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WO2013037914A1 - 4,5,6,7-tétrahydro-1h-pyrazolo[4,3-c]pyridines substituées, leur utilisation comme médicament, et préparations pharmaceutiques les contenant - Google Patents

4,5,6,7-tétrahydro-1h-pyrazolo[4,3-c]pyridines substituées, leur utilisation comme médicament, et préparations pharmaceutiques les contenant Download PDF

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Publication number
WO2013037914A1
WO2013037914A1 PCT/EP2012/067995 EP2012067995W WO2013037914A1 WO 2013037914 A1 WO2013037914 A1 WO 2013037914A1 EP 2012067995 W EP2012067995 W EP 2012067995W WO 2013037914 A1 WO2013037914 A1 WO 2013037914A1
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Prior art keywords
alkyl
phenyl
tetrahydro
methyl
pyridin
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Inventor
Laurent Bialy
Katrin Lorenz
Klaus Wirth
Klaus Steinmeyer
Gerhard Hessler
Josef Pernerstorfer
Joachim Brendel
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Sanofi SA
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Sanofi SA
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Priority to EA201490640A priority Critical patent/EA025240B1/ru
Priority to MX2014003181A priority patent/MX2014003181A/es
Priority to BR112014006180A priority patent/BR112014006180A2/pt
Publication of WO2013037914A1 publication Critical patent/WO2013037914A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the invention relates to 4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridine compounds of the formula I,
  • the compounds of formula I act on the TASK-1 (KCNK3) potassium channel.
  • the compounds are suitable for the treatment of several pathologies and are suitable as antiarrhythmic active ingredients, for the treatment and prophylaxis of atrial arrhythmias, for example atrial fibrillation (AF) or atrial flutter.
  • AF atrial fibrillation
  • atrial flutter for example atrial fibrillation (AF) or atrial flutter.
  • Potassium channels are widespread membrane proteins which, owing to their influences on cell membrane potentials, play an important role in many physiological processes.
  • the group of the potassium channels with four transmembrane segments is delimited from the two others in that their representatives each have two pore domains, which is why these channels are also referred to as K 2 p channels (Coetzee W.J. et al; Molecular diversity of K+ channels; Ann. New York Acad. Sci. 1999 (868), 233-285).
  • K 2 p channels are characterized in that the "leak” or “background” currents flow through them, which play an important role for the resting membrane potential and hence the excitability of nerve or muscle cells.
  • a family which is of particular interest among the K 2 p channels is that of the TASK channels (tandem of P domains in a weak inwardly rectifying K + channel, [TWIK]- related acid-sensitive K + channels), which include TASK-1 , TASK-3, and TASK-5 subtype (D.A. Bayliss, P. Barrett, Trends in Pharmacological Sciences, 2008, 29(1 1 ), 566-575).
  • KCNK3 or K2P3.1 TASK-1
  • KCNK9 or K2P9.1 TASK-3
  • KCNK15 or K2P15.1 TASK-5
  • the greatest homology within this family is possessed by the TASK-1 and TASK-3 channels with an amino acid identity of more than 50%. Dimerization of K 2 p channels forms functional potassium channels with a total of four pore units. The streams which flow through these channels are referred to in the literature as IKso stream.
  • heterodimerization of TASK-1 and TASK-3 is also possible in this context (Berg A.
  • Motoneurons express Heteromeric TWIK-related acid-sensitive K+ (TASK) Channels containing TASK-1 (KCNK3) and TASK-3 (KCNK9) subunits; J. Neuroscience 2004 (24), 6693 - 6702).
  • the TASK channels are notable in particular for their very strong dependence upon the extracellular pH in the physiological range (pK ca. 6,5-7,5).
  • the channels are inhibited at acidic pH and activated at alkaline pH. Owing to this pH dependence, the physiological function of a sensor which translates small changes in the extracellular pH to corresponding cellular signals is ascribed to the TASK channels (Duprat F., Lesage F., Fink M., Reyes R., Heurteaux C, Lazdunski M.; TASK, a human background K+ channel to sense external pH variations near physiological pH; EMBO J. 1997 (16), 5464 - 5471 ; Patel A.J., Honore E.; Properties and modulation of mammalian 2P domain K+ channels; Trends Neurosci. 2001 (24), 339 - 346).
  • TASK-1 knock-out mice show a mild phenotype and have been described and appear generally in good health and show normal breeding behaviour (Journal of Neuroscience (2005), 25(49), 1 1455-1 1467).
  • TASK-1 is expressed in the brain and also in spinal ganglia and some peripheral tissues, for example pancreas, placenta, uterus, lung, heart, kidney, small intestine and stomach.
  • TASK-1 has been detected in the chemosensitive cells of the brainstem and of the carotid bodies, and also the motor neurons of the hypoglossal nerve (Medhurst A.D., Rennie G., Chapman C.G., Meadows H., Duckworth M.D., Kelsell R.E., Glober 1.1., Pangalos M.N.; Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery; Mol. Brain Res. 2001 (86), 101 - 1 14).
  • TASK-1 potassium channels have been detected in motor neurons of the hypoglossal nerve, a motor cranial nerve which possesses the most important function for the maintenance and patency of the upper respiratory pathways, and locus coeruleus. It has been found that TASK-1 channels are involved in respiratory regulation in respiratory neurons of the brainstem, in carotid bodies and in motor neurons of the hypoglossal nerve, and also in neuroepithelial cells of the lung.
  • TASK-1 is a highly modulated pH-sensitive 'leak' K+ channel expressed in brainstem respiratory neurons; Respiration Physiology 2001 (129), 159 - 174).
  • An increase in the activity of chemosensitive neurons in conjunction with an activation of the motor neurons of the hypoglossal nerve through blockage of the TASK-1 channel can stimulate respiration and simultaneously stabilize the upper airways to protect them from collapse and occlusion. Moreover, snoring can be inhibited by stabilizing the upper airway via an increase in pharyngeal muscle activity.
  • the blockage of the TASK-1 ion channels is therefore useful in the treatment of respiratory disorders, for example of sleep apnea (Brendel, J.;
  • TASK-1 channels are responsible for programmed cell death (apoptosis) in granulosa cells, and that the cell death can be prevented by blocking the TASK-3.
  • TASK-1 /3 channels can be useful for the treatment of neurodegenerative disorders (Patel A.J., Lazdunski M., The 2P-domain K + channels: role in apoptosis and tumorigenesis, Pflugers Arch. 2004 (448), 261 - 273).
  • TASK-1 is relevant for setting the resting membrane potential and balancing neuronal excitability that is expressed on T cells and neurons, and is a key modulator of T cell immunity and neurodegeneration in autoimmune central nervous system inflammation.
  • TASK1 (-/-) mice showed a significantly reduced clinical severity and markedly reduced axonal degeneration compared with wild-type controls.
  • T cells from TASK1 (-/-) mice displayed impaired T cell proliferation and cytokine production, while the immune repertoire is otherwise normal.
  • TASK1 exhibits an independent neuroprotective effect which was demonstrated using both a model of acutely prepared brain slices cocultured with activated T cells as well as in vitro cultivation experiments with isolated optic nerves.
  • TASK-1 blockers are potent compounds useful for the therapy of inflammatory and degenerative central nervous system disorders (Bittner Stefan; Meuth Sven G; Gobel Kerstin; Melzer Nico; Herrmann Alexander M; Simon Ole J; Weisberger Andreas; Budde Thomas; Bayliss Douglas A; Bendszus Martin; Wiendl Heinz , Brain : a journal of neurology (2009), 132(Pt 9), 2501 -16).
  • TASK-1 a member of two-pore-domain (K2P) potassium channel family, has emerged as a target for the pharmacological treatment of atrial fibrillation recently.
  • Two-pore-domain (K2P) potassium channels mediate background potassium currents, stabilizing resting membrane potential and expediting action potential repolarization.
  • TASK-1 channels have been shown to play a role in cardiac repolarization, (Basic Res Cardiol. 201 1 Jan;106(1 ):75-87, Putzke C, Wemhoner K, Sachse FB, Rinne S, Schlichthorl G, Li XT, Jae L, Eckhardt I,
  • Atrial fibrillation (AF) and atrial flutter are extremely common cardiac rhythm disorder that causes substantial morbidity and contributes to mortality (Journal of Clinical Invest. 201 1 ;121 (8):2955-2968).
  • Presently available therapeutic approaches have major limitations, including limited efficacy and potentially serious side effects such as malignant ventricular arrhythmia induction or negative inotropic effects.
  • the occurrence of AF increases with age and frequently leads to fatal sequelae such as stroke.
  • the class I and III antiarrhythmics in use at present reduce the rate of recurrence of AF but are used to only a limited extent because of their potential proarrhythmic side effects and limited efficacy.
  • the growing incidence of AF emphasizes the importance of identifying appropriate treatments, particularly drugs, that are safe, effective, and associated with improved clinical outcomes.
  • the length of the action potential is essentially determined by the extent of repolarizing K + currents which flow out of the cells through various K + channels.
  • TASK-1 constitutes one of those repolarizing potassium currents. Its inhibition prolong the action potential and thereby refractoriness.
  • class III antiarrhythmics e.g. dofetilide, E4031 and d-sotalol
  • IK r the rapidly activating potassium channel
  • the therapeutic efficacy of the ⁇ blockers has been found to decline under the conditions of tachycardia (electrical tachycardic atrial
  • TASK-1 expression in the human heart has been shown to be restricted to the atria with no or very little expression in the ventricles.
  • a further advantage is that TASK-1 expression is not decreased but even slightly increased in atrial fibrillation patients compared with sinus rhythm patients, by contrast a decreased expression of other atrial K + channels has been reported in atrial fibrillation patients compared with sinus rhythm patients: see for example Basic. Res. Cardiol. 2003, 98, 137-148, Brundel B.J.J. M. et al., JACC 2001 , 37, 926-932).
  • TASK-1 is still expressed in the target patient population (Journal of Molecular Medicine 2004, 308-316;
  • an activation of the TASK-1 channel can be achieved by therapeutic concentrations of the inhalative anesthetics halothane and isoflurane (Patel A.J., Honore E., Lesage F., Fink M., Romey G., Lazdunski M.; Inhalational anesthetics activate two-pore-domain background K+ channels; Nature Neurosci. 1999 (2), 422-426).
  • Kv1 .5 blockers which also inhibit the TASK- 1 channel are described in the state of the art (Brendel, J.; Goegelein, H.; Wirth, K.; Kamm, W., WO 2007/124849, Brendel, J.; Englert, H.
  • Kv1 .5 blocker (Peukert, S., Brendel, J., Pirard, B., Brueggemann, A., Below, P., Kleemann, H.-W., Hemmerle, H., Schmidt, W.; Identification, Synthesis, and Activity of Novel Blockers of the Voltage-Gated Potassium Channel Kv1 .5.; Journal of Medicinal Chemistry (2003), 46(4), 486-498) has been stated to be a TASK-1 blocker (Streit, A. K.; Netter, M.
  • a Specific Two-pore Domain Potassium Channel Blocker Defines the Structure of the TASK-1 Open Pore; Journal of Biological Chemistry (201 1 ),
  • arachidonamide anandamide an endogenous ligand of the cannabinoid receptor
  • methanandamide homolog have been
  • TASK-1 blockers (Maingret F., Patel A.J., Lazdunski M., Honore E.;
  • the endocannabinoid anandamide is a direct and selective blocker of the
  • Doxapram which is used for the treatment of respiratory disorders has been stated to be a TASK-1 blocker (Cotten J.F., Keshavaprasad B., Laster M.J., Eger E.I., Yost C.S.; The Ventilatory Stimulant Doxapram Inhibits TASK Tandem Pore (K 2 p) Potassium
  • EP 0 086 422 A2 describes some N-acetylated tetrahydro-1 H-pyrazolo[4,3- c]pyridine compounds. However no biological activity has been described for these compounds therein.
  • a goal of the present invention is to provide efficient TASK-1 inhibitors suitable for the treatment and prevention of TASK-1 related conditions.
  • the present invention relates to TASK-1 blockers of the formula I
  • A (C6-Cio)-aryl or a five- or six-membered heteroaryl, comprising 1 -3
  • heteroatoms selected from the group N, O and S,
  • aryl and heteroaryl are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-0- and (Ci-C 6 )-alkyl-S-,
  • X (C6-Cio)-aryl or a five- or six-membered heteroaryl, comprising 1 -3
  • heteroatoms selected from the group N, O and S,
  • aryl and heteroaryl are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S-, (Ci-C 6 )-alkyl-O-C(O)- and (Ci-C 6 )-alkyl-SO 2 -, wherein one or more hydrogen atoms of the alkyl moieties may be replaced by fluorine;
  • R2 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-;
  • R3 H, (Ci-C 4 )-alkyl-;
  • R4 H, (Ci-C 4 )-alkyl-;
  • R5 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S-, (d- C 6 )-alkyl-O-(Ci-C 6 )-alkyl-, HO-(Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-(Ci-C 6 )-alkyl-, (C 6 -Cio)-aryl-, (C 6 -Cio)-aryl-(Ci-C 6 )-alkyl-, R7R6N-, heteroaryl, heteroaryl- (Ci-C6)-alkyl-, aliphatic heterocycle,
  • aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered aliphatic
  • heterocycles comprising an oxygen atom
  • aliphatic heterocycle may be optionally substituted with 1 to 3 substituents independently selected from the group of F, OH, (d-Ce)- alkyl-O- and (Ci-C 6 )-alkyl-, and
  • heteroaryl residues are five- or six-membered ring systems, comprising 1 -3 heteroatoms selected from the group N, O and S, and
  • aryl and heteroaryl are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CF 3 , (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-O-,
  • R6 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-,
  • one hydrogen atom of the alkyl group may be replaced by an OH or (Ci-C6)-alkyl-O- residue, and
  • R7 H, (Ci-C 6 )-alkyl-;
  • R5 is methyl and R2, R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4- methyl-phenyl, 4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl, 3,4- dichlorophenyl, and
  • R5 is methyl and R2, R3 and R4 are equal to H and X is a phenyl residue, the residue A is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyloxy-phenyl, 3-thfluoromethyl-phenyl, 2-thiophenyl or 4- methylthiophenyl, and
  • Another embodiment of the present invention relates to compounds, wherein
  • A phenyl or a five- or six-membered heteroaryl selected from the group
  • phenyl and heteroaryl are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-O- and (Ci-C 6 )-alkyl-S-,
  • X a five- or six-membered heteroaryl, comprising 1 -3 heteroatoms selected from the group N, O and S,
  • heteroaryl group is optionally substituted with 1 -3 residues selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-O- and (Ci-C 6 )-alkyl-S-, (Ci-C 6 )-alkyl-O-C(O)- and (Ci-C 6 )-alkyl-SO 2 -,
  • R2 H, (Ci-C 4 )-alkyl-, (C 3 -C 6 )-cycloalkyl-;
  • R3 H, (Ci-C 2 )-alkyl-;
  • R4 H, (Ci-C 2 )-alkyl-;
  • R5 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S-, (d-
  • aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered aliphatic
  • heterocycles comprising an oxygen atom
  • aliphatic heterocycle may be optionally substituted with 1 to 3 substituents independently selected from the group of F, OH, (C1-C-6)- alkyl-O- and (Ci-C 6 )-alkyl-, and
  • heteroaryl residues are five- or six-membered ring systems, comprising 1 -3 heteroatoms selected from the group N, O and S, and
  • aryl and heteroaryl are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CF 3 , (CrC6)-alkyl-, (Ci-C6)-alkyl-O-, CN, (Ci-C 2 )-alkyl-SO 2 -;
  • R6 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-,
  • one hydrogen atom of the alkyl group may be replaced by an OH- or (Ci-C6)-alkyl-O- residue, and
  • R7 H, (Ci-C 6 )-alkyl-;
  • phenyl residue is optionally substituted with 1 -3 rests selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, (d-C 4 )-alkyl-O- and (d-
  • X a five- or six-membered heteroaryl, selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol 2-yl, thiazol-4-yl, thiazol-5-yl,
  • heteroaryl group is optionally substituted with 1 -3 residues selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-O and (Ci-C 6 )-alkyl-S-, (Ci-C 6 )-alkyl-O-C(O)- and (Ci-C 6 )-alkyl-SO 2 -,
  • R2 H, (Ci-C 2 )-alkyl-, cyclopropyl-;
  • R3 H, methyl-
  • R4 H, methyl-
  • R5 H, (Ci-C 4 )-alkyl-, (C 3 -C 6 )-cycloalkyl-, (Ci-C 2 )-alkyl-O-, (Ci-C 2 )-alkyl-S-, (d- C 4 )-alkyl-O-methyl-, HO-(Ci-C 2 )-alkyl-, (C 3 -C 6 )-cycloalkyl-(Ci-C 2 )-alkyl-, phenyl, phenyl-(Ci-C 2 )-alkyl-, R7R6N-, heteroaryl, heteroaryl-(Ci-C 4 )-alkyl-, aliphatic heterocycle,
  • aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, and
  • aliphatic heterocycle may be optionally substituted with 1 or 2 substituents independently selected from the group of F, OH, (Ci-C 2 )- alkyl-O- and (Ci-C 4 )-alkyl-, and
  • phenyl residue is optionally substituted with 1-3 rests selected independently from F, CI, Br, CF 3 , (CrC 4 )-alkyl-, (Ci-C 4 )-alkyl-O-, CN, (Ci-C 2 )-alkyl-SO 2 - wherein the heteroaryl residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol- 5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-2-
  • heteroaryl residues are optionally substituted with 1 or 2 rests selected independently from F, CI, Br, CF 3 , (CrC 4 )-alkyl-, (Ci-C 4 )-alkyl- O-, CN, (Ci-C 2 )-alkyl-SO 2 -;
  • R6 H, (Ci-C 4 )-alkyl-, cyclopropyl,
  • one hydrogen atom of the alkyl group may be replaced by an OH, methoxy or ethoxy residue
  • R7 H, methyl-, ethyl
  • phenyl residue is optionally substituted with 1 or 2 rests selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , and (Ci-C 2 )-alkyl-S-;
  • X a five- or six-membered heteroaryl, selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol- 2-yl, thiazol-4-yl, thiazol-5-yl,
  • residues are optionally substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , (Ci-C 2 )-alkyl-S-, (Ci-C 2 )-alkyl-O-C(O)- and methyl-SO 2 -;
  • R2 H, methyl, ethyl, cyclopropyl
  • R3 and R4 H
  • R5 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, cyclopropyl or cyclobutyl;
  • Another embodiment of the present invention relates to compounds, wherein
  • A a five- or six-membered heteroaryl, comprising 1 -3 heteroatoms selected from the group N, O and S,
  • heteroaryl is substituted with 1-3 residues selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-O- and (d- C 6 )-alkyl-S-,
  • X phenyl, thiophen-2-yl or thiophen-3-yl
  • residues are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-O- and (d- C 6 )-alkyl-S-, (Ci-C 6 )-alkyl-O-C(O)- and (Ci-C 6 )-alkyl-SO 2 -,
  • R2 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-;
  • R3 H, (Ci-C 4 )-alkyl-;
  • R4 H, (Ci-C 4 )-alkyl-;
  • R5 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S-, (d-
  • aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered aliphatic heterocycles comprising an oxygen atom, and
  • aliphatic heterocycle may be optionally substituted with 1 to 3 substituents selected from the group of F, OH, (Ci-C6)-alkyl-O- and (Ci-
  • heteroaryl residues are five- or six-membered ring systems, comprising 1 -3 heteroatoms selected from the group N, O and S, and
  • aryl and heteroaryl are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CF 3 , (CrC6)-alkyl-, (Ci-C6)-alkyl-O-, CN, (Ci-C 2 )-alkyl-SO 2 -;
  • R6 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-,
  • one hydrogen atom of the alkyl group may be replaced by an OH- or (Ci-C 6 )-alkyl-O- residue, and
  • R7 H, (Ci-C 6 )-alkyl-;
  • A is not 4-methylthiophenyl if in compounds of formula I R5 is methyl and R2, R3 and R4 are hydrogen and X is phenyl.
  • A 2-pyridyl, 3-pyridyl or 4-pyridyl
  • pyridyl residues are substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , and (Ci-C 2 )-alkyl-S-;
  • X phenyl, thiophen-2-yl or thiophen-3-yl,
  • residues are substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , (d-C 2 )-alkyl-S-, (Ci-C 2 )-alkyl-0-C(0)- and methyl-SO 2 -;
  • R2 H, methyl, ethyl, cyclopropyl
  • R5 H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl
  • R5 cyclopropyl, cyclobutyl, cyclopentyl or (C3-C-6)-cycloalkyl-(Ci-C 2 )-alkyl-;
  • R5 (Ci-C 2 )-alkyl-O-, (Ci-C 2 )-alkyl-S-, or OCF 3 ,
  • R5 (Ci-C 4 )-alkyl-O-methyl-, HO-(Ci-C 2 )-alkyl-,
  • R5 phenyl or phenylmethyl-
  • phenyl residues are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CF 3 , (Ci-C 2 )-alkyl-, (Ci-C 2 )-alkyl-O-, CN, methyl-SO 2 -;
  • R5 R7R6N-, wherein
  • R6 H, (Ci-C 4 )-alkyl-, cyclopropyl,
  • one hydrogen atom of the alkyl group may be replaced by an OH, methoxy or ethoxy residue
  • R7 H, methyl-, ethyl
  • R5 heteroaryl, heteroaryl-(Ci-C6)-alkyl-,
  • heteroaryl residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol- 5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and
  • heteroaryl residues are optionally substituted with 1 or 2 rests selected independently from F, CI, Br, CF 3 , (CrC 4 )-alkyl-, (Ci-C 4 )-alkyl- O-, CN, (Ci-C 2 )-alkyl-SO 2 -;
  • R5 an aliphatic heterocycle
  • aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl and tetrahydrofuranyl, tetrahydropyranyl, and
  • aliphatic heterocycle may be optionally substituted with 1 or 2 substituents independently selected from the group of F, OH, (Ci-C 2 )- alkyl-O- and (Ci-C 4 )-alkyl-;
  • Another embodiment of the present invention relates to compounds, wherein
  • A is equal to phenyl
  • phenyl residue is optionally substituted with 1 -3 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, (d-C 4 )-alkyl-O- and (Ci-C 4 )-alkyl-S-,
  • X is equal to phenyl
  • phenyl group is optionally substituted with 1 , 2 or 3 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, (d-C 4 )-alkyl-O- (Ci-C 4 )-alkyl-S-, (Ci-C 4 )-alkyl-O-C(O)- and (Ci-C 4 )-alkyl-SO 2 -, wherein one or more hydrogen atoms of the alkyl moieties may be replaced by fluorine, and
  • R2 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-;
  • R3 H, (Ci-C 4 )-alkyl-;
  • R4 H, (Ci-C 4 )-alkyl-;
  • R5 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S-, (d- C 6 )-alkyl-O-(Ci-C 6 )-alkyl-, HO-(Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-(Ci-C 6 )-alkyl-, (C 6 -Cio)-aryl-, (C 6 -Ci 0 )-aryl-(Ci-C 6 )-alkyl-, R7R6N-, heteroaryl, heteroaryl- (Ci-C6)-alkyl-, aliphatic heterocycle,
  • aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered aliphatic
  • heterocycles comprising an oxygen atom
  • aliphatic heterocycle may be optionally substituted with 1 to 3 substituents selected from the group of F, OH, (Ci-C6)-alkyl-O- and (Ci- C6>-alkyl-, and
  • heteroaryl residues are five- or six-membered ring systems, comprising 1 -3 heteroatoms selected from the group N, O and S, and
  • aryl and heteroaryl are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CF 3 , (CrC6)-alkyl-, (Ci-C6)-alkyl-O-, CN, (Ci-C 2 )-alkyl-SO 2 -;
  • R6 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-,
  • one hydrogen atom of the alkyl group may be replaced by an OH- or (Ci-C6)-alkyl-O- residue, and
  • R7 H, (Ci-C 6 )-alkyl-;
  • R5 is methyl and R2, R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4- methyl-phenyl, 4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl, 3,4- dichlorophenyl, and
  • R5 is methyl and R2, R3 and R4 are equal to H and X is a phenyl residue, the residue A is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyloxy-phenyl or 3-trifluoromethyl-phenyl, and
  • a further embodiment of the present invention relates to compounds, wherein A is equal to phenyl,
  • phenyl residue is optionally substituted with 1-3 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, (Ci-C 4 )-alkyl-O- and (Ci-C 4 )-alkyl-S-,
  • X is equal to phenyl
  • phenyl group is optionally substituted with 1 , 2 or 3 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, (Ci-C 4 )-alkyl-O-, (Ci-C 4 )-alkyl-S-, (Ci-C 4 )-alkyl-O-C(O)- and (Ci-C 4 )-alkyl-SO 2 -, wherein one or more hydrogen atoms of the alkyl moieties may be replaced by fluorine, and
  • R2 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-;
  • R3 H, (Ci-C 4 )-alkyl-;
  • R4 H, (Ci-C 4 )-alkyl-;
  • R5 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-, (Ci-C 6 )-alkyl-O-, (Ci-C 6 )-alkyl-S-, (d- C 6 )-alkyl-O-(Ci-C 6 )-alkyl-, HO-(Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-(Ci-C 6 )-alkyl-, (C 6 -Cio)-aryl-, (C 6 -Ci 0 )-aryl-(Ci-C 6 )-alkyl-, R7R6N-, heteroaryl, heteroaryl- (Ci-C6)-alkyl-, aliphatic heterocycle,
  • aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered aliphatic
  • heterocycles comprising an oxygen atom
  • aliphatic heterocycle may be optionally substituted with 1 to 3 substituents selected from the group of F, OH, (Ci-C6)-alkyl-O- and (Ci-
  • heteroaryl residues are five- or six-membered ring systems, comprising 1 -3 heteroatoms selected from the group N, O and S, and
  • aryl and heteroaryl are optionally substituted with 1 -3 rests selected independently from F, CI, Br, CF 3 , (CrC6)-alkyl-, (Ci-C6)-alkyl-O-, CN, (Ci-C 2 )-alkyl-SO 2 -;
  • R6 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-,
  • one hydrogen atom of the alkyl group may be replaced by an OH- or (Ci-C 6 )-alkyl-O- residue, and
  • R7 H, (Ci-C 6 )-alkyl-;
  • R5 is methyl and R2, R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4- methyl-phenyl, 4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl, 3,4- dichlorophenyl, and
  • R5 is methyl and R2, R3 and R4 are equal to H and X is a phenyl residue, the residue A is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl- phenyl, 4-ethyloxy-phenyl, 3-trifluoromethyl-phenyl or 4-methylthiophenyl, and with the proviso if R5 is methyl and R2 is methyl and R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl.
  • phenyl residue is substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 and (Ci-C2)-alkyl-S-;
  • phenyl residue is substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , (d-C 2 )-alkyl-S-, (Ci-C 2 )-alkyl-0-C(0)- and methyl-SO 2 -,
  • R2 H, (Ci-C 2 )-alkyl-, cyclopropyl-;
  • R3 H, methyl-
  • R4 H, methyl-
  • R5 is equal to a heteroaryl or heteroaryl-(Ci-C6)-alkyl-, wherein the heteroaryl
  • residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol- 2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and
  • residues are optionally substituted with 1 or 2 residues selected independently from F, CI, Br, CF 3 , methyl, ethyl, methoxy, ethoxy, CN, methyl-SO 2 -,
  • R5 is equal to H
  • R5 is equal to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C 3 -C6)-cycloalkyl-
  • R5 is equal to (Ci-C 2 )-alkyl-O-, (Ci-C 2 )-alkyl-S-, or wherein
  • R5 is equal to (Ci-C 4 )-alkyl-O-methyl-, HO-(Ci-C 2 )-alkyl-,
  • R5 is equal to phenyl- or phenylmethyl-
  • phenyl residues are optionally substituted with 1 -3 residues selected independently from F, CI, Br, CF 3 , (CrC 2 )-alkyl-, (C 1 -C 2 )- alkyl-O-, CN, methyl-SO 2 -, and
  • R5 is equal to R7R6N-, wherein
  • R5 is equal to an aliphatic heterocycle
  • aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, and
  • aliphatic heterocycle may be optionally substituted with 1 or 2 substituents selected from the group of F, OH, (Ci-C 2 )-alkyl-O- and (Ci- C 4 )-alkyl-, and wherein one or more hydrogen atoms of the alkyl groups may be replaced by fluorine;
  • A phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 and (Ci-C2)-alkyl-S-;
  • phenyl residue is substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , (d-C 2 )-alkyl-S-, (Ci-C 2 )-alkyl-0-C(0)- and methyl-SO 2 -,
  • R2 H, (Ci-C 2 )-alkyl-, cyclopropyl-;
  • R3 H, methyl-
  • R4 H, methyl-
  • R5 is equal to (C 2 -C 4 )-alkyl
  • a further embodiment of the present invention are compounds of formula I, wherein
  • A (C6-Cio)-aryl or a five- or six-membered heteroaryl, comprising 1-3
  • heteroatoms selected from the group N, O and S,
  • aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-0- and (Ci-C 6 )-alkyl-S-,
  • X (C6-Cio)-aryl or a five- or six-membered heteroaryl, comprising 1-3
  • heteroatoms selected from the group N, O and S,
  • aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, CI, Br, CN, (Ci-C 6 )-alkyl-, (Ci-C 6 )-alkyl-0- and (Ci-C 6 )-alkyl-S-, (Ci-C 6 )-alkyl-0-C(0)- and (Ci-C 6 )-alkyl-SO 2 -, wherein one or more hydrogen atoms of the alkyl moieties may be replaced by fluorine;
  • R2 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-;
  • R3 H, (Ci-C 4 )-alkyl-;
  • R4 H, (Ci-C 4 )-alkyl-;
  • R5 is equal to a heteroaryl or heteroaryl-(Ci-C6)-alkyl-, wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, and
  • heteroaryl residues are optionally substituted with 1 -3 residues selected independently from F, CI, Br, CF 3 , (Ci-C-6)-alkyl-, (Ci-C-6)-alkyl-0-, CN, (Ci-C 2 )-alkyl-SO 2 -,
  • R2 and R4 are hydrogen and X is a 2,4-difluorophenyl residue
  • A is not pyridine-3-yl, 2-fluoro-phenyl, 3- fluoro-phenyl, 4-fluorophenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 3- trifluormethoxy-phenyl, 2-fluoro-5-methoxy-phenyl, and
  • R2 and R4 are hydrogen and X is phenyl
  • A is not phenyl, 3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4- chloro-phenyl, 4-methyl-phenyl, 4-ethyloxy-phenyl, 4-methyl-thiophenyl, 2- thiophenyl, and
  • R2 and R4 are hydrogen and A is 4-fluoro-phenyl X is not phenyl, 2-chloro-phenyl, 3,4-dichloro-phenyl,
  • R5 is equal to H, (C 2 -C 6 )-alkyl, CF 3 , CF 2 H, CFH 2 ,
  • R5 is equal to (C3-C6)-cycloalkyl or (C3-C6)-cycloalkyl-(Ci-C 4 )-alkyl-,
  • R5 is equal to (d-C 4 )-alkyl-O- or (Ci-C 4 )-alkyl-S-,
  • R5 is equal to (Ci-C 4 )-alkyl-O-(Ci-C 2 )-alkyl-, HO-(Ci-C 4 )-alkyl- or wherein
  • R5 is equal to phenyl-, phenyl-(Ci-C 4 )-alkyl-,
  • phenyl residues are optionally substituted with 1 -3 residues selected independently from F, CI, Br, CF 3 , (CrC6)-alkyl-, (Ci alkyl-O-, CN, (Ci-C 2 )-alkyl-SO 2 -, and
  • R5 is equal to R7R6N-, wherein
  • R6 H, (Ci-C 4 )-alkyl-, cyclopropyl-, wherein one hydrogen atom of the alkyl group may be replaced by an OH, methoxy or ethoxy residue and
  • R7 H, (Ci-C 2 )-alkyl-
  • R5 is equal to an aliphatic heterocycle
  • aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, and
  • aliphatic heterocycle may be optionally substituted with 1 or 2 substituents selected from the group of F, OH, (Ci-C 4 )-alkyl-O- and (Ci- C 4 )-alkyl-, and
  • residues are optionally substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 and (Ci-C 2 )-alkyl-S-;
  • phenyl residue is substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , (Ci-C 2 )-alkyl-S-, (Ci-C 2 )-alkyl-O-C(O)- and methyl-SO 2 -, or
  • residues are optionally substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H,
  • R2 H, (Ci-C 2 )-alkyl-, cyclopropyl-;
  • R3 H, (Ci-C 2 )-alkyl-;
  • R4 H, (Ci-C 2 )-alkyl-;
  • R5 is equal to a heteroaryl or heteroaryl-(Ci-C6)-alkyl-, wherein the heteroaryl
  • residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol- 2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and
  • residues are optionally substituted with 1 or 2 residues selected independently from F, CI, Br, CF 3 , methyl, ethyl, methoxy, ethoxy, CN, methyl-SO 2 -,
  • R2 and R4 are hydrogen and X is a 2,4-difluorophenyl residue
  • A is not pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro- phenyl, 4-fluorophenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy- phenyl, 2-fluoro-5-methoxy-phenyl, and
  • R5 is equal to H, (C 2 -C 4 )-alkyl, CF 3 ;
  • R5 is equal to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C3-C6)-cycloalkyl- (Ci-C 2 )-alkyl-,
  • R5 is equal to (Ci-C 2 )-alkyl-O- or (Ci-C 2 )-alkyl-S-,
  • R5 is equal to (Ci-C 4 )-alkyl-O-methyl-, HO-(Ci-C 2 )-alkyl-,
  • R5 is equal to phenyl-, phenyl-(Ci-C 2 )-alkyl-,
  • phenyl residues are optionally substituted with 1 -3 residues selected independently from F, CI, Br, CF 3 , (CrC 2 )-alkyl-, (Ci-C 2 )- alkyl-O-, CN, methyl-SO 2 -, and
  • R5 is equal to R7R6N-, wherein
  • R5 is equal to an aliphatic heterocycle
  • aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, and
  • aliphatic heterocycle may be optionally substituted with 1 or 2 substituents selected from the group of F, OH, (Ci-C2)-alkyl-O- and (Ci-
  • A is equal to phenyl
  • phenyl residue is optionally substituted with 1 -3 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, (d-C 4 )-alkyl-O- and (Ci-C 4 )-alkyl-S-, wherein one or more hydrogen atoms of the alkyl moieties may be replaced by fluorine, and
  • X is equal to phenyl
  • phenyl group is optionally substituted with 1 , 2 or 3 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, (Ci-C 4 )-alkyl-O-,
  • R2 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-;
  • R3 H, (Ci-C 4 )-alkyl-;
  • R4 H, (Ci-C 4 )-alkyl-;
  • R5 is equal to a heteroaryl or heteroaryl-(Ci-C6)-alkyl-, wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1 -3 heteroatoms selected from the group N, O and S, and
  • heteroaryl residues are optionally substituted with 1 -3 residues selected independently from F, CI, Br, CF 3 , (CrC6)-alkyl-, (Ci-C6)-alkyl-O-, CN, (Ci-C 2 )-alkyl-SO 2 -,
  • R2 and R4 are hydrogen and X is a 2,4-difluorophenyl residue
  • A is not pyridine-3-yl, 2-fluoro-phenyl, 3- fluoro-phenyl, 4-fluorophenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 3- trifluormethoxy-phenyl, 2-fluoro-5-methoxy-phenyl, and
  • R2 and R4 are hydrogen and X is phenyl
  • A is not phenyl, 3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4- chloro-phenyl, 4-methyl-phenyl, 4-ethyloxy-phenyl, 4-methyl-thiophenyl, 2- thiophenyl, and
  • R2 and R4 are hydrogen and A is 4-fluoro-phenyl
  • X is not phenyl, 2-chloro-phenyl, 3,4-dichloro-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4- ethyloxy-phenyl, or 4-acetoxyphenyl, and
  • R5 is equal to H, (C 2 -C 6 )-alkyl, CF 3 , CF 2 H, CFH 2 ,
  • R5 is equal to (C 3 -C 6 )-cycloalkyl or (C 3 -C 6 )-cycloalkyl-(Ci-C 4 )-alkyl-,
  • R5 is equal to (d-C 4 )-alkyl-O- or (Ci-C 4 )-alkyl-S-,
  • R5 is equal to (Ci-C 4 )-alkyl-O-(Ci-C 2 )-alkyl-, HO-(Ci-C 4 )-alkyl-,
  • R5 is equal to phenyl-, phenyl-(Ci-C 4 )-alkyl-, wherein the phenyl residues are optionally substituted with 1 -3 residues selected independently from F, CI, Br, CF 3 , (CrC6)-alkyl-, (C1-C3)- alkyl-O-, CN, (Ci-C 2 )-alkyl-SO 2 -, and
  • R5 is equal to R7R6N-, wherein
  • R5 is equal to an aliphatic heterocycle
  • aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, and
  • aliphatic heterocycle may be optionally substituted with 1 or 2 substituents selected from the group of F, OH, (Ci-C 4 )-alkyl-O- and (Ci-
  • R6 H, (Ci-C 6 )-alkyl-, (C 3 -C 6 )-cycloalkyl-,
  • one hydrogen atom of the alkyl group may be replaced by an OH- or (Ci-C6)-alkyl-O- residue, and
  • R7 H, (Ci-C 6 )-alkyl-; wherein one or more hydrogen atoms of the alkyl group may be replaced by fluorine.
  • phenyl residue is substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 and (Ci-C 2 )-alkyl-S-;
  • phenyl residue is substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 , (Ci-C 2 )-alkyl-S-, (Ci-C 2 )-alkyl-O-C(O)- and methyl-SO 2 -,
  • R2 H, (Ci-C 2 )-alkyl-, cyclopropyl-;
  • R3 H, methyl-
  • R4 H, methyl-
  • R5 is equal to a heteroaryl or heteroaryl-(Ci-C6)-alkyl-, wherein the heteroaryl
  • residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol- 2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and
  • residues are optionally substituted with 1 or 2 residues selected independently from F, CI, Br, CF 3 , methyl, ethyl, methoxy, ethoxy, CN, methyl-SO 2 -, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not pyrimidin-4-yl, pyridine-2-yl, 1 -methyl- pyrazol-3-yl or 1 -methyl-imidazol-2-yl,
  • R2 and R4 are hydrogen and X is a 2,4-difluorophenyl residue
  • A is not pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro- phenyl, 4-fluorophenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy- phenyl, 2-fluoro-5-methoxy-phenyl, and
  • R2 is methyl
  • R3 and R4 are hydrogen and A is 4-fluoro-phenyl
  • the residue X is not phenyl
  • R5 is equal to H, (C 2 -C 4 )-alkyl, CF 3 ;
  • R5 is equal to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C3-C6)-cycloalkyl- (Ci-C 2 )-alkyl-,
  • R5 is equal to (Ci-C 2 )-alkyl-O- or (Ci-C 2 )-alkyl-S-,
  • R5 is equal to (Ci-C 4 )-alkyl-O-methyl-, HO-(Ci-C 2 )-alkyl-,
  • R5 is equal to phenyl-, phenyl-(Ci-C 2 )-alkyl-,
  • phenyl residues are optionally substituted with 1 -3 residues selected independently from F, CI, Br, CF 3 , (CrC2)-alkyl-, (C1-C2)- alkyl-O-, CN, methyl-SO 2 -, and
  • R5 is equal to R7R6N-, wherein
  • R5 is equal to an aliphatic heterocycle
  • aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, and
  • aliphatic heterocycle may be optionally substituted with 1 or 2 substituents selected from the group of F, OH, (Ci-C2)-alkyl-O- and (Ci- C 4 )-alkyl-, and
  • R2, R3 and R4 are hydrogen, A is pyrimidin-2-yl and X is 2-fluoro- phenyl R1 is not methylsulfonyl.
  • phenyl residue is substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H, CFH 2 , methoxy, ethoxy, OCF 3 and (Ci-C2)-alkyl-S-;
  • R2 H, (Ci-C 2 )-alkyl-, cyclopropyl-;
  • R3 H, methyl-
  • R4 H, methyl-
  • R5 is equal to (C2-C 4 )-alkyl
  • A phenyl
  • phenyl residue is optionally substituted with 1 or 2 rests selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H,
  • X a five- or six-membered heteroaryl, selected from the group consisting of pyridine-2-yl, pyridine-3-yl and pyridine-4-yl;
  • residues are optionally substituted with 1 or 2 residues selected independently from F, CI, Br, CN, (Ci-C 4 )-alkyl-, CF 3 , CF 2 H,
  • R5 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, cyclopropyl or cyclobutyl;
  • Alkyl radicals have between 1 and 6, for example between 1 and 4 carbon atoms and may be straight-chain or branched. Alkyl radicals may also be straight-chain or branched if they are substituted or are present in other radicals, for example in an alkyloxy radical (alkoxy radical) or in a fluorinated alkyl radical. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert- butyl.
  • alkyl radicals may be replaced by fluorine atoms.
  • fluorinated alkyl radicals are CF 3 , CF 2 H and CFH 2 .
  • Substituted alkyl radicals may be substituted in any positions.
  • alkyloxy radicals are methoxy and ethoxy.
  • alkyl radicals which in the definition of a group in the compounds of the formula I are bonded to two adjacent groups, or linked to two groups, and may be regarded as divalent alkyl radicals (alkanediyl radicals, alkylene radicals), like in the case of the alkyl part of a substituted alkyl group, for example the group (Ci-C6)-alkyloxy-(CrC 6 )-alkyl- or the group heteroaryl-(Ci-C6)-alkyl-, in which groups and likewise in other groups the terminal hyphen denotes the free bond via which the group is bonded, and thus indicates via which subgroup a group composed of subgroups is bonded.
  • alkyl radicals which in the definition of a group in the compounds of the formula I are bonded to two adjacent groups, or linked to two groups, and may be regarded as divalent alkyl radicals (alkanediyl radicals, alkylene radicals), like in the case of the alkyl part
  • radicals can also be straight-chain or branched, the bonds to the adjacent groups can be located in any positions and can start from the same carbon atom or from different carbon atoms, and they can be unsubstituted or substituted by fluorine substituents independently of any other substituents.
  • divalent alkyl radicals are methylene, 1 ,1 -ethylene, 1 ,2-ethylene, 1 ,1 -propylene, 1 ,2- propylene, 2,2-propylene, 1 ,3-propylene, 1 ,1 -butylene, 1 ,4-butylene, etc.
  • cycloalkyl radicals having 3 to 6 C atoms are cyclopropyl, cyclobutyl, 1 - methylcyclopropyl-, 2-methylcyclopropyl-, cyclobutyl, 2-methylcyclobutyl-, 3- methylcyclobutyl-, cyclopentyl, 2-methylcyclopentyl-, 3-methylcyclopentyl-, cyclohexyl etc.
  • heteroaryl residues are five or six-membered rings, comprising 1 to 3 heteroatoms selected from the group N, O and S, wherein a heteroaryl ring for example comprises only one O or S atom.
  • heteroaryl groups are 2-thiophenyl, 3-thiophenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2- pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 2-imidazolyl, 4- imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5- isothiazolyl, for example 2-pyridyl, 3-pyridyl and 4-pyridyl.
  • heteroaryl residues for the group A are unsubstituted or substituted pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl and thiophen-3-yl, specific examples are substituted heteroaryl residues.
  • heteroaryl residues for the group X are unsubstituted or substituted pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl and thiazol-5-yl, specific examples are substituted heteroaryl residues.
  • heteroaryl residues for R5 are unsubstituted or substituted pyridine-2- yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3- yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl.
  • the heteroaryl residues may unsubstituted or substituted with one or two
  • substituents examples include F, CI, Br, methoxy, ethoxy, methyl, ethyl, NC-, CF 3 O-, CF 3 .
  • the aryl residue is phenyl, wherein one or two hydrogen may be replaced by substituents, for example selected from the group F, CI, methoxy, ethoxy, methyl, ethyl, NC-, CF 3 O-, CF 3 , CH 3 -SO 2 -.
  • Examples of an aliphatic heterocycle are selected from the group of morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl and tetrahydrofuranyl and tetrahydropyranyl, wherein these aliphatic heterocycle may be optionally substituted with 1 or 2 substituents, for example selected independently from the group of F, OH, methoxy, ethoxy, methyl and ethyl. If a radical is disubstituted or trisubstituted, the substituents may be identical or different. If the compounds of the formula I comprise one or more basic groups or one or more basic heterocycles, the invention also includes the corresponding
  • physiologically acceptable salts including trifluoroacetates, for example the pharmaceutically acceptable salts.
  • the compounds of the formula I which have one or more basic, i.e. protonatable, groups or comprise one or more basic heterocyclic rings, can also be used in the form of their physiologically tolerated acid addition salts with inorganic or organic acids, for example as hydrochlorides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates etc. Salts can be obtained from compounds of the formula I by conventional processes, for example by combining with an acid in a solvent or dispersant or else by anion exchange from other salts.
  • the compounds of the formula I may also be deprotonated on an acidic group and be used for example as alkali metal salts, for example sodium or potassium salts, or as ammonium salts, for example as salts with ammonia or organic amines or amino acids.
  • the compounds of the formula I may exist in stereoisomeric forms. The centers of asymmetry which are present may independently of one another have the S configuration or the R configuration. The invention includes all possible
  • stereoisomers for example enantiomers or diastereomers, and mixtures of two or more stereoisomeric forms, for example enantiomers and/or diastereomers, in any ratios.
  • the invention thus includes for example enantiomers in enantiopure form, both as levorotatory and as dextrorotatory antipodes, and in the form of mixtures of the two enantiomers in various ratios or in the form of racemates.
  • Individual stereoisomers can be prepared as desired by fractionating a mixture by
  • acyl chlorides can alternatively be prepared by standard procedures from the corresponding acids e.g. by reaction with thionyl chloride in the presence of catalytic amounts of DMF (see for example Dalisay, D. S.; Quach, T.; Nicholas, G. N.;
  • the diketones 2 are obtained and can be subjected to ring-closure with hydrazine hydrate to give the corresponding diverse 4,5,6,7-Tetrahydro-1 H-pyrazolo[4,3-c]pyridine intermediates 3.
  • R3,R4 substituted intermediates 5 can be accorded similarly as shown in Scheme 2.
  • N-Acetyl- piperidones 4 are obtained. They can be deprotonated with strong bases like lithium diisopropylamide (LDA) and reacted with mixed anhydrides formed by reaction of aryl or heteroarylcarbonic acids and isobutylchloroformate as described above.
  • LDA lithium diisopropylamide
  • the diketones obtained can be subjected to ring-closure with hydrazine hydrate to give the corresponding R3,R4 substituted 4,5,6,7-Tetrahydro-1 H-pyrazolo[4,3-c]pyridine intermediates 5.
  • 4,5,6,7-Tetrahydro-1 H-pyrazolo[4,3-c]pyridine intermediates can be successfully alkylated with a range of different aryl- and heteroaryl halogenides by heating in the presence of an excess amount of a base like K2CO3 in an inert solvent like CH 3 CN as shown in Scheme 3.
  • the corresponding substituted 4,5,6,7-Tetrahydro-1 H- pyrazolo[4,3-c]pyridine intermediates 6 were found to be TASK-1 blockers.
  • the group R5 may carry protecting groups which can be cleaved off by methods known in the prior art.
  • a hydroxyl group in R5 can be protected as a tert-butylether which can be cleaved off by an acid like HCI to give deprotected compounds 14 (Scheme 1 1 ).
  • the reaction is broadly applicable and not limited to the exact structure shown in Scheme 1 1 .
  • TASK-1 blockers 8 can be obtained by sulfonylation with alkylsulfonyl halogenides ((Ci-C6)-alkyl-SO2-) in inert solvents like CH2CI2 in the presence of a base like triethylamine as shown in Scheme 7.
  • reaction of intermediates 7 with 4- nitrophenylchloroformate leads to intermediates with can be reacted with diverse amines to give ureas 12 which have been found to be TASK-1 blockers and are novel compounds not described before.
  • the aryl or heteroaryl ring A can be modified when substituted by a bromide to give the corresponding nitriles as shown in Scheme 10 by reaction with Zn(CN) 2 in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium (0) (in analogy to Alterman, M.; Anders, H. Journal of Organic Chemistry, 2000 , vol. 65, 23 p. 7984 - 7989).
  • the reaction is not limited to pyridines as drawn in Scheme 10 but is applicable to a range of aryl and heteroaryl systems.
  • the novel compounds 13 which have not been previously described have been found to be TASK-1 blockers.
  • Scheme 1 1 A tert-butylether 8 can be cleaved off by an acid like HCI to give deprotected compounds 14 (Scheme 1 1 ).
  • the reaction is broadly applicable and not limited to the exact structure shown in Scheme 1 1 .
  • the working up and, if desired, the purification of the products and/or intermediates takes place by conventional methods such as extraction, chromatography or crystallization and conventional dryings.
  • the compounds of the formula I and/or their pharmaceutically compatible salts are suitable for the prevention and treatment of disorders which are caused by activation or by an activated TASK-1 , and also of disorders in which have TASK-1 - related damages appear secondary to another, primary cause.
  • the compounds of the formula I, and/or physiologically compatible salts thereof can also be used for the treatment and prevention of disorders where TASK-1 requires only partial inhibition, for example by using a lower dosage,
  • R5 is methyl and R2, R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl
  • residue X is phenyl, 4-fluoro-phenyl, 4-chloro- phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl, 3,4- dichlorophenyl, and
  • R5 is methyl and R2, R3 and R4 are equal to H and X is a phenyl residue, and the residue A is phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4- methyl-phenyl, 4-ethyloxy-phenyl, 3-trifluoromethyl-phenyl, 2-thiophenyl or 4- methylthiophenyl, and
  • These compounds can be employed to produce medicaments with a TASK-1 channel-blocking effect for the therapy and prophylaxis of TASK-1 channel- mediated diseases.
  • the compounds of the formula I and/or their pharmaceutically acceptable salts can further be used for the therapy or prophylaxis of cardiac arrhythmias, e.g. of arrhythmias that respond to the changes in the shape of the action potential, mainly a prolongation of the action potential, which is induced by TASK-1 blockade.
  • the compounds of the formula I and/or their pharmaceutically acceptable salts can be employed for terminating existent atrial fibrillation or flutter to restore the sinus rhythm (cardioversion).
  • the compounds reduce the susceptibility for a new development of atrial fibrillation events, thus the compounds are suitable for prophylactic treatment by maintenance of sinus rhythm (rhythm control).
  • the substances are devoid of a ventricular proarrhythmic risk (prolongation of the QT- interval and Torsades de pointe arrhythmias).
  • the compounds of the formula I and/or their pharmaceutically acceptable salts can be employed for producing a medicament for the treatment and/or prevention of arrhythmias, for example atrial trachyarrhythmias, atrial fibrillation and atrial flutter
  • the compounds of the formula I and/or their pharmaceutically acceptable salts are further suitable for producing a medicament for the therapy or prophylaxis of sleep- related respiratory disorders, central and obstructive sleep apneas, upper airway resistance syndrome, Cheyne-Stokes respiration, snoring, disrupted central respiratory drive, sudden child death, postoperative hypoxia and apnea, muscle- related respiratory disorders, respiratory disorders after long-term mechanical ventilation (weaning), respiratory disorders during adaptation in high mountains, acute and for respiratory disorders, chronic lung disorders with hypoxia and hypercapnia, chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome.
  • sleep- related respiratory disorders central and obstructive sleep apneas, upper airway resistance syndrome
  • Cheyne-Stokes respiration snoring, disrupted central respiratory drive, sudden child death, postoperative hypoxia and apnea
  • muscle- related respiratory disorders respiratory disorders after long-term mechanical ventilation (wean
  • the compounds of the formula I and/or their pharmaceutically acceptable salts are further suitable as a respiratory stimulant for the prevention and treatment of respiratory depression associated with anesthesia or procedural sedations for small interventions or for diagnostic purposes, for the treatment and prevention of respiratory depression by opioids in chronic pain treatment e.g. in cancer or palliative care or procedural sedations and/or for weaning from longterm mechanical ventilation.
  • the compounds of the formula I and/or their pharmaceutically acceptable salts are further suitable for the treatment and/or prevention of multiple sclerosis and inflammatory and degenerative disorders of the central nervous system.
  • the compounds of the invention of the formula I and their pharmaceutically acceptable salts can thus be used on animals, for example on mammals, and in particular on humans, as pharmaceuticals on their own, in mixtures with one another or in the form of pharmaceutical preparations (pharmaceutical compositions).
  • a further embodiment of the present invention is a pharmaceutical preparation comprising an effective amount of a compound of the formula I and/or of its pharmaceutically acceptable salts, together with pharmaceutically acceptable carriers and additives, alone or in combination with other pharmacological active ingredients or pharmaceuticals.
  • the pharmaceutical preparations usually comprise from 0.1 to 90 percent by weight of the compounds of the formula I and/or their pharmaceutically acceptable salts.
  • the pharmaceutical preparations can be produced in a manner known per se. For this purpose, the compounds of the formula I and/or their pharmaceutically acceptable salts are converted together with one or more solid or liquid pharmaceutical vehicles and/or excipients and, if desired, in combination with other pharmaceutical active ingredients into a suitable dosage form, which can then be used as pharmaceutical in human medicine or veterinary medicine.
  • pharmaceutically acceptable salts can moreover be administered for example orally, intravenously, intramuscular, subcutaneously, nasally, topically, pharyngeally or by inhalation, and the preferred administration depends on the individual case, for example on the particular manifestation of the disorder.
  • the compounds of the formula I can moreover be used alone or together with pharmaceutical excipients, in particular both in veterinary and in human medicine.
  • the pharmaceuticals comprise active ingredients of the formula I and/or their pharmaceutically acceptable salts generally in an amount of from 0.01 mg to 1 g per dose unit.
  • excipients are suitable for the desired pharmaceutical formulation.
  • solvents gel formers, suppository bases, tablet excipients and other active substance carriers it is possible to use for example antioxidants, dispersants, emulsifiers, antifoams, masking flavors, preservatives, solubilizers, agents for achieving a depot effect, buffer substances or colorants.
  • the active compounds are mixed with the additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and converted by conventional methods into suitable presentations such as tablets, coated tablets, two-piece capsules, aqueous, alcoholic or oily solutions.
  • suitable inert carriers which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. Preparation can take place both as dry and as wet granules.
  • Suitable as oily carriers or as solvents are, for example, vegetable or animal oils such as sunflower oil or fish liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol or sugar solutions or mixtures thereof.
  • further excipients, also for other administration forms are polyethylene glycols and polypropylene glycols.
  • the active compound for subcutaneous, intramuscular or intravenous administration, the active
  • the compounds of the formula I and/or their pharmaceutically acceptable salts may also be lyophilized and the resulting lyophilizates be used, for example, for producing products for injection or infusion.
  • suitable solvents are: water, physiological saline or alcohols, for example ethanol, propanol, glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else mixtures of the various solvents mentioned.
  • Suitable as pharmaceutical formulation for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I or their pharmaceutically acceptable salts in a
  • Such a preparation comprises the active ingredient normally in a concentration of about 0.1 to 10, in particular of about 0.3 to 3 percent by weight.
  • the dosage of the active ingredient to be administered or of the pharmaceutically acceptable salts thereof depends on the individual case and should be adapted to the circumstances of the individual case as usual for an optimal effect. Thus, it naturally depends on the frequency of administration and on the potency and duration of action of the particular compounds employed for therapy or prophylaxis, but also on the type and severity of the disease to be treated, and on the gender, age, weight and individual response of the human or animal to be treated, and on whether therapy is acute or prophylactic.
  • the daily dose of a compound of the formula I and/or its pharmaceutically acceptable salts for a patient weighing about 75 kg is normally at least 0.001 mg/kg to 100 mg/kg of body weight, preferably 0.01 mg/kg to 20 mg/kg.
  • Even higher dosages may also be necessary for acute episodes of the disease, for example in an intensive care unit. Up to 800 mg per day may be necessary.
  • the dose may be in the form of a single dose or be divided into a plurality, for example two, three or four, single doses.
  • Parenteral administration by injection or infusion, for example a continuous intravenous infusion, may also be advantageous, especially in the treatment of acute cases of cardiac arrhythmias, for example in an intensive care unit.
  • step 1 a mixture of morpholine (67.85 g, 0.779 mol), 1 - acetyl-4-piperidone (99.95 g, 0.708 mol) and para-toluenesulfonic acid (0.366 g, 2.1 mmol) in toluene (300 ml) was heated in a Dean-Stark trap apparatus for 16 h at reflux. Solvents were evaporated in vacuo to give 149 g of 1 -(4-Morpholin-4-yl-3,6- dihydro-2H-pyridin-1 -yl)-ethanone (1 ) which was used in the next step without any further purification. 3-(5-Acetyl-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile (3a)
  • Step 1
  • hydrochloride salt (7c) (0.050 g, 0.129 mmol), NaHCO3 (44 mg, 0.517 mmol), water (2 ml) and ethyl acetate (2 ml) was added cyclopropanecarbonyl chloride (13.5 mg, 0.129 mmol) and the mixture was stirred at 25°C for 16 h.
  • enantiomer 2 3-(4-Fluoro-phenyl)-1 -[(R)-1 -(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4, 5,6,7- tetrahydro-1 H-pyrazolo[4,3-c]pyridine
  • enantiomer 2 (9b) was obtained starting from 3-(4-Fluoro-phenyl)-1 -[1 -(4-fluoro-phenyl)-ethyl]-4,5,6,7-tetrahydro-1 H-pyrazolo[4,3- c]pyridine (enantiomer 2) (7f) by following a similar reaction as used for synthesis of (9a).
  • TASK-1 channels were expressed in Xenopus oocytes.
  • oocytes were isolated from Xenopus laevis and defoliculated.
  • TASK- 1 -encoding RNA synthesized in vitro was injected into oocytes.
  • TASK-1 currents were measured by two-microelectrode voltage clamp. Data were acquired and analyzed using a TEC-10cx amplifier (NPI Electronic, Tamm, Germany) connected to an ITC-16 interface (Instrutech Corp., Long Island, USA) and Pulse software (HEKA Elektronik, Lambrecht, Germany).
  • Oocytes were clamped to -90 mV and TASK-1 mediated currents were measured during 500 ms voltage pulses to 40 mV. Oocytes were continuously superfused with ND96 buffer containing: NaCI 96 mM, KCI 2 mM, CaCI 2 1 .8 mM, MgCI 2 1 mM, HEPES 5 mM (pH adjusted to 7.4 with NaOH). All experiments were performed at room temperature.
  • S2 extra-stimulus
  • the refractory period values are stated in percent of the basal values 15 minutes after injection. Mean values for the refractory periods are shown from three rates (150, 200 and 250/min).
  • the inhibitory values for the inhibition of episodes of arrhythmias refer to 3 measurements (3 timepoints) before administration vs. 3 measurements during the first hour after administration of the compounds.

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Abstract

La présente invention concerne des 4,5,6,7-tétrahydro-1H-pyrazolo[4,3-c]pyridines substituées de formule (I), leur utilisation comme médicament et des compositions pharmaceutiques les contenant. Les composés de formule (I) agissent sur le canal potassique TASK-1. Les composés sont appropriés pour traiter ou prévenir les arythmies auriculaires, par exemple la fibrillation auriculaire (FA) ou le flutter auriculaire.
PCT/EP2012/067995 2011-09-16 2012-09-13 4,5,6,7-tétrahydro-1h-pyrazolo[4,3-c]pyridines substituées, leur utilisation comme médicament, et préparations pharmaceutiques les contenant Ceased WO2013037914A1 (fr)

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EA201490640A EA025240B1 (ru) 2011-09-16 2012-09-13 ЗАМЕЩЕННЫЕ 4,5,6,7-ТЕТРАГИДРО-1H-ПИРАЗОЛО[4,3-c]ПИРИДИНЫ, ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ЛЕКАРСТВЕННОГО СРЕДСТВА И ФАРМАЦЕВТИЧЕСКИЕ ПРЕПАРАТЫ, СОДЕРЖАЩИЕ ИХ
MX2014003181A MX2014003181A (es) 2011-09-16 2012-09-13 4,5,6,7-tetrahidro-1h-pirazolo [4,3-c] piridinas sustituidas, su uso como medicamento y preparaciones farmacéuticas que las comprenden.
BR112014006180A BR112014006180A2 (pt) 2011-09-16 2012-09-13 4, 5, 6, 7-tetraidro-1h-pirazol [4, 3-c] piridinas substituídas, seu uso como medicamento e preparações farmacêuticas que compreendem as mesmas

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170044167A1 (en) * 2014-04-24 2017-02-16 Dart Neuroscience (Cayman) Ltd. Substituted 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole and 4,5,6,7-tetrahydro-2h-pyrazolo[4,3-c]pyridine compounds as glyt1 inhibitors
WO2017097792A1 (fr) * 2015-12-10 2017-06-15 Bayer Pharma Aktiengesellschaft Dérivés de 2-phényl-3-(pipérazinométhyl)imidazo[1,2-a]pyridine utilisés comme bloqueurs des canaux task-1 et task-2 pour traiter des troubles respiratoires liés au sommeil
JP2018500372A (ja) * 2014-12-30 2018-01-11 ノヴィラ・セラピューティクス・インコーポレイテッド Ｂ型肝炎感染症治療のための誘導体及び方法
US10040759B2 (en) 2014-11-05 2018-08-07 Dart Neuroscience (Cayman) Ltd. Substituted azetidinyl compounds as GlyT1 inhibitors
WO2018228907A1 (fr) * 2017-06-14 2018-12-20 Bayer Aktiengesellschaft Imidazopyrimidines à substitution diazabicyclique et leur utilisation pour traiter des maladies des voies respiratoires
US10414765B2 (en) 2015-12-10 2019-09-17 Bayer Pharma Aktiengesellschaft Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
WO2021207308A1 (fr) * 2020-04-09 2021-10-14 Disarm Therapeutics, Inc. Dérivés de pyrazole condensés utiles en tant qu'inhibiteurs de sarm1
WO2022167819A1 (fr) * 2021-02-08 2022-08-11 Cerevance, Inc. Nouveaux composés

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0086422A2 (fr) 1982-02-17 1983-08-24 GRUPPO LEPETIT S.p.A. Pyrazolo (4,3-c)pyridines à activité pharmacologique
WO2005016965A1 (fr) 2003-07-18 2005-02-24 Bayer Healthcare Ag Modulateurs des canaux potassium twik-1, task-1, girk1, sk2 ou pcn1 pour le traitement des arythmies, des coronaropathies ou de l'hypertension
WO2006136304A1 (fr) 2005-06-22 2006-12-28 Sanofi-Aventis Hétérocycles substitués, leur utilisation comme médicament et préparations pharmaceutiques les comprenant
WO2007124849A2 (fr) 2006-04-27 2007-11-08 Sanofi-Aventis Deutschland Gmbh Inhibiteurs du canal ionique task-1 et task-3
US20080188520A1 (en) * 2005-06-22 2008-08-07 Sanofi-Aventis Substituted heterocycles, their use as medicament, and pharmaceutical preparations comprising them
WO2011115804A1 (fr) * 2010-03-17 2011-09-22 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0086422A2 (fr) 1982-02-17 1983-08-24 GRUPPO LEPETIT S.p.A. Pyrazolo (4,3-c)pyridines à activité pharmacologique
WO2005016965A1 (fr) 2003-07-18 2005-02-24 Bayer Healthcare Ag Modulateurs des canaux potassium twik-1, task-1, girk1, sk2 ou pcn1 pour le traitement des arythmies, des coronaropathies ou de l'hypertension
WO2006136304A1 (fr) 2005-06-22 2006-12-28 Sanofi-Aventis Hétérocycles substitués, leur utilisation comme médicament et préparations pharmaceutiques les comprenant
US20080188520A1 (en) * 2005-06-22 2008-08-07 Sanofi-Aventis Substituted heterocycles, their use as medicament, and pharmaceutical preparations comprising them
WO2007124849A2 (fr) 2006-04-27 2007-11-08 Sanofi-Aventis Deutschland Gmbh Inhibiteurs du canal ionique task-1 et task-3
WO2011115804A1 (fr) * 2010-03-17 2011-09-22 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc

Non-Patent Citations (33)

* Cited by examiner, † Cited by third party
Title
ALTERMAN, M.; ANDERS, H., JOURNAL OF ORGANIC CHEMISTRY, vol. 65, no. 23, 2000, pages 7984 - 7989
BASIC RES CARDIOL., vol. 106, no. L, January 2011 (2011-01-01), pages 75 - 87
BASIC. RES. CARDIOL., vol. 98, 2003, pages 137 - 148
BAYLISS D.A.; TALLEY E.M.; SIROIS J.E.; LEI Q.: "TASK-1 is a highly modulated pH-sensitive 'leak' K+ channel expressed in brainstem respiratory neurons", RESPIRATION PHYSIOLOGY, 2001, pages 159 - 174
BERG A.P.; TALLEY E.M.; MANGER J.P.; BAYLISS D.A.: "Motoneurons express Heteromeric TWIK-related acid-sensitive K+ (TASK) Channels containing TASK-1 (KCNK3) and TASK-3 (KCNK9) subunits", J. NEUROSCIENCE, 2004, pages 6693 - 6702
BITTNER STEFAN; MEUTH SVEN G; GOBEL KERSTIN; MELZER NICO; HERRMANN ALEXANDER M; SIMON OLE J; WEISHAUPT ANDREAS; BUDDE THOMAS; BAYL, BRAIN : A JOURNAL OF NEUROLOGY, vol. 132, 2009, pages 2501 - 16
BRUNDEL B.J.J.M. ET AL., JACC, vol. 37, 2001, pages 926 - 932
BUCKLER K.J.; WILLIAMS B.A.; HONORE E.: "An oxygen-, acid-and anaesthetic-sensitive TASK-like background potassium channel in rat arterial chemoreceptor cells", J. PHYSIOL., 2000, pages 135 - 142
COETZEE W.J. ET AL.: "Molecular diversity of K+ channels", ANN. NEW YORK ACAD. SCI., 1999, pages 233 - 285
COTTEN J.F.; KESHAVAPRASAD B.; LASTER M.J.; EGER E.I.; YOST C.S.: "The Ventilatory Stimulant Doxapram Inhibits TASK Tandem Pore (K2P) Potassium Channel Function but Does Not Affect Minimum Alveolar Anesthetic Concentration", ANESTH. ANALG., 2006, pages 779 - 785, XP009103929, DOI: doi:10.1213/01.ane.0000194289.34345.63
D. M. RODEN: "Current status of class III antiarrhythmic drug therapy", AM. J. CARDIOL., vol. 72, 1993, pages 44B - 49B
D.A. BAYLISS; P. BARRETT, TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 29, no. 11, 2008, pages 566 - 575
DALISAY, D. S.; QUACH, T.; NICHOLAS, G. N.; MOLINSKI, T. F., ANGEWANDTE CHEMIE, vol. 48, 2009, pages 4367 - 4371
DUPRAT F.; LESAGE F.; FINK M.; REYES R.; HEURTEAUX C.; LAZDUNSKI M.: "TASK, a human background K+ channel to sense external pH variations near physiological pH", EMBO J., 1997, pages 5464 - 5471
ELLINGHAUS P. ET AL., J. THORACIC CARDIOVASCULAR SURGERY, vol. 129, 2005, pages 1383 - 1390
EUROPEAN JOURNAL OF PHYSIOLOGY, vol. 450, 2005, pages 201 - 208
JOURNAL OF CLINICAL INVEST, vol. 121, no. 8, 2011, pages 2955 - 2968
JOURNAL OF MOLECULAR MEDICINE, 2004, pages 308 - 316
JOURNAL OF NEUROSCIENCE, vol. 25, no. 49, 2005, pages 11455 - 11467
KNOBLOCH ET AL., NAUNYN-SCHMIEDBERG'S ARCH. PHARMACOL., vol. 366, 2002, pages 482 - 487
KNORR, R. ET AL., TETRAHEDRON LETT., vol. 30, 1989, pages 1927
LAURITZEN I.; ZANZOURI M.; HONORE E.; DUPRAT F.; EHRENGRUBER M.U.; LAZDUNSKI M.; PATEL A.J.: "K+- dependent cerebellar granule neuron apoptosis - Role of Task leak K+ channels", J. BIOL. CHEM., 2003, pages 32068 - 32076
MAINGRET F.; PATEL A.J.; LAZDUNSKI M.; HONORE E.: "The endocannabinoid anandamide is a direct and selective blocker of the background K+ channel TASK-1", EMBO J., 2001, pages 47 - 54, XP001203548, DOI: doi:10.1093/emboj/20.1.47
MEDHURST A.D.; RENNIE G.; CHAPMAN C.G.; MEADOWS H.; DUCKWORTH M.D.; KELSELL R.E; GLOBER I.I.; PANGALOS M.N.: "Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery", MOL. BRAIN RES., 2001, pages 101 - 114, XP002329245, DOI: doi:10.1016/S0169-328X(00)00263-1
NOZAKI, S., J. PEPTIDE RES., vol. 54, 1999, pages 162
PATEL A.J.; HONORE E.: "Properties and modulation of mammalian 2P domain K+ channels", TRENDS NEUROSCI., 2001, pages 339 - 346, XP004239821, DOI: doi:10.1016/S0166-2236(00)01810-5
PATEL A.J.; HONORE E.; LESAGE F.; FINK M.; ROMEY G.; LAZDUNSKI M.: "Inhalational anesthetics activate two-pore-domain background K+ channels", NATURE NEUROSCI., 1999, pages 422 - 426, XP002145560, DOI: doi:10.1038/8084
PATEL A.J.; LAZDUNSKI M.: "The 2P-domain K+ channels: role in apoptosis and tumorigenesis", PFLUGERS ARCH., 2004, pages 261 - 273, XP002329247, DOI: doi:10.1007/s00424-004-1255-8
PEUKERT, S.; BRENDEL, J.; PIRARD, B.; BRUEGGEMANN, A.; BELOW, P.; KLEEMANN, H.-W.; HEMMERLE, H.; SCHMIDT, W.: "Identification, Synthesis, and Activity of Novel Blockers of the Voltage-Gated Potassium Channel Kv1.5.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 4, 2003, pages 486 - 498, XP002292322, DOI: doi:10.1021/jm0210461
PUTZKE C; WEMHONER K; SACHSE FB; RINNE S; SCHLICHTH6RL G; LI XT; JAE L; ECKHARDT I; WISCHMEYER E; WULF H, CARDIOVASCULAR RESEARCH, vol. 75, 2007, pages 59 - 68
STREIT, A. K.; NETTER, M. F.; KEMPF, F.; WALECKI, M.; RINNE, S.; BOLLEPALLI, M. K; PREISIG-MUELLER, R.; RENIGUNTA, V.; DAUT, J.; B: "A Specific Two-pore Domain Potassium Channel Blocker Defines the Structure of the TASK-1 Open Pore", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 286, no. 16, 2011, pages 13977 - 13984
T. J. COLATSKY ET AL.: "Potassium channels as targets for antiarrhythmic drug action", DRUG DEV. RES., vol. 19, 1990, pages 129 - 140
WINTERS G ET AL: "Synthesis, in vitro [3H]prazosin displacement, and in vivo activity of 3-aryl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridines, a new class of antihypertensive agents", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 28, 1 January 1985 (1985-01-01), pages 934 - 940, XP002256019, ISSN: 0022-2623, DOI: 10.1021/JM00145A015 *

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