CA2102106A1 - Pyrrolidinones - Google Patents
PyrrolidinonesInfo
- Publication number
- CA2102106A1 CA2102106A1 CA002102106A CA2102106A CA2102106A1 CA 2102106 A1 CA2102106 A1 CA 2102106A1 CA 002102106 A CA002102106 A CA 002102106A CA 2102106 A CA2102106 A CA 2102106A CA 2102106 A1 CA2102106 A1 CA 2102106A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- substituted
- compound
- hydrogen
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000004040 pyrrolidinones Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 221
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- -1 2-imidazolyl Chemical group 0.000 claims description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 239000001257 hydrogen Substances 0.000 claims description 45
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 150000002431 hydrogen Chemical group 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 125000001153 fluoro group Chemical group F* 0.000 claims description 22
- 235000019000 fluorine Nutrition 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical class [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 10
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 8
- 230000000172 allergic effect Effects 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 208000026935 allergic disease Diseases 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical class Cl* 0.000 claims description 5
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 5
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 235000017168 chlorine Nutrition 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000005592 polycycloalkyl group Polymers 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 3
- 108010081348 HRT1 protein Hairy Chemical group 0.000 claims description 3
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 3
- XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 claims description 3
- 101100212791 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) YBL068W-A gene Proteins 0.000 claims description 3
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims description 3
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims description 2
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 2
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- ZRSVIQCPYIYIKX-UHFFFAOYSA-N methyl 4-[[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidin-1-yl]methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C(=O)CC(C=2C=C(OC3CCCC3)C(OC)=CC=2)C1 ZRSVIQCPYIYIKX-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 claims description 2
- 230000009466 transformation Effects 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 8
- 102000003390 tumor necrosis factor Human genes 0.000 claims 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- SUXHVTWOXBFQIA-FQEVSTJZSA-N n-[4-[[(4r)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidin-1-yl]methyl]phenyl]acetamide Chemical compound COC1=CC=C([C@H]2CC(=O)N(CC=3C=CC(NC(C)=O)=CC=3)C2)C=C1OC1CCCC1 SUXHVTWOXBFQIA-FQEVSTJZSA-N 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- DBRURKICGBSTER-GOSISDBHSA-N (4s)-1-[(4-aminophenyl)methyl]-4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one Chemical compound COC1=CC=C([C@@H]2CC(=O)N(CC=3C=CC(N)=CC=3)C2)C=C1OC1CCCC1 DBRURKICGBSTER-GOSISDBHSA-N 0.000 claims 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- AFFCCLBPSQWROV-UHFFFAOYSA-N 4-(3-cyclopentyloxy-4-methoxyphenyl)-1-[(2,4-diaminophenyl)methyl]pyrrolidin-2-one Chemical compound COC1=CC=C(C2CC(=O)N(CC=3C(=CC(N)=CC=3)N)C2)C=C1OC1CCCC1 AFFCCLBPSQWROV-UHFFFAOYSA-N 0.000 claims 1
- 101100439664 Arabidopsis thaliana CHR8 gene Proteins 0.000 claims 1
- 102100032404 Cholinesterase Human genes 0.000 claims 1
- 101000943274 Homo sapiens Cholinesterase Chemical group 0.000 claims 1
- GMTVBECLHDYSRJ-UHFFFAOYSA-N n-[3-acetamido-4-[[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidin-1-yl]methyl]phenyl]acetamide Chemical compound COC1=CC=C(C2CC(=O)N(CC=3C(=CC(NC(C)=O)=CC=3)NC(C)=O)C2)C=C1OC1CCCC1 GMTVBECLHDYSRJ-UHFFFAOYSA-N 0.000 claims 1
- SUXHVTWOXBFQIA-HXUWFJFHSA-N n-[4-[[(4s)-4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidin-1-yl]methyl]phenyl]acetamide Chemical compound COC1=CC=C([C@@H]2CC(=O)N(CC=3C=CC(NC(C)=O)=CC=3)C2)C=C1OC1CCCC1 SUXHVTWOXBFQIA-HXUWFJFHSA-N 0.000 claims 1
- TYSMZMFTQVFYKG-UHFFFAOYSA-N n-[4-[[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxopyrrolidin-1-yl]methyl]phenyl]-2-oxopropanamide Chemical compound COC1=CC=C(C2CC(=O)N(CC=3C=CC(NC(=O)C(C)=O)=CC=3)C2)C=C1OC1CCCC1 TYSMZMFTQVFYKG-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 222
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 195
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 193
- 239000000243 solution Substances 0.000 description 124
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 100
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 96
- 239000002904 solvent Substances 0.000 description 83
- 229910001868 water Inorganic materials 0.000 description 77
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 76
- 239000000203 mixture Substances 0.000 description 65
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 56
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- 239000012300 argon atmosphere Substances 0.000 description 45
- 238000003818 flash chromatography Methods 0.000 description 45
- 239000012044 organic layer Substances 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
- 229910052938 sodium sulfate Inorganic materials 0.000 description 41
- 235000011152 sodium sulphate Nutrition 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 239000000284 extract Substances 0.000 description 28
- 229910000027 potassium carbonate Inorganic materials 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 238000010992 reflux Methods 0.000 description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- 239000011347 resin Substances 0.000 description 23
- 229920005989 resin Polymers 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 19
- 238000000746 purification Methods 0.000 description 18
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 17
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 14
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 14
- 241000725303 Human immunodeficiency virus Species 0.000 description 13
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- 230000003197 catalytic effect Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 11
- 210000001616 monocyte Anatomy 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 210000001744 T-lymphocyte Anatomy 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 230000006433 tumor necrosis factor production Effects 0.000 description 9
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 150000001412 amines Chemical class 0.000 description 8
- 208000006673 asthma Diseases 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 206010017533 Fungal infection Diseases 0.000 description 7
- 108010044467 Isoenzymes Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 208000030507 AIDS Diseases 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 108010050619 Monokines Proteins 0.000 description 6
- 102000013967 Monokines Human genes 0.000 description 6
- 206010040070 Septic Shock Diseases 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
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- 235000012222 talc Nutrition 0.000 description 1
- 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 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69462491A | 1991-05-02 | 1991-05-02 | |
| US07/694,624 | 1991-05-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2102106A1 true CA2102106A1 (en) | 1992-11-03 |
Family
ID=24789624
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002102106A Abandoned CA2102106A1 (en) | 1991-05-02 | 1992-05-01 | Pyrrolidinones |
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|---|---|
| EP (1) | EP0584208A1 (cg-RX-API-DMAC10.html) |
| JP (1) | JPH06507405A (cg-RX-API-DMAC10.html) |
| CN (1) | CN1067244A (cg-RX-API-DMAC10.html) |
| AU (1) | AU1917092A (cg-RX-API-DMAC10.html) |
| CA (1) | CA2102106A1 (cg-RX-API-DMAC10.html) |
| IE (1) | IE921376A1 (cg-RX-API-DMAC10.html) |
| MX (1) | MX9202090A (cg-RX-API-DMAC10.html) |
| PT (1) | PT100441A (cg-RX-API-DMAC10.html) |
| WO (1) | WO1992019594A1 (cg-RX-API-DMAC10.html) |
| ZA (1) | ZA923210B (cg-RX-API-DMAC10.html) |
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| US5698711A (en) | 1991-01-28 | 1997-12-16 | Rhone-Poulenc Rorer Limited | Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group |
| GB9311281D0 (en) * | 1993-06-01 | 1993-07-21 | Rhone Poulenc Rorer Ltd | Novel composition of matter |
| GB9212673D0 (en) * | 1992-06-15 | 1992-07-29 | Celltech Ltd | Chemical compounds |
| US5679696A (en) * | 1992-07-28 | 1997-10-21 | Rhone-Poulenc Rorer Limited | Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic-or heteroatom-containing linking group |
| GB9222253D0 (en) * | 1992-10-23 | 1992-12-09 | Celltech Ltd | Chemical compounds |
| CA2400368A1 (en) | 1992-12-02 | 1994-06-09 | Allen J. Duplantier | Catechol diethers as selective pde iv inhibitors |
| US5814651A (en) * | 1992-12-02 | 1998-09-29 | Pfizer Inc. | Catechol diethers as selective PDEIV inhibitors |
| TW263495B (cg-RX-API-DMAC10.html) * | 1992-12-23 | 1995-11-21 | Celltech Ltd | |
| GB9226830D0 (en) * | 1992-12-23 | 1993-02-17 | Celltech Ltd | Chemical compounds |
| US5622977A (en) * | 1992-12-23 | 1997-04-22 | Celltech Therapeutics Limited | Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same |
| GB9304920D0 (en) * | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
| GB9304919D0 (en) * | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
| EP0710109B1 (en) * | 1993-06-18 | 2004-09-15 | Smithkline Beecham Corporation | Method for identifying a PDE IV inhibitor |
| DE69430747T2 (de) | 1993-07-28 | 2003-03-06 | Aventis Pharma Ltd., West Malling | Verbindungen als pde iv und tnf inhibitoren |
| US5665754A (en) * | 1993-09-20 | 1997-09-09 | Glaxo Wellcome Inc. | Substituted pyrrolidines |
| PT730587E (pt) * | 1993-11-26 | 2000-05-31 | Pfizer | 3-aril-2-isoxazolinas como agentes anti-inflamatorios |
| NZ274244A (en) * | 1993-11-26 | 1997-09-22 | Pfizer | Isoxazoline derivatives and medicaments |
| DE69433594T2 (de) * | 1993-12-22 | 2004-08-05 | Celltech R&D Ltd., Slough | Trisubstituierte phenyl-derivate, verfahren zu deren herstellung und deren verwendung als phosphodiesterase (typ iv) hemmstoffe |
| GB9326173D0 (en) * | 1993-12-22 | 1994-02-23 | Celltech Ltd | Chemical compounds and process |
| CA2143143A1 (en) * | 1994-03-08 | 1995-09-09 | Toshihiko Tanaka | 3-phenylpyrrolidine derivatives |
| AU1326795A (en) * | 1994-03-09 | 1995-09-25 | Pfizer Inc. | Isoxazoline compounds as 5-lipoxygenase inhibitors |
| FI963510L (fi) * | 1994-03-09 | 1996-09-06 | Pfizer | Isoksatsoliiniyhdisteitä TNF:n vapautumisen inhibiittoreina |
| US5672622A (en) * | 1994-04-21 | 1997-09-30 | Berlex Laboratories, Inc. | Treatment of multiple sclerosis |
| EP1380291A1 (en) * | 1994-04-21 | 2004-01-14 | Schering Aktiengesellschaft | PDE IV inhibitors for treating multiple sclerosis |
| DE69532238T2 (de) * | 1994-04-21 | 2004-10-21 | Schering Ag | Pde iv-inhibitoren zur behandlung der multiplen sklerose |
| US6060501A (en) * | 1994-06-02 | 2000-05-09 | Schering Aktiengesellschaft | Combined treatment of multiple sclerosis |
| US5998428A (en) * | 1995-05-31 | 1999-12-07 | Smithkline Beecham Corporation | Compounds and methods for treating PDE IV-related diseases |
| US6245774B1 (en) | 1994-06-21 | 2001-06-12 | Celltech Therapeutics Limited | Tri-substituted phenyl or pyridine derivatives |
| US5786354A (en) * | 1994-06-21 | 1998-07-28 | Celltech Therapeutics, Limited | Tri-substituted phenyl derivatives and processes for their preparation |
| GB9412571D0 (en) * | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| GB9412573D0 (en) | 1994-06-22 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| GB9412672D0 (en) * | 1994-06-23 | 1994-08-10 | Celltech Ltd | Chemical compounds |
| US5591776A (en) * | 1994-06-24 | 1997-01-07 | Euro-Celtique, S.A. | Pheynl or benzyl-substituted rolipram-based compounds for and method of inhibiting phosphodiesterase IV |
| US5563143A (en) * | 1994-09-21 | 1996-10-08 | Pfizer Inc. | Catechol diether compounds as inhibitors of TNF release |
| US5665737B1 (en) * | 1994-10-12 | 1999-02-16 | Euro Celtique Sa | Substituted benzoxazoles |
| EP0814809B1 (en) * | 1994-12-13 | 2003-08-13 | Euroceltique S.A. | Aryl thioxanthines |
| IL117090A (en) * | 1995-02-10 | 2000-07-26 | Schering Ag | Pharmaceutical compositions containing oxazolidinone derivatives |
| US6268373B1 (en) | 1995-06-07 | 2001-07-31 | Euro-Celtique S.A. | Trisubstituted thioxanthines |
| US5658940A (en) * | 1995-10-06 | 1997-08-19 | Celgene Corporation | Succinimide and maleimide cytokine inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1350582A (en) * | 1970-07-24 | 1974-04-18 | Ucb Sa | Cerivatives of 2-pyrrolidinone |
| JPS4916872A (cg-RX-API-DMAC10.html) * | 1972-04-21 | 1974-02-14 | ||
| JPS5238227B2 (cg-RX-API-DMAC10.html) * | 1972-06-14 | 1977-09-28 | ||
| JPS5232064B2 (cg-RX-API-DMAC10.html) * | 1972-06-14 | 1977-08-19 | ||
| JPS5182258A (ja) * | 1974-04-25 | 1976-07-19 | Yoshitomi Pharmaceutical | Pirorijinonjudotaino seizoho |
| US4476311A (en) * | 1980-03-12 | 1984-10-09 | The Purdue Frederick Company | Analgesic 4-carboxy-pyrrolidin-2-one compound |
| DE3823299A1 (de) * | 1988-07-07 | 1990-01-11 | Schering Ag | Substituierte phenyl-pyrrolidin-2-one, -oxazolidin-2-one und -imidazolidin-2-one, ihre herstellung sowie verwendung in arzneimitteln |
-
1992
- 1992-04-30 PT PT100441A patent/PT100441A/pt not_active Application Discontinuation
- 1992-05-01 CN CN92104385A patent/CN1067244A/zh active Pending
- 1992-05-01 WO PCT/US1992/003613 patent/WO1992019594A1/en not_active Ceased
- 1992-05-01 JP JP4511481A patent/JPH06507405A/ja active Pending
- 1992-05-01 CA CA002102106A patent/CA2102106A1/en not_active Abandoned
- 1992-05-01 EP EP92911583A patent/EP0584208A1/en not_active Withdrawn
- 1992-05-01 AU AU19170/92A patent/AU1917092A/en not_active Abandoned
- 1992-05-04 ZA ZA923210A patent/ZA923210B/xx unknown
- 1992-05-04 MX MX9202090A patent/MX9202090A/es unknown
- 1992-07-01 IE IE137692A patent/IE921376A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU1917092A (en) | 1992-12-21 |
| PT100441A (pt) | 1993-09-30 |
| ZA923210B (en) | 1993-03-31 |
| EP0584208A4 (cg-RX-API-DMAC10.html) | 1994-03-23 |
| JPH06507405A (ja) | 1994-08-25 |
| IE921376A1 (en) | 1992-11-04 |
| EP0584208A1 (en) | 1994-03-02 |
| WO1992019594A1 (en) | 1992-11-12 |
| CN1067244A (zh) | 1992-12-23 |
| MX9202090A (es) | 1992-11-01 |
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