TW201728B - - Google Patents

Description

Printed by the Central Bureau of Standards of the Ministry of Economic Affairs ^ 01728 A6 _ B6 V. Description of the invention (1) The present invention relates to an aryl hydroxyurea compound with anti-inflammatory activity and its preparation method, including any one or more of it Pharmaceutical blends of various active ingredients, and the use of such compounds in medicine. The European patent specification 0 0 5 54 1 8 discloses a group of compounds that act as the second animal of the milk animal II and I — Likou Oxygen. Decay carbonate metabolic pathway 5 —fat oxygenation and enzyme, and found that it has a inflammatory effect And related activities, other compounds that have been shown as 5-lipoxygenase and / or cyclooxygenase inhibitors include some naphthoxy derivatives, such as US Patent 3, 740, 43 7 or Proc. Ann. Symp „I n s t„ Basic Med. Sci., Royal College of Surgeons of England, October 1 9 8 2, ρ P 2 6 3-2 7 4 disclosed, the compounds shown in the latter reference materials include known nafazatron compounds. European patent 〇1 9 6 1 8 4 shows some hydroxamic acid derivatives as inhibitors of 5-lipoxygenase enzyme. European patent specification 〇 2 9 9 7 6 I reveals that the primary group belongs to European patent specification 0 1 9 6 The range of oxygen β-defective compounds disclosed in 1 8 4 is α-homogenated N-gauge aS-based oxo-acid acid. This compound has a particularly suitable inhibitory property of inhibitor 5-lipoxygenase. In the compounds disclosed in Europe 09696184, I found another group of sub-groups with particularly good pharmacology and 1 embedding property. The compound that can be proved by its two enantiomers is characterized by ®-methylated N-methyl group (please read the precautions on the back before filling out this page). Λ (Όιπν 78. 8. 3,000

A r-0-A r 1 —Y— C-N 5. Description of the invention (2) Urea 0 Thus, the present invention provides the compound represented by the chemical formula (1) and its base and physiologically functional calcined organism Η

OH ^^ CONR 1 R2

CH (please read the notes on the noodles before filling out this page) • Install · In

Ar is 4-halophenyl; set.

Ar is 1, 3—or 1 * 4-phenylene Y is CE) —CH = CH-; and R 1 and R 2 are selected from hydrogen and C. 4 alkyl, respectively. It is suitable for the compound shown in formula C 1) and its fan shoulder to exist in the form of CR) or C s) enantiomers, so the present invention includes the compound of formula CI). The quality of the compound is less than 5% C) Another individual enantiomer CR) _: Ή CS) envelope. With the isomers and its, forgive, and any comparable to this example, a mixture of heterologous combs, including containing substantially equal 1 The second is the enantiomeric racemic mixture. The more suitable compounds of the present invention include A4 (21 〇Χ297 public). Thread. Qi Shibu Central Standard Bureau printed crack 78. 8. 3,000 A6 B6 V. Description of the invention (3)

Ar is 4-fluorophenyl; and / or Αχ · 'is 1,3-phenylene; and / or 1 2 R and R are both ammonia; and their derivatives and physiologically functional derivatives. Chemical formula C 1) 之 化 # Among the particularly excellent 5-lipoxygenase inhibitory properties and antioxidant properties C, especially the persistence of its action) is CE) — Ν— {I — methyl-3 — [3-C4-Fluoroxy) phenyl] propan-2-yl-I-yl} -1 · ^ -hydroxyurea, preferably a racemic mixture of diastereomers. The alkali base suitable for compounds of the chemical formula C 1) is one in which Yang Linzi is acceptable, but the alkali temperature of non-physiologically acceptable Yang Zazi is within the scope of the present invention It can be used for non-pharmaceutical applications or as an intermediate for the preparation of compounds of formula C1) and their physiologically acceptable quaternary and physiologically functional derivatives. The base of the present invention includes ammonium base, metal bases such as sodium and potassium bases, alkaline earth metal bases and calcium and Hanwen, with organic bases C such as dicyclohexylamine and N-methyl-D-〗-amino groups Oxy-sorbitol), and amino acids C such as spermidine and lysine). ; '2 " Ministry of Central Standards Bureau seal-the above-mentioned chemical formula C1) compounds and their physiologically acceptable I absolutely and physiologically functional derivatives exist in the following discussion of the treatment of the present invention, pharmaceutical and synthetic aspects It is called "the compound of the present invention". One aspect of the present invention is to provide: 78. 8. 3,000 (please read the precautions on the back side first, then fill out this page). Order • Line. A 4 (210X297 public) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 201728 A6 ____B6 V. Description of the invention (4) C a) The compound of the present invention used for treatment C b) Contains the compound of the present invention, at least one anatomical body or excipient, and optionally one or more other species The pharmaceutical composition of therapeutic ingredients, Cc) Use of the compound of the present invention in the preparation of a medicament for the prevention or treatment of clinical conditions involving 5-lipoxygenase inhibitors or antioxidants; C d) Use of the compound of the present invention in Preparation of medicines for the prevention or treatment of the following diseases: ci) spasm symptoms, C ii) allergic conditions, C i Π) tumor formation, C iv) symptoms related to platelet aggregation, C v) inflammation symptoms, or C vi) movement Piper's sclerosis; (e) —Procedures for preventing or treating mammals such as humans) and 5-fat oxygenation 0§ Yang Zhao agent or clinical symptoms of antioxidants, which includes the treatment of the patients described in the treatment of effective Μ The co-organization of the invention; and (please read first Note on the back and then fill out this page). Pack · · Order · • Line · A 4 (210X297 public issue) 78. 8. 3,000 201728 A6 ____ B6 5. Description of the invention (5) C f) —Prevent or treat mammals C as a human) clinical symptoms, this clinical symptoms include: C i) spasticity, C ii) allergic symptoms, C iii) tumor formation, C iv) symptoms involving platelet aggregation, C v) inflammatory symptoms, Or C vi) Arteriosclerosis; this method comprises administering a therapeutically effective amount of the compound of the present invention to the patient described in Kazuto; C g) a method of preparing the compound of the present invention. Due to its 5-lipoxygen inhibitory properties, the compounds of the present invention can be used to prevent or treat the clinical symptoms of the twenty carbonic acid metabolism pathway between fat and oxygen, especially {please read the precautions on the back before filling in This page) • Installed • • Ordered. • Line. Symptoms of honey-induced leanness syndrome

V-shaped symptoms of coagulation, plate-shaped small hematoma and syphilitic inflammation and A4 (210X2972 #) 78 · 8. 3,000 201728 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs A6 B6 V. Description of invention (6) These will be This is discussed in order below. C i) Examples of spastic symptoms are those involved in the smooth muscle group, especially those involving airway smooth muscle contraction, such as internal asthma C includes spontaneous bronchial asthma and cardiac asthma), bronchitis and motile smooth contraction such as coronary artery palsy Convulsions C include those related to myocardial infarction, which may or may not) lead to weakened left ventricle and cause cardiac wheezing) and cerebral spasm or ** # hair ", and other dices include those caused by abnormal colon muscle constriction Intestinal diseases, such as the known "yang allergy syndrome", "deflated colon" and "mucinous colitis" and other symptoms. C ii Lao Symptoms of Laos are external wheezing, completely caused partly allergic skin diseases such as eczema, allergic intestinal diseases (including celiac disease), debilitating symptoms such as hay fever C It can additionally or selectively affect the upper respiratory tract), and allergic conjunctivitis 〇C iii), skinless, obese cell tumors and other forms of good azole and malignant proliferative proliferation, pay attention to It is that the effect of the present invention in preventing and treating tumors can be enhanced by the inhibitory effect of 5-lipoxygenated oxenol and the effectiveness of combating cell proliferation. C iv) Examples of symptoms of i-step and platelet aggregation are caused by thrombosis, including all or part of the "hair" from the beginning of the embolism, coronary artery embolism, # 脉 炎 和 # 脉 绣 塞 C 后 二 香Symptoms (please read the precautions on the back before writing this page) • Pack. • Order · A 4 (210X297 Gong Li) 9 78. 8. 3,000 ^ 01128 A 6 B6 5. Description of the invention (7) may also be inflamed related). C v) Inflammatory symptoms are Ca) lungs, Cb) joints, (c) gao, C d) intestines, C e) skin and C f) cardiac inflammatory symptoms, especially those involved in infiltrating inflamed tissues The example of this inflammatory symptom is: C a) Pulmonary inflammatory symptom includes asthma, cranial bronchitis and bismuth swollen fibers. Degeneration C which may additionally or selectively involve the intestine or other tissues).

Cb) Joint inflammation symptoms include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint symptoms.

Cc) Ocular inflammation symptoms include uveitis C including iritis) and conjunctivitis. (d) Symptoms of inflammation include Crohn's disease (localized enteritis), ulcerative colitis, and peripheral proctitis. C e) Inflammatory skin diseases include those associated with cell # colonization, such as psoriasis, eczema and dermatitis (whether it is an allergic origin) ° C f) Cardiac symptoms include coronary artery infarction injury. Printed by the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back first, then fill out this page). Hit the line. Other inflammation symptoms include diffuse inflammation of the group and the tissue rejection after transplant surgery. Because of its antioxidant properties, the compounds of the present invention can also be used πτ A4 (210X297 public) 78. 8. 3,000 ^ 01728 A6 B6 Printed by the Central Standards Bureau of the Ministry of Economic Affairs V. Description of invention (8) for prevention or treatment And the clinical symptoms of lecithin protective agents of this nature, such as arteriosclerosis and arthritis. Due to their unique properties, the compounds of the present invention can also be used to prevent or treat bacterial and microbial infections, dysmenorrhea, multiple sclerosis and clinical symptoms involving immunosuppressants, antispasmodics or analgesics. The compounds of the present invention also Has the activity of lowering blood cholesterol. In order to achieve the therapeutic effect, of course, the compound C of the present invention is hereinafter referred to as the active ingredient). The dosage will vary with the specific compound, the route of administration, the object of treatment, and the specific disorder or disease to be treated, suffering from the above clinical symptoms The appropriate dosage of milk animals is 0.1 μg to 500 mg compound / kg body weight. In the case of systemic administration, the dosage is usually 0.5 to 500 mg / compound / kg body weight. A milligram / kg body track, such as 5 to 25 mg / kg, is taken two or three times a day. In the case of local administration, such as skin or eyes), the appropriate range is 0.1 ng — 100 pg # / kg, usually about 0.1 μg / kg. In the case of oral administration to prevent or treat respiratory smooth muscle accommodation (such as asthma or bronchitis), the appropriate dose of the compound of the present invention may be specified over a period of time, but it is more preferably from 1 mg to 10 kg / kg Body weight, the most suitable clam is 1 € gram to 5 mg / kg ritual weight, such as 1 to 2¾ g / kg, in the case of lung administration, the dose should be 2 μg to 100 mg / kg, such as 20 μg To 0.5 mg / kg, special (please read the precautions on the back before filling in the hundred). Pack · • Order · • Line. A 4 (210X297 public) 11 78. 8. 3,000 Central Bureau of Economic Affairs of the Ministry of Economic Affairs Printed ^ 01728 A 6 ____B6__ Fifth, the description of the invention (9) is 0.1. To 0.5 mg / kg. Although the active ingredient can be administered alone, it is more preferable to administer it as a pharmaceutical blend containing the compound of the present invention and a pharmaceutically acceptable carrier or excipient and any one or more other therapeutic ingredients, of course the carrier Or the excipient must be compatible with other ingredients in the blend, and will not harm the patient, the active ingredient may account for 0. to 99.9% by weight of the blend, the typical single dose of the blend of the present invention contains milligrams to 1 Grams of active ingredients. When it is administered locally, the active ingredient should account for 1% to 2% by weight of the blend, but the active ingredient can be as high as 10% w / w. A blend suitable for oral administration through the nasal cavity usually contains (K1-20% v « / w, such as 2% w / w active ingredient. The blend of the present invention contains suitable for oral administration, transpulmonary, ocular, transrectal administration, injection administration (including subcutaneous, intramuscular and intravenous), intra-articular, Partially or in the form of nasal / oral administration. The blends of the present invention can easily exist in a single dosage form, and can also be prepared by any method known in the pharmaceutical art. All of these methods include the step of mixing the active ingredient with the carrier constituting one or more attached ingredients, usually blended The substance is mixed uniformly and tightly by mixing the active ingredient with a liquid carrier or a fine solid carrier (or both), and then shaping into the required shape if necessary. The compound of the present invention suitable for oral administration may be a discontinuous type such as Jiao Gong, tablets, tablets or lozenges, each of which contains a predetermined amount of active ingredients, (please read the precautions on the back before filling this page) • Installed • • Ordered. • Line 7R. 8. 3,000 2〇m8 A 6 B6 Printed by the Ministry of Economy Central Standards Bureau 5. Description of the invention (】 0) It can be in the form of powder or granules, formed in aqueous or non-aqueous liquids The solution or suspension may be in the form of oil-in-water or water-in-oil emulsion. The active ingredient may also be in the form of bolus, swift or paste. Tablet tide can be made by shrinking or molding the active ingredient and any one or more accessory ingredients. Compressed tablets can be compressed in a suitable machine by compressing the active ingredients in free-flowing form C (such as powder or granules) with a combination of 1, lubricants, inert diluents, and / or surface active or dispersed The mixture formed by the agent. Molded tablets can be prepared by molding in a suitable machine a mixture of powdered active ingredients moistened with an inert liquid diluent and a combined carrier. Recipes for administration of the formulation may be in the form of a sitting can, mixed with active ingredients and a carrier such as coconut oil, or may be in the form of an enema. Mixtures suitable for injection usually contain a sterile aqueous preparation with an active ingredient, which is preferably isobaric to the patient's blood. The compound suitable for intra-articular administration may be a sterile aqueous preparation containing the active ingredient (the active ingredient may be microcrystalline), such as an aqueous microcrystalline suspension. Micro-compounds and biodegradable polymer systems can also be used to administer active ingredients for intra-articular and ocular administration. Suitable formulations for topical administration include liquid and semi-liquid preparations such as lotions (from, lotions and preparations, water-in-water and oil-in-water emulsions and boxes, cartilage and pastes, solutions and suspensions such as drops. When taking eye drops, the active ingredients can be made into aqueous eye drops in the form of 0.1-1.0% w / v solution. {Please read the notes on the back side and fill in the nest page) • Packing · Order · Line . J3 78. 8. 3,000 zoma A6 B6 Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (11) Suitable inhalation preparations contain fine powder powders, which usually use various forms of a good amount of pressurized gas Sol, spray insert, or inhaler. The size of the powder or drops taken through the lungs through the oral cavity is usually about 0. 5-10 microns, preferably within the range of 1-5 microns to ensure that the size of the particles that can be introduced into the tracheal technique by nasal administration should be within the range of -10 to 500 microns to ensure that it stays in the nares. A well-dose inhaler is a pressurized aerosol disperser, usually containing a suspension or solution blend of active ingredients and liquefied propellant. When using this device, the metered volume is released through a valve on the conveyor The blend is usually 10 to 50 microliters to produce particles containing active ingredients. The suitable propellant contains some chlorofluorocarbon compounds, such as dichlorodifluoromethane, dichlorofluoromethane, two gas four Fluoroethane and its mixtures, blends may contain one or more latent solvents C (such as ethanol), surfactants (such as oleic acid or sorbose trioleate) antioxidants and suitable fragrances. A sprayer is a commercial device that uses a solution containing active ingredients or a floating liquid to make the pressurized gas C usually air or oxygen) through-a small Fenqiuri hole C venturi orifice) to generate acceleration or use ultrasound Stir into the therapeutic aerosol. The compound suitable for the sprayer is composed of active ingredients and liquid ceremonies. The content of active ingredients can be as high as the compound, less than 20% w / w. The carrier is usually water or a diluted aqueous alcohol solution, so it is advisable to add such as sodium chloride (please read the precautions on the back and then fill out this page) • Install _ • Order ·, line. A 4 (210X297 public) 14 78. 8. 3,000 printed by the Central Bureau of Standards of the Ministry of Economy A 6 B6 V. Description of the invention (12) Any additive with osmolarity of body fluids, optionally containing preservative C if the blend is not prepared aseptically), such as hydroxybenzoic acid Surfactants of methyl esters, antioxidants, fragrances, volatile oils, buffers. The formulation suitable for administration by inhaler contains finely powdered powder, which can be delivered by inhaler or placed into the nasal cavity by nasal inhalation. The powder in the inhaler is contained in a gel or cartridge C usually made of gelatin or plastic), which is broken or opened in place, the powder is sucked into the air through the inhalation device or transferred using a manual armature, inhaler The powder used may consist of the active ingredient alone or a powder mixture containing the active ingredient, a suitable powder release agent C (such as lactose) and any surfactant, the active ingredient usually accounting for 0 * 1-10 of the blend. w / w. In addition to the above ingredients, the blend of the present invention may contain a variety of additional ingredients such as 1 # release agents, buffers, fragrances, binders, surfactants, thickeners, lubricants, preservatives C such as hydroxypyridine Formic acid), antioxidant and emulsifier. The compound of the present invention is preferably combined with one or more other substances selected from antibiotics C (such as antibacterial agents), antimycobacterial agents, or antiviral agents, anti-weaver amines C, especially antihistamines with last-action effects), or The non-steroidal anti-inflammatory drug CNSAID) is used in combination. These mixed compounds can be administered at the same time, such as in the same blend or different blending functions, or within a short period of time in order to achieve the desired comprehensive treatment: nutritional efficacy, when the compounds are in the same blend When used in the substance, the blend of the present invention may contain 5 ^ 78. 8. 3,000 in addition to the compound of the present invention (please read the precautions on the back before filling in this page). Pack · A 4 (210X297 public) 15 ί: · Μ: νί · Printed by the Central Bureau of Standards

Cf, Q t%. A6 _ B6 V. Description of the invention (13) Parts 0 The composition containing the anti-osmium amine agent is suitable for preventing and treating asthma, and the suitable anti-histamine agent can be selected from European Patent Dish 008 5 9 5 9 and 0 1 1 7 3 0 2 show the anastomosis, the amount and dose of this anti-histamine can be selected from those cited in these two documents, a particularly suitable anti-histamine is CE)-3-C 6 — C 3 —pyrrolidinyl I — C 4 —methyl carbenyl) propanol 1E —siyl-C 2 —p-pyranoyl) propionate CE) — 3 — C 6— (3 —pyrrolidinyl 1 — C4 —Methoxy) Propyl 1 E monoalkenyl C 2 —Pyridyl) propionic acid. Other suitable anti-osmium amines are CE) — I — C4 monomethyl ketone) — I — [2 — pyroxyl) — 3 — I This tower burns a propanyl 1 — sieve, triprolidine. The composition containing NSAID is particularly suitable for the prevention and treatment of the above-mentioned symptoms of arthritis. I have found that the therapeutic effect of using this mixture in the treatment of arthritis symptoms is better than that of any kind of paddle alone, especially in the use of comprehensive During the treatment, it can reduce joint swelling and reduce the thickness of the synovial lining of the joint. In addition, when any of the prosthesis is used alone, it is impossible to detect the loss of protein and the loss of articular cartilage. Qi Shaoduo has the effect of infiltrating synovial tissue with leukocytes and other leukocytes. NS A ID C (especially those with high doses) is known to cause gastric ulcers. In addition to the observation of the improved therapeutic effect when using N SAID and the chemical combination of the present invention, the antioxidant properties of the latter can also be used to protect the soft cells. (Please read the precautions of the plan first and then fill this page) -¾ .. • Order. • Line · A 4 (210X297 Gonglu) 16 78. 8. 3,000 201728 A6 B6 V. Description of the invention (14) ^

Anti-ulcer effect of NSAID, so you can administer a larger dose of NSAID, please read the back < I matter, and less likely to cause the risk of ulcers. Therefore, the present invention also provides a pharmacologically adapted kiss suitable for oral or intra-articular injection, which comprises Compound C of the present invention as defined above) and at least one NSAID. Suitable NSAID inclusion items alminoprofen, amfenac sodium, aminoprofen, antitrazafen, antrafenine, auranofin, bendazac lysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen, cinmetacin, ciproquazone, clidanac, dexid, clozimate, dazid emorfozone, etodolac, fendosal, flunixin, fosfosal, ibuprofen, isoxepac, diacrein, diclofenac, difisalamine, difenpyramide, enfenamic acid, enolicam, epirizole, etersalate, etofenamate, fanetizole mesylate, fencloizac, fenclofenac, fenclofenac, fenclofenac, fenclofenac, fenclofenac , fluproquazone, flurbiprofen, fopirtoline, furcloprofen, furofenac, glucametacin, guaimesal, ibuproxam, indomethacin, isofezolac, isonixim, isoprofen, isoxicam, ketoprofen, lefetamine HC1, leflunomide, lofemizole f lon, lofemizole f lon meseclazone, miroprofen, nabumetone, naproxen, nictindole, nimesulide, orpanoxin, oxametacin, oxapad ol, oxaprozin, perisoxal citrate, pimeprofen, pimeCacin, piproxen, pirazolac, pirfenidone, piroxicara, pirprofen, pranoprofen, proglumetacin maleate, proquazone, pyridoxiprofen, sudoxicam, suprofen, talmetacin, talmetacin, talmetacin, talmetacin, talmetacin, talmetacin, talmetacin , tiflaraizole, timegadine, tioxaprofen, tolfenamic acid, tolpadol, tryptarnid, ufenamate and 'zidometacin. Ψ Central Standards Bureau printed 78. 8. 3,000 A6 B6 201728 V. Description of invention (15) The better NSAID is naproxen, flurbiprofen, ketoprofen itr aminoprofen, carprofen, clidanac, dexindoprofen, diclofenac, enfenamic acid, fenclofenac, flunoxaprofen, ibuprofen, indomethacin, isoprofen, loxoprofen, meclofenamate sodium, miroprofen, piroxtcam, pirprofen, pranoprofen, tiprofen, suprofen, suprofen The NSAIDs for the purpose of the invention are Clidanac, diclofenac, fill in ibuprofen, indomethacin, suprofen, naproxen, piroxicam, flurbiprofen, ketoprofen and tiaprofenic ac id. Page The following NSAIDs can also use C with the company symbol to represent C Chemical

Abstracts Index Guide, 1989) 480156S, AA861, AD1491, AD1590, AFP802, AFP860, AHR6293, A177B, AP504, AU8001, BAYo8276, BPPC, BW540C, BW755C, CHINOIN 127, CN100, C0893XX, CPP, D10242, DKA9, DKA9 EB382, EGYT2829, EL508, F1044, FZ, GP53633, GP650, GV3658, HG / 3, ITC1, ITF, ITF182, KB1043, KC8973, KCNTE16090, KME4, LA2851, LT696, LU20884, M7074, MED15, HG18311, MR714, MR714, MR714, MY309, ir N0164, 0N03144, PR823, PV102, PV108, QZ16, R830, RS2131, RU16029, RU26559, RUB265, SCR152, SH440, SIR133, SIR136, SIR92, SPAS510, SQ27239, ST281, SX1032, SY6001, SaH46798, TA60 , TEI615, TVX2706, TVX960, TZI615, U60257, UR2310, WY23205, WY41770, YM09561, YH13162, YS1033 ZK31945. Printed by the Central Standards Bureau of the Ministry of Economic Affairs ¾. A 4 (21〇X 297 public splash) 2017 ^ 8 A 6 B6 Hyun Printed by the Central Bureau of Standards of the Ministry of Economy V. Description of the invention (6) NSAI D also contains salicylates, especially aspirin, and oxadiazepines and their pharmaceutically acceptable salts. Generally, the compound of the present invention contains a non-toxic cell-protecting amount of the compound of the present invention and an effective non-toxic C but may have ulcers in the absence of the compound of the present invention) in an amount of NSAID. The amount of NSAID in the conjugate is determined by its desired efficacy. It is selected by the physician to match the patient's age, physical condition, general health status, etc., and the amount of the compound of the present invention contained in the composition is compounded The amount of NSAID is selected so as to provide sufficient protective effect of roe deer to improve the gastric ulcer function of preventing NSAID. The typical amount of the compound of the present invention and NSAID used in combination with oral or intra-articular administration is the same as described above. Another object of the present invention is to provide a method for preparing a compound of the present invention, which comprises a compound represented by the chemical formula R3 NHOH (Π) wherein R3 is as defined in the compound of the chemical formula C 1) a group represented by the following formula团 ———————— 78. 8. 3,000 (please read the precautions on the back before filling in this page) • Pack.. Order • • Line • V. Description of invention (17) A 6 B6 Economy Printed by the Central Business Administration of the Ministry of I • I Ar-O-Ar, a YC-I CH3 reacts with a suitable reagent under reaction conditions sufficient to convert NH groups to N-C〇NH2 groups; The conversion of the compound of the present invention into its corresponding 〇〇 reaction is usually carried out in a non-polar solvent (such as tetrahydrofuran, τ HF) with a Group 1 metal cyanate C (such as potassium cyanate) in the presence of an acid The compound of formula C II) is completed. The compound of formula C II) can be prepared by oximating the corresponding net in reagents such as Jingylamine in a suitable polar solvent C such as methanol), and sloppy using in situ reduction of oxime such as sodium cyanoborohydride / oxalic acid Get. Suitable ketones can be purchased from the market or corresponding aldehydes such as sodium hydroxide (N a ΟΗ) aqueous solution / propylene-or acetomethyl methyl acid acid dimethyl Sheng / anhydrous potassium carbonate in a suitable solvent C such as THF) Obtained by reaction. Appropriate aldehydes can be purchased from the market or by the corresponding chemical compound of 銀鳳 Compound #DMMF (DMF)) Please read the notes on the back first Jing Cunqi's manuscript) • Pack · • Order · • Line · 78. 8. 3.000 20¾¾¾ 5 A 6 ____ B6 V. Obtained by inventing bismuth (18). The bromine compound can be purchased from the market or can be obtained through the compound represented by the formula Ar〇S (where Ar and 〇 are as defined above and S is a Group I metal) and the compound represented by the formula Ar, Br C where Ar , As defined above) in a suitable solvent C such as] a methyl-2-pyrrolidinium) reaction, the lithiation reaction is usually at low temperature C such as a 60 Ό) steep use of butyl lithium in-non In polar solvents C such as THF), the aldehydes can also be treated with the corresponding dibromomethyl groups in a polar solvent system C such as ethanol / water) by disodium ethylenediamine tetraacetate C EDTA (2 Na) / Carbohydrate calcium Compounds, dibromomethyl compounds are commercially available, or are present in a non-polar solvent C such as C C1 4) in the presence of N-bromosuccinimide C NB S) / azoisobutyronitrile CAI BN) It is obtained by illuminating the compound C represented by the chemical formula Ar〇Ar, CH3 (where Ar, O, and Af, as defined above). The individual enantiomers of the compounds of the present invention can be obtained by fractionating the components of the racemic mixture, such as the use of asymmetric chromatography columns or the preparation and separation of suitable diastereomeric stereoisomers, or directly from the corresponding The chemical formula C Π) is obtained by asymmetric compound synthesis according to the above method. Printed by the Central Bureau of Standards (please read the precautions on the back before filling in this page) Formula C]]) The asymmetric compounds shown in the table can be blocked by the corresponding asymmetric Jie Jie such as a NCC〇2Me ) OC〇2 Me or · -ncboooboc compound C where B 0C is the third butoxy benzyl group) by acid or suitable hydrolysis to obtain raccoon, the latter compound can be obtained by a 4 (210X297 public) η 78. 8. 3,000 , 01728 A6 B6 V. Description of the invention (19) HN C BOC) OBOC is suitable for treatment in a non-polar solvent c) at low temperature in the presence of triphenylazin / azodicarboxylic acid diethyl _ ς B EAD) Prepared by the asymmetric alcohol A, or the corresponding asymmetric compound represented by the chemical formula C If}

OR

H ^, C = CH-C-N CH. R 'First back ν. Attention matters before filling ^ Ben tile) • Bo ·

Compounds represented by ID (both R4 and R5 are the third butoxycarbonyl group) and chemical formula 〇V)

Ar —〇— Ar '— T • Ordered • • Line · Printed by the Central Bureau of Standards of the Ministry of Economic Affairs-C where Ar, 0 and Ar f are as defined by the compound of the present invention. T is a suitable although not based on C) ), At high temperature, in the presence of ® Ba Ling C II), tri-C o-tolyl) phosphine and the presence of a suitable embalt C such as tri [n-tyl] amine. A4 (210X297 Gongmei) 22 ςΜ1Ξ8 Α6 Β6 By the Ministry of Economics and Trade, Central Standards Bureau Ing. V. Description of the invention (20) The asymmetric compound represented by the chemical formula C Yang can be used as HNCBOL in the presence of triphenylbenzene / dead Obtain the appropriate asymmetric alcohol B by OBOC treatment, or partially reduce the corresponding asymmetric alkyne to obtain quantification in a suitable catalyst C (such as platinum / barium sulfate) in a moist solution (such as pyridine) Hydrogenation. Asymmetrical alkyne can be obtained by treating the corresponding asymmetrical alcohol C with HN (: BOC) OBOC in the presence of triphenyl / dead. Suitable alcohols A, B and C can be purchased or used by the corresponding ketones. Asymmetric reducing agent C JACS j_〇J, 7 9 2 5 C 1 9 8 7) or it can be derived from racemic alcohols by derivatization and selective hydrolysis CJCS Chem. Comm. 5 9 7 0988) or It is prepared by separating the appropriate diastereomeric stereoisomer (C J. Med. Chem. T, 1558U988). The compound represented by the formula CIV) is commercially available or can be prepared according to the method described in the literature. The reaction of arbitrarily converting the compound of the present invention into the corresponding base may be carried out by reacting with a suitable base. In order to more clearly understand the present invention, the following examples will be described in detail. Synthetic real synthetic synthetic I (E) — {3 — [3 — (. 4 — gas phenoxy) acer] (R, S) methacrylpropen-2-ene-1-yl}-N-hydroxy $ Preparation Theory < (please read the precautions on the back of the moraine before filling in this page). Install. • Order A 4 (210X297 public) 23 V8, δ. Ϋ, υυυ Printed by the Ministry of Central Affairs Bureau Pack 201728 A6 __ B6 5. Description of the invention (21) C a) 3 — ς 4-Phenoxy) toluene 4 monofluorophenol CII 2.0 g, Aldrich) in anisole (250 ml) Over 1 hour, add dropwise to a stirred suspension of NaH C 26.4 g) in anisole C 250 ml). After the addition is complete, the mixture is stirred at room temperature for 16 hours, and then Add 3-bromotoluene C 188.1 g TDA-1 C tris [2 ¥ 1 ethoxy] amine, 158 ml) over 30 minutes (2-, after the addition is complete, the mixture is refluxed for 22 hours and then cooled To room temperature and add diethyl ether (200 mL), the mixture was filtered through Hyflo and the solution was washed with 2M HC1 as an aqueous solution, 1 M NaOH aqueous solution and water, then dried and evaporated under empty space, and the remaining oil was distilled Desired product C 101.9 g), boiling point 129-134 "C / 9 mmH g ° C b) 1 dibromomethyl 3- (4-fluorophenoxy) benzene Step C a) product (1 01.9 g) and NBS C 206.7 g) in CC1 4 (500 kl) heated to reflux, and then added AIBN C 100 mg), the mixture was illuminated with mercury intrusion lamp at 2 5 4 nm 7 Hours, during which the reflux is maintained, add another AIBN after 〇, 5, 1, 2, 4 and 6 hours respectively ((Please read the precautions on the back before you go to this page) • Line A 4 (210 father 297 male Luan) 24 78. 8. 3,000 201728 A6 B6 Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs V. Description of Invention (22) 100 mg), the mixture is cooled to the temperature of the whole temperature, and it is too empty and empty The filtrate was evaporated below to obtain the desired product as an orange oil (C 195.3 g). C c) 3 — C 4 -fluorophenoxy) benzaldehyde Step C b) product C 181.8 g) CaC〇3C 151 7 g) and EDTA. 2Na. 2Η, 0 C 37.7 g) and polar ethanol / water (2 C 1140 ml / 284 ml)) after refluxing for 20 hours, the mixture was cooled to room temperature, evaporated and evaporated under empty space Solution, and the residual oil was treated with ether C 500 ml), washed with 2 MHC1 aqueous solution, NaOH and NaHCO 3 aqueous solution and water, and then dried and evaporated under a void to obtain a viscous orange oily substance, which was passed through a silicone gel Chromatography secondary C using ether / 40-60 petroleum ether C1: 9) elution) to obtain the desired product C 69 · 6 g). (d) I — [3.4-fluorophenoxy) phenyl] butan-1 sieve-3-copper step C c.) product C 69 · 6 g, acetomethyl methyl acid Methyl ester C56.2 g) and anhydrous KCOn [88.9 g] and 2 3 THF C 500 mL) were refluxed for 24 hours. The mixture was cooled to room temperature, and the liquid was evaporated under high pressure. , Residual oily (please read the note Ϋ on the back before writing this page) • Installed • • Ordered., Line. A 4 (210X297 public) Ο 78. 8. 3,000 Printed by the Central Sample Bureau of the Ministry of Economic Affairs 201728 A6 _____ B6_ V. Description of the invention (23) The substance was treated in ether C 500 ml), washed with water, water and Na HC0 3 aqueous solution and water, dried and evaporated under the empty space to obtain the desired product (83. 4 grams). Ce) N— {1 — [3— C 4 -fluorophenoxy) phenyl] butane 2 —Xiyi 3 ~ yl} hydroxylamine (please read the precautions on the back first and then fill out this page) to 1 hour At the above time, pyridine C 63.6 g) was added dropwise to an agitated product from step C d) (82.5 g) and hydroxylamine acid C 33.6) in methanol C 1000 ml) After the addition of the solution, the mixture was stirred for 1.5 hours, and then cooled on ice / water $ and added anhydrous oxalic acid C 289 · 8 g), and then methanol C 750 ml) and sodium cyano krypton boride C 1〇1.2g) added to the mixture, when the time exceeds 3.5, after the addition is complete, the mixture is stirred for 2 hours at 〇 5 Ό, and then at room temperature for 20 hours, the mixture is over and empty The liquid was evaporated under low pressure. The remaining oil was treated in Etsune (〗 〖000 ml), rinsed with water and cooled in ice / water, and 10M Na0 < H aqueous solution was added to adjust the pH of the mixture to about 9. Remove the organic phase, extract the aqueous layer with diethyl ether, combine the organic layer and the extract 'rinse with water, dry, and evaporate under empty space to get the desired product' as a brown oil 92 · 7 g), after placement crystallizable. • Installed. Played. Thread armor 4 (210X297 male and female) 26 78. 8. 3,000 ^ 017 £ 8 5. Description of the invention (24) Cf) (Ε) — N— {3 — [3-C 4-Fluoride Macrooxy) phenyl]-(R, S) -methylpropan-2-ene-1-enyl} -N-hydroxyurea A6 B6 will be 2, M HC1 aqueous solution at a time of less than 0. C 645 ml) was added to a stirred solution containing step C e) product C 88.0 g), potassium cyanate C 79.2 g) and THF C 7 50 ml), and the mixture was added at 0 ° C after addition Stir for 2 hours, then mix it up, remove the organic layer, extract the aqueous layer with ethyl chloride, combine the organic layer and the extract, rinse with NaHp〇3 and water, dry and evaporate under empty space to obtain a colorless viscosity Solid, milled with diethyl ether / 40-60 petroleum C3: 2), then recrystallized with ethyl acetate / 40-60 petroleum ether (2: 1), a colorless solid C 67.8 g) melting point 1 3 3 . 5 — 135 Ό C decomposition), 20 MH / HNMR is consistent with the desired product of IR, elemental analysis: C64.81% C 64 · 54% (please read the notes on the back before writing this page) Η Ν %% 0);%% | 6 Central Ministry of Economic Affairs Synthesizing 2 (Ε) — Ν _ {3 — [3 — c 4 — gas phenoxy) group] 1 (r) Monomethylprop-2- (Si-1 1 yl)-N — hydroxy group Vein Preparation Armor 4 (210X297 Gongmei) 17 78. 8. 3,000 8 Production: 17 ο 2

AB 5. Description of the invention (25) (a) Butan-3-pyridine-2 CS) —alcohol butyryl-3-acetylene-2CS) —alcohol is based on the procedure of J. ivied. Chem ·, 31, 1558C1988). ) — Butane 3-alkyne 2- alcohol C Aldrich) analysis.

Cb) N, 0 -di-C third butoxycarbonyl) -N-C a 3-block-1 2 (· R) -yl] control group amine > in a 78 " C, after 1 hour meaning DEAD C 1 8 .0 g) was added dropwise to a writhing containing butadien-3-alkyne 2 (5) -alcohol C 5 5.0 g) obtained from step Ca), triben (258.0 g ) And N, 0—di (third butoxycarbonyl) hydroxylamine C 183.0 g, Fluka) and toluene C 1500 ml) solution, after the addition is complete, the mixture is warmed to the stem temperature, and then stirred for 2 hours , Add 40-60 petroleum ether (1500ml), use Hyflo to pass through the mixture and evaporate the liquid under the empty space to obtain the desired product (C 20 0.0g) as an oil. Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs ^-(Please read the precautions on the back before you stun this page)

Cc) N, 0 —di-C third butoxycarboxyl) —n — [butan-3 ~ ene_ 2 (R) -yl] hydroxylamine_step C b) product c 200.0 g, 5% w / w Pd / BaS〇4 (8.8g) and pyrene (looo ml) mixture A4 (210X297 public) 28 78. 8. 3,000 A6 B6 ^ 01728 5. Description of the invention (26) {Please read the back (Please pay attention to this page) r Every time you earn it and hydrogenate it under the atmosphere until it no longer absorbs hydrogen, pass the mixture with Hy f 1 〇, the liquid evaporates under empty space, and the remaining oil is in ether. 1000 ml), washed with 20% aqueous solution of citric acid and water, dried, and evaporated under empty space to obtain the desired product C 192.0 g) °

Cd) 1-molybdenum: a 3- (4-fluorophenoxy) benzene KOH aqueous solution C 49.0 g in 100 ml of water) was added to a stirred mixture containing 4 monofluorophenol C 84.0 g, Aldrich) and methanol C 2 5 0 Ml) of the solution, after the addition is complete, the mixture evaporates under empty space, pulverize the remaining solid and treat it with 1-methyl-2-pyrrolidine_ [300 ml), add 3-fluorohanbenzene C 13 1 · 3 grams,

Aldr ich), the mixture was refluxed for 24 hours, and then cooled to room temperature, solidified in water (C 1 500 ml) and extracted with ether, washed with 2M NaOΗ aqueous solution, 2M HC1 aqueous solution and water, dried and evaporated under void, remaining The oily product is distilled to obtain the desired product [】 3.0g), boiling point 85-10 0 C / 0.25 mmHg. Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs

Ce) (E) -N — {3 — [3 — C 4_ fluorophenoxy) phenyl] -1 (R) —methyl-in- 2 —ene-1 1-yl} hydroxylamine 4 (210X297 public ) 29 78. 8. 3,000 Printed A6 _B6 by the Central Bureau of Economics of the Ministry of Economic Affairs 5. Description of the invention (27) Step C c) Produced β C 100.7 g), Step C d) Product C 103.0 g), 3 (Tan A tolyl) C 10.0 g) and palladium acetate (4.0 g C) and tri-C n-butyl) amine C 300 ml) were mixed at 115 ° C for 3 hours. The mixture was cooled to about 90 ° C, Evaporate under emptiness, treat the residue in diethyl ether (100 mL), rinse with 33% w / v citric acid aqueous solution and overfloat with Hyflo, rinse the solution with 10 citric acid aqueous solution and water, dry and Evaporate under a void to obtain a viscous brown oil. Dissolve it in methanol (1000 ml) and concentrated acetic acid (100 ml). The mixture is refluxed for 1 hour, cooled to room temperature and evaporated under a void. Residual The material was dissolved in water (1000 mL) and lOMNaOH aqueous solution (125 mL), extracted with ether, rinsed the combined extracts with water, dried, evaporated under empty space, the rest was brown The material was chromatographed on silica gel, eluted first with ether / 40-60 petroleum ether C9: 丨), and then with ether to obtain the desired product as a yellow oil (21.9g). Cf) (E) —N— {3-—3- (4-Fluorophenoxy) phenyl] _1 (R) —methylpropan-2-en-1-yl — uryl urea ___ At 0X: under, take 1 Add more than 160 ml of 2MHC1 aqueous solution C to a mixed product containing step (e) (21.9 (please read the precautions on the back before filling out this page) • Pack · · hit · · line. A 4 (210X297 common eaves) J) 78. 8. 3,000 A6 B6 Seal of the Central Kneading Bureau of the Ministry of Economy-V. Description of the invention (28) g), Potassium cyanide (19.7 g) bite 1'1® 'C 19 0 Dang liter) solution, after adding ^, the mixture was stirred for 0.5 hours, and then added Xuan and NaCl aqueous solution, the organic layer was removed, the aqueous layer was extracted with ether, the organic layer and the extract were combined, and 2 M HC1 Aqueous solution, aqueous solution of NaCl and NaHCO, water, saturated NaCl aqueous solution was washed, dried and evaporated under empty space to obtain a frost-like solid, which was recrystallized by ethyl acetate / 40-60 petroleum ether C 2: 1) to obtain-colorless Material C 丨 7 · 7g, fusion bond 1 3 3- 1 3 5 (: C decomposition), 200 MHz 1 HNMR and IR are consistent with the desired product. Elemental analysis: C 64.10% C 64.54%) ; Η 5.47% (5.42¾); N 8.75% C 8.86%); C «D23 + 40.81-C (c = 1. 0, EtOH) ° D Synthesis Example 3 (E) —N- { 3-[3-C 4-fluorophenoxy) phenyl]-1 (S) -methylpropan-2-en-1-yl} -N-hydroxyurea ^ ____ (a) Dingyi 3 _ Acetylene 2 (R) — 蟫 (please read the precautions on the back before filling in this page) • Install · • Order ·-Fate ·

A 4 (210X297 public) JI 78. 8. 3,000 £ 〇i Willow A6 _ B6 V. Description of the invention (29) Ding_3 — Jueyi 2 (R) — alcohol is based on J. Med. Chem. 31, 1 The steps of 5 58 (1988) were obtained from the analysis of C soil) _ Dingyi 3_ block — —— 2 — alcohol CA 1 dri ch).

Cb) N, 0-di-C third butoxycarbonyl)-N- [but-3_ block one 2 (S)-yl] hydroxylamine __ at 70X, DEAD C 81.8 g after more than 1 hour) drop by drop Add to a writhing containing butyl-3-acetylene-2 (S) -alcohol (25.0 g), triphenyl 117-0 g) and N, 〇-ⅡC third butoxyl obtained from step (a) Carbonyl) hydroxylamine (83.2 g, Fluka) and toluene C760 ml) solution, after the addition is complete, the mixture is warmed to room temperature, the mixture is evaporated and evaporated under empty space, the remaining oily substance is quickly layered on the silicone rubber After two times of analysis, they were eluted with DCM and ethyl ether / 40-60 petroleum ether C 1: 4), respectively, to obtain the desired product as a light yellow oil (C 8.6 g).

Cc) N, 〇—diC third butoxycarboxyl) -N— [butan-3—lag 2 (S) —yl] product C 9 8.6 g, 10% w / w P4 /

Ba SO 4 C (2.2 g) and pyridine C (500 ml) are mixed while being hydrogenated at atmospheric pressure until they no longer absorb hydrogen, with Hyflo φλ iomv fi) J1 78. 8. 3,000 (please flash first, please pay attention to the back Matters to fill out this page) • Install.

• Hit · _ Coal · Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs £ 01 Qing A6 B6 5. Description of the invention (30) After too much mixing, the filtrate evaporates under empty space, and the remaining oily substance in the ether is C 5〇. Milliliter), washed with 20% w / v citrate aqueous solution and water, dried and evaporated under emptiness to obtain the desired product C 9 0.

Cd) 1-bromo-3- (4-fluorophenoxy) benzene 1-bromo-3_c4-fluorophenoxy) benzene is prepared according to the method of step Cd) of the above synthetic method 2. (e) (E) —N— {3 — [3 — C 4 -fluorophenoxy) phenyl] -1 (S) —methylpropane 2 —Si-1-1-yl} jing-ylamine _________ Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs (please read the precautions on the back and fill in this page) • Order · • Line · Step Cc) Product C 57.4g), Step (d) Product C 58-7g), A mixture of tri-C-o-tolyl) 瞵 (5.0 g) and palladium acetate (II) C (2.0 g) and tri-C-n-butyl) amine (150 ml) was mixed under 丨 丨 〇— 丨 2〇 " C After 3.5 hours, the mixture was cooled to room temperature, evaporated under emptiness, and the residue was treated with diethyl ether (500 mL), and filtered with Hyflo, and the filtrate was washed with 10% w / v citric acid aqueous solution and water, dried, and dried. Evaporate under a void to obtain a viscous brown oil, dissolve it in methanol (500 ml) and concentrated acid (》 ml). The mixture is refluxed for 1 hour, cooled to room temperature and evaporated under a void. (210X297 public love) 33 78. 8. 3,000 V. Description of the invention (Don't A6 B6, the residue is dissolved in water C 50 0 liters) and 10 Μ N aOH aqueous solution C 60 ml), extracted with ether, with water Rush The combined extracts were neutral, dried, and evaporated under emptiness. The residual brown oil was quickly chromatographed on silica gel, first discarded with Ethanol / 40-60 petroleum ether C 1; 1) C) and then C 9 : 1) Elution to obtain the desired product as a viscous light yellow oil C 32.5g).

Cf) (Ε) — Ν— {3 — [3 — C4-fluorophenoxy) phenyl] 1 1 (S) -methylpropan 2 —Ye Yiji hN —Hydroxyurea_; _ _ {Please first Read the precautions on the back and then fill out this page) • Installed · The central ministry of the Ministry of Economic Affairs is printed under 0 Ό, and the 2 M HC1 aqueous solution (C 71.4 ml) is added to the worries for more than 45 minutes Step (e) product C 32.5 g), potassium trihydrate C 29.3 g) and THF C 2 8 2 ml), after the addition is complete, the mixture is stirred at 0 * C for 45 minutes, and then saturated NaC 1 is added Aqueous solution, remove the organic layer, extract the aqueous layer with ether, combine the organic layer and the extract, rinse with 2MHC1 aqueous solution and water, dry and evaporate under a void to obtain a viscous solid, which is recrystallized from ethyl acetate— Colorless flake C 25.8 g), melting point 13 1-132.5 'C (decomposition), 200 ivfiz 1 HNMR and IR are consistent with the desired product, elemental analysis: C 64.37¾ C 64.54¾); Η 5.42% ^ 5 · 4 2 96) ί Ν 8-79% C 8-86%); • fight • • line • A 4 (210X297 Public Broadcasting) 34 78. 8. 3,000 ^ 017! 5. Description of the invention (32)

23 〔α〕-4 1. 6 1 Ό C c D Synthesis A6 B6 0, EtOH) 〇 (Ε) — Ν— {3— [3 — C 4 monophenoxy) phenyl] -1 (foot , 3) ~ Methyl Propyl 2-Heptyl} Yizhu-Hydroxyurea

Ca) (Ε) — 1 mono [3- (4-gas phenoxy) phenyl] Tuna 3- 颙 10 NN a 0Η aqueous solution C 2 ml) to one reed 3- C 4 monochlorophenoxy) benzene Formaldehyde C 23.3 g, Aldrich) and acetone (150 ml), and stirred vigorously, after a few minutes of stirring, the temperature was raised to 32Ό, the mixture was left for 5 minutes and then into 2 M HC 1 aqueous solution C 600 Ml), and extracted with ether / petroleum ether (1:〗, 40 ml). The extract was washed with water and saturated NaCl aqueous solution, dried with MgSOj, and after stripping, the ketoaldehyde synthesis product was obtained. To 300 ml of 茏 C, add 1 g of para-toluenesulfonic acid C (please read the precautions on the back and then fill out this page) • Pack · • hit * • line · the printed compound of the Central Bureau of Standards of the Ministry of Economic Affairs is heated 1 hour, then cooled, rinsed with saturated NaHCO 3 aqueous solution and saturated NaCl aqueous solution, dried with Mg SO Λ, 4, and stripped, and the rest was passed through a two-gas methane / 40-6 stone-on silica gel column ---- 33 '78. 8. 3,000 邀 4 (210X297 issued) £ 8 level of the Ministry of Economic Affairs Central Bureau of Printing and Printing A6 ___ B6_ V. Invention Ming (33) oil ether C1: 1, magnetic 3: 1) elution, the eluate was stripped to obtain the desired product C 19.0 g). (b) (E) — 1 — [3 — 4 -fluorophenoxy) phenyl]. Butene-3-ketone ΙΨ loss step C a) Product C 19.0 g) and hydroxylamine salt C 6.9 g ) Placed in methanol (100 ml C), added pyridine C (20 ml), the mixture was stirred for 1 hour, and then the mixture was stripped, dissolved in ether (200 ml), washed with 2MHC1 aqueous solution and saturated NaCl aqueous solution , Dried with MgS〇4 and stripped to obtain the desired product C 20.3 g). C c) (E) — N- {1 monomethyl_ 3 — [. 3 — C 4 monophenoxy :) phenyl] propan-2-enyl} hydroxylamine Step C b) product C20 g) Place in methanol (100 mL), add oxalic acid C (31.7 g), cool the mixture in an ice bath, add sodium borohydride (22 g) under N2 over 3 hours, and stir the mixture for another 1.5 hours , And then added sodium borohydride (2g), followed by storage and stirring for Η hours, the mixture was stripped, and the residue was partitioned between ethyl acetate (300 liters) and water (300 mL), and the organic layer was separated to Saturated (please first «read the notes on the back ^ and fill the nest page) k. • Order. • Line 4 (210X297 public) 16 78. 8. 3,000 ^ 0172» ^ 0172 »Central Bureau of Economic Development of the Ministry of Economic Affairs Printed A6 ___ B6 V. Description of the invention (34)

The NaHC〇3 aqueous solution and the NaCl aqueous solution were washed, and then the crude hydroxylamine product was stripped. (d) (E) — N — {1 monomethyl ~ 3 — [3- (4- gas phenoxy) phenyl] propan-2-ene-1 monoyl} —N — hydroxyurea _____ part The product of step C c) (6.0 g) was placed in THF C (60 ml), and potassium cyanate C (4.9 g) was added at 0 * C. After 15 minutes, 5 M HC1 aqueous solution (20 mg) was added dropwise , The mixture was earned for 10 minutes, and then added saturated 1 ^^ 1 aqueous solution (100 liters) and ether C 100 ml), the organic layer was separated, 2MHC1 aqueous solution loo ml) and saturated NaC1 aqueous solution (100 ml) Rinse 'Dried with MgS〇4, stripped to obtain the desired product, recrystallized with ethyl ethoxylate / petroleum ether to obtain 4.4 g, melting point 132-135 "C. Synthesis Example 5 (Ε) — Ν— {3 — [3 — C4 —gas phenoxy) phenyl] — 1 (S) —Methylpropion 2 —Tan-1 1-base} — Ν —Preparation of ureidourea_ (a) (E) = 1 — 〔3 — ς 4 — gas phenoxy) phenyl] butyl-Τ {please read the precautions on the back before filling in this page). Install. • Play • • Line • 78. 8. 3,000 A 4 (210X297 male No) ^ 01728 Printed by the Central Approval Bureau of the Ministry of Economic Affairs 35) —1 —ene_ 3 —one 3 — (4 —gas phenoxy—) benzaldehyde C 50.0 g, Aldrich), dimethyl acetomethyl succinate C 35.7 g, Lancaster) and anhydrous K2C. 3 C 5 9.4 g) 2: THF C 3 〇0 ml) was stirred for 20 hours under N2 and «-55Ό, the cooled mixture was filtered, the residue was rinsed with THF, the combined solution was under the empty space Evaporation yielded an orange oil, which was flash chromatographed on a silica gel column and eluted with ether / 40 -60 petroleum ether (1: 1, v / v) to obtain the desired product as a viscous light yellow oil. C 52.8 g). Cb) (Ε) — 1 (R) —Methyl 3 — [3 — C 4 — gas phenoxy) phenyl] propan-2-ene-1 monool __BH3 · THF c 1.0 Μ 96 ml) and a product C containing step Ca) (52.7 g) and THF solution C (volume of 96 ml) were added to a stirring (S) 3, 3--2 at 1 ^ 2 Peridopyrrolo [1,2-c] [〗, 3 * 2] oxyboronocyclopentane THF solution C 0 · 3 Μ, 33 ml, prepared according to the method shown in J 〇c 28 6 1 C1988) ) 'After adding' the mixture was stirred at room temperature for 15 minutes, After pouring into ice / 2 M HC1 aqueous solution C. 300 g / 300 ml), stir for 30 minutes 'with acetic acid C 3 x 30 0 milli -------' ~ 78. 8. 3,000 A 4 ( 210X297 Gongji) .................-(please read the precautions on the back before filling in this page) • ^.. 打.. 彩. A6 B6 Central Ministry of Economic Affairs Printed by the quasi-bureau. V. Description of the invention (36) l) Extraction. The combined extracts were washed with 2 MHC1 aqueous solution C 2U0 mL), saturated NaHCO 3 aqueous solution C 200 mL) and water (200 mL), washed with Na2S〇4 Dry and evaporate under empty space to obtain the desired product C (5.33 g) in the form of a viscous yellow oil. Partially crystallize with diethyl ether / 60-petroleum ether C 1: 丨 v / v) and pour out the mother liquor , Flash chromatography on silica gel to obtain the desired product, a light yellow oil (25.7 g), [α] = +8.7 β C c = 3.0, EtOH), 200 MHg NMR and IR and The presumed matchup is consistent. Cc) (E) — N, 0 — third butoxycarbonyl) -N — {1 (S) -methyl-3- 3- [3-(. 4- gas phenoxy) phenyl] propan-2-ene 1-1 1-hydroxylamine_DEAD C 2 4.5 g) methylpyridine solution C 50 mL) added to a portable drop containing step Cb) product C 25. 7 g), NsO—diC third butoxy Carbonyl) hydroxylamine ¢ 22.9 g, Fluka), triphenylbenzene C 36.8 g) and toluene C 375 ml), and this mixture is in the range of 65 to 70, after the addition, the mixture is Stir for 4 hours from 65 to 70 Ό, then add triphenylbenzene C 5.0 g), then add DEAD (3.3 g), (please read the notes on the back and fill this page). Install. • Play · • Line. Flat 4 (210X297 Eaves) 78. 8. 3,000 ο

AB 5. Description of the invention (JT7) The mixture was stirred for an additional hour at a temperature of 65 to 70. The heated mixture evaporated under a void to produce a brown oil, which was subjected to flash chromatography on a silica gel column. Using DCM and DCM / 40-60 petroleum ether / ether C3: 6: 0.25 v / v / v) as the eluent, the desired product was obtained as a viscous yellow oil C 20.3 g). £ 1) (£) -1 ^^ {1 (5) —Methyl-3- (3- (1—Phenoxyphenoxy) phenyl] propan-2-ene-1-1-yl} hydroxylamine (please first Read the precautions on the back and then fill out this page) • Pack. Add N28 and 〇1 trifluoroacetic acid C28 ml) to a stirred mixture containing step C c) product C 20.3 g) and DCM C 1] 2 ml) solution, after the addition, the mixture was stirred at room temperature for 3 hours, and then added diethyl ether (100 ml) and water (100 ml) in a vigorously stirred mixture at 0 " C 10N aqueous NaOH solution (32 ml) was added, the mixture was basified with excess saturated aqueous NaHCO3 solution, and extracted with ether C 200 ml), and the extract was saturated with saturated NaHCO 3 aqueous solution C 100 ml) and water [2 X 100. ML) Rinse, dry with Na2S〇4, evaporate under a void to obtain a viscous yellow oil. Flash chromatography on a silica gel column with ether / petroleum C 4) Rinse the product, melting point 83-8 4 Ό, [《]

25 D • Hit .. Line. -311 c .2 CHC1) ° 78. 8. 3,000 A 4 (210X297 public)! 0 V. Description of the invention (38) A6 B6

Ce) (E) — N— {1 (S) — Methyl-3- (3-C 4 monophenoxy) phenyl] propan-2-ene-1-yl} -N — — ureidourea ___ Step Cd) Product C0.29g) was placed in THF C 10ml), potassium cyanate (0-25g) was added at 0-C, after 15 minutes, 2MHC1 aqueous solution C2ml) was added dropwise, mixed After 2 hours of stirring, the product was added with NaCl and NaCl aqueous solution (· "Leng Sheng" and ether C50 ml), the organic layer was separated and washed with saturated NaCl aqueous solution C 50 ml), dried with Mg SO ^, and steamed. After the extraction, the desired product is obtained and recrystallized with ethyl acetate / petroleum. The yield is 0.26 g, the melting point is 119-120 * C〇C 0: 3 ^ -40.0 ° C c = 1 · 〇, D EtOH ) 〇Synthesis Example 6 (Please read the precautions on the back before filling in this tile) Central Ministry of Economic Affairs m quasi-bureau stamp (E) — N — {3 — [3 — C4 ~ · fluorophenoxy) phenyl] _ 1 (R, S) —Methylpropane-2-ene-1-one} —N Monohydroxyurea sodium salt preparation _ Synthesis Example I compound C 丨 0 grams) dissolved in an aqueous solution containing NaOH C 0. I 1 G in 25 ml of water) and methanol C30 ml) , Evaporate the methanol under the empty space, the remaining solution was freeze-dried after a 4 (210X297 public) 78. 8. 3,000 $ 1 8t 1 ο% 6 6 A β Five 'invention said Diao (39) get what you want' product, is Frost solid. 1 ^: 2 0 OMH ^ H NMR C DMSO—d 6, <5;】 · 10-1 · 2 1C 3 H, d, -CH3) 4. 75-4. 92 [1 H, m,> CH -) 5. 27-6. 14 C 2 H, bs, ~ NH2) s > -HC = CH-) 6. 2 2-6 · 5 1 C z and 6. 6 9 -7 · 3 7 C; No OH signal.

HH, m, aromatic) M-based blends: The "active ingredient" in the following blends is any of the compound C of the present invention as defined above, as any compound that is synthetically synthesized and listed as a 6) Compound A Sharpener Each lozenge (Zhong Xianwen's note on the back of the page ^ then slap this page). Hit the · Jiji Central Standards Bureau printed the active ingredient 5.0 mg lactose 8 2.0 " Starch 10.0 η Polyvinylpyrrolidone…, 2.0 / / Magnesium stearate 1.0 ft • 12 A 4 (210X297 public) 78. 8. 3, 〇〇〇 ^ 01 ^ 28 A6 B6 V. Description of the invention (40) Mixed active portion, lactose and starch, using polyethylene The granulated powder of the solution of Zuoweiluoyuan copper in pure water, dry the granules, add magnesium stearate, and squeeze to make lozenges C 100 mg / tablet). Buy B: Soft soft active ingredient white soft stone passes to 1.0 g I 0 0. 0 g. The active ingredient is dispersed in a small amount of excipients, gradually mixed into a large mass to form a smooth, uniform As a product, put this sheet into a foldable metal tube. (Please read the precautions on the back before filling. ¾ this page). Packing. • Example of printing paste from the Central Bureau of Economic Affairs of the Ministry of Economic Affairs C: the active ingredient Po 1 aw ax GP 2 0 0 anhydrous lanolin applied locally White bee hydroxy methyl oxalate distilled water to 1.0 g 2 0.0 g 2.0 g 2.5 g 0.1 g 10 0.0 g at 60 · 〇: heating P〇1 awa X, bee and lanolin, add the diameter base A 4 (210X297 Gong Li) 43 78. 8. 3,000 • Line.? 8 A6 B6 V. Description of invention (41) A solution of carbamic acid in methyl g, homogenized at high speed with sulfonate, temperature reduced to 50 ° C Active ingredients, lean and fast cooling. Example 10: Topical emulsion active ingredient sorbitol liver monolauric acid_ polysorbate 20 cetyl stearyl alcohol glyceryl hydroxybenzoate pure water BP · to 100 g g g g g ml Dissolve methyl hydroxy benzoate and glycerol in 70 ml of water at 75 ℃. Melt sorbitol liver monolaurate, polysorbate 20 and cetyl stearyl alcohol at 75 Ό, and add In the aqueous solution, homogenize the resulting latex, stir it and cool it down, add the active ingredient in the form of a dispersion in the remaining water, and fight until it is uniform. (Please read the precautions on the back before writing this page) _Pack · • Order. • Green. Printed Tribute Example of the Central Kneading Bureau of the Ministry of Economic Affairs E: Eye Drops Active Ingredient Methyl Hydroxybenzoate 0.5 g 0 · 0 1 gram A4 (210X297 male) 44 78. 8. 3,000 A6 B6 V. Description of invention (42) Propyl hydroxy carboxylate pure water B. P · up to 0.04 gram 100 ml hydroxy acetoacetate A and C The ester was dissolved in 70 ml of pure water at 75 ° C. The resulting solution was cooled, and then the active ingredient was added. The pure water was added to make the solution up to 〇〇 ml, and the sterile solution was filtered through a 0.22 micron pore size membrane filter. Method: Fill the solution into a suitable sterile container β 寊 冽 F: injection solution_active ingredient water for injection B .P. To .0 mg .0 ml active ingredient is dissolved in half the amount of water for injection, and then add water for injection to the required volume And after making it sterile, put the resulting solution in an ampoule under aseptic conditions. (Please read «Read the note 1f on the back side first, and then bury the hundred hundred) G: powder active ingredient for inhalation C ΰ · 5-7. O / um powder) 4 mg Sugar C30 - SOAim Powder) 46 1.0 mg Song mixed until homogeneous powder, the gel of Chen into the appropriate size of the passage stearyl

A6 B6 V. Description of the invention (43) C 50 mg / gel bismuth). Example Η: inhaled aerosol active ingredient C 0.5-7 · 0 pm powder) 2 0 0 mg sorbitol liver trioleate 10 0 mg sodium citrate C 0 · 5-7 · 0 sonic powder) 5 Milligrams of methanol 2 milligrams of three gas methane 4 · 2 grams of two gas difluoromethane to 1.0 ml (please read the precautions on the back before filling in this r) dissolve sorbitan trioleate and menthol In trifluorofluoromethane, add saccharin sodium and active ingredients to the mixture, and move it into a suitable aerosol furnace, inject difluorofluoromethane through the valve system, this composition is provided in every 100 / ιΙ dose 2 mg active ingredient. Biological data: Inhibition in vitro 5-The role of fat and oxygenation in brewing. The first study of the Central Ministry of Economic Affairs of the Ministry of Economic Affairs of India and the mice showed that the racemate of Synthetic Example 1 and the antithesis of 2 and 3 are consistent. Stereoisomers effectively inhibit the stimulation of leukotriene 6 4 C LTB4). The synthesis of C LTB4 is made from arachidonic acid via 5 A 4 (210X297 male dragon) 78. 8. 3,000 A6 B6 Group Jifang Central Bureau quasi seal ¾ 5. Description of the invention (44)-Compounds formed by the fat plus oxime pathway). After administration of the test compound, the concentration of ltb4 in the plasma is regularly measured and expressed as a percentage of the average control value. The procedure is based on the method disclosed by Br. J. Ph a rm ac ο 1. 9 4 528C1988), which is roughly as follows : 2 minutes after the collection, use a calcium stove carrier at 37 X :, A2 3 1 87 C final concentration ISpg / ml) to stimulate two blood samples C 0.5 ml) 30 minutes, after the incubation is complete, centrifuge sample C 12. 000 G, 2 points) and remove the cell-free plasma, and then use the specific radioimmunoassay to detect the concentration of LTB 4 plasma. The compounds of Synthetic Examples 1 to 3 can inhibit the LTB4 stab after ingestion to activate in vitro synthesis of damin, for example, when Synthetic Example] Oral administration of genoside at a dose of 2 g / kg can inhibit the above The synthesis of LTB · takes more than 6 hours, and the same compound is administered orally to the old 4 rats at a dose of 10 mg / kg, which can inhibit the synthesis of LTB4 by more than 50% for more than 0 hours. The enantiomers of Synthesis Examples 2 and 3 have troublesome work. In Vivo Inhibition 5-The effect of fat plus oxygen brewing is obtained by normal volunteers without aspirin's blood (please read the precautions on the back side before filling out this page). • Line. A 4 (210X297 public) 78. 8. 3,000 A6 _____B6 5. Description of the invention (45) To separate leukocytes from 1C blood and platelets, test compound DMS 0 solution C 10 μl, and finally Concentration of 0.01-100 μ) was added to the cell homogenate C 470 μl), the mixture was incubated at 37-C for 5 minutes, and then added arachidonic acid solution C 250 AM, 〇〇 household <, Concentration 5 / «M) and gasification to aqueous solution C 10 0 mM, 10 ^, the final concentration 2 mM), the mixture was incubated at 37 Ό for 5 minutes, the mixture was boiled to stop the reaction, leukotriene B 4 radiation Immunoassay. People who are stimulated with ionophores are annoyed with whole blood remission. The test results of the synthetic compounds 1 to 3 are as follows: (please read the precautions on the back before filling this page) • η · 1C 5〇〇Μ) Synthetic ranunculus homogenous whole blood 1 0.2 0 0.15 2 0 · 2 0 0.08 3 0.2 0 0.08 • tying • • line · Central Ministry of Economic Affairs, Ministry of Economic Affairs-Anti-oxidative shaving activity The chemical activity of the compound of the present invention is determined by its removal of peroxymethyl 4 (210X297 public ) 48 78. 8. 3,000 -0172B A6 B6 Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs 5. Description of the invention (46) The basic capability is measured, which is revealed by Bi〇chem. Phar m., 3 8 »1 465C1989) The method is determined by the ability of each compound to inhibit the peroxidation of linoleic acid. The rate constant C kAH for the removal of peroxy group of the synthetic compound No. 1 is obviously 0.408. The combined effect with NSAID is male New Zealand white cerium C 2. 5-3 kg). Intradermal injection of 4 mg eggs A solution of protein in 1 ml of Freund complete adjuvant immunizes, and immunize the animal again in the same way after H days! , 5 days after the second exemption, injecting 1 ml of egg white protein sterile solution C (5 mg / ml) into the joint cavity to induce arthritis in the right knee joint. After the antigen challenge C antigen challenge, the joint diameter is often measured with a hairpin gauge (according to the principle of clutter measurement). After W days, the animal is killed, the joint is washed with 1 ml of water clippers, and the resulting liquid is removed for white blood cell Total and classified counts. The sensitized animals are randomly divided into 5 to 8 groups, and the compound of Example I is synthesized, (E) — N — {1-methyl- 3- [3-C 4-fluorophenoxy) phenyl] propan A 2-ene-1 1-yl} -N-hydroxyurea C compound A) 0.25% Celacol as an auxiliary agent in a ball mill for 18 hours, and then put its suspension solution into the base, {please Read the precautions on the back before filling out this page) • ^. • Order · .Line. A 4 (210X297 public issue) 49 78. 8. 3,000 &lt;, 〇 Lecture 8 A6 B6 Printed by the Central Bureau of Economic Development of the Ministry of Economic Affairs 3. Description of the invention (47) Dissolve the sterile anti-inflammatory P inducing methine (A ind om ethaci η) in a small amount of IM trihydroxymethylaminomethane buffer PH 8 and then add 0.25% Cel a col until required Volume, the control group was dosed with 0.25% Celacol, and each animal was orally administered with excipient or Rongwu C (about 5 ml) every 24 hours, starting at 8 am every day from 1 hour before starting the antigen on day 0. At 4 o'clock in the afternoon, and at 2 o'clock in the middle of the night to take the medicine for 6-17 days. All medicines are administered orally through the stomach tube, and the administration of each group is as follows: 1-7: Control group C 5 罨 升 0.25 Celacol X 3/24 h) 8-Μ: 1 mg / kg indole A Asin dissolved in 0.25% Celacol X 3/24 h 15-21: 2 mg / kg compound A suspended in 0.25% Celacol x 3/24 h 22-28: 2 mg / kg compound A suspended in 0.25% Celacol plus Upper Ik / kg indomethacin dissolved in 0.25% Celacol joint swelling. The antigen challenge induced by the control group increased by 6-7 mm in joint diameter, which reached the maximum after 2 days of challenge. The joint swelling of the control group was in the experimental period {Please read the precautions on the back before filling in this page). Packing. Ordering .. Green. A 4 (210X297 public) 50 78. 8. 3,000 A6 ____B6_ 5. The description of the invention (you) is maintained, At this time, the animal was killed, and the diameter of the arthritic joint was about 5 mm larger than the contralateral joint. Compared with the vehicle-treated control group, the paddle-treated group did not reduce joint swelling for the first two days after the challenge, but from On day 3, compound A reduced swelling by 26% and indomethacin by 53%. The largest and most consistent effect of swelling reduction (up to 72%) is seen in the group receiving both compound A and indomethacin at the same time, as shown in Table 1: Table 1 {Please read the precautions on the back first (Write this page) .5t_ Lanjie swelling C mm) A tenth continuous arthritis meeting A indomethacin indomethacin control group • set · 1 2 3 8 14 line wins the Ministry of Economic Affairs Study on the removal of synovial fluid from the local printed synovial fluid, fixation, processing, excision and staining to enter the nail 4 (210X297 male) 51 78. 8. 3,000 ⑽ £ 8 A6 B6 V. Description of the invention (49) Line microscope The test was based on the inflamed synovial lining, lymphocyte leaching, and polymorphic leukocyte volume paralysis. The score was determined and the slides were read according to the principle of dimensional chaos. The synovial fluid removed from the arthritic joints of the control group of animals contained about 106 white blood cells, of which about 80% were polymorphic white blood cells. Compound A and indomethacin alone slightly reduced the average value in synovial fluid. White blood cell infiltrate, but the combination of compound A and indomethacin can get the maximum lightening effect, the results are shown in Table 2: _2 white blood cell C cell number X 丨 〇6) Compound A indomethacin A + indole A asin control group (please read the precautions on the back before filling in this page) • Install. • Hit. • Line. Analysis of proteoglycan in the cartilage of the Central Bureau of Economic Village Printing paste cartilage. A segment of cartilage is cut from the end of the femur and Before measuring the concentration of sulfated polyglucosamine (C GAGS), first immerse in papain, and express the amount of proteoglycan in the net weight of / ig GAG / mg cartilage, and use the control A 4 (210X297 public) 52 78. 8. 3,000 Α6 Β6 V. Description of the invention (50) Comparison of the cartilage obtained by the contralateral joint in the group. The articular cartilage removed from the arthritic joints of animals treated with excipients 14 days after the antigen challenge contained 43% less protein-containing protein, compound A or indomethacin than the cartilage removed from the contralateral joints of the same animal It can be used alone. Commanding the loss of proteoglycan-containing cartilage, but the most mitigating occurs when the group receiving compound A and indomethacin is received. The results are shown in Table 3 ^ _3 Loss of proteoglycan containing C%) Compound A Indomethacin A + Indomethacin control group 34 38 26 43 Histological evaluation of synovial lining Leukocytes and total tin in the synovial lining of a group receiving both Compound A and Indomethacin The cell counts were significantly reduced, and the results are shown in Table 4: (Please read the notes on the back * before filling in the hundred) • Policy ... Play · Green · Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs-78. 8. 3,000 1 »4 (210X297 public) ______—. — 8 7 15 ο

AB V. Description of the invention (51) Table 4 Compound A Indomethacin A + Indomethacin Control Lymphatic Cells 5 9 5 1 36 68 German Cells 3 67 36 5 2 55 43 5 Compound A The protective effect of pycnolol on PJ® inflammation, indomethacin is especially in the presence of non-steroidal anti-inflammatory drugs. Toxic materials The compounds in the synthetic examples were taken orally at a dose of up to 300 mg / kg and intraperitoneally at a dose of up to 100 mg / kg, and the harmful effects of death or combined weight were not observed. {Please read the precautions on the back before filling this page) A 4 (210X297 eaves) 54 78. 8. 3,000

Claims (1)

1Annex I (A): Patent Application No. 79100738 Chinese application patent scope amendment January 2002 82 5 1. The compound represented by the following formula (I) and its plague Η OHΗ I \ C〇NH.iH3 · (I) where X is a tooth. 2. CE) —N— {1-Methyl-3 [3- (4-fluorophenylamino) phenyl] propan-2-yl-1-yl-1-N—CR of light urea) or (S ) Enantiomers or mixtures in any ratio, and their physiologically acceptable contents. 3. A compound as claimed in item 2 of the patent application, wherein the compound is in the form of CR) enantiomers and is substantially free of (S) -isomers. 4. The compound as claimed in Item 2 of the patent application, wherein the compound is in the form of (S) enantiomer and is substantially free of CR) -isomer. 5. For example, if the compound of patent application No. 2 is applied, the compound is in racemic form. 6. A pharmaceutical composition for inhibiting 5-lipoxygenase, which contains the compound of claim 1 and a pharmaceutically acceptable carrier or excipient ▼ 4 (210X297 male ϋ) form. 7. The pharmaceutical composition as claimed in item 6 of the patent scope, wherein the compound as claimed in item 1 of the patent scope is CED-N— [1 monomethyl-3 (3- (4-fluorophenoxy) phenyl] C-2--A-1-yl} -N-CR) or CS) enantiomers via basal gland or a mixture of them in any ratio. 8. The pharmaceutical composition as claimed in item 7 of the patent scope, wherein the compound as claimed in item 1 of the patent scope is in the form of (R) enantiomer, and the substance is substantially free of ⑸-isomer. 9. The facial composition as claimed in item T7 of the patent scope, wherein the compound as claimed in item 1 of the patent scope is in the form of (S): enantiomer and there is substantially no CR) -isomer. 10. If the pharmaceutical composition according to item 7 of the patent application, ‘where the chemical compound according to item 1 of the patent application is in racemic form. 11. A pharmaceutical composition for inhibiting 5-fat aeration enzymes, which comprises a compound with a ratio of 2: 1 in the patent application, indomethacin, and an acceptable carrier Or excipients. 12. The pharmaceutical composition as claimed in item 6 of the patent scope, which is in the form of a lumbar pouch, a tablet, a recording agent, a diamond bond, a powder, granules, an aqueous or non-aqueous solution or suspension, an oil-in-water or water-in-oil emulsion , Big nine agent, SK agent or paste type. 13. The pharmaceutical composition according to claim 11 of the patent application is in the form of capsules, tablets, tablets, lozenges, lozenges, powders, granules, aqueous or non-aqueous solutions or suspensions, oil-in-water or water-in-oil emulsions, Big pill, sweetener or paste type 〇τ · ί (21βΧ »7mm) -01728 14. A method for preparing a compound as claimed in item 1 of the patent application, which contains the compound of formula (n) R3N Η Ο Η (Π) In the formula. R3 as defined in item 1 of the scope of patent application x- &lt; o) -o- &lt; ^ ci / react with acid (such as Sheng acid) and radon acid basket (such as potassium cyanate) in a suitable solvent at 〇t to convert 1 ^ -1 ^ group Into 1 ^ — 〇0 1 ^ 1 ^ 2 group; and arbitrarily convert the formed compound of formula (I) to the corresponding age. 15. The compound as claimed in item 1 of the patent application is commonly used in the preparation of drugs for the prevention or treatment of arteriosclerosis or arthritis. ▼ 4 (21βΧ2β7Λ **) 3