JP2015500215A - Lrrk2モジュレーターとしてのアミノピリミジン誘導体 - Google Patents
Lrrk2モジュレーターとしてのアミノピリミジン誘導体 Download PDFInfo
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- JP2015500215A JP2015500215A JP2014543865A JP2014543865A JP2015500215A JP 2015500215 A JP2015500215 A JP 2015500215A JP 2014543865 A JP2014543865 A JP 2014543865A JP 2014543865 A JP2014543865 A JP 2014543865A JP 2015500215 A JP2015500215 A JP 2015500215A
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- JP
- Japan
- Prior art keywords
- methoxy
- alkyl
- methyl
- trifluoromethyl
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 102000009784 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Human genes 0.000 title abstract 2
- 108010020246 Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Proteins 0.000 title abstract 2
- 150000005005 aminopyrimidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 166
- -1 chloro, methyl Chemical group 0.000 claims description 99
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 125000005843 halogen group Chemical group 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 30
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000003566 oxetanyl group Chemical group 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 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
- 230000002265 prevention Effects 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 claims description 4
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- 239000003814 drug Substances 0.000 claims description 4
- BXZCNGWQXCBHEP-UHFFFAOYSA-N 2-fluoro-5-methoxy-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzonitrile Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(F)C=2)C#N)OC)=N1 BXZCNGWQXCBHEP-UHFFFAOYSA-N 0.000 claims description 3
- WJLZAIIJHMGDNS-UHFFFAOYSA-N 2-n-(2-methoxy-4-methylsulfonylphenyl)-4-n-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=CC=2)S(C)(=O)=O)OC)=N1 WJLZAIIJHMGDNS-UHFFFAOYSA-N 0.000 claims description 3
- AHGXNSPHXORIQZ-UHFFFAOYSA-N 3-methoxy-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzonitrile Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=CC=2)C#N)OC)=N1 AHGXNSPHXORIQZ-UHFFFAOYSA-N 0.000 claims description 3
- VQTACLUNJOFGAM-UHFFFAOYSA-N 1-[2-fluoro-5-methoxy-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]piperidin-2-one Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(F)C=2)N2C(CCCC2)=O)OC)=N1 VQTACLUNJOFGAM-UHFFFAOYSA-N 0.000 claims description 2
- MMSUYYTWZDZASK-UHFFFAOYSA-N 1-[2-fluoro-5-methoxy-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]pyrrolidin-2-one Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(F)C=2)N2C(CCC2)=O)OC)=N1 MMSUYYTWZDZASK-UHFFFAOYSA-N 0.000 claims description 2
- UTLJKPXVNNEOTP-UHFFFAOYSA-N 2-chloro-4-[[5-chloro-4-(methylamino)pyrimidin-2-yl]amino]-5-methoxybenzoic acid Chemical compound C1=C(Cl)C(NC)=NC(NC=2C(=CC(=C(Cl)C=2)C(O)=O)OC)=N1 UTLJKPXVNNEOTP-UHFFFAOYSA-N 0.000 claims description 2
- CFZKTBMXXJUNLF-UHFFFAOYSA-N 2-n-(2-chloro-4-methylsulfonylphenyl)-4-n-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=CC=2)S(C)(=O)=O)Cl)=N1 CFZKTBMXXJUNLF-UHFFFAOYSA-N 0.000 claims description 2
- AYWCKKZCDGIQGU-UHFFFAOYSA-N 2-n-(2-methoxy-4-morpholin-4-ylsulfonylphenyl)-4-n-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=CC=2)S(=O)(=O)N2CCOCC2)OC)=N1 AYWCKKZCDGIQGU-UHFFFAOYSA-N 0.000 claims description 2
- RCMLVVZKHRURPJ-UHFFFAOYSA-N 2-n-(2-methoxy-5-methyl-4-methylsulfonylphenyl)-4-n-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(C)C=2)S(C)(=O)=O)OC)=N1 RCMLVVZKHRURPJ-UHFFFAOYSA-N 0.000 claims description 2
- RJNFWPNXSNQTBW-UHFFFAOYSA-N 2-n-(5-fluoro-2-methoxy-4-methylsulfonylphenyl)-4-n-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(F)C=2)S(C)(=O)=O)OC)=N1 RJNFWPNXSNQTBW-UHFFFAOYSA-N 0.000 claims description 2
- HFGQVGZJGVAUJQ-UHFFFAOYSA-N 2-n-[2-methoxy-4-(morpholin-4-ylmethyl)phenyl]-4-n-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(CN3CCOCC3)=CC=2)OC)=N1 HFGQVGZJGVAUJQ-UHFFFAOYSA-N 0.000 claims description 2
- ZGEDTVHQJLMDPW-UHFFFAOYSA-N 2-n-[5-fluoro-2-methoxy-4-(morpholin-4-ylmethyl)phenyl]-4-n-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(CN3CCOCC3)=C(F)C=2)OC)=N1 ZGEDTVHQJLMDPW-UHFFFAOYSA-N 0.000 claims description 2
- DLNHJRGDYSWBNT-UHFFFAOYSA-N 2-n-[5-fluoro-2-methoxy-4-(oxetan-3-yl)phenyl]-4-n-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(F)C=2)C2COC2)OC)=N1 DLNHJRGDYSWBNT-UHFFFAOYSA-N 0.000 claims description 2
- QXVMXBPPRRXMMZ-UHFFFAOYSA-N 4-[2-fluoro-5-methoxy-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]morpholin-3-one Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(F)C=2)N2C(COCC2)=O)OC)=N1 QXVMXBPPRRXMMZ-UHFFFAOYSA-N 0.000 claims description 2
- FDJDDPNOJDABJG-UHFFFAOYSA-N 4-[[5-chloro-4-(methylamino)pyrimidin-2-yl]amino]-3-methoxybenzoic acid Chemical compound C1=C(Cl)C(NC)=NC(NC=2C(=CC(=CC=2)C(O)=O)OC)=N1 FDJDDPNOJDABJG-UHFFFAOYSA-N 0.000 claims description 2
- QHUPHGLWVVOXED-UHFFFAOYSA-N 4-n-ethyl-2-n-(2-methoxy-5-methyl-4-methylsulfonylphenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NCC)=NC(NC=2C(=CC(=C(C)C=2)S(C)(=O)=O)OC)=N1 QHUPHGLWVVOXED-UHFFFAOYSA-N 0.000 claims description 2
- HYZJXVODIRZJGT-UHFFFAOYSA-N 4-n-ethyl-2-n-(5-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-8-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NCC)=NC(NC=2C=3OCCOC=3C(=CC=2)S(C)(=O)=O)=N1 HYZJXVODIRZJGT-UHFFFAOYSA-N 0.000 claims description 2
- LSLXBRTUIZNUQE-UHFFFAOYSA-N 4-n-methyl-2-n-(4-methylsulfonyl-2-propan-2-yloxyphenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=CC=2)S(C)(=O)=O)OC(C)C)=N1 LSLXBRTUIZNUQE-UHFFFAOYSA-N 0.000 claims description 2
- XYPLAVKOQQVFQI-UHFFFAOYSA-N 5-chloro-2-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzonitrile Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(C)C=2)C#N)Cl)=N1 XYPLAVKOQQVFQI-UHFFFAOYSA-N 0.000 claims description 2
- LZNKQRLLXOCSJT-UHFFFAOYSA-N 5-chloro-2-n-(2-methoxy-4-morpholin-4-ylphenyl)-4-n-methylpyrimidine-2,4-diamine Chemical compound C1=C(Cl)C(NC)=NC(NC=2C(=CC(=CC=2)N2CCOCC2)OC)=N1 LZNKQRLLXOCSJT-UHFFFAOYSA-N 0.000 claims description 2
- VUSYWQLOGDSXIH-UHFFFAOYSA-N 5-chloro-2-n-[2-(2-fluoroethoxy)-4-(morpholin-4-ylmethyl)phenyl]-4-n-methylpyrimidine-2,4-diamine Chemical compound C1=C(Cl)C(NC)=NC(NC=2C(=CC(CN3CCOCC3)=CC=2)OCCF)=N1 VUSYWQLOGDSXIH-UHFFFAOYSA-N 0.000 claims description 2
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- SMXBTJKMLBXOLB-UHFFFAOYSA-N 5-chloro-2-n-[2-methoxy-4-(trifluoromethyl)phenyl]-4-n-methylpyrimidine-2,4-diamine Chemical compound C1=C(Cl)C(NC)=NC(NC=2C(=CC(=CC=2)C(F)(F)F)OC)=N1 SMXBTJKMLBXOLB-UHFFFAOYSA-N 0.000 claims description 2
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- ZEMTWSFENJACPQ-UHFFFAOYSA-N 5-methoxy-2-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzonitrile Chemical compound C1=C(C(F)(F)F)C(NC)=NC(NC=2C(=CC(=C(C)C=2)C#N)OC)=N1 ZEMTWSFENJACPQ-UHFFFAOYSA-N 0.000 claims description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 29
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- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
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- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
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- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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- 230000002829 reductive effect Effects 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
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- 230000002459 sustained effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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Abstract
Description
パーキンソン病、レビー小体型認知症及びハンチントン病等の神経変性疾患は、何百人もの人々が罹患している。パーキンソン病は、およそ1000人に1人が罹患する慢性の進行性運動系障害であり、遺伝性パーキンソン病は、患者全体の5〜10%を占める。パーキンソン病は、中脳ドーパミンニューロンの進行的な喪失によって引き起こされ、患者は運動を管理及び制御する能力が低下する。主なパーキンソン病の症状は、震え、硬直、運動緩徐及び平衡障害である。多くのパーキンソン病患者は、また、情動変化、記憶喪失、会話障害及び睡眠障害等のその他の症状も経験する。
本発明は、式I:
[式中、
mは、0〜3であり;
Xは、−NRa−;−O−;又は−S(O)r−(ここで、rは、0〜2であり、そして、Raは、水素又はC1−6アルキルである)であり;
R1は、C1−6アルキル;C1−6アルケニル;C1−6アルキニル;ハロ−C1−6アルキル;C1−6アルコキシ−C1−6アルキル;ヒドロキシ−C1−6アルキル;アミノ−C1−6アルキル;C1−6アルキルスルホニル−C1−6アルキル;C3−6シクロアルキル(C1−6アルキルで場合により置換されている);C3−6シクロアルキル−C1−6アルキル(ここで、C3−6シクロアルキル部分は、C1−6アルキルで場合により置換されている);テトラヒドロフラニル;テトラヒドロフラニル−C1−6アルキル;オキセタニル;又はオキセタン−C1−6アルキルであるか;
又はR1及びRaは、これらが連結している原子と一緒になって、O、N及びSから選択される追加のヘテロ原子を場合により含むことができ、かつオキソ、ハロ又はC1−6アルキルで置換されている、3〜6員環を形成してよく;
R2は、ハロ;C1−6アルコキシ;シアノ;C1−6アルキニル;C1−6アルケニル;ハロ−C1−6アルキル;ハロ−C1−6アルコキシ;C3−6シクロアルキル(ここで、C3−6シクロアルキル部分は、C1−6アルキルで場合により置換されている);C3−6シクロアルキル−C1−6アルキル(ここで、C3−6シクロアルキル部分は、C1−6アルキルで場合により置換されている);テトラヒドロフラニル;テトラヒドロフラニル−C1−6アルキル;アセチル;オキセタニル;又はオキセタン−C1−6アルキルであり;
R3及びR4は、各々独立して、ハロ;C1−6アルキル;C1−6アルコキシ;C3−6シクロアルキルオキシ;ハロ−C1−6アルキル;又はハロ−C1−6アルコキシであるか;
又はR3及びR4は、これらが連結している原子と一緒になって、各々O、N及びSから独立して選択される1又は2個のヘテロ原子を場合により含む5又は6員環を形成してよく、その環は、R6で1回以上場合により置換されており;
R5は、C1−6アルキル−スルホニル;C3−6シクロアルキルスルホニル;C3−6シクロアルキル−C1−6アルキルスルホニル;シアノ;シアノ−C1−6アルキル;ヘテロシクリル(R6で1回以上場合により置換されている);ヘテロシクリル−C1−6アルキル(ここで、ヘテロシクリル部分は、R6で1回以上場合により置換されている);ハロ−C1−6アルキル;ヘテロシクリル−スルホニル(ここで、ヘテロシクリル部分は、R6で1回以上場合により置換されている);又はカルボキシであり;そして
R6は、C1−6アルキル;ハロ;ハロ−C1−6アルキル;又はオキソである]
で表される化合物又はその薬学的に許容しうる塩を提供する。
定義
特に明記しない限り、本明細書及び特許請求の範囲を含む本出願において使用される以下の用語は、下記の定義を有する。本明細書及び添付の特許請求の範囲において使用されるように、単数形の「a」、「an」及び「the」は、文脈が明確に他のことを示していない限り、複数形の指示対象を含むことに留意しなければならない。
一般的に、本出願において使用される命名及び化学名は、CambridgeSoft(商標)によるChembioOffice(商標)に基づいている。本明細書において構造中の炭素、酸素、硫黄又は窒素原子上に現れる任意の空の原子価は、特に指示のない限り、水素原子の存在を示す。窒素含有ヘテロアリール環が、窒素原子上に空の原子価を有すると示され、そして、Ra、Rb又はRc等の変数がヘテロアリール環上に示される場合、そのような変数は、空の原子価の窒素に結合又は連結していてもよい。キラル中心が構造中に存在するが、そのキラル中心について具体的な立体化学が示されない場合、キラル中心を伴う両方のエナンチオマーがその構造に包含される。本明細書に示される構造が複数の互変異性体形態で存在しうる場合、そのような互変異性体の全てがその構造に包含される。本明細書において構造中に表される原子は、そのような原子の全ての天然同位体を包含することが意図される。従って、例えば、本明細書において表される水素原子は、重水素及び三重水素を含むことを意味し、そして、炭素原子は、C13及びC14同位体を含むことを意味する。
本発明は、式I:
[式中、
mは、0〜3であり;
Xは、−NRa−;−O−;又は−S(O)r−(ここで、rは、0〜2であり、そして、Raは、水素又はC1−6アルキルである)であり;
R1は、C1−6アルキル;C1−6アルケニル;C1−6アルキニル;ハロ−C1−6アルキル;C1−6アルコキシ−C1−6アルキル;ヒドロキシ−C1−6アルキル;アミノ−C1−6アルキル;C1−6アルキルスルホニル−C1−6アルキル;C3−6シクロアルキル(C1−6アルキルで場合により置換されている);C3−6シクロアルキル−C1−6アルキル(ここで、C3−6シクロアルキル部分は、C1−6アルキルで場合により置換されている);テトラヒドロフラニル;テトラヒドロフラニル−C1−6アルキル;オキセタニル;又はオキセタン−C1−6アルキルであるか;
又はR1及びRaは、これらが連結している原子と一緒になって、O、N及びSから選択される追加のヘテロ原子を場合により含むことができ、かつオキソ、ハロ又はC1−6アルキルで置換されている、3〜6員環を形成してよく;
R2は、ハロ;C1−6アルコキシ;シアノ;C1−6アルキニル;C1−6アルケニル;ハロ−C1−6アルキル;ハロ−C1−6アルコキシ;C3−6シクロアルキル(ここで、C3−6シクロアルキル部分は、C1−6アルキルで場合により置換されている);C3−6シクロアルキル−C1−6アルキル(ここで、C3−6シクロアルキル部分は、C1−6アルキルで場合により置換されている);テトラヒドロフラニル;テトラヒドロフラニル−C1−6アルキル;アセチル;オキセタニル;又はオキセタン−C1−6アルキルであり;
R3及びR4は、各々独立して、ハロ;C1−6アルキル;C1−6アルコキシ;C3−6シクロアルキルオキシ;ハロ−C1−6アルキル;又はハロ−C1−6アルコキシであるか;
又はR3及びR4は、これらが連結している原子と一緒になって、各々O、N及びSから独立して選択される1又は2個のヘテロ原子を場合により含む5又は6員環を形成してよく、その環は、R6で1回以上場合により置換されており;
R5は、C1−6アルキル−スルホニル;C3−6シクロアルキルスルホニル;C3−6シクロアルキル−C1−6アルキルスルホニル;シアノ;シアノ−C1−6アルキル;ヘテロシクリル(R6で1回以上場合により置換されている);ヘテロシクリル−C1−6アルキル(ここで、ヘテロシクリル部分は、R6で1回以上場合により置換されている);ハロ−C1−6アルキル;ヘテロシクリル−スルホニル(ここで、ヘテロシクリル部分は、R6で1回以上場合により置換されている);又はカルボキシであり;そして
R6は、C1−6アルキル;ハロ;ハロ−C1−6アルキル;又はオキソである]
で表される化合物又はその薬学的に許容しうる塩を提供する。
mは、0〜1であり;
Xは、−NH−又は−O−であり;
R1は、C1−6アルキルであり;
R2は、ハロ;シアノ又はハロ−C1−6アルキルであり;
R3及びR4は、各々独立して、ハロ;C1−6アルキル又はC1−6アルコキシであり;
R5は、C1−6アルキル−スルホニル;シアノ;ヘテロシクリル(R6で1回以上場合により置換されている);ヘテロシクリル−C1−6アルキル(ここで、ヘテロシクリル部分は、R6で1回以上場合により置換されている);ハロ−C1−6アルキル;ヘテロシクリル−スルホニル(ここで、ヘテロシクリル部分は、R6で1回以上場合により置換されている);又はカルボキシであり;そして
R6は、オキソである。
N2−(2−メトキシ−4−(メチルスルホニル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、5−クロロ−N2−(2−メトキシ−4−(メチルスルホニル)フェニル)−N4−メチルピリミジン−2,4−ジアミン、2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)ベンゾニトリル、3−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)ベンゾニトリル、4−(5−クロロ−4−(メチルアミノ)ピリミジン−2−イルアミノ)−3−メトキシベンゾニトリル、(2−クロロ−4−メタンスルホニル−フェニル)−(5−クロロ−4−メトキシ−ピリミジン−2−イル)−アミン、N2−(2−クロロ−4−メタンスルホニル−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、5−クロロ−N2−(2−クロロ−4−メタンスルホニル−フェニル)−N4−メチル−ピリミジン−2,4−ジアミン、N2−(2−メトキシ−4−モルホリン−4−イルメチル−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、5−クロロ−2−メチル−4−(4−メチルアミノ−5−トリフルオロメチル−ピリミジン−2−イルアミノ)−ベンゾニトリル、2−(5−フルオロ−2−メトキシ−4−モルホリン−4−イルメチル−フェニルアミノ)−4−メチルアミノ−ピリミジン−5−カルボニトリル、4−エチルアミノ−2−(5−フルオロ−2−メトキシ−4−モルホリン−4−イルメチル−フェニルアミノ)−ピリミジン−5−カルボニトリル、5−メトキシ−2−メチル−4−(4−メチルアミノ−5−トリフルオロメチル−ピリミジン−2−イルアミノ)−ベンゾニトリル、5−クロロ−N2−[2−(2−フルオロ−エトキシ)−4−モルホリン−4−イルメチル−フェニル]−N4−メチル−ピリミジン−2,4−ジアミン、N2−(5−フルオロ−4−メタンスルホニル−2−メトキシ−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N2−(2−イソプロポキシ−4−メタンスルホニル−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、5−クロロ−N2−[2−(2−フルオロ−エトキシ)−4−メタンスルホニル−フェニル]−N4−メチル−ピリミジン−2,4−ジアミン、(5−クロロ−4−メトキシ−ピリミジン−2−イル)−[2−(2−フルオロ−エトキシ)−4−メタンスルホニル−フェニル]−アミン、N2−[2−(2−フルオロ−エトキシ)−4−メタンスルホニル−フェニル]−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N2−(5−クロロ−4−メタンスルホニル−2−メトキシ−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N2−[5−フルオロ−2−(2−フルオロ−エトキシ)−4−モルホリン−4−イルメチル−フェニル]−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N4−エチル−N2−[5−フルオロ−2−(2−フルオロ−エトキシ)−4−モルホリン−4−イルメチル−フェニル]−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N2−(4−メタンスルホニル−2−メトキシ−5−メチル−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、5−クロロ−N2−(2−メトキシ−4−モルホリノフェニル)−N4−メチルピリミジン−2,4−ジアミン、4−(5−クロロ−4−(メチルアミノ)ピリミジン−2−イルアミノ)−3−メトキシ安息香酸、N2−(2−メトキシ−4−(モルホリノスルホニル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N2−(2−メトキシ−4−(トリフルオロメチル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、5−クロロ−N2−(2−メトキシ−4−(トリフルオロメチル)フェニル)−N4−メチルピリミジン−2,4−ジアミン、2−クロロ−4−(5−クロロ−4−(メチルアミノ)ピリミジン−2−イルアミノ)−5−メトキシ安息香酸、1−(2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)フェニル)ピロリジン−2−オン、4−(2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)フェニル)モルホリン−3−オン、1−(2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)フェニル)ピペリジン−2−オン、N2−(5−フルオロ−2−メトキシ−4−(オキセタン−3−イル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N4−エチル−N2−(2−メトキシ−5−メチル−4−(メチルスルホニル)フェニル)−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N2−(4−(エチルスルホニル)−2−メトキシ−5−メチルフェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N2−(2−メトキシ−5−メチル−4−(メチルスルホニル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N2−(5−フルオロ−2−メトキシ−4−(モルホリノメチル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン及びN4−エチル−N2−(8−(メチルスルホニル)−2,3−ジヒドロベンゾ[b][1,4]ジオキシン−5−イル)−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン。
本発明の化合物は、下記に示し、説明する例示的合成反応スキームに記載する様々な方法によって製造することができる。
本発明は、少なくとも1つの本発明の化合物又は個々の異性体、異性体のラセミ混合物もしくは非ラセミ混合物、又はその薬学的に許容しうる塩もしくは溶媒和物を、少なくとも1つの薬学的に許容しうる担体、及び場合によりその他の治療及び/又は予防成分と一緒に含む医薬組成物を含む。
本発明の化合物は、パーキンソン病、レビー小体型認知症及びハンチントン病等の神経変性疾患を含むLRRK2媒介性疾患又は病状の処置に、また、一般的にそれを必要とする被験体の認知記憶の増強に有用である。
下記の調製例及び実施例は、当業者が本発明をより明確に理解し、実施できるように示す。これらは、本発明の範囲を制限するとものではなく、本発明の例示及び代表例としてのみ考えられるべきである。
AcOH 酢酸
AIBN 2,2’−アゾビス(2−メチルプロピオニトリル)
Atm. 気圧
(BOC)2O 二炭酸ジ−tert−ブチル
DavePhos 2−ジシクロヘキシルホスフィノ−2’−(N,N−ジメチルアミノ)ビフェニル
DCM ジクロロメタン/塩化メチレン
DIAD アゾジカルボン酸ジイソプロピル
DIPEA ジイソプロピルエチルアミン
DMAP 4−ジメチルアミノピリジン
DME 1,2−ジメトキシエタン
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
DPPF 1,1’−ビス(ジフェニルホスフィノ)フェロセン
Et2O ジエチルエーテル
EtOH エタノール/エチルアルコール
EtOAc 酢酸エチル
HATU 2−(1H−7−アザベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェートメタンアミニウム
HBTU O−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
HPLC 高速液体クロマトグラフィー
RP HPLC 逆相高速液体クロマトグラフィー
i−PrOH イソプロパノール/イソプロピルアルコール
LCMS 液体クロマトグラフ/質量分析
MeOH メタノール/メチルアルコール
MW マイクロ波
NBS N−ブロモスクシンイミド
NMP 1−メチル−2−ピロリジノン
PSI ポンド毎平方インチ
RT 室温
TBDMS tert−ブチルジメチルシリル
TFA トリフルオロ酢酸
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
スターラーバーを備えた250mLの丸底フラスコに、9.0gの5−フルオロ−2,4−ジクロロ−ピリミジン、40mLのメタノール及びエタノール中の15mLの8Mメチルアミンを加えた。反応物は熱くなり(穏やかな発熱)、室温で約30分間撹拌した。TLC(1:1 EtOAc:ヘプタン)及びLCMSでチェックしたところ、反応は完了していた。反応物を濃縮して、9.77gの粗物質を得て、これを、シリカカラムにてDCM中1%〜10%MeOHの勾配を35分間かけて流して精製し、6.77gの純粋な2−クロロ−5−フルオロ−N−メチルピリミジン−4−アミンを得た。
スターラーバーを備えた250mLの丸底フラスコに、1gの5−クロロ−2,4−ジクロロ−ピリミジン及び15mLのジエチルエーテルを加えた。混合物を氷浴中で0℃まで冷却し、次に、1当量のメタノール中のナトリウムメトキシド(120mgのナトリウムと4mLのメタノールを室温で反応させて調製した)をゆっくり加えた。反応物を室温で一晩撹拌し、LCMSでチェックした。白色の沈殿物を濾過し、固体を冷メタノールで洗浄した。乾燥した後、0.98gの純粋な2,5−ジクロロ−4−メトキシピリミジンを得て、この物質をさらに精製することなく使用した。
工程1: 2−メトキシ−4−(メチルスルホニル)アニリン
DMF(25mL)中の4−フルオロ−2−メトキシ−1−ニトロベンゼン(1.38g、8.06mmol)及びメチルメルカプタンナトリウム(0.622g、8.87mmol)の混合物を室温で18時間撹拌した。反応物を水で希釈し、EtOAcで抽出した。合わせた抽出物をブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮して、(3−メトキシ−4−ニトロフェニル)(メチル)スルファン(0.95g、59%)を得た。
アセトン(10mL)中の(3−メトキシ−4−ニトロフェニル)(メチル)スルファン(0.58g、2.9mmol)の懸濁液に、水(10mL)、メタノール(1.0mL)を加えた。混合物を氷浴で10分間冷却した後、オキソン(2.90g、4.72mmol)を4回に分けて4分間かけて加えた。反応物を0℃で15分間撹拌し、次に、室温まで放温した。反応物を室温で2時間撹拌した後、EtOAc(50mL)で希釈した。懸濁液を濾過し、その容量を1/3まで濃縮して、水(40mL)で希釈した。次に、混合物をEtOAcで抽出した。合わせた抽出物をブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮して、2−メトキシ−4−(メチルスルホニル)−1−ニトロベンゼン(0.67g、83%)を得た。
エタノール(10mL)中の2−メトキシ−4−(メチルスルホニル)−1−ニトロベンゼン(0.175g、0.76mmol)及びパラジウム炭素(10wt%、0.10g)の懸濁液を、水素下、1気圧で18時間撹拌した。反応物をセライトで濾過し、濃縮して、2−メトキシ−4−(メチルスルホニル)アニリン(0.15g、92%)を得た。
工程1: 1−ブロモ−2−フルオロ−5−メトキシ−4−ニトロベンゼン
メタノール(20mL)中の1−ブロモ−2,5−ジフルオロ−4−ニトロベンゼン(2.56g、0.011mmol)の溶液に、25%ナトリウムメトキシドのメタノール溶液(2.5mL)を加えた。混合物を室温で1.5時間撹拌した。次に、反応物を濃縮し、EtOAcに再溶解して、水で洗浄した。水性洗浄物をEtOAcで逆抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮して、1−ブロモ−2−フルオロ−5−メトキシ−4−ニトロベンゼン(2.65g、99%)を得た。
イソプロパノール(20mL)中の1−ブロモ−2−フルオロ−5−メトキシ−4−ニトロベンゼン(0.998g、3.99mmol)の溶液に、鉄(0.7g、12mmol)、塩化アンモニウム(0.64g、12mmol)及び水(2mL)を加えた。反応物を75℃で2時間撹拌し、次に、濾過して、濃縮した。残渣を水で希釈し、EtOAcで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮して、4−ブロモ−5−フルオロ−2−メトキシアニリン(0.82g、93%)を得た。
圧力管に、4−ブロモ−5−フルオロ−2−メトキシアニリン(0.24g、1.1mmol)、シアン化亜鉛(0.10g、0.87mmol)、Pd2(dba)3(100mg、0.11mmol)、DavePhos(86mg、0.22mmol)及びDMF(3mL)を加えた。反応物を密封し、100℃で6時間撹拌した。反応物を水で希釈し、EtOAcで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸ナトリウムで乾燥させ、濾過して、濃縮した。粗生成物をフラッシュクロマトグラフィーによって精製して、4−アミノ−2−フルオロ−5−メトキシベンゾニトリル(0.18g、77%)を得た。
1−ブタノール(1.5mL)中の2−メトキシ−4−(メチルスルホニル)アニリン(0.095g、0.47mmol)及び2−クロロ−N−メチル−5−(トリフルオロメチル)ピリミジン−4−アミン(0.10g、0.47mmol)の混合物に、TFA(0.036mL、0.047mmol)を加えた。反応物を、密封管中、100℃で1.5時間撹拌した。反応物を濃縮し、生成物を逆相HPLCによって単離して、N2−(2−メトキシ−4−(メチルスルホニル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン(0.18g、20%)を得た。1H NMR (400 MHz, DMSO) δ 8.58 (d, J = 12.9, 1H), 8.24 (d, J = 5.0, 2H), 7.53 (d, J = 10.1, 1H), 7.48 (s, 1H), 7.38 - 7.29 (m, 1H), 3.99 (s, 3H), 3.20 (s, 3H), 2.94 (d, J = 4.3, 3H); LRRK2 Ki = 0.002。
2−クロロ−N−メチル−5−(トリフルオロメチル)ピリミジン−4−アミンの代わりに、2−クロロ−5−クロロ−N−メチルピリミジン−4−アミンを使用して、5−クロロ−N2−(2−メトキシ−4−(メチルスルホニル)フェニル)−N4−メチルピリミジン−2,4−ジアミンを同様に調製した;1H NMR (400 MHz, DMSO) δ 8.64 (d, J = 8.6, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.51 (d, J = 8.6, 1H), 7.45 (s, 1H), 7.42 (d, J = 4.3, 1H), 3.99 (s, 3H), 3.18 (s, 3H), 2.93 (d, J = 4.5, 3H); LRRK2 Ki = 0.002。
1−ブタノール(2mL)中の4−アミノ−2−フルオロ−5−メトキシベンゾニトリル(66mg、0.40mmol)及び2−クロロ−N−メチル−5−(トリフルオロメチル)ピリミジン−4−アミン(0.10g、0.47mmol)の混合物に、TFA(0.05mL、0.07mmol)を加えた。反応物を、密封管中、75℃で2時間撹拌した。反応物を濃縮し、生成物を逆相HPLCによって単離して、2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)ベンゾニトリルを得た。1H NMR (400 MHz, DMSO) δ 8.57 (d, J = 13.4, 2H), 8.34 (s, 1H), 8.29 (d, J = 6.1, 1H), 7.56 - 7.42 (m, 3H), 3.93 (s, 3H), 2.95 (s, 3H); LRRK2 Ki = 0.022。
4−アミノ−2−フルオロ−5−メトキシベンゾニトリルの代わりに、4−アミノ−3−メトキシベンゾニトリルを使用して、3−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)ベンゾニトリルを同様に調製した:1H NMR (400 MHz, DMSO) δ 8.53 (d, J = 8.7, 1H), 8.23 (d, J = 8.4, 1H), 7.49 (s, 1H), 7.45 (d, J = 8.0, 1H), 7.35 (dd, J = 12.3, 7.3, 1H), 3.94 (s, 3H), 2.93 (d, J = 4.4, 3H); LRRK2 Ki = 0.008。
4−アミノ−2−フルオロ−5−メトキシベンゾニトリルの代わりに4−アミノ−3−メトキシベンゾニトリルを、そして、2−クロロ−N−メチル−5−(トリフルオロメチル)ピリミジン−4−アミンの代わりに5−クロロ−N4−メチルピリミジン−2,4−ジアミンを使用して、4−(5−クロロ−4−(メチルアミノ)ピリミジン−2−イルアミノ)−3−メトキシベンゾニトリルを同様に調製した:1H NMR (400 MHz, DMSO) δ 8.59 (d, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.42 (m, 3H), 3.94 (s, 3H), 2.92 (d, 3H); LRRK2 Ki = 0.008。
このアッセイを使用して、Kiapp、IC50又は阻害率値を決定することによって、LRRK2の活性を阻害する化合物の効力を決定した。ポリプロピレンプレート中、LRRK2、蛍光標識ペプチド基質、ATP及び試験化合物を一緒にインキュベートした。LabChip 3000(Caliper Life Sciences)を使用して、反応後、基質をキャピラリー電気泳動によってリン酸化物と非リン酸化物の2つの集団に分離した。各々の相対量は、蛍光強度によって定量した。LRRK2 Kiは、下記式に従って決定した:
Y=V0*(1−((x+Ki*(1+S/Km)+Et)/(2*Et)−(((x+Ki*(1+S/Km)+Et)^2−(4*Et*x))^0.5)/(2*Et)))。
5mM MgCl2中のLRRK2 G2019S:5.2nM(Invitrogen lot # 567054A)
1mM MnCl2中のLRRK2 G2019S:11nM(Invitrogen lot # 567054A)
5mM MgCl2中のLRRK2野生型:15nM(Invitrogen lot # 500607F)
5mM MgCl2中のLRRK2 I2020T:25nM(Invitrogen lot # 43594)
基質:1μM
ATP:130μM
キナーゼ反応時間:2時間
温度:周囲温度
総容量:20μl
5mM MgCl2中のG2019S:130μM
1mM MnCl2中のG2019S:1μM
5mM MgCl2中の野生型:80μM
5mM MgCl2中のI2020T:14μM
固体支持体:50μL容量の黒色ポリプロピレン384ウェルプレート(MatriCal cat # MP101-1-PP)
キナーゼ:LRRK2 G2019S(Invitrogen cat # PV4882)
LRRK2野生型(Invitrogen cat # PV4874)
基質:5FAM−GAGRLGRDKYKTLRQIRQ−CONH2
非結合プレート:384ウェル透明V底ポリプロピレンプレート(Greiner cat # 781280)
ATP:10mM ATP(Cell Signaling cat # 9804)
Triton X−100:Triton X−100
Brij−35:Brij−35(Pierce cat # 20150)
コーティング試薬#3:コーティング試薬#3(Caliper)
DMSO:DMSO(Sigma cat # 34869-100ML)
コンプリート反応バッファー:H2O/25mM Tris、pH8.0/5mM MgCl2/2mM DTT/0.01%Triton X−100
停止溶液:H2O/100mM HEPES、pH7.2/0.015%Brij−35/0.2%コーティング試薬#3/20mM EDTA
分離バッファー:H2O/100mM HEPES、pH7.2/0.015%Brij−35/0.1%コーティング試薬#3/1:200コーティング試薬#8/10mM EDTA/5%DMSO
段階希釈用に、34.6μlのDMSOを縦列3〜24に加えた。アッセイコントロール用に、37.5μlのDMSOを横列A及びPの縦列1及び2に加え、a、d及び50μlの25μM G−028831(Staurosporine)を横列Bの縦列1及び2に加えた。サンプル用に、100μMで開始するために、37.5μlのDMSOを縦列1及び2に加え、次に、12.5μlの10mMの化合物を加えた;10μMで開始するために、78μlのDMSOを縦列1&2に加え、次に、2μlの10mMの化合物を加えた;そして、1μMで開始するために、25μMの化合物(2μlの10mM 化合物+798μlのDMSO)を空の縦列1及び2に加えた。精密機械を使用して、1:3.16の段階希釈を実施した(「PLK_BM_serial_halflog」)。
ATPをコンプリートキナーゼバッファー中282.1μMに希釈した(最終濃度は、130μMであった)。
コンプリート反応バッファー中、基質を4μMに希釈した。等容量のコンプリート反応バッファーと4μMの基質を合わせ、ブランクを得た。等容量のコンプリート反応バッファーと4μMの基質を合わせ、合わせた溶液に2×最終LRRK2濃度を加えた。
50μlのポリプロピレンプレートに、5μl/ウェルのバッファー/基質をブランクウェルに手で加えた。Biomek FXを使用して、キナーゼ反応を開始した(「PLK SAR 23 ATP」)。下記を適切なウェルに加えた:
2μl化合物+23μlATP;
アッセイプレート中、5μl/ウェルの化合物/ATP;
アッセイプレート中、5μl/ウェルのキナーゼ/基質
ジョブ「LRRK2 IC50」を使用し、下記のジョブ設定でLabChip 3000を実行した:
圧力:−1.4psi
ダウンストリーム電圧:−500V
アップストリーム電圧:−2350V
ポストサンプルバッファーシップ時間:75秒
ポストダイバッファーシップ時間:75秒
最終遅延時間:200秒
このアッセイを使用して、Kiapp、IC50又は阻害率値を決定することによって、LRRK2の活性を阻害する化合物の効力を決定した。384ウェルプロキシプレート(F黒色、浅底ウェルプレート)中、LRRK2、Eu抗GST抗体、Alexa Fluor(登録商標)キナーゼトレーサー236及び試験化合物を一緒にインキュベートした。
最終アッセイ条件:
GST−LRRK2 G2019S 10nM
Eu抗GST抗体 2nM
キナーゼトレーサー236 8.5nM
キナーゼ反応時間:1時間
温度:周囲温度
総容量:15μl
DMSO:1%
384ウェルプロキシプレート(F黒色、浅底ウェル) Perkin Elmer cat# 6008260
キナーゼ:LRRK2 G2019S Invitrogen cat # PV4882(LOT 567054A)
Eu標識抗GST抗体 Invitrogen cat # PV5594
Alexa Fluor(登録商標)キナーゼトレーサー236 Invitrogen cat #PV5592
TRIS−HCl Sigma cat # T3253
EGTA Sigma cat # E3889
Brij−35:Sigma cat # B4184(30%w/v)
DMSO:Sigma cat # D8418
MgCl2 Sigma cat # M9272
反応バッファー:H2O/50mM Tris、pH7.4/10mM MgCl2/1mM EGTA/0.01%Brij35
100%DMSO中、試験化合物(10mM原液)を1:3.16(20μl+43.2μl)に段階希釈する。12pt曲線。反応バッファー中、各濃度1:33.3(3μl+97μl)に希釈する。5μlをアッセイプレートにスタンプする。最終トップ試験濃度100μM。
反応バッファー中、5μlのDMSO(3%)をトータル及びブランクウェルに加え、5μlのEu標識抗GST抗体(6nM)をブランクウェルに加えた。
5μlのLRRK2(30nM)/Eu標識抗GST抗体(6nM)混合物を化合物及びトータルウェルに加える。5μlのキナーゼトレーサー(25.5nM)を全てのウェルに加える。プレートを、プレートシェーカー上にて、室温で1時間インキュベートする(穏やかに振とうする)。Perkin Elmer EnVision読み取り機のHTRFプロトコルで読み取る。
比率:(665/620)*10000を計算する。全てのデータ点から平均バックグラウンド値を減算する。各試験値に対するコントロールの%を計算する。コントロールの%対化合物濃度をプロットする。Ki値を計算する(xlfit曲線フィッティング−Morrison式)。
式中、Et=4nM
kd(トレーサー)=8.5nM
トレーサー濃度(S)=8.5nM
パーキンソン病は、1−メチル−4−フェニルテトラヒドロピリジン(MPTP)(線条体ドーパミン(DA)神経末端マーカーの喪失をもたらす選択的な黒質線条体ドーパミン作動性神経毒)を投与することによって、マウス及び霊長類で再現することができる。本発明の化合物のパーキンソン病の処置における有効性を、MPTP誘導神経変性を使用し、Saporito et al., J. Pharmacology (1999) Vol. 288, pp. 421-427に記載されるプロトコルに一般的に従って評価することができる。
Claims (20)
- 式I:
[式中、
mは、0〜3であり;
Xは、−NRa−;−O−;又は−S(O)r−(ここで、rは、0〜2であり、そして、Raは、水素又はC1−6アルキルである)であり;
R1は、C1−6アルキルであり;
R2は、ハロ;C1−6アルコキシ;シアノ;C1−6アルキニル;C1−6アルケニル;ハロ−C1−6アルキル;ハロ−C1−6アルコキシ;C3−6シクロアルキル(ここで、C3−6シクロアルキル部分は、C1−6アルキルで場合により置換されている);C3−6シクロアルキル−C1−6アルキル(ここで、C3−6シクロアルキル部分は、C1−6アルキルで場合により置換されている);テトラヒドロフラニル;テトラヒドロフラニル−C1−6アルキル;アセチル;オキセタニル;又はオキセタン−C1−6アルキルであり;
R3及びR4は、各々独立して、ハロ;C1−6アルキル;C1−6アルコキシ;C3−6シクロアルキルオキシ;ハロ−C1−6アルキル;又はハロ−C1−6アルコキシであるか;
又はR3及びR4は、これらが連結している原子と一緒になって、各々O、N及びSから独立して選択される1又は2個のヘテロ原子を場合により含む5又は6員環を形成してよく、その環は、R6で1回以上場合により置換されており;
R5は、C1−6アルキル−スルホニル;又はシアノであり;そして
R6は、C1−6アルキル;ハロ;ハロ−C1−6アルキル;又はオキソである]
で表される化合物又はその薬学的に許容しうる塩。 - mが、0又は1である、請求項1に記載の化合物。
- Xが、−NH−又は−O−である、請求項1〜2のいずれか一項に記載の化合物。
- R1が、メチルである、請求項1〜3のいずれか一項に記載の化合物。
- R2が、ハロ;ハロ−C1−6アルキル;又はシアノである、請求項1〜4のいずれか一項に記載の化合物。
- R2が、クロロ又はトリフルオロメチルである、請求項1〜5のいずれか一項に記載の化合物。
- R3が、フルオロ、クロロ又はメトキシである、請求項1〜6のいずれか一項に記載の化合物。
- R3が、メトキシである、請求項1〜7のいずれか一項に記載の化合物。
- R4が、フルオロ、クロロ、メチル又はメトキシである、請求項1〜8のいずれか一項に記載の化合物。
- R5が、C1−6アルキル−スルホニルである、請求項1〜9のいずれか一項に記載の化合物。
- R5が、メタンスルホニル;又はシアノである、請求項1〜10のいずれか一項に記載の化合物。
- R5が、シアノである、請求項1〜9のいずれか一項に記載の化合物。
- R5が、メタンスルホニルである、請求項1〜11のいずれか一項に記載の化合物。
- 下記からなる群より選択される、請求項1〜13のいずれか一項に記載の化合物:
N2−(2−メトキシ−4−(メチルスルホニル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、5−クロロ−N2−(2−メトキシ−4−(メチルスルホニル)フェニル)−N4−メチルピリミジン−2,4−ジアミン、2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)ベンゾニトリル、3−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)ベンゾニトリル、4−(5−クロロ−4−(メチルアミノ)ピリミジン−2−イルアミノ)−3−メトキシベンゾニトリル、(2−クロロ−4−メタンスルホニル−フェニル)−(5−クロロ−4−メトキシ−ピリミジン−2−イル)−アミン、N2−(2−クロロ−4−メタンスルホニル−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、5−クロロ−N2−(2−クロロ−4−メタンスルホニル−フェニル)−N4−メチル−ピリミジン−2,4−ジアミン、N2−(2−メトキシ−4−モルホリン−4−イルメチル−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、5−クロロ−2−メチル−4−(4−メチルアミノ−5−トリフルオロメチル−ピリミジン−2−イルアミノ)−ベンゾニトリル、2−(5−フルオロ−2−メトキシ−4−モルホリン−4−イルメチル−フェニルアミノ)−4−メチルアミノ−ピリミジン−5−カルボニトリル、4−エチルアミノ−2−(5−フルオロ−2−メトキシ−4−モルホリン−4−イルメチル−フェニルアミノ)−ピリミジン−5−カルボニトリル、5−メトキシ−2−メチル−4−(4−メチルアミノ−5−トリフルオロメチル−ピリミジン−2−イルアミノ)−ベンゾニトリル、5−クロロ−N2−[2−(2−フルオロ−エトキシ)−4−モルホリン−4−イルメチル−フェニル]−N4−メチル−ピリミジン−2,4−ジアミン、N2−(5−フルオロ−4−メタンスルホニル−2−メトキシ−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N2−(2−イソプロポキシ−4−メタンスルホニル−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、5−クロロ−N2−[2−(2−フルオロ−エトキシ)−4−メタンスルホニル−フェニル]−N4−メチル−ピリミジン−2,4−ジアミン、(5−クロロ−4−メトキシ−ピリミジン−2−イル)−[2−(2−フルオロ−エトキシ)−4−メタンスルホニル−フェニル]−アミン、N2−[2−(2−フルオロ−エトキシ)−4−メタンスルホニル−フェニル]−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N2−(5−クロロ−4−メタンスルホニル−2−メトキシ−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N2−[5−フルオロ−2−(2−フルオロ−エトキシ)−4−モルホリン−4−イルメチル−フェニル]−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N4−エチル−N2−[5−フルオロ−2−(2−フルオロ−エトキシ)−4−モルホリン−4−イルメチル−フェニル]−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、N2−(4−メタンスルホニル−2−メトキシ−5−メチル−フェニル)−N4−メチル−5−トリフルオロメチル−ピリミジン−2,4−ジアミン、5−クロロ−N2−(2−メトキシ−4−モルホリノフェニル)−N4−メチルピリミジン−2,4−ジアミン、4−(5−クロロ−4−(メチルアミノ)ピリミジン−2−イルアミノ)−3−メトキシ安息香酸、N2−(2−メトキシ−4−(モルホリノスルホニル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N2−(2−メトキシ−4−(トリフルオロメチル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、5−クロロ−N2−(2−メトキシ−4−(トリフルオロメチル)フェニル)−N4−メチルピリミジン−2,4−ジアミン、2−クロロ−4−(5−クロロ−4−(メチルアミノ)ピリミジン−2−イルアミノ)−5−メトキシ安息香酸、1−(2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)フェニル)ピロリジン−2−オン、4−(2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)フェニル)モルホリン−3−オン、1−(2−フルオロ−5−メトキシ−4−(4−(メチルアミノ)−5−(トリフルオロメチル)ピリミジン−2−イルアミノ)フェニル)ピペリジン−2−オン、N2−(5−フルオロ−2−メトキシ−4−(オキセタン−3−イル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N4−エチル−N2−(2−メトキシ−5−メチル−4−(メチルスルホニル)フェニル)−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N2−(4−(エチルスルホニル)−2−メトキシ−5−メチルフェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N2−(2−メトキシ−5−メチル−4−(メチルスルホニル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン、N2−(5−フルオロ−2−メトキシ−4−(モルホリノメチル)フェニル)−N4−メチル−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン及びN4−エチル−N2−(8−(メチルスルホニル)−2,3−ジヒドロベンゾ[b][1,4]ジオキシン−5−イル)−5−(トリフルオロメチル)ピリミジン−2,4−ジアミン。 - (a)薬学的に許容しうる担体;及び
(b)請求項1〜14のいずれか一項に記載の化合物を含む、組成物。 - パーキンソン病を処置するための方法であって、それを必要とする被験体に、有効量の請求項1〜14のいずれか一項に記載の化合物を投与することを含む方法。
- パーキンソン病の予防又は治療において使用するための、請求項1〜14のいずれか一項に記載の式Iの化合物。
- パーキンソン病の予防又は治療に有用である、請求項15に記載の医薬組成物。
- パーキンソン病の予防又は治療のための医薬の調製のための、請求項1〜14のいずれか一項に記載の式Iの化合物の使用。
- 本明細書に記載される発明。
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