Synthesis, anticonvulsant activity and 5-HT1A, 5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-alkyl] derivatives of 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione.

The synthesis, physicochemical and pharmacological properties of new N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane- (8a-c, 10a-d) and [4.5]decane-1,3-dione (9a-c, 11a-d) derivatives were described. The antiepileptic effects of those compounds were examined by a maximal electroshock (MES) and a pentylenetetrazole (sc. PTZ) tests, and their neurotoxicity was determined using a rota-rod test. Compounds 8c, 9c, 10c, d, 11c, d with a CF(3) group at the 3-position of the 4-arylpiperazine fragment exhibited anti-seizure properties in the MES model; in contrast, their 2-CH(3) and 2-OCH(3) analogues were inactive in both the tests used. Moreover, since the investigated compounds belong to the class of long-chain arylpiperazines, their serotonin 5-HT(1A) and 5-HT(2A) receptor affinity was determined. The relationship between the length of alkylene spacer and 5-HT(1A)/5-HT(2A) receptor activity was observed. Compounds with an ethylene and a propylene bridge (10a-d and 11a-d) were 3-80-fold more potent (K(i) ranged from 3.1 to 94 nM for 5-HT(1A) and 32-465 nM for 5-HT(2A)) than their methylene analogues (8a-c and 9a-c; K(i) ranged from 81 to 370 nM for 5-HT(1A) and 126-1370 nM for 5-HT(2A)). The highest 5-HT(1A) receptor affinity was displayed by 2-OCH(3) and 3-CF(3) phenyl derivatives (10b, 11b: K(i)=6.8 and 5.7 nM, respectively, and 10c, 11c: K(i)=6.0 and 3.1 nM, respectively), while in the case of 5-HT(2A) receptor the highest affinity was observed for the 3-CF(3) phenyl derivatives 10c, d, 11c, d (K(i) ranged from 32 to 86 nM).

Synthesis, 5-HT1A and 5-HT2A receptor affinity of new 1-phenylpiperazinylpropyl derivatives of purine-2,6- and pyrrolidine-2,5-diones.

Two series of 1-phenylpiperazinylpropyl derivatives 10, 11, 16, 17 and 19-24, structurally related to previously described 5-HT1A or 5-HT2A ligands 4 and 1, respectively, were synthesized and their binding properties were determined. Structural modifications which involved 1,3-diazepine ring opening in 4 (compounds 10, 11, 15, 16) and replacement of spiroalkyl moiety in 1 by aryl substituent (19-24) did not improve binding affinity and selectivity of the tested compounds. The results showed, however, that the diazepine ring present in 4 or spiroalkyl ring in 1 are important for high 5-HT1A or 5-HT2A binding affinity and selectivity of these compounds.

Synthesis, physicochemical and anticonvulsant properties of new N-pyridyl derivatives of 3-phenyl- and 3,3-diphenyl-succinimides.

Synthesis and physicochemical properties of new N-pyridyl derivatives of 3-phenyl and 3,3-diphenylsuccinimides (1-12) have been described. The obtained compounds were evaluated in respect of their anticonvulsant activity. The N-pyridyl derivatives of 3-phenylsuccinimides (7-12) abolished the protection against MES- and scMET-induced seizures, whereas N-pyridyl derivatives of 3,3-diphenylsuccinimides (1-6) were inactive. After molecular modelling and quantum-chemistry calculations the theoretical activity test was applied (W. Kwiatkowski, J. Karolak-Wojciechowska, SAR and QSAR Envir. Res. 1 (1993) 233; Chem. Abstr. 120, 153001 (1994). J. Karolak-Wojciechowska, M. Blaszczyk, W. Kwiatkowski, J. Obniska, A. Zejc, J. Chem. Cryst. 27 (1997) 297; Chem. Abstr. 127, 277834k (1997)). The molecular electrostatic potential (MEP) of the active compounds differed significantly from that of the inactive ones.

Synthesis and anticonvulsant properties of new N-piperazinylalkyl imides of succinic acid.

A number of N-[(4-aryl)- or (4-methyl)-l-piperazinyl)alkyl]imides of 3-aryl or 3,3-pentamethylenesuccinic acid were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and pentylenetetrazole seizure threshold (scMet) tests. Structures of the novel compounds were confirmed by elemental and spectral analyses.

Synthesis and pharmacological investigation of new N-dimethylpyridyl and N-chloropyridyl substituted arylsuccinimides.

In the reaction of alpha-phenyl-, alpha-p-chlorophenyl-, alpha-m-chlorophenyl-, alpha-p-bromophenyl and alpha-m-bromophenyl succinic acids with various aminopyridines, N-(dimethylpyridine)-alpha- arylsuccinimides and N-(chloropyridine)-alpha-arylsuccinimides were obtained. The above compounds tested for their CNS activity did not show an anticonvulsant activity.

Structures of three N-pyridyl-2-phenylsuccinimides and structural evidence for substituent effects on anticonvulsant properties.

T = 295 K, Mo K alpha with lambda = 0.70930 A. Compound (I-6): C15H12N2O2, Mr = 252.26, monoclinic, P2(1)/c, a = 8.441 (3), b = 15.269 (1), c = 9.745 (2) A, beta = 92.34 (2) degrees, V = 1254.9 (19) A3, Z = 4, Dx = 1.335 g cm-3, mu = 0.85 cm-1, F(000) = 528, R = 0.0345 for 1682 observed reflections. Compound (I-10): C16H14N2O2, Mr = 266.30, monoclinic, P2(1)/n, a = 11.637 (1), b = 5.793 (1), c = 20.778 (2) A, beta = 105.26 (1) degrees, V = 1351.3 (25) A3, Z = 4, Dx = 1.309 g cm-3, mu = 0.82 cm-1, F(000) = 560, R = 0.0379 for 1840 observed reflections. Compound (I-11): C16H13C1N2O2, Mr = 300.74, triclinic, P1, a = 9.076 (3), b = 9.366 (1), c = 10.477 (3) A, alpha = 118.27 (2), beta = 93.85 (2), gamma = 105.26 (1) degree, V = 737.2 (15) A3, Z = 2, Dx = 1.350 g cm-3, mu = 2.61 cm-1, F(000) = 312, R = 0.0528 for 2018 observed reflections. The three N-pyridyl-2-phenylsuccinimides [N-(3-methyl-2-pyridyl)-2-p-chlorophenylsuccinimide (I-11); N-(3-methyl-2-pyridyl)-2-phenylsuccinimide (I-10) and N-(3-pyridyl)-2-phenylsuccinimide (I-6)], examined by means of X-ray structure analysis, have been previously subjected to extensive pharmacological screening, with regard to their anticonvulsive activity. Pharmacological properties of the compounds examined are clearly connected with the conformation of the molecules. The conformation of the molecules of biologically active derivatives (I-10) and (I-11) differs from the conformation of the inactive molecule of (I-6). This difference involves relative positioning of the pyridyl ring and the succinimide moiety. The Cl atom in (I-11) has only a minor effect on the conformation and geometry of the molecule in comparison with (I-10).

Synthesis and anticonvulsant properties of some arylsuccinate methylpyridylimides.

In reaction of alpha-phenyl, alpha-p-chlorophenyl and alpha-m-chlorophenylsuccinic acid with various aminopyridines, N-pyridyl-substituted succinimides (compounds 1-14) were obtained. These compounds were investigated for their CNS activity. Compounds 1, 2, 5, 6 and 7 displayed anticonvulsant properties in the maximum electroshock test. Compounds 5 and 6 were also active in the pentetrazole test.

Synthesis and anticonvulsant properties of N-methylpyridyl derivatives of m- and p-bromophenylsuccinimides.

The reaction of m- or p-bromophenylsuccinic acids with 2-aminomethylpyridines yielded respective N-methylpyridylimides 1-8. Only compounds 1 and 6 show anticonvulsant activity in the pentetrazole and electric seizures tests, but their therapeutic index is inferior to that of ethosuximide and valproic acid.

Synthesis of N-alkyloamino- or arylo-imide derivatives of succinic acid.

10 new imide derivatives of phenylsuccinic acid possessing alkyloamine, alkyloaryl or aryl groups at nitrogen atom were obtained.