Novel benzimidazole derivatives as dual histamine H1 and histamine H4 receptor ligands

Abstract

To provide a novel chemical class of dual H1R-H4R ligands and novel benzimidazoles derivatives as dual H1-H4 receptor antagonists or inverse agonists, their preparation, and their application in therapeutics.SOLUTION: The present application concerns novel benzimidazole enantiomeric derivatives, their process of preparation and their therapeutical uses as dual H1 and H4 receptor ligands.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present patent application relates to novel ligands of the H4-receptor, to processes for their preparation and to their therapeutic use. [Background technology]

[0002] The histamine H4 receptor (H4R) belongs to the superfamily of G-protein-coupled seven-transmembrane receptors and is expressed on the plasma membrane of various immunocompetent / inflammatory cells, such as eosinophils, basophils, mast cells, and dendritic cells. H4R plays a chemotactic role in regulating the influx of mast cells or eosinophils into inflammatory sites induced, for example, by histamine release, and thus plays a key role in the development of chronic inflammatory disorders. H4R also regulates the activity of eosinophils and several classes of lymphocytes. Therefore, blockade of H4R with antagonists or inverse agonists could be a novel therapeutic approach for diseases such as asthma, emphysema, allergic rhinitis, nasal congestion, bronchitis, chronic obstructive pulmonary disease, dermatitis, arthritis, psoriasis, colitis, etc., either alone or in combination with other classes of anti-inflammatory drugs already in use, namely, H1R antagonists. Furthermore, the use of H4R antagonists / inverse agonists may be of interest in various autoimmune diseases, such as type I diabetes, Crohn's disease, multiple sclerosis, lupus, etc. The anti-itch effect of some H4R antagonists in rodent models further suggests the use of these agents in pruritus (Bell et al., Br J Pharmacol, 2004, 142, 374).

[0003] Patent application WO2012 / 041860 describes compounds of the following general formula (I) as antagonists and / or inverse agonists of the H4 human receptor:

[0004] [ka]

[0005] The compound of formula (I) is described.

[0006] The histamine H1 receptor (H1R) belongs to the superfamily of G-protein-coupled seven-transmembrane receptors. Activation of H1 receptors on blood vessels and nerve endings is responsible for many of the symptoms of allergic rhinitis, allergic conjunctivitis, contact dermatitis, atopic dermatitis, ocular pruritus, chronic urticaria, eczema, prurigo, skin pruritus, plaque psoriasis, anaphylactic shock, and erythema multiforme.

[0007] H1-antihistamine compounds are at least partially effective in treating these diseases or conditions.

[0008] Thus, compounds exhibiting antagonist or inverse agonist activity at both human H1 and H4 receptors have been shown to be effective in treating a number of disease states, including anaphylactic shock, respiratory inflammatory and allergic diseases, adult respiratory distress syndrome, acute respiratory distress syndrome, respiratory infections, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, rhinorrhea, chronic empyema (sinusitis), allergies, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, non-seasonal and seasonal rhinitis, conjunctivitis, allergic conjunctivitis, nasal congestion, allergic congestion, otitis, nasal polyps, cough, female and male sexual dysfunction, overactive bladder conditions, urinary incontinence, bladder overactivity, benign prostatic hyperplasia, lower urinary tract symptoms, dermatitis. , atopic dermatitis, psoriasis, cutaneous pruritus, pruritus, urticaria, chronic urticaria, skin incision model of post-operative pain, allergic skin disease / pruritus and inflammation, allergic contact dermatitis, thromboembolism, atherosclerosis, myocardial infarction, angina pectoris, myocardial ischemia, cardiac arrhythmias, peripheral occlusive arterial disease, pulmonary arterial obstruction, deep vein thrombosis, hypotension, pulmonary hypertension, angioedema, malignant hypertension, heart failure, cardiac or renal failure, cerebrovascular accident and renal insufficiency, inflammatory bowel disease, Crohn's disease, ulcerative colitis, intestinal anaphylaxis, food allergies, post-inflammatory irritable bowel syndrome, peritonitis, rheumatoid arthritis, multiple sclerosis, lupus, osteoarthritis, joint pain, systemic inflammation, cancer, neuropathic pain, chronic eosinophilia, chronic diseases associated with mast cell proliferation, etc.

[0009] The combination of these two properties may improve the therapeutic efficacy of the compound, and therefore dual H4R-H1R antagonists / inverse agonists are of great interest. To date, this has only been explored in combination, as suitable dual H4R-H1R antagonists / inverse agonists are currently unavailable. For example, JNJ7777120 (an H4R ligand) and the H1R antagonist levocabastine both prevented eye-rubbing behavior, and the combination of these two agents resulted in even stronger inhibition of allergic conjunctivitis (Nakano Y et al., Eur J Pharmacol 2009; 608: 71-5). The combination of JNJ-39758979 (an H4R antagonist) and mepyramine (an H1R inverse agonist) showed synergistic activity in a mouse model of atopic dermatitis (Kochling H et al., J. Dermatol. Sci. 2017; 87; pp. 130-137), and may be a potential therapeutic agent for pruritus (Exp. Dermatol. 18; 2009; pp. 57-63), intestinal anaphylaxis (Wang M et al., Allergy 71; 2016; pp. 1561-1574), and allergic contact dermatitis (Matsushita A et al., Exp. Dermatol. 21; 2012; pp. 714-715).

[0010] Dual H1R-H4R antagonist / inverse agonists are not yet in clinical use, and therefore there is a need for such dual compounds that exhibit high efficacy and safety. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] Patent application WO2012 / 041860 [Non-patent literature]

[0012] [Non-Patent Document 1] Bell et al., Br J Pharmacol, 2004, 142,374 [Non-patent document 2] Nakano Y, Eur J Pharmacol 2009; 608: 71-5

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[0013] The present application relates to a new chemical class of dual H1R-H4R ligands, namely novel benzimidazole derivatives as dual H1-H4 receptor antagonists or inverse agonists, their preparation and their application in therapy. [Means for solving the problem]

[0014] The present inventors have surprisingly discovered that some enantiomers with defined stereochemistry of the derivatives disclosed in WO2012 / 041860 exhibit antagonist and / or inverse agonist activity at the human H1 receptor, in addition to the disclosed H4 activity. In other words, the enantiomers with defined stereochemistry, typically the (S) enantiomer, exhibit activity at both the human H1 receptor and the human H4 receptor. This is of great interest, as activity at both the H1 receptor and the H4 receptor translates into therapeutic utility for the compound in treating inflammatory and allergic disorders.

[0015] Furthermore, we unexpectedly discovered that the enantiomer (eutomer) that proved to be most active at the human H4 receptor also had the most activity at the human H1 receptor, whereas the enantiomer (distomer) that was less active at the human H4 receptor also had less activity at the human H1 receptor.

[0016] The general formula for these enantiomers is [ka] In the above equation * represents an asymmetric carbon with a defined stereochemistry, typically (S) stereochemistry; X represents H or F; R1, R2, R3, and R4, which may be the same or different, independently represent H, halogen, alkyl, or alkoxy; General formula (II) in which one of X, R1, R2, R3 and R4 does not represent H, and pharmaceutically acceptable salts, tautomers, hydrates and solvates thereof.

[0017] The compounds of formula (II) are novel. WO2012 / 041860 does not describe any of these specific enantiomers with the defined stereochemistry previously defined.

[0018] Unless otherwise specified, terms used herein before or after have the meanings ascribed to them below.

[0019] "Halo" or "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0020] "Alkyl," unless otherwise specified, refers to an aliphatic hydrocarbon group having 1 to 20 carbon atoms in the chain, which may be straight-chained or branched. Preferred alkyl groups have 1 to 12 carbon atoms in the chain, more preferably 1 to 6 or 1 to 4 carbon atoms in the chain, with lower alkyls preferably having 1 to 4 carbon atoms. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, and decyl.

[0021] "Alkoxy" refers to --O-alkyl, where alkyl is as defined above.

[0022] In one preferred embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol (S)-2-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride, monohydrate 2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol Enantiomer B 2-[(4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol Enantiomer B 2-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol Enantiomer B 2-[(4-chloro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol Enantiomer B 2-[(5-chloro-4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol Enantiomer B (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, (R)-para-methylmande acetic acid , and especially (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol (S)-2-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride, monohydrate (S)-2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(4-chloro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(5-chloro-4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, (R)-para-methylmande acetic acid , a compound selected from the group consisting of and their enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts, free forms, tautomers, hydrates and solvates.

[0023] The "B" enantiomer disclosed herein is one of two enantiomers of defined stereochemistry for a given racemic structure that exhibits high activity at both the H4 and H1 receptors.

[0024] Typically, this enantiomer is one of the two enantiomers with the longer retention time when the racemic mixture is subjected to chiral HPLC analysis, for example, on an analytical Chiralpak AD-H250X 4.6 mm column using an elution mixture comprising heptane / isopropanol and diethylamine (0.1%) at a flow rate of 1 ml / min.

[0025] As used herein, "enantiomer B" typically refers to the (S) enantiomer.

[0026] As used herein, "enantiomer A" typically refers to the (R) enantiomer.

[0027] The compounds of the present invention may also include tautomeric forms, which are encompassed by the present invention. In particular, in formula (II), benzimidazole may have tautomeric forms. 1H-benzimidazole is a tautomer of 3H-benzimidazole. Representative examples are shown below.

[0028] [ka]

[0029] The compounds of formula (II) can be provided in the form of a free base or in the form of an acid addition salt, which also form part of the present invention.

[0030] These salts are advantageously prepared with pharmaceutically acceptable acids, although salts with other acids, useful for example in the purification or isolation of compounds of formula (II), also form part of the invention.

[0031] According to one embodiment, the compound of formula (II) is (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride.

[0032] The hydrochloride salt may include various polymorphs in its anhydrous or solvated / hydrated state.

[0033] According to one embodiment, the anhydrous polymorph, referred to herein as Form I, can be prepared by precipitation under the following conditions: Transmission Mode Recorded values ​​between 2° and 50° The powder X-ray diffraction peaks are as follows, measured using a PANALYTICAL X'PERT PRO MPD diffractometer instrument:

[0034] The characteristic peaks in the anhydrous state are as follows:

[0035] [Table 1A]

[0036] [Table 1B]

[0037] According to one embodiment, the hydrated polymorph, referred to herein as Form II, is a monohydrate form, typically soluble under the following conditions: Transmission Mode Recorded values ​​between 2° and 50° The powder X-ray diffraction peaks are as follows, measured using a PANALYTICAL X'PERT PRO MPD diffractometer instrument:

[0038] The characteristic peaks of the monohydrate state are as follows:

[0039] [Table 2]

[0040] According to a further object, the present invention also relates to a process for the preparation of compounds of formula (II).

[0041] The compounds and methods of the present invention can be prepared in several ways that are well known to those skilled in the art. For example, compounds can be synthesized by the application or adaptation of the following methods, or variations thereof, that would be understood by those skilled in the art. Suitable modifications and substitutions will be readily apparent to, and well known to, those skilled in the art or are readily available in the scientific literature.

[0042] In particular, such methods can be found in RC Larock, Comprehensive Organic Transformations, VCH publishers, 1989.

[0043] It is understood that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms and may be isolated in optically active or racemic forms. Thus, unless a specific stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic, and all geometric isomeric forms of the structure are contemplated. Methods for preparing and isolating such optically active forms are well known in the art. For example, mixtures of stereoisomers can be separated by standard techniques, including, but not limited to, resolution of racemic forms, normal-phase, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, etc., or by chiral synthesis from any chiral starting material, or by intentional synthesis of the targeted chiral center.

[0044] The compounds of the present invention can be prepared by a variety of synthetic routes. The reagents and starting materials are commercially available or readily synthesized by well-known methods by one of ordinary skill in the art. Unless otherwise indicated, all alternatives are as previously defined.

[0045] In the reactions described hereinafter, reactive functional groups, such as hydroxy, keto, amino, imino, thio, or carboxy groups, may need to be protected to avoid their undesired participation in the reaction, if desired in the final product. Conventional protecting groups can be used according to standard practice, see, for example, T.W. Greene and P.G.M. Butts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991; J.F.W.M. Comie in Protective Groups in Organic Chemistry, Plenum Press, 1973.

[0046] Some reactions can be carried out in the presence of a base. There are no particular restrictions on the nature of the base used in this reaction, and any base conventionally used in this type of reaction can be used here as well, provided that it does not adversely affect other parts of the molecule. Examples of suitable bases include sodium hydroxide, potassium carbonate, triethylamine, alkali metal hydrides such as sodium hydride and potassium hydride, alkyl lithium compounds such as methyl lithium and butyl lithium, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide.

[0047] The reaction is usually carried out in a suitable solvent. A variety of solvents can be used provided that they do not adversely affect the reaction or the reagents involved. Examples of suitable solvents include hydrocarbons, which may be aromatic, aliphatic, or alicyclic hydrocarbons, such as hexane, cyclohexane, methylcyclohexane, toluene, and xylene; amides, such as N,N-dimethylformamide; alcohols, such as ethanol and methanol; and ethers, such as diethyl ether, methyl tert-butyl ether, methylcyclopentyl ether, and tetrahydrofuran.

[0048] The reaction can take place over a wide range of temperatures. In general, the inventors have found it convenient to carry out the reaction at temperatures between 0°C and 150°C (more preferably, between about room temperature and 100°C). The time required for the reaction can also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a time period of 3 to 20 hours is usually sufficient, provided that the reaction is carried out under the preferred conditions described above.

[0049] The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compound can be recovered by distilling off the solvent from the reaction mixture, or, if necessary, by distilling off the solvent from the reaction mixture, pouring the residue into water, then extracting with a water-immiscible organic solvent and distilling off the solvent from the extract. Furthermore, if desired, the product can be further purified by various well-known methods such as recrystallization, reprecipitation, or various chromatographic methods, especially column chromatography or preparative thin-layer chromatography.

[0050] Typically, the enantiomers of formula (II) of the present invention can be prepared by enantiomeric separation of the corresponding racemic mixture.

[0051] Separation of the two enantiomers can be achieved by chiral chromatography, including simulated moving bed chromatography, salt formation with chiral reagents, diastereomeric formation with chiral counterparts, and preferential crystallization.

[0052] Racemic mixtures of compounds of formula (II) can be prepared by application of the method disclosed in WO2012 / 041860. More specifically, these compounds have the following formula (III): [ka] (wherein X, R1, R2, R3, and R4 are defined as in general formula (II)). The compound of formula (IV): [ka] The compound can be prepared according to the embodiment by etherifying with a compound of formula (I).

[0053] The etherification reaction can be carried out in an inert solvent (toluene, chlorobenzene, dichloroethane) in an acidic medium (toluenesulfonic acid, methanesulfonic acid) at a temperature between room temperature and about 160°C.

[0054] Compounds of formula (III) can be prepared by application of the methods disclosed in WO2012 / 041860.

[0055] Alternatively, according to another embodiment, the compound of formula (I) has the following formula (V): [ka] (wherein R1, R2, R3, R4, and X are defined as in general formula (II)). can be prepared by methylation of the compound

[0056] This methylation can be carried out by reductive methods using a carbonylating compound and a reducing agent such as borohydride, cyanoborohydride, triacetoxyborohydride, hypophosphorous acid, formic acid, formic acid / triethylamine or hydrogen; when hydrogen or a hydrogen donor is used, a catalyst such as palladium can be added for this transformation.

[0057] Compounds of formula (V) can be prepared according to the methods disclosed in WO2012 / 041860.

[0058] Furthermore, compounds of formula (III) can be prepared from compounds of formula (II) by group interconversion or group transformation. Such reactions include, but are not limited to, reactions involving aromatic or heteroaromatic groups, such as halogen exchange reactions, copper-catalyzed ether formation, Sonogashira reaction, Heck reaction, Suzuki reaction, sulfide condensation, triflate substitution with Grignard reagents, copper-catalyzed ether formation, metal-catalyzed aromatic substitution of amines, and aromatic carbonylation reactions; reactions involving reactive groups, such as acylation, alkoxycarbonylation of nitrogen-containing groups, e.g., amines, amidines, guanidines, etc.; substitution of hydroxy with nucleophiles (Mitsunobu reaction, or activation and nucleophilic substitution reactions); hydrogenation of unsaturated groups (alkenyl to alkyl, alkynyl to alkenyl, alkynyl to alkyl); and Staudinger reaction of azido groups.

[0059] The process of the present invention may comprise the additional step of isolating the desired compound of formula (II).

[0060] Starting materials and / or reagents may be commercially available or can be readily prepared by one of ordinary skill in the art by application or adaptation of the procedures disclosed in the experimental section below.

[0061] According to another further object, the present invention further relates to a pharmaceutical composition comprising a compound of formula (II) as defined above, together with a pharmaceutically acceptable excipient.

[0062] The compounds of the present invention are dual antagonists and / or inverse agonists of H1R and H4R, and therefore the pharmaceutical compositions and compounds of the present invention may be useful in the treatment and / or prevention of diseases associated with impaired H1 and / or H4 function, such as inflammatory disorders.

[0063] The diseases include adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, sinusitis, chronic empyema, allergies, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, non-seasonal and seasonal rhinitis, conjunctivitis, allergic conjunctivitis, ocular pruritus, chronic urticaria, eczema, prurigo, skin pruritus, erythema multiforme exudativum, nasal congestion, allergic congestion, disorders of the genitourinary tract, female and male sexual dysfunction, overactive bladder conditions, urinary incontinence, bladder overactivity, benign prostate hypertrophy and lower urinary tract symptoms, etc., skin diseases, dermatitis, atopic dermatitis, and the treatment of psoriasis and skin pruritus, diseases of the cardiovascular system including thromboembolism, atherosclerosis, myocardial infarction, angina pectoris, myocardial ischemia and arrhythmia, peripheral occlusive arterial disease, pulmonary artery obstruction or deep vein thrombosis, hypotension, pulmonary hypertension, malignant hypertension, heart failure, cardiac or renal failure, cerebrovascular accident and renal insufficiency, diseases of the gastrointestinal tract including inflammatory bowel disease, Crohn's disease, ulcerative colitis, autoimmune diseases including rheumatoid arthritis, multiple sclerosis, cancer, pain, lymphoproliferative disorders.

[0064] According to a further object, the present invention further provides a method for manufacturing ... semiconductor device comprising: histamine H1, H2, H3, or H4 receptor antagonists, Leukotriene antagonists, 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase-activating protein (FLAP) antagonists CX1- and α2-adrenergic receptor agonists, vasoconstrictor sympathomimetics for decongestant use Xanthines such as theophylline and aminophylline Nonsteroidal anti-inflammatory drugs such as sodium cromoglycate and nedocromil sodium Ketotifen COX-1 inhibitors (NSAIDs) and selective COX-2 inhibitors Immunosuppressants Mucolytics or antitussives The present invention relates to a combination of compound (II) of the present invention with one or more therapeutic agent(s) selected from:

[0065] More particularly, the present invention further relates to a combination comprising a compound of formula (II) according to the invention and an H1R antagonist such as cetirizine, desloratadine, bepotastine or doxepin.

[0066] According to another further object, the present invention further relates to compounds of formula (II) for treating and / or preventing the above-mentioned conditions.

[0067] According to another further object, the present invention further relates to a method of treatment comprising administering to a patient in need thereof an effective amount of compound (II) of the present invention to treat and / or prevent the above conditions or disorders.

[0068] The compounds of the present invention exhibit interesting dual activity at H1 and H4 human receptors, good safety margins, good bioavailability, and good distribution profiles.

[0069] As used herein, the term "patient" refers to a warm-blooded animal such as a mammal, preferably a human or human child, that is afflicted with or susceptible to one or more of the diseases and conditions described herein.

[0070] As used herein, a "therapeutically effective amount" refers to an amount of a compound of the present invention that is effective in reducing, eliminating, treating, or controlling the symptoms of the diseases and conditions described herein. The term "control" is intended to refer to all processes that may slow, hinder, prevent, or halt the progression of the diseases and conditions described herein, but does not necessarily indicate complete elimination of all disease and condition symptoms, and is intended to include prophylactic treatment and chronic use.

[0071] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound has been modified by making acid or base salts thereof. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and salts prepared from organic acids such as acetic acid, propanoic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, and maleic acid. Still other salts include ammonium salts such as tromethamine, meglumine, and epolamine, and metal salts such as sodium, potassium, calcium, zinc, or magnesium. Hydrochloride and oxalate salts are preferred.

[0072] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is incorporated herein by reference.

[0073] Identification of subjects in need of treatment for the diseases and conditions described herein is well within the ability and knowledge of one of ordinary skill in the art. A clinician skilled in the art can readily identify subjects in need of such treatment through the use of clinical tests, physical examination, and medical / family history.

[0074] A therapeutically effective amount can be readily determined by the attending physician, as one skilled in the art, by the use of conventional methods and by observing results obtained under analogous circumstances. In determining a therapeutically effective amount, the attending physician will take into account several factors, including, but not limited to, the type of subject, its size, age, and general health, the specific disease involved, the relationship or severity of the disease, the responsiveness of the individual subject, the particular compound administered, the mode of administration, the bioavailability characteristics of the administered preparation, the selected dosage regimen, the use of co-agonists, and other relevant circumstances.

[0075] The amount of a compound of formula (II) required to achieve a desired biological effect may vary depending on several factors, including the dose of drug administered, the chemical properties (e.g., hydrophobicity) of the compound utilized, the potency of the compound, the type of disease, the condition of the patient, and the route of administration.

[0076] Generally, for parenteral administration, the compounds of the present invention can be provided in an aqueous physiological buffer solution containing 0.1-10% w / v compound. Typical dosage ranges are 1 μg to 0.1 g per kg of body weight per day, with a preferred dosage range of 0.01 mg to 10 mg per kg of body weight per day. Preferred daily dosages for adults include 1, 5, 50, 100, and 200 mg, with equivalent dosages for pediatrics. The preferred dosage of a drug to be administered will likely depend on variables such as the type and extent of progression of the disease or disorder, the general health of the individual patient, the relative biological availability of the selected compound, and the compound's excipient formulation and its route of administration.

[0077] The compounds of the present invention can be administered in unit dosage form, where the term "unit dose" refers to a single dose that can be administered to a patient and easily processed and packaged as a physically and chemically stable unit dose containing the active compound itself or as a pharmaceutically acceptable composition as described hereinafter. Thus, a typical daily dose range is 0.01 mg to 10 mg per kg of body weight. As a general guideline, a unit dose for humans is 0.1 mg to 1000 mg per day. The unit dose range is preferably 1 to 500 mg, administered once to four times daily, with 1 mg to 300 mg once daily being even more preferred. The compounds provided herein can be formulated into pharmaceutical compositions by mixing with one or more pharmaceutically acceptable excipients. Such compositions may be prepared for use in oral administration, particularly in tablet or capsule form, or parenteral administration, particularly in the form of a liquid solution, suspension or emulsion, or intranasal administration, particularly in the form of a powder, nasal drops or aerosol, or dermal administration, for example via a topical or transdermal patch, or ocular administration, or vaginal or intrauterine administration, particularly in the form of a pessary, or rectal administration.

[0078] The compositions can be conveniently administered in unit dosage form and prepared by any methods well known in the art of pharmacy, for example, as described in Remington: The Science and Practice of Pharmacy, 20th Edition; Gennaro, AR, Ed.; Lippincott Williams and Wilkins: Philadelphia, PA, 2000. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. Oral compositions generally include an inert diluent carrier or an edible carrier.

[0079] Tablets, pills, powders, capsules, troches, etc. may contain one or more of the following ingredients of similar nature or compounds: binders such as microcrystalline cellulose or gum tragacanth; diluents such as starch or lactose; disintegrants such as starch and cellulose derivatives; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate. Capsules may be in the form of hard or soft capsules, generally composed of gelatin compounds optionally containing plasticizers, and starch capsules. Furthermore, unit dosage forms may contain various other substances that modify their physical form, such as sugar coatings, shellac, or enteric agents. Other oral dosage forms, such as syrups or elixirs, may contain sweeteners, preservatives, dyes, colorings, and flavoring agents. Additionally, the active compounds may be incorporated into fast dissolving, slow release, or extended release preparations and formulations, where such extended release formulations are preferably bi-modal.

[0080] Preferred formulations include pharmaceutical compositions in which the compounds of the present invention are formulated for oral or parenteral administration, or more preferably, in which the compounds of the present invention are formulated as tablets. Preferred tablets contain lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc, in any combination. It is also an aspect of the present disclosure that the compounds of the present invention may be incorporated into food or liquids.

[0081] Liquid preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Liquid compositions may also contain binders, buffers, preservatives, chelating agents, sweeteners, flavorings, and colorants. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, acrylate copolymers, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include alcohol and water mixtures, hydrogels, buffered media, and saline. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers, in particular, may be useful excipients for controlling the release of active compounds. Intravenous vehicles may include fluid and nutrient replenishers, electrolyte replenishers such as Ringer's solution, dextrose-based replenishers, and the like. Other useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.

[0082] Other modes of administration include formulations for inhalation, including dry powder, aerosol, or drops. They can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycolate, and deoxycholate, or oil solutions for administration in the form of nasal drops or as gels for intranasal application. Formulations for oral administration include, for example, lozenges or pastilles, and may also contain flavorings such as sucrose or acacia, and other excipients such as glycolate. Formulations suitable for rectal administration are preferably presented as unit-dose suppositories containing a solid base carrier such as cocoa butter and may contain salicylate. Formulations for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers that can be used include petrolatum, lanolin, polyethylene glycol, alcohol, or combinations thereof. Formulations suitable for transdermal administration can be presented as discrete patches and may be lipid-soluble emulsions or buffered aqueous solutions dissolved and / or dispersed in a polymer or adhesive.

[0083] Other administrations include solutions, ointments or other formulations that are acceptable for ophthalmic administration. [Brief explanation of the drawings]

[0084] [Figure 1] FIG. 1 shows the VCD spectra of the two enantiomers of the racemic mixture of Example 1 in CD2Cl2 (half total subtracted). [Figure 2] FIG. 1 shows a comparison of the experimental VCD spectra of the two enantiomers of Example 1 in CD 2 Cl 2 (half-subtracted) with the spectrum calculated for conformer A2 (R enantiomer). [Figure 3] FIG. 1 shows the XRPD of (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride salt, phase I (anhydrous) and phase II (monohydrate). DETAILED DESCRIPTION OF THE INVENTION

[0085] Other features of the present invention will become apparent in the course of the following description of exemplary embodiments, which are given for the purpose of illustrating the invention and are not intended to limit it. [Example]

[0086] Melting points are determined on a Büchi capillary melting point apparatus.

[0087] Proton NMR spectra were recorded on a Varian 400 MHz NMR instrument. Deuterated chloroform was used as the solvent unless otherwise stated. Chemical shift values ​​δ are expressed in ppm. The following abbreviations are used to indicate signal patterns: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, ms = mass. Coupling constants are expressed in Hz. The recorded spectra are consistent with the proposed structures.

[0088] Example 1: (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol The synthesis of racemic 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol is described in patent application WO2012041860 (Example 581).

[0089] To a solution of racemic 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol (6.52 g) in dichloromethane (180 mL) were added trimethylamine (2.86 mL) and (1S)-methyl chloroformate (3.96 mL). The mixture was stirred at room temperature for 2 hours and then diluted with water. The organic phase was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography (Waters, AutoPurification HPLC / MS System, Sunfire Prep C18 OBD 5 μm 30 × 150 mm column, eluent: water / 0.1% formic acid (A) and acetonitrile / 0.1% formic acid (B), isocratic elution with a linear gradient of 73 / 27 A / B for 11 minutes, then 5 / 95 A / B for 4 minutes, sample diluted in methanol, multiple cycles). The second-eluting diastereomeric fraction (retention time 13 min) was collected, treated with sodium bicarbonate, and extracted with ethyl acetate. After drying over magnesium sulfate, the organic phase was concentrated under reduced pressure. The residue was diluted with ethanol and treated with potassium hydroxide (2.0 g) dissolved in water (10 mL) at room temperature for 30 min. After adjusting the pH to approximately 8 with 3 N aqueous HCl followed by aqueous sodium bicarbonate, the aqueous phase was extracted with ethyl acetate. The pooled extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient 95 / 5 / 0.5 to 90 / 10 / 0.5 dichloromethane / methanol / ammonia) to give (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol as a white powder exhibiting the following NMR spectrum: 1 H NMR (MeOD): 7.52 (m,2H), 7.20 (m,2H), 7.16 (m,1H), 7.02 (m,1H), 6.79 (m,1H), 6.25 (s,1H), 3.59 (m,1H), 2.74 (m,2H), 2.25 (s,3H), 2.20 (m,2H), 1.95 (m,2H), 1.78 (m,2H)). Exchangeable protons not reported.

[0090] Chiral HPLC analysis: Analytical Chiralpak AD-H, 250x4.6 mm column. Elution was performed with a mixture of heptane / isopropanol (95 / 5) containing diethylamine (0.1%) at a flow rate of 1 ml / min. The (S) enantiomer has a retention time of 27.7 min (retention time of the (R) enantiomer = 18.6 min). ee = 100%.

[0091] Example 2: (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride, monohydrate A solution of (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol (7.82 g) in acetone (100 mL) was treated with 1 equivalent of 37% hydrochloric acid at room temperature. After vigorously stirring for 3 hours, the solid was filtered, rinsed with acetone, and dried under reduced pressure to give 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride, monohydrate as a white powder exhibiting the following NMR spectrum: 1H NMR (MeOD): 7.55 (m,2H), 7.23 (m,2H), 7.10 (m,1H), 7.08 (m,1H), 6.83 (m,1H), 6.28 (s,1H), 3.89 (m,1H), 3.43-3.20 (ms,4H), 2.84 (s,3H), 2.20-1.90 (ms,4H). Exchangeable protons not reported. XRPD (major peaks, 2θ in °): 13.6, 15.1, 15.6, 16.4, 18.1, 20.3, 22.2, 27.6, 29.0

[0092] Example 3: (S)-2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol

[0093] [ka]

[0094] 3A 2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B was prepared from racemic 2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol and derivatization with (1R)-methyl chloroformate according to Example 1. The first eluting diastereomer was collected during preparative HPLC and then deprotected by treatment with potassium hydroxide to give 2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B as a white powder exhibiting the following NMR spectrum: 1H NMR (MeOD): 7.34 (m,1H), 7.27 (m,1H), 7.22 (m,1H), 7.11 (m,1H), 6.83 (m,1H), 6.79 (m,1H), 6.20 (s,1H), 3.57 (m,1H), 2.71 (m,2H), 2.22 (s,3H), 2.18 (m,2H), 1.93 (m,2H), 1.75 (m,2H). Exchangeable protons not reported.

[0095] Chiral HPLC analysis: Analytical Chiralpak AD-H, 250x4.6mm column. Elution was performed with a mixture of heptane / isopropanol (93 / 7) containing diethylamine (0.1%) at a flow rate of 1 ml / min. Enantiomer B has a retention time of 12.6 min (retention time of enantiomer A = 8.9 min). ee=99%. 3B

[0096] A mixture of 2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)hydroxymethyl]phenol (6.48 g), 4-hydroxy-1-methylpiperidine (12.75 g), and p-toluenesulfonic acid monohydrate (29.5 g) in toluene (350 mL) and N-methylpyrrolidone (35 mL) was heated under reflux using a Dean-Stark apparatus until complete conversion (1.5 h). Water was then added, and the mixture was vigorously stirred. After filtration of the insoluble material and adjustment of the pH to around 9, the aqueous phase was extracted several times with ethyl acetate. The recombined organic phase was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient 95 / 5 / 0.5 to 90 / 10 / 0.5 dichloromethane / methanol / ammonia) to give racemic 2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol as an off-white solid that melted at 144 °C.

[0097] 3C To a solution of 5-chloro-4-fluoro-1-(pyrrolidin-1-ylmethyl)-1H-benzimidazole (5.50 g) in tetrahydrofuran (30 mL) was added a 2 M solution of lithium diisopropylamide (19.4 mL) at −78°C and stirred at this temperature for 2 h. A cooled mixture of salicylaldehyde (4.58 g) and a 2 M solution of lithium diisopropylamide (20 mL) in tetrahydrofuran (30 mL) was then added. The mixture was stirred at −78°C for 50 min and then warmed to −10°C over 15 min. After hydrolysis with saturated aqueous ammonium chloride and adjustment of the pH to around 6 with concentrated hydrochloric acid, the organic phase was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by refluxing in dichloromethane for 15 min. After cooling, the solid was filtered to give 2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)hydroxymethyl]phenol.

[0098] 3D A solution of 5-chloro-4-fluoro-1H-benzimidazole (10.7 g), pyrrolidine (4.68 g), and formaldehyde (37% in water, 5.85 g) in ethanol (100 mL) was refluxed for 100 minutes. After concentration under reduced pressure, the residue was diluted with dichloromethane, dried over magnesium sulfate, and concentrated under reduced pressure to give 5-chloro-4-fluoro-1-(pyrrolidin-1-ylmethyl)-1H-benzimidazole.

[0099] 3E A mixture of 4-chloro-3-fluorobenzene-1,2-diamine (13.9 g) and formic acid (6.84 g) was stirred at 95°C for 35 minutes. After cooling, the mixture was diluted with water and ethyl acetate and acidified to pH 1-2. After filtration, the aqueous phase was washed with ethyl acetate, basified to pH 9-10 with sodium hydroxide, and extracted with ethyl acetate. The pooled extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization in dichloromethane to give 5-chloro-4-fluoro-1H-benzimidazole.

[0100] Example 4: (S)-2-[(4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol

[0101] [ka]

[0102] 4A 2-[(4-Methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B was prepared from racemic 2-[(4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol and derivatization with (1S)-methyl chloroformate according to Example 1. The second eluting diastereomer was collected during preparative HPLC and then deprotected by treatment with potassium hydroxide to give 2-[(4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B as a white powder exhibiting the following NMR spectrum: 1H NMR (MeOD): 7.33 (m,2H), 7.13 (m,1H), 7.09 (m,1H), 6.96 (m,1H), 6.81 (m,1H), 6.79 (m,1H), 6.21 (s,1H), 3.56 (m,1H), 2.70 (m,2H), 2.53 (s,3H), 2.21 (s,3H), 2.17 (m,2H), 1.92 (m,2H), 1.74 (m,2H). Exchangeable protons not reported.

[0103] Chiral HPLC analysis: Analytical Chiralpak AD-H, 250x4.6 mm column. Elution was performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1%) at a flow rate of 1 ml / min. Enantiomer B has a retention time of 8.4 min (retention time of enantiomer A = 7.2 min). ee = 98%.

[0104] 4B Racemic 2-[(4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol was prepared similarly to Procedures 3B, 3C, 3D, and 3E starting from 2,3-diaminotoluene.

[0105] Example 5: (S)-2-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol

[0106] [ka]

[0107] 5A 2-[(5-Fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B was prepared from racemic 2-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol and derivatization with (1S)-methyl chloroformate according to Example 1. During preparative HPLC, the second eluting diastereomer was collected and then deprotected by treatment with potassium hydroxide to give 2-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B as a white powder exhibiting the following NMR spectrum: 1H NMR (MeOD): 7.46 (m,1H), 7.32 (d,1H), 7.20 (m,1H), 7.12 (m,1H), 6.96 (m,1H), 6.80 (m,2H), 6.19 (s,1H), 3.56 (m,1H), 2.73 (m,2H), 2.23 (s,3H), 2.20 (m,2H), 1.93 (m,2H), 1.75 (m,2H). Exchangeable protons not reported.

[0108] Chiral HPLC analysis: Analytical Chiralpak AD-H, 250x4.6 mm column. Elution was performed with a mixture of heptane / isopropanol (90 / 10) containing diethylamine (0.1%) at a flow rate of 1 ml / min. Enantiomer B has a retention time of 15.6 min (retention time of enantiomer A = 9.5 min). ee = 97%.

[0109] 5B Racemic 2-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol was prepared analogously to Procedures 3B, 3C, 3D, and 3E starting from 1,2-diamino-4-fluorobenzene.

[0110] Example 6: (S)-2-[(4-chloro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol

[0111] [ka]

[0112] 6A 2-[(4-chloro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B was prepared from racemic 2-[(4-chloro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol and derivatization with (1S)-methyl chloroformate according to Example 1. During preparative HPLC, the second eluting diastereomer was collected and then deprotected by treatment with potassium hydroxide to give 2-[(4-chloro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B as a white powder exhibiting the following NMR spectrum: 1H NMR (MeOD): 7.43 (d,1H), 7.34 (d,1H), 7.21-7.10 (ms,3H), 6.85-6.78 (ms,2H), 6.22 (s,1H), 3.59 (m,1H), 2.74 (m,2H), 2.24 (s,3H), 2.22 (m,2H), 1.93 (m,2H), 1.76 (m,2H). Exchangeable protons not reported.

[0113] Chiral HPLC analysis: Analytical Chiralpak AD-H, 250x4.6 mm column. Elution was performed with a mixture of heptane / isopropanol (80 / 20) containing diethylamine (0.1%) at a flow rate of 1 ml / min. Enantiomer B has a retention time of 5.0 min (retention time of enantiomer A = 4.5 min). ee = 97%.

[0114] 6B Racemic 2-[(4-chloro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol was prepared analogously to Procedures 3B, 3C, 3D, and 3E starting from 2,3-diaminochlorobenzene.

[0115] Example 7: (S)-2-[(5-chloro-4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol

[0116] [ka]

[0117] 7A 2-[(5-chloro-4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B was prepared from racemic 2-[(5-chloro-4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol and derivatization with (1R)-methyl chloroformate according to Example 1. During preparative HPLC, the first eluting diastereomer was collected and then deprotected by treatment with potassium hydroxide to give 2-[(5-chloro-4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol enantiomer B as a white powder exhibiting the following NMR spectrum: 1H NMR (MeOD): 7.33 (d,1H), 7.30 (d,1H), 7.18 (d,1H), 7.12 (m,1H), 6.83-6.78 (ms,2H), 6.21 (s,1H), 3.56 (m,1H), 2.72 (m,2H), 2.56 (s,3H), 2.22 (s,3H), 2.17 (m,2H), 1.92 (m,2H), 1.76 (m,2H). Exchangeable protons not reported.

[0118] Chiral HPLC analysis: Analytical Chiralpak AD-H, 250x4.6 mm column. Elution was performed with a mixture of heptane / isopropanol (95 / 5) containing diethylamine (0.1%) at a flow rate of 1 ml / min. Enantiomer B has a retention time of 13.9 min (retention time of enantiomer A = 12.2 min). ee = 97%.

[0119] 7B Racemic 2-[(5-chloro-4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol was prepared analogously to Procedures 3B, 3C, 3D, and 3E starting from 6-chloro-2,3-diaminotoluene.

[0120] Example 8: (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride Approximately 2900 ml of acetone and 112 g of (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol (base) were charged to a reaction vessel. The mixture was warmed to approximately 40°C and stirred until the starting material dissolved. The solution was then filtered to remove any insoluble or extraneous particles. The temperature of the filtrate was adjusted to approximately 30°C, and approximately 47.5 g of HCl / MeOH (assay 26.4%, 1.1 equivalents) was added at 32-34°C over a period of 15-25 minutes. The mixture was stirred for 1-2 hours, filtered at 25-30°C, and washed with approximately 1000 ml of acetone. Five batches were finally mixed by stirring them at room temperature with 1750 ml of acetone for approximately 1 hour. The product was filtered and washed with 250 ml of acetone. Finally, the product was dried under reduced pressure at 45°C. Enantiomeric purity as determined by chiral HPLC (as in Example 1): 99.8% Assay by titration: 99.3% Acetone content by GC headspace: 0.3% XRPD (major peaks, 2θ in °): 8.6, 12.4, 13.1, 15.9, 16.8, 19.9, 20.4, 21.3, 23.4, 25.0, 25.7, 26.3, 26.9, 28.4, 30.1

[0121] Example 9: (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, (R)-p-methylmandelate A suspension of racemic 2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol (64.7 g) in methanol (450 mL) was warmed to reflux and then dissolved in methanol (150 mL) to give (R)-p- Methylmandelic acid (18.1 g). After refluxing for 2 hours, the mixture was cooled to room temperature and the white solid was filtered. Several recrystallizations were performed to give optically pure (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, (R)-p-methylmandelate, which exhibited the following NMR spectrum: 1H NMR (DMSO-d6): 12.45 (large s, 1H), 7.50 (m, 2H), 7.25 (d, 2H), 7.20 (d, 1H), 7.14 (m, 2H), 7.12-7.06 (ms, 3H), 6.82 (m, 1H), 6.11 (s, 1H), 4.77 (s, 1H), 2.75 (m, 2H), 2.32-2.20 (ms, 8H), 1.87 (m, 2H), 1.63 (m, 2H). Exchangeable protons not reported.

[0122] Example 10: (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride, monohydrate (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, (R)-p-methylmandelate (36.7 g) was diluted with water and aqueous sodium hydroxide. Ethyl acetate was then added and the pH was adjusted to approximately 8.5. After extracting the aqueous phase with ethyl acetate (5 times), the pooled extracts were dried over magnesium sulfate and concentrated under reduced pressure to give (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol as an off-white solid. After treatment with acetone (330 mL) and concentrated hydrochloric acid (1 equivalent) and vigorous stirring for 3 hours, the solid that formed was filtered, rinsed with acetone, and dried under reduced pressure to give (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride, monohydrate as a white solid exhibiting the following NMR spectrum: 1H NMR (MeOD): 7.55 (m, 2H), 7.23 (m, 2H), 7.10 (m, 1H), 7.08 (m, 1H), 6.83 (m, 1H), 6.28 (s, 1H), 3.89 (m, 1H), 3.43-3.20 (ms, 4H), 2.84 (s, 3H), 2.20-1.90 (ms, 4H). Exchangeable protons are not reported. XRPD (major peaks, 2θ in °): 6.3, 11.0, 13.7, 15.1, 15.7, 16.4, 18.1, 20.3, 22.1, 24.4, 27.6, and 29.1

[0123] Example 11: Experimental Infrared (IR) and Vibrational Circular Dichroism (VCD) Measurements IR and VCD spectra were collected using a 3000 scan, 4cm -1 Resolution, 1050~1700cm -1The spectra were recorded on an FVS-6000 VCD spectrometer in the 1000 Hz region. Samples of the distomer of Example 1 (20.8 mg in 400 μL of CD2Cl2) and Example 1 (14.06 mg in 300 μL of CD2Cl2) were placed in 200 μm pathlength cells with BaF2 windows. An overlay of the IR spectra observed for the two enantiomers is shown in Figure 1. They show identical IR peaks, with slightly higher intensity for the distomer of Example 1 due to its higher concentration. Figure 2 shows the solvent-subtracted experimental VCD spectra for the two enantiomers of Example 1 and the distomer of Example 1. Despite the slope of the baseline, the VCD spectra show the expected mirror-image relationship. To eliminate possible artifacts and the slope of the VCD baseline, the two VCD spectra were half-subtracted, as shown in Figure 1.

[0124] The absorption regions corresponding to the solvent were also removed. These are two common operations.

[0125] Calculating VCD Theoretical calculations were performed with Gaussian 09 software. Vibrational circular dichroism spectra were obtained by TD-DFT using the B3LYP functional and the 6-311G(d,p) basis set.

[0126] The R enantiomer was selected for the calculations. Theoretical VCD spectra were calculated for each possible conformer. Conformational analysis revealed the presence of two major conformers, designated A2 and B, at 96.1% and 3.6%, respectively. Four other conformers were found, but they represented a distribution of less than 0.3% and were therefore not considered in the calculations.

[0127] For each conformer A2 and B, three steps were performed: i) DFT optimization using Gaussian09-B3LYP-6-311G(d,p), ii) IR / VCD calculations using TDDFT using Gaussian09-B3LYP-6-311G(d,p), and iii) the calculated frequencies were multiplied by 0.97 to match the experimental values.

[0128] A comparison of the experimental VCD spectrum and the theoretical VCD spectrum of the most abundant conformer A2 is shown in Figure 2 .

[0129] The calculated spectrum is in excellent agreement with the experimental spectrum corresponding to the distomer sample from Example 1. VCD peaks with the same sign in experiment and theory are highlighted with arrows.

[0130] The theoretical VCD spectrum of conformer B was compared with the experimental VCD spectrum. The calculated spectrum matches the experimental VCD spectrum of the distomer sample in Example 1, especially with respect to the peaks highlighted by arrows. However, the match is not as good as that of conformer A2.

[0131] conclusion The very good agreement obtained by comparing the experimental VCD spectrum of the enantiomeric sample distomer of Example 1 with the calculated VCD spectrum of the R enantiomer in its most abundant (96%) conformer, A2, allows the absolute configuration R for the distomer of Example 1 and S for Example 1 to be determined with high confidence. Furthermore, this VCD study confirms the fact that in CD2Cl2 solution, the molecule exists exclusively in its A2 conformation.

[0132] As a result, the absolute configuration of Examples 1, 2, 8, 9, 10, and 12 is (S).

[0133] Example 12: Polymorphs Many phases and polymorphs have been found for (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol hydrochloride. The more stable phases are phase I, which corresponds to the anhydrous hydrochloride salt, and phase II, which corresponds to the hydrochloride monohydrate.

[0134] The samples are analyzed by powder X-ray diffraction in transmission mode (the sample is placed between Kapton® and polypropylene foil). Scan range: 2°~50° Step size 0.026° Acquisition time 20.4 seconds 20 scans

[0135] The diffractometer is an X'Pert PRO MPD Panalytical. The beam characteristics are as follows:

[0136] [Table 3]

[0137] The powder X-ray diffraction pattern is shown in FIG.

[0138] XRPD allows a full characterization of these two phases.

[0139] Phase I and Phase II each contain the following characteristic peaks by XRPD: XRPD of Phase I (characteristic peaks, 2θ in °): 8.6, 12.4, 13.1, 15.9, 16.8, 18.8, 19.9, 20.4, 21.3, 23.4, 25.0, 25.7, 26.3, 26.9, 28.4, and 30.1 XRPD of Phase II (characteristic peaks, 2θ in °): 6.3, 13.7, 15.1, 15.7, 16.4, 20.3, 22.1, 24.4, and 29.1

[0140] Example 13: Biological Data Example 13a: H1-H4 Bond The aforementioned property of the eutomers to recognize both receptors is shown in the table below. Activity at the human H1 receptor is measured by inhibition of agonist-induced stimulation of radioactive GTP-γ-S binding at the recombinant receptor. The activity is reported as a constant, Kb, with the lowest values ​​being the most potent. Affinity for the human H4 receptor is measured by binding competition. The affinity is reported as Ki, with the lowest values ​​being the most potent.

[0141] [Table 4A]

[0142] [Table 4B]

[0143] It is common for one enantiomer to exhibit higher affinity for a receptor than its mirror image. However, it was unexpected that an enantiomer with high affinity for the H4 receptor would also exhibit high affinity for the H1 receptor. This completely unexpected property is particularly intriguing because dual H1R-H4R receptor ligands have been sought for many years, but none have reached the clinical field, and only a few have been disclosed. Finding equivalently potent dual H1R-H4R ligands is known to be extremely difficult: "The amino acids forming the orthosteric binding pockets of hH1R and hH4R have minimal identity when compared with the human histamine receptor, making it potentially very difficult to develop ligands with equivalent affinities for hH1R and hH4R" (SG Hammer et al., Bioorg. Med. Chem. Lett. 26; 2016; pp. 292-300). The cited publication discloses ligands that exhibit micromolar affinity for both receptors. These very weak affinities make these compounds unsuitable for clinical development. The compounds of the present application exhibit nanomolar, i.e., thousand-fold stronger, affinities for both receptors.

[0144] Example 13b: hERG Binding Compounds that are antagonists or inverse agonists at the human H1 receptor bind to the hERG channel and are often found to cause arrhythmias that can lead to sudden cardiac arrest. This has led to the withdrawal of several drugs from the clinic. Therefore, this parameter was evaluated for the compounds of the present application.

[0145] It has been surprisingly discovered that the aforementioned eutomer represented by general formula (II) is the enantiomer that recognizes the hERG channel with the least affinity. This property is completely unexpected, since a recent publication (Bagdanoff et al., J. Med. Chem., 2015, 58(15), pp. 5781-5788) has shown that both enantiomers usually exhibit equal affinity for the hERG channel.

[0146] The differential recognition of the hERG channel by eutomers versus distomers is shown in the table below, with reported values ​​being inhibition constants determined by competitive binding.

[0147] [Table 5]

[0148] This property is not shared by structurally closely related compounds represented by general formula (I) of WO2012 / 041860 but not encompassed by general formula (II) of the present invention, as shown in the table below.

[0149] Comparative compounds of WO2012 / 041860: [Table 6]

[0150] The property of one single enantiomer recognizing both human H1 and human H4 receptors, together with its demonstrated tendency to efficiently discriminate between hERG channels, is therefore entirely unexpected and of great pharmaceutical interest.

[0151] As a result of these unexpected properties, the compounds of the present application exhibit outstanding properties in vitro. The compounds of the present application are potent antagonists or inverse agonists at both H1 and H4 human histamine receptors with low nanomolar or subnanomolar affinity. The compounds of the present application exhibit high selectivity for the hERG channel with respect to these receptors, with ratios ranging from 1600 to 129000. These properties are of paramount importance for pharmaceuticals, as they should result in compounds with a high safety margin.

[0152] Example 13c: In vivo testing Brain exposure : Compounds that act as antagonists or inverse agonists of histamine H1 receptors cannot enter the brain, which can lead to undesirable side effects such as sedation and weight gain. The efficiency of brain entry can be evaluated by orally administering the compound to mice and measuring the exposure in the brain and plasma for 8 hours. The results can be expressed as the ratio of exposure in the brain to that in plasma.

[0153] This property was compared between the compounds of the present invention and some comparative compounds from WO2012 / 041860.

[0154] Comparative compounds of WO2012 / 041860: [Table 7]

[0155] The results of the examples of the present invention are reported in the table below. [Table 8]

[0156] The ratio of brain to plasma exposure for the compounds of the present invention is clearly less than 1. This indicates that the compounds of the present invention do not significantly enter the brain. This property is groundbreaking in that it has not been previously suggested and is not shared by the compounds of patent application WO2012 / 041860, many of whose compounds were found to largely enter the brain.

[0157] Bioavailability Furthermore, compounds of the present invention were found to be bioavailable when administered orally to mice. Concentrations in the lungs were found to be interestingly high. This can be shown as cumulative exposure and area under the curve in the pharmacokinetic studies, as reported in the tables below.

[0158] [Table 9]

[0159] These in vivo results demonstrate that the compounds of the present application are well absorbed and do not efficiently cross the blood-brain barrier, but are efficiently distributed in therapeutically relevant organs such as the lung.

Claims

1. The (S) enantiomer of formula (II): 【Chemical 1】 During the ceremony, 【Chemistry 2】 represents an asymmetric carbon exhibiting (S) stereochemistry; X represents H or F; R1, R2, R3, and R4 are the same or different and independently represent H, halogen, alkyl, or alkoxy; At least one of X, R1, R2, R3, and R4 does not represent H; and pharmaceutically acceptable salts, tautomers, hydrates, and solvates thereof.

2. X represents F; R1, R2, R3, and R4 are the same or different and independently represent H, halogen, alkyl, or alkoxy; The (S) enantiomer of claim 1.

3. (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol (S)-2-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride, monohydrate (S)-2-[(5-chloro-4-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(4-chloro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(5-chloro-4-methyl-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenol (S)-2-[(1H-Benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, hydrochloride (S)-2-[(1H-benzoimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol, (R)-para-methylmandelic acid 3. The (S) enantiomer of claim 1 or 2, selected from the group consisting of:

4. A process for preparing the (S) enantiomer of formula (II) according to any one of claims 1 to 3, comprising a step of enantiomer separation of the corresponding racemic mixture.

5. the racemic mixture, - Formula (III): 【Chemistry 3】 (wherein X, R1, R2, R3, and R4 are as defined in claim 1 or 2). of the compound of formula (IV): 【Chemistry 4】 etherification with the compound or - Formula (V): 【Chemistry 5】 (wherein X, R1, R2, R3, and R4 are as defined in claim 1 or 2). Methylation of the piperidine nitrogen of the compound The method according to claim 4, wherein the compound is produced by any one of the following methods.

6. Inflammatory disorders, female and male sexual dysfunction, disorders of the genitourinary tract such as overactive bladder conditions, urinary incontinence, bladder overactivity, benign prostatic hyperplasia and lower urinary tract symptoms, dermatitis, atopic dermatitis, and skin diseases such as psoriasis and skin pruritus, pruritus, skin incision model of postoperative pain, allergic skin disease / pruritus and inflammation, allergic contact dermatitis, pruritus associated with liver or kidney failure, thromboembolism, atherosclerosis, myocardial infarction, angina pectoris, myocardial ischemia, cardiac arrhythmias, peripheral occlusive arterial disease, pulmonary artery obstruction, deep vein thrombosis, hypotension, pulmonary hypertension, angioedema, malignant hypertension, heart failure, cardiac or 4. A pharmaceutical composition comprising the (S) enantiomer of any one of claims 1 to 3 for use in the treatment and / or prevention of diseases of the cardiovascular system, including renal failure, cerebrovascular accidents and renal insufficiency, diseases of the gastrointestinal tract, including inflammatory bowel disease, Crohn's disease, ulcerative colitis, intestinal anaphylaxis, food allergies, post-inflammatory irritable bowel syndrome, peritonitis, autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, lupus, osteoarthritis, joint pain, systemic inflammation, cancer, pain, neuropathic pain, chronic eosinophilia, chronic diseases associated with mast cell proliferation, lymphoproliferative disorders.

7. 7. The pharmaceutical composition of claim 6, wherein the inflammatory disorder is selected from anaphylactic shock, respiratory inflammatory and allergic diseases, adult respiratory distress syndrome, acute respiratory distress syndrome, respiratory infections, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, rhinorrhea, chronic empyema, allergies, allergy-induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, non-seasonal and seasonal rhinitis, conjunctivitis, allergic conjunctivitis, otitis, nasal polyps, cough, ocular pruritus, chronic urticaria, eczema, prurigo, skin pruritus, erythema multiforme exudativum, nasal congestion, and allergic congestion.

8. A pharmaceutical composition comprising the (S) enantiomer of any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

9. A combination comprising the (S) enantiomer according to any one of claims 1 to 3 and an H1R antagonist.

10. A crystalline form of (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol in the hydrochloride salt anhydrous (Form I) form, characterized by the following powder X-ray diffraction peaks (characteristic peaks, in degrees 2θ): 8.6, 12.4, 13.1, 15.9, 16.8, 18.8, 19.9, 20.4, 21.3, 23.4, 25.0, 25.7, 26.3, 26.9, 28.4, and 30.

1.

11. A crystalline form of (S)-2-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-6-fluorophenol in the hydrochloride salt monohydrate (Form II) form, characterized by the following X-ray powder diffraction peaks (characteristic peaks, in degrees 2θ): 6.3, 13.7, 15.1, 15.7, 16.4, 20.3, 22.1, 24.4, and 29.1.

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