EP1685124A1 - Substituted nitrogen-containing six-membered amino-heterocycles as vanilloid-1 receptor antagonists for treating pain - Google Patents
Substituted nitrogen-containing six-membered amino-heterocycles as vanilloid-1 receptor antagonists for treating painInfo
- Publication number
- EP1685124A1 EP1685124A1 EP04798442A EP04798442A EP1685124A1 EP 1685124 A1 EP1685124 A1 EP 1685124A1 EP 04798442 A EP04798442 A EP 04798442A EP 04798442 A EP04798442 A EP 04798442A EP 1685124 A1 EP1685124 A1 EP 1685124A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amine
- pyrimidin
- trifluoromethylphenyl
- quinohn
- methyl
- 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.)
- Withdrawn
Links
- 208000002193 Pain Diseases 0.000 title claims abstract description 26
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 title claims description 4
- 108010025083 TRPV1 receptor Proteins 0.000 title description 2
- 229940044551 receptor antagonist Drugs 0.000 title description 2
- 239000002464 receptor antagonist Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 174
- 238000000034 method Methods 0.000 claims abstract description 125
- -1 haloC1-4alkyl Chemical group 0.000 claims abstract description 108
- 125000001424 substituent group Chemical group 0.000 claims abstract description 46
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 42
- 150000002367 halogens Chemical class 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 20
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 20
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 18
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000005557 antagonist Substances 0.000 claims abstract description 11
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 11
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical group C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims abstract description 9
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical group C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 6
- 229910052727 yttrium Inorganic materials 0.000 claims abstract description 6
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 206010011224 Cough Diseases 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 238000002560 therapeutic procedure Methods 0.000 claims abstract 2
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 134
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 111
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 105
- 238000011282 treatment Methods 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- WSBKQOFMPKHHDB-UHFFFAOYSA-N 2-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine Chemical compound NC1=CC=NC(C=2C=CC(=CC=2)C(F)(F)F)=N1 WSBKQOFMPKHHDB-UHFFFAOYSA-N 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- PPAULTVPKLVLII-UHFFFAOYSA-N 4,5-diaminopyrimidine Chemical compound NC1=CN=CN=C1N PPAULTVPKLVLII-UHFFFAOYSA-N 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- SZAQKMSBGFBBAA-UHFFFAOYSA-N nitroazaniumylidynemethane Chemical compound [O-][N+](=O)[N+]#[C-] SZAQKMSBGFBBAA-UHFFFAOYSA-N 0.000 claims description 4
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 claims description 4
- CTYDIMDTCLBVKV-UHFFFAOYSA-N 2-[5-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-amine Chemical compound NC1=CC=NC(C=2N=CC(=CC=2)C(F)(F)F)=N1 CTYDIMDTCLBVKV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- DMEUDSHBHKHLPD-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=C=C[N]1 DMEUDSHBHKHLPD-UHFFFAOYSA-N 0.000 claims description 3
- LXQBAENJKIOUFC-UHFFFAOYSA-N 5-fluoro-6-(8-methylquinolin-7-yl)-n-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine Chemical compound C1=CC2=CC=CN=C2C(C)=C1C(C=1F)=NC=NC=1NC1=CC=C(C(F)(F)F)C=C1 LXQBAENJKIOUFC-UHFFFAOYSA-N 0.000 claims description 2
- CXHCGWTVIFBZLM-UHFFFAOYSA-N 5-methyl-6-(1,5-naphthyridin-3-yl)-n-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine Chemical compound N1=CN=C(C=2C=C3N=CC=CC3=NC=2)C(C)=C1NC1=CC=C(C(F)(F)F)C=C1 CXHCGWTVIFBZLM-UHFFFAOYSA-N 0.000 claims description 2
- WPOPDTIVIZYYLO-UHFFFAOYSA-N 6-quinolin-7-yl-2-(2h-tetrazol-5-yl)-n-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1=CC(C(F)(F)F)=CC=C1NC1=CC(C=2C=C3N=CC=CC3=CC=2)=NC(C=2NN=NN=2)=N1 WPOPDTIVIZYYLO-UHFFFAOYSA-N 0.000 claims description 2
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical group CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- NHFDIUPJVYYTLG-UHFFFAOYSA-N carbononitridic isocyanide Chemical compound [C-]#[N+]C#N NHFDIUPJVYYTLG-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002527 isonitriles Chemical class 0.000 claims description 2
- LUCGBEPEAUHERV-UHFFFAOYSA-N pyridazin-4-amine Chemical compound NC1=CC=NN=C1 LUCGBEPEAUHERV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 238000003419 tautomerization reaction Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 1
- VQZGPLJDWPPNTG-UHFFFAOYSA-N 2-[4-(trifluoromethyl)phenyl]-6-[4-(trifluoromethyl)quinolin-7-yl]pyrimidin-4-amine Chemical compound FC(C1=CC=C(C=C1)C1=NC(=CC(=N1)N)C1=CC=C2C(=CC=NC2=C1)C(F)(F)F)(F)F VQZGPLJDWPPNTG-UHFFFAOYSA-N 0.000 claims 1
- KUACTMLHWVRWPI-UHFFFAOYSA-N 6-quinolin-5-yl-n-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine Chemical compound C1=CC(C(F)(F)F)=CC=C1NC1=CC(C=2C3=CC=CN=C3C=CC=2)=NC=N1 KUACTMLHWVRWPI-UHFFFAOYSA-N 0.000 claims 1
- NVHXMNNCHAFIHX-UHFFFAOYSA-N pyridazin-3-amine Chemical compound NC1=CC=C=N[N]1 NVHXMNNCHAFIHX-UHFFFAOYSA-N 0.000 claims 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 abstract description 25
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 15
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Chemical group C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 abstract description 13
- 201000010099 disease Diseases 0.000 abstract description 5
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 abstract description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 6
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 3
- 229910052739 hydrogen Inorganic materials 0.000 description 1412
- 238000005481 NMR spectroscopy Methods 0.000 description 245
- 239000007787 solid Substances 0.000 description 194
- 239000000203 mixture Substances 0.000 description 178
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 177
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 49
- 239000000243 solution Substances 0.000 description 49
- 235000019439 ethyl acetate Nutrition 0.000 description 46
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 44
- 229910052938 sodium sulfate Inorganic materials 0.000 description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 238000010992 reflux Methods 0.000 description 39
- XLQSXGGDTHANLN-UHFFFAOYSA-N 1-bromo-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(Br)C=C1 XLQSXGGDTHANLN-UHFFFAOYSA-N 0.000 description 37
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 36
- 239000002904 solvent Substances 0.000 description 33
- 239000007832 Na2SO4 Substances 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 31
- 235000011152 sodium sulphate Nutrition 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 239000000377 silicon dioxide Substances 0.000 description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 15
- GSKMWMFOQQBVMI-UHFFFAOYSA-N 2-bromo-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Br)N=C1 GSKMWMFOQQBVMI-UHFFFAOYSA-N 0.000 description 14
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 14
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 13
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- 239000012267 brine Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
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- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
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- 239000002244 precipitate Substances 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 9
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- 230000002265 prevention Effects 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
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- 239000000284 extract Substances 0.000 description 6
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
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- REGWSZXRRKGUAL-UHFFFAOYSA-N n-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-5-methyl-6-quinolin-7-ylpyrimidin-4-amine Chemical compound N1=CN=C(C=2C=C3N=CC=CC3=CC=2)C(C)=C1NC1=NC=C(C(F)(F)F)C=C1F REGWSZXRRKGUAL-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- VWINWYXSNLFXIG-UHFFFAOYSA-N n-[4-(trifluoromethyl)phenyl]-6-[4-(trifluoromethyl)quinolin-7-yl]pyrimidin-4-amine Chemical compound C1=CC(C(F)(F)F)=CC=C1NC1=CC(C=2C=C3N=CC=C(C3=CC=2)C(F)(F)F)=NC=N1 VWINWYXSNLFXIG-UHFFFAOYSA-N 0.000 description 1
- JLJWOORHVDXAHK-UHFFFAOYSA-N n-[4-(trifluoromethyl)phenyl]-6-[6-(trifluoromethyl)quinolin-7-yl]pyrimidin-4-amine Chemical compound C1=CC(C(F)(F)F)=CC=C1NC1=CC(C=2C(=CC3=CC=CN=C3C=2)C(F)(F)F)=NC=N1 JLJWOORHVDXAHK-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 1
- 229960000805 nalbuphine Drugs 0.000 description 1
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- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- AMKVXSZCKVJAGH-UHFFFAOYSA-N naratriptan Chemical compound C12=CC(CCS(=O)(=O)NC)=CC=C2NC=C1C1CCN(C)CC1 AMKVXSZCKVJAGH-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
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- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
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- 239000004031 partial agonist Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- DAFIBNSJXIGBQB-UHFFFAOYSA-N perfluoroisobutene Chemical compound FC(F)=C(C(F)(F)F)C(F)(F)F DAFIBNSJXIGBQB-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
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- 239000002831 pharmacologic agent Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
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- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
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- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
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- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical class N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- NWIJBOCPTGHGIK-UHFFFAOYSA-N quinolin-5-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=N1 NWIJBOCPTGHGIK-UHFFFAOYSA-N 0.000 description 1
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 description 1
- JLOLSBLXNMVKGY-UHFFFAOYSA-N quinolin-6-ylboronic acid Chemical compound N1=CC=CC2=CC(B(O)O)=CC=C21 JLOLSBLXNMVKGY-UHFFFAOYSA-N 0.000 description 1
- XCRPPAPDRUBKRJ-UHFFFAOYSA-N quinolin-7-ol Chemical compound C1=CC=NC2=CC(O)=CC=C21 XCRPPAPDRUBKRJ-UHFFFAOYSA-N 0.000 description 1
- FPSAXXSFDJDIRR-UHFFFAOYSA-N quinolin-7-yl trifluoromethanesulfonate Chemical compound C1=CC=NC2=CC(OS(=O)(=O)C(F)(F)F)=CC=C21 FPSAXXSFDJDIRR-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- DSDNAKHZNJAGHN-UHFFFAOYSA-N resinferatoxin Natural products C1=C(O)C(OC)=CC(CC(=O)OCC=2CC3(O)C(=O)C(C)=CC3C34C(C)CC5(OC(O4)(CC=4C=CC=CC=4)OC5C3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-UHFFFAOYSA-N 0.000 description 1
- DSDNAKHZNJAGHN-MXTYGGKSSA-N resiniferatoxin Chemical compound C1=C(O)C(OC)=CC(CC(=O)OCC=2C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]34[C@H](C)C[C@@]5(O[C@@](O4)(CC=4C=CC=CC=4)O[C@@H]5[C@@H]3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-MXTYGGKSSA-N 0.000 description 1
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- 230000004044 response Effects 0.000 description 1
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- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 description 1
- 229960000425 rizatriptan Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- ZSIBHYXMYKAYIR-UHFFFAOYSA-N sodium;6-chloro-2-methoxypyrimidin-4-amine;methanolate Chemical compound [Na+].[O-]C.COC1=NC(N)=CC(Cl)=N1 ZSIBHYXMYKAYIR-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical group [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003890 substance P antagonist Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical group C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 150000003527 tetrahydropyrans Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical class C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention is concerned with substituted nitrogen-containing six-membered amino-heterocycles and analogues and derivatives thereof as well as pharmaceutically acceptable salts thereof, which are useful as therapeutic compounds, particularly in the treatment of pain and other conditions ameliorated by the modulation of the function of the vanilloid-1 receptor (VRl).
- the pharmacologically active ingredient of chilli peppers has been recognised for some time to be the phenolic amide capsaicin.
- capsaicin The receptor for capsaicin, termed the vanilloid VRl receptor, was cloned by Caterina and colleagues at UCSF in 1997 (Nature, 398:816, 1997).
- VRl receptors are cation channels that are found on sensory nerves that innervate the skin, viscera, peripheral tissues and spinal cord. Activation of VRl elicits action potentials in sensory fibres that ultimately generate the sensation of pain.
- the VRl receptor is activated not only by capsaicin but also.by acidic pH and by noxious heat stimuli. It is also sensitized by a number of- . inflammatory mediators and thus appears to be a polym dal integrator of painful stimuli.
- the prototypical VRl antagonist is capsazepine (Walpole et al, J. Med. Chem., 37:1942, 1994) - VRl ICso of 420nM.
- a novel series of sub- micro molar antagonists has also been reported recently (Lee etal, Bio ⁇ rg. Med. Chem., 9:1713, 2001), but these reports provide no evidence for in vivo efficacy.
- VRl antagonists comprise predominantly VRl antagonists but encompass VRl partial antagonists and VRl partial agonists.
- Such compounds have been shown to be efficacious in animal models of pain.
- Related compounds are disclosed in WO-A-03099284 (Amgen Inc.). There is no disclosure of compounds in which Y is quinoline or isoquinoline. Preferred compounds of the present invention have improved pharmacokinetics with lower clearance and thus improved half-life.
- the present invention provides compounds of formula I: Y-J-L-Z (I) wherein: L is NR 1 , O, S or CH 2 ; J is a six-membered heterocycle containing one, two or three nitrogen atoms which is unsubstituted or substituted with up to three substituents, depending on the number of nitrogen atoms present, chosen independently from: halogen! hydroxy! nitro; cyano! isonitrile; C3- ⁇ cycloalkyl; Ci- ⁇ alkyl; C 2 -6alkenyl; C 2 -6alkynyl; Ci- ⁇ alkoxy!
- Q is phenyl, a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, or a six-membered heterocyclic ring containing one, two or three nitrogen atoms, optionally substituted by halogen, C ⁇ -4alkyl or wherein J is substituted at positions meta to each other by L and Y!
- Y is naphthalene or a fused 9- or 10-membered heteroaromatic system containing a six-membered heterocyclic ring, as defined above, or a phenyl ring, or a six-membered nitrogen-containing partially saturated ring, fused either to a six-membered heterocyclic ring as defined above or to a five-membered heterocyclic ring as defined above, Y being unsubstituted or substituted with one, two or three groups independently chosen from halogen, hydroxy, cyano, nitro, isonitrile, Ci- ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, haloCi- ⁇ alkyl, hydroxyCi- ⁇ alkyl, amino Ci- ⁇ alkyl, Ci- ⁇ alkoxy, Ci- ⁇ alkylthio, haloCi-ealkoxy,
- Z is phenyl, naphthyl, a six-membered heterocyclic ring containing one, two, or three nitrogen atoms or a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, Z being unsubstituted or substituted with one, two or three substituents independently chosen from halogen, hydroxy, cyano, nitro, isonitrile, Ci- ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, haloCi-ealkyl, hydroxyCi- ⁇ alkyl, aminoCi- ⁇ alkyl, Ci-ealkoxy, Ci-ealkylthio, haloCi-ealkoxy, -NR 2 R 3 , -CONR 2 R 3 , -S(O) n NR 2 R 3 , ' • • -NHCOR 1 , -NHS OnR 1
- each R 1 is H or Ci- ⁇ alkyl! ' . . " ⁇ ' ; each R 2 and R 3 is chosen from H and Ci- ⁇ alkyl, or R 2 and R 3 , together with' the nitrogen atom to which they are attached, may form a 4-6 membered ring 1 optionally containing an oxygen atom or a further nitrogen atom,, which ring is.. . . optionally substituted by Ci- ⁇ alkyl or Q! .
- each n is 0, 1 or 2!
- each p is 1, 2, 3 or 4! q is 2, 3 or 4! or a pharmaceutically acceptable salt thereof.
- L is preferably NR 1 , particularly NH.
- J is preferably unsubstituted or substituted by one or two substituents. Most preferably J is unsubstituted or monosubstituted. J may be disubstituted. J is thus preferably an unsubstituted or substituted pyrimidine, pyrazine, pyridazine or triazine. Pyrimidine is particularly favoured. J may be pyridine, which is unsubstituted or substituted, such as unsubstituted pyridine.
- Substituents on J are preferably chosen independently from halogen, hydroxy, nitro, cyano, Cwalkyl, C2-4alkenyl, C 2 -4alkynyl, C alkoxy, C ⁇ -4cycloalkoxy, hydroxyC ⁇ -4alkyl, aminoC ⁇ -4alkyl, haloC ⁇ -4alkyl, haloC ⁇ -4alkoxy, C ⁇ - 4 alkoxycarbonyl, -NR 2 R 3 , C ⁇ -4alkylthio, Q, CH 2 Q, OCH 2 Q, -(CH 2 ) P NR 2 R 3 , -CONR R 3 and -CO2H.
- Substituents on J may be chosen independently from halogen, hydroxy, nitro, cyano, C ⁇ -4alkyl, C 2 -4alkenyl, C2-4alkynyl, C ⁇ -4alkoxy, hydroxyC ⁇ -4alkyl, aminoC ⁇ -4alkyl, haloC ⁇ -4alkyl, haloC ⁇ -4alkoxy, C ⁇ - 4 alkoxycarbonyl, -NR 2 R 3 , -(CH 2 ) P NR 2 R 3 , -CONR 2 R 3 and -CO2H.
- substituents are independently chosen from halogen, hydroxy, nitro, amino, C ⁇ -4alkyl, haloC ⁇ -4alkyl, C3-5cycloalkyl and C ⁇ -4alkoxy.
- substituents can be chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro, amino, tertiarybutyl, hydroxymethyl, 2,6-dimethylmorpholino, bromo, methylthio, cyano, 2-methylpyrrolidino, morpholino, trifluoromethoxy, hydroxy, N-phenylpiperazinyl, 2,2,2-trifluoroethyl, morpholinomethyl, imidazomethyl, cyclopropylmethoxy, pyridomethoxy, morpholinoethoxy and tetrazolyl.
- any substituents are chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro and amino. More preferably any substituents are independently chosen from halogen, hydroxy,- nitro, amino, C ⁇ -4alkyl and C ⁇ -4alkoxy. Most preferably the substituent is fluoro, methyl, methoxy, nitro or amino. ⁇ ⁇ ;-, i- ' , Particular embodiments of J are pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-:.
- yl pyrimidin-4-yl, pyridazin-4-yl, l,3,5-triazin-2-yl, 5-methoxypyrimidin-4-yl, 5 methylpyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 2-methoxypyrimidin-4-yl, 2- methylpyrimidin-4-yl, 5-nitropyrimidin-4-yl and 5-aminopyrimidin-4-yl.
- J are 5-tertiarybutylpyrimidin-4-yl, 2r trifluoromethylpyrimidin-4-yl, 2-hydroxymethylpyrimidin-4-yl, (cis-2,6- dimethylmorphoHn-4-yUmethylpyrimidin-4-yl, 5-bromopyrimidin-4-yl, 2- methylthio-5-methylpyrimidin-4-yl, 2-cyano-5-methylpyrimidin-4-yl, 2-(2- methylpyrrolidin-l-yl)-5-methylpyrimidin-4-yl, 2-(morpholin-4-yl)-5- methylpyrimidin-4-yl, 2-(2,2,2-trifluoroethoxy)-5-methylpyrimidin-4-yl, 2-rnethyl- 5-aminopyrimidin-4-yl, 2"hydroxypyrimidin-4-yl, 2-cyanopyrimidin-4-yl, 2- (morpholin-4-yl)pyrimidin-4-yl,
- J may also be 2-chloropyrimidin-4-yl, 5-trifluoromethylpyridin-4-yl, 5" ethylpyrimidin-4-yl, 2-cyclopropyl-5-methylpyrimidin-4-yl, 5-isopropylpyrimidin- 4-yl or pyridin-4-yl.
- p can be one or two.
- Q can be pyridyl or phenyl. Q can be unsubstituted.
- Y is thus preferably an unsubstituted or substituted quinoline, quinazoline, quinoxaline, phthalazine, isoquinoline, cinnoline, naphthyridine, indole, indazole, benzimidazole, benzothiazole, benzoxazole, imidazopyridine, imidazopyridazine, imidazopyrimidine, pyrazolopyridine, pyrazolopyridazine, pyrazolopyrimidine or triazolopyridine.
- Y may be substituted benzimidazole attached to J via the benzene portion.
- Y may be quinoxaline attached to L via the benzene portion.
- Y may be naphthyridine such as l. ⁇ -naphthyridine.or 1,5-. . . i VJ ⁇ - . naphthyridine.
- Y is most preferably an unsubstituted or substituted quinoline, or; isoquinoline, particularly a quinoline. ;_ ⁇ ,. . . , . :, : :.
- Substituents on Y are preferably independently chosen from halogen, _ ⁇ ' ⁇ hydroxy, cyano, nitro, amino, C ⁇ -4alkyl, C2- 4 alkenyl, C2-4alkynyl, haloC ⁇ -4alkyl, . . .
- hydroxyC ⁇ -4alkyl, aminoC ⁇ -4alkyl, C ⁇ -4alkoxy and haloC ⁇ -4alkoxy Particular substituents are hydroxy, halogen, C ⁇ -4alkyl and haloC ⁇ -4alkyl such as hydroxy, fluorine, methyl, ethyl and trifluoromethyl.
- the substituents can be halogen, C ⁇ -4alkyl and haloC ⁇ -4alkyl such as fluorine, methyl and trifluoromethyl.
- Y is preferably unsubstituted or substituted with one or two substituents. More preferably Y is unsubstituted or monosubstituted.
- Y may be naphthalene or a fused 10-membered heteroaromatic ring.
- Y is generally a fused 10- membered heteroaromatic system.
- Particular values of Y include quinolin-8-yl, quinoline-7-yl, 3- methylquinolin-7-yl, quinolin-5-yl, quinolin-6-yl, 6-fluoroquinolin-7-yl, 8- fluoroquinolin-7-yl, 6-trifluoromethylquinolin-7-yl, 8-fluoroquinolin-7-yl and isoquinolin-7-yl.
- Y include 8-ethylquinolin-7-yl, 1,8- naphthyridin-7-yl, 4-trifluoromethylquinolin-7-yl, 5-fluoroquinolin-7-yl, 1,5- naphthyridin-7-yl, l-methyl-lH-benzimidazol-5-yl, lH-benzimidazol-6-yl, 3- fluoroquinolin-7-yl, 4-hydroxyquinolin-7-yl and quinoxalin-6-yl.
- Z is preferably a si ⁇ -membered ring such as pyridazinyl, phenyl or pyridyl, preferably phenyl or pyridyl.
- Z is preferably monosubstituted, particular para to the attachment to L.
- Particular embodiments of Z include 4- trifluoromethylphenyl, 3-trifluoromethylpyrid-6-yl and 2-trifluoromethylpyrid-5- yl.
- Further embodiments include 4-trifluoromethoxyphenyl and 2-fluoro-4- trifluoromethylphenyl.
- Yet further embodiments include 3- trifluoromethylpyridazin-6-yl and 3-fluoro-5-trifluoromethylpyridin-2-yl.
- Substituents on Z are preferably independently chosen from halogen, amino, C ⁇ -4alkyl, haloC ⁇ -4alkyl, hydroxyC ⁇ -4alkyl, aminoC ⁇ -4alkyl, C ⁇ -4alkoxy and haloC ⁇ -4alkoxy. Particular substituents are haloC ⁇ -4alkyl such as trifluoromethyl. Z may be substituted by halogen, haloC ⁇ -4alkyl or haloC ⁇ -4alkoxy. Thus Z may be substituted by trifluoromethyl, trifluoromethoxy or fluorine. Each R 1 is preferably hydrogen or C ⁇ -4alkyl such as methyl. R 1 is particularly hydrogen. ,,.. J ltl l . . . .
- Each R 2 and R 3 is preferably independently hydrogen or C ⁇ -4alkyl such as methyl.
- R 2 and R 3 are preferably hydrogen.
- R 2 and R 3 may form?a piperidine, . . .. ; piperazine or morpholine ring, R 2 and R 3 may then be substituted by C ⁇ -4alkyl,->- -• • phenyl or pyridyl, particularly when they form a piperazine ring. .. ' : ..
- a particularly preferred subclass of compounds is of formula la: , . Y-J-NH-Z .
- Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from hydroxy, halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, C ⁇ -4alkoxy, haloC ⁇ -4alkoxy, nitro and amino!
- J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from hydroxy, halogen, haloC alkyl, C alkyl, C3-5cycloalkyl, C ⁇ -4alkoxy, hydroxyC ⁇ -4alkyl, cyano, hydroxy, C ⁇ -4cycloalkoxy, C ⁇ -4alkylthio, haloC ⁇ -4alkoxy, nitro, Q, (CH2) Q, -NR 2 R 3 , -(CH 2 ) P NR 2 R 3 and -O(CH 2 ) P NR 2 R 3 ! wherein J is substituted at positions meta to each other by NH and Y!
- Z is phenyl or pyridyl optionally substituted with one or two substituents independently selected from halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, C ⁇ -4alkoxy, haloC ⁇ -4alkoxy, nitro and amino!
- Q is phenyl, a five-membered heterocyclic ring containing one, two, three or four heteroatoms chosen from O, N and S, at most one heteroatom being O or S, or a six-membered heterocyclic ring containing one, two or three nitrogen atoms, optionally substituted by C ⁇ -4alkyl!
- each R 2 and R 3 is chosen from H and C ⁇ -4alkyl, or R 2 and R 3 , together with the nitrogen atom to which they are attached, may form a six-membered ring optionally containing an oxygen atom or a further nitrogen atom, which ring is optionally substituted by C ⁇ -4alkyl or Q! p is 1, 2 or 3! or a pharmaceutically acceptable salt thereof.
- Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, ,
- J is pyridine, pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, C3-5cycloalkyl, C ⁇ -4alkoxy, haloC ⁇ -4alkoxy, nitro ⁇ and amino! wherein J is substituted at positions meta to each other by NH and Y!
- Z is phenyl or pyridyl optionally substituted with one or two substituents independently selected from halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, C ⁇ -4alkoxy, haloC ⁇ -4alkoxy, nitro and amino! or a pharmaceutically acceptable salt thereof.
- Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, C ⁇ -4alkoxy, haloCnalkoxy, nitro and amino!
- J is pyridazine, pyrazine, pyrimidine or triazine optionally substituted with one or two substituents independently chosen from halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, C ⁇ -4alkoxy, haloC ⁇ -4alkoxy, nitro and amino! wherein J is substituted at positions meta to each other by NH and Y! Z is phenyl or pyridyl optionally substituted with one or two substituents independently selected from halogen, haloC ⁇ -4alkyl, C alkyl, Cwalkoxy, haloC ⁇ -4alkoxy, nitro and amino! or a pharmaceutically acceptable salt thereof.
- Y is particularly quinoline or isoquinoline and is unsubstituted or monosubstituted.
- Preferred substituents include hydroxy, trifluoromethyl, fluorine, methyl and ethyl such as fluoro and methyl.
- Y may be quinoline.
- J can be unsubstituted, monosubstituted or disubstituted with substituents preferably chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro, amino, tertiarybutyl, hydroxymethyl, 2,6-dimethylmorpholino, bromo, methylthio, cyano, 2- methylpyrrolidino, morpholino, trifluoromethoxy, hydroxy, N-phenylpiperazinyl, 2,2,2-trifluoroethyl, morpholinomethyl, imidazomethyl, cyclopropylmethoxy, pyridomethoxy, morpholinoethoxy and tetrazolyl.
- substituents preferably chosen from chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, methoxy, nitro,
- the substituents are preferably chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl,. ,_ . methoxy, nitro and amino. ;: .: . . : J is preferably unsubstituted or monosubstituted with fluorine, methoxy,. methyl, amino or nitro. J is preferably pyrimidine. J may be pyridine; J iriay be triazine. :_ ;. ... ' Z is preferably monosubstituted at a position para to the point of " : - , attachment to NH. Z may be. substituted by F, CF3 or OCF3.
- the substituent is preferably CF3.
- Particularly preferred are compounds of formula la in which: Y is a quinoline or isoquinoline optionally substituted with one or two substituents independently chosen from halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, C ⁇ -4alkoxy, haloC ⁇ -4alkoxy, nitro and amino! J is pyrimidine optionally substituted with one or two substituents independently chosen from halogen, haloC ⁇ -4alkyl, C ⁇ -4alkyl, C3-scyclo alkyl,
- Preferred pharmaceutically acceptable salts are the besylate salts. Further particular embodiments include:
- alkyl or "alkoxy” as a group or part of a group means that the group is straight or branched.
- suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl.
- suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
- Alkylthio shall be construed in an analogous manner.
- Examples of “C3-7cycloalky ⁇ ” groups are cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl and methylcyclopropyl groups.
- hydroxyCi-ealkyl means a Ci-ealkyl group in which one or more (in particular 1 to 3, and especially l) hydrogen atoms have been replaced by hydroxy groups.
- Particularly preferred are hydroxyC ⁇ -3alkyl groups, for example, CH2OH, CH2CH2OH, CH(CH 3 )OH or C(CH 3 ) 2 OH, and most especially CH2OH.
- fluoroCi- ⁇ alkyl and fluoroCi- ⁇ alkoxy groups are fluoroC ⁇ -3alkyl and fluoroC ⁇ -3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3 and OCF3.
- alkenyl and alkynyl as a group or part of a group means that the group is straight or branched.
- suitable alkenyl groups include vinyl and allyl.
- a suitable alkynyl group is acetylene or propargyl.
- halogen means fluorine, chlorine, bromine and iodine. The most preferred halogens are fluorine -and chlorine, especially fluorine.
- 6-membered heterocycles are pyridine, pyrimidine, " pyrazine, pyridazine and triazine.
- 5-membered heterocycles are thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4- triazole, oxadiazole, thiadiazole and tetrazole.
- “Heterocyclic” in the above is interchangeable with “heteroaromatic”.
- the compounds of formula I may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
- the salts of the compounds of formula I will be non-toxic pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
- a further salt is the acid addition salt with benzenesulfonic acid.
- Preferred pharmaceutically acceptable salts of the compounds of the present invention are the besylate salts.
- the hydrochloride salt can also be used.
- Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
- suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts! and alkaline earth metal salts, e.g. calcium or magnesium salts.
- the salts may be formed by conventional means, such as by reacting the free base form of the compound of formula I with one or more equivalents of the.. appropriate acid in a solvent or medium in which the salt is insoluble; or in a -:, ⁇ -. solvent such as water which is removed in vacuo or by freeze drying or.by ' ; ... exchanging the anions of an existing salt for another anion on a suitable ion- - •• ⁇ ' '• exchange resin. ' .. . . . .
- the present invention also includes within its scope N-oxides of the ⁇ ] .. , i ; : compounds of formula I above. In general, such N-oxides may be formed on any available nitrogen atom.
- the N-oxides may be formed by conventional means, such as reacting the compound of formula I with oxone in the presence of wet alumina.
- the present invention includes within its scope prodrugs of the compounds of formula I above.
- prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
- a prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug” or “parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule.
- the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
- the present invention includes within its scope solvates of the compounds of formula I and salts thereof, for example, hydrates.
- the compounds according to the invention may have one or more asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers.
- compositions comprising one or more compounds of formula I in association with a pharmaceutically acceptable carrier or excipient.
- compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays-, 'drops, ampoules, auto- injector devices, suppositories, creams or gels!
- compositions for oral, parenteral, intrathecal, intranasal, sublingual, rectal or topical administration, or for administration by inhalation or insufflation.
- Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
- a pharmaceutical carrier e.g. conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- Favoured unit dosage forms contain from 1 to 500 mg, for example 1, 5, 10, 25, 50, 100, 300 or 500 mg, of the active ingredient.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or- peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable dispersing or. suspending agents for aqueous suspensions include synthetic and natural, gums- ; such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, . -__• • methylcellulose, polyvinyl-pyrrolidone or gelatin. ⁇ • •• '.
- a : ' . suitable dosage level is about 1.0 mg to 15 g per day, preferably about 5.0 mg to . 1 g per day, more preferably about 5 mg to 500 mg per day, especially 10 mg to 100 mg per day.
- the compounds may be administered on a regimen of 1 to 4 times per day. It will be appreciated that the amount of a compound of formula I required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
- the invention further provides a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, for use in treatment of the human or animal body.
- said treatment is for a condition which is susceptible to treatment by modulation (preferably antagonism) of VRl receptors.
- the compounds of the present invention will be of use in the prevention or treatment of diseases and conditions in which pain and/or inflammation predominates, including chronic and acute pain conditions. Such conditions include rheumatoid arthritis! osteoarthritis! post-surgical pain! musculo-skeletal pain, particularly after trauma! spinal pain!
- myofascial pain syndromes including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; episiotomy pain; burns, and especially primary hyperalgesia associated therewith; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, pain associated with cystitis and labour pain, chronic pelvic pain, chronic prostatitis and endometriosis!
- headache including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain
- ear pain episiotomy pain
- deep and visceral pain such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaec
- pain associated with nerve and root damage such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; itching conditions including pruritis, itch due to hemodialysis, and contact dermatitis; pain (as well as broncho-constriction and inflammation) due to exposure (e.g. via ingestion, inhalation, or eye contact) of mucous membranes to capsaicin and related irritants such as tear " gas,- hot peppers or ⁇ pepper spray!
- peripheral nerve disorders for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis
- itching conditions including pruritis, itch due to hemodialysis, and contact dermatitis
- neuropathic pain conditions such as diabetic neuropathy ⁇ chemotherapy-induced neuropathy and post-herpetic neuralgia! "non-painful" neuropathies; complex regional pain syndromes; pain associated with carcinoma, often referred to as cancer pain! central nervous system pain, such as pain due to spinal cord or brain stem damage, low back pain, sciatica and ankylosing spondylitis! gout! scar pain! irritable bowel syndrome! inflammatory bowel disease! urinary incontinence including bladder detrusor hyper-reflexia and bladder hypersensitivity!
- respiratory diseases including chronic obstructive pulmonary disease (COPD), chronic bronchitis, cystic fibrosis, asthma and rhinitis, including allergic rhinitis such as seasonal and perennial rhinitis, and non-allergic rhinitis! autoimmune diseases! and immunodeficiency disorders.
- COPD chronic obstructive pulmonary disease
- cystic fibrosis cystic fibrosis
- asthma chronic obstructive pulmonary disease
- rhinitis including allergic rhinitis such as seasonal and perennial rhinitis, non- allergic rhinitis and cough.
- the compounds of the present invention may also be useful in the treatment of depression.
- the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of physiological disorders that may be ameliorated by modulating VRl activity.
- the present invention also provides a method for the treatment or prevention of physiological disorders that may be ameliorated by modulating VRl activity, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
- the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of a disease or condition in which pain and/or inflammation predominates.
- the present invention provides a compound of formula I for use in the manufacture of a medicament for the treatment or prevention of respiratory diseases such as cough. ;
- the present invention also provides a method for the treatment or prevention of a disease or condition in which pain and/or inflammation __ ' predominates, which method comprises administration to a patient in need ' thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
- the present invention also provides a method for the treatment or prevention of respiratory diseases, such as cough, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
- a method for the treatment or prevention of respiratory diseases such as cough
- the compound of formula I and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or in combination.
- a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, as well as opioid analgesics, especially morphine, NR2B antagonists, bradykinin antagonists, anti-migraine agents, anticonvulsants such as oxcarbazepine and carbamazepine, antidepressants (such as TCAs, SSRIs, SNRIs, substance P antagonists, etc.), spinal blocks, gabapentin, pregabalin and asthma treatments (such as ⁇ 2 _ adrenergic receptor agonists or leukotriene U4antagonists (e.g.
- Specific anti-inflammatory agents include diclofenac, ibuprofen, indomethacin, nabumetone, ketoprofen, naproxen, piroxicam and sulindac, etodolac, meloxicam, rofecoxib, celecoxib, etoricoxib, parecoxib, valdecoxib and tilicoxib.
- Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine, propoxyphene and pentazocine! or a pharmaceutically acceptable salt thereof.
- Suitable anti-migraine agents of use in conjunction with a compound of the present invention include CGRP-antagonists, ergotamines or 5-HT ⁇ agonists, v.
- a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or 'excipient.
- a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a disease or condition in which pain and/or inflammation predominates.
- the compounds of formula I can be made by reacting a compound of formula II with a compound of formula III :
- reaction can be carried out in the presence of a base such as sodium tertiarybutoxide or sodium hydrogencarbonate and a coupling agent such as 2'-(dimethylamino)-2-biphenylyl palladium (II) chloride dinorbornylphosphine complex generally in a solvent such as toluene or tetrahydrofuran with heating to reflux for several hours to several days.
- a base such as sodium tertiarybutoxide or sodium hydrogencarbonate
- a coupling agent such as 2'-(dimethylamino)-2-biphenylyl palladium (II) chloride dinorbornylphosphine complex generally in a solvent such as toluene or tetrahydrofuran with heating to reflux for several hours to several days.
- reaction can be carried out in the presence of cesium carbonate, a coupling agent such as 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene and a catalyst such as Pd2(dba)3, generally in a solvent such as anhydrous dioxane at reflux for several hours.
- a coupling agent such as 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene and a catalyst such as Pd2(dba)3, generally in a solvent such as anhydrous dioxane at reflux for several hours.
- the reaction can also be carried out in the presence of a base such as diisopropylethylamine in a solvent such as an anhydrous dimethylformamide between 0°C and room temperature for about 2 hours.
- a compound of formula I can be made by reacting a compound of formula IV with a compound of formula V:
- reaction can be carried outj, under conditions suitable for a Suzuki Coupling Reaction (for review, see for instance A. Suzuki, Pure Appl. Chem., 1991, 63, 419-422), for example, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium( ⁇ ), tris(dibenzyhdeneacetone)dipalladium( ⁇ ),
- a palladium catalyst such as tetrakis(triphenylphosphine)palladium( ⁇ ), tris(dibenzyhdeneacetone)dipalladium( ⁇ )
- This group can be introduced by converting a methoxy group to a hydroxy group by refluxing with an acid catalyst such as aqueous hydrogen bromide for about five days, or boron tribromide in a solvent such as dichloromethane rising from 0°C to reflux and reacting for several hours.
- an acid catalyst such as aqueous hydrogen bromide for about five days, or boron tribromide in a solvent such as dichloromethane rising from 0°C to reflux and reacting for several hours.
- the hydroxy substituent is then reacted successively with trifluoromethanesulfonic acid anhydride in the presence of a base such as pyridine and a solvent such as dichloromethane at about room temperature for several hours!
- the B(OH)2 moiety can also be replaced by, for example, tributyltin.
- stannane group can be introduced either by adding a di(trialkyltin) compound to the reaction mixture or prereacting it with a compound of formula YC1 in the presence of lithium chloride, copper(l)iodide and a palladium catalyst and a solvent such as 1,4- dioxane at about 100°C for several hours.
- moiety Y When moiety Y is quinoline it can be made by reacting an aniline derivative with 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid) in a solvent such as acetonitrile, followed by trimethyl orthoformate generally at reflux for about three hours! or with an appropriate malonate ester under similar - •• - conditions. The product is heated in a high boiling solvent, such as Dowtherm A® for about one hour to obtain a quinolin-4(lH)-one. If a mixture of isomers.is obtained these can be separated either before or after aromatising the quinoline ' ⁇ which can be done by reacting with phosphorous oxychloride at about 80°C for about 1 hour.
- a solvent such as acetonitrile
- Trimethyl orthoformate generally at reflux for about three hours! or with an appropriate malonate ester under similar - •• - conditions.
- the product is heated in a high boiling solvent
- Quinolin-2(IH)-ones can be obtained by reacting with an appropriate acetoacetate derivative generally in a solvent such as toluene at about reflux for about 1 day, followed by addition of an acid such as toluene sulphonic acid and further heating at about reflux for about 1 day.
- Compounds of formula II can be made by reacting a compound of formula IV with a compound of formula VI: v-J-v (VI)
- a further process for making compounds of formula I involves reacting a compound of formula VII with a compound of formula VIII:
- L, L 1 and J are as defined above for a Suzuki or Stille Coupling Reaction.
- the LH moiety in the compound of formula IX can be made by reacting a chlorine moiety with aqueous ammonia in a solvent such as butanol generally under pressure at about 90°C for about 2 2 hours.
- These compounds can be made by reacting compounds bearing two hydroxy moieties with phosphorous oxychloride generally in a solvent such as anhydrous toluene at about reflux in the presence of a base such as triethylamine for about one hour.
- This compound when J is pyrimidine can be made by reacting a compound of formula X with a compound of formula XI:
- R 20 and R 21 are optional substituents on J as defined above, and R 19 are generally Ci- ⁇ alkyl groups.
- the reaction is carried out in a solvent such as ethanol generally for several hours in the presence of a strong base, such as sodium ethoxide.
- the amidine is usually introduced as the hydrochloride or acetate salt.
- Compounds of formula VI where L 1 is chlorine can be made in a variation of this process: when R 20 is SH a 6-hydroxy-4-oxo-l,4-dihydropyrimidin-2-thiolate results.
- the desired thioether can be made by reacting with the appropriate alkyliodide in a solvent such as DMF at about room temperature for several hours.
- This compound can be converted to a compound of formula VI in which ' L 1 is chlorine by reacting with POCI3 in an aprotic solvent such as diethylisopropylamide at about 100°C for several hours.
- Compounds of formula X can be made by bubbling ammonia gas through a solution containing a compound of formula XIII:
- R is an alkyl group and R 20 is as defined above, and the solvent is ROH at about -15°C.
- the compound of formula XIII can be made by reacting a compound of formula XIV:
- R 20 -CN (XIV) wherein R 20 is as defined above with an alcohol of formula ROH where R is as defined above in an aprotic solvent such as diethyl ether or the ether ROR and hydrogen chloride gas at about -15°C for about one hour.
- aprotic solvent such as diethyl ether or the ether ROR and hydrogen chloride gas at about -15°C for about one hour.
- a chlorine moiety can be removed by a reducing agent such as 10% palladium on carbon under a hydrogen atmosphere in the presence of a base such as triethylamine and a solvent such as methanol for several hours.
- a carboxy group can be converted to an amino group by reacting with diphenylphosphoryl azide in the presence of a base such as triethylamine in a solvent such as toluene.
- a Curtius rearrangement of the resulting azide by heating in a solvent such as toluene at reflux for about one hour, following by reacting with 2-methyl-2-propanol for about five hours in a solvent such as toluene and then deprotecting with an acid such as trifluoroacetic acid in a solvent such as dichloromethane yields the desired amine.
- a hydroxymethyl group can be converted to a morpholine derivative by reacting with an equivalent of methylsulfoxychloride in the presence of a base such as pyridine in a solvent such as dichloromethane for several hours at about room temperature, and then repeating the process at reflux.
- the resulting methylsulfoxy compound can then be reacted with the appropriate morpholine in a solvent such as DMF at about 90°C for several hours to yield the desired morpholine derivative.
- a solvent such as ethanol at a temperature of about 80°C for about 18 hours.
- Bromine groups can be introduced by reacting with a brominating agent such as N-bromosuccinimide in an aprotic solvent such as tetrachloromethane at reflux for about 90 minutes.
- a thioether can be converted to the sulfonyl analogue by reacting with Oxone® in a solvent such as methanol at about room temperature for several hours and then at reflux for about two hours.
- This compound can be converted to the cyanide analogue by reacting with a compound such as sodium cyanide in a solvent such as DMSO for about three days at about room temperature.
- the sulfonyl compound can be converted to the morpholine or pyrrolidine analogue by reacting with the appropriate morpholine or pyrrolidine in a solvent such as 1,4- dioxane at about 180°C for about 20 minutes in a microwave reactor.
- the sulfonyl compound can be converted to a haloalkoxy, alkoxy, cycloalkoxy or heterocyclylalkoxy analogue by reacting with the appropriate haloalcohol generally in a solvent such as tetrahydrofuran in the presence of a strong base such as sodium hydroxide at about 120°C for about six hours.
- Ethers can be converted to alcohols by reacting with hydrochloric acid in a protic solvent such as water for about 2 days at about reflux.
- a chlorine atom can be replaced by a haloalkyl group by reacting with the appropriate haloalkylamine in a solvent such as 1,4-dixane at about 160°C for about 20 minutes in a microwave oven.
- a cyano group can be derivatised to a tetrazolyl group by reacting with an azide such as sodium azide generally in the presence of ammonium chloride in a solvent such as DMF at about 120°C for about two hours.
- an azide such as sodium azide generally in the presence of ammonium chloride in a solvent such as DMF at about 120°C for about two hours.
- these compounds are commercially available or can be made from commercially available compounds by standard methods. Examples of appropriate methods can be found in the Descriptions.
- Pd(PPh3)4 (334 mg, 0.29 mmol) was added to a mixture of 2,4-dichloropyrimidine (861 mg, 5.78 mmol), quinoline-8-boronic acid (l.O g, 5.78 mmol), and 2M aqueous sodium carbonate (2.89 ml, 5.78 mmol) in a mixture of toluene (50 ml) and ethanol (10 ml). The mixture was degassed three times and heated at reflux overnight. The reaction mixture was cooled and diluted with EtOAc (50 ml), washed with water (2 x 100 ml), sat NaCl (100 ml), dried over Na2SO4, filtered and evaporated.
- Description 5 3-Chloro-5-(quinolin-8-yl)pyridazine
- Description 4 (1.40 g, 4.56 mmol) and phosphorous oxychloride (21.25 ml, 228 mmol) was warmed to 85°C then allowed to cool to room temperature.
- the excess phosphorous oxychloride was removed by evaporation and the residue partitioned between dichloromethane and sat NaHCO3.
- the organic layer was washed with sat NaCl, dried over Na2SO4 , filtered and evaporated.
- the residue was purified by column chromatography on silica:
- Description 11 7-(4.4.5.5-Tetramethyl-1.3.2-dioxaborolan-2-yl)quinoline
- Description 10 8.7 g, 31.4 mmol
- bis(pinacolato)diboron 8.8 g, 34.5 mmol
- potassium acetate 9.25 g, 94.2 mmol
- Pd(dppf)Ci2 860 mg, 0.94 mmol
- the mixture de-gassed three times and heated at 80°C overnight.
- the mixture was cooled and diluted with ethyl acetate (200 ml), washed with water (required a filtration through celite), sat.
- Description 23 2 -Methoxy 6- (q uinolin- 7- yl)pyrimidin-4-amine Prepared from Description 22 and Description 11 according to the procedure of Description 1 to give an orange solid (1.15 mg, 65%).
- Description 27 3-Methylquinolin-7-ol A mixture of Description 26 (6.0 g, 34.6 mmol) and 48% aqueous HBr (150 ml) was heated at reflux for 5 days. The mixture was cooled and basified by the careful addition of 33% aqueous ammonia. The resulting precipitate was removed by filtration, washed with water, and dried in-vacuo to give the title compound as a pink solid (4.6 g, 84%).
- Description 28 6-(3-Methylquinolin-7-yl)pyrimidin-4-amine Prepared from Description 27 according to the procedures of Descriptions 10, 11 and 14 respectively to give a hght brown solid (950 mg, 57%).
- the dichloromethane layer was dried over Na2SO 4 , filtered through a 1 inch plug of sihca and evaporated.
- the residue was dissolved in dichloromethane (200 ml) and trifluoroacetic acid (25 ml) added, and the resulting mixture stirred at room temperature overnight.
- the mixture was evaporated and the residue partitioned between dichloromethane and sat. K2CO3, the dichloromethane layer was dried over Na 2 SO4, filtered and evaporated.
- the residue was purified by column chromatography on sihca: (eluent with 15% EtOAc in isohexanes) to give the title compound as a pale yeUow oil (10.8 g, 87%).
- Description 49 4.6-Dichloro-5-methoxy-2-methylpyrimidine To a suspension of Description 48 (7.99 g, 51.2 mmol) and triethylamine (7.14 ml, 51.2 mmol) in anhydrous toluene (100 ml) heated at 100°C was added dropwise a solution of phosphorous oxychloride (10.5 ml, 112.6 mmol) in toluene (50 ml).
- Description 55 6-Metho ⁇ y-5-trifluo ⁇ -omethylpyrimidin-4-amine
- Description 54 8 g, 40.8 mmol
- butan-1-ol and ammonium hydroxide 50 ml
- the mixture was cooled and the resulting precipitate removed by filtration, and dried to give the title compound (3.3 g, 42%) as a white crystalline solid.
- Description 74 4.6-Dichloro-5-methyl-2-methylthiopyrimidine To a mixture of Description 73 (36 g, 209 mmol) and phosphorous oxychloride (390 ml, 4.18 mol) was added N,N-diethylisopropylamine (40.34 ml, 230 mmol) and the resulting mixture heated at 100°C overnight. The excess phosphorous oxychloride was removed by evaporation, and the residue dissolved in DCM (300 ml), and poured onto ice/water (500 ml). The mixture was stirred for 30 min, the organic layer was separated, and the aqueous phase extracted with a further portion of DCM (300 ml).
- Description 80 6-Chloro-2-methoxymethyl-5-methylpyrimidin-4-amine Prepared from Description 79 and methyl diethylmalonate according to the procedures of Descriptions 48, 49 and 16 respectively to give a white solid. ⁇
- Description 85 6-Trifluoromethyl-4.5-dihydrop ⁇ 7 ridazin-3(2H)-one
- a mixture of Description 84 (90.2 g, 279 mmol) and hydrazine hydrochloride (95.6 g, 1.4 mol) in glacial acetic acid (500 ml) was heated at reflux for 2 hours. The cooled reaction mixture was evaporated, and the residue basified by the careful addition of saturated aqueous K2CO3. Water (500 ml) was added, and the mixture extracted with dichloromethane (x 3). The combined dichloromethane layers were dried over Na 2 SO4 , filtered and evaporated to give the title compound as an oil which crystallised on standing (50 g, quant).
- ⁇ NMR 400 MHz,' CDCls) 2.62 (2 ; H, m), 2.78 (2 H, m), 9.57 (1 H, br s).
- Description 86 6-Trifluoromethylpyridazin-3(2H)-one To a solution of Description 85 (46.34 g, 279 mmol) in glacial acetic acid (300 ml) warmed at 100°C, was added dropwise a solution of bromine (14.29 ml, 279 mmol). After complete addition the heating was continued for 4 hours. The acetic acid was removed by evaporation and the residue partitioned between dichloromethane and water. The organic layer was washed with sat. NaHCO ⁇ , sat. NaCl, dried over Na 2 SO4, filtered and evaporated.
- Description 94 6-(l.8-Naphthyridin-2-yl)pyrimidin-4-amine To a mixture of Description 92 (2.52 g, 15.3 mmol), hexamethylditin (5.0 g, 15.3 mmol), lithium chloride (1.95 g, 45.9 mmol), and copper (I) iodide (291 mg, 1.53 mmol) in anhydrous 1,4-dioxane (50 ml) was added Pd(PPhs)4 (884 g, 0.77 mmol). The mixture was de-gassed three times, and heated at 100°C overnight.
- Description 102 2-Chloro-7-methoxy-4-trifluoromethylquinoline Prepared from Description 101 according to the procedure of Description 92 (8.63 g, 89%). ⁇ NMR (400 MHz, CDCls) 3.96 (3 H, s), 7.31 (l H, dd, J9.4 and 2.7), 7.43 (1 H, d, J2.7), 7.54 (l H , s), 7.98 (l H, dd, J9.4 and 2.0).
- Description 104 7-[6-Chloro-5-methyl-2-methylthiopyrimidin-4-yl]quinoline Prepared from Description 11 (3.2 g, 12 mmol) and Description 74 (5.2 g, 24 mmol) according to the procedure of Description 1 to give a solid (2.9g, 77%).
- X H NMR 400 MHz, CDCI3 2.43 (3 H, s), 2.60 (3 H, s), 7.49 (l H, dd, J8.3 and 4.2), 7.77 (1 H, dd, J8.4 and 1.7), 7.94 (l H, d, J8.4), 8.23 (l H, d, J8.3), 8.29 (l H, s), 8.98-9.00 (1 H, m).
- Description 107 To a stirred suspension of Description 107 (8.8 g, 37 mmol) in DMF (400 ml) under N2, was added teri-butanol (150 ml) and triethylamine (12 ml, 86 mmol), followed by diphenylphosphorylazide (9.5 ml, 44 mmol). The mixture was heated at 100°C for 3hours. The cooled reaction mixture was then evaporated and the residue was purified by column chromatography on silica (eluant: DCM to 4% MeOH in DCM). This gave Description 108 as a solid (2.12 g, 20%) and Description 109 as an orange solid (4.26 g, 55%).
- Description 110 4-Chloro-3-fluoro-7-methoxyquinoline A solution of Description 109 (4.26 g, 20 mmol) in THF (100 ml) was cooled in an ice/water bath and 48% fluoroboric acid (11 ml, 60 mmol) was carefully added. The mixture was stirred for 5min, and then a solution of sodium nitrite (1.55 g, 22 mmol) in water (3 ml) was added dropwise keeping the temperature of the reaction below 10°C. The mixture was stirred for 30 minutes in an ice/water bath. The resulting yellow sohd was filtered and washed with THF. The solid was then heated at 170°C until gas evolution had ceased.
- Description 112 6-(3-Aminophenyl)-5-methyl-N-[5-trifluoromethylpyridin-2- ' yl] p yrimidin-4- amine Prepared from Description 88 and (3-aminophenyl)boronic acid according to the procedure of Description 1 to give a light brown solid (1.58 g, 74%).
- Description 113 2.2-Dimethyl-5-(3-(5-methyl-6-5-trifluoromethylpyridin-2- ylamino ⁇ pyrimidin-4-yl)phenylaminomethylene)-1.3-dioxane- 4.6-dione Prepared from Description 112 according to the procedure of Description 34 to give a solid (1.13 g, 100%).
- Description 120 6-[4-Trifluoromethylquinolin-7-yl]pyrimidin-4-amine ⁇ _ Prepared from Description 103 according to the procedures of Descriptions 27,. 10, and 11 respectively then reaction of the product with 6-chloropyrimidirr4-amine. according to the procedure of Description 1 to give a solid.
- ⁇ NMR 500 MHz, ; CDCls) 5.03 (2 H, s), 5.65 (lH, s), 7.04 (l H, s), 7.74 (l H, d, J4.1), 8.25 (l H, ⁇ , : 8.6), 8.27 (1 H, s), 8.39 (l H, d J8.8), 9.10 (l H, d, J4.2).
- Description 141 6-Chloro-5-methyl-2-trifluoromethylpyrimidin-4-amine Prepared from Description 140 according to the procedure of Description 16 to give a white solid (2.5 g, 32%).
- Description 142 5-Methyl-6-quinolin-7-yl-2-trifluoromethylpyrimidin-4-amine Prepared from Description 141 and Description 11 according to the procedure of Description 1 (490 mg, 68%).
- X H NMR 400 MHz, DMSO-ofc
- 2.17 3 H, s
- 8.11 (l H, d, J8.4) 8.17 (l H, d, J0.6), 8.45 (1 H, d, J8.3), 8.99 (1 H, dd, J4.2 and 1.2).
- Example 1 4-Quinolin-8-yl-N-[4-trifluoromethylphenyl]pyrimidin-2-amine To a mixture of Description 1 (100 mg, 0.42 mmol) and 4-trifluoromethylaniline (0.052 ml, 0.42 mmol) in anhydrous toluene (15 ml) was added sodium tert- butoxide (60 mg, 0.62 mmol) and 2'-(dimethylamino)-2-biphenylyl palladium (II) chloride dinorbornylphosphine complex [Angew.
- Example 6 4-Quinolin-7-yl-N-[4-trifluoromethylphePyl]pyrimidin-2-amine Prepared from Description 13 and 4-trifluoromethylaniline to give a white solid (55 mg, 18%).
- ⁇ NMR (500 MHz, CDCls) 7.43 (2 H, d, ,75.2), 7.46 (l H, br s), 7.49 (1 H, dd, ,78.1 and 4.2), 7.63 (2 H, d, ,78.6), 7.88 (2 H, d, J8.6), 7.97 (l H, d, ,78.6), 8.23 (1 H, d, ,78.3), 8.31 (l H, dd, J8.6 and 1.7), 8.59 (l H, d, ,75.4), 8.78 (l H, s), 9.00 (1 H, dd, J4.2 and 1.7); m/z (ES + ) 367 (M+H + ).
- Example 8 5-Quinolin-7-yl-N-[4-trifluoromethylphenyl]pyridazin-3-amine • Prepared from Description 15 and 4-trifluoromethylanihne to give a pale yellow solid (25 mg, 8%).
- ⁇ NMR 500 MHz, DMSO-cfe
- 7.60 (lHy d, ,72.0), 7.63 (l H, dd, J8.4 and 4.2), 7.70 (2 H, d, ,78.6), 8.04 (3 H, m), 8.20 (l H, d, ,78.6), 8.47 (l H, d, ,78.1), 8.49 (1 H, s), 9.01 (l H, dd, J4.2 and 1.5), 9.35 (l H, d, ,72.0), 9.83 (l H, s);
- Example 9 6-Quinolin-7-yl-N-[5-trifluoromethylpyridin-2-yl1pyrimidin-4-amine Prepared from Description 14 and
- Example 12 5-Methyl-6-quinolin-7-yl-N-[4-trifluoromethylphenyl1pyrimidin-4- amine Prepared from Description 19 and 4-trifluoromethylbromobenzene to give. a white- solid (190 mg, 59%).
- Example 14 2-Methoxy-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4- amine Prepared from Description 23 and 4-trifluoromethylbromobe ⁇ zene to give an off white solid (130 mg, 41%).
- Example 17 6-Quinolin-5-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-ami ⁇ e Prepared from Description 30 and 4-trifluoromethylaniUne to give a white solid.
- ⁇ NMR (400 MHz DMSO-cfe) 7.16 (l H, d, ,71.2), 7.59 (l H, dd, J4.2 and 8.8), ' 7.72 (2 H, d, ,78.8), 7.83 (l H, dd, J 7.1 and 1.2), 7.88-7.91 (l H, m), 8.01 (2 H, d, J8.6), 8.17 (1 H, d, ,78.3), 8.69 (lH, d, ,78.6), 8.90 (l H, d, ,71.2), 8.98 (l H, dd, J 3.9 and 1.7), 10.20 (l H, s); m/z (ES + ) 367 (M+H + ).
- Example 18 6-Quinolin-6-yl-N- [4-trifluoromethylphenyl] pyrimidin-4-amine Prepared from Description 31 and 4-trifluoromethylbromobenzene to give a white solid.
- ⁇ NMR (400 MHz, DMSO- ⁇ ) 7.52 (l H, d, ,71.2), 7.63 (l H, dd, J8.3 and 4.2), 7.72 (2 H, d, J8.6), 8.00 (2 H, d, J8.6), 8.18 (l H, d, ,78.8), 8.40 (l H, dd, J 8.8 and 2.2), 8.57 (l H, dd, J8.3 and 1.2), 8.75 (l H, d, ,72.0), 8.88 (l H, d, ,71.2), 8.99 (1 H, dd, J4.2 and 1.7), 10.21 (l H, s); m/z (ES + ) 367 (M+H + ).
- Example 26 6-Quinolin-8-yl-N- [4-trifluoromethylphenyl]pyridazin-4- " amine - ⁇
- a mixture of Description 8 (100 mg, 0.38 mmol), quinoline-8-boronic acid. (126 mg, 0.73 mmol), 2M sodium carbonate (0.365 ml, 0.73 mmol), and Pd(dppf)Ci2 (10 mg,” 0.011 mmol) was heated at 170°C for 40 mins in a Smith microwave reactor. The mixture was diluted with dichloromethane (20 ml) and washed with water (2 x 20 ml), sat. NaCl (15 ml), dried over Na 2 SO4 , filtered and evaporated.
- Example 27 4-Qumolin-8-yl-N-[4-trifluoromethylphenyl]-1.3,5-triazin-2-amine
- Description 9 7.90 mg, 2.89 mmol
- quinoline-8-boronic acid 500 mg, 2.89 mmol
- 2M Sodium carbonate 2.89 ml, 5.78 mmol
- Pd(PPh3) 4 17.1 mg, 0.14 mmol
- Example 29 6-Quinolin-7-yl-N 4 -[4-trifluoromethylphenyllDyrimidine-4.5- diamine
- a nitrogen flushed solution of Example 28 80 mg, 0.195 mmol
- methanol 5 ml
- dichloromethane 5 ml
- 10% Palladium on carbon 10 mg
- the catalyst was removed by filtration and the filtrate evaporated.
- the residue was crystallised from dichloromethane/diethyl ether to give 60 mg (Yield 80%) as an off white solid.
- Examples 30-51 were made from the indicated compounds according to the procedure of Example 2.
- Example 52 7- (5 -Methyl- 6 - ⁇ 5 -trifluoromethylpyridin- 2 - ylaminol yrimidin- 4- yl)quinolinium benzenesulfonate
- Example 41 To a solution of Example 41 in DMF (40 ml) was added benzenesulfonic acid (1.05 eq., 4.3 g, 27.2 mmol) at 40°C. Isopropyl acetate (10 ml) was added into the solution, which was then seeded with the product (10 mg). The solution was aged for 30 min, then more isopropyl acetate (70 ml) was added over 1 ⁇ 2 hours, keeping the internal temperature at ca. 40°C. After addition, the batch was cooled to 20-25°C, aged for 2 hours, then filtered. The resulting cake was washed with isopropyl acetate (10 mL), then dried to give the title compound (13.4 g, 95 %).
- Examples 59 - 79 were made from the indicated compounds according to the procedure of Example 2.
- Example 62 6- (8- Ethylquinolin- 7-yl) -N- ⁇ -trifluoromethylpyridin- 2 - yl] pyrimidin- 4- amine Description 70 and 2-chloro-5-trifluoromethylpyridine gave a white sohd (70 mg, 30%).
- Example 68 A mixture of Example 68 (0.5 g, 1.18 mmol) and 48% aqueous HBr (5 ml) was heated at 90°C overnight. The cooled mixture was poured onto ice/water and carefully basified by the addition of ammonium hydroxide. The mixture was extracted with dichloromethane (x 3) and the combined dichloromethane layers were dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica (eluent: 4% [2M NH3 in MeOH] in DCM) to give the title compound as a yellow solid (160 mg, 32%).
- Example 81 2-[(c75-2.6-Dimethylmorpholin-4-yl)methyl]-5-methyl-6-quinolin-7- yl- N- [5 -trifluoromethyl yridin- 2 - yl] p yrimidin- 4-amine
- dichloromethane 15 ml was added pyridine (0.108 ml, 1.34 mmol) followed by methane sulfonyl chloride (0.094 ml, 1.22 mmol), and the resulting mixture stirred at room temperature overnight.
- Example 82 5-Methyl-6-(l.8-naphthyridin-2-yl)-N-[4-trifluoromethyl phenyl] pyrimidin- 4- amine
- Description 95 200 mg, 0.7 mmol
- Description 92 115 mg, 0.7 mmol
- Pd(PPhs)4 80 mg, 0.07 mmol
- hexamethylditin (0.145 ml, 0.7 mmol
- the mixture was heated at 190°C for 15 min in a microwave reactor (Personal Chemistry — Smith synthesizer).
- the cooled reaction mixture was loaded directly onto a silica gel chromatography column and eluted with 2% MeOH + 0.5% NH 4 OH in DCM.
- the product was further purified by mass directed HPLC to give the title compound as a white solid (50 mg, 18%).
- Example 90 6-(l77 " -Benzimidazol-6-yl)-N-[4-trifluoromethylphenyl]pyrimidin-4- amine
- Description 99 210 mg, 0.43 mmol
- tetrabutylammonium fluoride l.OM soln in THF 0.86 ml, 0.86 mmol
- the residue was purified by PREP-TLC (eluent: 7.5% MeOH in DCM +0.5% NH OH) to give the title compound as a white sohd.
- Example 7 A mixture of Example 7 (370 mg, 1 mmol) and N-bromosuccinimide (l80 mg,' 1 mmol) in chloroform (5 ml) was heated at reflux for 30 min. More N- " ' '• bromosuccinimide (100 mg, 0.56 mmol) was added and heating continued for 1 hour. The mixture was cooled, diluted with dichloromethane (15 ml), then washed with water, dried over Na2SO4 , filtered and evaporated. A 200 mg portion was purified by PREP-TLC (eluent: 5% MeOH in DCM + 0.5% NH 4 OH) to give the title compound as a white sohd (120 mg, 27%).
- PREP-TLC eluent: 5% MeOH in DCM + 0.5% NH 4 OH
- sodium cyanide 13 mg, 0.27 mmol
- the mixture was stirred at room temperature for 3 days, and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated.
- Example 95 5-Methyl-2-(2-methylpyrrolidin-l-yl)-6-quinolin-7-yl-N-[5- trifluoromethylpyridin-2-yl]pyrimidin-4-amine
- 2-methylpyrrohdine (220 ⁇ l, 2.2 mmol)
- the mixture was heated at 180°C for 20 min in a microwave (Personal Chemistry — Smith synthesizer).
- the cooled reaction mixture was loaded directly onto a silica gel chromatography column and eluted using 1:1 ethyl acetate-hexane to give a white solid (140 mg, 70%).
- Example 96 5-Methyl-2-morpholin-4-yl-6-ouinolin-7-yl-N-[5-trifluoromethyl pyridin-2-yl]pyrimidin-4-amme Prepared from Example 125 and morpholine according to the procedure of Example 95 to give a white solid (150 mg, 74%).
- Examples 98 and 99 7-(5-Methyl-6- ⁇ 5-trifluoromethylpyridin-2-ylamino ⁇ pyrimidin-4-yl)quinolin-4-ol (Example 98) and 5-5-methyl- 6- ⁇ 5-trifluoromethylpyridin-2-ylamino ⁇ pyrimidin-4- ylquinolin-4-ol (Example 99) Prepared from Description 113 according to the procedure of Description 35 to give the two title compounds which were separated by preparative HPLC to give 2 white solids, Example 98 (73mg, 8%).
- Example 100 2-Methyl-6-quinohn-7-yl-A ⁇ -[4-trifluoromethylphenyl1pyrimidine- 4,5-diamine Prepared from Description 125 and 4-aminobenzotrifluoride in 1,4-dioxane according to the procedure of Example 92 to give a white solid (40 mg, 42%).
- Example 101 4-Quinolin-7-yl-6- ⁇ 4-trifluoromethylphenylamino ⁇ pyrimidin-2-ol
- a suspension of Example 14 (2.4 g, 6.1 mmol) in 2N HCI (100 ml) was heated at reflux for 48 hours.
- the reaction mixture was cooled to room temperature and neutralised with sat. NaHCOs.
- the solid formed was filtered and dried overnight in a vacuum oven to give an off white solid (1.8 g, 80%).
- Example 102 2-Chloro-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4- amine Prepared from Example 101 according to the procedure of Description 36 to give a light brown solid.
- ⁇ NMR (500 MHz, DMSO-cfe) 7.54 (l H, s), 7.62 (l H, dd, J8.2 and 4.1), 7.73 (2 H, d, J8.5), 7.90 (2 H, d, J8.3), 8.14 (l H, d, J8.6), 8.20 (l H, dd, J8.5 and 1.6), 8.45 (l H, d, J8.1), 8.64 (l H, s), 9.00 (l H, dd, J4.1 and 1.6); m/z (ES + ) 401 (M+H + ).
- Example 103 2-Morpholin-4-yl-6-qumolin-7-yl-A ⁇ -[4-trifluoromethyl phenyl] pyrimidin-4-amine
- a suspension of Example 102 (50 mg, 0.12 mmol), morpholine (55 ⁇ l, O. ⁇ mmol) and 1,4-dioxane (2ml) were heated at 160°C for 20 mins in a microwave (Personal Chemistry - Smith synthesizer). The cooled reaction was loaded directly onto a preparative TLC plate and eluted using 4% MeOH in DCM to give a white solid (10 mg, 18%).
- Example 106 4-Methyl-6-quinolin-7-yl-N r -[4-trifluoromethylphenyl]-1.3.5- triazin-2-amine Prepared from Description 126 and Description 11 according to the procedure of Description 1 to give a white solid (80 mg, 18%).
- Example 107 2-(l.l-Dimethylethyl)-5-methyl-6-ouinolin-7-yl-A ⁇ -[4- trifluoromethylphenyllpyrimidin-4-amine
- Description 127 (0.12 g, 0.38 mmol) and 4-trifluoromethylaniline (0.12 g, 0.74 mmol) in dioxane (4 ml) was treated with 2N HCI in ether (0.5 ml) and the resulting solution heated at 170°Cfor 20 mins in a microwave" apparatus. The precipitate was collected by filtration and the desired product isolated by ion exchange chromatography as a white solid (45 mg, 27%).
- Example 111 2-(lH- " Imidazol-l-ylmethyl)-6-quinolin-7-yl-N-4-trifluoromethyl phenyllpyrimidin-4-amine
- a solution of methanesulphonic anhydride (28.6 mg, 0.164 mmol) in DCM (l ml) was added to an ice-cooled suspension of Example 110 (50 mg, 0.126 mmol) and triethylamine (61 ⁇ l, 0.442 mmol) in DCM (2 ml). The mixture was warmed to room temperature and stirred for 18 hours.
- Example 112 2 -Isopropyl- 5 -methyl- 6- q uinolin- 7-yl- TV- [4-trifluoromethyl phenyl] pyrimidin-4-amine
- Description 133 (248 mg, 0.832 mmol), 4-trifluoromethylanihne (209 ⁇ l, 1.66 mmol) and 5N HCI (5 drops) in dioxane were heated at 180°C for 30 mins in a microwave apparatus. A precipitate was observed and the mixture was filtered. The solid was washed with ethanol and partitioned between ethyl . ' " acetate and sodium carbonate solution (aq). The organic phase was washed with.
- Example 113 2-Methylthio-6-quinolin-7-yl-N : [4-trifluoromethylphenyl] pyrimidin-4-amine Prepared from Description 134 according to the procedure of Example 92.
- X H NMR 400 MHz, CDCls
- 2.69 (3 H, s), 7.02 (2 H, d, ,74.1), 7.47 (l H, dd, J8.2 and 4.1), 7.64 (4 H, q, ,77.8), 7.92 (l H, d, ,78.6), 8.21 (l H, d, J8.2), 8.29 (l H, dd, J 8.6 and 1.8), 8.69 (l H, s), 8.97 (l H, dd, J4.2 and 1.7); m/z (ES*) 413 (M+H + ).
- Example 126 Prepared from Example 126 according to the procedure of Example 93.
- X H NMR (360 MHz, DMSO-cfe) 7.65 (l H, dd, J8.2 and 4.2), 7.71 (l H, s), 7.80 (2 H, d, J 8.6), 7.92 (2 H, d, ,78.6), 8.18-8.26 (2 H, m), 8.48 (l H, d, ,77.4), 8.68 (l H, s), 9.03 (1 H, dd, J4.2 and 1.7), 10.65 (l H, s); /z (ES*) 392 (M+H + ).
- Example 115 2-Cvclopropylmethoxy-6-quinolin-7-yl-N-[4-trifluoromethyl phenyl] -pyrimidin-4-amine Prepared from Example 126 and cyclopropylmethanol according to the procedure of Example 97.
- Example 116 2-(Pyridin-3-ylmethoxy)-6-quinolin-7-yl-N-[4-trifluoromethyl phenyl] -pyrimidin-4-amine Prepared from Example 126 and pyridin-3-ylmethanol according to the procedure of Example 97.
- Example 114 (36 mg, 0.092 mmol), sodium azide (60 mg, 0.92 mmol) and ammonium chloride (49 mg, 0.92 mmol) were suspended in DMF (2ml) and heated to 120°C for 2 hours. The mixture was poured onto water (25 ml) and filtered, washing the residue with water. The residue was dissolved in DMSO and purified using mass-directed HPLC to give the title compound (5 mg, 9%). ⁇
- Example 120 6-Quinoxalin-6-yl-N-[4-trifluoromethylphenyl]pyrimidin-4- amine Prepared from Description 137 and 4-trifluoromethylbromobenzene according to the procedure of Example 2 to give a white sohd (40 mg, 14%).
- Example 124 5-Methyl-2-methylsulfonyl-6-quinolin-7-yl-N : [4- trifluoromethylphenyl]pyrimidin-4-amine
- oxone® 660 mg, 1.1 mmol
- the reaction mixture was stirred at room temperature overnight, then at reflux for 2 hours.
- the cooled reaction mixture was poured onto saturated aqueous NaHCOs solution and then extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated to give a white solid (250 mg, 100%).
- Example 126 2-Methylsulfonyl-6-quinolin-7-yl-N-[4-trifluoromethyl phenyl] pyrimidin-4-amine Prepared from Example 113 according to the procedure of Description'"123.
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GB0326217A GB0326217D0 (en) | 2003-11-10 | 2003-11-10 | Therapeutic agents |
GB0407748A GB0407748D0 (en) | 2004-04-05 | 2004-04-05 | Therapeutic agents |
US61713404P | 2004-10-08 | 2004-10-08 | |
PCT/GB2004/004719 WO2005047279A1 (en) | 2003-11-10 | 2004-11-09 | Substituted nitrogen-containing six-membered amino-heterocycles as vanilloid-1 receptor antagonists for treating pain |
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JP (1) | JP2007510706A (en) |
AU (1) | AU2004289518A1 (en) |
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US20050014753A1 (en) * | 2003-04-04 | 2005-01-20 | Irm Llc | Novel compounds and compositions as protein kinase inhibitors |
US20080058356A1 (en) * | 2003-12-15 | 2008-03-06 | Neurocrine Biosciences, Inc. | 2,6 Bisheteroaryl-4-Aminopyrimidines as Adenosine Receptor Antagonists |
US7301022B2 (en) | 2005-02-15 | 2007-11-27 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
AU2008236670B2 (en) | 2007-04-05 | 2011-12-01 | Amgen Inc. | Aurora kinase modulators and method of use |
KR101619341B1 (en) | 2008-01-28 | 2016-05-11 | (주)아모레퍼시픽 | Novel compounds isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor antagonistand pharmaceutical compositions containing the same |
WO2009117157A1 (en) | 2008-03-20 | 2009-09-24 | Amgen Inc. | Aurora kinase modulators and method of use |
CN101983197B (en) | 2008-04-18 | 2015-04-22 | 大熊制药株式会社 | A novel benzoxazine benzimidazole derivative, a pharmaceutical composition comprising the same, and a use thereof |
ES2645689T3 (en) | 2008-05-21 | 2017-12-07 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
EP2307394B1 (en) | 2008-07-02 | 2012-09-26 | Amorepacific Corporation | Sulphonamides as vanilloid receptor antagonist |
US9126935B2 (en) | 2008-08-14 | 2015-09-08 | Amgen Inc. | Aurora kinase modulators and methods of use |
PA8852901A1 (en) | 2008-12-22 | 2010-07-27 | Lilly Co Eli | PROTEIN CINASE INHIBITORS |
EP2408766A1 (en) | 2009-03-18 | 2012-01-25 | Schering Corporation | Bicyclic compounds as inhibitors of diacylglycerol acyltransferase |
EP2462123B1 (en) * | 2009-08-04 | 2013-10-02 | Merck Sharp & Dohme Corp. | 4,5,6-trisubstituted pyrimidine derivatives as factor ixa inhibitors |
KR101293384B1 (en) | 2010-10-13 | 2013-08-05 | 주식회사 대웅제약 | Novel pyridyl benzoxazine derivatives, pharmaceutical composition comprising the same, and use thereof |
EP2518070A1 (en) | 2011-04-29 | 2012-10-31 | Almirall, S.A. | Pyrrolotriazinone derivatives as PI3K inhibitors |
CN102558047B (en) * | 2011-12-14 | 2013-10-30 | 天津药物研究院药业有限责任公司 | Method for preparing 3-methylquinoline |
CN102702110A (en) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of 4-amino-5, 6-dichloropyrimidine |
UY35421A (en) | 2013-03-15 | 2014-10-31 | Nihon Nohyaku Co Ltd | CONDENSED HETEROCYCLIC COMPOUND OR ITS SALT, AGRICULTURAL OR HERITAGE INSECTICIDE THAT INCLUDES THE COMPOSITE AND METHOD OF USE OF THE INSECTICIDE |
ES2813875T3 (en) | 2014-01-01 | 2021-03-25 | Medivation Tech Llc | Compounds and procedures for use |
US10202373B2 (en) | 2014-01-14 | 2019-02-12 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
WO2018112843A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor |
JP2021515767A (en) | 2018-03-07 | 2021-06-24 | バイエル・アクチエンゲゼルシヤフト | Identification and use of ERK5 inhibitors |
WO2020102150A1 (en) | 2018-11-13 | 2020-05-22 | Incyte Corporation | Heterocyclic derivatives as pi3k inhibitors |
WO2020102198A1 (en) | 2018-11-13 | 2020-05-22 | Incyte Corporation | Heterocyclic derivatives as pi3k inhibitors |
US11396502B2 (en) | 2018-11-13 | 2022-07-26 | Incyte Corporation | Substituted heterocyclic derivatives as PI3K inhibitors |
CN111793022A (en) * | 2020-04-27 | 2020-10-20 | 滁州拜奥生物科技有限公司 | Preparation method of 3-methylquinoline |
RU2744470C1 (en) * | 2020-09-22 | 2021-03-09 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Волгоградский государственный технический университет" (ВолгГТУ) | Method for producing isothiobarbamine |
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US4788195A (en) * | 1986-01-13 | 1988-11-29 | American Cyanamid Company | 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines |
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KR20030024799A (en) * | 2000-07-20 | 2003-03-26 | 뉴로젠 코포레이션 | Capsaicin receptor ligands |
MXPA04011472A (en) | 2002-05-22 | 2005-02-14 | Amgen Inc | Amino-pyridine, -pyridine and pyridazine derivatives for use as vanilloid receptor ligands for the treatment of pain. |
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