# US 12,213,978 B2 · Madrasin-derivative compounds, composition and uses thereof for treating cancer

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- Number: US 12,213,978 B2
- Document ID: US12213978B2
- Status: Granted
- Kind: B2
- Application number: 17/293,506
- Filed: 2019-11-15
- Published: 2022-02-17
- Granted: 2025-02-04
- Earliest claimed: 2018-11-15
- Assignees: Inserm (Institut National De La Sante Et De La Recherche Medicale); Centre National De La Recherche Scientifique; Institut Gustave Roussy; Universite Paris-Saclay
- Applicants: Institut Gustave Roussy; Inserm (Institut National De La Santé Et De La Recherche MéDicale); Centre National De La Recherche Scientifique; Universite Paris-Saclay
- Inventors: Sébastien Apcher; Mouad Alami; Romain Darrigrand; Samir Messaoudi; Valérie Salgues; Zafiarisoa Dolor Renko; Expedite Yen-Pon
- Web page: https://patentgrep.com/patent/US12213978B2

## CPC

- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/661: Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion {or mevinphos}
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- C07D 239/84: Nitrogen atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The present invention relates to the fields of medicine and in particular cancer treatment. The invention more specifically relates to new compounds which are typically for use as a medicament. In particular, the invention relates to the use of these new compounds for increasing the presentation, typically the production and presentation, of Pioneer Translation Products (PTPs)-derived antigens by cells, in particular cancer cells, or changing the immunopeptidome, in a subject, and inducing or stimulating an immune response in the subject. The present disclosure also relates to uses of such compounds, in particular to prepare a pharmaceutical composition and/or to allow or improve the efficiency of a therapy in a subject in need thereof. The invention also discloses methods for treating a disease, in particular cancer, for preventing or treating cancer metastasis and/or cancer recurrence, in a subject. The present invention in addition provides kits suitable for preparing a composition according to the present invention and/or for implementing the herein described methods.

## Claims

### Claim 1

A composition comprising a compound and a pharmaceutically acceptable carrier, optionally together with at least one anticancer agent, the compound being selected from the group consisting of:
5,6-Dimethyl-2-((4-methyl-7-(2-morpholinoethoxy)quinazolin-2-yl)amino)pyrimidin-4(3H)-one
Sodium 2-((4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-4-methylquinazolin-7-yl phosphate
and
wherein:
R1 and R2 are independently selected from H, CH3 (Methyl), Cl (Chlorine), and a thiosugar, and
R3 is
wherein:
R4 is absent, H, CH3 (Methyl), C2H5 (Ethyl) or n-Propyl,
Z is CH2 or C═O,
n is 1, 2 or 3, and
X is O, N or CH.

### Claim 2 (depends on 1)

The composition according to claim 1, wherein:
the compound is 5,6-Dimethyl-2-((4-methyl-7-(2-morpholinoethoxy)quinazolin-2-yl)amino)pyrimidin-4(3H)-one

### Claim 3 (depends on 1)

The composition according to claim 1, wherein the compound is sodium 2-((4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-4-methylquinazolin-7-yl phosphate

### Claim 4 (depends on 1)

The composition according to claim 1, wherein the compound is
wherein:
R1 and R2 are independently selected from H, CH3 (Methyl), Cl (Chlorine), and a thiosugar, and
R3 is
wherein:
R4 is absent, H, CH3 (Methyl), C2H5 (Ethyl) or n-Propyl,
Z is CH2 or C═O,
n is 1, 2 or 3, and
X is O, N or CH.

### Claim 5

A kit comprising a compound and at least one anticancer agent in distinct containers, wherein the compound is selected from the group consisting of:
5,6-Dimethyl-2-((4-methyl-7-(2-morpholinoethoxy)quinazolin-2-yl)amino)pyrimidin-4(3H)-one
Sodium 2-((4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-4-methylquinazolin-7-yl phosphate
and
wherein:
R1 and R2 are independently selected from H, CH3 (Methyl), Cl (Chlorine), and a thiosugar, and
R3 is
wherein:
R4 is absent, H, CH3 (Methyl), C2H5 (Ethyl) or n-Propyl,
Z is CH2 or C═O,
n is 1, 2 or 3, and
X is O, N or CH.

### Claim 6

A method for treating a carcinoma, sarcoma or blastoma in a subject by ameliorating the disease state of the subject, wherein the method comprises administering a subject in need thereof with a compound selected from:
5,6-Dimethyl-2-((4-methyl-7-(2-morpholinoethoxy)quinazolin-2-yl)amino)pyrimidin-4(3H)-one
Sodium 2-((4,5-dimethyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-4-methylquinazolin-7-yl phosphate
and
wherein:
R1 and R2 are independently selected from H, CH3 (Methyl), Cl (Chlorine), and a thiosugar, and
R3 is
wherein:
R4 is absent, H, CH3 (Methyl), C2H5 (Ethyl) or n-Propyl,
Z is CH2 or C═O,
n is 1, 2 or 3, and
X is O, N or CH.

### Claim 7 (depends on 6)

The method according to claim 6, wherein the compound is used in combination with at least one anticancer agent and/or with radiotherapy.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the at least one anticancer agent is selected from a chemotherapeutic agent, an immune checkpoint blocker and an anti-cancer vaccine.

### Claim 9 (depends on 6)

The method according to claim 6, wherein the compound is selected from the compound of formula II or III, and the cancer is a sarcoma.

### Claim 10 (depends on 6)

The method according to claim 6, wherein the compound is the compound of formula II and the carcinoma is a melanoma.

### Claim 11 (depends on 6)

The method according to claim 6, wherein the compound stimulates an anti-cancer immune response in the subject.

### Claim 12 (depends on 6)

The method according to claim 6, wherein the compound induces or increases the presentation or the production and presentation of Pioneer Translation Products (PTPs)-derived antigens by cancer cells, or changes the immunopeptidome, in the subject.

### Claim 13 (depends on 6)

The method according to claim 6, wherein the subject is a mammal.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the mammal is a human being.

### Claim 15 (depends on 6)

The method according to claim 6, wherein the compound is the compound of formula III, and the cancer is a blastoma.