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    • 专利摘要:
    The present invention is a compound of formula (I) having a gastric recessive activity; Prodrugs, N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof. In the treatment of dyspepsia, irritable bowel syndrome and injuries associated with damaged or injured gastrointestinal relaxation, disclosed methods of preparation of the product, preparations comprising the product and its use as a medicament: Where A is a bivalent radical from a saturated or unsaturated homo-piperidinyl (here having one double bond, R 2 a divalent radical A is a hydrogen, hydroxy, C 1-4 alkyl, or C 1-4 alkyloxy Substituted); -a 1 = a 2 -a 3 = a 4 -represents an optionally substituted divalent radical; R 1 is hydrogen, C 1-6 alkyl, aryl 1 , C 1-6 alkyl substituted with aryl 1 , C 1-4 alkyloxycarbonyl, aryl 1 carbonyl, aryl 1 C 1-6 alkylcarbonyl, aryl 1 carbonylC 1-6 alkyl, aryl 1 oxycarbonyl, aryl 1 C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, trifluoromethyl, trifluoromethylcarbonyl, C 1-6 Alkylsulfonyl, aryl 1 sulfonyl, methanesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, or dimethylsulfamoyl; X is O, S, or NR 3 , wherein R 3 is hydrogen, C 1-6 alkyl, methanesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, dimethylsulfamoyl, aryl 2 carbonylC 1- 4 alkyl, C 1-4 alkyloxycarbonyl, aryl 2 and optionally with hydroxy substituted C 1-4 alkyl, or an aryl substituted by two C 1-4 alkyl-carbonyl C 1-4 alkyl; aryl 1 Optionally substituted phenyl, optionally substituted pyridinyl, naphthyl, quinolinyl, or 1,3-benzodioxolyl; aryl 2 is optionally substituted phenyl.
    公开号:KR20020062643A
    申请号:KR1020027006004
    申请日:2000-12-14
    公开日:2002-07-26
    发明作者:얀센프란스에두아르드；귈레몽제롬에밀조오지；솜멘프랑스와마리아
    申请人:얀센 파마슈티카 엔.브이.；
    IPC主号:
    专利说明:

    Substituted homopiperidinyl benzimidazole analogues as fundic relaxants
    [2] EP-A-0,079,545 discloses piperazinyl substituted benzimidazole derivatives having antihistamine activity.
    [3] Unexpectedly, it has been found that the novel compounds of formula (I) of the present invention have gastric releasing activity and are therefore useful for alleviating symptoms caused by impaired gastric rot on food intake.
    [4] The present invention relates to compounds of formula (I), their prodrugs, N-oxides, addition salts, quaternary amines and stereochemically isomeric forms:
    [5]
    [6] Where
    [7]
    [8] (Wherein R 2 is hydrogen, hydroxy, C 1-4 alkyl, or C 1-4 alkyloxy, and when R 2 is hydroxy or C 1-4 alkyloxy, R 2 is α of ring nitrogen When bonded at a position other than the -position, or when R 2 is hydroxy, R 2 is a radical (a-2), (a-3), (a-4), (a-5), (a-6) , (a-7), (a-8), (a-9), (a-10), (a-11), or (a-12) to bind at a position other than the vinyl position);
    [9] -a 1 = a 2 -a 3 = a 4 -is
    [10]
    [11] 2 represents a radical
    [12] Wherein each hydrogen atom in the radicals (b-1) to (b-11) is optionally halo, C 1-6 alkyl, nitro, amino, hydroxy, C 1-6 alkyloxy, polyhaloC 1- 6 alkyl, carboxyl, aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, mono- or di (C 1-4 alkyl) aminoC 1-6 alkyl, C 1-6 alkyloxycarbonyl Or;
    [13] Two hydrogen atoms on adjacent carbon atoms in the radicals (b-1) to (b-11) may optionally be replaced by — (CH 2 ) 4 —;
    [14] R 1 is hydrogen, C 1-6 alkyl, aryl 1 , C 1-6 alkyl substituted with aryl 1 , C 1-4 alkyloxycarbonyl, aryl 1 carbonyl, aryl 1 C 1-6 alkylcarbonyl, aryl 1 carbonylC 1-6 alkyl, aryl 1 oxycarbonyl, aryl 1 C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, trifluoromethyl, trifluoromethylcarbonyl, C 1-6 Alkylsulfonyl, aryl 1 sulfonyl, methanesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, or dimethylsulfamoyl;
    [15] X is O, S, or NR 3 (wherein R 3 is hydrogen; C 1-6 alkyl; methanesulfonyl; benzenesulfonyl; trifluoromethanesulfonyl; dimethylsulfamoyl; aryl 2 carbonylC 1- 4 alkyl; C 1-4 alkyloxycarbonyl; aryl 2 and optionally substituted C 1-4 alkyl hydroxy, aryl or the two C 1-4 alkyl substituted with a carbonyl C 1-4 alkyl), and;
    [16] Aryl 1 is phenyl; Phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, nitro, amino, cyano, and trifluoromethyl; Pyridinyl; Pyridinyl substituted with 1, 2, or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, amino, and diC 1-4 alkylamino; Naphthyl; Quinolinyl; 1,3-benzodioxolyl; Furanyl; Thienyl; Or benzofuranyl;
    [17] Aryl 2 is phenyl or 1, 2 or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, nitro, amino, cyano, and trifluoromethyl Substituted phenyl.
    [18] In all compounds of formula (I) the substituent R 1 is divalent To the ring nitrogen source of radicals.
    [19] The term prodrug, as used throughout this specification, means pharmacologically acceptable derivatives such as esters and amides, and the resulting biological transformation product of the derivative is the active drug as defined in the compound of formula (I). Goodman and Gilman, who describe prodrugs in general, The Pharmacological Basis of Therapeutics, 8 th ed., Mcgraw-hill, Int. Ed. 1992, "Biotrasformation of Drugs", p. 13-15].
    [20] As used in the above definitions, the term halogen is a generic name of fluoro, chloro, bromo and iodo; C 1-4 alkyl means straight and branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl and the like; C 1-6 alkyl includes C 1-4 alkyl and its higher homologues having 5 or 6 carbon atoms, for example 2-methylbutyl, pentyl, hexyl and the like; C 1-6 alkyl is, for a polyester for a C 1-6 alkyl, such as substituted poly be substituted with a halogen atom of not more than 1 to 6, difluoro-defines methyl or trifluoromethyl. Hydroxy-C 1-6 alkyl refers to C 1-6 alkyl substituted with hydroxy groups. AminoC 1-6 alkyl refers to C 1-6 alkyl substituted with an amino group. The term "sulfonyl" refers to the -SO 2 -group and "dimethylsulfamoyl" refers to the (CH 3 ) 2 N-SO 2 -group.
    [21] For therapeutic use, the salts of the compounds of formula (I) are those in which the counterions are pharmaceutically acceptable. However, non-pharmaceutically acceptable acids and base salts may also find use, for example, in the manufacture or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or unacceptable, are included within the scope of the present invention.
    [22] Pharmaceutically acceptable acid addition salts are meant to include therapeutically active non-toxic acid addition salt forms which compounds of formula (I) can form. Pharmaceutically acceptable acid addition salts can usually be obtained by treating the base form with an appropriate acid. Suitable acids, such as inorganic acids, such as hydrochloric acid, such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; Or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (ie ethanedioic acid), malonic acid, succinic acid (ie butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, Acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, cyclic acid, salicylic acid, p -aminosalicylic acid, palm acid and the like.
    [23] In contrast, the salt forms mentioned can be converted to the free base form by treatment with an appropriate base.
    [24] The term addition salt also includes solvates which the compounds of formula (I) and salts thereof may form. Such solvates are, for example, hydrates, alcoholates and the like.
    [25] As used herein, quaternary amines of compounds of formula (I) include basic nitrogens of compounds of formula (I) and suitable quarternizing agents such as optionally substituted C 1-6 alkyl halides, By phenylmethylhalide, for example methyl iodide or benzyl iodide, it is meant that compounds of formula (I) can be formed. Other reactants with good leaving groups can also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. Ion exchange resin columns can be used to select specific counterions.
    [26] The N-oxide form of the compound of formula (I), which may be prepared by methods known in the art, means a compound of formula (I) in which the nitrogen atom is oxidized to N-oxide.
    [27] The term "stereochemically isomeric form" as used herein is defined as all possible isomeric forms that a compound of formula (I) may have. Unless otherwise stated or defined, the chemical names of compounds refer to mixtures of all possible stereocompatible isomeric forms, which mixtures include all diastereomers and / or enantiomers of the basic molecular structure. More particularly, the stereocenter can have an R- or S-configuration; Substituents on saturated divalent cyclic (partially) radicals may have cis- or trans-coordination. Compounds having a double bond may have an E or Z-stereochemistry at the double bond. Stereochemically isomeric forms of the compounds of formula (I) are included within the scope of the present invention. Unless otherwise stated or defined, the chemical names of compounds refer to all possible stereoisomeric forms, which are mixtures comprising all diastereomers and enantiomers of the basic molecular structure. This material is used as an intermediate as described herein, which is used to prepare the final product of formula (I).
    [28] As used herein, the terms sheet and trans are according to chemical nomenclature and refer to the position of the ring site, in particular the homopiperidinyl cyclic substituent in the compound of formula (I).
    [29] The absolute stereochemical configuration of some compounds of formula (I) and the intermediates used in their preparation have not been determined experimentally. In this case, the first separated stereochemically isomeric form was referred to as "A" and the second separated "B" without further reference to the actual stereochemically isomeric form. However, where "A" and "B" have an enantiomeric relationship, "A" and "B" can be clearly characterized by their optical rotation, for example. One skilled in the art can determine the absolute configuration of the compounds using known methods, such as X-ray fractionation.
    [30] The first group of compounds
    [31] R 1 is hydrogen, C 1-6 alkyl, aryl 1 , C 1-6 alkyl substituted with aryl 1 , C 1-4 alkyloxycarbonyl, aryl 1 carbonyl, aryl 1 C 1-6 alkylcarbonyl, C 1-4 alkylcarbonyl, trifluoromethyl, trifluoromethylcarbonyl, C 1-6 alkylsulfonyl, aryl 1 sulfonyl, methanesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, or dimethyl Sulfamoyl;
    [32] R 3 is hydrogen, C 1-6 alkyl, methanesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, dimethylsulfamoyl, aryl 2 and C 1-4 alkyl optionally substituted with hydroxy, or aryl 2 Substituted C 1-4 alkylcarbonylC 1-4 alkyl;
    [33] Aryl 1 is phenyl; Phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, nitro, amino, cyano, or trifluoromethyl; Pyridinyl; Pyridinyl substituted with 1, 2, or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, amino, diC 1-4 alkylamino; Naphthyl; Quinolinyl; 1,3-benzodioxolyl.
    [34] Compounds of interest are compounds of formula (I), wherein X is NR 3 , wherein R 3 is C 1-4 alkyl substituted with hydrogen, dimethylsulfamoyl, or aryl 2 .
    [35] Other compounds of interest are divalent radicals A compound of formula (I) which is a radical of the formula (a-1), (a-3) or (a-4), wherein R 2 is hydrogen or hydroxy.
    [36] Certain compounds have a divalent radical -a 1 = a 2 -a 3 = a 4 -valent formula (b-1) wherein each hydrogen atom in the radical (b-1) is halo, C 1-6 alkyl, Hydroxy, or optionally substituted with C 1-6 alkyloxy).
    [37] Another specific compound is a divalent radical -a 1 = a 2 -a 3 = a 4 -valent formula (b-2), wherein each hydrogen atom in the radical (b-2) is halo, C 1-6 Optionally substituted with alkyl, hydroxy, or C 1-6 alkyloxy).
    [38] Another specific compound is a divalent radical -a 1 = a 2 -a 3 = a 4 -valent formula (b-4), wherein each hydrogen atom in the radical (b-4) is halo, C 1-6 Optionally substituted with alkyl, hydroxy, or C 1-6 alkyloxy).
    [39] Another specific compound is a divalent radical -a 1 = a 2 -a 3 = a 4 -valent formula (b-5), wherein each hydrogen atom in the radical (b-5) is halo, C 1-6 Optionally substituted with alkyl, hydroxy, or C 1-6 alkyloxy).
    [40] Preferred compounds of formula (I) are those of formula (I) wherein the radical R 1 is hydrogen, C 1-6 alkyl, phenylmethyl, or furanylmethyl.
    [41] The compounds of the present invention are usually used in the presence of polyphosphoric acid (PPA) or phosphorus oxychloride (POCl 3 ) in the temperature range from room temperature to the reflux temperature of the reaction mixture, or intermediates of formula (II) or functional derivatives thereof such as carboxylic acids Can be prepared by reacting with an intermediate of formula (III), optionally the reaction can be carried out in a reaction inert solvent:
    [42]
    [43] Compounds of formula (Ia), wherein compounds of formula (I) wherein R 2 is hydroxy, can be prepared by reacting an intermediate of formula (IV) with an intermediate of formula (V). Intermediates of formula (IV) are formulas in which two geminal hydrogen atoms have been replaced by carbonyl groups As a derivative of the intermediate of:
    [44]
    [45] Compounds of formula (I) may also be converted to others via reactions or functional group transformations known in the art.
    [46] For example, a compound of formula (I), wherein R 1 is phenylmethyl, is a compound of formula (I) wherein R 1 represents hydrogen by known debenzyl methods in the art. Can be switched. Debenzylation is the main distribution such as catalytic hydrogenation using a suitable catalyst such as platinum on charcoal, palladium on charcoal in a suitable solvent such as methanol, ethanol, 2-propanol, diethyl ether, tetrahydrofuran and the like. It can be carried out according to the known method of.
    [47] Of formula (Ic) compounds (wherein the compound of formula (I) the R 1 represented by R 1 'being other than hydrogen), the compound of formula (Ib) (wherein, the R 1 is hydrogen Formula (I) of Compound) can be prepared by N-alkylation with an alkylating agent of formula (VI):
    [48]
    [49] Formula (VI) and hereinafter W are appropriate leaving groups such as halo, such as chloro, bromo and the like; Or sulfonyloxy groups such as methanesulfonyloxy, 4-methylbenzenesulfonyloxy and the like. The N-alkylation reactions are usually reaction-inert solvents such as aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene and the like; Alkanols such as methanol, ethanol, 1-butanol and the like; Ketones such as 2-propanone, 2-methyl-2-pentanone and the like; Ethers such as tetrahydrofuran, 1,4-dioxane, 1,1'-oxybisethane and the like; Nonpolar aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like; Or in a mixture of the solvents. Suitable bases such as alkali or alkaline earth metal carbonates, hydrogen carbonate, alkoxides, hydrides, amides, hydroxides or oxides such as sodium carbonate, sodium bicarbonate, potassium carbonate, sodium methoxide, sodium ethoxide, Potassium t-butoxide, sodium hydride, sodium amide, sodium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide and the like; Organic bases such as amines such as N, N-diethylethaneamine, N- (1-methylethyl) -2-propanamine, 4-ethylmorpholine, pyridine and the like are added to liberate the reaction process. Acid can be selected. In some cases, addition of iodide salts, preferably alkali metal iodide salts, is appropriate. Rather elevated temperatures and agitation can enhance the reaction rate. In addition, N-alkylation can be carried out using known conditions of phase transfer catalysis.
    [50] In addition, compounds of formula (Ib), wherein compounds of formula (I) wherein R 1 is hydrogen, are alkylated using methods known in the art, for example, N-alkylation with suitable aldehydes or ketones. Or a compound of formula (I) wherein R 1 is hydrogen may be reacted with an acyl halide or acid anhydride.
    [51] In addition, compounds of formula (I), wherein X is NR 3 and R 3 represents methanesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, dimethylsulfamoyl, are known hydrolysis methods, eg For example, it can be converted to a compound of formula (I), wherein X is NH, by treatment with an aqueous acid such as HCl.
    [52] In addition, compounds of formula (I), wherein R 2 represents hydroxy, are treated with sodium hydride in tetrahydrofuran and added to the formula (I) using appropriate alkylation conditions to add C 1-6 alkyliodide. ), Wherein R 2 is C 1-6 alkyloxy.
    [53] Compound of formula (I), wherein divalent radical Represents a radical of the formula (a-1) or (a-7) and R 2 is hydroxy) is a known dehydrogenation method in the art, for example, from room temperature to the reflux temperature of the reaction mixture A compound of formula (I) wherein bivalent radicals are treated with methanesulfonylchloride in a reaction-inert solvent such as CH 2 Cl 2 , or with polyphosphoric acid (PPA) Represents a radical of the formula (a-3), (a-4), (a-8) or (a-9) and R 2 is hydrogen), optionally the reaction is carried out in a reaction-inert solvent Can be performed.
    [54] In contrast, compounds of formula (I) wherein bivalent radicals Represents a radical of the formula (a-2), (a-3), (a-4), (a-5), (a-6), (a-8) or (a-9) and R 2 is Hydrogen) is a compound of formula (I) which is known in the art, for example, by treatment with a suitable catalyst such as palladium on charcoal, rhodium on carbon or , Divalent radical Represents a radical of the formula (a-1) or (a-7) and R 2 is hydrogen).
    [55] Starting materials and some intermediates are known compounds and are commercially available or can be prepared according to conventional reaction methods commonly known in the art. For example, hexahydro-4H-azin-4-one, an intermediate of formula (IV), 1H-benzimidazole and 1H-imidazo [4,5-b] -pyridine, which are intermediates of formula (V) Commercially available.
    [56] The compounds of formula (I) prepared by the process described above can be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another according to known partitioning methods. Racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with appropriate chiral acid. The diastereomeric salt forms mentioned are subsequently separated, for example, by selective or splittable crystallization and the enantiomers are liberated therefrom by alkali. Another method of separating the enantiomeric form of the compound of formula (I) involves liquid phase chromatography using chiral stationary phases. The pure stereochemically isomeric forms mentioned may be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials when the reaction occurs stereospecifically. Preferably, when specific stereoisomers are required, the compounds mentioned will be synthesized by stereospecific methods of preparation. This method is advantageous to use enantiomerically pure starting materials.
    [57] With regard to the ability of the compounds of the present invention to relax the base of the stomach, the target compounds include gastroesophageal reflux, chest pain (including episodic chest pain, nocturnal chest pain, and food-induced chest pain), indigestion, premature satiety, bloat and It is useful for the treatment of symptoms related to loosening of the injured or injured stomach, such as loss of appetite.
    [58] Indigestion is described as an exercise disorder. Symptoms can be caused by delayed gastric emptying, a damaged gastrointestinal tract for food digestion, or hypersensitivity to gastric relaxation. Examples of indigestion are anorexia, satiety, premature satiety, nausea, vomiting, bloat and gas belching.
    [59] Warm-blooded animals, including humans (generally referred to herein as patients) who suffer from indigestion symptoms due to delayed gastric emptying, have normal gastrointestinal relaxation by administration of prokinetic agents such as cisapride and Indigestion symptoms can be alleviated.
    [60] The patient may have indigestion symptoms without impaired gastric emptying. Their indigestion symptoms can be caused from over-shrinkable bottoms that reduce elasticity and cause abnormalities in adaptive bottom relaxation. Indigestion symptoms can also result from hypersensitivity to the base of the stomach.
    [61] The overshrinkable bottom reduces the elasticity of the stomach. "Stomach elasticity" can be expressed as the ratio of the volume of the stomach to the pressure applied to the stomach wall. Stomach elasticity is associated with stomach tension resulting from tension contraction of the proximal stomach muscle fibers. By controlling the tension contraction (gastric tension), the upper part performs the storage action of the stomach.
    [62] Patients suffering from premature satiety feel full before they finish a normal meal, so they cannot eat normally. In general, at the start of a meal, the stomach exhibits adaptive relaxation, ie, the stomach will relax to accommodate food being digested. If the elasticity of the stomach is damaged and the relaxation of the upper base is damaged, this adaptive relaxation is impossible.
    [63] With regard to the use of the compounds of formula (I), the present invention also provides methods for treating warm-blooded animals, including humans (generally referred to herein as patients) who suffer from compromised gastric relaxation for food digestion. Thus, treatment options relieve patients suffering from symptoms such as gastroesophageal reflux, chest pain (including episodic chest pain, night chest pain, and food-induced chest pain), indigestion, premature satiety, bloating and anorexia It is provided to make.
    [64] Therefore, there is provided the use of a compound of formula (I) as a medicament, and in particular the use of a compound of formula (I) for the manufacture of a medicament for the treatment of disorders involving impaired gastric relaxation in relation to food digestion. Both prophylactic and therapeutic.
    [65] Damaged gastric hypoxia symptoms can also include, for example, Selective Seretonine Re-uptake Inhibitors (SSRI's) such as fluoxetine, paroxetine, fluvoxamine, citalopram, or serpraline; Or erythromycin, such as erythromycin and antibiotic macrolides, such as EM-523, EM-574, ABT-229, GM-611, (8R) -4 "-deoxy-6,9-epoxyrithromycin A , (8S) -4 "-deoxy-6,9-deoxycyrylthromycin A, A-81648, A-173508, A-182061, and KC-11458 can be caused by the absorption of have.
    [66] Another functional gastrointestinal disease is irritable bowel syndrome, one of which is believed to be associated with intestinal hypersensitivity to swelling. Therefore, it is believed that the compound of the present invention having gastrointestinal relaxation properties can reduce the symptoms of the subject suffering from IBS by controlling the hypersensitivity. Thus, there is provided the use of a compound of formula (I) for the manufacture of a medicament for the treatment of irritable bowel syndrome. Compounds of formula (I) may also be used to reduce pain associated with gastrointestinal hypersensitivity.
    [67] In order to prepare a pharmaceutical composition of the present invention, as an active ingredient, a pharmaceutically acceptable carrier which can take various forms depending on the form of the preparation intended for administration of an effective amount of a particular compound in the form of a base or an acid addition salt; Blend together in complete mixture. These pharmaceutical compositions are preferably in unit dosage forms suitable for oral, rectal or parenteral injection. For example, when the composition is prepared in oral dosage form, for example, in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, water, glycols, oils, alcohols and the like; Or in the case of powders, pills, capsules and tablets, useful pharmaceutical media such as solid carriers such as starches, sugars, kaolin, glidants, binders, disintegrants and the like can be used. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are explicitly used. In the case of parenteral compositions, the carrier may contain other ingredients, such as, for example, components that aid dissolution, but usually most contain sterile water. For example, injectable solutions can be prepared using a carrier comprising a saline solution, a glucose solution or a mixture thereof. Injectable suspensions may also be prepared using suitable liquid carriers, suspending agents and the like. In a composition suitable for transdermal administration, the carrier optionally comprises a penetration promoter and / or a suitable humectant, optionally in combination with minor amounts of additives that do not have a very harmful effect on the skin. The additives facilitate skin administration and / or help to prepare the necessary compositions. The composition can be administered in various ways, for example as a percutaneous patch, as a drop, as an ointment. Acid addition salts of formula (I) are more suitable for the preparation of aqueous compositions because of their apparent higher water solubility than the corresponding free base or free acid forms.
    [68] It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein and in the claims refers to physically discrete units suited for unit doses, each containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms include tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoon preparations, large spoon preparations, and the like, and these Are divided multiples.
    [69] Pharmaceutical compositions for oral administration include pharmaceutically acceptable excipients such as binders (eg, pregelatinized yellow starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) in a conventional manner; Fillers such as lactose, microcrystalline cellulose or calcium phosphate; Glidants (magnesium stearate, talc or silica); Disintegrants such as potato starch or sodium starch glycolate; Or solid dosage forms prepared with a humectant such as sodium lauryl sulfate, such as tablets (swallow and chewing forms), capsules or gelcaps. Tablets may be coated by methods known in the art.
    [70] Solutions for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be present as a dry product composed with water or a suitable carrier before use. The solution may optionally include a pharmaceutically acceptable additive, for example suspending agents such as sorbitol syrup, methylcellulose, hydroxy propyl methylcellulose or hydrogenated edible fats; Emulsifiers such as lecithin or acacia; Water-insoluble carriers such as almond oil, oily esters or ethyl alcohol; And preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid.
    [71] Pharmaceutically acceptable sweeteners are preferably saccharin, sodium or calcium saccharin, aspartame, acesulfame patassium, sodium cyclamate, allimem, dihydrochacon sweetener, monellin , Stevioside or sucralose (4,1 ', 6'-trichloro-4,1', 6'-trideoxy galacto sucrose), preferably saccharin, sodium or calcium saccharin, and optionally Bulk sweeteners such as sorbitol, mannitol, lactose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.
    [72] High sweeteners are commonly used at low concentrations. For example, for sodium saccharin, the concentration may be from 0.04% to 0.1% (w / v), preferably about 0.06% in low doses and about 0.08% in high doses, relative to the total volume of the final formulation. have. Bulk sweeteners may be used in an amount in a rather wide range, effectively ranging from about 10% to about 35%, preferably from about 10% to 15% (w / v).
    [73] Pharmaceutically acceptable flavors which can mask the bitter ingredients at low doses are preferably fruity flavours such as cherry, raspberry, black currant or strawberry flavors. Combining two flavors yields an excellent product. Higher doses require a slightly darker flavor, such as caramel chocolate flavor, mint cool flavor, fantasy flavor and a pharmaceutically acceptable dark flavor. Each flavourant may be present in the final composition in a concentration ranging from 0.05% to 1% (w / v). Combining such thick flavourants is advantageously used. Preferably, flavoring agents are used that do not change or lose taste and color under acidic conditions of the formulation.
    [74] The compounds of the present invention may be formulated for parenteral administration by injection, conveniently intravenously, intramuscularly or subcutaneously, for example by pill injection or continuous intravenous infusion. Injectable preparations may be present in unit dosage form with an additional preservative, eg, in ampoules or in multibatch containers. The composition may be present in the form of a suspending agent, solution or emulsion in an oily or aqueous carrier and may contain formulation reagents such as isotonic, suspending, stabilizing and / or dispersing agents. In addition, the active ingredient may be present in powder form so as to consist of sterile water which does not contain a suitable carrier, eg pyrogen, before use.
    [75] The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.
    [76] The technician can readily determine the daily effective amount from the test results shown below in the treatment of symptoms associated with injured or injured gastric dislocation. In general, the therapeutically effective amount is determined to be from about 0.001 mg to about 5 mg per kg body weight, preferably from about 0.01 mg to 0.5 mg per kg body weight. It may be appropriate to administer a therapeutically effective amount of two, three, four or more sub-doses at appropriate intervals during the day. Sub-doses can be formulated in unit dosage forms, eg, in unit form containing from 0.1 mg to 350 mg, and in particular from 1 to 200 mg of active ingredient per unit dosage form.
    [77] The exact dosage and frequency of administration will depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient, and other drugs the patient may take And are known to those skilled in the art. It is also clear that the effective daily amount may be reduced or increased depending on the response of the treated patient and / or the judgment of the physician prescribing the compound of the present invention. Therefore, the range of daily effective amounts described above is only a guideline.
    [1] The present invention relates to a novel compound of formula (I) having gastric relaxation activity. The present invention also relates to a method of preparing the compound, a pharmaceutical composition comprising the compound and the use of the compound as a medicament.
    [78] Experiment
    [79] In the method described below, the following abbreviations were used: “ACN” refers to acetonitrile; "THF" refers to tetrahydrofuran; "DCM" is dichloromethane; "DIPE" is diisopropyl ether; And “DMF” refers to N, N-dimethyl-formamide.
    [80] For some chemicals, formulas such as hydrogen gas for H 2 , nitrogen gas for N 2 , dichloromethane for CH 2 Cl 2 , methanol for CH 3 OH, ammonia for NH 3 , hydrochloric acid for HCl, and sodium hydroxide NaOH.
    [81] In some cases, the first separated stereochemically isomeric form is referred to as "A" and the second separated to "B" without further reference to the actual granulation configuration.
    [82] A. Preparation of Intermediates
    [83] Preparation Example A.1
    [84] A mixture of hexahydro-1- (phenylmethyl) -4H-azin-4-one (0.2 mol) and 4-toluene-sulfonylmethyl isocyanate (0.25 mol) in DMF (200 mL) was stirred at 0 ° C. A solution of potassium t-butoxide (0.4 mol) in a mixture of 2-methyl-2-propanol (200 mL) and 1,2-dimethoxyethane (200 mL) was added dropwise at 0 ° C. The mixture was allowed to reach room temperature and stirred continuously for 1 hour. The mixture was stirred in water and the mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated to yield 48 g of (±) -hexahydro-1- (phenylmethyl) -1H-azepine-4-carbonitrile (Intermediate 1).
    [85] Preparation Example A.2
    [86] Dimethyl sulfamoyl chloride (0.39 mL) was added to a mixture of 1H-imidazo [4,5-b] pyridine (0.26 mL) and triethylamine (0.65 mL) in toluene (500 mL). The mixture was stirred at 100 ° C. for 24 h. The solvent was evaporated. The residue was dissolved in DCM. The organic solution was washed with water and K 2 CO 3 (10%), dried, filtered and the solvent evaporated to 45.4 g (77%) of N, N-dimethyl-1H-imidazo [4,5-b A mixture of] pyridine-1-sulfonamide (intermediate 2) and N, N-dimethyl-3H-imidazo [4,5-b] pyridine-3-sulfonamide (intermediate 3) was obtained.
    [87] Preparation Example A.3
    [88] a) a mixture of ethyl hexahydro-4-oxoazepine-1-carboxylate (0.585 mol), 1,2-ethanediol (0.585 mol) and p-toluenesulfonic acid (0.0058 mol) in toluene (800 mL) Stir overnight and reflux with a water separator (10.5 mL was separated). The solvent was evaporated to afford 142.5 g of ethyl 1,4-dioxa-8-azaspiro [4,6] undecane-8-carboxylate (intermediate 4).
    [89] b) A mixture of intermediate 4 (0.585 mol) and KOH (5.85 mol) in 2-propanol (1200 mL) was stirred overnight and refluxed. The solvent was evaporated. The residue was stirred in water and the mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated to yield 57.7 g of 1,4-dioxa-8-azaspiro [4,6] undecane (intermediate 5).
    [90] c) a mixture of intermediate (5) (0.114 mol), 1- (2-bromoethyl) -4-methoxy-benzene (0.172 mol) and K 2 CO 3 (0.219 mol) in ACN (200 mL); Stir at 80 ° C for hours. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.2). Pure fractions were recovered and the solvent was evaporated to give 28.5 g of 8- [2- (4-methoxyphenyl) ethyl] -1,4-dioxa-8-azaspiro [4,6] undecane (Intermediate 6) Obtained.
    [91] d) A mixture of intermediate 6 (0.098 mol) in HCl (3N, 300 mL) and THF (300 mL) was stirred at 60 ° C. for 1 h. The mixture was basified with solid K 2 CO 3 and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated to afford 22.6 g of hexahydro-1- [2- (4-methoxyphenyl) ethyl] -4H-azin-4-one (intermediate 7). It was.
    [92] Preparation Example A.4
    [93] a) 5,6,7,8-tetrahydro-2 (1H) -quinolinone (0.134 mol) was added to sulfuric acid (200 mL) in small portions at 5 ° C. A small amount of HNO 3 (0.235 mol) was then added while maintaining the temperature below 10 ° C. The mixture was stirred at 5 ° C. for 1 hour, carefully poured into a small amount of ice water and stirred at 0 ° C. for 10 minutes. The precipitate was filtered and dried to yield 14.2 g (55%) of 5,6,7,8-tetrahydro-3-nitro-2 (1H) -quinolinone (intermediate 8).
    [94] b) A solution of intermediate 8 (0.072 mol) and BTEAC (0.0362 mol) in ACN (150 mL) was stirred at room temperature. Phosphoric trichloride (0.222 mol) was added in small portions. The mixture was stirred for 8 hours and refluxed. The solvent was evaporated to dryness. The residue was poured into water and NH 4 OH. The mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to afford 15 g of 2-chloro-5,6,7,8-tetrahydro-3-nitroquinoline (Intermediate 9).
    [95] c) A mixture of intermediate 9 (0.0658 mol) in NH 3 / CH 3 OH 7N (60 mL) was stirred at 120 ° C. for 12 h in an autoclave. The solvent was evaporated to dryness. The residue was dissolved in 2-propanone. The precipitate was filtered off and dried to yield 8.6 g of 5,6,7,8-tetrahydro-3-nitro-2-quinolinamine (intermediate 10). d) A mixture of intermediate (10) (0.031 mol) in methanol (100 mL) was hydrogenated at room temperature under 3.10 5 Pa (3 bar) pressure for 30 minutes in a Parr instrument. After hydrogen (3 equiv) uptake, the catalyst was filtered through celite, rinsed with methanol and the filtrate was evaporated to dryness. The product was further purified to yield 5.07 g of 5,6,7,8-tetrahydro-2,3-quinolinediamine (Intermediate 11).
    [96] B. Preparation of Final Compound
    [97] Preparation Example B.1
    [98] Polyphosphoric acid (PPA) (100 g) was heated to 160 ° C. Intermediate (1) (0.0467 mol) and 2,3-diaminopyridine (0.0513 mol) were added. The mixture was stirred for 1 h at 180 ° C., poured onto solid K 2 CO 3 and ice, washed with 10% K 2 CO 3 and extracted with DCM. The aqueous layer was washed with DCM. The organic layer was dried, filtered and the solvent was evaporated. This fraction was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 94/6 / 0.5). Pure fractions were recovered and the solvent was evaporated. Some of this fraction (6 g) was crystallized from DIPE and 2-propanone. The precipitate was filtered off and dried to give 3.16 g of (±) -2- [hexahydro-1- (phenylmethyl) -1H-azin-4-yl] -1H-imidazo [4,5-b] pyridine ( Compound 69) was obtained.
    [99] Similarly, compound (207) was prepared by reacting intermediate (1) with 2-amino benzenethiol.
    [100] Preparation Example B.2
    [101] Compound (69) (0.0653 mol) was separated into its enantiomer by chiral column chromatography (eluent: hexane / ethanol / Et 3 N 95/5 / 0.1; column; chiralpak AD 20 μm). The partitioned fractions were recovered and the solvent was evaporated and crystallized from DIPE or 2-propanone to give 4.64 g (23%) of (-)-2- [hexahydro-1- (phenylmethyl) -1H-azepine -4-yl] -1 H-imidazo [4,5-b] pyridine (Compound 80) [a] D 20 = -15.08 ° (c = 8.49 mg / ml in CH 3 OH); And 6.19 g (31%) of (+)-2- [hexahydro-1- (phenylmethyl) -1H-azin-4-yl] -1H-imidazo [4,5-b] pyridine (Compound 81 ) [a] D 20 = + 15.52 ° (c = 8.70 mg / ml in CH 3 OH).
    [102] Preparation Example B.3
    [103] N-butyllithium (1.6 M in hexanes, 0.164 mol) was added dropwise to a mixture of N- (1-methylethyl) -2-propanamine (0.164 mol) in THF (70 mL) at a flow of N 2 at −30 ° C. It was. The mixture was cooled to -70 ° C. 1-methyl-1H-imidazo [4,5-b] pyridine (0.0751 mol) in THF (70 mL) was added dropwise. The mixture was stirred for 1 hour. Hexahydro-1- (phenylmethyl) -4H-azepin-4-one (0.0787 mol) in THF (60 mL) was cooled to -70 ° C. The mixture was stirred for 2 h at −70 ° C., brought to 0 ° C., poured into water and NH 4 OH and extracted with DCM and a small amount of methanol. The organic layer was separated, dried, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.5). The desired fractions were recovered and the solvent evaporated to 8.8 g of (±) -hexahydro-4- (1-methyl-1H-imidazo [4,5-b] pyridin-2-yl) -1- (phenylmethyl) -1H-azin-4-ol (compound 152) was obtained.
    [104] Preparation Example B.4
    [105] A mixture of 81 (0.0068 mol) in methanol (20 mL) was hydrogenated at 40 ° C. under a pressure of 3.10 5 Pa (3 bar) using palladium on carbon (1 g) as catalyst. After absorbing hydrogen (1 equiv), the catalyst was filtered through celite and the filtrate was evaporated. The residue was crystallized from ACN. The precipitate was filtered and dried to afford 0.95 g of (A) -2- (hexahydro-1H-azin-4-yl) -1H-imidazo [4,5-b] pyridine (Compound 102).
    [106] Preparation Example B.5
    [107] K 2 CO 3 (0.011 mol) then 1- (chloromethyl) -4-methoxybenzene (0.011 mol) was added to a mixture of compound (87) (0.011 mol) in ACN (80 mL). The mixture was stirred overnight at room temperature. The solvent was evaporated to dryness. The residue was dissolved in DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 93/7 / 0.5). Pure fractions were recovered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried to give 1.2 g of (±) -2- [hexahydro-1-[(4-methoxy-phenyl) methyl] -1H-azin-4-yl] -1H-imidazo [4 , 5-b] pyridine (compound 101) was obtained.
    [108] Preparation Example B.6
    [109] Polyphosphoric acid (PPA) (10 g) was heated to 160 ° C. Compound 155 (0.0043 mol) was added. The mixture was stirred for 20 minutes, cooled, poured into ice water, saturated with K 2 CO 3 (powder) and extracted with CH 2 Cl 2 / CH 3 OH (95/5). The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was dissolved in CH 3 OH / CH 3 CN. The precipitate was filtered off, washed and dried to afford 1.55 g (20.9%) of 2- (2,3,6,7-tetrahydro-1H-azin-4-yl) -1H-imidazo [4,5-b ] Pyridine (compound 116) was obtained. The mother layer was evaporated to dryness to give 5.5 g of compound 116 and 2- (2,5,6,7-tetrahydro-1H-azin-4-yl) -1H-imidazo [4,5-b] pyridine A mixture of (compound 115) was obtained.
    [110] Preparation Example B.7
    [111] A mixture of compound 136 (0.0276 mol) in DCM (80 mL) was cooled to 5 ° C. 3-Chlorobenzenecarboperoxoic acid (0.044 mol) was added. The mixture was kept at 5 ° C. for 1 hour and then allowed to come to room temperature overnight. 10% K 2 CO 3 was added. The mixture was saturated with K 2 Co 3 (powder) and extracted with CH 2 Cl 2 / CH 3 OH. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 92/8 / 0.5). The pure fractions were recovered and the solvent was evaporated to give 6.5 g (74.7%) of (±) -1- (2,2-dimethyl-1-oxopropyl) -4- (1H-imidazo [4,5-b] Pyridin-2-yl) -1H-azepine, N4-oxide (Compound 161) was obtained.
    [112] Preparation Example B.8
    [113] 3-chlorobenzenecarboperoxoic acid (0.0157 mol) was added in small portions to a mixture of compound (69) (0.013 mol) in DCM (80 mL) at room temperature. The mixture was stirred for 4 hours at room temperature. NaHCO 3 saturated solution was added. The mixture was extracted with DCM, saturated with K 2 CO 3 and reextracted with CH 2 Cl 2 / 2-propanol. The organic layer was separated, dried, filtered and the solvent was evaporated at 40 ° C. or lower. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 88/12/1). Two pure fractions were recovered and the solvent was evaporated to give 2.3 g of (A) -2- [hexahydro-1- (phenylmethyl) -1H-azin-4-yl] -1H-imidazo [4,5 -b] pyridine, N4-oxide (Compound 113) and 1.6 g of (B) -2- [hexahydro-1- (phenylmethyl) -1H-azin-4-yl] -1H-imidazo [4, 5-b] pyridine, N4-oxide (Compound 114) was obtained.
    [114] Preparation Example B.9
    [115] 80% NaH (0.0195 mol) at 5 ° C. was dissolved in DMF (100 mL) (±) -2- [hexahydro-1- (phenylmethyl) -1H-azin-4-yl] -1H-imidazo [4 , 5-b] was added in small portions to a mixture of pyridine (0.0195 mol). The mixture was stirred for 15 minutes. 2-bromo-1-phenylethanone (0.0214 mol) was added. The mixture was stirred for 30 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.1). Three pure fractions were recovered and the solvent was evaporated, converted to hydrochloric acid salt (1: 2) with HCl / 2-propanol and crystallized from 2-propanol to give 3.3 g of (±) -2- [2- [hexa Hydro-1- (phenylmethyl) -1H-azin-4-yl] -3H-imidazo [4,5-b] pyridin-3-yl] -1-phenylethanone hydrochloride (1: 2) ( Compound 76) was obtained.
    [116] Preparation Example B.10
    [117] A solution of compound 143 (0.00838 mol) in 3N HCl (35 mL) and THF (35 mL) was stirred overnight at room temperature, neutralized with solid K 2 CO 3 and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 90/10 / 0.5). Pure fractions were recovered and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried to give 1.54 g of (±) -hexahydro-4- (1H-imidazo [4,5-b] pyridin-2-yl] -1-phenylmethyl) -1H-azepine-4 -Ol (Compound 149) was obtained.
    [118] Preparation Example B.11
    [119] A mixture of compound 54 and compound 55 in methanol (50 mL) was palladium on carbon (0.45 g) as catalyst and hydrogenated at 40 ° C. under 5.10 5 Pa (5 bar) pressure for 8 hours. After absorbing hydrogen (1 equiv), the catalyst was filtered through celite, washed with methanol and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 90/10/1). Pure fractions were recovered and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to give 1.8 g of compound (14).
    [120] Preparation Example B.12
    [121] A mixture of compound 27 (0.0059 mol) in methanol (100 mL) was stirred at 5 ° C. Sodium borohydride (0.0059 mol) was added in small portions under N 2 flow. The mixture was stirred for 2 hours at room temperature and hydrolyzed with water. Methanol was evaporated. The residue was dissolved in DCM and the mixture extracted. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was converted to ethanedioic acid salt (1: 2). The mixture was crystallized from 2-propanone. The precipitate was filtered off and dried to give 2.37 g of compound (29).
    [122] Preparation Example B.13
    [123] A mixture of compound 31 (0.00659 mol) and methyl iodide (0.00923 mol) in 2-propanone (80 mL) was stirred at room temperature for 12 hours. The precipitate was filtered off and washed with 2-propanone to yield 2.49 g of compound 154.
    [124] Preparation Example B.14
    [125] Compound (161) in 12N HCl (50 mL) was stirred overnight and refluxed. The solvent was evaporated to dryness. The residue was dissolved in 10% K 2 CO 3 and saturated with powdered K 2 CO 3. The mixture was extracted with CH 2 Cl 2 / CH 3 OH 90/10. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was crystallized from CH 3 OH / CH 3 CN / DIPE. The precipitate was filtered off and dried to give 1.2 g of compound 162.
    [126] Preparation Example B.15
    [127] A mixture of compound 126 (0.00594 mol) in 48% HBr in water (60 mL) was stirred at 90 ° C. for 12 h. The solvent was evaporated. The residue was washed with K 2 CO 3 solution and extracted with ethyl acetate and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate. The mixture was crystallized. The precipitate was filtered off and dried to yield 0.8 g of compound 127.
    [128] Preparation Example B.16
    [129] A mixture of 92 (0.006 mol) in methanol (20 mL) was hydrogenated at room temperature under 3.10 5 Pa (3 bar) pressure for 2 hours using Raney nickel (2 g) as catalyst. After absorbing hydrogen (3 equiv), the catalyst was filtered through celite and the filtrate was evaporated to yield 2.1 g of compound 105.
    [130] Preparation Example B.17
    [131] A mixture of triethylamine (2.9 mL) and compound (87) (0.0139 mol) in DCM (30 mL) was stirred at room temperature for 15 minutes. 3-pyridinecarboxylic acid (0.0209 mol) was added. A mixture of 1-hydroxy-1H-benzotriazole (0.0209 mol) in DCM (30 mL) was added at 5 ° C. under N 2 flow. A small amount of a mixture of N, N'-methanetetrayl-biscyclo-hexanamine (0.0209 mol) in DCM (30 mL) was added. The mixture was stirred for 6 hours at room temperature. The precipitate was filtered off. The filtrate was washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 92/8 / 0.5). Two fractions were recovered and the solvent was evaporated. The two fractions were mixed and crystallized from DCM and DIPE to give 2.3 g of compound 118.
    [132] Preparation Example B.18
    [133] Triethylamine (0.0111 mol) was added to a mixture of compounds (115) and (116) prepared in Preparation Example B.6 in DMF (40 mL). The mixture was cooled on an ice-bath. Methanesulfonyl chloride (0.01 mol) was added. The mixture was stirred for 1 hour at 5 ° C. and then overnight at room temperature. The solvent was evaporated to dryness. The residue was dissolved in a mixture of DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.1) and crystallized from 2-propanone and DIPE. The precipitate was filtered off and dried to yield 1.25 g of compound 180 (mp.> 260 ° C).
    [134] Preparation Example B.19
    [135] Triethylamine (0.0168 mol) was added to a mixture of compounds 115 (0.007 mol) and (116) (0.007 mol) prepared in Preparation Example B.6 in DMF (60 mL). The mixture was cooled at 5 ° C. and 2-phenylacetyl chloride (0.0154 mol) was added. The mixture was stirred at 5 ° C. for 1 hour and then at room temperature overnight, the solvent was evaporated to dryness and dissolved in a mixture of DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.2). Two fractions were recovered and the solvent was evaporated. The first fraction was crystallized from CH 3 CN / DIPE. The precipitate was filtered off and dried to afford 0.25 g of compound 182 (mp.> 169 ° C). The second fraction was crystallized from CH 3 CN / DIPE. The precipitate was filtered and dried to yield 1.55 g of compound 183 (mp.> 157 ° C).
    [136] Preparation Example B.20
    [137] Triethylamine (0.037 mol) followed by ethyl chloroformate (0.074 mol) was added in small portions at room temperature to a mixture of compound (87) (0.0185 mol) in toluene (60 mL). The mixture was stirred at 95 ° C. for 2 hours, poured into ice water and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97/3 / 0.5). One fraction was recovered and the solvent was evaporated to yield 3.7 g of compound 187.
    [138] Preparation Example B.21
    [139] A mixture of compound 187 (0.0083 mol) and potassium hydroxide (0.053 mol) in 2-propanol (30 mL) was stirred overnight, refluxed, poured into ice water, extracted with DCM and washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The mixture was dissolved in diethyl ether / DIPE. The precipitate was filtered, washed and dried to yield 1.45 g of compound 188 (mp.> 141 ° C).
    [140] Preparation Example B.22
    [141] A mixture of methyl 5,6-diaminoecotinate (0.0104 mol) and hexahydro-1- (phenylmethyl) -1H-azepine-4-carboxylic acid (0.0087 mol) in phosphooxychloride (50 mL) was added for 8 hours. Stir at 110 ° C for. The solvent was evaporated. The residue was basified with K 2 CO 3 / H 2 O. The mixture was saturated with K 2 CO 3 and extracted with a mixture of ethyl acetate and isopropanol. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.5) and crystallized from CH 3 CN / DIPE to give 1.02 g of Compound (217) ( mp.> 150 ° C.).
    [142] Preparation Example B.23
    [143] a) 3-amino-2-pyridinol (0.018 mol) in DCM (40 mL) was cooled to 5 ° C. Triethylamine (0.0216 mol) was added. A mixture of hexahydro-1- (phenylmethyl) -1H-azepine-4-carbonyl chloride (0.018 mol) in ACN (40 mL) was added. The mixture was stirred for 1 h at 5 ° C., then overnight at room temperature and poured into water. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue 12 was obtained without further purification.
    [144] b) A mixture of intermediate 12 (0.018 mol) in phosphooxychloride (80 mL) was stirred overnight and refluxed. Phosphooxychloride was evaporated to dryness. The residue was dissolved in 10% K 2 CO 3 and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 90/10 / 0.1), crystallized from ACN and converted to an ethanedioic acid salt to give 0.8 g of compound. (213) (mp.> 102 ° C.) was obtained.
    [145] Preparation Example B.24
    [146] A mixture of N- (2-amino-3-pyridyl) hexahydro-1- (phenylmethyl) -1H-azepine-3-carboxamide (0.0151 mol) and APTS (0.1 g) in xylene (150 mL) Was stirred for 12 h, refluxed, evaporated and dissolved in 10% K 2 CO 3 / CH 2 Cl 2 . The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 96/4 / 0.5 to 90/10 / 0.5). Pure fractions were recovered and crystallized from CH 3 CN / DIPE to afford 2.57 g of compound 195 (mp.> 139 ° C.).
    [147] Preparation Example B.25
    [148] Of N- (2-chloro-3-pyridinyl) hexahydro-1- (phenylmethyl) -1H-azepine-4-carboxamide (0.096 mol), Lawesson's reagent (0.0096 mol) in HMPT (33 mL) The mixture was stirred overnight at 150 ° C. The mixture was poured into K 2 CO 3 / ice and extracted from ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 97.5 / 2.5 / 0.1). Pure fractions were recovered and the solvent was evaporated. The residue was dissolved in 2-propanone and converted to ethanedioic acid salt. The precipitate was filtered off and dried to yield 0.52 g of compound 218 (mp. 163 ° C.).
    [149] Preparation Example B.26
    [150] A mixture of 1-chloroethyl chloroformate (0.0188 mol) in 1,2-dichloroethane (20 mL) was added dropwise to a mixture of compound 206 (0.0172 mol) in 1,2-dichloroethane (100 mL) at 0 ° C. It was. The mixture was brought to room temperature and stirred at 80 ° C. for 1 hour. The solvent was evaporated to dryness. Methanol (60 mL) was added. The mixture was left at room temperature for 12 hours, then stirred for 30 minutes and refluxed. The solvent was evaporated. 10% K 2 CO 3 / CH 2 Cl 2 was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from ACN to give 0.9 g of compound 220.
    [151] Preparation Example B.27
    [152] A mixture of compound 171 (0.015 mol) in THF (30 mL) was cooled to 0 ° C. Sodium hydride (60% in oil) was added in small portions. Dimethyl sulfate (0.0165 mol) was added in small portions. The mixture was stirred for 4 h from 0 ° C. to room temperature, poured into water and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.1) to afford 4.5 g of compound (175).
    [153] Preparation Example B.28
    [154] Carbamodithioic acid 4-[[[hexahydro-1- (phenylmethyl) -1H-azin-4-yl] carbonyl] amino] -3-pyridinyl diethyl ester in formic acid (50 mL) (0.00876 mol) ) Was stirred at 100 ° C. for 3 hours. The solvent was evaporated. The residue was poured on ice, basified with K 2 CO 3 (powder) and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was dissolved in 2-propanone and converted to hydrochloride salt. The precipitate was filtered off and dried to yield 1.16 g of compound 215 (mp. 184 C).
    [155] Preparation Example B.29
    [156] 2-benzofurancaraldehyde (0.00915 mol) NaBH 3 CN (0.001 mol) was then added to a mixture of compound (87) (0.0083 mol) in ACN (100 mL) at room temperature. Acetic acid (1.8 mL) was added at room temperature. The mixture was stirred for 2 h at rt, poured into 10% K 2 CO 3 and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was dissolved in methanol in 10 mL 2-propanone / HCl (5N). The mixture was stirred overnight, refluxed and the solvent was evaporated to dryness. The residue was dissolved in 10% K 2 CO 3 . The mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / NH 4 OH 95/5 / 0.2; 2-propanone / CH 3 CN). The precipitate was filtered off and dried to give 0.9 g of compound 236 (mp.> 125 ° C).
    [157] Tables 1 to 7 list the compounds prepared according to any of the above examples. The following abbreviations are used in the table: .C 2 H 2 O 4 represents the ethanedioate salt.
    [158] Table 1:
    [159]
    [160]
    [161]
    [162] Table 2:
    [163]
    [164]
    [165] Table 3:
    [166]
    [167]
    [168] Table 4:
    [169]
    [170]
    [171]
    [172]
    [173]
    [174]
    [175]
    [176] Table 5:
    [177]
    [178]
    [179]
    [180]
    [181]
    [182] Table 6:
    [183]
    [184]
    [185] Table 7:
    [186]
    [187]
    [188] C. Pharmacological Examples
    [189] C.1. Gastrotension measured in conscious dog by electric pressure regulator
    [190] False tension cannot be measured by the manometric method. Therefore, an electric pressure regulator was used. This allows the regulation of physiological patterns and gastrointestinal tract in conscious dogs and the effect of the test-compound on this strain.
    [191] The pressure regulator consists of an air injection system connected to an ultrathin flaccid polyethylene bag (maximum volume: ± 700 ml) by a double-lumen 14-french polyvinyl tube. While maintaining the pressure constant, the change in gastrotension was measured by recording the air volume change in the intragastric bag. The pressure (preselected) in the flaccid air-filled introduced into the stomach was kept constant while varying the air volume in the bag by the electrical feedback system.
    [192] Thus, gastric motility (contraction or relaxation) was measured with a pressure regulator as a change in gastric volume (reduction or increase in irradiation) at a constant intragastric pressure. The pressure regulator consists of a strain gauge connected to the injection-intake system by an electronic relay. Both the strain gauge and the injection system are connected to the ultrathin polyvinyl bag by a double-lumen polyvinyl tube. The dial of the pressure regulator selects the level of pressure maintained in the gastric bag.
    [193] Female beagles weighing 7-17 kg were trained and stabilized in the Pavlov frame. The gastric cannula was inserted under conventional anesthesia and sterile pretreatment. After median laparotomy, an incision was made about 2 cm in the upper part of the Lataset nerve through the gastric wall. A double pulsing of the suture chamber allowed the cannula to rest on the stomach wall and induce a tab wound in the proximal part of the quandrant. Give Dog two weeks to recover.
    [194] At the beginning of the test, the cannula was opened to remove any residual juice or food. If necessary, the stomach was washed with 40-50 mL of lukewarm water. The pressure regulator of the ultrathin bag was placed through the stomach cannula to the stomach bottom. To facilitate unfolding of the gastric bag during the test, the pressure was simply elevated to a maximum of 14 mmHg (about 1.87 kPa) and a dose of 150-200 mL was injected into the bag. This process was repeated twice.
    [195] After 60 minutes of stabilization under an intestinal pressure of 6 mmHg (about 0.81 kPa), test compounds were administered subcutaneously or duodenum at 2 mmHg (0.27 kPa). Test compounds were screened, ie, changes in gastric volume at 0.63 mg / kg. Different screening and routes were tested to see if the test compound showed efficacy during the screening. Table C-1 summarizes the mean value of the maximum change in volume (ml) for gastric relaxation in 1 hour after administration of the test compound (0.63 mg / kg) to S.C.
    [196] Table C-1:
    [197]
    权利要求:
    Claims (10)
    [1" claim-type="Currently amended] Compounds of formula (I), their prodrugs, N-oxides, addition salts, quaternary amines and stereochemically isomeric forms:

    Where

    (Wherein R 2 is hydrogen, hydroxy, C 1-4 alkyl, or C 1-4 alkyloxy, and when R 2 is hydroxy or C 1-4 alkyloxy, R 2 is α of ring nitrogen When bonded at a position other than the -position, or when R 2 is hydroxy, R 2 is a radical (a-2), (a-3), (a-4), (a-5), (a-6) , (a-7), (a-8), (a-9), (a-10), (a-11), or (a-12) to bind at a position other than the vinyl position);
    -a 1 = a 2 -a 3 = a 4 -is

    2 represents a radical
    Wherein each hydrogen atom in the radicals (b-1) to (b-11) is optionally halo, C 1-6 alkyl, nitro, amino, hydroxy, C 1-6 alkyloxy, polyhaloC 1- 6 alkyl, carboxyl, aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, mono- or di (C 1-4 alkyl) aminoC 1-6 alkyl, C 1-6 alkyloxycarbonyl Or;
    Two hydrogen atoms on adjacent carbon atoms in the radicals (b-1) to (b-11) may optionally be replaced by — (CH 2 ) 4 —;
    R 1 is hydrogen, C 1-6 alkyl, aryl 1 , C 1-6 alkyl substituted with aryl 1 , C 1-4 alkyloxycarbonyl, aryl 1 carbonyl, aryl 1 C 1-6 alkylcarbonyl, aryl 1 carbonylC 1-6 alkyl, aryl 1 oxycarbonyl, aryl 1 C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, trifluoromethyl, trifluoromethylcarbonyl, C 1-6 Alkylsulfonyl, aryl 1 sulfonyl, methanesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, or dimethylsulfamoyl;
    X is O, S, or NR 3 (wherein R 3 is hydrogen; C 1-6 alkyl; methanesulfonyl; benzenesulfonyl; trifluoromethanesulfonyl; dimethylsulfamoyl; aryl 2 carbonylC 1- 4 alkyl; C 1-4 alkyloxycarbonyl; aryl 2 and optionally substituted C 1-4 alkyl hydroxy, aryl or the two C 1-4 alkyl substituted with a carbonyl C 1-4 alkyl), and;
    Aryl 1 is phenyl; Phenyl substituted with 1, 2 or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, nitro, amino, cyano, and trifluoromethyl; Pyridinyl; Pyridinyl substituted with 1, 2, or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, amino, and diC 1-4 alkylamino; Naphthyl; Quinolinyl; 1,3-benzodioxolyl; Furanyl; Thienyl; Or benzofuranyl;
    Aryl 2 is phenyl or 1, 2 or 3 substituents each independently selected from halo, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy, nitro, amino, cyano, and trifluoromethyl Substituted phenyl.
    [2" claim-type="Currently amended] The bivalent radical of claim 1, wherein A compound of the formula (a-1), (a-3) or (a-4), wherein R 2 is hydrogen or hydroxy.
    [3" claim-type="Currently amended] The divalent radical -a 1 = a 2 -a 3 = a 4 -valent formula (b-1) wherein each hydrogen atom is halo, C 1-6 alkyl, hydroxy, or C Optionally substituted with 1-6 alkyloxy).
    [4" claim-type="Currently amended] The divalent radical -a 1 = a 2 -a 3 = a 4 -valent formula (b-2), wherein each hydrogen atom is halo, C 1-6 alkyl, hydroxy, or C Optionally substituted with 1-6 alkyloxy).
    [5" claim-type="Currently amended] The compound of any one of claims 1-4 wherein R 1 is hydrogen, C 1-6 alkyl, phenylmethyl, or furanylmethyl.
    [6" claim-type="Currently amended] 6. The compound of claim 1, wherein X is NR 3 , wherein R 3 is hydrogen, dimethylsulfamoyl, or C 1-4 alkyl substituted with aryl 2. 7 .
    [7" claim-type="Currently amended] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to 6.
    [8" claim-type="Currently amended] A method for preparing a pharmaceutical composition according to claim 7 by intimately mixing a therapeutically effective amount of a compound according to any one of claims 1 to 6 with a pharmaceutically acceptable carrier.
    [9" claim-type="Currently amended] The compound according to any one of claims 1 to 6 for use as a medicament.
    [10" claim-type="Currently amended] a) reacting an intermediate of formula (II), or a functional derivative thereof, with an intermediate of formula (III) in the presence of polyphosphoric acid (PPA) or phosphorus oxychloride (POCl 3 ) in the temperature range from room temperature to the reflux temperature of the reaction mixture (Optionally the reaction can be carried out in a reaction inert solvent);
    b) formula where two geminal hydrogen atoms are replaced by carbonyl groups Reacting an intermediate of formula (IV), defined as a derivative of intermediate of, with an intermediate of formula (V), to prepare a compound of formula (Ia), which is defined as a compound of formula (I) wherein R 2 is hydroxy;
    c) converting compounds of formula (I) to one another according to known reactions; If desired, the compound of formula (I) is converted to an acid addition salt, or vice versa, the acid addition salt of the compound of formula (I) is converted to the free base form with alkali; If desired, a process for preparing the compound of formula (I) by preparing its stereochemically isomeric form:

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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-12-21|Priority to EP99204441.2
    1999-12-21|Priority to EP99204441
    2000-12-14|Application filed by 얀센 파마슈티카 엔.브이.
    2002-07-26|Publication of KR20020062643A
    2007-05-08|Application granted
    2007-05-08|Publication of KR100715351B1
    优先权:
    申请号 | 申请日 | 专利标题
    EP99204441.2|1999-12-21|
    EP99204441|1999-12-21|
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