WO2007138431A2 - Antagonistes de l'éther histamine-3 azabicyclique - Google Patents

Antagonistes de l'éther histamine-3 azabicyclique Download PDF

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Publication number
WO2007138431A2
WO2007138431A2 PCT/IB2007/001367 IB2007001367W WO2007138431A2 WO 2007138431 A2 WO2007138431 A2 WO 2007138431A2 IB 2007001367 W IB2007001367 W IB 2007001367W WO 2007138431 A2 WO2007138431 A2 WO 2007138431A2
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WIPO (PCT)
Prior art keywords
methyl
octahydro
lsopropyl
azabicyclo
pyridin
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PCT/IB2007/001367
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English (en)
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WO2007138431A3 (fr
Inventor
Helen Berke
Harry Ralph Howard, Jr.
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Pfizer Products Inc.
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Publication of WO2007138431A2 publication Critical patent/WO2007138431A2/fr
Publication of WO2007138431A3 publication Critical patent/WO2007138431A3/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
    • C07D401/12—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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention is directed to compounds of formula I described herein, to a pharmaceutical composition comprising such compounds, and to methods of treatment of disorders or conditions that may be treated by antagonizing histamine-3 (H 3 ) receptors using such compounds.
  • the histamine-3 (H 3 ) receptor antagonists of the invention are useful for treating anxiety disorders, including, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder; mood adjustment disorders, including depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood; age-associated learning and mental disorders, including Alzheimer's disease; attention adjustment disorders, such as attention-deficit disorders, or other cognitive disorders due to general medical conditions; attention-deficit hyperactivity disorder; psychotic disorders including schizoaffective disorders and schizophrenia; sleep disorders, including narcolepsy and enuresis; obesity; dizziness, epilepsy, and motion sickness.
  • the H 3 receptor antagonists of the invention are also useful for treating, for example, allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the Gl tract, hyper- and hypo-motility and acidic secretion of the gastrointestinal tract, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), attention deficit hyperactivity disorder ADHD), hypo- and hyper-activity of the central nervous system (for example, agitation and depression), and other CNS disorders (such as schizophrenia and migraine).
  • allergy allergy-induced airway responses
  • congestion e.g., nasal congestion
  • hypotension e.g., cardiovascular disease
  • diseases of the Gl tract e.g., hyper- and hypo-motility and acidic secretion of the gastrointestinal tract
  • sleeping disorders e.g., hypersomnia, somnolence, and narcolepsy
  • attention deficit hyperactivity disorder ADHD e.g., hypo- and hyper
  • Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) that are commonly treated with antagonists of histamine or "antihistamines.” It has also been established that histamine receptors exist in at least two distinct types, referred to as H 1 and H 2 receptors.
  • H 3 receptor A third histamine receptor (H 3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H 3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature. (1983) 302, S32- 837).
  • the existence of the H 3 receptor has been confirmed by the development of selective H 3 receptor agonists and antagonists (Nature, (1987), 327, 117-123) and has subsequently been shown to regulate the release of the neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
  • H 3 histamine-3
  • the H 3 ligand may be an antagonist, agonist or partial agonist, see: (Imamura et al., Circulation Res., (1996) 78, 475-481 ); (Imamura et al., Circ. Res.. (1996) 78, 863-869); (Lin et al., Brain Res. (1990) 523, 325-330); (Monti et al., Neuropsvchopharmacology (1996) 15, 31-35); (Sakai et al., Life Sci.
  • Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer's disease and attention deficit hyperactivity disorder; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma," medullary thyroid carcinoma and melanoma; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere's disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.
  • cardiovascular disorders such as acute myocardial infarction
  • memory processes dementia and cognition disorders such as Alzheimer's disease and attention deficit hyperactivity disorder
  • neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions
  • cancer such as cutaneous carcinoma," medullary thyroid carcinoma and melanoma
  • respiratory disorders such as asthma
  • sleep disorders such as narcolepsy
  • vestibular dysfunction such as Meniere's disease
  • gastrointestinal disorders inflammation
  • H 3 receptor antagonists have also been previously described in, for example, WO 03/050099, WO 02/0769252, and WO 02/12224.
  • the histamine H 3 receptor (H 3 R) regulates the release of histamine and other neurotransmitters, including serotonin and acetylcholine.
  • H 3 R is relatively neuron specific and inhibits the release of certain monoamines such as histamine.
  • Selective antagonism of H 3 R raises brain histamine levels and inhibits such activities as food consumption while minimizing non-specific peripheral consequences.
  • Antagonists of the receptor increase synthesis and release of cerebral histamine and other monoamines. By this mechanism, they induce a prolonged wakefulness, improved cognitive function, reduction in food intake and normalization of vestibular reflexes.
  • EP 978512 and EP 982300 disclose non-imidazole alkyamines as histamine H 3 receptor antagonists.
  • WO 02/12190 Organic McNeil Pharmaceuticals
  • EP 1275647 Les Laboratoires Servier
  • novel octahydro-2H-pyrido[1 ,2-a]pyrazines that are selective H 3 receptor antagonists.
  • Other receptor antagonists have been described in WO 02/32893 and WO 02/06233.
  • the present invention is directed to histamine-3 (H 3 ) receptor antagonists useful for treating the conditions listed in the preceding paragraphs.
  • the compounds of this invention are highly selective for the H 3 receptor (vs.
  • the compounds of this invention selectively distinguish H 3 R from the other receptor subtypes H-iR, H 2 R.
  • novel compounds that interact with the histamine H 3 receptor would be a highly desirable contribution to the art.
  • the present invention provides such a contribution -A-
  • L is CR 3 R 4 ;
  • X is a halogen, CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 thioalkyl;
  • E is a 7-13 member bicyclic heterocycloalkyl group, containing at least one secondary nitrogen atom and up to 3 additional heteroatoms selected from N, O and S, up to two carbon-carbon double bonds and optionally substituted at available C and N positions with hydrogen, OH, CN, CF 3 , C 1 -C 6 alkyl, aryl, (C 1 -C 6 alkyl)-aryl or heteroaryl;
  • R 1 and R 2 are independently selected from hydrogen, C 1 -C 6 alkyl, aryl, (C 1 -C 6 alkyl)- aryl, heteroaryl, (C 1 -C 6 alkyl)-heteroaryl;
  • R 3 , R 4 , R 5 and R 6 are independently selected from C 1 -C 6 alkyl, optionally substituted at available positions with H, OH, F or C 1 -C 6 alkyl; or
  • R 3 and R 4 together with the carbon to which they are attached form a 3-7 member carbocyclic ring;
  • m is O, 1 , 2 or 3; and
  • n is 0, 1 , 2, 3 or 4.
  • alkyl refers to straight or branched chains of carbon atoms.
  • exemplary alkyl groups are C 1 -C 6 alkyl groups which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like, including all regioisomeric forms thereof, and straight and branched chain forms thereof.
  • alkyl is also used to denote straight or branched chains of carbon atoms having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl, and the like, as well as straight or branched chains of carbon atoms having one or more carbon-carbon triple bonds, such as ethynyl, propargyl, butynyl, and the like.
  • aryl denotes a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like.
  • alkoxy and aryloxy denote “O-alkyl” and "O-aryl", respectively.
  • cycloalkyl is also intended to denote a cyclic group comprising at least two fused rings, such as adamantanyl, decahydronaphthalinyl, norbornanyl, where the cyclic group may also have one or more carbon-carbon double bonds in one or both rings, such as in bicyclo[4.3.0]nona-3,6(1)-dienyl, dicyclopentadienyl, 1 ,2,3,4-tetrahydronaphthalinyl (tetralinyl), indenyl, and the like.
  • halogen represents chloro, fluoro, bromo, and iodo.
  • heteroaryl denotes a monocyclic or bicyclic aromatic group wherein one or more carbon atoms are replaced with heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Preferred heteroaryl groups are five- to fourteen- member rings that contain from one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur.
  • heteroaryl groups include benzo[b]thienyl, chromenyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiazolyl, thienyl, triazinyl, triazolyl, and xanthenyl.
  • heterocycloalkyl denotes a cycloalkyl system, wherein “cycloalkyl” is defined above, in which one or more of the ring carbon atoms are replaced with a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur.
  • heterocycloalkyl groups examples include azabicycloheptanyl, azetidinyl, benzazepinyl, 1 ,3- dihydroisoindolyl, indolinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, and, tetrahydro-2H-1 ,4-thiazinyl.
  • a cyclic group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended.
  • the term "pyridyl” includes 2-, 3-, or 4-pyridyl
  • thienyl includes 2- or 3-thienyl.
  • C 0 -C/ includes the embodiment where there are no carbons in a chain.
  • the groups "C 3 -C 7 cycloalkyl-C 0 -C 4 alkyl,” “C 6 -Ci 4 aryl-C 0 -C 4 alkyl,” “5-10- membered heteroaryl-C 0 -C 4 alkyl,” and "C 6 -Ci 4 aryl-C 0 -C 4 alkylene-O-C 0 -C 4 alkyl" include C 3 -
  • CrC 4 dialkylamino refers to a dialkylamino group in which each alkyl group is independently a C r C 4 alkyl group.
  • This invention is also directed to: a pharmaceutical composition for treating, for example, a disorder or condition that may be treated by antagonizing histamine-3 (H 3 ) receptors, the composition comprising a compound of formula I as described above, and optionally a pharmaceutically acceptable carrier; a method of treatment of a disorder or condition that may be treated by antagonizing histamine-3 (H 3 ) receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above; and a pharmaceutical composition for treating, for example, a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer's disease, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy-induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastrointestinal
  • This invention is also directed to a method of treatment of a disorder or condition selected from the group consisting of the disorders or conditions listed in the preceding paragraph, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above.
  • the histamine-3 (H 3 ) receptor antagonists of the invention are useful for treating, in particular, ADD, ADHD, obesity, anxiety disorders and respiratory diseases.
  • Respiratory diseases that may be treated by the present invention include adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis.
  • the pharmaceutical composition and method of this invention may also be used for preventing a relapse in a disorder or condition described in the previous paragraphs. Preventing such relapse is accomplished by administering to a mammal in need of such prevention a compound of formula I as described above.
  • the disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H 3 antagonist compound of general formula I and an effective dose of a histamine H 1 antagonist, such as cetirizine (ZyrtecTM), for the treatment of allergic rhinitis, nasal congestion and allergic congestion.
  • a histamine H 3 antagonist compound of general formula I an effective dose of a histamine H 1 antagonist, such as cetirizine (ZyrtecTM)
  • the disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H 3 antagonist compound of general formula I and an effective dose of a neurotransmitter reuptake blocker.
  • neurotransmitter reuptake blockers will include the serotonin-selective reuptake inhibitors (SSRI's) like sertraline (ZoloftTM), fluoxetine (ProzacTM), and paroxetine (PaxilTM), or non-selective serotonin, dopamine or norepinephrine reuptake inhibitors for treating depression and mood disorders.
  • SSRI's serotonin-selective reuptake inhibitors
  • ZoloftTM sertraline
  • fluoxetine ProzacTM
  • paroxetine PaxilTM
  • non-selective serotonin, dopamine or norepinephrine reuptake inhibitors for treating depression and mood disorders.
  • the compounds of the present invention may have optical centers and therefore may occur in different enantiomeric configurations.
  • Formula I as depicted above, includes all enantiomers, diastereomers, and other stereoisomers of the compounds depicted in structural formula I, as well as racemic and other mixtures thereof. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.
  • the present invention also includes isotopically labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopicaily labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • H 3 histamine-3 receptors
  • a "unit dosage form” as used herein is any form that contains a unit dose of the compound of formula I.
  • a unit dosage form may be, for example, in the form of a tablet or a capsule.
  • the unit dosage form may also be in liquid form, such as a solution or suspension.
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato star
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • Aerosol formulations for treatment of the conditions referred to above are preferably arranged so that each metered dose or "puff' of aerosol contains 20 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g to 100 mg.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • an active compound of this invention with a histamine H 1 antagonist, preferably cetirizine, for the treatment of subjects possessing any of the above conditions
  • these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
  • the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes.
  • the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a histamine H-i antagonist, preferably cetirizine, is present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • a proposed daily dose of an active compound of this invention in the combination formulation is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
  • a proposed daily dose of a histamine H-i antagonist, preferably cetirizine, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the histamine H 1 antagonist per unit dose which could be administered, for example, 1 to 4 times per day.
  • a preferred dose ratio of cetirizine to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.
  • Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 0.01 ⁇ g to about 100 mg of the active compound of this invention, preferably from about 1 ⁇ g to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time. Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains from about 0.01 mg to about 2000 mg of a histamine H 1 antagonist, preferably cetirizine, preferably from about 1 mg to about 200 mg of cetirizine.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • a histamine H-i antagonist, preferably cetirizine in combination with compounds of formula I are readily adapted to therapeutic use as antiallergy agents.
  • these antiallergy compositions containing a histamine H 1 antagonist, preferably cetirizine, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a histamine H 1 antagonist, preferably cetirizine, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of cetirizine; with from about 0.001 mg.
  • an active compound of this invention with a 5-HT re- uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions
  • these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages.
  • the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes.
  • the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • a proposed daily dose of an active compound of this invention in the combination formulation is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
  • a proposed daily dose of a 5-HT re-uptake inhibitor, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT re-uptake inhibitor per unit dose which could be administered, for example, 1 to 4 times per day.
  • a preferred dose ratio of sertraline to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.
  • Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • a 5-HT re-uptake inhibitor preferably sertraline
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • a 5-HT re-uptake inhibitor preferably sertraline
  • these antidepressant compositions containing a 5-HT reuptake inhibitor, preferably sertraline, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg.
  • Anxiety disorders include, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder.
  • Mood adjustment disorders include, for example, depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood.
  • Attention adjustment disorders include, for example, in addition to ADHD, attention deficit disorders or other cognitive disorders due to general medical conditions.
  • Psychotic disorders include, for example, schizoaffective disorders and schizophrenia; sleep disorders include, for example, narcolepsy and enuresis.
  • disorders or conditions which may be treated by the compound, composition and method of this invention are also as follows: depression, including, for example, depression in cancer patients, depression in Parkinson's patients, post-myocardial Infarction depression, depression in patients with human immunodeficiency virus (HIV), Subsyndromal Symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic depressive illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or major depression with dysthymia; dysthymia; phobias, including, for example, agoraphobia, social phobia or simple phobias; eating disorders, including, for example, anorexia nervosa or bulimia
  • the mammal in need of the treatment or prevention may be a mammal other than a human.
  • a compound of formula I which is basic in nature, is capable of forming a wide variety of different salts with various inorganic and organic acids.
  • the acid addition salts are readily prepared by treating the base compounds with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • the acids which are used to prepare the pharmaceutically acceptable acid salts of the active compound used in formulating the pharmaceutical composition of this invention that are basic in nature are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions.
  • Non-limiting examples of the salts include the acetate, benzoate, beta-hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1 ,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-1 ,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, oxalate, phenyl butyrate, phenyl propionate, phosphate, phthalate, phenylacetate, propanesulfonate, propiolate, propionate, pyr
  • A is a phenyl ring
  • the most preferred embodiment of the present invention includes the compounds of formula I in which A is a heteroaryl ring and E is either 3-aza-bicyclo[3.1.0]hexane or octahydro-indole.
  • Preferred compounds of formula I in accordance with the present invention are the following:
  • the most preferred examples of compounds according to the present invention include: 6-[4-(3-lsopropyl-3-azabicyclo[3.1.0]hex-6-ylmethoxy)-phenyl]-quinoline;
  • a suitably protected alcohol of the general formula Il is reacted with a phenol of the general formula III to give an ether intermediate of general formula IV, as shown in step a.
  • the reaction is most efficiently conducted using conditions often referred to as a Mitsunobu reaction, wherein the alcohol Il and the phenol III are combined to form an ether bond through the elimination of water.
  • This reaction is generally performed in the presence of a reagent like diethylazodicarboxylate (DEAD) and triphenylphosphine (Ph 3 P), in a reaction inert solvent such as THF or dichloromethane and at temperatures in the range of about 0 °C to about 40 0 C.
  • the intermediate aryl ether of formula IV so obtained may be purified (e.g., by chromatography on silica gel or alumina) or used without purification in the next step.
  • the starting reagents Il used in step a are commercially available or may be prepared according to procedures described in the chemical literature.
  • a suitable protecting group (P) for this reagent will include carboxybenzyl (CBZ) or tert-butoxycarbonyl (BOC) groups, and the like, which can prevent further reaction at the secondary nitrogen atom of the bicyclic heterocycloalkyl group E.
  • Such protecting groups would be unreactive under the conditions employed in the ether formation yet readily removed prior to replacement of the group P by a group R 1 as previously defined.
  • Recommended protecting groups for the amine nitrogen may be found in such references as T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, (Third Edition), John Wiley and Sons, Inc., NY (1999) and
  • phenols of formula III which contain a reactive group Z, are commercially available or prepared by methods described in the chemical literature.
  • step b the intermediate of general formula IV (described above) is reacted with an aryl or heteroaryl halide of general formula A-HaI, wherein A is as defined previously and Hal is a halogen (e.g., Cl, Br, I).
  • Hal a halogen
  • this step are generally referred to in the literature as the Suzuki reaction and are described in a number of publications including, e.g., M. Sato, N. Miyaura and A. Suzuki, Chemistry Letters (1989) 1405-1408; T. lihama, J. Fu, M.
  • step c of the process the protecting group (i.e., P) is removed from the intermediate of general formula V to give the intermediate amine of general formula Vl.
  • This transformation can be effected using one or more methods as disclosed in the chemical literature and known to one skilled in the art, depending on the nature of the group P. Efficient conditions for removal of a wide variety of amine protecting groups can be found in the Wuts and Greene reference listed above.
  • the secondary amine intermediate of formula Vl so derived may be used with or without prior purification in step d of the current process, wherein the intermediate of formula Vl can be converted to the title compound(s) of general formula I.
  • This conversion can be effected in a variety of manners, and the choice of procedure may be influenced by the nature and reactivity of any substituents present on the intermediate of formula Vl.
  • reaction inert solvent e.g., THF, dichloromethane, methanol, ethanol
  • Suitable reducing agents for this step may include one or more of the following: sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
  • Mass spectral (micromassZO) conditions Capillary(kV): 3.0; Cone (V): 20; Extractor (V): 3.0; RF Lens (V): 0; Source temp. ( 0 C): 120A/150P; Desolvation temp. ( 0 C): 150A/300P; Desolvation gas flow (L/hr): 500; Cone gas flow (L/hr): 100; LM Resolution: 15; HM Resolution: 15; Ion Energy: 0.2; Multiplier: 600. Splitter; Acurate by LC Packings, 1/10,000; Upchurch needle valve setting: 14; Make up pump (Waters 515) Flow (ml/min.): 1. PDA (Waters 996) Settings; Start/End wavelength (nm): 200/600; Resolution: 1.2; Sample Rate: 1 ; Channels: TIC, 254 nm and 220 nm.
  • the first eluting component (5 ⁇ -0H) was isolated as a pale yellow viscous oil.
  • 1 H-nmr 500 MHz, CDCI 3 ) ⁇ 1.00 (s, 3H), 1.10-1.27 (m, 2H), 1.28-1.35 (m, 1 H), 1.35-
  • 1 H-nmr 500 MHz, CDCI 3 ) ⁇ 1.05 (s, 3H), 1.45 (s, 9H), 1.30-1.70 (m, 7H), 1.80 (m, 1 H), 2.20 and 2.48 (2 bs, 1 H) 1 3.19 (bs, 1 H), 3.35 (m, 1 H), 3.45 (bs, 1 H) 1 3.82 (bs, 1 H).
  • 6-r4-(4,4,5,5-Tetram ⁇ thyl-ri,3,21dioxaborolan-2-yl)-phenoxymethvn-3-azabicy- clof3.1.01hexane-3-carboxylic acid tert-butyl ester Under N 2 , 6.0 g (28.0 mmol) of 6-hydroxymethyl-3-azabicyclo[3.1.0]hexane-3- carboxylic acid tert-butyl ester (prepared according to the method of J. Young and N.
  • the flask was then sealed and immersed in an oil bath preheated to 145-150 °C for 4 hr and allowed to cool to rt overnight.
  • the yellow mixture was filtered through a d.e. pad, washing the pad with additional ethanol.
  • the solvent was removed in vacuo to give a yellow waxy solid, which was chromatographed on a Biotage silica gel column (40x75 mm) eluting with 0.5% TEA in CH 2 CI 2 .
  • the major product band fractions were combined, concentrated in vacuo to a yellow solid and dried under vacuum, 0.311 g.
  • the dihydrochloride salt was prepared as above; m.p. 256.0-256.6 0 C.
  • the in vitro affinity of the compounds in the present invention at the rat or human histamine H 3 receptors can be determined according to the following procedure. Frozen rat frontal brain or frozen human post-mortem frontal brain is homogenized in 20 volumes of cold 50 mM Tris»HCI containing 2 mM MgCI 2 (pH to 7.4 at 4°C). The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is decanted and the membrane pellet re-suspended by Polytron in cold 50 mM Tris»HCI containing 2 mM MgCI 2 (pH to 7.4 at 4 0 C) and centrifuged again.
  • the final pellet is re-suspended in 50 mM Tris HCI containing 2 mM MgCI 2 (pH to 7.4 at 25 0 C) at a concentration of 12 mg/mL Dilutions of compounds are made in 10% DMSO / 50 mM Tris buffer (pH 7.4) (at 10 x final concentration, so that the final DMSO concentration is 1 %). Incubations are initiated by the addition of membranes (200 microliters) to 96-well V-bottom polypropylene plates containing 25 microliters of drug dilutions and 25 microliters of radioligand (1 nM final concentration 3 H-N-methylhistamine).

Abstract

L'invention concerne des composés de formule (I) tels que définis dans le descriptif, ou un sel de ceux-ci pharmaceutiquement acceptable; une composition pharmaceutique contenant un composé de formule (I), un procédé de traitement d'un trouble ou d'un état que l'on peut traiter en antagonisant des récepteurs de l'histamine H3, le procédé consistant à administrer au mammifère concerné un composé de formule (I) selon la description ci-dessus, et un procédé de traitement d'un trouble ou d'un état du groupe comprenant la dépression, les troubles de l'humeur, la schizophrénie, les troubles de l'anxiété, la maladie d'Alzheimer, le trouble déficitaire de l'attention (TDA), du trouble d'hyperactivité avec déficit de l'attention (TDA/H), de troubles psychotiques, de troubles du sommeil, de l'obésité, de vertiges, de l'épilepsie, du mal des transports, de maladies respiratoires, d'allergies, de réponses des voies respiratoires induites par une allergie, de la rhinite allergique, de la congestion nasale, de la congestion allergique, de la congestion, de l'hypotension, de maladies cardiovasculaires, de maladies du tractus gastro-intestinal, de l'hypermotilité et de l'hypomotilité du tractus intestinal, le procédé consistant à administrer au mammifère concerné un composé de formule (I).
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