Compounds and methods for treating fungal infections

Abstract

To provide compositions and methods of use thereof useful for treatment of fungal infections and diseases.SOLUTION: A pharmaceutical composition comprises: (i) a compound of the formula (I) in the figure or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof; and (ii) at least one pharmaceutically acceptable excipient. The pharmaceutical composition is in a dosage form for oral dosing or administration.SELECTED DRAWING: None

Claims

1. A pharmaceutical composition for treating or preventing fungal infections or fungal diseases in human subjects, (i) A therapeutically effective amount of the compound of formula (I): 【Chemistry 1】 or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates; and, (ii) comprising at least one pharmaceutically acceptable excipient, Here, The pharmaceutical composition is either an oral medication or a dosage form for oral administration, or A pharmaceutical composition in dosage form for administration or administration by injection; The pharmaceutical composition is administered to the subject according to the treatment regimen; The treatment regimen includes a loading dose and a maintenance dose; A loading dose is administered to the subject, followed by a maintenance dose; The loading dose comprises 2000 mg of the compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, administered once daily by 1.V. infusion on day 1 of treatment, or The loading dose consists of 1000 mg of the compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, administered twice daily by 1.V. infusion on the first day of treatment; The maintenance dose includes 600 mg to 1000 mg of the compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates. The maintenance dose is administered to the subject once daily, starting on the second day of treatment; Fungal infections are caused by invasive fungi; Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered to a subject over a period of up to 12 weeks and at least 1 week.

3. The pharmaceutical composition according to claim 1 or claim 2, which is administered to a subject over a period of six weeks.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the loading dose is administered to the subject by IV infusion over a period of 2 to 3 hours.

5. A maintenance dose comprising 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of the compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, according to any one of claims 1 to 4.

6. A maintenance dose comprising 800 mg of the compound of formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, and administered orally to a subject once daily, according to any one of claims 1 to 5.

7. A maintenance dose comprising 600 mg of the compound of formula (I), or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate thereof, and administered to a subject once daily by 1.V. infusion, according to any one of claims 1 to 5.

8. The loading dose is administered twice on the first day of treatment. A loading dose of 1000 mg of the compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, is administered by 1.V. infusion twice daily on day 1 of treatment. The maintenance dose is administered to the subject once daily, starting on the second day of treatment. The maintenance dose consists of 800 mg of the compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and is administered orally to the subject once daily; or The maintenance dose consists of 600 mg of the compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, and is administered to the subject once daily by 1.V. infusion. A pharmaceutical composition according to any one of claims 1 to 3.

9. The treatment regimen further comprises administering at least one antifungal agent to a subject in combination with a pharmaceutical composition comprising a compound of formula (I), or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates, or hydrates, The pharmaceutical composition according to any one of claims 1 to 8, wherein the at least one antifungal agent is azole, echinocandin, amphotericin B deoxycholate, amphotericin B cocreate, 5-fluorocytosin, terbinafine, griseofulvin, VL-2397, ibrexafungelb, orotomide F901318, or a combination thereof.

10. A pharmaceutical composition according to any one of claims 1 to 9, wherein a fungal infection or fungal disease is caused by the fungi Aspergillus fumigatus, Blastomyces, Ajeromyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Rhizopus mucor, Kuningamera, Apophysomyces, Absidia, Saxenea, Fly mold, Conidiobolus, Basidiobolus, Sporotrichus, Pneumocystis, Talaromyces, Asclepias, Fusarium, Skedosporium, or from fungi of the Mucorales order, or from any combination thereof.

11. The pharmaceutical composition according to any one of claims 1 to 9, wherein a fungal infection or fungal disease is caused by fungi of the order Cryptococcus, Aspergillus, Candida, Fusarium, Skedosporium, or fungi of the order Mucorales, or any combination thereof.

12. Fungal infections or diseases include Aspergillus fumigatus, Aspergillus flavus, Blastomyces dermatitidis, Ajeromyces dermatitidis, Candida albicans, Candida glabrata, Candida rugosa, Candida auris, Coccidioides idemithis, Coccidioides posadasi, Cryptococcus neoformans, Cryptococcus gattii, Histoplasma capsulatum, and Rhizopus stronifer. A pharmaceutical composition according to any one of claims 1 to 9, caused by Rhizopus arizus, Mucor indicus, Cunninghamera betletiere, Apophysomyces elegans, Absidia species, Saxenea species, Rhizomucor psyllus, Fly species, Conidiobolus species, Basidiobolus species, Sporotrix schenky, Pneumocystis girobesi, Talaromyces marnefei, Asclepias albicans, Fusarium solani, Skedosporium apiospermum, Rhizomucor psyllus, or any combination thereof.

13. A pharmaceutical composition according to any one of claims 1 to 9, wherein a fungal infection or fungal disease is caused by Cryptococcus or Candida.

14. The pharmaceutical composition according to any one of claims 1 to 9, wherein the fungal infection or fungal disease is caused by Cryptococcus neoformans, Cryptococcus gattii, or Candida auris.

15. The pharmaceutical composition according to any one of claims 1 to 9, wherein the fungal infection or fungal disease is caused by the fungus Candida.

16. The pharmaceutical composition according to any one of claims 1 to 9, wherein the fungal infection or fungal disease is caused by Candida auris.

17. The pharmaceutical composition according to any one of claims 1 to 9, wherein the fungal infection or fungal disease is caused by the fungus Aspergillus.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the fungal infection or fungal disease is azole-resistant and / or echinocandin-resistant.

19. The subject is immune-deficient, or The subjects are infected with HIV / AIDS, or have cancer, or The subject has cancer, or The cancer is acute myeloid leukemia (AML), or The subject has neutropenia, or The subject is currently receiving or has previously received cancer chemotherapy, or The subject is currently receiving, has previously received, or is currently receiving corticosteroid treatment. The subject is currently receiving, has previously received, or is currently receiving treatment with a TNF inhibitor. The subject is a transplant recipient. A pharmaceutical composition according to any one of claims 1 to 18.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the fungal infection or fungal disease is present in the bloodstream of the subject.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the subject has a reduced number of fungal colonies in the lungs after administration of the pharmaceutical composition.

22. The plasma concentration-time curve of the compound of formula (I) in the subject is given by t between less than 30 minutes and less than 180 minutes. ｍａｘ A pharmaceutical composition according to any one of claims 1 to 21, having the following:

23. The subjects were given the compound of formula (I) at maximum plasma concentrations of 12,000 ng / mL to 25,000 ng / mL (C ｍａｘ A pharmaceutical composition according to any one of claims 1 to 22, having )

24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the compound of formula (I), or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or hydrate is the compound of formula (I), or its solvate or hydrate.

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