CN109400571A - With α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt, preparation method and the usage - Google Patents

With α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt, preparation method and the usage Download PDF

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CN109400571A
CN109400571A CN201811606099.4A CN201811606099A CN109400571A CN 109400571 A CN109400571 A CN 109400571A CN 201811606099 A CN201811606099 A CN 201811606099A CN 109400571 A CN109400571 A CN 109400571A
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base
methyl
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piperazine
methoxyl group
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CN109400571B (en
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徐进宜
谢绍文
徐盛涛
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses have α with logical formula (I)1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt, also disclose the Preparation method and use of said derivative or its pharmaceutical salt.The present invention can be used for preparing treatment hyperplasia of prostate, hypertension, heart disease, atherosclerosis and pass through blocking α1Receptor treats the drug of disease.

Description

With α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its is pharmaceutical Salt, preparation method and the usage
Technical field
The present invention relates to field of medicinal chemistry, in particular to have α1Heterochromatic full -4- the ketone of receptor blocking activity is derivative Object or its pharmaceutical salt, preparation method and the usage.
Background technique
Benign prostatic hyperplasis (bnign prostatic hyperplasia, BPH) is a kind of middle-aging male urination function Energy disorder disease, is mainly mainly shown as prostate interstitial and glandular hyperplasia, forefront hylperadenosis, lower urinary tract symptom and wing occurs The symptoms such as Guang is outlet obstructed.Often merge in benign prostate patient and suffer from hypertension, the two has certain correlation, and high Blood pressure is the risk factor of Incidence of BPH.
Summary of the invention
Goal of the invention: it is an object of the present invention to provide with α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its Pharmaceutical salt.
It is a further object of the present invention to provide the preparation methods of said derivative or its pharmaceutical salt.
It is a further object of the present invention to provide a kind of pharmaceutical compositions.
Final object of the present invention is to provide said derivative or its pharmaceutical salt and increases in preparation treatment prostate Life, hypertension, heart disease, atherosclerosis and by block α1Purposes in drug of the receptor to treat disease.
The derivative of heterochromatic full -4- ketone compounds, the invention also discloses these heterochromatic full -4- ketone compounds are derivative The preparation method of object, the compound and the pharmaceutical composition containing the compound are in treatment hypertension, Atherosclerosis Change, heart failure, hyperplasia of prostate and by block α1Receptor treats the application in Other diseases or illness.
Technical solution: the present invention has α with logical formula (I)1Heterochromatic full -4- the ketones derivant of receptor blocking activity Or its pharmaceutical salt:
Wherein,
R1Selected from H, Cl, F, Br, I, C1-C10Alkane, the C of linear chain or branched chain3-C6Cycloalkane；
R2Selected from H, Cl, F, Br, CF3、CH3、NO2、OX、
X is selected from H, C1-C10The alkane of linear chain or branched chain；
Y is selected from H, Cl, Br, F, I, CN, NH2, NO2、CF3、OH、OCH3, COOH, COOCH3；
R3Selected from H, *-W-R4；
W is selected from
R4Selected from H, C1-C10Alkane, the C of linear chain or branched chain3-C6Cycloalkane, OCH3、OC2H5、Cl。
Further,
R1Selected from H, Cl, F, Br, I, CH3、CH2CH3；
R2Selected from H, Cl, F, Br, CF3, CH3、NO2、OH、OCH3、OCH2CH3、
Y is selected from H, OCH3；
R4Selected from OCH3、OC2H5、OH。
Further,
Described has α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt are appointed to be following It is a kind of:
6- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -7- different chroman-4-on of methoxyl group -3- methyl (A1)
6- (2- hydroxyl -3- (4- (2- anisyl) piperazine -1- base) propoxyl group) heterochromatic full -4- of -7- methoxyl group -3- methyl Ketone (A2)
6- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (A3)
6- (3- (4- (2- chlorphenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -7- methoxyl group -3- methyl (A4)
6- (2- hydroxyl -3- (4- tetrahydrofuran -2- carbonyl) piperazine -1- base) different chroman-4-on of -7- methoxyl group -3- methyl (A5)
6- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (A6)
6- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- first The different chroman-4-on of oxygroup -3- methyl (A7)
7- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -6- different chroman-4-on of methoxyl group -3- methyl (B1)
7- (3- (4- (2- methoxyphenyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (B2)
7- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (B3)
7- (3- (4- (2- chlorphenyl (piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -6- methoxyl group -3- methyl (B4)
7- (2- hydroxyl -3- (4- (tetrahydrofuran -2- carbonyl) piperazine -1- base) propoxyl group) -6- methoxyl group -3- methyl is heterochromatic Full -4- ketone (B5)
7- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (B6)
7- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- first The different chroman-4-on of oxygroup -3- methyl (B7)
8- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -7- different chroman-4-on of methoxyl group -3- methyl (C1)
8- (2- hydroxyl -3- (4- (2- methoxyphenyl) piperazine -1- base) propoxyl group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (C2)
8- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (C3)
8- (3- (4- (2- chlorphenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of 7- methoxyl group -3- methyl (C4)
8- (2- hydroxyl -3- (4- (tetrahydrofuran -2- carbonyl) piperazine -1- base) propoxyl group) 7- methoxyl group -3- methyl is heterochromatic Full -4- ketone (C5)
8- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (C6)
8- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- first The different chroman-4-on of oxygroup -3- methyl (C7).
A kind of pharmaceutical composition, it is one or more as described in any one of claim 1-3 containing therapeutically effective amount There is α with logical formula (I)1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt and pharmacy Upper acceptable carrier.
A kind of pharmaceutical composition, it is one or more as described in any one of claim 1-3 containing therapeutically effective amount There is α with logical formula (I) with structure shown in general formula I1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its Pharmaceutical salt and pharmaceutically acceptable auxiliary material.
Described has α with logical formula (I)1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its is pharmaceutically acceptable Salt preparation method, include the following steps:
(1)
(2)
Wherein,
(1) nucleophilic substitution occurs for compound 1a, 1b, 1c and alkali, by phenolic hydroxyl group with benzyl protection obtain compound 2a, 2b, 2c, then obtain primary alcohol compound 3a, 3b, 3c with sodium borohydride reduction aldehyde radical, compound 3a, 3b, 3c pull out after hydrogen with 2- bromine third Acetoacetic ester reaction, then compound 4a, 4b, 4c are obtained with basic hydrolysis, compound 4a, 4b, 4c are after oxalyl chloride is at acyl chlorides, with N, O- Weinreb amide compound 5a, 5b, 5c is made in dimethyl hydroxylamine hydrochloride, using 5a, 5b, 5c as substrate, t-BuLi is added and carries out Cyclization obtains compound 6a, 6b, 6c, then compound 6a, 6b, 6c is sloughed benzyl protecting group, obtains heterochromatic full -4- ketone Close object 7,8,9；
(2) under the conditions of alkali and organic solvent, heterochromatic full -4- ketone compounds 7,8,9 are obtained with epichlorohydrin reaction Midbody compound 10,11,12, midbody compound 10,11,12 is respectively with substituted-piperazinyl, the condition existing for zinc perchlorate Lower open loop, obtains final product A1-7, B1-7, C1-7.
Described has α with logical formula (I)1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its is pharmaceutically acceptable Salt preparation treatment hyperplasia of prostate, hypertension, heart disease, atherosclerosis and by block α1Receptor is treated Purposes in the drug of disease.
The utility model has the advantages that the present invention has the effect of significantly being depressured and reducing hyperplasia of prostate, it can be used for preparing treatment Hyperplasia of prostate, hypertension, heart disease, atherosclerosis and by block α1Receptor treats the drug of disease.
Specific embodiment
Embodiment 1
6- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -7- different chroman-4-on of methoxyl group -3- methyl (A1)
By midbody compound 10 (1mmol), substituted piperazine like compound (1mmol) and Zn (ClO4)2(0.1mmol) is mixed It closes, the methylene chloride of 2-5ml is added, oil bath is warming up to 80 DEG C, and opening reaction 10-15min is volatilized completely to methylene chloride.It produces Object chromatographs to obtain target product A1 through petrol ether/ethyl acetate (3: 1) column, and product is white solid yield 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.54 (s, 1H), 7.28 (m, 2H), 6.91 (m, 3H), 6.62 (s, 1H), 4.88 (s, 2H), 4.26 (m, 2H), 4.11 (m, 2H), 3.94 (s, 3H), 3.27 (s, 4H), 2.91 (m, 2H), 2.75-2.63 (m, 4H), 1.52 (d, J= 6.9Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.76,154.56,151.17,148.02,137.42,129.12, 122.40,119.84,116.12,110.13,106.21,169.72,154.36,147.79,137.37,122.19,109.90, 106.18,77.96,71.85,66.53,65.71,60.38,56.12,53.37,49.21,15.86；HRMS(ESI)calcd For C24H31N2O5 [M+H]+427.2155, found 427.2231.
Embodiment 2
6- (2- hydroxyl -3- (4- (2- anisyl) piperazine -1- base) propoxyl group) heterochromatic full -4- of -7- methoxyl group -3- methyl Ketone (A2)
Midbody compound 10 (1mmol) is operated by embodiment 1, obtains target product A2, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.39 (s, 1H), 7.11 (d, J=7.8Hz, 1H), 7.01 (m, 1H), 6.84 (m, 2H), 6.51 (s, 1H), 4.77 (m, 2H), 4.11 (m, 3H), 3.94 (m, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.44-3.23 (m, 7H), 3.05 (m, 1H), 1.41 (d, J=6.6Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.67, 158.42,154.50,148.01,138.10,137.31,125.19,123.96,122.23,121.08,111.83,109.89, 106.17,77.84,71.47,67.26,66.47,61.78,57.36,56.04,55.38,51.33,44.67,42.79, 15.79；HRMS(ESI)calcd for C25H31N2O6Na2[M-H+2Na]+501.1978 found 501.2232.
Embodiment 3
6- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (A3)
Midbody compound 10 (1mmol) is operated by embodiment 1, obtains target product A3, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.39 (s, 1H), 7.11 (d, J=7.5Hz, 1H), 7.00 (m, 1H), 6.82 (m, 2H), 6.51 (s, 1H), 4.76 (m, 2H), 4.14-3.94 (m, 8H), 3.81 (s, 3H), 3.42 (q, J=8.1Hz, 2H), 3.28 (m, 5H), 3.05 (m, 1H), 1.40 (m, 6H)；HRMS(ESI)calcd for C26H33N2O6Na2[M-H+2Na]+ 515.2134 found 515.2401.
Embodiment 4
6- (3- (4- (2- chlorphenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -7- methoxyl group -3- methyl (A4)
Midbody compound 10 (1mmol) is operated by embodiment 1, obtains target product A4, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.46 (s, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 7.23 (m, 1H), 7.03 (m, 1H), 6.58 (s, 1H), 4.85 (m, 2H), 4.21 (m, 1H), 4.13-4.01 (m, 5H), 3.89 (s, 3H), 3.55- 3.21 (m, 7H), 1.50 (d, J=6.69,3H)；HRMS(ESI)calcd for C24H28ClN2O5Na2[M-H+2Na]+ 505.1482 found 505.1744.
Embodiment 5
6- (2- hydroxyl -3- (4- tetrahydrofuran -2- carbonyl) piperazine -1- base) different chroman-4-on of -7- methoxyl group -3- methyl (A5)
Epoxide obtained in the previous step (10) (1mmol) is operated by embodiment 1, obtains target product A5, product For white solid yield 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.39 (s, 1H), 6.52 (s, 1H), 4.75 (s, 2H), 4.51 (t, J=5.7Hz, 1H), 4.11 (m, 2H), 3.98 (m, 2H), 3.9-3.7 (m, 5H), 3.60 (brs, 2H), 3.48 (brs, 2H), 2.5 (m, 6H), 2.12 (m, 1H), 2.0-1.7 (m, 3H), 1.39 (d, J=6.48Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.60,169.72,154.36,147.79,137.37,122.19,109.90,106.18,75.63, 71.74,68.91,66.36,65.94,60.36,55.99,53.64,53.14,53.00,45.16,41.78,28.36, 25.56 15.72；HRMS(ESI)calcd for C23H33N2O7[M+H]+449.2288 found 449.2275.
Embodiment 6
6- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (A6)
Midbody compound 10 (1mmol) is operated by embodiment 1, obtains target product A6, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.45 (s, 1H), 7.43 (t, J=0.78Hz, 1H), 6.94 (d, J= 3.33Hz, 1H), 6.55 (s, 1H), 6.42 (t, J=1.68Hz, 1H), 5.25 (s, 2H), 4.16 (m, 2H), 4.12 (m, 2H), 3.85 (s, 3H), 3.77 (brs, 4H), 3.43 (brs.1H), 2.67 (m, 2H), 2.58 (m, 4H), 1.44 (d, J=6.69Hz, 3H)；HRMS(ESI)calcd for C23H29N2O7[M+H]+445.1975 found 445.1977.
Embodiment 7
6- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- first The different chroman-4-on of oxygroup -3- methyl (A7)
Midbody compound 10 (1mmol) is operated by embodiment 1, obtains target product A7, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.38 (s, 1H), 6.98 (t, J=1.1Hz, 1H), 6.84-6.78 (m, 4H), 5.03-4.81 (m, 2H), 4.58-4.40 (m, 4H), 3.96-3.84 (m, 3H), 3.63 (s, 3H), 3.18-2.71 (m, 7H), 2.49-2.11 (m, 3H), 1.48 (d, J=6.8Hz, 3H)；HRMS(ESI)calcd for C27H33N2O8[M+H]+ 513.2231 found 513.2234.
Embodiment 8
7- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -6- different chroman-4-on of methoxyl group -3- methyl (B1)
Epoxide obtained in the previous step (11) (1mmol) is operated by embodiment 1, obtains target product B1, product For white solid yield 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.48 (s, 1H), 7.26 (t, J=8.7Hz, 2H), 6.99 (m, 3H), 6.67 (s, 1H), 4.84 (m, 2H), 4.21 (m, 2H), 4.09 (m, 2H), 3.89 (s, 3H), 3.21 (m, 4H), 2.81 (m, 2H), 2.62 (m, 4H), 1.50 (d, J=6.66Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.900, 153.344,151.122,149.086,136.785,129.150,122.788,119.926,116.130,108.398, 107.643,77.989,71.717,71.662,66.496,65.616,60.388,56.055,53.361,49.245, 15.886；HRMS(ESI)calcd for C24H31N2O5[M+H]+427.2233 found 427.2228.
Embodiment 9
7- (3- (4- (2- methoxyphenyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (B2)
Midbody compound 11 (1mmol) is operated by embodiment 1, obtains target product B2, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.22 (s, 1H), 7.09 (d, J=7.68Hz, 1H), 7.00 (t, J= 7.74Hz, 1H), 6.82 (t, J=7.38Hz, 2H), 6.53 (s, 1H), 4.73 (m, 2H), 4.10 (m, 3H), 3.96 (m, 3H), 3.76 (d, J=3.6Hz, 6H), 3.40-3.05 (m, 8H)；13C-NMR (75MHz, CDCl3) δ: 194.408,158.054, 154.007,152.907,148.432,136.385,124.911,123.630,122.040,120.658,114.407, 107.745,107.049,77.386,70.934,66.677,65.914,61.318,56.610,55.468,54.921, 50.957,44.090,42.056,15.330；HRMS(ESI)calcd for C25H31N2O6Na2[M-H+2Na]+501.1978 found 501.2242.
Embodiment 10
7- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (B3)
Midbody compound 11 (1mmol) is operated by embodiment 1, obtains target product B3, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.36 (s, 1H), 7.10 (d, J=7.71Hz, 1H), 6.99 (t, J= 6.5Hz, 1H), 6.80 (t, J=7.59Hz, 2H), 6.54 (s, 1H), 4.72 (m, 2H), 4.13-3.94 (m, 8H), 3.76 (s, 3H), 3.10-3.04 (m, 7H), 3.07 (m, 1H), 1.38 (m, 6H)；13C-NMR (75MHz, CDCl3) δ: 194.39, 157.995,153.559,152.950,148.487,136.344,125.080,124.138,122.049,120.486, 112.101,107.738,107.091,77.381,70.914,66.645,65.940,63.228,61.273,57.024, 55.448,50.865,44.102,42.139,15.331,14.319；HRMS(ESI)calcd for C26H33N2O6Na2[M-H+ 2Na]+515.2134 found 515.2397.
Embodiment 11
7- (3- (4- (2- chlorphenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -6- methoxyl group -3- methyl (B4)
Midbody compound 11 (1mmol) is operated by embodiment 1, obtains target product B4, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.46 (s, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 7.21 (m, 1H), 7.05 (m, 1H), 6.60 (s, 1H), 4.82 (s, 2H), 4.21 (m, 1H), 4.14-4.02 (m, 5H), 3.87 (s, 3H), 1.50 (d, J=6.69Hz, 3H), 3.50-3.27 (m, 8H)；13C-NMR (75MHz, CDCl3) δ: 194.93,158.49,153.22, 148.91,146.71,136.88,130.77,127.73,125.57,125.06,122.65,108.27,107.63,77.92, 71.30,67.37,66.42,61.74,55.99,54.95,51.45,44.30,42.23,15.84；HRMS(ESI)calcd for C24H28ClN2O5Na2[M-H+2Na]+505.1482 found 505.1747.
Embodiment 12
7- (2- hydroxyl -3- (4- (tetrahydrofuran -2- carbonyl) piperazine -1- base) propoxyl group) -6- methoxyl group -3- methyl is heterochromatic Full -4- ketone (B5)
Midbody compound 11 (1mmol) is operated by embodiment 1, obtains target product B5, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.39 (s, 1H), 6.58 (s, 1H), 4.77 (m, 2H), 4.50 (t, J= 5.7Hz, 1H), 4.30 (m, 2H), 4.02 (m, 2H), 3.9-3.7 (m, 5H), 3.65 (s, 4H), 2.4-2.6 (m, 6H), 2.17 (m, 1H), 1.90 (m, 3H), 1.43 (d, J=6.66Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.31,169.29, 152.69,148.46,136.29,122.25,107.86,107.13,77.40,75.27,71.09,68.53,65.89, 65.27,59.89,55.48,44.68,41.32,27.85,25.16,15.30；HRMS(ESI)calcd for C23H33N2O7[M +H]+449.2288 found 449.2285.
Embodiment 13
7- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (B6)
Midbody compound 11 (1mmol) is operated by embodiment 1, obtains target product B6, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.39 (d, J=5.16Hz, 2H), 6.92 (d, J=3.27Hz, 1H), 6.58 (s, 1H), 6.4 (t, J=1.56Hz, 1H), 4.75 (s, 2H), 4.15 (m, 2H), 4.12 (m, 2H), 3.84 (m, 7H), 2.55 (m, 6H), 1.41 (d, J=6.66Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.32,158.50,152.70,148.48, 147.19,143.28,136.29,122.27,116.10,110.82,107.88,107.16,77.41,71.10,65.90, 65.32,59.90,55.49,52.99,15.32；HRMS(ESI)calcd for C23H29N2O7[M+H]+445.1975, found 445.1979.
Embodiment 14
7- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- first The different chroman-4-on of oxygroup -3- methyl (B7)
Midbody compound 11 (1mmol) is operated by embodiment 1, obtains target product B7, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.41 (s, 1H), 6.96 (t, J=1.1Hz, 1H), 6.85-6.76 (m, 4H), 5.00-4.86 (m, 2H), 4.56-4.39 (m, 4H), 3.91-3.81 (m, 3H), 3.67 (s, 3H), 3.13-2.71 (m, 7H), 2.46-2.17 (m, 3H), 1.51 (d, J=6.8Hz, 3H)；HRMS(ESI)calcd for C27H33N2O8[M+H]+ 513.2231 found 513.2232.
Embodiment 15
8- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -7- different chroman-4-on of methoxyl group -3- methyl (C1)
Midbody compound 12 (1mmol) is operated by embodiment 1, obtains target product C1, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.85 (d, J=8.7Hz, 1H), 7.28 (m, 2H), 6.94 (d, J= 8.28Hz, 3H), 6.88 (t, J=7.27Hz, 1H), 5.25 (m, 1H), 4.84 (m, 1H), 4.20 (q, J=6.6Hz, 1H), 4.17-3.97 (m, 3H), 3.95 (s, 3H), 3.22 (m, 4H), 2.85 (m, 2H), 2.69-2.54 (m, 4H), 1.51 (d, J= 6.6Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.93,156.54,151.15,136.08,129.14,124.16, 123.23,119.91,116.14,111.08,77.75,75.43,75.30,66.29,66.25,62.91,60.19,55.92, 53.38,49.26,15.68；HRMS(ESI)calcd for C24H31N2O5[M+H]+427.2233 found 427.2223.
Embodiment 16
8- (2- hydroxyl -3- (4- (2- methoxyphenyl) piperazine -1- base) propoxyl group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (C2)
Midbody compound 12 (1mmol) is operated by embodiment 1, obtains target product C2, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.72 (d, J=8.4Hz, 1H), 7.10 (d, J=7.5Hz, 1H), 7.03 (m, 1H), 6.85 (m, 3H), 5.08 (d, J=15.6Hz, 1H), 4.68 (m, 1H), 4.06 (m, 3H), 3.92 (m, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.41-3.26 (m, 7H), 3.02 (m, 1H), 1.39 (d, J=6.6Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.43,158.02,156.02,154.09,141.74,135.49,125.01,123.75, 123.44,122.155,120.65,111.39,110.56,77.09,74.69,74.57,67.29,62.33,61.33, 56.97,55.35,54.94,50.90,44.09,42.02,15.11；HRMS(ESI)calcd for C25H31N2O6Na2[M-H+ 2Na]+501.1978 found 501.2242.
Embodiment 17
8- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (C3)
Midbody compound 12 (1mmol) is operated by embodiment 1, obtains target product C3, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.73 (d, J=8.7Hz, 1H), 7.12 (d, J=7.5Hz, 1H), 7.02 (t, J=7.56Hz, 1H), 6.84 (m, 3H), 5.10 (d, J=15.6Hz, 1H), 4.68 (m, 1H), 4.11-3.85 (m, 6H), 3.82 (s, 3H), 3.44-3.27 (m, 7H), 3.03 (m, 1H), 1.41-1.36 (m, 6H)；13C-NMR (75MHz, CDCl3) δ: 194.46,156.06,153.68,141.77,135.52,125.06,124.19,123.47,122.57,120.50,112.08, 110.54,77.12,74.67,74.54,67.33,67.28,63.24,62.34,61.27,57.30,55.35,50.81, 44.10,42.14,15.12,14.34；HRMS(ESI)calcd for C26H33N2O6Na2[M-H+2Na]+515.2134, found 515.2401.
Embodiment 18
8- (3- (4- (2- chlorphenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of 7- methoxyl group -3- methyl (C4)
Midbody compound 12 (1mmol) is operated by embodiment 1, obtains target product C4, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.82 (d, J=8.67Hz, 1H), 7.38 (m, 2H), 7.25 (m, 1H), 7.06 (m, 1H), 6.92 (d, J=8.7Hz, 1H), 5.15 (m, 1H), 4.76 (m, 1H), 4.19-4.03 (m, 6H), 3.99- 3.88 (d, J=5.97Hz, 3H), 3.56-3.22 (m, 8H), 1.48 (d, J=6.69Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.94,158.43,156.47,146.70,142.14,142.04,136.03,130.77,127.72,125.55, 125.18,124.13,123.10,111.02,77.66,75.19,75.02,68.01,67.94,62.80,61.74,55.90, 55.12,51.11,44.30,42.22,29.67,15.64；HRMS(ESI)calcd for C24H28ClN2O5Na2[M-H+2Na]+ 505.1482 found 505.1745.
Embodiment 19
8- (2- hydroxyl -3- (4- (tetrahydrofuran -2- carbonyl) piperazine -1- base) propoxyl group) 7- methoxyl group -3- methyl is heterochromatic Full -4- ketone (C5)
Midbody compound 12 (1mmol) is operated by embodiment 1, obtains target product C5, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.74 (d, J=8.64Hz, 1H), 6.86 (d, J=8.67Hz, 1H), 5.15 (m, 1H), 4.76 (m, 1H), 4.53 (t, J=5.88Hz, 1H), 4.10 (m, 1H), 4.01-3.73 (m, 8H), 3.63 (s, 2H), 3.52 (s, 2H), 2.50 (m, 6H), 2.18 (m, 1H), 1.93 (m, 3H), 1.40 (d, J=6.60Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.86,169.84,156.47,142.08,135.99,124.18,123.15,111.08,77.68, 75.78,75.30,75.18,69.05,66.40,66.35,62.83,60.21,55.91,45.22,41.85,28.39, 25.67 15.62；HRMS(ESI)calcd for C23H33N2O7[M+H]+449.2288 found 449.2277.
Embodiment 20
8- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (C6)
Midbody compound 12 (1mmol) is operated by embodiment 1, obtains target product C6, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.73 (d, J=8.37Hz, 1H), 7.41 (s, 1H), 6.92 (s, 1H), 6.85 (d, J=8.37Hz, 1H), 6.4 (s, 1H), 5.15 (d, J=4.68Hz, 1H), 5.11 (d, J=4.29Hz, 1H), 4.2- 3.9 (m, 4H), 3.84 (s, 3H), 3.76 (brs, 4H), 2.49 (brs, 4H), 1.39 (d, J=6.03Hz, 3H)；13C-NMR (75MHz, CDCl3) δ: 194.85,159,01,156.47,147.69,143.78,142.08,141.97,135.99, 128.74,124.14,123.12,116.56,111.30,111.08,77.66,75.34,75.22,66.50,66.44, 62.82,60.21,55.90,53.49,15.61；HRMS(ESI)calcd for C23H29N2O7[M+H]+445.1975, found 445.1970.
Embodiment 21
8- (3- (4- (2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine-2-carbonyl) piperazin-1-yl)- 2-hydroxypropoxy)-7-methoxy-3-methylisochroman-4-one
8- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- first The different chroman-4-on of oxygroup -3- methyl (C7)
Midbody compound 12 (1mmol) is operated by embodiment 1, obtains target product C7, product is white solid production Rate 60-80%；1H-NMR (300MHz, CDCl3) δ: 7.75 (d, J=8.37Hz, 1H), 6.87 (d, J=8.36Hz, 1H), 6.82-6.75 (m, 4H), 4.98-4.79 (m, 2H), 4.51-4.38 (m, 4H), 3.93-3.85 (m, 3H), 3.79 (s, 3H), 3.12-2.70 (m, 7H), 2.41-2.19 (m, 3H), 1.49 (d, J=6.8Hz, 3H)；HRMS(ESI)calcd for C27H33N2O8[M+H]+513.2231 found 513.2234.
Embodiment 22
Using the formula of table 1, tablet is prepared into conventional method.
1 formula composition of table
Title Content (g/1000 piece)
The product of embodiment 5 5g
Hypromellose E5 1.5g
Microcrystalline cellulose MCC102 1.8g
8% PVP K30 In right amount
Magnesium stearate 0.2g
Embodiment 23: performance test
One, the vasodilator activity experiment of compound
(1) experimental method
1. experiment pretreatment
(1) kreb nutrient solution: NaCl 111.2mM, KCl 5.0mM, CaCl22.5mM, MgSO41.2mM KH2PO41.0mM, NaHCO312.0mM, glucose 11.1mM.Preparation method: by NaCl, KCl, KH2PO4、MgSO4Together After dissolution, the CaCl of individually dissolution number is added2Solution uses NaHCO3It adjusts pH value to 7.4, saves at -4 DEG C, added before use Glucose；
(2) preparation of thoracic aortic ring: prepare about 180g to 200g male SD rat and (tonneau China experimental animal is tieed up by Beijing Technology Co., Ltd. provides), yellow Jackets (60mg/kg, ip) anesthesia, arteria carotis takes blood, and solution splits abdominal cavity, careful with cotton Push internal organ aside, exposure thoracoabdominal aorta is close to the careful blunt separation exposure blood vessel of backbone, avoids clamping or pulling the blood to be intercepted Pipeline section takes out thoracoabdominal aorta as early as possible.Thoracoabdominal aorta will be taken out and be placed in 95%O2+ 5%CO2- the 4 of mixed gas saturated process In DEG C Kreb nutrient solution, cotton swab carefully removes endothelium, careful to remove blood vessel peripheral adipose and connective tissue, uses aorta pectoralis The vascular circle of about 4mm is made in proximal part blood vessel.Vascular circle is hung in the 10mL bath of the Krebs nutrient solution of 37 DEG C of preheatings, Fixed one end, the other end are connected to safe alliance's bio signal by tonotransducer and amplify acquisition system, are being continually fed into 95%O2+ 5%CO2In the state of mixed gas, basal tension is gradually adjusted to 1.0g, and stablize 1h, every 15min changes 1 nutrient solution；
(3) pre-stimulation of potassium chloride is shunk: with more stimulation vascular circles of the KCl of 60mmol/L concentration, shrink vascular circle, When vascular circle stablizes stimulate the reaction, i.e., the caused shrinkage amplitude difference < 10% of continuous 2 times same stimulations starts to test；
(4) detection of vascularization endothelium: vascular circle is stimulated with the norepinephrine of 10-6mol/L concentration, makes vascular circle It shrinks, gives the acetylcholine of 10-5mol/L after reaching maximum shrinkage amplitude and measure its diastole amplitude.Acetylcholine is added Pre-shrunk vascular circle not diastole or diastole percentage are less than 10% afterwards, then it is assumed that endothelium has removed；
(5) after endothelium removal, the state to before stimulating is rinsed, then after stable 60min, during which every 15min is changed the liquid once, so Further experiment afterwards.After vascular circle reaches balance, 1 × 10 is firstly added in bath-6The norepinephrine (NA) of mol/L, Pre-stimulation sample makes its contraction, replaces nutrient solution, removes NA.NA (1 × 10 is added again after its balance-6Mol/L it) is stimulated Shrink (final concentration of 1 × 10-6Mol/L), after vascular circle contraction reaches maintenance level, various concentration is successively added with accumulative (1×10-8mol/L、1×10-7mol/L、1×10-6mol/L、1×10-5mol/L、1×10-4Mol/L test-compound), Test-compound diastole caused by antagonism NA of the different cumulative concentrations in vitro vascular circle is observed to act on.Solvent group and the positive The solvent solution of equal volume corresponding concentration is added in control group successively simultaneously with accumulative.After shrinking and reaching stable state, with tired The agonist NA of different cumulative concentrations is once added in product concentration method.After rinsing 45min, after being incubated for test-compound 15min, with tired The agonist NA of different cumulative concentrations is once added in product concentration method.A kind of each compound of sample test.
(2) data processing:
Contraction, diastole tension signal tonotransducer and Pclab biochips diagnosis in experimentation.System is logical It crosses eight channel connectors to be transferred on the computer being connected with Pclab system, carries out the record of experimental data.It is tested to calculate each Relative inhibition of each administration concentration of compound to each in vitro tissue, mean value use ± SEM expression.Utilize software Graphpad Prism mapping.Relative inhibition calculation formula is as follows:
(3) experimental result:
Naftopidil (Naftopidil, NAF) is the α of selectivity1Receptor antagonist is able to suppress α1Blood caused by receptor Pressure rises.It is positive control that we, which choose naftopidil, tests designed compound in 1 × 10-5mol/L, 1 × 10- To the inhibiting rate of vascular strip when 4mol/L concentration, experimental result is shown in Table 2.It is bright that test result shows that all compounds are all shown The activity of aobvious vasodilator activity, wherein compound A-13, A5, A6, A7, B1, B2, C1, C5 is the most prominent, with positive drug naphthalene piperazine Your activity of ground is suitable.From the point of view of whole structure-activity relationship, shown preferably in A class compound entirety than two class compound of B, C Activity；The activity for the compound that tetrahydrofuran -2- carbonyl replaces is universal preferable；Furans -2- carbonyl replaces to compound activity There is detrimental effect.From the point of view of the activity data of substituted benzene base class compound, chlorine substitution has negative impact to activity on phenyl ring； Methoxyl group, ethyoxyl, which replace, does not show apparent positive influence to activity.According to pharmacological screening as a result, we have chosen it Middle activity preferably compound has done further research, is detailed in the pA2 value measurement part of compound.
Influence of 2 compound of table to the in vitro thoracic aortic ring contraction of NA induced rat
Two, the pA2 value measurement of compound
(1) experimental method
SPF grades of male adult rats are taken (to provide) (180- by Beijing Vital River Experimental Animals Technology Co., Ltd. 230g), overdose of anesthesia is lethal, opens thoracic cavity and takes out aorta pectoralis rapidly, is put into the Krebs solution of oxygenation.Careful separation chest master Artery removes the fat, connective tissue and blood vessel subbranch of attachment, blood vessel is cut into the vascular circle sample of 3-4mm length, is gone Except endothelium.Vascular circle is inserted into the isosceles triangle bracket that two finer wires are made into, and bottom edge is isometric with vascular circle, and vertex penetrates Silk thread ligation.Sample is moved into rapidly to 10mL to fill in the thermostatic bath of Krebs solution, 95%O is persistently poured in bath2+ 5% CO2Mixed gas, 37 DEG C of temperature.Bath bottom is fixed in silk thread one end, and one end is connected in tonotransducer, passes through AD Instruments System of organism signal records tension variation.
Giving sample preload makes aorta pectoralis 1.5g, balances at least 60min, and during which every 15min replaces a Krebs Liquid.Vascular circle sample examines whether endothelium removes completely with acetylcholine.Machine returns to zero after balance, and cavity constant volume is given in 10mL It is primary to give sample KCl (80mM) stimulation, gives Noradrenaline (NA) (10 later-5M it) stimulates twice.Stablize wait shrink to reach After state, the agonist NA of different cumulative concentrations is sequentially added with cumulative concentration method.After rinsing 45min, it is incubated for test-compound After 15min, the agonist NA of different cumulative concentrations is sequentially added with cumulative concentration method.Each sample only tests a kind of tested material A kind of concentration.Naftopidil is positive control.
(2) experimental data
It is shunk in experimentation, diastole tension signal utilizes tonotransducer and System of organism signal passes through 12 Channel connector is transferred on the computer being connected with AD system, carries out data record.Maximum collapse grams caused by NA is set as Emax, each NA cumulative concentration is found out to its percentage, makes four NA amount effect relation curves with software Graphpad Prism (CRCs): CRC when tested material not being added；CRC after low concentration tested material is added；CRC in addition after concentration of test object；Add CRC after entering high concentration tested material.If tested material is competitive antagonist, four curves should move to right in parallel, that is to say, that Increase the concentration of agonist NA, the ceiling effect of CRC is constant.Each tested material is calculated to α with Schild Plot method1Receptor Parameter for antagonist (pA2).
(3) experimental result
With selective α1Receptor antagonist naftopidil is shown in Table 3 as positive drug, experimental result.From experimental result It sees, it is living that the compound with preferable vasodilator activity measured before shows stronger norepinephrine antagonism Property, therefore wherein compound A-45 has further selects representation compound A5 to carry out anti-in body with the comparable activity of positive drug The pharmacodynamic study of hypertensive activity is detailed in blood pressure lowering in compound body and tests.
3 preferred compound pA2 value of table
Compd. pA2±SEM (Slope±SEM)
A3 6.314±0.13 0.86±0.03
A5 6.724±0.18 0.81±0.05
A6 5.811±0.17 1.2±0.06
B1 6.207±0.17 0.99±0.04
A7 6.512±0.15 0.92±0.03
B2 5.658±0.16 0.87±0.03
Cl 6.528±0.19 1.1±0.05
C5 6.469±0.11 0.94±0.03
Naftopidil 6.844±0.09 0.88±0.02
Three, the internal blood pressure lowering experiment of compound
(1) laboratory apparatus: the noninvasive animal blood pressure of BP-2000 measures system, the production of Visitech company, the U.S.；Standard water Silver-colored sphygmomanometer, Yuyue Medical Apparatus Co., Ltd., Jiangsu.Spontaneous hypertensive rat (SHR), male, are tieed up purchased from Beijing by SPF grades Experimental animal Technology Co., Ltd., tonneau China.Drug and reagent: compound A-45, molecular weight 448, purity are greater than 95.0%, administration It is preceding to be made into suspension with 0.5%CMC-Na, it is formulated into required concentration, it is ready-to-use.
(2) experimental method:
Animal packet and administration: choosing male spontaneous hypertensive rat (SHR) rat 30 of 200~250g of weight, It is divided into blank control group, naftopidil group, compound A-45 group, every group 10.Dosage is 80mg/kg.Instrument setting: nothing is opened It creates animal blood pressure and measures system, instrument is calibrated with standard mercury sphygmomanometer, each parameter setting is as follows: maximum pressure 250mmHg 37 DEG C of measuring temperature, is predicted 3 times, is surveyed 20 times, each interval time 3s.Setting signal strength retrogression is to average arteries and veins Pressure when intensity 90% of fighting is as systolic pressure (SAP), and pressure when decaying to 20% is as diastolic pressure (DAP).Rat-tail label: According to tail sleeve method operability, rat-tail is divided into 4 sections, and 1,2,3 and 4 positions are successively labeled as from root of the tail to tail point, with 3,4 Placement position of the position middle section as infrared inductor, and with blue marking pen marker determination position.
Blood pressure determination: animal has acclimatization training twice respectively before the formal development of experiment, each 2h, and uninterrupted Its blood pressure is monitored, the relatively low person of blood pressure (SAP < 150mmHg, DAP < 110mmHg) discards.Selection compliance is good, blood pressure qualification Rat is grouped and is tested at random.It surveys before pressure and instrument is preheated to 37 DEG C, animal is put into fixator by number, rat-tail is worn Over-voltage cercoids is nested with infrared ray measurement device, pre-adaptation 10min, to occur rat normal pulse waveform diagram on computer monitor Afterwards, start to measure (animal may shake off when measurement, continue after retightening).After having surveyed, the data for choosing the normal person of waveform are made For valid data, the valid data of each time point are no less than 3, and ineligible person redeterminates, and take what is measured every time to put down Mean value is as a result.Each group first measure administration before blood pressure, thereafter by group be administered respectively, record administration before and administration after 0h, 1h, The blood pressure (systolic pressure, diastolic pressure, mean arterial pressure) and heart rate of 2h, 4h, 6h and 8h rat.
(3) experimental result:
The blood pressure (SAP, DAP, MAP) and heart rate (HR) result of groups of animals measurement are indicated with average value ± SD, are carried out certainly (pairing) the t- test statistics processing of body administration front and back.Compound antihypertensive activity is indicated so that the change rate of front and back blood pressure is administered, Change rate (%)=SAP (at 0h)-SAP (at 1-8h)/SAP (at 0h) × 100%.
Using naftopidil as positive drug, experimental result is shown in Table 4 and table 5 for internal anti-hypertension experiment.From experimental result See, blank control group blood pressure no difference of science of statistics before and after experiment, at the same positive drug naftopidil shown in 0-8h it is bright Aobvious antihypertensive effect, antihypertensive activity peak after 2h, and pharmacodynamic profile meets document report, and hypertension indicated above is real Test model success.Experimental result shows that the antihypertensive effect of compound A-45 peaks after 4h, diastolic pressure, contraction to SHR The Amplitude of Hypotensive of pressure is significantly stronger than positive drug naftopidil, reaches 25% or more to the maximum reducing amplitude of blood pressure, and do not cause Apparent alteration in heart rate, the above result shows that, compound A-45 has the side effect of good antihypertensive active and lower heart.
Antihypertensive activity (0-2h) in 4 compound A-45 body of table
Note: SAP: systolic pressure；DAP: diastolic pressure；HR: heart rate.* P < 0.1, * * p < 0.05
Antihypertensive activity (4-8h) in 5 compound A-45 body of table
Note: SAP: systolic pressure；DAP: diastolic pressure；HR: heart rate.* P < 0.1, * * p < 0.05
Four, influence experiment of the compounds of this invention to rat prostate tissue weight
(1) experimental method:
Hormone method prepares benign prostatic hyperplasia in rats model
SD rat is randomly divided into 10 groups: model group, sham-operation group, 2 dosage groups of naftopidil (10,30mg/kg), chemical combination 2 dosage groups (10,30mg/kg) of object A5,2 dosage groups (10,30mg/kg) of compound C1, compound C5 2 dosage Group (10,30mg/kg).In addition to sham-operation group, each group rat 3% yellow Jackets (36mg/kg) intraperitoneal injection of anesthesia is extractd Bilateral testes.Sham-operation group operation is the same, but does not ligature blood vessel, do not extract testis.Postoperative breeding observing one week.Except sham-operation group Outside, in daily early morning 8am testosterone propionate (Testosteronepropionate, TP) 5mg/kg is subcutaneously injected, even in each group It is 4 weeks continuous, while relative medicine is given in stomach-filling.
(2) experimental result
Influence of the preferred compound to rat prostate tissue weight
Next day after the last administration, arteria carotis sacrificed by exsanguination animal carefully separate each leaf prostate, are blotted with filter paper, horizontalization It is covered in ware, anti-moisture evaporation claims weight in wet base in electronic balance, and calculate volume, the results are shown in Table 6.
Influence of 6 preferred compound of table to benign prostatic hyperplasia in rats
Group Weight in wet base (mg) Volume (cm3)
Sham-operation group 648.4±38.4** 0.89±0.07**
Model group 1977.6±88.9 2.67±0.15
NAF(10.0mg/Kg) 1608.3±33.8* 1.65±0.03*
NAF(30mg/Kg) 877.4±37.5** 1.05±0.06**
A5(10mg/Kg) 1532.3±27.9* 1.55±0.04**
A5(30mg/Kg) 826.5±55.7** 1.01±0.03**
A7(10mg/Kg) 1622.2±36.3* 1.71±0.07*
A7(30mg/Kg) 904.5±42.5** 1.26±0.04**
C1(10mg/Kg) 1411.5±33.8* 1.72±0.07*
C1(30mg/Kg) 985.6±43.6** 1.29±0.08**
* P < 0.05**P < 0.01
Compared with model group, A5, A7, C1, C5 (10 and 30mg/kg), which amount to 6 dosage groups, can make prostata tissue wet Weight and volume reduce.Especially compound A-45 is similar to positive control NAF (30mg/kg) activity at high dose (30mg/kg).

Claims (7)

1. there is α with logical formula (I)1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt:
Wherein,
R1Selected from H, Cl, F, Br, I, C1-C10Alkane, the C of linear chain or branched chain3-C6Cycloalkane；
R2Selected from H, Cl, F, Br, CF3、CH3、NO2、OX、
X is selected from H, C1-C10The alkane of linear chain or branched chain；
Y is selected from H, Cl, Br, F, I, CN, NH2, NO2、CF3、OH、OCH3, COOH, COOCH3；
R3Selected from H, *-W-R4；
W is selected from
R4Selected from H, C1-C10Alkane, the C of linear chain or branched chain3-C6Cycloalkane, OCH3、OC2H5、Cl。
2. according to claim 1 have α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its is pharmaceutical Salt, wherein
R1Selected from H, Cl, F, Br, I, CH3、CH2CH3；
R2Selected from H, Cl, F, Br, CF3、CH3、NO2、OH、OCH3、OCH2CH3、
Y is selected from H, OCH3；
R3Selected from H, *-W-R4；
W is selected from
R4Selected from OCH3、OC2H5、OH。
3. according to claim 1 have α1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its is pharmaceutical Salt is following any:
6- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -7- different chroman-4-on of methoxyl group -3- methyl (A1)
6- (2- hydroxyl -3- (4- (2- anisyl) piperazine -1- base) propoxyl group) different chroman-4-on of -7- methoxyl group -3- methyl (A2)
6- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -7- methoxyl group -3- methyl (A3)
6- (3- (4- (2- chlorphenyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- different chroman-4-on of methoxyl group -3- methyl (A4)
6- (2- hydroxyl -3- (4- tetrahydrofuran -2- carbonyl) piperazine -1- base) -7- different chroman-4-on of methoxyl group -3- methyl (A5)
6- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -7- methoxyl group -3- methyl (A6)
6- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxy The different chroman-4-on of base -3- methyl (A7)
7- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -6- different chroman-4-on of methoxyl group -3- methyl (B1)
7- (3- (4- (2- methoxyphenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -6- methoxyl group -3- methyl (B2)
7- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -6- methoxyl group -3- methyl (B3)
7- (3- (4- (2- chlorphenyl (piperazine -1- base) -2- hydroxy propyloxy group) -6- different chroman-4-on of methoxyl group -3- methyl (B4)
7- (2- hydroxyl -3- (4- (tetrahydrofuran -2- carbonyl) piperazine -1- base) propoxyl group) -6- methoxyl group -3- methyl it is heterochromatic it is full - 4- ketone (B5)
7- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -6- methoxyl group -3- methyl (B6)
7- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -6- methoxy The different chroman-4-on of base -3- methyl (B7)
8- (2- hydroxyl -3- (4- phenylpiperazine -1- base) propoxyl group) -7- different chroman-4-on of methoxyl group -3- methyl (C1)
8- (2- hydroxyl -3- (4- (2- methoxyphenyl) piperazine -1- base) propoxyl group) different chroman-4-on of -7- methoxyl group -3- methyl (C2)
8- (3- (4- (2- ethoxyl phenenyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -7- methoxyl group -3- methyl (C3)
8- (3- (4- (2- chlorphenyl) piperazine -1- base) -2- hydroxy propyloxy group) 7- different chroman-4-on of methoxyl group -3- methyl (C4)
8- (2- hydroxyl -3- (4- (tetrahydrofuran -2- carbonyl) piperazine -1- base) propoxyl group) heterochromatic full -4- of 7- methoxyl group -3- methyl Ketone (C5)
8- (3- (4- (furans -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) different chroman-4-on of -7- methoxyl group -3- methyl (C6)
8- (3- (4- (2,3- dihydros-Isosorbide-5-Nitrae-benzdioxan -2- carbonyl) piperazine -1- base) -2- hydroxy propyloxy group) -7- methoxy The different chroman-4-on of base -3- methyl (C7).
4. a kind of pharmaceutical composition, one or more as claimed in any one of claims 1-3 containing therapeutically effective amount There is α with logical formula (I)1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its pharmaceutical salt, and pharmaceutically Acceptable carrier.
5. a kind of pharmaceutical composition, one or more as claimed in any one of claims 1-3 containing therapeutically effective amount There is α with logical formula (I) with structure shown in general formula I1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its can Medicinal salt and pharmaceutically acceptable auxiliary material.
6. described in claim 1 have α with logical formula (I)1Heterochromatic full -4- the ketones derivant of receptor blocking activity or its The preparation method of pharmaceutical salt, includes the following steps:
(1)
(2)
Wherein,
(1) nucleophilic substitution occurs for compound 1a, 1b, 1c and alkali, by phenolic hydroxyl group with benzyl protection obtain compound 2a, 2b, 2c, then obtain primary alcohol compound 3a, 3b, 3c with sodium borohydride reduction aldehyde radical, compound 3a, 3b, 3c pull out after hydrogen with 2 bromopropionic acid Ethyl ester reaction, then compound 4a, 4b, 4c are obtained with basic hydrolysis, compound 4a, 4b, 4c are after oxalyl chloride is at acyl chlorides, with N, O- bis- Weinreb amide compound 5a, 5b, 5c is made in methyl hydroxylamine hydrochloride, using 5a, 5b, 5c as substrate, t-BuLi is added and carries out ring It closes, obtains compound 6a, 6b, 6c, then compound 6a, 6b, 6c are sloughed into benzyl protecting group, obtain heterochromatic full -4- ketone chemical combination Object 7,8,9；
(2) under the conditions of alkali and organic solvent, heterochromatic full -4- ketone compounds 7,8,9 obtain centre with epichlorohydrin reaction Body compound 10,11,12, midbody compound 10,11,12 with substituted-piperazinyl, are opened under the conditions of existing for the zinc perchlorate respectively Ring obtains final product A1-7, B1-7, C1-7.
7. claim 1-3 is described in any item to have α with logical formula (I)1Heterochromatic full -4- the ketone of receptor blocking activity spreads out Biology or its pharmaceutical salt in preparation treatment hyperplasia of prostate, hypertension, heart disease, atherosclerosis and pass through blocking α1Purposes in drug of the receptor to treat disease.
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