WO2003104230A1 - 二環性ピリミジン誘導体 - Google Patents
二環性ピリミジン誘導体 Download PDFInfo
- Publication number
- WO2003104230A1 WO2003104230A1 PCT/JP2003/007200 JP0307200W WO03104230A1 WO 2003104230 A1 WO2003104230 A1 WO 2003104230A1 JP 0307200 W JP0307200 W JP 0307200W WO 03104230 A1 WO03104230 A1 WO 03104230A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- unsubstituted
- quaternary ammonium
- compound
- pyrimidine derivative
- Prior art date
Links
- -1 Bicyclic pyrimidine derivatives Chemical class 0.000 title claims abstract description 273
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 124
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 93
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 84
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 40
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 35
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 35
- 102100023698 C-C motif chemokine 17 Human genes 0.000 claims abstract description 32
- 101000978362 Homo sapiens C-C motif chemokine 17 Proteins 0.000 claims abstract description 31
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 208000026935 allergic disease Diseases 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 165
- 238000004519 manufacturing process Methods 0.000 claims description 76
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 58
- 125000006848 alicyclic heterocyclic group Chemical group 0.000 claims description 50
- 210000004027 cell Anatomy 0.000 claims description 46
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 102100036845 C-C motif chemokine 22 Human genes 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 230000000069 prophylactic effect Effects 0.000 claims description 11
- 125000002619 bicyclic group Chemical group 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 108010040471 CC Chemokines Proteins 0.000 claims description 5
- 102000001902 CC Chemokines Human genes 0.000 claims description 5
- 230000000172 allergic effect Effects 0.000 claims description 5
- 208000010668 atopic eczema Diseases 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 108010083701 Chemokine CCL22 Proteins 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 108010012236 Chemokines Proteins 0.000 claims description 2
- 102000019034 Chemokines Human genes 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 230000003285 pharmacodynamic effect Effects 0.000 claims 2
- 208000024556 Mendelian disease Diseases 0.000 claims 1
- 125000001453 quaternary ammonium group Chemical group 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 6
- 239000001257 hydrogen Substances 0.000 abstract description 5
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 4
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002054 transplantation Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 665
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 260
- 238000006243 chemical reaction Methods 0.000 description 229
- 239000000243 solution Substances 0.000 description 225
- 239000002904 solvent Substances 0.000 description 188
- 239000000203 mixture Substances 0.000 description 173
- 238000003786 synthesis reaction Methods 0.000 description 172
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 171
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 162
- 230000015572 biosynthetic process Effects 0.000 description 162
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 159
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 146
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 139
- 239000011541 reaction mixture Substances 0.000 description 92
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 82
- 239000012044 organic layer Substances 0.000 description 74
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 70
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 66
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 61
- 230000008569 process Effects 0.000 description 61
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 56
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 55
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 53
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 52
- 238000010898 silica gel chromatography Methods 0.000 description 49
- 238000004809 thin layer chromatography Methods 0.000 description 49
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 47
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 45
- 239000013078 crystal Substances 0.000 description 45
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 238000001914 filtration Methods 0.000 description 42
- 239000000706 filtrate Substances 0.000 description 41
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- 238000001816 cooling Methods 0.000 description 37
- 125000001424 substituent group Chemical group 0.000 description 35
- 238000012360 testing method Methods 0.000 description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 34
- 239000002253 acid Substances 0.000 description 34
- 239000002585 base Substances 0.000 description 33
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 33
- STXKJIIHKFGUCY-UHFFFAOYSA-N 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine Chemical compound C1=NC=C2CNCCC2=N1 STXKJIIHKFGUCY-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 32
- 230000027455 binding Effects 0.000 description 31
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 29
- 235000017557 sodium bicarbonate Nutrition 0.000 description 29
- 239000004793 Polystyrene Substances 0.000 description 28
- 229920002223 polystyrene Polymers 0.000 description 28
- 229910000029 sodium carbonate Inorganic materials 0.000 description 28
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- 239000000460 chlorine Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000725 suspension Substances 0.000 description 24
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- 238000010992 reflux Methods 0.000 description 23
- 239000008096 xylene Substances 0.000 description 23
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 22
- 229920001577 copolymer Polymers 0.000 description 22
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 21
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 18
- 239000012046 mixed solvent Substances 0.000 description 18
- 238000000844 transformation Methods 0.000 description 18
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 16
- 239000000427 antigen Substances 0.000 description 16
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- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 13
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- MYRTYDVEIRVNKP-UHFFFAOYSA-N divinylbenzene Substances C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 11
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- 125000003282 alkyl amino group Chemical group 0.000 description 10
- 229940125773 compound 10 Drugs 0.000 description 10
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- OQURWGJAWSLGQG-UHFFFAOYSA-N 1-isocyanatopropane Chemical compound CCCN=C=O OQURWGJAWSLGQG-UHFFFAOYSA-N 0.000 description 7
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- MDEUNLWIRLXZJC-UHFFFAOYSA-N 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine;hydrochloride Chemical compound Cl.C1NCCC2=NC(Cl)=NC(Cl)=C21 MDEUNLWIRLXZJC-UHFFFAOYSA-N 0.000 description 6
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- 125000002102 aryl alkyloxo group Chemical group 0.000 description 6
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 6
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
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- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- BNFFTDUFHKXVGG-UHFFFAOYSA-N tert-butyl 2h-pyrimidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CN=CC=C1 BNFFTDUFHKXVGG-UHFFFAOYSA-N 0.000 description 1
- FCMLWBBLOASUSO-UHFFFAOYSA-N tert-butyl 3-oxopiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(=O)C1 FCMLWBBLOASUSO-UHFFFAOYSA-N 0.000 description 1
- HYRSGTXIVIMOOX-UHFFFAOYSA-N tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1 HYRSGTXIVIMOOX-UHFFFAOYSA-N 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- JREYOWJEWZVAOR-UHFFFAOYSA-N triazanium;[3-methylbut-3-enoxy(oxido)phosphoryl] phosphate Chemical compound [NH4+].[NH4+].[NH4+].CC(=C)CCOP([O-])(=O)OP([O-])([O-])=O JREYOWJEWZVAOR-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 210000001944 turbinate Anatomy 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention provides an anti-inflammatory effect (for example, a cell infiltration inhibitory effect), thymus and activation-regulated chemokine [TARC; CC chemokine ligana 17 (CCL17)] and / or macrophage-derived chemokine [MDC; CC chemokine ligand 22 ( CCL22)], which is useful for the treatment and / or prevention of various diseases involving T cells such as allergic diseases and autoimmune diseases, or a pharmacologically acceptable bicyclic pyrimidine derivative thereof.
- TARC thymus and activation-regulated chemokine
- MDC macrophage-derived chemokine
- CCL22 macrophage-derived chemokine
- Bicyclic compounds containing a pyrimidine skeleton in their structure are disclosed as antipsychotics in WO 97/47601 and as metabotropic glutamate receptor 1 (mGluRl) antagonists in WO 2001/32632
- mGluRl metabotropic glutamate receptor 1
- WO2001 / 44246 discloses glycogen synthase kinase 3 (GSK3) inhibitors as International Publication WO2002 / 22601, International Publication WO2002 / 22602, International Publication WO2002 / 22604, and International Publication WO2002.
- TARC was discovered as a T cell migration factor [Journal of Biological Chemistry, 271: 21514 (1996)]
- MDC was discovered as a monocyte migration factor.
- TARC in particular, is produced from monocytes stimulated with Th2 cytokines and is therefore expected to be involved in allergic diseases [Journal of Biological Biology Chemistry]. , 271, 21514 (1996)], and subsequent analysis reports that both TARC and MDC are ligands for CCR4 [Journal of Biological Chemistry] Biological Chemistry), vol. 272, p. 15036 (1997), Journal of Biological Chemistry, vol. 273, p. 1764 (1998)].
- CCR4 is cloned as a receptor expressed on T cells and thymocytes, and is used for radiochemical and 'biophysical research communication' (Biochemical and Biophysical Research Communications, 218, 337 (1996)). ], And subsequent studies have reported that CCR4 is expressed mainly in T cells called the Th2 type [Journal of Experimental Medicine, Journal of Experimental Medicine, 187, 875. (1998), Journal of Immunology, 161 vol., 5027 (1998)].
- An object of the present invention is to have an anti-inflammatory effect (for example, a cell infiltration suppressing effect, etc.), a TARC and / or MDC function regulating effect (for example, a TARC and Z or MDC binding inhibition to T cells, etc.)
- Various diseases involving T cells such as allergic diseases, autoimmune diseases, rejection at the time of transplantation [e.g., asthma, allergic rhinitis, chronic rhinitis, eosinophilic sinusitis, eosinophilia rhinitis , Hay fever, conjunctivitis, atopic dermatitis, contact dermatitis, urticaria, psoriasis, cutaneous candidiasis, oral candidiasis, rheumatoid arthritis, various collagen diseases, systemic lupus erythematosus, constructiveren syndrome, organ transplantation Cell rejection, cancer, malignant lymphoma, leukemia, adult T-cell leukemia (ATL),
- the present invention relates to the following (1) to (43).
- n and n are the same or different and each represents an integer of 1 to 3, and m + n represents an integer of 4 or less;
- R 4 and R 5 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, Or unsubstituted aralkyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl Or a substituted or unsubstituted alicyclic heterocyclic alkyl, or R 4 and R 5 together with an adjacent nitrogen atom form a substituted or unsubstituted alicyclic heterocyclic group.
- R 4 and R 5 must not hydrogen atoms at the same time, when one of R 4 or R 5 is water atom, the other of R 4 or R 5 is a substituted or unsubstituted Pirazo Le - 3 I le and substituted or unsubstituted 1, 2, 4 is not in one Toriazoru 3 I le) represents,
- X represents a hydrogen atom, substituted or unsubstituted lower alkyl or halogen, and each X may be the same or different;
- R 8 and R 9 are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or Unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl or substituted Or represents an unsubstituted alicyclic heterocyclic alkyl),
- r represents an integer of 0 to 4,
- s represents 0 to a replaceable number
- G represents a nitrogen atom, CH, C (OH), C (CO 2 H) or C (CN),
- G is a nitrogen atom
- q represents an integer of 1-2
- G is CH, C (OH),
- R 6 represents a hydrogen atom, a substituted or unsubstituted lower alkyl or a substituted or unsubstituted cycloalkyl) or
- R 6A is as defined above for R 6
- bonds to G on the left side of each definition
- X A the force represents lower alkyl or halogen substituted or unsubstituted ,, or represent two X A is together such connection Okiso on the same carbon atom, each of X A when s is 2 or more May be the same or different,
- X a has the same meaning as X, and when r is 1 or more, each ⁇ «may be the same or different;
- R 8 A and R 9 A are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted Or unsubstituted aralkyl, substituted or unsubstituted Substituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic bicyclic alkyl, substituted or unsubstituted alicyclic heterocyclic Ring alkyl, amino lower alkyl or substituted or unsubstituted amidino), hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted cycloalkyl, substitute
- sb, rb, X B, and R 7B are the respective s, r, XA, and Xa and R7 synonymous,
- Q represents one 0—, one S—, one CH 2 — or one NR 6B — (wherein R 6B has the same meaning as R 6 above) or
- pc, rc, Ec, Xd and R6C are the respective p, r, E, X, and X «and R 6 synonymous,
- R 7C represents —NR 9 (wherein R 8 and R 9 have the same meanings as described above), a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group,
- Y is a single bond, 10— or 1 NRSD— (wherein, RSD has the same meaning as R 6 above) Represents], represents
- R 6D is as defined above
- R 6D has the same meaning as defined above
- R 6D is as defined above
- R 3 is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Represents a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl or a substituted or unsubstituted alicyclic heterocyclic alkyl.
- R 3 is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted Or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or Is an unsubstituted aromatic heterocyclic alkyl, a substituted or unsubstituted alicyclic heterocyclic alkyl or one NR 8B R 9B (wherein, R 8B and R 9B have the same meanings as R 8 and R 9 , respectively)
- R2 is - B- (CX 2) P - R7 (wherein, p, X, B and R 7 have the same meanings as defined above) according to any one of the above (1) to (5) Or a quaternary ammonium salt thereof or a pharmacologically acceptable salt thereof.
- R 2 is the formula (II)
- R 3 is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group
- R 2 is the formula (III)
- Pharmacologically acceptable salts thereof thereof.
- R 2 is the formula (IV)
- R 3 is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group
- the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof according to any one of the above (23) to (26).
- a quaternary ammonium salt is substituted with Z-Hal (where Z is a substituted or unsubstituted lower alkyl or substituted or unsubstituted) at any nitrogen atom in R 7 , R 7B , R 10 or R 7C .
- Hal represents halogen
- a medicament comprising, as an active ingredient, the bicyclic pyrimidine derivative according to any of the above (1) to (27), a quaternary ammonium salt thereof, or a pharmaceutically acceptable salt thereof.
- An anti-inflammatory agent comprising, as an active ingredient, the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof according to any of the above (1) to (27).
- thvmus and activation-regulated comprising the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof as an active ingredient according to any one of the above (1) to (27).
- a function regulator of chemokine [TARC; CC cnemoiane Hgand 17 (CCL17)] and / or macrophage-derived chemokine [MDC; CC chemokine Hgand 22 (CCL22)].
- TARC (CCL17) containing the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof as an active ingredient according to any of (1) to (27) above, and A therapeutic and / or prophylactic agent for a disease involving Z or MDC (CCL22).
- T cells containing the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof as an active ingredient according to any one of the above (1) to (27) Disease treatment and Z or prophylactic agents.
- An allergic monopathic disease comprising as an active ingredient the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (27).
- a therapeutic and / or prophylactic agent comprising as an active ingredient the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (27).
- a method comprising administering an effective amount of the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (27).
- An effective amount of the bicyclic pyrimidine derivative or the quaternary ammonium salt thereof or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (27) is administered.
- the lower alkyl moiety of lower alkyl and lower alkoxy includes, for example, straight-chain or branched alkyl having 1 to 10 carbon atoms, specifically, methyl, ethyl, propanol, isopropyl, butyl, isobutyl, sec— Butyl, tert-butyl, pentyl, isopentinole, neopentinole, tert-pentinole, hexinole, isohexinole, heptyl, octyl, isootatyl, nonyl, decyl and the like.
- cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, specifically, cyclopropinole, cycloptinole, cyclopentinole, cyclohexinole, cycloheptyl, cyclooctyl and the like.
- alkenyl for example, straight-chain, branched or cyclic alkenyl having 2 to 8 carbon atoms, specifically bier, aryl, 1-propenyl, butenyl, pentenyl, Hexeninole, hepteninole, octeninole, cyclopenteninole, cyclohexeninole,
- lower alkynyl for example, straight-chain or branched alkynyl having 2 to 6 carbon atoms, specifically, ethur, 1-propier, 2-propiel, butynyl, pentynyl, hexynyl, heptyl, otatur , Propanoregil and the like.
- the aryl portion of aryl and arylcarbonyl includes, for example, monocyclic, bicyclic or tricyclic aryl having 6 to 14 carbon atoms, specifically phenyl, naphthyl , Indenyl, anthranil and the like.
- the alkylene portion of aralkyl, aromatic heterocyclic alkyl and alicyclic heterocyclic alkyl has the same meaning as the above-mentioned lower alkyl (i) except that one hydrogen atom is removed, and is the alkylamino of the imino lower alkyl.
- the portion has the same meaning as that of the lower alkyl G) except that two hydrogen atoms on the same carbon atom are removed.
- the aryl moiety of aralkyl includes, in addition to the definition of aryl (V) above, for example, a bicyclic fused ring group fused to cycloalkyl, specifically, indanyl, 1, 2, 3, 4 -Tetrahydronaphthinole, 6,7,8,9-tetrahydro-15H-benzocyclyl heptyl and the like.
- aromatic heterocyclic group and the aromatic heterocyclic group moiety of the aromatic heterocyclic alkyl for example, a 5- or 6-membered member containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom
- a bicyclic or tricyclic condensed 3- to 8-membered condensed aromatic ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom Heterocyclic groups and the like.
- pyridyl pyrazur, pyrimidinyl, pyridazinyl, benzoimidazolyl, 2-oxobenzoimidazolinole, benzotriazolinole, benzofurinole, benzochenolinole, pricinole.
- the alicyclic heterocyclic group and the alicyclic heterocyclic group portion of the alicyclic heterocyclic alkyl include, for example, a 5-membered or 6-membered atom containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
- a cyclic heterocyclic group having a spiro structure in which a 3- to 8-membered ring is bonded, a nitrogen atom
- Examples include an alicyclic heterocyclic group containing at least one atom selected from an oxygen atom and a sulfur atom.
- Specific examples include pyrrolidinyl, 2-oxopyrrolidinyl, and 2,5-dioxopyrrolidinyl.
- alicyclic heterocyclic group formed together with the adjacent nitrogen atom for example, a 5- or 6-membered monocyclic alicyclic heterocyclic group containing at least one nitrogen atom (The monocyclic alicyclic heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom), and at least one bicyclic or tricyclic fused 3- to 8-membered ring.
- a condensed alicyclic heterocyclic group containing a nitrogen atom may contain another nitrogen atom, an oxygen atom or a sulfur atom; Specifically, tetrahydropyridyl, indolinyl, isoindolinyl, pyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidino, homopiperidino, piperazinyl, homopiperazininole, monoreholino, thiomorpholino, perhydroroazepinorele Roazoshi cycloalkenyl, Tetorahi Dorokinoriru, Tetorahi Doroisokinoriru, Okutahi Dorokinori Le, and the like.
- heterocyclic group formed together with R 3 and an adjacent nitrogen atom for example, a 5- or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group) (A heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom.), A condensed bicyclic or tricyclic condensed 3- to 8-membered ring containing at least one nitrogen atom Cyclic heterocyclic group (the condensed heterocyclic group may contain another nitrogen atom, oxygen atom or sulfur atom) and the like. Specific examples include pyridyl, tetrahydropyridyl, and indolinyl.
- Halogen represents each atom of fluorine, chlorine, and bromine and iodine.
- substituents in the substituted lower alkyl and substituted lower alkoxy the same or different, for example, having 1 to 3 substituents, cycloalkyl, lower alkanoyl, substituted lower alkanoyl (substituent (a) in the substituted lower alkanol) are the same or different and include, for example, halogens having 1 to 3 substituents, etc.), lower alkoxy, substituted lower alkoxy [the substituent in the substituted lower alkoxy is the substituent (a) in the substituted lower alkanol.
- aryloxy, substituted aryloxy are the same or different and are, for example, 1 to 3 substituents, cycloalkyl, lower alkanoyl, substituted lower alkanols]
- the substituent in the lower alkanol is the same as the above-mentioned substituted lower alkanol.
- lower alkoxy, substituted lower alkoxy [the substituent in the substituted lower alkoxy is the same as the substituent (a) in the above substituted lower alkanol], aryloxy, aralkyloxy, mono or Di-lower alkylamino, substituted mono- or di-lower alkylamino [Substituents (c) in the lower alkyl portion of the substituted mono- or di-lower alkylamino may be the same or different and include, for example, 1-3 substituents, halogen, hydroxy, carboxy.
- aryl part of aryl, aryloxy and aralkyloxy shown here, cycloalkyl, halogen, aromatic heterocyclic group, alicyclic heterocyclic group and lower alkyl, lower alkanol, lower alkoxy, lower alkanoyloxy, Lower alkoxycarbol, lower alkoxycarbonylamino, lower alkanoylamino, lower alkylthio, lower alkylsulfonyl and lower alkylsulfur
- the lower alkyl portion of -aryl is as defined above for aryl (v), cycloalkyl Gi), halogen ( ⁇ ), aromatic heterocyclic group (viii), alicyclic heterocyclic group (ix) and lower alkyl (
- the alkylene moiety of the aralkyloxy has the same meaning as that of the lower alkyl (i) except that one hydrogen atom is removed from the monoalkyl or di-lower alkylamino, mono- or di-lower alkylaminocarbonyl, and mono- or di-alkyl.
- the lower alkyl moiety of lower alkylaminocarbonylcarbonyl is the same as the lower alkyl (i), and the two lower alkyl moieties of di-lower alkylamino, di-lower alkylaminocarbonyl and di-lower alkylaminocarbonyloxy are They may be the same or different.
- Examples include a cyclic group, an aromatic heterocyclic alkyl, a substituted aromatic heterocyclic alkyl, an alicyclic heterocyclic alkyl and a substituted alicyclic heterocyclic alkyl.
- the alkylene part of the formula heterocyclic group, aralkyl, aromatic heterocyclic alkyl and alicyclic heterocyclic alkyl, and the aryl part of aralkyl are the above-mentioned lower alkyl (0, lower alkenyl (iii), aryl (v), aromatic It has the same meaning as the heterocyclic group (viii), the alicyclic heterocyclic group x), the alkylene part (vi) of aralkyl and the aryl part (vii) of aralkyl.
- substitute aryl, substitute aralkyl, replace Substituents in the aromatic heterocyclic group, the substituted alicyclic heterocyclic group, the substituted aromatic heterocyclic alkyl and the substituted aromatic heterocyclic alkyl may be the same or different, for example, lower alkyl having 1 to 3 substituents.
- the lower alkyl is the same as the lower alkyl (i)]
- lower alkoxy [the lower alkyl part of the lower alkoxy is the same as the lower alkyl (i)]
- halogen is the halogen (xii)
- the substituents in the substituted lower alkyl are the same or different and have, for example, 1 to 3 substituents, halogen [the halogen is the same as the above-mentioned halogen (xii)], and hydroxy.
- lower alkoxy [the lower alkyl portion of the lower alkoxy has the same meaning as the above lower alkyl ()], and cyano.
- substituents in the substituted amidino (XV) are the same or different and include, for example, lower alkyl having 1 or 2 substituents [the lower alkyl has the same meaning as the above lower alkyl] and cyano.
- the number that can be substituted refers to a number that can be substituted in the structure of the compound, and s is specifically 0 to [6+ (qx 2)] (where q is as defined above) Sb specifically represents an integer of 0 to 7, and among them, an integer of 0 to 3 is preferable.
- compound (I) the compound represented by the formula (I) is referred to as compound (I).
- compound (I) the compound represented by the formula (I).
- the quaternary ammonium salt of the compound (I) may be, for example, one to three nitrogen atoms among the nitrogen atoms in these structures, for example, Z—Hal (wherein, Z and Hal are as defined above, respectively) May be any quaternary ammonium salt formed by the addition of R 7 , R 7B , R 10 or R 7C in compound (I).
- -NR8R 9 or a NR 8A R 8 and R 9 or R 8A and R 9A are nitrogen atoms that are bound in the R 9A,
- R 7 , R 7B or R 7C is a substituted or unsubstituted alicyclic heterocyclic group (the alicyclic heterocyclic group is at least one of A nitrogen atom in the alicyclic heterocyclic group having the same meaning as defined above),
- R 1G is a substituted or unsubstituted alicyclic heterocyclic group (the alicyclic heterocyclic group is an alicyclic group containing at least one nitrogen atom in the definition of the alicyclic heterocyclic group (ix). Synonymous with the formula heterocyclic group) or ft-substituted or unsubstituted alicyclic heterocyclic alkyl (the alicyclic heterocyclic alkyl) The alicyclic heterocyclic group moiety of the alkyl is the same as the alicyclic heterocyclic group containing at least one nitrogen atom in the definition of the alicyclic heterocyclic group Gx)).
- Z_Hal (wherein Z and ⁇ 3 ⁇ are as defined above) is added to the unsubstituted alicyclic heterocyclic group or the substituted or unsubstituted alicyclic heterocyclic alkyl.
- the quaternary ammonium salt formed is preferably [N + HaTZ— (wherein Z and Hal are as defined above)] and the like.
- a non-toxic water-soluble salt is preferable, and for example, inorganic acids such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like are preferable.
- Organic salts such as salt, benzenesulfonate, benzoate, citrate, fumarate, dalconate, lactate, maleate, malate, oxalate, methanesulfonate, tartrate Acid addition salts, such as sodium salts, alkaline metal salts such as sodium salts, potassium salts, etc., alkaline earth metal salts such as magnesium salts, calcium salts, etc., metal salts such as aluminum salts, zinc salts, etc., ammonium, tetramethylammonium Organic salts such as ammonium salts, morpholine addition salts, piperidine addition salts, etc., or glycine addition salts, phenylalayun addition salts, lysine addition salts, aspartic acid addition salts, Amino acid addition salts such as motor Min acid addition salts.
- Acid addition salts such as sodium salts, alkaline metal salts such as sodium salts, potassium salts, etc., alkaline earth metal
- Compound (I) can be obtained, for example, by the following production methods 1 to 15. Manufacturing method 1:
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- tetrahydrofuran, dioxane, 1,2-dimethoxetane, benzene, tonolene, xylene , Dimethinolehonoremamide, dimethylacetoamide, N-methinolepyrrolidone, methanolone, ethanolanol, n-propanol, isopropyl alcohol and the like can be used alone or in combination, and among them, ethanol is preferable.
- the base examples include various alkali metals such as sodium methoxide, sodium methoxide and potassium tert-butoxide, and alkaline earth metal alkoxides.
- sodium methoxide or sodium methoxide is used. .
- the reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably between 50 ° C and 100 ° C, usually for 1 hour to 60 hours.
- Compound (VII) can be obtained by reacting compound (VI) obtained in step 1 with an excess amount of a chlorinating agent in a solvent inert to the reaction or in the absence of a solvent.
- a chlorinating agent for example, phosphorus oxychloride, phosphorus pentachloride and the like are used.
- the solvent inert to the reaction may be any solvent that is inert to the reaction, and is not particularly limited.
- solvent examples thereof include 1,2-dichloroethane, tetrahydrofuran, dioxane, 1,2-dimethoxetane, Chlorophonorem, benzene, toluene, xylene, ethyl ethyl diphosphate, triethylamine, pyridine, N, N-dimethylaniline and the like can be used alone or in combination.
- the reaction is carried out at a temperature between 0 ° C and the boiling point of the solvent, preferably at a temperature between 50 ° C and 110 ° C, usually for 1 hour to 24 hours.
- Compound (VII) obtained in Step 2 is reacted with a solvent inert to the reaction in the presence or absence of 1 to 10 equivalents of a base, in an amount of 1 to 6 equivalents, preferably 2 to 4 equivalents of chloroform.
- the solvent inert to the reaction may be any solvent that is inert to the reaction.
- 1,2-dichloroethane, chloroform, tetrahydrofuran, dioxane, 1,2-dimethyloxetane, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide , N-methylpyrrolidone, dimethylsulfoxide, acetonitrile and the like can be used alone or as a mixture thereof, and among them, 1,2-dichloroethane is preferable.
- the base for example, triethylamine, diisopropylethylamine and the like are used.
- the reaction is carried out at a temperature between room temperature and 120 ° C, preferably between 50 ° C and: 100 ° C, usually for 1 hour to 48 hours.
- Compound (IX) can be obtained by treating compound (VIII) obtained in step 3 with an alcohol.
- Examples of the alcohol include methanol, ethanol, and ⁇ -prono ⁇ . Nore, isopropyl alcohol, ⁇ -butanol and the like are used, and these are usually used also as a solvent.
- the reaction is carried out at a temperature between room temperature and the boiling point of the solvent, preferably at a temperature between 50 ° C and the boiling point of the solvent, usually for 10 minutes to 10 hours.
- Compound (X) is commercially available or, for example, Comprehensive Organic Transformations, second edition, by RC Larock, John's Wiley-and-Sounds, Inc. obtained according to the method described in (J 0 hn Wiley & Sons Inc. ) (1999 years) and the like.
- bases include organic compounds such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] indene-7-ene (DBU), N, N-dimethylethylamine, pyridine and quinoline.
- organic compounds such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] indene-7-ene (DBU), N, N-dimethylethylamine, pyridine and quinoline.
- Inorganic bases such as base, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, lithium diisopropylamide (LDA), sodium hydride, potassium hydride, and Amberlyst A -21 (made by Rohm and Haas), A basic anion-exchange resin such as AG1-X8 (manufactured by Bio-Rad), a base supported on a solid phase such as morpholinomethyl polystyrene, and the like are used, and among them, triethylamine is preferable.
- base potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, lithium diisopropylamide (LDA), sodium hydride, potassium hydride, and Amberlyst A -21 (made by Rohm and Haas)
- a basic anion-exchange resin such as AG1-X8 (manufactured by Bio-Ra
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, dioxane, 1,2 2-Dimethoxetane, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, water, etc. can be used alone or in combination.
- dichloromethane is preferred.
- the reaction is carried out at a temperature between 0 ° C and 100 ° C, preferably between room temperature and 50 ° C, usually for 1 hour to 1 week.
- Step 5 Compound (XI) obtained in Step 5 is reacted with a solvent inert to the reaction in the presence or absence of 1 equivalent to a large excess, preferably 1 equivalent to 10 equivalents of a base, 1 equivalent to a large excess, Preferably, 1 to 3 equivalents of R 4 R 5 NH (wherein R 4 and R 5 are as defined above: compound (XII)) are reacted to obtain compound (XIII). It can.
- Compound (XII) is commercially available or, for example, by Comprehensive 'Organic Transform anons, second edition, RC Larock, John Wiley & Sons. It can be obtained according to the method described in Incorporated (John Wiley & Sons Inc.) (1999).
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- examples thereof include tetrahydrofuran, dioxane, 1,2-dimethoxetane, and jetinole ethereol.
- Diisopropinolate ether, benzene, tonolene, xylene, ethinole acetate, acetonitrile, dichloromethane, chlorophonolem, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, pyridine And the like can be used alone or as a mixture thereof.
- tetrahydrofuran, dichloromethane, chloroform, and a mixed solvent thereof are preferable.
- the base examples include organic bases such as triethylamine, diisopropylethylamine, DBU, N, N_dimethylaniline, pyridine, and quinoline, potassium carbonate, Inorganic bases such as sodium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium hydride, potassium hydride, lithium hydride, Amberlyst A-21 Basic anion exchange resins such as AG-X8 (manufactured by Bio-Rad) and bases supported on a solid phase such as polyvinylinolepyridine and morpholinomethyl polystyrene. Among them, triethylamine is used. preferable.
- organic bases such as triethylamine, diisopropylethylamine, DBU, N, N_dimethylaniline, pyridine, and quinoline
- potassium carbonate Inorganic bases such as sodium carbonate, lithium carbonate, sodium
- the reaction is carried out at a temperature between 0 ° C and 100 ° C, preferably at a temperature between room temperature and 50 ° C, usually for 1 hour to 48 hours.
- Compound (XIII) obtained in Step 6 is reacted with a solvent inert to the reaction in an amount of 1 equivalent to a large excess, preferably in the presence or absence of 1 equivalent to 10 equivalents of a base, 1 equivalent to a large excess, Compound (IA) can be obtained by reacting preferably 1 to 3 equivalents of compound (XIV).
- Compound (XIV) may be commercially available or, for example, by Comprehensive Organic Transformations, second edition, by RC Larock, by Chillon Wylie -Obtained according to the method described in John Wiley & Sons Inc. (1999).
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include tetrahydrofuran, dioxane, 1,2-dimethoxetane, and diisopropinoleate. Benzene, tosoleene, xylene, ethinole acetate acetate, acetonitrile, chlorophonolem, 1,2-dichloromethane, dimethinole formamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, pyridine, etc., or a mixture thereof. Among them, dioxane, chloroform or a mixed solvent thereof is preferable.
- organic bases such as triethylamine, diisopropylethylamine, DBU, N, N-dimethylaniline, pyridine, quinoline, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydrogencarbonate, potassium hydroxide, Inorganic bases such as sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium hydride, potassium hydride, lithium hydride, Amberlyst A-21 (manufactured by Rohmand Haas), AG1-X8 (manufactured by Bio-Rad) And a base supported on a solid phase such as polybutylpyridine and morpholinomethylpolystyrene. Of these, triethylamine is preferable.
- the reaction is carried out at a temperature between room temperature and the boiling point of the solvent, preferably at a temperature between 50 ° C and 100 ° C, usually for 1 hour to 1 week.
- R 3 is R 3b (wherein, R 3b is a substituted or unsubstituted group having one CH 2 — at the binding site in the definition of R 3 above.
- Lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic alkyl or substituted or unsubstituted alicyclic heterocyclic alkyl (IB) can be obtained, for example, by the following production method.
- R 2 R 3b, R 4, R 5, m and n have the same meanings as defined above, R 3 w before Symbol R 3 b from the end of - is c3 ⁇ 4- minus the synonymous )
- reducing agent for example, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, borohydride supported on a solid phase, and the like are used.
- the solvent inert to the reaction may be any solvent that is inert to the reaction.
- the reaction is carried out at a temperature between 0 ° C and 100 ° C, preferably at a temperature between room temperature and 50 ° C, usually for 10 minutes to 72 hours.
- Compound (XVII) can be obtained by reacting compound (XVI) obtained in step 8 with compound (II) in the same manner as in the method shown in step 6 of production method 1.
- Preferred reaction conditions and a method for obtaining the compound (XII) are the same as those shown in Step 6 of Production Method 1.
- Compound (IB) can be obtained by reacting compound (XVII) obtained in step 9 with compound (XIV) in the same manner as in the method shown in step 7 of production method 1.
- Preferred reaction conditions and a method for obtaining the compound (XIV) are the same as those shown in Step 7 of Production Method 1.
- the compound (IC) in which A is a single bond and R 3 is a hydrogen atom is, for example, R 3 force S tert-butyl in the compound (IA) and A a force It can be obtained from the compound (IA-a) which is S—OC (20) —by the following production method.
- Compound (IC) can be obtained by treating compound (IA-a) obtained in Production Method 1 with an excess amount of an acid in a solvent or without a solvent.
- an acid for example, a carboxylic acid such as trifluoroacetic acid, a mineral acid such as hydrochloric acid, and a sulfonic acid such as trifluoromethanesulfonic acid and benzenesulfonic acid can be used. Among them, trifluoroacetic acid or hydrochloric acid is preferable.
- the solvent is not particularly limited.
- the reaction is carried out at a temperature between 0 ° C and 100 ° C, preferably at a temperature between 0 ° C and 50 ° C, usually for 10 minutes to 24 hours.
- the compound (IA) obtained by the production method 1 can also be obtained from the compound (IC) obtained by the production method 3 by the following production method.
- Compound (IA) can be obtained by reacting compound (IC) obtained in step 11 of production method 3 with compound (X) in the same manner as in the method shown in step 5 of production method 1. it can. Preferred reaction conditions and a method for obtaining the compound (X) are the same as those described in Production method 1, step 5.
- A is a single bond, and (wherein, R 3 a is synonymous with the) R 3 is R 3 a, Compound (ID), the method for producing 3 Step 1
- the compound (IC) obtained in 1 can be obtained by the following production method.
- Compound (IC) obtained in Step 11 of Production Method 3 is converted into a solvent inert to the reaction in an amount of 1 equivalent to excess, preferably 1 equivalent to 5 equivalents of a base, 1 equivalent to excess,
- the compound (ID) can be obtained by reacting with 1 to 5 equivalents of the compound (XVin).
- the solvent inert to the reaction may be any solvent which is inert to the reaction, and is not particularly limited. Examples thereof include dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide, and the like. Dimethylacetamide, N-methinolepyrrolidone, dimethylsulfoxide, tetrahydrofuran, dioxane, geethylether, diisopropinoleatenole, benzene, toluene, xylene, etinoleacetate, acetone, pyridine, etc. are used alone or in combination. Among them, tetrahydrofuran, dimethylformamide or dimethylsulfoxide is preferred.
- the base examples include inorganic bases such as potassium carbonate, sodium carbonate, lithium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, triethylamine, and the like.
- Organic bases such as diisopropylethylamine and DBU, basic anion exchange resins such as Amberlyst A-21 (manufactured by Rohm and Haas), AG1-X8 (manufactured by Bio-Rad), and solid phases such as morpholinomethyl polystyrene A base or the like supported on a carbon dioxide is used, and among them, carbon dioxide lime is preferable.
- reaction temperature and the required time vary depending on the reactivity of the compound (XVIII), but the reaction is usually carried out at a temperature between 0 ° C and the boiling point of the solvent, preferably at a temperature between room temperature and 120 ° C for 10 minutes. Q ⁇ 100 hours.
- R 3 a is R, if a substituted or unsubstituted Ariru or substituted or unsubstituted aromatic heterocyclic group, the reaction allowed to coexist catalytic amount of a metal complex may be promoting .
- the metal complex examples include a zero-valent palladium complex such as tris (dibenzylideneacetone) dipalladium (0) (Pd 2 (dba) 3 ), triphenylphosphine, triptylphosphine, 2,2′-bis (diphenylphosphino)
- a divalent palladium complex such as palladium (II) acetate (Pd (OAc) 2 ) can be used in the presence of a ligand such as 1,1,1′-binaphthyl (BINAP).
- the solvent and base used are the same as described above, but the solvent is preferably toluene, xylene or dimethylformamide, and the base is preferably potassium tert-butoxide, sodium tert-butoxide or phosphoric acid. A realm is preferred.
- the reaction is carried out at a temperature between room temperature and 150 ° C, preferably between 50 ° C and 120 ° C, usually for 1 hour to 100 hours.
- compounds (I), compounds (IF) having carboxy as a substituent in II 1 , R 2 or R 3 (the position and number of substitution of the carboxy are not particularly limited, but I 1 , R 2 or according to the definition of each group in R 3), in addition to the method shown in production method 1, manufacturing method 1, the production method 2, the compound obtained according to the process described in preparation 3 or preparation 4 (I ), II 1 , R 2 or R 3 as a substituent at a corresponding site in each of lower alkoxycarbol (the lower alkyl portion of the lower alkoxycarbonyl has the same meaning as the lower alkyl (i);
- the substitution position and the number of substitution of the alkoxycarbonyl are the same as the corresponding carboxy, and when the number of substitution is 2 or more, the lower alkyl moiety of the lower alkoxycarbonyl may be the same or different.
- IE or Can be obtained by the following method.
- Compound (IE) obtained in Production Method 1, Production Method 2 or Production Method 4 is replaced with the lower alkoxycarbonyl in II 1 , R 2 or R 3 with respect to Compound (IE) in a protic solvent.
- Compound (IF) can be obtained by treating with XI equivalent to excess base.
- the base examples include inorganic bases such as carbonated sodium, sodium carbonate, sodium hydrogencarbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, and Amberlyst A-21 (Rhone & Haas) And basic anion-exchange resins such as AG1-X8 (manufactured by Biorad) and the like, and among them, sodium hydroxide or AG1-X8 is preferable.
- inorganic bases such as carbonated sodium, sodium carbonate, sodium hydrogencarbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, and Amberlyst A-21 (Rhone & Haas)
- basic anion-exchange resins such as AG1-X8 (manufactured by Biorad) and the like, and among them, sodium hydroxide or AG1-X8 is preferable.
- protic solvent is not particularly limited, for example, methanol, ethanol, n -Propanol, isopropyl alcohol, n-butanol, water, etc. can be used alone or as a mixture thereof.
- the reaction is carried out at a temperature between 0 ° C and 100 ° C, preferably between 0 ° C and 50 ° C, usually for 10 minutes to 72 hours.
- the compound (IE) is replaced with the compound (IE) in the same manner as in the method shown in Step 11 of Production Method 3. IF).
- the reaction can be carried out by appropriately combining the above two methods.
- R 7 Ca among the definition of the R 7C, in one NR 8 R 9 (wherein, R 8 and R 9 have the same meanings as described above, respectively, or a substituted or unsubstituted alicyclic group bonded to the adjacent group through a nitrogen atom.] (XIV-a) and
- V is lower alkylsulfonyloxy (the lower alkyl part of the lower alkylsulfonyloxy is the same as the lower alkyl (i)), substituted or unsubstituted arylsulfonyloxy [of the arylsulfonyloxy]
- the aryl moiety is the same as the aryl (V)
- the substituted arylsulfonyloxy is the same or different, for example, a halogen having 1 to 3 substituents (the halogen is the same as the halogen (xii)).
- A) lower alkyl the lower alkyl is the same as the above-mentioned lower alkyl (the same as
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- tetrahydrofuran, dioxane, getyl ether, diisopropyl ether, benzene, tonylene, xylene, acetic acid Ethynole, acetonitrile, dichloromethane, chlorophonolem, dichloroethane, dimethinoleformamide, dimethylacetoamide, N-methylpyrrolidone, dimethylsulfoxide, pyridine, etc. can be used alone or in combination, and among them, dichloromethane Is preferred.
- Examples of the base include organic bases such as triethylamine, diisopropylethylamine, DBU, N, N-dimethylaerin, pyridine, and quinoline, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydroxide, and hydroxide.
- organic bases such as triethylamine, diisopropylethylamine, DBU, N, N-dimethylaerin, pyridine, and quinoline
- potassium carbonate sodium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydroxide, and hydroxide.
- Inorganic bases such as sodium, lithium hydroxide and potassium tert-butoxide; basic anion-exchange resins such as Amberlyst A-21 (manufactured by Rohm and Haas); AG1-X8 (manufactured by Bio-Rad); polyvinylpyridine; A base supported on a solid phase such as morpholinomethyl polystyrene or the like is used, and among them, triethylamine is preferable.
- the sulfonic acid halide include methanesulfonylinochloride, benzenesulfonyl chloride, and ⁇ -toluenesulfoyl chloride.
- sulfonic anhydride examples include methanesulfonic anhydride and anhydrous methanesulfonic anhydride. Toluenesulfonic acid and the like are used, and among them, methanesulfonyl chloride is preferable. .
- the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably between 0 ° C and 50 ° C, usually for 1 hour to 48 hours.
- Step 16 Compound (XX-a) or compound (XX-b) obtained in step 15 is mixed with a solvent inert to the reaction in the presence or absence of 1 equivalent to a large excess, preferably 1 equivalent to 10 equivalents of a base. By reacting with 1 to 10 equivalents, preferably 2 to 5 equivalents of compound (XXI) in the presence, compound (XXII-a) or compound (XXII-b) can be obtained, respectively.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- examples thereof include tetrahydrofuran, dioxane, dimethyl ether, diisopropinoleether, benzene, and the like. Tonolen, xylene, ethinole acetate, acetonitrile, dichloromethane, chlorohonolem, dichloroethane, dimethinoleformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, pyridine, etc. can be used alone or in combination. Among them, tetrahydrofuran, black form and mixed solvents thereof are preferred.
- the base examples include organic bases such as triethylamine, diisopropylethylamine, DBU, N, N-dimethylaniline, pyridine, and quinoline, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen carbonate, potassium hydroxide, and hydroxide.
- organic bases such as sodium, lithium hydroxide and potassium tert-butoxide; basic ion exchange resins such as Amberlist A-21 (manufactured by Rohm and Haas); AG1-X8 (manufactured by Bio-Rad); poly Bases supported on a solid phase such as vinylinolepyridine and morpholinomethylpolystyrene are used, and polyvinyl pyridine is preferable.
- the reaction is carried out at a temperature between room temperature and 200 ° C, preferably at a temperature between 50 ° C and 100 ° C, usually for 1 hour to 100 hours.
- compound (XIV-a) or compound (XIV-b) can be obtained.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include dichloromethane, chloroform, dichloroethane, dimethylformamide, and dimethylacetamide.
- N-methylpyrrolidone dimethyl sulfoxide, tetrahydrofuran, dioxane, getinoleatenole, diisopropylatenole, benzene, tonolene, xylene, etinoleacetate, acetonitrile, water, etc., alone or in combination. It can be used, of which dichloromethane is preferred.
- the acid for example, a carboxylic acid such as trifluoroacetic acid, a mineral acid such as hydrochloric acid, and a sulfonic acid such as trifluoromethanesulfonic acid and benzenesulfonic acid can be used. Among them, trifluoroacetic acid or hydrochloric acid is preferable.
- the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably at a temperature between 0 ° C and 50 ° C, usually for about 1 hour to 48 hours.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include dichloromethane, chloroform, dichloroethane, dimethylformamide, and dimethylacetamide.
- sodium triacetoxyborohydride for example, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, etc., or those in which they are supported on a solid phase can be used.
- sodium triacetoxyborohydride is used. preferable.
- titanium tetraisopropoxide titanium tetrachloride, boron trifluoride and the like can be used, and among them, titanium tetraisopropoxide is preferable.
- the reaction is carried out at a temperature between 0 ° C and: 100 ° C, preferably between 0 ° C and 50 ° C, usually for 1 hour to 48 hours.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- Examples thereof include dichloromethane, chloroform, dichloroethane, dimethylformamide, and dimethylacetamide. , N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, dioxane, getyl ether, diisopropyl ether, benzene, tonolene, xylene, ethyl acetate, acetonitrile, water, etc., alone or in combination And dichloromethane is particularly preferred.
- a carboxylic acid such as trifluoroacetic acid, a mineral acid such as hydrochloric acid, and a sulfonic acid such as trifluoromethanesulfonic acid and benzenesulfonic acid can be used.
- a carboxylic acid such as trifluoroacetic acid, a mineral acid such as hydrochloric acid, and a sulfonic acid such as trifluoromethanesulfonic acid and benzenesulfonic acid
- trifluoroacetic acid or hydrochloric acid is preferable.
- the reaction is carried out at a temperature between 0 ° C. and 150 ° C., preferably at a temperature between 0 ° (: and 50 ° C.) and is usually completed in 1 hour to 48 hours.
- q, s, X A and X a have the same meanings as described above, respectively, and Riob is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, of the above-mentioned Rio definitions.
- Substituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocycle Represents a group, substituted or unsubstituted aromatic heterocyclic alkyl or substituted or unsubstituted alicyclic heterocyclic alkyl, and ra represents an integer of 1 to 4.
- Rioc is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, among the definitions of Rio above.
- XIV-e is a commercially available product, or Comprehensive ⁇ Organic ⁇ Transformations Second Edition
- R 10d is a carbon atom of a bonding part from each alkylene moiety in the definition of R 10c .
- Compound (XXV) is reacted with 1 to 5 equivalents of compound (XXVI) or compound (XXVIII) in a solvent inert to the reaction in the presence of 1 to 10 equivalents of a reducing agent to give Compound (XXVII-d) or compound (XXVII-e) can be obtained.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- Examples include dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, dimethyl ether, Diisopropyl ether, benzene, toluene, xylene and the like can be used alone or in combination. Among them, dichloroethane is preferable.
- sodium triacetoxyborohydride for example, sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, etc., or those in which they are supported on a solid phase can be used.
- sodium triacetoxyborohydride is used. preferable.
- the reaction is carried out at a temperature between 0 ° C and: 100 ° C, preferably between 0 ° C and 50 ° C, usually for 1 hour to 48 hours.
- Compound (XXV) is commercially available or is available from Comprehensive Organic Transformations, second edition, by RC Larock, John 'Wiley' and 'Sounds, Inc. (John Wiley & Sons Inc.) (1999), Protective Groups in Organic Synthesis, third edition, ⁇ ⁇ ⁇ ⁇ W. Greene , John 'Wiley. and. Sons Incorporated Leyte each time (j 0 h n Wiley & Sons Inc.)
- Compound (XXVn-d) or compound (XXVII-e) obtained in Step 20 is treated with 1 equivalent to a large excess, preferably 1 equivalent to 10 equivalents of an acid in a solvent inert to the reaction. Yields the compound (XIV-d) or compound (XIV-e), respectively.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.Examples include dichloromethane, chlorophonolem, dichloroethane, dimethylformamide, dimethylacetamide, and the like.
- N-methylpyrrolidone dimethylsulfoxide, tetrahydrofuran, dioxane, getinoleether, diisopropylether, benzene, toluene, xylene, ethyl acetate, acetonitrinole, water, etc. can be used alone or in combination. Of these, dichloromethane is preferred.
- a carboxylic acid such as trifluoroacetic acid, a mineral acid such as hydrochloric acid, and a sulfonic acid such as trifluoromethanesulfonic acid and benzenesulfonic acid can be used.
- a carboxylic acid such as trifluoroacetic acid, a mineral acid such as hydrochloric acid, and a sulfonic acid such as trifluoromethanesulfonic acid and benzenesulfonic acid
- trifluoroacetic acid or hydrochloric acid is preferable.
- the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably between 0 ° C and 50 ° C, usually for 1 hour to 48 hours.
- Compound (XXV) can be obtained by reacting compound (XXV) with 1 to 5 equivalents of compound (XXIX) in a solvent inert to the reaction in the presence of 1 to 10 equivalents of a condensing agent.
- condensing agent examples include dicyclohexylcarbodiimide, disopropyl carbodiimide, N-ethyl- ⁇ '-(3-dimethylaminopropyl) carbodiimid or its hydrochloride, and ⁇ -ethyl-supported polystyrene.
- '_ (3-Dimethylaminopropyl) carbodiimide, polybenzyl supported ⁇ -benzyl- ⁇ '-cyclohexylcarbodiimide, benzotriazono-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, diphenylphosphoryl azide And the like.
- N-ethyl-1-N, 1- (3-dimethylaminopropyl) carbodiimide or its hydrochloride, or N-ethyl-N '_ (3-dimethylaminopropyl) supported on polystyrene Carposimide is preferred.
- This reaction is carried out in the presence of 1 to 5 equivalents of an additive as appropriate.
- the additive include N-hydroxysuccinate imide, 1-hydroxybenzotriazole, and 3-hydrazine.
- Use xy-4 oxo-3,4-dihydro-1,2,3-benzotriazine In particular, 1-hydroxybenzotriazole is preferable.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- examples thereof include dichloromethane, chloroform, dichloroethane, dimethylformamide, dimethylacetamide, and the like.
- N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, dimethyl ether, benzene, toluene, xylene, ethyl acetate, acetonitrile, etc. can be used alone or in combination.
- preferred are chloroform-form, tetrahydrofuran, or a mixed solvent thereof.
- the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably at a temperature between room temperature and 80 ° C, usually for 1 to 120 hours.
- the compound (XIV-f) is treated with 1 equivalent to a large excess, preferably 1 equivalent to 10 equivalents of an acid in a solvent inert to the reaction, to obtain the compound (XIV-f). Obtainable.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- examples include dichloromethane, chloroform, dichloroethane, dimethylformamide, and dimethylacetate.
- a carboxylic acid such as trifluoroacetic acid, a mineral acid such as hydrochloric acid, and a sulfonic acid such as trifluoromethanesulfonic acid and benzenesulfonic acid can be used.
- a carboxylic acid such as trifluoroacetic acid, a mineral acid such as hydrochloric acid, and a sulfonic acid such as trifluoromethanesulfonic acid and benzenesulfonic acid
- trifluoroacetic acid or hydrochloric acid is preferable.
- the reaction is carried out at a temperature between 0 ° C and: 150 ° C, preferably between 0 ° C and 50 ° C, usually for 1 hour to 48 hours.
- condensing agent examples include dicyclohexyl carbodiimide, diisopropyl rubodiimide, N-ethyl ⁇ ⁇ ⁇ '-(3-dimethylaminopropyl) canolebodiimide or its hydrochloride, and ⁇ -ethyl ⁇ ⁇ supported on polystyrene.
- This reaction is appropriately carried out in the presence of 1 to 5 equivalents of an additive.
- the additive include N-hydroxysuccinic acid imide, 1-hydroxybenzotriazole, and 3-hydroxy-4-oxo.
- 1,3,4-dihydro-11,2,3-benzotriazine can be used, and 1-hydroxybenzotriazole is particularly preferable.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited.
- Examples thereof include dichloromethane, chloroform, dichloroethane, dimethylformamide, and dimethylacetamide. , N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, getinoleatenole, benzene, tonolene, xylene, ethinole sulphate, cetonitrile, etc. It can be used, and among them, chloroform, tetrahydrofuran or a mixed solvent thereof is preferable.
- the reaction is carried out at a temperature between 0 ° C and: L50 ° C, preferably between room temperature and 80 ° C, usually for 1 to 120 hours.
- Compound ( ⁇ ) or compound (XXXXIV) obtained in step 24 is treated with 1 equivalent to a large excess, preferably 1 equivalent to 10 equivalents of an acid in a solvent inert to the reaction to give each compound.
- (XIV-g) or compound (XIV-h) can be obtained.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include dichloromethane, chloroform, dichloroethane, dimethylformamide, and dimethylacetamide.
- N-methylpyrrolidone dimethylsulfoxide, tetrahydrofuran, dioxane, getyl ether, diisopropyl ether, benzene, tonolene, xylene, ethyl ethyl acetate, acetonitrinole, water, etc., alone or in combination.
- Especially dicro Romethane is preferred.
- a carboxylic acid such as trifluoroacetic acid
- a mineral acid such as hydrochloric acid
- a snoroleic acid such as trifluoromethanesnoleic acid
- benzenesulfonic acid can be used, and among them, trifluoroacetic acid or hydrochloric acid is preferable.
- the reaction is carried out at a temperature between 0 ° C and 150 ° C, preferably between 0 ° C and 50 ° C, usually for 1 hour to 48 hours.
- Compound (XXV) was prepared in a solvent inert to the reaction in the presence of 1 equivalent to a large excess, preferably 1 equivalent to 10 equivalents of a base in the same manner as in the method shown in Step 16 of Production Method 7.
- Compound (XXVII-d) can be obtained by reacting with 1 to 10 equivalents, preferably 1 to 5 equivalents of compound (XXXIV) in the absence or presence.
- Compound (XXXV) was prepared in a solvent inert to the reaction in the presence of 1 equivalent to a large excess, preferably 1 equivalent to 3 equivalents of a base, in the same manner as in the method shown in Step 16 of Production Method 7.
- the compound (XXXVI) can be obtained by reacting with 1 equivalent to a large excess, preferably 1 equivalent to 10 equivalents of the compound (XXI) in the absence.
- the compound (XIV-i) was obtained from Protective Groups in Organic Synthesis, third edition; N 579-580, TW Greene, John-Willy, Protective Groups in Organic Synthesis, third edition. It can be obtained from the compound (XXXVI) obtained in Step 27 according to the method described in John Wiley & Sons Inc. (1999) and the like.
- Compound (XXXIX) can be obtained by reacting (XXIII) with 1 to 10 equivalents of compound (XXXVIII) in a reaction inert solvent in the presence of 1 to 10 equivalents of zinc.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. For example, dimethylformamide, dimethylacetamide,
- N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, getyl ether, benzene, toluene, xylene and the like can be used alone or in combination, and among them, tetrahydrofuran is preferable.
- the reaction is carried out at a temperature between 0 ° C and the boiling point of the solvent, preferably at a temperature between room temperature and the boiling point of the solvent, usually for 1 to 120 hours.
- Compound (XXXX) can be obtained by treating compound (XXXIX) obtained in step 29 with 1 to 10 equivalents of a reducing agent in a solvent inert to the reaction.
- a reducing agent for example, lithium aluminum hydride, diborane or various complexes thereof can be used.
- the solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. Examples thereof include tetrahydrofuran, 2-methyl / letetrahydrofuran, dioxane, and jeti / ether. ⁇ ⁇ , benzene, toluene, xylene and the like can be used alone or as a mixture thereof, and among them, tetrahydrofuran is preferable.
- the reaction is carried out at a temperature between 180C and the boiling point of the solvent, preferably at a temperature between 0C and room temperature, usually for 10 minutes to 10 hours.
- Compound (XXXXI) can be obtained by reacting with an equivalent amount of sulfonic acid halide or sulfonic anhydride.
- Compound (XIV-j) can be obtained by treating with 10 equivalents of an acid.
- production method 7- I3 steps 15 and 16, 16, 18, 20, 22, 24, 26, 27, etc.
- R 1 R 3 , A, n and m are as defined above, and R 2A is
- R 6, R 6C, R 7Ba, R 7Ca, R 10, R 10a, R 10b, R 10c, X A, X B, XX b, X c, X d, Y, E c, G, E, Q, pc, q, r, ra, rb, rc, s, and sb are as defined above, respectively.
- the compound (A) used in the production method 12 can be obtained as the compounds (IA) to (IF) described in the production methods 1 to 6, or according to the production methods.
- compound (A) is a compound ( ⁇ ) obtained according to the method described in step 6 of production method 1 or step 9 of production method 2 and R 2 A—H (wherein, R 2A is as defined above) ) Can be obtained according to the method described in Step 7 of Production Method 1.
- Preferred reaction conditions and the method of obtaining R 2A —H are the same as the conditions and the method of obtaining compound (XIV) shown in Step 7 of Production Method 1, respectively.
- the compound (I) having a desired functional group at a desired position can be obtained by appropriately combining the above methods and the like.
- Isolation and purification of the intermediates and products in the above-mentioned production methods are carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, etc. be able to. Further, purification methods commonly used in general parallel synthesis methods (such as combinatorial chemistry), for example, scavenger resins such as benzoyl alk-open polymer bound, poly 4-vinylinolepyridine, benzaldehyde polymer bound, and trityl chloride polymer bound.
- scavenger resins such as benzoyl alk-open polymer bound, poly 4-vinylinolepyridine, benzaldehyde polymer bound, and trityl chloride polymer bound.
- the purification can be performed by using a resin such as an ion-exchange resin such as AG 1-X8OH-resin (manufactured by Bio-Rad).
- a resin such as an ion-exchange resin such as AG 1-X8OH-resin (manufactured by Bio-Rad).
- the intermediate can be subjected to the next reaction without purification.
- the starting compounds or intermediates in the above-mentioned production methods may be present in the form of salts such as hydrochlorides, depending on reaction conditions and the like, but they can be used as they are or in free form.
- salts such as hydrochlorides, depending on reaction conditions and the like
- the salt of the starting compound or the intermediate when it is desired to use or obtain the starting compound or the intermediate in the form of a salt, when the salt of the starting compound or the intermediate is obtained, it may be used or obtained as it is.
- the starting compound or intermediate is obtained in the form of a salt and the starting compound or intermediate is to be used or obtained in a free form, the starting compound or intermediate is dissolved or suspended in an appropriate solvent, and a base such as aqueous sodium hydrogen carbonate solution is used. It can be converted to the free form by neutralizing with etc.
- Some of the compounds (I) may have isomers such as positional isomers, geometric isomers or optical isomers, and all possible isomers including these isomers and the isomers Mixtures in any ratio of are encompassed by the present invention.
- the compound (I) may be purified as it is when the salt of compound (I) is obtained, or when compound (I) is obtained in a free form, compound (I) May be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt.
- the compound (I) or a pharmacologically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Specific examples of the compound (I) are shown in Tables 1 to 25. However, the compounds of the present invention are not limited to these.
- N0- -HO.
Description
Claims
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US10/516,750 US7524852B2 (en) | 2002-06-07 | 2003-06-06 | Bicyclic pyrimidine derivatives |
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TW201945003A (zh) | 2018-03-01 | 2019-12-01 | 愛爾蘭商健生科學愛爾蘭無限公司 | 2,4-二胺基喹唑啉衍生物及其醫學用途 |
GB201810239D0 (en) | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
GB201819960D0 (en) | 2018-12-07 | 2019-01-23 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
CN115974868B (zh) * | 2022-11-07 | 2024-04-12 | 安徽理工大学 | 一种尿嘧啶衍生物的合成方法及其抗肺纤维化方面的潜在应用 |
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Also Published As
Publication number | Publication date |
---|---|
AU2003242252A1 (en) | 2003-12-22 |
JPWO2003104230A1 (ja) | 2005-10-06 |
US7524852B2 (en) | 2009-04-28 |
US20070037834A1 (en) | 2007-02-15 |
EP1552842A1 (en) | 2005-07-13 |
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