6,7-Benzomorphans, 5-hydroxy

Pentazocine (( )-2 -hydroxy-5,9-dimethyl-2 (3,3-dimethylallyl)-6,7-benzomorphan, Win 20,228, Talwin, LlXa). 

A mixture of 59.5 g (0.2 mol) 2-(4-methoxybenzyl)-l,3,3-trimethyl-4-piperidone hydrochloride and 53.8 g (0.4 mol) of aluminum trichloride and 54.0 g of nitrobenzene in 1500 ml of dry benzene are boiled under reflux for 1 h. After cooling the reaction mixture is extracted with 750 ml 4 N sodium hydroxide solution, the temperature being maintained below 35°C. The organic phase is separated and extracted with 750 ml 1 N hydrochloric acid. The acid aequeous phase is rendered alkali by the addition of 100 ml 25% ammonia and extracted three times with 250 ml chloroform. The collected chloroformic phases are dried with sodium sulfate and evaporated under reduced pressure. The residue, 46.7 g, is converted into the hydrochloride by reaction with iso-propanol/HCI and crystallized from a mixture of methanol and ethylacetate. 44.6 g of the 5-hydroxy-2 -methoxy-2,9,9-trimethyl-6,7-benzomorphan hydrochloride are obtained, melting point 233-236° C (dec.). 

Although the 11a- and /3-epimers of 3,ll-dimethyl-6-propyl-8-hydroxy-benzomorphans were synthesized and evaluated as analgesics in the early 1960s,(40,41) the corresponding 6-methyl-lla and 11/3-propyl isomers were not synthesized until 1975, when May s group(42) prepared the key pyridine intermediate, 4-methyl-3-propylpyridine, from the condensation of cyanoacetamide and ethyl 2-propylacetoacetate in methanolic potassium hydroxide. 

Benzomorphan pharmacodynamics is dictated by molecular geometry. ( )-ll/3-Alkylbenzomorphans are more active analgesics or mixed agonist/antagonists than their ( )-l la-alkyl counterparts, and the levo antipode is very largely responsible for the narcotic properties of both a- and /3-racemates. This is hardly surprising, as a-(-)-8-hydroxy-3-methyl-6,ll-diethyl-benzomorphan has been shown to have a configuration identical to that of (—)-morphine.(179)... 

SYNS 2-DIMETHYL LLYI 5,9-DIMETHY1 2 -HYDRO-XYBENZOMORPHAN 2-(3,3-DIMETHYLALLYL)-2, 2 -HYDROXY-5,9-DlMETHYL-6,7-BENZOMORPHAN FORTALGESIC FORTALIN FORTRAL 1,2,3,4,5,6-HEXAHYDRO-6,ll-DIMETHYI 3-(3-METHYL-2-BUTENYL)-2,6-METHANO-3-BENZAZOCINE 2 -HYDROXY-5,9-DIMETHYL-2-(3,3-DIMETHYLALLYL)-6,7-BENZOMORPHAN dl-2 -HYDROXV-5,9-DIMETHYI 2-(3,3-DIMETH i LALLYL)-6,7-BENZOMORPHAN II-C-2... 

Pentazocine, USP. Pentazocine. 1.2.3.4.S.6-hcubv-dro-cfs-6,11 -dimethyl-3-(3-mc ihyl-2-butenyl)-2.6-nKili ano3-benzazocin-8-ol. ci.v-2-dimethylallyl-5.9-dimcthyl-l -hydroxy-6,7-benzomorphan (Talwin). iKCurs as a uhic crystallinc powder that is insoluble in water and sparingh". soluble in alcohol. It forms a prly soluble hyclnx lilnidt salt, but is readily soluble as the lactate. 

In this study, as a first step in modeling opiate receptor interactions, we have considered the interaction of an ammonium ion and methyl sulfate or phosphate with the series of compounds shown in Figure 1. These compounds, as N-substitutents in rigid opiates such as 5,9 dimethyl, 2 hydroxy, 6,7 benzomorphans, exhibit a broad spectrum of pharmacological behavior from... 

Antagonist potencies measured in vitro in the guinea pig ileum system or in vivo by extent of withdrawal in addicted animals should closely parallel the affinity of opiates for the receptor site. Both antagonist potencies and stero-specific binding constants have been measured for a number of N-substituted 5,9 dimethyl 2 hydroxy 6,7 benzomorphan analogues (14, 15, 32). Table III gives these values for the compounds studied and shows the extent of correlation between the known affinities and potencies for four analogues. 

Benzomorphans. The 9fianalog (3a) of the isomeric 2,9-dimethyl-2 -hydroxy-6, 7-benzomorphans was 4 times as potent (EDjq=1.1 mg/kg) as the 9aanalog (3b) by the hot plate test. 13... 

Clarke and his co-workers have also prepared a nvimber of carbamates in the 5-phenyL series, one of these, 2-carbox-amide-2 -hydroxy-5-phenyl-6,7-benzomorphan, had weak analgesic activity in the hot-plate test and did not substitute for morphine in the addicted monkey. This compound has been reported to have codeine-like analgesic activity in man. ... 

The 8-keto benzomorphan derivative lb was prepared from ( - )5,9-a-dimethyl-2 -hydroxy-6,7-benzomorphan... 

Structure related to morphine. Synthesis of. alpha.-2-N-heptyl-2 -hydroxy-5,9-dimethyl-6,7-benzomorphan from 3,4-lutidine. II... 

Cyclobutylmethyl-5-ethyl-2 -hydroxy-9,9-dimethyl-6,7-benzomorphan, A"49.12 C21H32O... 

Tosyl chloride added to a soln. of 2-tosyl-8/ -hydroxy-6,7-benzomorphan in pyridine, and allowed to stand 48 hrs. at room temp. 2-tosyl-8j5-tosyloxy-6,7-benzomorphan (Y 94.3%) mixed with 1 1 water-acetone, and refluxed 6 hrs. -> 2-tosyl-8a-hydroxy-6,7-benzomorphan (Y 98.5%). J. J. Fauley and J.B. La-Pidus, J. Med. Chem. 16, 181 (1973). 

C2 2H2 3N3O2, 8,9-Dimethyl-14-phenyl-1,12,14-triazapentacyclo-[10.3.2 0.0 ". 0 °)pentadeca-8,16-diene-l3,15-dione, 42B, 234 C22H23N3O2, 9,1 0-Dimethyl-14-phenyl-1,12,14-triazapentacyclo-[l0.3.22-i, 0.0 " °.0 ]pentadeca-8,16-diene-l3,15-dione, 42B, 234 C22H27N3O 0.5 CHaO, 8-(1-(4-Methylphenyl)ethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one hemi-methanol solvate, 44B, 245 C22H28BrNO 0.5 H2O, (DL)-2 -Hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan hydrobromide hemihydrate, 46B, 299 C22H30N2O3, Quinidine ethanol solvate, 44B, 277... 

Benzomorphans - Very little new structure-activity information concerning benzomorphans appeared during 1973 sec-amine 8p-hydroxy-... 

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