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Tetrahydrocarbazoles and derivatives

a technology of tetrahydrocarbazoles and derivatives, applied in the field of compounds, can solve the problems of limiting the therapeutic potential of this approach, unphysiologically high levels of insulin, and ultimately reducing

Inactive Publication Date: 2005-09-29
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the substantial unfavorable side-effects limit the therapeutic potential of this approach.
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.

Method used

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  • Tetrahydrocarbazoles and derivatives
  • Tetrahydrocarbazoles and derivatives
  • Tetrahydrocarbazoles and derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

benzenesulfonyl-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-acetic acid methyl ester

[0307] To a stirred solution of 9 g (0.042 mol) of methyl phenylsulfonylacetate in 90 mL of MeOH at 0° C., 1.56 mL (0.008 mol, 0.2 eq) of a solution of sodium methoxide (5.4 M in MeOH) were added. After 15 min, 4.04 g (0.02 mol) of 2-cyclohexen-1-one were added. The reaction mixture was allowed to reach RT within 4 hours, diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with heptane / EtOAc 1:1 yielded 11.50 g (88%) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester as a racemic mixture of diastereomers, light yellow oil, MS: 311 (MH+).

[0308] To 5 g (0.016 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in glacial acetic acid (30 mL), 3.17 g (0.018 mol, 1.1 eq) of 4-chlorophenylhydrazine hydrochloride were added and the reaction mixture was ...

example 2

benzenesulfonyl-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-acetic acid methyl ester

[0309] In analogy to example 1.2, from benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester and (4-fluoro-phenyl)-hydrazine hydrochloride was prepared benzenesulfonyl-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-acetic acid methyl ester as a racemic mixture of diastereomers, light yellow solid, MS: 402 (MH+).

example 3

(RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester

3.1

[0310] To a stirred solution of 2 g (6.44 mmol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetic acid methyl ester in 40 mL of DMF at 0° C., 283 mg (7.09 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 1.37 g (9.66 mmol, 1.5 eq) of methyliodide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane / EtOAc 2:1, yielding 0.79 g (38%) of (RS,SR)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a white solid, MS: 325 (MH+) and 0.71 g (34%) of (RR,SS)-2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionic acid methyl ester as a white solid, MS: 325 (MH+).

3.2

[0311] To 0.14 g (0.43 mmol) (RS...

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Abstract

The present invention relates to compounds of the formula (I) wherein R1, R2, R3, R4, R5, X1, X2, X3, X4, n, and k are defined in the description and claims, and pharmaceutically acceptable salts and / or pharmaceutically acceptable esters thereof. The compounds are useful for in the treatment and prophylaxis of diseases which are modulated by LXRα and / or LXRβ agonists, including 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.

Description

FIELD OF THE INVENTION [0001] The present invention relates to compounds of the formula (I): and pharmaceutically acceptable salts and pharmaceutically acceptable esters thereof. [0002] It has been found that the compounds of the present invention are useful as liver-X-modulators. [0003] All documents cited or relied upon below are expressly incorporated herein by reference. BACKGROUND OF THE INVENTION [0004] Liver-X-Receptors (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, LXRα and LXRβ, have been described (Willy et al., Genes Dev. 1995, 9:1033-45; Song et al., Proc Natl Acad Sci USA.1994, 91:10809-13). LXRβ is ubiquitously expressed, while LXRα is predominantly expressed in cholesterol metabolizing tissues such as the liver, adipose, intestine and macrophage. The LXRs modulate a variety of physiological responses includin...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/40C07D209/70C07D209/86C07D209/88C07D401/12C07D403/06C07D403/12C07D411/06C07D411/14C07D413/06C07D413/14C07D417/06C07D471/04
CPCC07D209/70C07D209/88C07D417/06C07D413/06C07D413/14C07D403/12A61P1/00A61P1/16A61P1/18A61P25/00A61P25/28A61P29/00A61P3/00A61P3/10A61P31/00A61P31/04A61P31/10A61P3/04A61P3/06A61P43/00A61P7/00A61P9/00A61P9/10C07D401/12C07D209/86
Inventor DEHMLOW, HENRIETTAKUHN, BERNDMASCIADRI, RAFFAELLOPANDAY, NARENDRARATNI, HASANEWRIGHT, MATTHEW BLAKE
Owner F HOFFMANN LA ROCHE & CO AG
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