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Sulfonamides and derivatives thereof that modulate the activity of endothelin

  • US 6,632,829 B2
  • Filed: 11/05/2001
  • Issued: 10/14/2003
  • Est. Priority Date: 04/04/1996
  • Status: Expired due to Fees
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Assignments
First Claim
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1. A lyophilized powder, comprising a salt of compound of formula (A):

  • embedded imagewherein;

    Ar1 is a substituted with one or more substituents or an unsubstituted monocyclic or polycyclic heteroaryl group in which each substituent is independently selected from the group consisting of H, NH2, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, aryl, heteroaryl, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, and haloaryl, in which the aryl and alkyl portions are unsubstituted or substituted with any of the preceeding groups, and straight or branched chains of from about 1 up to about 12 carbons;

    A2 has the formula;

    embedded imagein which M is (CH2)mC(O)(CH2)r, (CH2)mC(O)NH(CH2)r, (CH2)m(CH═

    CH)(CH2)r, (CH2)mC(O)(CH2)sNH(CH2)r, (CH2)m(CH═

    CH)(CH2)r, C═

    N(OH)(CH2)r, (CH2)mC(O)(CH═

    CH)sNH(CH2)r, CH(OH)(CH2)r, CH(CH3)C(O)(CH2)r, CH(CH3)C(O)(CH2)m(CH═

    CH)(CH2)r, (CH2)r, (CH2)rO, (CH2)S(O)n wherein n is 0-2, C(O)O, in which m, s and r are each independently 0 to 6; and

    R1, R2, R3, R4 and R5 are each independently selected from (i) or (ii) as follows;

    (i) R1, R2, R3, R4 and R5 are each independently selected from among H, OH, NHR38, CONR38R39, NO2, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenyl sulfinyl, alkenylsulfonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkylaminocarbonyl)alkyl, acetoxy, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, amino acids, hexoses, O-glycosides, riboses, lower alkyl, —

    (CH2)xC(O)(CH2)x, —

    (CH2)x, (CH2)xN-lower alkyl, —

    (CH2)xC(O)NH2, a D-, L- or racemic amino acid, a primary or secondary amide, O-glycoside, a hexose or ribose, —

    S(O)2NH2, acetoxyalkyl, —

    (CH2)xCOOH, —

    (CH2)xCOOH—

    , CO2-lower alkyl, —

    COC(O)(CH2)xCH3, —

    (CH2)xN(CH3)2, a sulfonyl chloride, S(O)2NHR50, alkylaryl, alkylheteroaryl, C(O)NHR50, —

    (CH2)xOH and —

    C(O)N(H)N(H)M, in which each x is 0-3, or;

    (ii) at least two of R1, R2, R3, R4 and R5, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted or substituted by replacing one or more hydrogens with halide, loweralkyl, loweralkoxy or halo loweralkyl, and the others of R1, R2, R3, R4 and R5 are selected as in (i); and

    at least four of R1, R2, R3, R4 and R5 are not hydrogen, unless;

    (a) R1 and R3 are alkyl and R5 is R20, which is selected from the group consisting of aryl, heteroaryl, heterocyclyl, OH, CN, C(O)R16, CO2R16, SH, S(O)nR16 in which n is 0-2, a D, L or racemic amino acid, a ribose or hexose, an O-glycoside, a sulfonyl chloride, —

    (CH2)xOH, NHOH, NR12R16, NO2, N3, OR16, R12NCOR16 and CONR12R16, then R2 and R4 may be H;

    or (b) when M is —

    CONHC(R12)(R16)—

    , then R1, R2, R3, R4 and R5 may all be H;

    (c) when M is —

    COCHR6—

    , Ar1 is not an isoxazolyl, R1 is alkyl, and R3 and R4 form alkylenedioxy, then R2 and R5 may be H;

    R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;

    R6 is H, or substituted or unsubstituted alkyl or aryl;

    X is S, O or NR11, where R11 contains up to about 30 carbon atoms and is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R15 and S(O)nR15 in which n is 0-2;

    R15 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, or cycloalkynyl;

    R11 and R15 are unsubstituted or are substituted with one or more substituents each selected independently from Z;

    Z is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, amino acids, primary and secondary amides, O-glycosides, hexoses, riboses, alkylaryl, alkylheteroaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R16, OC(O)R16, CO2R16, OCO2R16, SH, S(O)nR16 in which n is 0-2, NHOH, NR12R16, NO2, N3, OR16, R12NCOR16 and CONR12R16;

    R16 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, chloride, NHR50, alkylaryl, alkylheteroaryl, or —

    (CH2)xOH in which each x is 0-3;

    R50 is hydrogen, lower alkyl, or lower alkoxy;

    R12, which is selected independently from R11 and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R17 and S(O)nR17 in which n is 0-2;

    R17 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;

    R12 and R16 may together form alkylene;

    each of R12, R15 and R16 may be further substituted with any group those set forth for Z.

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