Morphine esters

Synonyms 7 j8-Didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol-di-3-pyridinecarboxylate (ester) nicotinic acid morphine ester morphine dinicotinate Trade names Gewalan, Vilan... 

Synthesis of morphine esters, a) 3-Acetyl-d -morphine (I-e). Morphine base (50 mg) was dissolved in 2 ml acetic anhydride- e and remained at room temperature for 20 min. Water 5 ml) was added, and after the solution became homogenous, solid sodium carbonate was added to pH 8.5. The mixture was extracted with 3-20ml ether portions. The ether extracts were combined and evaporated to dryness. The product was eluted with 2% ethanol in benzene from 4.0 gram silica (adsorbosil-5) to give ( "e). b) 3-AcetyImorphine (I-b). Morphine base (50 mg) was treated with 2 ml acetic anhydride at room temperature for 20 minutes. 3-Ace ty Imorphine was isolated for mass analysis by the same procedure as (I-e). c) 6-Acetyl-ds--morphine (I-g). 3,6-Diacety 1- 3-morphine (50 mg) was converted to its hydrochloride with HCl (g) in anhydrous ether. The white precipitate was collected on a Buchner funnel. The product was then dissolved in 20 ml water and 0.1 gram hydroxylamine hydrochloride was added. After 2 minutes, solid sodium carbonate was added to pH 8.5 and the solution was extracted with 3-20 ml ether portions. 

An opium alkaloid Although it is an excellent analgesic its use is restricted because of the potential for addiction Heroin is the diacetate ester of morphine )... 

The most successful modifier is cinchonidine and its enantiomer cinchonine, but some work in expanding the repertoire of substrate/modifier/catalyst combinations has been reported (S)-(-)-l-(l-naphthyl)ethylamine or (//)-1 -(I -naphth T)eth Tamine for Pt/alumina [108,231], derivatives of cinchona alkaloid such as 10,11-dihydrocinchonidine [36,71], 2-phenyl-9-deoxy-10, 11-dihydrocinchonidine [55], and O-methyl-cinchonidine for Pt/alumina [133], ephedrine for Pd/alumina [107], (-)-dihydroapovincaminic acid ethyl ester (-)-DHVIN for Pd/TiOz [122], (-)-dihydrovinpocetine for Pt/alumina [42], chiral amines such as 1 -(1 -naphtln I)-2-(I -pyrro 1 idiny 1) ethanol, l-(9-anthracenyl)-2-(l-pyrrolidinyl)ethanol, l-(9-triptycenyl)-2-(l-pyrrol idi nyl)cthanol, (Z )-2-(l-pyrrolidinyl)-l-(l-naphthyl)ethanol for Pt/alumina [37,116], D- and L-histidine and methyl esters of d- and L-tryptophan for Pt/alumina [35], morphine alkaloids [113],... 

Metabolism Glucuronidation N-demethylation Ester hydrolysis to morphine Glucuronidation demethylation (CYP2D6) Ester hydrolysis N-demethylation N-Dealkylation, then hydroxylation N-Demethylation Plasma and tissue esterases... 

In a series of ten morphine 3-benzoates, large differences in rates of enzymatic hydrolysis were seen [122], In 80% human plasma at pH 7.4 and 37°, the unsubstituted 3-benzoate had a tm value of 0.6 h, whereas esters of 2,6-disubstituted benzoic acid were much more resistant to enzymatic attack (t1/2 ranging from 60 h for the dimethylbenzoate to 300 h for the dichloro-and dimethoxybenzoates). Although these results point to marked steric hindrance, electronic effects cannot be excluded but escape characterization because of the limited series. Furthermore, and as mentioned repeatedly in this text, the possibility of binding to plasma proteins is a complicating factor that should be kept in mind. 

D. Preechagoon, I. Brereton, C. Staatz, R. Prankerd, Ester Prodrugs of a Potent Analgesic, Morphine-6-sulfate Syntheses, Spectroscopic and Physicochemical Properties , Int. J. Pharm. 1998, 163, 177-190. 

C. Mignat, D. Heber, H. Schlicht, A. Ziegler, Synthesis, Opiod Receptor Affinity, and Enzymatic Hydrolysis of Sterically Hindered Morphine 3-Esters , J. Pharm. Sci. 1996, 85, 690 - 694. 

The azacycloheptane (XXX), the most active non-piperidine derivative of the reversed ester series (7 X pethidine), was a typical morphine-like analgesic it... 

It is a methyl ester of morphine and less potent analgesic than morphine. It is widely used as antitussive agent. Pholcodeine is also used as antitussive agent and causes less constipation (Details are given in chapter Drugs acting on respiratory system ). 

Esters (eg, heroin, remifentanil) are rapidly hydrolyzed by common tissue esterases. Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid. 

Takatori T, Yamamoto K, Yamaguchi T, Higaki K, Kimura T. Design of controlled -release morphine suppositories containing polyglycerol ester of fatty acid. Biol Pharm Bull 2005 28(8) 1480-1484. 

Contra Toxic D convulsive disorder Disp Liq SE 4- BP, sedation, constipation Interactions X Effects OF ampicillin esters, azole antifungals, Fe salts EMS Concurrent EtOH use can T sedation contains anhydrous morphine from opium OD May cause constipation and CNS depression activated charcoal may be effective, naloxone can be used for resp depression... 

Cimbura and Kofoed (50),mentioned earlier, used GLC to separate amphetamine and methamphetamine after acetylation with acetic anhydride in methanol. Derivatives were extracted using diethyl ether and chromatographed op columns of either 3% OV-17, OV-1, or SE-30. Column temperature was 160°C. They also reported the chromatographic determination of acetylated morphine on 3% SE-30, OV-1, or OV-17 at temperatures of 220°C. Cruickshank et al.(21) separated 21 amino acids as their trifluoroacetylated methyl esters. The column was 5% neopentyl glycol succinate on Gas Chrom P. Column temperatures were both isothermal and programmed 65°C for 20 min at 1.5°C/min then 2°C/min until 42.5 min then 4°C/min until 60 min then isothermal until about 75 min (see Figure 12.2). Chang et al. (19), used BSA/pyridine to form the TMS derivatives of levodopa, methyldopa, tyrosine. 

Nikethamide is a respiratory and heart stimulant, used beneficially against overdoses of barbiturates and morphine, Also known as Coramine, this compound (A, A-diethylnicolinamide) is made by reaction of nicotinic add esters or the add chloride with diethylamine. Its... 

The addition of two acetyl-ester groups to the morphine molecule produces a more lipophilic compound. Experimental evidence suggests that heroin and morphine may exert their effects via different receptor mechanisms.32 33... 

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