CN104710419B - Tetrahydropyridine [4,3-b] diindyl compound as well as preparation method and pharmaceutical application thereof - Google Patents

Tetrahydropyridine [4,3-b] diindyl compound as well as preparation method and pharmaceutical application thereof Download PDF

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CN104710419B
CN104710419B CN201510124427.7A CN201510124427A CN104710419B CN 104710419 B CN104710419 B CN 104710419B CN 201510124427 A CN201510124427 A CN 201510124427A CN 104710419 B CN104710419 B CN 104710419B
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diindyl
methoxyphenoxies
tetrahydrochysene
pyridine
tetrahydropyridine
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CN104710419A (en
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李嘉宾
孙崇振
陈孟华
江振洲
严明
薛晓文
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention discloses a tetrahydropyridine [4,3-b] diindyl compound, as well as a preparation method and a pharmaceutical application thereof. The structure formula of the tetrahydropyridine [4, 3-b] diindyl compound is shown in a formula (A), wherein R and R1 are 7,8 c1 10 alkyl, or R does not exist, R1 is 8 c1 10 alkoxy or 6 or 8 halo substituent; R2 is 2 c1 10 alkoxy substituent; n is 1 or 2. The invention further discloses a preparation method of the tetrahydropyridine [4, 3-b] diindyl compound showed by the formula (A) and an application in treating benign prostatic hyperplasia and lower urinary tract syndromes caused by the benign prostatic hyperplasia.

Description

Tetrahydropyridine [4,3-b] a pair of horses going side by side Benzazole compounds, its preparation method and medical usage
Technical field
The present invention relates to tetrahydropyridine [4,3-b] a pair of horses going side by side indole derivatives shown in the novel formula (A) of a class formation, its Synthetic method and prepare treatment α1The related disease of adrenocepter, especially benign prostatic hyperplasis and its cause Application in lower urinary tract symptoms medicine.The present invention relates to pharmaceutical chemistry and chemotherapy field.
Background technology
Benign prostatic hyperplasis (Benign Prostatic Hypertensia, hereinafter referred to as BPH) is common old age Male urinary system disease, its pathogenesis is complicated, and with various enzymes and receptor related, up to the present, the means for treating BPH have Conservative medication and surgical resection therapy.The chemicals for being clinically used to treat BPH mainly has two major classes：α1- AR antagonisms Agent and 5α-reductase inhibitor.Wherein α1- AR antagonist pharmaceuticals are obstructed by releasing lower urethra efferent nervous system, and regulation increases Raw prostate can reach the purpose for alleviating BPH symptoms quickly to the compressing of urethra and the increase of urethral region muscle tone, be mesh One of preceding most commonly used BPH medicines of clinical practice.But due to the α of early stage listing1The urethra choosing of-AR antagonist class medicines Selecting property is not strong, often with a series of side effects such as dizziness, orthostatic hypotensions, therefore can strengthen tissue selectivity to reduce painstaking effort The side effects such as pipe turn into α1The important research direction of-AR antagonists.
α1- AR belongs to the G- G-protein linked receptors of film combination, is distributed in vivo relatively broad, and signal is carried out by cell membrane Transduction, can excite various biochemical activities, be played an important role in a series of physiology courses are adjusted.Research shows：α1- AR is present 3 kinds of hypotypes, i.e. α1A-AR、α1B-AR、α1D- AR, and the α in prostate and urinary tract system1- AR is mainly A hypotypes, main distribution In prostate, urethra and trigone of urinary bladder, therefore α1A- AR is the promising target that current research treats BPH medicines.
The invention provides novel tetrahydropyridine [4,3-b] a pair of horses going side by side indoles α of a class formation1- AR antagonists, bioactivity Result of study shows that test-compound is to α1- AR acceptors have preferable antagonistic activity, point out such compound controlling in BPH There is potential application value in treatment.
The content of the invention
It is an object of the invention to provide a kind of new α1- AR antagonists.
The present invention also aims to provide a kind of new α1The preparation method of-AR antagonists.
The present invention also aims to provide a kind of new α1- AR antagonists answering in benign prostatic hyperplasis is treated With.
The purpose of the present invention is achieved through the following technical solutions：
This kind of α1- AR antagonist analog derivatives, with the structure shown in below general formula (A)：
Wherein：
R1It is 8-F, 8-OCH3, 6-Cl, 7,8-dimethyl
R2It is 2-OCH3
N is 1,2
α of the present invention1- AR antagonist analog derivatives are：
I1：Tetrahydrochysene -1H- pyridine [4, the 3-b] diindyls of the fluoro- 2- of 8- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5- Hydrochloride
I2：Tetrahydrochysene -1H- pyridine [4, the 3-b] diindyls of the fluoro- 2- of 8- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5- Hydrochloride
I3：8- methoxyl groups -2- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5- tetrahydrochysene -1H- pyridines [4,3-b] and Indole hydrochloride
I4：8- methoxyl groups -2- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5- tetrahydrochysene -1H- pyridines [4,3-b] and Indole hydrochloride
I5：Tetrahydrochysene -1H- pyridine [4, the 3-b] diindyls of the chloro- 2- of 6- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5- Hydrochloride
I6：Tetrahydrochysene -1H- pyridine [4, the 3-b] diindyls of the chloro- 2- of 6- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5- Hydrochloride
I7：7,8- dimethyl -2- (2- (2- ethoxy phenoxies) ethyl) -2,3,4,5- tetrahydrochysene -1H- pyridines [4,3-b] Diindyl hydrochloride
I8：7,8- dimethyl -2- (3- (2- ethoxy phenoxies) propyl group) -2,3,4,5- tetrahydrochysene -1H- pyridines [4,3-b] Diindyl hydrochloride
The preparation of compound shown in formula (A), method is as follows：
Reaction condition：A) EtOH, reflux；b)K2CO3/ DMF, 80 DEG C；c)HCl/CH3OH
Specific embodiment
Intermediate substitution -2,3,4,5, the preparation of-tetrahydropyridine (4,3-b) diindyl
Embodiment 1
8- fluoro- 2, the preparation of 3,4,5- tetrahydropyridines (4,3-b) diindyl hydrochloride
4- fluorophenyl hydrazine hydrochlorides 4.86g (30mmol), 4- piperidone hydrochlorides-hydrate 4.60g (30mmol) and 25mL Absolute ethyl alcohol is added in 100mL there-necked flasks, is refluxed 2 hours, stops reaction, naturally cools to room temperature, is stood overnight, mistake Filter, filter cake is washed with 50% ethanol-water solution 5mL, is dried, and obtains slightly yellow crystal 5.35g.Tied again with 80% ethanol 40mL again Crystalline substance, obtains yellow crystals 3.0g.Yield 44.2%, 220 DEG C of decomposition of m.p. ＞.
Embodiment 2
8- methoxyl group -2, the preparation of 3,4,5- tetrahydropyridines (4,3-b) diindyl hydrochloride
With reference to the preparation method of embodiment 1, by 4- methoxyphenyl hydrazine hydrochlorides 5.24g (30mmol) and 4- piperidones hydrochloric acid Salt-hydrate 4.06g (30mmol) synthesis, obtains pale powder 4.20g.Yield 58.7%, 220 DEG C of decomposition of m.p. ＞.
Embodiment 3
6- chloro- 2, the preparation of 3,4,5- tetrahydropyridines (4,3-b) diindyl hydrochloride
With reference to the preparation method of embodiment 1, by 2- chlorophenylhydxazine hydrochlorides 5.37g (30mmol) and 4- piperidone hydrochlorides- Hydrate 4.60g (30mmol) synthesizes, and obtains pale powder 2.50g.Yield 34.4%, 220 DEG C of decomposition of m.p. ＞.
Embodiment 4
7,8- dimethyl -2, the preparation of 3,4,5- tetrahydropyridines (4,3-b) diindyl hydrochloride
With reference to the preparation method of embodiment 1, by 3,4- dimethyl hydrazinobenzene hydrochloride salts 5.20g (30mmol) and 4- piperidones salt Hydrochlorate-hydrate 4.60g (30mmol) synthesis, obtains pale powder 5.0g.Yield 70.5%, 220 DEG C of decomposition of m.p. ＞.
Target compound (A) replaces aryloxyalkyl group -2, the synthesis of 3,4,5- tetrahydropyridines [4,3-b] diindyl hydrochloride
Embodiment 5
The fluoro- 2- of 8- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5- tetrahydropyridines [4,3-b] diindyl hydrochloride Prepare
8- fluoro- 2,3,4,5- tetrahydropyridines (4,3-b) diindyl 500mg (2.21mmol), 1- (2- methoxyphenoxies)- 2- bromoethanes 500mg (2.17mmol), K2CO3610mg and DMF 15mL are added in 100mL three-necked bottles, connect reflux condensing tube, Interior temperature meter, heating stirring, 80 DEG C of temperature control reacts 24 hours.After reaction stops, room temperature is naturally cooled to, filtered, decompression boils off one Half solvent, add water 50mL, ethyl acetate extraction (50mL × 3), merges organic phase, saturated common salt water washing (50mL × 3), nothing Aqueous sodium persulfate is dried overnight.Column chromatography is purified, and eluant, eluent is ethyl acetate: triethylamine=80: 1, brown oil 500mg is obtained, Yield 67.8%.
Upper step product is dissolved in 10mL absolute ethyl alcohols, hydrogen chloride methanol solution is added dropwise to pH ＜ 3, be stored at room temperature overnight, turned Enter refrigerator cold-storage placement, bottom has white solid to separate out, and filters, and absolute ethanol washing filter cake obtains white fine needle crystal 280mg, m.p.208-210 DEG C of
1H-NMR (300MHz, DMSO-d6)δ：11.54 (1H, s), 11.42 (1H, s), 7.34-7.31 (1H, m), 7.17- 7.14 (1H, m), 7.07-6.87 (5H, m), 4.67-4.64 (1H, m), 4.49-4.48 (3H, m), 3.84 (1H, m), 3.78 (3H, s), 3.75-3.59 (3H, m), 3.29-3.23 (1H, m), 3.10-3.06 (1H, m)；13C-NMR (75MHz, DMSO-d6) δ：157.5 (d,1JCF=173.1Hz), 150.0,147.7,133.5,133.1,125.7,122.9,121.4,115.2, 113.0,112.9,109.8,103.0,102.3,64.7,56.3,54.3,50.3,49.5,20.8；HRMS Calcd for C20H21FN2O2[M+H+] 341.1587, found 341.1662.
Embodiment 6
The fluoro- 2- of 8- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5- tetrahydropyridines [4,3-b] diindyl hydrochloride Prepare
With reference to the preparation method of embodiment 5, by 8- fluoro- 2,3,4,5- tetrahydropyridines (4,3-b) diindyl 500mg (2.21mmol) and 1- (2- methoxyphenoxies) -3- N-Propyl Bromides 500mg (2.05mmol) synthesize 8- fluoro- 2- (3- (2- methoxyl groups Phenoxy group) propyl group) -2,3,4,5- tetrahydropyridines (4,3-b) diindyl obtains brown oil 450mg, yield 62%.
By upper step product in hydrogen chloride methanol solution into salt, obtain canescence crystalline powder 200mg, m.p.198-210 DEG C of
1H-NMR (300MHz, DMSO-d6)δ：11.41 (1H, s), 11.17 (1H, s), 7.34-7.23 (2H, m), 6.98- 6.84 (5H, m), 4.62-4.59 (1H, m), 4.27-4.22 (1H, m), 4.07-4.04 (2H, m), 3.76-3.69 (4H, m), 3.50-3.21 (4H, m), 3.04-3.00 (1H, m), 2.35-2.28 (2H, m)；13C-NMR (75MHz, DMSO-d6)δ：157.5 (d,1JCF=172.6Hz), 149.8,148.4,133.5,133.2,125.8,122.1,121.4,114.5,112.9,112.7, 109.9,103.4,102.5,66.8,56.1,53.3,49.8,48.6,24.6,20.9；HRMS Calcd for C21H23FN2O2 [M+H+] 355.1744, found 355.1829.
Embodiment 7
8- methoxyl groups -2- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5- tetrahydropyridines [4,3-b] diindyl salt The preparation of hydrochlorate
With reference to the preparation method of embodiment 5, by 8- methoxyl group -2,3,4,5- tetrahydropyridines (4,3-b) diindyl 550mg (2.31mmol) and 1- (2- methoxyphenoxies) -2- bromoethanes 500mg (2.17mmol) synthesize 8- methoxyl groups -2- (2- (2- first Epoxide phenoxy group) ethyl) -2,3,4,5- tetrahydropyridines (4,3-b) diindyl obtains brown oil 650mg, yield 85.1%.
By upper step product in hydrogen chloride methanol solution into salt, obtain canescence crystalline powder 405mg, m.p.194-197 DEG C of
1H-NMR (300MHz, DMSO-d6)δ：11.57 (1H, s), 11.14 (1H, s), 7.25-7.23 (1H, m), 7.09- 6.89 (5H, m), 6.74-6.71 (1H, m), 4.70-4.67 (1H, m), 4.52-4.42 (3H, m), 3.87-3.80 (4H, m), 3.75-3.69 (5H, m), 3.62-3.58 (1H, m), 3.29-3.22 (1H, m), 3.07-3.03 (1H, m)；13C-NMR (75MHz, DMSO-d6)δ：154.0,150.0,147.7,131.8,131.5,125.9,122.8,121.4,115.1,113.0, 112.6,111.7,101.9,100.1,64.8,56.3,56.0,54.5,50.5,49.8,20.9；HRMS Calcd for C21H24N2O3[M+H+] 353.1787, found 353.1846.
Embodiment 8
8- methoxyl groups -2- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5- tetrahydropyridines [4,3-b] diindyl hydrochloric acid The preparation of salt
With reference to the preparation method of embodiment 5, by 8- methoxyl group -2,3,4,5- tetrahydropyridines (4,3-b) diindyl 500mg (2.10mmol) and 1- (2- methoxyphenoxies) -3- N-Propyl Bromides 500mg (2.05mmol) synthesize 8- methoxyl groups -2- (3- (2- first Epoxide phenoxy group) propyl group) -2,3,4,5- tetrahydropyridines (4,3-b) diindyl obtains green oil thing 430mg, yield 57.3%.
By upper step product in hydrogen chloride methanol solution into salt, obtain white powder crystallization 370mg, m.p.196-199 DEG C of
1H-NMR (300MHz, DMSO-d6)δ：11.11 (2H, s), 7.24-7.22 (1H, m), 7.00-6.86 (5H, m), 6.73-6.70 (1H, m), 4.64-4.60 (1H, m), 4.28-4.22 (1H, m), 4.09-4.06 (2H, m), 3.79-3.70 (7H, M), 3.56-3.39 (3H, m), 3.28-3.23 (1H, m), 3.02-2.98 (1H, m), 2.37-2.30 (2H, m)；13C-NMR (75MHz, DMSO-d6)δ：154.0,149.8,148.4,131.8,131.5,125.9,122.1,121.4,114.5,112.9, 112.5,111.7,102.0,100.5,66.8,56.1,56.0,53.4,50.0,48.9,24.6,21.0；HRMS Calcd for C22H26N203[M+H+] 367.1943, found 367.2023.
Embodiment 9
The chloro- 2- of 6- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5- tetrahydropyridines [4,3-b] diindyl hydrochloride Prepare
With reference to the preparation method of embodiment 5, by 6- chloro- 2,3,4,5- tetrahydropyridines (4,3-b) diindyl 550mg (2.26mmol) and 1- (2- methoxyphenoxies) -2- bromoethanes 500mg (2.05mmol) synthesize 6- chloro- 2- (2- (2- methoxyl groups Phenoxy group) ethyl) -2,3,4,5- tetrahydropyridines (4,3-b) diindyl obtains yellow oil 470mg, yield 60.8%.
By upper step product in hydrogen chloride methanol solution into salt, obtain white, needle-shaped crystals 260mg, m.p.173-176 DEG C of
1H-NMR (300MHz, DMSO-d6)δ：11.60 (1H, s), 11.07 (1H, s), 7.42-7.39 (1H, m), 7.22- 7.19 (1H, m), 7.11-6.92 (5H, m), 4.79-4.74 (1H, m), 4.54-4.49 (3H, m), 3.94-3.90 (1H, m), 3.81 (3H, s), 3.72-3.64 (3H, m), 3.23-3.17 (2H, m)；13C-NMR (75MHz, DMSO-d6)δ：154.6, 151.7,138.6,135.4,131.3,127.7,126.0,125.6,124.9,121.1,120.5,120.2,116.7, 107.1,68.7,59.7,59.5,55.1,54.5,24.9；HRMS Calcd for C20H21ClN2O2[M+HTen] 357.1292, found 357.1371.
Embodiment 10
The chloro- 2- of 6- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5- tetrahydropyridines [4,3-b] diindyl hydrochloride Prepare
With reference to the preparation method of embodiment 5, by 6- chloro- 2,3,4,5- tetrahydropyridines (4,3-b) diindyl 520mg (2.14mmol) and 1- (2- methoxyphenoxies) -3- N-Propyl Bromides 500mg (2.05mmol) synthesize 6- chloro- 2- (3- (2- methoxyl groups Phenoxy group) propyl group) -2,3,4,5- tetrahydropyridines (4,3-b) diindyl obtains yellow oil 640mg, yield 84.4%.
By upper step product in hydrogen chloride methanol solution into salt, obtain white, needle-shaped crystals 370mg, m.p.205-208 DEG C of
1H-NMR (300MHz, DMSO-d6)δ：11.58 (1H, s), 10.81 (1H, s), 7.47-7.45 (1H, m), 7.20- 7.18 (1H, m), 7.04-6.90 (5H, m), 4.72-4.67 (1H, m), 4.33-4.08 (3H, m), 3.84-3.81 (1H, m), 3.70 (3H, s), 3.53-3.43 (3H, m), 3.11-3.06 (2H, m), 2.33-2.32 (2H, m)；13C-NMR (75MHz, DMSO-d6)δ：149.1,147.4,133.6,130.7,126.6,121.7,121.3,120.6,120.2,116.3,115.9, 113.1,111.4,102.6,67.1,55.4,54.4,50.4,49.5,23.8,20.4；HRMS Calcd for C21H23ClN2O2[M+H+] 371.1448, found 371.1522.
Embodiment 11
7,8- dimethyl -2- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5- tetrahydropyridines [4,3-b] diindyl salt The preparation of hydrochlorate
With reference to the preparation method of embodiment 5, by 7,8- dimethyl -2,3,4,5- tetrahydropyridines (4,3-b) diindyl 550mg (2.30mmol) and 1- (2- methoxyphenoxies) -2- bromoethanes 500mg (2.17mmol) synthesis 7,8- dimethyl -2- (2- (2- Methoxyphenoxy) ethyl) -2,3,4,5- tetrahydropyridines (4,3-b) diindyl obtains brown oil 290mg, yield 38.2%.
By upper step product in hydrogen chloride methanol solution into salt, obtain canescence acicular crystal 140mg, m.p.201-204 DEG C of
1H-NMR (300MHz, DMSO-d6)δ：10.97 (1H, s), 10.67 (1H, s), 7.16-6.96 (6H, m), 4.77- 4.72 (1H, m), 4.46-4.45 (3H, m), 3.87-3.82 (4H, m), 3.78-3.63 (3H, m), 3.16-3.09 (2H, m), 2.29-2.27 (6H, m)；13C-NMR (75MHz, DMSO-d6)δ：149.8,147.4,135.6,130.2,129.5,127.4, 123.7,122.6,121.2,117.8,114.9,112.8,112.1,101.1,64.6,56.0,54.2,50.5,49.6, 20.5,20.3；HRMS Calcd for C22H26N2O2[M+H+] 351.1994, found351.2067.
Embodiment 12
7,8- dimethyl -2- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5- tetrahydropyridines [4,3-b] diindyl salt The preparation of hydrochlorate
With reference to the preparation method of embodiment 5, by 7,8- dimethyl -2,3,4,5- tetrahydropyridines (4,3-b) diindyl 500mg (2.10mmol) and 1- (2- methoxyphenoxies) -3- N-Propyl Bromides 500mg (2.05mmol) synthesis 7,8- dimethyl -2- (3- (2- Methoxyphenoxy) propyl group) -2,3,4,5- tetrahydropyridines (4,3-b) diindyl obtains brown oil 170mg, yield 22.8%.
By upper step product in hydrogen chloride methanol solution into salt, obtain canescence acicular crystal 80mg, m.p.199-202 DEG C of
1H-NMR (300MHz, DMSO-d6)δ：10.96 (1H, s), 10.22 (1H, s), 7.21 (1H, s), 7.13 (1H, s), 7.01-6.86 (4H, m), 4.68-4.64 (1H, m), 4.31-4.24 (1H, m), 4.11-4.07 (2H, m), 3.83-3.79 (1H, M), 3.68 (3H, s), 3.48-3.45 (3H, m), 3.14-3.00 (2H, m), 2.28-2.27 (8H, m)；13C-NMR (75MHz, DMSO-d6)δ：149.1,147.4,135.8,130.8,128.1,127.9,123.3,121.7,120.6,117.1,113.O, 111.3,111.2,100.8,67.3,55.5,54.3,50.5,50.1,23.7,20.5,19.1,18.7；HRMS Calcd for C23H28N2O2[M+H+] 365.2151, found 365.2212.
The biological activity test of embodiment 13
1st, Experiment name
Anococcygeal muscle contractile function is tested
2nd, experiment material
2.1 medicines and reagent
PHENYLEPHRINE HYDROCHLORIDE (Phenylephrine hydrochloride) Shanghai Hefeng Pharmaceutical Co., Ltd., can Cacaine (Cocaine) Qingdao pharmaceutical factory, hydrocortisone parenteral solution (Hydrocortisone) Yangzhou pharmaceutical factory, Propranolol (DL-Propranolol, Pro) SIGMA Products, prazosin (Prazosin, Pra) SIGMA Products.
3rd, experimental technique
3.1 prepare Krebsye liquid
NaCl, 118.4mmol/L；KCl, 4.7mmol/L；CaCl2, 2.52mmol/L；MgSO4, 1.2mmol/L； KH2PO4, 1.2mmol/L；NaHCO3, 25mmol/L；Glucose, 11.1mmol/L.
The preparation of 3.2 anus fingerexams and pA2Measure
Male Sprague-Dawley rat is taken, body weight 300-350g, stunning of tapping the head, arteria carotis bloodletting is lethal.Along lower abdomen Abdominal cavity is opened in center, exposes pubic symphysis, cuts off pubic symphysis from center and firmly is allowed to divide right and left, and finds rectum.About exist Pelvic entrance plane cuts rectum, along rectum rear wall careful separation from top to bottom, until nearly rectum end, it is seen that two parallel Strip musculature：One end is risen from distal rectal rear wall both sides, and the other end is as top tail cone, i.e. anus fingerexam.A little battalion is added dropwise Nutrient solution is finally ligatured in the connective tissue on sample, being separated off around anus fingerexam respectively at two ends threading, then cuts mark This, inserts in the Krebs liquid of logical oxygen.Sample is fixed in isolated organ perfusion system, bath temperature is 37 DEG C, nutrient solution pH It is 7.4.Tranquillization load is about 1g, balances 1h.Period changes liquid 6-8 times in groove.After baseline stability, start experiment.
First add cocainehydrochloride (6.0 × 10 in groove-2Mol/L) to final concentration of 30 μm of ol/L, hydrocortisone (100mg/20mL) extremely final concentration of 30 μm of ol/L, Propranolol (1.305 × 10-3Mol/L) to final concentration of 1 μm of ol/L.
After 20 minutes, start according to neophryn 20ml bath cumulant validity response curve medicine addition dosings.Often plus one Dosage, treats to maximum reaction occur, and after curve is stable, then adds next dosage.After contraction reaches maximum reaction, mark is rinsed This, every 5-10 minutes once, to sample diastole to baseline.Then, then in kind make Article 2 control curve.Article 2 After the baseline of curve flushing, can while above-mentioned pretreatment medicine is added addition prazosin (final concentration of 10nmol/L, 30nmol/L, 0.1 μm of ol/L) or test-compound respective concentration (tested by prerun and determined), done from low concentration, and one Sample is only with a compound.After 20 minutes, the change feelings of the dose-effect response curve of neophryn, observation and control curve are done in repetition Condition, obtains α1The pA of-receptor antagonist2Value.
(note：Cocaine, for suppressing nerve endings mediator reuptake, improves adrenergic receptor sensitiveness；Hydrogenation can Pine, for block nerves tip mediator reuptake；Propranolol, for the presumable β effects of blocking drugs；pA2Value, antagonism Parameter, refers to the negative logarithm of competitive antagonism medicine concentration when dose ratio is 2)
4th, experimental result：
Effect to anus fingerexam：
Numbering N pA2Value
I1 3 7.4349±0.2338
I2 3 7.5574±0.2023
I3 3 7.9787±0.1746
I4 3 7.8806±0.1044
I5 3 8.3939±0.2257
I6 3 6.5067±0.0733
I7 3 7.4627±0.0718
I8 3 6.6603±0.1539
Prazosin 3 8.9702±0.1082
I in table1-I8It is test-compound, prazosin is positive reference compound, the pA of compound2Value is bigger, represents Its antagonism α1The ability of-AR is stronger.Test result indicate that 8 test-compounds show good antagonistic activity, wherein I5Chemical combination Thing pA2Value is approached with control compound, and the compound is used as new α1Receptor antagonist is in the treatment side of benign prostatic hyperplasis There is potential application value in face.

Claims (4)

1. the parallel Benzazole compounds of tetrahydropyridine [4,3-b] of the class as shown in formula (A) and its pharmaceutically acceptable salt, Wherein, R and R1Respectively 7,8 C1-10 alkyl；Or R does not exist, R1It is the C1-10 alkoxies of 8 or the halogen of 6 or 8 Substitution base；R2For 2 C1-10 are alkoxy substituted；N is 1 or 2
2. a class according to claim 1 as shown in formula (A) tetrahydropyridine [4,3-b] a pair of horses going side by side Benzazole compounds and its Pharmaceutically acceptable salt, it is characterised in that：Described C1-10 alkyl is methyl, and C1-10 alkoxies are methoxyl group, halogen It is fluorine or chlorine.
3. a class according to claim 1 and 2 as shown in formula (A) tetrahydropyridine [4,3-b] a pair of horses going side by side Benzazole compounds And its pharmaceutically acceptable salt is：
I1：Tetrahydrochysene -1H- pyridine [4,3-b] the diindyl hydrochlorides of the fluoro- 2- of 8- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5-
I2：Tetrahydrochysene -1H- pyridine [4,3-b] the diindyl hydrochlorides of the fluoro- 2- of 8- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5-
I3：Tetrahydrochysene -1H- pyridine [4,3-b] the diindyl salt of 8- methoxyl groups -2- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5- Hydrochlorate
I4：Tetrahydrochysene -1H- pyridine [4,3-b] the diindyl salt of 8- methoxyl groups -2- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5- Hydrochlorate
I5：Tetrahydrochysene -1H- pyridine [4,3-b] the diindyl hydrochlorides of the chloro- 2- of 6- (2- (2- methoxyphenoxies) ethyl) -2,3,4,5-
I6：Tetrahydrochysene -1H- pyridine [4,3-b] the diindyl hydrochlorides of the chloro- 2- of 6- (3- (2- methoxyphenoxies) propyl group) -2,3,4,5-
I7：Tetrahydrochysene -1H- pyridine [4, the 3-b] diindyls of 7,8- dimethyl -2- (2- (2- ethoxy phenoxies) ethyl) -2,3,4,5- Hydrochloride
I8：Tetrahydrochysene -1H- pyridine [4, the 3-b] diindyls of 7,8- dimethyl -2- (3- (2- ethoxy phenoxies) propyl group) -2,3,4,5- Hydrochloride.
4. a class according to claim 1 as shown in formula (A) tetrahydropyridine [4,3-b] a pair of horses going side by side Benzazole compounds and its Pharmaceutically application of the acceptable salt in the lower urinary tract symptoms medicine for preparing treatment benign prostatic hyperplasis and its causing.
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