CN106699670A - Benzimidazolyl piperazine compounds, preparation method thereof and pharmaceutical composition - Google Patents

Benzimidazolyl piperazine compounds, preparation method thereof and pharmaceutical composition Download PDF

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CN106699670A
CN106699670A CN201610931229.6A CN201610931229A CN106699670A CN 106699670 A CN106699670 A CN 106699670A CN 201610931229 A CN201610931229 A CN 201610931229A CN 106699670 A CN106699670 A CN 106699670A
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alkyl
represent
halogen
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acceptable salt
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CN106699670B (en
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周延
张丽荣
周杰
周欣
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Original Pharmaceutical Port Life Science Research Liaoning Co ltd
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Liaoning Emmy Biopharmaceutical Industry Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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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  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention relates to benzimidazolyl piperazine compounds shown in formula (I), a preparation method thereof and pharmaceutical composition. In the formula, R1, R2, R3, R4, R5, R6, Y and Q are defined in the specification.

Description

Benzimidazolyl piperazine compounds and its preparation method and pharmaceutical composition
The application is September in 2013 entitled " benzimidazolyl piperazine compounds and its preparation method and the medicine of submission on the 10th Compositions ", the divisional application of the application for a patent for invention of Application No. 201310409084.X.
Technical field
The present invention relates to the benzimidazolyl piperazine compounds and its preparation method and pharmaceutical composition of a kind of formula (I), wherein R1、R2、R3、R4、R5、R6, Y and Q is as defined herein.
Background technology
Clinically there is multiclass 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 head dosage effects or postural hypotension, so as to limit this The extensive use clinically of class medicine；Ca2+Channel blocker, existing medicine includes Amlodipine, nifedipine, felodipine Deng, the clinically extensive use at present of this kind of medicine, but it there is also the risk for suppressing heart simultaneously.
Therefore, there is still a need for the new vasodilator drug of exploitation, to improve drug effect, reduces drug resistance or makes its poison secondary Effect is smaller, the need for satisfaction as far as possible clinically different patients.
The content of the invention
One aspect of the present invention provide a kind of compound, its be formula (I) benzimidazolyl piperazine compounds and Its pharmaceutically acceptable salt,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
R1By R7When monosubstituted, R7Represent H, halogen, CN, C1-C6Alkyl, C1-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；
R1By R7When polysubstituted, R7H, halogen, CN, C are represented independently of one another1-C6Alkyl, C1-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 many in above-mentioned group Individual halogen atom substitution；
R2Represent the C that H, halogen, CN, moieties are optionally replaced by one or more halogen atoms1-C6Alkyl or C1- C6Alkoxy；
R3、R4、R5、R6H, 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 replaced by one or more halogen atoms or undersaturated containing 1-8 carbon atom Straight or branched alkyl, the hetero atom that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen is substituted.
Another aspect of the present invention provides formula benzimidazolyl piperazine compounds of (I) and its pharmaceutically acceptable The preparation method of salt：
Scheme (one)
It is included at a temperature of 10-150 DEG C, makes substituted benzimidazole (A) with chloro alkyl bromide (B) in inorganic base and phase Generation N- chloro alkyl benzimidizole derivatives (C) is reacted in the presence of transfer catalyst in solvent, then under reflux, is made Its reacting generating compound (I-a) in solvent in the presence of organic base with N- substituted-piperazinyls (D)；
Or
Scheme (two)
It is included at a temperature of 10-150 DEG C, makes the benzimidazole (E) that N- hydroxyls replace with chloro alkyl bromide (F) inorganic Generation N- chlorinated alkoxies benzimidizole derivatives (G) is reacted in the presence of alkali in solvent, then under reflux, makes itself and N- Substituted-piperazinyl (D) reacts in the presence of organic base in solvent, generation compound (I-b)；
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
R1By R7When monosubstituted, R7Represent H, halogen, CN, C1-C6Alkyl, C1-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；
R1By R7When polysubstituted, R7H, halogen, CN, C are represented independently of one another1-C6Alkyl, C1-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 many in above-mentioned group Individual halogen atom substitution；
R2Represent the C that H, halogen, CN, moieties are optionally replaced by one or more halogen atoms1-C6Alkyl or C1- C6Alkoxy；
R3、R4、R5、R6H, 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 replaced by one or more halogen atoms or undersaturated containing 1-8 carbon atom Straight or branched alkyl, the hetero atom that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen is substituted.
Another aspect of the invention provides the benzimidazolyl piperazine compounds comprising formula (I) and/or its pharmacy The pharmaceutical composition of upper acceptable salt.
Brief description of the drawings
Fig. 1 compounds (II-2) (10-8-10-4mol·L-1) to adrenaline (10-5mol·L-1) shrink rabbit it is in vitro (numerical value is represented the cumulative concentration effect curve of vasorelaxation action with mean ± SEMN=7).
Fig. 2 compounds (II-3) (10-8-3×10-5mol·L-1) to adrenaline (10-5mol·L-1) shrink rabbit from (numerical value is represented the cumulative concentration effect curve of body vasorelaxation action with mean ± SEMN=6).
Fig. 3 compounds (II-2) (10-8-10-4mol·L-1) to potassium liquid (60mmolL high-1) shrink rabbit myocardium vessel (numerical value is represented the cumulative concentration effect curve of diastole effect with mean ± SEMN=8).
Fig. 4 compounds (II-3) (10-8-3×10-5mol·L-1) to potassium liquid (60mmolL high-1) shrink rabbit it is in vitro (numerical value is represented the cumulative concentration effect curve of vasorelaxation action with mean ± SEMN=8).
Fig. 5 compounds (II-2) (3 × 10-7Mol/L) antagonism norepinephrine NA (10-8-10-4Mol/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)。
Fig. 6 positive controls Doxazosin (10-7Mol/L) antagonism norepinephrine NA (10-8-6×10-5Mol/L) receive (numerical value is represented the cumulative concentration effect curve of contracting rabbit myocardium vessel with mean ± SEM*P<0.05, * * P<0.01,n =8).
Fig. 7 compounds (II-2) (3 × 10-6Mol/L) antagonism CaCl2(10-6-10-2Mol/L rabbit myocardium vessel) is shunk Cumulative concentration effect curve (numerical value is represented with mean ± SEM*P<0.05, * * P<0.01, n=7).
Fig. 8 Amlodipines (10-7Mol/L) antagonism CaCl2(10-6-10-2Mol/L the accumulation of rabbit myocardium vessel) is shunk (numerical value is represented concentration-response curve with mean ± SEM*P<0.05, * * P<0.01, n=5).
Fig. 9 compounds (II-2) (3 × 10-6Mol/L) antagonism serotonin (10-7-3×10-4Mol/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=8).
Specific embodiment
Herein, term " cyclic hydrocarbon radical " is including cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl or cyclooctyl etc..
Herein, term " aryl " is including 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 is including methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy and hexyloxy etc..
Herein, it is general, preferred, preferred, still more preferably, particularly preferred, most preferred definition Between can be mutually combined and use.
In some embodiments, the invention provides the benzimidazolyl piperazine compounds and its pharmaceutically of formula (I) Acceptable salt,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
R1By R7When monosubstituted, R7Represent H, halogen, CN, C1-C6Alkyl, C1-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；
R1By R7When polysubstituted, R7H, halogen, CN, C are represented independently of one another1-C6Alkyl, C1-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 many in above-mentioned group Individual halogen atom substitution；
R2Represent the C that H, halogen, CN, moieties are optionally replaced by one or more halogen atoms1-C6Alkyl or C1- C6Alkoxy；
R3、R4、R5、R6H, 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 replaced by one or more halogen atoms or undersaturated containing 1-8 carbon atom Straight or branched alkyl, the hetero atom that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen is substituted.
In preferred embodiments, the invention provides the benzimidazolyl piperazine compounds and its pharmacy of formula (I) Upper acceptable salt,
Wherein
R1Represent optionally by R7Monosubstituted 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, pyrimidine radicals, benzothiazolyl, benzene And isothiazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl, benzopyrazoles base, benzofuranyl, benzo pyrimidine Base, benzo pyridine radicals Huo quinoxalinyls；
R1By R7When monosubstituted, R7Preferably represent H, halogen, CN, C1-C4Alkyl, C1-C4Alkoxy, CHO, CO (C1-C4 Alkyl), COOH, COO (C1-C4Alkyl), NO2、NH2、NH(C1-C4Alkyl), N (C1-C4Alkyl)2, moieties in above-mentioned group Optionally replaced by 1-3 halogen atom；
R1By R7When polysubstituted, R7H, halogen, CN, C are preferably represented independently of one another1-C4Alkyl, C1-C4Alkoxy, CHO、CO(C1-C4Alkyl), COOH, COO (C1-C4Alkyl), NO2、NH2、NH(C1-C4Alkyl), N (C1-C4Alkyl)2, above-mentioned base Moieties are optionally replaced by 1-3 halogen atom in group；
R2H, halogen, CN, moieties are preferably represented optionally by the 1-3 C of halogen atom substitution1-C4Alkyl or C1-C4 Alkoxy；
R3、R4、R5、R6H, halogen, CN, C are preferably represented independently of one another1-C4Alkyl, C1-C4Alkoxy, CHO, CO (C1-C4Alkyl), COOH, COO (C1-C4Alkyl), moieties are optionally replaced by 1-3 halogen atom in above-mentioned group；
Q preferably represents CH2Or oxygen；
Y represents the saturation that is optionally replaced by one or more halogen atoms or undersaturated containing 1-6 carbon atom Straight or branched alkyl, the hetero atom that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen is substituted.
In a more preferred embodiment, the invention provides the benzimidazolyl piperazine compounds and its medicine of formula (I) Acceptable salt on,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is more preferably cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
The aryl or heteroaryl be more preferably phenyl, naphthyl, furyl, pyridine radicals, pyrimidine radicals, benzothiazolyl, Benzisothia oxazolyl, benzoxazolyl, benzoisoxazole base, benzimidazolyl, benzopyrazoles base, benzofuranyl or quinoxaline Base；
R1By R7When monosubstituted, R7More preferably represent H, F, Cl, Br, I, CN, C1-C4Alkyl, C1-C4Alkoxy, CHO, CO(C1-C4Alkyl), COOH, COO (C1-C4Alkyl), moieties are optionally replaced by 1-3 halogen atom in above-mentioned group；
R1By R7When polysubstituted, R7H, F, Cl, Br, I, CN, C are more preferably represented independently of one another1-C4Alkyl, C1-C4Alkane Epoxide, CHO, CO (C1-C4Alkyl), COOH, COO (C1-C4Alkyl), moieties are optionally former by 1-3 halogen in above-mentioned group Son substitution；
R2More preferably represent H, F, Cl, Br, CN, CH3、CF3；
R3、R4、R5、R6H, F, Cl, Br, I, CN, CH are more preferably represented independently of one another3、OCH3、COCH3Or COOCH3；
Q more preferably represents CH2Or oxygen；
Y more preferably represents methylene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, wherein the group Hydrogen atom is optionally replaced by one or more halogen atoms.
In embodiment still more preferably, the invention provides the benzimidazolyl piperazine compounds of formula (I) And its pharmaceutically acceptable salt,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is still more preferably cyclohexyl；
The aryl or heteroaryl are still more preferably phenyl, naphthyl, furyl, pyridine radicals, pyrimidine radicals, benzisoxa Thiazolyl, benzoisoxazole base, benzopyrazoles base, benzofuranyl Huo quinoxalinyls；
R1By R7When monosubstituted, R7Still more preferably represent H, F, Cl, CN, CH3、CF3Or OCH3；
R1By R7When polysubstituted, R7H, F, Cl, CN, CH are still more preferably represented independently of one another3、CF3Or OCH3；
R2Still more preferably represent H, Cl, CH3；
R3、R4、R6H is still more preferably represented independently of one another；
R5Still more preferably represent H, F, Cl, CN, COOCH3；
Q still more preferably represents CH2Or oxygen；
Y still more preferably represents ethylidene, propylidene or butylidene.
In particularly preferred embodiments, the invention provides formula (I) benzimidazolyl piperazine compounds and its Pharmaceutically acceptable salt,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is particularly preferably cyclohexyl；
The aryl or heteroaryl are particularly preferably phenyl, pyridine radicals, benzoisoxazole base Huo quinoxalinyls；
R1By R7When monosubstituted, R7Particularly preferably represent H, F, Cl, CH3、CF3Or OCH3；
R1By R7When polysubstituted, R7H, F, Cl, CH are particularly preferably represented independently of one another3、CF3Or OCH3；
R2Particularly preferably represent H or CH3；
R3、R4、R6H is particularly preferably represented independently of one another；
R5Particularly preferably represent H, F, Cl；
Q particularly preferably represents CH2Or oxygen；
Y particularly preferably represents ethylidene or propylidene.
In the most preferred embodiment, the invention provides the benzimidazolyl piperazine compounds and its medicine of formula (I) Acceptable salt on,
Wherein
R1Most preferably represent optionally by R7Monosubstituted or polysubstituted phenyl；
R1By R7When monosubstituted, R7Most preferably represent H, Cl or CF3；
R1By R7When polysubstituted, R7H, Cl or CF are most preferably represented independently of one another3；
R2Most preferably represent H；
R3、R4、R6H is most preferably represented independently of one another；
R5Most preferably represent H；
Q most preferably represents CH2；
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, more preferably containing the crystallization water of 0.5-3 molecules.
The pharmaceutically acceptable salt is more preferably hydrochloride, hydrogen bromide salt, sulfate or mesylate.
The pharmaceutically acceptable salt is optimal to be preferably hydrochloride.
The benzimidazolyl piperazine compounds of formula (I) are still more preferably following compound：
Compound wherein of the invention most preferably exists in the form of hydrochloride, for example compound (I-2) and (I-3) Most preferably exist in the form of the hydrochloride of formula (II-2) and (II-3) respectively：
In some embodiments, the preparation method of the benzimidazolyl piperazine compounds of offer formula (I) of the present invention：
Scheme (one)
It is included at a temperature of 10-150 DEG C, makes substituted benzimidazole (A) with chloro alkyl bromide (B) in inorganic base and phase Generation N- chloro alkyl benzimidizole derivatives (C) is reacted in the presence of transfer catalyst in solvent, then under reflux, is made Its reacting generating compound (I-a) in solvent in the presence of organic base with N- substituted-piperazinyls (D)；
Or
Scheme (two)
It is included at a temperature of 10-150 DEG C, makes the benzimidazole (E) that N- hydroxyls replace with chloro alkyl bromide (F) inorganic Generation N- chlorinated alkoxies benzimidizole derivatives (G) is reacted in the presence of alkali in solvent, then under reflux, makes itself and N- Substituted-piperazinyl (D) reacts in the presence of organic base in solvent, generation compound (I-b)；Wherein R1、R2、R3、R4、R5、R6With Y is as defined above.
The first step reaction of scheme () and scheme (two) depositing in inorganic base and phase transfer catalyst and inorganic base respectively Carried out in solvent under, the inorganic base is preferably sodium hydride, NaOH, sodium methoxide, caustic alcohol, sodium carbonate, carbonic acid Hydrogen sodium, hydrofining, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium carbonate or saleratus, more preferably sodium hydride or hydroxide Sodium；The phase transfer catalyst is preferably TBAB, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate or 1,4,7, 10,13,16- hexaoxacyclooctadecane-6s (i.e. 18 hat 6) etc., more preferably TBAB；It is molten used by first step reaction Agent is conventional solvent in the art, it is therefore preferable to water (except during using sodium hydride), 1-METHYLPYRROLIDONE (NMP) or N, N- Dimethylformamide (DMF) and its mixture；The reaction temperature of the first step is 10-150 DEG C, more preferably preferably 15-130 DEG C, 20- 100℃；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 () 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- Should solvent used be conventional solvent 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 inventive method preferably includes the step of making product generate pharmaceutically acceptable salt with corresponding acid reaction. Acid wherein used can for 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 for methyl alcohol, ethanol, propyl alcohol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methyl isopropyl Ketone, Methyl iso-butyl ketone (MIBK), acetonitrile, propionitrile, dimethylformamide, dimethylacetylamide, 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO) or Tetramethylene sulfone etc., ethyl acetate and/or ethanol.
In some embodiments, the invention provides the benzimidazolyl piperazine compounds comprising formula (I) and/or its The pharmaceutical composition of pharmaceutically acceptable salt.
Described pharmaceutical composition comprising 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 The plain derivative of dimension, 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 add other adjuvants such as flavouring agent and sweetener 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, 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.
The various formulations of pharmaceutical composition of the invention can be prepared using the conventional method of medical domain.
In some embodiments, the invention provides the benzimidazolyl piperazine compounds and its pharmaceutically of formula (I) Acceptable salt is used to prepare the purposes of vasodilator drug.
The benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of formula (I) of the invention have significant blood Pipe diastole is acted on.Preferably, the compound and its pharmaceutically acceptable salt have stronger blocking α1Acceptor, Ca2+Passage, 5-HT2AOne or more effect in acceptor.Can have as α at it1Receptor blocking pharmacon, Ca2+Channel blocker and 5-HT acceptors During dual or triple role in blocking agent, the compound can be by various action pathway collective effects, so as to play difference The advantage of approach, compensate for respective deficiency so that compound can play multiple advantage vasorelaxation action is realized.It is more excellent Selection of land, compound of the invention can possess α as effective three target spots vasodilator1Acceptor, Ca2+Passage, 5-HT2AReceive The triple blocking effects of body.Thus, its α in not exclusively blocking vascular smooth muscle1While acceptor, by blocking Ca2+Passage, example Such as produce resisting cardiac hypertrophy, protection vascular endothelial cell, antiatherosclerosis, suppression vascular smooth muscle hyperplasia or improve brain and follow Ring etc. is acted 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 the α of remaining1Acceptor can still participate in pressor reflex, so as to prevent body Position property low blood pressure；Simultaneously as 5-HT2AReceptor blocking is acted on, and is conducive to treatment heart failure and is improved occlusive vascular patient's Supply of blood flow, therefore the hypertension with heart failure, the hypertension with artery sclerosis, the blood high with vessel endothelium and induced endothelial can be treated Pressure, middle and advanced stage hypertension or some intractable hypertensions.
The benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of formula (I) of the invention and existing clinic Drug for hypertension is compared, with stronger antihypertensive activity, more preferable drug resistance and/or security higher.
Therefore the benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of formula (I) of the invention can be used to make 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 caused by vasopasm, myocardial ischemia disease, shock etc.；For renal ischaemia, Poor kidney and periperal vascular spasm (such as Buerger's disease, the Raynaud's disease caused by Renal vascular spasm Deng).
Additionally, the benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of formula (I) of the invention and 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 In the interior mammal diseases related medicine of vascular smooth muscle spasmus.
Prepare embodiment
The preparation of 1- (4- chlorobutyls) -1H- substituted benzimidazoles
Substitution 1H- benzimidazoles (0.10mol) is dissolved in 20% (weight ratio) sodium hydrate aqueous solution 200mL, plus Enter 4- chlorine NBB (34.3g, 0.20mol), TBAB 1.0g, mix 5 minutes, be to slowly warm up to 60 DEG C, stir Mix reaction 2 hours.Room temperature is cooled to, the extraction of 100mL dichloromethane is added, point liquid, water is added to dichloromethane 100mL extractions, Merge organic phase, washed through 100mL saturated brines, point liquid is evaporated organic phase and obtains grease.Grease is through neutral Al2O3Chromatography or Preparation HPLC is isolated and purified, and obtains 1- (4- chlorobutyls) -1H- substituted benzimidazoles, yield 30.0-65.0%.
The preparation of 1- (4- (4- (substituted-phenyl) piperazine -1- bases) butyl) -1H- substituted benzimidazoles (I)
1- (4- chlorobutyls) -1H- substituted benzimidazoles (0.036mol) is dissolved in 100ml acetonitriles, is separately added into and is taken For phenylpiperazine (0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), room Temperature stirring 10 minutes, then temperature rising reflux reaction 10-20 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, passed through Neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains formula (I) compound, yield 60.0-72.0%.
Embodiment 1
The preparation of 1- (4- (4- (3- chlorphenyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-1)
1H- benzimidazoles (11.8g, 0.10mol) are dissolved in 20% (weight ratio) sodium hydrate aqueous solution 200ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (1.0g, 0.003mol) are added, is mixed 5 minutes, heated up To 60 DEG C, stirring reaction 2 hours.Room temperature is cooled to, the extraction of 100ml dichloromethane is added, point liquid, water is added to dichloromethane 100ml is extracted, and merges organic phase, is washed through 100ml saturated brines, and point liquid is evaporated organic phase and obtains grease.Grease is through neutrality Al2O3Chromatography is purified, and obtains 1- (4- chlorobutyls) -1H- benzimidazole 12.5g, yield 60.0%.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into 3- trichlorophenyls piperazine (5.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-1) 6.8g, yield 61.4%.ESI-MS[M+H]+:m/z 369.2.(the step of compound (I-1) generates hydrochloride (II-1) with hydrochloric acid reaction is joined See embodiment 2 and embodiment 3.)
Embodiment 2
1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-2) and 1- (4- (4- (3- Trifluoromethyl) piperazine -1- bases) butyl) and -1H- benzimidazoles hydrochloride (II-2) preparation
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into 3- trifluoromethylphenypiperazine piperazines (6.91g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), is stirred at room temperature 10 minutes, then temperature rising reflux reaction 10-20 hours.Room temperature is cooled to, is filtered, filtrate It is concentrated to obtain grease, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-2) 7.6g, yield 62.8%.
Compound (I-2) (6.04g, 0.015mol) is dissolved in 80ml ethyl acetate and 8ml ethanol.Ice-water bath is cooled down Under the conditions of, the hydrogen chloride/ethyl acetate solution of 3mol/L is added dropwise, solution PH=3 are adjusted, it is warming up to 50 DEG C and stirs 20 minutes, cooling Crystallization, filtering is dried, and obtains compound (II-2) solid 5.9g, yield 89.7%.ESI-MS[M+H]+:m/z 403.2。
Embodiment 3
1- (4- (4- (2,3- dichlorophenyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-3) and 1- (4- (4- (2,3- Dichlorophenyl) piperazine -1- bases) butyl) and -1H- benzimidazoles hydrochloride (II-3) preparation
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into 2,3- dichlorophenylpiperazines (6.93g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), is stirred at room temperature 10 minutes, then temperature rising reflux reaction 10-20 hours.Room temperature is cooled to, is filtered, filtrate It is concentrated to obtain grease, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-3) 7.5g, yield 62.0%.
Compound (I-3) (6.05g, 0.015mol) is dissolved in 80ml ethyl acetate and 8ml ethanol.Ice-water bath is cooled down Under the conditions of, the hydrogen chloride/ethyl acetate solution of 3mol/L is added dropwise, solution PH=3 are adjusted, it is warming up to 50 DEG C and stirs 20 minutes, cooling Crystallization, filtering is dried, and obtains compound (II-3) solid 6.0g, yield 90.9%.ESI-MS[M+H]+:m/z 403.1。
Embodiment 4
The preparation of 1- (4- (4- (2- methoxyphenyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-4)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into 2- methoxyphenylpiperazderivatives (5.77g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, filtrate is through dense Contract to obtain grease, through neutral Al2O3Chromatography is purified, and methylene chloride/methanol mixed solvent elutes to obtain compound (I-4) 7.7g, Yield 70.6%.ESI-MS[M+H]+:m/z 365.2.(compound (I-4) generates its hydrochloride (II-4) with hydrochloric acid reaction Step is referring to embodiment 2 and embodiment 3.)
Embodiment 5
The preparation of 2- methyl isophthalic acids-(4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-5)
2- methyl isophthalic acid H- benzimidazoles (13.2g, 0.10mol) is dissolved in 20% (weight ratio) sodium hydrate aqueous solution In 200ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (1.0g, 0.003mol) are added, mix 5 points Clock, is warming up to 60 DEG C, stirring reaction 2 hours.Room temperature is cooled to, the extraction of 100ml dichloromethane is added, point liquid, water is added to two Chloromethanes 100ml is extracted, and merges organic phase, is washed through 100ml saturated brines, and point liquid is evaporated organic phase and obtains grease.Grease Through neutral Al2O3Chromatography is purified, and obtains 1- (4- chlorobutyls) -2- methyl isophthalic acid H- benzimidazole 13.7g, yield 61.5%.
1- (4- chlorobutyls) -2- methyl isophthalic acid H- benzimidazoles (8.02g, 0.036mol) is dissolved in 100ml acetonitriles, point Jia Ru not 3- trifluoromethylphenypiperazine piperazines (6.91g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodine Change potassium (5.0g, 0.03mol), be stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, filtrate It is concentrated to obtain grease, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-5) 8.1g, yield 64.9%.ESI-MS[M+H]+:m/z 417.2.(compound (I-5) generates its hydrochloride (II- with hydrochloric acid reaction 5) the step of, is referring to embodiment 2 and embodiment 3.)
Embodiment 6
The preparation of the fluoro- 1- of 6- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-6)
The fluoro- 1H- benzimidazoles (13.2g, 0.10mol) of 6- are dissolved in 20% (weight ratio) sodium hydrate aqueous solution In 200ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (1.0g, 0.003mol) are added, mix 5 points Clock, is warming up to 60 DEG C, stirring reaction 2 hours.Post-processed by the post-processing approach of the first step in embodiment 1, through neutrality Al2O3Chromatography is purified, and obtains 1- (4- chlorobutyls) fluoro- 1H- benzimidazoles 14.2g of -6-, yield 62.6%.
The fluoro- 1H- benzimidazoles (8.16g, 0.036mol) of 1- (4- chlorobutyls) -6- are dissolved in 100ml acetonitriles, respectively Add 3- trifluoromethylphenypiperazine piperazines (6.91g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodate Potassium (5.0g, 0.03mol), is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, filtrate warp Grease is concentrated to give, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-6) 8.5g, yield 67.4%.ESI-MS[M+H]+:m/z 421.2.(compound (I-6) generates its hydrochloride (II- with hydrochloric acid reaction 6) the step of, is referring to embodiment 2 and embodiment 3.)
Embodiment 7
The preparation of 1- (3- (4- phenylpiperazine -1- bases) propyl group) -1H- benzimidazoles (I-7)
1H- benzimidazoles (11.8g, 0.10mol) are dissolved in 20% (weight ratio) sodium hydrate aqueous solution 200ml, 3- chlorobromopropanes (31.4g, 0.20mol), TBAB (1.0g, 0.003mol) are added, is mixed 5 minutes, heated up To 60 DEG C, stirring reaction 2 hours.Room temperature is cooled to, the extraction of 100ml dichloromethane is added, point liquid, water is added to dichloromethane 100ml is extracted, and merges organic phase, is washed through 100ml saturated brines, and point liquid is evaporated organic phase and obtains grease.Grease is through neutrality Al2O3Chromatography is purified, and obtains 1- (3- chloropropyls) -1H- benzimidazole 12.0g, yield 62.0%.
1- (3- chloropropyls) -1H- benzimidazoles (6.98g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into Phenylpiperazine (4.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-7) 6.1g, yield 63.2%.ESI-MS[M+H]+:m/z 321.2.(the step of compound (I-7) generates its hydrochloride (II-7) with hydrochloric acid reaction Referring to embodiment 2 and embodiment 3.)
Embodiment 8
The preparation of 1- (3- (4- (3- fluorophenyls) piperazine -1- bases) propyl group) -1H- benzimidazoles (I-8)
1- (3- chloropropyls) -1H- benzimidazoles are prepared using the method in embodiment 7.
1- (3- chloropropyls) -1H- benzimidazoles (6.98g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into 3- fluorophenyls piperazine (6.91g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-8) 6.4g, yield 63.1%.ESI-MS[M+H]+:m/z 339.2.(the step of compound (I-8) generates its hydrochloride (II-8) with hydrochloric acid reaction Referring to embodiment 2 and embodiment 3.)
Embodiment 9
The preparation of 2- methyl isophthalic acids-(3- (4- (3- fluorophenyls) piperazine -1- bases) propyl group) -1H- benzimidazoles (I-9)
2- methyl isophthalic acid H- benzimidazoles (13.2g, 0.10mol) is dissolved in 20% (weight ratio) sodium hydrate aqueous solution In 200mL, 3- chlorobromopropanes (31.4g, 0.20mol), TBAB (1.0g, 0.003mol) are added, mix 5 points Clock, is warming up to 60 DEG C, stirring reaction 2 hours.Room temperature is cooled to, the extraction of 100mL dichloromethane is added, point liquid, water is added to two Chloromethanes 100mL is extracted, and merges organic phase, is washed through 100mL saturated brines, and point liquid is evaporated organic phase and obtains grease.Grease Through neutral Al2O3Chromatography is purified, and obtains 1- (3- chloropropyls) -2- methyl isophthalic acid H- benzimidazole 12.9g, yield 62.1%.
1- (3- chloropropyls) -2- methyl isophthalic acid H- benzimidazoles (7.49g, 0.036mol) is dissolved in 100ml acetonitriles, point Jia Ru not 3- trifluorophenyls piperazine (4.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, filtrate is through dense Contract to obtain grease, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-9) 6.67g, yield 63.1%.ESI-MS[M+H]+:m/z 353.2.(compound (I-9) generates its hydrochloride with hydrochloric acid reaction (II-9) the step of, is referring to embodiment 2 and embodiment 3.)
Embodiment 10
The preparation of 1- (4- (4- (3- cyano-phenyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-10)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is 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 at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-10) 6.7g, yield 62.4%.ESI-MS[M+H]+:m/z 360.2.(compound (I-10) generates the step of its hydrochloride (II-10) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 11
The preparation of 1- (4- (4- (4- aminomethyl phenyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-11)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into 4- aminomethyl phenyls piperazine (5.3g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-11) 6.4g, yield 60.7%.ESI-MS[M+H]+:m/z 349.2.(compound (I-11) generates the step of its hydrochloride (II-11) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 12
The preparation of 1- (4- (4- (2- furyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-12)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is 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 at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-12) 6.0g, yield 61.5%.ESI-MS[M+H]+:m/z 325.2.(compound (I-12) generates the step of its hydrochloride (II-12) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 13
The preparation of 1- (4- (4- (4- pyridine radicals) piperazine -1- bases) butyl) -1H- benzimidazoles (I-13)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is 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 at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-13) 6.3g, yield 62.1%.ESI-MS[M+H]+:m/z 336.2.(compound (I-13) generates the step of its hydrochloride (II-13) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 14
The preparation of 1- (4- (4- (2- pyrimidine radicals) piperazine -1- bases) butyl) -1H- benzimidazoles (I-14)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into 4- (2- pyrimidine radicals) piperazine (4.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), it is stirred at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-14) 6.1g, yield 60.1%.ESI-MS[M+H]+:m/z 337.2.(compound (I-14) generates the step of its hydrochloride (II-14) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 15
The preparation of 1- (4- (4- (1- cyclohexyl) piperazine -1- bases) butyl) -1H- benzimidazoles (I-15)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is 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 at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-15) 6.4g, yield 62.9%.ESI-MS[M+H]+:m/z 341.3.(compound (I-15) generates the step of its hydrochloride (II-15) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 16
The preparation of 1- (4- (4- (1- naphthyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-16)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is 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 at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-16) 6.8g, yield 59.1%.ESI-MS[M+H]+:m/z 385.2.(compound (I-16) generates the step of its hydrochloride (II-16) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 17
The preparation of 1- (4- (4- (2- quinoxalinyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-17)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100ml acetonitriles, is separately added into 4- (2- quinoxalinyls) piperazine (6.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and KI (5.0g, 0.03mol), is stirred at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.Room temperature is cooled to, is filtered, filtrate is through dense Contract to obtain grease, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-16) 6.9g, yield 59.6%.ESI-MS[M+H]+:m/z 387.2.(compound (I-17) generates its hydrochloride with hydrochloric acid reaction (II-17) the step of, is referring to embodiment 2 and embodiment 3.)
Embodiment 18
The preparation of 1- (4- (4- (3- (6- fluorobenzene Bing isoxazolyls)) piperazine -1- bases) butyl) -1H- benzimidazoles (I-18)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100mL acetonitriles, is separately added into The fluoro- 3- of 6- (piperazine -4- bases) benzoisoxazole (6.6g, 0.05mol), diisopropyl ethyl amine (15.5g, 0.12mol) and KI (5.0g, 0.03mol), temperature rising reflux reaction 15h after stirring mixing.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through column chromatography (neutral Al2O3) chromatography purifying, dichloromethane eluent obtains compound (I-18) 7.7g, yield 65.6%.ESI-MS[M+H]+:m/z 394.2.(compound (I-18) generates the step of its hydrochloride (II-18) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 19
The preparation of 1- (4- (4- (3- (6- fluorobenzene and isothiazolyl)) piperazine -1- bases) butyl) -1H- benzimidazoles (I-19)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100mL acetonitriles, is separately added into The fluoro- 3- of 6- (piperazine -4- bases) benzisothiazole (7.1g, 0.05mol), diisopropyl ethyl amine (15.5g, 0.12mol) and KI (5.0g, 0.03mol), temperature rising reflux reaction 15h after stirring mixing.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Shape thing, through column chromatography (neutral Al2O3) chromatography purifying, dichloromethane eluent obtains compound (I-19) 7.9g, yield 64.6%.ESI-MS[M+H]+:m/z 410.2.(compound (I-19) generates the step of its hydrochloride (II-19) with hydrochloric acid reaction Suddenly referring to embodiment 2 and embodiment 3.)
Embodiment 20
The preparation of 1- (4- (4- (3- benzopyrazoles base) piperazine -1- bases) butyl) -1H- benzimidazoles (I-20)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100mL acetonitriles, is separately added into 3- (piperazine -4- bases) benzopyrazoles (6.1g, 0.05mol), diisopropyl ethyl amine (15.5g, 0.12mol) and KI (5.0g, 0.03mol), temperature rising reflux reaction 15h after stirring mixing.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, Through column chromatography (neutral Al2O3) chromatography purifying, dichloromethane eluent obtains compound (I-20) 6.9g, yield 61.5%. ESI-MS[M+H]+:m/z 375.2.(the step of compound (I-20) and hydrochloric acid reaction generate its hydrochloride ((II-20)) referring to Embodiment 2 and embodiment 3.)
Embodiment 21
The preparation of 1- (4- (4- (3- (6- Fluorobenzofurs base)) piperazine -1- bases) butyl) -1H- benzimidazoles (I-21)
1- (4- chlorobutyls) -1H- benzimidazoles are prepared using the method in embodiment 1.
1- (4- chlorobutyls) -1H- benzimidazoles (7.51g, 0.036mol) is dissolved in 100mL acetonitriles, is 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), temperature rising reflux reaction 15h after stirring mixing.Room temperature is cooled to, is filtered, concentrating filter liquor obtains oily Thing, through column chromatography (neutral Al2O3) chromatography purifying, dichloromethane eluent obtains compound (I-21) 7.5g, yield 63.6%. ESI-MS[M+H]+:m/z 393.2.(the step of compound (I-21) and hydrochloric acid reaction generate its hydrochloride ((II-21)) referring to Embodiment 2 and embodiment 3.)
Embodiment 22
The system of 1- (4- (4- (3- (6- fluorobenzene Bing isoxazolyls)) piperazine -1- bases) propoxyl group) -1H- benzimidazoles (I-22) It is standby
1- hydroxybenzimidazoles (0.01mol) are dissolved in 10ml NMP, be dividedly in some parts 50% weight than sodium hydrogen The solid paraffin mixture of (0.01mol), stirring reaction 0.5h.Meanwhile, by 3- chlorobromopropanes (0.015mol), it is dissolved in 5ml In NMP, in adding above-mentioned solution, stirring reaction 12h at room temperature.Reaction solution is poured into 50ml water, ethyl acetate extraction (3 × 50mL), merge organic phase, through 30ml water washings, add anhydrous magnesium sulfate to dry organic phase, filter, solvent evaporated, grease Through neutral Al2O3Chromatography or preparation HPLC are isolated and purified, and obtain 1- (3- chlorine propoxyl group) benzimidazole, yield 75.0%.
1- (3- chlorine propoxyl group) benzimidazole (0.06mol) is dissolved in 150ml acetonitriles, 4- (3- (6- fluorine is separately added into Benzoisoxazole base)) 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 neutrality Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains 1- (4- (4- (3- (6- fluorobenzene Bing isoxazolyls)) piperazines Piperazine -1- bases) propoxyl group) -1H- benzimidazoles (I-22) 13.7g, yield 69.1%.ESI-MS[M+H]+:m/z396.2.(chemical combination The step of thing (I-22) generates its hydrochloride ((II-22)) with hydrochloric acid reaction is referring to embodiment 2 and embodiment 3.)
Embodiment 23
The preparation of 1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) propoxyl group) -1H- benzimidazoles (I-23)
1- (3- chlorine propoxyl group) benzimidazole is prepared using the method in embodiment 22.
1- (3- chlorine propoxyl group) benzimidazole (0.06mol) is dissolved in 150ml acetonitriles, 4- (3- trifluoros are separately added into Aminomethyl phenyl) piperazine (0.05mol), diisopropyl ethyl amine (0.2mol), and KI (0.05mol), mix at room temperature Stirring 10 minutes, then temperature rising reflux reaction 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutral Al2O3 Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains 1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) third Epoxide) -1H- benzimidazoles (I-23) 13.7g, yield 67.9%.ESI-MS[M+H]+:m/z 405.2.(compound (I-23) The step of generating its hydrochloride ((II-23)) with hydrochloric acid reaction is referring to embodiment 2 and embodiment 3.)
Embodiment 24
The preparation of 1- (4- (4- (3- chlorphenyls) piperazine -1- bases) propoxyl group) -1H- benzimidazoles (I-24)
1- (3- chlorine propoxyl group) benzimidazole is prepared using the method in embodiment 22.
1- (3- chlorine propoxyl group) benzimidazole (0.06mol) is dissolved in 150ml acetonitriles, 4- (3- chlorobenzenes are separately added into Base) piperazine (0.05mol), diisopropyl ethyl amine (0.2mol), and KI (0.05mol), 10 are mixed at room temperature Minute, then temperature rising reflux reacts 15h.Room temperature is cooled to, is filtered, concentrating filter liquor obtains grease, through neutral Al2O3Chromatography point From purifying, methylene chloride/methanol mixed solvent wash-out obtains 1- (4- (4- (3- chlorphenyls) piperazine -1- bases) propoxyl group) -1H- benzene And imidazoles (I-24) 12.2g, yield 66.1%.ESI-MS[M+H]+:m/z 371.2.(compound (I-24) is given birth to hydrochloric acid reaction Into the step of its hydrochloride ((II-24)) referring to embodiment 2 and embodiment 3.)
Embodiment 25
The preparation of the chloro- 1- of 6- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-25)
The chloro- 1H- benzimidazoles (15.2g, 0.10mol) of 6- are dissolved in 20% (weight ratio) sodium hydrate aqueous solution In 200ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (1.0g, 0.003mol) are added, mix 5 points Clock, is warming up to 60 DEG C, stirring reaction 2 hours.Post-processed by the post-processing approach of the first step in embodiment 1, through neutrality Al2O3Chromatography is purified, and obtains 1- (4- chlorobutyls) chloro- 1H- benzimidazoles 15.1g of -6-, yield 62.3%.
The chloro- 1H- benzimidazoles (8.71g, 0.036mol) of 1- (4- chlorobutyls) -6- are dissolved in 100ml acetonitriles, respectively Add 3- trifluoromethylphenypiperazine piperazines (6.91g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodate Potassium (5.0g, 0.03mol), is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, filtrate warp Grease is concentrated to give, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-25) 8.6g, yield 65.8%.ESI-MS[M+H]+:m/z 437.2.(compound (I-25) generates its hydrochloride with hydrochloric acid reaction The step of ((II-25)), is referring to embodiment 2 and embodiment 3.)
Embodiment 26
The system of 6- cyano group -1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-26) It is standby
6- cyano group -1H- benzimidazoles (14.3g, 0.10mol) is dissolved in 20% (weight ratio) sodium hydrate aqueous solution In 200ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (1.0g, 0.003mol) are added, mix 5 points Clock, is warming up to 60 DEG C, stirring reaction 2 hours.Post-processed by the post-processing approach of the first step in embodiment 1, through neutrality Al2O3Chromatography is purified, and obtains 1- (4- chlorobutyls) -6- cyano group -1H- benzimidazole 14.7g, yield 63.1%.
1- (4- chlorobutyls) -6- cyano group -1H- benzimidazoles (8.39g, 0.036mol) is dissolved in 100ml acetonitriles, point Jia Ru not 3- trifluoromethylphenypiperazine piperazines (6.91g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodine Change potassium (5.0g, 0.03mol), be stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, filtrate It is concentrated to obtain grease, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I- 26) 8.6g, yield 66.9%.ESI-MS[M+H]+:m/z 428.2.(compound (I-26) generates its hydrochloride with hydrochloric acid reaction The step of ((II-26)), is referring to embodiment 2 and embodiment 3.)
Embodiment 27
6- methoxycarbonyl groups -1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- benzimidazoles (I-27) Preparation
6- methoxycarbonyl group -1H- benzimidazoles (17.6g, 0.10mol) is dissolved in 20% (weight ratio) NaOH water-soluble In liquid 200ml, 4- chlorine NBB (34.3g, 0.20mol), TBAB (1.0g, 0.003mol) are added, mix 5 Minute, it is warming up to 60 DEG C, stirring reaction 2 hours.Post-processed by the post-processing approach of the first step in embodiment 1, through neutrality Al2O3Chromatography is purified, and obtains 1- (4- chlorobutyls) -6- methoxycarbonyl group -1H- benzimidazole 16.9g, yield 63.4%.
1- (4- chlorobutyls) -6- methoxycarbonyl group -1H- benzimidazoles (9.58g, 0.036mol) is dissolved in 100ml acetonitriles In, it is separately added into 3- trifluoromethylphenypiperazine piperazines (6.91g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), with And KI (5.0g, 0.03mol), it is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, Concentrating filter liquor obtains grease, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-27) 8.8g, yield 63.7%.ESI-MS[M+H]+:m/z 461.2.(compound (I-27) generates its salt with hydrochloric acid reaction The step of hydrochlorate ((II-27)), is referring to embodiment 2 and embodiment 3.)
Embodiment 28
The preparation of the chloro- 1- of 2- (5- (4- (3- trifluoromethyls) piperazine -1- bases) amyl group) -1H- benzimidazoles (I-28)
The chloro- 1H- benzimidazoles (15.2g, 0.10mol) of 2- are dissolved in 20% (weight ratio) sodium hydrate aqueous solution In 200ml, 5- chlorine bromo pentane silane (36.8g, 0.20mol), TBAB (1.0g, 0.003mol) are added, mix 5 points Clock, is warming up to 60 DEG C, stirring reaction 2 hours.Room temperature is cooled to, the extraction of 100ml dichloromethane is added, point liquid, water is added to two Chloromethanes 100ml is extracted, and merges organic phase, is washed through 100ml saturated brines, and point liquid is evaporated organic phase and obtains grease.Grease Through neutral Al2O3Chromatography is purified, and obtains 1- (5- chlorine amyl group) chloro- 1H- benzimidazoles 16.0g of -2-, yield 62.5%.
1- (5- chlorine amyl group) chloro- 1H- benzimidazoles (9.22g, 0.036mol) of -2- are dissolved in 100ml acetonitriles, respectively Add 3- trifluoromethylphenypiperazine piperazines (6.91g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and iodate Potassium (5.0g, 0.03mol), is stirred at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.Room temperature is cooled to, is filtered, filtrate warp Grease is concentrated to give, through neutral Al2O3Chromatography is purified, methylene chloride/methanol mixed solvent wash-out, obtains compound (I-5) 8.8g, yield 65.2%.ESI-MS[M+H]+:m/z 451.2.(compound (I-28) generates its hydrochloride with hydrochloric acid reaction The step of ((II-28)), is referring to embodiment 2 and embodiment 3.)
Embodiment 29
Compound (II-1)-(II-28) causes the diastole for shrinking rabbit myocardium vessel smooth muscle to act on to causing convulsion agent
1 experimental animal：
Rabbit, male and female dual-purpose, body weight 2.0-3.0kg is provided by Chinese Medical Sciences University's Experimental Animal Center.
2 medicines and reagent
Compound (II-1)-(II-28) is using the self-control of 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：NaCl 6.92 (concentration unit), KCl 0.35, MgSO40.29, KH2PO40.16, CaCl20.28, NaHCO32.1, Glucose 2.0 (g/L), pH 7.2.
High potassium solution：KCl will be added to be configured to containing K after the NaCl that equimolar number is removed in K-H liquid+The improvement of 60mmol/L 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 calcium potassium liquid high：By the CaCl in potassium liquid high2Remove, add the KCl of equimolar number, and add EDTA-2Na+ 0.1mmol/L, other compositions are constant.
The preparation of compound (II-1)-(II-28) solution：Certain mass compound sample is weighed, with 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 cuts thoracic cavity open rapidly, descending aorta is separated, by connective tissue and peripheral adipose tissue (if carrying out Serotonin receptor antagonistic experiment, also endothelial cell should be removed after removal using smooth stainless steel rod iron), be cut into 3-5mm vascular circles, then through vascular circle, one end is fixed on ventilation hook steel wire hook, and the other end is connected on tonotransducer, is put In the bath pipe for filling 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, changes once for every 20 minutes Nutrient solution, balance 2 hours, after start after baseline stability experiment.
6 specific test operations and result of the test
6.1 compounds (II-1)-(II-28) causes contraction rabbit myocardium vessel to be put down to causing convulsion agent adrenalin hydrochloride (AD) Sliding flesh diastole effect
After sample tension stability, one section of waveform is recorded, convulsion agent adrenalin hydrochloride (AD) (10 is caused to being added in bath pipe- 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, causes convulsion agent to induce with same concentration again and shrink.When after once to shrink maximum reaction once basic with preceding When consistent, accumulation adds compound (II-1)-(II-28) solution (1 × 10 for preparing-8-1×10-3Mol/L), marking wave Shape.As ordinate, maximum stretching reaction makees effect curve to diastole percentage with compound (II-1)-(II-28) for 100%, Wherein (II-2), the diastole of (II-3) is acted on most substantially, and the negative logarithm of its each concentration is that abscissa drafting amount effect curve is shown in Fig. 1 and Tu 2。
From Fig. 1,2, compound (II-2), (II-3) cause the sample that convulsion agent causes to shrink to AD has diastole to act on, It is presented certain dose dependent, the rabbit master that wherein compound (II-2) diastole AD causes to adrenergic diastole effect - the logEC of arterial contraction50It is 5.73 ± 0.03 to be worth, the Rabbit Aorta contraction that compound (II-3) diastole AD causes- logEC50Be worth is 6.01 ± 0.05.Compound (II-1)-(II-28) shrinks the diastole effect of rabbit myocardium vessel smooth muscle to AD As shown in table 1：
The compound of table 1 (II-1)-(II-28) shrinks the diastole effect of rabbit myocardium vessel smooth muscle to AD
Compound -logEC50 Compound -logEC50
II-1 5.03±0.04 II-15 4.47±0.04
II-2 5.73±0.03 II-16 4.29±0.03
II-3 6.01±0.05 II-17 4.53±0.03
II-4 4.96±0.03 II-18 4.86±0.06
II-5 4.78±0.04 II-19 4.18±0.04
II-6 4.63±0.06 II-20 4.23±0.05
II-7 4.29±0.05 II-21 4.05±0.03
II-8 4.71±0.04 II-22 4.55±0.04
II-9 4.37±0.03 II-23 4.72±0.03
II-10 4.26±0.05 II-24 4.52±0.04
II-11 4.05±0.04 II-25 4.79±0.05
II-12 4.35±0.06 II-26 4.19±0.04
II-13 4.41±0.05 II-27 4.31±0.04
II-14 4.22±0.04 II-28 3.99±0.03
6.2 compounds (II-1)-(II-28) causes contraction rabbit myocardium vessel smooth muscle to be relaxed to causing convulsion agent High potassium solution Zhang Zuoyong
After sample tension stability, one section of waveform is recorded, convulsion agent adrenalin hydrochloride (AD) (10 is caused to being added in bath pipe- 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, changes K-H liquid in bath pipe into potassium liquid induction high and shrink.When after once shrink maximum reaction with it is preceding once When basically identical, accumulation adds compound (II-1)-(II-28) solution (1 × 10 for preparing-8-1×10-3Mol/L), record Waveform.As ordinate, maximum stretching reaction makees effect song to diastole percentage with compound (II-1)-(II-28) for 100% Line.Wherein (II-2), the diastole of (II-3) is acted on most substantially, and the negative logarithm of its each concentration is that abscissa drafting amount effect curve is shown in Fig. 3 And Fig. 4.
From Fig. 3,4, the sample that compound (II-2) and (II-3) cause to potassium liquid high shrinks has obvious diastole to make With it is presented certain dose dependent, the family that compound (II-2) diastole potassium liquid high causes to adrenergic diastole effect - the logEC that rabbit aorta shrinks50It is 5.34 ± 0.02 to be worth, and the Rabbit Aorta that compound (II-3) diastole potassium liquid high causes is received - the logEC of contracting50Be worth is 5.49 ± 0.05.Compound (II-1)-(II-28) to cause convulsion agent High potassium solution cause contraction rabbit from The diastole effect of body vascular smooth muscle is as shown in table 2：
The compound of table 2 (II-1)-(II-28) shrinks the diastole effect of rabbit myocardium vessel smooth muscle to High potassium solution
Compound -logEC50 Compound -logEC50
II-1 5.05±0.03 II-15 4.52±0.05
II-2 5.34±0.02 II-16 4.19±0.03
II-3 5.49±0.05 II-17 4.31±0.04
II-4 4.79±0.05 II-18 4.74±0.06
II-5 4.53±0.03 II-19 4.06±0.03
II-6 4.41±0.04 II-20 3.93±0.02
II-7 3.79±0.03 II-21 3.75±0.03
II-8 4.41±0.05 II-22 4.64±0.04
II-9 4.28±0.03 II-23 4.42±0.05
II-10 3.96±0.05 II-24 4.52±0.04
II-11 3.85±0.04 II-25 4.53±0.03
II-12 4.15±0.06 II-26 3.99±0.05
II-13 4.52±0.05 II-27 4.06±0.04
II-14 4.05±0.04 II-28 3.85±0.04
Embodiment 30
Diastole study on mechanism of the compound (II-2) to rabbit myocardium vessel smooth muscle
1 experimental animal：
Rabbit, male and female dual-purpose, body weight 2.0-3.0kg is provided by Chinese Medical Sciences University's Experimental Animal Center.
2 medicines and reagent
Compound (II-2) is using the self-control of the method for embodiment 2.
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.
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, is purchased from Grandpharma (China) Co., Ltd., lot number 120105.
(R)-phenylephrine hydrochloride ((R)-Phenylephrine Hydrochloride), the uncommon love (Shanghai) of ladder is 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：NaCl 6.92 (concentration unit), KCl 0.35, MgSO40.29, KH2PO40.16, CaCl20.28, NaHCO32.1, Glucose 2.0 (g/L), pH 7.2.
High potassium solution：KCl will be added to be configured to containing K after the NaCl that equimolar number is removed in K-H liquid+The improvement of 60mmol/L 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 calcium potassium liquid high：By the CaCl in potassium liquid high2Remove, add the KCl of equimolar number, and add EDTA-2Na+ 0.1mmol/L, other compositions are constant.
The preparation of compound (II-2) solution：The sample of certain mass compound (II-2) is weighed, with 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 cuts thoracic cavity open rapidly, descending aorta is separated, by connective tissue and peripheral adipose tissue (if carrying out Serotonin receptor antagonistic experiment, also endothelial cell should be removed after removal using smooth stainless steel rod iron), be cut into 3-5mm vascular circles, then through vascular circle, one end is fixed on ventilation hook steel wire hook, and the other end is connected on tonotransducer, is put In the bath pipe for filling 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, changes once for every 20 minutes Nutrient solution, balance 2 hours, after start after baseline stability experiment.
6 experimental implementations and result of the test
Antagonism of 6.1 compounds (II-2) to family's rabbit vascular smooth muscle α receptor stimulating agents
6.1.1 compound (II-2) shrinks the influence of amount effect curve to norepinephrine accumulation
After sample tension stability, one section of waveform is recorded, norepinephrine (NA) (10 is added to being accumulated in bath pipe-8- 10-4Mol/L) until reaching maximum reaction, wave recording.Then sample is rinsed repeatedly with K-H liquid, after balance 1h, add chemical combination Thing (II-2) (3 × 10-7Mol/L), NA is added with same method again after 20 minutes.With maximum reaction for 100%, NA percentage of contractions are Ordinate, the negative logarithm of each concentration of NA is that abscissa draws amount effect curve, adds compound (II-2) (3 × 10-7Mol/L after), such as Fig. 5, NA amount effect curve are substantially parallel to move to right, and maximum reaction is almost unchanged, and statistics t inspections are carried out to each concentration-response percentage Afterwards, most P values<0.01, there is significant difference.Compound (II-2) antagonism NA shrinks the pA of Rabbit Aorta2Be worth is 7.37 ±0.08(pA2It is a kind of index for being used to represent competitive antagonist action intensity, its meaning is that activator can be made to bring up to original Come 2 times when, the negative logarithm (- log (B)) with the antagonist molar concentration needed for original concentration same effect can be produced.pA2 Value it is bigger explanation antagonist effect it is stronger.It is the result that numerical value with reference to the accompanying drawings is calculated by software).
6.1.2 positive control drug Doxazosin shrinks the influence of amount effect curve to norepinephrine accumulation
After sample tension stability, one section of waveform is recorded, to addition norepinephrine (NA) (10 in bath pipe-8-10-4mol/ L)(10-8-3×10-3Mol/L) until reaching maximum reaction, wave recording.Then sample, every 20 points are rinsed repeatedly with K-H liquid Clock changes a K-H liquid, balances 60 minutes, after baseline restorer is steady, adds Doxazosin (10-7Mol/L), after 15 minutes again with Norepinephrine (NA) (10 is added with method-8-6×10-5mol/L).With maximum reaction for 100%, NA percentage of contractions are vertical Coordinate, the negative logarithm of each concentration of NA is that abscissa draws amount effect curve, adds Doxazosin (10-7Mol/L after), such as Fig. 6, NA dose-effects Curve is substantially parallel to move to right, and maximum reaction is almost unchanged, after carrying out statistical test to each concentration-response percentage, most P values< 0.01, there is significant difference.Positive drug Doxazosin antagonism NA shrinks the pA of Rabbit Aorta2Be worth is 7.52 ± 0.04.
Checked through statistics t, the pA of compound (II-2) and positive control drug Doxazosin to NA2Compare between value, P ＞ 0.05, there was no significant difference between the two, illustrates antagonism and Doxazosin phase of the compound (II-2) to α receptor stimulating agents Closely.
6.2 compounds (II-2) are to family rabbit vascular smooth muscle calcium channel (Ca2+) antagonism
6.2.1 compound (II-2) 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 be incubated 40 minutes with without calcium K-H liquid, added Sample is depolarized 20 minutes without calcium potassium liquid high, then add CaCl to accumulation in bath pipe2(10-6-10-2Mol/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, balanced 60 minutes, treat base After line recovers 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 high without calcium Potassium liquid makes sample depolarize 20 minutes, while to addition compound (II-2) (3 × 10 in bath pipe-6Mol/L), after being incubated 20 minutes CaCl is added with the accumulation of same method again2(10-6-10-2Mol/L), until reaching maximum reaction, wave recording.It is with maximum reaction 100%, CaCl2Percentage of contraction during each concentration is ordinate, CaCl2The negative logarithm of each concentration is that abscissa draws amount effect curve, Add compound (II-2) (3 × 10-6Mol/L after), such as Fig. 7, 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, there is significant difference.Compound (II-2) antagonism CaCl2Shrink the pA of Rabbit Aorta2Be worth is 5.61 ± 0.04.
6.2.2 positive control drug Amlodipine is to CaCl2The influence of amount effect curve is shunk in accumulation
After sample tension stability, sample is rinsed 3 times with without calcium K-H liquid, and be incubated 40 minutes with without calcium K-H liquid, added Sample is depolarized 20 minutes without calcium potassium liquid high, then add CaCl to accumulation in bath pipe2(10-6-10-2Mol/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, balanced 60 minutes, treat base After line recovers 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 high without calcium Potassium liquid makes sample depolarize 20 minutes, while to addition Amlodipine (10 in bath pipe-7Mol/L), again with same after being incubated 15 minutes Method accumulation adds CaCl2(10-6-10-2Mol/L), until reaching maximum reaction, wave recording.With maximum reaction for 100%, CaCl2Percentage of contraction during each concentration is ordinate, CaCl2The negative logarithm of each concentration is that abscissa draws amount effect curve, adds ammonia Flordipine (10-7Mol/L after), such as Fig. 8, CaCl2Amount effect curve is substantially parallel to move to right, and maximum reaction is almost unchanged, to each concentration After reaction percentage carries out statistical test, most P values<0.01, there is significant difference.Amlodipine antagonism CaCl2Shrink The pA of Rabbit Aorta2Be worth is 6.99 ± 0.05.
Antagonism of 6.3 compounds (II-2) to family rabbit vascular smooth muscle serotonin (5-HT) receptor stimulating agent
After sample tension stability, one section of waveform is recorded, 5-HT (10 is added to being accumulated in bath pipe-7-3×10-4mol/L) Until reaching maximum reaction, wave recording.Then sample is rinsed repeatedly with K-H liquid, after balance 1.5h, add compound (II-2) (3×10-6Mol/L), 5-HT is added with same method again after 20 minutes.With maximum reaction for 100%, 5-HT percentage of contractions are vertical seat Mark, the negative logarithm of each concentration of 5-HT is that abscissa draws amount effect curve, adds compound (II-2) (3 × 10-6Mol/L after), such as scheme 9,5-HT amount effect curves are substantially parallel to move to right, and maximum reaction is almost unchanged, and statistical test is carried out to each concentration-response percentage Afterwards, P values<0.01, there is significant difference.Compound (II-2) antagonism 5-HT shrinks the pA of Rabbit Aorta2Value 5.71 ± 0.08。
The research of the relaxing the VSM mechanism of action of the compound (II-2) disclosed in this patent shows, the compound Contestable antagonism phyenlephrinium, the contraction of calcium ion and serotonin to blood vessel, can make the dose-effect of above-mentioned activator Oriented parallel is moved to right, do not reduce its maximum reaction, explanation is competitive antagonism, its antagonism norepinephrine (NA), calcium from The pA of son and serotonin (5-HT) to the contraction of blood vessel2Value be respectively 7.37 ± 0.08 (Doxazosin be 7.52 ± 0.04), 5.61 ± 0.04 (Amlodipine is 6.99 ± 0.05) and 5.71 ± 0.08 are (such as Fig. 3, Fig. 4, Fig. 5, Fig. 6 and Fig. 7 institute Show).Result shows that compound (II-2) is by blocking α1Acceptor, Ca2+Ion channel and blood vessel 5-HT2AAcceptor plays it Vasorelaxation action.
Embodiment 31
The acute toxicity testing of compound (II-2)
Kunming mouse (being provided by Chinese Medical Sciences University's experimental animal center) is taken, male and female half and half, body weight 18-22g is carried out Compound (II-2) simplifies probit method acute toxicity testing, gastric infusion LD50It is 361.88mg/kg (95% fiducial limit areas Between be 302.96-420.80mg/kg).
Embodiment 32
The Teratogenic effects of the mouse of compound (II-2)
Kunming mouse (being provided by Chinese Medical Sciences University's experimental animal center) 10, male and female half and half, by 120mg/kg/ are provided Its body weight gastric infusion compound (II-2).It is administered continuously 4 days, carries out Micronuclei In The Mouse Bone Marrow test within the 5th day.
Positive controls, give endoxan 60mg/kg/ days；Negative control group, gives physiological saline 0.1ml/10g/ My god.It is administered continuously 4 days, carries out Micronuclei In The Mouse Bone Marrow test within the 5th day.
The disconnected neck of mouse is put to death, femur and breastbone are separated rapidly, remove blood stains and muscle, subtract epiphysis, breastbone is with stopping Marrow is squeezed on the cleaning slide for having calf serum in drop in advance or is directly rushed the marrow in femur with calf serum by blood pincers To the slide of cleaning, push jack after being well mixed；Then the marrow piece for drying will be pushed away puts the staining jar for filling methyl alcohol into, Gu Fixed 15 minutes, taking-up is dried, and after marrow piece dries, with the Giemsa applications liquid of Fresh, (Giemsa storing solutions are a to be added 9 parts of the phosphate buffer of pH6.8), dye 10 minutes, thread water washes out Coplin liquid, is examined under a microscope after drying.
Test result indicate that：Compound (II-2) organizes the polychromatic erythrocyte containing micronucleus in 1000 polychromatic erythrocytes 2.0 ± 0.333 ‰ are accounted for, the polychromatic erythrocyte containing micronucleus accounts for 1 ‰, endoxan in 1000 polychromatic erythrocytes of blank group The polychromatic erythrocyte containing micronucleus accounts for 12 ‰ in 1000 polychromatic erythrocytes of group.Show the bone marrow micronucleus of compound (II-2) Result of the test is feminine gender.
Embodiment 33
Influence of the compound (II-2) to SD rat blood pressures
4 SD rats are anaesthetized through urethane (1.25mg/kg), after rat vital sign is steady, is inserted using arteria carotis communis Pipe method determines blood pressure.After blood pressure is steady, compound (II-2) is pressed into 4.0mg/kg body weight gastric infusions, observe and record to Blood pressure changes over time situation after medicine, and experimental result is shown in Table 3, table 4, the data of table 5.
Influence (n=4) of the compound of the table 3. (II-2) to urethane anesthetized rat diastolic pressure (DBP, mmHg)
Note：* P values are represented<0.05, * * represents P values<0.01
Influence (n=4) of the compound of the table 4. (II-2) to the systolic pressure (SBP, mmHg) of urethane anesthetized rat
Note：* P values are represented<0.05, * * represents P values<0.01
Influence (n=4) of the compound of the table 5. (II-2) to the mean arterial pressure (MAP, mmHg) of urethane anesthetized rat
Note：* P values are represented<0.05, * * represents P values<0.01
Test result indicate that：Compound (II-2) there is substantially step-down to make urethane (1.25mg/kg) anesthesia SD rats With administration can recover the level to administration after 3.5 hours.
Summary result shows：In in vitro animal experiment, compound (II-2) has significant relaxing the VSM Effect.Compound (II-2) is suitable with Doxazosin to the antagonism of α-adrenoceptor, its antagonism norepinephrine NA PA2It is 7.37 ± 0.08 to be worth, the pA of Doxazosin antagonism NA2It is 7.52 ± 0.04 to be worth, compound (II-2) antagonism CaCl2's pA2It is 5.61 ± 0.04 to be worth, the pA of its antagonism 5-HT2Be worth is 5.71 ± 0.08.In rat body in bulk testing, compound (II- 2) obvious antihypertensive effect is shown, its oral absorption is good, small toxicity, therapeutic index is big, and Teratogenic effects are negative, tool Have as new Mutiple Targets vasodilator drug, especially as the potential value of Novel blood pressure-reducing medicine exploitation.

Claims (9)

1. benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of formula (I),
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
R1By R7When monosubstituted, R7Represent H, halogen, CN, C1-C6Alkyl, C1-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-C6Alkane Base), S (O)2H or S (O)2(C1-C6Alkyl), moieties are optionally replaced by one or more halogen atoms in above-mentioned group；
R1By R7When polysubstituted, R7H, halogen, CN, C are represented independently of one another1-C6Alkyl, C1-C6Alkoxy, CHO, CO (C1-C6 Alkyl), 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 by one or more halogen in above-mentioned group Plain atom substitution；
R2Represent the C that H, halogen, CN, moieties are optionally replaced by one or more halogen atoms1-C6Alkyl or C1-C6Alkane Epoxide；
R3、R4、R5、R6H, halogen, CN, C are represented independently of one another1-C6Alkyl, C1-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；
Q represents CH2Or oxygen；
Y represents the saturation that is optionally replaced by one or more halogen atoms or undersaturated contains the 1-8 straight chain of carbon atom Or branched hydrocarbyl, wherein one or more carbon be optionally selected from oxygen, sulphur and nitrogen hetero atom substitute.
2. benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 1,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl or cyclooctyl；
The aryl or heteroaryl be phenyl, naphthyl, furyl, pyridine radicals, pyrimidine radicals, benzothiazolyl, benzisothia oxazolyl, Benzoxazolyl, benzoisoxazole base, benzimidazolyl, benzopyrazoles base, benzofuranyl, benzo pyrimidine radicals, benzo pyridine Base Huo quinoxalinyls；
R1By R7When monosubstituted, R7Represent H, halogen, CN, C1-C4Alkyl, C1-C4Alkoxy, CHO, CO (C1-C4Alkyl), COOH, COO(C1-C4Alkyl), NO2、NH2、NH(C1-C4Alkyl), N (C1-C4Alkyl)2, moieties are optionally by 1-3 in above-mentioned group Halogen atom replaces；
R1By R7When polysubstituted, R7H, halogen, CN, C are represented independently of one another1-C4Alkyl, C1-C4Alkoxy, CHO, CO (C1-C4 Alkyl), COOH, COO (C1-C4Alkyl), NO2、NH2、NH(C1-C4Alkyl), N (C1-C4Alkyl)2, moieties in above-mentioned group Optionally replaced by 1-3 halogen atom；
R2H, halogen, CN, moieties are represented optionally by the 1-3 C of halogen atom substitution1-C4Alkyl or C1-C4Alkoxy；
R3、R4、R5、R6H, halogen, CN, C are represented independently of one another1-C4Alkyl, C1-C4Alkoxy, CHO, CO (C1-C4Alkyl), COOH、COO(C1-C4Alkyl), moieties are optionally replaced by 1-3 halogen atom in above-mentioned group；
Q represents CH2Or oxygen；
Y represents the saturation that is optionally replaced by one or more halogen atoms or undersaturated contains the 1-6 straight chain of carbon atom Or branched hydrocarbyl, wherein one or more carbon be optionally selected from oxygen, sulphur and nitrogen hetero atom substitute.
3. benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 1,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
The aryl or heteroaryl be phenyl, naphthyl, furyl, pyridine radicals, pyrimidine radicals, benzothiazolyl, benzisothia oxazolyl, Benzoxazolyl, benzoisoxazole base, benzimidazolyl, benzopyrazoles base, benzofuranyl Huo quinoxalinyls；
R1By R7When monosubstituted, R7Represent H, F, Cl, Br, I, CN, C1-C4Alkyl, C1-C4Alkoxy, CHO, CO (C1-C4Alkyl), COOH、COO(C1-C4Alkyl), moieties are optionally replaced by 1-3 halogen atom in above-mentioned group；
R1By R7When polysubstituted, R7H, F, Cl, Br, I, CN, C are represented independently of one another1-C4Alkyl, C1-C4Alkoxy, CHO, CO (C1-C4Alkyl), COOH, COO (C1-C4Alkyl), moieties are optionally replaced by 1-3 halogen atom in above-mentioned group；
R2Represent H, F, Cl, Br, CN, CH3、CF3；
R3、R4、R5、R6H, F, Cl, Br, I, CN, CH are represented independently of one another3、OCH3、COCH3Or COOCH3；
Q represents CH2Or oxygen；
Y represents methylene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, wherein the hydrogen atom of the group is optionally Replaced by one or more halogen atoms.
4. benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 1,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is cyclohexyl；
The aryl or heteroaryl are phenyl, naphthyl, furyl, pyridine radicals, pyrimidine radicals, benzisothia oxazolyl, benzoisoxazole Base, benzopyrazoles base, benzofuranyl Huo quinoxalinyls；
R1By R7When monosubstituted, R7Represent H, F, Cl, CN, CH3、CF3Or OCH3；
R1By R7When polysubstituted, R7H, F, Cl, CN, CH are represented independently of one another3、CF3Or OCH3；
R2Represent H, Cl, CH3；
R3、R4、R6H is represented independently of one another；
R5Represent H, F, Cl, CN, COOCH3；
Q represents CH2Or oxygen；
Y represents ethylidene, propylidene or butylidene.
5. benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 1,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl；
The cyclic hydrocarbon radical is cyclohexyl；
The aryl or heteroaryl are phenyl, pyridine radicals, benzoisoxazole base Huo quinoxalinyls；
R1By R7When monosubstituted, R7Represent H, F, Cl, CH3、CF3Or OCH3；
R1By R7When polysubstituted, R7H, F, Cl, CH are represented independently of one another3、CF3Or OCH3；
R2Represent H or CH3；
R3、R4、R6H is represented independently of one another；
R5Represent H, F, Cl；
Q represents CH2Or oxygen；
Y represents ethylidene or propylidene.
6. benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 1,
Wherein
R1Represent optionally by R7Monosubstituted or polysubstituted phenyl；
R1By R7When monosubstituted, R7Represent H, Cl or CF3；
R1By R7When polysubstituted, R7H, Cl or CF are represented independently of one another3；
R2Represent H；
R3、R4、R6H is represented independently of one another；
R5Represent H；
Q represents CH2；
Y represents propylidene.
7. the benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 1, including 1- (4- (4- (3- trifluoromethyls) piperazine -1- bases) butyl) -1H- benzimidazoles or 1- (4- (4- (2,3- dichlorophenyls) piperazine -1- Base) butyl) -1H- benzimidazoles and its pharmaceutically acceptable salt.
8. benzimidazolyl piperazine compounds and its pharmaceutically acceptable salt of the formula (I) of claim 1, it is described pharmaceutically Acceptable salt is hydrochloride, hydrogen bromide salt, sulfate, mesylate, trifluoroacetate, tartrate, malate, amber Hydrochlorate, maleate, citrate, phosphate, lactate, acetonate, acetate, fumarate, oxaloacetate, second sulphur Hydrochlorate, oxalates, benzene sulfonate or isethionate；Pharmaceutically acceptable salt of the present invention preferably contains the crystallization water, more It is preferred that the crystallization water containing 0.5-3 molecules；The pharmaceutically acceptable salt is more preferably hydrochloride, hydrogen bromide salt, sulfate Or mesylate；The pharmaceutically acceptable salt is optimal to be preferably hydrochloride.
9. benzimidazolyl piperazine compounds and/or its pharmaceutically acceptable salt of the formula (I) comprising claim 1-8 Pharmaceutical composition.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3472854A (en) * 1965-08-19 1969-10-14 Sterling Drug Inc 1-((benzimidazolyl)-lower-alkyl)-4-substituted-piperazines
CN1154693A (en) * 1994-08-05 1997-07-16 美国辉瑞有限公司 Benzimidazole derivative having dopaminergic activity

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4250176A (en) * 1976-12-21 1981-02-10 Janssen Pharmaceutica N.V. Piperazine derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3472854A (en) * 1965-08-19 1969-10-14 Sterling Drug Inc 1-((benzimidazolyl)-lower-alkyl)-4-substituted-piperazines
CN1154693A (en) * 1994-08-05 1997-07-16 美国辉瑞有限公司 Benzimidazole derivative having dopaminergic activity

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