DE69931496T2 - INDOLVERBINDUNGEN ALS sPLA2 INHIBITOREN - Google Patents
INDOLVERBINDUNGEN ALS sPLA2 INHIBITOREN Download PDFInfo
- Publication number
- DE69931496T2 DE69931496T2 DE69931496T DE69931496T DE69931496T2 DE 69931496 T2 DE69931496 T2 DE 69931496T2 DE 69931496 T DE69931496 T DE 69931496T DE 69931496 T DE69931496 T DE 69931496T DE 69931496 T2 DE69931496 T2 DE 69931496T2
- Authority
- DE
- Germany
- Prior art keywords
- ethyl
- indol
- phenylmethyl
- acetic acid
- oxy
- 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.)
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 102000005473 Secretory Phospholipases A2 Human genes 0.000 title abstract description 4
- 108010031873 Secretory Phospholipases A2 Proteins 0.000 title abstract description 4
- 239000003112 inhibitor Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 15
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims description 17
- -1 indole compound Chemical class 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- HZAUNCLWBMBDSC-UHFFFAOYSA-N 2-(3-acetamido-1-benzyl-2-ethylindol-4-yl)oxyacetic acid Chemical compound CCC1=C(NC(C)=O)C2=C(OCC(O)=O)C=CC=C2N1CC1=CC=CC=C1 HZAUNCLWBMBDSC-UHFFFAOYSA-N 0.000 claims description 3
- HHVCTOCIDKVKPH-UHFFFAOYSA-N 2-[1-benzyl-2-ethyl-3-[(2,2,2-trifluoroacetyl)amino]indol-4-yl]oxyacetic acid Chemical compound CCC1=C(NC(=O)C(F)(F)F)C2=C(OCC(O)=O)C=CC=C2N1CC1=CC=CC=C1 HHVCTOCIDKVKPH-UHFFFAOYSA-N 0.000 claims description 3
- SRDYWEXFOFGVQQ-UHFFFAOYSA-N 2-[1-benzyl-3-[(2-bromoacetyl)amino]-2-ethylindol-4-yl]oxyacetic acid Chemical compound CCC1=C(NC(=O)CBr)C2=C(OCC(O)=O)C=CC=C2N1CC1=CC=CC=C1 SRDYWEXFOFGVQQ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000006203 morpholinoethyl group Chemical group [H]C([H])(*)C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 3
- HSFQHLFQIFVCNX-UHFFFAOYSA-N 2-[1-benzyl-3-(carbamothioylamino)-2-ethylindol-4-yl]oxyacetic acid Chemical compound CCC1=C(NC(N)=S)C2=C(OCC(O)=O)C=CC=C2N1CC1=CC=CC=C1 HSFQHLFQIFVCNX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 6
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- 230000001404 mediated effect Effects 0.000 abstract description 5
- 206010040070 Septic Shock Diseases 0.000 abstract description 3
- 230000036303 septic shock Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 61
- 239000000203 mixture Substances 0.000 description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 238000009472 formulation Methods 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 150000002475 indoles Chemical class 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
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- 238000004519 manufacturing process Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
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- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
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- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 6
- 102000015439 Phospholipases Human genes 0.000 description 6
- 108010064785 Phospholipases Proteins 0.000 description 6
- 229940114079 arachidonic acid Drugs 0.000 description 6
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
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- 230000003595 spectral effect Effects 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
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- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 3
- CICJSMPBNORTQN-UHFFFAOYSA-N 1-benzyl-2-ethyl-4-methoxyindole Chemical compound CCC1=CC2=C(OC)C=CC=C2N1CC1=CC=CC=C1 CICJSMPBNORTQN-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- 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
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
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Landscapes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Virology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9511498P | 1998-08-03 | 1998-08-03 | |
| US95114P | 1998-08-03 | ||
| PCT/US1999/017459 WO2000007590A1 (en) | 1998-08-03 | 1999-08-02 | INDOLE sPLA2 INHIBITORS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69931496D1 DE69931496D1 (de) | 2006-06-29 |
| DE69931496T2 true DE69931496T2 (de) | 2006-11-23 |
Family
ID=22249768
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69931496T Expired - Fee Related DE69931496T2 (de) | 1998-08-03 | 1999-08-02 | INDOLVERBINDUNGEN ALS sPLA2 INHIBITOREN |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US6451839B1 (enExample) |
| EP (1) | EP1100492B1 (enExample) |
| JP (1) | JP2002522385A (enExample) |
| AT (1) | ATE326963T1 (enExample) |
| CA (1) | CA2338855A1 (enExample) |
| DE (1) | DE69931496T2 (enExample) |
| ES (1) | ES2263283T3 (enExample) |
| WO (1) | WO2000007590A1 (enExample) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002522386A (ja) * | 1998-08-03 | 2002-07-23 | イーライ・リリー・アンド・カンパニー | インドールｓＰＬＡ２インヒビター |
| CN1450893A (zh) * | 2000-07-14 | 2003-10-22 | 伊莱利利公司 | 治疗脓毒症的方法 |
| ES2264708T3 (es) * | 2000-12-18 | 2007-01-16 | Eli Lilly And Company | Derivados tetraciclicos como inhibidores de la spla2. |
| US6992100B2 (en) | 2001-12-06 | 2006-01-31 | Eli Lilly And Company | sPLA2 inhibitors |
| AUPS282602A0 (en) | 2002-06-07 | 2002-06-27 | Garvan Institute Of Medical Research | Method of inhibiting cell proliferation |
| EP1610779B1 (en) * | 2003-03-31 | 2009-09-09 | Eli Lilly And Company | 3-oxo-1,3-dihydro-indazole-2-carboxylic acid amide derivatives as phospholipase inhibitors |
| CA2565387A1 (en) * | 2004-05-03 | 2005-11-17 | Ilypsa, Inc. | Modulation of lysophosphatidylcholine and treatment of diet-induced conditions |
| EP1948604A1 (en) * | 2005-11-03 | 2008-07-30 | Ilypsa, Inc. | Indole compounds having c4-acidic substituents and use thereof as phospholipase-a2 inhibitors |
| EP1960356A2 (en) * | 2005-11-03 | 2008-08-27 | Ilypsa, Inc. | Multivalent indole compounds and use thereof as phospholipase-a2 inhibitors |
| JP2009514883A (ja) * | 2005-11-03 | 2009-04-09 | イリプサ， インコーポレイテッド | アザインドール化合物およびホスホリパーゼａ２インヒビターとしてのその使用 |
| EP1948602A2 (en) * | 2005-11-03 | 2008-07-30 | Ilypsa, Inc. | Indole compounds having c4-amide substituents and use thereof as phospholipase-a2 inhibitors |
| MX2008005661A (es) * | 2005-11-03 | 2008-12-15 | Ilypsa Inc | Inhibidores de fosfolipasa, que incluyen inhibidores de fosfolipasa multivalente, y uso de los mismos, que incluyen como inhibidores de fosfolipasa localizadas en el lumen. |
| EP2211425A1 (en) | 2009-01-23 | 2010-07-28 | MTA S.p.A. | Female electrical terminal |
| CN107233337A (zh) | 2009-04-29 | 2017-10-10 | 阿马里纳药物爱尔兰有限公司 | 含有epa和心血管剂的药物组合物以及使用其的方法 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5312928A (en) * | 1991-02-11 | 1994-05-17 | Cambridge Neuroscience | Calcium channel antagonists and methodology for their identification |
| US5132319A (en) * | 1991-03-28 | 1992-07-21 | Merck Frosst Canada, Inc. | 1-(hydroxylaminoalkyl) indole derivatives as inhibitors of leukotriene biosynthesis |
| GB9204365D0 (en) * | 1992-02-28 | 1992-04-08 | Pfizer Ltd | Indoles |
| AU2945992A (en) * | 1992-11-27 | 1994-06-22 | Yason S.R.L. | Indole derivative having prolonged immunostimulating activity and pharmaceutical compositions therefrom |
| IL109311A0 (en) | 1993-04-16 | 1994-07-31 | Lilly Co Eli | 1H-indole-3-acetamide sPla2 inhibitors |
| IL109309A (en) | 1993-04-16 | 2000-06-29 | Lilly Co Eli | 1-H-indole-3-acetic acid hydrazide SPLA2 inhibitors and pharmaceutical compositions containing them |
| US6252084B1 (en) * | 1994-03-15 | 2001-06-26 | Eli Lilly And Company | 1H-indole-3-acetamide sPLA2 inhibitors |
| EP1950200B1 (en) * | 1994-04-01 | 2012-01-11 | Eli Lilly And Company | [[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-11H-indol-4-yl]oxy]acetic acid methyl ester as sPLA2 inhibitor |
| EP1039901A1 (en) * | 1997-11-14 | 2000-10-04 | Eli Lilly And Company | Treatment for alzheimer's disease |
-
1999
- 1999-08-02 CA CA002338855A patent/CA2338855A1/en not_active Abandoned
- 1999-08-02 US US09/762,069 patent/US6451839B1/en not_active Expired - Fee Related
- 1999-08-02 AT AT99938936T patent/ATE326963T1/de not_active IP Right Cessation
- 1999-08-02 DE DE69931496T patent/DE69931496T2/de not_active Expired - Fee Related
- 1999-08-02 ES ES99938936T patent/ES2263283T3/es not_active Expired - Lifetime
- 1999-08-02 JP JP2000563275A patent/JP2002522385A/ja not_active Withdrawn
- 1999-08-02 WO PCT/US1999/017459 patent/WO2000007590A1/en not_active Ceased
- 1999-08-02 EP EP99938936A patent/EP1100492B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE69931496D1 (de) | 2006-06-29 |
| ES2263283T3 (es) | 2006-12-01 |
| CA2338855A1 (en) | 2000-02-17 |
| US6451839B1 (en) | 2002-09-17 |
| WO2000007590A1 (en) | 2000-02-17 |
| EP1100492A4 (en) | 2001-10-24 |
| JP2002522385A (ja) | 2002-07-23 |
| ATE326963T1 (de) | 2006-06-15 |
| EP1100492A1 (en) | 2001-05-23 |
| EP1100492B1 (en) | 2006-05-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |