Krzysztof Walczyński

Non-imidazole histamine H3 ligands. Part I. Synthesis of 2-(1-piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazole derivatives as H3-antagonists with H1 blocking activities

New 2-(1-Piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazoles were prepared and tested as H1- and H3-receptor antagonists. A number of compounds showed weak H1-antagonistic activity, with pA2 values ranging from 5.5 to 6.1. The simple alkyl substituted, 2-[1-(4-methyl and 4-ethyl)piperazinyl] analogues show increasing, moderate H3-antagonistic activity (pA2 = 6.0, and pA2 = 7.0). The compounds with 4-phenylalkyl substitution, for both the piperazinyl and the hexahydro-1H-1,4-diazepin-1-yl homologues series, regardless of the different physicochemical properties of the para substituents at the phenyl ring, showed weak H3-antagonistic activity with pA2 values ranging from 4.4 to 5.6.

Non-Imidazole Histamine H3 Ligands, Part 2: New 2-Substituted Benzothiazoles as Histamine H3 Antagonists

New, non‐imidazole histamine H3 receptor antagonists were prepared and in vitro tested as H3 receptor antagonists measured as the electrically evoked contraction of the guinea‐pig jejunum. The 2‐(1‐piperidinyl)‐ and 2‐(1‐pyrrolidinyl)benzothiazoles show no or very poor activity; 2‐[1‐(4‐amino)piperidinyl]‐ and 2‐(1,2‐ethanediamino)‐ and 2‐(1,3‐propanediamino)derivatives of benzothiazole possess weak activity at H3 receptors, whereas 2‐(4‐piperidinyl)benzothiazoles and 2‐[1‐(4‐piperazinyl)]benzothiazoles show moderate to good activity. Lipophilic and not‐too‐bulky substituents like n‐propyl attached to the nitrogen at the piperazine or piperidine ring lead to potent H3 receptor antagonists with pA2 values ranging from 7.0 to 7.2. The structure‐activity relationships for different substitution patterns are discussed.

Histamine H1 receptor ligands. Part I. Novel thiazol-4-ylethanamine derivatives: synthesis and in vitro pharmacology.

A series of 2-substituted thiazol-4-ylethanamines have been synthesized and tested for their histaminergic H1-receptor activities. The compounds with 2-phenyl substitution, regardless of the different physicochemical properties of the meta-substituents at the phenyl ring, showed weak H1-agonistic activity with pD2 values ranging from 4.35 to 5.36. When the phenyl group was replaced by a benzyl group, the resulting compounds all exhibited weak H1-antagonistic activity (pA2: 4.14-4.82).

Histamine H1 receptor ligands. Part II. Synthesis and in vitro pharmacology of 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives

New 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives were prepared and tested in vitro as H1 receptor antagonists. The compounds with 2-phenylamino substitution with meta-halide substituents at the phenyl ring, showed weak H1-antagonistic activity (pA2: 4.62-5.04) and this activity was completely lost in the case of meta-methyl substituent (pA2 < 4). When the phenylamino group was replaced by benzhydryl groups of classic antihistamines, the resulting compounds exhibited slightly improved H1-antagonistic activity (at the meta-position pA2: 6.38-6.15; at the para-position pA2: 6.04-5.87).

Non-imidazole histamine H3 ligands, part IV: SAR of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine derivatives.

A series of 1-[[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propyl]piperazine derivatives have been prepared and in vitro tested as H(3)-receptor antagonists (the electrically evoked contraction of the guinea pig jejunum). It appeared that by comparison of homologous pairs the 1-[[2-thiazol-5-yl-(2-methyl-2-phenylalkylaminoethyl)]-4-n-propyl]piperazine derivatives (4c1-4c3) have slightly higher activity than their 1-[2-thiazol-5-yl-(2-methyl-2-alkylaminoethyl)]-4-n-propylpiperazine analogues (4b1-4b3). In the 2-methylalkylamide series (4a1-4a3) a somewhat lower activity was observed. The most potent compound of the series is the 1-[2-thiazol-5-yl-(2-methyl-2-phenylpropylaminoethyl)]-4-n-propylpiperazine (4c2) with pA(2)=8.27 (its alkyl analogue (4b2) showed pA(2)=7.53 and the corresponding amide (4a2) displayed pA(2)=7.36). Selected compounds (4b1, 4b2, 4c1 and 4c2) were also tested (in vitro) for H(1) antagonistic effects in vitro applying standard methods (guinea pig ileum). None showed any H(1) antagonistic activity (pA(2)<4).

Non-imidazole histamine H3 ligands: part V. synthesis and preliminary pharmacological investigation of 1-[2-thiazol-4-yl- and 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine derivatives

Series of 1-[2-thiazol-4-yl-(2-aminoethyl)]- and 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine derivatives have been prepared and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). It appeared that by comparison of homologous pairs, the 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazines (3a,b and 4a–d) have much higher potency than their analogous 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazines (2a–k). Based on the obtained results, we observed the 5-position of 2-methyl-2-R-aminoethyl substituents in the thiazole ring is favourable for histamine H3 receptor antagonist activity, whereas its presence in position 4 leads, almost in each case, to strong decrease of activity.

Structure-activity relationships of new 1-substitutedmethyl-4-[5-(N-methyl-N-propylamino)pentyloxy]piperidines and selected 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-methy-l-N-propyl)-pentanediamines as H3 -antagonists.

Novel, potent non‐imidazole histamine H3 receptor antagonists have been prepared and in vitro tested as H3‐receptor antagonists (the electrically evoked contraction of the guinea‐pig jejunum). The present compounds contain a 4‐hydroxypiperidine core, which behaves as a conformationally restricted version of the 3‐amino‐1‐propanol moiety common to the many previously described non‐imidazole H3 ligands. Detailed structure‐activity studies revealed that 1‐(2‐benzofuranylmethyl)‐ 5c (pA2 = 8.47 ± 0.05) and 1‐(3‐benzofuranylmethyl)‐4‐[5‐(N‐methyl‐N‐propyl)pentyloxy]piperidine 5d (pA2 = 8.15 ± 0.07) exhibit high potency for the H3 histamine receptor. In addition, the potency of selected 1‐[(N‐substituted‐N‐methyl)‐3‐propyloxy]‐5‐(N‐methyl‐N‐propyl)pentanediamines as antagonist of the H3 histamine receptor was also evaluated. Replacement of the 4‐hydroxypiperidine of the leads 7 and 5c by a highly flexible 3‐(methylamino)propyloxy chain yields compounds 6a (pA2 = 8.02) and 6b (pA2 = 6.23) with higher and lower potency than their piperidine analogues (7, pA2 = 7.79; 5c, pA2 = 8.47), respectively. The histaminergic H1 antagonism of selected compounds 5c, 5d and 6a has been established on the isolated guinea‐pig ileum by conventional methods; the pA2 values have compared with the potency of pyrilamine. None of them showed any H1‐antagonistic activity (pA2 < 4; for pyrilamine pA2 = 8.5).

New 1-Benzyl-4-hydroxypiperidine Derivatives as Non-imidazole Histamine H3 Receptor Antagonists

A series of 1‐benzyl‐4‐(3‐aminopropyloxy)piperidine and 1‐benzyl‐4‐(5‐aminopentyloxy)piperidine derivatives has been prepared. The 1‐benzyl‐4‐hydroxypiperidine derivatives obtained were evaluated for their affinities at recombinant human histamine H3 receptor, stably expressed in HEK 293T cells. All compounds investigated show moderate to pronounced in‐vitro affinities. The most potent antagonists in this series 9b2 (hH3R, pKi = 7.09), 9b1 (hH3R, pKi = 6.78), 9b5 (hH3R, pKi = 6.99), and 9b6 (hH3R, pKi = 6.97) were also tested in vitro as H3 receptor antagonists – the electrically evoked contraction of the guinea‐pig jejunum. The histaminergic H1 antagonism of selected compounds 9b1, 9b2, and 9b4–9b6 was established on the isolated guinea‐pig ileum by conventional methods; the pA2 values were compared with the potency of pyrilamine. The compounds did not show any H1 antagonistic activity (pA2 < 4; for pyrilamine pA2 = 9.53).

Synthesis and Preliminary Pharmacological Investigation of New N-Substituted-N-[ω-(ω-phenoxy-alkylpiperazin-1-yl)alkyl]guanidines as Non-Imidazole Histamine H3 Antagonists

Novel, potent non‐imidazole histamine H3 receptor antagonists were prepared. Detailed structure–activity studies revealed that N‐(4‐trifluoromethylbenzyl)‐N‐[4‐(7‐phenoxyheptylpiperazin‐1‐yl)butyl]guanidine (pA2 = 8.49 ± 0.05), 1h, and N‐(4‐nitrobenzyl)‐N‐[4‐(7‐phenoxyheptylpiperazin‐1‐yl)butyl]guanidine (pA2 = 8.43 ± 0.05), 1l, exhibit high affinity for the H3 histamine receptor. The most potent antagonists in this series, 1e, 1h, and 1l, were also in vitro tested as H1 receptor antagonists, showing weak H1‐antagonistic activity with pA2 = 6.70 ± 0.09, pA2 = 6.46 ± 0.09, and pA2 = 6.65 ± 0.11, respectively.

A steric approach for the design of antihistamines with low muscarinic receptor antagonism

For years, the clinical utility of histamine Hi-receptor antagonists (also known as antihistamines) has been hampered by two major side effects: (1) sedation, most likely resulting from blockade of histamine Hi-receptors in the central nervous system (CNS), and (2) muscarinic receptor antagonism, causing dry mouth, blurred vision, tachycardia and nervousness. The CNS depression of antihistamines can be avoided by designing drugs incapable of crossing the blood-brain barrier, e.g. by introducing polar and/or hydrophilic groups into the molecule. This has been the case for many of the now available non-sedating antihistamines. However, there is so far no reliable general method for reducing the muscarinic receptor blockade of antihistamines. Early studies on 3-methoxycyproheptadine enantiomers indicated that the antihistaminic and antimuscarinic activity of the compound reside in the opposite antipodes [1]. Thus (-)-3-methoxycyproheptadine is the antihistaminic eutomer showing more than 8-fold higher potency than (+)-3-methoxycyproheptadine whereas the latter is the antimuscarinic eutomer with almost 40-fold higher affinity than the former. In the present study, we have synthesized a series of optically active analogues of ebastine (Table 1) and examined the effect of chirality on their selectivity between histaminergic and muscarinic antagonism.