WO2007088450A2 - Chromane antagoniste du récepteur h-3 - Google Patents

Chromane antagoniste du récepteur h-3 Download PDF

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WO2007088450A2
WO2007088450A2 PCT/IB2007/000210 IB2007000210W WO2007088450A2 WO 2007088450 A2 WO2007088450 A2 WO 2007088450A2 IB 2007000210 W IB2007000210 W IB 2007000210W WO 2007088450 A2 WO2007088450 A2 WO 2007088450A2
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optionally substituted
alkyl
group
compound
formula
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PCT/IB2007/000210
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WO2007088450A3 (fr
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Todd William Butler
Travis T. Wager
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Pfizer Products Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4

Definitions

  • This invention is directed to compounds of formula I described herein, to a pharmaceutical composition comprising such compounds, and to methods of treatment of disorders or conditions that may be treated by antagonizing histarntne-3 (H3) receptors using such compounds.
  • H3 histarntne-3
  • 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, 832- 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.
  • H3 ligand may be an antagonist, agonist or partial agonist, see: ⁇ Imamura et al., Circ. Res., (1996) 78, 475-481); (Imamura et at., Circ. Res., (1996) 78, 863-869); (Un et al., Brain Res. (1990) 523, 325-330); (Monti et al., Neurapsychopharmacology (1998) 15, 31 35); ⁇ Sakai, et al., Life ScL (1991) 48, 2397-2404); (Mazurkiewiez- Kwiiecki and Nsonwah, Can.
  • Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognitive disorders such as Alzheimer's disease and attention-deficit hyperactivity disorder; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma, medullary thyroid carcinoma and melanoma; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere's disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.
  • cardiovascular disorders such as acute myocardial infarction
  • memory processes dementia and cognitive 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
  • H3 receptor antagonists have also been previously described in, for example, WO 03/050099, WO 02/0769252, WO 02/12224, and U.S. Patent Publication No. 2005/0171181 Al
  • 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 white minimizing non-specific peripheral consequences.
  • Antagonists of the receptor increase synthesis and release of cerebral histamine and other monoamines.
  • 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.
  • ADHD attention deficit hyperactive disorder
  • 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-imidazole neuroactive compounds such as beta histamines (Arrang, Eur. J. Pharm.
  • EP 978512 and EP 0982300A2 disclose non-imidazole aikyamines as histamine H3 receptor antagonists.
  • WO 02/12224 (Grtho McNeil Pharmaceuticals) describes non- imidazole bicyclic derivatives as histamine H3 receptor ligands.
  • Other receptor antagonists have been described in WO 02/32893 and WO 02/06233,
  • This invention is directed to hisfam ⁇ ne-3 (H3) receptor antagonists of the invention usefui 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).
  • the compounds of this invention selectively distinguish H3R from the other receptor subtypes H1R, H2R.
  • 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 chromane amines has a high and specific affinity to the histamine H3 receptor.
  • W, X, Y, and Z are independently selected from nitrogen or carbon; wherein the total number of said nitrogens for W, X, Y, and Z does not exceed two;
  • R 1 and R 2 are independently hydrogen, (GrC 8 )alkyI optionally substituted with 1 to 4 halogens, or (C 3 -C7)cycloalkyl-(C ⁇ rC 4 )alkyl; or optionally R 1 and R 2 , together with the nitrogen to which they are attached, form a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with 1 or 2 (C r CX))alkyl; and wherein one of the carbons of said heterocyclic ring -A-
  • R ⁇ is hydrogen, (C r C 8 )alkyI optionally substituted with 1 to 4 halogens, or (C;rC 7 )eycloalkyi-(Co-C 4 ⁇ alkyl, and wherein each (C o -C4)alkyl is optionally substituted with 1 to 4 ⁇ C,-C 4 )alkyl;
  • ⁇ Ci-C 4 )alkyl group optionally substituted with a substituent selected from the group consisting of OH, 1 to 4 (C 1 -C 4 )aikyl, ⁇ C 3 -C 7 )cycloalkyl, ⁇ Ci-C$)dialky)amino, (C «j-C 14 ⁇ aryt optionally substituted with a halogen and optionally substituted with (CrCr ⁇ Jaryloxy optionally substituted with 1 to 2 halogens, and 5 to 10-membered heteroaryl optionally substituted with a (Cs- C f oJaryl group and optionally substituted with 1 to 3 (CrC ⁇ Jalkyl groups; (C 3 -C 6 )cycloalkyl;
  • C 4 )alkylene is optionally substituted with 1 to 4 (Ci-C 4 alkyl); or optionally R 3 and R 4 , together with the nitrogen to which they are attached, form a 4-, 5-, 6- , or 7-membered saturated or unsaturated heterocyclic ring, wherein one of the carbons in said heterocyclic ring is optionally replaced by O 1 S, NR S or CO, and wherein said ring is optionally fused to a (Ce-C 10 )arylene and is optionally substituted at a ring carbon with a substituent selected from the group consisting of
  • (C 1 -C 4 )alkyI 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 ⁇ C 1 -C 2 ⁇ alkyl, 1 to 4 (C 1 -C 4 )alkyl, (C 3 - C 7 )cycloalkyl, and (C 6 -C 14 )aryl;
  • C 4 )alkylene Is optionally substituted with 1 to 4 (C 1 -C 4 )alkyl;
  • (C- ⁇ -Cs)alkyl optionally substituted with 1 to 4 halogens;
  • (C 1 -C 4 )alkyl group optionally substituted with a substituent selected from the group consisting of OH 1 one to four (C 1 - C 4 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )dialkylamino, (C 6 -C 14 )aryl optionally substituted with a halogen and optionally substituted with (C 3 -C 10 )aryloxy optionally substituted with one to two halogens, and 5-10-membered heteroaryl optionally substituted with a (C ⁇ -C t o)aryl group and optionally substituted with 1 to 3
  • C 4 )alkylene is optionally substituted with 1 to 4 (Gi-CJalkyl; or optionally R 3 and R 4 , together with the nitrogen to which they are attached, form a 4-, 5-, 6- , or 7-rnembered 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 ⁇ -C 1 o ⁇ arylene and is optionally substituted at a ring carbon with a substituent selected from the group consisting of
  • 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, ailergy, 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 mamma! in need of such treatment a compound of formula I.
  • 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, ailergy, allergy-
  • This invention is also directed to a pharmaceutical composition for treating aliergic rhinitis, nasal congestion or allergic congestion
  • a pharmaceutical composition for treating aliergic rhinitis, nasal congestion or allergic congestion comprising: (a) an HS 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.
  • the histarnine-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,
  • 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 HI antagonist, such as cetirizine (ZyrtecTM), chlorpheniramine ⁇ Chl ⁇ rtrimetonTM ⁇ , loratidine (ClaritinTM), fexofenadine (AllegraTM), or desloratadine (ClartnexTM) for the treatment of allergic rhinitis, nasal congestion, and allergic congestion.
  • a histamine H3 antagonist compound of general formula I an effective dose of a histamine HI antagonist, such as cetirizine (ZyrtecTM), chlorpheniramine ⁇ Chl ⁇ rtrimetonTM ⁇ , loratidine (ClaritinTM), fexofenadine (AllegraTM), or desloratadine (ClartnexTM) for the treatment of
  • 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.
  • neurotransmitter reuptake blockers will include the serotonin-selective reuptake inhibitors (SSRPs) like sertraline (Zoloft * TM), fluoxetine ⁇ ProzacTM), and paroxetine (PaxilTM), or non-selective serotonin, dopamine or norepinephrine reuptake inhibitors for treating ADD, ADHD, depression, mood disorders, or cognitive disorders.
  • SSRPs serotonin-selective reuptake inhibitors
  • Zoloft * TM sertraline
  • fluoxetine ⁇ ProzacTM fluoxetine ⁇ ProzacTM
  • PaxilTM paroxetine
  • 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.
  • 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.
  • isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and U C are incorporated, are useful in drug and/or substrate tissue distribution assays, Tritiated, Le 1 ., 3 H, and carbon-14, i.e., 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, cart 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. s
  • Anxiety disorders include, for example, generalized anxiety disorder, panic disorder, PTSD 1 and social anxiety disorder.
  • Mood adjustment disorders include, for example, depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood.
  • Attention adjustment disorders include, for example, in addition to ADHD, attention-deficit disorders or other cognitive disorders due to general medical conditions.
  • Psychotic disorders include, for example, schizoaffective disorders and schizophrenia; sleep disorders include, for example, narcolepsy and enuresis.
  • disorders or conditions which may be treated by the compound, composition and method of this invention are aiso 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 (HlV), Subsyndromal Symptomatic depression, depression in Infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic depressive illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or major depression with dysthymia; dysthym ⁇ a; phobias, including, for example, agoraphobia, social phobia or simple phobias; eating disorders, Including, for example, anorexia nervosa or
  • 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 menial 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; SSRI "poop out” syndrome, or a patient's failure to maintain a satisfactory response , to SSRI therapy after an initial period of satisfactory response;
  • Parkinson's diseases including, for example, dementia in Parkinson's disease, neuroleptic- induced parkinso
  • the mammal in need of the treatment or prevention may be a human.
  • the mammal in need of the treatment or prevention may be a mammal otherthan a human.
  • compositions 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, edisyiate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydroch ⁇ oride/chloride, hydrobrornide/brornide, hydroiodide/iodide, isethionate, lactate, malate, maleate, maionate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicot ⁇ nate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogert phosphate, saccharate, stearate, succinate, tartrate,
  • Suitable base salts are formed from bases that form non-toxic salts.
  • bases include the aluminium, arginine, benzathine, calcium, choline, diethylatnine, dioiam ⁇ ne, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tr ⁇ methamine and zinc salts.
  • Hernisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by stahl and Werrnuth (Wiley-VCH, Weinheim, Germany, 2002). ⁇
  • the compounds of the invention may exist in both unsolvated and soivatecl forms.
  • 'solvate' fs used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecuies, for example, etha ⁇ ol,
  • solvent molecuies for example, etha ⁇ ol
  • 'hydrate' is employed when said solvent is water.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopicaily substituted, e.g. D 2 O, dg-acetone, d 6 - DMSO,
  • 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.
  • 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.
  • ali 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 ail polymorphs and crystal habits thereof, prodrugs and isomers thereof ⁇ including optical, geometric and tautomeric isomers) as hereinafter defined and isotopicaliy- Iabeled compounds of formula I.
  • 'pro-drugs' of the compounds of formula I are also within the scope of the invention.
  • certain derivatives of compounds of formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula I having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, VoI, 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Sioreversibie Garriers in Drug Design',
  • halo as used herein includes fluoro, chloro, bromo and ⁇ odo.
  • alkyl includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
  • alkoxy 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-butexy.
  • alkylene includes a divalent radical derived from straight-chain or branched alkane.
  • aikylene radicals are methylene, ethylene (1,2-ethylene or 1,1-eihylene ⁇ , trirnethylene ⁇ 1,3-propylene) ( tetramethyiene (1,4-butytene), pentamethylene and hexamethylene.
  • eycloaikyl includes non-aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above.
  • examples of eycloaikyl include, but are not limited to, cyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • heterocycloalkyl refers 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 heterocycloalkyi groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • non-aromatic heterocydoalkyl groups are aziridinyl, azetidinyl, pyrroiidtnyl, piperidinyl, azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morphoitno, thiomorpholino, thioxanyi, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyrany!, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyi, dihydrofuranyl, pyrazolidinyl, imidazollnyl, Imidazolidinyl,
  • aryf 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.
  • heteroaryi includes monocyclic or bicyciic 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.
  • heteroaryl groups include, but are not limited to thiophenyl, furanyl, pyrrolyl, pyrazoiyl, imidazolyi, oxazoly!, is ⁇ xazolyl, thiazolyl, isothiazoiyl, triazoiyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, pyr ⁇ dinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiad ⁇ azinyl, isobenzofuranyl, benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolinyi, isoquinoiyl, cinnoiinyl, phthalaziny ⁇ , naphthyridinyl, quinazolinyl, quinoxalinyl, be
  • heterocyclic ring refers to both heteroaryl and heterocycloalkyl groups, as defined above.
  • 3-Bromophenol (2) is acetylated to give acetate (3) via treatment with acetic anhydride or preferably acetyl chloride in the presence of a rton-nudeoph ⁇ c amine base such as diisopropyiethylamine, triethylamine or preferably pyridine in a suitably inert solvent such as chloroform, 1,2-diohloroethane or preferably dichlorom ⁇ thane at temperatures ranging from -10*C to 8O 0 C where room temperature is preferred.
  • a rton-nudeoph ⁇ c amine base such as diisopropyiethylamine, triethylamine or preferably pyridine
  • a suitably inert solvent such as chloroform, 1,2-diohloroethane or preferably dichlorom ⁇ thane at temperatures ranging from -10*C to 8O 0 C where room temperature is preferred.
  • Rearrangement of acetate (3) to afford acetophenone (4) is performed In the presence of a strong Lewis acid where aluminum irichoride is preferred, in a solvent such as dichioromethane, carbon disulfide or preferably without solvent at temperatures ranging from 80 ⁇ 20O 0 C where 120° to 17O 0 C is preferred.
  • Vinylogous amide (5) may be synthesized by treatment of (4) with bis ⁇ dimethylamino)-tetf-butoxymethane (Bredereck's reagent) or preferably N 1 N- dimethylformamide dimethylacetal in xylene, toluene or preferably benzene at temperatures ranging from 50° to 12O 0 C, where 80°-110°C is preferred.
  • Ring closure of intermediate (5) to afford chromenorie (6) may be accomplished using a strong inorganic acid such as phosphoric acid, sulfuric acid or preferably concentrated hydrochloric acid in a suitably unreactive solvent such as chloroform, 1,2-diehioroethane or preferably dichioromethane at temperatures ranging from 0° to 100 0 C where 30-70 0 C is preferred,
  • a strong inorganic acid such as phosphoric acid, sulfuric acid or preferably concentrated hydrochloric acid in a suitably unreactive solvent such as chloroform, 1,2-diehioroethane or preferably dichioromethane at temperatures ranging from 0° to 100 0 C where 30-70 0 C is preferred
  • Chromanone ⁇ 7 ⁇ may be obtained by selective reduction of intermediate ⁇ 6 ⁇ with metal hydride reagents where dlisobutylaluminum hydride Is preferred in suitably inert solvents such as diethyl ether.diisopropyl ether or preferably THF at temperatures ranging from A 10 0 C to O 0 C where -80° to -40 0 C is preferred.
  • metal hydride reagents where dlisobutylaluminum hydride Is preferred in suitably inert solvents such as diethyl ether.diisopropyl ether or preferably THF at temperatures ranging from A 10 0 C to O 0 C where -80° to -40 0 C is preferred.
  • Dibromochromanone intermediate (8) may be synthesized by reaction of (7) with brominating agents such as copper (II) bromide or preferably elemental bromine in hal ⁇ genated solvents such as djchioromethane, chloroform or preferably carbon tetrachloride 5 at temperatures ranging form 10° to 80 ⁇ C, where ambient temperature is preferred.
  • brominating agents such as copper (II) bromide or preferably elemental bromine in hal ⁇ genated solvents such as djchioromethane, chloroform or preferably carbon tetrachloride 5 at temperatures ranging form 10° to 80 ⁇ C, where ambient temperature is preferred.
  • Conversion of intermediate (8) to aminochromenone ⁇ 9 ⁇ may be accomplished by treatment with alkylated amines in polar non-protic . solvents such ' as THF, DMF, NMP or preferably acetonitrtle In tie presence of an acid scavenging, non-nucleophilic tertiary amine
  • Aminochromanoi intermediate (10) may be obtained by in-situ 1,4 and subsequent 1,2 hydride reductions of (9) using metai hydride reagents where sodium borohydride is 15 preferred in suitably inert polar protic solvents such as isopropanol, methanol or preferably ethanol at temperatures ranging from 10 0 C to 7O 0 C where ambient temperature is preferred.
  • metai hydride reagents where sodium borohydride is 15 preferred in suitably inert polar protic solvents such as isopropanol, methanol or preferably ethanol at temperatures ranging from 10 0 C to 7O 0 C where ambient temperature is preferred.
  • Compounds of the general structure 11 may be formed by coupling the bromo intermediate of the general structure 10 with aryl or heteroaryl boronic acids with an
  • organopalladium catalyst such as tetrakis(triphenylphosphine)paliadtum (Q), dichloropalladlum blstriphenylphosphine or tris(dibenzyiid!ne-acet ⁇ ne)dipalladium, preferably tetrakis(triphenylphosphins)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 toluene
  • organopalladium catalyst such as tetrakis(triphenylphosphine)paliadtum (Q), dichloropalladlum blstriphenylphosphine or tris(dibenzyiid!ne-acet ⁇ ne)dipalladium, preferably tetrakis(triphenylphosphins)pal
  • a polar protic solvent such as water, methanol or ethanoi, preferably water, at a temperature of from about 1O 0 C to 1SO 0 C 1 preferably about SOMOO 0 C.
  • Ami ⁇ ochromene intermediate (12) may be formed by acid catalyzed elimination of the alcohol functionality of (10) through treatment with strong organic acids such as trifluoroacetic acid, acetic acid or preferably a mixture of concentrated sulfuric acid and acetic acid in suitably inert solvents such as dichlorornethane, 1,2-dichloroethane or preferably chloroform at temperature ranging from 20° to 120 0 C where 6G 0 -9G q C is preferred.
  • strong organic acids such as trifluoroacetic acid, acetic acid or preferably a mixture of concentrated sulfuric acid and acetic acid in suitably inert solvents such as dichlorornethane, 1,2-dichloroethane or preferably chloroform at temperature ranging from 20° to 120 0 C where 6G 0 -9G q C is preferred.
  • Step K Reduction of (12) to afford (14), a compound of formula (I), may be accomplished using hydrogenation catalyzed by reactive metals such as, for example, palladium (0), palladium hydroxide, rhodium or platinum in solvents such as ethanol, methanol or EtOAc or more preferentially through treatment with a metal hydride reagents such as sodium borohydride, sodium cyanoborohydride or preferably sodium triacetoxyborohydride in suitably inert solvents such as dichloromethane, 1,2-dichloroethane or preferably chloroform with 1-5 equivalents of acetic acid at temperatures ranging from -40° to 80 0 C where -20° to 30 0 C is preferred.
  • reactive metals such as, for example, palladium (0), palladium hydroxide, rhodium or platinum in solvents such as ethanol, methanol or EtOAc
  • a metal hydride reagents such as sodium borohydride, sodium
  • Hydrolysis of intermediate 12 to give isochromanone 13 may be accomplished by treatment with an aqueous solution of a carbonate base such as potassium carbonate, sodium carbonate or preferably sodium bicarbonate with an organic solvent co-solvent such as chloroform, dichloromethane, ether or preferably a mixture of dichioromethane and ether preferably at ambient temperature.
  • a carbonate base such as potassium carbonate, sodium carbonate or preferably sodium bicarbonate
  • organic solvent co-solvent such as chloroform, dichloromethane, ether or preferably a mixture of dichioromethane and ether preferably at ambient temperature.
  • Compound 14 of general formula (I) may also be prepared by reductive amination using isochromanone 13 and amine NHR 1 R 2 in the presence of a metal hydride such as sodium borohydride, sodium cyanoborohydride or preferably sodium triacetoxyborohydride in suitably inert solvents such as dichloromethane, 1,2-dichloroethane or preferably chloroform with 1-5 equivalents of acetic acid at temperatures ranging from -40° to 80 0 C where -20° to 3O 0 C Is preferred.
  • a metal hydride such as sodium borohydride, sodium cyanoborohydride or preferably sodium triacetoxyborohydride in suitably inert solvents such as dichloromethane, 1,2-dichloroethane or preferably chloroform with 1-5 equivalents of acetic acid at temperatures ranging from -40° to 80 0 C where -20° to 3O 0 C Is preferred.
  • the reductive amination may also be performed by first preparing the corresponding imine or iminium species through the agency of reagents such as titanium tetrachloride or titanium (V) isopropoxide in inert solvent such as chloroform, dichloromethane or 1,2 - dichtoroethane at temperatures ranging from --80° to O 0 C, followed by treatment of the so generated imine/im ⁇ n ⁇ um species in-situ with metal hydride reagents such as sodium borohydride, sodium cyanoborohyd ⁇ de or sodium trtacetoxyborohydride.
  • reagents such as titanium tetrachloride or titanium (V) isopropoxide in inert solvent such as chloroform, dichloromethane or 1,2 - dichtoroethane at temperatures ranging from --80° to O 0 C
  • metal hydride reagents such as sodium borohydride, sodium cyanoborohyd ⁇ de or sodium
  • Step Q Formation of chromanone intermediate (16) from chromanone (15) may be accomplished following the general conditions described in Scheme 1, step I.
  • Step P Formation of chromanone intermediate (16) from chromanone (15) may be accomplished following the general conditions described in Scheme 1, step I.
  • Formation of compound (14) of general formula I may be accomplished by treating intermediate (11) with a strong organic acid such astriflic acid or preferably trifluoroacetic acid in the presence of a hydride source where triethylsilane is preferred in a suitably inert solvent such as chloroform, dichloromethane, 1 ,2-dichloroethane or no added solvent where 1 ,2-dichloroethane is preferred at temperature ranging from ⁇ 40 ⁇ to 12O 0 C where ⁇ 70-110°C is preferred.
  • a strong organic acid such astriflic acid or preferably trifluoroacetic acid
  • a hydride source where triethylsilane is preferred in a suitably inert solvent
  • a suitably inert solvent such as chloroform, dichloromethane, 1 ,2-dichloroethane or no added solvent where 1 ,2-dichloroethane is preferred at temperature ranging from ⁇ 40 ⁇ to 12O 0
  • 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 enarttiomers 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).
  • HPLC high pressure liquid chromatography
  • the racemate (or a ra ⁇ emic 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- phenyiethylamine.
  • 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- phenyiethylamine.
  • 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.
  • Chirat compounds of the invention 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 O to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to
  • 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 Eiiel (Wiley, New York, 1994).
  • LAH lithium aluminum hydride MHz: megahertz
  • MIn mlnute(s) mlz ; mass to charge ratio (in mass spectrometry) obsd: observed
  • PPTs pyridinium p-toluenesulfonate
  • TsO p-toluenesulfonate
  • 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 spectra are reported in parts per million relative to the singlet of CDCl 3 at 7,24 ppm. Chemical shifts for 1S C NMR spectra are reported in parts per million downfield relative to the centerline of the triplet of CDCl 3 at 77.0 ppm. (Mass spectra analyses were performed on a APCI Gilson 215, micromass ZMD (50% Acetonitriie / 50% water) spectrometer.
  • the HCI salt was made as followed. 7-bromo-3-pyrro!id ⁇ n-1-ylchrornan-4-oI hydrochloride. To a suspension of 7-brom ⁇ -3- pyrrolldin-i-ylchr ⁇ ma ⁇ -4-oi (11.1 g, 37.2 mmol) in /FrOH (25OmL) was added concentrated HCI (3,4 mL, 37.2 mmol) and the solution was stirred at room temperatire for 3h. Then the suspension was evaporated to dryness and the residue was recrystailized from /PrOH (300 mL) and ether (200 mL) in fridge to afford 101865-123 (9,3 g, 75%) as a white crystals.
  • Example 1 S-fS ⁇ -Dihydro-S- ⁇ pyrrolWifl-i-y ⁇ H-chwmen ⁇ -ylJ-N-Isopropylbeiizamtde.
  • reaction mixture was evaporated to dryness, dissolved in DCE (10 mL) and added dropwise to a cold (ice bath) solution of STAB (0.56 g, 2.64 mmol) and acetic acid (0.4 mL, 6.60 rnmol) in DCE (10 mL).
  • the formed solution was vigorously stirred for 21 h.
  • water (20 mL) and 10N NaOH (to reach pH ⁇ 12) were added and organic layer was separated. The water one was extracted with chloroform (2 x 10 mL).
  • the reaction mixture was evaporated to dryness, dissolved in water ⁇ 100 mL) and saturated K2CO 3 was added.
  • the resulting suspension was extracted with ether ⁇ 300 mL) and EtOAc (Z x 200 mL). Combined organic layers were washed with 0.1 N K 2 CO 3 (2 x 205 mL) and brine (100 mL), dried over Na 2 SO 4 +SiO 2 (5 mL, 63-100 ⁇ m) and evaporated.
  • the HCI salt of the title compound was made as followed: ⁇ /-lsopropyl-4-(3- ⁇ yrrolidin-1-yl-3,4-dihydr ⁇ -2t ⁇ - chromen-7-yl)benzamfde Hydrochloride.
  • a 0.4 M solution of HCI in dioxane (17.S ml_, 7.0 mmol) was added to a solution of free base title compound (2.55 g, 7.0 rrtmol) in absolute dioxane (25 mL), The reaction mixture was evaporated to dryness, and the residue was crystallized from MeOH/EfeO (1:3). Yielding the HC!
  • reaction mixture was stirred at room temperature for 24 h.
  • the reaction was monitored by TLC ⁇ ethyl acetate/methanol 80:20; R f of product is 0,23).
  • Water (20 mL) was added to the reaction mixture.
  • the latter was alkalized to pH 11 with 3N NaOH and stirred for 5 rnin.
  • the organic layer was separated, and the aqueous one was subjected to extraction with d ⁇ chl ⁇ romethane (3 * 20 mL).
  • the combined extracts were dried with Na 2 SG, ? and evaporated to give analytically pure compound title compound as a brown powder. Yield: 497 mg (1.39 mmol, 77%).
  • Example 4 a-Methoxy-3-(3-pyrroIidin-i-yl-3,4-dihydro-2H-chromen-7-yl)pyridine. A solution of 7-(2-Methoxypyridln-3-yl)-2H-chromen-3(4H)-one.
  • the HCI salt of the title compound was made as followed: 2-Methoxy-3-(3-pyrro]idin-1-yl-3,4-d!hydro-2H-chromen-7- yl)pyridine Dihydrochloride. 4 M HGI/dioxane (0.66 mL, 2.S6 mmol) was added to a solution of compound 101918-071 (0.41g, 1.33 mmol) in absolute dioxane (5.0 mL). The reaction mixture was evaporated to dryness and crystallized from MeOH/Et 2 O (1:3). Yield of HCI salt 0.29 g ⁇ 0.83 mmol, 62.4%,) as white crystals.
  • the HCl salt of the title compound was prepared as followed; N-ethyl-3-(3,4-dihydro-3-((R)-2-methyl ⁇ yrrolidin-1-yl)- 2H-chromen-7-yl)benzamide hydrochloride.
  • To a solution of free base of the title compound ⁇ 0.318 g, 0.87 mmol) in dioxane (12 mL) was added dropwise OAU solution of HCI in dioxane (2.2 mL, 0,88 mmoi) and the resulting mixture was vigorously stirred for 5 minutes. Then the mixture was evaporated to dryness and the residue was crystallized from MeOHZEt 2 O to afford 101865-161 (0.306 g, 88%) as an orange crystals.
  • 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 1 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 1 a neurotransmitter re-uptake blocker and optionally a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • metabolites of compounds of formula I 1 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 hydroxyrnethyl 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 s R b ⁇ -NHR * 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 (1) contains an amide group, a carboxyiic acid derivative thereof (-CONlW ⁇ 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.
  • 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 pregelatlnized maize starph, polyvinylpyrroiidone or hydroxypropyl methylcellulose; fillers such as lactose, microcrystalline cellulose or calcium phosphate; lubricants such as magnesium siearate, 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 sorblc acid.
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • 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.
  • the active ingredient or ingredients in a composition may be in powder form for reconstttution with a suitable vehicle, for example, sterile pyrogen-free water, before use,
  • a suitable vehicle for example, sterile pyrogen-free water
  • active ingredient refers to a compound of the formula I, a histamine Hh antagonist, or a neurotransmitter re-uptake blocker.
  • 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 glyc ⁇ rides.
  • 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.
  • 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 propeliant, for example, dichlorodifluoromethane, trichlor ⁇ fluoromethane, di ⁇ hlorotetrafluoroethane, carbon dioxide or other suitable gas,
  • a suitable propeliant for example, dichlorodifluoromethane, trichlor ⁇ fluoromethane, di ⁇ hlorotetrafluoroethane, carbon dioxide or other suitable gas
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active 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 ⁇ g to about 1000 ⁇ g of the compound of formula I.
  • the overall daily dose with an aerosol will be within the range about 100 ⁇ g to about 10 mg.
  • Administrai ⁇ n 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 ⁇ g to about 10,000 ⁇ g of the compound of formula i and about 100 ⁇ g to about 30,000 ⁇ g of the histamine H 1 antagonist or the neurotransmitter reuptake blocker.
  • composition of the invention comprising a compound of formula i and a histamine H 1 antagonist or a neurotransmitter re-upta ⁇ e 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 filters, sterile aqueous media and various non-toxic organic solvents, etc.
  • Oral pharmaceutical formuiations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes,
  • 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
  • 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, Le. , in amounts which are sufficient to provide the desired unit dosage.
  • the compound of formula I and the histamine Hi antagonist may be administered together or 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.
  • the compound of formula I 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 I to the histamine H-j 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.
  • 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.
  • enteric layers or coatings such materials including a number of polymeric adds 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 Hi 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.
  • 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 mlVf Tris HCI containing 2 mU 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-methyI-histamine).
  • 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.

Abstract

L'invention concerne un composé représenté par la formule (I), tel que défini dans la description, ou un sel pharmaceutiquement acceptable de ce dernier; une composition pharmaceutique contenant un composé représenté par la formule (I), un procédé de préparation d'un composé représenté par la formule (I), une méthode de traitement d'un trouble ou d'une pathologie pouvant être traités par antagonisation des récepteurs H3 de l'histamine, le procédé consistant à administrer, à un mammifère nécessitant un tel traitement, un composé représenté par la formule (I) tel que susdécrit, et une méthode de traitement d'un trouble ou d'une pathologie sélectionnés dans le groupe comprenant la dépression, les troubles de l'humeur, la schizophrénie, les troubles anxieux, la maladie d'Alzheimer, le trouble de l'hyperactivité avec déficit de l'attention (THADA), les troubles psychotiques, les troubles cognitifs, les troubles du sommeil, l'obésité, l'étourdissement, l'épilepsie, le mal des transports, les maladies respiratoires, l'allergie, les réponses des voies aériennes induites par une allergie, la rhinite allergique, la congestion nasale, la congestion allergique, la congestion, l'hypotension, la maladie cardiovasculaire, les maladies du tractus gastro-intestinal, l'hypermotilité et l'hypomotilité et la sécrétion acide du tractus gastro-intestinal, la méthode consistant à administrer, à un mammifère nécessitant un tel traitement, un composé représenté par la formule (I) tel que susdécrit.
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WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
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WO2012131539A1 (fr) 2011-03-31 2012-10-04 Pfizer Inc. Nouvelles pyridones bicycliques
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