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Neuromedin b and somatostatin receptor agonists

  • US 6,903,074 B1
  • Filed: 06/05/2000
  • Issued: 06/07/2005
  • Est. Priority Date: 06/04/1999
  • Status: Expired due to Term
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Petitions
16
Forward Citations
4
Assignments
First Claim
Patent Images

1. A compound of formula (II):

  • embedded imageor a pharmaceutically acceptable salt thereof,whereinthe α

    -nitrogen of AA1, AA2, AA3, AA4, AA5, AA6, AA7, and AA8 each is, independently, optionally substituted with (C1-4)alkyl, (C3-4)alkenyl, (C3-4)alkynyl, or (C1-6)alkyl-C(O)—

    ;

    AA1 is absent or the D- or L-isomer of an amino acid selected from the group consisting of R11, Aac, Aic, Arg, Asn, Asp, Dip, Gln, Glu, Hyp, Lys, Mac, Macab, Orn, Pip, Pro, Ser, Ser(Bzl), Thr, Thr(Bzl), Pip, hArg, Bip, Bpa, Tic, Cmp, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, Iia, Alla, Aba, Gba, Car, Ipa, Iaa, Inip, Apa, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, Mnf, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α

    -Chpa, Cit, Nua, Pyp and an optionally substituted aromatic α

    -amino acid, wherein said optionally substituted aromatic α

    -amino acid is optionally substituted with one or more substituents selected from the group consisting of halogen, NO2, OH, CN, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, and NR9R10;

    AA2 is absent or the D- or L-isomer of an amino acid selected from the group consisting of R11, Aic, Arg, Hca, His, Hyp, Pal, F5-Phe, Phe, Pro, Trp, X0-Phe, Pip, hArg, Bip, Bpa, Tic, Cmp, Inc, Inp, Nip, Ppc, Htic, Thi, Tra, Cmpi, Tpr, Iia, Alla, Aba, Gba, Car, Ipa, Iaa, Inip, Apa, Mim, Thnc, Sala, Aala, Thza, Thia, Bal, Fala, Pala, Dap, Agly, Pgly, Ina, Dipa, Mnf, Inic, I-Iqc, 3-Iqc, C4c, 5-Iqs, Htqa, 4-Mqc, Thn, α

    -Chpa, Cit, Nua, and Pyp;

    AA3 is the D- or L-isomer of an amino acid selected from the group consisting of Cys, hCys, Pen, Tpa and Tmpa;

    AA4 is a D- or L-isomer of an amino acid selected from the group consisting of Trp, N-Met-Trp, β

    -Met-Trp, His, hHis, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala, and an optionally substituted aromatic α

    -amino acid, wherein said optionally substituted aromatic α

    -amino acid is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, NO2, OH, (C1-4)alkyl, (C2-4)alkenyl, (C2-4)alkynyl, Bzl, O-Bzl, and NR9R10;

    AA5 is a D- or L-isomer of an amino acid selected from the group consisting of 4-Pip-Gly, 4-Pip-Ala, cis-4-Acha, trans-4-Acha, trans-4-Amcha, hLys, Lys, Orn, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, and Pala, wherein the side-chain amino group of said amino acid is optionally mono- or di-substituted with R3 and R4;

    AA6 is a D- or L-isomer of an amino acid selected from the group consisting of Cys, hCys, Pen, Tpa, and Tmpa;

    AA7 is absent or a D- or L-isomer of an amino acid selected from the group consisting of R11, Aic, A3c, A4c, A5c, A6c, Abu, Aib, β

    -Ala, Arg, Bpa, Cha, Deg, Gaba, His, Ile, Leu, Nal, Nle, Pal, Phe, F5-Phe, Pro, Sar, Ser, Ser(Bzl), Thr, Thr(Bzl), Trp, N-Me-Art Trp, Val, N-Me-Val, hArg, Bip, Tic, Htic, Dip, Sala, Aala, Thza, Thia, Bal, Fala, Pala, and X0-Phe;

    AA8 is absent or the D- or L-isomer of an amino acid selected from the group consisting of R11, an optionally substituted aromatic α

    -amino acid, Maa, Maaab, Ser, Ser(Bzl), Thr, Thr(Bzl), Tyr, Phe(4-O-Bzl), F5-Phe, and X5-Phe;

    R1 and R2 each is, independently, H, E-, E(O)2S—

    , E(O)C—

    , EOOC—

    , R13, or absent;

    R3 and R4 each is, independently, (C1-12)alkyl, (C2-12)alkenyl, (C2-12)alkynyl, phenyl, naphthyl, phenyl-(C1-6)alkyl, phenyl-(C2-6)alkenyl, phenyl-(C2-6)alkynyl, naphthyl-(C1-6)alkyl, naphthyl-(C2-6)alkenyl, naphthyl-(C2-6)alkynyl, (cyclo(C3-7)alkyl)-(c1-6)alkyl, (cyclo(C3-7)alkyl)-(C2-6)alkenyl, (cyclo(C3-7)alkyl)-(c2-6)alkynyl, heterocyclyl-(C1-4)alkyl, heterocyclyl-(C2-4)alkenyl, heterocyclyl-(C2-4)alkynyl, 1-adamantyl, 2-adamantyl, 9-fluorenylmethyl, dicyclopropylmethyl, dimethylcyclopropylmethyl, or benzhydryl;

    R5 is —

    OR6, —

    NR7R8, or absent, wherein each R6, R7 and R8 is, independently, H, (C1-12)alkyl, (C2-12)alkenyl, (C2-12)alkynyl, phenyl, naphthyl, phenyl-(C1-6)alkyl, phenyl-(C2-6)alkenyl, phenyl-(C2-6)alkynyl, naphthyl-(C1-6)alkyl, naphthyl-(C2-6)alkenyl, naphthyl-(C2-6)alkynyl, 1-adamantyl, 2-adamantyl, 9-fluorenylmethyl, dicyclopropylmethyl, dimethylcyclopropylmethyl, or benzhydryl;

    R9 and R10 each is, independently, H, (C1-6)alkyl, (C3-4)alkenyl, (C3-4)alkynyl, 1-adamantyl, or 2-adamantyl;

    R11 is, independently for each occurrence, a D- or L-amino acid of the formula;

    embedded imagewherein m and n each is, independently, 1, 2, or 3, and p is 0, 1, or 2;

    R12 is, independently for each occurrence, an optionally substituted moiety of the formula;

    embedded imageR13 is a moiety according to the formula embedded imagewherein R21 is (C1-4)alkyl and s is 1, 2, 3, or 4;

    E is, independently for each occurrence, an optionally substituted moiety selected from the group consisting of (C1-12)alkyl, (C2-12)alkenyl, (C2-12)alkynyl, phenyl, naphthyl, phenyl-(1-6)alkyl, phenyl-(C2-6)alkenyl, phenyl-(C2-6)alkynyl, naphthyl-(C1-6)alkyl, naphthyl-(C2-6)alkenyl, naphthyl-(C2-6)alkynyl, (cyclo(C3-7)alkyl)-(C1-6)alkyl, (cyclo(C3-7)alkyl)-(C2-6)alkenyl, (cyclo(C3-7)alkyl)-(C2-6)alkynyl, heterocyclyl-(C1-4)alkyl, heterocyclyl-(C2-4)alkenyl, heterocyclyl-(C2-4)alkynyl, 1-adamantyl, 2-adamantyl, dicyclopropylmethyl, dimethylcyclopropylmethyl, 9-fluorenylmethyl, and benzhydryl;

    wherein the optionally substituted moiety defined for E is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, OH, Bzl, O-Bzl, NO2, CN, COOH, and SH;

    X0 is halogen, NO2, CH3, OH, Bzl, O-Bzl or CN;

    X1 is H, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, indolyl, imidazolyl, 1-naphthyl, 3-pyridyl, optionally ring-substituted benzyl, or a moiety which corresponds to the side-chain group of Arg, Leu, Gln, Lys, Tyr, His, Thr, Trp, Phe, Val, Ala, Lys, or His;

    wherein said optionally ring-substituted benzyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, (C1-6)alkoxy, mono- or di-(C1-6)alkylamino, (C1-4)alkyl, (C2-4)alkenyl, (C2-4)alkynyl, and N9R10;

    X2 and X3 each is, independently, H, halogen, OH, ═

    O, ═

    S, (c1-12)alkyl, (C2-12)alkenyl, (C2-12)alkynyl, phenyl, naphthyl, phenyl-(C1-6)alkyl, phenyl-(C2-6)alkenyl, phenyl-(C2-6)alkynyl, naphthyl-(C1-6)alkyl, naphthyl-(C2-6)alkenyl, naphthyl-(C2-6)alkynyl, (cyclo(C3-7)alkyl)-(C1-6)alkyl, (cyclo(C3-7)alkyl)-(C2-6)alkenyl, (cyclo(C3-7)alkyl)-(C2-6)alkynyl, heterocyclyl-(C1-4)alkyl, heterocyclyl-(C2-4)alkenyl, heterocyclyl-(C2-4)alkynyl, 1-adamantyl, 2-adamantyl, dicyclopropylmethyl, or dimethylcyclopropyl methyl;

    X4 is H, OH, or NH2; and

    X5 is halogen, NO2, CH3, OH, Bzl or O-Bzl;

    provided that;

    at least one of AA7 or AA8 is present;

    at least six amino acid residues are present;

    when AA1 is a D- or L-isomer of an amino acid selected from the group consisting of Mac or Macab, then AA8 is a D- or L-isomer of an amino acid selected from the group consisting of Maa and Maaab, and when AA8 is a D- or L-isomer of an amino acid selected from the group consisting of Maa and Maaab, then AA1 is a D- or L-isomer of Mac or of Macab, and AA1 is connected by a disulfide bond with AA8;

    AA2 can be D- or L-Hca only when AA1 is absent;

    when one of R1 or R2 is E(O)2S—

    , E(O)C—

    , EOOC—

    , or R13, the other is H;

    when R5 is absent, then one of R1 or R2 is also absent, and the N-terminal amino acid and C-terminal amino acid together form an amide bond;

    when one of X2 or X3 is C═

    O or C═

    S, the other is absent; and

    said compound of formula (I) is not of the formula;

    D-4-NO2-Phe-Phe(4-O-Bzl)-cyclo(D-Cys-D-Trp-Lys-Cys)Cha-Nal-NH2;

    or D-4-NO2-Phe-cyclo(D-Cys-Phe(4-O-Bzl)-D-Trp-Lys-Cys)-Val-Tyr-NH2.

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