(3S)-and (3R)-6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as P53 activators

Patent metadata

Field	Value
Publication number	US-12383537-B2
Application number	US-201917254048-A
Country	US
Kind code	B2
Filing date	May 2, 2019
Priority date	Jun 20, 2018
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

The present application relates to compounds of formula I, which are (3S)- and (3R)-6,7-bis(Hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles. The present application also relates to pharmaceutical compositions having the compounds and the use of these compounds in the treatment of conditions influenced by wild-type or mutant p53 forms. More specifically, these compounds represent a completely new chemical family of p53-activating agents and show a higher selectivity towards the p53-pathway compared to the reactivators of p53 currently under clinical trials. For some cancer types these compounds revealed to be more potent than the reactivators of p53 currently under clinical trials. In addition to these advantages, the presently disclosed compounds are not genotoxic and have no apparent undesirable toxic side effects.

First claim

The invention claimed is:

1. A method of treating cancer associated with wild-type or mutant p53 form comprising administering a composition comprising a compound or pharmaceutically acceptable salt of

wherein,
R 1 =H;
R 2 =phenyl;
R 3 =methyl,
wherein the compound is a 3S enantiomer or a pharmaceutically acceptable salt thereof, to a patient in need thereof,
wherein the compound activates p53-dependent activity in wild-type p53 protein and/or reactivates p53-dependent activity in mutant p53 protein expressed in cancer cells by directly binding to the wild-type p53 protein and/or mutant p53 protein, and
wherein the cancer is selected from the group consisting of colorectal cancer, skin cancer, bladder cancer and lung cancer.

2. The method according to claim 1 , wherein the cancer is colorectal cancer.

3. The method according to claim 1 , wherein the cancer is skin, lung, and bladder cancer.

4. A method of treating cancer associated with wild-type or mutant p53 form comprising administering a pharmaceutical composition comprising a composition comprising a compound or pharmaceutically acceptable salt of

wherein,
R 1 =H;
R 2 =phenyl;
R 3 =methyl,
wherein the compound is a 3S enantiomer or a pharmaceutically acceptable salt thereof, to a patient in need thereof,
wherein the compound activates p53-dependent activity in wild-type p53 protein and/or reactivates p53-dependent activity in mutant p53 protein expressed in cancer cells by directly binding to the wild-type p53 protein and/or mutant p53 protein to a patient in need thereof, and
wherein the cancer is selected from the group consisting of colorectal cancer, skin cancer, bladder cancer and lung cancer.

5. The method according to claim 4 , wherein the cancer is colorectal cancer.

6. The method according to claim 4 , wherein the cancer is skin, lung, or bladder cancer.

7. The method according to claim 4 , wherein the pharmaceutical composition is administered with a chemotherapeutic agent.

8. The method according to claim 4 , wherein the pharmaceutical composition is administered via topical, oral, parenteral or injectable route.

9. The method according to claim 1 , wherein the composition is administered via topical, oral, parenteral or injectable route.

Assignees

• Univ De Coimbra
• Univ Do Porto

Inventors

• Ataide Saraiva Lucilia Helena
• Gama Soares Joana Oliveira
• Vasconcelos Dias De Pinho E Melo Teresa Margarida
• Lopes Soares Maria Isabel
• Nogueira Ramos Rocha Helena Isabel

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• A61K45/06

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

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/429 Primary

  condensed with heterocyclic ring systems · CPC title