US 7,579,324 B2
Conjugates of biologically active compounds, methods for their preparation and use, formulation and pharmaceutical applications thereof
Michael Burnet, Kusterdingen (Germany); Jan-Hinrich Guse, Tubingen-Buhl (Germany); Hans-Jurgen Gutke, Stuttgart (Germany); Albert Beck, Nehren (Germany); Georgia Tsotsou, Tubingen (Germany); Irina Droste-Borel, Tubingen (Germany); Jeannette Reichert, Neustretten (Germany); Kattie Luyten, Tubingen (Germany); Maximilian Busch, Tubingen (Germany); Michael Wolff, Kusterdingen (Germany); Moussa Khobzaoui, Tubingen (Germany); Simona Margutti, Tubingen (Germany); Thomas Meindl, Tubingen (Germany); Gene Kim, Tubingen (Germany); and Laurence Barker, Tubingen (Germany)
Assigned to c-a-i-r biosciences GmbH, Tuebingen (Germany)
Filed on Feb. 14, 2003, as Appl. No. 10/367,105.
Claims priority of provisional application 60/357434, filed on Feb. 15, 2002.
Prior Publication US 2004/0087517 A1, May 06, 2004
Int. Cl. A01N 43/04 (2006.01); A61K 31/70 (2006.01); C07H 17/08 (2006.01)
U.S. Cl. 514—29  [514/183; 536/7.1; 536/7.2; 536/7.4] 3 Claims
 
1. A compound, wherein the compound is

OG Complex Work Unit Drawing
wherein:
X=N(R7)—CH2,
CH2—N(R7),
C(═O),
C(═NOR8),
CH(OR9),
CH(NR10R11),
C(═NR12),
OC(═O), or
C(═O)O,
Y=independently, linker,
Z=C(═O)-, or
CH(R16)-,
R1=H,
CH3,
(C2-C10)alkyl,
(C2-C10)alkenyl,
(C2-C10)alkynyl,
(C1-C8)[(C1-C4)alkoxy]alkyl,
(C2-C8)[(C1-C4)alkoxy]alkenyl,
(C6-C10)aryl-(C1-C5)alkyl,
(C2-C9)heteroaryl-(C1-C5)alkyl,
(C1-C4)alkyliden-NR18R19,
Y—R13,
C(═O)—Y—R15,
C(═O)—R15,
S(═O)k(C1-C10)alkyl,
S(═O)k(C2-C10)alkenyl,
S(═O)k(C2-C10)alkynyl,
S(═O)k(C6-C10)aryl,
S(═O)k(C2-C9)heteroaryl,
S(═O)k—Y—R15, or
S(═O)k—R15,
wherein k is 0, 1 or 2 and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl can optionally be substituted by one to three halogen, cyano, hydroxy, (C1-C4)alkyloxy, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)heterocycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, NR18R19, R18C(═O)—, R18C(═O)O—, R18OC(═O)—, R18C(═O)NH—, R16NHC(═O)—, R18R19NC(═O)— or R18OC(═O)—O—,
R2=H,
(1′,2′-cis)-OH,
(1′,2′-trans)-OH,
(1′,2′-cis)-OR15,
(1′,2′-trans)-OR15,
(1′,2′-cis)-SH,
(1′,2′-cis)-S—Y—R13,
or the R1 and R2 bearing atoms are connected via a -OC(═O)CHR16-element,
R3a, R3b=independently H,
R1,
OH,
OR11,
NR10R11,
or R3a═R3b═(═O),
(═NR1),
O(CH2)kO— wherein k is 2 or 3,
R4=H,
C(═O)—Y—R15, or
C(═O)—R15,
R5=H,
or R4, R5 are connected by -Z-,
R6=H, or
CH3,
R7=H,
CH3,
Y—R13,
C(═O)—Y—R15, or
C(═O)—R15,
R8=H,
Y—R13, or
C(═O)—R17,
R9=H,
(C1-C10)alkyl,
(C2-C10)alkenyl,
(C2-C10)alkynyl,
(C1-C8)[(C1-C4)alkoxy]alkyl,
(C2-C8)[(C1-C4)alkoxy]alkenyl,
(C6-C10)aryl-(C1-C5)alkyl, or
(C2-C9)heteroaryl-(C1-C5)alkyl,
R10,R11=independently H,
(C1-C10)alkyl,
(C2-C10)alkenyl,
(C2-C10)alkynyl,
(C3-C10)cycloalkyl,
(C6-C10)aryl, or
(C2-C9)heteroaryl,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl are optionally substituted by one to three halogen, cyano, hydroxy, (C1-C4)alkyloxy, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl), (C1-C6)heterocycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, NR18R19, R18C(═O)—, R18C(═O)O—, R18OC(═O)—, R18C(═O)NH—, R18NHC(═O)—, R18R19NC(═O)— or R18OC(═O)—O—,
or R10=H and
R11=Y—R13,
C(═O)—Y—R15,
C(═O)—R15,
S(═O)k(C1-C10)alkyl,
S(═O)k(C2-C10)alkenyl,
S(═O)k(C2-C10)alkynyl,
S(═O)k(C6-C10)aryl,
S(═O)k(C2-C9)heteroaryl,
S(═O)k—Y—R15, or
S(═O)k—R15,
wherein k is 0, 1 or 2 and alky, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl can be substituted as defined above,
R12=H,
(C1-C10)alkyl,
(C2-C10)alkenyl,
(C2-C10)alkynyl,
(C1-C8)[(C1-C4)alkoxy]alkyl,
(C2-C8)[(C1-C4)alkoxy]alkenyl,
(C6-C10)aryl-(C1-C5)alkyl,
(C2-C9)heteroaryl-(C1-C5)alkyl,
(C1-C4)alkyliden-NR18R19, or
Y—R13,
R13=independently, non-steroidal anti-inflammatory therapeutic agent,
R15=independently, non-steroidal anti-inflammatory therapeutic agent,
R16=independently, H,
CH3,
(C2-C10)alkyl,
(C2-C10)alkenyl,
(C2-C10)alkynyl,
(C1-C8)[(C1-C4)alkoxy]alkyl,
(C2-C8)[(C1-C4)alkoxy]alkenyl,
(C6-C10)aryl-(C1-C5)alkyl,
(C2-C9)heteroaryl-(C1-C5)alkyl,
(C1-C4)alkyliden-NR18R19, or
Y—R13,
R17=O—R20-aryl
optionally substituted by —X′—Y-non-steroidal anti-inflammatory therapeutic agent, or
X′-non-steroidal anti-inflammatory therapeutic agent wherein X′ is
S, O, or NH,
R18, R19=independently H,
(C1-C10)alkyl,
(C2-C10)alkenyl,
(C2-C10)alkynyl,
(C1-C8)[(C1-C4)alkoxy]alkyl,
(C2-C8)[(C1-C4)alkoxy]alkenyl,
(C6-C10)aryl-(C1-C5)alkyl, or
(C2-C9)heteroaryl-(C1-C5)alkyl,
R20=independently,
Halogen,
(C1-C3)alkyl,
NO2,
CN,
OCH3,
N(CH3)2,
N3,
SH, or
S(C1-C4)alkyl;
wherein the compound has at least one of R13, R15 or R17 comprising a non-steroidal anti-inflammatory therapeutic agent.