NO972236L - Dihydropyrimidiner og anvendelse derav - Google Patents
Dihydropyrimidiner og anvendelse deravInfo
- Publication number
- NO972236L NO972236L NO972236A NO972236A NO972236L NO 972236 L NO972236 L NO 972236L NO 972236 A NO972236 A NO 972236A NO 972236 A NO972236 A NO 972236A NO 972236 L NO972236 L NO 972236L
- Authority
- NO
- Norway
- Prior art keywords
- branched
- mmol
- straight
- methoxycarbonyl
- monofluoroalkyl
- Prior art date
Links
- 239000000203 mixture Substances 0.000 claims description 217
- 150000001875 compounds Chemical class 0.000 claims description 199
- -1 methylenedioxy group Chemical group 0.000 claims description 143
- 239000007787 solid Substances 0.000 claims description 142
- 238000000034 method Methods 0.000 claims description 60
- 125000000304 alkynyl group Chemical group 0.000 claims description 50
- 125000003342 alkenyl group Chemical group 0.000 claims description 48
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 46
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 42
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 125000004076 pyridyl group Chemical group 0.000 claims description 37
- 125000002541 furyl group Chemical group 0.000 claims description 36
- 125000002883 imidazolyl group Chemical group 0.000 claims description 36
- 125000001041 indolyl group Chemical group 0.000 claims description 36
- 125000001544 thienyl group Chemical group 0.000 claims description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 125000001624 naphthyl group Chemical group 0.000 claims description 32
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 27
- 210000001519 tissue Anatomy 0.000 claims description 25
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 24
- 210000001635 urinary tract Anatomy 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 claims description 19
- 229960004039 finasteride Drugs 0.000 claims description 19
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 15
- 241000700159 Rattus Species 0.000 claims description 14
- 239000003937 drug carrier Substances 0.000 claims description 14
- 206010003119 arrhythmia Diseases 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 230000036772 blood pressure Effects 0.000 claims description 12
- 235000012000 cholesterol Nutrition 0.000 claims description 12
- 201000001881 impotence Diseases 0.000 claims description 12
- 230000004410 intraocular pressure Effects 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- 210000002460 smooth muscle Anatomy 0.000 claims description 10
- 230000008485 antagonism Effects 0.000 claims description 9
- 230000002040 relaxant effect Effects 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 101100295738 Gallus gallus COR3 gene Proteins 0.000 claims description 6
- 229940123934 Reductase inhibitor Drugs 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 239000000829 suppository Substances 0.000 claims description 3
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 2
- MZAGXDHQGXUDDX-JSRXJHBZSA-N (e,2z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enamide Chemical compound [O-][N+](=O)C(C)C(/CC)=C/C(=N/O)/C(N)=O MZAGXDHQGXUDDX-JSRXJHBZSA-N 0.000 claims description 2
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004001 thioalkyl group Chemical group 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 101100294106 Caenorhabditis elegans nhr-3 gene Proteins 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 342
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 303
- 239000000243 solution Substances 0.000 description 249
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 200
- 239000002904 solvent Substances 0.000 description 200
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 191
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 158
- 235000019439 ethyl acetate Nutrition 0.000 description 140
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 135
- 239000000047 product Substances 0.000 description 133
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 120
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 110
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 105
- 239000000741 silica gel Substances 0.000 description 94
- 229910002027 silica gel Inorganic materials 0.000 description 94
- 239000003921 oil Substances 0.000 description 87
- 235000019198 oils Nutrition 0.000 description 87
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 83
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 81
- 238000004458 analytical method Methods 0.000 description 80
- 229910001868 water Inorganic materials 0.000 description 72
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 69
- 239000003480 eluent Substances 0.000 description 67
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 63
- 238000010992 reflux Methods 0.000 description 61
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
- 238000005160 1H NMR spectroscopy Methods 0.000 description 54
- 239000011541 reaction mixture Substances 0.000 description 53
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 51
- 238000004440 column chromatography Methods 0.000 description 49
- 238000003756 stirring Methods 0.000 description 47
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 44
- 238000003818 flash chromatography Methods 0.000 description 43
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000011734 sodium Substances 0.000 description 39
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 239000000843 powder Substances 0.000 description 33
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 31
- 229910021529 ammonia Inorganic materials 0.000 description 31
- 108020003175 receptors Proteins 0.000 description 31
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 30
- 102000005962 receptors Human genes 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 239000012043 crude product Substances 0.000 description 27
- 229910004298 SiO 2 Inorganic materials 0.000 description 26
- 239000000284 extract Substances 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 239000000725 suspension Substances 0.000 description 24
- 239000010410 layer Substances 0.000 description 23
- 229910000027 potassium carbonate Inorganic materials 0.000 description 22
- 238000001914 filtration Methods 0.000 description 21
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 21
- 239000012267 brine Substances 0.000 description 20
- 235000011181 potassium carbonates Nutrition 0.000 description 20
- 238000000746 purification Methods 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 19
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 150000003840 hydrochlorides Chemical class 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000005557 antagonist Substances 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 14
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 14
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 13
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000012300 argon atmosphere Substances 0.000 description 12
- HRWBYLLDHOHKKE-UHFFFAOYSA-N methyl 1-(3-aminopropyl)-4-phenylpiperidine-4-carboxylate Chemical compound C=1C=CC=CC=1C1(C(=O)OC)CCN(CCCN)CC1 HRWBYLLDHOHKKE-UHFFFAOYSA-N 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- 239000012258 stirred mixture Substances 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 239000006188 syrup Substances 0.000 description 11
- 235000020357 syrup Nutrition 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000012458 free base Substances 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 10
- WYJZKSPZJQCMII-UHFFFAOYSA-N 3-(4-pyridin-2-ylpiperidin-1-yl)propan-1-amine Chemical compound C1CN(CCCN)CCC1C1=CC=CC=N1 WYJZKSPZJQCMII-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- MDFRYRPNRLLJHT-UHFFFAOYSA-N methyl carbamimidate;sulfuric acid Chemical compound COC(N)=N.OS(O)(=O)=O MDFRYRPNRLLJHT-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000012746 preparative thin layer chromatography Methods 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 239000002299 complementary DNA Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- KUISDPUHRPZRFF-UHFFFAOYSA-N methyl 4-phenylpiperidine-4-carboxylate Chemical compound C=1C=CC=CC=1C1(C(=O)OC)CCNCC1 KUISDPUHRPZRFF-UHFFFAOYSA-N 0.000 description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
- 239000002480 mineral oil Substances 0.000 description 8
- 235000010446 mineral oil Nutrition 0.000 description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 7
- UQQYXHHJWCUHTL-UHFFFAOYSA-N 2-cyanoethyl 6-ethyl-2-methoxy-4-(4-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1C(OC)=NC(CC)=C(C(=O)OCCC#N)C1C1=CC=C([N+]([O-])=O)C=C1 UQQYXHHJWCUHTL-UHFFFAOYSA-N 0.000 description 7
- KVNQCSIGNRPHHM-UHFFFAOYSA-N 2-piperidin-4-ylpyridine Chemical compound C1CNCCC1C1=CC=CC=N1 KVNQCSIGNRPHHM-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 7
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 150000002466 imines Chemical class 0.000 description 7
- 102000042567 non-coding RNA Human genes 0.000 description 7
- 108091027963 non-coding RNA Proteins 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 235000009518 sodium iodide Nutrition 0.000 description 7
- OGZAFBXJGQWZRZ-UHFFFAOYSA-N 2-cyanoethyl 3-[(4-nitrophenyl)methylidene]-4-oxopentanoate Chemical compound N#CCCOC(=O)CC(C(=O)C)=CC1=CC=C([N+]([O-])=O)C=C1 OGZAFBXJGQWZRZ-UHFFFAOYSA-N 0.000 description 6
- PQIYSSSTRHVOBW-UHFFFAOYSA-N 3-bromopropan-1-amine;hydron;bromide Chemical compound Br.NCCCBr PQIYSSSTRHVOBW-UHFFFAOYSA-N 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 6
- RRZFDFYIDRCBCQ-UHFFFAOYSA-N 5-methyl-2,1,3-benzoxadiazole Chemical compound C1=C(C)C=CC2=NON=C21 RRZFDFYIDRCBCQ-UHFFFAOYSA-N 0.000 description 6
- JCDNJBPDDIPKQT-UHFFFAOYSA-N 5-o-methyl 3-o-(4-nitrophenyl) 2-[(4-methoxyphenyl)methylsulfanyl]-6-methyl-4-(4-nitrophenyl)-4h-pyrimidine-3,5-dicarboxylate Chemical compound C=1C=C([N+]([O-])=O)C=CC=1OC(=O)N1C(C=2C=CC(=CC=2)[N+]([O-])=O)C(C(=O)OC)=C(C)N=C1SCC1=CC=C(OC)C=C1 JCDNJBPDDIPKQT-UHFFFAOYSA-N 0.000 description 6
- UINJKXRLXUUEIS-UHFFFAOYSA-N 5-o-methyl 3-o-(4-nitrophenyl) 2-methoxy-6-(methoxymethyl)-4-(3,4,5-trifluorophenyl)-4h-pyrimidine-3,5-dicarboxylate Chemical compound COC1=NC(COC)=C(C(=O)OC)C(C=2C=C(F)C(F)=C(F)C=2)N1C(=O)OC1=CC=C([N+]([O-])=O)C=C1 UINJKXRLXUUEIS-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- FQMGLMFVLZFNJU-UHFFFAOYSA-N methyl 2-methoxy-6-(methoxymethyl)-4-(3,4,5-trifluorophenyl)-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1C(OC)=NC(COC)=C(C(=O)OC)C1C1=CC(F)=C(F)C(F)=C1 FQMGLMFVLZFNJU-UHFFFAOYSA-N 0.000 description 6
- DBSBBSVVUVSZRB-UHFFFAOYSA-N methyl 4-(3,4-difluorophenyl)-2-methoxy-6-(methoxymethyl)-1,4-dihydropyrimidine-5-carboxylate Chemical compound N1C(OC)=NC(COC)=C(C(=O)OC)C1C1=CC=C(F)C(F)=C1 DBSBBSVVUVSZRB-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 description 6
- NMXHPSVMXOESKU-UHFFFAOYSA-N 2-cyanoethyl 3-oxopentanoate Chemical compound CCC(=O)CC(=O)OCCC#N NMXHPSVMXOESKU-UHFFFAOYSA-N 0.000 description 5
- JPHKMYXKNKLNDF-UHFFFAOYSA-N 3,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1F JPHKMYXKNKLNDF-UHFFFAOYSA-N 0.000 description 5
- JKLWUGFUTWTCLP-UHFFFAOYSA-N 5-o-methyl 3-o-(4-nitrophenyl) 4-(3,4-difluorophenyl)-2-methoxy-6-methyl-4h-pyrimidine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)N=C(OC)N(C(=O)OC=2C=CC(=CC=2)[N+]([O-])=O)C1C1=CC=C(F)C(F)=C1 JKLWUGFUTWTCLP-UHFFFAOYSA-N 0.000 description 5
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- BFIUMOBOZAVTRR-UHFFFAOYSA-N methyl 2-[(4-methoxyphenyl)methylsulfanyl]-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyrimidine-5-carboxylate Chemical compound COC(=O)C1=C(C)N=C(SCC=2C=CC(OC)=CC=2)NC1C1=CC=C([N+]([O-])=O)C=C1 BFIUMOBOZAVTRR-UHFFFAOYSA-N 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- KFUYABXCXWEECZ-UHFFFAOYSA-N methyl 3-(3,4-difluorophenyl)-2-methoxy-6-methyl-4h-pyrimidine-5-carboxylate Chemical compound C1C(C(=O)OC)=C(C)N=C(OC)N1C1=CC=C(F)C(F)=C1 KFUYABXCXWEECZ-UHFFFAOYSA-N 0.000 description 1
- SEQNFEUXJQBTJS-UHFFFAOYSA-N methyl 3-(5-bromopentyl)-4-(3,4-difluorophenyl)-2,6-dimethyl-4h-pyrimidine-5-carboxylate Chemical compound COC(=O)C1=C(C)N=C(C)N(CCCCCBr)C1C1=CC=C(F)C(F)=C1 SEQNFEUXJQBTJS-UHFFFAOYSA-N 0.000 description 1
- BIWQCUBHYGNKRE-HSLMYDHPSA-N methyl 3-[(4s)-5-bromo-4-methylpentyl]-4-(3,4-difluorophenyl)-2,6-dimethyl-4h-pyrimidine-5-carboxylate Chemical compound COC(=O)C1=C(C)N=C(C)N(CCC[C@H](C)CBr)C1C1=CC=C(F)C(F)=C1 BIWQCUBHYGNKRE-HSLMYDHPSA-N 0.000 description 1
- QQILOEAPBDKCIQ-UHFFFAOYSA-N methyl 3-[[3-(bromomethyl)phenyl]methyl]-4-(3,4-difluorophenyl)-2,6-dimethyl-4h-pyrimidine-5-carboxylate Chemical compound C=1C=C(F)C(F)=CC=1C1C(C(=O)OC)=C(C)N=C(C)N1CC1=CC=CC(CBr)=C1 QQILOEAPBDKCIQ-UHFFFAOYSA-N 0.000 description 1
- RTUICKDSUGAXIU-UHFFFAOYSA-N methyl 4-(1-benzofuran-5-yl)-2-methoxy-6-methyl-1,4-dihydropyrimidine-5-carboxylate Chemical compound COC(=O)C1=C(C)N=C(OC)NC1C1=CC=C(OC=C2)C2=C1 RTUICKDSUGAXIU-UHFFFAOYSA-N 0.000 description 1
- MTONKBNJZCLTNO-UHFFFAOYSA-N methyl 4-(2,1,3-benzoxadiazol-5-yl)-2-methoxy-6-methyl-1,4-dihydropyrimidine-5-carboxylate Chemical compound COC(=O)C1=C(C)N=C(OC)NC1C1=CC2=NON=C2C=C1 MTONKBNJZCLTNO-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
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- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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- C—CHEMISTRY; METALLURGY
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
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- 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
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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US34061194A | 1994-11-16 | 1994-11-16 | |
PCT/US1995/015025 WO1996014846A1 (en) | 1994-11-16 | 1995-11-16 | Dihydropyrimidines and uses thereof |
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NO972236D0 NO972236D0 (no) | 1997-05-15 |
NO972236L true NO972236L (no) | 1997-07-01 |
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NO972236A NO972236L (no) | 1994-11-16 | 1997-05-15 | Dihydropyrimidiner og anvendelse derav |
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EP (1) | EP0790826A4 (et) |
JP (1) | JP3200070B2 (et) |
KR (1) | KR970706823A (et) |
CN (1) | CN1173132A (et) |
AR (1) | AR005238A1 (et) |
AU (1) | AU714640B2 (et) |
BG (1) | BG101607A (et) |
BR (1) | BR9509700A (et) |
CA (1) | CA2205384C (et) |
CO (1) | CO4950529A1 (et) |
CZ (1) | CZ151297A3 (et) |
EE (1) | EE9700209A (et) |
FI (1) | FI972087A (et) |
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IS (1) | IS4481A (et) |
MD (1) | MD970227A (et) |
MX (1) | MX9703518A (et) |
NO (1) | NO972236L (et) |
NZ (1) | NZ297278A (et) |
PL (1) | PL320263A1 (et) |
SK (1) | SK60097A3 (et) |
WO (1) | WO1996014846A1 (et) |
YU (1) | YU60696A (et) |
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1995
- 1995-11-16 PL PL95320263A patent/PL320263A1/xx unknown
- 1995-11-16 JP JP51635496A patent/JP3200070B2/ja not_active Expired - Fee Related
- 1995-11-16 SK SK600-97A patent/SK60097A3/sk unknown
- 1995-11-16 KR KR1019970703311A patent/KR970706823A/ko not_active Application Discontinuation
- 1995-11-16 EP EP95940748A patent/EP0790826A4/en not_active Withdrawn
- 1995-11-16 NZ NZ297278A patent/NZ297278A/xx unknown
- 1995-11-16 MX MX9703518A patent/MX9703518A/es unknown
- 1995-11-16 WO PCT/US1995/015025 patent/WO1996014846A1/en not_active Application Discontinuation
- 1995-11-16 MD MD97-0227A patent/MD970227A/ro unknown
- 1995-11-16 EE EE9700209A patent/EE9700209A/et unknown
- 1995-11-16 BR BR9509700A patent/BR9509700A/pt not_active Application Discontinuation
- 1995-11-16 CN CN95197348A patent/CN1173132A/zh active Pending
- 1995-11-16 CA CA002205384A patent/CA2205384C/en not_active Expired - Fee Related
- 1995-11-16 AU AU42398/96A patent/AU714640B2/en not_active Ceased
- 1995-11-16 CZ CZ971512A patent/CZ151297A3/cs unknown
- 1995-11-16 HU HU9801222A patent/HUT77941A/hu unknown
-
1996
- 1996-11-15 AR ARP960105207A patent/AR005238A1/es unknown
- 1996-11-15 YU YU60696A patent/YU60696A/sh unknown
- 1996-11-15 CO CO96060341A patent/CO4950529A1/es unknown
-
1997
- 1997-05-12 IS IS4481A patent/IS4481A/is unknown
- 1997-05-15 NO NO972236A patent/NO972236L/no unknown
- 1997-05-15 FI FI972087A patent/FI972087A/fi unknown
- 1997-06-12 BG BG101607A patent/BG101607A/xx unknown
- 1997-11-26 US US08/978,682 patent/US5942517A/en not_active Expired - Fee Related
-
1999
- 1999-04-14 US US09/291,553 patent/US6248747B1/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
PL320263A1 (en) | 1997-09-15 |
JPH10510247A (ja) | 1998-10-06 |
AU4239896A (en) | 1996-06-06 |
MX9703518A (es) | 1997-08-30 |
US5942517A (en) | 1999-08-24 |
NZ297278A (en) | 1999-06-29 |
US6248747B1 (en) | 2001-06-19 |
CZ151297A3 (cs) | 1998-07-15 |
EE9700209A (et) | 1998-04-15 |
EP0790826A1 (en) | 1997-08-27 |
HUT77941A (hu) | 1998-12-28 |
AU714640B2 (en) | 2000-01-06 |
BR9509700A (pt) | 1998-11-03 |
BG101607A (en) | 1998-02-27 |
CO4950529A1 (es) | 2000-09-01 |
WO1996014846A1 (en) | 1996-05-23 |
CA2205384C (en) | 2004-06-29 |
AR005238A1 (es) | 1999-04-28 |
KR970706823A (ko) | 1997-12-01 |
IS4481A (is) | 1997-05-12 |
JP3200070B2 (ja) | 2001-08-20 |
CN1173132A (zh) | 1998-02-11 |
SK60097A3 (en) | 1998-01-14 |
FI972087A0 (fi) | 1997-05-15 |
YU60696A (sh) | 1998-12-23 |
CA2205384A1 (en) | 1996-05-23 |
FI972087A (fi) | 1997-07-14 |
EP0790826A4 (en) | 1998-11-11 |
NO972236D0 (no) | 1997-05-15 |
MD970227A (ro) | 1999-05-31 |
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