Patent ID: 6750243
Filing Date: 2004-06-15
Classification: A61P,C07D

Abstract:
A compound of formula I, whereinR1 represents H, C1-4 alkyl (optionally substituted by one or more substituents selected from cyano, halo, OH, C(O)OR1a or C(O)N(R1b)R1c) or OR1d; R1d represents H, C(O)R11, SiR12R13R14 or C1-6 alkyl, which latter group is optionally substituted or terminated by one or more substituent selected from OR15 or (CH2)qR16; R12, R13 and R14 independently represent H, phenyl or C1-6 alkyl; R16 represents C1-4 alkyl, phenyl, OH, C(O)OR17 or C(O)N(H)R18; R18 represents H, C1-4 alkyl or CH2C(O)OR19; R15 and R17 independently represent H, C1-6 alkyl or C1-3 alkylphenyl; R1a, R1b, R1c, R11 and R19 independently represent H or C1-4 alkyl; and q represents 0, 1 or 2; Rx represents a structural fragment of formula IIa, â€ƒwherein the dotted lines independently represent optional bonds; A and E independently represent CH; D represents â€”CH&boxH;CH; X1 represents Oâ€”A3; A3represents C1-3 alkylene; R2 represents one or more optional substituents selected from C1-4 alkyl, C1-4 alkoxy (which latter two groups are optionally substituted by one or more halo substituent), methylenedioxy, halo, hydroxy, cyano, nitro, S(O)2NH2, C(O)OR26, SR26, S(O)R26a, S(O)2R26a or N(R27)R28; R3 represents one or more optional substituents selected from OH, C1-4 alkoxy, C1-6 alkyl (optionally substituted by one or more halo group), or N(R29a)R29b; R29a and R29b independently represent H, C1-4 alkyl or C(O)R30; R26 represents H or C1-4 alkyl; R26a represents C1-4 alkyl; R27 and R28 independently represent H, C1-4 alkyl or C(O)R30, or together represent C3-6 alkylene, thus forming a 4- to 7-membered ring, which ring is optionally substituted, on a carbon atom that is &agr; to the nitrogen atom, with an &boxH;O group; R30 represents, at each occurrence, H or C1-4 alkyl; Y independently represents CH2, (CH2)2 or CH&boxH;CH; Ry represents H or C1-4 alkyl; n represents 0, 1, 2, 3 or 4; and B represents a structural fragment of formula IIIa or IIIc â€ƒwherein X5, X6, X7 and X8 independently represent CH; R31 represents an optional substituent selected from halo, C1-4 alkyl (which group is optionally substituted by one or more halo group), N(R32)R33, OR34 or SR35; R32 and R33 independently represent H, C1-4 alkyl or C(O)R36; R34, R35 and R36 independently represent H or C1-4 alkyl; and one of D1 and D2 represents H, and the other represents H, ORa, NHRa, C(&boxH;X11)X12Rb, or D1 and D2 together represent a structural fragment of formula IVa: Ra represents H or â€”A5[X14]n[C(O)]rRe; Rb represents â€”A5[X14]n[C(O)]rRe; A5 represents, at each occurrence, a single bond or C1-12 alkylene (which alkylene group is optionally interrupted by one or more O, S(O)m and/or N(Rf) group, and is optionally substituted by one or more of halo, OH, N(H)C(O)Rg, C(O)N(Rg)Rh, C3-7-cycloalkyl (which cycloalkyl group is optionally interrupted by one or more O, S(O)m and/or N(Rf) group and/or is optionally substituted by one or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, &boxH;O or &boxH;S), Het and C6-10 aryl (which aryl and Het groups are themselves optionally substituted by one or more substituents selected from C1-6 alkyl (optionally substituted by one or more halo substituent), C1-6 alkoxy, halo, cyano, C(O)ORg, C(O)N(Rg)Rh and N(Rf)Rg)); Rc and Rd both represent H; or one of Rc and Rd represents H or C1-7 alkoxy and the other represents C1-7 alkyl (which alkyl group is optionally interrupted by one or more O atoms); or Rc and Rd together represent C3-8 cycloalkyl, which cycloalkyl group is interrupted by one or more O, S(O)m and/or N(Rf) group; Re represents, at each occurrence, H, C1-12 alkyl (which alkyl group is optionally interrupted by one or more O, S(O)m and/or N(Rf) group, and/or is optionally substituted by one or more substituents selected from halo, OH, N(H)C(O)Rg and C(O)N(Rg)Rh), A7â€”C3-7-cycloalkyl (which cycloalkyl group is optionally interrupted by one or more O, S(O)m and/or N(Rf) group and/or is substituted by one or more substituents selected from C1-6 alkyl, C1-6 alkoxy, halo, &boxH;O and &boxH;S), A7â€”C6-10 aryl or A7-Het (which aryl and Het groups are optionally substituted by one or more substituents selected from C1-6 alkyl (optionally substituted by one or more halo substituent), C1-6 alkoxy, halo, cyano, C(O)ORg, C(O)N(Rg)Rh and N(Rf)Rg); A7 represents a single bond or C1-7 alkylene (which alkylene group is optionally interrupted by one or more O, S(O)m and/or N(Rf) group, and/or are optionally substituted by one or more of halo, OH, N(H)CORg and CON(Rg)Rh); Het represents, at each occurrence, a five- to ten-membered heteroaryl group, which may be aromatic in character, containing one or more nitrogen, oxygen or sulphur atoms in the ring system; n and r independently represent 0 or 1; X11, X12 and X14 independently represent O or S; X13 represents O or N(Rf); Rf represents, at each occurrence, H, C1-4 alkyl or C(O)Rg; Rg and Rh independently represent, at each occurrence, H or C1-4 alkyl; and m represents, at each occurrence, 0, 1 or 2; or a pharmaceutically acceptable salt thereof; provided that:when A5 represents a single bond, then n and r both represent 0; when A5 represents C12 alkylene, then n represents 1; when A5 represents â€”CH2â€”, n is 1 and r is 0, then Re does not represent H; and the compound is not: (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl (R)- or (S)-1-hydroxy-7-methoxytetralin-1-yl (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl (R)- or (S)-1-hydroxy-7-methoxytetralin-1-yl 1-hydroxy-5-methoxytetralin-1-yl; 1-hydroxy-5,7-dimethyltetralin-1-yl 1-hydroxy-7-aminotetralin-1-yl 1-hydroxytetralin-1-yl 7-methoxytetralin-1-yl; (R)- or (S)-7-methoxy-1-methyltetralin-1-yl; 4-hydroxy-6-methoxychroman-4-yl; (S)- or (R)-1-hydroxy-4-methoxyindan-1-yl; 1-hydroxy-5-methoxytetralin-1-yl (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl 4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab(OH); 4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab(OMe); (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-; (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl; 7-methoxy-1-allyltetralin-1-yl-C(O)-Aze-Pab x HOAc; (S)- or (R)-1-hydroxy-7-chlorotetralin-1-yl-C(O)-Pro-Pab; 1-n-propyl-7-methoxytetralin-1-yl-C(O)-Aze-Pab x HOAc; 6-chloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab x HOAc; 4-hydroxychroman-4-yl-C(O)-Aze-Pab x HOAc; 6,8-dichloro-4-hydroxychroman-4-yl-C(O)-Aze-Pab x HOAC; 6-fluoro-4-hydroxychroman-4-yl-C(O)-Aze-Pab x HOAc; 4-hydroxy-6-methylchroman-4-yl-C(O)-Aze-Pab x HOAc; 8-chloro-4-hydroxy-6-methoxychroman-4-yl-C(O)-Aze-Pab x HOAc; 6-chloro-4-hydroxy-8-methylchroman-4-yl-C(O)-Aze-Pab x HOAc; (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(Oâ€”C(O)-i-Pr); (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(Oâ€”C(O)-Et); (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(Oâ€”C(O)-Ch); (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-allyl); (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-Bzl); (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab-(COâ€”O-methallyl); 1-hydroxy-7-aminotetralin-1-yl-C(O)-Aze-Pab(OH); (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-Pab(O-Val); (S)- or (R)-1-hydroxy-7-methoxytetralin-1-yl-C(O)-Aze-(Me)Pab; or 9-hydroxyfluoren-9-yl-C(O)-Aze-Pab x HOAc.