(2S) -2-AMINO-4-(2-AMINO-(3,4,5,6-TETRAHYDROPYRIMIDIN-4-YL) BUTANOYL AND ITS USE IN CYCLIC AND ACYCLIC PEPTIDES

• US 20040087603A1
• Filed: 11/06/2001
• Published: 05/06/2004
• Est. Priority Date: 11/06/2001
• Status: Active Grant

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Inventors: Rajopadhye, Milind
• Granted Patent: US 6,818,659 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07D 239/14 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
• CPC Class Codes: C07K 7/52 with only normal peptide links in the ring

Abstract

The present invention provides a novel amino acid of the formula:

and derivatives thereof that are useful as arginine substitutes in biological targeting moieties.

Claims

1. A compound of formula I:

3. A compound according to claim 1, wherein:

R¹ is selected from H, OMe, OEt, OBzl, Oallyl, and Ot-Bu;

alternatively, OR¹ is selected from OSu, OBt, OPfp, and Onp;

R² is Fmoc or Boc

R^2a is H;

R³ is H;

R⁴ is selected from Tos, Mtr, Pbf, Mts, Pmc, Boc, Mbs, NO₂, and Cbz;

R^4a is H;

alternatively, when R⁴ Boc, R^4a is Boc; and

,

alternatively, when R⁴ Cbz, R^4a is Cbz;

4. A compound according to claim 1, wherein the compound is selected from :

Fmoc-cyArg(Tos)-OH, Fmoc-cyArg(Mtr)-OH, Fmoc-cyArg(Pbf)-OH, Fmoc-cyArg(Mts)-OH, Fmoc-cyArg(Pmc)-OH, Fmoc-cyArg(Boc)2-OH, Boc-cyArg (Mbs)-OH, Boc-cyArg(Boc)2-OH, Boc-cyArg(Mtr)-OH, Boc-cyArg(NO2)-OH, Boc-cyArg(Pbf)-OH, Boc-cyArg(Pmc)-OH, Boc-cyArg(Tos)-OH, and Boc-cyArg(Cbz)2-OH;

wherein cyArg corresponds to the unmodified amino acid.

2. A compound formula Ia or Ib:

5. A process for making a compound of formula I:

6. A process according to claim 5, wherein reduction is performed by contacting the compound of formula II with trifluoroacetic acid and a trialkylsilane.

7. A process according to claim 6, wherein the trialkylsilane is triisopropylsilane.

8. A method of preparing an arginine-containing peptide, comprising:

synthesizing the peptide using a compound of formula I in place of arginine or protected arginine;

10. A compound according to claim 8, wherein the biological receptor is selected from the group:

Tuftsin, Thrombin catalytic site, Thrombin exosite, Factor XIIIa, Factor Xa, Factor IXa, Factor VIIa, Neurotensin, Bombesin, the Bradykinin receptors, and an intergrin selected from a_vb₃, a_IIbbb₃, a_vb₅, a₅b₁, a₂b₁, a₁b₁, and Mac-1

12. A compound according to claim 10, wherein the compound comprises an RGD, TKPR, or TKPPR segment wherein the arginine or arginine-mimetic has been replaced by the arginine mimic of formula III.

13. A compound according to claim 10, wherein the compound further comprises:

a chelator and 0-1 linking groups between the peptide and the chelator.

14. A compound according to claim 12, wherein the linking group is present.

9. A compound, comprising:

an acyclic or cyclic peptide that targets a biological receptor, wherein the peptide comprises an arginine mimic of formula IIIa or IIIb;

11. A compound according to claim 9, wherein the biological receptor is selected from the group:

Tuftsin, Thrombin catalytic site, Thrombin exosite, Factor XIIIa, Factor Xa, Factor IXa, Factor VIIa, and an intergrin selected from a_vb₃, a_IIbb₃, a_vb₅, a₅b₁, a₂b₁, a₁b₁, and Mac-1