IP Library › Granted Patent US 10,793,525

Granted Patent B2

US 10,793,525 · App. 15/528,317 · Granted Oct 6, 2020

13-cis-RAMBA retinamides that degrade MNKs for treating cancer

Inventors: Vincent Njar (Glen Burnie, MD); Hannah Mbatia (Germantown, MD); Vidya Ramamurthy (Baltimore, MD); Senthilmurugan Ramalingam (Baltimore, MD)

Assignee: UNIVERSITY OF MARYLAND, BALTIMORE

C07D233/56 A61K31/165 A61K31/203 A61K31/215 A61K31/4164 A61K31/4406 A61K31/4409 A61K31/505 A61P35/00 C07C403/20 C07D213/55 C07D213/56 C07D239/26 C07C2601/16

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Quick Facts

Patent No.: US 10,793,525
App. No.: 15/528,317
Granted: Oct 6, 2020
Kind: B2

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Abstract

The synthesis and in vitro and in vivo anti-breast and anti-prostate cancers activities of novel C-4 heteroaryl 13-cis retinamides that modulate Mnk-eIF4E and AR signaling are discussed. In both breast and prostate cancer cell lines, these compounds induce Mnk1/2 degradation to substantially suppress eIF4E phosphorylation. In prostate cancer cells, the compounds induce degradation of both full-length androgen receptor (fAR) and splice variant AR (AR-V7) to inhibit AR transcriptional activity. The consequences of these multiple activities resulted in inhibition of cell growth and migration and induction of apoptosis. Finally and importantly, the compounds demonstrate strong in vitro and in vivo anti-breast and anti-prostate cancer activities, with no apparent host toxicities.

Claims (119)

1. A process for treatment of breast cancer, prostate cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, benign prostatic hyperplasia, Kennedy's disease, or hematologic cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising as an active ingredient a compound having the following Formula 1:

wherein R is a heteroaryl group,

wherein R′ is a hydrogen, a halide, a hydroxyl group, an alkyl group, an ester group, an ether group, a benzyl group, a thio group, a Weinreb amide group, or a heterocyclic group, and

wherein n is an integer between 0 and 6, and

wherein when R′ is the hydroxyl group, the compound is not (2Z, 4E, 6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxyphenyl)-3, 7-dimethylnona-2,4,6,8-tetraenamide.

2. The process as claimed in claim 1 , wherein the process is for the treatment of breast cancer or prostate cancer.

3. The process as claimed in claim 2 , wherein R is an imidazole, and wherein the compound is selected from the following:

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-3, 7-dimethyl-N-phenylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(2-hydroxyphenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex- 1 -en- 1 -yl)-N-(4-fluorophenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(3-fluorophenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-benzyl-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxybenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-fluorobenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(3-fluorobenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide; and

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxyphenethyl)-3,7-dimethylnona-2,4,6,8-tetraenamide.

4. The process as claimed in claim 3 , wherein the compound is selected from the following:

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethyl-N-phenylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(3-fluorophenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide; and

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxybenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide.

5. The process as claimed in claim 1 , wherein R is an imidazole, and R′ is hydrogen, fluorine, or a hydroxyl group, and n is 0, 1, or 2.

6. The process as claimed in claim 2 , wherein R is a pyridine or a derivative thereof, and the compound is selected from the following:

(2Z,4E,6E,8E)-3,7-dimethyl-N-phenyl-9-(2,6,6-trimethyl-3-(pyridin-3-yl) cyclohexa-1,3-dien-1-yl)nona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-N-(4-hydroxybenzyl)-3,7-dimethyl-9-(2,6,6-trimethyl-3-(pyridin-3-yl)cyclohexa-1,3-dien-1-yl)nona-2,4,6,8-tetraenamide; and

(2Z,4E,6E,8E)-N-(4-hydroxyphenethyl)-3,7-dimethyl-9-(2,6,6-trimethyl-3-(pyridin-3-yl)cyclohexa-1,3-dien-1-yl)nona-2,4,6,8-tetraenamide.

7. The process as claimed in claim 2 , wherein R is a pyrimidine or a derivative thereof, and the compound is selected from the following:

(2Z,4E,6E,8E)-3,7-dimethyl-N-phenyl-9-(2,6,6-trimethyl-3-(pyrimidin-5-yl)cyclohexa-1,3-dien-1-yl)nona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-N-(4-hydroxybenzyl)-3,7-dimethyl-9-(2,6,6-trimethyl-3-(pyrimidin-5-yl)cyclohexa-1,3-dien-1-yl)nona-2,4,6,8-tetraenamide; and

(2Z,4E,6E,8E)-N-(4-hydroxyphenethyl)-3,7-dimethyl-9-(2,6,6-trimethyl-3-(pyrimidin-5-yl)cyclohexa-1,3-dien-1-yl)nona-2,4,6,8-tetraenamide.

8. A process for treatment of breast cancer, prostate cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, benign prostatic hyperplasia, Kennedy's disease, or hematologic cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising as an active ingredient a compound having the following Formula 1:

wherein R is a substituted or unsubstituted phenyl group,

wherein R′ is a hydroxyl group in the para position,

wherein n is 0, 1, or 2, and

wherein when R′ is the hydroxyl group, the compound is not (2Z,4E,6E,8E-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxyphenyl)-3, 7-dimethylnona-2,4,6,8-tetraenamide.

9. The process as claimed in claim 8 , wherein the process is for the treatment of breast cancer or prostate cancer.

10. The process as claimed in claim 9 , wherein R is a substituted phenyl group, and the compound is selected from the following:

(2Z,4E,6E,8E)-N-(4-hydroxybenzyl)-9-(3′-methoxy-2,4,4-trimethyl-4,5-dihydro-[1,1′-biphenyl]-3-yl)-3,7-dimethylnona-2,4,6,8-tetraenamide; and

(2Z,4E,6E,8E)-N-(4-hydroxyphenethyl)-9-(3′-methoxy-2,4,4-trimethyl-4,5-dihydro-[1,1′-biphenyl]-3-yl)-3,7-dimethylnona-2,4,6,8-tetraenamide.

11. A process for treatment of a Mnk 1-, Mnk 2-, and/or androgen receptor-associated condition, comprising administering to a subject in need thereof a pharmaceutical composition comprising as an active ingredient a compound having the following Formula 1:

wherein R is a heteroaryl group or a phenyl group,

wherein R′ is a hydrogen, a halide, a hydroxyl group, an alkyl group, an ester group, an ether group, a benzyl group, a thio group, a Weinreb amide group, or a heterocyclic group,

wherein n is an integer between 0 and 6, and

wherein when R′ is the hydroxyl group, the compound is not (2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxyphenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide.

12. The process as claimed in claim 11 , wherein R is an imidazole, and wherein the compound is selected from the following:

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethyl-N-phenylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol- 1 -yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(2-hydroxyphenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-fluorophenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(3-fluorophenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-benzyl-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxybenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-fluorobenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(3-fluorobenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide; and

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxyphenethyl)-3,7-dimethylnona-2,4,6,8-tetraenamide.

13. The process as claimed in claim 12 , wherein the compound is selected from the following:

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-3,7-dimethyl-N-phenylnona-2,4,6,8-tetraenamide;

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(3-fluorophenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide; and

(2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxybenzyl)-3,7-dimethylnona-2,4,6,8-tetraenamide.

14. The process as claimed in claim 11 , wherein the Mnk 1-, Mnk 2-, and/or androgen receptor-associated condition is breast cancer or prostate cancer.

15. A process for inhibiting at least one of (i) mitogen-activated protein kinase (MAPK)-interacting kinase (Mnk)-driven phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and (ii) androgen receptor signaling pathway, comprising administering a therapeutically effective amount of a compound having the following Formula 1:

wherein R is a heteroaryl group or a phenyl group,

wherein R′ is a hydrogen, a halide, a hydroxyl group, an alkyl group, an ester group, an ether group, a benzyl group, a thio group, a Weinreb amide group, or a heterocyclic group,

wherein n is an integer between 0 and 6, and

wherein when R′ is the hydroxyl group, the compound is not (2Z,4E,6E,8E)-9-(3-(1H-imidazol-1-yl)-2,6,6-trimethylcyclohex-1-en-1-yl)-N-(4-hydroxyphenyl)-3,7-dimethylnona-2,4,6,8-tetraenamide.

16. The process as claimed in claim 15 , wherein R is an imidazole, and wherein the compound is selected from the following: