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Pyrrylphenylethanones Related to Cathinone and Lefetamine: Synthesis and Pharmacological Activities')

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Pyrrylphenylethanones Related to Cathinone and Lefetamine: Synthesis and Pharmacological Activities') PyrrylphenylethanonesRelated to Cathinone and Lefetamine 403 Pyrrylphenylethanones Related to Cathinone and Lefetamine: Synthesis and Pharmacological Activities') Silvio Massa")', Roberto Di Santo", Antonello Main),Marino Artico"),Gian Car10 Pantaleonib),Raffaele Giorgib),and Maria Francesca Coppolinob) a) Dipartimento di Studi farmaceutici, Universita di Rma"La Sapienza", P. le Aldo Moro 5,1-00185 Roma (Italy) b, Caedra di Farmacologia medica, Universita di I'Aquila, Via S. Sisto 12.1-67100 1'Aquila (Italy) Received April 30,1991 The synthesis of various pynylphenylethanones resembling cathinone and Mit Cathinon und Lefetamin verwandte Pyrrylphenylethanone: Synthe- lefetamine is described starting from 2-chlon+l-(l-rnethyl-lH-pyrrol-2-yl~ se und pharmakologische Wirkungen 2-phenylethan-l-one. Some derivatives showed good antinociceptic activity, Die Synthese der Titelve&indungen, ausgehend von 2-CNor-l-(l-methyl- c.dle to that of morphine. The neuropsychopharmacological of IH-ppl-2-yl)-2-phenylethan-l -on, wird beschrieben. dieser Deri- title compounds has been atso studied to explore hiraction on C.N.S. Einige vate zeigen gute antinociceptive Eigenschaften, vergleichbar mit denen des Morphins. Das neumpsychophmnakologischeProf3 der Titelverbindungen wurde untersucht, um entspr. ZNS-Wiricungen zu studieren Research on simpler analogues of morphine 1 led to the discovery of These interesting data led us to synthesize various sub- lefetamine 2, a potent drug used as analgesic in clinical practice'). stituted aminopyrrylphenylethanones6 as an attempt to ac- Lefetamine belongs to the class of phenethylamines which include quire new potential analgesic agents. among others amphetamine 3 and two natural products, cathine (4) and This work is a part of our running program on lefetamine derivatives cathinone (3,found in khat exmts. Due to their shucaual similarity with bearing a pple moiety, one of which, N,N-dimethyl-l-pheny1-2-(W- amphetamine, the khatamines are miming the pharmacological profile of pyrrol-l-yl)ethylamine (7), showed analgesic effects comparable to those amphetamine producing similar central and peripheral effects. In particular of lefetamine, but devoid of its neurotoxic effects4)(Scheme I). cathinone (3,the major component of khat, increases the reaction time in All new derivatives here reported have been subjected to the hot-plate and in the writhing tests. Amphetamine also has analgesic phaxmacological screening for analgesic activity and neuro- effects as shown in various experimental psychopharmacological effects. We tested also our com- pounds in vivo in the phenylquinone-induced writhing assay for evaluating their interaction with central a2-receptors. Chemistry Friedel-Crafs aroylation of 1-methyl- lH-pyrrole with a- chlorophenacetyl chloride/AlC13 afforded the expected 2- 1 2 and 3-substituted pyrrylketones 8 and 9 (Scheme 2)? Reaction of 2-chloro-1-( l-methyl-lH-pyrro1-2-yl)-2-phe nylethan- 1-one (8) with potassium phthalimide furnished the phthalimidoketone 10, which led to 2-amino-1-( 1-me- thyl- lH-pyrro1-2-yl)-2-phenylethan-1-one 11 on treatment with hydrazine hydrate (Scheme 3). 3 4 5 _3AICI3 / x+Q&/ N/ N H3C' \ CH.. N/C"3 3 8, 8 9 Scheme 2 6 7 Compound 8 was also reacted with various amines to give Weme 1 aminoketones 12,13, and 14 (Scheme 4). Arch. Pharm. (Weitilwim) 325,403409 (1992) OVCH VerlilgsgesellschaftmbH, D-6940 Weinheim, 1992 0365-6233/92/0707-03 $3.50 + .25/0 404 Artico and coworkers In an attempt to prepare the aminoderivative 11 by reduc- 0 tive cleavage of the corresponding azide6’, we reacted chlo- + KNyJ-a roketone 8 with NaN3 (Scheme 5). However, the expected azido-derivative 16 was not formed, the only product isu- 0 lated being the diketone 15, probably formed by loss of N2 and ammonia. The structure of 15 has been confirmed by n JR-, NMR-, and GC-MS-spectra. Pharmacological Evaluation Derivatives 10-14 were pharmacologically tested in mice in order to explore their neuropsychopharmacological ef- fects (Table l), their antinociceptic activity (Table 2). and their interaction with central a2-receptors (Table 3). Scheme 3 10 11 Neuropsychopharmucological Effects All test derivatives, with the exception of compounds 10, 12b, 13c, and 14, decreased spontaneous motor activity in mice without affecting other neuropsychobehavioural acti- vities. Derivatives 11,12a, and 13f exhibited the highest sig- H3C’ H3C’ nificance (p < 0.001) like morphine. On the contrary, amphe- tamine increased strongly the spontaneous motor activity. 8 12 A significant decrease of the exploratory activity on the hole-board test was observed in the subsequent order mor- phine and amphetamine > 12b and 13c > 14. With our substances animals behaved as disinterested rather than se- date, with an amphetamine-like pharmacological profile. 0M As regards to myorelaxant action all test derivatives were devoid of myorelaxant and ataxic action, with only few ex- ceptions (compound 13g and, at minor extent, compound ci 13d). Significative low effects at the Rota-Rod test (action on motor coordination) were observed with derivatives 13c and 13g. With regard to the anticonvulsant activity, none of test compounds determined any protection from seizures. All compounds showed only a partial protection with particular reference (100% PP) to derivatives 10, 13c, and 13f. This H3C’ behaviour was similar to those of morphine (100% PP) and amphetamine (80% PP). 13 In conclusion, from data on neuropsychobehavioural screening we can observe that all test products did not show any exciting effect at the dose of 20 mg/kg i.p. In general they produced light sedation (decreasing of spontaneous motor activity) without alteration of exploratory activity on the hole-board. These effects can be correlated with a spe- cific antiphobic-anxiolytic activity, which needs to be con- firmed by further pharmacological studies with proper tests. It is interesting to note that these low sedative-anxiolytic effects are not accompanied by myorelaxation and ataxia. Antinociceptive Action. Hot-Plate Test O’W Data of essay on antinociceptic activity (hot-plate test) are H3C’ k H3C’ recorded in Table 2. Two derivatives, 10 and 12d, showed 8 high antinociceptic activity with the same significance (p < 1s Scheme 5 0.001) of both morphine and amphetamine. Good activity, Arch. Pharni. (Weinheim) 325.403409 (1992) F'ynylphenylethanonesRelated to Cathinone and Lefetamine 405 Table 1: Neurobehavioural effects of derivatives 10-14 (dose: 20 m&g ip.)on mice Compd or A8 Bb ?I" C; Dd E= Conlrols k s.Df % f S.D. X f S.D f S.D. x f S.D. 46 :ontrols 164.2106.4 25.627.56 I.2+0.44 106.W31.3 1.6f1.8 40 PP ***g *** 60 NP mphme L40.oL80.37 1 1.ui6.0 1.M1.41 120.M0 1.m1.22 100 PP 00 *** mpheiaminc 548.M29.83 10.4i6.0 I .4i0.54 120.M (40%) 1.21.64 80 PP 20 NP 10 125.2103.Y 24.Xk11.36 2.0 t1.2: 106.W1.3 1 .@I .22 loo PP *.* I1 EO.Of85.9 30.0f5.19 1.2f0.44 110.M22.3 0.4k0.89 40 PP *** 60 NP I2a 259.8k107.3 20.212.75 1.8933 97.6k25.0 7.ok9.87 40 PP ** 60 NP 12b 109.oL105.1 14.2k4.86 I .2+0.44 1 ll.mL67 2.821.48 40 PP 60 NP l2c 336.E91.50 23216.26 1.2M.44 112.E17.8 3.8t3.1 20 PP t 80 NP 12d 355.8kS5.43 27.2t3.56 2.4i2.6 120.E0 1.8i2.4 60 PP ** 40 NP 130 306.8k107.33 17.4fI5.0 1.6a.89 108.M26.83 1B1.73 40 PP *. 60 NP 13b 320.298.31 23.M.27 1.Of0 114.M13.4 O.eO.54 100 NP *(I 13c 406.6i265.3 14.6+5.X5 1.8H1.83 72.6344.8 3.4k1.34 100 PP ** b 13d 311.250.91 23.8M.14 5.w.71 107.6i27.7 3.4i3 .9 20 PP 10 NP 13e 350.6f57.7 I 27.6f5.54 2.0i1.41 120.MO 2.4i1.5 20 PP *** 80 NP 13f 252.6f120.8 .20.Xi4.96 1.8f0.83 116.E8.94 1.452.0 80 PP * * .* * 20 NP 13g 307.4i 153.0 18.M7.0 3.4i1.8 11625.21 4.22.38 20 PP 80 NP 14 378.6k244.7 15.211.34 i.4in.54 99.229.7 2.6f2.79 100 NI a Spontaneous motor activity in the open field (total number of movements in 5 min). bExploratory activity on the hole-board (total number of holes in 5 min). Myorelaxant action (traction tesr time in sec on the horizontal wire for fore-legs). ''Myorelaxant action (traction test how long the animals stayed on wire). * Motor coordination at Rota-Rod (total number of falls in 3 min). Maximal electroshock seizures: PP = % of survival of animals with seizures (partially protected); NP = % of deaths of animals with seizures (non-protec- ted). Average f standard deviation. Significance: (*) or (") 0.05 > p > 0.Q (**) or ("") 0.02 > p > 0.001; (.I*)or (On') p < 0.001. although with minor significance, was exerted by deriva- 10 is active, showing the best significance. The antinocicep tives 12a (0.02 > p > 0.01) and 11 (0.05 > p > 0.02). All tic activity was also retained significantly by the N-mono- other test derivatives did not show statistically significant substituted derivative 12d. The interesting pharmacological activity at the hot-plate test. profile of phthalimidoderivative 10 encourages further re- Derivatives 11, 12% and 12d exhibit some sedative ef- search on the synthesis and pharmacological screening of fects, whereas derivative 10 is devoid of any effects on the mono- and disubstituted amides of 11 in order to obtain new behavioural profile. For the latter compound positive effects analgesic agents of potential clinical usefulness.
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