JP2006131559A - Nitrogen-containing heterocyclic compound - Google Patents
Nitrogen-containing heterocyclic compound Download PDFInfo
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- JP2006131559A JP2006131559A JP2004323008A JP2004323008A JP2006131559A JP 2006131559 A JP2006131559 A JP 2006131559A JP 2004323008 A JP2004323008 A JP 2004323008A JP 2004323008 A JP2004323008 A JP 2004323008A JP 2006131559 A JP2006131559 A JP 2006131559A
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- -1 Nitrogen-containing heterocyclic compound Chemical class 0.000 title abstract description 263
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 42
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 24
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 22
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 125000003277 amino group Chemical group 0.000 claims abstract description 17
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 11
- 208000008589 Obesity Diseases 0.000 claims abstract description 11
- 235000020824 obesity Nutrition 0.000 claims abstract description 11
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 10
- 206010020772 Hypertension Diseases 0.000 claims abstract description 10
- 208000001076 sarcopenia Diseases 0.000 claims abstract description 10
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 claims abstract description 9
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 9
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 2
- 125000001424 substituent group Chemical group 0.000 claims description 69
- 150000003839 salts Chemical class 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 28
- 229940124597 therapeutic agent Drugs 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 125000005750 substituted cyclic group Chemical group 0.000 claims description 11
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 10
- 229940002612 prodrug Drugs 0.000 claims description 10
- 239000000651 prodrug Substances 0.000 claims description 10
- 206010019280 Heart failures Diseases 0.000 claims description 8
- 230000000069 prophylactic effect Effects 0.000 claims description 5
- 229940121373 acetyl-coa carboxylase inhibitor Drugs 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 20
- 230000002265 prevention Effects 0.000 abstract description 7
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 125000003003 spiro group Chemical group 0.000 abstract description 2
- 230000000747 cardiac effect Effects 0.000 abstract 1
- 230000007721 medicinal effect Effects 0.000 abstract 1
- 125000006574 non-aromatic ring group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
- 125000005843 halogen group Chemical group 0.000 description 69
- 239000002904 solvent Substances 0.000 description 52
- 239000003921 oil Substances 0.000 description 49
- 235000019198 oils Nutrition 0.000 description 49
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 39
- 235000002639 sodium chloride Nutrition 0.000 description 39
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 34
- 238000000034 method Methods 0.000 description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 32
- 238000000746 purification Methods 0.000 description 31
- 239000000243 solution Substances 0.000 description 31
- 238000002360 preparation method Methods 0.000 description 25
- 230000002829 reductive effect Effects 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 150000002430 hydrocarbons Chemical group 0.000 description 22
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 21
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 20
- 239000004215 Carbon black (E152) Substances 0.000 description 19
- 229930195733 hydrocarbon Natural products 0.000 description 19
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 18
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 18
- 239000008103 glucose Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 17
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 17
- 108010018763 Biotin carboxylase Proteins 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 101000677540 Homo sapiens Acetyl-CoA carboxylase 2 Proteins 0.000 description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 125000000217 alkyl group Chemical group 0.000 description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 14
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 13
- 125000003710 aryl alkyl group Chemical group 0.000 description 13
- 239000000872 buffer Substances 0.000 description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 13
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 11
- 102100021334 Bcl-2-related protein A1 Human genes 0.000 description 11
- 101000894929 Homo sapiens Bcl-2-related protein A1 Proteins 0.000 description 11
- 206010056997 Impaired fasting glucose Diseases 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 10
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 10
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- AVQCLRKABAZVMZ-UHFFFAOYSA-N 4-phenylmethoxycarbonylmorpholine-2-carboxylic acid Chemical compound C1COC(C(=O)O)CN1C(=O)OCC1=CC=CC=C1 AVQCLRKABAZVMZ-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 8
- 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 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000007995 HEPES buffer Substances 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 description 8
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 108091008146 restriction endonucleases Proteins 0.000 description 8
- 241000701447 unidentified baculovirus Species 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 125000002541 furyl group Chemical group 0.000 description 7
- 125000001041 indolyl group Chemical group 0.000 description 7
- 125000001624 naphthyl group Chemical group 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
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- 238000012360 testing method Methods 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- XGWFJBFNAQHLEF-UHFFFAOYSA-N 9-anthroic acid Chemical compound C1=CC=C2C(C(=O)O)=C(C=CC=C3)C3=CC2=C1 XGWFJBFNAQHLEF-UHFFFAOYSA-N 0.000 description 6
- 206010006895 Cachexia Diseases 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 6
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 6
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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- 125000005493 quinolyl group Chemical group 0.000 description 6
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Abstract
Description
本発明は、アセチル−CoAカルボキシラーゼ(本明細書中、ACCと略記することがある)阻害作用を有し、肥満症、糖尿病、高血圧症、高脂血症、心不全、糖尿病性心筋症、メタボリックシンドローム、筋肉減少症などの予防・治療に有用な含窒素複素環化合物に関する。 The present invention has an inhibitory action on acetyl-CoA carboxylase (sometimes abbreviated as ACC in the present specification), and is obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, metabolic syndrome Further, the present invention relates to a nitrogen-containing heterocyclic compound useful for prevention / treatment of sarcopenia and the like.
ACCは、アセチル−CoAをマロニル−CoAに変換する酵素であり、脂肪酸代謝での律速反応を触媒する。ACC触媒反応の産物であるマロニル-CoAは、カルニチンパルミトイルトランスフェラーゼ−1(CPT−1)のフィードバック阻害により、ミトコンドリアの脂肪酸酸化を阻害する。従って、ACCは肝臓と骨格筋での炭水化物と脂肪酸利用のバランスを制御するのに、また、肝臓、骨格筋、脂肪組織でのインスリン感受性を制御するのに鍵となる役割を演ずる。 ACC is an enzyme that converts acetyl-CoA to malonyl-CoA and catalyzes a rate-limiting reaction in fatty acid metabolism. Malonyl-CoA, the product of the ACC catalytic reaction, inhibits mitochondrial fatty acid oxidation by feedback inhibition of carnitine palmitoyltransferase-1 (CPT-1). Thus, ACC plays a key role in controlling the balance of carbohydrate and fatty acid utilization in the liver and skeletal muscle, and in controlling insulin sensitivity in the liver, skeletal muscle, and adipose tissue.
ACC阻害によるマロニル−CoAレベルの低下は、脂肪酸利用の増加、肝臓によるTG豊富なリポ蛋白質(VLDL)の分泌低下、膵臓によるインスリン分泌の制御、さらには肝臓、骨格筋、脂肪組織でのインスリン感受性の改善を促し得る。 Decreased malonyl-CoA levels due to ACC inhibition are increased fatty acid utilization, decreased secretion of TG-rich lipoprotein (VLDL) by the liver, regulation of insulin secretion by the pancreas, and insulin sensitivity in the liver, skeletal muscle, and adipose tissue Can be improved.
また、脂肪酸利用を促進し、デノボ脂肪酸合成を抑制することによって、ACC阻害作用を有する化合物の慢性投与は、低脂肪食事を消費する肥満被験体において、肝臓と脂肪組織のTG含量を激減させ、身体脂肪を選択的に減少させ得る。 In addition, chronic administration of a compound having an ACC inhibitory action by promoting fatty acid utilization and suppressing de novo fatty acid synthesis drastically reduces the TG content of liver and adipose tissue in obese subjects consuming a low fat diet, It can selectively reduce body fat.
従って、ACC阻害作用を有する化合物は、メタボリックシンドローム、肥満症、高血圧症、糖尿病、アテローム性動脈硬化と関連する心臓血管系疾患などの予防および治療に極めて有用である。 Therefore, a compound having an ACC inhibitory action is extremely useful for the prevention and treatment of metabolic syndrome, obesity, hypertension, diabetes, cardiovascular diseases associated with atherosclerosis, and the like.
一方、含窒素複素環化合物としては以下の化合物が報告されている。
(1)小コンダクタンス型Ca2+依存性カリウムチャネル遮断作用を有し、消化管運動機能不全、学習記憶障害などの治療剤として有用な、式:
On the other hand, the following compounds have been reported as nitrogen-containing heterocyclic compounds.
(1) It has a small conductance type Ca 2+ -dependent potassium channel blocking action and is useful as a therapeutic agent for gastrointestinal motility dysfunction, learning memory impairment, etc.
[式中、環Aは、置換されていてもよいベンゼン環を;R10は水素原子などを;R2は水素原子、置換されていてもよい複素環基を;BはN、CHを;R3は置換されていてもよいアミノ基、置換されていてもよい含窒素脂肪族複素環式基を;YはCH2、COを示す。]
で表される化合物(特許文献1参照)。
[Wherein, ring A represents an optionally substituted benzene ring; R 10 represents a hydrogen atom or the like; R 2 represents a hydrogen atom or an optionally substituted heterocyclic group; B represents N or CH; R 3 represents an optionally substituted amino group, an optionally substituted nitrogen-containing aliphatic heterocyclic group; Y represents CH 2 or CO. ]
The compound represented by (refer patent document 1).
(2)ACC阻害作用を有し、メタボリックシンドローム、動脈硬化、糖尿病、肥満などの治療剤として有用な、式: (2) A compound having an ACC inhibitory effect and useful as a therapeutic agent for metabolic syndrome, arteriosclerosis, diabetes, obesity and the like:
[式中、A−BはN−CH、CH−Nを;Kは(CH2)r(rは2−4の整数を示す。)を;mおよびnはそれぞれ1−3の整数を;DはCO、SO2を;Eは置換されていてもよい2−4環性環などを;GはCO、SO2、CR7R8(R7およびR8はそれぞれ水素原子などを示す。)を;JはOR1、NR2R3、CR4R5R6(R1、R2、R3、R4、R5およびR6はそれぞれ水素原子などを示す。)を示す。]
で表される化合物(特許文献2参照)。
[Wherein, AB represents N—CH and CH—N; K represents (CH 2 ) r (r represents an integer of 2-4); m and n each represent an integer of 1-3; D represents CO or SO 2 ; E represents an optionally substituted 2-4 ring or the like; G represents CO, SO 2 or CR 7 R 8 (R 7 and R 8 each represent a hydrogen atom or the like. J represents OR 1 , NR 2 R 3 , CR 4 R 5 R 6 (R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each represents a hydrogen atom or the like). ]
The compound represented by (refer patent document 2).
(3)トリプターゼ阻害作用を有し、炎症性疾患、心筋梗塞、糖尿病性網膜症などの治療剤として有用な、式: (3) It has a tryptase inhibitory action and is useful as a therapeutic agent for inflammatory diseases, myocardial infarction, diabetic retinopathy, etc.
[式中、Arはアリール、ヘテロアリール(Ar上の−CR1R2NH2の結合位置は含有環基の結合位置に対してベータ位である。)を;R1およびR2はそれぞれ水素原子、低級アルキルを;R3はアリール、ヘテロアリールなどを;R4は水素原子、アシルなどを;nは0−4の整数を示す。]
で表される化合物(特許文献3参照)。
[Wherein, Ar is aryl, heteroaryl (the bonding position of —CR 1 R 2 NH 2 on Ar is a beta position relative to the bonding position of the containing ring group); R 1 and R 2 are each hydrogen; Atom, lower alkyl; R 3 represents aryl, heteroaryl, etc .; R 4 represents a hydrogen atom, acyl, etc .; n represents an integer of 0-4. ]
The compound represented by (refer patent document 3).
(4)血小板凝集抑制作用、血管拡張作用、抗高脂血作用などを有する循環器官用剤として有用な、式: (4) Useful as a circulatory organ agent having platelet aggregation inhibitory action, vasodilatory action, antihyperlipidemic action, etc.
[式中、Arは置換されていてもよいフェニル、ナフチル、キノリル、インドリルなどを;XはCO、SO2を;QはO、単結合を;ZはC1−3アルキレン、−C(R5)(R6)−(R5およびR6はそれぞれアルキルを示す。)を;R4はOH、NH(CH2)mCOOH(mは1−3の整数を示す。)を示す。]
で表される化合物(特許文献4参照)。
[Wherein Ar represents an optionally substituted phenyl, naphthyl, quinolyl, indolyl, etc .; X represents CO, SO 2 ; Q represents O, a single bond; Z represents C 1-3 alkylene, —C (R 5 ) (R 6 ) — (R 5 and R 6 each represents alkyl); R 4 represents OH, NH (CH 2 ) m COOH (m represents an integer of 1-3). ]
The compound represented by (refer patent document 4).
(5)カルモジュリン拮抗作用などを有し、血管拡張薬、脳循環改善薬、狭心症治療薬、血圧降下剤として有用な、式: (5) It has a calmodulin antagonistic action and is useful as a vasodilator, a cerebral circulation improving agent, an angina pectoris, and a blood pressure lowering agent.
[式中、Rは水素原子、低級アルキルを;R1およびR2はそれぞれ水素原子などを;ZはN(R3)(R4)(R3およびR4は水素原子を示し、両者で複素環(低級アルキル、アシル、フェニル(ハロゲン、低級アルキルなどで置換されていてもよい。)などで置換されていてもよい。)を形成してもよい。)を示す。]
で表される化合物(特許文献5参照)。
[Wherein, R represents a hydrogen atom and lower alkyl; R 1 and R 2 represent a hydrogen atom, respectively; Z represents N (R 3 ) (R 4 ) (R 3 and R 4 represent a hydrogen atom, A heterocyclic ring (which may be substituted with lower alkyl, acyl, phenyl (which may be substituted with halogen, lower alkyl, etc.), etc.). ]
(Refer patent document 5).
(6)慢性関節リウマチ治療剤として有用な、式: (6) Formula useful as a therapeutic agent for rheumatoid arthritis:
[式中、X1はNH2、OHを;X2はCO、COO、CONH、SO2を;R1はアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリールなどを;R2は水素原子、アルキル、置換されていてもよいアリールを;R3はアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリールなど、または−(CH2)m’−A’(m’は1−4の整数を;A’はハロゲンなどを示す。)を示す。]
で表される化合物(特許文献6参照)。
Wherein X 1 is NH 2 , OH; X 2 is CO, COO, CONH, SO 2 ; R 1 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, etc .; R 2 is a hydrogen atom, alkyl, optionally substituted aryl; R 3 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, etc., or — (CH 2 ) m ′ -A '(M' represents an integer of 1-4; A 'represents halogen or the like). ]
(Refer patent document 6).
(7)TNF産生分泌阻害作用、レトロウィルスのロングタームリピート転写活性化阻害作用を有し、敗血症ショック、骨関節炎、非インスリン依存性糖尿病、アテローム性動脈硬化症などの治療剤として有用な、式: (7) TNF production secretion inhibitory action, retroviral long term repeat transcription activation inhibitory action, useful as a therapeutic agent for septic shock, osteoarthritis, non-insulin dependent diabetes, atherosclerosis, etc. :
[式中、X1はNH2、OHを;X2はCO、COO、CONH、SO2を;R1はアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリールなどを;R2は水素原子、アルキル、置換されていてもよいアリールを;R3はアルキル、置換されていてもよいアリール、置換されていてもよいヘテロアリールなど、または−(CH2)m’−A’(m’は1−4の整数を;A’はハロゲンなどを示す)を示し、R2とR3はピリミジン環と共に置換されていてもよいキナゾリンまたは置換されていてもよいピリドピリミジンを形成してもよい。]
で表される化合物(特許文献7、8参照)。
[Wherein X 1 is NH 2 , OH; X 2 is CO, COO, CONH, SO 2 ; R 1 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, etc .; R 2 is a hydrogen atom, alkyl, optionally substituted aryl; R 3 is alkyl, optionally substituted aryl, optionally substituted heteroaryl, etc., or — (CH 2 ) m ′ -A '(M' represents an integer of 1-4; A 'represents halogen or the like), and R 2 and R 3 represent an optionally substituted quinazoline or an optionally substituted pyridopyrimidine together with a pyrimidine ring. It may be formed. ]
(Refer to patent documents 7 and 8).
しかしながら、本発明の化合物についての報告はない。 However, there are no reports on the compounds of the present invention.
ACC阻害作用を有し、肥満症、糖尿病、高血圧症、高脂血症、心不全、糖尿病性心筋症、メタボリックシンドローム、筋肉減少症などの予防・治療に有用であり、かつ薬効、作用時間、特異性、低毒性などの点で優れた性質を有する化合物の開発が望まれている。 Has ACC inhibitory action, is useful for prevention and treatment of obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, metabolic syndrome, sarcopenia, etc. Development of a compound having excellent properties in terms of properties and low toxicity is desired.
本発明者らは、芳香環または2個以上のヘテロ原子を含む非芳香族複素環が結合した環状アミンを化学構造上の特徴として有する、式 The present inventors have a chemical structure characterized by a cyclic amine to which an aromatic ring or a non-aromatic heterocycle containing two or more heteroatoms is bonded.
[式中、
Eは、置換されていてもよい環状基(ただし、該環状基はスピロ環基でない。また、該環状基が単環基であるとき、該環状基は、置換基として、置換されていてもよい環状基を少なくとも2個有する。)を;
DおよびGは、独立してカルボニル基またはスルホニル基を;
環Pは、置換されていてもよい含窒素5または6員非芳香族複素環を;
環Qは、置換されていてもよい芳香環または置換されていてもよい非芳香族複素環(ただし該非芳香族複素環は2個以上のヘテロ原子を含む)を;
AおよびLは、独立してC、CHまたはNを;
Jは、置換されていてもよい炭化水素基、置換されていてもよいヒドロキシ基、置換されていてもよい複素環基または置換されていてもよいアミノ基を示す。]
で表される化合物またはその塩(ただし、「4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-2-(モルホリン-4-イルカルボニル)モルホリン」を除く)[以下、化合物(I)と称することがある。]が、優れたACC阻害作用を有し、肥満症、糖尿病、高血圧症、高脂血症、心不全、糖尿病性心筋症、メタボリックシンドローム、筋肉減少症などの予防・治療に有用であることを初めて見出した。この知見に基づいて、本発明者らは、鋭意研究を行い、本発明を完成するに至った。即ち、本発明は、
(1)化合物(I);
(2)Eが置換されていてもよい芳香環基である化合物(I);
(3)化合物(I)のプロドラッグ;
(4)化合物(I)またはそのプロドラッグを含有してなる医薬;
(5)化合物(I)またはそのプロドラッグを含有してなるアセチル−CoAカルボキシラーゼ阻害剤;
(6)肥満症、糖尿病、高血圧症、高脂血症、心不全、糖尿病性心筋症、メタボリックシンドロームまたは筋肉減少症の予防・治療剤である前記(4)の医薬;
などに関する。
[Where:
E represents an optionally substituted cyclic group (provided that the cyclic group is not a spirocyclic group. When the cyclic group is a monocyclic group, the cyclic group may be substituted as a substituent. Having at least two good cyclic groups);
D and G independently represent a carbonyl group or a sulfonyl group;
Ring P represents an optionally substituted nitrogen-containing 5- or 6-membered non-aromatic heterocyclic ring;
Ring Q is an optionally substituted aromatic ring or an optionally substituted non-aromatic heterocycle (wherein the non-aromatic heterocycle contains 2 or more heteroatoms);
A and L independently represent C, CH or N;
J represents a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted. ]
Or a salt thereof (excluding “4- [1- (9-anthrylcarbonyl) piperidin-4-yl] -2- (morpholin-4-ylcarbonyl) morpholine”) [hereinafter, a compound Sometimes referred to as (I). For the first time, it has an excellent ACC inhibitory action and is useful for the prevention and treatment of obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, metabolic syndrome, sarcopenia, etc. I found it. Based on this knowledge, the present inventors have conducted intensive studies and completed the present invention. That is, the present invention
(1) Compound (I);
(2) Compound (I), wherein E is an optionally substituted aromatic ring group;
(3) prodrugs of compound (I);
(4) A medicament comprising compound (I) or a prodrug thereof;
(5) An acetyl-CoA carboxylase inhibitor comprising compound (I) or a prodrug thereof;
(6) The medicament according to (4), which is a prophylactic / therapeutic agent for obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, metabolic syndrome or sarcopenia;
And so on.
本発明化合物は、ACC阻害作用を有し、肥満症、糖尿病、高血圧症、高脂血症、心不全、糖尿病性心筋症、メタボリックシンドローム、筋肉減少症などの予防・治療に有用である。 The compound of the present invention has an ACC inhibitory action and is useful for the prevention and treatment of obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, metabolic syndrome, sarcopenia and the like.
以下、式(I)中の各記号の定義について詳述する。
なお、本明細書中、「ハロゲン原子」は、特に断りのない限り、フッ素、塩素、臭素およびヨウ素を意味する。
Jで示される「置換されていてもよい炭化水素基」の「炭化水素基」としては、例えば、C1-10アルキル基、C2-10アルケニル基、C2-10アルキニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C4-10シクロアルカジエニル基、C6-14芳香族炭化水素基、C7-13アラルキル基、C8-13芳香族炭化水素アルケニル基、C3-10シクロアルキル−C1-6アルキル基などが挙げられる。
Hereinafter, the definition of each symbol in formula (I) will be described in detail.
In the present specification, “halogen atom” means fluorine, chlorine, bromine and iodine unless otherwise specified.
Examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by J include C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group, C 3− 10 cycloalkyl group, C 3-10 cycloalkenyl group, C 4-10 cycloalkadienyl group, C 6-14 aromatic hydrocarbon group, C 7-13 aralkyl group, C 8-13 aromatic hydrocarbon alkenyl group And C 3-10 cycloalkyl-C 1-6 alkyl group.
ここで、C1-10アルキル基としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、イソペンチル、ネオペンチル、1−エチルプロピル、ヘキシル、イソヘキシル、1,1−ジメチルブチル、2,2−ジメチルブチル、3,3−ジメチルブチル、2−エチルブチル、ヘプチル、オクチル、ノニル、デシルなどが挙げられる。
C2-10アルケニル基としては、例えば、エテニル、1−プロペニル、2−プロペニル、2−メチル−1−プロペニル、1−ブテニル、2−ブテニル、3−ブテニル、3−メチル−2−ブテニル、1−ペンテニル、2−ペンテニル、3−ペンテニル、4−ペンテニル、4−メチル−3−ペンテニル、1−ヘキセニル、3−ヘキセニル、5−ヘキセニル、1−ヘプテニル、1−オクテニルなどが挙げられる。
C2-10アルキニル基としては、例えば、エチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1−ペンチニル、2−ペンチニル、3−ペンチニル、4−ペンチニル、1−ヘキシニル、2−ヘキシニル、3−ヘキシニル、4−ヘキシニル、5−ヘキシニル、1−ヘプチニル、1−オクチニルなどが挙げられる。
Here, examples of the C 1-10 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
Examples of the C 2-10 alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1 -Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned.
Examples of the C 2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
C3-10シクロアルキル基としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、ビシクロ[2.2.1]ヘプチル、ビシクロ[2.2.2]オクチル、ビシクロ[3.2.1]オクチル、ビシクロ[3.2.2]ノニル、ビシクロ[3.3.1]ノニル、ビシクロ[4.2.1]ノニル、ビシクロ[4.3.1]デシル、アダマンチルなどが挙げられる。
C3-10シクロアルケニル基としては、例えば、2−シクロペンテン−1−イル、3−シクロペンテン−1−イル、2−シクロヘキセン−1−イル、3−シクロヘキセン−1−イルなどが挙げられる。
C4-10シクロアルカジエニル基としては、例えば、2,4−シクロペンタジエン−1−イル、2,4−シクロヘキサジエン−1−イル、2,5−シクロヘキサジエン−1−イルなどが挙げられる。
C6-14芳香族炭化水素基としては、例えば、フェニル、ナフチル、アントリル、フェナントリル、アセナフチレニル、ビフェニリルなどが挙げられる。なかでもフェニル、1−ナフチル、2−ナフチルなどが好ましい。
C7-13アラルキル基としては、例えば、ベンジル、フェネチル、ナフチルメチル、ビフェニリルメチルなどが挙げられる。
C8-13芳香族炭化水素アルケニル基としては、例えば、スチリルなどが挙げられる。
C3-10シクロアルキル−C1-6アルキル基としては、例えば、シクロヘキシルメチルなどが挙げられる。
Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, and bicyclo [3. 2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like. Can be mentioned.
Examples of the C 3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
Examples of the C 4-10 cycloalkadienyl group include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, and the like. .
Examples of the C 6-14 aromatic hydrocarbon group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like. Of these, phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.
Examples of the C 7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.
Examples of the C 8-13 aromatic hydrocarbon alkenyl group include styryl and the like.
Examples of the C 3-10 cycloalkyl-C 1-6 alkyl group include cyclohexylmethyl and the like.
前記したC1-10アルキル基、C2-10アルケニル基およびC2-10アルキニル基は、置換可能な位置に1ないし3個の置換基を有していてもよい。
このような置換基としては、例えば、
(1)C3-10シクロアルキル基(例、シクロプロピル、シクロヘキシル);
(2)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC6-14芳香族炭化水素基(例、フェニル、ナフチル);
(3)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、チエニル、フリル、ピリジル、オキサゾリル、チアゾリル、テトラゾリル、オキサジアゾリル、ピラジニル、キノリル、インドリル);
(4)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)、オキソ基およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、テトラヒドロフリル、モルホリニル、チオモルホリニル、ピペリジニル、ピロリジニル、ピペラジニル、ジオキソリル、ジオキソラニル、1,3−ジヒドロ−2−ベンゾフラニル、チアゾリジエニル);
(5)C1-6アルキル基(例、メチル、エチル)、C1-6アルキル−カルボニル基(例、アセチル、イソブタノイル、イソペンタノイル)およびC1-6アルコキシ−カルボニル基(例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、tert−ブトキシカルボニル)から選ばれる置換基でモノあるいはジ置換されていてもよいアミノ基;
(6)C1-6アルキルスルホニルアミノ基(例、メチルスルホニルアミノ);
(7)アミジノ基;
(8)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル−カルボニル基(例、アセチル、イソブタノイル、イソペンタノイル);
(9)1〜3個のハロゲン原子で置換されていてもよいC1-6アルコキシ−カルボニル基(例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、tert−ブトキシカルボニル);
(10)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル);
(11)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)でモノあるいはジ置換されていてもよいカルバモイル基;
(12)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)でモノあるいはジ置換されていてもよいチオカルバモイル基;
(13)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)でモノあるいはジ置換されていてもよいスルファモイル基;
(14)カルボキシル基;
(15)ヒドロキシ基;
(16)1〜3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ、エトキシ);
(17)1〜3個のハロゲン原子で置換されていてもよいC2-6アルケニルオキシ基(例、エテニルオキシ);
(18)C3-10シクロアルキルオキシ基(例、シクロヘキシルオキシ);
(19)C7-13アラルキルオキシ基(例、ベンジルオキシ);
(20)C6-14芳香族炭化水素オキシ基(例、フェニルオキシ、ナフチルオキシ);
(21)C1-6アルキル−カルボニルオキシ基(例、アセチルオキシ、tert−ブチルカルボニルオキシ);
(22)チオール基;
(23)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキルチオ基(例、メチルチオ、エチルチオ);
(24)C7-13アラルキルチオ基(例、ベンジルチオ);
(25)C6-14芳香族炭化水素チオ基(例、フェニルチオ、ナフチルチオ);
(26)スルホ基;
(27)シアノ基;
(28)アジド基;
(29)ニトロ基;
(30)ニトロソ基;
(31)ハロゲン原子;
(32)C1-6アルキルスルフィニル基(例、メチルスルフィニル);
などが挙げられる。
Wherein the C 1-10 alkyl group, C 2-10 alkenyl and C 2-10 alkynyl group may have 1 to 3 substituents at substitutable positions.
As such a substituent, for example,
(1) C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl);
(2) C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms, hydroxy group, C 1-6 alkoxy group (eg, methoxy, ethoxy) and halogen atom A C 6-14 aromatic hydrocarbon group (eg, phenyl, naphthyl) optionally substituted by 1 to 3 substituents selected from:
(3) C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms, hydroxy group, C 1-6 alkoxy group (eg, methoxy, ethoxy) and halogen atom An aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from (for example, thienyl, furyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, indolyl);
(4) C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms, hydroxy group, C 1-6 alkoxy group (eg, methoxy, ethoxy), oxo group And a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (eg, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, dioxolyl, dioxolanyl, 1,3- Dihydro-2-benzofuranyl, thiazolidienyl);
(5) C 1-6 alkyl group (eg, methyl, ethyl), C 1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl) and C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) Amino group optionally mono- or di-substituted with a substituent selected from ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl);
(6) C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino);
(7) amidino group;
(8) a C 1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl) optionally substituted by 1 to 3 halogen atoms;
(9) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl) optionally substituted by 1 to 3 halogen atoms;
(10) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted by 1 to 3 halogen atoms;
(11) a carbamoyl group which may be mono- or di-substituted with a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms;
(12) a thiocarbamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms;
(13) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms;
(14) carboxyl group;
(15) hydroxy group;
(16) a C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with 1 to 3 halogen atoms;
(17) a C 2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms;
(18) C 3-10 cycloalkyloxy group (eg, cyclohexyloxy);
(19) C 7-13 aralkyloxy group (eg, benzyloxy);
(20) C 6-14 aromatic hydrocarbon oxy group (eg, phenyloxy, naphthyloxy);
(21) C 1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(22) a thiol group;
(23) a C 1-6 alkylthio group (eg, methylthio, ethylthio) optionally substituted by 1 to 3 halogen atoms;
(24) C 7-13 aralkylthio group (e.g., benzylthio);
(25) C 6-14 aromatic hydrocarbon thio group (eg, phenylthio, naphthylthio);
(26) a sulfo group;
(27) a cyano group;
(28) an azido group;
(29) a nitro group;
(30) Nitroso group;
(31) a halogen atom;
(32) C 1-6 alkylsulfinyl group (eg, methylsulfinyl);
Etc.
また、前記「炭化水素基」として例示した、C3-10シクロアルキル基、C3-10シクロアルケニル基、C4-10シクロアルカジエニル基、C6-14芳香族炭化水素基、C7-13アラルキル基、C8-13芳香族炭化水素アルケニル基およびC3-10シクロアルキル−C1-6アルキル基は、置換可能な位置に1ないし3個の置換基を有していてもよい。
このような置換基としては、例えば、
(1)前記したC1-10アルキル基等における置換基として例示した置換基;
(2)ハロゲン原子、カルボキシル基、C1-6アルコキシ−カルボニル基(例、メトキシカルボニル、エトキシカルボニル)およびカルバモイル基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル、エチル);
(3)ハロゲン原子、カルボキシル基、C1-6アルコキシ−カルボニル基(例、メトキシカルボニル、エトキシカルボニル)およびカルバモイル基から選ばれる1ないし3個の置換基で置換されていてもよいC2-6アルケニル基(例、エテニル、1−プロペニル);
(4)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基、ヒドロキシ基、C1-6アルコキシ基およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC7-13アラルキル基(例、ベンジル);
(5)オキソ基;
などが挙げられる。
In addition, the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group, the C 4-10 cycloalkadienyl group, the C 6-14 aromatic hydrocarbon group, the C 7 exemplified as the “hydrocarbon group”. -13 aralkyl group, C 8-13 aromatic hydrocarbon alkenyl group and C 3-10 cycloalkyl-C 1-6 alkyl group may have 1 to 3 substituents at substitutable positions. .
As such a substituent, for example,
(1) Substituents exemplified as substituents in the aforementioned C 1-10 alkyl group and the like;
(2) a halogen atom, a carboxyl group, C 1-6 alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl) to 1 selected from and carbamoyl groups optionally substituted with 1-3 substituents C 1-6 An alkyl group (eg, methyl, ethyl);
(3) C 2-6 optionally substituted by 1 to 3 substituents selected from a halogen atom, a carboxyl group, a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) and a carbamoyl group An alkenyl group (eg, ethenyl, 1-propenyl);
(4) substituted with 1 to 3 substituents selected from a C 1-6 alkyl group, a hydroxy group, a C 1-6 alkoxy group and a halogen atom which may be substituted with 1 to 3 halogen atoms An optionally substituted C 7-13 aralkyl group (eg, benzyl);
(5) an oxo group;
Etc.
Jで示される「置換されていてもよいヒドロキシ基」としては、例えば、それぞれ置換されていてもよい、C1-10アルキル基、C2-10アルケニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C6-14芳香族炭化水素基、C7-13アラルキル基、C8-13芳香族炭化水素アルケニル基、C1-6アルキル−カルボニル基(例、アセチル、イソブタノイル、イソペンタノイル)、5または6員芳香族複素環基、縮合芳香族複素環基などから選ばれる置換基で置換されていてもよいヒドロキシ基が挙げられる。
ここで、C1-10アルキル基、C2-10アルケニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C6-14芳香族炭化水素基、C7-13アラルキル基およびC8-13芳香族炭化水素アルケニル基としては、それぞれ前記Jで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示したものが挙げられる。
5または6員芳香族複素環基としては、後述のJで示される「置換されていてもよい複素環基」における「複素環基」として例示した「芳香族複素環基」のうち5または6員環基であるものが挙げられる。なかでも、フリル、チエニル、チアゾリル、オキサゾリル、イミダゾリル、トリアゾリル、ピラゾリル、ピリミジニルなどが好ましい。
縮合芳香族複素環基としては、後述のJで示される「置換されていてもよい複素環基」における「複素環基」として例示した「芳香族複素環基」のうち縮合環基であるものが挙げられる。なかでも、インドリルなどが好ましい。
Examples of the “optionally substituted hydroxy group” represented by J include, for example, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aromatic hydrocarbon group, C 7-13 aralkyl group, C 8-13 aromatic hydrocarbon alkenyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, An isopentanoyl), a 5- or 6-membered aromatic heterocyclic group, a hydroxy group which may be substituted with a substituent selected from a condensed aromatic heterocyclic group and the like.
Here, C 1-10 alkyl group, C 2-10 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aromatic hydrocarbon group, C 7-13 aralkyl group and Examples of the C 8-13 aromatic hydrocarbon alkenyl group include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by J above.
Examples of the 5- or 6-membered aromatic heterocyclic group include 5 or 6 of the “aromatic heterocyclic group” exemplified as the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by J described later. What is a member ring group is mentioned. Of these, furyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyrazolyl, pyrimidinyl and the like are preferable.
The condensed aromatic heterocyclic group is a condensed ring group among the “aromatic heterocyclic groups” exemplified as the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by J described later. Is mentioned. Of these, indolyl and the like are preferable.
該C1-10アルキル基、C2-10アルケニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C6-14芳香族炭化水素基、C7-13アラルキル基、C8-13芳香族炭化水素アルケニル基、C1-6アルキル−カルボニル基、5または6員芳香族複素環基および縮合芳香族複素環基は、それぞれ置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、
(1)ハロゲン原子;
(2)ヒドロキシ基;
(3)シアノ基;
(4)ハロゲン原子、カルボキシル基、C1-6アルコキシ−カルボニル基(例、メトキシカルボニル、tert−ブトキシカルボニル)およびカルバモイル基から選ばれる1または2個の置換基で置換されていてもよいC1-6アルキル基;
(5)ハロゲン原子、カルボキシル基およびC1-6アルコキシ−カルボニル基(例、tert−ブトキシカルボニル)から選ばれる1または2個の置換基で置換されていてもよいC1-6アルコキシ基;
(6)C1-6アルキルチオ基(例、メチルチオ、エチルチオ);
(7)C1-6アルキル−カルボニル基(例、アセチル、イソブタノイル、イソペンタノイル);
(8)カルボキシル基;
(9)C1-6アルコキシ−カルボニル基(例、メトキシカルボニル、エトキシカルボニル);
(10)C1-10アルキル基(例、メチル、エチル、プロピル、イソプロピル、ネオペンチル)でモノあるいはジ置換されていてもよいカルバモイル基;
(11)C1-10アルキル基(例、メチル、エチル、プロピル、イソプロピル、ネオペンチル)でモノあるいはジ置換されていてもよいアミノ基;
(12)C1-6アルキル−カルボニルアミノ基(例、アセチルアミノ);
(13)C1-6アルキル基(例、メチル、エチル)、カルボキシル基、C1-6アルコキシ−カルボニル基(例、メトキシカルボニル、エトキシカルボニル)およびカルバモイル基から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、フリル、チエニル、オキサゾリル、チアゾリル、イソオキサゾリル、テトラゾリル、オキサジアゾリル、チアジアゾリル、ピリジル);
(14)C1-6アルキルスルフィニル基(例、メチルスルフィニル);
(15)C1-6アルキルスルホニル基(例、メチルスルホニル);
等が挙げられる。
The C 1-10 alkyl group, C 2-10 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aromatic hydrocarbon group, C 7-13 aralkyl group, C 8 -13 aromatic hydrocarbon alkenyl group, C 1-6 alkyl-carbonyl group, 5- or 6-membered aromatic heterocyclic group and condensed aromatic heterocyclic group each have 1 to 3 substituents at substitutable positions. You may have. As such a substituent, for example,
(1) a halogen atom;
(2) hydroxy group;
(3) a cyano group;
(4) C 1 which may be substituted with one or two substituents selected from a halogen atom, a carboxyl group, a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, tert-butoxycarbonyl) and a carbamoyl group -6 alkyl groups;
(5) a C 1-6 alkoxy group which may be substituted with one or two substituents selected from a halogen atom, a carboxyl group and a C 1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl);
(6) C 1-6 alkylthio group (eg, methylthio, ethylthio);
(7) C 1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl);
(8) carboxyl group;
(9) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl);
(10) a carbamoyl group which may be mono- or di-substituted with a C 1-10 alkyl group (eg, methyl, ethyl, propyl, isopropyl, neopentyl);
(11) an amino group which may be mono- or di-substituted with a C 1-10 alkyl group (eg, methyl, ethyl, propyl, isopropyl, neopentyl);
(12) a C 1-6 alkyl-carbonylamino group (eg, acetylamino);
(13) 1 to 3 substituents selected from a C 1-6 alkyl group (eg, methyl, ethyl), a carboxyl group, a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) and a carbamoyl group An aromatic heterocyclic group optionally substituted by (eg, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl);
(14) a C 1-6 alkylsulfinyl group (eg, methylsulfinyl);
(15) C 1-6 alkylsulfonyl group (eg, methylsulfonyl);
Etc.
Jで示される「置換されていてもよい複素環基」における「複素環基」としては、「芳香族複素環基」および「非芳香族複素環基」が挙げられる。
該芳香族複素環基としては、例えば、環構成原子として炭素原子以外に酸素原子、硫黄原子および窒素原子から選ばれるヘテロ原子を1ないし4個含有する5〜7員の単環式芳香族複素環基および縮合芳香族複素環基が挙げられる。該縮合芳香族複素環基としては、例えば、これら5〜7員の単環式芳香族複素環基と、1ないし2個の窒素原子を含む5または6員環、1個の硫黄原子を含む5員環またはベンゼン環などが1ないし2個縮合した基等が挙げられる。
芳香族複素環基の好適な例としては、
フリル(例、2−フリル、3−フリル)、チエニル(例、2−チエニル、3−チエニル)、ピリジル(例、2−ピリジル、3−ピリジル、4−ピリジル)、ピリミジニル(例、2−ピリミジニル、4−ピリミジニル、5−ピリミジニル、6−ピリミジニル)、ピリダジニル(例、3−ピリダジニル、4−ピリダジニル)、ピラジニル(例、2−ピラジニル)、ピロリル(例、1−ピロリル、2−ピロリル、3−ピロリル)、イミダゾリル(例、1−イミダゾリル、2−イミダゾリル、4−イミダゾリル、5−イミダゾリル)、ピラゾリル(例、1−ピラゾリル、3−ピラゾリル、4−ピラゾリル)、チアゾリル(例、2−チアゾリル、4−チアゾリル、5−チアゾリル)、イソチアゾリル(例、4−イソチアゾリル)、オキサゾリル(例、2−オキサゾリル、4−オキサゾリル、5−オキサゾリル)、イソオキサゾリル、オキサジアゾリル(例、1,2,4−オキサジアゾール−5−イル、1,3,4−オキサジアゾール−2−イル)、チアジアゾリル(例、1,3,4−チアジアゾール−2−イル)、トリアゾリル(例、1,2,4−トリアゾール−1−イル、1,2,4−トリアゾール−3−イル、1,2,3−トリアゾール−1−イル、1,2,3−トリアゾール−2−イル、1,2,3−トリアゾール−4−イル)、テトラゾリル(例、テトラゾール−1−イル、テトラゾール−5−イル)、トリアジニル(例、1,2,4−トリアゾール−1−イル、1,2,4−トリアゾール−3−イル)などの単環式芳香族複素環基;
キノリル(例、2−キノリル、3−キノリル、4−キノリル、6−キノリル)、イソキノリル(例、3−イソキノリル)、キナゾリル(例、2−キナゾリル、4−キナゾリル)、キノキサリル(例、2−キノキサリル、6−キノキサリル)、ベンゾフリル(例、2−ベンゾフリル、3−ベンゾフリル)、ベンゾチエニル(例、2−ベンゾチエニル、3−ベンゾチエニル)、ベンゾオキサゾリル(例、2−ベンゾオキサゾリル)、ベンズイソオキサゾリル(例、7−ベンズイソオキサゾリル)、ベンゾチアゾリル(例、2−ベンゾチアゾリル)、ベンズイミダゾリル(例、ベンズイミダゾール−1−イル、ベンズイミダゾール−2−イル、ベンズイミダゾール−5−イル)、ベンゾトリアゾリル(例、1H−1,2,3−ベンゾトリアゾール−5−イル)、インドリル(例、インドール−1−イル、インドール−2−イル、インドール−3−イル、インドール−5−イル)、インダゾリル(例、1H−インダゾール−3−イル)、ピロロピラジニル(例、1H−ピロロ[2,3-b]ピラジン−2−イル、1H−ピロロ[2,3-b]ピラジン−6−イル)、イミダゾピリジニル(例、1H−イミダゾ[4,5-b]ピリジン−2−イル、1H−イミダゾ[4,5-c]ピリジン−2−イル、2H−イミダゾ[1,2-a]ピリジン−3−イル)、イミダゾピラジニル(例、1H−イミダゾ[4,5-b]ピラジン−2−イル)、ピラゾロピリジニル(例、1H−ピラゾロ[4,3-c]ピリジン−3−イル)、ピラゾロチエニル(例、2H−ピラゾロ[3,4-b]チオフェン−2−イル)、ピラゾロトリアジニル(例、ピラゾロ[5,1-c][1,2,4]トリアジン-3-イル)などの縮合芳香族複素環基;などが挙げられる。
Examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by J include “aromatic heterocyclic group” and “non-aromatic heterocyclic group”.
Examples of the aromatic heterocyclic group include 5- to 7-membered monocyclic aromatic heterocycles containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms. Examples thereof include a cyclic group and a condensed aromatic heterocyclic group. Examples of the condensed aromatic heterocyclic group include these 5- to 7-membered monocyclic aromatic heterocyclic groups, 5- or 6-membered rings containing 1 to 2 nitrogen atoms, and 1 sulfur atom. And a group in which one or two 5-membered rings or benzene rings are condensed.
As preferable examples of the aromatic heterocyclic group,
Furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl) 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3- Pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4 -Thiazolyl, 5-thiazolyl), isothiazolyl (eg, 4-isothiazolyl), oxazolyl (eg, 2) Oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl, oxadiazolyl (eg, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazole-1) -Yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), triazinyl (eg, 1 , 2,4-triazol-1-yl, 1,2,4-triazol-3-yl) and the like;
Quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl) , 6-quinoxalyl), benzofuryl (eg, 2-benzofuryl, 3-benzofuryl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl), Benzisoxazolyl (eg, 7-benzisoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5- Yl), benzotriazolyl (eg, 1H-1,2,3-benzotriazole- -Yl), indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (eg, 1H-indazol-3-yl), pyrrolopyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl), imidazopyridinyl (eg, 1H-imidazo [4,5-b] Pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 2H-imidazo [1,2-a] pyridin-3-yl), imidazopyrazinyl (eg, 1H-imidazo [ 4,5-b] pyrazin-2-yl), pyrazolopyridinyl (eg, 1H-pyrazolo [4,3-c] pyridin-3-yl), pyrazolothienyl (eg, 2H-pyrazolo [3,4- b] Thiophen-2-yl), pyrazolotriazinyl (eg, pyrazolo [5,1-c] [1,2,4] triazin-3-yl) Aromatic heterocyclic group; and the like.
該非芳香族複素環基としては、例えば、環構成原子として炭素原子以外に酸素原子、硫黄原子および窒素原子から選ばれるヘテロ原子を1ないし4個含有する5〜7員の単環式非芳香族複素環基および縮合非芳香族複素環基が挙げられる。該縮合非芳香族複素環基としては、例えば、これら5〜7員の単環式非芳香族複素環基と、1ないし2個の窒素原子を含む5または6員環、1個の硫黄原子を含む5員環またはベンゼン環などが1ないし2個縮合した基等が挙げられる。
非芳香族複素環基の好適な例としては、ピロリジニル(例、1−ピロリジニル)、ピペリジニル(例、ピペリジノ)、モルホリニル(例、モルホリノ)、チオモルホリニル(例、チオモルホリノ)、ピペラジニル(例、1−ピペラジニル)、ヘキサメチレンイミニル(例、ヘキサメチレンイミン−1−イル)、オキサゾリジニル(例、オキサゾリジン−3−イル)、チアゾリジニル(例、チアゾリジン−3−イル)、イミダゾリジニル(例、イミダゾリジン−3−イル)、ジヒドロイソインドリル(例、1,3−ジヒドロ−2H−イソインドール−2−イル)、ジオキソリル(例、1,3−ジオキソール−4−イル)、ジオキソラニル(例、1,3−ジオキソラン−4−イル)、ジヒドロオキサジアゾリル(例、4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル)、2−チオキソ−1,3−オキサゾリジン−5−イル、テトラヒドロピラニル(例、4−テトラヒドロピラニル)、4,5,6,7-テトラヒドロ−1−ベンゾフラニル(例、4,5,6,7−テトラヒドロ−1−ベンゾフラン−3−イル)、インダニル(例、インダン−5−イル)、クロメニル(例、4H−クロメン−2−イル、2H−クロメン−3−イル)、ジヒドロイソキノリニル(例、1,2−ジヒドロイソキノリン−4−イル)、テトラヒドロイソキノリニル(例、1,2,3,4−テトラヒドロイソキノリン−4−イル)、ジヒドロフタラジニル(例、1,4−ジヒドロフタラジン−4−イル)、ピラゾリジニル(例、ピラゾリジン−1−イル)、テトラヒドロキノリニル(例、1,2,3,4−テトラヒドロキノリン−4−イル)などが挙げられる。
Jで示される「置換されていてもよい複素環基」における「複素環基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、前記Jで示される「置換されていてもよい炭化水素基」の「炭化水素基」として例示したC3-10シクロアルキル基が有していてもよい置換基として例示したものが挙げられる。
Jで示される「置換されていてもよい複素環基」としては、1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびC3−10シクロアルキル基から選ばれる1または2個の置換基で置換されていてもよい含窒素非芳香族複素環基(例、ピロリジニル、イミダゾリジニル、ピラゾリジニル、ピペリジニル、ピペラジニル、モルホリニル、チオモルホリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル)などが好ましい。
Examples of the non-aromatic heterocyclic group include a 5- to 7-membered monocyclic non-aromatic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. Examples include heterocyclic groups and fused non-aromatic heterocyclic groups. Examples of the fused non-aromatic heterocyclic group include these 5- to 7-membered monocyclic non-aromatic heterocyclic groups, 5- or 6-membered rings containing 1 to 2 nitrogen atoms, and one sulfur atom. And groups having 1 to 2 condensed 5-membered rings or benzene rings.
Suitable examples of the non-aromatic heterocyclic group include pyrrolidinyl (eg, 1-pyrrolidinyl), piperidinyl (eg, piperidino), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-pyrrolidinyl). Piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimin-1-yl), oxazolidinyl (eg, oxazolidine-3-yl), thiazolidinyl (eg, thiazolidin-3-yl), imidazolidinyl (eg, imidazolidin-3- Yl), dihydroisoindolyl (eg, 1,3-dihydro-2H-isoindol-2-yl), dioxolyl (eg, 1,3-dioxol-4-yl), dioxolanyl (eg, 1,3-dioxolane) -4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2,4- Oxadiazol-3-yl), 2-thioxo-1,3-oxazolidine-5-yl, tetrahydropyranyl (eg, 4-tetrahydropyranyl), 4,5,6,7-tetrahydro-1-benzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), indanyl (eg, indan-5-yl), chromenyl (eg, 4H-chromen-2-yl, 2H-chromen-3-yl) , Dihydroisoquinolinyl (eg, 1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolinyl (eg, 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl ( Examples, 1,4-dihydrophthalazin-4-yl), pyrazolidinyl (eg, pyrazolidin-1-yl), tetrahydroquinolinyl (eg, 1,2,3,4-tetrahydro) Quinolin-4-yl) and the like.
The “heterocyclic group” in the “optionally substituted heterocyclic group” represented by J may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include a substituent that the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by J may have. What was illustrated as a group is mentioned.
The “optionally substituted heterocyclic group” represented by J is 1 selected from a C 1-6 alkyl group and a C 3-10 cycloalkyl group optionally substituted with 1 to 3 halogen atoms. Or a nitrogen-containing non-aromatic heterocyclic group (eg, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl) which may be substituted with two substituents, etc. Is preferred.
Jで示される「置換されていてもよいアミノ基」としては、例えば、それぞれ置換されていてもよい、C1-10アルキル基、C2-10アルケニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C6-14芳香族炭化水素基、C7-13アラルキル基およびC8-13芳香族炭化水素アルケニル基などから選ばれる1または2個の置換基で置換されていてもよいアミノ基が挙げられる。
ここで、C1-10アルキル基、C2-10アルケニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C6-14芳香族炭化水素基、C7-13アラルキル基およびC8-13芳香族炭化水素アルケニル基としては、それぞれ前記Jで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示したものが挙げられる。
Examples of the “optionally substituted amino group” represented by J include a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, C Substituted with 1 or 2 substituents selected from 3-10 cycloalkenyl group, C 6-14 aromatic hydrocarbon group, C 7-13 aralkyl group, C 8-13 aromatic hydrocarbon alkenyl group, etc. A good amino group can be mentioned.
Here, C 1-10 alkyl group, C 2-10 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aromatic hydrocarbon group, C 7-13 aralkyl group and Examples of the C 8-13 aromatic hydrocarbon alkenyl group include those exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by J above.
これらC1-10アルキル基、C2-10アルケニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C6-14芳香族炭化水素基、C7-13アラルキル基およびC8-13芳香族炭化水素アルケニル基は、それぞれ置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、
ハロゲン原子;
C1-6アルコキシ−カルボニル基(例、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル);
C1-6アルキル−カルボニル基;
シアノ基;
C1-10アルキル基(例、メチル、エチル、プロピル、イソプロピル、ネオペンチル)でモノあるいはジ置換されていてもよいカルバモイル基;
ヒドロキシ基;
カルボキシル基;
等が挙げられる。
These C 1-10 alkyl group, C 2-10 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aromatic hydrocarbon group, C 7-13 aralkyl group and C 8 The -13 aromatic hydrocarbon alkenyl group may have 1 to 3 substituents at substitutable positions. As such a substituent, for example,
A halogen atom;
A C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl);
A C 1-6 alkyl-carbonyl group;
A cyano group;
A carbamoyl group optionally mono- or disubstituted with a C 1-10 alkyl group (eg, methyl, ethyl, propyl, isopropyl, neopentyl);
A hydroxy group;
Carboxyl group;
Etc.
Jで示される「置換されていてもよいアミノ基」は、好ましくは、1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル、プロピル、イソプロピル)およびC3−10シクロアルキル基(例、シクロペンチル、シクロヘキシル、アダマンチル)から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基などである。 The “optionally substituted amino group” represented by J is preferably a C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl) optionally substituted with 1 to 3 halogen atoms. And an amino group which may be mono- or di-substituted with a substituent selected from a C 3-10 cycloalkyl group (eg, cyclopentyl, cyclohexyl, adamantyl).
Jとしては、「置換されていてもよいアミノ基」および「置換されていてもよい複素環基」が好ましく、さらに、
1)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびC3−10シクロアルキル基から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基;
2)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびC3−10シクロアルキル基から選ばれる1または2個の置換基で置換されていてもよい含窒素非芳香族複素環基(例、ピロリジニル、イミダゾリジニル、ピラゾリジニル、ピペリジニル、ピペラジニル、モルホリニル、チオモルホリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル)などが好ましい。
J is preferably an “optionally substituted amino group” and an “optionally substituted heterocyclic group”.
1) an amino group which may be mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 3-10 cycloalkyl group which may be substituted with 1 to 3 halogen atoms;
2) A nitrogen-containing non-substituted group optionally substituted with 1 or 2 substituents selected from a C 1-6 alkyl group and a C 3-10 cycloalkyl group optionally substituted with 1 to 3 halogen atoms Aromatic heterocyclic groups (eg, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl) and the like are preferable.
Eで示される「置換されていてもよい環状基」における「環状基」としては、例えば、芳香族炭化水素基、非芳香族環状炭化水素基、複素環基などが挙げられる。 Examples of the “cyclic group” in the “optionally substituted cyclic group” represented by E include an aromatic hydrocarbon group, a non-aromatic cyclic hydrocarbon group, a heterocyclic group, and the like.
該芳香族炭化水素基としては、例えば、C6-14芳香族炭化水素基が挙げられる。ここで、C6-14芳香族炭化水素基としては、前記Jで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示したC6-14芳香族炭化水素基などが挙げられる。C6-14芳香族炭化水素基としては、アントリル(例、9−アントリル)、ナフチル(例、1−ナフチル、2−ナフチル)などが好ましい。 Examples of the aromatic hydrocarbon group include C 6-14 aromatic hydrocarbon groups. Here, the C 6-14 aromatic hydrocarbon group, such as exemplified C 6-14 aromatic hydrocarbon group as "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by J Is mentioned. As the C 6-14 aromatic hydrocarbon group, anthryl (eg, 9-anthryl), naphthyl (eg, 1-naphthyl, 2-naphthyl) and the like are preferable.
該非芳香族環状炭化水素基としては、例えば、ベンゼン環とそれぞれ縮合していてもよい、C3-10シクロアルキル基、C3-10シクロアルケニル基およびC4-10シクロアルカジエニル基などが挙げられる。ここで、C3-10シクロアルキル基、C3-10シクロアルケニル基およびC4-10シクロアルカジエニル基としては、それぞれ前記Jで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示したものが挙げられる。
非芳香族環状炭化水素基としては、インダニル(例、1−インダニル)、テトラヒドロナフチル(例、1,2,3,4−テトラヒドロナフタレン−1−イル)、フルオレニル(例、9−フルオレニル)などが挙げられる。
Examples of the non-aromatic cyclic hydrocarbon group include a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, and a C 4-10 cycloalkadienyl group, which may be condensed with a benzene ring, respectively. Can be mentioned. Here, the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group, and the C 4-10 cycloalkadienyl group are each represented by the “optionally substituted hydrocarbon group” represented by J above. What was illustrated as a "hydrocarbon group" is mentioned.
Non-aromatic cyclic hydrocarbon groups include indanyl (eg, 1-indanyl), tetrahydronaphthyl (eg, 1,2,3,4-tetrahydronaphthalen-1-yl), fluorenyl (eg, 9-fluorenyl) and the like. Can be mentioned.
該複素環基としては、前記Jで示される「置換基を有していてもよい複素環基」における「複素環基」として例示したものが挙げられる。 Examples of the heterocyclic group include those exemplified as the “heterocyclic group” in the “heterocyclic group optionally having substituents” represented by J.
Eで示される「置換されていてもよい環状基」における「環状基」は、スピロ環基を含まない。 The “cyclic group” in the “optionally substituted cyclic group” represented by E does not include a spiro ring group.
Eで示される「置換されていてもよい環状基」における「環状基」としては、芳香環基(芳香族炭化水素基、芳香族複素環基)が好ましく、特に、
アントリル、ナフチル、ピリジル、ピリミジニル、チアゾリル、イソチアゾリル、キノリル、イソキノリル、キノキサリル、ベンゾフラニル、ベンズイソオキサゾリル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、イミダゾピリジニル、ピラゾロピリジニル、ピラゾロチエニル、ピラゾロトリアジニルなどが好ましい。
The “cyclic group” in the “optionally substituted cyclic group” represented by E is preferably an aromatic ring group (aromatic hydrocarbon group, aromatic heterocyclic group).
Anthryl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl, quinoxalyl, benzofuranyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indolyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolothienyl, pyra Zolotriazinyl and the like are preferable.
Eで示される「置換されていてもよい環状基」における「環状基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。
このような置換基としては、例えば、前記Jで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示したC3-10シクロアルキル基が有していてもよい置換基として例示したものが挙げられる。
The “cyclic group” in the “optionally substituted cyclic group” represented by E may have 1 to 3 substituents at substitutable positions.
As such a substituent, for example, the substituent that the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by J may have What was illustrated as a group is mentioned.
該置換基は、好ましくは
(1)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル、イソプロピル);
(2)ヒドロキシ基;
(3)1〜3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ、エトキシ);
(4)C3−10シクロアルキル基(例、シクロヘキシル);
(5)ハロゲン原子;
(6)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC6−14芳香族炭化水素基(例、フェニル);
(7)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC7−13アラルキル基(例、ベンジル);
(8)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、ピリジル、チエニル、フリル);
などである。
The substituent is preferably (1) a C 1-6 alkyl group (eg, methyl, ethyl, isopropyl) optionally substituted with 1 to 3 halogen atoms;
(2) hydroxy group;
(3) a C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted by 1 to 3 halogen atoms;
(4) C 3-10 cycloalkyl group (eg, cyclohexyl);
(5) halogen atom;
(6) C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms, hydroxy group, C 1-6 alkoxy group (eg, methoxy, ethoxy) and halogen atom A C 6-14 aromatic hydrocarbon group (eg, phenyl) optionally substituted with 1 to 3 substituents selected from:
(7) C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms, hydroxy group, C 1-6 alkoxy group (eg, methoxy, ethoxy) and halogen atom A C 7-13 aralkyl group (eg, benzyl) optionally substituted by 1 to 3 substituents selected from:
(8) C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 halogen atoms, hydroxy group, C 1-6 alkoxy group (eg, methoxy, ethoxy) and halogen atom An aromatic heterocyclic group (eg, pyridyl, thienyl, furyl) optionally substituted by 1 to 3 substituents selected from:
Etc.
Eで示される「置換されていてもよい環状基」の「環状基」が単環基であるときは、置換基として、置換されていてもよい環状基を少なくとも2個有する。この置換基としての「置換されていてもよい環状基」の「環状基」およびその置換基としては、前記Eで示される「置換されていてもよい環状基」の「環状基」および該「環状基」の置換基として例示した置換基がそれぞれ挙げられる。
Eは、好ましくは、
(1)C6-14芳香族炭化水素基(好ましくはフェニル)から選ばれる少なくとも2個の置換基を有するピリジル;
(2)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル、イソプロピル)、1〜3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよいアントリルまたはナフチル;または
(3)i)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル、イソプロピル)、ii)ヒドロキシ基、iii)1〜3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ、エトキシ)、ハロゲン原子、1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC6−14芳香族炭化水素基(例、フェニル)およびvi)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、ピリジル、チエニル、フリル)などから選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、キノリル、イソキノリル、キノキサリル、ベンゾフリル、ベンズイソオキサゾリル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、イミダゾピリジニル、ピラゾロピリジニルまたはピラゾロチエニルなどである。
When the “cyclic group” of the “optionally substituted cyclic group” represented by E is a monocyclic group, it has at least two optionally substituted cyclic groups. The “cyclic group” of the “optionally substituted cyclic group” as the substituent and the substituent include the “cyclic group” of the “optionally substituted cyclic group” and the “ Examples of the substituent of the “cyclic group” include the substituents exemplified above.
E is preferably
(1) pyridyl having at least two substituents selected from C 6-14 aromatic hydrocarbon groups (preferably phenyl);
(2) C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms (eg, methyl, ethyl, isopropyl), C 1- optionally substituted with 1 to 3 halogen atoms 6 anthryl or naphthyl optionally substituted with 1 to 3 substituents selected from alkoxy groups (eg, methoxy, ethoxy) and halogen atoms; or (3) i) substituted with 1 to 3 halogen atoms An optionally substituted C 1-6 alkyl group (eg, methyl, ethyl, isopropyl), ii) a hydroxy group, iii) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (eg, , Methoxy, ethoxy), halogen atom, C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms (eg, methyl, ethyl), hydroxy group, C 1-6 alkoxy group (eg, methoxy) , Ethoxy) 1 to 3 substituents C 6-14 aromatic substituted with optionally substituted hydrocarbon group selected from finely halogen atom (e.g., phenyl) and vi) optionally substituted with 1 to 3 halogen atoms It may be substituted with 1 to 3 substituents selected from a good C 1-6 alkyl group (eg, methyl, ethyl), a hydroxy group, a C 1-6 alkoxy group (eg, methoxy, ethoxy) and a halogen atom. Quinolyl, isoquinolyl, quinoxalyl, benzofuryl, benzisoxazolyl, benz, each of which may be substituted with 1 to 3 substituents selected from good aromatic heterocyclic groups (eg, pyridyl, thienyl, furyl), etc. And imidazolyl, benzotriazolyl, indolyl, imidazolpyridinyl, pyrazolopyridinyl or pyrazolothienyl.
環Pは、「置換されていてもよい含窒素5または6員非芳香族複素環」であり、該「含窒素5または6員非芳香族複素環」は、その構成原子である窒素原子がE−D−で置換されているのに加えて、さらに置換されていてもよい。この「置換されていてもよい含窒素5または6員非芳香族複素環」における「含窒素5または6員非芳香族複素環」としては、例えば、環構成原子として炭素原子以外に少なくとも1個の窒素原子を含み、さらに、酸素原子、硫黄原子および窒素原子から選ばれるヘテロ原子を1ないし2個含有してもよい5または6員の単環式非芳香族複素環および縮合非芳香族複素環が挙げられる。該縮合非芳香族複素環としては、例えば、これら5または6員の単環式非芳香族複素環と、1ないし2個の窒素原子を含む6員環、1個の硫黄原子を含む5員環またはベンゼン環とが縮合した環等が挙げられる。 Ring P is an “optionally substituted nitrogen-containing 5- or 6-membered non-aromatic heterocyclic ring”, and the “nitrogen-containing 5- or 6-membered non-aromatic heterocyclic ring” includes a nitrogen atom that is a constituent atom thereof. In addition to being substituted with ED-, it may be further substituted. Examples of the “nitrogen-containing 5- or 6-membered non-aromatic heterocycle” in the “optionally substituted nitrogen-containing 5- or 6-membered non-aromatic heterocycle” include, for example, at least one ring atom other than a carbon atom. 5 or 6-membered monocyclic non-aromatic heterocycle and condensed non-aromatic heterocycle, which may further contain 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms A ring is mentioned. Examples of the fused non-aromatic heterocycle include, for example, these 5- or 6-membered monocyclic non-aromatic heterocycles, 6-membered rings containing 1 to 2 nitrogen atoms, and 5-membered members containing 1 sulfur atom. Examples thereof include a ring or a ring condensed with a benzene ring.
該「含窒素5または6員非芳香族複素環」の好適な例としては、ピロリジン、ピペリジン、モルホリン、チオモルホリン、ピペラジン、オキサゾリジン、チアゾリジン、イミダゾリジン、オキサゾリジン、チアゾリジン、ジヒドロイソインドール、オキサジアゾールなどが挙げられ、なかでも、ピペリジン、ピペラジンなどが好ましい。 Suitable examples of the “nitrogen-containing 5- or 6-membered non-aromatic heterocycle” include pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxazolidine, thiazolidine, imidazolidine, oxazolidine, thiazolidine, dihydroisoindole, oxadiazole Among them, piperidine, piperazine and the like are preferable.
環Pで示される「置換されていてもよい含窒素5または6員非芳香族複素環」における「含窒素5または6員非芳香族複素環」は、置換可能な位置に1ないし3個(好ましくは1個または2個)の置換基を有していてもよい。このような置換基としては、例えば、前記Jで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示したC3-10シクロアルキル基における置換基として例示したものが挙げられる。 In the “optionally substituted nitrogen-containing 5- or 6-membered non-aromatic heterocycle” represented by ring P, 1 to 3 “nitrogen-containing 5- or 6-membered non-aromatic heterocycle” are substituted at substitutable positions ( It may preferably have 1 or 2 substituents. Examples of such a substituent include those exemplified as the substituent in the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by J above. Can be mentioned.
環Pとしては、ピペリジン、ピペラジンなどが好ましい。 As the ring P, piperidine, piperazine and the like are preferable.
環Qは、AおよびLと一緒になって形成される、「置換されていてもよい芳香環」または「置換されていてもよい非芳香環複素環」であり、該「芳香環」および該「非芳香環複素環」は、その環構成基であるLがJ−G−で置換されているのに加えて、さらに置換されていてもよい。 Ring Q is an “optionally substituted aromatic ring” or “optionally substituted non-aromatic heterocyclic ring” formed together with A and L, and the “aromatic ring” and the The “non-aromatic heterocyclic ring” may be further substituted in addition to the fact that L as the ring-constituting group is substituted with JG-.
該「置換されていてもよい芳香環」における「芳香環」としては、例えば、芳香族炭化水素、芳香族複素環などが挙げられる。ここで、芳香族炭化水素、芳香族複素環としては、前記Eで示される「置換されていてもよい環状基」における「環状基」として例示した「芳香族炭化水素基」、前記Jで示される「置換基を有していてもよい複素環基」における「複素環基」として例示した「芳香族複素環基」にそれぞれ対応する環が挙げられる。
環Qで示される「置換されていてもよい芳香環」における「芳香環」としては、ベンゼンなどが好ましい。
Examples of the “aromatic ring” in the “optionally substituted aromatic ring” include aromatic hydrocarbons and aromatic heterocycles. Here, as the aromatic hydrocarbon and aromatic heterocycle, the “aromatic hydrocarbon group” exemplified as “cyclic group” in the “optionally substituted cyclic group” represented by E, and represented by J above Rings respectively corresponding to the “aromatic heterocyclic group” exemplified as the “heterocyclic group” in the “heterocyclic group optionally having substituents” mentioned above.
As the “aromatic ring” in the “optionally substituted aromatic ring” represented by ring Q, benzene and the like are preferable.
該「置換されていてもよい非芳香族複素環」における「非芳香族複素環」としては、例えば、前記Jで示される「置換されていてもよい複素環基」における「複素環基」として例示した「非芳香族複素環基」に対応する環のうち、2個以上のヘテロ原子を含むものが挙げられ、例えば、モルホリン、チオモルホリン、ピペラジン、オキサゾリジン、チアゾリジン、イミダゾリジン、オキサゾリジン、チアゾリジンなどが挙げられる。 Examples of the “non-aromatic heterocyclic ring” in the “optionally substituted non-aromatic heterocyclic ring” include, for example, the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by J above. Examples of the ring corresponding to the exemplified “non-aromatic heterocyclic group” include those containing two or more heteroatoms, such as morpholine, thiomorpholine, piperazine, oxazolidine, thiazolidine, imidazolidine, oxazolidine, thiazolidine, etc. Is mentioned.
環Qで示される「置換されていてもよい非芳香族複素環」における「非芳香族複素環」としては、モルホリン、ピペラジンなどが好ましい。 As the “non-aromatic heterocycle” in the “optionally substituted non-aromatic heterocycle” represented by ring Q, morpholine, piperazine and the like are preferable.
環Qで示される「置換されていてもよい芳香環」における「芳香環」および「置換されていてもよい非芳香環複素環」における「非芳香環複素環」は、置換可能な位置に1ないし3個の置換基を有していてもよい。
このような置換基としては、例えば、前記Jで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示したC3-10シクロアルキル基における置換基として例示したものが挙げられる。
該置換基は、好ましくは1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル−カルボニル基(例、アセチル、イソブタノイル、イソペンタノイル)などである。
The “aromatic ring” in the “optionally substituted aromatic ring” represented by the ring Q and the “non-aromatic ring heterocycle” in the “optionally substituted non-aromatic ring heterocycle” have 1 at the substitutable position. Or may have 3 substituents.
Examples of such a substituent include those exemplified as the substituent in the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by J above. Can be mentioned.
The substituent is preferably a C 1-6 alkyl-carbonyl group (eg, acetyl, isobutanoyl, isopentanoyl) which may be substituted with 1 to 3 halogen atoms.
環Qとしては、1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル−カルボニル基でそれぞれ置換されていてもよい、モルホリン、ピペラジンおよびベンゼンなどが好ましい。 Ring Q is preferably morpholine, piperazine, benzene, or the like, each of which may be substituted with a C 1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms.
Aとしては、N、Cが好ましい。
Lとしては、CH、Cが好ましい。
Gとしては、カルボニル基が好ましい。
Dとしては、カルボニル基が好ましい。
As A, N and C are preferable.
L is preferably CH or C.
G is preferably a carbonyl group.
D is preferably a carbonyl group.
化合物(I)は、「4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-2-(モルホリン-4-イルカルボニル)モルホリン」を含まない。 Compound (I) does not include “4- [1- (9-anthrylcarbonyl) piperidin-4-yl] -2- (morpholin-4-ylcarbonyl) morpholine”.
化合物(I)の好適な例としては、以下の化合物が挙げられる。
Eが、
(1)C6-14芳香族炭化水素基(好ましくはフェニル)から選ばれる少なくとも2個の置換基を有するピリジル;
(2)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル、イソプロピル)、1〜3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよいアントリルまたはナフチル;または
(3)i)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル、イソプロピル)、ii)ヒドロキシ基、iii)1〜3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ、エトキシ)、ハロゲン原子、1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC6−14芳香族炭化水素基(例、フェニル)およびvi)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル、エチル)、ヒドロキシ基、C1-6アルコキシ基(例、メトキシ、エトキシ)およびハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、ピリジル、チエニル、フリル)から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、キノリル、イソキノリル、キノキサリル、ベンゾフリル、ベンズイソオキサゾリル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、イミダゾピリジニル、ピラゾロピリジニルまたはピラゾロチエニル;
Dが、カルボニル基;
Gが、カルボニル基;
環Pが、ピペリジンまたはピペラジン;
環Qが、1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル−カルボニル基でそれぞれ置換されていてもよい、モルホリン、ピペラジンまたはベンゼン;
Aが、CまたはN;
Lが、CHまたはC;
Jが、
1)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびC3−10シクロアルキル基から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基;または
2)1〜3個のハロゲン原子で置換されていてもよいC1-6アルキル基およびC3−10シクロアルキル基から選ばれる1または2個の置換基で置換されていてもよい含窒素非芳香族複素環基(例、ピロリジニル、イミダゾリジニル、ピラゾリジニル、ピペリジニル、ピペラジニル、モルホリニル、チオモルホリニル、テトラヒドロキノリニル、テトラヒドロイソキノリニル);
である化合物。
Preferable examples of compound (I) include the following compounds.
E
(1) pyridyl having at least two substituents selected from C 6-14 aromatic hydrocarbon groups (preferably phenyl);
(2) C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms (eg, methyl, ethyl, isopropyl), C 1- optionally substituted with 1 to 3 halogen atoms 6 anthryl or naphthyl optionally substituted with 1 to 3 substituents selected from alkoxy groups (eg, methoxy, ethoxy) and halogen atoms; or (3) i) substituted with 1 to 3 halogen atoms An optionally substituted C 1-6 alkyl group (eg, methyl, ethyl, isopropyl), ii) a hydroxy group, iii) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (eg, , Methoxy, ethoxy), halogen atom, C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms (eg, methyl, ethyl), hydroxy group, C 1-6 alkoxy group (eg, methoxy) , Ethoxy) 1 to 3 substituents C 6-14 aromatic substituted with optionally substituted hydrocarbon group selected from finely halogen atom (e.g., phenyl) and vi) optionally substituted with 1 to 3 halogen atoms It may be substituted with 1 to 3 substituents selected from a good C 1-6 alkyl group (eg, methyl, ethyl), a hydroxy group, a C 1-6 alkoxy group (eg, methoxy, ethoxy) and a halogen atom. Quinolyl, isoquinolyl, quinoxalyl, benzofuryl, benzisoxazolyl, benzimidazolyl, each optionally substituted with 1 to 3 substituents selected from a good aromatic heterocyclic group (eg, pyridyl, thienyl, furyl) , Benzotriazolyl, indolyl, imidazopyridinyl, pyrazolopyridinyl or pyrazolothienyl;
D is a carbonyl group;
G is a carbonyl group;
Ring P is piperidine or piperazine;
Morpholine, piperazine or benzene, wherein ring Q is each optionally substituted with a C 1-6 alkyl-carbonyl group optionally substituted with 1 to 3 halogen atoms;
A is C or N;
L is CH or C;
J
1) an amino group which may be mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 3-10 cycloalkyl group which may be substituted with 1 to 3 halogen atoms; or
2) A nitrogen-containing non-substituted group optionally substituted with 1 or 2 substituents selected from a C 1-6 alkyl group and a C 3-10 cycloalkyl group optionally substituted with 1 to 3 halogen atoms Aromatic heterocyclic groups (eg, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl);
A compound that is
化合物(I)の塩としては、薬理学的に許容される塩が好ましく、このような塩としては、例えば、無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩などが挙げられる。
無機塩基との塩の好適な例としては、ナトリウム塩、カリウム塩などのアルカリ金属塩;カルシウム塩、マグネシウム塩などのアルカリ土類金属塩;アルミニウム塩;アンモニウム塩などが挙げられる。
有機塩基との塩の好適な例としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、トロメタミン[トリス(ヒドロキシメチル)メチルアミン]、tert−ブチルアミン、シクロヘキシルアミン、ベンジルアミン、ジシクロヘキシルアミン、N,N−ジベンジルエチレンジアミンなどとの塩が挙げられる。
無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。
有機酸との塩の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸などとの塩が挙げられる。
塩基性アミノ酸との塩の好適な例としては、アルギニン、リジン、オルニチンなどとの塩が挙げられる。
酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸などとの塩が挙げられる。
上記した塩の中でも無機酸との塩および有機酸との塩が好ましく、さらに塩酸塩、トリフルオロ酢酸塩、フマル酸塩などが好ましい。
As the salt of compound (I), a pharmacologically acceptable salt is preferable. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and an organic acid. And salts with basic or acidic amino acids.
Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid , Salts with p-toluenesulfonic acid and the like.
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
Among the above-mentioned salts, salts with inorganic acids and organic acids are preferable, and hydrochlorides, trifluoroacetates, fumarates and the like are more preferable.
化合物(I)のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により化合物(I)に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物(I)に変化する化合物、胃酸等により加水分解などを起こして化合物(I)に変化する化合物である。化合物(I)のプロドラッグとしては、化合物(I)のアミノ基がアシル化、アルキル化、リン酸化された化合物(例、化合物(I)のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、(5−メチル−2−オキソ−1,3−ジオキソレン−4−イル)メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、tert−ブチル化された化合物など);化合物(I)の水酸基がアシル化、アルキル化、リン酸化、ホウ酸化された化合物(例、化合物(I)の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物など);化合物(I)のカルボキシル基がエステル化、アミド化された化合物(例、化合物(I)のカルボキシル基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、(5−メチル−2−オキソ−1,3−ジオキソレン−4−イル)メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物など)等が挙げられる。これらの化合物は自体公知の方法によって化合物(I)から製造することができる。
また、化合物(I)のプロドラッグは、広川書店1990年刊「医薬品の開発」第7巻分子設計163頁から198頁に記載されているような、生理的条件で化合物(I)に変化するものであってもよい。
また、化合物(I)は、同位元素(例、3H、14C、35S、125Iなど)などで標識されていてもよい。
さらに、化合物(I)は、無水物であっても、水和物であってもよい。
A prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) upon hydrolysis by gastric acid or the like. Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (eg, hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Compound, dimethylaminomethylcarbonylated compound, etc.); the carboxyl group of compound (I) is esterified, Mido compound (e.g., carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, and the like). These compounds can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
Compound (I) may be labeled with an isotope (eg, 3 H, 14 C, 35 S, 125 I, etc.).
Furthermore, compound (I) may be an anhydride or a hydrate.
化合物(I)またはそのプロドラッグ(以下、単に本発明化合物と略記することがある)は、毒性が低く、そのまま、または薬理学的に許容し得る担体などと混合して医薬組成物とすることにより、哺乳動物(例、ヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル等)に対して、後述する各種疾患の予防または治療剤として用いることができる。
ここにおいて、薬理学的に許容し得る担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤;液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤などとして配合される。また必要に応じて、防腐剤、抗酸化剤、着色剤、甘味剤などの製剤添加物を用いることもできる。
Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) has low toxicity and should be used as it is or mixed with a pharmacologically acceptable carrier to form a pharmaceutical composition. Thus, it can be used as a preventive or therapeutic agent for various diseases described below for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.).
Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. Further, if necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used.
賦形剤の好適な例としては、乳糖、白糖、D−マンニトール、D−ソルビトール、デンプン、α化デンプン、デキストリン、結晶セルロース、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、アラビアゴム、プルラン、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウムなどが挙げられる。
滑沢剤の好適な例としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカなどが挙げられる。
結合剤の好適な例としては、α化デンプン、ショ糖、ゼラチン、アラビアゴム、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、結晶セルロース、白糖、D−マンニトール、トレハロース、デキストリン、プルラン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドンなどが挙げられる。
崩壊剤の好適な例としては、乳糖、白糖、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロースなどが挙げられる。
Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like can be mentioned.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferable examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.
溶剤の好適な例としては、注射用水、生理的食塩水、リンゲル液、アルコール、プロピレングリコール、ポリエチレングリコール、ゴマ油、トウモロコシ油、オリーブ油、綿実油などが挙げられる。
溶解補助剤の好適な例としては、ポリエチレングリコール、プロピレングリコール、D−マンニトール、トレハロース、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム、サリチル酸ナトリウム、酢酸ナトリウムなどが挙げられる。
懸濁化剤の好適な例としては、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリンなどの界面活性剤;例えば、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロースなどの親水性高分子;ポリソルベート類、ポリオキシエチレン硬化ヒマシ油などが挙げられる。
Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
Preferable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
等張化剤の好適な例としては、塩化ナトリウム、グリセリン、D−マンニトール、D−ソルビトール、ブドウ糖などが挙げられる。
緩衝剤の好適な例としては、リン酸塩、酢酸塩、炭酸塩、クエン酸塩などの緩衝液などが挙げられる。
無痛化剤の好適な例としては、ベンジルアルコールなどが挙げられる。
防腐剤の好適な例としては、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸などが挙げられる。
抗酸化剤の好適な例としては、亜硫酸塩、アスコルビン酸塩などが挙げられる。
着色剤の好適な例としては、水溶性食用タール色素(例、食用赤色2号および3号、食用黄色4号および5号、食用青色1号および2号などの食用色素)、水不溶性レーキ色素(例、前記水溶性食用タール色素のアルミニウム塩など)、天然色素(例、β−カロチン、クロロフィル、ベンガラなど)などが挙げられる。
甘味剤の好適な例としては、サッカリンナトリウム、グリチルリチン酸二カリウム、アスパルテーム、ステビアなどが挙げられる。
Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.
Preferable examples of the soothing agent include benzyl alcohol.
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfite and ascorbate.
Suitable examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, and edible blue Nos. 1 and 2), water-insoluble lake dyes (E.g., an aluminum salt of the water-soluble edible tar dye), natural dyes (e.g., [beta] -carotene, chlorophyll, bengara, etc.).
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
前記医薬組成物の剤形としては、例えば、錠剤(舌下錠、口腔内崩壊錠を含む)、カプセル剤(ソフトカプセル、マイクロカプセルを含む)、顆粒剤、散剤、トローチ剤、シロップ剤、乳剤、懸濁剤などの経口剤;および注射剤(例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤、点滴剤など)、外用剤(例、経皮製剤、軟膏剤など)、坐剤(例、直腸坐剤、膣坐剤など)、ペレット、経鼻剤、経肺剤(吸入剤)、点眼剤等の非経口剤が挙げられ、これらはそれぞれ経口的あるいは非経口的に安全に投与できる。
これらの製剤は、速放性製剤または徐放性製剤などの放出制御製剤(例、徐放性マイクロカプセルなど)であってもよい。
医薬組成物は、製剤技術分野において慣用の方法、例えば、日本薬局方に記載の方法等により製造することができる。以下に、製剤の具体的な製造法について詳述する。
なお、医薬組成物中の本発明化合物の含量は、剤形、本発明化合物の投与量などにより異なるが、例えば、約0.1〜100重量%である。
Examples of the dosage form of the pharmaceutical composition include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, Oral preparations such as suspensions; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions, etc.), external preparations (eg, transdermal preparations, ointments, etc.) ), Suppositories (eg, rectal suppositories, vaginal suppositories, etc.), pellets, nasal preparations, pulmonary preparations (inhalants), ophthalmic preparations and the like, and these are oral or parenteral, respectively. Safe administration.
These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (eg, sustained-release microcapsules).
The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia. Below, the specific manufacturing method of a formulation is explained in full detail.
The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
経口剤を製造する際には、必要により、味のマスキング、腸溶性あるいは持続性を目的として、コーティングを行ってもよい。
コーティングに用いられるコーティング基剤としては、例えば、糖衣基剤、水溶性フィルムコーティング基剤、腸溶性フィルムコーティング基剤、徐放性フィルムコーティング基剤などが挙げられる。
When producing an oral preparation, it may be coated for the purpose of taste masking, enteric properties or sustainability, if necessary.
Examples of the coating base used for coating include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like.
糖衣基剤としては、白糖が用いられ、さらに、タルク、沈降炭酸カルシウム、ゼラチン、アラビアゴム、プルラン、カルナバロウなどから選ばれる1種または2種以上を併用してもよい。
水溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロースなどのセルロース系高分子;ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタアクリレートコポリマーE〔オイドラギットE(商品名)、ロームファルマ社〕、ポリビニルピロリドンなどの合成高分子;プルランなどの多糖類などが挙げられる。
腸溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルメチルセルロース フタレート、ヒドロキシプロピルメチルセルロース アセテートサクシネート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロースなどのセルロース系高分子;メタアクリル酸コポリマーL〔オイドラギットL(商品名)、ロームファルマ社〕、メタアクリル酸コポリマーLD〔オイドラギットL−30D55(商品名)、ロームファルマ社〕、メタアクリル酸コポリマーS〔オイドラギットS(商品名)、ロームファルマ社〕などのアクリル酸系高分子;セラックなどの天然物などが挙げられる。
徐放性フィルムコーティング基剤としては、例えば、エチルセルロースなどのセルロース系高分子;アミノアルキルメタアクリレートコポリマーRS〔オイドラギットRS(商品名)、ロームファルマ社〕、アクリル酸エチル−メタクリル酸メチル共重合体懸濁液〔オイドラギットNE(商品名)、ロームファルマ社〕などのアクリル酸系高分子などが挙げられる。
上記したコーティング基剤は、その2種以上を適宜の割合で混合して用いてもよい。また、コーティングの際に、例えば、酸化チタン、三二酸化鉄等のような遮光剤を用いてもよい。
As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) Synthetic polymers such as polyvinyl pyrrolidone; polysaccharides such as pullulan.
Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) , Rohm Pharma Co., Ltd.], acrylic polymer such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.] A natural product such as shellac.
Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.], ethyl acrylate-methyl methacrylate copolymer suspension Acrylic polymers such as suspensions (Eudragit NE (trade name), Rohm Pharma) are listed.
Two or more of the coating bases described above may be mixed and used at an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.
本発明化合物は、毒性(例、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、癌原性)が低く、副作用も少なく、哺乳動物(例えば、ヒト、ウシ、ウマ、イヌ、ネコ、サル、マウス、ラット等、特にヒト)に対し、各種疾患の予防または治療剤、または診断薬として用いることができる。
本発明化合物は、優れたACC(アセチル−CoAカルボキシラーゼ)阻害作用を有する。ここで、ACCとしては、肝臓、脂肪組織、膵臓特異的アイソザイム(ACC1);筋肉特異的アイソザイム(ACC2);などが挙げられる。
The compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, It can be used as a prophylactic or therapeutic agent for various diseases or a diagnostic agent for monkeys, mice, rats, etc. (especially humans).
The compound of the present invention has an excellent ACC (acetyl-CoA carboxylase) inhibitory action. Examples of ACC include liver, adipose tissue, pancreas-specific isozyme (ACC1); muscle-specific isozyme (ACC2);
本発明化合物は、肥満症、糖尿病(例、1型糖尿病、2型糖尿病、妊娠糖尿病等)、高脂血症(例、高トリグリセリド血症、高コレステロール血症、低HDL血症、食後高脂血症等)、高血圧症、心不全、糖尿病性心筋症、メタボリックシンドローム、筋肉減少症などの予防・治療剤として用いることができる。 The compound of the present invention has obesity, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, postprandial hyperlipidemia) Etc.), hypertension, heart failure, diabetic cardiomyopathy, metabolic syndrome, sarcopenia and the like.
糖尿病の判定基準については、1999年に日本糖尿病学会から新たな判定基準が報告されている。
この報告によれば、糖尿病とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl以上、75g経口ブドウ糖負荷試験(75gOGTT)2時間値(静脈血漿におけるグルコース濃度)が200mg/dl以上、随時血糖値(静脈血漿におけるグルコース濃度)が200mg/dl以上のいずれかを示す状態である。また、上記糖尿病に該当せず、かつ、「空腹時血糖値(静脈血漿におけるグルコース濃度)が110mg/dl未満または75g経口ブドウ糖負荷試験(75gOGTT)2時間値(静脈血漿におけるグルコース濃度)が140mg/dl未満を示す状態」(正常型)でない状態を、「境界型」と呼ぶ。
Regarding the criteria for determining diabetes, a new criterion was reported in 1999 by the Japan Diabetes Society.
According to this report, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. This is a state in which the blood glucose level (glucose concentration in venous plasma) is at least 200 mg / dl as needed. In addition, the above-mentioned diabetes does not apply, and “fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or 75 g oral glucose tolerance test (75 gOGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl. A state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
また、糖尿病の判定基準については、1997年にADA(米国糖尿病学会)から、1998年にWHOから、新たな判定基準が報告されている。
これらの報告によれば、糖尿病とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl以上であり、かつ、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が200mg/dl以上を示す状態である。
As for the criteria for determining diabetes, new criteria were reported from ADA (American Diabetes Association) in 1997 and from WHO in 1998.
According to these reports, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, and a 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma) is 200 mg / dl. This is a state showing dl or more.
また、上記報告によれば、耐糖能不全とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl未満であり、かつ、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が140mg/dl以上200mg/dl未満を示す状態である。さらに、ADAの報告によれば、空腹時血糖値(静脈血漿におけるグルコース濃度)が110mg/dl以上126mg/dl未満の状態をIFG(Impaired Fasting Glucose)と呼ぶ。一方、WHOの報告によれば、該IFG(Impaired Fasting Glucose)のうち、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が140mg/dl未満である状態をIFG(Impaired Fasting Glycemia)と呼ぶ。 According to the above report, glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl and a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose) is a state in which the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.
本発明化合物は、上記した新たな判定基準により決定される糖尿病、境界型、耐糖能不全、IFG(Impaired Fasting Glucose)およびIFG(Impaired Fasting Glycemia)の予防・治療剤としても用いられる。さらに、本発明化合物は、境界型、耐糖能不全、IFG(Impaired Fasting Glucose)またはIFG(Impaired Fasting Glycemia)から糖尿病への進展を防止することもできる。 The compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.
本発明化合物は、例えば、糖尿病性合併症[例、神経障害、腎症、網膜症、白内障、大血管障害、骨減少症、糖尿病性高浸透圧昏睡、感染症(例、呼吸器感染症、尿路感染症、消化器感染症、皮膚軟部組織感染症、下肢感染症等)、糖尿病性壊疽、口腔乾燥症、聴覚の低下、脳血管障害、末梢血行障害等]、骨粗鬆症、悪液質(例、癌性悪液質、結核性悪液質、糖尿病性悪液質、血液疾患性悪液質、内分泌疾患性悪液質、感染症性悪液質または後天性免疫不全症候群による悪液質)、脂肪肝、多嚢胞性卵巣症候群、腎臓疾患(例、糖尿病性ネフロパシー、糸球体腎炎、糸球体硬化症、ネフローゼ症候群、高血圧性腎硬化症、末期腎臓疾患等)、筋ジストロフィー、心筋梗塞、狭心症、脳血管障害(例、脳梗塞、脳卒中)、アルツハイマー病、パーキンソン病、不安症、痴呆症、インスリン抵抗性症候群、シンドロームX、高インスリン血症、高インスリン血症における知覚障害、腫瘍(例、白血病、乳癌、前立腺癌、皮膚癌等)、過敏性腸症候群、急性または慢性下痢、炎症性疾患(例、慢性関節リウマチ、変形性脊椎炎、変形性関節炎、腰痛、痛風、手術または外傷後の炎症、腫脹、神経痛、咽喉頭炎、膀胱炎、肝炎(非アルコール性脂肪性肝炎を含む)、肺炎、膵炎、腸炎、炎症性腸疾患(炎症性大腸疾患を含む)、潰瘍性大腸炎、胃粘膜損傷(アスピリンにより引き起こされた胃粘膜損傷を含む)等)、小腸粘膜損傷、吸収不良、精巣機能障害、内臓肥満症候群、筋肉減少症などの予防・治療剤としても用いることができる。
本発明化合物は、上記した各種疾患(例、心筋梗塞などの心血管イベント)の2次予防および進展抑制にも用いられる。
The compound of the present invention can be used, for example, for diabetic complications [eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection (eg, respiratory infection, Urinary tract infection, digestive tract infection, skin soft tissue infection, lower limb infection, etc.), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood flow disorder, etc.], osteoporosis, cachexia ( Eg, cancer cachexia, tuberculosis cachex, diabetic cachexia, bloody cachexia, endocrine cachexia, infectious cachexia or acquired immunodeficiency syndrome), fatty liver, multiple Cystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy, end-stage renal disease, etc.), muscular dystrophy, myocardial infarction, angina, cerebrovascular disorder (Eg, cerebral infarction, stroke), Alzheimer's disease, -Kinson's disease, anxiety, dementia, insulin resistance syndrome, syndrome X, hyperinsulinemia, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (eg leukemia, breast cancer, prostate cancer, skin cancer, etc.), irritable bowel syndrome , Acute or chronic diarrhea, inflammatory diseases (eg, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout, surgery or post-traumatic inflammation, swelling, neuralgia, sore throat, cystitis, hepatitis (non- Alcoholic steatohepatitis), pneumonia, pancreatitis, enteritis, inflammatory bowel disease (including inflammatory bowel disease), ulcerative colitis, gastric mucosal damage (including gastric mucosal damage caused by aspirin)) It can also be used as a prophylactic / therapeutic agent for small intestinal mucosal damage, malabsorption, testicular dysfunction, visceral obesity syndrome, sarcopenia and the like.
The compound of the present invention is also used for secondary prevention and suppression of progression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).
本発明化合物の投与量は、投与対象、投与ルート、対象疾患、症状などによっても異なるが、例えば、成人の糖尿病患者に経口投与する場合、通常1回量として約0.01〜100mg/kg体重、好ましくは0.05〜30mg/kg体重、さらに好ましくは0.1〜10mg/kg体重であり、この量を1日1回〜3回投与するのが望ましい。 The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. For example, when administered orally to an adult diabetic patient, the dose is usually about 0.01 to 100 mg / kg body weight. It is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.
本発明化合物は、該化合物の作用の増強または該化合物の投与量の低減などを目的として、糖尿病治療剤、糖尿病性合併症治療剤、抗高脂血症剤、降圧剤、抗肥満剤、利尿剤、抗血栓剤などの薬剤(以下、併用薬剤と略記する)と組み合わせて用いることができる。この際、本発明化合物と併用薬剤の投与時期は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。さらに、本発明化合物と併用薬剤とは、それぞれの活性成分を含む2種類の製剤として投与されてもよいし、両方の活性成分を含む単一の製剤として投与されてもよい。
併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物と併用薬剤の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせなどにより適宜選択することができる。例えば、投与対象がヒトである場合、本発明化合物1重量部に対し、併用薬剤を0.01〜100重量部用いればよい。
The compound of the present invention is used for the purpose of enhancing the action of the compound or reducing the dose of the compound, etc., for treating diabetes, treating diabetic complications, antihyperlipidemic agent, antihypertensive agent, antiobesity agent, diuresis It can be used in combination with a drug such as an agent or an antithrombotic drug (hereinafter abbreviated as a concomitant drug). In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject, or may be administered with a time difference. Further, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
なお、糖尿病治療剤としては、例えばインスリン製剤(例、ウシ、ブタの膵臓から抽出された動物インスリン製剤;大腸菌またはイーストを用い、遺伝子工学的に合成したヒトインスリン製剤;インスリン亜鉛;プロタミンインスリン亜鉛;インスリンのフラグメントまたは誘導体(例、INS−1等)、経口インスリン製剤)、インスリン抵抗性改善剤(例、ピオグリタゾンまたはその塩(好ましくは塩酸塩)、ロシグリタゾンまたはその塩(好ましくはマレイン酸塩)、レグリキサン(Reglixane)(JTT-501)、GI-262570、ネトグリタゾン(Netoglitazone)(MCC-555)、DRF-2593、BM-13.1258、KRP-297、R-119702、リボグリタゾン(Rivoglitazone)(CS-011)、FK-614、WO99/58510に記載の化合物(例えば(E)-4-[4-(5-メチル-2-フェニル-4-オキサゾリルメトキシ)ベンジルオキシイミノ]-4-フェニル酪酸)、WO01/38325に記載の化合物、テサグリタザール(Tesaglitazar)(AZ−242)、ラガグリタザール(Ragaglitazar)(NN-622)、ムラグリタザール(Muraglitazar)(BMS-298585)、ONO-5816、BM-13-1258、LM-4156、MBX-102、LY-519818、MX-6054、LY-510929、バラグリタゾン(Balaglitazone)(NN-2344)、T-131またはその塩、THR-0921)、PPARγアゴニスト、PPARγアンタゴニスト、PPARγ/αデュアルアゴニスト、α−グルコシダーゼ阻害剤(例、ボグリボース、アカルボース、ミグリトール、エミグリテート)、ビグアナイド剤(例、フェンホルミン、メトホルミン、ブホルミンまたはそれらの塩(例、塩酸塩、フマル酸塩、コハク酸塩))、インスリン分泌促進剤[スルホニルウレア剤(例、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド、グリピザイド、グリブゾール等)、レパグリニド、セナグリニド、ナテグリニド、ミチグリニドまたはそのカルシウム塩水和物]、GPR40アゴニスト、GLP-1受容体アゴニスト[例、GLP-1、GLP-1MR剤、NN-2211、AC-2993(exendin-4)、BIM-51077、Aib(8,35)hGLP-1(7,37)NH2、CJC-1131]、アミリンアゴニスト(例、プラムリンチド)、フォスフォチロシンフォスファターゼ阻害剤(例、バナジン酸ナトリウム)、ジペプチジルペプチダーゼIV阻害剤(例、NVP−DPP−278、PT−100、P32/98、LAF−237、P93/01、TS-021、MK−431、BMS-477118等)、β3アゴニスト(例、AJ−9677、AZ40140等)、糖新生阻害剤(例、グリコーゲンホスホリラーゼ阻害剤、グルコース−6−ホスファターゼ阻害剤、グルカゴン拮抗剤)、SGLT(sodium-glucose cotransporter)阻害剤(例、T−1095)、11β−ヒドロキシステロイドデヒドロゲナーゼ阻害薬(例、BVT-3498)、アジポネクチンまたはその作動薬、IKK阻害薬(例、AS-2868)、レプチン抵抗性改善薬、ソマトスタチン受容体作動薬(例、WO01/25228、WO03/42204、WO98/44921、WO98/45285およびWO99/22735記載の化合物)、グルコキナーゼ活性化薬(例、Ro-28-1675)が挙げられる。 Examples of diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast; insulin zinc; protamine insulin zinc; Insulin fragment or derivative (eg, INS-1 etc.), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate) , Reglixane (JTT-501), GI-262570, Netoglitazone (MCC-555), DRF-2593, BM-13.1258, KRP-297, R-119702, Riboglitazone (CS- [0111], FK-614, compounds described in WO99 / 58510 (eg (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-pheny Butyric acid), compounds described in WO01 / 38325, Tesaglitazar (AZ-242), Ragaglitazar (NN-622), Muraglitazar (BMS-298585), ONO-5816, BM-13-1258 LM-4156, MBX-102, LY-519818, MX-6054, LY-510929, Balaglitazone (NN-2344), T-131 or a salt thereof, THR-0921), PPARγ agonist, PPARγ antagonist, PPARγ / α dual agonist, α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate), biguanide (eg, phenformin, metformin, buformin or salts thereof (eg, hydrochloride, fumarate, succinic acid) Salt)), insulin secretagogues [sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexami ), Repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate], GPR40 agonist, GLP-1 receptor agonist [eg, GLP-1, GLP-1MR agent, NN -2211, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH 2 , CJC-1131], amylin agonist (eg, pramlintide), phosphotyrosine phosphatase Inhibitor (eg, sodium vanadate), dipeptidyl peptidase IV inhibitor (eg, NVP-DPP-278, PT-100, P32 / 98, LAF-237, P93 / 01, TS-021, MK-431, BMS -477118 etc.), β3 agonist (eg, AJ-9679, AZ40140 etc.), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, Glucagon antagonists), SGLT (sodium-glucose cotransporter) inhibitors (eg, T-1095), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498), adiponectin or agonists thereof, IKK inhibitors (eg, AS -2868), leptin sensitizers, somatostatin receptor agonists (eg, compounds described in WO01 / 25228, WO03 / 42204, WO98 / 44921, WO98 / 45285 and WO99 / 22735), glucokinase activators (eg, Ro-28-1675).
糖尿病性合併症治療剤としては、例えばアルドース還元酵素阻害剤(例、トルレスタット、エパルレスタット、ゼナレスタット、ゾポルレスタット、ミナルレスタット、フィダレスタット、CT−112)、神経栄養因子およびその増加薬(例、NGF、NT−3、BDNF、WO01/14372に記載のニューロトロフィン産生・分泌促進剤(例えば、4−(4−クロロフェニル)−2−(2−メチル−1−イミダゾリル)−5−[3−(2−メチルフェノキシ)プロピル]オキサゾール))、神経再生促進薬(例、Y−128)、PKC阻害剤(例、ルボキシスタウリン メシレート(ruboxistaurin mesylate;LY−333531))、AGE阻害剤(例、ALT946、ピマゲジン、ピラトキサチン、N-フェナシルチアゾリウム ブロマイド(ALT766)、ALT-711、EXO-226、ピリドリン(Pyridorin)、ピリドキサミン)、活性酸素消去薬(例、チオクト酸)、脳血管拡張剤(例、チアプリド、メキシレチン)、ソマトスタチン受容体作動薬(例、BIM23190)、アポトーシスシグナルレギュレーティングキナーゼ-1(ASK-1)阻害薬が挙げられる。
抗高脂血症剤としては、例えばスタチン系化合物(例、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、イタバスタチン、ロスバスタチン、ピタバスタチンまたはそれらの塩(例、ナトリウム塩、カルシウム塩))、スクアレン合成酵素阻害剤(例、WO97/10224に記載の化合物、例えば、N−[[(3R,5S)-1-(3-アセトキシ-2,2-ジメチルプロピル)-7-クロロ-5-(2,3-ジメトキシフェニル)-2-オキソ-1,2,3,5-テトラヒドロ-4,1-ベンゾオキサゼピン-3-イル]アセチル]ピペリジン-4-酢酸)、フィブラート系化合物(例、ベザフィブラート、クロフィブラート、シムフィブラート、クリノフィブラート)、ACAT阻害剤(例、アバシマイブ(Avasimibe)、エフルシマイブ(Eflucimibe))、陰イオン交換樹脂(例、コレスチラミン)、プロブコール、ニコチン酸系薬剤(例、ニコモール(nicomol)、ニセリトロール(niceritrol))、イコサペント酸エチル、植物ステロール(例、ソイステロール(soysterol)、ガンマオリザノール(γ−oryzanol))が挙げられる。
Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112), neurotrophic factors and their increasing agents (eg, NGF). , NT-3, BDNF, neurotrophin production / secretion promoter (for example, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- ( 2-methylphenoxy) propyl] oxazole)), nerve regeneration promoter (eg, Y-128), PKC inhibitor (eg, ruboxistaurin mesylate (LY-333531)), AGE inhibitor (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), ALT -711, EXO-226, pyridoline (Pyridorin), pyridoxamine), active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, tiapride, mexiletine), somatostatin receptor agonists (eg, BIM23190), apoptosis Signal regulating kinase-1 (ASK-1) inhibitors.
Antihyperlipidemic agents include, for example, statin compounds (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin or their salts (eg, sodium salt, calcium salt)), squalene synthesis Enzyme inhibitors (eg, compounds described in WO 97/10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2, 3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid), fibrate compounds (eg, bezafibrate, Clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg, Avasimibe, Eflucimibe), anion exchange resins (eg, cofionate) Restyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol), ethyl icosapentate, plant sterols (eg, soysterol, gamma oryzanol) .
降圧剤としては、例えばアンジオテンシン変換酵素阻害剤(例、カプトプリル、エナラプリル、デラプリル)、アンジオテンシンII拮抗剤(例、カンデサルタン シレキセチル、ロサルタン、エプロサルタン、バルサルタン、テルミサルタン、イルベサルタン、タソサルタン、1-[[2'-(2,5-ジヒドロ-5-オキソ-4H-1,2,4-オキサジアゾール-3-イル)ビフェニル-4-イル]メチル]-2-エトキシ-1H-ベンズイミダゾール-7-カルボン酸)、カルシウム拮抗剤(例、マニジピン、ニフェジピン、アムロジピン、エホニジピン、ニカルジピン)、カリウムチャンネル開口薬(例、レブクロマカリム、L-27152、AL 0671、NIP-121)、クロニジンが挙げられる。
抗肥満剤としては、例えば中枢性抗肥満薬(例、デキスフェンフルラミン、フェンフルラミン、フェンテルミン、シブトラミン、アンフェプラモン、デキサンフェタミン、マジンドール、フェニルプロパノールアミン、クロベンゾレックス;MCH受容体拮抗薬(例、SB-568849;SNAP-7941;WO01/82925およびWO01/87834に含まれる化合物);ニューロペプチドY拮抗薬(例、CP-422935);カンナビノイド受容体拮抗薬(例、SR-141716、SR-147778);グレリン拮抗薬;11β−ヒドロキシステロイドデヒドロゲナーゼ阻害薬(例、BVT-3498))、膵リパーゼ阻害薬(例、オルリスタット、ATL-962)、β3アゴニスト(例、AJ-9677、AZ40140)、ペプチド性食欲抑制薬(例、レプチン、CNTF(毛様体神経栄養因子))、コレシストキニンアゴニスト(例、リンチトリプト、FPL-15849)、摂食抑制薬(例、P-57)が挙げられる。
Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1-[[2 ' -(2,5-Dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid ), Calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (eg, lebucromacarim, L-27152, AL 0671, NIP-121), clonidine.
Anti-obesity agents include, for example, central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (Eg, SB-568849; SNAP-7941; compounds included in WO01 / 82925 and WO01 / 87834); neuropeptide Y antagonists (eg, CP-422935); cannabinoid receptor antagonists (eg, SR-141716, SR -147778); ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498)), pancreatic lipase inhibitor (eg, orlistat, ATL-962), β3 agonist (eg, AJ-9677, AZ40140), Peptide appetite suppressant (eg, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonist (eg, lynchtrypto, FPL-15849), intake Inhibitors (eg, P-57) are mentioned.
利尿剤としては、例えば、キサンチン誘導体(例、サリチル酸ナトリウムテオブロミン、サリチル酸カルシウムテオブロミン)、チアジド系製剤(例、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンチルヒドロクロロチアジド、ペンフルチジド、ポリチアジド、メチクロチアジド)、抗アルドステロン製剤(例、スピロノラクトン、トリアムテレン)、炭酸脱水酵素阻害剤(例、アセタゾラミド)、クロルベンゼンスルホンアミド系製剤(例、クロルタリドン、メフルシド、インダパミド)、アゾセミド、イソソルビド、エタクリン酸、ピレタニド、ブメタニド、フロセミドが挙げられる。 Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, ethacrynic acid, Piretanide, bumetanide, furosemide.
抗血栓剤としては、例えば、ヘパリン(例、ヘパリンナトリウム、ヘパリンカルシウム、ダルテパリンナトリウム(dalteparin sodium)など)、ワルファリン(例、ワルファリンカリウムなど)、抗トロンビン薬(例、アルガトロバン(aragatroban)など)、血栓溶解薬(例、ウロキナーゼ(urokinase)、チソキナーゼ(tisokinase)、アルテプラーゼ(alteplase)、ナテプラーゼ(nateplase)、モンテプラーゼ(monteplase)、パミテプラーゼ(pamiteplase)など)、血小板凝集抑制薬(例、塩酸チクロピジン(ticlopidine hydrochloride)、シロスタゾール(cilostazol)、イコサペント酸エチル、ベラプロストナトリウム(beraprost sodium)、塩酸サルポグレラート(sarpogrelate hydrochloride)など)などが挙げられる。 Examples of the antithrombotic agent include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, aragatroban), Thrombolytic drugs (eg, urokinase, tisokinase, alteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride) ), Cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, and the like.
以下、化合物(I)の製造法について説明する。化合物(I)は、例えば、以下に詳述する[製造法]、あるいはこれらに準ずる方法によって製造することができる。
なお、下記の[製造法]において、原料化合物として用いられる化合物は、それぞれ塩として用いてもよい。このような塩としては、化合物(I)の塩として例示したものが用いられる。
下記の各製造法において、アルキル化反応、加水分解反応、アミノ化反応、エステル化反応、アミド化反応、エステル化反応、エーテル化反応、酸化反応、還元反応などを行う場合、これらの反応は、自体公知の方法に従って行われる。このような方法としては、例えばオーガニック ファンクショナル グループ プレパレーションズ(ORGANIC FUNCTIONAL GROUP PREPARATIONS)第2版、アカデミックプレス社(ACADEMIC PRESS, INC.)1989年刊;コンプリヘンシブ・オーガニック・トランスフォーメーション (Comprehensive Organic Transformations) VCH Publishers Inc.,1989年刊などに記載の方法などが挙げられる。
Hereafter, the manufacturing method of compound (I) is demonstrated. Compound (I) can be produced, for example, by the [Production method] described in detail below or a method analogous thereto.
In the following [Production method], the compounds used as raw material compounds may each be used as a salt. As such salt, those exemplified as the salt of compound (I) can be used.
In the following production methods, when performing alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, esterification reaction, etherification reaction, oxidation reaction, reduction reaction, etc., these reactions are: This is performed according to a method known per se. Such methods include, for example, Organic Functional Group PREPARATIONS 2nd edition, Academic Press, Inc., 1989; Comprehensive Organic Transformation (Comprehensive Organic Transformation). VCH Publishers Inc. , 1989, and the like.
[製造法]
化合物(I)は、例えば、下記アミド化反応によって製造される。
(アミド化反応)
[Production method]
Compound (I) is produced, for example, by the following amidation reaction.
(Amidation reaction)
[式中の記号は前記と同意義を示す]
上記「アミド化反応」には、下記の「脱水縮合剤を用いる方法」および「カルボン酸ないしスルホン酸の反応性誘導体を用いる方法」などが含まれる。
[The symbols in the formula are as defined above]
The “amidation reaction” includes the following “method using a dehydration condensing agent” and “method using a reactive derivative of carboxylic acid or sulfonic acid”.
i)脱水縮合剤を用いる方法
化合物(III)、1ないし5当量の化合物(II)、および1ないし2当量の脱水縮合剤を、不活性溶媒中で反応させる。必要に応じ、1ないし1.5当量の1−ヒドロキシベンゾトリアゾール(HOBt)、触媒量ないし5当量の塩基などの共存下に反応を行ってもよい。
上記「脱水縮合剤」としては、例えば、ジシクロヘキシルカルボジイミド(DCC)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(EDC・HCl)などが挙げられる。これらのなかでも、EDC・HClが好ましい。
上記「不活性溶媒」としては、例えば、ニトリル系溶媒、アミド系溶媒、ハロゲン化炭化水素系溶媒、エーテル系溶媒などが挙げられる。これらは、二種以上を適宜の割合で混合して用いてもよい。
ここで、ニトリル系溶媒としては、例えば、アセトニトリル、プロピオニトリルなどが用いられる。なかでも、アセトニトリルが好ましい。
アミド系溶媒としては、例えば、N,N−ジメチルホルムアミド(DMF)、N,N−ジメチルアセトアミド、N−メチルピロリドンなどが用いられる。なかでも、DMFが好ましい。
ハロゲン化炭化水素系溶媒としては、例えば、ジクロロメタン、クロロホルム、1,2−ジクロロエタン、四塩化炭素などが用いられる。なかでも、ジクロロメタンが好ましい。
エーテル系溶媒としては、例えば、ジエチルエーテル、テトラヒドロフラン(THF)、1,4−ジオキサン、1,2−ジメトキシエタンなどが用いられる。なかでも、THFが好ましい。
上記「塩基」としては、
1)例えば、アルカリ金属またはアルカリ土類金属の水素化物(例、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウム)、アルカリ金属またはアルカリ土類金属のアミド類(例、リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド)、アルカリ金属またはアルカリ土類金属の低級(C1−6)アルコキシド(例、ナトリウムメトキシド、ナトリウムエトキシド、カリウムtert−ブトキシド)などの強塩基;
2)例えば、アルカリ金属またはアルカリ土類金属の水酸化物(例、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウム)、アルカリ金属またはアルカリ土類金属の炭酸塩(例、炭酸ナトリウム、炭酸カリウム、炭酸セシウム)、アルカリ金属の炭酸水素塩(例、炭酸水素ナトリウム、炭酸水素カリウム)などの無機塩基;および
3)例えば、トリエチルアミン、ジイソプロピルエチルアミン、N−メチルモルホリンなどのアミン類;例えば、ピリジン、4−ジメチルアミノピリジン、DBU(1,8−ジアザビシクロ〔5.4.0〕ウンデス−7−エン)、DBN(1,5−ジアザビシクロ〔4.3.0〕ノン−5−エン)、イミダゾール、2,6−ルチジンなどの塩基性複素環化合物などの有機塩基などが挙げられる。
これらの塩基のなかでも、トリエチルアミン、4−ジメチルアミノピリジンなどが好ましい。
反応温度は、通常、室温(本明細書中、室温とは1ないし30℃の温度を意味する)である。反応時間は、例えば、1ないし24時間である。
i) Method using dehydrating condensing agent Compound (III), 1 to 5 equivalents of compound (II), and 1 to 2 equivalents of dehydrating condensing agent are reacted in an inert solvent. If necessary, the reaction may be performed in the presence of 1 to 1.5 equivalents of 1-hydroxybenzotriazole (HOBt), a catalytic amount to 5 equivalents of a base and the like.
Examples of the “dehydration condensing agent” include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), and the like. Among these, EDC · HCl is preferable.
Examples of the “inert solvent” include nitrile solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents, and the like. These may be used as a mixture of two or more at an appropriate ratio.
Here, as the nitrile solvent, for example, acetonitrile, propionitrile and the like are used. Of these, acetonitrile is preferable.
As the amide solvent, for example, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone and the like are used. Of these, DMF is preferable.
Examples of the halogenated hydrocarbon solvent include dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like. Of these, dichloromethane is preferred.
Examples of the ether solvent include diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and the like. Of these, THF is preferable.
As the above “base”,
1) For example, alkali metal or alkaline earth metal hydrides (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride), alkali metal or alkaline earth metal amides (eg, lithium amide, Sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide), alkali metal or alkaline earth metal lower (C 1-6 ) alkoxide ( Strong bases such as eg sodium methoxide, sodium ethoxide, potassium tert-butoxide);
2) For example, alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate) , Potassium carbonate, cesium carbonate), inorganic bases such as alkali metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate); and 3) amines such as, for example, triethylamine, diisopropylethylamine, N-methylmorpholine; , Pyridine, 4-dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] undes-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene) , Organic bases such as basic heterocyclic compounds such as imidazole and 2,6-lutidine .
Of these bases, triethylamine, 4-dimethylaminopyridine and the like are preferable.
The reaction temperature is usually room temperature (in the present specification, room temperature means a temperature of 1 to 30 ° C.). The reaction time is, for example, 1 to 24 hours.
ii)カルボン酸ないしスルホン酸の反応性誘導体を用いる方法
化合物(II)の反応性誘導体と1ないし5当量(好ましくは1ないし3当量)の化合物(III)とを、不活性溶媒中で反応させる。必要に応じ、1ないし10当量、好ましくは1ないし3当量の塩基の共存下に反応を行ってもよい。
化合物(II)の「反応性誘導体」としては、例えば、酸ハライド(例、酸クロリド、酸ブロミド)、混合酸無水物(例、C1−6アルキル−カルボン酸、C6−10アリール−カルボン酸またはC1−6アルキル炭酸との酸無水物)、活性エステル(例、置換基を有していてもよいフェノール、HOBtまたはN−ヒドロキシスクシンイミドとのエステル)などが挙げられる。
上記「置換基を有していてもよいフェノール」における「置換基」としては、例えば、ハロゲン原子、ニトロ基、ハロゲン化されていてもよいC1−6アルキル基、ハロゲン化されていてもよいC1−6アルコキシ基が挙げられる。置換基の数は、例えば1ないし5個である。
ここで、「ハロゲン化されていてもよいC1−6アルキル基」としては、例えば、1ないし5個、好ましくは1ないし3個のハロゲン原子を有していてもよいC1−6アルキル基(例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル)が挙げられる。具体例としては、メチル、クロロメチル、ジフルオロメチル、トリクロロメチル、トリフルオロメチル、エチル、2−ブロモエチル、2,2,2−トリフルオロエチル、ペンタフルオロエチル、プロピル、3,3,3−トリフルオロプロピル、イソプロピル、ブチル、4,4,4−トリフルオロブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、イソペンチル、ネオペンチル、5,5,5−トリフルオロペンチル、ヘキシル、6,6,6−トリフルオロヘキシルなどが挙げられる。
また「ハロゲン化されていてもよいC1−6アルコキシ基」としては、例えば、1ないし5個、好ましくは1ないし3個のハロゲン原子を有していてもよいC1−6アルコキシ基(例、メトキシ、エトキシ、プロポキシ、ブトキシ、ペンチルオキシ、ヘキシルオキシ)などが挙げられる。具体例としては、例えば、メトキシ、ジフルオロメトキシ、トリフルオロメトキシ、エトキシ、2,2,2−トリフルオロエトキシ、プロポキシ、イソプロポキシ、ブトキシ、4,4,4−トリフルオロブトキシ、イソブトキシ、sec−ブトキシ、ペンチルオキシ、イソペンチルオキシ、ヘキシルオキシなどが挙げられる。
また、「置換基を有していてもよいフェノール」の具体例としては、例えば、フェノール、ペンタクロロフェノール、ペンタフルオロフェノール、p−ニトロフェノールなどが挙げられる。
反応性誘導体は、好ましくは酸ハライドである。
上記「不活性溶媒」としては、例えば、エーテル系溶媒、ハロゲン化炭化水素系溶媒、芳香族系溶媒、脂肪族炭化水素系溶媒、ニトリル系溶媒、アミド系溶媒、ケトン系溶媒、スルホキシド系溶媒、水などが挙げられる。これらは、二種以上を適宜の割合で混合して用いてもよい。なかでも、アセトニトリル、THF、ジクロロメタン、クロロホルムなどが好ましい。
ここで、エーテル系溶媒、ハロゲン化炭化水素系溶媒、ニトリル系溶媒およびアミド系溶媒としては、前述の「脱水縮合剤を用いる方法」において例示したものが用いられる。
芳香族系溶媒としては、例えば、ベンゼン、トルエン、キシレン、ピリジンなどが用いられる。
脂肪族炭化水素系溶媒としては、例えば、ヘキサン、ペンタン、シクロヘキサンなどが用いられる。
ケトン系溶媒としては、例えば、アセトン、メチルエチルケトンなどが用いられる。
スルホキシド系溶媒としては、例えば、ジメチルスルホキシド(DMSO)などが用いられる。
上記「塩基」としては、前述の「脱水縮合剤を用いる方法」と同様のものが用いられ、好ましくは、水素化ナトリウム、炭酸カリウム、炭酸ナトリウム、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、炭酸水素カリウム、トリエチルアミン、ピリジンなどである。
反応温度は、通常、−20℃ないし50℃、好ましくは室温である。
反応時間は、通常、5分間ないし40時間、好ましくは30分間ないし18時間である。
上記製造法において、原料化合物として用いられる化合物(III)は、自体公知の方法、例えば、WO03/72197号パンフレットに記載の方法あるいはこれに準ずる方法により製造することができる。また、化合物(II)は、自体公知の方法により製造することができる。
ii) Method using a reactive derivative of carboxylic acid or sulfonic acid The reactive derivative of compound (II) is reacted with 1 to 5 equivalents (preferably 1 to 3 equivalents) of compound (III) in an inert solvent. . If necessary, the reaction may be carried out in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base.
Examples of the “reactive derivative” of compound (II) include acid halides (eg, acid chloride, acid bromide), mixed acid anhydrides (eg, C 1-6 alkyl-carboxylic acid, C 6-10 aryl-carboxylic acid). Acid or acid anhydride with C 1-6 alkyl carbonate), active ester (eg, ester with optionally substituted phenol, HOBt or N-hydroxysuccinimide) and the like.
Examples of the “substituent” in the above “optionally substituted phenol” include, for example, a halogen atom, a nitro group, an optionally halogenated C 1-6 alkyl group, and an optionally halogenated atom. A C1-6 alkoxy group is mentioned. The number of substituents is, for example, 1 to 5.
Here, as the "C 1-6 alkyl group which may be halogenated", for example, 1 to 5, preferably 1 to 3 C 1-6 alkyl group which may have a halogen atom (Eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl). Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoro Propyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6- And trifluorohexyl.
As the "optionally halogenated C 1-6 optionally alkoxy group", for example, 1 to 5, preferably 1 to 3 halogen atoms a C 1-6 alkoxy group which may have a (e.g. Methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy) and the like. Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy , Pentyloxy, isopentyloxy, hexyloxy and the like.
Specific examples of “optionally substituted phenol” include phenol, pentachlorophenol, pentafluorophenol, p-nitrophenol, and the like.
The reactive derivative is preferably an acid halide.
Examples of the “inert solvent” include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, aliphatic hydrocarbon solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, Water etc. are mentioned. These may be used as a mixture of two or more at an appropriate ratio. Of these, acetonitrile, THF, dichloromethane, chloroform and the like are preferable.
Here, as the ether solvent, the halogenated hydrocarbon solvent, the nitrile solvent, and the amide solvent, those exemplified in the aforementioned “method using a dehydration condensing agent” are used.
As the aromatic solvent, for example, benzene, toluene, xylene, pyridine and the like are used.
As the aliphatic hydrocarbon solvent, for example, hexane, pentane, cyclohexane or the like is used.
As the ketone solvent, for example, acetone, methyl ethyl ketone, or the like is used.
As the sulfoxide solvent, for example, dimethyl sulfoxide (DMSO) is used.
As the “base”, those similar to the above-mentioned “method using a dehydration condensing agent” are used, and preferably sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, Potassium hydrogen carbonate, triethylamine, pyridine and the like.
The reaction temperature is usually −20 ° C. to 50 ° C., preferably room temperature.
The reaction time is usually 5 minutes to 40 hours, preferably 30 minutes to 18 hours.
In the above production method, compound (III) used as a raw material compound can be produced by a method known per se, for example, the method described in WO03 / 72197 pamphlet or a method analogous thereto. Compound (II) can be produced by a method known per se.
このようにして得られた化合物(I)において、分子内の官能基は、自体公知の化学反応を組み合わせることにより目的の官能基に変換することもできる。ここで、化学反応の例としては、酸化反応、還元反応、アルキル化反応、加水分解反応、アミノ化反応、エステル化反応、アリールカップリング反応、脱保護反応などが挙げられる。 In the compound (I) thus obtained, the functional group in the molecule can be converted to the target functional group by combining a chemical reaction known per se. Here, examples of the chemical reaction include an oxidation reaction, a reduction reaction, an alkylation reaction, a hydrolysis reaction, an amination reaction, an esterification reaction, an aryl coupling reaction, and a deprotection reaction.
上記製造法において、原料化合物が置換基としてアミノ基、カルボキシ基、ヒドロキシ基、カルボニル基を有する場合、これらの基にペプチド化学などで一般的に用いられるような保護基が導入されていてもよく、反応後に必要に応じて保護基を除去することにより目的化合物を得ることができる。
アミノ基の保護基としては、例えば、ホルミル基、C1−6アルキル−カルボニル基(例、アセチル、プロピオニル)、C1−6アルコキシ−カルボニル基(例、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル)、ベンゾイル基、C7−10アラルキル−カルボニル基(例、ベンジルカルボニル)、C7−14アラルキルオキシ−カルボニル基(例、ベンジルオキシカルボニル、9−フルオレニルメトキシカルボニル)、トリチル基、フタロイル基、N,N−ジメチルアミノメチレン基、置換シリル基(例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、tert−ブチルジメチルシリル、tert−ブチルジエチルシリル)、C2−6アルケニル基(例、1−アリル)などが挙げられる。これらの基は、ハロゲン原子、C1−6アルコキシ基(例、メトキシ、エトキシ、プロポキシ)およびニトロ基から選ばれる1ないし3個の置換基で置換されていてもよい。
カルボキシ基の保護基としては、例えば、C1−6アルキル基(例、メチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチル)、C7−11アラルキル基(例、ベンジル)、フェニル基、トリチル基、置換シリル基(例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、tert−ブチルジメチルシリル、tert−ブチルジエチルシリル)、C2−6アルケニル基(例、1−アリル)などが挙げられる。これらの基は、ハロゲン原子、C1−6アルコキシ基(例、メトキシ、エトキシ、プロポキシ)およびニトロ基から選ばれる1ないし3個の置換基で置換されていてもよい。
ヒドロキシ基の保護基としては、例えば、C1−6アルキル基(例、メチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチル)、フェニル基、トリチル基、C7−10アラルキル基(例、ベンジル)、ホルミル基、C1−6アルキル−カルボニル基(例、アセチル、プロピオニル)、ベンゾイル基、C7−10アラルキル−カルボニル基(例、ベンジルカルボニル)、2−テトラヒドロピラニル基、2−テトラヒドロフラニル基、置換シリル(例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、tert−ブチルジメチルシリル、tert−ブチルジエチルシリル)、C2−6アルケニル基(例、1−アリル)などが挙げられる。これらの基は、ハロゲン原子、C1−6アルキル(例、メチル、エチル、n−プロピル)、C1−6アルコキシ(例、メトキシ、エトキシ、プロポキシ)またはニトロ基から選ばれる1ないし3個の置換基で置換されていてもよい。
カルボニル基の保護基としては、例えば、環状アセタール(例、1,3−ジオキサン)、非環状アセタール(例、ジ−C1−6アルキルアセタール)などが挙げられる。
上記した保護基の除去方法は、自体公知の方法、例えば、プロテクティブ グループス イン オーガニック シンセシス(Protective Groups in Organic Synthesis)、 John Wiley and Sons 刊(1980)に記載の方法などに準じて行うことができる。具体的には、酸、塩基、紫外光、ヒドラジン、フェニルヒドラジン、N−メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウム、トリアルキルシリルハライド(例えば、トリメチルシリルヨージド、トリメチルシリルブロミドなど)などを使用する方法、還元法などが用いられる。
In the above production method, when the raw material compound has an amino group, a carboxy group, a hydroxy group, or a carbonyl group as a substituent, a protective group generally used in peptide chemistry or the like may be introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction.
Examples of the protecting group for the amino group include a formyl group, a C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl), a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl). ), Benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) ) And the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group (eg, methoxy, ethoxy, propoxy) and a nitro group.
Examples of the protecting group for the carboxy group include a C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), a C 7-11 aralkyl group (eg, benzyl), a phenyl group, and trityl. Group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group (eg, methoxy, ethoxy, propoxy) and a nitro group.
Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), a phenyl group, a trityl group, and a C 7-10 aralkyl group (eg, benzyl). ), Formyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl), benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl Group, substituted silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like. These groups are 1 to 3 selected from a halogen atom, C 1-6 alkyl (eg, methyl, ethyl, n-propyl), C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy) or a nitro group. It may be substituted with a substituent.
Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
The protecting group removal method described above can be carried out according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide, trimethylsilyl bromide, etc.) The method used, the reduction method, etc. are used.
上記製造法により得られた化合物(I)は、公知の手段、例えば、溶媒抽出、液性変換、転溶、晶出、再結晶、クロマトグラフィーなどによって単離精製することができる。 Compound (I) obtained by the above production method can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.
化合物(I)が、光学異性体、立体異性体、位置異性体、回転異性体を含有する場合には、これらも化合物(I)として含有されるとともに、自体公知の合成手法、分離手法によりそれぞれを単品として得ることができる。例えば、化合物(I)に光学異性体が存在する場合には、該化合物から分割された光学異性体も化合物(I)に包含される。
ここで、光学異性体は自体公知の方法により製造することができる。
When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by a known synthesis method and separation method, respectively. Can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).
Here, the optical isomer can be produced by a method known per se.
化合物(I)は、結晶であってもよい。
化合物(I)の結晶(以下、本発明の結晶と略記することがある)は、化合物(I)に自体公知の結晶化法を適用して、結晶化することによって製造することができる。
Compound (I) may be a crystal.
Crystals of compound (I) (hereinafter sometimes abbreviated as crystals of the present invention) can be produced by crystallization by applying a crystallization method known per se to compound (I).
本明細書中、融点は、例えば、微量融点測定器(ヤナコ、MP−500D型またはBuchi、B−545型)またはDSC(示差走査熱量分析)装置(SEIKO、EXSTAR6000)等を用いて測定される融点を意味する。
一般に、融点は、測定機器、測定条件などによって変動する場合がある。本明細書中の結晶は、通常の誤差範囲内であれば、本明細書に記載の融点と異なる値を示す結晶であってもよい。
本発明の結晶は、物理化学的性質(例、融点、溶解度、安定性など)および生物学的性質(例、体内動態(吸収性、分布、代謝、排泄)、薬効発現など)に優れ、医薬として極めて有用である。
In the present specification, the melting point is measured using, for example, a micro melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point.
In general, the melting point may vary depending on the measurement equipment, measurement conditions, and the like. The crystal in the present specification may be a crystal exhibiting a value different from the melting point described in the present specification as long as it is within a normal error range.
The crystal of the present invention is excellent in physicochemical properties (eg, melting point, solubility, stability, etc.) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), drug efficacy, etc.), and pharmaceuticals. As extremely useful.
本発明は、以下の参考例、実施例、実験例および製剤例によって、さらに詳しく説明されるが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
なお、参考例および実施例中の略号は次の意味を有する。
s:シングレット、d:ダブレット、t:トリプレット、q:クワルテット、m:マルチプレット、br:ブロード、J:カップリング定数、
また、参考例および実施例中、%は特記しない限り重量%を示す。
The present invention will be described in more detail with reference to the following Reference Examples, Examples, Experimental Examples and Formulation Examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention. Also good.
In addition, the symbol in a reference example and an Example has the following meaning.
s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad, J: coupling constant,
In the Reference Examples and Examples,% indicates% by weight unless otherwise specified.
参考例1
1-ベンジル 4-tert-ブチル 2-(モルホリン-4-イルカルボニル)ピペラジン-1,4-ジカルボキシレート
Reference example 1
1-Benzyl 4-tert-butyl 2- (morpholin-4-ylcarbonyl) piperazine-1,4-dicarboxylate
1-[(ベンジルオキシ)カルボニル]-4-(tert-ブトキシカルボニル)ピペラジン-2-カルボン酸(2.95 g, 8.10 mmol)、モルホリン(0.847 ml, 9.71 mmol)とHOBt(1.24 g, 8.10 mmol)のDMF(10 ml)溶液に、EDC.HCl(1.55 g, 8.10 mmol)を氷冷下加え、室温で16時間攪拌した。反応液を酢酸エチルに溶かし、0.5N 塩酸、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をNH-シリカゲルカラムクロマトグラフィー(展開溶媒;酢酸エチル)に通して、表題化合物3.51 g(定量的)を油状物として得た。これ以上精製することなく次工程に進んだ。 1-[(Benzyloxy) carbonyl] -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid (2.95 g, 8.10 mmol), morpholine (0.847 ml, 9.71 mmol) and HOBt (1.24 g, 8.10 mmol) DMF in (10 ml) solution, EDC. HCl (1.55 g, 8.10 mmol) under ice-cooling, followed by stirring at room temperature for 16 hours. The reaction solution was dissolved in ethyl acetate, washed with 0.5N hydrochloric acid, aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was passed through NH-silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (3.51 g, quantitative) as an oil. Proceed to the next step without further purification.
参考例2
ベンジル 2-(モルホリン-4-イルカルボニル)ピペラジン-1-カルボキシレート
Reference example 2
Benzyl 2- (morpholin-4-ylcarbonyl) piperazine-1-carboxylate
参考例1で得られた1-ベンジル 4-tert-ブチル 2-(モルホリン-4-イルカルボニル)ピペラジン-1,4-ジカルボキシレート(3.51 g, 8.10 mmol)に4N塩化水素-酢酸エチル(40 ml)を加え、2時間後に溶媒を減圧下留去した。残渣を水に溶かし、炭酸カリウムを加えて塩基性とした後、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して、表題化合物2.51 g(収率92.9%)を油状物として得た。これ以上精製することなく次工程に進んだ。 1-benzyl 4-tert-butyl 2- (morpholin-4-ylcarbonyl) piperazine-1,4-dicarboxylate (3.51 g, 8.10 mmol) obtained in Reference Example 1 was added to 4N hydrogen chloride-ethyl acetate (40 ml), and after 2 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in water, basified with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.51 g, yield 92.9%) as an oil. Proceed to the next step without further purification.
参考例3
ベンジル 4-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]-2-(モルホリン-4-イルカルボニル)ピペラジン-1-カルボキシレート
Reference example 3
Benzyl 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2- (morpholin-4-ylcarbonyl) piperazine-1-carboxylate
参考例2で得られたベンジル 2-(モルホリン-4-イルカルボニル)ピペラジン-1-カルボキシレート(2.51 g, 7.53 mmol)、tert-ブチル 4-オキソピペリジン-1-カルボキシレート(1.53 g, 7.53 mmol)と酢酸(0.431 ml, 7.53 mmol)のTHF(30 ml)溶液にトリアセトキシ水素化ホウ素ナトリウム(2.39 g, 11.3 mmol)を加え、室温で16時間攪拌した後、溶媒を減圧下留去した。残渣に酢酸エチルを加え、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン-酢酸エチル=1:1から酢酸エチル)で精製して、表題化合物1.73 g(収率44.5%)を油状物として得た。
EI(pos) 517.2 [M+H]+
Benzyl 2- (morpholin-4-ylcarbonyl) piperazine-1-carboxylate (2.51 g, 7.53 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.53 g, 7.53 mmol) obtained in Reference Example 2 ) And acetic acid (0.431 ml, 7.53 mmol) in THF (30 ml) were added sodium triacetoxyborohydride (2.39 g, 11.3 mmol), and the mixture was stirred at room temperature for 16 hours, and then the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane-ethyl acetate = 1: 1 to ethyl acetate) to give 1.73 g (yield 44.5%) of the title compound as an oil. Obtained as a thing.
EI (pos) 517.2 [M + H] +
参考例4
tert-ブチル 4-[3-(モルホリン-4-イルカルボニル)ピペラジン-1-イル]ピペリジン-1-カルボキシレート
Reference example 4
tert-Butyl 4- [3- (morpholin-4-ylcarbonyl) piperazin-1-yl] piperidine-1-carboxylate
参考例3で得られたベンジル 4-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]-2-(モルホリン-4-イルカルボニル)ピペラジン-1-カルボキシレート(1.72 g, 3.32 mmol)と10% パラジウム炭素(50%含水品、1 g)にTHF(20 ml)を加え、水素雰囲気下に室温で16時間攪拌した。反応液をセライトろ過し、溶媒を減圧下留去することにより、表題化合物1.27 g(定量的)を油状物として得た。これ以上精製することなく次工程に進んだ。 Benzyl 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2- (morpholin-4-ylcarbonyl) piperazine-1-carboxylate (1.72 g, 3.32 mmol) obtained in Reference Example 3 THF (20 ml) was added to 10% palladium carbon (50% water-containing product, 1 g), and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give the title compound (1.27 g, quantitative) as an oil. Proceed to the next step without further purification.
参考例5
tert-ブチル 4-[3-(モルホリン-4-イルカルボニル)-4-(トリフルオロアセチル)ピペラジン-1-イル]ピペリジン-1-カルボキシレート
Reference Example 5
tert-butyl 4- [3- (morpholin-4-ylcarbonyl) -4- (trifluoroacetyl) piperazin-1-yl] piperidine-1-carboxylate
参考例4で得られたtert-ブチル 4-[3-(モルホリン-4-イルカルボニル)ピペラジン-1-イル]ピペリジン-1-カルボキシレート(1.27 g, 3.32 mmol)をTHF(20 ml)に溶かし、氷冷下でトリエチルアミン(0.693 ml, 4.98 mmol)とトリフルオロ酢酸無水物(0.563 ml, 3.99 mmol)を加え、室温で3時間攪拌した後、溶媒を減圧下留去した。残渣に酢酸エチルを加え、炭酸水素ナトリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去して、表題化合物1.31 g(収率82.4%)を油状物として得た。
EI(pos) 479.2 [M+H]+
Dissolve tert-butyl 4- [3- (morpholin-4-ylcarbonyl) piperazin-1-yl] piperidine-1-carboxylate (1.27 g, 3.32 mmol) obtained in Reference Example 4 in THF (20 ml). Triethylamine (0.693 ml, 4.98 mmol) and trifluoroacetic anhydride (0.563 ml, 3.99 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1.31 g (yield 82.4%) of the title compound as an oil.
EI (pos) 479.2 [M + H] +
参考例6
4-{[4-(ピペリジン-4-イル)-1-(トリフルオロアセチル)ピペラジン-2-イル]カルボニル}モルホリン 二塩酸塩
Reference Example 6
4-{[4- (Piperidin-4-yl) -1- (trifluoroacetyl) piperazin-2-yl] carbonyl} morpholine dihydrochloride
参考例5で得られたtert-ブチル 4-[3-(モルホリン-4-イルカルボニル)-4-(トリフルオロアセチル)ピペラジン-1-イル]ピペリジン-1-カルボキシレート(1.31 g, 2.74 mmol)に4N塩化水素-酢酸エチル(15 ml)を加えた。反応液を2時間攪拌した後、溶媒を減圧下留去して、表題化合物1.22 g(収率98.2%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Tert-Butyl 4- [3- (morpholin-4-ylcarbonyl) -4- (trifluoroacetyl) piperazin-1-yl] piperidine-1-carboxylate (1.31 g, 2.74 mmol) obtained in Reference Example 5 4N hydrogen chloride-ethyl acetate (15 ml) was added. The reaction mixture was stirred for 2 hours, and the solvent was evaporated under reduced pressure to give the title compound (1.22 g, yield 98.2%) as an oil. Proceed to the next step without further purification.
参考例7
1-ベンジル 4-tert-ブチル 2-[(ジエチルアミノ)カルボニル]ピペラジン-1,4-ジカルボキシレート
Reference Example 7
1-Benzyl 4-tert-butyl 2-[(diethylamino) carbonyl] piperazine-1,4-dicarboxylate
1-[(ベンジルオキシ)カルボニル]-4-(tert-ブトキシカルボニル)ピペラジン-2-カルボン酸(5.26 g, 14.4 mmol)とジエチルアミン(1.79 ml, 17.3 mmol)を用いて、参考例1と同様の操作を行うことにより、表題化合物1.78 g(収率29.4%)を油状物として得た。これ以上精製することなく次工程に進んだ。 1-[(Benzyloxy) carbonyl] -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid (5.26 g, 14.4 mmol) and diethylamine (1.79 ml, 17.3 mmol) were used as in Reference Example 1. By performing the operation, 1.78 g (yield 29.4%) of the title compound was obtained as an oily substance. Proceed to the next step without further purification.
参考例8
ベンジル 2-[(ジエチルアミノ)カルボニル]ピペラジン-1-カルボキシレート
Reference Example 8
Benzyl 2-[(diethylamino) carbonyl] piperazine-1-carboxylate
参考例7で得られた1-ベンジル 4-tert-ブチル 2-[(ジエチルアミノ)カルボニル]ピペラジン-1,4-ジカルボキシレート(1.78 g, 4.24 mmol)を用いて、参考例2と同様の操作を行うことにより、表題化合物1.14 g(収率83.5%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using 1-benzyl 4-tert-butyl 2-[(diethylamino) carbonyl] piperazine-1,4-dicarboxylate (1.78 g, 4.24 mmol) obtained in Reference Example 7, the same procedure as in Reference Example 2 was performed. To give 1.14 g (yield 83.5%) of the title compound as an oil. Proceed to the next step without further purification.
参考例9
ベンジル 4-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]-2-[(ジエチルアミノ)カルボニル]ピペラジン-1-カルボキシレート
Reference Example 9
Benzyl 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2-[(diethylamino) carbonyl] piperazine-1-carboxylate
参考例8で得られたベンジル 2-[(ジエチルアミノ)カルボニル]ピペラジン-1-カルボキシレート(582 mg, 1.82 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(399 mg, 2.00 mmol)を用いて、参考例3と同様の操作を行うことにより、表題化合物916 mg(収率99.9%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Benzyl 2-[(diethylamino) carbonyl] piperazine-1-carboxylate (582 mg, 1.82 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (399 mg, 2.00 mmol) obtained in Reference Example 8 Using the same procedure as in Reference Example 3, the title compound (916 mg, yield 99.9%) was obtained as an oil. Proceed to the next step without further purification.
参考例10
tert-ブチル 4-{3-[(ジエチルアミノ)カルボニル]ピペラジン-1-イル}ピペリジン-1-カルボキシレート
Reference Example 10
tert-butyl 4- {3-[(diethylamino) carbonyl] piperazin-1-yl} piperidine-1-carboxylate
参考例9で得られたベンジル 4-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]-2-[(ジエチルアミノ)カルボニル]ピペラジン-1-カルボキシレート(916 mg, 1.82 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物515 mg(収率76.7%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using the benzyl 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2-[(diethylamino) carbonyl] piperazine-1-carboxylate (916 mg, 1.82 mmol) obtained in Reference Example 9 The title compound was obtained in the same manner as in Reference Example 4 to give the title compound (515 mg, yield 76.7%) as an oil. Proceed to the next step without further purification.
参考例11
tert-ブチル 4-[3-[(ジエチルアミノ)カルボニル]-4-(トリフルオロアセチル)ピペラジン-1-イル]ピペリジン-1-カルボキシレート
Reference Example 11
tert-butyl 4- [3-[(diethylamino) carbonyl] -4- (trifluoroacetyl) piperazin-1-yl] piperidine-1-carboxylate
参考例10で得られたtert-ブチル 4-{3-[(ジエチルアミノ)カルボニル]ピペラジン-1-イル}ピペリジン-1-カルボキシレート(515 mg, 1.40 mmol)を用いて、参考例5と同様の操作を行うことにより、表題化合物584 mg(収率90.0%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using tert-butyl 4- {3-[(diethylamino) carbonyl] piperazin-1-yl} piperidine-1-carboxylate (515 mg, 1.40 mmol) obtained in Reference Example 10, the same as in Reference Example 5 By the operation, 584 mg (yield 90.0%) of the title compound was obtained as an oily substance. Proceed to the next step without further purification.
参考例12
N,N-ジエチル-4-(ピペリジン-4-イル)-1-(トリフルオロアセチル)ピペラジン-2-カルボキサミド
Reference Example 12
N, N-diethyl-4- (piperidin-4-yl) -1- (trifluoroacetyl) piperazine-2-carboxamide
参考例11で得られたtert-ブチル 4-[3-[(ジエチルアミノ)カルボニル]-4-(トリフルオロアセチル)ピペラジン-1-イル]ピペリジン-1-カルボキシレート(584 mg, 1.26 mmol)を用いて、参考例6と同様の操作を行うことにより、表題化合物550 mg(定量的)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using tert-butyl 4- [3-[(diethylamino) carbonyl] -4- (trifluoroacetyl) piperazin-1-yl] piperidine-1-carboxylate (584 mg, 1.26 mmol) obtained in Reference Example 11 Then, by performing the same operation as in Reference Example 6, 550 mg (quantitative) of the title compound was obtained as an oil. Proceed to the next step without further purification.
参考例13
tert-ブチル 3-[(ジエチルアミノ)カルボニル]-5-オキソピペラジン-1-カルボキシレート
Reference Example 13
tert-Butyl 3-[(diethylamino) carbonyl] -5-oxopiperazine-1-carboxylate
4-(tert-ブトキシカルボニル)-6-オキソピペラジン-2-カルボン酸(800 mg, 3.28 mmol)とジエチルアミン(0.407 ml, 3.93 mmol)を用いて、参考例1と同様の操作を行うことにより、表題化合物301 mg(収率30.7%)を油状物として得た。これ以上精製することなく次工程に進んだ。 By performing the same operation as in Reference Example 1 using 4- (tert-butoxycarbonyl) -6-oxopiperazine-2-carboxylic acid (800 mg, 3.28 mmol) and diethylamine (0.407 ml, 3.93 mmol), The title compound (301 mg, yield 30.7%) was obtained as an oil. Proceed to the next step without further purification.
参考例14
N,N-ジエチル-6-オキソピペラジン-2-カルボキサミド 塩酸塩
Reference Example 14
N, N-diethyl-6-oxopiperazine-2-carboxamide hydrochloride
参考例13で得られたtert-ブチル 3-[(ジエチルアミノ)カルボニル]-5-オキソピペラジン-1-カルボキシレート(301 mg, 1.01 mmol)を用いて、参考例6と同様の操作を行い、ジイソプロピルエーテルで粉末にすることにより、表題化合物237 mg(定量的)を得た。これ以上精製することなく次工程に進んだ。 Using tert-butyl 3-[(diethylamino) carbonyl] -5-oxopiperazine-1-carboxylate (301 mg, 1.01 mmol) obtained in Reference Example 13, the same operation as in Reference Example 6 was performed, and diisopropyl Trituration with ether gave 237 mg (quantitative) of the title compound. Proceed to the next step without further purification.
参考例15
tert-ブチル 4-{3-[(ジエチルアミノ)カルボニル]-5-オキソピペラジン-1-イル}ピペリジン-1-カルボキシレート
Reference Example 15
tert-Butyl 4- {3-[(diethylamino) carbonyl] -5-oxopiperazin-1-yl} piperidine-1-carboxylate
参考例14で得られたN,N-ジエチル-6-オキソピペラジン-2-カルボキサミド 塩酸塩(237 mg, 1.01 mmol)、tert-ブチル 4-オキソピペリジン-1-カルボキシレート(220 mg, 1.11 mmol)、酢酸(0.058 ml, 1.01 mmol)とトリエチルアミン(0.168 ml, 1.21 mmol)のTHF(5 ml)-メタノール(5 ml)混合溶液にトリアセトキシ水素化ホウ素ナトリウム(320 mg, 1.51 mmol)を加え、室温で3日間攪拌した後、溶媒を減圧下留去した。残渣に酢酸エチルを加え、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン-酢酸エチル=1:1から酢酸エチル-メタノール=5:1)で精製して、表題化合物87.6 mg(収率22.8%)を油状物として得た。
EI(pos) 383.1 [M+H]+
N, N-diethyl-6-oxopiperazine-2-carboxamide hydrochloride (237 mg, 1.01 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (220 mg, 1.11 mmol) obtained in Reference Example 14 , Acetic acid (0.058 ml, 1.01 mmol) and triethylamine (0.168 ml, 1.21 mmol) in THF (5 ml) -methanol (5 ml) mixed solution was added sodium triacetoxyborohydride (320 mg, 1.51 mmol) at room temperature. Then, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane-ethyl acetate = 1: 1 to ethyl acetate-methanol = 5: 1) to give 87.6 mg (yield) of the title compound. 22.8%) as an oil.
EI (pos) 383.1 [M + H] +
参考例16
N,N-ジエチル-6-オキソ-4-(ピペリジン-4-イル)ピペラジン-2-カルボキサミド 二塩酸塩
Reference Example 16
N, N-diethyl-6-oxo-4- (piperidin-4-yl) piperazine-2-carboxamide dihydrochloride
参考例15で得られたtert-ブチル 4-{3-[(ジエチルアミノ)カルボニル]-5-オキソピペラジン-1-イル}ピペリジン-1-カルボキシレート(87.6 mg, 0.229 mmol)を用いて、参考例6と同様の操作を行い、ジイソプロピルエーテルで粉末にすることにより、表題化合物75.9 mg(収率93.2%)を得た。これ以上精製することなく次工程に進んだ。 Using the tert-butyl 4- {3-[(diethylamino) carbonyl] -5-oxopiperazin-1-yl} piperidine-1-carboxylate (87.6 mg, 0.229 mmol) obtained in Reference Example 15, The same operation as in No. 6 was performed, and powdered with diisopropyl ether to obtain 75.9 mg (yield 93.2%) of the title compound. Proceed to the next step without further purification.
参考例17
ベンジル 2-[(ジエチルアミノ)カルボニル]モルホリン-4-カルボキシレート
Reference Example 17
Benzyl 2-[(diethylamino) carbonyl] morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(4.35 g, 16.4 mmol)とジエチルアミン(1.87 ml, 18.0 mmol)を用いて、参考例1と同様の操作を行い、ジイソプロピルエーテルで粉末にすることにより、表題化合物4.68 g(収率89.2%)を得た。これ以上精製することなく次工程に進んだ。 Use 4-[(benzyloxy) carbonyl] morpholine-2-carboxylic acid (4.35 g, 16.4 mmol) and diethylamine (1.87 ml, 18.0 mmol) in the same manner as in Reference Example 1, and powder it with diisopropyl ether. As a result, 4.68 g (yield: 89.2%) of the title compound was obtained. Proceed to the next step without further purification.
参考例18
N,N-ジエチルモルホリン-2-カルボキサミド
Reference Example 18
N, N-diethylmorpholine-2-carboxamide
参考例17で得られたベンジル 2-[(ジエチルアミノ)カルボニル]モルホリン-4-カルボキシレート(4.68 g, 14.6 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物2.39 g(収率87.9%)を得た。これ以上精製することなく次工程に進んだ。 Using the benzyl 2-[(diethylamino) carbonyl] morpholine-4-carboxylate (4.68 g, 14.6 mmol) obtained in Reference Example 17, the same operation as in Reference Example 4 was performed to give 2.39 g ( Yield 87.9%) was obtained. Proceed to the next step without further purification.
参考例19
ベンジル 4-{2-[(ジエチルアミノ)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート 塩酸塩
Reference Example 19
Benzyl 4- {2-[(diethylamino) carbonyl] morpholin-4-yl} piperidine-1-carboxylate hydrochloride
参考例18で得られたN,N-ジエチルモルホリン-2-カルボキサミド(2.39 g, 12.8 mmol)とベンジル 4-オキソピペリジン-1-カルボキシレート(3.29 g, 14.1 mmol)を用いて、参考例3と同様の操作を行い、得られた油状物に4N塩化水素-酢酸エチル(3.2 ml)を加え、ジイソプロピルエーテルで粉末にすることにより、表題化合物5.65 g(定量的)を得た。これ以上精製することなく次工程に進んだ。 Using N, N-diethylmorpholine-2-carboxamide (2.39 g, 12.8 mmol) obtained in Reference Example 18 and benzyl 4-oxopiperidine-1-carboxylate (3.29 g, 14.1 mmol), Reference Example 3 and The same operation was performed, 4N hydrogen chloride-ethyl acetate (3.2 ml) was added to the obtained oil, and powdered with diisopropyl ether to give 5.65 g (quantitative) of the title compound. Proceed to the next step without further purification.
参考例20
N,N-ジエチル-4-(ピペリジン-4-イル)モルホリン-2-カルボキサミド 塩酸塩
Reference Example 20
N, N-diethyl-4- (piperidin-4-yl) morpholine-2-carboxamide hydrochloride
参考例19で得られたベンジル 4-{2-[(ジエチルアミノ)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート 塩酸塩(5.50 g, 12.5 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物3.32 g(収率87.0%)を得た。これ以上精製することなく次工程に進んだ。 Using benzyl 4- {2-[(diethylamino) carbonyl] morpholin-4-yl} piperidine-1-carboxylate hydrochloride (5.50 g, 12.5 mmol) obtained in Reference Example 19, the same as in Reference Example 4 By performing the operation, 3.32 g (yield: 87.0%) of the title compound was obtained. Proceed to the next step without further purification.
参考例21
ベンジル 2-[(ジイソプロピルアミノ)カルボニル]モルホリン-4-カルボキシレート
Reference Example 21
Benzyl 2-[(diisopropylamino) carbonyl] morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(2.60 g, 10.0 mmol)および塩化チオニル(12 ml)の混合物を3時間加熱還流した後、過剰の塩化チオニルを減圧留去した。残渣に酢酸エチル(25 ml)を加え、ジイソプロピルアミン(1.21 g, 12.0 mmol)およびトリエチルアミン(1.51 g, 15.0 mmol)を添加し、室温で1時間攪拌した。反応液を水洗後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製して、表題化合物2.36 g(収率67.8%)を油状物として得た。
EI(pos) 349 [M+H]+
A mixture of 4-[(benzyloxy) carbonyl] morpholine-2-carboxylic acid (2.60 g, 10.0 mmol) and thionyl chloride (12 ml) was heated to reflux for 3 hours, and then excess thionyl chloride was distilled off under reduced pressure. Ethyl acetate (25 ml) was added to the residue, diisopropylamine (1.21 g, 12.0 mmol) and triethylamine (1.51 g, 15.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound (2.36 g, yield 67.8%) as an oil.
EI (pos) 349 [M + H] +
参考例22
ベンジル 2-[(シクロペンチルアミノ)カルボニル]モルホリン-4-カルボキシレート
Reference Example 22
Benzyl 2-[(cyclopentylamino) carbonyl] morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(2.60 g, 10.0 mmol)とシクロペンチルアミン(1.28 g, 15.0 mmol)を用いて、参考例21と同様の操作を行い、酢酸エチル-ヘキサンで結晶化させることにより、表題化合物2.37 g(収率71.4%)を得た。
EI(pos) 333 [M+H]+
4-[(Benzyloxy) carbonyl] morpholine-2-carboxylic acid (2.60 g, 10.0 mmol) and cyclopentylamine (1.28 g, 15.0 mmol) were used in the same manner as in Reference Example 21, and ethyl acetate-hexane was used. To give 2.37 g (yield 71.4%) of the title compound.
EI (pos) 333 [M + H] +
参考例23
ベンジル 2-[(1-アダマンチルアミノ)カルボニル]モルホリン-4-カルボキシレート
Reference Example 23
Benzyl 2-[(1-adamantylamino) carbonyl] morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(2.60 g, 10.0 mmol)と1-アダマンタンアミン(2.27 g, 15.0 mmol)を用いて、参考例21と同様の操作を行い、酢酸エチル-ヘキサンで結晶化させることにより、表題化合物3.70 g(収率92.9%)を得た。
EI(pos) 399 [M+H]+
Using 4-[(benzyloxy) carbonyl] morpholine-2-carboxylic acid (2.60 g, 10.0 mmol) and 1-adamantanamine (2.27 g, 15.0 mmol), the same operation as in Reference Example 21 was carried out, and ethyl acetate Crystallization with -hexane gave 3.70 g (yield 92.9%) of the title compound.
EI (pos) 399 [M + H] +
参考例24
ベンジル 2-{[ビス(2,2,2-トリフルオロエチル)アミノ]カルボニル}モルホリン-4-カルボキシレート
Reference Example 24
Benzyl 2-{[bis (2,2,2-trifluoroethyl) amino] carbonyl} morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(2.60 g, 10.0 mmol)と2,2,2-トリフルオロエチルアミン(2.71 g, 15.0 mmol)を用いて、参考例21と同様の操作を行うことにより、表題化合物0.89 g(収率20.8%)を油状物として得た。
EI(pos) 429 [M+H]+
Operation similar to Reference Example 21 using 4-[(benzyloxy) carbonyl] morpholine-2-carboxylic acid (2.60 g, 10.0 mmol) and 2,2,2-trifluoroethylamine (2.71 g, 15.0 mmol) To give 0.89 g (yield 20.8%) of the title compound as an oil.
EI (pos) 429 [M + H] +
参考例25
ベンジル 2-{[シクロヘキシル(メチル)アミノ]カルボニル}モルホリン-4-カルボキシレート
Reference Example 25
Benzyl 2-{[cyclohexyl (methyl) amino] carbonyl} morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(2.60 g, 10.0 mmol)とN-メチルシクロヘキサンアミン(1.28 g, 15.0 mmol)を用いて、参考例21と同様の操作を行うことにより、表題化合物3.17 g(収率88.0%)を油状物として得た。
EI(pos) 361 [M+H]+
By performing the same operation as in Reference Example 21 using 4-[(benzyloxy) carbonyl] morpholine-2-carboxylic acid (2.60 g, 10.0 mmol) and N-methylcyclohexaneamine (1.28 g, 15.0 mmol) The title compound (3.17 g, yield 88.0%) was obtained as an oil.
EI (pos) 361 [M + H] +
参考例26
ベンジル 2-(モルホリン-4-イルカルボニル)モルホリン-4-カルボキシレート
Reference Example 26
Benzyl 2- (morpholin-4-ylcarbonyl) morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(2.60 g, 10.0 mmol)とモルホリン(1.30 g, 15.0 mmol)を用いて、参考例21と同様の操作を行うことにより、表題化合物2.70 g(収率80.8%)を油状物として得た。
EI(pos) 335 [M+H]+
By performing the same operation as in Reference Example 21 using 4-[(benzyloxy) carbonyl] morpholine-2-carboxylic acid (2.60 g, 10.0 mmol) and morpholine (1.30 g, 15.0 mmol), the title compound 2.70 g (yield 80.8%) was obtained as an oil.
EI (pos) 335 [M + H] +
参考例27
ベンジル 2-[(6-フルオロ-2-メチル-3,4-ジヒドロキノリン-1(2H)-イル)カルボニル]モルホリン-4-カルボキシレート
Reference Example 27
Benzyl 2-[(6-fluoro-2-methyl-3,4-dihydroquinolin-1 (2H) -yl) carbonyl] morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(2.60 g, 10.0 mmol)と6-フルオロ-2-メチル-1,2,3,4-テトラヒドロキノリン(1.81 g, 11.0 mmol)を用いて、参考例21と同様の操作を行い、酢酸エチル-ヘキサンで結晶化させることにより、表題化合物3.67 g(収率89.0%)を得た。
EI(pos) 413 [M+H]+
Using 4-[(benzyloxy) carbonyl] morpholine-2-carboxylic acid (2.60 g, 10.0 mmol) and 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (1.81 g, 11.0 mmol) Then, the same operation as in Reference Example 21 was performed, and crystallization was performed with ethyl acetate-hexane to obtain 3.67 g (yield: 89.0%) of the title compound.
EI (pos) 413 [M + H] +
参考例28
ベンジル 2-(3,4-ジヒドロイソキノリン-2(1H)-イルカルボニル)モルホリン-4-カルボキシレート
Reference Example 28
Benzyl 2- (3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) morpholine-4-carboxylate
4-[(ベンジルオキシ)カルボニル]モルホリン-2-カルボン酸(2.60 g, 10.0 mmol)と1,2,3,4-テトラヒドロイソキノリン(1.99 g, 15.0 mmol)を用いて、参考例21と同様の操作を行うことにより、表題化合物3.16 g(収率83.1%)を油状物として得た。
EI(pos) 381 [M+H]+
Similar to Reference Example 21, using 4-[(benzyloxy) carbonyl] morpholine-2-carboxylic acid (2.60 g, 10.0 mmol) and 1,2,3,4-tetrahydroisoquinoline (1.99 g, 15.0 mmol) By the operation, 3.16 g (yield: 83.1%) of the title compound was obtained as an oily substance.
EI (pos) 381 [M + H] +
参考例29
N,N-ジイソプロピルモルホリン-2-カルボキサミド
Reference Example 29
N, N-diisopropylmorpholine-2-carboxamide
参考例21で得られたベンジル 2-[(ジイソプロピルアミノ)カルボニル]モルホリン-4-カルボキシレート(2.37 g, 6.80 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物1.31 g(収率90.3%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using the benzyl 2-[(diisopropylamino) carbonyl] morpholine-4-carboxylate (2.37 g, 6.80 mmol) obtained in Reference Example 21, the same operation as in Reference Example 4 was performed to give 1.31 g of the title compound. (Yield 90.3%) was obtained as an oil. Proceed to the next step without further purification.
参考例30
N-シクロペンチルモルホリン-2-カルボキサミド
Reference Example 30
N-cyclopentylmorpholine-2-carboxamide
参考例22で得られたベンジル 2-[(シクロペンチルアミノ)カルボニル]モルホリン-4-カルボキシレート(2.37 g, 7.13 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物1.22 g(収率86.5%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using the benzyl 2-[(cyclopentylamino) carbonyl] morpholine-4-carboxylate (2.37 g, 7.13 mmol) obtained in Reference Example 22, the title compound 1.22 g was prepared in the same manner as in Reference Example 4. (Yield 86.5%) was obtained as an oil. Proceed to the next step without further purification.
参考例31
N-(1-アダマンチル)モルホリン-2-カルボキサミド
Reference Example 31
N- (1-adamantyl) morpholine-2-carboxamide
参考例23で得られたベンジル 2-[(1-アダマンチルアミノ)カルボニル]モルホリン-4-カルボキシレート(3.70 g, 9.28 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物2.35 g(収率95.9%)を油状物として得た。これ以上精製することなく次工程に進んだ。 The title compound was obtained by the same procedures as in Reference Example 4 using benzyl 2-[(1-adamantylamino) carbonyl] morpholine-4-carboxylate (3.70 g, 9.28 mmol) obtained in Reference Example 23. 2.35 g (95.9% yield) was obtained as an oil. Proceed to the next step without further purification.
参考例32
N,N-ビス(2,2,2-トリフルオロエチル)モルホリン-2-カルボキサミド
Reference Example 32
N, N-bis (2,2,2-trifluoroethyl) morpholine-2-carboxamide
参考例24で得られたベンジル 2-{[ビス(2,2,2-トリフルオロエチル)アミノ]カルボニル}モルホリン-4-カルボキシレート(0.89 g, 2.07 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物0.52 g(収率85.2%)を油状物として得た。これ以上精製することなく次工程に進んだ。 The same as Reference Example 4 using benzyl 2-{[bis (2,2,2-trifluoroethyl) amino] carbonyl} morpholine-4-carboxylate (0.89 g, 2.07 mmol) obtained in Reference Example 24 By performing the above operations, 0.52 g (yield: 85.2%) of the title compound was obtained as an oil. Proceed to the next step without further purification.
参考例33
N-シクロヘキシル-N-メチルモルホリン-2-カルボキサミド
Reference Example 33
N-cyclohexyl-N-methylmorpholine-2-carboxamide
参考例25で得られたベンジル 2-{[シクロヘキシル(メチル)アミノ]カルボニル}モルホリン-4-カルボキシレート(3.17 g, 8.79 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物1.69 g(収率85.3%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using the benzyl 2-{[cyclohexyl (methyl) amino] carbonyl} morpholine-4-carboxylate (3.17 g, 8.79 mmol) obtained in Reference Example 25, the same procedure as in Reference Example 4 was performed to give the title. 1.69 g (yield 85.3%) of the compound was obtained as an oil. Proceed to the next step without further purification.
参考例34
2-(モルホリン-4-イルカルボニル)モルホリン
Reference Example 34
2- (morpholin-4-ylcarbonyl) morpholine
参考例26で得られたベンジル 2-(モルホリン-4-イルカルボニル)モルホリン-4-カルボキシレート(2.70 g, 8.07 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物1.42 g(収率88.2%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using the benzyl 2- (morpholin-4-ylcarbonyl) morpholine-4-carboxylate (2.70 g, 8.07 mmol) obtained in Reference Example 26, the same operation as in Reference Example 4 was performed to give the title compound 1.42. g (yield 88.2%) was obtained as an oil. Proceed to the next step without further purification.
参考例35
6-フルオロ-2-メチル-1-(モルホリン-2-イルカルボニル)-1,2,3,4-テトラヒドロキノリン
Reference Example 35
6-Fluoro-2-methyl-1- (morpholin-2-ylcarbonyl) -1,2,3,4-tetrahydroquinoline
参考例27で得られたベンジル 2-[(6-フルオロ-2-メチル-3,4-ジヒドロキノリン-1(2H)-イル)カルボニル]モルホリン-4-カルボキシレート(3.67 g, 8.09 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物2.02 g(収率81.8%)を油状物として得た。これ以上精製することなく次工程に進んだ。 The benzyl 2-[(6-fluoro-2-methyl-3,4-dihydroquinolin-1 (2H) -yl) carbonyl] morpholine-4-carboxylate (3.67 g, 8.09 mmol) obtained in Reference Example 27 was used. Using the same procedure as in Reference Example 4, the title compound (2.02 g, yield 81.8%) was obtained as an oil. Proceed to the next step without further purification.
参考例36
2-(モルホリン-2-イルカルボニル)-1,2,3,4-テトラヒドロイソキノリン
Reference Example 36
2- (morpholin-2-ylcarbonyl) -1,2,3,4-tetrahydroisoquinoline
参考例28で得られたベンジル 2-(3,4-ジヒドロイソキノリン-2(1H)-イルカルボニル)モルホリン-4-カルボキシレート(3.16 g, 8.30 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物1.66 g(収率81.4%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using benzyl 2- (3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) morpholine-4-carboxylate (3.16 g, 8.30 mmol) obtained in Reference Example 28, the same procedure as in Reference Example 4 was performed. To give 1.66 g (yield 81.4%) of the title compound as an oil. Proceed to the next step without further purification.
参考例37
ベンジル 4-{2-[(ジイソプロピルアミノ)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート
Reference Example 37
Benzyl 4- {2-[(diisopropylamino) carbonyl] morpholin-4-yl} piperidine-1-carboxylate
参考例29で得られたN,N-ジイソプロピルモルホリン-2-カルボキサミド(1.31 g, 6.11 mmol)とベンジル 4-オキソピペリジン-1-カルボキシレート(2.38 g, 10.2 mmol)を用いて、参考例3と同様の操作を行うことにより、表題化合物2.25 g(収率85.5%)を油状物として得た。
EI(pos) 432 [M+H]+
Using N, N-diisopropylmorpholine-2-carboxamide (1.31 g, 6.11 mmol) obtained in Reference Example 29 and benzyl 4-oxopiperidine-1-carboxylate (2.38 g, 10.2 mmol), Reference Example 3 and The same operation was performed to obtain 2.25 g (yield: 85.5%) of the title compound as an oil.
EI (pos) 432 [M + H] +
参考例38
tert-ブチル 4-{2-[(シクロペンチルアミノ)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート
Reference Example 38
tert-butyl 4- {2-[(cyclopentylamino) carbonyl] morpholin-4-yl} piperidine-1-carboxylate
参考例30で得られたN-シクロペンチルモルホリン-2-カルボキサミド(1.22 g, 6.15 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(2.10 g, 10.5 mmol)を用いて、参考例3と同様の操作を行い、酢酸エチル-ヘキサンで結晶化させることにより、表題化合物1.73 g(収率73.9%)を粉末として得た。
EI(pos) 382 [M+H]+
Using N-cyclopentylmorpholine-2-carboxamide (1.22 g, 6.15 mmol) obtained in Reference Example 30 and tert-butyl 4-oxopiperidine-1-carboxylate (2.10 g, 10.5 mmol), Reference Example 3 and The same operation was performed, and crystallization was performed with ethyl acetate-hexane to obtain 1.73 g (yield 73.9%) of the title compound as a powder.
EI (pos) 382 [M + H] +
参考例39
tert-ブチル 4-{2-[(1-アダマンチルアミノ)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート
Reference Example 39
tert-Butyl 4- {2-[(1-adamantylamino) carbonyl] morpholin-4-yl} piperidine-1-carboxylate
参考例31で得られたN-(1-アダマンチル)モルホリン-2-カルボキサミド(2.35 g, 8.88 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(2.70 g, 13.5 mmol)を用いて、参考例3と同様の操作を行い、酢酸エチル-ヘキサンで結晶化させることにより、表題化合物2.59 g(収率64.6%)を粉末として得た。
EI(pos) 448 [M+H]+
Using N- (1-adamantyl) morpholine-2-carboxamide (2.35 g, 8.88 mmol) obtained in Reference Example 31 and tert-butyl 4-oxopiperidine-1-carboxylate (2.70 g, 13.5 mmol), The same operation as in Reference Example 3 was performed, and crystallization was performed with ethyl acetate-hexane to obtain 2.59 g (yield: 64.6%) of the title compound as a powder.
EI (pos) 448 [M + H] +
参考例40
tert-ブチル 4-(2-{[ビス(2,2,2-トリフルオロエチル)アミノ]カルボニル}モルホリン-4-イル)ピペリジン-1-カルボキシレート
Reference Example 40
tert-butyl 4- (2-{[bis (2,2,2-trifluoroethyl) amino] carbonyl} morpholin-4-yl) piperidine-1-carboxylate
参考例32で得られたN,N-ビス(2,2,2-トリフルオロエチル)モルホリン-2-カルボキサミド(0.52 g, 1.76 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(0.62 g, 3.11 mmol)を用いて、参考例3と同様の操作を行うことにより、表題化合物0.60 g(収率71.4%)を油状物として得た。
EI(pos) 478 [M+H]+
N, N-bis (2,2,2-trifluoroethyl) morpholine-2-carboxamide (0.52 g, 1.76 mmol) obtained in Reference Example 32 and tert-butyl 4-oxopiperidine-1-carboxylate (0.62 g, 3.11 mmol) was used in the same manner as in Reference Example 3 to give the title compound (0.60 g, yield 71.4%) as an oil.
EI (pos) 478 [M + H] +
参考例41
tert-ブチル 4-(2-{[シクロヘキシル(メチル)アミノ]カルボニル}モルホリン-4-イル)ピペリジン-1-カルボキシレート
Reference Example 41
tert-butyl 4- (2-{[cyclohexyl (methyl) amino] carbonyl} morpholin-4-yl) piperidine-1-carboxylate
参考例33で得られたN-シクロヘキシル-N-メチルモルホリン-2-カルボキサミド(1.69 g, 7.46 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(2.62 g, 13.1 mmol)を用いて、参考例3と同様の操作を行い、酢酸エチル-ヘキサンで結晶化させることにより、表題化合物2.05 g(収率67.2%)を粉末として得た。
EI(pos) 410 [M+H]+
Using N-cyclohexyl-N-methylmorpholine-2-carboxamide (1.69 g, 7.46 mmol) obtained in Reference Example 33 and tert-butyl 4-oxopiperidine-1-carboxylate (2.62 g, 13.1 mmol), The same operation as in Reference Example 3 was performed, and crystallization was performed with ethyl acetate-hexane to obtain 2.05 g (yield: 67.2%) of the title compound as a powder.
EI (pos) 410 [M + H] +
参考例42
tert-ブチル 4-[2-(モルホリン-4-イルカルボニル)モルホリン-4-イル]ピペリジン-1-カルボキシレート
Reference Example 42
tert-butyl 4- [2- (morpholin-4-ylcarbonyl) morpholin-4-yl] piperidine-1-carboxylate
参考例34で得られた2-(モルホリン-4-イルカルボニル)モルホリン(1.42 g, 7.09 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(2.41 g, 12.1 mmol)を用いて、参考例3と同様の操作を行うことにより、表題化合物2.01 g(収率74.1%)を油状物として得た。
EI(pos) 384 [M+H]+
Using 2- (morpholin-4-ylcarbonyl) morpholine (1.42 g, 7.09 mmol) obtained in Reference Example 34 and tert-butyl 4-oxopiperidine-1-carboxylate (2.41 g, 12.1 mmol), The same operation as in Example 3 was performed to give the title compound (2.01 g, yield 74.1%) as an oil.
EI (pos) 384 [M + H] +
参考例43
tert-ブチル 4-{2-[(6-フルオロ-2-メチル-3,4-ジヒドロキノリン-1(2H)-イル)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート
Reference Example 43
tert-butyl 4- {2-[(6-fluoro-2-methyl-3,4-dihydroquinolin-1 (2H) -yl) carbonyl] morpholin-4-yl} piperidine-1-carboxylate
参考例35で得られた6-フルオロ-2-メチル-1-(モルホリン-2-イルカルボニル)-1,2,3,4-テトラヒドロキノリン(2.02 g, 7.25 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(2.65 g, 13.3 mmol)を用いて、参考例3と同様の操作を行い、酢酸エチル-ヘキサンで結晶化させることにより、表題化合物2.29 g(収率68.5%)を粉末として得た。
EI(pos) 462 [M+H]+
6-Fluoro-2-methyl-1- (morpholin-2-ylcarbonyl) -1,2,3,4-tetrahydroquinoline (2.02 g, 7.25 mmol) obtained in Reference Example 35 and tert-butyl 4-oxo The same operation as in Reference Example 3 was carried out using piperidine-1-carboxylate (2.65 g, 13.3 mmol), and crystallized with ethyl acetate-hexane to give 2.29 g (yield 68.5%) of the title compound as a powder. Got as.
EI (pos) 462 [M + H] +
参考例44
tert-ブチル 4-[2-(3,4-ジヒドロイソキノリン-2(1H)-イルカルボニル)モルホリン-4-イル]ピペリジン-1-カルボキシレート
Reference Example 44
tert-butyl 4- [2- (3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) morpholin-4-yl] piperidine-1-carboxylate
参考例36で得られた2-(モルホリン-2-イルカルボニル)-1,2,3,4-テトラヒドロイソキノリン(1.66 g, 6.73 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(2.48 g, 12.4 mmol)を用いて、参考例3と同様の操作を行うことにより、表題化合物2.31 g(収率79.9%)を油状物として得た。
EI(pos) 430 [M+H]+
2- (morpholin-2-ylcarbonyl) -1,2,3,4-tetrahydroisoquinoline (1.66 g, 6.73 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.48) obtained in Reference Example 36 g, 12.4 mmol) was used in the same manner as in Reference Example 3 to give the title compound (2.31 g, yield 79.9%) as an oil.
EI (pos) 430 [M + H] +
参考例45
N,N-ジイソプロピル-4-(ピペリジン-4-イル)モルホリン-2-カルボキサミド 二塩酸塩
Reference Example 45
N, N-diisopropyl-4- (piperidin-4-yl) morpholine-2-carboxamide dihydrochloride
参考例37で得られたベンジル 4-{2-[(ジイソプロピルアミノ)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート(1.00 g, 2.31 mmol)を用いて、参考例4と同様の操作を行った。得られる油状物に4N塩化水素-酢酸エチルを加え、生じた粉末を酢酸エチルで洗浄することにより、表題化合物0.73 g(収率84.9%)を得た。
1H NMR (DMSO-d6) δ1.12-1.34 (12H, m), 2.00 (2H, m), 2.32 (2H, m), 2.88 (2H, m), 3.14 (2H, m), 3.47-3.33 (6H, m), 4.01-4.13 (3H, m), 4.82 (1H, d, J = 9.4 Hz), 9.00 (1H, d, J = 9.9 Hz), 9.38 (1H, d, J = 9.9 Hz), 12.05 (1H, br).
EI(pos) 298 [M+H]+
Using benzyl 4- {2-[(diisopropylamino) carbonyl] morpholin-4-yl} piperidine-1-carboxylate (1.00 g, 2.31 mmol) obtained in Reference Example 37, the same procedure as in Reference Example 4 was performed. Went. 4N Hydrogen chloride-ethyl acetate was added to the obtained oil, and the resulting powder was washed with ethyl acetate to give the title compound (0.73 g, yield 84.9%).
1 H NMR (DMSO-d 6 ) δ1.12-1.34 (12H, m), 2.00 (2H, m), 2.32 (2H, m), 2.88 (2H, m), 3.14 (2H, m), 3.47- 3.33 (6H, m), 4.01-4.13 (3H, m), 4.82 (1H, d, J = 9.4 Hz), 9.00 (1H, d, J = 9.9 Hz), 9.38 (1H, d, J = 9.9 Hz) ), 12.05 (1H, br).
EI (pos) 298 [M + H] +
参考例46
N-シクロペンチル-4-(ピペリジン-4-イル)モルホリン-2-カルボキサミド 二塩酸塩
Reference Example 46
N-cyclopentyl-4- (piperidin-4-yl) morpholine-2-carboxamide dihydrochloride
参考例38で得られたtert-ブチル 4-{2-[(シクロペンチルアミノ)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート(1.73 g, 4.53 mmol)を用いて、参考例6と同様の操作を行い、得られる粉末を酢酸エチルで洗浄することにより、表題化合物1.20 g(収率76.9%)を得た。
1H NMR (DMSO-d6) δ1.47 (4H, m), 1.63 (2H, m), 1.79 (2H, m), 1.98 (2H, m), 2.30 (2H, m), 2.88 (2H, m), 3.04 (2H, m), 3.43 (5H, m), 4.03 (3H, m), 4.50 (1H, d), 8.03 (1H, br), 8.87 (1H, br), 9.20 (1H, br), 12.09 (1H, br).
EI(pos) 282 [M+H]+
Similar to Reference Example 6 using tert-butyl 4- {2-[(cyclopentylamino) carbonyl] morpholin-4-yl} piperidine-1-carboxylate (1.73 g, 4.53 mmol) obtained in Reference Example 38 The obtained powder was washed with ethyl acetate to obtain 1.20 g (yield 76.9%) of the title compound.
1 H NMR (DMSO-d 6 ) δ 1.47 (4H, m), 1.63 (2H, m), 1.79 (2H, m), 1.98 (2H, m), 2.30 (2H, m), 2.88 (2H, m), 3.04 (2H, m), 3.43 (5H, m), 4.03 (3H, m), 4.50 (1H, d), 8.03 (1H, br), 8.87 (1H, br), 9.20 (1H, br ), 12.09 (1H, br).
EI (pos) 282 [M + H] +
参考例47
N-(1-アダマンチル)-4-(ピペリジン-4-イル)モルホリン-2-カルボキサミド 二塩酸塩
Reference Example 47
N- (1-adamantyl) -4- (piperidin-4-yl) morpholine-2-carboxamide dihydrochloride
参考例39で得られたtert-ブチル 4-{2-[(1-アダマンチルアミノ)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート(2.59 g, 5.78 mmol)を用いて、参考例6と同様の操作を行い、得られる粉末を酢酸エチルで洗浄することにより、表題化合物1.91 g(収率81.9%)を得た。
1H NMR (DMSO-d6) δ1.62 (6H, m), 1.93 (6H, m), 2.01 (5H, m), 2.31 (2H, m), 2.86 (2H, m), 3.06 (2H, m), 3.44 (5H, m), 4.08 (2H, m), 4.45 (1H, d, J = 9.0 Hz), 7.23 (1H, s), 8.94 (1H, br), 9.33 (1H, br), 12.15 (1H, br).
EI(pos) 348 [M+H]+
Using tert-butyl 4- {2-[(1-adamantylamino) carbonyl] morpholin-4-yl} piperidine-1-carboxylate (2.59 g, 5.78 mmol) obtained in Reference Example 39, Reference Example 6 The title compound was washed with ethyl acetate to give the title compound (1.91 g, yield 81.9%).
1 H NMR (DMSO-d 6 ) δ1.62 (6H, m), 1.93 (6H, m), 2.01 (5H, m), 2.31 (2H, m), 2.86 (2H, m), 3.06 (2H, m), 3.44 (5H, m), 4.08 (2H, m), 4.45 (1H, d, J = 9.0 Hz), 7.23 (1H, s), 8.94 (1H, br), 9.33 (1H, br), 12.15 (1H, br).
EI (pos) 348 [M + H] +
参考例48
4-(ピペリジン-4-イル)-N,N-ビス(2,2,2-トリフルオロエチル)モルホリン-2-カルボキサミド 二塩酸塩
Reference Example 48
4- (Piperidin-4-yl) -N, N-bis (2,2,2-trifluoroethyl) morpholine-2-carboxamide dihydrochloride
参考例40で得られたtert-ブチル 4-(2-{[ビス(2,2,2-トリフルオロエチル)アミノ]カルボニル}モルホリン-4-イル)ピペリジン-1-カルボキシレート(0.60 g, 1.25 mmol)を用いて、参考例6と同様の操作を行い、得られる粉末を酢酸エチルで洗浄することにより、表題化合物0.40 g(収率76.8%)を得た。
EI(pos) 378 [M+H]+
Tert-Butyl 4- (2-{[bis (2,2,2-trifluoroethyl) amino] carbonyl} morpholin-4-yl) piperidine-1-carboxylate (0.60 g, 1.25 The same procedure as in Reference Example 6 was performed, and the resulting powder was washed with ethyl acetate to obtain 0.40 g (yield 76.8%) of the title compound.
EI (pos) 378 [M + H] +
参考例49
N-シクロヘキシル-N-メチル-4-(ピペリジン-4-イル)モルホリン-2-カルボキサミド 二塩酸塩
Reference Example 49
N-cyclohexyl-N-methyl-4- (piperidin-4-yl) morpholine-2-carboxamide dihydrochloride
参考例41で得られたtert-ブチル 4-(2-{[シクロヘキシル(メチル)アミノ]カルボニル}モルホリン-4-イル)ピペリジン-1-カルボキシレート(2.05 g, 5.00 mmol)を用いて、参考例6と同様の操作を行い、得られる粉末を酢酸エチルで洗浄することにより、表題化合物1.63 g(収率85.3%)を得た。
EI(pos) 310 [M+H]+
Using tert-butyl 4- (2-{[cyclohexyl (methyl) amino] carbonyl} morpholin-4-yl) piperidine-1-carboxylate (2.05 g, 5.00 mmol) obtained in Reference Example 41, Reference Example The same operation as in No. 6 was performed, and the resulting powder was washed with ethyl acetate to give the title compound (1.63 g, yield 85.3%).
EI (pos) 310 [M + H] +
参考例50
2-(モルホリン-4-イルカルボニル)-4-(ピペリジン-4-イル)モルホリン 二塩酸塩
Reference Example 50
2- (morpholin-4-ylcarbonyl) -4- (piperidin-4-yl) morpholine dihydrochloride
参考例42で得られたtert-ブチル 4-[2-(モルホリン-4-イルカルボニル)モルホリン-4-イル]ピペリジン-1-カルボキシレート(2.01 g, 5.24 mmol)を用いて、参考例6と同様の操作を行い、得られる粉末を酢酸エチルで洗浄することにより、表題化合物1.43 g(収率76.9%)を得た。
EI(pos) 284 [M+H]+
Using tert-butyl 4- [2- (morpholin-4-ylcarbonyl) morpholin-4-yl] piperidine-1-carboxylate (2.01 g, 5.24 mmol) obtained in Reference Example 42, The same operation was performed, and the resulting powder was washed with ethyl acetate to obtain 1.43 g (yield 76.9%) of the title compound.
EI (pos) 284 [M + H] +
参考例51
6-フルオロ-2-メチル-1-{[4-(ピペリジン-4-イル)モルホリン-2-イル]カルボニル}-1,2,3,4-テトラヒドロキノリン 二塩酸塩
Reference Example 51
6-Fluoro-2-methyl-1-{[4- (piperidin-4-yl) morpholin-2-yl] carbonyl} -1,2,3,4-tetrahydroquinoline dihydrochloride
参考例43で得られたtert-ブチル 4-{2-[(6-フルオロ-2-メチル-3,4-ジヒドロキノリン-1(2H)-イル)カルボニル]モルホリン-4-イル}ピペリジン-1-カルボキシレート(2.29 g, 4.96 mmol)を用いて、参考例6と同様の操作を行い、得られる粉末を酢酸エチルで洗浄することにより、表題化合物2.00 g(収率93.5%)を得た。
EI(pos) 362 [M+H]+
Tert-butyl 4- {2-[(6-fluoro-2-methyl-3,4-dihydroquinolin-1 (2H) -yl) carbonyl] morpholin-4-yl} piperidine-1 obtained in Reference Example 43 -Carboxylate (2.29 g, 4.96 mmol) was used in the same manner as in Reference Example 6, and the resulting powder was washed with ethyl acetate to give the title compound (2.00 g, yield 93.5%).
EI (pos) 362 [M + H] +
参考例52
2-{[4-(ピペリジン-4-イル)モルホリン-2-イル]カルボニル}-1,2,3,4-テトラヒドロイソキノリン 二塩酸塩
Reference Example 52
2-{[4- (Piperidin-4-yl) morpholin-2-yl] carbonyl} -1,2,3,4-tetrahydroisoquinoline dihydrochloride
参考例44で得られたtert-ブチル 4-[2-(3,4-ジヒドロイソキノリン-2(1H)-イルカルボニル)モルホリン-4-イル]ピペリジン-1-カルボキシレート(2.31 g, 5.37 mmol)を用いて、参考例6と同様の操作を行い、得られる粉末を酢酸エチルで洗浄することにより、表題化合物1.73 g(収率80.1%)を得た。
EI(pos) 330 [M+H]+
Tert-Butyl 4- [2- (3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) morpholin-4-yl] piperidine-1-carboxylate (2.31 g, 5.37 mmol) obtained in Reference Example 44 Was used for the same operation as in Reference Example 6, and the obtained powder was washed with ethyl acetate to give the title compound (1.73 g, yield 80.1%).
EI (pos) 330 [M + H] +
参考例53
1-ベンジル 4-tert-ブチル 2-[(エチルアミノ)カルボニル]ピペラジン-1,4-ジカルボキシレート
Reference Example 53
1-Benzyl 4-tert-butyl 2-[(ethylamino) carbonyl] piperazine-1,4-dicarboxylate
1-[(ベンジルオキシ)カルボニル]-4-(tert-ブトキシカルボニル)ピペラジン-2-カルボン酸(1.50 g, 4.12 mmol)と70%エチルアミン水溶液(0.319 ml, 4.94 mmol)を用いて、参考例1と同様の操作を行うことにより、表題化合物1.61 g(定量的)を油状物として得た。
EI(pos) 392 [M+H]+
Reference Example 1 using 1-[(benzyloxy) carbonyl] -4- (tert-butoxycarbonyl) piperazine-2-carboxylic acid (1.50 g, 4.12 mmol) and 70% aqueous ethylamine solution (0.319 ml, 4.94 mmol) The title compound (1.61 g, quantitative) was obtained as an oil by an operation similar to that described above.
EI (pos) 392 [M + H] +
参考例54
ベンジル 2-[(エチルアミノ)カルボニル]ピペラジン-1-カルボキシレート
Reference Example 54
Benzyl 2-[(ethylamino) carbonyl] piperazine-1-carboxylate
参考例53で得られた1-ベンジル 4-tert-ブチル 2-[(エチルアミノ)カルボニル]ピペラジン-1,4-ジカルボキシレート(1.61 g, 4.12 mmol)を用いて、参考例2と同様の操作を行うことにより、表題化合物1.07 g(収率89.5%)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using 1-benzyl 4-tert-butyl 2-[(ethylamino) carbonyl] piperazine-1,4-dicarboxylate (1.61 g, 4.12 mmol) obtained in Reference Example 53, the same as Reference Example 2 By the operation, 1.07 g (yield 89.5%) of the title compound was obtained as an oily substance. Proceed to the next step without further purification.
参考例55
ベンジル 4-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]-2-[(エチルアミノ)カルボニル]ピペラジン-1-カルボキシレート
Reference Example 55
Benzyl 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2-[(ethylamino) carbonyl] piperazine-1-carboxylate
参考例54で得られたベンジル 2-[(エチルアミノ)カルボニル]ピペラジン-1-カルボキシレート(1.07 g, 3.67 mmol)とtert-ブチル 4-オキソピペリジン-1-カルボキシレート(805 mg, 4.04 mmol)を用いて、参考例3と同様の操作を行うことにより、表題化合物1.37 g(収率78.6%)を油状物として得た。
EI(pos) 475.3 [M+H]+
Benzyl 2-[(ethylamino) carbonyl] piperazine-1-carboxylate (1.07 g, 3.67 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (805 mg, 4.04 mmol) obtained in Reference Example 54 The title compound was obtained in the same manner as in Reference Example 3 to give 1.37 g (yield 78.6%) of the title compound as an oil.
EI (pos) 475.3 [M + H] +
参考例56
tert-ブチル 4-{3-[(エチルアミノ)カルボニル]ピペラジン-1-イル}ピペリジン-1-カルボキシレート
Reference Example 56
tert-butyl 4- {3-[(ethylamino) carbonyl] piperazin-1-yl} piperidine-1-carboxylate
参考例55で得られたベンジル 4-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]-2-[(エチルアミノ)カルボニル]ピペラジン-1-カルボキシレート(1.36 g, 2.87 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物976 mg(定量的)を油状物として得た。これ以上精製することなく次工程に進んだ。 Using benzyl 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2-[(ethylamino) carbonyl] piperazine-1-carboxylate (1.36 g, 2.87 mmol) obtained in Reference Example 55 In the same manner as in Reference Example 4, the title compound (976 mg, quantitative) was obtained as an oil. Proceed to the next step without further purification.
参考例57
tert-ブチル 4-[3-[(エチルアミノ)カルボニル]-4-(トリフルオロアセチル)ピペラジン-1-イル]ピペリジン-1-カルボキシレート
Reference Example 57
tert-butyl 4- [3-[(ethylamino) carbonyl] -4- (trifluoroacetyl) piperazin-1-yl] piperidine-1-carboxylate
参考例56で得られたtert-ブチル 4-{3-[(エチルアミノ)カルボニル]ピペラジン-1-イル}ピペリジン-1-カルボキシレート(976 mg, 2.87 mmol)を用いて、参考例5と同様の操作を行うことにより、表題化合物1.25 g(収率99.9%)を油状物として得た。
EI(pos) 437.3 [M+H]+
Same as Reference Example 5 using tert-butyl 4- {3-[(ethylamino) carbonyl] piperazin-1-yl} piperidine-1-carboxylate (976 mg, 2.87 mmol) obtained in Reference Example 56 To give the title compound (1.25 g, yield 99.9%) as an oil.
EI (pos) 437.3 [M + H] +
参考例58
N-エチル-4-(ピペリジン-4-イル)-1-(トリフルオロアセチル)ピペラジン-2-カルボキサミド
Reference Example 58
N-ethyl-4- (piperidin-4-yl) -1- (trifluoroacetyl) piperazine-2-carboxamide
参考例57で得られたtert-ブチル 4-[3-[(エチルアミノ)カルボニル]-4-(トリフルオロアセチル)ピペラジン-1-イル]ピペリジン-1-カルボキシレート(1.24 g, 2.84 mmol)を用いて、参考例6と同様の操作を行った。得られる油状物にジイソプロピルエーテルを加え、表題化合物1.16 g(定量的)を得た。これ以上精製することなく次工程に進んだ。 The tert-butyl 4- [3-[(ethylamino) carbonyl] -4- (trifluoroacetyl) piperazin-1-yl] piperidine-1-carboxylate (1.24 g, 2.84 mmol) obtained in Reference Example 57 was used. The same operation as in Reference Example 6 was performed. Diisopropyl ether was added to the resulting oil to give 1.16 g (quantitative) of the title compound. Proceed to the next step without further purification.
参考例59
N,N-ジエチル-3-(ピリジン-4-イル)ベンズアミド
Reference Example 59
N, N-diethyl-3- (pyridin-4-yl) benzamide
3-ブロモ-N,N-ジエチルベンズアミド(3.00 g, 11.7 mmol)、ピリジン-4-イルボロン酸(2.88 g, 23.4 mmol)、2規定炭酸ナトリウム水溶液(11.7 ml)のTHF(120 ml)溶液に窒素雰囲気下でテトラキストリフェニルホスフィンパラジウム(406 mg, 0.351 mmol)を加え、1日間加熱還流した。反応液を室温まで冷却した後、酢酸エチルを加え、水層を分離し、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン-酢酸エチル=1:1から酢酸エチル)で精製して、表題化合物2.05 g(収率68.8%)を油状物として得た。
EI(pos) 255.2 [M+H]+
3-Bromo-N, N-diethylbenzamide (3.00 g, 11.7 mmol), pyridin-4-ylboronic acid (2.88 g, 23.4 mmol), 2N aqueous sodium carbonate solution (11.7 ml) in THF (120 ml) with nitrogen Tetrakistriphenylphosphine palladium (406 mg, 0.351 mmol) was added under an atmosphere, and the mixture was heated to reflux for 1 day. The reaction mixture was cooled to room temperature, ethyl acetate was added, the aqueous layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent; hexane-ethyl acetate = 1: 1 to ethyl acetate) to give 2.05 g (yield 68.8%) of the title compound as an oil. Obtained as a thing.
EI (pos) 255.2 [M + H] +
参考例60
tert-ブチル 4-{3-[(ジエチルアミノ)カルボニル]フェニル}ピペリジン-1-カルボキシレート
Reference Example 60
tert-butyl 4- {3-[(diethylamino) carbonyl] phenyl} piperidine-1-carboxylate
参考例59で得られたN,N-ジエチル-3-(ピリジン-4-イル)ベンズアミド(1.73 g, 6.80 mmol)とロジウム炭素(700 mg)の酢酸(40 ml)懸濁液を0.5 MPaの水素雰囲気下に80℃で5時間攪拌した。反応終了後、ロジウム炭素をろ過で除き、ろ液を減圧下濃縮した。得られた残渣、炭酸カリウム(2.82 g, 20.4 mmol)のTHF(50 ml)−水(50 ml)混合溶液に、二炭酸ジtert-ブチル(1.56 ml, 6.80 mmol)を加え16時間攪拌した。反応液に酢酸エチルを加え、水層を分離した。該水層を0.5N 塩酸、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチル=3:1から1:1)に通して、表題化合物1.23 g(収率50.2%)を油状物として得た。
EI(pos) 361.0 [M+H]+
A suspension of N, N-diethyl-3- (pyridin-4-yl) benzamide (1.73 g, 6.80 mmol) obtained in Reference Example 59 and rhodium carbon (700 mg) in acetic acid (40 ml) was added at 0.5 MPa. The mixture was stirred at 80 ° C. for 5 hours under hydrogen atmosphere. After completion of the reaction, rhodium carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. Di-tert-butyl dicarbonate (1.56 ml, 6.80 mmol) was added to a THF (50 ml) -water (50 ml) mixed solution of the obtained residue and potassium carbonate (2.82 g, 20.4 mmol), and the mixture was stirred for 16 hours. Ethyl acetate was added to the reaction solution, and the aqueous layer was separated. The aqueous layer was washed with 0.5N hydrochloric acid, aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was passed through silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1 to 1: 1) to give 1.23 g (yield 50.2%) of the title compound as an oil. Obtained as a thing.
EI (pos) 361.0 [M + H] +
参考例61
N,N-ジエチル-3-(ピペリジン-4-イル)ベンズアミド 塩酸塩
Reference Example 61
N, N-diethyl-3- (piperidin-4-yl) benzamide hydrochloride
参考例60で得られたtert-ブチル 4-{3-[(ジエチルアミノ)カルボニル]フェニル}ピペリジン-1-カルボキシレート(1.23 g, 3.41 mmol)を用いて、参考例6と同様の操作を行うことにより、表題化合物906 mg(収率89.7%)を得た。これ以上精製することなく次工程に進んだ。 Perform the same operation as in Reference Example 6 using tert-butyl 4- {3-[(diethylamino) carbonyl] phenyl} piperidine-1-carboxylate (1.23 g, 3.41 mmol) obtained in Reference Example 60. Gave 906 mg (yield 89.7%) of the title compound. Proceed to the next step without further purification.
参考例62
ベンジル 4-{3-[(ジエチルアミノ)カルボニル]-4-ニトロフェニル}ピペラジン-1-カルボキシレート
Reference Example 62
Benzyl 4- {3-[(diethylamino) carbonyl] -4-nitrophenyl} piperazine-1-carboxylate
N,N-ジエチル-5-フルオロ-2-ニトロベンズアミド(5.60 g, 23.3 mmol)、ベンジル ピペラジン-1-カルボキシレート(9.00 ml, 46.6 mmol)と炭酸カリウム(3.22 g, 23.3 mmol)のDMSO(45 ml)懸濁液を60℃で1時間攪拌した。反応液に酢酸エチルを加え、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチル=1:1から酢酸エチル)に通して、表題化合物9.21 g(収率89.4%)を油状物として得た。
EI(pos) 441.2 [M+H]+
DMSO of N, N-diethyl-5-fluoro-2-nitrobenzamide (5.60 g, 23.3 mmol), benzyl piperazine-1-carboxylate (9.00 ml, 46.6 mmol) and potassium carbonate (3.22 g, 23.3 mmol) (45 ml) The suspension was stirred at 60 ° C. for 1 hour. Ethyl acetate was added to the reaction mixture, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was passed through silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1 to ethyl acetate) to give 9.21 g (yield 89.4%) of the title compound as an oil. Got as.
EI (pos) 441.2 [M + H] +
参考例63
ベンジル 4-{4-アミノ-3-[(ジエチルアミノ)カルボニル]フェニル}ピペラジン-1-カルボキシレート
Reference Example 63
Benzyl 4- {4-amino-3-[(diethylamino) carbonyl] phenyl} piperazine-1-carboxylate
参考例62で得られたベンジル 4-{3-[(ジエチルアミノ)カルボニル]-4-ニトロフェニル}ピペラジン-1-カルボキシレート(605 mg, 1.37 mmol)の90%酢酸(20 ml)溶液に亜鉛粉末(4.49 g, 68.7 mmol)を加え、室温で30分間攪拌した。反応混合物をろ過し、ろ液を減圧下濃縮した。残渣に酢酸エチルを加え、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去することにより、表題化合物564 mg(定量的)を油状物として得た。これ以上精製することなく次工程に進んだ。 Zinc powder in 90% acetic acid (20 ml) solution of benzyl 4- {3-[(diethylamino) carbonyl] -4-nitrophenyl} piperazine-1-carboxylate (605 mg, 1.37 mmol) obtained in Reference Example 62 (4.49 g, 68.7 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (564 mg, quantitative) as an oil. Proceed to the next step without further purification.
参考例64
ベンジル 4-{3-[(エチルアミノ)カルボニル]フェニル}ピペラジン-1-カルボキシレート
Reference Example 64
Benzyl 4- {3-[(ethylamino) carbonyl] phenyl} piperazine-1-carboxylate
参考例63で得られたベンジル 4-{4-アミノ-3-[(ジエチルアミノ)カルボニル]フェニル}ピペラジン-1-カルボキシレート(564 mg, 1.37 mmol)をエタノール(7 ml)と硫酸(2.3 ml)に溶解後、亜硝酸ナトリウム(190 mg, 2.75 mmol)を加え、3時間攪拌した。反応溶液に銅紛(175 mg, 2.75 mmol)を加え、2時間攪拌した後、反応混合物をろ過し、ろ液を減圧下濃縮した。残渣に酢酸エチルを加え、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチル=1:1から酢酸エチル)に通して、表題化合物392 mg(収率77.6%)を油状物として得た。
1H NMR (DMSO-d6) δ1.24 (3H, t, J = 6.0 Hz), 3.20 (4H, m), 3.48 (2H, m), 3.66 (4H, m), 5.17 (2H, s), 6.13(1H, m), 7.02(1H, dd, J = 6.0, 3.0 Hz), 7.14(1H, d, J = 6.0 Hz), 7.26-7.40(7H, m).
EI(pos) 367.9 [M+H]+
Benzyl 4- {4-amino-3-[(diethylamino) carbonyl] phenyl} piperazine-1-carboxylate (564 mg, 1.37 mmol) obtained in Reference Example 63 was added to ethanol (7 ml) and sulfuric acid (2.3 ml). After being dissolved in sodium nitrite (190 mg, 2.75 mmol) was added and stirred for 3 hours. Copper powder (175 mg, 2.75 mmol) was added to the reaction solution, and the mixture was stirred for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was passed through silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1 to ethyl acetate) to give 392 mg (yield 77.6%) of the title compound as an oil. Got as.
1 H NMR (DMSO-d 6 ) δ1.24 (3H, t, J = 6.0 Hz), 3.20 (4H, m), 3.48 (2H, m), 3.66 (4H, m), 5.17 (2H, s) , 6.13 (1H, m), 7.02 (1H, dd, J = 6.0, 3.0 Hz), 7.14 (1H, d, J = 6.0 Hz), 7.26-7.40 (7H, m).
EI (pos) 367.9 [M + H] +
参考例65
ベンジル 4-{3-[(ジエチルアミノ)カルボニル]フェニル}ピペラジン-1-カルボキシレート
Reference Example 65
Benzyl 4- {3-[(diethylamino) carbonyl] phenyl} piperazine-1-carboxylate
参考例64で得られたベンジル 4-{3-[(エチルアミノ)カルボニル]フェニル}ピペラジン-1-カルボキシレート(392 mg, 1.07 mmol)のTHF(5 ml)溶液に60%水素化ナトリウム(64.0 mg, 1.60 mmol)とヨウ化エチル(0.102 ml, 1.28 mmol)を加え、60℃で16時間攪拌した。反応溶液に酢酸エチルを加え、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン:酢酸エチル=1:1から1:3)に通して、表題化合物205 mg(収率48.6%)を油状物として得た。
EI(pos) 396.0 [M+H]+
To a solution of benzyl 4- {3-[(ethylamino) carbonyl] phenyl} piperazine-1-carboxylate (392 mg, 1.07 mmol) obtained in Reference Example 64 in THF (5 ml), 60% sodium hydride (64.0 mg, 1.60 mmol) and ethyl iodide (0.102 ml, 1.28 mmol) were added, and the mixture was stirred at 60 ° C. for 16 hours. Ethyl acetate was added to the reaction solution, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was passed through silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1 to 1: 3) to give 205 mg (yield 48.6%) of the title compound as an oil. Obtained as a thing.
EI (pos) 396.0 [M + H] +
参考例66
N,N-ジエチル-3-(ピペラジン-1-イル)ベンズアミド
Reference Example 66
N, N-diethyl-3- (piperazin-1-yl) benzamide
参考例65で得られたベンジル 4-{3-[(ジエチルアミノ)カルボニル]フェニル}ピペラジン-1-カルボキシレート(205 mg, 0.518 mmol)を用いて、参考例4と同様の操作を行うことにより、表題化合物135 mg(定量的)を得た。これ以上精製することなく次工程に進んだ。 By performing the same operation as in Reference Example 4 using benzyl 4- {3-[(diethylamino) carbonyl] phenyl} piperazine-1-carboxylate (205 mg, 0.518 mmol) obtained in Reference Example 65, 135 mg (quantitative) of the title compound were obtained. Proceed to the next step without further purification.
実施例1
4-{[4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-1-(トリフルオロアセチル)ピペラジン-2-イル]カルボニル}モルホリン
Example 1
4-{[4- [1- (9-anthrylcarbonyl) piperidin-4-yl] -1- (trifluoroacetyl) piperazin-2-yl] carbonyl} morpholine
参考例6で得られた4-{[4-ピペリジン-4-イル-1-(トリフルオロアセチル)ピペラジン-2-イル]カルボニル}モルホリン 二塩酸塩(206 mg, 0.456 mmol)、アントラセン-9-カルボン酸(101 mg, 0.456 mmol)、HOBt(70 mg, 0.456 mmol)とトリエチルアミン(0.14 ml, 1.00 mmol)のDMF(1 ml)溶液にEDC.HCl(87.5 mg, 0.456 mmol)を氷冷下加え、室温で16時間攪拌した。反応液を酢酸エチルに溶かし、炭酸水素ナトリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒;ヘキサン-酢酸エチル=1:1から酢酸エチル)で精製して、表題化合物226 mg(収率85.0%)を油状物として得た。
EI(pos) 583.2 [M+H]+
4-{[4-Piperidin-4-yl-1- (trifluoroacetyl) piperazin-2-yl] carbonyl} morpholine dihydrochloride (206 mg, 0.456 mmol) obtained in Reference Example 6, anthracene-9- Add EDC . HCl (87.5 mg, 0.456 mmol) to a DMF (1 ml) solution of carboxylic acid (101 mg, 0.456 mmol), HOBt (70 mg, 0.456 mmol) and triethylamine (0.14 ml, 1.00 mmol) under ice cooling. And stirred at room temperature for 16 hours. The reaction solution was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane-ethyl acetate = 1: 1 to ethyl acetate) to give 226 mg (yield 85.0%) of the title compound as an oil. Obtained as a thing.
EI (pos) 583.2 [M + H] +
実施例2
4-({4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]ピペラジン-2-イル}カルボニル)モルホリン
Example 2
4-({4- [1- (9-anthrylcarbonyl) piperidin-4-yl] piperazin-2-yl} carbonyl) morpholine
実施例1で得られた4-{[4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-1-(トリフルオロアセチル)ピペラジン-2-イル]カルボニル}モルホリン(226 mg, 0.388 mmol)と炭酸カリウム(161 mg, 1.16 mmol)にメタノール(3 ml)と水(1 ml)を加え、16時間攪拌した。反応液に酢酸エチルを加え、炭酸カリウム水溶液と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、得られた残渣をジイソプロピルエーテル-ヘキサン(1:1)で粉末にすることにより、表題化合物162 mg(収率85.7%)を得た。
EI(pos) 487.1 [M+H]+
4-{[4- [1- (9-anthrylcarbonyl) piperidin-4-yl] -1- (trifluoroacetyl) piperazin-2-yl] carbonyl} morpholine obtained in Example 1 (226 mg, Methanol (3 ml) and water (1 ml) were added to 0.388 mmol) and potassium carbonate (161 mg, 1.16 mmol), and the mixture was stirred for 16 hours. Ethyl acetate was added to the reaction mixture, washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was triturated with diisopropyl ether-hexane (1: 1) to give the title compound (162 mg, yield 85.7%).
EI (pos) 487.1 [M + H] +
実施例3
4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N,N-ジエチル-1-(トリフルオロアセチル)ピペラジン-2-カルボキサミド
Example 3
4- [1- (9-Anthrylcarbonyl) piperidin-4-yl] -N, N-diethyl-1- (trifluoroacetyl) piperazine-2-carboxamide
参考例12で得られたN,N-ジエチル-4-(ピペリジン-4-イル)-1-(トリフルオロアセチル)ピペラジン-2-カルボキサミド(550 mg, 1.26 mmol)とアントラセン-9-カルボン酸(307 mg, 1.38 mmol)を用いて、実施例1と同様の操作を行うことにより、表題化合物328 mg(収率45.8%)を油状物として得た。
EI(pos) 569.1 [M+H]+
N, N-diethyl-4- (piperidin-4-yl) -1- (trifluoroacetyl) piperazine-2-carboxamide (550 mg, 1.26 mmol) obtained in Reference Example 12 and anthracene-9-carboxylic acid ( 307 mg, 1.38 mmol), and the same operation as in Example 1 was carried out to give 328 mg (yield 45.8%) of the title compound as an oil.
EI (pos) 569.1 [M + H] +
実施例4
4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N,N-ジエチルピペラジン-2-カルボキサミド
Example 4
4- [1- (9-Anthrylcarbonyl) piperidin-4-yl] -N, N-diethylpiperazine-2-carboxamide
実施例3で得られた4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N,N-ジエチル-1-(トリフルオロアセチル)ピペラジン-2-カルボキサミド(306 mg, 0.538 mmol)を用いて、実施例2と同様の操作を行うことにより、表題化合物234 mg(収率92.1%)を油状物として得た。
EI(pos) 473.1 [M+H]+
4- [1- (9-anthrylcarbonyl) piperidin-4-yl] -N, N-diethyl-1- (trifluoroacetyl) piperazine-2-carboxamide (306 mg, 0.538 mmol) obtained in Example 3 ) To give the title compound 234 mg (yield 92.1%) as an oil.
EI (pos) 473.1 [M + H] +
実施例5
4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N,N-ジエチル-6-オキソピペラジン-2-カルボキサミド
Example 5
4- [1- (9-Anthrylcarbonyl) piperidin-4-yl] -N, N-diethyl-6-oxopiperazine-2-carboxamide
参考例16で得られたN,N-ジエチル-6-オキソ-4-(ピペリジン-4-イル)ピペラジン-2-カルボキサミド 二塩酸塩(74.2 mg, 0.209 mmol)とアントラセン-9-カルボン酸(51.1 mg, 0.230 mmol)を用いて、実施例1と同様の操作を行い、油状物を得た。得られる油状物にジイソプロピルエーテルを加え、表題化合物72.8 mg(収率71.4%)を粉末として得た。
EI(pos) 487.2 [M+H]+
N, N-diethyl-6-oxo-4- (piperidin-4-yl) piperazine-2-carboxamide dihydrochloride (74.2 mg, 0.209 mmol) obtained in Reference Example 16 and anthracene-9-carboxylic acid (51.1 mg, 0.230 mmol), and the same operation as in Example 1 was performed to obtain an oily substance. Diisopropyl ether was added to the resulting oil to give 72.8 mg (yield 71.4%) of the title compound as a powder.
EI (pos) 487.2 [M + H] +
実施例6
4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N,N-ジエチルモルホリン-2-カルボキサミド
Example 6
4- [1- (9-Anthrylcarbonyl) piperidin-4-yl] -N, N-diethylmorpholine-2-carboxamide
参考例20で得られたN,N-ジエチル-4-(ピペリジン-4-イル)モルホリン-2-カルボキサミド 塩酸塩(200 mg, 0.654 mmol)とアントラセン-9-カルボン酸(160 mg, 0.719 mmol)を用いて、実施例1と同様の操作を行うことにより、表題化合物197 mg(収率63.5%)を得た。
EI(pos) 474.0 [M+H]+
N, N-diethyl-4- (piperidin-4-yl) morpholine-2-carboxamide hydrochloride (200 mg, 0.654 mmol) and anthracene-9-carboxylic acid (160 mg, 0.719 mmol) obtained in Reference Example 20 The title compound was obtained in the same manner as in Example 1 to obtain 197 mg of the title compound (yield 63.5%).
EI (pos) 474.0 [M + H] +
実施例7
4-[1-(2,6-ジフェニルイソニコチノイル)ピペリジン-4-イル]-N,N-ジエチルモルホリン-2-カルボキサミド
Example 7
4- [1- (2,6-Diphenylisonicotinoyl) piperidin-4-yl] -N, N-diethylmorpholine-2-carboxamide
参考例20で得られたN,N-ジエチル-4-(ピペリジン-4-イル)モルホリン-2-カルボキサミド 塩酸塩(170 mg, 0.556 mmol)と2,6-ジフェニルイソニコチン酸(168 mg, 0.556 mmol)を用いて、実施例1と同様の操作を行うことにより、表題化合物143 mg(収率48.8%)を得た。
EI(pos) 527.0 [M+H]+
N, N-diethyl-4- (piperidin-4-yl) morpholine-2-carboxamide hydrochloride (170 mg, 0.556 mmol) and 2,6-diphenylisonicotinic acid (168 mg, 0.556) obtained in Reference Example 20 The title compound was obtained in the same manner as in Example 1 to obtain 143 mg (yield: 48.8%).
EI (pos) 527.0 [M + H] +
実施例8
N,N-ジエチル-4-(1-{[2-(2-チエニル)キノリン-4-イル]カルボニル}ピペリジン-4-イル)モルホリン-2-カルボキサミド
Example 8
N, N-diethyl-4- (1-{[2- (2-thienyl) quinolin-4-yl] carbonyl} piperidin-4-yl) morpholine-2-carboxamide
参考例20で得られたN,N-ジエチル-4-(ピペリジン-4-イル)モルホリン-2-カルボキサミド 塩酸塩(195 mg, 0.638 mmol)と2-(2-チエニル)キノリン-4-カルボン酸(163 mg, 0.638 mmol)を用いて、実施例1と同様の操作を行うことにより、表題化合物296 mg(収率91.6%)を得た。
EI(pos) 507.3 [M+H]+
N, N-diethyl-4- (piperidin-4-yl) morpholine-2-carboxamide hydrochloride (195 mg, 0.638 mmol) and 2- (2-thienyl) quinoline-4-carboxylic acid obtained in Reference Example 20 (163 mg, 0.638 mmol) was used in the same manner as in Example 1 to obtain 296 mg (yield 91.6%) of the title compound.
EI (pos) 507.3 [M + H] +
実施例9
4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N-エチル-1-(トリフルオロアセチル)ピペラジン-2-カルボキサミド
Example 9
4- [1- (9-Anthrylcarbonyl) piperidin-4-yl] -N-ethyl-1- (trifluoroacetyl) piperazine-2-carboxamide
参考例58で得られたN-エチル-4-(ピペリジン-4-イル)-1-(トリフルオロアセチル)ピペラジン-2-カルボキサミド(1.16 g, 2.84 mmol)とアントラセン-9-カルボン酸(631 mg, 2.84 mmol)を用いて、実施例1と同様の操作を行うことにより、表題化合物856 mg(収率55.6%)を油状物として得た。
EI(pos) 541.3 [M+H]+
N-ethyl-4- (piperidin-4-yl) -1- (trifluoroacetyl) piperazine-2-carboxamide (1.16 g, 2.84 mmol) obtained in Reference Example 58 and anthracene-9-carboxylic acid (631 mg , 2.84 mmol), and the same operation as in Example 1 was performed to give the title compound (856 mg, yield 55.6%) as an oil.
EI (pos) 541.3 [M + H] +
実施例10
4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N-エチルピペラジン-2-カルボキサミド
Example 10
4- [1- (9-Anthrylcarbonyl) piperidin-4-yl] -N-ethylpiperazine-2-carboxamide
実施例9で得られた4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N-エチル-1-(トリフルオロアセチル)ピペラジン-2-カルボキサミド(855 mg, 1.58 mmol)を用いて、実施例2と同様の操作を行うことにより、表題化合物525 mg(収率74.7%)を油状物として得た。
EI(pos) 445.2 [M+H]+
4- [1- (9-anthrylcarbonyl) piperidin-4-yl] -N-ethyl-1- (trifluoroacetyl) piperazine-2-carboxamide (855 mg, 1.58 mmol) obtained in Example 9 was used. Using the same procedure as in Example 2, the title compound (525 mg, yield 74.7%) was obtained as an oil.
EI (pos) 445.2 [M + H] +
実施例11
3-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-N,N-ジエチルベンズアミド
Example 11
3- [1- (9-Anthrylcarbonyl) piperidin-4-yl] -N, N-diethylbenzamide
参考例61で得られたN,N-ジエチル-3-(ピペリジン-4-イル)ベンズアミド 塩酸塩(140 mg, 0.472 mmol)とアントラセン-9-カルボン酸(105 mg, 0.472 mmol)を用いて、実施例1と同様の操作を行うことにより、表題化合物139 mg(収率63.4%)を油状物として得た。
EI(pos) 465.0 [M+H]+
Using N, N-diethyl-3- (piperidin-4-yl) benzamide hydrochloride (140 mg, 0.472 mmol) obtained in Reference Example 61 and anthracene-9-carboxylic acid (105 mg, 0.472 mmol), The same operation as in Example 1 was performed to obtain 139 mg (yield: 63.4%) of the title compound as an oil.
EI (pos) 465.0 [M + H] +
実施例12
3-[4-(9-アントリルカルボニル)ピペラジン-1-イル]-N,N-ジエチルベンズアミド
Example 12
3- [4- (9-Anthrylcarbonyl) piperazin-1-yl] -N, N-diethylbenzamide
参考例66で得られたN,N-ジエチル-3-(ピペラジン-1-イル)ベンズアミド(135 mg, 0.517 mmol)とアントラセン-9-カルボン酸(115 mg, 0.517 mmol)を用いて、実施例1と同様の操作を行うことにより、表題化合物173 mg(収率72.2%)を油状物として得た。
EI(pos) 466.0 [M+H]+
Using N, N-diethyl-3- (piperazin-1-yl) benzamide (135 mg, 0.517 mmol) and anthracene-9-carboxylic acid (115 mg, 0.517 mmol) obtained in Reference Example 66, an Example The same operation as in 1 was carried out to obtain 173 mg (yield 72.2%) of the title compound as an oil.
EI (pos) 466.0 [M + H] +
実施例13−182では、参考例45-52で得られた8種類のアミン(60.0 μmol)と各種カルボン酸(65.0 μmol)を用いて、実施例1に示した方法と同様の方法により、表題化合物をギ酸塩として得た。これらの化合物を表1−表7に示す。なお、表中の化合物は、式 In Examples 13-182, the titles of the titles were obtained in the same manner as in Example 1 using the 8 types of amines (60.0 μmol) obtained in Reference Examples 45-52 and various carboxylic acids (65.0 μmol). The compound was obtained as a formate salt. These compounds are shown in Table 1 to Table 7. The compounds in the table are represented by the formula
として示され、また、表中の第1段目は実施例番号、第2段目は収量(mg)、第3段目は収率(%)、第4段目はEI(pos)[M+H]+をそれぞれ示す。 In the table, the first stage is an example number, the second stage is yield (mg), the third stage is yield (%), the fourth stage is EI (pos) [M + H] + is shown respectively.
実験例1
以下の方法により、本発明化合物のACC1阻害作用を評価した。
(1)ヒトACC1遺伝子のクローニングと組換えバキュロウイルスの調製
ヒトACC1遺伝子は、ヒト肝臓cDNAライブラリー(Clontech社)を鋳型とし、以下に示すPrimer 1およびPrimer 2を用いたPCRによりクローニングした。Primer1およびPrimer 2は、ヒトACC1遺伝子の塩基配列(Genbank Accession U19822)情報より、SalI、NotI制限酵素認識配列を加えて作製した。
Primer 1 5’AAAAGTCGACCCACCATGGATGAACCTTCTCCCTTGGCCC
Primer 2 5’AAAAGCGGCCGCCTACGTAGAAGGGGAGTCCATAGTG
PCRはPyrobest DNA polymerase(タカラバイオ株式会社)を用いて実施した。得られたPCR産物をpT7 Blue vector(Novagen社)にクローニングし、塩基配列を確認後、制限酵素SalI、NotIで消化した。得られるDNA断片を、制限酵素SalI、NotIで消化したpFAST-BacHTc(インビトロジェン社)へ挿入し、発現プラスミドACC1/pFAST-BacHTcを作製した。
該発現プラスミドおよびBAC-TO-BAC Baculovirus Expression System (インビトロジェン社)を用いて、組換えバキュロウイルスのウイルスストックBAC−ACC1を調製した。
Experimental example 1
The ACC1 inhibitory action of the compound of the present invention was evaluated by the following method.
(1) Cloning of human ACC1 gene and preparation of recombinant baculovirus The human ACC1 gene was cloned by PCR using Primer 1 and Primer 2 shown below using a human liver cDNA library (Clontech) as a template. Primer1 and Primer2 were prepared by adding SalI and NotI restriction enzyme recognition sequences based on the information on the base sequence of the human ACC1 gene (Genbank Accession U19822).
Primer 1 5'AAAAGTCGACCCACCATGGATGAACCTTCTCCCTTGGCCC
Primer 2 5'AAAAGCGGCCGCCTACGTAGAAGGGGAGTCCATAGTG
PCR was performed using Pyrobest DNA polymerase (Takara Bio Inc.). The obtained PCR product was cloned into pT7 Blue vector (Novagen), and after confirming the nucleotide sequence, it was digested with restriction enzymes SalI and NotI. The obtained DNA fragment was inserted into pFAST-BacHTc (Invitrogen) digested with restriction enzymes SalI and NotI to prepare an expression plasmid ACC1 / pFAST-BacHTc.
Using the expression plasmid and BAC-TO-BAC Baculovirus Expression System (Invitrogen), recombinant baculovirus virus stock BAC-ACC1 was prepared.
(2)ACC1タンパクの調製
SF-9細胞(インビトロジェン社)を昆虫細胞用培地(10%ウシ胎児血清(トレース社)、50mg/L Gentamicin(インビトロジェン社)、0.1% Pluronic F-68(インビトロジェン社)を含むSf-900IISFM培地(インビトロジェン社))1Lに1×106 cells/mLとなるように播種し、2L容マイヤーを用いて27℃、100rpmで振盪培養した。
培養24時間後に組換えバキュロウイルスBAC-ACC1を10mL添加し、さらに3日間の培養を行った。培養液を1000×gで5分間遠心分離し、ウィルス感染細胞を得た。該細胞をリン酸生理緩衝液(インビトロジェン社)で洗浄して同条件で遠心分離後、得られる細胞を-80℃で凍結保存した。
凍結保存した細胞を氷中で融解後、Complete Protease Inhibitor(ベーリンガー社)を添加した10% Glycerol、0.13M NaCl、1mM EDTA、25mM Sodiumβ−Glycerophosphate、1mM Sodium Orthovanadate を含む25mM HEPES緩衝液 (pH7.5)100 mLに懸濁した。得られる懸濁液をポリトロンホモジナイザー(キネマティカ社)を用いて20,000 rpm, 30秒の条件で3回ホモジナイズした。得られる細胞破砕液を185700×g, 50分間の遠心分離により清澄化後、0.45μmフィルターを用いたろ過を行った。ろ過液をNi-NTA Super Flow Gel (キアゲン社) 12mLを詰めたカラムに流速約5 mL/minで通した。カラムを緩衝液A(0.3M NaClを含む50mM HEPES(pH7.5))で洗浄し、更に20mM Imidazoleを含む緩衝液Aで洗浄した後、100mM Imidazoleを含む緩衝液Aで溶出した。溶出液を分画分子量30Kのビバスピン20(ビバサイエンス社)で濃縮した。得られる濃縮液を10mM MgCl2、2mM Dithiothreitol、10mM Tripotassium Citrate、0.3M NaClを含む50mM HEPES(pH7.5)で平衡化したSephadex G-25(アマシャムバイオサイエンス社)358mLを用いて透析した。透析内液を分画分子量30Kのビバスピン20(ビバサイエンス社)で濃縮した後、濃縮液を0.22μmフィルターでろ過し、ACC1を得た。得られたACC1は-80℃で凍結保存した。
(2) Preparation of ACC1 protein
SF-9 cells (Invitrogen) were added to insect cell culture medium (10% fetal bovine serum (Trace), 50 mg / L Gentamicin (Invitrogen), 0.1% Pluronic F-68 (Invitrogen) Sf-900IISFM medium (Invitrogen) Invitrogen)) 1 L was seeded at 1 × 10 6 cells / mL, and cultured with shaking using 2 L Meyer at 27 ° C. and 100 rpm.
After 24 hours of culture, 10 mL of recombinant baculovirus BAC-ACC1 was added, and further cultured for 3 days. The culture solution was centrifuged at 1000 × g for 5 minutes to obtain virus-infected cells. The cells were washed with phosphate physiological buffer (Invitrogen) and centrifuged under the same conditions, and the resulting cells were stored frozen at -80 ° C.
After thawing the cryopreserved cells in ice, 25 mM HEPES buffer (pH 7.5) containing 10% Glycerol, 0.13 M NaCl, 1 mM EDTA, 25 mM Sodium β-Glycerophosphate, 1 mM Sodium Orthovanadate with Complete Protease Inhibitor (Boehringer) added. ) Suspended in 100 mL. The resulting suspension was homogenized three times using a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 seconds. The obtained cell lysate was clarified by centrifugation at 185700 × g for 50 minutes, followed by filtration using a 0.45 μm filter. The filtrate was passed through a column packed with 12 mL of Ni-NTA Super Flow Gel (Qiagen) at a flow rate of about 5 mL / min. The column was washed with buffer A (50 mM HEPES (pH 7.5) containing 0.3 M NaCl), further washed with buffer A containing 20 mM Imidazole, and then eluted with buffer A containing 100 mM Imidazole. The eluate was concentrated with Vivapine 20 (Viva Science) having a molecular weight cut off of 30K. The resulting concentrated solution was dialyzed against 358 mL of Sephadex G-25 (Amersham Biosciences) equilibrated with 50 mM HEPES (pH 7.5) containing 10 mM MgCl 2 , 2 mM Dithiothreitol, 10 mM Tripotassium Citrate, and 0.3 M NaCl. The dialyzed internal solution was concentrated with Vivaspin 20 (Vivascience) having a molecular weight cut off of 30K, and then the concentrated solution was filtered with a 0.22 μm filter to obtain ACC1. The obtained ACC1 was stored frozen at -80 ° C.
(3)ACC1阻害活性の測定
上記(2)で得られたACC1(0.93mg/ml)を酵素反応用緩衝液(50mM HEPES (pH7.5), 10mM MgCl2, 10mM Tripottasium Citrate, 2mM Dithiothreitol , 0.75mg/ml Fatty acid free BSA)で8μg/mlの濃度に希釈後、384 well assay plate(Nunc 265196)の各ウェルに10μlずつ添加した。
以後、後述の実験例2−(3)と同様にして、ACC1阻害率(%)を求め、IC50値を算出した。
結果を[表8]に示す。
(3) Measurement of ACC1 inhibitory activity ACC1 (0.93 mg / ml) obtained in (2) above was used as a buffer for enzyme reaction (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 10 mM Tripottasium Citrate, 2 mM Dithiothreitol, 0.75 mg / ml Fatty acid free BSA) was diluted to a concentration of 8 μg / ml, and 10 μl was added to each well of a 384 well assay plate (Nunc 265196).
Thereafter, in the same manner as in Experimental Example 2- (3) described later, the ACC1 inhibition rate (%) was determined, and the IC 50 value was calculated.
The results are shown in [Table 8].
表8に示されるように、本発明化合物は、優れたACC1阻害作用を有する。 As shown in Table 8, the compound of the present invention has an excellent ACC1 inhibitory action.
実験例2
以下の方法により、本発明化合物のACC2阻害作用を評価した。
(1)ヒトACC2遺伝子のクローニングと組換えバキュロウイルスの調製
ヒトACC2遺伝子は、ヒト骨格筋cDNAライブラリー(Clontech社)を鋳型とし、以下に示すPrimer 1およびPrimer 2を用いたPCRによりクローニングした。Primer1およびPrimer 2は、ヒトACC2遺伝子の塩基配列(Genbank Accession U89344)情報より、SalI、XbaI制限酵素認識配列を加えて作製した。
Primer 1 5’AAAAGTCGACCCACCATGGTCTTGCTTCTTTGTCTATCTTG
Primer 2 5’TTTTTCTAGATCAGGTAGAGGCCGGGCTGTCCATG
PCRはPyrobest DNA polymerase(タカラバイオ株式会社)を用いて実施した。得られたPCR産物をpT7 Blue vector(Novagen社)にクローニングし、塩基配列を確認後、制限酵素SalI、XbaIで消化した。得られるDNA断片を、制限酵素SalI、XbaIで消化したpFAST-BacHTa(インビトロジェン社)へ挿入し、発現プラスミドACC2/pFAST-BacHTaを作製した。
該発現プラスミドを鋳型とし、以下に示すPrimer 3およびPrimer 4を用いたPCRにより、ミトコンドリア移行配列を除去したACC2を発現させるためのプラスミドを作製した。
Primer 3 5’CCAGGTCGACCCGCCAACGGGACTGGGACACAAGG
Primer 4 5’CGCACTCTCAGTTTCCCGGATTCCC
PCRはPyrobest-DNA polymerase(タカラバイオ株式会社)を用いて実施した。得られたPCR産物をpT7Blue vector(Novagen)にクローニングし、塩基配列を確認後、制限酵素SalI、AflIIで消化した。得られるDNA断片を、制限酵素SalI、AflIIで消化したpFAST-BacHTa(インビトロジェン社)へ挿入し、発現プラスミドACC2mito7/pFAST-BacHTaを作製した。
該発現プラスミドおよびBAC-TO-BAC Baculovirus Expression System (インビトロジェン社)を用いて、組換えバキュロウイルスのウイルスストックBAC−ACC2(N terminal deletion(以下Nd))を調製した。
Experimental example 2
The ACC2 inhibitory action of the compound of the present invention was evaluated by the following method.
(1) Cloning of human ACC2 gene and preparation of recombinant baculovirus The human ACC2 gene was cloned by PCR using Primer 1 and Primer 2 shown below using a human skeletal muscle cDNA library (Clontech) as a template. Primer1 and Primer2 were prepared by adding SalI and XbaI restriction enzyme recognition sequences based on the information on the base sequence (Genbank Accession U89344) of the human ACC2 gene.
Primer 1 5'AAAAGTCGACCCACCATGGTCTTGCTTCTTTGTCTATCTTG
Primer 2 5'TTTTTCTAGATCAGGTAGAGGCCGGGCTGTCCATG
PCR was performed using Pyrobest DNA polymerase (Takara Bio Inc.). The obtained PCR product was cloned into pT7 Blue vector (Novagen), and after confirming the base sequence, digested with restriction enzymes SalI and XbaI. The obtained DNA fragment was inserted into pFAST-BacHTa (Invitrogen) digested with restriction enzymes SalI and XbaI to prepare an expression plasmid ACC2 / pFAST-BacHTa.
Using the expression plasmid as a template, a plasmid for expressing ACC2 from which the mitochondrial translocation sequence was removed was prepared by PCR using Primer 3 and Primer 4 shown below.
Primer 3 5'CCAGGTCGACCCGCCAACGGGACTGGGACACAAGG
Primer 4 5'CGCACTCTCAGTTTCCCGGATTCCC
PCR was performed using Pyrobest-DNA polymerase (Takara Bio Inc.). The obtained PCR product was cloned into pT7Blue vector (Novagen), and after confirming the nucleotide sequence, it was digested with restriction enzymes SalI and AflII. The obtained DNA fragment was inserted into pFAST-BacHTa (Invitrogen) digested with restriction enzymes SalI and AflII to prepare an expression plasmid ACC2mito7 / pFAST-BacHTa.
Using the expression plasmid and BAC-TO-BAC Baculovirus Expression System (Invitrogen), virus stock BAC-ACC2 (N terminal deletion (hereinafter referred to as Nd)) of recombinant baculovirus was prepared.
(2)ACC2(Nd)タンパクの調製
SF-9細胞(インビトロジェン社)を昆虫細胞用培地(10%ウシ胎児血清(トレース社)、50mg/L Gentamicin(インビトロジェン社)、0.1% Pluronic F-68(インビトロジェン社)を含むSf-900IISFM培地(インビトロジェン社))2Lに0.5×106 cells/mLとなるように播種し、Waveバイオリアクター(Wave社)を用いて27℃、20rpm、揺動角度6度、酸素濃度30%で振盪培養した。
培養4日目に3Lの昆虫細胞用培地を加え揺動角度を8度にし、さらに培養を行った。培養5日目に組換えバキュロウイルスBAC-ACC2(Nd)を100mL添加し、さらに昆虫細胞用培地5Lを加え、揺動角度を11度として3日間の培養を行った。培養液を1000×gで10分間遠心分離し、ウィルス感染細胞を得た。該細胞をリン酸生理緩衝液(インビトロジェン社)で洗浄して同条件で遠心分離後、得られる細胞を-80℃で凍結保存した。
凍結保存した細胞を氷中で融解後、Complete Protease Inhibitor(ベーリンガー社)を添加した10% Glycerol、0.13M NaCl、1mM EDTA、25mM Sodiumβ−Glycerophosphate、1mM Sodium Orthovanadate を含む25mM HEPES緩衝液 (pH7.5)900 mLに懸濁した。得られる懸濁液をポリトロンホモジナイザー(キネマティカ社)を用いて20,000 rpm, 30秒の条件で3回ホモジナイズした。得られる細胞破砕液を31000×g, 60分間の遠心分離により清澄化後、0.45μmフィルターを用いたろ過を行った。ろ過液をNi-NTA Super Flow Gel (キアゲン社) 60mLを詰めたカラムに流速約5 mL/minで通した。カラムを緩衝液A(0.3M NaClを含む50mM HEPES(pH7.5))で洗浄し、更に20mM Imidazoleを含む緩衝液Aで洗浄した後、100mM Imidazoleを含む緩衝液Aで溶出した。溶出液を分画分子量30Kのビバスピン20(ビバサイエンス社)で濃縮した。得られる濃縮液を10mM MgCl2、2mM Dithiothreitol、10mM Tripotassium Citrate、0.3M NaClを含む50mM HEPES(pH7.5)に対して透析した。透析内液を0.22μmフィルターでろ過し、ACC2(Nd)を得た。得られたACC2(Nd)は-80℃で凍結保存した。
(2) Preparation of ACC2 (Nd) protein
SF-9 cells (Invitrogen) were added to insect cell culture medium (10% fetal bovine serum (Trace), 50 mg / L Gentamicin (Invitrogen), 0.1% Pluronic F-68 (Invitrogen) Sf-900IISFM medium (Invitrogen) Invitrogen)) 2 L was seeded at 0.5 × 10 6 cells / mL, and cultured with shaking using a Wave bioreactor (Wave) at 27 ° C., 20 rpm, rocking angle 6 °, and oxygen concentration 30%.
On the fourth day of culture, 3 L of insect cell culture medium was added to make the rocking angle 8 °, and further culture was performed. On the fifth day of culture, 100 mL of recombinant baculovirus BAC-ACC2 (Nd) was added, 5 L of insect cell medium was further added, and the culture was performed for 3 days at an oscillation angle of 11 degrees. The culture solution was centrifuged at 1000 × g for 10 minutes to obtain virus-infected cells. The cells were washed with phosphate physiological buffer (Invitrogen) and centrifuged under the same conditions, and the resulting cells were stored frozen at -80 ° C.
After thawing the cryopreserved cells in ice, 25 mM HEPES buffer (pH 7.5) containing 10% Glycerol, 0.13 M NaCl, 1 mM EDTA, 25 mM Sodium β-Glycerophosphate, 1 mM Sodium Orthovanadate with Complete Protease Inhibitor (Boehringer) added. ) Suspended in 900 mL. The resulting suspension was homogenized three times using a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 seconds. The obtained cell lysate was clarified by centrifugation at 31000 × g for 60 minutes, and then filtered using a 0.45 μm filter. The filtrate was passed through a column packed with 60 mL of Ni-NTA Super Flow Gel (Qiagen) at a flow rate of about 5 mL / min. The column was washed with buffer A (50 mM HEPES (pH 7.5) containing 0.3 M NaCl), further washed with buffer A containing 20 mM Imidazole, and then eluted with buffer A containing 100 mM Imidazole. The eluate was concentrated with Vivapine 20 (Viva Science) having a molecular weight cut off of 30K. The resulting concentrated solution was dialyzed against 50 mM HEPES (pH 7.5) containing 10 mM MgCl 2 , 2 mM Dithiothreitol, 10 mM Tripotassium Citrate, 0.3 M NaCl. The dialyzed solution was filtered with a 0.22 μm filter to obtain ACC2 (Nd). The obtained ACC2 (Nd) was stored frozen at −80 ° C.
(3)ACC2阻害活性の測定
上記(2)で得られたACC2(Nd)(1.1mg/ml)を酵素反応用緩衝液(50mM HEPES (pH7.5), 10mM MgCl2, 10mM Tripottasium Citrate, 2mM Dithiothreitol , 0.75mg/ml Fatty acid free BSA)で6.4μg/mlの濃度に希釈後、384 well assay plate(Nunc 265196)の各ウェルに10μlずつ添加した。ついで、各ウェルに、ジメチルスルホキシド(DMSO)に溶解した試験化合物を酵素反応用緩衝液で希釈した溶液5μlずつを添加し、30℃で60分間インキュベーションした。ついで、各ウェルに、基質溶液(50mM KHCO3, 200uM ATP, 200uM Acetyl-CoA)5μlずつを添加し、30℃で20分間反応させた(試験化合物添加群)。
また、試験化合物を添加しない以外、上記と同様の反応を行った(試験化合物非添加群)。さらに、試験化合物およびAcetyl-CoAを添加しない以外、上記と同様の反応を行った(コントロール群)。
このようにして得られる各反応液にマラカイトグリーン液5μlずつを添加し攪拌することにより反応を停止させた。得られる反応液を室温で20分間放置した後、wallac1420(Perkin Elmer社)を用いて吸光度(620nm)を測定した。なお、前記マラカイトグリーン液は、A液(0.12%マラカイトグリーン溶液。5N H2SO4で調製、遮光し4℃で保存)、B液(7.5%アンモニウムモリブデート水溶液。用時調製)およびC液(11% Tween 20水溶液。室温保存)を、A液:B液:C液=100:25:2の割合(容積比)で混合することにより調製した。
ついで、ACC2阻害率(%)を計算式:
(1−(試験化合物添加群の吸光度−コントロール群の吸光度)÷(試験化合物非添加群の吸光度−コントロール群の吸光度))×100
により求め、IC50値を算出した。
結果を[表9]に示す。
(3) Measurement of ACC2 inhibitory activity ACC2 (Nd) (1.1 mg / ml) obtained in (2) above was used as a buffer for enzyme reaction (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 10 mM Tripottasium Citrate, 2 mM) Dithiothreitol, 0.75 mg / ml Fatty acid free BSA) was diluted to a concentration of 6.4 μg / ml, and 10 μl was added to each well of a 384 well assay plate (Nunc 265196). Next, 5 μl each of a test compound dissolved in dimethyl sulfoxide (DMSO) diluted with an enzyme reaction buffer was added to each well and incubated at 30 ° C. for 60 minutes. Next, 5 μl of a substrate solution (50 mM KHCO 3 , 200 uM ATP, 200 uM Acetyl-CoA) was added to each well and reacted at 30 ° C. for 20 minutes (test compound addition group).
Moreover, except not adding a test compound, reaction similar to the above was performed (test compound non-addition group). Further, a reaction similar to the above was carried out except that the test compound and Acetyl-CoA were not added (control group).
The reaction was stopped by adding 5 μl of malachite green solution to each reaction solution thus obtained and stirring. The resulting reaction solution was allowed to stand at room temperature for 20 minutes, and then the absorbance (620 nm) was measured using wallac1420 (Perkin Elmer). The malachite green solution is a solution A (0.12% malachite green solution. Prepared with 5N H 2 SO 4 and stored at 4 ° C. protected from light), solution B (7.5% ammonium molybdate aqueous solution, prepared at the time of use) and solution C. (11% Tween 20 aqueous solution, stored at room temperature) was prepared by mixing at a ratio (volume ratio) of liquid A: liquid B: liquid C = 100: 25: 2.
Next, the ACC2 inhibition rate (%) is calculated using the following formula:
(1− (absorbance of test compound added group−absorbance of control group) ÷ (absorbance of no test compound added group−absorbance of control group)) × 100
IC 50 value was calculated.
The results are shown in [Table 9].
表9に示されるように、本発明化合物は、優れたACC2阻害作用を有する。 As shown in Table 9, the compound of the present invention has an excellent ACC2 inhibitory action.
製剤例1(カプセルの製造)
1)実施例1の化合物 30 mg
2)微粉末セルロース 10 mg
3)乳糖 19 mg
4)ステアリン酸マグネシウム 1 mg
計 60 mg
1)、2)、3)および4)を混合して、ゼラチンカプセルに充填する。
Formulation Example 1 (Manufacture of capsules)
1) Compound of Example 1 30 mg
2) Fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.
製剤例2(錠剤の製造)
1)実施例1の化合物 30 g
2)乳糖 50 g
3)トウモロコシデンプン 15 g
4)カルボキシメチルセルロースカルシウム 44 g
5)ステアリン酸マグネシウム 1 g
1000錠 計 140 g
1)、2)、3)の全量および30gの4)を水で練合し、真空乾燥後、整粒を行う。この整粒末に14gの4)および1gの5)を混合し、打錠機により打錠する。このようにして、1錠あたり実施例1の化合物30mgを含有する錠剤1000錠を得る。
Formulation Example 2 (Manufacture of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The total amount of 1), 2), and 3) and 30 g of 4) are kneaded with water, dried in a vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
本発明化合物は、ACC(アセチル−CoAカルボキシラーゼ)阻害作用を有し、肥満症、糖尿病、高血圧症、高脂血症、心不全、糖尿病性心筋症、メタボリックシンドローム、筋肉減少症などの予防・治療に有用である。 The compound of the present invention has an ACC (acetyl-CoA carboxylase) inhibitory action, and is used for the prevention and treatment of obesity, diabetes, hypertension, hyperlipidemia, heart failure, diabetic cardiomyopathy, metabolic syndrome, sarcopenia, etc. Useful.
Claims (6)
[式中、
Eは、置換されていてもよい環状基(ただし、該環状基はスピロ環基でない。また、該環状基が単環基であるとき、該環状基は、置換基として、置換されていてもよい環状基を少なくとも2個有する。)を;
DおよびGは、独立してカルボニル基またはスルホニル基を;
環Pは、置換されていてもよい含窒素5または6員非芳香族複素環を;
環Qは、置換されていてもよい芳香環または置換されていてもよい非芳香族複素環(ただし該非芳香族複素環は2個以上のヘテロ原子を含む)を;
AおよびLは、独立してC、CHまたはNを;
Jは、置換されていてもよい炭化水素基、置換されていてもよいヒドロキシ基、置換されていてもよい複素環基または置換されていてもよいアミノ基を示す。]
で表される化合物またはその塩(ただし、「4-[1-(9-アントリルカルボニル)ピペリジン-4-イル]-2-(モルホリン-4-イルカルボニル)モルホリン」を除く)。 formula
[Where:
E represents an optionally substituted cyclic group (provided that the cyclic group is not a spirocyclic group. When the cyclic group is a monocyclic group, the cyclic group may be substituted as a substituent. Having at least two good cyclic groups);
D and G independently represent a carbonyl group or a sulfonyl group;
Ring P represents an optionally substituted nitrogen-containing 5- or 6-membered non-aromatic heterocyclic ring;
Ring Q is an optionally substituted aromatic ring or an optionally substituted non-aromatic heterocycle (wherein the non-aromatic heterocycle contains 2 or more heteroatoms);
A and L independently represent C, CH or N;
J represents a hydrocarbon group which may be substituted, a hydroxy group which may be substituted, a heterocyclic group which may be substituted or an amino group which may be substituted. ]
Or a salt thereof (excluding “4- [1- (9-anthrylcarbonyl) piperidin-4-yl] -2- (morpholin-4-ylcarbonyl) morpholine”).
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