Treatment of filarial diseases

Patent metadata

Field	Value
Publication number	US-10238677-B2
Application number	US-201615542208-A
Country	US
Kind code	B2
Filing date	Jan 8, 2016
Priority date	Jan 9, 2015
Publication date	Mar 26, 2019
Grant date	Mar 26, 2019

Abstract

The present invention pertains to prevention of and/or treatment for filariasis. In particular, the present invention pertains to the use of tylosin A and its analogs and derivatives to prevent or treat filarial worm infection and/or diseases associated with filarial worm infection. The present invention also pertains to pharmaceutical compositions comprising tylosin A or an analog or derivative thereof for use in preventing or treating filarial worm infection and/or diseases associated with filarial worm infection.

First claim

What is claimed is:

1. A method of preventing or treating filariasis in a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of tylosin A or a salt thereof.

2. The method of claim 1 , wherein the subject is a human.

3. The method of claim 1 , wherein the filariasis is lymphatic filariasis or subcutaneous filariasis.

4. The method of claim 1 , wherein the filariasis is caused by Onchocerca volvulus, Wuchereria bancrofti, Brugia malayi, Brugia timori , or Dirofilaria immitis.

5. A method of preventing or treating filariasis caused by Onchocerca volvulus, Wuchereria bancrofti, Brugia malayi, Brugia timori , or Dirofilaria immitis in a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of a compound of Formula (I):

or a salt thereof, wherein:
R 1 represents hydrogen or —C(O)R 3 , wherein R 3 represents an optionally substituted C 1 -C 6 -alkyl or C 1 -C 6 -haloalkyl;
R 2 represents —C(O)C(R 4 )(R 5 )(R 6 ), wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, and C 3 -C 8 -cycloalkyl C 1 -C 4 -alkyl; and each of R 5 and R 6 are independently selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, and C 3 -C 8 -cycloalkyl -C 1 - C 4 -alkyl; or
R 2 represents —C(O)N(R 7 )(R 8 ), wherein each of R 7 and R 8 are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, and C 3 -C 8 -cycloalkyl -C 1 - C 4 -alkyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form an optionally substituted saturated or partially saturated heterocyclic ring; or
R 2 represents —CH 2 -A 1 , wherein A 1 represents a 6-to 10-membered aryl or a 5-to 10-membered heteroaryl and A 1 is unsubstituted or substituted with one or more R A , wherein each R A is independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, and —O —R 9 , where R 9 represents C 1 -C 6 -alkyl;
R 10 represents hydrogen or —C(O)R 11 , wherein R 11 represents an optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, heteroaryl, C 3 -C 8 -cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, or C 3 -C 8 -cycloalkyl —C 1 - C 4 -alkyl; and
each of a and b independently represents either a single bond or a double bond.

6. The method of claim 5 , wherein R 10 is —C(O)R 11 .

7. The method of claim 6 , wherein R 11 is C 1 -C 6 -alkyl.

8. The method of claim 6 , wherein both a and b represent a double bond and wherein R 1 is —C(O)CH 3 , R 2 is —C(O)N(CH 2 CH 3 ) 2 , and R 11 is —CH 2 CH 3 ; R 1 is hydrogen, R 2 is —C(O)N(CH 2 CH 3 ) 2 ,and R 11 is —CH 2 CH 3 ; R 1 is —C(O)CH 2 CH 3 , R 2 is —C(O)N(CH 2 CH 3 ) 2 , and R 11 is —CH 2 CH 3 ; R 1 is —C(O)CH 3 , R 2 is

and R 11 is —CH 2 CH 3 ; R 1 is hydrogen, R 2 is

and R 11 is —CH 2 CH 3 ; R 1 is —C(O)CH 3 , R 2 is —C(O)N(CH 2 CH 3 ) 2 ,and R 11 is —CH 3 ; R 1 is hydrogen, R 2 is —C(O)N(CH 2 CH 3 ) 2 ,and R 11 is —CH 3 ; R 1 is hydrogen, R 2 is —C(O)N(CH 2 CH 3 ) 2 , and R 11 is —CH(CH 3 ) 2 ; R 1 is —C(O)CH 3 , R 2 is

and R 11 is —CH 3 ; R 1 is hydrogen, R 2 is

and R 11 is —CH 3 ; R 1 —C(O)CH 3 , R 2 is

and R 11 is —CH(CH 3 ) 2 ; or R 1 is hydrogen, R 2 is

and R 11 is —CH(CH 3 ) 2 .

9. The method of claim 5 , wherein the compound has a structure corresponding to Formula (I -1):

or a salt thereof.

10. The method of claim 9 , wherein R 1 is hydrogen.

11. The method of claim 9 , wherein R 1 is —C(O)R 3 .

12. The method of claim 11 , wherein R 3 is methyl, isopropyl, or n-butyl.

13. The method of claim 9 , wherein R 2 is —C(O)N(R 7 )(R 8 ) and each of R 7 and R 8 are independently selected from the group consisting of C 1 -C 6 -alkyl, aryl, and C 3 -C 8 -cycloalkyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form an optionally substituted saturated or partially saturated heterocyclic ring.

14. The method of claim 13 , wherein the heterocyclic ring is a pyrrolidine, a piperidine, an azepane, or a morpholine.

15. The method of claim 9 , wherein R 2 is —CH 2 -A 1 and A 1 is an unsubstituted phenyl or a phenyl substituted with one or more R A .

16. The method of claim 15 , wherein R A is halogen.

17. The method of claim 9 , wherein both a and b represent a double bond.

18. The method of claim 17 , wherein R 1 is —C(O)CH 3 and R 2 is

R 1 is —C(O)CH 3 and R 2 is

R 1 is —C(O)CH 3 and R 2 is

R 1 is —C(O)CH 3 and R 2 is

R 1 is —C(O)CH(CH 3 ) 2 and R 2 is

R 1 is —C(O)CH(CH 3 ) 2 and R 2 is

R 1 is —C(O)CH(CH 3 ) 2 and R 2 is

R 1 is —C(O)CH(CH 3 ) 2 and R 2 is

R 1 is —C(O)CH(CH 3 ) 2 and R 2 is

R 1 is hydrogen and R 2 is

R 1 is —C(O)(CH 2 ) 3 CH 3 and R 2 is

R 1 is —C(O)CH 3 and R 2 is —C(O)C(CH 3 ) 3 ; R 1 is —C(O)CH(CH 3 ) 2 and R 2 is —C(O)C(CH 3 ) 3 ; R 1 is hydrogen and R 2 is —C(O)C(CH 3 ) 3 ; R 1 is —C(O)CH 3 and R 2 is —C(O)N(CH 2 CH 3 ) 2 ; R 1 is —C(O)CH 3 and R 2 is —C(O)N(CH 3 )(C 6 H 5 ); R 1 is —C(O)CH 3 and R 2 is

Assignees

• Abbvie Inc
• Liverpool School Tropical Medicine

Inventors

• Von Geldern Thomas W
• Kempf Dale J
• Marsh Kennan C
• Taylor Mark John
• Ward Stephen Andrew
• Ford Louise
• Turner Joseph

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• C07H17/08

  Hetero rings containing eight or more ring members, e.g. erythromycins · CPC title

• A61K31/365

  Lactones · CPC title

• A61K31/7048 Primary

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• Y02A50/421

  Cross-Sectional Technologies · mapped topic