Inflammopharmacology 14 (2006) 62–71 0925-4692/06/020062-10 DOI 10.1007/s10787-006-1498-4 © Birkhäuser Verlag, Basel, 2006
Inflammopharmacology
Short Communication Synthesis and evaluation of 2,6-piperidinedione derivatives as potentially novel compounds with analgesic and other CNS activities S. A. El Batran*1, A. E. N. Osman2, M. M. Ismail3 and A. M. El Sayed3 1
Pharmacology Department, National Research Center, Dokki, Cairo, Egypt, Fax +20-2337-0931, e-mail:
[email protected]. Department of Organic Chemistry, Faculty of Pharmacy, Cairo University, Egypt 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University Nasr City, Cairo, Egypt 2
Received 12 March 2005; accepted 14 November 2005
Abstract. New 2,6-piperidinediones 2a–g and 4a–d were prepared by initial condensation of aromatic aldehydes or cycloalkanones with cyanoacetamide to give α-cyanocinnamides la–g or cycloalkylidenes 3a,b which underwent Michae1 addition with ethyl cyanoacetate or diethylmalonate. Compounds 4a–d were alkylated by various alkyl halides to produce the N-alkylated 2,6-piperidinedione derivatives 5a–m. Some new selected compounds 2a–c,f, 4a–d & 5e,h,j were pharmacologically evaluated for potential anticonvulsant, sedative and analgesic activities. These compounds exhibited significant anticonvulsant and analgesic effects after a single I.P. administration 100 mg/kg b.wt. . On the other hand all the investigated compounds induced hypnotic activity and prolonged the phenobarbital sodium- induced sleep as compared with the control group and the most potent compound was found to be 2f. Key words: Carbamazepine; Phenobarbital sodium; Novalgine; Anticonvulsant; Sedative; Analgesic
Introduction 2,6-Piperidinedione derivatives have been reported to exhibit anticonvulsant (Marshall and Vallance 1954; Jochheim and Gerberding,1955 ; Danuta et al.,1975; Wong et al.,1986; Yuji et al.,1988; Richard et al.,1990), and sedative-hypnotic activities (Jochheim and Gerberding,1955 ; Somers ,1956; Yao-Hua et al.,1969; Yuji et al., 1988; Fischer and Ambre ,1976; Osman et al.2003). Others have been shown to pos* Corresponding author
sess analgesic action (Stiz et al.,2000). Consequently, it was decided to synthesize certain new 2,6-piperidinedione derivatives by changing the substituents in P-4, P-l and /or P-3 to exhibit their pharmacological activities. Experimental Pharmacological experiments Animals Rats of both sexes weighing 150–200 g and mice weighing 18–20g were used in the experiments. Food and water was provided ad libitum. Rats and mice were obtained from the animal house colony, National Research Center, Dokki, Cairo, Egypt. All animal procedures were performed after approval from the Ethics Committee of the National Research Center and in accordance with the recommendations for the proper care and use of laboratory animals (NIH publication No. 85-23, revised 1985). Anticonvulsant test This effect was assessed according to the method reported by Rizzo et al.(1971) . Electrical stimulation was applied to the rat ear by using 515 Master shoker (Laffayette Inst. Co.) internal resistance is set to 400 kg. Percent increase in voltage required to induce an electric shock in treated animals is taken as a measure of anticonvulsant activity. The anticonvulsant effect of an intraperitoneal single dose of the tested compounds (100mg/kg b.wt.) and was compared to that of carbamazepine (Tegretol) (100 mg/kg b.wt.) as a reference
Vol. 14, 2006
Synthesis and evaluation of 2,6-piperidinedione derivatives
anticonvulsant drug . The reaction time was measured at 1, 3 and 24 hours after administration of tested compounds or carbamazepine. Sedative test “potentiation of phenobarbital sleeping time” Male mice weighing 20–25g were divided into 12 groups, each consisted of six animals and were injected i.p. according to the following: Group 1 received 100 mg/kg b.wt of phenobarbital sodium and served as control group. The other groups received 100 mg/kg b.wt of the tested compounds. After 60 min., the treated groups were injected with 100 mg/kg b.wt of phenobarbital sodium. The animals were observed in order to determine the onset and the duration of sleep as evidenced by loss of righting reflex. The mean onset and duration of sleep produced by the compounds were compared statistically with those of the positive control values using Students t-test (Karli et al.,1998). Analgesic test This effect was evaluated according to the method of Charlier et al. (1961) , by using electric current as a noxious stimulus applied to the rat tail by means of 515 Master shocker (Laffayette Inst. Co.) using alternative current of 50 cycles/sec. for 0.2 second. The minimum voltage required for the animal to emit a cry was recorded for the negative control group and the treated groups. The tested compounds were injected intraperitonealy at a dose level of 100mg/kg b.wt. The last group was injected with dipyrone (Novalgin) (50mg/kg b.wt. ,i.p.) . The reaction time was measured after one and two hours after the administration of the tested compounds or dipyrone. Statistical analysis The data are presented as (means + standard error) using the Students t-test for determination of the level of significance p
