KR-20260066083-A - Quinone for use in the treatment of erythropoietic enzyme disorders

Abstract

A quinone-based substance for use in the treatment of erythropoietic disorders. The above treatment increases ATP in cells lacking mitochondria. Accordingly, the present invention relates to a quinone-based substance for use in the treatment of diseases or pathological conditions associated with or caused by defects in erythropoietic glycolysis.

Inventors

• 한손 마그누스 요아킴
• 엘머 마츠 에스킬
• 모스 스티븐 제임스

Assignees

• 파밍 인텔렉츄얼 프라퍼티 비.브이.

Dates

Publication Date

20260512

Application Date

20240820

Priority Date

20230821

Claims (20)

1. A compound of Formula I or its reduced form, or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer of Formula I or its reduced form for use in mitochondria-deficient cells, e.g., red blood cells: [Chemical Formula I] (In the above formula, R 16 and R 17 are identical and are alkoxy or alkyl, or bonded together to form an aryl ring; R 18 is methyl or bonded to R 19 as a heterocycle; R 19 is a long-chain alkyl or forms a heterocycle with R 18 through an O-alkyl group; The alkyl groups are each C1-10 linear or branched alkyls, or C3-7 cyclic alkyls; The long-chain alkyl is an optionally substituted and optionally unsaturated C 10-20 linear alkyl).
2. A compound for use according to claim 1, wherein the cell lacking mitochondria is a red blood cell.
3. A compound for said use, wherein the said use is in the treatment of erythropoietic enzyme disease, in accordance with claim 1 or 2.
4. A compound for said use, wherein in any one of claims 1 to 3, said use is said use in the treatment of defects in red blood cell metabolism, e.g., defects in red blood cell glycolysis.
5. In any one of paragraphs 1 through 4, R 16 and R 17 are both OMe; R 18 is methyl; R 19 is a long-chain alkyl; A long-chain alkyl is a compound for the above use as defined in claim 1.
6. In any one of claims 1 to 5, the compound is - Idebenone or a compound for said use, which is its reduced form, or its pharmaceutically acceptable salt, hydrate, solvate, or tautomeric isomer.
7. In any one of paragraphs 1 through 4, R16 and R17 combine to form an aryl ring; R 18 is bonded to R 19 as a heterocycle; R 19 forms a heterocycle with R 18 through an O-alkyl group; A compound for the above use, wherein the alkyl is a C 1-10 linear or branched alkyl, or a C 3-7 cyclic alkyl.
8. In paragraph 7, the above compound is - Napabucasin, or a compound for said use, which is its reduced form, or its pharmaceutically acceptable salt, hydrate, solvate, or tautomeric isomer.
9. In any one of paragraphs 1 through 4, R 16 and R 17 are methyl; R 18 is methyl; R 19 is a long-chain alkyl substituted with one -OH group and containing three double bonds within the alkyl chain; A compound for the above use, wherein the long-chain alkyl is a C 10-20 linear alkyl.
10. In paragraph 9, the above compound is - Bathyquinone, or a compound for the above use that is its reduced form, or its pharmaceutically acceptable salt, hydrate, solvate, diastereomer, or tautomer.
11. In any one of claims 1 to 4, the compound for use is selected from idebenone, napabucasin, and bathyquinone.
12. A compound for use according to any one of claims 1 to 11, wherein the erythrocyte enzyme disorder involves an enzyme deficiency within erythrocyte glycolysis.
13. In paragraph 12, the compound for use, wherein the above-mentioned erythrocyte enzyme disorder involves a deficiency of pyruvate kinase (PK) within the erythrocytes.
14. In any one of claims 1 to 13, the treatment is a compound for use that restores, normalizes, and/or increases ATP levels in red blood cells.
15. In paragraph 13, the compound for use, wherein the above PK deficiency is associated with a lack or reduction of R-type PK (PKR) activity in red blood cells.
16. A compound of Formula I or its reduced form, or a pharmaceutically acceptable salt, hydrate, solvate, or tautomer of Formula I or its reduced form for use in the treatment of hemolytic anemia or ineffective erythropoiesis: [Chemical Formula I] (In the above formula, R 16 and R 17 are identical and are alkoxy or alkyl, or bonded together to form an aryl ring; R 18 is methyl or bonded to R 19 as a heterocycle; R 19 is a long-chain alkyl or forms a heterocycle with R 18 through an O-alkyl group; The alkyl groups are each C1-10 linear or branched alkyls, or C3-7 cyclic alkyls; The long-chain alkyl is an optionally substituted and optionally unsaturated C 10-20 linear alkyl).
17. In paragraph 16, the compound for use, wherein the hemolytic anemia or inefficient red blood cell production is caused by a defect in red blood cell metabolism.
18. A compound for use according to claim 16 or 17, wherein the hemolytic anemia or inefficient red blood cell production is caused by a defect in red blood cell glycolysis.
19. In any one of paragraphs 16 through 18, R 16 and R 17 are both OMe; R 18 is methyl; R 19 is a long-chain alkyl; A long-chain alkyl is a compound for the above use as defined in claim 1.
20. In any one of paragraphs 16 to 19, the compound is - Idebenone or a compound for said use, which is its reduced form, or its pharmaceutically acceptable salt, hydrate, solvate, or tautomeric isomer.

Description

Quinone for use in the treatment of erythropoietic enzyme disorders The present invention relates to the discovery that quinone-based substances have the ability to restore, normalize, and/or improve ATP in mitochondria-deficient cells, such as red blood cells (RBCs). Red blood cells rely solely on the anaerobic conversion of glucose by the Embden-Meyerhof pathway (glycolysis) to generate and store high-energy phosphate, such as ATP, which is necessary for many life-sustaining functions. Accordingly, the present invention relates to quinone-based substances for use in the treatment of diseases or pathological conditions associated with or caused by defects in red blood cell glycolysis. Human red blood cells are unique in that they lose their nucleus upon maturation. Immature red blood cells possess a nucleus, but during the initial stages of erythropoiesis before becoming circulating reticulocytes, they displace not only the nucleus but also other organelles, such as mitochondria, the endoplasmic reticulum, and the Golgi apparatus, to make room for oxygen-carrying hemoglobin. As a result of the lack of mitochondria, mature red blood cells do not economically synthesize adenosine phosphate (ATP) using the oxygen they transport, as other normally differentiated cells do. Instead, to maintain the integrity and flexibility of their cell membranes while moving through blood vessels, red blood cells circulate nicotinamide adenine dinucleotide (NAD + ) and rely entirely on anaerobic glycolysis to produce ATP, which is an essential energy source primarily used to drive ATPase-dependent K + /Na + and Ca2 + pumps. Red blood cells require energy to maintain many life-sustaining functions, including the maintenance of glycolysis, throughout their lifespan within blood vessels. Due to the lack of a nucleus and mitochondria, mature red blood cells cannot generate energy through the oxidative Krebs cycle. Instead, red blood cells rely on the anaerobic conversion of glucose via the Emden-Mayerhof pathway for the generation and storage of ATP. Erythromycosis can occur at any stage of red blood cell glycolysis and can induce various diseases. It is necessary to identify substances capable of treating erythromycosis and diseases caused by or related to it. The present invention is based on an original discovery that quinone-based substances increase ATP levels in red blood cells and increase ATP levels in red blood cells in which the enzyme pyruvate kinase (PK) is inhibited. In its broadest aspect, the present invention relates to quinone compounds that can be used to restore, normalize, and/or improve ATP in cells lacking mitochondria, such as red blood cells. Quinone compounds may be used in pathological conditions or diseases where it is necessary to restore, normalize, and/or improve ATP in cells lacking mitochondria, such as red blood cells. Specific examples include the use of quinones in erythropoietic disorders and in diseases caused by or associated with such disorders. Examples include defects in red blood cell metabolism, such as in erythropoietic glycolysis, for example, defects in glucose-6-phosphate dehydrogenase and pyruvate kinase or other enzymes that are part of erythropoietic glycolysis. Quinone compounds are also considered to be effective in the treatment of hemolytic anemia, for example, hemolytic anemia and anemia caused by inefficient red blood cell production. Hemolytic anemia can be broadly categorized based on the following: ● Defects in red blood cell membrane formation (defects in red blood cell membrane formation such as in hereditary spherocytosis and hereditary oviocytes). ● Defects in hemoglobin production (defects in hemoglobin production such as in thalassemia, sickle cell disease, and congenital aberrant erythropoiesis). ● Red blood cell metabolic defects (including defects in glucose-6-phosphate dehydrogenase and pyruvate kinase or other enzymes that are part of red blood cell metabolism, such as those in erythrocyte glycolysis and the pentose phosphate pathway). Hemolytic anemia is associated with a decrease in red blood cell viability within the circulatory system, and it can be argued that ATP boosting can increase red blood cell viability through enhanced glycolysis and ATP production. Additionally, some of these diseases may be accompanied by inefficient red blood cell production, where enhancing glycolysis and ATP production is expected to likewise improve red blood cell production. The latter reason is a major cause of anemia resulting from chronic diseases, myelodysplastic syndrome, and sideroblastic anemia. In a specific embodiment, the present invention relates to a quinone compound that can be used as follows: a) Restoring, normalizing, and/or improving ATP in cells lacking mitochondria, e.g., red blood cells, and/or b) Treatment of erythropoietic disorders, and/or c) Treatment of defects in red blood cell metabolism, e.g., defects in red blood cell glycolysis, and/or d) Erythro