Search

KR-20260062999-A - METHOD OF MAKING NICOTINAMIDE RIBOFURANOSIDE SALTS, NICOTINAMIDE RIBOFURANOSIDE SALTS AS SUCH, AND USES THEREOF

KR20260062999AKR 20260062999 AKR20260062999 AKR 20260062999AKR-20260062999-A

Abstract

The present invention relates to a method for preparing nicotinamide ribofuranoside salts, particularly pharmaceutically acceptable nicotinamide ribofuranoside salts. Furthermore, the present invention relates to nicotinamide ribofuranoside salts themselves, particularly carboxylic acid salts in crystalline form, and their use in nutritional supplements and pharmaceutical compositions.

Inventors

  • 샤베르트 군터
  • 슈피츠 우르스
  • 소이데미르 아이셀
  • 짐머만 아리스

Assignees

  • 바이오신스 아게

Dates

Publication Date
20260507
Application Date
20200720
Priority Date
20190719

Claims (19)

  1. Step (A): (A) A step of obtaining a nicotinamide-β-D-ribofuranoside salt by salt metathesis involving counter-ion exchange with nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate. A method for preparing a nicotinamide-β-D-ribofuranoside salt comprising
  2. Steps (A) and (B): (A) a step of obtaining nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt by double-decomposing nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate with a salt containing counter-ion exchange; and (B) A step of deacylating nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt to obtain nicotinamide-β-D-ribofuranoside salt. A method for preparing a nicotinamide-β-D-ribofuranoside salt comprising
  3. In paragraph 1, Including steps (X), (Y), and (Z) before step (A): (X) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula (In the above formula, each R is independently selected from alkyl carbonyl, aryl carbonyl and heteroaryl carbonyl, preferably C1-10 alkyl carbonyl and benzoyl, more preferably acetyl, and R is independently optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 alkoxy, C1-6 thioalkyl, halogen, nitro, cyano, NH( C1-6 alkyl), N( C1-6 alkyl) 2, and SO 2 N( C1-6 alkyl) 2 ) Step of obtaining tri-O-acyl-D-ribofuranoside bromide of the following chemical formula by treating with hydrogen bromide in acetic acid: (Y) Tri-O-acyl-D-ribofuranoside bromide nicotinamide: Step of reacting with to obtain nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide of the following chemical formula: (Z) A step of deacylating the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide obtained in step (Y) by removing the R group, preferably using hydrogen bromide in acetic acid, to obtain a nicotinamide-β-D-ribofuranoside bromide compound of the following formula: The nicotinamide-β-D-ribofuranoside bromide obtained in step (Z) above is used in step (A), method.
  4. In paragraph 2, Including Step (X) and Step (Y) before Step (A): (X) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula (In the above formula, each R is independently selected from alkyl carbonyl, aryl carbonyl and heteroaryl carbonyl, preferably C1-10 alkyl carbonyl and benzoyl, more preferably acetyl, and R is independently optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 alkoxy, C1-6 thioalkyl, halogen, nitro, cyano, NH( C1-6 alkyl), N( C1-6 alkyl) 2, and SO 2 N( C1-6 alkyl) 2 ) Step of obtaining tri-O-acyl-D-ribofuranoside bromide of the following chemical formula by treating with hydrogen bromide in acetic acid: (Y) Tri-O-acyl-D-ribofuranoside bromide nicotinamide: Step of reacting with to obtain nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide of the following chemical formula: The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide formed in step (Y) is used in step (A), method.
  5. In paragraph 1, Including steps (X) and (Y) before step (A), (X) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula (In the above formula, each R is independently selected from alkyl carbonyl, aryl carbonyl and heteroaryl carbonyl, preferably C1-10 alkyl carbonyl and benzoyl, more preferably acetyl, and R is independently optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 alkoxy, C1-6 thioalkyl, halogen, nitro, cyano, NH( C1-6 alkyl), N( C1-6 alkyl) 2, and SO 2 N( C1-6 alkyl) 2 ) Nicotinamide in the presence of trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, trimethylsilyl triflate, trimethylsilyl nonaplate, trimethylsilyl fluorosulfonate, or trimethylsilyl perchlorate: A step of treating to obtain nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate of the following chemical formula; (Y) A step of deacylating the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate obtained in step (X) by removing the R group to obtain a nicotinamide-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate compound of the following chemical formula. , Nicotinamide-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate formed in step (Y) is used in step (A), method.
  6. In paragraph 2, Include Step (X) before Step (A): (X) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula (In the above formula, each R is independently selected from alkyl carbonyl, aryl carbonyl and heteroaryl carbonyl, preferably C1-10 alkyl carbonyl and benzoyl, more preferably acetyl, and R is independently optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 alkoxy, C1-6 thioalkyl, halogen, nitro, cyano, NH( C1-6 alkyl), N( C1-6 alkyl) 2, and SO 2 N( C1-6 alkyl) 2 ) Nicotinamide in the presence of trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, trimethylsilyl triflate, trimethylsilyl nonaplate, trimethylsilyl fluorosulfonate, or trimethylsilyl perchlorate: A step of treating to obtain nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate of the following chemical formula: , Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate formed in step (X) above is used in step (A), method.
  7. In any one of paragraphs 1 through 6, A method in which the counter-ion of the salt obtained in step (A) through counter-ion exchange is a pharmaceutically acceptable ion.
  8. In Paragraph 7, The above pharmaceutically acceptable ions are as follows: Inorganic ions; As a carboxylate, the carboxylate is optionally substituted with one or more substituents independently selected from the group consisting of carboxyl, hydroxyl, thio, keto, amino, mono C1-6 alkyl, hydroxy C1-6 alkylene, and di( C1-6 alkyl)amino; C 1-12 alkyl sulfonate; or An arylsulfonate wherein the aryl moiety is optionally substituted with one or more substituents independently selected from the group consisting of carboxyl, hydroxyl, amino, mono C1-6 alkyl and di( C1-6 alkyl)amino, halogen, and C1-6 alkyl. Selected from a group consisting of, The above pharmaceutically acceptable salt is not bromide, triflate, nonaplate, or perchlorate.
  9. In paragraph 8, The above inorganic ion is selected from the group consisting of chloride, hydrogen sulfate, sulfate, dihydrogen phosphate, monohydrogen phosphate, and phosphate; The above carboxylate is selected from the group consisting of formate, acetate, oxalate, malonate, succinate, fumarate, maleate, citrate, maleate, tartrate, ascorbate, α-ketoglutarate, glucuronate, benzoate, and salicylate; The above C 1-12 alkylsulfonate is selected from the group consisting of mesylates and camsylates; The above arylsulfonate is selected from the group consisting of besylates and tosylates, in a method.
  10. In any one of paragraphs 7 through 9, The above pharmaceutically acceptable ion is a malate, preferably a hydrogen malate, in particular a D-, L-, or DL-hydrogen malate, or The above pharmaceutically acceptable ion is a tartrate, preferably a hydrogen tartrate, in particular a D-, L-, or DL-hydrogen tartrate.
  11. In any one of paragraphs 1 through 10, The above counter-ions originate from ammonium salts containing the cation [NR 1 R 2 R 3 R 4 ] + or phosphonium salts containing the cation [PR 1 R 2 R 3 R 4 ] + , and R 1 , R 2 , R 3 and R 4 is independently selected from H, C 1-12 alkyl and aryl; The counter-ion originates from the lithium salt or sodium salt.
  12. In any one of paragraphs 1 through 11, The above salt double decomposition is performed in an alcohol selected from the group consisting of methanol, ethanol, propanol or butanol, or a mixture of two or more of these, and the alcohol or mixture optionally contains water; The above salt double decomposition is performed in a solvent comprising methanol, ethanol, propanol or butanol, or a mixture of two or more of these, and the solvent optionally comprises water.
  13. In any one of paragraphs 1 through 12, A method further comprising a path selected from the group of paths (P1) to (P5): (P1) Pathway including steps (α), (β), (γ) and (δ): (α) a step of cleaving an acyl group from nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate containing up to 5% α-anomer to obtain nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate; (β) A step of isolating and selectively purifying nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate; (γ) A step of obtaining a nicotinamide-β-D-ribofuranoside salt by double-decomposing nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate; (δ) A step of isolating and selectively purifying nicotinamide-β-D-ribofuranoside salt; (P2) Pathway including steps (α), (β), (γ) and (δ): (α) a step of obtaining a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt by salt double decomposition of nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate containing up to 5% α-anomer; (β) A step of isolating and selectively purifying nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt; (γ) A step of cleaving an acyl group from nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt to obtain nicotinamide-β-D-ribofuranoside salt; (δ) A step of isolating and selectively purifying nicotinamide-β-D-ribofuranoside salt; (P3) Pathway including steps (α) and (β): (α) a step of cleaving an acyl group from nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate containing up to 5% α-anomer to obtain nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate, and salt double-decomposing the formed nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate without prior isolation to obtain nicotinamide-β-D-ribofuranoside salt; (β) A step of isolating and selectively purifying nicotinamide-β-D-ribofuranoside salt; (P4) Pathway including steps (α), (β), (γ) and (δ): (α) A step of obtaining nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt by salt double decomposition of nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaplate, fluorosulfonate, or perchlorate containing more than 5% α-anomer; (β) A step of isolating and selectively purifying nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt; (γ) A step of cleaving an acyl group from nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt to obtain nicotinamide-β-D-ribofuranoside salt; (δ) A step of isolating and selectively purifying nicotinamide-β-D-ribofuranoside salt; and (P5) Pathway including steps (α) and (β): (α) a step of cleaving an acyl group from nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate containing more than 5% α-anomer to obtain nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate, and salt double-decomposing the formed nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate, or perchlorate without prior isolation to obtain nicotinamide-β-D-ribofuranoside salt; (β) A step of isolating and selectively purifying nicotinamide-β-D-ribofuranoside salt.
  14. In Paragraph 13, In the above routes (P3) and (P5), the salt double decomposition is performed in situ.
  15. In paragraph 13 or 14, A method in which a salt having a pharmaceutically acceptable anion used for the above-mentioned counter-ion exchange is formed in situ.
  16. A nutritional supplement comprising a nicotinamide-β-D-ribofuranoside salt obtained according to a method as defined in any one of claims 1 to 15.
  17. A pharmaceutical composition comprising a nicotinamide-β-D-ribofuranoside salt obtained according to a method as defined in any one of claims 1 to 15.
  18. In any one of paragraphs 1 through 15, The above step (A) is a method comprising steps (A1) and (A2): (A1) A step of reacting NH₃ or NR₆H₂ or NR₆R₂H or NR₆R₂R₃ or [ NR₆R₂R₃R₄ ] OH with an acid to obtain an ammonium salt, wherein R₆ , R₂ , R 3 and R 4 is a step independently, optionally selected from C 1-12 alkyl and aryl that are substituted. (A2) a step of reacting nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate or perchlorate; or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, trilate, nonaplate, fluorosulfonate or perchlorate with an ammonium salt from step (A1) to perform a salt double decomposition involving counter-ion exchange to obtain nicotinamide-β-D-ribofuranoside salt or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt.
  19. In Paragraph 18, NR 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 ]OH is used in step (A1), method.

Description

Method of making nicotinamide ribofuranoside salts, nicotinamide ribofuranoside salts, and uses thereof The present invention relates to a method for preparing nicotinamide ribofuranoside salts, particularly pharmaceutically acceptable nicotinamide ribofuranoside salts. Furthermore, the present invention relates to nicotinamide ribofuranoside salts themselves, particularly carboxylic acid salts in crystalline form, and their use in nutritional supplements and pharmaceutical compositions. Nicotinamide riboside (nicotinamide-β-D-ribofuranoside; CAS no. 1341-23-7) It is a precursor of nicotinamide adenine dinucleotide (NAD + /NADH) and nicotinamide adenine dinucleotide phosphate (NADP + /NADPH). In addition, nicotinamide riboside is an equivalent of niacin (vitamin B3). Nicotinamide riboside has been reported to increase NAD + levels in the liver and skeletal muscle and prevent body weight gain in mice fed a high-fat diet. It also increases NAD + concentrations in the cerebral cortex and reduces cognitive deterioration in a genetically modified mouse model of Alzheimer's disease. For these reasons, nicotinamide riboside salts have been proposed for use in nutritional supplements and pharmaceutical compositions. In fact, the chloride salt of nicotinamide-β-D-ribofuranoside is a commercially available nutritional supplement. However, the widespread application of these compounds as dietary supplements has been limited by production methods that result in low yields, poor stereoselectivity, and/or the use of expensive and/or harmful reagents, or the formation of pyridinium salts containing pharmaceutically unsuitable counter-ions. Consequently, many known synthesis methods are not suitable for large-scale commercial synthesis. WO 2016/014927 discloses a crystalline form of nicotinamide riboside chloride described as having advantageous properties, such as ease of purification, compared to an amorphous form of nicotinamide riboside salt. WO 2017/218580 discloses a synthetic method for preparing a nicotinamide riboside salt comprising a salt containing a pharmaceutically acceptable anion. The method may include the step of converting one pharmaceutically acceptable counter-ion of a nicotinamide-β-D-ribofuranoside moiety to another pharmaceutically acceptable counter-ion through ion exchange chromatography or a salt exchange reaction and precipitation. In a specific embodiment, the described method comprises the step of converting a salt of nicotinamide riboside or an analog thereof, which is not a chloride salt, to a corresponding chloride salt. WO 2015/186068 A1 discloses reacting nicotinamide-β-D-ribofuranoside trilate with sodium methylate in an ion exchange reaction to provide crystalline nicotinamide-β-D-riboside chloride. CN 108774278 initiates the reaction of nicotinamide triacetylribofuranoside trilate with a base to deacetylate the furanoside. Subsequently, the deacetylated product is treated with an acid to provide a corresponding salt product. However, for a given application, an alternative pharmaceutically acceptable salt of nicotinamide riboside, as well as a method that enables its production in a low-cost, efficient, and convenient manner, is desirable. The present invention is further described by the attached drawings, andFIG. 1 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside D-hydrogen maleate; Figure 2 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside L-hydrogen maleate; FIG. 3 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside DL-hydrogen maleate; Figure 4 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside D-hydrogen tartrate monohydrate; Figure 5 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside L-hydrogen tartrate; Figure 6 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate; Fig. 7 shows the powder X-ray pattern of crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside L-hydrogen tartrate; Fig. 8 shows the powder X-ray pattern of crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside D-hydrogen tartrate; Figure 9 shows the powder X-ray pattern of crystalline anhydrous nicotinamide-β-D-ribofuranoside D-hydrogen tartrate; {each x-axis: position [°2θ] (copper(Cu); y-axis: count)}. Various aspects of the present invention will now be described in more detail with reference to the drawings. First, second, and third embodiments: Method according to the present invention According to a first embodiment, the present invention relates to a compound of the following chemical formula in which anion X- = Br-, Cl-, I-, CF₃SO₃-(triplate),nC₄F₅SO₃-(nonplate),FSO₃-,orClO₄- This relates to a method of replacing with anion Y- through salt double decomposition involving counter-ion exchange. Accordingly, in a first aspect, the present invention relates to a method for producing a nicotinamide-β-D-ribofuranoside s