UA75145C2 - Pyrrolidine oxadiazole and thiadiazole derivatives, pharmaceutical composition based thereon, a method for producing thereof (variants) - Google Patents

Info

Publication number

UA75145C2

UA75145C2 UA20031211897A UA20031211897A UA75145C2 UA 75145 C2 UA75145 C2 UA 75145C2 UA 20031211897 A UA20031211897 A UA 20031211897A UA 20031211897 A UA20031211897 A UA 20031211897A UA 75145 C2 UA75145 C2 UA 75145C2

Authority

UA

Ukraine

Prior art keywords

biphenyl

ylcarbonyl

oxadiazol

methyloxime

pyrrolidinone

Prior art date

2001-06-18

Links

• Espacenet
• Global Dossier
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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
• NXDWUAQXIVWQRL-UHFFFAOYSA-N oxadiazole;pyrrolidine Chemical compound C1CCNC1.C1=CON=N1 NXDWUAQXIVWQRL-UHFFFAOYSA-N 0.000 title abstract description 9
• 150000004867 thiadiazoles Chemical class 0.000 title abstract 2
• 238000004519 manufacturing process Methods 0.000 title description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 259
• 238000000034 method Methods 0.000 claims abstract description 116
• -1 preterm labor Chemical compound 0.000 claims abstract description 69
• 101800000989 Oxytocin Proteins 0.000 claims abstract description 38
• XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 claims abstract description 38
• 102100031951 Oxytocin-neurophysin 1 Human genes 0.000 claims abstract description 38
• 229960001723 oxytocin Drugs 0.000 claims abstract description 38
• XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 claims abstract description 36
• 102000004279 Oxytocin receptors Human genes 0.000 claims abstract description 23
• 108090000876 Oxytocin receptors Proteins 0.000 claims abstract description 23
• 238000011282 treatment Methods 0.000 claims abstract description 23
• 208000005107 Premature Birth Diseases 0.000 claims abstract description 16
• 206010036590 Premature baby Diseases 0.000 claims abstract description 13
• 208000005171 Dysmenorrhea Diseases 0.000 claims abstract description 11
• 206010013935 Dysmenorrhoea Diseases 0.000 claims abstract description 11
• 238000002360 preparation method Methods 0.000 claims abstract description 10
• 230000002265 prevention Effects 0.000 claims abstract description 10
• 230000001404 mediated effect Effects 0.000 claims abstract description 9
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims abstract description 9
• UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims abstract description 4
• 239000004305 biphenyl Substances 0.000 claims description 379
• 125000001072 heteroaryl group Chemical group 0.000 claims description 49
• 125000003118 aryl group Chemical group 0.000 claims description 48
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 48
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 39
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 33
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
• 150000003839 salts Chemical class 0.000 claims description 19
• 239000001257 hydrogen Substances 0.000 claims description 15
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
• 235000010290 biphenyl Nutrition 0.000 claims description 12
• 150000004820 halides Chemical class 0.000 claims description 12
• 229920006395 saturated elastomer Polymers 0.000 claims description 12
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
• 125000005842 heteroatom Chemical group 0.000 claims description 11
• 125000000217 alkyl group Chemical group 0.000 claims description 10
• 210000003754 fetus Anatomy 0.000 claims description 10
• 230000002028 premature Effects 0.000 claims description 10
• 102000005962 receptors Human genes 0.000 claims description 10
• 108020003175 receptors Proteins 0.000 claims description 10
• 125000002252 acyl group Chemical group 0.000 claims description 9
• BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 8
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
• 125000000304 alkynyl group Chemical group 0.000 claims description 8
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
• 125000003277 amino group Chemical group 0.000 claims description 7
• 230000027455 binding Effects 0.000 claims description 7
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
• 125000004442 acylamino group Chemical group 0.000 claims description 5
• 229910052799 carbon Inorganic materials 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 208000035475 disorder Diseases 0.000 claims description 5
• 229940126601 medicinal product Drugs 0.000 claims description 5
• 230000003042 antagnostic effect Effects 0.000 claims description 4
• 230000000903 blocking effect Effects 0.000 claims description 4
• 239000012634 fragment Substances 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 3
• 125000005251 aryl acyl group Chemical group 0.000 claims description 3
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
• 125000006267 biphenyl group Chemical group 0.000 claims description 3
• JUOXYWXXPHUSAI-UHFFFAOYSA-N ethylamino acetate Chemical compound CCNOC(C)=O JUOXYWXXPHUSAI-UHFFFAOYSA-N 0.000 claims description 3
• 125000005253 heteroarylacyl group Chemical group 0.000 claims description 3
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
• 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 2
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
• FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
• KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 2
• 150000001412 amines Chemical group 0.000 claims description 2
• 125000004104 aryloxy group Chemical group 0.000 claims description 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
• 125000000623 heterocyclic group Chemical group 0.000 claims description 2
• ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims 2
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 1
• XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims 1
• WKJOQYHMXRVQDK-UHFFFAOYSA-N 2-(dimethylamino)acetamide Chemical compound CN(C)CC(N)=O WKJOQYHMXRVQDK-UHFFFAOYSA-N 0.000 claims 1
• NIXQLMVKRBUSPF-UHFFFAOYSA-N 3-(dimethylamino)propanamide Chemical compound CN(C)CCC(N)=O NIXQLMVKRBUSPF-UHFFFAOYSA-N 0.000 claims 1
• ZMDWVDOBEGZQJC-UHFFFAOYSA-N 3-piperidin-1-ylpropanamide Chemical compound NC(=O)CCN1CCCCC1 ZMDWVDOBEGZQJC-UHFFFAOYSA-N 0.000 claims 1
• 201000005569 Gout Diseases 0.000 claims 1
• 125000002877 alkyl aryl group Chemical group 0.000 claims 1
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 1
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims 1
• 125000004430 oxygen atom Chemical group O* 0.000 claims 1
• 150000003235 pyrrolidines Chemical class 0.000 abstract description 23
• 230000000694 effects Effects 0.000 abstract description 15
• 208000006399 Premature Obstetric Labor Diseases 0.000 abstract description 12
• 239000005557 antagonist Substances 0.000 abstract description 8
• 230000006806 disease prevention Effects 0.000 abstract 1
• 239000000543 intermediate Substances 0.000 description 134
• 239000000243 solution Substances 0.000 description 110
• 239000000203 mixture Substances 0.000 description 104
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
• 238000005481 NMR spectroscopy Methods 0.000 description 62
• 239000011541 reaction mixture Substances 0.000 description 60
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 56
• 239000007858 starting material Substances 0.000 description 56
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 55
• 238000006243 chemical reaction Methods 0.000 description 46
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 45
• 239000002904 solvent Substances 0.000 description 43
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 38
• 239000000047 product Substances 0.000 description 36
• 238000003818 flash chromatography Methods 0.000 description 34
• 125000001424 substituent group Chemical group 0.000 description 34
• 239000003921 oil Substances 0.000 description 30
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 28
• 235000019341 magnesium sulphate Nutrition 0.000 description 28
• 239000002253 acid Substances 0.000 description 27
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
• 235000019439 ethyl acetate Nutrition 0.000 description 23
• 230000015572 biosynthetic process Effects 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• 239000003795 chemical substances by application Substances 0.000 description 21
• 229910000029 sodium carbonate Inorganic materials 0.000 description 21
• 238000003786 synthesis reaction Methods 0.000 description 21
• 229940125782 compound 2 Drugs 0.000 description 20
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
• 239000012074 organic phase Substances 0.000 description 18
• 229910052700 potassium Inorganic materials 0.000 description 17
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
• 239000012043 crude product Substances 0.000 description 15
• 239000007787 solid Substances 0.000 description 15
• 238000003756 stirring Methods 0.000 description 15
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
• 239000003480 eluent Substances 0.000 description 14
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
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• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 9
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• 150000002825 nitriles Chemical class 0.000 description 9
• 238000000746 purification Methods 0.000 description 9
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
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