KR970707083A - 매트릭스 메탈로프로테아제 억제제(Matrix metalloprotease inhibitors) - Google Patents
매트릭스 메탈로프로테아제 억제제(Matrix metalloprotease inhibitors) Download PDFInfo
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- KR970707083A KR970707083A KR1019970703394A KR19970703394A KR970707083A KR 970707083 A KR970707083 A KR 970707083A KR 1019970703394 A KR1019970703394 A KR 1019970703394A KR 19970703394 A KR19970703394 A KR 19970703394A KR 970707083 A KR970707083 A KR 970707083A
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- Prior art keywords
- compound
- formula
- phenyl
- salt
- carboxy
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- 239000011159 matrix material Substances 0.000 title claims abstract 4
- 239000003475 metalloproteinase inhibitor Substances 0.000 title 1
- -1 stromelysine Proteins 0.000 claims abstract 63
- 150000001875 compounds Chemical class 0.000 claims abstract 55
- 150000003839 salts Chemical class 0.000 claims abstract 28
- 241000124008 Mammalia Species 0.000 claims abstract 4
- 201000010099 disease Diseases 0.000 claims abstract 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims 13
- 125000003118 aryl group Chemical group 0.000 claims 13
- 125000001072 heteroaryl group Chemical group 0.000 claims 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 9
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 7
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- 235000010290 biphenyl Nutrition 0.000 claims 4
- 239000004305 biphenyl Substances 0.000 claims 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- 239000003054 catalyst Substances 0.000 claims 3
- 125000004475 heteroaralkyl group Chemical group 0.000 claims 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 2
- 239000005977 Ethylene Substances 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 125000004442 acylamino group Chemical group 0.000 claims 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- YXVFYQXJAXKLAK-UHFFFAOYSA-N p-hydroxybiphenyl Natural products C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims 1
- BSDBRFAGCUJYJG-UHFFFAOYSA-N 2-(4-phenylphenoxy)ethanamine Chemical group C1=CC(OCCN)=CC=C1C1=CC=CC=C1 BSDBRFAGCUJYJG-UHFFFAOYSA-N 0.000 claims 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims 1
- BPMBNLJJRKCCRT-UHFFFAOYSA-N 4-phenylbenzonitrile Chemical group C1=CC(C#N)=CC=C1C1=CC=CC=C1 BPMBNLJJRKCCRT-UHFFFAOYSA-N 0.000 claims 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims 1
- 206010027476 Metastases Diseases 0.000 claims 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims 1
- 230000002159 abnormal effect Effects 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 239000000908 ammonium hydroxide Substances 0.000 claims 1
- 239000000010 aprotic solvent Substances 0.000 claims 1
- 206010003246 arthritis Diseases 0.000 claims 1
- 150000001502 aryl halides Chemical class 0.000 claims 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 230000004927 fusion Effects 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 230000008595 infiltration Effects 0.000 claims 1
- 238000001764 infiltration Methods 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 230000009401 metastasis Effects 0.000 claims 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 208000028169 periodontal disease Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 claims 1
- 210000001519 tissue Anatomy 0.000 claims 1
- 102000005741 Metalloproteases Human genes 0.000 abstract 2
- 108010006035 Metalloproteases Proteins 0.000 abstract 2
- 102000029816 Collagenase Human genes 0.000 abstract 1
- 108060005980 Collagenase Proteins 0.000 abstract 1
- 102000013382 Gelatinases Human genes 0.000 abstract 1
- 108010026132 Gelatinases Proteins 0.000 abstract 1
- 229960002424 collagenase Drugs 0.000 abstract 1
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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- 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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- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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- 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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- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
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- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
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- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
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- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07C327/12—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton containing rings
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Abstract
화학식(I)의 화합물 및 약제학적으로 허용되는 이의 염은 스트로멜리신, 젤라티나제, 마트릴리신 및 콜라게나제와 같은, 매트릭스 메탈로프테아제를 억제하며, 당해 매트릭스 메탈로프테아제의 억제에 의해 완화되는 질환 상태를 갖고 있는 포유동물의 치료시 유용하다.
Description
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Claims (34)
- 하기 화학식(I)의 화합물 또는 약제학적으로 허용되는 이의 염.상기 화학식에서, R1은 머캅토, 아세틸티오, 카복시, 하이드록시카바모일, N-하이드록시포밀아미노, 알콕시카보닐, 아릴옥시카보닐, 아르알콕시카보닐, 벤질옥시카바모일 또는 화학식의 그룹(여기서, R6은 아릴 또는 헤테로아릴이다)이고, R2는 알킬, 사이클로알킬, 아릴, 헤테로사이클로알킬 또는 헤테로아릴이며, R3은 알킬, 사이클로알킬, 아르알킬 또는 헤테로아르알킬이고, R7은 아릴, 헤테로아릴 또는 헤테로사이클로알킬이며, X는 화학식 -(CH2)m-Y-(CH2)n-의 그룹(여기서, Y는 0, S 또는 단일 결합이고, m은 0 내지 4의 정수이며, n은 0 내지 4의 정수이고, m+n은 0 내지 4의 정수이다)이고, p는 0 내지 4의 정수이되, 단 p가 0이 아닌 경우에, R2-X는 비페닐알킬이다.
- 제1항에 있어서, R1이 카복시이고, R3이 사이클로헥실이며, R7이 치환되거나 비치환된 페닐 또는 N-모노폴리노이며, X가 프로판-1, 3-디일이고, p가 2 또는 3인 화합물 또는 이의 염.
- 제2항에 있어서, R7이 4-(아미노설포닐) 페닐 또는 N-모르폴리노인 화합물 이의 염.
- 제1항에 있어서, R2가 알킬, 치환되거나 비치환된 페닐 또는 하기 화학식의 그룹인 화합물 또는 이의 염.상기 식에서, A는 CH2, O, NH, S, CH2-CH2또는 NH-CH2이고 R10은 H, 알킬, 알콕시, 알킬아미노 또는 아실아미노이며, R11은 H 또는 할로이고,R7은 4-피리딜 또는 치환되거나 비치환된 페닐이며, p는 0이다.
- 제4항에 있어서, R1은 카복시, 하이드록시카바모일 또는 N-하이드록시포밀아미노이고, R2가 페닐, 비페닐, 4-(피리딜) 페닐 또는 2-메틸프로필이며, R3이 3급 부틸, 4-아미노부틸, 디메틸아미노부틸, 4-(N, N'-디에틸구아니도) 부틸, 프로필, 2-메틸프로필, 1-하이드록시이소프로필, 1-하이드록시에틸 또는 사이클로헥실이고, X가 단일 결합, 에틸렌 또는 프로판-1, 3-디일인 화합물 또는 이의 염.
- 제4항에 있어서, R2가 비페닐인 화합물 또는 이의 염.
- 제6항에 있어서, R1이 카복시, N-하이드록시포밀아미노 또는 하이드록시카바모일이고, R3이 알킬이며, R7이 4-피리딜인 화합물 또는 이의 염.
- 제7항에 있어서, R3이 3급 부틸이고, X가 프로판-1, 3-디일인 화합물 또는 이의 염.
- 제8항에 있어서, R1이 카복시, N-하이드록시포밀아미노 또는 하이드록시카바모일인 화합물 또는 이의 염.
- 제4항에 있어서, R2가 하기 화학식의 그룹인 화합물 또는 이의 염.상기 식에서, A는 CH2이고, R10은 H 또는 아실아미노이여, R11은 H이고, R7은 치환되거나 비치환된 페닐이며, X는 프로판-1, 3-디일이다.
- 제10항에 있어서, R1이 카복시, 하이드록시카바모일 또는 N-하이드록시포밀아미노이고, R3이 알킬이며, R7이 알콕시카보닐페닐인 화합물 또는 이의 염.
- 제11항에 있어서, R1이 카복시이고, R3이 2-메틸프로필이며, R7이 4-(메톡시카보닐) 페닐인 화합물 또는 이의 염.
- 제6항에 있어서, R7이 치환되거나 비치환된 페닐인 화합물 또는 이의 염.
- 제13항에 있어서, R1이 카복시이고, R3이 알킬 또는 사이클로알킬이며, X가 프로판-1, 3-디일인 화합물 또는 이의 염.
- 제14항에 있어서, R3이 사이클로헥실이고, R7이 4-(하이드록시에틸아미노설포닐) 페닐 또는 4-(디메틸아미노에틸아미노설포닐) 페닐이거나, R3이 4-(아미노)부틸 또는 4-(이소프로필아미노) 부틸이고 R7이 4-(에톡시카보닐) 페닐이거나, R3이 1-하이드록시이소프로필이고 R7이 페닐이거나, R3이 3급 부틸인 화합물 또는 이의 염.
- 제15항에 있어서, R7이 4-(N-모르폴리노프로필아미노설포닐) 페닐, 4-(메틸아미노설포닐) 페닐, 4-(하이드록시에틸아미노설포닐) 페닐 또는 4-(메틸설피닐) 페닐인 화합물 또는 이의 염.
- 제4항에 있어서, R1이 카복시이고, R2가 페닐이며, R3이 알킬 또는 사이클로알킬이고, R7이 치환되거나 비치환된 페닐인 화합물 또는 이의 염.
- 제17항에 있어서, R3이 4-(아미노)부틸이고 R7이 4-(에톡시카보닐) 페닐이며 X가 프로판-1, 3-디일이거나, R3이 (N, N'-디에틸구아니도)-N-부틸이고 R7이 4-(에톡시카보닐) 페닐이며 X가 프로필렌이거나, R3이 사이클로헥실이고 R7이 4-(N, N-디메틸아미노에틸아미노설포닐) 페닐이며 X가 에틸렌인 화합물 또는 이의 염.
- 제4항에 있어서, R1이 머캅토, 카복시, 하이드록시카바모일 또는 N-하이드록시포밀아미노이고, R2가 2-메틸프로필이며, R3이 알킬, 사이클로알킬 또는 헤테로아르알킬이고, R7이 치환되거나 비치환된 페닐이며, X가 단일 결합인 화합물 또는 이의 염.
- 제19항에 있어서, R1이 하이드록시카바모일이고, R3이 프로필, 2-메틸프로필, 사이클로헥실 또는 3-메닐인돌릴이며, R7이 4-(메톡시) 페닐, 4-(카복시) 페닐, 4-(메톡시카보닐) 페닐 또는 4-(디메틸아미노에틸카바모일) 페닐인 화합물 또는 이의 염.
- 제20항에 있어서, R7이 4-(디메틸아미노에틸카바모일) 페닐 또는 4-(메톡시카보닐) 페닐인 화합물 또는 이의 염.
- 제19항에 있어서, R1이 N-하이들고시포밀아미노이고, R3이 2-메틸프로필이며 R7이 4-(메톡시카보닐) 페닐이거나, R1이 카복시이고 R3이 사이클로헥실 또는 2-메틸프로필이며 R7이 4-(메톡시카보닐) 페닐이거나, R1이 머캅토이고 R3이 2-메틸프로필이며 R7이 4-(메톡시카보닐) 페닐인 화합물 또는 이의 염.
- 제4항에 있어서, R1이 카복시이고, R2가 4-(2-하이드록시에틸) 페닐, 4-(2-하이드록시프로필) 페닐, 4-(2-하이드록시부틸) 페닐, 4-피리딜페닐, 비페닐, 4'-(아미노에톡시) 비페닐, 4'-(시아노) 비페닐 또는 4'-(하이드록시) 비페닐이며, R3이 2-메틸프로필이고, R7이 4-(메톡시카보닐) 페닐이며, X가 프로판-1, 3-디일인 화합물 또는 이의 염.
- 제23항에 있어서 R2가 나-(피리딜) 페닐인 화합물 또는 이의 염.
- 제1항의 화합물 또는 이의 염 및 약제학적으로 허용되는 부형제를 포함하는 약제학적 조성물.
- 치료학적 유효량의 제1항의 화합물 또는 이의 염을 이를 필요로 하는 포유동물에 투여함을 포함하는, 포유동물의 매트릭스 메탈로프로테이나제 활성의 억제 방법.
- 치료학적 유효량의 제1항의 화합물 또는 이의 염을 이를 필요로 하는 포유동물에 투여함을 포함하는, 관절염, 비정상적 창상 유합, 조직 궤향화, 골 흡수성 질환, 당뇨병, 종양 침윤, 종양 전이 및 치근막 질환으로 이루어진 그룹으로부터 선택되는 매트릭스 메틸로프로테이나제 매개된 질환의 치료 방법.
- 하기 화학식의 화합물.상기 화학식에서, R2는 알킬, 아릴 또는 헤테로아릴이고, X는 화학식-(CH2)m-Y-(CH2)n의 그룹(여기서, Y는 0, S 또는 단일 결합이고, m은 0 내지 4의 정수이며, n은 0 내지 4의 정수이고, m+n은 0 내지 4의 정수이다)이거나 R2와 X는 함께 저급 알케닐이다.
- 하기 화학식(Ⅲ)의 화합물을 팔라듐/탄소 촉매의 존재하에서 수소화시킴을 포함하는, 화학식(Ⅴ)의 화합물의 제조 방법.상기 화학식에서, R2는 아릴 또는 헤테로아릴이다.
- 제29항에 있어서, 화학식(Ⅲ)의 화합물이 N-(2R)-(3급 부톡시키보닐) 메틸-4-펜테노일)-4S-페닐메틸-2-옥시졸리디논을 염기 및 팔라듐 촉매의 존재하에서 R2-할라이드와 접촉시킴으로써 제조되는 방법.
- 화학식(Ⅳ)의 화합물을 나트륨 헥사메틸디실라지드 및 3급 부틸브로모아세테이트와 접촉시킴을 포함하는, 화학식(Ⅴ)의 화합물의 제조 방법.상기 화학식에서, R2는 아릴 또는 헤테로아릴이다.
- 화학식 (Ⅵ)의 화합물.상기 화학식에서, R2는 아릴 또는 헤테로아릴이다.
- (a) 하기 화학식(Ⅶ)의 화합물을 피리딘 중의 과량의 메실 클로라이드와 접촉시킨 다음, 염기성 조건하에서 환류시키고, (b) 단계 (a)에서 R2가 수소인 경우에, 단계(a)의 생성물을 염기 및 팔라듐 촉매의 존재하에서 아릴 할라이드 또는 헤테로아릴 할라이드와 반응시킴을 포함하는, 화학식(Ⅵ)의 화합물의 제조 방법.상기 화학식에서, R2는 하기 화학식(Ⅶ)에서는 수소, 아릴 또는 헤테로아릴이고 화학식(Ⅵ)에서는 아릴 또는 헤테로아릴이다.
- (A) 하기 화학식(D)의 화합물을 염기 및 아미드 커플링 시약의 존재하에 화학식(F)의 화합물과 접촉시켜, 상응하는 화학식(I)의 화합물을 수득하거나, (B) X 및 R2가 함께 비치환되거나 아릴 또는 헤테로아릴 치환된 알케닐인, 상응하는 화합물을 촉매적으로 수소화시키니거나, (C) R1이 알콕시카보닐 또는 아르알콕시카보닐인 화학식(I)의 화합물을 온화한 산성 조건하에서 처리하여, R1이 카복시인 상응하는 화학식(I)의 화합물을 수득하거나, (D) R1이 카복시인 화학식(I)의 화합물을 O-벤질하이드록실아민과 접촉시켜, R1이 벤질옥시카바모일인 상응하는 화학식(I)의 화합물을 수득하거나, (E) R1이 벤질옥시카바모일인 화학삭(I)의 화합물을 촉매적으로 수소화시켜, R1이 벤질옥시카바모일인 상응하는 화학식(I)의 화합물을 수득하거나, (F) R1이 카복시인 화학식(I)의 화합물을 하이드록실아민과 접촉시켜, R1이 하이드록시카바모일인 상응하는 화학식 (I)의 화합물을 수득하거나, (G) 화학식(P-6)의 화합물을 촉매적으로 수소화시켜, R1이 N-하이드록시포밀아미노인 상응하는 화학식(I)의 화합물을 수득하거나, (H) R1이 아세틸티오인 화학식(I)의 화합물을 비양성자성 용매중에서 수산화 암모늄으로 처리하여, R1이 머캅토인 상응하는 화학식(I)의 화합물을 수득함을 포함하는, 화학식(I)의 화합물 제조 방법.상기 화학식에서, R1은 화학식(I)에서는 머캅토, 아세틸티오, 카복시, 벤질옥시카바모일, 하이드록시카바모일, N-하이드록시포밀아미노, 알콕시카보닐, 아르알콕시카보닐, 벤질옥시카바모일 또는 화학식(여기서, R6은 아릴 또는 헤테로아릴이다)의 그룹이고, 화학식(F)에서는 알콕시카보닐, 아르알콕시카보닐, 아릴- 또는 헤테로아릴티오메틸포스피노일 또는 아세틸티오이며, R2는 알킬, 아릴 또는 헤테로아릴이고, R3은 알킬, 사이클로알킬, 아르알킬 또는 헤테로아르알킬이며, X는 화학식 -(CH2)m-Y-(CH2)n의 그룹(여기서, Y는 0, S 또는 단일 결합이고, m은 0 내지 4의 정수이며, n은 0 내지 4의 정수이고, m+n은 0 내지 4의 정수이다)이며, R7은 아릴, 헤테로아릴 또는 헤테로사이클로알킬이고, p는 0 내지 4의 정수이다.※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
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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 |
KR100418808B1 (ko) * | 1994-01-20 | 2004-07-23 | 브리티쉬 바이오테크 파마슈티칼스 리미티드 | 금속단백질분해효소억제제 |
DE69529100T2 (de) * | 1994-01-22 | 2003-07-17 | British Biotech Pharm | Metalloproteinaseinhibitoren |
US5514716A (en) * | 1994-02-25 | 1996-05-07 | Sterling Winthrop, Inc. | Hydroxamic acid and carboxylic acid derivatives, process for their preparation and use thereof |
-
1994
- 1994-11-22 US US08/343,158 patent/US6037472A/en not_active Expired - Fee Related
-
1995
- 1995-11-21 JP JP8517109A patent/JPH10509719A/ja not_active Ceased
- 1995-11-21 AU AU42897/96A patent/AU705439B2/en not_active Ceased
- 1995-11-21 UA UA97052347A patent/UA58488C2/uk unknown
- 1995-11-21 WO PCT/US1995/015530 patent/WO1996016027A1/en not_active Application Discontinuation
- 1995-11-21 NZ NZ297676A patent/NZ297676A/en unknown
- 1995-11-21 EP EP95941493A patent/EP0793643A1/en not_active Withdrawn
- 1995-11-21 PL PL95321024A patent/PL182639B1/pl not_active IP Right Cessation
- 1995-11-21 RU RU97110062/04A patent/RU2163232C2/ru not_active IP Right Cessation
- 1995-11-21 CN CN95197409A patent/CN1111520C/zh not_active Expired - Fee Related
- 1995-11-21 KR KR1019970703394A patent/KR100432602B1/ko not_active IP Right Cessation
- 1995-11-21 AR ARP950100248A patent/AR001999A1/es not_active Application Discontinuation
- 1995-11-21 HU HU9701970A patent/HUT77533A/hu unknown
- 1995-11-21 BR BR9509802A patent/BR9509802A/pt not_active Application Discontinuation
- 1995-11-21 CZ CZ971565A patent/CZ156597A3/cs unknown
- 1995-11-22 TR TR95/01472A patent/TR199501472A2/xx unknown
- 1995-11-22 ZA ZA959948A patent/ZA959948B/xx unknown
-
1997
- 1997-05-21 NO NO972307A patent/NO972307L/no unknown
- 1997-05-21 FI FI972160A patent/FI972160A/fi not_active IP Right Cessation
-
1999
- 1999-12-21 US US09/468,762 patent/US6579890B1/en not_active Expired - Fee Related
-
2003
- 2003-04-16 US US10/418,012 patent/US20030212067A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
NZ297676A (en) | 1999-10-28 |
WO1996016027A1 (en) | 1996-05-30 |
AU4289796A (en) | 1996-06-17 |
CN1111520C (zh) | 2003-06-18 |
FI972160A0 (fi) | 1997-05-21 |
EP0793643A1 (en) | 1997-09-10 |
RU2163232C2 (ru) | 2001-02-20 |
JPH10509719A (ja) | 1998-09-22 |
ZA959948B (en) | 1997-05-22 |
UA58488C2 (uk) | 2003-08-15 |
HUT77533A (hu) | 1998-05-28 |
CN1173170A (zh) | 1998-02-11 |
US20030212067A1 (en) | 2003-11-13 |
CZ156597A3 (en) | 1997-11-12 |
US6037472A (en) | 2000-03-14 |
PL182639B1 (pl) | 2002-02-28 |
KR100432602B1 (ko) | 2004-09-21 |
AU705439B2 (en) | 1999-05-20 |
FI972160A (fi) | 1997-05-22 |
BR9509802A (pt) | 1997-09-30 |
US6579890B1 (en) | 2003-06-17 |
NO972307D0 (no) | 1997-05-21 |
AR001999A1 (es) | 1998-01-07 |
PL321024A1 (en) | 1997-11-24 |
NO972307L (no) | 1997-07-22 |
TR199501472A2 (tr) | 1996-07-21 |
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