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BR-112020024077-B1 - Polycyclic carbamoylpyridone derivative and pharmaceutical composition comprising it.

BR112020024077B1BR 112020024077 B1BR112020024077 B1BR 112020024077B1BR-112020024077-B1

Abstract

The present invention relates to a compound represented by Formula (I): wherein ring A is a substituted or unsubstituted heterocycle; ring C is a benzene ring or similar; R1 is halogen or similar; R2a and R2b are each independently hydrogen or similar; R3 is substituted or unsubstituted alkyl or similar; R4 is hydrogen or similar; and n is an integer from 1 to 3.

Inventors

  • Yoshiyuki Taoda
  • YUTO UNOH

Assignees

  • SHIONOGI & CO., LTD

Dates

Publication Date
20260310
Application Date
20190530
Priority Date
20180531

Claims (20)

  1. 1. Compound, characterized by the fact that it is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  2. 2. Compound, characterized by the fact that the compound is: or a pharmaceutically acceptable salt thereof.
  3. 3. Compound, characterized by the fact that the compound is: or a pharmaceutically acceptable salt thereof.
  4. 4. Compound, characterized by the fact that the compound is: or a pharmaceutically acceptable salt thereof.
  5. 5. Compound, characterized by the fact that the compound is: or a pharmaceutically acceptable salt thereof.
  6. 6. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle thereof or pharmaceutically acceptable diluent thereof.
  7. 7. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 2, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle thereof or pharmaceutically acceptable diluent thereof.
  8. 8. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 3, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle thereof or pharmaceutically acceptable diluent thereof.
  9. 9. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 4, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle thereof or pharmaceutically acceptable diluent thereof.
  10. 10. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 5, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle thereof or pharmaceutically acceptable diluent thereof.
  11. 11. Compound, characterized by the fact that it is selected from the group consisting of:
  12. 12. Compound, characterized by the fact that the compound is:
  13. 13. Compound, characterized by the fact that the compound is:
  14. 14. Compound, characterized by the fact that the compound is:
  15. 15. Compound, characterized by the fact that the compound is:
  16. 16. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 11, and a pharmaceutically acceptable vehicle thereof or a pharmaceutically acceptable diluent thereof.
  17. 17. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 12, and a pharmaceutically acceptable vehicle thereof or a pharmaceutically acceptable diluent thereof.
  18. 18. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 13, and a pharmaceutically acceptable vehicle thereof or a pharmaceutically acceptable diluent thereof.
  19. 19. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 14, and a pharmaceutically acceptable vehicle thereof or a pharmaceutically acceptable diluent thereof.
  20. 20. Pharmaceutical composition, characterized in that it comprises the compound, as defined in claim 15, and a pharmaceutically acceptable vehicle thereof or a pharmaceutically acceptable diluent thereof.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel compound having an antiviral effect. More specifically, the present invention relates to a polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity and a medicament, particularly an anti-HIV drug including the same. PREVIOUS TECHNIQUE [0002] Among viruses, the human immunodeficiency virus (hereinafter abbreviated to HIV), a type of retrovirus, is known to cause acquired immunodeficiency syndrome (hereinafter abbreviated to AIDS). Several guidelines currently recommend treatment-naïve patients a combination of an integrase inhibitor (dolutegravir, etc.) as a primary drug with two nucleic acid reverse transcriptase inhibitors (ABC + 3TC, FTC + TAF, etc.) differing in resistance profile, as a therapeutic drug for AIDS. Due to their strong efficacy and high safety, these combinations show a high level of satisfaction compared to initial therapeutic drugs. However, initiating treatment after detection of HIV infection is recommended due to the emergence of such a safe and prognostically good drug. Furthermore, the medication period becomes longer because people infected with HIV have a life expectancy closer to that of healthy people. If adverse reactions occur with nucleic acid reverse transcriptase inhibitors, or if a resistant virus appears due to long-term medication, there is no other convenient treatment method. Therefore, there is an ongoing movement to phase out nucleic acid reverse transcriptase inhibitors. Thus, establishing a two-drug treatment is desirable. Therefore, developing a main drug that can be combined with an integrase inhibitor is desirable. Furthermore, developing a therapeutic drug with a longer medication interval, i.e., a long-acting injection where treatment is completed with only one injection at 1 month or longer intervals, is desired to alleviate medication fatigue attributable to long-term medication and improve patients' QOL (quality of life) so that patients enjoy their daily lives more. [0003] To meet these demands, an integrasecabotegravir inhibitor is under development as a long-acting injection at Ph3. Additionally, the non-nucleic acid reverse transcriptase inhibitor, rilpivirine, is also under development as a long-acting injection. Establishing a treatment method is being attempted with these two drugs. However, these drugs are injected once a month or two months and need to be injected at a total of 3 or 4 pain sites. Thus, the development of a drug with which treatment is completed with one injection every 3 months with less pain at a lower dose is desired to further improve patients' QOL. [0004] Raltegravir and elvitegravir as first-generation oral agents and dolutegravir as a second-generation oral agent have already been released as integrase inhibitors. When a previously untreated patient uses dolutegravir, no resistant mutations appear. However, dolutegravir, when used to treat a patient infected with a virus resistant to a first-generation integrase inhibitor, may cease to be effective due to the subsequent addition of a resistant mutation. Thus, the development of an inhibitor having a higher resistance barrier than dolutegravir is also desired. [0005] Polycyclic, bicyclic or superior carbamoylpyridone derivatives are known as one of the anti-HIV drugs having an integrase inhibitory effect (Patent Documents 1 to 29). Among them, Patent Document 3 describes a carbamoylpyridotriazine derivative. However, none of the documents describes an optically active tricyclic or polycyclic carbamoylpyridone derivative, which is the compound of the present application. PRIOR ART REFERENCES Patent Document [Patent Document 1] WO 2006/088173 [Patent Document 2] WO 2006/116764 [Patent Document 3] WO 2007/049675 [Patent Document 4] WO 2011/129095 [Patent Document 5] WO 2014/099586 [Patent Document 6] WO 2014/100323 [Patent Document 7] WO 2014/104279 [Patent Document 8] WO 2014/183532[Patent Document 9] WO 2014/200880[Patent Document 10] WO 2015/039348[Patent Document 11] WO 2015/048363[Patent Document 12] WO 2015/089847[Patent Document Patent 13] WO 2015/095258[Patent Document 14] WO 2015/006731[Patent Document 15] WO 2015/006733[Patent Document 16] WO 2015/199167[Patent Document 17] WO 2016/090545[Patent Document 18] WO 2016/094198[Patent Document 19] WO 2016/094197[Patent Document 20] WO 2016/106237[Patent Document 21] WO 2016/154527 [Patent Document 22] WO 2016/161382[Patent Document Patent 23] WO 2016/187788[Patent Document 24] WO 2016/191239[Patent Document 25] WO 2017/087256[Patent Document 26] WO 2017/087257[Patent Document 27] WO 2017/106071[Patent Document 28] WO 2017/113288[Patent Document 29] WO 2017/116928 SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION [0006] An object of the present invention is to provide a novel long-acting compound having integrase-inhibiting activity with a high-strength barrier. WAYS TO SOLVE THE PROBLEM [0007] The present inventors have condu