Lactacystin analogs

• US 20060052424A1
• Filed: 11/12/2003
• Published: 03/09/2006
• Est. Priority Date: 04/12/1995
• Status: Abandoned Application

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Schreiber, Stuart L., Jamison, Timothy F., Fenteany, Gabriel, Standaert, Robert F.
• Application Number:
  US10/706,877
• Publication Number:
  US 20060052424A1
• Time in Patent Office: Days
• US Class Current: 514/369
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 495/10 Spiro-condensed systems
• CPC Class Codes: C12N 9/6421 from mammals

Abstract

Compounds related to lactacystin and lactacystin β-lactone, pharmaceutical compositions containing the compounds, and methods of use.

Claims

1. A method of treating cancer, comprising administering to a subject an effective anti-cancer amount of a pharmaceutical composition having the formula:

3. The method of claim 1 or 2, wherein the cancer is selected from carcinoma, lymphoma, sarcoma, and myeloma.

4. The method of claim 1 or 2, wherein said cancer is selected from adenocarcinoma, acinic cell adenocarcinoma, adrenal cortical carcinomas, alveoli cell carcinoma, anaplastic carcinoma, basaloid carcinoma, basal cell carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, renaladinol carcinoma, embryonal carcinoma, anometroid carcinoma, fibrolamolar liver cell carcinoma, follicular carcinomas, giant cell carcinomas, hepatocellular carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, leptomanigio carcinoma, medullary carcinoma, melanotic carcinoma, menigual carcinoma, mesometonephric carcinoma, oat cell carcinoma, squamal cell carcinoma, sweat gland carcinoma, transitional cell carcinoma, tubular cell carcinoma, amelioblastic sarcoma, angiolithic sarcoma, botryoid sarcoma, endometrial stroma sarcoma, ewing sarcoma, fascicular sarcoma, giant cell sarcoma, granulositic sarcoma, immunoblastic sarcoma, juxaccordial osteogenic sarcoma, Kaposi'"'"'s sarcoma, leukocytic sarcoma, lymphatic sarcoma, medullary sarcoma, myeloid sarcoma, austiogenci sarcoma, periosteal sarcoma, reticulum cell sarcoma, round cell sarcoma, spindle cell sarcoma, synovial sarcoma, and telangiectatic audiogenic sarcoma, neural blastoma, glioblastoma, astrocytoma, melanoma, leiomyo sarcoma, multiple myeloma, Hemangioma, Hodgkin'"'"'s disease, Burkitt'"'"'s lymphoma, and nodular poorly-differentiated lymphocytic lymphoma, nodular mixed lymphocytic lymphoma, nodular histiocytic lymphoma, and diffuse lymphomas.

5. The method of claim 1 or 2, wherein Z¹ is NH or NR_a.

6. The method of claim 1 or 2, wherein A¹ is —

(CH₂)_m—

Y—

(CH₂)_n—

R³X³ and Y is CHX⁴ in the (R) or (S) configuration.

7. The method of claim 6, wherein Y is CHX⁴ in the (S) configuration and X³ is H.

8. The method of claim 7, wherein m and n are each 0.

9. The method of claim 1 or 2, wherein Z² is CHR¹ in the (R) configuration and R¹ is C_1-6 alkyl.

11. The method of claim 1, wherein R² is OR_f and R_f is H.

2. A method of treating cancer, comprising administering to a subject an effective anti-cancer amount of a pharmaceutical composition having the formula:

10. The method of claim 2, wherein X² is O and Z³ is O.