HRP20000712A2 - PYRAZOLOPYRIMIDINONE cGMP PDE5 INHIBITORS FOR THE TREATMENT OF SEXUAL DYSFUNCTION - Google Patents

Info

Publication number

HRP20000712A2

HRP20000712A2 HR20000712A HRP20000712A HRP20000712A2 HR P20000712 A2 HRP20000712 A2 HR P20000712A2 HR 20000712 A HR20000712 A HR 20000712A HR P20000712 A HRP20000712 A HR P20000712A HR P20000712 A2 HRP20000712 A2 HR P20000712A2

Authority

HR

Croatia

Prior art keywords

pyridin

mmol

title compound

preparation

compound

Prior art date

1998-04-20

Links

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• 238000011282 treatment Methods 0.000 title claims description 6
• ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 title claims description 5
• 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 title claims 2
• 239000002590 phosphodiesterase V inhibitor Substances 0.000 title claims 2
• 201000001880 Sexual dysfunction Diseases 0.000 title 1
• DOTPSQVYOBAWPQ-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-3-one Chemical compound N1=CN=C2C(=O)N=NC2=C1 DOTPSQVYOBAWPQ-UHFFFAOYSA-N 0.000 title 1
• 231100000872 sexual dysfunction Toxicity 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 618
• 239000000203 mixture Substances 0.000 claims description 248
• 238000000034 method Methods 0.000 claims description 127
• -1 2-(morpholin-4-yl)ethyl Chemical group 0.000 claims description 65
• 238000006243 chemical reaction Methods 0.000 claims description 62
• 150000003839 salts Chemical class 0.000 claims description 45
• 239000012453 solvate Substances 0.000 claims description 31
• 125000000217 alkyl group Chemical group 0.000 claims description 28
• 125000001424 substituent group Chemical group 0.000 claims description 21
• 206010057671 Female sexual dysfunction Diseases 0.000 claims description 17
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 15
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
• 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 14
• 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 14
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
• 229910052739 hydrogen Inorganic materials 0.000 claims description 13
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
• 125000005843 halogen group Chemical group 0.000 claims description 10
• 229910052799 carbon Inorganic materials 0.000 claims description 9
• 238000009472 formulation Methods 0.000 claims description 9
• 238000007363 ring formation reaction Methods 0.000 claims description 9
• 241000124008 Mammalia Species 0.000 claims description 8
• 238000009109 curative therapy Methods 0.000 claims description 8
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000001188 haloalkyl group Chemical group 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
• 230000008569 process Effects 0.000 claims description 8
• 238000011321 prophylaxis Methods 0.000 claims description 8
• 206010002383 Angina Pectoris Diseases 0.000 claims description 7
• 201000001320 Atherosclerosis Diseases 0.000 claims description 7
• 206010071445 Bladder outlet obstruction Diseases 0.000 claims description 7
• 206010007559 Cardiac failure congestive Diseases 0.000 claims description 7
• 206010013935 Dysmenorrhoea Diseases 0.000 claims description 7
• 208000010228 Erectile Dysfunction Diseases 0.000 claims description 7
• 208000010412 Glaucoma Diseases 0.000 claims description 7
• 206010019280 Heart failures Diseases 0.000 claims description 7
• 206010020772 Hypertension Diseases 0.000 claims description 7
• 206010021639 Incontinence Diseases 0.000 claims description 7
• 241001465754 Metazoa Species 0.000 claims description 7
• 208000018262 Peripheral vascular disease Diseases 0.000 claims description 7
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 7
• 208000003800 Urinary Bladder Neck Obstruction Diseases 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 201000009961 allergic asthma Diseases 0.000 claims description 7
• 201000010105 allergic rhinitis Diseases 0.000 claims description 7
• 208000006673 asthma Diseases 0.000 claims description 7
• 230000015572 biosynthetic process Effects 0.000 claims description 7
• 206010006451 bronchitis Diseases 0.000 claims description 7
• 208000023819 chronic asthma Diseases 0.000 claims description 7
• 201000010099 disease Diseases 0.000 claims description 7
• 208000035475 disorder Diseases 0.000 claims description 7
• 206010016256 fatigue Diseases 0.000 claims description 7
• 125000000623 heterocyclic group Chemical group 0.000 claims description 7
• 201000001881 impotence Diseases 0.000 claims description 7
• 230000002028 premature Effects 0.000 claims description 7
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 125000003386 piperidinyl group Chemical group 0.000 claims description 6
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 6
• 230000025033 vasoconstriction Effects 0.000 claims description 6
• 125000002393 azetidinyl group Chemical group 0.000 claims description 5
• 229940079593 drug Drugs 0.000 claims description 5
• 230000005764 inhibitory process Effects 0.000 claims description 5
• 230000008991 intestinal motility Effects 0.000 claims description 5
• 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• UVDGHQGDUKNVRA-UHFFFAOYSA-N 3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-2-(pyridin-2-ylmethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound N1=C(C(NC(=N2)C=3C(=NC=C(C=3)S(=O)(=O)N3CCN(C)CC3)OCCOC)=O)C2=C(CC)N1CC1=CC=CC=N1 UVDGHQGDUKNVRA-UHFFFAOYSA-N 0.000 claims description 3
• MPNWKIDRINJSMK-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethyl-4-oxidopiperazin-4-ium-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-ylmethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound N1=C(C(NC(=N2)C=3C(=NC=C(C=3)S(=O)(=O)N3CC[N+]([O-])(CC)CC3)OCCOC)=O)C2=C(CC)N1CC1=CC=CC=N1 MPNWKIDRINJSMK-UHFFFAOYSA-N 0.000 claims description 3
• QDPNAMRLQRQPMR-UHFFFAOYSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-ylmethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OCCOC)C(C=2NC(=O)C3=NN(CC=4N=CC=CC=4)C(CC)=C3N=2)=C1 QDPNAMRLQRQPMR-UHFFFAOYSA-N 0.000 claims description 3
• WKISNFXGTYNPOO-OAHLLOKOSA-N 3-ethyl-5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-[(2r)-1-methoxypropan-2-yl]oxypyridin-3-yl]-2-methyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound C1CN(CC)CCN1S(=O)(=O)C1=CN=C(O[C@H](C)COC)C(C=2NC(=O)C3=NN(C)C(CC)=C3N=2)=C1 WKISNFXGTYNPOO-OAHLLOKOSA-N 0.000 claims description 3
• ZDRAMJRYRRRBJN-UHFFFAOYSA-N 5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-propyl-2-(pyridin-2-ylmethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound N1=C(C(NC(=N2)C=3C(=NC=C(C=3)S(=O)(=O)N3CCN(C)CC3)OCCOC)=O)C2=C(CCC)N1CC1=CC=CC=N1 ZDRAMJRYRRRBJN-UHFFFAOYSA-N 0.000 claims description 3
• INFYRZAJYPRAJM-UHFFFAOYSA-N 5-[5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridin-3-yl]-3-propyl-2-(pyridin-2-ylmethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound N1=C(C(NC(=N2)C=3C(=NC=C(C=3)S(=O)(=O)N3CCN(CC)CC3)OCCOC)=O)C2=C(CCC)N1CC1=CC=CC=N1 INFYRZAJYPRAJM-UHFFFAOYSA-N 0.000 claims description 3
• 241000282412 Homo Species 0.000 claims description 3
• 125000003342 alkenyl group Chemical group 0.000 claims description 3
• 229910052794 bromium Inorganic materials 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
• 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 2
• XPLAHBQULJNNLX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-3-ol Chemical compound C1=CC=C2OC(O)COC2=C1 XPLAHBQULJNNLX-UHFFFAOYSA-N 0.000 claims description 2
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
• QNQGEMHZYKZNBS-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-(1-pyridin-2-ylethyl)-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2C(C)C1=CC=CC=N1 QNQGEMHZYKZNBS-UHFFFAOYSA-N 0.000 claims description 2
• UACYIMXLEVRBDV-UHFFFAOYSA-N 5-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridin-3-yl]-3-ethyl-2-[(6-methoxypyridin-2-yl)methyl]-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCOC1=NC=C(S(=O)(=O)N2CCN(CC)CC2)C=C1C(NC(=O)C1=N2)=NC1=C(CC)N2CC1=CC=CC(OC)=N1 UACYIMXLEVRBDV-UHFFFAOYSA-N 0.000 claims description 2
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
• 206010047139 Vasoconstriction Diseases 0.000 claims description 2
• 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000001589 carboacyl group Chemical group 0.000 claims description 2
• 125000002541 furyl group Chemical group 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
• 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 claims 2
• 101150098694 PDE5A gene Proteins 0.000 claims 2
• 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 claims 2
• 230000002265 prevention Effects 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 801
• 238000002360 preparation method Methods 0.000 description 467
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 464
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 452
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 349
• 239000007787 solid Substances 0.000 description 206
• 239000000243 solution Substances 0.000 description 201
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 199
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 154
• 235000019439 ethyl acetate Nutrition 0.000 description 118
• 238000010898 silica gel chromatography Methods 0.000 description 99
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 96
• 239000011541 reaction mixture Substances 0.000 description 93
• 238000010828 elution Methods 0.000 description 89
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 81
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 70
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 70
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
• 239000003480 eluent Substances 0.000 description 68
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
• 239000006260 foam Substances 0.000 description 60
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 57
• 239000003921 oil Substances 0.000 description 56
• 235000019198 oils Nutrition 0.000 description 56
• UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 53
• 239000012267 brine Substances 0.000 description 51
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 51
• IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 49
• 239000000725 suspension Substances 0.000 description 45
• 239000012071 phase Substances 0.000 description 44
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
• 238000010992 reflux Methods 0.000 description 43
• 239000000284 extract Substances 0.000 description 41
• 239000000741 silica gel Substances 0.000 description 41
• 229910002027 silica gel Inorganic materials 0.000 description 41
• 238000004587 chromatography analysis Methods 0.000 description 40
• 239000008346 aqueous phase Substances 0.000 description 36
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 35
• 239000000706 filtrate Substances 0.000 description 34
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
• 239000012043 crude product Substances 0.000 description 31
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 30
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• 239000007832 Na2SO4 Substances 0.000 description 27
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
• 229910052938 sodium sulfate Inorganic materials 0.000 description 27
• 235000011152 sodium sulphate Nutrition 0.000 description 27
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 26
• 235000017557 sodium bicarbonate Nutrition 0.000 description 26
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 24
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
• 239000000047 product Substances 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 21
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 21
• 239000000126 substance Substances 0.000 description 21
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 20
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
• 239000010410 layer Substances 0.000 description 20
• 239000012074 organic phase Substances 0.000 description 20
• 239000002904 solvent Substances 0.000 description 20
• 239000012258 stirred mixture Substances 0.000 description 18
• 239000011734 sodium Substances 0.000 description 17
• FRDAATYAJDYRNW-UHFFFAOYSA-N 3-methyl-3-pentanol Chemical compound CCC(C)(O)CC FRDAATYAJDYRNW-UHFFFAOYSA-N 0.000 description 16
• 239000007864 aqueous solution Substances 0.000 description 15
• XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 14
• 102100024085 Alpha-aminoadipic semialdehyde dehydrogenase Human genes 0.000 description 14
• 101710135349 Venom phosphodiesterase Proteins 0.000 description 14
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
• 229910000024 caesium carbonate Inorganic materials 0.000 description 14
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
• 229920006395 saturated elastomer Polymers 0.000 description 14
• 239000002253 acid Substances 0.000 description 13
• 229910021529 ammonia Inorganic materials 0.000 description 13
• 239000002244 precipitate Substances 0.000 description 13
• 229910000029 sodium carbonate Inorganic materials 0.000 description 13
• PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 12
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
• 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 12
• 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 12
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
• 150000001412 amines Chemical group 0.000 description 12
• 238000004128 high performance liquid chromatography Methods 0.000 description 12
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 12
• 229940001593 sodium carbonate Drugs 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 239000000543 intermediate Substances 0.000 description 11
• ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 description 10
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
• 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 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
• 229960000583 acetic acid Drugs 0.000 description 9
• 235000011114 ammonium hydroxide Nutrition 0.000 description 9
• 238000002425 crystallisation Methods 0.000 description 9
• 230000008025 crystallization Effects 0.000 description 9
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 9
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• 230000001419 dependent effect Effects 0.000 description 1
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• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
• 239000012971 dimethylpiperazine Substances 0.000 description 1
• 238000004090 dissolution Methods 0.000 description 1
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• RUCHDNJKZWSJHB-UHFFFAOYSA-N ethyl 1-methyl-5-propylpyrazole-3-carboxylate Chemical compound CCCC1=CC(C(=O)OCC)=NN1C RUCHDNJKZWSJHB-UHFFFAOYSA-N 0.000 description 1
• CRXLZXRQHKPEPI-UHFFFAOYSA-N ethyl 2-(1,3-dimethoxypropan-2-yloxy)-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxylate Chemical compound N1=C(OC(COC)COC)C(C(=O)OCC)=CC(S(=O)(=O)N2CCN(CC)CC2)=C1 CRXLZXRQHKPEPI-UHFFFAOYSA-N 0.000 description 1
• HCLAEHJOSXXVTN-UHFFFAOYSA-N ethyl 2-(2-ethoxyethoxy)-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxylate Chemical compound C1=C(C(=O)OCC)C(OCCOCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 HCLAEHJOSXXVTN-UHFFFAOYSA-N 0.000 description 1
• RAMPAHSDWDDYQU-UHFFFAOYSA-N ethyl 2-(2-methoxyethoxy)-5-nitropyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC([N+]([O-])=O)=CN=C1OCCOC RAMPAHSDWDDYQU-UHFFFAOYSA-N 0.000 description 1
• CUTZNJFNVRXERH-UHFFFAOYSA-N ethyl 2-(2-methoxyethoxy)pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=CN=C1OCCOC CUTZNJFNVRXERH-UHFFFAOYSA-N 0.000 description 1
• YOXICXXCICYQKS-UHFFFAOYSA-N ethyl 2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxylate Chemical compound N1=C(OCC)C(C(=O)OCC)=CC(S(=O)(=O)N2CCN(CC)CC2)=C1 YOXICXXCICYQKS-UHFFFAOYSA-N 0.000 description 1
• ZFMHNOYNFAKUDY-UHFFFAOYSA-N ethyl 2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylpyridine-3-carboxylate Chemical compound N1=C(OCC)C(C(=O)OCC)=CC(S(=O)(=O)N2CCN(C)CC2)=C1 ZFMHNOYNFAKUDY-UHFFFAOYSA-N 0.000 description 1
• NRGZULIPVLBOHE-UHFFFAOYSA-N ethyl 2-ethoxy-5-nitropyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC([N+]([O-])=O)=CN=C1OCC NRGZULIPVLBOHE-UHFFFAOYSA-N 0.000 description 1
• WJIBAKMAWMCQDU-UHFFFAOYSA-N ethyl 2-ethoxypyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=CN=C1OCC WJIBAKMAWMCQDU-UHFFFAOYSA-N 0.000 description 1
• ZPSRHLWRTVNGSM-UHFFFAOYSA-N ethyl 2-methyl-5-propylpyrazole-3-carboxylate Chemical compound CCCC=1C=C(C(=O)OCC)N(C)N=1 ZPSRHLWRTVNGSM-UHFFFAOYSA-N 0.000 description 1
• NIMKIMUBJFWPTD-UHFFFAOYSA-N ethyl 5,5-dimethyl-2,4-dioxohexanoate Chemical compound CCOC(=O)C(=O)CC(=O)C(C)(C)C NIMKIMUBJFWPTD-UHFFFAOYSA-N 0.000 description 1
• CBCJCAKYANYTBJ-UHFFFAOYSA-N ethyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-(1-methylpiperidin-4-yl)oxypyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(S(=O)(=O)N2CCN(CC)CC2)=CN=C1OC1CCN(C)CC1 CBCJCAKYANYTBJ-UHFFFAOYSA-N 0.000 description 1
• IEGDGYGLWILZLJ-UHFFFAOYSA-N ethyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-(2-methoxyethoxy)pyridine-3-carboxylate Chemical compound N1=C(OCCOC)C(C(=O)OCC)=CC(S(=O)(=O)N2CCN(CC)CC2)=C1 IEGDGYGLWILZLJ-UHFFFAOYSA-N 0.000 description 1
• OXOCYPHQWDXTBM-UHFFFAOYSA-N ethyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-(3-methoxypropoxy)pyridine-3-carboxylate Chemical compound N1=C(OCCCOC)C(C(=O)OCC)=CC(S(=O)(=O)N2CCN(CC)CC2)=C1 OXOCYPHQWDXTBM-UHFFFAOYSA-N 0.000 description 1
• QLJKAEXRXFFQIC-UHFFFAOYSA-N ethyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-(oxan-4-yloxy)pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(S(=O)(=O)N2CCN(CC)CC2)=CN=C1OC1CCOCC1 QLJKAEXRXFFQIC-UHFFFAOYSA-N 0.000 description 1
• XSNYQCXIGIJDQN-CQSZACIVSA-N ethyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-[(3r)-oxolan-3-yl]oxypyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(S(=O)(=O)N2CCN(CC)CC2)=CN=C1O[C@@H]1CCOC1 XSNYQCXIGIJDQN-CQSZACIVSA-N 0.000 description 1
• XSNYQCXIGIJDQN-AWEZNQCLSA-N ethyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-[(3s)-oxolan-3-yl]oxypyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(S(=O)(=O)N2CCN(CC)CC2)=CN=C1O[C@H]1CCOC1 XSNYQCXIGIJDQN-AWEZNQCLSA-N 0.000 description 1
• TZEXUTQSDJTATA-UHFFFAOYSA-N ethyl 5-amino-2-ethoxypyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC(N)=CN=C1OCC TZEXUTQSDJTATA-UHFFFAOYSA-N 0.000 description 1
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• FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
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• 238000005984 hydrogenation reaction Methods 0.000 description 1
• IBTWUVRCFHJPKN-UHFFFAOYSA-N hydron;pyridine-3-carboxylic acid;chloride Chemical compound Cl.OC(=O)C1=CC=CN=C1 IBTWUVRCFHJPKN-UHFFFAOYSA-N 0.000 description 1
• XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
• JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
• 238000001727 in vivo Methods 0.000 description 1
• 230000001939 inductive effect Effects 0.000 description 1
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• 238000007918 intramuscular administration Methods 0.000 description 1
• 125000002346 iodo group Chemical group I* 0.000 description 1
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• HRBRJUGUEMJODN-UHFFFAOYSA-N methanol pentane Chemical compound CO.CO.CCCCC HRBRJUGUEMJODN-UHFFFAOYSA-N 0.000 description 1
• MKCLFUHWBHMTRY-UHFFFAOYSA-N methyl 2-propoxypyridine-3-carboxylate Chemical compound CCCOC1=NC=CC=C1C(=O)OC MKCLFUHWBHMTRY-UHFFFAOYSA-N 0.000 description 1
• YJXPDYQUIWDXTI-UHFFFAOYSA-N methyl 5-(4-ethylpiperazin-1-yl)sulfonyl-2-propoxypyridine-3-carboxylate Chemical compound C1=C(C(=O)OC)C(OCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 YJXPDYQUIWDXTI-UHFFFAOYSA-N 0.000 description 1
• ILIZIRZNLURXBS-UHFFFAOYSA-N methyl 5-(4-methylpiperazin-1-yl)sulfonyl-2-propoxypyridine-3-carboxylate Chemical compound C1=C(C(=O)OC)C(OCCC)=NC=C1S(=O)(=O)N1CCN(C)CC1 ILIZIRZNLURXBS-UHFFFAOYSA-N 0.000 description 1
• ZGCWVTIIBZFVRV-UHFFFAOYSA-N methyl 5-amino-2-propoxypyridine-3-carboxylate Chemical compound CCCOC1=NC=C(N)C=C1C(=O)OC ZGCWVTIIBZFVRV-UHFFFAOYSA-N 0.000 description 1
• SBOLYFYRPOUEFU-UHFFFAOYSA-N methyl 5-nitro-2-propoxypyridine-3-carboxylate Chemical compound CCCOC1=NC=C([N+]([O-])=O)C=C1C(=O)OC SBOLYFYRPOUEFU-UHFFFAOYSA-N 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
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• YJRGRZJKGMBHIB-UHFFFAOYSA-N n,n-dimethyl-3-piperazin-1-ylpropan-1-amine Chemical compound CN(C)CCCN1CCNCC1 YJRGRZJKGMBHIB-UHFFFAOYSA-N 0.000 description 1
• SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
• XHXVAJHZTIXQQD-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]-5-[(4-butoxyphenyl)methyl]-2,6-dimethylpyrimidin-4-amine Chemical compound C1=CC(OCCCC)=CC=C1CC1=C(C)N=C(C)N=C1NP(=O)(N1CC1)N1CC1 XHXVAJHZTIXQQD-UHFFFAOYSA-N 0.000 description 1
• BVNIREPGHLFKNZ-UHFFFAOYSA-N n-methylcyclopropanecarboxamide Chemical compound CNC(=O)C1CC1 BVNIREPGHLFKNZ-UHFFFAOYSA-N 0.000 description 1
• 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
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• 238000005580 one pot reaction Methods 0.000 description 1
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• 238000007254 oxidation reaction Methods 0.000 description 1
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• 238000007911 parenteral administration Methods 0.000 description 1
• 210000003899 penis Anatomy 0.000 description 1
• 239000003444 phase transfer catalyst Substances 0.000 description 1
• 235000011007 phosphoric acid Nutrition 0.000 description 1
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• UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
• 108091008695 photoreceptors Proteins 0.000 description 1
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• 235000015320 potassium carbonate Nutrition 0.000 description 1
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• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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• SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 1
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
• STIKETVNLGXQCS-UHFFFAOYSA-N pyridazin-3-ylmethanol Chemical compound OCC1=CC=CN=N1 STIKETVNLGXQCS-UHFFFAOYSA-N 0.000 description 1
• GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
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• CFEXPOIGPXHNAM-UHFFFAOYSA-M sodium;2-(1,3-dimethoxypropan-2-yloxy)-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxylate Chemical compound [Na+].C1CN(CC)CCN1S(=O)(=O)C1=CN=C(OC(COC)COC)C(C([O-])=O)=C1 CFEXPOIGPXHNAM-UHFFFAOYSA-M 0.000 description 1
• XZDHGSJSAAEMQB-UHFFFAOYSA-M sodium;2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylpyridine-3-carboxylate Chemical compound [Na+].C1=C(C([O-])=O)C(OCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 XZDHGSJSAAEMQB-UHFFFAOYSA-M 0.000 description 1
• MVFQAAOBHFCZEU-UHFFFAOYSA-M sodium;5-(4-ethylpiperazin-1-yl)sulfonyl-2-(1-methylpiperidin-4-yl)oxypyridine-3-carboxylate Chemical compound [Na+].C1CN(CC)CCN1S(=O)(=O)C(C=C1C([O-])=O)=CN=C1OC1CCN(C)CC1 MVFQAAOBHFCZEU-UHFFFAOYSA-M 0.000 description 1
• QAUXNYQUWJTZGD-UHFFFAOYSA-M sodium;5-(4-ethylpiperazin-1-yl)sulfonyl-2-(oxan-4-yloxy)pyridine-3-carboxylate Chemical compound [Na+].C1CN(CC)CCN1S(=O)(=O)C(C=C1C([O-])=O)=CN=C1OC1CCOCC1 QAUXNYQUWJTZGD-UHFFFAOYSA-M 0.000 description 1
• YCOGRNHGLLVACL-UHFFFAOYSA-M sodium;5-(4-ethylpiperazin-1-yl)sulfonyl-2-(propylamino)pyridine-3-carboxylate Chemical compound [Na+].C1=C(C([O-])=O)C(NCCC)=NC=C1S(=O)(=O)N1CCN(CC)CC1 YCOGRNHGLLVACL-UHFFFAOYSA-M 0.000 description 1
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• HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 description 1
• 238000010998 test method Methods 0.000 description 1
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• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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• GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
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• 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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