WO2007088450A2 - Chromane antagonist of the h-3 receptor - Google Patents

Chromane antagonist of the h-3 receptor Download PDF

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Publication number
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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French (fr)
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WO2007088450A3 (en
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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

This invention is directed to a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition containing a compound of formula (I), a process of preparation of a compound of formula (I), a method of treatment of a disorder or condition that may be treated by antagonizing histamine H3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula (I) as described above, and a method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer's disease, attention-deficit hyperactivity disorder (ADHD), psychotic disorders, cognitive 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 GI 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) as described above.

Description

_-|_
CHROMANE ANTAGONISTS QF 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 histarntne-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, 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.
A number of diseases or conditions may be treated with histarrtϊne-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 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. 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-Kwileckl and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75- 78); (Haas et a!., 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. (1S9 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 Btozovskl, Exp. Brain Res, (1987) 67, 61-69); (Tedford et al., 4. Pharmacol. Exp. Ther. (1995) 275, 598-604); (Tedford et al., Soc. Neurasci. 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 a!., J. Pharmacol. Exp. Ther. (1997) 281, 1085); (Adam Szelag, "Role of histamine H3-receptors in the proliferation of neoplastic cells in vitro", Med. ScL Monit, 4(5); 747- 755, (1998)); (Fitzsimons, C1 H, Ouran, 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, R1C. Voliinga and H. Timmerman, "The medicinal chemistry and therapeutic potentials of Itgand 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. iinuma, "Histamine and Seizures: Implications for the treatment of epilepsy", CNS Drugs, 5(5); 321-330, (1995}); (K. Hurukami, H. Yokoyama, K. Onodera, K. Iinuma 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., Gustiri 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 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.
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. 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 WO 96/38142 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 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 hisfamϊne-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). In particular, the compounds of this invention selectively distinguish H3R from the other receptor subtypes H1R, H2R. )n 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 chromane 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:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein
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;
R1 and R2 are independently hydrogen, (GrC8)alkyI optionally substituted with 1 to 4 halogens, or (C3-C7)cycloalkyl-(C<rC4)alkyl; or optionally R1 and R2, 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 (CrCX))alkyl; and wherein one of the carbons of said heterocyclic ring -A-
that is separated by at least two atoms from said nitrogen in said heterocyclic ring is optionally replaced by O, S, NR6, or C=O; wherein Rβis hydrogen, (CrC8)alkyI optionally substituted with 1 to 4 halogens, or (C;rC7)eycloalkyi-(Co-C4}alkyl, and wherein each (Co-C4)alkyl is optionally substituted with 1 to 4 {C,-C4)alkyl;
R3 is hydrogen, (CrCe}alkyl, halo, 5-6 memfaered aryl optionally fused to a 5 to 6 membered aryl, 5-6 memfaered heteroaryl, {CrC8)alkoxy, hydroxy!, methylene hydroxy!, - (C=O)NR4Ra, and S(O)s{Ci-G4)alkyl, where p is 1 or 2; wherein R4 and R5 are each independently selected from the group consisting of hydrogen;
(CrCB)alkyi optionally substituted with 1 to 4 halogens;
{Ci-C4)alkyl group optionally substituted with a substituent selected from the group consisting of OH, 1 to 4 (C1-C4)aikyl, {C3-C7)cycloalkyl, {Ci-C$)dialky)amino, (C«j-C14}aryt optionally substituted with a halogen and optionally substituted with (CrCrøJaryloxy optionally substituted with 1 to 2 halogens, and 5 to 10-membered heteroaryl optionally substituted with a (Cs- CfoJaryl group and optionally substituted with 1 to 3 (CrC^Jalkyl groups; (C3-C6)cycloalkyl;
Figure imgf000005_0001
-(C0-C3)alkyl-O-{C1-C3)alkyl optionally substituted with (Ct-C^alkyl;
-(C1-C3)alkyl-C(=O)O-(C,-C3)alkyl;
3-8-membered heieroeycloalkyl optionally substituted with one or more
(CrC4)alkyl-carbotiyl groups; (Ce-Cio)ary!sulfønyl optionally substituted with one or more (Ci-C2)alkyl;
5-10-membered heteroaryl; and {C5-C14)aryf-(CirC4)alkylene-O-(Co-C4)alkyll wherein each {C0-C4)alkyl and each (C0-
C4)alkylene is optionally substituted with 1 to 4 (Ci-C4 alkyl); or optionally R3 and R4, 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 O1 S, NRS or CO, and wherein said ring is optionally fused to a (Ce-C10)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 (CrCaJalky), (C-|-C4)alkoxy optionally substituted with one or more (C1-C2)BIkOXy and optionally substituted with one or more (C1-C4}dialkylaminocarbonyll and 1 to 2 {CrC4}alkyl optionally and independently substituted with one or more (C1-C2)ali<oxy; wherein Rs is selected from the group consisting of hydrogen; (C1-C8)alkyl optionally substituted with 1 to 4 halogens;
5-10-membered heteroaryt optionally substituted with a substituent selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C2)aIkoxy, {C6-C10)aryl, (C1- C4)alkylarninocarbonyl, and cyano;
(C1-C4)alkyI group optionally substituted with a substituent selected from the group consisting of (C1-C2)alkoxycarbonyl, 5-10-membered heteroaryl optionally substituted with one or more {C1-C2}alkyl, 1 to 4 (C1-C4)alkyl, (C3- C7)cycloalkyl, and (C6-C14)aryl;
{C6-C10)aryl optionally substituted with 1 or 2 (C1-C2)alkyl; (C1 -C4)alkylGarbαnyl; and (C6-C14}ary!-(Co-C4)alkylene-0-(CQ-C4}alkyl, wherein each (C0-C4)alkyl and each (C0-
C4)alkylene Is optionally substituted with 1 to 4 (C1 -C4)alkyl;
A preferred embodiment includes compounds of claim 1 wherein W, X, Y, and Z are carbon; R1 and R2, together with the nitrogen to which they are attached, form a 4-, S-, 6- or 7- membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or two (C1 -C4)alkyl; and wherein one of the carbons of said heterocyclic ring that is separated by at least two atoms from said nitrogen in said heterocyclic ring is optionally replaced by O1 S, NR8, or C=O, wherein R6 is hydrogen, (C1-C8 alkyl optionally substituted with i to 4 halogens, or
(C3-C7)cycioalkyl-(C0-C4 )alkyl, and wherein each (C0-C4)alkyl is optionally substituted with one to four (C1-C4)alkyl; and R3 is (C1-C6)aIkoxy, -(C=O)NR4R5, and SO2(C1-C4)alkyl; wherein R4 and Rs are each independently selected from the group consisting of hydrogen;
(C-ι-Cs)alkyl optionally substituted with 1 to 4 halogens; (C1 -C4)alkyl group optionally substituted with a substituent selected from the group consisting of OH1 one to four (C1 -C4)alkyl, (C3-C7)cycloalkyl, (C1 -C4)dialkylamino, (C6-C14)aryl optionally substituted with a halogen and optionally substituted with (C3-C10)aryloxy optionally substituted with one to two halogens, and 5-10-membered heteroaryl optionally substituted with a (Cβ-Cto)aryl group and optionally substituted with 1 to 3
(C1-Gi)aikyi groups; (C3-Cτ)cyc!oalkyl; (C6-C14)aryi; -(Co-Cs)alkyl-O-(C1-C3)alky! optionally substituted with (d-C^alkyl;
-(CrC3)alkyl-C(=O)O-(CrCs)alM;
3-8-membered heterocycloalkyl optionally substituted with one or more
(C1-C4}aikyl-carbonyl groups;
(Ce-C10)arylsulfonyi optionally substituted with one or more (C1-C2JaIKyI; 5-10-membered heteroaryl; and
(Cβ-C14)aryKCtrC4)al(«ylene-O-(Co-C4}alkyi, wherein each (Co-C4)alkyl and each (C0-
C4)alkylene is optionally substituted with 1 to 4 (Gi-CJalkyl; or optionally R3 and R4, 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, NR5 or CO, and wherein said ring is optionally fused to a (Cβ-C1o}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 (C1-Cz)alkyl, (C1-C4JaIkOXy optionally substituted with one or more (C1-C2)HIkOXy and optionally substituted with one or more (C-rCPalkylaminocarbonyi, and 1 to 2 (CrC4)alkyl optionally and independently substituted with one or more (CrC2)alkoxy.
Another preferred embodiment includes compounds of claim 1 wherein W, X, Y, and Z are independently selected from nitrogen or carbon; wherein the total number of said nitrogens for W, X, Y, and 2 equals one; R1 and R2, together with the nitrogen to which they , are attached, form a 4-, S-, 6- or 7- mernbered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or two (C1-C4)alkyl; and wherein one of the carbons of said heterocyclic ring that is separated by at least two atoms from said nitrogen in said heterocyclic ring is optionally replaced by O, S1 NR9, or C=O1 wherein Rβ is hydrogen, (C1-Cβ)alkyl optionally substituted with 1 to 4 halogens, or
(C3-C7)cycloaikyl-(Co-C4)alkylt and wherein each (Co-C4)alkyi is optionally substituted with one to four (C1-C^)alkyl; and R3 is (C1-Ce)aikoxy. Preferred and exemplary embodiments of the invention include the following compounds of formula I:
{3S,4R}-7-(4-IVIethoxy-phenyi)-3-pyiTolidin-1-yl-chroman-4-ol» 1-[7-(4-Methoxy-phenyl)-chroman-3-yI]-ρyrrolidine, N-Ethy l-3-(3-pyrro!idin-1 -yl-chroman-7-yl)-benzamide, N-Isopropyl-3-(3-pyrrolid[n-1-y(-0hroman-7-yl)-ben2amide, 2-Methoxy-3-(3-pyrrolidin-1-yI-chrornan-7~yl}-pyridine, N-lsopropyl-3-[3-((R)-2-metriyl-pyrroIid!n-1-yl}-chroman-7-yll-ber)zamide, 1-[7-(4-Methanesulfonyl-phenyl)-chroman-3-ylI-pyrroIidine, N-Ethy!-3-[3-({R)-2-methy!-pyrrolϊdirt-1 -yl)-chroman-7-ylf-ben2amide, and N-JsopropyM-(3-ρyrroIidin-1-y)-ehroman-7-yl)-benzamide.
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.
This invention is also directed to 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.
In the general formula 1 according to the present invention, when a radical is mono- or poly-substituted, said substituentfs) can be located at any desired position(s), unless otherwise stated. Also, when a radical is polysubstltuted, said substituents can be identical or different, unless otherwise stated,
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,
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 HI antagonist, such as cetirizine (Zyrtec™), chlorpheniramine {Chlørtrimeton™}, loratidine (Claritin™), fexofenadine (Allegra™), or desloratadine (Clartnex™) 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 (SSRPs) 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 and chlorine, such as 2H, 3H1 13C, 11C1 14C, 15N, 1βO, 17O, 1SO, 31P, 32P, 35S, 18F, and 38GI, 123I respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and UC are incorporated, are useful in drug and/or substrate tissue distribution assays, Tritiated, Le1., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, Le1, 2H, 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
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Anxiety disorders include, for example, generalized anxiety disorder, panic disorder, PTSD1 and social anxiety disorder. Mood adjustment disorders include, for example, depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood. Attention adjustment disorders include, for example, in addition to ADHD, attention-deficit disorders or other cognitive disorders due to general medical conditions. Psychotic disorders include, for example, schizoaffective disorders and schizophrenia; sleep disorders include, for example, narcolepsy and enuresis.
Examples of the disorders or conditions which may be treated by the compound, composition and method of this invention are 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; dysthymϊa; 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, pbenobarbita! 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 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; 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 otherthan 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, edisyiate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochϊoride/chloride, hydrobrornide/brornide, hydroiodide/iodide, isethionate, lactate, malate, maleate, maionate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotϊnate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogert 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, diethylatnine, dioiamϊne, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, trαmethamine and zinc salts.
Hernisalts 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 Werrnuth (Wiley-VCH, Weinheim, Germany, 2002). ■
The compounds of the invention may exist in both unsolvated and soivatecl forms.
The term '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, ethaπol, The term 'hydrate' is employed when said solvent is water.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopicaily substituted, e.g. D2O, dg-acetone, d6- DMSO,
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 Halebϊian (August 1975}.
Hereinafter 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.
As indicated, so-called 'pro-drugs' of the compounds of formula I are also within the scope of the invention. Thus 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',
Pergamon Press, 1987 {ed. E. B Roche, American Pharmaceutical Association).
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. lncluded 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 counterioπ is optically active, for example, d-lactate or l-iysine, or racemic, for example, dl-tartrate or dl-arginine.
Unless otherwise indicated, the term "halo", as used herein includes fluoro, chloro, bromo and ϊodo.
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-butexy.
Unless otherwise indicated, the term "alkylene", as used herein, includes a divalent radical derived from straight-chain or branched alkane. Examples of aikylene radicals are methylene, ethylene (1,2-ethylene or 1,1-eihylene}, trirnethylene {1,3-propylene)( tetramethyiene (1,4-butytene), pentamethylene and hexamethylene.
Unless otherwise indicated, the term "eycloaikyl", as used herein, unless otherwise indicated, 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.
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 heterocycloalkyi groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of 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, 3-azabicyclo[3,i.0]hexany!, 3-azablcyclo[4.1.0]heptanyl, quinolizlnyl, quinuclidinyl, i,4-dioxasρiro[4.5Jdecyl, i,4-dioxasρiro[4.4]nαnyi, 1,4- dioxaspiro[4.3]octyl, and 1,4-dioxaspiro[4.2]heptyl,
Unless otherwise indicated, the term "aryf, 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 "heieroaryi" as used herein, 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. Examples of heteroaryl groups include, but are not limited to thiophenyl, furanyl, pyrrolyl, pyrazoiyl, imidazolyi, oxazoly!, isσxazolyl, thiazolyl, isothiazoiyl, triazoiyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, pyrϊdinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiadϊazinyl, isobenzofuranyl, benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolinyi, isoquinoiyl, cinnoiinyl, phthalazinyϊ, naphthyridinyl, quinazolinyl, quinoxalinyl, benzoxazolyi, benzothia∑olyl, benzimidazotyl, benzofuranyl, benzothiopbenyl, pyrrolopyraziny!, 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.
Figure imgf000015_0001
3-Bromophenol (2) is acetylated to give acetate (3) via treatment with acetic anhydride or preferably acetyl chloride in the presence of a rton-nudeophϊϋc amine base such as diisopropyiethylamine, triethylamine or preferably pyridine in a suitably inert solvent such as chloroform, 1,2-diohloroethane or preferably dichloromεthane at temperatures ranging from -10*C to 8O0C 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 80^20O0C where 120° to 17O0C is preferred.
Vinylogous amide (5) may be synthesized by treatment of (4) with bis{dimethylamino)-tetf-butoxymethane (Bredereck's reagent) or preferably N1N- dimethylformamide dimethylacetal in xylene, toluene or preferably benzene at temperatures ranging from 50° to 12O0C, 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 1000C where 30-700C 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 100C to O0C where -80° to -400C 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 halαgenated 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
10 such as diisopropylethylamine or preferably trlethylamine, at temperatures ranging from 10° to
800C where room temperature is preferred.
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 100C to 7O0C 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
20 organopalladium catalyst such as tetrakis(triphenylphosphine)paliadtum (Q), dichloropalladlum blstriphenylphosphine or tris(dibenzyiid!ne-acetσne)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
25. or preferably dimethoxyethane and a polar protic solvent such as water, methanol or ethanoi, preferably water, at a temperature of from about 1O0C to 1SO0C1 preferably about SOMOO0C.
The compounds so formed may be further derivatized using standard reactions familiar to those skilled in the art. Step J:
30 Amiπochromene 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 1200C where 6G0-9GqC is preferred.
35 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 800C where -20° to 300C is preferred.
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. Step M:
Compound 14 of general formula (I) may also be prepared by reductive amination using isochromanone 13 and amine NHR1R2 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 800C where -20° to 3O0C 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 O0C, followed by treatment of the so generated imine/imϊnϊum species in-situ with metal hydride reagents such as sodium borohydride, sodium cyanoborohydπde or sodium trtacetoxyborohydride.
An alternative preparation of compounds of the formula (I) is shown in Scheme 2. Scheme 2
Figure imgf000019_0001
15 R4 - Br, I, triflatβ
Figure imgf000019_0002
14
Steps Formula I deoxygenation
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 brominated intermediate (17) from intermediate (16) may be done following the bromination conditions describe in Scheme 1, step F. βtep Q:
Intermediate (17) may be converted to animated intermediate (18) following the general conditions described in Scheme 1, step G. Step R:
Reduction of intermediate (18) to form intermediate (11) may be accomplished following the general conditions described in Scheme 1, step H. βtep S:
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 ~40β to 12O0C where ~70-110°C is preferred.
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). -
Alternatively, the racemate (or a raσemic 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. 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 (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 O to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to
5% by volume of an alkylamine, typically 0.1% diethy (amine. 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 Eiiel (Wiley, New York, 1994).
In the examples below the following terms are intended to have the following, general meaning:
DlPEA: diisopropylethylamine
DMF: dlmethyfαrmamide
MgSO4: magnesium sulfate
DMA: dimethyl acetamide LRMS: low resolution mass spectrometry
0C: degrees Celsius calcd: calculated d: day(s); doublet (spectral)
DGE: 1,2-dichloroethane
EtOAc: ethyl acetate g: grams hr: hours
Hz; hertz
J: coupling constant (in NMR)
L: liter(s)
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
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; thfn layer chromatography
Ts: tosyl, p-toluenesulfønyl
TsOH: p-toluenesulfoπic acid
TSP: 2,4,6-tripropyl-1,3>5l2,4,6-trioxatriphosphorinane-2,4,6-trioxide (CAS # 68957- 94-8) 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 KMnO4 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 1H, respectively, and 100 MHz or 125 MHz for 13C NMR, respectively. Chemical shifts for proton 1H NMR spectra are reported in parts per million relative to the singlet of CDCl3 at 7,24 ppm. Chemical shifts for 1SC NMR spectra are reported in parts per million downfield relative to the centerline of the triplet of CDCl3 at 77.0 ppm. (Mass spectra analyses were performed on a APCI Gilson 215, micromass ZMD (50% Acetonitriie / 50% water) spectrometer.
The following intermediates may be prepared by the procedures shown:
Intermediate 1
3-Bromophenyl acetate.
To a cold (ice bath) solution of 3-bromophenol (150 g, 867 tnmol) and pyridine (70.0 mL, 867 mmol) in CH2CI2 (1000 ml) acetyl chloride (61.7 rnL, 867 mmol) was added in a dropwise manner during 1 h and the mixture was then stirred for 18 h at room temperature. Then to the resulting solution was added water (500 mL), the organic layer was separated and the water one was extracted with CH2CI2 (4 x 150 rnL), The combined organic layers were washed with 2.5N NaHSO4 (3 x 150 mL), 3N NaOH (3 x 150 mL), water (2 x 200 mL) and brine (2 x 200 mL), dried over Na2SO4 and evaporated to give the title compound as a pink liquid (36.0 g, 86 %). GC/MS data: 214 (M)+ (Calculated for CgH7BrO2 215.04). (calc. rnonoisotopic mass is (M)+ 213.96). 1H NMR data (DMSO-d6): 7.44-7.48 (ddd, 1H1 J, = 1.0 Hz, J2 = 2.0 Hz, J3 = 8.1 Hz, Ar-H), 7.43 (t, 1H, J = 2.1 Hz, Ar-H), 7.38 (t, 1H, J = 8.1 Hz, Ar- H)1 7.14-7.18 (ddd, 1H, J, = 1.0 Hz, J2= 2.2 Hz, J3 = 8.1 Hz1 Ar-H), 2.26 (s, 3H, CH3). Intermediate 2
1-(2-bromo-6-hydroxypherjy!)ethanone,
The mixture of 3-Bromophenyl acetate (36.0 g, 167 mmol) and uohydrous AlCl3 (33.5 g 251 mmol) was heated to 140 - 150 0C for 2 h. To the resulting black solid was added 100 ml of 5% HCI and the mixture was heated on boiling wafer bath until the solid material dissolved. After cooling to the room temperature the precipitated brown oil was extracted with CH2Cl2 (3 x 150 ml) and to the organic layer was added 300 ml of 5N NaOH. The formed precipitate was dissolved In water, organic layer was separated and the water one was acidified to pH ~ 2 and extracted with EfOAc (5 x 150 mL). Combined extracts were dried over Na2SO4 and evaporated to give the title compound as beige crystals (35.8 g, 99%).GC/MS data: 214 (M)+ (Calculated for C8H7BrO2 215.05), (calc. monoisαtopic mass is (M)* 213.96). 1H NMR data (DMSO-d6): 11.97 (s, 1H, OH), 7.78 (d, 1H, J=8.3 Hz, Ar-H), 7.19 (d, 1H, J=2.0 Hz, Ar-H), 7.13 (dd, 1H, J,=8.3 Hz1 J2=ZO Hz1 Ar-H), 2.60 (s, 3H, CH3).
Intermediate 3
(2£)-1-(4-bromo-2-hydroxyphenyl)-3-(dlmethylamlno)prop-2-en-1-one. To a solution of i-(2-bromo-6-hydroxyphenyI)ethanone (35.8 g, 167 mmol) in dry benzene (800 mL) was added N.N-dimethylformamide dimethylacetal (44 mL, 333 mmol) and the solution was heated to reflux for 4 h. The reaction mixture was then evaporated to dryness, dissolved in CHCI3 (300 rr»L) and filtered through SiO2 (63-100 μm, 200 mL) to give after evaporation the title compound (31,9 g, 71%) as a bright yellow solid. LC/MS data; 270.0 (M+Hf (Calculated for C11H12BrNO2 270.13). (calc. monoisotopic mass is 269.01, calc. monoisotopic mass (M+Hf = 270.01). 1H NMR data (DMSO-d6): 14.96 (s, 1H, OH), 7.93 (d, 1H, J=12.0 Hz, =CH), 7.87 (d, 1H, J = 9.0 Hz, Ar-H), 7.03 (d, 1H, J = 2.2 Hz, Ar-H)1 6,99 (dd, 1H, J1=S-O Hz7 J2=2.2 Hz, Ar-H), 5.94 (d, 1H, J=12.0 Hz, =CH), 3.21 (s, 3H, CH3), 3.00 (S, 3H1 CH3).
Intermediate 4 7-Bromo-4W-chromen-4-one.
To a solution of (2£)-1-(4-bromo-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one (31.9 g, 118 mmol) in CH2CI2 (900 mL) was added concentrated HCI (100 mL) and the reaction mixture was heated to reflux upon vigorous stirring for 40 minutes. Then the reaction mixture was allowed to cool to room temperature, the organic layer was separated and the water one was extracted with CH2CI2 (100 mL). Combined organic layers were washed with 3M K2CO3 (2 x 10OmL), dried over Na2SO4 and evaporated to give the title compound (26.3 g, 99%) as a pale yellow solid. LC/MS data: 224.9 (M+Hf (Calculated for CgH5BrO2 225.04) (calc. monoisotopic mass is 223.95, calc. monoisotopic mass (M+Hf = 224.95). 1H NMR data (DMSO-d6): 8.29 (d, 1H, J=5.8 Hz, =CH), 7.99 (d, 1H, J=2.0 Hz, Ar-H), 7,94 (d, 1H, J = 8.5 Hz, Ar-H), 7.66 (dd, 1H, J,=8,5, J2=I .7 Hz, Ar-H), 6.38 (d, 1H, J=5.8 Hz1 =CH).
Intermediate 5 7-Bromo-2,3-dϊhydro-4W-chromen-4-one.
The solution of 7-Bromo-4H-chromen-4-one (26.0 g, 116 mmol) in absolute THF (500 mL) was stirred under argon for 1 h and then it was cooled to -80 0C. To a suspension formed a solution of diisobutylaluminum hydride 1M In heptane (173 mL, 173 mmol) was added during 30 minutes and the resulting mixture was stirred at -80 0C for additional 30 minutes. The solution was quenched by mixture of SiO2 (52 g) and H2O (52 mL), allowed to warm to 00C. Then SiO2 was filtered, washed with EtOAc and the solution was evaporated to dryness. The residue was dissolved in CHCI3 (400 mL), washed with 1 N NaOH (300 mL), dried over Na2SO4 and evaporated. The resulting solid was purified by column chromatography on SiO2 (63-100 μm, 1200 mL) in CHCI3 (80 - 100%) gradient in hexane to afford 101865-076 (18.1 g, 69%) as a pale yellow solid. LC/MS data: 226.9 V(M+Hf (Calculated for C8H7BrO2 227.06) (calc. monoisotopic mass is 225.96, calc. monoisotopic mass (M+Hf = 226.96). 1H NMR data (DMSO-d6): 7.66 (d, 1H1 J=8.3 Hz, Ar-H), 7.33 (d, 1H, J=2.0 Hz, Ar-H), 7.25 (dd, 1H, ^=8.3 Hz1 J2=L 7 Hz, Ar-H), 4.56 (t 2H, CH2 , J=6.6 Hz)1 2.80 (t, 2H, CH2 , J=S,6 Hz). lnter.med.iate 6 3,3,7-fribromo-2,3-dihydro-4H-chromen-4-one.
To a vigorously stirring solution of 7-Bromo-2,3-dihydro-4W-chromen-4-oιie (20.0 g,
88.1 mmoi) in CCI4 (400 mL) was added dropwise a solution of bromine (10 mL, 194 mmoi) in CCI4 {100 mL) over 45 minutes. The resulting solution was stirred for 50 minutes and CHCl3
(100 mL) was added to the solution to dissolve the precipitate, The solution was washed with 10% NaHSO3 (75 mL), dried over Na2SC^ and evaporated to dryness to give the title compound (32,5 g, 86%) as a yellowish solid. LC/MS data; 302.9 (M-Br)* (Calculated for C9HsBr3O2 384.85). (calo. monoisotopic mass is 38171, calc. monoisotopio mass (M-Br)+= 302.9). 1H NMR data (DMSO-dδ): 7.82 (d, 1H, J = 8.6 Hz, Ar-H), 7.51 (d, 1H, J = 2.0 Hz, Ar- H)1 7.42 (dd, 1H1 J1= 8.3, «4=1.7 Hz, Ar-H)1 5.02 (s, 2H, CH2).
Intermediate 7
7-forσmø-3-pyrrol idln-1 -y)-2,3-dihydro-4W-chromer!-4-one.
To a suspension of 3,3J-tribromo-2,3-dihydro-4W-chromen-4-one (32.5 g, 84.4 rnmαl) in acetonitrile (650 mL) was added pyrrolidine {8.50 mL, 101 mmoi), Et3N (23.5 mL, 169 mmoi) and the formed solution was stirred during 16 h at room temperature under argon. The resulting solution was evaporated to dryness, dissolved in EtOAc (500 mL), washed with water (3 x 200 mL), brine (100 rnL), dried over Na2SG^ and evaporated. The residue was purified by column chromatography on SiO2 (63-100 μm, 800 mL) on EtOAc (0 - 2%) gradient In CHCIs to afford 101865-118 (121 g, 49%) as a yellow solid. LC/MS data: 294.0 (M+Hf {Calculated for C13H12BrNO2294,14). (calc. monoisotopic mass Is 293.01, calc. monoisotopic mass (Nl+Hf = 294.01). 1H NMR data (DMSO-dδ): 7.99 (d, 1H, J = 8.6 Hz1 Ar-H), 7.92 (d, 1H, J = 17 Hz1 Ar-H), 7.79 (s, 1H1 =CH), 7.56 (dd, 1H, J1= 8.6, J2=IT Hz, Ar-H)1 3.16-3.23 (m, 4H, pyrrolidine-CHjj), 1.81-1.88 (m, 4H1 pyrrolidine-CH2). Intermediate 8
7-btamo-3-p)tttottdin-1-ytchtomm-4Ol
To a solution of 7-bromo-3-pyrrolidin-1-yl-2,3-dihydro-4W-chromen-4-one (12.1 g,
41.2 mmoi) in EtOH (1200 mL) was portionaϋy added NaBH4 (15.7 g, 412 mmoi) and the suspension was vigorously stirred for 14 h. To the solution formed was added water (100 mL) and the solution was evaporated to driness. The residue was dissolved in CHCl3 (300 mL), washed with water (3 x 100 mL), dried over Na2SO4 and evaporated to dryness to afford 101865-122 (11.1 g, 92%) as a white solid. LC/MS data: 298.1 (M+Hf, (Calculated for C13H16BrNO2 298.18). (calc. monoisotopic mass is 297.04, monoisotopic mass (M+Hf= 298.04). 1H NMR data (DMSO-d6): 7.19 (d, 1H, J = 8.1 Hz, Ar-H), 7.06 (dd, 1H, J1= 8.1, J2=2.0 Hz, Ar-H), 7.00 (d, 1H, J = 2.0 Hz, Ar-H), 5.01 (br d, 1H, J=4.2 Hz, OH), 4.5S (m, 1H, CH), 4.24 {ddd, 1H1 J1=I 0.6 Hz, J2=3.7 Hz, J3=1.5 Hz, CH), 4.05 (t, 1H, J = 10.6 Hz, CH), 2,68-2.72 (m, 2H, ρyrrolidlne-CH2), 2.57-2.62 (m, 2H, pyrrolidine-CHz), 2.44 (dt, 1H, J<,=10.6 Hz, Jt=3.2 Hz, CH)1 1.73-1,66 (m, 4H, pyrrolidine-CH2). The HCI salt was made as followed. 7-bromo-3-pyrro!idϊn-1-ylchrornan-4-oI hydrochloride. To a suspension of 7-bromσ-3- pyrrolldin-i-ylchrσmaπ-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. LC/MS data: 298.1 (M+H)*, (Calculated for C13H16BrNO2298.18). (calc. monoϊsotøpic mass is 297.04, rnonoisotopic mass (M+H)*= 298,04). 1H NMR data (OMSO-d6); 9.85 (br s, 1H, NH+), 7.31 (d, 1H, J = 8.3 Hz, Ar-H), 7.20 Wd, 1H, J1= 8.3, J2=2.0 Hz, Ar-H), 7.13 (d, 1H, J = 2.0 Hz, Ar-H), 6.72 (br d, 1H1 J=5.1 Hz, OH), 4-89-4.94 (m, 1H, CH), 4.54 (ddd, 1H, J1=ICB Hz, J2=3.7 Hz, J3=LO Hz, CH), 4.16 (t, 1H, J = 10.8 Hz, CH), 2.69-2.81 (m, 2H, pyrrø!idine-CH2), 2.52-2.64 (m, 1H, CH), 3.17-3.38 (m, 2H, pyrroIidine-CH2+H2O), 1.83-209 (m+m, 4H, pyrrolϊdine-CH2).
Intermediate 9 S^S^-dihydro-Φhydroxy-a-tpyrroiωin-i-yϊJ^H-chromeh-T-ylJbenzolc acid.
To a stirring solution of 7-broιno-3-pyrrolidin-1-ylchroman-4-ol (5 g, 17 mmol) in DlVlE (50 mL) in the atmosphere of argon were added successively Pd(PPh3)4 (0.80 g, 0.68 mmol) and 3-carboxyphenyiborαnic acid (5.08 g, 30 mmol). After 15 minutes of stirring 3M NaaCO^ (34 mL, 102 mmol) was added dropwise. The mixture was heated to reflux for 48 h. Then it was cooled, acidified' to pH ~ 4 by HCI (cone ), evaporated to dryness and co-evaporated with dioxane and with DR/SF. The title compound was used in the next step without purification.
Intermediate 10 3-(3,4-dJhydro-4-hydroxy-3-{pyrrolidin-'t-yl)-2H-chromen-7-yl)-N- jsopropylbenzamide.
To a cold (ice bath) solution of 3-(3,4-dihydro-4-hydroxy-3-(pyrrolidϊn-1-yl)-2H- chromen-7-yl)benzoic acid (11.53 g, 34 mmol) in DMF (120 mL) was added IPrNH2 (14.6 mL, 170 mmol) and Et3N (18,6 mL) (to reach pH ~ 9). Then BOP (21 g, 48 mmol) was added and the mixture was stirred at room temperature for 48 h. The reaction mixture was evaporated to dryness, dissolved in water (100 mL) and saturated K2CO3 (50 mL) was added. The resulting suspension was extracted with ether (400 mL). Etherial layer was washed with 0.1 N K2CO3 (2 x 100 mL) and brine (100 mL), dried over Na2SO4 and evaporated. The column chromatography of the residue on SiO2 (600 mL, 63-100 μm) in CHCl3 → FrOH (8%) gradient gave after evaporation the title compound (3.76 g, 29%) as a pale yellow solid. LC/MS data: 381.1 (M+H)* (Calculated for C23H28N2O3 380.48). (calc. monoisotopic mass Is 380.21, calc. monoisotopic mass (M+H)* = 381.21). 1H NMR data (DMSO-d6): 8.30 (d, 1H, J = 7.8 Hz, NH), 8.06 (s, 1H, Ar-H), 7.82 (d, 1H, J = 7.8 Hz, Ar-H), 7.76 (ci, 1H, J = 8,1 Hz, Ar-H), 7,51 (t, 1H1 J = 7,7 Hz, Ar-H)1 7,36 (d, 1H, J = 8,1 Hz, Ar-H), 7,25 (dd, 1H, J1 = 17 HE, J2 = 7.8 Hz, Ar-H), 7.15 (d, 1H, J = 1.5 Hz, Ar-H), 4.88-5.04 (br s, 1H1 OH)1 4,66 (br s, 1H1 CH), 4.27 (dd, 1H, J1 = 27 Hz, J2 = 10.5 Hz, CH), 4.03-4.17 {m, 2H, CH), 2.69-2.79 (m, 2H, pyrrolidine-CH2), 2.56-2,68 (m, 2H, pyrrolidine-CH2). Z45-2.53 (m, 1H, CH+DMSO), 1.67-1,76 (m, 4H, pyrroltdine-CHa), 1.18 (d, 6H, J = 6.6 Hz, CH3).
Example 1 S-fS^-Dihydro-S-^pyrrolWifl-i-y^^H-chwmen^-ylJ-N-Isopropylbeiizamtde. A solution of 3-(3t4-dihydro-4-hydroxy-3-(pyrrolidin-1-yl)-2H-chromen-7-yl)-N- isøprøpytbenzamide (O.δ g, 1.32 rnmoi) in a mixture of DCE (20 mL) and TFA (17 rnL) was refluxed for 24 h. After this time LC/MS showed no SM by ELSD. The 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. Then 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). Organic layers were combined, dried over Na2SO4 with SiO2 (1 mL, 63-100 μm), evaporated and co-evaporated with CCI4 to give the title compound (270 mg, 56%) as a yellow soiid. LC/MS data: 365.1 (M+H)+ (Calculated for C23H28N2O2 364.49). (calc. monoisotopic mass is 364.22, calc, monoisotopic mass (M+H)+ = 365.22). 1H NMR data (DMSO-d6): 8.29 (d, 1H, J = 7,8 Hz1 NH)1 8,05 (S, 1H, Ar-H), 7.80 (d, 1H, J = 7.5 Hz, Ar-H), 7.74 (d, 1H, J = 7.7 Hz, Ar-H), 7.49 (t 1H, J = 7.7 Hz, Ar-H), 7,15-7.21 (m, 2H, Ar-H), 7.11 (s, 1H, Ar-H), 4.30-4.34 (m, 1H, CH), 4.07-4.17 (m, 1H, CH), 3.92 (dd, 1H, J, = 7.7 Hz, J2 = 10.7 Hz, CH), 3.01 (dd, 1H1 J1 = 3.9 Hz1 J2 = 15.4 Hz1 CH), 2.78 (dd, 1H, J1 = 8.0 Hz, J2 = 16.3 Hz, CH), 2,55-2.68 (m, 5H, CH+pyrrolidine-CH2), 1.65-1.74 (m, 4H, py!Tθlidine-CH2), 1.18 (d, 6H, J = 6.6 Hz1 CHs), The HCI salt of the title compound was prepared as followed. 3-(3,4- D!hydro-3-(pyrrofidin-1-yl)-2H-chromen-7-yl)-N-isopropylbenzamide hydrochloride. To a solution of 3-(3.4-Dihydro-3-(pyrrolid!n-1-yl)-2H-chromen-7-yl)-N-isopropylbenzamide (647 mg, 1.78 mmol) in dioxane (8 mL) was added dropwise 0.4M solution of HCl in dioxane (4.45 mL) and the resulting mixture was vigorously stirred for 5 minutes. Then the mixture was evaporated to dryness and the residue was crystallized from MeOHZEt2O to afford 101865- 155 (592 mg, 83%) as a beige crystals. LC/MS data: 365.2 (M+Hf (Calculated for CSsH2SN2O2 364.49). (calc. monoisotopic mass is 364.22, calc. monoisotopic mass (M+H)+ = 365.22). 1H NMR data (DMSO-d6): 1108 (m, 1H, NH+), 8.34 (d, 1H, J = 8.1 Hz, NH), 8.07 (s, 1H, Ar-H), 7,83 (d, 1H, J = 7,8 Hz, Ar-H), 7.77 (d, 1H, J = 7.8 Hz, Ar-H), 7.51 (dd, 1H, J1=J2 = 7.8 Hz, Ar-H), 7.33 (dd, 1H, J1 = 1.7 Hz, J2 = 7.8 Hz1 Ar-H), 7.27 (d, 1H, J = 8.1 Hz, Ar-H), 7.25 (d, 1H1 J = 1.7 Hz, Ar-H), 4.51 (br d, 1H, J=10.5 Hz, CH), 4.34 (dd, 1H, J1 = 7.3 Hz, J2 = 11.0 Hz, CH), 4.08-4.17 (mr 1H, CH)1 3.81-3.90 (m, 1H, CH), 3.55-3.65 (m, 2H, pyrrolidine- CH2), 3.18-3.37 (m, 4H, CH+pyrroIidine-CH2+H2θ), 1.97-2.10 (m, 2H, ρyrrolidine-CH2), 1.84- 1.96 (m, 2H1 pyrrolidine-CH2), 1.19 (d, 6H, J = 6.6 Hz, CH3),
Intermediate 11 W-ethyJ-3-{3,4-dihydro-4-hydroxy-3-(pyrroHdin-1-yl}-2H-chromen-7- yl)benzamide.
To a cold (ice bath) solution of 3-{3,4-dihydro-4-hydroxy-3-{pyrrolidin-1-yI)-2H- chromert-7-y[)benzoic acid {-34 mmøl) in DMF {120 mL) was added EtNH2-HCl {13.86 g, 170 mmol) and EtsN {5 mL) {to reach pH ~ 9). Then BOP {22.54 g, 51 mmol) was added ant the mixture was stirred at room temperature for 24 h. The reaction was monitored by LC/MS {the peak with (M+H)*=340.0 attributed to 101918-056 should disappear).The reaction mixture was evaporated to dryness, dissolved in water {100 mL) and saturated K2CO3 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 K2CO3 (2 x 205 mL) and brine (100 mL), dried over Na2SO4+SiO2 (5 mL, 63-100 μm) and evaporated. The resulting residue was washed with EtOAo {50 mL) and dried in the vacuum of an oil pump to give the title compound (3.86 g, 31%) as a pa!e yellow solid. LC/MS data; 367.2 (M+HJ* (Calculated for CzaHasMaOs 366.45). {calo. monoisotoplc mass is 366.19, caϊc. monoisotopio mass (M+H)* ■= 367.19). 1H NMR data {DMSO-d6): 8.56 (t, 1H, J = 5.2 Hz, NH), 8.07 (s, 1H, Ar-H), 7.81 (d, 1H1 J = 7,8 Hz, Ar-H), 7.77 (d, 1H, J = 8.4 Hz, Ar-H), 7.52 {dd, 1H, J1 = J2 = 6.8 Hz, Ar-H)1 7.36 (d, 1H, J = 6.8 Hz, Ar-H), 7.26 (dd, 1H, J1 = 1.7 Hz. J2 = 7.8 Hz, Ar-H), 7.11 (d, 1H, J = 1.7 Hz, Ar-H), 4.91-5.07 (br s, 1H, OH), 4.67 (br s, 1H, CH), 4.28 (dd, 1H1 J, = 2.7 Hz1 J2 = 10,3 Hz, CH)1 4.10 (t, 1H, J = 10,5 Hz1 CH)1 3.27-3.35 (m, 2H, CH2+H2O), 2.71-2.80 (rn, 2H, pyrro)idine-CH2), 2,60-2.70 (m, 2H1 pyrroIidine-CH2), 2.47-2.58 (ITi, 1H1 CH+DMSO), 168-177 (m. 4H, pyrrolrdine-CHj), 1.14 (t, 3H, J = 7.2 Hz, CH3).
Example 2 S-p^-DJhydro-a-tpyrrolidin-i-ylJ-aH-cihronien-T-ytJ-N-ethylbenzamtde.
A solution of N-ethyl-3-{3,4-dlhydro-4-hydroxy-3-(pyrrolidin-1-yl)-2H-chromen-7- y!)benzamide (0.50 g, 1.4 mmol} in a mixture of DCE (20 mL) and TFA (18 mL) was refluxed for 24 h. After this time LC/MS showed no SM by ELSO. The reaction mixture was evaporated to dryness, dissolved in OCE (10 mL) and added dropwise to a cold (ice bath) solution of STAB (0.58 g, 2.74 mmol) and acetic acid (0.4 mL, 6.85 mmo!) in DCE (10 mL). The formed solution was vigorously stirred for 21 h. Then water (20 mL) and 1ON NaOH (to reach pH ~ 12) were added and organic layer was separated. The water one was extracted with chloroform (2 x 10 mL). Organic layers were combined, dried over Na^SO4 with SiO2 (1 mL, 63-100 μm), evaporated and co-evaporated with CCI4 to give 101865-152 (374 mg, 78%) as a yellow solid. LC/MS data: 351.2 (M+Hf (Calculated for C22H213N2O2 350.46). (caic. monoisotopic mass is 350.20, caic. monoisotopic mass (M+H)* = 351.20). 1H NMR data (DMSO-dδ): 8.54 (t, 1H, J = 5.2 Hz, NH), 8,OS (s, 1H1 Ar-H), 7.79 (d, 1H1 J = 7.8 Hz, Ar-H), 7.75 (d, 1H, J = 8.3 Hz1 Ar-H)1 7.50 (dd, 1H, J1 = J2 = 7.8 Hz, Ar-H)1 7.16-7.21 (m, 2H, Ar-H), 7.11 (S1 1H, Ar-H), 4.07-4.17 (m, 1H, CH), 3.92 (dd, 1H, J1 = 7.6 Hz, J2 = 10.5 Hz, CH)1 3.27- 3.34 (m, 2H1 CH2+H2O), 3.01 {dd, 1H, J1 = 4.7 Hz, J2 = 16.1 Hz, CH)1 2,76 (dd, 1H, J1 = 8.3 Hz, J2 = 15.9 Hz1 CH), 2.56-2.68 (m, 5H, CH+pyrrolidine-CH∑), 1.65-1.74 (m, 4H, pyrrolidine- CHa), 1.14 (t, 3H, J = 7.1 Hz, CH3). The HCI salt of the title compound was made as followed. 3-(3,4-Dihydro-3-(pyrrolidin-1-yl)-2H-chromen-7-yl)-N-ethyibenzamide hydrochloride. To a solution of 3-(3,4-Dihydro-3-(pyrroiidin-1-yl)-2H-chromen-7-y!)-N-ethyIbenzamide (808 mg, 2.31 tnmol) in dioxane (30 mL) was added dropwfse 0.4M solution of HCI In dioxane (6.77 mL) and the resulting mixture was vigorously stirred for 5 minutes. Then the mixture was evaporated to dryness and the residue was crystallized from MeOHZEt2O to afford 101865- 156 (625 mg. 70%) as a beige crystals. LC/MS data: 351.1 (M+H)* (Calculated for C22H2J5N2O2 350,46). (caic. monoisotopic mass is 350.20, caic. monoisotopic mass (M+H)4" = 351.20). 1H NMR data (DMSO-dδ): 10.98 (m, 1H, NH*). 8.59 (t, 1H, J = 5.4 Hz, NH), 8.09 (s, 1H, Ar-H)1 7.82 (d, 1H, J = 7.6 Hz1 Ar-H), 7.78 (d. 1H1 J = 8.3 Hz, Ar-H)1 7.52 (dd, 1H, J1 = J2 = 7.6 Hz, Ar-H)1 7.34 (dd. 1H1 J1 = 1.7 Hz, J2= 7.7 Hz, Ar-H). 7.27 (d, 1H, J = 8.1 Hz1 Ar-H), 7.24 (d, 1H1 J = 1.7 Hz1 Ar-H), 4.51 (br d, 1H1 J=10.5 Hz, CH), 4.35 (dd, 1H, J, = 7.1 Hz, J2 = 11.5 Hz, CH), 3.81-3.91 (m, 1H, CH), 3.55-3.65 (m, 2H, pyrroIidine-CH2). 3.18-3.36 (m, 6H, CH+CH2+ pyrroIidine-CH2+H2O), 1.97-2.10 (m, 2H, pyrrolidine-CH2), 1.84-1.95 (m, 2H1 ρyrrolidine-CH2). 1.14 (t, 3H, J = 7.2 Hz, CH3). intermediate 12 4-(4-Hydroxy-3-pyrroIidiπ-1-y!-3,4-dihydro-2fir-chromen-7-yl}beπzoic Acid. 7-brσmo-3-pyrroIidin-1-ylchrσmart-4-ol (10.0 g, 0.034 moi) was dissolved in DME (6 mL). (PPh3J4Pd (0.78 g, 0.68 mrnol) and 4-carbαxyberizene boronic acid (6.8 g, 0.041 mol) were added in a flow of argon. The reaction mixture was stirred in a flow of argon for 20 min. Then a 3 IV! solution of Na2CO3 (68 mL, 0.2 mol) was added. The mixture was refluxed for 48 h and acidified with HCI to pH 4. The reaction mass was evaporated to dryness, and then coevaporated sequentially with dioxane and with DMF. The dry title compound was used for the next stage without purification. Intermediate 13
4-(4-Hydroxy-3-pyrroϊidin-1-yl-3,4-dihydro-2W-chromeπ-7-yi)-/V- isopropy Ibenzam ide. 4-(4-Hydroxy-3-pyrrolidin-1-yI-3,4-dihydro-2W-chromen-7-y!)benzoic Acid
(-0.034 mol) was dissolved in DMF (120 mL), and the solution was cooled In an Ice bath, ϊsopropylamine (14.5 mL, 0.170 mol) and BOP (22.5 g, 0.051 mol) were added. The mixture was stirred for 15 min under cooling with ice, then for 24 h at room temperature. The reaction was monitored by LC/MS , When complete, the reaction was evaporated to dryness. Water {100 ml), ethyl acetate {300 mL), and a saturated solution of K2CO3 (50 mL) were added, The mixture was vigorously stirred, and the liquid phase was decanted. H2O {50 mL) was added to the residual mass, and the product was extracted with ethyl acetate. The organic layer was washed with 0,1 N K2CO3 (2 * 250 mL), brine (100 mL), dried with Na2SO4 + SiO2 (5 mL), and evaporated. The residue was purified by chromatography (silica gel 83-100 μm, 800 mL; chioroform/isopropano! 100:0 -→ 92:8). The solvent was evaporated to give the title compound as beige crystals. Yield: 3.1 g {0.008 mof, 24%). LC/MS data: 381.2 (M+Hf (calculated for 023HJ8HAS 380.49). (CaIc, monoisotopic mass is 380.21, CaIc. monoisotopϊc mass (M+Hf is 381.21). 1H NMR data (DMSO-dδ): 8.22 (d, 1H, NH1 J = 7,6 Hz), 7.91 (d, 2H, ArH, J = 8.3 Hz)1 7.71 (d, 2H, ArH, J=8.3 Hz)1 7.35 (d, IH, ArH1 J = δ.1 Hz), 7.25 (dd, 1H, ArH, J1 = 7.6. Hz J2 = 1.7 Hz)1 7.11 (d, 1H1 ArH, J = 1.5 Hz)1 5.96 (d, 1H, J = 3.9 Hz), 4.66 (s, 1H)1 4,27 {dd, 1H, J1 = 10.8. Hz J2 = 2.9 Hz), 4.05-4.16 (m, 2H), 3.24-3.27 (m, 1H, CH3), 2.58-Z78 (m, 4H α, 2CH2), 1.71 (S1 4H β, 2CH2), 1.18 (d, 6H1 2Me, J = 6.6 Hz). Intermediate 14
JV-lsopropyl-4-(3-pyrrolfdir)-1-yl-2W-chromen-7-yl)ben2amide. Compound 4-{4-Hydroxy-3-pyrrolidin-1-yl-3,4-dihydro-2H-chromen-7-yl)-Λf- isoprapylbenzamide {2.78 g, 7.31 rrtrnol) was dissolved In dichloroethane (96 mL). TFA {96 mL, 1.24 moϊ) was added in a flow of argon, and the mixture was refluxed for 48 h. The reaction was monitored by TLC (ethyl acetate/methanol 80:20): the spot of the starting compound should disappear. The reaction mass was evaporated to dryness, and the crude title compound was used for the next stage without purification. '
Example 3 W-lsopropjfl^-ξS-pyrrolfdiπ-i-yl-S^-dJhydro-SW-chromen-T-yllbenzamide.
Λ/-lsopropyl-4-(3-pyrrolidin-1-yl-2H-chromen-7-yl)benzamide (2,65 g, 7.31 mmol) was dissolved in dichioroethane (90 mL). This solution was added dropwise to a mixture of STAB (3.10 g, 14.62 mmol) and AcOH (2.1 mL, 36,55 mmol) in dichloroethane (10 mL) cooled to 0 "C in a flow of argon. The reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC {ethyl acetate/methanol 80:20; R< of the title compound is 0.3), Water (100 mL) was added. The reaction mixture was alkalized to pH 11 with 3N NaOH and stirred for 5 min. The organic layer was separated, and the aqueous one was subjected to extraction with dichlorornethane (3 x 100 mL). The combined extracts were dried with Na2SO4 and evaporated to give analytically pure title compound as a cream-colored powder, Yield' 2.58 g (7.07 mmol, 97%). LC/MS data: 365.2 (M+Hf (calculated for C23H28N2O2364.5) (CaIc. monoisotopic mass Is 364.22. CaIc. monoisotopic mass (M+Hf is 365.22).1H NMR data (DMSO-d6): 8.20 (d, 1H, NH, J = 7.8 Hz), 7.89 (d, 2H1 ArH, J = 8.6 Hz), 7.69 (d, 2H1 ArH1 J=8.6 Hz), 7.18 (Cf, 2H, ArH, J = 1.5 Hz), 7.07 (s, 1H, ArH), 4.28-4.36 (m, 1H)1 4.05-4.15 (m, 1H), 3.89-3.96 {m, 1H)1 3,01 (dd, 1H1 J1 = 16.4, Hz J2 = 5.1 Hz), 2.73-2.62 (m, 1H), 2.55-2.67 (m, 5H α, 2CH2 +CH), 1.69 (s, 4H β, 2CH2), 117 (d, 6H, 2Me, J = 6.6 Hz). The HCI salt of the title compound was made as followed: Λ/-lsopropyl-4-(3-ρyrrolidin-1-yl-3,4-dihydrα-2tø- 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! salt of the title compound: 2.29 g (5.57 mmol, 81%) as white crystals, LC/MS data: 365,2 (M+Hf (calculated for C23H23N2O2364.5) (CaIc. monoisoiopic mass is 364.22. CaIc. monoisotopte mass (M+H)+ is 365.22). 1H NMR data (DMSO-d6): 10.78 (s, 1H, NH), 8.23 (d, 1H, NH, J = 7.8 Hz), 7.92 (d, 2H, ArH, J =8.3 Hz), 7.72 (d, 2H, ArH, J=8.3 Hz), 7.33 (dd, 1H, ArH, J1 = 8.1Hz, J2 = 17 Hz), 7.27 (d, 1H, ArH1 J = 8.1 Hz), 7.21 (d, 1H, ArH, J = 148 Hz), 4.49 (d, 1H, J = 10.5 Hz), 4.32-4.40 (m, 1H), 4,06- 4.16 (m, 1H), 3.81-3.91 (m, 1H), 3.56-3.66 (m, 2H), 3.15-3.28 (m, 3H α, 2CH2), 1.64-2.11 (m, 4H β, 2CH2), 118 (d, 6H, 2Me, J = 6.6 Hz). intermediate 1 S T-^iyiethylsulfonylJphenylJ-S-pyrrolidJn-i-ylchroman^-ol.
To a stirred solution of 7-bromø-3-ρyrrolidϊn-1-ytehroman-4-øt (3.13 g, 9.36 mmol) in DME (60 mL) in the atmosphere of argon were added successively Pd(PPh3)4 (0.86 g, 0.75 mmol) and 4-(methanesulfonyl)phenyifc>oronlc acid CAS # 149104-88-1 (2.8 g, 14 mmol). After δ minutes of stirring, 3M Na2CO3 (19 ml, 56,2 mrnol) was added dropwise. The mixture was refluxed for 20 h and cooled. The organic layer was separated, and the water one was extracted with EtOAc (3 * 10 mL). The combined organic layers were dried over NaaSCs+slca gel (1 mL, 63-100 μm), and evaporated. The column chromatography on silica gel (100 mL, 63-100 μm) first in EtOAc (0, 20, 50, 100%) gradient in CHCl3 then in IWeOH (0 → 8%) gradient in EtOAo gave 101865-127 (164 g, 47%) as an orange solid. LC/MS data: 374.1 (M+Hf (calculated TOrC2OH23NO4S 373.47). (CaIc. rnonoisαtopϊc mass is 373.13, calc. monoisotopic mass (M+Hf is 374.13). 1H NMR data (DMSO-dS); 7.97 (d, 2H, J = 8.6 Hz1 Ar- H), 7.90 (d, 2H, J = 8.6 Hz, Ar-H), 7.39 (d, 1H, J = 7.8 Hz, Ar-H), 7.28 (d, 1H, J = 8.1 Hz, Ar- H), 7.16 (brs, 1H1 Ar-H), 4.93-5.08 (m, 1H, OH), 4.68 (br s, 1H1 CH), 4.25-4.34 (m, 1H1 CH), 4.11 (t, 1H, J = 10,5 Hz, CH), 3.24 (s, 3H, SCH3), 2,70-2.81 (m, 2H, pyrrolidine-CHa), 2.58- 2.69 (m, 2H, pyrroIidine-CH2), 2.47-2.53 (m, 1H, CH+DMSO), 1.67-1.77 {m, 4H, pyrroltdine- CH2). Jπtermediate 16
1-{7-[4-(fnethylsuIfonyI)phenyI]-2W-chromen-3-yl}pyrrolidine. 7-[4-(Methylsulfonyl)phenyl]-3-pyrrolidin-1-yichroman-4-oi {673 mg, 1.80 mmol) was dissolved in dichloroethane {24 ml) in a flow of argon. TFA (24 mL, 306 mol) was added, and the reaction mixture was refluxed for 4 days, The reaction was monitored by LC/MS; the peak with (M+H)*=374.1. The reaction mass was evaporated to dryness and used for the next stage without purification. Example 3
^^-l44Meth)/^su^fon≠}ph6^yll-3,4^dih^fάm-2H-chtomen■S-γ]}p)frτo\idme. A solution of 1-{7-[4-(methylsuIfonyl)phenyl]-2W-chromen-3-yI}pyrroIidine (639 g, 180 mmol) in dichloroethane {15 mL) was added dropwise to a mixture of STAB (753 mg, 3.60 mrnol) and AcOH {0.5 mL, 9,0 rnmoi) in dichloroethane {10 mL} cooled to 0 "C in a flow of argon. The reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC {ethyl acetate/methanol 80:20; Rf 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 dϊchlαromethane (3 * 20 mL). The combined extracts were dried with Na2SG,? and evaporated to give analytically pure compound title compound as a brown powder. Yield: 497 mg (1.39 mmol, 77%). LC/MS data: 358.1 (M+H)+ {calculated for Ca0H23NOaS 357.47). (CaIc. monoisotoplc mass is 357.14, cale. monoisotopie mass {M+Hf is 358.1). 1H NMR data (DMSO-d6): 7.86 (d, 2H, NH, J = 8.6 Hz)1 7.89 <d, 2H, ArH, J = 8.6 Hz), 7.22 (s, 2H, ArH1), 7.12 (s, 1H, ArH), 4.33 (d, 1H, J = 10.2 Hz), 3.91-3.98 (m, 1H), 3.24 (s, 3H1 Me), 2.97-3.08 (m, 1H), 2.76-2.84 (m, 1H), 2.55-2.68 (m, 6H α, 2CH2 +CH), 1.65-1.75 (m, 4H β, 2CH2). The HCI salt of the title compound was generated as followed: H7-t4-{Methylsuifonyl)phenyl]- 3,4-dihydro-2W-chromen-3-yl}pyrro!idine Hydrochloride. 0.4 M HCI/dioxane (4,33 ml, 1.73 mmol) was added to a solution of free base title compound (618 mg, 1.73 mmol) in absolute dtoxane {10.0 mL). The reaction mixture was evaporated to dryness and crystallized from
IVSeOHZEt2O (1:3). Yield of the titile compound as the HCI salt, 515 mg (1.3 rnmoi, 75.6%,} as yellow crystals. LCMB data: 358.1 (M+Hf {calculated for C20H23NO2S 357.47). (CaIc, monolsofopic mass is 357.14, calc. monoisofoplc mass {M+H)* is 358.1). 1H NMR data (DMSO-dβ): 10.73 (s. 1H, NH), 7.98 (d, 2H, NH, J = 8.6 Hz), 7.98 (d, 2HA ArH, J = 8.6 Hz), 7.36 (dd, 1H, ArH, J1 = 8.1 Hz, J2 = 1.7 Hz), 7.31 {d, 1 H, ArH, J = 17 Hz), 4.49 (d, 1H, J = 11.2 Hz), 4.34-4.40 (m, 1H), 3.82-3.92 (m, 1H)1 3.56-3.66 (m, 2H), 3.17-3.28 (m, 6H), 1.83- 2.09 (m, 4H (J1 2CH2).
Intermediate 17 7-(2-WIethoxypyridin-3-yi)-3-pyrroliditi-1-ylchroman-4-ol. To a stirred solution of 7-bromo-3-pyrrolidin-1-ylchroman-4-ol (2.0 g, 6.71 mmol) in
DME (40 mL) in the atmosphere of argon were added successively Pd(PPh3).* (0.39 g, 0.34 mmol) and 2-methoxyρyrϊdine-3-boronic acid (1.55 g, 10.1 mmol). After 5 minutes of stirring 2M Na2CO3 {17 mL, 33.6 mmol) was added dropwise. The mixture was refluxed for 7 h and cooled. The organic layer' was separated, and the water one was subjected to extraction with ether (3 x 50 mL). The combined organic layers were dried over Na2SO,) + silica gel (1 ml, 63-100 μm) and evaporated. The column chromatography on SiO2 (100 mL, 63-100 μm) first in EtOAc {0, 50, 100%) gradient in CHCI3, then in MeOH (0 → 8%) gradient in EtOAc gave 2.2 g of a solidifying yellow oil that appeared to contain Ph3PO (12% by LC/MS (ELSD)). The substance was dissolved in Et2O (25 mL). Water (25 mL) was added, and the mixture was acidified with NaHSO/, to pH ~ 2. The ethereal layer was separated, and the water one was subjected to extraction with ether (25 mL). The water layer was then alkalized to pH ~ 12 with K2CO3 (sat.), and the product was extracted with CHCl3 {3 x 25 mL). The combined organic layers were dried over Na2SO4+SiO2 (2 rrsL, 63-100 μm) and evaporated to give the title compound {1.2 g, 36%) as a yellow solid. LClMB data; 327.1 (M+H)+ (calculated for C19H22N2O3 326.39). (Calc. rnonoϊsotopic mass is 326.16, calc. monoisotopic mass (M+H)+ is 327.16). 1H NMR data (DMSO-d6): S.1S (dd, 1H, J1 = 1.7 Hz, J2 = 41 .9 Hz, Ar-H)1 7.70 (dd, 1H, J1 = 17 Hz1 J2 = 7.3 Hz1 Ar-H), 7.29 (d, 1H, J = 8.1 Hz, Ar-H), 7.04-7.08 (m, 2H, Ar-H)1 6.95 (d, 1H, J = 1.5 Hz, Ar-H), 4.88-5.03 (m, 1H, OH)1 4.64 {br s. 1H, CH), 4.25 (dd, 1H, J1 = 2.4 Hz1 J2 = 10.3 Hz1 CH), 4.08 (t, 1H1 J = 11,7 Hz1 CH), 3.86 (s, 3H, OCH3), 2.69-2.80 <m. 2H, pyrrolfdine-CHa), 2.57-2.68 (m, 2H1 pyrrolidine-CH2), 2.43-2.56 (m, 1H, CH+DMSO), 166-1.78 (m, 4H, pyrrolidine-CHa). intermediate 18
7-(2-Methoxypyridin-3-yl)-2H-chromerι-3(4H)-one.
7-(2-Methoxypyridin-3-yl)-3-pyrrolidin-1-ylchroman~4-ol (0.80 g, 2.46 mmol) was dissolved in AcOH (9.3 mL, 162.6 mmol). Concentrated H2SO4 (3.2 mL, 59.04 mmol) was added, and the mixture was refluxed at 80 °C for 6 h. The reaction was monitored by TLC (ethyl acetate/methanol 80:20); the spot of the starting alcohol should disappear. Water {20 mL) and ether/dichioromethane mixture (2:1) (20 mL) were added. The mixture was neutralized with a saturated solution of NaHCOa to pH 8. The organic layer was separated, and the aqueous one was subjected to extraction with ether/dichloromethane mixture (2:1) {3 x 20 mL). The combined extracts were dried with Na2SO4 and evaporated to dryness. The residue was dried by coevaporation with chloroform. The dry residue was used for the next stage without additional . 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. (0.63 g, 2.46 mmol) in chloroform (10 mL) was added dropwise to a mixture of STAB (1.04 g, 4.92 mmol), pyrrolidine {0.31 mL, 3.69 mmol), and AcOH (0,70 mL, 12.30 mmol) in chloroform (10 mL) cooled to - 20 "C in a flow of argon. The reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC {ethyl acetate/methanol 80:20; Rf of product 101918-071 is 0,3). Water H2O (20 mL} was added. The mixture was alkalized to pH 11 with 3N NaOH and stirred for 5 min. The organic layer was separated, and the aqueous one was subjected to extraction with chloroform (3 * 20 mL). The combined extracts were dried with Na2SO4+ silica gel and evaporated. The residue was recrystallized from ethyl acetate to afford the title compound as yellow crystals. Yield: 0.26 g {0.85 mmol, 348%). LC/MS data: 311.2 (M+H)+ {calculated for C19H22N2O2310.4). {Calc, monoisotopic mass is 310.17, calc. monoisotopic mass (M+H)+ is 311,17). 1H NMR data (DMSO-dδ): 8.14 (dd, 1H, ArH, J1 = 4.9 Hz, J2 = 1.9 Hz), 7.69 {dd, 1H, ArH, J1 = 7.1 Hz, J2 = 2.0 Hz), 7.12 (d, 1H1 ArH, J = 7.8 Hz), 7.06 (dd, 1H, ArH, J1 = 7.3 Hz, J2 = 4.9 Hz), 6.99 {dd, 1H, ArH, J1 = 7,8 Hz, J2 = 1.7 Hz), 8.92 (d, 1H, J = 1.5 Hz), 4.26-4.33 (m, 1H), 3.89-3.94 (m, 1H), 3.87 {s, 3H, Me), 2.9S-3.04 (m, 1H), 2.71-2.82 {m, 1H), 2.54-26S (m, 5H α, 2CH2, CH), 1.64-1.75.{m, 4H β, 2CH2). 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/Et2O (1:3). Yield of HCI salt 0.29 g {0.83 mmol, 62.4%,) as white crystals. LC/MS data: 311.1 (M+H)+ (calculated for C19H22N2O2 310.4), (Calc. monoisotopic mass is 310.17, calc. monoisotopic mass (M+H)+ is 311.17). 1H NMR data (DMSO-d6): 10.96 (s, 1H1 NH), 8.17 (dd, 1H, ArH1 J1 = 4.9 Hz, J2 = 1.9 Hz), 7.72 (dd, 1H1 ArH, J1 = 7.3 Hz, J2 = 2.0 Hz), 7.22 (d, 1H, ArH, J = 7,8 Hz), 7,13 {dd, 1H1 ArH, J1 = 7.8 Hz, J2 = 1.7 Hz), 7.10-7.03 (m, 2« ArH), 4.24-4.49 (m, ?H ), 3.57 (s, 3H, Me), 3.79-3.85 {m, 1H), 3.56-3.66 (m, 2H), 3,16-3.36 (m, 4H α, 2CH2), 1.83-2.11 (tn, 4H β, 2CH2), Intermediate 19 N-ethyl-3-(3,4-dihydro-3-oxo-2H-chromen-7-yl)benzamide. A solution of N-ethyl-3-{3)4-dihydro-4-hydroxy-3-(pyrrolidin-1-yl)-2H-chromen-7- yl)benzamide (1.95 g, 5,33 mmol) in a mixture of DCE (80 mL) and TFA (70 mL) was refluxed for 23 h. After this time LC/MS showed no SM by ELSD. The reaction mixture was evaporated to dryness, dissolved In EtOAc (100 mL) and washed with saturated NaHCO3 (1SO mL). Water layer was extracted with EtOAc {2 x 50 mL). Organic layers were combined, dried over Na2SO4+SiO2 (2 mL, 63-100 μm), evaporated to dryness and co-evaporated with CHCl3. The substance was immediately used in the next step as a solution in CHCl3 (50 mL) without further purification because of its instability.
Example S N-ethyl-3-(3,4-dihydro-3-((R)-2-methylpyrrolidin-1-yl)-2H-chrornen-7- yl)benzamide.
To a cold (ice bath) vigorously stirring solution of (R)-2-methyipyrrolidine (0.68 g, 8.0 mmol, prepared as a solution in 10 mL of CHCl3 after washing of the solution of (R)-2- methylpyrrolidine hydrobromide (1.32 g, 8.0 mmo!) with 1ON NaOH (10 mL)), STAB (2.26 g, 10.7 mmol} and AcOH (1.53 mL, 26.7 mmol) in CHCi3 (30 mL) was added dropwise a solution of N-ethyl-3-(3,4-dihydro3-oxo-2H-chromen-7-yl)benzamϊde in CHCl3 (50 mL). After 5 min the cold bath was removed and the mixture was stirred during 15 h at room temperature. Then water (100 mL) and 1ON NaOH (to reach pH ~ 12) were added, organic layer was separated and the water one was extracted with CHCl3 (3 x 25 mL}. The combined organic layers were ' dried over Na2SO4^SiO2 (2 mL, 63-100 μrn), evaporated to dryness and co-evaporated with CCI4. The resulting brown oil (1.65 g) was chromatographed on SiO2 (100 mL, 63-100 μm) in CHCl3 → EtOAc →- yeOH (5%) gradient to give 101865-159 (0.319 g, 16 % per 2 steps). LC/MS data: 365.2 (M+H)* (Calculated for C23H2SN2O2 364.48). (cab. nπonoisotopic mass is 364.22, calc. monoisotopic mass (M+H)* = 365.22). 1H NMR data (DMSO-d6): 8.55 (t, 1H1 J = 5.2 Hz, NH), 8.06 (br s, 1H, Ar-H), 7.79 (d, 1H, J = 7.8 Hz, Ar-H), 7.75 (d, 1H, J = 7.8 Hz, Ar- H), 7.50 (dd, 1H, J1 = J2 = 7.8 Hz, Ar-H), 7.17-7.22 (m, 2H, Ar-H), 7.11 (d, 1H, J = 5.6 Hz, Ar- H), 4.29 (brt, 1H, J = 11.0 Hz, CH), 3.85-3.98 (m, 1H, CH), 3.25-3.34 (m, 3H1 CH+CHa), 2.56- 3.20 (m, 5H, CH+pyrroiϊdine-CH^ 1.28-2.07 (m, 4H1 CH* pyrrolidIne-CH2), 1.14 (t 3H, J = 7.4 Hz, CHs), 100 (dd, 3H, J1 = 7.1 Hz, J2 = 9.6 Hz, pyrroidine-CH3). The HCl salt of the title compound was prepared as followed; N-ethyl-3-(3,4-dihydro-3-((R)-2-methylρyrrolidin-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 MeOHZEt2O to afford 101865-161 (0.306 g, 88%) as an orange crystals. LC/MS data: 365.2 (M+Hf (Calculated for C23H28N2O2 364.48), (calc. monoisotopic mass is 364.22, calc. monoisotopic mass (M+Hf = 365.22). 1H NMR data (DMSO-d6): 10.34-10.96 (m, 1H, NH*), 8.54-8.63 (rn, 1H, NH), 8.09 (br s, 1H, Ar-H), 7.82 (d, 1H1 J = 8.1 Hz1 Ar-H), 7.78 (d, 1H» J = 7,8 Hz1 Ar-H), 7.52 (dd, 1H, J1 = J2 = 7.8 Hz, Ar-H), 7.24-7.35 (m, 3H1 Ar-H), 3.71-4.61 (m, 4H, CH), 3.12- 3.66 (m, 5H, pyrrolidine-CHa+CH≤+HaO), 1.21-2.27 (m, 8H, CH+ρyrro)idine-CH2+CHa). 1.15 (t, 3H1 J = 7.3 Hz, CH3).
Intermediate 20 3-(3,4-dihydro-3-oxo-2H-chromen-7-yl}-N-isopropyibenzamide.
A solution of 3-(3,4-dihydro-4-hydroxy-3-(pyrrolidin-1-yl)-2H-chromen-7-yl)-N- isopropylbenzamide (2.54 g, 6.68 mmol) in a mixture of DCE (100 mL) and TFA (90 mL) was refluxed for 23 h. After this time LC/MS showed no SM by ELSD. The reaction mixture was evaporated to dryness, dissolved in EtOAc (120 mL) and washed with saturated NaHCO3 (200 mL). Water layer was extracted with EtOAc (2 x 75 mL). Organic layers were combined, dried over Na2Sθ4+SiQ2 (2 mL, 63-100 μm). evaporated to dryness and co-evaporated with CHCb- The title compound was immediately used in the next step as a solution in CHCl3 (70 ml_) without further purification because of its instability.
Example β
3-{3,4-dihyciro-3-((R)-2-methylpyrrofϊdin-1-yl>-2H-chromen-7-yI}-N- isøpropylbenzamide.
To a cold (ice bath) vigorously stirring solution of (R)-2-methylpyrrolldlne (0.85 g, 10 mmol, prepared as a solution in 10 mL of CHCl3 after washing of the solution of (R)-2- methylpyrrolkSne hydrobromlde (1.66 g, 10 mmol) with 10N NaOH (10 mL)), STAB (2.84 g, 13.4 mrnol) and AcOH (1,9 mL, 33.4 mmol) in CHGI^ (40 mL) was added dropwise a solution of 3-(3,4-dlhydro-3-oxo-2H-chromen-7-yl)-N-lsopropyibenzamide In CHCl3 (70 mL). After 5 mln the cold bath was removed and the mixture was stirred during 15 h at room temperature. Then water {100 mL} and 1ON NaOH (to reach pH ~ 12) were added, organic layer was separated and the water one was extracted with CHCIa (3 x 30 mL). The combined organic layers were dried over Na2SC^SiO2 {2 mL, 63-100 μm}, evaporated to dryness and co- evaporated with CCI4. The resulting brown oil (3.3 g) was chromatographed on SiO2 (150 nriL, 63-100 μm) in CHCl3 -> EtOAc → MeOH (4%) gradient to give the title compound (0.746 g, 29 % per 2 steps). LC/MS data: 379,2 (IV!+H)+ (Calculated for C24H30N2O2 378.51), (calα monoisofopic mass is 378.23, calc. monoisotopic mass (M+H)4" = 379.23). 1H NWlR data (DMSO-dδ): 8.29 <d, 1H, J = 7.6 Hz, NH), 8.05 (br s, 1H, Ar-H), 7.80 (d, 1H, J = 7.7 Hz1 Ar-H), 7.74 (d, 1H, J = 7.9 Hz, Ar-H), 7.49 (dd, 1H, J1 = J2 = 7.6 Hz, Ar-H)1 7.17-7.22 (m, 2H, Ar-H), 7.11 (d, 1H, J = 5.9 Hz, Ar-H), 4.29 (br t, 1H, J = 12.0 Hz, CH), 4.07-4.18 (m, 1H, CH), 3.85- 3.98 (m, 1H, CH)1 2.56-3.20 {m, 6H, CH+pyrrolidine-CH2), 1.27-2.07 (m, 4H, CH+ pyrrølidine- CHa), 1.18 (d, 6H1 J = 6.6 Hz, CH3), 1.00 (dd, 3H1 J1 = 6.1 Hz, J2 = 9.3 Hz, pyrrolidine-CHs). The HCI salt of the title compound was prepared as followed: N-ethyl-3-{3,4-dihydrα-3-((R}-2- methylpyrrolidin-1-yl)-2H-chrσrnen-7-yl)benzamide hydrochloride.
To a solution of free base (0.74 g, 1.96 mmol) in djoxane (10 mL) was added dropwise 0.4M solution of HCI in dioxane (4.9 mL, 196 mmol) and tie resulting mixture was vigorously stirred for 5 minutes. Then the mixture was evaporated to dryness and the residue was crystallized from MeOHZEt2O to afford 101865-162 (0.399 g, 49%) as an orange crystals. LC/MS data: 379.2 (M+H)+ (Calculated for C24H3oN202 378.51). (calc. monoisotopic mass is 378.23, calc. monoisotopic mass (M+H)* = 379.23). 1H NMR data (DMSO-d6): 11.10-10.47 (m, 1H, NH+), 8.31 (d, 1H, J = 7.8 HZ, NH), 8.07 {br S, 1H, Ar-H), 7.82 (d, 1H, J = 7.8 Hz, Ar- H)1 7.77 (d, 1H, J = 7.3 Hz, Ar-H), 7.51 (dd, 1H, J1 = J2 = 7.6 Hz, Ar-H), 7.24-7.35 {m, 3H, Ar- H), 3.72-4.59 (m, 5H1 CH), 3.14-3,67 (m, 4H, CH+pyrroiidine-CH2+H20), 1.22-2.29 (m, 7H, pyrrσlldine-CH?+CH3), 1.19 (d, 6H, J = 6.6 Hz1 CH3). lntermediafe 21 7-(4-rnethoxypheny1}-2,3-dihydrochromen-4-one.
4-Oxo-3,4-dihydro-2H-chromen-7-yl trifiuoromethanesulfonate {Koch, Btggers, JOC1 1994, 69, 1216) (2.50 g, 8,44 mmol), 4~methσxyphenylboronic acid (192g, 12.63 mmol), potassium carbonate (1.Og, 8.4 mmol), potassium phosphate tribasic (2.7 g, 12.72 mmol) and tetrakt$(iriphenylphosphine)palladium (0) (0.49g, 0,42 mmol) in dioxane (25 mL) were refluxed for 20 h, cooled, filtered through diatornaceous earth and concentrated. The residue was dissolved in EtOAc and washed with water and brine, dried (MgSO4) and concentrated to afford an orange solid (3.32g), Chromatography on silica gel using 50% to 75% CH2CI2/hexanes yielded 1 ,43g (67%) of the title compound as a flaky white solid: NMR (CDCI3) δ 7.90 (d, J = 8,3 Hz, 1H), 7.53 (d, J = 8.7 Hz1 2H), 7.21 (dd, J = 7.9, 1.9 Hz1 1H), 7.12 (d, J = 17 Hz, 1H), 4.5S (t, J = 6,4 Hz, 2H), 3.84 (s, 3H), 2.81 (t, J = 6.4 Hz1 2H); 13C- NMR (CDCIs) δ 191.7, 162.4, 160.4, 148.7, 132.1, 128.6, 127.8, 120.2, 119.8, 115.4, 114.6, 67.4, 55.6, 38.0. Intermediate 22
3,3-Dibronto-7-(4-methoxyphenyl)-2,3-dihydrochromen-4-one
7-(4-Methoxyρhenyi)-2,3-dihydrochromen~4-one (143g, 5.62 mmol) and coρper{ll)bromlde [2.QAQ1 11.82 mmol) slurried in EtOAc (60 mL) were refluxed. Two additional portions of copper(ll)bromide (i,3g, 5,82 mmoi - each) were added at 2Qh and 4Oh and after ~64h total reaction time, the mixture was cooled, filtered and washed with water and brine. After drying (MgSO4), the organics were concentrated to afford 2.33g (100%) of the title compound as a yellow solid: NMR (CDCI3) δ 8.02 (d, J =8.3 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.34 (dd, J - 8.3, 1.7 Hz, 1H)17.20 (d, J - 1.7 Hz, 1H)16.9S (d. J = 9.1 Hz, 2H), 4.74 (S1 2H), 3.85 (s, 3H). Intermediate 23
7-(4-iyethoxypltenyl)-3-(pyrrolidJin-1-yl)-4H-chrowteii-4-one
3,3-Dibromo-7-(4-methoxyphenyl)-2,3-dihydrochromen-4-one (2.24g, 5.44 mmoi), pyrrolidine (0.91 mL, 10.90 mmol) and triethylamine (1.55 mL, 11.1 mmol) in CH3CN (70 mL) were stirred at room temperature for 7Oh. The yellow precipitate that formed was collected, rinsed with water and ether and air dried to afford 0,96 g (55%) of the title compound: NMR (CDCI3) δ 8.23 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.51-7,49 (m, 2H)1 7.40 (s, 1H)1 6.97 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H), 3.26-3.21 (m, 4H), 1.97-1.90 (m, 4H).
Intermediate 24 7-(4-methoxypheny])-3-(pyrrolidrn-1-yl)-3,4-dihydro-2H-chromen»4-oI A slurry of 7-{4-methoxyphenyl)-3-(pyrrolidin-1-yl)-4H-criromen-4-one {0.90g, 2.80 mmo!) in THF/EtOH (23 mL/14 ml) was treated with sodium borohydride (tig, 29.1 mmol) and stirred for 18h at room temperature. The resulting orange solution was quenched with 20 mL water and concentrated at 400C. The residue was partitioned between EtOAc and water, the separated organics were washed with water and brine, dried (MgSO4) and concentrated to yield a ~9;1 mixture of cis/trans isomers as a yellow solid (Q.88g), Flash chromatography using EtOAc as eluent afforded first 37 mg of ~S:1 trans: cis material. Later column fractions were concentrated, triturated with ether and recrystallized from EtOAc to yield 411 mg of the cis isomer as a flaky, light orange tinged solid. Trans isomer data: NMR (CDCI3) δ 7.47 (d, J = 9.1 Hz, 2H), 7.36 (d, J = 7.9 Hz, 1H),
7.12 (dd, J = 8.3, 1.9 Hz, 1H), 7,01 (d, J = 1.7 Hz, 1H), 6.93 (d, J = 8.7 Hz, 2H), 4.77 (d, J = 4.6 Hz, 1H), 4.33-4.23 (m, 2H), 3.82 (s, 3H)1 2.90-2.58 (m, 5H), 1.77-1.73 (m, 4H); R, = 0.36 {20% MeOH/EtOAc).
Cis isomer data: NMR (CDCI3) δ 7.49 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.15 (dd, J = 8.3, 1.9 Hz1 1H), 7.04 (d, J = 1.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 5.30 (br s, 1H), 4.32-4.27 (m, 1H)1 4.22 (br t, J = 10.6 Hz, 1H), 3.84 {s, 3H), 2.99 (br s, 2H), 2,90-2.68 (m, 3H), 1.91 (brs, 4H); Rf = 0.22 (20% MeOH/EtOAo).
Example 7 1-(7-(4-Methoxyphenyl)-3,4-<Hhydro-2H-crιromen-3-y()ρyrrotId[ne Trlfluoroacetic acid (2 mL) was added to a solution of cis-7-{4-methoxyphenyl)-3-
(pyrroIidln-i-yI)-3,4-dthydro-2H-chromen-4-oϊ (0,05 g, 0,154 mmol) and triethylsllane (0.1 mL, 0.626 mmol) in 1,2-dichIoroethane (2 mL). This mixture was refluxed for 16h, cooled and concentrated. The residue was dissolved in EtOAc and washed with aq. K2CO3 and brine, dried (MgSO4) and concentrated to give a 45 mg of a tan colored solid. Flash chromatography using EtOAc and 10% MeOH/EtOAc for elution yielded 37 mg (78%) of the title compound as a light yellow solid: R, = 0.35 (20% IVteQH/EtOAc); NMR (CDCi3) δ 7.50 (d, J = 8.7 Hz, 2H), 7.12-7.06 (m, 2H), 7.02 (d, J = 1.7 Hz1 1H)1 6.95 (d, J = 8.7 Hz, 2H), 4.43 (sym mult, 1H), 3.90 (t, J = 9.8 Hz, 1H), 3.84 (S1 3H), 3.05-2.99 (ItI, 1H)1 2.89-2.83 (m, 1H), 2.80-2.64 (m, 5H), 1.92-1.65 (m, 4H); 13C-NiVIR (CDCI3) δ 159.3, 154.8, 140.5, 133.5, 130,5, 128.2, 119,3, 114.5, 114.4, 69.4, 57.8, 55.6, 52.1, 31.9, 23.5; IVIS(APCI) m/z calcd. for C20H23NO2, 309.2, found, 310.3 (M+1).
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 I1 a histamine H1 antagonist and optionally a pharmaceutically acceptable carrier. The composition of the present invention may also be a composition comprising a compound of formula I1 a neurotransmitter re-uptake blocker and optionally a 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 I1 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 (-CH3 -* -CH2OH); (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 (-NRsRb → -NHR* or -NHRb); (iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHRa → -NH2); (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.
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 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.
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 reconstttution 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 Hh 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 glycβrides. 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 propeliant, for example, dichlorodifluoromethane, trichlorσfluoromethane, diσhlorotetrafluoroethane, 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 H1 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. Administraiøn 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 H1 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 H1 antagonist or the neurotransmitter reuptake blocker. Administration may be several times dally, 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 H1 antagonist or a neurotransmitter re-uptaκe 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, 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 H1 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. When administered separately, the compound of formula I and the histamine H1 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 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. 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 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.
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 mlVf Tris HCI containing 2 mU MgCI2 (pH to 7.4 at 4 0C). 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 0C) and centrifuged again. The final pellet is resuspended in 50 mM Tris HCI containing 2 mM MgCI2 (pH to 7.4 at 25 0C) at a concentration of 12 mg/mL Dilutions of compounds are made in 10% DMSO / 50 mM Tris buffer {pH 7.4) (at 10 x final concentration, so that the final DMSO concentration is 1%). Incubations are initiated by the addition of membranes (200 microliters) to 96 well V-bottom polypropylene plates containing 25 microliters of drug dilutions and 25 microliters of radioligand (1 nM final concentration 3H-N-methyI-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.

Claims

CLAtIVlS
1. A compound of formula
Figure imgf000044_0001
or a pharmaceutically acceptable salt thereof, wherein W1 X, Y, and Z are independently selected from nitrogen or carbon; wherein the total number of said nitrogens for W, X, Y, and 2 does not exceed two;
R1 and R2 are independently hydrogen, (C^C^alkyl optionally substituted with 1 to 4 halogens, or {G$-C6)cycIoalkyl-{Co-C4)all<yl; or optionally R1 and R2, together with the nitrogen to which they are attached, form a 4-, 5-, 6- or 7-membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with 1 or 2 (C1-C4)alkyl; and wherein one of the carbons of said heterocyclic ring that is separated by at least two atoms from said nitrogen in said heterocyclic ring, is optionally replaced by O1 S1 NR6, or C=O; wherein Rβis hydrogen, {CrC8)ajkyl optionally substituted with 1 to 4 halogens, or (Cs-G^eycloalkyKCo-COalkyl, and wherein each (C0-C4)a!kyl is optionally substituted with 1 to 4 {CrC4}aikyl;
R3 is hydrogen, (CrCβ}alkyl, halo, 5-6 membered aryl optionally fused to a 5 to 6 membered aryl, 5-6 membered heteroaryi, (CrCβ)alkoxy, hydroxy!, methylene hydroxyl, - (C=O)NR4Rs, and S(O)?(C,-C4)alkyi, where p is 1 or 2; wherein R4 and Rδ are each independently selected from the group consisting of hydrogen;
(CrCβ)alkyl optionally substituted with 1 to 4 halogens; (C1-C4)alkyl group optionally substituted with a substituent selected from the group consisting of OH, 1 to 4 (C1 -Chalky I, {C$:C7)cydoalky(, (C1-C})dialkylamlno, (Cδ-C-t4)aryl optionaliy substituted with a halogen and optionally substituted with (Ce-C10)aryloxy optionally substituted 'with 1 to 2 halogens, and δ to 10-membered heteroaryi optionally substituted with a (C6- C1o)ary! group and optionally substituted with 1 to 3 (Gi-C,s)alkyl groups; (C3-C7)cycloalkyl;
(Cβ-C14)aryl;
-{Co-C3)alkyl-0-(CrC3)alkyl optionally substituted with (d-C^alkyl; -.(C1-Cg)alkyI-C(=O)0-(C1-C!5)alkyl; 3-8-membered heterocycloalkyl optionally substituted with one or more
(CrCOalkyl-carbonyl groups;
(C6-Cio)arylsulfonyl optionally substituted with one or more (Ci-C2)alkyl; 5-10-membered heteroaryl; and (Cβ-C14)aryl-(G0-C4)alkyiene-O-{C0-C4}alkyl, wherein each (Co-C4)alkyl and each (C0-
C4)alky!ene is optionally substituted with 1 to 4 (C1-C4 alkyl); or optionally R3 and R4, 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, S, NRδ or CO, and wherein said ring is optionally fused to a (C6-C10)aryIene and is optionally substituted at a ring carbon with a substituent selected from the group consisting of
-OH, 5-10-memberεd heteroaryl optionally substituted with one or more halogens and optionally substituted with one . or more (C1-C2)alkyl, {C]-C4)aikoxy optionally substituted with one or more (CrC2)alkoxy and optionally substituted with one or more (C^palkylaminocarbonyl, and 1 to 2 {C1-C4)alkyl optionally and independently substituted with one or more {Ci-C2)alkαxy; wherein Rs is selected from the group consisting of hydrogen;
{C-i-cyalky! optionally substituted with 1 to 4 halogens; 5-10-membered heteroaryl optionally substituted with a substituent selected from the group consisting of halogen. (CrC4}alkyl, (CrC2)alkoxy, {Cβ-Grø)aryl, (C1- C4)aikylamiπocarbonyl, and cyano;
(C-s-C4)a1kyl group optionally substituted with a substituent selected from the group consisting of {C-rC2)alkoxyearbonyl, 5-10-membered heteroaryl optionally substituted with one or more (d-cyalkyl, 1 to 4 (Ci-CXOalkyl, (C3-
C?)cycloalkyl, and {Ca-C-πJaryl; (Cβ-C10)aryl optionally substituted with 1 or 2 {CrC2)alkyl; (CrC4)alkylcarbonyl; and
(Ce-C14}ary!-(CrC4)alkylene-0-(Co-C4)alkyl, wherein each (C0-C4)alkyl and each (C0- C4)alkylene is optionally substituted with 1 to 4 {d-C^Jalkyi;
2. A compound of claim 1 wherein
W1 X, Y, and 2 are carbon;
R1 and R2, together wtth 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 one or two (C-f-G,<)alkyl; and wherein one of the carbons of said heterocyclic ring that is separated by at least two atoms from said nitrogen in said heterocyclic ring is optionally replaced by O, S, NRβ, or C=O1 wherein R8 is hydrogen, (C1-C8 alkyl optionally substituted with 1 to 4 halogens, or
(C3-C7)cycloalkyl-(C0-C4)alkyl, and wherein each (Co-C4)alkyl is optionally substituted with one to four (C1-C4JaIkyI; and R3 is (C1-C6)alkoxy, -(C=O)NR4R5, and SO2(C1-C4)alkyl; wherein R4 and Rs are each independently selected from the group consisting of hydrogen;
{C1-C6)aIkyI optionally substituted with 1 to 4 halogens;
(C1-C4)aIkyI group optionally substituted with a substituent selected from the group consisting of OH, one to four (C1 -C4)alkyl, (C3-C7)cycIoalkyl, (C1 -C4)dialkylamino, (Cβ-C14)aryl optionally substituted with a halogen and optionally substituted with {C6-C10)aryloxy optionally substituted with one to two halogens, and 5-10-membered heteroaryl optionally substituted with a (C3-C10)aryl group and optionally substituted with 1 to 3 (C1 -C4)alkyl groups;
(C3-C7)cycloalkyl; (C6-C14)aryl; (C1-C3)alkyl;
-(C0-C3)alkyl-O-(C1-C3)alkyl optionally substituted with - -(C1-C3)alkyl-C{=O)O-{C1-C3)alkyl; 3-8-membered heterocycloalkyl optionally substituted with one or more
(C1-C4)alkyl-carbonyl groups;
(C6-C10)arylsulfonyl optionally substituted with one or more (GrC^alkyl; 5-10-membered heteroaryl; and
(Cβ-C14)aryl-(Co-C4)alkylene-0-(C0-C4)alkyl, wherein each {C0-C4)alkyl and each (C0- C4)alkylene is optionally substituted with 1 to 4 (C1 -C4)alky!; or optionally R3 and RA, together with the nitrogen to which they are attached, form a A-, 5-, 6- , or 7-membered saturated or unsaturated heterocyclic ring, wherein one of the carbons in said heterocyclic ring is optionally replaced by O, S, NR5 or CO, and wherein said ring is optionally fused to a (C6-C10)aryiene 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 (C1-C2)alkyI, (C1-C4)alkoxy optionally substituted with one or more (C1-C2)aIkoxy and optionally substituted with one or more (C1 -C4)dialkylaminocarbonyl, - and 1 to 2 (CrC4)alkyl optionally and independently substituted with one or more (C1-C2)alkoxy.
3. The compound of claim 1 wherein W, X, Y, and Z are independently selected from nitrogen or carbon; wherein the total number of said nitrogens for W, X1 Y, and Z equals one; R1 and R2, together with the nitrogen to which they are attached, form a A-, 5-, 6- or 7- membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one or two ((VCjJalkyl; and wherein one of the carbons of said heterocyclic ring that is separated by at least two atoms from said nitrogen in said heterocyclic ring is optionally replaced by O1 S, NRδ, or C=O, wherein Rs is hydrogen, (CrCβ5alkyl optionally substituted with 1 to 4 halogens, or
(C3-G7)cycloalkyi-(GO-C4)alkyl, and wherein each (Co-C4)alkyl is optionally substituted with one to four (CrC^alkyl; and
R3 is {CrCβ)alkoxy.
4. A compound of claim 1 selected from the group consisting of (3S,4R)-7-{4-Methoxy-phenyi)-3-pyrrolidin-1-yl-chrornan-4-ol, 1-[7-(4-Methoxy-phenyl)-chroman-3-yl]-pyrrolidine,
N-Ethyl-S-CS-pyrrolidin-i-yl-chroman-T-yO-benzamide,
N-lsopropyl-3-(3-pyrroItdln-1-y^hroman-7-yl)-benzamϊde,
2-Methoxy-3-{3-pyrrolidin-1-yl-chroman-7-yl)-pyridine,
N-Isopropyl-S-tS^CR^-methyl-pyrrolidin-i-ylJ-chroman^-yll-berjzamide, 1 -f 7-{4-Methanesulfonyt-pheny l)-chroman-3-yl]-pyrrolidine,
N-Ethyl-S-lS-CCRJ^-methyl-pyrrolidin-i-yil-chroman^-ylj-benzamide,
N-isøprøpyI-4-(3-pyrro(idin-1-yl-ehroman-7-yI)-benzamide, and pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition for treating a disorder or condition that may be treated by antagonizing histamfne-3 receptors, the composition comprising a compound of formula I as described in claim 1, and optionally a pharmaceutically acceptable carrier,
6. A method of treatment of a disorder or condition that may be treated by antagonizing histamine-3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described in claim 1.
7; The method of claim 6 selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, cognitive disorders, Alzheimer's disease, attention-deficit disorder, attention-deficit hyperactivity disorder, 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 as described in claim 1.
8. The method of claim 7, wherein the disorder or condition is selected from the group consisting of anxiety disorders, attention-deficit hyperactivity disorder, attention-deficit disorder, respiratory diseases, obesity, cognitive disorders, and psychotic disorders.
9. The method of claim 7, wherein the disorder or condition is a respiratory disease selected from the group consisting of adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis.
10. 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.
11. The pharmaceutical composition according to claim 10, wherein said H1 receptor antagonist is selected from the group consisting of cetirizine chlorpheniramine, loratidine, fexofenadine, and desloradine,
12. A pharmaceutical composition for treating attention-deficit disorder, atterrtion- deficit hyperactivity disorder, 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.
13. The pharmaceutical composition according to claim 12, wherein the neurotransmitter re-uptake blocker is selected from the group consisting of sertraline, fluoxetine and paroxetine.
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Cited By (44)

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WO2013151982A1 (en) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Methods and compounds useful in treating pruritus, and methods for identifying such compounds
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WO2014125394A1 (en) 2013-02-13 2014-08-21 Pfizer Inc. HETEROARYL-SUBSTITUTED HEXAHYDROPYRANO [3,4-d][1,3] THIAZIN-2-AMINE COMPOUNDS
WO2014125397A1 (en) 2013-02-15 2014-08-21 Pfizer Inc. SUBSTITUTED PHENYL HEXAHYDROPYRANO[3,4-d][1,3]THIAZIN-2-AMINE COMPOUNDS
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US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
WO2018234953A1 (en) 2017-06-22 2018-12-27 Pfizer Inc. Dihydro-pyrrolo-pyridine derivatives
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CN113237970A (en) * 2021-04-23 2021-08-10 上海应用技术大学 High performance liquid chromatography separation method of R, S isomer of 5,7-difluorochroman-4-ol

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009006A1 (en) * 1989-12-07 1991-06-27 Aktiebolaget Astra New bicyclic amino-substituted compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009006A1 (en) * 1989-12-07 1991-06-27 Aktiebolaget Astra New bicyclic amino-substituted compounds

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WO2012172449A1 (en) 2011-06-13 2012-12-20 Pfizer Inc. Lactams as beta secretase inhibitors
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US8933221B2 (en) 2011-08-31 2015-01-13 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2013030713A1 (en) 2011-08-31 2013-03-07 Pfizer Inc. Hexahydropyrano [3,4-d][1,3] thiazin-2-amine compounds
WO2013151982A1 (en) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Methods and compounds useful in treating pruritus, and methods for identifying such compounds
US8962616B2 (en) 2012-05-04 2015-02-24 Pfizer Inc. Heterocyclic substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
WO2013164730A1 (en) 2012-05-04 2013-11-07 Pfizer Inc. Heterocyclic substituted hexahydropyrano [3,4-d] [1,3] thiazin- 2 -amine compounds as inhibitors of app, bace1 and bace 2.
US9642855B2 (en) 2012-06-29 2017-05-09 Pfizer Inc. Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors
WO2014001973A1 (en) 2012-06-29 2014-01-03 Pfizer Inc. NOVEL 4-(SUBSTITUTED-AMINO)-7H-PYRROLO[2,3-d]PYRIMIDINES AS LRRK2 INHIBITORS
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US9260455B2 (en) 2012-09-20 2016-02-16 Pfizer Inc. Alkyl-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
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US9193726B2 (en) 2012-09-21 2015-11-24 Pfizer Inc. Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders
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US8916564B2 (en) 2012-09-21 2014-12-23 Pfizer Inc. Substituted pyrido[1,2-a]pyrazines for the treatment of neurodegenerative and neurological disorders
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US9198917B2 (en) 2012-12-11 2015-12-01 Pfizer Inc. Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
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US9403846B2 (en) 2012-12-19 2016-08-02 Pfizer Inc. Carbocyclic- and heterocyclic-substituted hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds
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US9611264B1 (en) 2015-09-24 2017-04-04 Pfizer Inc. N-[2-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides
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