JP2005519932A - p38阻害薬として有用なニコチンアミド誘導体 - Google Patents
p38阻害薬として有用なニコチンアミド誘導体 Download PDFInfo
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- JP2005519932A JP2005519932A JP2003567878A JP2003567878A JP2005519932A JP 2005519932 A JP2005519932 A JP 2005519932A JP 2003567878 A JP2003567878 A JP 2003567878A JP 2003567878 A JP2003567878 A JP 2003567878A JP 2005519932 A JP2005519932 A JP 2005519932A
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- Prior art keywords
- optionally substituted
- alkyl
- phenyl
- methyl
- compound
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- 239000012826 P38 inhibitor Substances 0.000 title description 2
- 150000005480 nicotinamides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 109
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims abstract description 32
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims abstract description 32
- 230000000694 effects Effects 0.000 claims abstract description 15
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 102000004127 Cytokines Human genes 0.000 claims abstract description 9
- 108090000695 Cytokines Proteins 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 65
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 25
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 6
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- -1 t-butoxy Chemical group 0.000 description 76
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 72
- 230000002829 reductive effect Effects 0.000 description 64
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 49
- 239000000243 solution Substances 0.000 description 49
- 230000014759 maintenance of location Effects 0.000 description 47
- 239000002904 solvent Substances 0.000 description 45
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 239000000203 mixture Substances 0.000 description 37
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 36
- 239000000377 silicon dioxide Substances 0.000 description 35
- 238000007429 general method Methods 0.000 description 31
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 25
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 25
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 18
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 18
- 229910000029 sodium carbonate Inorganic materials 0.000 description 18
- 239000007787 solid Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 14
- 101150003085 Pdcl gene Proteins 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 239000007821 HATU Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 235000011056 potassium acetate Nutrition 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- NMLPKVQVDDARTN-UHFFFAOYSA-N 6-chloro-n-(cyclopropylmethyl)pyridine-3-carboxamide Chemical compound C1=NC(Cl)=CC=C1C(=O)NCC1CC1 NMLPKVQVDDARTN-UHFFFAOYSA-N 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 239000002502 liposome Substances 0.000 description 10
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- KLNMZIVXZVZTSK-UHFFFAOYSA-N 6-chloro-n-[(3-methoxyphenyl)methyl]pyridine-3-carboxamide Chemical compound COC1=CC=CC(CNC(=O)C=2C=NC(Cl)=CC=2)=C1 KLNMZIVXZVZTSK-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 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 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- LMUKBBLEUSPBDV-UHFFFAOYSA-N 6-chloro-n-(4-methoxyphenyl)pyridine-3-carboxamide Chemical compound C1=CC(OC)=CC=C1NC(=O)C1=CC=C(Cl)N=C1 LMUKBBLEUSPBDV-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 7
- HNPFSBAFFHLEOL-UHFFFAOYSA-N 6-chloro-n-[2-[(4-methylpiperazin-1-yl)methyl]phenyl]pyridine-3-carboxamide Chemical compound C1CN(C)CCN1CC1=CC=CC=C1NC(=O)C1=CC=C(Cl)N=C1 HNPFSBAFFHLEOL-UHFFFAOYSA-N 0.000 description 6
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- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
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Abstract
Description
R1は、水素、C1-6アルコキシ、ハロゲンおよびヒドロキシから選択される3個以下の基によって置換されていても良いC1-6アルキル、C2-6アルケニル、1以上のC1-6アルキル基によって置換されていても良いC3-7シクロアルキル、R5およびR6から選択される3個以下の基によって置換されていても良いフェニル、ならびにR5およびR6から選択される3個以下の基によって置換されていても良いヘテロアリールから選択され;
R2は、水素、C1-6アルキルおよび1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキルから選択され;
あるいは(CH2)mR1およびR2が、それらが結合している窒素原子と一体となって、3個以下のC1-6アルキル基によって置換されていても良い4〜6員の複素環を形成しており;
R3は、クロロまたはメチルであり;
R4は、基-NH-CO-R7または-CO-NH-(CH2)q-R8であり;
R5は、C1-6アルキル、C1-6アルコキシ、1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキル、-CONR9R10、-NHCOR10、-SO2NHR9、-(CH2)sNHSO2R10、ハロゲン、CN、OH、-(CH2)sNR11R12およびトリフルオロメチルから選択され;
R6は、C1-6アルキル、C1-6アルコキシ、ハロゲン、トリフルオロメチルおよび-(CH2)sNR11R12から選択され;
R7は、水素、C1-6アルキル、1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキル、トリフルオロメチル、R13および/またはR14によって置換されていても良い-(CH2)rヘテロアリール、ならびにR13および/またはR14によって置換されていても良い-(CH2)rフェニルから選択され;
R8は、水素、C1-6アルキル、1以上のC1-6アルキル基によって置換されていても良いC3-7シクロアルキル、CONHR9、R13および/またはR14によって置換されていても良いフェニル、ならびにR13および/またはR14によって置換されていても良いヘテロアリールから選択され;
R9およびR10はそれぞれ独立に、水素およびC1-6アルキルから選択され;
あるいはR9とR10が、それらが結合している窒素原子と一体となって、酸素、硫黄およびN-R15から選択される1個の更なるヘテロ原子を有していても良い5〜6員の複素環を形成しており、前記環は2個以下のC1-6アルキル基によって置換されていても良く;
R11は、水素、C1-6アルキルおよび1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキルから選択され;
R12は、水素およびC1-6アルキルから選択され;
あるいはR11とR12が、それらが結合している窒素原子と一体となって、酸素、硫黄およびN-R15から選択される1個の更なるヘテロ原子を有していても良い5員もしくは6員の複素環を形成しており;
R13は、C1-6アルキル、C1-6アルコキシ、1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキル、-CONR9R10、-NHCOR10、ハロゲン、CN、-(CH2)sNR11R12、トリフルオロメチル、1以上のR14基によって置換されていても良いフェニルおよび1以上のR14基によって置換されていても良いヘテロアリールから選択され;
R14は、C1-6アルキル、C1-6アルコキシ、ハロゲン、トリフルオロメチルおよび-NR11R12から選択され;
R15は、水素およびメチルから選択され;
XおよびYはそれぞれ独立に、水素、メチルおよびハロゲンから選択され;
Zはハロゲンであり;
mは0、1、2、3および4から選択され、得られる炭素鎖の各炭素原子はC1-6アルキルおよびハロゲンから独立に選択される2個以下の基によって置換されていても良く;
nは、0、1および2から選択され;
qは、0、1および2から選択され;
rは、0および1から選択され;
sは、0、1、2および3から選択される。
6-(5-シクロプロピルカルバモイル-3-フルオロ-2-メチル-フェニル)-N-シクロプロピルメチル-ニコチンアミド;
6-(5-シクロプロピルカルバモイル-3-フルオロ-2-メチル-フェニル)-N-(1-シクロプロピルエチル)-ニコチンアミド;
6-(5-シクロプロピルカルバモイル-3-フルオロ-2-メチル-フェニル)-N-(2,2-ジメチルプロピル)-ニコチンアミド;
6-(5-シクロプロピルカルバモイル-3-フルオロ-2-メチル-フェニル)-N-(2-メチルプロピル)-ニコチンアミド;および
6-(5-シクロプロピルカルバモイル-3-フルオロ-2-メチル-フェニル)-N-(1-メチルプロピル)-ニコチンアミド
などがある。
6-(5-シクロプロピルカルバモイル-3-フルオロ-2-メチル-フェニル)-N-シクロブチルメチル-ニコチンアミド;
6-(5-シクロプロピルカルバモイル-3-フルオロ-2-メチル-フェニル)-N-シクロブチル-ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(2,4,5-トリフルオロベンジル)ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(2,5-ジフルオロベンジル)ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(3,4-ジフルオロベンジル)ニコチンアミド;
N-(3-クロロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
N-(4-クロロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
N-(3-クロロ-2-フルオロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
N-(2-クロロ-3,6-ジフルオロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(2,3-ジフルオロ-4-メチルベンジル)ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(2,3,5-トリフルオロベンジル)ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(3-フルオロ-4-メチルベンジル)ニコチンアミド;
N-(5-クロロ-2-フルオロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
N-(2-クロロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(4-フルオロベンジル)ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(2,3,4-トリフルオロベンジル)ニコチンアミド;
N-ベンジル-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-[3-(トリフルオロメチル)ベンジル]ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(1,1-ジメチルブチル)ニコチンアミド;
N-(4-クロロ-2-フルオロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-[4-(トリフルオロメチル)ベンジル]ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-[(5-メチル-2-フリル)メチル]ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(2,3-ジフルオロベンジル)ニコチンアミド;
N-(3-クロロ-4-フルオロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(4-メチルベンジル)ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-[(3-メチルチエン-2-イル)メチル]ニコチンアミド;
N-(3-クロロ-2,6-ジフルオロベンジル)-6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(1-エチル-1-メチルプロピル)ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(2-フルオロベンジル)ニコチンアミド;
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(tert-ペンチル)ニコチンアミド;および
6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}-N-(3-メチルベンジル)ニコチンアミド
などがある。
i.R7CO2H、HATU、DIPEA、DMF;
ii.ビス(ピナコラト)ジボロン、PdCl2dppf、KOAc、DMF;
iii.SOCl2;
iv.R1(CH2)mR2NH、Na2CO3、アセトン;
v.Na2CO3、テトラキス(トリフェニルホスフィン)パラジウム、プロパン-2-オール。
i.SOCl2;
ii.R8(CH2)qNH2、Na2CO3、アセトン;
iii.ビス(ピナコラト)ジボロン、PdCl2dppf、KOAc、DMF;
iv.SOCl2;
v.R1(CH2)mR2NH、Na2CO3、アセトン;
vi.Na2CO3、テトラキス(トリフェニルホスフィン)パラジウム、プロパン-2-オール。
i.ビス(ピナコラト)ジボロン、PdCl2dppf、KOAc、DMF;
ii.R8(CH2)qNH2、HATU、DIPEA、DMF;
iii.SOCl2;
iv.R1(CH2)mR2NH、Na2CO3、DCM;
v.Na2CO3、テトラキス(トリフェニルホスフィン)パラジウム、プロパン-2-オール。
i.NaHCO3、テトラキス(トリフェニルホスフィン)パラジウム、プロパン-2-オール;
ii.R1(CH2)mR2NH、HATU、DIPEA、DMF。
i.SOCl2;
ii.R8(CH2)qNH2、Na2CO3、DCM;
iii.NaH、n-BuLi、THF、(iPrO)3B;
iv.SOCl2;
v.R1(CH2)mR2NH、Na2CO3、DCM;
vi.NaHCO3、テトラキス(トリフェニルホスフィン)パラジウム、プロパン-2-オール。
以下の実施例は、本発明の例示的実施形態であり、いかなる形でも本発明の範囲を限定するものではない。試薬は市販されているか、あるいは文献の手順に従って製造される。
6-ブロモニコチン酸(200mg、0.99mmol)を塩化チオニル(2ml)中で2.5時間加熱還流した。反応液を放冷して室温とし、過剰の塩化チオニルを減圧下で留去した。残留物をアセトン(4ml)に溶かし、シクロプロピルメチルアミン(71mg、0.10mmol)および炭酸ナトリウム(500mg)を溶液に加えた。反応液を室温で4時間撹拌し、濾過し、濾液を減圧下で減量して乾固させて、6-クロロ-N-シクロプロピルメチルニコチンアミドをクリーム色固体として得た。NMR:δH[2H6]-DMSO 8.82,(2H、m)、8.23,(1H、dd)、7.63,(1H、d)、3.14,(2H、t)、1.01,(1H、m)、0.44,(2H、m)、0.22,(2H、m)。
6-ブロモニコチン酸(200mg、0.99mmol)を塩化チオニル(2ml)中で3時間加熱還流した。反応液を放冷して室温とし、過剰の塩化チオニルを減圧下で留去した。残留物をDCM(2ml)に溶かし、p-アニシジン(123mg、0.10mmol)および炭酸ナトリウム(500mg)を溶液に加えた。反応液を室温で4時間撹拌し、濾過し、濾液を減圧下で減量して乾固させて、6-クロロ-N-(4-メトキシフェニル)ニコチンアミドを得た。NMR:δH[2H6]-DMSO 10.37,(1H、b)、8.94,(1H、d)、8.34,(1H、dd)、7.70,(1H、d)、7.66,(2H、m)、6.95,(2H、m)、3.75,(3H、s)。
6-ブロモニコチン酸(200mg、0.99mmol)を塩化チオニル(2ml)中で3時間加熱還流した。反応液を放冷して室温とし、過剰の塩化チオニルを減圧下で留去した。残留物をDCM(2ml)に溶かし、3-メトキシベンジルアミン(137mg、0.10mmol)および炭酸ナトリウム(500mg)を溶液に加えた。反応液を室温で4時間撹拌し、濾過し、濾液を減圧下で減量して乾固させて、6-クロロ-N-(3-メトキシベンジル)ニコチンアミドを得た。NMR:δH[2H6]-DMSO 9.29,(1H、t)、8.88,(1H、d)、8.28,(1H、dd)、7.66,(1H、d)、7.25,(1H、t)、6.90,(2H、m)、6.83,(1H、m)、4.47,(2H、d)、3.74,(3H、s)。
6-ブロモニコチン酸(200mg、0.99mmol)を塩化チオニル(2ml)中で3時間加熱還流した。反応液を放冷して室温とし、過剰の塩化チオニルを減圧下で留去した。残留物をDCM(2ml)に溶かし、3-メチルスルホニルアミノベンジルアミン(200mg、0.10mmol)および炭酸ナトリウム(500mg)を溶液に加えた。反応液を室温で4時間撹拌し、濾過し、濾液を減圧下で減量して乾固させて、6-クロロ-N-(3-メチルスルホニルアミノベンジル)ニコチンアミドを得た。NMR:δH[2H6]-DMSO 9.30,(1H、t)、8.88,(1H、d)、8.28,(1H、dd)、7.67,(1H、d)、7.23,(1H、t)、7.10,(1H、s)、7.04,91H、d)、6.97,(1H、d)、4.45,(2H、d)、2.90,(3H、s)。
6-ブロモニコチン酸(200mg、0.99mmol)を塩化チオニル(2ml)中で3時間加熱還流した。反応液を放冷して室温とし、過剰の塩化チオニルを減圧下で留去した。残留物をDCM(2ml)に溶かし、1-(2-アミノベンジル)-4-メチルピペラジン(205mg、0.10mmol)および炭酸ナトリウム(500mg)を溶液に加えた。反応液を室温で4時間撹拌し、濾過し、濾液を減圧下で減量して乾固させて、6-クロロ-N-[2-(4-メチルピペラジン-1-イル)フェニル]ニコチンアミドを得た。NMR:δH[2H6]-DMSO 11.62,(1H、s)、8.95,(1H、d)、8.32,(1H、dd)、8.25,(1H、d)、7.77,(1H、d)、7.34,(1H、m)、7.28,(1H、m)、7.10,(1H、m)、3.73,(2H、s)、2.56-2.20,(8H、b)、2.12,(3H、s)。
3-ヨード-4-メチル-N-(3-ピリジン-2-イル-フェニル)ベンズアミド(中間体7)(83mg、0.20mmol)、ビス(ピナコラト)ジボロン(100mg、0.39mmol)、酢酸カリウム(97mg、1.0mmol)およびPdCl2dppf(12mg)をDMF(2.5ml)中80で4時間加熱した。冷却した反応液をシリカに吸収させ、ボンド−エルート(bond-elut)(10g、シリカ)に乗せ、酢酸エチル/シクロヘキサン勾配(0%から100%)で溶離した。溶媒を減圧下で生成物分画から留去し、残留物をエーテルで磨砕して、4-メチル-N-(3-ピリジン-2-イル-フェニル)-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-ベンズアミドを白色固体として得た(31mg)。LCMS:保持時間3.69分、MH+415。
3-ヨード-4-メチル安息香酸(154mg、0.59mmol)を塩化チオニル(2ml)中80℃で3時間加熱した。反応液を放冷して室温とし、過剰の塩化チオニルを減圧下で留去した。残留物をアセトン(3ml)に溶かし、2-(3-アミノフェニル)ピリジン(100mg、0.59mmol)および炭酸ナトリウム(400mg)を溶液に加えた。反応液を室温で11日間撹拌し、濾過し、濾液を減圧下で減量して乾固させた。残留物をエーテルに溶かし、ボンド−エルート(1g、シリカ)で濾過し、エーテルで洗浄した。溶媒を合わせた濾液および洗浄液から留去して、3-ヨード-4-メチル-N-(3-ピリジン-2-イル-フェニル)ベンズアミドをクリーム色泡状物として得た。NMR:δHCDCl38.70,(1H、dt)、8.33,(1H、d)、8.18,(1H、t)、7.93-7.89,(2H、m)、7.79-7.75,(4H、m)、7.50,(1H、t)、7.35,(1H、d)、7.26,(1H、m)、2.51,(3H、s)。
N-シクロプロピル-3-ヨード-4-メチルベンズアミド(中間体9)(1.1g、3.64mmol)、ビス(ピナコラト)ジボロン(1.85g、7.28mmol)、酢酸カリウム(1.79g、18.2mmol)およびPdCl2dppf(55mg)を、DMF(30ml)中85℃で4.5時間加熱した。冷却した反応液をシリカに吸収させ、ボンド−エルート(10g、シリカ)に乗せ、酢酸エチル/シクロヘキサン勾配(0%から100%)で溶離した。溶媒を減圧下で生成物分画から留去し、残留物をシクロヘキサンで磨砕して、N-シクロプロピル-4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-ベンズアミドを白色固体として得た(650mg)。NMR:δH[2H6]-DMSO 8.40,(1H、d)、8.06,(1H、d)、7.76,(1H、dd)、7.23,(1H、d)、2.82,(1H、m)、2.48,(3H、s)、1.30,(12H、s)、0.66,(2H、m)、0.56,(2H、m)。
3-ヨード-4-メチル安息香酸(1.0g、3.8mmol)を塩化チオニル(10ml)中80℃で2時間加熱した。反応液を放冷して室温とし、過剰の塩化チオニルを減圧下で留去した。残留物をDCM(10ml)に溶かし、シクロプロピルアミン(0.32ml)および炭酸ナトリウム(2.0g)を溶液に加えた。反応液を室温で18時間撹拌し、濾過し、濾液を減圧下で減量して乾固させた。残留物をエーテルで磨砕して、N-シクロプロピル-3-ヨード-4-メチルベンズアミドを白色固体として得た(1.1g)。NMR:δH[2H6]-DMSO 8.46,(1H、d)、8.24,(1H、d)、7.74,(1H、dd)、7.38,(1H、d)、2.82,(1H、m)、2.38,(3H、s)、0.67,(2H、m)、0.55,(2H、m)。
4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-安息香酸(中間体17)(2.0g、7.63mmol)、DIPEA(4ml、22.89mmol)およびHATU(3.05g、8.02mmol)をDMF(20ml)に溶かし、室温で15分間撹拌した。シクロプロピルメチルアミン(568mg、8.01mmol)を加え、反応液を室温で18時間撹拌した。溶媒を減圧下で留去し、反応液を酢酸エチル(250ml)と水(50ml)との間で分配した。有機相を塩酸(2N、50ml)および重炭酸ナトリウム水溶液(1M、50ml)で洗浄し、脱水し(硫酸マグネシウム)、溶媒を減圧下で留去した。残留物をシリカに吸収させ、シクロヘキサン/酢酸エチル(4:1)を溶離液とするフラッシュカラムクロマトグラフィーによって精製した。溶媒を減圧下で生成物分画から留去して、N-シクロプロピルメチル-4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-ベンズアミドを得た(1.73g)。LCMS:保持時間3.47分、MH+316。NMR:δH[2H6]-DMSO 8.54,(1H、t)、8.11,(1H、d)、7.82,(1H、dd)、7.26,(1H、d)、3.12,(2H、t)、1.32,(12H、s)、1.03,(1H、m)、0.42,(2H、m)、0.22,(2H、m)。
4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-安息香酸(2.0g、7.63mmol)、DIPEA(4ml、22.89mmol)およびHATU(3.05g、8.02mmol)をDMF(20ml)に溶かし、室温で15分間撹拌した。2-アミノチアゾール(801mg、8.01mmol)を加え、反応液を室温で18時間撹拌した。溶媒を減圧下で留去し、反応液を酢酸エチル(250ml)と水(50ml)との間で分配した。有機相を塩酸(2N、50ml)および重炭酸ナトリウム水溶液(1M、50ml)で洗浄し、脱水し(硫酸マグネシウム)、溶媒を減圧下で留去した。残留物をシリカに吸収させ、シクロヘキサン/酢酸エチル(4:1)を溶離液とするフラッシュカラムクロマトグラフィーによって精製した。溶媒を減圧下で生成物分画から留去して、4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-N-(チアゾール-2-イル)-ベンズアミドを得た(1.72g)。LCMS:保持時間3.66分、MH+345。NMR:δH[2H6]-DMSO 12.65,(1H、b)、8.32,(1H、d)、8.08,(1H、dd)、7.56,(1H、d)、7.35,(1h、d)、7.28,(1H、d)、2.54,(3H、s)、1.34,(12H、s)。
4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-安息香酸(2.0g、7.63mmol)、DIPEA(4ml、22.89mmol)およびHATU(3.05g、8.02mmol)をDMF(20ml)に溶かし、室温で15分間撹拌した。2-アミノチアジアゾール(810mg、8.01mmol)を加え、反応液を室温で18時間撹拌した。溶媒を減圧下で留去し、反応液を酢酸エチル(250ml)と塩酸(2N、150ml)との間で分配した。水相を酢酸エチルで抽出した(250mlで2回)。合わせた有機抽出液を脱水し(硫酸マグネシウム)、溶媒を減圧下で留去した。残留物をシリカに吸収させ、シクロヘキサン/酢酸エチル(4:1と次に1:1)を溶離液とするフラッシュカラムクロマトグラフィーによって精製した。溶媒を減圧下で生成物分画から留去して、4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-N-(チアジアゾール-2-イル)-ベンズアミドを得た(0.95g)。LCMS:保持時間3.34分、MH+346。NMR:δH[2H6]-DMSO 13.08,(1H、b)、9.22,(1H、s)、8.35,(1H、d)、8.11,(1H、dd)、7.38,(1H、d)、2.55,(3H、s)、1.34,(12H、s)。
N-(3-ヨード-4-メチルフェニル)-3-フラミド(中間体15)(2.5g、7.64mmol)、ビス(ピナコラト)ジボロン(2.13g、8.41mmol)、酢酸カリウム(825mg、8.41mmol)およびPdCl2dppf(312mg、0.38mmol)のDMF(20ml)溶液を80℃で20時間加熱した。冷却した反応液をシリカに吸収させ、ボンド−エルート(シリカ、10g)に乗せ、シクロヘキサン/酢酸エチル勾配で溶離した。生成物分画を減圧下で濃縮し、DMF(40ml)に溶かし、ビス(ピナコラト)ジボロン(7.76g、30.57mmol)、酢酸カリウム(3.0g、30.57mmol)およびPdCl2dppf(249mg、0.306mmol)と80℃で23時間反応させた。冷却した反応液をシリカに吸収させ、ボンド−エルートに乗せ(シリカ、2×10g)、シクロヘキサン/酢酸エチル勾配で溶離した。生成物分画を減圧下で濃縮して、N-[4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-フェニル]-3-フラミドを得た。LCMS:保持時間3.55分、MH+328。NMR:δH[2H6]-DMSO 9.86,(1H、b)、8.36,(1H、m)、7.86-7.82,(2H、m)、7.77,(1H、t)、7.14,(1H、d)、6.99,(1H、m)、2.41,(3H、s)、1.30,(12H、s)。
N-(3-ヨード-4-メチルフェニル)チオフェン-3-アミド(中間体16)(2.64g、7.64mmol)、ビス(ピナコラト)ジボロン(2.13g、8.41mmol)、酢酸カリウム(825mg、8.41mmol)およびPdCl2dppf(312mg、0.38mmol)のDMF(20ml)溶液を80℃で20時間加熱した。冷却した反応液をシリカに吸収させ、ボンド−エルート(シリカ、10g)に乗せ、シクロヘキサン/酢酸エチル勾配で溶離した。生成物分画を減圧下で濃縮し、DMF(20ml)に溶かし、ビス(ピナコラト)ジボロン(1.77g、7.0mmol)、酢酸カリウム(687mg、7.0mmol)およびPdCl2dppf(143mg、0.175mmol)と80℃で16時間反応させた。冷却した反応液をシリカに吸収させ、ボンド−エルート(シリカ、10g)に乗せ、シクロヘキサン/酢酸エチル勾配で溶離した。生成物分画を減圧下で濃縮して、N-[4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-フェニル]チオフェン-3-アミドを得た。LCMS:保持時間3.65分、MH+344。NMR:δH[2H6]-DMSO 9.99,(1H、b)、8.35,(1H、s)、7.90,(1H、d)、7.85,(1H、dd)、7.63,(2H、m)、7.14,(1H、d)、2.42,(3H、s)、1.30,(12H、s)。
3-フロン酸(2.4g、21.45mmol)およびHATU(8.15g、21.45mmol)のDMF(25ml)溶液を室温で15分間撹拌した。HOBT(2.9g、21.45mmol)、3-ヨード-4-メチルアニリン(5.0g、21.45mmol)およびDIPEA(11.2ml、64.35mmol)を加え、反応液を室温で16時間撹拌した。溶媒を減圧下で留去し、残留物を酢酸エチル(100ml)と炭酸ナトリウム水溶液(10%、100ml)との間で分配した。水層を酢酸エチル(50ml)で抽出し、合わせた有機相を塩酸(2N、75ml)、水(75ml)および塩水(75ml)で洗浄した。有機相を脱水し(硫酸マグネシウム)、シリカ上に吸収させた。シリカをフラッシュシリカカラムに乗せ、シクロヘキサン/酢酸エチル(3:1)で溶離した。溶媒を減圧下で生成物分画から留去して、N-(3-ヨード-4-メチルフェニル)-3-フラミドを得た。LCMS:保持時間3.52分、MH+328。NMR:δH[2H6]-DMSO 9.92,(1H、b)、8.36,(1H、d)、8.23,(1H、d)、7.80,(1H、t)、7.66,(1H、dd)、7.29,(1H、d)、6.98,(1H、d)、2.33,(3H、s)。
チオフェン-3-カルボン酸(2.75g、21.45mmol)およびHATU(8.15g、21.45mmol)のDMF(25ml)溶液を室温で15分間撹拌した。HOBT(2.9g、21.45mmol)、3-ヨード-4-メチルアニリン(5.0g、21.45mmol)およびDIPEA(11.2ml、64.35mmol)を加え、反応液を室温で16時間撹拌した。溶媒を減圧下で留去し、残留物を酢酸エチル(100ml)と炭酸ナトリウム水溶液(10%、100ml)との間で分配した。水層を酢酸エチル(50ml)で抽出し、合わせた有機相を塩酸(2N、75ml)、水(75ml)および塩水(75ml)で洗浄した。有機相を脱水し(硫酸マグネシウム)、シリカ上に吸収させた。シリカをフラッシュシリカカラムに乗せ、シクロヘキサン/酢酸エチル(4:1)で溶離した。溶媒を減圧下で生成物分画から留去して、N-(3-ヨード-4-メチルフェニル)チオフェン-3-アミドを得た。LCMS:保持時間3.69分、MH+344。NMR:δH[2H6]-DMSO 10.06,(1H、b)、8.34,(1H、m)、8.29,(1H、d)、7.70,(1H、dd)、7.66,(1H、dd)、7.62,(1H、dd)、7.30,(1H、d)、2.34,(3H、s)。
3-ヨード-4-メチル安息香酸(10g、38.16mmol)、ビス(ピナコラト)ジボロン(14.5g、57.24mmol)、酢酸カリウム(18.73g、190.8mmol)およびPdCl2dppf(3.12g、3.8mmol)のDMF(200ml)溶液を80℃で21時間加熱した。冷却した反応液から溶媒を減圧下で留去し、残留物を酢酸エチル(300ml)および塩酸(2N、300ml)に溶かし、セライトで濾過した。有機相を分離し、水相を酢酸エチルで抽出した(300mlで2回)。合わせた有機抽出液を塩水(500ml)で洗浄し、脱水した(硫酸マグネシウム)。溶媒を減圧下で留去し、残留物をシリカ上に吸収させ、シリカフラッシュカラムに乗せた。それをシクロヘキサン/酢酸エチル(5:1)で溶離した。生成物分画を減圧下で濃縮して、4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)安息香酸を得た。LCMS:保持時間3.65分。NMR:δH[2H6]-DMSO 12.83,(1H、b)、8.23,(1H、d)、7.89,(1H、dd)、7.29,(1H、d)、2.51,(3H、s)、1.30,(12H、s)。
ビス(ピナコラト)ジボラン(7.24g、28.5mmol)を、N-(3-ヨード-4-メチルフェニル)-2-ピロリジン-1-イル-イソニコチンアミド(中間体19)(7.73g、19mmol)のジメチルホルムアミド(100ml)溶液、酢酸カリウム(9.32g、95mmol)およびPdCl2dppfの混合物に加え、反応液を窒素雰囲気下で80℃にて16時間加熱した。反応液を冷却し、溶媒を減圧下で除去した。残留物をクロロホルム(150ml)に取り、水(100mlで3回)および塩水(100ml)で洗浄し、硫酸マグネシウムで脱水し、濾過し、溶媒を減圧下で除去した。残留物をカラムクロマトグラフィーによって精製した(20:80酢酸エチル:シクロヘキサンから50:50酢酸エチル:シクロヘキサン)。N-[4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-フェニル]-2-ピロリジン-1-イル-イソニコチンアミドを白色固体として得た(1.5g、3.7mmol).。LCMS:保持時間2.90分、MH+408。NMR:δH-CDCl38.27(1H、d)、7.99(1H、dd)、7.76(1H、b)、7.65(1H、d)、6.20(1H、d)、6.82(1H、b)、6.77(1H、b)、3.52(4H、見かけ上t)、2.52(3H、s)、2.25(4H、m)。
N-(3-ヨード-4-メチルフェニル)-2-クロロ-イソニコチンアミド(中間体20)(7.00g、18.8mmol)のピロリジン(20ml)溶液を、窒素雰囲気下に80℃で16時間加熱した。過剰のピロリジンを減圧下で除去し、残留物をジエチルエーテル(20ml)で磨砕した。得られた固体を濾過によって回収し、真空乾燥して、N-(3-ヨード-4-メチルフェニル)-2-ピロリジン-1-イル-イソニコチンアミドを淡黄色固体として得た(7.73g、18mmol)。LCMS:保持時間2.77分、MH+408。NMR:δH[2H6]-DMSO 10.29(1H、s)、8.29(1H、d)、8.20(1H、d)、7.71(1H、dd)、7.72(1H、dd)、6.97(1H、brd)、6.88(1H、b)、3.45(2H、見かけ上t)、3.09(2H、m)、2.35(3H、s)、1.98(2H、m)、1.82(2H、m)。
2-クロロイソニコチン酸(3.3g、21mmol)、HATU(8.75g、23mmol)、ジイソプロピルエチルアミン(10.9ml、63mmol)および4-ヨード-3-メチルアニリン(5.00g、21mmol)のジメチルホルムアミド(50ml)溶液を窒素下に16時間加熱した。反応液を冷却し、減圧下で除去し、残留物を塩化メチレン(150ml)に取った。有機溶液を水(100mlで3回)および塩水(100ml)で洗浄し、硫酸マグネシウムで脱水し、濾過し、溶媒を減圧下で除去した。残留物をカラムクロマトグラフィーによって精製して(40:60酢酸エチル:シクロヘキサン)、2-クロロ-N-(3-ヨード-4-メチルフェニル)-イソニコチンアミドを白色固体として得た(7.00g、18.8mmol)。LCMS:保持時間3.59分、MH+373。NMR:δH[2H6]-DMSO 10.52(1H、s)、8.62(1H、d)、8.29(1H、d)、7.99(1H、b)、7.87(1H、dd)、7.70(1H、dd)、7.34(1H、d)、2.36(3H、s)。
6-ブロモニコチン酸(200mg、0.99mmol)を塩化チオニル(2ml)中で2.5時間加熱還流した。反応液を放冷して室温とし、過剰の塩化チオニルを減圧下で留去した。残留物をアセトン(4ml)に溶かし、シクロプロピルメチルアミン(71mg、0.10mmol)および炭酸ナトリウム(500mg)を溶液に加えた。反応液を室温で4時間撹拌し、濾過し、濾液を減圧下で減量して乾固させて、6-クロロ-N-シクロプロピルメチルニコチンアミドをクリーム色固体として得た。NMR:δH[2H6]-DMSO 8.82,(2H、m)、8.23,(1H、dd)、7.63,(1H、d)、3.14,(2H、t)、1.01,(1H、m)、0.44,(2H、m)、0.22,(2H、m)。
6-ブロモニコチン酸(100mg、0.5mmol)を塩化チオニル(0.63ml)中95℃で2時間加熱した。過剰の塩化チオニルを減圧下で留去し、残留物をDCM(2ml)に溶かした。この溶液に、アミン(0.5mmol)および炭酸ナトリウム(100mg)を加え、反応液を室温で2時間撹拌した。反応液を濾過し、残留物をDCMで洗浄した。合わせた濾液および洗浄液を減量して乾固させて、所望の6-クロロニコチンアミドを得た。
一般法Aを用いて、6-クロロ-N-シクロブチルメチルニコチンアミドをシクロブチルメチルアミンから製造した。
一般法Aを用いて、6-クロロ-N-(1-メチルプロピル)ニコチンアミドを1-メチルプロピルアミンから製造した。
3-ブロモ-N-シクロプロピル-5-フルオロ-4-メチルベンズアミド(中間体35、900mg)、ビスピナコラトジボロン(4.5g)、酢酸カリウム(2.1g)およびPdCl2dppf(75mg)をDMF(40ml)中で混合し、100℃で18時間加熱した。冷却した反応液をシリカに吸収させ、SPE(Si2×10g)に乗せた。SPEを酢酸エチル/シクロヘキサン勾配(0%から6.25%酢酸エチル)で溶離した。溶媒を減圧下で生成物分画から留去し、残留物をシクロヘキサンから再結晶して、N-シクロプロピル-5-フルオロ-4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-ベンズアミド(260mg)を得た。
3-フルオロ-4-メチル安息香酸(462mg、3.0mmol)を、臭素(2.31ml、45mmol)および鉄粉(252mg、4.5mmol)の撹拌混合物に窒素下で加えた。反応液を20℃で4時間撹拌し、、16時間放置した。チオ硫酸ナトリウム溶液(200ml)を加え、生成物を酢酸エチルで抽出した(150mlで3回)。酢酸エチル抽出液を合わせ、減圧下で溶媒留去した。粗生成物(異性体の混合物)をジメチルホルムアミド(7ml)に溶かした。シクロプロピルアミン(208μL、3.0mmol)、HOBT(405mg、3.0mmol)、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(575mg、3.0mmol)およびDIPEA(525μL、3.0mmol)を、前記撹拌溶液に加えた。反応液を20℃で5時間撹拌した。溶媒を減圧下で除去し、残留物を酢酸エチルと水との間で分配した。合わせた酢酸エチル抽出液を炭酸水素ナトリウム水溶液および塩酸(0.5M)の順序で洗浄し、脱水した(硫酸マグネシウム)。酢酸エチルを減圧下で留去し、残留物をシクロヘキサン:酢酸エチル(6:1)を溶離液とするシリカbiotageクロマトグラフィーによって精製して、3-ブロモ-N-シクロプロピル-5-フルオロ-4-メチルベンズアミドを得た(359mg、44%)。
N-シクロプロピル-5-フルオロ-3-ヨード-4-メチルベンズアミド(中間体37、5g)のTHF(75ml)溶液を冷却して0℃とし、水素化ナトリウム(60%、1.23g)を10分間かけて少量ずつ加えた。発泡が停止したら、反応液を冷却して-75℃とし、n-ブチルリチウム(1.6Mヘキサン溶液、20ml)を、温度を-70℃より低温に維持しながら25分間かけて加えた。ホウ酸トリイソプロピル(8ml)を反応液に10分間かけて加え、反応液を-70℃で4時間撹拌した。反応を水(20ml)で停止し、混合物を昇温させて5℃とした。反応液を減圧下で濃縮し、残留物を飽和塩化アンモニウムと酢酸エチルとの間で分配した。有機相を飽和塩化アンモニウム、塩水で洗浄し、脱水し(硫酸ナトリウム)、減圧下で減量して乾固させた。残留物をDCM/酢酸エチルに溶かし、酢酸エチル/DCM勾配(5%から100%酢酸エチル)と次にメタノールを溶離液とするシリカでのカラムクロマトグラフィーによって精製した。生成物分画を合わせ、溶媒を減圧下で留去して、{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ボロン酸を得た。LCMS:MH+238、保持時間2.19分。
N-ヨードコハク酸イミド(22.5g)を、3-フルオロ-4-メチル安息香酸(15.4g)のトリフルオロメタンスルホン酸(100ml)溶液に0℃で3時間かけて少量ずつ加え、反応液を次に終夜で昇温させて室温とした。反応混合物を氷/水(400ml)に投入し、沈殿を濾過し、水で洗浄した。残った固体を酢酸エチルに溶かし、チオ硫酸ナトリウム水溶液(2回)、次に塩水で洗浄し、脱水し(硫酸マグネシウム)、溶媒を減圧下で留去した。残留物を塩化チオニル(30ml)と混合し、100℃で2.5時間加熱した。過剰の塩化チオニルを冷却した反応液から減圧下で除去し、残留物をDCM(100ml)に溶かした。炭酸ナトリウム(25g)およびシクロプロピルアミン(13ml)を溶液に加え、反応液を室温で72時間撹拌した。反応液を濾過し、残留物DCMおよび酢酸エチルで洗浄した。合わせた濾液および洗浄液から溶媒を減圧下で留去した。残留物をシリカに吸収させ、酢酸エチル/シクロヘキサン勾配(22%から28%酢酸エチル)で溶離を行うフラッシュシリカカラムでクロマトグラフィー精製した。適切な分画を減圧下で減量して乾固させて、N-シクロプロピル-5-フルオロ-3-ヨード-4-メチルベンズアミドを得た。
N-シクロプロピル-5-フルオロ-4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-ベンズアミド(3.2g)、6-クロロニコチン酸メチル(1.73g)、テトラキス(トリフェニルホスフィン)パラジウム(210mg)および炭酸水素ナトリウム水溶液(1M、30ml)をプロパン-2-オール(100ml)中で混合し、90℃で18時間加熱した。反応液を放冷し、プロパン-2-オールを減圧下で除去した。残留物を酢酸エチルと炭酸水素ナトリウム水溶液(1M)との間で分配した。水相を塩酸(2N)で酸性とし、酢酸エチルで抽出した(2回)。有機抽出液を塩水で洗浄し、脱水し(硫酸マグネシウム)、減圧下で減量して乾固させた。得られた泡状物をエーテルで磨砕して、6-{5-[(シクロプロピルアミノ)カルボニル]-3-フルオロ-2-メチルフェニル}ニコチン酸を固体として得た。
2-エチルシクロプロピルカルボキサミド(250mg、2.2mmol)のTHF溶液を加熱還流した。ボラン−ジメチルスルフィド(1MのDCM溶液、3.2ml、3.2mmol)を30分間かけて滴下し、反応液を16時間還流した。塩酸(6N、0.5ml)を滴下し、混合物を30分間加熱還流した。冷却した反応液混合物を水(20ml)で希釈し、エーテル(50ml)で洗浄し、水酸化ナトリウム(6N)で塩基性とした。水相をエーテル(50mlで3回)および酢酸エチル(50ml)で抽出した。合わせた有機抽出液を脱水し(硫酸マグネシウム)、塩化水素(3.3Mメタノール溶液)で酸性とし、減圧下で減量して乾固させて、(2-エチルシクロプロピル)メチルアミン(230mg)を得た。
2-クロロピリジン(0.05mmol)、フェニルピナコールボラン(0.05mmol)、テトラキス(トリフェニルホスフィン)パラジウム(1mg)および炭酸ナトリウム水溶液(0.25ml)のプロパン-2-オール(1ml)溶液を、85℃で窒素下に18時間加熱した。冷却した反応液を酢酸エチル(4ml)およびメタノール(2ml)で希釈し、SCXボンド−エルート(1g)で濾過した。生成物を10%アンモニア(比重0.88)のメタノール溶液で溶離した。溶媒を留去し、残留物をエーテルで磨砕した。
6-クロロニコチンアミド(25mg)、N-シクロプロピル-5-フルオロ-4-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-ベンズアミド(中間体34、15mg)、テトラキス(トリフェニルホスフィノ)パラジウム(2mg)および炭酸水素ナトリウム水溶液(1M、0.5ml)をプロパン-2-オール(2ml)中で混合し、18時間加熱還流した。プロパン-2-オールを留去し、残留物を酢酸エチル/シクロヘキサン(1:2)で希釈した。溶液をSPE(Si、2g)に乗せ、酢酸エチル/シクロヘキサン(1:2)で溶離し、次に酢酸エチルで溶離した。溶媒を酢酸エチル分画から留去し、残留物をエーテルで磨砕して、所望の生成物を白色固体として得た。
中間体38(40μmol)のDMF(0.5ml)溶液をHATU(1.12当量)およびDIPEA(3当量)で処理した。振盪すると溶液が形成され、それをアミン(1.2〜2.0当量)のDMF(0.5ml)溶液に加えた。振盪後、反応液を室温で終夜放置した。溶媒を減圧下で除去し、残留物をクロロホルム(1.0ml)に溶かし、SPE(NH2、0.5g)に乗せた。生成物をクロロホルム(1.5ml)、酢酸エチル(1.5ml)およびメタノール/酢酸エチル(1:9、1.5ml)で溶離した。生成物分画から溶媒を減圧下で留去した。
DCM:塩化メチレン
DIPEA:N,N-ジイソプロピルエチルアミン
DME:ジメトキシエタン
DMF:ジメチルホルムアミド
DMSO:ジメチルスルホキシド
HATU:O-(7-アザベンゾトリアゾール-1-イル)-N,N,N′,N′-テトラメチルウロニウムヘキサフルオロホスフェート
HOBT:1-ヒドロキシベンゾトリアゾール水和物
SPE:ボンド−エルート(固相抽出カラム)。
p38アッセイで用いたペプチド基質は、ビオチン-IPTSPITTTYFFFRRR-アミドであった。p38タンパク質およびMEK6タンパク質を、大腸菌発現系から均質となるまで精製した。融合タンパク質に、N末端にグルタチオン-S-トランスフェラーゼ(GST)でタグ付けした。阻害薬の6%DMSO中の溶液15μLを用いた場合または用いない場合で1.5μM ATPの0.08μCi[g-33P]ATPとの混合物15μLに加えた、1.5μMペプチドおよび10mM Mg(CH3CO2)2の100mM HEPES(pH7.5)中の溶液存在下での30nM MEK6タンパク質および120nM p38タンパク質の反応混合物20μLをインキュベートすることで、最大活性化を得た。対照は、50mM EDTA存在下(陰性対照)または非存在下(陽性対照)での反応とした。室温で60分間反応を進行させ、250mM EDTA50μLを加えることで反応停止し、ストレプトアビジンSPAビーズ(Amersham)150μLと0.5mg/反応で混合した。Dynatech Microfluor白色U底プレートを封止し、ビーズを終夜沈殿させた。それらのプレートを、Packard TopCountで60秒間カウントした。生データを%I=100×(1-(I-C2)/(C1-C2))(式中、IはバックグラウンドのCPMであり、C1は陽性対照であり、C2は陰性対照である)に適合させることでIC50値を得た。
αP38を社内で得た。SB4777790-RリガンドをMgCl2、CHAPS、DTTおよびDMSOを含むHEPESで希釈した。それを、Black NUNC384ウェルプレートのブランクウェルに加えた。αP38をそのリガンド混合物に加え、次に対照および化合物の入った384ウェルプレートの残りに加えた。プレートをLJLアナリスト(Analyst)で読み取り、蛍光異方性を用いて化合物の阻害を計算した。
実施例に記載の化合物を上記の方法に従って調べたところ、10μMより小さいIC50値を有していた。
Claims (13)
- 下記式(I)の化合物。
R1は、水素、C1-6アルコキシ、ハロゲンおよびヒドロキシから選択される3個以下の基によって置換されていても良いC1-6アルキル、C2-6アルケニル、1以上のC1-6アルキル基によって置換されていても良いC3-7シクロアルキル、R5およびR6から選択される3個以下の基によって置換されていても良いフェニル、ならびにR5およびR6から選択される3個以下の基によって置換されていても良いヘテロアリールから選択され;
R2は、水素、C1-6アルキルおよび1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキルから選択され;
あるいは(CH2)mR1およびR2が、それらが結合している窒素原子と一体となって、3個以下のC1-6アルキル基によって置換されていても良い4〜6員の複素環を形成しており;
R3は、クロロまたはメチルであり;
R4は、基-NH-CO-R7または-CO-NH-(CH2)q-R8であり;
R5は、C1-6アルキル、C1-6アルコキシ、1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキル、-CONR9R10、-NHCOR10、-SO2NHR9、-(CH2)sNHSO2R10、ハロゲン、CN、OH、-(CH2)sNR11R12およびトリフルオロメチルから選択され;
R6は、C1-6アルキル、C1-6アルコキシ、ハロゲン、トリフルオロメチルおよび-(CH2)sNR11R12から選択され;
R7は、水素、C1-6アルキル、1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキル、トリフルオロメチル、R13および/またはR14によって置換されていても良い-(CH2)rヘテロアリール、ならびにR13および/またはR14によって置換されていても良い-(CH2)rフェニルから選択され;
R8は、水素、C1-6アルキル、1以上のC1-6アルキル基によって置換されていても良いC3-7シクロアルキル、CONHR9、R13および/またはR14によって置換されていても良いフェニル、ならびにR13および/またはR14によって置換されていても良いヘテロアリールから選択され;
R9およびR10はそれぞれ独立に、水素およびC1-6アルキルから選択され;
あるいはR9とR10が、それらが結合している窒素原子と一体となって、酸素、硫黄およびN-R15から選択される1個の更なるヘテロ原子を有していても良い5〜6員の複素環を形成しており、前記環は2個以下のC1-6アルキル基によって置換されていても良く;
R11は、水素、C1-6アルキルおよび1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキルから選択され;
R12は、水素およびC1-6アルキルから選択され;
あるいはR11とR12が、それらが結合している窒素原子と一体となって、酸素、硫黄およびN-R15から選択される1個の更なるヘテロ原子を有していても良い5員もしくは6員の複素環を形成しており;
R13は、C1-6アルキル、C1-6アルコキシ、1以上のC1-6アルキル基によって置換されていても良い-(CH2)q-C3-7シクロアルキル、-CONR9R10、-NHCOR10、ハロゲン、CN、-(CH2)sNR11R12、トリフルオロメチル、1以上のR14基によって置換されていても良いフェニルおよび1以上のR14基によって置換されていても良いヘテロアリールから選択され;
R14は、C1-6アルキル、C1-6アルコキシ、ハロゲン、トリフルオロメチルおよび-NR11R12から選択され;
R15は、水素およびメチルから選択され;
XおよびYはそれぞれ独立に、水素、メチルおよびハロゲンから選択され;
Zはハロゲンであり;
mは0、1、2、3および4から選択され、得られる炭素鎖の各炭素原子はC1-6アルキルおよびハロゲンから独立に選択される2個以下の基によって置換されていても良く;
nは、0、1および2から選択され;
qは、0、1および2から選択され;
rは、0および1から選択され;
sは、0、1、2および3から選択される。] - R1が、C1-6アルキル、C2-6アルケニル、1以上のC1-6アルキル基によって置換されていても良いC3-7シクロアルキル、R5およびR6から選択される3個以下の置換基によって置換されていても良いフェニル、R5およびR6から選択される3個以下の置換基によって置換されていても良いヘテロアリールから選択される請求項1に記載の化合物。
- R2が水素である請求項1または請求項2に記載の化合物。
- R3がメチルである請求項1〜3のいずれかに記載の化合物。
- Xがフッ素である請求項1〜4のいずれかに記載の化合物。
- R7が、C1-6アルキル、-(CH2)q-C3-7シクロアルキル、トリフルオロメチル、R13および/またはR14によって置換されていても良い-(CH2)rヘテロアリール、ならびにC1-6アルキル、C1-6アルコキシ、-(CH2)q-C3-7シクロアルキル、-CONR9R10、-NHCOR10、ハロゲン、CN、トリフルオロメチル、1以上のR14基によって置換されていても良いフェニルおよび/または1以上のR14基によって置換されていても良いヘテロアリールによって置換されていても良い-(CH2)rフェニルから選択される請求項1〜5のいずれかに記載の化合物。
- R8が、C3-7シクロアルキル、CONHR9、R13および/またはR14によって置換されていても良いヘテロアリール、ならびにC1-6アルキル、C1-6アルコキシ、-(CH2)q-C3-7シクロアルキル、-CONR9R10、-NHCOR10、ハロゲン、CN、トリフルオロメチル、1以上のR14基によって置換されていても良いフェニルおよび/または1以上のR14基によって置換されていても良いヘテロアリールによって置換されていても良いフェニルから選択される請求項1〜6のいずれかに記載の化合物。
- 実施例1〜123のいずれかで定義される請求項1に記載の化合物。
- 1以上の製薬上許容される担体、希釈剤または賦形剤との混合で請求項1〜8のいずれかに記載の化合物を含む医薬組成物。
- p38キナーゼ活性が介在するまたはp38キナーゼの活性によって産生されるサイトカイン類が介在する状態または疾患状態を治療する方法において、その処置を必要とする患者に対して請求項1〜8のいずれかに記載の化合物を投与する段階を有する方法。
- 治療において使用するための請求項1〜8のいずれかに記載の化合物。
- p38キナーゼ活性が介在するまたはp38キナーゼの活性によって産生されるサイトカイン類が介在する状態または疾患状態の治療において使用するための医薬の製造における請求項1〜8のいずれかに記載の化合物の使用。
- 請求項1〜8のいずれかに記載の式(I)の化合物を製造する方法において、
(a)下記式(II)の化合物:
(b)下記式(VIII)の化合物:
(c)上記で定義される式(II)の化合物を下記式(IX)の化合物:
を有する方法。
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PCT/GB2003/000554 WO2003068747A1 (en) | 2002-02-12 | 2003-02-10 | Nicotinamide derivates useful as p38 inhibitors |
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