CA2302361A1 - Inhibiteurs de proteases - Google Patents
Inhibiteurs de proteases Download PDFInfo
- Publication number
- CA2302361A1 CA2302361A1 CA002302361A CA2302361A CA2302361A1 CA 2302361 A1 CA2302361 A1 CA 2302361A1 CA 002302361 A CA002302361 A CA 002302361A CA 2302361 A CA2302361 A CA 2302361A CA 2302361 A1 CA2302361 A1 CA 2302361A1
- Authority
- CA
- Canada
- Prior art keywords
- nr1r2
- nr1c
- 6alkyl
- phenyl
- thiazol
- 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
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 10
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 28
- 108090000625 Cathepsin K Proteins 0.000 claims abstract description 24
- -1 -C3-7cycloalkyl Chemical group 0.000 claims abstract description 22
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 10
- 239000004365 Protease Substances 0.000 claims abstract description 10
- 239000011159 matrix material Substances 0.000 claims abstract description 10
- 108091005804 Peptidases Proteins 0.000 claims abstract description 9
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
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- 125000005842 heteroatom Chemical group 0.000 claims abstract description 6
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- 208000007565 gingivitis Diseases 0.000 claims abstract description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 5
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- 238000006731 degradation reaction Methods 0.000 claims abstract description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- 235000019000 fluorine Nutrition 0.000 claims abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 3
- 102000004171 Cathepsin K Human genes 0.000 claims abstract 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 71
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 52
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 52
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 31
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- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
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- 239000003112 inhibitor Substances 0.000 description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 238000004949 mass spectrometry Methods 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 14
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- 239000012267 brine Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
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- 108090000790 Enzymes Proteins 0.000 description 11
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- NMOBOJWSHIZFLK-UHFFFAOYSA-N tert-butyl n-benzyl-n-[n'-[4-[3-(4-methoxybutoxy)phenyl]-1,3-thiazol-2-yl]carbamimidoyl]carbamate Chemical compound COCCCCOC1=CC=CC(C=2N=C(N=C(N)N(CC=3C=CC=CC=3)C(=O)OC(C)(C)C)SC=2)=C1 NMOBOJWSHIZFLK-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
-
- A—HUMAN NECESSITIES
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
La présente invention se rapporte à des composés représentés par la formule (I) dans laquelle X, X¿1?, X¿2? et X¿3? sont indépendamment sélectionnés parmi -H, -alkyle C¿1-6?, -alkyle C¿1-6? substitué par 1-3 atomes de fluor, -cycloalkyle C¿3-7?, -CN, -C(O)R¿1?, -C(O)OR¿1?, -C(O)NR¿1?R¿2?, -C(NR¿1?)NR¿1?R¿2?, -C(NCN)NR¿1?R¿2?, -C(NCN)SR¿3?, -NO¿2?, -NR¿1?SO¿2?R¿3?, -NR¿1?C(O)R¿1?, -NR¿1?R¿2?, -NR¿1?(C=NR¿1?)NR¿1?R¿2?, -NR¿1?C(O)NR¿1?R¿2?, -NR¿1?C(O)R¿1?, -NR¿1?C(O)OR¿3?, -NR¿1?C(NCN)SR¿3?, -NR¿1?C(NCN)NR¿1?R¿2?, -NR¿1?C(O)C(O)NR¿1?R¿2?, NR¿1?C(O)C(O)R¿2?, -Cl, Br, -I, -F, -OR¿1?, -O(CH¿2?)¿q?OR¿3?, - O(CH¿2?)¿2?OH, -OC(O)R¿1?, -O(CH¿2?)¿q?C(O)NR¿1?R¿2?, O(CH¿2?)¿q?C(O)R¿1?, -SR¿1?, -SO¿2?NR¿1?R¿2? ou -S(O)¿m?R¿3?; m est égal à 0, 1 ou 2; q est égal à 1 ou 2; n est égal à 0, 1 ou 2; R¿1? est -H, -alkyle C¿1-6?, -CF¿3? ou -CH¿2?CF¿3?; ou bien lorsque R¿1? et R¿2? sont pris conjointement comme NR¿1?R¿2?, ils peuvent former, avec l'azote, un cycle ayant de 5 à 7 éléments constitué de carbone ou de carbone associé à un ou plusieurs hétéroatomes supplémentaires sélectionnés parmi O, N ou S; R¿2? est -H, -alkyle C¿1-6?, -CF¿3? ou -CH¿2?CF¿3?; R¿3? est -alkyle C¿1-6?, -CF¿3? ou -CH¿2?CF¿3?; et X¿4? est -H, -alkyle C¿1-6?, -cycloalkyle C¿3-7?, -COAr, -COOalkyle C¿1-6?, ou COOAr. Ces composés inhibent les protéases, et notamment la cathepsine. L'invention se rapporte également à des compositions pharmaceutiques contenant ces composés, ainsi qu'à des procédés permettant de traiter à l'aide de ces compositions les maladies liées à une déperdition osseuse excessive ou à une dégradation matricielle ou cartilagineuse, et notamment l'ostéoporose; les maladies gingivales telles que les gingivites et la parodontite; l'arthrite, et plus particulièrement, l'arthrose et la polyarthrite rhumatoïde; la maladie osseuse de Paget; l'hypercalcémie résultant de malignité et les maladies métaboliques osseuses.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5752797P | 1997-09-04 | 1997-09-04 | |
| US60/057,527 | 1997-09-04 | ||
| PCT/US1998/018289 WO1999011637A1 (fr) | 1997-09-04 | 1998-09-03 | Inhibiteurs de proteases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2302361A1 true CA2302361A1 (fr) | 1999-03-11 |
Family
ID=22011125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002302361A Abandoned CA2302361A1 (fr) | 1997-09-04 | 1998-09-03 | Inhibiteurs de proteases |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1015438A4 (fr) |
| JP (1) | JP2001514257A (fr) |
| AU (1) | AU9300298A (fr) |
| CA (1) | CA2302361A1 (fr) |
| CO (1) | CO4970736A1 (fr) |
| MA (1) | MA26540A1 (fr) |
| PE (1) | PE115699A1 (fr) |
| SA (1) | SA98190653A (fr) |
| WO (1) | WO1999011637A1 (fr) |
| ZA (1) | ZA988064B (fr) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030144175A1 (en) | 1998-12-23 | 2003-07-31 | Smithkline Beecham Corporation | Protease inhibitors |
| WO2001034599A1 (fr) | 1999-11-10 | 2001-05-17 | Smithkline Beecham Corporation | Inhibiteurs de protease |
| US6583137B1 (en) | 1999-11-10 | 2003-06-24 | Smithkline Beecham Corporation | Protease inhibitors |
| AU1474801A (en) | 1999-11-10 | 2001-06-06 | Smithkline Beecham Corporation | Protease inhibitors |
| HUP0300068A2 (en) | 2000-03-21 | 2003-05-28 | Smithkline Beecham Corp | Protease inhibitors, their preparation, their use and pharmaceutical compositions containing them |
| US6699866B2 (en) | 2001-04-17 | 2004-03-02 | Sepracor Inc. | Thiazole and other heterocyclic ligands for mammalian dopamine, muscarinic and serotonin receptors and transporters, and methods of use thereof |
| JP2005515254A (ja) | 2002-01-17 | 2005-05-26 | スミスクライン ビーチャム コーポレーション | カテプシンｋ阻害剤として有用なシクロアルキルケトアミド誘導体 |
| KR100962972B1 (ko) | 2002-07-26 | 2010-06-09 | 주식회사유한양행 | 1-페닐피페리딘-3-온 유도체 및 그의 제조방법 |
| DE102004008141A1 (de) | 2004-02-19 | 2005-09-01 | Abbott Gmbh & Co. Kg | Guanidinverbindungen und ihre Verwendung als Bindungspartner für 5-HT5-Rezeptoren |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59225172A (ja) * | 1983-06-03 | 1984-12-18 | Yamanouchi Pharmaceut Co Ltd | 新規グアニジノチアゾ−ル誘導体及びその製法 |
-
1998
- 1998-09-01 MA MA25238A patent/MA26540A1/fr unknown
- 1998-09-03 WO PCT/US1998/018289 patent/WO1999011637A1/fr not_active Ceased
- 1998-09-03 CA CA002302361A patent/CA2302361A1/fr not_active Abandoned
- 1998-09-03 JP JP2000508676A patent/JP2001514257A/ja not_active Withdrawn
- 1998-09-03 EP EP98945850A patent/EP1015438A4/fr not_active Withdrawn
- 1998-09-03 ZA ZA988064A patent/ZA988064B/xx unknown
- 1998-09-03 CO CO98050517A patent/CO4970736A1/es unknown
- 1998-09-03 AU AU93002/98A patent/AU9300298A/en not_active Abandoned
- 1998-09-04 PE PE1998000830A patent/PE115699A1/es not_active Application Discontinuation
- 1998-10-17 SA SA98190653A patent/SA98190653A/ar unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2001514257A (ja) | 2001-09-11 |
| CO4970736A1 (es) | 2000-11-07 |
| AU9300298A (en) | 1999-03-22 |
| SA98190653A (ar) | 2005-12-03 |
| EP1015438A4 (fr) | 2000-11-08 |
| ZA988064B (en) | 1999-05-28 |
| MA26540A1 (fr) | 2004-12-20 |
| PE115699A1 (es) | 2000-01-13 |
| WO1999011637A1 (fr) | 1999-03-11 |
| EP1015438A1 (fr) | 2000-07-05 |
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