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WO2007138110A2 - Compounds that interact with ion channels, in particular with ion channels from the kv family - Google Patents

Compounds that interact with ion channels, in particular with ion channels from the kv family Download PDF

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Publication number
WO2007138110A2
WO2007138110A2 PCT/EP2007/055404 EP2007055404W WO2007138110A2 WO 2007138110 A2 WO2007138110 A2 WO 2007138110A2 EP 2007055404 W EP2007055404 W EP 2007055404W WO 2007138110 A2 WO2007138110 A2 WO 2007138110A2
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WO
WIPO (PCT)
Prior art keywords
thιazole
alkyl
phenyl
carboxylιc acid
aryl
Prior art date
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PCT/EP2007/055404
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French (fr)
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WO2007138110A3 (en
Inventor
Petra Blom
Olivier Defert
Titus Kaletta
Dirk Casimir Maria Leysen
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Devgen N.V.
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Publication of WO2007138110A2 publication Critical patent/WO2007138110A2/en
Publication of WO2007138110A3 publication Critical patent/WO2007138110A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to compounds that interact with ion channels.
  • the invention relates to compounds that interact with ion channels from the Kv family, and in particular from the Kv4 subfamily.
  • the invention also relates to methods for preparing said compounds, to pharmaceutical compositions that contain said compounds, and to the use of said compounds in methods for treatment of the human and animal body and/or to the use of said compounds in the preparation of such pharmaceutical compositions.
  • the compounds of the invention for example can be used in the prevention and/or treatment of conditions or diseases associated with ion channels, in particular in the prevention and/or treatment of conditions and diseases associated with ion channels of the Kv family, and more in particular in the prevention and/or treatment of conditions and diseases associated with ion channels of the Kv4 family.
  • Kv4 channels as well as their encoding sequences, their biological function/activity and their disease associations have been described in the art, see for example Bahring et al., J.Biol.Chem., Vol. 276, no. 26, 233888-23894 (2001 ); Baldwin et al., Neuron 7: 471-483 (1991 ); Dixon et al., Circ. Res. 79: 659-688 (1996); Dilks et al., J. Neurophysiol. 81 : 1974-1977 (1999); Kuo et al., Cell, Vol. 107, 801-813 (2001 ); Pak et al., Proc. Natl. Acad.
  • Kv4 channels are inter alia involved in membrane depolarisation and repolarisation events, e.g. as part of and/or following neuronal firing and/or as part of the cycle of muscle contraction/relaxation.
  • Kv4 channels are believed to be involved in the native A-type currents that are generated by various types of primary cells (Dilks et al., supra), in particular in muscle and neuronal cells.
  • Kv4.2 and Kv4.3 transcripts have been found in most neurons, and in particular in CNS neurons (see Serodio and Rudy, supra, who discuss the distribution of Kv4 channels in rat brain); as well as in heart muscle (see Dixon et al. and by Serodio et al., both supra, who discuss the abundance and distribution of Kv4 transcripts in the hearts of rat, dog and human).
  • Kv4 channels activate and inactivate at subthreshold potentials, inactivate with time constants that change very little as a function of voltage (even at very negative potentials), and recover very fast from inactivation (see Rudy and Serodio, supra).
  • Kv4 channels are inter alia believed to play an important role in the modulation of the firing rate, action potential initiation, shaping burst pattern and postsynaptic signal integration (Dilks et al., and Bahring et al., supra), and are believed to be associated with the physiological states/disorders that result from such activity (Serodio and Rudy, supra).
  • the Kv4 channels are inter alia believed to play a major role in the calcium- independent A-type currents in the cardiac muscle (the "transient outward current” or “l t0 "), and in particular in the cardiac ventricular muscle, and are thus believed to be involved in early repolarization and hence the overall duration of the action potential and the length of the refractory period (Serodio and Rudy, supra). Because of this, Kv4 channels are believed to be associated with (the susceptibility to) cardiac disorders such as arrhythmia and other types of heart failure (Kuo et al., supra).
  • Kv4.1 also known as mShai
  • Kv4.2 also known as RK5
  • Kv4.3 three mammalian Kv4 genes - referred to as Kv4.1 (also known as mShai ), Kv4.2 (also known as RK5) and Kv4.3, respectively - have been cloned and characterized, i.e. from rat and dog (Dixon et al, Serodio et al., Ohya et al. and Takimoto et al., all supra) and from human (Dilks et al., and Bahring et al., supra; see also for example WO 98/42833 and US-A-6, 395,477).
  • sequences of genes encoding mammalian Kv4 channels are also available from publicly accessible databases such as GenBank/NCBI, e.g. Kv4.1 from mouse (accession number NP_032449 and A38372); Kv4.1 from human (accession number BAA96454, AAF65617 and AF65516); Kv4.2 from mouse (accession number NP_062671 and AAD16972), Kv4.2 from rat (accession number NP 113918); Kv4.2 from human (accession number AAD22053 and CAB56841 ); Kv4.3 from mouse (accession numbers NM_019931 and AF384170), Kv4.3 from rat (accession number U42975) and Kv4.3 from human (accession number XM_052127).
  • GenBank/NCBI e.g. Kv4.1 from mouse (accession number NP_032449 and A38372); Kv4.1 from human (accession number BAA96454, AAF
  • the Kv4 channels in mammals also have a high degree of sequence identity (>70%) with, and thus are considered closely related to, the Shal-Wke gene product, which encodes a potassium channel in Drosophila melanogaster (see Baldwin et al, supra, and also WO 01/58952).
  • an assay for determining the influence of a compound on Kv channels in which a transgenic line of Caenorhabditis elegans expressing a heterologous Kv channel, such as a human Kv4.3 channel, is used, is described in the International application WO 03/097682 by Applicant.
  • Other assays and techniques for determining the influence of a test compound on ion channels in general, and on a Kv channel in particular, such as FLIPR-techniques and use of oocytes will be clear to the skilled person, and are also mentioned in WO 03/097682.
  • Such assays can be used to determine whether a compound "interacts with" such an ion channel.
  • a compound is considered to "interact with" an ion channel, such as an ion channel of the Kv family and in particular of the Kv4 subfamily, if such a compound acts as an antagonist of said ion channel and/or of the biological function(s) and/or pathways associated with said ion channels, and in particular if such a compound can fully or partially “block” such an ion channel.
  • an ion channel such as an ion channel of the Kv family and in particular of the Kv4 subfamily
  • compounds that interact with ion channels can find use as pharmaceutically active agents, in particular for the prevention and/or treatment of diseases and disorders associated with the ion channels with which the compound interact.
  • compounds that interact with ion channels from the Kv 4 subfamily, and in particular with Kv4.3 ion channels could be used in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of cardiac disorders such as arrhythmia, hypertension-induced heart disorders such as hypertension-induced cardiac hypertrophy (e.g.
  • disorders of the nervous system and neurological disorders such as epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, Alzheimer's disease, encephalomyelitis, multiple sclerosis, demyelinating disease, and Parkinson's syndrome.
  • a major drawback of some of the known compounds involves that the drugs do not work in a selective manner, i.e. they do not select between different ion channels. For instance, many of these compounds also block a potassium channel called the human ether-a-go-go related gene (hERG) potassium channel. Compounds that block this channel with high potency may cause reactions which are fatal. This undesired blockade can cause acquired long QT syndrome, a disorder that puts patients at risk for life-threatening arrhythmias. Cardiac arrhythmias are the leading cause of sudden death in the United States, according to the American Heart Association. The FDA now requires that every drug be assayed for hERG block before it is approved. Even medicines that might be beneficial for the vast majority of patients do not make it to the market - or have been pulled from the market - if they block hERG.
  • hERG human ether-a-go-go related gene
  • the present invention relates to compounds of Formula I, II, III, IV, V or Vl stereoisomers, tautomers, racemics or a pharmaceutically acceptable salt and/or solvate thereof,
  • L 1 is selected from -NH-, -CH 2 -, -SO 2 -,
  • L 2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, wherein A 1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, al
  • R 2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R 6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4, with the proviso that when L 1 is NH in formula I, R 1 is selected from halogen, aryl or alkylhetero,
  • the present invention relates to a method for synthesizing a compound having one of the structural Formula I, II, III, IV, V or Vl, comprising the step of condensing a compound of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII:
  • the compounds of the present invention are particularly useful for the preparation of a medicament in the prevention and/or treatment of conditions or diseases associated with ion channels of the Kv4 family.
  • Non-limiting examples of said conditions or diseases associated with ion channels of the Kv4 family can be selected from the group comprising (i) cardiac disorders including arrhythmias including Brugada Syndrome; hypertension-induced heart disorders including hypertension-induced cardiac hypertrophy; cardiac failure; and (ii) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome.
  • Arrhythmias include (i) atrial Arrhythmias such as but not limited to Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff-Parkinson-White (WPW) syndrome; (ii) Ventricular Arrhythmias such as but not limited to Premature ventricular contraction (PVC), ventricular tachycardia (VT), ventricular fibrillation and bradicardias; (iii) Others such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrio-ventricular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias.
  • atrial Arrhythmias such as but not limited to Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick
  • the present invention provides for the use of a compound of the invention for the preparation of a medicament for treating cardiac disorders such as atrial fibrillation, atrial flutter and/or Brugada Syndrome.
  • the present invention provides for the use of a compound of the invention for the preparation of a medicament for treating disorders of the nervous system such as Alzheimer's disease.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to the invention.
  • Said composition is particularly useful in the prevention and/or treatment of conditions or diseases associated with ion channels of the Kv4 family such as the one cited herein.
  • Said composition is particularly suited for example in the treatment of cardiac disorders and disorders of the nervous system.
  • the compounds of the present invention interact with ion channels of the Kv1 subfamily, and especially with Kv1.5 channels.
  • the present invention also provides a method of treating cardiac disorders comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention.
  • the present invention provides a method of treating disorders of the nervous system comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention.
  • the invention relates to a compound of Formula I, II, IV, V or Vl,
  • the dotted line represents an optional double bond.
  • alkyl by itself or as part of another substituent, refers to a straight or branched saturated hydrocarbon group joined by single carbon-carbon bonds having 1 to 10 carbon atoms, for example 1 to 8 carbon atoms, for example 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • C- ⁇ _ 4 alkyl means an alkyl of one to four carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ferf-butyl, 2-methylbutyl, pentyl iso-amyl and its isomers, hexyl and its isomers, heptyl and its isomers and octyl and its isomer.
  • optionally substituted alkyl refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents) at any available point of attachment.
  • substituents include halogen, hydroxyl, carbonyl, nitro, amino, oximes, imines, azido, hydrazino, cyano, alkyl, aryl, heteroaryl, cycloalkyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid, acylamino, alkyl esters, carbamates, thioamides, urea, sulfonamides and the like.
  • alkyl When the term “alkyl” is used as a suffix following another term, as in “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one or two (preferably one) substituent(s) selected from the other, specifically-named group, also as defined herein.
  • hydroxyalkyl includes 2-hydroxyethyl, 1-(hydroxymethyl)-2-methylpropyl, 3,4- dihydroxybutyl, and so forth.
  • Alkoxyalkyl refers to an alkyl group substituted with one to two of
  • R' is alkyl as defined below.
  • aralkyl or “(aryl)alkyl refers to a substituted alkyl group as defined above wherein at least one of the alkyl substituents is an aryl as defined below, such as benzyl.
  • hydroxyalkyl refers to a -R a -OH group wherein R a is alkylene as defined herein.
  • cycloalkyl by itself or as part of another substituent, includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic or polycyclic alkyl groups wherein each cyclic moiety has from 3 to 8 carbon atoms, for example 3 to 7 carbon atoms, for example 3 to 6 carbon atoms, for example 3 to 5 carbon atoms.
  • the further rings of multi-ring cycloalkyls may be fused, bridged and/or joined through one or more spiro unions.
  • Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl, cycloheptyl, cyclooctyl and the like.
  • Examples of polycyclic cycloalkyl radicals include decahydronaphthyl, bicyclo [5.4.0] undecyl, adamantyl, and the like.
  • An "optionally substituted cycloalkyl” refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl. When the suffix "ene” is used in conjunction with a cyclic group, this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups.
  • alkenyl by itself or as part of another substituent, refers to a straight or branched alkyl chain containing at least one unsaturation in the form of a single carbon to carbon double bond and having 2 to 10 carbon atoms, for example 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms.
  • alkenyl groups are ethenyl, 2-propenyl, 2- butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2-heptenyl and its isomers, 2-octenyl and its isomers, 2,4-pentadienyl and the like.
  • An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1 to 3 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl.
  • alkynyl by itself or as part of another substituent, refers to a straight or branched alkyl chain containing at least one unsaturation in the form of a single carbon to carbon triple bond and having 2 to 10 carbon atoms, for example 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms.
  • alkynyl groups are ethynyl, 2-propynyl, 2-butynyl,
  • An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl.
  • alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed “alkylene” groups.
  • alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2- dimethylethylene, pentamethylene and hexamethylene.
  • alkenyl groups as defined above and alkynyl groups as defined above, respectively are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene” and "alkynylene” respectively.
  • alkyl groups as defined are trivalent, i.e., with three single bonds for attachment to three other groups, they are termed “alkylyne” or “alkyline” groups.
  • alkylyne include, methine, 1 ,1 ,2-ethyline, and the like.
  • aryl as used herein by itself or as part of another group refers but is not limited to 5 to 14 carbon-atom homocydic (i.e., hydrocarbon) monocyclic, bicyclic or tricyclic aromatic rings or ring systems containing 1 to 4 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic.
  • the aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto.
  • aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-, 3-, A-, 5-, 6-, 7- or 8-azulenyl, 1- or 2-naphthyl, 1-, 2- or 3-indenyl, 1-, 2- or 9-anthryl, 1- 2-, 3-, 4- or 5- acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1-, 2-, 3-, 4- or 10-phenanthryl, 1- or 2-pentalenyl, 1 , 2-, 3- or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,4
  • the aryl ring can optionally be substituted by one or more aromatic substituents.
  • An "optionally substituted aryl” refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, or 1 to 2 substituents) at any available point of attachment.
  • Non-limiting examples of such substituents are selected from halogen, hydroxyl, carbonyl, nitro, amino, azido, hydrazine, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 15 , alkylcarbonyloxy, fused heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, thiol, alkylthio, haloaryl, carboxyl, acylamino, alkyl esters, carbamate, thioamide, urea, or sulfonamide, and the like, wherein R 15 is alkyl or cycloalkyl.
  • aryloxy denotes a group -O-aryl, wherein aryl is as defined above
  • heteroaryl as used herein by itself or as part of another group refers but is not limited to
  • heteroaryl can be 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, A- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- isothiazolyl, 2-, 4- or 5-thiazolyl, 1 ,2,3-triazol-1-, -2-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3-, -4- or -5-yl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3- thiadiazol-4- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl,
  • heterocyclyl or “heterocyclo” as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows.
  • the rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms.
  • An "optionally substituted heterocyclyl" refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted aryl.
  • heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, indolinyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4
  • aralkyl by itself or as part of another substituent refers to a group having as alkyl moiety the aforementioned alkyl attached to one of the aforementioned aryl rings.
  • aralkyl radicals include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3- (2-naphthyl)-butyl, and the like.
  • cycloalkylalkyl by itself or as part of another substituent refers to a group having one of the aforementioned cycloalkyl groups attached to one of the aforementioned alkyl chains.
  • examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cydopentylethyl, 1-cydohexylethyl, 2-cyclopentylethyl, 2- cyclohexylethyl, cyclobutylpropyl, cyclopentyl propyl, 3-cyclopentyl butyl, cyclohexylbutyl and the like.
  • heterocyclyl-alkyl by itself or as part of another substituents refers to a group having one of the aforementioned heterocyclyl group attached to one of the aforementioned alkyl group, i.e., to a group -R b -R c wherein R b is alkylene or alkylene substituted by alkyl group and R c is a heterocyclyl group.
  • acyl by itself or as part of another substituent refers to an alkanoyl group having 2 to 6 carbon atoms or a phenylalkanoyl group whose alkanoyl moiety has 1 to 4 carbon atoms, i.e.; a carbonyl group linked to a radical such as, but not limited to, alkyl, aryl, more particularly, the group
  • acyl therefore encompasses the group alkylcarbonyl (-COR 11 ), wherein R 11 is alkyl.
  • Said acyl can be exemplified by acetyl, propionyl, butyryl, valeryl and pivaloyl, benzoyl, phenylacetyl, phenylpropionyl and phenylbutytyl.
  • alkylamino by itself or as part of another substituent refers to a group consisting of an amino groups attached to one or two independently selected and optionally substituted alkyl groups, cycloalkyl groups, aralkyl or cycloalkylalkyl groups i.e., -N(R 6 )(R 7 ) wherein R 6 and R 7 are each independently selected from hydrogen, cycloalkyl, aralkyl, cycloalkylalkyl or alkyl.
  • Non-limiting examples of alkylamino groups include methylamino (NHCH 3 ), ethylamino (NHCH 2 CH 3 ), n- propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, ferf-butylamino, n- hexylamino, and the like.
  • amino refers to the group -NH 2 .
  • aminoalkyl refers to the group -R b -NR d R e wherein R b is alkylene or substituted alkylene, R d is hydrogen or alkyl or substituted alkyl as defined herein, and R e is hydrogen or alkyl as defined herein.
  • carboxyl refers to the group -CO 2 H.
  • a carboxyalkyl is an alkyl group as defined above having at least one substituent that is -CO 2 H.
  • alkoxy by itself or as part of another substituent refers to a group consisting of an oxygen atom attached to one optionally substituted straight or branched alkyl group, cycloalkyl group, aralkyl or cycloalkylalkyl group.
  • suitable alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, ferf-butoxy, hexanoxy and the like.
  • alkyhetero by itself or as part of another substituents refers to a group consisting of a hetero atom attached to one optionally substituted alkyl group, cycloalkyl group, aralkyl or cycloalkylalkyl group.
  • alkylhetero groups include alkylthio and alkylamino.
  • alkylthio by itself or as part of another substituent refers to a group consisting of a sulfur atom attached to one optionally substituted alkyl group, cycloalkyl group, aralkyl or cycloalkylalkyl group.
  • alkylthio groups include methylthio (SCH 3 ), ethylthio (SCH 2 CH 3 ), n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, ferf-butylthio, n-hexylthio, and the like.
  • acylamino by itself or as part of another substituent refers to a group consisting of an amino group attached to one or two independently selected acyl groups as described before.
  • these represent imides such as phtalimides, maleimides and the like, and are encompassed in the meaning of the term acylamino.
  • halo or halogen as a group or part of a group is generic for fluoro, chloro, bromo or iodo.
  • haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • Non- limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifl uoroethyl and the like.
  • haloaryl alone or in combination, refers to an aryl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • haloalkoxy alone or in combination refers to a group of Formula -O-alkyl wherein the alkyl group is substituted by 1 , 2 or 3 halogen atoms.
  • haloalkoxy includes -OCF 3 and -OCHF 2 .
  • sulfonamide or “sulfonamidyl” alone or in combination refers to a group of Formula -S0 2 -NR d R e wherein R d is hydrogen or alkyl or substituted alkyl as defined herein, and R e is hydrogen or alkyl as defined herein.
  • pyrrolydinylenealkylene alone or in combination refers to a group of Formula
  • optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl or "a group selected from alkyl, cycloalkyl, alkenyl or alkynyl, each group being optionally substituted” means "optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl", wherein the substituents are the same as that described above for substituted alkyl.
  • substituted is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • compounds of the invention or a similar term is meant to include the compounds of general Formula I, II, III, IV, V or Vl and any subgroup thereof.
  • This term also refers to the compounds as depicted in Tables 1 and 2 and their derivatives, N- oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues.
  • the /V-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called ⁇ /-oxide.
  • a compound means one compound or more than one compound.
  • Asterisks (*) are used herein to indicate the point at which a mono-, bi- or trivalent radical depicted is connected to the structure to which it relates and of which the radical forms part.
  • pro-drug means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug.
  • the reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated.
  • Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component.
  • pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Pro-drugs are characterized by increased bio-availability and are readily metabolized into the active inhibitors in vivo.
  • the present invention provides compounds having one of the following structural formula VII, VIII, IX, X, Xl, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, or XXX,
  • L 1 is selected from -NH-, -CH 2 -, -SO 2 -,
  • L 2 is a group selected from C-
  • R 2 is selected from hydrogen, halogen, hydroxyl, hydroxyC-
  • 4 alkylamino or cycloalkyl s is an integer selected from 0, 1 , 2, 3 or 4, with the proviso that when L 1 is NH in formula I, R 1 is selected from halogen, C 5 . 14 aryl or C- ⁇ _ 4 alkylhetero, or when L 1 is NH in formula I and R 1 is hydrogen or C 1-4 alkyl, L 2 is pyrrolydinyleneC-
  • the present invention provides compounds having one of the structural Formula VIII, IX, X, Xl, XII, or XXX, wherein
  • R 1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero
  • R 2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R 6 is alkyl, alkylamino or cyd
  • R 4 is hydrogen
  • R 5 is hydrogen or alkyl
  • L 2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, and wherein A 1 is a group selected from aryl, heterocydyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalk
  • the present invention provides compounds having one of the structural Formula XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, wherein
  • R 2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R 6 is alkyl, alkylamino or cydoalkyl, s is an integer selected from 0, 1 , 2, 3 or 4,
  • R 4 is hydrogen
  • L 2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, and wherein A 1 is a group selected from aryl, heterocydyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalk
  • the present invention provides compounds structural Formula VII, wherein A 1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R 6 is alkyl, alkylamino or cycloalkyl, R 2 is selected
  • R 1 is hydrogen or alkyl and L 2 is pyrrolydinylenealkylene optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, or
  • R 1 is selected from halogen, aryl or alkylhetero
  • L 2 is a group selected from alkylene, cydoalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy.
  • the present invention provides compounds structural Formula VIII, wherein A 1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R 6 is alkyl, alkylamino or cycloalkyl, R 2 is selected
  • the present invention provides compounds as described hereinabove, wherein A 1 is a group selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, tetrazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, 2H-thiopyranyl, 4H-thiopyranyl, benzofuryl, benzothienyl, benzimidazolonyl, 2,3-dihydro-1 ,4-
  • the present invention provides compounds as described hereinabove, wherein A 1 is a group selected from 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1- , 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- isothiazolyl, 2-, 4- or 5-thiazolyl, 1 ,2,3-triazol-1-, -2-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3-, -4- or -5-yl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,5-
  • the present invention provides compounds as described hereinabove, wherein A 1 is a group selected from phenyl, 2-, 3-, A-, 5-, 6-, 7-, 8-quinolinyl, 2,3-dihydro-1 ,4- benzodioxinyl, 6-indolyl, 1-napthyl, 2-naphtly, indanyl, 1 ,3-dihydrobenzoimidazol2-one, 1 , 2, 3, A- tetrahydronapthtlanel-1-yl, 2-benzofuran-5-yl, pyridin-4-yl, pyridin-3-yl, 1 ,3-benzodioxolyl, benzimidazolonyl, 2- thienyl, 3-th ⁇ enyl, or 5-(2,3-d ⁇ hydro)benzofuranyl, each group being optionally substituted with one to four substituent independently selected from F, Cl, Br, -CH 3
  • R 2 is selected from hydrogen, nitro, -SO 2 -NH 2 , F, Cl, Br, OH, -CH 3 , -OCH 3 , -NO 2 , -CO 2 H,
  • the present invention provides compounds having the structural formula XXXI,
  • L 2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, R 1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero, and
  • R 2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R 6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4, and R 8 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl
  • R 2 is selected from hydrogen, nitro, -SO 2 -NH 2 , F, Cl, Br, OH, -CH 3 , -OCH 3 , -NO 2 , -CO 2 H,
  • the present invention provides compounds as described heremabove, wherein R 2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido. cyano. alkyl. aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO 2 R 6 , alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R 6 is alkyl, alkylamino or cycloalkyl.
  • the present invention provides compounds as described heremabove wherein R 2 is selected from hydrogen, thienyl, methyl, ethyl, propyl, isopropyl, butyl, fert-butyl, chloro, fluoro, bromo, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy or phenoxy
  • R 1 is hydrogen, bromo, fluoro, chloro, methyl, phenyl, methylthio or ethylthio.
  • the present invention provides compounds as described hereinabove wherein R 7 is selected from hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy.
  • R 7 is selected from hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy.
  • the present invention also relates to methods for the preparation of the compounds according to the present invention, using for example structurally related compounds.
  • the compounds of the present invention can be prepared using the non-limiting methods described hereunder and in the examples.
  • the method for preparing the compounds of the invention comprises the step of condensation of a compound of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII:
  • the reaction can generally be performed by condensing the compound of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII with a compound of Formula XXIX.
  • the condensation can be performed via the formation of the acyl chloride of the acid of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII and then by the coupling of said acyl chloride with the amine of Formula XXIX.
  • the condensation can be performed by using a suitable coupling agent, in a suitable solvent, in the presence of suitable base.
  • the suitable coupling agent can be selected from the group comprising dicyclo-hexylcarbodiimide, hydroxybenzotriazole, o-benzotriazol-1-yl-N,N,N',N-4-tetramethyluronium hexafluorophosphate and the like and mixture thereof.
  • the suitable solvent can be selected from the group comprising dichloromethane, dimethylformamide and the like or mixture thereof.
  • suitable base comprise potassium carbonate, diisopropylethylamine, triethylamine, triisopropylamine and the like.
  • the condensation can be realized via formation of the corresponding acyl chloride and then coupling with the desired amine.
  • a suitable coupling agent such as hydroxybenzotriazole (HOBT), o- benzotriazol-1-yl-N,N,N',N-4-tetramethyluronium hexafluorophosphate (TBTU) and the like at a suitable molar ratio, for example between 1 :1 to 1 :3 relative to the acid derivative; in a suitable solvent or solvent mixture, such as dichloromethane (DCM) or dimethylformamide (DMF) and the like; at a suitable temperature, usually between O 0 C and the boiling point of the solvent used; for a suitable period of time, usually between 0.25 hr and 48 hrs; in the presence of a suitable base, for example an organic base such as potassium carbonate (K 2 CO 3 ), diisopropylethylamine (DIEA), triethylamine (TE
  • K 2 CO 3 potassium carbonate
  • the starting material for this reaction is either commercially available or can be prepared in a manner known per se.
  • the compounds of the present invention may then be isolated from the reaction mixture and may optionally be further purified, using techniques known per se, such as evaporation of the solvent, washing, trituration, recrystallisation from a suitable solvent or solvent mixture, and chromatographic techniques, such as column chromatography -for example using silica gel or C18 as solid phase- or preparative thin layer chromatography.
  • stereoisomer as used herein, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. It will be clear to the skilled person that some of the compounds of the invention may contain one or more asymmetric carbon atoms that serve as a chiral center, which may lead to different optical forms (e.g. enantiomers or diastereoisomers). Unless otherwise mentioned or indicated, the chemical designation of a compound herein encompasses all such optical forms in all possible configurations as well as the mixture of all possible stereochemical ⁇ isomeric forms, which said compound may possess.
  • Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemical ⁇ isomeric forms of the compounds of the invention either in pure form or in admixture with each other are intended to fall within the scope of the present invention.
  • the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, and stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.
  • Suitable protective groups as well as methods and conditions for inserting them and removing them, will be clear to the skilled person and are generally described in the standard handbooks of organic chemistry, such as Greene and Wuts, "Protective groups in organic synthesis", 3 rd Edition, Wiley and Sons, 1999, which is incorporated herein by reference in its entirety. It will also be clear to the skilled person that compounds of the invention in which one or more functional groups have been protected with suitable functional groups can find use as intermediates in the production and/or synthesis of the compounds of the invention, and as such form a further aspect of the invention. The present invention further encompasses compounds obtainable by the methods according to the invention.
  • the compounds of the invention interact with ion channels as shown in the examples below, in particular with ion channels from the Kv family, more in particular with ion channels from the Kv4 subfamily, and especially with Kv4.3 channels.
  • interact with is meant that the compounds of the invention act as antagonists of said ion channel(s) and/or of the biological function(s) and/or pathways associated with these channels, and in particular that the compounds of the invention can fully or partially “block” said channels.
  • the compounds of the invention interact with ion channels from an animal, preferably a vertebrate animal, more preferably a warm-blooded animal, even more preferably a mammal, and most preferably a human being.
  • the compounds of the invention act as antagonists of said ion channels and/or of the biological functions or pathways associated therewith.
  • the compounds of the invention block said ion channels.
  • compounds of Formula I or Il above that are particularly active against Kv4.3 ion channels and Kv1.5 ions channels and wherein the percentage inhibition measured after application of the compound and relative to the blank is equal or above 10%, preferably above 15%, more preferably above 20%, yet more preferably above 30%, yet more preferably above 50% as determined by a suitable assay, such as the assay used in the Examples below.
  • the compounds of the invention act as antagonists of ion channels from the Kv family and/or of the biological functions or pathways associated therewith. Also, preferably, the compounds of the invention block ion channels from the Kv family.
  • the compounds of the invention act as antagonists of ion channels from the Kv4 subfamily and/or of the biological functions or pathways associated therewith. Also, preferably, the compounds of the invention block ion channels from the Kv4 sub family. According to a yet further embodiment, the compounds of the invention act as antagonists of the Kv4.3 ion channel and/or of the biological functions or pathways associated therewith. Also, most preferably, the compounds of the invention block the Kv4.3 ion channel.
  • the compounds of the invention which block the Kv4.3 ion channels also block ion channels of the Kv1 subfamily, especially the Kv1.5 ion channel.
  • Whether a compound of the invention interacts with an ion channel can be determined using a suitable technique or assay, such as the assays described in the examples.
  • the compounds of the invention can therefore generally be used (1 ) as antagonists of ion channels and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of ion channels, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with said ion channels.
  • the compounds of the invention that interact with ion channels from the Kv family can be used (1 ) as antagonists of ion channels from the Kv family and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of ion channels from the Kv family, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with ion channels from the Kv family.
  • the compounds of the invention that interact with ion channels from the Kv4 subfamily can be used (1 ) as antagonists of ion channels from the Kv4 subfamily and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of ion channels from the Kv4 subfamily, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with ion channels from the Kv4 sub family.
  • the compounds of the invention that interact with the Kv4.3 ion channels from the Kv4 subfamily can in particular be used (1 ) as antagonists of the Kv4.3 ion channel and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of the Kv4.3 ion channel, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with the Kv4.3 ion channel.
  • the compounds of the invention that interact with ion channels from the Kv1 subfamily can be used (1 ) as antagonists of ion channels from the Kv1 subfamily and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of ion channels from the Kv1 subfamily, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with ion channels from the Kv1 sub family.
  • the compounds of the invention that interact with the Kv 1.5 ion channels from the Kv1 subfamily can in particular be used (1 ) as antagonists of the Kv1.5 ion channel and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of the Kv1.5 ion channel, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with the Kv1.5 ion channel.
  • the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a medicament. Furthermore, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as an ion channel blocker. In addition, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a blocker of an ion-channel of the Kv4 family of ion channels. In particular, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a blocker of an ion-channel of the Kv4.3 family of ion-channels.
  • the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a blocker of an ion channel of the Kv1 family of ion channels.
  • the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a blocker of an ion channel of the Kv1.5 family of ion channels.
  • the present invention further provides for the use of a compound according to the invention for the preparation of a medicament in the prevention and/or treatment of conditions or diseases associated with ion channels of the Kv4 and/or Kv1 family.
  • conditions and diseases associated with the Kv4.3 ion channel include (i) cardiac disorders including arrhythmias including Brugada Syndrome; hypertension-induced heart disorders including hypertension-induced cardiac hypertrophy; cardiac failure; and (ii) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome.
  • Arrhythmias include (i) atrial Arrhythmias such as but not limited to Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff-Parkinson-White (WPW) syndrome; (ii) Ventricular Arrhythmias such as but not limited to Premature ventricular contraction (PVC), ventricular tachycardia (VT), ventricular fibrillation and bradicardias; (iii) Others such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrio-ventricular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias; and the compounds of the invention that interact with Kv4.3 ion channels can be used in the prevention and/or treatment of such conditions and diseases.
  • Similar conditions and diseases are associated with the Kv1.5 ion channel and can be used in prevention and/or treatment of such conditions and diseases.
  • class III anti-arrhythmic drugs exert their effects by a blockade of cardiac potassium channels, resulting in a prolongation of repolarization and refractoriness.
  • l(Kur) the ultra-rapid delayed rectifier current was identified in human atrial but not ventricular tissue. Consequently, it contributes to the repolarisation of the action potential in the atrium only.
  • the Kv1.5 protein is supposed to be a critical cardiac voltage- gated potassium channel to form the l(Kur). Compounds inhibiting Kv1.5 would delay repolarisation of the action potential in the atrium and consequently prolong the atrial refractory period.
  • the present invention also relates to the use of the compounds that interact with Kv1.5 ion channels for prevention and/or treatment of the conditions and diseases given above and related with Kv4.3 ion channel associated diseases.
  • Preferred compounds for use in treating these conditions or diseases are compounds that show activity for both the Kv4.3 and the Kv1.5 ion channel.
  • the compounds are suitable for the treatment and/or prevention of various disorders: (i) cardiac disorders including arrhythmias including Brugada Syndrome; hypertension-induced heart disorders including hypertension- induced cardiac hypertrophy; cardiac failure; and (ii) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome.
  • cardiac disorders including arrhythmias including Brugada Syndrome
  • hypertension-induced heart disorders including hypertension- induced cardiac hypertrophy
  • cardiac failure and
  • disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome.
  • Arrhythmias include (i) atrial Arrhythmias such as but not limited to Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff- Parkinson-White (WPW) syndrome; (ii) Ventricular Arrhythmias such as but not limited to Premature ventricular contraction (PVC), ventricular tachycardia (VT), ventricular fibrillation and bradicardias; (iii) Others such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrio-ventricular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias.
  • atrial Arrhythmias such as but not limited to Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome
  • the compounds may be employed for the termination of existing atrial fibrillation or flutters for the recovery of the sinus rhythm (cardio version). Moreover, the substances may reduce the susceptibility to the formation of new fibrillation events (maintenance of the sinus rhythm, prophylaxis).
  • the compounds according to the invention can also be used as heart rate control agents, angina pectoris including relief of Prinzmetal's symptoms, vasospastic symptoms and variant symptoms; gastrointestinal disorders including reflux esophagitis, functional dyspepsia, motility disorders (including constipation and diarrhea), and irritable bowel syndrome, disorders of vascular and visceral smooth muscle including asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease, inflammatory and immunological disease including inflammatory bowel disease, rheumatoid arthritis, graft rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis and atherosclerosis, cell poliferative disorders including restenosis and cancer (including leukemia), disorders of the auditory system, disorders of the visual system including macular degeneration and cataracts, diabetes including diabetic retinopathy, diabetic
  • inhibitors of the K1 subfamily of voltage-gated K+ channels compounds according to the present invention are useful to treat a variety of disorders including resistance by transplantation of organs or tissue, graft-versus-host diseases brought about by medulla ossium transplantation, rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenic microorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bull
  • the compounds of the present invention are antiarrhythmic agents which are useful in the prevention and treatment (including partial alleviation or cure) of arrhythmias.
  • compounds within the scope of the present invention are particularly useful in the selective prevention and treatment of supraventricular arrhythmias such as atrial fibrillation, Brugada syndrome, and atrial flutter.
  • Whether a compound of the invention interacts with an ion channel such as with an ion channel of the Kv family, for example an ion channel of the Kv4 or Kv1 subfamily, such as the Kv4.3 or the Kv1.5 ion channel, respectively, can be determined using a suitable technique or assay, such as the assays and techniques referred to herein or other suitable assays or techniques known in the art.
  • the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug, such as an ester.
  • a pharmaceutically acceptable acid-addition and/or base-addition salt e.g. obtained with non-toxic organic or inorganic acid or base
  • solvate includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like.
  • suitable inorganic solvent e.g. hydrates
  • organic solvent such as but not limited to alcohols, ketones, esters and the like.
  • the pharmaceutically acceptable salts of the compounds according to the invention include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tos, to
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such a sarginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others.
  • Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutic amount of a compound according to the invention.
  • terapéuticaally effective amount means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
  • the pharmaceutical composition can be prepared in a manner known per se to one of skill in the art. For this purpose, at least one compound having Formula I, II, III, IV, V or Vl, one or more solid or liquid pharmaceutical excipients and, if desired, in combination with other pharmaceutical active compounds, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human medicine or veterinary medicine.
  • the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration, for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • Such suitable administration forms which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US- A-6,372,778, US-A-6, 369,086, US-A-6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.
  • Such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenz
  • the formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, and the like.
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers.
  • cyclodextrins are ⁇ -, ⁇ - or ⁇ -cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxyl groups of the anhydroglucose units of the cyclodextrin are substituted with alkyl, particularly methyl, ethyl or isopropyl, e.g.
  • ⁇ -CD randomly methylated ⁇ -CD
  • hydroxyalkyl particularly hydroxyethyl, hydroxypropyl or hydroxybutyl
  • carboxyalkyl particularly carboxymethyl or carboxyethyl
  • alkylcarbonyl particularly acetyl
  • alkoxycarbonylalkyl or carboxyalkoxyalkyl particularly carboxymethoxypropyl or carboxyethoxypropyl
  • alkylcarbonyloxyalkyl particularly 2-acetyloxypropyl.
  • complexants and/or solubilizers are ⁇ -CD, randomly methylated ⁇ -CD, 2,6-dimethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2- hydroxyethyl- ⁇ -CD, 2-hydroxypropyl- ⁇ -CD and (2-carboxymethoxy)propyl- ⁇ -CD, and in particular 2-hydroxypropyl- ⁇ -CD (2-HP- ⁇ -CD).
  • mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxyl groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl.
  • the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin.
  • the present invention also encompasses cyclodextrin complexes consisting of a compound according to the invention and a cyclodextrin.
  • the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.
  • a solid dispersion defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components.
  • a solid solution When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution".
  • Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.
  • the term "a solid dispersion” also comprises dispersions that are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
  • the water-soluble polymer is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 2O 0 C solution.
  • Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC.
  • HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble.
  • Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule.
  • Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
  • Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
  • Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal- coating polymer layer.
  • Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
  • the above preparations may be prepared in a manner known per se, which usually involves mixing the active substance(s) to be used with the one or more pharmaceutically acceptable carriers, which necessary under aseptic conditions.
  • the pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
  • unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
  • the compounds can be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred.
  • the compound of the invention will generally be administered in an effective amount, which, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • an effective amount will usually be between 0.01 to 1000 mg, more often between 0.1 and 500 mg, such as between 0.1 and 250 mg, for example about 0.1 , 1 , 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion.
  • the amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated.
  • the invention relates to a composition and in particular a composition for pharmaceutical use, which contains at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for pharmaceutical use).
  • a suitable carrier i.e. a carrier suitable for pharmaceutical use.
  • the invention also relates to the use of a compound of the invention in the preparation of such a composition.
  • said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions.
  • suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch.
  • the preparation can be carried out both as dry and as moist granules.
  • suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
  • Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof.
  • Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms.
  • these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
  • compositions When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents.
  • the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • the compound according to the invention if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion.
  • the compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations.
  • Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g.
  • injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
  • these formulations When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • the compounds according to the invention were found to act as antagonist of ion channels from the Kv family more in particular from the Kv4 subfamily and/or of the biological functions or pathways associated therewith.
  • the compounds according to the invention were also found to act as antagonist of ion channels from the Kv1 subfamily and/or of the biological functions or pathways associated therewith.
  • the compounds of the invention can therefore be used (1 ) as antagonists of ion channels and/or of the biological functions or pathways associated therewith, i.e. in an vitro, in vivo or therapeutic setting; (2) as blockers of ion channels, i.e. in an vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with said ion channels.
  • the compounds according to the invention showed very low activity or no activity with respect to the hERG channel, and are thereby selective.
  • conditions and diseases associated with the Kv4.3 ion channel include cardiac disorders such as arrhythmia, Brugada syndrome, hypertension-induced heart disorders such as hypertension-induced cardiac hypertrophy (e.g. ventricular hypertrophy), and disorders of the nervous system such as epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease, multiple sclerosis, demyelinating disease and Parkinson's syndrome.
  • the compounds according to the present invention interact with Kv 4.3 ion channels and can be used in the prevention and/or treatment of such conditions and diseases.
  • conditions and diseases associated with the Kv1.5 ion channel in particular in humans, include the same diseases and disorders as mentioned above as for the Kv4.3 ion channel.
  • the compounds according to the invention that interact with Kv1.5 ion channel are particularly useful in the prevention and/or treatment of atrial tachyarrhythmias such as atrial fibrillation or Brugada syndrome.
  • the present invention also relates to the use of the compounds according to the invention or to a pharmaceutical composition comprising said compounds in the treatment of cardiac disorders such as arrhythmia, Brugada syndrome, hypertension-induced heart disorders such as hypertension-induced cardiac hypertrophy (e.g. ventricular hypertrophy), and disorders of the nervous system such as epilepsy, stroke, spinal cord injury, traumatic brain injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease, multiple sclerosis, demyelinating disease and Parkinson's syndrome.
  • the present invention also relates to the use of the compounds according to the invention or to a pharmaceutical composition comprising said compounds in the treatment of cardiac disorders such as arrhythmia.
  • the present invention also relates to the use of the compounds according to the invention or to a pharmaceutical composition comprising said compounds in the treatment of disorders of the nervous system.
  • a method of treating cardiac disorders comprises administering to an individual in need of such treatment a pharmaceutical composition comprising the compounds according to the invention.
  • a method of treating disorders of the nervous system comprises administering to an individual in need of such treatment a pharmaceutical composition comprising the compounds according to the invention.
  • the above compounds and compositions may be of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also -for economically important animals such as cattle, pigs, sheep, chicken, fish, etc.- enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal.
  • the invention relates to a composition for veterinary use that contains at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for veterinary use).
  • the invention also relates to the use of a compound of the invention in the preparation of such a composition.
  • the above compounds and compositions may be of value as insecticides.
  • the invention will now be illustrated by means of the following synthetic and biological examples, which do not limit the scope of the invention in any way.
  • Example 1 Preparation of the compounds according to the present invention The practice of the present invention will employ, unless otherwise indicated, conventional techniques of synthetic organic chemistry, biological testing, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. Unless indicated otherwise, the purity of the compounds was confirmed by liquid chromatography/mass spectrometry (LC/MS), according to method A as follows: Method A (gradient 5 min):
  • HPLC Waters Alliance 2690 with photodiode array detector Waters 996. Mass spectrometer: Micromass Platform ZMD LC. Ionization: electrospray (polarity: negative and positive).
  • Phase Tosohaas TSK-gel super ODS (100 A, 2 ⁇ m), column: 4.6x50 mm; Solvent A: Water and formic acid (26.5 mM); Solvent B: Acetonitrile and formic acid (17 mM); Flow: 2.75 ml/min; Gradient 5 mn: From 100 % A & 0 % B to 20% A & 80 % B in 3 min. lsocratic 80 % B for 1 min. From 80 % B & 20% A to 0 %B and 100% A in 0.5 min. lsocratic 100 % A for 0.5 min
  • NMR spectra were determined on a Varian Mercury 300 MHz NMR using the indicated solvent as an internal reference. Melting points were determined on a B ⁇ chi B-540 and are non-corrected. All reagents used were either obtained commercially or were prepared in a manner known per se.
  • Protocol A The acid derivative (1.0 eq.) is dissolved in a mixture of DMF and DIEA (3.0 to 5.0 eq.). A solution of TBTU (1.3 eq.) and HOBt (0.3 eq.) in DMF is added and the mixture is stirred at room temperature for 5 to 30 minutes. The amine (1.0 eq.) is added and the reaction mixture is stirred at room temperature for a period of 20 min to 24 hours. DMF is removed under reduced pressure. The residue is diluted with EtOAc or DCM and washed with 0.5N HCI, 0.5N NaOH and water/brine or with 1 N NaHCO 3 and water/brine or with 1 N Na 2 CO 3 and water/brine. The organic layer is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography, semi-prep HPLC or by recrystallization. Protocol B:
  • the bromide (1.0 eq.), the amine (1.0 eq.), cesium carbonate (1.4 eq.), BINAP (0.1 eq.) and palladium acetate (0.1 eq.) are dissolved in dry 1 ,4-dioxane and dry DMF.
  • the mixture in heated under nitrogen atmosphere in the microwave at 17O 0 C for 20 minutes.
  • the solvent is removed under reduced pressure.
  • the residue is purified by flash chromatography, semi-prep HPLC or by recrystallization.
  • the sulfanyl derivative (1.0 eq.) is dissolved in acetic acid. Hydrogen peroxide (1 ml) is added and the mixture is stirred at room temperature for 3 days. The mixture is dissolved in water and extracted with ethyl acetate. The combined organic layers are dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified by semi-prep HPLC.
  • Ethyl 2-oxo-3-piperidinecarboxylate (1.0 eq.) is dissolved in dry THF under nitrogen atmosphere. The mixture is cooled to O 0 C and sodium hydride (3.0 eq.) is added in small portions. The mixture is stirred at O 0 C for 20 minutes and benzylchloride (1.0 eq.) is added dropwise. The mixture is stirred at O 0 C for 2 hours. The mixture is poured in ice-water and extracted with EtOAc. The combined organic layers are dried over MgSO 4 and the solvent is removed under reduced pressure.
  • Protocol E The corresponding ester (1.0 eq.) is dissolved in ethanol and a base such as 1 N LiOH or 1 N NaOH or 2N NaOH (1.0 to 5.0 eq.) is added. The mixture is stirred at room temperature to 7O 0 C for 1 to 24 hours. The mixture is extracted with DCM and the water layer is acidified with 20% aqueous potassium hydrogen sulfate solution and extracted with DCM or the solvent is removed under reduced pressure, water is added and acidified with 1 N HCI. The combined organic layers from the acidic extraction are dried over MgSO 4 and the solvent is removed under reduced pressure or the precipitate is filtered and dried.
  • a base such as 1 N LiOH or 1 N NaOH or 2N NaOH (1.0 to 5.0 eq.
  • the 2,4-dibromo-thiazole derivative (1.0 eq.) is dissolved in DMSO.
  • DIEA (1.0 eq.) and the amine (4.0 eq.) are added.
  • the mixture is heated under nitrogen atmosphere in the microwave at 13O 0 C for 2 hours.
  • the reaction mixture is diluted with DCM and washed with water.
  • the water layer is extracted with DCM and the combined organic layers are dried over MgSC ⁇ .
  • the solvent is removed under reduced pressure and the compound is purified by flash chromatography and recrystallization from MeOH.
  • the amine (2.0 eq.), the 2-bromo-thiazole derivative (1.0 eq.) and potassium carbonate (1.2 eq.) are suspended in DMF.
  • the mixture is heated in the microwave at 17O 0 C for 25 to 60 minutes.
  • the solvent is removed under reduced pressure.
  • the residue is taken up in DCM.
  • the organic layer is washed with water, dried over MgSO4 and the solvent is removed under reduced pressure.
  • the compound is recrystallized from ethanol.
  • thioamide (1 eq.) or thiourea (1 eq.) is dissolved in ethanol.
  • 2-Chloro-3-oxo-butyric acid ethyl ester (1.2 to 1.5 eq.) or 2-bromo-3-oxo-3-phenyl-propionic acid ethyl ester (1.2 to 1.5 eq.) is added and the mixture is stirred at 65 0 C for 30 minutes to 24 hours.
  • the solvent is removed under reduced pressure or the precipitate is filtered.
  • the acid derivative (1 eq.) is dissolved in DCM and cooled. HOBt (0.3 eq.), the corresponding amine (1 eq.) and DCC (1 eq.) are added.
  • the reaction mixture is stirred at room temperature for a period of 1 to 24 hours, cooled to O 0 C, filtered and washed with DCM.
  • the filtrate is washed with 1 N HCI and 2N NaHCO 3 .
  • the organic layer is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography, semi-prep HPLC or by recrystallization.
  • Oxalylchloride (1.2 eq.) and DMF (2 drops) are added to a suspension of the acid (1 eq.) in DCM.
  • the suspension is stirred at room temperature until a clear solution is obtained.
  • the reaction mixture is cooled to O 0 C and the amine (1.5 eq.) and DIEA (3 eq.) are added.
  • the reaction mixture is stirred for a period between 1 to 3 hours.
  • the reaction mixture is diluted with DCM, washed with 1 N HCI and 2N Na 2 CO 3 .
  • the organic layer is dried over MgSO 4 and the solvent is removed under reduced pressure.
  • the residue is purified by flash chromatography, semi-prep HPLC or by recrystallization.
  • the ester (1.0 eq.) is dissolved in TFA and the mixture is stirred at room temperature for 20 to 30 minutes. The reaction mixture is poured into cold water and the precipitate is filtered.
  • Protocol P Thionylchloride is added to the acid (1.0 eq.) and DMF (3 drops) is added. The mixture is stirred at 5O 0 C for 5 minutes. The excess thionylchloride is removed under reduced pressure. The amine (1.0 eq.) is dissolved in DCM and DIEA (3.0 to 4.0 eq.) is added. A solution of the acylchloride (1.0 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 5 to 30 minutes. The mixture is diluted with DCM and washed with water. The organic layer is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified by semi-prep HPLC.
  • Protocol Q n-Butyllithium (1.5 eq.) is added to a solution of DIEA (1.4 eq.) in dry THF under argon atmosphere at -78 0 C. A solution of 2-bromo-3-phenyl-thiophene (1.0 eq.) in dry THF is added dropwise. The mixture is stirred at -78 0 C for 1 hour. 2-Methoxy benzaldehyde (1.3 eq.) is added and the mixture is stirred at -78 0 C for 1 hour. The cold reaction mixture is poured into a bilayer system of EtOAc and brine. The aqueous layer is extracted with EtOAc. The combined organic layers are dried over MgSO 4 and the solvent is removed under reduced pressure.
  • DBU (3.0 eq.) is added to a suspension of the amine (3.0 eq.), MO(CO) 6 (1.0 eq.), Herrmann's palladacycle (0.05 eq.), Fu's salt (0.1 eq.) and the bromide (1.0 eq.) in 1 ,4-dioxane.
  • the reaction mixture is heated in the microwave at 15O 0 C for 15 minutes.
  • the reaction mixture is diluted with 1 N HCI and extracted with EtOAc.
  • the organic layer is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography.
  • Chlorotrimethylsilane (6.0 eq.) is added to a suspension of sodium iodide (6.0 eq.) in acetonitrile under nitrogen atmosphere and stirred for 15 minutes at room temperature.
  • a solution of the alcohol (1.0 eq.) in acetonitrile is added.
  • the reaction mixture is stirred at room temperature for 15 minutes.
  • the reaction mixture is diluted with water and extracted with Et 2 O.
  • the combined organic layers are washed with aqueous sodium thiosulfate and brine.
  • the organic layer is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography.
  • a suspension of the bromide (1.0 eq.), the amine (1.05 eq.), Xantphos (0.03 eq.), Pd 2 (dba) 3 (0.02 eq.) and Cs 2 CO 3 (1.5 eq.) in 1 ,4-dioxane is heated in the microwave at 15O 0 C for 30 minutes.
  • the reaction mixture is filtered, diluted with EtOAc and washed with water and brine.
  • the organic layer is dried over MgSO 4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography.
  • the present invention further encompasses compounds as illustrated in Table 2 as well as stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or a pharmaceutically acceptable salt and/or solvate thereof.
  • the structural formulas of the acid used and intermediates are listed in Table 1. The following abbreviations are used hereunder.
  • P protocol, ES+: molecular ion obtained by electrospray in positive ion mode.
  • Electrophysiological measurements were performed as described in WO 2006/058905 under example 3 which is hereby incorporated by reference. Data analysis
  • Test system and test method for the hERG experiment is performed as described in WO 2006/058905 under example 3 "Test system and test method for the hERG experiment" which is hereby incorporated by reference. Data analysis
  • the compounds showing a selectivity >5 (ratio value) for Kv4.3 vs. hERG are considered as being very selective toward Kv4.3 channels. So in addition to being active on Kv4.3 ions channels at very low concentration, the compounds according to the invention are very selective toward Kv4.3 ions channels when compared to the hERG channel.
  • Table 2 shows the effect on Kv4.3 of a non-limiting number of compounds according to the invention.
  • the compounds were investigated at one concentration (1 ⁇ M) on the Kv4.3-mediated potassium channel, in a patch clamp assay following a protocol as described in Example 2. The results are shown in Table 2.
  • "%inh Kv4.3” means the % inhibition measured after application of the compound and relative to the blank. Results of % inhibition Kv4.3 are represented as follows: “+++” means above 50%; “++” means between 50% and 20%; and “+” means below 20%.
  • ND means no data yet. Unless otherwise specified, the tests were performed at 1 ⁇ M for Kv4.3 % inhibition.
  • Patch Clamp Assays using the Kv1.5 ion channel may be performed as described in WO 2006/058905 under example 4 which is hereby incorporated by reference.
  • Example 4 Ex-vivo organ studies in rats and guinea pigs
  • Example 5 In vivo studies in mice In vivo studies in mice may be performed as described in WO 2006/058905 under example 6 which is hereby incorporated by reference.
  • Example 6 Ex-vivo organ studies in rabbits
  • Systemic cardiovascular parameters The surface lead Il ECG was obtained from the limb electrodes. A heparinized catheter was placed in the left femoral artery to continuously monitor the systemic blood pressure.
  • Electrophysiology of the atrium A standard 6-French quadrupolar electrode catheter (Cordis- Webster) was positioned at the top of the right atrium to electrically pace the sinus nodal area and record the local electrogram, including the spontaneous beating rate (the sinoatrial rate: SAR). A second 6-French quadrupolar electrode catheter was positioned at the inter-atrial septum of the right atrium to electrically induce atrial fibrillation. A third 6-French quadrupolar electrode catheter was positioned in the esophagus to record the left atrial electrogram.
  • SAR sinoatrial rate
  • MAP 90 Electrophysiology of the ventricle
  • a bi-directional steerable monophasic action potential (MAP) recording / pacing combination catheter (EP Technologies lnc , 1675P, Sunnyvale, CA, USA) was positioned at the endocardium of the right ventricle to obtain MAP signals
  • the interval (in ms) at 90% repolarization was defined as MAP 90 Examination through electrical pacing of the heart
  • IACT Inter-atrial conduction time
  • Atrial effective refractory period The functional refractory period of the atrium was assessed by pacing with 5 beats of basal stimuli in a cycle length of 400, 300 or 200 ms followed by an additional stimulus at various coupling intervals
  • AF atrial fibrillation
  • MAP 90 Ventricular MAP duration
  • the heart was electrically paced using a cardiac stimulator with the electrodes of the combination catheter which had been placed in the right ventricle
  • the MAP 90 was measured during ventricular rhythm and at a pacing cycle length of 1000, 750, 600, 500, 400 or 300 ms
  • Ventricular effective refractory period The effective refractory period of the right ventricle was assessed by pacing consisting of 5 beats of basal stimuli in a cycle length of 1000, 750, 600, 500, 400 or 300 ms followed by an additional stimulus after various coupling intervals Starting in late diastole the coupling interval ⁇ /as s h ortened consecutively by 5-10 rns until refractoriness occurred
  • the duration of the terminal repolarization period of the ventricle namely, phase 3 repolarization of the action potential, was estimated using the difference between the MAP 90 and VERP at the same site
  • Atrial fibrillation was induced by the burst pacing protocol, which was repeated consecutively 10 times at each time point When the atrial fibrillation was maintained for >30 s, it was terminated electrically In this case, the duration of atrial fibrillation was calculated as 30 s
  • AF atrial fibrillation
  • AF duration mean duration of AF based on 10 inductions for AF less than 5 minutes, 5 inductions for AF>5 minutes, or minimum of 2 inductions if AF sustained for >20 minutes x 2
  • AF cycle length mean duration of AF based on 10 inductions for AF less than 5 minutes, 5 inductions for AF>5 minutes, or minimum of 2 inductions if AF sustained for >20 minutes x 2
  • AF cycle length right atrial ERP and conduction velocity determined by epicardial mapping (cycle length of 150 and 300 ms), right ventricular ERPs, QT interval and QRS duration (during ventricular pacing at cycle lengths of 250 and 350-400 ms) and blood pressure
  • the present invention encompasses compounds 1 to 161 and stereoisomers, tautomers, racemics or a pharmaceutically acceptable salt and/or solvate thereof.

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Abstract

The present invention relates to compounds that interact with ion channels. In particular, the invention relates to compounds having the structural Formula having the structural Formula (I), (II), (III), (IV), (V), (VI) stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or a pharmaceutically acceptable salt and/or solvate thereof, Formula (I), (II), (III), (IV), (V), (VI) wherein X1, X2, X3, X4, t, s, A1, L1, L2, R1, R2, and R4 have the same meaning as that defined in claim 1. The invention also relates to methods for preparing said compounds, to pharmaceutical compositions comprising said compounds, and to the use of said compounds in methods for treatment of the human and animal body.

Description

Compounds that interact with ion channels, in particular with ion channels from the Kv family
Field of the invention
The present invention relates to compounds that interact with ion channels. In particular, the invention relates to compounds that interact with ion channels from the Kv family, and in particular from the Kv4 subfamily. The invention also relates to methods for preparing said compounds, to pharmaceutical compositions that contain said compounds, and to the use of said compounds in methods for treatment of the human and animal body and/or to the use of said compounds in the preparation of such pharmaceutical compositions. The compounds of the invention for example can be used in the prevention and/or treatment of conditions or diseases associated with ion channels, in particular in the prevention and/or treatment of conditions and diseases associated with ion channels of the Kv family, and more in particular in the prevention and/or treatment of conditions and diseases associated with ion channels of the Kv4 family. Other aspects, embodiments, uses and advantages of the invention will become clear from the further description below. Background to the invention
Kv4 channels, as well as their encoding sequences, their biological function/activity and their disease associations have been described in the art, see for example Bahring et al., J.Biol.Chem., Vol. 276, no. 26, 233888-23894 (2001 ); Baldwin et al., Neuron 7: 471-483 (1991 ); Dixon et al., Circ. Res. 79: 659-688 (1996); Dilks et al., J. Neurophysiol. 81 : 1974-1977 (1999); Kuo et al., Cell, Vol. 107, 801-813 (2001 ); Pak et al., Proc. Natl. Acad. Sci USA 88; 4386-4390 (1991 ); Ohya et al., FEBS Lett. 420:47-53 (1997); Roberts and Tamkun, Proc. Natl. Acad. Sci USA 88; 1798-1802; Rudy et al., MoI. Cell. Neurosci. 2; 89-102 (1991 ); Serodio et al., J. Neurophysiol 75: 2174-2179 (1996); Serodio and Rudy, J. Neurophysiol. 79: 1081-1091 (1998); and Takimoto et al., Circ. Res. 81 : 553-539 (1997), and the further references cited therein. Generally, being voltage-gated potassium channels, Kv4 channels are inter alia involved in membrane depolarisation and repolarisation events, e.g. as part of and/or following neuronal firing and/or as part of the cycle of muscle contraction/relaxation.
In particular, and as mentioned in the above references, Kv4 channels are believed to be involved in the native A-type currents that are generated by various types of primary cells (Dilks et al., supra), in particular in muscle and neuronal cells. Kv4.2 and Kv4.3 transcripts have been found in most neurons, and in particular in CNS neurons (see Serodio and Rudy, supra, who discuss the distribution of Kv4 channels in rat brain); as well as in heart muscle (see Dixon et al. and by Serodio et al., both supra, who discuss the abundance and distribution of Kv4 transcripts in the hearts of rat, dog and human). It has also been found that, compared to Kv-type channels from other families such as Kv1-type channels, Kv4 channels activate and inactivate at subthreshold potentials, inactivate with time constants that change very little as a function of voltage (even at very negative potentials), and recover very fast from inactivation (see Rudy and Serodio, supra). In neuronal cells, and in particular in neurons in the brain, Kv4 channels are inter alia believed to play an important role in the modulation of the firing rate, action potential initiation, shaping burst pattern and postsynaptic signal integration (Dilks et al., and Bahring et al., supra), and are believed to be associated with the physiological states/disorders that result from such activity (Serodio and Rudy, supra).
In the heart, the Kv4 channels are inter alia believed to play a major role in the calcium- independent A-type currents in the cardiac muscle (the "transient outward current" or "lt0"), and in particular in the cardiac ventricular muscle, and are thus believed to be involved in early repolarization and hence the overall duration of the action potential and the length of the refractory period (Serodio and Rudy, supra). Because of this, Kv4 channels are believed to be associated with (the susceptibility to) cardiac disorders such as arrhythmia and other types of heart failure (Kuo et al., supra).
So far, three mammalian Kv4 genes - referred to as Kv4.1 (also known as mShai ), Kv4.2 (also known as RK5) and Kv4.3, respectively - have been cloned and characterized, i.e. from rat and dog (Dixon et al, Serodio et al., Ohya et al. and Takimoto et al., all supra) and from human (Dilks et al., and Bahring et al., supra; see also for example WO 98/42833 and US-A-6, 395,477).
The sequences of genes encoding mammalian Kv4 channels are also available from publicly accessible databases such as GenBank/NCBI, e.g. Kv4.1 from mouse (accession number NP_032449 and A38372); Kv4.1 from human (accession number BAA96454, AAF65617 and AF65516); Kv4.2 from mouse (accession number NP_062671 and AAD16972), Kv4.2 from rat (accession number NP 113918); Kv4.2 from human (accession number AAD22053 and CAB56841 ); Kv4.3 from mouse (accession numbers NM_019931 and AF384170), Kv4.3 from rat (accession number U42975) and Kv4.3 from human (accession number XM_052127).
The above references also indicate that further channels from the Kv4 family may be identified and cloned in future, for example from neurons in the brain that show Kv4-like subthreshold-operating A channels, but do not show abundant expression of Kv4.1 , Kv4.2 and/or Kv4.3 transcripts (see Serodio and Rudy, supra) or other suitable tissues/cells.
As mentioned above, the Kv4 channels in mammals also have a high degree of sequence identity (>70%) with, and thus are considered closely related to, the Shal-Wke gene product, which encodes a potassium channel in Drosophila melanogaster (see Baldwin et al, supra, and also WO 01/58952).
An assay for determining the influence of a compound on Kv channels, in which a transgenic line of Caenorhabditis elegans expressing a heterologous Kv channel, such as a human Kv4.3 channel, is used, is described in the International application WO 03/097682 by Applicant. Other assays and techniques for determining the influence of a test compound on ion channels in general, and on a Kv channel in particular, such as FLIPR-techniques and use of oocytes, will be clear to the skilled person, and are also mentioned in WO 03/097682. Such assays can be used to determine whether a compound "interacts with" such an ion channel. As mentioned below and for the purposes of the present description and attached claims, a compound is considered to "interact with" an ion channel, such as an ion channel of the Kv family and in particular of the Kv4 subfamily, if such a compound acts as an antagonist of said ion channel and/or of the biological function(s) and/or pathways associated with said ion channels, and in particular if such a compound can fully or partially "block" such an ion channel.
In view of the biological functions and disease associations mentioned above, compounds that interact with ion channels can find use as pharmaceutically active agents, in particular for the prevention and/or treatment of diseases and disorders associated with the ion channels with which the compound interact. By means of non-limiting example, compounds that interact with ion channels from the Kv 4 subfamily, and in particular with Kv4.3 ion channels (e.g. the compounds as further described herein below) could be used in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of cardiac disorders such as arrhythmia, hypertension-induced heart disorders such as hypertension-induced cardiac hypertrophy (e.g. ventricular hypertrophy), and disorders of the nervous system and neurological disorders such as epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, Alzheimer's disease, encephalomyelitis, multiple sclerosis, demyelinating disease, and Parkinson's syndrome.
A major drawback of some of the known compounds involves that the drugs do not work in a selective manner, i.e. they do not select between different ion channels. For instance, many of these compounds also block a potassium channel called the human ether-a-go-go related gene (hERG) potassium channel. Compounds that block this channel with high potency may cause reactions which are fatal. This undesired blockade can cause acquired long QT syndrome, a disorder that puts patients at risk for life-threatening arrhythmias. Cardiac arrhythmias are the leading cause of sudden death in the United States, according to the American Heart Association. The FDA now requires that every drug be assayed for hERG block before it is approved. Even medicines that might be beneficial for the vast majority of patients do not make it to the market - or have been pulled from the market - if they block hERG.
Thus, in addition to being able to modulate a particular Kv channel, it is desirable to find compounds that are selective to Kv channel when compared to the hERG channel. Thus, there is a need to find compounds that modulate the Kv channel, while not inhibiting the hERG channel.
There remains an urgent need in the art for finding new compounds, which overcome the above- mentioned drawbacks.
It is therefore an object of the invention to provide compounds that interact with ion channels, in particular with ion channels from the Kv family, more in particular with ion channels from the Kv4 subfamily, and especially with Kv4.3 channels, in particular in vertebrates, more in particular in warm-blooded animals, even more in particular in mammals, and especially in human beings. It is a further object of the present invention to provide compounds that interact with ion channels, in particular Kv ion channels and which are selective to Kv ion channels when compared to the hERG channel.
Summary of the invention
In a first aspect the present invention relates to compounds of Formula I, II, III, IV, V or Vl stereoisomers, tautomers, racemics or a pharmaceutically acceptable salt and/or solvate thereof,
Figure imgf000005_0001
Figure imgf000005_0002
IV V Vl wherein
X1 is selected from -N=, or -CH=,
X2 is selected from -N=, or -CH=,
X3 is selected from -CH2-, -CR5=, or O, wherein R5 is selected from hydrogen, alkyl, or aryl, t is an integer selected from 1 or 2, R1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero,
X4 is selected from -N= or CR3, wherein R4 is hydrogen or R4 and R3 together with the carbon atoms to which they are attached form an aryl or a heteroaryl ring, each ring being optionally substituted by one or more substituents independently selected from halo, alkyl, aryl, alkoxy, haloalkyl or haloalkoxy,
L1 is selected from -NH-, -CH2-, -SO2-,
L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, wherein A1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl,
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4, with the proviso that when L1 is NH in formula I, R1 is selected from halogen, aryl or alkylhetero, or when L1 is NH in formula I and R1 is hydrogen or alkyl, L2 is pyrrolydinylenealkylene optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, and wherein the dotted line represent an optional double bond.
In a second aspect, the present invention relates to a method for synthesizing a compound having one of the structural Formula I, II, III, IV, V or Vl, comprising the step of condensing a compound of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII:
Figure imgf000006_0001
XXIII XXIV XXV XXVI
Figure imgf000006_0002
XXVII XXVIII with a compound of Formula XXIX:
Figure imgf000006_0003
XXIX hereby obtaining a compound of Formula I, II, III, IV, V or Vl,
Figure imgf000006_0004
Figure imgf000007_0001
IV V Vl wherein X1, X2, X3, X4, t, s, A1, L1, L2, R1, R2, and R4 have the same meaning as that defined hereinabove. It was surprisingly found that the compounds of the invention interact with ion channels as shown in the examples below, in particular with ion channels from the Kv family, more in particular with ion channels from the Kv4 subfamily, and especially with Kv4.3 channels. Kv4.3 ions channels are associated to various conditions or diseases. In a further aspect, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a medicament. The compounds of the present invention are particularly useful for the preparation of a medicament in the prevention and/or treatment of conditions or diseases associated with ion channels of the Kv4 family. Non-limiting examples of said conditions or diseases associated with ion channels of the Kv4 family can be selected from the group comprising (i) cardiac disorders including arrhythmias including Brugada Syndrome; hypertension-induced heart disorders including hypertension-induced cardiac hypertrophy; cardiac failure; and (ii) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome. Arrhythmias include (i) atrial Arrhythmias such as but not limited to Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff-Parkinson-White (WPW) syndrome; (ii) Ventricular Arrhythmias such as but not limited to Premature ventricular contraction (PVC), ventricular tachycardia (VT), ventricular fibrillation and bradicardias; (iii) Others such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrio-ventricular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias.
In an embodiment, the present invention provides for the use of a compound of the invention for the preparation of a medicament for treating cardiac disorders such as atrial fibrillation, atrial flutter and/or Brugada Syndrome. In another embodiment, the present invention provides for the use of a compound of the invention for the preparation of a medicament for treating disorders of the nervous system such as Alzheimer's disease.
In yet another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to the invention. Said composition is particularly useful in the prevention and/or treatment of conditions or diseases associated with ion channels of the Kv4 family such as the one cited herein. Said composition is particularly suited for example in the treatment of cardiac disorders and disorders of the nervous system.
It was also surprisingly found that the compounds of the present invention interact with ion channels of the Kv1 subfamily, and especially with Kv1.5 channels.
The present invention also provides a method of treating cardiac disorders comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention. In another embodiment, the present invention provides a method of treating disorders of the nervous system comprising administrating to an individual in need of such treatment a pharmaceutical composition according to the invention. Description of the invention
Thus, in a first aspect, the invention relates to a compound of Formula I, II, IV, V or Vl,
Figure imgf000008_0001
Figure imgf000008_0002
IV V Vl stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or a pharmaceutically acceptable salt and/or solvate thereof, with the proviso that when L1 is NH in formula I, R1 is selected from halogen, aryl or alkylhetero, or when L1 is NH in formula I and R1 is hydrogen or alkyl, L2 is pyrrolydinylenealkylene optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, wherein X1, X2, X3, X4, s, t, A1, L1, L2, R1, R2, R3, R4 have the same meaning as that defined hereinabove. The dotted line represents an optional double bond.
When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise:
The term "alkyl" by itself or as part of another substituent, refers to a straight or branched saturated hydrocarbon group joined by single carbon-carbon bonds having 1 to 10 carbon atoms, for example 1 to 8 carbon atoms, for example 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, C-ι_4alkyl means an alkyl of one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ferf-butyl, 2-methylbutyl, pentyl iso-amyl and its isomers, hexyl and its isomers, heptyl and its isomers and octyl and its isomer.
The term "optionally substituted alkyl" refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents) at any available point of attachment. Non-limiting examples of such substituents include halogen, hydroxyl, carbonyl, nitro, amino, oximes, imines, azido, hydrazino, cyano, alkyl, aryl, heteroaryl, cycloalkyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid, acylamino, alkyl esters, carbamates, thioamides, urea, sulfonamides and the like.
When the term "alkyl" is used as a suffix following another term, as in "hydroxyalkyl," this is intended to refer to an alkyl group, as defined above, being substituted with one or two (preferably one) substituent(s) selected from the other, specifically-named group, also as defined herein. For example, "hydroxyalkyl" includes 2-hydroxyethyl, 1-(hydroxymethyl)-2-methylpropyl, 3,4- dihydroxybutyl, and so forth. "Alkoxyalkyl" refers to an alkyl group substituted with one to two of
OR', wherein R' is alkyl as defined below. For example, "aralkyl" or "(aryl)alkyl" refers to a substituted alkyl group as defined above wherein at least one of the alkyl substituents is an aryl as defined below, such as benzyl.
The term "hydroxyalkyl" refers to a -Ra-OH group wherein Ra is alkylene as defined herein.
The term "cycloalkyl" by itself or as part of another substituent, includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups containing 1 to 3 rings, including monocyclic, bicyclic or polycyclic alkyl groups wherein each cyclic moiety has from 3 to 8 carbon atoms, for example 3 to 7 carbon atoms, for example 3 to 6 carbon atoms, for example 3 to 5 carbon atoms. The further rings of multi-ring cycloalkyls may be fused, bridged and/or joined through one or more spiro unions. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl, cycloheptyl, cyclooctyl and the like. Examples of polycyclic cycloalkyl radicals include decahydronaphthyl, bicyclo [5.4.0] undecyl, adamantyl, and the like. An "optionally substituted cycloalkyl" refers to a cycloalkyl having optionally one or more substituents (for example 1 to 3 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl. When the suffix "ene" is used in conjunction with a cyclic group, this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups.
The term "alkenyl" by itself or as part of another substituent, refers to a straight or branched alkyl chain containing at least one unsaturation in the form of a single carbon to carbon double bond and having 2 to 10 carbon atoms, for example 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2- butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2-heptenyl and its isomers, 2-octenyl and its isomers, 2,4-pentadienyl and the like. An optionally substituted alkenyl refers to an alkenyl having optionally one or more substituents (for example 1 to 3 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl.
The term "alkynyl" by itself or as part of another substituent, refers to a straight or branched alkyl chain containing at least one unsaturation in the form of a single carbon to carbon triple bond and having 2 to 10 carbon atoms, for example 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Examples alkynyl groups are ethynyl, 2-propynyl, 2-butynyl,
3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers, 2-heptynyl and its isomers, 2- octynyl and its isomers and the like. An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted alkyl.
Where alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene" groups. Non-limiting examples of alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2- dimethylethylene, pentamethylene and hexamethylene. Similarly, where alkenyl groups as defined above and alkynyl groups as defined above, respectively, are divalent radicals having single bonds for attachment to two other groups, they are termed "alkenylene" and "alkynylene" respectively.
Where alkyl groups as defined are trivalent, i.e., with three single bonds for attachment to three other groups, they are termed "alkylyne" or "alkyline" groups. Non-limiting example of such alkylyne include, methine, 1 ,1 ,2-ethyline, and the like. The term "aryl" as used herein by itself or as part of another group refers but is not limited to 5 to 14 carbon-atom homocydic (i.e., hydrocarbon) monocyclic, bicyclic or tricyclic aromatic rings or ring systems containing 1 to 4 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic. The aromatic ring may optionally include one to three additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1-, 2-, 3-, A-, 5-, 6-, 7- or 8-azulenyl, 1- or 2-naphthyl, 1-, 2- or 3-indenyl, 1-, 2- or 9-anthryl, 1- 2-, 3-, 4- or 5- acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1-, 2-, 3-, 4- or 10-phenanthryl, 1- or 2-pentalenyl, 1 , 2-, 3- or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,4- dihydronaphthyl, dibenzo[a,d]cylcoheptenyl, 1-, 2-, 3-, 4- or 5-pyrenyl. The aryl ring can optionally be substituted by one or more aromatic substituents. An "optionally substituted aryl" refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, or 1 to 2 substituents) at any available point of attachment. Non-limiting examples of such substituents are selected from halogen, hydroxyl, carbonyl, nitro, amino, azido, hydrazine, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R15, alkylcarbonyloxy, fused heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, thiol, alkylthio, haloaryl, carboxyl, acylamino, alkyl esters, carbamate, thioamide, urea, or sulfonamide, and the like, wherein R15 is alkyl or cycloalkyl. The term "aryloxy" as used herein denotes a group -O-aryl, wherein aryl is as defined above.
The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to
5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 3 rings which are fused together or linked covalently, typically containing 5 to 8 atoms; at least one of which is aromatic in which one or more carbon atoms in one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. An "optionally substituted heteroaryl" refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted aryl.
Non-limiting examples of heteroaryl can be 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, A- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- isothiazolyl, 2-, 4- or 5-thiazolyl, 1 ,2,3-triazol-1-, -2-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3-, -4- or -5-yl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3- thiadiazol-4- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,5-thiadiazol-3- or -4-yl, 1 ,3,4-thiadiazolyl, 1- or 5-tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, A-, 5- or 6-pyrimidinyl, 2-, 3-, A-, 5- 6-2H- thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 2-, 3-, A-, 5-, 6- or 7-benzofuryl, 1-, 3-, 4- or 5-isobenzofuryl, 2-, 3-, A-, 5-, 6- or 7-benzothienyl, 1-, 3-, 4- or 5-isobenzothienyl, 1-, 2-, 3-, A-, 5-, 6- or 7-indolyl, 2- or 3-pyrazinyl, 1 ,4-oxazin-2- or -3-yl, 1 ,4-dioxin-2- or -3-yl, 1 ,4-thiazin-2- or -3-yl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazin-2-, -A- or -6-yl, thieno[2,3-b]furan-2-, -3-, -A-, or -5-yl, 1-, 2-, 4- or 5- benzimidazolyl, 1-, 3-, A-, 5-, 6- or 7-benzopyrazolyl, 3-, A-, 5-, 6- or 7-benzisoxazolyl, 2-, A-, 5-, 6- or 7-benzoxazolyl, 3-, A-, 5-, 6- or 7-benzisothiazolyl, 2-, A-, 5-, 6- or 7-benzothiazolyl, 1-, 2- thianthrenyl, 3-, 4- or 5-isobenzofuranyl, 1-, 2-, 3-, 4- or 9-xanthenyl, 1-, 2-, 3- or 4-phenoxathiinyl, 2-, 3-pyrazinyl, 1-, 2-, 3-, A-, 5-, 6-, 7- or 8-indolizinyl, 2-, 3-, 4- or 5-isoindolyl, 1-, 2-, 3-, A-, 5-, 6- or 7-indazolyl, 2-, 6-, 7- or 8-purinyl, A-, 5- or 6-phthalazinyl, 2-, 3- or 4-naphthyridinyl, 2-, 5- or 6- quinoxalinyl, 2-, A-, 5-, 6-, 7- or 8-quinazolinyl, 1-, 2-, 3- or 4-quinolizinyl, 2-, 3-, A-, 5-, 6-, 7-, or 8- quinolinyl(quinolyl), 2-, A-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, A-, 5-, 6-, 7- or 8- isoquinolinyl(isoquinolyl), 3-, A-, 5-, 6-, 7- or 8-cinnolinyl, 2-, A-, 6- or 7-pteridinyl, 1-, 2-, 3-, 4- or 9- carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- phenanthridinyl, 1-, 2-, 3- or 4-acridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-perimidinyl, 2-, 3-, A-, 5-, 6-, 7-, 8-, 9- or 10-(1 ,7)phenanthrolinyl, 1- or 2-phenazinyl, 1-, 2-, 3-, A-, or 10-phenothiazinyl, 3- or A- furazanyl, 1-, 2-, 3-, A-, or 10-phenoxazinyl, azepinyl, diazepinyl, dibenzo[b,f]azepinyl, dioxanyl, thietanyl, oxazolyl dibenzo[a,d]cylcoheptenyl, or additionally substituted derivatives thereof.
The terms "heterocyclyl" or "heterocyclo" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 13 member monocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom- containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. An "optionally substituted heterocyclyl" refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or 1 to 2 substituents), selected from those defined above for substituted aryl.
Exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, indolinyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro- 2H-pyranyl, phthalazinyl, azepinyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,4-dioxanyl, 2,5- dioximidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 6H-1 ,2,5-thiadiazinyl, 2H-1 ,5,2-dithiazinyl, 2H-oxocinyl, 1 H- pyrrolizinyl, tetrahydro-1 ,1-dioxothienyl, N- formylpiperazinyl, 2,3-dihydrobenzo[1 ,4]dioxin-2-yl, 2,3- dihydrobenzo[1 ,4]dioxin-6-yl, and morpholinyl. The term "aralkyl" by itself or as part of another substituent refers to a group having as alkyl moiety the aforementioned alkyl attached to one of the aforementioned aryl rings. Examples of aralkyl radicals include benzyl, phenethyl, dibenzylmethyl, methylphenylmethyl, 3- (2-naphthyl)-butyl, and the like.
The term "cycloalkylalkyl" by itself or as part of another substituent refers to a group having one of the aforementioned cycloalkyl groups attached to one of the aforementioned alkyl chains. Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cydopentylethyl, 1-cydohexylethyl, 2-cyclopentylethyl, 2- cyclohexylethyl, cyclobutylpropyl, cyclopentyl propyl, 3-cyclopentyl butyl, cyclohexylbutyl and the like. The term "heterocyclyl-alkyl" by itself or as part of another substituents refers to a group having one of the aforementioned heterocyclyl group attached to one of the aforementioned alkyl group, i.e., to a group -Rb-Rc wherein Rb is alkylene or alkylene substituted by alkyl group and Rc is a heterocyclyl group.
The term "acyl" by itself or as part of another substituent refers to an alkanoyl group having 2 to 6 carbon atoms or a phenylalkanoyl group whose alkanoyl moiety has 1 to 4 carbon atoms, i.e.; a carbonyl group linked to a radical such as, but not limited to, alkyl, aryl, more particularly, the group
-COR11, wherein R11 can be selected from alkyl, aryl, substituted alkyl, or substituted aryl, as defined herein. The term acyl therefore encompasses the group alkylcarbonyl (-COR11), wherein R11 is alkyl. Said acyl can be exemplified by acetyl, propionyl, butyryl, valeryl and pivaloyl, benzoyl, phenylacetyl, phenylpropionyl and phenylbutytyl.
The term "alkylamino" by itself or as part of another substituent refers to a group consisting of an amino groups attached to one or two independently selected and optionally substituted alkyl groups, cycloalkyl groups, aralkyl or cycloalkylalkyl groups i.e., -N(R6)(R7) wherein R6 and R7 are each independently selected from hydrogen, cycloalkyl, aralkyl, cycloalkylalkyl or alkyl. Non-limiting examples of alkylamino groups include methylamino (NHCH3), ethylamino (NHCH2CH3), n- propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, ferf-butylamino, n- hexylamino, and the like.
The term "oxo" or "keto" as used herein refers to the group =0.
The term "amino" refers to the group -NH2.
The term "aminocarbonyl" refers to the group -(C=O)-NH2.
The term "aminoalkyl" refers to the group -Rb-NRdRe wherein Rb is alkylene or substituted alkylene, Rd is hydrogen or alkyl or substituted alkyl as defined herein, and Re is hydrogen or alkyl as defined herein.
The term "alkylaminocarbonyl" refers to a group -(C=0)-NRdRe wherein Rd is hydrogen or alkyl or substituted alkyl as defined herein, and Re is alkyl or substituted alkyl as defined herein.
The term "alkylaminocarbonylamino" refers to a group -NH(C=0)-NRdRe or -NR'(C=0)-NRdRe wherein Rd is hydrogen or alkyl or substituted alkyl as defined herein, and Re is alkyl or substituted alkyl as defined herein, wherein R' is alkyl or substituted alkyl.
The term "carboxyl" refers to the group -CO2H. Thus, a carboxyalkyl is an alkyl group as defined above having at least one substituent that is -CO2H.
The term "alkoxycarbonyl" refers to a carboxyl group linked to an alkyl radical i. e. to form -C(=0)0Re, wherein Re is as defined above for alkyl.
The term "alkylcarbonyloxy" refers to a -0-C(=0)Re wherein Re is as defined above for alkyl.
The term "alkylamidyl" or "alkylamide" refers to an alkylcarbonylamino group of Formula -NH(C=O)R or -NR'(C=0)R, wherein R and R' are each independently alkyl or substituted alkyl.
The term "alkylcarbonylaminoalkyl" refers to a group -Rb-NRd-C(=0)-Re wherein Rb is alkylene or alkylene substituted by alkyl, Rd is hydrogen or alkyl as defined herein, and Re is alkyl as defined herein.
The term "alkoxy" by itself or as part of another substituent refers to a group consisting of an oxygen atom attached to one optionally substituted straight or branched alkyl group, cycloalkyl group, aralkyl or cycloalkylalkyl group. Non-limiting examples of suitable alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, ferf-butoxy, hexanoxy and the like.
The term "alkyhetero" by itself or as part of another substituents refers to a group consisting of a hetero atom attached to one optionally substituted alkyl group, cycloalkyl group, aralkyl or cycloalkylalkyl group. Non-limiting examples of alkylhetero groups include alkylthio and alkylamino.
The term "alkylthio" by itself or as part of another substituent refers to a group consisting of a sulfur atom attached to one optionally substituted alkyl group, cycloalkyl group, aralkyl or cycloalkylalkyl group. Non-limiting examples of alkylthio groups include methylthio (SCH3), ethylthio (SCH2CH3), n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, ferf-butylthio, n-hexylthio, and the like.
The term "acylamino" by itself or as part of another substituent refers to a group consisting of an amino group attached to one or two independently selected acyl groups as described before. In case the two acyl groups of a dicarboxylic acid are attached to the amino group these represent imides such as phtalimides, maleimides and the like, and are encompassed in the meaning of the term acylamino.
The term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo or iodo.
The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non- limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1 -trifl uoroethyl and the like.
The term "haloaryl" alone or in combination, refers to an aryl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
The term "haloalkoxy" alone or in combination refers to a group of Formula -O-alkyl wherein the alkyl group is substituted by 1 , 2 or 3 halogen atoms. For example, "haloalkoxy" includes -OCF3 and -OCHF2.
The term "sulfonamide" or "sulfonamidyl" alone or in combination refers to a group of Formula -S02-NRdRe wherein Rd is hydrogen or alkyl or substituted alkyl as defined herein, and Re is hydrogen or alkyl as defined herein. The term "pyrrolydinylenealkylene" alone or in combination refers to a group of Formula
N-(CH2^* wherein t is an integer selected from 0, 1 , 2 or 3, and wherein q is an integer selected from 1 , 2, 3 or 4.
As used herein, the term "optionally substituted alkyl, cycloalkyl, alkenyl or alkynyl" or "a group selected from alkyl, cycloalkyl, alkenyl or alkynyl, each group being optionally substituted" means "optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl", wherein the substituents are the same as that described above for substituted alkyl.
Whenever the term "substituted" is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. Whenever used in the present invention the term "compounds of the invention" or a similar term is meant to include the compounds of general Formula I, II, III, IV, V or Vl and any subgroup thereof. This term also refers to the compounds as depicted in Tables 1 and 2 and their derivatives, N- oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters and metabolites, as well as their quaternized nitrogen analogues. The /V-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called Λ/-oxide.
As used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound. Asterisks (*) are used herein to indicate the point at which a mono-, bi- or trivalent radical depicted is connected to the structure to which it relates and of which the radical forms part.
The term "pro-drug" as used herein means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th Ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing pro-drugs generally is hereby incorporated. Pro-drugs of the compounds of the invention can be prepared by modifying functional groups present in said component in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent component. Typical examples of pro-drugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Pro-drugs are characterized by increased bio-availability and are readily metabolized into the active inhibitors in vivo.
In a particular embodiment, the present invention provides compounds having one of the following structural formula VII, VIII, IX, X, Xl, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, or XXX,
Figure imgf000016_0001
VIl VIII IX
Figure imgf000016_0002
X Xl XII
Figure imgf000016_0003
XVl XVII XVIII
Figure imgf000016_0004
XIX XX XXI
Figure imgf000016_0005
XXII XXX wherein X5 is selected from -N= or -CH=, R7 is selected from hydrogen, alkyl, aryl, alkoxy, halo, haloalkyl, or haloalkoxy, wherein n is an integer selected from 1 , 2, 3 or 4 and A1, L1, L2, R1, R2, R4, R5, s, t, X3 and X4 have the same meaning as that defined hereinabove.
Preferably, the present invention relates to compound of formula I to XXII and XXX, wherein X1 is selected from -N=, or -CH=, X2 is selected from -N=, or -CH=,
X3 is selected from -CH2-, -CR5=, or O, wherein R5 is selected from hydrogen, C1-4alkyl, or C5-14aryl,
X5 is selected from -N= or -CH=, t is an integer selected from 1 or 2, R1 is selected from hydrogen, halogen, C1-4alkyl, C5-14aryl, C3.8cycloalkyl, C2-6alkenyl, C2-6alkynyl, heteroalkyl or C-|.4alkylhetero,
X4 is selected from -N= or CR3, wherein R4 is hydrogen or R4 and R3 together with the carbon atoms to which they are attached form an C5.14aryl or a heteroaryl ring, each ring being optionally substituted by one or more substituents independently selected from halo, C1-4alkyl, C5-14aryl, C1- 4alkoxy, haloC-ι_4alkyl or haloC-ι_4alkoxy,
L1 is selected from -NH-, -CH2-, -SO2-,
L2 is a group selected from C-|.4alkylene, C3_8cycloalkylene, pyrrolydinyleneC-|.4alkylene or Ca-scycloalkylenoxyC-i^alkylene, each group being optionally substituted with one or more substituents independently selected from C-ι_4alkyl, C5.14aryl, halo, haloC-ι_4alkyl or haloC-ι_4alkoxy, wherein A1 is a group selected from C5-14aryl, C5.12heterocyclyl or C5.12heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyC-ι_4alkyl, nitro, azido, cyano, C-ι_4alkyl, C5.14aryl, C5.14arylalkyl, C5.12heteroaryl,
Figure imgf000017_0001
C3.8cycloalkyl, acyl, C-ι_4alkylamino, C-ι_4alkylaminocarbonyl, -SO2R6, C-ι_4alkylcarbonyloxy, C5.12heterocyclyl, haloC-ι_4alkyl, C-ι_4alkylcarbonyl, C5.14aryloxy, C5.14arylcarbonyl, haloC-ι_4alkoxy, C-ι_4alkoxy, C1_4alkylthio, carboxyl, acylamino, thioamide, C-ι_4alkyloxycarbonyl, or sulfonamidyl, wherein R6 is
Figure imgf000017_0002
C-ι_4alkylamino or C3.8cydoalkyl,
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyC-|.4alkyl, nitro, azido, cyano, C1-4alkyl, C5.14aryl, C5.12heteroaryl, C5.12heteroarylC-|.4alkyl, C5_14arylC1_4alkyl, C3.8cydoalkyl, acyl, C-|.4alkylamino, C-|.4alkylaminocarbonyl, -SO2R6, C-|.4alkylcarbonyloxy, C5.12heterocyclyl, haloC-ι_4alkyl, C-ι_4alkylcarbonyl, C5.14aryloxy, C5.14arylcarbonyl, haloC-ι_4alkoxy, C-ι_4alkoxy, C-ι_4alkylthio, carboxyl, acylamino, thioamide, C-ι_4alkyloxycarbonyl, or sulfonamidyl, wherein R6 is C1-4alkyl, C-|.4alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4, with the proviso that when L1 is NH in formula I, R1 is selected from halogen, C5.14aryl or C-ι_4alkylhetero, or when L1 is NH in formula I and R1 is hydrogen or C1-4alkyl, L2 is pyrrolydinyleneC-|.4alkylene optionally substituted with one or more substituents independently selected from C1-4alkyl, C5.14aryl, halo, haloC-ι_4alkyl or haloC-ι_4alkoxy.
According to a preferred embodiment, the present invention provides compounds having one of the structural Formula VIII, IX, X, Xl, XII, or XXX, wherein
R1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero, R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cydoalkyl, s is an integer selected from 0, 1 , 2, 3 or 4,
R4 is hydrogen, R5 is hydrogen or alkyl,
L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, and wherein A1 is a group selected from aryl, heterocydyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cydoalkyl.
According to another embodiment, the present invention provides compounds having one of the structural Formula XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII, wherein
X4 is -N=,
X3 is -CR5=, wherein R5 is selected from hydrogen, alkyl, or aryl, R1 is selected from hydrogen, halogen, alkyl, aryl, cydoalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero,
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cydoalkyl, s is an integer selected from 0, 1 , 2, 3 or 4,
R4 is hydrogen,
L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, and wherein A1 is a group selected from aryl, heterocydyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl.
In a particular embodiment, the present invention provides compounds structural Formula VII, wherein A1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4, and wherein
R1 is hydrogen or alkyl and L2 is pyrrolydinylenealkylene optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, or
R1 is selected from halogen, aryl or alkylhetero, and L2 is a group selected from alkylene, cydoalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy.
In a particular embodiment, the present invention provides compounds structural Formula VIII, wherein A1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4, R1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero, and L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy.
In another particular embodiment, the present invention provides compounds as described hereinabove, wherein A1 is a group selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, tetrazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, 2H-thiopyranyl, 4H-thiopyranyl, benzofuryl, benzothienyl, benzimidazolonyl, 2,3-dihydro-1 ,4-benzodioxinyl, 1 ,3-benzodioxolyl, indolyl, benzimidazolyl, benzopyrazolyl, benzisoxazolyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, naphthyl, quinolinyl, quinazolyl, isoquinolinyl, indanyl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cydoalkyl, and wherein L1, L2, R1, R2, R4, X1, X2, X3, X4, s, and t, have the same meaning as that defined herein.
In another particular embodiment, the present invention provides compounds as described hereinabove, wherein A1 is a group selected from 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1- , 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5- isothiazolyl, 2-, 4- or 5-thiazolyl, 1 ,2,3-triazol-1-, -2-, -4- or -5-yl, 1 ,2,4-triazol-1-, -3-, -4- or -5-yl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl, 1 ,2,5-thiadiazol-3- or -4-yl, 1- or 5-tetrazolyl, phenyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, A-, 5- or 6-pyrimidinyl, 2-, 3-, A-, 5- 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 2-, 3-, A-, 5-, 6- or 7-benzofuryl, 2-, 3-, A-, 5-, 6- or 7-benzothienyl, benzimidazolonyl, 6- 2,3-dihydro-1 ,4- benzodioxinyl, 1 ,3-benzodioxolyl, 1-, 2-, 3-, A-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, A-, 5-, 6- or 7-benzopyrazolyl, 3-, A-, 5-, 6- or 7-benzisoxazolyl, 2-, A-, 5-, 6- or 7-benzoxazolyl, 3-, A-, 5-, 6- or 7-benzisothiazolyl, 2-, A-, 5-, 6- or 7-benzothiazolyl, 1- or 2- naphthyl, 2-, 3-, A-, 5-, 6-, 7-, 8-quinolinyl, 2-, A-, 5-, 6-, 7- or 8-quinazolyl, 1-, 3-, A-, 5-, 6-, 7-, 8-isoquinolinyl, indanyl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cydoalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocydyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, and wherein R6 is alkyl, alkylamino or cydoalkyl. In a further embodiment, the present invention provides compounds as described hereinabove, wherein A1 is a group selected from phenyl, 2-, 3-, A-, 5-, 6-, 7-, 8-quinolinyl, 2,3-dihydro-1 ,4- benzodioxinyl, 6-indolyl, 1-napthyl, 2-naphtly, indanyl, 1 ,3-dihydrobenzoimidazol2-one, 1 , 2, 3, A- tetrahydronapthtlanel-1-yl, 2-benzofuran-5-yl, pyridin-4-yl, pyridin-3-yl, 1 ,3-benzodioxolyl, benzimidazolonyl, 2- thienyl, 3-thιenyl, or 5-(2,3-dιhydro)benzofuranyl, each group being optionally substituted with one to four substituent independently selected from F, Cl, Br, -CH3, tert-butyl,
-OCH3, -NO2, -CO2H, -C(=O)-N(CH3)2, -O-C(=O)-CH3,
Figure imgf000021_0001
, -CH2-CH3, phenyl, morpholino, -SO2-CH3, -CF3, -OCF3, -OCHF2, -CH2-NH-C(O)-CH3, -S-CH3,-C(=O)-CH3, -C(=O)O-CH3, -C(=O)NH2, -N(CHs)2, -SO2-N(CH3)2, phenoxy, benzoyl, -C(CH3)3, -O-(CH2)2-CH3, -OH or -CN, wherein L2 is selected from -CH2-, -(CH2)2-, -(CH2J3-, -CH(CH2OH)-, -CH(CH2-O-CH3)-, -CH(CH3)-, -CH(CH2-CH3)-, -CH(CO2H)-, -CH(CO2CH3)-, -(CH2)2-O-CH2-, -CH(,CH2-N(CH3)2)-, -(CH2)2-CH=,
Figure imgf000021_0002
wherein R2 is selected from hydrogen, nitro, -SO2-NH2, F, Cl, Br, OH, -CH3, -OCH3, -NO2, -CO2H,
-C(=O)-N(CH3)2, -O-C(=O)-CH3, X-J , *
Figure imgf000021_0003
, -N-morpholino,
-CH2-CH3, phenyl, -SO2-CH3, -CF3, -OCF3, -OCHF2, -CH2-NH-C(=O)-CH3, -S-CH3, -C(=O)-CH3, -C(=O)O-CH3, -C(=0)0- CH2-CH3, -C(=O)NH2, -N(CH3J2, -SO2-N(CH3)2, phenoxy, benzoyl, -C(CH3J3, -0-(CH2J2-CH3, or -CN, and wherein R1, R4, R5 and X4 have the same meaning as that defined herein.
In a further embodiment, the present invention provides compounds having the structural formula XXXI,
Figure imgf000021_0004
XXX! wherein
L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, R1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero, and
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4, and R8 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein Re is alkyl, alkylamino or cycloalkyl, r is an integer selected from O, 1 , 2, 3 or 4.
In a further embodiment, the present invention provides compounds having the structural formula XXXI, wherein R8 is selected from F, Cl, Br, -CH3, fert-butyl, -OCH3, -NO2, -CO2H, -C(=O)-N(CH3)2,
-O-C(=O)-CH3,
Figure imgf000022_0001
,-CH2-CH3, phenyl, morpholino, -SO2-CH3, -CF3, -
OCF3, -OCHF2, -CH2-NH-C(=O)-CH3, -S-CH3, -C(=O)-CH3, -C(=O)O-CH3, -C(=O)NH2, -N(CH3J2, -SO2-N(CH3)2, phenoxy, benzoyl, -C(CH3)3, -O-(CH2)2-CH3, -OH or -CN, r is selected from O, 1 , 2 or 3,
L2 is selected from -CH2-, -(CH2J2-, -(CH2)3-, -CH(CH2OH)-, -CH(CH2-O-CH3)-, -CH(CH3)-, -CH(CH2-CH3)-, -CH(CO2H)-, -CH(CO2CH3)-, -(CH2J2-O-CH2-, -CH(,CH2-N(CH3)2)-, -(CH2J2-CH=,
Figure imgf000022_0002
R2 is selected from hydrogen, nitro, -SO2-NH2, F, Cl, Br, OH, -CH3, -OCH3, -NO2, -CO2H,
-C(=O)-N(CH3)2, -O-C(=O)-CH3, *-* , * Nχ^ , \-J , s' , -N-morpholino,
-CH2-CH3, phenyl, -SO2-CH3, -CF3, -OCF3, -OCHF2, CH2-NH-C(=O)-CH3, -S-CH3, -C(=O)-CH3, -C(=O)O-CH3, -C(=0)0- CH2-CH3, -C(=O)NH2, -N(CH3J2, -SO2-N(CH3J2, phenoxy, benzoyl, -C(CH3J3, -0-(CH2J2-CH3, or -CN, and s is O, 1 , 2 or 3. In a further embodiment, the present invention provides compounds as described heremabove, wherein R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido. cyano. alkyl. aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl.
In a further embodiment, the present invention provides compounds as described heremabove wherein R2 is selected from hydrogen, thienyl, methyl, ethyl, propyl, isopropyl, butyl, fert-butyl, chloro, fluoro, bromo, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy or phenoxy In a further embodiment, the present invention provides compounds as described hereinabove wherein R1 is hydrogen, bromo, fluoro, chloro, methyl, phenyl, methylthio or ethylthio. In a further embodiment, the present invention provides compounds as described hereinabove wherein R7 is selected from hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy. The present invention also relates to methods for the preparation of the compounds according to the present invention, using for example structurally related compounds. In an embodiment of the present invention, the compounds of the present invention can be prepared using the non-limiting methods described hereunder and in the examples.
In a preferred embodiment, the method for preparing the compounds of the invention comprises the step of condensation of a compound of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII:
Figure imgf000023_0001
XXIII XXIV XXV XXVI
Figure imgf000023_0002
XXVII XXVIII with a compound of Formula XXIX:
Figure imgf000023_0003
XXIX
The reaction can generally be performed by condensing the compound of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII with a compound of Formula XXIX.
The condensation can be performed via the formation of the acyl chloride of the acid of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII and then by the coupling of said acyl chloride with the amine of Formula XXIX. In another embodiment, the condensation can be performed by using a suitable coupling agent, in a suitable solvent, in the presence of suitable base. The suitable coupling agent can be selected from the group comprising dicyclo-hexylcarbodiimide, hydroxybenzotriazole, o-benzotriazol-1-yl-N,N,N',N-4-tetramethyluronium hexafluorophosphate and the like and mixture thereof. The suitable solvent can be selected from the group comprising dichloromethane, dimethylformamide and the like or mixture thereof. Non limiting examples of suitable base comprise potassium carbonate, diisopropylethylamine, triethylamine, triisopropylamine and the like.
As described above, the condensation can be realized via formation of the corresponding acyl chloride and then coupling with the desired amine. In another embodiment the condensation can be performed using a suitable coupling agent, such as hydroxybenzotriazole (HOBT), o- benzotriazol-1-yl-N,N,N',N-4-tetramethyluronium hexafluorophosphate (TBTU) and the like at a suitable molar ratio, for example between 1 :1 to 1 :3 relative to the acid derivative; in a suitable solvent or solvent mixture, such as dichloromethane (DCM) or dimethylformamide (DMF) and the like; at a suitable temperature, usually between O0C and the boiling point of the solvent used; for a suitable period of time, usually between 0.25 hr and 48 hrs; in the presence of a suitable base, for example an organic base such as potassium carbonate (K2CO3), diisopropylethylamine (DIEA), triethylamine (TEA), triisopropylamine and the like, in an amount between 0.1 and 5.0 equivalents.
The starting material for this reaction is either commercially available or can be prepared in a manner known per se.
The compounds of the present invention may then be isolated from the reaction mixture and may optionally be further purified, using techniques known per se, such as evaporation of the solvent, washing, trituration, recrystallisation from a suitable solvent or solvent mixture, and chromatographic techniques, such as column chromatography -for example using silica gel or C18 as solid phase- or preparative thin layer chromatography.
The term "stereoisomer" as used herein, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. It will be clear to the skilled person that some of the compounds of the invention may contain one or more asymmetric carbon atoms that serve as a chiral center, which may lead to different optical forms (e.g. enantiomers or diastereoisomers). Unless otherwise mentioned or indicated, the chemical designation of a compound herein encompasses all such optical forms in all possible configurations as well as the mixture of all possible stereochemical^ isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemical^ isomeric forms of the compounds of the invention either in pure form or in admixture with each other are intended to fall within the scope of the present invention.
More generally, from the above, it will be clear to the skilled person that some of the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, and stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.
It will also be clear that when the desired compounds of the invention, and/or the starting materials, precursors and/or intermediates used in the preparation thereof, contain functional groups that are sensitive to the reaction conditions used in the preparation of the compounds of the invention (i.e. that would undergo undesired reactions under those conditions if they were not suitably protected) can be protected during said reaction with one or more suitable protective group, which protective group can then be suitably removed after either completion of said reaction and/or as a later or final step in the preparation of the compounds of the invention. Protected forms of the inventive compounds are included within the scope of the present invention. Suitable protective groups, as well as methods and conditions for inserting them and removing them, will be clear to the skilled person and are generally described in the standard handbooks of organic chemistry, such as Greene and Wuts, "Protective groups in organic synthesis", 3rd Edition, Wiley and Sons, 1999, which is incorporated herein by reference in its entirety. It will also be clear to the skilled person that compounds of the invention in which one or more functional groups have been protected with suitable functional groups can find use as intermediates in the production and/or synthesis of the compounds of the invention, and as such form a further aspect of the invention. The present invention further encompasses compounds obtainable by the methods according to the invention.
It was surprisingly found that the compounds of the invention interact with ion channels as shown in the examples below, in particular with ion channels from the Kv family, more in particular with ion channels from the Kv4 subfamily, and especially with Kv4.3 channels. By "interact with" is meant that the compounds of the invention act as antagonists of said ion channel(s) and/or of the biological function(s) and/or pathways associated with these channels, and in particular that the compounds of the invention can fully or partially "block" said channels. Preferably, the compounds of the invention interact with ion channels from an animal, preferably a vertebrate animal, more preferably a warm-blooded animal, even more preferably a mammal, and most preferably a human being.
In an embodiment of the present invention, the compounds of the invention act as antagonists of said ion channels and/or of the biological functions or pathways associated therewith. Preferably, the compounds of the invention block said ion channels.
In the invention, particular preference is given to compounds of Formula I or Il above that are particularly active against Kv4.3 ion channels and Kv1.5 ions channels and wherein the percentage inhibition measured after application of the compound and relative to the blank is equal or above 10%, preferably above 15%, more preferably above 20%, yet more preferably above 30%, yet more preferably above 50% as determined by a suitable assay, such as the assay used in the Examples below. In a further embodiment, the compounds of the invention act as antagonists of ion channels from the Kv family and/or of the biological functions or pathways associated therewith. Also, preferably, the compounds of the invention block ion channels from the Kv family.
In a yet further embodiment, the compounds of the invention act as antagonists of ion channels from the Kv4 subfamily and/or of the biological functions or pathways associated therewith. Also, preferably, the compounds of the invention block ion channels from the Kv4 sub family. According to a yet further embodiment, the compounds of the invention act as antagonists of the Kv4.3 ion channel and/or of the biological functions or pathways associated therewith. Also, most preferably, the compounds of the invention block the Kv4.3 ion channel.
According to a further aspect, the compounds of the invention which block the Kv4.3 ion channels, also block ion channels of the Kv1 subfamily, especially the Kv1.5 ion channel.
Whether a compound of the invention interacts with an ion channel can be determined using a suitable technique or assay, such as the assays described in the examples.
The compounds of the invention can therefore generally be used (1 ) as antagonists of ion channels and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of ion channels, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with said ion channels.
In particular, the compounds of the invention that interact with ion channels from the Kv family can be used (1 ) as antagonists of ion channels from the Kv family and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of ion channels from the Kv family, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with ion channels from the Kv family.
More in particular, the compounds of the invention that interact with ion channels from the Kv4 subfamily can be used (1 ) as antagonists of ion channels from the Kv4 subfamily and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of ion channels from the Kv4 subfamily, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with ion channels from the Kv4 sub family.
Even more in particular, the compounds of the invention that interact with the Kv4.3 ion channels from the Kv4 subfamily can in particular be used (1 ) as antagonists of the Kv4.3 ion channel and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of the Kv4.3 ion channel, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with the Kv4.3 ion channel. According to a further embodiment, the compounds of the invention that interact with ion channels from the Kv1 subfamily can be used (1 ) as antagonists of ion channels from the Kv1 subfamily and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of ion channels from the Kv1 subfamily, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with ion channels from the Kv1 sub family.
More in particular, the compounds of the invention that interact with the Kv 1.5 ion channels from the Kv1 subfamily can in particular be used (1 ) as antagonists of the Kv1.5 ion channel and/or of the biological functions or pathways associated therewith, i.e. in an in vitro, in vivo or therapeutic setting; (2) as blockers of the Kv1.5 ion channel, i.e. in an in vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with the Kv1.5 ion channel.
In a further aspect, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a medicament. Furthermore, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as an ion channel blocker. In addition, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a blocker of an ion-channel of the Kv4 family of ion channels. In particular, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a blocker of an ion-channel of the Kv4.3 family of ion-channels. Further, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a blocker of an ion channel of the Kv1 family of ion channels. In particular, the present invention provides a compound of Formula I, II, III, IV, V or Vl for use as a blocker of an ion channel of the Kv1.5 family of ion channels.
The present invention further provides for the use of a compound according to the invention for the preparation of a medicament in the prevention and/or treatment of conditions or diseases associated with ion channels of the Kv4 and/or Kv1 family.
Such diseases and disorders will be clear to the skilled person. For example, conditions and diseases associated with the Kv4.3 ion channel, in particular in humans, include (i) cardiac disorders including arrhythmias including Brugada Syndrome; hypertension-induced heart disorders including hypertension-induced cardiac hypertrophy; cardiac failure; and (ii) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome. Arrhythmias include (i) atrial Arrhythmias such as but not limited to Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff-Parkinson-White (WPW) syndrome; (ii) Ventricular Arrhythmias such as but not limited to Premature ventricular contraction (PVC), ventricular tachycardia (VT), ventricular fibrillation and bradicardias; (iii) Others such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrio-ventricular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias; and the compounds of the invention that interact with Kv4.3 ion channels can be used in the prevention and/or treatment of such conditions and diseases. Similar conditions and diseases are associated with the Kv1.5 ion channel and can be used in prevention and/or treatment of such conditions and diseases. For instance, class III anti-arrhythmic drugs exert their effects by a blockade of cardiac potassium channels, resulting in a prolongation of repolarization and refractoriness. l(Kur), the ultra-rapid delayed rectifier current was identified in human atrial but not ventricular tissue. Consequently, it contributes to the repolarisation of the action potential in the atrium only. The Kv1.5 protein is supposed to be a critical cardiac voltage- gated potassium channel to form the l(Kur). Compounds inhibiting Kv1.5 would delay repolarisation of the action potential in the atrium and consequently prolong the atrial refractory period. Assuming high selectivity of a Kv1.5 inhibitor over hERG, such inhibitor would not interfere with ventricular repolarization, which has been associated with pro-arrhythmia, e.g. torsades de pointes. Therefore, Kv 1.5 inhibitors are of special interest in the treatment of atrial tachyarrhythmias such as atrial fibrillation. Therefore, according to a further embodiment, the present invention also relates to the use of the compounds that interact with Kv1.5 ion channels for prevention and/or treatment of the conditions and diseases given above and related with Kv4.3 ion channel associated diseases. Preferred compounds for use in treating these conditions or diseases are compounds that show activity for both the Kv4.3 and the Kv1.5 ion channel. For example, the compounds are suitable for the treatment and/or prevention of various disorders: (i) cardiac disorders including arrhythmias including Brugada Syndrome; hypertension-induced heart disorders including hypertension- induced cardiac hypertrophy; cardiac failure; and (ii) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome. Arrhythmias include (i) atrial Arrhythmias such as but not limited to Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff- Parkinson-White (WPW) syndrome; (ii) Ventricular Arrhythmias such as but not limited to Premature ventricular contraction (PVC), ventricular tachycardia (VT), ventricular fibrillation and bradicardias; (iii) Others such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrio-ventricular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias.
According to a more specific embodiment, the compounds may be employed for the termination of existing atrial fibrillation or flutters for the recovery of the sinus rhythm (cardio version). Moreover, the substances may reduce the susceptibility to the formation of new fibrillation events (maintenance of the sinus rhythm, prophylaxis). The compounds according to the invention can also be used as heart rate control agents, angina pectoris including relief of Prinzmetal's symptoms, vasospastic symptoms and variant symptoms; gastrointestinal disorders including reflux esophagitis, functional dyspepsia, motility disorders (including constipation and diarrhea), and irritable bowel syndrome, disorders of vascular and visceral smooth muscle including asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, peripheral vascular disease (including intermittent claudication), venous insufficiency, impotence, cerebral and coronary spasm and Raynaud's disease, inflammatory and immunological disease including inflammatory bowel disease, rheumatoid arthritis, graft rejection, asthma, chronic obstructive pulmonary disease, cystic fibrosis and atherosclerosis, cell poliferative disorders including restenosis and cancer (including leukemia), disorders of the auditory system, disorders of the visual system including macular degeneration and cataracts, diabetes including diabetic retinopathy, diabetic nephropathy and diabetic neuropathy, muscle disease including myotonia and wasting, peripheral neuropathy, cognitive disorders, migraine, memory loss including Alzheimer's and dementia, CNS mediated motor dysfunction including Parkinson's disease, and ataxia, epilepsy, and other ion channel mediated disorders.
As inhibitors of the K1 subfamily of voltage-gated K+ channels compounds according to the present invention are useful to treat a variety of disorders including resistance by transplantation of organs or tissue, graft-versus-host diseases brought about by medulla ossium transplantation, rheumatoid arthritis, systemic lupus erythematosus, hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetes mellitus, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, infectious diseases caused by pathogenic microorganisms, inflammatory and hyperproliferative skin diseases, psoriasis, atopical dermatitis, contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupuserythematosus, acne, Alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns and leukotriene B4-mediated diseases, Coeliaz diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Good-pasture's syndrome, hemolyticuremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergy sensitivity, cutaneous T cell lymphoma, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia osses dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth, muscular dystrophy, Pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis, pigentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenis, metastatis of carcinoma and hypobaropathy, disease caused by histamine or Ieukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, nonA/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, "acute-on-chronic" liver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.
The compounds of the present invention are antiarrhythmic agents which are useful in the prevention and treatment (including partial alleviation or cure) of arrhythmias. As inhibitors of Kv1.5, compounds within the scope of the present invention are particularly useful in the selective prevention and treatment of supraventricular arrhythmias such as atrial fibrillation, Brugada syndrome, and atrial flutter.
Whether a compound of the invention interacts with an ion channel, such as with an ion channel of the Kv family, for example an ion channel of the Kv4 or Kv1 subfamily, such as the Kv4.3 or the Kv1.5 ion channel, respectively, can be determined using a suitable technique or assay, such as the assays and techniques referred to herein or other suitable assays or techniques known in the art.
For pharmaceutical use, the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug, such as an ester. As used herein and unless otherwise stated, the term "solvate" includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like. Such salts, hydrates, solvates, etc. and the preparation thereof will be clear to the skilled person; reference is for instance made to the salts, hydrates, solvates, etc. described in US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733. The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such a sarginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.
In another embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutic amount of a compound according to the invention.
The term "therapeutically effective amount" as used herein means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. The pharmaceutical composition can be prepared in a manner known per se to one of skill in the art. For this purpose, at least one compound having Formula I, II, III, IV, V or Vl, one or more solid or liquid pharmaceutical excipients and, if desired, in combination with other pharmaceutical active compounds, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human medicine or veterinary medicine. Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds. By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration, for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US- A-6,372,778, US-A-6, 369,086, US-A-6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, and the like. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ α-, β- or γ-cydodextrins or their derivatives. In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.
Appropriate cyclodextrins are α-, β- or γ-cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxyl groups of the anhydroglucose units of the cyclodextrin are substituted with alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyalkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyalkyl, particularly carboxymethyl or carboxyethyl; alkylcarbonyl, particularly acetyl; alkoxycarbonylalkyl or carboxyalkoxyalkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; alkylcarbonyloxyalkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl- β-CD, 2-hydroxyethyl-β-CD, 2- hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and (2-carboxymethoxy)propyl- β-CD, and in particular 2-hydroxypropyl- β-CD (2-HP- β-CD). The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxyl groups are etherified with different groups such as, for example, hydroxypropyl and hydroxyethyl. An interesting way of formulating the compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331. Although the formulations described therein are with antifungal active ingredients, they are equally interesting for formulating the compounds. Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavors. In particular, the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin. The present invention also encompasses cyclodextrin complexes consisting of a compound according to the invention and a cyclodextrin. More in particular, the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.
The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. The term "a solid dispersion" also comprises dispersions that are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
The water-soluble polymer is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 2O0C solution. Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
It may further be convenient to formulate the compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal- coating polymer layer. Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof. The above preparations may be prepared in a manner known per se, which usually involves mixing the active substance(s) to be used with the one or more pharmaceutically acceptable carriers, which necessary under aseptic conditions. Reference is again made to US-A-6,372,778, US-A- 6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.
The compounds can be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred.
The compound of the invention will generally be administered in an effective amount, which, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.01 to 1000 mg, more often between 0.1 and 500 mg, such as between 0.1 and 250 mg, for example about 0.1 , 1 , 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences. It will be understood, however, that specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition.
Thus, in a further aspect, the invention relates to a composition and in particular a composition for pharmaceutical use, which contains at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for pharmaceutical use). The invention also relates to the use of a compound of the invention in the preparation of such a composition.
In accordance with the method of the present invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
For an oral administration form, the compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. For subcutaneous or intravenous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
The compounds according to the invention were found to act as antagonist of ion channels from the Kv family more in particular from the Kv4 subfamily and/or of the biological functions or pathways associated therewith. The compounds according to the invention were also found to act as antagonist of ion channels from the Kv1 subfamily and/or of the biological functions or pathways associated therewith.
The compounds of the invention can therefore be used (1 ) as antagonists of ion channels and/or of the biological functions or pathways associated therewith, i.e. in an vitro, in vivo or therapeutic setting; (2) as blockers of ion channels, i.e. in an vitro, in vivo or therapeutic setting; and/or (3) as pharmaceutically active agents, in particular in (the preparation of pharmaceutical compositions for) the prevention and/or treatment of conditions or diseases associated with said ion channels. In addition, the compounds according to the invention showed very low activity or no activity with respect to the hERG channel, and are thereby selective.
As indicated above, due to the blocking activity on the above mentioned ion channels the compounds according to the present invention are particularly useful in the prevention and/or treatment of conditions or diseases associated with ion channels from the Kv family. Such diseases and disorders will be clear to the skilled person. For example, conditions and diseases associated with the Kv4.3 ion channel, in particular in humans, include cardiac disorders such as arrhythmia, Brugada syndrome, hypertension-induced heart disorders such as hypertension-induced cardiac hypertrophy (e.g. ventricular hypertrophy), and disorders of the nervous system such as epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease, multiple sclerosis, demyelinating disease and Parkinson's syndrome. The compounds according to the present invention interact with Kv 4.3 ion channels and can be used in the prevention and/or treatment of such conditions and diseases. In addition, conditions and diseases associated with the Kv1.5 ion channel, in particular in humans, include the same diseases and disorders as mentioned above as for the Kv4.3 ion channel. The compounds according to the invention that interact with Kv1.5 ion channel are particularly useful in the prevention and/or treatment of atrial tachyarrhythmias such as atrial fibrillation or Brugada syndrome.
Therefore, in another embodiment, the present invention also relates to the use of the compounds according to the invention or to a pharmaceutical composition comprising said compounds in the treatment of cardiac disorders such as arrhythmia, Brugada syndrome, hypertension-induced heart disorders such as hypertension-induced cardiac hypertrophy (e.g. ventricular hypertrophy), and disorders of the nervous system such as epilepsy, stroke, spinal cord injury, traumatic brain injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease, multiple sclerosis, demyelinating disease and Parkinson's syndrome. In a further embodiment, the present invention also relates to the use of the compounds according to the invention or to a pharmaceutical composition comprising said compounds in the treatment of cardiac disorders such as arrhythmia. In another further embodiment, the present invention also relates to the use of the compounds according to the invention or to a pharmaceutical composition comprising said compounds in the treatment of disorders of the nervous system.
A method of treating cardiac disorders comprises administering to an individual in need of such treatment a pharmaceutical composition comprising the compounds according to the invention. A method of treating disorders of the nervous system comprises administering to an individual in need of such treatment a pharmaceutical composition comprising the compounds according to the invention.
It is also envisaged that the above compounds and compositions may be of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also -for economically important animals such as cattle, pigs, sheep, chicken, fish, etc.- enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal. Thus, in a further aspect, the invention relates to a composition for veterinary use that contains at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for veterinary use). The invention also relates to the use of a compound of the invention in the preparation of such a composition. It is also envisaged that the above compounds and compositions may be of value as insecticides. The invention will now be illustrated by means of the following synthetic and biological examples, which do not limit the scope of the invention in any way.
Examples
Example 1 : Preparation of the compounds according to the present invention The practice of the present invention will employ, unless otherwise indicated, conventional techniques of synthetic organic chemistry, biological testing, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. Unless indicated otherwise, the purity of the compounds was confirmed by liquid chromatography/mass spectrometry (LC/MS), according to method A as follows: Method A (gradient 5 min):
HPLC: Waters Alliance 2690 with photodiode array detector Waters 996. Mass spectrometer: Micromass Platform ZMD LC. Ionization: electrospray (polarity: negative and positive).
Method:
Phase: Tosohaas TSK-gel super ODS (100 A, 2μm), column: 4.6x50 mm; Solvent A: Water and formic acid (26.5 mM); Solvent B: Acetonitrile and formic acid (17 mM); Flow: 2.75 ml/min; Gradient 5 mn: From 100 % A & 0 % B to 20% A & 80 % B in 3 min. lsocratic 80 % B for 1 min. From 80 % B & 20% A to 0 %B and 100% A in 0.5 min. lsocratic 100 % A for 0.5 min
NMR spectra were determined on a Varian Mercury 300 MHz NMR using the indicated solvent as an internal reference. Melting points were determined on a Bϋchi B-540 and are non-corrected. All reagents used were either obtained commercially or were prepared in a manner known per se.
Methods of preparation
Compounds of Formula I, II, III, IV, V or Vl may be prepared according to the following schemes and the knowledge of one skilled in the art.
Protocol A: The acid derivative (1.0 eq.) is dissolved in a mixture of DMF and DIEA (3.0 to 5.0 eq.). A solution of TBTU (1.3 eq.) and HOBt (0.3 eq.) in DMF is added and the mixture is stirred at room temperature for 5 to 30 minutes. The amine (1.0 eq.) is added and the reaction mixture is stirred at room temperature for a period of 20 min to 24 hours. DMF is removed under reduced pressure. The residue is diluted with EtOAc or DCM and washed with 0.5N HCI, 0.5N NaOH and water/brine or with 1 N NaHCO3 and water/brine or with 1 N Na2CO3 and water/brine. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography, semi-prep HPLC or by recrystallization. Protocol B:
The bromide (1.0 eq.), the amine (1.0 eq.), cesium carbonate (1.4 eq.), BINAP (0.1 eq.) and palladium acetate (0.1 eq.) are dissolved in dry 1 ,4-dioxane and dry DMF. The mixture in heated under nitrogen atmosphere in the microwave at 17O0C for 20 minutes. The solvent is removed under reduced pressure. The residue is purified by flash chromatography, semi-prep HPLC or by recrystallization.
Protocol C:
The sulfanyl derivative (1.0 eq.) is dissolved in acetic acid. Hydrogen peroxide (1 ml) is added and the mixture is stirred at room temperature for 3 days. The mixture is dissolved in water and extracted with ethyl acetate. The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by semi-prep HPLC.
Protocol D:
Ethyl 2-oxo-3-piperidinecarboxylate (1.0 eq.) is dissolved in dry THF under nitrogen atmosphere. The mixture is cooled to O0C and sodium hydride (3.0 eq.) is added in small portions. The mixture is stirred at O0C for 20 minutes and benzylchloride (1.0 eq.) is added dropwise. The mixture is stirred at O0C for 2 hours. The mixture is poured in ice-water and extracted with EtOAc. The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure.
Protocol E: The corresponding ester (1.0 eq.) is dissolved in ethanol and a base such as 1 N LiOH or 1 N NaOH or 2N NaOH (1.0 to 5.0 eq.) is added. The mixture is stirred at room temperature to 7O0C for 1 to 24 hours. The mixture is extracted with DCM and the water layer is acidified with 20% aqueous potassium hydrogen sulfate solution and extracted with DCM or the solvent is removed under reduced pressure, water is added and acidified with 1 N HCI. The combined organic layers from the acidic extraction are dried over MgSO4 and the solvent is removed under reduced pressure or the precipitate is filtered and dried.
Protocol F:
LDA (1.2 eq., 1 ,8 M in benzene, heptane, THF) is added slowly to a stirred solution of 2,4-dibromo- thiazole (1.0 eq.) in THF at -780C. The mixture is stirred at -780C for 30 minutes and the corresponding benzylisocyanate (1.5 eq.) is added. The mixture is stirred at -780C for another 30 minutes before it is slowly allowed to warm up to room temperature. Ice-water is added carefully and the mixture is extracted with EtOAc. The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography. Protocol G:
The 2,4-dibromo-thiazole derivative (1.0 eq.) is dissolved in DMSO. DIEA (1.0 eq.) and the amine (4.0 eq.) are added. The mixture is heated under nitrogen atmosphere in the microwave at 13O0C for 2 hours. The reaction mixture is diluted with DCM and washed with water. The water layer is extracted with DCM and the combined organic layers are dried over MgSC^. The solvent is removed under reduced pressure and the compound is purified by flash chromatography and recrystallization from MeOH.
Protocol H:
The 4-bromo-thiazole-derivative (1.0 eq.) is dissolved in 1 ,4-dioxane and a saturated Na2CO3 solution in water. Phenyl boronic acid (10.0 eq.) and tetrakis(triphenylphosphine) palladium(O) (0.2 eq.) are added. The mixture is heated in the microwave at 12O0C for 10 minutes. The two layers are separated. The organic layer is diluted with EtOAc and washed with water. The organic layer is dried over MgSθ4 and the solvent is removed under reduced pressure. The compound is purified by semi-prep HPLC. Protocol I:
The amine (2.0 eq.), the 2-bromo-thiazole derivative (1.0 eq.) and potassium carbonate (1.2 eq.) are suspended in DMF. The mixture is heated in the microwave at 17O0C for 25 to 60 minutes. The solvent is removed under reduced pressure. The residue is taken up in DCM. The organic layer is washed with water, dried over MgSO4 and the solvent is removed under reduced pressure. The compound is recrystallized from ethanol.
Protocol J:
The thioamide (1 eq.) or thiourea (1 eq.) is dissolved in ethanol. 2-Chloro-3-oxo-butyric acid ethyl ester (1.2 to 1.5 eq.) or 2-bromo-3-oxo-3-phenyl-propionic acid ethyl ester (1.2 to 1.5 eq.) is added and the mixture is stirred at 650C for 30 minutes to 24 hours. The solvent is removed under reduced pressure or the precipitate is filtered.
Protocol K:
The acid derivative (1 eq.) is dissolved in DCM and cooled. HOBt (0.3 eq.), the corresponding amine (1 eq.) and DCC (1 eq.) are added. The reaction mixture is stirred at room temperature for a period of 1 to 24 hours, cooled to O0C, filtered and washed with DCM. The filtrate is washed with 1 N HCI and 2N NaHCO3. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography, semi-prep HPLC or by recrystallization.
Protocol L:
A suspension of the bromide (1 eq.), the amine (1.6 eq.) and PTSA (0.85 eq.) in 1 ,4-dioxane is heated in the microwave at 15O0C for a period between 30 minutes to 3 hours. The reaction mixture is diluted with EtOAc, washed with 1 N HCI and saturated Na2CO3 and the aqueous layer is extracted with EtOAc. The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography, semi-prep HPLC or by recrystallization. Protocol M:
Oxalylchloride (1.2 eq.) and DMF (2 drops) are added to a suspension of the acid (1 eq.) in DCM. The suspension is stirred at room temperature until a clear solution is obtained. The reaction mixture is cooled to O0C and the amine (1.5 eq.) and DIEA (3 eq.) are added. The reaction mixture is stirred for a period between 1 to 3 hours. The reaction mixture is diluted with DCM, washed with 1 N HCI and 2N Na2CO3. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography, semi-prep HPLC or by recrystallization.
Protocol N:
A solution of the benzimidine (1.0 eq.) in DMF is cooled to O0C and the isothiocyanate (1.0 eq.) is added followed by DBU (1 eq.). The mixture is stirred at room temperature for 30 minutes and the ferf-butyl bromoacetate (1 eq.) is added followed by DBU (2.0 eq.). The reaction mixture is stirred at room temperature for 30 minutes to 1 hour and at 4O0C for 10 minutes to 30 minutes. The reaction mixture is cooled and water is added. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with 0.5N HCI, 1 N NaHCO3 and brine. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure.
Protocol O:
The ester (1.0 eq.) is dissolved in TFA and the mixture is stirred at room temperature for 20 to 30 minutes. The reaction mixture is poured into cold water and the precipitate is filtered.
Protocol P: Thionylchloride is added to the acid (1.0 eq.) and DMF (3 drops) is added. The mixture is stirred at 5O0C for 5 minutes. The excess thionylchloride is removed under reduced pressure. The amine (1.0 eq.) is dissolved in DCM and DIEA (3.0 to 4.0 eq.) is added. A solution of the acylchloride (1.0 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 5 to 30 minutes. The mixture is diluted with DCM and washed with water. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by semi-prep HPLC.
Protocol Q: n-Butyllithium (1.5 eq.) is added to a solution of DIEA (1.4 eq.) in dry THF under argon atmosphere at -780C. A solution of 2-bromo-3-phenyl-thiophene (1.0 eq.) in dry THF is added dropwise. The mixture is stirred at -780C for 1 hour. 2-Methoxy benzaldehyde (1.3 eq.) is added and the mixture is stirred at -780C for 1 hour. The cold reaction mixture is poured into a bilayer system of EtOAc and brine. The aqueous layer is extracted with EtOAc. The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure.
Protocol R:
DBU (3.0 eq.) is added to a suspension of the amine (3.0 eq.), MO(CO)6 (1.0 eq.), Herrmann's palladacycle (0.05 eq.), Fu's salt (0.1 eq.) and the bromide (1.0 eq.) in 1 ,4-dioxane. The reaction mixture is heated in the microwave at 15O0C for 15 minutes. The reaction mixture is diluted with 1 N HCI and extracted with EtOAc. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography.
Protocol R:
Chlorotrimethylsilane (6.0 eq.) is added to a suspension of sodium iodide (6.0 eq.) in acetonitrile under nitrogen atmosphere and stirred for 15 minutes at room temperature. To this suspension a solution of the alcohol (1.0 eq.) in acetonitrile is added. The reaction mixture is stirred at room temperature for 15 minutes. The reaction mixture is diluted with water and extracted with Et2O. The combined organic layers are washed with aqueous sodium thiosulfate and brine. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography.
Protocol S:
A suspension of the bromide (1.0 eq.), the amine (1.05 eq.), Xantphos (0.03 eq.), Pd2(dba)3 (0.02 eq.) and Cs2CO3 (1.5 eq.) in 1 ,4-dioxane is heated in the microwave at 15O0C for 30 minutes. The reaction mixture is filtered, diluted with EtOAc and washed with water and brine. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography.
Reaction scheme compound 3 and 1 :
Figure imgf000042_0001
Reaction scheme compound 4:
Figure imgf000043_0001
Pd(OAc)2, BINAP Cs2CO3, Dioxane
Figure imgf000043_0002
Reaction scheme compound 8:
Figure imgf000043_0003
Reaction scheme compounds 9. 10, 12 and 14
Figure imgf000043_0004
The present invention further encompasses compounds as illustrated in Table 2 as well as stereoisomers, tautomers, racemics, prodrugs, metabolites thereof, or a pharmaceutically acceptable salt and/or solvate thereof. The structural formulas of the acid used and intermediates are listed in Table 1. The following abbreviations are used hereunder. P: protocol, ES+: molecular ion obtained by electrospray in positive ion mode.
Table 1
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Example 2: Patch Clamp Assays
Cell Culture:
Cell culture was performed as described in WO 2006/058905 under example 3 which is hereby incorporated by reference.
Preparation of solutions:
The solutions were prepared as described in WO 2006/058905 under example 3 which is hereby incorporated by reference.
Electrophysiological measurements: Electrophysiological measurements were performed as described in WO 2006/058905 under example 3 which is hereby incorporated by reference. Data analysis
Data analysis was performed as described in WO 2006/058905 under example 3 which is hereby incorporated by reference.
The results of the Patch Clamp experiments are shown in Table 2. The compounds according to the invention were found to be particularly active against Kv4.3 ion channels.
In order to be maximally useful in treatment, it is also advisable to assess the side reactions which might occur. Thus, in addition to being able to modulate a particular calcium channel, it is shown that the compounds according to the invention had high selectivity for Kv4.3 versus the hERG channel.
Test system and test method for the hERG experiment
Test system and test method for the hERG experiment is performed as described in WO 2006/058905 under example 3 "Test system and test method for the hERG experiment" which is hereby incorporated by reference. Data analysis
Data analysis is performed as described in WO 2006/058905 under example 3 "Test system and test method for the hERG experiment" which is hereby incorporated by reference.
The compounds showing a selectivity >5 (ratio value) for Kv4.3 vs. hERG (Patch Clamp test) are considered as being very selective toward Kv4.3 channels. So in addition to being active on Kv4.3 ions channels at very low concentration, the compounds according to the invention are very selective toward Kv4.3 ions channels when compared to the hERG channel.
In addition, Table 2 shows the effect on Kv4.3 of a non-limiting number of compounds according to the invention. Unless provided otherwise, the compounds were investigated at one concentration (1 μM) on the Kv4.3-mediated potassium channel, in a patch clamp assay following a protocol as described in Example 2. The results are shown in Table 2. In Table 2, "%inh Kv4.3": means the % inhibition measured after application of the compound and relative to the blank. Results of % inhibition Kv4.3 are represented as follows: "+++" means above 50%; "++" means between 50% and 20%; and "+" means below 20%. As used herein the term "ND" means no data yet. Unless otherwise specified, the tests were performed at 1 μM for Kv4.3 % inhibition.
Example 3: Patch Clamp Assays using the Kv1.5 ion channel
Patch Clamp Assays using the Kv1.5 ion channel may be performed as described in WO 2006/058905 under example 4 which is hereby incorporated by reference. Example 4: Ex-vivo organ studies in rats and guinea pigs
Ex-vivo organ studies in rats and guinea pigs may be performed as described in WO 2006/058905 under example 5 which is hereby incorporated by reference.
Example 5: In vivo studies in mice In vivo studies in mice may be performed as described in WO 2006/058905 under example 6 which is hereby incorporated by reference. Example 6: Ex-vivo organ studies in rabbits
Ex-vivo organ studies in rabbits were performed as described in WO 2006/058905 under example 7 which is hereby incorporated by reference. Compounds tested in this pre-clinical model for predicting Long-QT or risk of torsades de pointes in human were negative, torsades de pointes scores were equal or below to 0. This suggests that the compounds are unlikely to cause pro-arrhythmic events in humans.
Example 7: in Vitro studies in human atrial myocytes
In Vitro studies in human atrial myocytes may be performed as described in WO 2006/058905 under example 9 which is hereby incorporated by reference.
Example 8: in vivo study in dogs
Protocol 1
Generation of the chronic atrio-ventricular block in the canine model
Experiments were carried out in beagles according to the Guidelines for Animal Experiments. The persistent atrioventricular block (AV) was induced by means of electro surgery. Animals were allowed to develop chronic AV block for more than 8 weeks prior pharmacological studies.
Induction of anesthesia:
Dogs were anesthetized with pentobarbital sodium (30 mg/kg, intravenous).
Systemic cardiovascular parameters: The surface lead Il ECG was obtained from the limb electrodes. A heparinized catheter was placed in the left femoral artery to continuously monitor the systemic blood pressure.
Electrophysiology of the atrium: A standard 6-French quadrupolar electrode catheter (Cordis- Webster) was positioned at the top of the right atrium to electrically pace the sinus nodal area and record the local electrogram, including the spontaneous beating rate (the sinoatrial rate: SAR). A second 6-French quadrupolar electrode catheter was positioned at the inter-atrial septum of the right atrium to electrically induce atrial fibrillation. A third 6-French quadrupolar electrode catheter was positioned in the esophagus to record the left atrial electrogram. Electrophysiology of the ventricle A bi-directional steerable monophasic action potential (MAP) recording / pacing combination catheter (EP Technologies lnc , 1675P, Sunnyvale, CA, USA) was positioned at the endocardium of the right ventricle to obtain MAP signals The interval (in ms) at 90% repolarization was defined as MAP90 Examination through electrical pacing of the heart
Inter-atrial conduction time (IACT) The sinus nodal area was electrically driven in a cycle length of 400, 300 or 200 ms
Atrial effective refractory period (AERP) The functional refractory period of the atrium was assessed by pacing with 5 beats of basal stimuli in a cycle length of 400, 300 or 200 ms followed by an additional stimulus at various coupling intervals
Induction of atrial fibrillation (AF) A 60 V pacing pulse of 10 ms width and rectangular shape was used for the induction of AF (about 1 5 times of the diastolic threshold voltage) The inter-atrial septum was paced at a cycle length of 60 ms (1 ,000 bpm) for 10 s (=burst pacing) via the distal electrode pair of the catheter using a stimulator and the isolation unit In this study, AF was defined as a period of rapid and irregular atrial rhythm resulting in an irregular baseline of the ECG AF duration was measured after induction
Ventricular MAP duration (MAP90) The heart was electrically paced using a cardiac stimulator with the electrodes of the combination catheter which had been placed in the right ventricle The MAP90 was measured during ventricular rhythm and at a pacing cycle length of 1000, 750, 600, 500, 400 or 300 ms
Ventricular effective refractory period (VERP) The effective refractory period of the right ventricle was assessed by pacing consisting of 5 beats of basal stimuli in a cycle length of 1000, 750, 600, 500, 400 or 300 ms followed by an additional stimulus after various coupling intervals Starting in late diastole the coupling interval ω/as shortened consecutively by 5-10 rns until refractoriness occurred
The duration of the terminal repolarization period of the ventricle, namely, phase 3 repolarization of the action potential, was estimated using the difference between the MAP90 and VERP at the same site
Study Protocol The systemic blood pressure, ECG and MAP signals were monitored
1 ) Sinoatrial rate, ventricular rate and mean blood pressure were recorded
2) (t + 0 1 mm) Inter-atrial conduction time
3) (t + 1 mm) Atrial effective refractory period
4) (t + 3 mm) Ventricular MAP90 5) (t + 4 mm) Ventricular effective refractory period 6) (t + 5 mm) Atrial fibrillation was induced by the burst pacing protocol, which was repeated consecutively 10 times at each time point When the atrial fibrillation was maintained for >30 s, it was terminated electrically In this case, the duration of atrial fibrillation was calculated as 30 s
Following the basal assessment, three doses between 0,1 to 10 mg/kg were infused within 2 - 10 mm and each parameter was assessed several times 10 mm to 60 mm after the start of the infusion
Protocol 2
Preparation of the animals
Experiments were carried out in mongrel dogs according to the Guidelines for Animal Experiments AV block was created with radiofrequeπcy ablation and electrodes implanted for atrial tachypacing (ATP, 400 bpm) and EP study (EPS) and ventricular escape pacing (80 bpm) according to standard procedures in the lab The dogs were given standard pain and antibiotic therapy as needed The atria were then paced at 400 bpm and the ventricles paced at 80 bpm for 1 week
After 1 week of atrial tachypacing, dogs were anesthetized with morphine and α-chloralose and prepared for open-chest study A thoracotomy was performed and the heart exposed Mapping electrode arrays were sewn to the atria to measure conduction parameters
Quantitative measurements were then obtained, including AF (atrial fibrillation) vulnerability (percentage of sites at which AF can be induced by a single extrastimulus), AF duration (mean duration of AF based on 10 inductions for AF less than 5 minutes, 5 inductions for AF>5 minutes, or minimum of 2 inductions if AF sustained for >20 minutes x 2), AF cycle length, right atrial ERP and conduction velocity determined by epicardial mapping (cycle length of 150 and 300 ms), right ventricular ERPs, QT interval and QRS duration (during ventricular pacing at cycle lengths of 250 and 350-400 ms) and blood pressure Apart from vulnerability measurements, which were obtained at multiple atrial sites, a" ot^er atria! parameters were measured (Wing pacing at the right or iefi atrial appendages For ERP and conduction measurements, a basic train of 15 beats were followed by a single extrastimulus during a 1-s pause to observe the response and (for the ventricles) to allow for hemodynamic recovery from tachypacing AF vulnerability was tested at a basic cycle length (S1S1 interval) of 300 ms, with single premature S2 extrastimuli delivered at each site by setting the coupling interval initially to 200 ms, and then decreasing by 10 ms decrements until AF is induced or failure to capture occurs, indicating that the ERP has been reached All S1 and S2 stimuli will be 2-ms duration, twice threshold current The S1 S2 will then be set to 25 ms longer than the ERP, and the same procedure repeated with 5 ms decrements The ERP was established by the longest S1S2 interval at which capture fails on 2 separate determinations with 5-ms accuracy, and AF inducibility was considered as positive if AF is induced at least once with a single extrastimulus during ERP testing At least 5 different sites were used for ERP testing/AF inducibility determination in each dog Induction of AF for AF duration measurements was with a burst of atrial tachypacing at 10-20 Hz, with 10 times threshold stimuli After baseline measurements, the compounds were administered intravenously at doses of 0.2, 1 and 5mg/kg over 5 min.
Compounds tested in this pre-clinical canine model for atrial fibrillation exhibited in vivo activity. (1 ) The atrial effective refractory period was prolonged, which is in line with the in vitro Kv4.3 / Kv1.5 activity. (2) The ventricular effective refractory period as well as the QT interval were only slightly changed, demonstrating that the compounds are atrial selective. Again, this is in line with the selectivity profile of the compounds. (3) Improvement of atrial fibrillation parameters such as AF duration or atrial vulnerability showed the promise for these compounds to become atrial-selective anti-arrhythmic drugs.
Table 2 Effects of test compounds on the Kv4.3 mediated current
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
The present invention encompasses compounds 1 to 161 and stereoisomers, tautomers, racemics or a pharmaceutically acceptable salt and/or solvate thereof.

Claims

Claims
1. A compound having the structural Formula I1 II, III, IV, V or Vl, stereoisomers, tautomers, racemics, or a pharmaceutically acceptable salt and/or solvate thereof,
Figure imgf000074_0001
Figure imgf000074_0002
IV V Vl wherein
X is selected from -N=, or -CH=,
X2 is selected from -N=, or -CH=,
X3 is selected from -CH2-, -CR5=, or O, wherein R5 is selected from hydrogen, alkyl, or aryl, t is an integer selected from 1 or 2,
R1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero,
X4 is selected from -N= or CR3, wherein R4 is hydrogen or R4 and R3 together with the carbon atoms to which they are attached form an aryl or a heteroaryl ring, each ring being optionally substituted by one or more substituents independently selected from halo, alkyl, aryl, alkoxy, haloalkyl or haloalkoxy,
L1 is selected from -NH-, -CH2-, -SO2-,
L2 is a group selected from alkylene, cycloalkyleπe, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, wherein A1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R is alkyl, alkylamino or cycloalkyl,
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarboπyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamiπo, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1, 2, 3 or 4, with the proviso that when L1 is NH in formula I, R1 is selected from halogen, aryl or alkylhetero, or when L1 is NH in formula I and R1 is hydrogen or alkyl, L2 is pyrrolydinylenealkylene optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, wherein the dotted line represent an optional double bond. 2. A compound according to claim 1 , having one of the structural Formula
Figure imgf000075_0001
VII VIII IX
Figure imgf000075_0002
X Xl XII
Figure imgf000075_0003
XVI XVII XVIII
Figure imgf000076_0001
wherein X5 is selected from -N= or -CH=, R7 is selected from hydrogen, alkyl, aryl, alkoxy, halo, haloalkyl, or haloalkoxy, wherein n is an integer selected from 1, 2, 3 or 4 and A1, L1, L2, R1, R2, R4, R5, s, t, X3 and X4 have the same meaning as that defined in claim 1.
3. A compound according to claim 1 or 2, having one of the structural Formula VIII1 IX, X, Xl, XII, or XXX,
Figure imgf000076_0002
VIII IX
Figure imgf000076_0003
Xl XII XXX wherein
R i1 : is. selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero,
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from O1 1, 2, 3 or 4,
R4 is hydrogen, R5 is hydrogen or alkyl,
L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, and wherein A1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl.
4. A compound according to claim 1 or 2, having one of the structural Formula XIII, XIV, XV, XVI,
XVII, XVIII, XIX, XX, XXI or XXII,
Figure imgf000077_0001
XXII wherein X4 is -N=,
X3 is -CR5=, wherein R5 is selected from hydrogen, alkyl, or aryl,
R1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkyl hetero, R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfoπamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4,
R4 is hydrogen,
L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, and wherein A1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl
5. A compound according to claim 1 or 2, having the structural Formula VII,
Figure imgf000078_0001
VII wherein A1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl,
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkytcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4, and wherein
R1 is hydrogen or alkyl and L2 is pyrrolydinylenealkylene optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy, or
R1 is selected from halogen, aryl or alkylhetero, and L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy.
6. A compound according to any of claims 1 to 3, having the structural Formula VII,
Figure imgf000079_0001
VIII wherein A1 is a group selected from aryl, heterocyclyl or heteroaryl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl. wherein R6 is alky!, alkylarnino or cycloalkyl,
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, s is an integer selected from 0, 1, 2, 3 or 4,
R1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero, and
L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy. 7 A compound according to any of claims 1 to 6, wherein A1 is a group selected from furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1 ,2,3-tπazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1,2,4-thiadιazolyl, 1 ,2,5- thiadiazolyl, tetrazolyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, 2H-thiopyranyl, 4H-thiopyranyl, benzofuryl, benzothienyl, benzimidazolonyl, 2,3-dihydro-1 ,4-benzodιoxinyl, 1 ,3-benzodιoxolyl, indolyl, benzimidazolyl, benzopyrazolyl, benzisoxazolyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, naphthyl, quinolinyl, quinazolyl, isoquinolinyl, indanyl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxy!, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, and wherein L1, L2, R1, R2, R4, X1, X2, X3, X4, s, and t, have the same meaning as that defined in any of claims 1 to 6. 8. A compound according to any of claims 1 to 7, wherein A1 is a group selected from 2- or 3- furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-ιmidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, A- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-ιsothiazolyl, 2-, 4- or 5-thiazolyl, 1 ,2,3-tπazol-1-, - 2-, -4- or -5-yl, 1,2,4-triazol-1-, -3-, -4- or -5-yl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yl, 1 ,2,4-thiadιazol-3- or -5-yl, 1 ,2,5-thiadiazol-3- or -4-yl, 1- or 5- tetrazolyl, phenyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, A-, 5- or 6-pyπmιdιnyl, 2-, 3-, 4-, 5-
6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, benzimidazolonyl, 6- 2,3-dιhydro-1 ,4-benzodioxiπyl, 1 ,3-benzodioxolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimιdazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-beπzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisothιazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 1- or 2- naphthyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-quinolinyl, 2-, 4-, 5-, 6-,
7- or 8-quιnazolyl, 1-, 3-, A-, 5-, 6-, 7-, 8-isoquinolιnyl, indanyl, each group being optionally substituted by one or more substituents independently selected from halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl.
9. A compound according to any of claims 1 to 8, wherein R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl.
10. A compound according to any of claims 1 to 9, wherein A1 is a group selected from phenyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-quinolinyl, 2,3-dihydro-1 ,4-benzodioxinyl, 6-indolyl, 1-napthyl, 2-naphtly, indanyl, 1 ,3-dihydrobenzoimidazol2-one, 1 , 2, 3, 4-tetrahydronapthtlanel-1-yl, 2-benzofuran-5- yl, pyridin-4-yl, pyridin-3-yl, 1 ,3-benzodioxolyl, benzimidazolonyl, 2- thienyl, 3-thienyl, or 5-(2,3- dihydro)benzofuranyl, each group being optionally substituted with one to four substituent independently selected from F, Cl, Br, -CH3, tert-butyl, -OCH3, -NO2, -CO2H, -C(=O)-N(CH3)2,
■γ> ./-Λ -γ>
-O-C(=O)-CH3, 1^ , W 1 ^-s -CH2-CH3, phenyl, morpholino, -SO2-CH3, -CF3, -OCF3, -OCHF2, -CH2-NH-C(=O)-CH3, -S-CH3, -C(=O)-CH3, -C(=0)0-CH3, -C(=O)NH2, -N(CH3J2. -SO2-N(CHa)2, phenoxy, benzoyl, -C(CH3)3, -O-(CH2)2-CH3, -OH or -CN, wherein L2 is selected from -CH2-, -(CH2J2-. -(CH2J3-, -CH(CH2OHJ-, -CH(CH2-O-CH3J-,
-CH(CH3)-, -CH(CH2-CH3)-, -CH(CO2H)-, -CH(CO2CH3)-, -(CH2J2-O-CH2-, -CH(,CH2-N(CH3)2)-,
Figure imgf000081_0001
wherein R2 is selected from hydrogen, nitro, -SO2-NH2, F, Cl, Br, OH, -CH3, -OCH3, -NO2,
-CO2H, -C(=O)-N(CH3)2, -O-C(=O)-CH3,
Figure imgf000081_0002
, -N-morpholino, -CH2-CH3, phenyl, -SO2-CH3, -CF3, -OCF3, -OCHF2, -CH2-N H-C(=O)-CH3, -S-CH3, -C(O)-CH3,
-C(O)O-CH3, -C(O)O- CH2-CH3, -C(O)NH2, -N(CH3J2, -SO2-N(CH3)2, phenoxy, benzoyl, -C(CH3)3, -0-(CH2J2-CH3, or -CN, and wherein R1, R4, R5 and X4 have the same meaning as that defined in claim 1.
11. A compound according to any of the previous claims having the structural formula XXXI,
Figure imgf000081_0003
wherein
L2 is a group selected from alkylene, cycloalkylene, pyrrolydinylenealkylene or cycloalkylenoxyalkylene, each group being optionally substituted with one or more substituents independently selected from alkyl, aryl, halo, haloalkyl or haloalkoxy,
R1 is selected from hydrogen, halogen, alkyl, aryl, cycloalkyl, alkenyl, alkynyl, heteroalkyl or alkylhetero, and
R2 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alkyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alky], alkylamino or cycloalkyl, s is an integer selected from 0, 1 , 2, 3 or 4,
R8 is selected from hydrogen, halogen, hydroxyl, hydroxyalkyl, nitro, azido, cyano, alky), aryl, heteroaryl, heteroarylalkyl, cycloalkyl, acyl, alkylamino, alkylaminocarbonyl, -SO2R6, alkylcarbonyloxy, heterocyclyl, haloalkyl, alkylcarbonyl, aryloxy, arylcarbonyl, haloalkoxy, alkoxy, alkylthio, carboxyl, acylamino, alkyl esters, thioamide, alkyloxycarbonyl, or sulfonamidyl, wherein R6 is alkyl, alkylamino or cycloalkyl, r is an integer selected from 0, 1 , 2, 3 or 4 A compound according to any of the previous claims, wherein R2 is selected from hydrogen, thienyl, methyl, ethyl, propyl, isopropyl, butyl, ferf-butyl, chloro, fluoro, bromo, methoxy, ethoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy or phenoxy A compound according to any of the previous claims, wherein R1 is hydrogen, bromo, fluoro, chloro, methyl, phenyl, methylthio or ethylthio A compound according to any of claims 2 to 13, wherein R7 is selected from hydrogen, methyl, ethyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy A compound according to any of the previous claims, wherein said compound is selected from the group comprising 2-(2-methoxy-phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid benzylamide, 4-ethylsulfanyl-2-(2-methoxy-phenylamιno) -thιazole-5-carboxylιc acid benzylamide, 4-bromo-2-(2-methoxy-phenylamιno)-thιazole-5-carboxylιc acid benzylamide, N- ((1S,2S)-2-benzyloxycyclopent-1-yl)-5-(2-methoxy-phenylamιno)-nιcotιnamιde, 4-(2-methoxy- phenylamιno)-pyrιdιne-2-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, N- ((1S,2S)-2-benzyloxycyclopent-1-yl)-3-(2-methoxy-phenylamιno)-benzarnιde, 2-(2-methoxy- benzenesulfonyl)-thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 1- benzyl-2-oxo-pιperιdιne-3-carboxylιc acid ((1S 2S)-2-hpn7yloYycydopent-i-y!)-amde, 2-(2,3- dιhydro-ιndol-1-yl)-4-methyl-thιazole-5-carboxylιc acid ((1S, 2S) )-2-benzyloxycyclopent-1-yl)- amide, 4-methyl-2-pyrazol-1-yl-thιazole-5-carboxylιc acid ((1S, 2S) )-2-beπzyloxycyclopent-1- yl)-amιde, N-((1 S,2S)-2-benzyloxy-cyclopentyl-2-phenylamιno-benzamιde, 2-(2,3-dιhydro- benzo[1,4]oxazιn-4-yl)-4-methyl-thιazole-5-carboxylιc acid ((1S.2S) )-2-benzyloxycyclopent-1 - yl)-amιde, 2-(4-tπfluoromethyl-benzyl-thιazole-5-carboxylιc acid ((1S, 2S) )-2- benzyloxycyclopent-1 -yl)-amιde, 2-(2-methoxy-phenylamιno)-4-methyl-thιazole-5-carboxylιc acid (1-benzyl-pyrrolιdιn-3-yl)-amιde, 2-(phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid benzylamide, 2-(2-methoxy-phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid 2-chloro-6- methyl-benzylamide, 2-(4-bromo-phenylamιno)-4-bromo-thιazole-5-carboxylιc acid 4-nιtro- benzylamide, 2-(benzenesulfonyl)-4-methyl-thιazole-5-carboxylιc acid benzylamide, 2- (benzenesulfonyl)-4-phenyl-thιazole-5-carboxylιc acid benzylamide, 2-(benzenesulfonyl)-4- bromo-thιazole-5-carboxylιc acid benzylamide, 2-methoxy-2-(benzenesulfonyl)-4-bromo- thιazole-5-carboxylιc acid benzylamide, 2-methoxy-2-(benzenesulfonyl)-4-phenyl-thιazole-5- carboxylic acid benzylamide, 2-(2-methoxy-benzenesulfonyl)-4-phenyl-thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2-(2-methoxy-benzenesulfonyl)-4-bromo- thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2-(4-bromo- phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid 4-nιtro-benzylamιde, 2-(4-chloro- phenylamino^-phenyl-thiazole-δ-carboxylic acid ((R)-I -naphthalen-2-yl-ethyl)-amιde, 2-(4- chloro-phenylamιno)-4-bromo-thιazole-5-carboxylιc acid ((R)-I -naphthalen-2-yl-ethyl)-amιde, 2- (4-bromo-phenylamιno)-4- bromo-thιazole-5-carboxylιc acid 4-methoxy-benzylamιde, 2-(4- bromo-phenylamιno)-4- phenyl-thιazole-5-carboxylιc acid 4-methoxy-benzylamιde, 2-(2- methoxy-phenylamιno)-4-bromo-thιazole-5-carboxylιc acid 4-dιmethylamιno-benzylamιde, 2-(2- methoxy-phenylaminoH-phenyl-thiazole-δ-carboxylic acid 4-dιmethylamιno-benzylamιde, 2-(4- bromo-phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid 4-fluoro-3-trιfluoromethyl- benzylamide, 2-(4-bromo-phenylamιno)-4-bromo-thιazole-5-carboxylιc acid 4-fluoro-3- tπfluoromethyl-benzylamide, 2-(4-bromo-phenylamιno)-4-bromo-thιazole-5-carboxylιc acid 3,5- dimethoxy-benzylamide, 2-(4-bromo-pheπylamιno)-4-phenyl-thιazole-5-carboxylιc acid 3,5- dimethoxy-benzylamide, 2-(2-methoxy-phenylannιno)-4- bromo-thιazole-5-carboxylιc acid 2- chloro-6-methyl-benzylamιde, 2-(2-methoxy-phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid 4-thιophen-2-yl-benzylamιde, 2-(2-methoxy-phenylamιno)-4- bromo-thιazole-5-carboxylιc acid 4-thιophen-2-yl-benzylaιmιde, 2-(2-methoxy-phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid 4-terf-butyl-benzylamιde, 2-(2-methoxy-phenylamιno)-4-bromo-thιazole-5-carboxylιc acid 4-tert- butyl-benzylamide 2-(2-methoxy-phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid 4-bromo- benzylamide, 2-(2-methoxy-phenylamιno)-4-bromo-thιazole-5-carboxylιc acid 4-bromo- benzylamide, 2-(pyrιdιn-4-ylamιno)-4-phenyl-thιazole-5-carboxylιc acid benzylamide, 2-(pyrιdιn- 4-ylamιno)-4-bromo-thιazole-5-carboxylιc acid benzylamide, 2-(benzofuran-5-ylamιno)-4- phenyl-thιazole-5-carboxylιc acid benzylamide, 2-(benzofuran-5-ylamιno)-4-bromo-thιazole-5- carboxylic acid benzylamide, 2-(2 3-dιhydro-benzo[1 ,4]dιoxιn-6-ylamιno-4-phenyl-thιazole-5- carboxyhr acid benz>β3m.'de, 2-(2,3-dιhydro beπzo[1,4]dιθλιn-8-yiarrιιno-4-bromu-tπιazoie-5- carboxylic acid benzylamide, 4-phenyl-2-(quιnolιn-8-ylamιno)-thιazole-5-carboxylιc acid benzylamide, 4-ethylsulfanyl-2-(quιnolιn-8-ylamιno)-thιazole-5-carboxylιc acid benzylamide, 4- bromo-2-(quιnolιn-8-ylamιno)-thιazole-5-carboxylιc acid benzylamide, 2-(2-methoxy- phenylamιno)-4-phenyl-thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl) amide,
2-(2-methoxy-phenylamιno)-4-bromo-thιazole-5-carboxylιc acid ((1 S,2S)-2-benzyloxycyclopent- 1-yl) amide, 4-phenyl-2-(pyrιdιn-4-ylamιno)-thιazole-5-carboxylιc acid ((1S,2S)-2- benzyloxycyclopent-1-yl) amide, 2-(pyrιdιn-4-ylsulfonyl)-4-methyl-thιazole-5-carboxylιc acid ((1 S,2S)-2-benzyloxycyclopent-1 -yl)-amιde, 2-(pyrιdιn-4-ylsulfonyl)- thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2-(pyrιdιn-4-ylsulfonyl)- 4-phenyl-thιazole-5- carboxylic acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2-(benzofuran-5-ylsulfonyl)- A- bromo-thιazole-5-carboxylιc acid ((1 S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2-(benzofuran-5- ylsulfonyl)- 4-methyl-thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2- (benzofuran-5-ylsulfonyl)- 4-phenyl-thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1- yl)-amιde, 2-(benzofuran-5-ylamιno)-4-phenyl-thιazole-5-carboxylιc acid ((1S,2S)-2- benzyloxycyclopent-1-yl) amide, 2-(benzofuran-5-ylamιno)-4-bromo-thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl) amide, 2-(2,3-dιhydro-benzo[1,4]dιoxιπ-6-ylsulfonyl)- 4- bromo-thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2-(2,3-dιhydro- benzo[1 ,4]dιoxιn-6-ylsulfonyl)- 4-methyl-thιazole-5-carboxylιc acid ((1S,2S)-2- benzyloxycyclopeπt-1-yl)-amιde, 2-(2,3-dιhydro-benzo[1,4]dιoxιn-6-ylsulfonyl)-thιazole-5- carboxylic acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2-(2,3-dιhydro-benzo[1 ,4]dιoxιn-6- ylamιno-4-phenyl-thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl) amide, 2-(2,3- dιhydro-benzo[1 ,4]dιoxιn-6-ylamιno-4-bromo-thιazole-5-carboxylιc acid ((1S,2S)-2- benzyloxycyclopeπt-1-yl) amide, 2-(quιnolιn-8-ylsulfonyl)-thιazole-5-carboxylιc acid ((1S,2S)-2- benzyloxycyclopent-1-yl)-amιde, 2-(quιnolιn-8-ylsulfonyl)-4-methyl-thιazole-5-carboxylιc acid {(1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 2-(quιnolιn-8-ylsulfonyl)-4-bromo-thιazole-5- carboxylic acid ((1S,2S)-2-benzyloxycyclopent-1-yl)-amιde, 4-phenyl-2-(quιπolιπ-8-ylamιno)- thιazole-5-carboxylιc acid ((1S,2S)-2-benzyloxycyclopent-1-yl) amide, 4-bromo-2-(quιnolιn-8- ylamino)-thiazole-5-carboxylic acid ((1S,2S)-2-benzyloxycyclopent-1-yl) amide, 3-[5-(( 1S.2S)-
2-benzyloxy-cyclopent-1-ylcarbamoyl)-4-bromo-thιazol-2-ylamιπo]-benzoιc acid ethyl ester, 3- [5-(( 1 S,2S)-2-benzyloxy-cyclopent-1 -ylcarbamoyl)-4-bromo-thιazol-2-ylsulfonyl]-benzoιc acid ethyl ester, 3-[5-(( 1 S,2S)-2-benzyloxy-cyclopent-1 -ylcarbamoyl)-4-methyl-thιazol-2-ylsulfonyl]- benzoic acid ethyl ester, 3-[5-(( IS^S^-benzyloxy-cyclopent-i-ylcarbamoylH-phenyl-thiazol- 2-ylamιno]-benzoιc acid ethyl ester, 2-(2,3-dιhydro-ιndol-1-yl)-4-methyl-thιazole-5-carboxylιc acid benzylamide, 2-(2,3-dιhydro-ιndol-1-yl)-4-phenyl-thιazole-5-carboxylιc acid benzylamide, 2-(2,3-dιhydro-ιπdol-1-yl)-thιazole-5-carboxylιc acid benzylamide, 2-(7-methoxy-2,3-dιhydro- ιndol-1-yl)-4-methyl-thιazole-5-carboxylιc acid benzylamide, 2-(7-methoxy-2,3-dιhydro-ιndol-1- yl)-4-methyl-thιazole-5-carboxylιc acid ((1S.2S) ^-benzyloxycyclopent-i-yO-amide, 2-(7- methoxy^.S-dihydro-indol-i-ylH-bromo-thiazole-δ-carboxylic acid ((1S,2S) )-2- benzyloxycycloppnt-1-yl)-amιde, 2-(2,3-d!hydro-benzθLi ,4]oxazιn-4-yi)-4-brurrio-iπιazoie -5- carboxylic acid ((1S, 2S) ^-benzyloxycyclopent-i-yO-amide, 2-(5-methoxy-2,3-dιhydro- benzo[1 ,4]oxazιn-4-yl)-4-methyl-thιazole -5-carboxylιc acid ((1S.2S) )-2-benzyloxycyclopent-1- yl)-amιde, 2-(5-methoxy-2,3-dιhydro-benzo[1 ,4]oxazιn-4-yl)-4-methyl-thιazole -5-carboxylιc acid benzylamide, 2-(2,3-dιhydro-benzo[1 ,4]oxazιn-4-yl)-4-methyl-thιazole -5-carboxylιc acid benzylamide, 2-(2,3-dιhydro-benzo[1 ,4]oxazιπ-4-yl)-4-bromo-thιazole -5-carboxylιc acid benzylamide, 2-(2,3-dιhydro-benzo[1 ,4]oxazιn-4-yl)-4-phenyl-thιazole -5-carboxylιc acid benzylamide 4-phenyl-2-pyrazol-1-yl-thιazole-5-carboxylιc acid ((1 S.2S) )-2- benzyloxycyclopent-1-yl)-amιde, 4-bromo-2-pyrazol-1-yl-thιazole-5-carboxylιc acid ((1S.2S) )-2- benzyloxycyclopent-1-yl)-amide, 4-phenyl-2-pyrazol-1-yl-thιazole-5-carboxylιc acid benzylamide, 2-pyrazol-1-yl-thιazole-5-carboxylιc acid benzylamide, 4-bromo-2-(3methyl- pyrazol-1-yl)-thιazole-5-carboxylιc acid benzylamide, 4-phenyl-2-(3methoxy-pyrazol-1-yl)- thιazole-5-carboxylιc acιd-4-chloro-benzylamιde, 4-bromo-2-(3-methoxy-pyrazol-1-yl)-thιazole- 5-carboxylιc acid ((1S, 2S) )-2-(4-methoxy-benzyloxy)cyclopent-1-yl)-amιde, 2-(2-methoxy- benzyl)-thiazole-5-carboxylic acid ((1 S, 2S) )-2-benzyloxycyclopent-1-yl)-amιde, 4-methy-2- (quinoliπ-8-ylmethylene)-thiazole-5-carboxylic acid benzylamide, 2-(2-methoxy-benzyl)- 4bromo-thiazole-5-carboxylic acid (3-5-bιmethoxy-benzylamιde), 2-pyrazol-1 -yl-4-phenyl- thiazole-5-carboxylic acid (1-benzyl-pyrrolidiπ-3-yl)-amide, 2-(benzenesulfonyl)-4-phenyl- thiazole-5-carboxylic acid (1-benzyl-pyrrolιdιn-3-yl)-amide, 2-(benzyl)-4-bromo-thiazole-5- carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide, N-((1S,2S)-2-benzyloxycyclopent-1-yl)-5-(2- methoxy-benzylamιno)-nicotιnamide, N-((1S,2S)-2-benzyloxycyclopent-1-yl)-2-(2- methoxypheπylsulfonyl)-nicotιnamide, N-benzyl-2-(2-methoxypheπylsulfonyl)-nicotιnamιde, 4- (2-methoxy-benzyl)-pyπdιne-2-carboxylιc acid 4-chlorobenzylamide, 4-(phenylamιno)-pyrιdine- 2-carboxylic acid benzylamide, 2-anιlino-N-(1-benzylpyrrolidin-3-yl)benzamide, 4-(2-methoxy- phenylsulfonyl)-pyridιne-2-carboxylic acid benzylamide, N-(4-chlorobenzyl)-1-(2- methoxybenzyl)-2-oxopiperidine-3-carboxamιde, 4-(2methoxyanιlιno)-N-(1-benzylpyrrolidin-3- yl)pyrιdιne-2-carboxamide, 3-(2-methoxyanilιno)-N-(1-benzylpyrrolidιn-3-yl)benzamide, 3-(2- methoxy)benzyl)-N-(1-benzylpyrrolidin-3-yl)benzamide, N-(1-benzylpyrrolidιn-3-yl)-3-(pyridin-4- ylamιno)benzamιde, N-(1-benzylpyrrolidin-3-yl)-2-oxo-1-(pyridin-4-ylmethyl)piperidine-3- carboxamide, N,1-dιbenzyl-2-oxopiperιdιne-3-carboxamide, N-benzyl-2-oxo-1-(pyridin-4- ylmethyl)piperιdιne-3-carboxamide, N-(2-chloro-6-methylbenzyl)-1-(2-methoxybenzyl)-2- oxopιperιdine-3-carboxamιde, 1-(4-bromobenzyl)-N-(4-nιtrobenzyl)-2-oxopιperιdιne-3- carboxamide, 2-anιlino-N-benzylbenzamιde, N,2-dιbenzylbenzamιde, N-benzyl-2- (phenylsulfonyl)benzamιde, 1-anιlιno-N-(1-benzylpyrrolιdιn-3-yl)-2-oxopιperιdιne-3- carboxamide, N-benzyl-2-[(2-methoxyphenyl)sulfonyl]benzamιde, N-benzyl-2-(pyrιdιn-4- ylamιno)benzamιde, 2-(3-tπfluoromethyl-benzyl-thιazole-5-carboxylic acid ((1S, 2S) )-2- benzyloxycyclopent-1-yl)-amιde, N-(2,4-dιmethoxybenzyl)-2-[3-(trιfluoromethyl)benzyl]-1 ,3- thιazole-5-carboxamιde, N-(4-fluorobenzyl)-2-[3-(trιfluoromethyl)benzyl]-1 ,3-thiazole-5- carboxamide, 2-(4-chloro-benzyl-4-methyl-thiazole-5-carboxylic acid ((1S,2S) )-2- benzyloxycydopent-i-y!)-amide, 2-(3,4-dimelhoxy-benzyl-4-memy!-tMiazo!e-5-carbuxyiic acid ((1S, 2S) ^-benzyloxycyclopent-i-yO-amide, N-[4-(difluoromethoxy)benzyl]-2-[3-
(trιfluoromethyl)benzyl]-1 ,3-thiazole-5-carboxamide, 2-(8-hydroxy-3,4-dihydroquιnolin-1(2H)-yl)- 4-methyl-1 ,3-thιazole-5-carboxylic acid ((1S.2S) )-2-benzyloxycyclopent-1-yl)-amιde, N-(4- fluorobenzyl)-2-[(2-methoxyphenyl)amino]-4-phenyl-1 ,3-thιazole-5-carboxamιde, N-[4-
(difluoromethoxy)benzyl]-4-phenyl-2-{[3-(trifluoromethyl)phenyl]amιno}-1 ,3-thiazole-5- carboxamide, N-(4-chlorobenzyl)-2-[(2-methoxyphenyl)amιno]-4-phenyl-1 ,3-thiazole-5- carboxamide, N-[4-(difluoromethoxy)benzyl]-2-[(2-methoxyphenyl)amino]-4-(trifluoromethyl)- 1 ,3-thiazole-5-carboxamide, 2-[3-(tπfluoromethyl)benzyl]-N-{2-[3-(trifluoromethyl)phenyl]ethyl}- 1 ,3-thιazole-5-carboxamide, N-[2-(2-methylphenyl)ethyl]-2-[3-(trifluoromethyl)benzyl]-1 ,3- thiazole-5-carboxamide, N-[4-(dιfluoromethoxy)benzyl]-4-methyl-2-[3-(tπfluoromethyl)benzyl]- 1 ,3-thiazole-5-carboxamide, 2-(4-chlorobenzyl)-N-(2,4-dimethoxybenzyl)-4-methyl-1 ,3-thiazole- 5-carboxamide, 2-(4-chlorobenzyl)-N-(4-fluorobenzyl)-4-methyl-1 ,3-thiazole-5-carboxamide, 2- (4-chlorobenzyl)-N-[4-(difluoromethoxy)benzyl]-4-methyl-1,3-thiazole-5-carboxamide, 2-(4- chlorobenzyl)-N-[4-(dιfluoromethoxy)benzyl]-4-phenyl-1 ,3-thιazole-5-carboxamιde, 2-(4- chlorobenzylH-methyl-N-(4<;hlorobenzyl)-1 ,3-thιazole-5-carboxamιde, 2-(4-fluorobenzyl)-N-[4- (dιfluoromethoxy)benzyl]-4-phenyl-1 ,3-thιazole-5-carboxamιde, N-(4-chlorobenzyl)-2-[3-
(trιfluoromethyl)benzyl]-1 ,3-thιazole-5-carboxamιde, N-benzyl-2-[(4-fluorophenyl)amιno]-4- phenyl-1 ,3-thiazole-5-carboxamide, N-(4-chlorobeπzyl)-2-[(4-fluorophenyl)amιno]-4-phenyl-1 ,3- thιazole-5-carboxamιde, N-[4-(dιfluoromethoxy)benzyl]-2-[(4-fluorophenyl)amιno]-4-phenyl-1,3- thιazole-5-carboxamιde, N-benzyl-2-[(3-fluorophenyl)amιno]-4-phenyl-1 ,3-thιazole-5- carboxamide, N-[4-chlorobenzyl]-2-[(3-fluorophenyl)amino]-4-phenyl-1,3-thiazole-5- carboxamide, N-[4-(dιfluoromethoxy)benzyl]-2-[(3-fluorophenyl)amιno]-4-phenyl-1 ,3-thιazole-5- carboxamide, N-benzyl-2-[(1-fluorophenyl)amιπo]-4-phenyl-1 ,3-thιazole-5-carboxamιde, N-[4- chlorobenzyl]-2-[(1-fluorophenyl)amιno]-4φhenyl-1 ,3-thιazole-5-carboxamιde, N-[4-
(dιfluoromethoxy)benzyl]-2-[(1-fluorophenyl)amιno]-4-phenyl-1 ,3-thιazole-5-carboxamιde, N-[4- (dιfluoromethoxy)benzyl]-2-[(1-methoxyphenyl)amιno]-4-phenyl-1 ,3-thιazole-5-carboxamιde, N- [1 ,4-(dιmethoxy)benzyl]-2-[(1-methoxyphenyl)amιno]-4-phenyl-1 ,3-thιazole-5-carboxamιde, 2- (2,3-dιhydro-benzo[1 ,4]oxazιπ-4-yl)-4-methyl-thιazole -5-carboxylιc acid 4- difluoromethoxybenzylamide, N-(4-dιfluoromethoxybenzyl)-2-[1-(methoxy)benzyl]-4-phenyl-1 ,3- thιazole-5-carboxamιde, or 2-(7-methyl-3,4-dιhydro-1 ,8-naphthyrιdιn-1(2H)-yl)-4-methyl-1 ,3- thιazole-5-carboxylιc acid ((1S, 2S) J^-benzyloxycyclopent-i-yO-amide Method for synthesizing a compound having the structural Formula I, II, III, IV, V or Vl comprising the step of condensing a compound of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII
Figure imgf000086_0001
XXIII XXIV XXV XXVI
Figure imgf000086_0002
XXVII XXVIII with a compound of Formula XXIX
Figure imgf000086_0003
XXIX hereby obtaining a compound of Formula I1 II, III, IV, V or Vl,
Figure imgf000087_0001
Figure imgf000087_0002
IV V Vl wherein X1, X2, X3, X4, t, s, A1, L1, L2, R1, R2, R4,have the same meaning as that defined in any of claims 1 to 14.
17. A method according to claim 16, wherein the condensation is performed via the formation of the acyl chloride of the compound of Formula XXIII, XXIV, XXV, XXVI, XXVII, or XXVIII and then by the coupling of said acyl chloride with the compound of Formula XXIX. 18 A method according to claim 17, wherein the condensation is performed using a suitable coupling agent, in a suitable solvent, in the presence of suitable base.
19. A method according to claim 18, wherein the suitable coupling agent is selected from the group comprising hydroxybenzotriazole, o-benzotriazol-1 -yl-N,N,N',N4-tetramethyluronium hexafluorophosphate and the like. 20. A method according to claim 18 or 19, wherein the suitable solvent is selected from the group comprising dichloromethane, dimethylformamide and the like or mixture thereof.
21. A method according to any of claims 18 to 20, wherein the suitable base is selected from the group comprising potassium carbonate, diisopropylethylamine, triethylamine, triisopropylamine and the like. 22 A method according to any of claims 18 to 21 , wherein said base is used in an amount between 0 1 and 5.0 equivalents.
23. A compound obtainable by the method of any of claims 16 to 22.
24. A compound according to any of claims 1 to 15 and 23 for use as a medicament.
25. Use of a compound according to any of claims 1 to 15 and 23 as an ion channel blocker. 26. Use of a compound according to claim 25 as a blocker of an ion channel of the Kv4 family of ion-channels.
27. Use of a compound according to claim 25 as a blocker of an ion channel of the Kv1 family of ion channels. 28 Use of a compound according to claim 25 or 26 as a blocker of an ion channel of the Kv4.3 family of ion-channels.
29. Use of a compound according to claim 25 or 27 as a blocker of an ion-channel of the Kv1 5 family of ion channels. 30 Use of a compound according to any of claims 1 to 15 and 23 for the preparation of a medicament for the prevention and/or treatment of conditions or diseases associated with ion channels of the Kv4 family.
31. Use according to claim 30, wherein said conditions or diseases associated with ion channels of the Kv4 family, preferably Kv4 3 ion channels is selected from the group comprising (a) cardiac disorders including arrhythmias including (i) atrial arrhythmias such as Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff-Parkinson-White (WPW) syndrome, (iι) ventricular arrhythmias such as Premature ventricular contraction (PVC), ventricular tachycardia (VT), ventricular fibrillation and bradicardias; (ιii) other arrhythmias such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrioventricular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias cardiac disorders, hypertension-induced heart disorders including hypertension- induced cardiac hypertrophy; cardiac failure, and (b) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome.
32 Use of a compound according to any of claims 1 to 15 and 23 for the preparation of a medicament for the prevention and/or treatment of conditions or diseases associated with ion channels of the Kv1 family. 33 Use according to claim 32, wherein said conditions or diseases associated with ion channels of the Kv1 family, preferably Kv1.5 ion channels, is selected from the group comprising (a) cardiac disorders including arrhythmias including (ι) atrial arrhythmias such as Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff-Parkinson- White (WPW) syndrome, (iι) ventricular arrhythmias such as Premature ventricular contraction
(PVC), ventricular tachycardia (VT)1 ventricular fibrillation and bradicardias; (ιiι) other arrhythmias such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrio-ventπcular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias cardiac disorders; hypertension-induced heart disorders including hypertension-induced cardiac hypertrophy; cardiac failure; and (b) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome.
34. Use according to claim 30 or 32 for the preparation of a medicament for treating a cardiac disorder selected from the group comprising atrial fibrillation, atrial flutter and Brugada syndrome.
35. Use according to claim 30 or 32 for the preparation of a medicament for treating disorders of the nervous system.
36. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to any of claims 1 to 15 and 23. 37. Use of a pharmaceutical composition according to claim 36 for the treatment of conditions or diseases associated with ion channels of the Kv4 family, preferably the Kv4.3 ion channel.
38. Use according to claim 37, wherein said conditions or diseases associated with ion channels of the Kv4 family is selected from the group comprising (a) cardiac disorders including arrhythmias including (i) atrial arrhythmias such as Atrial fibrillation, Atrial flutter, Premature atrial contraction (PAC), Sick sinus syndrome, Atrioventricular block, Sinus arrhythmia, Sinus tachycardia, Supraventricular tachycardia (SVT), and Wolff-Parkinson-White (WPW) syndrome; (ii) ventricular arrhythmias such as Premature ventricular contraction (PVC), ventricular tachycardia (VT), ventricular fibrillation and bradicardias; (iii) other arrhythmias such as Brugada Syndrome, Adams-Stokes disease, bundle branch block, HIS bundle block, atrio- ventricular (AV) block, other heart conduction abnormalities, long Q-T syndrome, syncope and bradycardias cardiac disorders; hypertension-induced heart disorders including hypertension- induced cardiac hypertrophy; cardiac failure; and (b) disorders of the nervous system and neurological disorders including epilepsy, stroke, traumatic brain injury, spinal cord injury, anxiety, insomnia, encephalomyelitis, Alzheimer's disease multiple sclerosis, demyelinating disease, and Parkinson's Syndrome.
39. Use of a pharmaceutical composition according to claim 36 for the treatment of conditions or diseases associated with ion channels of the Kv1 family, preferably the Kv1.5 ion channel.
40. Use of a pharmaceutical composition according to claim 39 for the treatment of a cardiac disorder selected from the group comprising atrial fibrillation, atrial flutter and Brugada syndrome.
41. Use of a pharmaceutical composition according to claim 39 for the treatment of disorders of the nervous system.
42. Method of treating cardiac disorders comprising administrating to an individual in need of such treatment a pharmaceutical composition according to claim 36.
43. Method of treating disorders of the nervous system comprising administrating to an individual in need of such treatment a pharmaceutical composition according to claim 36.
PCT/EP2007/055404 2006-06-01 2007-06-01 Compounds that interact with ion channels, in particular with ion channels from the kv family WO2007138110A2 (en)

Applications Claiming Priority (4)

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US80984306P 2006-06-01 2006-06-01
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US8168634B2 (en) 2006-10-19 2012-05-01 Ucb Pharma S.A. Thiazole derivatives as kinase inhibitors
WO2008047109A1 (en) * 2006-10-19 2008-04-24 Ucb Pharma S.A. Thiazole derivatives as kinase inhibitors
WO2008074835A1 (en) * 2006-12-20 2008-06-26 Novartis Ag 2-substituted 5-membered heterocycles as scd inhibitors
JP2010513403A (en) * 2006-12-20 2010-04-30 ノバルティス アーゲー 2-Substituted 5-membered heterocycles as SCD inhibitors
US8258160B2 (en) 2006-12-20 2012-09-04 Novartis Ag SCD1 inhibitors triazole and tetrazole compounds
US9029411B2 (en) 2008-01-25 2015-05-12 Millennium Pharmaceuticals, Inc. Thiophenes and uses thereof
US9139589B2 (en) 2009-01-30 2015-09-22 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796314B2 (en) 2009-01-30 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9090601B2 (en) 2009-01-30 2015-07-28 Millennium Pharmaceuticals, Inc. Thiazole derivatives
US8796271B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796268B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
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US8765746B2 (en) 2010-10-13 2014-07-01 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
WO2012061926A1 (en) * 2010-11-08 2012-05-18 Zalicus Pharmaceuticals Ltd. Bisarylsulfone and dialkylarylsulfone compounds as calcium channel blockers
US9248122B2 (en) 2012-11-28 2016-02-02 Grünenthal GmbH Heteroquinoline-3-carboxamides as KCNQ2/3 modulators
WO2014082739A1 (en) * 2012-11-28 2014-06-05 Grünenthal GmbH Substituted amino-arylcarboxamides as kcnq2/3 modulators
US9284286B2 (en) 2012-11-28 2016-03-15 Grünenthal GmbH Specific carboxamides as KCNQ2/3 modulators
WO2014121106A1 (en) * 2013-01-31 2014-08-07 The Regents Of The University Of Michigan Methods and compositions for treating atrial fibrillation
EP2881390A1 (en) * 2013-12-04 2015-06-10 Sanofi Thienomethylpiperazine derivatives as inhibitors of soluble epoxide hydrolase
WO2015082474A1 (en) * 2013-12-04 2015-06-11 Sanofi Thienomethylpiperazine derivatives as inhibitors of soluble epoxide hydrolase
US9776991B2 (en) 2013-12-04 2017-10-03 Sanofi Thienomethylpiperazine derivatives as inhibitors of soluble epoxide hydrolase
US10214508B2 (en) 2014-06-13 2019-02-26 Takeda Pharmaceutical Company Limited Nitrogen-containing heterocyclic compound
WO2015190564A1 (en) * 2014-06-13 2015-12-17 武田薬品工業株式会社 Nitrogen-containing heterocyclic compound
US10537558B2 (en) 2015-06-01 2020-01-21 Bantam Pharmaceutical, Llc Substituted pyrazole and pyrrole compounds and methods for using them for inhibition of initiation of translation and treatment of diseases and disorders relating thereto
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JP2018521119A (en) * 2015-06-01 2018-08-02 バンタム、ファーマシューティカル、リミテッド、ライアビリティー、カンパニーＢａｎｔａｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌ， Ｌｌｃ Substituted pyrazole and pyrrole compounds and methods of using them to inhibit translation initiation and to treat diseases and disorders related thereto
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