US 2018/0022780 A1 · STABILIZATION ADRENOMEDULLIN DERIVATIVES AND USE THEREOF

Abstract

The invention relates to novel, biologically active, stabilized Adrenomedullin (ADM) compounds. The invention further relates to the compounds for use in a method for the treatment and/or prevention of diseases, especially of cardiovascular, edematous and/or inflammatory disorders, and to medicaments comprising the compounds for treatment and/or prevention of cardiovascular, edematous and/or inflammatory disorders.

A compound of formula (I)

wherein X1 is selected from the group consisting of
*—(CH2)m1—S—#, wherein m1 is 0-6;
#—(CH2)m2—S—*, wherein m2 is 0-6;
*—(CH2)m3—#, wherein m3 is 1-8;
*—(CH2)m4—(CH2═CH2)—(CH2)n1—#, wherein m4 is 0-6, n1 is 0-6, with the proviso that m4+n1=0-6;
*—(CH2)m5—(CH≡CH)—(CH2)n2—#, wherein m5 is 0-6, and n2 is 0-6, with the proviso that m5+n2=0-6;
*—(CH2)m6—CO—NH—(CH2)n3—#, wherein m6 is 0-4, and n3 is 0-4, with the proviso that m6+n3=0-6;
#—(CH2)m7—CO—NH—(CH2)n4—*, wherein m7 is 0-4, and n4 is 0-4, with the proviso that m7+n4=0-6;
*—SO—(CH2)m8—#, wherein m8 is 0-6;
#—SO—(CH2)m9—*, wherein m9 is 0-6;
*—SO2—(CH2)m10—#, wherein m10 is 0-6;
#—SO2—(CH2)m11—*, wherein m11 is 0-6;
*-5-6 membered heteroaryl-#;
*—O—(CH2)m12—#, wherein m12 is 0-6;
#—O—(CH2)m13—*, wherein m13 is 0-6;
*—CH2—S—(CH2)m14—#, wherein m14 is 0-6;
#—CH2—S—(CH2)m15—*, wherein m15 is 0-6;
*—CH2—O—(CH2)m16—#, wherein m16 is 0-6;
#—CH2—O—(CH2)m17—*, wherein m17 is 0-6;
*—(CH2)m18—NH—CO—CH2—NH—CO—(CH2)n5—#, wherein m18 is 0-3, and n5 is 0 or 1, with the proviso that m18+n5=0-3;
#—(CH2)m19—NH—CO—CH2—NH—CO—(CH2)n6—*, wherein m19 is 0-3, and n6 is 0 or 1, with the proviso that m19+n6=0-3;
*—(CH2)m20—NH—CO—CH(CH3)—NH—CO—(CH2)n7—#, wherein m20 is 0-3, and n7 is 0 or 1, with the proviso that m20+n7=0-3;
#—(CH2)m21—NH—CO—CH(CH3)—NH—CO—(CH2)n8—*, wherein m21 is 0-3, and n8 is 0 or 1, with the proviso that m21+n8=0-3;
*—(CH2)m22—NH—CO—CH(CH2—C(CH3)2)—NH—CO—(CH2)n9—#, wherein m22 is 0-3, and n9 is 0 or 1, with the proviso that m22+n9=0-3;
#—(CH2)m23—NH—CO—CH(CH2—C(CH3)2)—NH—CO—(CH2)n10—*, wherein m23 is 0-3, and n10 is 0 or 1, with the proviso that m23+n10=0-3;
*—(CH2)m24—NH—CO—CH(CH(CH3)C2H5)—NH—CO—(CH2)n11—#, wherein m24 is 0-3, and n11 is 0 or 1, with the proviso that m24+n11=0-3;
#—(CH2)m25—NH—CO—CH(CH(CH3)C2H5)—NH—CO—(CH2)n12—*, wherein m25 is 0-3, and n12 is 0 or 1, with the proviso that m25+n12=0-3;
*—(CH2)m26—NH—CO—CH(CH2(C6H5))—NH—CO—(CH2)n—#, wherein m26 is 0-3, and n13 is 0 or 1, with the proviso that m26+n13=0-3;
#—(CH2)m27—NH—CO—CH(CH2(C6H5))—NH—CO—(CH2)n14—*, wherein m27 is 0-3, and n14 is 0 or 1, with the proviso that m27+n14=0-3;
*—(CH2)m28—NH—CO—(CH2)3—NH—CO—(CH2)n15—#, wherein m28 is 0 or 1, and n15 is 0 or 1, with the proviso that m28+n15=0-1;
#—(CH2)m29—NH—CO—(CH2)3—NH—CO—(CH2)n16—*, wherein m29 is 0 or 1, and n16 is 0 or 1, with the proviso that m29+n16=0-1;
*—(CH2)m30—NH—CO—NH—(CH2)n17—#, wherein m30 is 0-5, and n17 is 0-5, with the proviso that m30+n17=0-5;
#—(CH2)m31—NH—CO—NH—(CH2)n18—*, wherein m31 is 0-5, and n18 is 0-5, with the proviso that m31+n18=0-5;
*—(CH2)m32—O—CO—NH—(CH2)n19—#, wherein m32 is 0-5, and n19 is 0-5, with the proviso that m32+n19=0-5;
#—(CH2)m33—O—CO—NH—(CH2)n20—*, wherein m33 is 0-5, and n20 is 0-5, with the proviso that m33+n20=0-5;
*—(CH2)m34—O—CO—O—(CH2)n21—#, wherein m 34 is 0-5, and n21 is 0-5, with the proviso that m34+n21=0-5;
*—(CH2)m35—NH—CO—(CH2)n22—NH—(CH2)p1—, wherein m35 is 0-4, n22 is 0-4, and p1 is 0-4, with the proviso that m35+n22+p1=0-4;
and
*—(CH2)m36—NH—CO—(CH═CH)—CO—NH—(CH2)n23—#, wherein m36 is 0-2, and n23 is 0-2, with the proviso that m36+n23=0-2;
wherein * and # reflect where X1 is bound within the ring structure;
and
X2 is absent, is hydrogen, or is an amino acid or amino acid sequence selected from the group consisting of G14, K14, F14, SEQ ID NO:
1 [Y1RQSMNNFQGLRSF14], SEQ ID NO:
2 [R2QSMNNFQGLRSF14], SEQ ID NO:
3 [Q3SMNNFQGLRSF14], SEQ ID NO:
4 [S4MNNFQGLRSF14], SEQ ID NO:
5 [M5NNFQGLRSF14], SEQ ID NO:
6 [N6NFQGLRSF14], SEQ ID NO:
7 [N7FQGLRSF14], SEQ ID NO:
8 [F8QGLRSF14], SEQ ID NO:
9 [Q9GLRSF14], SEQ ID NO:
10 [G10LRSF14], SEQ ID NO:
11 [L11RSF14], SEQ ID NO:
12 [R12SF14], and SEQ ID NO:
13 [S13F14], which is covalently linked by an amide bond to the N-terminal G15 of the amino acid sequence of formula (I), wherein any amino acid of X2 may optionally be replaced by a natural or unnatural amino acid;
wherein A is L-Alanine;
R is L-Arginine;
N is L-Asparagine;
D is L-Aspartic acid;
Q is L-Glutamine;
G is L-Glycine;
H is L-Histidine;
I is L-Isoleucine;
L is L-Leucine;
K is L-Lysine;
M is L-Methionine;
F is L-Phenylalanine;
P is L-Proline;
S is L-Serine;
T is L-Threonine;
Y is L-Tyrosine;
V is L-Valine;
wherein the numbering of amino acids in formula (I) and in the definition of X2 refers to the corresponding human ADM sequence;
X3 is absent or is a heterologous moiety which is covalently linked to the N-terminus or to a functional group of the side chain of any amino acid of X2, to the N-terminus of G15 or to Z;
Z is absent or is a cleavable linker covalently bound between the N terminus of any amino acid of X2 or of G15 and X3 or between a functional group of the side chain of any amino acid of X2 and X3
wherein if X3 is absent, then
Z is also absent and X2 is hydrogen or is an amino acid or amino acid sequence as defined above;
wherein if X3 is a heterologous moiety, then
X2 is absent or is an amino acid or amino acid sequence as defined above;
Z is absent or is a cleavable linker covalently bound between the N terminus of any amino acid of X2 or of G15 and X3 or between a functional group of the side chain of any amino acid of X2 and X3;
or a physiologically acceptable salt, a solvate or a solvate of a salt thereof.

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Stabilization adrenomedullin derivatives and use thereof

Life of this patent

Stabilization adrenomedullin derivatives and use thereof

Life of this patent

Abstract

Claims17