Cytotoxic boronic acid peptide analogs

• US 5,159,060 A
• Filed: 01/21/1992
• Issued: 10/27/1992
• Est. Priority Date: 05/27/1988
• Status: Expired due to Fees

• Current Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Original Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Inventors: Ames, Matthew M., Kinder, David H.
• Primary Examiner(s): GRIFFIN, RONALD
• Application Number:
  US07/823,674
• Time in Patent Office: 280 Days
• Field of Search: 530/402, 530/331, 514/18, 514/19, 514/64
• US Class Current: 530/331
• 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: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0804 and aliphatic
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A method is provided for inhibiting growth of cancer cells comprising contacting said cells with an effective growth-inhibiting amount of a compound of the formula (II): ##STR1## or a physiologically acceptable salt thereof, wherein A¹ and A² are individually L-amino acid residue selected from the group consisting of Ala, Pro, Gly, Glu, Leu, Lys, Phe, Ser, Vl, Ile, Arg, Tyr, Thr, Asp, Asn and Gly; R¹ is C₁ -C₆ (alkyl) which is unsubstituted or is substituted with an aromatic substituent or one or more in-chain bivalent groups selected from the group consisting of --O--, --CO--, --S--, --NH--, --CONH--, CH═CH--, and --SO₂ --; Y¹ and Y² are each H, or taken together form a moiety derived from a dihydroxy compound, and R¹ is H or an N-terminal protecting group.

Claims

1. A method for preparing a compound of formula (I):

##STR10## wherein A¹ is an L-amino acid residue selected from the group consisting of Ala, Pro, Gly, Glu, Leu, Lys, Phe, Ser, Val, Ile, Arg, Tyr, Thr, Asp, Asn and Gly;

R¹ is C_1-6 (alkyl) which is unsubstituted or is substituted with an aromatic substituent or one or more in-chain bivalent groups selected from the group consisting of --O--, --CO--, --S--, --NH--, --CONH--, --CH═

CH-- and --SO₂ --;

Y¹ and Y² taken together form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S or O; and

R² is an N-terminal protecting group;

comprising the steps of;

(a) converting an N-protected amino acid of the formula R² --(A¹)--OH into a compound of the formula R² (A¹)--N₃ wherein A¹ and R² are as defined above, and --OH represents the hydroxy moiety of the amino acid CO₂ H substituent; and

(b) reacting the compound of the formula R² (A¹)N₃ with a compound of the formula;

##STR11## wherein Y¹, Y² and R¹ are as defined above, and R₃, R₄, R₅, R₆, R₇, and R₈ are individually C₁ -C₄ -(alkyl), under desilating conditions to yield the compound of formula I.

2. The method of claim 1 further comprising cleaving said moiety derived from a dihydroxy group to yield the compound of formula I wherein Y¹ ═

Y² ═

H.

3. The method of claim 2 wherein said moiety is cleaved with BCl₃.

4. The method of claim 1 further comprising removing the N-terminal protecting group to yield the compound of formula I wherein R² ═

H;

with the proviso that the heteroatom or heteroatoms in the dihydroxy compound cannot be 0.

5. The method of claim 2 further comprising removing the N-terminal protecting group to yield a compound of formula I wherein R² ═

H.

6. The method of claims 4 or 5 wherein said N-terminal protecting group is cleaved by hydrogenolysis.

7. The method of claim 1 wherein R² (A¹)OH is reacted with diphenylphosphonyl azide in the presence of diisopropylmethylamine in step (a).

8. The method of claim 1 wherein step B is carried out in the presence of tetrabutylammonium fluoride-dihydrofluoride.

9. A method of preparing a compound of formula (II):

##STR12## wherein A¹ and A² are individually L-amino acid residues selected from the group consisting of Ala, Pro, Gly, Glu, Leu, Lys, Phe, Ser, Val, Ile, Arg, Tyr, Thr, Asp, Asn and Gly;

R¹ is C_1-6 (alkyl) which is unsubstituted or is substituted with an aromatic substituent or one or more in-chain bivalent groups selected from the group consisting of --O--, --CO--, --S--, --NH--, --CONH--, --CH═

CH-- and --SO₂ --;

Y¹ and Y² taken together form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S or O; and

R² is an N-terminal protecting group;

comprising the steps of;

(a) converting an N-protected amino acid of the formula R² (A¹)OH into a compound of the formula R² (A¹)N₃, wherein R² and A¹ are as defined above, and OH represents the hydroxy moiety of the amino acid CO₂ H substituent; and

(b) reacting the compound of the formula R² (A¹)N₃ with a compound of the formula;

##STR13## wherein A², R¹, Y¹ and Y² are as defined hereinabove, to yield the compound of formula II.

10. The method of claim 9 further comprising cleaving said moiety derived from a dihydroxy group to yield a compound of the formula II, wherein Y¹ ═

Y² ═

H.

11. The method of claim 10 wherein said moiety is cleaved with BCl₃.

12. The method of claim 9 further comprising removing the N-terminal protecting group to yield the compound of formula II, wherein R² ═

H;

with the proviso that the heteroatom or heteroatoms in the dihydroxy compound cannot be 0.

13. The method of claim 10 further comprising removing the N-terminal protecting group to yield a compound of formula II wherein R² ═

H.

14. The method of claims 12 or 13 wherein said N-terminal protecting group is cleaved by hydrogenolysis.

15. The method of claim 9 wherein R² (A¹)OH is reacted with diphenylphosphoryl azide in the presence of diisopropylethylamine in step (a).