CN1131215C - 环和杂环N－取代的α－亚氨基异羟肟酸和羧酸 - Google Patents
环和杂环N－取代的α－亚氨基异羟肟酸和羧酸 Download PDFInfo
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- CN1131215C CN1131215C CN96198294A CN96198294A CN1131215C CN 1131215 C CN1131215 C CN 1131215C CN 96198294 A CN96198294 A CN 96198294A CN 96198294 A CN96198294 A CN 96198294A CN 1131215 C CN1131215 C CN 1131215C
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- tetrahydroisoquinoline
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- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
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- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- OUHCLAKJJGMPSW-UHFFFAOYSA-L magnesium;hydrogen carbonate;hydroxide Chemical compound O.[Mg+2].[O-]C([O-])=O OUHCLAKJJGMPSW-UHFFFAOYSA-L 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
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- AWJLBFXUZYCIIH-UHFFFAOYSA-N n-hydroxypyridine-2-carboxamide Chemical compound ONC(=O)C1=CC=CC=N1 AWJLBFXUZYCIIH-UHFFFAOYSA-N 0.000 description 1
- BMJQSBWFMNSBSO-UHFFFAOYSA-N n-hydroxypyridine-2-carboxamide;hydrochloride Chemical compound Cl.ONC(=O)C1=CC=CC=N1 BMJQSBWFMNSBSO-UHFFFAOYSA-N 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003822 preparative gas chromatography Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
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Abstract
式I化合物适用于制备治疗在其过程中降解基质的金属蛋白酶活性增加的疾病的药物。
Description
本发明涉及环和杂环N-取代的α-亚氨基异羟肟酸和羧酸、其制备方法及其作为药物的应用。
EP 0606046公开了某些芳基磺酰氨基异羟肟酸衍生物及其作为基质金属蛋白酶抑制剂的作用。
为了寻找可用于治疗结缔组织疾病的其它有效化合物，经过努力，现已发现本发明的亚氨基异羟肟酸衍生物是金属蛋白酶的抑制剂。
本发明涉及式I化合物
和/或式I化合物的任何立体异构形式、和/或式I化合物的生理耐受盐，其中在第i)种情况下：R1是a)式II基团
b)式III基团
c)式IV基团
其中Z是杂环或取代杂环基，例如1)吡咯，2)噻唑，3)吡唑，4)吡啶，5)咪唑，6)吡咯烷，7)哌啶，8)噻吩，9)噁唑，10)异噁唑，11)吗啉或12)哌嗪，d)萘基，e)被R2基团一-或三-取代的萘基，或f)式V基团
其中o是1或2，且环碳原子中的一个可以被-O-或-S-置换，并且Q作为结构式I的一部分
1)是结构部分VI
2)是结构部分VII3)是结构部分VIII
4)是结构部分IX或5)是结构部分X
其中D是NR4或S，R2是1)苯基或2)被下列基团一-至三-取代的苯基2.1羟基，2.2-O-R10，其中R10是1)(C1-C6)-烷基，2)(C3-C6)-环烷基，3)苄基或4)苯基，2.3-COOH，2.4(C1-C6)-烷基，2.5(C3-C6)-环烷基-O-(C1-C4)-烷基，2.6卤素，2.7-CN，2.8-NO2，2.9-CF3，2.10-O-C(O)-R10，并且R10如上所定义，2.11-O-C(O)-苯基，苯基被R3基团一-或二-取代，2.12-C(O)-O-R10，并且R10如上所定义，2.13亚甲二氧基(Methylendioxo)，2.14-C(O)-NR11R12，其中R11和R12可以相同或不同，它们各自为1)氢原子，2)(C1-C4)-烷基或3)苄基或4)R11和R12与和其相连的氮原子一起形成吡咯烷、哌啶、吗啉或哌嗪基，或者2.15-NR13R14，其中R13是氢原子或(C1-C4)-烷基，并且R14是1)氢原子，2)(C1-C4)-烷基，3)苄基，4)-C(O)-R10或5)-C(O)-O-R10，R3和R4彼此相同或不同，它们各自为1)氢原子，2)(C1-C5)-烷基，3)(C1-C5)-烷氧基，4)卤素，5)羟基，6)-O-C(O)-R10，并且R10如上所定义，或者7)R3和R4结合在一起形成-O-CH2-O-基团，R5是a)氢原子，b)(C1-C5)-烷基，或c)苄基，以及R6、R7和R8彼此相同或不同，它们各自为a)氢原子，或b)在第i)种情况下，具有2.1至2.14条目下R2的含义，并且n是0、1或2，m是0、1或2，n与m之和为1、2或3，或者在第ii)种情况下R1是1)苯基或2)被R2基团一-至三-取代的苯基，其中R2如上在第i)种情况下条目2.1至2.15中所定义，Q是结构部分X，并且R6、R7和R8彼此相同或不同，它们各自如上所定义，n是1，并且m是1，或者在第iii)种情况下R1、Q、R6、R7和R8彼此相同或不同，并且它们各自如上对第ii)种情况所定义，m和n是0、1或2，并且其中m与n的含义不同，以及X是a)共价键，b)-O-，c)-S-，d)-S(O)-，e)-S(O)2-，f)-C(O)-或g)-C(OH)-，以及Y是a)-O-或b)-S-，并且A是HO-NH-C(O)-或HO-C(O)-以及B是a)-(CH2)q-，其中q是0、1、2、3或4，或者b)-CH＝CH-。
优选的是以下式I化合物和/或式I化合物的生理耐受盐和/或式I化合物的任何立体异构形式，其中在第i)种情况下，R1是式II或III基团，并且Q是结构部分VI、VII、VIII或X，在第ii)种情况下，R1是苯基或者被甲氧基一-至三-取代的苯基，并且Q是结构部分X，或在第iii)种情况下，R1是苯基，Q是结构部分X，n是0并且m是2，以及A是HO-NH-C(O)-或HO-C(O)-，B是共价键，X是氧原子或共价键，并且R2是苯基或者被下列基团取代的苯基a)羟基，b)-O-R10，其中R10是(C1-C3)-烷基或苄基，c)(C1-C2)-烷基，d)氟或氯，e)-CN，f)-CF3，或g)NR13R14，其中R13和R14各自为(C1-C3)-烷基，R3、R4、R5、R6、R7和R8彼此相同或不同，它们各自为a)氢原子，b)甲氧基，c)亚甲基二氧基，d)氨基或e)羟基。
特别优选的是以下化合物R-2-(联苯基磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-氯联苯基磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-氯联苯基磺酰基)-1，2，3，4-四氢异喹啉-3-甲酸，R-2-(4-苯氧基苯磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-苯氧基苯磺酰基)-1，2，3，4-四氢异喹啉-3-甲酸，R-2-(4-(4-二甲氨基苯氧基)苯磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-二甲氨基联苯基磺酰基)-1，2，3，4-四氢异喹啉-3-甲酸，R-2-(4-苯甲酰基苯磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-甲氧基苯磺酰基)-7-羟基-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-甲氧基苯磺酰基)-7-硝基-1，2，3，4-四氢异喹啉-3-异羟肟酸，2-(4-甲氧基苯磺酰基)-6，7-亚丙基-1，2，3，4-四氢异喹啉-1-异羟肟酸，R-5-(4-甲氧基苯磺酰基)-4，5，6，7-四氢-1H-咪唑并-(4，5-c)-吡啶-6-异羟肟酸，R-2-(4-甲氧基苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-c)-吲哚-3-异羟肟酸，R-2-(4-苯氧基苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-c)-吲哚-3-异羟肟酸。
此外，尤其值得推荐的是其中在氨基与酸基之间的中心碳原子为R对映体的那些式I化合物。
术语卤素的含义是氟、氯、溴或碘。术语烷基或烷氧基应理解为其中的碳链可以是直链、支链或环状的基团，环烷基是例如3-至6-元单环如环丙基、环丁基、环戊基或环己基。
“式V的杂环”包括例如硫代吗啉、哌啶、吗啉或哌嗪。
合适的式I化合物的生理耐受盐是例如碱金属、碱土金属和铵盐，包括有机铵碱或碱性氨基酸的盐。
本发明还提供了式I化合物和/或式I化合物的生理耐受盐和/或式I化合物的任何立体异构形式的制备方法，该方法包括a)将式XI的亚氨基酸与(C1-C4)-醇或苄醇反应其中基团Q以及m和n如在式I中所定义，得到式XII化合物其中Rx是(C1-C4)-烷基或苄基，或者b)在碱存在下，或者如果需要，在脱水剂存在下，将通过方法a)制备的式XII化合物与式XIII化合物反应
其中R1如在式I中所定义，Rz是氯原子、咪唑基或-OH，得到式XIV化合物
其中Q、R1、n和m如在式I中所定义，Rx如在式XII中所定义，或者c)将通过方法a)制备的式XII化合物与碱反应，然后与式XIII化合物反应，得到式XIV化合物，或者d)将式XI化合物与式XIII化合物反应，得到式XV化合物
其中Q、R1、n和m如在式I中所定义，或者e)使式XIV化合物反应生成式XV化合物，或者f)将通过方法b)或c)制备的式XIV化合物与式XVI的羟胺反应
(XVI) H2N-ORy其中Ry是氢原子或氧保护基，得到式I化合物，并且如果需要，除去氧保护基，或者g)将通过方法d)或e)制备的式XV化合物与式XVI的羟胺反应，得到式I化合物，或者h)通过与对映体纯的酸或碱形成盐、在手性固定相上进行色谱分离或者用手性对映体纯的化合物例如氨基酸进行衍生，分离所得非对映体，并除去手性助剂，将按照方法f)或g)制备的基于其化学结构以对映体形式存在的式I化合物分离成纯的对映体，或者i)将按照方法f)、g)或h)制备的式I化合物以游离形式分离，或者如果存在酸性或碱性基团，任选地将其转化为生理耐受的盐。
如果使用(C1-C4)-醇，则方法步骤a)的反应在氯化氢气体或亚硫酰氯存在下、在常规条件下进行。使用合适的醇和酸例如对甲苯磺酸，在苯或甲苯中制备相应的式XII的苄基酯。例如，可以采用异丁烯和硫酸，按照已知方法制备叔丁酯。
在碱性化合物例如N-甲基吗啉(NMM)、N-乙基吗啉(NEM)、三乙胺(TEA)、二异丙基乙胺(DIPEA)、吡啶、可力丁、咪唑或碳酸钠存在下，在溶剂例如四氢呋喃(THF)、二甲基甲酰胺(DMF)、二甲基乙酰胺、二噁烷、乙腈、甲苯、氯仿或二氯甲烷中，或甚至在水存在下，进行方法步骤b)的反应。优选在NMM存在下、在THF中，使用式XIII的磺酰氯进行该反应，
在碱例如氢氧化钾、氢氧化锂或氢氧化钠存在下进行方法步骤c)的反应。
在含水有机溶剂体系中，优选在THF和水中，在碱例如碳酸钠和式XIII化合物存在下，进行方法步骤d)的反应。此外，可以在无溶剂、有碱或无碱的情况下在减压条件下(例如可由油泵达到)进行该反应。
通过例如碱性或优选酸性水解，或者如果是苄基衍生物，则通过氢解，由式XIV化合物得到式XV化合物(方法步骤e)。如果是碱性水解，则必须用另一种酸，例如用稀盐酸进行处理，从羧酸盐中将游离羧酸释放出来。
在形成羧酰胺的常规条件下，在合适的溶剂例如乙醇或二甲基甲酰胺中，进行方法步骤f)的反应。
在方法步骤g)，将式XV的羧酸活化。活性羧酸是例如酰卤、酰基叠氮化物、混合酸酐和碳酸酯。优选的是酰氯或酰氟、混合酸酐和新戊酰氯的碳酸酯、氯甲酸乙酯、氯甲酸异丙酯或氯甲酸异丁酯；活性酯，例如氰基乙酯、邻硝基苯酯或对硝基苯酯、琥珀酰亚氨基或邻苯二甲酰亚氨基，以及可用偶合剂(如二异丙基碳化二亚胺(DIC)、羰基二咪唑(CDI)、二环己基碳化二亚胺(DCC)或四氟硼酸苯并三唑基四甲基(TBTU))得到的活性羧酸，如果需要，可以在偶合剂中加入羟基苯并三唑(HObt)或氧代羟基苯并三嗪(HOObt)，优选的溶剂是非质子传递溶剂。
所用原料和试剂可以按照已知方法制备，或者可以是商购的。
其中n和m是1的合适的式XI的亚氨基酸是例如，1，2，3，4-四氢异喹啉-3-甲酸、1，2，3，4-四氢-9H-吡啶并(3，4-b)-吲哚-3-甲酸或任意1-或3-取代的4，5，6，7-四氢-1H-咪唑并-(4，5-c)-吡啶-6-甲酸。该化合物优选在酸例如盐酸或硫酸存在下，采用Pictet-Spengler方法(参见W.M.Whaley，有机反应(Organic Reactions)6(1951)151)，用甲醛将相应的氨基酸环合进行制备。
如果是其中n为0且m为2的式XI的亚氨基酸，则可以使用例如，1，2，3，4-四氢-9H-吡啶并(3，4-b)-吲哚-1-甲酸和6，7-亚丙基-1，2，3，4-四异喹啉-1-甲酸作为原料。为了制备后一化合物，用苯磺酰基氮丙啶(arziridine)将1，2-二氢化茚按Friedel-Crafts反应烷基化。在HBr/冰醋酸中，将得到4-(2-苯磺酰氨基乙基)-1，2-二氢化茚与乙醛酸进行环合反应；然后在HBr/冰醋酸中，用碘/红磷裂解苯磺酰基。
其中n是1且m是0的式XI化合物的实例是二氢吲哚-2-甲酸。例如，通过催化氢化吲哚-2-甲酸制备上述化合物。此外，可以提及的是，将2-氯苯丙氨酸或2-羟基-3-(2-氯苯基)丙酸环化，得到式XI的亚氨基酸。
如果式I化合物存在非对映体或对映体，并且在所选择的合成中以其混合物形式获得，则可以通过以下方法将其分离成纯的立体异构体：在任选手性载体物质上进行色谱分离，或者，如果外消旋的式I化合物或式XI化合物可以形成盐，则将其与作为助剂的旋光性的碱或酸形成的非对映体的盐分级结晶。用于分离对映体的薄层色谱或柱色谱的合适手性固定相是，例如，改性二氧化硅载体(所谓的Pirkle相)和高分子量碳水化合物如三乙酰基纤维素。为了进行分析，还可以在本领域专业人员已知的适当衍生化之后，采用利用手性固体相的气相色谱法。为进行外消旋羧酸的对映体分离，用旋光活性的、通常市售的碱，例如(-)-尼古丁、(+)-和(-)-苯乙胺、奎宁碱、L-赖氨酸或L-和D-精氨酸形成具有不同溶解度的非对映体的盐。分离固体形式的难溶性成分，从母液中除去更易溶的非对映体，并由如此得到的非对映体的盐得到纯的对映体。以基本同样的方式，可以用旋光活性的酸例如(+)-樟脑-10-磺酸、D-和L-酒石酸、D-和L-乳酸以及(+)和(-)-扁桃酸，将含有碱性基团例如氨基的式I外消旋化合物转化为纯的对映体。还可以用适当活化的或任意N-保护的对映体纯的氨基酸将含有醇或胺官能团的手性化合物转化为相应的酯或酰胺，或者相反，用羧基保护的对映体纯的氨基酸将手性羧酸转化为酰胺，或者，用对映体纯的羟基羧酸例如乳酸将手性羧酸转化为相应的手性酯。然后，通过采用结晶或在合适的固定相上进行色谱分离来分离存在的非对映体，然后除去引入的手性分子部分(采用合适的方法进行)，可以利用对映体纯的氨基酸或醇基的手性分离异构体。
酸性或碱性式I化合物可以以其盐或游离的形式存在。优选生理耐受的盐，例如碱金属盐或碱土金属盐或盐酸盐、氢溴酸盐、硫酸盐、半硫酸盐、所有可能的磷酸盐以及氨基酸盐、生物碱或羧酸盐。
可以使用游离形式的羟胺，它是由羟胺盐和合适的碱在溶液中得到的或O-保护形式的羟胺，或者在任何情况下也可以是其盐的形式的羟胺。游离羟胺的制备方法是文献中已知的，并且可以在例如醇溶液中进行制备。优选使用盐酸与醇盐例如甲醇钠、氢氧化钾或叔丁醇钾的混合物。
O-保护的羟胺衍生物优选含有这样保护基，该保护基可以在温和的条件下除去。特别优选的保护基是甲硅烷基、苄基和缩醛类。特别适用于此目的的保护基是O-三甲基甲硅烷基、O-叔丁基二甲基甲硅烷基、O-苄基、O-叔丁基和O-四氢吡喃基衍生物。
如果用于制备式I化合物的原料和中间体在例如基团R1、R2、R3、R4、R5、R6、R7和R8中含有如羟基、巯基、氨基或羧基的官能基，则可以以适当保护的形式使用。
在所有这样的情况下均需引入保护基，其中在所需的化学反应中，预期不希望的副反应发生在除反应中心之外的其他位置(T.W.Greene，有机合成中的保护基，Wiley，New York，1991)。
可在将式XII化合物转化为式I化合物之前或之后，将所用的保护基除去。
特别适用的助剂和碱是：HObt、HOObt、N-羟基琥珀酰亚胺(HOSu)、TEA、NMM、NEM、DIPEA、咪唑。优选的反应溶剂是：二氯甲烷(DCM)、THF、乙腈、N，N-二甲基乙酰胺(DMA)、DMF和N-甲基吡咯烷酮(NMP)。
根据所用溶剂的沸点和性质，优选的温度是-78℃至+90℃。特别优选的是-20至+30℃。
按照本身已知的方法，由可以形成盐的式I化合物、包括其立体异构形式，制备生理耐受的盐。羧酸和异羟肟酸与碱性试剂形成稳定的碱金属盐、碱土金属盐或任意取代的铵盐，碱性试剂例如是氢氧化物、碳酸盐、碳酸氢盐、醇盐和氨或有机碱(例如三甲胺或三乙胺、乙醇胺或三乙醇胺)或碱性氨基酸(例如赖氨酸、鸟氨酸或精氨酸)。如果式I化合物具有碱性基团，还可以用强酸制备稳定的酸加成盐。适用于此目的的是无机酸和有机酸，例如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、4-溴苯磺酸、环己基酰氨基磺酸、三氟甲磺酸、乙酸、草酸、酒石酸、琥珀酸或三氟乙酸。
本发明还涉及药物，该药物含有有效量的至少一种式I化合物和/或式I化合物的生理耐受盐和/或式I化合物的任何立体异构形式，以及可药用的和生理耐受的赋形剂、添加剂和/或其他活性化合物和助剂。
根据药理学性质，本发明化合物适用于预防和治疗所有在其过程中降解基质的金属蛋白酶活性增加的那些疾病。这些疾病包括退化性关节疾病例如骨关节病、脊椎病、关节损伤后或者半月板或髌骨损伤或韧带撕裂后关节较长时间固定后的软骨萎缩(Knorpelschwund)。此外，所述疾病还包括结缔组织疾病，例如胶原病、牙周疾病、创伤愈合疾病和运动器官慢性疾病例如炎症、与免疫或代谢有关的急性或慢性关节炎性皮疹(Arthritiden)、关节病、肌痛和骨代谢疾病。式I化合物还适用于治疗溃疡、动脉粥样硬化和狭窄。式I化合物还可以明显抑制细胞肿瘤坏死因子(TNFα)的释放，因而适用于治疗炎症、癌病、转移瘤形成、恶病质、厌食和败血性休克。
本发明的药物一般经口和非肠道给药。也可以经直肠或经皮给药。
本发明还涉及药物的制备方法，该方法包括用可药用和生理耐受的赋形剂，以及如果需要，加入其他合适的活性化合物、添加剂或助剂，将至少一种式I化合物配制成适于给药的形式。
合适的固体药物制剂是例如颗粒剂、粉末、包衣片、片剂、(微)胶囊、栓剂、糖浆、汁剂、悬浮液、乳液、滴剂或注射溶液以及延长活性化合物释放的制剂，在这些制剂中使用常规助剂，例如赋形剂、崩解剂、粘合剂、包衣剂、膨胀剂、助流剂或润滑剂、矫味剂、甜味剂和加溶剂。可以提及的经常使用的助剂是碳酸镁、二氧化钛、乳糖、甘露醇和其他糖、滑石、乳蛋白、明胶、淀粉、纤维素及其衍生物、动物和植物油例如鱼肝油、葵花油、花生油或芝麻油、聚乙二醇，以及溶剂例如无菌水和一元醇或多元醇如甘油。
优选将药物制剂制备成剂量单位形式，并以此形式给药，每一剂量单位含有预定量的本发明式I化合物作为活性成分。如果是固体剂量单位如片剂、胶囊、包衣片或栓剂，该剂量可以高达约1000毫克，但是优选约50-300毫克，如果是安瓿形式的注射溶液，该剂量可以高达约300毫克，优选约10-100毫克。
如果是治疗体重约70公斤的成年患者-根据式I化合物的功效，日剂量约为20毫克至1000毫克活性化合物，优选约100毫克-500毫克。当然，在某些情况下，可以适当提高或降低日剂量。该日剂量可以以单一剂量单位的形式或者以几个较小的剂量单位形式单次给药，以及按照特定的时间间隔多次分小剂量给药。
用Varian公司的200MHz装置记录1H-NMR图谱，通常使用四甲基硅烷(TMS)做内标，并在室温(RT)进行。在每种情况下指明所用溶剂。通常，用质谱法(FAB-、ESI-MS)测定最终产物。温度数据以摄氏度表示，RT表示室温(22℃-26℃)。所用的缩写或者给予解释或者与常规方式相应。
制备实施例
按照与实施例13、24-26、28、29、31和32中所述类似的方法制备表1中的化合物1-12、14-23、27、30和33。
在实施例4-9中，首先如“Tic-sulfonation”所述(参见实施例13)，用对-(实施例4、6、9)或间-(实施例5、7、8)硝基苯磺酰氯进行磺化反应。然后，在本领域技术人员已知的标准条件下，在大气压下，在10％Pd-活性炭存在下、在甲醇中，用氢将硝基氢化，得到胺。
在所有情况下，还可以使用实施例13中所述的Tic苄基酯进行磺化反应。在随后的氢化中，同时将苄基酯裂解并还原，得到胺。然后将在两种情况下得到的相同产物对-或间-氨基苯磺酰Tic如下进行进一步反应：实施例4：
首先，在标准条件(三乙胺/DMAP/乙酸酐)下进行乙酰化：然后，按照实施例25所述将以高产率得到的N-乙酰基化合物进行进一步反应，得到异羟肟酸。实施例5和6：
为了制备异羟肟酸，按照与实施例13所述同样的方法将对氨基苯磺酰-Tic活化，不同的是使用双倍量的氯甲酸乙酯和N-甲基吗啉。一步完成不可逆的N-乙氧羰基化反应，并将羧酸活化。实施例7、8和9：
在本领域专业人员已知的Schotten-Baumann条件下，将上述对-或间-氨基苯磺酰-Tic酰化。为此，使用实施例7：水杨酰氯，实施例8：对甲氧基苯甲酰氯，实施例9：氯甲酸苄基酯。如实施例25所述进行进一步反应，得到异羟肟酸。实施例13：R-2-(4-苯氧基苯磺酰)-1，2，3，4-四氢异喹啉-3-异羟肟酸一般方法：对甲苯磺酸的Tic苄基酯
将1摩尔Tic(游离氨基酸)、10摩尔苄醇和1摩尔对甲苯磺酸一水合物溶解或悬浮在1.2升甲苯中，并用分水器加热回流。反应结束时，蒸发溶剂，将固体结晶残余物多次吸收在乙醚中并吸滤，然后用油泵真空干燥。产量：定量。1H-NMR：(200MHz，δin ppm，DMSO-d6)9.7(s，br.，2H，prot.NH)，7.5-7.25(2m，7H，芳族，7.1(d，2H，芳族.p-TsOH)，5.3(s，2H，CH2苄基)；4.7(dd，1H，CHα)；4.4″d″，2H，CH2)；3.4-3.1(m，2H，CH2)；2.3(s，1H，CH3p-TsOH).Tic磺化
在0℃，将0.1摩尔Tic在50毫升2N氢氧化钠水溶液中的溶液(游离氨基酸17.7克)与细粉化的磺酰氯(105毫摩尔)混合，然后加入14.2克(110毫摩尔)二异丙基乙胺和50毫升丙酮或THF。10分钟后移去冰浴，在室温再搅拌或多或少均匀的溶液6小时。然后将反应混合物浓缩，与300毫升乙酸乙酯混合，并用4N盐酸酸化。分离有机相，水相用各50毫升的乙酸乙酯萃取两次。合并的有机相用饱和氯化钠溶液振摇萃取，用硫酸钠干燥。蒸馏除去溶剂，得到油状或固体残余物状的磺化四氢异喹啉甲酸，在某些情况下，可以将产物从乙酸乙酯/石油醚中重结晶进行纯化，但是通常所得产物的纯度足以用于下一步反应。13a R-2-(4-苯氧基苯磺酰)-1，2，3，4-四氢异喹啉-3-甲酸甲酯
在1.7毫升(0.01摩尔)N-乙基吗啉存在下，将1.92克(0.01摩尔)R-1，2，3，4-四氢异喹啉-3-甲酸甲酯和2.7克(0.01摩尔)4-苯氧基苯磺酰氯在50毫升无水THF中的溶液加热回流8小时。除去溶剂，将残余物吸收在二氯甲烷中，所得溶液依次用5％柠檬酸、5％碳酸氢钠溶液和2次用水萃取。有机相用硫酸钠干燥并浓缩，得到酯，无需纯化，即将所得酯用于下一步反应。产量：4.0克(理论值的95％)13a。13b R-2-(4-苯氧基苯磺酰)-1，2，3，4-四氢异喹啉-3-甲酸
在室温下，向4.0克(9.5毫摩尔)酯(13a)在50毫升异丙醇中的溶液中加入9.5毫升1N氢氧化钠水溶液，然后搅拌该溶液24小时。用1N盐酸将该混合物酸化，并减压蒸发至干。将残余物吸收在甲苯中，所得溶液用5％柠檬酸萃取，有机相用硫酸钠干燥，并减压浓缩。产量：3.4克羧酸13b(理论值的83％)熔点：147℃。13c R-2-(4-苯氧基苯磺酰)-1，2，3，4-四氢异喹啉-3-异羟肟酸
将3.4克(8.3毫摩尔)羧酸13b溶解在30毫升DMF中，并在-20℃依次与1.4克(12毫摩尔)N-乙基吗啉和1.13克(8.3毫摩尔)氯甲酸异丁酯混合。活化30分钟后，将该混合物与4.37克(41.5毫摩尔)O-三甲基甲硅烷基羟胺混合，并在室温搅拌4小时。向该混合物中加入250毫升乙酸乙酯和500毫升水，并用柠檬酸酸化。分离有机相，萃取水相4次，合并的有机相用硫酸钠干燥，并减压浓缩。从甲苯/乙酸乙酯(1∶1)中重结晶，得到标题化合物13。产量：2.9克(理论值的82％)，熔点：170℃(分解)。实施例17：
在标准条件下，使用反-β-苯乙烯磺酰氯将Tic-苄基酯磺化(参见实施例13)。在随后的氢化(H2，Pd/C)中，脱苄基和双键的氢化一步完成。然后按照实施例25的方法形成异羟肟酸。实施例20、21和22：
原料是市售的7-羟基-Tic。按照方法的方案d)，在标准条件下进行磺化。经常规处理后，得到2-和7-二磺化的7-羟基-Tic混合物和单独的2-磺化的7-羟基-Tic。但是，在此阶段不需要分离两种化合物。在标准条件下直接进行转化，得到异羟肟酸。如同预期的那样，在活化过程中部分7-羟基发生乙氧羰基化作用。因此，异羟肟酸产物的混合物含有所有三种产物，这些产物可以用硅胶60经色谱、经制备薄层色谱或HPLC分离。实施例23：
制备7-硝基-Tic的原料是对映体纯的市售(R)-Tic-OH或(S)-Tic-OH。按照E.D.Bergann，J.Am.Chem.Soc.74，4947(1952)或按照E.Erlenmever，A.Lipp.Liebigs Ann.Chem.219，218(1983)的方法，通过用硝化酸硝化，制备7-硝基-Tic。其中形成6-和7-硝基异构体混合物，并且反应混合物中还含有未硝化的原料。首先在标准条件下将该混合物磺化，然后进行分离。之后在硅胶60上经色谱分离三种磺酰胺的混合物。依次得到含有原料/6-硝基-和6-硝基-/7-硝基-(4-甲氧基苯磺酰基)-Tic的混合馏分；最后，洗脱出纯的7-硝基化合物馏分。按照与实施例25类似的方法，采用常规方法，可以将该物质转化为异羟肟酸。实施例24：2-(4-甲氧基苯磺酰基)-6，7-亚甲基二氧基-1，2，3，4-四氢异喹啉-3-异羟肟酸
由羧酸制备相应的羧酸苄基酯的方法与一般方法相应(参见实施例13)。按照与实施例25a类似的方法进行磺化或苄基酯的裂解。如实施例25b所述进行游离磺化羧酸的反应。
用乙醚处理后，得到结晶形式的产物。产量为140毫克，理论值的57％；熔点166℃。实施例25：2-(4-甲氧基苯磺酰基)-6，7，8-三甲氧基-1，2，3，4-四氢异喹啉-3-异羟肟酸25a 2-(4-甲氧基苯磺酰基)-6，7，8-三甲氧基-1，2，3，4-四氢异喹啉-3-甲酸
按照一般方法(参见实施例13)制备苄基酯。使用1.2克(3.05毫摩尔)苄基酯进行磺化。将其溶解在20毫升THF中，并在0℃与0.63克(3.05毫摩尔)4-甲氧基苯磺酰氯混合。加入0.32毫升N-甲基吗啉，并在0℃至室温搅拌反应混合物过夜。然后将该混合物与20毫升乙酸乙酯混合，用浓度为10％碳酸钠溶液和饱和氯化钠溶液萃取。有机相用硫酸钠干燥，过滤并减压浓缩。剩余的残余物在减压条件下，经硅胶60色谱色谱纯化，用乙酸乙酯/石油醚/冰醋酸(20/10/1)洗脱。合并纯的产物馏分(600毫克)，浓缩后，在50毫升乙醇中，用100毫克10％Pd/C直接氢化。反应结束后，分离催化剂，并将剩余的溶液减压浓缩。得到330毫克(理论值的66％)产物。25b 2-(4-甲氧基苯磺酰基)-6，7，8-三甲氧基-1，2，3，4-四氢异喹啉-3-异羟肟酸
将实施例25a得到的330毫克(0.75毫摩尔)羧酸溶解在15毫升THF中，并在-20℃依次与0.07毫升(0.75毫摩尔)氯甲酸乙酯和0.15毫升(1.5毫摩尔)N-甲基吗啉(NMA)混合。在此温度保持30分钟后，将该混合物与0.474毫升O-三甲基甲硅烷基羟胺(3.75毫摩尔)混合。在室温保持6小时后，向该混合物中加入30毫升乙酸乙酯，然后用浓度为20％的柠檬酸溶液和饱和氯化钠溶液萃取。有机相用硫酸钠干燥，并减压浓缩，得到290毫克透明的粘稠油，将该油从乙醚中结晶。实施例26：2-(吗啉代磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸26a 2-(吗啉代磺酰基)-1，2，3，4-四氢异喹啉-3-甲酸甲酯
在搅拌下，将在20毫升THF中的4.2克(0.025摩尔)吗啉-N-磺酰氯滴加至4.8克(0.025摩尔)1，2，3，4-四氢异喹啉-3-甲酸甲酯和2.9克(0.025摩尔)N-乙基吗啉溶液中。在室温搅拌该混合物2小时，然后再加热回流2小时使反应进行完全。向反应溶液中加入氯仿，然后用浓度为5％的柠檬酸、5％碳酸氢钠溶液和水处理。有机相用硫酸钠干燥并蒸发至干。酯(26a)的产量：7.5克(理论值的92％)。26b 2-(吗啉代磺酰基)-1，2，3，4-四氢异喹啉-3-甲酸
按照13b的方法，用7.5克(0.023摩尔)26a进行反应。羧酸26b的产量：6.7克(理论值的93％)。26c 2-(吗啉代磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸
将2.3克(7.5毫摩尔)羧酸26b溶解在40毫升无水THF中，并在-20℃依次与1.2克(12毫摩尔)N-甲基吗啉和1.1克(7.5毫摩尔)氯甲酸异丁酯混合。30分钟后，将该混合物与3.9克(37.5毫摩尔)O-三甲基甲硅烷基羟胺混合，并在室温再搅拌5小时。加入200毫升水，用稀盐酸酸化该混合物，并用二氯甲烷反复萃取。合并的有机相用硫酸钠干燥，并减压浓缩。所得油在减压条件下经硅胶60色谱纯化，用乙酸乙酯/二氯甲烷(1∶1)做流动相。产物馏分从乙酸乙酯中重结晶，得到结晶状的异羟肟酸26c。产量：1.4克(理论值的55％)，熔点：164-165℃(分解)。实施例28：1-(4-甲氧基苯磺酰基)二氢吲哚-2-异羟肟酸28a 1-(4-甲氧基苯磺酰基)二氢吲哚-2-甲酸
在50℃和0.02毫巴下，在缓慢并连续旋转的Kugelrohr中，将1克(6.1毫摩尔)二氢吲哚-2-甲酸和2.5克(12.2毫摩尔)4-甲氧基苯磺酰氯保持4小时。然后将棕色结晶产物吸收在碳酸钠溶液中，用乙醚萃取两次。水相用6N盐酸酸化，并用乙酸乙酯萃取4次。合并的有机相用饱和氯化钠溶液萃取，用硫酸钠干燥，并减压浓缩。用油泵真空除去剩余的溶剂。产量：1.34克(理论值的65％)1H-NMR：(DMSO-d6)7.8；7.1(2d，4H，芳族.p-TsOH)；7.4-7.0(m，4H，芳族)；4.9(dd，1H，CHα)；3.8(2，3H，OMe)；3.4-2.9(2dd，2H，CH2)28b 1-(4-甲氧基苯磺酰基)二氢吲哚-2-异羟肟酸
将1.3克(3.9毫摩尔)实施例28a的1-(4-甲氧基苯磺酰基)二氢吲哚-2-甲酸溶解在10毫升N，N-二甲基乙酰胺(DMA)中，并在-20℃依次与0.37毫升(1当量)氯甲酸乙酯和0.81毫升N-甲基吗啉混合。活化30分钟后，将该混合物与3.8毫升(19.5毫摩尔)O-三甲基甲硅烷基羟胺混合，并在室温再搅拌4小时。将该混合物用乙酸乙酯稀释，用柠檬酸酸化，并在除去水相后，用饱和氯化钠溶液洗涤。有机相用硫酸钠干燥，过滤并减压浓缩。所得油在减压条件下经硅胶60色谱纯化，用二氯甲烷/乙酸乙酯/乙酸(5.5/3.5/1)做流动相。合并产物馏分(显示阳性氯化铁(III)反应)并浓缩。然后将结晶产物与乙醚混合，并减压除去剩余的溶剂。产量：400毫克(理论值的33％)，熔点：142℃。实施例29：R-5-(4-甲氧基苯磺酰基)-4，5，6，7-四氢-1H-咪唑并-(4，5-c)-吡啶-6-异羟肟酸盐酸盐29a：R-3，5-二(4-甲氧基苯磺酰基)-4，5，6，7-四氢-1H-咪唑并-(4，5-c)-吡啶-6-甲酸
在冰冷却下，向6.1克(30毫摩尔)4，5，6，7-四氢-1H-咪唑并-(4，5-c)-吡啶-6-甲酸盐酸盐在50毫升水中的溶液中依次加入15毫升2N氢氧化钠和4.5克(42毫摩尔)碳酸钠。在搅拌下，加入在40毫升乙醚中的13.7克(67毫摩尔)4-甲氧基苯磺酰氯。在室温再搅拌反应混合物24小时，然后在用冰冷却下，用5N盐酸调节反应混合物至pH3-4，并用乙酸乙酯萃取。有机相用硫酸钠干燥，过滤并浓缩至干，得到11.9克(理论值的78％)油状所需产物。29b：R-5-(4-甲氧基苯磺酰基)-4，5，6，7-四氢-1H-咪唑并-(4，5-c)-吡啶-6-甲酸盐酸盐
在冰冷却和搅拌下，以1小时的间隔，向11.0克(24毫摩尔)二磺化的中间体在300毫升甲醇中的溶液中滴加各23.5毫升1N的氢氧化钠溶液。6小时后，最后加入15毫升1N氢氧化钠，并在室温搅拌该混合物过夜。减压除去甲醇，然后用5N盐酸调节该混合物至pH5。吸滤出沉淀的结晶，并用P205减压干燥。产量：5.2克(理论值的60％)29b熔点：264-265℃(分解)29c：R-5-(4-甲氧基苯磺酰基)-4，5，6，7-四氢-1H-咪唑并-(4，5-c)-吡啶-6-异羟肟酸盐酸盐
将在60毫升DMF中的8.0克(24毫摩尔)化合物29b与4.27克(24毫摩尔)四甲基氢氧化铵混合，然后在0℃与2.7克(24毫摩尔)N-乙基吗啉混合，并分批地与5.2克(24毫摩尔)碳酸二叔丁酯(di-tert-butyl dicarbonate)混合。搅拌反应混合物过夜，将其倒入冰水中，用稀盐酸调节至pH5，并用乙酸乙酯反复萃取。合并干燥的有机相，除去溶剂后，得到10.5克BOC-保护的29b，该产物直接用于制备异羟肟酸。
为此，将10.5克(23毫摩尔)上述化合物溶解在150毫升无水THF中，并在-20℃与4.4克(38毫摩尔)N-乙基吗啉和3.4克(25毫摩尔)氯甲酸异丁酯混合。搅拌该混合物1小时，然后加入10.9克(0.1摩尔)O-三甲基甲硅烷基羟胺，保持-20℃的温度1小时。在室温搅拌4小时后，用1N盐酸将反应混合物调节至pH＝1，与300毫升水混合，并用二氯甲烷反复萃取。合并的有机相用硫酸钠干燥并减压浓缩至干。
为了裂解BOC保护基，将8.1克剩余的油吸收在50毫升二氯甲烷中，并在0℃滴加25毫升三氟乙酸。在室温搅拌反应混合物4小时，然后减压浓缩。用二氯甲烷浸提残余物，然后溶解在0.1N盐酸中，过滤并冻干。异羟肟酸29的产量：5.2克(理论值的56％)熔点：110℃。实施例31：R-2-(4-甲氧基苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-b)-吲哚-3-异羟肟酸31a R-2-(4-甲氧基苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-b)-吲哚-3-甲酸
在加入10.5毫升2N氢氧化钠后，在搅拌下，将2.16克(10毫摩尔)1，2，3，4-四氢-9H-吡啶并-(3，4-b)-吲哚-3-甲酸在10毫升丙酮和10毫升水的混合物中的溶液与2.06克(10毫摩尔)4-甲氧基苯磺酰氯混合。在室温搅拌该溶液18小时，除去丙酮，用浓盐酸调节溶液至pH1。滤出所得沉淀，用水洗涤并干燥。产量：2.7克羧酸31a(理论值的85％)熔点：232-234℃31b R-2-(4-甲氧基苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-b)-吲哚-3-异羟肟酸
将2.5克(7.4毫摩尔)羧酸31a溶解在40毫升无水DMF中，并在-20℃依次与1.4毫升(12毫摩尔)N-乙基吗啉和0.97毫升(7.4毫摩尔)氯甲酸异丁酯混合。活化30分钟后，加入4.53毫升(37毫摩尔)O-三甲基甲硅烷基羟胺，然后在室温搅拌该混合物19小时。用柠檬酸将该混合物调节至pH3.5，然后用乙酸乙酯反复萃取。合并的有机相用硫酸钠干燥，减压浓缩，并通过硅胶色谱纯化，用二氯甲烷/甲醇(95∶5)作洗脱剂。产量：2.4克异羟肟酸(理论值的91.5％)熔点：87℃。实施例32：R-2-(4-苯氧基苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-b)-吲哚-3-异羟肟酸
按照实施例31的方法制备熔点：110-111℃实施例33：R-2-(4-吗啉代苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-b)-吲哚-3-异羟肟酸
按照实施例31的方法制备熔点：125℃(分解)实施例42：R-2-[4-(4-氯苯氧基)苯磺酰基]-1，2，3，4-四氢异喹啉-3-甲酸
将8.2克(46.4毫摩尔)R-1，2，3，4-四氢异喹啉-3-甲酸与46.4毫升1N氢氧化钠和50毫升丙酮混合，并溶解在水中。在-5℃和搅拌下，滴加在50毫升THF中的14.1克(46.4毫摩尔)4-(4-氯苯氧基)苯磺酰氯，并在加入一半后，将反应混合物与6.0克(46.4毫摩尔)二异丙基乙胺混合。将该混合物搅拌过夜，滤出沉淀，用2N盐酸调节滤液至pH＝3，并用二氯甲烷反复萃取。合并的有机相用硫酸钠干燥，过滤并减压蒸发至干。从甲苯中重结晶，并减压干燥，得到标题化合物。产量：16.1克(理论值的78％)，熔点：168-169℃。
表1：通式I的异羟肟酸
对于国际阶段不予以考虑(原文如此)
表2：通式I的羧酸
药理学实施例
人stomelysine和中性白细胞胶原酶催化结构域酶促活性的说明与测定。
按照Ye等所述(生物化学(Biochemistry)31(1992)11231-5)制备两种酶。为了测定酶的活性或酶的抑制作用，将70微升缓冲溶液和10微升酶溶液与10微升浓度为10％(v/v)的二甲基亚砜水溶液一起保温15分钟，后者中任意含有酶抑制剂。加入含有1毫摩尔/升底物的10微升浓度为10％(v/v)的二甲基亚砜水溶液之后，通过荧光光谱(328nm(ex)/393nm(em))监测酶的反应。酶的活性被描述成吸光度的增加/分钟。测定表3中所列出的IC50值，该值表示导致50％酶抑制的抑制剂浓度。该缓冲溶液含有0.05 Brij(Sigma，Deisenhofen，德国)和0.1摩尔/升tris/HCl、0.1摩尔/升氯化钠、0.01摩尔/升氯化钙(pH＝7.5)以测定直至实施例33(包括实施例33在内)的异羟肟酸，或者为测定自实施例34的羧酸、包含0.1摩尔/升哌嗪-N，N′-二[2-乙磺酸]pH＝6.5。
所述酶溶液含有5微克/毫升按照Ye等所述方法制备的一种酶结构域。底物溶液含有1毫摩尔/升荧光底物(7-甲氧基香豆素-4-基)乙酰基-Pro-Leu-Gly-Leu-3-(2′，4′-二硝基苯基)-L-2，3-二氨基丙酰基-Ala-Arg-NH2(Bachem，Heidelberg，德国))。表3
2.蛋白多糖降解实验实验原理：
| 实施例编号 | StromelysineIC50[M] | 中性白细胞胶原酶IC50[M] |
| 1 | 3*10-7 | 2*10-8 |
| 2 | 2*10-8 | 2*10-9 |
| 3 | 3*10-8 | 2*10-9 |
| 4 | 7*10-7 | 1*10-7 |
| 5 | 6*10-6 | 3*10-7 |
| 6 | 5*10-7 | 3*10-8 |
| 8 | 3*10-6 | 2*10-7 |
| 9 | 4*10-7 | 8*10-7 |
| 10 | 3*10-7 | 1*10-7 |
| 11 | 4*10-7 | 7*10-8 |
| 12 | 4*10-7 | 2*10-7 |
| 13c | 2*10-8 | 2*10-9 |
| 14 | 3*10-8 | 2*10-9 |
| 15 | 1*10-7 | 1*10-8 |
| 17 | 1*10-7 | 2*10-8 |
| 18 | 3*10-8 | 3*10-9 |
| 19 | 2*10-6 | 3*10-7 |
| 20 | 1*10-8 | 1*10-9 |
| 21 | 2*10-8 | 2*10-9 |
| 22 | 3*10-8 | 8*10-9 |
| 23 | 8*10-8 | 8*10-9 |
| 24 | 6*10-8 | 2*10-8 |
| 25 | 4*10-7 | 3*10-7 |
| 26 | 6*10-6 | 3*10-7 |
| 27 | 3*10-8 | 4*10-9 |
| 实施例编号 | StromelysineIC50[M] | 中性白细胞胶原酶IC50[M] |
| 28 | 2*10-6 | 7*10-7 |
| 29 | 2*10-8 | 4*10-9 |
| 31 | 2*10-8 | 3*10-9 |
| 32 | 6*10-8 | 7*10-9 |
| 33 | 3*10-7 | 7*10-8 |
| 34 | 5*10-7 | 1*10-8 |
| 35 | 1*10-7 | 5*10-9 |
| 36 | 3*10-6 | |
| 39 | 1*10-7 | 1*10-9 |
| 41(13b) | 2*10-7 | 9*10-9 |
| 42 | 5*10-7 | 2*10-8 |
| 43 | 2*10-6 | 2*10-7 |
| 44 | 2*10-7 | 3*10-8 |
| 45 | 3*10-6 | 3*10-7 |
| 46 | 3*10-6 | 3*10-7 |
| 50 | 6*10-7 | 3*10-8 |
| 51 | 5*10-7 | 2*10-8 |
| 52 | 1*10-6 | 4*10-8 |
| 53 | 5*10-7 | 2*10-8 |
| 57 | 2*10-6 | 1*10-7 |
在蛋白多糖降解实验中，测量天然牛聚集蛋白聚糖(Aggrecan)(最重要的关节软骨蛋白多糖)的降解程度。用单克隆抗体5-D-4测定释放的蛋白多糖片段，该抗体可识别位于聚集蛋白聚糖G2结构域羧基末端的硫酸角质素侧链。因此，该实验主要用于测定发生于聚集蛋白聚糖球间结构域的病理学重要降解。
在加入式I化合物和Stromelysine-1催化结构域形式的酶之后，测定降解后剩余的透明质酸结合的聚集蛋白聚糖的量。测定出的聚集蛋白聚糖越多，酶的残留活性越小。在表3中以IC50值表示初始酶活性(＝100％残留活性)降低一半(＝50％残留活性)时式I化合物的浓度。实验方案说明：
在室温，将各含100微升透明质酸溶液(25微克/毫升透明质酸(Sigma)的PBS溶液)的96孔微滴板(Nunc，Maxisorp)的每孔培养12小时。吸滤除去透明质酸溶液，在室温，用各100毫升浓度为5％的牛血清白蛋白(BSA)、0.05％吐温20的PBS溶液使各孔中剩余的游离蛋白结合位点饱和1小时。然后，在室温，通过用各100微升牛鼻蛋白多糖(ICI)(200微克/毫升，在1×PBS中，5毫克/毫升BSA，0.05％吐温20)培养各孔1小时，用蛋白多糖涂覆各孔。每孔用1×PBS、0.1％吐温20洗涤两次以除去游离的蛋白多糖。然后为了进行分析，将加有相应浓度实验用抑制剂的、在100微升降解缓冲液(Verdaupuffer)(100mM MES pH6.0，100mM氯化钠，10mM氯化钙，0.05％Brij)中的60ng纯化的Stromelysine-1催化结构域(重组表达和纯化，参见Ye等(1992))移入每孔中，并在室温培养3小时。用1×PBS、0.1％吐温20洗涤每孔两次，然后将孔用100微升检测抗体溶液(单克隆抗体克隆5-D-4(ICI)，能与蛋白多糖的硫酸胶质素侧链免疫反应，在1×PBS、5毫克/毫升BSA、0.05％吐温20中稀释1∶1000)培养。每孔用1×PBS、0.1％吐温20洗涤两次，然后在室温，用每孔100微升检测用抗体溶液(山羊抗鼠IgG，用过氧化酶标记(Dianova)，在1×PBS、5毫克/毫升BSA、0.05％吐温20中稀释1∶1000)进行结合检测抗体的免疫反应1小时。如上所述再洗涤每孔两次，然后用各100微升2毫克/毫升ABTS开始颜色反应，用双氧水活化。在ELISA读数器中，在405mm波长处对反应产物进行测量。结果示于表4中。表4
| 实施例编号 | 蛋白多糖降解IC50[M] |
| 2 | 8.5*10-8 |
| 9 | 1.6*10-6 |
| 13c | 5.1*10-8 |
| 14 | 6.7*10-9 |
| 18 | 4.1*10-8 |
| 20 | 1.3*10-7 |
| 21 | 6.5*10-8 |
| 29 | 2.5*10-8 |
Claims (13)
1.式I化合物
或式I化合物的任何立体异构形式、或式I化合物的生理耐受盐，其中在第i)种情况下：R1是a)式II基团b)式III基团
c)式IV基团其中Z是吗啉杂环基d)式V基团
其中o是1或2，且环碳原子中的一个可以被-O-或-S-置换，并且Q作为结构式I的一部分
1)是结构部分VI或5)是结构部分X
其中D是NR4或S，R2是1)苯基或2)被下列基团一-至三-取代的苯基2.1羟基，2.2-O-R10，其中R10是1)C1-C6-烷基，2)C3-C6-环烷基，3)苄基或4)苯基，2.3-COOH，2.4C1-C6-烷基，2.5C3-C6-环烷基-O-C1-C4-烷基，2.6卤素，2.7-CN，2.8-NO2，2.9-CF3，2.10-O-C(O)-R10，并且R10如上所定义，2.11-O-C(O)-苯基，苯基被R3基团一-或二-取代，2.12-C(O)-O-R10，并且R10如上所定义，2.13亚甲二氧基，2.14-C(O)-NR11R12，其中R11和R12可以相同或不同，它们各自为1)氢原子，2)C1-C4-烷基或3)苄基或4)R11和R12与和其相连的氮原子一起形成吡咯烷、哌啶、吗啉或哌嗪基，或者2.15-NR13R14，其中R13是氢原子或C1-C4-烷基，并且R14是1)氢原子，2)C1-C4-烷基，3)苄基，4)-C(O)-R10或5)-C(O)-O-R10，且R10如上所定义R3和R4各自为1)氢原子，R6、R7和R8彼此相同或不同，它们各自为a)氢原子，或b)在第i)种情况下，具有2.1至2.14条目下R2的含义，并且n是0、1或2，m是0、1或2，n与m之和为1、2或3，或者在第ii)种情况下R1是1)苯基或2)被R2基团一-至三-取代的苯基，其中R2如上在第i)种情况下条目2.1至2.15中所定义，Q是结构部分X，并且R6、R7和R8彼此相同或不同，它们各自如上所定义，n是1，并且m是1，或者在第iii)种情况下R1、Q、R6、R7和R8彼此相同或不同，并且它们各自如上对第ii)种情况所定义，m和n是0、1或2，并且其中m与n的含义不同，以及X是a)共价键，b)-O-，c)-S-，d)-S(O)-，e)-S(O)2-，f)-C(O)-或g)-C(OH)-，以及Y是a)-O-或b)-S-，并且A是HO-NH-C(O)-或HO-C(O)-以及B是a)-(CH2)q-，其中q是0、1、2、3或4。
2.权利要求1的式I化合物或式I化合物的生理耐受盐或式I化合物的任何立体异构形式，其中在第i)种情况下，R1是式II或III基团，并且Q是结构部分VI或X，在第ii)种情况下，R1是苯基或者被甲氧基一-至三-取代的苯基，并且Q是结构部分X，或在第iii)种情况下，R1是苯基，Q是结构部分X，n是0并且m是2，以及A是HO-NH-C(O)-或HO-C(O)-，B是共价键，X是氧原子或共价键，并且R2是苯基或者被下列基团取代的苯基a)羟基，b)-O-R10，其中R10是C1-C3-烷基或苄基，c)C1-C2-烷基，d)氟或氯，e)-CN，f)-CF3，或g)NR13R14，其中R13和R14各自为C1-C3-烷基，R3和R4各自为氢原子，R6、R7和R8彼此相同或不同，它们各自为a)氢原子，b)甲氧基，c)亚甲基二氧基，d)氨基或e)羟基。
3.权利要求1或2的式I化合物，其中所述化合物选自R-2-(联苯基磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-氯联苯基磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-氯联苯基磺酰基)-1，2，3，4-四氢异喹啉-3-甲酸，R-2-(4-苯氧基苯磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-苯氧基苯磺酰基)-1，2，3，4-四氢异喹啉-3-甲酸，R-2-(4-(4-二甲氨基苯氧基)苯磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-二甲氨基联苯基磺酰基)-1，2，3，4-四氢异喹啉-3-甲酸，R-2-(4-苯甲酰基苯磺酰基)-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-甲氧基苯磺酰基)-7-羟基-1，2，3，4-四氢异喹啉-3-异羟肟酸，R-2-(4-甲氧基苯磺酰基)-7-硝基-1，2，3，4-四氢异喹啉-3-异羟肟酸，2-(4-甲氧基苯磺酰基-6，7-亚丙基-1，2，3，4-四氢异喹啉-1-异羟肟酸，R-5-(4-甲氧基苯磺酰基)-4，5，6，7-四氢-1H-咪唑并-(4，5-c)-吡啶-6-异羟肟酸，R-2-(4-甲氧基苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-c)-吲哚-3-异羟肟酸，R-2-(4-苯氧基苯磺酰基)-1，2，3，4-四氢-9H-吡啶并-(3，4-c)-吲哚-3-异羟肟酸。
4.权利要求1或2所述的式I化合物，其中在氨基与异羟肟酸基之间的中心碳原子为R对映体形式。
5.权利要求1-4中一项所述的式I化合物的制备方法，该方法包括a)将式XI的亚氨基酸与C1-C4-醇或苄醇反应
其中基团Q以及m和n如权利要求1-4任一项中所定义，得到式XII化合物
其中Rx是C1-C4-烷基或苄基，或者b)在碱存在下，将通过方法a)制备的式XII化合物与式XIII化合物反应
其中R1如权利要求1-4任一项中所定义，Rz是氯原子、咪唑基或-OH，得到式XIV化合物
其中Q、R1、n和m如权利要求1-4任一项中所定义，Rx如在式XII中所定义，或者c)将通过方法a)制备的式XII化合物与碱反应，然后与式XIII化合物反应，得到式XIV化合物，或者d)将式XI化合物与式XIII化合物反应，得到式XV化合物
其中Q、R1、n和m如权利要求1-4任一项中所定义，或者e)使式XIV化合物反应生成式XV化合物，或者f)将通过方法b)或c)制备的式XIV化合物与式XVI的羟胺反应
(XVI) H2N-ORy其中Ry是氢原子或氧保护基，得到式I化合物，并且如果需要，除去氧保护基，或者g)将通过方法d)或e)制备的式XV化合物与式XVI的羟胺反应，得到式I化合物，或者h)通过与对映体纯的酸或碱形成盐、在手性固定相上进行色谱分离或者用手性对映体纯的化合物进行衍生，分离所得非对映体，并除去手性助剂，将按照方法f)或g)制备的基于其化学结构以对映体形式存在的式I化合物分离成纯的对映体，或者i)将按照方法f)、g)或h)制备的式I化合物以游离形式分离，或者如果存在酸性或碱性基团，任选地将其转化为生理耐受的盐。
6.权利要求5所述的制备方法，其中在步骤(h)中所用的手性对映体纯的化合物为氨基酸。
7.药物组合物，该药物组合物含有有效量的至少一种权利要求1-4中一项所述的式I化合物和/或式I化合物的生理耐受盐和/或式I化合物的任何立体异构形式，以及生理耐受的助剂和赋形剂，还任意含有其他添加剂和/或其他活性化合物。
8.权利要求1-4中一项所述的至少一种式I化合物在制备预防和治疗在其过程中降解基质的金属蛋白酶活性增加的疾病的药物中的用途。
9.权利要求8的用途，所述用途是用于治疗结缔组织疾病，牙周疾病，创伤愈合疾病，运动器官慢性疾病或者退化性关节疾病，或者用于治疗溃疡、动脉粥样硬化和狭窄，或者抑制肿瘤坏死因子的释放，或用于治疗炎症、癌病、转移瘤形成、恶病质、厌食和败血性休克。
10.权利要求9的用途，其中所述结缔组织疾病是胶原病。
11.权利要求9的用途，其中所述运动器官慢性疾病为炎症、与免疫或代谢有关的急性和慢性关节炎性皮疹、关节病、肌病和骨代谢疾病。
12.权利要求9的用途，其中所述退化性关节疾病为骨关节病、脊椎病、关节损伤后或者半月板或髌骨损伤或韧带撕裂后关节较长时间固定后的软骨萎缩。
13.权利要求7的药物的制备方法，该方法包括用生理耐受的助剂和赋形剂，以及如果需要，加入添加剂和/或其他活性化合物，将至少一种权利要求1-4中一项所述的式I化合物和/或式I化合物的生理耐受盐和/或式I化合物的任何立体异构形式配制成适于给药的形式。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19542189.2 | 1995-11-13 | ||
| DE1995142189 DE19542189A1 (de) | 1995-11-13 | 1995-11-13 | Cyclische N-substituierte alpha-Iminohydroxamsäuren |
| DE1996112298 DE19612298A1 (de) | 1996-03-28 | 1996-03-28 | Heterocyclische N-substituierte alpha-Iminohydroxamsäuren |
| DE19612298.8 | 1996-03-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1202156A CN1202156A (zh) | 1998-12-16 |
| CN1131215C true CN1131215C (zh) | 2003-12-17 |
Family
ID=26020318
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96198294A Expired - Fee Related CN1131215C (zh) | 1995-11-13 | 1996-11-04 | 环和杂环N－取代的α－亚氨基异羟肟酸和羧酸 |
Country Status (20)
| Country | Link |
|---|---|
| US (3) | US6207672B1 (zh) |
| EP (1) | EP0861236B2 (zh) |
| JP (1) | JP4638560B2 (zh) |
| KR (1) | KR100475206B1 (zh) |
| CN (1) | CN1131215C (zh) |
| AT (1) | ATE213232T1 (zh) |
| AU (1) | AU707707B2 (zh) |
| BR (1) | BR9611479B1 (zh) |
| CA (1) | CA2237590C (zh) |
| CZ (1) | CZ297550B6 (zh) |
| DE (1) | DE59608740D1 (zh) |
| DK (1) | DK0861236T4 (zh) |
| ES (1) | ES2170884T5 (zh) |
| HU (1) | HU223086B1 (zh) |
| MX (1) | MX9803753A (zh) |
| PL (1) | PL186869B1 (zh) |
| PT (1) | PT861236E (zh) |
| RU (1) | RU2164914C2 (zh) |
| TR (1) | TR199800849T2 (zh) |
| WO (1) | WO1997018194A1 (zh) |
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- 1996-11-04 CZ CZ0145398A patent/CZ297550B6/cs not_active IP Right Cessation
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- 1996-11-04 WO PCT/EP1996/004776 patent/WO1997018194A1/de not_active Ceased
- 1996-11-04 PL PL96326702A patent/PL186869B1/pl not_active IP Right Cessation
- 1996-11-04 BR BRPI9611479-7A patent/BR9611479B1/pt not_active IP Right Cessation
- 1996-11-04 US US09/068,497 patent/US6207672B1/en not_active Expired - Lifetime
- 1996-11-04 KR KR10-1998-0703715A patent/KR100475206B1/ko not_active Expired - Fee Related
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- 1996-11-04 AU AU75624/96A patent/AU707707B2/en not_active Ceased
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- 1996-11-04 HU HU9903405A patent/HU223086B1/hu not_active IP Right Cessation
- 1996-11-04 CA CA2237590A patent/CA2237590C/en not_active Expired - Fee Related
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- 1996-11-04 RU RU98111153/04A patent/RU2164914C2/ru not_active IP Right Cessation
- 1996-11-04 AT AT96938052T patent/ATE213232T1/de active
- 1996-11-04 DK DK96938052T patent/DK0861236T4/da active
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| EP0468231A2 (de) * | 1990-07-05 | 1992-01-29 | F. Hoffmann-La Roche Ag | Guanidine |
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