Ragaglitazar
NNC-61-0029, (-) – DRF-2725, NN-622,
(−)DRF 2725
cas 222834-30-2
222834-21-1 (racemate)
Hyperlipidemia; Hypertriglyceridemia; Lipid metabolism disorder; Non-insulin dependent diabetes
PPAR alpha agonist; PPAR gamma agonist
(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACID,
(2S)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid, DRF, 1nyx
Molecular Formula: C25H25NO5
Molecular Weight: 419.4697 g/mol
Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARalpha Agonists, PPARgamma Agonists
Phase III
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J Med Chem 2001,44(16),2675
(−)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPARα and PPARγ. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.
Scheme 1 a
a (a) NaH, DMF, 0−25 °C, 12 h; (b) triethyl 2-ethoxy phosphosphonoacetate, NaH, THF, 0−25 °C, 12 h; (c) Mg/CH3OH, 25 °C, 12 h; (d) 10% aq NaOH, CH3OH, 25 °C, 6 h; (e) (1) pivaloyl chloride, Et3N, DCM, 0 °C, (2) (S)-2-phenyl glycinol/Et3N; (f) 1 M H2SO4, dioxane/water, 90−100 °C, 80 h.
Compound 6 is prepared from phenoxazine using a synthetic route shown in Scheme 1. Phenoxazine 7 upon reaction with p-bromoethoxy benzaldehyde 89 gave benzaldehyde derivative 9. Reacting 9 with triethyl 2-ethoxy phosphonoacetate afforded propenoate 10 as a mixture of geometric isomers. Reduction of 10 using magnesium methanol gave propanoate 11, which on hydrolysis using aqueous sodium hydroxide gave propanoic acid 12 in racemic form. Resolution of 12 using (S)(+)-2-phenyl glycinol followed by hydrolysis using sulfuric acid afforded the propanoic acid 6 in (−) form.
Nate, H.; Matsuki, K.; Tsunashima, A.; Ohtsuka, H.; Sekine, Y. Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. II. 2-(phenylpiperazinoalkoxyphenyl)thiazolidine-3-thiocarboxyamides and corresponding carboxamides. Chem. Pharm. Bull. 1987, 35, 2394−2411
(S)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-eth-oxypropanoic Acid (6). as a white solid, mp: 89−90 °C.
[α]D 25 = − 12.6 (c = 1.0%, CHCl3).
1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J = 7.0 Hz, 3H), 1.42−1.91 (bs, 1H, D2O exchangeable), 2.94−3.15 (m, 2H), 3.40−3.65 (m, 2H), 3.86−4.06 (m, 3H), 4.15 (t, J = 6.6 Hz, 2H), 6.63−6.83 (m, 10H), 7.13 (d, J = 8.5 Hz, 2H). Mass m/z (relative intensity): 419 (M+, 41), 197 (15), 196 (100), 182 (35), 167 (7), 127 (6), 107 (19).
Purity by HPLC: chemical purity: 99.5%; chiral purity: 94.6% (RT 27.5).
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