Cytotoxic boronic acid peptide analogs

• US 5,106,948 A
• Filed: 08/28/1990
• Issued: 04/21/1992
• Est. Priority Date: 05/27/1988
• Status: Expired due to Fees

• Current Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Original Assignee: MAO Foundation For Medical Education and Research
• Inventors: Ames, Matthew M., Kinder, David H.
• Primary Examiner(s): NOT, DEFINED
• Assistant Examiner(s): Kraus, E. J.
• Application Number:
  US07/574,294
• Time in Patent Office: 602 Days
• Field of Search: 514/64, 514/18, 514/19, 530/331, 530/402
• 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 49/0039 Coumarin dyes
• 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 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 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 from a moiety derived from a dihydroxy compound, and R¹ is H or an N-terminal protecting group.

Claims

1. A method of inhibiting growth of a cancer cell comprising contacting said cell with an effective growth-inhibiting amount of a compound of the formula (II):

##STR10## or a physiologically acceptable salt thereof, wherein A 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 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 having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteratom or heteroatoms which can be N, S or O;

with the proviso that where the heteroatom is O, R² cannot be H; and

R² is H or an N-terminal protecting group.

2. The method of claim 1 wherein Y¹ ═

Y² ═

H.

3. The method of claim 1 wherein R is benzyl, methyl, isopropyl, 2-butyl or isobutyl.

4. The method of claim 1 wherein R² is H or benzyloxycarbonyl.

5. The method of claim 1 wherein A² is Ala, Pro, Gly or Val.

6. The method of claim 1 wherein A¹ is Ala.

7. The method of claim 1 wherein the cancer cell is a sarcoma, melanoma, carcinoma, lymphoma or leukemia cell.

8. The method of claim 1 wherein an amount of said compound of formula II is administered to a human cancer patient which is effective to inhibit the growth of said cancer.

9. The method of claim 8 wherein said amount of said compound of formula II is administered parenterally in combination with a pharmaceutically-acceptable liquid carrier.

10. The method of claim 9 wherein said amount of said compound of formula II is administered intravenously.