JP-2022518944-A5 -

Dates

Publication Date

20221219

Application Date

20200130

Description

The foregoing description is merely illustrative of the present invention. Various alternatives and modifications can be devised without departing from the present invention. Therefore, the present invention is intended to encompass all alternatives, changes, and differences included in the appended claims. For example, the present invention provides the following items: (Item 1) A daily regimen for the treatment of pulmonary arterial hypertension, comprising two separate dosage forms, each containing approximately 600 mg to 800 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate. (Item 2) A daily dose regimen of item 1, each dosage form containing RVT-1201, wherein (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is substantially shown in Figure 1. (Item 3) A daily dosing regimen of item 1 or 2, characterized in that the dosage form is an oral medication. (Item 4) A daily dosing regimen according to any of items 1 to 3, characterized in that each dosage form further contains a pharmaceutically acceptable amount of excipients. (Item 5) A daily regimen for the treatment of pulmonary arterial hypertension, characterized by containing 1200 mg to 1600 mg of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate. (Item 6) A daily dose regimen of item 5, characterized in that (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is substantially as shown in item 1. (Item 7) A daily dose regimen of item 5 or 6, characterized by further comprising excipients in pharmaceutically acceptable doses. (Item 8) A method for treating pulmonary arterial hypertension comprising administering (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate to a human patient in an amount of 1200 mg to 1600 mg per day. (Item 9) The method of item 8, characterized in that (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is substantially as shown in Figure 1. (Item 10) Administer the dose orally, using the method described in item 8 or 9. (Item 11) Administer 600mg to 800mg in BID, using one of the methods described in items 8 to 11. (Item 12) A method to reduce serotonin biosynthesis levels by at least 50% within 14 days of the start of treatment by administering (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate in amounts of approximately 800 mg to 1600 mg per day to human patients. (Item 13) The method of item 12, characterized in that (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is substantially as shown in Figure 1. (Item 14) Administer the dose orally, using the method described in item 12 or 13. (Item 15) Administer approximately 400 mg to 800 mg via BID, using one of the methods described in items 12 to 14. (Item 16) Method 12 involves administering a dose selected from the groups consisting of approximately 400 mg BID, 600 mg BID, and 800 mg BID. (Item 17) A method is used in which an effective dose of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate is administered daily to human patients, and within 14 days after administration, (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid has an AUC of 0 tau ≥ 2530 ng.hr/mL. (Item 18) Method 17, in which the dosage is approximately 800 mg to 1600 mg per day. (Item 19) Method 18 involves administering approximately 400 mg to 800 mg via BID. (Item 19) A method for administering an effective dose of (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate to human patients daily and achieving a reduction of more than 50% in urinary 5-HIAA within 14 days after administration. (Item 20) Method 19, in which the dosage is approximately 800 mg to 1600 mg per day. (Item 21) Method 20 involves administering a dose of approximately 400 mg to 800 mg via BID. (Item 22) A method for treating pulmonary arterial hypertension, comprising administering (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidine-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate daily to human patients in need, in an amount sufficient to cause the AUC 0-tau of (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-tr