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WO2004072041A1 - Tetrahydroquinoleines utilisees comme agonistes des recepteurs hepatiques - Google Patents

Tetrahydroquinoleines utilisees comme agonistes des recepteurs hepatiques Download PDF

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Publication number
WO2004072041A1
WO2004072041A1 PCT/EP2004/001277 EP2004001277W WO2004072041A1 WO 2004072041 A1 WO2004072041 A1 WO 2004072041A1 EP 2004001277 W EP2004001277 W EP 2004001277W WO 2004072041 A1 WO2004072041 A1 WO 2004072041A1
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Prior art keywords
phenyl
cyclohexyl
cycloalkyl
moiety
compounds
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PCT/EP2004/001277
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WO2004072041A8 (fr
Inventor
Hana Koutnikova
Claire Marsol
Michael Sierra
Evelyne Klotz
Anne Braun-Egles
Jürgen LEHMANN
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CARE X SA
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CARE X SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to specific compounds and pharmaceutically acceptable salts thereof; methods for synthesizing these compounds; compositions comprising at least one of these compounds or a pharmaceutically acceptable salt thereof; and methods for modulating liver-X receptors (LXRs) activity.
  • the present invention further concerns methods for treating and/or preventing a disease or disorder selected from the group consisting of dyslipidemia, including hyperlipidemia, dyslipoproteinemia, including hyperlipoproteinemia, disorders related to cholesterol or bile acid metabolisms, including hypercholesterolemia, gall stone or gall bladder disorders, cardiovascular disease, including atherosclerotic cardiovascular diseases, coronary artery diseases, peripheral vascular diseases, cerebrovascular diseases, thrombotic disorders, restenosis or septic shock, CNS diseases including those affecting cognitive function or age related disorders such as Alzheimer's disease, Syndrome X, a liver-X receptor-associated disorder, obesity, pancreatitis, hypertension, renal disease, cancer, rheumatoid arthritis, inflammation, skin proliferative disorders, including ps
  • Lipoproteins are macromolecular complexes formed among others by lipids (e.g. cholesterol and/or triglycerides) and apolipoproteins (e.g. apolipoproteins A, B, C and/or E) that allow lipids to circulate in the blood.
  • lipids e.g. cholesterol and/or triglycerides
  • apolipoproteins e.g. apolipoproteins A, B, C and/or E
  • the chylomicrons density ⁇ 0.94 g/mL
  • VLDL ; d 0.94-1.006 g/mL
  • LDL particles are responsible for the delivery of cholesterol from the liver (where it is synthesized or obtained from dietary sources) to extrahepatic tissues in the body
  • HDL particles play a major role in the transport of cholesterol from peripheral tissues to the liver (i.e. "reverse cholesterol transport” or RCT) where it is ⁇ catabolized and eliminated.
  • lipid metabolism disorders of lipid metabolism, or dyslipidemias, are described in terms of elevation of lipid (cholesterol and/or triglycerides) in general (i.e. total cholesterol and/or triglyceride levels) , and more specifically in lipoprotein particles LDL, IDL and VLDL, or reduction in cholesterol carried in HDL.
  • lipid cholesterol and/or triglycerides
  • NCPEP National Cholesterol Education Program
  • LDL-c low-density lipoprotein cholesterol
  • HDL-c high-density lipoprotein cholesterol
  • TG triglycerides
  • Lpa lipoprotein a
  • LDL-c and/or VLDL-c leads to a reduction in coronary heart disease mortality and morbidity (for a review, e.g., see
  • HDL being implicated in the transport of cholesterol from peripheral tissues to the liver, low concentrations of
  • HDL-c as a percentage of total plasma cholesterol may lead to a failure to efficiently export lipid from the vessel wall, leading to atherosclerotic plaque development, and hence increased cardiovascular risk.
  • Clinical data have shown that there is a 2% to 3% decrease in coronary risk for each 1 mg/dL increase in HDL-c, thus it is commonly called the "good" cholesterol.
  • high levels of plasma HDL-c are not only protective against coronary artery disease, but may actually induce regression of atherosclerotic plaques (e.g., Libby, 2001, Am. J. Cardiol.,
  • VLDL or chylomicron remnants are taken up by the liver.
  • LDLr LDL receptors
  • the VLDL particles are hydrolyzed via the lipoprotein lipase (LPL) to form IDL particles.
  • LPL lipoprotein lipase
  • the liver takes up about 60% of the IDL via the LDLr and the remainder is hydrolyzed by the hepatic lipase (HL) to produce LDL particles.
  • the major role of LDL is to transport cholesterol to the peripheral tissues.
  • cells may synthesise cholesterol, or acquire exogenous cholesterol through upregulation of LDLr resulting in the increased uptake of LDL- c.
  • the LDLr is responsible for removing 60 to 80% of the LDL particles.
  • Increased intracellular cholesterol inhibits the activity of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, and decreases the synthesis of LDLr in order to limit the further uptake of cholesterol into the cell.
  • LDL-c can be modified, e.g.
  • HDL is regarded as essential for reverse cholesterol transport (RCT) , i.e. the removal of cholesterol from peripheral tissue and its transport back to the liver.
  • RCT reverse cholesterol transport
  • Nascent HDL pre beta-HDL
  • ABCA-1 ATP-binding cassette transporter 1
  • HDL 2 may (i) deliver cholesterol to the liver through interactions with hepatic HDL receptors (also called SR-B1 ) and be converted back to HDL 3 ; (ii) exchange lipids with other lipoprotein classes through Cholesteryl Ester Transfer Protein (CETP) mediated transfer; or (iii) be taken up as a whole by the liver.
  • LCAT lecithin-cholesterol acyltransferase
  • CE cholesteryl esters
  • HDL-c however, each has its own drawbacks and limitations in terms of efficacy, side-effects and qualifying patient populations : '
  • statins which are inhibitors of 3-Hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase (the rate- limiting enzyme in cholesterol biosynthesis)
  • HMG-CoA 3-Hydroxy-3- methylglutaryl-coenzyme A reductase
  • statins are mevastatin, lovastatin (MevacorTM, Merck) , pravastatin (PravacholTM, Sankyo / Bristol-Myers Squibb) and simvastatin (ZocorTM, Merck) .
  • statins examples include fluvastatin (LescolTM, Novartis) , atorvastatin (LipitorTM, Pfizer) and rosuvastatin (CrestorTM, AstraZeneca) , cerivastatin (BaycolTM, Bayer) and pitavastatin.
  • This class of drugs significantly reduces TG (10-37%), total cholesterol (15-45%), LDL-c (20-50%), but with only a modest (2-12%) increase in HDL-c concentrations.
  • benefits from these therapies not only vary from subject to subject, but is additionally associated with side effects.
  • fibric acid derivatives affect the expression of genes implicated in the regulation of HDL and TG-rich lipoproteins as well as fatty acid metabolism via the activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) .
  • the current fibrates are all low potency PPAR-alpha agonists (i.e., they require high micromolar concentrations for receptor activation) , which may explain why high doses are required for their clinical activity.
  • Clofibrate and gemfibrozil are two of the oldest known fibrates, while bezafibrate, fenofibrate and ciprofibrate illustrate the second generation.
  • the new fibrates reduce TGs (20-60%) and increase HDL-c (10-35%), however, the effects of these drugs on serum cholesterol are variable and it is not always possible to predict which patients will benefit from treatment.
  • prevention of coronary heart disease was observed in male patients between 40-55 without history or symptoms of existing coronary heart disease, it is not clear to what extent these findings can be extrapolated to other patient populations (e.g., women, older and younger males) . Indeed, no efficacy was observed in patients with established coronary heart disease.
  • fibrates have been approved for use as hypolipidemic drugs, but have not received approval as hypercholesterolemia agents. Additionally, serious side-effects are associated with the use of fibrates including toxicity such as malignancy (e.g. gastrointestinal cancer) , gallbladder disease and an increased incidence in non-coronary mortality. Other side effects are nausea, diarrhea, indigestion, headache, loss of libido, skin rash, and drowsiness occurs less frequently. Toxicological studies have shown that the liver, muscle and kidney are potential target organs and tissues. Moreover, the fibrates are contraindicated in pregnant or lactating women, or patients with severe liver or renal impairment or existing gallbladder disease.
  • bile acid sequestrants (iii) bile acid sequestrants (BAS) / cholesterol absorption inhibitors.
  • the bile acid sequestrants anion- exchange resins
  • anion- exchange resins are non-systemic drugs acting by binding bile acids within the intestinal lumen, thus interfering with their re-absorption and enhancing their fecal excretion. This leads to the increased hepatic conversion of cholesterol to bile acid via upregulation of cholesterol 7beta-hydroxylase activity.
  • the liver's increased requirement for cholesterol is partially met through an increased hepatic removal of circulating LDL-c via up-regulation of hepatic LDL receptors.
  • cholestyramine which is a copolymer of polystyrene and divinylbenzene or colestipol which is the hydrochloride salt of a copolymer of diethylenetriamine and 1 - chloro-2 , 3-epoxypropane .
  • Both cholestyramine and colestipol are effective cholesterol-lowering drugs in monotherapy as well as in combination with statins, fibrates, niacin or probucol (see below) , however, the BAS use is limited due to the need of large doses to achieve efficacy and their side effect profile (i.e.
  • colesevelam a third generation bile acid sequestrant with increased in vi tro potency, has shown similar LDL-lowering efficacy at much lower doses without the side effects associated with the other bile acid sequestrants.
  • colesevelam is limited to the treatment of persons with moderate hypercholesterolemia (e.g., Davidson et al, 1999, Arch. Intern. . Med. , 159, 1893-1900).
  • Ezetimibe (ZetiaTM, Schering-Plough) is a cholesterol absorption inhibitor preventing the absorption of cholesterol by inhibiting the transfer of dietary and biliary cholesterol across the intestinal wall.
  • nicotinic acid (niacin) derivatives reduce TG (20-
  • niacin is not very well tolerated. Nearly all patients suffer from serious side effects, including itching, flushing and gastrointestinal intolerance. Additionally, current guidelines do not recommend the use of niacin in patients with diabetes because it can exacerbate gout and worsen glycemic control.
  • HRT Hormone Replacement Therapy
  • HRT is associated with side effects including an increased relative risk of breast and endometrial cancer with each year of treatment, as well as a risk of venous and pulmonary thromboembolism and possibly with ovarian cancer, induction of gall bladder disease, thromboembolic disease, hepatic adenoma, elevated blood pressure, glucose intolerance, and hypercalcemia .
  • estrogen modulators such as tamoxifen, toremifene and raloxifene
  • tamoxifen, toremifene and raloxifene are used in postmenopausal women in the treatment of breast cancer and in the prevention of osteoporosis. All these drugs have been demonstrated to further reduce total cholesterol and LDL-c. Unlike HRT, tamoxifen, toremifene and raloxifene have been shown not to increase the risk of breast and endometrial cancer.
  • Plant sterols and stanols inhibit the intestinal absorption of cholesterol and as a result lower plasma LDL-c concentrations. They are found, in varying degrees, naturally in almost all vegetables. The most abundant of the phytosterols is beta-sitosterol and the fully saturated derivative of beta-sitosterol is sitostanol. Plant sterols are absorbed to a small extent while plant stanols are virtually non-absorbable . Thus, intestinal levels of stanols will be prolonged compared to that of sterols, which may explain why plant stanols appear to be more effective in decreasing cholesterol absorption and reducing serum LDL levels . Plant stanols have also been shown to reduce serum cholesterol levels in patients on statin therapy.
  • Sterol and stanol esters can be used as food additives to allow adequate amounts to be consumed without affecting food quality or dietary habits.
  • Low fat stanol or sterol ester-containing margarines in combination with a low fat diet have been shown to reduce LDL- c levels in hypercholesterolemic subjects. Unless consumed at extraordinarily high levels, practically no side effects have been observed.
  • liver X receptors (LXR-alpha, NR1 H3 , and LXR-beta, NR1H2) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. These proteins contain a central DNA-binding domain consisting of two zinc- finger motifs and a large ligand-binding domain with a lipophilic core that specifically binds small lipid molecules such as naturally occurring oxidized derivatives of cholesterol, including 22 (R) -hydroxycholesterol, 24 (S)- hydroxycholesterol , and 24, 25 (S) -epoxycholesterol (see, Lehmann, et al . , 1997, J. Biol. Chem. , 272, 3137-3140).
  • LXR-alpha is highly expressed in liver, and is also found in adipose, intestine, kidney and macrophages. LXR- beta expression is detectable in nearly every tissue examined.
  • cholesterol homeostasis-related genes have been identified as direct LXRs target genes, e.g., ATP-binding cassette transporters A1 (ABCA1 ) , G1 (ABCG1 ) , G5 (ABCG5) and G8 (ABCG8) , cholesterol 7-alpha-hydroxylase (CYP7A1 ) , phospholipid transfer protein (PLTP) , cholesteryl ester transfer protein (CETP) , Apolipoprotein E (ApoE) , stearoyl CoA desaturasesl and 2 (Scd1 , Scd2) (Sun et al . , J. Biol. Chem.
  • LPL lipoprotein lipase
  • ACC acetyl-CoA carboxylase
  • LXRs exert an important atheroprotective effect in macrophages and that systemic administration of an LXR agonist reduced atherosclerosis in mouse models. More recent studies have further demonstrated that activation of the LXR pathway antagonizes inflammatory gene expression and reduces inflammation, thus raising the possibility that LXR agonists have utility in the treatment of other chronic inflammatory diseases (Joseph et al . , 2003, Nat. Med. , 9, 213 - 219).
  • LXR-beta share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities, they activate distinct target genes and thus their respective activation can result in distinct in vivo pharmacological effects, especially in the context of lipid metabolism.
  • LXRs especially LXR-alpha
  • LXR-alpha have been shown to be exciting new targets for the development of therapeutic compounds that by modulating LXRs activity are likely to have utility at least in the treatment and/or prevention of diseases or disorder that are associated, directly or indirectly, with dyslipidemia, dyslipoproteinemia and/or disorders related to cholesterol metabolism, as well as vascular or inflammatory diseases or disorders, or diseases or disorders associated with deficiency of at least one LXRs target gene expression.
  • LXRs modulating compounds are provided, e.g., in US20020193357 , US20020048572 , US6316503, WO0224632, WO0103705.
  • Schultz et al . , 2000, Gene and Dev. , 14, 2831-2838 have further shown that LXR agonists may have pharmacologic effects that are both desirable
  • the general problem underlying the invention is to develop new modulators of the LXRs activity.
  • the Applicant has now identified compounds of general formula (I) below, their derivatives, their analogues, their pharmaceutically acceptable solvates or salts and pharmaceutical compositions containing them or mixtures thereof.
  • Another objective of the present invention is to provide compounds of the general formula (I) and their derivatives, their analogues, their pharmaceutically acceptable solvates or salts and pharmaceutical compositions containing them or mixtures thereof, which may have agonist activity against LXRs.
  • said agonist presents a partial agonist activity against LXRs.
  • Another objective of the present invention is to provide compounds of the general formula (I) and their derivatives, their analogues, their pharmaceutically acceptable solvates or salts and pharmaceutical compositions containing them or mixtures thereof having enhanced activities towards LXRs without undesirable effects or with reduced undesirable effects .
  • Still another objective of the present invention is to provide methods which use the compounds or compositions of the Invention as the active ingredient for the treatment and/or prophylaxis of various diseases and conditions which can be controlled by LXRs, including metabolic or cell proliferative disorders such as, for example, diseases and conditions related to pathologic levels or ratios of lipids (e.g. dyslipidemia, including hyperlipidemia, dyslipoproteinemia, including hyperlipoproteinemia, disorders related to cholesterol or bile acid metabolisms, including hypercholesterolemia, gall stone or gall bladder disorders) ; as well as vascular or inflammatory diseases or disorders (e.g.
  • cardiovascular disease including atherosclerotic cardiovascular diseases, coronary artery diseases, peripheral vascular diseases, cerebrovascular diseases, thrombotic disorders , restenosis, rheumatoid arthritis, or septic- shock); diseases or disorders associated with malfunctioning (including deficiency) of the expression of at least one LXRs target gene; CNS diseases including those affecting cognitive function or age related disorders such as Alzheimer's disease ; diseases or disorders related to lipid storage such as obesity, diabetes (including type 2 diabetes) , hypertension ; skin proliferative disorders, including psoriasis, atopic dermatitis or acne ; sexual impotence, renal disease and cancers .
  • Still another objective of the present invention is to provide methods which use the compounds or compositions of the Invention as the active ingredient for lowering one or more of the following biological entities in the treated patient: triglycerides, fatty acids, total cholesterol, LDL-c, VLDL-c, bile acid and the like.
  • Still another objective of the present invention is to provide methods which use the compounds or compositions of the Invention as the active ingredient for increasing the HDL-c level .
  • Another objective of the present invention is to provide methods which use the compounds or compositions of the
  • Another objective of the present invention is to provide methods of treatment and/or prophylaxis as above mentioned resulting, in the treated patient, in enhanced beneficial effects (e.g. lowering serum cholesterol, increasing HDL-c serum levels, enhancing RCT) without adverse effects or with reduced adverse effects .
  • enhanced beneficial effects e.g. lowering serum cholesterol, increasing HDL-c serum levels, enhancing RCT
  • LXRs is intended to designate both LXR-alpha and/or LXR-beta without distinction.
  • the present invention concerns compounds of the general formula (I) :
  • R 1 is a moiety selected in the group consisting of -H, C n' H 2n + i , a cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety or a cycloheptyl) , a -(CH 2 ) n - cycloalkyl moiety (e.g.
  • R 2 , R 3 , R 4 , R 11 are, independently from one another, a moiety selected in the group consisting of :
  • a, b and ⁇ are, independently from one another, an integer ranging from 0 to 4 ;
  • Ai and A 2 are, independently from one another, a moiety selected in the group consisting of -CO-, -O- -S0 2 -, -CH-, -CH2-, -NH-, -N(C n ,H2n '+ i) .
  • -N( cycloalkyl)- [e.g. -N (cyclohexyl) - or -N (phenyl)-] and -CHOH- ;
  • R 8 , R 9 , R 10 , R 12 are independently from one another, a moiety selected in the group consisting of :
  • R 5 , R 6 and R 7 are, independently from one another, a moiety of the following general formula : -(R 11 ) n -R 12 ;
  • a 3 , A and A 5 are, independently from one another, a atom selected in the group consisting of C, N, 0 and S ;
  • R 13 , R 14 , R 15 are, independently from one another, a moiety selected in the group consisting of H, -Cl, - CF 3 , -F, -Br, -CN, -Cn ' H 2n'+ i i a cycloalkyl moiety (e.g. a cyclohexyl or a phenyl moiety or a cycloheptyl) , -(CH 2 ) n C0 2 H, -CH(CH 2 ) 2
  • a cycloalkyl moiety e.g. a cyclohexyl or a phenyl moiety or a cycloheptyl
  • -0-(CH 2 ) n - cycloalkyl e.g. -0- (CH 2 ) n -cyclohexyl or -0-(CH 2 ) n - phenyl) , -0- (CH 2 ) n C0 2 H, -COH, -CO-C n' H 2n , +1 , -CO- (CH 2 ) n -cycloalkyl
  • cycloalkyl e.g. -S0 2 -CO-cyclohexyl or -S0 2 -CO- phenyl
  • cycloalkyl e.g. -S0 2 -CO-cyclohexyl or -S0 2 -CO- phenyl
  • -0-S0 2 H e.g. -S0 2 -CO-cyclohexyl or -S0 2 -CO- phenyl
  • -0-S0 2 -CO- (CH 2 ) n - cycloalkyl e.g.
  • -NH-CO- (CH 2 ) n -cycloalkyl e.g. -NH-CO- (CH 2 ) n - cyclohexyl or -NH-CO- (CH 2 ) n -phenyl
  • -NH-CO-cycloalkyl e.g.
  • -S- (CH 2 ) n -cycloalkyl e.g. -S- (CH 2 ) n -cyclohexyl or -S-(CH 2 ) n - phenyl)
  • -S-CO- (CH 2 ) n - cycloalkyl e.g. -S-CO- (CH 2 ) n -cyclohexyl or -S-CO- (CH 2 ) n -phenyl
  • -S-CO- (cycloalkyl e.g.
  • N(R 16 ) (R 16* ) , -NR 15 -S0 2 CF 3 , -NR 16 -S0 2 (C n' H 2 n '+ i ) , with R 16 and R 16* are, independently from one another, a moiety selected in the group consisting of H and a C-
  • R 18 is a moiety selected in the group consisting of H, -C n >H2 '+ _ / -(CH2) n C0 2 H, -CH(CH 2 ) 2 , - (CH 2 ) n -CO-C n' H n'+ i , -OH, -OCF3, -OC n , H 2 n '+ ⁇ ,-0- (CH 2 ) n C0 2 H, -COH, -CO-C n , H 2n'+ ⁇ , -CO- (CH 2 ) n C0 2 H, -O-benzoyl, -S0 2 H, -S0 2 -Cn'H 2n ' + i , -0-S0 2 H, -0-S0 2 -C n' H2n' +. , -N0 2 ,
  • n is, independently from one another, an integer ranging from
  • n' is, independently from one another, an integer ranging from
  • 1 to 8 preferably from 1 to 4, preferably from 1 to 3 and more preferably from 1 to 2.
  • the moiety is :
  • a mono carbocyclic ring i.e. a cyclic carboalkyl, with A 3 , A and A 5 are C
  • a mono heterocyclic ring i.e. a cyclic heteroalkyl, with at least one A 3 , A 4 and/or A 5 is selected in the group consisting of N, S and O
  • a bi- carbocyclic ring i.e. a bicyclic carboalkyl with A 3 , A 4 and A 5 are C
  • a bi- heterocyclic ring i.e. a bicyclic ' heteroalkyl with at least one cyclic ring is containing at least one A 3 , A 4 and/or A 5 selected in the group consisting of N, S and 0.
  • said carbocyclic and/or heterocyclic ring (including both mono and bi) can be unsaturated, or partially or completely saturated, and is containing from 5 to 10 atoms
  • Examples of said carbocyclic and/or heterocyclic rings are :
  • the substituting moiety is localized in position para or meta.
  • At least one moiety selected in the group R 5 , R 6 and R 7 is a hydrogen-bound acceptor.
  • At least one moiety selected in the group R 5 , R 6 and R 7 is in position 6 or/and position 7 with :
  • (I) is containing a cycloalkyl, said cycloalkyl being itself substituted with at least one moiety R 17 , with R 17 is a moiety selected in the group consisting of H, -Cl, - CF 3 , -F, -Br, -CN, -C n /H 2n'+1.
  • R 17 is a moiety selected in the group consisting of H, -Cl, - CF 3 , -F, -Br, -CN, -C n /H 2n'+1.
  • a cycloalkyl moiety e.g.
  • a cyclohexyl or a phenyl moiety or a cycloheptyl , -(CH 2 ) n C0 2 H, -CH(CH 2 ) 2 , -(CH 2 ) n -CO-CpenH 2n +1 , -(CH 2 ) n -CO-cycloalkyl (e.g. -(CH 2 ) n -
  • -NH-CO- (CH 2 ) n-cycloalkyl e.g. -NH-CO- (CH 2 ) n - cyclohexyl or -NH-CO- (CH 2 ) n -phenyl
  • -NH-CO-cycloalkyl e.g. -NH-CO-cyclohexyl or -NH-CO-phenyl
  • -SH e.g. -SC n ⁇ 2 n '+ .
  • -S- (CH 2 ) n -cycloalkyl e.g.
  • R 16 and R 16* are, independently from one another, a moiety selected in the group consisting of H and a C 1 - 4 alkyl moiety.
  • Such a derivative of compound of formula (I) is considered as a special embodiment of the present invention.
  • alkyl as used herein, alone or in combination, is intended to designate a straight or branched chain, or cyclic carbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multi-moities .
  • an alkyl moiety will have from 1 to 24 carbon atoms, with those moieties having 10 or fewer carbon atoms being preferred in the present invention.
  • the alkyl moieties of the invention are lower alkyl.
  • a "lower alkyl” e.g. C n >H 2n'+ i
  • n' ⁇ 8 preferably six or fewer carbon atoms (e.g. n' ⁇ 6) , and even more preferably 4 or fewer carbon atoms (i.e. C-
  • a C ⁇ _ 4 alkyl moiety according to the invention will have from 1 to 2 carbon atoms, with those moieties having 1 carbon atom being preferred in the present invention.
  • saturated alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, (cyclohexyl) methyl, cyclopropylmethyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n- heptyl, isoheptyl, n-octyl, and the like.
  • an unsaturated alkyl moiety is one comprising one or more double bonds or triple bonds.
  • unsaturated alkyl moieties include, but are not limited to, aromatic cycles such as phenyl and benzyl.
  • alkyl is intended to further include those derivatives of alkyl comprising at least one heteroatom, selected from the group consisting of 0, N and/or S (i.e. at least one carbon atom is replaced with one heteroatom) .
  • These alkyl derivatives are widely named "heteroalkyl” and as alkyl above described are intended to designate, by themselves or as part of another substituent, stable straight or branched chains, or cyclic moieties, or combinations thereof.
  • the nitrogen and sulfur atoms when present in the said heteroalkyl are further oxidized and/or the nitrogen heteroatom is quaternized.
  • the heteroatom may be placed at any position of the heteroalkyl moiety, including the position at which the alkyl moiety is attached to the remainder of the molecule.
  • cycloalkyl and heterocycloalkyl by themselves or as part of another substituent, are intended to designate cyclic versions of the above “alkyl” and “heteroalkyl”, respectively. They include bicyclic, tricyclic and polycyclic versions thereof.
  • n is an integer ranging from 0 to 4, more particularly from 0 to 2, and even more particularly from 0 to 1. In a special case it is 0.
  • the compounds of formula I are comprising several moieties and/or atoms that can be present many times throughout one particular formula I (e.g. A 1 -A 5 , R 3 , R 4 , R 8 , R 9 ...) ; it should be understood that each individual moieties and/or atoms throughout the formula I in a particular compound can be chosen independently from one another.
  • _ 4 alkyl is intended to designate a straight or branched chain, which may be fully saturated, mono- or polyunsaturated, having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, iso- propyl , and the like.
  • a C ⁇ _ 4 alkyl moiety will have from 1 to 2 carbon atoms, with those moieties having 1 carbon atom being preferred in the present invention.
  • An unsaturated alkyl moiety is one comprising one or more double bonds or triple bonds .
  • analogues, derivatives, solvates or salts of compounds of the present invention include both the structural derivatives and analogues of said compounds, their pharmaceutically acceptable solvates or salts, their stereoisomers , esters, prodrug forms, or their polymorphs. All these type of compounds are herein designated by the generic term “compounds” .
  • the compounds of the present invention may be utilized in the form of a pharmaceutically acceptable salt thereof.
  • the physiologically acceptable salts of the compounds of Formula (I) and/or (II) include conventional salts prepared with pharmaceutically acceptable acids or bases, depending on the particular substituents found on the compounds described herein for dosing in mammals, especially humans.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, formic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, perchloric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, lactic, propionic, isobutyric, palmoic, maleic, glutamic, hydroxymaleic, malonic, benzoic, succinic, glycolic, suberic, fumaric, mandelic, phthalic, salicylic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, hydroxynaphthoic, hydroiodic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, formic, monohydr
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, lithium, calcium, aluminium, ammonium, barium, zinc, organic amino, or magnesium salt, N, N 1 -dibenzylethylenediamine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine salts (e.g. chloroprocaine) and the like.
  • salts of amino acids such as arginate and the like
  • salts of organic acids like glucuronic or galactunoric acids and the like
  • certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present invention may be utilized in the form of a pharmaceutically acceptable solvate thereof.
  • solvates may be prepared by conventional methods such as dissolving the compounds of formula (I) and/or (II) in solvents such as methanol, ethanol and the like.
  • References hereinafter to a compound according to the invention include both compounds of Formula (I) and/or (II) and their pharmaceutically acceptable salts and solvates.
  • stereocenters exist in compounds of Formula (I) and/or (II) . Accordingly, the present invention includes all possible stereoisomers including optical and geometric isomers of Formula (I) and/or (II) . It further includes not only racemic compounds, or racemic mixtures thereof, but also the optically active isomers as well.
  • a compound of Formula (I) and/or (II) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by a stereospecific synthesis from either optically pure starting material or any convenient intermediate.
  • the present invention is intended to include all tautomeric forms of the compounds.
  • diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chr ⁇ matography.
  • Pure stereoisomers may also be prepared synthetically from the appropriate stereochemically pure starting materials, or by using stereoselective reactions.
  • the relative stereochemistry of the compounds of the Invention is SYN.
  • the compounds of the present invention might be in a prodrug form.
  • a prodrug is in most cases a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. Therefore, prodrugs of a compound of general formula (I) and/or (II) is a compound which has chemically or metabolically cleavable groups and which readily undergoes chemical changes under physiological conditions to provide a compound of formula (I) and/or (II) in vivo .
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, alkyl esters prepared by reaction of the parent acid compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine .
  • Particularly preferred alkyl esters as prodrugs are formed from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, and N,N-diethylglycolamido .
  • Methyl ester prodrugs may be prepared by reaction of the ' acid form of a compound of general formula (I ) in a medium such as methanol with an acid or base esterification catalyst (e.g., NaOH, H 2 S0 4 ) .
  • Ethyl ester prodrugs are prepared in similar fashion using ethanol in place of methanol. Details regarding prodrugs are available for example in US 5,498,729.
  • Those skilled in the art are further able to prepare various polymorphs of a compound of general formula (I) and/or (II) for example by crystallization of compound of formula (I) and/or (II) under different conditions. For example, he can use different solvents or mixtures commonly used for crystallization. Similarly, he can crystallize compounds of general formula (I) and/or (II) at different temperatures, according to various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other ' techniques .
  • the compounds of the invention may be labeled in a variety of ways.
  • the compounds may contain radioactive isotopes such as, for example H 3 (tritium) or C 14 at one or more of the atoms that constitute compounds of general formula (I) and/or (II) .
  • the compounds may be advantageously joined directly, covalently or noncovalently, or through a linker molecule, to a wide variety of other moieties, which may provide function as carriers, labels, adjuvents, coactivators, stabilizers, etc.
  • labeled and joined compounds are contemplated within the present invention.
  • the present invention concerns more specifically compound selected in the group consisting of :
  • composition comprising at least one compound of the general formula (I) and/or (II) as above disclosed.
  • the compounds and compositions of the present invention are further characterized by their properties towards nuclear receptor LXRs. More specifically, representative compounds and compositions of the Invention were demonstrated to have pharmacological activity in in vitro and in vivo assays, e.g., they are capable of specifically modulating a cellular physiological response to reduce an associated pathology or provide or enhance a prophylaxis. More specifically, the Applicant has shown that the compounds of general formula (I) and/or (II) are first able to interact with at least one LXR receptor, more specifically with LXR-alpha or LXR-beta; they are thus named LXR, LXR-alpha or LXR-beta ligands, respectively.
  • More preferred compounds are those, which are able to interact at least with the ligand binding domain (LBD) of at least one LXR receptor, more specifically with the LBD of LXR-alpha (i.e. amino acids 164-447 for human LXR-alpha
  • the compounds and compositions of the invention are those which bind to the LBD of at least one LXR receptor, more specifically with the LBD of LXR-alpha or of LXR-beta, with an affinity of less than about 1 uM and more than about 1nM, with concentrations in the range of about 10 to about 500nM being preferred.
  • the compounds or compositions of the Invention are those which bind to the LBD of LXR-alpha (i.e. LXR-alpha ligands).
  • the compounds of the Invention can include racemic compounds, racemic mixtures thereof, or optically active isomers. Accordingly the said measured affinity can vary for one special compound of the Invention depending on its racemic status.
  • the compounds and compositions of the invention are those which under their form of racemate are binding to the LBD of at least one LXR receptor, more specifically with the LBD of LXR-alpha, with an affinity of less than about 1 uM and more than about 1nM, and which under the dextrogyre or levogyre form have an affinity of less than about 500nM, more specifically less than about 250nM.
  • FRET Fluorescence Resonance Energy Transfer
  • CARLA CoActivator-dependent Receptor Ligand Assay
  • GST-pull down assays or two-hybrid assays see Experimental Section
  • the compounds of the present invention modulate the transcriptional activity of LXRs (i.e. they are useful for modulating LXRs functions) .
  • “Modulate the transcriptional activity of LXRs” means that the compounds of the present invention are able to effect transcriptional activation and/or to inhibit or silence transcription of genes which are transcriptionally modulated (i.e. activated and/or inhibited or silenced) by the said nuclear receptors and thus the biological and/or pharmacological effects mediated by these nuclear receptors.
  • the compounds and compositions of the present invention are able to modulate the transcriptional activity of either LXR-alpha or LXR-beta, i.e. they are useful for modulating either LXR-alpha or LXR-beta function, and thus the biological/pharmacological responses mediated by said nuclear receptors, respectively.
  • LXR- alpha functions may be first evaluated in vi tro for their ability to modulate LXR receptors biological effects using biochemical assays (see, for example, the assays above mentioned; e.g. AlphaScreenTM technology) or in cell-based assays.
  • biochemical assays see, for example, the assays above mentioned; e.g. AlphaScreenTM technology
  • cell-based assays For example, a system for reconstituting ligand- dependent transcriptional control has been developed by Evans et al . , 1988, Science, 240, 889-95 and has been termed "co- transfection” or "cis-trans” assay. This assay is described in more detail in US 4,981,784 and US 5,071,773, which are incorporated herein by reference.
  • the co-transfection assay provides a method to evaluate the ability of a compound to modulate the transcriptional response initiated by a nuclear receptor, for example LXRs.
  • the co- transfection assay is a functional, rapid assay that monitors hormone or ligand activity, is a good predictor of the in vivo activity, and can be used to quantitate the pharmacological potency and utility of such ligands in treating various disease states (Berger et al . , 1992, J. Steroid Biochem Molec . Biol., 41, 733-38).
  • the co-transfection assay involves the introduction of various plasmids by transient transfection into a mammalian cell : at least a plasmid which contains a nuclear receptor receptor cDNA (e.g.
  • LXR-alpha or LXR-beta directs constitutive expression of the encoded receptor ; and at least a plasmid which contains a cDNA that encodes for a readily quantifiable protein, e.g., firefly luciferase, chloramphenicol acetyl transferase (CAT) , or alkaline phosphatase (SPAP or . SEAP) , under control of a promoter containing at least one LXR response element, which confers LXR dependence on the transcription of the reporter gene.
  • This assay can be used to accurately measure efficacy and potency of interaction and modulating activity of a reference ligand compound or of a tested compound. Actually, when added to the assay, if the reference or tested compound binds to the nuclear receptor, the later undergoes a conformation change that promotes or inhibits transcription of the reporter genes .
  • Voegel et al . (1998, EMBO J. 17, 507-519) have proposed the use of transient transfection assays with a GAL4 reporter plasmid and chimeras containing various peptide fragments (i.e. putative or identified LBD of LXRs or LXR- alpha/beta) fused to the GAL4 DBD (DNA Binding Domain) .
  • the resultant construct is introduced into cells (e.g. HEK293, yeast,...) together with UAS-containing reporter construct (e.g. luciferase) .
  • the co-transfected cells are then treated with chemical compounds and reporter activity is measured. Individual compounds are evaluated relative to a control (e.g. without compound) and the EC 50 is determined as the concentration necessary to produce 50% of the maximal reporter activity observed with a reference ligand compound previously identified and used in the art.
  • Examples of adapted cell models are HepG2 (liver - ATCC HB-8065) , THP-1 (macrophage - ATCC TIB-202) , Caco-2 or HT-29 (Intestine - ATCC HTB-37 and ATCC HTB-38, respectively) .
  • the modulator effect of the compounds and compositions of the Invention on the expression of LXRs target genes can be tested in animal model, such as for example mice strain C57/BL6 (Schultz - infra) or hamster or rabbit.
  • the examined target gene are selected in the group consisting of LXRs target gene encoding products implicated in lipogenesis (e.g.
  • LXR-alpha animal models e.g., LXR-alpha (+/-) and (-/-) mice
  • LXR-alpha (+/-) and (-/-) mice can be used for evaluation of the present compounds and compositions (see, for example, Peet, et al . 1998, Cell, 93, 693-704).
  • the modulating property of the compounds and compositions of the present invention towards LXRs can be characterized in a cell-based assay or a peptide-sensor assay as presented above and are defined by their ability to improve, mimic, compete or block the effects of a LXRs full agonist or reference molecule, such as the naturally occurring sterols 24 (S), 25-epoxycholesterol and 24 (S) -hydroxycholesterol, or synthetic reference LXR full agonist e.g. T0901317 (Tularik) , F3MethylAA (Merck) or GW3965 (Glaxo SmithKline) .
  • a LXRs full agonist or reference molecule such as the naturally occurring sterols 24 (S), 25-epoxycholesterol and 24 (S) -hydroxycholesterol, or synthetic reference LXR full agonist e.g. T0901317 (Tularik) , F3MethylAA (Merck) or GW3965 (
  • the compounds and compositions of the present invention are LXRs and/or LXRs LBD agonists. According to another embodiment, the compounds and compositions of the present invention are specific agonist towards LXR-alpha and/or LXR-alpha LBD. According to another embodiment, the compounds and compositions of the present invention are specific agonist towards LXR-beta and/or LXR- beta LBD.
  • agonist is meant a compound or composition which when combined with an intracellular receptor stimulates or increases a reaction typical for the receptor, e.g., transcription activation activity. In one embodiment, said agonist is a LXR-alpha agonist, i.e.
  • a LXR ligand which potentiates, stimulates, induces or otherwise enhances the transcriptional activity of a LXR-alpha receptor, e.g., such as by mimicking a natural physiological ligand for the receptor.
  • said agonist is a LXR-beta agonist, i.e. a LXR ligand which potentiates, stimulates, induces or otherwise enhances the transcriptional activity of a LXR-beta receptor, e.g., such as by mimicking a natural physiological ligand for the receptor.
  • a drug that produces at least the possible maximal effect i.e. the maximal effect produced by a full agonist such as for example the above cited reference molecules
  • full agonist A drug that produces at least the possible maximal effect
  • the compounds and compositions of the present invention are LXRs and/or LXRs LBD full agonists, and more particularly LXR-alpha and/or LXR-alpha LBD full agonists and/or LXR-beta and/or LXR-beta LBD full agonists.
  • the compounds and compositions of the present invention are full agonists in the sense that their maximal efficacy (illustrated by their Vmax and/or E ax) is at least about 100% of the maximal efficacy (illustrated by Vmax and/or Emax) of the reference T0901317 (Tularik) or GW3965 (Glaxo SmithKline) measured under identical conditions (see the Experimental section).
  • their maximal efficacy is comprised between about 100% and about 120% of the T0901317 (Tularik) and/or GW3965 (Glaxo SmithKline) maximal efficacy.
  • the compounds and compositions of the present invention are LXRs and/or LXRs LBD partial-agonists.
  • the compounds and compositions of the present invention are LXR- alpha and/or LXR-alpha LBD partial-agonists, and/or LXR-beta and/or LXR-beta LBD partial-agonists.
  • a drug that produces less than the possible maximal effect i.e. the maximal effect produced by a full agonist, or reference molecule
  • partial agonist A drug that produces less than the possible maximal effect (i.e. the maximal effect produced by a full agonist, or reference molecule) is called "partial agonist" .
  • the partial agonist property of the compounds and compositions of the present invention can be defined by reference to T0901317 (Tularik) which is a full LXR agonist.
  • T0901317 Tularik
  • other full LXR agonist such as the F3MethylAA (Merck) or GW3965 (Glaxo SmithKline) as reference molecules.
  • the compounds and compositions of the present invention are partial agonists in the sense that their maximal efficacy (illustrated by their Vmax and/or Emax) is less than about 70%, preferably less than about 50%, of the maximal efficacy (illustrated by Vmax and/or Emax) of the T0901317 or GW3965 measured under identical conditions (see the Experimental section).
  • their maximal efficacy is comprised between about 70% and about 5% of the T0901317 or GW3965 maximal efficacy; in more special embodiments it is comprised between about 60% and about 10% of the T0901317 or GW3965 maximal efficacy; and in even more special embodiments it is comprised between about 30% and about 20% of the T0901317 or GW3965 maximal efficacy.
  • Potency and efficacy are the two key features in analyzing ligand agonist, including partial agonist, property.
  • Potency can be calculated through dose response experiment in a given functional assay e.g. co-transfection assay (see above) . It represents the dose of compound necessary to achieve 50 % of maximal effect (EC50) . This value is closely related to the Kd obtained in a binding assay and therefore related to the affinity of the compound for the receptor. Identification of compounds with low potency is important to achieve target specificity and the development of low dosed pharmaceutical compositions to be administered to patients.
  • Efficacy determines the maximum effect that can be achieved in a functional assay that assesses the compound tested effect on the LXRs, and more particularly LXR-alpha and/or LXR-beta, in a co-transfection assay.
  • the Applicants postulate that too high level of efficacy can be associated with detrimental undesirable side effects.
  • the compounds and compositions of the present invention have a potency (EC50) less than about 1 OuM, preferably less than about 1uM. More specifically, it is comprised between about 2uM and about 1nM, with concentrations in the range of about 10 to about 500nM being preferred.
  • the potency (EC50) measured with the racemate can differ from the EC50 measured with the purified enantiomer (dextrogyre or levogyre) .
  • the compounds of the present invention are selective of LXRs, and more specifically of LXR alpha. This means in particular that the said compounds are not binding with high affinity and/or potency with other nuclear receptors . This further means that the compounds and compositions of the present invention are not able to modulate function of other nuclear receptors.
  • the compounds and compositions of the present invention are binding with PXR and/or FXR with an EC50 superior to about 10 ⁇ M.
  • the compounds and compositions of the present invention are not able to modulate PPARs function, and more specifically PPAR-beta and/or PPAR-gamma and/or PPAR-alpha functions.
  • PPAR modulating activities may be measured by assays widely known to one skilled in the art such as for example those which are disclosed in WO0200611.
  • LXRs modulators One of the major drawbacks of the previously developed LXRs modulators was illustrated by their LXRs target gene activation profiles. More specifically, the known LXRs agonists (e.g. the reference molecules presented above) are able to activate genes involved both in cholesterol trafficking (e.g. ATP-binding cassette transporters A1 (ABCA1 ) , G1 (ABCG1 ) , G5 (ABCG5) and G8 (ABCG8), ApoE, LPL, PLTP, CETP) , ' hypertriglyceridemia (e.g. Angptl3) and lipogenesis (e.g. FAS, SREBPlc / SREPBla, SCD-1, ACC).
  • cholesterol trafficking e.g. ATP-binding cassette transporters A1 (ABCA1 ) , G1 (ABCG1 ) , G5 (ABCG5) and G8 (ABCG8), ApoE, LPL, PLTP, CETP
  • Said expression profile leads in vivo to beneficial effects (i.e. increasing HDL-c, increasing RCT) but also to adverse effects (e.g. strong increase in plasma and/or liver triglycerides TG levels) .
  • beneficial effects i.e. increasing HDL-c, increasing RCT
  • adverse effects e.g. strong increase in plasma and/or liver triglycerides TG levels
  • LXRs agonists including partial agonists, that present low adverse LXRs activation of lipogenic genes while maintaining the beneficial LXRs activation of genes implicated in RCT promoting.
  • the compounds and compositions of the present Invention have the ability to increase the expression of at least one LXRs target gene involved in cholesterol trafficking.
  • said LXRs target gene involved in cholesterol trafficking is selected in the group consisting of ATP-binding cassette transporters A1 (ABCA1 ) , G1 (ABCG1 ) , G5 (ABCG5) , G8 (ABCG8), ApoE, LPL, PLTP and CETP.
  • said compounds and compositions are able to increase the expression of said gene in at least one tissue selected from the group consisting of liver, macrophage and intestine, and the like (e.g.
  • the compounds and compositions of the Invention are able to induce the expression of the ABCA1 gene .in cell model (e.g. THP-1) to a level comparable to the one observed under the same conditions with a reference compound, e.g. GW3965.
  • Level comparable means that the induction of the compound or composition under identical conditions is about identical, i.e. is about 70%, preferably about 80%, even preferably about 90%, advantageously 100% or more of the induction level observed under the same conditions with the reference compound.
  • the compounds and compositions of the present Invention have the ability to increase the expression of at least one LXRs target genes involved in cholesterol trafficking as above described and have a limited ability to increase the expression of at least one LXRs target genes involved in lipogenesis, including hypertriglyceridemia.
  • said LXRs target genes involved in lipogenesis are selected from the group consisting of FAS, SREBPlc, SCD-1, Angptl3 and ACC.
  • said "limited ability" is measured in at least one tissue selected from the group consisting of liver, adipose tissue, macrophage, intestine, and the like (e.g.
  • said compounds and compositions are able to increase the expression of ABCA-1 and ⁇ have a limited ability to increase the expression of FAS and/or SREBPlc and/or Angptl3.
  • “limited ability” means that the compounds and compositions of the Invention induce the expression of the gene involved in lipogenesis (e.g. FAS and/or SREBPlc and/or Angptl3) in a cell model (e.g. HepG2) to a level that is greatly reduced compared to the one observed in the same conditions with a reference compound, e.g.
  • the induction with the compound or composition under identical conditions is less than at least 70%, preferably less than about 50%, even preferably less than about 40 %, advantageously less than about 30% and more advantageously less than about 20% of the induction level observed under the same conditions with the reference compound.
  • the reference compound T0901317 exhibits the following increase of the expression of FAS (about 87%) and/or Angptl3 (about 79%) and ABCA1 (about 69%) (see Experiments Section) .
  • said "increase of the expression of at least one LXRs target genes" by the compounds and compositions of the present Invention is actually the illustration of the decrease or remove of an inhibition of said expression, said decrease or remove resulting from the action of the said compounds and compositions.
  • the measurement of the expression of at least one LXRs target genes can be performed by methods well known in the art, such as for example mRNA levels determination by RNAse protection assay (RPA) (Hylemon et al . , 1992, J. Biol. Chem., 267, 16866-16871 ) .
  • RPA RNAse protection assay
  • the compounds and compositions of the invention are further characterized by their biological/pharmacological activities, and more specifically present beneficial activities towards cholesterol metabolism by lowering, or at least by preventing increase of, one or more of the following biological entities in ' a patient: triglycerides, fatty acids, total cholesterol, LDL-c, VLDL-c, bile acid and the like.
  • the compounds and compositions of the Invention are further characterized by their biological/pharmacological activities towards HDL-c by increasing its plasma level.
  • the compounds and compositions of the invention are characterized by their biological/pharmacological activities towards HDL-c and TG by increasing the HDL-c plasma level without increasing the TG plasma level and/or TG liver level.
  • the compounds or compositions of the Invention have the property to enhance thecholestrerol efflux and/or the Reverse Cholesterol Transport (RCT) .
  • the compounds and compositions of the present invention when administered to a patient, do not lead to adverse effects, or are associated with reduced adverse effects, and more specifically do not lead or are not associated with liver adverse effects (e.g. hepatomegaly) or with peroxisome proliferation.
  • liver adverse effects e.g. hepatomegaly
  • peroxisome proliferation are examined for example by measuring liver enzymes (ALT, AST, Alkaline phosphatase) , plasma glucose, plasma free fatty acids, plasma insulin, body weight, liver weight, kidney weight , etc...
  • the compounds and compositions of the invention are further characterized by their biological/pharmacological activities towards atherosclerosis by lowering in a treated patient (including animal models such as LDLR-/- and ApoE-/- mice or in old obese monkey) the atherosclerosis plaque (i.e. the compounds and compositions of the invention have anti- atherosclerotic effects) .
  • Methods for measurement of atherosclerosis are available, e.g. angiographic methods, noninvasive ultrasound based methods (e.g. Beaudry and Spence, 1989, Clin. Exp. Hypertens. , 11, 943-956).
  • the compounds and compositions of the present invention due to their agonistic, particularly partial agonistic, property towards natural physiological ligands of the LXR receptors, especially towards LXR-alpha, can serve as pharmaceuticals for controlling the biological effects of LXRs-mediated transcriptional control and the subsequent physiological effects produced thereby. More specifically they are capable of specifically modulating a cellular physiological response to reduce an associated pathology or provide or enhance a prophylaxis .
  • the compounds and compositions of the present invention are LXRs and/or LXRs LBD antagonists. According to another embodiment, the compounds and compositions of the present invention are specific antagonists towards LXR-alpha and/or LXR-alpha LBD. According to another embodiment, the compounds and compositions of the present invention are specific antagonists towards LXR-beta and/or LXR-beta LBD.
  • antagonists is meant a compound or composition which when combined with an intracellular receptor reduces or inhibits a reaction typical for the receptor, e.g., transcription activation activity.
  • said antagonists is a LXR-alpha antagonists, i.e.
  • the present invention further concerns a composition
  • a composition comprising at least one compound of the invention as disclosed above and a pharmaceutically acceptable carrier or diluent.
  • pharmaceutical compositions may be prepared by conventional techniques, e.g. as described in Remington,
  • compositions of the present invention are associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, tablets, aerosols, solutions, suspensions or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compounds can be adsorbed on a granular solid container for example in a sachet.
  • liquid oral pharmaceutical compositions are in the form of, for example, suspensions, elixirs and solutions; solid oral pharmaceutical compositions are in the form of, for example, powders, capsules, caplets, gelcaps and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • suitable carriers or diluents are, without being limited, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides , pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone .
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides , polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, including but not limited to amphipathic lipids such as phosphatidylcholines , sphingomyelins, phosphatidylethanolamines , phophatidylcholines, cardiolipins , phosphatidylserines , phosphatidylglycerols, phosphatidic acids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyl dimethylammonium propanes, and stearylamine, neutral lipids such as triglycerides, and combinations thereof. They may either contain cholesterol or may be cholesterol-free.
  • amphipathic lipids such as phosphatidylcholines , sphingomyelins, phosphatidylethanolamines , phophatidylcholines, cardiolipins , phosphatidylserines , phosphatidyl
  • compositions of the invention can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds .
  • compositions of the invention will typically be those which contain an effective amount of a compound of the invention, i.e. a LXRs modulating amount.
  • LXRs modulating amount refers to that amount of a compound that is needed to produce a desired effect in any one of the cell-based assays, biochemical assays or animal models described above.
  • an effective amount, or LXRs modulating amount, of a compound of the invention is a concentration of the said compound that will produce a 50% (EC 50 ) increase in LXR activity in a cell-based reporter gene assay, or a biochemical peptide sensor assay such as the assays described above (relative to an untreated control) .
  • the pharmaceutical compositions herein may contain between about 0.1 mg and about 1000 mg, preferably about 100 ug to about 500 mg, even more preferably about 5ug to about 50 mg, of the compound, advantageously about 10 mg and may be constituted into any form suitable for the mode of administration selected.
  • the tablets or pills of the pharmaceutical composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, alcohol and cellulose acetate.
  • compositions of the Invention may be advantageously combined and/or used in combination with at least one additional agent.
  • additional agent examples include other lipid-lowering or cholesterol-lowering agents, different from the compounds of the Invention.
  • administration in conjunction with the subject compositions enhances the efficacy of such agents.
  • Exemplary cholesterol-lowering agents include lipid-lowering or cholesterol-lowering agents, different from the compounds of the Invention.
  • hypocholesterolemic and/or lipid-lowering (hypolipemic) agents include those above disclosed, such as bile acid sequestrants such as quaternary amines (e.g. cholestyramine and colestipol) or colesevelam; nicotinic acid and its derivatives (e.g. niacin) ; probucol ; Ezetimibe (ZetiaTM,
  • rosuvastatin (CrestorTM, AstraZeneca) , cerivastatin (BaycolTM, Bayer) and pitavastatin) ; fibric acids such as clofibrate, gemfibrozil, bezafibrate, fenofibrate and ciprofibrate; probucol; raloxifene and its derivatives; and mixtures thereof.
  • the additional agent can be selected in the group consisting in natural or synthetic PPAR (alpha, beta and/or gamma) and/or FXR and/or RXR modulators (agonist or antagonist) and/or anti-inflammatory compounds (e.g. glucocorticoids) .
  • PPAR alpha, beta and/or gamma
  • FXR and/or RXR modulators agonist or antagonist
  • anti-inflammatory compounds e.g. glucocorticoids
  • Naturally occurring ligands that modulate the activity of PPAR include but are not limited to, fatty acids such as arachidonic acid derivatives or metabolites such as eicosanoids (e.g. various isomeric forms of 8-hydroxytetraenoic acid) and cyclopentenone prostaglandins (e.g. prostaglandins in the J and A series and their metabolites), long-chain fatty acids and their derivatives, e.g. 9- and 13-cis-hydroxyoctadecadienoic acid (HODE) (Nagy et al., 1998, Cell, 17, 93, 229-240 ; Chinetti et al . , 2001, Z.
  • fatty acids such as arachidonic acid derivatives or metabolites such as eicosanoids (e.g. various isomeric forms of 8-hydroxytetraenoic acid) and cyclopentenone prostaglandins (e.g. prostaglandins in the J and
  • said natural PPAR ligand is a prostaglandin J2 or delta-12-prostaglandin J2 (PGJ2) metabolite, and more particularly it is 15-deoxy-delta- 12, 14-prostaglandin J2 [15-deoxy-Delta (12 , 14) -PGJ (2) or 15d- PGJ2] .
  • PGJ2 prostaglandin J2 or delta-12-prostaglandin J2
  • Synthetic ligands that modulate the activity of PPAR are for example antidyslipidemic fibrates (e.g. clofibrate, fenofibrate, benzofibrate, ciprofibrate, gemfibrozil), thiazolidine derivatives (e.g. thiazolidinediones) , glitazones (e.g. rosiglitazone) , oxazolidine derivatives (e.g. oxazolidinediones) , alpha-alkylthio, alpha-alkoxy and carboxylic acid derivatives of thiazolidines and oxazolidines (Hulin et al . 1996, J. Med.
  • antidyslipidemic fibrates e.g. clofibrate, fenofibrate, benzofibrate, ciprofibrate, gemfibrozil
  • thiazolidine derivatives e.g
  • N-2-L- tyrosine derivatives e.g. N- (2-Benzoylphenyl) -L-tyrosine ; Henke et al . , 1998, J. Med. Chem., 41, 5020-5036
  • FMOC-L- Leucine WO0200611
  • phenyl acetic acid derivatives Bohray et al . , 1998, j. Med. Chem. , 41 , 1619-1630
  • indole- thiazolidinedione derivatives Lihray et al . , 1998, j. Med. Chem. , 41 , 1619-1630
  • FXR agonists Compounds disclosed or described in the following articles, patents and patent applications which have FXR agonist activity are incorporated by reference herein: US 20020120137, US 20030181420, compound GW4064 (B . Goodwin et al., 2000, Molecular Cell 6, 517-526).
  • Other examples of FXR agonists useful according to the present invention are bile acids (Chiang, 2002, Endocr . Rev., 23, 443-63).
  • RXR specific agonists include, but are not limited to, 9-cis- retinoic acid, 4- (1 - (3 , 5 , 5, 8 , 8-pentamethyl-5, 6 , 7 , 8-tetrahydro- 2-naphthyl) -ethenyl) benzoic acid (3-methyl-TTNEB; LGD 1069), LG 100268 (i.e.
  • additional agents which can be comprised in, or alternatively be used in combination with, the compositions of the Invention are antidiabetic and/or hypoglycemic agents (e.g. sulfonylurea or/and biguanide derivatives) , insulin, insulin derivative, insulin secretagogue, insulin sensitizer, or insulin mimetic or those listed above (such as glitazones, PPAR modulators, etc..) ; other examples are mitotic inhibitors, alkylating agents, antimetabolites, nucleic acid intercalating agents, topoisomerase inhibitors, agents which promote apoptosis, or agents which increase immune responses to tumors (e.g cytokine chosen from alpha-, beta- and gamma-interferon, interleukins , and in particular IL-2, IL-4, IL-6, IL-10 or IL-12, tumour necrosis factors (TNFs) and colony stimulating factors (for example GM-CSF, C-CSF and M
  • the terms "used in combination with” mean that the compound of the Invention can be used simultaneously or consecutively or so as to be staggered over time. Simultaneously refers to a co- administration.
  • the separate components of the combination can be mixed to form a single composition prior to being administered, or can be administered at the same time to the patient. It is also possible to administer them consecutively, that is to say one after the other, irrespective of which component of the combination according to the invention is administered first.
  • a mode of administration which is staggered over time or is intermittent and which stops and restarts at intervals which may or may not be regular. It is pointed out that the routes and sites of administration of the two components can be different.
  • the time interval between the administrations is not critical and can be defined by the skilled person. It is possible to recommend an interval of from 10 min to 72 h, advantageously of from 30 min to 48 h, preferably of from 1 to 24 h and, very preferably, of from 1 to 6 h.
  • Another aspect of the present invention is a method for modulating the LXRs functions in a cell, a tissue and/or a patient in need thereof.
  • the cell, tissue or patient is contacted with a sufficient concentration of at least one compound or composition of the Invention for either an agonistic (including partial agonistic) or antagonistic effect to be detected.
  • the Invention concerns a method for modulating the LXR-alpha and/or LXR-beta functions in a cell, a tissue and/or a patient in need thereof.
  • the Invention concerns a method for modulating the LXR-alpha functions in a cell, a tissue and/or a patient in need thereof.
  • the present invention concerns a method for increasing the expression of .at least one LXRs target gene, more specifically a LXR-alpha target gene, involved in cholesterol trafficking in a cell, a tissue and/or a patient in need thereof.
  • the cell, tissue or patient is contacted with a sufficient concentration of at least one compound or composition of the Invention for increased expression of at least one LXRs target genes involved in cholesterol trafficking to be detected.
  • the present invention concerns a method for increasing the expression of at least one LXRs target gene involved in cholesterol trafficking in a cell, a tissue and/or a patient in need thereof, wherein the cell, tissue or patient is contacted with a sufficient concentration of at least one partial agonist, and more specifically with a sufficient concentration of at least one partial agonist of the Invention or composition (including combination) comprising it.
  • the present invention concerns a method for increasing the expression of at least one LXRs target gene involved in cholesterol trafficking in a cell, a tissue and/or a patient in need thereof, wherein the cell, tissue or patient is contacted with a sufficient concentration of at least one partial LXR-alpha agonist, said partial agonist having a Vmax of about 60%.
  • said partial agonist having a Vmax of about 60% is a partial LXR-alpha agonist of the Invention or a composition (including combination) comprising it.
  • LXRs target genes involved in cholesterol trafficking means a gene the expression of which is, at least partially, controlled by LXRs, and the expression product of which is implicated in the cholesterol transport efflux, and more specifically in the Reverse Cholesterol Transport (RCT) .
  • said "LXRs target genes involved in cholesterol trafficking” is a gene the promoter of which comprises at least one LXR response element and the expression product of which is implicated in the cholesterol transport efflux, and more specifically in the Reverse Cholesterol Transport (RCT) [see e.g., Kwiterovich, 2000, Am. J. Cardiol., 86, 5L-10L].
  • said LXRs target gene is selected in the group consisting of ATP-binding cassette transporters A1 (ABCA1 ) , G1 (ABCG1 ) , G5 (ABCG5) and G8 (ABCG8) .
  • the present invention concerns a method for modulating expression of a gene involved in cholesterol trafficking.
  • said gene is selected in the group consisting of ATP-binding cassette transporters A1 (ABCA1 ) , G1 (ABCG1 ) , G5 (ABCG5) , G8 (ABCG8), ApoE, LPL, PLTP and CETP.
  • the present invention concerns a method for increasing the expression of at least one LXRs target genes involved in cholesterol trafficking with a limited ability to increase or to repress the expression of at least one LXRs target genes involved in lipogenesis in a cell, a tissue and/or a patient in need thereof.
  • the cell, tissue or patient is contacted with a sufficient concentration of at least one compound or composition of the Invention for increased expression of at least one LXRs target genes involved in cholesterol trafficking to be detected.
  • LXRs target genes involved in lipogenesis means a gene the expression of which is, at least partially, controlled by LXRs, and the expression product of which is implicated in lipogenesis, and more specifically in triglycerides synthesis.
  • said "LXRs target genes involved in lipogenesis” is a gene the promoter of which comprises at least one LXR response element and the expression product of which is implicated in lipogenesis, and more specifically in triglycerides synthesis.
  • said LXRs target genes involved in lipogenesis is selected in the group consisting of FAS, SREBPlc, SCD-1, ACC and Angptl3.
  • the present invention concerns a method for modulating expression of a gene involved in lipogenesis.
  • said gene is selected in the group consisting of FAS, SREBPlc, SCD-1, ACC and Angptl3.
  • a further aspect of the present invention is a method for the treatment of a patient, including man, in particular in the treatment of diseases and conditions where modification of the effects of LXRs, including LXR-alpha and/or LXR-beta, is of therapeutic benefit, the method comprising administering to the patient in need a therapeutically effective amount of at least one compound of the Invention, or a pharmaceutically composition (including combination with additional agent) as above disclosed.
  • the present invention concerns a method for the treatment of a patient, including man, in particular in the treatment of diseases and conditions where modification of the effects of LXRs, including LXR-alpha and/or LXR-beta, is of therapeutic benefit, the method comprising administering to the patient in need a therapeutically effective amount of at least one partial agonist, and more specifically with a therapeutically effective amount of at least one partial agonist of the Invention or composition (including combination with additional agent) comprising it.
  • the present invention concerns a method for the treatment of a patient, including man, in particular in the treatment of diseases and conditions where modification of the effects of LXRs, including LXR-alpha and/or LXR-beta, is of therapeutic benefit, the method comprising administering to the patient in need a therapeutically effective amount of at least one partial LXR-alpha agonist, said partial agonist having a Vmax of about 60%.
  • said partial agonist having a Vmax of about 60% is a partial LXR- alpha agonist of the Invention or a composition (including combination with additional agent) comprising it.
  • treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.
  • Diseases and conditions where modification of the effects of LXRs is of therapeutic benefit means LXRs-mediated diseases or pathologic conditions wherein the observed disorder is associated, at least partially, with the deregulation, disturbance, hypersensitivity, or malfunctioning of cells expressing LXR nuclear receptors, or more specifically in which the disease or pathologic conditions is caused by one or more genes that are under the transcription control of LXRs, or said disease or pathological condition causing genes are post-translationally modified in response to the treatment with an LXRs ligand.
  • diseases and conditions are further called “diseases and conditions which can be controlled by LXRs” . Examples of these cells are those from liver, skeletal muscle, kidney, skin, heart, CNS, adipose tissues, spleen, intestine, or cells of the monocyte lineage.
  • said cell type is a hepatocyte, an adipocyte, an intestinal cell or a macrophage.
  • diseases or pathologic conditions are those associated with impaired metabolism of lipids, e.g. cholesterol and/or triglycerides, and more specifically those related to pathologic levels or ratios of lipids (e.g. dyslipidemia, including hyperlipidemia, dyslipoproteinemia, including hyperlipoproteinemia, hypertriglyceridemia, disorders related to cholesterol or bile acid metabolisms, including hypercholesterolemia, gall stone or gall bladder disorders) ; as well as vascular or inflammatory diseases or disorders (e.g.
  • cardiovascular disease including atherosclerotic cardiovascular diseases, coronary artery diseases, peripheral vascular diseases, cerebrovascular diseases, thrombotic disorders , restenosis, rheumatoid arthritis, or septic shock); diseases or disorders associated with malfunctioning (including deficiency) of the expression of at least one LXRs target gene; CNS diseases including those affecting cognitive function or age related disorders such as neurodegenerative diseases (e.g. Alzheimer's disease) ; diseases or disorders related to lipid storage such as obesity, diabetes (including type 2 diabetes and Syndrome X) , hypertension ; pancreatitis ; skin proliferative disorders, including psoriasis, atopic dermatitis or acne ; sexual impotence, renal disease and cancers.
  • CNS diseases including those affecting cognitive function or age related disorders such as neurodegenerative diseases (e.g. Alzheimer's disease) ; diseases or disorders related to lipid storage such as obesity, diabetes (including type 2 diabetes and Syndrome X) , hypertension ; pancreatiti
  • Hyperlipidemia' s characteristics of raised plasma concentrations of triglyceride, raised low density lipoprotein cholesterol (LDL-c) concentrations, and low concentrations of high density lipoprotein cholesterol (HDL-c) are known independent risk factors for atherosclerosis and its clinical sequelae, ischemic heart disease or coronary heart disease.
  • Atherogenesis is the process by which lipids accumulate in the intimal lining of arteries leading to the formation of plaques and hardening of the vessel wall or atherosclerosis. Although the exact mechanism leading to atherogenesis is still not well understood, abnormalities of lipid and lipoprotein metabolism, coagulation, hyperinsulinism and glycation all seem to contribute significantly to the process (Bierman, E. L., Arterio. Throm.
  • Hyperlipidemia in clinical practice defined by the upper 10 percent of the distribution of plasma lipid levels in a population, i.e., serum cholesterol of 205 mg/dl or higher, serum triglycerides of 200 mg/dl, is usually recommended for treatment. Routine measurements of concentrations of cholesterol and triglycerides in the plasma have become widespread in clinical practice which permits the identification of patients with asymptomatic hyperlipidemia. Guidelines are available for diagnosis and monitoring responses to therapy. The lowering of plasma lipid concentrations reduces the number and size of atherogenic plaques on the intima of blood vessels.
  • the Invention concerns a method for the treatment of hyperlipidemia, obesity, type II diabetes, atherosclerosis, ischemic heart disease, peripheral vascular disease, cerebral vascular disease, hypercholesterolemia, hypertriglyceridemia, pancreatitis or coronary artery disease or hyperlipoproteinemia using at least one compound or pharmaceutical compositions (including combinations with additional agent) of the Invention.
  • the present invention concerns a method for the treatment of hyperlipidemia, obesity, type II diabetes, atherosclerosis, ischemic heart disease, peripheral vascular disease, cerebral vascular disease, hypercholesterolemia, hypertriglyceridemia, pancreatitis or coronary artery disease or hyperlipoproteinemia using at least one partial LXR-alpha agonist, and more specifically at least one partial agonist of the Invention or composition (including combination with additional agent) comprising it.
  • the present invention concerns a method for the treatment of hyperlipidemia, obesity, type II diabetes, atherosclerosis, ischemic heart disease, peripheral vascular disease, cerebral vascular disease, hypercholesterolemia, hypertriglyceridemia, pancreatitis or coronary artery disease orhyperlipoproteinemia using at least one partial LXR-alpha agonist, said partial agonist having a Vmax of about 60%.
  • said partial LXR-alpha agonist having a
  • Vmax of about 60% is a partial agonist of the Invention or a composition comprising it.
  • this aspect of the invention involves administering to a patient in need of such treatment an amount of at least one compound or a composition
  • the amount is effective to lower the LDL-c and more preferably also to increase the HDL-c levels in said patient. Even more preferably, said amount is effective to lower the LDL-c, and more preferably to additionally increase the HDL-c levels in said patient, without increasing the TG level (measured in plasma and/or liver) .
  • the phrase "amount... effective to” refers to levels of compound of the present invention sufficient to provide circulating concentrations high enough to accomplish the desired effect.
  • Such a concentration typically falls in the range of about 10 nM up to 2 uM; with concentrations in the range of about 100 nM up to 500 nM being preferred.
  • concentrations typically falls in the range of about 10 nM up to 2 uM; with concentrations in the range of about 100 nM up to 500 nM being preferred.
  • the Invention concerns a method for the enhancement of the Reverse Cholesterol Transport (RCT) in a patient in need by administering at least one compound, a composition or a combination of the invention.
  • RCT Reverse Cholesterol Transport
  • the Invention concerns a method for lowering the atherosclerosis plaque in a patient in need by administering at least one compound, a composition or a combination of the invention.
  • the Invention concerns a method for reducing the risk for coronary heart disease by improving levels of HDL-cholesterol (HDLc) , reducing the levels of triglycerides (TG) with the potential to reduce LDL- cholesterol (LDL-c) in a patient in need by administering at least one compound, a composition or a combination of the invention.
  • HDLc HDL-cholesterol
  • TG triglycerides
  • LDL-c LDL- cholesterol
  • disease or pathologic condition according to the invention is an inflammatory disease including, but not limited to, T-lymphocyte activation and other T-lymphocyte-related disorders ; inflammatory cytokine (e.g. TNF-alpha, interleukin (IL) -1 -alpha, IL-1-beta, IL-2, IL-6) production ; activation of nuclear factors that promote transcription of genes encoding inflammatory cytokines .
  • these nuclear transcription factors include but are not restricted to, nuclear factor-kappaB (NF-kappaB) , activated protein-1 (AP-1 ) , nuclear factor of activated T cells (NFAT) .
  • the present invention concerns a method of treating and/or preventing diseases or conditions in a patient, comprising the step of administering to said individual a pharmacologically effective dose of a compound or composition (including combination with additional agent) of the invention said administration resulting in improving the clinical status of said patient.
  • the term "patient” means a mammal, e.g., a primate, e.g., a human.
  • pharmaceutically effective dose an amount of a pharmaceutical compound or composition having a therapeutically relevant effect in the frame of treatment and/or prevention of conditions mediated by LXRs such as those disclosed above.
  • a therapeutically relevant effect relieves to some extent one or more symptoms of conditions mediated by LXRs in a patient or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of said conditions, e.g. hypercholesteremia, hypertriglyceridemia, total cholesterol, HDLc, LDLc and/or TG levels, etc...
  • a pharmaceutically effective dose of a compound or composition means an amount that decreases total cholesterol, decreases LDL-c, preferably also increases HDL-c, and advantageously does not increase TG levels (measured in plasma and/or liver of the treated patient) .
  • the compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used-. A most preferable dosage is about 0.1 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, on the therapeutic effect that is intended to be achieved, the form in which the dosage is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge. Dosages and treatment schedules are readily attainable by routine experimentation to those having ordinary skill in this art.
  • the compounds are dispensed in unit dosage form comprising from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • the compounds or compositions (including combinations with additional agent) of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the treatment can be adapted to administer the compounds or compositions (including combinations) of the invention in a single weekly or monthly dose.
  • doses employed for adult human treatment will typically be in the range of 0.02 - 5000 mg per adult human per day, e.g., 1-1500 mg per adult human per day.
  • compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 30 mg/kg of body weight per day. Particularly, the range is from about 0.03 to about 15 mg/kg of body weight per day, and more particularly, from about 0.05 to about 10 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 2 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of ' the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result m the need to adjust dosages.
  • Toxicity and therapeutic efficacy of the compounds included in the compound or composition of the invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., .for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population) .
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, special care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, leads to a reduction of side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half- maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half- maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography .
  • the route of administration of the compound or composition of the present invention may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral or intratumoral route being preferred.
  • the present invention further concerns compounds and compositions (including combinations with additional agent) of the present invention for use in therapy. Similarly, it concerns the use of at least one compound or composition (including combinations with additional agent) according of the present invention for the manufacture of a medicament for the treatment of diseases and conditions where modification of the effects of LXRs is of therapeutic benefit (see above) . It further concerns the use of at least one partial LXR-alpha agonist, said partial agonist having a Vmax of about 60%, for the manufacture of a medicament for the treatment of diseases and conditions where modification of the effects of LXRs is of therapeutic benefit. Examples of these diseases and conditions are provided above .
  • the present invention concerns the use of at least one compound or composition (including combinations with additional agent) according of the present invention for the manufacture of a medicament for the treatment of individuals requiring lower total cholesterol levels and/or TG level.
  • the compounds and compositions (including combinations with additional agent) of the present invention may also find use in a variety of in vitro and in vivo assays, including diagnostic assays.
  • various allotypic LXRs gene expression processes may be distinguished in sensitivity assays with the subject compounds and compositions, or panels thereof.
  • labeled versions of the subject compounds and compositions e.g. in radioligand displacement assays.
  • the invention provides the compounds and compositions of the invention comprising a detectable label, " which may be spectroscopic (e.g. fluorescent), radioactive, etc.
  • Tetrahydroquinolines of formula [I] are obtained by an imino Diels-Alder reaction (Buonora et al . , 2001, Tetrahedron, 57, 6099-6138) like described in the reaction above.
  • the said "three component" reaction is carried out with amines, aldehydes and appropriate dienophiles in suitable solvents, such as acetonitrile, dichloromethane, ether, THF, toluene, fluorinated alcohols, with acidic catalysis, such as TFA or Lewis Acid catalysts (chiral or not) and with heating where necessary (Spanedda et al . , 2003, Tetrahedron Letters, 44, 217-219 ; Sundararajan et al .
  • suitable solvents such as acetonitrile, dichloromethane, ether, THF, toluene, fluorinated alcohols
  • acidic catalysis such as TFA or Lewis Acid catalysts (chiral or not) and with heating where necessary
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may be converted to the desired moiety by known methods .
  • the substituting moiety R 1 , ' R 2 , R 3 , R 4 , R 5 , R 5 and/or R 7 may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the individual isomers of compound (I) may be separated using, for example, column chromatography, HPLC or recrystallisation.
  • DHQ derivatives can be prepared by two different routes : either condensation of an amine with dimethyl acetylenedicarboxylate, followed by a Friedels-Crafts acylation-cyclisation (Carling et al . , 1992, J. Med. Chem. 35 1942-1953) or condensation of substituted 2 ' -acetophenone with the appropriate aldehyde, followed by acid catalyzed cyclisation(Zheng-Yu Yang et al, 1998, J. Med. Chem. 41, 1155- 1162) .
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R s and/or R 7 may be converted to the desired moiety by known methods.
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the PPC derivative intermediate is prepared by combining Br- or OTf-benzene with amino nitrile in the presence of metal catalyst, preferably Pd and phosphine ligands (WO 02/088069), followed by hydrolyzing the nitrile to amide and then reacting with alkyl chloroformate in presence of lithium t-butoxide. PPC derivative is then reduced under NaBH 4 condition followed by cyclisation in acidic medium in order to obtain tetrahydroquinolines of formula [I] .
  • metal catalyst preferably Pd and phosphine ligands
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may be converted to the desired moiety by known methods.
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the individual isomers of compound (I) may be separated using, for example, column chromatography, HPLC or reerystaliisation.
  • the aldehyde (1 eq) is added to a solution of 2 ' ⁇ aminoacetophenone (R 5 , R ⁇ , R 7 , 2 ' -aminoacetophenone) (1 eq) in ethanol.
  • a solution of 15% aqueous NaOH (1.1 eq) is then added.
  • the solution is stirred at room temperature for 6 to 24h and then filtered.
  • the resulting precipitate, 1-(2-amino- phenyl) -propenone derivative, is used without further purification.
  • the 1 - (2-amino-phenyl) -propenone derivative is mixed with acetic acid and orthophosphoric acid and heated at 100°C for 30 min. After cooling, the mixture is poured into ice and the precipitate filtered. The crude product is purified by column chromatography in order to obtain pure 2 , 3-dihydro-1 H- quinolin-4-one (DHQ) derivatives.
  • DHQ 3-dihydro-1 H- quinolin-4-one
  • Example 2 Synthesis of N- (1 ,2 , 3 , 4-Tetrahydro-quinolin-4-yl) - amide of the invention.
  • Tetrahydroquinolines of formula [I] are obtained by an imino Diels-Alder reaction (Buonora et al . , 2001, Tetrahedron, 57, 6099-6138) like described in the reaction above.
  • the said "three component" reaction is carried out with amines, aldehydes and appropriate dienophiles in suitable solvents, such as acetonitrile, dichloromethane, ether, THF, toluene, fluorinated alcohols, with acidic catalysis, such as TFA or Lewis Acid catalysts (chiral or not) and with heating where necessary (Spanedda et al . , 2003, Tetrahedron Letters, 44, 217-219 ; Sundararajan et al .
  • suitable solvents such as acetonitrile, dichloromethane, ether, THF, toluene, fluorinated alcohols
  • acidic catalysis such as TFA or Lewis Acid catalysts (chiral or not) and with heating where necessary
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may be converted to the desired moiety by known methods.
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the individual isomers of compound (I) may be separated using, for example, column chromatography, HPLC or reerystallisation.
  • the DHQ derivatives can be prepared by two different routes : either condensation of an amine with dimethyl acetylenedicarboxylate, followed by a Friedels-Crafts acylation-cyclisation (Carling , 1992, J. Med. Chem., 35, 1942-1953) or condensation of substituted 2 ' -acetophenone with the appropriate aldehyde, followed by acid catalyzed cyclisation (Yi , 1998, J. Med. Chem., 41, 1155-1162).
  • R-i group on the nitrogen atom is made according to methods known to those skilled in the art e.g. alkylation with methyl iodide in the presence of a base.
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may be converted to the desired moiety by known methods.
  • the substituting moiety R , R , R , R , R and/or R may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the PPC derivative intermediate is prepared by combining Br- or OTf-benzene with amino nitrile in the presence of metal catalyst, preferably Pd and phosphine ligands (WO 02/088069), followed by hydrolyzing the nitrile to amide and then reacting with alkyl chloroformate in presence of lithium t-butoxide. PPC derivative is then reduced under NaBH 4 condition followed by cyclisation in acidic medium in order to obtain tetrahydroquinolines of formula (I) .
  • metal catalyst preferably Pd and phosphine ligands
  • R 1 group on the nitrogen atom is made according to methods known to those skilled in the art e.g. alkylation with methyl iodide in the presence of a base. If, in any of the other processes mentioned herein, the substituting moiety R 1 ., R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 is different from the one required, the substituting moiety may be converted to the desired moiety by known methods .
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the individual isomers of compound (I) may be separated using, for example, column chromatography, HPLC or recrystallisation.
  • Tetrahydroquinolines of formula [I] are obtained by an imino Diels-Alder reaction (Buonora et al . , 2001, Tetrahedron, 57, 6099-6138) like described in the reaction above.
  • the said "three component" reaction is carried out with amines, aldehydes and appropriate dienophiles in suitable solvents, such as acetonitrile, dichloromethane, ether, THF, toluene, fluorinated alcohols, with acidic catalysis, such as TFA or Lewis Acid catalysts (chiral or not) and with heating where necessary (Spanedda et al . , 2003, Tetrahedron Letters, 44, 217-219 ; Sundararajan et al .
  • suitable solvents such as acetonitrile, dichloromethane, ether, THF, toluene, fluorinated alcohols
  • acidic catalysis such as TFA or Lewis Acid catalysts (chiral or not) and with heating where necessary
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may be converted to the desired moiety by known methods.
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the individual isomers of compound (I) may be separated using, for example, column chromatography, HPLC or reerystaliisation.
  • the DHQ derivatives can be prepared by two different routes: either condensation of an amine with dimethyl acetylenedicarboxylate, followed by a Friedels-Crafts acylation-cyclisation (Carling , 1992, J. Med. Chem., 35, 1942-1953) or condensation of substituted 2 ' -acetophenone with the appropriate aldehyde, followed by acid catalyzed cyclisation (Yi , 1998, J. Med. Chem., 41, 1155-1162).
  • R-i group on the nitrogen atom is made according to methods known to those skilled in the art e.g. alkylation with methyl iodide in the presence of a base. If, in any of the other processes mentioned herein, the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 is different from the one required, the substituting moiety may be converted to the desired moiety by known methods .
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the individual isomers of compound (I) may be separated using, for example, column chromatography, HPLC or recrystallisation.
  • the PPC derivative intermediate is prepared by combining Br- or OTf-benzene with amino nitrile in the presence of metal catalyst, preferably Pd and phosphine ligands (WO 02/088069), followed by hydrolyzing the nitrile to amide and then reacting with alkyl chloroformate in presence of lithium t-butoxide. PPC derivative is then reduced under NaBH 4 condition followed by ' cyclisation in acidic medium in order to obtain tetrahydroquinolines of formula (I) .
  • metal catalyst preferably Pd and phosphine ligands
  • R 1 group on the nitrogen atom is made according to methods known to those skilled in 1 the art e.g. alkylation with methyl iodide in the presence of a base.
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may be converted to the desired moiety by known methods.
  • the substituting moiety R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and/or R 7 may also need protection against the conditions under which reactions are carried out, accordingly, a protecting group may be used which is removed after reactions have been completed.
  • the individual isomers of compound (I) may be separated using, for example, column chromatography, HPLC or recrystallisation.
  • Example 1 Synthesis of N- (1 ,2 ,3, 4-Tetrahydro-quinolin-4-yl) - amide of the invention.
  • Example 5.2 Example procedure for synthesis of quinoline preparation of 2- [2- (2 , 4-dichloro-phenyl) -6-trifluoromethoxy- quinolin-3-yl] -ethanol (5.02, CRX000540)

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Abstract

La présente invention concerne des composés spécifiques et leurs sels de qualité pharmaceutique ; des méthodes destinées à la synthèse de ces composés ; des compositions comprenant au moins un de ces composés ou un de ces sels de qualité pharmaceutique ; ainsi que des méthodes destinées à la modulation de l'activité des récepteurs X du foie (LXR). La présente invention concerne également des méthodes destinées au traitement et/ou à la prévention d'une maladie ou d'un trouble sélectionné dans le groupe comprenant la dyslipidémie, y compris l'hyperlipidémie, la dyslipoprotéinémie, y compris l'hyperlipoprotéinémie, les troubles liés aux métabolismes du cholestérol ou de l'acide biliaire, y compris l'hypercholestérolémie, les troubles de calculs biliaires ou de vésicule biliaire, la maladie cardio-vasculaire, y compris les maladies cardio-vasculaires athéroscléreuses, les coronaropathies, les acrosyndromes vasculaires, les maladies vasculaires cérébrales, les troubles thrombotiques, les resténoses ou les chocs septiques, les maladies du SNC, y compris celles qui affectent la fonction cognitive, ou les troubles liés à l'âge, tels que la maladie d'Alzheimer, le syndrome X, un troubles associé au récepteur X du foie, l'obésité, la pancréatite, l'hypertension, la maladie rénale, le cancer, la polyarthrite rhumatoïde, l'inflammation, les troubles cutanés prolifératifs, y compris le psoriasis, la dermatite atopique ou l'acné, et l'impuissance sexuelle. Ces méthodes consistent à administrer une dose thérapeutique d'une composition comprenant au moins un composé ou un de ses sels de qualité pharmaceutique de l'invention.
PCT/EP2004/001277 2003-02-12 2004-02-11 Tetrahydroquinoleines utilisees comme agonistes des recepteurs hepatiques Ceased WO2004072041A1 (fr)

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JP2008528560A (ja) * 2005-01-27 2008-07-31 レ ラボラトワール セルヴィエ 新規な複素環式オキシム誘導体、それらの製造方法及びそれらを含む医薬組成物
US20080200451A1 (en) * 2005-06-13 2008-08-21 Kai Schiemann Tetrahydroquinolines for Use as Modulators of the Mitotic Motor Protein Eg5
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
US7749995B2 (en) 2006-05-11 2010-07-06 Janssen Pharmaceutica Nv 3,4-dihydro-2h-benzo[1,4]oxazine and thiazine derivatives as CETP inhibitors
US7928238B2 (en) 2006-05-11 2011-04-19 Janssen Pharmaceutica Nv 1,2,3,4-tetrahydro-quinoline derivatives as CETP inhibitors
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
US8084611B2 (en) 2006-03-30 2011-12-27 Mitsubishi Tanabe Pharma Corporation Process for preparing tetrahydroquinoline derivatives
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
JP2013541551A (ja) * 2010-10-20 2013-11-14 エフ．ホフマン−ラ ロシュ アーゲー Ａｍｐｋ活性化剤として使用されるテトラヒドロキノリン誘導体
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10669296B2 (en) 2014-01-10 2020-06-02 Rgenix, Inc. LXR agonists and uses thereof
US11174220B2 (en) 2019-12-13 2021-11-16 Inspirna, Inc. Metal salts and uses thereof
US11214536B2 (en) 2017-11-21 2022-01-04 Inspirna, Inc. Polymorphs and uses thereof

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JP2008528560A (ja) * 2005-01-27 2008-07-31 レ ラボラトワール セルヴィエ 新規な複素環式オキシム誘導体、それらの製造方法及びそれらを含む医薬組成物
US20080200451A1 (en) * 2005-06-13 2008-08-21 Kai Schiemann Tetrahydroquinolines for Use as Modulators of the Mitotic Motor Protein Eg5
JP2008545805A (ja) * 2005-06-13 2008-12-18 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング 有糸分裂モータータンパク質ｅｇ５の調節剤の形態で使用されるテトラヒドロキノリン
US8207345B2 (en) * 2005-06-13 2012-06-26 Merck Patent Gmbh Tetrahydroquinolines for use as modulators of the mitotic motor protein Eg5
US8084611B2 (en) 2006-03-30 2011-12-27 Mitsubishi Tanabe Pharma Corporation Process for preparing tetrahydroquinoline derivatives
US7749995B2 (en) 2006-05-11 2010-07-06 Janssen Pharmaceutica Nv 3,4-dihydro-2h-benzo[1,4]oxazine and thiazine derivatives as CETP inhibitors
US7928238B2 (en) 2006-05-11 2011-04-19 Janssen Pharmaceutica Nv 1,2,3,4-tetrahydro-quinoline derivatives as CETP inhibitors
US8012963B2 (en) 2006-05-11 2011-09-06 Janssen Pharmaceutica N.V. 3,4-dihydro-2H-benzo[1,4]oxazine and thiazine derivatives as CETP inhibitors
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2012033353A2 (fr) 2010-09-07 2012-03-15 서울대학교 산학협력단 Composés de sesterterpène et leur utilisation
JP2013541551A (ja) * 2010-10-20 2013-11-14 エフ．ホフマン−ラ ロシュ アーゲー Ａｍｐｋ活性化剤として使用されるテトラヒドロキノリン誘導体
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
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WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
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US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10669296B2 (en) 2014-01-10 2020-06-02 Rgenix, Inc. LXR agonists and uses thereof
WO2017123568A2 (fr) 2016-01-11 2017-07-20 The Rockefeller University Méthodes pour le traitement de troubles associés à des cellules suppressives dérivées de cellules myéloïdes
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
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Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
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CR1 Correction of entry in section i

Free format text: IN PCT GAZETTE 35/2004 UNDER (72, 75) REPLACE "LEHMANN, JÜRGER" BY "LEHMANN, JÜRGEN" AND UNDER (74)THE ADDRESS SHOULD READ "SIEBERTSTRASSE 4, 81675 MÜNICH (DE)."

122 Ep: pct application non-entry in european phase