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US-20260125356-A1 - TREATMENT OF LEISHMANIASIS

US20260125356A1US 20260125356 A1US20260125356 A1US 20260125356A1US-20260125356-A1

Abstract

The presentation invention relates to compounds of formula (I) and pharmaceutical compositions thereof. The compounds may be used to treat an infection, such as a parasitic infection or a bacterial infection. In some embodiments, the compounds may be used to treat leishmaniasis.

Inventors

  • Paul Denny
  • Patrick STEEL
  • Vanessa LYNE

Assignees

  • THE UNIVERSITY OF DURHAM

Dates

Publication Date
20260507
Application Date
20231013
Priority Date
20221017

Claims (20)

  1. 1 . A compound of formula (I): wherein X 1 is CR 1 , C(R 1 ) 2 , N, NR 1 , O or S; X 2 is CR 2 , C(R 2 ) 2 , N, NR 2 , O or S; X 3 is CR 3 , C(R 3 ) 2 , N, NR 3 , O or S; X 4 is a bond or NR 4 , O or S; L 1 is optionally substituted C 1-12 alkylene, optionally substituted C 2-12 alkenylene, optionally substituted C 2-12 alkynylene or -(L 4 O) m L 5 -; L 2 is a bond or is optionally substituted C 1-12 alkylene, optionally substituted C 2-12 alkenylene, optionally substituted C 2-12 alkynylene or -(L 4 O) m L 5 -; L 3 is an optionally substituted 5 to 10 membered heteroarylene or an optionally substituted C 6-10 arylene; L 4 is optionally substituted C 1-6 alkylene, optionally substituted C 2-6 alkenylene or optionally substituted C 2-6 alkynylene; L 5 is a bond or optionally substituted C 1-6 alkylene, optionally substituted C 2-6 alkenylene or optionally substituted C 2-6 alkynylene; R 1 , R 2 and R 3 are each independently H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkynyl, optionally substituted C 2-12 alkenyl, OR 13 , SR 13 , NR 13 R 14 , COR 13 , COOR 13 , CONR 13 R 14 , CN or a halogen; R 4 is H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl or optionally substituted C 2-12 alkynyl; R 5 , R 7 and R 8 are independently absent or H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkynyl, optionally substituted C 2-12 alkenyl, OR 13 , SR 13 , NR 13 R 14 , COR 13 , COOR 13 , CONR 13 R 14 , CN or a halogen; R 6 is H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkynyl, optionally substituted C 2-12 alkenyl, OR 13 , SR 13 , NR 13 R 14 , COR 13 , COOR 13 , CONR 13 R 14 , CN or a halogen; R 9 is absent or is H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl or optionally substituted C 2-12 alkynyl; or R 6 and R 9 together with the atoms to which they are attached combine to form an optionally substituted 5 or 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl; R 10 is H, halogen, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl or optionally substituted C 2-12 alkenyl; R 11 is absent or H, halogen, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl or optionally substituted C 2-12 alkenyl; or R 6 and R 10 together with the atoms to which they are attached combine to form an optionally substituted 5 or 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl; or R 10 and R 11 together form an oxo group; R 12 is NR 13 R 14 , an optionally substituted 5 to 10 membered heteroaryl or an optionally substituted 3 to 10 membered heterocycle, where the heteroaryl or heterocycle contain at least one nitrogen; R 13 and R 14 are independently H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl or optionally substituted C 2-12 alkynyl; n is 0 or 1; and m is an integer between 1 and 5; or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof.
  2. 2 . The compound of claim 1 , wherein the compound is a compound of formula (Ib):
  3. 3 . The compound of claim 2 , wherein the compound is a compound of formula (Ibi):
  4. 4 . The compound of claim 1 , wherein n is 0, optionally wherein X 1 is CR 1 and R 5 , R 7 and R 8 are absent.
  5. 5 . (canceled)
  6. 6 . The compound according to claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 is optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkynyl, optionally substituted C 2-12 alkenyl, OR 13 , SR 13 , NR 13 R 14 , COR 13 , COOR 13 , CONR 13 R 14 , CN or a halogen, optionally wherein at least one of R 1 and R 6 is optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkynyl, optionally substituted C 2-12 alkenyl, OR 13 , SR 13 , NR 13 R 14 , COR 13 , COOR 13 , CONR 13 R 14 , CN or a halogen.
  7. 7 . (canceled)
  8. 8 . The compound according to claim 6 , wherein one of R 1 and R 6 is COOR 13 or CONR 13 R 14 , and R 13 and R 14 are independently H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl, optionally wherein R 6 is CONHMe.
  9. 9 . (canceled)
  10. 10 . The compound according to claim 1 , wherein R 1 , R 2 and R 3 are H.
  11. 11 . The compound according to claim 1 , wherein X 4 is O.
  12. 12 . The compound according to claim 1 , wherein L 1 is optionally substituted C 1-6 alkylene, optionally substituted C 2-6 alkenylene, optionally substituted C 2-6 alkynylene or -(L 4 O) m L 5 -, and L 4 and L 5 are optionally substituted C 1-3 alkylene, optionally substituted C 2-3 alkenylene or optionally substituted C 2-3 alkynylene and m is 1, 2 or 3, preferably wherein L 1 is optionally substituted C 2-3 alkylene, optionally substituted C 2-3 alkenylene or optionally substituted C 2-3 alkynylene.
  13. 13 . The compound according to claim 1 , wherein R 12 is NR 13 R 14 , an optionally substituted 5 or 6 membered heteroaryl or an optionally substituted 5 or 6 membered heterocycle, where the heteroaryl or heterocycle contain at least one nitrogen, and R 13 and R 14 are independently H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl, optionally wherein R 12 is an optionally substituted 5 or 6 membered heterocycle, where the heterocycle contains at least one nitrogen.
  14. 14 . (canceled)
  15. 15 . The compound according to claim 1 , wherein L 2 is a bond or optionally substituted C 1-6 alkylene, optionally substituted C 2-6 alkenylene or optionally substituted C 2-6 alkynylene, and preferably wherein L 2 is a bond.
  16. 16 . The compound according to claim 1 , wherein R 9 is H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl or optionally substituted C 2-6 alkynyl, and preferably is H.
  17. 17 . The compound according to claim 1 , wherein R 10 and R 11 together form an oxo group.
  18. 18 . The compound according to claim 1 , wherein L 3 is an optionally substituted 5, 6 or 9 membered heteroarylene or an optionally substituted phenylene, and preferably is
  19. 19 . The compound according to claim 1 , wherein the compound is a compound of formula (100) or (101):
  20. 20 . A pharmaceutical composition comprising a compound of formula (I), as defined by claim 1 , or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof, and a pharmaceutically acceptable vehicle.

Description

The invention relates to compounds of formula (I), which may be used in the treatment of microbial infections. In particular, compounds of formula (I) are effective at treating leishmaniasis. The invention extends to novel compositions, therapies and methods for treating, preventing or ameliorating a microbial infection. The Neglected Tropical Disease (NTD) leishmaniasis is endemic in over 90 countries worldwide, affecting approximately 12 million people per year with 350 million people living at risk of disease. The causative agent, Leishmania species, are sand fly borne kinetoplastid protozoan parasites and infection leads to a wide spectrum of clinical manifestations in endemic areas, from self-healing but scarring cutaneous leishmaniasis (CL) to fatal visceral disease (VL). Largely due to elimination efforts in south Asia, the global burden of VL has decreased substantially in the past decade. However, due to forced migration, the cases of CL have substantially increased in the same period (0.7-1 million per year). Current treatment of CL largely relies on the pentavalent antimonials such as sodium stibogluconate (Pentostam) and meglumine antimoniate (Glucantime) which have been in clinical use for over 70 years despite their associated problems, which include severe side-effects such as cardiotoxicity and the fact that they require parenteral administration. Animals can also be infected and serve as reservoirs of disease. In particular, the disease affects dogs throughout southern Europe, South America and the southern USA. Furthermore, the owners of infected companion animals seek their treatment and veterinary drugs are extremely limited in both number and efficacy. Accordingly, there is a recognised need to develop new and effective therapies for this NTD. The present invention arose from the inventors' work in attempting to address this problem. In accordance with a first aspect of the invention, there is provided a compound of formula (I): wherein X1 is CR1, C(R1)2, N, NR1, O or S; X2 is CR2, C(R2)2, N, NR2, O or S;X3 is CR3, C(R3)2, N, NR3, O or S;X4 is a bond or NR4, O or S;L1 is optionally substituted C1-12 alkylene, optionally substituted C2-12 alkenylene, optionally substituted C2-12 alkynylene or -(L4O)mL5-;L1 is a bond or is optionally substituted C1-12 alkylene, optionally substituted C2-12 alkenylene, optionally substituted C2-12 alkynylene or -(L4O)mL5-;L3 is an optionally substituted 5 to 10 membered heteroarylene or an optionally substituted C6-10 arylene;L4 is optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene or optionally substituted C2-6 alkynylene;L5 is a bond or optionally substituted C1-6 alkylene, optionally substituted C2-6 alkenylene or optionally substituted C2-6 alkynylene;R1, R2 and R3 are each independently H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkynyl, optionally substituted C2-12 alkenyl, OR18, SR13, NR13R14, COR13, COOR13, CONR13R14, CN or a halogen;R4 is H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl or optionally substituted C2-12 alkynyl;R5, R7 and R8 are independently absent or H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkynyl, optionally substituted C2-12 alkenyl, OR13, SR13, NR13R14, COR13, COOR13, CONR13R14, CN or a halogen;R6 is H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkynyl, optionally substituted C2-12 alkenyl, OR13, SR13, NR13R14, COR13, COOR13, CONR13R14, CN or a halogen; R9 is absent or is H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl or optionally substituted C2-12 alkynyl; or R6 and R9 together with the atoms to which they are attached combine to form an optionally substituted 5 or 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl;R10 is H, halogen, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl or optionally substituted C2-12 alkenyl; R11 is absent or H, halogen, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl or optionally substituted C2-12 alkenyl; or R6 and R10 together with the atoms to which they are attached combine to form an optionally substituted 5 or 6 membered heterocycle or an optionally substituted 5 or 6 membered heteroaryl; or R10 and R11 together form an oxo group;R12 is NR13R14, an optionally substituted 5 to 10 membered heteroaryl or an optionally substituted 3 to 10 membered heterocycle, where the heteroaryl or heterocycle contain at least one nitrogen;R13 and R14 are independently H, optionally substituted C1-12 alkyl, optionally substituted C2-12 alkenyl or optionally substituted C2-12 alkynyl;n is 0 or 1; andm is an integer between 1 and 5;or a pharmaceutically acceptable complex, salt, solvate, tautomeric form or polymorphic form thereof. Advantageously, the inventors have found that compounds of formula (I) can be used to treat leishmaniasis. The term “alkyl”, as used herein, unless o