TW202427B - - Google Patents

Description

Μ 024S7 V. Description of the invention (/) The present invention relates to 3-cycloalkylpropionamide, its bite, its preparation method, its pharmaceutical composition and its application as a medicine. The present invention provides compound (I) and its aging hair:

I) in the formula Ri pseudo C3-6 cycloalkyl; R 2 hydrogen atom or C i .. 3 alkyl; R3, R6 and R7 may be the same or different, pseudo hydrogen atom, halogen atom, nitrile group, azide Group, -N02, straight-chain or branched Ci_6 alkyl group, straight-chain or branched Ci_6 alkyl gas group, Cl-s alkylthio group, COR 'group (wherein R' is a hydroxyl group, Ci-3 alkyl or alkyl group) Gas group), or selected from-(CH2) m-CF3, -0- (CH2) m-CF3, -S- (CH2) m -CF3, / F -CF2-Hal, -0-CF2-Hal,- (CF2) n -C ——Hal1 ^ Hal, (please read the back-end precautions # fill in this page) Binding · Order-Ministry of Economic Affairs 屮 央 栉 准 · x; cx 工 消 炸 炸 社 社 印 51

-〇- (CF2) n -CF / F -Hal "-S- (CF2) n -C — Hal, Hal, 'Hal, and -0- (CF2) n-CF-CF3, Hal, 3-Original paper 5 Good standards for the use of China National Standards (CNS) fM regulations ^ (210x297 male dragons) V. Description of the invention (> where it is either 2 11 pseudo Π 3 or and Λ fi Π 6 or \ J / sub raw halogen for each The same or not in the same phase can be used as a pseudo 7 R and a configurational alteration of each other. There is a 0 I ί compound with the inclusion of the original version. The interpreter explained the basic hex ring or pentyl ring group. Butylcyclopropane refers to alkane cyclopropyl straight or isopropyl or propyl isopropyl, propylpropyl ethyl, propylethyl methyl, acetylmethyl methane is 3 as-Example 1 yl C alkyl words 6 so -Branches or chains of C1 Hexyl or Pentylbutyl or ‘Base Gas C’ Base Gas B / Base Gas A is as example base gas alkyl S iso- or S-base. E thiopropyl or thiothio Θhe漾 基 豸 pentyl-ethyl pentyl 0 £, 丁 Μ 基 2 A ¾ Double is T 殳 like ⑦ or] * points 0 ^ Μ ^ ^ or ½ straight, ❻ or 6 bases, «1-ylpropyl C1 Thioisopropyl and age or 〇 machine, the child has salt or Ammonium iodine machine and or not, bromine plus magnesium, add, atmosphere from calcium ', calcium fluoride, lithium salt, potassium salt age, window Ghana, such as 0, such as amine machine, salt amine, such as (please first (Read this page to fill in the code of precautions and fill out this page) Methylpropionate (, triamine and, hexanoic acid, ammonium amine, alcohol, and diethylacetate, -dipicolinate N-methyl nicotinic acid, methidine, dimethoxine,, amine pyridine amine Ethylpyridine,. 'Amininol, carbediludi, bis, alkane, amine, methylamine, benzyl, £, quinolinyl, methyl 6 R »' Sub 5 R, original 4S R or, bromine 3 R, middle nitrogen The formula is the gas-combined hydrogenation system 0, the amine good homosaccharide is less specified or the base is the same as the original phase N- 为 和 可 乙 7, this paper method scale is used in the "« Jiashu standard (CNS) V 4 Specification (210x297 gong) Jingerbeiyang Standard · / (. JA 工 工 殺 業 Cooperation Duin 3i ^ 02427 Λ fi __HJJ_ V. Description of invention U) group, third butyl, methoxy, methylthio, Trifluoromethyl, trifluoromethoxy, trifluoromethylthio, pentafluoroethyl, bromodifluoromethoxy, ethyl blue, hydroxycarboxy, methyl carbonyl, nitro, azido or nitrile '; Or R4 and R5 — Starting from -0-CH2-0-, and 3, R4 and R7 are as described above; r2 is a atom or methyl group, and 1 ^ is as described above. The compound to be optimized according to the present invention is the formula R 1 pseudocyclopropyl; R2 pseudo hydrogen atom or methyl; R 3, R 4, RS, R 6 and R 7 may be the same or different, pseudo hydrogen, fluorine, chlorine or iodine atom, A Base, -N02 or -CF3g. Particularly preferred compounds include: 1- (4-nitroanilin formaldehyde) -2-cyclopropyl-2-fluoropropionitrile; 1- (4-nitroaniline formamide) -2-cyclopropyl-2-fluoro Propiononitrile; 1- (4-Amino-3-toluylaminoformamide) -2-cyclopropyl-2-gasopropionitrile; 1- (3-methyl-4-trifluorotoluylaminoformaldehyde) -2 -Chenpropyl-2-gas propionitrile; 1- (4-cyano-3-tolylcarbaldehyde) -2-Hunpropyl-2-gas propionitrile; and its ageing salts. The compounds of the present invention can be prepared according to the following processes, for example, and the present invention also includes such processes. The aforementioned compound (I) can be installed, for example, by compound (II) (please read first, please pay attention to the details and write this page). Thread.

The 5lt scale of this paper uses the Chinese Sleepy Family (CNS) specifications (210x297): .024 ^ 7 Λ (; '___ Π_6_ V. Invention description (♦) (where R 2, R 3, R 4, R 5 , RS and R 7 as described above) and sodium hydride, if necessary in the presence of a catalyst such as imidazole, and then the resulting intermediate and compound (in) are reacted,

Hal-CO R 1 (III) where Hal is a pseudo halogen atom, and Ri is as described above. The reaction of the compound (III) and sodium hydride is preferably carried out in an anhydrous organic solvent such as tetrahydrofuran. The compound (I I) is conveniently composed of the compound (I V) (please read the back-to-back precautions first #pot write this page) Chinese

Compounding and \) / As mentioned before 7 R and binding-binding line

The Ministry of Economic Affairs and the Central Standard: 5 industrial and low-cost cooperation Du Yin 32. In, for the next best in the relatively existing anti-amine sub-biological chemical derivative ι β (Neng Ji Sui Jichen or two V; or ΪΙΚ Heya Idi and Ivjlg i-propylated heterodi-or furfural tetra-_i fusing organically with water and using it as if it were traveling in the bio-generating energy officer. Alkane, nitrogen, and nitrogen are as examples. Use the Chinese National Standard (CNS) TM specification (210x29V). 5. Description of the invention (· Γ) It can be obtained, for example, from the on-site reaction of cyanoacetic acid and penta-vaporized phosphide. The preparation method of compound (II) can be referred to A. Nohara.T · Ishiguro et al. Were prepared in the following way in the "Journal of Medicinal Chemistry", 1 9 8 5 2 8 (5), pages 5 5 9-5 6 6:

CHO

CHO

〇_ / NHCOCH2CN Ministry of Economic Affairs Standards " JA Gongxiao cooperation Du Yinhong The compound used in the aforementioned process [IV_ > is generally a known product, or it can be diazotized according to the known manufacturing method, and then reduced corresponding Nitroaniline was obtained. For the preparation method of the nitroaniline used, for example, see TP. Sura et al., "Synthetic Communications", 18 (16-17), 1988, page 2161-5. Some aniline ClVj can be based on European Patent No. 206, 951 It is prepared by the method of or obtained from the reduction of the corresponding nitrobenzene (some are known); but some nitrobenzene is novel and can be prepared according to the method described in the following examples. Compound (Π in essence It is acidic. The compound (U salt added with U is preferably obtained by reacting an inorganic or organic base with an approximate stoichiometric ratio of compound tD. This salt can be prepared directly from the corresponding acidic compound without having to isolate the intermediate. The compound of the present invention has a valuable property, and it is worth mentioning that its anti-inflammatory activity is obvious. It can use special antigens to slow down the activity of immune cells and inhibit inflammation caused by irritants. These properties will be further explained in the experimental part. (Please read the back-end notes #code to write this page) Binding-order _ line '51c scale side paper used in the paper a Η 家 見 1MCNS) Ή Regulations (210x297 Public) 024 ^? V. Description of the invention (k) Λ G Π 6 Do salt and alkali plus permissible Ht 〇Physical medicine and its use and use I) It can be hungry, salt and alkalinization, and it is added to the previous and it is clear that it is made in this Chinese formula for physical and chemical. 〇The substance should be the same as the substance. The substance can be different from or in the same phase as amflurohydrogen. It is based on proton iodine or bromomethoxytrifluoromethanetrifluoride, diyl bromide sulfur, methyl, ethylfluorooxypentamethyl. , -Yl thiobutane trifluoro third yl ethyl gas methyl, fluoro acetyl triethyl-yl, I methyl ester or carbonyl group hydroxymonoorthonitrile q or R7 group and m6 R stack 3 group R nitrile Radical 0- carbonyl- 2 gas H C A-

If the preface is like 1Χ R or the preface is like hydrogen 傜 (please read first and back to the attention of the matter # fill in this page) The Chinese medicine is the compound medicine of Jiate for the purpose of making it clear. Base and A 6 R or, sub 5 R original, 0 4 R pseudo, and or fluorinated 0 are the same or not in phase 3 F: C-there is or something, it is better to combine No. 2 and Yuki, _ The child is the original iodine § WB tu.- to? Propyl propane gas «; II 2 2 f I 基基 丙 丙 琛琛 I -2 2 II \ J / \ J / Ester methyl methylaminoamine benzene The nitrocyanine Ministry of Economy's Shiyang standard is: ^ Industry and Consumer Price Cooperatives Yinyu C; Gas; Nitrile 2-Rapron $ propyl m ^ m-Propane-2 ring-2 yl 2-ylpropanyl) -propanal ring -2 A 2) -yl} -acrylamide toluene methyl methylamine fluoroamine benzotriazole---7 even 7 nitromethine «0 methylamine benzotriamine-4-ylmethylnitropropyl Gas-2-ylpropane salt age plus its 5fc scale for paper use in the middle of a family of standard (CNS) TM specifications (210x297 g) 2024V? Λ 0 _Π_6_ V. Description of the invention (7) · These can be For example for the treatment of rheumatoid arthritis and immunity or Chronic inflammation of immunological (e.g., graft - to - graft disease in a subject, transplantation reactions, uveitis). The usual dosage depends on the compound used. The patient to be treated and the condition, the new daily oral dosage is, for example, 0.1 mg to 2QG mg. The present invention also provides a pharmaceutical composition, which contains at least one of the aforementioned compounds (the I domain is pharmacologically approved to be added with an emu salt, in combination with one or more pharmaceutical carriers and / or excipients. When used as a medicine, the compound ω and its Age salt can be made into oral preparation, rectal preparation or parenteral preparation. These preparations can be solid or liquid, for example, in the form commonly used in human medicine, such as thick tablets or coated tablets, waist capsule (including false capsules) , Granules, plugs, solutions, such as injection solutions, all of these can be prepared according to the usual method, even if the active ingredients are mixed with excipients commonly used in pharmaceutical compositions, such as talc, gum arabic, starch, lactose, Coconut stearate oil, aqueous or non-aqueous carriers, animal or vegetable fats, various derivatives of scallion derivatives glycols, wetting, dispersing or emulsifying agents and preservatives. The present invention also provides treatment of wind-induced arthritis in humans or animals And immune or non-immune chronic inflammation method, pseudo-administer an effective amount of the aforementioned compound (I domain plus its first permission plus _ 俩. This is more relevant to the new class of compounds (JI): this paper ft scale With China National Long quasi (CNS) ΤΜ size (210x297 male dragon) (Please read - Note * ^ back while the dry clay lump matters # write the page) installed · line · 024¾ ^ V. invention is described in (?)

P R

Λ (i Π fi 丄: R „II) Ministry of Economic Affairs 屮 楉 渉 准 工 消 " Cooperative Society Seal 31 (where R2, R3, iU, R5, 1 ^ 6 and 117 are as mentioned above, which are novel industrial products, It can be used as an intermediate for the production of compound I. Preferably compound (II), where R 3, R 6 and ϋ 7 are each a hydrogen atom: I pseudomethyl; and Rs is as described above but not a nitrogen atom or Methyl group. The following is a non-limiting example of the scope of the present invention: Window example 1 1- (4-trifluorotoluylaminomethyl) -2-propan-2-propionitrile; Step A: 4-Trifluoromethyl nitroacetanilide is not cooled, at 8.6 g, 1.01 mole cyanoethyl truncated aniline and 13.5 ml, 0.1 mole 4- (trifluoromethyl) aniline / 100 * L dry four To the argon furan solution was mixed with 16.4 ml, 0.1G5 of diisopropyl nitrated diimine and pressed for 10 minutes. When added, the temperature of the solution increased from 20 ° to 60 ° C. The mixture was stirred at room temperature 16 After filtration, the filtrate was evaporated to dryness to obtain a solid residue. It was suspended in 100 liters of ethyl alcohol, stirred at room temperature for 1 hour, with 50 * liter of ethyl alcohol, 2 X 1 0 0 1 liter of diazomethane and 2 X 1000 ml of hexane Wash. Dry at room temperature for 3 hours at 60 ° C to obtain 18.8 5 g of diseased substance (yield 83%), melting point 195-6 ° C (colorless crystals). 10- This paper 5 good-scale use in medium SH Family Standard (CNS) fM specification (210x297 mm) (Please read the back to the first note ^ Item # Item write this page) Μ Λ Π 6 5. Description of the invention (9) Step B: 1-(4-three Fluorotoluylaminomethyl) -2-cyclopropyl-2-gas propionitrile was treated with 80% hydrogenated sodium oil dispersion (Q. 8 8g, 0.0 2 8 6 mol) under dry nitrogen 3 · 0g, 0.013mol 4'-trifluoromethyl cyanoacetaldehyde aniline / 10Qml dry tetrahydrofuran suspension, stirred at room temperature for 30 minutes. Then with 1.3Qml, 0.0143mol earrings propane carbonyl nitrogen drop treatment The thick suspension of sodium salt was stirred for 10 minutes at room temperature for 16 hours. 1 ml of water was added and the mixture was stirred for 10 minutes, acidified with 2 N hydrogen acid and extracted with ethyl acetate. The organic extract was dried over magnesium sulfate , Evaporate under reduced pressure. Warm the solid residue with 15 ml of difluoromethane and dilute with diethyl ether to give 2.7 g (70% yield) of the title compound as colorless crystals, melting point 2 1 2-3 ° C (ethanol ). (Please read the precautions before writing this page) f. The standard of the Ministry of Economic Affairs and the printing of 3G by A Gongxiao Cooperative Co., Ltd. can be prepared by the same method. Example 2 1- (3-Amino aniline group A m)-2 -Chen propyl-2 -oxypropionitrile Example 3 1- (4-«tef TO toluylmethyl m)-2-C-butyl butyl-2-gas propane m; M. 4 1- ( 4-Difluorotoluidinemethyl m)-2 -Chenpentyl-2 -propionitrile; Example 5 1- (4- Fluoroanilidene m)-2 -Cyclopropyl-2 -Gasopropionitrile Example 6 1 -(4-azinopropylmethyl m)-2 -propenyl-2 propionitrile example 7 1- (4 -bromoanilinyl m)-2 -chenpropyl-2 -gas propionitrile example 8 1- ( 4-Trifluorotolylaniline m)-2 -Hunpropyl-2 -pyrrolidine Example 9 1-(4 -Nitroanilinem)-2 -cyclopropyl-2 -pyrrolid Example 10 1-(3, 4 -diazoaniline m)-2-m propyl-2 -oxypropyl m; Example 11 1-(4-iodoaniline m)-2 -hypromyl_ 2 -Gasopropanol Example 8 1-(4-iodoanilide m)-2-m Propane m -2 -Propylene Sri; Step A: 4'-iodocyanoacetanilide _ line · 5B scale side paper of this paper is used in China National Standard (CNS) TM specification (210X29 / public)

Λ fi HG k.024 ^? V. Description of the invention (θ) In a water bath at room temperature, in 35.25 g, 0.17 mol phosphorus pentachloride / 250 ml dry dichloromethane suspension, stir and add 14. 41 grams, 0.17 mole cyanoacetic acid, 2 minutes. Heat to reflux for 0.5 hours, then flush with nitrogen for 2 minutes. 24.75 g, 0.113 mol 4-iodoaniline was added, the mixture was stirred under reflux for 2 hours, cooled, and poured into 30Q ml of water. Stir the mixture for 1 hour and filter to make the solid residue and sodium sulfonate solution ▼ Stir the solution, filter, wash the solid with water and ethyl yeast in order, and dry in vacuum at 60 ° C. This gave 29.51 g (91% yield) of 4'-iodoacetamide, melting point 2 1 6-8 ° C. Step B: 1- (4-iodoanilinylcarboxamide) -2-cyclopropyl-2-fluoropropionitrile In Example 1, Step B, the title compound can be obtained from the previously obtained 4'-iodofluoroacetanilide. Example 1 2 1- (4-Bromo-3-tolylcarbaldehyde) -2-cyclopropyl-2-propanal; Step fee SA: 4-bromo-3-methylcyanoacetanilide at 40 ° C was stirred 0.457 g, 5. 37 mol cyanoacetic acid / 30 ml dry methane solution and 1. 00 g, 5. 3 7 er 4-bromo-3-toluidine, added 1.135 g, 5.5 milligrams Mole dicyclohexyl sulfonated diimine / 5 ml diazomethane for 2 minutes. At the time of addition, the temperature of the solution did not exceed 4Q ° C. After stirring for 1 hour, the solution was finally cooled to room temperature. When cooling, the crystals precipitated the two Phenomenon and passed the cat. Wash the solid three times with diazomethane. Evaporate the filtrate to dryness and remove the solid residue. Cylindrical chromatography solidified the residue, washed with diazomethane gradually increasing the percentage of ethyl acetate, and the yield was 87%. Step B: 1-(4 -Bromo-3 -toluylmethylformamide)-2 -cyclopropyl-2 -propionitrile-1 2-This paper is used in the national standard (CNS) T4 specification (210X29V Mm) (please read the precautions in advance), install it. Ordered by the Ministry of Economic Affairs, Biyang and Mongong Daidai Cooperative Society 1i u 024 ^ Λ fi Π β Economic Ministry, Biyang # quasi · -Gongxiaoting Cooperative Printed 3i V. Description of the invention (") Under dry nitrogen, stirring continuously, with a catalytic amount of imidazole to treat 300 mg, 1.19 mmol (1 equivalent) 4-bromo-3-carboxamide plus Compound / 12 ml of dry tetrahydrofuran solution. Add 626 mg, 2.2 equivalents, 2.61 mmol of sodium hydride in 8D% oil dispersion, and stir at room temperature for 15 minutes t. Add 0.0843 ml, 124 mg, 1.85 millimoles (1 equivalent) of cyclopropane carbonyl gas to the resulting sodium salt for 3 minutes, stir at room temperature for 2 hours. Β Pour the reaction mixture into a minimum amount of water, with 1M hydrogen The acid was acidified to PH 2 and the mixture was stirred for about 1 minute until all solid precipitated. The solid was filtered, washed with water, and then washed with a minimum amount of ether to obtain the title compound as milky white crystals (yield: 83%). Example 1 3 1- (3,4-Methylenedigas tolylaminomethyl) -2-cyclopropyl-2-gaspropionitrile Step A: 3,4-Methylenedigas cyanoacetanilide in the room Stirring at a temperature of 685 mg, 3.29 mmol, (1.5 eq) phosphorus pentachloride / 10 ml dry methane suspension, adding 279 mg, 3.29 mmol (1.5 eq) cyanoacetic acid for 1 min . The mixture was heated to reflux for 30 minutes and then flushed with nitrogen for 2 minutes. 300 mg, 2.19 mM 3,4-methylenedioxyaniline was added, heated to reflux for 10 minutes, then cooled at room temperature and poured into 10 ml of water. Stir the mixture vigorously for 30 minutes, filter the solid residue, wash the ethyl acetate and ethyl acetate with water at least in order, and the amount of deer is 3 3 0 «Yan (49%). Step Β: 1-(3, 4 -Methylenedigas aniline aminoformamide)-2 -cyclopropanone-2-oxypropyl nitrate 13 This paper is used in the national standard (CNS) ΤΊ specifications (2 ] 0X297 Gongmei) (please read the note beforehand and write this page again) Install · Order _ Line · r Λ fi 15 (i 5. Description of the invention (| >) Example 1 Step 3 , 4, -Methylenedichlorocyanoacetanilide, to obtain the title compound. Example 1 3, the following compounds can be obtained: Example 14: 2-gas-3-cyclopropyl-3-gas-N-methyl -N- (4-chlorobenzene) propionaldehyde amine Example 15: 1- (4-chloro-2-tolylmethyl) -2-cyclopropyl-2-oxopropionitrile. 16: 1- (3, 4-Difluoroanilinocarbaldehyde) -2-cyclopropyl-2-pyriopropionitrile Example 17: 1- (4-Methoxyanilinocarbamide) -2-cyclopropyl-2-pyropropionitrile poured 1 8 : 1- (4-Aminoanilinocarbaldehyde) -2-cyclopropyl-2-pyropropionitrile Example 19: 1- (3,5-Dihydroanilinocarbamide) -2-cyclopropyl-2-oxo Propionitrile Example 20: 1- (4-Gas-3-methylanilinomethyl _)-2-cyclopropyl-2-Gasopropionitrile Example 21: 1- (3-Trifluorotoluidine formaldehyde) -2 -Hengpropyl-2-gas propionitrile Example 22: 1- (4-tolylaminoformamide) -2-cyclopropyl-2-gas propionitrile Example 23: 1- (4-chloro-3-trifluoro Toluyl formaldehyde) 2-cyclopropyl-2-pyrrolidone Example 24: 1- (anilinomethyl IS) -2-propan-2-yl propionitrile Example 25: 1- (3-methyl -4-Trifluorotoluylmethyl _) -2 -cyclopropyl-2- 2-propargyl sapphire by the Ministry of Agriculture, the Ministry of Industry and Industry " Cooperative Society Printed 3i (please read the back-end precautions # 塡 写Wooden sheet) Example—26: 1- (4-iodo-3-toluidine methyl K)-2-2-methylpropyl-2-propionitrile 1-(4-overview-3-toluyl methyl K)- 2-Cyclopropylpyridine-2-gas propylene M Example 28: Bu (4-atmosphere-3-toluidine ketamine K)-2-cyclopropyl money-2 gas propane M _ Bu [4-(2, 2, 2 -Sanyiyiqi) Benji-Jiyi] -2 -Chenpropyl-2 -Cypropropyl 14 This paper is printed on the Chinese standard (CNS) < fM regulations tt (2) 0x297 ) The standard of the Ministry of Economic Affairs and printed by the β Gong Xiao Zhi Cooperative Society rt'14 Λ fi _ Π 6_ V. Description of the invention (β) Example 30: 1- (3-methyl-4-nitroaniline formaldehyde) -2- Cyclopropyl-2-gas propionitrile Example 31: 1- (4-third butyl anilinoformamide) -2-cyclopropyl-2-gas propionitrile Example 32: 1- (3-methylanilino group Alpha-enzyme) -2-cyclopropyl-2-fluoropropionitrile Example 33: 1- (4-trifluoromethylthioanilinoformamide) -2-cyclopropyl-2-fluoropropane Example 34: 1- (4-Methoxycarbonylanilinomethyl) -2-propen-2-pyropropionitrile Example 35: 1- (4-Acetylanilinomethan) -2-cyclopropyl- 2-Gasopropionitrile Example 3 6 "-1- (3,4-Dimethoxyanilinyl methyl)) -2-cyclopropyl-2-Gasopropionitrile Example 37 1- (3-Atmosphere-4 -Tolylamino formaldehyde) -2-cyclopropyl-2-pyriopropionitrile Example 3 8: Bu (4-methylthioanilide formaldehyde) -2-hypromyl-2-pyropropionitrile M 39 = 1- ( 3-Ethyl-4-nitroanilinocarbaldehyde) -2-cyclopropyl-2-gas propionitrile Example 40: 2-cyano-3-cyclopropyl-3-gas-N-methyl-N- ( 3-Methyl-4-trifluorotoluene) propan Samine Example 41: Bu (4-bromodifluoromethane-3-toluylmethylformamide) -2-cyclopropyl-2-gas propionitrile Example 42: 2-Gas-3-cyclopropyl-3-Gas-N-methyl-N- (4-cyanobenzene) propanalamine Example 43: 2-cyano-3-cyclopropyl-3-Gasomethyl-N -(4-Nitrobenzene) propanal amine M 44 1-(3 -methyl-4 -trimethylmethanil aniline hexamidine) -2 -cyclopropyl-2 -gas propionitrile Example 45: 1- ( 3-Methyl-4-pentafluoroethylanilinyl-pyridine) -2-cyclopropyl-2-gas propylene on paper 51c scale side use medium 01 sleepy home standard (CNS) < fM specification (210X29 / grand ) (Please read the back-to-back precautions first and then write the wooden page hard) 装. 线- Standards of the Margin Department · >!·; A Industrial and Consumer Cooperation Du Yin 3i Λ 6 Π 6 V. Description of the invention (< 4) Example 4fi: 2-Gas-3-cyclopropyl-3-Gas- N-methyl-N- (4-bromo-3-toluene) propionamide Example 47: 1- (4-gas-3-ethylanilinyl formaldehyde) 2-cyclopropyl-2-gas propionitrile Example 48 : 1- (4-Carboxanilinyl formaldehyde) -2-cyclopropyl-2-gas propionitrile Example 41 used: > 1- (Naobiyun methyl nitrogen) -2-methan-4-amine Rongxi production method As follows: Dissolve 0.92 g of sodium in 30 cm 3 of ethanol and add 6 g of 2-methyl-4-nitrophenol. The solvent was evaporated under reduced pressure, and then benzene was added. The resulting sodium salt was added to a mixture containing 24 cm 3 of dimethyl formaldehyde amine, 30 cm 3 of dibromodifluoromethane and a small amount of ethanethiol as a catalyst. The mixture was heated at 70 ° C for 1 Q hours, then poured into ice and extracted with ethyl acetate. Sequentially wash with 0.5M aqueous sodium hydroxide solution and water, dry and remove the solvent under reduced pressure "elute with ethyl acetate / hexane 4:96 on the silica gel, extract 3.35 g of 1- (bromodifluoromethane) -2- Methyl-4-aminobenzene is converted in the presence of activated carbon to obtain the desired product. Example 44 used the 2-Shenshi-4-amine-1-trimethoprene starting material method as follows: In a sealed flask at 175 ° C, heat 0.3g of 1- (bromodifluoromethane) -2 -Methyl-4-nitrobenzene, 0.12Q grams of antimony tri-gasified and Q.Q2 grams of antimony pentanitride as catalyst for 4 hours. The mixture was diluted with water, dried, and the solvent was evaporated under reduced pressure, so that the resulting 0.13 g of 2-methyl-4-nitrogen-1-trifluoromethane was kryptonized in the presence of activated carbon. Deer. Example 4 5 used? -Jiamou-4 -anti-〗-7Γ plaque 7, the beginning method is as follows: The 51k scale of the paper is used in the middle of the country a «Bi ΚΝ5) > ίΜ« ΙίΜ2Κ1χ297 public concession) (please read the book first Matters needing attention # code qiaomu page) installed · A fi _HG_

V. Description of the invention (I Under argon, mix 2.36 g of 1-iodo-2-methyl-4-nitrobenzene and 2. 2 g of copper powder in a 3 cm dimethyl methyl Samine in a sealed container (Wash with water and acetone in advance and dry under reduced pressure, see " Crg, Synthesis Coll. &Quot; Volume II, 1948, page 445.) Cool the mixture to-60 ° C, add 11.5 g of pentafluoroethyl Iodide). Mix at 160 ° C and 3.5 bar pressure for 16 hours, then cool in ice and return to room temperature. The mixture was poured into ice, extracted with ethyl acetate, washed with water, dried, and evaporated to remove the solvent. It is eluted by chromane with 2-3% difluoromethane in digasification silica chromatography, and the resulting 1.5 grams of 2-methyl-4-nitro-1-pentafluoroethylbenzene is hydrogenated in the presence of 粑. What you want. Spectral data, yield, melting point and analytical data are recorded in Table I. Example 49: A tablet (1 tablet) is prepared from the following composition: 20 mg of the compound of Example 1 and 130 mg of excipient (containing lactose, starch, talc, magnesium stearate). Example 50 U tablets (tablets) were prepared from the following composition: 20 mg of the compound of Example 2 (please read the general notes first and fill in this page) to pack-line_ 0 acid hard rock smooth powder 0 sugar milk Contains the package / (\ dosage form fug «ο The Ministry of Economic Affairs Shiyang standard 杓 only work consumer cooperation cooperatives printed and printed on the paper standard side use Η home sample Bi (CNS) TM specifications (210x297 public) r; ifJ42 66 ΛΒ economy Ministry of the Central Standards and only work to eliminate the cooperative printed 31

(Please read the back-end notes first #fill this page) 2 ο ίΜ 66 ΛΒ • / J ° / J 1Γ, Li 10.9 7.22 (2'd); 2.15 (l'm) 31 (2 'den; 1.18 (2H, Ta) DMSO 丨 12.27 (1H, S); 8.19 {2H, dr7.79 {2H, d); 2.20 (lH, m); ° .s (4H, m) CDC13 丨 15.61 (1H, S ) 3 · 66 (1'Π0; 2.24-H CDC13, 15 · S1 (1H, S) 3.22 (lH, m); 1.85 (8H SC13-15. S (1H, S) 7_06 (2H, wa); 2 , 15 (1H SC13 丨 15.77 (l's) 7.33 (2H, d); 2.14 (1H SC13-15.76 (1H, S) 7.38 (2Η-); 2.14 (1Η CDC13 丨 15.71 (1H, S ) 7.26 (2'3); 2.14 (1H CDC13 — 15.76 (1H, S) 7.76 (l's); 7.64 (4H, S);-7.72 (1H, S); 7.64-'s) ; M) 7.61 (1H, S); 7.42 (2'm); m); 1.32 (2H, m); 1.16 (2H, m) 7.s (lH, s); 7.44 (s, d); m ); Ll (2H, m); 1.16 (2H, m) 7,62 (1H, S); 7.48 (2H, d); m); 1.32 (2Η, τα); 1.25 (2'm) 7-67 (2Hi; 7..53 (lH, s); 3); 1.34 (2'm); l-6 (2'm) 7,73 (1H, S); 7.53 {2H, d); CDC13 丨 l -64 (l'sr7,77 (lH, s); 7.64 (4H, S); 2 16 (1Η, Π0; 1 37 (2H, Tnrl 18 (2'm) SC13 i 157 ° (1H, S); 7.65 (1H, S); 7.63 (l's); 7.25 (3'm); 2.16 (1Η, η); 1 * 34 (2H, m); 1.18 (2-Tn) 芄 昄 氺 ^ $ (please read the notes on the back of this page to write this page) Mian-cl ^ nllowiiwFS 282 ″ 26 C13H11N202C1 262.69 C15H13N202F3 310.28 C16H15N203F3 324.31 C13H11N202F 246.24 C13H11Z2 ° 2C1 262.69 C13HllN202Br 307 · 15 C13H11N202I · 1Λ C14H112203F3 312.2 ^ C13H11N304 273 · 25 Ministry of Economic Affairs t Central Development Co., Ltd. 53. 18.25 44.s 3, h3 7. Yamaichi 35.83 59 _ 4 Office f 22 10.66 13 · 49 59.35- ^. 30 10.67 13. 51 so · ® ** 3.61 26.02 63_ 41 4.50 11.38 13.00 26 Office 17 Office 66s sss 58 3 03 44- ^ 22 10 2ot1 ° 224 ° 28 Lat 56,76 3 -7 厶 ^ 56,81 3 .- ^ 1 ° Mountain H%-02 18.37 02 18 · 43 64 17.58 63 17.63 46 19 * 25 45 19.25 s M3. 49 65 13.52 x%-Regulation 4 A VI / Nsi (c quasi-country country a-medium-sized ruler

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(Please read the note to the back * '? 事 ## 虞 Sad page) Pack :: order :: line 7-"-1 2 ο 6 6 ΛΠ Ming 18 乳 n / J 1t19 立 20 1 * 7 15 13 12 11 Lingyi DMSO 丨 11.89 (1H, S); 7.74 (4H, m); 2.2 P9 (4H, m) DMSO-11.89 (1H, S); 7.66 (2H, S); 7.18 (1H, S) ; 2.19 (lH, m); 0.s (4H, m) DMSO-ll.536 (lH, s); B.04 (lH, m); 7.52 (lH, m); 7.45 (lH, m) ); 2.l9 (lH, m); 0.95 (4H, m) DMSO-10.97 (1H, S); 7.54 (2H, m); 7.39 (153), 2.34 (3H, S); 2.19 (lH, m) m); ls (4H, m) CDC13-15.89 (lH, sr7.44 (1H, S); 7.10 (1H, 3); 6.7 8 (2H, m); 5.99 (2H, S); 2. 10; 1.26 (4H, m) SC13-17.09 (1H, S); 7.44 (2H, d); 7.23 (2H, dr 3-34 (3H, S); 2.13 (lH, m); 1.24 (2H , m); ls (2H, m) DMSO-10.807 (1H, S); 7.72 {lH, m); 7.35 (lH, m); 7.27 (lH, m); 2.22 (353); 2.19 (lH , mrl'o2 (4H, m) DMSO-11.20 (1H, S); 7.80 (lH, m); 7.37 (2H, m); 2.19 (lH, mrl. 01 (4H, m) > 1 (Please first (Please read the notes on the back page) Line_ C14H11N302 253 .932 C13K10Z2C12 2VO7 · 132 C14H14hf202 242.2 C13H1 0C12Z2O2 2 < x > 7_ First Office C14H13N202BI: 321. C14H12N22 272.266 C14H13N202C1 276 .72 C14H13N202C1 276.714 C13H10N202F2 264.23 Ministry of Economic Affairs Standards / (·; β 工 消 1 \ '' Cooperatives 5. 21 52.55 3.3VOVDkLJ23.86 66,21 4 .37 16. 55 60.76 10.13 12.81 60.69 4-7,7 10.10 12.002 59. S 3 .03110. S 14 · 3Β 60.77 f73 10.12 12.82 52 52 61 61 35 Office 21 Office IS嶶 65 Office 52.55 3 52,37 3

310g II 3 23-86 λ.5 9.37 丨 000οο ^ ίοMfs 1000.65 24.10 s 10.2U3I Office 7 10.18 IC suppression ΚΛ · material f: provocative: ΧΛ »standard 4 f \ J / s CN quasi-home s β middle-use side Ruler Zhang Ben

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207 I 3280 (NH), 2220 (CN), 1620, 1520, 1470, 1400, 1340, 13G5, 126P1220, 1080, 1020, 975,910, CO90, CO2Q, 755, 685, 655, 620 117 I 3290 (NH), 222G (CN), 1600, 1450, 1415, 1350, 1320, 1265, 124 5,119 5,1180, 109 0,1065, ISO, 99 0,92 0,89 5,805,77 0,755,69 5 1B6-C0I 3395 (NH ), 2204 (CNr163, ° 1600, 15B0, 1545, 1409, 1346, 1310, 1156, 1110, 1097, 1037, 1027, 03800, 27, 51 163-5 I 32B4 (NH), 2000ON), 1623, 1599, 1565 '1525, 1469, 1400, 1371, 1338, 1301, 1250, 123B, B82 140-2-3280 (NH), 2002ΟΝΓ 1620, 1573, 1560, 1540, 1491, 1341, 1204, 886 300 I 32B0 (ZΚ) , 21votns (CM), 21 厶 5W (C2), 1630, 158CO, lcnull, ltnoo, 1410, 1332, 1309, 1254, 1230, 877, B21 3380 (NHr2002oNr1621, 1602, 1578, 1551, 1540, 1502, 1477, 135, ° 128 ° 1220, 1150, 1071, 8S 22316 1 3300, 3120, 2VO30, 2220, 1630, Mtn.70 ~ 15U10 ~ 1500 ~ M office, M.120, 1380, 1350, 1290, 1270, 1240, 1090, 1070, 1040 Jingyibeiyang central quasi / -JA 工 消 在 Cooperation Duinin rolled paper standard universal as 斓 榣 准 (CNS) «M Grid (210x297; a :) 37S (NH), 2035ON), 1545, 1520, 1495, 1460, 1400, 1310, 1260, 1240 '1170, 1130, 1060, 1025 8-0 (please read the notes first Matter 4 · Fill in this page) 装 · ^ 024 ^ V. Description of the invention (> 丨) u > 〇ro νο

CD ro NJ σ »Λ 6 W 6 Μ Νί N > fvj N > LT1 · & · CJ f〇μ-» DMSO-12.01 (li's); 7.63 (3I'm); 2.45 (3's); 2.21 (1'no; 0.88-h, e SC13 I 15.87 (1H, S); 7.52 (2H, m); 7.42 (2H, m); 7.95 (2H, m); 4.34 (2H , q); 2; 1_33 (2H, Tn); DMSO-11.65 (l's); 8.02 (1Η-); 7.65 (2Η, Γη); 2.53 (3's); 2.17 (lH, m); ° 95 (4'm)

CDS I 7 · 00 (1H rt η- »—tn CO OD ♦ U1 fsj ^ CD l ·-» • V work U),

.49 (1H, S); 7.24 (2H, Tn); 1.33 (2H, m); 1,16 (2H, £ DMSO 丨 11.49 (l's); 8.23 (lH, m); 7,81 (lH, m ); 7.67 (1'm); 2.22 (lxm); 1.07 (4 H, m) DMSO, IP 68 (1H, s); 7.53 (2H, 5; 7, 36 (2Hi; 7.17 (1-dan; 2 t 20 (l'm); l. 09 CDC13 * 15.S (1H, S); 7.59 {2H, d); 7.43 {2H, d); 2-9 (3's); 2 · 15 (1H, In); 1,35 (2'm); 1, 19 (2H, m) CDC13-15.73 (1H, S); 7.77 (lH, d); 7,45 (1H, S); 7.37 (lH, dr7.06 (lH, ddr2.43 (3H, s); 2.14 (l'm); 1.34 (2'm); 1.17 (2H, m) DMSO 1 11_ 7.36 (IHi U1 ro ' m re o, > (/) n:,. 8 · 12 (1H, s); 7.68 (ΙΗ, τπ); mr0'9r4H, m) ^ Erli (please read the backnote first " Matter ^: fill in the wooden page) Binding-Order C14H13N304 287, 28 C14H13FN202 260.27 01 ^^ 13 ^ 3 02 267.29 C15X13F32203 326.28 C14H11N202F3 296.24 C14H14N2〇2 2- ^ 2. 26 C14H1QC1F3N202 3: 30-15C13H20 31. · 28 C14H13IN202 368,18 The Ministry of Economic Affairs standardizes and only works to support the cooperative's printing disaster 58.53 55 · 22 67. ^ 1 50.85 50.11 68, 41 68.40 58.07 58. 00 45.67 56.76 5 · 3 ° 5. 37 Γ22 f 30 3, 56 5.03 Office, ^ 0 4.02 f 56 U > UJ U) u > •. T! H- > 〇 CD 〇 \ tn n; ^

^ • 46 19.25 11.s 丨 B-7 10.72 ro3 lat 10.73 12.27 I 12 · 32 I 9.03 18.37 ^ -04 18.27 7.61 34_47 10,-^ 6 ^-° 15.72 丨 8.51 ° 14-3 I paper 5 good-size edges In use "Η home« quasi (CNS)> fM regulations «5 (210x29 / mm) Η% towering storage: ^ 0 .. Ν% X%

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AAAAAA person AAA 108,5-110 179 丨 81; Ml-2 12Ϊ 16Ϊ 158-60 188-vd 1-05101 10Ϊ; Ul-3 Central Ministry of Economic Affairs Qin M Industry and Consumers Cooperative Society printed 5i 32809H), 2212ΠΝ), 1621 , 1597, 1570, 1527, 1490, 1346, 1310, 1130 (sr1110, 1090, 892, 829 3 3 603Γ3 3 22 (mr2 2 00 (mr1710 (sr157s (sr152 4 (sr14 299r 14 09 (s), 1348 (3 ), 1318 (mr1275 {s), 12413), 1189 (3), 1107 (mr 1081 (m) 'vo853), 8943), 7633) 3300, 2920, 2840, 2200, 1660, 1580, 1510, 1450, 1345 , 1305, 1260,124 0,1175,1065,103 5,9CO0,915'CO90,870, S5,820,805,7 60 3 29-P2905,2820,221, ° 157 5,1550,1505,14 60,14 3 5,1410,1395, 13 55,129 0,1270,12 5 ° 1225,1160,1130,1080,102 0,89 0,84-PB05, 760,710, so, 680 32VO0, 2200, 1U16U1, 1520, 1 ^ 90, 1 ^^ 0, 1 ^ 05, 13030, 13 Office 0, 1305, 1250, 1230, 11B0, 1080, 1040, 995, 885, 865, 810, so 3280, 220U1, 1570, 1U12U1, one office BU1 , 13VO5, 1360, 130U1, 1280, 123U1, 10B ° 106, 0VO7 ° 009-. ° 815, 7 60,65 3290 (s), 2210 (s), 1610 (3), 1570 (sr1525 (sr1410 (sr. 133 ° .sr'124 ° .sris 2220,1560, 1460, 1380, 1320 , 1170, 1130, 1050 3260, 2970, 2210, 1910, 1590,1410, 1350, 1300, 1270, 1195, 112 0,1095, 1070,102 0,99 5,950,905,87 0,84 0,82 5,805,770,73- P675 > 1 {基} 令 J Ar R2. R1 族 一 .c 無 #Optional: c ^ though (Tao Mi 丨 Two) ............... t .... ... Dream ...... (please note IU1 first " 意 事 # * Fill Ben Jia) one χ Λ- a paper scale for the Chinese National Standard B (CNS) «P4 regulations tM210x297 Public: «:) 5. Description of the invention (y) t * JU) U > cd

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U) U) LJ U > N) M β CDC13-15.62 (1H, S); 7.66 (2H, d); 7.58 (2H, d); 2.16 (153); 1.35 (2H, m); r19 (2H, mr192,51; 167.s; 138.71; 137.41; 129.39 (q, J = 309HZ); 121.41; 120-40; 15.91; 11.19 CDC13-1.14-1.25 (2H, m); 1.31-1.41 (2H, mr 2.10- 2.20 (lH, mr3.92 (3H, s); 7.59 (2H, d, J = 8,6 Hz); 7.66 (1H, S); 8- 05 (2H'd, J = co, 4) ; 15.s {lH, s) DMSO-11.86 (1H, S); 7.92 (25mr7.69 (2H, m); 2.52 (3H, m); 2-17 (lH, m); 0.8B ( 4H, m) DMSO-10.44 (1H, S); 7.22 (lH, m); 7.11 (6.95 (153); 3.76 (6H, S); 2.19 (lH, mr1.07 (4H, E DMSO-11.21 (1H, S); 7.81 (1H, S); 7.28 (2H, S); 2.30 (3H, S); 2.19 (153); 0.98 (lH, m) DMSO-10.66 (1H, s); 7.52 (2H , m); 7.27 (2H, m); 2.52 (3H, S); 2.20 (lH, m); l.o6 (4H, m) DMSO 丨 10.65 (1H, S); 7.37 (2H, 3); 7.26 {lH, 3r 6.97 (153); 2,32 (3H, S); 2.19 (1H, 3); 1,08 (4H, m) (please read first, please pay attention to 亊 项 # 蜞 write this page) Installation · Line · C15H14N203 270.29 C15H16N204 288.31 C14H13C1N202 276.72 C14H1 M202S 274 k 01554 ^ 20 ^ 286-29 C17H20N2O2 284 '36 C14H14N202 2- ^ 2. 28 014 ^ 11 ^ 3 ^ 2025 328,32 The Ministry of Economic Affairs, the central government, printed by the hA industrial consumer price cooperative 61.sw. 1 Office 10.21 11.69 6 ° 77 4 .74! 12 12,81 62.49 5.59 9.72 66.66 5.22 1Ρ36 62 · 93 4,93 9 · 78 Mountain 77 51.22 3 · 38 8 · 53 17 · 36 69. Office 1 ^ .82 11,56 71.81 * 7.g, 35 Specification 4.T \ — / S CN quasi-home country a with a ruler on paper V. Description of the invention (Μ ·)

U) VD DMSO-11.82 (1H, S-NH); 8.00 (lH, d, J = 9HZ, H-5); 7.71 (lH, dd, J = 9HZ, J = 2HZ, H-6); 7. 63 (lH, d, J " 2HZ, H-2); 2.91 (25q, Jm7. 4HZm.thyl-CH2); 2.28-2.16 (l? M, cyclopropyl 1-Hi; 1.24 (3H, t, JH7 .4Hz, -CH3); 0.97-0.87 (4H, m, cyclopropyl j 0DC13-16.99 (1H, S); 7.69 (lH, d); 7.23 (2H, d); 3,37 (3H, S) ; 2.53 (3H, S); 2.14 (lH, m); 1.15 (4H, m); 1.15 (4H, m) n16K15F3z2〇2 324.31 C: 15H15N3〇4 301.30 Λ 6 Π 6 (please read the precautions before writing the wooden page) Pack. Order-line. Ministry of Economic Affairs standard and β work consumption *: Cooperative printing 3i 59.26 4 · 66 8 · 64 M7 · 57 59.80 5.02 13.95 c «w > 5 material- + ½: 3m: ΧΛ > Use the Chinese SB standard (〇 old) 4 rules (Λ (210χ2ί) 7g tf) 7ί42 ο 6 6 ΛΠ Shiyang standard of the Ministry of Economics Χ; Η 工 消 1Ϊ-cooperative du printing

(Please read the back note * 'Item # -filling the wood page first) 装-线 · 本 纸 5fc scale side-use middle a Η 極 楳 半 (CNS) Ή 規 怙 (2l0xWY /,: >) Ο Λ 6 Π 6 V. Description of the invention 03 〇 \ Μ CDC13-16.75 (1H, S); 7.76 (2Ηα); 7.37 (2Har · 3.39 (3H, S); 2.10 (lH, m); 1.18 (4H, m) SC13-16.69 (1H, S); B.33 (2H, d); 7.45MH, dr 3.42 (3H, S); 2.10 (lH, pentet); l.ls (4H, m) CDC13-15.70 (1H , S); 7.48 (lH, sr7.33 (4H, 3); 2.32 (3H, S); 2.12 (3H, S); 1.31 (2H, m); 1.17 (2H, 3) CDC13-15.62 (lH, s); 7.62 (lH, s); 7.46 (3H, m); 2-49 (3H, t, J = 3HZ); 2. 13 (lH, m); 1.34 (2H, 3); 1, 19 (2H, m) CDC13-17,16 (1H, S); 7.60 (lH, d); 7.13 (lH, d); 6.96 (lHad); 3.30 (3H, sr2.44 (3H, sr 2.13ilH >pentet); 1.13 (4H, m) CDC13-15_82 (1H, S, 0H); 7-57 (lH, s, -NHr 7.31-7.26 (3H, m, aromatic ..r2.75 (2H, q, J = 6HZ, ethyl -CH2r2-.18-2'oB {lH, m, cyclopropyl l-Hrll \ 36-l, 10 (4H, m, cyclopropyl.); 1.24 (3H, t, J = 7.sz, 6thyl .-CH3) SC13-15.72 (1H, S); 7.54 (1H, S); 7.33 (3η, 3γ. 2.32 (3H, S); 2.15 (153); 1,33 (2H, mr1. 17 (2H, m) > (please read the note on the back first · I item #filling the wood page) Binding · Order 'C14H122: 2〇 ^ 272 .26 C15K15C12202 290.7U1 C15H15B1TN2〇2 335.21

C15H13N302 267. 2VD C14H13N304 2037. 28 C15H13F3N203 326.28 C16H13F5N202 360.2VO clulHlurorF ^ NWOS 387.19 Line · 61.7ch office 1P29 61.9-7 5.20VO.63 12,19 53.701 office · UIM 3,3σ \ 23 · 84 53: · 6 Office 7.7OT 26 · 37 55.22 4.02 8.59 17.47 58. 53 4 · 56 14 .63 67. Office One Office. Νοο 15.72 9.81 46.53 3.38 7.24 20.2 ΚΛ > «« ># > -8 This paper is used for 5k scale CNAS Standard Specification (210x297); ":) The Ministry of Economic Affairs, the Central Bureau of Economics and Social Security, Π 工 旻 見 社會 社 記 印 31 Λ fi Π 6 V. Description of the invention (ο) Pharmacological activity: cattle servant. Fen Credit method test 1 Deer # Stem Introduce:> Rat g-float (P Π-R) Make each group (6-12) rats (CFHB male, weight 160-18Q g) orally carry test compounds or controls After the body, 1 mg of carrageenan / 0.2 ml of saline solution was injected from the right hind sole. Inject blank saline into the sole of the control. After 3 hours, the paw edema response was evaluated. Test 2 " Wake-up vortex-sensitive white mice: > Xiongtang net sleep II) T Η-Μ) Each group (8 to 10 live) white mice (male CD-1, weight 25-30 grams) were injected subcutaneously 1 mg of "Methylated Bovine Serum Albumin" (MBSA) /0.2 ml of saline and "Freund's" complete adjuvant (FCA) emulsion caused allergy. The control group was injected with saline / FCA emulsion only. Seven days later, 0.1 mg of MBSA / 0.05 ml of saline was injected from the right posterior plantar toe, and after another day, the DTH paw edema reaction was evaluated. The control sole was injected with blank saline. Before the injection of MBSA-hour. After 6 hours. And on days 4, 5, 6, orally once. On the 7th day, the test compound or control was taken orally twice.》 A: 4Ja__i

Symptom-type allergy old E Zhi _ Zhan_ kinky_8 ^ _1 丨) .1 · 丨 丨 Two RJL make every group (8 to 12 pairs) old E (CF Η B male. Body Μ 1 6 0- 180 g) 0.1 ml of FCA was injected subcutaneously from the base of the tail, causing allergy. The control group was injected with Freund's incomplete axis agent. On the 7th day of the allergic reaction, the human toes were injected from the right rear sole. 4 mg of tuberculosis bacteria antigen / 0.2 ml of saline. Another trip 2 4 hours-2 9- This paper is scaled with Chinese SJ (CNS ) IM specifications (210x297 public) (Please read the notes before you write this page hard) Install · Line ·

5. Description of the invention (β)-After the evaluation of D Τ Η foot edema reaction. The control sole was injected with blank saline. The test compound was taken orally 1 hour before, 6 hours after the injection of the antigen, and on the 4th, 5th, and 6th days, and twice on the 7th day. The test results are listed in Table II. The dosage unit is mg / g orally. (Please read the note on the back of this page first. Sun Yao writes this page) Installation · Line. This paper is used in a small country iMCNS) lM regulations «(210x297 Gonghe) V. Description of invention (>,) Ministry of Economic Affairs Central Standard · Knowledge = 3 Printed by Cooperative Society

Η »Η1 Η» M CJtOMOVDOOOONUI ^ CJiOH t-iCDCJliOVD ^ rOtO ^ MUJW ^ Inhibition half test 1 _ | (50) i (50) (50) (50). 1 (50) (50) 1 (50) ( 50) (50) (50) (50) (50) (50) • Dose O ^ CD〇 \ CD (^ 〇N ^ JOU1 uicd VD ^ Cn ^ 〇lVD ^ O > VDCD ^ LnUl Inhibition rate < Η > Trial 2 (30) (100) (100) (100) (30) (30) (30) (30) (30) (30) (100) (30) (100) Dose 53 25 -1 19 i 46 74 61 53 104 30 66 39 22 Inhibition rate test 3 (10) (50) (50) (50) (10) (3) (3) (3) (3) (10) (50) (10) (10) Dosage > II ................ (....... installed .....! 1..line (please first 1 «) read back Note ^ 'Item # -fill ^ this page) ss home standard (CNS) 〒 4 specifications (210x2W / i ^ Λ 6 Η 6 central standard of the Ministry of Economic Affairs and printed by the HC Gongxiao Cooperative Society) (W) LOLOtOtOtOtOtOMMH-K »»-»CJ〇〇) ^ J〇NUl〇VDOD〇% CJt ^. 1 U) t U) u > to to ^ CJ to« ooDroio ^ ooM ^ ONCTk ^ cr »Inhibition half ( 50〉 (50) (50) (50) (50) (50) (50) (50) (50) (50) (50) (50) Den 1φ Η VD ^ -CT \ 〇 \ U1〇3 ^ U ) ^ J〇DU1 ^ J Suppression half to (100) (30) (30) (30) (30) (30) (3 0) (100) (30) (30) (10) (3) 剞 量 CJMUl ^ UiCn ^ O ^^ CT »· ^ V〇u> gt; 〇j_» 〇VDfO · ^, JOD, JVO inhibition half η (10 ) (50) (10) (10) (50) (10) (10) (10) (10) (10) (30) (30) Dose U) A II (Li-) ....... ........ * ....... 装 ..... 玎 线 (please note Ml-ift first ^ * Item # -fill in this page) 5J of this paper: China S home standard (CNS) TM specifications (210x297 g; ":

Claims (1)

6. Scope of Patent Application No. 8010915S "3-Hunyl-Prosperyl Derivatives" Patent Case (Amended in February 1982) 1. Such as the following compound (I) and its sickle addition: (Please read the precautions on the back before writing this page) Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ¾ where β i 傜 C, -6 cycloalkyl; R2 pseudo hydrogen atom or Ci-3 alkyl; R3 One of the substituents represents a hydrogen atom or. -* Alkyl group, another substituent represents a hydrogen atom: one of R5 and Re substituents represents a hydrogen atom, the other two can be the same or different Or branched therapy, window atom, guess " 'group, -κο2. Straight or branched, C 1-6 alkyl, straight or branched Cl-ε alkyl gas group, C: t- ε alkyl sulfide Group, C 0 R 1 group (where _ _ 傜 hydroxyl group, C 1 s alkyl or alkyl group), or selected from-cut mountain-% '_〇- (CH mountain-CF3, -S- (CH on -CF3 , ./F-, -F2_Hal, -0_-CF2_Hal,-(CF2) n -c -Hal1, Η3Ι2: installed .. ΓΓ Taizhile is only applicable to the same as the same fixed f Γ \ · C, buckle R Λ W ', eight, Six, in which m is 〇, 1, 2 or 3; η 傜 1, 2, or 3; Hal. Hali, Hal2. And Hal3 may be the same or different, each is a halogen atom; or R 4 and R 5 — From% -0 -C Η 2 一 0-> R 3, R 6 and R 7 * ^ 傜 as the former. According to ψ, the compound 1 of the first item of the patent scope, where RH, R 4, R, R 6 and R 7 may be the same or different, hydrogen, gas, chlorine, m or iodine atom 1 methylethyl t second butyl methyl group, methylthio, trioxymethyl »trifluoromethyl π group> Three gas methylthio) pentafluoroethyl, bromodioxymethyl gas »ethyl« hydroxycarboxymethyl gas m group »nitro, or m group: or R ^, and R 5-from -0 -C Η: 2 ~ 0-, and 彐, R.4 and R, as described in the business ;; R 2 hydrogen atom or methyl group * and R 1 as described in Item 1 of the Shen Fan Fan Garden 〇 Patent according to Φ The compound of item 1 or 2 of the scope, in the formula {Mu first 5? ^ Contrary precautions and then fill in this book.-.. 抆 济 部 屮 央 标 标 As Industrial and consumer cooperation Du Yinhong R i is cyclopropyl; R 2 pseudo hydrogen atom or methyl; R 3, R 4, RS,)? 6 and ruler? It can be the same or different, 3 hydrogen, hydrogen, nitrogen or iodine atom, methyl, ^ 02 or -0. 4. Based on the application of the compound "5 surrounding item 1", selected from: 1-('丨 -Nitroaniline S Φ filling) -2, Chen propyl-2-propanol; 1-(4 -m-fluorenylmethylmethine) -2-Chenpropyl-2-fenpropanil; 1-U-簌 -3-tolylaminomethyl S)-2-cyclopropyl-2-Μpropyl ester; 1- (3 -Methyl-4 -tris-toluidinemethyl BΞ)-2 -Chenpropyl-2 -oxypropionitrile 1-(4-Tweezer-3 -Tolylmethyl blue) -2 -Now'propyl -2 -Gas propylene fat; —2 — • Hit: " Mu recognized: t K 玟 坫 川 十 KW UT SUT: Ping (CNS), p (210 X 29? Public father) A7 B7 C7 D7 Six, apply for patent scope 5 · A method for preparing the compound Π) as described in item 1 of the patent application garden, as listed in compound (II) £ CN 0 (II (please pay attention to the face before writing this page) Chinese Renmin term 3 to accept R and hydrogen β and R »V) #. S 义 R, 定 * 所 R, 项 围Fan Li * Please Φ If the match is in the middle, it must be a combination of the compound and the fit, and the response will be reversed. The existing squint should respond to the midterm of the institution. 1A The plaque Fan Li specializes in Shen Ru XR and子 原 0 0 IX a Η Chinese-style Fan Lizhe please 'Shen Ruzhong (I its thing, the legally obtained items make the 5th law often follow the norm, and Li Shi specifically needs to apply for the stated root 6. Salt into Add to change to change. Ordered. Married .. Central Bureau of Standards of the Ministry of Economic Affairs R-Consumer Cooperation Du-printed chemical compound 0 item line 5 into the middle of the park. Furfuran tetrahydrate is not in 0. On the contrary, it is hydrogen and vanadium. Li Zhuan Shen V) Such as (I in the combination of things, the legal term is 5I) Bin I Hua (Fu Wu Fan He Li Hua Zhi Zhi Xiang Shen 5 according to the root of this paper is also applicable China National Standards (CNS) Grade A 4 (210 X 297 mm) A7 B7 C7 D7 (IV) (where R2, R3, I? 4, R5, RS and ruler 7 are as described in item i) and the following compound [V] or its functional derivatives [from reaction, A CN (V) (Please read the precautions on the back before filling in this page) HO Ο In or based on it) I, (v «Law of the two compound or the chemical amine and sub 7V)-Π B The difference between Fanhejili and Chuangzhuan, please apply for the second application 7 in accordance with the first anti-8 IgL benefit ^ Is »! (7Jffi 谪 s 二 Ϊ 翔 -J 申 官 ί enter the middle alkyl cyanide or furan氲 四 如 剤 湤 机 有 水 不下 下 Deposit legal item 8 or (V 7 物 合 合 化 范利利 专 专 7 鰪 第 申 围 講 范根利 9 Specializes in the use of its chlorine 0 B Cyanogen is the product of the bio-energy officer. Ordered. Printed by the Ministry of Economic Affairs Central Bureau of Industry and Commerce W Co., Ltd. Consumer Cooperatives. It is the cyanide ethyl cyanide in its legal system. 9th Fan Fanli Special Request Ψ According to the production site 0 Chlorine pentahydrate and acid vinegar cyanide plus 0 allowable mh £ rational 0 or its combination of items. 1—Η jAra 0 國 范利 专 謓 Φ The roots are the roots Saltable cost paper is again applicable to the Chinese National Standard (CNS) A4 specifications (210 X 297 mm). 6. Applying for a patent Fan Garden A7 B7 C7 D7 0 Permitted I: rationalizing or combining items 1 Fan Li specially requested Φ according to the root of the use of phlegm to eliminate the use of pseudo-salt into the plus 0 allowable rationale 0 or the combination of the other items of the garden Fan Li Zhuan Φ according to root or sexually transmitted diseases and Yan Jieguan 0 Therapeutic wind treatment C is based on the use of phlogritis, which is slower than that of slow use.合 化 ¾Contains * ※ Like, ® Μ or physical epidemic is as small as reasonably slow ia tt ^ ^ SM plus ^ such as * non 1 $ | to accept or receive Fan Li C, please read the precautions on the f side before writing (This page) 0 shape or \ and 0 release dilute can be received and received 1- * rational 0 6Ε a more or species combined below —Installation. Order. Printed by Chinese Industrial and Commercial Cooperatives, Central Standards Bureau of the Ministry of Economic Affairs, Lizi Special, please apply for hydrogen. According to the root and chlorine, the chlorine is R7. Item X in the statement And Dan 6 > R narration ’So R3 in this paper scale is applicable to China National Standard (CNS) A 4 specifications (210 X 297 mm).