Quinolinyl and benzothiazolyc PPAR-gamma modulators
An alkyl and aryl technology, applied in the field of regulating PPARγ receptors, can solve problems such as side effects that limit clinical use
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[0070] Compound preparation
[0071] The compounds of the invention can be prepared using standard synthetic methods. Schemes 1-3 illustrate exemplary methods for preparing compounds of formula (Ia). Those skilled in the art will understand that compounds of other structural types can be synthesized in a similar manner.
[0072] Preparation of compounds
[0073] As shown in Scheme 1, compounds of the present invention can be prepared starting from commercially available 2-chloro-5-nitrobenzonitrile (i) with phenol, thiophenol or optionally protected aniline in the presence of base and heat Subsequent treatment of i affords the adduct (ii). with H 2 Reduction of the nitro group in ii in the presence of Raney nickel catalyst affords the aniline derivative (iii). With a suitable arylsulfonyl halide (Ar 1 SO 2 Cl) Sulfonation of iii in the presence of a base (usually a tertiary amine) yields the target compound (iv). Compound iii can also be transformed into related compo...
Embodiment 1
[0110] The following benzenesulfonyl chlorides were prepared from the corresponding commercially available anilines by the method of R.V. Hoffman (Org. Syn. Col. Vol. VII, 508-511) for carrying out the given examples.
[0111] 2-Chloro-4-tert-butylbenzenesulfonyl chloride (1a). Yield 34%. 1 H NMR (CDCl 3 ) δ8.06 (1H, d, J = 8.4Hz), 7.62 (1H, s), 7.48 (1H, d, J = 8.4Hz), 1.37 (9H, s); melting point 68.8°C.
[0112] 2-Trifluoromethyl-4-chlorobenzenesulfonyl chloride (1b). Yield 76%, solid. 1 H NMR (CDCl 3 ) 8.325 (d, J=8.4Hz, 1H), 7.966 (br s, 1H), 7.829 (br d, J=8.4Hz, 1H). Melting point 37.0℃
[0113] e-Chloro-4-methylbenzenesulfonyl chloride (1c). Yield 47%, oil. 1 H NMR (CDCl 3 ) 8.02 (1H, d, J = 8.8Hz), 7.46 (1H, s), 7.28 (1H, d, J = 8.8Hz), 2.47 (3H, s).
Embodiment 2
[0115] 2.1 2.2 2.3
[0116] Compound 2.3
[0117] Compound 2.1 was prepared by adapting the published method of Albert and bArlin (J. Chem. Soc. 2384-2396 (1959)). 3-Aminoquinoline (15.0 g, 105 mmol) was suspended in a mixture of 10N HCl (40 mL), ice (21 g) and water (100 ml) at 0-5°C, then sodium nitrite (7.6 g, 110 mmol) was added slowly. The mixture was then added in portions to another solution of potassium ethyl xanthate (20.8 g, 125 mmol) in water (60 ml) at 45°C. Heat to mix for 1 hour then cool. The mixture was then extracted with ether. The ether solution was washed with 2N NaOH solution, water and brine, then dried over magnesium sulfate. After filtration, the solvent was removed to give a brown oil (15g), which was then dissolved in ethanol (150ml) and refluxed with KOH (25g) under nitrogen overnight. The ethanol solvent was then removed in vacuo and the residue was partitioned between water and ether. The ether solution was discarded. The aqueous solution ...
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