Compounds, compositions and methods comprising oxadiazole derivatives
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/4245
C07D-271/06
출원번호
US-0526399
(2012-06-18)
등록번호
US-8796321
(2014-08-05)
발명자
/ 주소
Jones, Graham Peter
Doyle, Kevin James
출원인 / 주소
PATH Drug Solutions
대리인 / 주소
Foley & Lardner LLP
인용정보
피인용 횟수 :
0인용 특허 :
60
초록▼
The present invention relates to compositions and methods for treating a disease in an animal, which disease is responsive to inhibiting of functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide by administering to a mammal in need thereof an effective amount of a compound
The present invention relates to compositions and methods for treating a disease in an animal, which disease is responsive to inhibiting of functional cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide by administering to a mammal in need thereof an effective amount of a compound defined herein (including those compounds set forth in Tables 1-2 or encompassed by formulas I-IV) or compositions thereof, thereby treating the disease. The present invention particularly, relates to a method of treating diarrhea and polycystic kidney disease.
대표청구항▼
1. A pharmaceutical composition comprising from about 0.01 mg/kg/day to about 100 mg/kg/day of a compound of formula A: or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier. 2. The pharmaceutical composition of claim 1, formulated for oral or pediatric
1. A pharmaceutical composition comprising from about 0.01 mg/kg/day to about 100 mg/kg/day of a compound of formula A: or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier. 2. The pharmaceutical composition of claim 1, formulated for oral or pediatric administration. 3. A pharmaceutical composition comprising about 0.01 mg/kg/day to about 100 mg/kg/day of a monophosphate of a compound of formula A: or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier, wherein the phenolic hydroxy group of the compound of formula A is converted to the monophosphate. 4. The pharmaceutical composition of claim 3, formulated for oral or pediatric administration. 5. A method for treating diarrhea in a human patient, comprising administering to the human patient from about 0.01 mg/kg/day to about 100 mg/kg/day of a compound of formula A: or a pharmaceutically acceptable salt thereof. 6. The method of claim 5, wherein the patient is suffering from a diarrhea of one or more of the group of secretory diarrhea, infectious diarrhea, inflammatory diarrhea, or diarrhea associated with chemotherapy. 7. The method of claim 5, wherein the compound is administered orally. 8. The method of claim 5, wherein the compound is administered once daily. 9. A method for treating diarrhea in a human patient, comprising administering to the human patient from about 0.01 mg/kg/ day to about 100 mg/kg/day of a monophosphate of a compound of formula A: or a pharmaceutically acceptable salt thereof, wherein the phenolic hydroxy group of the compound of formula A is converted to the monophosphate. 10. The method of claim 9, wherein the diarrhea is secretory diarrhea, infectious diarrhea, inflammatory diarrhea, or diarrhea associated with chemotherapy. 11. The method of claim 9, wherein the compound is administered orally. 12. The method of claim 9, wherein the compound is administered once daily. 13. A process of preparing a compound of formula I: or a salt thereof, wherein:X and Y are different and are either N or O;R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aryloxy and substituted aryloxy;R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;or when p is 0, R1 and R2 together with the atoms bound thereto, form a heterocycle or substituted heterocycle;R3 and R4 are each independently halo;R5 is selected from the group consisting of hydrogen and hydroxyl;R6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; andp is 0, 1, 2, or 3;the process comprising contacting a compound of formula I-A: wherein X, Y, and R3-R6 are defined as above, with a compound of formula R1(CH2)pNHR2, wherein R1, R2, and p are defined as above, under amide forming conditions to provide the compound of formula I or the salt thereof. 14. The process of claim 13, wherein if R6 is alkyl or substituted alkyl, the process further comprising contacting the compound of formula II under deprotection condition to provide a compound of formula I-B: 15. A process of preparing a compound of formula II or a salt thereof, wherein:R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aryloxy and substituted aryloxy;R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;or when p is 0, R1 and R2 are taken together with the atoms bound thereto, form a heterocycle or substituted heterocycle;R3 and R4 are each independently halo;R5 is selected from the group consisting of hydrogen and hydroxyl;R6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; andp is 0 or 1;the process comprising contacting a compound of formula I-3: wherein R3-R6 are defined as above,with a compound of formula R1 (CH2)pNHR2, wherein R1, R2, and p are defined as in formula II above, under amide forming conditions to provide the compound of formula II or the salt thereof. 16. The process of claim 15, wherein if R6 is alkyl or substituted alkyl, the process further comprising contacting the compound of formula II under deprotection condition to provide a compound of formula II-B: or a salt thereof. 17. A process of preparing a compound of formula III: or a salt thereof, wherein:R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aryloxy and substituted aryloxy;R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;or when p is 0, R1 and R2 are taken together with the atoms bound thereto, form a heterocycle or substituted heterocycle;R3 and R4 are each independently halo;R5 is selected from the group consisting of hydrogen and hydroxyl;R6 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; andp is 0 or 1;the process comprising contacting a compound of formula II-2: wherein R3-R6 are defined as in formula HI above,with a compound of formula R1(CH2)pNHR2, wherein R1 , R2, and p are defined as in formula III above, under amide forming conditions to provide the compound of formula III or the salt thereof. 18. The process of claim 17, wherein if R6 is alkyl or substituted alkyl, the process further comprising contacting the compound of formula HI under deprotection condition to provide a compound of formula III-A: or a salt thereof. 19. The process of claim 15, wherein: R1 is aryl substituted with an optionally substituted aryloxy;R2 is hydrogen, alkyl, or substituted alkyl;R3 and R4 are each independently halo;R5 is hydrogen;R6 is hydrogen or substituted alkyl; andp is 1. 20. The compound of claim 15, wherein R1 is phenyl substituted with an optionally substituted aryloxy. 21. The process of claim 15, wherein R2 is hydrogen. 22. The process of claim 15, wherein R3 and R4 are each independently chloro or bromo. 23. The process of claim 15, wherein: R1 is phenyl substituted with a phenoxy group or is phenyl substituted with a substituted phenoxy group, which substituted phenoxy group is substituted with 1 or 2 substituents selected from halo, amino, substituted amino, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1- C3 alkyl, and substituted C1-C3 alkyl;R2 is hydrogen;R3 and R4 are each independently chloro or bromo; andR6 is hydrogen or substituted alkyl. 24. The process of claim 16, wherein R1 is phenyl substituted with a phenoxy group or is phenyl substituted with a substituted phenoxy group, which substituted phenoxy group is substituted with 1 or 2 substituents selected from halo, amino, substituted amino, C1-C3 alkoxy, substituted C1-C3 alkoxy, C1- C3 alkyl, and substituted C1-C3 alkyl;R2 is hydrogen;R3 and R4 are each independently chloro or bromo;or a salt thereof.
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