CA2492723C - Novel 2,5-disubstituted pyrimidine derivatives - Google Patents
Novel 2,5-disubstituted pyrimidine derivatives Download PDFInfo
- Publication number
- CA2492723C CA2492723C CA2492723A CA2492723A CA2492723C CA 2492723 C CA2492723 C CA 2492723C CA 2492723 A CA2492723 A CA 2492723A CA 2492723 A CA2492723 A CA 2492723A CA 2492723 C CA2492723 C CA 2492723C
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- Prior art keywords
- alkyl
- salts
- solvates
- optionally substituted
- compounds
- Prior art date
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- -1 2,5-disubstituted pyrimidine Chemical class 0.000 title claims abstract description 41
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 82
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 12
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 88
- 150000003839 salts Chemical class 0.000 claims description 43
- 239000002904 solvent Substances 0.000 claims description 36
- 239000012453 solvate Substances 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 230000013016 learning Effects 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 7
- 230000015654 memory Effects 0.000 claims description 7
- 238000011321 prophylaxis Methods 0.000 claims description 7
- 229910052723 transition metal Inorganic materials 0.000 claims description 7
- 150000003624 transition metals Chemical class 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 230000008447 perception Effects 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 2
- 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 claims 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 abstract description 12
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 110
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 58
- 238000005160 1H NMR spectroscopy Methods 0.000 description 57
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 40
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 40
- 239000000047 product Substances 0.000 description 40
- 239000000203 mixture Substances 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 229910052786 argon Inorganic materials 0.000 description 20
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 239000003480 eluent Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 239000012153 distilled water Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- LSAKKLSYDAJLJW-UHFFFAOYSA-N 3-(5-bromopyrimidin-2-yl)-1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridine Chemical compound FC1=CC=CC=C1CN1C2=NC=CC=C2C(C=2N=CC(Br)=CN=2)=N1 LSAKKLSYDAJLJW-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 206010012289 Dementia Diseases 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 7
- 238000000825 ultraviolet detection Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- ARGVUMAIXYASDG-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-[5-(2-fluoropyridin-4-yl)pyrimidin-2-yl]pyrazolo[3,4-b]pyridine Chemical compound C1=NC(F)=CC(C=2C=NC(=NC=2)C=2C3=CC=CN=C3N(CC=3C(=CC=CC=3)F)N=2)=C1 ARGVUMAIXYASDG-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- 208000006011 Stroke Diseases 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 150000003278 haem Chemical class 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000008602 contraction Effects 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- YGKPEWRENKJYRP-UHFFFAOYSA-N tributyl-(2-fluoropyridin-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=NC(F)=C1 YGKPEWRENKJYRP-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108010078321 Guanylate Cyclase Proteins 0.000 description 3
- 102000014469 Guanylate cyclase Human genes 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 108090000526 Papain Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 3
- 229940055729 papain Drugs 0.000 description 3
- 235000019834 papain Nutrition 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RMKRIFDFDRKORJ-MRXNPFEDSA-N (3r)-1-[2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]pyrrolidin-3-ol Chemical compound C1[C@H](O)CCN1C1=CN=C(C=2C3=CC=CN=C3N(CC=3C(=CC=CC=3)F)N=2)N=C1 RMKRIFDFDRKORJ-MRXNPFEDSA-N 0.000 description 2
- JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 2
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- UIJXHKXIOCDSEB-MRVPVSSYSA-N tert-butyl (3r)-3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](O)C1 UIJXHKXIOCDSEB-MRVPVSSYSA-N 0.000 description 1
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Classifications
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- 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
-
- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10232572A DE10232572A1 (de) | 2002-07-18 | 2002-07-18 | Neue 2,5-disubstituierte Pyrimidinderivate |
| DE10232572.3 | 2002-07-18 | ||
| PCT/EP2003/007238 WO2004009589A1 (de) | 2002-07-18 | 2003-07-07 | Neue 2,5-disubstituierte pyrimidinderivate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2492723A1 CA2492723A1 (en) | 2004-01-29 |
| CA2492723C true CA2492723C (en) | 2012-09-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2492723A Expired - Fee Related CA2492723C (en) | 2002-07-18 | 2003-07-07 | Novel 2,5-disubstituted pyrimidine derivatives |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US7091198B1 (https=) |
| EP (1) | EP1525202B1 (https=) |
| JP (1) | JP2006502119A (https=) |
| AU (1) | AU2003257437A1 (https=) |
| CA (1) | CA2492723C (https=) |
| DE (2) | DE10232572A1 (https=) |
| ES (1) | ES2256779T3 (https=) |
| WO (1) | WO2004009589A1 (https=) |
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| JP4605952B2 (ja) * | 2001-08-29 | 2011-01-05 | 株式会社日立製作所 | 蓄電装置及びその制御方法 |
| MXPA05011387A (es) * | 2003-04-23 | 2005-12-01 | Pharmacia & Upjohn Co Llc | Pirimidinonas y pirimidinotionas sustituidas. |
| US20050065178A1 (en) * | 2003-09-19 | 2005-03-24 | Anwer Basha | Substituted diazabicycloakane derivatives |
| US7399765B2 (en) | 2003-09-19 | 2008-07-15 | Abbott Laboratories | Substituted diazabicycloalkane derivatives |
| JPWO2005047286A1 (ja) * | 2003-11-13 | 2007-05-31 | 小野薬品工業株式会社 | スピロ複素環化合物 |
| JP2009528703A (ja) * | 2006-03-02 | 2009-08-06 | アイスモス・テクノロジー・リミテッド | 非感光領域に対して高い割合の感光領域を有するフォトダイオード |
| DE102007026392A1 (de) * | 2007-06-06 | 2008-12-11 | Bayer Healthcare Ag | Lösungen für die Perfusion und Konservierung von Organen und Geweben |
| TW201004963A (en) * | 2008-07-03 | 2010-02-01 | Targacept Inc | Derivatives of oxabispidine as neuronal nicotinic acetylcholine receptor ligands |
| US20110053923A1 (en) | 2008-12-22 | 2011-03-03 | Astrazeneca | Chemical compounds 610 |
| DE102010021637A1 (de) | 2010-05-26 | 2011-12-01 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung |
| DE102010040234A1 (de) * | 2010-09-03 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Verfahren zur Herstellung von 5-Flour-1H-pyrazolo[3,4-b]pyridin-3-carbonitril |
| DE102010043380A1 (de) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Benzyl-substituierte Carbamate und ihre Verwendung |
| DE102010043379A1 (de) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 6-Fluor-1H-Pyrazolo[4,3-b]pyridine und ihre Verwendung |
| EP2453000A1 (en) * | 2010-11-08 | 2012-05-16 | Infineum International Limited | Lubricating Oil Composition comprising a hydrogenated imide derived from a Diels-Alder adduct of maleic anhydride and a furan |
| PE20142359A1 (es) | 2011-11-25 | 2015-01-09 | Bayer Pharma AG | Procedimiento de preparacion de 5-fluoro-1h-pirazolopiridinas sustituidas |
| CN105102457A (zh) | 2013-02-21 | 2015-11-25 | 阿德弗里奥药品有限责任公司 | {4,6-二氨基-2-[1-(2-氟苄基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基氨基甲酸甲酯的形式 |
| WO2015106268A1 (en) | 2014-01-13 | 2015-07-16 | Ironwood Pharmaceuticals, Inc. | USE OF sGC STIMULATORS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS |
| CN107580495A (zh) | 2015-05-06 | 2018-01-12 | 拜耳制药股份公司 | 单独和与PDE5抑制剂组合的sGC刺激剂、sGC活化剂用于治疗伴随系统性硬化症(SSc)的指溃疡(DU)的用途 |
| WO2017013010A1 (de) | 2015-07-23 | 2017-01-26 | Bayer Pharma Aktiengesellschaft | Stimulatoren und/oder aktivatoren der löslichen guanylatzyklase (sgc) in kombination mit einem inhibitor der neutralen endopeptidase (nep inhibitor) und/oder einem angiotensin aii-antagonisten und ihre verwendung |
| CN105367569B (zh) * | 2015-11-18 | 2017-10-27 | 浙江京新药业股份有限公司 | 一种化合物及其作为利奥西呱中间体的应用 |
| CN105367567B (zh) * | 2015-11-18 | 2017-11-28 | 浙江京新药业股份有限公司 | 一种化合物及其在制备利奥西呱中的应用 |
| AU2016371762A1 (en) | 2015-12-14 | 2018-06-21 | Cyclerion Therapeutics, Inc. | Use of sGC stimulators for the treatment of gastrointestinal sphincter dysfunction |
| CA3039735A1 (en) | 2016-10-11 | 2018-04-19 | Bayer Pharma Aktiengesellschaft | Combination containing sgc activators and mineralocorticoid receptor antagonists |
| US10918639B2 (en) | 2016-10-11 | 2021-02-16 | Bayer Pharma Aktiengesellschaft | Combination containing SGC stimulators and mineralocorticoid receptor antagonists |
| US11180493B2 (en) | 2016-11-08 | 2021-11-23 | Cyclerion Therapeutics, Inc. | SGC stimulators |
| WO2018111795A2 (en) | 2016-12-13 | 2018-06-21 | Ironwood Pharmaceuticals, Inc. | Use of sgc stimulators for the treatment of esophageal motility disorders |
| CA3100096A1 (en) | 2018-05-15 | 2019-11-21 | Bayer Aktiengesellschaft | 1,3-thiazol-2-yl substituted benzamides for the treatment of diseases associated with nerve fiber sensitization |
| KR20210031931A (ko) | 2018-07-11 | 2021-03-23 | 사이클리온 테라퓨틱스, 인크. | 미토콘드리아 장애의 치료를 위한 sGC 자극제의 용도 |
| WO2020164008A1 (en) | 2019-02-13 | 2020-08-20 | Bayer Aktiengesellschaft | Process for the preparation of porous microparticles |
| CN112457308B (zh) * | 2019-09-09 | 2024-01-02 | 上海长森药业有限公司 | 新型三环芳香杂环化合物，及其制备方法、药物组合物和应用 |
| CN118772140B (zh) * | 2023-04-07 | 2026-04-17 | 四川大学 | 一类化合物及其在治疗hDHODH介导的疾病中的用途 |
Family Cites Families (8)
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|---|---|---|---|---|
| DE19649460A1 (de) | 1996-11-26 | 1998-05-28 | Bayer Ag | Neue substituierte Pyrazolderivate |
| DE19834045A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | (4-Amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridin |
| DE19834047A1 (de) * | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituierte Pyrazolderivate |
| DE19846514A1 (de) * | 1998-10-09 | 2000-04-20 | Bayer Ag | Neue Heterocyclyl-methyl-substituierte Pyrazole |
| DE10054278A1 (de) * | 2000-11-02 | 2002-05-08 | Bayer Ag | Verwendung von Stimulatoren der löslichen Guanylatcyclase zur Behandlung von Osteoporose |
| AR031176A1 (es) * | 2000-11-22 | 2003-09-10 | Bayer Ag | Nuevos derivados de pirazolpiridina sustituidos con piridina |
| JP4295505B2 (ja) * | 2000-11-22 | 2009-07-15 | バイエル アクチェンゲゼルシャフト | 新規なラクタム置換ピラゾロピリジン誘導体 |
| DE10057754A1 (de) * | 2000-11-22 | 2002-05-23 | Bayer Ag | Neue Sulfonamid-substituierte Pyrazolopyridinderivate |
-
2002
- 2002-07-18 DE DE10232572A patent/DE10232572A1/de not_active Withdrawn
-
2003
- 2003-07-07 US US10/521,538 patent/US7091198B1/en not_active Expired - Fee Related
- 2003-07-07 JP JP2004522411A patent/JP2006502119A/ja not_active Ceased
- 2003-07-07 EP EP03764943A patent/EP1525202B1/de not_active Expired - Lifetime
- 2003-07-07 CA CA2492723A patent/CA2492723C/en not_active Expired - Fee Related
- 2003-07-07 WO PCT/EP2003/007238 patent/WO2004009589A1/de not_active Ceased
- 2003-07-07 AU AU2003257437A patent/AU2003257437A1/en not_active Abandoned
- 2003-07-07 ES ES03764943T patent/ES2256779T3/es not_active Expired - Lifetime
- 2003-07-07 DE DE50302202T patent/DE50302202D1/de not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP1525202A1 (de) | 2005-04-27 |
| US7091198B1 (en) | 2006-08-15 |
| DE10232572A1 (de) | 2004-02-05 |
| CA2492723A1 (en) | 2004-01-29 |
| JP2006502119A (ja) | 2006-01-19 |
| AU2003257437A1 (en) | 2004-02-09 |
| WO2004009589A1 (de) | 2004-01-29 |
| US20060167016A1 (en) | 2006-07-27 |
| DE50302202D1 (de) | 2006-04-06 |
| EP1525202B1 (de) | 2006-01-11 |
| ES2256779T3 (es) | 2006-07-16 |
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