Bisaminoquinolines and bisaminoacridines compounds and methods of their use

Patent metadata

Field	Value
Publication number	US-12343339-B2
Application number	US-202017613648-A
Country	US
Kind code	B2
Filing date	May 24, 2020
Priority date	May 24, 2019
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

The disclosure is directed to bisaminoquinolines and bisaminoacridines as autophagy inhibitors for treating cancer and other disease states and conditions.

First claim

What is claimed:

1. A compound of formula I, II, or III:

or a pharmaceutically acceptable salt thereof,
wherein
A is

wherein X is F, Cl, or Br and R is H, C 1-6 alkyl, or —C(O)C 1-6 alkyl;

B is

wherein X′ is F, Cl, or Br and R′ is H, C 1-6 alkyl, or —C(O)C 1-6 alkyl;

R 1 is H, C 1-6 alkyl, —C(O)C 1-6 alkyl, alkaryl, or alkheteroaryl;
R 2 is H, C 1-6 alkyl, —C(O)C 1-6 alkyl, alkaryl, or alkheteroaryl;
R 3 is H, C 1-6 alkyl, —C(O)C 1-6 alkyl, alkaryl, or alkheteroaryl;
R 4 is H, C 1-6 alkyl, —C(O)C 1-6 alkyl, alkaryl, or alkheteroaryl;
R 5 is H, C 1-6 alkyl, —C(O)C 1-6 alkyl, alkaryl, or alkheteroaryl;
R 6 is H, C 1-6 alkyl, —C(O)C 1-6 alkyl, alkaryl, or alkheteroalkyl;
n is 1, 2, 3, 4, or 5;
m is 1, 2, 3, 4, or 5;
j is 1, 2, 3, 4, or 5; and
k is 1, 2, 3, 4, or 5.

2. The compound of claim 1 that is a compound of formula I, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 that is a compound of formula II, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 that is a compound of formula III, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein n is 1-3.

6. The compound of claim 1 , wherein m is 1-3.

7. The compound of claim 1 , wherein j is 1-3.

8. The compound of claim 1 , wherein k is 1-3.

9. The compound of claim 1 , wherein (i) A is

and B is

or (ii) A is

and B is

or (iii) A is

and B is

10. The compound of claim 1 , wherein one or both of X and X′ is Cl.

11. The compound of claim 1 , wherein one or both of R and R′ is C 1-6 alkyl.

12. The compound of claim 1 , wherein one or more of R 1 to R 6 is H.

13. The compound of claim 1 , wherein one or more of R 1 to R 6 is C 1-6 alkyl.

14. The compound of claim 1 , wherein one or more of R 1 to R 6 is-C(O)C 1-6 alkyl.

15. The compound of claim 1 , wherein one or more of R 1 to R 6 is alkaryl.

16. The compound of claim 1 , wherein one or more of R 1 to Reis alkheteroaryl.

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. A method of ameliorating cancer, rheumatoid arthritis, malaria, antiphospholipid antibody syndrome, lupus, chronic urticaria or Sjogren's disease in a subject comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , further comprising administering to the subject an additional chemotherapeutic agent.

20. The method of claim 18 , wherein the cancer is a carcinoma, cancer of the esophagus, head, kidney, liver, lung, nasopharyngeal, neck, ovary, pancreas, prostate, and stomach; a leukemia, a malignant lymphoma, a malignant melanoma; myeloproliferative diseases; a sarcoma, a tumor of the central nervous system, a germ-line tumor, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma, or a mixed type of neoplasia.

21. The method of claim 20 , wherein said leukemia is acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, neutrophilic leukemia and stem cell leukemia; the lymphoma is Burkitt's lymphoma, Non-Hodgkin's lymphoma or B-cell lymphoma; the sarcoma is Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma or synovial sarcoma; the tumor of the central nervous system is a glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, or Schwannoma; the germ-line tumor is bowel cancer, breast cancer, prostate cancer, cervical cancer or uterine cancer; the lung cancer is small cell lung cancer, mixed small cell and non-small cell cancer, pleural mesothelioma, metastatic pleural mesothelioma, small cell lung cancer or non-small cell lung cancer; the mixed neoplasia is carcinosarcoma and Hodgkin's disease and said tumors of mixed origin is Wilms' tumor and teratocarcinoma; the cancer is ovarian, breast, colon, head and neck, medulloblastoma or B-cell lymphoma; or the cancer is melanoma or non-small cell lung cancer.

22. The method of claim 18 , wherein the disease state or condition is malaria.

23. A method of inhibiting autophagy in a biological system comprising exposing the biological system to a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , that is:

Assignees

• Univ Pennsylvania

Inventors

• Winkler Jeffrey
• Amaravadi Ravi K

Classifications

• C07D219/10

  attached in position 9 · CPC title

• C07D215/42 Primary

  attached in position 4 · CPC title

• A61K31/4706

  4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D219/12

  Amino-alkylamino radicals attached in position 9 · CPC title