Linked biaryl compounds
AssigneeTularik Inc.
InventorsHiroyuki Abe, Jonathan Houze, Hisashi Kawasaki, Frank Kayser, Rajiv Sharma, Samuel Sperry
Life of this patent
Estimating the term…
Abstract
Compounds, compositions and methods that are useful for the treatment of metabolic disorders, inflammatory diseases and cancer are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in lipid metabolism, inflammation and cell proliferation. The subject compounds are linked biaryl compounds.
Claims111
A compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2-Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2;
- with the proviso that said compound is not
- 3-amino-4-[4-(phenylmethoxy)phenoxy]phenoxylacetic acid,
- 4-[3,5-diiodo-4-(phenylmethoxy)phenoxy]-3,5-diiodobenzenepropanoic acid or
- 4-[4-(benzyloxy)-3-iodophenoxy]-3,5-diiodohydrocinnamic acid.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent and a compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2-Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2.
A method for treating a metabolic disorder, cardiovascular disease, an inflammatory condition, a neoplastic disease, an immune disorder, a shock state, a disorder of gastrointestinal motility or a disease of the central nervous system, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2.
A method for elevating HDL cholesterol levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2-Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2.
A method for reducing triglyceride levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2-Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2
A method for treating diabetes, decreasing insulin resistance or lowering blood pressure, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2-Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2.
A method for treating a condition or disorder responsive to PPARδ modulation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2-Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2.
A method for treating a condition or disorder mediated by PPARδ, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2-Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2.
A method for modulating PPARδ, comprising contacting a cell with a compound having the formula (Ia):
- R1O2C—CRaRb—Y—Ar1—X—Ar2-Z1-Z2-Ar3 Ia
- or a pharmaceutically acceptable salt or prodrug thereof, wherein
- X is selected from the group consisting of O, S(O)m, CR′R″ and SO2NR″;
- Y is O or CR′R″;
- Z1 and Z2 are independently selected from the group consisting of O, S(O)m, (CR′R″)n, N(R″), C(O)NR″ and CR′R″C(O)NR′″;
- alternatively, Z1 and Z2 may be combined to form (C2-C4)alkenyl;
- Ar1 and Ar2 are independently an aromatic group;
- Ar3 is aryl;
- R1 is selected from the group consisting of hydrogen, (C1-C8)alkyl and aryl(C1-C4)alkyl;
- Ra and Rb are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- each R′, R″ and R′″ is independently selected from the group consisting of hydrogen, (C1-C4)alkyl, aryl and aryl(C1-C4)alkyl;
- the subscript m is an integer from 0 to 2;
- and
- the subscript n is an integer from 1 to 2.
Dependencies are inferred from the claim text.