WO2007099423A1 - 1-pyrrolidine indane derivatives as histamine-3 receptor antagonists - Google Patents

Abstract

The invention is directed to compounds of the formula (I) as defined herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition containing a compound of formula (I), a method of treatment of a disorder or condition that may be treated by antagonizing histamine H3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula (I) as described above, and a method of treatment of 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 method comprising administering to a mammal in need of such treatment a compound of formula (I) as described above.

Description

-PYRROLIDINE INDANE DERIVATIVES AS HISTAMINE-3 RECEPTOR ANTAGONISTS

_"BACKGROUND OF THE INVENTION

5 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 (H₃) receptors using such compounds. The histamine-3 (H₃) 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 H₃ 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 0 hypo-motiiity 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).

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 H₁ and H₂ receptors.

A third histamine receptor (H₃ receptor) is believed to play a role in neurotransmission in the central nervous system, where the H₃ receptor is thought to be disposed 0 presynaptically on histaminergic nerve endings (Nature. 302, S32- 837 (1983)). The existence of the H₃ receptor has been confirmed by the development of selective H₃ 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. 5 A number of diseases or conditions may be treated with histamine-3 receptor ligands wherein the H₃ 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., Neuropsvchopharmacoloαv (1996) 15, 31- 35); (Sakai et al., Life Sci, (1991) 48, 2397-2404); (Mazurkiewiez-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78); (Panula, P. et al., Neuroscience (1998) 44, 465-481); (Wada et al., Trends in Neuroscience (1991) 14,⁴¹⁵); {Monti et al., Eur. J. Pharmacol. (1991) 205, 283); (Haas et al., Behav. Brain Res. (1995) 66, 41-44); (De Almeida and Izquierdo, Arch. Int. Pharmacodvn. (1986) 283, 193-198); (Kamei et al., Psvchopharmacoloqy (1990) 102, 312-318); (Kamei and Sakata, Japan. J. Pharmacol. (199 1) S. 437-482); (Schwartz et al., Psvchopharmacology; The Fourth Generation of Progress, Bloom and Kupfer (eds.), Raven Press, New York, (1995) 3, 97); (Shaywitz et al., Psvchopharmacoloqy (1984) 82, 73-77); (Dumery and Blozovski, EXP. Brain Res. (1987) 67, 61-69); (Tedford et ai., J. Pharmacol. Exp. Ther. (1995) 275, 598-604); (Tedford -et al., Soc. Neurosci. Abstr. (1996) 22, 22); (Yokoyama et al., Eur. J. Pharmacol. (1993) 234, 129); {Yokoyama and linuma, CNS Drugs (1996) 5, 321); (Onodera et aL, Prog Neurobiol. (1994) 42. 685); (Leurs and Timmerman, Prog. Drug Res. (1992) 39,127); (The Histamine 4-I3 Receptor, Leurs and Timmerman (ed.), Elsevier Science, Amsterdam, The Netherlands (1998); (Leurs et al., Trends in Pharm. Sci. (1998) t9, 177-183); (Phillips et al., Annual Reports in Medicinal Chemistry (1998) 33, 31-40); (Matsubara et al., Eur. J. Pharmacol. (1992) 224, 145); (Rouleau et a!.. J. Pharmacol. Exp. Ther. (1997) 281. 1085); (Adam Szelag, "Role of histamine H₃-receptors in the proliferation of neoplastic cells in vitro", Med. Sci. Monit. 4(5): 747- 755, (1998)); (Fitzsimons, C, H. Duran, F. Labombarda, B. Molinari and E. Rivera, "Histamine receptors signalling in epidermal tumor cell lines with H-ras gene alterations", Inflammation Res.. 47 (Suppl. 1): S50-S51, (1998)); (R. Leurs, R.C. Vollinga and H. Timmerman, "The medicinal chemistry and therapeutic potentials of ligand of the histamine H₃ receptor", Progress in Drug Research 45: 170-165, (1995)); {R. Levi and N.C.E. Smith, "Histamine H3-receptors: A new frontier in myocardial ischemia", J. Pharm. Exp. Ther.. 292: 825-830, (200O)); (Hatta, E., K Yaεuda and R. Levi, "Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia", J. Pharm. Exp. Ther.. 283: 494-500, (1997); (H. Yokoyama and K. linuma, "Histamine and Seizures: Implications for the treatment of epilepsy", CNS Drugs. 5f5); 321- 330, (1995)5; (K. Hurukami, H. Yokoyama, K. Onodera, K. linuma and T. Watanabe, AQ-O 145, "A newly developed histamine H₃ 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 H₃ receptors in isolated perfused rabbit lungs", European Journal of Pharmacology 277(2-3):243-50. (1995)); and (Dimitriadou, et al., "Functional relationship between mast cells and C- sensitive nerve fibres evidenced by histamine H₃-receptor modulation in rat lung and spleen", Ciinical Science 87(25:151-63. (1994), 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.

H₃ receptor antagonists have also been previously described in, for example, WO 03/050099, WO 02/0769252, and WO 02/12224. The histamine H₃ receptor (H₃R) regulates the release of histamine and other neurotransmitters, including serotonin and acetylcholine. H₃R is relatively neuron specific and inhibits the release of certain monoamines such as histamine. Selective antagonism of H₃R 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. Accordingly, 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.

The majority of histamine H₃ 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 H₃ receptor activity but with poor potency. EP 978512 and EP 982300 disclose non-imidazole alkyamines as histamine H₃ receptor antagonists. WO 02/12224 (Ortho McNeil Pharmaceuticals) describes non- imidazole bicyclic derivatives as histamine H₃ receptor ligands, and EP 1275647 (Les Laboratoires Setvier) has disclosed novel octahydro-2H-pyrido[1,2-a]pyrazines that are selective H₃ receptor antagonists.

The present invention is directed to histamine-3 (H₃) receptor antagonists useful for treating the conditions listed in the preceding paragraphs. The compounds of this invention are highly selective for the H₃ receptor (vs. other histamine receptors), and possess remarkable drug disposition properties (pharmacokinetics). In particular, the compounds of this invention selectively distinguish H₃R from the other receptor subtypes H₁R, H₂R. In view of the increased level of interest in histamine H₃ receptor agonists, inverse agonists and antagonists in the art, novel compounds that interact with the histamine H₃ receptor would be -A-

a highly desirable contribution to the art. 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 H₃ receptor.

SUMMARY OF THE INVENTION

This invention is directed to compounds of the formula I:

I or the pharmaceutically acceptable salt{s) thereof, wherein: R¹ and R² are independently selected from hydrogen, (Ci-Ce)-alkyl, (Co-C₃)-alkyl-aryi, optionally substituted with up to 3 fluorine atoms, or

R¹ and R² 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

NR⁶R⁷;

R³ is (C₁-C_e)-aikyl, aryl or heteroaryl, optionally substituted with up to 3 fluorine atoms;

R⁴ is hydrogen, halogen, (Ci-C₆)-alky! or (C₃-C₇)-cycloalkyl, (C_rC₆}-alkoxyl or (C₃- C₇)-cycloalkoxyi (optionally substituted with up to 3 fluorine atoms), aryl, heteroaryl;

R⁶ is (CR⁸R⁹)_m-{CR¹⁰R¹¹)_p-B, wherein R⁸, R^p, R¹⁰ and R¹¹ 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, pipeπdine, azepine, morpholine, thiomorpholine, piperazine or 1 ,4-diazepine) or NR¹²R¹³;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are independently selected from hydrogen, C₁-C₆ alky!, (C₁-C₆ alkyl)-aryl, (C₁-C₆ alkyl)-heteroaryl; or

R¹² and R¹³ 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 NR¹²R¹³ is not NH₂. m is O, 1, 2, 3 or 4; n is O, 1, 2 or 3; and p is 0 to 3. Where cis and trans isomers are possible for an embodiment of the inventive compound of formula I, both cis and trans isomers are to be included within the scope of the invention.

The term "alkyl" refers to straight or branched chains of carbon atoms. Exemplary alkyl groups are Ci-C₆ 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. The term "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. The term "aryl" denotes a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. The terms "alkoxy" and "aryloxy" denote "O-alkyl" and "O-aryl", respectively. The term "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. Examples of cycjoaikyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as cyclopentenyl, cyciopentadienyi, cyclohexenyl, cyclohexadienyl, and the like. As used herein, the term "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. The term "halogen" represents chloro, fluoro, bromo, and iodo. The term "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. Examples of preferred heteroaryl ^■ groups 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.

The term "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. Examples of such 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. For example, the term "pyridyl" includes 2-, 3-, or 4-pyridyl, and the term "thienyl" includes 2- or 3-thienyl.

The term "Co-C₄" includes the embodiment where there are no carbons in a chain.

Thus, for example, the groups "C₃-C₇ cycloalkyl-C₀-C₄ alkyl," "C₆-C₁₄ aryl-C₀-C₄ alky!/ "5-10- membered heteroaryl-Co-C₄ alkyl," and "C₆-Ci₄ aryl-C₀-C₄ alkylene-O-C₀-C₄ alkyl" include C₃-

C₇ cycloalkyl, C₆-C₁₄ aryl, 5-10-membered heteroaryl, and G₆-C₁₄ aryl- 0-C₀-C₄ alkyl, respectively.

The term "C₁-C₄ dialkyiamino" refers to a dialkylamino group in which each alkyl group is independently a Ci-C₄ 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, and optionally a pharmaceutically acceptable carrier. 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 (H₃) 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 H₃ antagonist compound of general formula I and an effective dose of a histamine H₁ antagonist, such as cetirizine (Zyrtec™), for the treatment of allergic rhinitis, nasal congestion and allergic congestion.

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 H₃ antagonist compound of general formula I and an effective dose of a neurotransmitter reuptake blocker. Examples of neurotransmitter reuptake blockers will include the serotonin-selective reuptake inhibitors (SSRl's) like sertraline (Zoloft™), fluoxetine (Prozac™), and paroxetine (Paxil™), 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 I₁ 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. Examples of 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 ²H₁ ³H, ¹³C, ¹¹C, ¹⁴C₁ ¹⁶N, ¹⁸0, ¹⁷0, ³¹P₁ ³²P, ³⁵S, ¹⁸F, and ³⁶CI₁ 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 °H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴G, isotopes are partlcularly preferred for their ease of preparation and detectabiϋty. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, 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.

"Antagonizing histamine-3 (H₃) receptors," as used herein, refers to acting as a histamine-3 receptor antagonist

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. Thus, 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.

For oral administration, 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 εtearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. 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).

For buccal administration, 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. Alternatively, the active ingredient maybe in powder form for reconεtitution 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.

For intranasal administration or administration by inhalation, 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 propeilaήt, e.g., dichlorodifluoromethane, irichlαrofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, 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 (made, for example, from gelatin) 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 (e.g., attention deficit hyperactivity disorder) in the average human are preferably arranged so that each metered dose or "puff of aerosol contains 20 μg to 1000 μg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 μg 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, In connection with the use of an active compound of this invention with a histamine

Hi antagonist, preferably cetirizine, for the treatment of subjects possessing any of the above conditions, it is to be noted that 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. More particularly, 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. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, 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 (a formulation containing an active compound of this invention and a histamine H₁ antagonist) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above 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 H₁ 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 μg to about 100 mg of the active compound of this invention, preferably from about 1 μg 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. As previously indicated, a histamine H₁ antagonist, preferably cetirizine, in combination with compounds of formula I are readily adapted to therapeutic use as antiallergy agents. In general, 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 I₁ although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.

)n connection with the use of 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, it is to be noted that 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. More particularly, 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. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, 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 (a formulation containing an active compound of this invention and a 5-HT reuptake inhibitor) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above 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 μg to about 100 mg of the active compound of this invention, preferably from about 1 μg 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

As previously indicated, a 5-HT re-uptake inhibitor, preferably sertraline, in combination with compounds of formula I are readily adapted to therapeutic use as antidepressant agents. In general, 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. 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, although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen. 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. Examples of the 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 nervosa; chemical dependencies, including, for example, addictions to alcohol, ***e, amphetamine and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson's diseases, including, for example, dementia in Parkinson's disease, neuroleptic- induced parkinsonism or tardive dyskinesias; headache, including, for example, headache associated with vascular disorders; withdrawal syndrome; age-associated learning and mental disorders; apathy; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; conduct disorder; cyclothymic disorder; somatoform disorders such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatoform NOS; incontinence; inhalation disorders; intoxication disorders; mania; oppositional defiant disorder; peripheral neuropathy; post- traumatic stress disorder; late luteal phase dysphoric disorder; specific developmental disorders; SSRl "poop out" syndrome, or a patient's failure to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders including Tourette's disease.

As an example, the mammal in need of the treatment or prevention may be a human. As another example, 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, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate, xylenesulfonate, acid phosphate, acid citrate, bitartrate, succinate, gluconate, saccharate, nitrate, methanesuifonate and pamoate [i.e., 1,1'-methyiene-bis-(2- hydroxy-3-naphthoate)] salts. Preferred embodiments of the present invention include the compounds of formula I in which

(A): R¹ and R²together with the nitrogen to which they are attached form a piperidine ring; or

(B): R¹ and R²together with the nitrogen to which they are attached form a pyrrolidine ring; or

(C): R¹ and R² together with the nitrogen to which they are attached form a rnorpholine ring; or

The most preferred embodiment of the present invention includes the compounds of formula I in which R¹ and R² together with the nitrogen to which they are attached form a pyrrolidine ring, n is equal to one, R³ and R" are both hydrogen and R⁵O 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:

1-[2-(3-Pyrrolidin-1-yIindan-5-yloxy)-ethy]]-piperidine;

1-[2-(5-Pyrrolidin-1-y!-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-piperidine; 4-[2-(5-Pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-morpholine; 1-[2-(5-Pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-pyrroiidine; i-β-fδ-Pyrrolidin-i-yl-δJAΘ-tetrahydro-SH-benzocyclohepten^-yloxyJ-ethyϊ}- piperidine; 4-[2-(5-Pyrrolidin-1-yi-6,7_l8_l9-tetrahydro-5H-benzocyclohepten-2-yloxy)-ethyi]- morpholine;

2-(2-Morpholin-4-ylethoxy)-6,7,8,9-tetrahydro-5H-ben2θcyclohepten-5-yl]- dimethylamine; 4-[2-(2-Pyrrolidin-1-ylethoxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl]- morpholine; i-β-fS-Pyrrolidin-i-yl-β^.δ.Wetrahydro-δH-benzocyclohepten-S-yloxyVpropylj- pyrrolidine;

1-[1-(5-Pyrrolidin-1-y!-6_>7,8,9-tetrahydro-5H-benzocyclohepten-3-yloxy)-propyl]- pyrrolidine;

1-[3-(3-Pyrrolidin-1-ylindan-5-y!oxy)-propyl]-ρiperidine;

2-[6-(2-Piperidin-1-ylethoxy)-indan-1-yl]-2,3-dihydro-1H-isoindole;

[6-(2-Dimethylamino-ethoxy)-3,3-dimethyl-indan-1-yl]<limethylamine;

[7-(1-Aza-bicyc|o[2.2.1]hept-3-yloxy)-1_l2,3,4-tetrahydro-naphthalen-1-yl]- dimethylamine;

1-Methyi-2-(8-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-ρiperidine;

[5-{1-Methyl-piperidin-2-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-diethylamine;

4-[5-(1-Ethyl-pyrrolidin-2-ylmethoxy)-1_l2,3,4-tetrahydro-naphthalen-1-yl]-thio- morpholine; Benzyl-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-methylamine;

Pyridin-4-ylmethy!-[2-(1-pyrroiidin-1-ylindan-5-yloxy)-ethyl3-methylamine;

Pyrimidin-4-ylmethyl-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyl3-methylarnine;

Pyrimidin-4-yl-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-methylamine;

2-[2-(1-Pyrrolidin-1-y)indan-5-yloxy)-ethyi]-octahydropyrido[1,2-a]pyrazine; {5-[2-(4-Methyi-ρiperazin-1-yi)-ethoxy]-indan-1-yl}-dimethylamine;

4-[2-(1-Piperidiπ-1-ylindan-5-yloxy)-ethyl]-thiomorpholine;

4-[2-(1-Piperidin-1-ylindan-δ-yloxy)-ethyl]-thiomorpholine 1-oxide;

4-[2-(1-Piperidin-1-ylindan-5-yloxy)-ethyl3-thiomorpholine 1 , 1-dioxide,

1-{5-[1-(1-Methyl-pyrrolidin-3-yl)-ethoxy]-indan-1-yi}-piperidine; I.S-Dimethyl^i-pyrrolidin-i-ylindan-S-yloxymethO-pyrrotidine;

1-[2-(6-F!uoro-1-pyrrolidin-1-ylindan-5-yloxy5-ethyi]-piperidine;

1-[2-(6-Methoxy-1-pyrro]idin-1-ylindan-5-yloxy)-ethyl]-2-methyl-piperidine;

1-[2-{3-Methoxy-5-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]- piperidine; 3-[2-{6-Chloro-1-pyrrolidin-1-yliπdan-5-yloxy)-ethyl]-oxazolidin-2-one;

2-[1-Pyrrolidin-1-y|-6-(3-ρyrrolidin-1-ylpropoxy)-indan-5-yl]-pyridine;

[6-(3-Dimethylamino-propoxy)-5-pyrimidin-2-ylindan-1-yl]-dimethylamine; 9-Methyl-3-(3-pyrrolidin-1-ylindan-5-yloxy)-9-aza-bicyc!o[3.3.1]nonane;

2-[2-(3-Pyrrolidin-1-ylindan-5-y!oxy)-ethyl]-1-aza-bicyclo[2.2.1]heptane;

2-[2-(3-Pyrrolidin-1-yiindan-5-y!oxy)-ethy!]-1-aza-bicycloI2.2.2]octane; .

1-[2-(5-Pyrrolidin-1-yi-3-trifluoromethoxy-5,6,7,8-tetrahydro-naphthalen-2-yioxy)- ethylj-piperidine;

^-(S-Cyclopentyloxy-S-pyrrolidin-i-yl-S.βJ.δ-tetrahydro-naphthalen^-yloxyJ-ethyl]- dimethylamine;

2-[3-Pyrrolidin-1-yl-6-(2-pyrroiidin-1-ylethoxy)-indan-5-yl]-pyridine;

2-[3-Pyrrolidin-1-yl-6-(2-pyrrolidin-1-ylethoxy)-indan-5-yl]-oxazole; 1-{3-[1-(2-Methyl-pyrro!idin-1-yl)-indan-5-yIoxy]-propyl}-azepane;

1.[5.(3-Pjperidin-1-ylpropoxy)-indan-1-yn-octahydroindole;

[5-(3-Dimethyiamino-2,2-dimethyl-propoxy)-indan-1-yl]-isopropyl-methyiamine;

1-[5-(1,3-Dimethyl-pyrrolidin-3-ylmethoxy)-indan-1-yl3-2-methyl-piperidine;

2-{1-Morpholin~4-ylindan-5-yloxymethyI)-hexahydroρyrro!izine; ^-(i-Aza-bicycloIS.S.Ijnon-S-yloxyJ-T-chioro-I^.S^-tetrahydro-naphthalen-i-yl]- dimethylamine;

2-(1-Piperidin-1-ylindan-5-yIoxy)-octahydro-quino)izine;

7-(1-Morpholin-4-ylindan-5-yloxy)-octahydro-indolizine;

4-[5-(1-Methyl-piperidin-4-yIoxy)-indan-1-yl]-morpholine; [5-(2,6-Dimethyi-piperidin-4-yloxy)-indan-1-yI]-diethylamine;

[S-tθ-Aza-bicyclotS.S.Ilnon-S-yioxyj-indaπ-i-yπ-diethylamine;

[5-(1,4-Dimethyl-piperidin-4-yloxy)-indan-1-yl]-dimethylamine;

3-[2-(1-Pyrrolidin-1-yiindan-5-y!oxy)-ethyi]-oxazolidine;

Dibenzyl-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-amine; Bis-ρyridin-2-ylmethyl-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-amine;

1-[2-(1-Pyrrolidin-1-ylindan-5-yloxy)-ethyl]-azepane;

1-Methyl-4-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-[1,4]diazepane;

A-[2-{ 1 -Pyrrolidin-1 -y Ii ndan-5-yioxy )-ethy I]-[1 ,4]oxazepa ne;

Diethyl-[2-(6-fluoro-1-pyrrolidin-1-ylindan-5-yloxy)-ethyI]-amine; [2-(6-Fluoro-1-pyrrolidiπ-1-ylindan-5-yloxy)-1,1-dimethyl-ethyl]-dime{hylamine;

[4-(6-Chloro-1-pyrrolidin-1-ylindan-5-yloxy)-butyi]-dimethylamine;

Diisopropyl-[4-(1-pyrrolidin-1-ylindan-5-yloxy)-butyl]-amine;

3-(1-Pyrrolidin-1-ylindan-5-yloxy)-1-aza-bicyclo[3.3.13nonane;

[δ^i-Aza-bicycloIS.S.Ijnon-S-yloxy^δ-methoxy-indan-i-ylj-dimethylamine; [6-(1-Aza-bicycloI3.3.1]noπ-3-yloxy)-7-chloro-1,2,3,4-tetrahydro-naphthalen-1-yl]- dimethylamine; and

^-(i-Pyrrolidin-i-ylindan-S-yloxyJ-cyclopentyll-dimethylamine. The most preferred examples of compounds according to the present invention include:

1-[2-(1-Pyrrolidin-1-ylindan-5-yIoxy)-ethyl]-piperidine;

1-Benzyl-3-(1-pyrrolidin-1-yIindan-5-yloxy)-pyrrolidine; 1-Benzyl-3-(1-pyrrolidin-1-ylindan-5-y!oxy)-pyrrolidine;

1-[3-(1-Pyrrolidin-1-ylindaπ-5-yloxy)-2,2-dimethyl-propyl]-diethylamine;

1-[2-(1-Pyrrolidin-1-y!indan-5-yloxy)-ethyl]-diisopropylamine;

1-[3-(1-Pyrrolidin-1-ylindan-5-yloxy)-propyl]-piperidine;

1-[3-(1-Piperidin-1-ylindan-5-yloxy)-propyl]-diethylamine; 1-Benzyi-3-{1-piperidin-1-ylindan-5-yioxy)-pyrro]idine;

1-[3-(1-Piperidin-1-ylindan-5-yloxy)-propyl]-piperidine; i-^-fi-Morpholin-i-yliridan-S-yloxy^^-dimethylpropyll-diethylamine;

1-[3-(1-Morpholin-1-ylindan-5-yloxy)-2,2-dimethylpropyl]-pyrrolidine;

1-[3-(i-Morpholin-1-ylindan-5-yloxy)-propyl]-piperidine; 1-[2-(1-Piperidin-1-yiindan-5-yloxy)-ethyl]-piperidine;

1-[3-(1-Morphoiin-1-ylindan-5-yloxy)-propyl3-diethylamine;

1 -[3-{ 1 -Pyrrol idin-1 -yli ndan-4-yloxy )-propy l]-piperidine;

1-Benzyl-3-{1-pyrrolidin-1-ylindan-4-yloxy)-pyrrolidine;

1-Benzyl-2-[(1-ρyrrolidin-1-yllndan-4-yloxy)methyi]-pyrrolidine; 1-Benzyl-3-(1-pyrrolidin-1-ylindan-4-yloxy)-pyrrolidine;

1-[3-(1-Pyrrolidin-1-ylindan-4-yloxy)-propyl]-diethylamine;

1-Benzyl-3-(1-pyrrolidin-1-ylindan-4-yloxy)-piperidine;

N-IVIethyl-[2-(1-piperidin-1-ylindan-4-yloxy)-ethyl]-isopropylamine;

1-Ben∑yl-4-(1-piperidin-1-ylindan-4-yloxy)-piperidine; [2-(1-Piperidin-1-ylindan-4-yloxy)-ethyl]-diethylamine;

N-Benzyl-[2-(1-piperidin-1-ylindan-4-yloxy)-ethyl]-methylamine;

1-Methyl-2-[(1-piperidin-1-ylindan-4-yloxy)methyl}-pyrrolidine;

1-[2-(1-Piperidin-1-ylindan-4-yloxy)-ethyl]-ρiρeridine;

[3-(1-Piperidin-1-ylindan-4-yloxy)-propyl]-dimethylamine; [3-(1-Piρeridin-1-ylindan-4-yloxy)-2,2-dimethyl-propyl]-dimethylamine;

1-Benzyl-2-[{1-piperidin-1-ylindan-4-yloxy)methyl]-pyrrolidine;

1-Benzyl-3-(1-piperidin-1-ylindan-4-yloxy)-pyrrolidine;

1-[3-(1-Piperidin-1-ylindan-4-yloxy)-propyl]-diethylamine; and

1-[3-(1-Morpholin-1-ylindan-4-yloxy)-propyl]-piperidine.

Detailed Description of the Invention The compounds of formula I according to the invention may be prepared by the general procedure shown in Schemes 1 and 2.

Scheme 1

Thus, 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 HNR¹R² 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. For example, 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 (TiCI₄) or titanium isopropoxide (Ti(O-IPr)₄) to produce an intermediate imine of the general formula VHI:

through the elimination of water. Alternatively, refluxing a solution of Il and amine HNR¹R² in a solvent like toluene in the presence of a catalytic amount of para-toluenesulfonic acid, with provision for removal of the water by using a Dean-Stark trap or activated molecular sieves, may also be employed to effectively produce the intermediate imine VIII. This imine may then be converted in sjtu, or in a separate step following its isolation, to the amino-phenol intermediate III. This can be accomplished by reduction of the C=N double bond of VIII using, for example, boron reagents like sodium borohydride (NaBH₄), sodium cyanoborohydride (NaBHsCN), sodium triacetoxyborohydride (NaBH(OAc)₃) and the like, in reaction inert solvents like dichloromethane, methanol, THF or dioxane. Alternatively, the imine VIJI can be reduced using catalytic hydrogenation conditions, e.g., employing hydrogen gas (H₂) 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 ⁰C up to the boiling point of the solvent employed and at pressures in the range of about one to five atmospheres of hydrogen gas. Other related examples for the transformation of similar compounds may be found in the literature, for example: Barney, CL et aj, Tetrahedron Letters. 1990, 31:5547; Bringmann, G et a], Justus Liebiqs Annalen Chemie. 1990, 795; ibid, Tetrahedron Letters. 1989, 30:317; Eleveld, MB et al, Tetrahedron Letters. 1984, 25(45): 5187.

Subsequently, 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 R⁵-A, wherein R⁵ is as defined previously and A is a leaving group including halogen (e.g., Cl, Br, I)₁ mesylate (i.e., -OSO₂CH₃, or -OMs) or tosylate (i.e., -OSO₂C₆H₅, or -OTs), in the presence of a base and in a reaction inert solvent, as depicted in pathway b. 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.

Scheme 2

The compounds of the present invention, i.e., those of general formula I, may also be prepared via the routes shown in Scheme 2. Thus, 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. For example, 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. Alternatively, a ketone of the general formula VII, wherein L¹ is a suitable leaving group (i.e., F, OMs, etc.), may be reacted with a reagent of general formula R⁵-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.). In some situations, it may also be advantageous to initially convert the intermediate ketone IV to the corresponding benzylic alcohol of general formula V (pathway f.) by using a reducing agent such as NaBH₄ in a solvent like methanol, then to activate the benzylic alcohol V (pathway g.) to produce an intermediate of formula Vl in which L² is a leaving group (e.g., OMs, OTs₁ Cl), and finally to displace the leaving group L² with a suitable 1° or 2° amine of formula HNR¹R² (pathway h.}. in the examples and descriptions that follow, the abbreviations used are intended to have the following, general meaning: bm: broad multipiet (NMR) bs: broad singlet (NMR) dd: doublet of doublets (NMR) d.e.: diatomaceous earth, filter agent DMA: dimethylacetamide DMF: dϊmethyformamide DSMO: dimethylsulfoxide LRMS: low resolution mass spectrometry calcd; calculated d; doublet (NMR) EtOAc: ethyl acetate J: coupling constant (NMR) LAH: lithium aluminum hydride m: multipiet (in NMR) min: minute(s) mfe: mass to charge ratio (in mass spectrometry) obsd: observed Rf: retention factor (in chromatography)

Rt: retention time (in chromatography) rt: room temperature s: singlet (NMR), second(s) t: triplet THF: tetrahydrofuran tic: thin layer chromatography

Solvents were purchased and used without purification. Yields were calculated for material judged homogenous by thin layer chromatography and NMR. Thin layer chromatography was performed on Merck Kieselgel 60 F 254 plates eluting with the solvents indicated, visualized by a 254 nm UV lamp, and stained with either an aqueous KMnO₄ solution or an ethanolic solution of 12-molybdophosphoric acid. Flash column chromatography was performed with using either pre-packed Biotage*' or ISCO® columns using the size indicated. Nuclear magnetic resonance (NMR) spectra were acquired on a Unity 400 or 500 at 400 MHz or 500 MHz for ¹H, respectively, and 100 MHz or 125 MHz for ¹³C NMR₁ respectively. Chemical shifts for proton ¹H NMR spectra are reported in parts per million relative to the singlet of CDCI₃ at 7.24 ppm. Chemical shifts for ¹³C NMR spectra are reported in parts per million downfield relative to the centerline of the triplet of CDCI₃ at 77.0 ppm. Mass spectra analyses were performed on an APCI Gilson 215, micromass ZMD (50% Acetonitrile / 50% water) spectrometer.

Reactions under microwave conditions were done using 2-5mL round bottom vials, fitted with septa. The vials containing the reactants were inserted into the reaction chamber of a EMRYS™ Creator microwave apparatus (maximum power of 300 W) from Personal Chemistry Inc., 25 Birch St., Bldg C, Suite 304, Milford, MA 01757 and heated to the appropriate temperature for a the prescribed period of time. HPLC was performed according to the following methods:

Method A: Preparative conditions (Waters 600 & Waters 2767 Sample Manager); Column: Waters Symmetry C₁₆, δμm, 30 x 150 mm steel column, part # WAT248000, serial # M12921A01; solvent A - 0.1% Trifluoroacetic acid/water; solvent B - Acetonitrile; volume of injection: 850 μl_; time 0.0, 100% solvent A, 0% solvent B, flow 20; time 2.0, 100% solvent A, 0% solvent B₁ flow 20; time 12.0, 0% solvent A₁ 100% solvent B, flow 20; time 15.0, 0% solvent A, 100% solvent B₁ 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 (micromaεsZO) conditions; Capillary(kV): 3.0; Cone (V): 20; Extractor (V): 3.0; RF Lens (V): 0.5; Source temp. (⁰C): 120; Desolvation temp. (⁰C): 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 C₁₉ column, 5μm, 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 μL; 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. (⁰C): 120; Desolvation temp. (⁰C): 360; Desolvation gas flow (UhT): 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/miα): 1. PDA (Waters 996) Settings; Start/End wavelength (nm): 200/600; Resolution: 1.2; Sample Rate: 1;. Channels: TIC₁ 254 nm and 220 nm.

Method C: Preparative conditions (Waters 600 & Waters 2767 Sample Manager);

Column: Waters Symmetry C₁₆, 5μm, 30 x 150 mm steel column, part # WAT248000, serial #

M12921A01; solvent A - 0.1% Trifluoroacetic acid/water; solvent B - Acetonitrile; volume of injection: 850 μL; time 0.0, 90% solvent A, 10% solvent B, flow 20; time 10.0, 0% solvent A, 100% solvent B₁ flow 20; time 12.0, 0% solvent A, 100% solvent B, flow 20.

Mass spectral (micromassZO) conditions; Capillary(kV): 3.0; Cone (V); 20; Extractor (V): 3.0; RF Lens (V): 0.5; Source temp. (⁰C): 120; Desolvation temp. (⁰C): 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 following intermediates and examples were prepared by the general procedures described above: Intermediate 1-1

1 -Pyrrolidin-1 -yli ndan-5-ol.

A mixture of 5-hydroxy-indanone (0.296 g, 2.0 mmol, Aldrich Chemical Co.) and pyrrolidine (0.284 g, 0.334 mL, 4.0 mmol) in anhydrous DMA was treated with titanium isopropoxide (1.71 g, 1.78 mL, 6.0 mmol) and heated while stirring under a N≤ atmosphere for 4 h. After cooling to rt, a solution of sodium triacetoxyborohydride (1.696 g, 8.0 mmol), 3 mL DMA and 7 mL dichloromethane was added and the mixture was stirred under Na at rt for an additional 24 h. The crude reaction mixture was poured over a mixture of 75 mL of saturated aqueous NaHCO₃ and 30 mL of 20% n-butanol in ethyl acetate. After stirring this mixture for 15 min, the aqueous layer was separated and washed with 50 mL of 20% n-BuOH in EtOAc, the organic layers were combined, dried and concentrated in vacuo. Flash chromatography was used to purify the crude phenol, which was stored as a 0⁷.3 M DMSO solution until used in the next step.

Mass spectrum (LC/MS, m/z) caicd for C₁₃Hi₇NO: 203.29; obsd. 204.13 (M+1). In the same manner, the following amino-phenols were also prepared:

Intermediate 1-2

1-Piperidin-1-ylindan-5-ol,

Mass spectrum (LCIUS, m/z) calcd for C₁₄H₁₉NO: 217.31; obsd. 218.16 (M+1).

Intermediate 1-3

1-Morpholin-4-ylindan-5-ol.

Mass spectrum (LC/MS, m/z) calcd for C₁₃Hi₇NO₂: 219.29; obsd. 220.15 (M+1). Intermediate 2-1

1-Pyrrolidin-1-ylindan-4-ol.

Mass spectrum (LC/MS, m/z) calcd for C₁₃H₁₇NO: 203.29; obsd. 204.17 (M+1).

Intermediate 2-2

1 -PSperid in-1 -ylindan-4-ol.

Mass spectrum (LC/MS, m/z) calcd for C₁₄H₁₈NO: 217.31; obsd. 218.22 (M+1).

Intermediate 2-3

1 -Morpholin-4-ylindan-4-ol.

Mass spectrum (LC/MS, m/z) calcd for C₁₃H₁₇NO₂: 219.29; obsd. 220.19 (M+1). Example 1

1-f2-{1-Pyrrolidin-1-viindan-5-yloxy)-ethvn-piperidine.

1-{2-hydroxyethyl)-piperidiπe (0.258 g, 0.266 mL, 2.0 mmol, Aldrich Chemical Co, Milwaukee, Wl) in 5.0 mL of dichloromethane was treated with methanεsulfonyl chloride (0.23 g, 0.155 mL, 2.0 mmol) and stirred under N₂ at rt for 1.5 h. The solvent was removed in vacuo and the residue was redissolved in anhydrous DMSO to make a 0.225 M solution.

1-Pyrrolidin-1-yiindan-5-ol (0.5 mL of the 3.0 M solution in DMSO described as Intermediate 1-1) was combined with 1.0 mL of the 0.225 M mesylate solution prepared above and stirred under N₂, in the presence of cesium carbonate (0.489 g, 1.5 mmol Cs₂CO₃), at 80 ⁰C for 2 h. After cooling to rt, the crude reaction mixture was filtered, the filter was washed with 2.0 mL of EtOAc, and the solvent was removed in vacuo to give the crude product.

Mass spectrum (LC/MS, m/z) calcd for C₂₀H₃₀N₂O: 314.24; obsd. 315.1954 (M+1). in the same manner, the following compounds were also prepared:

Determination of Biological Activity

The in vitro affinity of the compounds in the present invention at the rat or human histamine H₃ 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 MgCI₂ (pH to 7.4 at 4⁰C). 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 MgCI₂ (pH to 7.4 at 4 ⁰C) and centrifuged again. The final pellet is re-suspended in 50 mM Tris HCI containing 2 mM MgCI₂ (pH to 7.4 at 25 ⁰C) 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 ³H-N-methylhistamine). After a 1-hour incubation, assay samples are rapidly filtered through Whatman GF/8 filters and rinsed with ice-cold 50 mM Tris buffer (pH 7.4) using a Skatron cell harvester. Radioactivity is quantified using a BetaPlate scintillation counter. The percent inhibition of specific binding can then be determined for each dose of the compound, and an IC50 or Ki value can be calculated from these results. When tested using the above method for determination of binding activity using rat tissue, the compounds of examples 1-48 had Ki values of less than 1 μM.

Claims

CLAiMS

1 , A com pound of formula I

I or the pharmaceutically acceptable εalt{s) thereof, wherein:

R¹ and R² are independently selected from hydrogen, (C₁-C₃)-alkyl, (C₀-C₃)-alkyl-aryl, optionally substituted with up to 3 fluorine atoms, or

R¹ and R² together with the nitrogen to which they are attached form a 3-10 member mono- or bi-cyciic ring system, optionally with up to three heteroatomε selected from N, O, S included and with 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-C₆ alkyl, aryl, heteroaryl, F, OH or

NR⁶R⁷;

R³ is (Ci-C_β)-alkyl, aryl or heteroaryl, optionally substituted with up to 3 fluorine atoms;

R⁴ is hydrogen, halogen, (Ci-Cβ)-alkyl or (C₃-C₇)-cycloalkyl, (Ci-C₆)-alkoxyl or (C₃- C₇)~cycloalkoxy! (optionally substituted with up to 3 fluorine atoms), aryl, heteroaryl;

R⁵ is (CR⁸RV(CR¹⁰R¹VB, where R⁸, R⁹, R¹⁰ and R¹¹ 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 heterocycloalkyl containing up to 3 heteroatoms selected from N,

O, S (e.g., azetidine, pyrrolidine, pipεridine, azepine, morpholine, thiomorpholine, piperazine or 1,4-diazepine) or NR¹²R¹³;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are independently selected from hydrogen, C₁-C₆ alkyl, (C₁-Cg alkyl)-aryl, (C₁-C₆ alkyl)-heteroaryi; or R¹² and R¹³ together with the nitrogen to which they are attached form a 3-10 member mono- or bi-cyclic ring system (e.g., azepine, piperidine, pyrrolidine or morpholine), and with the proviso that NR¹²R¹³ is not NH₂. m is O, 1, 2, 3 or 4; n is O, 1, 2 or 3; and p is O to 3.

2. The compound of Claim 1, wherein R¹ and R² together with the nitrogen to which they are attached form a pyrrolidine ring.

3. The compound of claim 1, wherein R¹ and R² together with the nitrogen to which they are attached form a piperidine ring.

4. The compound of claim 1, wherein R¹ and R² together with the nitrogen to which they are attached form a morpholine ring. 5. The compounds of claim 1 selected from the group consisting of:

1-[2-(3-Pyrrolidin-1-ylindan-5-yloxy)-ethyl]-piperidine; 1-(2-(5-Pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-piperidine; 4.[2-{5-Pyrrolidin-1-yl-5,6,7,8-tetrahydro-naρhthalen-2-yloxy)-ethyi]-morρholine; i-p-fδ-PyrroIidin-i-yl-S.BJ.δ-tetrahydro-naphthalen^-yloxyJ-ethyQ-pyrrolidine; i-β-fδ-Pyrrolidin-i-yl-ej.δ.θ-tetrahydro-SH-benzocyclohepten-Σ-yloxyJ-ethyl]- piperidine;

4-[2-(5-Pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-ben2ocyclohepten-2-yloxy)-ethyl]- morpholine;

2-{2-Morpholin-4-y|ethoxy)-6,7,8,9-tetrahydro-5H-ben2ocyclohepten-5-yl]- dimethylamine;

4-[2-(2-Pyrrolidin-1-ylethoxy)-6,7_l8,9-tetrahydro-5H-benzocyclohepten-5-yl]- morpholine;

1-[2-(5-Pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-3-yloxy)-propyl]- pyrrolidine; 1-[1-(5-Pyrrolidin~1-yl-6J,8,9-tetrahydro-5H-benzocyclohepten-3-yloxy)-propyl]- pyrrolidine;

1-[3-(3-Pyrrolidin-1-ylindan-5-yloxy)-propyl]-piperidine; 2-[6-(2-Piperidin-1-ylethoxy)-indan-1-yl]-2,3-dihydro-1H-isoindole; [6-(2-Dimethylamino-ethoxy)-3,3-dimethyI-indan-1-yl3-dirnethylamine; [7-(1-Aza-bicyclo[2.2.1]hept-3-yloxy)-1,2,3,4-tetrahydro-naphthaien-1-yi]- dimethylamine;

1-Methyl-2-{8-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-ρiperidine; [5-( 1-Methyl-piperidtn-2-ylmethoxy)-1 ,2, 3,4-tetrahydro-naphthalen-1-yl]-diethylamine; 4-[5-(1-EthyI-pyrrolidin-2-ylmethoxy)-1_l2₍3,4-tetrahydro-naphthalen-1-yl]-thio- morpholine;

Benzyl-[2-(1-pyrroiidin-1-ylindan-5-yloxy)-ethyl]-methylatnine; Pyridin-4-ylmethyl-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-methylamine; Pyrimϊdin-4-ylmethyl-[2-(1-ρyrrolidin-1-ylindan-5-yloxy)-ethyl]-methylamine; Pyrimidin-4-yl-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyi]-methylamine; 2-[2-(1-Pyrrolidin-1-ylindan-5-yloxy)-ethyi]-octahydropyrido[1,2-a3pyrazine;

{5-[2-(4-methyl-piperazin-1-yl)-ethoxy]-indan-1-y|}-dimethylamine; 4-[2-(1-Piperidin-1-ylindan-5-yloxy)-ethyl]-thiomorpholine; 4-[2-(1-Piperidin-1-ylindan-5-yloxy)-ethyl]-thiomorpholine 1-oxide;

4-[2-(1-Piperidin-1-ylindan-5-yloxy)-ethyl3-thiomorpholine 1,1-dioxide;

1-{5-[1-(1-Methyl-pyrrolidin-3-yl)-ethoxy]-indan-1-yl}-piperidine;

1,

5-Dimethyl-2-(1-pyrrolidin-1-ylindan-5-yloxymethl)-pyrrotidine; 1-[2-(6-Fluoro-1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-piperidine;

1-[2-(6-Methoxy-1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-2-methyl-piperidine;

1-[2-(3-Methoxy-5-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]- piperidiπe;

3-[2-(6-Chloro-1-pyrro1idin-1-ylindan-5-yloxy)-ethyl]-oxazoiidin-2-one; 2-[1-Pyrrolιdin-1-yl-6-(3-pyrrolidin-1-ylpropoxy5-indan-5-yl]-pyridine;

[6-(3-Dimethylamiπo-proρoxy)-5-ρyrimidin-2-yiindan-1-yl]-dimethylamine;

9-Methyl-3-(3-pyrrolidin-1-yIindan-5-yloxy)-9-aza-bicyclo[3.3.1]nonane;

2-[2-(3-Pyrrolidin-1-ylindan-5-yloχy)-ethyt]-1-aza-bicyclo[2.2.1]heptane;

2-[2-(3-PyrroIidin-1-ylindan-5-yloxy)-ethyl]-1-aza-bicyclo[2,2.2]octane; 1-[2-(5-Pyrrolidin-1-yl-3-trifluoromethoxy-5,6,7,8-tetrahydro-naphthaien-2-yloxy)- ethylj-piperidine;

[2-(3-CycIopentyloxy-5-pyrrolidin-1-yl-5,6,7,8-tetrahydro-naphthaien-2-yioxy)-ethyl]- dimethylarnine;

2-t3-Pyrrolidin-1-yl-6-(2-pyrro!idin-1-y)ethoxy)-indan-5-yl]-pyridine; 2-[3-Pyrrolidin-1-yl-6-(2-pyrrolidin-1-ylethoxy)-tndan-5-yl]-oxazole;

1-{3-[1-(2-Methyl-pyrrolidin-1-yl)-indan-5-yloxy]-proρyl}-azepane;

1-[5-(3-Piperidin-1-ylpropoxy)-indan-1-yl]-ociahydroindo!e;

[5-(3-Dimethy]amino-2,2-dimethyl-propoxy)-indan-1-yl)-isopropyl-methylamine;

1-[5-(1,3-Dimethyl-pyrrolidin-3-ylmethoxy)-indan-1-yl]-2-methyl-piperidine; 2-(1-Morpholin-4-ylindan-5-yloxymethyl)-hexahydropyrrolizine;

^-(i-Aza-bicycloIS.S.^non-S-yloxyJ-T-chloro-I^.S^-tetrahydro-naphthalen-i-yl]- dimethylamine;

2-(1-Piperidin-1-ylindan-5-yIoxy)-octahydro-quinolizine;

7-(1-Morpholin-4-ylindan-5-yloxy)-octahydro-indoliziπe; 4-[5-(1-Methyl-piperidin-4-yloxy)-indan-1-yl]-morpholine;

[5-(2,6-Dimethyl-piperidin-4-yioxy)-iτidan-1-yl]-diethyIamine;

[S-fθ-Aza-bicycloIS.S.Ilnon-S-yloxyJ-indan-i-ylJ-diethylamine;

[5-(1,4-Dimethyl-piperidin-4-yloxy)-indan-1-yl]-dimethylamine;

3-[2-(1-Pyrrolidin-1-ylindan-5-yloxy)-ethyl]-oxazolidine; Dibenzyl-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyi]-amine;

Bis-pyridin-2-ylmethyl-[2-(1-pyrrolidin-1-ylindan-5-yioxy)-ethyl]-amine;

1-[2-(1-Pyrrolidin-1-ylindan-5-yloxy)-ethyl]-azeρane; 1-Methyl-4-[2-(1-pyrrolidin-1-ylindan-5-yloxy)-ethyl]-[1,4]diazepane;

4-[2-(1-Pyrrolidin-1-ylindan-5-yloxy)-ethyl]-[1,4]oxazepane;

Diethyl-[2-(6-fluoro-1-pyrrolidin-1-ylindan-5-yloxy)-ethyI]-amine;

[2-(6-Fluoro-1-pyrrolidin-1 -ylindan-5-yloxy)-1 , 1-dimethyl-ethylj-dimethylamine; [4-(6-Chloro-1-pyrrolidin-1-ylindan-5-yloxy}-butyl]-dimethy!amiπe;

Diisopropyl-[4-(1-pyrroiidin-1-ylindaπ-5-yloxy)-butyl]-amine;

3-{1-Pyrrotidin-1-yHndan-5-yloxy)-1-aza-bicyclo[3.3.1]honane; ^'

[S-fi-Aza-bicyclop.S.ijnon-S-yioxyJ-β-methoxy-indan-i-ylJ-dimethylamine;

[6-(1-Aza-bicycloI3.3.1]non-3-yloxy)-7-chloro-1₍2,3,4-tetrahydro-naphthalen-1-yl]- dimethylamine; and

[S^I-Pyrrolidin-i-ylindan-δ-yloxyJ-cyclopentylJ-dimethylamine.

6. The compounds of claim 1 selected from the group consisting of:

1-[2-(1-Pyrrolidin-1-ylindan-5-y!oxy)-eihyl]-piperidine;

1-Benzyl-3-{1-ρyrrolidin-1-ylindan-5-y)oxy)-pyrrolidine; 1 -Benzyl-3-( 1 -py rrolid in-1 -ylindan-5-y loxy )-py rrolidine;

1-[3-(1-Pyrroiidin-1-ylindan-5-yloxy)-2,2-dimethyl-propyl]-diethylamine;

1 -[2-( 1 -Pyrrol idin-1 -yli ndan-5-y loxy )-ethy l]-diisopropy lami ne;

1-[3-(1-Pyrrolidin-1-ylindan-5-yloxy)-propyl]-piperidine;

1-[3-(1-Piperidin-1-ylindan-5-yloxy)-propyl]-diethylamine; 1-Benzyl-3-{1-piperidin-1-ylindan-5-yloxy)-ρyrroiidine;

1 -[3-( 1 -Piρeridin-1 -ylindan-5-y loxy )-propy l]-piperid ine; i-IS-fi-Morpholin-i-ylindan-S-yloxy^Σ-dimethylpropylJ-diethylamine;

1-[3-(1-Morpholin-1-ylindan-5-yloxy)-2,2-dimethylρropyl]-pyrrolidine;

1-[3-(1-Morpholin-1-ylindan-5-yloxy)-propyl]-piperidine; 1-[2-(1-Piperidin-1-ylindan-5-yloxy)-ethyl3-piperidine;

1-[3-(1-Morpholin-1-ylindan-5-yloxy)-propyl]-diethylamine;

1-[3-{1-Pyrrolidiπ-1-ylindan-4-yloxy)-propyl]-piρeridine;

1-Benzyl-3-(1-pyrrolidin-1-ylindan-4-yloxy)-pyrrolidine;

1-Benzyl-2-[(1-pyrrolidin-1-ylindan-4-yloxy)methyl]-pyrro!idine; 1-Benzyl-3-(1-ρyrrolidin-1-ylindan-4-yloxy)-pyrrolidine;

1-[3-(1-Pyrrolidin-1 -ylindan-4-yloxy)-propyl]-diethylamine;

1-Benzyl-3-(1-pyrrolidin-1-ylindan-4-y!oxy)-piperidine;

N-methyl-[2-(1-piperidin-1-ylindan-4-yloxy)-ethyl]-isopropylamine;

1-Benzyl-4-(1-piperidin-1-ylindan-4-yloxy)-piρeridine; [2-(1-Piperidin-1-ylindan-4-yloxy)-ethyl]-diethylamine;

N-Benzyl-[2-(1-piperldin-1-ylindan-4-y!oxy)-ethyI]-methylamine;

1-Methyl-2-[(1-piperidin-1-ylindan-4-yloxy)methyl]-pyrrolidine; 1-[2-(1-Piperidin-1-ylindan-4-yloxy)-ethyl]-piperidine; [3-(1-Piρeridin-1-ylindan-4-yloxy)-propyl]-dimethylamine; [3-(1-Piperidin-1-ylindan-4-yloxy)-2,2-dimethyl-propyl]-dimethylamine; 1-Benzyl-2-[(1-piperidin-1-yliπdan-4-yioxy)methyl3-pyrrolidiπe; 1-Benzyl-3-(1-piperidin-1-yiindan-4-yloxy)-pyrroiidine;

1-[3-{1-Piperidin-1-ylindan-4-yloxy)-propyl]-diethy!amine; and 1-[3-(1-Morpholin-1-ylindan-4-yloxy)-propyl]-piperidine.

7. The compound of claim 1, wherein R¹ and R² together with the nitrogen to which they are attached form a pyrrolidine ring, n is equal to one, R³ and R⁴ are both hydrogen and R⁵O is attached at position c.

8. A method of treatment of a disorder or condition that may be treated by antagonizing histamine-3 (H₃) receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described in Claim 1.

9. A method of treatment of 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 method comprising administering to a mammal in need of such treatment a compound of formula I as described in Claim 1.

10. The method of Claim 9, wherein the disorder or condition is selected from the group consisting of anxiety disorders, attention deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), respiratory diseases, and obesity.

11. The method of Claim 9, wherein the disorder or condition is a respiratory disease selected from the group consisting of adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis. ^■

12. A pharmaceutical composition for treating allergic rhinitis, nasal congestion or allergic congestion comprising: a) an H₃ receptor antagonist compound of formula 1; or a pharmaceutically acceptable salt thereof; b) an H₁ receptor antagonist such as cetirizine; or a pharmaceutically acceptable salt thereof; and c) a pharmaceutically acceptable carrier; wherein the active ingredients (a) and (b) above are present in amounts that render the composition effective in treating allergy rhinitis, nasal congestion or allergic congestion.

13. A pharmaceutical composition for treating depression and mood disorder comprising: a) an H₃ receptor antagonist or a pharmaceutically acceptable salt thereof; b) a neurotransmitter uptake blocker, or c) a pharmaceutically acceptable salt thereof; wherein the active ingredients (a) and (b) above are present in amounts that render the composition effective in treating depression and mood disorder.

14. The composition according to claim 13 wherein the H₃ receptor antagonist and the neurotransmitter blocker are given simultaneously.

15. The composition according to claim 12 wherein the H₃ receptor antagonist and the H-, receptor antagonist are given simultaneously.

16. The pharmaceutical composition of claim 13 wherein the neurotransmitter uptake blocker are selected from SSRI; sertraline, fluoxetine and paroxetine.