MX2012007329A - Compuestos de n-(1h-indazol-4-il) imidazo [1, 2-a] piridin-3-carboxamida substituida como inhibidores de cfms. - Google Patents
Compuestos de n-(1h-indazol-4-il) imidazo [1, 2-a] piridin-3-carboxamida substituida como inhibidores de cfms.Info
- Publication number
- MX2012007329A MX2012007329A MX2012007329A MX2012007329A MX2012007329A MX 2012007329 A MX2012007329 A MX 2012007329A MX 2012007329 A MX2012007329 A MX 2012007329A MX 2012007329 A MX2012007329 A MX 2012007329A MX 2012007329 A MX2012007329 A MX 2012007329A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- formula
- compound
- methyl
- ethyl
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 22
- AYAOSDNSSUARDZ-UHFFFAOYSA-N n-(1h-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide Chemical class C1=CC=CN2C(C(NC=3C=4C=NNC=4C=CC=3)=O)=CN=C21 AYAOSDNSSUARDZ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 293
- 238000011282 treatment Methods 0.000 claims abstract description 47
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 40
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 201000010099 disease Diseases 0.000 claims abstract description 32
- 201000011510 cancer Diseases 0.000 claims abstract description 27
- 208000002193 Pain Diseases 0.000 claims abstract description 23
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 18
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 17
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 265
- 238000002360 preparation method Methods 0.000 claims description 141
- 125000003545 alkoxy group Chemical group 0.000 claims description 115
- 125000001424 substituent group Chemical group 0.000 claims description 114
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 60
- 229910052757 nitrogen Inorganic materials 0.000 claims description 53
- 239000002585 base Substances 0.000 claims description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 39
- 125000005842 heteroatom Chemical group 0.000 claims description 33
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 230000008878 coupling Effects 0.000 claims description 30
- 238000010168 coupling process Methods 0.000 claims description 30
- 238000005859 coupling reaction Methods 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 125000006413 ring segment Chemical group 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- 229920006395 saturated elastomer Polymers 0.000 claims description 24
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 23
- 241000124008 Mammalia Species 0.000 claims description 21
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 19
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 18
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 17
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 17
- 229910052763 palladium Inorganic materials 0.000 claims description 17
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate Chemical compound [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims description 12
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 8
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 238000002560 therapeutic procedure Methods 0.000 claims description 7
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 6
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 6
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 6
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 claims description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 3
- 150000001723 carbon free-radicals Chemical class 0.000 claims description 3
- 239000007822 coupling agent Substances 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004521 1,3,4-thiadiazol-2-yl group Chemical group S1C(=NN=C1)* 0.000 claims description 2
- JUQWFONZRDXAAB-UHFFFAOYSA-N 1-methyl-1-oxidopiperazin-1-ium Chemical compound C[N+]1([O-])CCNCC1 JUQWFONZRDXAAB-UHFFFAOYSA-N 0.000 claims description 2
- 238000010306 acid treatment Methods 0.000 claims description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 150000002831 nitrogen free-radicals Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 441
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 379
- -1 piperidinylmethyl Chemical group 0.000 description 359
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 255
- 239000000203 mixture Substances 0.000 description 224
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 154
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 137
- 239000011541 reaction mixture Substances 0.000 description 136
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 132
- 230000002829 reductive effect Effects 0.000 description 132
- 239000000243 solution Substances 0.000 description 128
- ZMBYQTGAXZOMOO-UHFFFAOYSA-N imidazo[1,2-a]pyridine-3-carboxamide Chemical compound C1=CC=CN2C(C(=O)N)=CN=C21 ZMBYQTGAXZOMOO-UHFFFAOYSA-N 0.000 description 112
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 112
- 235000019439 ethyl acetate Nutrition 0.000 description 99
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 92
- 239000000047 product Substances 0.000 description 89
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 72
- 238000004587 chromatography analysis Methods 0.000 description 67
- 239000000741 silica gel Substances 0.000 description 67
- 229910002027 silica gel Inorganic materials 0.000 description 67
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 66
- 238000006243 chemical reaction Methods 0.000 description 61
- 239000007787 solid Substances 0.000 description 61
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 57
- 239000002904 solvent Substances 0.000 description 50
- 239000001257 hydrogen Substances 0.000 description 46
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 45
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- 239000000463 material Substances 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 37
- 235000005152 nicotinamide Nutrition 0.000 description 36
- 239000011570 nicotinamide Substances 0.000 description 36
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 36
- 229910052938 sodium sulfate Inorganic materials 0.000 description 34
- 235000011152 sodium sulphate Nutrition 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000012467 final product Substances 0.000 description 33
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 32
- 239000000377 silicon dioxide Substances 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 29
- 239000012074 organic phase Substances 0.000 description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 125000004432 carbon atom Chemical group C* 0.000 description 25
- 239000000725 suspension Substances 0.000 description 24
- 239000012267 brine Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 238000012746 preparative thin layer chromatography Methods 0.000 description 22
- 210000002540 macrophage Anatomy 0.000 description 21
- 229960003010 sodium sulfate Drugs 0.000 description 21
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 19
- 239000012071 phase Substances 0.000 description 19
- 229910000027 potassium carbonate Inorganic materials 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 18
- 235000011114 ammonium hydroxide Nutrition 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 16
- 239000008346 aqueous phase Substances 0.000 description 16
- 239000012298 atmosphere Substances 0.000 description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 239000000908 ammonium hydroxide Substances 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 208000003076 Osteolysis Diseases 0.000 description 14
- 239000000010 aprotic solvent Substances 0.000 description 14
- 150000002170 ethers Chemical class 0.000 description 14
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 229910000024 caesium carbonate Inorganic materials 0.000 description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
- 238000003556 assay Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 125000001153 fluoro group Chemical group F* 0.000 description 11
- 125000003386 piperidinyl group Chemical group 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 10
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 10
- 210000002997 osteoclast Anatomy 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 125000004193 piperazinyl group Chemical group 0.000 description 10
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 10
- AOTAXYVEONHYHY-UHFFFAOYSA-N 3-iodo-4-nitro-2h-indazole Chemical compound [O-][N+](=O)C1=CC=CC2=C1C(I)=NN2 AOTAXYVEONHYHY-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000015320 potassium carbonate Nutrition 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 208000028389 Nerve injury Diseases 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 230000008764 nerve damage Effects 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- HAYGNOATIFULJK-UHFFFAOYSA-N 3-[[3-ethyl-1-[(6-methylpyridin-2-yl)methyl]indazol-4-yl]carbamoyl]imidazo[1,2-a]pyridine-7-carboxylic acid Chemical compound C12=CC=CC(NC(=O)C=3N4C=CC(=CC4=NC=3)C(O)=O)=C2C(CC)=NN1CC1=CC=CC(C)=N1 HAYGNOATIFULJK-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 125000002393 azetidinyl group Chemical group 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 210000001616 monocyte Anatomy 0.000 description 7
- 125000002757 morpholinyl group Chemical group 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 7
- WJFDCFHWFHCLIW-UHFFFAOYSA-N 2-(bromomethyl)-6-methylpyridine Chemical compound CC1=CC=CC(CBr)=N1 WJFDCFHWFHCLIW-UHFFFAOYSA-N 0.000 description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 208000001132 Osteoporosis Diseases 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- DOGXPDFZEQXZDS-UHFFFAOYSA-N imidazo[1,2-a]pyridine-3-carboxylic acid Chemical compound C1=CC=CN2C(C(=O)O)=CN=C21 DOGXPDFZEQXZDS-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
- 238000003760 magnetic stirring Methods 0.000 description 6
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Classifications
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- 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
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Cardiology (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28872909P | 2009-12-21 | 2009-12-21 | |
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| KR101779630B1 (ko) * | 2009-12-21 | 2017-09-18 | 어레이 바이오파마 인크. | ｃＦＭＳ 억제제로서 치환된 Ｎ-（１Ｈ-인다졸-４-일）이미다조［１,２-ａ］피리딘-３-카복사미드 화합물 |
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| WO2017023984A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof |
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| US10231956B2 (en) | 2015-08-03 | 2019-03-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
| WO2017024015A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
| WO2017023993A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-indol-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
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