Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof

• US 10,344,029 B2
• Filed: 08/24/2018
• Issued: 07/09/2019
• Est. Priority Date: 04/01/2014
• Status: Active Grant

• Current Assignee: Washington University In St Louis
• Original Assignee: Washington University In St Louis
• Inventors: Hawkins, William, Mach, Robert, Spitzer, Dirk, Vangveravong, Suwanna, Van Tine, Brian
• Primary Examiner(s): Bernhardt, Emily A
• Application Number:
  US16/111,842
• Publication Number:
  US 20190002457A1
• Time in Patent Office: 319 Days
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 451/14 containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
• CPC Class Codes: C07D 471/08 Bridged systems

Abstract

The present disclosure provides compounds of structural Formula III:

or a salt thereof, wherein Y is chosen from

Further provided are pharmaceutical compositions comprising these compounds, and methods for treating cancer, such as pancreatic cancer or synovial sarcoma, using the compounds and compositions.

Claims

1. A compound of structural Formula III:

2. A compound or salt thereof in accordance with claim 1, wherein Z¹ is C₁-C₁₀ alkyl.

3. A compound or salt thereof in accordance with claim 1, wherein Z² is C₁-C₁₀ alkyl.

4. A compound or salt thereof in accordance with claim 1, wherein Z³ is C₁-C₁₀ alkyl.

5. A compound or salt thereof in accordance with claim 1, wherein Z¹, Z², and Z³ are each independently C₁-C₁₀ alkyl.

6. A compound or salt thereof in accordance with claim 1, wherein Y is

7. A compound or salt thereof in accordance with claim 5, wherein Y is

8. A compound or a salt thereof in accordance with claim 1, wherein the salt is an oxalate or a hydrochloride salt.

9. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

10. A method of treating a pancreatic cancer or a synovial sarcoma in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound of claim 1, or a salt thereof.

11. The method according to claim 10, wherein the subject is a human.

12. A method of treating a pancreatic cancer or a synovial sarcoma in a subject in need thereof, comprising the sequential or co-administration of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and an additional anticancer drug.

13. The method according to claim 12, wherein the anticancer drug is chosen from an alkylating agent, anthracycline, antimetabolite agent, crosslinking agent, DNA replication inhibitor, intercalator, microtubule disruptor, PARP inhibitor, radiomimetic agent, radiosensitizer, strand break agent, and topoisomerase II inhibitor.

14. The method according to claim 12, wherein the anticancer drug is chosen from aminoglutethimide, amsacrine, anastrozole, asparaginase, barasertib, bcg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, olaparib, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine.

15. The method of claim 12, wherein the method further comprises administering radiation therapy.

16. The method of claim 12, wherein the method further comprises administering surgery, thermoablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

17. A method for treating pancreatic cancer or synovial sarcoma, comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 9 to a patient in need thereof.