Patent ID: 6794518
Filing Date: 2004-09-21
Classification: A61K,A61P,C07D,C07K

Abstract:
A compound of the formula:(Q)dâ€”Lnâ€”Sf wherein,Q is independently a compound of Formulae (Ia) or (Ib): â€ƒor stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein: X1d is CH, Câ€”Wdâ€”Xdâ€”Yd, or Câ€”Ln; X2d is CH, or Câ€”Wdâ€”Xdâ€”Yd; X3d is CR11d, or Câ€”Wd Xdâ€”Yd; X4d is CR11d; â€ƒprovided that when R1d is R10de then one of X1d and X2d is Câ€”Wdâ€”Xdâ€”Yd, and when R10d is R10de then X3d is Câ€”Wdâ€”Xdâ€”Yd; R1d is selected from: R1de, C1-C6 alkyl substituted with 0-1 R15d or 0-1 R21d, C3-C6 alkenyl substituted with 0-1 R15d or 0-1 R21d, C3-C7 cycloalkyl substituted with 0-1 R15d or 0-1 R21d, C4-C11 cycloalkylalkyl substituted with 0-1 R15d or 0-1 R21d, aryl substituted with 0-1 R15d or 0-2 R11d or 0-1 R21d, and aryl(C1-C6 alkyl)-substituted with 0-1 R15d or 0-2 R11d or 0-1 R21d; R1de is selected from: Ad and Bd are independently â€”CH2â€”, â€”Oâ€”, â€”N(R2d)â€”, or â€”C(&boxH;O)â€”; A1d and B1d are independently â€”CH2â€” or â€”N(R3d)â€”; Dd is â€”N(R2d)â€”, â€”Oâ€”, â€”Sâ€”, â€”C(&boxH;O)â€” or â€”SO2â€”; Edâ€”Fd is â€”C(R4d)&boxH;C(R5d)â€”, â€”N&boxH;C(R4d)â€”, â€”C(R4d)&boxH;Nâ€”, or â€”C(R4d)2C(R5d)2â€”; Jd, Kd, Ld and Md are independently selected from: â€”C(R4d)â€”, â€”C(R5d)â€” and â€”Nâ€”, provided that at least one of Jd, Kd, Ld and Md is not â€”Nâ€”; R2d is selected from: H, C1-C6 alkyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl; (C1-C6 alkyl)aminocarbonyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, heteroaryl(C1-C6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl)carbonyl-, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl, aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro; R3d is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl)-; R4d and R5d are independently selected from: H, C1-C4 alkoxy, NR2dR3d, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, arylcarbonyl, or alternatively, when substituents on adjacent atoms, R4d and R5d can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3, and NO2; Ud is selected from: â€”(CH2)ndâ€”, â€”(CH2)nd(CR7d&boxH;CR8d)(CH2)mdâ€”, â€”(CH2)nd(C&boxH;C)(CH2)mdâ€”, â€”(CH2)tdQ(CH2)mdâ€”, â€”(CH2)ndO(CH2)mdâ€”, â€”(CH2)ndN(R6d)(CH2)mdâ€”, â€”(CH2)ndC(&boxH;O)(CH2)mdâ€”, â€”(CH2)nd(C&boxH;O)N(R6d)(CH2)mdâ€” â€”(CH2)ndN(R6d)(C&boxH;O)(CH2)mdâ€”, and â€”(CH2)ndS(O)pd(CH2)mdâ€”; wherein one or more of the methylene groups in Ud is optionally substituted with R7d; Qd is selected from 1,2-cycloalkylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 2,4-pyridinylene, and 3,4-pyridazinylene; R6d is selected from: H, C1-C4 alkyl, or benzyl; R7d and R8d are independently selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C0-C6 alkyl)-; R10d is selected from: H, R1de, C1-C4 alkoxy substituted with 0-1 R21d, N(R6d)2, halogen, NO2, CN, CF3, CO2R17d, C(&boxH;O)R17d, CONR17dR20d, â€”SO2R17d, â€”SO2NR17dR20d, C1-C6 alkyl substituted with 0-1 R15d or 0-1 R21d, C3-C6 alkenyl substituted with 0-1 R15d or 0-1 R21d, C3-C7 cycloalkyl substituted with 0-1 R15d or 0-1 R21d, C4-C11 cycloalkylalkyl substituted with 0-1 R15 d or 0-1 R21d, aryl substituted with 0-1 R15d or 0-2 R11d or 0-1 R21d, and aryl(C1-C6 alkyl)- substituted with 0-1 R15d or 0-2 R11d or 0-1 R21d; R10de is selected from: H, C1-C4 alkoxy substituted with 0-1 R21d, N(R6d)2, halogen, NO2, CN, CF3, CO2R17d, C(&boxH;O)R17d, CONR17dR20d, SO2R17d, â€”SO2NR17dR20d, C1-C6 alkyl substituted with 0-1 R15d or 0-1 R21d, C3-C6 alkenyl substituted with 0-1 R15d or 0-1 R21d, C3-C7 cycloalkyl substituted with 0-1 R15d or 0-1 R21d, C4-C11 cycloalkylalkyl substituted with 0-1 R15d or 0-1 R21d, aryl substituted with 0-1 R15d or 0-2 R11d or 0-1 R21d, and aryl(C1-C6 alkyl)- substituted with 0-1 R15d or 0-2 R11d or 0-1 R21d; R11d is selected from H, halogen, CF3, CN, NO2, hydroxy, NR2dR3d, C1-C4 alkyl substituted with 0-1 R21d, C1-C4 alkoxy substituted with 0-1 R21d, aryl substituted with 0-1 R21d, aryl(C1-C6 alkyl)- substituted with 0-1 R21d, (C1-C4 alkoxy)carbonyl substituted with 0-1 R21d, (C1-C4 alkyl)carbonyl substituted with 0-1 R21d, C1-C4 alkylsulfonyl substituted with 0-1 R21d, and C1-C4 alkylaminosulfonyl substituted with 0-1 R21d; Wd is selected from: â€”(C(R12d)2)qdC(&boxH;O)N(R13d)â€”, and â€”C(&boxH;O)â€”N(R13d)â€”(C(R12d)2)qdâ€”; Xd is â€”C(R12d)(R14d)â€”C(R12d)(R15d)â€”; or alternatively, Wd and Xd can be taken together to be R12d is selected from H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C4-C10 cycloalkylalkyl, (C1-C4 alkyl)carbonyl, aryl, and aryl(C1-C6 alkyl)-; R13d is selected from H, C1-C6 alkyl, C3-C7 cycloalkylmethyl, and aryl(C1-C6 alkyl)-; R14d is selected from: H, C1-C6 alkylthio(C1-C6 alkyl)-, aryl(C1-C10 alkylthioalkyl)-, aryl(C1-C10 alkoxyalkyl)-, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C6 hydroxyalkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-, heteroaryl(C1-C6 alkyl)-, aryl, heteroaryl, CO2R17d, C(&boxH;O)R17d, and CONR17dR20d, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be substituted independently with 0-1 R16d or 0-2 R11d; R15d is selected from: H, R16d, C1-C10 alkyl, C1-C10 alkoxyalkyl, C1-C10 alkylaminoalkyl, C1-C10 dialkylaminoalkyl, (C1-C10 alkyl)carbonyl, aryl(C1-C6 alkyl)carbonyl, C1-C10 alkenyl, C1-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C1-C6 alkyl)-, heteroaryl(C1-C6 alkyl)-, aryl, heteroaryl, CO2R17d, C(&boxH;O)R17d, CONR17dR20d, SO2R17d, and SO2NR17dR20d, provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be substituted independently with 0-2 R11d; Yd is selected from: â€”COR19d, â€”SO3H, â€”PO3H, tetrazolyl, â€”CONHNHSO2CF3, â€”CONHSO2R17d, â€”CONHSO2NHR17d, â€”NHCOCF3, â€”NHCONHSO2R17d, â€”NHSO2R17d, â€”OPO3H2, â€”OSO3H, â€”PO3H2, â€”SO3H, â€”SO2NHCOR17d, â€”SO2NHCO2R17d, R16d is selected from: â€”N(R20d)â€”C(&boxH;O)â€”Oâ€”R17d, â€”N(R20d)â€”C(&boxH;O)â€”R17d, â€”N(R20d)â€”C(&boxH;O)â€”NHâ€”R17d, â€”N(R20d)SO2â€”R17d, and â€”N(R20d)SO2â€”NR20dR17d; R17d is selected from: C1-C10 alkyl optionally substituted with a bond to Ln, C3-C11 cycloalkyl optionally substituted with a bond to Ln, aryl(C1-C6 alkyl)- optionally substituted with a bond to Ln, (C1-C6 alkyl)aryl optionally substituted with a bond to Ln, heteroaryl(C1-C6 alkyl)- optionally substituted with a bond to Ln, (C1-C6 alkyl)heteroaryl optionally substituted with a bond to Ln, biaryl(C1-C6 alkyl)- optionally substituted with a bond to Ln, heteroaryl optionally substituted with a bond to Ln, aryl optionally substituted with a bond to Ln, biaryl optionally substituted with a bond to Ln, and a bond to Ln, wherein said aryl, biaryl or heteroaryl groups are also optionally substituted with 0-3 substituents selected from the group: C1-C4 alkyl, C1-C4 alkoxy, aryl, heteroaryl, halo, cyano, amino, CF3, and NO2; R18d is selected from: â€”H, â€”C(&boxH;O)â€”Oâ€”R17d, â€”C(&boxH;O)â€”R17d, â€”C(&boxH;O)â€”NHâ€”R17d, â€”SO2â€”R17d, and â€”SO2â€”NR20dR17d; R19d is selected from: hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy, aryloxy, aryl(C1-C6 alkoxy)-, C3-C10 alkylcarbonyloxyalkyloxy, C3-C10 alkoxycarbonyloxyalkyloxy, C2-C10 alkoxycarbonylalkyloxy, C5-C10 cycloalkylcarbonyloxyalkyloxy, C5-C10 cycloalkoxycarbonyloxyalkyloxy, C5-C10 cycloalkoxycarbonylalkyloxy, C7-C11 aryloxycarbonylalkyloxy, C8-C12 aryloxycarbonyloxyalkyloxy, C8-C12 arylcarbonyloxyalkyloxy, C5-C10 alkoxyalkylcarbonyloxyalkyloxy, C5-C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10-C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R11d)(R12d)Nâ€”(C1-C10 alkoxy)-; R20d is selected from: H, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl)-; R21d is selected from: COOH and NR6d2; md is 0-4; nd is 0-4; td is 0-4; pd is 0-2; qd is 0-2; and rd is 0-2; â€ƒwith the following provisos: (1) td, nd, md and qd are chosen such that the number of atoms connecting R1d and Yd is in the range of 10-14; and (2) nd and md are chosen such that the value of nd and md is greater than one unless Ud is â€”(CH2)tdQd(CH2)mdâ€”; â€ƒor Q is a peptide selected from the group: R1 is L-valine, D-valine or L-lysine optionally substituted on the &square; amino group with a bond to Ln; R2 is L-phenylalanine, D-phenylalanine, D-1-naphthylalanine, 2-aminothiazole-4-acetic acid or tyrosine, the tyrosine optionally substituted on the hydroxy group with a bond to Ln; R3 is D-valine; R4 is D-tyrosine substituted on the hydroxy group with a bond to Ln; provided that one of R1 and R2 in each Q is substituted with a bond to Ln, and further provided that when R2 is 2-aminothiazole-4-acetic acid, K is N-methylarginine; provided that at least one Q is a compound of Formula Ia or Ib; d is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; Ln is a linking group having the formula: ((W)hâ€”(CR6R7)g)xâ€”(Z)kâ€”((CR6aR7a)gâ€²â€”(W)hâ€²)xâ€²; W is independently selected at each occurrence from the group: O, S, NH, NHC(&boxH;O), C(&boxH;O)NH, NR8C(&boxH;O), C(&boxH;O)N R8, C(&boxH;O), C(&boxH;O)O, OC(&boxH;O), NHC(&boxH;S)NH, NEC(&boxH;O)NH, SO2, SO2NH, (OCH2CH2)20-200, (CH2CH2O)20-200, (OCH2CH2CH2)20-200, (CH2CH2CH2O)20-200, and (aa)tâ€²; aa is independently at each occurrence an amino acid; Z is selected from the group: aryl substituted with 0-3 R10, C3-10 cycloalkyl substituted with 0-3 R10, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R10; R6, R6a, R7, R7a, and R8 are independently selected at each occurrence from the group: H, &boxH;O, COOH, SO3H, PO3H, C1-C5 alkyl substituted with 0-3 R10, aryl substituted with 0-3 R10, benzyl substituted with 0-3 R10, and C1-C5 alkoxy substituted with 0-3 R10, NHC(&boxH;O)R11, C(&boxH;O)NHR11, NHC(&boxH;O)NHR11, NHR11, R11, and a bond to Sf; R10 is independently selected at each occurrence from the group: a bond to Sf, COOR11, C(&boxH;O)NHR11, NHC(&boxH;O)R11, OH, NHR11, SO3H, PO3H, â€”OPO3H2, â€”OSO3H, aryl substituted with 0-3 R11, C1-5 alkyl substituted with 0-1 R12, C1-5 alkoxy substituted with 0-1 R12, and a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R11; R11 is independently selected at each occurrence from the group: H, alkyl substituted with 0-1 R12, aryl substituted with 0-1 R12, a 5-10 membered heterocyclic ring system having 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R12, C3-10 cycloalkyl substituted with 0-1 R12, and a bond to Sf; R12 is abond to Sf; k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; hâ€² is selected from 0, 1, and 2; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; gâ€² is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; tâ€² is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; x is selected from 0, 1, 2, 3, 4, and 5; xâ€² is selected from 0, 1, 2, 3, 4, and 5; Sf is a surfactant which is a lipid or a compound of the formula: A9 is selected from the group: OH and OR27; A10 is OR27; R27 is C(&boxH;O)C1-20 alkyl; E1 is C1-10 alkylene substituted with 1-3 R28; R28 is independently selected at each occurrence from the group: R30, â€”PO3Hâ€”R30, &boxH;O, â€”CO2R29, â€”C(&boxH;O)R29, â€”C(&boxH;O)N(R29)2, â€”CH2OR29, â€”OR29, â€”N(R29)2, C1-C5 alkyl, and C2-C4 alkenyl; R29 is independently selected at each occurrence from the group: R30, H, C1-C6 alkyl, phenyl, benzyl, and trifluoromethyl; R30 is a bond to Ln; or a pharmaceutically acceptable salt thereof.