Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-12-23
2004-12-07
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S434000
Reexamination Certificate
active
06828446
ABSTRACT:
BACKGROUND
Liver X-receptors (LXRs) are nuclear receptors that regulate the metabolism of several important lipids, including cholesterol and bile acids. Most of the cholesterol in plasma is transported on three major lipoprotein classes; VLDL cholesterol (VLDL-C), LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). Total cholesterol is the sum of all three lipoproteins. Both VLDL-C and LDL-C are associated with atherogenic processes while HDL-C is believed to facilitate cholesterol removal from tissues (e.g. atherosclerotic plaques) and thus have a protective effect on coronary heart disease.
LXR represents a novel intervention point to regulate the reverse cholesterol transport (RCT) pathway, i.e., the removal of cholesterol from peripheral tissues/cells and subsequent uptake via the liver for disposal. Removal of cellular cholesterol requires active transport of free cholesterol across the plasma membrane and onto HDL particles. This transfer of cholesterol from inside the cell and onto HDL in the plasma is mediated by ATP binding cassette 1 (ABCA1) transporter protein. The observation that LXR is a key transcriptional activator of ABCA1 in the macrophage, suggests that induction of LXR will lead to an increase in cholesterol efflux from the macrophage. In addition, it is known that LXR regulates the induction of other genes involved in RCT such as apoE and cholesterol ester transport protein (CETP), suggesting that activating the LXR pathway should also lead to increased uptake of cholesterol by the liver. Thus, activation of LXR by a small molecule ligand will lead to an up-regulation of ABCA1 and induction of the reverse cholesterol transport pathway thereby increasing cholesterol efflux to HDL-C and reducing the cholesterol content of atherosclerotic plaques.
SUMMARY OF THE INVENTION
In general, the present invention is directed to selective LXR modulators, small molecule compounds corresponding to Formula I and the isomers, tautomers, salts and prodrugs thereof:
wherein:
the X ring and the M ring are independently aromatic rings;
M
1
, M
2
, M
3
, M
4
, and M
5
are independently a bond, carbon, nitrogen, oxygen or sulfur, provided, however, no more than one of M
1
, M
2
, M
3
, M
4
, and M
5
is a bond;
M
11
, M
22
, M
33
, M
44
, and M
55
are independently an electron pair, hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, hydrocarbyloxy, substituted hydrocarbyloxy, mercapto, halo, heterocyclo, cyano, nitro, amino, acylamino, acylthio, or acyloxy, or any adjacent two of M
11
, M
22
, M
33
, M
44
, and M
55
form a fused ring with the atoms of the M ring to which they are bonded; provided, however, M
11
, M
22
, M
33
, M
44
, and M
55
is not present when M
1
, M
2
, M
3
, M
4
, or M
5
, respectively, is a bond;
p and q are independently 0, 1, or 2;
X
1
, X
2
, X
3
, and X
4
are independently a bond, carbon, nitrogen, oxygen or sulfur, provided, however, no more than one of X
1
, X
2
, X
3
, and X
4
is a bond;
X
11
, X
22
, X
33
, and X
44
, are independently an electron pair, hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, hydrocarbyloxy, substituted hydrocarbyloxy, mercapto, halo, heterocyclo, cyano, nitro, amino, acylamino, acylthio, acyloxy, or acyl; provided, however, X
11
, X
22
, X
33
, or X
44
is not present when X
1
, X
2
, X
3
or X
4
, respectively, is a bond;
X
50
is carbon, sulfur or sulfoxide,
X
51
is oxygen, sulfur, or NX
52
,
X
52
is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
X
53
is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or amino.
The present invention is further directed to a process for the treatment or prevention of a condition in a mammal which is modulated by LXR. The process comprises administering to a mammal in need thereof a therapeutically effective dose of a compound of Formula I or an isomer, tautomer, salt or prodrug thereof.
Other aspects of the invention will be in part apparent and in part pointed out hereinafter.
REFERENCES:
patent: 3378586 (1968-04-01), Krapcho
patent: 3755605 (1973-08-01), Moore
patent: 5011851 (1991-04-01), Meanwell
patent: 5639616 (1997-06-01), Liao et al.
patent: 5690904 (1997-11-01), MacWhorter et al.
patent: 6316503 (2001-11-01), Li et al.
patent: RE37770 (2002-06-01), Elias et al.
patent: 2001/0020030 (2001-09-01), Stewart et al.
patent: 2002/0013334 (2002-01-01), Robl et al.
patent: 2002/0048572 (2002-04-01), Shan et al.
patent: 2002/0165394 (2002-11-01), Dumas et al.
patent: 0 135 894 (1985-04-01), None
patent: 0453658 (1991-10-01), None
patent: 0 558 062 (1993-09-01), None
patent: WO 91/00277 (1991-01-01), None
patent: WO 91/00281 (1991-01-01), None
patent: WO 96/19493 (1996-06-01), None
patent: WO 96/34851 (1996-11-01), None
patent: WO 2000044715 (2000-08-01), None
patent: WO 00/54759 (2000-09-01), None
patent: WO 00/55118 (2000-09-01), None
patent: WO 00/56710 (2000-09-01), None
patent: WO 01/60818 (2001-08-01), None
patent: WO 02/20463 (2002-03-01), None
patent: WO 02/24632 (2002-03-01), None
patent: WO 02/46141 (2002-06-01), None
patent: WO 02/46172 (2002-06-01), None
patent: WO 02/46181 (2002-06-01), None
Yale et al, Journal of Medicinal Chemistry, vol. 13, No. 4, pp. 713-722, Dec. 1969.*
Ames et al, Journal of Chemical Society, Perkin Transactions 1, vol. 6, pp. 539-543, 1978.*
American Chemical Society, Database accession No. 2002:740157 Chemcats, CAS Registry No. 257861-66-8, XP002266175.
American Chemical Society, Database accession No. 2002:740158 Chemcats, CAS Registry No. 257861-68-0, XP002266174.
American Chemical Society, Database accession No. 1973:478762 Caplus, CAS Registry No. 43092-87-1 Caplus, XP002266127.
American Chemical Society, Database accession No. 1957:98876 Caplus, CAS Registry No. 102002-73-3 Caplus, XP002266129.
Catsoulacos, P., “Synthesis of Substituted Dihydrodibenzothiazepines and Related Compounds”, Laboratory of Pharmaceutical Chemistry, 1970, 409-411, XP-002268164.
American Chemical Society, Database accession No. 1998:610157 Chemcats, CAS Registry No. 271775-52-1, XP002266301.
American Chemical Society, Database accession No. 1998:610156 Chemcats, CAS Registry No.0271775-51-0, XP002266302.
Catsoulacos, P., “Synthesis of Subsitituted Dihydrodibenzothiazepines and Related Compounds”, Laboratory of Pharmaceutical Chemistry, 1970, 409-411, XP-002268164.
Chemical Abstracts, vol. 79, No. 13, abstract No.: 78762, XP002266125.
Chemical Abstracts, vol. 93, No. 7, abstract No. 71730, XP002266126.
Chemical Abstracts Serivce Registry Handbook, 2000 Supplement, CAS Registry No. 256285-97-9 through 260528-41-4, XP002266173.
Chemical Abstracts Service Registry Handbook, 2000 Supplement, CAS REgistry No. 271534-00-0 through 276887-31-1, XP002266300.
Connor, et al., “Influence of Substrate Structure on Copper(1)-assisted Cyanide Substitution in Aryl Halides”, 1990, J Chem Soc Perkin Trans 1: 1127-32, XP001021533.
International Search Report for PCT US 02/41083, dated Feb. 9, 2004.
Mounetou et al., “Synthesis of N-[2-(2-Methylpropoxy)Ethyl]-N-(2-[(4-Methoxy)Phenylmethylthio]phenyl)-1-Pyrrolidineethanamine (E)-2-Butenedioate (1:1) Salt (Cerm 12816): A Potential Anti-Aginal Drug”, Journal of Labelled Compounds and Radiopharmaceuticals, 1998, 41(3): 181-189, , p. 184 scheme 2, compound 6, XP002266165.
Nandi, et al., “An Unusual Cleavage of a C-S Bond with Concurent S-Arylation Under Palladium-Copper Catalysis”, Tetrahedron Letters, 2000, 7259-7262.
Okamoto et al., “A Cholesteryl Ester Transfer Protein Inhibitor Attenuates Atherosclerosis in Rabbits”, Nature, 2000, 406: 203-207 XP02266120.
Prasad et al., “Chemistry and Synthesis of Some Dihydro-2H-1,4-Benzothiazine Derivatives”, Canadian Journal of Chemistry, 1966, 44:1247-1258, XP001027730.
Protiva, et al., Antihistamin-Substanzen XLV.* Homophenothiazin-Analogon Des Chlorpromazins Und Einige Verwandte Verbindungen, Forshungsinstitut für Pharmazie und Biochemie, Praha, 1958, 207-211, EP-002268156.
Specklin et al., Bull Soc Chim Fr, 1951, 621-626, p. 624 table V, XP000616273.
Chandrakumar Nizal S.
Cox Phillip B.
Dalton Christopher R.
Malecha James W.
Tollefson Michael B.
Davis Zinna Northington
Pharmacia Corporation
Senniger Powers
LandOfFree
Aromatic thioether liver X-receptor modulators does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aromatic thioether liver X-receptor modulators, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aromatic thioether liver X-receptor modulators will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3304853