TW212170B - - Google Patents

Description

Λ 6 Β6 212170 V. Description of the invention (1) The present invention relates to 3-phenyl-2-enylamide derivatives, their physiologically functional group derivatives, pharmaceutical compositions containing them and the use of the aforementioned compounds in therapy And preparation, especially as muscle relaxants, anti-spasmodics and antispasmodics. The sleep and sedative effects of certain 3-phenyl-2-enamide derivatives (commonly known as their common name, cinnamamide) have been determined by Iott and β tianse η, J. Am. Ph arm. A ss 〇 . ., 2 3 7 8 8 (1 9 3 4) and VanHeyningen e_t_ a 1 ·, J · Med. Chem., 9_, 6 7 5 (1 9 6 6). In US Patent No. 4 1 096 74, cinnamamide derivatives are shown, which have the effect of treating spasms of mammals and their use in relaxing muscles, for example, for treating higher skeletal muscle tone. European Patent Case ◦ 3 8 1 5 ◦ No. 8 shows the use of certain cinnamamides to relax muscle tone, for example, to treat muscle paralysis or spastic paralysis, such as brain damage. The main limited side effects of many clinically effective muscle relaxants and antispasmodic agents are sedation and loss of mutual aid in patients, which severely restrict the use of these compounds. Similar side effects have been discovered with drugs used to treat anxiety (such as benzodiazepine). Although these effects may be temporary, patients under the aforementioned treatments are often unable to engage in certain occupations. This side effect of latent muscle relaxant compounds can be disadvantageously determined by experimental studies on the effectiveness of muscle relaxants and inhibitory potential ( 〇1 * 1! 8〇6-V. Res., 2383, (1982)) 0 The size of this paper is 5 Gen. The Chinese a family 樒 准 (CNS) A 4 specifications (2κι X297 public waste) (please read the back of the first Matters needing attention will be written on this page) Installed. Line-Ministry of Economic Affairs Standards: ^ 工 消 汾 合作社 卬 ^ -3-

Wsl .. this year l Nan? Ci d 4, Amendment page of the Chinese manual of the case Amendment in April 1982 V. Description of the invention (2) Now, we have found that certain 3-phenyl-2-enolamines have effective muscle relaxant activity, but their The disadvantages of the loss of side effects of static and mutual aid are significantly lower than those of known muscle relaxants. It has also been found that these compounds have anti-spasmodic and antispasmodic activity. According to the present invention, a 3-phenyl-2-enolamine derivative represented by the general formula (I) is provided: (Please read the precautions on the UMP first and then write the image page)

CKCONHR2 (X)-installed · Printed by R3 Employee Consumer Cooperative of the Ministry of Economic Affairs, R 3 shows the base: its prerequisite (i) (ii) or its equivalent such as ^ alkyl carbon atom R1 shows 匚} ^ alkane The radical, R2 represents Η or C3-6 · cycloalkyl and one or more ring substitution conditions selected from a halogen atom and a perhalo Ci-4 alkyl is: when R1 represents methyl and R2 represents cyclopropyl, Then one of R3 or R3 is at the 2_ position; and the compound of the aforementioned general formula (I) is not 3- (4-monochlorophenyl) ~ 2-butenamide; salt or other physiological functional group derivative. As used herein,, in alkyl # or in a part of a group, means straight-chain or branched-chain alkyl. The aforementioned alkyl group preferably has 1 to 3, and more preferably a methyl group or an ethyl group, especially a methyl group. The general formula (I) compounds include the formula, R1 shows methyl group and / this paper scale is applicable to the national standard (CNS) A 4 specifications (210 X 297 mm)

Order 212170 The Ministry of Economic Affairs, the Ministry of Economic Affairs, the Ministry of Economic Affairs and the Ministry of Economics and Social Development Cooperative Society sucks Λ 6 Β6 V. Description of the invention (3) Or, R2 shows cyclopropyl and / or one of R3 or R3 shows 2-position = ring substituent , It is preferably a bromo group, a gas group or an iodine group or a perhalomethyl group, for example, a trifluoromethyl group; or its salt or other physiological functional group derivatives. The most ideal compound of general formula (I) includes a single ring substituent in the formula where only 2 shows methyl, and / or R2 shows cyclopropyl and / or R3 shows 2-position, preferably bromo, chloro, iodine Group or trifluoromethyl group; or its alkali salts or other physiological functional group derivatives. (E) isomers with compounds of general formula (I) or their alkali salts or other physiological functional group derivatives are preferred. The most ideal compound of general formula (I) is: 1. (E) —3- (2-Bromophenyl) -N-cyclopropyl-2-butenamide; 2. (E) —N—Ring Propyl-3- (2- (trifluoromethyl) phenyl))-2-butenalamine; 3. (E) -N-cyclopropyl-3- (2-iodophenyl) -2-butan Enilamide; 4 · (E) — N —cyclopropyl-3- (2, 3-dichlorophenyl) — 2-butenamide; 5. (E) — 3— (2 — atmosphere phenyl ) -N-cyclopropyl-2-butenamide; and 6. (E) -3- (2-bromophenyl) -2-butenamide. The compound of the above general formula (I) and its halide salt, or other physiological functional group derivatives are hereinafter referred to as the compounds of the present invention. I understand that the compound of general formula (I) can be in various geometric isomer forms (please read the precautions on the back before writing this page). Binding · Order-This paper uses the Chinese National Standards (CNS) A4 specifications (210X297 Gonglu) -5-212iri; 0 Λ 6 B 6 Ministry of Economic Affairs, Central Standard X; A Gong Xiaoping Cooperative Society 嬬 λ'ι4 5. Description of the invention (4) or a mixture of them in any proportion. The scope of the present invention includes the use of the aforementioned geometric isomer forms or mixtures of them in any ratio (including the individual E and Z isomers of compounds of general formula (I) and mixtures thereof). v Other physiological functional group derivatives mean other compounds that can provide (directly or indirectly) the aforementioned compound or active metabolite or its residue when administered to the receptor. Examples of alkali salts according to the present invention include salts, for example, derived from a suitable base, such as alkali metal (for example, sodium), earth metal (for example, magnesium) salts, ammonium and NX, (wherein X represents Ci-4 alkane base). For therapeutic use, the salts of the compounds of general formula (I) will be physiologically acceptable, that is, they are derived from physiologically acceptable bases. However, it can also be found that non-physiologically acceptable base salts are used in compound preparation or purification. All salts derived from physiologically acceptable bases or unacceptable bases are considered to be within the scope of the present invention. Another object according to the present invention is to provide the use of the compound of the present invention in the treatment of medicines, especially to treat or prevent-symptoms caused by abnormally increased muscle tone,-spasm symptoms, and-anxiety disorders. Therefore, the aforementioned compounds are particularly useful for skeletal muscles in relaxation paralysis, hypertonia and hyperkinetic symptoms. In particular, the aforementioned compounds can be used for the treatment and systemic relaxation such as spinal cord injury, Bajinsheng's syndrome, arthritis, finger spasm, epileptic continuous state and tonic spasm and especially for relaxation such as myositis, Zan spondylitis, (please read the notes on the back before filling in this page) Strictly installed ·-Thread · This paper uses the standard of the Chinese standard (CNS) f 4 specifications (210x297 Gonglu) — 6 1 Λ 6 Β6 212170 V. Description of the invention (5) (Please read the precautions on the back before writing this page) Cerebral palsy, muscle palsy in the symptoms of cerebrovascular disease and multiple sclerosis. The aforementioned compounds can also be used to treat musculoskeletal paralysis induced by lotus movement, for example, lower back pain. Spasmodic states in which the aforementioned compounds can be used include major seizures, minor seizures, psychotic seizures and focal seizures. The compounds of the present invention can also be used to treat anxiety disorders, including systemic anxiety disorders, obsessions and obsessive-compulsive disorders, panic disorder, phobia, isolation anxiety and post-traumatic stress disorder. Further uses of the aforementioned compounds are as muscle relaxants and anti-anxiety agents before surgery. Further pseudo-objects of the present invention include: a) A method of treating or preventing the symptoms associated with abnormally increased muscle tension, spasticity and anxiety in a host (eg, mammals including humans and moles), including Non-toxic amounts of the compounds of the present invention are used to treat the aforementioned mammals. The Shiyang Standard of the Ministry of Economic Affairs is based on the "consumer cooperative" 51b) The use of the compound of the present invention in the manufacture of a medicament for the treatment or prevention of abnormally increased muscle tone, spasm symptoms or anxiety. The above compound of the present invention can be used in combination with other therapeutic agents for treating symptoms associated with abnormally increased muscle tone. Examples of the aforementioned therapeutic agents include analgesics such as codeine, aceta-minophen, phenacetin or ibu-profen. To provide the pharmaceutical composition of the compound of the present invention, in this paper, the paper scale is used in the Chinese National Standard (CNS) A 4 specifications (210 X 297 g; Ij :) 212170 Λ 6 Β6 V. Description of the invention (6) Also known as As an active ingredient, it can be administered by any suitable route, including oral, rectal, nasal, topical (including buccal and sublingual), transvaginal and parenteral (including subcutaneous and intramuscular , Intravenously and subcutaneously). I also understand that the ideal route will depend on the symptoms and age of the recipient, the nature of the disease and the active ingredients selected. Treatment, for example, increased muscle tone, spasm and anxiety, the number of individual active ingredients depends on many factors, including the severity of the symptoms being treated and the type of recipient, and the final care is provided by the doctor The staff decides. Ministry of Economic Affairs Shiyang # 芈 乃 U 工 消 " Cooperative Societies (please read the notes on the back first to fill out this page) Generally, for the aforementioned symptoms, the compound of general formula (I) or its alkaline salt or other physiological functions The appropriate dose of the base derivative (estimated by the parent compound) is daily ◦. 05-1 00nig / kg body weight recipients, preferably 0.1-50 mg / kg body weight per day, more preferably 0.5-20 mg / day kg body weight, the most suitable is 0.5-20 rag / kg and the most appropriate is 3 mg / kg body weight per day. The required quantity should be taken in 2, 3, 4, 5, 6 or more divided doses at appropriate intervals throughout the day. The divided doses can be administered in unit dosage forms, for example, each unit dosage form contains 1 _ 1 5 0 0 0 mg. It is preferably 5-lOOOOmg, particularly preferably 10-700 rag. Although the active ingredient can be administered alone, it is preferably provided as a pharmaceutical composition. The composition of the present invention comprises at least one active ingredient as described above and one or more acceptable carriers and optionally other therapeutic agents. Each carrier must be compatible with other ingredients in the composition and not harm the patient. The composition includes suitable for oral, rectal, #, local (including meridian and sublingual), vaginal or non-intestinal (including subcutaneous, intramuscular, intravenous and percutaneous paper scales for the use of China National Standards (CNS ) A 4 specifications (210x297 gong) -8-Ministry of Economic Affairs standard x; u industrial consumer cooperative co., Ltd. Η4 Λ 6 B6 Fifth, the description of the invention (within (7)) the composition to be administered. The aforementioned composition is advantageously present in unit dosage form and can be prepared by any known method in the pharmaceutical art. The aforementioned method includes the step of mixing the active ingredient with a carrier containing one or more accessory ingredients. Generally, the composition consists of uniformly and completely mixing the active ingredient with a liquid carrier or a finely separated solid carrier or two carriers, and if necessary, shaping the aforementioned product. The composition of the present invention suitable for oral administration can be prepared as a separate unit, such as Capsules, lozenges or tablets, each containing a predetermined amount of active ingredients; powders or granules; solutions or suspensions in water or non-water; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. The active ingredient can also be in the form of giant nine, syrup or paste. Agent H can be made by compression or molding, optionally containing one or more incidental ingredients. Compressed tablets can be composed of active ingredients in a free-flowing form (such as powder or granules) compressed in a suitable machine, optionally mixed with binders (eg, povidone, gelatin, hydroxypropyl methylcellulose), lubricants, inert diluents, Preservatives, disintegrants (eg, sodium starch gluconate, cross-linked povidone, croscarmellose sodium), surfactants or dispersants. Molded tablets can be made from powdered compounds that are wetted with an inert liquid diluent in a suitable machine. The H agent can be arbitrarily coated or marked and can be prepared so that it can be used, for example, hydroxypropyl methylcellulose in different proportions to slowly release or control the release of the active ingredient to provide the desired release pattern. The tablets can be optionally enteric coated for partial release into the intestine rather than the stomach. The composition suitable for oral administration as described above may also contain a substance for neutralizing stomach acid ................................. · .Line. ·. · / (Please read the precautions on the back before filling in. Write this page) The size of this paper uses the Chinese National Standard (CNS) A 4 specifications (210x297 public waste) -9-Λ 6 B6 Economy部 屮 央 # Zunzhuo U Gong Xiaozheng Cooperative Society Printed 31 V. Description of the invention (8) Buffers. The aforementioned buffers can be selected from various organic or inorganic reagents, such as weak acids or bases and their conjugated salts. Components for local administration include lozenges (which contain active ingredients in flavored substrates, which are usually sucrose or tragacanth); oral medicines (which contain active ingredients in medicinal substrates (such as gelatin and Glycerin) or sucrose and gum arabic); and mouthwash (which contains the active ingredients in a suitable liquid carrier). The composition for rectal administration may be a suppository containing a suitable base, which contains, for example, cocoa cream or Salicylic acid ester. The composition suitable for transvaginal administration can be a uterine sleeve, tampon, cream, gel paste, foam or Sprinkle composition, which contains an appropriate carrier such as known in this art in addition to the active ingredient. Suitable for parenteral administration The composition includes aqueous or non-aqueous isotonic inert injection solution, which may contain antioxidants, buffer , Disinfectant and solution, which make the composition isotonic with the blood of the recipient; and aqueous and non-aqueous inert suspension, which may contain suspending agent and thickening agent; and fat particles or other micro The particle system is used to deliver compounds to blood components or one or more organs. The aforementioned composition can be present in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in freeze-dried (Lyophilized) conditions (only need to add an inert liquid carrier before use, such as water for injection). Temporary injection solutions and suspensions can be made from the aforementioned various sterile powders, granules and tablets. Suitable for subdermal administration The composition can be in the form of a separate patch that stays in close contact with the recipient's dermis for a long time. The aforementioned patch suitably contains activity (please read the notes on the back of the spring ^ fill This page) Install * ^ r_ -Line · This paper scale uses the Chinese National Standard (CNS) A 4 specifications (210x297) and Λ 6 Β 6 212X ^ 0 Fifth, the invention description (9) (Please read the precautions on the back first (Fill in this page again) The composition is the concentration, for example, any buffered aqueous solution of Ο.1-2M. As for a special possibility, the active compound can be delivered by patch by ion electrophoresis, such as Pharmaceutical Research, 3/6 , 318. (1986) is generally described. The ideal unit-dose composition is composed of daily doses or units, divided into daily doses (as described in this article), or an appropriate percentage of the active compound composition. It should be noted that in addition to the ingredients specifically mentioned above, the composition of the present invention may contain other agents conventionally used in the art in question. For example, the composition suitable for oral administration may further contain sweeteners, thickeners, and spices. The compound of general formula (I) can be prepared in any conventional manner and according to the present invention, for example, by any method described below. Therefore, the present invention includes compounds of the general formula (I) and their alkali salts, as well as the preparation methods of other physiological functional group derivatives, which include: (A) Let the general formula (I) compounds:

The standard of the Ministry of Economic Affairs, “Standard of Industrial and Consumer Cooperatives ^ (where R3 is as defined in formula (I) and X represents a leaving group) reacts with compounds of formula (Π):

PcH II CHCOR4 (Work 11) -11-This paper uses the Chinese Standards (CNS) A 4 specifications (210X297) and 2 2 ο 66 ΛΒ 5. Invention Description (10) (In the formula, R4 shows a NHR2 R2 and only 2 are as defined in the general formula (I)); (B) Let the compound of the general formula (IV):

CiR1) = 〇 (IV) (where R2 and Ruler 3 are as defined in the general formula (I)) and the W i 11 i g reagent shown in the general formula (V) reacts under the conditions of W i t t i g:

YCH2C0R (V) (wherein R4 is as defined above and Y is -P (= 〇) (〇R) 2, where R represents alkyl, aryl or aralkyl, or Y represents triarylphosphine) ( C) Dehydrate the compound of the general formula (VD): (Please read the precautions on the back and fill in this page again) Ministry of Economic Affairs Central Standard Industry & Consumer Affairs Cooperative Print ^

C (R-) — €:-: 2C0R OH (VII) (where R2, R3 and R4 are as defined above), the 5fc scale of the paper is used in the Chinese Standard (CNS) A 4 specification (210x297 public Luan) ) -12-

• C (R) = CHCOZ V. Description of the invention (ll) (D) Let compound (VIII) of general formula (VII) (where R1 and only 3 are as defined above and Z shows the leaving group) and general formula ( To) compound reaction: (please read the notes on the back ¾ fill this page)

Η-R (IX) installed. The Ministry of Economic Affairs # 華工 消 f? Cooperative Society 卬 14 (where R4 is as defined above), and thereafter, or simultaneously, any one or more of the following transformations: (i ) Conversion of the compound of general formula (I) thus formed into its salts, or other physiological functional group derivatives; (ii) When the base salt of the compound of general formula (I), or other physiological functional group derivatives, is formed The derivative becomes a compound of general formula (I), or a different derivative thereof. In method A), the compound of general formula (I) and the compound of general formula (M) are usually in the presence of a catalyst (such as a transition metal catalyst, for example, a catalyst, especially acetic acid), in the presence of an organic base (such as triethylamine ) In the presence and in a suitable polar solvent (for example, acetonitrile, dimethylformamide (DMF) or methanol), it is appropriate to react at high temperature. The reaction can be carried out in the presence of a phosphorus reagent (such as tri-0-tolylphosphine or other triarylphosphine). This paper is used in the ifc scale of the Chinese standard (CNS) A 4 specifications (210 X 297 public; ίί :) -13- Λ 6 Β6 2121 ^ V. Description of the invention (12) 0 (Please read the precautions on the back before filling in this page) Compounds of general formula (I) are commercially available or can be known from the synthetic techniques of compounds of similar structure The method is made, and the reference materials in this regard are listed in the following textbooks, but they are for illustration only. i) " Protective Groups in Organic Chemistry'1 ed · J · F · W · McOmie, Plenum Press (1973), ISBN 0-306 · 30717-0; ii) " Compendium of Organic Synthetic Methods 11 ed · I · T. Harrison and S. Harrison, Wiley_Interscien-ce, Vol.I (1971) ISBN 0.47 Bu 35550-X, Vol.II (1974) ISBN 0-471-35551-8 and Vol.Ill (ed · LS · Hegedus and L. Wade) (1977) ISBN 0-471-36752-4 l and iii) Rodd1s " Chemistry of Carbon Compounds H second edition, Elsevier Publishing Company 〇Ministry of Economic Affairs Compounds of formula (m) (wherein R2 and only 4 are as defined above) are advantageously made directly from compounds of formula (m) (wherein, as defined above and R4 represents hydroxyl), for example, by using appropriate Amines, such as in the presence of dicyclohexyl metadiimide (DCC), or by conversion of a compound of general formula (I) into an activated derivative (such as an acid halide, for example, acid chloride, or anhydride ). In the case of acid chlorides, by reacting with thiochloride, it is followed by appropriate amines in organic bases (such as this paper 55: Standard SB Family Standard (CNS) A 4 specifications (210x297))-14- Λ 6 B6

2121'VO 5. Description of the invention (13) TEA or excess amine) Reaction. (Please read the precautions on the back before filling in this page) The compound of general formula (Π) (wherein, the hydroxy group is as defined above) can be purchased from the market or prepared by methods known to those skilled in the art. In method B), the compound of general formula (IV) and the Wittig reagent represented by general formula (V) in the presence of a strong emu (such as sodium hydride or lithium hydride) and in an inert solvent (for example, dimethylaminoethane (DME). The relative proportion of the E and Z isomers of the compound of formula (I) thus formed will be determined by the nature of the alkyl, aryl or aralkyl groups in the phosphorus-containing base in the Wi 11 ig reagent The compound of general formula (IV) can be purchased from the market or prepared by a method familiar with the knowledge of this person of art. Ding Shimin, Ministry of Economic Affairs χ; π 工 Consumer Cooperation Du Yin! Ii compound of general formula (V) (In the formula, Y and R4 are as defined above) It can be made by the method known in the art, but it is usually composed of the compound of the general formula (V) (wherein R4 is as defined above and Y represents an appropriate leaving group, For example, a halogen atom, such as a chlorine or bromine atom, is obtained by treatment with an appropriate phosphating reagent (such as a trialkylphosphite or triarylphosphine). The compound of formula (V) (where R4 is as defined above) The Y represents a leaving group) can be a compound of the general formula (V) (wherein Y represents the aforementioned leaving group and R4 represents another suitable leaving group For example, a halogen atom, such as a chlorine or bromine atom. The aforementioned compound (for example, C1C0CH2C1) is commercially available or can be obtained by a method known to those skilled in the art or easily obtained from the chemical literature. In Method C ), For the dehydration of compounds of general formula (νπ), an appropriate dehydrating agent (for example, acetic anhydride) can be used, usually in acid (such as p-toluene paper, the Chinese S Home Standard (CNS) A4 specification (210x297 Gong Lu) —15 — 2121 ^ 0 Λ 6 Β 6 V. Description of the invention (14) Sulfonic acid). The compound of general formula (VD) is advantageous to the compound of general formula (IV) as defined in method B). The compound of formula (V) (in the formula, R4 is as defined above and Υ shows bromine atom) is prepared by reaction (Reformatski reaction) in the presence of zinc. The prepared compound of general formula (VD) can be separated or dehydrated on the spot. The compound of general formula (V) (wherein R4 is as defined above and Y represents a bromine atom) can be similar to the compound of general formula (V) above (wherein R4 is as defined above and Y represents an appropriate leaving group) It is prepared by a method. In this case, bromine and the compound of general formula (IV) are commercially available or can be prepared by a method familiar to those skilled in the art. Method D) can be obtained by treating the compound of general formula (VI) with the compound of general formula (IX), usually in an inert solvent such as T H F or benzene. Compounds of general formula (IX) are commercially available or can be prepared by methods familiar to those skilled in the art. The Ministry of Economic Affairs Standard n Gongxiao & Co., Ltd. 51 (please read the precautions on the back and fill in this page again) Compounds of general formula (VB) (where Rz, R3 and Z are as defined above) can be represented by the general formula (VI) Compounds (where R2 and R3 are as defined above and Z represents a hydroxyl group), for example, when Z will become a halogen atom, by using a halogenating agent (such as oxalo) in an inert solvent (such as benzene) Medium treatment, or when Z will become ROC (0) 0-base (where R is as defined above), by using an appropriate alkyl chloroformate in the presence of an organic base (such as TEA) and an inert solvent (such as THF). The resulting compound of general formula (VI) can be isolated or immediately aminated on the spot. The compound of general formula (I) can also be directly derived from the compound of general formula (VI) (formal paper scales are free to use the Chinese standard (CNS) A 4 specifications (210x297 public waste) _ 1fi _ " Λ 6 Β6 212170 In the description (15) (please read the precautions on the back before filling in this page), and 113 are as defined above and Z shows the hydroxy group) The compound of general formula (IX) (where R4 is as defined above) in an appropriate solvent The compound of formula (W) (where R2 and ruler 3 are as defined above and Z represents a hydroxy group) is beneficial to the compound of formula (W) (where R 2 and R3 are as defined above) Z shows an appropriate leaving group, such as an alkoxy group, for example, (E) -methyl-3- (2-bromophenyl) -2-butenoate, where R2 shows methyl and R3 shows 2-bromo The base Z represents a methoxy group), prepared by hydrolysis in a polar solvent (eg, ethanol) in the presence of a base (such as sodium hydroxide) or an acid (such as hydrochloric acid). The compound of general formula (VI) (where Z represents an alkyl chloride group) can be obtained by dehydrating the compound of general formula (VE) (where R7 and R3 are as defined above and R4 = Z). The aforementioned compound can be prepared by the Reformatski reaction described in the above method C). The compound of general formula (I) can be converted into a pharmaceutically acceptable base salt by conventional means, for example, by treatment with an appropriate base. The present invention also includes the following novel intermediates, which are of special value for the preparation of compounds of general formula (I) (wherein R 2 and R 2 are as defined above and R 3 represents 2-bromo): Jinghong Ministry of Central Standards · Gongzhong Cooperative Co., Ltd. 14 1. (E) — 3 — (2-bromophenyl) -2-butenoic acid. 2. (E) -3— (2-Bromophenyl) ethyl 2-butenoate. 3. (E) —3- (2-Bromophenyl) -2-butenoic acid methyl ester. 4. (E) —3 -— (2-Bromophenyl) -2-butenoic acid vapor. 17-Original paper 55: Standard and easy to use a family standard (CNS) A 4 specifications (210x297 public waste) Λ 6 Β6 212170 V. Invention description (16) (please read the precautions on the back and fill in this page) below The examples illustrate the invention, but do not limit the scope of the invention. Example 1: Preparation of (Ε) — 3 — (2-bromophenyl) -N—cyclopropyl-2-butenamide A) Preparation of 2-chloro-N—cyclopropylacetamide at 0 * 〇 Next, 100m and ether chloroacetaldehyde chloride (33 · 8g, 〇. 3 moles) solution was added dropwise within 30 minutes, while stirring was added to 40Omi2 ether in cyclopropylamine (34.2g, 0. 6 moles, Aldrich). After 30 minutes at this temperature, while heating on the steam bath, the ether was distilled off with a stream of nitrogen. The residue was dissolved in dichloromethane (400 miM) and washed sequentially with 100 mi? Dilute hydrochloric acid (1 N), aqueous sodium bicarbonate solution (5%) and distilled water. The volatiles were rotary evaporated in vacuo Removed, and the residue was recrystallized with dichloromethane / hexane to obtain 26.4g (66%) 2-gas-N-cyclopropylethanamine, m.P. 80-83 ° C. Elemental analysis: Theoretical value (C5H8C1N〇): C, 4 4.96; Η, 6.04; Ν, 10. 4 8; C1, printed by the Ministry of Economic Affairs Standards and Industrial Consumer Cooperatives ^ 2 6.54 measured value: C, 4 5. 0 4; Η, 6. 0 6; Ν, 10. 4 5; C 1, 26. 52. Β) Preparation of ((cyclopropylamine methyl) methyl) phosphonate diethyl ester at 1 10¾ Next, use 2_chloro-N_cyclopropylacetamide (20 paper 56: standard side use China S home standard (CNS) A 4 specifications (210x297 g) and -18-Λ 6 Β6 212x ^ 0 V. Description of the invention (17) g, 0.15 moles) was added portionwise to triethyl phosphite (28 g, 0.17 moles, Aldrich). Reheat the solution to 1551C for 30 minutes, cool to 125t :, and then remove the volatiles by distillation (under an evacuated vacuum (15 mmHg) and this temperature). The residual oil was stirred with pentane (200mi2) while cooling in an ice bath to induce crystallization. Filtration yielded 5.2 g (14%) ((璟 propylaminecarboxamide) methyl) diethylphosphonate white crystals; m.p. 51 — 56 ° C. The liquid was concentrated and cooled to give 25.3 g (71%) of the second product; m.p. 50 — 56 ° C. An analytical sample was obtained by recrystallization from methylene chloride / hexane, m.p. 55 — 57 * 0. Elemental analysis: Theoretical value (C3H: eN〇4P): C, 4 5. 96; H, 7.71; N, 5.95 Measured value: C, 4 5. 8 5; Η, 7.7 6; N, 5. 9 〇〇C) Preparation (Ε) _3 — (2-bromophenyl) -N — cyclopropyl_2-butenamide in NaH (80% mineral oil dispersion), (0.67 g, 28 mmoles , Aldrich) (in the dimethoxyethane chamber (25m)), add dimethoxyethane (60mi) in the ((cyclopropylamine methyl)) methyl diphosphonate (5 . 0g, 21 mmoles) solution. After 1.5 hours, add 2'-bromoacetophenone (4.08, 2111111〇163, six 1 £ 11 '丨 £ ^) solution (in 6〇1715 dimethoxyethane ), Let the mixture warm to room temperature overnight. Pour the reaction mixture into 1 piece of paper at 5k scale and use the Chinese Sleeper Standard (CNS) A4 specifications (210x297 gong) (please read the notes on the back and fill in this page). Thread-Λ 6 Β6 212170 V. Description of the invention (18); The mixture was extracted with dichloromethane on ice water. The residue was chromatographed on silica gel 60 using dichloromethane-ethyl acetate (9: 丨) as the eluent. Containing only (E)-3-(3-bromophenyl)-N-chloropropyl-2-butenamide part and rotary evaporation in vacuo to give 2. 2g colorless oil. Milled with pentane to obtain 1.85g (33%) (E) — 3 — (2-bromophenyl) -N-cyclopropyl-2-buteneamide, m.p. 82-84t ^; NMR (DMS Ο-de): 8. 0 4 (d, 1 H, J_ = 4.0 2 Hz, NH), 7.6 4-7. 19 (m, 4 H, Ar), 5. 64 ( d

, 1 H, < J_ = 1. 36Hz, = CH), 2. 68 (m, lH, NCH), 2.36 (d, 3H, J_ = 1.17 Hz, CH3), 0. 68-0. 35 (2m's , 4H, CH 2 CH 2); steady-state nOe: irradiation at 2. 3 6, observed 4. 9 96 nOe at 7. 2 5 and 1. 3 96 nOe at 5. 6 4 〇 Elemental analysis: theoretical value ( C / 3H / 4BrNO): C, 55.73; H, 5. 0 4; N, 5. 0 0 0. Found: C, 5 5. 8 2; H, 5. 0 9; N, 4.95. Example 2: Preparation of (E) — 3 — (2-bromophenyl) -N —cyclopropyl-2-butenamide (A) Preparation of (E) — N —cyclopropyl-2-butane: (: The 5 gram scale of the acetamide paper uses the Chinese Standard (CNS) A4 specifications (210x297) (please read the remarks on the back to fill in this page) Cooperative Society 卬 奴 -20-έβ6 2121 ^ 0 5. Description of the invention (19) Within 15 minutes, add thiochloride (24m5, ◦. 33 mol) dropwise to benzene (crotonic acid in 400rniH) ( 25.8 g, 0.30 mol, Aldrich) in a stirred solution (moisture was removed by a drying tube containing Drier ite). The resulting clear solution was removed in a part of the solvent (100 miM by distillation (at atmospheric pressure)) Heat for 3 hours under reflux. Stir the residual solution, ice-cold (ice bath) and treat with cyclopropylamine (20.6 g, 0.36 mol, Aldrich) dropwise, followed by triethylamine (41.8 mo 1, ◦. 3 0 mo 1) Treatment. A white solid precipitated. Water (50m5) was added to the mixture and the resulting layers were separated. The aqueous layer was saturated with NaC 1 and extracted with dichloromethane (5X100m). Synthesis The organic layer was dried on Na2S〇4, filtered and concentrated to obtain a solid residue, which was then subjected to ball-to-ball distillation at a temperature of 0.1 lt〇rr (the temperature of the reaction flask was 9 ° C 1-10 ° C); , 31.2 g (83¾), mp 63-65 ° C; NMR (DMSO -d 6) 'δ 7. 9 1 (brs, 1 Η, NH), 6. 48 — 6. 66 (m, 1H, = CHCH 3), 5.7 9 (dxd, J = 1.6, J = 15.2Hz, 1H, = CHC〇), 2.65 (m, 1H, NCH), 1.74 (dxd, J = 1. 7, J = 6.8 Hz, 3 H, CH3), 0.39 and 0.60 (2m's, 4H, CH2CH2) 〇 Elemental analysis: theoretical value (CzHnNO. ◦. Ih2〇): c, 66 . 22; H, 8. 8 9; N, 11. 〇3 (please read the note t. On the back side and then ** write this page) Order--Line-This paper is used in the national standard (CNS) A 4 Specifications (210X297) and -21-Λ 6 Β6 212Γ &0; V. Description of the invention (20) Measured values: C, 66.1 Ο; Η, 8.9 ◦; Ν, (Please read the notes on the back first Matters will be written on this page) 11. 0 7〇 (Β) Preparation of ME) -3-(2-bromophenyl) -Ν-cyclopropyl-2-buteneamide 1.2-dibromobenzene ( Aldrich) (2. 36g, 10. Ommol ), (E) — N — Cyclopropyl-2-butanolamine (1. 30g, 100.0 mmol), triethylamine (1.0 lg, 10 • 0 mmo D, Trinyl 0-toluene A mixture of phosphine (Aldrich) (0.2 4 S, 0.8 mmol), acetic acid rake (Aldrich) (0.04 S, 0.2 mmol) and acetonitrile (25 mi?) At 120C, bottle It was heated in a triangular flask with a closed mouth for 18 hours. The mixture was cooled to ambient temperature, filtered; concentrated and chromatographed on silica gel 60 using ethyl acetate-hexane (gradient from 1: 4 to 1: 1) as the eluent. It contains only part of (Ε) — 3 — (2-bromophenyl) -N —cyclopropyl-2-buteneamide and is evaporated in vacuo to give 1.2 g (42.8% )product. Analysis obtained by recrystallization from dichloromethane / hexane Ministry of Economic Affairs Central Standards Persuasion Cooperative Printing Co., Ltd. 31 Samples and the compounds prepared in Example 1 are composed of m.p. (8 2 — 8 4 l!) And N MR proved to be the same compound. Elemental analysis: Theoretical value (C ^ H ^ BrNO): C, 55.73; H, 5. 04; N, 5. 〇〇; B r, 28. 5 2 〇 Found value: C, 5 5. 8 1; Η, 5. ◦ 6; Ν, 5. 01; Br, 28. 44〇 scale Xiao to SEm? Standard (⑽ 甲 娜 (2U1XM7 public waste) ~--22-Λ 6 13 6 V. Description of the invention (21) Example 3: Preparation of (E) -3- (2-bromophenyl) -N-cyclopropyl-2-butenamide A) Preparation of (E) -3- (2-bromophenyl)- Ethyl 2-butenoate 2'-Ethoxybenzyl (Aldrich, 14 · .7g, 74 mmol), Bell powder (Mallinckrodt, 9. Og), ethyl acetate (Aldrich, 18.5 g) , 1 1 1 mmol), crystals, benzene (100 min and diethyl ether (100 miH). The stirred mixture was heated under nitrogen reflux for 2 hours. The resulting gray suspension was cooled to ambient temperature, filtered and the filtrate was concentrated to a yellow foam Under cooling, the residue was dissolved in acetic anhydride (50min, treated with p-toluenesulfonic acid (50mg, Aldrich) and heated at 70-8 ° C for 5 hours. Cooled to ambient temperature , Concentrated in vacuo and chromatographed on Water sprep 5000, using ethyl acetate-hexane (1: 133 ) As an eluent. It contains only (E) — 3 — (2 —bromophenyl) a 2__ ethyl crotonate and is in the standard riux consumer cooperative society 庬 54 (Please read the back Matters needing attention-fill in this page) 3.0 g (15%) of clarified oil obtained by air rotary evaporation; NMR (

DMS 0-d 6) '· δ 7.67-7.23 (m, 4H fAr), 5.72 (d, iH> J = i.4Hz, = CH), 4.13 (q, 2H, CH2〇) , 2. 37 (d, 3H, J = l, 4HZ, CH3), 1.21 (t, 3 H »C H_3 CH2O). Steady-state nOe * irradiation at 2. 3 7 δ, observed 2% n〇e at 7. 4 5 δ and 1% n 0 eat 5. 7 2 δ Original paper 5 good-scale edge-use medium SS home sample standard (CHS) A 4 specifications (210x297 public waste) Λ 6 Β6 212170 V. Description of the invention (22) Elements Analysis: Theoretical value (C ^ H ^ Br〇2): C, 53.55; H, 4.87; Br, 2 9. 6 9 〇 Found: C, 5 3. 6 1; Η, 4. 8 3; Β r , 2 9.7 6 0 Β) Preparation (Ε) -3-(2-bromophenyl) -2-butenoic acid

(Ε) —3 — (2-bromophenyl) -2-butenoic acid (2.7 g, 10.0 mm〇l), ethanol (20mjn and 1N

The mixture of NaOH (11. Omi) was stirred at ambient temperature overnight. The solution was concentrated in vacuo, diluted with water (30m5) and extracted with diethyl ether. The aqueous layer was acidified by adding concentrated HC1 (1.2m5) and extracted with diethyl ether. The ether layer was dried over Na 2 SO 4, filtered, concentrated and chromatographed on silica gel 60, eluting with ethyl acetate, vinegar-dioxymethane (1: 4). The white crystal product (1.0 g, 41.7%) was obtained by combining only the part containing (E) — 3 — (2-bromophenyl) -2-butenoic acid. m. p. 109-1 1 1 ° C; NMR (DMS Ο-d β): δ 12. 43 (brs, 1 Η, C 0 0 Η), 7. 67-7. 22 (m, 4 Η, A r), 5. 66 (d, 1 Η, J = 1.4 Hz, = CH), 2. 34 (d, 3 Η »J— 1. 4Hz, CHj); steady-state nOe: irradiation at 2. 345 »Observed 1% nOe at 7. 2 9 5 and 1% noe at 5. 6 6 5 〇 Elemental analysis: Theoretical value (C; GH3Br〇2): C, 4 9. 8 2 CHS Standard A 4 specifications (210x297 public waste) (please read the note # on the back of the page #. Fill in this page) Installation · Order · The Ministry of Economic Affairs Standard is Mgongxiao Cooperative Co., Ltd. 51 -24-2121 ^ 0 Λ 6 Β6 V. Description of the invention (23); Η, 3.7 6; B r, 33. 14 measured value · C, 4 9.9 2; H, 3. 7 7; B r 3 3. 2 1 〇C) Preparation of (E) — 3 — (2-bromophenyl) -N-cyclopropyl-2-butenamide in benzene (50mi2) (E) — 3 — (2 — Ministry of Economic Affairs屮 yang standard yi ί 工 工 合 合 社 印 一 2-butenoic acid (1 1. 7 g, 13. and concentrated to obtain (E) light yellow oil; I propylamine (◦. 9 g, compound (6 ◦ m again) Sequentially use saturated NaHC 50 m β) and common salt to dry, filter and in the true). Dichloromethane with a g, 30%), its NMR verification and example elemental analysis: theoretical value 5 5. B r, measured value : C, 5 5 5.01 bromophenyl) .〇g, 4.0 Ommol) and grass cool gas (8 mmol, Aldrich) solution under reflux for 2 hours a 3- (2-mophenyl)-2-butyric acid gas R: 1773, 161 lcm_2. The ring 16 mmol, Aldrich) was added to the acid gas in benzene, and the mixture was stirred at room temperature overnight. The solution was washed in accordance with 0 3 (50 m ^), 1 NHC 1 (water (50 m 3?), Concentrated in the air over Na 2 S ◦ 4 to obtain a cloudy oil (0.9 g hexane and then Crystallization to give white crystal product (0.3 by the mixed mp (8 2-8 4 ° C) and the compound prepared in 1. The same. (Ci3Hi4B r NO): C, 7 3; Η, 5. 0 4; Ν, 5. 00; 2 8.5 2 0 .77; Η, 5. 02; Ν,; Β r, 2 8.4 4. (Please read Note 5 on the back and then write this page) f Install ·- Thread · This paper scale uses the Chinese National Standard (CNS) Grade 4 specifications (210x297 g) and -25-Λ 6 Β6 212170 V. Description of invention (24) (please read the phonetic notation on the back? Matters and then fill out this page) Example 4: Preparation of (Ε) — 3 — (2-bromophenyl) -N —cyclopropyl-2-butenamide. Ethyl chloroformate (Aldrich, 0.13g, 1.24 mmol) was added dropwise To 〇Ί〇 under (E)-3-(2-bromophenyl)-2-butenoic acid (〇. 30g, 1. 24 mmol), triethylamine (◦. 12g, 1. 24mmol) and four In the furan (51mi) solution. After 2 hours at 0 ° C, the precipitated triethylamine hydrochloride was filtered off and tetrahydrofuran (1 m 32) cyclopropylamine (71 mg, 1.24 mmo 1) solution was added dropwise to the ice-cold filtrate. Stir overnight at ambient temperature, concentrate and chromatograph on silica gel 60 using ethyl acetate A dichloromethane (1: 19) as an eluent. The synthesis contains only (E)-3-(2-bromophenyl) -N-cyclopropyl-2-butenamide part to get 0. 21 g (60%) product. The analytical sample obtained by recrystallization from dichloromethane / hexane was proved to be the same as the compound prepared in Example 1 by mixed mp (82-84 ° C) and NMR. Elemental analysis: theory Value (CuHi4BrN0): C, 5 5. 7 3; Η, 5. 0 4; Ν, 5. 0 0; Β r, 2 8. 5 2 〇 measured values: C, 5 5. 7 1; Η, 5 .〇4; Ν, 5. 0 1; Β r, 28. 6 0 〇 Example 5:-This paper standard general Chinese National Standards (CNS) A 4 specifications (210x297 Gonglu) -26-Λ 6 Β6 212Π0 five Description of the invention (25) Preparation (Z) — 3 — (2-bromophenyl) -N-cyclopropyl-2-butenaldiamine synthesis from Example 1C contains only (Z) — 3 — (2-bromo Phenyl) -Ν-cyclopropyl-2-butenamide part 1.7g white solid was obtained by rotary evaporation in the air. Milled with pentane to obtain 1.31g (2 3%) (Z) — 3-(2-bromophenyl) _N —cyclopropyl-2-monobutenamide, mp 144_146t: NMR (DMS Ο- d β): δ 7. 82 (d, 1 Η, Ν Η), 7. 5 5-7. Ο 5 (m, 4 Η, A r), 5.9 Ο (d, 1Η, J = l. 47Hz, = CH), 2. 48 (m ， 1 Η, Ν C Η), 1. 97 (d, 3 Η, J = 1. 4 7 Hz, CH3), Ο. 57-0. 27 (2m ' s, 4Η, C Η 2 C Η 2); steady-state nOe: irradiation at 1.9 7. observed 8.2% nOe at 7.1 and 1 7.0% nOe at 5.9 〇. Elemental analysis: Theoretical value (Ci3H; 4BrN0): C, 55. 7 3; Η, 5. 0 4; Ν, 5. 〇〇 Found value: C, 5 5. 7 3; Η, 4. 9 9; Ν, 4.99. Example 6: Preparation of (Ε) —Ν—cyclopropyl-3- (2- (trifluoromethyl)) phenyl) -2-buteneamide This compound is similar to the method of Example 1, but with 2 — (Three (please read the notes on the back of the page first and then fill in this page) 装 装 · Ministry of Economic Affairs, Central Standards / ί ·; π 工 消 輽 cooperative cooperative print 51 This paper size is used in China National Standards (CNS) A 4 Specifications (210x297 public ¢) -27-Λ 6 Β 6 2121 ^ 3 V. Description of the invention (26) Fluoromethyl) Acetophenone (Aldrich) is prepared by replacing 2-bromoacetophenone. The layered solution containing (Ε) -Ν-cyclopropyl- 3-(2-(difluoromethyl)) -2-phenyl)-2-butenylamide in the vacuum evaporates. Collect the solid and rehydrate with ethanol and water; 77: 潳 Yuejing and every 0 • 7 4 S (10%) (E) -N-cyclopropyl — 3 — (2 — (difluoromethyl)) benzene Radical) -2-butenamide • 1 m • P ♦ = 1 1 4 — 1 1 6 1C «NMR (DM s 0 — d €) • • δ 8 • 0 6 (dt 1 Η t jL_ = 4. 1 6 Η Z 9 N Η) t 7 • 7 6 — 7 • 3 6 (m, 4 Η, A Γ) 1 5 «6 2 (df 1 H 9 J = 1.3 1 Hz, = C Η) 2 • 7 〇 (mt 1 Η 1 NC Η), 2. 4〇 (d 9 3 Η, J = 1 «〇7 H z $ C Η 3) i 0. 6 6 —〇 * 4 0 (2 mts» 4 Η 9 CH 2〇Η 2); S teady-staten Oe = i Γ radiatio η at 2. 4 0 5, ob served 4.9% nOe at 7.4 an d 1 • 4 •% η Oe at 5.6 2 8 〇 Elemental analysis: theoretical value (cl 4 Η i 4 F 3N 0): C, 6 2 * 4 5 9 Η 9 5 • 2 4 t N s 5 • 2 〇ο measured value: C, 6 2 3 7 ; H 9 5 2 8; N > 5. 1 9 〇 Example 7: Preparation (Ε) — Ν ί 录 录 propyl 3 — (2, 3 — monochlorobenzyl) A 2-butenamide This compound is based on the method similar to Example 1, using 2, 3 · — (this paper i '& · standard uses the Chinese Tianjia Standard (CNS) A 4 specification (210x297 public waste) (please Read the notes on the back first and then fill out this page) Outfit-Printed by the Ministry of Economic Affairs of Shiyang, is printed by Π 工 price trade cooperative! 5i -28-Λ 6 Β 6 212170 V. Description of invention (27) (Please read the back side first Note this page again) Dichloro) Acetophenone (Maybridge) was prepared by replacing 2 · -molylacetophenone in Example 1C. The chromatographic solution containing (Ε) —Ν — cyclopropyl-3- — (2, 3-dichlorophenyl) -2-butenamide was rotavaped. The solid was collected and dried again; yield: 6.73g (47%); m.p. lll-llS ^ JNMR (DMS Ο-d β): δ 8. 0 8 (d, 1 Η, J_ = 4. 0 6 Η z, Ν Η), 7.6 2-7. 21 (m, 3 Η, Ar), 5. 69 (d, 1 Η, J = 1. 2 2 Η ζ, = C Η), 2. 67 (m, lH, NCH), 2.63 (d, 3H, J_ = 〇.97Hz, CH3), 0. 66 — ◦. 37 (2m's »4H, CH2CH2) 〇Elemental analysis: theoretical value (Ci3H: 3C12N 〇): C, 57.80; H, 4.85; N, 5.18; C1, 26.25.2 〇 Found: C, 57.71; Η, 4.83; N, 5. 1 3; C 1, 26. 3 4 〇 Example 8: Ministry of Economic Affairs Standards ^ Yi Gong Consumers " Cooperative Society 卬 列 4 Preparation (E) — 3 — (2 — Chlorophenyl) N-Jing Pro The base 2-butenamide is a compound similar to Example 1, but with 2-chloro-acetophenone (Aldrich) instead of 2'-bromoacetophenone in Example 1C. The chromatographic solution containing (E) _3— (2-gas phenyl) _N_cyclopropyl-2-butenamide in a vacuum evaporates. Collect solid paper 5 good-size edges and use China National Standard (CNS) A4 specifications (210X297 public waste) -29-Λ 6 Β6 2121 ^ 0 5. Description of the invention (28) and dry; yield, 28. 30g (32 %), m. Ρ · (please read the notes on the back of the rabbit before filling in this page) 92.5-94t:; NMR (DMS0-d6) · δ 8 .05 (d, 1 Η, J = 3.8 6 Η z, N Η), 7. 48-7. 22 (m, 4H, Ar), 5. 68 (d, 1 H, 丄 = 1.28Hz, = CH), 2.68 (m, 1 Η, NCH) , 2. 38 (d, 3 H, J = 1.44 Hz, CH 3), 0. 68-0. 37 (2m's.4H, CH sC H 2); steady-state nOe: irradiation at 2. 3 8 5 » Observed 4% nOe at 7.3 and 1% nOe at 5. 6 8 δ 〇 Elemental analysis: theoretical value (C ^ H ^ CINO): c, 66. 2 4; Η, 5. 9 9; N, 5. 9 4; Cl, 1 5.4.04 Measured values: C, 66.3 4; H, 6.03; N, 5.90; C1, 15.10 0 Example 9: Ministry of Economic Affairs The central standard is prepared by printing and absorbing (Z) — 3 — (2-chlorophenyl) _N_fepropyl-2-butenamide in the U Industry Consumer Cooperatives. This compound is similar to the method in Example 1, but with 2 ′ monochloro Acetophenone (Aldrich) replaces 2-bromo in Example 1C Based on acetophenone. The chromatographic solution containing (Z) —3— (2-aminophenyl-N-cyclopropyl-2-butenamide) was subjected to rotary evaporation and the solid was collected and dried; yield, 3.52g (4%) , M. P. 125 — 132 * 0 This paper scale uses the Chinese a standard (CNS) A 4 specifications (210x297 mm) -30-7 i 2 1 2 66 ΛΒ V. Description of the invention (29); NMR ( DMS 0-d 6): δ 7.83 (d, 1 Η, ΝΗ), 7. 38-7.06 (m, 4H, Ar), 5.9 2 (d, 1 Η, J = 1.4 5 Η ζ, = C Η), 2.48 (m, 1 Η, NCH), 1. 98 (d, 3 Η, J = 1. 41Hz, CHa), 0.57-0.24 (2 m 's. 4 Η, C Η 2C Η 2); steady-state nOe: irradiation at 1. 9 8 δ. Observed 5% nOe at 7.1 and 1 4% nOe at 5.9 2 δ element analysis: theoretical value (C ^ H ^ CINO): C, 66. 2 4; Η, 5. 9 9; Ν, 5. 94; C 1, 15.04. Found: C, 6 6. 3 3; Η, 6. 〇 4; Ν , 5. 8 8; C 1, 15. 11. Example 1 Ο: Preparation of (Ε) — Ν — cyclopropyl-3- — (2-gas phenyl) — 2-butenamide amine standard of the Ministry of Economic Affairs Π 工 消 揰 Cooperation Du 卬,; i (Please read the note on the back first (Fill in this page again) This compound was obtained by a method similar to Example 1, but using 2′-gas-based acetophenone (Aldrich) instead of 2′-bromoacetophenone to crack. The chromatography solution was subjected to rotary evaporation, The solid was collected and dried again; yield, 8.50 g (55%), mp 59-5.62〇C; NMR (DMS 0-d 6): δ 8.08 (d, 1 H, J =

3. 8 2 Η ζ, Ν H), 7. 37-7. 15 (m, 4 H, Ar), 5.89 (d, 1 Η, J = 1.2 1 Η ζ, = the original paper il: Scale Xiao uses the Chinese S family standard (CNS) A 4 specifications (210x297 g) -31-Λ 6 Β6 212170 V. Description of the invention (30) CH), 2.67 (m, 1 Η, NC Η), 2.40 ( s (please read the notes on the back first • fill in this page)

, 3 H, CH 3), 0 · 66 — 0.3 7 (2 m 's. 4 H, CH 2 CH 2); steady-state nOe: irradiation at 2. 4 9 δ. Observed 5.3% nOe at 7.3 and 0.7% nOe at 5. 8 9 δ 〇 elemental analysis: theoretical value (CuHhFNO): C, 71.21; Η, 6.4 4; N, 6.39 〇 measured value: C, 7 1 3 Ο; Η, 6. 4 6; N, 6 ♦ 3 5 〇 Example 1 1: Preparation (Ε)-3-(3-chlorophenyl) -N-cyclopropyl-2-butenamide Tetrahydrofuran (12〇mS) of (Ε) _3 — (3_ chlorophenyl) -2- butyric acid (E. Van Heyningen eta 1, J. Med. Chem., 9_, 675 (1966) (5. 0 0 g, 254 mmole) and triethylamine (2.57 g, 2 5 4 mmo 1 e), the Ministry of Economic Affairs, Biaoyang Standard Industrial Explosive Cooperative Society ^ chloroformic acid in tetrahydrofuran (2 0 mj?) Was added to the stirred ice-cooled solution Ethyl ester (2.76 g, 254 mmole). After 30 minutes, tetrahydrofuran (cyclobutanamine in 30 min (1.1 g, 254 mmole, Aldrich) was slowly added. The reaction mixture was at ambient temperature Stir for 15 hours. The reaction mixture was rotary evaporated in vacuo, and the residue in ethyl acetate and 5% The sodium acetate aqueous solution is divided between. The ethyl acetate layer is washed with 1 N hydrogen acid and brine. The ethyl acetate solution is dried (sodium sulfide) and used at the standard of the Chinese paper (CNS) A4 specifications ( 210x297 g) -32-9Λ Γ Ministry of Economic Affairs 尮 k Admittance: 1 Industrial and Consumers Union Λ 6 Β6 V. Description of the invention (31) Air rotary evaporation 0 Residual yellow solid in silicone 6 0 (4 0 1 6 3 m > E. Merck No. 9 3 8 5) purification by flash chromatography 9 using ethyl acetate-hexane (1 ♦ ♦ 4) as the eluent 〇 comprehensively contains (E) a 3 — ( 3 monochlorophenyl) -N — cyclobutyl-2-buteneamide and evaporated to obtain 3 »9 3 S (6 1%) product fm. P • 8 9 — 9 0 V; N Μ R (D Μ S 0-d 6) • • δ 8 • 2 (b Γ d, 1 Η t N Η), 7.5 4-7. 3 5 (m 9 4 Η t A r) f 6 ♦ 2 1 (d, 1 Η > J = 1 • 3 Η Z 1 = C Η), 4 • 2 8 (m, 1 Η 9 Ν C Η) 9 2 • 4 5 (d > 3 Η, J_ 1 • 2 Η ζ, C Η 3), 2 • 3 2 — 1 • 5 5 (mt 6 Η , (C Η 2) 3) 1 丨 S t eady- S t at e nOe: ir ra di ati on at 2. 4 5 »obse r ved] L 8.].% NOe at 7« 5 and -0. 2% nOe at 6. 2 1 0 Elemental analysis: Theoretical value (c 1 4 Η i 6 C 1 Ν 0): c > 6 7 • 3 3 f Η, 6 • 4 6; N t 5 • 6 1 ο Found: cf 6 7 • 3 4; Η, 6 * 4 6; N > 5 • 5 8 0 Example 1 2: Preparation (E) — 3 — (2 monobromophenyl) — N-cyclobutyl — 2 — Butenamide This compound is similar to the method in Example 3, except that cyclobutylamine (Aldr ich) is substituted for the cyclopropylamine in Example 3 C. The solid is recrystallized from methane-hexane Obtained white crystal product (1.1 g 16 4% on paper with 5fe scale, Chinese Standard (CNS) A4 specification (210x297)) (please read the phonetic information on the back and then write this page) -1T. 线. -33-Λ 6 Β6 212i ^ 〇 Fifth, the description of the invention (32), ρ. 128-13〇υ; ΝΜΚ (DMSO- (please Read the Zhuyin on the back first? Please fill in this page again) J v · δ 8. 2 2 (d, 1 H, J_ = 7.7 Η z,, Tu x 7 · 66 — 7. 20 (m, 4H, Ar),

In HJ »^ 6 8 (d, 1 H, J_ = 1. 4 H z., = CH), 4 25 (m, 1H.NCH), 2. 36 (d, 3H, j = l, 3 H z , CH 3), 2. 2 0-1. 58 (3 m. S 6 H »(CH a) 3); steady-state nOe: irrad — iation at 2. 3 6 5 .observed 4% nOe at 7. 2 4 8 and 1 96 nOe at 5. 6 δ δ 〇 Elemental analysis: theoretical value (C24H26B r NO) _: C, 5 7. 16; H, 5. 48; N, 4. 76; B r, 2 7 . 1 6 〇 measured value: C, 5 7. ◦ 8; H, 5. 5 Ο; N, 4. 72; Br, 27. 08. Example 1 3: Preparation of (E) — 3 — (2-chlorophenyl) -N-cyclopropyl-2-pentenylamide This compound is similar to the method in Example 1, but with 2′-aminobenzene Propylene (BL Jenson, SE Burke and SE Thomas, Tet rahedron, 34.1627-1637) (1978)) replaces 2 · -bromoacetophenone in Example 1C to produce a comprehensive containing (E) -3 -(2-chlorophenyl) -n-cyclopropyl-2 — penteneamide chromatographic solution and rotary evaporation in vacuum to obtain 6. 60 g of the paper standard for easy use and sleep Η family standard (CNS ) A4 specifications (210x297 g) and Λ 6 Β6 printed by the Ministry of Economic Affairs of the Central Standards Cooperative Society 51 mm- V. Description of the invention (33) (37¾) (E)-3 — (2 —chlorophenyl) -N — Cyclopropyl-2-pentenolamine, mp = 148 — 150 ° C; NMR (DMS 0-d: δ 8. 0 6 (d, 1 Η, J_ = 3. 9Ηζ, ΝΗ), 7.50 -7. 22 (3m · s, 4H, Ar), 5.64 (s, lH, = CH), 3.01 (q, 2 Η, J_ = 7.5 Η ζ, C Η 2C =), 2. 70 (m, 1 Η, NCH), 0.86 (t, 3 Η, J_ = 7.5 Η ζ, C Η 3), 0.68-0.40 (2 m 's, 4- Η. C Η 2〇Η ζ); stea dy-state nOe: irradiation at 3. 0 1 δ .observed 1 9. Ύ% nOe at 0. 8 6 δ and 1.1% n 0 eat-5. 6 4 δ. Elemental analysis: theoretical value (C: 4H / 5C1, N, 0): C, 67. 3 3; Η, 6. 4 6; Ν, 5. 61; C 1, 14. 19. Found: C, 6 7. 3 5; Η, 6. 4 8; Ν, 5.6 2; C 1, 14. 12〇 Example 1 4: Preparation (Ε)-Ν-cyclopropyl 3-(2-iodophenyl)-2-butenamide A) Preparation of ((cyclopropylamine formyl) methyl) diisopropylphosphonate This compound was prepared in a similar manner to Example 1 B, but using triisopropylphosphite and pentane instead of triethylphosphite Get: Yield, 385g (48.7%) fluffy white solid; mp 58-60t: (please read the note on the back-matters before writing this page) Binding _ This paper? Standard use Chinese standard (CNS standard) ) A4 specifications (210x297 g) -35-Λ 6 Β6 212170 V. Description of the invention (34); The analysis sample is recrystallized with hexane. Elemental analysis: Theoretical value: C; iH22N〇4P: C, 50.18; Η, 8.4 2; N, 5.32. Found: C, 5 0.08; Η, 8. 4 4; Ν, 5. 2 6 〇Β) Preparation (Ε)-Ν-cyclopropyl 3-(2-iodophenyl)-2 one Butenamide This compound is similar to the method of Example 1, but replaces 2'-bromoacetophenone in Example 1C with 2-iodoacetophenone (Aldrich) and uses ((cyclopropylamine methyl (A) Diisopropyl methyl) phosphonate substitution. The chromatographic solution containing (E) -N-cyclopropyl-3- (2-iodophenyl) -2-butyrylamide in a rotary evaporation in vacuum. The residue was recrystallized with methane-dichloromethane to give 1.7 g (51%) of white crystalline product, m.p. 120-122 ° C; NMR (DMS Ο-d β): δ 8.04 (d, 1 Η, J_ = 4.0. Η ζ, Ν Η), 7.8 8-7.〇〇 (m, 4H, Ar), 5. 57 (d, 1 Η, J_ = 1.4Hz, = CH), 2.68 (m, l H, CH), 2.34 (d, 3H, 丄 = 1. 3 Η ζ, C Η 3), 0. 68-0. 35 (ζ m 's .4 Η t C Η 2 C Η 2); steady-state nOe: irradiation at 2 · 3 4 5, 〇bserved 5% η 0 eat 7 · 〇4 δ and 1% nOe at 5. 5 7 5 CNS) 肀 4 specifications (210x297 Gonglu) (please read the phonetic note on the back 〖Items and then fill out this page) Binding · Line · -36-2121 ^ 0 λ6 _____ Β6__ V. Description of the invention (35) Element analysis: theoretical value (CuHhINO): C, 47.73; H, 4.31; N, 4.28; I, 3 8.7 9 0 Found: C, 47.63; Η, 4.33.3; Ν, 4.26; I, 38. 86〇Pharmaceutical composition: In the following formulation example, * active ingredient 〃 can be any compound of general formula (I) or alkali salt or other physiological functional group derivative, for example, the compounds of Examples 1 to 14. Example 1 5: Tablet composition: The following compositions A, B, and C are obtained by using bofephenone solution wet granules (please read the note t on the back before filling in this page) Ministry of Economic Affairs Standard ^ Gongxiaofen Cooperative Society made all the ingredients, and then added magnesium stearate and compressed it. Cyanogen A Π18 / tablet ΠΚ / tablet (a) Active ingredient 2 5 0 2 5 0 (b) Lactose B. P. 2 10 2 6 (c) Pofefenone BP · 15 9 (d) Starch Sodium konconate 2 0 12 (e) Magnesium stearate 5 3 5 0 0 3 0 0 The size of this paper is easy to use Chinese a family standard (CNS) A 4 specifications (210x297) -37--2121 ^ 0

V. Description of the invention (36) Sweet product B Λ6 13 6 mg / tablet mg / tablet (a) Active ingredient 2 5 0 2 5 0 (b) Lactose 15 0 one (c) Avicel PH 101 6 0 2 6 (d) Pofefenone BP 15 9 (e) Sodium starch gluconate 2〇1 2 (f) Magnesium stearate 5 3 5 0 0 3 0 0 (Please read the notes on the back of the rabbit first. Page) 3 5 9 Printed by the Ministry of Economic Affairs Standard XJM Industrial Consumer Cooperation Co., Ltd. New product C πκ / Η Active ingredient 100 〇 Lactose 2 0 0 Dianfen 50 〇Pofenone 5 Magnesium stearate 4 The following composition D and E are made by directly compressing and mixing the ingredients. The lactose in the composition E is a direct compression type (Dairy Crest- " Zeparox "). ○ Original paper 5 Good-scale, easy-to-use Chinese a family standard (CNS) A 4 specifications (210X297 and) -38-212170 Λ 6 B6 5. Description of the invention (37) Composition D mg / tablet active ingredient 2 5 0 Pregelatinized starch 1 5〇4 0 0 Composition E m2 / Η active ingredient 2 5 0 Lactose 15 0 Av i ce1 10 0 5 0 0 (Please read Note 1 on the back before filling in this page) Composition F (Controlled Release Composition) This composition is composed of wet granulated ingredients (below) using a solution of bofephenone (below), Subsequently, magnesium stearate was added and compressed. mg / tablet (a) Active ingredient 500 (b) Hydroxypropyl methylcellulose 1 1 2 (Methocel K4M Premium) (c) Lactose B · P · 5 3 (d) Pofefenone B. P. 28

(e) Magnesium stearate _Z 7 0 0 This paper 56 ^ standard general medium S® home appliance standard (CNS) A 4 specifications (210x297 g) Line · Shiyang standard of the Ministry of Economic Affairs along ΠWorks Rehabilitation Cooperative 卬 ¾- 39-212170 Λ 6 Β6 5. Description of the invention (38) Example 1 6: Capsule composition A The capsule composition consists of mixing the ingredients of composition D in Example 15 above and filling it into a di-H type hard gelatin capsule. be made of. Composition B (infra standard of Infra Ministry of Economics ^: printed by Gongxiaofen Cooperative) is made in a similar manner. Composition R rnsz / Corydalis (a) Active ingredient 2 5 0 (b) Lactose B. P 14 3 (c) Sodium starch gluconate 2 5 (d) Magnesium stearate 2 4 2 0 Composition c II15Z / Bi IS (a) active ingredient 2 5 0 (b) Macrogo1 4000 Β · Ρ. 3 5 0 6 0 0 (please read the precautions on the back before writing this page) Binding-Order 'Line-Original Paper 56: Standard Use the Chinese S Family Standard (CNS) A4 specifications (210x297 g) -40-2i2i1: 〇Λ 6 B6 V. Description of the invention (39) Composition D HK / Pluvialis active ingredient 2 5 0 Lecithin 10 0 Peanut oil 10 0 4 5 0 The gum g of composition D consists of dispersing the active ingredients in lecithin and peanut oil and filling the dispersion into soft elastic gelatin capsules. Composition E (Controlled Release Capsule) The following controlled release capsule composition consists of extruding ingredients a, b, and c using an extruder, followed by making the extrudate elliptical and drying. Nine capsules are dried and coated to control the release film (d) and filled into two-piece hard-shell gelatin capsules. (Please read the note i on the back and then write this page) The Ministry of Economic Affairs Standards Advise H Gongxiao " Cooperative Society 卬 3i mg / Wacocoa (a) Active Ingredient 2 5 0 (b) Microcrystalline Cellulosin 1 2 5 (c) Lactose BP 1 2 5 (d) Ethylcellulose 1 3 5 1 3 Example 1 7: This paper has a standard of 5 Gen. Chinese Standard (CNS) A4 (210x297 g) -41 -C-* r ^

6β AR V. Description of the invention (40) Injectable composition Active ingredient 95% ethanol and PEG 400, 1: 1 ratio No leaching water q 0. 2 0 0 g

to 10 mL Dissolve the ingredients in 95% ethanol and PEG 400 (1: 1). Water is added to the batch to the required volume and filtered through a sterile microporous filter into a sterile 10mi amber glass bottle (Class 1) and sealed with a sterile closure and sealing wax. Example 18: Syrup

Active ingredient 0.2 5 8 sorbitol solution 1.5 〇s ethylene glycol 2. 〇〇g sodium benzoate '0. 〇〇5 g flavor, Peach 17.42.3169 〇. 〇1 25 mL of purified water q · S · to 5. 0 0 mL (Please read the precautions on the back before writing this page) Binder. The Ministry of Economic Affairs Standard · -τπ 工 消 " Cooperative Society Seal 31 Dissolve the active ingredient in ethylene glycol and large Part of the purified water mixture. The sodium benzoate aqueous solution was added to the solution, followed by the sorbitol solution and finally the flavor. Add to the required volume with purified water and mix evenly. Example 1 9: This paper scale uses the Chinese National Standard (CNS) Grade 4 specifications (210x297 g) -42-

SI 5. Description of the invention (41) 搃 切 mg / 掠 切 active ingredient 250 stearin, BP (Witepsol H15-Dynamit NoBei) 1 7 7 0 1 2 0 2 0 1/5 of Witepsol at a maximum of 4 5 ° C H15 is melted in the steam jacketed pot. The active ingredients are sieved through a 200M sieve and Si 1 ver son equipped with a cutting head is added to the molten substrate while mixing until a uniform dispersion is obtained. Keeping the mixture at 4 5 t :, add the remaining Wi-tePS〇l H15 to the suspension and stir to ensure that it is evenly mixed. All suspensions were passed through a 250M stainless steel sieve and cooled to 40 ° C with continuous stirring. Under 38 -40¾, fill 2.0g of the mixture into a suitable 2m β plastic mold. Allow suppositories to cool to room temperature. (Please read the phonetic ff item on the back first and then fill in this page.) Ingredients 2 5 〇Anhydrous glucose 3 8 0 Potato starch 3 6 3 Magnesium stearate 7 10 0 0/6 Paper 5 Good standard Chinese National Standard (CNS) A 4 specifications (210x297 Gonglu) -43-Λ 6 Β 6 212170 V. Description of the invention (42) (please read the notes on the back of the page first and then fill in this page) directly mix the above ingredients and compress the resulting mixture directly to prepare a vaginal suppository. Example 12: Muscle relaxant activity The muscle relaxant activity of the compound of general formula (I) was measured using the Straub tai 1 test described in K.O. Ellis and J.F. Carpenter Neuropharmacol, 13.21 1 (1974). St-raub t a i 1 The test result is E D 5. (Nig / kg) records. E D 5 〇 Image is defined as the dose of compound to avoid the 50% Straub tail of the mole rats. The compound was administered by oral gavage 6 minutes before the score. The side effects of these compounds were measured using the flying squirrel 1 * 〇1〇1 * 〇 £ 1 test method as described in G.D. Novakand J.M.-Zwolshei. J. Pharmacological Methods, 1 〇.175 (1 9 8 3). 1? (^ 〇1 * 〇 £ 1 The result is reported in ED5 (mg / kg). ED5 is the dose that causes 50% of the animal to be unable to maintain the position of the rotating drum at 1 1 r .p .m. The Ministry of Economy ’s standard XJn Gongxiao f? Cooperative Society ’s antagonism of the Straub tail induced by morphine represents the effectiveness of muscle relaxants and failure in the rotorod test represents sedation and mutual inability. The measurement of the bb value of traubtai 1 including the anti-effect is a method for evaluating the side effects of muscle relaxants (G.D. Novak, Drug Dev. Res., 2, 3 8 3 (1 9 8 2). Chinese standard (CNS> A4 specifications (210x297 g) 44-V. Description of the invention (43) The following example Straub compound tail ρ · o. ED 5 〇mg / kg

Ro t o t od P. O. ED 5 〇, mg / kg Λ 6 Β6

Rotorod /

Straub Tail tati 2 5 4 5 8 (Please read the precautions on the back $ to write this page) Ministry of Economic Affairs Xiaoyang Zhuo Zhuo Consumer Industry Cooperative Society 3i Example 2 2: Antispasmodic activity: compound of general formula (I) The antispasmodic activity was determined by the method using Mehta 4 aj_., J. Med. Chem., 24.465 (1981). The antispasmodic activity is based on ED5. (Rag / kg). Avoid the spasm of E D5 induced by the maximum electric shock. It is customary to avoid 50% of the animal's dose of leg extension afterwards. ED5 to avoid spasms induced by Metarazol. To avoid the dosage of 50% animal spasm. Examples of compounds shown below

i · p · ED a 〇, MES

nig / kg (rat) MET MES—Maximum Electric Shock ME T—metrazol 9. 6 3. 6 This paper scale is easy to use Chinese National Standard (CNS) A 4 specifications (210x297 g; ¢) -45-Λ 6 Β 6 212170 V. Description of the invention (44) Example 2 3: Resolving activity: The resolving activity of the compounds of the present invention uses Geller and Seifter, J. Modified by Pollard and Howard, Psychopharmacology, β 2, 117 (1 9 7 9). Psychopharmacolgia, 482 (1 960) method. Clinically effective analgesics increase penalties. The solution of the compound is considered to be the dose required to increase the penalty by 50% in domestic rats. Example p.o.ED5〇, nig / kg servant, compound ___ 1 16 (please read the notes / events on the back first, then fill out this page) Outfit-Ministry of Economic Affairs 吮 央 満 准 是 Π 工 消 " Cooperative Society 卬 51

Claims (1)

A7 212170 B7 1 ^ ------ 1 'Repair 32. 7. 2 i 1______aa. 1 1, _ ± 1 6. Patent application area 1 Bu 1… "Attachment 1 (A): No. 81100323 Patent application Chinese application patent patent garden amendments In July 1982, a compound represented by general formula (I) was amended: CHCCtlHH (1) R1 represents Ci-6 alkyl, R2 represents H or C3-6 cycloalkyl and one or more ring substitution formulas selected from halogen atoms and perhalo Cl-4 alkyl, R 3 represents group; The prerequisites are: (i) when R1 represents methyl and R2 represents cyclopropyl, then one of R3 or R3 is in the 2-position; and (ii) the compound of the aforementioned general formula (I) is not 2-butene Acetylamine; (4 monochlorobenzene (please read the precautions on the back before filling in this page) • Skirt. Order. Line · Printed by the Central Standard of the Ministry of Economic Affairs and 8 Industrial and Consumer Cooperatives or its salt 2. Methyl and — The position R 1 is shown as the compound of the first item in the scope of patent application, in the formula, R1 is Gong / or, R2 is cyclopropyl and / or one of R3 or R3 is on 2; or its salt. • If applying for a patent The compound of item 1 or 2 in the scope, where the methyl group and / or R2 is cyclopropyl and / or the original paper standard in R3 or R3 is the Chinese National Standard (CNS) A4 specification (210 X 297 public goods ) -1 A7 B7 C7 D7 2121 ^ 0 Sixth, apply for a patent fan circle-showing bromo, chloro, iodo or trifluoromethyl and tied on two positions: or its salt. 4 · If applying for a patent Scope item 1 or 2 The compound, in the formula, R1 represents a methyl group and / or R2 represents a cyclopropyl group and / or R3 is as defined in item 1 or 2 of the patent application scope and is located at the 2-position; or its salt. 5. The compound of the 3rd item of the Patent Area, where R1 represents a methyl group and / or R2 represents a cyclopropyl group and / or R3 is as defined in item 1 or 2 of the patent application scope and is located at the 2-position; or鹸 盐. 6 · A compound of general formula (I) or its (E) isomer of ponge salt such as item 1 or 2 of the patent scope. 7. A compound of item 1 of the patent scope is: : (E) — N — cyclopropyl-3 — (2— (trityl) phenyl)) —2-butenamide; (E) — N—cyclopropyl-3 — (2 — stele Phenyl) _ 2 -butyramide; '(E) — N —cyclopropyl-3 — (2,3-dichlorophenyl) -2-buteneamide; (E) —3 — (2-chlorophenyl) -N-cyclopropyl-2-buteneamide; (E) '-3-(2-bromophenyl) -2-buteneamide: or its salt. 8. (E) —3 — (2 —Bromophenyl) —N-cyclopropyl-2-butenamide. 9. Eg salt of the compound as claimed in item 1 or 2 of patent scope. This standard is applicable to China National Standard (CNS) Grade 4 (210 X 297 mm) ---------------------- installed ----- -tr ----- 1 m (Please read the precautions on the back before filling the nest page) Printed by the Employees Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs Ϊ Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 8 A7 __ D7 Scope of patent application 10. For example, if you apply for the compound of item 1 or 2 of the Fanfan Garden, it is for use in medical treatment. 11. If the compound of patent application 1 or 2 is applied, it is used to manufacture a substance for treating or preventing the symptom caused by abnormally increased muscle tone. 12. If the compound of patent application item 1 or 2 is used, it is used to manufacture a medicine for treating or preventing spasm symptoms. 13. For example, the compound of item 1 or 2 of the patent application is used in the manufacture of anxiety for the treatment of anxiety. 14. A pharmaceutical composition acting as a muscle relaxant, antispasmodic agent or anxiolytic agent, which comprises a compound as described in patent application No. 1 and a pharmaceutically acceptable carrier. 1 5. If the pharmaceutical composition according to item 14 of the patent application scope is for oral administration. 16. If the pharmaceutical composition of item 15 of the patent application is applied, it is in the form of tablets or capsules. 1 7. A method of manufacturing a compound as claimed in item 1 of the patent scope, which includes: (A) a compound of general formula (II): (In the formula, R3 knows that the paper size as specified in the general formula (I) of item 1 of the patent application park is applicable to the Chinese In-house Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back first Matters will be written on this page)-Binding _ Order. Α7 Β7 C7 D7 6. The scope of the patent application and X shows the leaving group) Reaction with compounds of general formula (III): R 9 CH 2 CHCOR 4 (XII) (where , R4 represents a NHR2 and R1 and R2 are as defined in the general formula (I) of item 1 of the scope of patent application); (B) Let the compound of the general formula (IV): C (R) == 〇 (IV) (In the formula, R1 and R3 are as defined in the general formula (1) of item 1 of the patent application scope) and the Wittig reagent shown in the general formula (V) reacts under Wittig conditions YCH2COR V (Please read the precautions on the back before writing this page) • Installed-Ordered. Thread · Printed by the Central Standard of the Ministry of Economic Affairs, R-Consumer Cooperative (where R4 is as defined above and Y is -P (= 〇 ) (〇r) 2, where R represents C 1-4 aryl group 'aryl group or aryl aryl group, or γ represents triaryl scale) (C) Dehydration of the compound of general formula (VII): This paper scale applies to China National Standard (CNS) A 4 specifications (210 X 297 mm) A7 B7 C7 D7 6. Scope of patent application (In the formula, R1, R3 and R4 are as defined above), (D) Let the compound of general formula (Y1II): (In the formula, R1 and R3 are as defined above and Z shows the leaving group) Reaction with the compound of general formula (IX): Η-R IX ------------------- ----- install ------ order ---- Γ line (please read the precautions on the back before writing this page) Employee Consumer Cooperative Printed by Ministry of Economic Affairs Central Standards Bureau «(In the formula, R4 knows (Defined above), and thereafter, or simultaneously, one or more of any of the following conversions: (i) Convert the compound of general formula (I) thus formed into its salt: (ii) When the compound of general formula (I) is formed In the case of salt, the aforementioned derivatives are converted into compounds of general formula (I). The size of this paper is in accordance with the Chinese National Standard (CN ’S) A4 specifications (210 X 297 mm) (Annex III CA): Chinese Supplementary Information for Patent Application No. SI 100323 212170 Supporting data submitted in April 1982 15 Formula ⑴ Compound Ε1 Ε2 Ε3 Straub Tail po ED 50 Rotorod po ED50 Rotorod / Siraub Tail CH3 Cyclopropyl 2-Br 24 35 1.5 CH3 cyclopropyl 3-Bγ > 180 inactive CH3 cyclopropyl 2-F 69 120 1,7 CH3 cyclopropyl 3-F 122 71 0.6 CH3 cyclopropyl 4-F 122 CH3 cyclopropyl 2 -C1 33 40 1.2 CH3 Cyclopropyl 3-CI 48 50 1.1 CH3 Cyclopropyl 2-CF3 25 33 1.3 CH3 Cyclopropyl 3-CF3 51 69 U The foregoing data confirms that, with the known 3- and / or 4-- Compared with substituted compounds, the results obtained in the present invention 2-substituted compounds are unexpected. Straub Tail test data proves that, in all cases, the 2-substituted compounds are more effective muscle relaxants (especially seen in the comparison of 2-Br and 3-Br). In addition, it can be seen from the Rotorod / Straubfcb value (the larger the fcb tan, the better) that, overall, the substituted compound 2 of the present invention has a better safety profile. Τ4 (210X297 公 X) 2121 ^ 0 3-the molybdenum derivative is inactive in the Rotorod test (the activity is not observed in the agent set greater than 180rog / kg po), therefore, its EDso cannot be calculated, and because it cannot be calculated EDso, it is not possible to determine the safety profile. Τ4 (210X297 public installation) y