Development of Synthetic Narcotic Drugs


Synthetic Analgesics


Pages: 11 to 14
Creation Date: 1956/01/01

Development of Synthetic Narcotic Drugs

The history of synthetic drugs with morphine-like effect is relatively short, dating back only to 1939, when Eisleb ([1] , [2] ) produced the now famous 1-methyl-4-phenylpiperidine-4-carboxylic acid ethyl ester (pethidine, dolantin, demerol, dolosal. etc.). Research had, however, been carried out previously for a number of years in an effort to produce synthetic substances similar to morphine in structure. This work was to a large extent undertaken by Small, Eddy and their co-workers ([3] ) at the United States Public Health Service. The experiments were carried out under the presumption that the analgesic effect of morphine was inherent in the phenanthrene, dibenzofuran and carbazole nucleus, these products being found to be break-down products of morphine. The earlier efforts, however, did not lead to any synthetic compound with an appreciable analgesic effect.

As is often the case in organic chemistry, the results obtained were not exactly those looked for. Eisleb & Schaumann were searching for a compound which could be a substitute for atropine ([4] ). As will be seen from the following formula, atropine contains a piperidine nucleus:

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In testing the compounds which Eisleb produced ([4] ), it was found that some of them, besides their spasmolytic properties, had also pronounced analgesic qualities. The compound which showed the best results was the carboxylic acid ester, which was subsequently marketed in Germany under the name of dolantin, and which was first thought to be non-addiction producing and therefore advertised as such. This assumption was later found to be wrong.

On the basis of this most interesting finding, research was intensified, and a great many compounds were discovered possessing morphine-like effect ([5] ). One of the most important was methadone and its derivatives, which although originally discarded by German scientists as being too toxic, was later found, when tested in America, to possess, used dose by dose, the same analgesic effect as morphine itself ([6] ).

There are today a large number of compounds which have been synthesized and shown to have morphine-like activity. Up to the present about thirty have been put under international control. These compounds may be classified in five major groups, according to their different basic chemical structure.

Pethidine group:

Pethidine (1-methyl-4-phenylpiperidine-4-carboxylic acid ethyl ester) ([7] );

Bemidone (1-methyl-4-(3-hydroxyphenyl)-piperidine-4-car-boxylic acid ethyl ester, 1-methyl-4-metahydroxyphenyl-piperidine-4-carboxylic acid ethyl ester) ([7] );

Ketobemidone (4-(3-hydroxyphenyl)-l-methyl-4-piperidyl ethyl ketone, 1-methyl-4-metahydroxyphenyl-4-propionyl-piperidine) ([7] );

Alphaprodine (α-1,3-dimethyl-4-phenyl-4-propionoxypi-peridine) ([7] );

Betaprodine (β -1,3-dimethyl-4-phenyl-4-propionoxypiperidine) ([7] );

Betameprodine (β-1-methyl-3-ethyl-4-phenyl-4-propionoxypiperidine) ([9] );

1-[2-(p-aminothenyl-ethyl]-4-phenylpiperidine-4- carboxylic acid ethyl ester (1-[2-(p-aminophenyl)-ethyl]4- carbetho-xy-4-phenylpiperidine) ([12] );

1-(2-hydroxy-2-phenyl-ethyl)- 4-phenylpiperidine- 4-carboxylic acid ethyl ester (4-carbethoxy-1-(2-hydroxy-2-phenyl-ethyl)-4-phenylpiperidine) ([12] );

1-methyl-4-phenylpiperidine-4-carboxylic acid isopropyl ester and other esters of 1-methyl-4-phenylpiperidine-4-carboxylic acid ([11] ).

Methadone Group:

Methadone (4,4-diphenyl-6-dimethylaminoheptanone-3,6- dimethylamino-4,4-diphenyl-3-heptanone) ([7] );

Isomethadone (4,4-diphenyl-5-methyl-dimethylaminohexa-none-3, 6-dimethylamino-5-methyl-4,4-diphenyl-3-hexanone) ([7] );

Alpha-methadol (α-4,4-diphenyl-6-dimethylaminoheptanol- 3, α-6-dimethylamino-4,4-diphenyl-3-heptanol) ([7] , [9] , [10] );

Beta-methadol (β-4,4-diphenyl-6-dimethylamino-3-heptanol, β-6-dimethylamino-4,4-diphenyl-3-heptanol) ([7] , [11] );

Alpha-acetylmethadol (α-4,4-diphenyl-6-dimethylamino-3-acetoxyheptane, α-6-dimethylamino-4,4-diphenyl-3-acetoxyheptane) ([7] , [8] , [10] );

Beta-acetylmethadol (β-4,4-diphenyl-4-dimethylamino-3-acetoxyheptane, β 6-dimethylamino-4,4-diphenyl-3-acetoxyheptane) ([7] , [8] , [10] );

Phenadoxone (4,4-diphenyl-6-morpholinoheptanone-3, 6- morpholino-4,4-diphenyl-3-heptanone) ([7] );

4,4-Diphenyl-6-dimethylamino-3-hexanone ([11] );

4-Morpholino-2,2-diphenyl. ethyl butyrate (ethyl-2,2-diphenyl-4-morpholinobutyrate) ([12] );

4-Dimethylamino-l,2-diphenyl-3-methyl-2-propionoxybutane ([12] );

4,4-Diphenyl-6-piperidino-3-heptanone (6-piperidino-4,4- diphenylheptan-3-one) ([11] ).

Morphinan group:

Levorphan ((-)-3-hydroxy-N-methylmorphinan) ([10] );

Racemorphan ((±)-3-hydroxy-N-methylmorphinan) ([7] , [9] , [10] );

Levomethorphan ((-)-3-methoxy-N-methylmorphinan) ([9] , [10] );

Racemethorphan ((±)-3-methoxy-N-methylmorphinan)([9] ); 3-Hydroxy-N-phenethylmorphinan ([12] ).

Dithienylbutenylamine group:

Dimethylthiambutene (3-dimethylamino-1,1 -di-(2’-thienyl) -1-butene) ([10] );

Ethylmethylthiambutene (3-ethylmethylamino-1,1-di-(2'-thienyl)-1-butene) ([10] );

Diethylthiambutene (3-diethylamino-1,1 -di-)2’-thienyl (-1-butene) ([10] , [12] ).

Hexamethylenimine Group:

1,3-Dimethyl-4-phenyl-4-propionoxyhexamethyleneimine ([12] ).

Few of these compounds are at present used clinically to any great extent, the majority being still in the stage of pharmacological or clinical trial. The following are at present used in medicine:

Synthetic Analgesics


Pethidine is by far the most widely used synthetic drug with morphine-like effect. Besides its analgesic properties it also has spasmolytic action, which gives it a certain advantage over morphine in cases where pain is caused by spasms.

The world manufacture of pethidine, according to the reports of the Permanent Central Opium Board ([13] ), is as follows:



1950 7,423
1951 12,154
1952 11,612
1953 10,320
1954 12,555
(See also diagram 1)


Manufacture of morphine, pethidine and methadone in the world


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In some countries, the consumption of pethidine has greatly increased, as may be seen from the figures given below, by way of example, on the consumption of pethidine per million inhabitants in the United States of America, the United Kingdom and France ([13] ).


(Kg per million inhabitants)





1950 34.55 15.21 8.18
1951 36.68 17.54 4.88
1952 42.23 18.61 3.92
1953 41.81 19.34 4.85
1954 44.15 23.43 5.46
(See also diagram 2 where pethidine and morphine consumption are compared.)


Consumption of morphine and pethidine in the United States of America


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Diagramm 3


(in kg per million habitants)

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Ketobemidone was first produced by Eisleb ([14] ). It has been reported to have an analgesic activity as strong as that of morphine ([15] ). The first clinical experiments on former addicts gave the impression that it was a particularly dangerous drug ([7] ), therefore production was not initiated in the U.S.A. Ketobemidone is, however, being produced in two countries-Switzerland and Denmark ([13] ). The world consumption of this drug totalled 64 kg in 1954, and the estimated requirement for 1956 is a little over 72 kg ([16] ).

The Economic and Social Council, at its eighteenth session (1954) ([17] ), took a resolution urging governments to prohibit the manufacture, import and export of this drug, its salts, preparations and preparations of its salts; as a result, a great number of countries have discontinued the manufacture and use of Ketobemidone or have stated their intention to do so.


Alphaprodine, which was first prepared by Berger, Ziering & Lee (1947) ([18] ) is reported to be from three to five times as active as pethidine. Owing to its short analgesic action it has been found useful in obstetrical analgesia ([19] ), and the world production was 24 kg. in 1953 and 52 kg. in 1954 ([13] ).


Methadone has approximately the same analgesic effect as morphine ([20] ) and, next to pethidine, is the synthetic drug most extensively used in the world.

The annual manufacture and consumption was the following ([13] ):


Manufacture (Kg)

Consumption (Kg)

1951 521 388
1952 381 395
1953 395 489
1954 609 553


Phenadoxone, a slightly stronger analgesic than methadone (21), is manufactured only on a small scale, the world production in 1954 being 38 kg. ([13] ).

Racemorphan and Levorphan

Racemorphan and levorphan are compounds which chemically closely resemble morphine. The active principle of racemorphan is levorphan. Levorphan is more than twice as efficient as an analgesic as morphine, and its effect lasts longer ([22] ). The world production of this drug was 12 kg in 1954 ([13] ).

Synthetic Antitussives

About 90 per cent of the morphine produced in the world is converted into codeine and other antitussives. The total consumption of codeine was 68,473 kg in 1954 ([13] ). As far as the synthetic antitussives are concerned, only 6-dimethylamino-4,4-diphenylhexanone, a component of an antitussive preparation, and dextromethorphan are on the market. The main synthetic substances which have shown antitussive activity are: methadone, D-methadone, D-isomethadone, 6-dimethylamino-4,4-diphenylhexanone, dextromethorphan.



EISLEB, O. & SCHAUMANN, O. (1939) Deutsch med. Wschr., 65, 967.


Germany, Patent No. 679281.


SMALL, L. F. & al. (1938) Publ. Hlth. Rep. (Wash.), Suppl. No. 138.


SCHAUMANN, O. (1940) Arch. exp. Path. Pharmacol, 196, 109.


United States of America, Office of the Publication Board, Department of Commerce, Report No. P.B.981, p. 85.


SCOTT, C. C. & CHEN, K. K. (1946). Pharmacol., 87, 63.


World Health Organization (1949), Official Records of the World Health Organization, No. 19, p. 32.


World Health Organization, Techn. Rep. Ser. 1950, No. 21.


World Health Organization, Techn. Rep. Ser. 1952, No. 57.


World Health Organization, Techn. Rep. Ser. 1954, No. 76.


World Health Organization, Techn. Rep. Ser. 1955, No. 95.


World Health Organization, Techn. Rep. Ser. 1956, No. 102.


Permanent Central Opium Board, Report to the Economic and Social Council on the Work of the Board in 1955, Geneva 1955, Doc. No. E/OB/11.


EISLEB, O. (1942) Med. Chem. 4, 213.


CAHEN, R. L., EPSTEIN, H.J. & KREMENTZ, C. S. (1948) J. Pharmacol. 94, 328.


Drug Supervisory Body, Estimated World Requirements of Narcotic Drugs in 1956, Geneva 1955, Doc. E/DSB/13.


United Nations, Economic and Social Council, Official Records, Eighteenth Session (1954), Doc. No. E/2654.


BERGER, L., Ziering, A., & Lee, L. (1947) J. Org. Chem. 12, 904.


GROSS, E.G., HOLLAND, H.L. & SCHUELER, F.W. (1948) J. appl. Physiol., 1, 298.


LEIMBACH, D. G. & EDDY, N. B. (1954) J. Pharmacol., 110, 135.


EDDY, N.B. & al. (1950) J. Pharmacol., 98, 121.


FROMBERG, K. (1951) Arch. int. Pharmacodyn., 85, 387.