US 6,982,251 B2
Substituted 2-azetidinones useful as hypocholesterolemic agents
Anima Ghosal, Edison, N.J. (US); Shmuel Zbaida, East Brunswick, N.J. (US); Swapan K. Chowdhury, Warren, N.J. (US); Robert M. Iannucci, Hampton, N.J. (US); Wenqing Feng, Chatham, N.J. (US); Kevin B. Alton, Cedar Knolls, N.J. (US); James E. Patrick, Belle Mead, N.J. (US); and Harry R. Davis, Berkeley Heights, N.J. (US)
Assigned to Schering Corporation, Kenilworth, N.J. (US)
Filed on Jun. 11, 2002, as Appl. No. 10/166,942.
Application 10/166942 is a continuation in part of application No. 10/023295, filed on Dec. 17, 2001, abandoned.
Claims priority of provisional application 60/256875, filed on Dec. 20, 2000.
Prior Publication US 2003/0105028 A1, Jun. 05, 2003
Int. Cl. A61K 31/7056 (2006.01); A61K 31/397 (2006.01); A61K 31/675 (2006.01); C07H 17/02 (2006.01); C07D 25/08 (2006.01)
U.S. Cl. 514—23 27 Claims
 
1. A compound represented by the Formula (IA):
OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt or solvate thereof, wherein in Formula (IA):
R1 is selected from the group consisting of H, G, G1, G2, —SO3H and —PO3H;
G is selected from the group consisting of: H,
OG Complex Work Unit Drawing
wherein R, Ra and Rb are each independently selected from the group consisting of H, —OH, halo, —NH2, azido, (C1-C6)alkoxy(C1-C6)alkoxy or —W—R30;
W is independently selected from the group consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R31)—, —NH—C(O)—N(R31)— and —O—C(S)—N(R31)—;
R2 and R6 are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl and aryl(C1-C6)alkyl;
R3, R4, R5, R7, R3a and R4a are each independently selected from the group consisting of H, (C1-C6)alkyl, acetyl, aryl(C1-C6)alkyl, —C(O)(C1-C6)alkyl and —C(O)aryl;
R30 is independently selected from the group consisting of R32-substituted T, R32-substituted-T-(C1-C6)alkyl, R32-substituted-(C2-C4)alkenyl, R32-substituted-(C1-C6)alkyl, R32-substituted-(C3-C7)cycloalkyl and R32-substituted-(C3-C7)cycloalkyl(C1-C6)alkyl;
R31 is independently selected from the group consisting of H and (C1-C4)alkyl;
T is independently selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;
R32 is independently selected from 1-3 substituents which are each independently selected from the group consisting of H, halo, (C1-C4)alkyl, —OH, phenoxy, —CF3, —NO2, (C1-C4)alkoxy, methylenedioxy, oxo, (C1-C4)alkylsulfanyl, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, —N(CH3)2, —C(O)—NH(C1-C4)alkyl, —C(O)—N((C1-C4)alkyl)2, —C(O)—(C1-C4)alkyl, —C(O)—(C1-C4)alkoxy and pyrrolidinylcarbonyl; or R32 is a covalent bond and R31, the nitrogen to which it is attached and R32 form a pyrrolidinyl, piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or a (C1-C4)alkoxycarbonyl-substituted pyrrolidinyl, piperidinyl, N-methylpiperazinyl, indolinyl or morpholinyl group;
G1 is represented by the structure:
OG Complex Work Unit Drawing
wherein R33 is independently selected from the group consisting of R34-substituted alkyl, (R35)(R36)alkyl-,
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R34 is one to three substituents, each R34 being independently selected from the group consisting of HOOC—, HS—, (CH3)S—, H2N—, (NH2)(NH)C(NH)—, (NH2)C(O)—, HOOCCH(NH3+)CH2SS—;
OG Complex Work Unit Drawing
R35 is independently selected from the group consisting of H and NH2—;
R36 is independently selected from the group consisting of H, unsubstituted alkyl, R34-substituted alkyl, unsubstituted cycloalkyl, R34-substituted cycloalkyl, HOOCCH2CH2—, HSCH2—, HOOCCH2—, (CH3)SCH2CH2—, HOCH2—, H2N(CH2)4—, H2NCH2CHOH(CH2)2—, CH3(OH)CH—, (NH2)(NH)CNH(CH2)3—, H2NC(O)CH2—, HOOCCH(NH3+)CH2SSCH2— and H2NCO(CH2)2— wherein when R35 is H, R36 is not H or unsubstituted alkyl;
G2 is represented by the structure:
OG Complex Work Unit Drawing
wherein R37 and R38 are each independently selected from the group consisting of (C1-C6)alkyl and aryl;
R26 is one to five substituents, each R26 being independently selected from the group consisting of:
a) H;
b) —OH;
c) —OCH3;
d) fluorine;
e) chlorine;
f) —O-G;
g) —O-G1;
h) —O-G2;
i) —SO3H; and
j) —PO3H;
provided that when R1 is H, R26 is not H, —OH, —OCH3 or —O-G;
Ar1 is aryl, R10-substituted aryl, heteroaryl or R10-substituted heteroaryl;
Ar2 is aryl, R11-substituted aryl, heteroaryl or R11-substituted heteroaryl;
L is selected from the group consisting of:
a) a covalent bond;
b) —(CH2)q—, wherein q is 1-6;
c) —(CH2)e-E-(CH2)r—, wherein E is —O—, —C(O)—, phenylene, —NR22— or
d) —S(O)0-2—, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
e) —(C2-C6)alkenylene-;
f) —(CH2)f—V—(CH2)g—, wherein V is C3-C6cycloalkylene, f is 1-5 and
g) g is 0-5, provided that the sum of f and g is 1-6; and
h)
OG Complex Work Unit Drawing
wherein M is —O—, —S—, —S(O)— or —S(O)2—;
X, Y and Z are each independently selected from the group consisting of —CH2—, —CH(C1-C6)alkyl- and —C(di-(C1-C6)alkyl)-;
R8 is selected from the group consisting of H and alkyl;
R10 and R11 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of (C1-C6)alkyl, —OR19, —O(CO)R19, —O(CO)OR21, —O(CH2)1-5OR19, —O(CO)NR19R20, —NR19R20, —NR19(CO)R20, —NR19(CO)OR21, —NR19(CO)NR20R25, —NR19SO2R21, —COOR19, —CONR19R20, —COR19, —SO2NR19R20, S(O)0-2R21, —O(CH2)1-10—COOR19, —O(CH2)1-10CONR19R20, —(C1-C6 alkylene)—COOR19, —CH═CH—COOR19, —CF3, —CN, —NO2 and halo;
R15 and R17 are each independently selected from the group consisting of —OR19, —OC(O)R19, —OC(O)OR21, —OC(O)NR19R20;
R16 and R18 are each independently selected from the group consisting of H, (C1-C6)alkyl and aryl;
or R15 and R16 together are ═O, or R17 and R18 together are ═O;
d is 1, 2 or 3;
h is 0, 1, 2, 3 or 4;
s is 0 or 1;
t is 0 or 1;
m, n and p are each independently selected from 0-4;
provided that at least one of s and t is 1, and the sum of m, n, p, s and t is 1-6; provided that when p is 0 and t is 1, the sum of m, n and p is 1-5; and provided that when p is 0 and s is 1, the sum of m, t and n is 1-5;
v is 0 or 1;
j and k are each independently 1-5, provided that the sum of j, k and v is 1-5;
Q is a bond, —(CH2)q—, wherein q is 1-6, or, with the 3-position ring carbon of the azetidinone, forms the spiro group
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wherein R12 is
OG Complex Work Unit Drawing
R13 and R14 are each independently selected from the group consisting of —CH2—, —CH(C1-C6 alkyl)-, —C(di-(C1-C6) alkyl), —CH═CH— and —C(C1-C6 alkyl)=CH—; or R12 together with an adjacent R13, or R12 together with an adjacent R14, form a —CH═CH— or a —CH═C(C1-C6 alkyl)- group;
a and b are each independently 0, 1, 2 or 3, provided both are not zero; provided that when R13 is —CH═CH— or —C(C1-C6 alkyl)=CH—, a is 1; provided that when R14 is —CH═CH— or —C(C1-C6 alkyl)=CH—, b is 1; provided that when a is 2 or 3, the R13's can be the same or different; and provided that when b is 2 or 3, the R14's can be the same or different;
and when Q is a bond and L is
OG Complex Work Unit Drawing
then Ar1 can also be pyridyl, isoxazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyrazinyl, pyrimidinyl or pyridazinyl;
R19 and R20 are each independently selected from the group consisting of H, (C1-C6)alkyl, aryl and aryl-substituted (C1-C6)alkyl;
R21 is (C1-C6)alkyl, aryl or R24-substituted aryl;
R22 is H, (C1-C6)alkyl, aryl (C1-C6)alkyl, —C(O)R19 or —COOR19;
R23 and R24 are each independently selected from the group consisting of 1-3 substituents which are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, —COOH, NO2, —NR19R20, —OH and halo; and
R25 is H, —OH or (C1-C6)alkoxy.