SPIROCHROMANE ANTAGONISTS OF THE H-3 RECEPTOR

Background of the Invention

This invention is directed to compounds of formula I described herein, to a pharmaceutical composition comprising such compounds, and to methods of treatment of disorders or conditions that may be treated by antagonizing histamine-3 (H3) receptors using such compounds.

Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) that are commonly treated with antagonists of histamine or "antihistamines." It has also been established that histamine receptors exist in at least two distinct types, referred to as 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 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.

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., Circ. 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., Neuropsychopharmacology (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); (Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75- 78); (Haas et al., Behav. Brain Res. (1995) 66, 41-44); (De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986) 283, 193-198); (Kamei et al., Psychopharmacology (1990) 102, 312- 318); (Kamei and Sakata, Japan. J. Pharmacol. (199 1) 57, 437-482); (Schwartz et al., Psychopharmacology; The fourth Generation of Progress, Bloom and Kupfer (eds.), Raven Press, New York, (1995) 3 97); (Shaywitz et al., Psychopharmacology (1984) 82, 73-77); (Dumery and Blozovski, Exp. Brain Res. (1987) 67, 61-69); (Tedford et al., 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 H3 Receptor, Leurs and Timmerman (ed.), Elsevier Science, Amsterdam, The Netherlands (1998); (Leurs et al., Trends in Pharm. Sci. (1998) 19, 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 al., 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, (2000)); (Hatta, E., K Yasuda 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, 5(5); 321 -330, (1995)); (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", Clinical Science 87(2):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 receptors 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 disease, mood and attention adjustments, including attention deficit hyperactive disorder (ADHD), 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 WO96/38142. Non-imidazole 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 0982300A2 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. Other receptor antagonists have been described in WO02/32893 and WO02/06233.

This invention is directed to histamine-3 (H3) receptor antagonists of the invention 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 H1 R, 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 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 spirochromane amines has a high and specific affinity to the histamine H3 receptor. Summary of the Invention

This invention is directed to a compound of formula I:

' or a pharmaceutically acceptable salt thereof, wherein

R ² is (Ci-C ₄ )alkyl;

R ¹ is selected from the group consisting of phenyl, naphthyl, 5 to 6-membered heteroaryl, and

C(=O)NR ³ R ⁴ ; wherein said heteroaryl contains 1 to 4 heteroatoms independently selected from N, O, and S; and wherein said phenyl, naphthyl, and heteroaryl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (CrC ₆ )alkyl,

(C ₁ -C ₆ )BIkOXy, carbonyl, carboxyl, cyano, nito, -C(=O)(C ₁ -C ₆ )alkyl, -C(=O)NR ₃ R ₄ , and -SO _p (C ₁ -C ₄ )alkyl, wherein p is 1 or 2; wherein R ³ and R ⁴ are each independently selected from the group consisting of

hydrogen;

(CrC _a )alkyl optionally substituted with -OH or 1 to 4 halogens; (Ci-C ₄ )alkyl optionally substituted with a substituent selected from the group consisting of OH, 1 to 4 (CrC ₄ )alkyl groups, bicyclo[2.2.1]hept-2-ene, (C ₃ - C ₇ )cycloalkyl, (CrC^dialkylamino, (C ₆ -Ci ₄ )aryl optionally substituted with a halogen and optionally substituted with (C ₆ -Ci ₀ )aryloxy optionally substituted with 1 to 2 halogens, and 5-10-membered heteroaryl optionally substituted with (C ₆ -C ₁₀ )aryl and optionally substituted with 1 to 3 (C-|-C ₄ )alkyl groups; (C ₃ -C ₇ )cycloalkyl optionally substituted with hydroxy (C ₁ -C ₄ JaIRyI; (C ₆ -C ₁₄ )aryl;

-(C ₂ -C ₃ )alkyl-O-(CrC ₃ )alkyl optionally substituted with (C _r C ₃ )alkyl; -(C ₂ -C ₃ )alkyl-S-(C _r C ₃ )alkyl optionally substituted with (C _r C ₃ )alkyl; -(C ₁ -C ₃ )alkyl-C(=O)O-(C ₁ -C ₃ )alkyl; 3 to 8-membered heterocycloalkyl; (C ₆ -C ₁₀ )arylsulfonyl optionally substituted with one or more (CrC ₂ )alkyl;

5 to 10-membered heteroaryl; and (C ₆ -Ci ₄ )aryl-(Co-C ₄ )alkylene-0-(C ₀ -C ₄ )alkyl, wherein each (C ₀ -C ₄ )alkyl and each (C ₀ -

C ₄ )alkylene is optionally substituted with 1 to 4 (CrC ₄ )alkyl; or optionally R ³ and R ⁴ , together with the nitrogen to which they are attached, form a 3 to 7- membered saturated or unsaturated heterocyclic ring, wherein one of the carbons in said heterocyclic ring is optionally replaced by O, S, NR ⁵ or CO, and wherein said ring is optionally fused to a (C ₆ -C ₁₀ )arylene and is optionally substituted at a ring carbon with a substituent selected from the group consisting of

-OH, 5-10-membered heteroaryl optionally substituted with one or more halogens and optionally substituted with one or more (CrC ₂ )alkyl, 5 to 6 membered aryl, (C ₁ -

C ₄ )alkoxy optionally substituted with one or more (d-C ₂ )alkoxy and optionally substituted with one or more optionally and independently substituted with one or more (C _r C ₂ )alkoxy; wherein R ⁵ is selected from the group consisting of hydrogen;

(CrC ₈ )alkyl optionally substituted with 1 to 4 halogens;

5-10-membered heteroaryl optionally substituted with a substituent selected from the group consisting of halogen, (C-|-C ₄ )alkyl, (C ₁ -C ₂ JaIkOXy, (C ₆ -C ₁₀ )aryl, (C ₁ - C ₄ )alkylaminocarbonyl, and cyano; (C^C^alkyl group optionally substituted with a substituent selected from the group consisting of (C ₁ -C ₂ )alkoxycarbonyl, 5-10-membered heteroaryl optionally

substituted with one or more (Ci-C ₂ )alkyl, 1 to 4 (C^C^alkyl, and (C ₃ -

C ₇ )cycloalkyl;

(C ₆ -C ₁₀ )aryl optionally substituted with 1 or 2 (C _r C ₂ )alkyl; (Ci-C ₄ )alky)carbonyl; and (C ₆ -C ₁₄ )aryl-(Co-C ₄ )alkylene-0-(Co-C ₄ )alkyl, wherein each (C ₀ -C ₄ )alkyi and each (C ₀ -

C ₄ )alkylene is optionally substituted with 1 to 4 (CrC ₄ )alkyl.

A preferred embodiment includes compounds of claims 1 wherein

R ² is ethyl; R ¹ is C(=O)NR ³ R ⁴ ; wherein R ³ and R ⁴ are each independently (C _r C ₄ )aIkyl optionally substituted with a substituent selected from the group consisting of OH, 1 to 4 (CrC ₄ )alkyl groups, bicyclo[2.2.1]hept-2-ene, (C ₃ -C ₇ )cycloalkyl, (C _r C ₄ )dialkylamino, (C ₆ -C ₁₄ )aryl optionally substituted with a halogen and optionally substituted with (C ₆ -C ₁₀ )aryloxy optionally substituted with 1 to 2 halogens, and 5-10-membered heteroaryl optionally substituted with (C ₆ -C ₁₀ )aryl and optionally substituted with 1 to 3

(CrC ₄ )alkyl groups;

Another preferred embodiment includes compounds of claims 1 wherein R ² is ethyl; and

R ¹ is phenyl or 5 to 6-membered heteroaryl, wherein said heteroaryl contains 1 to 4 heteroatoms independently selected from N, O, and S; and wherein said phenyl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, (Ci-CβJalkyI, (C ₁ - C ₆ )alkoxy, carbonyl, carboxyl, cyano, nito, -C(=O)(CrC ₆ )alkyl, -C(=O)NR ₃ R ₄ , and -

SO _p (C ₁ -C ₄ )alkyl, wherein p is 1 or 2; wherein R ³ and R ⁴ are each independently (C _r C ₄ )alkyI optionally substituted with a substituent selected from the group consisting of OH, 1 to 4 (CrC ₄ )alkyl groups, bicyclo[2.2.1]hept-2-ene, (C ₃ -C ₇ )cycloalkyl, (CrC ₄ )dialkylamino, (C ₆ -C ₁₄ )aryl optionally substituted with a halogen and optionally substituted with

(C ₆ -Cio)aryloxy optionally substituted with 1 to 2 halogens, and 5-10-membered heteroaryl optionally substituted with (C ₆ -C ₁₀ )aryl and optionally substituted with 1 to 3 (C ₁ -C ₄ )alkyl groups.

Preferred and exemplary embodiments of the present invention include the following compounds of formula I:

N-methyl-N-(2-thienylmethyl)-1 '-ethyl-3,4-dihydrospiro[chromene-2,4 ^l -piperidine]-6- carboxamide,

N-^^methylthioJethyO-i'-ethyl-S^-dihydrospirofchromene^^' -piperidinel-e-carboxamide, N-(2-furylmethyl)-N-methyl-1'-ethyl-3,4-dihydrospiro[chromen e-2,4'-piperidine]-6- carboxamide,

N-cyclopenty]-N-methyl-1'-ethyl-3,4-dihydrospiro[chromene -2,4'-piperidine]-6-carboxannide, 6-[(2-ethylaziridin-1 -yl)Garbonyl]-1'-ethyl-3,4-dihydrospiro[chromene-2,4'-piperi dine], e^e-methoxypyridin-S-yO-i'-ethyl-S^-dihydrospirotchromene^^' -piperidine], 6-[4-(methylsulfonyl)phenyl]-1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine], 4-(1 '-ethyl-Sλ-dihydrospirotchromene^^'-piperidinl-δ-yObenzoic acid,

N-[(3-methyl-2-thienyl)methyl]-1'-ethyl-3,4-dihydrospiro[ chromene-2,4'-piperidine]-6- carboxamide,

1-[4-(1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidin]-6-yl)pheny l]ethanone, 6-(2,5-dihydro-1 H-pyrrol-1-ylcarbonyl)-1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine], 3-(1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidin]-6-yl)-4-me thoxybenzaldehyde, 6-(2,3,4-trimethoxyphenyl)1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine], 6-(2-methoxypyridin-3-yl)-1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine], [3-(1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidin]-6-yl)pheny l]methanol, 1-[2-(1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidin]-6-yi)pheny l]ethanone, 6-[4-(ethylsulfonyl)phenyl]-1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine], 1 '-ethyl-6-pyrimidin-5-yl-3,4-dihydrospiro[chromene-2,4'-pipe ridine], 6-(2-ethoxypyridin-3-yl)-1 '-ethyl-3,4-dihydros ^' piro[chromene-2,4'-piperidine], 6-(4-ethoxyphenyl)-1 '-ethyl-3,4-dihydrospirotchromene-2,4'-piperidine] _I 6-(2-ethoxyphenyl)-1'-ethyl-3,4-dihydrospiro[chromene-2,4'-p iperidine], 1 '-ethyl-6-pyridin-3-yl-3,4-dihydrospirotchromene-2,4'-piperi dine],

6-(4-methyl-3-nitrophenyl)-1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine], 6-(3,4,5-trimethoxyphenyl)-1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine], methyl 4-(1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidin]-6-yl)benzo ate, 1 '-ethyI-6-(4-fluorophenyl)-3,4-dihydrospiro[chromene-2,4'-pi peridine], r-ethyl-6-(4-fluorophenyl)-3,4-dihydrospiro[chromene-2,4'-pi peridine], 3-(1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidin]-6-yl)benzo ic acid, N-^^i '-ethyl-S^-dihydrospirotchromene^^'-piperidinj-δ-yOphenyOac etamide, 6-[3-(1 H-pyrazol-1 -yl)phenyl]1 '-ethyl-3,4-dihydrospiro[chromene-2,4'-pipeπdine], and 6-(2-methoxy-5-methylphenyl)-1'-ethyl-3,4-dihydrospiro[chrom ene-2,4'-piperidine]. This invention is also directed to pharmaceutical composition for treating a disorder or condition that may be treated by antagonizing histamine-3 receptors, the composition comprising a compound of formula I and optionally a pharmaceutically acceptable carrier.

This invention is also directed to 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.

This invention is also directed to a method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, cognitive disorders, Alzheimer's disease, attention-deficit disorder (ADD), attention- deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy- induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastro- intestinal tract, the method comprising administering to a mammal in need of such treatment a compound of formula I.

This invention is also directed to a pharmaceutical composition for treating allergic rhinitis, nasal congestion or allergic congestion comprising: (a) an H3 receptor antagonist compound of formula I or a pharmaceutically acceptable salt thereof; (b) an H1 receptor antagonist 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. This invention is also directed to a pharmaceutical composition for treating ADD,

ADHD, depression, mood disorders, or cognitive disorders comprising: (a) an H3 receptor antagonist compound of Formula I or a pharmaceutically acceptable salt thereof; (b) a neurotransmitter re-uptake blocker or a pharmaceutically acceptable salt thereof; (c) a pharmaceutically acceptable carrier; wherein the active ingredients (a) and (b) above are present in amounts that render the composition effective in treating depression, mood disorders, and cognitive disorders.

In the general formula I according to the present invention, when a radical is mono- or poly-substituted, said substituent(s) can be located at any desired position(s), unless otherwise stated. Also, when a radical is polysubstituted, said substituents can be identical or different, unless otherwise stated.

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™), chlorpheniramine (Chlortrimeton™), loratidine (Claritin™), fexofenadine (Allegra™), or desloratadine (Clarinex™) 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 (SSRI's) like sertraline (Zoloft™), fluoxetine (Prozac™), and paroxetine (Paxil™), or non-selective serotonin, dopamine or norepinephrine reuptake inhibitors for treating ADD, ADHD, depression, mood disorders, or cognitive disorders. The compounds of the present invention may have optical centers and therefore may occur in different enantiomeric configurations. Formula I, as depicted above, includes all enantiomers, diastereomers, and other stereoisomers of the compounds depicted in structural formula I, as well as racemic and other mixtures thereof. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.

The present invention also includes isotopically labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ O, ¹⁵ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ CI, ¹²³ I, respectively. Compounds of the present invention and pharmaceutically acceptable salts of said compounds which contain the aforementioned isotopes and/or- other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, Le ₁ , ³ H, and carbon-14, Le ₁ , ¹⁴ C, isotopes are particularly

preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, Le ₁ , ² H, 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. Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

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. Cognitive disorders include, for example, ADHD, attention-deficit disorder (ADD) or other attention adjustment or 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 ₁ bipolar depression BP II, or major depression with dysthymia; dysthymia; • phobias, including, for example, agoraphobia, social phobia or simple phobias; eating disorders, including, for example, anorexia nervosa or bulimia nervosa; chemical dependencies, including, for example, addictions to alcohol, cocaine, 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; posttraumatic stress disorder; late luteal phase dysphoric disorder; specific developmental disorders; SSRI "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.

Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties,

Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The compounds of the invention may exist in both unsolvated and solvated forms.

The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

Included within the scope of the invention are complexes such as clathrates, drug- host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be

ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

Hereinafter all references to compounds of formula I include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof. The compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula I.

Compounds of formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine. Unless otherwise indicated, the term "halo", as used herein includes fluoro, chloro, bromo and iodo.

Unless otherwise indicated, the term "alkyl", as used herein includes includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl. Unless otherwise indicated, the term "alkoxy", as used herein, includes straight-chain and branched alkoxy groups and includes for example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.

Unless otherwise indicated, the term "alkylene", as used herein, includes a divalent radical derived from straight-chain or branched alkane. Examples of alkylene radicals are methylene, ethylene (1 ,2-ethylene or 1 ,1 -ethylene), trimethylene (1 ,3-propylene), tetramethylene (1 ,4-butylene), pentamethylene and hexamethylene.

Unless otherwise indicated, the term "cycloalkyl", as used herein, unless otherwise indicated, includes non-aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Unless otherwise indicated, the term "heterocycloalkyl", as used herein, refer to non-aromatic cyclic groups containing one or more heteroatoms, prefereably from one to four

heteroatoms, each preferably selected from oxygen, sulfur and nitrogen. The heterocycloalkyl groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocycloalkyl groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, quinolizinyl, quinuclidinyl, 1 ,4-dioxaspiro[4.5]decyl, 1 ,4-dioxaspiro[4.4]nonyl, 1 ,4- dioxaspiro[4.3]octyl, and 1 ,4-dioxaspiro[4.2]heptyl.

Unless otherwise indicated, the term "saturated heterocycle", as used herein, includes a saturated monocyclic groups having 4 to 7 ring members, which contains 1 nitrogen atom. Examples of saturated heterocycles are azetidinyl, pyrrolidinyl and piperidinyl. Unless otherwise indicated, the term "aryl", as used herein, includes and organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, napthyl, indenyl, and fluroenyl. "Aryl" encompases fused ring groups wherein at least one ring is aromatic.

Unless otherwise indicated, the term "heteroaryl" as used herein, includes monocyclic or bicyclic heteroaryl groups having 5 to 9 and 9 to 14 ring members respectively, which contain 1 , 2, 3 or 4 heteroatom(s) selected from nitrogen, oxygen and sulphur. The heteroaryl group can be unsubstituted, monosubstituted or disubstituted. Examples of heteroaryl groups include, but are not limited to thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiadiazinyl, isobenzofuranyl, benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolyl, cinnolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, pyrrolopyrazinyl, pyrrolopyridinyl, and imidazopyridinyl.

Unless otherwise indicated, the term "heterocyclic ring", as used herein, refers to both heteroaryl and heterocycloalkyl groups, as defined above. Detailed Description of the Invention

The compound of formula I according to the invention may be prepared by the general procedure shown in Scheme 1.

Scheme 1

Formula I ■ Formula I

In Scheme 1 , compounds of the formula (I) are prepared as follows. Step A: Following the general procedure described by M. Yamato.etal. (Chem.Pharm. Bull.

(1981), 29(12), 3494-8), hydroxyacetophenone 2, N-t-butoxycarbonyl-4-piperidone 3 are condensed in the presence of a secondary amine base such as morpholine, piperidine or preferably pyrrolidine, in an alcohol solvent such as isopropanol, ethanol or preferably methanol with heating between 50 ^a C and 110 ^B C, where refluxing temperature is preferred to afford the spirochromanone amine 4. Step B:

Intermediate of the general structure 4 may be converted to the spirochromanol amine intermediate of the general structure 5 via treatment with metal hydride reducing agents such as sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride or preferably sodium borohydride in suitably inert solvents such as THF, methanol or preferably ethanol at temperatures ranging from -10 ^s C to 80 ^a C where 10 ^s C to 40 ^B C is preferable.

Step C:

Deoxygenation and removal of the BOC protecting group of intermediate of general structure 5 to afford spirochromane amine intermediate of general structure 6 may be

accomplished by treatment with a strong organic acid, where trifluoroacetic acid is preferred, in the presence of a hydride source such as preferably triethylsilyl hydride in a suitably inert solvent such as methylene chloride, carbon tetrachloride, 1 ,2-dichloroethane or preferably with no added solvent at temperatures ranging from 50 ⁵ -130 ^s C where 90 ^s -120 ^s C is preferred. Step D:

Intermediate of general structure 6 may be alkylated with C _r C ₄ alkyl chlorides or preferably bromides or iodides in the presence of an organic amine base such as triethylamine or diisopropyl-ethyl amine or an inorganic carbonate base such as cesium carbonate, sodium carbonate or preferably potassium carbonate in a suitably non-reactive solvent such as THF or preferably acetone at temperatures ranging from 0 ^s -80 ^B C where ambient temperature is preferred to afford intermediate of general structure 7. Step E:

Carboxylation of intermediate of general structure 7 may be achieved first by lithium- halogen exchange using a lithium base such as tert-butyl lithium, sec-butyl lithium or preferably n-butyl lithium in an inert solvent such as diethyl ether or preferably THF at temperatures ranging from -110 ^s --30 ² C where -80 ^s ~50 ^a C is preferred, and subsequent treatment with dry ice or preferably gaseous carbon dioxide to afford intermediate of general structure 8.

Step F: Acid intermediate of the general structure 8 may be reacted with a primary or secondary amines of general formula HNR ³ R ⁴ , where R ³ and R ⁴ are as defined in the specification amine, in the presence of a coupling reagent such as dicyclohexyl carbodiimide, carbonyl diimidazole, tripropylphosphonic anhydride, alkyl chloroformate, bis(2-oxo-3- oxazolidinyl)phosphinic chloride, benzotriazol-1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, O(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluranium hexafluorophosphate or any other such standard literature reagents in the presence of a trialkyl amine base, such as triethyl amine or diisopropylethyl amine, wherein O(benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluranium hexafluorophosphate and diisopropylethyl amine are a preferred combination in a reaction inert solvent, where ethyl acetate, from -78 ⁰ C to 40 ⁰ C, where room temperature is preferred to afford the λ/-acylated compounds of the general structure 10, a compound of Formula I. Step G:

Compounds of the general structure 9, a compound of Formula I may be formed by coupling the bromo intermediate of the general structure 7 with aryl or heteroaryl boronic acids with an organopalladium catalyst such as tetrakis(triphenylphosphine)palladium (0), dichloropalladium bistriphenylphosphine or tris(dibenzylidine-acetone)dipalladium, preferably tetrakis(triphenylphosphine)palladium (0) and an alkali metal base, such as sodium

carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide, preferably sodium carbonate, in a solvent system containing dimethoxyethane or preferably toluene and a polar protic solvent such as water, methanol or ethanol, preferably a mixture of water and ethanol, at a temperature of from about 10 ^s C to 150 ^a C, preferably about 50 ^s -100 ^s C.

Rotomers are possible for an embodiment of the inventive compound of formula I and are within the scope of the invention.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). -

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine. The > resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).

In the examples below the following terms are intended to have the following, general meaning:

DIPEA: diisopropylethylamine DMF: dimethyformamide

MgSO ₄ : magnesium sulfate

DMA: dimethyl acetamide

LRMS: low resolution mass spectrometry

⁰ C: degrees Celsius calcd: calculated d: day(s); doublet (spectral)

DCE: 1 ,2-dichloroethane

EtOAc: ethyl acetate g: grams

HBTU: O-(benzotriazoI-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate hr: hours Hz: hertz

J: coupling constant (in NMR)

L: liter(s)

LAH: lithium aluminum hydride

MHz: megahertz Min: minute(s) m/z : mass to charge ratio (in mass spectrometry) obsd: observed

PPTs: pyridinium p-toluenesulfonate

TsO: p-toluenesulfonate Rf: retention factor (in chromatography)

Rt: retention time (in chromatography) rt: room temperature s: singlet (NMR); second(s)

STAB: sodium triacetoxyborohydride t: triplet

TFA: trifluoroacetic acid

TFAA: trifluoroacetic anhydride

THF: tetrahydrofuran

TLC: thin layer chromatography Ts: tosyl, p-toluenesulfonyl

TsOH: p-toluenesulfonic acid

T ₃ P: 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide

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 plates eluting with the solvents indicated, visualized by a

254 nm UV lamp, and stained with either an aqueous KMnO ₄ solution or an ethanolic solution of 12-molybdophosphoric acid. Flash column chromatography unless otherwise stated, 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 ¹ H, respectively, and 100 MHz or 125 MHz for ¹³ C NMR, respectively. Chemical shifts for proton ¹ H NMR speGtra are reported in parts per million

relative to the singlet of CDCI ₃ at 7.24 ppm. Chemical shifts for ¹³ C NMR spectra are reported in parts per million downfield relative to the centerline of the triplet of CDCI ₃ at 77.0 ppm. Mass spectra analyses were performed on a APCI Gilson 215, micromass ZMD (50% Acetonitrile / 50% water) spectrometer. The following intermediates may be prepared by the procedures shown:

Step 1 :

Intermediate 1

Spiro[2H-1 -benzopyran-2,4'-piperidine]-1 '-carboxylic acid, 6-bromo-3,4- dihydro-4-oxo-, 1,1-dimethylethyl ester. A mixture of 5'-bromo-2'-hydroxyacetophenone (50.0 g, 232.5 mmol), t-butyl 4-oxo-1- piperidinecaboxylate (46.3 g, 232.4 mmol) and pyrrolidine (50 ml_, 599.0 mmol) in methanol (500 mL) was refluxed for 17h, then cooled and concentrated. The red colored residue was dissolved in EtOAc (600 mL) and washed with water (2 x 200 mL), aqueous ~3M citric acid (2x 150 mL), water and brine. The organics were dried (Mg SO ₄ ) and concentrated to a thick, light orange foamy tar. Hexanes (~ 100 mL) was added and the vessel walls were scratched to induce crystallization. Another 150 mL hexanes was added and the mixture was stirred for 66 hrs, then filtered, rinsed with hexanes and air dried to afford 73.2 g (79%) of the title compound as a dull yellow solid: NMR (CDCI ₃ ) δ 7.94 (d, J = 2.5 Hz, 1 H), 7.54 (dd, J = 8.7, 2.5 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 1 H), 3.85 (br s, 2H), 3.16 (br t, J = 11.6 Hz, 2H), 2.69 (s, 2H), 1.98 (br d, J= 13.3 Hz, 2H), 1.62-1.54 (m, 2H), 1.43 (s, 9H). Step 2

Intermediate 2 teit-Butyl 6-bromo-4-hydroxy-3,4-dihydro-1'W-spiro[chromene-2,4'-piperi dine]- 1 '-carboxylate. Spiro[2H-1-benzopyran-2,4'-piperidine]-1 '-carboxylic acid, 6-bromo-3,4-dihydro-4-

OXO-, 1 ,1 -dimethylethyl ester (73.2 g, 184.7 mmol) was slurried in EtOH (1500 mL), stirred for 30 min and then sodium borohydride (7.Og, 185.0 mmol) was added. Over 15 min all solids dissolved to give an orange solution. The mixture was carefully quenched with water and then concentrated. The residue was partitioned between EtOAc (750 mL) and water (200 mL) . The organics were washed again with water and then brine, dried (MgSO ₄ ) and concentrated to a thick orange oil. Re-concentration from diethyl ether and then hexanes following by evacuation under high vacuum afforded 73.8g (100%) of the title compound as a light yellow- orange foam: NMR (CDCI ₃ ) δ 7.55 (dd, J = 2.5, 0.8 Hz, 1H), 7.26 (dd, J = 8.7, 2.5 Hz, 1H), 6.72 (d, J = 8.7 Hz, 1 H), 4.82 (dd, J = 13.3, 6.6 Hz, 1 H), 3.83 (br s, 2H), 3.27-3.00 (m, 2H), 2.11 (dd, J = 13.7, 6.2 Hz, 1 H), 1.99-1.73 (m, 4H), 1.68-1.40 (m, 11 H).

Step 3

Intermediate 3

6-Bromo-3,4-dihydrospiro[chrornene-2,4'-piperidine].

Triethylsilane (100 mL, 626.1 mmol) was added to a solution te/t-butyl 6-bromo-4- hydroxy-3,4-dihydro-1 η-spiro[chromene-2,4'-piperidine]-1 '-carboxylate (63.8g, 160.2 mmol) in trifluoroacetic acid (600 mL) and the resulting mixture was refluxed for 7.5 hrs. After cooling, the reaction was concentrated. Diethyl ether (400 mL) was added and the mixture was stirred to break up the solids then filtered and air dried to afford 57.44g (90%) of the trifluoroacetate salt of the title compound as a yellow solid: NMR (DMSOd ₆ ) δ 8.79 (br s, 1 H), 8.61 (br s, 1 H), 7.27 (d, J = 2.5 Hz, 1 H), 7.21 (dd, J = 8.7, 2.5 Hz, 1 H), 3.20-3.10 (m, 2H), 3.10-2.95 (m, 2H), 2.72 (t, J = 6.6 Hz, 2H), 1.85-1.69 (m, 6H). Step 4

Intermediate 4 β-Bromo-i '-ethyl-S^-dihydrospirotchromene^^'-piperidine]. 6-Bromo-3,4-dihydrospiro[chromene-2,4'-piperidine].) (15.Og, 37.86 mmol), potassium carbonate (21.Og, 151.9 mmol) and ethyl iodide (3.3 mL, 41.3 mmol) were stirred in acetone (300 mL) for 16h. The reaction was filtered through Celite and concentrated. The residue was partitioned between CH ₂ CI ₂ and 1 N NaOH. The organic phase was washed with brine, dried (MgSO ₄ ) and concentrated to give an orange oil with yellow solid. This material was redissolved in -200 mL of 2:1 EtOAc/ ethyl ether and filtered to remove insoluble impurities. Concentration yielded 11.46 g (98%) of the title compound as a slightly cloudy, light orange oil: NMR (CDCI ₃ ) δ 7.17-7.13 (m, 2H), 6.69 (d, J = 9.5 Hz, 1 H), 2.74-2.65 (m, 4H), 2.44 (q, J = 7.2 Hz, 2H), 2.34 (dt, J = 11.6, 2.5 Hz, 2H), 1.83-1.73 (m, 4H), 1.65 (dt, J = 11.4, 4.5 Hz, 2H), 1.09 (t, J = 7.3 Hz. 3H). Step 5

Intermediate 5

Preparation of 1 '-ethyl-S^-dihydrospirofchromene^^'-piperidinel-β-carboxyli c acid. nBuLi (2.5 M/hexanes, 12.9 mL, 32.25 mmol) was added over 2min to a -78 ^a C solution of 6-bromo-1'-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine] (10.Og, 32.23 mmol) in THF (10OmL). After stirring at -78 ^e C for 2h, carbon dioxide gas was bubbled into the mixture for 30 min. After warming to rt, the reaction was concentrated. 1 N aq. HCI (33 mL) was added and the mixture was stirred well to break up the solids, then this was extracted with EtOAc (2x75 mL). The aqueous phase was then concentrated to dryness to afford a hygroscopic, light yellow solid. This was stirred for 2h with THF (50 mL) to help remove residual lithium bromide, filtered and dried under nitrogen to yield 8.2 g of the title compound as a hygroscopic, light yellow powder: NMR (DMSO-d _B ) δ 7.64 (d, J = 2.1 Hz, 1H), 7.60 (dd, J

= 8.7, 2.1 Hz, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 2.73-2.64 (m,4H), 2.53-2.36 (m, 4H) ₁ 1.76-1.62 (m, 6H), 1.01 (t, J = 7.3 Hz, 3H); LCMS m/z calcd. for C ₁₆ H ₂₁ NO ₃ , 275.2, found, 276.2 (M+1 ). Example 1 β^Pyrrolidin-i-ylcarbonylJ-i'-ethyl-S^-dihydrospirofchromen e^^'-piperidine]. To a solution of 1 '-ethyl-S^-dihydrospirofchromene^^'-piperidinel-e-carboxylic acid (Step 5) (0.2Og, 0.726 mmol) in λ/, λ/-dimethylacetamide (3 ml_) was added diisopropyl- ethylamine (0.13 mL, 0.728 mmol), pyrrolidine (0.065 mL, 0.779 mmol) and a solution of O-

(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluranium hexafluorophosphate (0.275g, 0.725 mmol) in DMF (4 mL). This mixture was stirred at rt for 16h, concentrated, re-dissolved in EtOAc and washed with 1 N aq. LiCI, water and brine. After drying (MgSO ₄ ), the organics were concentrated to afford an orange-yellow oil (0.161 g). An additional portion of material was obtained by concentrating the aqueous washes and rinsing the resulting salts with MeOH.

This rinse was combined with the previous portion of crude product. This was purified by flash chromatography, flushing first with 20% MeOH/EtOAc and then eluting with 20% MeOH/EtOAc +1% NH ₄ OH to yield 0.164g, (69%) of the title compound as a hygroscopic orange solid, the HCI salt of which had: NMR (MeOH-d ₄ ) δ 7.38-7.34 (m, 2H), 6.98 (d, J = 8.3

Hz, 1 H), 3.65-3.48 (m, 6H), 3.34-3.21 (m overlapping MeOH signal, 4H), 2.88 (t, J = 6.8 Hz,

2H), 2.12-1.89 (m, 10H), 1.38 (t, J = 7.3 Hz, 3H); LCMS m/z calcd. for C ₂₀ H ₂₈ N ₂ O ₂ , 328.2, found, 329.3 (M+1). Examples 2-26

The following examples (2-26) were prepared using this general protocol: Portions of boronic acid solutions (0.5M in EtOH , 0.5 mL) and 1.0 mL of 0.1 M EtOH solution of 6-bromo-3,4-dihydrospiro[chrornene-2,4'-piperidine] were added to reaction vials. To these, as bulk, were manually added 0.200 mL of 1.5 M Na ₂ CO ₃ solution in water and 0.2 mL of 0.025 M tetrakis(triphenylphosphine) palladium (O)solution in toluene. Vials were capped and shaken at 85 ^a C for 18 hours. Added 2.5 mL EtOAc and 1.5mL 1 N NaOH to reaction vials. The vials were capped, shaken well, and vortexed if needed. The top layers were transferred to MCX cartridges (pre-conditioned with 2 x 3.0 mL MeOH). The loaded columns were rinsed with 5.0 mL EtOAc and 5.0 mL MeOH (discarded). The columns were placed over tared collection tubes and eluted with 5.0 mL 1 N NH3/MeOH. The eluted material was then evaporated to dryness and purified by HPLC using the following conditions: Column: 21.2 x 50 mm Phenomenex Synergy Max-RP C12, 4um Flow rate: 25 mL/min; Injection volume: 900 uL in DMSO (10-30 mg) Solvents: A: Water; B: Acetonitrile; C: 1% aq. TFA Gradients: Determined based on retention time in pre-purification analyses. Range from Focused Gradient 1 (5% B to 10% B over first 2.0 minutes, to 90% B over next 2.0

minutes, C held at 5% all 4.0 minutes); to Focused Gradient 6 (55% B to 85% B over first 2.0 minutes, to 90% B over next 2.0 minutes, C held at 5% all 4.0 minutes).

Detectors: DAD, MS: ES (+) mode.

Fraction Collection: Triggered by selected ion recording MS; one tube per injection.

Examples 27-46

The following example (27-46) we ^' re prepared using this general protocol: Portions of amine solutions (0.25M in 0.5M DIPEA/DMA , 0.200 mL) and 0.200 mL of 1'-ethyl-3,4-dihydrospiro[chromene-2,4'-piperidine]-6-carbox ylic acid solution (0.25M in 0.5M DIPEA/DMA) were added to reaction vials. To these, as bulk, were manually added 0.200 mL of 0.25 M HBTU solution in dry DMF. The vials were capped and shaken at RT for 24 hours. 2.0 mL DCE and 2.0 mL 1 M NaOH were added, and the mixtures were shake well, vortexed (if needed ). The bottom phase was aspirated to hydromatrix cartridges situated over tared collection tubes. DCE (2.0 mL) was added to the material remaining in the reaction vials, then this bottom layer was also aspirated to the hydromatrix cartridges. The hydromatrix cartridges were then eluted with 4.5 mL DCE. The resulting filtrates were evaporated to dryness and purified by HPLC using the following conditions: ^'

Column: 21.2 x 50 mm Phenomenex Synergy Max-RP C12, 4um

Flow rate: 25 mL/min; Injection volume: 900 uL in DMSO (10-30 mg)

Solvents: A: Water; B: Acetonitrile; C: 1% aq. TFA

Gradients: Determined based on retention time in pre-purification analyses. Range from

Focused Gradient 1 (5% B to 10% B over first 2.0 minutes, to 90% B over next 2.0 minutes, C held at 5% all 4.0 minutes); to Focused Gradient 6 (55% B to 85% B over first 2.0 minutes, to

90% B over next 2.0 minutes, C held at 5% all 4.0 minutes).

Detectors: DAD, MS: ES (+) mode.

Fraction Collection: Triggered by selected ion recording MS; one tube per injection.

quation 2. General Reaction for Amide Formation

The composition of the present invention may be a composition comprising a compound of formula I and optionally a pharmaceutically acceptable carrier. The composition of the present invention may. also be a composition comprising a compound of formula I, a histamine H ₁ antagonist and optionally a pharmaceutically acceptable carrier. The composition of the present invention may also be a composition comprising a compound of formula I, a neurotransmitter re-uptake blocker and optionally a ¹ pharmaceutically acceptable carrier.

The composition of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. The composition may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous or through an implant) nasal, vaginal, sublingual, rectal or topical administration or in a form suitable for administration by inhalation or insufflation.

Pharmaceutically acceptable salts of compounds of formula I may be prepared by one or more of three methods: (i) by reacting the compound of formula I with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

Also included within the scope of the invention are metabolites of compounds of formula I, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include: (i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH ₃ → -CH ₂ OH); (ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR → - OH); (iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR ^a R ^b → -NHR ^a or -NHR ^b ); (iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR ^a -> -NH ₂ ); (v) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONR°R ^d → COOH). lsotopically labeled compounds of formula I of this invention can generally be prepared by carrying out the procedures disclosed in the preceeding Schemes and/or in the Examples and Preparations, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

For oral administration, the pharmaceutical composition may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents such as pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose; fillers such as lactose, microcrystalline cellulose or calcium phosphate; lubricants such as magnesium stearate, talc or silica; disintegrants such as potato starch or sodium starch glycolate; or wetting agents such as sodium lauryl sulphate. 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 such as sorbitol syrup,

methyl cellulose or hydrogenated edible fats; emulsifying agents such as lecithin or acacia, non-aqueous vehicles such as almond oil, oily esters or ethyl alcohol; and preservatives such as 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 composition 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, for example, in ampoules or in multi-dose containers, with an added preservative. The composition 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 or ingredients in a composition may be in powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. The term "active ingredient" as used herein refers to a compound of the formula I, a histamine H ₁ antagonist, or a neurotransmitter re-uptake blocker.

The composition of the invention may also be formulated in a rectal composition such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. A composition for vaginal administration is preferably a suppository that may contain, in addition to the active ingredient or ingredients, excipients such as cocoa butter or a suppository wax. A composition for nasal or sublingual administration is also prepared with standard excipients well known in the art.

For intranasal administration or administration by inhalation, the composition may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, 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 ingredient or ingredients. Capsules and cartridges, made, for example, from gelatin, for use in an inhaler or insufflator may be formulated containing a powder mix of an active ingredient or ingredients and a suitable powder base such as lactose or starch. The active ingredient or ingredients in the composition may range in size from nanoparticles to microparticles. ■

An exemplary dose of the composition of the invention comprising a compound of formula I for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to herein is about 0.01 to about 1000 mg of the compound of formula I per unit dose which could be administered, for example, 1 to 3 times per day.

An exemplary dose of the composition of the invention comprising a compound of formula I and a histamine Hi antagonist or a neurotransmitter re-uptake blocker for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to herein is about 0.01 to about 500 mg of the compound of formula I and of about 0.01 mg to about 500 mg of the histamine H ₁ antagonist or the neurotransmitter reuptake blocker per unit dose which could be administered, for example, 1 to 3 times per day.

Aerosol formulations for treatment of the conditions referred to herein in the average adult human are preferably arranged so that each metered dose or "puff" of aerosol contains about 20 μg to about 1000 μg of the compound of formula I. The overall daily dose with an aerosol will be within the range about 100 μg to about 10 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. Aerosol formulations containing a compound of formula I and a histamine H ₁ antagonist or a neurotransmitter re-uptake blocker are preferably arranged so that each metered dose or "puff" of aerosol contains about 100 μg to about 10,000 μg of the compound of formula I and about 100 μg to about 30,000 μg of the histamine H ₁ antagonist or the neurotransmitter reuptake blocker. Administration may be several times daily, for example 1 , 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time. The composition of the invention comprising a compound of formula I and a histamine H-i antagonist or a neurotransmitter re-uptake blocker may optionally contain a pharmaceutically acceptable carrier and may be administered in both single and multiple dosages as a variety of different dosage forms, such as tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. The pharmaceutically acceptable 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. In general, the compound of formula I is present in such dosage forms at concentration levels ranging from about 0.1% to about 99.9% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage, and the histamine H ₁ antagonist or the neurotransmitter re-uptake blocker is present in such dosage forms at concentration levels ranging from about 0.1% to about 99.9% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.

The compound of formula I and the histamine H-, antagonist may be administered together or separately/ When administered separately, the compound of formula I and the histamine H ₁ antagonist may be administered in either order, provided that after administration of the first of the two active ingredients, the second active ingredient is administered within 24 hours or less, preferably 12 hours or less.

The compound of formula I and the neurotransmitter re-uptake blocker may be administered together or separately. When administered separately, the compound of formula 1 and the neurotransmitter re-uptake blocker may be administered in either order, provided that after administration of the first of the two active ingredients, the second active ' ingredient is administered within 24 hours or less, preferably 12 hours or less.

A preferred dose ratio of compound of formula 1 to the histamine H ₁ antagonist or to the neurotransmitter re-uptake blocker for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to herein is from about 0.001 to about 1000, preferably from about 0.01 to about 100. The composition may be homogeneous, wherein by homogeneous it is meant that the active ingredient or ingredients are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid composition is then subdivided into unit dosage forms of the type described herein containing from about 0.1 to about 1000 mg of the active ingredient or ingredients. Typical unit dosage forms contain from about 1 to about 300 mg, for example about 1 , 2, 5, 10, 25, 50 or 100 mg, of the active ingredient or, ingredients. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The dosage of the active ingredient or ingredients in the composition and methods of this invention may be varied; however, it is necessary that the amount of the active ingredient or ingredients in such a composition be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, the particular compounds administered, the duration of the treatment, and other factors. All dosage ranges and dosage levels mentioned herein refer to each active ingredient present in the pharmaceutical composition of the present invention, as well as those used in the methods of the present invention. Generally, dosage levels of between about 0.01 and about 100 mg/kg of body weight daily are administered to humans and other mammals. A preferred dosage range in humans is about 0.1 to about 50 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses. A preferred dosage range in mammals other than humans is about 0.01 to about 10.0 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses. A more preferred dosage

range in mammals other than humans is about 0.1 to about 5.0 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses.

The pharmaceutical composition comprising the compound of formula I and the histamine H ₁ antagonist or the neurotransmitter re-uptake blocker may be administered at dosages of a therapeutically effective amount of the compound of formula I and of the second active ingredient in single or divided doses.

The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age. However, some variation in dosage will necessarily occur depending upon the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

The dosage amounts set forth in this description and in the appended claims may be used, for example, for an average human subject having a weight of about 65 kg to about 70 kg. The skilled practitioner will readily be able to determine any variation in the dosage amount that may be required for a subject whose weight falls outside the about 65 kg to about 70 kg range, based upon the medical history of the subject. The pharmaceutical combinations may be administered on a regimen of up to 6 times per day, preferably 1 to 3 times per day, such as 2 times per day or once daily. 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 HCI 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 resuspended by Polytron in cold 50 mM Tris HCI containing 2 mM MgCI2 (pH to 7.4 at 4 ⁰ C) and centrifuged again. The final pellet is resuspended in ^' 50 mM Tris HCI containing 2 mM MgCI2 (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 3H-N-methyl-histamine). After a 1 hour incubation, assay samples are rapidly filtered through Whatman GF/B 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 calculated.

A person of ordinary skill in the art could adapt the above procedure to other assays.