Johannes-Peter Stasch

Martin Luther University Halle-Wittenberg, Halle-on-the-Saale, Saxony-Anhalt, Germany

Are you Johannes-Peter Stasch?

Claim your profile

Publications (63)

  • [Show abstract] [Hide abstract] ABSTRACT: The application relates to novel substituted annulated pyrimidines of formula I, to methods for the prodn. thereof, to the use thereof alone or in combination for the treatment and/or prophylaxis of diseases, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular diseases. Compds. of formula I wherein ring Q is 5- to 6-membered monocyclic heteroaryl and 8- to 9-membered bicyclic heteroaryl; L is CR5aR5b(CR6aR6b)0-2; R5a is H, F, OH, etc.; R5b is H, F, CN, etc.; R6a is H, F, OH, etc.; R6b is H, F, CF3, etc.; R1 is H, halo, (un)substituted C3-7 cycloalkyl, etc.; R2 is CF3, C1-6 alkyl, Ph, etc.; R3 is H, C1-4 alkyl, (un)substituted C3-8 cycloalkyl; R4 is H, (un)substituted C1-10 alkyl, (un)substituted C3-8 cycloalkyl, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. II was prepd. by amidation of 2-[1-(2-fluorobenzyl)-1H-pyr
    Patent · Mar 2016
  • [Show abstract] [Hide abstract] ABSTRACT: The application relates to novel amino-substituted annulated pyrimidines of formula I, to methods for the prodn. thereof, to the use thereof alone or in combination for the treatment and/or prophylaxis of diseases, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular diseases. Compds. of formula I wherein A is N and C; R1 is substituted Ph, substituted pyridyl, trifluoropropyl, etc.; R2 is H and C1-4 alkyl; R3 is substituted C1-6 alkyl; R4 and R5 are independently substituted C1-4 alkyl; R6 is H; R7 is H and F; R8 is H, Cl, F, etc.; and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. II was prepd. by amidation of 2-[5-fluoro-6-methyl-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one with 3-fluoro-2-(fluoromethyl)propan-1,2-diamine. The invention com
    Patent · Mar 2016
  • [Show abstract] [Hide abstract] ABSTRACT: The invention relates to novel substituted quinoline-4-carboxamides of formula I and II, to methods for their prodn., their use alone or in combination for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, esp. for the treatment and/or prophylaxis of cardiovascular diseases. Compds. of formula I and II wherein A is CH2, CD2, CHCH3; R1 is (un)substituted C3-7 cycloalkyl, (un)substituted Ph, (un)substituted pyridyl, etc.; R2 is H, C1-4 alkyl, cyclopropyl, difluoromethyl, etc.; R3 is H, halo, C1-4 alkyl, etc. R4 is H and C1-4 alkyl; R5 is substituted C1-4 alkanediyl, substituted propanediamino, substituted (methylamino)ethanol, etc.; R6 is H; R7 is H, halo, CN, etc.; R8 is H, CN and halo; and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. III was prepd. by amidation of 8-[(2,6-difluorobenzyl)oxy]chinolin-4-carboxylic acid with 1-(3,4-difluorphenyl)cycl
    Patent · Feb 2016
  • Daniela Fliegner · Christoph Gerdes · Jörg Meding · Johannes-Peter Stasch
    [Show abstract] [Hide abstract] ABSTRACT: Cardiovascular diseases are still the first leading cause of death and morbidity in developed countries. Experimental cardiology research and preclinical drug development in cardiology call for appropriate and especially clinically relevant in vitro and in vivo studies. The use of animal models has contributed to expand our knowledge and our understanding of the underlying mechanisms and accordingly provided new approaches focused on the improvement of diagnostic and treatment strategies of various cardiac pathologies. Numerous animal models in different species as well as in small and large animals have been developed to address cardiovascular complications, including heart failure, pulmonary hypertension, and thrombotic diseases. However, a perfect model of heart failure or other indications that reproduces every aspect of the natural disease does not exist. The complexity and heterogeneity of cardiac diseases plus the influence of genetic and environmental factors limit to mirror a particular disease with a single experimental model. Thus, drug development in the field of cardiology is not only very challenging but also inspiring; therefore animal models should be selected that reflect as best as possible the disease being investigated. Given the wide range of animal models, reflecting critical features of the human pathophysiology available nowadays increases the likelihood of the translation to the patients. Furthermore, this knowledge and the increase of the predictive value of preclinical models help us to find more efficient and reliable solutions as well as better and innovative treatment strategies for cardiovascular diseases.
    Article · Nov 2015 · Handbook of experimental pharmacology
  • Alexandros Vakalopoulos · Markus Follmann · Johannes-Peter Stasch · [...] · Volkhart Min-Jian. Li
    [Show abstract] [Hide abstract] ABSTRACT: The invention relates to 6-chloro-substituted imidazo[1,2-a]pyridino-3-carboxamides, to methods for their prodn., their use alone or in combination for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, esp. for the treatment and/or prophylaxis of cardiovascular diseases. Example compd. I was prepd. by amidation of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridin-3-carboxylic acid with 4-fluoro-2-methylbutan-1,2-diamine dihydrochloride. The invention compds. were evaluated for their guanylate cyclase stimulatory activity. From the assay, it was detd. that example compd. I exhibited MEC value of 0.1 μM. [on SciFinder(R)]
    Patent · Nov 2015
  • Alexandros Vakalopoulos · Markus Follmann · Johannes-Peter Stasch · [...] · Volkhart Min-Jian. Li
    [Show abstract] [Hide abstract] ABSTRACT: The invention relates to novel substituted imidazo[1,2-a]pyridino-3-carboxamides to methods for their prodn., their use alone or in combination for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, esp. for the treatment and/or prophylaxis of cardiovascular diseases. Example compd. trans-I was prepd. by Cbz-deprotection of trifluoracetate salt of trans-benzyl-{1-[({6-bromo-2-methyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-5,5,5-trifluoro-2-methylpentan-2-yl}carbamate. The invention compds. were evaluated for their guanylate cyclase stimulatory activity. From the assay, it was detd. that example compd. I exhibited MEC value of 0.09 μM. [on SciFinder(R)]
    Patent · Nov 2015
  • [Show abstract] [Hide abstract] ABSTRACT: The invention relates to novel substituted imidazo[1,2-a]pyridino-3-carboxamides of formula I, to methods for their prodn., their use alone or in combination for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, esp. for the treatment and/or prophylaxis of cardiovascular diseases. Compds. of formula I wherein A is CH2, CD2, CHCH3; R1 is (un)substituted C3-7 cycloalkyl, (un)substituted Ph, (un)substituted pyridyl, etc.; R2 is H, C1-4 alkyl, cyclopropyl, difluoromethyl, etc.; R3 is substituted NHC1-4 alkenediyl, substituted propanediamino, substituted (methylamino)ethanol, etc.; R4 is H; R5 is H, halo, CN, etc.; R6 is H; and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. II was prepd. by Boc-deprotection of {1-[({8-[(2,6-difluorobenzyl)oxy]-2-methyl-6-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl}carbonyl)amino]-2-methylbutan-2-yl}carbamic acid tert-Bu est
    Patent · Nov 2015
  • [Show abstract] [Hide abstract] ABSTRACT: The invention relates to novel substituted imidazo[1,2-a]pyridines of formula I, to methods for their prodn., their use alone or in combination for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, esp. for the treatment and/or prophylaxis of cardiovascular diseases. Compds. of formula I wherein A is CH2, CD2, CHCH3; R1 is (un)substituted C3-7 cycloalkyl, (un)substituted Ph, (un)substituted pyridyl, etc.; R2 is C1-4 alkyl, cyclopropyl, difluoromethyl, etc.; R3 is substituted pyridinonyl and substituted pyrimidinyl, substituted pyrimidinonyl; R4 is H; R5 is H, halo, CN, etc.; R6 is H and halo; and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. II was prepd. by redn. of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethyl-3-{6-[(2-nitropropan-2-yl)oxy]pyridin-3-yl}imidazo[1,2-a]pyridine. The invention compds. were evaluated for their guanylate cyclase stimulator
    Patent · Nov 2015
  • [Show abstract] [Hide abstract] ABSTRACT: In cardiovascular diseases, reduced responsiveness of soluble guanylate cyclase (sGC) to nitric oxide (NO) upon long-term application has led to the development of NO-independent sGC stimulators (heme-dependent) and sGC activators (heme-independent). Any direct inotropic or lusitropic effects of these compounds on isolated cardiac myocytes, however, remain to be elucidated. Here, we analyzed the dose-dependent effects of clinical relevant concentrations (10(-10)-10(-5)M) of the sGC activator cinaciguat and the sGC stimulator riociguat on the contraction, relaxation, and calcium transients of isolated field-stimulated cardiac myocytes from healthy rats. For comparison, we used isoproterenol, which induced a dose-dependent significant increase in cell contractility, relaxation, and calcium transients, verapamil that significantly decreased these parameters (both at 10(-9)-10(-5)M) and 8-(4-Chlorophenylthio)-guanosine3',5'-cyclic monophosphate (8-pCPT-cGMP) that induced a negative inotropic effect at 10(-5)M accompanied by a slight increase in relaxation. In contrast, neither cinaciguat nor riociguat significantly influenced any measured parameters. Furthermore, isoproterenol significantly increased intracellular cAMP levels that were not influenced by cinaciguat or riociguat (all at 10(-6)M). Otherwise, riociguat and cinaciguat (both at 10(-6)M) significantly enhanced intracellular cGMP generation. This accumulation was significantly augmented by cinaciguat in the presence of the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 25µM), whereas ODQ blocked cGMP generation by riociguat. However, blocking of sGC did not influence cell contractility. Our results demonstrate that, in isolated cardiac myocytes from healthy rats, the increase in cGMP levels induced by cinaciguat and riociguat at clinical relevant concentrations is not associated with acute direct effects on cell contraction and relaxation.
    Article · Sep 2015 · European journal of pharmacology
  • [Show abstract] [Hide abstract] ABSTRACT: The invention relates to substituted imidazo[1,2-a]pyridino-3-carboxamides of formula I, to processes for prepg. them and to their use in the treatment and/or prophylaxis of diseases, more particularly in the treatment and/or prophylaxis of cardiovascular diseases. Compds. of formula I wherein A is CH2, CD2, CHCH3; R1 is C1-4 alkyl, (un)substituted C3-7 cycloalkyl, (un)substituted Ph and (un)substituted pyridyl; R2 is H, C1-4 alkyl, cyclopropyl, difluoromethyl, etc.; R3 is substituted 3- to 7-membered carbocyclyl, substituted 4- to 7-membered heterocyclyl, substituted Ph, etc.; R4 is H; R5 is H, halo, CN, etc.; R6 is H, CN and halo; and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. II was prepd. by amidation of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridin-3-carboxylic acid with 2-aminopropanonitrile hydrochloride. The invention compds. were evaluated for their guanylate cyclase stimulatory activity. From the assay
    Patent · Sep 2015
  • Source
    Full-text Article · Sep 2015 · BMC pharmacology & toxicology
  • [Show abstract] [Hide abstract] ABSTRACT: The title compds. I [A = CH2, CD2, CH(Me); R1 = (un)substituted alkyl, cycloalkyl, Ph; R2 = H, alkyl, alkoxyalkyl, cyclopropyl, CH2F, CHF2 or CF3; R3 = H; R4 = H, halo, CN, ethynyl, etc.; R5 = H; E = N or CR6 (wherein R6 = H, D, halo, CN, CHF2, etc.); L = CR13aR13b(CR14aR14b)m (m = 0-2; R13a = H, CF3, alkyl; R13b = H, CHF2, CF3, (un)substituted alkyl, cycloalkyl; or R13a and R13b, together with the carbon atom to which they are attached, form a 3-6 membered carbocycle); R14a = H, F, alkyl, OH; R14b = H, F, alkyl, CF3], useful alone or in combinations for treating and/or preventing diseases, in particular for treating and/or preventing cardiovascular diseases, were prepd. and formulated. E.g., a multi-step synthesis of II, starting from 2-amino-3-hydroxypyridine and 2,6-difluorobenzyl bromide, was described. Exemplified compds. I were evaluated in various biol. tests (data given for representative compds. I). [on SciFinder(R)]
    Patent · Aug 2015
  • Article · Aug 2015
  • Source
    Johannes-Peter Stasch · Jens Schlossmann · Berthold Hocher
    [Show abstract] [Hide abstract] ABSTRACT: Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD). Therefore, new classes of drugs - sGC stimulators and activators - are being investigated in preclinical models under conditions where nitric oxide is deficient. In preclinical models with different etiologies of CKD, the sGC stimulators BAY 41-2272, BAY 41-8543, BAY 60-4552, riociguat and vericiguat and the sGC activators cinaciguat, ataciguat, BI 703704 and GSK2181236A have shown consistently renoprotective effects. Clinical trials are required to confirm these findings in humans, and to ascertain whether these agents could provide a future alternative to guideline-recommended treatments. Copyright © 2015. Published by Elsevier Ltd.
    Full-text Article · Apr 2015 · Current Opinion in Pharmacology
  • [Show abstract] [Hide abstract] ABSTRACT: The invention relates to a new type of substituted imidazo[1,2-a]pyrazine-carboxamides of formula I, to a method for producing same, to the use thereof alone or in combinations for treating and/or preventing diseases and to the use thereof for producing medicaments for treating and/or preventing diseases, in particular for treating and/or preventing cardiovascular diseases. Compds. of formula I wherein A is CH2, CD2, CHCH3; R1 is (un)substituted C3-7 cycloalkyl, (un)substituted Ph, (un)substituted pyridyl, etc.; R2 is H, C1-4 alkyl, cyclopropyl, difluoromethyl, etc.; R3 is substituted methanediyl, substituted ethanediyl, substituted 1,3-propanediyl, etc.; R4 is H; R5 is H, halo, CN, etc.; and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. II was prepd. by amidation of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyrazin-3-carboxylic acid with (2S)-2-hexanamine. The invention compds. were evaluated for their guanylate cyclas
    Patent · Feb 2015
  • [Show abstract] [Hide abstract] ABSTRACT: The invention relates to a new type of substituted pyrazolo[1,5-a]-pyridine-3-carboxamides of formula I, to a method for producing same, to the use thereof alone or in combinations for treating and/or preventing diseases and to the use thereof for producing medicaments for treating and/or preventing diseases, in particular for treating and/or preventing cardiovascular diseases. Compds. of formula I wherein A is CH2, CD2, CHCH3; R1 is (un)substituted C3-7 cycloalkyl, (un)substituted Ph and (un)substituted pyridyl, etc.; R2 is H, C1-4 alkyl, cyclopropyl, difluoromethyl, etc.; R3 is substituted methanediyl, substituted ethanediyl, substituted 1,3-propanediyl, etc.; R4 is H; R5 is H, halo, CN, etc.; R6 is H and halo; and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. II .bul. HCO2H was prepd. by amidation of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-carboxylic acid with 1,2-diamino-2-methylpropane. The invention c
    Patent · Feb 2015
  • [Show abstract] [Hide abstract] ABSTRACT: The invention relates to novel benzyl-1H-pyrazolo[3,4-b]pyridines I [in which R1 is H or F; R2 is H or F, R3 is H, Cl or F; R4 is H, Cl, F or Me; with the proviso that, at least two of R1, R2, R3 and R4 are different form H; R5 is H or F; R6 is Me; R7 is Me; or R6 and R7 together with the carbon to which they are attached forma cyclopropyl ring], as well as their N-oxides, slats, solvates, N-oxide salts and solvates of their N-oxides and salts. Thus, 3-[1-(2,3-Difluorobenzyl)-5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-7,7-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazin-6-one (II) was prepd. from 2-chloro-5-fluoro-6-methylnicotinonitrile via hydrazinolysis to give 5-fluoro-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-amine (III; R' = NH2); one-pot nitrosation then iodination to give III (R' = iodo); N-alkylation with 1-(bromomethyl)-2,3-difluorobenzene to give pyrazolopyridine IV (R'' = iodo); cyanation to give IV (R'' = CN);. Hydrolysis and imination to give IV [R'' = C(:NH)NH2]; hydrazinolysis t
    Patent · Jan 2015
  • [Show abstract] [Hide abstract] ABSTRACT: The invention relates to novel 3-aryl-substituted imidazo[1,2-a]pyridines of formula I, to processes for prepg. them and to their use in the treatment and/or prophylaxis of diseases, more particularly in the treatment and/or prophylaxis of cardiovascular diseases. Compds. of formula I wherein A is CH2, CD2, CHCH3; R1 is (un)substituted C3-7 cycloalkyl, (un)substituted Ph and (un)substituted pyridyl; R2 is C1-4 alkyl, cyclopropyl, difluoromethyl, etc.; R3 is Ph and 5- to 10-membered heteroaryl; R4 is H; R5 is H, halo, CN, etc.; R6 is H and halo; and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts, are claimed. Example compd. II was prepd. by cross-coupling of 3-bromo-8-[(2,6-difluorobenzyl)oxy]-2- methylimidazo[1,2-a]pyridine with 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The invention compds. were evaluated for their guanylate cyclase stimulatory activity. From the assay, it was detd. that example compd. II exhibited IC50 value of 0.
    Patent · Dec 2014
  • Marcel Dautzenberg · Antje Kahnert · Johannes-Peter Stasch · Armin Just
    [Show abstract] [Hide abstract] ABSTRACT: We studied the influence of soluble guanylate (sGC) on renal blood flow (RBF), glomerular filtration rate (GFR), and RBF autoregulation and its role in mediating the hemodynamic effects of endogenous nitric oxide (NO). Arterial pressure (AP), heart rate (HR), RBF, GFR, urine flow (UV), and the efficiency and mechanisms of RBF autoregulation were studied in anesthetized rats during iv. infusion of sGC activator cinaciguat before and (except GFR) also after inhibition of NO-synthase (NOS) by L-NAME. Cinaciguat (0.1, 0.3, 1, 3, 10 µg*kg-1*min-1, n=7) reduced AP and increased HR, but did not significantly alter RBF. In clearance experiments (FITC-sinistrin, n=7) GFR was not significantly altered by cinaciguat (0.1 and 1 µg*kg(-1)*min(-1)), but RBF slightly rose (+12%) and filtration fraction (FF) fell (-23%). RBF autoregulatory efficiency (67 vs. 104%) and myogenic response (33 vs. 44 units) were slightly depressed (n=9). NOS inhibition (n=7) increased AP (+38 mmHg), reduced RBF (-53%), and greatly augmented the myogenic response in RBF autoregulation (97 vs. 35 units) attenuating the other regulatory mechanisms. These changes were reversed by 77%, 78%, and 90% by 1 µg*kg(-1)*min(-1) cinaciguat. In vehicle controls (n=3), in which cinaciguat-induced hypotension was mimicked by aortic compression, the NOS inhibition-induced changes were not affected. We conclude that sGC activation leaves RBF and GFR well maintained despite hypotension and only slightly impairs autoregulation. The ability to largely normalize AP, RBF, RBF autoregulation and renovascular myogenic response after NOS inhibition indicates that these hemodynamic effects of NO are predominantly mediated via sGC.
    Article · Sep 2014 · American journal of physiology. Renal physiology
  • Markus Follmann · Johannes-Peter Stasch · Gorden Redlich · Dieter. Lang
    [Show abstract] [Hide abstract] ABSTRACT: The invention relates to new benzyl-substituted pyrazolopyridines, to processes for prepg. them and to their use in the treatment and/or prophylaxis of diseases, more particularly in the treatment and/or prophylaxis of cardiovascular diseases. Example compd. I was prepd. by a multistep procedure starting with 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-carbonitrile and was sepn. into corresponding enantiomers. The invention compds. were evaluated for their guanylate cyclase stimulatory activity. From the assay, it was detd. that example compds. I-(R) and I-(S) exhibited MEC value of 0.1 μM and 0.3 μM. [on SciFinder(R)]
    Patent · Sep 2014