US 7,414,048 B2
4,5-dihydro-isoxazole derivatives and their pharmaceutical use
Eddy Jean Edgard Freyne, Rumst (Belgium); José Ignacio Andrés-Gil, Madrid (Spain); Frederik Dirk Deroose, Drongen (Belgium); Davy Petrus Franciscus Maria Petit, Boom (Belgium); Maria Encarnacion Matesanz-Ballesteros, Toledo (Spain); and Rosa Maria Alvarez Escobar, Toledo (Spain)
Assigned to Janssen Pharmaceutica, N.V., Beerse (Belgium)
Filed on Mar. 31, 2003, as Appl. No. 10/403,543.
Application 10/403543 is a division of application No. 09/807149, granted, now 6,583,141, previously published as PCT/EP99/07803, filed on Oct. 07, 1999.
Claims priority of application No. 98203394 (EP), filed on Oct. 09, 1998.
Prior Publication US 2004/0019059 A1, Jan. 29, 2004
Int. Cl. C07D 413/14 (2006.01); A61K 31/501 (2006.01); A61K 31/496 (2006.01)
U.S. Cl. 514—217.1  [514/254.03; 514/254.04; 514/326; 514/364; 514/378; 548/125; 548/131; 548/143; 548/240; 540/603; 544/367; 546/209] 12 Claims
 
1. A compound of formula (I)

OG Complex Work Unit Drawing
wherein m, n and p are each independently 0 or 1 and q is 0, 1, 2, 3, 4 or 5;
* indicates an asymmetric carbon atom which can be R or S;
-A1=A2-A3=A4- is a bivalent radical of formula
—CH═CH—CH═CH—  (a-7);
B is a bivalent radical of formula

OG Complex Work Unit Drawing
D is Ar1 or Het1;
Q is a bivalent radical of formula

OG Complex Work Unit Drawing

OG Complex Work Unit Drawing
wherein X1 and X2 are each independently S or O, t is 0, 1 or 2;
X3 is independently S, O or NR26; X4 and X5 are each independently N or CH,
L is Ar1 or Het1;
R1 is selected from hydrogen, halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(3-6)cycloalkylC(1-6)alkyl, C(3-6)cycloalkyloxy, haloC(1-6)alkyl , cyano, guanidino, nitro and NR17R18;
R2 and R3 are each independently selected from hydrogen, halo, C(1-6)alkyloxy and C(1-6)alkyl where the alkyl moiety may be optionally substituted by one or more hydroxy;
R4 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl and C(3-6)cycloalkenyl;
R5, R6, R9 and R10 are each independently selected from hydrogen, hydroxy, halo, C(1-6)alkyl, (where the alkyl moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR17R18, (SO2)R16, (C═O)R16, Ar1 and Het1), C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy [where the alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, (═O), NR17R18, (SO2)R16, (C═O)R16, Ar1 and Het1], cyano, (C═O)R25, (C═O)OR16, (SO2)R16, aminocarbonyloxy, aminoC(1-6)alkyl, NR17R18, N3, Ar1 and Het1; or
R5 and R6 or R9 and R10 together with the carbon atom to which they are attached, form a Het1 or a C(3-14) carbocyclic radical optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR23R24, (C═O)R22, C(6-14)aryl and C(3-14)heterocycle), cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy (where the aryloxy moiety may be optionally substituted by halo) and C(3-14)heterocycle;
R7 and R8 are each independently selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, hydroxyC(1-6)alkyl and C(1-6)alkyloxy;
R11 is selected from hydrogen, hydroxy and C(1-6)alkyloxy (where the alkyloxy moiety may be optionally substituted by (C═O)R16);
R12 is selected from hydrogen and hydroxy;
R13 is selected from hydrogen, hydroxy, halo, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, (═O), NR17R18, (SO2)R16, (C═O)R16, Ar1 and Het1), aminocarbonyloxy, aminoC(1-6)alkyl, NR17R18, N3, Ar1 and Het1;
R14 and R15 are each independently selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(3-6)cycloalkyl, C(1-6)alkyloxy, cyano, (C═O)R16, Ar1 and Het1), C(1-14)arylC(1-6)alkyl, (C═O)R16, (C═O)OR16, (C═S)R16, (SO2)R16, Ar1 and Het1; or
R14 and R15 together with the N atom to which they are attached, form a C(3-14)heterocycle optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl and C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxy, (C═O)R16, Ar1 and Het1), C(6-14)arylthio, C(1-14)aryloxy, cyano, (C═O)R16, (C═O)OR16, (SO2)R16, NR17R18, Ar1 and Het1;
R16 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxycarbonyl, NR17R18, Ar1 and Het1]), NR17R18, C(6-14)alkoxy Ar1 or Het1;
R17 and R18 are each independently selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(3-6)cycloalkyl, C(1-6)alkyloxy, (C═O)R19, Ar1 and Het1), (C═O)R19, (SO2)R19, Ar1 and Het1; or
R17 and R18 together with the N atom to which they are attached, form a C(3-14)heterocycle optionally substituted by 1, 2 or 3 substituents independently selected from hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, C(1-6)alkyloxy, (C═O)R19, Ar1 and Het1), NR20R21, (C═O)R19, (═NH), S-Ar1, Ar1 and Het1;
R19 is selected from C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, (C═O)R22, NR20R21, Ar1 and Het1), phenyloxy, NR20R21, Ar1 and Het1;
R20 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, NH(C═O)R22 and C(1-6)alkyloxy;
R21 is selected from hydrogen, hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(1-6)alkyloxycarbonyl, Ar1 and Het1;
Ar1 is a C(6-14)aryl (or C(6-14)arylidene when D is Ar1) optionally substituted by one or more substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR23R24, (C═O)R22, C(1-14)aryl and C(3-14)heterocycle), cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy (where the aryloxy moiety may be optionally substituted by halo) and C(3-14)heterocycle;
Het1 is a C(3-14)heterocycle (or C(3-14)heterocyclidene when D is Het1) optionally substituted by one or more substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from hydroxy, halo, C(1-6)alkyloxy, NR23R24, (C═O)R22, C(6-14)aryl and C(3-14)heterocycle), cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy (where the aryloxy moiety may be optionally substituted by halo) and C(3-14)heterocycle;
R22 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(1-6)alkyloxy, haloC(1-6)alkyl, NR23R24 and

OG Complex Work Unit Drawing
R23 and R24 are each independently selected from hydrogen, C(1-6)alkyl and

OG Complex Work Unit Drawing
R25 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy (where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkyloxy moiety may be optionally substituted by one or more substituents independently selected from halo, C(1-6)alkyloxycarbonyl, NR17R18, Ar1 and Het1), C(1-14)aryloxy, Ar1 and Het1;
R26 is selected from hydrogen, C(1-6)alkyl and phenyl;
or a N-oxide, addition salt, quaternary amine or stereochemically isomeric form thereof.