* 0.000 description 11
• 201000010099 disease Diseases 0.000 description 11
• ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 10
• ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 10
• 239000007788 liquid Substances 0.000 description 10
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
• 102000013009 Pyruvate Kinase Human genes 0.000 description 9
• 108020005115 Pyruvate Kinase Proteins 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 239000007983 Tris buffer Substances 0.000 description 9
• 230000004913 activation Effects 0.000 description 9
• 239000003795 chemical substances by application Substances 0.000 description 9
• 125000004122 cyclic group Chemical group 0.000 description 9
• 125000001183 hydrocarbyl group Chemical group 0.000 description 9
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
• 229910052757 nitrogen Inorganic materials 0.000 description 9
• 229910052760 oxygen Inorganic materials 0.000 description 9
• 125000001424 substituent group Chemical group 0.000 description 9
• 239000000725 suspension Substances 0.000 description 9
• 238000011282 treatment Methods 0.000 description 9
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 9
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
• 239000012190 activator Substances 0.000 description 8
• 125000003710 aryl alkyl group Chemical group 0.000 description 8
• RNBGYGVWRKECFJ-ARQDHWQXSA-N beta-D-fructofuranose 1,6-bisphosphate Chemical compound O[C@H]1[C@H](O)[C@@](O)(COP(O)(O)=O)O[C@@H]1COP(O)(O)=O RNBGYGVWRKECFJ-ARQDHWQXSA-N 0.000 description 8
• 125000004452 carbocyclyl group Chemical group 0.000 description 8
• 125000000753 cycloalkyl group Chemical group 0.000 description 8
• 238000000605 extraction Methods 0.000 description 8
• 125000002950 monocyclic group Chemical group 0.000 description 8
• 238000000746 purification Methods 0.000 description 8
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
• XOHUEYCVLUUEJJ-UHFFFAOYSA-N 2,3-Bisphosphoglyceric acid Chemical compound OP(=O)(O)OC(C(=O)O)COP(O)(O)=O XOHUEYCVLUUEJJ-UHFFFAOYSA-N 0.000 description 7
• 239000012074 organic phase Substances 0.000 description 7
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
• 239000003814 drug Substances 0.000 description 5
• 235000019441 ethanol Nutrition 0.000 description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
• 238000007918 intramuscular administration Methods 0.000 description 5
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• 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 5
• BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 5
• 229930029653 phosphoenolpyruvate Natural products 0.000 description 5
• KMQGFHIJWMYRCN-UHFFFAOYSA-N 4-(4-nitrobenzoyl)piperazin-2-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)N1CC(=O)NCC1 KMQGFHIJWMYRCN-UHFFFAOYSA-N 0.000 description 4
• FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
• 101001091538 Homo sapiens Pyruvate kinase PKM Proteins 0.000 description 4
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• POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 4
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• 239000002671 adjuvant Substances 0.000 description 4
• 125000003342 alkenyl group Chemical group 0.000 description 4
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• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
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• 150000001768 cations Chemical class 0.000 description 4
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• AWBATCRJRRJIGP-UHFFFAOYSA-N n-[4-(3,5-dimethylpiperazine-1-carbonyl)phenyl]quinoline-8-sulfonamide Chemical compound C1C(C)NC(C)CN1C(=O)C(C=C1)=CC=C1NS(=O)(=O)C1=CC=CC2=CC=CN=C12 AWBATCRJRRJIGP-UHFFFAOYSA-N 0.000 description 4
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• XLIKYSFZVYNBAP-UHFFFAOYSA-N 2-oxo-n-[4-[4-(thiophen-3-ylmethyl)piperazine-1-carbonyl]phenyl]-1,3-dihydrobenzimidazole-5-sulfonamide Chemical compound C=1C=C(NS(=O)(=O)C=2C=C3NC(=O)NC3=CC=2)C=CC=1C(=O)N(CC1)CCN1CC=1C=CSC=1 XLIKYSFZVYNBAP-UHFFFAOYSA-N 0.000 description 3
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