Peptidyl prodrugs and methods of making and using the same

• US 5,952,294 A
• Filed: 07/31/1996
• Issued: 09/14/1999
• Est. Priority Date: 07/31/1996
• Status: Expired due to Fees

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Wipf, Peter, Lazo, John S.
• Primary Examiner(s): CELSA, BENNETT M
• Application Number:
  US08/690,013
• Time in Patent Office: 1,140 Days
• Field of Search: 514/15, 514/2, 514/18, 514/19, 424/185.1, 424/193.1, 424/457, 536/23.1
• US Class Current: 514/1.3
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids

Abstract

Peptidyl prodrugs of therapeutic agents having an activating function are sclosed. These therapeutic agents having activating functions include those having an amino, thiol, or hydroxyl function. Methods of making and using these prodrugs are also disclosed.

Claims

1. A spontaneously activated prodrug having the formula:

##STR5## wherein R is a peptide group having between about 1 and 10 amino acids which are attached to the rest of the prodrug by its main chain carboxyl terminus;

R¹ is selected from the group consisting of a carbon substituent and hydrogen;

Y is nitrogen substituted by hydrogen or a carbon substituent; and

Z is ara-C which is linked by its amino group to the carbonyl of the prodrug which allows for the spontaneous release of ara-C.

2. The prodrug of claim 1, wherein R is a peptide group having between about 1 and 5 amino acid groups.

3. The prodrug of claim 2, wherein R is a peptide group having 2 amino acid groups.

4. The prodrug of claim 3, wherein R is an α

,α

-disubstituted amino acid.

5. The prodrug of claim 1, wherein R is selected from the group consisting of 2-aminoisobutyric acid, isovaline, 2-methylserine, tert-leucine, 2-methylphenylalanine, 2,2-dipropylglycine and β

-alanine.

6. The prodrug of claim 1, wherein R is selected from the group consisting of 2,2-dialkyl and 2,2-diaryl amino acids.

7. The prodrug of claim 1 having a half-life in a patient of between about 10 minutes and 10 days.

8. A method of therapeutically treating a patient having an illness comprising the steps of:

a) incorporating into a suitable pharmaceutical carrier a spontaneously activated prodrug having the formula;

##STR6## wherein R is a peptide group having between about 1 and 10 amino acids which are attached to the rest of the prodrug by its main chain carboxyl terminus;

R¹ is selected from the group consisting of a carbon substituent and hydrogen;

Y is nitrogen substituted by hydrogen or a carbon substituent; and

Z is ara-C which is linked by its amino group to the carbonyl of the prodrug which allows for the spontaneous release of ara-C; and

b) administering a therapeutically effective amount of said compound incorporated in said carrier to a patient;

wherein said prodrug is spontaneously activated in said patient.

9. The method of claim 8 wherein said patient has an illness selected from the group consisting of leukemia, lymphoma and neoplastic meningitis.

10. The method of claim 8 wherein said carrier is selected from the group consisting of physiologic saline, dextrose, water and autologous spinal fluid.

11. The method of claim 8 including administering said compound incorporated in said carrier to a patient subcutaneously.

12. The method of claim 8, including administering said compound incorporated in said carrier to a patient intrathecally.

13. The method of claim 8, including administering said compound incorporated in said carrier to a patient intravenously.

14. A method of administering a spontaneously activated prodrug having the formula:

##STR7## wherein R is a peptide group having between about 1 and 10 amino acids which are attached to the rest of the prodrug by its main chain carboxyl terminus;

R¹ is selected from the group consisting of a carbon substituent and hydrogen;

Y is nitrogen substituted by hydrogen or a carbon substituent; and

Z is ara-C which is linked by its amino group to the carbonyl of the prodrug which allows for the spontaneous release of ara-C,

comprising the step of administering said prodrug to a patient every 2 to 10 half lives.