WO2017052394A1 - Composés d'imidazopyridine et leur utilisation comme ligands du récepteur 5-ht6 - Google Patents

Composés d'imidazopyridine et leur utilisation comme ligands du récepteur 5-ht6 Download PDF

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WO2017052394A1
WO2017052394A1 PCT/PL2015/050049 PL2015050049W WO2017052394A1 WO 2017052394 A1 WO2017052394 A1 WO 2017052394A1 PL 2015050049 W PL2015050049 W PL 2015050049W WO 2017052394 A1 WO2017052394 A1 WO 2017052394A1
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Prior art keywords
imidazo
pyridine
piperazin
isopropyl
sulfonyl
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PCT/PL2015/050049
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English (en)
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Paweł ZAJDEL
Miroslav SOURAL
Barbora LEMROVÁ
Andrzej Bojarski
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Uniwersytet Jagielloński
Palacký University Olomouc
Instytut Farmakologii Polskiej Akademii Nauk
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Priority to PCT/PL2015/050049 priority Critical patent/WO2017052394A1/fr
Publication of WO2017052394A1 publication Critical patent/WO2017052394A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the invention relates to novel imidazo[4,5-c]pyridine and imidazo[4,5-£]pyridine derivatives having pharmacological activity, process for theirs preparation, formulations and their use in the treatment of diseases.
  • Serotonin (5-Hydroxytryptamine; 5-HT) is implicated in diverse physiological and pathophysiological pathways. It mediates its function via activation with specific receptors. Seven types of 5-HT receptors have been identified to date. One of the recent additions to the serotonin receptors superfamily constitute 5-HT 6 subtype. Human 5-HT 6 receptors are positively coupled to adenyl cyclase. They are almost exclusively distributed in the central nervous system (CNS), displaying the highest density in limbic, striatal and cortical regions (Hannon et al.).
  • 5-HT 6 modulators have been identified as potentially useful in the treatment or prophylaxis of attention deficit hyperactivity disorder (ADHD), schizophrenia, behavioral disorders: anxiety, depression, maniac depression, obsessive compulsive disorders, mood disorders, panic attacks, (several antipsychotic and antidepressant drugs display high affinity for 5-HT 6 receptors), Parkinson's disease, epilepsy, treatment of diseases associated with neurodegeneration, withdraw from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, and pain.
  • ADHD attention deficit hyperactivity disorder
  • schizophrenia behavioral disorders: anxiety, depression, maniac depression, obsessive compulsive disorders, mood disorders, panic attacks
  • severe antipsychotic and antidepressant drugs display high affinity for 5-HT 6 receptors
  • Parkinson's disease epilepsy
  • treatment of diseases associated with neurodegeneration withdraw from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, and pain.
  • 5-HT 6 ligands are also expected to be useful in the treatment or prophylaxis of obesity,
  • 5-HT6 modulators The progress in development of 5-HT6 modulators has been comprehensively reviewed by Holenz et al, Ivachtchenko et al, and recently by Benjamu et al .
  • One of the major class of compounds with enhanced affinity and selectivity for 5-HT6 receptors is represented by indole-like derivatives.
  • 4-piperazinyl-l-arylsulfonylindoles were reported in US 2003/0045527 Al, US 2005/0176705 Al, and US 2005/0256106 Al). Additionally, 4- piperazinyl-l-aiylsulfonylbenzimidazoles were disclosed in US 2010/0120779 Al .
  • the goal of the present invention relates to providing potent and selective 5-HT 6 modulators based on lH-imidazo[4,5 -£]pyridine and lH-imidazo[4,5 -c]pyridine scaffold, as compounds useful for the treatment of CNS disorders.
  • lH-imidazo[4,5 -c]pyridines behaved as potent anti-HCV agents, A2A adenosine receptor antagonists, and protein kinase B inhibitors; or displayed antitumor, and anti-hypertensive activities.
  • 1H- imidazo[4,5 -£]pyridines showed anticancer, antimalarial, antifungal, antiviral, or anticonvulsant properties (Lemrova et al., 2014).
  • Compounds capable selectively modulating 5-HT 6 receptors may be antagonists or inverse agonists.
  • alkyl denotes a univalent saturated branched or straight hydrocarbon chain. Unless otherwise stated such chains can contain from 1 to 5 carbon atoms. Representative of such alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl and structural isomers thereof. The given moiety is defined as Ci-salkyl.
  • the term 'aryl' embraces monocyclic or fused carbocyclic aromatic group.
  • the term 'heteroaryl' embraces monocyclic or fused bicyclic aromatic group having at least one heteroatom as a ring atom. Said heteroatoms are selected from N, O, S atoms.
  • heteroaryl group examples include but not limited to furyl, thienyl, pyrroryl, oxazolyl, thiazolyl, imidazolyl, thiazolyl, triazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pirymidinyl, pyrazinyl, 1,3,5-triazinyl, phenyl, lH-indazol-7-yl, lH-indazol-6-yl, lH-indol-2-yl, lH-indol- 3-yl, lH-indol-6-yl, lH-indol-7-yl, isoindolyl, l-benzofuran-2-yl, l-benzofuran-3-yl, indanyl, indenyl, l-benzothien-3-yl, l-benzothien
  • 'Halo' or 'Halogen' means chloro, fluoro, bromo or iodo.
  • substituted' means that the specified group or moiety bears one or more substituents. Where any group may carry multiple substituents, and a variety of possible substituents is provided, the substituents are independently selected, and need not to be the same.
  • the term 'unsubstituted' or when substitution is not indicated means that the specified group bears no substituents others than H atoms.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, enantiomer, N-oxide, a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • a 1 and A 2 are different and selected from nitrogen or carbon atom;
  • Ri represents H or C1-C3 alkyl, preferably Ri represents H or methyl;
  • R 2 represents hydrogen, an unsubstituted C1-C5 alkyl, an C1-C5 alkyl substituted with one or more halogen atoms, hydroxyl, a branched C1-C5 alkyl, a 5 to 6 membered aryl or a 5 to 6 membered heteroaryl, optionally substituted with one or more substituents selected from C1-C2 alkyl, one or more halogen atoms, C1-C2 alkoxy, halogen, nitro, hydroxyl, cyano, amino, alkylamino, carboxamide, preferably R 2 represents hydrogen, an unsubstituted C1-C5 alkyl, a 6 membered aryl, a 6 membered aryl substituted with halogen atom or C1-C2 alkoxy or 5 membered heteroaryl;
  • - T represents -CH 2 - , -S0 2 - or C1-C2 alkyl linking group substituted with R 3 ;
  • R 3 represents a 5 to 6 membered unsubstituted aryl, a 8 to 10 membered biaryl, a 5 to 6 membered heteroaryl, a 8 to 10 membered heteroaryl, optionally substituted with one or more substituents selected from C1-C3 alkyl, an C1-C3 alkyl substituted with one or more halogen atoms, C1-C3 alkoxy, C2-C4 alkenyl, halogen, nitro, hydroxyl, cyano, amino, alkylamino, carboxamide, preferably R 3 represents a 6 membered aryl or heteroaryl, a 6 membered aryl substituted with one or more halogen atoms, C1-C2 alkoxy or an C1-C3 alkyl substituted with one or more halogen
  • a 1 , A 2 , Ri, R 2 and R 3 are as defined above and T represents -CH 2 -, -CH 2 -CH 2 -or -CH(CH 3 )-.
  • Ri, R 2 and R 3 are as defined above, A 1 is carbon, A 2 is nitrogen and T represents -S0 2 - .
  • the invention particularly relates to a compound of the general formula (I) or a tautomer, stereoisomer, N-oxide or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, wherein:
  • a 1 and A 2 are selected from the group comprising nitrogen and carbon atoms, whereby one of A 1 and A 2 represents nitrogen atom and the another one of A 1 and A 2 represents carbon atom,
  • - Ri represents independently H or Ci-C 3 alkyl
  • R 2 represents hydrogen, an unsubstituted alkyl(Ci-C 5 ) group, an alkyl(Ci-C 5 ) group substituted with one or more halogen atoms, hydroxyl, a branched alkyl (C 1 -C5) group, unsubstituted aryl (5-6 membered), heteroaryl (5-6 membered), optionally substituted with one or more substituents selected from alkyl(Ci-C 2 ) group, one or more halogen atoms, alkoxy(Ci-C 2 ) group, halogen, nitro, hydroxyl, cyano, amino, alkylamino, carboxamide,
  • R 3 represents unsubstituted aryl (5-6 membered), biaryl (8-10 membered), heteroaryl (5-6 membered), heteroaryl (8-10 membered), optionally substituted with one or more substituents selected from alkyl(Ci-C 3 ) group, an alkyl(Ci-C 3 ) group substituted with one or more halogen atoms, alkoxy(Ci-C 3 ) group, alkenyl(C 2 -C4), halogen, nitro, hydroxyl, cyano, amino, alkylamino, carboxamide.
  • the invention particularly relates to a compound of the general formula (I) or a tautomer, stereoisomer, N-oxide or a pharmacologically acceptable salt, hydrate or solvate of any of the foregoing, wherein: - A 1 is carbon and A 2 is nitrogen,
  • - Ri represents independently H or Ci-C 3 alkyl
  • R-2 represents hydrogen, an unsubstituted alkyl(Ci-C 5 ) group, an alkyl(Ci-C 5 ) group substituted with one or more halogen atoms, hydroxyl, a branched alkyl (C 1 -C5) group, unsubstituted aryl (5-6 membered), heteroaryl (5-6 membered), optionally substituted with one or more substituents selected from alkyl(Ci-C 2 ) group, one or more halogen atoms, alkoxy(Ci-C 2 ) group, halogen, nitro, hydroxyl, cyano, amino, alkylamino, carboxamide,
  • R3 represents unsubstituted aryl (5-6 membered), biaryl (8-10 membered), heteroaryl (5-6 membered), heteroaryl (8-10 membered), optionally substituted with one or more substituents selected from alkyl(Ci-C3) group, an alkyl(Ci-C3) group substituted with one or more halogen atoms, alkoxy(Ci-C3) group, alkenyl(C2-C4), halogen, nitro, hydroxyl, cyano, amino, alkylamino, carboxamide.
  • the invention relates to racemates, as well as the individual stereoisomers of the compounds having formula (I).
  • one aspect of the invention provides a method for the treatment, control or prevention of such diseases, disorders or conditions in a mammal which comprises administering to such mammal a therapeutically effective amount of a compound of formula I.
  • the diseases, disorders or conditions for which the compounds of the present invention are useful in treating or preventing include, but are not limited to: schizophrenia, anxiety, depression, maniac depression, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, panic attacks, attention deficit hyperactivity disorder, attention deficit disorder, Parkinson's disease, Huntington's disease, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, neuropathic pain, obesity and type-2 diabetes, functional bowel disorder, Irritable Bowel Syndrome.
  • compositions for treating disorders resulting from disturbance of 5- HT 6 transmission comprising a compound of formula (I), prodrugs, pharmaceutically acceptable salts and solvates thereof, and a pharmaceutically acceptable carrier;
  • compositions for treating a disorder or condition chosen from the disorders listed herein comprising a compound of formula (XIV) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
  • the invention also provides the use of a compound or salt according to formula (I) for the manufacture of medicament.
  • the subject of the invention is a compound as defined in above for its use in the manufacture of a medicament.
  • Next subject of the invention is a compound as defined above for its use in the prevention or treatment of diseases, disorders or conditions resulting from disturbance of 5- HT 6 transmission.
  • Further subject of the invention is a compound as defined above for its use in the prevention or treatment of schizophrenia, anxiety, depression, maniac depression, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, panic attacks, attention deficit hyperactivity disorder, attention deficit disorder, Parkinson's disease, Huntington's disease, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, neuropathic pain, obesity and type-2 diabetes, functional bowel disorder, Irritable Bowel Syndrome.
  • the invention further relates to combination therapies wherein a compound of the invention, of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administrated concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed.
  • a therapeutic agent or agents used in the combination with the compound of invention relates to the compounds used for treating a disorder or conditions chosen from the disorders listed in the invention, with the mechanism of action that synergistically ameliorate the positive outcomes of therapy.
  • the compounds of the invention exert 5-HT 6 receptor antagonist properties. This activity of the compounds of the invention is readily demonstrated, for example, using one or more of the assays described herein or known in the art.
  • the invention also provides methods of preparing the compounds of the invention and the intermediates used in those methods.
  • the compounds of formula I can be prepared e.g. using the reactions and techniques described below. Generally, compounds described in the scope of this patent application can be synthesized by the route described in Scheme 1 and the Examples.
  • resin 2 Amination of resin 2 with solution of appropriate amine in aprotic polar solvent such as DMSO, DMF or NMP.
  • resin 3 can be obtained by the reaction of 2,4-dichloro-3-nitropyridine with appropriate amine in aprotic polar solvents such as DMSO, DMF and NMP in a presence of a tertiary base such as TEA, DIEA, DBU and subsequent reaction of the intermediate with resin 1 in aprotic polar solvents such as DMSO, DMF and NMP in a presence of a tertiary base such as TEA, DIEA, DBU.
  • target compounds can be obtained with application of traditional solution-phase chemistry using suitably N-protected piperazine.
  • the protecting group is typically acid labile, but is not limited to benzyloxycarbonyl (BOC), t- butoxycarbonyl (Boc) or trityl (Trt). All reaction steps leading to final compounds are based on the same reaction conditions as for the solid-phase strategy described above.
  • the final step (cleavage of Boc-protecting group) is performed by reaction with acids such as HC1 or TFA.
  • Isolation and purification of the compounds and intermediates described herein can be affected, by any suitable separation or purification procedures such as, for example, filtration, extraction, crystallization, column chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures. Suitable separation and isolation procedures may be taken from preparation and Examples. However, other equivalent separation or isolation procedures could be used, also.
  • the compounds of the present invention may contain one asymmetric center and can thus occur as racemates and racemic mixtures or single enantiomers.
  • Formula (I) shows the structure of the class of compounds without preferred stereochemistry.
  • the independent syntheses of these isomers, or their chromatographic separation may be achieved as known in the art by appropriate modification of the methodology disclosed therein.
  • Their absolute stereochemistry may be determined by the X- ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing as asymmetric center of known absolute configuration.
  • the racemic mixture of compounds can be separated directly by chromatographic methods utilizing chiral stationary phases: methods well-known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well-known in the art.
  • Some of the crystalline forms for the compounds may exist as polymorphs: as such intended to belong to the invention.
  • some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such solvents also fall within the scope of this invention.
  • the compounds of the invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction and disease.
  • Example 1 3-benzyl-2-methyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 2 3-(2-chlorobenzyl)-2-methyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 3 3-(3-chlorobenzyl)-2-methyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 4 l-(3-chlorobenzyl)-2-methyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 5 2-methyl-3-(2-methylbenzyl)-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 6 3-(2-Methoxybenzyl)-2-methyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 7 l-(4-fluorobenzyl)-2-methyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 8 3-(2-chlorobenzyl)-2-ethyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 10 3-(2-fluorobenzyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 11 2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 12 3-(2,5-difluorobenzyl)-2-ethyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]py-ridine.
  • Example 13 2-ethyl-3-(3-fluorophenethyl)-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 14 l-(2-fluorobenzyl)-2-isopropyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 15 3-(3-chlorobenzyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 16 3-(3-chlorobenzyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 17 3-(3-fluorobenzyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 18 2-Isopropyl-3-(3-methoxybenzyl)-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 19 3-(4-chlorobenzyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 20 3 -(3 -fluorobenzyl)-2-isopropyl-7-(3 -methylpiperazin- 1 -yl)-3H-imidazo[4, 5- b]pyridine.
  • Example 21 (S)-3-(3-fluorobenzyl)-2-isopropyl-7-(3-methylpiperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 22 l-(4-fluorobenzyl)-2-isopropyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 23 2-isopropyl-7-(piperazin-l-yl)-3-(pyridin-4-ylmethyl)-3H-imidazo[4,5- b]pyridine.
  • Example 24 3 -( 1 -(3 -fluorophenyl)ethyl)-2-isopropyl-7-(piperazin- 1 -yl)-3H-imidazo[4,5- b]pyridine.
  • Example 25 (S)-3-(l-(3-fluorophenyl)ethyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 26 (R)-3-(l-(3-chlorophenyl)ethyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 27 (R)-3-(l-(3-chlorophenyl)ethyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 28 3-(2-chlorobenzyl)-2-(pentan-3-yl)-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 29 3-(3-methylbenzyl)-2-(pentan-3-yl)-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 31 3-(2-chlorobenzyl)-2-neopentyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 32 3-(3-methylbenzyl)-2-neopentyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 33 3-(3-methoxybenzyl)-2-neopentyl-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 34 3-(3-chlorobenzyl)-7-(piperazin-l-yl)-2-(thiophen-2-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 35 7-(piperazin-l-yl)-2-(thiophen-2-yl)-3-(3-(trifluoromethyl)benzyl)-3H- imidazo[4,5-b]pyridine.
  • Example 36 3-benzyl-2-(4-fluorophenyl)-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 37 3-(2-fluorobenzyl)-2-(4-fluorophenyl)-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 38 3-(3-chlorobenzyl)-2-(4-fluorophenyl)-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 39 3 -(3 -fluorobenzyl)-2-(4-fluorophenyl)-7-(piperazin- 1 -yl)-3H-imidazo[4, 5- b] pyridine.
  • Example 40 2-methyl-l-(phenylsulfonyl)-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 41 l-((3-fluorophenyl)sulfonyl)-2-methyl-4-(piperazin-l-yl)-lH-imidazo[4,5- c] pyridine.
  • Example 42 2-ethyl- 1 -((3 -methylphenyl)sulfonyl)-4-(piperazin- 1 -yl)- lH-imidazo[4, 5- c]pyridine.
  • Example 43 l-((4-aminophenyl)sulfonyl)-2-ethyl-4-(piperazin-l-yl)-lH-imidazo[4,5- c]pyridine.
  • Example 44 2-ethyl-l-((3-fluorophenyl)sulfonyl)-4-(piperazin-l-yl)-lH-imidazo[4,5- c]pyridine.
  • Example 45 2-isopropyl-l-(phenylsulfonyl)-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 46 3-((3-chlorophenyl)sulfonyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5- c]pyridine.
  • Example 47 1 -((3 -fluorophenyl)sulfonyl)-2-i sopropyl-4-(3 -methylpiperazin- 1 -yl)- 1 H- imidazo[4,5-c]pyridine.
  • Example 48 2-isopropyl- 1 -((3 -methoxyphenyl)sulfonyl)-4-(piperazin- 1 -yl)- lH-imidazo[4, 5- c]pyridine.
  • Example 49 3-((4-fluorophenyl)sulfonyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5- c]pyridine.
  • Example 50 l-((3-chlorophenyl)sulfonyl)-2-cyclopentyl-4-(piperazin-l-yl)-lH-imidazo[4,5- c]pyridine.
  • Example 51 2-butyl- 1 -((3 -chlorophenyl)sulfonyl)-4-(piperazin- 1 -yl)- lH-imidazo[4, 5- c]pyridine.
  • Example 52 2-butyl-l-((4-fluorophenyl)sulfonyl)-4-(piperazin-l-yl)-lH-imidazo[4,5- c]pyridine.
  • Example 53 2-butyl-l-((4-methoxyphenyl)sulfonyl)-4-(piperazin-l-yl)-lH-imidazo[4,5- c]pyridine.
  • Example 54 l-((3-chlorophenyl)sulfonyl)-2-(4-methoxyphenyl)-4-(piperazin-l-yl)-lH- imidazo[4,5-c]pyridine.
  • the compounds of the present invention contain at least one asymmetric center and thus occur as racemates and racemic mixtures or single enantiomers. Also, mixture of enantiomers being enriched in one of enantiomers are available by the method of the invention.
  • N-oxides of the compounds mentioned above belong to the invention.
  • Tertiary amines may or may not give rise to N-oxide metabolites. The extent to what N-oxidation takes place varies from trace amounts to a near quantitative conversion.
  • N-oxides may be more active than their corresponding tertiary amines, or less active. While N-oxides can easily be reduced to their corresponding tertiary amines by chemical means, in human body this happens to varying degrees.
  • Some N-oxides undergo nearly quantitative reductive conversion to the corresponding tertiary amines, in other cases is a mere trace reaction, or even completely absent.
  • the compound of the invention may exist in various forms, for example polymorphs, solvates and amorphous forms. Some of the crystalline forms of the compounds may exist as polymorphs: as such intended to belong to the invention. In addition, some of the compounds may form solvates with water (i.e. hydrates), or common organic solvents. Such hydrates and solvates are also encompassed by the scope of present invention. Examples thereof include 1/10 hydrates hydrate, 1/4 hydrate, monohydrate, dihydrochloride, dihydrate, dihydrochloride 3/2 hydrate, and the like. Amorphous forms are non-crystalline materials with no long range order, and generally do not give a distinctive powder X-ray diffraction pattern.
  • the invention provides a compound according of the formula (I) or pharmaceutically acceptable salt thereof for use in the therapy in treating CNS diseases, disorders or conditions associated with disturbances of the serotoninergic systems.
  • pharmaceutically acceptable salt refers to those salts that are, within the scope medical judgment, suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when finally isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic acids, including inorganic or organic acids (Berge, 1977).
  • the "free base” form may be regenerated by contacting the salt with a base, and isolating the parent compound in the conventional matter.
  • treatment refers to any treatment a mammalian, for example human condition or disease, and includes: (i) inhibiting the disease or condition, i.e., arresting its development, (ii) relieving the disease or condition, i.e.; causing the condition to regress, or (iii) stopping the symptoms of the disease.
  • medical therapy intendeds to include prophylactic, diagnostic and therapeutic regimens carries out in vivo or ex vivo on humans or other mammals.
  • Said psychotropic diseases, disorders or conditions are selected from the group comprising schizophrenia, anxiety, depression, maniac depression, obsessive compulsive disorders, mood disorders, migraine, aggression, sleep disorders, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, eating disorders, anorexia, bulimia, panic attacks, attention deficit hyperactivity disorder, attention deficit disorder, autism, Parkinson's disease, Huntington's disease, pain, neuropathic pain, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines.
  • the invention further relates to combination therapies wherein a compound of the invention, of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention, is administrated concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed.
  • a compound of the invention, of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of the invention is administrated concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for treating one or more of the conditions listed.
  • Such other therapeutic agent(s) may be administrated prior to, simultaneously with, of following the administration of the compounds of the invention.
  • the therapeutic agent or agents used in the combination with the compound of invention relates to the compounds used for treating a disorder or conditions chosen from the disorders listed in the invention, with the mechanism of action that synergistically ameliorate the positive outcomes of therapy.
  • terapéuticaally effective amount refers to an amount of a therapeutic agent to treat a condition treatable by administrating a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or ameliorative response in as tissue system, animal or human. It is not useful to specify an exact effective amount in advance.
  • the term "combination preparation” comprises both true combinations, meaning a compound of formula (I) and one or more other medicaments physically combined in one preparation such as a tablet or injection fluid, comprising a compound of formula (I) and one or more other medicaments in separate dosage forms, together with instruction for use, optionally with further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings.
  • the pharmacotherapy by definition is simultaneous.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof or diluent/diluents, and optionally one or more other therapeutic ingredients.
  • the carrier/carriers) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • composition encompasses a product comprising specified ingredients in predetermined amount or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts.
  • this term encompasses a product comprising one or more active ingredients, and an optimal carrier comprising inert ingredients, as well as any product that results, directly or indirectly from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interaction of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredients into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into desired formulation.
  • the pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of disease.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
  • total daily dose administration to a patient a single or individual doses may be in amounts, for example from 0.001 to 10 mg/kg body weight daily, and more usually 0.01 to 1000 mg per day, of total active ingredients.
  • the invention also provides the use of a compound or salt according to formula (I) for the manufacture of medicament.
  • Solvents and chemicals were purchased from Aldrich (Milwaukee, IL, www.sigmaaldrich.com), Acros (Geel, Belgium, www.acros.cz) and Fisher (Pittsburgh, PA, www.fishersci.com).
  • Wang resin 100-200 mesh, 1% DVB, 1.0 mmol/g
  • 4-(4-Formyl-3- methoxyphenoxy)butyric acid were obtained from AAPPTec (Louisville, KY, www.aapptec.com). Synthesis was carried out on Domino Blocks in disposable polypropylene reaction vessels (Torviq, Niles, MI, www.torviq.com).
  • Labquake Tube Rotator Therm olyne, Dubuque, IA, www.barnsteadthermolyne.com was used for gentle but efficient tumbling of resin slurry.
  • the LC/MS analyses were carried out on UHPLC-MS system consisting of UHPLC chromatograph Acquity with photodiode array detector and single quadrupole mass spectrometer (Waters), using X-Select C18 column at 30 °C and flow rate of 600 ⁇ L/min.
  • Mobile phase was (A) 0.01 M ammonium acetate in water, and (B) acetonitrile, linearly programmed from 10% to 80% B over 2.5 min, kept for 1.5 min. The column was re- equilibrated with 10%) of solution B for 1 min.
  • the ESI I source operated at discharge current of 5 ⁇ , vaporizer temperature of 350 °C and capillary temperature of 200 °C.
  • Example 1-54 Intermediate 5 was treated with 50% TFA in DCM (4 mL) for 1 h. The cleavage cocktail was collected, and the resin was washed with 50% TFA in DCM (3 ⁇ ). The liquid phases were combined and evaporated under a stream of nitrogen. The resulting residue was dissolved in MeOH and purified by semipreparative HPLC. The final compounds were obtained with purity > 95% (UPLC) in 46 % yield.
  • Example 1 3-benzyl-2-methyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 4 l-(3-chlorobenzyl)-2-methyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 7 l-(4-fluorobenzyl)-2-methyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 10 3-(2-fluorobenzyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 13 2-ethyl-3-(3-fluorophenethyl)-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 14 l-(2-fluorobenzyl)-2-isopropyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 17 3-(3-fluorobenzyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 20 3 -(3 -fluorobenzyl)-2-isopropyl-7-(3 -methylpiperazin- 1 -yl)-3H-imidazo[4, 5- b]pyridine.
  • White solid, MS [M-H] + 368.5.
  • Example 22 l-(4-fluorobenzyl)-2-isopropyl-4-(piperazin-l-yl)-lH-imidazo[4,5-c]pyridine.
  • Example 28 3-(2-chlorobenzyl)-2-(pentan-3-yl)-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 29 3-(3-methylbenzyl)-2-(pentan-3-yl)-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 30 3-(4-fluorobenzyl)-2-(pentan-3-yl)-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • Example 32 3-(3-methylbenzyl)-2-neopentyl-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 33 3-(3-methoxybenzyl)-2-neopentyl-7-(piperazin-l-yl)-3H-imidazo[4,5- b]pyridine.
  • White solid, MS [M-H] + 394.3; 1H NMR (500 MHz, OMSO-d 6 ) ⁇ ppm 0.94 (s, 9 H) 2.61 (s, 2 H) 2.84 (br. s., 4 H) 3.64 (s, 3 H) 3.80 (br.
  • Example 35 7-(piperazin-l-yl)-2-(thiophen-2-yl)-3-(3-(trifluoromethyl)benzyl)-3H- imidazo[4,5-b]pyridine.
  • Example 36 3-benzyl-2-(4-fluorophenyl)-7-(piperazin-l-yl)-3H-imidazo[4,5-b]pyridine.
  • Example 39 3 -(3 -fluorobenzyl)-2-(4-fluorophenyl)-7-(piperazin- 1 -yl)-3H-imidazo[4, 5- b]pyridine.
  • Example 46 3-((3-chlorophenyl)sulfonyl)-2-isopropyl-7-(piperazin-l-yl)-3H-imidazo[4,5- c]pyridine.
  • Example 47 1 -((3 -fluorophenyl)sulfonyl)-2-i sopropyl-4-(3 -methylpiperazin- 1 -yl)- 1 H- imidazo[4,5-c]pyridine.
  • White solid, MS [M-H] + 385.3.
  • Example 48 2-isopropyl- 1 -((3 -methoxyphenyl)sulfonyl)-4-(piperazin- 1 -yl)- lH-imidazo[4, 5- c]pyridine.
  • White solid, MS [M-H] + 416.2.
  • Example 50 l-((3-chlorophenyl)sulfonyl)-2-cyclopentyl-4-(piperazin-l-yl)-lH-imidazo[4,5- c]pyridine.
  • White solid, MS [M-H] + 446.5.
  • Example 51 2-butyl- 1 -((3 -chlorophenyl)sulfonyl)-4-(piperazin- 1 -yl)- lH-imidazo[4, 5- c]pyridine.
  • Example 54 l-((3-chlorophenyl)sulfonyl)-2-(4-methoxyphenyl)-4-(piperazin-l-yl)-lH- imidazo[4,5-c]pyridine.
  • White solid, MS [M-H] + 484.3.
  • Test Example 1 A - in vitro evaluation
  • Radioligand binding assays were employed for determining the affinity and the selectivity profile of the synthesized compounds for cloned serotonin: 5-HT I A, 5-HT 2 A, 5-HT 6 , 5-HT 7 and dopamine D 2L receptors, all stably expressed in HEK293 cells except 5-HT 2 A which was stably expressed in CHO-K1 cells.
  • HEK293 cells with stable expression of human serotonin 5-HT I AR, 5-HT 6 , 5-HT 7b R or dopamine D 2L R (all prepared with the use of Lipofectamine 2000) were maintained at 37°C in a humidified atmosphere with 5% C0 2 and were grown in Dulbeco's Modifier Eagle Medium containing 10% dialysed foetal bovine serum and 500 mg/ml G418 sulphate.
  • cells were subcultured in 10 cm diameter dishes, grown to 90% confluence, washed twice with prewarmed to 37°C phosphate buffered saline (PBS) and were pelleted by centrifugation (200 g) in PBS containing 0.1 mM EDTA and 1 mM dithiothreitol. Prior to membrane preparations pellets were stored at -80°C.
  • PBS phosphate buffered saline
  • CHO-K1 cells with stable expression of human serotonin 5-HT 2 AR were purchased from PerkinElmer BioSignal Inc and were maintained according to manufacturer's protocol.
  • the composition of the assay buffers was as follows: for 5-HTi A R: 50 mM Tris-HCl, 0.1 mM EDTA, 4 mM MgCl 2 , 10 mM pargyline and 0.1% ascorbate; for 5-HT 2A R: 50 mM Tris-HCl, 4 mM MgCl 2 and 0.1% ascorbate; for 5- HT 6 R: 50 mM Tris-HCl, 0.5 mM EDTA and 4 mM MgCl 2 , for 5-HT 7b R: 50 mM Tris-HCl, 4 mM MgCl 2 , 10 mM pargyline and 0.1% ascorbate; for dopamine D 2L R: 50 mM
  • the assay samples contained as radioligands: 1.5 nM [ 3 H]- 8-OH-DPAT (135.2 Ci/mmol) for 5-HTi A R; 2nM [ 3 H]-Ketanserin (53.4 Ci/mmol) for 5- HT 2A R; 2 nM [ 3 H]-LSD (83.6 Ci/mmol) for 5-HT 6 R; 0.6 nM [ 3 H]-5-CT (39.2 Ci/mmol) for 5-HT 7 R or 2.5 nM [ 3 H]-Raclopride (76.0 Ci/mmol).
  • Non-specific binding is defined withlO ⁇ of 5-HT in 5-HT I AR and 5-HT 7 R binding experiments, whereas 20 ⁇ of mianserin, 10 ⁇ of methiothepine or 1 ⁇ of (+)butaclamol were used in 5-HT 2 AR, 5-HT 6 R and D 2L assays, respectively.
  • Membrane preparation and general assay procedures for cloned receptors were adjusted to 96-microwell format based on described protocols (Perkin Elmer).
  • Table IB The binding data of the library members for 5-HTIA, 5-HT 2 A, 5-HT 6 , 5-HT 7 and D 2 receptors.
  • Test Example 2 in vitro functional activity ago-/antago-nism) on human 5-HT 6 receptors
  • Test and reference compounds were dissolved in dimethyl sulfoxide (DMSO) at a concentration of 1 mM.
  • Serial dilutions were prepared in 96-well microplate in assay buffer and 8 to 10 concentrations were tested.
  • DMSO dimethyl sulfoxide
  • a cellular aequorin-based functional assay was performed with recombinant CHO-Kl cells expressing mitochondrially targeted aequorin, human GPCR and the promiscuous G protein al6 for 5-HT6. Assay was executed according to previously described protocol [1]. After thawing, cells were transferred to assay buffer (DMEM/HAM's F12 with 0.1% protease free BSA) and centrifuged. The cell pellet was resuspended in assay buffer and coelenterazine h was added at final concentrations of 5 ⁇ . The cells suspension was incubated at 16 °C, protected from light with constant agitation for 16 h and then diluted with assay buffer to the concentration of 100,000 cells/ml.
  • assay buffer DMEM/HAM's F12 with 0.1% protease free BSA
  • Table 2A The agonist and antagonist effect of the selected library members for 5-HT 6 receptors.

Abstract

L'invention concerne de nouveaux dérivés d'imidazo[4,5-c]pyridine et d'imidazo[4,5-b]pyridine de formule (I) en tant qu'antagonistes des récepteurs de 5-HT6, en particulier destinés à être utilisés dans la prévention ou le traitement de la schizophrénie, de l'anxiété, de la dépression, du syndrome maniaco-dépressif, de l'épilepsie, des troubles obsessionnels compulsifs, des troubles de l'humeur, de la migraine, de la maladie d'Alzheimer, du déclin cognitif lié à l'âge, d'un trouble cognitive léger, des troubles du sommeil, des troubles de l'alimentation, de l'anorexie, de la boulimie, des attaques de panique, du trouble d'hyperactivité avec déficit de l'attention, du trouble déficitaire de l'attention, de la maladie de Parkinson, de la maladie de Huntington, du sevrage de l'abus de cocaïne, d'éthanol, de nicotine ou des benzodiazépines, de la douleur, de la douleur neuropathique, de l'obésité et du diabète de type 2, d'un trouble fonctionnel de l'intestin, du syndrome de l'intestin irritable.
PCT/PL2015/050049 2015-09-23 2015-09-23 Composés d'imidazopyridine et leur utilisation comme ligands du récepteur 5-ht6 WO2017052394A1 (fr)

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