KR100385662B1 - 매트릭스 메탈로프로테아제 억제제 - Google Patents
매트릭스 메탈로프로테아제 억제제 Download PDFInfo
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- KR100385662B1 KR100385662B1 KR10-2000-7007583A KR20007007583A KR100385662B1 KR 100385662 B1 KR100385662 B1 KR 100385662B1 KR 20007007583 A KR20007007583 A KR 20007007583A KR 100385662 B1 KR100385662 B1 KR 100385662B1
- Authority
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- South Korea
- Prior art keywords
- phenyl
- amino
- carbonyl
- propyl
- 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.)
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 118
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 107
- 238000002360 preparation method Methods 0.000 claims description 88
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
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- YHBRWHVZWMGWDM-YFVAEKQCSA-N tert-butyl (3r)-3-[[(2s)-3,3-dimethyl-1-oxo-1-[[(1r)-1-phenylethyl]amino]butan-2-yl]carbamoyl]hex-5-enoate Chemical compound CC(C)(C)OC(=O)C[C@@H](CC=C)C(=O)N[C@@H](C(C)(C)C)C(=O)N[C@H](C)C1=CC=CC=C1 YHBRWHVZWMGWDM-YFVAEKQCSA-N 0.000 description 1
- IESXDQCTNQRLAD-MJBUKCDHSA-N tert-butyl (e,3r)-3-[[(2s)-3,3-dimethyl-1-oxo-1-[[(1r)-1-phenylethyl]amino]butan-2-yl]carbamoyl]-6-(3-fluoro-4-phenylphenyl)hex-5-enoate Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@H](C)C=1C=CC=CC=1)C(C)(C)C)CC(=O)OC(C)(C)C)\C=C\C(C=C1F)=CC=C1C1=CC=CC=C1 IESXDQCTNQRLAD-MJBUKCDHSA-N 0.000 description 1
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- IDHYBBZEYAYMPA-KWRQTKKFSA-N tert-butyl (e,3r)-3-[[(2s)-3,3-dimethyl-1-oxo-1-phenylmethoxybutan-2-yl]carbamoyl]-6-[4-(3-methoxyphenyl)-3-methylphenyl]hex-5-enoate Chemical compound COC1=CC=CC(C=2C(=CC(\C=C\C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCC=3C=CC=CC=3)C(C)(C)C)=CC=2)C)=C1 IDHYBBZEYAYMPA-KWRQTKKFSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
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- WVMSIBFANXCZKT-UHFFFAOYSA-N triethyl(hydroxy)silane Chemical compound CC[Si](O)(CC)CC WVMSIBFANXCZKT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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
- C07D317/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
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Abstract
Description
효소 | 다른 명칭 | 바람직한 기질 |
MMP-1 | 콜라게나아제-1, 간질성 콜라게나아제 | 콜라겐 I, II, III, VII, X, 젤라틴 |
MMP-2 | 젤라티나아제 A, 72kDa 젤라티나아제 | 젤라틴, 콜라겐 IV, V, VII, X, 엘라스틴, 파이브로넥틴; 프로-MMP-13을 활성화함 |
MMP-3 | 스트로멜리신-1 | 프로테오글리캔, 라미닌, 파이브로넥틴, 젤라틴 |
MMP-7 | 펌프, 매트릴리신 | 프로테오글리캔, 라미닌, 파이브로넥틴, 젤라틴, 콜라겐 IV, 엘라스틴; 프로-MMP-1 및 -2를 활성화함 |
MMP-8 | 콜라게나아제-2, 호중구 콜라게나아제 | 콜라겐 I, II, III |
MMP-9 | 젤라티나아제 B, 92kDa 젤라티나아제 | 젤라틴, 콜라겐 IV, V, 엘라스틴 |
MMP-12 | 대식세포 메탈로엘라스타제 | 엘라스틴, 콜라겐 IV, 파이브로넥틴, 프로-MMP-2 및 -3을 활성화함 |
MMP-13 | 콜라게나아제-3 | 콜라겐 I, II, III, 젤라틴 |
MMP-14 | MT-MMP-1 | 프로-MMP-2 및 -13을 활성화함, 젤라틴 |
MMP-15 | MT-MMP-2 | 알려지지 않음 |
MMP-16 | MT-MMP-3 | 프로-MMP-2를 활성화함 |
MMP-17 | MT-MMP-4 | 알려지지 않음 |
Claims (40)
- 하기 화학식 I의 화합물 또는 그의 제약상 허용되는 염 또는 이들의 용매 화합물인 물질.<화학식 I>상기 식에서,R1은 H, OH, C1-4알킬, C1-4알콕시 또는 C2-4알케닐이고,R2는 C1-6알킬 또는 벤질이고,R3, R5및 R6은 각각 독립적으로 H 및 F로부터 선택되고,R4는 CH3, Cl 또는 F이고,X는 HO 또는 HONH이고,Y는 직접 결합 또는 0이고,Z는 하기 화학식 a 또는 화학식 b의 기이고,<화학식 a><화학식 b>[여기서, R10은 C1-4알킬, C1-4알콕시메틸, 히드록시(C2-4알킬), 카르복시(C1-4알킬) 또는 (아미노 또는 디메틸아미노)C2-4알킬이고,R11은 할로 및 메틸로부터 독립적으로 선택되는 3 개 이하의 치환기에 의해 치환될 수 있는 페닐, 나프틸 또는 피리딜이고,R14는 H, OH, CH3또는 할로임]Ar은 하기 화학식 c의 기이다.<화학식 c>[여기서, A는 CR12이며 B는 CR13이고,R7및 R9는 각각 독립적으로 H 또는 F이고,R8및 R13은 각각 독립적으로 H, F, Cl, CN, CONH2, CH3또는 OCH3이고,R12는 H, C1-6알킬, CN, 히드록시(C2-6알킬), (아미노 또는 디메틸아미노)C2-6알킬, CONH2, OH, 할로, C1-6알콕시, (C1-6알콕시)메틸, 피페라지닐카르보닐, 피페리디닐, C(NH2)=NOH 또는 C(=NH)=NHOH이고, 단, R8, R12및 R13중 두 개 이상은 H임]
- 제1항에 있어서, R1은 H, OH, C1-4알킬 또는 C1-4알콕시인 물질.
- 삭제
- 제1항 또는 제2항에 있어서, Z는 화학식 a,[여기서, R10은 C1-4알킬, C1-4알콕시메틸 또는 히드록시(C2-4알킬)이고, R11은 할로 및 메틸로부터 독립적으로 선택되는 3 개 이하의 치환기에 의해 치환될 수 있는 페닐 또는 피리딜임]의 기이거나, 또는인 물질.
- 제1항 또는 제2항에 있어서, R3은 H인 물질.
- 제1항 또는 제2항에 있어서, R4는 Y가 O인 경우 F이고, R4는 Y가 직접 결합인 경우 Cl 또는 CH3인 물질.
- 제1항 또는 제2항에 있어서, R5는 H인 물질.
- 제1항 또는 제2항에 있어서, R6은 H인 물질.
- 삭제
- 제1항 또는 제2항에 있어서, R1은 H, OH, n-프로필 또는 에톡시인 물질.
- 삭제
- 제1항 또는 제2항에 있어서, Z는 화학식 a,[여기서, R10은 C1-4알킬, C1-4알콕시메틸 또는 히드록시(C2-4알킬)이고, R11은 페닐, 피리딘-4-일 또는 피리딘-3-일임]의 기이거나, 또는인 물질.
- 제1항 또는 제2항에 있어서, Ar은 하기 화학식 c의 기인 물질.<화학식 c>상기 식에서,A는 CR12이며, B는 CR13이고, R7, R8및 R9는 H이다.
- 제1항 또는 제2항에 있어서, R1은 H인 물질.
- 삭제
- 제1항 또는 제2항에 있어서, Z는 화학식 a,[여기서, R10은 CH3, CH20CH3또는 CH2OH이고, R11은 페닐, 피리딘-4-일 또는 피리딘-3-일임]의 기이거나, 또는인 물질.
- 제1항 또는 제2항에 있어서, Ar은 하기 화학식 c의 기인 물질.<화학식 c>상기 식에서,A는 CR12이며, B는 CR13이고, R7, R8및 R9는 H이고,R12는 H, C1-6알킬, CN, 히드록시(C2-6알킬), (아미노 또는 디메틸아미노)C2-6알킬, CONH2, OH, 할로, C1-6알콕시, (C1-6알콕시)메틸, C(NH2)=NOH 또는 C(=NH)=NHOH이고,R13은 H, OCH3, CN, CONH2, CH3또는 F이다.
- 제1항 또는 제2항에 있어서, R2는 이소프로필, t-부틸 또는 벤질인 물질.
- 제1항 또는 제2항에 있어서, Z는인 물질.
- 제1항 또는 제2항에 있어서, Ar은 페닐, 3-메톡시페닐, 4-시아노페닐, 3-시아노페닐, 3-카르바모일페닐 또는 4-히드록시아미디노페닐인 물질.
- 제1항 또는 제2항에 있어서, R2는 t-부틸인 물질.
- 제1항 또는 제2항에 있어서, Ar은 페닐 또는 3-메톡시페닐인 물질.
- 제1항에 있어서, R1은 H, OH, n-프로필 또는 에톡시이고,R2는 t-부틸, 이소프로필 또는 벤질이고,Z는 화학식 a,[여기서, R10은 CH3, CH20CH3또는 CH2OH이고, R11은 페닐, 피리딘-4-일 또는 피리딘-3-일임]의 기이거나, 또는이고,R3은 H이고,R4는 CH3, Cl 또는 F이고,R5는 H이고,R6은 H이고,Ar은 페닐, 3-메톡시페닐, 4-시아노페닐, 3-시아노페닐, 3-카르바모일페닐 또는 4-히드록시아미디노페닐인 물질.
- 제1항에 있어서,N1-[(1S)-2,2-디메틸-1-({[(1R)-1-페닐에틸]아미노}카르보닐)프로필]-(N4-히드록시)-(2R)-2-{3-[3-메틸-(4-페닐)페닐]프로필}부탄디아미드,N1-[(1S)-2,2-디메틸-1-({[(1R)-1-페닐에틸]아미노}카르보닐)프로필]-(2R)-2-[3-(3-플루오로-4-페녹시페닐)프로필]-(N4-히드록시)부탄디아미드,N1-[(1S)-2,2-디메틸-1-({[(1R)-1-페닐에틸]아미노}카르보닐)프로필]-(N4-히드록시)-(2R)-2-{3-[3-메틸-4-페닐)페닐]프로필}-(3S)-프로필부탄디아미드,(3R)-3-({[(1S)-2,2-디메틸-1-({[(1S)-2-메톡시-1-페닐에틸]아미노}카르보닐)프로필]아미노}카르보닐)-6-[(3-메틸-4-페닐)페닐]헥산산,(3R)-3-({[(1S)-2,2-디메틸-1-({[(1S)-2-메톡시-1-페닐에틸]아미노}카르보닐)프로필]아미노}카르보닐)-6-[(3'-메톡시-2-메틸비펜-4-일)헥산산,(2R)-N-1-[(1S)-2,2-디메틸-1-({[(1S)-2-메톡시-1-페닐에틸]아미노}카르보닐)프로필]-2-{3-[(3-메틸-4-페닐)페닐]프로필}-(N-4-히드록시)부탄디아미드,(3R)-3-[({({[(1S)-2-메톡시-1-페닐에틸]아미노}카르보닐)-(1S)-2-페닐에틸]아미노}카르보닐)-6-[3-메틸-(4-페닐)페닐]헥산산,(N4, 3S)-디히드록시-N1-[(1S)-2,2-디메틸-1-({[(1S)-2-메톡시-1-페닐에틸]아미노}카르보닐)프로필]-(2R)-2-{3-[3-메틸-(4-페닐)페닐]프로필}부탄디아미드,(N4, 3S)-디히드록시-N1-[(1S)-2,2-디메틸-1-({[(1R)-1-페닐에틸]아미노}카르보닐)프로필]-(2R)-2-{3-[(3'-메톡시-2-메틸비펜-4-일)프로필}부탄디아미드, 및(N4, 3S)-디히드록시-N1-[(1S)-2,2-디메틸-1-({[(1S)-2-메톡시-1-페닐에틸]아미노}카르보닐)프로필]-(2R)-2-{3-[(3'-메톡시-2-메틸비펜-4-일)프로필}부탄디아미드의 화합물중에서 선택되는 물질.
- 삭제
- 제1항, 제2항, 제4항 내지 제8항, 제10항, 제12항 내지 제14항 및 제16항 내지 제24항 중 어느 한 항에 따른 물질과 함께 상용성 보조제, 희석제 또는 담체를 포함하는, 조직 파괴, 욕창, 결장 궤양, 십이지장 궤양, 관절염에서의 조직 파괴, 이영양성 수포성 표피박리증, 포진성 피부염 및 만성 또는 급성 심장 또는 뇌 경색증으로부터 선택된 질병 치료 또는 예방을 위한 제약 조성물.
- 삭제
- 삭제
- 삭제
- X1이 CO2(t-부틸 또는 메틸) 잔기인 화학식 II의 화합물을 가수분해하는 바와 같이 하기 화학식 II의 화합물을 변형시키는 것을 포함하는, X가 OH인 제1항에 따른 물질의 제조 방법.<화학식 II>상기 식에서,X1은 카르복시로 변형될 수 있는 기이고,다른 치환기들은 제1항에서 정의된 바와 같다.
- X가 OH인 화학식 I의 화합물을 히드록실아민 또는 히드록실아민 유도체와 반응시키는 것을 포함하는, X가 NHOH이고, R1, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제1항에 정의된 바와 같은 제1항에 따른 물질의 제조 방법.
- 펩타이드 커플링제의 존재하에서 X가 OH인 화학식 I의 화합물을 O-알릴히드록실아민 또는 그의 염과 반응시켜 하기 화학식 III의 화합물을 제공한 후, 적합한 촉매의 존재하에 암모늄 포르메이트에 의해 처리하는 것을 포함하는, X가 NHOH이고, R1, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제1항에 정의된 바와 같은 제1항에 따른 물질의 제조 방법.<화학식 III>
- 하기 화학식 IV의 화합물을 히드록실아민 또는 그의 염과 반응시키는 것을 포함하는, X가 NHOH이고, R1은 OH이고, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제1항에 정의된 바와 같은 제1항에 따른 물질의 제조 방법.<화학식 IV>
- 촉매의 존재하에 하기 화학식 V의 화합물을 하기 화학식 VI의 화합물과 교차-커플링시켜 하기 화학식 VIIa 및(또는) VIIb의 화합물을 제조한 후, 올레핀 잔기를 환원시키고 보호된 산 잔기 X2를 탈보호시키는 것을 포함하는, X가 OH이고, R1, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제1항에 정의된 바와 같은 제1항에 따른 물질의 제조 방법.<화학식 V><화학식 VI><화학식 VIIa><화학식 VIIb>상기 식에서, X2는 CO2CH3또는 (C02)(t-부틸)기와 같은 보호된 산이고, LG는 I, Br 또는 OSO2CF3와 같은 교차-커플링 이탈기이고, R1, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제1항에 정의된 바와 같다.
- 하기 화학식 II의 화합물 또는 그의 염 또는 이들의 용매 화합물.<화학식 II>상기 식에서, X1, R1, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제30항에 정의된 바와 같다.
- 하기 화학식 III의 화합물 또는 그의 염 또는 이들의 용매 화합물.<화학식 III>상기 식에서, R1, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제32항에 정의된 바와 같다.
- 하기 화학식 IV의 화합물 또는 그의 염 또는 이들의 용매 화합물.<화학식 IV>상기 식에서, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제33항에 정의된 바와 같다.
- 하기 화학식 VIIa 또는 VIIb의 화합물 또는 그의 염 또는 이들의 용매 화합물.<화학식 VIIa><화학식 VIIb>상기 식에서, X2, R1, R2, R3, R4, R5, R6, Y, Ar 및 Z는 제34항에 정의된 바와 같다.
- 삭제
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GBGB9800510.1A GB9800510D0 (en) | 1998-01-09 | 1998-01-09 | Therapeutic agents |
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GB9811843.3 | 1998-06-02 | ||
GBGB9811843.3A GB9811843D0 (en) | 1998-06-02 | 1998-06-02 | Therapeutic agents |
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CO (1) | CO4990971A1 (ko) |
CZ (1) | CZ20002459A3 (ko) |
DE (1) | DE69819206T2 (ko) |
DK (1) | DK1047665T3 (ko) |
DZ (1) | DZ2701A1 (ko) |
EA (1) | EA002971B1 (ko) |
ES (1) | ES2209244T3 (ko) |
HN (1) | HN1998000199A (ko) |
HR (1) | HRP20000460A2 (ko) |
HU (1) | HUP0101300A3 (ko) |
IL (1) | IL136889A0 (ko) |
IS (1) | IS5531A (ko) |
MA (1) | MA26594A1 (ko) |
NO (1) | NO20003506L (ko) |
NZ (1) | NZ504683A (ko) |
OA (1) | OA11435A (ko) |
PA (1) | PA8466101A1 (ko) |
PE (1) | PE20000176A1 (ko) |
PL (1) | PL342763A1 (ko) |
PT (1) | PT1047665E (ko) |
SI (1) | SI1047665T1 (ko) |
SK (1) | SK10112000A3 (ko) |
TN (1) | TNSN99002A1 (ko) |
TR (1) | TR200001909T2 (ko) |
WO (1) | WO1999035124A1 (ko) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6352976B1 (en) | 1998-12-31 | 2002-03-05 | Aventis Pharmaceuticals Inc. | Selective inhibitors of MMP-12 |
ATE232544T1 (de) * | 1998-12-31 | 2003-02-15 | Aventis Pharma Inc | Selektive inhibitoren des mmp-12 |
JP2001055327A (ja) * | 1999-06-11 | 2001-02-27 | Fuji Chemical Industries Ltd | 新規なヒドロキサム酸誘導体を含む医薬 |
GB0025310D0 (en) * | 2000-10-16 | 2000-11-29 | Pfizer Ltd | Process |
US6452041B1 (en) | 2000-10-16 | 2002-09-17 | Pfizer Inc. | Olefination process to itaconate and succinate derivatives |
CZ20032503A3 (cs) * | 2001-02-16 | 2004-02-18 | Allelix Neuroscience, Inc. | Inhibitory GlyT - 1 |
GB0126389D0 (en) * | 2001-11-02 | 2002-01-02 | Pfizer Ltd | Wafer |
PA8578101A1 (es) * | 2002-08-13 | 2004-05-07 | Warner Lambert Co | Derivados de heterobiarilo como inhibidores de metaloproteinasa de la matriz |
US20040138103A1 (en) * | 2002-11-07 | 2004-07-15 | Procyte Corporation | Compositions containing peptide copper complexes and metalloproteinase inhibitors and methods related thereto |
ATE457716T1 (de) | 2002-12-30 | 2010-03-15 | Angiotech Int Ag | Wirkstofffreisetzung von schnell gelierender polymerzusammensetzung |
JP4921167B2 (ja) * | 2003-08-23 | 2012-04-25 | ヴァーナリス アールアンドディー リミテッド | メタロプロテイナーゼ阻害剤としてのヒドロキサム酸誘導体 |
ES2545688T3 (es) * | 2006-09-29 | 2015-09-15 | F. Hoffmann-La Roche Ag | Método de evaluación del riesgo de progresión de enfermedad de pacientes con artritis reumatoide |
CN104788333B (zh) * | 2015-03-19 | 2017-03-22 | 中国医科大学 | 2‑取代‑9,10‑蒽醌类化合物、制备方法及其用途 |
CN116287790B (zh) * | 2023-03-22 | 2025-04-25 | 云南奥宇环保科技有限公司 | 一种溶剂萃取锗并制取锗精矿的方法 |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5892112A (en) | 1990-11-21 | 1999-04-06 | Glycomed Incorporated | Process for preparing synthetic matrix metalloprotease inhibitors |
GB9215665D0 (en) | 1992-07-23 | 1992-09-09 | British Bio Technology | Compounds |
CA2149640A1 (en) | 1992-11-25 | 1994-06-09 | Kevin T. Chapman | Carboxy-peptidyl derivatives as antidegenerative active agents |
ES2134939T3 (es) | 1993-04-27 | 1999-10-16 | Celltech Therapeutics Ltd | Derivados de peptidilo como inhibidores de metaloproteinas. |
GB9308695D0 (en) | 1993-04-27 | 1993-06-09 | Celltech Ltd | Peptidyl derivatives |
GB9320660D0 (en) | 1993-10-07 | 1993-11-24 | British Bio Technology | Inhibition of cytokine production |
UA48121C2 (uk) | 1993-11-04 | 2002-08-15 | Сінтекс (С.Ш.А.) Інк. | Інгібітори матричних металопротеаз і фармацетична композиція на їх основі |
US6037472A (en) * | 1993-11-04 | 2000-03-14 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
EP0740652B1 (en) | 1994-01-20 | 1998-05-06 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
EP0905126B1 (en) | 1994-01-22 | 2002-12-04 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
JPH10500986A (ja) | 1994-05-28 | 1998-01-27 | ブリテッシュ バイオテック ファーマシューティカルズ リミテッド | 金属タンパク質分解酵素阻害剤 |
US5461746A (en) * | 1995-01-17 | 1995-10-31 | Tdw Delaware, Inc. | Magnetic cleaning pig |
GB9507799D0 (en) * | 1995-04-18 | 1995-05-31 | British Biotech Pharm | Metalloproteinase inhibitors |
US5691381A (en) | 1995-04-18 | 1997-11-25 | The Dupont Merck Pharmaceutical Company | Hydroxamic and carbocyclic acids as metalloprotease inhibitors |
CA2217859A1 (en) | 1995-05-10 | 1996-11-14 | David Alan Owen | Peptidyl compounds which inhibit metalloproteinase and tnf liberation and their therapeutic use |
US6110896A (en) | 1995-05-10 | 2000-08-29 | Darwin Discovery, Ltd. | Peptidyl compounds and their therapeutic use |
US5917090A (en) * | 1995-06-30 | 1999-06-29 | British Biotech Pharmaceuticals Ltd. | Matrix metalloproteinase inhibitors |
GB9513331D0 (en) | 1995-06-30 | 1995-09-06 | British Biotech Pharm | Matrix metalloproteinase inhibitors |
US5840974A (en) * | 1996-12-04 | 1998-11-24 | Britisch Biotech Pharmaceuticals, Ltd. | Metalloproteinase inhibitors |
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1998
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- 1998-12-23 WO PCT/EP1998/008565 patent/WO1999035124A1/en active IP Right Grant
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- 1998-12-23 JP JP2000527526A patent/JP3621884B2/ja not_active Expired - Fee Related
- 1998-12-23 EA EA200000628A patent/EA002971B1/ru not_active IP Right Cessation
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1999
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- 1999-01-04 PE PE1999000004A patent/PE20000176A1/es not_active Application Discontinuation
- 1999-01-06 DZ DZ990002A patent/DZ2701A1/xx active
- 1999-01-06 TN TNTNSN99002A patent/TNSN99002A1/fr unknown
- 1999-01-06 MA MA25419A patent/MA26594A1/fr unknown
- 1999-01-07 AR ARP990100048A patent/AR014270A1/es not_active Application Discontinuation
- 1999-01-07 AP APAP/P/1999/001436A patent/AP1059A/en active
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2000
- 2000-04-11 US US09/546,756 patent/US6350907B1/en not_active Expired - Fee Related
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