US2014100172A1PendingUtilityA1
Cancer Imaging and Treatment
Est. expiryFeb 27, 2026(expired)· nominal 20-yr term from priority
Inventors:Hans-Jürgen WesterNorman KoglinMarkus SchwaigerHorst KasslerBurkhardt LauferOliver DemmerMartina Anton
A61P 43/00A61P 35/00A61K 51/08C07K 7/64A61K 51/088A61P 35/04G01N 33/575A61K 38/12A61K 47/48246
47
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Claims
Abstract
Provided herein are compounds useful for diagnostic imaging and/or therapeutic purposes. Each compound comprises a ligand for the chemokine receptor CXCR4, which has a binding affinity for the CXCR4 receptor, measured as IC50 in the presence of 125 I-CPCR4, of 250 nM or lower. The ligand is a cyclic oligopeptide moiety having a motif B-Arg or B-(Me)Arg within the cyclic moiety, wherein B is a basic amino acid, a derivative thereof, or phenylalanine, provided that the motif is B-Arg when B is a N α -methyl derivative of a basic amino acid, and provided that the cyclic oligopeptide moiety has a sequence other than cyclo[D-Tyr-Arg-Arg-NaI-Gly] or cyclo[D-Tyr-Orn-Arg-NaI-Gly].
Claims
exact text as granted — not AI-modified1 . A compound, or a pharmaceutically acceptable salt or ester thereof, the compound having a binding affinity for a CXCR4 receptor, measured as IC50 in the presence of 125 I-CPCR4, of 250 nM or lower, wherein the compound is a cyclic oligopeptide moiety having a motif B-Arg or B-(Me)Arg within the cyclic moiety, and wherein B is a basic amino acid, a derivative thereof, or phenylalanine, provided that the motif is B-Arg when B is a N α -methyl derivative of a basic amino acid, and provided that the cyclic oligopeptide moiety has a sequence other than cyclo[D-Tyr-Arg-Arg-NaI-Gly] or cyclo[D-Tyr-Orn-Arg-NaI-Gly], NaI being L-3-(2-naphthyl)alanine.
2 . The compound of claim 1 , wherein the cyclic oligopeptide moiety has the sequence:
cyclo[D-Tyr/(Me)D-Tyr-B-Arg/(Me)Arg-Z-(Ala) n -X] wherein:
B is as defined in claim 1 ;
Z is an amino acid containing an aromatic group in its side chain;
X selected from Ala, Gly, Dap (diaminopropionic acid), Dab (diaminobutyric acid), or N-substituted derivatives thereof; and
n is 1 or 0.
3 . The compound of claim 2 , wherein B is selected from Arg, Orn, D-Orn, Cit and His, or N-substituted derivatives thereof.
4 . The compound of claim 2 , wherein B is N α -substituted with a Me group.
5 . The compound of claim 2 , wherein B is Orn or D-Orn, the ornithine residue being substituted at N δ with one or two groups selected from fluorobenzoyl (FB), fluoropropionyl (FP), acetyl (Ac), amido (Am), Me, 1-naphthylmethyl (N1), 2-naphthylmethyl (N2), benzyl (Bz) and acyl spacer moieties, wherein the acyl spacer moiety is an acyl group containing a chain of 1-14 carbons, optionally interrupted by heteroatoms, and having a nucleophilic functional group at its end distal to the ornithine N δ , or the ornithine residue being substituted at N α with a Me group.
6 . The compound of claim 6 , wherein the acyl spacer moiety is selected from aminohexanoyl (Ahx), triethyleneglycolamino acyl (TGAS), (Ahx) 2 , (Ahx) 3 , (TGAS) 2 and (TGAS) 3 .
7 . The compound of claim 6 , wherein Orn is substituted at N δ with FB, FP, Ac, Am, N1, N2, Me and N1, Me and N2, Bz, Bz and FB, Bz and FP, Me and FB, Me and FP, or Me.
8 . The compound of claim 6 , wherein D-Orn is substituted at N δ with FB, FP, Me and FB, or Me and FP, and optionally substituted at N α with Me.
9 . The compound of claim 2 , wherein Z is selected from NaI, (Me)NaI, Dap(FB) or AMS (FB) (an oxime of aminooxy serine and 4-fluorobenzaldehyde).
10 . The compound of claim 2 , wherein X is selected from Gly, (Me)Gly, Ala, Dap Dap(FP), Dab, Dab(FP), Dab(FB), or Dap(FB).
11 . The compound of claim 2 , wherein the cyclic oligopeptide moiety has the sequence: cyclo[D-Tyr B-Arg-Z-X], provided that not more than one of the residues in the sequence is N α -methylated.
12 . The compound of claim 2 , wherein the cyclic oligopeptide moiety has the sequence: cyclo[D-Tyr/(Me)D-Tyr-B-Arg/(Me)Arg-Z-X], wherein B is selected from Arg, (Me)Arg, Orn, Cit, Orn(FB), Orn(FP), Orn(Ac), Orn(Am), Orn(N1), Orn(N2), Orn(Me, N1), Orn(Me, N2), Orn(Me), Orn(Bz), Orn(Bz,FB), Orn(Ahx), Orn(Ahx 2 ), Orn(Ahx 3 ), Orn(TGAS), Orn(TGAS 2 ), Orn(TGAS 3 ), Orn(Me,FB), D-Orn(FB), (Me)D-Orn(FB), (Me)D-Orn(Me,FB), His and Phe, provided that not more than one of the residues in the said sequence may be N α -methylated.
13 . The compound of claim 2 , wherein the first residue is D-Tyr, the third residue is Arg, Z is NaI, and X is Gly.
14 . The compound of claim 2 , wherein the cyclic oligopeptide moiety has a sequence selected from:
cyclo[D-Tyr-(Me)Arg-Arg-Nal-Gly]
cyclo[D-Tyr-Arg-(Me)Arg-Nal-Gly]
cyclo[D-Tyr-Arg-Arg-Nal-(Me)Gly];
cyclo[D-Tyr-Cit-Arg-Nal-Gly]
cyclo[D-Tyr-Arg-Arg-Nal-Ala-Gly]
cyclo[D-Tyr-Arg-Arg-Nal-Ala-Ala]
cyclo[D-Tyr-(Me)Arg-Arg-Nal-(Me)Gly]
cyclo[D-Tyr-(Me)Arg-Arg-(Me)Nal-Gly]
cyclo[(Me)D-Tyr-Arg-Arg-Nal-Ala-Gly]
cyclo[(Me)D-Tyr-Arg-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(FB)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(FP)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Ac)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Am)-Arg-Nal-Gly]
cyclo[D-Tyr-Arg-Arg-Nal-Dap(FP)]
cyclo[D-Tyr-Orn(N1)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(N2)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Me, N1)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Me, N2)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Me)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Bz)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Bz, FB)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Ahx)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(Ahx3)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(TGAS)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(TGAS2)-Arg-Nal-Gly]
cyclo[D-Tyr-Orn(TGAS3)-Arg-Nal-Gly]
cyclo[D-Tyr-D-Orn(Me, FB)-Arg-Nal-Gly]
cyclo[D-Tyr-D-Orn(FB)-Arg-Nal-Gly]
cyclo[D-Tyr-(Me)D-Orn(FB)-Arg-Nal-Gly]
cyclo[D-Tyr-(Me)D-Orn(Me, FB)-Arg-Nal-Gly]
cyclo[D-Tyr-His-Arg-Nal-Gly]
or
cyclo[D-Tyr-Phe-Arg-Nal-Gly].
15 . The compound of claim 1 which has been modified by the attachment of one or more hydrophilic moieties.
16 . A pharmaceutical composition comprising the compound of claim 1 together with one or more pharmaceutically acceptable excipients.
17 . A method for treating a neoplastic condition, the method comprising administering to a subject having a neoplasia the compound of claim 1 .
18 . The compound of claim 1 further comprising a cytotoxic moiety.
19 . The compound of claim 18 , wherein the cyclic oligopeptide moiety has the sequence:
cyclo[D-Tyr/(Me)D-Tyr-B-Arg/(Me)Arg-Z-(Ala) n -X] wherein:
B is selected from Arg, Orn, D-Orn, Cit and His, or N-substituted derivatives thereof;
Z is an amino acid containing an aromatic group in its side chain;
X selected from Ala, Gly, Dap, Dab, or N-substituted derivatives thereof; and
n is 1 or 0.
20 . The compound of claim 19 , wherein B is selected from Arg, (Me)Arg, Orn, Cit, Orn(FB), Orn(FP), Orn(Ac), Orn(Am), Orn(N1), Orn(N2), Orn(Me, N1), Orn(Me, N2), Orn(Me), Orn(Bz), Orn(Bz,FB), Orn(Ahx), Orn(Ahx 2 ), Orn(Ahx 3 ), Orn(TGAS), Orn(TGAS 2 ), Orn(TGAS 3 ), Orn(Me,FB), D-Orn(FB), (Me)D-Orn(FB), (Me)D-Orn(Me,FB), His and Phe, provided that not more than one of the residues in the said sequence may be N α -methylated.
21 . The compound of claim 19 , wherein Z is selected from NaI, (Me)NaI, Dap(FB) or AMS (FB).
22 . The compound of claim 19 , wherein X is selected from Gly, (Me)Gly, Ala, Dap Dap(FP), Dab, Dab(FP), Dab(FB), or Dap(FB).
23 . The compound of claim 18 , wherein the cytotoxic moiety is bound directly to the cyclic oligopeptide moiety or the cytotoxic moiety is attached to the cyclic oligopeptide moiety by a spacer.
24 . The compound of claim 18 , wherein the cytotoxic moiety is a chemotherapeutic compound.
25 . A method for treating a neoplastic condition, the method comprising administering to a subject having a neoplasia the compound of claim 18 .
26 . The method of claim 25 , wherein the neoplasia has, or is suspected of having, metastatic potential.
27 . A pharmaceutical composition comprising the compound of claim 18 together with one or more pharmaceutically acceptable excipients.
28 . The compound of claim 1 further comprising a detectable label.
29 . The compound of claim 28 , wherein the cyclic oligopeptide moiety has the sequence:
cyclo[D-Tyr/(Me)D-Tyr-B-Arg/(Me)Arg-Z-(Ala) n -X] wherein:
B is selected from Arg, Orn, D-Orn, Cit and His, or N-substituted derivatives thereof;
Z is an amino acid containing an aromatic group in its side chain;
X selected from Ala, Gly, Dap, Dab, or N-substituted derivatives thereof; and
n is 1 or 0.
30 . The compound of claim 28 , wherein the detectable label is a fluorescent moiety, a magnetic or paramagnetic moiety, or a radionuclide.Join the waitlist — get patent alerts
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