Etretinate

Satzinger, G. U.S. Patent 3/)72,653 January 8,1963 assigned to Warner-Lambert Pharmaceutical Co. 

Chemicai Name Ethyl all-trans-0- 4-methoxy-2 -trimethylphenyl)-3,7-dimethyl-2,4, 8-nonatetraenoate 

Trade Name Manufacturer Country Year Introduced 

5-(4-Methoxy-2,3,6-trimethylphenyl)-3-methylpenta-2,4-diene-1-triphenylphos-phonium bromide Sodium hydride 

3-Formylcrotonic acid butyl ester Potassium hydroxide Ethyl iodide Potassium carbonate 

5-(4-M ethoxy-2,3,6-trimethylph enyl)-3-methy I penta-2,4-diene-1-triphenyl phos-phonium bromide Sodium hydride 

228 g of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-1-triphenylphos-phonium bromide are introduced under nitrogen gassing into 910 ml of dimethylformamide and treated with cooling at B C to 10°C within 20 minutes with 17.5 g of a suspension of sodium hydride (about 50% by weight) in mineral oil. The mixture is stirred for 1 hour at about 10°C, then treated at 5°C to 8°C dropwise with 61.8 g of 3-formylcrotonic acid butyl ester, heating for 2 hours at 65°C, subsequently introduced into 8 liters of ice water, and, after the addition of 300 g of sodium chloride, thoroughly extracted with a total of 18 liters of hexane. The extract is washed 5 times with 1 liter of methanol/water (6 4 parts by volume) each time and 2 times with 1.5 liter of water each time, dried over sodium sulfate and evaporated under reduced pressure to leave 9-(4-methoxy-2,3,6-trimethvlphenvl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester, MP 80°C to 81 °C as the residue. 

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The free acid analogue of the antipsoriatic agent etretinate (103) is prepared in substantially the same way as the parent compound. Thus, the aldehyde group in 98 is converted finally to the pho.sphonate (101) by sequential reduction (99), conversion to the chloride (100), and finally reaction with triethyl phosphite. Condensation of the ylide from 101 with the benzaldehyde 102 gives etretinate (103) saponification affords acitretin (104) [25]. 

Up to now, far more than 5000 retinoic acid analogs have been synthesized, out of which the following three generations have been established for therapy of various disorders First, the nonaromatic retinoids (3-carotene (provitamin A), alWraras-retinoic acid (RA) (tretinoin) and 13-cis-RA (isotretinoin), second, the monoaromatic retinoid derivatives trimethyl-methoxyphenyl analog of RA (etretinate) and9-(4-methoxy-2,3,6-trimethylphenyl)-... 

Etretinate 0 i COOR Oral 0.25-1.0 mg/kg/d Generalized pustular psoriasis, exfoliative psoriasis, plaque psoriasis ... 

Systemic treatment of 13-cis retinoic acid frequently leads to cheilitis and eye irritations (e.g., unspecific cornea inflammation). Also other symptoms such as headache, pruritus, alopecia, pains of joints and bone, and exostosis formation have been reported. Notably, an increase of very low density lipoproteins and triglycerides accompanied by a decrease of the high density lipoproteins has been reported in 10-20% of treated patients. Transiently, liver function markers can increase during oral retinoid therapy. Etretinate causes the side effects of 13-cis retinoid acid at lower doses. In addition to this, generalized edema and centrilobulary toxic liver cell necrosis have been observed. 

C3H7NO 68-12-2) see Acrivastine Amlexanox Amrinone Etretinate Fluvastatin sodium Gitaloxin Glymidine Isradipine Lonazolac Nomegestrol acetate Sulfaperin... 

C2H,BrMg 925-90-6) see Amfebutamone Dicthylstilbestrol Elhylestrenol Etretinate Fomocaine Indanorex Ketobemidone Mepivacaine Methadone Methallenestril Methohexital Normethadone Olprinone hydrochloride Retinol cthylmalonic acid diethyl ester see under diethyl ethylmalonate ethylmercaptan... 

C gH, P 603-35-0) see Acrivastine Betacarotene Calcipotriol Canthaxanthin Cefixime cis-Cefprozil Etretinate llopfost Imiquimod Isotretinoin Repaglinide Retinol Tretinoin... 

OiFFerential effects of and etretinate on serum cytokine levels in patients with psoriasis... 

Ethyl vinyl ether, 1 254, 258 derivation from ethanol, 10 557 physical properties of, l 255t Ethynylation, acetylene, 1 181, 231-249 Etretinate, 25 790 Etridiazole, 23 629... 

K. M. Knights, R. Gasser, W. Klemisch, In vitro Metabolism of Acitretin by Human Liver Microsomes Evidence for an Acitretinoyl-Coenzyme A Thioester Conjugate in the Transesterification to Etretinate , Biochem. Pharmacol. 2000, 60, 507-516. 

Ethinyl Estradiol 74 Ethmozne 50 Ethynodiol Diacetate 74 Etidonate 34 Etodolac 34 Etretinate ... 

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