TW513415B - 4-aminoalkoxy-1H-benzoimidazoles having dopamine D2 agonist activity and pharmaceutical composition thereof - Google Patents

Abstract

This invention relates to D2 dopaminergic compounds of the formula wherein: R1 is hydrogen, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, straight-chain or branched alkyl group having up to 6 carbons or benzyl optionally substituted by one to three substituents selected from halogen, amino, nitro, hydroxy, and C1-C6 alkoxy; R2 is hydrogen or C1-C6 alkyl; R3 is hydrogen, straight-chain or branched alkyl group having up to 10 carbon atoms, cyclohexylmethyl, -(CH2)mAr where Ar is phenyl, naphthalenyl, thienyl, furanyl, or pyridinyl, each may be substituted by halogen, trifluoromethyl and C1-C6 alkyl; or NR2R3 is 1,2,3,4-tetrahydroquinolin-1-yl or 1,2,3,4-tetrahydroisoquinolin-2-yl; Y=hydrogen, halogen, or lower alkyl; m=1 or 2; n=1-2; or a pharmaceutically acceptable salt thereof. These D2 dopaminergic compounds are useful in the treatment of schizophrenia, Parkinson's disease, Tourette's syndrome, and drug or alcohol addiction.

Description

513415 Μ B7 V. Description of the invention (I) Field of the invention The present invention is pseudo-broader than 4-amine alkoxyindazole, which has dopamine D2 promoting activity, and therefore can be used to treat schizophrenia, Parkinson's disease, Trowley (T 〇ure 11 e) 's disease, 5 drugs or alcohol. BACKGROUND OF THE INVENTION Efforts to mediate antipsychotic activity with dopamine receptor enhancers have been successful (Dorsini TA dv. Biochem. P sychopharmac ο 1.. 1 8, 6 4 5-6 4 8, 1 9 7 7 ; T a hi hi i ϊ ga et al., Science, 2 0 0, 5 6 7-5 6 8, 1 9 7 5; and T a hi hi inga et al., Psychiatry, 3 9 8-4 0 2, 1 9 8 (3). A method for determining substantial activity on a dopamine D 2 receptor has recently been reported (L. Ahti et al., Mol. Phar., 4 2 5 4 3 2-4 3 8, 1 9 9 3) The actual activity can be predicted using the ratio of the "low affinity promoter" (L ow A g) state on the receptor and the "high affinity promoter" U igh A g) state on the receptor. 卽 L ow A g / H igh A g. This ratio is related to the compound's full force, partial force, and tangerine resistance activity, which shows the ability of the compound to remove antipsychotic effects. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) According to the present invention, it provides a group of compounds that can be used as antipsychotics. The compound of the present invention is dopamine with different degrees of substantial activity to promote rain, and part of it is a selective autoreceptor promoter, so it is part of the promoting surface (that is, only the autoreceptor is activated instead of D 2 dopamine Receptor). Therefore, it can provide a functionally regulated dopamine system in the brain, and it does not overdo the interfering process of the dopamine receptors, which is a serious side effect often caused by the clinical drug of schizophrenia. Activating the dopa saddle autoreceptor can reduce nerve firing and inhibit dopamine synthesis and release. Therefore, it can provide methods to control the paper size. Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 513415 A7 B7 V. Description of the invention ( The system of dopamine production is overly counter-intuitive. The compounds of wood invention also have a high degree of substance. This amine can be promoted by badol 0, and it can cause disease and disease. The quality of amine dipamine is often different. The reason for treatment is that you can use the pieces to make arts. You can substitute for the exogenous precursor cone. 合物 合 化 明 发 本 (Symptoms Senjinpa) ο Ming therapy PS said Wuhehua Mingfa 〇9 Benli 06 Yuzhuan 2, I would like to apply for the number of J J Zhongyi technology before the ft-like structure of ft-like structure of the compound azole benzene like group | apply for A 6

Use the medicine to suppress the attachment plate, ffe as its N or for its active therapy pr: installed I ---- 邋 (Please read the precautions on the back before filling this page)

, 1T diseased heart and blood, absolutely no way, the formulator has been fixed from the β-selection 5. Base is 3 {is

R contains or

4 R planed unhalogenated or chronic kidney disease, 基 or 意 基 3 t A-based nonhydroxyl Γ intermediate courtyard U, # 其} _ and benzene α, (¾ ,: containing 丨f 5 Benzene 磉 R 2 ffl 4 R, fipR hydrogen and radical ΛΙ-Ν containing, oxygen IES 璟 ″ di u JJ /, Fu} R I. AI impurity low and slow, and! _ ο ί

4 R N

R ΙΛ 弋 / 1 is taken from the halogen halide printed by the consumer co-operative of the Central Standards Bureau of the Ministry of Economic Affairs. 60 in the base!-| Sheep ο alkane 83 chemistry. Amine 3 polycoagulation

Ε D

ΝΗ

This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 513415 A7 B7 V. Description of the invention Buxue and often different strips are used for cycle treatment.

4 R

U.1 R oxane s hexylsulfonium methyl is amine amine hydrazone or carboxyl, alkyl cyanide or cyanohydrin is

6 R

3 R and 匚 R are shown in the form i-i.

R3 or Η is its (please read the precautions on the back before filling in this page. Chinese Fluorine or Triyl, Alkanes A is diphenyl nitroamine

2 R

m R 2 Η c in the L-chain. C >? Γ Dv, A hydrogen hydrogen m is 丨

Or halogen fluorene can be selected directly. 3 7 ~ > 1X radical is 5 with ethyl gas. * Any, 7 I $ radical, S radical, and other radicals are methyl benzyl or A and C. Substitute benzene to substitute for any radicals fftfc or oxyalkyl methylhexyl alkaneici phen ti Ω Η ί_ Keenan 0 · fu ηημ- Order the Ministry of Economic Affairs Central Standards Bureau negative work consumer cooperative to print oxane

3 R phthaloline 6 • hydrazone 1 C chlorine and tetrayl 4-methyl 3 ′ gas 2 1,2 1, is a halogen, and the radical is selected; the radical alkane or hydroxytetraline is 0 iso

Y m Π-based or low-based oxalane or low-based alkanoyl halogen This paper is in accordance with the Chinese National Standard (CNS) A4 (210X 297 mm) 513415 A7 B7 V. Description of the invention U) Free pharmaceutical allowance Acid addition salts can be prepared by conventional methods in the form of inorganic or organic acids, such as fumaric acid, maleic acid, benzic acid, ascorbic acid, pimelic acid, succinic acid, bismethylene salicylic acid, formazan Sulfonic acid, ethanesulfonic acid, acetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, menthol, lactic acid, hydroxysuccinic acid, phenylglycolic acid, lauric acid, citraconic acid, aspartic acid, hard Fatty acid, hexadecanoic acid, itaconic acid, carboxylic acid, p-aminobenzic acid, glutamic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfonic acid, phosphoric acid and nitric acid, but not limited to this. In the compound of formula I I I, R 1 is hydrogen can be prepared by the following scheme:

Process I (Please read the notes on the back before filling out this page) Clothing. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Those compounds of formula I I I where R 1 is not hydrogen can be prepared by the following procedures: The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 513415 Α7 Β7 5. Description of the invention (

Process II

2 (n = 1 or 2 ^ R2

H2NNH2-^ 10% Pd / C or Ruanlai Nickel Ethanol

pk ^ NH2 h R1—C02H 2. HC1 ±

(Please read the precautions on the back before filling this page) In the compound of formula III, R2 is hydrogen, and the secondary amine can be protected by trifluoroacetamidine, which can be prepared by the following process:

Process I I I Η

h2nnh2 -► G alcohol Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 3l

3 · HCl h HC1 salt The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 513415 A7 ~ ___ B7________ V. Description of the invention U) Those in the intermediate product of the compound of formula III where Y is halogen can be prepared by the following process :

2 in = 1) 2 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, the following is an example of the preparation of a representative compound of the present invention. 0 Intermediate product 1 4- (2-Chloroethylaminobenzimidazole will contain 4-hydroxybenzo. Oxazole (3.lg, 32.4 ttmo 1) triphenylline (1 2.75 y 48.6 mm [ο 1), and tetrahydrofuran containing 2-chloroethanol (5.2 g, 64.8 οιη tol) (7 5 m 丨 1) solution, and slowly add it to tetraethylfuran containing diethyl azide dicarboxylate (8 • 5 g, 48.7 m mol) during 0-5 ° C and 30 minutes. 7 5! B 1) Medium 〇 Warm to 2 3 ° C and stir for 4 8 hours. Evaporate the solvent in vacuo to obtain a dark brown oil. Chromatography (silica gel, ethyl acetate-1% 2 M NH 3 in methanol) Purification yielded 2.9 g (6 3.8%) of a solid. The title compound was obtained as a white solid by recrystallization from ethyl acetate. Melting point 1 53- 154 ° C. Elemental analysis: C 9 Η 9 C 1 N 2 〇 Calculated value: C, 54.97; H, 4.6.1; N, 14.2 5 actual value: C, 54.86 Η, 4.38; Ν, 14.26 Intermediate product 2 a (η = 1) 2-(2 -fluorenylethoxy) -5-nitro-aniline will contain 2-amino-3 -nitro (32 · 〇g , 0.208 fficruο 1), 1, 2-2: gas ethane (260g, 2.65iainol) potassium sulfonate (35g, 0.252nimol) and 2-butane (Please read the precautions on the back before filling in this (Page) · Equipment · -mouth- " Μ-3 _11 — This paper size applies to China National Standard (CNS) A4 (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 513415 A7 B7 V. Description of the invention ( 9) The mixed solution of China (750 HI 1) was refluxed for 2 4 hours. Cooled, filtered and the solid was washed with ethyl acetate (50 Ιιιι 1). The filtrate was concentrated to an oily residue and dissolved in ethyl acetate (500 m 1 ). The organic layer was washed with 1 N Na 0 H (250 m 1), water (500 m 1), and brine (2 X 50 f) m 1), and dried over anhydrous magnesium sulfate. The filtrate was concentrated and triturated with hexane to obtain 37.8 g (84.6%) orange solid, melting point 7 1-7 3 ° C, MS (+) PBEI m / e 2 1 6/2 1 8 (M f) 〇 Elemental analysis: C 9 Ή s C 1 Ν 2 〇3 Calculated value: C, 4 4 · 3 6; Η, 4 · 1 9; N, 1 2 · 9 3 Actual value: C, 4 4 · 4 5 ·, Η, 4 · Ο 2; N, 1 2. 9 7 The method of imitation is used, and 1,3-dibromopropane can be used to obtain intermediate fluorene 2 b, 2-(3-bromopropoxy) -6-Nitro-aniline as a yellow solid, melting point 8 8-8 9 3C; MS ΕΙ πϊ / e 2 7 4/2 7 6 (M +) 〇 Elemental analysis: C 9 H u R r N 2 〇: 5 Calculated value ·, C, 3 9 · 2 9; H, 4 · 0 3; N, 1 0 · 1 8 Actual letter: C, 3 9 · 71; H, 3 · 9 1; N, 1 0 · 2 7 Intermediate 3 a 2- (2-benzylamine ethylchloro) -6_nitro-aniline will contain 2- (2-chloroethylchloro) -6 »nitro-aniline (Ri !, 3.0 g, 13.8 m π 1) and benzylamine (9 · 0 g 5 8 4 · 0 in fli ο 1) heated to 1 0 0-1 1 iTC 6 small

Time. The excess of benzylamine was removed by vacuum evaporation (7 0-7 5 ° C / 0. 1). Pour to 1 N N a 0 H (3 0 0 m)) and extract with ethyl acetate (2 X, 3 0 0 μm 1). Combine the organic layers and wash with water (2 X, 300) and saline (300 m1). The ethyl acetate layer was dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent in vacuo gave 5.1 g of crude red. Chromatography (500 § SiO, ethyl acetate: 2M NH3 in methanol This paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back before filling this page)) Install.

1.1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 513415 A7 B7 V. Description of the invention (not) = 2 (3: Γ) Purified to obtain 3.54 g (89.3%) red semi-solid, melting point 3 3-6 0 ° C; MS El m / e 2 8 7 (M +) 〇 Elemental analysis: 03 Calculated: C, 6 2 · 7 1; H 5 5 · 9 6; N, 1 4, 6 2 Actual Value: C, 6 2, 6 4; H 5 6. 0 4; N, 1 4. 2 3 Following the method of hydration, using 4-methyl-benzylamine, pheno-2-methylamine,]-naphthylmethyl Amine,], 2,3,4-tetrahydroisofluorene can be obtained as: 2- [2- (4-methylbenzylamine) ethoxy] -6-nitro-aniline as a yellow solid (89% ): Melting point 5 5-5 7 ° C; MSEI m / e 3 0 1 (Μ +). Elemental analysis: C ie Ν 3 Ο 3 Calculated value: C, 6 3. 7 7; Η, · 3 6; Ν, 1 3 · 9 4 Actual value: C 5 6 3. 3 2; Η, 6 · 3 7 ·, N, 1 3 · 8 2 & 2-Nitro-2- 2-[(3-chlophen-2-ylmethyl) amino] ethoxy] aniline as a red semi-solid (8.85%).

Elemental analysis: C i3 H15 N 3 〇3 S Calculated value: C, 53.23; Η, 5.15; N, 14.32 Actual value: C 5 5 2 · 8 6 ·, Η, 4 9 3; Ν,] 4. 1 5 ^ 2- [2-[(Cai-b-methyl) amino] ethoxy] -6-nitro-aniline as a yellow solid (76.3%): melting point 6 6-6 7 ° C; MS ET m / e 3 3 7 (Μ +) 〇 Elemental analysis: C 13 Η i9 Ν 3 Ο 3 Calculation letter: C, 6 7. 6 4; H, 5 · 6 8; Ν, 1 2 · 4 5 Actual value : C, 6 7 · 2 Ο; hydrazone, 5. 6 6; Ν, 1 2 · 2 6 & 2-[2-(3,4 ~ dihydro-1 fluorene-isofluorin-2-yl) ethyl Oxygen] ~ 6 -Nitra-1 0-This paper size is in accordance with Chinese National Standard (CNS) Α4 size (210X 297 mm) (Please read the precautions on the back before filling this page) € Clothes · Order 513415 A7 B7 5 2. Description of the invention ($) A yellow solid of aniline (87.I%: melting point 9 5-9 6 ° C; EI m / e 3 1 3 (Μ +)) Analysis: C Η ίο Ν 3 1 0 9 Calculated: C, 6 5.16; Η, (3.11; Ν, 13.41 Actual: C, 8 4.8 7; Η, (3.11: Ν, 13.40 In accordance with this procedure, use 2-(3 -bromo-propyl Base) -6 ~ nitro-aniline (2 6, η = 2) and benzylamine, printed by U 2-(3-benzylamino-propanyl) -6-nitrate printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -Aniline viscous orange solid (85.5%); MS Ε I m / e 3 Ο 1 (Μ +) 〇 Elemental analysis: Cie Η 19 Ν 3 Ο 3 Calculated value: C, 6 3 · 7 7; Ιί, 6 · 3 6; Ν, 1 3 · 9 4 actual value: C, β 3 · 6 6; hydrazone, 6.. 2 8; Ν, 1 3 · 8 9 uses 4 -chloro-2- (2-Chloroethylchloro) -6-nitro-aniline (7) and benzylamine, 4-chloro-benzylamine are available. · 2-(2 -benzylamino-ethoxy) -4 -chloro- 6-Nitro-aniline orange solid (54%); melting point 8 7-8 8 DC; MS E Ϊ ro / e 3 2 1/3 2 3 (M +). Elemental analysis: C 15 Η C 1 Ν 3 Ο 3 Calculated values: C, 55 · 99; Η, 5.01; Ν, 13.06 Actual values: C, 5 5 · 8 5; Η, 4 · 9 Ο; Ν, 1 3 · 1 3 Li-2- [2- (4-chloro-benzylamino) ethoxy] -chloro-6-nitro-aniline orange solid (8 3 · (1%), melting point 1 1 fi -1 1 8 ° C; MS El m / e 3 2 1/3 2 3 (M +). Elemental analysis: C] 3 Ηπ C]? N? 0 2 Calculated value: C, 5 0 · 5 8; Td , 4 · 2 4; N, 1 1 · 8 0 Actual value: C, 5 0 · 6 5; 11, 4 · 1. 3; N 5 1 1 · 5 1 (Please read the precautions on the back before filling in this Page) Clothing

、 1T This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297mm) 513415 A7 B7 V. Description of the invention Value element

ii C 8 2 5 Η Ν Nitrosamine Benzene I r \ oxyoxyethyl \ 1 / amine amine benzyl trifluoroanalysis value solid content calculation interstitial pigment calculated orange yuan% ¾ p (5 Η 16 Η Η ( Please read the precautions on the back before filling this page.) Clothing. Tetraaminobenzene t ™ \ ethoxyethyl \ j / amine propionyl 1 t t SF2: 3 3 I Η 6 8 solid π, color cc C Tangerine ::: 4a t; 4

Μ / {V ο 2 ethoxyethylamine benzyl aniline two containing will be printed on the base gas ethyl amine amine benzylamine phenyl nitrate Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs% ο 1L slow liquid mixture containing alcohol ethyl Contains to slow alcohol B to heat ΠN will filter through P 5 2 to cool 0 Hours small 6 a_ Stir and warm. Same as ° c ester of ethyl acetate and then condensed with air filtration to wash 0 alcohol B. Medium release X 2 / V The water layer machine has water and salt, and is thinner than the DEK solution. It removes the evaporative true filter 咼 I is dry and dry. The acid sulfur water has no%. The paper size is applicable to China National Standard (CNS) A4 specifications. (210X 297mm) 513415 A7 B7 V. Description of the invention (") Production of crude products produced by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, a brown viscous oil. This material can be directly used in the next step without purification. Following the above-mentioned preparation method, 2- [2- (4-methyl-benzylamino) ethoxy-6-nitro-aniline (3-b) 5 2-nitro is used. -6-Γ 2-(U-rich phen-2 -ylmethyl) amino] ethyl chloride] aniline (li), 2-1 2- [(Dream-1 ~ ylmethyl) amino] ethyl chloride ~ 6 -Nitro-aniline (d_) 5 2 ~ IL 2-(3, 4 -dihydro- 1 Η-isoiffolin-2 -yl) ethoxy] -6 -nitro-aniline (3_e · ), And 2-(3 -benzylamine-propoxy) »6 ~ nitro-benzylamine (11 _) can be obtained: 4b 3-Γ 2 4 -methyl-benzylamino) ethoxy] -benzene -1,2 ~ Didiamine mixed with white solid (79.4%), melting point 7 7-7 9 ° C JMSEI m / e 2 7 1 () 〇 Elemental analysis * Ci6 H21 N 3 0 Calculated value: C, 7 0.8 2; Η, 7.80; Ν, 1 5. 4 9 Richness value: c, 7 0.5 3; Η, 7.89; Ν, 1 5. 5 0 4 c 3-{2 r (_phen -2 -Methyl) amino- * ethoxy) benzene-1,2-amine Perkin oil (70,0%); MS EI μ / e 2 6 3 (Μ +) 0 £ d 3 {2 [(fluoren-1-ylmethyl) amino] ethoxy} benzene-], 2 : Black oil of amine tetrahydrate (8 2 0%); MS El m / e 3 0 7 (Μ +) 〇 Elemental analysis: C 丄 丨 ^ H2i N 3 0 * 0. 2 5 Η 2 0 Calculated value : C, 7 3.1 7; Η, 6.95; Ν, 1 3. 4. 7 actual value: C, 7 3.2 9; Η, 8.88; Ν, 1 3. 3 0 4 e 3-[2- (3, 4 -Diamino-1 H-isofluorin-2-yl) ethylchloro]-benzene-1, 2-Ling solid (95%), melting point 7 6-77 ° C 〇 It is dihydrogen Chloric acid 0.4 Η 2 0 salt: Μ SEI m / e 2 83 (Μ ") Ο -13- (Please read the precautions on the back before filling this page)

、 1T This paper size applies Chinese National Standard (CNS) A4 specification (210X 297mm) 513415 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (^) Elemental analysis: C 17 H 2 .. Ν 3 0 · 2 HC 1 · 0 · 4 Η 2 0 Calculated values: C, 5 6 · ΐ 7; Η, 6 · fi Ο; Ν, 1 1 · 5 6 actual value * c, 5 6, 1 5; Η , 6.88; Ν, 11, 2 5 4 f 3 3 -benzylamino-propoxy] -benzene-1,2-:: 'Amine amber oil> MSEI / e 2 7 1 f Μ +) 〇Elemental analysis; Cie Η 21 N 3 0 * (κ 3 Η 2 〇 value; c, 8 9, 4 4; Η, 7. 87; Ν, 15. 18 actual value; c, fi 9. 47; Η , 7.82; N, 15.3. 3 0 Similar to the above-mentioned production method 5 2-[2-(4-chloro-benzylamino) ethylchloro] -4 -chloro-6 ~ nitro-aniline (2 above) And replacing 10% Pd / C with Raney nickel 4 g 3-[2-(4 -chloro-benzylamino) ethoxy] -4 -chloro-benzene-1, 2 -di Amine light brown solid (5.0%), melting point 10-9-1 1 CTC Elemental analysis: C L5 Η 17 C 1 2 N,; 0 Calculated value: C, 5 5. 2 3; Η, 5. .25; S 5 12. 8 8 Actual value: C, 5 5. 0 4; Η, 5 .09; N, 1 2. 6 2 4 b 3-L 2-(4 -fluoro-benzylamino) ethoxy] -benzene-1,2-didiamine as a white solid (8 2.4% ), Melting point? 0-7 1 ° C 〇Elemental analysis; Cis Η JB FN 3; Calculated value: 0 · Π .IH 2 〇: C, 6 5. 12; Thallium, 6. 62; N, 1 5.16 Actual value: c, 8 4. 9 4; hydrazone, 6. .52; N, 1 4. 9 3 4 i 3-[2-(4 -difluoromethyl-benzylamino) ethoxy] 'benzene-1, 2 -di Amine white solid Mga Έ ^ (8 7 2%), melting point 9 4-95 ° C 〇-14- (Please read the notes on the back before filling this page) Standard (CNS) A4 specification (210X 297 mm) 513415 A7 B7 5. Description of the invention (G) Elemental analysis C 16 H is F 3 N Calculation letter: C, 5 9. 0 7; Η, 5.5 8; Ν, 12 , 9 2 Actual fluorene: C, 58. 9 3; hydrazone, 5, 2 4; Ν, 1 2. 7 8 4 j 3 1 [2-(3 -Benzyl-propylamino) ethoxy J -benzene- 1, 2-„* Amine oil (72%) MS {+) FAB ιϊ! / E 2 86 (Μ + Η +) 〇 Intermediate 5 a N-[2-(Amine-3-nitrate) -Phenoxy) -ethyl]-N-benzyl-2,2, 1-fluoroethoxyamine will contain 2-( 2 -benzylamine-ethoxy) -6-nitro-aniline (3_a J 0.5 g, 1. 7 4 m in ο 1), — " ethylamine (0 · 5 11) and dichloromethane ( i 〇ΙΏ 1) was slowly added to the trifluoroacetic anhydride (0.3 2 is 1, 2.2 6 ία 〇 2 hours later, the reaction solution was poured to 1 NN a 0Η (5 (1 ffi 1) and Extraction with dichloromethane. Wash the organic layer with water (2 X 50 in 1) and brine (50 ϊπ 1), and dry in anhydrous sulfuric acid _ drying filter m cut ^ ^-Λ.-. ^ \ \ v Remove solvent to get crude yellow substance. Recrystallize from ethyl acetate-hexane to obtain 0.5 5 g (81 • 1%) of a yellow solid, melting point 1 34-1 35 ° C;; M SEI hi / e 38 3 (M) 10 element Analysis; C 1? Η 18 F 3 N 3 0 4 Calculated value C? 5 3. 27; Η, 4.. 2 1; N, 1 0 8 9 6 Actual value: C, 5 3. 0 9; Η, 4 , 3 5; N, 10. 3 3 (Please read the notes on the back before filling this page).

1, 1T The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the above-mentioned production method, using 2- (2-benzylamino-ethylchloro) -4-chloro-6-nitro-aniline (_! _!) To obtain: 5 b 2- (2-Amino-5-chloro-3-nitro-phenylchloro) ethyl] -N-benzyl-2,2,2-trifluoroethyl-amine as a yellow solid (7 6 · 9%), melting point 10 6 -1 0 8 0C; MS (+) FAB ra / e 4 1 8/4 2 0 (M + H) 4 〇-1 D-This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) 513415 A7 B7 V. Description of the invention (κ element analysis C ifi Η Calculate nr Η Real value ο 5 3 Η 6 Intermediate amine 8 2 6, ethyl (1 fluorooxy Group I 3-phenyl- amine amine diethylbenzyl-ethyl 2-Π fluoro-tri-N containing, 2 will, 2 groups 4 nitrate ο-3, a a | (5-amineamineoxy ethyl benzyl% ο Contains alcohol and alcohol, alcohol and alcohol cold_ 1 empty oil 逑. Concentrated Q is really thick on time and space 1Π. Sticky imitation of small true, 滹 color-based filter i, m ο through ester οο, ethyl ί.π ° c acid solution 2C ethyl salt is dropped to food and then steamed. 1 liquid is mixed and filtered to stir the water temperature. Wash the same with alcohol and add P to slow 60 Slow 5-touch? SI5 will ^ ^ ^ of _, / ΠΜ) force X (2 over brown water, which is dry 丨 layer dryer _ with sulfuric acid release water without dilute n, 0 πυ ^ < 7T rate product production crude% -------- clothing-(Please read the precautions on the back before filling out this page), 1T use! Shiji, benzyl method N system ~ Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperatives Printed in 4 colors 9 "-, J1K8 F / i Press 3--t IC-of / jI $ 87H > 丨 L 3 W. 7 ~ 0 J Ν Ν θ Γ ~ I B / 基 Λ 基 Fluoro m group 卞 卞 一Di FI-\ | NJ Ν 2 + Τ Amino si Amine B-5 (9 2 »Fluoro-based oil 7 Triamine thick chlorine analysis value calculation Intermediate factor calculation Real time element 〇 \) / 2 papers Standards are applicable to China National Standard (CNS) A4 specifications (210X 297 mm). Chlorobenzene% base: nitrate 3 printed by the Consumers Cooperative of Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs 513415 A7 B7 5. Description of the invention (A) 4-Chloro-2 ~ (2 ™ chloro-ethoxy) -6-_yl-aniline will contain 2- (2-aero-ethoxy) -β-nitro-aniline (main soil, 3 0. 0 g 5 Ο β ί 4 —〇1), N-chlorobutamine and acetonitrile (1.3L) were refluxed for 4 hours. Concentrate in vacuo and dilute with ethyl acetate (50 0 Nii). The organic layer was washed with water (2X, 250 ail) and brine (250 in 1), dried over anhydrous sulphuric acid, filtered, and evaporated in vacuo to obtain an orange solid. Crystallize from ethyl acetate to hexane to obtain 33.5 g (35.3%) of an orange solid, melting point 10-9-110. (]; MS El ffl / e 2 5 0/2 5 2/2 ο 4 (Μ 4) 〇 Elemental analysis: C 3 Η s C 1 2 Ν 2 〇3 Calculated value: C, 38,27; Η, 3.21 ; Ν, 11 · 16 actual value: C, 3 8 ·] 5; Η, 3. 1 0; Ν 5 1 0 · 9 6 Example 1 [2 ~ (1Η-benzoxazol-4-yloxy) Ethyl] benzylamine heated 4-(2 -chloroethoxy) -benzoxazole (1.0.39 g, 1.98 in in ο 1) and benzylamine (9 m 1) to 1 0 0-1 i 0 ° C 3.5 hours. Concentrate the solvent in vacuum (50-(TC / 0. Ί mm), pour the reaction solution to 1 NN a 0 Η (50 in 1) and use ethyl acetate. Ester extraction (2 X, 50 m 1). Combine the organic layers, wash with water (100 m 1) and brine (100 hi 1), dry over anhydrous sulfuric acid, filter, and evaporate the solvent in vacuo. 0.58 g of a viscous yellow oil was obtained. Purification by chromatography (6S) g silica, dichloroethane-0, 5% 2 M N Η 3 in methanol) gave 0, 3 6 4 g (6 8 · 7%). ) Yellow oil. Dissolve it in ethyl acetate-methanol and treat with excess hydrogen chloride to give the title compound (0.3g, 5S.5%) as a white solid, melting point 2 56 ~ 2 5 9 ° C; MS Ε ΐ m / e 2 β 7 (Μ + ). This paper size applies to Chinese National Standard (CNS) A4 size (210X 297 mm) (Please read the notes on the back before filling in this I) · Clothing · Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative 513415 A7 B7 V. Description of the invention (4) Elemental analysis: C 18 Η 27 N 3 0 · 2 HC 1 · 0.5 Η 2 〇 Calculated value: C 5 5 5 · Ο 2; Η, 5. 7 7; Ν, 1 2 · 0 3 Actual value: C, 5 5 · 2 6; Hf, 5 · 6 9; N, 1 2. 0 3 Example 2 Benzyl- [2-(2-methyl-1 fluorene-benzoxazole- 4-Alkyloxy) ethyl] amine is 3-(2-benzylamineethoxy) -benzene-1,2-diamine (Earth 0.35 g, 3 6 mm 1) and acetic acid ( 1 (1 m]) at reflux for 14 hours. The solvent was concentrated in vacuo (50-60 ° C / 0.1 1 «) and the residue was dissolved in ethyl acetate (50 ml). The organic tincture was washed with 1 NN a 0 H (50 0 κι 1), water (100 m 1) and brine (100 m 1), dried over anhydrous sulfuric acid, filtered, and the solvent was evaporated under vacuum to obtain Crude. Purification by layering (35 g of silica gel, ethyl acetate-1% 2 M N Η 3 in methanol) gave 0.29 g (76.3%) of a brown solid foam soda ash. It was immersed in ethyl acetate · methanol, and treated with an excess of N hydrogen chloride to obtain the title compound ((K 3 3 g, 90.0%)) as a white solid, m.p.> 2 50 ° C; MS El m / e 281 (M +) 〇 Elemental analysis: C π H j9 N 3 0 · 2 HC 1

Calculated: C, 5 7 · 6 3; H, 5 · 9 7; Ν, 1] · 6 I Actual: C, 57.23; Η, 5.89; Ν, 12.86 Example 3 Benzyl- [2_ (2 ~ 3 Fluoromethyl-iH-benzoxazol-4-yloxy) ethyl] amine N- [2-(], 2-diamino-phenyl-3-yloxy) -ethyl] benzyl -2,2,2-Trifluoroacetamidamine (6a, i.Og, 2.83 ramol) and trifluoroacetic acid (10 ml) were refluxed for 4 hours. The solvent was concentrated in vacuo (50-60 ° C / Q. 1 ϊπ κι) and the residue was dissolved in ethyl acetate (150 ml). The organic layer was washed with IN Na0H (50ml), water (100ml) and brine (10Ginl), dried over anhydrous magnesium sulfate, filtered, and vacuum-steamed_ 1 8-This paper applies to Chinese National Standard (CNS) A4 size (210 '乂 297mm) (Please read the notes on the back before filling this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 513415 A7 B7 V. Description of the invention () A thick oily substance can be obtained by removing the solvent. Purification by chromatography [1 4 0 8 Si—, ethyl acetate-hexane-2 MN N Η 3 in methanol (] 0:] 0: Π] to obtain 0.86 g (70.7%) ^ benzyl- 2,2,2-trifluoro 1- [2- (trifluoromethyl-1} 1-benzoxazol-4-yloxy) ethyl] ethanamine as a brown solid; MS EI ffi / e 4 3 1 (Μ +) 〇 N-benzyl-2,2,2-difluoroL 2- (difluoromethyl-1Η-benzoxazole-4 -yloxy) ethyl] acetamide ( 0 · 7 8 g, 1 · 8 0 m is ο 1), 6%; methanol (35 ml) and potassium carbonate (1.7 g) are refluxed for 3 hours. Cool to 25 ° C, and pour water (2 Π 0 m 1) and extracted with ethyl acetate (3 X, 150 m 1). The organic layer was washed with water (200 ml) and brine (2 0! Hi), and sulfuric acid in -fnr m water _Dried, filtered, and distilled off the solvent in vacuo to obtain the solid JE koji residue. Crystallized from ethyl acetate to obtain 0.50 g (8.3. 5 ° / 〇) benzyl- [2--(2-difluoromethyl) Benzoxazole-4 -yloxy) ethyl] amine reference 0 " 2 5 ethyl acetate as a white solid, melting point 130-13 1 ° G; MS E I m / e; 3 3 5 (M +) 0 Elemental Analysis: C i? Hie F 3 Ν 3 0 * I 3. 2 5 C 4 Η 8 〇2 Calculated value: C, 6 0. 50; Η, 5.! 3 8; N, 11 7 6 actual value: C? 6 0. 5 4; fluorene, 4.! B 5; N, 12 Γ7 2 benzyl-t 2- (2-~ 'fluoromethyl-: iH-benzoxazol-4-yloxy) ethyl > amine * 0. 2 5 ethyl acetate (0.4 ^, 2. 6 11 m 〇1) was dissolved in an ethyl acetate-methanol mixture, and treated with an excess of 1 N hydrogen chloride to obtain the title compound (0.35 g, 79.1 %) As a white solid, melting point 194-19 5CC; MS Ε I 1/0 3 3 5 (M +) 〇 Elemental analysis: Π 17 Η 19 Ν-:; 0 • HC 1 Calculation: C 5 5 7 , 6 3! * Η, 5.! 37; N, 11 .8 1 Actual value: C, 5 7. 2 3 1 Η, 5 J 3 9; N, 12.8 fi-1 9- This paper size applies China National Standard (CNS) A4 specification (210'〆297 mm) (Please read the precautions on the back before filling this page) Clothing, 1T Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 513415 A7 B7 V. Description of the invention (D) Example 4 (4-methylbenzyl)-[2- (2-trifluoromethyl-1H-benzene Benzoxazol-4-yloxy) ethyl] amine method 5 of Example 2 uses 3- [2- (4-methyl-benzylamino) ethylchloro) -benzene-1, 2-diamine ( (Above) and trifluoroacetic acid can be obtained: (4-methylbenzyl)-[2-(2-trifluoromethyl-1 fluorene-benzoxazole-4-yloxy) ethyl] amine 0 · 2 5 ethyl acetate as a white solid, melting point 1 54-15 8 ° C; MS El i / e 349 (Μ +) 0 Elemental analysis: CisHisF3 Ν3 0 * 0. 2 5 C 4 Hr 0 2 Calculated value: C , 6 1 · 4 5; H, 5 · 4 3, · N, 1 1 · 3 1 Actual value: C, 6 1 · 4 7; H, 5 · 4 0; N, 1 2 · 2 7 (4- Methyl benzyl)-[2- (2-difluoromethyl-1H-benzimidazol-4-yloxy) ethyl] amine diacid white solid (9 0 · 1%), melting point 2 3 0- 2 3 3 $ MS EI 1 / e 3 4 9 (Μ +) 〇 Analysis: C 18 Η? F 3 Ν 3 0 * 2 Η C 1 Calculated: C 9 5 1. .20; Η, 4.77; Ν, ί 3.95 actual value: C 5 5 0 .92; Η, 4.69; Ν,! 9.89 Example 5 [2-(2-benzyl-1 fluorene-benzoxazole-4 -yloxy) ethyl]-( 4-methylbenzyl) amine in the same manner as in Example 2 using 3- (2- (4-methyl-benzylamino) ethoxy-benzene M, 2 -Diamine (2) and Phenylacetate are available ...

[2- (2-benzyl-1'-benzoxazol-4-yloxy) ethyl]-(4-methylbenzyl) amine dihydrochloride white solid U 5 · 8%), melting point > 2 5 0 ° C-2 0-This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) (Please read the precautions on the back before filling this page). Order 513415 A7 B7 V. Invention Description (θ

s M / m -r 6 3 s 8 4 5,, 2 4 4 H 6 8 24,, ccc analysis value calculation unit calculation 6 yuan example ο 6 2 5 _— 一 1I ^ ~~ _ C .. Η 6 8 2 6 4 one! 3 Benzyl benzyl I 4 / | \ '2 rir ^ ethyl ethene pentafluoride 2 2 2 acene I Η benzyl ethyl rs ethoxy amine 3 2 cases of imityloxyethyl \ 1 | / amine amine benzyl 1 yl toluene to obtain propyl fluoride pentoic acid and 4/4 bl / IV amine di {(yl)-* oxyl group 4-methyl --_ 4 {midacene Η — 1—I! \) / Ethyl Fluoride Pentasine Fixing White Matter Hydrate 5 2 11 Amine J Ethyl ----------- (Please read the precautions on the back before filling this page ). Analytical value of 3 points 5. Prime solution Π element solution ° c ο 9 I 5 8% melt 5 F Is Η: Η c 4 5 Η β 9 S Μ 2 Η 5 2 M / \ 9 9 3 Θ / 1 β 9 、 1Τ value of real 3 3 3 3 5 5 6 6 7 Benzyltoluene ——1! \ Ί / ethyl ethylene fluoropentamine 1J · ethyl ethyl J basic oxygen fixation of white hydrochloric acid chloride% 7 9 solution ρ ο 8% molten S Μ + Μ / {V 9 9 3 Θ / 印 Calculation of the element value printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic AffairsΗ 19 c

in F 6 3, group C methylamine I: group 3 value ~ i real? Hope} Example blind base 2 5 3 2 ο C Η

3 4 H-methyl methyl fluoride Three paper sizes are applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 4 5 Zolconophenoxy 513415 A7 B7 V. Description of the invention (/) Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs The method of printing example 2 can be obtained by using 3-{(_phen-2 -ylmethyl) amino] ethoxy} -benzene-1,2-diamine (4 cj and --C ^ S acid : M phen-2 -ylmethyl-C 2-(2 -trifluoromethyl-1 pyrene -benzo-B-pyridinium-4 -yloxy) ethyl] amine L 6 hydrochloric acid Pro UXL brown solid (58.3%), melting point 1 8 4 cc% MS EI in / e 3 4 1 (M +) Elemental analysis: C 3 H IB FEN III 0 · 1. 6 HC 1 Calculated value c, 4 4. 98?? , 4 .04; N 5 10 .3 8 Actual value: c, 4 4. 9 9 Η, 4 .05; N 5 10 • 33 Example 8 Benzyl- [3 2-trifluoromethyl- 1 Η-benzene Benzozole-4 -yloxy) propyl J amine Example 2 method using 3- (3-benzylamino-propoxy) -benzene-1,2-amine (· 4 -f) and fluorine Acetic acid Obtained: benzyl-r 3 -f 2 -trifluoromethyl-1 H -benzoxazole + yloxy) propylamine hemihydrate as a brown solid body (57.6%), melting point 50- 70 ° C > MSEI m / e 3 4 9 (M +) 0 Elemental analysis; C is H ip F, i N 彐 0 * 0. 5Η 2 〇 Calculated value: C, 6 0. 3 3 Η, 5. 34; Ν J 11 .7 3 actual value: c, 6 0. 3 4 fluorene, 5. 30; Ν 11 .84 group- [3-(2 -trifluoromethyl-1 benzoxazole + yloxy ) Propyl] amine. —I α chloric acid m stxl white solid (98%;), melting point 19 4-1 7 7 ° C > MS: EI 1 / e 34 9 (M +) 〇 Elemental analysis: c JB H 18 F-:; Calculated value of N 彐 0 * 2 Η Cl; C, 5 1, 2 0 Η, 4.77; Ν 5 9. 9 5 Actual value: c, 5 1. .9; Η, 4 .49; Ν, 9. 86-2 2-(Please read the notes on the back before filling out this page) «Installation ·

、 1T This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 513415 A7 B7 V. Description of the invention (M) Example 3 Basic — f 2-[2-(], 1, 2, 2, 2 -Pentafluoroethyl)-1 H-benzenemazole-4 -verylchloroethyl ethyl} amine method 2 using Ν-f '1- (1,2,2 1 gyl-benzene-3- Alkoxy) -ethyl Λ-N-benzyl-2, 2, 2, 2-difluoroacetamidamine (i_a) and pentafluoropropionic acid can be obtained: benzyl- {2 _ |: 2-(1, 1 ， 2,2,2-pentafluoroethyl) -1 fluorene-benzo-Bwawa-4-yloxyj ethyl} amine as a white solid (59.8%), melting point 15 2 -1 5 3 ° C Decomposition MS Ε I Η 1 / e 3 8 5 (M +) 〇 Elemental analysis; C 1 :: Hie F,, N 彐 0 Calculated value: C, δ 6. .11 Η, 4.. 1 9; N 5 1 0 .9 1 Actual value: C, 5 6. 0 2 5 Η, 4. 1 〇; N 5 10 .7 3 benzyl-{2 a \ [2- (1, 1, 2, 2, 2-5 Fluoroethyl)-1'-benzoxazole (Please read the precautions on the back first (Fill in this page), 1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs-4 -yloxy] ethyl} amine hydrochloride 0.75 white hydrate (6.94%), Melting point 1 2 0-1 3 5 eC; MS (+) ES was m / e 3 8 6 (M + Η +). Elemental analysis: CisH16F5 Ν3 0 · Ο. 75Η 2 〇 Calculation: C, 4 9 · R?; Η, 4 · 2 8; Ν, 9 · 6 5 Actual letter: C, 4 9 · 8 8; Η, 3 · 9 5; N, 9.6 6 cases 10 fluorenyl-butylmethyl-f 2-(2 -trifluoromethyl-] fluorene-benzoxazole-4 -yloxy] ethyl] amine The method of 2, using 3- {2 _ [(Le-ylmethyl) amino] ethenyl) -benzyl-1, 2-diamine () and trifluoroacetic acid can be obtained: "2-(2 -trifluoromethyl-1 Η ~ benzoxazole-4 -yloxy-23-this paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 513415 A7 B7 V. Invention Explanation (") λ ethyl] amine as a white solid (6 3 .1 ° / 〇)? Melting point] 3 0 ~ 1 3 3 ° 0; Μ Ε I hi / e 3 8 5 (Μ +) 〇 element Analysis: C2i Η is F 3 N 3 0 Calculation: C, 6 5. 4 5; H, 4. 7 1; Ν, 1 0.90 Actual value: C, 8 5. 2 8; H, 4. 4 3; Ν, 1 0.57 Zero-1 -ylmethyl-r 2- (2-trifluoromethyl-1 1 fluorene-benzoxazole-4 ~ yloxy > ethyl) amine hydrochloride as a white solid 9 4 • 8%), melting point 2 0 8-2 η 9 ° C decomposition; MS Ε I m / e 3 8 5 (Μ +) 〇 Elemental analysis: C21 Η is F 5 N 3 0 · HC 1 Calculated value: C, 5 9. 7 9; Η? 4. 5 4; Ν, 9 • 96 actual value: C, 5 9. 3 9; Η, 4. 4 5; Ν, 9. 8 1 (Please read the Please fill in this page again.) Example 1 1 Enzyme-2 -ylmethyl- [2-(1 Η -benzoxazole-4 ~ yloxy) ethyl] amine method of Example 2, use 3-{(Wanpan-2_ylmethyl) amino] ethoxy) -benzene-1, 2-diamine (and formic acid is available: phen-2-ylWyl- [2-UH-benzene Viscosity oil of amidolazolyloxy) ethyl] amine tetrahydrate (63. 2%); MS E I m / e 2 7 3 (M +). τπ prime analysis: C μ H d 3 〇S * Ο. 2 5 Η 2 〇 Calculated value: C, fi 〇 H Η, 5. 6 2; Ν, ΐ 5 · 1 2 Actual value: C, 60.85; Η, 5,49; Ν, 15.39 _phen-2 -ylmethyl-Γ2- (1 fluorene-benzoxazol-4-yloxy) ethyl] amine dihydrochloride hemihydrate as a white solid (6 9.2%); melting point 2 4 8 -252 CC; MS El m / e 2 7 3 (M +) c -2 4-This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm). Printed by the Central Consumers ’Cooperative of the Ministry of Economic Affairs 513415 A7 B7 Printed by the Central Consumers’ Cooperative of the Ministry of Economic Affairs ’Consumer Cooperatives V. Description of Invention (4) 7Π Analysis: C 14 Η 15 N 3 〇S · 2. OHC 1 · 0, 2 5 H 2 Bina AA- mesh ten appreciation: C, 4 7.3 3; Η, 5.11; N, 11.83 actual value: C, 4 6.6.9 5; H, 5,13; N, 11.73 Example 1 2 (4- Methylbenzyl)-| '2- "2-(], 1,2,2,3,3,3-heptafluoropropyl) -1} 1-benzoxazolyloxy] ethyl) amine The method of Example 2 using 3- (4-methyl-benzylamino) ethoxy] -benzene-I, 2-diamine (0) and heptafluorobutyric acid can obtain: (4-methylbenzyl) -{2-[2-(], I · 2, 2,3,3,3-heptafluoropropyl)-] fluorene-benzimidazol-4-ylchloro] ethyl} amine as a white solid (63.7%), melting point] 4 4-1 4 f ) ° C; MS Ε I id / e 4 4 9 (Μ +). Elemental analysis: C Η 1? F 3 Ν 3 〇 Calculated values: C, 5 3 · 4 6; H, 4 · 0 4; Ν, 9 · 3 5 Actual value: f :, 5 3 · 2 3; H, 3, 6 9; Ν 5 9,1] (4 -Mehenhen)-{2-: 2-(1,1,2 2,3,3,3 _ heptafluoropropyl) ~ 1 Η-Judoxazole-4-yloxy] ethyl} amine 1.5 hydrochloride as a white solid (87. Β%); ] 98 — 199.5 ° C; MS El m / e 4 4 9 (M +) 〇 Elemental analysis: C ′. 9 HF 7 N 3 〇 * 1 · 5 HC 1 Calculated value: C, 47.66; H, N, 8.34 Actual price: C, 4 7 · 4 7; H, 3 · 7 6; N, 8 · 2 4 Example 1 3 2- Γ2- (2-trifluoromethyl-fluorene-benzofluoren-4-yloxy Ethyl] 2,3,4-tetrahydroiso__ The method of Example 2 uses 3-Γ 2-(3,4 -dihydro_ 1 Η -isoxoline-2--2 5-this paper Standards apply Chinese National Standard (CNS) Α4 specifications (21〇X 297 mm) (Please read the precautions on the back before filling this page) Clothes · Order 513415 A7 B7 V. Description of the invention (/) oxyethyl v) ^ aniline ethanoic acid trifluoromethane and trifluoromethyl ethoxyl I 4 exhausted imidazobenzene tetrasodium color fixation white substance tetrahydrate if iso % ¾ melting ° c element 18 ο 2 偾 calculation Η C value of real methylfluoro tri-t-ethyl ethyl \ ί / alkoxy 4 1 oxazobenzo fixed color white chlorohydrogen diquine hydrochloride η ^四 4% isohydrogen (please read the precautions on the back before filling in this purchase) clothing. Point melting point ° c ο) / 18 Η 19 C Calculate the element C value I 2 I Chlorooxy 1 4 I _ Pyrophenylethylamine. VV / V · 2 of 2 cases / 1- oxyphenylethyl, amine 2 S ί f ^ E T fluorotrifluoro 2-Acid 5-Ethylfluramine T32 and benzylethyl TTV printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs.

/ TJ E elementary elementary calculation 偾 实 实) / H 2% 7 azole 1 眯 1 ~ 17 benzo point oxy group ° c This paper size applies Chinese National Standard (CNS) A4 specifications (210X 297) (%) 513415 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (<) Benzyl- [2-(β-chloro-2 fluoromethyl-1 Η Η-笨 眯 眯 4-基Oxy) ethyl-amine as a white solid (73.4%), melting point 2 10 -2 1 2 ° C; MS -E I m / e 3 6 9 (M +) ο Elemental analysis: Cj7 Η 15 C 3 F Ν 3 〇 * HC 1 Calculated value: C, 50. 26: Η, 3. 9 7; Ν, 1 0. 3 4 actual value: C, 5 0. 2 9; Η, 3 · 8 1; Ν, 1 0. 3 2 Example 1 5 4-Chloro-benzyl-Γ 2- (6-chloro-2-trifluoromethyl-1H-benzoxazol-4-ylchloro) -ethyl] amine The method of Example 2 can be obtained by using 3- [2- (4-chloro-benzylamino) ethoxy] -4-chloro-benzene-1,2-diamine (present) and trifluoroacetic acid: 4 -Chloro_benzyl- Γ 2-ί 8-chloro-2-fluoromethyl ~ 1 Η-benzoxazole-4 -yloxy)-ethyl J carbamate Color solid (? 9.6%), melting point 19!-19 3 ° C;: Μ Ε I m / e 4 0 3/4 0 5/4 0 7 (Μ +) 〇 Elemental analysis: C | 7 Η Μ C 1 a F Ξ ^ Ν 3 0 * C 4 Η 4 〇4 Design letter: C, 4 8. 4 8 Η, 3. 4 9; Ν 5 8.08 letter: C, 4 8. 17 3 Η, 3 .2 6; Ν 8.11 Example 1 8 (4-chloro-benzyl)-2-r 2-(2 fluoromethyl-1 fluorene-benzoxazole-4-yloxy) -ethyl J amine Method of Example 2 > (4 -Chlorochloride can be obtained by using 3-[2-(4-fluoro-benzylamino) ethoxy] -benzene-1, 2-_. Amine (4 A) and thiofluoroacetic acid -Benzyl}-2-plant 2-(2-difluoromethyl- 1 ii ~ benzobenzo 11- 4 -yloxy) -ethyl] amine hydrochloride hemihydrate white solid (5 0.4%) This paper size applies to Chinese National Standard (CNS) A4 (210X 297mm) (Please read the precautions on the back before filling this page)

513415 A7 B7 V. Description of the invention (4 Black melting ρ 〇 // Calcium element Η Blind calculation 111-1 Π Real letter Η Example Ethyl ethyl I \ 7-yloxy I 4 Izozolo benzo I I 7 Amine ) -Methylfluorobenzyl-1 „rL ί Ν). 3 II 3JJ 4 I use {make? S, two methods 2--square 1, Zhi- radical 2 Example" j fluoroformyl trioxyphenyl methyl fluoride Triphenylethyl \ f / Benzylamine Benzyl trifluoromethyl Fluoride Trimethyl chloride Fluoryl trifluorochloride: The substrate obtains oxygen solid ketochromic acid 4 white and 2 * U | ----- ^^ 衣-(Please read the precautions on the back before filling in this page) CCJP,, occ C 9 U: + * 8-Analyze Qianxin's 18-point interstitial voxel meter melting point Η Η

、 1T Examples of amine propyl 1 phenyl 3 ethyl methyltrichlorotrichloro-4 ί 1? Printed Example of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of Pyridene ； B cc I Π.} 7% ί Amine-to-body (3 ketoformic acid methyl color ethane fluoro white 3 0 1 one | the use of three 2-salt and-(acyloxyethyl \) / group Aminopropylphenoxy 1 4-azole_acene% ¾ 9tHJ, the size of the fused paper is applicable to the Chinese National Standard (CNS) Α4 size (210X 297 mm) 513415 Printed by the Central Consumers Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperatives Element element education /! Calculate ΪΙ ^ ίϊ 111-lnr Xinji Shiji 9 Keqi 0 also promotes the device to accept the secretion SB Leucamine Baduo is a chemical compound Mingfa Liba Drug 0 Treatment of multiple symptoms It is listed as a trust and can be used for C's Morin release and release, and the symptomatic and singular amines can be divided into quinones, which are often used to promote the use of sacred drugs. After receiving 2 D ο amine entanglement and multi-drug therapy, hematoxylin and esophagus therapy should be treated with pharmacological agents. Vado body from amines and fixed (Please read the notes and then fill in the back of this page)

Same as "not repairing d ¢, i §trηα π its} ¾ shot αΠΓΒΙ, π put Ifamr, -.3 force ϊηο fixed U plate ΰ at JQ s' it Y p net f flat. E 1 e _ affinity c And _—- r / \ i, Θ ο ΓΛ ancient question 7t R-i-: 9 Γ square p and 1 e 0 n device, lt * T1 3 *-. 〇0 JT Π-, subject to 7 i Wash 2 5 ffl quasi-H clear β, Ώ 檫 3, amine 36Γa, filter bar, 101 91 over-cultivation S.% 9 ee 1 Vr 5 R: N weaving concentrated _ _ under the substance '' quality uniform test The brain-like striae B of the set of human-weaving group is strong, the person and the person are equal to each other > m is the order of the actual cleansing and clearing of the brain, n marginalization 10 side test at the quality test 均 will be mixed with the same solution and shot Γ} Let θ Γ, ρ ο i V be ρ 1 rhH, sf Tear one (ο T1 PX and G dd y. Method -1 Η Square er is calculated by the number of calculators 〇 Shoot fruit release CD test ο Test 6 „4 d The ar and ck chemistry tables are issued in lieu of Ming S) 1C This paper size is applicable to the Chinese National Standard (CNS) A4 specifications (210X 297 mm) 513415 A7 B7 V. Description of the invention () Example number IC50 (nM) D2 Quin. IC5〇 (nM) D2 Spiper ratio 1 26.75 one—— 2 8.85 339 38.3 3 0.36 23.7 65.8 4 0.74 29.9 40.4 5 54.8 2159 39.4 6 1.44 66.5 46.2 7 1.03 37.35 36.3 8 86.76 1456 16.8 9 1.41 41.88 29.7 10 0.86 81.5 94.8 11 52.8 -----12 5.12 118.0 23.0 13 8.00 314.4 39.4 14 1.42 150.5 106 15) 7.77 395.0 50.8 16 0.74 49.0 66.2 17 1.16 87.0 75.0 18 0.56--------------- * Clothing --- (Please read the precautions on the back before (Fill in this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Therefore, the compound of the present invention can affect the synthesis of the neurotransmitter dopamine, and thus can be used to treat dopamine system abnormalities, such as schizophrenia, Parkinson's disease, and Toles Disease, alcohol dependence, caffeine addiction, and drug addiction. The solid carrier used in the pharmaceutical composition containing the wood invention compound may contain more than one as a fragrance, lubricating surface, stabilizer, suspending agent, filling agent, solubilizing surface, compression agent, binding agent or particle dispersing agent or capsule-making agent. . In powder, the carrier may be a finely divided solid and mixed with a finely divided active ingredient. In the tablet, the active ingredients are mixed in an appropriate proportion to have compressive properties. 3 (1-This paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 mm). Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 513415 A7 B7 V. Description of the invention (Qiao) The carrier is filled with the desired shape and large Φ. The powder and lozenge should contain up to 99% of active ingredients. _ When the solid carrier can be calcium phosphate, magnesium stearate, 5 sugar, lactose , Dextrin, powder, Minggu, cellulose, methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidine, low melting wax, and ion exchange resin. Liquid carriers can be used to prepare solutions, suspensions, Emulsions, slurries, and additives. The actives of the present invention can be dissolved or suspended in a pharmaceutically acceptable carrier, such as water, an organic solvent, a liquid mixture or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives, such as a dissolving agent. , Emulsifiers, buffers, preservatives, sweeteners, fragrances, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers or osmotic agents. Suitable liquid carriers are suitable for Oral and parenteral administration, water (preferably containing saccharin additives, such as cellulose derivatives, preferably carboxymethylcellulose sodium solution), alcohols (including monohydric alcohols and polychlorohydrins, such as ethylene glycol ) And its derivatives and oils (such as layered coconut oil and peanut oil). For non-parenteral administration, the carrier may be an oil ester such as ethyl oleate and isopropyl myristate. Non-liquid carriers can be used in non-liquid forms纟 B product is administered as a non-yang stomach. Liquid pharmaceutical composition is a solution or suspension can be administered intramuscularly, intraperitoneally or subcutaneously. No solution can be administered intravenously. Oral administration may be Liquid or solid composition form. The official preparation is to prepare the compound into a dosage form such as a tablet or capsule. In this case, the composition can be divided into smaller doses to contain the appropriate amount of activity; The form can be a packaging composition, such as a small package of powder, vials, ampoules, pre-packed syringes or sachets containing liquids. This unit dose can be in accordance with the Chinese National Standard Season (CNS) A4 specification (210X297 mm) ) (Please read the notes on the back before filling in this page ^ 衣 I ----! 1 Order 5134 15 A7 B7 V. Description of the Invention (K) The capsule or lozenge, or may be any appropriate number of components in this packaging form. The dosage for the treatment of a specific mental illness shall be determined by the health. Its variables include the specific mental illness type, disease & Size, age, and anti-mushroom form. (Please read the precautions on the back before filling out this page) -18s =-=-:-1-gi 3 si Ε-ί- -I- Order the staff consumption of the Central Standards Bureau of the Ministry of Economic Affairs The paper size printed by the cooperative is applicable to the Chinese National Standard (CNS) A4 (210X 297 mm)

Claims (1)

513415 __———— ～ ------- I ^ 1 '? * • T nd I ---------?: Taxi _ ------ Sixth, the scope of patent application 87th 1 0 1 27 No. 5 "Aminoalkoxy-1 -1-benzimidazole compounds and their pharmaceutical compositions with synergistic effects of dopamine receptors" (Amended in September 2011) Application scope of patents A compound of formula (I), _R3 R2 where R is hydrogen'difluoromethyl'pentafluoroethyl, heptafluorodiyl, linear or branched Ci-6 alkyl or benzyl, which may be selected from 1 to 3 substituents from halogen, amine , Nitro, hydroxyl, and Ci I alkoxy substituted R2 is hydrogen or C1-6 alkyl; R3 is hydrogen, straight or branched Ci_ig alkyl, cyclohexylmethyl,-(CH ^ Ar where Ar is Phenyl, naphthyl, thienyl, furyl, or pyridyl, each of which may be substituted with a substituent selected from halogen, trifluoromethyl and CV6 alkyl; or NR2R3 is 1,2,3,4-tetrahydroquinoline -Bulkyl or tetrahydroisoquinoline-2 -yl; 513415 6. The scope of the patent application is y for hydrogen, halogen or Ch group; m = 1 or 2; η = 1 to 2; or a pharmaceutically acceptable salt thereof. 2 · For example, the compound in the scope of patent application, wherein R3 is benzyl 'substituted benzyl, thienylmethyl, tetrahydroisoquinolinyl, furanmethyl' or cyclohexylmethyl, and R1 is trifluoromethyl or Pentafluoroethyl. 3. The compound according to item 1 of the scope of patent application, which is [2_ (丨 Η_benzimidazol-4-yloxy) ethyl] benzylamine or a pharmaceutically acceptable salt thereof. 4 · 如Transformation of the first scope of patent application Substance, which is benzyl- [2- (2-methyl-1Η-benzimidazol-4-yloxy) ethyl] amine or a pharmaceutically acceptable salt thereof. 5. If the compound of the scope of application for item 1, It is benzyl- [2- (2-trifluoromethyl_1 ^ benzimidazol-4-yloxy) ethyl] amine or a pharmaceutically acceptable salt thereof. 6 · As a compound in the first item of the scope of patent application, It is (4-methylbenzyl) -2- (2-trifluoromethyl-1Η-benzimidazol-4-yloxy) ethyl] amine or a pharmaceutically acceptable salt thereof. 7. As in the first patent application Compound of the present invention, which is [2- (2_benzyl-1′-benzimidazol-4-yloxy) ethyl]-(4-methylbenzyl) amine or a pharmaceutically acceptable salt thereof. Δ. If a patent is applied for The compound in the range item 1, which is (4-methylbenzyl) _ 丨 2- [2- (1,1,2,2,2-pentafluoroethylbull 111-benzimidazole-4- 513415 The scope of the patent application is based on oxy] ethyl} amine or a pharmaceutically acceptable salt thereof. 9. The compound in the scope of patent application No. 1 is thiophene-2-ylmethyl- [2- (2-trifluoromethyl- 1H-benzimidazol-4-yloxy) ethyl] amine or a pharmaceutically acceptable salt thereof. 10. For a compound in the scope of patent application item 1, which Benzyl- [3- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) propyl] amine or a pharmaceutically acceptable salt thereof. 11. For a compound in the scope of patent application No. 1, it is Benzyl- {2- [2- (1,1,2,2,2-pentafluoroethyl) -111-benzimidazol-4-yloxy] ethyl} amine or a pharmaceutically acceptable salt thereof. 12. For example, the compound in the scope of patent application No. 1 is naphthalene-1 -ylmethyl- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) ethyl] amine or its pharmaceutical Allow salt. The compound according to item 1 of the scope of patent application is thiophene-2-ylmethyl- [2- (1 〔-benzimidazol-4-yloxy) ethyl] amine or a pharmaceutically acceptable salt thereof. 14. For example, the compound in the scope of patent application No. 1 is (4-methylbenzyl)-{2- [2- (1,1,2,2,3,3,3-heptafluoropropyl) -111 -Benzimidazole-4-yloxy] ethyl} amine or a pharmaceutically acceptable salt thereof. 15. For example, the compound in the scope of patent application No. 1 is 2-[2-(2 -trifluoromethyl-1H -benzimidazol-4-yloxy) ethyl] -1,2, 3,4 -Tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof. 16. For example, the compound in the first item of the scope of patent application, which is benzyl- [2-513415 6. The scope of the patent application (6-chloro-2-trifluoromethyl-1H-benzimidazole-4-yloxy) -Ethyl] amine or a pharmaceutically acceptable salt thereof. 17. The compound according to item 1 of the scope of patent application, which is 4-chloro-benzyl- [2- (6-chloro-2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl Methyl] amine or a pharmaceutically acceptable salt thereof. 18. The compound according to item 1 of the scope of patent application, which is (4-fluoro-benzyl) -2- [2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) · ethyl Methyl] amine or a pharmaceutically acceptable salt thereof. 19. For example, the compound in the scope of application for patent No. 1 is [2- (2-trimethyl-1H-benzimidazole-4-oxo) -ethyl] _ (4-trifluoromethyl -Benzyl) -amine or a pharmaceutically acceptable salt thereof. 20. The compound according to item 1 of the scope of patent application, which is (3-phenylphenyl)-[2- (2-trifluoromethyl-1H-benzimidazol-4-yloxy) -ethyl] amine Or its pharmaceutically acceptable salt. 21. A medicinal composition having a synergistic effect of dopamine receptors, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound in the patent application item 1 or a pharmaceutically acceptable salt thereof. 22. The pharmaceutical composition according to item 21 of the patent application, which is used for treating schizophrenia. 23. The pharmaceutical composition of claim 21 in the scope of patent application, which is used to treat Parkinson's disease. 24. The pharmaceutical composition according to item 21 of the scope of patent application, which is used for the treatment of Toll (T o u 1 · e t t e). -4- 415415, patent application scope 25. The pharmaceutical composition of item 21 in the scope of patent application, which is used to treat drugs or alcohol addiction.