Synthesis and structure-activity relationships of N-substituted 2-[(2-imidazolylsulfinyl)methyl]anilines as a new class of gastric H+/K(+)-ATPase inhibitors.

A series of N-substituted 2-[(2-imidazolylsulfinyl)methyl]anilines (3) was synthesized and evaluated for its biological activity against gastric H+/K(+)-ATPase prepared from rabbit stomach and gastric acid secretions in Heidenhain pouch dogs. Monoalkyl substituents on the nitrogen atom of the aniline moiety markedly inhibited the enzyme activity to the same degree as omeprazole, a representative H+/K(+)-ATPase inhibitor. Most of these compounds, administered at 3 mg/kg i.v. inhibited histamine-stimulated gastric acid secretion. The inhibitory activity of these derivatives on the enzymes at pH 6.0 was more potent than that at pH 7.4, and was distinctly correlated to stability in aqueous solution at pH 5.0.     

Structure-activity relationships of 2-aminothiazole derivatives as inducible nitric oxide synthase inhibitor

Nitric oxide synthase (NOS) has been divided into two major sub-enzymes, i.e. inducible NOS (iNOS) and constitutive NOS (cNOS). Although nitric oxide (NO) plays an important role as host defense mediator, excessive production of NO by iNOS has been involved in the pathology of many inflammatory diseases. Recently, we reported that the 2-imino-1,3-oxazolidine (1a) weakly inhibits iNOS and that introduction of an alkyl moiety on the oxazolidine ring of 1a enhances the inhibitory activity and selectivity for iNOS. In our search for better iNOS inhibitors, we focused our efforts on the 2-aminothiazole scaffold 3 as it possesses a ring similar to that of 1a. In this study, we evaluated the inhibitory activity of a series of 2-aminothiazole derivatives against both iNOS and neuronal NOS (nNOS). Our results show that introduction of appropriately-sized substituents at the 4- and 5-position of the 2-aminothiazole ring improves the inhibitory activity and selectivity for iNOS. We also found that the selectivity of 5a [5-(1-methyl)ethyl-4-methylthiazol-2-ylamine] and 5b [5-(1,1-dimethyl)ethyl-4-methylthiazol-2-ylamine] for iNOS was similar to that of oxazolidine derivative 1b (4-methyl-5-propyl-2-imino-1,3-oxazolidine) and much higher than that of L-NAME. However, we could not enhance the inhibitory activity against iNOS by introducing an alkyl substituent into the 2-aminothiazole ring as we could in the case of oxazolidine one. On the other hand, introduction of bulky or hydrophilic substituent at any position of the 2-aminothiazole ring remarkably decreased or even abolished the inhibitory activity against NOS.     

A novel class of inhibitors for human and rat steroid 5alpha-reductases: synthesis and biological evaluation of indoline and aniline derivatives. III

While searching for novel nonsteroidal inhibitors of human and rat prostatic 5alpha-reductases, we found a new series of indoline and aniline derivatives that showed potent inhibitory activities for both enzymes. Among them, 3-chloro-4-?[1-(4-phenoxybenzyl)indolin-5-yl]oxylbenzoic acid (2e, YM-36117) showed a more potent inhibitory activity for the human enzyme than ONO-3805 with an IC50 value of 5.3 nM and a reduced rat prostatic dihydrotestosterone (DHT) concentration by oral administration. The synthesis and the structure-activity relationships of these indoline and aniline derivatives are presented.     

Studies on antiallergic agents. I. Synthesis and antiallergic activity of novel pyrazine derivatives.

Various pyrazine derivatives were synthesized and their antiallergic activity was examined. The inhibitory activity on allergic histamine release of the compounds bearing a 5-tetrazolyl group was more potent than that of the corresponding carboxyl derivatives. The introduction of -CONH- or -NHCO- between the pyrazine ring and the 5-tetrazolyl group as a spacer greatly enhanced the activity. N-(1H-Tetrazol-5-yl)-2-pyrazinecarboxamide (I-3) was estimated to exhibit nearly the same potency as disodium cromoglycate (DSCG). The structure-activity relationship among various derivatives modified by introducing some substituents onto the 3-, 5- or 6-position of the pyrazine ring of I-3 was investigated. The activity remained unchanged or was reduced when such substituents as methyl, chloro, methoxy, methylamino and dimethylamino were introduced at the 3- or 5-position. In contrast, 6-substitution with various alkylamino groups more or less increased the activity. Among them, the 6-dimethylamino (I-17c) and 6-(1-pyrrolidinyl) (I-34) derivative were proved to be most potent. The IC50 values (concentration which produces 50% inhibition of the allergic histamine release) of I-17c and I-34 were determined to be 4.7 x 10(-10) and 4.6 x 10(-10) M, respectively. These two compounds produced a potent inhibitory activity on passive cutaneous anaphylaxis (PCA) in rat, not only by the intravenous route (ED50 = 0.0096 mg/kg for both compounds) but also by the oral route (ED50 = 0.19 and 0.18 mg/kg, respectively). On the other hand, when the pyrazine ring of some representative compounds was replaced with a pyridine ring, the inhibitory activity on histamine release was significantly reduced.     

Preparation of 2-aryl and 2-aryloxymethyl imidazo[1,2-a]pyridines and related compounds

A series of substituted 2-aryl imidazo[1,2-a]pyridines has been prepared in which a variety of substituents are introduced on the 4′-position of the phenyl ring and on the 3, 5 , 6 or 7 position of the heterocyclic ring. Most examples have acetamido, bromo, cyano, or formyl substituents at the 4′-position. Analogous imidazo-[2,1-b]fhiazoles and imidazo[1,2-a]pyrimidines have also been prepared. Another series of compounds consisting of 4′-formylphenoxymethyl derivatives of imidazole, the three positional isomers of pyridine, thiazole, benzimidazole and ring-substituted imidazo[1,2-a]pyridines has been prepared. 2-(4′-Formylphenylethenyl) derivatives of imidazole and imidazo[1,2-a]pyridine were also prepared.     

Studies on antiulcer drugs. VI. 4-Furyl-2-guanidinothiazoles and related compounds as potent histamine H2-receptor antagonists.

A series of 4-furyl-2-guanidinothiazole derivatives and related compounds were synthesized and evaluated for histamine H2-receptor antagonist and gastric acid antisecretory activities. Among them, compounds I-17, I-48 and I-49 showed high activities in these tests. In addition, compound I-17 possessed potent inhibitory activities on each of the gastric ulcers induced by stress, ethanol and HCl-aspirin. On the other hand, compound I-48 demonstrated antimicrobial activity against Helicobacter Pylori and the potency was far stronger than that of clinically used H2-antagonists. Some structure-activity relationships are discussed.     

Modification and structure-activity relationship of a small molecule HIV-1 inhibitor targeting the viral envelope glycoprotein gp120

This paper describes selected modification and structure-activity relationship of the small molecule HIV-1 inhibitor, 4-benzoyl-1-[(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2-(R)-methylpiperazine (BMS-378806). The results revealed: i) that both the presence and configuration (R vs. S) of the 3-methyl group on the piperazine moiety are important for the antiviral activity, with the 3-(R)-methyl derivatives showing the highest activity; ii) that the electronegativity of the C-4 substituent on the indole or azaindole ring seems to be important for the activity, with a small, electron-donating group such as a fluoro or a methoxy group showing enhanced activity, while a nitro group diminishes the activity; iii) that the N-1 position of the indole ring is not eligible for modification without losing activity; and iv) that bulky groups around the C-4 position of the indole or azaindole ring diminish the activity, probably due to steric hindrance in the binding. We found that a synthetic bivalent compound with two BMS-378806 moieties being tethered by a spacer demonstrated about 5-fold enhanced activity in an nM range against HIV-1 infection than the corresponding monomeric inhibitor. But the polyacrylamide-based polyvalent compounds did not show inhibitory activity at up to 200 nM.     

配体结构对含2-甲基咪唑及N-乙基咪唑的NAMI 衍生物水解及溶液稳定性的影响

制备并用UV、循环伏安(CV)和NMR 法研究了NAMI(新抗肿瘤转移抑制剂, trans-[RuCl₄(DMSO)(imidazole)]Na·2DMSO)衍生物trans-[RuCl₄(DMSO)(2-MeIm)]Na·2DMSO (2-MeIm＝2-甲基咪唑, 化合物1)和trans-[RuCl₄(DMSO)-(N-EtIm)]Na·2DMSO (N-EtIm＝N-乙基咪唑, 化合物2)的水解机理-动力学、溶液稳定性和电化学性质. 化合物1 和化合物2 与NAMI 相似, 在pH 7.40 的缓冲溶液中发生两步脱氯水解反应(I 氯水解及II 氯水解) (分步反应); 在酸性溶液(pH 5.00)中脱DMSO 水解. 通过线性拟合得到各水解反应速率常数k_obs 及半衰期t_1/2. 结果表明化合物在酸性溶液中的稳定性相对较高. 在NAMI 衍生物咪唑环的N 位引入乙基比在2 位引入甲基生成的化合物稳定. 含氮配体相同时,NAMI-A(新抗肿瘤转移抑制剂, A: 该系列中的第一个化合物, trans-[RuCl₄(DMSO)(imidazole)][Himidazole])衍生物略比相应的NAMI 衍生物稳定.     

Synthesis and platelet aggregation inhibitory activities of 3-(2-oxopropylidene)azetidin-2-one derivatives. II.

A series of 3-acylidene-4-methylazetidin-2-one derivatives bearing various substituents at the 1-position of the azetidin-2-one ring was synthesized. These compounds were evaluated for platelet aggregation inhibitory activities. Most of the compounds synthesized showed potent inhibitory activities against rabbit platelet aggregation induced by adenosine diphosphate or collagen in vitro. Structure-activity relationships are also discussed.     

Orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activity of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives containing a tertiary amine moiety

The search for orally active CCR5 antagonists was performed by chemical modification of the 1-benzothiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compounds containing a tertiary amine moiety. Replacement of methyl group with a 2-(C(2-4) alkoxy)ethoxy group at the 4-position on the 7-phenyl group of the 1-benzothiepine ring resulted in both enhanced activity and significant improvement in the pharmacokinetic properties upon oral administration in rats. Introduction of C(2-4) alkyl, phenyl or (hetero)arylmethyl groups as the 1-substituent on the 1-benzazepine ring together with the 2-(butoxy)ethoxy group led to further increase of activity. Among the 1-benzazepine derivatives, the isobutyl (6i), benzyl (6o) or 1-methylpyrazol-4-ylmethyl (6s) compounds were found to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activity (IC(50)=2.7 nM) and inhibitory effect (IC(50)=1.2 nM) on membrane fusion, together with good pharmacokinetic properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives and their biological activity are described.     

Substituent cross-interaction effects on the electronic character of the C=N bridging group in substituted benzylidene anilines--models for molecular cores of mesogenic compounds. A 13C NMR study and comparison with theoretical results

13C NMR chemical shifts delta(C)(C=N) were measured in CDCl3 for a wide set of mesogenic molecule model compounds, viz. the substituted benzylidene anilines p-X-C6H4CH=NC6H4-p-Y (X = NO2, CN, CF3, F, Cl, H, Me, MeO, or NMe2; Y = NO2, CN, F, Cl, H, Me, MeO, or NMe2). The substituent dependence of delta(C)(C=N) was used as a tool to study electronic substituent effects on the azomethine unit. The benzylidene substituents X have a reverse effect on delta(C)(C=N): electron-withdrawing substituents cause shielding, while electron-donating ones behave oppositely, the inductive effects clearly predominating over the resonance effects. In contrast, the aniline substituents Y exert normal effects: electron-withdrawing substituents cause deshielding, while electron-donating ones cause shielding of the C=N carbon, the strengths of the inductive and resonance effects being closely similar. Additionally, the presence of a specific cross-interaction between X and Y could be verified. The electronic effects of the neighboring aromatic ring substituents systematically modify the sensitivity of the C=N group to the electronic effects of the benzylidene or aniline ring substituents. Electron-withdrawing substituents on the aniline ring decrease the sensitivity of delta(C)(C=N) to the substitution on the benzylidine ring, while electron-donating substituents have the opposite effect. In contrast, electron-withdrawing substituents on the benzylidene ring increase the sensitivity of delta(C)(C=N) to the substituent on the aniline ring, while electron-donating substituents act in the opposite way. These results can be rationalized in terms of the substituent-sensitive balance of the electron delocalization (mesomeric effects). The present NMR characteristics are discussed as regards the computational literature data. Valuable information has been obtained on the effects of the substituents on the molecular core of the mesogenic model compounds.     

Condensed thienopyrimidines. IV. Synthesis and gastric antisecretory activity of 2,3-dihydro-5H-oxazolothienopyrimidine derivatives

2,3-Dihydro-5H-oxazolo[3,2-a]thieno[3,2-d]-(2a--d), [3,4-d]-(2e--h), and [2,3-d]pyrimidine derivatives (2i,j) were synthesized and evaluated for gastric antisecretory activity. These analogues (2) were prepared stepwise starting from formylthiophenecarbamates (4). The structure-activity relationships of these compounds are discussed.     

Synthesis and antitumor activity of benzimidazolyl-1,3,5-triazine and benzimidazolylpyrimidine derivatives

Triamino-substituted 1,3,5-triazine and pyrimidine derivatives were synthesized and tested for antitumor activities using some human cancer cell lines and murine leukemia cell lines. All the compounds having benzimidazolyl and morpholino groups as substituents on the 1,3,5-triazine ring showed antitumor activity. Pyrimidine derivatives having the same groups as substituents also showed antitumor activity. Among them, the compounds having 1-benzimidazolyl, morpholino and cis-2,3-dimethylmorpholino groups as substituents on the 1,3,5-triazine ring or pyrimidine ring exhibited the most potent antitumor activity, and these compounds exhibited no or very weak aromatase inhibitory activity. In contrast, the compounds having imidazolyl group instead of benzimidazolyl group as a substituent on the 1,3,5-triazine ring showed a potent aromatase inhibitory activity.     

Reactivity of Hydroxy and Amino Derivatives of 2‐Phenyl‐1H‐imidazoline and 2‐Phenyl‐1H‐imidazole toward Isocyanates: Synthesis of Appropriate Carbamates and Ureas

Reactivity of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline and 2‐(4‐hydroxyphenyl)‐1H‐imidazole toward substituted phenyl isocyanates was studied. When mentioned imidazoline was treated with 2.5 equiv of substituted phenyl isocyanate, three N,O‐dicarboxamides were prepared (substituents are H, 4‐NO₂, and 4‐CH₃). Subsequently, N,O‐diacetylated 2‐(4‐hydroxyphenyl)‐1H‐imidazoline was prepared and selective deprotection method was developed for preparation of 1‐acetyl‐2‐(4‐hydroxyphenyl)‐1H‐imidazoline using diethylamine in acetone. Six carbamates derived from this imidazoline were then prepared using 1.1 equiv of substituted phenyl isocyanates (substituents are H, 4‐CH₃, 4‐OCH₃, 4‐NO₂, 4‐CN, and 3‐CF₃). Finally, two carbamates were prepared from 2‐(4‐hydroxyphenyl)‐1H‐imidazole (substituents are 4‐NO₂ and 4‐CN). No reactivity to imidazole ring was observed in this case. Eight derivatives were subjected to antimycobacterial screening. Concurrently, reactivity of 2‐(2‐aminophenyl)‐ and 2‐(2‐hydroxyphenyl)‐1H‐imidazole toward aliphatic and aromatic isocyanates was studied. Eight ureas were prepared using equivalent mixture of 2‐(2‐aminophenyl)‐1H‐imidazole and isocyanate (Et, Pr, isoPr, terc‐Bu, Cy, Ph, 4‐CH₃C₆H₄, 4‐CNC₆H₄). Similar attempts to obtain related carbamates from 2‐(2‐hydroxyphenyl)‐1H‐imidazole lead only to three substituted phenyl carbamates (substituents are 4‐CH₃, 4‐NO₂, and 4‐CN). In both cases, no reactivity to imidazole ring was observed again.     

Orally active CCR5 antagonists as anti-HIV-1 agents 2: synthesis and biological activities of anilide derivatives containing a pyridine N-oxide moiety

In order to develop orally active CCR5 antagonists, we investigated 1-benzoxepine derivatives containing new polar substituents, such as phosphonate, phosphine oxide or pyridine N-oxide moieties, as replacements for the previously reported quaternary ammonium moiety. Among these compounds, the 2-(alpha-hydroxybenzyl)pyridine N-oxide 5e exhibited moderate CCR5 antagonistic activity and had an acceptable pharmacokinetic profile in rats. Subsequent chemical modification was performed and compound (S)-5f possessing the (S)-configuration hydroxy group was found to be more active than the (R)-isomer. Replacement of the 1-benzoxepine ring with a 4-methylphenyl group by a 1-benzazepine ring with a 4-[2-(butoxy)ethoxy]phenyl group enhanced the activity in the binding assay. In addition, introduction of a 3-trifluoromethyl group on the phenyl group of the anilide moiety led to greatly increased activity in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound (S)-5s showed the most potent CCR5 antagonistic activity (IC(50)=7.2 nM) and inhibitory effect (IC(50)=5.4 nM) in the fusion assay, together with good pharmacokinetic properties in rats.     

Phosphorescent iridium complexes based on 2-phenylimidazo[1,2-a]pyridine ligands: tuning of emission color toward the blue region and application to polymer light-emitting devices

A series of new blue-phosphorescent iridium(III) complexes 1-14 with ligands of 2-phenylimidazo[1,2-a]pyridine (pip) derivatives were successfully prepared, and their electrochemical, photophysical, and electroluminescent (EL) properties were systematically investigated. It was found that the emission maxima are significantly dependent on the substituents on the phenyl ring in the range of 489-550 nm. For instance, electron-withdrawing groups such as F and CF3 shift the emission maxima to shorter wavelengths by lowering the HOMO levels (complexes 4-8), whereas the extended pi-conjugation leads to bathochromic shifts (2, 3). To obtain further information about the frontier orbital, substitution effects on the imidazole part were also investigated here, and it was found that electron-withdrawing or -donating substituents on the imidazole ring affected the emission maxima (9, 557 nm; 10, 525 nm). These results including their oxidation potentials suggest that the HOMO of the pip-based complex is a mixture of Ir-d, phenyl-pi, and imidazole-pi orbitals. From this viewpoint, combination of electron-withdrawing substituents on the phenyl ring with the use of another ancillary ligand enabled further blue shifts (13, 468, 499 nm; 14, 464, 494 nm). This new system based on pip is one of the rare examples of iridium complexes whose emissions can be tuned to the blue region. Preliminary polymer light-emitting devices (PLEDs) employing the Ir complexes were fabricated, and the devices showed moderate EL efficiencies.     

Stereocontrolled Preparation of Spirocyclic Ethers by Intramolecular Trapping of Oxonium Ions with Allylsilanes

The stereoselectivity of the spontaneous intramolecular cyclization of 2-(benzenesulfonyl)-2-(4-((trimethylsilyl)methyl)-4-pentenyl)tetrahydropyrans substituted by alkyl groups at various ring positions has been examined. For the 4- and 6-methyl derivatives, formation of the spirocyclic center occurs exclusively anti to the methyl. The outcome in the 5-methyl example is a 3.7:1 syn/anti split. For the trans-4,6-dimethyl derivative, the substituents act in a reinforcing manner and direct cyclization uniquely in one direction. Both the cis and trans bicyclic ethers ring close on that pi-surface of the intermediate oxonium ion syn to the angular hydrogen. The results are rationalized in terms of the predilection of the associated oxonium ions for nucleophilic capture via a chairlike or twist-boat transition state.     

Thromboxane A2 receptor antagonists. III. Synthesis and pharmacological activity of 6,6-dimethylbicyclo[3.1.1]heptane derivatives with a substituted sulfonylamino group at C-2

Four stereoisomers of the title compounds based on side chain ring junctions, (+)-7a, (+)-7b, (-)-7c and (-)-24, were synthesized from (-)-myrtenol and (+)-nopinone. The (1R,2R,3S,5S)-isomer (+)-7b had the most potent inhibitory activity against platelet aggregation and did not show partial agonist activity (shape change of platelets). We also synthesized the antipode, (-)-7b, and derivatives of (+)-7b with various kinds of substituents at the sulfonylamino group, 34a-n and p. The one-carbon homologated compound, (+)-58, was also prepared. The inhibitory activities of these compounds against platelet aggregation were measured.     

Theoretical interpretation of the reactivity of the imidazole ring in transformations at the meso carbon atom

Quantum-mechanical calculations by the Pariser-Parr-Pople (PPP) SCF MO and Hückel MO methods explain the previously observed dependence of the reactivities of imidazole derivatives in reactions at the meso carbon atom on the nature of the aromatic nuclei and substituents bonded to the imidazole ring in the 4 and 5 positions.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 99–106, January, 1973.     

C-5 functionalization of trisubstituted imidazoles with azodicarbonyl compounds

Certain 1,2,4-trisubstituted imidazoles underwent electrophilic attack of azodicarbonyl compounds on the 5-position to form 5-(1,2-dialkoxycarbonyl)hydrazino- and 5-(4-phenyl-3,5-dioxo-1,2,4-triazolidin-1-yl)imidazole derivatives in moderate to high yields. The reaction was highly susceptible to the nature and the substitution pattern of the substituents on the imidazole ring. Thus 1,4-di- or 1,2,5-trisubstitued imidazoles, and 2-methylsulfinylimidazoles gave no reaction. Reductive cleavage of the tetrasubstituted imidazoles with zinc dust-acid gave the 1- or 1,2-cleaved product depending upon the reaction temperature, but the hydrazino moiety remained intact.