WO2013027001A1 - Composés et leur utilisation pour le traitement de troubles associés au récepteur h3 de l'histamine - Google Patents

Composés et leur utilisation pour le traitement de troubles associés au récepteur h3 de l'histamine Download PDF

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WO2013027001A1
WO2013027001A1 PCT/GB2012/000673 GB2012000673W WO2013027001A1 WO 2013027001 A1 WO2013027001 A1 WO 2013027001A1 GB 2012000673 W GB2012000673 W GB 2012000673W WO 2013027001 A1 WO2013027001 A1 WO 2013027001A1
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methyl
ylidene
cyclobutylpiperidin
phenyl
piperidine
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PCT/GB2012/000673
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English (en)
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Parminder Kaur Ruprah
Kevin John Merchant
Louise Marie Walsh
Catrina Morven KERR
Charlotte Fieldhouse
David HARRISSON
Stephanie MAINE
Katherine Hazel
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Takeda Pharmaceutical Company Limited
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Publication of WO2013027001A1 publication Critical patent/WO2013027001A1/fr

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    • 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
    • C07D401/02—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
    • C07D401/10—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 aromatic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
    • C07D211/82—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring 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
    • C07D401/02—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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D417/10—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 aromatic rings

Definitions

  • the present invention relates to compounds and their uses, and in particular to compounds having a piperidinylalkene scaffold and their therapeutic use in the treatment or prevention of conditions having an association with the histamine H3 receptor.
  • the H3 receptor was first identified pharmacologically in 1983 as an autoreceptor that regulates the production of histamine (1).
  • the receptor was later cloned in 1999 (2).
  • It is a constitutively active G protein-coupled receptor that is expressed predominantly in the central nervous system (CNS) and modulates a variety of CNS functions both centrally and peripherally. It is expressed on the presynaptic terminals of CNS neurones and acts as a negative modulator of release of neurotransmitters such as histamine, acetylcholine, norepinephrine, serotonin and dopamine (3).
  • the ability of the H3 receptor to regulate the release of a wide range of neurotransmitters has fuelled research into the development of antagonists / inverse agonists which have potential in behavioural and physiological conditions, for example CNS disorders such as narcolepsy, disorders of wakefulness, cognition or attention, pain and in suppression of food intake.
  • CNS disorders such as narcolepsy, disorders of wakefulness, cognition or attention, pain and in suppression of food intake.
  • Histaminergic neurones are located in the tuberomammillary nucleus of the posterior hypothalamus and project their axons into brain regions including the hypothalamus, thalamus, cerebral cortex, amygdala, and septum. Activity of histaminergic neurons is closely linked with the sleep / wake cycle and numerous reports in the literature have established that the H3 receptor plays a role in cognition and sleep / wake related processes, based on studies with known H3 receptor antagonists and their effects in animal models (4, 5, 6). H3 antagonist compound A-349821 is currently in preclinical development and has been shown to demonstrate cognition-enhancing effects in the rat (7) ⁇
  • the histaminergic system is one of the targets of leptin signalling in the hypothalamus.
  • Known H3 antagonist clobenpropit increases histamine release in the hypothalamus of mice and has the effect of reducing energy intake in both lean and obese mice (8).
  • the role of the H3 receptor in obesity has been further substantiated through studies with antagonists thioperamide and ciproxifan and more recently with non-imidazole compounds (10).
  • the non-selective antagonist thioperamide has an antinociceptive effect in a number of acute pain models (11). H3 antagonists have been suggested for the treatment of neuropathic pain (12). In addition GSK207040 and GSK334429 are selective non- imidazole H3 antagonist compounds that display high affinity for both rat and human H3 receptors. Both compounds reduced tactile allodynia in the rat, suggesting H3 antagonists have therapeutic potential in the treatment of neuropathic pain (13).
  • non-imidazole compounds have been at the forefront of research, for example A-349821 (7) and GS 207040 / GSK334429 (13).
  • ABT-239 is currently being investigated for use in attention deficit hyperactivity disorder, Alzheimer's Disease and schizophrenia (14).
  • US patent US 4,166,814 discloses a series of piperidine derivatives, including 4,4' -(1,4- phenylenedimethylidyne)bis[l,2,2,6,6-pentamethyl]-piperidine, as light stabilisers for plastics.
  • Ri represents H or Cj -6 alkyl
  • R 2 represents Ci. 6 alkyl, wherein each R 2 may be the same or different;
  • p 0, 1, 2, 3 or 4;
  • n 1 or 2;
  • n 1 or 2; provided that both and m and n do not represent 2;
  • R 3 represents Ci-6 alkyl, -Qi-C 3-6 cycloalkyl or -Q 2 -3-6 membered monocyclic heterocyclyl, wherein each may be optionally substituted by one or more substituents, independently selected from halogen, C
  • Qi and Q 2 independently represent a covalent bond or Ci -3 alkylene
  • Xi, X 2 , X 3 and X4 independently represent CH or N; wherein no more than 2 of Xi, X 2 , X3 and X 4 represent N;
  • R4 independently represents halogen, Ci -6 alkyl, haloCi-6 alkyl, Ci-6 alkoxy or haloCi. 6 alkoxy;
  • q 0, 1 or 2;
  • a I represents a covalent bond or C
  • Li represents a covalent bond or -NR 6 -, -0-, b -NR 7 CO- a , b -CONR 8 - a , -C(O)-, b - NR 7 S0 2 - a , b -S0 2 NR s - a , -S(0) 2 -, in which a represents the point of attachment to Ai and b represents the point of attachment to R5;
  • R 6 , R 7 and R 8 independently represent H or C] -6 alkyl
  • Rs represents -(CH 2 )i -30Ci_ 6 alkyl, or -Q3-C 3 . 8 cycloalkyl, -Q 4 -heteroaryl, -Q 5 - heterocyclyl, -Qg-aryl; in which the C 3 - 8 cycloalkyl, heteroaryl, heterocyclyl and aryl are optionally substituted with one or more R 9 ; wherein each R 9 may be the same or different;
  • R 5 when A i represents optionally substituted C
  • Q3, Q4, Q5 and Q 6 independently represent a covalent bond or C1.3 alkylene
  • each Ci- 6 alkyl, C -6cycloalkyl, aryl, heteroaryl or heterocyclyl present as or as part of R9 is optionally substituted with one or more Rn, wherein each R i7 may be the same or different;
  • 6 independently represent H or C1.3 alkyl
  • Rn represents halogen, Ci -6 alkyl, haloC
  • . 6 alkyl, - CN, -NO2, 0, -ORig , C0 2 R, 9, -COR,9, -NR, 9 R 20 , -CONR, 9 R 20 , -NR, 9 COR 20; -NR I 9 S0 2 R 2 o or -S0 2 NR 19 R 2 o;
  • Rj8 represents H, Ci-ealkyl or -haloCi -6 alkyl
  • Ri9 and R 20 independently represent H or Ci -6 alkyl
  • the compounds of the invention have been found to modulate the histamine H3 receptor.
  • the compounds possess antagonist or inverse agonist properties at this receptor.
  • the compounds may have the potential to display useful selectivity for the H3 receptor.
  • any group in the compound of formula (1) above is referred to as being optionally substituted, this group may be unsubstituted or substituted by one or more substituents. Typically any such group will be unsubstituted, or substituted by one, two or three substituents.
  • 'halogen' refers to a fluorine, chlorine, bromine or iodine atom, unless otherwise specified.
  • -6 alkyl refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • -6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert butyl, n-pentyl, isopentyl, neopentyl and hexyl.
  • C 0 alkyl indicates that the group is absent i.e. there is a direct bond between the groups.
  • 'C x . y alkylene' refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from 'C x . y alkyl' above.
  • C e alkylene groups include methylene, methyl methylene, dimethylmethylene, ethylene, propylene and methylpropylene.
  • 'C x . y alkoxy' refers to an -0-C x . y alkyl group wherein C x-y alkyl is as defined herein.
  • Examples of C )- alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • 'haloC x-y alkyl' refers to a C x-y alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen.
  • examples of such groups include fluoroethyl, trifluoromethyl and trifluoroethyl.
  • 'C1 -3 hydroxyalkyl' refers to a Ci- 3 alkyl group as defined herein wherein at least one hydrogen atom is replaced with hydroxyl.
  • Examples of Ci -3 hydroxyalkyl groups include hydroxymethyl and hydroxyethyl.
  • the term 'C x . y cycloalkyl' as used herein refers to a saturated monocyclic hydrocarbon ring of x to y carbon atoms.
  • C 3 . 8 cycloalkyl refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms.
  • C3.8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the term 'heterocyclyl' refers to a 4-7 membered monocyclic ring or a 8-12 membered bicyclic, bridged or spiro-fused ring, any of which may be saturated or partially unsaturated, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen, silicon or sulphur.
  • Examples of such monocyclic groups include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrpfuranyl, dihydropyrany], tetrahydropyranyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, tetrahydropyridazinyl, dihydropyridazinyl, t
  • N-linked 4-7 membered monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
  • Examples of such 8-12 membered bicyclic, bridged or spiro-fused rings include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro-lH-3- benzazepine, tetrahydroisoquinolinyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, octahydro- 1 H-isoindolyl, octahydro- lH-indolyl, octahydro- 1 H-cyclopenta[b]pyridinyl, octahydro- 1 H-cyclopenta[c]pyridinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.1]heptanyl, oxaspiro[4.5]decanyl and
  • any heterocyclyl ring may be attached to the rest of the molecule through any available C or N atom.
  • Optional substituents may be present on any available C or N atom.
  • heteroaryl refers to a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur.
  • Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, triazinyl, tetrazinyl and the like.
  • bicyclic aromatic rings examples include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and imidazopyridyl.
  • any heteroaryl ring may be attached to the rest of the molecule through any available C or N atom.
  • Optional substituents may be present on any available C or N atom.
  • the nitrogen atom may be oxidized.
  • pyridyl as the 'heteroaryl' may be its N-oxide.
  • 'aryP refers to a C6-12 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl and tetrahydronaphthalenyl.
  • salts with inorganic bases include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids. Salts with acids may, in particular, be employed in some instances.
  • salts' of compounds of Formula (1) of the present invention include but are not limited to acid addition salts (for example, phosphates, nitrates, sulphates, borates acetates, maleates, citrates, fumarates, succinates, methanesulfonates, benzoates, salicylates and hydrohalides), and salts of amino acids (such as glycine, alanine, valine, leucine, isoleucine, cysteine, methionine, proline).
  • Further pharmaceutically acceptable salts include quaternary ammonium salts of the compounds of formula (1).
  • Compounds of formula (1) and their salts may be in the form of a solvate, which is included in the scope of the invention.
  • Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • the compound of Formula (1) of the present invention may be in either hydrate or non- hydrate form.
  • compounds of the invention may be prepared as isomeric mixtures or racemates, although the invention relates to all such enantiomers or isomers, whether present in an optically pure form or as mixtures with other isomers.
  • Individual enantiomers or isomers may be obtained by methods known in the art, such as optical resolution of products or intermediates (for example chiral chromatographic separation (e.g. chiral HPLC)), or an enantiomeric synthesis approach.
  • compounds of the invention may exist as alternative tautomeric forms (e.g. keto/enol, amide/imidic acid)
  • the invention relates to the individual tautomers in isolation, and to mixtures of the tautomers in all proportions.
  • the invention also extends to all conformational ring isomers.
  • the compounds of the invention bear one or more radiolabels.
  • radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (1), or may be introduced by coupling the compounds of formula (1) to chelating moieties capable of binding to a radioactive metal atom.
  • Such radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
  • Ri represents H.
  • represents Ci-3 alkyl, typically methyl.
  • R when present generally represents C ) -3 alkyl, typically methyl or ethyl.
  • p 0 or 1.
  • n 1 In other embodiments, n represents 2.
  • n 1 or 2.
  • m represents 2 and n represents 1.
  • Qi typically represents a covalent bond or -CH 2 -.
  • Q 2 typically represents a covalent bond.
  • R 3 represents C)- alkyl, C 3-6 cycloalkyl, -CH 2 -C 3 . 6 cycloalkyl or 3-6 membered heterocycloalkyl, each of which may be optionally substituted.
  • R 3 3-6 membered heterocycloalkyl include pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiophenyl, and tetrahydrothiopyrany 1.
  • Suitable R 3 optional substituents include halogen, typically fluorine.
  • R 3 examples include ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, - CH 2 -cyclopropyl and tetrahydrofuranyl, each of which may be optionally substituted.
  • R 3 examples include ethyl, isopropyl, isobutyl, cyclobutyl, 3- fluorocyclobutyl, cyclopentyl, -CH 2 -cyclopropyl and tetrahydrofuran-3-yl.
  • R 3 represents Cj.6 alkyl or optionally substituted C 3-6 cycloalkyl.
  • R 3 represents optionally substituted C3.6 cycloalkyl, typically cyclobutyl or cyclopropyl. In a further particular embodiment, R 3 represents cyclobutyl.
  • Xi represents CH. In other embodiments, Xi represents N. 5 In some embodiments, X 2 represents CH. In other embodiments, X 2 represents N. In some embodiments, X 3 represents CH. In other embodiments, X 3 represents N. In some embodiments, X 4 represents CH. In other embodiments, X 4 represents N. In some embodiments i, X 2 , X3 and X 4 each represent CH.
  • one of the groups i, X 2 , X 3 or X 4 represents N and the rest 10 represent CH.
  • R4 represents halogen
  • q represents 0.
  • q represents 0 or 1.
  • specific R examples include fluoro or chloro.
  • Ai represents a covalent bond or a straight or branched C ]- 15 alkylene optionally substituted by one or more hydroxy.
  • Typical examples of Ai include a covalent bond or optionally substituted methylene, (methyl)methylene, (dimethyl)methylene, ethylene and (methyl)propylene.
  • Ai include a covalent bond, -CH 2 -, -CH(OH)-, -C(C3 ⁇ 4) 2 -, C(CH 3 )(OH)-, -CH(OH)CH 2 - d , -CH 2 CH(OH)- d and -(CH 2 )2-C(CH3)(OH)- d , wherein d 20 represents the point of attachment to the Xi, X 2 , X 3 , X 4 containing ring.
  • Ai represents a covalent bond or -CH 2 -.
  • L include a covalent bond, -NH-, - N(CH 3 )-, -0-, b -NHCO- a , b - CONH- a , -C(O)-, b -N(CH 3 )S0 2 - a , b -NHS0 2 - a , b -S0 2 NH- a and -S(0) 2 .
  • Li represents a covalent bond.
  • Typical examples of -L] -Ai - include a covalent bond, Ci_ alkylene, -NR6-C 1.6 alkylene- , -0-Ci. 6 aIkylene-, -NR7CO-, -NR 7 CO-C
  • - include a covalent bond, -CH 2 -, -CH(OH)-,
  • R5 represents -(CH )) .30Ci-6 alkyl, or -Q3-C3-8 cycloalkyl, -Q 4 - monocyclic heteroaryl, -Q 5 -heterocyclyl or -Q 6 -monocyclic aryl; in which the C 3 .g cycloalkyl, heteroaryl, heterocyclyl and aryl are optionally substituted with one or more R9; wherein each R 9 may be the same or different; and when Ai represents optionally substituted C[. 6 alkylene, R 5 also represents H or Ci. 6 alkyl.
  • R 5 represents -Q -C 3 -8 cycloalkyl, -Q 4 -heteroaryl or -Q 5 - heterocyclyl; in which the C 3 .g cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with one or more R9, each of which may be the same or different.
  • Q 3 , Q 4 and Q 5 independently represent a covalent bond or methylene.
  • R5 Ca-gcycloalkyl, heteroaryl and heterocyclyl groups present when R 5 represents -Q3-C3.8 cycloalkyl, -Q4-heteroaryl or -Qs-heterocyclyl respectively include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyridazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, imidazolidinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, azepanyl, oxepanyl, octahydrocyclopenta[c]pyrrolyl, azabicyclo[3.2.1
  • R 5 is typically unsubstituted or mono- or di-substituted. R5 may also be tri-substituted. In one embodiment R 5 is unsubstituted. In another embodiment R 5 is monosubstituted. In another embodiment R 5 is disubstituted. In a further embodiment, R 5 is tri- substituted. In one embodiment, R9 represents halogen, C
  • . 6 alkyl, haloCi.6 alkyl, 0, -Co. 6 alkyl- OR10, -Co-6 alkyl-CORi i , -C 0 .
  • 6 alkyl-heteroaryl include monocyclic heteroaryl groups, including thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridinyl, triazinyl and tetrazinyl, each of which may be substituted with one or more Rp, each of which may be the same or different.
  • Ri typically represents Ci-6 alkyl, generally methyl.
  • R9 Co-6alkyl-heteroaryl examples include pyrimidin-2-yl, 3-methyl- 1 ,2,4- oxadiazolyl or pyrazol- l-yl.
  • R 5 examples include -(CH 2 ) 2 -OCH 3 , -(CH 2 ) 2 -OCH 2 CH 3 , -(CH 2 ) 3 -OCH 3 , cyclopropyl, 3-ethylcarboxylate-l -hydroxycyclobutan-l -yl, 3-methoxymethyl-l- hydroxycyclobutan-l -yl, cyclopentyl, 1 -hydroxycyclopentanl -yl, 2-(methoxy methyl)- 1- hydroxy-cyclopentan- 1 -yl, 4-methoxy- 1 -hydroxy-cycloheptan- 1 -yl, 1 - hydroxycyclohexan-l -yl, 4-methoxy-l -hydroxycyclohexan-l -yl, 3-methoxy- - hydroxycyclohexan- 1 -yl, 2-methoxy- 1 -hydroxycyclohexan- 1 -yl, 4-is
  • R 5 represents 4-methoxy-l -hydroxycyclohexan-l-yl, 4- ethoxy- 1 -hydroxycyclohexan- 1 -yl, 4-methoxy-4-methyl- 1 -hydroxycyclohexan- 1 -yl, 4- isopropoxy- 1 -hydroxycyclohexan- 1 -y 1, 4-methoxy- 1 -fluorocyclohexan-1 -y 1, 4- (methoxymethyl)-l-hydroxycyclohexan-l-yl, 4-hydroxytetrahydropyran-4-yl, 4- fluorotetrahydropyran-4-yl and l ,5-dimethyl-lH-pyrazol-4-yl.
  • represents a covalent bond or -CH 2 -
  • represents a covalent bond
  • R5 represents -Q 3 -C3 -8 cycloalkyl, -Q 4 -heteroaryl or -Q 5 -heterocyclyl; in which the C 3 - 8 cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with one or more R9, each of which may be the same or different.
  • Ai represents a covalent bond or -CH -
  • Li represents a covalent bond
  • R.5 represents an optionally substituted 5 to 6 membered mo a ring of formula Rs a :
  • R 5a represents a C3.8 cycloalkyl or heterocyclyl ring, each optionally substituted with one or more R9;
  • R9 a represents -C 0 . 6 alkyl-ORio or -F and * represents the point of attachment to A
  • In one embodiment represents optionally substituted cyclohexyl or optionally substituted tetrahydropyran-4-yl.
  • R 9a typically represents -OH, -OCH 3 , -C(CH 3 ) 2 OH, -CH 2 OCH 3 or -F.
  • R1 ⁇ 2 represents -OH or -F.
  • novel compounds include each of the novel compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts thereof.
  • the compound of formula (1) is selected from the group consisting of:
  • Particularly useful compounds in accordance with the invention include each of the compounds described in the accompanying examples, and pharmaceutically acceptable salts thereof.
  • compositions of this invention comprise any of the compounds of the first aspect of the present invention, or pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred.
  • the pharmaceutical W compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection 5 or infusion techniques.
  • compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • suitable dispersing or wetting agents such as, for example, Tween 80
  • suspending agents such as, for example, Tween 80
  • injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • a nontoxic parenterally-acceptable diluent or solvent for example, as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as that
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • flavouring and/or colouring agents may be added.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • the pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation.
  • compositions are 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 solubilising or dispersing agents known in the art.
  • the compounds of the present invention may be administered in a dose of around 1 to around 20,000 ⁇ g/kg per dose, depending on the condition to be treated or prevented, and the characteristics of the subject being administered with the compound. In many instances, the dose may be around 1 to around 1500 g/kg per dose.
  • the dosing regimen for a given compound could readily be determined by the skilled person having access to this disclosure.
  • the pharmaceutical composition of the invention additionally comprises one or more additional active pharmaceutical ingredients.
  • additional active ingredients may be agents known to the skilled person to be useful in the treatment or prevention of the diseases mentioned in the present disclosure, or comorbidities thereof.
  • the present invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in therapy.
  • the invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity.
  • the invention also provides a method of treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity, the method comprising the administration, to a subject in need of such treatment or prevention, of a therapeutically effective amount of a compound according to the first aspect of the invention, or a composition according to the second aspect.
  • the condition to be treated may be selected from sleep disorders (such as narcolepsy and hypersomnia), cognitive disorders (such as dementia and schizophrenia), attentional disorders (such as attention deficit hyperactivity disorder), neurodegenerative disorders (such as AD), schizophrenia, epilepsy, pain (such as neuropathic pain) and obesity.
  • sleep disorders such as narcolepsy and hypersomnia
  • cognitive disorders such as dementia and schizophrenia
  • attentional disorders such as attention deficit hyperactivity disorder
  • neurodegenerative disorders such as AD
  • schizophrenia epilepsy
  • pain such as neuropathic pain
  • condition may be selected from schizophrenia, Alzheimer's Disease (AD) and dementia.
  • condition may be selected from narcolepsy, pain and obesity.
  • the condition may be selected from narcolepsy, neuropathic pain and obesity.
  • the present invention provides the use of a compound according to the first aspect of the invention in the preparation of a medicament for the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity.
  • a condition whose development or symptoms are linked to histamine H3 receptor activity.
  • Such conditions may be selected from those described above.
  • compounds according to formula (1), wherein Ri represents H may be prepared by a process which comprises reacting a compound of formula (I) with a compound of formula (II):
  • R 2 , R 3) R4, R5, n, m, p, q, Ai, Li, X ⁇ , X 2 , X 3 and X 4 are as herein defined.
  • the reaction may be achieved by treatment with a suitable reducing agent, for example, sodium triacetoxyborohydride under acidic conditions e.g. in the presence of an organic acid such as acetic acid in a suitable solvent, such as a halogented hydrocarbon e.g. dichloromethane.
  • a suitable reducing agent for example, sodium triacetoxyborohydride under acidic conditions e.g. in the presence of an organic acid such as acetic acid in a suitable solvent, such as a halogented hydrocarbon e.g. dichloromethane.
  • compounds of formula (1) wherein Ri represents H, A] and Li each represent a covalent bond and R 5 represents an aryl or heteroaryl group, may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
  • , X 2 , X 3 and X4 are as herein defined, LGi represents a suitable leaving group, R 5a represents R 5 aryl or heteroaryl and -B(OZ) 2 represents boronic acid or a ester derivative thereof.
  • LGi typically represents halogen e.g. bromine.
  • B(OZ) 2 typically represents boronic acid or boronic acid pinacol ester.
  • reaction may conveniently be achieved by reaction in the presence of a suitable catalyst, such as palladium under basic conditions e.g. in the presence of an inorganic base such as sodium carbonate in an approriate solvent such as a cylic ether e.g. dioxane at elevated temperature.
  • a suitable catalyst such as palladium under basic conditions e.g. in the presence of an inorganic base such as sodium carbonate in an approriate solvent such as a cylic ether e.g. dioxane at elevated temperature.
  • R21 represents H or C1.3 alkyl
  • R 5 is as herein defined
  • Rs b represents an optionally substituted C 3- g cycloalkyl or optionally substituted heterocyclyl ring and * represents the point of attachment
  • R 2 i represents H or C1.3 alkyl
  • R 5 is as herein defined
  • R 5b represents an optionally substituted C3.8 cycloalkyl or optionally substituted heterocyclyl ring
  • * represents the point of attachment
  • the reaction may conveniently be effected by initial reaction of a compound (III) with alkyllithium in the presence of an acid e.g. a Lewis acid such as borontrifluoride, followed by treatment with an epoxide in an appropriate solvent e.g. a cyclic ether such as THF.
  • an acid e.g. a Lewis acid such as borontrifluoride
  • an epoxide in an appropriate solvent e.g. a cyclic ether such as THF.
  • compounds of formula (1) where L ( represents a covalent bond and R$ represents an oxadiazolyl group, may be prepared by conversion of an intermediate of formula (V):
  • Suitable conditions include treatment under basic conditions e.g. an inorganic base such as. sodium hydride, with acetamidoxime in an appropriate solvent e.g. THF.
  • Alternative conditions include treatment with acetylhydrazide in the presence of trimethylaluminium, followed by treatment with POCI3 under reflux.
  • compounds of formula (1) wherein A] represents C 1.6 alkylene, L] represents -O- and R5 represents H may be prepared by treating a compound of formula (V) with a suitable reducing agent e.g. lithium aluminium hydride in an appropriate solvent e.g. a cyclic ether such as THF.
  • a suitable reducing agent e.g. lithium aluminium hydride in an appropriate solvent e.g. a cyclic ether such as THF.
  • compounds of formula (1), wherein Li represents -NR 7 CO- may be prepared by process which comprises reacting a compound of formula (V) with R 5 R 7 NH. Suitable conditions include reaction in the presence of trimethylaluminium or bis(trimethylaluminum)-l,4-diazabicyclo[2.2.2]octane adduct in a suitable solvent such as a cyclic ether e.g. THF.
  • a suitable solvent such as a cyclic ether e.g. THF.
  • Compounds according to formula (1) wherein Li represents -CO- and R 5 represents N-linked heterocyclyl may be prepared in an analogous method.
  • an intermediate of formula (V) may be converted to the corresponding acid chloride using standard techniques such as reaction with LiOH followed by treatment with oxalyl chloride, which may then be reacted with R5R7NH in a suitable solvent e.g. a halogented hydrocarbon e.g. dichioromethane.
  • a suitable solvent e.g. a halogented hydrocarbon e.g. dichioromethane.
  • an intermediate of formula (I) may be prepared by a process which comprises reacting a compound of formula (IA) or (IB) with a compound of formula (VI):
  • R , R4, Rs, n, m, p, q, Ai, Lj, Xi, X 2 , X3 and X4 are as herein -defined and Hali represents halogen.
  • Ha typically represents bromine
  • the reaction is conventiently effected by the treatment under basic conditions e.g. an inorganic base such as potassium carbonate or sodium hydride in a suitable solvent such as a halogented hydrocarbon e.g. dichioromethane or an ether such as tetrahydrofuran. Reaction may be achieved at elevated temperature in the presence of catalyst such as a crown ether e.g. 18-crown-6 or 15-crown-5.
  • a suitable solvent such as a halogented hydrocarbon e.g. dichioromethane or an ether such as tetrahydrofuran.
  • Reaction may be achieved at elevated temperature in the presence of catalyst such as a crown ether e.g. 18-crown-6 or 15-crown-5.
  • a deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
  • the protecting groups may be removed using methods well known to those skilled in the ait.
  • the compounds of formula (1) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1 - hydroxy-2-napthoate (xinafoate), methanesulphonate or -toluenesulphonate salt.
  • an acid addition salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate,
  • Novel intermediates form a further aspect of the invention.
  • Spectra were recorded using a Bruker 400 Avance instrument fitted with a 5 mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2, 1 software. Alternatively, spectra were recorded on a JEOL ECX 300 instrument. Purity was assessed using UPLC with UV (photodiode array) detection over a wide range of wavelengths, normally 220-450 nm, using a Waters Acquity UPLC system.
  • UV photodiode array
  • Q A represents -C0 2 Ci. 6 alkyl, CN, C 1 -6 alkyl, halogen or -A r
  • Hal represents halogen
  • Q A represents -CO2CL6 alkyl.CN, 0,. 6 alkyl, halogen or
  • Hal represents halogen
  • Q A -C0 2 C 1-6 alkyl, C 1-6 alkyl, CN, halogen or -A r L r 5
  • Reagents and conditions a) Potassium carbonate, 18-crown-6, DCM, reflux; b) NaH, 15-crown-5, 50 °C, 1 h
  • Q A -C0 2 C 1-6 alkyl, C,. 6 alkyl, CN, halogen or -A L R 5
  • R 5a represents heteroaryl or aryl, each optionally substitued
  • Step b Example 11 N'-Acetyl-4-[(l -cyclobutylpiperidin-4-ylidene)methyl]benzohydrazide (Int 10) (67 mg, 0.2 mmol) was heated to reflux in POCl 3 (2 ml) for lh. The reaction was allowed to cool to r.t. and was then concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq. NaHC0 3 and the layers separated.
  • Step b Example 12 Prepared in an analogous manner to Intermediate 5 via Scheme 3, method A and Scheme 4 starting with [4-(5-methyl-l,2,4-oxadiazol-3-yl)benzyl](triphenyl) phosphonium bromide (Int 11) and using cyclobutanone in step b of Scheme 3.
  • Qc represents R5R7NH or R 5 N-linked optionally substituted heterocyclyl.
  • Qc represents R5R7NH or R5 N-Iinked optionally substituted heterocyclyl.
  • Reagents and conditions a) LiOH, EtOH, THF, H 2 0; b)i) (COCl) 2 , DMF, DCM ii) R5R7NH or R5 N-linked optionally substituted heterocyclyl, DCM
  • Qc represents -NR7-R5 or R5 N-linked optionally substituted heterocyclyl
  • Hal 2 represents CI or F
  • Reagents and conditions a) NaH, D F, R 5 -L
  • Intennediate 34 was prepared in an analogous manner to Intermediate 33 starting with reri-butyl 4-(4-(bromomethyl)benzylidene)piperi dine- 1 -carboxyl ate (Int 32) and using pyridazin-3(2H)-one. Used as isolated in next step. Step b Example 38
  • Reagents and conditions a) TBAF, THF; b) NaH, Mel, DMF or NaHMDS, Mel, DMF
  • tert-butyl 4-(4- ⁇ [(3 S)-3 - ⁇ [tert-butyl (dimethyl)silyl] oxy ⁇ -2-oxopyrrolidin- 1 - yl]methyl ⁇ benzylidene)piperidine- 1 -carboxylate Prepared in an analogous manner to Example 37 (NaH) via Scheme 21 starting from /er/-butyl 4-(4-(bromomethyl)ben2ylidene)piperidine-l-carboxylate (Int 32) and using (3S)-3- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ pyrrolidin-2-one.
  • Reagents and conditions a) LiOH, THF, MeOH, H 2 0; b) Me 2 NH.HCl, EDC.HCl, HOAt, DIPEA, DCM

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Abstract

La présente invention concerne des composés de formule (1) et leurs sels pharmaceutiquement acceptables, dans laquelle R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, m, n, p, q, Q1, Q2, Q3, Q4, Q5, Q6, X1, X2, X3, X4, A1 et L1 sont tels que définis dans la description, leurs procédés de préparation, des compositions pharmaceutiques les contenant et leur utilisation en thérapie.
PCT/GB2012/000673 2011-08-22 2012-08-21 Composés et leur utilisation pour le traitement de troubles associés au récepteur h3 de l'histamine WO2013027001A1 (fr)

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WO2018073602A1 (fr) 2016-10-20 2018-04-26 Almac Discovery Limited Dérivés de pipéridine utilisés comme inhibiteurs de la protéase spécifique de l'ubiquitine 7
US10933052B2 (en) 2017-11-17 2021-03-02 Cellix Bio Private Limited Compositions and methods for the treatment of eye disorders
CN113521048A (zh) * 2020-07-24 2021-10-22 中国医学科学院医药生物技术研究所 多取代苯类化合物在制备认知障碍性疾病的药物中的用途及结构和制备方法
WO2022113008A1 (fr) 2020-11-27 2022-06-02 Richter Gedeon Nyrt. Antagonistes/agonistes inverses du récepteur h3 de l'histamine pour le traitement d'un trouble du spectre autistique
RU2776482C2 (ru) * 2016-07-26 2022-07-21 Олмак Дискавери Лимитед Фармацевтические соединения
US11858910B2 (en) 2018-08-24 2024-01-02 Sunshine Lake Pharma Co., Ltd. Pyridinylmethylenepiperidine derivatives and uses thereof

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018020242A1 (fr) 2016-07-26 2018-02-01 Almac Discovery Limited Composés pharmaceutiques
CN109790146A (zh) * 2016-07-26 2019-05-21 阿尔麦克探索有限公司 药物化合物
US11053213B2 (en) * 2016-07-26 2021-07-06 Almac Discovery Limited Pharmaceutical compounds
RU2776482C2 (ru) * 2016-07-26 2022-07-21 Олмак Дискавери Лимитед Фармацевтические соединения
CN109790146B (zh) * 2016-07-26 2022-08-23 阿尔麦克探索有限公司 药物化合物
WO2018073602A1 (fr) 2016-10-20 2018-04-26 Almac Discovery Limited Dérivés de pipéridine utilisés comme inhibiteurs de la protéase spécifique de l'ubiquitine 7
EP4026832A1 (fr) 2016-10-20 2022-07-13 Almac Discovery Limited Dérivés de pipéridine comme inhibiteurs de la protéase 7 spécifique de l'ubiquitine
US10933052B2 (en) 2017-11-17 2021-03-02 Cellix Bio Private Limited Compositions and methods for the treatment of eye disorders
US11858910B2 (en) 2018-08-24 2024-01-02 Sunshine Lake Pharma Co., Ltd. Pyridinylmethylenepiperidine derivatives and uses thereof
CN113521048A (zh) * 2020-07-24 2021-10-22 中国医学科学院医药生物技术研究所 多取代苯类化合物在制备认知障碍性疾病的药物中的用途及结构和制备方法
CN113521048B (zh) * 2020-07-24 2023-04-14 中国医学科学院医药生物技术研究所 多取代苯类化合物在制备认知障碍性疾病的药物中的用途及结构和制备方法
WO2022113008A1 (fr) 2020-11-27 2022-06-02 Richter Gedeon Nyrt. Antagonistes/agonistes inverses du récepteur h3 de l'histamine pour le traitement d'un trouble du spectre autistique

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