Ein neuer Typ von analgetischen Antiphlogistica, 1. Mitt. Basisch substituierte 2,3-Dihydro-2-phenyl-benzo[b]thiophen-1,1-dioxide

A Novel Type of Analgesic Antiphlogistics, I: 2,3-Dihydro-2-phenylbenzo[b]thiophene 1,1-Dioxides with Basic Substituents In the course of extensive investigations on various topics of benzo[b]thiophene chemistry addition reactions of bases to substituted benzo[b]thiophene 1,1-dioxides were studied. By addition of secondary amines to 2-phenylbenzo[b]thiophene 1,1-dioxides the title compounds were obtained. They are potent as non-narcotic analgesics and as antiinflammatory agents.     

Ein neuer Typ von analgetischen Antiphlogistica, 2. Mitt. Benzo[b]thienyl-piperazine

A Novel Type of Analgesic Antiphlogistics, II: Benzo[b]thienyl-piperazines In continuation of our work on antiphlogistic benzo[b]thiophene 1,1-dioxides novel compounds of type I were synthesized by the addition of piperazine(s) onto 2-phenylbenzo[b]thiophene 1,1-dioxides and (in some cases) by subsequent substitutions. Utilizing the reversibility of the addition reaction, the basic substituent at position 3 of such compounds can be replaced by other groups.     

Review Central & Peripheral Nervous Systems: Glycine-site NMDA receptor antagonists

The patent literature on antagonists for the glycine site of the NMDA receptor, covering the two years prior to July 1995, is reviewed. Compound classes reported include quinoxaline-2,3-diones; imidazolopyrazinones; triazolopyrimidones; pyridazinoquinolines; benz[b]azepine-2,5-diones; 1,2,4-benzothiadiazine-1,1-dioxides; 2-carboxyindoles; 2-quinolones; miscellaneous other compounds, and kynurenine-derived molecules. Glycine site antagonists have an improved therapeutic index relative to other classes of NMDA antagonists, and show considerable therapeutic promise for CNS disorders, including cerebral ischaemia, epilepsy, head injury and schizophrenia. However, despite apparently extensive effort, very few compounds are entering clinical development. This is probably due to the difficulty in achieving suitable in vivo activity, because antagonists with high affinity for the glycine site are mostly acidic and do not easily cross the blood-brain barrier. Glycine site antagonists with useful in vivo activity are currently limited to the N-hydroxypyr-rolidinones, R(+)-HA-966 and L-687,414 (Merck); the quinoxaline-2,3-diones, ACEA 1021 (Ciba/CoCensys) and SM-18400 (Sumitomo); and the 4-hydroxy-2-quinolone, L-701,324 (Merck).     

Synthesis and biological activities of some N-hydroxymethylene and N-methoxymethylene thiazines

A series of new 3,5-diaryl-N-hydroxymethylene-1,4-thiazine-1,1-dioxides and 3,5-diaryl-N-methoxymethylene-tetrahydro-1,4-thiazines-1,1-dioxides were synthesized and their antimicrobial activities were tested against Gram-positive (Bacillus subtilis, Streptococci) and Gram-negative bacteria (Escherichia coli and Klebsiella penumoniae) and against the fungi Penicillium inclobium and Aspergillus flavus. The synthesized compounds have been characterized on the basis of elemental analyses, infrared spectroscopy (IR), and nuclear magnetic resonance (NMR).     

Sulfogriseofulvin Derivatives. Synthesis by [4+2]Cycloaddition,Structure, Properties,Crystal Structure Analysis,and Antifungal Activity of Spiro[1,3-benzoxathiole-2,1′-cyclohex-2′-en]-4′-one 3,3-Dioxides

Syntheses of substituted, especially of fluoro substituted benzoxathiole 1,1-dioxides, are described. These derivatives were transformed via the Peterson olefination into substituted 2-alkylidene derivatives 27. Diels-Alder reactions of 27 with 1,1-dimethoxy- and 1-methoxy-3-trimethylsiloxy-1,3-butadiene ( 30, 32 ) gave sulfone analogues 31 of griseofulvin (named sulfogriseofulvins). From Z- 27 , a number of cis-isomers with the relative stereochemistry of griseofulvin (cis- 31 ) was prepared, and from E-isomers of 27 , compounds (trans- 31 ) with relative stereochemistry of epigriseofulvin were obtained. Some related compounds ( 33, 38 ) are synthesized by slight modifications. The stereochemistry is established by spectroscopic methods and crystal structure analyses. The compounds 31 were tested against three species of dermatophytes. The biological activities were all significantly lower than that of griseofulvin.     

From the H2 receptor gene to reclassification of the H2 receptor antagonists

From previous studies it is known that long-term stimulation of the histamine H₂ receptor results in receptor downregulation. Two different pathways are involved in the downregulation process of the H₂ receptor: a cAMP-dependent and cAMP-independent agonist-dependent pathway. Recently, it became evident that in the absence of an agonist the H₂ receptor expressed in CHO cells already stimulate cAMP production, also referred to as spontaneous activity. The spontaneous activity can be inhibited by several H₂ antagonists, previously thought to act as competitive antagonists, and these antagonists are referred to as inverse agonists. Some antagonists, e.g. burimamide, are not able to inhibit the spontaneous activity and are referred to as neutral antagonists. Inverse agonism appears to be the mechanistic basis of upregulation. Only inverse agonists and not neutral antagonists induce receptor upregulation after long-term treatment as these compounds inhibit the spontaneous receptor activity and thus the basal receptor downregulation. Moreover it might also explain previously reported observations after long-term treatment of gastric ulcers, such as intragastric hyperacidity.     

Iminiumkohlensäurederivat-Salze, 7. Mitt. Teil I: Elektrophile Reaktionen von 2-Methylthio-5,6-dihydro-4H1,3-thiaziniumiodiden, 2-Methylthio-4,5-dihydrothiazoliumiodiden und 2-Methylthio-5-methylthiazoliumiodiden mit N-Nucleophilen

Iminium Carbonic Acid Derivative Salts VII, Part I: Electrophilic Reactions of 2-Methylthio-5,6-dihydro-4H-1,3-thiazinium Iodides, 2-Methylthio-4,5-dihydrothiazolium Iodides, and 2-Methylthio-5-methylthiazolium Iodides with N-Nucleophiles Cyclic salts of the dithiocarbonic acid diester imidium type ( 3, 5 ) react with NH₂-nucleophiles to the cyclic isothioureas 6 – 8 . Some of these compounds were oxidized to cyclic isothiourea-S,S-dioxides ( 9, 10 ).     

Substituierte Tetrahydro-1,4-thiazin-1,1-dioxide

Substiuted Tetrahydro-1,4-thiazine-1,1-dioxides Tetrahydro-1,4-thiazine-1,1-dioxides are prepared by reaction of dimethyl sulfonyldiacetate with heteroaromatic aldehydes and methylamine. The configuration and conformation of these compounds are studied by ¹H-NMR spectra. The substituents at C-2, -3, -5 and -6 have the relative configuration 2,6/3,5-cis, 2,3/5,6-trans.     

CXCR2 modulators: a patent review (2009 – 2013)

Introduction: Small-molecule antagonists of CXC chemokine receptor 2 (CXCR2) have attracted a considerable amount of attention due to the key central role that this receptor plays in inflammatory conditions. Recently, several CXCR2 receptor antagonists have demonstrated promising proof of activity in early pulmonary clinical trials, which has stimulated additional efforts to identify new CXCR2 receptor antagonists.

Areas covered: During the period 2009 – 2013, there were numerous patent publications from various companies claiming the discovery of novel CXCR2 receptor antagonists. Herein, an interpretation of these new patent publications combined with emerging disclosures from the peer-reviewed literature during this time frame is given. This review highlights the preferred or representative compounds from the patent applications along with relevant biological characterization.

Expert opinion: Many of the new CXCR2 receptor antagonists described in this review represent closely related analogs to previously disclosed clinical candidates. With the recent discontinuation of several CXCR2 receptor antagonists in the clinic, additional clinical trial information for CXCR2 receptor antagonists, both past and present, will determine the long-term therapeutic potential of these compounds for the treatment of a variety of inflammatory disorders.     

Herstellung und Eigenschaften von β-Ketopropansultonen und -sultamen

Synthesis and Properties of p-Oxopropanesultones and -sultames The 1,2-oxathiolan-4-one 2,2-dioxides 5 and the isothiazolidin-4-one 1,1-dioxides 6 were prepared by ester condensation. All compounds show pK_a, values around 4. The stability against alkali, especially of the sultones 5, is remarkable.     

Synthesis and Neuropeptide Y Y1 Receptor Antagonistic Activity of N,N-Disubstituted ω-Guanidino- and ω-Aminoalkanoic Acid Amides

Potent arpromidine-type histamine H₂ receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y₁ receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted ω-guanidino and ω-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr³⁶ in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y₁ antagonists in human erythroleukemia (HEL) cells (Ca²⁺ assay) achieving pKB values in the range of 6.3–6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H₂ receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y₁ antagonists than the ethylene homologs. Concerning the spacer in the ω-amino or ω-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the corresponding strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.     

Synthesis of 2-substituted-6,8-dichloro-3,4-dihydro-3-oxo-2H-1,4-benzothiazine-1,1-d ioxides and -1-oxides as glycine-NMDA receptor antagonists

A number of 2-substituted-3,4-dihydro-3-oxo-6,8-dichloro-2H-1, 4-benzothiazine-1,1-dioxides (1-2a-b) and -1-oxides (3-4a-b) bioisosters of RPR 104632 in which the 3-carboxylic group was replaced by a carbonyl group were synthesized. Comparative in vitro pharmacological studies on this series of RPR 104632 analogs were performed using receptor binding assays. None of these compounds showed detectable binding affinity for the glycine-NMDA receptor.     

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, pK_i = 7.09), 9b1 (hH₃R, pK_i = 6.78), 9b5 (hH₃R, pK_i = 6.99), and 9b6 (hH₃R, pK_i = 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).     

The effect of three H2 receptor antagonists on the disposition of cyclosporin a in the in situ perfused rat liver model

The in situ, perfused rat liver model was used to investigate the effect of three H₂ receptor antagonists on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H₂-receptor antagonist-treated groups) of male Sprague-Dawley rats (300–350 g). All animals received CyA, 2.5 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg), or famotidine (0.4 mg). Perfusated and bile samples were collected and assayed for CyA, AM1, and the H₂ receptor antagonists by HPLC. Results indicated that CyA perfusate concentrations in the controls and cimetidine and ranitidine-treated groups were not significantly different, although levels in the famotidine group were significantly higher at all times (p<0.05), except 30 min, compared to the controls. However, examination of the AM1 perfusate and bile data and the apparent metabolic clearance data indicated that CyA metabolism was still occurring, despite the presence of the H₂ receptor antagonist. It is suggested that the absence of a interaction may be attributed to a lack of specificity of the H₂ receptor antagonists for CYP3A, the isoenzyme responsible for CyA metabolism.     

Evaluation of WO 2012/177618 A1 and US-2014/0179750 A1: novel small molecule antagonists of prostaglandin-E2 receptor EP2

Recent studies underscore that prostaglandin-E₂ exerts mostly proinflammatory effects in chronic CNS and peripheral disease models, mainly through a specific prostanoid receptor EP2. However, very few highly characterized EP2 receptor antagonists have been reported until recently, when Pfizer and Emory University published two distinct classes of EP2 antagonists with good potency, selectivity and pharmacokinetics. The purpose of this article is to evaluate recently published patents WO 2012/177618 A1 and US-2014/0179750 A1 from Emory, which describe a number of cinnamic amide- and amide-derivatives as a potent antagonists of EP2 receptor, and their neuroprotective effects in in vitro and in an in vivo model. A selected compound from this patent(s) also attenuates prostate cancer cell growth and invasion in vitro, suggesting these compounds should be developed for therapeutic use.     

Evaluation of 2‐benzylidene‐1‐tetralone derivatives as antagonists of A1 and A2A adenosine receptors

Antagonists of the adenosine receptors (A₁ and A_2A) are thought to be beneficial in neurological disorders, such as Alzheimer's and Parkinson's disease. The aim of this study was to explore 2‐benzylidene‐1‐tetralone derivatives as antagonists of A₁ and/or A_2A adenosine receptors. In general, the test compounds were found to be selective for the A₁ adenosine receptor, with only three test compounds possessing affinity for both the A₁ and A_2A adenosine receptor. The 2‐benzylidene‐1‐tetralones bearing a hydroxyl substituent at either position C5, C6 or C7 of ring A displayed favourable adenosine A₁ receptor binding, while C5 hydroxy substitution led to favourable A_2A adenosine receptor affinity. Interestingly, para‐hydroxy substitution on ring B in combination with ring A bearing a hydroxy at position C6 or C7 provided the 2‐benzylidene‐1‐tetralones with both A₁ and A_2A adenosine receptor affinity. Compounds 4 and 8 displayed the highest A₁ and A_2A adenosine receptor affinity with values below 7 μm . Both these compounds behaved as A₁ adenosine receptor antagonists in the performed GTP shift assays. In conclusion, the 2‐benzylidene‐1‐tetralone derivatives can be considered as lead compounds to design a new class of dual acting adenosine A₁/A_2A receptor antagonists that may have potential in treating both dementia and locomotor deficits in Parkinson's disease.     

Synthesis and Pharmacology of Combined Histamine H1-/H2-Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

The classical histamine H₁-receptor antagonists diphenhydramine ( 3a ) and cyproheptadine ( 9 ) and their derivatives ( 3b—d, 10 ) were connected with a 2-guanidinothiazole containing structure ( 28 ) derived from the H₂-receptor antagonist tiotidine in order to obtain combined H₁-/H₂-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H₁- and H₂-receptor antagonist activity at the isolated guinea-pig ileum (H₁) and the isolated guinea-pig right atrium (H₂), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H₁-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative ( 30–32, 34 ), however, cause a decrease of H₂-receptor antagonist potency compared to the diphenhydramines ( 29a—d, 33a—d ). Using nitroethenediamine as the polar group is apparently more favourable to H₁- and H₂-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H₁-receptor antagonist moiety ( 29c, d ) display the most potent H₁- and H₂-receptor antagonist effects. The presented concept is a very promising way to combine H₁- and H₂-receptor antagonist properties in one molecule.     

Syntheses and gastric acid antisecretory properties of the H2-receptor antagonist. N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d]isot hiazol-3-amine 1,1-dioxide and related derivatives

The synthesis and gastric acid antisecretory properties of several N-substituted thieno[3,4-d]isothiazol-3-amine 1,1-dioxides and analogues are described. Two of the more potent compounds, N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d] isothiazol-3-amine 1,1-dioxide (6a) and N-[4-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno[3,4-d] isothiazol-3-amine 1,1-dioxide, showed greater potencies as H2-receptor antagonists (in vitro) than ranitidine. They also had potent gastric acid antisecretory activities in vivo, inhibiting basal acid secretion in the rat, histamine-stimulated acid secretion in the dog, and food-stimulated acid secretion in the dog. These were selected for further pharmacological evaluation.     

Azines and Diazines as Potential Histamine H3-Receptor Antagonists

In search of structure-activity relationships among histamine H₃-receptor antagonists the imidazole ring of known H₃-receptor antagonists was replaced by different heteroaromatic ring systems. Thus, azines and diazines with ether ( 6 – 13 ) and carbamate ( 15 – 24 ) moieties as functional groups were synthesized. The obtained compounds did not show significant H₃-receptor antagonist activity in vitro (rat brain cortex) or in vivo (mice brain). The new compounds were also screened for H₁-receptor antagonist activity on the isolated guinea-pig ileum and for H₂-receptor antagonist activity on the isolated spontaneously beating guinea-pig right atrium. The substances showed only weak antagonistic activity at both histamine receptors, H₁ and H₂.     

Design,Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

A series of novel 1,8‐naphthyridine‐3‐carboxamides as 5‐HT₃ receptor antagonists were synthesized with an intention to explore the antidepressant activity of these compounds. The title carboxamides were designed using ligand‐based approach keeping in consideration the structural requirement of the pharmacophore of 5‐HT₃ receptor antagonists. The compounds were synthesized using appropriate synthetic route from the starting material nicotinamide. 5‐HT₃ receptor antagonism of all the compounds, which was denoted in the form of pA₂ value, was determined in longitudinal muscle myenteric plexus preparation from guinea‐pig ileum against 5‐HT₃ agonist, 2‐methyl‐5‐HT. Compound 8g (2‐methoxy‐1, 8‐naphthyridin‐3‐yl) (2‐methoxy phenyl piperazine‐1‐yl) methanone was identified as the most active compound, which expressed a pA₂ value of 7.67. The antidepressant activity of all the compounds was examined in mice model of forced swim test (FST); importantly, none of the compounds was found to cause any significant changes in the locomotor activity of mice at the tested dose levels. In FST, the compounds with considerably higher pA₂ value exhibited promising antidepressant‐like activity, whereas compounds with lower pA₂ value did not show antidepressant‐like activity as compared to the control group.