WO2007099423A1 - Dérivés de 1-pyrrolidine indane en tant qu'antagonistes du récepteur d'histamine 3 - Google Patents

Dérivés de 1-pyrrolidine indane en tant qu'antagonistes du récepteur d'histamine 3 Download PDF

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Publication number
WO2007099423A1
WO2007099423A1 PCT/IB2007/000414 IB2007000414W WO2007099423A1 WO 2007099423 A1 WO2007099423 A1 WO 2007099423A1 IB 2007000414 W IB2007000414 W IB 2007000414W WO 2007099423 A1 WO2007099423 A1 WO 2007099423A1
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Prior art keywords
yloxy
ylindan
pyrrolidin
ethyl
piperidin
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PCT/IB2007/000414
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English (en)
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Harry Ralph Howard, Jr.
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Pfizer Products Inc.
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Publication of WO2007099423A1 publication Critical patent/WO2007099423A1/fr

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    • 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
    • C07D295/04—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 substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • 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
    • 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
    • C07D295/04—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 substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • This invention is directed to compounds of formula 1 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 0 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 5 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
  • Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay 5 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 0 presynaptically on histaminergic nerve endings (Nature. 302, S32- 837 (1983)).
  • the existence of the H 3 receptor has been confirmed by the development of selective H 3 receptor agonists and antagonists (Nature, ' 327, 117-123 (1987)) 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 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., Neuropsvchopharmacolo ⁇ v (1996) 15, 31- 35); (Sakai et al., Life Sci, (1991) 48, 2397-2404); (Mazurkiewiez-Kwilecki and Nsonwah, Can. J.
  • Watanabe, AQ-O 145 "A newly developed histamine H 3 antagonist, decreased seizure susceptibility of electrically induced convulsions in mice", Meth. Find. Exp. Clin. Pharmacol., 17(C): 70-73, (1995); (Delaunois A., Gustin P., Garbarg M., and Ansay M., "Modulation of acetylcholine, capsaicin and substance P effects by histamine H 3 receptors in isolated perfused rabbit lungs", European Journal of Pharmacology 277(2-3):243-50.
  • 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.
  • the receptor is an important target for new therapeutics in Alzheimer's disease, mood and attention adjustments, including attention deficit hyperactive disorder (ADHO), cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and motion sickness, and various forms of anxiety.
  • ADHD attention deficit hyperactive disorder
  • cognitive deficiencies including cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and motion sickness, and various forms of anxiety.
  • histamine H 3 receptor antagonists to date resemble histamine in possessing an imidazole ring that may be substituted, as described, for example, in WO 96/38142.
  • Non-imidazoie neuroactive compounds such as beta histamines (Arrang, Eur. J. Pharm. 1985, 111:72-84) demonstrated some histamine H 3 receptor activity but with poor potency.
  • EP 978512 and EP 982300 disclose non-imidazole alkyamines as histamine H 3 receptor antagonists.
  • WO 02/12224 (Ortho McNeil Pharmaceuticals) describes non- imidazole bicyclic derivatives as histamine H 3 receptor ligands, and EP 1275647 (Les Laboratoires Setvier) has disclosed novel octahydro-2H-pyrido[1,2-a]pyrazines that are selective H 3 receptor antagonists.
  • 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. other histamine receptors), and possess remarkable drug disposition properties (pharmacokinetics).
  • the compounds of this invention selectively distinguish H 3 R from the other receptor subtypes H 1 R, H 2 R.
  • novel compounds that interact with the histamine H 3 receptor would be -A-
  • the present invention provides such a contribution to the art being based on the finding that a novel class of aryl ether diamines exhibits a high and specific affinity to the histamine H 3 receptor.
  • This invention is directed to compounds of the formula I:
  • R 1 and R 2 are independently selected from hydrogen, (Ci-Ce)-alkyl, (Co-C 3 )-alkyl-aryi, optionally substituted with up to 3 fluorine atoms, or
  • R 1 and R 2 together with the nitrogen to which they are attached form a 3-10 member mono- or bi-cyclic ring system, optionally with up to three additional heteroatoms selected from N, O and S, up to two unsaturated C-C or C-N bonds, and with optional substitution on available carbon or nitrogen atoms in said rings by (Ci-Cg)-alkyl, aryl, heteroaryl, F, OH or
  • R 3 is (C 1 -C e )-aikyl, aryl or heteroaryl, optionally substituted with up to 3 fluorine atoms;
  • R 4 is hydrogen, halogen, (Ci-C 6 )-alky! or (C 3 -C 7 )-cycloalkyl, (C r C 6 ⁇ -alkoxyl or (C 3 - C 7 )-cycloalkoxyi (optionally substituted with up to 3 fluorine atoms), aryl, heteroaryl;
  • R 6 is (CR 8 R 9 ) m - ⁇ CR 10 R 11 ) p -B, wherein R 8 , R p , R 10 and R 11 together with the carbon to which they are attached form a 3-10 member mono- or bi-cyclic ring system;
  • B is a 4-7 member heterocycloaiky! containing up to 3 heteroatoms selected from N, O, S (e.g., azetidine, pyrrolidine, pipe ⁇ dine, azepine, morpholine, thiomorpholine, piperazine or 1 ,4-diazepine) or NR 12 R 13 ;
  • N O
  • S e.g., azetidine, pyrrolidine, pipe ⁇ dine, azepine, morpholine, thiomorpholine, piperazine or 1 ,4-diazepine
  • R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from hydrogen, C 1 -C 6 alky!, (C 1 -C 6 alkyl)-aryl, (C 1 -C 6 alkyl)-heteroaryl; or
  • R 12 and R 13 together with the nitrogen to which they are attached form a 3-10 member mono- or bi-cyc!ic ring system (e.g., azepine, piperidine, pyrrolidine or morpholine), and with the proviso that NR 12 R 13 is not NH 2 .
  • m is O, 1, 2, 3 or 4;
  • n is O, 1, 2 or 3; and
  • p is 0 to 3.
  • alkyl refers to straight or branched chains of carbon atoms.
  • exemplary alkyl groups are Ci-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 denotes a cyclic group of carbon atoms, where the ring formed by the carbon atoms may be saturated or may comprise one or more carbon-carbon double bonds in the ring.
  • cycjoaikyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as cyclopentenyl, cyciopentadienyi, cyclohexenyl, cyclohexadienyl, and the like.
  • 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 (tetralinyi), 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 examples include benzo[b3thienyl, chromenyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyi, 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 include azabicycloheptanyl, azetidinyl, benzazepinyl, 1,3- dihydroisoindolyl, indoiinyl, 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.
  • pyridyl includes 2-, 3-, or 4-pyridyl
  • thienyl includes 2- or 3-thienyl.
  • Co-C 4 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 -C 14 aryl-C 0 -C 4 alky!/ "5-10- membered heteroaryl-Co-C 4 alkyl,” and "C 6 -Ci 4 aryl-C 0 -C 4 alkylene-O-C 0 -C 4 alkyl" include C 3 -
  • C 1 -C 4 dialkyiamino refers to a dialkylamino group in which each alkyl group is independently a Ci-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 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 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 of the gastrointestinal tract, the composition comprising 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.
  • 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 (SSRl's) like sertraline (ZoloftTM), fluoxetine (ProzacTM), and paroxetine (PaxilTM), or 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 1 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 1 3 H, 13 C, 11 C, 14 C 1 16 N, 18 0, 17 0, 31 P 1 32 P, 35 S, 18 F, and 36 CI 1 respectively.
  • lsotopically 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-isotopicaily 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.
  • the 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, microcrystaliine cellulose or calcium phosphate); lubricants (e.g., magnesium ⁇ tearate, 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, microcrystaliine cellulose or calcium phosphate
  • lubricants e.g., magnesium ⁇ tearate, talc or silica
  • 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 ethy! 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 ethy! 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 maybe in powder form for recon ⁇ titution 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 propeila ⁇ t, e.g., dichlorodifluoromethane, irichl ⁇ rofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propeila ⁇ t e.g., dichlorodifluoromethane, irichl ⁇ rofluoromethane, 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 (e.g., depression) 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
  • Hi antagonist preferably cetirizine
  • 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.
  • such 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 Hi 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 Hi 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 Hi 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 1 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 Hi 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-, 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. to about 100 mg per kg of body weight per. day of a compound of formula I, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula I 1 although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.
  • an active compound of this invention with a 5-HT reuptake 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.
  • Aerosoi 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 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
  • 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,
  • 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 il, 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 human.
  • 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, nydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate, phenylbutyrate, pheny [propionate, phosphate, phthalate, phenylacetate, propanesulfonate, propiolate, propionate,
  • the most preferred embodiment of the present invention includes the compounds of formula I in which R 1 and R 2 together with the nitrogen to which they are attached form a pyrrolidine ring, n is equal to one, R 3 and R" are both hydrogen and R 5 O is attached at position c.
  • Preferred embodiments of the present invention also include any combination of the foregoing embodiments (A)-(C).
  • Preferred compounds of formula I in accordance with the present invention are the foliowing:
  • a ketone of the general formula II wherein the hydroxyl (-OH) group is unprotected, is reacted with a 1° or 2° amine of the general formula HNR 1 R 2 to generate an intermediate amino-phenol of general formula III (pathway a.).
  • This transformation can be accomplished using one or more of the methods and procedures available to those skilled in the art.
  • a ketone of formula Il and a 2° amine can be combined in a reaction inert aprotic solvent, like chloroform or dichloromethane, in the presence of a Lewis acid reagent like titanium tetrachloride (TiCI 4 ) or titanium isopropoxide (Ti(O-IPr) 4 ) to produce an intermediate imine of the general formula VHI:
  • a Lewis acid reagent like titanium tetrachloride (TiCI 4 ) or titanium isopropoxide (Ti(O-IPr) 4
  • This can be accomplished by reduction of the C N double bond of VIII using, for example, boron reagents like sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBHsCN), sodium triacetoxyborohydride (NaBH(OAc) 3 ) and the like, in reaction inert solvents like dichloromethane, methanol, THF or dioxane.
  • boron reagents like sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBHsCN), sodium triacetoxyborohydride (NaBH(OAc) 3 ) and the like, in reaction inert solvents like dichloromethane, methanol, THF or dioxane.
  • the imine VIJI can be reduced using catalytic hydrogenation conditions, e.g., employing hydrogen gas (H 2 ) and a suitable metal catalyst like Raney nickel (RaNi), palladium on carbon (Pd/C) or similar catalysts in a reaction inert solvent like methanol or ethanol and at temperatures in the range of about 20 0 C up to the boiling point of the solvent employed and at pressures in the range of about one to five atmospheres of hydrogen gas.
  • a suitable metal catalyst like Raney nickel (RaNi), palladium on carbon (Pd/C) or similar catalysts in a reaction inert solvent like methanol or ethanol and at temperatures in the range of about 20 0 C up to the boiling point of the solvent employed and at pressures in the range of about one to five atmospheres of hydrogen gas.
  • a suitable metal catalyst like Raney nickel (RaNi), palladium on carbon (Pd/C) or similar catalysts in a reaction inert solvent like methanol or ethanol and at temperatures in
  • the phenolic OH group present in the Intermediate of formula 111. can be converted to an ether product of the general formula I by alkylation of III with a reagent of the genera] formula R 5 -A, wherein R 5 is as defined previously and A is a leaving group including halogen (e.g., Cl, Br, I) 1 mesylate (i.e., -OSO 2 CH 3 , or -OMs) or tosylate (i.e., -OSO 2 C 6 H 5 , or -OTs), in the presence of a base and in a reaction inert solvent, as depicted in pathway b.
  • halogen e.g., Cl, Br, I
  • Suitable bases will include sodium, potassium or cesium carbonate(s), sodium or potassium bicarbonate(s), sodium or potassium tert-butoxide(s), sodium or potassium hydride(s) and the like, with cesium carbonate being preferred.
  • Suitable solvents will include DMF, DMSO, DMA, THF and the like, with DMSO preferred.
  • the compounds of the present invention may also be prepared via the routes shown in Scheme 2.
  • a phenolic ketone of the general formula H may be converted to an ether (pathway c.) by methods generally known to one skilled in the art.
  • the phenol Il can be reacted with a reagent of general formula R s -A in the presence of a base, as described for pathway b. in Scheme 1 to produce a ketone of general formula IV.
  • a ketone of the general formula VII wherein L 1 is a suitable leaving group (i.e., F, OMs, etc.), may be reacted with a reagent of general formula R 5 -OH in the presence of a suitable base and in a reaction inert solvent to produce an intermediate of general formula IV (pathway e.).
  • the ketone IV so obtained may then be converted, using reductive amination conditions as previously described in Scheme I (pathway a.), to the desired products of general formula I (pathway d.).
  • a reducing agent such as NaBH 4
  • L 2 is a leaving group (e.g., OMs, OTs 1 Cl)
  • HNR 1 R 2 pathway h. ⁇ .
  • Method A Preparative conditions (Waters 600 & Waters 2767 Sample Manager); Column: Waters Symmetry C 16 , ⁇ m, 30 x 150 mm steel column, part # WAT248000, serial # M12921A01; solvent A - 0.1% Trifluoroacetic acid/water; solvent B - Acetonitrile; volume of injection: 850 ⁇ l_; time 0.0, 100% solvent A, 0% solvent B, flow 20; time 2.0, 100% solvent A, 0% solvent B 1 flow 20; time 12.0, 0% solvent A 1 100% solvent B, flow 20; time 15.0, 0% solvent A, 100% solvent B 1 flow 20; time 15.1, 100% solvent A, 0% solvent B, flow 20; time 20.0, 100% solvent A, 0% solvent B, flow 20.
  • Mass spectral (microma ⁇ sZO) conditions Capillary(kV): 3.0; Cone (V): 20; Extractor (V): 3.0; RF Lens (V): 0.5; Source temp. ( 0 C): 120; Desolvation temp. ( 0 C): 360; Desolvation gas flow (Uhr): 450; Cone gas flow (L/hr): 150; LM Resolution: 15; HM Resolution: 15; Ion Energy: 0.2; Multiplier; 550. 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.
  • Method B Preparative conditions (Waters 600 & Waters 2767 Sample Manager); Column: Waters Xterra PrepMS C 19 column, 5 ⁇ m, 30 x 150 mm steel column, part # 186001120, serial # T22881T 09; solvent A - 0.1% Trifluoroacetic acid/water; solvent B - Acetonitrile; volume of injection: 1050 ⁇ L; time 0.0, 100% solvent A, 0% solvent B, flow 20; time 2.0, 100% solvent A, 0% solvent B, flow 20; time 12.0, 0% solvent A, 100% solvent B, flow 20; time 14.0, 0% solvent A, 100% solvent B, flow 20; time 14.1, 100% solvent A, 0% solvent B, flow 20; time 19.1, 100% solvent A, 0% solvent B, flow20.
  • Mass spectral (micromassZO) conditions Capillary(kV): 3.0; Cone (V): 20; Extractor
  • V 3.0; RF Lens (V): 0.5; Source temp. ( 0 C): 120; Desolvation temp. ( 0 C): 360; Desolvation gas flow (UhT): 450; Cone gas flow (L/hr): 150; LM Resolution: 15; HM Resolution: 15; Ion Energy: 0.2; Multiplier: 550.
  • Mass spectral (micromassZO) conditions Capillary(kV): 3.0; Cone (V); 20; Extractor (V): 3.0; RF Lens (V): 0.5; Source temp. ( 0 C): 120; Desolvation temp. ( 0 C): 360; Desolvation gas flow (L/hr): 450; Cone gas flow (Uhr): 150; LM Resolution: 15; HM Resolution: 15; Ion Energy: 0.2; Multiplier: 550. 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 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»HC! containing 2 mM MgCI 2 (pH to 7.4 at 4 0 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) ou un sel acceptable du point de vue pharmaceutique de ceux-ci; une composition pharmaceutique contenant un composé de formule (I); un procédé de traitement d'un trouble ou d'une affection qui peut être traité par l'antagonisme des récepteurs H3 de l'histamine, le procédé consistant à administrer à un mammifère un composé de formule (I); et un procédé de traitement d'un trouble ou d'une affection sélectionné dans le groupe constitué de la dépression, de troubles de l'humeur, de la schizophrénie, d'angoisses, de la maladie d'Alzheimer, du 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 à un mammifèreun composé de formule (I).
PCT/IB2007/000414 2006-03-02 2007-02-19 Dérivés de 1-pyrrolidine indane en tant qu'antagonistes du récepteur d'histamine 3 WO2007099423A1 (fr)

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