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  • C07D209/80—[b, c]- or [b, d]-condensed
  • C07D209/82—Carbazoles; Hydrogenated carbazoles
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to compounds of the formula (I): and pharmaceutically acceptable salts and pharmaceutically acceptable esters thereof.
• LXRs Liver-X-Receptors
• the LXRs are members of the nuclear hormone receptor superfamily. The LXRs are activated by endogenous oxysterols and regulate the transcription of genes controlling multiple metabolic pathways. Two subtypes, LXR ⁇ and LXR ⁇ , have been described (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc Natl Acad Sci USA.1994, 91:10809-13). LXR ⁇ is ubiquitously expressed, while LXR ⁇ is predominantly expressed in cholesterol metabolizing tissues such as the liver, adipose, intestine and macrophage.
• the LXRs modulate a variety of physiological responses including regulation of cholesterol absorption, cholesterol elimination (bile acid synthesis), and transport of cholesterol from peripheral tissues via plasma lipoproteins to the liver.
• the LXRs are also involved in glucose metabolism, cholesterol metabolism in the brain, cell differentiation, and inflammation.
• HDL-C plasma high-density lipoprotein cholesterol
• HDL The protective function of HDL derives from its role reverse cholesterol transport.
• HDL mediates the removal of cholesterol from cells in peripheral tissues, including macrophage foam cells in the atherosclerotic lesions of the arterial wall.
• HDL delivers its cholesterol to the liver and sterol-metabolizing organs for conversion to bile and elimination in feces.
• the estimated age-adjusted prevalence among Americans age 20 and older who have HDL-C of less than 35 mg/dl is 16% (males) and 5.7% (females).
• a substantial increase of HDL-C is currently achieved by treatment with niacin in various formulations.
• the substantial unfavorable side-effects limit the therapeutic potential of this approach.
• Type II diabetes is also called non-insulin dependent diabetes mellitus (NIDDM) and has been shown to afflict 80-90% of all diabetic patients in developed countries.
• NIDDM non-insulin dependent diabetes mellitus
• the pancreatic Islets of Langerhans continue to produce insulin.
• the target organs for insulin action mainly muscle, liver and adipose tissue
• the body continues to compensate by producing unphysiologically high levels of insulin, which ultimately decreases in the later stages of the disease, due to exhaustion and failure of pancreatic insulin-producing capacity.
• T2D is a cardiovascular-metabolic syndrome associated with multiple co-morbidities, including insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.
• the first line of treatment for dyslipidemia and diabetes at present generally involves a low-fat and low-glucose diet, exercise and weight loss.
• compliance can be moderate, and as the disease progresses, treatment of the various metabolic deficiencies becomes necessary with lipid-modulating agents such as statins and fibrates for dyslipidemia, and hypoglycemic drugs, e.g. sulfonylureas, metformin, or insulin sensitizers of the thiazolidinedione (TZD) class of PPAR ⁇ -agonists, for insulin resistance.
• lipid-modulating agents such as statins and fibrates for dyslipidemia, and hypoglycemic drugs, e.g. sulfonylureas, metformin, or insulin sensitizers of the thiazolidinedione (TZD) class of PPAR ⁇ -agonists, for insulin resistance.
• LXRs are also known to control the efflux of cholesterol from the macrophage foam cell of the atherosclerotic lesion, and agonists of LXRs have been shown to be atheroprotective (Joseph and Tontonoz, Curr. Opin. Pharmacol. 2003, 3:192-7).
• modulators of LXRs would be effective treatments for the atherosclerotic disease which underlies the cardiovascular morbidity and mortality of stroke and heart disease.
• LXR modulators can also show superior therapeutic efficacy on HDL-raising and atheroprotection, with additional effects on diabetes, compared to current therapies.
• novel compounds of the present invention have been found to bind to and selectively activate LXR ⁇ or LXR ⁇ or coactivate LXR ⁇ and LXR ⁇ . Consequently, cholesterol absorption is reduced, HDL cholesterol is increased, and inflammatory atherosclerosis is reduced. Since multiple facets of combined dyslipidemia and cholesterol homeostasis are addressed by LXR modulators, novel compounds of the present invention have an enhanced therapeutic potential compared to the compounds already known in the art. They can therefore be used in the treatment and prophylaxis of diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists.
• Such diseases include increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such as Alzheimer's disease or impaired/improvable cognitive function.
• the novel compounds of the present can further be used for treatment and prophylaxis of age-related macular degeneration.
• the present invention also relates to pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier and/or adjuvant. Furthermore, the present invention relates to the use of such compounds as therapeutic active substances as well as their use for the preparation of medicaments for the treatment or prophylaxis of diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists. The invention further relates to processes for the preparation of the compounds of formula I.
• the present invention relates to a method for the prophylaxis or therapeutic treatment of diseases modulated by LXR ⁇ and/or LXR ⁇ agonist, such as increased lipid and chloesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such as Alzheimer's disease or impaired/improvable cognitive function, said method comprising administering a compound of formula I to a human being or animal.
• diseases modulated by LXR ⁇ and/or LXR ⁇ agonist such as increased lipid and chloesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome
• the invention relates to compounds of the formula (I) wherein
• Preferred compounds of formula (I) as defined above are those, wherein
• halogen refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
• alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. Lower-alkyl groups as described below also are preferred alkyl groups.
• lower alkyl refers to a branched or straight-chain monovalent alkyl radical of one to six carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
• lower alkenyl signifies a straight-chain or branched hydrocarbon residue comprising an olefinic bond and 2 to 8, preferably 2 to 6, particularly preferred 2 to 4 carbon atoms.
• alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-but-2-enyl and isobutenyl.
• lower alkynyl stands for a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propinyl or ethinyl.
• cycloalkyl refers to a monovalent carbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
• aryl refers to either an aromatic monocyclic system containing six carbon atoms or an aromatic bicyclic system containing 10 carbon atoms.
• aryl includes a phenyl or naphthyl ring system, preferably the phenyl group.
• alkylaryl refers to an aryl group which is bound via an alkyl group, e.g. benzyl.
• heteroaryl refers to an aromatic 5- or 6-membered ring which can comprise 1-4 heteroatoms selected from nitrogen, oxygen and/or sulphur, such as furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl.
• heteroaryl also includes a heteroaryl as defined above fused to one or more other cycle be it a heterocycle, aryl, or heteroaryl, for example benzothiazolyl.
• alkylheteroaryl refers to a heteroaryl group which is bound via an alkyl group.
• salts embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
• Preferred salts are phosphates, citrates, fumarates, formates, hydrochlorides, hydrobromides and methanesulfonic acid salts.
• esters embraces esters of the compounds of formula (I), in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
• inorganic or organic acids such as, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
• compounds of formula (I) are preferred wherein n is 1, X 2 is carbon and R 1 is directly attached to the X 2 carbon.
• R 1 is selected from the group consisting of halogen, preferably Cl, cyano, nitro, SO 2 Me, lower alkyl, and N(Me) 2 are more particulary preferred.
• Another preferred embodiment relates to compounds wherein R 1 is selected from the group consisting of halogen, cyano, nitro, SO 2 Me, lower alkyl, N(Me) 2 , NHMe and piperidinyl.
• compounds of formula (I) are preferred wherein n is 2, and each R 1 is halogen. More preferably, X 2 is carbon, and one of the two R 1 groups is directly attached to the X 2 carbon.
• compounds of formula (I) are preferred wherein k is 0 or 1, more preferably wherein k is 0. Compounds wherein k is 0 and wherein k is 1 individually constitute preferred embodiments.
• R 3 of formula (I) is H, halogen or methyl.
• R 3 is F or methyl. F and methyl individually constitute preferred embodiments.
• R 4 is aryl or heteroaryl, all being optionally substituted with from one to five substituents independently selected from the group consisting of halogen, alkyl, —OR 41 , lower alkynyl, and NR 42 R 43 , wherein R 41 is lower alkyl or —H, R 42 and R 43 independently from each other are hydrogen or alkyl, or NR 42 R 43 is piperidinyl or pyrrolidinyl, or R 4 is lower alkyl
• R 4 is selected from the group consisiting of napthyl, pyridinyl, methyl, phenyl or mono-or di-substituted phenyl, wherein the phenyl substituents are halogen, N(lower alkyl) 2 or OR 41 , and wherein R 41 is defined as above, are also preferred.
• R 4 is aryl, heteroaryl, or lower alkyl.
• R 4 is selected from the group consisiting of napthyl, pyridinyl, methyl, phenyl or mono-or di-substituted phenyl, wherein the phenyl substituents are halo or OR 41 , and wherein R 41 is lower alkyl or hydrogen.
• R 4 is aryl or heteroaryl which is optionally subsituted at one or more positions with lower alkyl. More particularly, compounds wherein R 4 is selected from the group consisiting of phenyl; mono-or di-substituted phenyl wherein the one or more substituents are halo or OR 41 ; naphthyl; pyridinyl; or methyl are preferred.
• R 4 is phenyl, or mono- or di-susbituted phenyl wherein the one or more substituents is halogen, more preferably R 4 is phenyl, 4-chlorophenyl, 3-fluorophenyl, or 3,4-difluorophenyl.
• R 4 is phenyl, 3-bromophenyl or 3-dimethylaminophenyl.
• R 5 is selected from the group consisting of said heteroaryl being optionally substituted at one or more positions with one or more susbtituents independently selected from the group consisting of H, halogen, lower alkyl and (CH 2 ) v R 53 , wherein R 51 is selected from the group consisting of H, alkyl, and alkylaryl, said alkylaryl being optionally substituted at one or more positions with one or more of lower alkyl, —CN, halogen, —COOR 54 , and —CH 2 OR 54 , wherein R 54 is alkyl or —H; —R 52 is lower alkyl or —H; R 53 is H, alkyl, cycloalkyl, —COOR 55 , —N(R 55 )(R 56 ), —CH 2 OH, —CN, —CONH 2 , —CH 2 OR 55 or —CONR 55 R 56 , wherein R
• R 5 is selected from the group consisting of wherein R 51 is selected from the group consisting of H; alkyl; alkylaryl optionally mono- or di-substituted at with one or more of lower alkyl, —CN, halogen, or —COOR 54 wherein R 54 is alkyl or —H; and R 52 is lower alkyl or H and, wherein m is defined as before.
• compounds of formula (I) wherein R 5 is selected from the group consisting of said heteroaryl being optionally substituted at one or more positions with one or more substituents independently selected from the group consisting of H, halogen, lower alkyl and (CH 2 ) v R 53 are also preferred, wherein m, v and R 53 are defined as before.
• the heteroaryl is selected from the group consisting of wherein v and R 53 are defined as before, R 58 is independently selected from H, halogen and lower alkyl, D 1 is 0 or S, and D 2 is O, S, or NR 58 , and wherein, when said compound contains two (CH 2 ) v R 53 groups, said groups may be optionally joined together along with the atoms to which they are attached to form a ring.
• preferred compounds of formula (I) are those wherein R 5 is selected from the group consisting of wherein aryl is selected from the group consisting of: wherein R 53 is described as before, and wherein X 5 , X 6 , X 7 , X 8 and X 9 are selected from carbon and nitrogen with the proviso that no more than two of X 5 , X 6 , X 7 , X 8 and X 9 can be N at one time, and wherein m and v are defined as before.
• m is 0.
• aryl is phenyl substituted with —(CH 2 ) v R 53 , wherein R 53 and v are as described above.
• R 5 is a heteroaryl selected from the group consisting of oxadiazolyl, oxazolyl and benzothiazolyl, which heteroaryl is optionally substituted with lower alkyl, lower alkoxy carbonyl or phenyl, which phenyl is optionally substituted with carboxy, lower alkyl carbonyl, carbamoyl or di (lower alkyl) carbamoyl.
• R 5 is 5-methyl-(1,3,4)oxadiazol-2-yl, 5-(4-benzoic acid methyl ester)-(1,3,4)oxadiazol-2-yl, 5-(4-benzoic acid)-(1,3,4)oxadiazol-2-yl, 5-(4-benzamide)-(1,3,4)oxadiazol-2-yl, 5-(4-dimethylbenzamide)-(1,3,4)oxadiazol-2-yl, 4-(carboxylic acid methyl ester)-oxazo-2-yl or benzothiazol-2-yl.
• Preferred compounds of formula (I) are those of formula (Ia) wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, k, X 1 , X 2 , X 3 and X 4 are defined as before.
• R 3 is halogen or alkyl.
• R 1 , R 2 , R 3 , R 4 , R 5 , n, k, X 1 , X 2 , X 3 and X 4 are defined as before.
• R 3 is halogen or alkyl.
• Preferred compounds of general formula (I) are those selected from the group consisting of
• Particularly preferred compounds of the general formula (I) are those selected from the group consisting of
• the compounds of formula (I) can contain several asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereo isomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
• optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or eluent).
• the compounds of formula (I), the pharmaceutically acceptable salts of the compounds of formula (I) and the pharmaceutically acceptable esters of the compounds of formula (I) individually constitute preferred embodiments of the present invention. Particularly preferred are compounds of formula (I).
• the compounds of the general formula (I) in this invention may be derivatized at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
• the present invention also relates to a process for the manufacture of compounds of formula (I) as described above, the process comprising reacting a compound of formula (II) wherein R 2 , R 3 , R 4 , R 5 , and k have the significances given above, with a compound of formula III wherein R 1 , n, X 1 , X 2 , X 3 , and X 4 have the significances given above, and optionally converting the compound of formula I to a pharmaceutically acceptable salt and/or a pharmaceutically acceptable ester.
• Reactions of a compound of formula (II) with a hydrazine of formula (III) can be carried out by procedures known in the art and as described in Scheme 1 below.
• a substituted aryl hydrazine with a compound of formula (II) pure acetic acid between RT and 40° C. when k is 1, and between RT and 75° C. when k is 0, can be employed in the modified Fischer-Indole synthesis.
• reaction can take place at. 120° C. in a sealed tube.
• compounds of formula (I) when compounds of formula (I) contain an R 5 group that is a tertiary amide, compounds of formula I can be carried out by procedures known in the art and as described in Scheme 5 and Scheme 6 below.
• the invention further relates to compounds of formula (I) as defined above, when manufactured according to a process as defined above.
• the compounds-of formula (I) of the present invention can be used as medicaments for the treatment and/or prevention of diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists.
• diseases are increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, inflammatory diseases such as colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such as Alzheimer's disease or impaired/improvable cognitive function.
• compounds of formula (I) for in the treatment of atherosclerosis, low HDL cholesterol levels, non-insulin dependent diabetes mellitus, and metabolic syndrome is preferred.
• the compounds of formula (I) can further be used for treatment and prophylaxis of age-related macular degeneration.
• the invention therefore also relates to pharmaceutical compositions comprising a compound of formula (I) as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
• the invention relates to compounds as defined above for use as therapeutic active substances, particularly as therapeutic active substances for the treatment and/or prophylaxis of diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists.
• diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists.
• Preferred examples of such diseases are atherosclerosis, increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and inflammatory diseases.
• the invention relates to a method for the treatment and/or prophylaxis of diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists, such as e.g. atherosclerosis, increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and/or inflammatory diseases, the method comprising administering a compound of formula (I) to a human or animal.
• diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists, such as e.g. atherosclerosis, increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and/or inflammatory diseases
• the method comprising administering a compound of formula (I) to a human or animal.
• a method for the treatment and/or prophylaxis of diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists comprising administering a compound as defined above to a human being or animal in particular, wherein said disease is selected from the group consisiting of increased lipid and cholesterol levels, particularly low HDL-cholesterol and/or high LDL-cholesterol, atherosclerotic diseases, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidmia, sepsis, inflammatory diseases including colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such as Alzheimer's disease or impaired/improvable cognitive function.
• the invention further relates to the use of compounds as defined above for the treatment and/or prophylaxis of diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists such as atherosclerosis, increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and/or inflammatory diseases.
• diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists such as atherosclerosis, increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and/or inflammatory diseases.
• the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prophylaxis of diseases which are modulated by LXR ⁇ and/or LXR ⁇ agonists such as atherosclerosis, increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and/or inflammatory diseases.
• LXR ⁇ and/or LXR ⁇ agonists such as atherosclerosis, increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, non-insulin dependent diabetes mellitus, metabolic syndrome, dyslipidemia, Alzheimer's disease, sepsis, and/or inflammatory diseases.
• the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below or in the examples or by methods known in the art. In case it is not otherwise indicated all substituents mentioned in Schemes 1, 2a, 2b, 3, 4, 5, and 6 are defined as before. Substituent R 2 means hydrogen and is therefore not always mentioned.
• step a Michael addition of a sulfonyl derivative 2 to a cyclic 2-enone 1, at RT in MeOH containing 10-20% of NaOMe or in THF or acetonitrile in the presence of bases such as K 2 CO 3 or Cs 2 CO 3 , leads to the corresponding 3-substituted cyclic ketone 3 (step a).
• the alkylation of 3 may be carried out with NaH in DMF at 0° C. followed by the addition of the electrophile R 3 —X (MeI, N-fluorobenzenesulfonimide for example) to give 4 as a racemic mixture of diastereomers (step b).
• the two diastereomers (RS,SR) and (RR,SS) may be separated by column chromatography on silica gel at this stage.
• R 1 and R 4 can be be transformed into other functional groups at this stage of the synthesis using standard procedures commonly known to those of the art. Typical examples are the replacement of an iodo- or bromo-substituent by an amino group using Buchwald coupling conditions or replacement of a iodo- or bromo-substituent by a 1-alkynylo-group using Sonogashira coupling conditions. These alkynyl moieties can be further modified to alkyl residues by hydrogentation.
• R 5 may be converted to other residues by formations listed for R 1 and R 4 or by conversion of an alkoxycarbonyl group into a carboxyl group by hydrolysis in presence of LiOH or NaOH, of a carboxyl group into a aminocarbonyl group using a primary or secondary amine and a peptide coupling reagent such as e.g. EDCI, of an alkoxycarbonyl group into a hydroxyalkyl residue by reduction with LiAlH 4 , or of an hydroxyalkyl residue into an ether moiety by alkylation.
• a peptide coupling reagent such as e.g. EDCI
• nitrogen of the tetrahydrocarbazoles, 1,2,3,3a,4,8b-tetrahydro-cyclopenta[b]indoles and related heterocycles may be BOC- or Z-protected prior to these transformations.
• Scheme 2a describes the synthesis of the sulfonyl derivatives starting with the alkylation of thiols 1 with an electrophile of formula 2 in the presence of a base to give the sulfides 3.
• the preferred bases are either K 2 CO 3 using acetone as solvent or NaH in DMF (step a).
• the sulfides 3 are subsequently oxidized to the corresponding sulfonyl derivatives 4 with either oxone (potassium peroxymonosulfate) in MeOH at RT over night, or with mCPBA in CHCl 3 or CH 2 Cl 2 at RT (step b).
• sulfinic acid sodium salt 5 either commercially available or prepared from the corresponding sulfinic acid and a base, may be treated with the electrophile 6 to afford sulfon derivatives 4 (e.g. Y.Nagao, S.Yamada, E. Fujita, Tet. Lett. 1983, 2291-2294).
• the oxadiazole 4 may be prepared by treatment of the hydrazide 2 in POCl 3 in the presence of a carboxylic acid R 53 —(CH 2 ) v —COOH at reflux (route d).
• An additional mode of preparation of derivatives 4 is the treatment of the hydrazide 2 in trimethyl orthoformate with POCl 3 .
• Method B Alternatively, 2 is treated at RT in THF with 3 (for X ⁇ Cl) for 2 hours. After evaporation of the solvent, the mixture is refluxed in dioxane over night in the presence of molecular sieves.
• the resulting sulfides 4 are oxidized to the sulfonyl derivatives of formula 5 with mCPBA at RT in CHCl 3 (step c).
• esters of type 1 (prepared using the procedure described above) are converted to secondary amides 2 by reaction with a primary amine and KCN in a sealed tube (step a).
• TFA mediated deprotection in CH 2 Cl 2 leads to the final compounds 4 (step c).
• Functional groups present on R 1 or R 53 can—if desired or required—be transformed into other functional groups at a suitable stage of the synthesis using standard procedures commonly known to those of the art.
• Typical examples are the transformation of an alkoxycarbonyl group into a carboxyl group by hydrolysis in presence of LiOH, of a carboxcyl group into a aminocarbonyl group using a primary or secondary amine and a peptide coupling reagent such as e.g. EDCI, replacement of a iodo- or bromo-substituent by an amino group using Buchwald coupling conditions or replacement of a iodo- or bromo-substituent by a 1-alkynylo-group using.
• a peptide coupling reagent such as e.g. EDCI
• the nitrogen of the tetrahydrocarbazoles, 1,2,3,3a,4,8b-tetrahydro-cyclopenta[b]indoles and related hetero cycles may be BOC- or Z-protected prior to these transformations.
• Mammalian expression vectors were constructed to express full-length human LXR ⁇ and LXR ⁇ .
• Bacterial expression vectors were constructed to produce glutathione-s-transferase (GST) fused to the ligand binding domains (LBD) of human LXR ⁇ (aa 164 to 447) and human LXR ⁇ (aa 155 to 460).
• GST glutathione-s-transferase
• LBD ligand binding domains
• the portions of the sequences encoding the LBDs were amplified from full-length clones by PCR and then subcloned into the plasmid vectors. Final clones were verified by DNA sequence analysis (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc Natl Acad Sci USA.1994, 91:10809-13).
• LXR ⁇ and LXR ⁇ receptor binding were assayed in buffer consisting of 50 mM HEPES, pH 7.4, 10 mM NaCl, 5 mM MgCl 2 .
• 500 ng of GST-LXR ⁇ -LBD or 700 ng of GST-LXR ⁇ -LBD fusion proteins were bound to 80 ⁇ g or 40 ⁇ g SPA beads (Pharmacia Amersham) respectively, in a final volume of 50 ⁇ l by shaking.
• the resulting slurry was incubated for 1 h at RT and centrifuged for 2 min at 1300 ⁇ g.
• Radioligand eg. 100,000 dpm of (N-(2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-phenyl]-benzenesulfonamide)
• was added eg. 100,000 dpm of (N-(2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-phenyl]-benzenesulfonamide)
• All binding assays were performed in 96-well plates and the amount of bound ligand was measured on a Packard TopCount using OptiPlates (Packard). Dose response curves were performed within a range of concentration from 10 ⁇ 11 M to 10 ⁇ 4 M.
• Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM medium containing 10% FBS at 37° C. in a95% O2:5% CO 2 atmosphere. Cells were seeded in 6-well plates at a density of 10 5 Cells/well and then batch-transfected with either the full-length-LXR ⁇ or full-length-LXR ⁇ expression plasmids plus a reporter plasmid expressing luceriferase under the control of LXR response elements. Transfection was accomplished with the Fugene 6 reagent (Roche Molecular Biochemicals) according to the suggested protocol. Six hours following transfection, the cells were harvested by trypsinization and seeded in 96-well plates at a density of 10 4 cells/well.
• the compounds according to formula (I) have an activity in at least one of the above assays (EC50 or IC50) of 0.1 nM to 100 ⁇ M, preferably 0.1 nM to 1 ⁇ M. ( ⁇ M means micromolar).
• the compounds of formula I and/or pharmaceutically-acceptable salts and/or pharmaceutically-acceptable esters can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.
• the production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
• Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
• lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules.
• Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules).
• Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
• Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
• Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
• Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
• Usual stabilizers preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
• the dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes into consideration. Depending on severity of the disease and the precise pharmacokinetic profile the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
• pharmaceutical preparations contain about 1-500 mg, more preferably 1-100 mg, of a compound of formula I.
• BOC t-butyloxycarbonyl
• CH 2 Cl 2 dichloromethane
• CCl 4 tetrachloromethane
• mCPBA m-chloroperbenzoic acid
• CuI copper iodide
• DMAP 4-dimethylaminopyridine
• DMF dimethylformamide
• EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
• EtOAc ethylacetate
• EtOH ethanol
• Et 2 O diethylether
• Et 3 N triethylamine
• eq equivalent
• Huenig's base iPr 2
• NEt N-ethyl diisopropylamine
• LiAlH 4 lithium aluminum hydride
• MeOH methanol
• NaH sodium hydride
• NaOtBu sodium tert.
• NBS N-bromosuccinimide
• RT room temperature
• THF tetrahydrofuran
• NaHCO 3 sodium bicarbonate
• NH 4 Cl ammonium chloride
• TFA trifluoroacetic acid
• NaOH sodium hydroxide.

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