CN109400571B - Having a 1 Isochroman-4-ketone derivative with receptor blocking activity or pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents

Having a 1 Isochroman-4-ketone derivative with receptor blocking activity or pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDF

Info

Publication number
CN109400571B
CN109400571B CN201811606099.4A CN201811606099A CN109400571B CN 109400571 B CN109400571 B CN 109400571B CN 201811606099 A CN201811606099 A CN 201811606099A CN 109400571 B CN109400571 B CN 109400571B
Authority
CN
China
Prior art keywords
methoxy
methylisochroman
pharmaceutically acceptable
isochroman
piperazin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201811606099.4A
Other languages
Chinese (zh)
Other versions
CN109400571A (en
Inventor
徐进宜
谢绍文
徐盛涛
刘洁
王超磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN201811606099.4A priority Critical patent/CN109400571B/en
Publication of CN109400571A publication Critical patent/CN109400571A/en
Application granted granted Critical
Publication of CN109400571B publication Critical patent/CN109400571B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a compound having alpha and a general formula (I) 1 Isochroman-4-ketone derivative with receptor blocking activity or its medicinal salt, and its preparation process and use. The invention can be used for preparing medicines for treating prostatic hyperplasia, hypertension, heart disease, atherosclerosis and blocking alpha 1 -a drug for the treatment of a disease.

Description

Having an alpha 1 Isochroman-4-ketone derivative with receptor blocking activity or pharmaceutically acceptable salt thereof, and preparation method and application thereof
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a compound with alpha 1 Isochroman-4-ketone derivative with receptor blocking activity or medicinal salt thereof, and a preparation method and application thereof.
Background
Benign Prostatic Hyperplasia (BPH) is a disorder of urination dysfunction in middle-aged and elderly men, and is mainly manifested by interstitial and glandular hyperplasia of the prostate, enlargement of the prostate, lower urinary tract symptoms, obstruction of the bladder outlet and the like. Patients with benign prostate often have hypertension in combination, which has some correlation, and hypertension is a risk factor for the onset of benign prostatic hyperplasia.
Disclosure of Invention
The purpose of the invention is as follows: the object of the present invention is to provide a catalyst having alpha 1 -receptor blocking active isochroman-4-one derivatives or pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a process for producing the above derivative or a pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide a pharmaceutical composition.
The last object of the present invention is to provide the use of the above derivatives or their pharmaceutically acceptable salts for the preparation of a medicament for the treatment of prostatic hyperplasia, hypertension, heart disease, atherosclerosis and by blocking alpha 1 -the use of the receptor in a medicament for the treatment of a disease.
Derivatives of isochroman-4-one compounds, process for preparing these isochroman-4-one compounds, use of said compounds and pharmaceutical compositions containing them for treating hypertension, atherosclerosis, heart failure, prostatic hyperplasia and by blocking alpha 1 The use of the receptor for the treatment of other diseases or conditions.
The technical scheme is as follows: the invention has alpha of the general formula (I) 1 -receptor blocking active isochroman-4-one derivatives or pharmaceutically acceptable salts thereof:
Figure BDA0001921546990000011
wherein,
R 1 selected from H, cl, F, br, I, C 1 -C 10 Straight or branched alkanes, C 3 -C 6 Cycloalkanes of (a);
R 2 selected from H, cl, F, br, CF 3 、CH 3 、NO 2 、OX、
Figure BDA0001921546990000012
X is selected from H and C 1 -C 10 Linear or branched alkanes;
y is selected from H, cl, br, F, I, CN, NH 2 ，NO 2 、CF 3 、OH、OCH 3 、COOH，COOCH 3 ；
R 3 Selected from H, O-W-R 4 ；
W is selected from
Figure BDA0001921546990000021
R 4 Selected from H, C 1 -C 10 Straight or branched alkanes, C 3 -C 6 Cycloalkane of (i) OCH 3 、OC 2 H 5 、Cl。
Further, the air conditioner is provided with a fan,
R 1 selected from H, cl, F, br, I, CH 3 、CH 2 CH 3 ；
R 2 Selected from H, cl, F, br, CF3, CH 3 、NO 2 、OH、OCH 3 、OCH 2 CH 3 、
Figure BDA0001921546990000022
Y is selected from H and OCH 3 ；
Figure BDA0001921546990000023
R 4 Is selected from OCH 3 、OC 2 H 5 、OH。
Further, the air conditioner is characterized in that,
said has an alpha 1 -a receptor blocking active isochroman-4-one derivative or a pharmaceutically acceptable salt thereof, being any one of:
6- (2-hydroxy-3- (4-phenylpiperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (A1)
6- (2-hydroxy-3- (4- (2-methoxyphenyl) piperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (A2)
6- (3- (4- (2-ethoxyphenyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A3)
6- (3- (4- (2-chlorophenyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A4)
6- (2-hydroxy-3- (4-tetrahydrofuran-2-carbonyl) piperazin-1-yl) -7-methoxy-3-methylisochroman-4-one (A5)
6- (3- (4- (furan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A6)
6- (3- (4- (2, 3-dihydro-1, 4-benzodioxan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A7)
7- (2-hydroxy-3- (4-phenylpiperazin-1-yl) propoxy) -6-methoxy-3-methylisochroman-4-one (B1)
7- (3- (4- (2-methoxyphenyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B2)
7- (3- (4- (2-ethoxyphenyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B3)
7- (3- (4- (2-chlorophenyl (piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B4)
7- (2-hydroxy-3- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) propoxy) -6-methoxy-3-methylisochroman-4-one (B5)
7- (3- (4- (furan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B6)
7- (3- (4- (2, 3-dihydro-1, 4-benzodioxan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B7)
8- (2-hydroxy-3- (4-phenylpiperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (C1)
8- (2-hydroxy-3- (4- (2-methoxyphenyl) piperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (C2)
8- (3- (4- (2-ethoxyphenyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (C3)
8- (3- (4- (2-chlorophenyl) piperazin-1-yl) -2-hydroxypropoxy) 7-methoxy-3-methylisochroman-4-one (C4)
8- (2-hydroxy-3- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) propoxy) 7-methoxy-3-methylisochroman-4-one (C5)
8- (3- (4- (furan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (C6)
8- (3- (4- (2, 3-dihydro-1, 4-benzodioxan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (C7).
A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) according to any one of claims 1 to 3 having an alpha 1 -a receptor blocking active isochroman-4-one derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula (I) having the structure of formula (I) as defined in any one of claims 1 to 3 having an alpha 1 -isochroman-4-one derivatives with receptor blocking activity or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.
Said compound having the general formula (I) having alpha 1 -a process for the preparation of receptor blocking active isochroman-4-one derivatives or pharmaceutically acceptable salts thereof comprising the steps of:
(1)
Figure BDA0001921546990000041
(2)
Figure BDA0001921546990000051
wherein,
(1) Nucleophilic substitution reaction is carried out on compounds 1a, 1b and 1c and alkali, phenolic hydroxyl is protected by benzyl to obtain compounds 2a, 2b and 2c, aldehyde group is reduced by sodium borohydride to obtain primary alcohol compounds 3a, 3b and 3c, the compounds 3a, 3b and 3c are subjected to hydrogen extraction and then react with ethyl 2-bromopropionate, alkali hydrolysis is carried out to obtain compounds 4a, 4b and 4c, the compounds 4a, 4b and 4c are subjected to oxalyl chloride to form acyl chloride, and then react with N, O-dimethylhydroxylamine hydrochloride to obtain Weinreb amide compounds 5a, 5b and 5c, the compounds 5a, 5b and 5c are taken as substrates, t-BuLi is added for cyclization to obtain compounds 6a, 6b and 6c, and then benzyl protecting groups of the compounds 6a, 6b and 6c are removed to obtain isochroman-4-ketone compounds 7,8 and 9;
(2) Under the condition of alkali and organic solvent, 7,8 and 9 isochroman-4-ketone compounds react with epichlorohydrin to obtain intermediate compounds 10, 11 and 12, the intermediate compounds 10, 11 and 12 respectively react with substituted piperazine, and ring opening is carried out in the presence of zinc perchlorate to obtain final products A1-7, B1-7 and C1-7.
Said compound having the general formula (I) having alpha 1 Use of derivatives of isochroman-4-ones or pharmaceutically acceptable salts thereof with receptor blocking activity for the preparation of a medicament for the treatment of prostatic hyperplasia, hypertension, heart disease, atherosclerosis and by blocking alpha 1 -the use of the receptor in a medicament for the treatment of a disease.
Has the advantages that: the invention has obvious effects of reducing blood pressure and prostate hyperplasia, and can be used for preparing medicines for treating prostate hyperplasia, hypertension, heart disease, atherosclerosis and treating diseases by blocking alpha 1 -a drug for the treatment of a disease.
Detailed Description
Example 1
Figure BDA0001921546990000061
6- (2-hydroxy-3- (4-phenylpiperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (A1)
The intermediate compound 10 (1 mmol), the substituted piperazine compound (1 mmol) and Zn (ClO 4) 2 (0.1 mmol), adding 2-5ml of dichloromethane, heating to 80 ℃ in an oil bath, and carrying out open reaction for 10-15min until the dichloromethane is completely volatilized. Performing petroleum ether/ethyl acetate (3: 1) column chromatography on the product to obtain a target product A1, wherein the yield of the product is 60-80% of white solid; 1H-NMR (300MHz, CDCl3). Delta.: 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.
Example 2
Figure BDA0001921546990000062
6- (2-hydroxy-3- (4- (2-methoxyphenyl) piperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (A2)
The intermediate compound 10 (1 mmol) was used in example 1 to obtain the desired product A2 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 ) 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 C 25 H 31 N 2 O 6 Na 2 [M-H+2Na] + 501.1978，found 501.2232.
example 3
Figure BDA0001921546990000071
6- (3- (4- (2-ethoxyphenyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A3)
Will be intermediateThe procedure of example 1 was followed for preparation of compound 10 (1 mmol) to give the desired product A3 in the form of a white solid at a yield of 60-80%; 1 H-NMR(300MHz，CDCl 3 )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 C 26 H 33 N 2 O 6 Na 2 [M-H+2Na] + 515.2134，found 515.2401.
example 4
Figure BDA0001921546990000072
6- (3- (4- (2-chlorophenyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A4)
The intermediate compound 10 (1 mmol) was used in example 1 to obtain the desired product A4 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )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 C 24 H 28 ClN 2 O 5 Na 2 [M-H+2Na] + 505.1482，found 505.1744.
example 5
Figure BDA0001921546990000073
6- (2-hydroxy-3- (4-tetrahydrofuran-2-carbonyl) piperazin-1-yl) -7-methoxy-3-methylisochroman-4-one (A5)
The epoxy compound (10) (1 mmol) obtained in the previous step was used in the procedure of example 1 to obtain the desired product A5 in the form of a white solid with a yield of 60-80%; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 23 H 33 N 2 O 7 [M+H] + 449.2288，found 449.2275.
example 6
Figure BDA0001921546990000081
6- (3- (4- (furan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A6)
The intermediate compound 10 (1 mmol) was used in example 1 to obtain the desired product A6 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )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＝6.69 Hz，3H)；HRMS(ESI)calcd for C 23 H 29 N 2 O 7 [M+H] + 445.1975，found 445.1977.
example 7
Figure BDA0001921546990000082
6- (3- (4- (2, 3-dihydro-1, 4-benzodioxan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A7)
Intermediate compound 10 (1 mmol) was reacted as in example 1 to afford the desired product A7 in 60-80% yield as a white solid; 1 H-NMR(300MHz，CDCl 3 )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 C 27 H 33 N 2 O 8 [M+H] + 513.2231，found 513.2234.
example 8
Figure BDA0001921546990000091
7- (2-hydroxy-3- (4-phenylpiperazin-1-yl) propoxy) -6-methoxy-3-methylisochroman-4-one (B1)
The epoxy compound (11) (1 mmol) obtained in the previous step was used in the same manner as in example 1 to obtain the desired product B1 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )δ：7.48(s，1H)，7.26(t，J＝8.7 Hz，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)； 13 C-NMR(75MHz， CDCl 3 )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 C 24 H 31 N 2 O 5 [M+H] + 427.2233，found 427.2228.
example 9
Figure BDA0001921546990000092
7- (3- (4- (2-methoxyphenyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B2)
The intermediate compound 11 (1 mmol) was used in example 1 to obtain the desired product B2 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 25 H 31 N 2 O 6 Na 2 [M-H+2Na] + 501.1978，found 501.2242.
example 10
Figure BDA0001921546990000101
7- (3- (4- (2-ethoxyphenyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B3)
The intermediate compound 11 (1 mmol) was used in example 1 to obtain the desired product B3 in the form of a white solid with a yield of 60-80%; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 26 H 33 N 2 O 6 Na 2 [M-H+2Na] + 515.2134，found 515.2397.
example 11
Figure BDA0001921546990000102
7- (3- (4- (2-chlorophenyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B4)
The intermediate compound 11 (1 mmol) was used in example 1 to obtain the desired product B4 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 24 H 28 ClN 2 O 5 Na 2 [M-H+2Na] + 505.1482，found 505.1747.
example 12
Figure BDA0001921546990000111
7- (2-hydroxy-3- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) propoxy) -6-methoxy-3-methylisochroman-4-one (B5)
The intermediate compound 11 (1 mmol) was used in example 1 to obtain the desired product B5 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 23 H 33 N 2 O 7 [M+H] + 449.2288，found 449.2285.
example 13
Figure BDA0001921546990000112
7- (3- (4- (furan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B6)
Intermediate compound 11 (1 mmol) was reacted as in example 1 to afford the desired product B6 in the form of a white solid in 60-80% yield; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 23 H 29 N 2 O 7 [M+H] + 445.1975，found 445.1979.
example 14
Figure BDA0001921546990000121
7- (3- (4- (2, 3-dihydro-1, 4-benzodioxan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -6-methoxy-3-methylisochroman-4-one (B7)
Intermediate compound 11 (1 mmol) was reacted as in example 1 to afford the desired product B7 in the form of a white solid in 60-80% yield; 1 H-NMR(300MHz，CDCl 3 )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 C 27 H 33 N 2 O 8 [M+H] + 513.2231，found 513.2232.
example 15
Figure BDA0001921546990000122
8- (2-hydroxy-3- (4-phenylpiperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (C1)
The intermediate compound 12 (1 mmol) was used in example 1 to obtain the desired product C1 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 24 H 31 N 2 O 5 [M+H] + 427.2233，found 427.2223.
example 16
Figure BDA0001921546990000131
8- (2-hydroxy-3- (4- (2-methoxyphenyl) piperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (C2)
The intermediate compound 12 (1 mmol) was used in example 1 to obtain the desired product C2 in a yield of 60-80% as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 25 H 31 N 2 O 6 Na 2 [M-H+2Na] + 501.1978，found 501.2242.
example 17
Figure BDA0001921546990000132
8- (3- (4- (2-ethoxyphenyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (C3)
Intermediate compound 12 (1 mmol) was processed as in example 1 to give the desired product C3 in 60-80% yield as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 26 H 33 N 2 O 6 Na 2 [M-H+2Na] + 515.2134，found 515.2401.
example 18
Figure BDA0001921546990000141
8- (3- (4- (2-chlorophenyl) piperazin-1-yl) -2-hydroxypropoxy) 7-methoxy-3-methylisochroman-4-one (C4)
Intermediate compound 12 (1 mmol) is prepared as in example1, obtaining a target product C4, wherein the yield of the product is 60-80% of a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-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 C 24 H 28 ClN 2 O 5 Na 2 [M-H+2Na] + 505.1482，found 505.1745.
example 19
Figure BDA0001921546990000142
8- (2-hydroxy-3- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) propoxy) 7-methoxy-3-methylisochroman-4-one (C5)
Intermediate compound 12 (1 mmol) was used as in example 1 to afford the desired product C5 in 60-80% yield as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 23 H 33 N 2 O 7 [M+H] + 449.2288，found 449.2277.
example 20
Figure BDA0001921546990000151
8- (3- (4- (furan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (C6)
Intermediate compound 12 (1 mmol) was reacted as in example 1 to give the desired product C6 in 60-80% yield as a white solid; 1 H-NMR(300MHz，CDCl 3 )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)； 13 C-NMR(75MHz，CDCl 3 )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 C 23 H 29 N 2 O 7 [M+H] + 445.1975， found 445.1970.
example 21
Figure BDA0001921546990000152
8-(3-(4-(2，3-dihydrobenzo[b][1，4]dioxine-2-carbonyl)piperazin-1-yl)-2-hydroxypropoxy)-7-methoxy-3- methylisochroman-4-one
8- (3- (4- (2, 3-dihydro-1, 4-benzodioxan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (C7)
Intermediate compound 12 (1 mmol) was reacted as in example 1 to afford the desired product C7 in 60-80% yield as a white solid; 1 H-NMR(300MHz，CDCl 3 )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 C 27 H 33 N 2 O 8 [M+H] + 513.2231，found 513.2234.
example 22
Tablets were prepared by a conventional method using the formulation of Table 1.
TABLE 1 formulation composition
Name (R) Content (g/1000 tablets)
Product of example 5 5g
Hydroxypropyl methylcellulose E5 1.5g
Microcrystalline cellulose MCC102 1.8g
8% Povidone K30 Proper amount of
Stearic acid magnesium salt 0.2g
Example 23: performance testing
1. Vasodilation Activity assay of Compounds
(I) Experimental method
1. Pretreatment of the experiment
(1) Preparing a kreb nutrient solution: 111.2mM NaCl, 5.0mM KCl, caCl 2 2.5mM，MgSO 4 1.2mM， KH 2 PO 4 1.0mM，NaHCO 3 12.0mM, glucose 11.1mM. The preparation method comprises the following steps: mixing NaCl, KCl and KH 2 PO 4 、 MgSO 4 Dissolving the above materials together, adding CaCl with single dissolving number 2 Solution with NaHCO 3 Adjusting pH to 7.4, storing at-4 deg.C, and adding glucose before use;
(2) Preparing a thoracic aorta ring: approximately 180g to 200g male SD rats (provided by Beijing Wintolite, inc.) were prepared, anesthetized with pentobarbital sodium (60 mg/kg, ip), blood was taken from the carotid artery, the abdominal cavity was dissected, the internal organs were carefully removed with cotton, the thoracic and abdominal aorta was exposed, the exposed blood vessels were carefully detached bluntly and closely attached to the spine, the vessel segment to be cut was prevented from being grasped or pulled, and the thoracic and abdominal aorta was removed as soon as possible. Placing the removed thoracoabdominal aorta at 95% 2 +5％CO 2 Mixed gas saturated in Kreb's nutrient solution at-4 deg.C, endothelium was carefully removed with a cotton swab, perivascular fat and connective tissue were carefully removed, and a vascular ring of about 4mm was made using the thoracic aorta proximal blood vessel. Suspending the vascular ring in 10mL bath of Krebs nutrient solution preheated at 37 deg.C, fixing one end, connecting the other end to Tailian biological signal amplification and collection system via tension transducer, continuously introducing 95% O 2 +5％CO 2 Gradually adjusting the basic tension to 1.0g under the condition of mixed gas, stabilizing for 1h, and changing the nutrient solution every 15min for 1 time;
(3) Pre-stimulated shrinkage of potassium chloride: stimulating the vascular ring for multiple times by KCl with the concentration of 60mmol/L to enable the vascular ring to contract, and starting an experiment when the vascular ring has stable response to stimulation, namely the contraction amplitude difference caused by the same stimulation for 2 times is less than 10%;
(4) Detection of vascularized endothelium: norepinephrine at a concentration of 10-6mol/L stimulates the vascular ring to contract the vascular ring, and acetylcholine is administered at a concentration of 10-5mol/L after reaching the maximum amplitude of contraction and the amplitude of relaxation is measured. Namely, the blood vessel ring which is preshrunk after the acetylcholine is added does not relax or the percent of relaxation is less than 10 percent, the endothelium is considered to be removed;
(5) After removal of endothelium, the vessel was washed to the pre-stimulated state and allowed to stabilize for 60minThe solution was changed every 15min and further experiments were performed. When the vascular ring reaches equilibrium, 1X 10 is added into the bath -6 mol/L Noradrenaline (NA), pre-stimulating the specimen to contract, changing the nutrient solution, and removing NA. After equilibration, NA (1X 10) was added again -6 mol/L) to stimulate contraction (final concentration of 1X 10) -6 mol/L), after the vasoconstriction reaches a stable level, adding different concentrations (1 × 10) in sequence by an accumulation method -8 mol/L、1×10 -7 mol/L、1×10 -6 mol/L、1×10 -5 mol/L、 1×10 -4 mol/L) of the test compound, observing the relaxation effect of the test compound on the isolated blood vessel ring caused by antagonistic NA at different accumulated concentrations. The solvent group and the positive control group are added with solvent solution with equal volume and corresponding concentration by an accumulation method. After the contraction reaches a stable state, agonist NA with different cumulative concentrations is added once by a cumulative concentration method. After washing for 45min, the test compounds were incubated for 15min, and then agonist NA was added at different cumulative concentrations once in cumulative concentrations. One compound was tested for each specimen.
(II) data processing:
in the experimental process, the contraction and relaxation tension signals are collected and processed by a tension transducer and a Pclaib biological signal. The system is transmitted to a computer connected with the Pclab system through an eight-channel connector, and experimental data are recorded. The relative inhibition of each administered concentration of each test compound to each ex vivo tissue was calculated and the mean value is represented by ± SEM. Plotted using the software Graphpad Prism. The relative inhibition rate calculation formula is as follows:
Figure BDA0001921546990000171
(III) experimental results:
naftopidil (NAF) is an optional alpha 1 Receptor antagonists capable of inhibiting alpha 1 The blood pressure rise caused by the receptor. Naftopidil is selected as a positive control, the inhibition rate of the designed compound on the vascular strip at the concentration of 1 x 10 < -5 > mol/L and 1 x 10 < -4 > mol/L is tested, and the experimental result is shown in table 2.The test result shows that all the compounds show obvious vasodilation activity, wherein the activity of the compounds A3, A5, A6, A7, B1, B2, C1 and C5 is the most prominent and is equivalent to the activity of the positive drug naftopidil. From the integral structure-activity relationship, the A compound shows better activity than the B and C compounds on the whole; the activity of the tetrahydrofuran-2-carbonyl substituted compound is generally better; furan-2-carbonyl substitution adversely affects the activity of the compound. From the activity data of the substituted phenyl compounds, chlorine substitution on the benzene ring has negative influence on the activity; methoxy and ethoxy substitution did not show significant positive effect on activity. Based on the results of pharmacological screening, we selected the compound with better activity for further study, see the part of pA2 value determination of the compound.
TABLE 2 Effect of Compounds on NA-induced contraction of isolated thoracic aortic rings in rats
Figure BDA0001921546990000181
2. Determination of pA2 value of Compounds
(I) Experimental method
Adult SPF male rats (180-230 g) were collected, anesthetized to death by overdose, the thoracic cavity was opened, the thoracic aorta was rapidly removed, and oxygenated Krebs solution was added thereto. The thoracic aorta was carefully isolated, adherent fat, connective tissue and small branches of the blood vessel were removed, the blood vessel was cut into a 3-4mm long vascular ring specimen, and the endothelium was removed. The blood vessel ring is inserted into an isosceles triangle bracket made of two thin steel wires, the bottom side of the bracket is as long as the blood vessel ring, and the top point of the bracket is threaded with silk threads for ligation. Rapidly transferring the specimen into 10mL constant temperature bath containing Krebs solution, and continuously charging the bath with 95% of 2 +5％CO 2 Mixed gas, temperature 37 ℃. One end of the silk thread is fixed at the bottom of the bath, and the other end is connected with a tension transducer, and the tension change is recorded by an AD Instruments biological signal acquisition and processing system.
Applying specimen preload to make thoracic aorta 1.5g balanced for at least 60min, wherein the time is every 15minThe Krebs solution was changed once. The vascular ring specimen is examined whether the endothelium is completely removed by acetylcholine. After equilibration the machine was zeroed, the chamber was brought to 10mL, the specimen was given a KCl (80 mM) stimulus once, followed by Noradrenaline (NA) (10) -5 M) two stimulations. After the contraction reaches a stable state, agonist NA with different cumulative concentrations is added in sequence by a cumulative concentration method. After 45min of washing, the test compounds were incubated for 15min, and then agonist NA was added sequentially at different cumulative concentrations by cumulative concentration method. Each specimen is tested for only one concentration of one test substance. Naftopidil was the positive control.
(II) Experimental data
In the experimental process, the contraction and relaxation tension signals are transmitted to a computer connected with the AD system through a 12-channel connector by using a tension transducer and a biological signal acquisition and processing system, and data recording is carried out. The maximum number of grams of shrinkage due to NA was defined as E max The cumulative concentration of each NA was determined as a percentage thereof, and four NA dose-response curves (CRCs) were generated using software Graphpad Prism: CRC when no test substance is added; CRC after addition of low concentration of test substance; CRC after addition of medium concentration test substance; CRC after addition of high concentrations of test substance. If the test substance is a competitive antagonist, the four curves should be shifted to the right in parallel, that is to say the concentration of the agonist NA is increased and the maximum effect of CRC is unchanged. Calculation of alpha for each test object pair by Schild Plot method 1 Antagonistic parameters of the receptor (pA 2).
(III) results of the experiment
With selectivity alpha 1 The receptor antagonist naftopidil is used as a positive drug, and the experimental results are shown in table 3. From the experimental results, the previously measured compounds with better vasodilation activity all show stronger norepinephrine antagonistic activity, wherein the compound A5 has the activity equivalent to that of a positive drug, so that the representative compound A5 is further selected to carry out pharmacodynamic study on the in-vivo antihypertensive activity, and the in-vivo antihypertensive experiment of the compound is detailed.
TABLE 3 preferred Compound pA2 values
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
3. In vivo hypotensive test of Compounds
The experimental instrument comprises the following steps: BP-2000 noninvasive animal blood pressure measuring system, manufactured by Visitech corporation of America; standard mercury sphygmomanometer, jiangsu yunzheng medical equipment ltd. Spontaneous Hypertensive Rats (SHR), male, SPF grade, purchased from Experimental animals technology, inc. of Viton, beijing. Drugs and reagents: compound A5, molecular weight 448, purity greater than 95.0%, was formulated into a suspension prior to administration using 0.5% CMC-Na, formulated to the desired concentration and ready for use.
(II) experimental method:
animal grouping and administration: 30 male Spontaneous Hypertension (SHR) rats with the weight of 200-250 g are selected and divided into a blank control group, a naftopidil group and a compound A5 group, and 10 rats are selected in each group. The dosage is 80mg/kg. The instrument is set up: starting a noninvasive animal blood pressure measuring system, calibrating an instrument by using a standard mercury sphygmomanometer, and setting the following parameters: the maximum pressure is 250mmHg, the temperature is measured at 37 deg.C, 3 times are predicted, and 20 times are measured, each time with interval of 3s. The pressure at which the signal intensity decays to 90% of the mean pulse intensity is set as the systolic pressure (SAP) and the pressure at which the signal intensity decays to 20% is set as the diastolic pressure (DAP). Rat tail labeling: according to the operability of the tail sleeve method, the rat tail is divided into 4 sections, the sections from the tail root to the tail tip are marked as 1, 2,3 and 4, the middle sections of the sections 3 and 4 are used as the placing sections of the infrared sensor, and the measuring sections are marked by a blue marker pen.
Blood pressure measurement: before the experiment is formally carried out, the animals are respectively subjected to adaptive training twice, each time lasts for 2 hours, and the blood pressure of the animals is continuously monitored, and the animals with lower blood pressure (SAP < 150mmHg, DAP < 110 mmHg) are discarded. Selecting rats with good compliance and qualified blood pressure to perform random grouping and test. Preheating the instrument to 37 deg.C before measuring pressure, placing animal in the fixer according to serial number, passing the tail of mouse through the tail pressing device, sleeving infrared measuring device, pre-adapting for 10min, and starting measurement after normal pulse oscillogram of rat appears on computer monitor (animal may break away during measurement and continue after re-fixing). And after the measurement is finished, selecting the data of the normal waveform as effective data, determining the effective data of not less than 3 at each time point, re-measuring the data of the non-conforming persons, and taking the average value of each measurement as a result. The blood pressure before administration was measured for each group, and thereafter, the blood pressure (systolic pressure, diastolic pressure, mean arterial pressure) and heart rate of rats were recorded before administration and at 0h, 1h, 2h, 4h, 6h and 8h after administration, respectively.
(III) experimental results:
blood pressure (SAP, DAP, MAP) and Heart Rate (HR) results for each group of animals are presented as mean. + -. SD and are statistically processed by the (paired) t-test before and after self-administration. The hypotensive activity of the compound was expressed as the rate of Change in blood pressure before and after administration, change rate (%) = SAP (at 0 h) -SAP (at 1-8 h)/SAP (at 0 h) × 100%.
In vivo antihypertensive experiments naftopidil was used as the positive drug, and the experimental results are shown in tables 4 and 5. From the experimental results, the blank control group has no statistical difference in blood pressure before and after the experiment, meanwhile, the positive drug naftopidil shows an obvious blood pressure reducing effect within 0-8h, the blood pressure reducing activity reaches the peak after 2h, the pharmacodynamic characteristics accord with the literature reports, and the success of the hypertension experimental model is shown. The experimental result shows that the blood pressure reducing effect of the compound A5 reaches a peak after 4 hours, the blood pressure reducing amplitude of the compound A5 to the diastolic pressure and the systolic pressure of SHR is obviously stronger than that of the positive drug naftopidil, the maximum blood pressure reducing amplitude of the compound A5 to the blood pressure reaches more than 25%, and obvious heart rate change is not caused, and the results show that the compound A5 has good antihypertensive activity and lower side effect on the heart.
TABLE 4 Compound A5 in vivo hypotensive Activity (0-2 h)
Figure BDA0001921546990000201
Figure BDA0001921546990000211
Note: SAP: contracting pressure; DAP: diastolic blood pressure; HR: heart rate. * P < 0.1, P < 0.05
TABLE 5 Compound A5 in vivo hypotensive Activity (4-8 h)
Figure BDA0001921546990000212
Note: SAP: contracting pressure; DAP: diastolic blood pressure; HR: heart rate. * P < 0.1, P < 0.05
4. Experiment on influence of the Compound of the present invention on the weight of rat prostate tissue
The experimental method comprises the following steps:
hormone method for preparing rat prostatic hyperplasia model
SD rats were randomly divided into 10 groups: model group, sham group, naftopidil 2 dose group (10, 30 mg/kg), compound A5 2 dose group (10, 30 mg/kg), compound C1 2 dose group (10, 30 mg/kg), compound C5 2 dose group (10, 30 mg/kg). Except for the sham operation group, rats in each group were anesthetized by intraperitoneal injection with 3% sodium pentobarbital (36 mg/kg), and bilateral testes were removed. The sham group was operated as before, but without ligation of the vessels and removal of the testis. Feeding and observing for one week after operation. Except for the sham operation group, 5mg/kg of Testosterone Propionate (TP) was subcutaneously injected in the early morning of 8am every day for 4 weeks while the corresponding drugs were administered by gavage.
(II) results of the experiment
Effect of preferred Compounds on rat prostate tissue weight
The following day after the last dose, animals were sacrificed by carotid exsanguination, the leaf prostates were carefully separated, blotted dry with filter paper, covered in a petri dish, evaporated from moisture, weighed wet on an electronic balance, and the volume calculated, the results are shown in table 6.
TABLE 6 Effect of preferred Compounds on prostate hyperplasia in rats
Group of Wet weight (mg) Volume (cm) 3 )
Artificial operation group 648.4±38.4** 0.89±0.07**
Model set 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 the model group, the group of 6 doses A5, A7, C1 and C5 (10 and 30 mg/kg) all reduced the wet weight and volume of the prostate tissue. In particular, compound A5 was similar in activity at high doses (30 mg/kg) to the positive control NAF (30 mg/kg).

Claims (4)

1. Having an alpha 1 -a receptor blocking active isochroman-4-one derivative or a pharmaceutically acceptable salt thereof,
6- (2-hydroxy-3- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (A5)
6- (3- (4- (2, 3-dihydro-1, 4-benzodioxan-2-carbonyl) piperazin-1-yl) -2-hydroxypropoxy) -7-methoxy-3-methylisochroman-4-one (A7)
8- (2-hydroxy-3- (4-phenylpiperazin-1-yl) propoxy) -7-methoxy-3-methylisochroman-4-one (C1).
2. A pharmaceutical composition comprising a therapeutically effective amount of one or more ofThe polymer of claim 1 having an alpha 1 -a receptor blocking active isochroman-4-one derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds having an alpha according to claim 1 1 -isochroman-4-one derivatives with receptor blocking activity or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.
4. Claim 1 having an alpha 1 -use of a receptor blocking active isochroman-4-one derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of prostatic hyperplasia.
CN201811606099.4A 2018-12-26 2018-12-26 Having a 1 Isochroman-4-ketone derivative with receptor blocking activity or pharmaceutically acceptable salt thereof, and preparation method and application thereof Active CN109400571B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201811606099.4A CN109400571B (en) 2018-12-26 2018-12-26 Having a 1 Isochroman-4-ketone derivative with receptor blocking activity or pharmaceutically acceptable salt thereof, and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201811606099.4A CN109400571B (en) 2018-12-26 2018-12-26 Having a 1 Isochroman-4-ketone derivative with receptor blocking activity or pharmaceutically acceptable salt thereof, and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN109400571A CN109400571A (en) 2019-03-01
CN109400571B true CN109400571B (en) 2022-11-08

Family

ID=65461956

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811606099.4A Active CN109400571B (en) 2018-12-26 2018-12-26 Having a 1 Isochroman-4-ketone derivative with receptor blocking activity or pharmaceutically acceptable salt thereof, and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN109400571B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117343036A (en) * 2023-03-20 2024-01-05 江苏联环药业股份有限公司 Isochroman compound, and pharmaceutical composition and application thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101817808A (en) * 2010-04-29 2010-09-01 中国药科大学 Flavones derivative as well as preparation method and application thereof as alpha1 receptor antagonist
CN101928244A (en) * 2010-07-13 2010-12-29 中国药科大学 Structural analogue and derivative of isochromanone-4 compound with cardiovascular activity, preparation method and application thereof
CN102382032A (en) * 2010-08-30 2012-03-21 广州医学院 1-(phenyl)-4-[3-(4-indoxyl)-2-hydroxypropyl]piperazine derivative and salts thereof as well as preparation method and application thereof
CN102977068A (en) * 2012-05-03 2013-03-20 中国药科大学 Nitric oxide donor type isochromanone derivatives, preparation methods and uses thereof
CN102875516B (en) * 2012-10-30 2015-06-03 中国药科大学 Isochromanone derivatives with beta-receptor blocking activity, and preparation method and application thereof
CN104387375A (en) * 2014-09-24 2015-03-04 中国药科大学 Hydrogen sulfide donor type isochromanone derivatives, preparation method and uses thereof
CN105218529B (en) * 2015-09-23 2018-11-27 中国药科大学 Heterochromatic full -4- ketones derivant, preparation method and medical usage with cholinesterase inhibition

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Novel hybrids of natural isochroman-4-one bearing N-substituted isopropanolamine as potential antihypertensive candidates;Renren Bai et al;《Bioorganic & Medicinal Chemistry》;20130314;第21卷;第2495-2502页 *
Structure Modification and Biological Evaluation of the Derivatives of(士)7，8-Dihydroxy-3-Methyl-Isochromanone-4;Ren ren Bai等;《2009长三角药物化学研讨会论文集》;20091231;第32-33页 *

Also Published As

Publication number Publication date
CN109400571A (en) 2019-03-01

Similar Documents

Publication Publication Date Title
JP4316794B2 (en) Isoquinoline derivatives and pharmaceuticals
EA003510B1 (en) Farnesyl protein transferase inhibitors for treating arthropathies
EP2687531B1 (en) Tetrahydrocarboline derivative
CN104513229A (en) Quinazoline derivatives and preparation method thereof
CN104203242A (en) Substituted quinolines as Bruton&#39;s tyrosine kinases inhibitors
CN105452227B (en) The crystalline form of { [1- cyano -5- (4- chlorophenoxies) -4- hydroxy-isoquinolin -3- carbonyls]-amino }-acetic acid
WO2020099929A1 (en) A crystalline spirocyclic compound inhibitor of tryptophan hydroxylase 1 (tph1) for treating diseases or disorders associated with peripheral serotonin
CN103261192A (en) 5-methyl-1-(naphthalen--yl)-1h-pyrazole derivatives and their use in potentiating the effect of opioid analgesics
CN102762554A (en) (r)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2h-pyran-4-ol, a partial agonist of 5-ht4 receptors
CN109400571B (en) Having a 1 Isochroman-4-ketone derivative with receptor blocking activity or pharmaceutically acceptable salt thereof, and preparation method and application thereof
TW201036940A (en) Cinamic compounds and derivatives therefrom for the inhibition of histone deacetylase
CN115304590B (en) 2H-benzotriazole derivatives, preparation method thereof and pharmaceutical composition containing same
CN103965175B (en) 4 (substitution phenylamino) quinazoline compounds, its preparation method and applications
JP7050336B2 (en) Deuterated compounds and their pharmaceutical uses
WO2012122805A1 (en) Medicine for treating ischemic brain injury and its sequelae and preparation method thereof
CA2851741C (en) Derivative of butylphthalide and preparation method and use thereof
KR20110044544A (en) Novel imidazole derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for the prevention and treatment of melanoma containing the same as an active ingredient
CN109761958B (en) Fasudil composite salt and preparation method and application thereof
RU2701728C2 (en) New polycrystalline form of tenofovir prodrug and method for production thereof and use thereof
CN109535068B (en) Pyridine substituted chalcone compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof
JP2008503567A (en) Pharmaceutical composition for prevention and treatment of metabolic bone disease containing α-arylmethoxyacrylate derivative
JP5698741B2 (en) 13a- (S) Deacidified Tyrophorinine Salt, Pharmaceutical Composition and Use
CN104974221A (en) Dipeptide and tripeptide proteasome inhibitors as well as preparation method and pharmaceutical application thereof
CN115350182A (en) Application of WZ4141 or pharmaceutically acceptable salt thereof in preparing medicines for treating or relieving inflammation
EP1844775B1 (en) Therapeutic agent for the treatment of herpes progenitalis after development of lesions

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB03 Change of inventor or designer information

Inventor after: Xu Jinyi

Inventor after: Xie Shaowen

Inventor after: Xu Shengtao

Inventor after: Liu Jie

Inventor after: Wang Chaolei

Inventor before: Xu Jinyi

Inventor before: Xie Shaowen

Inventor before: Xu Shengtao

CB03 Change of inventor or designer information
GR01 Patent grant
GR01 Patent grant