WO2006108107A1 - Composes et compositions contenant de la diarylamine et utilisation de ces derniers comme modulateurs des recepteurs nucleaires des hormones steroides - Google Patents

Composes et compositions contenant de la diarylamine et utilisation de ces derniers comme modulateurs des recepteurs nucleaires des hormones steroides Download PDF

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WO2006108107A1
WO2006108107A1 PCT/US2006/012915 US2006012915W WO2006108107A1 WO 2006108107 A1 WO2006108107 A1 WO 2006108107A1 US 2006012915 W US2006012915 W US 2006012915W WO 2006108107 A1 WO2006108107 A1 WO 2006108107A1
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alkyl
compound
aryl
formula
halo
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PCT/US2006/012915
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English (en)
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Pierre-Yves Michellys
Ke Wen
Michael H. Petrassi
Wei Pei
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Irm Llc
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Priority to MX2007012449A priority Critical patent/MX2007012449A/es
Priority to JP2008505543A priority patent/JP2008536835A/ja
Priority to AU2006232109A priority patent/AU2006232109A1/en
Priority to CA002603250A priority patent/CA2603250A1/fr
Priority to BRPI0608934-8A priority patent/BRPI0608934A2/pt
Priority to EP06749458A priority patent/EP1865775A1/fr
Publication of WO2006108107A1 publication Critical patent/WO2006108107A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Steroid hormone nuclear receptors represent a subset of the nuclear hormone receptor superfamily. So named according to the cognate ligand which complexes with the receptor in its native state, the . steroid hormone nuclear receptors include the glucocorticoid receptor (GR), the androgen receptor (AR), the mineralocorticoid receptor (MR), the estrogen receptor (ER), and the progesterone receptor (PR).
  • GR glucocorticoid receptor
  • AR the androgen receptor
  • MR mineralocorticoid receptor
  • ER estrogen receptor
  • PR progesterone receptor
  • MR is expressed in epithelial tissues, heart, kidneys, brain, vascular tissues ' and bone.
  • Aldosterone is the endogenous ligand of MR and is primarily synthesized in the adrenal glands, heart, brain and blood vessels.
  • aldosterone Several detrimental effects are attributable to aldosterone, for example: sodium/water retention, renal fibrosis, vascular inflammation, vascular fibrosis, endothelial dysfunction, coronary inflammation, decrease in coronary blood flow, ventricular arrhythmias, myocardial fibrosis, ventricular hypertrophy and direct damage to cardiovascular systems, primarily the heart, vasculature and kidneys.
  • Aldosterone action on all target organs is through activation of the MR receptor.
  • GR is expressed in almost all tissues and organ systems and is crucial for the integrity of the function of the central nervous system and the maintenance of cardiovascular, metabolic, and immune homeostasis.
  • diarylamine compounds comprising a diarylamine structure.
  • such diarylamine compounds are diheteroarylamine compounds.
  • one of the heteroaryl groups of such diheteroarylamine compounds comprises a phthalazine structure; in further or alternative embodiments, one of the heteroaryl groups of such diheteroarylamine compounds comprises a five-membered ring comprising a CN group.
  • such compounds comprising a diarylamine structure for the modulation of a nuclear receptor.
  • such diarylamine compounds are diheteroarylamine compounds.
  • one of the heteroaryl groups of such diheteroarylamin e compounds comprises a phthalazine stracture; in further or alternative embodiments, one of the heteroaryl groups of such diheteroarylarnine compounds comprises a five-membered ring comprising a CN group.
  • such compounds comprising a diarylamine structure in the treatment of a disease or condition, or to produce a medicament for the treatment of a disease or condition, in which modulation of at least one nuclear receptor activity can prevent, inhibit or ameliorate the pathology and/or symptoms of the disease or condition.
  • such diarylamine compounds are diheteroarylamine compounds.
  • one of the heteroaryl groups of such diheteroarylamine compounds comprises a phthalazine structure; in further or alternative embodiments, one of the heteroaryl groups of such diheteroarylamine compounds comprises a five-membered ring comprising a CN group, m
  • the nuclear receptors are steroid hormone nuclear receptors.
  • compositions comprising such a compound comprising a diarylamine structure.
  • such diarylamine compounds are diheteroarylamine compounds.
  • one of the heteroaryl groups of such diheteroarylamine compounds comprises a phthalazine structure; in further or alternative embodiments, one of the heteroaryl groups of such diheteroarylamine compounds comprises a five-membered ring comprising a CN group.
  • methods for making such compounds comprising a diarylamine structure In one embodiment, such diarylamine compounds are diheteroarylamine compounds.
  • one of the heteroaryl groups of such diheteroarylamine compounds comprises a phthalazine structure; in further or alternative embodiments, one of the heteroaryl groups of such diheteroarylamine compounds comprises a five-membered ring comprising a CN group.
  • R 1 is selected from the group consisting of H, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -I ⁇ -alkyl, -Lrcycloalkyl, -L 1 - heteroalkyl, -Lrhaloalkyl, -L 1 -ETyI, -L ⁇ heterocycloalkyl, and -L 1 -heteroaryl, wherein L 1 is selected f rom a bond,O, NH; S, -C(O)-, -C(S)-, -C(O)O-, -C(O)NH
  • R 3 , R 3 -, R 4 , R 5 , R 6 , R 6 -, R 8 and Rg are independently selected from H, halogen, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -L 3 -alkyl, -Lrcycloalkyl, -L 3 -heteroalkyl, -L 3 -haloalkyl, -L 3 -aryl, -L ⁇ heterocycloalkyl, and -L 3 -heteroaryl, wherein L 3 is selected from a bond, O, NH, S, -C(O)-, -C(S)-, -C(O)O-, - C(O)NH-, -S(O)-, -S(O) 2 , and -S(O)NH-; wherein said optional substituents
  • R 1 is alkyl.
  • R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl.
  • R 2 is selected from the group H, alkyl, and -C(O)-alkyl.
  • R 3 is H.
  • R 4 is H.
  • R 5 is H.
  • R 6 is H.
  • R 7 is an optionally subsituted group selected from L 4 - aryl, -Lj-heterocycloalkyl, and -L 4 -heteroaryl.
  • L 4 is selected from a bond, O, NH, OCH 2 , NHCH 2 , S, d-Cealkylene, -C(O)-, -C(O)O-, and -C(O)NH-
  • R 1 is selected from the group consisting of H, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -I ⁇ -alkyl, -Lrcycloalkyl, -L 1 - heteroalkyl, -Li-haloalkyl, -I ⁇ -aryl, -Li-heterocycloalkyl, and -Lrheteroaryl, wherein L 1 is selected from a bond, O, NH, S, -C(O)-, -C(S)-, -C(O)O-, -C(O)NH-, -S(O)
  • the compound of Formula (1) directly contacts at least one steroid hormone nuclear receptor.
  • this aspect the contacting occurs in vitro, hi a further or alternative embodiment of this aspect the contacting occurs in vivo.
  • R 1 is alkyl.
  • R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl. sec-butyl tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl.
  • R 2 is selected from the group H, alkyl, and -C(O)-alkyl.
  • R 3 is H.
  • R 4 is H.
  • R 5 is H.
  • R 6 is H.
  • R 7 is an optionally subsituted group selected from L 4 - aryl, -Li-heterocycloalkyl, and -L 4 -heteroaryl.
  • L 4 is selected from a bond, O, NH, OCH 2 , NHCH 2 , S, Q-Cealkylene, -C(O)-, -C(O)O-, and -C(O)NH-
  • Another aspect is a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound having the structure of Formula (1),
  • R 1 is selected from the group consisting of H, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -Li-alkyl, -Li-cycloalkyl, -L 1 - heteroalkyl, -Li-haloalkyl, -Li-aryl, -Lrheterocycloalkyl, and -Lj-heteroaryl, wherein L 1 is selected from a bond, O, NH, S, -C(O)-, -C(S)-, -C(O)O-, -C(O)NH-, -
  • R 2 is selected from the group consisting of H and an optionally substituted moiety selected from -L 2 -alkyl, -L 2 -cycloalkyl, -L 2 -heteroalkyl, - L 2 ⁇ haloalkyl, -L 2 -aryl, -L 2 -heterocycloalkyl, and -L 2 -heteroaryl, wherein L 2 is selected from a bond,-C(O>, -C(S)-, -C(O)O-, -C(O)NH-, -S(O)-, -S(O) 2 , and -S(O)NH-; wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-Q.
  • R 3 , R 3' , R 4 , R 5 , R 6 , R 6' , Rg and Rg are independently selected from H, halogen, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -L 3 -alkyl, -L 3 -cycloalkyl, -L 3 -heteroalkyl, -L 3 -haloalkyl, -L 3 -aryl, -Lj-heterocycloalkyl, and -L 3 -heteroaryl, wherein L 3 is selected from a bond, O, NH, S, -C(O)-, -C(S)-, -C(O)O-, - C(O)NH-, -S(O)-, -S(O) 2 , and -S(O)NH-; wherein said optional
  • the one or more excipients are suitable for parenteral administration. In a further or alternative embodiment of this aspect the one or more excipients are suitable for oral administration. In a further or alternative embodiment of this aspect the one or more excipients are suitable for ophthalmic administration.
  • L is N. In a further or alternative embodiment of this aspect Z is N. In a further or alternative embodiment of this aspect X is S. In a further or alternative embodiment of this aspect L is N and X is S. In a further or alternative embodiment of this aspect Z is N and X is S.
  • the compound has one of the following structures:
  • R 1 is alkyl.
  • R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl.
  • R 2 is selected from the group H, alkyl, and -C(O)-alkyl.
  • R 3 is H.
  • R 4 is H.
  • R 5 is H.
  • R 6 is H.
  • R 7 is an optionally subsituted group selected from L 4 - aryl, -L 4 -heterocycloalkyl, and -L 4 -heteroaryl.
  • L 4 is selected from a bond, O, NH, OCH 2 , NHCH 2 , S, Q-Qalkylene, -C(O)-, -C(O)O-, and -C(O)NH- [0026]
  • the compound having the structure of Formula (1) is selected from
  • a disease in an animal in which modulation of steroid hormone nuclear receptor activities can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases
  • R 1 is alkyl.
  • R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl.
  • R 2 is selected from the group H, alkyl, and -C(O)-alkyl.
  • R 3 is H.
  • R 4 is H.
  • R 5 is H.
  • R 6 is H.
  • R 7 is an optionally subsituted group selected from L 4 - aryl, -Lrheterocycloalkyl, and -L 4 -heteroaryl.
  • L 4 is selected from a bond, O, NH, OCH 2 , NHCH 2 , S, Q-Cealkylene, -C(O)-, -C(O)O-, and -C(O)NH-
  • the steroid hormone nuclear receptor is selected from the group consisting of a glucocorticoid receptor, a mineralocorticoid receptor, an androgen receptor, an estrogen receptor, and a progesterone receptor.
  • the method further comprising administration of a therapeutically effective amount of a second substance, wherein the second substance is used in the treatment of a disease or condition selected from the group consisting of hypokalemia, hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart disease, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
  • a disease or condition selected from the group consisting of hypokalemia, hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart disease, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
  • the second substance is selected from the group consisting of an anti-obesity agent, an anti-hypertensive agent, an inotropic agent, an hypolipidemic agent, an angiotensin converting enzyme (ACE) inhibitor, an inhibitor of the Na- K-ATPase membrane pump, an neutralendopeptidase (NEP) inhibitor, an ACE/NEP inhibitor, an angiotensin II antagonist, a ⁇ -adrenergic receptor blocker, an inotropic agent, a calcium channel blocker, and a 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA) inhibitor.
  • ACE angiotensin converting enzyme
  • NEP neutralendopeptidase
  • an ACE/NEP inhibitor an angiotensin II antagonist
  • HMG-CoA 3-hydroxy-3-methyl-glutaryl coenzyme A reductase
  • the compound of Formula (1) is administered prior to the second substance. In a further or alternative embodiment, the compound of Formula (1) is administered with the second substance. In a further or alternative embodiment, the compound of Formula (1) is administered after the second substance. In a further or alternative embodiment, the compound of Formula (1) and the second substance are administered in the same pharmaceutical composition.
  • R 1 is selected from the group consisting of H, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -Li-alkyl, -L 1 - cycloalkyl, -I ⁇ -heteroalkyl, -I ⁇ -haloalkyl, -I ⁇ -aryl, -Li-heterocycloalkyl, and -Li-heteroaryl, wherein L 1 is selected from
  • R 3 , R 3 -, R 4 , R 5 , R 6 , R 6 -, R 8 and R 9 are independently selected from H, halogen, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -L 3 -alkyl, -L 3 -cycloalkyl, -L 3 -heteroalkyl, -L 3 -haloalkyl, -L 3 -aryl, -L 3 - heterocycloalkyl, and -L 3 -heteroaryl, wherein L 3 is selected from a bond, O, NH, S, -C(O)-, - C(S)-, -C(O)O-, -C(O)NH-, -S(O)-, -S(O) 2 , and -S
  • R 10 and R 11 are independently selected from Ci-C 6 alkyl and d-C 6 haloalkyl, or R 10 and R n together form an optionally substituted 3 to 8-membered heterocyclic ring;
  • X is O, N or S;
  • Y is O, N or S; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.
  • R 1 is alkyl.
  • R 1 is selected from the group: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, 2-hexyl, and 3-hexyl.
  • R 2 is selected from the group H, alkyl, and -C(O)-alkyl.
  • R 3 is H.
  • R 4 is H.
  • R 5 is H.
  • R 6 is H.
  • R 7 is an optionally subsituted group selected from L 4 - aryl, -L 4 -heterocycloalkyl, and -L 4 -heteroaryl.
  • L 4 is selected from a bond, O, NH, OCH 2 , NHCH 2 , S, Q-Cealkylene, -C(O)-, -C(O)O-, and -C(O)NH-
  • the steroid hormone nuclear receptor is selected from the group consisting of a glucocorticoid receptor, a mineralocorticoid receptor, an androgen receptor, an estrogen receptor, and a progesterone receptor.
  • methods for preparing a compound having the structure of Formula (1) comprising admixing a compound of Formula (D): ith a compound having the structure: under suitable reaction conditions.
  • alkenyl group refers to a hydrocarbon chain having one or more double bonds therein.
  • the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkenyl groups include, but are not limited to, (C 2 -C 8 )alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl.
  • alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a "cycloalkenyl” group), and can be unsubstituted or substituted.
  • alkoxy as used herein, includes -O-(alkyl), where alkyl is as defined herein.
  • C 1-6 alkoxy includes, but is not limited to, methoxy, ethoxy, and the like.
  • An alkoxy group can be unsubstituted or substituted.
  • alkyl refers to a hydrocarbon group having from 1 to 10 carbon atoms and can include straight, branched, cyclic, saturated and/or unsaturated features. Whenever it appears herein, a numerical range such as “1 to 10" refers to each integer in the given range; e.g. '1to 10 carbon atoms" or “C 1-10 " or “(C 1 -C 10 )” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated.
  • the alkyl moiety may be a "saturated alkyl" group, which means that it does not contain any alkene or alkyne moieties.
  • Representative saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2- propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl- 1-pentyl, 3 -methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl- 2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, sec-butyl, t-
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • An "alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an "alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • Representative unsaturated alkyl groups include, but are not limited to, ethenyl, propenyl, butenyl and the like. An alkyl group can be unsubstituted or substituted.
  • Substituted alkyl groups include, but are not limited to, halogen-substituted alkyl groups, such as, by way of example only, trifluoromethyl, pentafluoroethyl, and the like.
  • alkynyl group refers to a hydrocarbon chain having one or more triple bonds therein.
  • the triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group.
  • Suitable alkynyl groups include, but are not limited to, (C 2 -C 6 )alkynyl groups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-l-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.
  • the alkynyl moiety may be branched or straight chain, and can be unsubstituted or substituted.
  • amide refers to a chemical moiety with formula -C(O)NHR or -NHC(O)R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclic (bonded through a ring carbon). Amides can be formed from any amine or carboxyl side chain on the compounds described herein.
  • aromatic refers to a closed ring structure which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl and heterocyclic aryl (or “heteroaryl” or “heteroaromatic") groups.
  • the carbocyclic or heterocyclic aromatic group may contain from 5 to 20 ring atoms.
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • An aromatic group can be unsubstituted or substituted.
  • aryloxy as used herein, includes -O-aryl group, wherein aryl is as defined herein. An aryloxy group can be unsubstituted or substituted.
  • bond refers to a covalent bond between two atoms, either of which may be part of a larger moiety.
  • Carbocyclic or "cycloalkyl,” as used herein, refer to a compound which contains one or more covalently closed ring structures, and that the atoms forming the backbone of the ring are all carbon atoms. Such a group may have from 3 to 20 ring carbon atoms and be saturated, partially unsaturated, or fully unsaturated monocyclic, fused bicyclic, spirocyclic, bridged polycyclic or polycyclic ring comprising carbon and hydrogen atoms.
  • Carbocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a carbocyclic aromatic group includes, but is not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as, by way of example only, dibenzosuberenone, and dibenzosuberone.
  • a carbocyclic group can be unsubstituted or substituted.
  • esters refers to a chemical moiety with formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, and heterocyclic (bonded through a ring carbon). Any hydroxy or carboxyl side chain on the compounds described herein can be esterified.
  • the procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.
  • An ester group can be unsubstituted or substituted.
  • heteroalkyl “heteroalkenyl” and “heteroalkynyl,” as used herein, include optionally substituted alkyl, alkenyl and alkynyl moieties and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a “heteroalkyl” “heteroalkenyl” and “heteroalkynyl” group can be unsubstituted or substituted.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, sulfur.
  • an iV-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • a polycyclic heteroaryl group may be fused or non- fused.
  • a heteroaryl group can be unsubstituted or substituted.
  • heterocyclic refers to ring structures in which the ring backbone contains at least one atom selected from nitrogen, oxygen, and sulfur.
  • heterocyclic aromatic groups include, but are not limited to, acridinyl, benzo[l,3]dioxole, benzimidazolyl, benzindazolyl, benzoisooxazolyl, benzokisazolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzothiazolyl, benzo[b]thienyl, benzothiophenyl, benzothiopyranyl, benzotriazolyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, furazanyl, furopyridinyl, furyl, iinidazolyl, indazolyl, indolyl, indolidinyl, indoliziny
  • a heterocyclic group can be unsubstituted or substituted.
  • non-aromatic heterocyclic groups include, but are not limited to, are azepinyl, azepan-2-onyl, azetidinyl, diazepinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, dioxolanyl, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, dithianyl, dithiolanyl, homopiperidinyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, morpholinyl, oxazepinyl, oxepanyl, oxetanyl, oxylanyl, piperidino, piperidyl, piperidinonyl, piperazinyl, pyranyl, pyrazoliny
  • the heterocyclic group may be fused or non-fused.
  • the terms referring to the groups also encompass all possible tautomers.
  • halogen means fluoro, chloro, bromo or iodo.
  • Preferred halogen groups are fluoro, chloro and bromo.
  • haloalkyl refers to alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halogen groups or with combinations thereof.
  • the te ⁇ n membered ring can embrace any cyclic structure.
  • the term “membered” is meant to denote the number of skeletal atoms that constitute the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, and thiophene are 5-membered rings.
  • moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • protecting group refers to a chemical moiety which blocks some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
  • reactant refers to a nucleophile or electrophile used to create covalent linkages.
  • sulfonyl refers to the presence of a sulfur atom, which is optionally linked to another moiety such as an alkyl group, an aryl group, or a heterocyclic group.
  • Aryl or alkyl sulfonyl moieties have the formula -SO 2 R', wherein R' is alkyl or aryl as defined herein, and include, but are not limited to, methylsulfonyl, ethylsulfonyl and phenylsulfonyl groups.
  • a sulfonyl group can be unsubstituted or substituted.
  • a phenylsulfonyl is optionally substituted with 1 to 3 substituents independently selected from halogen, alkyl, and alkoxy.
  • substituents independently selected from halogen, alkyl, and alkoxy.
  • the te ⁇ n "acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
  • the term "agonist,” as used herein, refers to a molecule such as a compound, a drug, an enzyme activator or a hormone modulator which enhances the activity of another molecule or the activity of a receptor site.
  • antagonist refers to a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone modulator, which diminishes, or prevents the action of another molecule or the activity of a receptor site.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease.
  • An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study.
  • the terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
  • the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
  • An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
  • metabolite refers to a derivative of a compound which is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist and an antagonist.
  • pharmaceutically acceptable refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salt of a compound, as used herein, refers to a salt that is pharmaceutically acceptable.
  • the term "pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • the term "fixed combination” means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g.
  • composition refers to a mixture of an active compound with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • a prodrug refers to a drug or compound m which metabolic processes within the body converts the drug or compound into a pharmacological active form.
  • subject or “patient” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • treat include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • the mineralocorticoids are so named for their role in the metabolism of minerals, sodium, and potassium.
  • the traditional role for these steroids has been in the regulation of fluid and electrolyte balance in epithelial tissues responsive to their effects, such as the kidney and the distal colon.
  • MR In visceral tissues, such as the kidney and the gut, MR regulates sodium retention, potassium excretion, and water balance in response to aldosterone.
  • Elevations in aldosterone levels, or excess stimulation of mineralocorticoid receptors are linked to several pathological conditions or pathological disease states including, Conn's Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Barter's Syndrome, congestive heart failure (CHF), and conditions associated with excess catecholamine levels.
  • Conn's Syndrome primary and secondary hyperaldosteronism
  • increased sodium retention increased magnesium and potassium excretion (diuresis)
  • diuresis increased water retention
  • hypertension isolated systolic and combined systolic/diastolic
  • arrhythmias myocardial fibrosis
  • myocardial infarction Barter's Syndrome
  • CHF
  • MR expression in the brain appears to play a role in the control of neuronal excitability, in the negative feedback regulation of the hypothalamic- pituitary-adrenal axis, and in the cognitive aspects of behavioral performance.
  • mineralocorticoid receptors, and modulation of MR activity are involved in anxiety and major depression.
  • expression of MR may be related to differentiation of breast carcinomas.
  • Compounds which selectively modulate MR would be of clinical importance in the treatment of or prevention of a variety of diseases and conditions, including, but not limited to, cancer, breast cancer, Conn's Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Barter's Syndrome, congestive heart failure (CHF), conditions associated with excess catecholamine levels, cognitive dysfunctions, psychoses, cognitive conditions, memory disturbances, mood conditions, depression, bipolar condition , anxiety conditions, and personality conditions.
  • diseases and conditions including, but not limited to, cancer, breast cancer, Conn's Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and
  • GR Glucocorticoid receptor
  • Glucocorticoids a class of corticosteroids, are endogenous hormones with profound effects on the immune system and multiple organ systems. They suppress a variety of immune and inflammatory functions by inhibition of inflammatory cytokines such as IL-I, IL-2, IL-6, and TNF, inhibition of arachidonic acid metabolites including prostaglandins and leukotrienes, depletion of T-lymphocytes, and reduction of the expression of adhesion molecules on endothelial cells, hi addition to these effects, glucocorticoids stimulate glucose production in the liver and catabolism of proteins, play a role in electrolyte and water balance, reduce calcium absorption, and inhibit osteoblast function.
  • inflammatory cytokines such as IL-I, IL-2, IL-6, and TNF
  • arachidonic acid metabolites including prostaglandins and leukotrienes
  • depletion of T-lymphocytes depletion of T-lymphocytes
  • GR is expressed in almost all tissues and organ systems and is crucial for the integrity of the function of the central nervous system and the maintenance of cardiovascular, metabolic, and immune homeostasis.
  • Glucocorticoids e. g. Cortisol, corticosterone, and cortisone
  • the glucocorticoid receptor have been implicated in the etiology of a variety of pathological conditions or pathologic disease states.
  • Cortisol hypo-secretion is implicated in the pathogenesis of diseases resulting in muscle weakness, increased melanin pigmentation of the skin, weight loss, hypotension, and hypoglycemia.
  • glucocorticoids has been correlated to Cushing's Syndrome and can also result in obesity, hypertension, glucose intolerance, hyperglycemia, diabetes mellitus, osteoporosis, polyuria, and polydipsia.
  • Compounds which selectively modulate GR would be of clinical importance in the treatment of or prevention of a variety of diseases and conditions, including, but not limited to, inflammation, tissue rejection, auto-immunity, malignancies such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Thl/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypocalcaemia, hyperglycemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, Little's syndrome, inflammatory bowel disease, systemic lupus erythe
  • AndroRen receptor (AR) [0093] Androgens bind to a specific receptor, the androgen receptor (AR), inside the cells of target tissues.
  • the AR is expressed in numerous tissues of the body and is the receptor through which the physiological as well as the pathophysiological effects of endogenous androgen ligands, such as testosterone (T) and dihydrotestosterone (DHT), are expressed.
  • T testosterone
  • DHT dihydrotestosterone
  • the AR is composed of three main functional domains: the ligand binding domain (LBD), the DNA- binding domain, and amino-terminal domain.
  • a compound that binds to the AR and mimics the effects of an endogenous AR ligand is referred to as an AR agonist, whereas a compound that inhibits the effects of an endogenous AR ligand is termed an AR antagonist.
  • Binding of androgen to the receptor activates it and causes it to bind to DNA binding sites adjacent to target genes. From there it interacts with coactivator proteins and basic transcription factors to regulate the expression of the gene. Thus, via its receptor, androgens cause changes in gene expression in cells. These changes ultimately have consequences on the metabolic output, differentiation or proliferation of the cell that are visible in the physiology of the target tissue.
  • Compounds which selectively modulate AR would be of clinical importance in the treatment of or prevention of a variety of diseases and conditions, including, but not limited to, prostate cancer, benign prostatic hyperplasia, hirsutism in women, alopecia, anorexia nervosa, breast cancer, acne, musculoskeletal conditions, such as bone disease, hematopoietic conditions, neuromuscular disease, rheumatological disease, wasting disease, cancer, AIDS, cachexia, for hormone replacement therapy (HRT), employed in male contraception, for male performance enhancement, for male reproductive conditions, and primary or secondary male hypogonadism.
  • HRT hormone replacement therapy
  • Estrogen receptor [0095] Estrogens play important roles in the development and homeostasis of the reproductive, central nervous, skeletal, and cardiovascular systems of both males and females.
  • the estrogen receptor (ER) is expressed in a number of tissues including prostate, bladder, ovary, testis, lung, small intestine, vascular endothelium, and various parts of the brain.
  • Compounds which selectively modulate ER would be of clinical importance in the treatment of or prevention of a variety of diseases and conditions, including, but not limited to, prostate cancer, testicular cancer, ovarian cancer, lung cancer, cardiovascular diseases, neurodegenerative conditions, urinary incontinence, CNS conditions, multiple sclerosis, GI tract conditions, osteoporosis, bone loss, bone fractures, osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma, cartilage degeneration, endometriosis, uterine fibroid disease, breast cancer, uterine cancer, hot flashes, impairment of cognitive function, cerebral degenerative conditions, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity and incontinence.
  • Progesterone receptor (PR) Pro
  • Progesterone is a steroid hormone known primarily for its role in development and maintenance of the reproductive system.
  • Progesterone is the natural ligand for the PR and when bound a receptor/ligand complex is formed. This complex binds to specific gene promoters present in the cell's DNA and modulates the production of mRNA and protein encoded by that gene.
  • Synthetic ligands for PR can be agonists, which mimic the action of the natural hormone, or they can be antagonists, which inhibits the effect of the hormone.
  • Progesterone has been implicated in a wide range of biological processes outside of the reproductive tract. In the peripheral nervous system progesterone promotes myelination of regenerating nerves. Progesterone is synthesized by Schwann cells (the cell type which produces myelin), and PR has been detected in primary Schwann cell cultures from rats, suggesting the presence of an autocrine loop. Progesterone appears to promote myelin formation by binding to PR and stimulating transcription of the transcription factor Krox-20, which in turn stimulates transcription of several myelin protein genes. Thus, both local and systemic production of progesterone may contribute to neurofibroma growth.
  • Schwann cells the cell type which produces myelin
  • Compounds which selectively modulate PR would be of clinical importance in the treatment of or prevention of a variety of diseases and' conditions, 'including, but not limited to, hormone dependent breast cancers, uterine and ovarian cancers, non-malignant chronic diseases and conditions such as fibroids, hormone dependent prostate cancer, and in hormone replacement therapy.
  • Compounds of Formula (1), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof modulate the activity of steroid hormone nuclear receptors and, as such, are useful for treating diseases or conditions in which aberrant steroid hormone nuclear receptor activity contributes to the pathology and/or symptoms of a disease or condition.
  • L is CR 9 or N; Z is CR 8 or N; X is O, N or S; and Y is O, N or S.
  • Substituents R 3 , R 3 ', R 4 , R 5 , R 6 , R 6 -, R 8 , and Rg are independently selected from H, halogen, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -L 3 -alkyl, -L 3 -cycloalkyl, -L 3 -heteroalkyl, -L 3 -haloalkyl, -L 3 - aryl, -L ⁇ -heterocycloalkyl, and -L 3 -heteroaryl, wherein L 3 is selected from a bond, O, NH, S, - C(O)-, -C(S)-, -C(O)O- (either orientation), -C(O)NH- (either orientation), -S(O)-, -S(O) 2 , and - S(O)NH- (either orientation); wherein the
  • Substituents R 7 , R 8 , and R 9 are independently selected from the group consisting of H, halogen, and an optionally substituted moiety selected from -L 4 -H, -L 4 -alkyl, -L 4 -cycloalkyl, -L 4 -heteroalkyl, -L 4 -haloalkyl, -L 4 -aryl, - L 4 -heterocycloalkyl, and -L 4 -heteroaryl, wherein L 4 is selected from a bond, O, NH, OCH 2 , NHCH 2 , S, d-C 6 alkylene ,-C(O)-, -C(S)-, -C(O)O- (either orientation), -C(O)NH- (either orientation), -S(O)-, -S(O) 2 , and -S(O)NH- (either orientation); wherein said optional substituents are
  • substituent R 1 is selected from the group consisting of H, OH, NH 2 , SH, NO 2 , CN, and an optionally substituted moiety selected from -L ⁇ alkyl, -L 1 - cycloalkyl, -L ⁇ heteroalkyl, -Li-haloalkyl, -Li-aryl, -Lrheterocycloalkyl, and -L 1 -heteroaryl, wherein L 1 is selected from a bond, O, NH, S 5 -C(O)-, -C(S)-, -C(O)O- (either orientation), - C (O)NH - (either orientation), S(O)-, -S(O) 2 , and -S(O)NH- (either orientation); wherein said optional substituents are selected from halogen, OH, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alky
  • substituents R 2 and R 3 taken together may form an optionally substituted 4 to 8-membered ring; wherein the ring is heterocyclic, cycloalkyl, or aryl.
  • Certain embodiments of Formula (1) are shown below as Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21), Formula (22), Formula (23), Formula (24) and Formula (25).
  • Compounds of Formula (A), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, are considered modulators of the activity of steroid hormone nuclear receptors and, as such, are useful for treating diseases or conditions in which aberrant steroid hormone nuclear receptor activity contributes to the pathology and/or symptoms of a disease or condition.
  • R a is selected from the group consisting of H, halogen, CN, OH, NO 2 , N 3 , NH 2 , SH, and an optionally substituted moiety selected from -L 3 -alkyl, -L 3 -cycloalkyl, -L 3 - heteroalkyl, -L 3 -haloalkyl, -L 3 -aryl, -L 3 -heterocycloalkyl, and -L 3 ⁇ heteroaryl, wherein L 3 is selected from a bond, O, NH, S, -C(O)-, -C(S)-, -C(O)O- (either orientation), -C(O)NH- (either orientation), -S(O)-, -S(O) 2 , and -S(O)NH- (either orientation); wherein the optional substituents
  • Compounds of Formula (B), pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, are considered modulators of the activity of steroid hormone nuclear receptors and, as such, are useful for treating diseases or conditions in which aberrant steroid hormone nuclear receptor activity contributes to the pathology and/or symptoms of a disease or condition.
  • the ring structure J is a heterocycle. In certain embodiments the ring structure J contains at least two heteroatoms, and in further embodiments the heteroatoms of ring structure J are selected from N, O or S.
  • the substituents for compounds of Formula (B) are as with compounds of Formula (1) and Formula (A). Synthesis of the Compounds
  • the starting material used for the synthesis of the compounds of Formula (1) and compounds having the structures described in the prior section as described herein can be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo.), or the starting materials can be synthesized.
  • the compounds described herein, and other related compounds having different substituents can be synthesized using techniques and matenals known to those of skill in the art, such as described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., VoIs.
  • Groups such as trityl, dimethoxytrityl, acetal and t- butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.
  • Allyl blocking groups are useful in then presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a Pdo-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • blocking/protecting groups may be selected from:
  • the synthetic schemes to obtain compounds of Formula (1) may depend on the identity of L and Z.
  • compounds of Formula (2), in which L is N and Z is N may be synthesized according to the exemplary reaction Schemes Ia, Ib, 2a and 2b; compounds of Formula (3) in which L is N and Z is C may be synthesized, according to the exemplary reaction Scheme 4a and 4b; compounds of Formula (4) in which L is C and Z is N may be synthesized, according to the exemplary reaction Scheme 6a and 6b; and compounds of Formula (5) in which L is N and Z is N may be synthesized, according to the exemplary reaction Scheme 6a and 6b.
  • R7 is — R'
  • compounds of Formula (2) can be synthesized according to reaction scheme Ib, wherein anhydride compounds (A) are alkylated or acylated to give compounds of Formula (B). Treatment of compounds of Formula (B) with hydrazine yields the intermediate compounds with Formula (C), which are transformed into chloro- compounds (D) by a chlorination step. Amination of the chloro- compounds (D) with cyano substituted amino compounds produce compounds of Formula (2).
  • compounds of Formula (2) may be synthesized according to the reaction scheme 2a or reaction scheme 2b, wherein a phosphonium salt (F) is successively acylated or alkylated, treated with hydrazine, and then chlorinated to afford chloro-phthalazine compounds (D).
  • Amination of (D) followed by bromination and cyanation (scheme 2a) gives compounds of Formula (2), or alternatively amination of chloro-phthalazine compounds (D) with cyano substituted amino compounds (scheme 2b) also yields compounds of Formula (2).
  • the compounds of Formula (2) may be synthesized according to reaction Scheme 3, wherein the initial Suzuki coupling of dicloro-compounds of Formula (G) with a vinyliguous boronic acid gives compounds of Formula (H), which are animated to give the amino-compounds of Formula (I).
  • Oxidative cleavage of the styrene substituent on the amino-compounds of Formula (I) affords the amino-compounds with an aldehyde substituent (Formula (J)), which may be used for further transformations such as, by way of example only, olefmation, grignard additions, and aldol chemistry, as a method to change the R 7 substituent.
  • the compounds of Formula (2) may also be synthesized according to reaction Scheme 4, wherein the dichloro-compound (G) is subjected to a nucleophilic substitution with an alcohol or an amine to obtain compounds of Formula (K), which is followed by an amination reaction to afford compounds of Formula (L).
  • the X-R' substituent on compounds of Formula (L) may be modified to change the R 7 group in compounds of Formula (2).
  • R7 is X-R'
  • the compounds of Formula (2) may also be synthesized according to reaction Scheme 5, in which the sequences of the steps in Scheme 4 have been reversed, wherein the dichloro-compound (G) is subjected to amination to afford compounds of Formula (M) which is followed by a nucleophilic substitution with an alcohol or an amine to obtain compounds of Formula (L).
  • the X-R' substituent on compounds of Formula (L) may be modified to change the R 7 group in compounds of Formula (2).
  • R 7 is X-R 1
  • Compounds of Formula (2) may also be synthesized according to reaction Scheme 6 and 7, wherein an unsubstituted amine group is substituted with various R 2 groups.
  • phthalazine compounds of Formula (22) is shown, by way of example only, in reaction Scheme 8, wherein an aryl substrate is condensed onto a phthalic anhydride compound to afford an indene-1-one compound.
  • Animation of the chloro-phthalazine compound produces the corresponding amino compound, wherein bromination of this amino compound followed by cyanation (for example using Zn(CN) 2 and Pd(PPh 3 ) 4 under microwave irradiation) affords the phthalazine compounds of Formula (22).
  • R' is Aryl wherein: R 7 is — R'
  • phthalazine compounds of Formula (22) is shown, by way of example only, in reaction Scheme 9, wherein the diclorophthalazine is subjected to a Suzuki coupling with a vinyliguous boronic acid and the resulting styrene substituted chlorophthalazine is animated, thereby creating the styrene substituted aminophthalazine.
  • Oxidative cleavage of the styrene affords an aldehyde which may be used for further transformations such as, by way of example only, olefination, Grignard additions, and aldol chemistry, as a method to change the R 7 substituent and obtain various phthalazine compounds of Formula (22).
  • the phthalazine compounds of Formula (22) may also be synthesized as shown, by way of example only, in reaction Scheme 10, wherein dichlorophthalazine compounds are subjected to a nucleophilic substitution with an alcohol or an amine to obtain substituted chlorophthalazine compounds which are aminated to afford substituted amino-phthalazine compounds.
  • the X-R' substituent on the amino-phthalazine compounds may be modified to change the R 7 group in compounds of Formula (22).
  • the phthalazine compounds of Formula (22) may also be synthesized as shown, by way of example only, in reaction Scheme 11 , wherein the steps of Scheme 8 have been reversed.
  • the dichlorophthalazine compounds are initially aminated to afford substituted amino-phthalazine compounds which are then subjected to a nucleophilic substitution with an alcohol or an amine to obtain substituted aminophthalazine compounds.
  • the X-R' substituent on the amino-phthalazine compounds may be modified to change the R 7 group in compounds of Formula (22).
  • the phthalazine compounds of Formula (22) may also be synthesized as shown, by way of example only, in reaction Scheme 12, wherein substitution of the amine group yields compounds of Formula (22).
  • Compounds of Formula (3) occur when L is N and Z is C. Such compounds can be synthesized according to reaction Scheme 13 a, wherein chloro-compounds (O) are obtained by chlorination of compounds of Formula (N)- The chloro-compounds are then animated to yield compounds of Formula (P), which are brominated and then cyanated to afford compounds of 0 Formula (3).
  • compounds of Formula (3) can be synthesized according to reaction Scheme 13b, wherein chlorination of compounds of Formula (N), followed by amination with an 5 amine compound comprising a cyano substitutent yields compounds of Formula (3).
  • compounds of Formula (4) can be synthesized according to reaction Scheme 15b, wherein chlorination of compounds of Formula (Q), followed by animation with an amine compound comprising a cyano substitutent yields compounds of Formula (4).
  • isoquinoline compounds of Formula (24) is shown, by way of example only, in reaction Scheme 16, wherein an isoquinolinol compound is chloridized with POCl 3 or other chlorination reagents, to afford the corresponding chloro-isoquinoline compound.
  • Animation of the chloro-isoquinoline compound produces the corresponding amino compound, wherein bromination of followed by cyanation (for example using Zn(CN) 2 and Pd(PPh 3 ) 4 under microwave irradiation) affords the isoquinoline compounds of Formula (24).
  • the starting isoquinoline compounds used in the synthesis of compounds of Formula (23) and Formula (24), as shown in reaction Scheme 14 and reaction Scheme 16, may be synthesized by known methods, including, but not limited to, the Gabriel-Colman rearrangement, the Bischler-Napieralski reaction, the Pictet-Gams isoquinoline synthesis, and the Pictet- Spengler isoquinoline synthesis.
  • a non limiting example of the synthesis of an isoquinoline is shown in reaction Scheme 17 (the substituent R' may be in either cis or trans orientation).
  • R 7 is — R 1
  • Compounds of Formula (5) occur when L is C and Z is C. Such compounds can be synthesized according to reaction Scheme 18a, wherein chloro-compounds (U) are obtained by chlorination of compounds of Formula (T). The chloro-compounds are then aminated to yield compounds of Formula (V), which are brominated and then cyanated to afford compounds of Formula (5).
  • naphthalene compounds of Formula (25) is shown, by way of example only, in reaction Scheme 19, wherein a naphthalene compound is chloridized to afford the corresponding chloro-naphthalene compound. Animation of the chloro-naphthalene compound produces the corresponding amino compound, wherein bromination of followed by cyanation (for example using Zn(CN) 2 and Pd(PPh 3 ) 4 under microwave irradiation) affords the naphthalene compounds of Formula (25).
  • the form and other characteristics of the compounds described herein can be applied to compounds having the structure of Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21), Formula (22), Formula (23), Formula (24), Formula (25), Formula (A), Formula (B), as well as to all of the specific compounds that fall within the scope of these generic formula.
  • Compounds of Formula (1) can be prepared as a pharmaceutically acceptable salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • a metal ion for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.
  • Compounds of Formula (1) can be prepared as a pharmaceutically acceptable acid addition salt (which is a type of a pharmaceutically acceptable salt) by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic
  • compounds of Formula (1) can be prepared as a pharmaceutically acceptable base addition salts (which is a type of a pharmaceutically acceptable salt) by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base, including, but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like
  • inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds of Formula (1) can be conveniently prepared or formed during the processes described herein.
  • hydrates of compounds of Formula (1) can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • Compounds of Formula (1) include crystalline forms, also known as polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound.
  • Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • Compounds of Formula (1) in unoxidized form can be prepared from N-oxides of compounds of Formula (1) by treating with a reducing agent, such as, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like in a suitable inert organic solvent, such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 8O 0 C.
  • a reducing agent such as, but not limited to, sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • a suitable inert organic solvent such as, but not limited to, acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 8O 0 C.
  • Prodrugs are generally drug precursors that, following administration to a subject and subsequent absorption, are converted to an active, or a more active species via some process, such as conversion by a metabolic pathway. Some prodrugs have a chemical group present on the prodrug that renders it less active and/or confers solubility or some other property to the drug. Once the chemical group has been cleaved and/or modified from the prodrug the active drug is generated. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug a compound of Formula (1) which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • prodrug a compound of Formula (1) which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues.
  • prodrugs to date has been to increase the effective water solubility of the therapeutic compound for targeting to regions where water is the principal solvent. See, e.g., Fedorak et al, Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm.
  • prodrug derivatives of compounds of Formula (1) can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al.,
  • prodrugs can be prepared by reacting a non-derivatized compound of Formula (1) with a suitable carbamylating agent, such as, but not limited to, 1,1- acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • a suitable carbamylating agent such as, but not limited to, 1,1- acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein are included within the scope of the claims. Indeed, some of the herein- described compounds may be a prodrug for another derivative or active compound.
  • Sites on the aromatic ring portion of compounds of Formula (1) can be susceptible to various metabolic reactions, therefore incorporation of appropriate substituents on the aromatic ring structures, such as, by way of example only, halogens can reduce, minimize or eliminate this metabolic pathway.
  • the compounds described herein may be labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds of Formula (1) may possess one or more chiral centers and each center may exist in the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof.
  • Compounds of Formula (1) can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds described herein, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981, herein incorporated by reference in its entirety.
  • the compounds and methods provided herein may exist as geometric isomers.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • compounds may exist as tautomers.
  • AU tautomers are included within the formulas described herein are provided by compounds and methods herein.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion may also be useful for the applications described herein.
  • compositions and formulations described herein can be applied to compounds having the structure of Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), Formula (8), Formula (9), Formula (10), Formula (11), Formula (12), Formula (13), Formula (14), Formula (15), Formula (16), Formula (17), Formula (18), Formula (19), Formula (20), Formula (21), Formula (22), Formula (23), Formula (24), Formula (25), Formula (A), Formula (B), as well as to all of the specific compounds that fall within the scope of these generic formula.
  • a pharmaceutical composition refers to a mixture of a compound of Formula (1) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical composition containing compounds of Formula (1) can be administered in therapeutically effective amounts as pharmaceutical compositions by any conventional form and route known in the art including, but not limited to: intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.
  • pharmaceutical composition containing compounds of Formula (1) in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody.
  • the liposomes will be targeted to and taken up selectively by the organ, hi addition, the pharmaceutical composition containing compounds of Formula (1) may be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • compounds of Formula (1) can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art.
  • Such carriers enable the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, hi soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols, hi addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets, lozenges, or gels formulated in conventional manner.
  • Parental injections may involve for bolus injection or continuous infusion.
  • the pharmaceutical composition of Formula (1) may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds of Formula (1) can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Formulations suitable for transdermal administration of compounds having the structure of Formula (1) may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • transdermal delivery of the compounds of Formula (1) can be accomplished by means of iontophoretic patches and the like. Additionally, transdermal patches can provide controlled delivery of the compounds Formula (1). The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. An absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the compounds of Formula (1) maybe in a form as an aerosol, a mist or a powder.
  • Pharmaceutical compositions of Formula (1) are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or
  • the compounds of Formula (1) may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas
  • conventional suppository bases such as cocoa butter or other glycerides
  • synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • therapeutically effective amounts of compounds of Formula (1) provided herein are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • compositions comprising a compound of Formula (1) may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the pharmaceutical compositions will include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound of Formula (1) described herein as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form.
  • compositions described herein include the use of JV- oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity.
  • compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • compositions can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • the pharmaceutical compositions may include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers.
  • the pharmaceutical compositions can also contain other therapeutically valuable substances.
  • Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The compositions may be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions may also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • the compounds of Formula (1) can be used in the preparation of medicaments for the treatment of diseases or conditions in which steroid hormone nuclear receptor activity contributes to the pathology and/or symptomology of the disease.
  • a method for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions containing at least one compound of Formula (1), or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject [0159]
  • the compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments.
  • compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. It is considered well within the skill of the art for one to determine such therapeutically effective amounts by routine experimentation (including, but not limited to, a dose escalation clinical trial).
  • compositions containing the compound(s) described herein can be used to treat a disease-state or condition selected from: arteriosclerosis, neurological diseases, cancer, Conn's Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, Barter's Syndrome, congestive heart failure (CHF), conditions associated with excess catecholamine levels, cognitive dysfunctions, psychoses, cognitive conditions, memory disturbances, mood conditions, depression, bipolar condition , anxiety conditions, personality conditions, inflammation, tissue rejection, auto-immunity, malignancies such as leukemias and lymphomas, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granul
  • the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition, m the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (i. e., a "drug holiday").
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant ⁇ i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • synergistic effects can occur with compounds of Formula (1) and other substances used in the treatment of hypokalemia, hypertension, congestive heart failure, renal failure, in particular chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart disease, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction.
  • anti-obesity agents such as orlistat, anti-hypertensive agents, inotropic agents and hypolipidemic agents including, but not limited to,, loop diuretics, such as ethacrynic acid, furosemide and torsemide
  • loop diuretics such as ethacrynic acid, furosemide and torsemide
  • angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolepril
  • inhibitors of the Na-K- ATPase membrane pump such as digoxin
  • ACE/NEP inhibitors such as omapatrilat, sampatrilat, and fasidotril
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
  • the compound provided herein may be administered either simultaneously with the biologically active agent(s), or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein in combination with the biologically active agent(s).
  • the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example o nly either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than four weeks.
  • the combination methods, compositions and formulations are not to be limited to the use of only two agents; we envision the use of multiple therapeutic combinations
  • the compounds of Formula (1) may also be used in combination with procedures that may provide additional or synergistic benefit to the patient.
  • patients are expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of Formula (1) and /or combinations with other therapeutics are combined with genetic testing to determine whether that individual is a carrier of a mutant gene that is known to be correlated with certain diseases or conditions.
  • the compounds of Formula (1) and combination therapies can be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary.
  • the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, preferably within the first 48 hours of the onset of the symptoms, more preferably within the first 6 hours of the onset of the symptoms, and most preferably within 3 hours of the onset of the symptoms.
  • the initial administration can be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof.
  • a compound is preferably administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
  • the length of treatment can vary for each subject, and the length can be determined using the known criteria.
  • the compound or a formulation containing the compound can be administered for at least 2 weeks, preferably about 1 month to about 5 years, and more preferably from about 1 month to about 3 years.
  • the pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compound.
  • the unit dosage may be in the form of a package containing discrete quantities of the formulation.
  • Non- . . limiting examples are packaged tablets or capsules, and powders m vials or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.
  • the daily dosages appropriate for the compounds of Formula (1) described herein are from about 0.03 to 2.5 mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from about 1 to 50 mg active ingredient.
  • the foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD 5O (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED50.
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with minimal toxicity.
  • kits and articles of manufacture are also described herein.
  • Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • Suitable containers include, for example, bottles, vials, syringes, and test tubes.
  • the containers can be formed from a variety of materials such as glass or plastic.
  • the container(s) can comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein.
  • the container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit will typically may comprise one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
  • materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
  • a set of instructions will also typically be included.
  • a label can be on or associated with the container.
  • a label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.
  • 3 -Hydroxy-2-(py ⁇ dme-4-yl)mden- 1 -one can be synthesized by the following procedure.
  • a mixture of phthalic anhydride (6g, 40.5 mmol) and 4-picoline (4.0 ml, 40.6 mmol) is heated to 170 °C for 24 hours.
  • the resulting materials are stirred in boiling ethanol, filtered, and washed with ethanol and diethyl ether, yielding 4.85g of the title compound.
  • 1 H NMR (DMSO-rftf) 8.72 (d, 2H), 8.18 (d, 2H), 7.50 (m, 4H).
  • 3-Hydroxy-2-(pyridine-3-yl)mden-l-one can be synthesized by the following procedure. Sodium methanolate (24.3 g, 0.45 mol) is slowly added to an ice-cooled solution of phthalide (2Og, 0.15 mol), 3-pyridinecarboxaldehyde (14.1 mL, 0.15 mol), and ethyl propionate (75 mL) in methanol (150 ml). The reaction mixture warms to room temperature and after 15 minutes at room temperature the reaction mixture is heated to 65 C for 2.5 hours, and then cooled back to room temperature.
  • 4-(pyridine-4-yl)methyl-2H-phthalazin-l-one can be synthesized by the following procedure.
  • a suspension of 3- ⁇ ydroxy-2-(pyridine-4-yl)inden-l-one (4.85g, 21.8 mmol) in hydrazine monohydrate (25 ml) is Heated to 110 0 C for 8 hours, during which new white precipitate forms. Cooling the reaction mixture to 0 0 C, followed by filtration, and washing with ethanol and diethyl ether afford 4.1g of 4-(pyridine-4-yl)methyl-2H-phthalazin-l-one.
  • Example 3a Synthesis of l-Chloro-4-(4-pyridylmethyl ' )phthalazine.
  • l-Chloro-4-(4-pyridylmethyl)phthalazine can be synthesized by the following procedure. To 4-(pyridine-4-yl)methyl-2H-phthalazin-l-one (2.73g, 11.5 mmol) in acetonitrile (42ml) and HCl/dioxane (4N, 5.74 ml, 23 mmol) is added phosphoryl chloride (2.64 ml, 28.9 mmol). The reaction mixture is stirred at 55 0 C for 30 hours, after which a solution OfNaHCO 3 (11.2Og) in water (137 ml) is added to the ice-cooled white suspension.
  • N-(4-tert-butylthiazole-2-yl)-4-((pyridine-4yl)methyl)phthalazin- 1 -amine can be synthesized by the following procedure.
  • a mixture of l-Chloro-4-(4-pyridylmethyl)phthalazine, (lOOmg, 0.39 mmol), 4-te7*t-butylthiazole-2-amine (91 mg, 59 mmol) and K 2 CO 3 (161 mg, 1.17 mmol) is suspended in 1 ml DMF in a microwave reaction tube, and irradiated to 170 0 C for 30 minutes. The reaction mixture is then dissolved in ethyl acetate, and washed with water and brine.
  • Example 5a Synthesis of N-(4-tert-butyl-5-bromotliiazole-2-vD-4-((pyridine- 4vDmethyDphthalazin- 1 -amine.
  • Example 6a Synthesis of 2-d-(9-pyridin-4-vDmethyl)phthalazin-4-ylamino)-4-tert- butylthiazole-5-carbonitrile.
  • Example 6h Synthesis of 4-tert-Butyl-2-(4-fomiyl-phthalazin-l-ylammo)-thiazole-5- carbonitrile.
  • PHT-8 4-tert-Butyl-2-(4-formyl-phthalazin-l-ylamino)-thiazole-5-carbonitrile
  • PHT-8 is prepared via a standard Suzuki coupling of diclorophthalazine and E-styryl boronic, utilizing Pd(PPh 3 ) 4 and K 3 PO 4 in dioxane at reflux, to afford l-chloro-4-styryl-phthalazine.
  • Example 6i Synthesis of 4-tert-Butyl-2-[4-(cvano-phenyl-methyl)-phthalazin-l-ylaminol- thiazole-5-carbonitrile.
  • PHT-9 4-tert-Butyl-2-[4-(cyano-phenyl-methyl)-phthalazin- 1 -ylamino]-thiazole-5- carbonitrile (PHT-9) can be synthesized by the following the procedure according to Scheme 8. Phenyl-acetonitrile is mixed with dichlorophthalazine and tBuOK and heated.
  • the resulting compound (l-chloro-4-(cyano-phenyl-methyl)-phthalazine) is coupled to 2-amino-4-tert-butyl- thiazole-5-carbonitrile using CuI (0.1 mol equiv), K 3 PO 4 (3 mol equiv) and N,N,N',N'- tetramethyl-ethane-l,2-diamine (5 mol equiv) in dioxane at 180 °C under microwave irradiation for 30 minutes. After cooling, water is added and the solution is extracted with ethyl acetate (EtOAc). The organic layers are combined, washed with water and brine, then dried over MgSO 4 .
  • EtOAc ethyl acetate
  • Example 6k Synthesis of 4-tert-Butyl-2-(4-r( ' pyridm-3-vhiiethyl ' )-aminol-phthalazin-l- ylamino) -thiazole-5-carbonitrile
  • Example 6o Synthesis of 2-(l-(9-pyridin-4-yl s )methyl) ⁇ hthalazin-4-yl-JV-acetylaminoV4- tert-butylthiazole-5-carbonitriJe
  • Example 7a Parenteral Composition [0196] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of Formula (1) is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.
  • Example 7b Oral Composition [0197] To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of Formula (1) is mixed with 750 mg of lactose. The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration.
  • Example 8 Functional Assay of Mineralocorticoid Receptor Antagonism [0198] The MR antagonist activity of the compounds is determined in a mammalian two hybrid reporter system. The N-terminus of MR (MR-NT, sequence coding amino acid 1-597) is fused to the activation domain of the VP 16 gene.
  • the ligand binding domain of MR (MR-LBD, sequence encoding amino acid 672-984) is fused to the DNA binding domain of the yeast Gal4 gene.
  • the MR gene is cloned from a human kidney cDNA library with PCR. [0199] The assay is performed in 384 well plates. Briefly, 293T cells (ATCC) are transfected with expression vectors for Gal4-MR-LBD and VP 16-MR NT, and a luciferase reporter vector containing Gal4 binding sequence (pG5-Luc). Cells are plated in 384 well plates immediately after transfection (approximately 3 x 10 4 cells/well in 50 ⁇ l medium).
  • the medium is supplemented with 3% charcoal-dextran treated fetal bovine serum (Hyclone).
  • Hyclone charcoal-dextran treated fetal bovine serum
  • the cells are then stimulated with 0.4 nM final concentration of aldosterone (Acros) and incubated at 37°C for another 24 hours before the luciferase activity is assayed with 20 ⁇ l of Bright-Glo (Promega) using a luminometer (CLIPR).
  • the expression of luciferase is used as an indicator of aldosterone-induced MR trans-activation.
  • Each compound is tested in duplicates with 12- concentration titration.
  • IC 50 values (defined as the concentration of test compound required to antagonize 50% of aldosterone-induced MR activity) are determined from the dose-response curve.
  • Example 9 Functional Assay of Glucocorticoid Receptor Antagonism [0200]
  • the GR antagonist activity of the compounds is determined in a mammalian two hybrid reporter system.
  • the ligand binding domain of GR (GR-LBD, sequence encoding amino acid 541-778) is fused to the DNA binding domain of the yeast Gal4 gene.
  • the GR gene is cloned from a human lung cDNA library with PCR.
  • the assay is performed in 384 well plates: COS-7 cells (ATCC) are transfected with expression vectors for Gal4-GR-LBD and a luciferase reporter vector containing Gal4 binding sequence (pG5-Luc). Cells are plated in 384 well plates immediately after transfection (approximately 8000 cells/well in 50 ⁇ l medium). The medium is supplemented with 3% charcoal-dextran treated fetal bovine serum (Hyclone). Twenty four hours after transfection, compounds prepared in DMSO are transferred to the cells.
  • the cells are then stimulated with 10 nM final concentration of dexamethasone (Sigma) and incubated at 37 0 C for another 24 hours before the luciferase activity is assayed with 20 ⁇ l of Bright-Glo (Promega) using a luminometer (CLIPR).
  • CLIPR luminometer
  • the expression of luciferase is used as an indicator of dexamethasone-induced GR trans-activation.
  • Each compound is tested in duplicates with a 12-concentration titration.
  • IC 50 values (defined as the concentration of test compound required to antagonize 50% of dexamethasone-induced GR activity) are determined from the dose-response curve.
  • Example 10 Functional Assay of Progesterone Receptor Antagonism
  • the PR antagonist activity of the compounds is determined by progesterone-induced alkaline phosphatase activity in the T-47D cell line (ATCC).
  • ATCC T-47D cell line
  • progesterone specifically induces de novo synthesis of a membrane-associated alkaline phosphatase enzyme in a time and dose-dependent manner (Di Lorenzo et al., Cancer Research, 51: 4470-4475 (1991)).
  • the alkaline phosphatase enzymatic activity can be measured with a chemiluminescent substrate, such as CSPD ® (Applied Biosystems).
  • CSPD ® chemiluminescent substrate
  • T-47D cells are plated in 384 well plates at a density of approximately 2.5 x 10 4 cells/well in 50 ⁇ l medium supplemented with 10% fetal bovine serum. Twenty four hours later, the medium is aspirated. New medium that is free of phenol red and serum is added to the cells. Compounds prepared in DMSO are transferred to the cells. The cells are then stimulated with 3 nM final concentration of progesterone (Sigma) and incubated at 37°C for another 24 hours before the alkaline phosphatase is assayed with 25 ⁇ l of CSPD ® (Applied Biosystems) using a luminometer (CLIPR).
  • progesterone Sigma
  • alkaline phosphatase is used as an indicator of progesterone-induced PR trans-activation.
  • Each compound is tested in duplicates with a 12-concentration titration.
  • IC 5O values (defined as the concentration of test compound required to antagonize 50% of progesterone-mduced PR activity) are determined from the dose-response curve.
  • Example 11 Functional Assay of Androgen Receptor Antagonism
  • the AR antagonist activity of the compounds is determined with the MDA-Kb2 cell line (ATCC), which stably expresses the MMTV luciferase reporter.
  • the MMTV promoter is a mouse mammary tumor virus promoter that contains androgen receptor response elements.
  • the MDA-kb2 cells is derived from the MDA-MB-453 cells, which has been shown to express high levels of functional, endogenous androgen receptor (Wilson et al., Toxicological Sciences, 66: 69-81 (2002)).
  • AR ligands such as dihydrotestosterone
  • the assay is performed in 384 well plates. Briefly, MDA-kb2 cells are plated in 384 well plates at a density of approximately 2.4 x 10 4 cells/well in 50 ⁇ l medium. The medium is supplemented with 5% charcoal-dextran treated fetal bovine serum (Hyclone). Twenty four hours later, compounds prepared in DMSO are transferred to the cells. The cells are then stimulated with 0.3 nM final concentration of dihydrotestosterone (Sigma) and incubated at 37 0 C for another 24 hours before the luciferase activity is assayed with 20 ⁇ l of Bright-Glo (Promega) using a luminometer (CLIPR).
  • CLIPR luminometer
  • luciferase is used as an indicator of dihydrotestosterone-induced AR trans-activation.
  • Each compound is tested in duplicates with a 12-concentration titration.
  • ICs 0 values (defined as the concentration of test compound required to antagonize 50% of dihydrotestosterone-induced AR activity) are determined from the dose- response curve.
  • test compounds were evaluated using the functional assays described above for the different steroid hormone nuclear receptors.
  • the ability of exemplary test compounds to antagonize 50% of the specified steroid hormone nuclear receptor is shown in Table 2 as a range of IC 5O values.
  • Table 2 Ranges of IC ⁇ n values for test compounds required to antagonize 50% of the specified steroid hormone nuclear receptor.

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Abstract

L'invention concerne des composés comprenant un élément structurel diarylamine. L'invention se rapporte également à des procédés de fabrication desdits composés, à des procédés d'utilisation des composés pour moduler l'activité des récepteurs nucléaires des hormones stéroïdes, et à des compositions pharmaceutiques et des médicaments renfermant lesdits composés. L'invention porte aussi sur des procédés d'utilisation des composés, compositions pharmaceutiques et médicaments précités pour traiter et/ou prévenir des maladies et états associés à l'activité des récepteurs nucléaires des hormones stéroïdes.
PCT/US2006/012915 2005-04-06 2006-04-06 Composes et compositions contenant de la diarylamine et utilisation de ces derniers comme modulateurs des recepteurs nucleaires des hormones steroides WO2006108107A1 (fr)

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MX2007012449A MX2007012449A (es) 2005-04-06 2006-04-06 Compuestos y composiciones que contienen diaril-amina, y su uso como moduladores de los receptores nucleares de hormonas esteroideas.
JP2008505543A JP2008536835A (ja) 2005-04-06 2006-04-06 ジアリールアミン含有化合物および組成物、ならびにステロイドホルモン核受容体のモジュレータとしてのそれらの使用
AU2006232109A AU2006232109A1 (en) 2005-04-06 2006-04-06 Diarylamine-containing compounds and compositions, and their use as modulators of steroid hormone nuclear receptors
CA002603250A CA2603250A1 (fr) 2005-04-06 2006-04-06 Composes et compositions contenant de la diarylamine et utilisation de ces derniers comme modulateurs des recepteurs nucleaires des hormones steroides
BRPI0608934-8A BRPI0608934A2 (pt) 2005-04-06 2006-04-06 compostos e composições contendo diarilamina, e seu uso como moduladores de receptores nucleares de hormÈnios esteróides
EP06749458A EP1865775A1 (fr) 2005-04-06 2006-04-06 Composes et compositions contenant de la diarylamine et utilisation de ces derniers comme modulateurs des recepteurs nucleaires des hormones steroides

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BRPI0608934A2 (pt) 2010-02-17
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CA2603250A1 (fr) 2006-10-12
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