EP-4735434-A1 - NEW 1,3,5-TRIAZINE DERIVATIVE AND ITS APPLICATION

Abstract

A new derivative of tryptamine-1,3,5-triazine, which is N 2 -(2-(1H-indol-3-yl)ethyl)-6-morpholino-N 4 -phenethyl-1,3,5-triazine-2,4-diamine hydrochloride of formula 1 for use in the treatment of colorectal cancer.

Inventors

• KULAGA, Damian
• DRABCZYK, ANNA
• SIEMINSKA, Izabela

Assignees

• Politechnika Krakowska Im. Tadeusza Kosciuszki
• Uniwersytet Rolniczy im. Hugona Kollataja w Krakowie

Dates

Publication Date

20260506

Application Date

20240619

Claims (2)

1. 1. A new derivative of tryptamine-l,3,5-triazine, which is N 2 -(2-(lH-i ndol-3- yl)ethyl)-6-morpholino-N 4 -phenethyl-l,3,5-triazine-2,4-diamine hydrochloride of formula 1.
2. 2. A new tryptamine-l,3,5-triazine derivative according to claim 1 for use in the treatment of colorectal cancer.

Description

NEW 1,3,5-TRIAZINE DERIVATIVE AND ITS APPLICATION TECHNICAL FIELD The subject of the invention is a new tryptamine-l,3,5-triazine derivative of formula 1 and its use in the treatment of colorectal cancer. BACKGROUND ART The new tryptamine-l,3,5-triazine derivative in the form of a hydrochloride salt of the general formula 1, which is the subject of the invention, is a compound hitherto unknown in the literature. The closest solution in terms of chemical structure to the described new compound is a series of 1,3,5-triazine derivatives published by Kutag D. et al. in a series of three articles: "Aminotriazines with indole motif as novel, 5-HT7 receptor ligands with atypical binding mode" Bioorg. Chem. 2020, 104, 104254, "Design and synthesis of new potent 5-HT7 receptor ligands as a candidate for the treatment of central nervous system diseases" Eur. J. Med. Chem. 2022, 227, 113931 and "Design, Synthesis and Biological Evaluation of Novel 1,3,5-Triazines: Effect of Aromatic Ring Decoration on Affinity to 5-HT7 Receptor" Int. J. Mol. Sci. 2022, 23(21), 13308. Colorectal cancer (CRC) is one of the most lethal types of malignancy. It is estimated that over 1.9 million new cases were diagnosed in 2020. Modern oncological therapy mainly involves the resection of the tumor with a wide margin of healthy tissue, while chemotherapy is used as a supportive method. In the case of chemotherapy, several drugs are known (5-FU, folinic acid, oxaliplatin and capecitabine) which, in addition to destroying tumor cells, negatively affect healthy tissues, causing a number of side effects. Currently, the FDA (U.S. Food and Drug Administration) has approved three compounds for the treatment of colorectal cancer - cetuximab, panitumumab and bevacizumab. Despite their effectiveness, they have side effects and not every patient can be qualified for their use due to potential mutations of the EGF receptor or its low expression. In the case of small-molecules, only regorafenib has been approved by the FDA, among others for the treatment of colorectal cancer, but due to similar drawbacks, therapy with this drug is limited. One of the important molecular targets that can be used in the treatment of CRC is the FOXM1 (Forkhead Box M) protein - an oncogenic transcription factor, the overexpression of which is associated with tumor growth, as well as with the angiogenesis process and the mechanism of metastasis formation, and plays a key role in the mechanism of resistance to typical anticancer drugs. The compound STL427944 is known to have cytotoxic effects on colorectal cancer cells. The result of its use is the inhibition of FOXM1 protein production, described by Comacho C. and Gartel A. in Cell Death & Disease (2021) 12:704 "Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells" . This compound, described by formula 2, is a representative of hydrazones, comprising a 1,3,5-triazine motif connected by a hydrazone moiety to a phenyl ring, which in turn is substituted with a 2-furancarboxylic acid ester in the third position. For the SW480 cell line (human primary colorectal cancer cells), it showed weak FOXM1 inhibition at a concentration of 25 pM, and significant inhibition at a concentration of -50pM. According to the authors, this compound also showed activity on other types of cancer cells including LNCaP (prostate cancer), PC3 (prostate cancer) and A549 (non-small cell lung cancer). DISCLOSURE OF THE INVENTION The essence of the invention is a new tryptamine-l,3,5-triazine derivative, which is N2-(2-(lH-indol-3-yl)ethyl)-6-morpholino-N4-phenethyl-l,3,5-triazine- 2,4-diamine hydrochloride of formula 1, for use in the treatment of colorectal cancer, as a substance that inhibits the production of FOXM1 protein. The new compound, N2-(2-(lH-indol-3-yl)ethyl)-6-morpholino-N4- phenethyl-l,3,5-triazine-2,4-diamine hydrochloride of formula 1, is obtained in the sequence of four reactions: 1. tryptamine of formula 3 is alkylated with cyanuric chloride of formula 4 to obtain an intermediate of formula 5; 2. the intermediate of formula 5 is subjected to a condensation reaction with morpholine of formula 6 to obtain an intermediate product of formula 7; 3. the intermediate product of formula 7 is reacted with 2-phenylethylamine of formula 8, which produces the second intermediate, a base of formula la; 4. the second intermediate, the base of formula la, is converted into the final hydrochloride compound of formula 1 using HCI 4M solution in dioxane. It turned out unexpectedly that, despite the close structural similarity to known serotonin 5-HT7 receptor ligands, the described compound being N2-(2- (lH-indol-3-yl)ethyl)-6-morpholino-N4-phenethyl-l,3,5-triazine-2,4-diamine hydrochloride of formula 1 has antiproliferative effects on SW480 and SW620 cell lines (human colorectal cancer cells) by blocking the production of the FOXM1 protein, while the line o