TW200401771A - Novel compound - Google Patents

Abstract

Compound of formula (I): which is; 3-({[({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)carbonyl]-amino}methyl)-N-ethylbenzamide; and salts and solvates thereof, a process for its preparation, pharmaceutical formulations containing it and its use in therapy.

Description

200401771 发明 Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel compound, a method for preparing the compound, a pharmaceutical formulation containing the compound, and its use in medicine. [Prior art] Inflammation is the main reaction of tissue damage or microbial invasion, which is characterized by white blood cells adhering to the endothelium, exuding and activating in tissues. Activation of white blood cells can lead to the production of toxic oxidizing substances (for example, superoxide anions) and release particulate products (for example, peroxidases and proteases). Circulating white blood cells include neutrophils, eosinophils, basophils, monocytes, and lymphocytes. Different forms of inflammation involve different types of invasive leukocytes, and their specific types are regulated by the expression of adhesion molecules, cytokines, and chemokines in the tissue. The main function of white blood cells 4 is to protect the host from the invasion of organic organisms (for example, bacteria and parasites). When the tissue is damaged or infected, a series of changes will occur, and these changes will cause white blood cells to be locally recruited from the circulation and enter the tissues of the buckle. Recruitment of white blood cells is in a controlled state, which causes foreign cells or dead cells to be orderly destroyed or phagocytosed, followed by tissue repair, and inflammatory infiltration subsides. However, in the case of chronic inflammatory conditions, the recruitment of white blood cells is often inappropriate, so the resolution of inflammation cannot be properly controlled, and the inflammatory response will cause tissue destruction. Increasing evidence shows that it is characterized by bronchial inflammation of asthma, which is a specific type of immunity mediated by cells, among which the cytokine product, for example, is released by T-helper cell 2 (Th2) lymphocytes Il_4 and IL-5 will coordinate the aggregation and activation of granulocytes (especially eosinophils, followed by basophils 84387 200401771 cells). By the release of cytotoxic basic proteins, pro-inflammatory mediators and oxygen free radicals, eosinophils will produce mucosal damage 'and stimulate the mechanisms that cause bronchial hypersensitivity reactions. Therefore, in the case of asthma, blocking the recruitment and activation of Th2 cells and eosinophils may have anti-inflammatory properties. In addition, eosinophils are associated with other types of diseases, such as rhinitis, eczema, allergic bowel syndrome, and parasitic infections. Chemokinins are a large family of small proteins that will participate in the luck and recruitment of white blood cells (see Luster, New Eng. J. Med., 338, 436_445 (1998)). These substances can be released by a variety of cells, and their role is to attract and activate different types of cells, including eosinophils, basophils, neutrophils, macrophages, T lymphocytes and B lymphocytes. Based on the difference in the spacing of the two retained cysteine residues near the amine end of the chemokine protein, chemokines are divided into two main groups: cxc_ (a) and cc- (p) chemokine. Chemokinin binds to specific cell surface receptors, which are involved in the G protein-coupled protein family of seven transmembrane functional sites (see Luster, 1998). Activation of the chemokinin receptor will lead to a variety of responses, including increased intracellular concentration, changes in cell shape, improved expression of cell adhesion molecules, cell degranulation, and enhanced cell migration (chemotaxis). To date, we have identified multiple CC-type chemokinin receptors. The CC type chemokinin receptor 4 (CCR-3), which is important for the present invention, is mainly expressed on eosinophils, and also on eosinophils, mast cells, and Th2 cells. I know that chemokinins that act on CCR-3, such as rantES, MCP-3 and 84387 200401771 MCP-4, can recruit and activate eosinophils. I am particularly interested in eotaxin and eotaxin-2, which have specific binding to CCR-3. The location and function of CCR-3 chemokine shows that it plays an important role in the development of allergic diseases, for example, asthma 5. Therefore, CCR-3 is used in all major cell types involved in inflammatory allergic reactions. Specific approach. Chemokinin acting on CCR-3 is produced in response to inflammatory stimuli, and its role is to aggregate and activate these types of cells at the site of inflammation (for example, see J. Exp by Griffiths et al. Med., 179, 881-887 (1994), J. Exp. Med., Lloyd et al., 191, 265-273 (2000)). In addition, the monoclonal antibody against CCR-3 can completely inhibit the interaction between eotaxin and eosinophils (see Heath, H. et al. J. Clin. Invest. 99 (2), 178-184 (1997)), In an animal model of asthma, antibodies against CCR-3 specific chemokine eotaxin can reduce bronchial hypersensitivity and pulmonary eosinophilia (Gonzalo et al. J. Exp. Med ·, 188, 157-167 (1998)). Therefore, multiple pieces of evidence indicate that antagonists of the CCR-3 receptor are highly likely to have therapeutic use for a range of inflammations. In addition to its important role in inflammatory diseases, chemokine and its receptors also play an important role in infectious diseases. Mammalian cytomegalovirus, herpes simplex virus, and chickenpox virus all show homologs of chemokinin receptors, which can be activated by human CC-type chemokinins such as RANTES and MCP-3 receptors (see Curr · by Wells and Schwartz. Opin Biotech. 8,741-748, 1997). In addition, human chemokinin receptors, such as CXCR-4, CCR-5, and CCR-3, can be used as mammalian cells caused by microorganisms such as human immunodeficiency virus-10- 84387 200401771 (HIV). Co-receptor of infection. Therefore, antagonists of chemokine receptors (including CCR-3 antagonists) can be used to block HIV infection of CCR-3 expressing cells or prevent viruses (eg, cytomegalovirus) from manipulating immune cell responses. International Patent Application Publication No. WO 01/24786 (Shionogi & Co-Ltd.) Discloses certain aryl or heteroaryl derivatives for the treatment of diabetes.

WO 00/69830 (Torrey Pines Institute for Molecular Studies) discloses certain diazo ring compounds and a wide variety of substances containing such compounds for conducting biological screening. WO 00/18767 (Neurogen Corporation) discloses certain piperine derivatives as dopamine D4 receptor antagonists. U.S. Patent No. 603 1097 and WO 99/21848 (Neurogen Corporation) disclose certain amine isoquinoline derivatives that serve as ligands for dopamine receptors. WO 99/06384 (Recordati Industria Chimica) discloses piperin derivatives for treating neuromuscular dysfunction of the lower urethra. WO 98/56771 (Schering Aktiengesellschaft) discloses certain chirping derivatives as anti-inflammatory agents. WO 97/47601 (Yoshitomi Pharmaceutical Industries Ltd.) discloses certain fused # heterocyclic compounds as dopamine D receptor blockers. WO 96/39386 (Schering Corporation) discloses certain piperidine derivatives as neurokinin antagonists. WO 96/02534 (Byk Gulden Lomberg Chemische Fabrik GmbH) discloses certain piperidinothiopyridines for controlling Borrelia bacteria. WO 95/32196 (Merck Sharp & Dohme Limited) discloses certain piperin, piperidine and tetrahydropyridine derivatives useful as 5-HTlD-a antagonists. U.S. Patent No. 5,3 89,63 5 (E.I. Du Pont de Nemours and Company) discloses certain substituted micon as an angiotensin II antagonist used as a blood vessel 84387-11-200401771. European Patent Application Publication No. 0 306 440 (Schering Aktiengesellschaft) discloses certain milts used as cardiovascular agents. [Summary] We have now discovered a novel compound as a CCR-3 antagonist. The compound can block the migration / chemotaxis of eosinophils, so it has anti-inflammatory properties. The compound therefore has potential medicinal value, and especially prevents tissue damage caused by eosinophils, basophils, and Th2 cells in certain diseases involving these cell types, especially those allergic diseases , Which includes (but is not limited to) bronchial asthma, allergic rhinitis, and atopic dermatitis. Therefore, according to one aspect of the present invention, it will provide a compound having a chemical formula 及其, a salt thereof, and a medicament, the chemical formula ⑴ being:

Its chemical name is: 3-({[(([(((2S) -4- (3,4-dichlorobenzyl) morpholine-2_yl] methyl} amino) chino] -amino} methyl ) -N-ethylbenzamide. —_ Suitable salts of the compound of formula (I) include physiologically acceptable salts and physiologically unacceptable salts, but are salts which can be used in the preparation of compounds of the formula (I) and physiologically acceptable salts thereof. Where appropriate, the salt of the acid plus -12-84387 200401771 can be derived from inorganic or organic acids, such as hydrochloride, chlorobromide, sulfate, phosphate, acetate, benzoate, citrate , Succinate, milk salt, tartrate salt, §Ma salt, maleate salt, bulkyl-2-naphthalate, dihydroxyarsinate, formate, formate or trifluoroacetate. Examples of the hydrate include a hydrate. The compound of formula (I) and its salt and vehicle can be prepared by the method described below 'which will constitute another aspect of the present invention. According to the present invention, a method for preparing a compound having the formula ⑴ includes coupling a compound having the formula (II) or a salt thereof with ethylamine ··

Thereafter, if necessary, one or more of the following steps may be optionally performed: (i) the removal of the protecting group; (ii) the preparation of a suitable salt or vehicle of a compound prepared in this way. A mixture of tetramethylenefuran and n, n-dimethylformamide (for example, a carbodiimide-based reagent, for example, i _ (: ethylcarbodiimide hydrochloride), and an agent For example, the coupling of active hydroxy compounds (eg, hydroxy "compounds of formula (II) will be performed in any suitable solvent. For example, these solvents can be polar organic solvents, for example, in the appropriate dehydration It belongs to 1 'dimethylaminopropyl) -3- and optionally, in the presence of activated 1-¾-benzobenzotriazine) 84387 -13- 200401771, and can also be tested appropriately, for example, Tertiary amines, for example, in the presence of N, N-diisopropylethylamine, and under general coupling conditions, at any temperature that allows the desired product to reach a suitable rate of formation, after a suitable reaction time (for example and (12-24 hours), to produce the products we need. Suitable reaction temperatures include a range between 18 ° C and 25 ° C. The products of the reaction are isolated and purified by ordinary methods. Compounds of formula (II) can be prepared by a hydrolysis reaction of compounds of formula (III):

The hydrolysis reaction can be performed at a suitable temperature (for example, their temperature between 18 ° C and 25 ° C), in a suitable solvent (for example, an aqueous solution of an alcohol, for example, a mixture of methanol and water). ), And the presence of a suitable catalyst (for example, a test aqueous solution, for example, a steel hydroxide aqueous solution), β The reaction will be completed in a suitable time (for example, 12-24 hours). _ Compounds of formula (III) can be prepared by reacting compounds of formula (IV) with compounds of formula (V):

84387 -14- 200401771 The reaction between a compound of formula (IV) and a compound of formula (V) in a suitable solvent (for example, a polar organic solvent, for example, N, N-dimethylformamide ) And an appropriate base (for example, tertiary amines, such as N, N-diisopropylethylamine), and at an appropriate temperature (for example, they are between 18 ° C to 25 ° C Temperature), the reaction will be completed in a suitable reaction time (for example, 60-100 hours). The compound of formula (IV) can be prepared by reacting the compound of formula (VI) with 4-nitrophenyl chloroformate.

Cl (VI) The reaction between a compound of formula (VI) and 4-nitrophenyl chloroformate at an appropriate temperature (for example, their temperature between -5 ° C to + 5 ° C) In a suitable solvent (for example, an inert organic solvent, such as dichloromethane), and in the presence of a suitable base (for example, a tertiary amine, such as triethylamine), the The reaction will be completed in an appropriate time (for example, '3-5 hours). A compound of formula (VI) can be prepared by reacting (a), (b) or (c). Reaction (a): Reaction of a compound of formula (IX) with a compound of formula (X):

-15-

84387 200401771 Among them, A is a protected amine group, suitably a phthalimide imide group, and then the protective group of the amine group is removed to form a compound having a chemical formula (VIR):

Then analyze the enantiomer of the compound i having the chemical formula (VIR); or; reaction (b): the reaction of the compound having the chemical formula (IX) and the compound having the chemical formula (XA) as defined above:

Among them, A is as defined for the compound of formula (X) above, and then the protective group of the amine group is removed to form a compound of formula (VI). Reaction (c): hydrolysis of a compound of formula (VII):

The enantiomers of the compounds of formula (VIR) are then resolved. In reaction (a) and reaction (b), the intermediate diol 84387 -16- 200401771 (VIBR) and (when the compound of formula (IX) and the compound of formula (X) or (XA) are reacted) VIB) The cyclization reaction is generally performed under the following Mitsunobu conditions: In general, a mixture of a compound of formula (IX) and a compound of formula (X) or (XA) is dissolved in a suitable solvent (for example, tetrahydrofuran ), And stirred at an appropriate temperature (generally the reflux temperature of the solvent) and an inert atmosphere (suitably a nitrogen atmosphere) for 20-24 hours. Then more solvent is added and the mixture is cooled, suitably to 0-5 ° C. An appropriate phosphine compound (triphenylphosphine as appropriate) was added and the mixture was stirred until the solids were completely dissolved. Keep the temperature below 7 ° C and add an appropriate azo compound, suitably diisopropyl azodicarboxylate, within a certain time (appropriately 10-15 minutes). After the mixture is allowed to stand for a period of time (appropriately 2-3 hours), it is heated to a certain temperature (appropriately 20-25t). After leaving it to stand for a period of time (appropriately 4-6 hours), phosphine and azo compounds are further added. After further standing for a period of time (appropriately 20-24 hours), the reaction mixture is concentrated to near dryness. Add the appropriate alcohol (propan-2-ol as appropriate) and repeat the concentration step 骡. The steps of adding alcohol and concentrating were then repeated. Further alcohol is added and the mixture is heated to a temperature (appropriately between 65 and 75 ° C). After a period of time (appropriately 20-45 minutes), the resulting paste is cooled to a certain temperature (appropriately 20-25 ° C) and allowed to stand for a period of time (appropriately 1.5-3 hours), The product was then isolated by filtration. The filter bed was washed with a large amount of alcohol and dried at 35-45 ° C and under vacuum to form protected compounds of formula (VIR) or (VI), respectively. A typical method for removing the protecting group from the product is as follows: Protect the compound of the chemical formula (VIR) and the compound of the chemical formula (VI) in a suitable form.

84387 200401771 The paste formed in a polar solvent (for example, water) is heated to a higher temperature (appropriately 70-75 ° C), and then treated with concentrated inorganic acid (appropriately concentrated sulfuric acid) dropwise. The mixture is heated to a higher temperature (appropriately the reflux temperature of the solvent) and maintained for a period of time (appropriately 20-24 hours), then the reaction mixture is cooled to 20-25 ° C and an appropriate non-polar solvent (for example , Dichloromethane). Add lye (suitably 0.880 ammonia solution) dropwise and keep the temperature between 20-25 ° C. A further non-polar solvent was added, and the aqueous phase was subsequently separated and further extracted with a non-polar solvent. The combined organic phases were washed with water and evaporated to dryness. The residue was re-dissolved and the non-polar solvent was evaporated to obtain a compound of formula (VIR) or formula (VI). The above-mentioned preparation method of the protected form of the compound having the chemical formula (VIR) and the compound having the chemical formula (VI) can also be carried out in two stages, wherein the intermediate compound having the chemical formula (VIBR) or the chemical formula (VIB) is isolated separately:

Among them, A is defined as A8 of the compound having the chemical formula (X) and the chemical formula (XA) above. Generally speaking, a mixture of a compound of formula (IX) and a compound of formula (X) or (XA) is dissolved in an appropriate solvent (for example, tetrahydrofuran) at an appropriate temperature (generally the reflux temperature of the solvent) Stir for a certain period of time (appropriately 20-24 hours) under an inert atmosphere (suitably nitrogen atmosphere). Further add the compound of formula (IX), and heat the mixture to an appropriate temperature of -18-84387 200401771 (usually the reflux temperature of the solvent), and then keep it under an inert atmosphere (appropriately a nitrogen atmosphere) for a period of time (appropriate) For 3-6 hours). The reaction mixture is then cooled to a certain temperature (appropriately 20-25 ° C), and an appropriate co-solvent (for example, diisopropyl acid) is added to allow the mixture to sink. After filtering, further washing with co-solvent and vacuum drying, the compounds with chemical formula (VIBR) or chemical formula (VIB) were isolated. Then, the protected form of the compound having the chemical formula (VIR) or the chemical formula (VI) can be prepared from the compound having the chemical formula (VIBR) or the chemical formula (VIB), and the preparation conditions are the same as the chemical formula (VI) The conditions required for the reaction of the compound of IX) with the compound of formula (X) or (XA) are similar, except that the reflux step is omitted before adding the phosphine and azo compound. In general, the reaction (c) is to dissolve the compound of formula (VII) in a suitable solvent (for example, a mixed solution of methanol and water) with stirring, and add an appropriate test (for example, 4A carbonate). The mixture is stirred at an appropriate temperature (for example, 20-25 ° C) for an appropriate time (for example, 16-20 hours). The organic solvent was then removed by vacuum evaporation. Thereafter, water was added, and the mixture was extracted with an appropriate organic solvent (for example, ethyl acetate). The combined organic phases are then washed with water and a saturated aqueous solution of steel chloride, and then dehydrated with a suitable desiccant (for example, sulfuric acid # 3), filtered, and the organic solvent is evaporated in vacuo. The crude product was then purified by flash chromatography. The method of separating a compound of formula (VI) from a racemic product (ie, a compound of formula (VIR)) can be carried out by methods already known to those skilled in the art, for example, by preparation Orthotropic high performance liquid chromatography (paraisotropic HPLC) or stepwise separation from diastereomeric salts -19- 84387 200401771 crystal method. Compounds of formula (VII) can be prepared by reacting compounds of formula (VIII) with 3,4-dichlorobenzyl chloride:

π (VIII) In general, the reaction of a compound of formula (VIII) with 3,4-difluorofluorenyl chloride is in a suitable solvent (eg, Ν, Ν-dimethylformamide) and in an inert atmosphere. (For example, nitrogen monoxide), and the addition of a suitable base (for example, potassium carbonate) and a suitable activator (for example, sodium iodide). Then, the mixture is stirred at an appropriate temperature (for example, 20-25 ° C) and maintained for an appropriate time (for example, 16-20 hours), and then the volatile components are removed under a vacuum condition. The compound of formula (VIII) can be prepared by using an α, α, α-trifluoroethyl acetate solution dissolved in a suitable organic solvent (for example, diethyl ether) under an inert atmosphere (for example, nitrogen Gas), prepared by treating a solution of morpholin-2-yl-methylamine dissolved in a suitable organic solvent (for example, methanol). Then, the mixture is stirred at an appropriate temperature (for example, a temperature range of 20-25 ° C) for 20-40 minutes, and then the volatile components are removed under vacuum. The residue is then dissolved in a suitable organic solvent (for example, methanol) and the volatile components are removed under vacuum. Compounds of formula (V) are well known to us and can be disclosed by general methods (for example, they are equal to those disclosed in Ein * · J. Med · Chem · (1993), 28 (7-8), 625-32 Method) preparation. Ethylamine, 4-nitrophenyl chloroformate, 2-[(3,4-dichlorobenzyl) amino] ethanol, 2- (ethylene oxide-2-ylmethyl) -1Η- -20- 84387 200401771 isoindole-1,3 (2H) -dione, 3,4-dichlorofluorenyl chloride, morpholin-2-ylmethylamine, 2-[(3,4-dichlorobenzyl) amino ] Ethanol and 〇1, 〇1, (1-trifluoroethyl acetate are both well-known and commercially available compounds, or these compounds can be similar to my well-known methods (for example, the standard reference for synthetic methods (For example, methods disclosed in J. March, Advanced Organic Chemistry, Third Edition (1985), Wiley Inter science). Novel compounds refer to compounds of formula (II), ( III), (IV), (VI), (VII), (VIBR), and (VIB) compounds. Therefore, the present invention provides a compound of formula (II). It also provides a compound of formula (III) A compound of the formula (IV) is also provided. A compound of the formula (VI) is also provided. A compound of the formula (VII) is also provided. A compound having the chemical formula (VIBR). A compound having the chemical formula (VIB) is also provided. A suitable protecting group in any of the above reactions is a group commonly used in the art. Formation and removal of such protection The methods of groups are their general methods applicable to protected molecules, for example, standard references for synthetic methods (for example, PJ Kocienski, Protecting Groups (Protecting Groups), (1994), Thieme) The method of discussion. For any of the aforementioned reactions or methods, general heating or cooling methods can be used, for example, a hot plate and an ice / saline bath, respectively. Depending on the situation, general Purification methods, for example, 84387 -21-200401771 can use crystallization or column chromatography. Salts and vehicles of compounds of formula (I) can be obtained by compounds of formula (I) or appropriate salts thereof. Or the vehicle is prepared and isolated by general methods. The compounds of the present invention can be tested for in vitro biological activity by the following analytical methods: (a) CCR-3 binding圻 The affinity of novel compounds for CCR-3 was analyzed by CCR-3 competition combined with SPA (Scintillation Approximation Analysis) method. A membrane (2.5 μg / well) prepared from K562 cells stably expressing CCR-3 was taken and Wheat germ agglutinin SPA microspheres (Amersham Pharmaceuticals) were mixed and cultured at 4 ° C in binding buffer (HEPES: 50 mM; CaCl2: 1 mM; MgCl2: 5 mM; 0.5% BSA) 1 ·5 hours. Then add 20 pM of [125I] eotaxin (Amersham Pharmaceuticals) and compounds in increasing concentrations (between 1 pM and 30 μM) and incubate in 96-well plates at 22 ° C for 2 hours, then in Microbeta plates Count on the counter. The total analysis volume was 100 microliters. Substitute competitive binding data into a four-parameter logic formula for analysis. Data are expressed as mean pIC5G (negative logarithm of compound concentration when [125I] eotaxin binding is inhibited by 50%) obtained from at least two experiments. (b) Eosinophil chemotactic analysis The inhibitory effect of this compound on eosinophil chemotactic analysis was analyzed. The eosinophil cell line was obtained by purifying circulating blood around the human body using a standard CD16 cell depletion reaction. The equipment used was a Miltenyi cell separation column and a magnetic Super Macs magnet (Motegi &- 22- 84387 200401771

Kita, 1998; J. Immunology · 16: 4340-6). The cells were resuspended in RPMI 1640/10% FCS solution and cultured with calcein-AM (Molecular Probes) at 37 ° C for 30 minutes. After culturing, the eosinophils were centrifuged at 400 g for 5 minutes and resuspended in RPMI / FCS solution at a concentration of 2.2 million cells / ml. Then, incubate at 37 ° C for 30 minutes at increasing concentrations of the compound of the present invention (between 1 pM and 30 μM). Cells in the control reaction group were cultured using RPMI / FCS only. The activator eotaxin (EC8G concentration) was added to a 96-well chemotaxis assay plate (5 micron filter: Receptor Technologies). Add fibrinoblasts (50 μl, 2 million cells / ml cells) to the grid on the filter plate, and incubate at 37 ° C for 45 minutes. After removing the cells left on the chemotaxis assay plate, the number of migrating pupal eosinophils was quantitatively read on a fluorescent plate reader. The inhibitory effect of the compounds of the present invention on the chemotactic properties of eosinophils was analyzed by substituting data into a four-parameter logical formula. The value of the function pKi (fpK0 is calculated using the following formula (Lazareno & Birdsall, 1995. Br. J. Pharmacol 109: 1110_9): fpKi = busy 50 l agonist j The compound of the present invention is combined with CCR-3 And / or eosinophil chemotactic assays (Analytical Methods (a) and (b)). When the compound of the present invention is tested by the CCR-3 binding assay, its pIC5 () value 9.2. When the compound of the present invention is tested by the CCR-3 eosinophil chemotactic assay, its fpKi value is 10.0. Examples of conditions in which the compound of the present invention has a potent anti-inflammatory effect are -23- 84387 200401771 including · Respiratory diseases such as bronchitis (including chronic bronchitis), bronchiectasis, asthma (including asthma reactions caused by allergens), chronic obstructive pulmonary disease (COPD), cystic fibrosis, sinusitis, and rhinitis. = Intestinal diseases are also included, for example, inflammatory diseases of the intestine, including inflammatory bowel disease (for example, ^ ', Crohn's disease or ulcerative colitis) and due to exposure to radioactive substances or allergens Inflammatory bowel disease On the other hand, the compounds of the present invention are useful in the treatment of nephritis, skin diseases \ for example, 'dryness, wet therapy, allergic dermatitis, and hypersensitivity reactions] and central nervous system diseases (for example, Alzheimer's disease, meningitis, multiple sclerosis), HIV and AIDS dementia. The compounds of the present invention can also be used to treat nasal polyps, conjunctivitis, or cancer pain. The compounds of the present invention have potential for effective treatment of conditions -Examples include cardiovascular diseases, such as atherosclerosis, peripheral vascular disease, and idiopathic eosinophilia.… And self-touching chemicals can be used as immunosuppressive agents and therefore can be used for Treatment of immune-dependent diseases', for example, tissue rejection after allogeneic transplantation, rheumatoid arthritis, and diabetes. / The compounds of the present invention can also be used to make metabolism. :: Mingxin: The main diseases that the compound can treat include: asthma , ⑶ 叩 and Jilang rhinitis and perennial rhinitis cause upper respiratory inflammatory diseases. Those who are familiar with this technique should understand that fSp ^ H ^ + and heart treatment < range Extending to preventive treatment and the treatment of established conditions. As mentioned above, the present invention can be used as a therapeutic drug with other aspects of the present invention. It also provides compounds having the formula ⑴ Or 84387 -24-200401771 its physiologically acceptable salt or vehicle, which will be used as an active therapeutic agent. Therefore, another aspect of the present invention is to provide a compound of formula ⑴ or a physiologically acceptable salt Or vehicle, which will be used for the treatment of inflammatory conditions (for example, asthma or rhinitis). Another aspect of the present invention is to provide a compound having the formula VII or a chemically acceptable salt thereof or Use of a vehicle for the manufacture of a medicament for the treatment of an inflammatory condition, such as asthma or rhinitis. Another aspect of the present invention is to provide a method for treating an inflammatory condition (e.g., asthma or rhinitis) in a human or animal subject, which method comprises administering an effective dose of a compound of formula VII or a physiologically acceptable Accept the vehicle. The compounds according to the invention can be formulated in any convenient form for administration. Therefore, the present invention further provides a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt or vehicle thereof, and optionally one or more physiologically acceptable dilutions. Agent or vehicle. The invention also provides a method for preparing such pharmaceutical formulations, which comprises compounding a compound of formula (I) or a physiologically acceptable salt or vehicle thereof with one or more physiologically acceptable diluents or solvents. Agent. Oral Compounds of the present invention can, for example, be prepared as oral, nasal, buccal, parenteral or rectal administration, preferably in the form of a medicament.砩 oral form

Oral lozenges or capsules can contain general excipients (for example, eight doses, such as syrup, acacia gum, gelatin, sorbitol, Scutellaria H starch paste, cellulose or polyvinylpyrrolidone), filling Agents (for example, A multi-mouth, lactose, 84387 -25- 200401771, Yoshitsugi, Tachibana, 隹 sugar, corn flour, phosphate or sorbitol), lubricants (for example, magnesium stearate, hard Fatty acid, talc, polyethylene glycol, or silica), dehydrating agents (such as' potato starch, croscarmellose sodium, sodium starch glycolate), or wetting agents (such as dodecyl sulfate steel) ). Bonding agents can be dyed and coated by methods well known to those skilled in the art. ',,,'-Cold oral liquid preparations can be used, for example, aqueous or oily suspensions, rosal, saccharine, sugar, etc., or silk-drying products can be formulated with water or other appropriate vehicles before use. These liquid preparations may contain: J 'Kato,! L and J such as' suspending agent (for example, sorbitol; vitamins: glucose / sugar, gelatin, methylcellulose, chitosan Base I; dihard or hydrogenated edible fats, etc.), emulsifiers (for example, lecithin, 1st sugar sugar oleate or acacia gum), non-aqueous vehicles (including edible oil ' For example, 'almond oil, refined nougat oil, or ethanol) or preservatives (for example: Bingzhizhibai, Pingchong salt, flavouring agents, food or sweeteners (for example, mannitol). Pigments and 7 Oral administration group of human makeup, in the form of tablets. ° Domain-general tincture or sugar coating. The present invention: Compounds can also be made into suppositories, generally suppository bases, such as cocoa butter or other glycerol. 5 There are compounds of the present invention # 万 了 is made into parenteral preparations, for example, or continuous infusion, and can be. Dawan / Wangshe vial, small volume injection ㈣ 王 早 ^ 彳 type exists, for example%, 杳 tile, device, which is added with antiseptic /:,: The form of 'Wang Shezhai' or multi-dosage type Rotten Heart Composition can be used in water Non-aqueous 84387 '26-200401771 A solution, suspension or emulsion formed in a sexual vehicle and may contain formulating agents such as antioxidants, buffers, bacteriostatic agents and / or osmotic pressure regulators. Or' active ingredients It can be in the form of a powder, which is formulated with a suitable vehicle (for example, 'sterilized non-pyrogenic water) before use. A dry solid preparation can be prepared by aseptically filling sterile powder into individual sterile containers or The sterile liquid is filled into each sterile container in a sterile manner and freeze-dried. The compound and the pharmaceutical preparation according to the present invention can also be combined with other agents, such as τ ′ antihistamine agent, anticholinergic agent , Anti-inflammatory agents such as adrenal corticosteroids (for example, fluticasone propionate, beclomethasone dipropionate, mometasone: ^ mannate, triamcinolone ) Acetone, budesonide) or other non-steroidal anti-inflammatory agents (NSAIDs) (e.g., Segan fei steel, nedocromii sodium, pDE-4 inhibitors, White beetle antagonist, iNOS inhibitor, tryptase and elastase inhibitor, beta-2 integrin antagonist and adenine nucleoside 2a agonist), or p-adrenal stimulant (for example, samoterol ( salmeter〇1), salbutamol (salbutamol), formoterol, fenoterol (teroterol), terbutaline and salts thereof, or anti-infectives (for example, Antibiotic agents and antiviral agents). It should be understood that when the compound of the present invention is used in combination with other agents usually administered by inhalation or nasal administration, the formed pharmaceutical composition can be administered by inhalation or nasal administration. A suitable dosage of the compound of the present invention may be, for example, up to 500 mg / kg body weight, preferably 0.01 to 500 mg / kg body weight, more preferably 0.01 to 100 mg / kg body weight, and the frequency of administration may be Any appropriate frequency -27- 84387 200401771 rate, such as 1 to 4 times a day. The precise dosage course will of course depend on the condition being treated by the patient, the age and condition of the patient, and the medication to be selected, the dosage. > In the scope of this specification and the patent application below, unless the context otherwise stipulates, the words "including" and variations thereof "including" and "including" shall be understood as implying the inclusion of the stated integer or step or Integer group, extension does not mean that it does not include any other integers or steps or groups of integers or steps. [Embodiment] jjjg experimental method LC / MS A Μ This system uses 3 microns ABZ + PLUS (3.3 cm x 4 · 6 mm , Inner diameter) of the column, dissolve with the following solutions: A a volume / volume percentage of 0.01% formic acid + volume / weight percentage of 0.0077% ammonium acetate aqueous solution; B_ 95: 5 (acetonitrile: water) + Formic acid with a volume percentage of 0.05% and a flow rate of 3 ml / min. The following gradient formula was used: 100% A, 0.7 minutes; A + B mixture, with a gradient of 0-100% 8, 3.5 minutes; Keep in 100% 3 solvent for 1.1 minutes; re-use 100% A solvent, 0.2 minutes. Thermal spraying spectrum Thermal spraying mass spectrometry was performed on HP 5989A engine mass spectrometer, + ve thermal spraying, heat source temperature is 250 ° C, the probe temperature is 12 °. (] (Column) and 190 °. (¼ 4) '^ Wood quality f range is 100-85 amu. The compound dissolved in 10 microliters of solvent mixture was injected at a rate of 0.7 ml / min, said solvent mixture containing 65% Methanol and 35% ammonium acetate aqueous solution of 0.055 M. The method of taking Γ leather away from the hand, 84387 -28- 200401771 SCX "refers to isoii Flash SCX-2 continuous acid solid phase extraction column. All temperatures The units are: C. Compound name 1 ^ Name of substance 1-: 2,2,2-trigas- > ^ (? 4-2-A methyl group, acetamidine under nitrogen, in To a homogeneous solution of morpholin-2-ylmethylamine (3.1 g) and methanol (70 ml) was added an α, α, α-trifluoroethyl acetate ether solution (5 ml of α, α, α-trifluoro Ethyl acetate was dissolved in 20 ml of ether, the α, α, α-trifluoroacetic acid ethyl acetate was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine and dehydrated.) The mixture was stirred at 22 ° C for 30 minutes, Then all the volatiles were removed under vacuum. The residue was dissolved in methanol (methanol) and the volatiles were removed again under vacuum to give the title compound as a white frangible foam. (4.9 g) Thermal spray mass spectrum: m / z 2 13 [MH +].

Name 2: N_U4- (3,4-dibenzyl)? 4-2-?] Methyl 9 X Gas ethyl amine 1 Under a nitrogen blanket, the compound containing the name 1 (3 · 3g) Team ice dimethylformamide (50ml) was added potassium carbonate (246g) and sodium iodide (2.12g). A solution containing 3,4-dichlorobenzyl chloride (2 ml) in N, N-dimethylformamide (100 liters) was added dropwise to the mixture. The mixture was mixed at 22 ° C for 8 hours, after which the volatiles were removed under vacuum. The residue was partitioned between dichloromethane (100 ml) and a saturated aqueous sodium carbonate solution (50 ml). The organic phase was subsequently washed with saturated aqueous sodium carbonate (2 x 50 ml) and water (50 ml), then dehydrated with magnesium sulfate, filtered and the solvent was evaporated in vacuo to give a pale yellow oil. Qian was subjected to chest post flash chromatography on a 90 vermiculite column to purify 84387 -29- 200401771 (using a 25% solution of ethyl acetate in a ring of burned solution) to give the title compound (2.97 g) as a colorless oil. B (: degree 8 (system eight): 1 ^ 2.63 minutes; mass spectrum: 111/2 371 [1 ^ +]. 1 compound name _. Called 3_: "4- (3,4- two donated sheep) Porphyrin-2-methylpyridamine was added to a stirred solution of the compound 2 (2.97 g) in methanol (15 ml) and water (5 ml), and potassium carbonate (5.53 g) was added. The mixture was heated at 22 ° C. Stir for 18 hours, then remove the methanol under vacuum. Add water (25 ml) and extract the mixture with ethyl acetate @ § (3x30 ml). Wash with water (5 ml) and saturated aqueous sodium chloride (10 ml) The combined organic phases were then dehydrated and dried over sodium sulfate, filtered and the solvent was removed under vacuum to give a pale yellow oil. The oil was purified by Biotage flash chromatography on a 90 g silica column (using 75: 8: 1 bis gas methane / ethanol / 〇.880 ammonia solution). Combine the required fractions and evaporate the solvent in vacuo to give the title compound (185 g) as a colorless oil. LC / MS (System A): Rt 1.77 Minutes; mass spectrum: m / z 275 [ΜΗ +]. Weigh 4: [4- (3,4-dichlorobenzylhydrazine)? H-based 1 amine (another synthesis method) ( 3,4-dichlorobenzyl) amino] ethanol (CAS No. 40172-06-3, 0.980 g) and 2- (ethylene oxide-2-ylmethyl) -iH-isoindole-1,3 ( A mixture of 2H) -diketones (ΐ · ΐ 克) was heated at 80.0 ° for 3 hours. The resulting solid matter was treated with concentrated shiwa acid (1.5¾ liters) and thereafter at 15.0 ° C. Stir for 24 hours. Treat the resulting mixture with water (100 mL), then wash with ethyl acetate (2 x 100 mL). Check the dark aqueous phase to about pH 12 with 5 M aqueous sodium hydroxide solution, then use acetic acid Extract with ethyl acetate (2 × 100 mL). Wash the combined organic extracts with water and brine, dehydrate (Na 2 g 04) and concentrate at -30- 84387 200401771 in vacuo to give the title compound as a brown oil (ι 02 g ). LLMS (System A): Rt. 6 minutes. Chemical compound m 氪 芊) morpholine-2_ 某 1 methyl benzene by preparative HPLC, the name 3 compound (racemic mixture, 8 Gram) is a single enantiomer. This separation method is performed by using a 2.0 cm Chiralpak AD 20 mechanical meter column and a self-assembled DAc system of Merck Pharmaceuticals. 'Combined with 95: 5: 0.1 (volume ratio) of heptane: absolute ethanol: diethylamine / hydration / valley separation (flow rate of 55 ml / minute, dissolution time of 40 minutes, UV measurement wavelength 225 nm); Sample-loaded preparation ... 400 mg of the sample was dissolved in 20¾ liters of absolute ethanol: system eluent with a volume ratio of 3: 2. The title compound (2.49 g) was prepared in the following manner: preparative HPLC with a residence time of 23.0 minutes. Weigh 5 (Another combination method. Heat a slurry of water (8.5 ml) containing the compound 7 of the name (1.00 g) to 75 ^, and then add concentrated sulfuric acid (2.5 ml) dropwise. Then, heat the mixture to reflux Temperature. After 23 hours, the mixture was cooled to 22 ° C and then treated with dichloromethane (6 ml). Subsequently, 880 aqueous ammonia (7 ml) was added dropwise under cooling. More monochloromethane (10 ml) was added. The aqueous phase was separated and extracted with more dichloromethane (10 liters). The combined organic phases were washed with water (5 ml) and evaporated to dryness. The resulting residue was re-dissolved in dichloromethane and the solvent was re-evaporated. , To give an oily product (662 mg). Name 嵇 6 ·· l- 「r2SV4- (3j-dichloro 芊) ming 4-2-some 1 formic acid Π: Π addition salt will give the compound 3 (0.613 g ) Dissolved in methanol (12.3 ml). -31-84387 200401771 D-tartaric acid (0.335 g) was added and the suspension was heated to reflux temperature for 50 minutes. The mixture was cooled to 0-5 ° C and filtered through Sediment was isolated to give the title compound (0.4 g) as a white solid. ee: 76% ee analytical palm HPLC (Chiralpak AD column, 4.6x250 mm, eluent MeOH: EtOH: butylamine ratio 50: 50 ·· 0.1, flow rate 0.5 ml / min, 11 \ ^ Detection wavelength 22〇11111)): 1 ^ 8.9 minutes. Chemical Jv name f Ran 7. 2-f4- (3,4- two gas-卞 某 吗 成 -2- 荜 1- 异 4 丨 口 朵_173 · Dione under nitrogen blanketing will be "[[3,4_Dichloroethenyl] amino] ethanol (2038 g) and (S) _2 (% ethoxy-2-yl-methyl)" A mixture of -1Η-iso4budol_l, 3 (2H) _dione (2.032 g) in tetrahydrodecane (3.3 ml) was stirred and heated to reflux temperature. After 21.5 hours, more tetrahydrofuran ( 12.5 ml) and the mixture was cooled to 3 ° C. To this mixture was added triphenylphosphine (2.793 g) and stirred until all solids were dissolved. Then, the temperature was kept below 7.0, and at Diisopropyl azodicarboxylate (21 ml) was added over 12 minutes. After 2.25 hours, the resulting mixture was heated to 22 ° C. After 5.3 hours, more di-privylphosphine (121¾ g) and azo were added Diisopropyl diisopropionate (q.q9ml). After 22.5 hours, The reaction mixture was concentrated to near dryness. Propane-2-ol (12 mL) was added and the concentration step was repeated before repeating this process again. Add more prop-2-ol (12 mL) and heat the mixture to 7 0 ° C. After 0.5 hours, the slurry was cooled to 22t, and the product was collected by filtration after another 2 hours. The filter bed was washed with propan-2-ol (2x4 ml) and then at 40 ° C. Vacuum drying was performed at 0 ° to obtain the product (2.622 g). -32- 84387 200401771 ϋ. Name 8 ·· | Υg) -4- (3,4-Digasoyl)? 4-2-A 1-methyl sulphate _acid_4_ nitrate The ester was added dropwise to a solution containing 4 mg of chloroformic acid (2.92 g) in anhydrous dichloromethane (10 ml) under a temperature of 0C and nitrogen in 10 minutes, containing the compound with the name $ (4.0 g ) With triethylamine (2.07 ml) in anhydrous digas methane (5 ml). The mixture was warmed to room temperature and stirred for 2.5 hours. The evaporation agent was then removed by evaporation, and the residue was purified by silica gel by Biotage flash chromatography, and then dissolved with a 25-50% solution of ethyl acetate in cyclohexane to give the title compound (3.8 g). LC_MS (System A) · Rt 3 · 1 minute. Mass spectrum: m / z 440 [ΜΗ +].

Carbonyl 1 amine, a certain 1 benzyl, a benzamidine beer, 3-aminomethyl-benzoic acid methyl ester (0.1817 g), which has been evenly beaten (such as 1 plant

Med · Chem · 1993, 28 (7-8), 624-632) solution of N, N-dimethylformamide (4 ml) was added with N, N-dimethyl compound containing the compound of the name 8 (0.4612 g) Formamidine (4 ml) solution. N, N • diisopropylethylamine (0365 ml) was added and the mixture was at 20 ° C. (: Stir for 4 hours. This mixture was allowed to stand for another 67 hours, and then diluted with methanol (about 5 ml), and then the mixture was passed through a 2x10 g SCX ion exchange column (IST Isololute Flash SCX treated with methanol in advance). -2). The exchange column was dissolved with methanol and 100 / 0.08 of ammonia in methanol, and the separated ammonia fractions were combined and evaporated in vacuo. The resulting residue was subjected to Biotage ™ flash chromatography. Silica gel purification and dissociation with 200: 8: 1 dichloromethane / ethanol / 0.880 ammonia solution to give the title compound (0.4237 g) as a pale yellow gel. 84387 -33- 200401771 LC / MS (System A): Rt = 2.59 minutes, m / z 466, 468 [MH +]. Called chloro 芊 a) 噍 _9_ early 1 base amine 蕤 蕤 1 1 amine）) 甲 苽 苽 苽 苽 苽 苽 苽 苽 已 含 名称To a solution of 9 compound (0.3869 g) in methanol (10 ml) and hot propan-2-ol (7 ml) was added 2 M aqueous sodium hydroxide solution (0.85 ml) and water (5 ml). The mixture was stirred at 2 ° C for 20 hours, and then the solvent was evaporated under vacuum to obtain a white solid. This solid was re-dissolved in water, and 2M hydrochloric acid was added, and the resulting solution was adjusted to a pH value of about 6. Pass the mixture through a 2x10g SCX ion exchange column (1ST Isolute Flash SCX-2) which was previously treated with methanol. The exchange column was dissolved with methanol and 5% triethylamine in methanol. It was found that the product had Dissolve to combine the first separated methanol> Spring separation to evaporate the solvent to recover the crude product. The solid was re-dissolved in water and 2M hydrochloric acid was added, and the pH of the resulting solution was adjusted to about 1. Make the The mixture was passed through a 2750 g SCX ion exchange column (1ST Isolute Flash SCX-2) which had been previously treated with methanol. The exchange column was dissolved with methanol and 5% triethylamine in methanol. The first triethylamine was separated. The fractions were combined and then the solvent was evaporated under true conditions to give the title compound (0.186 g) as a light brown oil. LC / MS (System A) · Rt = 2.45 minutes, m / z 452, 454 [MH +] Example 1: 3-({[(((| ~ (28) -_ 4 二 (3,4- 二 翥.Character base)? 啦 -2- 莘 ~ | 甲某} ticks>) carbonyls 1 amines) a certain VN-Eumen 苽 a 苽 credit on 2 (TC, in the mixed evenly containing the name 1 〇 Compound (0035 g) in N, N-dimethylformamide (1 ml) was added with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 0.0208 g) and 1-side benzotriazole 84387 -34- 200401771 (0.012 g) in a solution of N, N-dimethylformamide (1 ml). Then N, N-diiso A solution of propylethylamine (0.0196 ml) and 2M ethylamine in tetrahydrofuran (0.282 ml), and then the mixture was stirred at 20 ° C. for 8 hours. Diluted with methanol (about 2 liters) The resulting mixture was then passed through a 5 g SCX ion exchange column (IST Isololute Flash scx_ 2) previously treated with methanol. The exchange column was dissolved with methanol and a methanol solution of 〇〇880880 Initially, the ammonia-soluble fraction was evaporated in vacuo, and the obtained residue was further purified by silica gel using Biotage ™ flash chromatography, and then separated by dichloromethane / ethanol / 0.880 ammonia falling solution at 100: 8: 1 to obtain a colorless glass. Status mark Title compound (00 gram). LC / MS (System A) · Rt — 2.35 minutes, m / z 479, 481 [MH +]. 84387 -35-

Claims (1)

200401771 The patent application park: 1. A compound with the chemical formula (1), its salt and its intermediate: 2. · A method for preparing a compound having the formula ⑴, or a salt or a vehicle thereof, which method comprises coupling a compound having the formula (") or a salt thereof with ethylamine. 3. 4. For example, the compound in the scope of patent application No. 1 , Which is used as a medical agent for > Taiwan medical treatment of or suffering from 'inflammatory diseases of humans or animals' medicinal preparations' which includes effective doses of the compounds in the scope of patent claims i and their Physiologically acceptable carrier. 5. 6. A pharmaceutical composition comprising a compound as claimed in item i of the patent application and a physiologically acceptable carrier thereof. A compound of formula (II): 84387 200401771 8. — a compound of formula (IV): 9. A compound of formula (VI): 〇 CF3C (0) NH ^ X ^ kv ^ 〇Vs ^ h3c, 10 ·-a compound of formula (VII): 84387 -2-200401771 11. A compound having the chemical formula (VIBR): Where A is a protected amine group. 12. — a compound of formula (VIB) Where A is a protected amine group. 84387 200401771 Dyeing and designated representative map: (1) The designated representative map in this case is: (). (2) A brief description of the component symbols in this representative map: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 84387