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Arylsulfonamidobenzylic compounds Number:7,071,358 from the United States Patent and Trademark Office (PTO) owispatent

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Title: Arylsulfonamidobenzylic compounds

Abstract: Arylsulfonamidobenzyl alcohols, amines and sulfonamides are provided which are useful in treating lipid disorders, metabolic diseases and cell-proliferative diseases.

Patent Number: 7,071,358 Issued on 07/04/2006 to Jiao,   et al.

Inventors: Jiao; Xian Yun (San Mateo, CA); Kayser; Frank (San Francisco, CA); McKendry; Sharon (Redwood Shores, CA); Piper; Derek E. (Foster City, CA); Shiau; Andrew K. (San Francisco, CA)
Assignee: Amgen Inc. (Thousand Oaks, CA)
Appl. No.: 354922
Filed: January 29, 2003

Current U.S. Class: 564/92 ; 544/335; 546/333; 548/205; 548/252; 548/309.7; 548/336.1; 548/375.1; 548/561; 549/65; 556/465; 560/12; 562/430; 564/82
Current International Class: C07C 311/37 (20060101); A61K 31/18 (20060101)
Field of Search: 514/604,524,440,398,399,394,365,381,357,256,403,539,562,492,427,445 564/82,92 560/12 562/430 556/465 548/561,375.1,252,205,309.7,336.1,336 549/65 546/333 544/335

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6156766 December 2000 Arita et al.
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WO 00/46203 Aug., 2000 WO

Other References

Chkanikov, et al. "Hexafluoroacetone and Methyl Trifluoropyruvate as Precursors of Modified Esters of n-acyl-n-phenyl-.alpha.-amino acids," Bulletin of the Russian Academy of Sciences, 41(8) Part 2 pp. 1415-1424. cited by other .
Gilbert, et al. "Perhalo ketones--(VI) aromatic amino derivs. of the penhaloacetones," Database 'Online accession No. 16091fXP-002151155, Russian Abstract. cited by other .
Miryan, et al.: "Derivatives of pyridinecarboxylic acids. Synthesis and antiexudative effect of fluorinated derivatives of nicotinamide and isonicotinamide," Database Chemabs'Online? Chemical Abstract Service, accession No. 86:139798 XP-002151153; (1977), 11(1), 70-2 Russian Abstract. cited by other .
Polishchuk, V. R., et al.: "Electron paramagnetic resonance spectra of 2-arylpolyfluoroisopropyl radicals," Database Chemabs 'Online? Chemcial Abstract Service, accession No. 91: 4737 CA XP-002151154, (1979), (3) pp. 659-661, Russian Abstract. cited by other.

Primary Examiner: Kumar; Shailendra
Attorney, Agent or Firm: Jones Day
Parent Case Text


CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of Provisional Application Ser. No. 60/353,497 filed Jan. 30, 2002, and is related in subject matter to co-pending application Ser. No. 10/354,923, filed on even date herewith, entitled "Heterocyclic Arylsulfonamidobenzylic Compounds," the disclosures of which are incorporated herein by reference.
Claims


What is claimed is:

1. A compound having the formula: ##STR00113## wherein R.sup.1 is a member selected from the group consisting of ##STR00114## wherein R.sup.11 is a member selected from the group consisting of halogen, nitro, cyano, R.sup.12, OR.sup.12, SR.sup.12, NHR.sup.12, N(R.sup.12).sub.2, (C.sub.4 C.sub.8)cycloalkyl, (C.sub.5 C.sub.8)cycloalkenyl, COR.sup.12, CO.sub.2R.sup.12, CONHR.sup.12, CON(R.sup.12).sub.2, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl and heteroaryl(C.sub.1 C.sub.4)alkyl; wherein each R.sup.12 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl or two R.sup.12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R.sup.11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR.sup.13, NHSO.sub.2R.sup.14 and NHC(O)R.sup.13, and any aryl or heteroaryl portions of R.sup.11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.14, OR.sup.13, SR.sup.13, N(R.sup.13).sub.2, NHSO.sub.2R.sup.14, NHC(O)R.sup.13, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.13 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl and each R.sup.14 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl; or optionally, R.sup.11 is combined with either X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S; each R.sup.18 is independently selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl, aryl and heteroaryl; X is a member selected from the group consisting of H, NH.sub.2, NHR.sup.15, NHSO.sub.2R.sup.15, OH or OR.sup.15, wherein R.sup.15 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl or halo(C.sub.1 C.sub.8)alkyl, or is combined with R.sup.11 as described above; Y is fluoro(C.sub.1 C.sub.4)alkyl, or is combined with R.sup.11 as described above; R.sup.2 is a member selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R.sup.2 is combined with R.sup.4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S; R.sup.3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; the subscript n is an integer of from 0 to 3; and each R.sup.4 is independently selected from the group consisting of halogen, cyano, nitro, R.sup.17, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2R.sup.17, N(R.sup.17).sub.2 and CON(R.sup.17).sub.2, wherein each R.sup.17 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; and pharmaceutically acceptable salts thereof.

2. A compound of claim 1, wherein X is OH.

3. A compound of claim 1, wherein X is OH and R.sup.1 has the formula: ##STR00115## wherein R.sup.11 is a member selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, indolyl, benzimidazolyl, benzothienyl and benzothiazolyl, each of said R.sup.11 groups being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.1 C.sub.8)haloalkyl, phenyl(C.sub.1 C.sub.6)alkyl and phenyl(C.sub.2 C.sub.6)heteroalkyl.

4. A compound of claim 3, wherein R.sup.11 is phenyl, optionally substituted with from one to two substituents independently selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.1 C.sub.8)haloalkyl, phenyl(C.sub.1 C.sub.6)alkyl and phenyl(C.sub.2 C.sub.6)heteroalkyl.

5. A compound of claim 4, wherein R.sup.2 is selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino.

6. A compound of claim 5, wherein R.sup.3 is a member selected from the group consisting of phenyl, pyridyl, thienyl and thiazolyl, optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.

7. A compound of claim 6, wherein the subscript n is an integer of from 0 to 2, and each R.sup.4 is independently selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl and halo(C.sub.1 C.sub.8)alkyl.

8. A compound of claim 3, wherein R.sup.11 is pyridyl, optionally substituted with from one to two substituents independently selected from the group consisting of halogen, cyano, nitro, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.1 C.sub.8)haloalkyl, phenyl(C.sub.1 C.sub.6)alkyl and phenyl(C.sub.2 C.sub.6)heteroalkyl.

9. A compound of claim 8, wherein R.sup.2 is selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino.

10. A compound of claim 9, wherein R.sup.3 is a member selected from the group consisting of phenyl, pyridyl, thienyl and thiazolyl, optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.

11. A compound of claim 10, wherein the subscript n is an integer of from 0 to 2, and each R.sup.4 is independently selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl and halo(C.sub.1 C.sub.8)alkyl.

12. A compound of claim 3, wherein R.sup.11 is pyridazinyl or pyrrolyl, optionally substituted with from one to two substituents independently selected from the group consisting of halogen, cyano, nitro, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.1 C.sub.8)haloalkyl, phenyl(C.sub.1 C.sub.6)alkyl and phenyl(C.sub.2 C.sub.6)heteroalkyl.

13. A compound of claim 1, wherein X is OH and R.sup.1 has the formula: ##STR00116## wherein R.sup.11 is a member selected from the group consisting of phenyl, pyridyl, pyrrolyl and pyridazinyl, each of said R.sup.11 groups being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.1 C.sub.8)haloalkyl, phenyl(C.sub.1 C.sub.6)alkyl and phenyl(C.sub.2 C.sub.6)heteroalkyl.

14. A compound of claim 13, wherein R.sup.11 is phenyl, optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.1 C.sub.8)haloalkyl, phenyl(C.sub.1 C.sub.6)alkyl and phenyl(C.sub.2 C.sub.6)heteroalkyl.

15. A compound of claim 14, wherein R.sup.2 is selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino.

16. A compound of claim 15, wherein R.sup.3 is a member selected from the group consisting of phenyl, pyridyl, thienyl and thiazolyl, optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2--C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.

17. A compound of claim 16, wherein the subscript n is an integer of from 0 to 2, and each R.sup.4 is independently selected from the group consisting of halogen, (C.sub.1 C.sub.8)alkyl and halo(C.sub.1 C.sub.8)alkyl.

18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: ##STR00117## wherein R.sup.1 is a member selected from the group consisting of ##STR00118## wherein R.sup.11 is a member selected from the group consisting of halogen, nitro, cyano, R.sup.12, OR.sup.12, SR.sup.12, NHR.sup.12, N(R.sup.12).sub.2, (C.sub.4 C.sub.8)cycloalkyl, (C.sub.5 C.sub.8)cycloalkenyl, COR.sup.12, CO.sub.2R.sup.12, CONHR.sup.12, CON(R.sup.12).sub.2, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl and heteroaryl(C.sub.1 C.sub.4)alkyl; wherein each R.sup.12 is (C.sub.1 C.sub.8)alkyl, (C.sub.3--C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl or two R.sup.12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R.sup.11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR.sup.13, NHSO.sub.2R.sup.14 and NHC(O)R.sup.13, and any aryl or heteroaryl portions of R.sup.11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.14, OR.sup.13, SR.sup.13, N(R.sup.13).sub.2, NHSO.sub.2R.sup.14, NHC(O)R.sup.13, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.13 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl and each R.sup.14 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl; or optionally, R.sup.11 is combined with X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S; each R.sup.18 is independently selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl, aryl and heteroaryl; X is a member selected from the group consisting of H, NH.sub.2, NHR.sup.15, NHSO.sub.2R.sup.15, OH and OR.sup.15, wherein R.sup.15 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl or halo(C.sub.1 C.sub.8)alkyl, or is combined with R.sup.11 as described above; Y is fluoro(C.sub.1 C.sub.4)alkyl, or is combined with R.sup.11 as described above; R.sup.2 is a member selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R.sup.2 is combined with R.sup.4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S; R.sup.3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; the subscript n is an integer of from 0 to 3; and each R.sup.4 is independently selected from the group consisting of halogen, cyano, nitro, R.sup.17, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2R.sup.17, N(R.sup.17).sub.2 and CON(R.sup.17).sub.2, wherein each R.sup.17 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; and pharmaceutically acceptable salts thereof.

19. A pharmaceutical composition of claim 18, wherein said compound is a compound of any of claims 3 17.

20. A method of modulating LXR function in a cell, said method comprising contacting said cell with an LXR-modulating amount of a compound of the formula: ##STR00119## wherein R.sup.1 is a member selected from the group consisting of ##STR00120## wherein R.sup.11 is a member selected from the group consisting of halogen, nitro, cyano, R.sup.12, OR.sup.12, SR.sup.12, NHR.sup.12, N(R.sup.12).sub.2, (C.sub.4 C.sub.8)cycloalkyl, (C.sub.5 C.sub.8)cycloalkenyl, COR.sup.12, CO.sub.2R.sup.12, CONHR.sup.12, CON(R.sup.12).sub.2, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl and heteroaryl(C.sub.1 C.sub.4)alkyl; wherein each R.sup.12 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl or two R.sup.12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R.sup.11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR.sup.13, NHSO.sub.2R.sup.14 and NHC(O)R.sup.13, and any aryl or heteroaryl portions of R.sup.11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.14, OR.sup.13, SR.sup.13, N(R.sup.13).sub.2, NHSO.sub.2R.sup.14, NHC(O)R.sup.13, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.13 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl and each R.sup.14 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl; or optionally, R.sup.11 is combined with X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S; each R.sup.18 is independently selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl, aryl and heteroaryl; X is a member selected from the group consisting of H, NH.sub.2, NHR.sup.15, NHSO.sub.2R.sup.15, OH and OR.sup.15, wherein R.sup.15 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl or halo(C.sub.1 C.sub.8)alkyl, or is combined with R.sup.11 as described above; Y is fluoro(C.sub.1 C.sub.4)alkyl, or is combined with R.sup.11 as described above; R.sup.2 is a member selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R.sup.2 is combined with R.sup.4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S; R.sup.3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; the subscript n is an integer of from 0 to 3; and each R.sup.4 is independently selected from the group consisting of halogen, cyano, nitro, R.sup.17, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2R.sup.17, N(R.sup.17).sub.2 and CON(R.sup.17).sub.2, wherein each R.sup.17 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; and pharmaceutically acceptable salts thereof.

21. A method of treating obesity, diabetes, hypercholesterolemia, atherosclerosis or hyperlipoproteinemia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula: ##STR00121## wherein R.sup.1 is a member selected from the group consisting of ##STR00122## wherein R.sup.11 is a member selected from the group consisting of halogen, nitro, cyano, R.sup.12, OR.sup.12, SR.sup.12, NHR.sup.12, N(R.sup.12).sub.2, (C.sub.4 C.sub.8)cycloalkyl, (C.sub.5 C.sub.8)cycloalkenyl, COR.sup.12, CO.sub.2R.sup.12, CONHR.sup.12, CON(R.sup.12).sub.2, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl and heteroaryl(C.sub.1 C.sub.4)alkyl; wherein each R.sup.12 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl or two R.sup.12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R.sup.11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR.sup.13, NHSO.sub.2R.sup.14 and NHC(O)R.sup.13, and any aryl or heteroaryl portions of R.sup.11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.14, OR.sup.13, SR.sup.13, N(R.sup.13).sub.2, NHSO.sub.2R.sup.14, NHC(O)R.sup.13, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.13 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl and each R.sup.14 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl; or optionally, R.sup.11 is combined with X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S; each R.sup.18 is independently selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl, aryl and heteroaryl; X is a member selected from the group consisting of H, NH.sub.2, NHR.sup.15, NHSO.sub.2R.sup.15, OH and OR.sup.15, wherein R.sup.15 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl or halo(C.sub.1 C.sub.8)alkyl, or is combined with R.sup.11 described above; Y is fluoro(C.sub.1 C.sub.4)alkyl, or is combined with R.sup.11 as described above; R.sup.2 is a member selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R.sup.2 is combined with R.sup.4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S; R.sup.3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; the subscript n is an integer of from 0 to 3; and each R.sup.4 is independently selected from the group consisting of halogen, cyano, nitro, R.sup.17, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2R.sup.17, N(R.sup.17).sub.2 and CON(R.sup.17).sub.2, wherein each R.sup.17 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; or a pharmaceutically acceptable salt thereof.

22. A method of treating an LXR-mediated condition in a subject, said method comprising administering to said subject an LXR-modulating amount of a compound of the formula: ##STR00123## wherein R.sup.1 is a member selected from the group consisting of ##STR00124## wherein R.sup.11 is a member selected from the group consisting of halogen, nitro, cyano, R.sup.12, OR.sup.12, SR.sup.12, NHR.sup.12, N(R.sup.12).sub.2, (C.sub.4 C.sub.8)cycloalkyl, (C.sub.5 C.sub.8)cycloalkenyl, COR.sup.12, CO.sub.2R.sup.12, CONHR.sup.12, CON(R.sup.12).sub.2, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl and heteroaryl(C.sub.1 C.sub.4)alkyl; wherein each R.sup.12 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl or two R.sup.12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R.sup.11 are optionally substituted with from one to three substituents independently selected from the group consisting of halogen, OR.sup.13, NHSO.sub.2R.sup.14 and NHC(O)R.sup.13, and any aryl or heteroaryl portions of R.sup.11 are optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.14, OR.sup.13, SR.sup.13, N(R.sup.13).sub.2, NHSO.sub.2R.sup.14, NHC(O)R.sup.13, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.13 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl and each R.sup.14 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl; or optionally, R.sup.11 is combined with X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from the group consisting of N, O and S; each R.sup.18 is independently selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl, aryl and heteroaryl; X is a member selected from the group consisting of H, NH.sub.2, NHR.sup.15, NHSO.sub.2R.sup.15, OH and OR.sup.15, wherein R.sup.15 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl or halo(C.sub.1 C.sub.8)alkyl, or is combined with R.sup.11 as described above; Y is fluoro(C.sub.1 C.sub.4)alkyl, or is combined with R.sup.11 as described above; R.sup.2 is a member selected from the group consisting of H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino, or optionally R.sup.2 is combined with R.sup.4 to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S; R.sup.3 is a member selected from the group consisting of aryl and heteroaryl, said aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16 phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; the subscript n is an integer of from 0 to 3; and each R.sup.4 is independently selected from the group consisting of halogen, cyano, nitro, R.sup.17, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2R.sup.17, N(R.sup.17).sub.2 and CON(R.sup.17).sub.2, wherein each R.sup.17 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring; or a pharmaceutically acceptable salt thereof.

23. A method in accordance with claim 22, wherein said condition is selected from the group consisting of obesity, diabetes, hypercholesterolemia, atherosclerosis and hyperlipoproteinemia.

24. A method in accordance with claim 23, wherein said compound is administered in combination with an anti-hypercholesterolemic agent.

25. A method in accordance with claim 22, wherein said compound is an LXR agonist.
Description


STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

Not Applicable

REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK.

Not Applicable

BACKGROUND OF THE INVENTION

Cholesterol is used for the synthesis of bile acids in the liver, the manufacture and repair of cell membranes, and the synthesis of steroid hormones. There are both exogenous and endogenous sources of cholesterol. The average American consumes about 450 mg of cholesterol each day and produces an additional 500 to 1,000 mg in the liver and other tissues. Another source is the 500 to 1,000 mg of biliary cholesterol that is secreted into the intestine daily; about 50 percent is reabsorbed (enterohepatic circulation). Excess accumulation of cholesterol in the arterial walls can result in atherosclerosis, which is characterized by plaque formation. The plaques inhibit blood flow, promote clot formation and can ultimately cause heart attacks, stroke and claudication. Development of therapeutic agents for the treatment of atherosclerosis and other diseases associated with cholesterol metabolism has been focused on achieving a more complete understanding of the biochemical pathways involved. Most recently, liver X receptors (LXRs) were identified as key components in cholesterol homeostasis.

The LXRs were first identified as orphan members of the nuclear receptor superfamily whose ligands and functions were unknown. Two LXR proteins (.alpha. and .beta.) are known to exist in mammals. The expression of LXR.alpha. is restricted, with the highest levels being found in the liver, and lower levels found in kidney, intestine, spleen, and adrenals (see Willy, et al., Genes Dev. 9(9):1033 45 (1995)). LXR.beta. is rather ubiquitous, being found in nearly all tissues examined. Recent studies on the LXRs indicate that they are activated by certain naturally occurring, oxidized derivatives of cholesterol, including 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol and 24,25(S)-epoxycholesterol (see Lehmann, et al., J. Biol. Chem. 272(6):3137 3140 (1997)). The expression pattern of LXRs and their oxysterol ligands provided the first hint that these receptors may play a role in cholesterol metabolism (see Janowski, et al., Nature 383:728 731 (1996)).

As noted above, cholesterol metabolism in mammals occurs via conversion into steroid hormones or bile acids. The role of LXRs in cholesterol homeostasis was first postulated to involve the pathway of bile acid synthesis, in which cholesterol 7.alpha.-hydroxylase (CYP7A) operates in a rate-limiting manner. Support for this proposal was provided when additional experiments found that the CYP7A promoter contained a functional LXR response element that could be activated by RXR/LXR heterodimers in an oxysterol- and retinoid-dependent manner. Confirmation of LXR function as a transcriptional control point in cholesterol metabolism was made using knockout mice, particularly those lacking the oxysterol receptor LXR.alpha. (see Peet, et al., Cell 93:693 704 (1998)).

Mice lacking the receptor LXR.alpha. (e.g., knockout or (-/-) mice) lost their ability to respond normally to increases in dietary cholesterol and were unable to tolerate any cholesterol in excess of that synthesized de novo. LXR.alpha. (-/-) mice did not induce transcription of the gene encoding CYP7A when fed diets containing additional cholesterol. This resulted in an accumulation of large amounts of cholesterol and impaired hepatic function in the livers of LXR.alpha. (-/-) mice. These results further established the role of LXR.alpha. as the essential regulatory component of cholesterol homeostasis. LXR.alpha. is also believed to be involved in fatty acid synthesis. Accordingly, regulation of LXR.alpha. (e.g., use of LXR.alpha. agonist or antagonists) could provide treatment for a variety of lipid disorders including obesity and diabetes.

In view of the importance of LXRs, and particularly LXR.alpha.s to the delicate balance of cholesterol metabolism and fatty acid biosynthesis, we describe modulators of LXRs which are useful as therapeutic agents or diagnostic agents for the treatment of disorders associated with bile acid and cholesterol metabolism, including cholesterol gallstones, atherosclerosis, lipid storage diseases, obesity, and diabetes. The agents described herein are also useful for disease states associated with serum hypercholesterolemia, such as coronary heart disease.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds having the formula:

##STR00001## wherein R.sup.1 is selected from:

##STR00002## wherein R.sup.11 is selected from halogen, nitro, cyano, R.sup.12, OR.sup.12, SR.sup.12, NHR.sup.12, N(R.sup.12).sub.2, (C.sub.4 C.sub.8)cycloalkyl, (C.sub.5 C.sub.8)cycloalkenyl, COR.sup.12, CO.sub.2R.sup.12, CONHR.sup.12, CON(R.sup.12).sub.2, aryl, aryl(C.sub.1 C.sub.4)alkyl, heteroaryl and heteroaryl(C.sub.1 C.sub.4)alkyl; wherein each R.sup.12 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl or two R.sup.12 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring and any alkyl portions of R.sup.11 are optionally substituted with from one to three substituents independently selected from halogen, OR.sup.13, NHSO.sub.2R.sup.14 and NHC(O)R.sup.13, and any aryl or heteroaryl portions of R.sup.11 are optionally substituted with from one to five substituents independently selected from halogen, cyano, nitro, R.sup.14, OR.sup.13, SR.sup.13, N(R.sup.13).sub.2, NHSO.sub.2R.sup.14, NHC(O)R.sup.13, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.13 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl and each R.sup.14 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl. Optionally, R.sup.11 is combined with either X or Y to form a five- to six-membered monocyclic or fused bicyclic ring containing from 0 to 3 heteroatoms selected from N, O and S.

Each R.sup.18 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, halo(C.sub.1 C.sub.8)alkyl, aryl and heteroaryl.

In each of the R.sup.1 groups above, the component X represents H, NH.sub.2, NHR.sup.15, NHSO.sub.2R.sup.15, OH or OR.sup.15, wherein R.sup.15 is (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl or halo(C.sub.1 C.sub.8)alkyl; and the component Y is fluoro(C.sub.1 C.sub.4)alkyl.

Returning to formula I, R.sup.2 is selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.2 C.sub.8)heteroalkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.3 C.sub.8)cycloalkyl and (C.sub.4 C.sub.8)cycyloalkyl-alkyl, wherein any alkyl portions of R.sup.2 are optionally substituted with from one to three substituents independently selected from halogen, nitro, cyano, hydroxy, oxo and amino; and R.sup.3 is selected from aryl and heteroaryl, the aryl or heteroaryl group being optionally substituted with from one to five substituents independently selected from halogen, cyano, nitro, R.sup.16, OR.sup.16, SR.sup.16, COR.sup.16, CO.sub.2R.sup.16, NHR.sup.16, N(R.sup.16).sub.2, CONHR.sup.16, CON(R.sup.16).sub.2, NHSO.sub.2R.sup.16, NHC(O)R.sup.16, phenyl, phenyl(C.sub.1 C.sub.8)alkyl, and phenyl(C.sub.2 C.sub.8)heteroalkyl; wherein each R.sup.16 is independently selected from (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl and halo(C.sub.1 C.sub.8)alkyl, or two R.sup.16 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring. Optionally, R.sup.2 and R.sup.4 are combined to form a five- to six-membered fused ring containing from 1 to 3 heteroatoms selected from N, O and S.

The subscript n is an integer of from 0 to 3, indicating the presence or absence of substituents on the phenyl ring core of formula I. Each of the R.sup.4 substituents is independently selected from halogen, cyano, nitro, R.sup.17, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2R.sup.17, N(R.sup.17).sub.2 and CON(R.sup.17).sub.2, wherein each R.sup.17 is independently selected from H, (C.sub.1 C.sub.8)alkyl, (C.sub.3 C.sub.8)alkenyl, (C.sub.3 C.sub.8)alkynyl, (C.sub.2 C.sub.8)heteroalkyl or halo(C.sub.1 C.sub.8)alkyl, or two R.sup.17 groups attached to the same nitrogen atom are combined to form a five- to eight-membered ring.

In addition to the compounds provided in formula I, pharmaceutically acceptable salts thereof are also provided.

In yet another aspect, the present invention provides methods for modulating LXR in a cell by administering to or contacting the cell with a composition containing a compound of Formula I above.

In still another aspect, the present invention provides methods for treating LXR-responsive diseases by administering to a subject in need of such treatment a composition containing a compound of Formula I. These methods are particularly useful for the treatment of pathology such as obesity, diabetes, hypercholesterolemia, atherosclerosis, and hyperlipoproteinemia. In certain embodiments, the compound can be administered to the subject in combination with an additional anti-hypercholesterolemic agent, for example, bile acid sequestrants, nicotinic acid, fibric acid derivatives or HMG CoA reductase inhibitors.

The present compounds can exert their effects either systemically (the compounds permeate the relevant tissues, such as liver, upon entrance into the bloodstream) or locally (for example, by modulating LXR function of intestinal epithelial cells following oral administration, without necessitating the compounds' entrance into the bloodstream). In some disease states, some preferred compounds will be those with good systemic distribution, while, in other instances, preferred compounds will be those that can work locally on the intestinal track or on the skin without penetrating the bloodstream.

Certain compounds of the present invention are antiproliferative and can be used in compositions for treating diseases associated with abnormal cell proliferation (e.g., cancer). Other diseases associated with an abnormally high level of cellular proliferation include restenosis, where vascular smooth muscle cells are involved, inflammatory disease states, where endothelial cells, inflammatory cells and glomerular cells are involved, myocardial infarction, where heart muscle cells are involved, glomerular nephritis, where kidney cells are involved, transplant rejection, where endothelial cells are involved, infectious diseases such as HIV infection and malaria, where certain immune cells and/or other infected cells are involved, and the like. Infectious and parasitic agents per se (e.g. bacteria, trypanosomes, fungi, etc) are also subject to selective proliferative control using the subject compositions and compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

Not applicable.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (i.e. C.sub.1 C.sub.8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

The term "alkenyl", by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C.sub.2 C.sub.8 means two to eight carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and higher homologs and isomers thereof.

The term "alkynyl", by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e. C.sub.2 C.sub.8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.

The term "alkylene" by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include --CH.sub.2--CH.sub.2--O--CH.sub.3, --CH.sub.2--CH.sub.2--NH--CH.sub.3, --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3, --CH.sub.2--S--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2, --S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3, --CH.dbd.CH--O--CH.sub.3, --Si(CH.sub.3).sub.3, --CH.sub.2--CH.dbd.N--OCH.sub.3, and --CH.dbd.CH--N(CH.sub.3)--CH.sub.3. Up to two heteroatoms may be consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3 and --CH.sub.2--O--Si(CH.sub.3).sub.3.

Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by --CH.sub.2--CH.sub.2--S--CH.sub.2CH.sub.2-- and --CH.sub.2--S--CH.sub.2--CH.sub.2--NH--CH.sub.2--. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Accordingly, a cycloalkyl group has the number of carbon atoms designated (i.e., C.sub.3 C.sub.8 means three to eight carbons) and may also have one or two double bonds. A heterocycloalkyl group consists of the number of carbon atoms designated and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The terms "halo" and "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include alkyl substituted with halogen atoms, which can be the same or different, in a number ranging from one to (2m'+1), where m' is the total number of carbon atoms in the alkyl group. For example, the term "halo(C.sub.1 C.sub.4)alkyl" is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group). The term "perhaloalkyl" means, unless otherwise stated, alkyl substituted with (2m'+1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example the term "perhalo(C.sub.1 C.sub.4)alkyl" is meant to include trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl and the like.

The term "acyl" refers to those groups derived from an organic acid by removal of the hydroxy portion of the acid. Accordingly, acyl is meant to include, for example, acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the like.

The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl and 1,2,3,4-tetrahydronaphthalene.

The term "heteroaryl" refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.

For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") is meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be a variety of groups selected from: --OR', .dbd.O, .dbd.NR', .dbd.N--OR', --NR'R'', --SR', halogen, --SiR'R''R''', --OC(O)R', --C(O)R', --CO.sub.2R', --CONR'R'', --OC(O)NR'R'', --NR''C(O)R', --NR'--C(O)NR''R''', --NR'--SO.sub.2NR''R''', --NR''CO.sub.2R', --NH--C(NH.sub.2).dbd.NH, --NR'C(NH.sub.2).dbd.NH, --NH--C(NH.sub.2).dbd.NR', --S(O)R', --SO.sub.2R', --SO.sub.2NR'R'', --NR''SO.sub.2R, --CN and --NO.sub.2, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred. R', R'' and R''' each independently refer to hydrogen, unsubstituted (C.sub.1 C.sub.8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C.sub.1 C.sub.4)alkyl groups. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, --NR'R'' is meant to include 1-pyrrolidinyl and 4-morpholinyl. Typically, an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl


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