US 2009/0062358 A1Published application

Peroxisome proliferator activated receptor alpha agonists

OwnerIvan Collado Cano, Samuel James Dominianni +14inventors

InventorsIvan Collado Cano, Samuel James Dominianni, Garret Jay Etgen, JR., Cristina Garcia-Paredes, Richard Duane Johnston, Michael Edward Letourneau, Nathan Bryan Mantlo, Michael John Martinelli, Daniel Ray Mayhugh, Ashraf Saeed, Richard Craig Thompson, Xiaodong Wang, David Scott Coffey, Christopher Randall Schmid, Jeffrey Thomas Vicenzi, Yanping Xu

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Abstract

The present invention is directed to compounds represented by the following structural formula, and pharmaceutically acceptable salts, solvates and hydrates thereof, R1 is a substituted or unsubstituted group selected from C1-C8 alkyl, aryl-C0-2-alkyl, heteroaryl-C0-2-alkyl, C3-C6 cycloalkylaryl-C0-2-alkyl or phenyl. W is O or S. R2 is H or a substituted or unsubstituted group selected from C1-C6 alkyl, C3-C6 cycloalkyl and heteroaryl. X is a C2-C5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S. Y is C, O, S, NH or a single bond. Furthermore, E is (CH2)nCOOH, wherein n is 0, 1, 2 or 3, or C(R3)(R4)A, wherein A is an acidic functional group such as carboxyl, carboxamide substituted or unsubstituted sulfonamide, or substituted or unsubstituted tetrazole. R3 is H, saturated or unsaturated C1-C5 alkyl, C1-C5 alkoxy. Additionally, R4 is H, halo, a substituted or unsubstituted group selected from C1-C5 alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, arylC0-C4alkyl and phenyl, or R3 and R4 are combined to form a C3-C4 cycloalkyl.

Claims94

Dependent claims

A compound represented by the following structural

Formula I:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R1 is selected from the group consisting of hydrogen, substituted or unsubstituted group selected from C1-C8 alkyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, C3-C6 cycloalkylaryl-C0-2-alkyl, and —CH2—C(O)—R17-R18, wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) W is O or S;
(c) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, sulfonamide, amide, OR10 and C3-C6 cycloalkyl;
(d) X is an optionally substituted C1-C5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(e) Y is C, O, S, NH or a single bond;
and
(f) E is selected from the group consisting of hydrogen, C(R3)(R4)A, A, substituted or unsubstituted selected from the group consisting of (CH2)n COOR19, C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, thio-C1-4-alkyl, thioaryl, C1-4alkoxyaryl, C1-4alkoxy C1-4alkyl, aminoaryl, and aminoC1-4alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is an functional group selected from the group consisting of carboxyl, C1-C3alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C1-C5
alkyl, C1-C5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C1-C5
alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, aryl C0-C4 alkyl and phenyl, or R3 and R4 are combined to form a C3-C4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted arylmethyl and optionally substituted C1-C4alkyl;
(g) R8 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, and halo;
(h) R9 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C1-C4 alkyl, substituted or unsubstituted heteroaryl, C1-C6 allyl, and OR10;
and
(i) R10 is independently selected from the group consisting of hydrogen and C1-C4 alkyl.

20 more elements

A compound represented by the following structural

formula:
and pharmaceutically acceptable salts, solvates and
hydrates thereof, wherein:
(a) R1 is selected from the group consisting of hydrogen, substituted or unsubstituted group selected from C1-C8 alkyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, C3-C6 cycloalkylaryl-C0-2-alkyl, and —CH2—C(O)—R17-R18, wherein R17 is O or NH and R18 is optionally substituted benzyl;
(b) W is O or S;
(c) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C1-C6 alkyl, C1-C6 alkyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, sulfonamide, amide, OR10 and C3-C6 cycloalkyl;
(d) X is an optionally substituted C1-C5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(e) Y is C, O, S, NH or a single bond;
and
(f) E is selected from the group consisting of hydrogen, C(R3)(R4)A, A, substituted or unsubstituted selected from the group consisting of (CH2)n COOR19, C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, thio-C1-4-alkyl, thioaryl, C1-4alkoxyaryl, C1-4alkoxy C1-4alkyl, aminoaryl, and aminoC1-4alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is a functional group selected from the group consisting of carboxyl, C1-C3alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C1-C5
alkyl, C1-C5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C1-C5
alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, aryl C0-C4 alkyl and phenyl, or R3 and R4 are combined to form a C3-C4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted arylmethyl and optionally substituted C1-C4 alkyl;
(g) R8 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, and halo;
(h) R9 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C1-C4 alkyl, substituted or unsubstituted heteroaryl, C1-C6 allyl, and OR10;
(i) R10 is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
(j) Z is C0-C3 alkylene, O, S, N, O—(C0-C2 alkylene), S—(C0-C2 alkylene), and N—(C0-C2 alkylene);
and
(k) — is an optional bond to form a double bond.

22 more elements

A compound of the formula:

wherein
(a) R1 is hydrogen or is selected from the group consisting of a substituted or unsubstituted group selected from C1-C8 alkyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, and C3-C6 cycloalkylaryl-C0-2-alkyl;
(b) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, sulfonamide, amide, OR10 and C3-C6 cycloalkyl;
(c) X is an optionally substituted C1-C5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(d) Y is C, O, S, NH or a single bond;
and
(e) E is selected from the group consisting of hydrogen, (CH2)nCOOR19, C(R3)(R4)A, substituted or unsubstituted selected from the group consisting of C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, thio-C1-4-alkyl, thioaryl, C1-4alkoxyaryl, C1-4alkoxy C1-4alkyl, aminoaryl, and aminoC1-4alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is a functional group selected from the group consisting of carboxyl, C1-C3alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C1-C5
alkyl, C1-C5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C1-C5
alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, aryl C0-C4 alkyl and phenyl, or R3 and R4 are combined to form a C3-C4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted C1-C4alkyl and optionally substituted arylmethyl;
(f) R8 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, and halo;
(g) R9 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C1-C4 alkyl, substituted or unsubstituted heteroaryl, C1-C6 allyl, and OR10;
and
(h) R10 is independently selected from the group consisting of hydrogen and C1-C4 alkyl;
and
(i) R15 is selected from the group consisting of hydrogen and an optionally substituted substituent selected from the group consisting of C1-C4 alkyl, aryl, and benzyl.

19 more elements

A compound of the formula:

wherein
(a) R1 is hydrogen or is selected from the group consisting of a substituted or unsubstituted group selected from C1-C8 alkyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, and C3-C6 cycloalkylaryl-C0-2-alkyl;
(b) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, sulfonamide, amide, OR10 and C3-C6 cycloalkyl;
(c) X is an optionally substituted C1-C5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(d) Y is C, O, S, NH or a single bond;
and
(e) E is selected from the group consisting of hydrogen, substituted or unsubstituted selected from the group consisting of (CH2)nCOOR19, C(R3)(R4)A, C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, thio-C1-4-alkyl, thioaryl, C1-4alkoxyaryl, C1-4alkoxy C1-4alkyl, aminoaryl, and aminoC1-4alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is an acidic functional group selected from the group consisting of carboxyl, C1-C3alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C1-C5 alkyl, C1-C5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C1-C5
alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, aryl C0-C4 alkyl and phenyl, or R3 and R4 are combined to form a C3-C4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted C1-C4alkyl and optionally substituted arylmethyl;
(f) R8 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, and halo;
(g) R9 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C1-C4 alkyl, substituted or unsubstituted heteroaryl, C1-C6 allyl, and OR10;
and
(h) R10 is independently selected from the group consisting of hydrogen and C1-C4 alkyl.

16 more elements

A compound of the formula:

wherein
(a) R1 is hydrogen or is selected from the group consisting of a substituted or unsubstituted group selected from C1-C8 alkyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, and C3-C6 cycloalkylaryl-C0-2-alkyl;
(b) R2 is H or a substituted or unsubstituted group
selected from the group consisting of C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, heteroaryl-C0-4-alkyl, sulfonamide, amide, OR10 and C3-C6 cycloalkyl;
(c) X is an optionally substituted C1-C5 alkylene linker wherein one carbon atom of the linker may be replaced with O, NH or S;
(d) Y is C, O, S, NH or a single bond;
and
(e) E is selected from the group consisting of hydrogen, substituted or unsubstituted selected from the group consisting of (CH2)nCOOR19, C(R3)(R4)A, C1-C6 alkyl, C1-C6 allyl, aryl-C0-4-alkyl, thio-C1-4-alkyl, thioaryl, C1-4alkoxyaryl, C1-4alkoxy C1-4alkyl, aminoaryl, and aminoC1-4alkyl, and wherein
(i) n is 0, 1, 2 or 3,
(ii) A is an acidic functional group selected from the group consisting of carboxyl, C1-C3alkylnitrile, carboxamide, substituted or unsubstituted sulfonamide, substituted or unsubstituted acylsulfonamide and substituted or unsubstituted tetrazole;
(iii) R3 is H, saturated or unsaturated C1-C5
alkyl, C1-C5 alkoxy, and
(iv) R4 is H, halo, a substituted or
unsubstituted group selected from C1-C5
alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl, aryl C0-C4 alkyl and phenyl, or R3 and R4 are combined to form a C3-C4 cycloalkyl;
(v) R19 is selected from the group consisting of hydrogen, optionally substituted C1-C4 alkyl and optionally substituted arylmethyl;
(f) R8 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, and halo;
(g) R9 is independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkylenyl, halo, substituted or unsubstituted aryl, substituted or unsubstituted aryl-C1-C4 alkyl, substituted or unsubstituted heteroaryl, C1-C6 allyl, and OR10;
and
(h) R10 is independently selected from the group consisting of hydrogen and C1-C4 alkyl.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/828,446Filed 26 Jul 2007
Priority: 10 Nov 2000
Published: 5 Mar 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification21 codes

C07C 281/06
Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these…:…
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics

Family

Application60/247,317Us provisional application · filed 10 Nov 2000
Application10/415,673Division · filed 11 Sep 2003
Application11/828,446Division
US 2004/0102500 A1Published application
US 7,304,062 B2Related patent
US 2009/0062358 A1This patent

From the US filing history. Foreign family members aren’t listed.