×

Substituted 2-azetidinones useful as hypocholesterolemic agents

  • US 6,982,251 B2
  • Filed: 06/11/2002
  • Issued: 01/03/2006
  • Est. Priority Date: 12/20/2000
  • Status: Expired due to Fees
0
Associated Cases
0
Associated Defendants
0
Product Citations
0
Petitions
13
Forward Citations
1
Assignment
First Claim
Patent Images

1. A compound represented by the Formula (IA):

  • embedded imageor 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, embedded imagewherein 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;

    embedded imagewherein R33 is independently selected from the group consisting of R34-substituted alkyl, (R35)(R36)alkyl-, embedded imageR34 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—

    ;

    embedded imageR35 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;

    embedded imagewherein 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) embedded imagewherein 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 embedded imagewherein R12 is embedded imageR13 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 embedded imagethen 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.

View all claims
  • 1 Assignment
Timeline View
Assignment View
    ×
    ×