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EnglishThe invention is related to the prepn. of title compds. M-L-M' [M, M' = independently the residues of metalloproteases inhibitors of formula RS(O)nNR1CR2R3G; R = -Ar-X-Ar'; Ar = (un)substituted (hetero)arylene; Ar' = H, (un)substituted (hetero)aryl; X = a single bond, alkylene, O, S, CO, etc.; R1 = H, OH, alk(en)yl, etc.; R2, R3 = independently H, alkyl optionally substituted by OH or C1-4-alkoxy groups or a Zn binding group selected from CO2H, COORb, CONHOH, CONRbOH, P(:O)(OH)2, etc.; Rb = alkyl, (hetero)arylalkyl; or any of R2 or R3 groups is linked to R1 so as to form a 5-7 membered heterocyclyl, optionally substituted by ≥1 oxo groups; G = alkyl, (hetero)aryl, arylalkyl, (CH2)1-6NR4R5; R4 = H, CORc, COORc, SO2Rc, CONHRc, SO2NHRc; Rc = cycloalkyl, alkyl, (hetero)aryl, alkylheterocyclyl, etc.; R5 = H, or NR4R5 = (un)substituted benzocondensed 4-6 membered heterocycle; L = a bond, C1-20-hydrocarbyl optionally interrupted by≥1 groups selected from (hetero)arylene, O, COO, SO2, NH, etc.; with the exclusion of specified compds.], e.g., I, and their pharmaceutically acceptable salts, to their pharmaceutical compns., and to their use as inhibitors of metalloproteases (MMP) useful in the treatment of degenerative disorders. Thus, dimeric hydrxamic acid I was prepd. by a multi-step synthesis using biphenyl-4-sulfonyl chloride, O-benzylhydroxylamine hydrochloride, tert-Bu (2S)-2-hydroxy-4-[[(phenylmethoxy)carbonyl]amino]butanoic acid, and 4-[[3-[[(4-chloro-4-oxobutyl)amino]carbonyl]benzoyl]amino]butanoyl chloride. I inhibited MMP-2, MMP-13 and MMP-14 with IC50 values of 3.7 nM, 2.4 nM and 31 nM, resp. and may be useful for the treatment of degenerative disorders involving those same enzymes.
| Titolo: | Aryl-sulphonamidic dimers as metalloproteases inhibitors |
| Autori interni: | |
| Anno di deposito: | 2010 |
| Abstract: | The invention is related to the prepn. of title compds. M-L-M' [M, M' = independently the residues of metalloproteases inhibitors of formula RS(O)nNR1CR2R3G; R = -Ar-X-Ar'; Ar = (un)substituted (hetero)arylene; Ar' = H, (un)substituted (hetero)aryl; X = a single bond, alkylene, O, S, CO, etc.; R1 = H, OH, alk(en)yl, etc.; R2, R3 = independently H, alkyl optionally substituted by OH or C1-4-alkoxy groups or a Zn binding group selected from CO2H, COORb, CONHOH, CONRbOH, P(:O)(OH)2, etc.; Rb = alkyl, (hetero)arylalkyl; or any of R2 or R3 groups is linked to R1 so as to form a 5-7 membered heterocyclyl, optionally substituted by ≥1 oxo groups; G = alkyl, (hetero)aryl, arylalkyl, (CH2)1-6NR4R5; R4 = H, CORc, COORc, SO2Rc, CONHRc, SO2NHRc; Rc = cycloalkyl, alkyl, (hetero)aryl, alkylheterocyclyl, etc.; R5 = H, or NR4R5 = (un)substituted benzocondensed 4-6 membered heterocycle; L = a bond, C1-20-hydrocarbyl optionally interrupted by≥1 groups selected from (hetero)arylene, O, COO, SO2, NH, etc.; with the exclusion of specified compds.], e.g., I, and their pharmaceutically acceptable salts, to their pharmaceutical compns., and to their use as inhibitors of metalloproteases (MMP) useful in the treatment of degenerative disorders. Thus, dimeric hydrxamic acid I was prepd. by a multi-step synthesis using biphenyl-4-sulfonyl chloride, O-benzylhydroxylamine hydrochloride, tert-Bu (2S)-2-hydroxy-4-[[(phenylmethoxy)carbonyl]amino]butanoic acid, and 4-[[3-[[(4-chloro-4-oxobutyl)amino]carbonyl]benzoyl]amino]butanoyl chloride. I inhibited MMP-2, MMP-13 and MMP-14 with IC50 values of 3.7 nM, 2.4 nM and 31 nM, resp. and may be useful for the treatment of degenerative disorders involving those same enzymes. |
| Handle: | http://hdl.handle.net/11568/120216 |
| Appare nelle tipologie: | 6.1 Brevetto |
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