Naltrexone

Indications

Naltrexone, an orally active opioid receptor antagonist, restores erectile function in some patients with idiopathic ED.

Manufacturing Process

Codeine is a component of gum opium and can also be produced by methylation of morphine using known prior art techniques.A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g, 180.2 mmol), triethylamine (18.25 g, 180.2 mmol) and 4-dimethylaminopyridine (0.5 g) in dry ethyl acetate (620 ml) was stirred at rt. under nitrogen for 12 hr, added saturated aqueous sodium bicarbonate solution until no acetic anhydride detected. The organic portion was separated, washed with water (3times 120 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 6-acetylcodeine as white solids (34.0 g, 99% yield).Preparation of 6-acetylnorcodeine hydrochloride.A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl chloroformate (5.51 g, 37.8 mmol), and proton sponge (1.0 g) in methylene chloride (80 ml) was heated at reflux for 80 min. The reaction mixture was evaporated in vacuo to dryness. The residue was chromatographed on silica gel with ethyl acetate to give 6-acetyl-17-(1-chloroethoxycarbonyl)norcodeine as an oil (12.13 g), which was dissolved in methanol with a few drops of conc. HCl. The solution was heated at reflux for 1 hr and evaporated in vacuo to almost dryness. The residue was added hexane and filtered to give 6- acetylnorcodeine hydrochloride (10.7 g, 100% yield).Preparation of norcodeine hydrochloride.A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethyl chloroformate (5.56 g, 38.1 mmol), and proton sponge (1.0 g) in methylene chloride (50 ml) was heated at reflux for 50 min. The reaction mixture was evaporated in vacuo to about 30 ml. Methanol (25 ml) and concentrated HCl (2 ml) were added. The solution was heated at reflux for 40 min. and evaporated in vacuo to almost dryness. The residue was added hexane and filtered to give norcodeine hydrochloride (8.8 g, 93% yield).Preparation of 17-cyclopropylmethylnorcodeine.A mixture of norcodeine hydrochloride (11.48 g, 27.8 mmol), (chloromethyl)cyclopropane (5.14 g, 55.6 mmol), sodium carbonate (14.73 g, 139.0 mmol), and potassium iodide (4.61 g, 27.8 mmol) in ethanol (250 ml) was heated at reflux for 20 hr, cooled, and evaporated in vacuo to dryness. The residue was basified with NH4OH, and extracted with methylene chloride. The extract was washed with water and evaporated in vacuo to dryness. The residue (11.7 g) was chromatographed on silica gel with a eluting solvent system of methanol/ethyl acetate (10/90) to give 17- cyclopropylmethylnorcodeine (10.68 g, 91% yield).Preparation of 17-cyclopropylmethylnorcodeinone.To a solution of DMSO (14.50 g, 185.6 mmol) in methylene chloride (80 ml) at -78°C, was added a solution of oxalyl chloride (11.78 g, 92.8 mmol) in methylene chloride (20 ml) in 20 min. After stirring at -78°C for 20 min., a solution of 17-cyclopropylmethylnorcodeine (9.0 g, 26.5 mmol) in methylene chloride (40 ml) was added dropwise in 50 min. The reaction mixture was stirred at -74° to -76°C for 3 hr, added triethylamine (9.39 g, 92.8 mmol), allowed to warm up to rt., added methylene chloride (200 ml), washed with water (10 times 50 ml), and evaporated in vacuo to dryness. The residue was mixed with hexane and filtered to give 17-cyclopropylmethylnorcodeinone (8.85 g, 99% yield).Preparation of 17-cyclopropylmethylnorcodeinone dienol acetate.A mixture of 17-cyclopropylmethylnorcodeinone (3.55 g, 10.5 mmol), acetic anhydride (20 ml, 210.4 mmol), sodium acetate (1.3 g, 15.8 mmol), and toluene (6 ml) was heated at 71°-73°C for 14 hr. The reaction mixture was cooled, added methylene chloride (250 ml), water (50 ml), and sodium bicarbonate (73.5 g), stirred for 4 hr, and filtered. The organic portion of the filtrate was separated, washed with water (30 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness. The residue (3.94 g) was chromatographed on silica gel with 100% ethyl acetate to give 17- cyclopropylmethylnorcodeinone dienol acetate (2.87 g, 72% yield).Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone. A solution of 17-cyclopropylmethylnorcodeinone (0.20 g, 0.59 mmol), formic acid (90%, 0.304 g), water (0.504 g), EtOAc (0.27 g), and hydrogen peroxide (30%, 0.17 g) was heated at 42°-43°C for 15 hr, added water (20 ml), basified with Na2CO3 (1.02g), and extracted with EtOAc (80 ml and 2 times 20 ml). The combined extract was washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give 17-cyclopropylmethyl-14- hydroxynorcodeinone (0.10 g, 56% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone.A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (1.00 g, 2.63 mmol), formic acid (8 ml, 90%), and hydrogen peroxide (0.37 g, 30%, 3.26 mmol) was heated at 44°-45°C for 6 hr, added water (20 ml) and ethyl acetate (80 ml), basified with sodium bicarbonate. The organic portion was separated, washed with water (15 ml), dried over anhydrous sodium sulfate and evaporated in vacuo to dryness, the residue (0.9 g) was chromatographed on silica gel with methanol/methylene chloride (2.5/97.5) to give 17- cyclopropylmethyl-14-hydroxynorcodeinone (0.72 g, 78% yield).Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone.A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (0.5 g, 1.31 mmol), 3-chloroperbenzoic acid (0.36 g, 2.10 mmol) and oxalic acid (0.27 g, 2.90 mmol) in acetic acid (7 ml) was stirred at rt. overnight, added cold water (35 ml), basified with sodium carbonate, and extracted with methylene chloride (100 ml). The extract was washed with water (2 times 30 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness. The residue (0.41 g) was chromatographed on silica gel to give 17- cyclopropylmethyl-14-hydroxynorcodeinone (0.34 g, 74% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.Preparation of 3-methylnaltrexone.A mixture of 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.30 g, 0.85 mmol) and Pd/C (5%, 0.45 g) in ethanol (35 ml) was hydrogenated in a Parr hydrogenator at rt. under 28 psi of hydrogen gas. The mixture was filtered. The filtrate was evaporated in vacuo to dryness to give 3-methylnaltrexone (0.30 g, 99% yield).Preparation of naltrexone from 3-methylnaltrexone.A solution of 3-methylnaltrexone (0.48 g, 1.35 mmol) in methylene chloride (30 ml) was cooled with an ice-water bath, and then added a solution of boron tribromide (5.4 ml, 1 M solution in methylene chloride, 5.4 mmol). The reaction mixture was stirred at rt. for 15 hr, basified with NH4OH, and extracted with methylene chloride (60 ml). The extract was washed with water (2 times 15 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to give naltrexone (0.45 g, 98% yield).

Therapeutic Function

Narcotic analgesic

Biological Functions

Naltrexone (Trexan) is three to five times as potent as naloxone and has a duration of action of 24 to 72 hours, depending on the dose. It is used orally in the treatment of opioid abstinence. Naltrexone exhibits a large firstpass effect in the liver. However, the major metabolite, 6-β-naltrexol, is also a pure opioid antagonist and contributes to the potency and duration of action of naltrexone. Administration of naltrexone orally blocks the subjective effects of abused opioids and is used to decrease the craving for opioids in highly motivated recovering addicts. However, high doses of the opioids can overcome the naltrexone blockade and lead to seizures or respiratory depression and death. In addition, it has been reported recently that naltrexone can reduce the craving for alcohol in alcoholic patients. Naltrexone also has been used with success in treating apneic episodes in children, an effect hypothesized to be due to blockade of β-endorphin–induced respiratory depression. Naltrexone can induce hepatotoxicity at doses only five times the therapeutic dose and should be used with care in patients with poor hepatic function or liver damage. Side effects of the use of naltrexone are more frequently observed than following naloxone administration. Such side effects include headache, difficulty sleeping, lethargy, increased blood pressure, nausea, sneezing, delayed ejaculation, blurred vision, and increased appetite.

Biological Activity

Naltrexone is derived from oxymorphone and exhibit agonist activity only at doses that are of little clinical significance. In the absence of opioid drugs, naloxone does not cause analgesia, respiratory depression, or sedation. However, when administered with an opioid analgesic, the effects produced by the opioid agonist are promptly reversed. The ability to antagonize opioids at all of the different opioid receptors makes naloxone useful for the treatment of opioid overdose. Naltrexone has a similar profile, but it is orally active and has a significantly longer half-life.

Synthesis

Naltrexone, (-)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one (3.1.93), is an N-cyclopropylmethyl derivative of oxymorphone (3.1.82). One of the methods of synthesis is analogous to the synthesis of naloxone, which consists of using cyclopropylmethylbromide instead of allylbromide.

Definition

ChEBI: An organic heteropentacyclic compound that is naloxone substituted in which the allyl group attached to the nitrogen is replaced by a cyclopropylmethyl group. A mu-opioid receptor antagonist, it is used to treat alcohol dependence.

Brand name

Vivitrol (Alkermes).

General Description

Naltrexone is a pure opioid antagonist at allopioid receptor subtypes with the highest affinity for theμ-receptor. Naltrexone is orally bioavailable and blocksthe effects of opiate agonists for approximately 24 hoursafter a single dose of 50 mg. It produces no opioid agonisteffects and is devoid of any intrinsic actions other thanopioid receptor blockade. Theoretically, it should workwell to treat opioid dependence but in clinical practice,patients have shown poor compliance and high relapserates. Naltrexone has also been studied to treat alcohol dependencewith mixed results. To address the complianceissues and effectively remove the “choice” of taking theantagonist, naltrexone was developed into an extendedreleaseinjectable microsphere formulation for IM injectiononce a month (Vivitrol). This formulation providessteady-state plasma concentrations of naltrexone threefoldto fourfold higher than the 50-mg oral dose 4 times aday. Currently, Vivitrol is only indicated for the treatmentof alcohol dependence. A Cochrane review found insufficientevidence from randomized controlled trials toevaluate its effectiveness for treating opioid dependence. Currently, phase II and phase III clinical trials ofan implantable pellet form of naltrexone are being conductedfor treating opioid dependence.The CYP450 system is not involved in naltrexonemetabolism. Naltrexone is reduced to the active antagonist6-β-naltrexol by dihydrodiol dehydrogenase, a cytosolicenzyme. Naltrexone has a black box warning, because ithas the potential to cause hepatocellular injury when givenin excessive doses.