Compounds, compositions and methods comprising oxadiazole derivatives
AssigneePATH Drug Solutions
InventorsGraham Peter Jones, Kevin James Doyle
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Abstract
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.
Claims24
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.
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.
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.
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.
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;
- and
- p 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.
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;
- and
- p 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.
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;
- and
- p 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.
Dependencies are inferred from the claim text.