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

Patent metadata

Field	Value
Publication number	US-10344029-B2
Application number	US-201816111842-A
Country	US
Kind code	B2
Filing date	Aug 24, 2018
Priority date	Apr 1, 2014
Publication date	Jul 9, 2019
Grant date	Jul 9, 2019

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.

First claim

The invention claimed is:

1. A compound of structural Formula III:

or a salt thereof, wherein:
each of Z 1 and Z 3 is independently chosen from a bond, C 1 -C 10 alkyl, C 2 -C 10 alkyenyl, (CH 2 ) a (OCH 2 CH 2 ) b (CH 2 ) c —, —(CH 2 ) a N(R 1 )(CH 2 ) c —, —(CH 2 ) a N(R 1 )C(O)(CH 2 ) c —, —(CH 2 ) a (C(O)N(R 1 )(CH 2 ) c —, —(CH 2 ) a N(R 1 )C(O)N(R 1 )(CH 2 ) c —;
Z 2 is chosen from C 1 -C 10 alkyl, C 2 -C 10 alkenyl, (CH 2 ) a (OCH 2 CH 2 ) b (CH 2 ) c —, —(CH 2 ) a (CH 2 CH 2 O) b (CH 2 ) c —, —(CH 2 ) a O(CH 2 ) c —, —(CH 2 ) a S(CH 2 ) c —, —(CH 2 ) a N(R 1 )(CH 2 ) c —, —(CH 2 ) a N(R 1 )C(O)(CH 2 ) c —, —(CH 2 ) a C(O)N(R 1 )(CH 2 ) c —, and —(CH 2 ) a N(R 1 )C(O)N(R 1 )(CH 2 ) c —;
wherein each of Z 1 , Z 2 , and Z 3 can be optionally substituted with one or more groups chosen from halo, oxo, and C 1 -C 10 alkyl;
each R 1 is independently chosen from hydrogen, C 1 -C 10 alkyl, and C 1 -C 10 acyl;
each a and c is an integer independently chosen from 0, 1, 2, 3, and 4;
each b is an integer independently chosen from 1, 2, 3, 4, 5, and 6; and
Y is chosen from

2. A compound or salt thereof in accordance with claim 1 , wherein Z 1 is C 1 -C 10 alkyl.

3. A compound or salt thereof in accordance with claim 1 , wherein Z 2 is C 1 -C 10 alkyl.

4. A compound or salt thereof in accordance with claim 1 , wherein Z 3 is C 1 -C 10 alkyl.

5. A compound or salt thereof in accordance with claim 1 , wherein Z 1 , Z 2 , and Z 3 are each independently C 1 -C 10 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.

Assignees

• Univ Washington

Inventors

• Hawkins William
• Mach Robert
• Spitzer Dirk
• Vangveravong Suwanna
• Van Tine Brian

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• C07D451/14 Primary

  containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title