CA2440419C - Azacycloalkyl substituted acetic acid derivatives for use as mmp inhibitors. - Google Patents
Azacycloalkyl substituted acetic acid derivatives for use as mmp inhibitors. Download PDFInfo
- Publication number
- CA2440419C CA2440419C CA2440419A CA2440419A CA2440419C CA 2440419 C CA2440419 C CA 2440419C CA 2440419 A CA2440419 A CA 2440419A CA 2440419 A CA2440419 A CA 2440419A CA 2440419 C CA2440419 C CA 2440419C
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- CA
- Canada
- Prior art keywords
- pharmaceutically acceptable
- compound
- acid
- aryl
- acceptable salt
- 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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- 229940124761 MMP inhibitor Drugs 0.000 title description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 114
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 33
- 239000001257 hydrogen Substances 0.000 claims abstract description 33
- 125000002252 acyl group Chemical group 0.000 claims abstract description 27
- 241000124008 Mammalia Species 0.000 claims abstract description 23
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims abstract description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims abstract description 11
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims abstract description 11
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 10
- -1 perhydrofuranyl Chemical group 0.000 claims description 88
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 201000008482 osteoarthritis Diseases 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 230000004054 inflammatory process Effects 0.000 claims description 9
- 230000004968 inflammatory condition Effects 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 208000019693 Lung disease Diseases 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000005841 biaryl group Chemical group 0.000 claims description 3
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 claims description 2
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000005557 thiazolylene group Chemical group 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 62
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- 239000000651 prodrug Substances 0.000 abstract description 17
- 229940002612 prodrug Drugs 0.000 abstract description 17
- 230000001419 dependent effect Effects 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 82
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 82
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 59
- 239000000203 mixture Substances 0.000 description 52
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- 239000000243 solution Substances 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 36
- 238000000034 method Methods 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
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- 230000000694 effects Effects 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
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- 230000005764 inhibitory process Effects 0.000 description 17
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
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- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 150000005347 biaryls Chemical group 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27581901P | 2001-03-14 | 2001-03-14 | |
| US60/275,819 | 2001-03-14 | ||
| US27857201P | 2001-03-22 | 2001-03-22 | |
| US60/278,572 | 2001-03-22 | ||
| PCT/EP2002/002808 WO2002072577A2 (en) | 2001-03-14 | 2002-03-13 | Azacycloalkyl substituted acetic acid derivatives for use as mmp inhibitors. |
Publications (2)
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| CA2440419A1 CA2440419A1 (en) | 2002-09-19 |
| CA2440419C true CA2440419C (en) | 2010-05-04 |
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|---|---|---|---|
| CA2440419A Expired - Fee Related CA2440419C (en) | 2001-03-14 | 2002-03-13 | Azacycloalkyl substituted acetic acid derivatives for use as mmp inhibitors. |
Country Status (10)
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|---|---|
| US (2) | US20040235896A1 (enExample) |
| EP (1) | EP1373262B1 (enExample) |
| JP (2) | JP4294321B2 (enExample) |
| AT (1) | ATE467629T1 (enExample) |
| AU (1) | AU2002256672A1 (enExample) |
| CA (1) | CA2440419C (enExample) |
| DE (1) | DE60236350D1 (enExample) |
| ES (1) | ES2345977T3 (enExample) |
| PT (1) | PT1373262E (enExample) |
| WO (1) | WO2002072577A2 (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6670477B2 (en) * | 2001-03-14 | 2003-12-30 | Novartis Ag | Synthesis of enantiomerically enriched 4-piperidinylglycine |
| JP4219810B2 (ja) * | 2001-10-26 | 2009-02-04 | 塩野義製薬株式会社 | Mmp阻害作用を有するスルホンアミド誘導体 |
| AU2003239599B8 (en) | 2002-05-29 | 2008-08-14 | Merck Sharp & Dohme Corp. | Compounds useful in the treatment of anthrax and inhibiting lethal factor |
| JP2007537256A (ja) | 2004-05-11 | 2007-12-20 | メルク エンド カムパニー インコーポレーテッド | N−スルホン化アミノ酸誘導体調製のためのプロセス |
| US20080119513A1 (en) * | 2004-09-06 | 2008-05-22 | Fumihiko Watanabe | Sulfonamide Derivative Selectively Inhibiting Mmp-13 |
| CN101404987A (zh) * | 2006-01-20 | 2009-04-08 | 史密丝克莱恩比彻姆公司 | 磺酰胺衍生物在治疗代射和神经系统疾病中的用途 |
| US11207312B2 (en) | 2017-07-17 | 2021-12-28 | Merck Sharp & Dohme Corp. | Metallo-beta-lactamase inhibitors and methods of use thereof |
Family Cites Families (14)
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|---|---|---|---|---|
| US5506242A (en) * | 1993-01-06 | 1996-04-09 | Ciba-Geigy Corporation | Arylsufonamido-substituted hydroxamic acids |
| US5552419A (en) * | 1993-01-06 | 1996-09-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
| PT766664E (pt) * | 1994-06-22 | 2000-08-31 | British Biotech Pharm | Inibidores de metaloproteinases |
| US5817822A (en) * | 1994-06-24 | 1998-10-06 | Novartis Corporation | Certain alpha-azacycloalkyl substituted arylsulfonamido acetohydroxamic acids |
| US6124333A (en) * | 1995-06-22 | 2000-09-26 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| CN100413859C (zh) * | 1996-01-23 | 2008-08-27 | 盐野义制药株式会社 | 磺化的氨基酸衍生物及含有它的金属蛋白酶抑制剂 |
| AU7294098A (en) * | 1997-05-09 | 1998-11-27 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
| PT877019E (pt) * | 1997-05-09 | 2002-05-31 | Hoechst Ag | Acidos diaminocarboxilicos substituidos |
| BR9810841A (pt) * | 1997-07-31 | 2001-07-10 | Procter & Gamble | Inibidores de metaloprotease alicìclicos |
| DK0895988T3 (da) * | 1997-08-08 | 2002-09-09 | Pfizer Prod Inc | Arylsulfonylaminohydroxamsyrederivater |
| DE69822839T2 (de) * | 1997-08-08 | 2004-08-19 | Pfizer Products Inc., Groton | Derivate von aryloxyarylsulfonylamino hydroxyaminsäuren |
| SK13352002A3 (sk) * | 2000-03-21 | 2003-05-02 | The Procter & Gamble Company | Metaloproteázové inhibítory s vedľajším heterocyklickým reťazcom |
| SK12842002A3 (sk) * | 2000-03-21 | 2003-02-04 | The Procter And Gamble Company | Heterocyklický vedľajší reťazec obsahujúci N-substituované inhibítory metaloproteáz a farmaceutický prípravok s ich obsahom |
| JP4292321B2 (ja) * | 2001-12-07 | 2009-07-08 | 内山工業株式会社 | ガスケット |
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2002
- 2002-03-13 CA CA2440419A patent/CA2440419C/en not_active Expired - Fee Related
- 2002-03-13 ES ES02726168T patent/ES2345977T3/es not_active Expired - Lifetime
- 2002-03-13 EP EP02726168A patent/EP1373262B1/en not_active Expired - Lifetime
- 2002-03-13 AU AU2002256672A patent/AU2002256672A1/en not_active Abandoned
- 2002-03-13 DE DE60236350T patent/DE60236350D1/de not_active Expired - Lifetime
- 2002-03-13 PT PT02726168T patent/PT1373262E/pt unknown
- 2002-03-13 WO PCT/EP2002/002808 patent/WO2002072577A2/en not_active Ceased
- 2002-03-13 US US10/471,245 patent/US20040235896A1/en not_active Abandoned
- 2002-03-13 JP JP2002571493A patent/JP4294321B2/ja not_active Expired - Fee Related
- 2002-03-13 AT AT02726168T patent/ATE467629T1/de active
-
2006
- 2006-11-02 US US11/591,861 patent/US20070060569A1/en not_active Abandoned
-
2009
- 2009-01-26 JP JP2009014415A patent/JP2009137997A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| PT1373262E (pt) | 2010-07-26 |
| US20040235896A1 (en) | 2004-11-25 |
| EP1373262A2 (en) | 2004-01-02 |
| AU2002256672A1 (en) | 2002-09-24 |
| DE60236350D1 (de) | 2010-06-24 |
| WO2002072577A3 (en) | 2002-11-14 |
| EP1373262B1 (en) | 2010-05-12 |
| JP2004536788A (ja) | 2004-12-09 |
| CA2440419A1 (en) | 2002-09-19 |
| JP2009137997A (ja) | 2009-06-25 |
| JP4294321B2 (ja) | 2009-07-08 |
| ATE467629T1 (de) | 2010-05-15 |
| WO2002072577A2 (en) | 2002-09-19 |
| US20070060569A1 (en) | 2007-03-15 |
| ES2345977T3 (es) | 2010-10-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |