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KR-20260065836-A - Method for preparing oxadiazolylaminobenzodiazepine derivatives

KR20260065836AKR 20260065836 AKR20260065836 AKR 20260065836AKR-20260065836-A

Abstract

The present invention relates to a method for preparing the following compound (I) or a method for preparing a pharmaceutically acceptable salt or solvate thereof: . The above compound (I) and pharmaceutical composition are useful as respiratory syncytial virus (RSV) inhibitors.

Inventors

  • 크로포드, 스코트
  • 후, 웨이펑
  • 헬블, 조셉
  • 셰퍼드, 코디
  • 왕, 타오

Assignees

  • 이난타 파마슈티칼스, 인코포레이티드

Dates

Publication Date
20260511
Application Date
20240808
Priority Date
20230809

Claims (16)

  1. A method for preparing the following compound (I) comprising the following steps: (a) A step of reacting compound (A) with 1,1'-carbonyldiimidazole to produce compound (B): (b) Step of reacting compound (B) with compound (W) to produce compound (C): ; and (c) a step of reacting compound (C) with a dehydrating agent selected from the group consisting of N,N-dimethylsulfamoyl chloride, methyl N-(triethylammoniumsulfonyl)carbamate, phosphorus trichloride, and phosphorus pentachloride to produce compound (I): .
  2. In paragraph 1, The above step (c) is performed in the presence of a base, method.
  3. In paragraph 2, A method in which the base is selected from the group consisting of 1,4-diazabicyclo[2.2.2]octane, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1-methylimidazole, diisopropylethylamine, sodium bicarbonate, potassium phosphate, sodium hydroxide, and N-methylmorpholine.
  4. In any one of paragraphs 1 through 3 The above dehydrating agent is N,N-dimethylsulfamoyl chloride.
  5. In paragraph 1, The above dehydrating agent is N,N-dimethylsulfamoyl chloride, and the above step (c) is performed in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene, method.
  6. In any one of paragraphs 1 through 5, The above step (a) is performed in a solvent selected from the group consisting of acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dimethylacetamide, N-methyl-2-pyrrolidone, sulfolane, dioxane, and mixtures of two or more of these, a method.
  7. In paragraph 6, The above step (a) is performed in acetonitrile.
  8. In paragraph 6 or 7, The above step (a) is performed at a temperature of about 20°C to about 80°C, a method.
  9. In paragraph 8, A method in which the above step (a) is performed at a temperature of about 40°C.
  10. In any one of paragraphs 1 through 9, The above step (b) is performed in a solvent selected from the group consisting of acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, N-methyl-2-pyrrolidone, sulfolane, dioxane, and mixtures of two or more of these, in a method.
  11. In Paragraph 10, The above step (b) is performed in N-methyl-2-pyrrolidone, a method.
  12. In Article 10 or Article 11, The above step (b) is performed at a temperature of about 10°C to about 50°C, about 30°C to about 50°C, about 30°C to about 40°C, or about 35°C, in a method.
  13. In any one of paragraphs 1 through 12, A method further comprising the step of recrystallizing the above compound (I).
  14. In Paragraph 13, The above compound (I) is recrystallized through the following steps: (i) dissolving the compound (I) in a first solvent selected from the group consisting of ethyl acetate, ethanol, methanol, 2-methyltetrahydrofuran, dimethyl sulfoxide, dimethylformamide, and mixtures of two or more of these; and (ii) replacing the solvent of step (i) with a second solvent selected from the group consisting of toluene, heptane, ethanol, isopropanol, methyl t-butyl ether, water, and mixtures of two or more of these to induce crystallization of the compound (I) (provided that if the first solvent is ethanol, the second solvent is not ethanol).
  15. In Paragraph 14, A method in which the first solvent is acetone, ethanol, or a combination thereof.
  16. In paragraph 14 or 15, A method in which the second solvent is ethanol, heptane, or methyl t-butyl ether.

Description

Method for preparing oxadiazolylaminobenzodiazepine derivatives Related applications This application enjoys the benefit of priority to U.S. Preliminary Application No. 63/531,701, filed August 9, 2023. All teachings set forth in said application are incorporated herein by reference. Technology field The present invention relates to a biologically active compound useful as a respiratory syncytial virus (RSV) inhibitor and a method for preparing a pharmaceutical composition. Specifically, the present invention relates to a method for preparing an oxadiazolylaminobenzodiazepine derivative capable of inhibiting RSV activity and treating RSV infection. Human respiratory syncytial virus (HRSV) is a negative-strand single-RNA paramyxovirus (KM. Empey, et al, Rev. Anti-Infective Agents , 2010, 50(1 May), 1258-1267). RSV is a major cause of acute lower respiratory tract infections (ALRI) and affects patients of all ages. In adults, symptoms are usually mild and resemble a mild cold. However, in infants and young children, the virus can cause lower respiratory tract infections, including bronchiolitis or pneumonia, often requiring hospitalization. Almost all children are infected with RSV before the age of three. High-risk groups are known for the likelihood that RSV infection will progress to acute lymphoblastic leukemia (ALRL). Premature infants and/or infants with lung or heart disease have the highest risk of developing ALRL. Additional high-risk groups include the elderly, adults with chronic heart and/or lung disease, stem cell transplant recipients, and immunocompromised patients. Palivizumab is a monoclonal antibody used prophylactically to prevent HRSV infection in high-risk infants, such as premature infants and those with heart and/or lung disease. However, its general use is limited due to the high cost of treatment. Ribavirin has also been used to treat HRSV infection, but its efficacy is limited. There is a significant medical need for new and effective HRSV treatments that are generally available to people of all ages. Several RSV fusion inhibitors have been disclosed in the following literature: W02010/103306, WO2012/068622, WO2013/096681, WO2014/060411, WO2013/186995, WO2013/186334, WO2013/186332, W02012/080451, W02012/080450, W02012/080449, W02012/080447, W02012/080446, WO 2015/110446, WO 2017/009316, WO 2017/015449 and J Med. Chem. 2015, 58, 1630-1643. Examples of other N-protein inhibitors for the treatment of HRSV are disclosed in the following literature: W02004/026843, J. Med. Chem. 2006, 49, 2311-2319 and J. Med. Chem. 2007, 50, 1685-1692. Examples of L-protein inhibitors for the treatment of HRSV are disclosed in the following literature: WO2011/005842, W02005/042530, Antiviral Res . 2005, 65, 125-131 and Bioorg. Med. Chem. Lett . 2013, 23, 6789-6793. Examples of nucleoside/polymerase inhibitors are WO2013/242525 and J. Med. Chem. It is disclosed in literature such as 2015, 58, 1862-1878. It is necessary to develop a therapeutic agent for the treatment of HRSV and a method for manufacturing said therapeutic agent. Detailed description of the invention The present invention provides a method for preparing the following compound (I): One embodiment of the present invention provides a method for preparing compound (I) comprising the following steps: (a) A step of reacting compound (A) with 1,1'-carbonyldiimidazole to produce compound (B): (b) Step of reacting compound (B) with compound (W) to produce compound (C): ; and (c) A step of reacting compound (C) with a dehydrating agent to produce compound (I). Step (a) In a preferred embodiment, step (a) is performed in a suitable solvent such as, but not limited to, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dimethylacetamide, N-methyl-2-pyrrolidone, sulfolane, dioxane, or a mixture of two or more of these. Preferably, the solvent is acetonitrile. In a preferred embodiment, step (a) is performed at a temperature of about 20°C to about 80°C, preferably about 35°C to about 45°C, more preferably about 40°C. In a specific embodiment, step (a) is performed for about 1 hour to about 24 hours, preferably about 3 hours to about 6 hours, more preferably about 4 hours. In a preferred embodiment, the process of the present invention further comprises the step of separating compound (B), preferably in a substantially pure form. Step (b) In a preferred embodiment, step (b) is performed in a suitable solvent such as, but not limited to, acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, N-methyl-2-pyrrolidone, sulfolane, dioxane, or a mixture of two or more of these. Preferably, the solvent is N-methyl-2-pyrrolidone. In a preferred embodiment, step (b) is performed at a temperature of about 10°C to about 50°C, preferably at a temperature of about 30°C to about 50°C, more preferably at a temperature of about 35°C. In one embodiment, step (a) is carried out for about 6 hours to about 72 hours, preferably