CN103833658B - BTA base piperazine compounds and its preparation method and pharmaceutical composition - Google Patents

BTA base piperazine compounds and its preparation method and pharmaceutical composition Download PDF

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CN103833658B
CN103833658B CN201310409567.XA CN201310409567A CN103833658B CN 103833658 B CN103833658 B CN 103833658B CN 201310409567 A CN201310409567 A CN 201310409567A CN 103833658 B CN103833658 B CN 103833658B
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compound
acceptable salt
alkyl
bta
btas
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CN103833658A (en
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周延
张丽荣
周杰
周欣
王朋
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Original Pharmaceutical Port Life Science Research Liaoning Co ltd
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Shenyang Neptune Biotechnology Co Ltd
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Priority to CN201310409567.XA priority Critical patent/CN103833658B/en
Priority to EP13857383.7A priority patent/EP2924032B1/en
Priority to US14/647,378 priority patent/US9802929B2/en
Priority to JP2015543244A priority patent/JP2016500084A/en
Priority to PCT/CN2013/001441 priority patent/WO2014079154A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the BTA base piperazine compounds shown in a kind of formula (I) and its preparation method and pharmaceutical composition, wherein R, Rl、R2、R3、R4, Q and Y be as defined herein.

Description

BTA base piperazine compounds and its preparation method and pharmaceutical composition
Technical field
The present invention relates to a kind of BTA base piperazine compounds of formula (I) and its preparation method and pharmaceutical composition, wherein R、R1、R2、R3、R4, Y and Q be as defined herein.
Background technology
Multiclass clinically be present at present can be with vasodilatory medicine, for example, α1Receptor blocking pharmacon class medicine, including piperazine azoles Piperazine, Doxazosin, Terazosin etc., these medicines have obvious first dosage effect or postural hypotension, so as to limit this The extensive use of class medicine clinically；Ca2+Channel blocker, existing medicine include Amlodipine, nifedipine, felodipine Deng the clinically extensive use at present of, this kind of medicine, but its there is also the risk for suppressing heart simultaneously.
Therefore, there is still a need for the vasodilator drug that exploitation is new, to improve drug effect, to meet clinically different suffer from as far as possible The needs of person.
The content of the invention
One aspect of the present invention provides a kind of BTA base piperazine compounds of formula (I) and its can pharmaceutically connect The salt received,
Wherein
R is represented optionally by R5Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
R is by R5When monosubstituted, R5Represent H, halogen, CN, C1-C6Alkyl, C2-C6Alkoxy, CHO, CO (C1-C6Alkyl), COOH、COO(C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkyl), S (O) (C1- C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally taken by one or more halogen atoms in above-mentioned group Generation；
R is by R5When polysubstituted, R5H, halogen, CN, C are represented independently of one another1-C6Alkyl, C2-C6Alkoxy, CHO, CO (C1-C6Alkyl), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkane Base), S (O) (C1-C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally by one or more in above-mentioned group Individual halogen atom substitution；
R1、R2、R3、R4H, halogen, CN, C are represented independently of one another1-C6Alkyl, C1-C6Alkoxy, CHO, CO (C1-C6Alkane Base), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkyl), S (O) (C1-C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally former by one or more halogens in above-mentioned group Son substitution；
Q represents CH2Or oxygen；
Y represents the saturation that is optionally substituted by one or more halogen atoms or undersaturated containing 1-8 carbon atom Straight or branched alkyl, wherein one or more carbon are optionally substituted by the hetero atom selected from oxygen, sulphur and nitrogen；
Condition is
The heteroaryl is not pyrimidine radicals, benzopyrazoles base, Thienopyrimidine Ji, oxazoles and pyrimidine radicals or purine radicals；
When R is to represent methylene or ethylidene by the mono-substituted aryl of Cl and Y, R1-R4It is not all H；
When R is by CF3Mono-substituted aryl and when Y represents methylene, R1-R4It is not all H；
When Y represents methylene, R1-R4It is not all H；
Work as R2And R3It is OCH3When, R5It is not H.
Another aspect of the present invention provides formula BTA base piperazine compounds of (I) and its pharmaceutically acceptable The preparation method of salt：
(scheme one)
At a temperature of being included in 10-150 DEG C, BTA (A) is set to be urged with chloro alkyl bromide (B) in inorganic base and phase transfer Reaction generates N- chloro alkyl benzotriazole derivatives (C) in solvent in the presence of agent, then under reflux, makes itself and N- Substituted-piperazinyl (D) reaction generation compound (I-a) in solvent in the presence of organic base；
Or
Scheme (two)
At a temperature of being included in 10-150 DEG C, make the BTA (E) that N- hydroxyls substitute with chloro alkyl bromide (F) inorganic Reaction generates N- chlorinated alkoxies benzotriazole derivatives (G) in solvent in the presence of alkali, then under reflux, makes itself and N- Substituted-piperazinyl (D) reacts in the presence of organic base in solvent, generation compound (I-b)；
Wherein
R is represented optionally by R5Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
R is by R5When monosubstituted, R5Represent H, halogen, CN, C1-C6Alkyl, C2-C6Alkoxy, CHO, CO (C1-C6Alkyl), COOH、COO(C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkyl), S (O) (C1- C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally taken by one or more halogen atoms in above-mentioned group Generation；
R is by R5When polysubstituted, R5H, halogen, CN, C are represented independently of one another1-C6Alkyl, C2-C6Alkoxy, CHO, CO (C1-C6Alkyl), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkane Base), S (O) (C1-C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally by one or more in above-mentioned group Individual halogen atom substitution；
R1、R2、R3、R4H, halogen, CN, C are represented independently of one another1-C6Alkyl, C1-C6Alkoxy, CHO, CO (C1-C6Alkane Base), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkyl), S (O) (C1-C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally former by one or more halogens in above-mentioned group Son substitution；
Y represents the saturation that is optionally substituted by one or more halogen atoms or undersaturated containing 1-8 carbon atom Straight or branched alkyl, wherein one or more carbon are optionally substituted by the hetero atom selected from oxygen, sulphur and nitrogen；
Condition is
The heteroaryl is not pyrimidine radicals, benzopyrazoles base, Thienopyrimidine Ji, oxazoles and pyrimidine radicals or purine radicals；
When R is to represent methylene or ethylidene by the mono-substituted aryl of Cl and Y, R1-R4It is not all H；
When R is by CF3Mono-substituted aryl and when Y represents methylene, R1-R4It is not all H；
When Y represents methylene, R1-R4It is not all H；
Work as R2And R3It is OCH3When, R5It is not H.
Another aspect of the invention provides BTA base piperazine compounds and/or its pharmacy comprising formula (I) The pharmaceutical composition of upper acceptable salt.
Brief description of the drawings
Fig. 1 compounds (II-3) (10-8-10-5mol·L-1) to adrenaline AD (10-5mol·L-1) shrink rabbit from (numerical value is represented the cumulative concentration effect curve of body vasorelaxation action with mean ± SEMN=8).
Fig. 2 compounds (II-1) (10-8-3×10-5mol·L-1) to adrenaline AD (10-5mol·L-1) shrink rabbit (numerical value is represented the cumulative concentration effect curve of myocardium vessel diastole effect with mean ± SEMN=7).
Fig. 3 compounds (II-6) (10-9-10-6Mol/L) to adrenaline AD (10-5Mol/L rabbit myocardium vessel) is shunk (numerical value is represented the cumulative concentration effect curve of diastole effect with mean ± SEMN=7).
Fig. 4 compounds (II-3) (3 × 10-7-3×10-5mol·L-1) to high potassium liquid (60mmolL-1) shrink rabbit from (numerical value is represented the cumulative concentration effect curve of body vasorelaxation action with mean ± SEMN=8).
Fig. 5 compounds (II-1) (10-7-3×10-5mol·L-1) to high potassium liquid (60mmolL-1) shrink rabbit it is in vitro (numerical value is represented the cumulative concentration effect curve of vasorelaxation action with mean ± SEMN=6).
Fig. 6 compounds (II-6) (10-8-10-4Mol/L rabbit myocardium vessel diastole) is shunk to high potassium liquid (60mmol/L) (numerical value is represented the cumulative concentration effect curve of effect with mean ± SEMN=7).
Fig. 7 compounds (II-3) (3 × 10-6Mol/L), positive control Doxazosin (10-7Mol/L) antagonism noradrenaline Plain NA (3 × 10-7-10-4Mol/L) (numerical value is represented the cumulative concentration effect curve of contraction rabbit myocardium vessel with mean ± SEM* P ＜ 0.05, * * P ＜ 0.01, n=6).
Fig. 8 compounds (II-3) (10-5Mol/L), Amlodipine (10-7Mol/L) antagonism CaCl2(10-5-3×10- 1Mol/L) (numerical value is represented the cumulative concentration effect curve of contraction rabbit myocardium vessel with mean ± SEM* P ＜ 0.05, * * P ＜ 0.01, n=5).
Fig. 9 compounds (II-3) (3 × 10-6Mol/L) antagonism serotonin (10-8-3×10-4Mol/L) shrink rabbit from (numerical value is represented the cumulative concentration effect curve of body blood vessel with mean ± SEM* P ＜ 0.05, * * P ＜ 0.01, n= 5)。
Figure 10 compounds (II-6) (3 × 10-8Mol/L) antagonism phyenlephrinium (10-6-6×10-3Mol/L house) is shunk (numerical value is represented the cumulative concentration effect curve of rabbit myocardium vessel with mean ± SEM* P ＜ 0.05, * * P ＜ 0.01, n =8).
Figure 11 compounds (II-6) (10-5Mol/L) antagonism CaCl2(10-5-10-2Mol/L rabbit myocardium vessel) is shunk (numerical value is represented cumulative concentration effect curve with mean ± SEM* P ＜ 0.05, * * P ＜ 0.01, n=7).
Figure 12 compounds (II-6) (10-7Mol/L) antagonism serotonin (10-8-3×10-4Mol/L it is in vitro) to shrink rabbit (numerical value is represented the cumulative concentration effect curve of blood vessel with mean ± SEM* P ＜ 0.05, * * P ＜ 0.01, n=5).
Embodiment
Herein, term " cyclic hydrocarbon radical " includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl or cyclooctyl etc..
Herein, term " aryl " includes phenyl, naphthyl or indenyl etc..
Herein, term " heteroaryl " include furyl, pyridine radicals, pyrimidine radicals, benzothiazolyl, benzisothia oxazolyl, Benzoxazolyl, benzoisoxazole base, benzimidazolyl, benzopyrazoles base, benzofuranyl, benzo pyrimidine radicals, benzo pyridine Base Huo quinoxalinyls etc..
Herein, term " halogen " includes fluorine, chlorine, bromine or iodine.
Herein, term " alkyl " includes straight or branched alkyl." the C1-C6The example of alkyl " group include methyl, Ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, tertiary pentyl or n-hexyl Deng.
Herein, term " alkoxy " includes-O- alkyl, and wherein alkyl includes straight or branched alkyl." the C1-C6Alkane The example of epoxide " group includes methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy and hexyloxy etc..
Herein, in general, it is preferable, preferred, still more preferably, it is particularly preferred, extremely particularly preferred, Most preferably use can be mutually combined between definition.
In some embodiments, the invention provides the BTA base piperazine compounds of formula (I) and its pharmaceutically Acceptable salt,
Wherein
R is represented optionally by R5Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
R is by R5When monosubstituted, R5Represent H, halogen, CN, C1-C6Alkyl, C2-C6Alkoxy, CHO, CO (C1-C6Alkyl), COOH、COO(C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkyl), S (O) (C1- C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally taken by one or more halogen atoms in above-mentioned group Generation；
R is by R5When polysubstituted, R5H, halogen, CN, C are represented independently of one another1-C6Alkyl, C2-C6Alkoxy, CHO, CO (C1-C6Alkyl), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkane Base), S (O) (C1-C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally by one or more in above-mentioned group Individual halogen atom substitution；
R1、R2、R3、R4H, halogen, CN, C are represented independently of one another1-C6Alkyl, C1-C6Alkoxy, CHO, CO (C1-C6Alkane Base), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkyl), S (O) (C1-C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally former by one or more halogens in above-mentioned group Son substitution；
Q represents CH2Or oxygen；
Y represents the saturation that is optionally substituted by one or more halogen atoms or undersaturated containing 1-8 carbon atom Straight or branched alkyl, wherein one or more carbon are optionally substituted by the hetero atom selected from oxygen, sulphur and nitrogen；
Condition is
The heteroaryl is not pyrimidine radicals, benzopyrazoles base, Thienopyrimidine Ji, oxazoles and pyrimidine radicals or purine radicals；
When R is to represent methylene or ethylidene by the mono-substituted aryl of Cl and Y, R1-R4It is not all H；
When R is by CF3Mono-substituted aryl and when Y represents methylene, R1-R4It is not all H；
When Y represents methylene, R1-R4It is not all H；
Work as R2And R3It is OCH3When, R5It is not H.
In preferred embodiments, the invention provides the BTA base piperazine compounds of formula (I) and its pharmacy Upper acceptable salt,
Wherein
R is represented optionally by R5Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is preferably cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl or cyclooctyl；
The aryl or heteroaryl are preferably phenyl, naphthyl, furyl, pyridine radicals, benzothiazolyl, benzisothiazole Base, benzoxazolyl, benzoisoxazole base, benzimidazolyl, benzofuranyl, benzo pyrimidine radicals, benzo pyridine radicals Huo Kui Evil Quinoline base；
R is by R5When monosubstituted, R5Preferably represent H, halogen, CN, C1-C6Alkyl, C2-C6Alkoxy, CHO, CO (C1-C6Alkane Base), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S(C1-C6Alkyl), S (O) (C1-C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally taken by 1-3 halogen atom in above-mentioned group Generation；
R is by R5When polysubstituted, R5H, halogen, CN, C are preferably represented independently of one another1-C6Alkyl, C2-C6Alkoxy, CHO、CO(C1-C6Alkyl), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), N (C1-C6Alkyl)2、SH、S (C1-C6Alkyl), S (O) (C1-C6Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), in above-mentioned group moieties optionally by One or more halogen atom substitutions；
R1、R2、R3、R4H, halogen, CN, C are preferably represented independently of one another1-C6Alkyl, C1-C6Alkoxy, CHO, CO (C1-C6Alkyl), COOH, COO (C1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C1-C6Alkyl), S (O) (C1-C6 Alkyl), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally substituted by 1-3 halogen atom in above-mentioned group；
Q represents CH2Or oxygen；
Y represents the saturation that is optionally substituted by one or more halogen atoms or undersaturated containing 1-8 carbon atom Straight or branched alkyl, wherein one or more carbon are optionally substituted by the hetero atom selected from oxygen, sulphur and nitrogen；
Condition is
When R is to represent methylene or ethylidene by the mono-substituted aryl of Cl and Y, R1-R4It is not all H；
When R is by CF3Mono-substituted aryl and when Y represents methylene, R1-R4It is not all H；
When Y represents methylene, R1-R4It is not all H；
Work as R2And R3It is OCH3When, R5It is not H.
In a more preferred embodiment, the invention provides the BTA base piperazine compounds of formula (I) and its medicine Acceptable salt on,
Wherein
R is represented optionally by R5Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is more preferably cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
The aryl or heteroaryl are more preferably phenyl, naphthyl, furyl, pyridine radicals, benzothiazolyl, benzisothia Oxazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl, benzofuranyl Huo quinoxalinyls；
R is by R5When monosubstituted, R5More preferably represent H, halogen, CN, C1-C4Alkyl, C2-C4Alkoxy, CHO, CO (C1-C4 Alkyl), COOH, COO (C1-C4Alkyl), moieties are optionally substituted by 1-3 halogen atom in above-mentioned group；
R is by R5When polysubstituted, R5H, halogen, CN, C are more preferably represented independently of one another1-C4Alkyl, C2-C4Alkoxy, CHO、CO(C1-C4Alkyl), COOH, COO (C1-C4Alkyl), moieties are optionally by 1-3 halogen atom in above-mentioned group Substitution；
R1、R2、R3、R4H, F, Cl, Br, I, CN, CH are more preferably represented independently of one another3、OCH3、COCH3Or COOCH3；
Q represents CH2Or oxygen；
Y more preferably represents ethylidene, propylidene, butylidene, pentylidene or hexylidene, wherein the group optionally by One or more halogen atom substitutions；
Condition is
When R is by Cl or CF3Mono-substituted aryl and when Y represents methylene, R1-R4It is not all H；
Work as R2And R3It is OCH3When, R5It is not H.
In embodiment still more preferably, the invention provides the BTA base piperazine compounds of formula (I) And its pharmaceutically acceptable salt,
Wherein
R is represented optionally by R5Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is still more preferably cyclohexyl；
The aryl or heteroaryl still more preferably for phenyl, naphthyl, furyl, pyridine radicals, benzisothia oxazolyl, Benzoisoxazole base, benzofuranyl Huo quinoxalinyls；
R is by R5When monosubstituted, R5Still more preferably represent H, F, Cl, CN, CH3Or CF3；
R is by R5When polysubstituted, R5H, F, Cl, CN, CH are still more preferably represented independently of one another3Or CF3；
R1、R4H is still more preferably represented independently of one another；
R2、R3H, F, Cl, CN, CH are still more preferably represented independently of one another3Or COOCH3；
Q represents CH2Or oxygen；
Y still more preferably represents ethylidene, propylidene or butylidene；
Condition is
When R is by Cl or CF3Mono-substituted aryl and when Y represents methylene, R1-R4It is not all H.
In particularly preferred embodiments, the invention provides the BTA base piperazine compounds of formula (I) and its Pharmaceutically acceptable salt,
Wherein
R is represented optionally by R5Monosubstituted or polysubstituted aryl or heteroaryl；
The aryl or heteroaryl are particularly preferably phenyl, benzisothia oxazolyl, benzoisoxazole base or benzofuran Base；
R is by R5When monosubstituted, R5Particularly preferably represent H, F, Cl, CN, CH3Or CF3；
R is by R5When polysubstituted, R5H, F, Cl, CN, CH are particularly preferably represented independently of one another3Or CF3；
R1、R4H is particularly preferably represented independently of one another；
R2、R3H, F or Cl are particularly preferably represented independently of one another；
Q represents CH2Or oxygen；
Y particularly preferably represents ethylidene or propylidene；
Condition is
When R is by Cl or CF3Mono-substituted aryl and when Y represents methylene, R1-R4It is not all H.
In the particularly preferred embodiment of pole, the invention provides the BTA base piperazine compounds of formula (I) and Its pharmaceutically acceptable salt,
Wherein
R is represented optionally by R5Monosubstituted or polysubstituted aryl or heteroaryl；
The aryl or heteroaryl are very particularly preferably phenyl, benzoisoxazole base or benzisothia oxazolyl；
R is by R5When monosubstituted, R5Very particularly preferably represent H, F, Cl or CF3；
R is by R5When polysubstituted, R5H, F, Cl or CF are very particularly preferably represented independently of one another3；
R1、R2、R3、R4H is very particularly preferably represented independently of one another；
Y very particularly preferably represents ethylidene or propylidene,
Condition is
When R is by Cl or CF3Mono-substituted aryl and when Y represents methylene, R1-R4It is not all H.
In the most preferred embodiment, the invention provides the BTA base piperazine compounds of formula (I) and its medicine Acceptable salt on,
Wherein
R is most preferably represented optionally by R5Monosubstituted or polysubstituted phenyl or benzisothia oxazolyl；
R is by R5When monosubstituted, R5Most preferably represent H, Cl or CF3；
R is by R5When polysubstituted, R5H, Cl or CF are most preferably represented independently of one another3；
R1、R2、R3、R4H is most preferably represented independently of one another；
Y most preferably represents propylidene.
The pharmaceutically acceptable salt is preferably hydrochloride, hydrogen bromide salt, sulfate, mesylate, trifluoracetic acid Salt, tartrate, malate, succinate, maleate, citrate, phosphate, lactate, acetonate, acetic acid Salt, fumarate, oxaloacetate, esilate, oxalates, benzene sulfonate or isethionate.Pharmacy of the present invention Upper acceptable salt preferably contains the crystallization water of the crystallization water, the more preferably molecule containing 0.5-3.
The pharmaceutically acceptable salt is more preferably hydrochloride, hydrogen bromide salt, sulfate or mesylate.
The optimal pharmaceutically acceptable salt is preferably hydrochloride.
The BTA base piperazine compounds of formula (I) are still more preferably following compound：
Wherein compound of the invention most preferably exists in the form of hydrochloride, such as compound (I-1), (I-3) (I-6) most preferably exists in the form of formula (II-1), (II-3) and (II-6) hydrochloride respectively：
In some embodiments, the preparation method of the BTA base piperazine compounds of offer formula (I) of the present invention：
(scheme one)
At a temperature of being included in 10-150 DEG C, BTA (A) is set to be urged with chloro alkyl bromide (B) in inorganic base and phase transfer Reaction generates N- chloro alkyl benzotriazole derivatives (C) in solvent in the presence of agent, then under reflux, makes itself and N- Substituted-piperazinyl (D) reaction generation compound (I-a) in solvent in the presence of organic base；
Or
Scheme (two)
At a temperature of being included in 10-150 DEG C, make the BTA (E) that N- hydroxyls substitute with chloro alkyl bromide (F) inorganic Reaction generates N- chlorinated alkoxies benzotriazole derivatives (G) in solvent in the presence of alkali, then under reflux, makes itself and N- Substituted-piperazinyl (D) reacts in the presence of organic base in solvent, generation compound (I-b)；Wherein R, R1、R2、R3、R4With Y such as Upper definition.
The reaction of the first step of scheme (one) and scheme (two) respectively inorganic base and phase transfer catalyst and in the presence of in Carried out in solvent, the inorganic base is preferably sodium hydride, sodium hydroxide, sodium methoxide, caustic alcohol, sodium carbonate, sodium acid carbonate, hydrogen Change potassium, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium carbonate or saleratus, more preferably sodium hydride or sodium hydroxide；It is described Phase transfer catalyst is preferably TBAB, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate or Isosorbide-5-Nitrae, and 7,10,13,16- Hexaoxacyclooctadecane-6 (i.e. 18 hat 6) etc., more preferably TBAB；First step reaction solvent used is this area Interior conventional solvent, it is therefore preferable to water when sodium hydride (use except), 1-METHYLPYRROLIDONE (NMP) or N, N- dimethyl formyl Amine (DMF) and its mixture；The reaction temperature of the first step is 10-150 DEG C, preferably 15-130 DEG C, more preferably 20-100 DEG C；Reaction Time can select according to the experience of those skilled in the art, such as 0.5-20 hours, preferably 1-15 hours.
The second step of scheme (one) and scheme (two) reacts each comfortable organic base, more preferably in organic base and KI In the presence of carried out in solvent, the organic base is preferably diisopropyl ethyl amine, diethylamine, triethylamine, pyridine, tertiary fourth Amine, cyclopropylamine, di-n-butylamine, diisopropylamine or 1,2- dimethyl propylamine, more preferably diisopropyl ethyl amine；Second step is anti- Solvent that should be used is solvent conventional in the art, it is therefore preferable to acetonitrile, DMF, dimethyl sulfoxide (DMSO) (DMSO) or butanone and its Mixture；Reaction time can select according to the experience of those skilled in the art, such as 1-30 hours, preferably 5-25 hours.
The step of the inventive method preferably includes making product generate pharmaceutically acceptable salt with corresponding acid reaction. Acid wherein used can be hydrochloric acid, bromine hydracid, sulfuric acid, methanesulfonic acid, trifluoracetic acid, tartaric acid, malic acid, butanedioic acid, maleic acid, Citric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, fumaric acid, oxaloacetic acid, ethyl sulfonic acid, oxalic acid, benzene sulfonic acid or isethionic acid, more Preferably hydrochloric acid, bromine hydracid, sulfuric acid or methanesulfonic acid, most preferably hydrochloric acid.The salt-forming steps preferably enter in a solvent OK, solvent for use can be methanol, ethanol, propyl alcohol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methyl isopropyl Ketone, Methyl iso-butyl ketone (MIBK), acetonitrile, propionitrile, dimethylformamide, dimethyl acetamide, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO) or Tetramethylene sulfone etc., ethyl acetate and/or ethanol.
In some embodiments, the invention provides the BTA base piperazine compounds comprising formula (I) and/or its The pharmaceutical composition of pharmaceutically acceptable salt.
Described pharmaceutical composition include effective dose (such as 0.1-99.5 weight %) formula (I) compound and/or its salt with And pharmaceutically acceptable carrier.The carrier is such as, but not limited to, diluent (such as water), excipient；Adhesive, it is such as fine Tie up plain derivative, gelatin, polyvinylpyrrolidone etc.；Filler such as starch etc.；Burst apart agent such as calcium carbonate, sodium acid carbonate；Lubrication Agent such as calcium stearate or magnesium stearate etc..Furthermore it is also possible to other adjuvants such as flavouring agent and sweetener are added in the composition. For it is oral when, conventional solid pharmaceutical preparation such as tablet, pulvis or capsule etc. can be prepared into；During for injecting, it can be made It is standby into parenteral solution.The specific dosage of described pharmaceutical composition can be according to the state of an illness of clinical trial results and patient, age etc. by curing Teacher determines.
It is prepared by the method that the various formulations of the pharmaceutical composition of the present invention can use medical domain conventional.
In some embodiments, the invention provides the BTA base piperazine compounds of formula (I) and its pharmaceutically Acceptable salt is used for the purposes for preparing vasodilator drug.
The BTA base piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of the present invention have significant blood Pipe diastole acts on.Preferably, the compound and its pharmaceutically acceptable salt have stronger blocking α1Acceptor, Ca2+Passage, 5-HT2AOne or more effects in acceptor.Can have at it and be used as α1Receptor blocking pharmacon, Ca2+Channel blocker and 5-HT acceptors During dual or triple role in blocking agent, the compound can be by a variety of action pathway collective effects, so as to play difference Approach the advantages of, compensate for respective deficiency so that compound can play multiple advantage realize vasorelaxation action.It is more excellent Selection of land, compound of the invention can be used as effective three target spots vasodilator, that is, possess α1Acceptor, Ca2+Passage, 5-HT2ABy The triple blocking effects of body.Thus, it is not exclusively blocking the α of vascular smooth muscle1While acceptor, by blocking Ca2+Passage, example Resisting cardiac hypertrophy, protection vascular endothelial cell, antiatherosclerosis, suppression vascular smooth muscle hyperplasia or improvement brain is such as produced to follow Ring etc. acts on, and/or by blocking sinoatrial node calcium channel, reducing heart rate, effectively prevents tachycardia and palpitaition, so as to prevent head The generation of agent effect；And due to three kinds of blocking effects, make remaining α1Acceptor can still participate in pressor reflex, so as to prevent body Position property low blood pressure；Simultaneously as 5-HT2AReceptor blocking acts on, and is advantageous to treat heart failure and improves occlusive vascular patient's Supply of blood flow, therefore the hypertension with heart failure, the hypertension with artery sclerosis, the high blood with vessel endothelium and induced endothelial can be treated Pressure, middle and advanced stage hypertension or some intractable hypertensions.
BTA base piperazine compounds and its pharmaceutically acceptable salt and the existing clinic of the formula (I) of the present invention Drug for hypertension is compared, and has stronger antihypertensive activity, more preferable drug resistance and/or higher security.
Therefore the BTA base piperazine compounds of the formula (I) of the present invention and its pharmaceutically acceptable salt can be used for making Standby vasodilation class medicine, it is diseases related (such as treating vascular smooth muscle spasmus：Hypertension, heart failure, angina pectoris, Coronary heart disease etc.)；For the cerebral ischemia diseases as caused by vasopasm, myocardial ischemia disease, shock etc.；For renal ischaemia, The poor kidney as caused by Renal vascular spasm and periperal vascular spasm (such as Buerger's disease, Raynaud's disease Deng).
In addition, the present invention formula (I) BTA base piperazine compounds and its pharmaceutically acceptable salt with it is other Resisting vascular smooth muscle anticonvulsant drug (such as Amlodipine, Sertraline, captopril, benazepil, Valsartan, Propranolol, with And other diuretics etc.) share and can produce obvious synergy, therefore treatment can be prepared together with other medicines include the mankind The diseases related medicine of mammal vascular smooth muscle spasmus inside.
Prepare embodiment
1- (4- chlorobutyls) -1H- substitutes the preparation of BTA
Substitution 1H- BTAs (0.10mol) are dissolved in 30% (weight ratio) sodium hydrate aqueous solution 100ml, added Enter 4- chlorine NBB (34.3g, 0.20mol), TBAB (0.8g, 0.0025mol), mix 5 minutes.Reaction solution 60 DEG C are to slowly warm up to, stirring reaction 2 hours.Room temperature is cooled to, adds the extraction of 100ml dichloromethane, liquid separation, aqueous phase adds two Chloromethanes 100ml is extracted, and merges organic phase, is washed through 100ml saturated brines, liquid separation, is evaporated organic phase and obtains grease.Grease Through neutral Al2O3Chromatography or preparation HPLC isolate and purify, and obtain 1- (4- chlorobutyls) -1H- substitution BTAs, yield 30.0- 85.0%.
The preparation of 1- (4- (4- (substituted aryl) piperazine -1- bases) butyl) -1H- BTAs (I)
1- (4- chlorobutyls) -1H- BTAs (0.036mol) are dissolved in 100ml acetonitriles, are separately added into substitution virtue Base piperazine (0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), room temperature is stirred Mix 10 minutes, then temperature rising reflux reaction 10-20 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and the elution of methylene chloride/methanol mixed solvent, obtains formula (I) compound, yield 60.0-75.0%.
Embodiment 1
The preparation of 1- (4- (4- (3- chlorphenyls) piperazine -1- bases) butyl) -1H- BTAs (I-1)
BTA (11.9g, 0.10mol) is dissolved in 30% (weight ratio) sodium hydrate aqueous solution 100ml, added 4- chlorine NBB (34.3g, 0.20mol), TBAB (0.8g, 0.0025mol), mix 5 minutes.Reaction solution delays Slowly 60 DEG C are warming up to, stirring reaction 2 hours.Room temperature is cooled to, adds the extraction of 100ml dichloromethane, liquid separation, aqueous phase adds two Chloromethanes 100ml is extracted, and is merged organic phase, through 100ml saturated common salt water washings, liquid separation, is evaporated organic phase and obtains grease.Oily Thing is through neutral Al2O3Chromatography purifies, and dichloromethane eluent obtains 1- (4- chlorobutyls) -1H- BTA 17.0g, yield 81.0%.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 3- chlorophenylpiperazines (5.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-1) 7.8g, yield 70.3%.
Compound (I-1) (5.55g, 0.015mol) is dissolved in 50ml ethyl acetate.Under ice-water bath cooling condition, drop Add concentration 3mol/L hydrogen chloride/ethyl acetate solution, to reaction solution PH=2, stir 10 minutes, filter, dry, obtain chemical combination Thing (II-1) solid 5.4g, yield 88.0%.ESI-MS[M+H]+：M/z370.1.
Embodiment 2
The preparation of 1- (4- (4- (3- fluorophenyls) piperazine -1- bases) butyl) -1H- BTAs (I-2)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0-036mol) are dissolved in 100ml acetonitriles, are separately added into 3- fluorophenyls piperazine (5.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-2) 7.3g, yield 68.9%.ESI-MS[M+H]+：M/ z354.2.(the step of compound (I-2) generates its hydrochloride (II-2) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 3
The preparation of 1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- BTAs (I-3)
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 3- trifluoromethylphenypiperazine piperazines (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, Through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-3) 7.8g, yield 64.5%.
Compound (I-3) (6.05g, 0.015mol) is dissolved in 50ml ethyl acetate.Under ice-water bath cooling condition, drop Add concentration 3mol/L hydrogen chloride/ethyl acetate solution, to reaction solution PH=2, stir 10 minutes, filter, dry, obtain chemical combination Thing (II-3) solid 5.6g, yield 84.8%.ESI-MS[M+H]+：M/z404.2.
Embodiment 4
The preparation of the fluoro- 1- of 6- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- BTAs (I-4)
The fluoro- 1H- BTAs (13.7g, 0.10mol) of 6- are dissolved in 30% (weight ratio) sodium hydrate aqueous solution In 100ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (0.8g, 0.0025mol) are added, mixes 5 Minute.Reaction solution is to slowly warm up to 60 DEG C, stirring reaction 2 hours.Locate after being carried out by the post-processing approach of the first step in embodiment 1 Reason, isolates and purifies through preparation HPLC, obtains 1- (4- chlorobutyls) fluoro- 1H- BTAs 8.9g of -6-, yield 39.0%.
The fluoro- 1H- BTAs (8.2g, 0.036mol) of 1- (4- chlorobutyls) -6- are dissolved in 100ml acetonitriles, respectively Add 3- trifluoromethylphenypiperazine piperazines (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, Through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-4) 8.3g, yield 65.7%.ESI-MS[M+H ]+：M/z422.2.(the step of compound (I-4) generates its hydrochloride (II-4) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3。)
Embodiment 5
5,6- dimethyl -1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- BTAs (I-5) Prepare
It is water-soluble that 5,6- dimethyl -1H- BTAs (14.7g, 0.10mol) are dissolved in 30% (weight ratio) sodium hydroxide In liquid 100ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (0.8g, 0.0025mol) are added, is mixed 5 minutes.Reaction solution is to slowly warm up to 60 DEG C, stirring reaction 2 hours.Enter by the post-processing approach of the first step in synthetic example 1 Row post processing, isolates and purifies through preparation HPLC, obtains 1- (4- chlorobutyls) -5,6- dimethyl -1H- BTA 17.4g, yield 73.2%.
1- (4- chlorobutyls) -5,6- dimethyl -1H- BTAs (8.56g, 0.036mol) are dissolved in 100ml acetonitriles In, it is separately added into 3- trifluoromethylphenypiperazine piperazines (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), with And KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains Grease, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-5) 9.1g, yield 70.3%.ESI- MS[M+H]+：M/z432.2.(the step of compound (I-5) and hydrochloric acid reaction generate its hydrochloride (II-5) referring to embodiment 1 and Embodiment 3.)
Embodiment 6
The preparation of 3- (4- (4- (1H- BTA -1- bases) butyl) piperazine -1- bases) benzisothiazole (I-6)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 3- (piperazine -1- bases) benzisothiazole (6.58g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodate Potassium (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Thing, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-6) 8.2g, yield 69.6%.
Compound (I-6) (5.89g, 0.015mol) is dissolved in 50ml ethyl acetate and 5ml ethanol.Ice-water bath cools down Under the conditions of, concentration 3mol/L hydrogen chloride/ethyl acetate solution is added dropwise, to reaction solution PH=2, stirs 10 minutes, filters, do It is dry, obtain compound (II-6) solid 5.5g, yield 85.5%.ESI-MS[M+H]+：M/z393.2.
Embodiment 7
The preparation of 3- (4- (4- (1H- BTA -1- bases) butyl) piperazine -1- bases) benzoisoxazole (I-7)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 3- (piperazine -1- bases) benzoisoxazole (6.1g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodate Potassium (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Thing, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-6) 8.0g, yield 70.9%.ESI-MS[M+ H]+：M/z377.2.(the step of compound (I-7) generates its hydrochloride (II-7) with hydrochloric acid reaction is referring to embodiment 1 and implements Example 3.)
Embodiment 8
The preparation of the fluoro- 3- of 6- (4- (4- (1H- BTA -1- bases) butyl) piperazine -1- bases) benzoisoxazole (I-8)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 6- fluorine 3- (piperazine -1- bases) benzoisoxazole (6.1g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-8) 8.3g, yield 70.0%.ESI-MS [M+H]+：M/z395.2.(the step of compound (I-8) generates its hydrochloride (II-8) with hydrochloric acid reaction is referring to embodiment 1 and in fact Apply example 3.)
Embodiment 9
The preparation of the fluoro- 3- of 6- (4- (3- (1H- BTA -1- bases) propyl group) piperazine -1- bases) benzoisoxazole (I-9)
BTA (11.9g, 0.10mol) is dissolved in 30% (weight ratio) sodium hydrate aqueous solution 100ml, added 3- chlorobromopropanes (30.2g, 0.20mol), TBAB (0.8g, 0.0025mol), mix 5 minutes.Reaction solution delays Slowly 60 DEG C are warming up to, stirring reaction 2 hours.Room temperature is cooled to, adds the extraction of 100ml dichloromethane, liquid separation, aqueous phase adds two Chloromethanes 100ml is extracted, and is merged organic phase, through 100ml saturated common salt water washings, liquid separation, is evaporated organic phase and obtains grease.Oily Thing is through neutral Al2O3Chromatography purifies, and dichloromethane eluent obtains 1- (3- chloropropyls) -1H- BTA 15.6g, yield 80.0%.
1- (3- chloropropyls) -1H- BTAs (7.02g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into The fluoro- 3- of 6- (piperazine -1- bases) benzoisoxazole (6.6g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-9) 7.9g, yield 69.3%.ESI-MS [M+H]+：M/z380.2.(the step of compound (I-9) generates its hydrochloride (11-9) with hydrochloric acid reaction is referring to embodiment 1 and in fact Apply example 3.)
Embodiment 10
The preparation of 1- (3- (4- (2,3- dichlorophenyl) piperazine -1- bases) propyl group) -1H- BTAs (1-10)
1- (3- chloropropyls) -1H- BTAs are prepared using the method in embodiment 9.
1- (3- chloropropyls) -1H- BTAs (7.02g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 2,3- dichlorophenylpiperazines (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-10) 8.2g, yield 70.2%.ESI-MS[M+H]+：M/ z389.1.(the step of compound (I-10) generates its hydrochloride (II-10) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 11
The preparation of 1- (3- (4- (3- aminomethyl phenyls) piperazine -1- bases) propyl group) -1H- BTAs (I-11)
1- (3- chloropropyls) -1H- BTAs are prepared using the method in embodiment 9.
1- (3- chloropropyls) -1H- BTAs (7.02g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 3- aminomethyl phenyls piperazine (5.3g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-11) 7.5g, yield 74.6%.ESI-MS[M+H]+：M/ z335.2.(the step of compound (I-11) generates its hydrochloride (II-11) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 12
The preparation of 1- (4- (4- (3- cyano-phenyls) piperazine -1- bases) butyl) -1H- BTAs (I-12)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 3- cyano-phenyls piperazine (5.6g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-12) 7.6g, yield 70.5%.ESI-MS[M+H]+：M/ z360.2.(the step of compound (I-12) generates its hydrochloride (II-12) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 13
The preparation of 1- (5- (4- (3- trifluoromethyls) piperazine -1- bases) amyl group) -1H- BTAs (I-13)
BTA (11.9g, 0.10mol) is dissolved in 30% (weight ratio) sodium hydrate aqueous solution 100ml, added 5- chlorine bromo pentane silane (36.8g, 0.20mol), TBAB (0.8g, 0.0025m0l), mix 5 minutes.Reaction solution delays Slowly 60 DEG C are warming up to, stirring reaction 2 hours.Room temperature is cooled to, adds the extraction of 100ml dichloromethane, liquid separation, aqueous phase adds two Chloromethanes 100ml is extracted, and is merged organic phase, through 100ml saturated common salt water washings, liquid separation, is evaporated organic phase and obtains grease.Oily Thing is through neutral Al2O3Chromatography purifies, and dichloromethane eluent obtains 1- (5- chlorine amyl group) -1H- BTA 15.8g, yield 71.0%.
1- (5- chlorine amyl group) -1H- BTAs (8.0g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 3- Trifluoromethylphenypiperazine piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0-03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-13) 7.7g, yield 61.5%.ESI-MS[M+H]+：M/ z417.2.(the step of compound (I-13) generates its hydrochloride (II-13) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 14
The preparation of 1- (4- (4- (2- furyls) piperazine -1- bases) butyl) -1H- BTAs (I-14)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 4- (2- furyls) piperazine (4.6g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 20h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-14) 7.0g, yield 71.3%.ESI-MS[M+H]+：m/ z325.2.(the step of compound (I-14) generates its hydrochloride (II-14) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 15
The preparation of 1- (4- (4- (4- pyridine radicals) piperazine -1- bases) butyl) -1H- BTAs (I-15)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 4- (4- pyridine radicals) piperazine (4.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 20h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-15) 6.6g, yield 65.3%.ESI-MS[M+H]+：m/ z336.2.(the step of compound (I-15) generates its hydrochloride (II-15) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 16
The preparation of 1- (4- (4- cyclohexylpiperazin -1- bases) butyl) -1H- BTAs (I-16)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 4- (1- cyclohexyl) piperazine (5.1g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 20h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-16) 6.5g, yield 63.7%.ESI-MS[M+H]+：m/ z341.2.(the step of compound (I-16) generates its hydrochloride (II-16) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 17
The preparation of 1- (4- (4- (1- naphthyls) piperazine -1- bases) butyl) -1H- BTAs (I-17)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 4- (1- naphthyls) piperazine (6.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 20h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutrality Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-17) 6.9g, yield 60.1%.ESI-MS[M+H]+：m/ z385.2.(the step of compound (I-17) generates its hydrochloride (II-17) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 18
The preparation of 1- (4- (4- (2- quinoxalinyls) piperazine -1- bases) butyl) -1H- BTAs (I-18)
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into 4- (2- quinoxalinyls) piperazine (6.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 20h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, Through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-18) 7.3g, yield 62.7%.ESI-MS[M+H ]+：m/z387.2.(the step of compound (I-18) generates its hydrochloride (II-18) with hydrochloric acid reaction is referring to embodiment 1 and implements Example 3.)
Embodiment 19
The system of 1- (4- (4- (3- (the fluoro- benzisothia oxazolyls of 6-)) piperazine -1- bases) butyl) -1H- BTAs (I-19) It is standby
1- (4- chlorobutyls) -1H- BTAs are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into The fluoro- 3- of 6- (piperazine -4- bases) benzisothiazole (6.6g, 0.05mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 20h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-19) 8.2g, yield 66.5%.ESI-MS [M+H]+：m/z410.2.(the step of compound (I-19) and hydrochloric acid reaction generate its hydrochloride (II-19) referring to embodiment 1 and Embodiment 3.)
Embodiment 20
1- (the preparations of 3- (4- (3- (the fluoro- benzofuranyls of 6-) piperazine -1- bases) propyl group) -1H- BTAs (I-20)
1- (3- chloropropyls) -1H- BTAs are prepared using the method in embodiment 9.
1- (3- chloropropyls) -1H- BTAs (7.55g, 0.036mol) are dissolved in 100ml acetonitriles, are separately added into The fluoro- 3- of 6- (piperazine -4- bases) benzofuran (6.6g, 0.05mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodine Change potassium (5.0g, 0.03mol), be stirred rear temperature rising reflux reaction 20h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Thing, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-20) 7.9g, yield 69.1%.ESI-MS[M +H]+：m/z379.2.(the step of compound (I-20) generates its hydrochloride (II-20) with hydrochloric acid reaction is referring to embodiment 1 and in fact Apply example 3.)
Embodiment 21
The preparation of the chloro- 1- of 6- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- BTAs (I-21)
The chloro- BTAs of 6- (15.3g, 0.10mol) are dissolved in 30% (weight ratio) sodium hydrate aqueous solution 100ml In, 4- chlorine NBB (34.3g, 0.20mol), TBAB (0.8g, 0.0025mol) are added, is mixed 5 minutes. Reaction solution is to slowly warm up to 60 DEG C, stirring reaction 2 hours.Room temperature is cooled to, adds the extraction of 100ml dichloromethane, liquid separation, aqueous phase Add dichloromethane 100ml extractions, merge organic phase, through 100ml saturated common salt water washings, liquid separation, be evaporated organic phase obtain it is oily Shape thing.Grease is through neutral Al2O3Chromatography purifies, and dichloromethane eluent obtains the chloro- 1- of 6- (4- chlorobutyls) -1H- BTAs 19.2g, yield 79.0%.
The chloro- 1- of 6- (4- chlorobutyls) -1H- BTAs (8.75g, 0.036mol) are dissolved in 100ml acetonitriles, respectively Add 3- trifluoromethylphenypiperazine piperazines (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, Through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-21) 8.5g, yield 64.7%.ESI-MS[M+H ]+：m/z437.2.(the step of compound (I-21) generates its hydrochloride (II-21) with hydrochloric acid reaction is referring to embodiment 1 and implements Example 3.)
Embodiment 22
The system of 6- cyano group -1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- BTAs (I-22) It is standby
6- cyano group-BTA (14.4g, 0.10mol) is dissolved in 30% (weight ratio) sodium hydrate aqueous solution 100ml In, 4- chlorine NBB (34.3g, 0.20mol), TBAB (0.8g, 0.0025mol) are added, is mixed 5 minutes. Reaction solution is to slowly warm up to 60 DEG C, stirring reaction 2 hours.Room temperature is cooled to, adds the extraction of 100ml dichloromethane, liquid separation, aqueous phase Add dichloromethane 100ml extractions, merge organic phase, through 100ml saturated common salt water washings, liquid separation, be evaporated organic phase obtain it is oily Shape thing.Grease is through neutral Al2O3Chromatography purifies, and dichloromethane eluent obtains 6- cyano group -1- (4- chlorobutyls) -1H- benzos three Azoles 17.8g, yield 76.0%.
6- cyano group -1- (4- chlorobutyls) -1H- BTAs (8.42g, 0.036mol) are dissolved in 100ml acetonitriles, point Not Jia Ru 3- trifluoromethylphenypiperazine piperazines (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodate Potassium (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Thing, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-22) 8.5g, yield 66.4%.ESI-MS[M +H]+：m/z428.2.(the step of compound (I-22) generates its hydrochloride (II-22) with hydrochloric acid reaction is referring to embodiment 1 and in fact Apply example 3.)
Embodiment 23
6- methoxycarbonyl groups -1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- BTAs (I-23) Preparation
6- methoxycarbonyl groups-BTA (17.7g, 0.10mol) is dissolved in 30% (weight ratio) sodium hydrate aqueous solution In 100ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (0.8g, 0.0025mol) are added, mixes 5 Minute.Reaction solution is to slowly warm up to 60 DEG C, stirring reaction 2 hours.Room temperature is cooled to, adds the extraction of 100ml dichloromethane, point Liquid, aqueous phase add dichloromethane 100ml extractions, merge organic phase, through 100ml saturated common salt water washings, liquid separation, be evaporated organic Mutually obtain grease.Grease is through neutral Al2O3Chromatography purifies, and dichloromethane eluent obtains 6- methoxycarbonyl groups -1- (4- neoprenes Base) -1H- BTA 19.5g, yield 73.0%.
6- methoxycarbonyl groups -1- (4- chlorobutyls) -1H- BTAs (9.61g, 0.036mol) are dissolved in 100ml acetonitriles In, it is separately added into 3- trifluoromethylphenypiperazine piperazines (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), with And KI (5.0g, 0.03mol), it is stirred rear temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains Grease, through neutral Al2O3Chromatography purifies, and dichloromethane eluent, obtains compound (I-23) 8.8g, yield 63.4%.ESI- MS[M+H]+：m/z461.2.(the step of compound (I-23) generates its hydrochloride (II-23) with hydrochloric acid reaction is referring to embodiment 1 With embodiment 3.)
Embodiment 24
1- (the systems of 4- (4- (3- (the fluoro- benzoisoxazole bases of 6-) piperazine -1- bases) propoxyl group) -1H- BTAs (I-24) It is standby
I-hydroxybenzotriazole (0.01mol) is dissolved in 10ml NMP, be added portionwise 50% weight than sodium hydrogen The solid paraffin mixture of (0.01mol), stirring reaction 0.5h.Meanwhile by 3- chlorobromopropanes (0.015mol), be dissolved in 5ml In NMP, add in above-mentioned solution, at room temperature stirring reaction 12h.Reaction solution is poured into 50ml water, ethyl acetate extraction (3 × 50mL), merge organic phase, through 30ml water washings, add anhydrous magnesium sulfate and dry organic phase, filtering, solvent evaporated, grease Through neutral Al2O3Chromatography or preparation HPLC isolate and purify, and obtain 1- (3- chlorine propoxyl group) BTA, yield 75.0%.
1- (3- chlorine propoxyl group) BTA (0.06mol) is dissolved in 150ml acetonitriles, is separately added into 4- (3- (6- Fluoro- benzoisoxazole base)) piperazine (0.05mol), diisopropyl ethyl amine (0.2mol), and KI (0.05mol), room Temperature descends mixing 10 minutes, then temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, passes through Neutral Al2O3Chromatography purifies, and the elution of methylene chloride/methanol mixed solvent, obtains 1- (4- (4- (3- (the fluoro- benzoisoxazoles of 6- Base) piperazine -1- bases) propoxyl group) -1H- BTAs (I-24) 13.4g, yield 67.6%.ESI-MS[M+H]+：m/z396.2. (the step of compound (I-24) generates its hydrochloride (II-24) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 25
The fluoro- 1- of 6- (4- (4- (3- (the fluoro- benzisothia oxazolyls of 6-) piperazine -1- bases) propoxyl group) -1H- BTAs (I- 25) preparation
The fluoro- I-hydroxybenzotriazoles of 6- (0.01mol) are dissolved in 10ml NMP, be added portionwise 50% weight than sodium hydrogen The solid paraffin mixture of (0.01mol), stirring reaction 0.5h.Meanwhile by 3- chlorobromopropanes (0.015mol), be dissolved in 5ml In NMP, add in above-mentioned solution, at room temperature stirring reaction 12h.Reaction solution is poured into 50ml water, ethyl acetate extraction (3 × 50mL), merge organic phase, through 30ml water washings, add anhydrous magnesium sulfate and dry organic phase, filtering, solvent evaporated, grease Through neutral Al2O3Chromatography or preparation HPLC isolate and purify, and obtain the fluoro- 1- of 6- (3- chlorine propoxyl group) BTA, yield 75.0%.
The fluoro- 1- of 6- (3- chlorine propoxyl group) BTA (0.06mol) is dissolved in 150ml acetonitriles, is separately added into 4- (3- (the fluoro- benzisothia oxazolyls of 6-)) piperazine (0.05mol), diisopropyl ethyl amine (0.2mol), and KI (0.05mol), At room temperature mix 10 minutes, then temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, Through neutral Al2O3Chromatography purifies, and the elution of methylene chloride/methanol mixed solvent, obtains the fluoro- 1- of 6- (4- (4- (3- (the fluoro- benzos of 6- Isothiazolyl) piperazine -1- bases) propoxyl group) -1H- BTAs (I-25) 14.1g, yield 65.6%.ESI-MS[M+H]+：m/ z430.1.(the step of compound (I-25) generates its hydrochloride (II-25) with hydrochloric acid reaction is referring to embodiment 1 and embodiment 3.)
Embodiment 26
Compound (II-1)-(II-25) is to causing convulsion agent to cause the diastole for shrinking rabbit myocardium vessel smooth muscle to act on
1 experimental animal：
Rabbit, male and female dual-purpose, body weight 2.0-3.0kg, provided by Chinese Medical Sciences University's Experimental Animal Center.
2 medicines and reagent
Compound (II-1)-(II-25) is made by oneself using embodiment method；
Sodium chloride (NaCl)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20120413；
Potassium chloride (KCl)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20111123；
Anhydrous magnesium sulfate (MgSO4)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20101029；
Anhydrous calcium chloride (CaCl2)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20110314；
Sodium acid carbonate (NaHCO3)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20120507；
Glucose (Glucose)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20120512；
Potassium dihydrogen phosphate (KH2PO4)：It is purchased from Tianjin great Mao chemical reagent factory products, lot number：20110928；
Sodium chloride injection (NaCl)：It is purchased from Zhiying Pharmaceutical Factory, Shenyang, lot number：12021001；
Adrenalin hydrochloride parenteral solution (Epinephrine Hydrochloride Injection) specification：1mg/1ml, It is purchased from Grandpharma (China) Co., Ltd., lot number 120105；
Noradrenaline bitartrate (Norepinephrine Bitartrate Injection) specification 2mg/1ml, Grandpharma (China) Co., Ltd., lot number 120304.
3 laboratory apparatus
HSS-1 (B) type thermostatic bath：Chengdu Instruement Factory；
RM6240B type multi-path physiology signal acquiring processing systems：Chengdu Instruement Factory；
JZJ01 type muscle tone transducers：Chengdu Instruement Factory；
YPJ01 type pressure transducers：Chengdu Instruement Factory；
TG-328A photoelectric analytical balances：Shanghai balance equipment factory；
T-500 type electronic balances：Changshu Shuan Jie testers factory；
Micropipettor：Shanghai Rong Tai Biochemical Engineering Co., Ltd；
Electric-heated thermostatic water bath：Tianjin Stettlen Instrument Ltd..
The preparation of 4 nutrient solutions
Krebs-Henseleit (K-H) physiological solution：NaCl6.92 (concentration unit), KCl0.35, MgSO40.29, KH2PO40.16, CaCl20.28, NaHCO32.1, Glucose2.0 (g/L), pH7.2.
High potassium solution：KCl is added after the NaCl that equimolar number will be removed in K-H liquid to be configured to contain K+60mmol/L improvement K-H liquid.
Without calcium K-H liquid：By the CaCl in K-H liquid2Remove, add the KCl of equimolar number, and add EDTA-2Na+ 0.1mmol/L, other compositions are constant.
Without the high potassium liquid of calcium：By the CaCl in high potassium liquid2Remove, add the KCl of equimolar number, and add EDTA-2Na+ 0.1mmol/L, other compositions are constant.
The preparation of compound (II-3) solution：Certain mass compound (II-3) sample is weighed, using distilled water as solvent It is diluted to series concentration (10-10-10-3Mol/L), it is standby.
The preparation of 5 rabbit myocardium vessel smooth muscle samples
Rabbit, animal is hit after swooning and split thoracic cavity rapidly, descending aorta is separated, by connective tissue and peripheral adipose tissue It (if carrying out Serotonin receptor antagonistic experiment, should also use smooth stainless steel rod iron to remove endothelial cell) after removal, be cut into 3-5mm vascular circles, then steel wire hook pass through vascular circle, one end is fixed on ventilation hook, and the other end is connected on tonotransducer, is put In filling in the bath pipe of 20ml nutrient solutions, tension variation is recorded by recorder.37 ± 0.5 DEG C of keeping temperature in bath pipe, and with The speed of 1-2 bubble per second is passed through mixed gas (95%O2+ 5%CO2).Sample initial load 1.5g, is changed once for every 20 minutes Nutrient solution, balance 2 hours, start to test after baseline stability.
6 specific test operations and result of the test
6.1 compounds (II-1)-(II-25) is to causing convulsion agent adrenalin hydrochloride (AD) to cause contraction rabbit myocardium vessel to be put down Sliding flesh diastole effect
After sample tension stability, one section of waveform is recorded, is added into bath pipe and causes convulsion agent adrenalin hydrochloride (AD) (10- 5Mol/L) induction is shunk, and after maximum collapse is reached, fully rinses sample, changes within every 20 minutes a K-H liquid, is balanced 60 minutes, After baseline restorer is steady, convulsion agent induction is caused to shrink with same concentration again.When after once shrink maximum reaction with it is preceding once basic When consistent, accumulation adds (II-1)-(II-25) solution (1 × 10 prepared-8-1×10-3Mol/L), wave recording.With (II-1)-(II-25) diastole percentage is ordinate, and maximum stretching reaction makees effect curve for 100%.Wherein (II-3), (II-1) and (II-6) diastole effect it is most obvious, its each concentration bear logarithm be abscissa draw amount effect curve, see respectively Fig. 1, Fig. 2 and Fig. 3.
By can be seen that in Fig. 1, compound (II-3) causes sample caused by convulsion agent to shrink to AD diastole effect, and it is on kidney Certain dose dependent is presented in the diastole effect of parathyrine, Rabbit Aorta contraction caused by compound (II-3) diastole AD- logEC50It is worth for 6.19 ± 0.03；Likewise, by can be seen that in Fig. 2, compound (II-1) is acted on adrenergic diastole Certain dose dependent is presented ,-the logEC that Rabbit Aorta caused by its diastole AD shrinks50It is worth for 6.01 ± 0.02；By scheming It can be seen that in 3 ,-the logEC that Rabbit Aorta caused by compound (II-6) diastole AD shrinks50It is worth for 8.07 ± 0.06.
The diastole that compound (II-1)-(II-25) shrinks rabbit myocardium vessel smooth muscle to AD acts on as shown in table 1：
The diastole that the compound of table 1 (II-1)-(II-25) shrinks rabbit myocardium vessel smooth muscle to AD acts on
Compound -logEC50 Compound -logEC50
II-1 6.01±0.02 II-14 4.45±0.04
II-2 5.52±0.03 II-15 4.15±0.03
II-3 6.19±0.03 II-16 4.26±0.06
II-4 5.41±0.03 II-17 3.88±0.04
II-5 4.39±0.04 II-18 3.83±0.05
II-6 8.07±0.06 II-19 4.05±0.03
II-7 4.89±0.05 II-20 4.52±0.03
II-8 5.31±0.04 II-21 5.21±0.04
II-9 5.56±0.03 II-22 4.01±0.04
II-10 5.72±0.05 II-23 4.26±0.03
II-11 5.47±0.04 II-24 4.88±0.04
II-12 4.51±0.05 II-25 4.28±0.05
II-13 4.39±0.04
6.2 compounds (II-1)-(II-25) is to causing convulsion agent High potassium solution to cause contraction rabbit myocardium vessel smooth muscle to be relaxed Zhang Zuoyong
After sample tension stability, one section of waveform is recorded, is added into bath pipe and causes convulsion agent adrenalin hydrochloride (AD) (10- 5Mol/L) induction is shunk, and after maximum collapse is reached, fully rinses sample, changes within every 20 minutes a K-H liquid, is balanced 60 minutes, After baseline restorer is steady, shunk with the high potassium liquid induction of convulsion agent is caused.When after once shrink maximum reaction with it is preceding once basically identical When, accumulation adds (II-1)-(II-25) solution (1 × 10 prepared-8-1×10-3Mol/L), wave recording.With (II-1)- (II-25) diastole percentage is ordinate, and maximum stretching reaction makees effect curve for 100%.Wherein the diastole of (II-3) is made With more apparent, it is that abscissa draws amount effect curve that its each concentration, which bears logarithm, sees Fig. 4；Wherein (II-1) also has obvious diastole Effect, its amount effect curve are shown in Fig. 5.
Figure 4, it can be seen that compound (II-3) causes sample caused by convulsion agent to shrink to high potassium liquid diastole effect, it is right Certain dose dependent is presented in the diastole effect of high potassium liquid, and Rabbit Aorta caused by the high potassium liquid of compound (II-3) diastole is received - the logEC of contracting50It is worth for 5.55 ± 0.03；Likewise, visible in Fig. 5, diastole effect of the compound (II-1) to high potassium liquid is also in Now certain dose dependent ,-logEC that Rabbit Aorta caused by the high potassium liquid of its diastole shrinks50It is worth for 5.64 ± 0.01；Figure - logEC visible in 6, that Rabbit Aorta caused by the high potassium liquid of compound (II-6) diastole shrinks50It is worth for 4.77 ± 0.06.
Compound (II-1)-(II-25) shrinks the diastole of rabbit myocardium vessel smooth muscle to causing convulsion agent High potassium solution to cause Effect is as shown in table 2：
The diastole that the compound of table 2 (II-1)-(II-25) shrinks rabbit myocardium vessel smooth muscle to High potassium solution acts on
Compound -logEC50 Compound -logEC50
II-1 5.64±0.01 II-14 3.85±0.04
II-2 5.13±0.03 II-15 3.73±0.03
II-3 5.55±0.03 II-16 3.92±0.02
II-4 4.61±0.03 II-17 3.54±0.03
II-5 3.94±0.04 II-18 3.43±0.04
II-6 4.77±0.06 II-19 3.85±0.03
II-7 4.49±0.05 II-20 4.46±0.03
II-8 5.31±0.04 II-21 4.91±0.04
II-9 5.43±0.03 II-22 4.31±0.03
II-10 5.33±0.04 II-23 4.11±0.02
II-11 5.22±0.04 II-24 4.58±0.04
II-12 4.61±0.05 II-25 3.88±0.02
II-13 3.93±0.04
Embodiment 27
Diastole study on mechanism of the compound (II-3) to rabbit myocardium vessel smooth muscle
1 experimental animal：
Rabbit, male and female dual-purpose, body weight 2.0-3.0kg, provided by Chinese Medical Sciences University's Experimental Animal Center.
2 medicines and reagent
Compound (II-3) is made by oneself using the method for embodiment 3；
Sodium chloride (NaCl)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20120413；
Potassium chloride (KCl)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20111123；
Anhydrous magnesium sulfate (MgSO4)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20101029；
Anhydrous calcium chloride (CaCl2)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20110314；
Sodium acid carbonate (NaHCO3)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20120507；
Glucose (Glucose)：It is purchased from Tianjin great Mao chemical reagent factories, lot number：20120512；
Potassium dihydrogen phosphate (KH2PO4)：It is purchased from Tianjin great Mao chemical reagent factory products, lot number：20110928；
Sodium chloride injection (NaC1)：It is purchased from Zhiying Pharmaceutical Factory, Shenyang, lot number：12021001；
Adrenalin hydrochloride parenteral solution (Epinephrine Hydrochloride Injection) specification：1mg/1ml, It is purchased from Grandpharma (China) Co., Ltd., lot number 120105；
Noradrenaline bitartrate (Norepinephrine Bitartrate Injection) specification 2mg/1ml, Grandpharma (China) Co., Ltd., lot number 120304；
Carclura (Doxazosin Mesylate)：It is purchased from Suizhou Jia Ke medication chemistries Co., Ltd, lot number： 20110305；
Amlodipine besylate tablets (Amlodipine Besylate Tablets)：Pfizer inc is purchased from, is advised Lattice：5mg/ piece lot numbers：1205018；Adrenalin hydrochloride parenteral solution (Epinephrine Hydrochloride Injection) Specification：1mg/1ml, it is purchased from Grandpharma (China) Co., Ltd., lot number 120105；
(R)-phenylephrine hydrochloride ((R)-Phenylephrine Hydrochloride), the uncommon love (Shanghai) of ladder are changed Into industrial development Co., Ltd, lot number：GJ01-TESP；
Serotonin Creatinine Sulfate Monohydrate (5-HT), Tokyo HuaCheng Industry Co., Ltd, Lot number：AZ01-TBKD；
Heparin sodium injection (Heparin sodium)：Ten thousand nation's pharmacy specifications：2ml/12500 units, lot number：101115；
Ethylurethanm (Urethane)：China Medicine (Group) Shanghai Chemical Reagent Co., lot number：C30191228；
Ethylenediamine tetra-acetic acid (EDTA), Tianjin great Mao chemical reagent factory products, lot number：20050809.
3 laboratory apparatus
HSS-1 (B) type thermostatic bath：Chengdu Instruement Factory；
RM6240B type multi-path physiology signal acquiring processing systems：Chengdu Instruement Factory；
JZJ01 type muscle tone transducers：Chengdu Instruement Factory；
YPJ01 type pressure transducers：Chengdu Instruement Factory；
TG-328A photoelectric analytical balances：Shanghai balance equipment factory；
T-500 type electronic balances：Changshu Shuan Jie testers factory；
Micropipettor：Shanghai Rong Tai Biochemical Engineering Co., Ltd；
Electric-heated thermostatic water bath：Tianjin Stettlen Instrument Ltd..
The preparation of 4 nutrient solutions
Krebs-Henseleit (K-H) physiological solution：NaCl6.92 (concentration unit), KCl0.35, MgSO40.29, KH2PO40.16, CaCl20.28, NaHCO32.1, Glucose2.0 (g/L), pH7.2.
High potassium solution：KCl is added after the NaCl that equimolar number will be removed in K-H liquid to be configured to contain K+60mmol/L improvement K-H liquid.
Without calcium K-H liquid：By the CaCl in K-H liquid2Remove, add the KCl of equimolar number, and add EDTA-2Na+ 0.1mmol/L, other compositions are constant.
Without the high potassium liquid of calcium：By the CaCl in high potassium liquid2Remove, add the KCl of equimolar number, and add EDTA-2Na+ 0.1mmol/L, other compositions are constant.
The preparation of compound (II-3) solution：Certain mass compound (II-3) sample is weighed, using distilled water as solvent It is diluted to series concentration (10-10-10-4Mol/L), it is standby.
The preparation of 5 rabbit myocardium vessel smooth muscle samples
Rabbit, animal is hit after swooning and split thoracic cavity rapidly, descending aorta is separated, by connective tissue and peripheral adipose tissue It (if carrying out Serotonin receptor antagonistic experiment, should also use smooth stainless steel rod iron to remove endothelial cell) after removal, be cut into 3-5mm vascular circles, then steel wire hook pass through vascular circle, one end is fixed on ventilation hook, and the other end is connected on tonotransducer, is put In filling in the bath pipe of 20ml nutrient solutions, tension variation is recorded by recorder.37 ± 0.5 DEG C of keeping temperature in bath pipe, and with The speed of 1-2 bubble per second is passed through mixed gas (95%O2+ 5%CO2).Sample initial load 1.5g, is changed once for every 20 minutes Nutrient solution, balance 2 hours, start to test after baseline stability.
6 experimental implementations and result of the test
Antagonism of 6.1 compounds (II-3) to family's rabbit vascular smooth muscle α receptor stimulating agents
6.1.1 compound (II-3) accumulates the influence for shrinking amount effect curve to norepinephrine
After sample tension stability, one section of waveform is recorded, the accumulation addition norepinephrine (NA) (3 × 10 into bath pipe-7-6×10-5Mol/L) until reaching maximum reaction, wave recording.Then sample is rinsed repeatedly with K-H liquid, after balancing 1h, add Enter compound (II-3) (3 × 10-6Mol/L), NA (3 × 10 is added with same method again after 20 minutes-7-3×10-4Mol/L).With most Big reaction is that 100%, NA percentage of contractions are ordinate, and it is that abscissa draws amount effect curve, additionization that each concentration of NA, which bears logarithm, Compound (II-3) (3 × 10-6Mol/L after), such as Fig. 7, NA amount effect curves are substantially parallel to move to right, and maximum reaction is almost unchanged, to each After concentration-response percentage carries out statistics t inspections, most P values ＜ 0.01, significant difference be present.Compound (II-3) antagonism NA shrinks the pA of Rabbit Aorta2It is worth for 6.02 ± 0.13.
6.1.2 positive control drug Doxazosin accumulates the influence for shrinking amount effect curve to norepinephrine
Sample is rinsed repeatedly with K-H liquid on the basis of upper step, after balancing 1h, adds Doxazosin (10-7Mol/L), 15 NA is added with same method again after minute.With maximum reaction be 100%, NA percentage of contractions for ordinate, NA (3 × 10-7-3×10- 4Mol/L it is that abscissa draws amount effect curve that) each concentration, which bears logarithm, adds medicine Doxazosin (10-7Mol/L after), such as Fig. 7, NA Amount effect curve is substantially parallel to move to right, and maximum reaction is almost unchanged, more after carrying out statistics t inspections to each concentration-response percentage , significant difference be present in number P values ＜ 0.01.Medicine Doxazosin antagonism NA shrinks the pA of Rabbit Aorta2Be worth for 7.16 ± 0.24。
Examined through statistics t, pA of the compound (II-3) with positive control drug Doxazosin to NA2Compare between value, P ＜ 0.01, the difference of highly significant between the two be present, illustrate compound (II-3) to the antagonism of α receptor stimulating agents than sandy Azoles piperazine is weak.
6.2 compounds (II-3) are to family rabbit vascular smooth muscle calcium channel (Ca2+) antagonism
6.2.1 compound (II-3) is to CaCl2The influence of rabbit vascular concentration effect curve is shunk in accumulation
After sample tension stability, sample is rinsed 3 times with without calcium K-H liquid, and is incubated 40 minutes with without calcium K-H liquid, is added Sample is set to depolarize 20 minutes without the high potassium liquid of calcium, then accumulation adds CaCl into bath pipe2(10-5-3×10-2Mol/L), until Reach maximum reaction, wave recording.Then sample is rinsed repeatedly with K-H liquid, changes within every 20 minutes a K-H liquid, balance 60 minutes, After baseline restorer is steady, sample is rinsed 3 times with without calcium K-H liquid again, and is incubated 40 minutes with without calcium K-H liquid, adds nothing The high potassium liquid of calcium makes sample depolarize 20 minutes, while adds compound (II-3) (10 into bath pipe-5Mol/L), it is incubated 20 minutes Accumulated again with same method afterwards and add CaCl2(10-5-3×10-1Mol/L), until reaching maximum reaction, wave recording.Reacted with maximum For 100%, CaCl2Percentage of contraction during each concentration is ordinate, CaCl2It is that abscissa draws dose-effect song that each concentration, which bears logarithm, Line, add compound (II-3) (10-5Mol/L after), such as Fig. 8, CaCl2Amount effect curve is substantially parallel to move to right, and maximum reaction is almost It is constant, after carrying out statistical test to each concentration-response percentage, most P values ＜ 0.01, significant difference be present.Compound (II-3) antagonism CaCl2Shrink the pA of Rabbit Aorta2It is worth for 6.56 ± 0.032.
6.2.2 positive control drug Amlodipine is to CaCl2The influence of amount effect curve is shunk in accumulation
On the basis of upper step, sample is then rinsed repeatedly with K-H liquid, changes within every 20 minutes a K-H liquid, balances 60 points Clock, after baseline restorer is steady, sample is rinsed 3 times with without calcium K-H liquid again, and be incubated 40 minutes with without calcium K-H liquid, added Sample is depolarized 20 minutes without the high potassium liquid of calcium, while Amlodipine (10 is added into bath pipe-7Mol/L), after being incubated 15 minutes Accumulated again with same method and add CaCl2(10-5-3×10-2Mol/L), until reaching maximum reaction, wave recording.It is with maximum reaction 100%, CaCl2Percentage of contraction during each concentration is ordinate, CaCl2It is that abscissa draws amount effect curve that each concentration, which bears logarithm, Add Amlodipine (10-7Mol/L after), such as Fig. 8, CaCl2Amount effect curve is substantially parallel to move to right, and maximum reaction is almost unchanged, right After each concentration-response percentage carries out statistical test, most P values ＜ 0.01, significant difference be present.Amlodipine antagonism CaCl2Shrink the pA of Rabbit Aorta2It is worth for 7.15 ± 0.288.
Antagonism of 6.3 compounds (II-3) to family rabbit vascular smooth muscle serotonin (5-HT) receptor stimulating agent
After sample tension stability, one section of waveform is recorded, the accumulation addition 5-HT (10 into bath pipe-8-3×10-4Mol/L) Until reaching maximum reaction, wave recording.Then sample is rinsed repeatedly with K-H liquid, after balancing 1.5h, add compound (II-3) (3×10-6Mol/L), 5-HT is added with same method again after 20 minutes.It is that 100%, 5-HT percentage of contractions are sat to be vertical with maximum reaction Mark, it is that abscissa draws amount effect curve that each concentration of 5-HT, which bears logarithm, adds compound (II-3) (3 × 10-6Mol/L after), such as scheme 9,5-HT amount effect curves are substantially parallel to be moved to right, and maximum reaction is almost unchanged, and statistical test is carried out to each concentration-response percentage Afterwards, significant difference be present in P values ＜ 0.01.Compound (II-3) antagonism 5-HT shrinks the pA of Rabbit Aorta2Value 6.726 ± 0.089。
Embodiment 28
Diastole study on mechanism of the compound (II-6) to rabbit myocardium vessel smooth muscle
The preparation of experimental animal, medicine and reagent, laboratory apparatus, nutrient solution used in the present embodiment, and the in vitro blood of rabbit The preparation method of pipe smooth muscle sample is identical with embodiment 27, and specific test operation and result of the test are as follows.
Antagonism of 1 compound (II-6) to family's rabbit vascular smooth muscle α receptor stimulating agents
1.1 compounds (II-6) accumulate the influence for shrinking amount effect curve to phyenlephrinium
After sample tension stability, one section of waveform is recorded, the accumulation addition phyenlephrinium (10 into bath pipe-6-6×10- 3Mol/L) until reaching maximum reaction, wave recording.Then sample is rinsed repeatedly with K-H liquid, after balancing 1h, add compound (II-6)(3×10-8Mol/L), phyenlephrinium is added with same method again after 20 minutes.With maximum reaction for 100%, benzene adrenal gland Plain percentage of contraction is ordinate, and it is that abscissa draws amount effect curve that each concentration of phyenlephrinium, which bears logarithm, adds compound (II-6)(3×10-8Mol/L after), such as Figure 10, phyenlephrinium amount effect curve is substantially parallel to move to right, and maximum reaction is almost unchanged, After carrying out statistics t inspections to each concentration-response percentage, most P values ＜ 0.01, significant difference be present.Compound (II-6) Antagonism phyenlephrinium shrinks the PA of Rabbit Aorta2It is worth for 8.45 ± 0.03；
2 compounds (II-6) are to family rabbit vascular smooth muscle calcium channel (Ca2+) antagonism
2.1 compounds (II-6) are to CaCl2The influence of rabbit vascular concentration effect curve is shunk in accumulation
After sample tension stability, sample is rinsed 3 times with without calcium K-H liquid, and is incubated 40 minutes with without calcium K-H liquid, is added Sample is set to depolarize 20 minutes without the high potassium liquid of calcium, then accumulation adds CaCl into bath pipe2(10-5-10-2Mol/L), until reaching Maximum reaction, wave recording.Then sample is rinsed repeatedly with K-H liquid, change within every 20 minutes a K-H liquid, balance 60 minutes, treat base After line recovers steady, sample is rinsed 3 times with without calcium K-H liquid again, and is incubated 40 minutes with without calcium K-H liquid, adds no calcium height Potassium liquid makes sample depolarize 20 minutes, while adds compound (II-6) (10 into bath pipe-5Mol/L), after being incubated 20 minutes again Accumulated with same method and add CaCl2(10-5-10-2Mol/L), until reaching maximum reaction, wave recording.It is with maximum reaction 100%, CaCl2Percentage of contraction during each concentration is ordinate, CaCl2It is that abscissa draws amount effect curve that each concentration, which bears logarithm, Add compound (II-6) (10-5Mol/L after), such as Figure 11, CaCl2Amount effect curve is substantially parallel to move to right, and maximum reaction is hardly Become, after carrying out statistical test to each concentration-response percentage, most P values ＜ 0.01, significant difference be present.Compound (II- 6) antagonism CaCl2Shrink the PA of Rabbit Aorta2It is worth for 5.36 ± 0.26.
Antagonism of 3 compounds (II-6) to family rabbit vascular smooth muscle serotonin (5-HT) receptor stimulating agent
After sample tension stability, one section of waveform is recorded, the accumulation addition 5-HT (10 into bath pipe-8-3×10-4Mol/L) Until reaching maximum reaction, wave recording.Then sample is rinsed repeatedly with K-H liquid, after balancing 1.5h, add compound (II-6) (10-7Mol/L), 5-HT is added with same method again after 20 minutes.With maximum reaction be 100%, 5-HT percentage of contractions for ordinate, It is that abscissa draws amount effect curve that each concentration of 5-HT, which bears logarithm, adds compound (II-6) (10-7Mol/L after), such as Figure 12,5-HT Amount effect curve is substantially parallel to move to right, and maximum reaction is almost unchanged, after carrying out statistical test to each concentration-response percentage, P values , significant difference be present in ＜ 0.01.Compound (II-6) antagonism 5-HT shrinks the PA of Rabbit Aorta2Value 8.86 ± 0.14.
Summary result of the test：In in vitro animal experiment, compound (II-1), (II-3), (II-6) are respectively provided with significantly Relaxing the VSM effect.Wherein, compound (II-3) has stronger antagonism, its antagonism NA PA to α acceptors2 It is worth for 6.02 ± 0.13, Doxazosin antagonism NA PA2It is worth for 7.16 ± 0.24, compound (II-3) antagonism CaCl2PA2Value For 6.56 ± 0.032, Amlodipine antagonism CaCl2PA2It is worth for 7.15 ± 0.288, compound (II-3) is to 5-HT2AAcceptor has There is stronger antagonism, its antagonism 5-HT PA2It is worth for 6.726 ± 0.089；Compound (II-6) antagonism phyenlephrinium PA2It is worth for 8.45 ± 0.03, antagonism CaCl2PA2It is worth for 5.36 ± 0.26, antagonism 5-HT PA2Value 8.86 ± 0.14.Experiment As a result illustrate that compound (II-3) and (II-6) belong to the vasodilator activity molecule of new Mutiple Targets mechanism, available for preparing blood vessel Diastole medicine, it is particularly applied to Novel blood pressure-reducing class medicine.

Claims (8)

1. the BTA base piperazine compounds and its pharmaceutically acceptable salt of formula (I),
Wherein R represents 3- chlorphenyls, R1、R2、R3And R4H is represented independently of one another, and Q represents CH2And Y represents propylidene, as changes Compound 1- (4- (4- (3- chlorphenyls) piperazine -1- bases) butyl) -1H- BTAs；Or
R represents 3- trifluoromethyls, R1、R2、R3And R4H is represented independently of one another, and Q represents CH2And Y represents propylidene, it is Compound 1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- BTAs；Or
R represents benzisothia oxazolyl, R1、R2、R3And R4H is represented independently of one another, and Q represents CH2And Y represents propylidene, as changes Compound 3- (4- (4- (1H- BTA -1- bases) butyl) piperazine -1- bases) benzisothiazole.
2. the BTA base piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 1, wherein the medicine On acceptable salt be hydrochloride, hydrobromate, sulfate, mesylate, trifluoroacetate, tartrate, malate, Succinate, maleate, citrate, phosphate, lactate, acetonate, acetate, fumarate, oxaloacetate, Esilate, oxalates, benzene sulfonate or isethionate.
3. the BTA base piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 2, wherein the medicine Acceptable salt contains the crystallization water on.
4. the BTA base piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 3, wherein the medicine The crystallization water of acceptable salt molecule containing 0.5-3 on.
5. the BTA base piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 2, wherein the medicine Acceptable salt is hydrochloride, hydrobromate, sulfate or mesylate on.
6. the BTA base piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 2, wherein the medicine Acceptable salt is hydrochloride on.
7. prepare the BTA base piperazine compounds of any one of claim 1-6 formula (I) and its pharmaceutically acceptable Salt preparation method：
At a temperature of 10-150 DEG C, make BTA (A)
With chloro alkyl bromide (B)
Reaction generates N- chloro alkyl benzotriazole derivatives (C) in solvent in the presence of inorganic base and phase transfer catalyst
Then under reflux, N- chloro alkyl benzotriazole derivatives (C) are made
With N- substituted-piperazinyls (D)
Reaction generates compound (I-a) in solvent in the presence of organic base
8. the BTA base piperazine compounds of the formula (I) comprising any one of claim 1-6 and/or its can pharmaceutically connect The pharmaceutical composition for the salt received.
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