SK166595A3 - Imides as inhibitors of tnp-alpha, preparation method thereof, pharmaceutical agent and use - Google Patents
Imides as inhibitors of tnp-alpha, preparation method thereof, pharmaceutical agent and use Download PDFInfo
- Publication number
- SK166595A3 SK166595A3 SK1665-95A SK166595A SK166595A3 SK 166595 A3 SK166595 A3 SK 166595A3 SK 166595 A SK166595 A SK 166595A SK 166595 A3 SK166595 A3 SK 166595A3
- Authority
- SK
- Slovakia
- Prior art keywords
- group
- alkyl
- carbon atoms
- compound
- alkoxy
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 12
- 239000003112 inhibitor Substances 0.000 title abstract description 3
- 150000003949 imides Chemical class 0.000 title description 6
- 239000008177 pharmaceutical agent Substances 0.000 title 1
- -1 Cyclic imides Chemical class 0.000 claims abstract description 141
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 78
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 72
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims abstract description 62
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 60
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 49
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 48
- 125000001424 substituent group Chemical group 0.000 claims abstract description 41
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 39
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 36
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims abstract description 32
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 30
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 27
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 22
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 18
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims abstract description 16
- 230000010076 replication Effects 0.000 claims abstract description 12
- 229930192474 thiophene Natural products 0.000 claims abstract description 9
- 125000002541 furyl group Chemical group 0.000 claims abstract description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims abstract description 5
- 125000001980 alanyl group Chemical group 0.000 claims abstract description 4
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims abstract description 4
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims abstract description 4
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims abstract description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 4
- 125000001041 indolyl group Chemical group 0.000 claims abstract description 4
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims abstract description 4
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims abstract description 4
- 125000001998 leucyl group Chemical group 0.000 claims abstract description 4
- 125000001288 lysyl group Chemical group 0.000 claims abstract description 4
- 125000002073 methionyl group Chemical group 0.000 claims abstract description 4
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 4
- 125000005493 quinolyl group Chemical group 0.000 claims abstract description 4
- 125000002072 seryl group Chemical group 0.000 claims abstract description 4
- 125000001239 threonyl group Chemical group 0.000 claims abstract description 4
- 125000002233 tyrosyl group Chemical group 0.000 claims abstract description 4
- 125000002114 valyl group Chemical group 0.000 claims abstract description 4
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 114
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 76
- 238000000034 method Methods 0.000 claims description 73
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 44
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 43
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 41
- 125000004742 propyloxycarbonyl group Chemical group 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 238000010992 reflux Methods 0.000 claims description 25
- 241000124008 Mammalia Species 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 13
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 8
- 230000001177 retroviral effect Effects 0.000 claims description 7
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 4
- QGLQAPPNLSDXHB-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)-3-phenylpropanamide Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C(=O)N)CC1=CC=CC=C1 QGLQAPPNLSDXHB-UHFFFAOYSA-N 0.000 claims description 4
- QQNDEDWAPQTWHF-UHFFFAOYSA-N 6-(2,6-dioxopiperidin-3-yl)pyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C1C2=NC=CC=C2C(=O)N1C1CCC(=O)NC1=O QQNDEDWAPQTWHF-UHFFFAOYSA-N 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- FRFCSAWULULVRP-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)benzo[e]isoindole-1,3-dione Chemical compound O=C1C(C2=CC=CC=C2C=C2)=C2C(=O)N1C1CCC(=O)NC1=O FRFCSAWULULVRP-UHFFFAOYSA-N 0.000 claims description 3
- VYIBCOSBNVFEIW-UHFFFAOYSA-N 3-phenylpropanamide Chemical compound NC(=O)CCC1=CC=CC=C1 VYIBCOSBNVFEIW-UHFFFAOYSA-N 0.000 claims description 3
- GHTLZEXBRLQMFS-UHFFFAOYSA-N methyl 3-(3,4-dimethoxyphenyl)-3-(1,3-dioxoisoindol-2-yl)propanoate Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(CC(=O)OC)C1=CC=C(OC)C(OC)=C1 GHTLZEXBRLQMFS-UHFFFAOYSA-N 0.000 claims description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 2
- MFTBZAQYQVSYJB-UHFFFAOYSA-N 2-amino-n-(2,6-dioxopiperidin-3-yl)-3-phenylpropanamide Chemical compound C1CC(=O)NC(=O)C1NC(=O)C(N)CC1=CC=CC=C1 MFTBZAQYQVSYJB-UHFFFAOYSA-N 0.000 claims description 2
- VUAMNSYJJRFBMG-UHFFFAOYSA-N 5-(2,6-dioxopiperidin-3-yl)-1h-pyrrolo[3,4-d]imidazole-4,6-dione Chemical compound O=C1C=2NC=NC=2C(=O)N1C1CCC(=O)NC1=O VUAMNSYJJRFBMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 2
- 229960003433 thalidomide Drugs 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 3
- 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 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 2
- ZIMWCUUEMGFXNW-VIFPVBQESA-N 2-[[(1s)-4-amino-1-carboxy-4-oxobutyl]carbamoyl]benzoic acid Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)C1=CC=CC=C1C(O)=O ZIMWCUUEMGFXNW-VIFPVBQESA-N 0.000 claims 1
- JOAOKNHCUKCBBE-VIFPVBQESA-N 2-[[(2s)-1-amino-4-carboxy-1-oxobutan-2-yl]carbamoyl]benzoic acid Chemical compound OC(=O)CC[C@@H](C(=O)N)NC(=O)C1=CC=CC=C1C(O)=O JOAOKNHCUKCBBE-VIFPVBQESA-N 0.000 claims 1
- GKPXSGPDRIUIAD-UHFFFAOYSA-N 3-(3,4-dimethoxyphenyl)-3-(1,3-dioxoisoindol-2-yl)propanamide Chemical compound C1=C(OC)C(OC)=CC=C1C(CC(N)=O)N1C(=O)C2=CC=CC=C2C1=O GKPXSGPDRIUIAD-UHFFFAOYSA-N 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 claims 1
- 108090000790 Enzymes Proteins 0.000 claims 1
- 108700012920 TNF Proteins 0.000 claims 1
- 230000003247 decreasing effect Effects 0.000 claims 1
- KHSUAOZAHBLWRE-UHFFFAOYSA-N methyl 3-(3,4-diethoxyphenyl)-3-(1,3-dioxoisoindol-2-yl)propanoate Chemical compound C1=C(OCC)C(OCC)=CC=C1C(CC(=O)OC)N1C(=O)C2=CC=CC=C2C1=O KHSUAOZAHBLWRE-UHFFFAOYSA-N 0.000 claims 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims 1
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- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 179
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 106
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- 235000019439 ethyl acetate Nutrition 0.000 description 30
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- VRHAQNTWKSVEEC-UHFFFAOYSA-N ethyl 1,3-dioxoisoindole-2-carboxylate Chemical compound C1=CC=C2C(=O)N(C(=O)OCC)C(=O)C2=C1 VRHAQNTWKSVEEC-UHFFFAOYSA-N 0.000 description 24
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Classifications
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P17/00—Drugs for dermatological disorders
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/06—Antipsoriatics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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Applications Claiming Priority (2)
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| US8751093A | 1993-07-02 | 1993-07-02 | |
| PCT/US1994/007411 WO1995001348A2 (en) | 1993-07-02 | 1994-07-01 | Imides as inhibitors of tnp alpha |
Publications (1)
| Publication Number | Publication Date |
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| SK166595A3 true SK166595A3 (en) | 1997-01-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| SK1665-95A SK166595A3 (en) | 1993-07-02 | 1994-07-01 | Imides as inhibitors of tnp-alpha, preparation method thereof, pharmaceutical agent and use |
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| EP1661566A3 (en) * | 1996-08-05 | 2008-04-16 | Myriad Genetics, Inc. | Use of beta-sheet mimetics as protease and kinase inhibitors and as inhibitors of transcription factors |
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| KR19980074060A (ko) * | 1997-03-21 | 1998-11-05 | 김윤배 | 신규한 치환된 3,4-디알콕시페닐 유도체 |
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| US6831057B2 (en) | 1997-10-28 | 2004-12-14 | The University Of North Carolina At Chapel Hill | Use of NF-κB inhibition in combination therapy for cancer |
| US5955476A (en) * | 1997-11-18 | 1999-09-21 | Celgene Corporation | Substituted 2-(2,6-dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing inflammatory cytokine levels |
| EP1710242A1 (en) * | 1997-11-18 | 2006-10-11 | Celgene Corporation | Substituted 2-(2,6-Dioxo-3-Fluoropiperidine-3-YL)-Isoindolines and their use to reduce TNF-alpha levels |
| EP1064277B1 (en) | 1998-03-16 | 2005-06-15 | Celgene Corporation | 2-(2,6-dioxopiperidin-3-yl)isoindoline derivatives, their preparation and their use as inhibitors of inflammatory cytokines |
| US6020358A (en) * | 1998-10-30 | 2000-02-01 | Celgene Corporation | Substituted phenethylsulfones and method of reducing TNFα levels |
| US7629360B2 (en) * | 1999-05-07 | 2009-12-08 | Celgene Corporation | Methods for the treatment of cachexia and graft v. host disease |
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| DE10053275A1 (de) * | 2000-10-27 | 2002-05-02 | Dresden Arzneimittel | Neue 7-Azaindole, deren Verwendung als Inhibitoren der Phosphodiesterase 4 und Verfahren zu deren Herstellung |
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| US20100129363A1 (en) * | 2002-05-17 | 2010-05-27 | Zeldis Jerome B | Methods and compositions using pde4 inhibitors for the treatment and management of cancers |
| EP1556033A4 (en) * | 2002-05-17 | 2006-05-31 | Celgene Corp | METHODS AND COMPOSITIONS USING CYTOKINE INHIBITOR SELECTIVE MEDICAMENTS FOR THE TREATMENT AND MANAGEMENT OF CANCERS AND OTHER DISEASES |
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