Morphine dihydromorphinone

The anodic activity has been only observed in those morphine derivatives exhibiting phenolic functions such as psuedomorphine, dihydro-morphine, dihydromorphinone, nalorphine, apomorphine etc. On the other hand codeine, ethylmorphine, thebaine, benzylmorphine or dia-cetylmorphine (heroine) are inactive. 

Heaton, A.M., and Blumberg, A.G. (1969) Thin-layer chromatographic detection of barbiturates, narcotics, and amphetamines in urine of patients receiving psychotropic drugs. Journal of Chromatography, 41,367-370. Ono, M., and Engelke, B.F. (1969) Procedures for assured identification of morphine, dihydromorphinone, codeine, norcodeine, methadone, quinine, methamphetamine, etc., in human urine. Bulletin in Narcotics, 21, 31-40. 

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. 

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). 

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... 

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. 

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. 

The alkaloid contents of transformed and non-transformed calli were analyzed by an ELISA and an HPLC. The crude extract can be immediately subjected to the ELISA analysis as described above (sections 3.1, 3.4) using morphine-specific monoclonal antibody [145]. The morphine-specific antibody used has a high affinity for morphine, codeine, ethylmorphine, dihydromorphine, and dihydrocodeine, less reactivity with dihydromorphinone, dihydrocodeinone, and norcodeine, but almost no reactivity with naloxone and naltrexone [145]. 

Liras 3 used an OV-17 column for Investigations on the metabolism of morphine and codeine by Arthrobacter species, and gave the gas chromatographic parameters of eight oxidized compounds, found as metabolites (14-hydroxymorphine, 14-hydroxymorphinone, 14-hydroxydihydro-morphinone, dihydromorphinone, codeinone, 14-hydroxycodeine, 14-hydroxycodeionone and 14-hydroxydihydrocodeinone). 

Dihydromorphinone [xii] is also obtainable directly from morphine by rearrangement on heating solutions of the alkaloid in alcohol with [521-5] or without [526] acid, with [521-3] or without [524-6] hydrogen, in the presence of noble metal catalysts. 

Dihydrocodeinone and dihydromorphinone can be prepared by the catalytic rearrangement of codeine [i] and morphine respectively on heating solutions of the base in alcohol, with [48-52] or without [53] acid, with [48-50] or without [51-53] hydrogen, in the presence of noble metal catalysts. The yields reported by Knoll and Co. for this method are up to 95 per cent. [52], but Rapoport claims that the maximum is about 50 per cent. [47]. As a by-product in this rearrangement phenolic bases were noted and these may be made the principal products by modifying the conditions. In this way thebainone-A [xix] can be prepared from codeine, and its analogue, O-desmethylthebainone-A, from morphine in 60 per cent, yield [54] (see Chap. XV). 

The traditional method of drag development, at least in this century, has been to develop leads by first using, and then by isolating and identifying, the active chemical constituents from natural products, some of which may have been medicinally in use since antiquity. With the advent of modem organic chemistry some of these purified compounds were used directly (e.g., morphine, cocaine, atropine, quinine), and, once their chemical structures were ascertained, they became leads for hoped-for chemical modifications to achieve improved efficacy, less toxicity, or, at least, higher potency (e.g., dihydromorphinone, homatropine, acetylsalicylic acid). 

FIGURE 1.7 (a) Dihydromorphinone is more potent than morphine but is equally efficacious, (b) Propranolol is a competitive antagonist at adrenergic receptors. 

Dihydromorphinone (1 mg IM SC) is a semisynthetic narcotic analgesic, which is far more potent than morphine and has a duration of action of 4 to 6 hours. 

Kametani et al. reported the fifth formal total synthesis of morphine and sinomenine (41) via racemic sinoacutine (43a) and thebaine (480). Gafil reviewed the literature on the preparation of dihydrocodeinone (48a) and dihydromorphinone (48b), and he developed his own procedure for the preparation of these two substances (yield ca. 40-47%) (500). 

Hydrogenation of morphine in warm strong acid in the presence of palladium yields dihydromorphinone. Dihydromorphinone was patented by Knoll and Company (D.R.P. 365683) in 1923 and introduced under the trade name of dilaudid (77). One gram of dihydromorphinone hydrochloride dissolves in about 3 ml. of water. 

Three drug substances , namely morphine, normorphine, and dihydromorphinone... 

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