The synthesis of analgesics, particularly of morphine-like compounds, has always been a point of major interest in drug research. For decades, scientists throughout the world have attempted to develop effective analgesics by "re-building" themorphine molecule, considering its constitution a combination of certain "basic skeletons" from which they started their syntheses.
Author: Gustav Ehrhart
Pages: 28 to 32
Creation Date: 1956/01/01
The synthesis of analgesics, particularly of morphine-like compounds, has always been a point of major interest in drug research. For decades, scientists throughout the world have attempted to develop effective analgesics by "re-building" themorphine molecule, considering its constitution a combination of certain "basic skeletons" from which they started their syntheses.
For years the phenanthrene structure of morphine formed the focus of interest of this work, which, however, was not crowned by success. Strong, effective analgesics were not found in this way.
In this article we wish to report on a trend which the pharmaceutical laboratories with which the author is associated have followed for about fifteen years and which le to a series of variously acting synthetic drugs. During the last ten years many interested pharmaceutical-chemical research laboratories throughout the world have joined in the work of further developing these preparations.
The substances concerned are principally compounds with a central quaternary carbon atom - on the one side derivatives of 4-phenyl-piperidine, and on the other those of the diphenytmethane series.
Derivatives of 4-phenylpiperidine
In 1939, O. Eisleb ([1] ) synthesized at Farbwerke Hoechs the ethyl ester of N-methyl-4-phenyl--4-piperidinecarboxyli acid (known by the trade name of Dolantin ®). Its morphine-like effect was discovered by O. Schaumann ([2] ) Outside Germany, this compound is known and marketed under various names, such as Pethidine, Demerol ®, Cen tralgin, ®Meperidin and others.
Eisleb's synthesis of Dolantin consisted in the condensation of benzyl cyanide with di-(chloroethyl)-methylamine under the influence of sodium amide to N-methyl4-phenyl - 4-cyanopiperidine, subsequent hydrolysis of this compound to, the carboxylic acid and esterification to N-methyl-4-phenyl-4-piperidine--carboxylic acid ethyl ester :
A disadvantage of this smooth and simple synthesis is the use of the highly irritating nitrogen mustard gas. In order to avoid this substance we have developed several modifi- cations of this synthesis for the large-scale manufacture of Dolantin. The following scheme represents one of these methods in which the piperidine ring is formed in two stages:
As an analgesic, Dolantin is not as powerful as morphine, but it has the great advantage of affecting the respiratory centre far less than the latter. Besides, it is a good antispasmodic and is successfully used in the treatment of colic pain. It is employed as an analgesic in obstetrics, and Dolantin has lately also been given before anaesthesia. In the modern methods of controlled lowering of blood pressure and artificial induction of hibernation, Dolantin has almost completely ousted morphine.
Once the analgesic effect of the 4-phenylpiperidine derivative was recognized, the synthesis of further similar compounds exerted a great attraction for the synthesist and many Dolantin derivatives were produced. We wish to mention only Cliradon®,which, like morphine, has a hydroxy group attached to the phenyl nucleus and a propionyl radical instead of the carbethoxy radical.
The condensation of disubstituted acetoniltriles with basic halogenated compounds represented a further advance in the synthesis of pharmaceutically effective substances with a quaternary central carbon atom. The reaction occurred according to the general scheme and gave rise to the formation of nitriles substituted by basic radicals ([3] ).
This opened up a wide field of new reactions and numerous new compounds. Even to-day almost all laboratories throughout the world which are interested in these substances are engaged in work for further variations of these compounds and carry out pharmacological and clinical tests with regard to their efficiency. For the resulting basic nitriles must be subjected to a great variety of chemical reactions. We wish to mention only the most important ones:
(A) On treatment with Grignard reagents they are converted into ketones of powerful analgesic action which, in some cases, even surpasses the intensity of morphine.
(B) The reduction of the ketones gives rise to carbinols. Although of no direct pharmalogical importance, esterification of the carbinols restores the analgesic action.
(C) By splitting off the cyanide group under the influence of sodium amide, substituted amines with good antispasmodic and antihistaminic action are obtained.
(D) On partial hydrolysis of the cyanide group, basic acid amides are produced with good antispasmodic properties which are due to the neurotropic group.
(E) Hydrolysis of the nitril group to carboxylic acids and subsequent esterification yield basic esters which possess an analgesic action.
When considering further the numerous modifications which can be produced from these substances by aromatic, hydroaromatic or heterocyclic substituents on the central carbon atom, by alterations in the aliphatic side chain or various substitutions on the nitrogen atom, the great variety of compounds which have already been synthesized and are still synthesized becomes quite obvious. In consideration of the different effects displayed by these new compounds it is not surprising that the number of synthesized and tested compounds lies far above 1,000. When estimating the number of publications which have appeared on different methods which may be employed for the synthesis of known recognized substances (partly in order to avoid infringement of patents), 500 is by no means too high an estimate.
(A) The most outstanding preparation amongst the ketones is diphenyldimethyl-aminoheptanone, a powerful analgesic, which is known in Germany as Polamidon ®and in other countries as Methadon, Amidon, Ketelgin ®, Adanon ®, Dolophin®,etc. The synthesis of Polamidon is smooth and clear : 3 diphenylacetonitrile is condensed with dimethylamino-propyl chloride under the influence of sodium amide in benzene. A nitrile is formed which is treated with ethylmagnesium bromide, giving a Grignard compound which is then treated with hydrochloric acid and thus hydrolysed to the ketone.
As can be seen from the scheme, condensation with a branched-chain halogen base always yields a mixture of two isomeric nitriles. This surprising isomerization has formed the object of numerous investigations. Nowadays one is inclined to take the view that this transformation is effected by the Na-compound of diphenylacetonitrile. In separating the two isomeric nitriles, their different solubilities are made use of. The analgesic effect of Isopolamidon is slightly less than that of Polamidon. Both Polamidon and Isopolamidon possess an asymmetric carbon atom. In both cases, synthesis gives rise to the inactive racemate of ketones which can be resolved by means of tartaric acid under definite conditions of reaction. In most cases, however, the racemic nitrile is resolved and the optically active nitrile then treated with the Grignard reagent. From the pharmacological point of view it is interesting to observe that practically only the 1-form of both Polamidon and Isopolamidon has an analgesic effect, whereas the d-form has hardly any effect. The analgesic action of 1-Polamidon is eight times stronger than that of morphine.
Following this first synthesis of Polamidon, other methods have been employed for the synthesis of this group of substances. We wish to mention the work of Easton, Gardner and Stevens ([4] ), and that of Morrison and Rinderknecht ([5] ). This is not the place to discuss in detail the large number of similarly constituted ketones, but it must be pointed out that in spite of all the numerous variations of the Polamidon molecule no more popular preparation of this group has been found.
Asymmetric carbon atom.
(B) As mentioned before, reduction of the ketones gives rise to carbinoles of the type which have no analgesic properties but form powerful analgesics if they are esterified with acid chlorides or anhydrides. Sometimes their action surpasses even that of the ketones. In clinical use, however, they have not proved as valuable as the ketones. By splitting off the CN radical under the influence of sodium amide in an inert solvent (the CN-group is replaced by a hydrogen atom and is used in the formation of sodium cyanamide) - a reaction described already in "Liebig's Annalen" ([3] ) - basic diphenylalkanes are formed which are important antispasmodics. From diphenylpiperidinoethyl-acetonitrile, 1:1 diphenyl-3-piperidinopropane, a constituent of Aspasan and a valuable musculotropic antispasmodic is thus obtained. Its action is about ten to twelve times greater than that of papaverine, a naturally occurring alkaloid.
The introduction of heterocyclic ring systems instead of the phenyl radical constituted an important advance. In this way the antihistamine Avil ® (known in the U.S.A. as Trimeton ®) was produced.
(C) The synthesis of Avil is generally accomplished by one of the following two methods:
(1) 2-Bromopyridin is treated with benzyl cyanide in the presence of sodium amide to give phenyl-pyridyl (2) -acetonitrile.
This is condensed in known manner with dimethylamino-ethylchloride under the influence of sodium amide and finally the cyanide group split off as described above.
(2) The second method was developed by Sperber et al ([6] ) and the research laboratories at Hoechst, independently of each other. It starts with benzylpyridine, which is directly condensed with dimethylaminoethyl chloride to 1-phenyl-1-pyridyl-3-dimethylaminopropane.
Numerous antihistamines of similar constitution were also synthesized and valuable drugs obtained. A particularly strong effect is exercised by the p-chloro-compound Which is marketed under the trade name of Chlor-Trimeton.
(D) Partial hydrolysis of the diphenylacetonitriles carrying basic substituents is accomplished with sulphuric acid or alcoholic potash and produces basic diphenylacetamides.
Their analgesic effect is low; but as neurotropic antispasmodics they are very valuable. For instance, the action of diphenylpiperidinoethylacetamide, a constituent of the antispasmodic Efosin ®, surpasses even that of atropine.
(E) Finally, we wish to mention the group of esters which can be produced by hydrolysis of the above-mentioned nitriles with sulphuric acid, followed by esterification, in one single operation.
The esters are good analgesics, but their action is inferior to that of the ketones. They are therefore of no great interest in clinical use.
We have now described two types of compounds whose pharmacological action is very similar - i.e., derivatives of 4-phenylpiperidine and diphenylmethane. It is only natural to look for similarities in their chemical constitution which might account for this analogy. In order to attempt an explanation, we are now writing the formula of morphine in a different way from the usual one, showing a constitution published for the first time by O. Schaumann ([7] ):
This formula emphasizes and justifies the conception of morphine as a 4-phenylpiperidine derivative, and, furthermore, we recognize the central quaternary carbon atom mentioned before as common to all the compounds described. We have thus found a parallel between Dolantin (or Cliradon) and diphenylmethane on the one side and morphine on the other.
But we should not forget that all this is more or less an assumption, and that the explanation of the pharmacological action of the described compounds is only an attempt and by no means definitive.
The connexion between the pharmacological action and the constitution of a compound is an old problem in medical and chemical research; but a critical observer must notice that not much progress has yet been made in solving this complicated question. Of course, some fundamental connexions have been recognized, and the experienced synthesist is able to foretell the possible action of a chemicalcompound, but in the end all these prophecies are only empirical. As long as the mechanism of action of most drugs is unknown and only assumed, we cannot claim to know the actual connexion between constitution and effect. Even today, we might well obtain absolutely surprising and unexpected results when testing a new compound for its pharmacological effect - a fact proving our ignorance in this matter, but on the other hand, being a continuous incentive and encouragement to the chemist and pharmacologist in the search for new drugs.
EISLEB, O. : Ber. dtsc., chem. Ges., 1941, 74, 1441.
002SCHAUMANN, O. : Arch. f. exp. Path. u. Pharm., 1940, 196,109.
003BOCKMÜHL, M.; EHRHART, G.; SCHAUMANN, O. Liebigs Annalen,: 1948, 561,52.
004EASTON, N.R.; GARDNER, J. H.; STEVENS, J.R.: Journal Am. Chem. Soc., 1947, 69,2941.
005MORRISON, A.L.; RINDERKNECHT, H.: J. Chem. Soc. (London), 1950, 1478.
006SPERBER, N.; PAPA, D.; SCHWENK, E.; SHERLOCK, M.; FRICANO, R. : Journal Am. Chem. Soc., 1951, 73, 5752.
007SCHAUMANN, O. : Pharmazie,1949, 4,364
