Kynuramines represent their own class of biogenic amines. They are formed either by decarboxylation of kynurenines or pyrrole ring cleavage of indoleamines. N(2)-formylated compounds formed in this last reaction can be deformylated either enzymatically by arylamine formamidases or hemoperoxidases, or photochemically. The earlier literature mainly focussed on cardiovascular effects of kynuramine, 5-hydroxykynuramine and their N(1),N(1)-dimethylated analogs, including indirect effects via release of catecholamines or acetylcholine and interference with serotonin receptors. After the discovery of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) and N(1)-acetyl-5-methoxykynuramine (AMK) as major brain metabolites of melatonin, these compounds became of particular interest. They were shown to be produced enzymatically, pseudoenzymatically, by various free radical-mediated and via photochemical processes. In recent years, AFMK and AMK were shown to scavenge reactive oxygen and nitrogen species, thereby forming several newly discovered 3-indolinone, cinnolinone and quinazoline compounds, and to protect tissues from damage by reactive intermediates in various models. AMK is of special interest due to its properties as a potent cyclooxygenase inhibitor, NO scavenger forming a stable nitrosation product, inhibitor and/or downregulator of neuronal and inducible NO synthases, and a mitochondrial metabolism modulator. AMK easily interacts with aromates, forms adducts with tyrosyl and tryptophanyl residues, and may modify proteins.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.2009.00701.x

Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines

5-HT3 receptors.

The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as angiogenesis, cancer, atherosclerosis, diabetic retinopathy or autoimmune diseases, in mammals.

Novel angiogenesis inhibitors

Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure–biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.

Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications.

The ligand binding modes of a series of fentanyl derivatives are examined using a combination of conformational analysis and molecular docking to the μ-opioid receptor. Condensed-phase molecular dynamics simulations are applied to evaluate potential relationships between ligand conformation and fentanyl substitution and to generate probable “bioactive” structures for the ligand series. Automated docking of the largely populated solution conformers identified a common binding site orientation that places the N-phenethyl group of fentanyl deep in a crevice between transmembrane (TM) helices II and III while the N-phenylpropanamide group projected toward a pocket formed by TM-III, -VI, and -VII domains. An analysis of the binding modes indicates the most potent fentanyl derivatives adopt an extended conformation both in solution and in the bound state, suggesting binding affinity may depend on the conformational preferences of the ligands. The results are consistent with ligand binding data derived from chim...

Molecular Docking Reveals a Novel Binding Site Model for Fentanyl at the μ-Opioid Receptor

Cyclische Analoga des Fentanyls wurden dargestellt und pharmakologisch untersucht. Durch Verknupfung der Acyl-Seitenkette mit C-2 des Aromaten und der damit verbundenen Anderung der stereochemischen Struktur geht die analgetische Wirkung des Fentanyls verloren, jedoch besitzen die Verbindungen starke antihistiaminische Eigenschaften.



Synthesis and Pharmacological Activities of Cyclic Analogues of Fentanyl.



Cyclic analogues of fentanyl were synthesized and pharmacologically tested. Cyclisation of the acyl group with C-2 of the aromatic ring yielded a change in stereochemical structure. Therefore the analgesic activity of fentanyl was lost and strong antihistaminic activities appeared.

Potentielle Analgetika, 5. Mitt.: Über die Synthese und pharmakologische Wirkung cyclischer Analoga des Fentanyls

Nach reduktiver N-Alkylierung von 2-Amino-phenylessigsaureamid und 2-Amino-hydrozimt-saureamid mit N-substituierten Piperidonen-(4) konnten durch anschliesende interne Cyclisierung 1-(Piperidinyl-4)-indolinone-(2) und 1-(Piperidinyl-4)-3,4-dihydrocarbostyrile dargestellt werden.



Synthesis of 1-(Piperidinyl-4)-indolinones-(2) and -3,4-dihydrocarbostyriles



Reductive alkylation of 2-amino-phenylacetamide and 2-amino-phenylpropionamide with N-substituted piperidones-(4) gave by following internal cyclisation 1-(piperidinyl-4)-indolinones-(2) and 1-(piperidinyl-4)-3,4-dihydrocarbostyriles.

Darstellung von 1‐(Piperidinyl‐4)‐indolinonen‐(2) und ‐3,4‐dihydrocarbostyrilen 3. Mitt.: Über potentielle Analgetika

Das bei der Mannich-Reaktion von o-Carbathoxyamino-acetophenon mit Paraformaldehyd und Dimethylamin-hydrochlorid erhaltene Kondensationsprodukt wurde als ein Gemisch von o-Carbathoxyamino-β-dimethylamino-propiophenon und o-Carbathoxyamino-α-dimethylaminomethyl-acrylophenon identifiziert. Durch Variation der Versuchsbedingungen konnte das Acrylophenonderivat als Hauptprodukt erhalten werden. Es war durch Saurekatalyse in 1-N-Carbathoxy-3-dimethylaminomethyl-4-oxo-1,2,3,4-tetrahydrochinolin uberfuhrbar.



Synthesis of o-Acylamino-β-dimethylamino-propiophenones



The aminomethylation product of o-carbethoxyamino-acetophenone, paraformaldehyde and dimethylamine-hydrochloride was identified as a mixture of o-carbethoxyamino-β-dimethylamino-propiophenone and o-carbethoxyamino-α-dimethylaminomethyl-acrylophenone. Variations of test conditions yielded the acrylophenone derivative as main product. By acid catalysis it was possible to convert this product into 1-N-carbethoxy-3-dimethylaminomethyl-4-oxo-1,2,3,4-tetrahydroquinoline.

Über die Synthese von o-Acylamino-ß-dimethylamino-propiophenonen 1. Mitt.: Verhalten von o-Nitro- und o-Carbäthoxyamino-acetophenon bei der Mannich-Reaktion

Der von Makino und Takahashi sowie Joh als 2-Nitro-5-methoxy-β-dimethylamino-propiophenon bezeichnete Korper wurde als 2-Nitro-5-methoxy-α-dimethylaminomethyl-acrylophenon identifiziert. Nach einer fruher beschriebenen Methode zur Darstellung von 2-Nitro-β-dimethylamino-propiophenon war es moglich, 2-Nitro-5-methoxy- und 2-Nitro-5-benzyloxy-acetophenon normal zu aminomethylieren. –Die Synthese von 2-Amino-5-methoxy-, 2-Amino-5-benzyloxy- und 2-Amino-5-hydroxy-β-dimethylamino-propiophenon sowie ihrer Acetylderivate wird beschrieben.



Synthesis of o-Acylamino-β-dimethylamino-propiophenones



The compound synthetized by Makino and Takahashi and by Joh described as 2-nitro-5-methoxy-β-dimethylamino-propiophenone, was identified as 2-nitro-5-methoxy-α-dimethylaminomethyl-acrylophenone. By a method previously described for the synthesis of 2-nitro-β-dimethylami-no-propiophenone, the normal aminomethylation of 2-nitro-5-methoxy- and 2-nitro-5-benzyloxy-acetophenone was possible. – The synthesis of 2-amino-5-methoxy-, 2-amino-5-benzyloxy-and 2-amino-5-hydroxy-β-dimethylamino-propiophenone and their acetyl derivatives is described.

Über die Synthese von o-Acylamino-β-dimethylaminopropiophenonen Mitt.: Aminomethylierung von 2-Nitro-5-methoxy-und 2-Nitro-5-benzyloxyacetophenon

Die bei der Mannich-Reaktion mit o-Carbathoxyamino- und o-Nitro-acetophenon zu Acrylophenonderivaten fuhrende Sekundarreaktion zwischen den Aminomethylierungsprodukten und Formaldehyd konnte auf folgende Weise nahezu vollstandig vermieden werden: durch Verhindern des Zerfalls von intermediar entstehendem Dimethylaminomethylol in seine Komponenten wird die Bildung des Carbonium-Imonium-Kations derart beschleunigt, das fur die Nebenreaktion erforderlicher freier Formaldehyd rasch aus dem Reaktionsmedium verschwindet. — Die Synthese von o-Carbathoxyamino-, o-Nitro- und o-Amino-β-dimethylamino-propiophenon sowie seines Formyl- und Acetylderivates wird beschrieben.



Synthesis of o-Acylamino-β-dimethylamino-propiophenones



The reaction between formaldehyde and aminomethylation products of o-carbethoxyamino-and o-nitro-acetophenone leading to acrylophenone derivatives could be avoided in the following way: by blocking the decomposition of the intermediary resulting dimethylaminomethylol in its components, the formation of the carbonium-imonium-cation was accelerated and free formaldehyde necessary for the reaction was quickly eliminated from the reaction mixture. — The synthesis of o-carbethoxyamino-, o-nitro- and o-amino-β-dimethylamino-propiophenone and its formyl and acetyl derivatives is described.

W. Back

Papers

Potentielle Analgetika, 5. Mitt.: Über die Synthese und pharmakologische Wirkung cyclischer Analoga des Fentanyls

Darstellung von 1‐(Piperidinyl‐4)‐indolinonen‐(2) und ‐3,4‐dihydrocarbostyrilen 3. Mitt.: Über potentielle Analgetika

Über die Synthese von o-Acylamino-ß-dimethylamino-propiophenonen 1. Mitt.: Verhalten von o-Nitro- und o-Carbäthoxyamino-acetophenon bei der Mannich-Reaktion

Über die Synthese von o-Acylamino-β-dimethylaminopropiophenonen Mitt.: Aminomethylierung von 2-Nitro-5-methoxy-und 2-Nitro-5-benzyloxyacetophenon

Über die Synthese von o‐Acylamino‐β‐dimethylamino‐propiophenonen 2. Mitt.: Aminomethylierung von o‐Carbäthoxyamino‐ und o‐Nitro‐acetophenon1)