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Drug Design: New Non-narcotic Analgesics

Tech Area / Field

  • CHE-OTH/Other/Chemistry
  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry

8 Project completed

Registration date

Completion date

Senior Project Manager
Zalouzhny A A

Leading Institute
Institute of Chemical Sciences, Kazakstan, Almaty

Supporting institutes

  • State Research Institute of Organic Chemistry and Technology, Russia, Moscow\nNovokuznetsk Chemico-Pharmaceutical Institute, Russia, Kemerovo reg., Novokuznetsk


  • Oklahoma State University, USA, OK, Stillwater\nTezukayama College, Japan, Nara\nUniversity of Bath, UK, Bath\nCardiff University, UK, Cardiff

Project summary

At the present time one of the most pressing problems for contemporary medicine remains the control of severe pain. There are a number of types of cancer, together with cardiovascular and other diseases, which have an associated pain syndrome. For this reason the development of new highly effective analgesic drugs for adoption in medical practice is an active area of research throughout the world. Particular emphasis is being paid to the development of central action analgesics which have no or minimal narcotic potential, the so-called “ideal analgesics”. Unfortunately, the most efficient and specific analgesics now in widespread use (e.g. Morphine, Promedol, Fentanyl, Buprenorphine, Moradol, Tramal, etc.) have some narcotic effects, i.e. repeated usage may lead to narcotic addiction. Their widespread use can therefore potentially encourage increasing use of illegal narcotics and their more widespread availability. Serious undesirable side effects are known for practically all known narcotic analgesics such as inhibition of the respiratory and cardiovascular systems and the gastrointestinal tract as well as other systems of vital importance. An overdose of narcotics is the most common cause of death in drug addicts. On the other hand, the narcotic’s toxic effects may be offset by opiate antagonists such as Nalocson or Natrelocson, substances which have structural features similar to portions of the Morphine molecule.

The discovery of the opiate receptor system (sites in the cell membrane) and the isolation of their endogenous ligands (endorphins and enkephalins) represented a major breakthrough in our understanding of the pharmacology of pain relief and the action of pain-relieving substances. It has been shown that opiate receptors may combine with specific structural molecular fragments in both agonists (Morphine, and other synthetic analgesics) and antagonists (Nalocson or Natrelocson). The existence of three types of opiate receptor site have been demonstrated.

The aim of this Project is to develop new non-narcotic analgesic pharmaceuticals and (or) effective opiate antagonists. Our approach will be based on the development of advanced methods for the synthesis of new polyfunctional piperidine derivatives from a range of available synthons. As these new polyfunctional piperidines become available during our research, the influence of the structural changes on their analgesic behaviour and bioactivity will be studied. Such an approach will allow potential non-narcotic analgesics to be identified.

This research strategy has been developed as a result of the analysis of literature data relating to similar Morphine analgesic substances. The principal question to be answered initially was: what structural fragments in drug molecules are obligatory for analgesic activity? In this connection great attention has been devoted to piperidine derivatives. Thus in 1939 Eisleb and Schaumann first demonstrated in their simplest form the structural fragments of Morphine responsible for analgesic action:

A major achievement in the creation of effective analgesic pharmaceuticals has been the synthesis and investigation of the pharmaceuticals properties of piperidine-type analgesics such as fentanylcitrate.

Several series of interesting compounds which have both piperidine and pyridine heterocycles in their structures were patented in 1985. In these systems the two heterocyclic rings were linked by using an oxygen or sulphur atom, or by an amino or other various organic groups.

The most effective agent in this category was found to be Ampertolin which contains a sulphur link.

Investigations to find novel effective analgesics based on 4-phenylpiperidine have been carried out in our laboratory (Laboratory of Medicinal Chemistry, ICS, Republic Kazahstan) since the early 1970s. Some of these substances display a higher analgesic activity than Morphine and Promedol and when introduced in anaesthetic doses they do not induce narcotic effects. Among of these products Prosidol demonstrated the highest effectiveness.

Prosidol is now widely used in medicinal practice for relieving painful sensations of various types. A weak inhibitory effect on intestinal peristalsis has also been observed with this agent. Besides its analgesic effects, Prosidol has a local anaesthetic and a strong antitussive effect. In contrast to Promedol and Morphine, Prosidol has no observed influence on the cardiovascular system and its effective period of analgesia is 2-8 h. No development of addiction to Prosidol was observed even after extensive use over 1 month for the relief of severe pain in incurable cancer patients. Moreover, clinic investigations have demonstrated that Prosidol may have potential for the treatment of opiate addiction. The results of pre-clinical and clinical studies of this analgesic have been discussed at conferences and in pharmacological journals. Prosidol has been patented in the Russian Federation, the Republic of Kazahstan, Switzerland, Italy and Great Britain.

Subsequent screening has led us to create other Prosidol structural analogues with promising characteristics. For example, Butatol which has already passed pre-clinical testing.

More recently our activities have been focused on studying the effects of various substituents at nitrogen and on carbon atoms C3 and C4 on the piperidine ring and, in particular, the way in which their spatial orientation affects the overall pharmacological properties of the molecule. Thus different 4,4-substituted piperidines including those with Ph, PhCC, CH=CH2, C2H5, H, NHPh, N(COR1)Ph, OH, OCOR1 (R1=CH3, C2H5, Ph) groups at the C4 position have been synthesised by the addition of nucleophilic agents to the carbonyl groups of 4-piperidone. Many of the substances produced have demonstrated bioactivity including analgesic, local anaesthetic, and antiarythmical effects.

Other procedures affording novel biologically active compounds have also been elaborated, for instance:

Together with acylation, various methods for modifying the hydroxyl group at the 4-position have also been studied — an illustrative example is:

It can be clearly seen that their unique biological activity, their ease of synthesis and the ready availability of starting reagents make novel piperidine derivatives a group of compounds still showing considerable promise in the continuing search for non-narcotic analgesics. The carbonyl group of 4-piperidones has high synthetic “capabilities” and this can be exploited to provide access to a range of new compounds. Starting from various 1-(alkoxyalkyl)- or 1-(arylalkyl)-4-piperidones we plan to synthesise new 1,4,4-trisubstituted piperidines including those with amino, hydroxy, ether, thioether and other organic groups as substituents at the 4 position. Further wide variations can be achieved by heterocyclisation with the participation of the carbonyl group with the aim of generating polycyclic systems.

The purposes of this Project and the anticipated results clearly involve a reorientation of the team's former activities and therefore correspond with the aims of the ISTC. The qualifications and the unique experience of the scientists involved, and the technical and research facilities available will ensure that the Project can be brought to a successful conclusion.

Selected References:

1) Kurbat N.M., Praliyev K.D., et al. “Neuropharmacological activity of piperidine derivatives” (Review) Khim. pharm. Zh. (Rus.), 25 (7), 20, (1991); C.A 1991, v. 115, N 17, 173937 g.;

2) O.D. Schaumann. A new class compounds with spasmolytic and central analgesic action derived from 1-methyl-4-phenylpiperidine-4-carboxylic acid ethyl ester. (Dolantine) Arch. Exptl. Path. Pharmacol. 196, 109 (1940); C.A. 1941, v.35, 2976;

3) P.A.J. Jansen and J.F. Gardocki US Patent N 3141823 publ. 21.07.64 “Method for producing analgesia”. C.A 1964, v. 61, N 9, 10689;

4) J. Gardocki and J. Yelnosky Some of pharmacologic actions of fentanyl citrate. Toxicol. Appl. Pharmacol. 6 (1), 48, (1964); C.A 1964, v. 60, N 11, 13750 f.;

5) Sim E.P. and Dimoglo A.S. “Signs of analgesic activity in the series of phentanyl analogues” Khim. pharm. Zh. (Rus.), 28 (9), 46, 1994; C.A 1995, v. 123, N 25, 329261 k.;

6) Scheffer G., Engel J., Jakovlev V., Nickel B., Thiemer K. “Neue Pyridin-2-ether beziehungsweise Pyridin-2-thioether mit einem stickstoffhaltigen cycloaliphatischen Ring”. Eur. Pat.Appl. EP 0 149 088 publ. 24.07.85; C.A 1985, v. 103, N 25, 215189 z.;

7) Praliev K.D., Salita T.A. et al. “Synthesis of piperidine and decahydroquinoline derivatives, their analgesic and psychotropic properties. XXI. 1-methyl-4-vinylethynylpiperidine-4-ol and its complex esters” Khim. pharm. Zh. (Rus.), 20 (9), 1044, (1986), and papers cited therein; C.A 1987, v. 106, N 5, 32795;

8) Praliev K.D., Yu V.K. et al. “Synthesis and stereochemistry of phenylethynylation of 1-(2-ethoxyethyl)-3-methylpiperidine-4-on” Khim. pharm. Zh. (Rus.), 20 (6), 679, (1986); C.A 1987, v. 107, N 9, 77593 f.;

9) Yesenaliyeva M.Z., Kurbat N.M., Praliev K.D., et al. “Synthesis and pharmacological activity of 1-[2-(3,4-dimethoxyphenil) ethyl]-4-hydroxypiperidine derivatives” Khim. pharm. Zh. (Rus.), 25 (4), 22, (1991); C.A 1991, v. 115, N 5, 49366 z.;

10 Praliev K.D., Yu V.K., et al. “Synthesis and spatial structure of 1-(2-ethoxyethyl)-3-methyl-4-amino-piperidines” Khim. pharm. Zh. (Rus.), 23 (9), 1070, (1989); C.A 1990, v. 112, N 21, 198072 x.;

11) Praliev K.D., Belikova N.A. et al. “1-(4-phenoxybutyne-2-yl)-4-phenyl-4-hydroxypiperidine analogues of des-methylprodine” Khim. pharm. Zh. (Rus.), 24 (4), 25, (1990); C.A 1990, v. 113, A2, 97418 e.;

12) Praliev K.D., Yu V.K. et al. Patent USSR N 1833618 publ. 28.01.91 “1-(3-n.-butoxypropyl)-4-oxopiperidine in the synthesis of hydrogen chloride 1-(3-n.-butoxypropyl)-4-phenyl-4-propyonyloxypiperidine with analgesic activity”;

13) Bazhikova K.B., Praliev K.D., Poplavskaya I.A. “Synthesis and some transformations of 1-(2-ethoxyethyl)-4-hydroxyprolyn-1-yl) piperidines” Izv. MS - AS Rep. Kaz., Ser. Khim. N 3, 112, (1998);

14) Praliev K.D., Botbaeva K.A., Poplavskaya I.A. “Synthesis of 1-(2-ethoxyethyl)-4-hydroxy-4-(3-dialkylamino-1-propyn-1-yl) piperidines” Izv. MS - AS Rep. Kaz., Ser. Khim. N 3, 43, (1998);

15) Patent RK N 527 publ. 1994 “1-(2-ethoxyethyl)-4-phenyl-4-propionyloxypiperidine hydrogen chloride with analgesic activity” (Prosidol);

16) Patent Rus.Fed. N 126908 publ. 29.07.94 “1-(2-ethoxyethyl)-4-phenyl-4-propionyloxypiperidine hydrogen chloride with analgesic activity” (Prosidol);

17) Switzerland Pat. N 678622 publ. 15.10.91. “1-(2-aethoxyathyl)-4-phenyl-4-propionyloxypiperidine hydrogen chloride” (Prosidol);

18) Italy Pat. N 1232984 publ. 13.03.92. “Cloridrato Di 1-(2-etossietil)-4-fenil-4-propionilossi”;

19) Great Britain Pat. N 2234241 publ. 22.07.92. “1-(2-ethoxyethyl)-4-phenyl-4-propionyloxypiperidine and salts thereof”;

20) Praliev K.D., Yu V.K. “Pharmacologically active 1-(2-ethoxyethyl) piperidines” // International Conference on Natural Products and Physiologically Active Substances (ICNPAS-98). Book of Abstacts, p.142, 1998, Novosibirsk, Russia;

21) Praliev K.D., Yu V.K. “Prosidol - new high effective anagesic agent” // Ibid (ICNPAS-98). Book of Abstacts, p.143, 1998, Novosibirsk, Russia.