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WO2011121309A1 - Dérivés phénylsulfonyle et leur utilisation comme antagonistes de l'histamine h3 - Google Patents

Dérivés phénylsulfonyle et leur utilisation comme antagonistes de l'histamine h3 Download PDF

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WO2011121309A1
WO2011121309A1 PCT/GB2011/000501 GB2011000501W WO2011121309A1 WO 2011121309 A1 WO2011121309 A1 WO 2011121309A1 GB 2011000501 W GB2011000501 W GB 2011000501W WO 2011121309 A1 WO2011121309 A1 WO 2011121309A1
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optionally substituted
methyl
alkyl
compound
cycloalkyl
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Parminder Kaur Pooni
Kevin John Merchant
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • 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
    • 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
    • C07D207/08—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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 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
    • C07D211/56—Nitrogen atoms
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to compounds and their uses, and in particular to compounds having a phenyl sulfonyl 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).
  • 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 GSK207040 / GSK334429 (13).
  • ABT-239 is currently being investigated for use in attention deficit hyperactivity disorder, Alzheimer's Disease and schizophrenia (14).
  • Patent Applications WO 2008/048609, WO 2008/005338 and WO 2007/075688 claim phenylsulfonyl and phenylsulfonamide derivatives as modulators of H3.
  • International Patent Application WO2010/026365 discloses a class of N-heterocyclic sulfonamide derivatives as N-myristoyl transferase inhibitors, in which the substituent "A" is an optionally substituted nitrogen-containing heteroaryl group.
  • International Patent Application WO2008/109154 discloses a number of bicyclic sulphonamide derivatives as chemokine receptor modulators.
  • W represents N or CH
  • R] represents H or C1.3 alkyl
  • R 2 represents a N-containing heterocyclyl ring or a -Ci -3 alkylene-N-containing heterocyclyl group, in which any N-containing heterocyclyl comprising or present on R 2 may be optionally substituted with one or more substituents independently selected from Ci-3 alkyl, C 3 . 6 cycloalkyl and -Ci-3 alkylene-C 3-6 cycloalkyl;
  • Ri and R 2 and the N atom to which they are attached may join to form an optionally substituted azacyclic ring, wherein the azacyclic ring may be optionally substituted with one or more substituents independently selected from Ci-3 alkyl and C 3-6 cycloalkyl;
  • R 3 represents H or Ci -3 alkyl
  • R4 represents optionally substituted C 3 . 6 cycloalkyl, heteroaryl or heterocyclyl; or R 3 and R4 and the N atom to which they are attached may join to form an optionally substituted heterocyclyl ring;
  • R4 or the heterocyclyl ring -NR 3 R4 may be optionally substituted with one or more Ci -3 alkyl groups; or a pharmaceutically acceptable salt thereof,
  • 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. Based on the high affinity for the 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 or two substituents, generally one substituent.
  • C x-y alkyl' refers to a linear or branched saturated hydrocarbon group containing from x to y carbon atoms.
  • C1.3 alkyl refers to a linear or branched saturated hydrocarbon group containing from 1 to 3 carbon atoms.
  • -3 alkyl groups include methyl, ethyl, n-propyl and isopropyl.
  • 'C1.3 alkylene' refers to a divalent hydrocarbon group obtained by removing one hydrogen atom from 'C x . y alkyl' above.
  • Examples of C 1.3 alkylene groups include methylene, ethylene and methylmethylene.
  • C x-y cycloalkyl' refers to a saturated monocyclic hydrocarbon ring of x to y carbon atoms.
  • C3-6 cycloalkyl refers to a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms.
  • Examples of C3 -6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • '-Ci-3 alkylene-C 3 - 6 cycloalkyl' refers to a C1-3 alkyl group as defined herein in which one of the H atoms is replaced with a C -g cycloalkyl ring as defined herein. Examples include -methyl-cyclopropyl, -ethyl-cyclopropyl, -methyl-cyclobutyl, -ethyl- cyclobutyl, -methyl-cyclopentyl and -ethyl-cyclopentyl.
  • heterocyclyl' refers to a 4-7 membered, non-aromatic monocyclic group which may be saturated or partially unsaturated, which contains 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur.
  • monocyclic groups include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydr
  • -containing heterocyclyl' refers to a 4-7 membered saturated monocyclic ring containing at least one, typically one or two, nitrogen atoms and optionally 1 to 4 other heteroatoms selected from oxygen and sulphur.
  • examples of such rings include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
  • any heterocyclyl ring may be attached to the rest of the molecule through any available C or N atom.
  • 'azacyclic ring' refers to a 4 to 7 membered, non-aromatic monocyclic or bridged saturated or partially unsaturated ring containing at least one nitrogen atom, typically one or two nitrogen atoms.
  • examples of such rings include pyrrolidinyl, azetidinyl, piperidinyl, azepanyl, piperazinyl and 2,5-diazabicyclo[2.2.1]heptanyl.
  • '-C 1-3 alkylene-N-containing heterocyclyP refers to a C1-3 alkyl group as defined herein in which one of the H atoms is replaced with a N-containing heterocyclyl ring as defined herein.
  • Examples include -methyl-pyrrolidinyl, -ethyl-pyrrolidinyl, -methyl- piperidinyl, -ethyl-piperidinyl, -mefhyl-morpholinyl and - ethyl-morpholinyl.
  • heteroaryl' refers to a 5-6 membered monocyclic aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulphur.
  • monocyclic aromatic groups include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like.
  • any heteroaryl ring may be attached to the rest of the molecule through any available C or N atom.
  • the nitrogen atom may be oxidized.
  • pyridyl as the 'heteroaryl' may be its N-oxide.
  • 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).
  • solvates may be formed with common organic solvents, including but not limited to, 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.
  • General methods for the preparation of salts are well known to the person skilled in the art. Pharmaceutical acceptability of salts will depend on a variety of factors, including formulation processing characteristics and in vivo behaviour, and the skilled person would readily be able to assess such factors having regard to the present disclosure.
  • 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.
  • the invention relates to the individual tautomers in isolation, and to mixtures of the tautomers in all proportions.
  • 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.
  • radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
  • W represents N. In other embodiments W represents CH. W preferably represents N.
  • Ri represents H. In other embodiments represents Ci -3 alkyl, typically methyl. Suitably Ri represents H or methyl.
  • any N-containing heterocyclyl comprising or present on R 2 may suitably be unsubstituted or mono- or di-substituted, typically unsubstituted or monosubstituted.
  • any N-containing heterocyclyl comprising or present on R 2 is linked to the rest of the compound of formula (1) through a C atom.
  • the point of attachment to the rest of the compound of formula (1) may represent a chiral centre.
  • the chiral centre is racemic.
  • the chiral centre is the (R) enantiomer.
  • the chiral centre is the (S) enantiomer.
  • R 2 include optionally substituted pyrrolidinyl, piperidinyl,-methyl- pyrrolidinyl or -methyl-morpholinyl, wherein the pyrrolidinyl, piperidinyl and morpholinyl are linked to the rest of the compound of formula (1) through a C atom.
  • Suitable substituents that may be present on any N-containing heterocyclyl comprising or present on R 2 include methyl, ethyl, isopropyl, cyclobutyl and -methyl-cyclopropyl.
  • R 2 examples include l-methylpiperidin-4-yl, l-ethylpiperidin-4-yl, 1- ethylpiperidin-3-yl, l -ethylpyrrolidin-3-yl, l-isopropylpyrrolidin-3-yl, 1- cyclobutylpyrrolidin-3-yl, l-(cyclopropylmethyl)pyrrolidin-3-yl, (1 -methylpyrrolidin-3- yl)methyl and (4-ethylmo holin-2-yl)methyl.
  • R 2 represents an optionally substituted N-containing heterocyclyl ring linked to the rest of the compound of formula (1) through a C atom.
  • R 2 represents optionally substituted C-linked pyrrolidinyl, preferably optionally substituted pyrrolidin-3-yl. In further preferred embodiments R 2 represents l-ethylpyrrolidin-3-yl.
  • W represents N
  • Ri and R 2 and the N atom to which they are attached are joined to form an optionally substituted piperazinyl or C 1-3 alkylene bridged piperazinyl ring; in which the piperazinyl ring may be optionally substituted with one or more substituents independently selected from Ci -3 alkyl and C 3-6 cycloalkyl.
  • Suitable examples of -NR t R 2 rings include optionally substituted piperazinyl or 2,5- diazabicylo[2.2.1]heptan-2-yl.
  • Suitable optional substituents include ethyl and cyclopentyl.
  • Specific examples of -NRiR 2 rings include 4-cyclopentylpiperazin-l-yl and 5-ethyl-2,5-diazabicylo[2.2.1]heptan-2-yl.
  • R 3 represents H. In other embodiments R 3 represents C 1.3 alkyl, typically methyl. Suitably R 3 represents H or methyl.
  • R include optionally substituted cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl or pyridinyl.
  • R4 is typically unsubstituted. When R4 is substituted, a preferred substituent is methyl.
  • R 3 represents H or d -3 alkyl and R4 represents optionally substituted C 3-6 cycloalkyl or heterocyclyl.
  • R4 represents cyclopentyl, tetrahydrofuranyl or tetrahydropyranyl. In certain particular embodiments R4 represents cyclopentyl. In other particular embodiments R 4 represents tetrahydrofuranyl. In further particular embodiments R4 represents tetrahydropyranyl.
  • R3 and R4 and the N atom to which they are attached are joined to form an optionally substituted pyrrolidinyl ring, typically 2-methylpyrrolidin-l- yi.
  • Particularly useful compounds in accordance with the invention include each of the compounds described in the accompanying examples, and pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a compound according to the first aspect of the invention, together with one or more pharmaceutically acceptable excipients, wherein the provisos to the first aspect do not apply. In an embodiment, the said provisos do apply.
  • 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,
  • 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 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, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical 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.
  • the sterile 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.
  • suitable 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 described in Ph. Helv, or a similar alcohol.
  • 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 case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or 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.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such 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, wherein the provisos to the first aspect do not apply. In an embodiment, the said provisos do apply.
  • 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, wherein the provisos to the first aspect do not apply. In an embodiment, the said provisos do apply.
  • 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, wherein the provisos to the first aspect do not apply. In an embodiment, the said provisos do apply.
  • the condition is a disorder of the central nervous system.
  • 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
  • obesity such as narcolepsy 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, wherein the provisos to the first aspect do not apply.
  • a condition whose development or symptoms are linked to histamine H3 receptor activity
  • the provisos to the first aspect do not apply.
  • Such conditions may be selected from those described above.
  • the said provisos do apply.
  • the symbols Ri, R 2 , R 3 , Rj and W when used in the formulae depicted are to be understood to represent those groups as described above in relation to formula (1) unless otherwise indicated.
  • the methods of addition and removal of such protecting groups are those which would conventionally be used in relation to the particular molecule-type or group being protected, for example the methods described in standard works of reference in synthetic methodology, such as Kocienski (2004) Protecting Groups. 4th Edn. Georg Thieme Verlag.
  • 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 compounds of formula (1), where W represents N may be prepared by a process which comprises reacting a compound of formula (iii) with a compound of formula (iv):
  • Ri, R 2 , R 3 and R4 are as defined above and Wi represents N.
  • the reaction may conveniently be effected at ambient temperature by reaction with a reducing agent, such as sodium borohydride, in a suitable solvent e.g. tetrahydrofuran.
  • the starting material of formula (iii) may be prepared by a process which comprises reacting commercially available 4-formylbenzene- 1 -sulfonyl chloride of formula (i) with a compound of formula (ii):
  • the reaction may conveniently be effected at ambient temperature in a suitable solvent such as an halogenated hydrocarbon e.g. dichloromethane in the presence of an organic base such as triethylamine.
  • a suitable solvent such as an halogenated hydrocarbon e.g. dichloromethane
  • an organic base such as triethylamine.
  • the compounds of formula (1), where W represents CH may be prepared by a process which comprises reacting a compound of formula (x) with a compound of formula (xi):
  • Ri and R4 are as herein defined, W 2 represents CH, R 2a represents optionally substituted heterocyclyl or C ( - 3 alkylene-heterocyclyl and PG represents a protecting group.
  • the protecting group is typically trifiuoromethylacetyl.
  • the reaction may be conveniently achieved by treatment with a suitable base e.g. potassium rt-butoxide in a suitable solvent such as DMSO at elevated temperature under microwave conditions.
  • a suitable base e.g. potassium rt-butoxide
  • a suitable solvent such as DMSO
  • the resulting material may then be deprotected using standard conditions e.g. heating in an alcoholic solvent such as ethanol in the presence of an inorganic base e.g. sodium hydroxide, to give a compound of formula (1).
  • the starting materials of formula (x) and (xi) may be prepared using methods known to those skilled in the art or methods analogous to those described in the Examples.
  • Novel intermediates form a further aspect of the invention.
  • Nuclear magnetic resonance (NMR) spectra were recorded at 400MHz; the chemical shifts ( ⁇ ) are reported in parts per million. Spectra were recorded using a Bruker 400 Avance instrument fitted with a 5mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2.1 software.
  • Preparative HPLC was performed using an Agilent Technologies 1100 Series system typically using Waters 19mm id x 100mm long CI 8 columns such as XBridge or SunFire 5 ⁇ materials at room temperature.
  • Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.1% formic acid or 0.1% ammonia.
  • Room temperature in the following schemes means the temperature ranging from 20°C to 25°C.
  • Schemes 1.1 and 1.2 serve to illustrate the methodologies that may be employed to synthesize the exemplified compounds of formula (1) and intermediates used in the synthesis of the exemplified compounds of formula (1).
  • W 2 represents CH
  • R 2a represents optionally substituted heterocyclyl or Ci. 3 alkylene-heterocyclyl and R ⁇ and R are as herein defined.
  • Examples 2 to 20 were prepared in a similar manner to the methodology described for Example 1 and according to Scheme 1, using either commercially available or known amines for both step a and step b. Where known amines have been used the CAS registry number is quoted.
  • step a Using l-ethyl-3-aminopiperidine (CAS RN 6789-94-2) in step a and cyclopentylamine in step b.
  • step a Using 1-(4- ⁇ ⁇ ⁇ -2 ⁇ 1 ⁇ 6 ⁇ 3 ⁇ 3! ⁇ (CAS RN 141814-56-4) in step a and cyclopentylamine in step b.
  • Example 8 was prepared using (3S)-l-ethyl-3-aminopyrrolidine dihydrochloride (Int 2) in step a and cyclopentylamine in step b.
  • Example 16 was prepared using l-cyclobutylpyrrolidin-3-amine (Int 3) in step a and cyclopentylamine in step b.
  • step b Using l-ethyl-3-aminopyrrolidine in step a and 3-aminopyridine (CAS RN 462-08-8) in step b.
  • step b Using l-ethyl-3-aminopyrrolidine in step a and tetrahydro-2H-pyran-4-amine (CAS RN: 38041-19-9) in step b.
  • step b Using l -ethyl-3-aminopyrrolidine in step a and 2-methylpyrrolidine (CAS RN: 41720-98- 3) in step b.
  • reaction mixture was diluted with ethanol (10 mL) and 2M NaOH (5 mL) was added and the reaction was heated to reflux for 1 hour.
  • the reaction mixture was extracted with ethyl acetate and washed with 5% aqueous ammonia (x 3). The organic layer was dried over magnesium sulphate and evaporated.
  • the residue was purified on Biotage silica gel column eluting 15% (10% methanol/ammonia) in DCM to yield N-(4-((l- (cyclopropylmethyl)pyrrolidin-3-yl)methylsulfonyl)benzyl)cyclopentanamine (0.04 g, 0.120 mmol, 1 1.95 % yield).
  • the ability of compounds to bind to the H3 receptor was determined by measuring the reduction in tritiated N-a-methyl-histamine ( 3 H-NaMH) binding in a competition binding assay. Changes in the levels of bound radio-label were monitored by scintillation counting with a Trilux Microbeta (Perkin Elmer).
  • Membranes were prepared from CHO- 1 cells stably expressing human H3 receptor; routinely grown as monolayers in Ham's F12 medium (Invitrogen) supplemented with 10% Foetal Clone III (Hyclone), 500 ⁇ g/mL G418 (Invitrogen), 5 ⁇ g/mL blasticidine S (Invivogen) and 50 ⁇ g/mL Gentamicin (Sigma) in 5% C0 2 at 37°C. Cells were grown to 80-95% confluency, rinsed once with lx PBS (Invitrogen) and detached by incubating with lx PBS containing 0.02% EDTA (Sigma) for 10 m at room temperature.
  • Cells were collected by centrifugation at 900 xg, 4°C for 10 min. Cells were rinsed once with lx PBS and re-suspended in ice cold homogenisation buffer (50mM Tris-HCl (pH 7.4), 2.5mM EDTA, 5mM MgCl 2 , 200mM Sucrose) at lxlO 7 cells/mL and kept on ice. Cells were homogenised on ice and debris removed by centrifugation at 500 x g, 4°C for 5 min. The resulting supernatant was centrifuged at 75,600 xg, 4°C for 60 min. Membranes were suspended in homogenisation buffer, protein concentration was determined (BCA Protein Assay kit (Pierce)), diluted to 2.2 mg/mL, dispensed into lmL aliquots and stored at -80 °C.
  • BCA Protein Assay kit Pieris
  • Membranes were thawed on ice, sonicated with 4 cycles of 20 pulses (50% amplitude, 0.5 pulse) (UP200S Hielscher) on ice, diluted in assay buffer (50mM Tris-HCl (pH7.4), 5mM MgCl 2 ) to 62.5 ⁇ g/mL. Compound was serially diluted in DMSO before being diluted 1 : 10 with assay buffer. 5 ⁇ g of membrane in 80 ⁇ of assay buffer was added per well of a 96 well polystyrene plate (Corning). 10 ⁇ of compound was added per well.
  • the assay was initiated by the addition of 10 ⁇ of 20nM H-NaMH per well and incubated for one h at room temperature with shaking. Total binding was determined in the presence of 1% DMSO and non-specific binding was determined by the inclusion of 1 ⁇ R-a-methyl- histamine (RaMH). Incubations were then filtered through filtermat A (Perkin Elmer) and washed three times with assay buffer. Filtermats were dried at 42°C for two h, scintillant added and the level of bound radioactivity determined.
  • IC50 values for compounds were determined from seven point log scale dose-response studies and represent the concentration of compound required to inhibit 50% of the specific binding of 2nM 3 H-NaMH (difference between total and non-specific binding). Curves were generated using the average of duplicate wells for each data point and analyzed using nonlinear regression of sigmoidal dose response (variable slope).
  • the functional activity of compounds at the H3 receptor was determined by measuring changes in the level of intracellular cAMP using a cAMP response element driven luciferase reporter assay. The changes in luciferase expression were monitored by a luminescence plate reader, Analyst HT (MDS Analytical). Increases in intracellular cAMP were readily detected upon activation of protein kinase A by forskolin (Sigma) and suppression of this response observed with the application of the H3 receptor agonist RaMH (Sigma).
  • CHO(dhfr + )-cre-luc cells stably expressing human H3 receptor were routinely grown as monolayers in Minimal Essential Medium a (MEMa) (Invitrogen) supplemented with 10% dialysed FBS (Hyclone), in 5% C0 2 at 37°C. 48 h prior to assay, cells were seeded in clear-base white walled 384-well plates (Corning) at a density of 5000 cells/well. On the day of assay, growth media was removed and replaced with 15 ⁇ of assay buffer (MEMa, 5 mg/mL fatty acid free BSA (Sigma)) per well. Cells were then incubated for 30 m at 37°C, 5% C0 2 .
  • MEMa Minimal Essential Medium a
  • FBS dialysed FBS
  • Compound was serially diluted in DMSO before being diluted 1 : 10 with assay buffer.
  • 2.5 ⁇ of compound diluted in assay buffer was added and cells incubated for 5 m at 37°C, 5% C0 2 .
  • 2.5 ⁇ of each reagent was then added in the following order: RaMH (10 nM), isobutylmethylxanthine (l-methyl-3-(2-methylpropyl)- 7H-purine-2,6-dione; IBMX) (500 ⁇ ) (Sigma) and forskolin (1 ⁇ ).
  • Cells were then incubated for 90 m at 37°C, 5% C0 2 , followed by 30 m at room temperature.
  • 25 ⁇ of Steadylite reagent Perkin Elmer was added, plates were sealed and placed on a shaker for 5 min. The level of light output to determine the level of luciferase expression was then measured.
  • IC 5 o values for compounds were determined from ten point half log scale dose-response studies and represent the concentration of compound required to prevent 50% inhibition of forskolin stimulated cells in the presence of RotMH alone. Curves were generated using the average of duplicate wells for each data point and analyzed using nonlinear regression of four parameter dose response.
  • Witkin JM Nelson DL. Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system. Pharmacol. Ther. 2004; 103: 1-20

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Abstract

L'invention concerne un composé répondant à la formule (1) dans laquelle W représente N ou CH ; R1 représente H ou un groupe alkyle en C1-3 ; R2 représente un cycle hétérocyclyle contenant N ou un groupe hétérocyclyle contant un groupe alkylène en C1-3 -N ; dans lequel chaque groupe hétérocyclyle contenant N constituant ou présent sur R2 peut être éventuellement substitué ; ou, lorsque W représente N, R1 et R2 et l'atome de N auquel ils sont attachés peuvent être joints pour former un cycle azacylique éventuellement substitué, le cycle azacylique pouvant être éventuellement substitué ; R3 représente H ou un groupe alkyle en C1-3 ; R4 représente un groupe cycloalkyle, hétéroaryle ou hétérocyclyle en C3-6 éventuellement substitué ; ou R3 et R4 et l'atome de N auquel ils sont attachés peuvent être joints pour former un cycle hétérocyclyle éventuellement substitué ; ou l'un de ses sels pharmaceutiquement acceptable. On a découvert que les composés de l'invention modulaient le récepteur d'histamine H3.
PCT/GB2011/000501 2010-03-31 2011-03-31 Dérivés phénylsulfonyle et leur utilisation comme antagonistes de l'histamine h3 Ceased WO2011121309A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005173A1 (fr) * 1990-09-25 1992-04-02 Agouron Pharmaceuticals, Inc. Composes tricycliques substitues
WO1993013079A1 (fr) 1991-12-20 1993-07-08 Agouron Pharmaceuticals, Inc. Quinazolines anti-folates
US20020147192A1 (en) * 2000-09-15 2002-10-10 Gary Bridger Chemokine receptor binding heterocyclic compounds
WO2004089410A1 (fr) 2003-04-03 2004-10-21 Kyowa Hakko Kogyo Co., Ltd. Medicament preventif ou curatif pour les douleurs nevropathiques
WO2007075688A2 (fr) 2005-12-21 2007-07-05 Schering Corporation Derives substitues de l'aniline utilisables en tant qu'antagonistes de l'histamine h3
WO2008005338A1 (fr) 2006-06-29 2008-01-10 Arena Pharmaceuticals, Inc. Modulateurs du récepteur h3 de l'histamine utiles dans le traitement de troubles liés audit récepteur
WO2008048609A1 (fr) 2006-10-17 2008-04-24 Arena Pharmaceuticals, Inc. Modulateurs biphénylsulfonyle et de phényl-hétérorarylsulfonyle du recepteur h3 de l'histamine utiles pour le traitement de troubles associés à celui-ci
WO2008109154A1 (fr) 2007-03-08 2008-09-12 Altiris Therapeutics, Inc. Modulateurs de récepteur de chimiokine
WO2010026365A1 (fr) 2008-09-02 2010-03-11 University Of Dundee Inhibiteurs de n-myristoyl-transférase

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005173A1 (fr) * 1990-09-25 1992-04-02 Agouron Pharmaceuticals, Inc. Composes tricycliques substitues
WO1993013079A1 (fr) 1991-12-20 1993-07-08 Agouron Pharmaceuticals, Inc. Quinazolines anti-folates
US20020147192A1 (en) * 2000-09-15 2002-10-10 Gary Bridger Chemokine receptor binding heterocyclic compounds
WO2004089410A1 (fr) 2003-04-03 2004-10-21 Kyowa Hakko Kogyo Co., Ltd. Medicament preventif ou curatif pour les douleurs nevropathiques
WO2007075688A2 (fr) 2005-12-21 2007-07-05 Schering Corporation Derives substitues de l'aniline utilisables en tant qu'antagonistes de l'histamine h3
WO2008005338A1 (fr) 2006-06-29 2008-01-10 Arena Pharmaceuticals, Inc. Modulateurs du récepteur h3 de l'histamine utiles dans le traitement de troubles liés audit récepteur
WO2008048609A1 (fr) 2006-10-17 2008-04-24 Arena Pharmaceuticals, Inc. Modulateurs biphénylsulfonyle et de phényl-hétérorarylsulfonyle du recepteur h3 de l'histamine utiles pour le traitement de troubles associés à celui-ci
WO2008109154A1 (fr) 2007-03-08 2008-09-12 Altiris Therapeutics, Inc. Modulateurs de récepteur de chimiokine
WO2010026365A1 (fr) 2008-09-02 2010-03-11 University Of Dundee Inhibiteurs de n-myristoyl-transférase

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
A. A. HANCOCK, BIOCHEM. PHARMACOL., vol. 71, 2006, pages 1103
A. A. HANCOCK, M. E. BRUNE, EXPERT OPIN. INVESTIG. DRUGS, vol. 14, 2005, pages 223
D. FARZIN, L. ASGHARI, M. NOWROUZI, PHARMACOL. BIOCHEM. BEHAV., vol. 72, 2002, pages 751
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 13 September 2009 (2009-09-13), XP002653487, retrieved from STN Database accession no. 1183355-02-3 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 14 September 2009 (2009-09-14), XP002653486, retrieved from STN Database accession no. 1184185-62-3 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 15 September 2009 (2009-09-15), XP002639709, retrieved from STN Database accession no. 1184647-93-5 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2 September 2009 (2009-09-02), XP002653489, retrieved from STN Database accession no. 1179212-60-2 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 28 February 2007 (2007-02-28), XP002639710, retrieved from STN Database accession no. 923887-86-9 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 3 September 2009 (2009-09-03), XP002653488, retrieved from STN Database accession no. 1179594-96-7 *
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 31 August 2009 (2009-08-31), XP002653490, retrieved from STN Database accession no. 1178286-59-3 *
ESBENSHADE T.A ET AL., J. PHARMACOL. EXP. THER., vol. 313, no. 1, 2005, pages 165 - 75
ESBENSHADE T.A. ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 68, 2004, pages 933 - 945
J.-M. ARRANG, M. GARBARG, J.-C. SCHWARTZ, NATURE, vol. 302, 1983, pages 832
MEDHURST A.D. ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 73, 2007, pages 1182 - 94
MONTI J.M ET AL.: "Effect of Selective activation or blockade of the hitamine H3 receptor on sleep and wakefulness", EUR. J. PHARMACOL., vol. 205, 1991, pages 283 - 287
MORIMOTO T, YAMAMOTO Y, YAMATODANI A.: "Leptin facilitates histamine release from the hypothalamus in rats", BRAIN RES., vol. 868, 2000, pages 367 - 9, XP027200612
PASSANI MB, LIN J-S, HANCOCK A, CROCHET S, BLANDINA P.: "The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders", TRENDS PHARMACOL. SCI., vol. 25, 2004, pages 618 - 25, XP004629292, DOI: doi:10.1016/j.tips.2004.10.003
S. J. HILL, C. GANELLIN, H. TIMMERMANS, J. C. SCHWARTZ, N. SHANKLEY, J. M. YOUNG, W. SCHUNACK, R. LEVI, H. L. HAAS., PHARMACOL. REV., vol. 49, 1997, pages 253
T. W. LOVENBERG, B. L. ROLAND, S. J. WILSON, X. JIANG, J. PYATI, A. HUVAR, M. R. JACKSON, M. G. ERLANDER, MOL. PHARMACOL., vol. 55, 1999, pages 1101
WITKIN JM, NELSON DL.: "Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system", PHARMACOL. THER., vol. 103, 2004, pages 1 - 20, XP002439416, DOI: doi:10.1016/j.pharmthera.2004.05.001

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