Dihydromorphinone

Dihydromorphinone, Cj,Hjg03N, and derivatives. Dihydromorphinone (LIII MeO HO) is formed when morphine in solution is treated with relatively large quantities of platinum or palladium catalyst under various conditions.It melts at 262-3° and yields an oxime, m.p. > 234°. The hydrochloride is the drug known as dilaudid. On 0-methyla-tion dihydromorphinone yields dihydrocodeinone (see above), and when dissolved in ether and treated with methyllithium the corresponding tertiary alcohol, 6-methyldihydromorphine, CigHggOgN, m.p. 209-211°, Wd ° 14i7° (EtOH), is formed. This on methylation with diazomethane gives 6-methyldihydrocodeine as described above (Small and Rapoport... 

Numerous derivati es of morphine have been devised for use in medicine including acyl derivatives, of which diacetylmorphine (C], Hj,03N, Ac2, m.p. 173°, [a]J°° — 166° (MeOH) B. HCl. 2H2O, m.p. 231-2°) is the best known, alkyl and other ethers such as the ethyl-and benzyl-morphines, dihydro- and dihydroketo-compounds such as dihydromorphine, dihydrocodeine, dihydromorphinone, dihydrocodeinone and hydroxydihydrocodcinone, and the deoxy-compounds, e.g., dihydro-deoxymorphine and methyldihydrodeoxymorphine. 

The inifial sfeps in fhe mefabolism of morphine and codeine by Pseudomonas putida MIO involve oxidafion of fhe C-6 hydroxy group and subsequenf reducfion of fhe 7,8-olefinic bond, forming hydromorphone (dihydromorphinone) and hydrocodone (dihydrocodeinone), respectively (Scheme 4) [52], These products have important industrial appUcations hydromorphone is an analgesic some seven times more potent than morphine [53],... 

Schemes Transformation steps involved in the oxidation of morphine by incubation with Pseudomonas putida MIO, which gave hydromorphone (dihydromorphinone), 14 d-hydroxymorphine, 14 8-hydroxymorphinone, and dihydromorphine [52]...

Dihydromorphinone is 3-4 times more powerful than morphine and dihydrocodeinone is just a little less than morphine in potency. Their pitfall is an addiction liability, as great if not greater than morphine. To produce Hydrogenate morphine or codeine in a warm, strongly acidic solution, in a large excess of palladium or platinum catalyst, as per instructed in the reductions chapter. 

Dihydrothebaine can be converted to dihydromorphinone by hydrolysis, but I could not find the specifics to this operation. 

The A double bond is not essential to the activity of morphine. Dihydromorphine or dihydromorphinone are active compounds with a reduced duration of action but increased activity. 

Potency refers to the lowest dose that will produce a maximum effect. Efficacy refers to the inherent ability to exert an effect. Morphine in a dose of 10 mg given subcutaneously produces analgesia but a 2-mg dose of dihydromorphinone (Dilaudid) can accomplish the same degree of analgesia. Therefore, morphine and dihydromorphinone are equally efficacious, but dihydromorphinone is more potent than morphine (Figure 1.8). 

In this synthetic derivative of codeine, a ketone group replaces the -OH of codeine at position 6 and two H atoms are added at positions 7 and 8. It thus bears the same relation to codeine as dihydromorphinone (Dilaudid ) does to morphine. It is marketed as the tartrate under the trade names Dicodid and Hycodan and is used chiefly for the relief of cough. 

Dihydromorphinone is used in the same manner as morphine for the relief of pain but in much smaller doses — usually 1 to 2 mg. For cough, a dose about half that size is used. Administered orally, dihydromorphinone, is more effective than morphine, and it may also be administered in a rectal suppository. It is principally indicated for acute pain of short duration. 

Oxymorphone (Numorphan ), dihydromorphinone hydrochloride, is also about ten times as active as morphine and has a rapid onset of action that lasts for about 6 h. It is administered subcutaneously or intramuscularly in doses of 1 ml (1.5 mg) or as a rectal suppository (2 and 5 mg). 

Reduction of the amide (123 R1 = R2 = OMe) with sodium aluminium hydride gave a mixture of the bases (125 R1 = R2 = OMe), (127), and (130),165 and the last of these lost carbon monoxide when heated with tris(tri-phenylphosphine)rhodium chloride in benzene to give the dimethyl ketal of 14/3-methylcodeinone, which could be hydrolysed to 14j8-methylcodeinone, the 7,8-dihydro-derivative of which proved to be identical with material previously prepared by a different route (see Volume 9, p. 116). The corresponding morphinone and dihydromorphinone have been prepared.164... 

Descriptions of methods for the estimation or detection of morphine and/or codeine in urine,213-218 body fluids,219 blood,220 blood stains,221 hair,222 and opium,223 for the examination of illicit heroin,224-226 and for the estimation of dihydromorphinone in plasma227 have been published, the effect of formaldehyde on the estimation of morphine has been examined,228 and a bioassay for morphine and naloxone has been described.229... 

Since a nitro substituent is more electron-withdrawing than a chloro substituent, it was anticipated by Archer and his colleagues that replacing the p-chloro atom on the cinnamoylamino moiety with a p-nitro group would make the cinnamoylamino function a better Michael acceptor [106]. 5/ -Methyl-14/ -(4-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO, 55) was found to be an irreversible fi selective antagonist, MET-... 

The synthesis of TAMO is outlined in Scheme 3.11. The 3-hydroxy group of 14/ -amino-7,8-dihydromorphinone (71) [114] was protected with tert-bu-... 

N-oxides of morphine and several morphine derivatives have been prepared by the action of isopropanol/H202 on the appropriate tertiary base.(156) At best, the N-oxides were weak analgesics, but dihydromorphinone N-oxide and codeine N-oxide did exhibit good antitussive properties/157 ... 

During the total synthesis of ( )3-deoxy-7,8-dihydromorphinone (72), a morphine derivative lacking aromatic ring substitution,<166,167) two novel aromatic ring substituted analogs were isolated as intermediates, 4,5-epoxy-2-hydroxy-N-methylmorphinan-6-one (71, R = H) and a related 1-bromo derivative (70), together with their respective methyl ethers. No biological data on these were reported. 

Similar observations(218) have been made for a series of 7-alkanoyldihy-drocodeinones and -dihydromorphinones. Acylation of the 6-morpholino cnamine, 130, gave the /3-diketones, 131. 7-Alkanoyldihydrocodeinones (131, R2 = Me) were consistently weaker analgesics (MW) than their dihydromor-phinone counterparts (131, R2 = H). 

Sargent and Joshi(385) have transformed dihydrocodeinone, via a Hofmann degradation product, to the dihydromorphinone position isomer 225. It had an MHP (sc) ED50 of 24.6 mg/kg, about one third codeine. 

Some oxidation of morphine occurs to dihydromorphinone (260) in animals, but this was not detected in the urine of dependent humans/428 O-Methylation of morphine to codeine has been reported/442 443 but other studies(444,445) have failed to confirm this pathway. 

Kotick s group have studied a number of dihydromorphinone derivatives (3) with N-CPM and N-CBM substituents.(32,33) The parent compounds have dual actions, the CPM member being the more potent antagonist and the CBM... 

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