Bartolini, Alessandro

Dei, Silvia

Galeotti, Nicoletta

Ghelardini, Carla

Gualtieri, Fulvio

Guandalini, Luca

Manetti, Dina

Martini, Elisabetta

Romanelli, Maria Novella

Scapecchi, Serena

Teodori, Elisabetta

English

Florence Research

4-Aminopiperidine Derivatives as a New Class of Potent CognitionEnhancing DrugsDina Manetti,a Elisabetta Martini,a Carla Ghelardini,b Silvia Dei,a Nicoletta Galeotti,bLuca Guandalini,a Maria Novella Romanelli,a Serena Scapecchi,a Elisabetta Teodori,aAlessandro Bartolinib and Fulvio Gualtieria,*aDipartimento di Scienze Farmaceutiche, Universita` di Firenze, Via G. Capponi 9, I-50121 Firenze, ItalybDipartimento di Farmacologia Preclinica e Clinica, Universita` di Firenze, Viale G. Pieraccini 6, I-50139 Firenze, ItalyReceived 15 January 2003; revised 31 March 2003; accepted 24 April 2003Abstract—Extrusion of one of the nitrogens of the piperazine ring of potent nootropic drugs previously described gave 4-amino-piperidine analogues that maintained high cognition enhancing activity in the mouse passive avoidance test. One of the new com-pounds (9, active at 0.01 mg/kg ip) may represent a new lead for the development of cognition enhancers useful to treat thecognitive deficit produced by neurodegenerative pathologies like Alzheimer’s disease.# 2003 Elsevier Science Ltd. All rights reserved.Cognitive dysfunction is one of the main symptomsaccompanying ageing, stroke, head injury and neuro-degenerative diseases like Alzheimer’s disease. Cogni-tion enhancers,1 often referred to as nootropics, can bedefined as drugs able to facilitate attentional abilitiesand acquisition, storage and retrieval of information,and to attenuate the impairment of cognitive functionsassociated with age and age-related pathologies.2 Bydefinition, this class of drugs improves declining ofcognitive functions but does not change the rate ofprogression of neurodegeneration.3Recently, we described a new class of compounds with a1,4-diazabicyclo[4.3.0]nonan-9-one structure4 (Chart 1)that showed a very potent cognition enhancing activityon mouse passive avoidance assay. These compoundswere related to the family of piracetam-likenootropics1,57 by the presence of the 2-pyrrolidinonering. However, high activity was maintained when the2-pyrrolidinone ring was opened to give the corre-sponding piperazine derivatives8 (Chart 1), suggestingthat in this class of compounds the 2-oxopyrrolidinemoiety is not critical for pharmacological action. Bothseries of compounds were effective also in other beha-vioural tests such as social learning and Morris watermaze.810Continuing to explore structure–activity relationshipsin the series of piperazine compounds, we havedesigned a new series of compounds carrying a4-aminopiperidine ring. Formally, they can be con-sidered analogues where one of the nitrogen atoms ofpiperazine has been moved out of the six-member cycle(Chart 2). Besides the side chains that were present inthe leads DM232 and DM235, we have added the iso-propylsulfonyl group, present in a series of compoundsactive as allosteric modulators of AMPA receptor.11,12As a matter of fact, an ongoing research aimed todefine the mechanism of action of DM232, DM235and related compounds seems to suggest the involve-ment of AMPA receptors. (C. Ghelardini, personalcommunication).Compounds 5, 6, 11 and 12 have been synthesised asshown in Scheme 1. 1-Acetyl-4-piperidone and 1-ben-zoyl-4-piperidone, commercially available, and 1-pro-pionyl-4-piperidone (17), obtained from 4-piperidonemonohydrate hydrochloride with propionyl chloride,were transformed in 18–20 by reductive alkylationwith benzylamine, titanium(IV) isopropoxide andsodium cyanoborohydride.13 The compounds werethen hydrogenated14 to obtain 21–23. Compound 2315was treated with acetyl or propionyl chloride toobtain 5 and 6 respectively, while 2116 and 22 weretreated with 4-fluorobenzenesulfonyl chloride to give1117 and 12.0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.doi:10.1016/S0960-894X(03)00437-2Bioorganic & Medicinal Chemistry Letters 13 (2003) 2303–2306*Corresponding author. Tel.: +39-05527-57295; fax: +39-0552-40776; e-mail: fulvio.gualtieri@unifi.itThe synthetic pathways used to obtain compounds 7–10and 13–16 are reported in Scheme 2. Commerciallyavailable 4-amino-1-benzylpiperidine was treated withthe proper acyl chloride or isopropylsulfonyl chloride;the intermediates 24,18 25,19 2620 and 30 were thenhydrogenated to give 27,21 28,22 2923 and 31. Inter-mediates 27 and 28 were treated with 4-fluoro-benzenesulfonyl chloride24 to give 9 and 10 and withisopropylsulfonyl chloride to give 13 and 14, whereas 29was treated with acetyl or propionyl chloride to give 7and 8. Finally, reaction of 31 with acetyl or propionylchloride gave 15 and 16 respectively. Chemical andphysical characteristics of compounds 5–16 are reportedin Table 1.Cognition enhancing activity was evaluated by the anti-amnesic test (mouse passive-avoidance test). The testwas performed according to the step-through methoddescribed by Jarvik and Kopp,25 slightly modified byus.4,26 In short, mice receive a punishment when enter-ing a dark room in the training session and remember itin the session of the following day, unless their memoryis impaired by the amnesic drug. The parameter mea-sured is the entry latency time (expressed in seconds)occurring between the time the mouse is placed in thelight and the time it enters the dark room. On the firstday there is the training session, while on the second daythe mice are placed again in the light and the newlatency time is measured on animals treated oruntreated with the nootropic drug. A drug is activewhen, at a given dose, it restores in the scopolamine-treated mice the retention time of those treated onlywith saline. The highest active doses of the investigatedChart 1.Chart 2.Scheme 1. (a) CH3CH2COCl, K2CO3, CHCl2 60C: 17, 72%; (b)benzylamine, (iPrO)4Ti, NaBH3CN, EtOH: 18, 85%, 19, 68%, 20,26%; (c) HCOONH4, Pd/C 10%, MeOH: 21, 74%, 22, 97%, 23, 75%;(d) CH3COCl, NaHCO3, CHCl3: 5, 45%, CH3CH2COCl, N(Et)3,CHCl3: 6, 94%; (e) 4-F-benzenesulfonyl chloride, N(Et)3, CH3CN: 11,86%, 12, 82%.Scheme 2. (a) XCOCl, NaHCO3, CHCl3: 24, 79%, 25, 99%, NEt3,CHCl3: 26, 99%, 15, 55%, 16, 42%; (b) HCOONH4, Pd/C 10%,MeOH: 27, 98%, 28, 73%, 29, 88%, 31, 50%; (c) isopropylsulfonylchloride, N(Et)3, CH3CN: 30, 57%; (d) 4-F-benzenesulfonyl chlorideor isopropylsulfonyl chloride, N(Et)3, CH3CN: 9, 59%, 10, 84%, 13,43%, 14, 76%; (e) XCOCl, N(Et)3, CHCl3: 7, 47%, 8, 97%.2304 D. Manetti et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2303–2306compounds did not altered animals’ gross behaviourand were devoid of any behavioural side effect, asdemonstrated by the Irwing test.27 The results obtainedwith the new molecules are reported in Table 2, com-pared with those of the parent compounds 1–4.The data reported show that the new series of com-pounds maintains potent cognition enhancing activity,being effective at doses between 0.01 and 10 mg/kg ip,while a typical nootropic drug like piracetam, under thesame conditions in experiments performed in parallelwith our compounds, is active at a dose of 30 mg/kg ip.8In particular, compound 9 is active at a dose of 0.01 mg/kg ip, which is in the same range of that of DM 235, themost potent among the parent compounds.8 Therefore,it may be concluded that transforming the piperazinemoiety into a 4-aminopiperidine one does not alter thepharmacological behaviour of the original compounds.In the new series, the two nitrogen atoms are notequivalent and two regio-isomers are possible for eachcouple of substituents. Overall, the regio-isomers showsimilar potencies as cognition enhancers. In this respect,the isomers bearing the aromatic substituents on thepiperidine nitrogen seem to be slightly more potent(compare 9/11, 10/12, 13/15) than their counterparts,even if the reverse is true for the couple 5/7 and thecouples 6/8 and 14/16 show the same potency. Finally,the introduction of the isopropylsulfonic group did notproduce remarkable results, even if compound 13 wasfound active at the dose of 1 mg/kg ip.In conclusion, we have identified a new class of potentcognition enhancing drugs, among which compound 9deserves further study and can be a useful new lead todevelop drugs with cognition enhancing properties.AcknowledgementsThis research was financed with the funds of ItalianMinistry of Instruction University and Research(MIUR).References and Notes1. Gualtieri, F.; Manetti, D.; Romanelli, M. N.; Ghelardini,C. Curr. Pharm. Des. 2002, 8, 125.2. Parnetti, L.; Senin, U.; Mecocci, P. Drugs 1997, 53, 752.3. Hirai, S. Alz. Dis. Ass. Dis. 2000, 14, S11.4. Manetti, D.; Ghelardini, C.; Bartolini, A.; Bellucci, C.; Dei,S.; Galeotti, N.; Gualtieri, F.; Romanelli, M. N.; Scapecchi,S.; Teodori, E. J. Med. Chem. 2000, 43, 1969.5. Froestl, W.; Maitre, L. Pharmacopsychiatry 1989, 22, 54.6. Gouliaev, A. H.; Binau Moster, J.; Vedso, M.; Senning, A.Org. Prep. Proceed. Int. 1995, 27, 273.7. Gouliaev, A. H.; Senning, A. Brain Res. Rev. 1994, 19, 180.8. Manetti, D.; Ghelardini, C.; Bartolini, A.; Dei, S.; Galeotti,N.; Gualtieri, F.; Romanelli, M. N.; Teodori, E. J. Med.Chem. 2000, 43, 4499.9. Ghelardini, C.; Galeotti, N.; Gualtieri, F.; Manetti, D.;Bucherelli, C.; Baldi, E.; Bartolini, A. Drug Dev. Res. 2002, 56,23.10. Ghelardini, C.; Galeotti, N.; Gualtieri, F.; Romanelli,M. N.; Bucherelli, C.; Baldi, E.; Bartolini, A. N.S. Arch.Pharmacol. 2002, 365, 419.11. Ornstein, P. L.; Zimmerman, D. M.; Arnold, M. B.;Bleisch, T. S.; Cantrell, B.; Simon, R.; Zarrinmayeh, H.;Baker, S. R.; Gates, M.; Tizzano, J. P.; Bleakman, D. J. Med.Chem. 2000, 43, 4354.Table 1. Chemical and physical characteristics of compounds 5–16 a bN R1 R2 Mp ( C) Analysis5 COCH3 A 136–137 C14H18N2O26 COC2H5 A 70–71 C15H20N2O27 A COCH3 133–135 C14H18N2O28 A COC2H5 107–108 C15H20N2O29 COCH3 B 187–188 C13H17FN2O3S10 COC2H5 B 162–163 C14H19FN2O3S11c B COCH3 131–132 C13H17FN2O3S12 B COC2H5 135–136 C14H19FN2O3S13 COCH3 C 90–91 C10H20N2O3S14 COC2H5 C 85–86 C11H22N2O3S15 C COCH3 78–79 C10H20N2O3S16 C COC2H5 79–80 C11H22N2O3SaAll compounds crystallized from petrol ether.bThe analytical results are within0.4% of the theoretical values. 1Hand 13CNMR and IR spectra are consistent with the proposed structure.cThis compound is among the ones claimed in a recent patent (see ref 17).Table 2. Nootropic effect of compounds 1–4 and 5–16 on mousepassive avoidance test, using scopolamine (S) as amnesing drugDruga (numberof animals)Minimal effectivedose mg/kg (ip)Entry latency (s)1st day 2nd day Saline (13) — 15.05.9 95.68.8 80.6Scopolamine (6) 1.5 16.64.7 44.58.3* 27.91b 102 (DM235)b,c 0.01–0.0013b 0.014b 0.015 (18) 10 12.84.5 113.510.2** 100.76 (7) 0.1 18.04.7 121.011.3** 103.07 (11) 1 16.53.7 99.89.9** 83.38 (7) 0.1 19.75.3 122.810.4** 103.19 (9) 0.01 14.53.8 90.612.5*** 76.110 (10) 0.1 17.63.9 103.49.5** 85.811 (8) 0.1 23.55.3 126.813.8** 92.612 (16) 10 15.64.7 108.28.4** 103.013 (21) 1 14.32.8 89.78.5*** 75.414 (19) 10 14.23.5 102.810.5** 88.615 (18) 10 15.13.7 99.311.3** 84.216 (16) 10 14.53.2 96.910.6** 82.4*P<0.01 with respect to mice treated with saline. **P<0.01;***P<0.05 with respect to mice treated with scopolamine.aAll compounds dissolved in saline.bSee ref 9.cSee ref 10.D. Manetti et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2303–2306 230512. Zarrinmayeh, H.; Bleakman, D.; Gates, M.; Yu, H.; Zim-merman, D. M.; Ornstein, P. L.; McKennon, T.; Arnold,M. B.; Wheeler, W. J.; Skolnick, P. J. Med. Chem. 2001, 44,302.13. Mattson, R. J.; Pham, H. M.; Lenck, D. J.; Cowen, K. A.J. Org. Chem. 1990, 55, 2552.14. ElAim, B.; Anantharanaiah, G. M.; Royer, G. P.; Means,G. E. J. Org. Chem. 1979, 44, 3442.15. Bhattacharayya, S.; Neidigh, K. A.; Avery, M. A.; Wil-liamson, J. S. Syn. Lett. EN 1999, 11, 1781.16. Suedo, N. Eur. Pat. Appl. EP 625,507, 1994.17. Yamada, A.; Aoki, S. PCT Int. Appl. WO 0,042,011,2000.18. Archibald, J.; Fairbrother, P.; Jackson, J. L. J. Med.Chem. 1974, 17, 739.19. Peglion, J. L.; Colpaert, F. Eur. Pat. Appl. EP 457,686,1991.20. Harper, N.; Chignell, C. F. J. Med. Chem. 1964, 7, 729.21. Zenitz, B. L. US 3,124,586,1964; Chem Abst. 1964, 61,18188.22. Schnorrenberg, G.; Dollinger, H.; Esser, F.; Brien, H.;Jung, B.; Speck, G. Gen. Offen. DE 19,519,245, 1996.23. Archibald, J. L.; Alps, B. J.; Cavalla, J. F.; Jackson, J. L.J. Med. Chem. 1971, 14, 1054.24. Stetter, H.; Reinartz, W. Chem. Ber. 1972, 105, 2773.25. Jarvik, M. E.; Kopp, R. Psycol. Rep. 1967, 21, 221.26. The apparatus for the passive avoidance test consists ofa two-compartment acrylic box with a lighted compartmentconnected to a darkened one by a guillotine door. In theoriginal method, mice received a punishing electrical shockas soon as they entered the dark compartment, while in ourmodified method, after entry into the dark compartment,mice receive a non-painful punishment consisting of a fall(from 40 cm) into a cold water bath (10 C). For this purpose,the dark chamber was constructed with a pitfall floor. Thelatency times for entering the dark compartment were mea-sured in the training test (first day) and after 24 h in the reten-tion test (second day). Mice who did not enter after 60 s latencywere excluded from the experiment. For memory disruption,mice were ip injected with the amnesic drug scopolamine. Allinvestigated drugs, dissolved in saline, were given ip 20 minbefore the training session, while amnesic drug was injectedimmediately after termination of the training session. Themaximum entry latency allowed in the retention session was120 s. The degree of received punishment memory (fall into coldwater) was expressed as the increase in seconds between train-ing and retention latencies.27. Irwing, S. Psychopharmacology 1966, 13, 222.2306 D. Manetti et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2303–2306

4-Aminopiperidine derivatives as a new class of potent cognition enhancing drugs

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4-Aminopiperidine derivatives as a new class of potent cognition enhancing drugs

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