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Lisuride, terguride and derivatives thereof for use in the prophylaxis and/or treatment of fibrotic changes

一种特麦角脲、麦角乙脲的技术，应用在麦角乙脲,特麦角脲和通式（I）的衍生物领域，能够解决大副作用、临床表现恶化等问题，达到预期寿命延长的效果

Inactive Publication Date: 2013-12-25
ZINOXA PHARMA UG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Importantly, the aforementioned pulmonary vasodilators even worsen the clinical picture quite often [Ulrich-Somaini, S., 2009]
All these products so far used for symptomatic treatment also have considerable side effects in some cases

Method used

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  • Lisuride, terguride and derivatives thereof for use in the prophylaxis and/or treatment of fibrotic changes
  • Lisuride, terguride and derivatives thereof for use in the prophylaxis and/or treatment of fibrotic changes
  • Lisuride, terguride and derivatives thereof for use in the prophylaxis and/or treatment of fibrotic changes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] pharmacological properties

[0130] 1.A. 5-HT of lisuride and terguride 2B Antagonism

[0131] by 5-HT 2B The trophic effects of serotonin, mediated by signal transduction, have been detected in many cell types, mainly fibroblasts. They are responsible for excessive vascular remodeling processes and organ remodeling. Organ remodeling has been demonstrated as a direct or indirect activation of 5-HT via active metabolites for a variety of compounds associated with the triggering of pathological heart valve changes and pulmonary hypertension 2B occurs as a consequence of the receptor. These compounds include pergolide, cabergoline, fenfluramine (via the active metabolite methylergometrine), MDA and MDMA (ecstasy), bromocriptine, methysergide (via the active metabolite ergonovine) and ergotamine. Among ergoline compounds, the 5-HT 2B The determinant of the agonism of the receptor appears to be the β-orientation of the 8-substituent.

[0132] 1.B. 5-HT of lisuride an...

Embodiment 2

[0140] Antiproliferative effects of lisuride and terguride

[0141] Propagate mesenchymal-derived human smooth muscle cells (Promo cells) in 6 plates containing Promo cell medium until a tight monolayer forms, following the manufacturer's recommendations, and then plate 5x10 4 Cells per batch were seeded in the same medium on 24-well plates. Then by adding 10 -8 mol / l of 5-HT to stimulate cell growth. To determine cell growth, 3H-thymidine (Amersham) was subsequently added to the cell cultures and the cell cultures were incubated for 24 hours. After cell attachment, the medium was replaced with standard medium containing 0.2% fetal calf serum to stop growth and incubated again for 48 hours.

[0142] Then, to test the antiproliferative effect of the substances described, the cell cultures were firstly preincubated at a test substance concentration of 10 μmol / l. Then by adding 5-HT to the highest final concentration of 10 -8 mol / l to stimulate cell growth. To measure cell ...

Embodiment 3

[0147] pulmonary hypertension

[0148] The role of lisuride and terguride in monocrotaline-induced pulmonary hypertension was studied in rats [Reiter, R. et al., 2007]. Monocrotaline (MCT), a toxin derived from the plant of the species Lilium monocrota, damages the endothelial cells of the pulmonary arteries after a single injection in rats, subsequently causing vascular smooth muscle hypertrophy and permanent severe pulmonary hypertension. MCT-induced pulmonary hypertension in the rat is a well-established and validated model of human pulmonary hypertension, and all currently approved therapeutic agents have shown effects in this model, at least when they are used prior to toxicity-induced tissue remodeling.

[0149] MCT (60 mg / kg) was administered subcutaneously as a single injection into male Sprague-Dawley rats, and the same volume of isotonic saline solution was injected into control animals. On days 14-28 of the experiment, 0.25 mg / kg lisuride or 2.5 mg / kg terguride wer...

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Abstract

The present invention relates to the use of 5-HT2 receptor antagonists and in particular of 8-alpha-ergolines such as lisuride, terguride and the derivatives thereof as 5-HT2B and 5-HT2A receptor antagonists and antioxidants in preferably higher-dosed and preferably continuous use for the treatment, progression prophylaxis and general prophylaxis of organ fibroses and other pathological organ remodeling caused by mesenchymal proliferation.

Description

technical field [0001] Subject of the present invention are lisuride, terguride and derivatives of general formula (I) [0002] [0003] R 1 : Allyl, alkinyl (alkinyl) [0004] R 2 : Ethyl, n-propyl, isopropyl, allyl [0005] R 3 : hydrogen, methyl, ethyl, n-propyl, isopropyl, -CH 2 Oh [0006] Wherein the bond between C9 / C10 is a single bond or a double bond, [0007] It is used for preventing and / or treating fibrotic lesions in organs and their vascular structures in humans or animals to prevent and / or reverse these fibrotic lesions in organs and their vascular structures. Furthermore, the subject-matter of the invention is also pharmaceutical formulations and special applications, combinations with additional active ingredients and pharmaceutical formulations in combination with additional active ingredients. Background technique [0008] There is a spectrum of diseases in which pathological fibrotic and sclerotic lesions in organs and organ systems are caused ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/19A61K31/48A61K9/00A61K9/70A61P9/12
CPCA61K9/0024A61K9/19A61K9/7061A61K31/48A61K45/06A61K9/0019A61K31/437C07D457/12A61P19/04A61P9/12A61K2300/00
Inventor 莱茵哈德·霍洛维斯基海因茨·帕拉约翰内斯·塔克
Owner ZINOXA PHARMA UG
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