Struktur-Wirkungsbeziehungen bei Histaminanaloga, 14. Mitt. 4-Aminomethyl-benzimidazole und 9-Amino-naphth[1,2-d]imidazole

4-(Aminomethyl)benzimidazoles and 9-Aminonaphth[1,2-d]imidazoles Syntheses of the bicyclic histamine analogues 4-(aminomethyl)benzimidazole ( 3a ) and 4-aminomethyl-4,5,6,7-tetrahydrobenzimidazole ( 3b ) and of the tricyclic analogues 9-amino-6,7,8,9-tetrahydronaphth[1,2-d]imidazole (6b) and 9-amino-4,5,5a,6,7,8,9,9a-octahydronaphth[1,2-d]-imidazole ( 6c ) are described.     

Synthesis and hypoglycemic activity of substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines.

A series of alkyl- and halo-substituted 8-(1-piperazinyl)imidazo[1,2-a]pyrazines were prepared using two approaches, the condensation of alpha-halocarbonyl derivatives with an aminopyrazine or the oxidation-dehydration of a [(beta-hydroxyalkyl)amino]pyrazine. These imidazo[1,2-a]pyrazines were evaluated for their binding affinity to the alpha 1, alpha 2, beta 1, and beta 2 adrenergic receptors as well as their ability to lower blood glucose in insulin resistant hyperglycemic ob/ob mice. Modifications on 8-(1-piperazinyl)imidazo[1,2-a]pyrazine (4) reduced alpha 2 binding, lowered hypoglycemic potency, and showed variations in binding to the alpha 1, beta 1, and beta 2 adrenergic receptors. In addition to 4, the 2-methyl, 3-methyl, and 5-methyl 8-(1-piperazinyl)imidazo[1,2-a]pyrazines (16k, 25m, and 16f, respectively) displayed high affinity for the alpha 2 receptor and were potent hypoglycemic agents when compared to 2-amino-7,8-dihydro-4-(1-piperazinyl)-6H-thiopyrano[3,2- d]pyrimidine (MTP-1403, 2). Receptor binding was modified by use of a 4-methylpiperazine moiety which reduced alpha 1 and beta 1 binding while retaining some hypoglycemic activity. The structure-activity relationship for heterocyclic alkyl and halo substitution on biological activity is discussed.     

Investigation of the Conformational Influences on the Estrogenic Activity of 1,2-Bis(2,6-dichloro-4-hydroxyphenyl)-ethylenediamines and of their Platinum(II) Complexes,II: Synthesis and Studies on the Estrogenic Activity of cis- and trans[Bis(2,6-dichloro-4-hydroxybenzylamine)]dihaloplatinum(II)-Complexes

2,6-Dichloro-4-hydroxybenzylamine ( 1 ) and its N-methyl ( 2 ) and N-ethyl ( 3 ) derivatives were synthesized and tested for estrogen receptor affinity as well as for estrogenic activity. In contrast to their related highly active 1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines (meso- 4 - meso- 6 ) none of the benzylamines showed hormonal activity. The coordination of the benzylamine 1 to platinum did not lead to an estrogenic compound. The reasons for the different activity of [meso-1,2(bis-2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatium(II) (meso- 4 -PtCl₂) and cis[bis(2,6-dichloro-4-hydroxybenzylamine)]dichloroplatinum(II) (cis-1-PtCl₂), the latter of which can be considered as a ring-opened counterpart of the highly active meso- 4 -PtCl₂, are thoroughly discussed under inclusion of conformational facts. The results of this and the preceding work show, that the pharmacophore meso-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (meso- 4 ) which is exclusively responsible for the estrogenic activity of meso- 4 -PtCl₂ causes comparable hormonal effects in two different conformations with O-O distances of about 8 Å (complex) and of about 12 Å (diamine). Therefore, we discuss two binding sites for estrogens in their receptor.     

Comparison of two classes of non-peptide drugs as antagonists of neutrophil receptors for f-Met-Leu-Phe. Pyrazolons and iodinated radiographic contrast agents.

The radiographic contrast agent sodium diatrizoate (DTR) reportedly inhibits f-Met-Leu-Phe-induced chemotaxis in human neutrophils. DTR is also an ingredient of Ficoll-Paque, a density centrifugation medium widely used to purify human polymorphonuclear leukocytes (PMNs). Exposure of PMNs to DTR during preparation had no detrimental effect on subsequent binding characteristics of tritiated f-Met-Leu-Phe, probably owing to a rapid dissociation of DTR from the PMN receptors. DTR competed directly with f-Met-Leu-Phe for receptor binding, but was 160- and 640-fold less potent than phenylbutazone and 1,2-diphenyl-4-[3-(1-naphthyl)-propyl]-3,5-pyrazolidinedione (DPN; an analog of phenylbutazone), respectively. Iohexol and the methylamide of DTR did not compete with [3H]f-Met-Leu-Phe in receptor binding, supporting the existence of a definite interaction between iodinated aromatic molecules and the f-Met-Leu-Phe receptor. DTR did not inhibit prostaglandin synthesis, as did DPN. Both drugs inhibited chemotactic peptide-induced release of superoxide anion in a concentration-dependent manner, and were relatively selective for f-Met-Leu-Phe, as opposed to C5a. Both drugs at 10 microM interfered non-selectively with chemotactic peptide-induced beta-glucuronidase release from PMNs. Available non-peptide antagonists of f-Met-Leu-Phe exhibited other pharmacodynamic properties that could make them unsuitable for future in vivo studies designed to probe the physiological role of the receptor.     

Herbizide, 2. Mitt. 2-Trifluormethylpyrimido[1,2-a]benzimidazole

Herbicides, II: 2-(Trifluoromethyl)pyrimido[1,2-a]benzimidazoles The condensation of 2-aminobenzimidazole (1) with the trifluoromethyl-β-diketones 2a-f furnishes the 2-(trifluoromethyl)pyrimido[1,2-a]benzimidazoles 3a-f . Marked herbicidal activity is exhibited by 3a.     

3H-TVX Q 7821: identification of 5-HT1 binding sites as target for a novel putative anxiolytic

Summary In order to clarify the mechanism of action of the putative nonbenzodiazepine anxiolytic TVX Q 7821 [2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazol-3-(2H)one-1,1-dioxidehydrochloride], binding studies with the radio labelled compound were performed.³H-TVX Q 7821 bound apidly, reversibly and in a saturable manner with high affinity to calf brain structures with preference for the hippocampus (K _D 1.62 nmol/l;B _max 320 fmol/mg protein).³H-TVX Q 7821 binding was displaced only by 5-hydroxytryptamine and its agonists and antagonists including spiperone, but was not displaced by a variety of other neurotransmitters and drugs. The 5-HT₂ receptor antagonist ketanserin was a weak displacer. The hippocampal binding sites for³H-TVX Q 7821 were pharmacologically very similar to the 5-HT₁-binding sites in this region. TVX Q 7821 is likely to be an important tool in research on functional aspects of 5-HT₁ binding sites.     

Untersuchungen zur Eiweißbindung von Arzneistoffen durch kontinuierliche Ultrafiltration, 5. Mitt. Einfluß der S-Oxidation auf die Proteinbindung von Methylthioderivaten des Warfarins

Protein Binding of Drugs Determined by Continuous Ultrafiltration, V: Effect of S-Oxidation on the Protein Binding of Methylthio Derivatives of Warfarin The binding of three methylthio derivatives of warfarin to human serum albumin has been determined by continuous ultrafiltration. 4′-(Methylthio)warfarin S-oxide (2) has a free fraction that is seven to nine times as large as that of warfarin itself in the therapeutically used plasma concentrations (2.5–12.5 μmol/l). As 2 is effective in the same dose as warfarin and shows better pharmacokinetics it might improve the safety of oral anticoagulants.     

Cyclische Aldehydderivate als Alkylierungsreagenzien, 2. Mitt. Aminoalkylderivate von 6-Chlor- und 6-Methylthiopurin und von Uracil

Cyclic Aldehyde Derivatives as Alkylating Reagents, II: Aminoalkyl Derivatives of 6-Chloro-and 6-(Methylthio)purine and of Uracil The iminium salt 2 , formed in situ from 3-methyl-1,3-oxazolidine (1) with iodotrimethylsilane, reacts with 6-(methylthio)purine to give the unstable aminoalkylation product 3a . From uracil and 1 the C-Mannich base 5 is obtained, an aza-acyclo analog of pseudouridine. For comparison of stabilities the N-Mannich bases 3b – 3d and as substrates for biological studies the ureido derivatives 4a – 4e have been sythesized.     

1,2-Dihydro-3,1-benzoxazin-4-one and 4H-1,2-dihydro-pyrido-[2,3-d]- [1,3]-oxazin-4-one derivatives as potential prodrugs. Part I: Synthesis.

1-Mono- and previously unknown 1,2-disubstituted 1,2-dihydro-3,1-benzoxazin-4-ones 7 and 9, potential prodrugs of flufenamic acid (6) and mefenamic acid (8), and 4H-1,2-dihydro-pyrido-[2,3-d]-[1,3]-oxazin-4-ones 11, potential prodrugs of niflumic acid (10), were prepared; the structures of all new compounds wereconfirmed by spectroscopic methods.     

栾树种子的化学成分研究

目的：分离鉴定栾树(Koelreuteria paniculata Laxm.)种子的化学成分。 方法：分别用石油醚回流提取和95% EtOH浸提, 硅胶柱色谱分离, IR,MS,UV,¹HNMR,¹³CNMR等方法确定结构。 结果：分得8个化合物,分别为3/-O-十四烷酰基-1-腈基-2-甲基-1,2-丙烯(1), 3-O-二十碳-14,15-烯酰基-1-腈基-2-甲基-1,2-丙烯(2), 3-O-二十碳-14,15-烯酰基-4-O-十八烷酰基-1-腈基-2-氧代亚甲基-1,2-丙烯(3), 3-O-(6′-亚油酰基-葡萄糖)-β-谷甾醇(4), 1-O-β-D-葡萄糖-2-O-油酸-3-O-十六烷酸甘油酯（5), 1-O-十六烷酸甘油酯（6), 14,15-二十碳烯酸（7),三油酸甘油酯（8)。 结论：1～3为新化合物, 4～8系首次从该植物中分得, 并归属其波谱信号。     

Synthesis and Chemotactic Activity of the fMLP Analog HCO-Hmb-Leu-Phe-OMe

The new fMLP analog HCO-Hmb-Leu-Phe-OMe ( 1 ), containing (S)-2-hydroxy-4-(methylthio)butyric acid (Hmb) in place of L -methionine at the N-terminal position, has been synthesized and fully characterized. The peptide 1 has been designed in order to improve the understanding of the role exerted by the formamido group in the binding interaction with the formylpeptide chemotactic receptors. Chemotaxis, superoxide anion production, and lysozyme release have been measured for both 1 and its deformylated analog Hmb-Leu-Phe-OMe 2 . Results indicate that a strong hydrogen bond of the OH·…O?C type may complement a weak H-bonding interaction involving the formylic proton as H-bond donor.     

2-Amino-1,4-naphthochinone und 4-Amino-1,2-naphthochinone als Nucleophile - ein Vergleich

2-Amino-1,2-naphthoquinones and 4-Amino-1,2-naphthoquinones as Nucleophiles - a Comparison Contrary to the behavior of 4-amino-1,2-naphthoquinone ( 1 ). 2-amino-1,4-naphthoquinone ( 2 ) (Scheme 3) reacts initially with methyleniminium salts by kinetic control to the N-aminomethyl compounds 3 -HX - 6 -HX, which subsequently generate the thermodynamic stable C-Mannich products 7 -HX - 10 -HX. Under the same conditions the 2-N-substituted 1,4-naphthoquinones 11 - 13 immediately yield the 3-aminomethyl derivatives 14 -HX - 16 -HX. Comparative experiments with the isomeric 2-phenylamino-1,4-naphthoquinone ( 12 ) and 4-phenylamino-1,2-naphthoquinone ( 17 ) using different aminomethylation methods always show a higher reactivity of the ortho-quinonoid compound. A similar reactivity pattern was observed for the cyclization of the N-primary and secondary amino-quinones 1,2, 12, 17 - 22 , which produce the tetrahydropyrimidines 23 - 43 with 1 mole of primary amine and 2 moles of formaldehyde.     

A comparative study on the metabolism of d-limonene and 4-vinylcyclohex-1-ene by hepatic microsomes

1. Rat liver microsomes converted d-limonene to the 1,2-epoxide (1-methyl-4-(1′-methylethenyl)-7-oxabicyclo[4,1,0]heptane), the 8,9-epoxide (1-methyl-4-(1′-methyl-1′,2′-epoxyethyl)cyclohex-1-ene), and the 8,9-glycol (2-(4′-methylcyclohex-3′-en-1′-yl) propane-1,2-diol) in the presence of NADPH. The 8,9-glycol was formed in the highest yield, the 1,2-epoxide in next highest yield, and the 8,9-epoxide was formed in low yield.

2. The absence of the 1,2-glycol (1-methyl-4-(1′-methylethenyl)cyclohexene-1,2-diol) as a microsomal metabolite of d-limonene was attributed to the very low rate of microsomal hydrolysis of the 1,2-epoxide: about 1% of the rate for the 8,9-epoxide.

3. The epoxide hydrolase inhibitor, 3,3,3-trichloropropene 1,2-oxide, completely inhibited microsomal hydrolysis of the 8,9-epoxide formed from d-limonene, and resulted in its accumulation in the reaction medium without yielding any detectable amount of the 8,9-glycol.

4. From comparison with a study on the microsomal metabolism of 4-vinylcyclohex-1 -ene, the biological selectivity in the microsomal oxidation of the d-limonene double bonds was attributed to a steric hindrance effect of the C₁-methyl group.

5. In the less hindered 4-vinylcyclohex-1-ene molecule, microsomal epoxidation occurred preferentially at the C₁-double bond, a site readily epoxidizable by chemical oxidants. Hydrolysis of 4-vinylcyclohex-1-ene epoxides by microsomal epoxide hydrolase also occurred at higher rate with the less alkyl-substituted vinyl epoxide moiety.

6. d-Limonene, 4-vinylcyclohex-1-ene, and their epoxides were all non-mutagenic toward Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537, and TA 1538 in the presence and in the absence of a PCB-induced rat liver 9000?g supernatant fraction fortified with a NADPH-generating system.     

3-substituted-1,2-benzisoxazoles: novel antipsychotic agents.

A series of 3-substituted-6-fluoro-1,2-benzisoxazoles (II) was synthesized and evaluated for potential antipsychotic activity. Many of the compounds displayed potent antipsychotic-like activity in the apomorphine induced climbing in mice (CMA) or spiroperidol binding assays, and compound 42 (HRP 392, 1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-(2-methoxyphenyl) piperazine) was selected for more detailed antipsychotic evaluation in a battery of preclinical assays. The results of these studies suggests that 42 is a potential antipsychotic drug with less propensity for EPS than some standard neuroleptics in monkeys. The compound was advanced for toxicological evaluation.     

Metabolism and DNA binding of 5,6-dimethylchrysene in mouse skin.

5,6-Dimethylchrysene (5,6-diMeC) is a weaker tumor initiator on mouse skin than 5-methylchrysene (5-MeC). To investigate the reasons for the unexpectedly low activity of 5,6-diMeC, we have studied its metabolism and DNA binding in mouse skin, particularly with respect to metabolic activation via its anti-1,2-diol 3,4-epoxide. The metabolism of 5,6-diMeC was first examined with liver 9000g supernatant from Aroclor 1254 pretreated rats. Three major metabolites were identified as 1- or 7-hydroxy-5-(hydroxymethyl)-6-MeC, 1,2-dihydroxy-1,2-dihydro-5,6-diMeC (5,6-diMeC-1,2-diol), and 1-hydroxy-5,6-diMeC. The formation of 5,6-diMeC-1,2-diol was then assessed in mouse epidermis, following topical application of [3H]5,6-diMeC. Levels of 5,6-diMeC-1,2-diol in epidermis exceeded those of 5-MeC-1,2-diol formed from 5-MeC under similar conditions. The binding of [3H]5,6-diMeC and that of [3H]5-MeC to mouse epidermal DNA were then compared. 5,6-DiMeC-deoxyribonucleoside adducts were prepared as markers by reaction of anti- and syn-5,6-diMeC-1,2-diol 3,4-epoxide with calf thymus DNA. HPLC analysis of enzymatic hydrolysates of mouse epidermal DNA, isolated 18 h after topical treatment with [3H]5,6-diMeC or [3H]5-MeC, demonstrated the formation from [3H]5,6-diMeC of two major adducts produced by reaction of its anti-1,2-diol 3,4-epoxide with deoxyguanosine and deoxyadenosine, respectively, while the major adduct formed from [3H]5-MeC resulted from reaction with deoxyguanosine, in agreement with previous results. Total DNA binding of [3H]5-MeC as well as formation of deoxyguanosine adducts exceeded that of [3H]5,6-diMeC by 3-4-fold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Novel polyacetylenes from Coreopsis tinctoria Nutt.

Phytochemical investigation of the 95% EtOH extract of Coreopsis tinctoria Nutt. resulted in the isolation of two novel polyacetylenes, (2S)-(3Z,11E)-decadiene-5,7,9-triyne-1,2-diol (1) and (2R)-(3E,11Z)-decadiene-5,7,9-triyne-1,2-diol (2), together with two known polyacetylenes (3 and 4). The structures of these novel compounds were determined by extensive two-dimensional nuclear magnetic resonance, high-resolution mass spectrometry, and optical rotation. Compounds 1, 2, and 4 were evaluated for their anti-proliferative activities against C26 cell growth and inhibitory effects on the lipo-poly-saccharides-induced nitric oxide production using murine macrophage RAW 264.7 cells. However, compounds 1, 2, and 4 just showed weak activities.     

The binding of oxicam derivatives to human serum albumin

The binding characteristics of several oxicam derivatives (tenoxicam, 4-hydroxy-2-methyl-N-phenyl-2H-1,2-benzothiazixine-3- carboxamide-1,1-dioxide (CP 14,304), 4-hydroxy-2-methyl-N-2-(3-methyl)-pyridyl-2H-1,2-benzothiazixine-3 -carboxamide- 1,1-dioxide (CP 16,460), piroxicam, meloxicam [corrected], isoxicam, 5-hydroxy-piroxicam) to 2% and 4% human serum albumin (HSA) were determined using a modified ultrafiltration process. The binding properties to HSA were characterized by determining the overall binding constant, the apparent binding constant, the slope, the free reaction energy, and the unbound portion of the drug. The following results were obtained: 1. These oxicam derivatives show a high affinity to HSA. The unbound fraction amounts to 1-3%. 2. The affinity of the compounds to HSA decreases in the order mentioned above. 3. Doubling of the HSA concentration reduces the unbound fraction, to the half, with piroxicam being the only exception.     

5-Lipoxygenase inhibitors

Ether containing compounds are claimed as inhibitors of 5-lipoxygenase (5-LO), useful in treating allergic and inflammatory diseases. Data are given for 11 compounds in an in vitro assay of inhibition of calcium ionophore-induced LTB₄ biosynthesis in human whole blood. In US5268379 (101] the syntheses of 22 compounds are described as examples, and the structure of an additional 24 compounds are described in a table. Two particularly preferred and specifically claimed compounds are 4-methoxy-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy)-trans-prop-1-enyi]tetra hydropyran (1) and 3-(4-methoxytetrahydropyran-4-yl)-N-[(1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)met hyll-trans-propenyl amide (2).     

Non-Steroidal Anti-inflammatory Agents: Novel Pyrazolyl-, 1,2-Oxazolyl-, and 1,3-Diazinyl Derivatives of 4(3H)-Quinazolinones

Four novel series of 4(3H)-quinazolinone derivatives have been prepared by cyclization of the key intermediates 3-aryl-2-(3-aryl-3-oxopropenyl)-4-(3H)-quinazolinones with different reagents: 3-aryl-1-iminocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolinones, 3-aryl-2-(3-aryl-1-thiocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolinones, 3-aryl-2-(3-aryl-4,5-dihydro-1,2-oxazol-5-yl)-4(3H)-quinazolinones, and 3-aryl-2-(4-aryl-2-thioxo-1,2,5,6-tetrahydro-1,3-diazin-6-yl)-4(3H)-quinazolinones. The anti-inflammatory activity of representatives of these compounds is comparable to or higher than that of proquazone.