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WO2007069053A1 - Antagonistes benzimidazoliques du récepteur h-3 - Google Patents

Antagonistes benzimidazoliques du récepteur h-3 Download PDF

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Publication number
WO2007069053A1
WO2007069053A1 PCT/IB2006/003611 IB2006003611W WO2007069053A1 WO 2007069053 A1 WO2007069053 A1 WO 2007069053A1 IB 2006003611 W IB2006003611 W IB 2006003611W WO 2007069053 A1 WO2007069053 A1 WO 2007069053A1
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Prior art keywords
methyl
carboxylic acid
benzoimidazole
piperidin
amide
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English (en)
Inventor
Travis T. Wager
Scot Richard Mente
Todd William Butler
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Pfizer Products Inc
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Pfizer Products Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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 histamine-3 (H3) receptors using such compounds.
  • H3 histamine-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.
  • H3 receptor histamine receptor
  • H3 ligand may be an antagonist, agonist or partial agonist, see: (Imamura et al., Circ. Res., (1996) 78, 475-481); (Imamura et. al., Circ. Res., (1996) 78, 863-869); (Lin et al., Brain Res. (1990) 523, 325-330); (Monti et al., Neuropsychopharmacology (1996) 15, 31 35); (Sakai, et al., Life Sci. (1991) 48, 2397-2404); (Mazurkiewiez- Kwilecki and Nsonwah, Can. J. Physiol.
  • Watanabe, AQ-O 145 "A newly developed histamine H3 antagonist, decreased seizure susceptibility of electrically induced convulsions in mice", Meth. Find. Exp. Clin. Pharmacol., 17(C): 70-73, (1995); (Delaunois A., Gustin P., Garbarg M., and Ansay M., "Modulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungs", European Journal of Pharmacology 277(2-3):243-50, (1995)); and (Dimitriadou, et al., "Functional relationship between mast cells and C- sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen", Clinical Science 87(2):151-63, (1994).
  • Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and 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 A1.
  • the histamine H3 receptor (H3R) regulates the release of histamine and other neurotransmitters, including serotonin and acetylcholine.
  • H3R is relatively neuron specific and inhibits the release of certain monoamines such as histamine.
  • Selective antagonism of H3R receptors raises brain histamine levels and inhibits such activities as food consumption while minimizing non-specific peripheral consequences.
  • Antagonists of the receptor increase synthesis and release of cerebral histamine and other monoamines.
  • the receptor is an important target for new therapeutics in Alzheimer disease, mood and attention adjustments, including attention deficit hyperactive disorder (ADHD), attention deficiet disorder (ADD), cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and motion sickness, and various forms of anxiety.
  • ADHD attention deficit hyperactive disorder
  • ADD attention deficiet disorder
  • cognitive deficiencies obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and motion sickness, and various forms of anxiety.
  • 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 alkyamines as histamine H3 receptor antagonists.
  • WO 02/12224 (Ortho McNeil Pharmaceuticals) describes non- imidazole bicyclic derivatives as histamine H3 receptor ligands. Other receptor antagonists have been described in WO 02/32893 and WO 02/06233.
  • This invention is directed to histamine-3 (H3) receptor antagonists of the invention useful for treating the conditions listed in the preceding paragraphs.
  • the compounds of this invention are highly selective for the H3 receptor (vs. other histamine receptors), and possess remarkable drug disposition properties (pharmacokinetics).
  • the compounds of this invention selectively distinguish H3R from the other receptor subtypes H1R, H2R.
  • novel compounds, such as those directed to the invention herein, that interact with the histamine H3 receptor would be a highly desirable contribution to the art.
  • R 1 is selected from the group consisting of (C 1 -C 6 )alkyl, (Ci-C 6 )alkyl-aryl, (C r C 6 )alkyl-(C 3 -C 6 )cycloalkyl, and aryl optionally substituted with 1 to 4 substituents selected from the group consisting of halo, methoxy, CN, CO-NH(CrC 6 )alkyl, and CO-N((C r C 6 )alkyl) 2 ;
  • R 2 is selected from the group consisting of (C 3 -C 6 )cycloalkyl, piperidine, morpholine, pyrrolidine, amino (CrC 6 )alkyl, amino di-(C r C 6 )alkyl, aminobenzyl,
  • R 2 may be optionally substituted with 1 to 3 substituents selected independently from hydroxyl, (C r C 6 )alkyl, aryl, and heteroaryl;
  • R 3 is (C r C 6 )alkyl, (C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, heteroaryl or (C r C 6 )alkylaryl;
  • R 4 is (CrC ⁇ )alkyl; and n is O, 1 , 2, 3, or 4.
  • a preferred embodiment of the invention includes those compounds of formula I wherein R 1 is (C r C 6 )alkyl, R 2 is (C 3 -C 6 )cycloalkyl, R 3 (C r C 6 )alkyl, and n is 2.
  • the most preferred embodiment of the invention includes those compounds of formula I wherein R 1 is (Ci-C 6 )alkyl, R 2 is pyrrolidine, R 3 is methyl, R 4 is ethyl, and n is 2.
  • This invention is also directed to pharmaceutical composition for treating a disorder or condition that may be treated by antagonizing histamine-3 receptors, the composition comprising a compound of formula I and optionally a pharmaceutically acceptable carrier.
  • This invention is also directed to a method of treatment of a disorder or condition that may be treated by antagonizing histamine-3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I.
  • This invention is also directed to a method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, cognitive disorders, Alzheimer's disease, attention-deficit disorder (ADD), attention- deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy- induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastro- intestinal tract, the method comprising administering to a mammal in need of such treatment a compound of formula I.
  • a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, cognitive disorders, Alzheimer's disease, attention-deficit disorder (ADD), attention- deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy- induced airway responses, allergic rhinitis
  • This invention is also directed to a pharmaceutical composition for treating allergic rhinitis, nasal congestion or allergic congestion comprising: (a) an H3 receptor antagonist compound of formula I or a pharmaceutically acceptable salt thereof; (b) an H1 receptor antagonist or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the active ingredients (a) and (b) above are present in amounts that render the composition effective in treating allergy rhinitis, nasal congestion or allergic congestion.
  • This invention is also directed to a pharmaceutical composition for treating ADD,
  • ADHD, depression, mood disorders, or cognitive disorders comprising: (a) an H3 receptor antagonist compound of Formula I or a pharmaceutically acceptable salt thereof; (b) a neurotransmitter re-uptake blocker or a pharmaceutically acceptable salt thereof; (c) a pharmaceutically acceptable carrier; wherein the active ingredients (a) and (b) above are present in amounts that render the composition effective in treating depression, mood disorders, and cognitive disorders.
  • the histamine-3 (H3) receptor antagonists of the invention are useful for treating, in particular, ADD, ADHD, obesity, anxiety disorders and respiratory diseases.
  • Respiratory diseases that may be treated by the present invention include adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis.
  • the pharmaceutical composition and method of this invention may also be used for preventing a relapse in a disorder or condition described in the previous paragraphs. Preventing such relapse is accomplished by administering to a mammal in need of such prevention a compound of formula I as described above.
  • the disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H3 antagonist compound of general formula I and an effective dose of a histamine H1 antagonist, such as cetirizine (ZyrtecTM), chlorpheniramine (ChlortrimetonTM), loratidine (ClaritinTM), fexofenadine (AllegraTM), or desloratadine (ClarinexTM) for the treatment of allergic rhinitis, nasal congestion, and allergic congestion.
  • a histamine H3 antagonist compound of general formula I and an effective dose of a histamine H1 antagonist, such as cetirizine (ZyrtecTM), chlorpheniramine (ChlortrimetonTM), loratidine (ClaritinTM), fexofenadine (AllegraTM), or desloratadine (ClarinexTM) for the treatment of allergic rhinitis, nasal 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.
  • neurotransmitter reuptake blockers will include the serotonin-selective reuptake inhibitors (SSRI's) like sertraline (ZoloftTM), fluoxetine (ProzacTM), and paroxetine (PaxilTM), 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 1 as well as racemic and other mixtures thereof. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.
  • the present invention also includes isotopically labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 0, 17 O, 15 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, 123 I, respectively.
  • Compounds of the present invention and pharmaceutically acceptable salts of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, Le 1 , 3 H, and carbon-14, Le 1 , 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, Le 1 , 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Anxiety disorders include, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder.
  • Mood adjustment disorders include, for example, depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood.
  • Cognitive disorders include, for example, ADHD, attention-deficit disorder (ADD) or other attention adjustment or cognitive disorders due to general medical conditions.
  • Psychotic disorders include, for example, schizoaffective disorders and schizophrenia; sleep disorders include, for example, narcolepsy and enuresis.
  • disorders or conditions which may be treated by the compound, composition and method of this invention are also as follows: depression, including, for example, depression in cancer patients, depression in Parkinson's patients, post-myocardial infarction depression, depression in patients with human immunodeficiency virus (HIV), Subsyndromal Symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic depressive illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or major depression with dysthymia; dysthymia; phobias, including, for example, agoraphobia, social phobia or simple phobias; eating disorders, including, for example, anorexia nervosa or bulimia
  • the mammal in need of the treatment or prevention may be a human.
  • the mammal in need of the treatment or prevention may be a mammal other than a human.
  • 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, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluor
  • Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see "Handbook of Pharmaceutical Salts: Properties,
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • 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.
  • references to compounds of formula I include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula I.
  • halo as used herein includes fluoro, chloro, bromo and iodo.
  • the term as used herein includes saturated, straight-chain or branched hydrocarbon group having from 1 to 6 carbon atoms and includes for example methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. This also applies if the alkyl group carries substituents or is a substituent for another group, e.g. in -O-(C r Ce)alkyl and -C(O)(C 1 -C 6 )alkyl.
  • 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-butoxy.
  • (C 3 -C 6 )cycloalkyl includes saturated monocyclic carbocyclic group having 3 to 6 carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl 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.
  • heteroaryl as used herein, includes monocyclic or bicyclic heteroaryl groups having 5 to 9 and 9 to 14 ring members respectively, which contain 1 , 2, 3 or 4 heteroatom(s) selected from nitrogen, oxygen and sulphur. The heteroaryl group can be unsubstituted, monosubstituted or disubstituted.
  • heteroaryl groups include, but are not limited to thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazdlyl, pyranyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiadiazinyl, isobenzofuranyl, benzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolinyl, isoquinolyl, cinnolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, benzoxazolyl,
  • the compound of formula I according to the invention may be prepared by the general procedure shown in Scheme 1.
  • Step A Substitution of a halo group, preferable chloride, of (1 ) can be accomplished using standard condition that appear in the literature. For example, Chauhan et al. have shown that reaction of an aryl nitro chloride with an amine in the presence of a base results in the substitution product (Chauhan, S. M. S.; Singh, Ram; Geetanjali; SYNCAV; Synth. Commun.; EN; 33; 16; 2003; 2899 - 2906).
  • Reduction of the nitro group, (2) can be accomplished by reaction of (2) in a reaction- inert-solvent, where preferred solvents are low boiling alcohols, where methanol or ethyl alcohol is preferred in the presence of an acid, where HCI is preferred.
  • the reduction is accomplished using a catalyst, where Pd/C is preferred in the presence of hydrogen, around 45 psi, at a reaction temperature of about room temperature to the reflux temperature of the solvent employed, where the reaction temperature is about 45 0 C is preferred to afford the reduced product, (3).
  • Alternative reduction conditions can be employed, such as those used by Ates-Alagoz, et al (Ates-Alagoz, Zeynep; Buyukbingol, Erdem; HCOMEX; Heterocycl. Commun.; EN; 7; 5; 2001 ; 455 - 460).
  • Acylation of (3) can be accomplished using well-established conditions that appear in the literature, and known to one skilled in the art. Reaction of (3) with an acid chloride in the presence of tertiary amine base, where triethylamine is preferred in a reaction inert solvent, where chlorinated solvents are preferred, such as, methylene chloride or 1 ,2-dichloroethane, at room temperature affords the acylated product.
  • Step D Heterocyclic ring formation can be accomplished by reaction of the acylated product from Step C in ethanol with an inorganic acid, where HCI is preferred, at a reaction temperature from about 50 °C to the reflux temperature of the solvent employed to give the cyclized product (4).
  • Step E Hydrolysis of the ester (4) can be accomplished using standard conditions that appear in the literature, or known to one skilled in the art. Reaction of ester (4) in ethanol with aqueous sodium or potassium hydroxide, where aqueous sodium hydroxide is preferred, at a reaction temperature of about 50 0 C to the reflux temperature of the solvents employed gives the acid (5). Step F:
  • Intermediate of the general structure (5) may be reacted with primary or secondary amines of general formula (6 or 7) as defined in the specification, in the presence of a coupling reagent such as dicyclohexyl carbodiimide, carbonyl diimidazole, tripropylphosphonic anhydride, alkyl chloroformate, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, benzotriazol-1-yloxy-tris(dimethylamino)phosphoniurn hexafluorophosphate, or any other such standard literature reagents in the presence of a trialkyl amine base, such as triethyl amine or diisopropylethyl amine, wherein tripropylphosphonic anhydride and triethylamine are a preferred combination in a reaction inert solvent, where ethyl acetate, from -78 0 C to 40 0 C, where room temperature is preferred to afford either the
  • Removal of the BOC protecting group of the compound of formula (8) can be accomplished using conditions described in the literature.
  • the preferred method of protecting group removal is by reaction of (8) in a reaction inert solvent, where methylene chloride is preferred with an acid where preferred acids are TFA, and aqueous HCI at a reaction temperature from about 0 0 C to the reflux temperature of the solvent employed, where about room temperature is preferred to give a new compound of the formula (9).
  • Suitable solvents include, among others, tetrahydrofuran (THF) and 1 ,2-dichloroethane (DCE) and the reactions may be conducted with or without the addition of an organic acid (e.g., acetic acid).
  • reaction of (9) in a reaction inert solvent, where methylene chloride/DMA is preferred, with an ketone, or aldehyde, where R 1 is defined in the specification, in the presence of tetramethylammonium triacetoxyborohydride, in the presence of diisopropylethylamine, at a reaction temperature of about room temperature gives a compound of the formula I.
  • intermediates of general formula (9) may be reacted with a R 1 -halide, where R 1 is defined in the specification.
  • Reaction of (9) in ethyl alcohol, in the presence of an inorganic base, where potassium carbonate is preferred, with an R 1 -halide, at a reaction temperature of about 80 0 C gives a compound of the formula I.
  • Step K Substitution reactions of the general conversion from (12) to amino compounds of the general formula (13) are well presented in the literature. For example, Senanayake, Chris H. et al. (Tetrahedron Lett.; EN; 40; 38; 1999; 6875 - 6880) have reported a fluoride-catalyzed TGME-mediated amination process for chloroimidazoles. Reaction of (12) in the presence of R 2 , where R 2 is a primary or secondary amine as defined in the specification, in the presence of cesium fluoride, in DMSO at a reaction temperature of about 50- 110 0 C gives amino intermediates of the general structure (13).
  • Rotomers are possible for an embodiment of the inventive compound of formula I and are within the scope of the invention.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). -
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to
  • 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. EHeI (Wiley, New York, 1994).
  • DIPEA diisopropylethylamine
  • LAH lithium aluminum hydride MHz: megahertz
  • PPTs pyridinium p-toluenesulfonate
  • TsO p-toluenesulfonate
  • TLC thin layer chromatography
  • Ts tosyl, p-toluenesulfonyl
  • T 3 P 2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide
  • Solvents were purchased and used without purification. Yields were calculated for material judged homogenous by thin layer chromatography and NMR. Thin layer chromatography was performed on plates eluting with the solvents indicated, visualized by a
  • Method C Preparative conditions (Waters 600 & Waters 2767 Sample Manager); Column: Waters Symmetry C 18 , 5 ⁇ m, 30 x 150 mm steel column, part # WAT248000, serial # M12921A01; solvent A - 0.1 % Trifluoroacetic acid/water; solvent B - Acetonitrile; volume of injection: 850 ⁇ L; time 0.0, 90% solvent A, 10% solvent B, flow 20; time 10.0, 0% solvent A, 100% solvent B, flow 20; time 12.0, 0% solvent A, 100% solvent B, flow 20.
  • Step 1 Amidation protocol, First, prepare a 0.2 M solution of amine (template) in anhydrous DMF, add neat TEA to aid dissolution when salt is present. Prepare a 0.2 M solution of carboxylic acid in anhydrous DMF. Prepare a 0.5 M solution of TEA in anhydrous DMF. Prepare a 0.5 M solution of HATU in anhydrous DMF. Dispense 250 ⁇ L of the 0.2 M carboxylic acid solution to appropriate vials. Dispense 300 ⁇ L of the 0.5 M TEA solution to all vials. Dispense 100 ⁇ L of the 0.5 M HATU solution to all vials.
  • TAA Triethylamine
  • NMM N-methylmorpholine
  • N-ethyt-i-isobutyl ⁇ -cvclopentyl-N-d-ethylpiperidin ⁇ -v ⁇ -IH-benzimidazole-S- carboxamide hydrochloride A 20 mL screw cap vial, equipped with a magnetic stirring bar, was charged with N- ethyl-1 -isobutyl-2-cyclopentyl-N-(1 -tert-butoxycarbonylpiperidin-4-yl)-1 H-benzimidazole-5- carboxamide (168 mg, 0.33 mmol), DCM (2 mL), and TFA (0.6 mL). The mixture was stirring for 1 h at RT, then evaporated and dried to give clear gum.
  • Methyl 3-nitro-4-(propylamino)benzoate (60.0 g, 0.252 mol) was dissolved under vigorous stirring in anhydrous 1 ,2-dimethoxyethane (400 mL).
  • Activated charcoal (3.0 g) was added to the solution, and the obtained suspension was refluxed for 2 h and then cooled to 30 0 C.
  • the catalyst Pd/C (10%) (1.8 g) was then added to the mixture, and the latter was heated to 45 0 C.
  • Hydrazine monohydrate 37.8 g, 0.755 mol
  • Methyl 2-oxo-1 -propyl-2,3-dihydro-1 //-benzimidazole-5-carboxylate Methyl 3-amino-4-(propylamino)benzoate (56.8 g, ⁇ 0.27 mol) was dissolved in anhydrous dioxane (300 mL). 1,1 '-Carbonyldiimidazole (CDI; 49.95 g, 0.308 mol) was added to this solution in several small portions with stirring. The reaction mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, and the residue was dissolved in chloroform (1 L).
  • CDI 1,1 '-Carbonyldiimidazole
  • Methyl 2-bromo-1 -propvl-IH-benzimidazole-5-carboxvlate Phosphoryl bromide (POBr 3 ) (73.4 g, 0.256 mol) was dissolved in dichloroethane (300 mL). Methyl 2-oxo-1-propyl-2,3-dihydro-1A7-benzimidazole-5-carboxylate (30.0 g, 0.128 mol) was added to this solution in several small portions with stirring, and the obtained mixture was refluxed until TLC (chloroform/methanol 30:1) indicated disappearance (-24 h) of the starting material.
  • Phosphoryl bromide (POBr 3 ) 73.4 g, 0.256 mol
  • Methyl 2-oxo-1-propyl-2,3-dihydro-1A7-benzimidazole-5-carboxylate 30.0 g, 0.128 mol
  • reaction mixture was carefully diluted with ice-water with cooling and then neutralized with solid Na 2 CO 3 to reach pH 7.
  • the obtained mixture was diluted with dichloromethane (to reach a volume of organic layer ⁇ 2 L).
  • the organic layer was separated and washed with brine (1 L) and water (2 x 600 mL).
  • the final emulsion was dried over MgSO 4 and then Na 2 SO 4 .
  • the organic solution was concentrated under reduced pressure to give a pale-gray solid, which was then placed onto a column containing silica gel (750 g).
  • the target product was removed with chloroform ( ⁇ 2 L).
  • the filtrate was concentrated under reduced pressure to furnish the title compound as a white solid in 83% (31.5 g) yield.
  • Methyl 2-morpholin-4-yl-1 -propyl-1 tf-benzimidazole-5-carboxylate A mixture of Methyl 2-bromo-1-propyl-1/-/-benzimidazole-5-carboxylate (15.0 g, 0.05 mol), morpholine (10.7 g, 0.123 mol), Cs 2 CO 3 (23.0 g, 0.071 mol), CsF (10.7 g, 0.071 mol), and DMSO (150 mL) was placed into a reactor vessel of a MILESTONE Microwave Labstation. The reaction mixture was irradiated with microwaves with stirring at an internal temperature of 11O 0 C for 5 h. The reaction mixture was then decanted from precipitated inorganic salts, and the latter was washed with chloroform (2 x 200 mL). The organic mother liquid (DMSO-solution) was diluted with water
  • the rinsing liquid was mixed with organic mother liquid (DMSO-solution), and the combined solution was diluted with aqueous 15% solution of citric acid to reach pH 3.
  • the aqueous layer was extracted with dichloromethane (4 x 250 mL) and then with chloroform (4 x 250 mL).
  • the combined extracts were washed with brine (2 x 150 mL), dried over Na 2 S ⁇ 4 and concentrated under reduced pressure.
  • the residue was placed into a column containing silica gel, and the product was eluted with ethyl acetate under TLC control.
  • the extracts were combined and concentrated under reduced pressure to give the title compound in 70% (28.6 g) yield.
  • Methyl 4-[(cyclopropylmethyl)amino]-3-nitrobenzoate (60.1 g, 0.24 mol) was suspended under vigorous stirring in anhydrous methanol (700 mL).
  • the resulting mixture was heated to 40-45 0 C under vigorous stirring, and hydrazine monohydrate (30 mL) was added dropwise to the suspension over 1 h, keeping the temperature below 55 0 C.
  • Methyl 1 -(cvclopropylmethyl)-2-oxo-2.3-dihvdro-1 H-benzimidazol ⁇ -5- carboxylate The Methyl 3-amino-4-[(cyclopropylmethyl)amino]benzoate (53.9 g, -0.245 mol) was dissolved in anhydrous dioxane (400 mL). 1,1 '-Carbonyldiimidazole (CDI; 51.7 g, 0.319 mol) was added to this solution in several small portions under stirring. The reaction mixture was stirred at room temperature for 6 h and then stirred overnight. The solvent was removed under reduced pressure, and the residue was mixed with water (1 L).
  • CDI 1,1 '-Carbonyldiimidazole
  • the obtained mixture was diluted with dissolved HCI (1 :1 ) (200 mL) to reach pH 2.
  • the formed precipitate was separated by filtration, washed with water (3 x 200 mL), hexane/ether (1 :1) mixture (2 x 500 mL) and then with neat ether (500 mL) and dried to give the title compound as a light-pink powder in 94% (56.6 g) yield.
  • the reaction mixture was carefully diluted with ice-water under cooling and then neutralized with solid Na 2 CO 3 to reach pH 7.
  • the obtained mixture was diluted with dichloromethane to increase the volume of the organic layer to ⁇ 2.5 L.
  • the organic layer was separated and washed with brine (1 L) and water (2 x 500 mL).
  • the final emulsion was dried over MgSO 4 and then over Na 2 SO 4 .
  • the organic solution was concentrated under reduced pressure to give pale-gray solid that was placed onto a column containing silica gel (1 kg), and eluted with chloroform ( ⁇ 2 L).
  • the filtrate was concentrated under reduced pressure to furnish the title compound as a white solid in 75% (38.6 g) yield.
  • Methyl 4-chloro-3-nitrobenzoate (72.01 g, 0.334 mol) was suspended in freshly distilled acetonitrile (360 mL) under stirring.
  • Anhydrous sodium acetate (41.1 g, 0.5 mol) and then a 30% w/w aqueous solution of methylamine (69 mL, 0.67 mol) were added to this suspension under vigorous stirring.
  • the obtained mixture was refluxed for 7 h while the course of the reaction was monitored by TLC (chloroform/CCI 4 1 :2).
  • the yellow precipitate was separated by filtration and mixed with a solution of K 2 CO 3 (25 g) in water (500 mL). The mixture was stirred for 30 min and then filtered.
  • the yellow precipitate was washed with water to attain pH 7.
  • the filtrate was concentrated under reduced pressure to a volume of ⁇ 200 mL and then mixed with a solution of K 2 CO 3 (5 g) in water (100 mL). The mixture was stirred for 30 min and then filtered. The yellow precipitate was washed with water to attain pH 7. Two above precipitates were combined and dried to give the title compound as a yellow powder in 96% (67.63 g) yield.
  • Methyl 3-amino-4-(methylamino)benzoate Methyl 4-(methylamino)-3-nitrobenzoate (63.06 g, 0.3 mol) was suspended under vigorous stirring in methanol (700 mL).
  • the resulting mixture was heated to 40-45 0 C under vigorous stirring, and hydrazine monohydrate (60 mL, 1.2 mol) was added dropwise to the suspension for 3 h.
  • the temperature of the reaction mixture was kept below 55 0 C.
  • the obtained mixture was stirred at 50-55 0 C for 3 h and then kept overnight at room temperature.
  • the reaction mixture was heated again to 40-45 0 C under vigorous stirring, and additional amount of hydrazine hydrate (5 mL) was added to the mixture.
  • the suspension was refluxed for 2 h under vigorous stirring, then cooled, and diluted with chloroform (1000 mL).
  • the mixture was passed through Celite (the upper layer 2 cm thick, the diameter of 17 cm) and silica gel (the lower layer 5 cm) to remove Raney nickel.
  • the layers were washed with the chloroform/methanol 1 :1 mixture (5 x 600 mL).
  • the filtrate was concentrated under reduced pressure.
  • the residue was diluted with benzene (100 mL), and the mixture was concentrated under reduced pressure to remove water. This operation was repeated to give the title compound as a brown crystalline solid in 99% (53.6 g) yield.
  • Phosphoryl bromide (POBr 3 ) (102.4 g, 0.357 mol) was dissolved in dichloroethane (400 mL). Methyl 1-methyl-2-oxo-2,3-dihydro-1W-benzimidazole-5-carboxylate (36.7 g, 0.178 mol) was added to this solution in several small portions under stirring, and the obtained suspension was refluxed until the starting substance disappeared (TLC monitoring, chloroform/1 ,2-dimethoxyethane 10:1).
  • the reaction mixture was cooled on an ice-bath and then carefully neutralized for 3 h with water (50 mL) and then with a solution of Na 2 CO 3 (100 g) in water (800 mL) (strong foaming!).
  • the obtained mixture was extracted with chloroform (2 L).
  • the layers were separated, and the aqueous layer was extracted again with chloroform (500 mL).
  • the organic layers were combined, washed with water (3 x 250 mL), and dried over CaCI 2 .
  • the organic solution was concentrated under reduced pressure to give a pale-gray solid that was recrystallized from acetonitrile to give the title compound as white solid in 77.5% (37.1 g) yield.
  • reaction mixture was irradiated with microwaves under stirring at 110 0 C for 9 h. Then the reaction mixture was poured into ice-cold water (1.5 L) with stirring. The obtained mixture was acidified with citric acid to attain pH 5, and the product was extracted with chloroform (3 x 400 mL). The extract was washed with water (2 x 200 mL) and with the 5% NaCI aqueous solition
  • Methyl 2-r(fra ⁇ s-4-hvdroxycvclohexy0amino1-1 -methyl-1 H-benzimidazole-5- carboxylate A mixture of Methyl 2-bromo-1 -methyl-1 H-benzimidazoIe-5-carboxylate (37.0 g, 0.137 mol), frans-4-aminocyclohexanol (38.0 g, 0.33 mol), cesium fluoride CsF (29.24 g, 0.29 mol), and DMSO (350 mL) was stirred at 110 °C for 6 h and kept overnight at room temperature (TLC control, silica gel, chloroform/ethanol 20:1 ). The reaction mixture was poured into cold water (1.5 L). The precipitate was separated by filtration and recrystallized from acetonitrile (900 mL) to give the title compound in 84% (35.0 g) yield. lntermediate 34
  • Methyl 2-rbenzvKmethyl)amino1-1 -methyl-1 H-benzimidazole-5-carboxylate A mixture of Methyl 2-bromo-1 -methyl-1 W-benzimidazole-5-carboxylate (31.0 g, 0.115 mol), benzyl(methyl)amine (33.5 g, 0.277 mol), cesium fluoride (24.5 g, 0.161 mol), and DMSO (250 mL) was stirred at 110-115 0 C for 7 h in a flask equipped with a KOH tube to protect the mixture from atmospheric CO 2 and kept overnight at room temperature. The reaction mixture was poured into ice-cold water (750 mL). The oily precipitate rapidly solidified.
  • Methyl 1 -methyl-2-f(2-phenylethyl)amino1-1 H-benzimidazole-5-carboxylate A mixture of Methyl 2-bromo-1-methyl-1 H-benzimidazole-5-carboxylate (30.0 g, 0.111 mol), phenethyiamine (32.4 g, 0.267 mol), cesium fluoride (23.7 g, 0.156 mol), and DMSO (240 mL) was stirred at 110-115 °C for 8 h. The reaction mixture was cooled and poured into ice-cold water (1.25 L) under stirring. The sticky precipitate was separated by decantation, washed with water, and dissolved in chloroform (1.8 L).
  • the aqueous layer was extracted with chloroform (3 x 300 mL).
  • the organic extracts were combined, washed with a 10% aqueous solution of citric acid (2 x 900 mL), and dried over Na 2 SO 4 .
  • the inorganic precipitate was separated by filtration and washed with chloroform (180 mL).
  • the combined extracts were concentrated under a reduced pressure to give the title compound as a viscous yellow oil in 94% (32.57 g) yield.
  • the pale-yellow turbid filtrate was diluted with a solution of KHSO 4 (32.9 g, 0.24 mol) in water (100 mL) to attain pH ⁇ 4.
  • the white precipitate was separated by filtration, washed with water (2 x 250 mL), acetone (50 mL), and dried to give the title compound as a pale-yellow crystalline solid in 73% (22.72 g) yield.
  • LRMS m/z Calcd for C17 H17 N3 02 295.3; obsd LCMS APCI (M+1 ) m/z 296.1.
  • Methyl 1 -methyl-2-pyrrolidin-1 -yl-1 H-benzimidazole-5-carboxylate A mixture of Methyl 2-bromo-1 -methyl-1 W-benzimidazole-5-carboxylate (40.0 g, 0.149 mol), pyrrolidine (25.37 g, 30 mL, 0.357 mol), cesium fluoride CsF (31.61 g, 0.208 mol), and DMSO (240 mi_) was placed into a reactor of a MILESTONE Microwave Labstation. The reaction mixture was irradiated with microwaves under stirring at an internal temperature of 115 0 C for 8 h, cooled, and poured into ice-cold water (1 L).
  • the formed precipitate was separated by filtration, washed with cold water (2 * 50 mL), hexane (2 * 100 mL), and dried.
  • the product was mixed with ether (250 mL) and acetonitrile (20 mL), and the mixture was placed into an ultrasonic bath for 1.5 h.
  • the precipitate was separated by filtration, washed with ether (2 x 50 mL), and dried to give the title compound in 75% (28.82 g) yield.
  • the reaction mixture was poured into cold water (1.2 L) under stirring to form a pale-yellow emulsion.
  • the product was extracted with chloroform (4 x 300 mL).
  • the combined chloroform extracts were washed with water (4 x 300 mL), dried over MgSO 4 , and concentrated under reduced pressure to give a pale-yellow crystal solid that was washed with ether (200 mL) using an ultrasonic bath.
  • the white crystals were separated by filtration and dried to give the title compound in 74% (27.3 g) yield.
  • Example 8 2-(4-Hvdroxy-cyclohexylamino)-1 -methyl-1 H-benzoimidazole-5-carboxylic acid methyl-(1-methyl-piperidin-4-yl)-amide.
  • Reagent A 1 -Methyl-2-pyrrolidin-1 -yi-1 H- benzoimidazole-5-carboxylic acid
  • Reagent B Methyl-(1-methyl-piperidin-4-yl)-amine.
  • Example 21 r3-(E-hyl-methyl-amino)-pyrrolidin-1 -yll-r2-(3-hvdroxy-piperidin-1 -yl)-1 -propyl- 1H-benzoimidazol-5-v ⁇ -methanone.
  • This reaction was conducted using the conditions described in General Procedure B: using the appropriate starting materials, A, B and C.
  • Reagent A Methyl-pyrrolidin-3-yl- carbamic acid tert-butyl ester
  • Reagent B 2-(3-Hydroxy-piperidin-1-yl)-1-propyl-1 H- benzoimidazole-5-carboxylic acid
  • Reagent C 2-(3-Hydroxy-piperidin-1-yl)-1-propyl-1 H- benzoimidazole-5-carboxylic acid
  • Reagent C 2-(3-Hydroxy-piperidin-1-yl)-1-propyl
  • Example 22 f3-( Ethyl-methyl-amino)-pyrrolidin-1 -v ⁇ -(2-morpholin-4-yl-1 -propyl-1 H- benzoimidazol-5-yl)-methanone.
  • This reaction was conducted using the conditions described in General Procedure B: using the appropriate starting materials, A, B and C.
  • Reagent A Methyl-pyrrolidin-3-yl- carbamic acid tert-butyl ester
  • Reagent B 2-Morpholin-4-yl-1-propyl-1 H-benzoimidazole-5- carboxylic acid
  • Reagent C and Acetaldehyde.
  • Reagent A 4-(2-Methoxy-ethylamino)- piperidine-1-carboxylic acid tert-butyl ester
  • Reagent B 1-Cyclopropylmethyl-2-(2-methyl- piperidin-1-yl)-1 H-benzoimidazole-5-carboxylic acid
  • Reagent C and Acetaldehyde.
  • Reagent A 4-Ethylamino-piperidine-1- carboxylic acid tert-butyl ester
  • Reagent B 1-Cyclopropylmethyl-2-(2-methyl-piperidin-1-yl)- 1 H-benzoimidazole-5-carboxylic acid
  • Reagent C and Acetaldehyde.
  • Reagent A 4-Ethylamino-piperidine-1- carboxylic acid tert-butyl ester
  • Reagent B 1-Cyclopropylmethyl-2-((S)-2-methoxy-1-methyl- ethylamino)-1 H-benzoimidazole-5-carboxylic acid
  • Reagent C and Acetaldehyde.
  • Example 28
  • Reagent A 4-Methylamino-azepane-1- carboxylic acid tert-butyl ester
  • Reagent B 2-(Cyclopropylmethyl-amino)-1-methyl-1 H- benzoimidazole-5-carboxylic acid
  • Reagent C and Acetaldehyde.
  • Reagent A 4-Ethylamino-piperidine-1- carboxylic acid tert-butyl ester
  • Reagent B i-Methyl ⁇ -pyrrolidin-i-yl-I H-benzoimidazole- ⁇ - carboxylic acid
  • Reagent C and Acetaldehyde.
  • Reagent A 4-Methylamino-azepane-1- carboxylic acid tert-butyl ester
  • Reagent B 2-Morpholin-4-yl-1 -propyl-1 H-benzoimidazole-5- carboxylic acid
  • Reagent C and Acetaldehyde.
  • the product was purified by HPLC
  • Example 32 i-Methyl- ⁇ -pyrrolidin-i-vt-IH-benzoimidazole-S-carboxylic acid (1-ethyl-azepan- 4-vD-methyl -amide.
  • Reagent A 4-Methylamino-azepane-1- carboxylic acid tert-butyl ester
  • Reagent B 1-Methyl-2-pyrrolidin-1-yl-1 H-benzoimidazole-5- carboxylic acid
  • Reagent C and Acetaldehyde.
  • the product was purified by HPLC
  • Reagent A 4-Methylamino-azepane-1- carboxylic acid tert-butyl ester
  • Reagent B 2-(3-Hydroxy-piperidin-1-yl)-1 -propyl-1 H- benzoimidazole-5-carboxylic acid
  • Reagent C and Acetaldehyde.
  • Reagent A Methyl-pyrrolidin-3-yl- carbamic acid tert-butyl ester
  • Reagent B 2-(3-Hydroxy-piperidin-1-yl)-1-propyl-1 H- benzoimidazole-5-carboxylic acid
  • Reagent C Propionaldehyde
  • Example 36 1-Methyl-2-pyrrolidin-1 -yl-1 H-benzoimidazole-5-carboxylic acid (2-methoxy- e-hylM1-propyl-piperidin-4-yl)-amide.
  • Reagent A 4-(2-Methoxy-ethylamino)- piperidine-1-carboxylic acid tert-butyl ester
  • Reagent B 1-Methyl-2-pyrrolidin-1-yl-1 H- benzoimidazole-5-carboxylic acid
  • Reagent C and Propionaldehyde.
  • Example 37 1 -Methyl-2-pyrrolidin-1 -yl-1 H-benzoimidazole-5-carboxylic acid ethyl-(1 -propyl- piperidin-4-vO-amide.
  • Reagent A 4-Ethylamino-piperidine-1- carboxylic acid tert-butyl ester
  • Reagent B i-Methyl ⁇ -pyrrolidin-i-yl-I H-benzoimidazole- ⁇ - carboxylic acid
  • Reagent C Propionaldehyde
  • Example 38 1 -Methyl-2-pyrrolidin-1 -yl-1 H-benzoimidazole-5-carboxylic acid (4-methyl-1 - propyl-piperidin-4-yl)-amide.
  • This reaction was conducted using the conditions described in General Procedure B: using the appropriate starting materials, A, B and C.
  • Reagent A Amino-4-methyl-piperidine- 1-carboxylic acid tert-butyl ester
  • Reagent B 1-Methyl-2-pyrrolidin-1-yl-1 H-benzoimidazole-5- carboxylic acid, Reagent C, and Propionaldehyde.
  • Reagent A 4-Methylamino-azepane-1- carboxylic acid tert-butyl ester
  • Reagent B 2-(3-Hydroxy-piperidin-1-yl)-1-propyl-1 H- benzoimidazole-5-carboxylic acid
  • Reagent C Propionaldehyde
  • Reagent A 4-Methylamino-azepane-1- carboxylic acid tert-butyl ester
  • Reagent B 1-Cyclopropylmethyl-2-(2-methyl-piperidin-1-yl)- 1 H-benzoimidazole-5-carboxylic acid
  • Reagent C Propionaldehyde
  • Reagent A 4-Methylamino-azepane-1- carboxylic acid tert-butyl ester
  • Reagent B 2-Cyclopentylamino-1 -methyl-1 H-benzoimidazole-
  • Reagent A 4-Methylamino-azepane-1- carboxylic acid tert-butyl ester
  • Reagent B 1-Cyclopropylmethyl-2-((S)-2-methoxy-1-methyl- ethylamino)-1 H-benzoimidazole-5-carboxylic acid
  • Reagent C and Propionaldehyde.
  • the composition of the present invention may be a composition comprising a compound of formula I and optionally a pharmaceutically acceptable carrier.
  • the composition of the present invention may also be a composition comprising a compound of formula I, a histamine H 1 antagonist and optionally a pharmaceutically acceptable carrier.
  • the composition of the present invention may also be a composition comprising a compound of formula I, a neurotransmitter re-uptake blocker and optionally a pharmaceutically acceptable carrier.
  • the composition of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • 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.
  • parenteral e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous or through an implant
  • 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 that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include: (i) where the compound of formula (I) contains a methyl group, an hydroxymethyl derivative thereof (-CH 3 ⁇ -CH 2 OH); (ii) where the compound of formula (I) contains an alkoxy group, an hydroxy derivative thereof (-OR -> -
  • (I) contains a secondary amino group, a primary derivative thereof (-NHR a -» -NH 2 ); (v) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONR c R d ⁇ COOH).
  • lsotopically labeled compounds of formula I of this invention can generally be prepared by carrying out the procedures disclosed in the preceeding Schemes and/or in the Examples and Preparations, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the pharmaceutical composition may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents such as pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose; fillers such as lactose, microcrystalline cellulose or calcium phosphate; lubricants such as magnesium stearate, talc or silica; disintegrants such as potato starch or sodium starch glycolate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents such as sorbitol syrup, methyl cellulose or hydrogenated edible fats; emulsifying agents such as lecithin or acacia, non-aqueous vehicles such as almond oil, oily esters or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid.
  • 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 reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
  • active ingredient refers to a compound of the formula I, a histamine Hi 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 glycerides.
  • a composition for vaginal administration is preferably a suppository that may contain, in addition to the active ingredient or ingredients, excipients such as cocoa butter or a suppository wax.
  • a composition for nasal or sublingual administration is also prepared with standard excipients well known in the art.
  • the composition may be conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active 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 1 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.
  • Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • Aerosol formulations containing a compound of formula I and a histamine H 1 antagonist or a neurotransmitter re-uptake blocker are preferably arranged so that each metered dose or "puff' of aerosol contains about 100 ⁇ 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.
  • Administration may be several times daily, for example 1 , 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • composition of the invention comprising a compound of formula I and a histamine Hi antagonist or a neurotransmitter re-uptake blocker may optionally contain a pharmaceutically acceptable carrier and may be administered in both single and multiple dosages as a variety of different dosage forms, such as tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like.
  • the pharmaceutically acceptable carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • Oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes.
  • the compound of formula I is present in such dosage forms at concentration levels ranging from about 0.1 % to about 99.9% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage, and the histamine H t antagonist or the neurotransmitter re-uptake blocker is present in such dosage forms at concentration levels ranging from about 0.1% to about 99.9% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • the compound of formula I and the histamine H 1 antagonist may be administered together or separately. When administered separately, the compound of formula I and the histamine H 1 antagonist may be administered in either order, provided that after administration of the first of the two active ingredients, the second active ingredient is administered within 24 hours or less, preferably 12 hours or less.
  • the compound of formula I and the neurotransmitter re-uptake blocker may be administered together or separately.
  • 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 1 antagonist or to the neurotransmitter re-uptake blocker for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to herein is from about 0.001 to about 1000, preferably from about 0.01 to about 100.
  • the composition may be homogeneous, wherein by homogeneous it is meant that the active ingredient or ingredients are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid composition is then subdivided into unit dosage forms of the type described herein containing from about 0.1 to about 1000 mg of the active ingredient or ingredients.
  • Typical unit dosage forms contain from about 1 to about 300 mg, for example about 1 , 2, 5, 10, 25, 50 or 100 mg, of the active ingredient or ingredients.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • 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 acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the dosage of the active ingredient or ingredients in the composition and methods of this invention may be varied; however, it is necessary that the amount of the active ingredient or ingredients in such a composition be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, the particular compounds administered, the duration of the treatment, and other factors. All dosage ranges and dosage levels mentioned herein refer to each active ingredient present in the pharmaceutical composition of the present invention, as well as those used in the methods of the present invention. Generally, dosage levels of between about 0.01 and about 100 mg/kg of body weight daily are administered to humans and other mammals. A preferred dosage range in humans is about 0.1 to about 50 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses.
  • a preferred dosage range in mammals other than humans is about 0.01 to about 10.0 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses.
  • a more preferred dosage range in mammals other than humans is about 0.1 to about 5.0 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses.
  • the pharmaceutical composition comprising the compound of formula I and the histamine H 1 antagonist or the neurotransmitter re-uptake blocker may be administered at dosages of a therapeutically effective amount of the compound of formula I and of the second active ingredient in single or divided doses.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age. However, some variation in dosage will necessarily occur depending upon the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the dosage amounts set forth in this description and in the appended claims may be used, for example, for an average human subject having a weight of about 65 kg to about 70 kg.
  • the skilled practitioner will readily be able to determine any variation in the dosage amount that may be required for a subject whose weight falls outside the about 65 kg to about 70 kg range, based upon the medical history of the subject.
  • the pharmaceutical combinations may be administered on a regimen of up to 6 times per day, preferably 1 to 3 times per day, such as 2 times per day or once daily. Determination of Biological Activity
  • the in vitro affinity of the compounds in the present invention at the rat or human histamine H3 receptors can be determined according to the following procedure. Frozen rat frontal brain or frozen human post-mortem frontal brain is homogenized in 20 volumes of cold 50 mM Tris HCI containing 2 mM MgCI 2 (pH to 7.4 at 4 0 C). The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is decanted and the membrane pellet resuspended by Polytron in cold 50 mM Tris HCI containing 2 mM MgCI2 (pH to 7.4 at 4 0 C) and centrifuged again.
  • the final pellet is resuspended in 50 mM Tris HCI containing 2 mM MgCI2 (pH to 7.4 at 25 0 C) at a concentration of 12 mg/mL. Dilutions of compounds are made in 10% DMSO / 50 mM Tris buffer (pH 7.4) (at 10 x final concentration, so that the final DMSO concentration is 1%). Incubations are initiated by the addition of membranes (200 microliters) to 96 well V-bottom polypropylene plates containing 25 microliters of drug dilutions and 25 microliters of radioligand (1 nM final concentration 3H-N-methyl-histamine).
  • 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.

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Abstract

La présente invention concerne un composé de formule (I) telle que définie ici, ou un de ses sels pharmaceutiquement acceptables ; une composition pharmaceutique contenant un composé de formule (I), un procédé de préparation d'un composé de formule (I), un procédé de traitement d'un trouble ou d'une maladie qui peut être traité en antagonisant les récepteurs histaminiques H3, le procédé comprenant l'administration à un mammifère nécessitant un tel traitement d'un composé de formule (I) tel que décrit ci-dessus, et un procédé de traitement d'un trouble ou d'une maladie choisi dans le groupe comprenant la dépression, les troubles de l'humeur, la schizophrénie, les troubles de l'anxiété, la maladie d'Alzheimer, le trouble d'hyperactivité avec déficit de l'attention (THADA), le trouble de déficit de l'attention (TDA), les troubles psychotiques, les troubles cognitifs, les troubles du sommeil, l'obésité, le vertige, l'épilepsie, le mal des transports, les maladies respiratoires, l'allergie, les réactions d'origine allergique des voies respiratoires, la rhinite allergique, la congestion nasale, la congestion allergique, la congestion, l'hypotension, les maladies cardiovasculaires, les maladies du système gastro-intestinal, l'hypermotilité et l'hypomotilité et la sécrétion acide dans le système gastro-intestinal, le procédé comprenant l'administration à un mammifère nécessitant un tel traitement d'un composé de formule (I) tel que décrit ci-dessus.
PCT/IB2006/003611 2005-12-14 2006-12-07 Antagonistes benzimidazoliques du récepteur h-3 Ceased WO2007069053A1 (fr)

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