CN111170938A - 作为大麻素受体激动剂的5,6-双取代的吡啶-2-甲酰胺 - Google Patents
作为大麻素受体激动剂的5,6-双取代的吡啶-2-甲酰胺 Download PDFInfo
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- CN111170938A CN111170938A CN202010029759.8A CN202010029759A CN111170938A CN 111170938 A CN111170938 A CN 111170938A CN 202010029759 A CN202010029759 A CN 202010029759A CN 111170938 A CN111170938 A CN 111170938A
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- Prior art keywords
- cyclopropylmethoxy
- pyridine
- carboxamide
- amino
- methyl
- Prior art date
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- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical class NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229940121376 cannabinoid receptor agonist Drugs 0.000 title abstract description 4
- 239000003537 cannabinoid receptor agonist Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 209
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 208000002193 Pain Diseases 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 12
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 11
- -1 alkoxyazetidinyl Chemical group 0.000 claims description 235
- 238000000034 method Methods 0.000 claims description 76
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 208000020016 psychiatric disease Diseases 0.000 claims description 21
- 208000028017 Psychotic disease Diseases 0.000 claims description 20
- 206010020751 Hypersensitivity Diseases 0.000 claims description 19
- 208000026935 allergic disease Diseases 0.000 claims description 19
- 230000007815 allergy Effects 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 15
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 claims description 14
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 12
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 11
- 206010003246 arthritis Diseases 0.000 claims description 11
- 206010014599 encephalitis Diseases 0.000 claims description 11
- 208000026278 immune system disease Diseases 0.000 claims description 11
- 208000004296 neuralgia Diseases 0.000 claims description 11
- 208000021722 neuropathic pain Diseases 0.000 claims description 11
- 201000004792 malaria Diseases 0.000 claims description 10
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 10
- 208000006673 asthma Diseases 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 8
- 125000005059 halophenyl group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- MAFKTWZURAOPCI-UHFFFAOYSA-N 3-[6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]-1,1-dioxo-1,3-thiazolidine-4-carboxamide Chemical compound C1C(OC)CN1C1=CC=C(C(=O)N2C(CS(=O)(=O)C2)C(N)=O)N=C1OCC1CC1 MAFKTWZURAOPCI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 6
- IXMCJACYFJDRFX-UHFFFAOYSA-N C1(CC1)COC1=C(C=CC(=N1)C(=O)NC(C(=O)OCC)(CC)CC)N1CC(C1)OC Chemical compound C1(CC1)COC1=C(C=CC(=N1)C(=O)NC(C(=O)OCC)(CC)CC)N1CC(C1)OC IXMCJACYFJDRFX-UHFFFAOYSA-N 0.000 claims description 5
- IVSMYRNWWFHIKJ-UHFFFAOYSA-N COC(=O)C(C)(C)NC(=O)C1=NC(OCC2CC2)=C(C=C1)C1=CC=C(Cl)C=C1 Chemical compound COC(=O)C(C)(C)NC(=O)C1=NC(OCC2CC2)=C(C=C1)C1=CC=C(Cl)C=C1 IVSMYRNWWFHIKJ-UHFFFAOYSA-N 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 239000007822 coupling agent Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000002393 azetidinyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 4
- KHCYMZHRGVCYOE-UHFFFAOYSA-N n-(cyclopropylmethoxy)pyridine-2-carboxamide Chemical compound C=1C=CC=NC=1C(=O)NOCC1CC1 KHCYMZHRGVCYOE-UHFFFAOYSA-N 0.000 claims description 4
- GYEDEPHMOZXBNO-INIZCTEOSA-N C1(CC1)C1(CN(C1)C=1C=CC(=NC1OCC1CC1)C(=O)N1[C@@H](CC(C1)(F)F)C(=O)N)F Chemical compound C1(CC1)C1(CN(C1)C=1C=CC(=NC1OCC1CC1)C(=O)N1[C@@H](CC(C1)(F)F)C(=O)N)F GYEDEPHMOZXBNO-INIZCTEOSA-N 0.000 claims description 3
- RZTQGNGZPDOCMX-AWEZNQCLSA-N C1(CC1)COC1=C(C=CC(=N1)C(=O)N1[C@@H](CC(C1)(F)F)C(=O)N)N1CC(C1)(C)F Chemical compound C1(CC1)COC1=C(C=CC(=N1)C(=O)N1[C@@H](CC(C1)(F)F)C(=O)N)N1CC(C1)(C)F RZTQGNGZPDOCMX-AWEZNQCLSA-N 0.000 claims description 3
- BJEAZVONSZMYLQ-FUKCDUGKSA-N C1(CC1)COC1=C(C=CC(=N1)C(=O)N1[C@@H](CC(C1)(F)F)C(=O)N)N1CC2(C(C2)(F)F)CC1 Chemical compound C1(CC1)COC1=C(C=CC(=N1)C(=O)N1[C@@H](CC(C1)(F)F)C(=O)N)N1CC2(C(C2)(F)F)CC1 BJEAZVONSZMYLQ-FUKCDUGKSA-N 0.000 claims description 3
- CUFRWCNHIJFMPN-UHFFFAOYSA-N C1(CC1)COC1=C(C=CC(=N1)C(=O)NC(CC)(CC)C(NC)=O)C1=CC=CC=C1 Chemical compound C1(CC1)COC1=C(C=CC(=N1)C(=O)NC(CC)(CC)C(NC)=O)C1=CC=CC=C1 CUFRWCNHIJFMPN-UHFFFAOYSA-N 0.000 claims description 3
- IMDOYSQNCCGMSP-INIZCTEOSA-N ClC1=CC=C(C=C1)C1=C(C=CC(=N1)C(=O)N1[C@@H](CC(C1)(F)F)C(=O)N)OCC1CC1 Chemical compound ClC1=CC=C(C=C1)C1=C(C=CC(=N1)C(=O)N1[C@@H](CC(C1)(F)F)C(=O)N)OCC1CC1 IMDOYSQNCCGMSP-INIZCTEOSA-N 0.000 claims description 3
- OMMFPEXBRQUFCE-UHFFFAOYSA-N ClC1=CC=C(C=C1)C=1C=CC(=NC1SC)C(=O)NC(C(=O)OC)(C)C Chemical compound ClC1=CC=C(C=C1)C=1C=CC(=NC1SC)C(=O)NC(C(=O)OC)(C)C OMMFPEXBRQUFCE-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000006809 haloalkylaminocarbonyl group Chemical group 0.000 claims description 2
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000003566 oxetanyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 102100036214 Cannabinoid receptor 2 Human genes 0.000 abstract description 6
- 239000000556 agonist Substances 0.000 abstract description 6
- 101710187022 Cannabinoid receptor 2 Proteins 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000000203 mixture Substances 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- 239000007787 solid Substances 0.000 description 46
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 43
- 239000000243 solution Substances 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- 239000002904 solvent Substances 0.000 description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- 125000006239 protecting group Chemical group 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 239000012267 brine Substances 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- RBDFMUHRMMDRHC-UHFFFAOYSA-N 2-bromo-1-ethyl-2h-pyridine Chemical compound CCN1C=CC=CC1Br RBDFMUHRMMDRHC-UHFFFAOYSA-N 0.000 description 16
- LESSBBNJOCTDLE-UHFFFAOYSA-N 6-(cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carboxylic acid Chemical compound C1C(OC)CN1C1=CC=C(C(O)=O)N=C1OCC1CC1 LESSBBNJOCTDLE-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 15
- 239000007832 Na2SO4 Substances 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000009833 condensation Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 11
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- 239000012442 inert solvent Substances 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000005457 ice water Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- ZOCVYDBVGCMDHA-UHFFFAOYSA-N methyl 5-bromo-6-(cyclopropylmethoxy)pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(Br)C(OCC2CC2)=N1 ZOCVYDBVGCMDHA-UHFFFAOYSA-N 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 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 8
- QGVWIIQJCHMZSJ-UHFFFAOYSA-N 2-(3-aminooxetan-3-yl)acetamide Chemical compound NC(=O)CC1(N)COC1 QGVWIIQJCHMZSJ-UHFFFAOYSA-N 0.000 description 8
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 8
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- 239000012317 TBTU Substances 0.000 description 8
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 8
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- 238000002425 crystallisation Methods 0.000 description 8
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- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- QOGFVKATFSDNGB-UHFFFAOYSA-N 2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine Chemical compound CC1=NC(C(C)(C)N)=NO1 QOGFVKATFSDNGB-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- KNIPTWZOFFXGRD-UHFFFAOYSA-N 6-(4-chlorophenyl)-5-(cyclopropylmethoxy)pyridine-2-carboxylic acid Chemical compound C=1C=C(Cl)C=CC=1C1=NC(C(=O)O)=CC=C1OCC1CC1 KNIPTWZOFFXGRD-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- ROVTZDCTDACOLT-UHFFFAOYSA-N ClC=1C=C(C=CC1)C1=C(C=CC(=N1)C(=O)O)OCC1CC1 Chemical compound ClC=1C=C(C=CC1)C1=C(C=CC(=N1)C(=O)O)OCC1CC1 ROVTZDCTDACOLT-UHFFFAOYSA-N 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 238000010976 amide bond formation reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
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Abstract
本发明涉及作为大麻素受体激动剂的5,6‑双取代的吡啶‑2‑甲酰胺。具体地,本发明涉及式(I)的化合物,其中R1至R4如说明书中和权利要求中定义。式(I)的化合物是大麻素受体2的激动剂,并且因此可用于治疗各种疾病如疼痛、骨质疏松、炎症等。
Description
本申请是PCT国际申请日为2015年4月1日,PCT国际申请号为 PCT/EP2015/057144、中国国家申请号为2015800167835、发明名称为《作为大麻素受体激动剂的5,6-双取代的吡啶-2-甲酰胺》的申请的分案申请。
本发明涉及用于在哺乳动物中治疗和/或预防的有机化合物,并且特别是大麻素受体2的优选的反向激动剂的化合物。
本发明特别涉及式(I)的化合物
其中
R1是烷硫基、环烷基烷氧基、卤代苯基或卤素;
R2是苯基、卤代苯基、环烷基烷氧基、烷氧基氮杂环丁烷基、2- 氧杂-6-氮杂螺[3.3]庚基、(卤代烷基)(羟基)吡咯烷基、卤代-5-氮杂螺[2.4] 庚基、(烷基)(卤代)氮杂环丁烷基或(环烷基)(卤代)氮杂环丁烷基;
R3和R4中的一个是氢并且另一个是-(CR5R6)m-(CH2)n-R7;
或R3和R4与它们连接的氮原子一起形成氨基羰基-二氧代-噻唑烷基或(氨基羰基)(卤代)吡咯烷基;
R5和R6独立地选自氢、烷基、环烷基烷基和烷硫基烷基;
或R5和R6与它们连接的碳原子一起形成氧杂环丁烷基;
m是0或1;
n是0或1;
或其药用盐或酯。
式(I)的化合物特别用于治疗或预防疼痛(pain)、神经性疼痛(neuropathicpain)、哮喘(asthma)、骨质疏松(osteoporosis)、炎症(inflammation)、精神疾病(psychiatric diseases)、精神病(psychosis)、肿瘤(oncology)、脑炎 (encephalitis)、疟疾(malaria)、变态反应(allergy)、免疫性病症(immunological disorders)、关节炎(arthritis)、胃肠道病症(gastrointestinal disorders)、精神异常(psychiatricdisorders)、类风湿性关节炎(rheumatoid arthritis)、精神病和变态反应。
大麻素受体是一类细胞膜受体,属于G蛋白-偶联受体超家族。目前存在两种已知亚型,称为大麻素受体1(CB1)和大麻素受体2(CB2)。CB1 受体主要表达在中枢神经(即杏仁核小脑,海马体)系统中并且在外周中以较少量表达。由CNR2基因编码的CB2主要在免疫系统的细胞,如巨噬细胞和T-细胞上(Ashton,J.C.等Curr Neuropharmacol 2007,5(2),73-80; Miller,A.M.等Br J Pharmacol 2008,153(2),299-308;Centonze,D.,等 Curr PharmDes 2008,14(23),2370-42),和在胃肠系统中(Wright,K.L. 等Br J Pharmacol 2008,153(2),263-70)外周表达。CB2受体还广泛分布于脑中,其中它主要发现于小胶质细胞而非神经元上(Cabral,G.A.等Br J Pharmacol 2008,153(2):240-51)。
在过去十年对CB2受体配体的兴趣稳步上升(目前30-40件专利申请/ 年)。不同来源的证据支持这样的观点:通过CB2受体的脂内源性大麻素信号传导代表哺乳动物保护性医疗设备的一个方面(Pacher,P.Prog Lipid Res 2011,50,193)。通过选择性CB2受体激动剂或反向激动剂/拮抗剂(取决于疾病和其阶段)对其的调节在大量疾病中保持唯一的治疗潜能。对于 CB2反向激动剂/拮抗剂,对于很多病理状况证明了治疗可能性:所述病理状况包括疼痛(Pasquini,S.J Med Chem 2012,55(11):5391),神经性疼痛(Garcia-Gutierrez,M.S.Br J Pharmacol 2012,165(4):951),精神病症 (Garcia-Gutierrez,M.S.Br JPharmacol 2012,165(4):951),精神病 (Garcia-Gutierrez,M.S.Br J Pharmacol 2012,165(4):951),骨质疏松和炎症(Sophocleous,A.Calcif Tissue Int 2008,82(Suppl.1):Abst OC18),精神疾病和精神病(Garcia-Gutierrez,M.S.Br J Pharmacol 2012,165(4):951),肿瘤(Preet,A.Cancer Prev Res 2011,4:65),脑炎和疟疾(Zimmer,A.WO2011045068),变态反应和炎症(Ueda,Y.Life Sci 2007,80(5):414),脑炎和疟疾(Zimmer,WO 2011045068),哮喘(Lunn,C.A.J Pharmacol Exp Ther 2006,316(2):780),免疫性病症(Fakhfouri,G.Neuropharmacology 2012, 63(4):653),类风湿性关节炎(Chackalamannil,S.US 7776889),关节炎(Lunn, C.A.J Pharmacol Exp Ther 2006,316(2):780),和胃肠道病症(Barth,F.FR 2887550)。
本发明的化合物结合和调节CB2受体并且具有较低的CB1受体活性。
在本说明书中,术语“烷基”,单独或组合地表示具有1至8个碳原子的直链或支链烷基,特别是具有1至6个碳原子的直链或支链烷基,更特别是具有1至4个碳原子的直链或支链烷基。直链和支链C1-C8烷基的实例为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、异构的戊基、异构的己基、异构的庚基和异构的辛基,特别是甲基、乙基、丙基、丁基和戊基。烷基的特别的实例是甲基、乙基、异丙基、丁基、异丁基、叔丁基和戊基。甲基、乙基和异丁基是式(I)的化合物中烷基的特别实例。
术语“环烷基”,单独或组合地表示具有3至8个碳原子的环烷基环,并且特别是具有3至6个碳原子的环烷基环。环烷基的实例是环丙基、环丁基、环戊基和环己基、环庚基和环辛基。“环烷基”的特别的实例是环丙基和环己基。
术语“烷氧基”,单独或组合地表示式烷基-O-的基团,其中术语″烷基″具有之前给出的含义,如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。特别的“烷氧基”是甲氧基和乙氧基。
术语“氧基”,单独或组合,表示-O-基团。
术语“氧代”,单独或组合,表示=O基团。
术语“卤素”或“卤代”,单独或组合地表示氟、氯、溴或碘,并特别是氟、氯或溴,更特别是氟和氯。术语“卤代”,与另一基团组合地表示所述基团被至少一个卤素的取代,特别是被一至五个卤素,特别是一至四个卤素,即一、二、三或四个卤素的取代。
术语“羟基(hydroxyl)”和“羟基(hydroxy)”,单独或组合地表示-OH基团。
术语“羰基”,单独或组合地表示-C(O)-基团。
术语“氨基”,单独或组合地表示伯氨基(-NH2),仲氨基(-NH-),或叔氨基(-N-)。
术语“氨基羰基”,单独或组合地表示-C(O)-NH2、-C(O)-NH-或-C(O)-N- 基团。
术语“硫基”,单独或组合地表示-S-基团。
术语“药用盐”是指保持游离碱或游离酸的生物有效性和性质的那些盐,它们不是生物学上或其他方面不适宜的。所述盐用无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸,特别是盐酸,以及有机酸如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸、 N-乙酰基半胱氨酸形成。此外,这些盐可以通过无机碱或有机碱向游离酸的加入而制备。得自无机碱的盐包括,但是不限于,钠、钾、锂、铵、钙、镁盐。得自有机碱的盐包括,但是不限于以下物质的盐:伯、仲和叔胺,取代的胺,包括天然存在的取代的胺、环状胺和碱性离子交换树脂,如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N- 乙基哌啶、哌啶、聚胺树脂。式(I)的化合物也可以以两性离子的形式存在。特别优选的式(I)的化合物的药用盐是盐酸、氢溴酸、硫酸、磷酸和甲磺酸的盐。
″药用酯″表示通式(I)的化合物可以在官能团处衍生化以提供衍生物,其能够体内转化回母体化合物。这种化合物的实例包括生理上可接受的和易代谢的酯衍生物,如甲氧基甲酯,甲硫基甲酯和新戊酰基氧基甲酯。此外,类似于易代谢的酯的、能够在体内产生通式(I)母体化合物的、通式(I) 化合物的生理上可接受的任何等同物均在本发明的范围内。
如果原料之一或式(I)化合物含有一个或多个在一个或多个反应步骤的反应条件下不稳定或具有反应性的官能团,则可以应用本领域周知的方法在关键步骤之前引入合适的保护基(如例如T.W.Greene和P.G.M.Wuts 在“Protective Groups in OrganicChemistry”,第3版,1999,Wiley,New York 中所述)。这样的保护基可以在合成的稍后阶段使用文献中所述的标准方法除去。保护基的实例是叔丁氧羰基(Boc),氨基甲酸9-芴基甲酯(Fmoc),氨基甲酸2-三甲基甲硅烷基乙酯(Teoc),苄氧羰基(Cbz)和对甲氧基苄氧基羰基(Moz)。
式(I)化合物可以含有几个不对称中心,并且其存在形式可以是光学纯对映异构体,对映异构体的混合物,如例如外消旋物,非对映异构体的混合物,非对映异构体外消旋物或非对映异构体外消旋物的混合物。
术语“不对称碳原子”表示具有四个不同取代基的碳原子。根据 Cahn-Ingold-Prelog Convention,不对称碳原子可以为“R”或“S”构型。
本发明尤其涉及:
式(I)的化合物,其中R1是环烷基烷氧基或卤代苯基;
式(I)的化合物,其中R1是环丙基甲氧基或氯苯基;
式(I)的化合物,其中R2是苯基、卤代苯基、环烷基烷氧基或烷氧基氮杂环丁烷基;
式(I)的化合物、其中R2是苯基、氯苯基、环丙基甲氧基或甲氧基氮杂环丁烷基;
式(I)的化合物、其中R5和R6独立地选自氢和烷基;
式(I)的化合物、其中R5和R6独立地选自氢、甲基、乙基和异丁基;
本发明还涉及式(I)的化合物,其选自:
2-[[5-(4-氯苯基)-6-甲硫基吡啶-2-羰基]氨基]-2-甲基丙酸甲酯;
2-[[5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-羰基]氨基]-2-甲基丙酸甲酯;
6-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]-5-苯基吡啶-2-甲酰胺;
6-(3-氯苯基)-5-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2- 甲酰胺;
N-[(2S)-1-氨基-3-环丙基-1-氧代丙-2-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(2-氧杂-6- 氮杂螺[3.3]庚-6-基)吡啶-2-甲酰胺;
6-(3-氯苯基)-5-(环丙基甲氧基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-3-环丙基-1-氧代丙-2-基]-5,6-双(环丙基甲氧基)吡啶-2- 甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲硫基-1-氧代丁-2-基]-6-氯-5-(环丙基甲氧基)吡啶 -2-甲酰胺;
6-氯-5-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;
3-[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]-1,1-二氧代-1,3-噻唑烷-4-甲酰胺;
2-[[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]氨基]-2-乙基丁酸乙酯;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;
6-(环丙基甲氧基)-N-[(1-羟基环己基)甲基]-5-(3-甲氧基氮杂环丁烷-1- 基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-N-[3-(2-氟乙基氨基甲酰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-N-[3-(3-氟氮杂环丁烷-1-羰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-N-[3-(3-氟丙基氨基甲酰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
(2S)-1-[6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2- 羰基]-4,4-二氟吡咯烷-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-[3-羟基 -3-(三氟甲基)吡咯烷-1-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(2,2-二氟 -5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酰胺;
(2S)-1-[6-(环丙基甲氧基)-5-(2,2-二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(2,2- 二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-氟-3-甲基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
(2S)-1-[6-(环丙基甲氧基)-5-(3-氟-3-甲基氮杂环丁烷-1-基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(3-氟 -3-甲基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-甲酰胺;
(2S)-1-[5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-甲酰胺;
(2S)-1-[6-(4-氯苯基)-5-(环丙基甲氧基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)-N-[3-(3-氟丙基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;和
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(4-氯苯基)-5-(环丙基甲氧基) 吡啶-2-甲酰胺。
本发明还特别涉及式(I)的化合物,其选自
2-[[5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-羰基]氨基]-2-甲基丙酸甲酯;
6-(3-氯苯基)-5-(环丙基甲氧基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
3-[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]-1,1-二氧代-1,3-噻唑烷-4-甲酰胺;
2-[[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]氨基]-2-乙基丁酸乙酯;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;和
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(4-氯苯基)-5-(环丙基甲氧基) 吡啶-2-甲酰胺。
除非另有指示,在下述方案中R1-R7具有如上所定义的意义。
具有通式I的化合物的合成可以例如根据以下方案完成。
按照根据方案1的程序,化合物AA(X=Cl,Br,I或三氟甲磺酸盐或酯;R’=H、甲基、乙基、异丙基、叔丁基或例如在T.W.Greene等人,Protective Groups in OrganicChemistry,John Wiley和Sons Inc.New York 1999,第3版中描述的另一合适的保护基团)可以用作起始材料。AA是可商购的,文献中描述的,可以由本领域技术人员合成,可以如方案3和6 描述或如实验部分所述的合成。
方案1
化合物AC可以由AA通过如下制备:在合适的催化剂,特别是钯催化剂并且更特别是乙酸钯(II)/三苯基膦混合物或氯化钯(II)-dppf(1,1′-双(二苯基膦基)二茂铁)配合物和碱如三乙胺、碳酸钠或碳酸钾的存在下,在惰性溶剂如二甲基甲酰胺、甲苯、四氢呋喃、乙腈和二甲氧基乙烷中,偶联式AB的适当取代的芳基金属物种(M是例如三氟硼酸盐[BF3]-K+、硼酸 B(OH)2或硼酸频哪醇酯基团)(步骤a),特别是芳基硼酸或芳基硼酸酯基团。
通过本领域技术人员公知的方法皂化通式AC的酯(R’≠H)-在四氢呋喃/乙醇或另一合适的溶剂中在0℃至所使用的溶剂的回流温度的温度使用例如LiOH,NaOH或KOH水溶液-得到通式II的酸(步骤b)。
化合物I可以由II和相应的式III的胺通过合适的酰胺键形成反应制备(步骤c)。这些反应是本领域中已知的。例如偶联剂如N,N’-羰基-二咪唑 (CDI),N,N’-二环己基碳二亚胺(DCC),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),1-[双(二甲基氨基)-亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶-3-氧化物六氟磷酸盐(HATU),1-羟基-1,2,3-苯并三唑(HOBT),O-苯并三唑-1-基-N,N,N’,N’-四甲基脲四氟硼酸盐(TBTU),和O-苯并三唑 -N,N,N’,N’-四甲基-脲-六氟-磷酸盐(HBTU)可以用于影响该转化。方便的方式是在室温,在惰性溶剂如例如二甲基甲酰胺中使用例如HBTU和碱如 N-甲基吗啉。
备选地,通式AA的酯(R’≠H)可以通过本领域技术人员公知的方法皂化-在四氢呋喃/乙醇或另一合适的溶剂中在0℃至所使用的溶剂的回流温度的温度,使用例如LiOH、NaOH或KOH水溶液-得到通式AD 的酸(步骤b’)。
化合物AE可以由AD和相应的式III的胺制备通过合适的酰胺键形成反应(步骤c’)。这些反应是本领域中已知的。例如偶联剂如N,N’-羰基-二咪唑(CDI),N,N’-二环己基碳二亚胺(DCC),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI),1-[双(二甲基氨基)-亚甲基]-1H-1,2,3-三唑并 [4,5-b]吡啶-3-氧化物六氟磷酸盐(HATU),1-羟基-1,2,3-苯并三唑 (HOBT),O-苯并三唑-1-基-N,N,N’,N’-四甲基脲四氟硼酸盐(TBTU),和O-苯并三唑-N,N,N’,N’-四甲基-脲-六氟-磷酸盐(HBTU)可以用于影响该转化。方便的方法是在室温在惰性溶剂如例如二甲基甲酰胺中的使用例如 HBTU和碱如N-甲基吗啉。
化合物I可以由AE通过如下制备:在合适的催化剂,尤其是钯催化剂并且更特别是乙酸钯(II)/三苯基膦混合物或氯化钯(II)-dppf(1,1′-双(二苯基膦基)二茂铁)配合物和碱如三乙胺、碳酸钠或碳酸钾的存在下,在惰性溶剂如二甲基甲酰胺、甲苯、四氢呋喃、乙腈和二甲氧基乙烷中,偶联式 AB的适当取代的芳基金属物种(步骤a’),特别是芳基硼酸或芳基硼酸酯。
胺III是可商购的,文献中描述的,可以由本领域技术人员或如实验部分中所描述的合成。
如果起始材料:式AA,AB或III的化合物中的一种含有一个或多个在一个或多个反应步骤的反应条件下不稳定或具有反应性的官能团,可以利用本领域公知方法在关键步骤之前引入适当的保护基团(P)(如例如T.W. Greene等人,Protective Groups in OrganicChemistry,John Wiley and Sons Inc.New York 1999,第3版所述的)。这样的保护基团可以使用在合成的较晚阶段本领域中已知的标准方法去除。
如果式AA至AE,II或III的一个或多个化合物含有手性中心,可以获得式I的甲基吡啶为非对映异构体或对映异构体的混合物,其可以通过本领域中公知的方法如(手性)HPLC或结晶来分离。外消旋化合物可以例如经由非对映异构盐通过结晶或通过特定色谱方法使用手性吸附剂或手性洗脱剂分离对映体分离为其对映体。
按照根据方案2的程序,化合物BA(R’=H、甲基、乙基、异丙基、叔丁基或例如在T.W.Greene等人,Protective Groups in Organic Chemistry, John Wiley and SonsInc.New York 1999,第3版中描述的另一合适的保护基团)可以用作起始材料。BA可商购的,文献中描述的,或可以由本领域技术人员合成。
方案2
化合物BB可以由BA通过如下制备:用合适的氧化剂在本领域技术人员已知的条件(步骤a)下氧化,例如通过用3-氯过苯甲酸在二氯甲烷中在环境温度处理。
化合物BB向6-氯或6-溴-甲基吡啶AA’(X=Cl,Br)的转变可以例如通过在没有另外的溶剂的情况下或在合适的溶剂如氯仿中在20℃至溶剂的沸点的温度,用磷酰三氯或磷酰三溴处理,或通过使用文献中已知的其他条件实现(步骤b)。
6-氯-或溴-甲基吡啶AA’(X=Cl,Br)可以通过在碱如氢化钠的存在下,在有或没有惰性溶剂如二甲基甲酰胺的情况下,在室温至溶剂的回流温度的温度,特别是在室温,与适当取代的伯醇或仲醇BC反应而转化为化合物BD(步骤c)。
化合物BD可以通过如下进一步加工为化合物I:i)如方案1的步骤b 中所述的皂化(对于R’≠H的化合物BD)(步骤d);ii)如方案1的步骤c 中所述的酰胺键形成(步骤e)。
备选地,化合物AA’(R’=甲基、乙基、异丙基、叔丁基或例如在T.W. Greene等人,Protective Groups in Organic Chemistry,John Wiley and Sons Inc.New York 1999,第3版中描述的另一合适的保护基团)可以:i)如方案1 的步骤b中所述转变为其酸同类物AA’(R’=H);ii)通过如方案1的步骤 c中所述的用胺III的处理转化为相应的酰胺;和iii)如步骤c中所述与醇 BC反应,得到化合物I。
如果起始材料:式BA,BC或III的化合物中的一种含有一个或多个在一个或多个反应步骤的反应条件下不稳定或具有反应性的官能团,可以利用本领域公知的方法在关键步骤之前引入适当保护基团(P)(如例如在 T.W.Greene等人,Protective Groups inOrganic Chemistry,John Wiley and Sons Inc.New York 1999,第3版中所述的)。这样的保护基团可以在合成的较晚阶段使用本领域中已知的标准方法去除。
如果式BA至BD,AA',II或III的一个或多个化合物含有手性中心,可以获得式I的甲基吡啶为非对映异构体或对映异构体的混合物,其可以通过本领域中公知的方法如(手性)HPLC或结晶来分离。外消旋化合物可以例如经由非对映异构盐通过结晶或通过特定色谱方法使用手性吸附剂或手性洗脱剂分离对映体分离为其对映体。
按照根据方案3的程序,化合物CA(R’=H、甲基、乙基、异丙基、叔丁基或例如在T.W.Greene等人,Protective Groups in Organic Chemistry, John Wiley and SonsInc.New York 1999,第3版中所述的另一合适的保护基团)可以用作起始材料。CA是可商购的(例如对于R’=甲基:5-溴-6-氯- 吡啶-2-甲酸甲酯CAN 1214353-79-3),文献中描述的,或可以由本领域技术人员合成。
方案3
化合物AA”可以由CA通过如下制备:在钯催化剂如乙酸钯(II)/丁基 -1-金刚烷基膦和碱如碳酸铯的存在下,在惰性溶剂如甲苯中,在50℃至溶剂的沸点之间的温度,偶联式CB的适当取代的芳基金属物种(M是例如三氟硼酸盐[BF3]-K+、硼酸B(OH)2或硼酸频哪醇酯基团)(步骤a),例如有机三氟硼酸钾盐,或在合适的催化剂,尤其是钯催化剂并且更特别是乙酸钯(II)/三苯基膦混合物或氯化钯(II)-dppf(1,1′-双(二苯基膦基)二茂铁)配合物和碱如三乙胺、碳酸钠或碳酸钾的存在下,在惰性溶剂如二甲基甲酰胺、甲苯、四氢呋喃、乙腈或二甲氧基乙烷中,偶联芳基硼酸或芳基硼酸酯。任选地,化合物CB还可以是胺,其通过本领域技术人员公知的方法,例如使用钯催化剂如三(二亚苄基丙酮)二钯/二甲基双二苯基-膦基呫吨和碱如碳酸铯,在溶剂如1,4-二烷,优选在溶剂的沸点,偶联到CA。
化合物AA'可以通过如下进一步加工为化合物I:i)如方案2的步骤c 中所述的与化合物BC的反应,以生成化合物BD;ii)如方案1的步骤b 中所述的皂化;和iii)如方案1的步骤c中所述的酰胺键形成。
此外,化合物CA可以如方案2的步骤c中所述的通过用化合物BC 的处理转变为化合物CC(步骤b)。
之后化合物CC至化合物BD的转化可以如对于CA到AA”的转化所讨论的实现(步骤a)。
化合物BD可以通过如下进一步加工为化合物I:i)如方案1的步骤b 中所述的皂化;ii)如方案1的步骤c中所述的酰胺键形成。
备选地,化合物CC(R’=甲基、乙基、异丙基、叔丁基或例如在T.W. Greene等人,Protective Groups in Organic Chemistry,John Wiley and Sons Inc.New York 1999,第3版中所述的另一合适的保护基团)可以:i)如方案1 的步骤b中所述转变为其酸同类物CC(R’=H);ii)通过如方案1的步骤 c中所述的用胺III处理,转化为相应酰胺CD;和iii)如步骤a中所述与 CB反应,得到化合物I。
此外,化合物I还可以利用以下反应顺序合成:i)如方案1的步骤b 所述的,皂化化合物CA(R’=甲基,乙基,异丙基,叔丁基或例如在T.W. Greene等人,Protective Groupsin Organic Chemistry,John Wiley and Sons Inc.New York 1999,第3版中描述的另一合适的保护基团),得到其酸同类物CC(R’=H);ii)如方案1的步骤c中所述的用胺III处理转变为相应的酰胺;iii)如步骤a中所述的与化合物CB反应;和iV)如步骤c中所述的与化合物BC反应。任选地,步骤iii)和步骤iv)可以互换。
如果起始材料:式CA,CB或BC的化合物中的一种含有一个或多个在一个或多个反应步骤的反应条件下不稳定或具有反应性的官能团,可以利用本领域公知的方法在关键步骤之前引入适当保护基团(P)(如例如在 T.W.Greene等人,Protective Groups inOrganic Chemistry,John Wiley and Sons Inc.New York 1999,第3版中所述的)。这样的保护基团可以在合成的较晚阶段使用本领域中已知的标准方法去除。
如果式CA,CB或BC的一个或多个化合物含有手性中心,可以获得式AA”和BD的甲基吡啶为非对映异构体或对映异构体的混合物,其可以通过本领域中公知的方法,例如(手性)HPLC或结晶来分离。外消旋化合物可以例如由非对映异构盐通过结晶或通过特定色谱方法使用手性吸附剂或手性洗脱剂分离对映体经分离为其对映体。
按照根据方案4的程序,化合物DA(X=Cl,Br,I或三氟甲磺酸酯; R’=H、甲基、乙基、异丙基、叔丁基或例如在T.W.Greene等人,Protective Groups in OrganicChemistry,John Wiley and Sons Inc.New York 1999,第3 版中描述的另一合适的保护基团)可以用作起始材料。DA是可商购的,文献中描述的,或可以由本领域技术人员合成。
方案4
化合物BA可以由DA通过如下制备:在钯催化剂如乙酸钯(II)/丁基-1- 金刚烷基膦和碱如碳酸铯的存在下,在惰性溶剂如甲苯中,在50℃至溶剂沸点的温度,将偶联式CB的适当取代的芳基金属物种(M是例如三氟硼酸盐[BF3]-K+,硼酸B(OH)2或硼酸频哪醇酯基团)(步骤a),例如有机三氟硼酸钾盐,或在合适的催化剂,尤其是钯催化剂并且更特别是乙酸钯(II)/ 三苯基膦混合物或氯化钯(II)-dppf(1,1′-双(二苯基膦基)二茂铁)配合物和碱如三乙胺、碳酸钠或碳酸钾的存在下,在惰性溶剂如二甲基甲酰胺、甲苯、四氢呋喃、乙腈和二甲氧基乙烷中,偶联芳基硼酸或芳基硼酸。任选地,化合物CB也可以是胺,其通过本领域技术人员公知的方法,例如使用钯催化剂如三(二亚苄基丙酮)二钯/二甲基双二苯基-膦基呫吨和碱如碳酸铯,在溶剂如1,4-二烷中,优选在溶剂的沸点,偶联到DA。此外,化合物AA’可以应用本领域技术人员公知的方法,例如使用硫醇的钠盐,在溶剂如环丁砜中,在0℃至溶剂的沸点之间的温度,通过与硫醇(thiole)AB(M 是H)反应,转变为硫醚。
化合物BB可以由BA通过如方案2的步骤a中所述的用合适的氧化剂氧化制备(步骤b)。
化合物BB到6-氯-或6-溴-甲基吡啶AA’(X=Cl,Br)的转变可以如方案2的步骤b中所述实现(步骤c)。
化合物AC可以由AA'通过如下制备:在合适的催化剂,尤其是钯催化剂并且更特别是乙酸钯(II)/三苯基膦混合物或氯化钯(II)-dppf(1,1′-双(二苯基膦基)二茂铁)配合物和碱如三乙胺、碳酸钠或碳酸钾的存在下,在惰性溶剂如二甲基甲酰胺、甲苯、四氢呋喃、乙腈和二甲氧基乙烷中,偶联式AB的适当取代的芳基金属物种(M是例如三氟硼酸盐[BF3]-K+、硼酸 B(OH)2或硼酸频哪醇酯基团)(步骤d),特别是芳基硼酸或芳基硼酸酯。化合物AC可以通过如下进一步加工为化合物I:i)如方案1的步骤b中所述的皂化(步骤e);ii)如方案1的步骤c中所述的酰胺键形成(步骤f)。
如果起始材料:式DA,CB,AB或III的化合物中的一种含有一个或多个在一个或多个反应步骤的反应条件下不稳定或具有反应性的官能团,可以利用本领域公知的方法在关键步骤之前引入适当保护基团(P)(如例如在T.W.Greene等人,Protective Groups inOrganic Chemistry,John Wiley and Sons Inc.New York 1999,第3版中所述的)。这样的保护基团可以在合成的较晚阶段使用本领域中已知的标准方法去除。
如果式DA,CB,BA,BB,AA',AB,AC,II或III的一个或多个化合物含有手性中心,可以获得式I的甲基吡啶为非对映异构体或对映异构体的混合物,其可以通过本领域中公知的方法,例如(手性)HPLC或结晶来分离。外消旋化合物可以例如经由非对映异构盐通过结晶或通过特定色谱方法使用手性吸附剂或手性洗脱剂分离对映体分离为其对映体。
本发明还涉及一种制备式(I)的化合物的方法,所述方法包括式(A)的化合物在NHR3R4、酰胺键形成偶联剂和碱的存在下反应,
其中R1至R4如上文所定义。
酰胺键形成偶联剂的实例是N,N’-羰基-二咪唑(CDI),N,N’-二环己基碳二亚胺(DCC),1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI), 1-[双(二甲基氨基)-亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶-3-氧化物六氟磷酸盐(HATU),1-羟基-1,2,3-苯并三唑(HOBT),O-苯并三唑-1-基 -N,N,N’,N’-四甲基脲四氟硼酸盐(TBTU)和O-苯并三唑-N,N,N’,N’-四甲基-脲-六氟-磷酸盐(HBTU)。
合适的碱的实例叔胺碱如三乙胺、N-甲基吗啉、N,N-二异丙基乙胺或 4-(二甲基氨基)-吡啶。
反应温度是例如室温。
方便的方法是在惰性溶剂如例如二甲基甲酰胺中,在室温使用例如 TBTU和碱,例如N-乙基-N-异丙基丙-2-胺。
本发明的另一实施方案提供药物组合物或药物,其包含本发明的化合物和治疗惰性载体,稀释剂或赋形剂,以及使用本发明的化合物制备这种组合物和药物的方法。在一个实例中,可以将式(I)化合物通过如下配制:在环境温度在合适的pH,并在期望的纯度程度,与生理学上可接受的载体即在所采用的剂量和浓度对受者无毒的载体混合成盖仑给药形式。制剂的pH主要取决于具体的用途和化合物的浓度,但是优选在约3至约8范围内的任意处。在一个实例中,将式(I)化合物在乙酸盐缓冲液中在pH 5 配制。在另一个实施方案中,式(I)化合物是无菌的。可以将化合物例如作为固体或非晶组合物,作为冻干的制剂或作为水溶液储存。
以与良好医疗实践相一致的方式将组合物配制,定剂量,和给药。在此考虑的因素包括所治疗的具体病症,所治疗的具体哺乳动物,个体患者的临床状况,病症的原因,药剂的输送位置,给药方法,给药的时间安排,和执业医师已知的其他因素。
本发明的化合物可以通过任何合适的方式给药,包括口服、局部(包括含服和舌下)、直肠、阴道、经皮、肠胃外、皮下、腹膜内、肺内、皮内、鞘内和硬膜外和鼻内,并且,如果需要局部治疗,则病灶内给药。肠胃外输液包括肌肉内、静脉内、动脉内、腹膜内或皮下给药。
本发明的化合物可以以任何方便的给药形式给药,例如,片剂、散剂、胶囊、溶液剂、分散剂、混悬剂、糖浆剂、喷雾剂、栓剂、凝胶、乳剂、贴剂等。这样的组合物可以含有药物制剂中的常规组分,例如,稀释剂、载体、pH调节剂、甜味剂、填充剂和其他活性剂。
典型的制剂通过混合本发明的化合物和载体或赋形剂制备。合适的载体和赋形剂是本领域技术人员周知的并详述于,例如,Ansel,Howard C.,等,Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia:Lippincott,Williams&Wilkins,2004;Gennaro,Alfonso R.,等Remington:The Science and Practice ofPharmacy.Philadelphia:Lippincott, Williams&Wilkins,2000;和Rowe,Raymond C,Handbook of Pharmaceutical Excipients.Chicago,Pharmaceutical Press,2005中。制剂还可以包括一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、助悬剂、防腐剂、抗氧化剂、遮光剂(opaquing agent)、助流剂、加工助剂、着色剂、甜味剂、加香剂、增味剂、稀释剂和其他已知添加剂,以提供药物(即,本发明的化合物或其药物组合物)的优良存在形式或协助制备药物产品(即,药品)。
本发明因此还涉及:
式(I)的化合物,其用作治疗活性物质;
一种药物组合物,其包含式(I)的化合物和治疗惰性载体;
式(I)的化合物用于治疗或预防疼痛、神经性疼痛、哮喘、骨质疏松、炎症、精神疾病、精神病、肿瘤、脑炎、疟疾、变态反应、免疫性病症、关节炎、胃肠道病症、精神异常、类风湿性关节炎、精神病或变态反应的用途;
式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防疼痛、神经性疼痛、哮喘、骨质疏松、炎症、精神疾病、精神病、肿瘤、脑炎、疟疾、变态反应、免疫性病症、关节炎、胃肠道病症、精神异常、类风湿性关节炎、精神病或变态反应;
式(I)的化合物,其用于治疗或预防疼痛、神经性疼痛、哮喘、骨质疏松、炎症、精神疾病、精神病、肿瘤、脑炎、疟疾、变态反应、免疫性病症、关节炎、胃肠道病症、精神异常、类风湿性关节炎、精神病或变态反应;和
一种用于治疗或预防疼痛、神经性疼痛、哮喘、骨质疏松、炎症、精神疾病、精神病、肿瘤、脑炎、疟疾、变态反应、免疫性病症、关节炎、胃肠道病症、精神异常、类风湿性关节炎、精神病或变态反应的方法,所述方法包括将有效量的式(I)的化合物对需要其的患者给药。
现在将利用以下实施例描述本发明,所述实施例不具有限制特性。
实施例
缩写
BINAP=2,2′-双(二苯基膦基)-1,1′-联萘;bp=沸点;DIEA=N-乙基-N- 异丙基丙-2-胺;DMF=二甲基甲酰胺;DMSO=二甲基-亚砜;dppf=1,1′- 双(二苯基膦基)二茂铁;EI=电子碰撞;EtOAc=乙酸乙酯;HATU= 2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基异脲六氟磷酸盐(V); HBTU=O-苯并三唑-N,N,N',N’-四甲基-脲-六氟-磷酸盐;HPLC=LC=高效液相色谱;iPrOAc=乙酸异丙酯;ISP=离子喷射,对应于ESI(电喷射);MS=质谱;NMM=N-甲基吗啉;NMR数据以相对于内部四甲基硅烷以百万分率(δ)报告,并且参比来自样品溶剂的氘锁信号(d6-DMSO,除非另有说明);偶联常数(J)以赫兹(Hertz)记;m-CPBA=间氯过苯甲酸; mp=熔点;MTBE=2-甲氧基-2-甲基丙烷;Rt=保留时间;TBTU=O-(苯并三唑-1-基)-N,N,N’,N’-四甲基-脲-四氟硼酸盐;TEMPO=2,2,6,6-四-甲基哌啶1-氧基自由基;THF=四氢呋喃;tlc=薄层色谱。
实施例1
2-[[5-(4-氯苯基)-6-甲硫基吡啶-2-羰基]氨基]-2-甲基丙酸甲酯
在氩气氛下将5-(4-氯苯基)吡啶-2-甲酸甲酯(CAN 86574-76-7,4.5g,18.2mmol)溶解在二氯甲烷(50mL)中,得到棕色溶液。将3-氯过苯甲酸 (4.92g,28.5mmol)在搅拌下分五个部分经1h加入。在氩下将反应混合物搅拌18h。加入另外的3-氯过苯甲酸(2.35g,13.6mmol)并继续搅拌24h。将反应混合物倒入500mL冷的10%Na2SO3水溶液中并且用CH2Cl2(2x 500mL)萃取。将有机层用饱和NaHCO3水溶液(1x 500mL)和盐水(1x400 mL)洗涤。合并有机层,经Na2SO4干燥,并且在真空中浓缩至30mL的体积。在搅拌下加入庚烷(50mL)。固体沉淀。继续搅拌0.5h,将固体滤出,用30mL庚烷洗涤,并在减压下干燥,得到标题化合物(3.45g,72%),为灰白色固体,LC-MS(UV峰面积/ESI)91%,264.0420[MH+]。
b)6-氯-5-(4-氯苯基)吡啶-2-甲酸甲酯
将磷酰氯(7.85g,4.69mL,51mmol)加入至5-(4-氯苯基)-1-氧化物- 吡啶-1--2-甲酸甲酯(实施例1a,1.5g,5.69mmol)在氯仿(4mL)中的溶液终。将反应混合物在80℃搅拌18h,倒入冰冷的饱和K2CO3水溶液(150 mL)中并用CH2Cl2(2x200mL)萃取。将合并的有机层用盐水(2x100mL) 洗涤,经MgSO4干燥并在真空中浓缩。将粗制材料通过急骤色谱(硅胶,70g,庚烷中0%至100%乙酸异丙酯)纯化并且将得到的材料用10mL iPrOAc/庚烷9∶1研磨。将固体滤出并在真空中干燥,得到标题化合物(777 mg,48%),为无色固体,LC-MS(UV峰面积/ESI)91%,282.008[MH+]。
c)5-(4-氯苯基)-6-甲硫基-吡啶-2-甲酸
在氩气氛下将硫代甲醇钠(62.1mg,886μmol)加入至6-氯-5-(4-氯苯基)吡啶-2-甲酸甲酯(实施例1b,50mg,177μmol)在环丁砜(1.5mL)中的溶液中。在环境温度将混合物搅拌24h,倾倒到冰水/乙酸异丙酯1/1上并用1N HCl酸化。将有机层经Na2SO4干燥,过滤去并在真空中浓缩,得到粗制标题化合物(51mg,定量),为黄色固体,其不进一步纯化即用于下一反应步骤。
d)2-[[5-(4-氯苯基)-6-甲硫基吡啶-2-羰基]氨基]-2-甲基丙酸甲酯
将5-(4-氯苯基)-6-甲硫基-吡啶-2-甲酸(实施例1c,52mg,186μmol),2-氨基异丁酸甲酯(CAN 13257-67-5,79mg,670μmol),HATU(255mg, 670μmol)和DIEA(87mg,116μL,670μmol)在DMF(1.5mL)中的溶液在环境温度搅拌3天。将混合物倒入乙酸异丙酯中并用水、饱和Na2CO3水溶液和1N HCI洗涤。将有机层经Na2SO4干燥,过滤去并在真空中浓缩,得到黄色油状物,将其通过急骤色谱(硅胶,50g,庚烷中0%至100%乙酸异丙酯)纯化,得到标题化合物(64mg,92%),为无色蜡状固体,MS(ISP): 379.2[MH+]。
实施例2
2-[[5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-羰基]氨基]-2-甲基丙酸甲酯
a)5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-甲酸
在氮气氛下,将5-溴-6-(环丙基甲氧基)吡啶-2-甲酸(CAN 1415898-37-1,100mg,0.37mmol),4-氯苯基硼酸(CAN 1679-18-1,57mg,0.40mmol), Pd(dppf)Cl2xCH2Cl2(14mg,0.02mmol),Na2CO3(2N,291mg,3mmol) 在DMF(5mL)中的溶液在100℃反应过夜。将反应混合物倒入水中并用乙酸乙酯(20mL)萃取。将水层用浓HCl调节至pH 2,用乙酸乙酯(3x20mL)萃取,用盐水(6x20mL)洗涤,经Na2SO4干燥并在减压下浓缩。将粗产物通过色谱经硅胶使用石油醚/乙酸乙酯=4/1纯化,得到标题化合物(0.05g, 49%),为黄色固体。
b)2-[[5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-羰基]氨基]-2-甲基丙酸甲酯
在环境温度向5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-甲酸(实施例2a, 100mg,0.325mmol)在DMF(5mL)中的溶液中加入NMM(131mg,1.3 mmol)和HBTU(247mg,0.65mmol)。将混合物在环境温度搅拌1小时。将2-氨基异丁酸甲酯(CAN 13257-67-5,41mg,0.352mmol)加入至混合物中。将溶液在环境温度搅拌过夜,用水(15mL)稀释,用EtOAc(3x15mL) 萃取。将合并的有机层用水(2x10mL)和盐水(10mL)洗涤并蒸发至干燥。将残留物通过用石油醚/乙酸乙酯=8∶1洗脱的硅胶色谱纯化,得到标题化合物(0.4g,30%),为白色固体,LC-MS:403.1[MH+]。1H NMR(300MHz, CDCl3):δ8.47(bs,1H),7.81(d,1H,J=7.5Hz),7.74(d,1H,J=7.5 Hz),7.56(dd,2H,J1=6.6Hz,J2=1.8Hz),7.41(dd,2H,J1=6.9Hz, J2=2.1Hz),4.30(d,2H,J=5.1Hz),3.80(s,3H),1.72(s,6H),1.40- 1.20(m,1H),0.64-0.60(m,2H),0.42-0.38(m,2H)。
实施例3
类似于实施例2b中描述的程序,将5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-甲酸(实施例2a)与2-唑-2-基丙-2-胺(CAN 1211519-76-4)缩合,得到标题化合物(83mg,32%),为无色油状物,LC-MS:411.9[MH+]。1H NMR (300MHz,CDCl3):δ8.74(s,1H),7.80-7.71(m,2H),7.57-7.53(m, 3H),7.42-7.39(m,2H),7.10(s,1H),4.31(d,2H,J=6.9Hz),1.91(s, 6H),1.35-1.25(m,1H),0.64-0.59(m,2H),0.42-0.38(m,2H)。
实施例4
类似于实施例2b中描述的程序,将5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-甲酸(实施例2a)与2-(5-甲基-1,2,4-二唑-3-基)丙-2-胺(CAN 1153831-97-0)缩合,得到标题化合物(88mg,48%),为白色固体,LC-MS: 427.1[MH+]。1H NMR(300MHz,CDCl3):δ8.58(bs,1H),7.80(d,1H, J=7.5Hz),7.73(d,1H,J=7.5Hz),7.56(d,2H,J=8.4Hz),7.41(dd,2H,J1=6.6Hz,J2=1.8Hz),4.30(d,2H,J=7.2Hz),2.60(s,3H),1.89 (s,6H),1.40-1.20(m,1H),0.64-0.62(m,2H),0.40-0.37(m,2H)。
实施例5
a)6-(环丙基甲氧基)-5-苯基-吡啶-2-甲酸
类似于实施例2a中描述的程序,将5-溴-6-(环丙基甲氧基)吡啶-2-甲酸(CAN1415898-37-1,2g,7mmol)与苯基硼酸(CAN 98-80-6,1.07g,9mmol) 反应,得到标题化合物(1.3g,66%),为白色固体,LC-MS:270.1[MH+]。
类似于实施例2b中描述的程序,将6-(环丙基甲氧基)-5-苯基-吡啶-2- 甲酸(实施例5a)与2-唑-2-基丙-2-胺(CAN 1211519-76-4)缩合,得到标题化合物(41mg,29%),为白色固体,LC-MS:378.2[MH+]。1H NMR(300MHz, CDCl3):δ8.75(s,1H),7.81-7.74(m,2H),7.64-7.61(m,3H),7.46- 7.34(m,4H),7.11(s,1H),4.32(d,2H,J=6.9Hz),1.91(s,6H),1.43 -1.37(m,1H),0.65-0.59(m,2H),0.43-0.39(m,2H)。
实施例6
6-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]-5-苯基吡啶-2-甲酰胺
类似于实施例2b中描述的程序,将6-(环丙基甲氧基)-5-苯基-吡啶-2- 甲酸(实施例5a)与2-氨基-2-乙基-N-甲基-丁酰胺(CAN 1415898-90-6)缩合,得到标题化合物(29mg,20%),为白色固体,LC-MS:396.1[MH+]。1H NMR (300MHz,CDCl3):8.98(bs,1H),7.81(dd,2H,J1=12.0 Hz,J2=7.5 Hz), 7.65(dd,2H,J1=8.4Hz,J2=1.2Hz),7.49-7.37(m,3H),6.21(bs,1H), 4.38(d,2H,J=6.9Hz),2.93(d,3H,J=4.5Hz),2.67-2.57(m,2H),1.82-1.72(m,2H),1.40-1.25(m,1H),0.87(t,6H,J=7.5Hz),0.68- 0.62(m,2H),0.42-0.38(m,2H)。
实施例7
6-(3-氯苯基)-5-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶 -2-甲酰胺
将30%H2O2(15mL)加入至5-(环丙基甲氧基)吡啶-2-甲酸(CAN 1266787-40-9,0.44g,2.28mmol)在乙酸(20mL)中的溶液中。将混合物在 60℃搅拌过夜。在减压下将溶剂去除,得到粗制标题化合物(0.2g,42%),其不进一步纯化即用于下一反应步骤,LC-MS:210.1[MH+]。1H NMR(300 MHz,CD3OD):δ8.24-8.13(m,2H),7.37-7.11(m,1H),3.97- 3.90,(m,2H),1.21-1.86(m,1H),0.61-0.55(m,2H),0.34-0.29 (m,2H)。
b)6-溴-5-(环丙基甲氧基)吡啶-2-甲酸
将5-(环丙基甲氧基)-1-氧化物-吡啶-1--2-甲酸(实施例7a,(3.0g,14.3mmol)加入至POBr3(30g)在二氯甲烷(10mL)中的溶液中。将混合物在 40℃搅拌过夜。加入冰水,将混合物用二氯甲烷(3x100mL)萃取并合并有机层。去除溶剂,加入1N NaOH溶液并将混合物用二氯甲烷(2x40mL) 洗涤。将水层用1N HCl酸化,用二氯甲烷(3x100mL)萃取,经Na2SO4干燥并浓缩,得到粗制标题化合物(1.0g,32%)。1H NMR(300MHz,CDCl3):δ8.07-8.04(m,1H),7.15-7.13(m,1H),3.99-3.96,(m,2H), 1.37-1.32(m,1H),0.74-0.68(m,2H),0.47-0.42(m,2H)。
c)6-(3-氯苯基)-5-(环丙基甲氧基)吡啶-2-甲酸
类似于实施例2a中描述的程序,将6-溴-5-(环丙基甲氧基)吡啶-2-甲酸 (实施例7b,0.3g,1.1mmol)与3-氯苯基硼酸(CAN 63503-60-6,0.21g, 1.3mmol)反应,得到标题化合物(60mg,18%),LC-MS:304.0[MH+]。
d)6-(3-氯苯基)-5-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶 -2-甲酰胺
类似于实施例2b中描述的程序,将6-(3-氯苯基)-5-(环丙基甲氧基)吡啶-2-甲酸(实施例7d)与2-氨基-2-乙基-N-甲基-丁酰胺(1415898-90-6)缩合,得到标题化合物(5mg,9%),为白色固体,LC-MS:430.2[MH+]。1H NMR (300MHz,CD3OD):δ9.45(bs,1H),8.21-8.07(m,2H),8.01(d,1H, J=8.7Hz),7.60(d,1H,J=8.7Hz),7.51-7.41(m,2H),4.05(d,2H, J=6.9Hz),2.82(s,3H),2.70-2.50(m,2H),1.90-1.75(m,2H),1.40 -1.20(m,2H),0.78(t,6H,J=7.5Hz),0.70-0.65(m,2H),0.45-0.40 (m,2H)。
实施例8
a)6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸
在氮气氛下,将3-甲氧基氮杂环丁烷(38mg,0.44mmol),BINAP(23 mg,0.037mmol),Pd2(dba)3(17mg,0.02mmol)和Cs2CO3(240mg,0.735 mmol)加入至5-溴-6-(环丙基甲氧基)吡啶-2-甲酸(CAN 1415898-37-1,100 mg,0.37mmol)在甲苯(4mL)中的溶液中。将反应混合物在110℃搅拌过夜并随后在减压下浓缩。将残留物溶解在水中并用乙酸乙酯(30mL)萃取。通过加入1N HCl将水层调节至pH 2。通过过滤收集得到的沉淀并且在真空中干燥。经硅胶使用石油醚/乙酸乙酯=1/2的色谱纯化,提供标题化合物(35mg,34%),为黄色固体,LC-MS:265.2[MH+]。
类似于实施例2b中描述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a)与2-(5-甲基-1,2,4-二唑-3-基)丙 -2-胺(CAN 1153831-97-0)缩合,得到标题化合物(47mg,33%),为无色油状物,LC-MS:402.2[MH+]。1H NMR(300MHz,CDCl3):δ8.25(bs,1H), 7.59(d,1H,J=8.1Hz),6.55(d,1H,J=7.8Hz),4.35-4.15(m,5H), 3.90-3.80(m,2H),3.33(d,3H,J=1.2Hz),2.56(s,3H),1.83(s,6H), 1.40-1.20(m,1H),0.65-0.61(m,2H),0.39-0.36(m,2H)。
实施例9
类似于实施例2b中描述的程序,将6-(3-氯苯基)-5-(环丙基甲氧基)吡啶-2-甲酸(实施例7d)与2-(5-甲基-1,2,4-二唑-3-基)丙-2-胺(CAN 1153831-97-0)缩合,得到标题化合物(20mg,29%),为白色固体,LC-MS: 427.2[MH+]。1H NMR(300MHz,CD3OD):δ8.11(d,1H,J=1.8Hz), 8.02-7.95(m,2H),7.58(d,1H,J=8.7Hz),7.50-7.40(m,2H),4.04(d, 2H,J=6.9Hz),2.58(s,3H),1.82(s,6H),1.40-1.20(m,2H),0.68-0.64 (m,2H),0.44-0.40(m,2H)。
实施例10
N-[(2S)-1-氨基-3-环丙基-1-氧代丙-2-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺
类似于实施例2b中描述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a)与(2S)-2-氨基-3-环丙基-丙酰胺 (CAN 156077-93-9)缩合,得到标题化合物(40mg,36%),为白色固体, LC-MS:389.1[MH+]。1H NMR(300MHz,CDCl3):δ8.05(d,1H,J=7.8 Hz),7.66(d,1H,J=7.5Hz),6.57(d,1H,J=7.8Hz),6.50(bs,1H), 5.45(bs,1H),4.64(dd,1H,J1=13.8Hz,J2=6.6Hz),4.35-4.25(m, 3H),4.14(d,2H,J=7.2Hz),3.95-3.85(m,2H),3.34(s,3H),1.95- 1.65(m,2H),1.35-1.20(m,1H),0.90-0.75(m,1H),0.64-0.15(m, 8H)。
实施例11
6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺
a)6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)吡啶-2-甲酸甲酯
在氮气氛下,将化合物5-溴-6-(环丙基甲氧基)吡啶-2-甲酸甲酯(CAN 1415899-20-5,0.51g,1.8mmol),2-氧杂-6-氮杂螺[3.3]庚烷乙二酸酯(CAN 1254966-66-9,0.29mg,1.8mmol),Pd2(dba)3(33mg,0.035mmol),BINAP (45mg,0.07mmol)和Cs2CO3(1.76mg,5.4mmol)在甲苯(50mL)中的混合物在110℃搅拌过夜。浓缩后,将残留物在水(30mL)和EtOAc(30mL) 之间分配。将水相用EtOAc(2×20mL)萃取。将合并的有机相用盐水(30mL) 洗涤,经无水Na2SO4干燥,过滤并浓缩,得到残留物,其通过柱色谱,用石油醚-乙酸乙酯(1∶1)洗脱纯化,得到目标化合物(0.4g,73%),为黄色固体,LC-MS:305.1[MH+]。
b)6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)吡啶-2-甲酸
将6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)吡啶-2-甲酸甲酯 (实施例11a,0.4g,1.3mmol)和LiOHxH2O(0.17g,3.9mmol)在THF/H2O (15mL)中的混合物在环境温度搅拌3小时。在去除有机溶剂后,将水(10 mL)加入至残留物中,并将混合物用EtOAc(3x15mL)萃取。将合并的有机相用盐水(20mL)洗涤,经无水Na2SO4干燥,过滤并浓缩,得到目标化合物(0.38g,99%),LC-MS:291.2[MH+]。
c)6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺
类似于实施例2b中描述的程序,将6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)吡啶-2-甲酸(实施例11b)与2-噻唑-2-基丙-2-胺(CAN 1082393-38-1)缩合,得到标题化合物(20mg,15%),为白色固体,LC-MS: 415.1[MH+]。1H NMR(300MHz,CDCl3):δ8.65(bs,1H),7.68(d,1H, J=3.0Hz),7.63(d,1H,J=7.8Hz),7.25(s,1H),6.56(d,1H,J=7.8Hz),4.84(s,4H),4.25-4.15(m,6H),1.93(s,6H),1.40-1.25(m,1H), 0.69-0.63(m,2H),0.42-0.37(m,2H)。
实施例12
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(2-氧杂-6- 氮杂螺[3.3]庚-6-基)吡啶-2-甲酰胺
类似于实施例2b中描述的程序,将6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)吡啶-2-甲酸(实施例11b)与(2S)-2-氨基-4-甲基-戊酰胺(CAN 687-51-4)缩合,得到标题化合物(76mg,71%),为浅黄色固体,LC-MS: 403.2[MH+]。1H NMR(300MHz,CDCl3):δ7.72(d,1H,J=8.1Hz), 7.64(d,1H,J=7.8Hz),6.56(d,1H,J=7.8Hz),6.46(bs,1H),5.41(bs, 1H),4.84(s,4H),4.62-4.55(m,1H),4.21-4.05(m,6H),1.90-1.60(m, 3H),1.31-1.25(m,1H),0.94(t,6H,J=6.6Hz),0.68-0.62(m,2H), 0.40-0.35(m,2H)。
实施例13
6-(3-氯苯基)-5-(环丙基甲氧基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺
类似于实施例2b中描述的程序,将6-(3-氯苯基)-5-(环丙基甲氧基)吡啶-2-甲酸(实施例7d)与2-噻唑-2-基丙-2-胺(CAN 1082393-38-1)缩合,得到标题化合物(20mg,28%),为白色固体,LC-MS:428.1[MH+]。1H NMR(300 MHz,CD3OD):δ8.16(d,1H,J=1.8Hz),8.06-8.03(m,1H),7.98(d, 1H,J=8.4Hz),7.72(d,1H,J=3.3Hz),7.60(d,1H,J=8.7Hz),7.51 -7.44(m,3H),4.05(d,2H,J=6.9Hz),1.93(s,6H),1.40-1.20(m, 1H),0.70-0.60(m,2H),0.45-0.40(m,2H)。
实施例14
N-[(2S)-1-氨基-3-环丙基-1-氧代丙-2-基]-5,6-双(环丙基甲氧基)吡啶-2- 甲酰胺
a)5,6-双(环丙基甲氧基)吡啶-2-甲酸
在30min内将氢化钠(2.4g,0.1mol)加入至冰冷的环丙基甲醇溶液(20 mL)中。加入5-溴-6-氯-吡啶-2-甲酸甲酯(CAN 1214353-79-3,5g,0.02mol)。将反应混合物加热至100℃达2小时。冷却到环境温度后,通过加入水将反应混合物猝灭。在减压下去除溶剂,加入水并且使用1N HCl将pH带至3。通过过滤收集得到的沉淀,并将溶液用乙酸乙酯(3x30mL)萃取。将合并的有机层用盐水(3x30mL)洗涤,并经Na2SO4干燥。在通过蒸发去除溶剂后,将粗产物通过硅胶色谱,用石油醚/乙酸乙酯=1∶1洗脱来纯化,得到标题化合物(4.7g,86%),为白色固体,LC-MS:264.2[MH+]。
b)N-[(2S)-1-氨基-3-环丙基-1-氧代丙-2-基]-5,6-双(环丙基甲氧基)吡啶 -2-甲酰胺
类似于实施例2b中描述的程序,将5,6-双(环丙基甲氧基)吡啶-2-甲酸 (实施例14a)与(2S)-2-氨基-3-环丙基-丙酰胺(CAN 156077-93-9)缩合,得到标题化合物(20mg,28%),为白色固体,LC-MS:374.2[MH+]。1H NMR(300 MHz,DMSO-d6):δ8.21(d,1H,J=7.8Hz),7.60-7.25(m,2H),7.34 (d,1H,J=8.1Hz),7.11(bs,1H),4.44(dd,1H,J1=13.2Hz,J2=7.5Hz), 4.24(d,2H,J=7.2Hz),3.89(d,2H,J=6.9Hz),1.80-1.65(m,1H),1.60-1.45(m,1H),1.40-1.20(m,2H),0.75-0.50(m,4H),0.50-0.30 (m,5H),1.50-1.25(m,2H)。
实施例15
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺
类似于实施例2b中描述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a)与(2S)-2-氨基-4-甲基-戊酰胺(CAN 687-51-4)缩合,得到标题化合物(90mg,81%),为白色固体,LC-MS:391.2 [MH+]。1H NMR(300MHz,CDCl3):δ7.75(d,1H,J=8.4Hz),7.60(d, 1H,J=7.8Hz),7.11(bs,1H),8.21(d,1H,J=7.8Hz),6.76(bs,1H), 4.66-4.59(m,1H),4.30-4.00(m,5H),3.90-3.80(m,2H),3.32(s, 3H),1.90-1.60(m,3H),1.35-1.20(m,1H),1.00-0.85(m,6H),0.63 -0.57(m,2H),0.37-0.32(m,2H)。
实施例16
N-[(2S)-1-氨基-4-甲硫基-1-氧代丁-2-基]-6-氯-5-(环丙基甲氧基)吡啶 -2-甲酰胺
a)6-(环丙基甲氧基)-5-(三氟甲氧基)吡啶-2-甲酸和6-氯-5-(环丙基甲氧基)吡啶-2-甲酸
向6-氯-5-(三氟甲氧基)-2-吡啶甲酸(CAN 1221171-90-9,1.0g,4.14 mmol)在DMSO(16mL)中的溶液中加入粉末氢氧化钾(929mg,16.6mmol) 和环丙基甲醇(335μL,4.14mmol)。在室温搅拌16小时后,加入更多的环丙基甲醇(335μL,4.14mmol)并将混合物在50℃搅拌4小时。冷却后,将混合物加入至1N氢氧化钠溶液/冰/水(50mL)中并用MTBE(100mL) 洗涤。将有机相用1N氢氧化钠溶液(20mL)萃取。将水相合并,用2N HCl (50mL)酸化并用MTBE(2x 150mL)萃取。将有机相用冰水/盐水(1∶1,2x 150mL)洗涤,合并,用Na2SO4干燥,过滤并在真空中浓缩。残留物为标题化合物的1∶1混合物,为通过静置固化的棕色油状物;LC-MS(UV峰面积/ESI)51.2%,278.0628[MH+]和48.8%,228.0425[MH+]。
b)N-[(2S)-1-氨基-4-甲硫基-1-氧代丁-2-基]-6-氯-5-(环丙基甲氧基)吡啶-2-甲酰胺
将6-(环丙基甲氧基)-5-(三氟甲氧基)吡啶-2-甲酸和6-氯-5-(环丙基甲氧基)吡啶-2-甲酸(实施例16a,100mg),(2S)-2-氨基-4-(甲硫基)-丁酰胺盐酸盐(1∶1)(CAN16120-92-6,73.3mg,0.397mmol),DIEA(309μL,1.8mmol) 和TBTU(127mg,0.397mmol)的混合物在DMF(4mL)中的溶液在室温搅拌20h。将粗制反应混合物在真空中浓缩并通过急骤色谱(硅胶,庚烷中 0%至100%乙酸乙酯)纯化,得到标题化合物(32mg,25%),为浅黄色固体;LC-MS(UV峰面积/ESI)96%,358.0988[MH+]。
实施例17
6-氯-5-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺
a)6-(环丙基甲氧基)-5-(三氟甲氧基)吡啶-2-甲酸和6-氯-5-(环丙基甲氧基)吡啶-2-甲酸
向6-氯-5-(三氟甲氧基)-2-吡啶甲酸(CAN 1221171-90-9,1.0g,4.14 mmol)在DMSO(16mL)中的溶液中加入粉末氢氧化钾(929mg,16.6 mmol)和环丙基甲醇(335μL,4.14mmol)。在室温搅拌16小时后,加入更多的环丙基甲醇(335μL,4.14mmol)并且将混合物在50℃搅拌4小时。冷却后,将混合物加入至1N氢氧化钠溶液/冰/水(50mL)中并用MTBE(100mL)洗涤。将有机相用1N氢氧化钠溶液(20mL)萃取。将水相合并,用2N HCl(50mL)酸化并用MTBE(2x150mL)萃取。将有机相用冰水/盐水(1∶1,2x150mL)洗涤,合并,用Na2SO4干燥,过滤并在真空中浓缩。残留物是标题化合物的1∶1混合物,为通过静置固化的棕色油状物;LC-MS (UV峰面积/ESI)51.2%,278.0628[MH+]和48.8%,228.0425[MH+]。
b)6-氯-5-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺
将6-(环丙基甲氧基)-5-(三氟甲氧基)吡啶-2-甲酸和6-氯-5-(环丙基甲氧基)吡啶-2-甲酸(实施例17a,50mg),2-氨基-2-乙基-N-甲基-丁酰胺 (CAN 1415898-90-6,0.198mmol),DIEA(154μL,0.9mmol)和TBTU(63.7 mg,0.198mmol)的混合物在DMF(2mL)中的溶液在室温搅拌20h。将粗制反应混合物在真空中浓缩并通过急骤色谱(硅胶,庚烷中0%至100%乙酸乙酯)纯化,得到标题化合物(18mg,28%),为灰白色固体;LC-MS(UV 峰面积/ESI)98%,354.1581[MH+]。
实施例18
将6-(环丙基甲氧基)-5-(三氟甲氧基)吡啶-2-甲酸和6-氯-5-(环丙基甲氧基)吡啶-2-甲酸(实施例16a,50mg),(αS)-α-(环丙基甲基)-5-甲基-1,2,4- 二唑-3-甲胺(CAN1415898-68-8,0.198mmol),DIEA(154μL,0.9mmol) 和TBTU(63.7mg,0.198mmol)的混合物在DMF(2mL)中的溶液在室温搅拌20h。将粗制反应混合物在真空中浓缩并通过急骤色谱(硅胶,庚烷中 0%至100%乙酸乙酯)纯化,得到标题化合物(20mg,29%),为黄色油状物;LC-MS(UV峰面积/ESI)89%,377.1377[MH+]。
实施例19
3-[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]-1,1-二氧代-1,3-噻唑烷-4-甲酰胺
a)3-叔丁氧基羰基-1,1-二氧代-1,3-噻唑烷-4-甲酸甲酯
将m-CPBA(698mg,4.04mmol)加入至噻唑烷-3,4-二甲酸O3-叔丁酯 O4-甲酯(CAN63664-10-8,0.5g,2.02mmol)在二氯甲烷(4mL)中的冰冷溶液。将悬浮液在环境温度搅拌2h。加入另外的m-CPBA(349mg,2.02 mmol)并在环境温度继续搅拌过夜。将反应混合物倾倒到冰水/饱和 NaHCO3-水溶液(50mL)上。分层并将水层用二氯甲烷(2x50mL)萃取。将合并的有机层用冰水/盐水(30mL)洗涤,经Na2SO4干燥并在真空中浓缩,得到黄色油状物,其通过柱色谱经硅胶(庚烷/AcOEt 0-20%于120min)纯化,得到标题化合物(362mg,64%),为无色油状物,MS(ESI)180.1 [MH-Boc+]。
b)3-叔丁氧基羰基-1,1-二氧代-1,3-噻唑烷-4-甲酸
将3-叔丁氧基羰基-1,1-二氧代-1,3-噻唑烷-4-甲酸甲酯(实施例19a, 0.35g,1.25mmol)和水合氢氧化锂(63.1mg,1.5mmol)在THF(3.5mL)和水(1.05mL)中的溶液在环境温度搅拌20h。将反应混合物倾倒到冰/0.1N HCl(25mL)上并用EtOAc(2x25mL)萃取。将合并的萃取物用冰/盐水 (25mL)洗涤,经Na2SO4干燥并过滤。在减压下去除溶剂提供标题化合物(306mg,92%),为无色泡沫,MS(ESI)264.05[M-H-]。
c)4-氨基甲酰基-1,1-二氧代-1,3-噻唑烷-3-甲酸叔丁酯
将羰基二咪唑(520mg,3.21mmol)加入至3-叔丁氧基羰基-1,1-二氧代-1,3-噻唑烷-4-甲酸(实施例19b,304mg,1.15mmol)在DMF(1mL)中的冰冷的悬浮液中。将混合物在环境温度搅拌2h。在使用水浴的冷却下,在环境温度将NH3气体鼓泡通过溶液10min。在环境温度继续搅拌过夜。将混合物倒入30mL冰/水/1N HCl中并用EtOAc(2x30mL)萃取。将合并的提取物用冰/盐水(20mL)洗涤,经Na2SO4干燥并在真空中浓缩,得到标题化合物(197mg,65%),为白色固体,MS(ESI)263.1[M-H-]。
d)1,1-二氧代-1,3-噻唑烷-4-甲酰胺盐酸盐
将二烷中4M氯化氢溶液(4.73mL,18.9mmol)加入至4-氨基甲酰基-1,1-二氧代-1,3-噻唑烷-3-甲酸叔丁酯(实施例19c,500mg,1.89mmol) 在二氯甲烷(10mL)中的冰冷的溶液中。将混合物在环境温度搅拌4d。在减压下去除溶剂,得到标题化合物(388mg,定量),为白色固体,MS(ESI): 198.99[M-H-]。
e)3-[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]-1,1- 二氧代-1,3-噻唑烷-4-甲酰胺
将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例 8a,30mg,108μmol),1,1-二氧代-1,3-噻唑烷-4-甲酰胺盐酸盐(实施例19d, 26mg,129μmol),2-溴-1-乙基吡啶四氟硼酸盐(33mg,119μmol)和 DIEA(42mg,55μL,323μmol)在THF(3mL)中的溶液在环境温度搅拌 24h。蒸发提供黄色油状物,将其溶解在冰冷的饱和NaHCO3水溶液(75mL) 和乙酸乙酯(75mL)中。分层并将水层用EtOAc(75mL)萃取。将合并的萃取物用冰水/0.1N HCI(75mL)和冰水/盐水(75mL)洗涤,经Na2SO4干燥并过滤。去除溶剂后,获得黄色固体,将其从EtOAc中重结晶,得到标题化合物(15mg,33%),为灰白色固体,MS(ISP):425.5[MH+]。
实施例20
2-[[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]氨基]-2-乙基丁酸乙酯
将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例 8a,20.4mg,73.3μmol),DIPEA(23.7mg,32.0μL,183μmol)和4-(4,6- 二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉-4-氯化物(22.3mg,277μmol)在二氯甲烷(1mL)中的溶液在环境温度搅拌30min。加入2-氨基-2-乙基-丁酸乙酯盐酸盐(CAN 1135219-29-2,14.3mg,73.3μmol)并将反应混合物在环境温度搅拌过夜。加入二氯甲烷(8mL)并将混合物用1M NaHCO3水溶液(3x10mL),水(10mL)和盐水(15mL)洗涤。将有机相经MgSO4干燥,过滤并在减压下去除溶剂。经10g SiO2柱,使用庚烷∶EtOAc(4∶1)的急骤色谱提供标题化合物(25.6mg,83.2%),为无色油状物,LC-MS(ESI):420.7 [MH+]。
实施例21
a)4-(2-(4-氟苯甲酰基)肼基)-2-甲基-4-氧代丁-2-基氨基甲酸叔丁酯
将4-氟苯基酰肼(benzohydrazide)(CAN 456-06-4,2.13g,13.8mmol) 加入至3-(叔丁氧基羰基氨基)-3-甲基丁酸(CAN 129765-95-3,3g,13.8 mmol),DIPEA(5.35g,7.23mL,41.4mmol)和HBTU(5.24g,13.8mmol) 在DMF(100mL)中的溶液中。将反应混合物在环境温度搅拌18h并随后在真空中浓缩。加入EtOAc(150mL)并将溶液用饱和NaHCO3水溶液(2x 50mL),1M HCl(2x50mL)和盐水(2x50mL)洗涤。将水层用EtOAc(100 mL)反萃取。合并有机层,经MgSO4干燥并在真空中浓缩。将粗制材料通过色谱(硅胶,300g,EtOAc∶庚烷1∶1)纯化,得到标题化合物(1.29g,26%),为无色油状物,MS(ISP):354.3[MH+]。
将DIPEA(1.42g,1.91mL,11.0mmol)和六氯乙烷(1.12g,4.75mmol) 加入至4-(2-(4-氟苯甲酰基)肼基)-2-甲基-4-氧代丁-2-基氨基甲酸叔丁酯(实施例21a,1.29g,3.65mmol)和三苯基膦(1.44g,5.48mmol)在乙腈(60mL) 中的溶液中。将反应混合物在环境温度搅拌18h并随后在真空中浓缩。加入二氯甲烷(100mL)并将混合物用水(50mL)和盐水(50mL)洗涤。将水层用二氯甲烷(100mL)反萃取。将合并的萃取物经MgSO4干燥并在真空中浓缩。将粗制材料通过急骤色谱(硅胶,50g,庚烷中0%至100%EtOAc)纯化,得到标题化合物(0.988g,81%),为白色固体,MS(ISP):336.3[MH+]。
向N-[2-[5-(4-氟苯基)-1,3,4-二唑-2-基]-1,1-二甲基-乙基]氨基甲酸叔丁酯(实施例21b,0.98g,2.92mmol)在二烷(30mL)中的溶液中加入HCl 在二烷中的4M溶液(3.65mL,14.6mmol)。将反应混合物在环境温度搅拌5d。加入另外在二烷中的4M HCl溶液(15mL)并在环境温度继续搅拌3d。加入tBuOMe(25mL),过滤出沉淀并在真空中干燥,得到标题化合物(620mg,78%),MS(ISP):236.2[MH-Cl+]。
类似于实施例20中所述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a,20.8mg,74.7μmol)与1-[5-(4-氟苯基)-1,3,4-二唑-2-基]-2-甲基-丙-2-胺盐酸盐(实施例21c,20.3mg,74.7 μmol)缩合,得到标题化合物(22.8mg,62%),为无色油状物,LC-MS(ESI): 496.7[MH+]。
实施例22
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺
类似于实施例20中所述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a,20.2mg,72.6μmol)与2-(3-氨基氧杂环丁烷-3-基)乙酰胺盐酸盐(对应游离碱的CAN 1417638-25-5,22.1mg, 79.8μmol)缩合,得到标题化合物(24mg,85%),为白色粉末,LC-MS(ESI): 391.1984[MH+]。
实施例23
6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺
类似于实施例20中所述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a,19.7mg,70.8μmol)与2-氨基-2- 乙基-N-甲基-丁酰胺盐酸盐(CAN 1432507-42-0,21.5mg,77.9μmol)缩合,得到标题化合物(23.3mg,81%),为白色粉末,LC-MS(ESI):405.5[MN+]。
实施例24
6-(环丙基甲氧基)-N-[(1-羟基环己基)甲基]-5-(3-甲氧基氮杂环丁烷-1- 基)吡啶-2-甲酰胺
类似于实施例20中所述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a,21.7mg,78.0μmol)与1-(氨基甲基)环己醇盐酸盐(CAN19968-85-5,23.7mg,85.8μmol)缩合,得到标题化合物(19.8mg,65%),为无色油状物,LC-MS(ESI):390.7[MH+]。
实施例25
6-(环丙基甲氧基)-N-[(1-羟基环己基)甲基]-5-(3-甲氧基氮杂环丁烷-1- 基)吡啶-2-甲酰胺
a)N-[1-乙基-1-(2-氟乙基氨基甲酰基)丙基]氨基甲酸叔丁酯
类似于实施例20中所述的程序,将2-(叔丁氧基羰基氨基)-2-乙基-丁酸(CAN139937-99-8,100mg,432μmol)与2-氟乙胺盐酸盐(CAN 460-08-2, 43.0mg,432μmol)缩合,得到标题化合物(71mg,59%),为白色粉末, LC-MS(ESI):277.6[MH+]。
b)N-乙基-N-异丙基丙-2-胺盐酸盐
将N-[1-乙基-1-(2-氟乙基氨基甲酰基)丙基]氨基甲酸叔丁酯(71mg,257μmol)在氯化氢在二乙醚中的2M溶液(1.03mL,2.06mmol)中的溶液在环境温度搅拌14h。在减压下去除溶剂,得到粗制N-乙基-N-异丙基丙 -2-胺盐酸盐(63mg,定量),其不进一步纯化即用于下一反应步骤,LC-MS (ESI):177.3[MH+]。
c)6-(环丙基甲氧基)-N-[(1-羟基环己基)甲基]-5-(3-甲氧基氮杂环丁烷 -1-基)吡啶-2-甲酰胺
类似于实施例20中所述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a,20mg,71.9μmol)与N-乙基-N-异丙基丙-2-胺盐酸盐(23.2mg,31.4μL,180μmol)缩合,得到标题化合物(21.2 mg,54%),LC-MS(ESI):435.3[M-H-]。
实施例26
6-(环丙基甲氧基)-N-[3-(3-氟氮杂环丁烷-1-羰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺
a)N-[1-乙基-1-(3-氟氮杂环丁烷-1-羰基)丙基]氨基甲酸叔丁酯
类似于实施例20中所述的程序,将2-(叔丁氧基羰基氨基)-2-乙基-丁酸(CAN139937-99-8,150mg,649μmol)与3-氟氮杂环丁烷盐酸盐(CAN 617718-46-4,72.3mg,649μmol)缩合,得到标题化合物(72mg,39%), LC-MS(ESI):289.2[MH+]。
b)2-氨基-2-乙基-1-(3-氟氮杂环丁烷-1-基)丁-1-酮盐酸盐
类似于实施例25b中所述步骤,将N-[1-乙基-1-(3-氟氮杂环丁烷-1- 羰基)丙基]氨基甲酸叔丁酯(72mg,250μmol)用氯化氢在二乙醚中的2M 溶液处理,得到标题化合物(56mg,定量),其不进一步纯化即用于下一反应步骤,LC-MS(ESI):189.1[游离胺,M-H+]。
c)6-(环丙基甲氧基)-N-[3-(3-氟氮杂环丁烷-1-羰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺
类似于实施例20中所述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a,20mg,71.9μmol)与2-氨基-2-乙基 -1-(3-氟氮杂环丁烷-1-基)丁-1-酮盐酸盐(16.1mg,71.9μmol)缩合,得到标题化合物(5.8mg,18%),LC-MS(ESI):449.3[MH+]。
实施例27
6-(环丙基甲氧基)-N-[3-(3-氟丙基氨基甲酰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺
a)N-[1-乙基-1-(3-氟丙基氨基甲酰基)丙基]氨基甲酸叔丁酯
类似于实施例20中所述的程序,将2-(叔丁氧基羰基氨基)-2-乙基-丁酸(CAN139937-99-8,150mg,649μmol)与3-氟丙-1-胺盐酸盐(CAN 64068-31-1,73.6mg,649μmol)缩合,得到标题化合物(128mg,68%),为白色粉末,LC-MS(ESI):191.2[M-Boc+2H]+.
b)2-氨基-2-乙基-1-(3-氟氮杂环丁烷-1-基)丁-1-酮盐酸盐
类似于实施例25b中所述步骤,将N-[1-乙基-1-(3-氟丙基氨基甲酰基) 丙基]氨基甲酸叔丁酯(44mg,152μmol)用氯化氢在二乙醚中的2M溶液处理,得到标题化合物(43mg,定量),其不进一步纯化即用于下一反应步骤, LC-MS(ESI):191.1[MH+]。
c)6-(环丙基甲氧基)-N-[3-(3-氟丙基氨基甲酰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺
类似于实施例20中所述的程序,将6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酸(实施例8a,20mg,71.9μmol)与2-氨基-2-乙基-N-(3-氟丙基)丁酰胺(16.3mg,71.9μmol)缩合,得到标题化合物(17.4mg, 54%),LC-MS(ESI):451.5[MH+]。
实施例28
(2S)-1-[6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2- 羰基]-4,4-二氟吡咯烷-2-甲酰胺
a)6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2-甲酸甲酯
在5mL梨形烧瓶中,将5-溴-6-(环丙基甲氧基)吡啶-2-甲酸甲酯(CAN 1415899-20-5,100mg,350μmol),3-(三氟甲基)吡咯烷-3-醇盐酸盐(CAN 1334147-81-7,67mg,350μmol)和碳酸铯(285mg,874μmol)与甲苯(4mL) 合并,得到白色悬浮液。将混合物抽真空并用氩吹扫。加入乙酸钯(II)(3.92 mg,17.5μmol)和外消旋-2,2′-双(二苯基膦基)-1,1′-联萘(15.2mg,24.5μmol)。将反应混合物加热至80℃并搅拌2d。将反应混合物用EtOAc稀释并经C盐过滤。将滤液蒸发,得到黄色油状物,将其通过制备型TLC(硅胶, 2.0mm,庚烷/EtOAc 1∶1,用100mL CH2Cl2/EtOAc 1∶1洗脱)纯化,得到标题化合物(65mg,75%),为白色固体,MS(ESI):347.2[MH+]。
b)6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2-甲酸
类似于实施例11b中所述的程序,将6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2-甲酸甲酯(95mg,264μmol)用水合氢氧化锂皂化,得到标题化合物(84mg,92%),为灰白色固体,MS(ESI):347.2[MH+]。
c)(2S)-1-[6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶 -2-羰基]-4,4-二氟吡咯烷-2-甲酰胺
将6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2-甲酸(15mg,43.3μmol),(S)-4,4-二氟吡咯烷-2-甲酰胺盐酸盐(CAN 426844-51-1, 8.08mg,43.3μmol),2-溴-1-乙基吡啶四氟硼酸盐(13.0mg,47.6μmol) 和DIEA(16.8mg,22.2μL,130μmol)在THF(1600μL)中的混合物在环境温度搅拌1d,倾倒到冰水上并用1N HCl(20mL)酸化至pH 2。将混合物用EtOAc(2x30mL)萃取并将有机层用冰水/盐水(20mL)洗涤。将有机层合并,经Na2SO4干燥并在真空中浓缩,得到黄色油状物,将其通过制备型HPLC纯化,得到标题化合物(6.2mg,30%),为浅黄色固体,MS(ESI): 479.3[MH+]。
实施例29
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2-甲酸(实施例28b,15mg,43.3μmol)与(S)-2- 氨基-4-甲基戊酰胺盐酸盐(CAN 687-51-4,7.22mg,43.3μmol)在2-溴-1- 乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(15mg, 76%),为黄色油状物,MS(ESI):459.4[MH+]。
实施例30
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(2,2-二氟 -5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酰胺
a)6-(环丙基甲氧基)-5-(2,2-二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酸甲酯
类似于实施例28a中所述的程序,将5-溴-6-(环丙基甲氧基)吡啶-2- 甲酸甲酯(CAN 1415899-20-5,70mg,246μmol)与1,1-二氟-5-氮杂螺[2.4] 庚烷盐酸盐(CAN1215071-12-7,42mg,246μmol)反应,得到标题化合物 (65mg,78%),为黄色油状物,MS(ESI):339.3[MH+]。
b)6-(环丙基甲氧基)-5-(2,2-二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酸
类似于实施例11b中所述的程序,将6-(环丙基甲氧基)-5-(2,2-二氟-5- 氮杂螺[2.4]庚-5-基)吡啶-2-甲酸甲酯(69mg,204μmol)用水合氢氧化锂皂化,得到标题化合物(67mg,定量),为灰白色固体,MS(ESI):325.2[MH+]。
c)N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(2,2-二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将6-(环丙基甲氧基)-5-(2,2-二氟-5- 氮杂螺[2.4]庚-5-基)吡啶-2-甲酸(15.3mg,47.2μmol)与(S)-2-氨基-4-甲基戊酰胺盐酸盐(CAN687-51-4,7.86mg,47.2μmol)在2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(11mg,53%),为无色油状物,MS(ESI):437.3[MH+]。
实施例31
(2S)-1-[6-(环丙基甲氧基)-5-(2,2-二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺
类似于实施例28c中所述的程序,将6-(环丙基甲氧基)-5-(2,2-二氟-5- 氮杂螺[2.4]庚-5-基)吡啶-2-甲酸(实施例30b,15.3mg,47.2μmol)与 (S)-4,4-二氟吡咯烷-2-甲酰胺盐酸盐(CAN 426844-51-1,8.8mg,47.2μmol) 在2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物 (13mg,59%),为白色固体,MS(ESI):457.3[MH+]。
实施例32
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(2,2- 二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将6-(环丙基甲氧基)-5-(2,2-二氟-5- 氮杂螺[2.4]庚-5-基)吡啶-2-甲酸(实施例30b,15.3mg,47.2μmol)与2-(3- 氨基氧杂环丁烷-3-基)乙酰胺(CAN 1417638-25-5,6.14mg,47.2μmol)在 2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(9 mg,43%),为白色固体,MS(ESI):437.3[MH+]。
实施例33
N-I(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-氟-3-甲基氮杂环丁烷-1-基)吡啶-2-甲酰胺
a)6-(环丙基甲氧基)-5-(3-氟-3-甲基-氮杂环丁烷-1-基)吡啶-2-甲酸甲酯
类似于实施例28a中所述的程序,将5-溴-6-(环丙基甲氧基)吡啶-2- 甲酸甲酯(CAN 1415899-20-5,59mg,207μmol)与3-氟-3-甲基氮杂环丁烷盐酸盐(CAN 1427379-42-7,26mg,207μmol)反应,得到标题化合物(53 mg,87%),为黄色油状物,MS(ESI):295.3[MH+]。
b)6-(环丙基甲氧基)-5-(3-氟-3-甲基-氮杂环丁烷-1-基)吡啶-2-甲酸
类似于实施例11b中所述的程序,将6-(环丙基甲氧基)-5-(3-氟-3-甲基-氮杂环丁烷-1-基)吡啶-2-甲酸甲酯(53.8mg,183μmol)用水合氢氧化锂皂化,得到标题化合物(55mg,定量),为灰白色固体,MS(ESI):281.2[MH+]。
c)N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-氟-3- 甲基氮杂环丁烷-1-基)吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将6-(环丙基甲氧基)-5-(3-氟-3-甲基 -氮杂环丁烷-1-基)吡啶-2-甲酸(15.3mg,54.6μmol)与(S)-2-氨基-4-甲基戊酰胺盐酸盐(CAN687-51-4,9.1mg,54.6μmol)在2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(19mg,87%),为浅黄色油状物,MS(ESI):393.3[MH+]。
实施例34
(2S)-1-[6-(环丙基甲氧基)-5-(3-氟-3-甲基氮杂环丁烷-1-基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺
类似于实施例28c中所述的程序,将6-(环丙基甲氧基)-5-(3-氟-3-甲基 -氮杂环丁烷-1-基)吡啶-2-甲酸(实施例33b,15.3mg,54.6μmol)与(S)-4,4- 二氟吡咯烷-2-甲酰胺盐酸盐(CAN 426844-51-1,10.2mg,54.6μm01)在 2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(20 mg,88%),为白色固体,MS(ESI):413.3[MH+]。
实施例35
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(3-氟 -3-甲基氮杂环丁烷-1-基)吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将6-(环丙基甲氧基)-5-(3-氟-3-甲基 -氮杂环丁烷-1-基)吡啶-2-甲酸(实施例33b,15.3mg,54.6μmol)与2-(3- 氨基氧杂环丁烷-3-基)乙酰胺(CAN 1417638-25-5,7.1mg,54.6μmol)在 2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(10 mg,48%),为灰白色固体,MS(ESI):393.3[MH+]。
实施例36
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-甲酰胺
a)5-(3-环丙基-3-氟-氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-甲酸甲酯
类似于实施例28a中所述的程序,将5-溴-6-(环丙基甲氧基)吡啶-2- 甲酸甲酯(CAN 1415899-20-5,60mg,210μmol)与3-环丙基-3-氟氮杂环丁烷盐酸盐(CAN 936548-77-5,31.8mg,210μmol)反应,得到标题化合物(61mg,91%),为黄色油状物,MS(ESI):321.3[MH+]。
b)5-(3-环丙基-3-氟-氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-甲酸
类似于实施例11b中所述的程序,将5-(3-环丙基-3-氟-氮杂环丁烷-1- 基)-6-(环丙基甲氧基)吡啶-2-甲酸甲酯(56.7mg,177μmol)用水合氢氧化锂皂化,得到标题化合物(60mg,定量),为灰白色固体,MS(ESI):307.2[MH+]。
c)N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-5-(3-环丙基-3-氟氮杂环丁烷 -1-基)-6-(环丙基甲氧基)吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将5-(3-环丙基-3-氟-氮杂环丁烷-1- 基)-6-(环丙基甲氧基)吡啶-2-甲酸(15.1mg,49.3μmol)与(S)-2-氨基-4-甲基戊酰胺盐酸盐(CAN687-51-4,8.21mg,49.3μmol)在2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(15mg,72%),为无色油状物,MS(ESI):419.3[MH+]。
实施例37
(2S)-1-[5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺
类似于实施例28c中所述的程序,将5-(3-环丙基-3-氟-氮杂环丁烷-1- 基)-6-(环丙基甲氧基)吡啶-2-甲酸(实施例36b,15.1mg,49.3μmol)与 (S)-4,4-二氟吡咯烷-2-甲酰胺盐酸盐(CAN 426844-51-1,9.2mg,49.3μmol) 在2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物 (21mg,95%),为白色固体,MS(ESI):439.3[MH+]。
实施例38
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将5-(3-环丙基-3-氟-氮杂环丁烷-1- 基)-6-(环丙基甲氧基)吡啶-2-甲酸(实施例36b,15.1mg,49.3μmol)与2-(3- 氨基氧杂环丁烷-3-基)乙酰胺(CAN 1417638-25-5,6.42mg,49.3μmol)在 2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(12 mg,56%),为无色油状物,MS(ESI):419.3[MH+]。
实施例39
(2S)-1-[6-(4-氯苯基)-5-(环丙基甲氧基)吡啶-2-羰基]-4,4-二氟吡咯烷 -2-甲酰胺
类似于实施例28c中所述的程序,将6-(4-氯苯基)-5-(环丙基甲氧基) 吡啶-2-甲酸(CAN 1364677-94-0,26mg,86μmol)与(S)-4,4-二氟吡咯烷-2- 甲酰胺盐酸盐(CAN426844-51-1,16mg,86μmol)在2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(15mg,39%),为白色固体,LC-MS(ESI):436.1249。
实施例40
类似于实施例28c中所述的程序,将6-(4-氯苯基)-5-(环丙基甲氧基) 吡啶-2-甲酸(CAN 1364677-94-0,34mg,112μmol)与2-(5-甲基-1,2,4-二唑-3-基)丙-2-胺盐酸盐(CAN 1240526-27-5,19.9mg,112μmol)在2-溴-1- 乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(46mg, 96%),为浅橙色油状物,MS(ESI):427.2[MH+]。
实施例41
5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)-N-[3-(3-氟丙基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将5-(3-环丙基-3-氟-氮杂环丁烷-1- 基)-6-(环丙基甲氧基)吡啶-2-甲酸(实施例36b,10mg,33μmol)与2-氨基 -2-乙基-N-(3-氟丙基)丁酰胺盐酸盐(CAN 1613239-88-5,8mg,36μmol)在 2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(5 mg,32%),为白色固体,MS(ESI):m/e=479.3[MH+]。
实施例42
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(4-氯苯基)-5-(环丙基甲氧基) 吡啶-2-甲酰胺
类似于实施例28c中所述的程序,将6-(4-氯苯基)-5-(环丙基甲氧基) 吡啶-2-甲酸(CAN 1364677-94-0,35mg,115μmol)与(S)-2-氨基-4-甲基戊酰胺盐酸盐(CAN 687-51-4,19mg,115μmol)在2-溴-1-乙基吡啶四氟硼酸盐和DIEA的存在下缩合,得到标题化合物(30mg,63%),为白色固体,MS(ESI):416.2[MH+]。
实施例43
药理学试验
进行以下试验以确定式I化合物的活性:
放射性配体结合测定
本发明化合物对大麻素CB1受体的亲和性使用建议量的表达人CNR1 或CNR2受体的人胚胎肾(HEK)细胞的膜制品(PerkinElmer)各自分别结合1.5或2.6nM[3H]-CP-55,940(Perkin Elmer)作为放射性配体确定。结合在总体积为0.2ml的结合缓冲液(对于CB1受体50mM Tris,5mM MgCl2,2.5 mM EDTA,和0.5%(wt/vol)无脂肪酸BSA,pH 7.4,和对于CB2受体50mM Tris,5mM MgCl2,2.5mM EGTA,和0.1%(wt/vol)无脂肪酸BSA,pH 7.4) 中进行,在30℃振荡1h。通过经涂布有0.5%聚乙烯亚胺的微过滤板 (UniFilter GF/B过滤板;Packard)快速过滤将反应终止。对于Ki使用非线性回归分析(Activity Base,ID Business溶液,Limited)来分析结合的放射性,对于[3H]CP55,940的Kd值从饱和试验确定。式(I)化合物显示对于CB2 受体的优异的亲和性。
在上述测定(Ki)中,根据式(I)的化合物具有0.5nM和10μM的活性。在上述测定(Ki)中,特定的式(I)的化合物具有0.5nM至3μM的活性。在上述测定(Ki)中,其他的特定的式(I)的化合物具有0.5nM至100nM的活性.
cAMP测定
将表达人CB1或CB2受体的CHO细胞在实验之前17-24小时以50.000 细胞/孔接种在具有透明平底的黑色96孔平板(Corning Costar#3904)中、在DMEM(InvitrogenNo.31331)中,补充1x HT,具有10%胎牛血清,并在湿润的培养箱中在5%CO2和37℃下温育。将培养基用具有1mM IBMX 的Krebs Ringer Bicarbonate缓冲液交换,并且在30℃温育30分钟。加入化合物至最终测定体积为100μl,并且在30℃温育30分钟。使用 cAMP-Nano-TRF检测试剂盒(Roche Diagnostics),通过加入50μl裂解试剂 (Tris,NaCl,1.5%TritonX100,2.5%NP40,10%NaN3)和50μl检测溶液(20 μM mAb Alexa700-cAMP 1∶1,和48μM钌-2-AHA-cAMP)终止测定,并且室温振荡2h。通过装备有ND:YAG激光器作为激发源的TRF读出器(Evotec Technologies GmbH)测量时间分辨能量转移。将平板测量两次,在355nm 激发和分别在730(带宽30nm)或645nm(带宽75nm)以100ns的延迟和 100ns的栅极(gate)发射,总暴露时间是10s。FRET信号的计算如下:FRET =T730-Alexa730-P(T645-B645),P=Ru730-B730/Ru645-B645,其中T730 是在730nM测量的测试孔,T645是在645nm测量的测试孔,B730和 B645是分别在730nm和645nm的缓冲液对照。cAMP含量从跨度为从 10μM至0.13nM cAMP的标准曲线的函数来测定。
使用Activity Base分析(ID Business溶液,Limited)测定EC50值。从对于参比化合物的该测定产生的宽范围的大麻素激动剂的EC50值与科学文献中公开的值吻合。
在上述测定中,根据本发明的化合物具有0.5nM至10μM的人CB2 EC50。特定的根据本发明的化合物具有0.5nM至1μM的人CB2 EC50。根据本发明的进一步特定的化合物具有0.5nM至100nM的人CB2 EC50。在放射性配体和cAMP测定二者,或这两种测定之一中,它们呈现相对于人 CB1受体至少10倍的选择性。
对于代表性的本发明的化合物获得的结果在下表中给出。
实施例A
可以以常规方式制备含有下列成分的薄膜包衣片剂:
筛分活性成分,并将活性成分与微晶纤维素混和,并将混合物用聚乙烯吡咯烷酮的水溶液制粒。然后将颗粒与淀粉羟乙酸钠和硬脂酸镁混和并且压制,分别获得120或350mg的核。将所述核用上述薄膜包衣的水溶液 /悬浮液包衣。
实施例B
可以以常规方式制备含有下列成分的胶囊:
<u>成分</u> | <u>每片</u> |
式(I)的化合物 | 25.0mg |
乳糖 | 150.0mg |
玉米淀粉 | 20.0mg |
滑石 | 5.0mg |
筛分组分并混合和填充到2号胶囊中。
实施例C
注射液可以具有下列组成:
式(I)的化合物 | 3.0mg |
聚乙二醇400 | 150.0mg |
乙酸 | 适量至获得pH 5.0 |
注射液用水 | 加至1.0ml |
将活性成分溶解在聚乙二醇400和注射用水(一部分)的混合物中。通过加入乙酸将pH调到5.0。加入余量的水将体积调到1.0ml。将溶液过滤,使用适当过量装入小瓶中并灭菌。
Claims (20)
1.一种式(I)的化合物
其中
R1是烷硫基、环烷基烷氧基、卤代苯基或卤素;
R2是苯基、卤代苯基、环烷基烷氧基、烷氧基氮杂环丁烷基、2-氧杂-6-氮杂螺[3.3]庚基、(卤代烷基)(羟基)吡咯烷基、卤代-5-氮杂螺[2.4]庚基、(烷基)(卤代)氮杂环丁烷基或(环烷基)(卤代)氮杂环丁烷基;
R3和R4中的一个是氢,并且另一个是-(CR5R6)m-(CH2)n-R7;
或R3和R4与它们连接的氮原子一起形成氨基羰基-二氧代-噻唑烷基或(氨基羰基)(卤代)吡咯烷基;
R5和R6独立地选自氢、烷基、环烷基烷基和烷硫基烷基;
或R5和R6与它们连接的碳原子一起形成氧杂环丁烷基;
m是0或1;
n是0或1;
或其药用盐或酯。
2.根据权利要求1所述的化合物,其中R1是环烷基烷氧基或卤代苯基。
3.根据权利要求1或2所述的化合物,其中R1是环丙基甲氧基或氯苯基。
4.根据权利要求1至3中任一项所述的化合物,其中R2是苯基、卤代苯基、环烷基烷氧基或烷氧基氮杂环丁烷基。
5.根据权利要求1至4中任一项所述的化合物,其中R2是苯基、氯苯基、环丙基甲氧基或甲氧基氮杂环丁烷基。
6.根据权利要求1至5中任一项所述的化合物,其中R5和R6独立地选自氢和烷基。
7.根据权利要求1至6中任一项所述的化合物,其中R5和R6独立地选自氢、甲基、乙基和异丁基。
10.根据权利要求1至9中任一项所述的化合物,其选自
2-[[5-(4-氯苯基)-6-甲硫基吡啶-2-羰基]氨基]-2-甲基丙酸甲酯;
2-[[5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-羰基]氨基]-2-甲基丙酸甲酯;
6-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]-5-苯基吡啶-2-甲酰胺;
6-(3-氯苯基)-5-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-3-环丙基-1-氧代丙-2-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(2-氧杂-6-氮杂螺[3.3]庚-6-基)吡啶-2-甲酰胺;
6-(3-氯苯基)-5-(环丙基甲氧基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-3-环丙基-1-氧代丙-2-基]-5,6-双(环丙基甲氧基)吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲硫基-1-氧代丁-2-基]-6-氯-5-(环丙基甲氧基)吡啶-2-甲酰胺;
6-氯-5-(环丙基甲氧基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;
3-[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]-1,1-二氧代-1,3-噻唑烷-4-甲酰胺;
2-[[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]氨基]-2-乙基丁酸乙酯;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;
6-(环丙基甲氧基)-N-[(1-羟基环己基)甲基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-N-[3-(2-氟乙基氨基甲酰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-N-[3-(3-氟氮杂环丁烷-1-羰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-N-[3-(3-氟丙基氨基甲酰基)戊-3-基]-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
(2S)-1-[6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-[3-羟基-3-(三氟甲基)吡咯烷-1-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(2,2-二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酰胺;
(2S)-1-[6-(环丙基甲氧基)-5-(2,2-二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(2,2-二氟-5-氮杂螺[2.4]庚-5-基)吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-氟-3-甲基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
(2S)-1-[6-(环丙基甲氧基)-5-(3-氟-3-甲基氮杂环丁烷-1-基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(3-氟-3-甲基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-甲酰胺;
(2S)-1-[5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)吡啶-2-甲酰胺;
(2S)-1-[6-(4-氯苯基)-5-(环丙基甲氧基)吡啶-2-羰基]-4,4-二氟吡咯烷-2-甲酰胺;
5-(3-环丙基-3-氟氮杂环丁烷-1-基)-6-(环丙基甲氧基)-N-[3-(3-氟丙基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;和
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(4-氯苯基)-5-(环丙基甲氧基)吡啶-2-甲酰胺。
11.根据权利要求1至10中任一项所述的化合物,其选自
2-[[5-(4-氯苯基)-6-(环丙基甲氧基)吡啶-2-羰基]氨基]-2-甲基丙酸甲酯;
6-(3-氯苯基)-5-(环丙基甲氧基)-N-[2-(1,3-噻唑-2-基)丙-2-基]吡啶-2-甲酰胺;
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
3-[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]-1,1-二氧代-1,3-噻唑烷-4-甲酰胺;
2-[[6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-羰基]氨基]-2-乙基丁酸乙酯;
N-[3-(2-氨基-2-氧代乙基)氧杂环丁烷-3-基]-6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)吡啶-2-甲酰胺;
6-(环丙基甲氧基)-5-(3-甲氧基氮杂环丁烷-1-基)-N-[3-(甲基氨基甲酰基)戊-3-基]吡啶-2-甲酰胺;和
N-[(2S)-1-氨基-4-甲基-1-氧代戊-2-基]-6-(4-氯苯基)-5-(环丙基甲氧基)吡啶-2-甲酰胺。
13.根据权利要求12所述的方法制造的根据权利要求1至11中任一项所述的化合物。
14.根据权利要求1至11中任一项所述的化合物,其用作治疗活性物质。
15.一种药物组合物,其包含根据权利要求1至11中任一项所述的化合物和治疗惰性载体。
16.根据权利要求1至11中任一项所述的化合物用于治疗和预防疼痛、神经性疼痛、哮喘、骨质疏松、炎症、精神疾病、精神病、肿瘤、脑炎、疟疾、变态反应、免疫性病症、关节炎、胃肠道病症、精神异常、类风湿性关节炎、精神病或变态反应的用途。
17.根据权利要求1至11中任一项所述的化合物用于制备药物的用途,所述药物用于治疗或预防疼痛、神经性疼痛、哮喘、骨质疏松、炎症、精神疾病、精神病、肿瘤、脑炎、疟疾、变态反应、免疫性病症、关节炎、胃肠道病症、精神异常、类风湿性关节炎、精神病或变态反应。
18.根据权利要求1至11中任一项所述的化合物,其用于治疗或预防疼痛、神经性疼痛、哮喘、骨质疏松、炎症、精神疾病、精神病、肿瘤、脑炎、疟疾、变态反应、免疫性病症、关节炎、胃肠道病症、精神异常、类风湿性关节炎、精神病或变态反应。
19.一种用于治疗或预防疼痛、神经性疼痛、哮喘、骨质疏松、炎症、精神疾病、精神病、肿瘤、脑炎、疟疾、变态反应、免疫性病症、关节炎、胃肠道病症、精神异常、类风湿性关节炎、精神病或变态反应的方法,所述方法包括将有效量的如权利要求1至11中任一项所限定的化合物对需要其的患者给药。
20.如上文所述的发明。
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