Enzyme-activated anti-tumor prodrug compounds

• US 6,855,689 B2
• Filed: 05/23/2002
• Issued: 02/15/2005
• Est. Priority Date: 05/14/1999
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Firestone, Raymond A., Telan, Leila A.
• Primary Examiner(s): Weber, Jon
• Assistant Examiner(s): KAM, CHIH MIN
• Application Number:
  US10/154,507
• Publication Number:
  US 20020147138A1
• Time in Patent Office: 999 Days
• Field of Search: 435/23, 435/218, 435/226, 514/2, 530/300, 530/402, 424/1.53, 424/193.1, 424/9.1
• US Class Current: 514/1.3
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 47/65 Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/1008 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

Disclosed are enzyme-activated anti-tumor and anti-metastatic prodrug compounds. The specific enzymes are collagenase(IV) and elastase. Also disclosed are methods of making and using such compounds.

Claims

1. A prodrug compound comprising:

a targeting-peptide chosen from SEQ ID NO;

6 or SEQ ID NO;

7, wherein the targeting-peptide has L or L and D amino acid residues and wherein the targeting-peptide is optionally covalently capped by a terminal amino capping group Z;

a linker group covalently attached to the targeting-peptide at the carboxy terminus; and

a cytotoxic drug covalently attached to the linker;

wherein;

the targeting-peptide is an amino acid sequence which is catalytically cleaved by elastase;

the linker group is a bond or a self-immolating linker; and

Z is an amino protecting group chosen from tert-butyloxycarbonyl, benzyloxycarbonyl or an adhesion peptide;

wherein there is an optional spacer molecule between Z and the targeting-peptide.

2. The prodrug compound according to claim 1 wherein the cytotoxic drug is selected from doxorubicin, mitomycin, paclitaxel, camptothecin, vincristine, vinblastine, fluorouracil, methotrexate, TNP-470, thalidomide and squalamine.

3. The prodrug compound according to claim 2 wherein the cytotoxic compound is doxorubicin.

4. The prodrug compound according to claim 3 wherein there is a spacer molecule between Z and the targeting-peptide.

5. The prodrug compound according to claim 4 wherein Z is an adhesion peptide selected from SEQ ID NO:

3 and SEQ ID NO;

4, wherein Z has L or L and D amino acid residues.

6. A pharmaceutical composition comprising a therapeutically effective amount of a prodrug compound according to claim 1.