Compounds and methods for modulation of estrogen receptors Number:7,435,729 from the United States Patent and Trademark Office (PTO) owispatent Compounds that modulate the estrogen receptor (ER) are disclosed, as well as pharmaceutical compositions containing the same. In a specific embodiment, the compounds are selective modulators for ER-.beta. over ER-.alpha.. Methods are disclosed for modulating ER-.beta. in cell and/or tissues expressing the same, including cells and/or tissue that preferentially express ER-.beta.. More generally, methods for treating estrogen-related conditions are also disclosed, including conditions such as is breast cancer, testicular cancer, osteoporosis, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, prostatic carcinomas, obesity, hot flashes, skin effects, mood swings, memory loss, urinary incontinence, hairloss, cataracts, natural hormonal imbalances, and adverse reproductive effects associated with exposure to environmental chemicals.<H modulation, receptors, Compounds, and, m, 7435729.html, Patent, pto, 7435729

Title: Compounds and methods for modulation of estrogen receptors

Abstract: Compounds that modulate the estrogen receptor (ER) are disclosed, as well as pharmaceutical compositions containing the same. In a specific embodiment, the compounds are selective modulators for ER-.beta. over ER-.alpha.. Methods are disclosed for modulating ER-.beta. in cell and/or tissues expressing the same, including cells and/or tissue that preferentially express ER-.beta.. More generally, methods for treating estrogen-related conditions are also disclosed, including conditions such as is breast cancer, testicular cancer, osteoporosis, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, prostatic carcinomas, obesity, hot flashes, skin effects, mood swings, memory loss, urinary incontinence, hairloss, cataracts, natural hormonal imbalances, and adverse reproductive effects associated with exposure to environmental chemicals.

Patent Number: 7,435,729 Issued on 10/14/2008 to Gayo-Fung, et al.

Inventors: Gayo-Fung; Leah Marie (San Diego, CA), Stein; Bernd M. (San Diego, CA)
Assignee: Signal Pharmaceuticals, LLC (San Diego, CA)

Appl. No.: 10/731,666

Filed: December 8, 2003

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
10085999	Feb., 2002	6686351
09527750	Aug., 2002	6436923
60240909	Mar., 1999

Current U.S. Class: 514/217.01 ; 514/269; 514/277; 514/307; 514/339; 514/345; 514/357; 514/415

Current International Class: A01N 43/00 (20060101); A01N 43/40 (20060101); A01N 43/42 (20060101); A61K 31/505 (20060101)

Field of Search: 546/144,140 540/593,597

References Cited [Referenced By]

U.S. Patent Documents


3234090	February 1966	Huebner et al.
3274123	September 1966	Lednicer
3277106	October 1966	Bencze
5552412	September 1996	Cameron et al.
6291456	September 2001	Stein et al.

Foreign Patent Documents


842 661	May., 1998	EP
1 113 007	Apr., 2001	EP
1143833	Nov., 1987	JP
WO 92/18498	Oct., 1992	WO
WO 96/21656	Jul., 1996	WO
WO 00/39120	Jul., 2000	WO
WO 00/55137	Sep., 2000	WO

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Primary Examiner: Hartley; Michael G.
Assistant Examiner: Gembeh; Shirley V
Attorney, Agent or Firm: Jones Day

Parent Case Text

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of U.S. application Ser. No. 10/085,999, filed Feb. 27, 2002 now U.S. Pat. No. 6,686,351, allowed, which is a division of U.S. application Ser. No. 09/527,750, filed Mar. 17, 2000, now U.S. Pat. No. 6,436,923, issued Aug. 20, 2002, which claims the benefit of U.S. Provisional Application No. 60/240,909, filed Mar. 17, 1999, the disclosure of each of which is incorporated by reference herein in its entirety.

Claims

The invention claimed is:

1. A method for modulating ER-.beta. in a breast cancer cell or bone cancer cell expressing ER-.beta., comprising contacting the cell with an effective amount of a compound having the structure: ##STR00243## or a pharmaceutically acceptable salt thereof; wherein a is 0, 1 or 2; A, B and C are independently CH, CR or N; D is --(CH.sub.2).sub.r-- or --(CH.sub.2).sub.nC(.dbd.O)(CH.sub.2).sub.m--; R.sub.1 represents one or two substituents independently selected from --X--Y; R.sub.2 is C.sub.1-8 alky, C.sub.6-12aryl, C.sub.7-12aralkyl, --C(.dbd.O)R.sub.5, a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from O, NR.sub.c and S(O).sub.q, or a bicyclic ring system contain a five- or six-membered heterocycle fused to phenyl, wherein each of the above groups are optionally substituted with one to three substituents independently selected from --X--Y or R.sub.4; and R.sub.3 is hydrogen, --R.sub.6, --(CH.sub.2).sub.sC(.dbd.O)R.sub.6, --(CH.sub.2).sub.sC(.dbd.O)OR.sub.6, --(CH.sub.2).sub.sC(.dbd.O)NR.sub.6R.sub.7, --(CH.sub.2).sub.sC(.dbd.O)NR.sub.6(CH.sub.2).sub.nC(.dbd.O)R.sub.7R.sub.- 8, --(CH.sub.2).sub.sNR.sub.6C(.dbd.O)R.sub.7, --(CH.sub.2)NR.sub.6C(.dbd.O)NR.sub.7R.sub.8, --(CH.sub.2).sub.sNR.sub.6R.sub.7, --(CH.sub.2).sub.sOR.sub.6, --(CH.sub.2).sub.sSO.sub.qR.sub.6 or --(CH.sub.2).sub.sSO.sub.2NR.sub.6R.sub.7, and wherein R.sub.4 is at each occurrence independently halogen, hydroxy, carboxy, C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, acyloxy, C.sub.1-4thio, C.sub.1-4alkylsulfinyl, C.sub.1-4alkylsulfonyl, (hydroxy)C.sub.1-4alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, --C(.dbd.O)OH, --C(.dbd.O)OR, --OC(.dbd.O)R, --C(.dbd.O)NHR, --C(.dbd.O)NRR, --C(.dbd.O)NHOR, --SO.sub.2NHR, --NHSO.sub.2R, --CN, --NO.sub.2, C.sub.1-4alkylamino, C.sub.1-4dialkylamino, --NHC(.dbd.O)R, NHC(.dbd.O)(CH.sub.2).sub.s(five- or six-membered heterocycle), a five- or six-membered heterocycle, or a five-or six-membered heterocycle fused to phenyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are at each occurrence independently hydrogen, C.sub.1-8alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, or a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from 0, NR.sub.c and S(O).sub.q, wherein each of the above groups are optionally substituted with one to three substituents independently selected from R.sub.4; X is at each occurrence independently a direct bond; --(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --O(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --S(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --NR.sub.c(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --O(CH.sub.2).sub.nCR.sub.aR.sub.b--; --NR.sub.c(CH.sub.2).sub.nCR.sub.aR.sub.b--; --OCHR.sub.cCHR.sub.d--; or --SCHR.sub.cCHR.sub.d--; Y is at each occurrence independently halogen; --R.sub.e; --NR.sub.eR.sub.f; ##STR00244## optionally fused on adjacent carbon atoms with one or two phenyl or cycloalkyl rings, and with each carbon optionally and independently substituted with carbonyl or with one or two substituents independently selected from R.sub.4, with any two R.sub.4 substituents on a single carbon atom optionally being taken together to form a five- or six-membered heterocycle, and with each nitrogen atom optionally and independently substituted with R.sub.4, wherein W is --NR.sub.e--, --O--, --S-- or --CR.sub.eR.sub.f--; or a bridged or fused C.sub.5-12bicyclic amine optionally substituted with one to three substituents independently selected from R.sub.4; or where --X--Y is ##STR00245## Z is CH.sub.2, CH.dbd.CH, C.ident.C, O, NR.sub.c, S(O).sub.q, C(.dbd.O), C(OH)R.sub.c, C(.dbd.O)NR.sub.c, NR.sub.cC(.dbd.O), C(.dbd.O)NR.sub.c, NR.sub.cC(.dbd.O) or ##STR00246## G is O, S or NR.sub.e; n and m are at each occurrence independently 0, 1, 2 or 3; p is at each occurrence independently 1, 2 or 3; q is at each occurrence independently 0, 1 or 2; r is at each occurrence independently 1, 2, 3, 4 or 5; s is at each occurrence independently 0, 1, 2, 3 or 4; R is at each occurrence independently C.sub.1-6alkyl; R.sub.a and R.sub.b are at each occurrence independently C.sub.1-8alkyl or taken together form a C.sub.3-8cyclic alkyl; R.sub.c and R.sub.d are at each occurrence independently hydrogen or C.sub.1-4alkyl; and R.sub.e and R.sub.f are at each occurrence independently hydrogen, C.sub.6-12aryl, C.sub.1-8alkyl, C.sub.7-12aralkyl, a five- or six-membered heterocycle, or a five- or six membered heterocycle fused to phenyl; or wherein R.sub.e or R.sub.f form a 3-8 membered nitrogen-containing heterocyclic alkyl with R.sub.a or R.sub.b; and wherein each R.sub.e and R.sub.f are optionally substituted with up to three substituents independently selected from R.sub.4.

2. The method of claim 1 wherein the cell preferentially expresses ER-.beta. over ER-.alpha..

3. The method of claim 2 wherein the cell is a breast cancer cell.

4. A method for modulating ER-.beta. in breast cancer tissue or bone cancer tissue expressing ER-.beta., comprising contacting the tissue with an effective amount of a compound having the structure: ##STR00247## or a pharmaceutically acceptable salt thereof; wherein a is 0, 1 or 2; A, B and C are independently CH, CR or N; D is --(CH.sub.2).sub.r-- or --(CH.sub.2).sub.nC(.dbd.O)(CH.sub.2).sub.m--; R.sub.1 represents one or two substituents independently selected from --X--Y; R.sub.2 is C.sub.1-8 alkyl C.sub.6-12aryl, C.sub.7-12aralkyl, --C(.dbd.O)R.sub.5, a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from O, NR.sub.c and S(O).sub.q, or a bicyclic ring system contain a five- or six-membered heterocycle fused to phenyl, wherein each of the above groups are optionally substituted with one to three substituents independently selected from --X--Y or R.sub.4; and R.sub.3 is hydrogen, --R.sub.6, --(CH.sub.2).sub.sC(.dbd.O)R.sub.6, --(CH.sub.2).sub.sC(.dbd.O)OR.sub.6, --(CH.sub.2).sub.sC(.dbd.O)NR.sub.6R.sub.7, --(CH.sub.2).sub.sC(.dbd.O)NR.sub.6(CH.sub.2).sub.nC(.dbd.O)R.sub.7R.sub.- 8, --(CH.sub.2).sub.sNR.sub.6C(.dbd.O)R.sub.7, --(CH.sub.2).sub.sNR.sub.6C(.dbd.O)NR.sub.7R.sub.8, --(CH.sub.2).sub.sNR.sub.6R.sub.7, --(CH.sub.2).sub.sOR.sub.6, --(CH.sub.2).sub.sSO.sub.qR.sub.6 or --(CH.sub.2).sub.sSO.sub.2NR.sub.6R.sub.7; and wherein R.sub.4 is at each occurrence independently halogen, hydroxy, carboxy C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, acyloxy, C.sub.1-4thio, C.sub.1-4alkylsulfinyl, C.sub.1-4alkylsufonyl, (hydroxy)C.sub.1-4alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, --C(.dbd.O)OH, --C(.dbd.O)OR, --OC(.dbd.O)R, --C(.dbd.O)NHR, --C(.dbd.O)NRR, --C(.dbd.O)NHOR, --SO.sub.2NHR, --NHSO.sub.2R, --CN, --NO.sub.2, C.sub.1-4alkylamino C.sub.1-4dialkylamino, --NHC(.dbd.O)R, NHC(.dbd.O)(CH.sub.2).sub.s(five- or six-membered heterocycle), a five- or six-membered heterocycle, or a five-or six-membered heterocycle fused to phenyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are at each occurrence independently hydrogen, C.sub.1-8alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, or a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from 0, NR.sub.c and S(O).sub.q, wherein each of the above groups are optionally substituted with one to three substituents independently selected from R.sub.4; X is at each occurrence independently a direct bond; --(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --O(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --S(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --NR.sub.c(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --O(CH.sub.2).sub.nCR.sub.aR.sub.b--; --NR.sub.c(CH.sub.2).sub.nCR.sub.aR.sub.b--; --OCHR.sub.cCHR.sub.d--; or --SCHR.sub.cCHR.sub.d--; Y is at each occurrence independently halogen; --R.sub.e; --NR.sub.eR.sub.f; ##STR00248## optionally fused on adjacent carbon atoms with one or two phenyl or cycloalkyl rings, and with each carbon optionally and independently substituted with carbonyl or with one or two substituents independently selected from R.sub.4, with any two R.sub.4 substituents on a single carbon atom optionally being taken together to form a five- or six-membered heterocycle, and with each nitrogen atom optionally and independently substituted with R.sub.4, wherein W is --NR.sub.e--, --O--, --S-- or --CR.sub.eR.sub.f--; or a bridged or fused C.sub.5-12bicyclic amine optionally substituted with one to three substituents independently selected from R.sub.4; or where --X--Y is ##STR00249## Z is CH.sub.2, CH.dbd.CH, C.ident.C, O, NR.sub.c, S(O).sub.q, C(.dbd.O), C(OH)R.sub.c, C(.dbd.O)NR.sub.c, NR.sub.cC(.dbd.O), C(.dbd.O)NR.sub.c, NR.sub.cC(.dbd.O) or ##STR00250## G is O, S or NR.sub.e; n and m are at each occurrence independently 0, 1, 2 or 3; p is at each occurrence independently 1, 2 or 3; q is at each occurrence independently 0, 1 or 2; r is at each occurrence independently 1, 2, 3, 4 or 5; s is at each occurrence independently 0, 1, 2, 3 or 4; R is at each occurrence independently C.sub.1-6alkyl; R.sub.a and R.sub.b are at each occurrence independently C.sub.1-8alkyl or taken together form a C.sub.3-8cyclic alkyl; R.sub.c and R.sub.d are at each occurrence independently hydrogen or C.sub.1-4alkyl; and R.sub.e and R.sub.f are at each occurrence independently hydrogen, C.sub.6-12aryl C.sub.1-8alkyl, C.sub.7-12aralkyl, a five- or six-membered heterocycle, or a five- or six membered heterocycle fused to phenyl; or wherein R.sub.e or R.sub.f form a 3-8 membered nitrogen-containing heterocyclic alkyl with R.sub.a or R.sub.b; and wherein each R.sub.e and R.sub.f are optionally substituted with up to three substituents independently selected from R.sub.4.

5. The method of claim 4 wherein the tissue preferentially expresses ER-.beta. over ER-.alpha..

6. The method of claim 5 wherein the tissue is of bone.

7. A method for treating an estrogen-related condition comprising administering to a patient in need thereof an effective amount of a compound having the structure: ##STR00251## or a pharmaceutically acceptable salt thereof; wherein a is 0, 1 or 2; A, B and C are independently CH, CR or N; D is --(CH.sub.2).sub.r-- or --(CH.sub.2).sub.nC(.dbd.O)(CH.sub.2).sub.m--; R.sub.1 represents one or two substituents independently selected from --X--Y; R.sub.2 is C.sub.1-8alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, --C(.dbd.O)R.sub.5, a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from O, NR.sub.c and S(O) .sub.q, or a bicyclic ring system contain a five- or six-membered heterocycle fused to phenyl, wherein each of the above groups are optionally substituted with one to three substituents independently selected from --X--Y or R.sub.4; and R.sub.3 is hydrogen, --R.sub.6, --(CH.sub.2).sub.sC(.dbd.O)R.sub.6, --(CH.sub.2).sub.sC(.dbd.O)OR.sub.6, --(CH.sub.2).sub.sC(.dbd.O)NR.sub.6R.sub.7, --(CH.sub.2).sub.sC(.dbd.O)NR.sub.6(CH.sub.2).sub.nC(.dbd.O)R.sub.7R.sub.- 8, --(CH.sub.2).sub.sNR.sub.6C(.dbd.O)R.sub.7, --(CH.sub.2).sub.sNR.sub.6C(.dbd.O)NR.sub.7R.sub.8, --(CH.sub.2).sub.sNR.sub.6R.sub.7, --(CH.sub.2).sub.sOR.sub.6, --(CH.sub.2).sub.sSO.sub.qR.sub.6 or --(CH.sub.2).sub.sSO.sub.2NR.sub.6R.sub.7; and wherein R.sub.4 is at each occurrence independently halogen, hydroxy, carboxy, C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, acyloxy, C.sub.1-4thio, C.sub.1-4alkylsulfinyl, C.sub.1-4alkylsulfonyl, (hydroxyl)C.sub.1-4alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, --C(.dbd.O)OH, --C(.dbd.O)OR, --OC(.dbd.O)R, --C(.dbd.O)NHR, --C(.dbd.O)NRR, --C(.dbd.O)NHOR, --SO.sub.2NHR, --NHSO.sub.2R, --CN, --NO.sub.2, C.sub.1-4alkylamino, C.sub.1-4dialkylamino, --NHC(.dbd.O)R, NHC(.dbd.O)(CH.sub.2).sub.s(five- or six-membered heterocycle), a five- or six-membered heterocycle, or a five- or six-membered heterocycle fused to phenyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are at each occurrence independently hydrogen, C.sub.1-8alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, or a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from 0, NR.sub.c and S(O).sub.q, wherein each of the above groups are optionally substituted with one to three substituents independently selected from R.sub.4; X is at each occurrence independently a direct bond; --(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --O(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --S(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --NR.sub.c(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --O(CH.sub.2).sub.nCR.sub.aR.sub.b--; --NR.sub.c(CH.sub.2).sub.nCR.sub.aR.sub.b--; --OCHR.sub.cCHR.sub.d--; or --SCHR.sub.cCHR.sub.d--; Y is at each occurrence independently halogen; --R.sub.e; --NR.sub.eR.sub.f; ##STR00252## optionally fused on adjacent carbon atoms with one or two phenyl or cycloalkyl rings, and with each carbon optionally and independently substituted with carbonyl or with one or two substituents independently selected from R.sub.4, with any two R.sub.4 substituents on a single carbon atom optionally being taken together to form a five- or six-membered heterocycle, and with each nitrogen atom optionally and independently substituted with R.sub.4, wherein W is --NR.sub.e--, --O--, --S-- or --CR.sub.eR.sub.f--; or a bridged or fused C.sub.5-12bicyclic amine optionally substituted with one to three substituents independently selected from R.sub.4; or where --X--Y is ##STR00253## Z is CH.sub.2, CH.dbd.CH, C.ident.C, O, NR.sub.c, S(O).sub.q, C(.dbd.O), C(OH)R.sub.c, C(.dbd.O)NR.sub.c, NR.sub.cC(.dbd.O), C(.dbd.O)NR.sub.c, NR.sub.cC(.dbd.O) or ##STR00254## G is O, S or NR.sub.e; n and m are at each occurrence independently 0, 1, 2 or 3; p is at each occurrence independently 1, 2 or 3; q is at each occurrence independently 0, 1 or 2; r is at each occurrence independently 1, 2, 3, 4 or 5; s is at each occurrence independently 0, 1, 2, 3 or 4; R is at each occurrence independently C.sub.1-6alkyl; R.sub.a and R.sub.b are at each occurrence independently C.sub.1-8alkyl or taken together form a C.sub.3-8cyclic alkyl; R.sub.c and R.sub.d are at each occurrence independently hydrogen or C.sub.1-4alkyl; and R.sub.e and R.sub.f are at each occurrence independently hydrogen, C.sub.6-12aryl, C.sub.1-8alkyl, C.sub.7-12aralkyl, a five- or six-membered heterocycle, or a five- or six membered heterocycle fused to phenyl; or wherein R.sub.e or R.sub.f form a 3-8 membered nitrogen-containing heterocyclic alkyl with R.sub.a or R.sub.b; and wherein each R.sub.e and R.sub.f are optionally substituted with up to three substituents independently selected from R.sub.4, wherein the estrogen-related condition is breast cancer or bone cancer.

Description

TECHNICAL FIELD

This invention is generally directed to estrogen antagonists and agonists, including pharmaceutical compositions and uses thereof, and more specifically to compounds which selectively modulate estrogen receptor-beta (ER-.beta.) activity.

BACKGROUND OF THE INVENTION

The estrogen hormone has a broad spectrum of effects on tissues in both females and males. Many of these biological effects are positive, including maintenance of bone density, cardiovascular protection, central nervous system (CNS) function, and the protection of organ systems from the effects of aging. However, in addition to its positive effects, estrogen also is a potent growth factor in breast and endometrium that increases the risk of cancer.

Until recently, it has been assumed that estrogen binds to a single estrogen receptor (ER) in cells, causing conformational changes that result in release from heat shock proteins and binding of the receptor as a dimer to the so-called estrogen response element in the promoter region of a variety of genes. Further, pharmacologists have generally believed that non-steroidal small molecule ligands compete for binding of estrogen to ER, acting as either antagonists or agonists in each tissue where the estrogen receptor is expressed. Thus, such ligands have traditionally been classified as either pure antagonists or agonists. This is no longer believed to be correct.

Progress over the last few years has shown that ER associates with co-activators (e.g., SRC-1, CBP and SRA) and co-repressors (e.g., SMRT and N--CoR) that modulate the transcriptional activity of ER in a tissue-specific and ligand-specific manner. In addition, evidence now suggests that the majority of estrogen-regulated genes do not have a classical estrogen response element. In such cases, ER interacts with the transcription factors critical for regulation of these genes. Transcription factors known to be modulated in their activity by ER include, for example, AP-1, NF-.kappa.B, C/EBP and Sp-1.

Given the complexity of ER signaling, as well as the various types of tissue that express ER and its co-factors, it is now believed that ER ligands can no longer simply be classified as either pure antagonists or agonists. Therefore, the tem "selective estrogen receptor modulator" (SERM) has been coined. SERMs bind to ER, but may act as an agonist or antagonist of estrogen in different tissues and on different genes. For example, two of the most well known drugs that behave as SERMs are Tamoxifen (Astra-Zeneca Pharmaceuticals) and Raloxifene (Eli Lilly & Co.). Studies with these two compounds, as well as other SERMs now in development, have demonstrated that the affinity of a SERM for its receptor in many cases does not correlate with its biological activity. Therefore, ligand-binding assays traditionally used in screening for novel ER modulators have not distinguished between tissue-selectivity and agonist/antagonist behavior.

In addition to Tamoxifen and Raloxifene, a number of other compounds have been disclosed to have estrogenic activity, such as those disclosed by Lednicer et al. (J. Med. Chem. 12, 881, 1969) and Bencze et al. (J. Med. Chem. 10, 138, 1967), as well as those disclosed in U.S. Pat. Nos. 3,234,090, 3,277,106, and 3,274,213. Further, estrogen agonists/antagonists of the following structure are disclosed in published PCT WO 96/21656 to Cameron et al.:

##STR00001##

More recently, a second estrogen receptor, ER-.beta., has been identified and cloned (Katzenellenbogen and Korach Endocrinology 138, 861-2 (1997); Kuiper et al., Proc. Natl. Acad. Sci. USA 93, 5925-5930, 1996; Mosselman et al., FEBS Lett. 392, 49-53, 1996). ER-.beta., and the classical ER renamed ER-.alpha., have significantly different amino acid sequences in the ligand binding domain and carboxy-terminal transactivation domains (.about.56% amino acid identity), and only 20% homology in their amino-terminal transactivation domain. This suggests that some ligands may have higher affinity to one receptor over the other. Further, ligand-dependent conformational changes of the two receptors, and interaction with co-factors, will result in very different biological actions of a single ligand. In other words, a ligand that acts as an agonist on ER-.alpha. may very well serve as an antagonist on ER-.beta.. An example of such behavior has been described by Paech et al. (Science 277, 1508-1510, 1997). In that paper, estrogen is reported to activate an AP-1 site in the presence of ER-.alpha., but to inhibit the same site in the presence of ER-.beta.. In contrast, Raloxifene (Eli Lilly & Co.) and Tamoxifen and ICI-182,780 (Zeneca Pharmaceuticals) stimulate the AP-1 site through ER-.beta., but inhibit this site in the presence of ER-.alpha.. Another example has been described by Sun et al. (Endocrinology 140, 800-4, 1999), wherein the R,R-enantiomer of a tetrahydrochrysene is reported to be an agonist on ER-.alpha., but a complete antagonist on ER-.beta., while the S,S-enantiomer is an agonist on both receptors.

Furthermore, ER-.alpha. and ER-.beta. have both overlapping and different tissue distributions, as analyzed predominantly by RT-PCR or in-situ hybridization due to a lack of good ER-.beta. antibodies. Some of these results, however, are controversial, which may be attributable to the method used for measuring ER, the species analyzed (rat, mouse, human) and/or the differentiation state of isolated primary cells. Very often tissues express both ER-.alpha. and ER-.beta., but the receptors are localized in different cell types. In addition, some tissues (such as kidney) contain exclusively ER-.alpha., while other tissues (such as uterus, pituitary and epidymis) show a great predominance of ER-.alpha. (Couse et al., Endocrinology 138, 4613-4621, 1997; Kuiper et al., Endocrinology 138, 863-870, 1997). In contrast, tissues expressing high levels of ER-.beta. include prostate, testis, ovaries and certain areas of the brain (Brandenberger et al., J. Clin. Endocrinol. Metab. 83, 1025-8, 1998; Enmark et al., J. Clinic. Endocrinol. Metabol. 82, 4258-4265, 1997; Laflamme et al., J. Neurobiol. 36, 357-78, 1998; Sar and Welsch, Endocrinology 140, 963-71, 1999; Shughrue et al., Endocrinology 138, 5649-52, 1997a; Shughrue et al., J. Comp. Neurol. 388, 507-25, 1997b); Chang and Prins, The Prostate 40, 115-124, 1999.

The development of ER-.alpha. (Korach, Science 266, 1524-1527, 1994) and ER-.beta. (Krege et al., Proc. Natl. Acad. Sci. USA 95, 15677-82, 1998) knockout mice further demonstrate that ER-.beta. has different functions in different tissues. For example, ER-.alpha. knockout mice (male and female) are infertile, females do not display sexual receptivity and males do not have typical male-aggressive behavior (Cooke et al., Biol. Reprod. 59, 470-5, 1998; Das et al., Proc. Natl. Acad. Sci. USA 94, 12786-12791, 1997; Korach, 1994; Ogawa et al., Proc. Natl. Acad. Sci. USA 94, 1476-81, 1997; Rissman et al., Endocrinology 138, 507-10, 1997a; Rissman et al., Horm. Behav. 31, 232-243, 1997b). Further, the brains of these animals still respond to estrogen in a pattern that is similar to that of wild type animals (Shughrue et al., Proc. Natl. Acad. Sci. USA 94, 11008-12, 1997c), and estrogen still inhibits vascular injury caused by mechanical damage (Iafrati et al., Nature Med. 3, 545-8, 1997). In contrast, mice lacking the ER-.beta. develop normally, are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice (Krege et al., 1998), have normal breast development and lactate normally. The reduction in fertility is believed to be the result of reduced ovarian efficiency, and ER-.beta. is the predominant form of ER in the ovary, being localized in the granulosa cells of maturing follicles. ER-.beta. knockout mice display signs of prostatic hyperplasia with aging, which suggests that ER-.beta. may normally protect against abnormal growth (Krege et al., 1998). ER-.alpha./ER-.beta. double knockout mice are viable, but infertile, and display a postnatal reversal of the ovaries (Couse et al., Science 286, 2328-2331, 1999).

In summary, compounds which serve as estrogen antagonists or agonists have long been recognized for their significant pharmaceutical utility in the treatment of a wide variety of estrogen-related conditions, including conditions related to the brain, bone, cardiovascular system, skin, hair follicles, immune system, bladder and prostate (Barkhem et al., Mol. Pharmacol. 54, 105-12, 1998; Farhat et al., FASEB J. 10, 615-624, 1996; Gustafsson, Chem. Biol. 2, 508-11, 1998; Sun et al., 1999; Tremblay et al., Endocrinology 139, 111-118, 1998; Turner et al., Endocrinology 139, 3712-20, 1998). In addition, a variety of breast and non-breast cancer cells have been described to express ER, and serve as the target tissue for specific estrogen antagonists (Brandenberger et al., 1998; Clinton and Hua, Crit. Rev. Oncol. Hematol. 25, 1-9, 1997; Hata et al., Oncology 55 Suppl 1, 35-44, 1998; Rohlff et al., Prostate 37, 51-9, 1998; Simpson et al., J Steroid Biochem Mol Biol 64, 137-45,1998; Yamashita et al., Oncology 55 Suppl 1, 17-22, 1998).

With the recent identification of the ER-.beta., and the recognition that ER-.alpha. and ER-.beta. have different biological roles, ER-selective modulators would similarly possess significant clinical utility. Since ER-.beta. is expressed strongly in a number of tissues including prostrate, bladder, ovary, testis, lung, small intestine, vascular endothelium, and various parts of the brain, compounds that selectively modulate ER-.beta. would be of clinical importance in the treatment of a variety of diseases or conditions, such as prostate cancer, testicular cancer, cardiovascular diseases, neurodegenerative disorders, urinary incontinence, CNS, GI tract conditions, and bone and other cancers. Such compounds would have minimal effect on tissues that contains ER-.alpha., and thus exhibit different side-effect profiles. For example, while estrogen replacement therapy is associated with a variety of beneficial effects (such as bone protection, cardiovascular effect, prevention of hot flashes, dementia, bone metabolism, etc.), such therapy also has adverse effects (such as breast and endometrial cancer, thrombosis, etc.). Some of these adverse effects are believed to be mediated by ER-.alpha. or ER-.beta. specific mechanisms. Thus, ER-.beta. antagonists or agonists will display different therapeutic profiles compared to ER-.alpha. antagonists or agonists, and would be preferentially beneficial in tissues expressing high levels of ER-.beta. (see, e.g., Nilsson et al., TEM 9, 387-395, 1998; Chang and Prins, The Prostate 40, 115-124, 1999). Furthermore, a number of investigators have shown that environmental chemicals and phytoestrogens preferentially interact with ER-.beta. by triggering biological responses similar to that of estrogen (see, e.g., Kuiper et al., Endocrinology 139, 4252-4263, 1998). Thus, compounds that antagonize ER-.beta. would also be important in regulating interactions with chemicals, affecting health, reproductive capacity and the like.

Accordingly, there is a need in the art for estrogen antagonists and agonists, including pharmaceutical compositions and methods relating to the use thereof. There is also a need for compounds that selectively modulate ER-.beta.. The present invention fulfills these needs, and provides further related advantages.

SUMMARY OF THE INVENTION

In brief, the present invention is generally directed to estrogen antagonists and/or agonists, including pharmaceutical compositions containing the same, as well as to methods for treating estrogen-related conditions. Such conditions are more specifically discussed below, and generally include (but are not limited to) obesity, breast cancer, osteoporosis, endometriosis, cardiovascular disease, prostate cancer, menopausal syndromes, hair loss (alopecia), type-II diabetes, Alzheimer's disease, urinary incontinence, GI tract conditions, spermatogenesis, vascular protection after injury, endometriosis, learning and memory, CNS effects, plasma lipid levels, acne, cataracts, hirsutism, other solid cancers (such as colon, lung, ovarian, testis, melanoma, CNS, and renal), multiple myeloma, and lymphoma.

More specifically, the estrogen antagonists and/or agonists of this invention are compounds having the following structure (I):

##STR00002## including stereoisomers and pharmaceutically acceptable salts thereof, wherein A, B, C, D, R.sub.1, R.sub.2, R.sub.3 and .alpha. are as identified in the following detailed description. In addition, pharmaceutical compositions are also disclosed containing one or more compounds of structure (I), in combination with a pharmaceutically acceptable carrier or diluent.

In another embodiment, methods are disclosed for modulating cells and/or tissues that express ER-.beta. by contacting the cell and/or tissue with an effective amount of a compound of structure (I). In an embodiment, the cell and/or tissue preferentially expresses ER-.beta. over ER-.alpha., such as cell and/or tissue of bone, bladder, uterus, ovary, prostate, testis, epididymis, gastrointestinal (GI) tract, kidney, breast, heart, vessel wall, immune system, lung, pituitary, hippocampus and hypothalamus.

In still a further embodiment, the present invention discloses methods for treating an estrogen-related condition by administering to an warm-blooded animal in need thereof an effective amount of a compound of structure (I) formulated as a pharmaceutical composition suitable for administration to the animal. In representative embodiments, the estrogen-related condition is breast cancer, osteoporosis, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, obesity, prostate cancer, menopausal syndromes, type-II diabetes, Alzheimer's disease, urinary incontinence, GI tract conditions, spermatogenesis, vascular protection after injury, endometriosis, learning and memory, CNS effects, plasma lipid levels, acne, hirsutism, other solid cancers (such as colon, lung, ovarian, testis, melanoma, CNS, and renal), multiple myeloma, lymphoma, prostatic carcinomas, obesity, hot flashes, skin effects, mood swings, memory loss, and/or adverse reproductive effects associated with exposure to environmental chemicals. In other embodiments, methods are disclosed for inhibiting a cyctokine, such as IL-6 and GM-CSF, in an animal in need thereof, as well as methods for treating cancer associated therewith.

These and other aspects of this invention will be evident upon reference to the attached drawings and the following detailed description. To that end, certain references are cited herein each of which are hereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate proliferation of Tamoxifen resistant LCC1 and LCC2 breast cancer cell lines when exposed to a representative compound of this invention.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the present invention is directed to compounds that have activity as estrogen antagonists and/or agonists, as well as pharmaceutical compositions containing one or more of such compounds and methods related to the same. As estrogen antagonists and/or agonists, the compounds of this invention have utility in the treatment of a wide range of estrogen-related conditions. In this context, the term "treatment" includes both treatment and/or prevention of an estrogen-related condition. Thus, the compounds of this invention may be administered as a therapeutic and/or prophylactic agent. An estrogen "agonist" is a compound that binds to ER and mimics the action of estrogen in one or more tissues, while an "antagonist" binds to ER and blocks the action of estrogen in one or more tissues. Further, the term "estrogen-related condition" encompasses any condition associated with elevated or depressed levels of estrogen, a selective estrogen receptor modulators (SERM), ER-.alpha.or ER-.beta..

Accordingly, the compounds of the present invention may also be used within a method for treating estrogen-related conditions, including (but not limited to) breast cancer, osteoporosis, endometriosis, cardiovascular disease, hypercholesterolemia, prostatic hypertrophy, prostatic carcinomas, obesity, hot flashes, skin effects, mood swings, memory loss, menopausal syndromes, hair loss (alopecia), type-II diabetes, Alzheimer's disease, urinary incontinence, GI tract conditions, spermatogenesis, vascular protection after injury, endometriosis, learning and memory, CNS effects, plasma lipid levels, acne, hirsutism, other solid cancers (such as colon, lung, ovarian, testi, melanoma, CNS, and renal), multiple myeloma, cataracts, lymphoma, and adverse reproductive effects associated with exposure to environmental chemicals.

In one aspect of this invention, it has been found that the compounds of this invention are selective estrogen receptor modulators and, more specifically, are selective to ER-.beta.. Accordingly, in this aspect of the invention, the compounds have utility as agents for treatment of osteoporosis, hormonally regulated cancer, combination treatment of cancer (such as with taxol cisplatin or chemotherapy), women's gynecologic health issues, and health conditions resulting from exposure to environmental chemicals.

The compounds of this invention have the following structure (I):

##STR00003## including stereoisomers and pharmaceutically acceptable salts thereof, wherein a is 0, 1 or 2; A, B and C are independently CH, CR or N; D is --(CH.sub.2).sub.r-- or --(CH.sub.2).sub.nC(.dbd.O)(CH.sub.2).sub.m--; R.sub.1 represents one or two substituents independently selected from --X--Y; R.sub.2 is C.sub.1-8alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, --C(.dbd.O)R.sub.5, a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from O, NR.sub.c and S(O).sub.q, or a bicyclic ring system contain a five- or six-membered heterocycle fused to phenyl, wherein each of the above groups are optionally substituted with one to three substituents independently selected from --X--Y or R.sub.4; and R.sub.3 is hydrogen, --R.sub.6, --(CH.sub.2).sub.sC(.dbd.O)R.sub.6, --(CH.sub.2).sub.sC(.dbd.O)OR.sub.6, --(CH.sub.2).sub.sC(.dbd.O)NR.sub.6R.sub.7, --(CH.sub.2).sub.sC(.dbd.O)NR.sub.6(CH.sub.2).sub.nC(.dbd.O)R.sub.7R.sub.- 8, --(CH.sub.2).sub.sNR.sub.6C(.dbd.O)R.sub.7, --(CH.sub.2).sub.sNR.sub.6C(.dbd.O)NR.sub.7R.sub.8, --(CH.sub.2).sub.sNR.sub.6R.sub.7, --(CH.sub.2).sub.sOR.sub.6, --(CH.sub.2).sub.sSO.sub.2R.sub.6 or --(CH.sub.2).sub.sSO.sub.2NR.sub.6R.sub.7; and wherein R.sub.4 is at each occurrence independently halogen, hydroxy, carboxy, C.sub.1-6alkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkyl, C.sub.1-4acyloxy, C.sub.1-4thio, C.sub.1-4alkylsulfinyl, C.sub.1-4alkylsulfonyl, (hydroxy)C.sub.1-4alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, --C(.dbd.O)OH, --C(.dbd.O)OR, --OC(.dbd.O)R, --C(.dbd.O)NHR, --C(.dbd.O)NRR, --C(.dbd.O)NHOR, --SO.sub.2NHR, --NHSO.sub.2R, --CN, --NO.sub.2, --NH.sub.2, C.sub.1-4alkylamino, C.sub.1-4dialkylamino, --NHC(.dbd.O)R, NHC(.dbd.O)(CH.sub.2).sub.s (five- or six-membered heterocycle), a five- or six-membered heterocycle, or a five- or six-membered heterocycle fused to phenyl; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are at each occurrence independently hydrogen, C.sub.1-8alkyl, C.sub.6-12aryl, C.sub.7-12aralkyl, or a five- or six-membered heterocycle or heterocyclealkyl containing up to two heteroatoms selected from O, NR.sub.c and S(O).sub.q, wherein each of the above groups are optionally substituted with one to three substituents independently selected from R.sub.4; X is at each occurrence independently a direct bond; --(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --O(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --S(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --NR.sub.c(CH.sub.2).sub.nZ(CH.sub.2).sub.m--; --O(CH.sub.2).sub.nCR.sub.aR.sub.b--; --NR.sub.c(CH.sub.2).sub.nCR.sub.aR.sub.b--; --OCHR.sub.cCHR.sub.d--; or --SCHR.sub.cCHR.sub.d--; Y is at each occurrence independently halogen;

##STR00004## optionally fused on adjacent carbon atoms with one or two phenyl or cycloalkyl rings, and with each carbon optionally and independently substituted with carbonyl or with one or two substituents independently selected from R.sub.4, with any two R.sub.4 substituents on a single carbon atom optionally being taken together to form a five- or six-membered heterocycle, and with each nitrogen atom optionally and independently substituted with R.sub.4, wherein W is --NR.sub.e--, --O--, --S-- or --CR.sub.cR.sub.f--; or a bridged or fused C.sub.5-12bicyclic amine optionally substituted with one to three substituents independently selected from R.sub.4; or where --X--Y is

##STR00005## Z is CH.sub.2, CH.dbd.CH, C--C, O, NR.sub.c, S(O).sub.q, C(.dbd.O), C(OH)R.sub.c, C(.dbd.O)NR.sub.c, NR.sub.cC(.dbd.O), C(.dbd.O)NR.sub.c, NR.sub.cC(.dbd.O) or

##STR00006## G is O, S or NR.sub.e; n and m are at each occurrence independently 0, 1, 2 or 3; p is at each occurrence independently 1, 2 or 3; q is at each occurrence independently 0, 1 or 2; r is at each occurrence independently 1, 2, 3, 4 or 5; s is at each occurrence independently 0, 1, 2, 3 or 4; R is at each occurrence independently C.sub.1-6alkyl; R.sub.a and R.sub.b are at each occurrence independently C.sub.1-8alkyl or taken together form a C.sub.3-8acyclic alkyl; R.sub.c and R.sub.d are at each occurrence independently hydrogen or C.sub.1-4alkyl; and R.sub.e and R.sub.f are at each occurrence independently hydrogen, C.sub.6-12aryl, C.sub.1-8alkyl, C.sub.7-12aralkyl, a five- or six-membered heterocycle, or a five- or six-membered heterocycle fused to phenyl; or wherein R.sub.e or R.sub.f form a 3-8 membered nitrogen-containing heterocyclic alkyl with R.sub.a or R.sub.b; and wherein each R.sub.e and R.sub.f are optionally substituted with up to three substituents independently selected from R.sub.4.

As used herein, the above terms have the following meaning:

"Halogen" means F, Cl, Br and I.

"C.sub.1-4alkyl", "C.sub.1-6alkyl" and "C.sub.1-8alkyl" means a straight chain or branched, cyclic or non-cyclic, saturated or unsaturated carbon chain having from 1 to 4, 6 or 8 carbon atoms, respectively. In one embodiment, the C.sub.1-X alkyl (where X is 4, 6 or 8 as disclosed above) is a fully saturated, straight chain alkyl such as methyl, ethyl, n-propyl, r-butyl, n-pentyl, n-hexyl and the like. In another embodiment, the C.sub.1-X alkyl is a fully saturated cyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, or an alkyl(cycloalkyl) moiety such as methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, methylenecyclohexyl, and the like, or an unsaturated cyclic alkyl. In still a further embodiment, the C.sub.1-X alkyl is a fully saturated, branched alkyl such as iso-propyl, iso-butyl, tert-butyl, iso-pentyl, iso-hexyl, and the like. In yet another embodiment, the C.sub.1-X alkyl is an unsaturated straight chain alkyl such as ethylenyl, propylenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, and the like.

"C.sub.6-12aryl" means a carbocyclic aromatic moiety containing from 6 to 12 carbon atoms. In one embodiment, the C.sub.6-12aryl is phenyl, tetralinyl or napthalenyl, and typically is phenyl.

"C.sub.7-12aralkyl" means an arene containing from 7 to 12 carbon atoms, and has both aliphatic and aromatic components. In one embodiment, the C.sub.7-12 aralkyl is benzyl, ethylenephenyl, propylenephenyl, and the like.

"Five- or six-membered heterocycle" means a heterocyclic ring containing up to two heteroatoms selected from O, NR.sub.c and S(O).sub.q, and wherein the number of carbon and heteroatoms of the ring total 5 or 6, including both saturated and unsaturated, aromatic and non-aromatic ring systems, such as pyridinyl, pyrimidinyl, furanyl, thienyl, triazenyl, imidazolyl, thiazolyl, pyrazolyl, pyridazinyl, pyrazinyl, and the like.

"Five- or six-membered heterocyclealkyl" means a C.sub.1-6alkyl having at least one hydrogen replaced with a five- or six-membered heterocyle, such as --CH.sub.2(hererocycle), and the like.

"C.sub.1-Xalkoxy" means a --O(C.sub.1-Xalkyl), where x is 4, 6 or 8.

"C.sub.1-4acyloxy" means --OC(.dbd.O)C.sub.1-4alkyl.

"C.sub.1-4thio" means --SC.sub.1-4alkyl.

"C.sub.1-4alkylsulfinyl" means --SOC.sub.1-4alkyl.

"C.sub.1-4alkylsulfonyl" means --SO.sub.2C.sub.1-4alkyl.

"(hydroxy)C.sub.1-4alkyl" means C.sub.1-4alkyl wherein a hydrogen atom has been substituted by hydroxyl.

"C.sub.1-4alkylamino" means --NHC.sub.1-4alkyl.

"C.sub.1-4dialkylamino" means --N(C.sub.1-4alkyl)(C.sub.1-4alkyl).

"C.sub.1-4haloalkyl" means a C.sub.1-4alkyl having at least one hydrogen replaced with halogen, such as trifluoromethyl and the like.

In one aspect of structure (I), A and B are both CH, C is N, D is --CH.sub.2--, and the compounds of this invention have the following structure (IIa) when a is 1, (IIb) when a is 0, and (IIc) when a is 2:

##STR00007##

In other aspects of this invention, the compounds of structure (I) have the following structures (III), (IV), (V) or (VI):

##STR00008##

In one embodiment of structure (IIa), R.sub.2 is phenyl optionally substituted with one, two or three substituents independently selected from R.sub.4, R.sub.3 is hydrogen, and the compounds of this invention have the following structure (IIa-1):

##STR00009##

In another embodiment of structure (IIa), R.sub.2 is pyridinyl optionally substituted with one, two or three substituents independently selected from R.sub.4, R.sub.3 is hydrogen, and the compounds of this invention have the following structures (IIa-2) or (IIa-3):

##STR00010##

In another embodiment of structure (IIa), R.sub.1 is

##STR00011## at the 4-position, R.sub.3 is hydrogen, and the compounds of this invention have the following structure (IIa-4):

##STR00012##

IIa-4

In yet further embodiments, the compounds of this invention have the following structure (IIa-5) or (IIa-6):

##STR00013##

In still further embodiments, the compounds of this invention have the following structure (IIa-7):

##STR00014##

In another embodiment, compounds of this invention have the following structure (VII):

##STR00015##

For purpose of illustration, representative compounds of structure (VII) are set forth in the Table 1.

TABLE-US-00001 TABLE 1 Representative Compounds of Structure (VII) Cpd No. a A B C R.sub.1 R.sub.2 100 1 CH CH N Halogen Phenyl 101 1 CH CH N ##STR00016## Phenyl 102 1 CH CH N ##STR00017## 4-Fluorophenyl 103 1 CH CH N ##STR00018## 2-Methoxypyridin-5-yl 104 2 CH CH N ##STR00019## 4-Fluorophenyl 105 0 CH CH N ##STR00020## 4-Fluorophenyl 106 1 CH CH N ##STR00021## 2-Hydroxypyridin-5-yl 107 1 CH CH N ##STR00022## 2-Aminopyridin-5-yl 108 1 CH CH N ##STR00023## 4-Methoxyphenyl 109 1 CH CH N ##STR00024## 4-Hydroxyphenyl 110 1 CH CH N ##STR00025## 4-Fluorophenyl 111 1 CH CH N ##STR00026## 4-Fluorophenyl 112 1 CH CH N ##STR00027## Cyclohexyl 113 1 CH CH N ##STR00028## Benzyl 114 1 CH CH N ##STR00029## 2-Thienyl 115 1 CH CH N ##STR00030## 3-Thienyl 116 1 N CH N ##STR00031## 4-Fluorophenyl 117 1 N N N ##STR00032## 4-Fluorophenyl 118 1 CH CH N ##STR00033## Isopropyl 119 1 CH CH N ##STR00034## 4-Fluorophenyl 120 1 CH CH N ##STR00035## 3-Fluoro-4-hydroxyphenyl 121 1 CH CH N ##STR00036## 4-Fluorophenyl 122 1 CH CH N ##STR00037## 4-Fluorophenyl 123 1 CH CH N ##STR00038## 4-Fluorophenyl 124 1 CH CH N ##STR00039## 4-Fluorophenyl 125 1 CH CH N ##STR00040## 4-Fluorophenyl 126 1 CH CH N ##STR00041## 4-Fluorophenyl 127 1 CH CH N ##STR00042## 4-Fluorophenyl 128 1 CH CH N ##STR00043## 4-Fluorophenyl 129 1 CH CH N ##STR00044## 4-Fluorophenyl 130 1 CH CH N ##STR00045## 4-Fluorophenyl 131 1 CH CH N ##STR00046## 4-Fluorophenyl 132 1 CH CH N ##STR00047## 4-Fluorophenyl 133 1 CH CH N ##STR00048## 4-Fluorophenyl 134 1 CH CH N ##STR00049## 4-Fluorophenyl 135 1 CH CH N ##STR00050## 4-Fluorophenyl 136 1 CH CH N ##STR00051## 4-Fluorophenyl 137 1 CH CH N ##STR00052## 4-Fluorophenyl 138 1 CH CH N ##STR00053## 4-Fluorophenyl 139 1 CH CH N ##STR00054## 4-Fluorophenyl 140 1 CH CH N ##STR00055## 4-Fluorophenyl

In still a further embodiment, D of structure (I) is carbonyl--that is, --(CH.sub.2).sub.nC(.dbd.O)(CH.sub.2).sub.m-- wherein both n and in are zero--and the compounds of this invention have the following structure (VIII):

##STR00056##

In one aspect of this embodiment, R.sub.3 is hydrogen and compounds of this invention have the following structure (VIIIa):

##STR00057##

For purposes of illustration, representative compounds of structure (VIIIa) are set forth in Table 2.

TABLE-US-00002 TABLE 2 Representative Compounds of Structure (VIIIa) Cpd. No. a A B C R.sub.1 R.sub.2 141 1 CH CH N ##STR00058## Phenyl 142 1 CH CH N ##STR00059## 4-Fluoro-phenyl 143 1 CH CH N ##STR00060## 2-Methyl-4-fluorophenyl 144 1 CH CH N ##STR00061## 2-Methoxy-pyridin-5-yl 145 1 CH CH N ##STR00062## Pyrimidin-5-yl 146 1 CH CH N ##STR00063## 4-Fluoro-phenyl 147 1 CH CH N ##STR00064## 4-Fluoro-phenyl 148 1 CH CH N ##STR00065## 4-Fluoro-phenyl 149 1 CH CH N ##STR00066## 4-Fluoro-phenyl 150 1 CH CH N ##STR00067## 4-Fluoro-phenyl 151 1 N CH N ##STR00068## 4-Fluoro-phenyl 152 1 N N N ##STR00069## 4-Fluoro-phenyl

In yet a further embodiment, D of structure (I) is --(CH.sub.2).sub.r-- and the compounds of this invention have the following structure (IX):

##STR00070##

In one aspect of this embodiment, R.sub.3 is hydrogen and compounds of this invention have the following structure (IXa):

##STR00071##

For purposes of illustration, representative compounds of structure (IXa) are set forth in Table 3.

TABLE-US-00003 TABLE 3 Representative Compounds of Structure (IXa) Cpd. No. a A B C r R.sub.1 R.sub.2 153 1 CH CH N 2 ##STR00072## 4-Fluorophenyl 154 1 CH CH N 2 ##STR00073## 2-Thienyl 155 1 CH CH N 2 ##STR00074## 2-Methyl-4-fluorophenyl 156 1 CH CH N 2 Hydrogen Phenyl 157 1 CH CH N 3 ##STR00075## 4-Fluorophenyl 158 1 CH CH N 3 --OCH.sub.3 4-Fluorophenyl 159 CH CH N 4 --F 4-Fluorophenyl 160 CH CH N 4 ##STR00076## 4-Fluorophenyl 161 CH CH N 5 Hydrogen 4-Fluorophenyl 162 CH CH N 5 ##STR00077## 4-Fluorophenyl

As noted above, compounds of this invention have structure (I), wherein a is 1, 2 or 3, yielding a fused, bicyclic six-five-, six-six- or six-seven-membered ring system. In a typical embodiment, a is 1.

With regard to the A and B moieties, in a typical embodiment both A and B are CH, yielding a benzene ring substituted with the R.sub.1 moiety. Other representative groups in this regard include those embodiments wherein either A or B is nitrogen, or wherein both A and B are nitrogen.

Representative C moieties include both nitrogen and CH. In a typical embodiment, the C moiety is nitrogen.

D moieties of this invention include --(CH.sub.2).sub.r-- and --(CH.sub.2).sub.nC(.dbd.O)(CH.sub.2).sub.m--. When D is --(CH.sub.2).sub.r--, r is typically 1 or 2, and more typically 1--such that D moiety is methylene. In the embodiment wherein D is --(CH.sub.2).sub.nC(.dbd.O)(CH.sub.2).sub.m--, n and m are typically 0, 1 or 2. In one embodiment, both n and m are zero, and D is carbonyl.

R.sub.1 groups of this invention have the formula --X--Y. As used herein, R.sub.1 designates either one or two R.sub.1 substuents. In the case of two R.sub.1 substituents, each of the R.sub.1 substituents may be the same or different. Typically, R.sub.1 refers to a single substituent as represented by --X--Y.

In one embodiment, X is --(CH.sub.2).sub.nZ(CH.sub.2).sub.m-- and Y has the following structure:

##STR00078## Representative R.sub.1 groups in this regard include those wherein n is zero and Z is oxygen, and having the following structure:

##STR00079## For example, when W is oxygen, p and q are both 1, representative R.sub.1 groups include the following (wherein m is, for example, 2 or 3):

##STR00080##

Other embodiments in this regard include those wherein Y is --NR.sub.eR.sub.f, and having the following structure: <