CN103833658A - Benzotriazole-based piperazine compound as well as preparation method and pharmaceutical composition thereof - Google Patents

Benzotriazole-based piperazine compound as well as preparation method and pharmaceutical composition thereof Download PDF

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CN103833658A
CN103833658A CN201310409567.XA CN201310409567A CN103833658A CN 103833658 A CN103833658 A CN 103833658A CN 201310409567 A CN201310409567 A CN 201310409567A CN 103833658 A CN103833658 A CN 103833658A
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benzotriazole
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halogen
monosubstituted
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CN103833658B (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 BEILEI BIOLOGICAL PHARMACEUTICAL Co Ltd
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Priority to JP2015543244A priority patent/JP2016500084A/en
Priority to EP13857383.7A priority patent/EP2924032B1/en
Priority to US14/647,378 priority patent/US9802929B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention relates to a benzotriazole-based piperazine compound as well as a preparation method and a pharmaceutical composition thereof. The benzotriazole-based piperazine compound is represented by a formula (I), wherein R, R1, R2, R3, R4, Q and Y are defined in the description.

Description

Benzotriazole base piperazine compounds and method for making thereof and pharmaceutical composition
Technical field
The present invention relates to benzotriazole base piperazine compounds and method for making and the pharmaceutical composition of a kind of formula (I), wherein R, R 1, R 2, R 3, R 4, Y and Q be as defined in literary composition.
Background technology
Exist clinically at present the multiclass can vasodilatory medicine, for example, α 1receptor blocking agent class medicine, comprises Prazosin, Doxazosin, terazosin etc., and these medicines have obvious first dosage effect or postural hypotension, thereby have limited the widespread use clinically of such medicine; Ca 2+channel blocker, existing medicine comprises amlodipine, nifedipine, felodipine etc., the widespread use clinically at present of this class medicine, but also there is the risk that suppresses heart in it simultaneously.
Therefore, still need to develop new vasodilator drug, to improving drug effect, to meet different patients' needs clinically as far as possible.
Summary of the invention
One aspect of the present invention provides benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of a kind of formula (I),
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
R is by R 5when monosubstituted, R 5represent H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R is by R 5when polysubstituted, R 5represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R 1, R 2, R 3, R 4represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
Q represents CH 2or oxygen;
Y represents the straight or branched alkyl of the saturated or undersaturated 1-8 of the containing carbon atom optionally being replaced by one or more halogen atoms, and the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes;
Condition is
Described heteroaryl is not pyrimidyl, benzopyrazoles base, Thienopyrimidine Ji, oxazole pyrimidyl or purine radicals;
When R is when being represented methylene radical or ethylidene by the mono-substituted aryl of Cl and Y, R 1-R 4be not H entirely;
When R is by CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
In the time that Y represents methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
Another aspect of the present invention provides the benzotriazole base piperazine compounds of formula (I) and the preparation method of pharmacy acceptable salt thereof:
(scheme one)
Figure BDA0000379885250000031
Be included at the temperature of 10-150 DEG C, benzotriazole (A) and chloro alkyl bromide (B) are reacted under the existence of mineral alkali and phase-transfer catalyst in solvent and generate N-chloro alkyl benzotriazole derivatives (C), then reflux under, make itself and N-substituted-piperazinyl (D) under the existence of organic bases in solvent reacting generating compound (I-a);
Or
Scheme (two)
Be included at the temperature of 10-150 DEG C, make the benzotriazole (E) that N-hydroxyl replaces under the existence of mineral alkali, in solvent, react and generate N-chlorinated alkoxy benzotriazole derivatives (G) with chloro alkyl bromide (F), then under refluxing, it is reacted under the existence of organic bases with N-substituted-piperazinyl (D) in solvent, generate compound (I-b);
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
R is by R 5when monosubstituted, R 5represent H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R is by R 5when polysubstituted, R 5represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R 1, R 2, R 3, R 4represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
Y represents the straight or branched alkyl of the saturated or undersaturated 1-8 of the containing carbon atom optionally being replaced by one or more halogen atoms, and the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes;
Condition is
Described heteroaryl is not pyrimidyl, benzopyrazoles base, Thienopyrimidine Ji, oxazole pyrimidyl or purine radicals;
When R is when being represented methylene radical or ethylidene by the mono-substituted aryl of Cl and Y, R 1-R 4be not H entirely;
When R is by CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
In the time that Y represents methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
Another aspect of the present invention provides the benzotriazole base piperazine compounds of contained (I) and/or the pharmaceutical composition of its pharmacy acceptable salt.
Brief description of the drawings
Fig. 1. compound (II-3) (10 -8-10 -5molL -1) to suprarenin AD (10 -5molL -1) (numerical value represents with mean ± SEM to shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect
Figure BDA0000379885250000041
n=8).
Fig. 2. compound (II-1) (10 -8-3 × 10 -5molL -1) to suprarenin AD (10 -5molL -1) (numerical value represents with mean ± SEM to shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect
Figure BDA0000379885250000042
n=7).
Fig. 3. compound (II-6) (10 -9-10 -6mol/L) to suprarenin AD (10 -5mol/L) (numerical value represents with mean ± SEM the cumulative concentration effect curve of contraction rabbit myocardium vessel diastole effect
Figure BDA0000379885250000051
n=7).
Fig. 4. compound (II-3) (3 × 10 -7-3 × 10 -5molL -1) to high potassium liquid (60mmolL -1) (numerical value represents with mean ± SEM to shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect
Figure BDA0000379885250000052
n=8).
Fig. 5. compound (II-1) (10 -7-3 × 10 -5molL -1) to high potassium liquid (60mmolL -1) (numerical value represents with mean ± SEM to shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect
Figure BDA0000379885250000053
n=6).
Fig. 6. compound (II-6) (10 -8-10 -4mol/L) to the cumulative concentration effect curve of high potassium liquid (60mmol/L) contraction rabbit myocardium vessel diastole effect, (numerical value represents with mean ± SEM
Figure BDA0000379885250000054
n=7).
Fig. 7. compound (II-3) (3 × 10 -6mol/L), positive control Doxazosin (10 -7mol/L) antagonism norepinephrine NA (3 × 10 -7-10 -4mol/L) (numerical value represents with mean ± SEM the cumulative concentration effect curve of contraction rabbit myocardium vessel
Figure BDA0000379885250000055
* P < 0.05, * * P < 0.01, n=6).
Fig. 8. compound (II-3) (10 -5mol/L), amlodipine (10 -7mol/L) antagonism CaCl 2(10 -5-3 × 10 -1mol/L) (numerical value represents with mean ± SEM the cumulative concentration effect curve of contraction rabbit myocardium vessel
Figure BDA0000379885250000056
* P < 0.05, * * P < 0.01, n=5).
Fig. 9. compound (II-3) (3 × 10 -6mol/L) antagonism serotonin (10 -8-3 × 10 -4mol/L) (numerical value represents with mean ± SEM the cumulative concentration effect curve of contraction rabbit myocardium vessel
Figure BDA0000379885250000057
* P < 0.05, * * P < 0.01, n=5).
Figure 10. compound (II-6) (3 × 10 -8mol/L) antagonism phyenlephrinium (10 -6-6 × 10 -3mol/L) (numerical value represents with mean ± SEM the cumulative concentration effect curve of contraction rabbit myocardium vessel
Figure BDA0000379885250000058
* P < 0.05, * * P < 0.01, n=8).
Figure 11. compound (II-6) (10 -5mol/L) antagonism CaCl 2(10 -5-10 -2mol/L) (numerical value represents with mean ± SEM the cumulative concentration effect curve of contraction rabbit myocardium vessel
Figure BDA0000379885250000059
* P < 0.05, * * P < 0.01, n=7).
Figure 12. compound (II-6) (10 -7mol/L) antagonism serotonin (10 -8-3 × 10 -4mol/L) (numerical value represents with mean ± SEM the cumulative concentration effect curve of contraction rabbit myocardium vessel
Figure BDA00003798852500000510
* P < 0.05, * * P < 0.01, n=5).
Embodiment
Herein, term " cyclic hydrocarbon radical " comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group etc.
Herein, term " aryl " comprises phenyl, naphthyl or indenyl etc.
Herein, term " heteroaryl " comprises furyl, pyridyl, pyrimidyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzopyrazoles base, benzofuryl, benzo pyrimidyl, benzo pyridyl Huo quinoxalinyl etc.
Herein, term " halogen " comprises fluorine, chlorine, bromine or iodine.
Herein, term " alkyl " comprises straight or branched alkyl.Described " C 1-C 6alkyl " example of group comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl or n-hexyl etc.
Herein, comprise-O-of term " alkoxyl group " alkyl, wherein alkyl comprises straight or branched alkyl.Described " C 1-C 6alkoxyl group " example of group comprises methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy and hexyloxy etc.
Herein, general, preferred, preferred, further between preferred, particularly preferred, extremely particularly preferred, most preferred definition, can mutually be used in combination.
In some embodiments, the invention provides benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula (I),
Figure BDA0000379885250000061
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
R is by R 5when monosubstituted, R 5represent H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R is by R 5when polysubstituted, R 5represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R 1, R 2, R 3, R 4represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
Q represents CH 2or oxygen;
Y represents the straight or branched alkyl of the saturated or undersaturated 1-8 of the containing carbon atom optionally being replaced by one or more halogen atoms, and the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes;
Condition is
Described heteroaryl is not pyrimidyl, benzopyrazoles base, Thienopyrimidine Ji, oxazole pyrimidyl or purine radicals;
When R is when being represented methylene radical or ethylidene by the mono-substituted aryl of Cl and Y, R 1-R 4be not H entirely;
When R is by CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
In the time that Y represents methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
In preferred embodiments, the invention provides benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula (I),
Figure BDA0000379885250000071
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
Described cyclic hydrocarbon radical is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group;
Described aryl or heteroaryl are preferably phenyl, naphthyl, furyl, pyridyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzofuryl, benzo pyrimidyl, benzo pyridyl Huo quinoxalinyl;
R is by R 5when monosubstituted, R 5preferably represent H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
R is by R 5when polysubstituted, R 5preferably represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R 1, R 2, R 3, R 4preferably represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
Q represents CH 2or oxygen;
Y represents the straight or branched alkyl of the saturated or undersaturated 1-8 of the containing carbon atom optionally being replaced by one or more halogen atoms, and the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes;
Condition is
When R is when being represented methylene radical or ethylidene by the mono-substituted aryl of Cl and Y, R 1-R 4be not H entirely;
When R is by CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
In the time that Y represents methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
In a more preferred embodiment, the invention provides benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula (I),
Figure BDA0000379885250000091
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
Described cyclic hydrocarbon radical is more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
Described aryl or heteroaryl are more preferably phenyl, naphthyl, furyl, pyridyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzofuryl Huo quinoxalinyl;
R is by R 5when monosubstituted, R 5more preferably represent H, halogen, CN, C 1-C 4alkyl, C 2-C 4alkoxyl group, CHO, CO (C 1-C 4alkyl), COOH, COO (C 1-C 4alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
R is by R 5when polysubstituted, R 5more preferably represent independently of one another H, halogen, CN, C 1-C 4alkyl, C 2-C 4alkoxyl group, CHO, CO (C 1-C 4alkyl), COOH, COO (C 1-C 4alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
R 1, R 2, R 3, R 4more preferably represent independently of one another H, F, Cl, Br, I, CN, CH 3, OCH 3, COCH 3or COOCH 3;
Q represents CH 2or oxygen;
Y more preferably represents ethylidene, propylidene, butylidene, pentylidene or hexylidene, and wherein said group is optionally replaced by one or more halogen atoms;
Condition is
When R is by Cl or CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
In preferred embodiment further, the invention provides benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula (I),
Figure BDA0000379885250000101
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
Described cyclic hydrocarbon radical is still more preferably cyclohexyl;
Described aryl or heteroaryl are still more preferably phenyl, naphthyl, furyl, pyridyl, benzisothiazole base, benzoisoxazole base, benzofuryl Huo quinoxalinyl;
R is by R 5when monosubstituted, R 5still more preferably represent H, F, Cl, CN, CH 3or CF 3;
R is by R 5when polysubstituted, R 5still more preferably represent independently of one another H, F, Cl, CN, CH 3or CF 3;
R 1, R 4still more preferably represent independently of one another H;
R 2, R 3still more preferably represent independently of one another H, F, Cl, CN, CH 3or COOCH 3;
Q represents CH 2or oxygen;
Y still more preferably represents ethylidene, propylidene or butylidene;
Condition is
When R is by Cl or CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely.
In particularly preferred embodiments, the invention provides benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula (I),
Figure BDA0000379885250000102
Wherein
R represents optionally by R 5monosubstituted or polysubstituted aryl or heteroaryl;
Described aryl or heteroaryl be phenyl, benzisothiazole base, benzoisoxazole base or benzofuryl particularly preferably;
R is by R 5when monosubstituted, R 5particularly preferably represent H, F, Cl, CN, CH 3or CF 3;
R is by R 5when polysubstituted, R 5particularly preferably represent independently of one another H, F, Cl, CN, CH 3or CF 3;
R 1, R 4particularly preferably represent independently of one another H;
R 2, R 3particularly preferably represent independently of one another H, F or Cl;
Q represents CH 2or oxygen;
Y particularly preferably represents ethylidene or propylidene;
Condition is
When R is by Cl or CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely.
In utmost point particularly preferred embodiment, the invention provides benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula (I),
Figure BDA0000379885250000111
Wherein
R represents optionally by R 5monosubstituted or polysubstituted aryl or heteroaryl;
Described aryl or the heteroaryl utmost point be phenyl, benzoisoxazole base or benzisothiazole base particularly preferably;
R is by R 5when monosubstituted, R 5the utmost point particularly preferably represents H, F, Cl or CF 3;
R is by R 5when polysubstituted, R 5the utmost point particularly preferably represents H, F, Cl or CF independently of one another 3;
R 1, R 2, R 3, R 4the utmost point particularly preferably represents H independently of one another;
The Y utmost point particularly preferably represents ethylidene or propylidene,
Condition is
When R is by Cl or CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely.
In the most preferred embodiment, the invention provides benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula (I),
Figure BDA0000379885250000121
Wherein
R most preferably represents optionally by R 5monosubstituted or polysubstituted phenyl or benzisothiazole base;
R is by R 5when monosubstituted, R 5most preferably represent H, Cl or CF 3;
R is by R 5when polysubstituted, R 5most preferably represent independently of one another H, Cl or CF 3;
R 1, R 2, R 3, R 4most preferably represent independently of one another H;
Y most preferably represents propylidene.
Described pharmacy acceptable salt is preferably hydrochloride, hydrogen bromide salt, vitriol, mesylate, trifluoroacetate, tartrate, malate, succinate, maleate, Citrate trianion, phosphoric acid salt, lactic acid salt, pyruvate salt, acetate, fumarate, oxaloacetate, esilate, oxalate, benzene sulfonate or isethionate.Pharmacy acceptable salt of the present invention, preferably containing crystal water, more preferably contains the crystal water of 0.5-3 molecule.
Described pharmacy acceptable salt is more preferably hydrochloride, hydrogen bromide salt, vitriol or mesylate.
Described pharmacy acceptable salt optimum is preferably hydrochloride.
The benzotriazole base piperazine compounds of formula (I) is still more preferably following compound:
Figure BDA0000379885250000122
Figure BDA0000379885250000131
Figure BDA0000379885250000141
Figure BDA0000379885250000151
Wherein compound of the present invention most preferably exists with the form of hydrochloride, for example compound (I-1), (I-3) and (I-6) most preferably exist with the form of formula (II-1), (II-3) and hydrochloride (II-6) respectively:
Figure BDA0000379885250000152
In some embodiments, the invention provides the preparation method of the benzotriazole base piperazine compounds of formula (I):
(scheme one)
Figure BDA0000379885250000153
Be included at the temperature of 10-150 DEG C, benzotriazole (A) and chloro alkyl bromide (B) are reacted under the existence of mineral alkali and phase-transfer catalyst in solvent and generate N-chloro alkyl benzotriazole derivatives (C), then reflux under, make itself and N-substituted-piperazinyl (D) under the existence of organic bases in solvent reacting generating compound (I-a);
Or
Scheme (two)
Figure BDA0000379885250000161
Be included at the temperature of 10-150 DEG C, make the benzotriazole (E) that N-hydroxyl replaces under the existence of mineral alkali, in solvent, react and generate N-chlorinated alkoxy benzotriazole derivatives (G) with chloro alkyl bromide (F), then under refluxing, it is reacted under the existence of organic bases with N-substituted-piperazinyl (D) in solvent, generate compound (I-b); Wherein R, R 1, R 2, R 3, R 4as above define with Y.
The first step reaction of scheme () and scheme (two) respectively mineral alkali and phase-transfer catalyst and existence under in solvent, carry out, described mineral alkali is preferably sodium hydride, sodium hydroxide, sodium methylate, sodium ethylate, sodium carbonate, sodium bicarbonate, potassium hydride KH, potassium hydroxide, potassium methylate, potassium ethylate, salt of wormwood or saleratus, is more preferably sodium hydride or sodium hydroxide; Described phase-transfer catalyst is preferably Tetrabutyl amonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate or Isosorbide-5-Nitrae, and 7,10,13,16-hexaoxacyclooctadecane-6 (i.e. 18 hats 6) etc., are more preferably Tetrabutyl amonium bromide; It is solvent conventional in this area that the first step is reacted solvent used, is preferably water (except while using sodium hydride), N-Methyl pyrrolidone (NMP) or DMF (DMF) and composition thereof; The temperature of reaction of the first step is 10-150 DEG C, preferably 15-130 DEG C, more preferably 20-100 DEG C; Reaction times can be selected according to those skilled in the art's experience, for example 0.5-20 hour, preferably 1-15 hour.
The second step of scheme () and scheme (two) reacts each comfortable organic bases, more preferably under the existence of organic bases and potassiumiodide, in solvent, carries out, described organic bases is preferably diisopropyl ethyl amine, diethylamine, triethylamine, pyridine, TERTIARY BUTYL AMINE, cyclopropylamine, Di-n-Butyl Amine, Diisopropylamine or 1,2-dimethyl propylamine is more preferably diisopropyl ethyl amine; It is solvent conventional in this area that second step reacts solvent used, is preferably acetonitrile, DMF, dimethyl sulfoxide (DMSO) (DMSO) or butanone and composition thereof; Reaction times can be selected according to those skilled in the art's experience, for example 1-30 hour, preferably 5-25 hour.
The inventive method also preferably includes the step that makes product and corresponding acid-respons generate pharmacy acceptable salt.Wherein acid used can be hydrochloric acid, bromine hydracid, sulfuric acid, methylsulfonic acid, trifluoracetic acid, tartrate, oxysuccinic acid, succsinic acid, toxilic acid, citric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, fumaric acid, oxaloacetic acid, ethyl sulfonic acid, oxalic acid, Phenylsulfonic acid or isethionic acid, be more preferably hydrochloric acid, bromine hydracid, sulfuric acid or methylsulfonic acid, be most preferably hydrochloric acid.Described salify step is preferably carried out in solvent, solvent for use can be methyl alcohol, ethanol, propyl alcohol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methyl isopropyl Ketone, methyl iso-butyl ketone (MIBK), acetonitrile, propionitrile, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO) or tetramethylene sulfone etc., ethyl acetate and/or ethanol.
In some embodiments, the invention provides the benzotriazole base piperazine compounds of contained (I) and/or the pharmaceutical composition of its pharmacy acceptable salt.
Formula (I) compound and/or its salt and pharmaceutically acceptable carrier that described pharmaceutical composition comprises significant quantity (for example 0.1-99.5 % by weight).Described carrier is such as, but not limited to, thinner (as water), vehicle etc.; Tackiness agent, as derivatived cellulose, gelatin, polyvinylpyrrolidone etc.; Weighting agent is as starch etc.; Burst apart agent as calcium carbonate, sodium bicarbonate; Lubricant is as calcium stearate or Magnesium Stearate etc.In addition, can also in composition, add other auxiliarys as flavouring agent and sweeting agent.When oral, can be prepared into conventional solid preparation as tablet, pulvis or capsule etc.; While being used for injecting, can be prepared into injection liquid.The concrete dosage of described pharmaceutical composition can be determined by doctor according to clinical experiment result and patient's the state of an illness, age etc.
The various formulations of pharmaceutical composition of the present invention can adopt the method for medical field routine to be prepared.
In some embodiments, the invention provides the benzotriazole base piperazine compounds of formula (I) and pharmacy acceptable salt thereof the purposes for the preparation of vasodilator drug.
Benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula of the present invention (I) have significant vasorelaxation action.Preferably, described compound and pharmacy acceptable salt thereof have stronger blocking-up α 1acceptor, Ca 2+passage, 5-HT 2Aone or more effects in acceptor.Can have as α at it 1receptor blocking agent, Ca 2+when dual or triple role in channel blocker and 5-HT receptor blocking agent, this compound can be by multiple action pathway acting in conjunction, thereby can bring into play different approaches advantage, made up deficiency separately, make compound to bring into play multiple advantage realizing vasorelaxation action.More preferably, compound of the present invention can be used as effective three target spot vasodilators, possesses α 1acceptor, Ca 2+passage, 5-HT 2Athe triple blocking effects of acceptor.Thus, it is not exclusively blocking the α of vascular smooth muscle 1when acceptor, by blocking-up Ca 2+passage, for example produce resisting cardiac hypertrophy, protection vascular endothelial cell, atherosclerosis, inhibition vascular smooth muscle hyperplasia or improve the effects such as cerebral circulation, and/or by blocking-up sinus node calcium channel, reducing heart rate, effectively prevent tachycardia and palpitaition, thereby prevent the generation of first-dose response; And due to three kinds of blocking effects, make remaining α 1acceptor still can participate in pressor reflex, thereby prevents postural hypotension; Meanwhile, due to 5-HT 2Areceptor blocking effect, be conducive to the supply of blood flow for the treatment of heart failure and improving occlusion vascular disease patient, therefore can treat with the hypertension of heart failure, with arteriosclerotic hypertension, hypertension, middle and advanced stage hypertension or some intractable hypertension with vessel endothelium and induced endothelial.
The benzotriazole base piperazine compounds of formula of the present invention (I) and pharmacy acceptable salt thereof, compared with existing clinical antihypertensive drug, have stronger antihypertensive activity, better resistance and/or higher security.
Therefore the benzotriazole base piperazine compounds of formula of the present invention (I) and pharmacy acceptable salt thereof can be used for preparing vasorelaxation class medicine, are used for the treatment of vascular smooth muscle spasm diseases related (as: hypertension, heart failure, stenocardia, coronary heart disease etc.); For the cerebral ischemia diseases being caused by vasospasm, myocardial ischemia disease, shock etc.; For renal ischaemia, the poor kidney being caused by kidney vasospasm and periperal vascular spasm (as thromboangiitis obliterans, Raynaud disease etc.).
In addition, the benzotriazole base piperazine compounds of formula of the present invention (I) and pharmacy acceptable salt thereof and other resisting vascular smooth muscle spasm medicine (for example amlodipine, Sertraline, captopril, benazepril, valsartan, Proprasylyte, and other hydragog(ue) etc.) share and can produce obvious synergy, therefore can prepare the Mammals blood vessel smooth muscle spasm diseases related medicine for the treatment of including the mankind together with other medicines.
preparation Example
1-(4-chlorobutyl)-1H-replaces the preparation of benzotriazole
To replace 1H-benzotriazole (0.10mol) is dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025mol), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction, merges organic phase, through the washing of 100ml saturated brine, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al 2o 3chromatography or preparation HPLC separation and purification, obtain 1-(4-chlorobutyl)-1H-and replace benzotriazole, yield 30.0-85.0%.
The preparation of 1-(4-(4-(substituted aryl) piperazine-1-yl) butyl)-1H-benzotriazole (I)
1-(4-chlorobutyl)-1H-benzotriazole (0.036mol) is dissolved in 100ml acetonitrile, add respectively substituted aryl piperazine (0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), stirring at room temperature 10 minutes, then temperature rising reflux reaction 10-20 hour.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtains formula (I) compound, yield 60.0-75.0%.
Embodiment 1
The preparation of 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole (I-1)
By benzotriazole (11.9g, 0.10mol) be dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025mol), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out obtains 1-(4-chlorobutyl)-1H-benzotriazole 17.0g, yield 81.0%.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-chloro-phenyl-piperazine (5.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-1) 7.8g, yield 70.3%.
Compound (I-1) (5.55g, 0.015mol) is dissolved in 50ml ethyl acetate.Under ice-water bath cooling conditions, drip hydrogenchloride/ethyl acetate solution of concentration 3mol/L, to reaction soln PH=2, stir 10 minutes, filter, dry, obtain compound (II-1) solid 5.4g, yield 88.0%.ESI-MS[M+H] +：m／z370.1。
Embodiment 2
The preparation of 1-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-2)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0-036mol) be dissolved in 100ml acetonitrile, add respectively 3-fluorophenyl piperazine (5.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-2) 7.3g, yield 68.9%.ESI-MS[M+H] +：m／z354.2。(step that compound (I-2) and hydrochloric acid reaction generate its hydrochloride (II-2) is referring to embodiment 1 and embodiment 3.)
Embodiment 3
The preparation of 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-3)
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-3) 7.8g, yield 64.5%.
Compound (I-3) (6.05g, 0.015mol) is dissolved in 50ml ethyl acetate.Under ice-water bath cooling conditions, drip hydrogenchloride/ethyl acetate solution of concentration 3mol/L, to reaction soln PH=2, stir 10 minutes, filter, dry, obtain compound (II-3) solid 5.6g, yield 84.8%.ESI-MS[M+H] +：m／z404.2。
Embodiment 4
The preparation of the fluoro-1-of 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-4)
By fluoro-6-1H-benzotriazole (13.7g, 0.10mol) be dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025mol), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Carry out aftertreatment by the post-treating method of the first step in embodiment 1, through preparation HPLC separation and purification, obtain the fluoro-1H-benzotriazole of 1-(4-chlorobutyl)-6-8.9g, yield 39.0%.
By the fluoro-1H-benzotriazole of 1-(4-chlorobutyl)-6-(8.2g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-4) 8.3g, yield 65.7%.ESI-MS[M+H] +：m／z422.2。(step that compound (I-4) and hydrochloric acid reaction generate its hydrochloride (II-4) is referring to embodiment 1 and embodiment 3.)
Embodiment 5
The preparation of 5,6-dimethyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-5)
By 5,6-dimethyl-1H-benzotriazole (14.7g, 0.10mol) be dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025mol), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Carry out aftertreatment by the post-treating method of the first step in synthetic example 1, through preparation HPLC separation and purification, obtain 1-(4-chlorobutyl)-5,6-dimethyl-1H-benzotriazole 17.4g, yield 73.2%.
By 1-(4-chlorobutyl)-5,6-dimethyl-1H-benzotriazole (8.56g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-5) 9.1g, yield 70.3%.ESI-MS[M+H] +：m／z432.2。(step that compound (I-5) and hydrochloric acid reaction generate its hydrochloride (II-5) is referring to embodiment 1 and embodiment 3.)
Embodiment 6
The preparation of 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole (I-6)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-(piperazine-1-yl) benzisothiazole (6.58g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-6) 8.2g, yield 69.6%.
Compound (I-6) (5.89g, 0.015mol) is dissolved in 50ml ethyl acetate and 5ml ethanol.Under ice-water bath cooling conditions, drip hydrogenchloride/ethyl acetate solution of concentration 3mol/L, to reaction soln PH=2, stir 10 minutes, filter, dry, obtain compound (II-6) solid 5.5g, yield 85.5%.ESI-MS[M+H] +：m／z393.2。
Embodiment 7
The preparation of 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole (I-7)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-(piperazine-1-yl) benzoisoxazole (6.1g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-6) 8.0g, yield 70.9%.ESI-MS[M+H] +：m／z377.2。(step that compound (I-7) and hydrochloric acid reaction generate its hydrochloride (II-7) is referring to embodiment 1 and embodiment 3.)
Embodiment 8
The preparation of the fluoro-3-of 6-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole (I-8)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 6-fluorine 3-(piperazine-1-yl) benzoisoxazole (6.1g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-8) 8.3g, yield 70.0%.ESI-MS[M+H] +：m／z395.2。(step that compound (I-8) and hydrochloric acid reaction generate its hydrochloride (II-8) is referring to embodiment 1 and embodiment 3.)
Embodiment 9
The preparation of the fluoro-3-of 6-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole (I-9)
By benzotriazole (11.9g, 0.10mol) be dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 3-chlorobromopropane (30.2g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025mol), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out obtains 1-(3-chloropropyl)-1H-benzotriazole 15.6g, yield 80.0%.
By 1-(3-chloropropyl)-1H-benzotriazole (7.02g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively the fluoro-3-of 6-(piperazine-1-yl) benzoisoxazole (6.6g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-9) 7.9g, yield 69.3%.ESI-MS[M+H] +：m／z380.2。(step that compound (I-9) and hydrochloric acid reaction generate its hydrochloride (11-9) is referring to embodiment 1 and embodiment 3.)
Embodiment 10
The preparation of 1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole (1-10)
Adopt the method in embodiment 9 to prepare 1-(3-chloropropyl)-1H-benzotriazole.
By 1-(3-chloropropyl)-1H-benzotriazole (7.02g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 2,3-dichlorophenyl piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-10) 8.2g, yield 70.2%.ESI-MS[M+H] +：m／z389.1。(step that compound (I-10) and hydrochloric acid reaction generate its hydrochloride (II-10) is referring to embodiment 1 and embodiment 3.)
Embodiment 11
The preparation of 1-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole (I-11)
Adopt the method in embodiment 9 to prepare 1-(3-chloropropyl)-1H-benzotriazole.
By 1-(3-chloropropyl)-1H-benzotriazole (7.02g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-aminomethyl phenyl piperazine (5.3g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-11) 7.5g, yield 74.6%.ESI-MS[M+H] +：m／z335.2。(step that compound (I-11) and hydrochloric acid reaction generate its hydrochloride (II-11) is referring to embodiment 1 and embodiment 3.)
Embodiment 12
The preparation of 1-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-12)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-cyano-phenyl piperazine (5.6g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-12) 7.6g, yield 70.5%.ESI-MS[M+H] +：m／z360.2。(step that compound (I-12) and hydrochloric acid reaction generate its hydrochloride (II-12) is referring to embodiment 1 and embodiment 3.)
Embodiment 13
The preparation of 1-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzotriazole (I-13)
By benzotriazole (11.9g, 0.10mol) be dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 5-chlorine bromo pentane silane (36.8g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025m0l), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out obtains 1-(5-chlorine amyl group)-1H-benzotriazole 15.8g, yield 71.0%.
By 1-(5-chlorine amyl group)-1H-benzotriazole (8.0g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0-03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-13) 7.7g, yield 61.5%.ESI-MS[M+H] +：m／z417.2。(step that compound (I-13) and hydrochloric acid reaction generate its hydrochloride (II-13) is referring to embodiment 1 and embodiment 3.)
Embodiment 14
The preparation of 1-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-14)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(2-furyl) piperazine (4.6g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-14) 7.0g, yield 71.3%.ESI-MS[M+H] +：m/z325.2。(step that compound (I-14) and hydrochloric acid reaction generate its hydrochloride (II-14) is referring to embodiment 1 and embodiment 3.)
Embodiment 15
The preparation of 1-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-15)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(4-pyridyl) piperazine (4.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-15) 6.6g, yield 65.3%.ESI-MS[M+H] +：m/z336.2。(step that compound (I-15) and hydrochloric acid reaction generate its hydrochloride (II-15) is referring to embodiment 1 and embodiment 3.)
Embodiment 16
The preparation of 1-(4-(4-cyclohexyl piperazine-1-yl) butyl)-1H-benzotriazole (I-16)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(1-cyclohexyl) piperazine (5.1g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-16) 6.5g, yield 63.7%.ESI-MS[M+H] +：m/z341.2。(step that compound (I-16) and hydrochloric acid reaction generate its hydrochloride (II-16) is referring to embodiment 1 and embodiment 3.)
Embodiment 17
The preparation of 1-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-17)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(1-naphthyl) piperazine (6.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-17) 6.9g, yield 60.1%.ESI-MS[M+H] +：m/z385.2。(step that compound (I-17) and hydrochloric acid reaction generate its hydrochloride (II-17) is referring to embodiment 1 and embodiment 3.)
Embodiment 18
The preparation of 1-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-18)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(2-quinoxalinyl) piperazine (6.4g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-18) 7.3g, yield 62.7%.ESI-MS[M+H] +：m/z387.2。(step that compound (I-18) and hydrochloric acid reaction generate its hydrochloride (II-18) is referring to embodiment 1 and embodiment 3.)
Embodiment 19
The preparation of 1-(4-(4-(3-(the fluoro-benzisothiazole base of 6-)) piperazine-1-yl) butyl)-1H-benzotriazole (I-19)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzotriazole.
By 1-(4-chlorobutyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively the fluoro-3-of 6-(piperazine-4-yl) benzisothiazole (6.6g, 0.05mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-19) 8.2g, yield 66.5%.ESI-MS[M+H] +：m/z410.2。(step that compound (I-19) and hydrochloric acid reaction generate its hydrochloride (II-19) is referring to embodiment 1 and embodiment 3.)
Embodiment 20
1-(the preparation of 3-(4-(3-(the fluoro-benzofuryl of 6-) piperazine-1-yl) propyl group)-1H-benzotriazole (I-20)
Adopt the method in embodiment 9 to prepare 1-(3-chloropropyl)-1H-benzotriazole.
By 1-(3-chloropropyl)-1H-benzotriazole (7.55g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively the fluoro-3-of 6-(piperazine-4-yl) cumarone (6.6g, 0.05mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 20h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-20) 7.9g, yield 69.1%.ESI-MS[M+H] +：m/z379.2。(step that compound (I-20) and hydrochloric acid reaction generate its hydrochloride (II-20) is referring to embodiment 1 and embodiment 3.)
Embodiment 21
The preparation of the chloro-1-of 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-21)
By chloro-6-benzotriazole (15.3g, 0.10mol) be dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025mol), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out obtains the chloro-1-of 6-(4-chlorobutyl)-1H-benzotriazole 19.2g, yield 79.0%.
By chloro-6-1-(4-chlorobutyl)-1H-benzotriazole (8.75g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-21) 8.5g, yield 64.7%.ESI-MS[M+H] +：m/z437.2。(step that compound (I-21) and hydrochloric acid reaction generate its hydrochloride (II-21) is referring to embodiment 1 and embodiment 3.)
Embodiment 22
The preparation of 6-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-22)
By 6-cyano group-benzotriazole (14.4g, 0.10mol) be dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025mol), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out obtains 6-cyano group-1-(4-chlorobutyl)-1H-benzotriazole 17.8g, yield 76.0%.
By 6-cyano group-1-(4-chlorobutyl)-1H-benzotriazole (8.42g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-22) 8.5g, yield 66.4%.ESI-MS[M+H] +：m/z428.2。(step that compound (I-22) and hydrochloric acid reaction generate its hydrochloride (II-22) is referring to embodiment 1 and embodiment 3.)
Embodiment 23
The preparation of 6-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-23)
By 6-methoxycarbonyl-benzotriazole (17.7g, 0.10mol) be dissolved in 30% (weight ratio) aqueous sodium hydroxide solution 100ml, add 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide (0.8g, 0.0025mol), mix and blend 5 minutes.Reaction solution is slowly warming up to 60 DEG C, stirring reaction 2 hours.Be cooled to room temperature, add 100ml dichloromethane extraction, separatory, water adds methylene dichloride 100ml extraction again, merges organic phase, through the water washing of 100ml saturated common salt, separatory, evaporate to dryness organic phase obtains oily matter.Oily matter is through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out obtains 6-methoxycarbonyl-1-(4-chlorobutyl)-1H-benzotriazole 19.5g, yield 73.0%.
By 6-methoxycarbonyl-1-(4-chlorobutyl)-1H-benzotriazole (9.61g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.9g, 0.03mol), diisopropyl ethyl amine (15.5g, 0.12mol), and potassiumiodide (5.0g, 0.03mol), be uniformly mixed rear temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-23) 8.8g, yield 63.4%.ESI-MS[M+H] +：m/z461.2。(step that compound (I-23) and hydrochloric acid reaction generate its hydrochloride (II-23) is referring to embodiment 1 and embodiment 3.)
Embodiment 24
1-(the preparation of 4-(4-(3-(the fluoro-benzoisoxazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole (I-24)
I-hydroxybenzotriazole (0.01mol) is dissolved in 10ml NMP, adds the solid paraffin mixture of the sodium hydrogen (0.01mol) of 50% weight ratio, stirring reaction 0.5h in batches.Meanwhile, by 3-chlorobromopropane (0.015mol), be dissolved in 5ml NMP, add in above-mentioned solution stirring reaction 12h under room temperature.Reaction solution is poured in 50ml water, and ethyl acetate extraction (3 × 50mL), merges organic phase, through 30ml water washing, adds anhydrous magnesium sulfate drying organic phase, filter, and solvent evaporated, oily matter is through neutral Al 2o 3chromatography or preparation HPLC separation and purification, obtain 1-(3-chlorine propoxy-) benzotriazole, yield 75.0%.
1-(3-chlorine propoxy-) benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(the fluoro-benzoisoxazole base of 6-)) piperazine (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain 1-(4-(4-(3-(the fluoro-benzoisoxazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole (I-24) 13.4g, yield 67.6%.ESI-MS[M+H] +：m/z396.2。(step that compound (I-24) and hydrochloric acid reaction generate its hydrochloride (II-24) is referring to embodiment 1 and embodiment 3.)
Embodiment 25
The fluoro-1-of the 6-(preparation of 4-(4-(3-(the fluoro-benzisothiazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole (I-25)
Fluoro-6-I-hydroxybenzotriazole (0.01mol) is dissolved in 10ml NMP, adds the solid paraffin mixture of the sodium hydrogen (0.01mol) of 50% weight ratio, stirring reaction 0.5h in batches.Meanwhile, by 3-chlorobromopropane (0.015mol), be dissolved in 5ml NMP, add in above-mentioned solution stirring reaction 12h under room temperature.Reaction solution is poured in 50ml water, and ethyl acetate extraction (3 × 50mL), merges organic phase, through 30ml water washing, adds anhydrous magnesium sulfate drying organic phase, filter, and solvent evaporated, oily matter is through neutral Al 2o 3chromatography or preparation HPLC separation and purification, obtain the fluoro-1-of 6-(3-chlorine propoxy-) benzotriazole, yield 75.0%.
Fluoro-6-1-(3-chlorine propoxy-) benzotriazole (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(the fluoro-benzisothiazole base of 6-)) piperazine (0.05mol), diisopropyl ethyl amine (0.2mol), and potassiumiodide (0.05mol), mix and blend 10 minutes under room temperature, then temperature rising reflux reaction 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through neutral Al 2o 3chromatographic separation purifying, methylene chloride/methanol mixed solvent wash-out, obtain the fluoro-1-of 6-(4-(4-(3-(the fluoro-benzisothiazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole (I-25) 14.1g, yield 65.6%.ESI-MS[M+H] +：m/z430.1。(step that compound (I-25) and hydrochloric acid reaction generate its hydrochloride (II-25) is referring to embodiment 1 and embodiment 3.)
Embodiment 26
Compound (II-1)-(II-25) cause the diastole effect of shrinking rabbit myocardium vessel unstriated muscle 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-25) adopt embodiment method to make by oneself;
Sodium-chlor (NaCl): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120413;
Repone K (KCl): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20111123;
Anhydrous magnesium sulfate (MgSO 4): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20101029;
Calcium Chloride Powder Anhydrous (CaCl 2): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20110314;
Sodium bicarbonate (NaHCO 3): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120507;
Glucose (Glucose): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120512;
Potassium primary phosphate (KH 2pO 4): be purchased from Tianjin great Mao chemical reagent factory product, lot number: 20110928;
Sodium chloride injection (NaCl): be purchased from Zhiying Pharmaceutical Factory, Shenyang, lot number: 12021001;
Adrenalin hydrochloride injection liquid (Epinephrine Hydrochloride Injection) specification: 1mg/1ml, 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 apparatuss
HSS-1 (B) type thermostatic bath: Chengdu Instruement Factory;
RM6240B type multi-path physiology signal acquiring processing system: Chengdu Instruement Factory;
JZJ01 type muscle tone transverter: Chengdu Instruement Factory;
YPJ01 type pressure transducer: Chengdu Instruement Factory;
TG-328A photoelectric analytical balance: Shanghai balance equipment factory;
T-500 type electronic balance: Changshu Shuan Jie testing tool factory;
Micropipet: Shanghai Rong Tai biochemical engineering company limited;
Electric-heated thermostatic water bath: Tianjin Stettlen Instrument Ltd..
The preparation of 4 nutritive mediums
Krebs-Henseleit (K-H) physiological solution: NaCl6.92 (concentration unit), KCl0.35, MgSO 40.29, KH 2pO 40.16, CaCl 20.28, NaHCO 32.1, Glucose2.0 (g/L), pH7.2.
High potassium solution: will add KCl to be mixed with containing K after the NaCl of the mole numbers such as removal in K-H liquid +the improvement K-H liquid of 60mmol/L.
Without calcium K-H liquid: by the CaCl in K-H liquid 2remove, the KCl of mole number such as add, and add EDTA -2na +0.1mmol/L, other components unchanged.
Without the high potassium liquid of calcium: by the CaCl in high potassium liquid 2remove, the KCl of mole number such as add, and add EDTA -2na +0.1mmol/L, other components unchanged.
The preparation of compound (II-3) solution: take the sample of certain mass compound (II-3), taking distilled water as solvent cut to series concentration (10 -10-10 -3mol/L), for subsequent use.
The preparation of 5 rabbit myocardium vessel unstriated muscle samples
Rabbit, animal is hit after dizzy and cuts rapidly thoracic cavity open, separate descending aorta, (if carry out Serotonin receptor antagonistic experiment, also should use smooth stainless steel rod iron remove endotheliocyte) by reticular tissue and after fatty tissue is removed around, be cut into 3-5mm vascular circle, then steel wire hook is through vascular circle, and one end is fixed on ventilation hook, and the other end is connected on tonotransducer, be placed in the bath pipe that fills 20ml nutritive medium, record tension variation by registering instrument.Bathe 37 ± 0.5 DEG C of the interior maintenance of pipe temperature, and pass into mixed gas (95%O with the speed of a 1-2 per second bubble 2+ 5%CO 2).Sample initial load 1.5g, changes one time of nutrition liquid for every 20 minutes, and balance 2 hours starts experiment after baseline stability.
6 concrete test operation and test-results
6.1 compounds (II-1)-(II-25) cause contraction rabbit myocardium vessel hypotensive activity to causing convulsion agent adrenalin hydrochloride (AD)
After sample tension stability, record one section of waveform, add and cause convulsion agent adrenalin hydrochloride (AD) (10 to bathing in pipe -5mol/L) induction is shunk, and when reaching after maximum collapse, fully rinses sample, within every 20 minutes, changes one time K-H liquid, and balance 60 minutes, after baseline restorer is steady, is again used same concentration to cause convulsion agent induction and shunk.When after once shrink maximum reaction with front when once basically identical, accumulation adds (II-1)-(II-25) solution (1 × 10 preparing -8-1 × 10 -3mol/L), wave recording.Taking the diastole percentage ratio of (II-1)-(II-25) as ordinate zou, maximum stretching reaction is 100% to make effect curve.Wherein (II-3), (II-1) and diastole effect (II-6) are the most obvious, and the negative logarithm of its each concentration is that X-coordinate is drawn amount effect curve, sees respectively Fig. 1, Fig. 2 and Fig. 3.
By finding out in Fig. 1, compound (II-3) causes to AD sample that convulsion agent causes and shrinks and have diastole effect, it presents certain dose-dependently to adrenergic diastole effect, shrink-logEC of the Rabbit Aorta that compound (II-3) diastole AD causes 50value is 6.19 ± 0.03; Same, by finding out in Fig. 2, compound (II-1) also presents certain dose-dependently to adrenergic diastole effect, shrink-logEC of the Rabbit Aorta that its diastole AD causes 50value is 6.01 ± 0.02; By finding out in Fig. 3, shrink-logEC of the Rabbit Aorta that compound (II-6) diastole AD causes 50value is 8.07 ± 0.06.
Compound (II-1)-(II-25) as shown in table 1 to the diastole effect of AD contraction rabbit myocardium vessel unstriated muscle:
Table 1 compound (II-1)-(II-25) diastole effect to AD contraction rabbit myocardium vessel unstriated muscle
Compound -logEC 50 Compound -logEC 50
II-1 6.01±0.02 II-14 4.45±0.04
II-2 5.52±0.03 II-15 4.15±0.03
II-3 6.19±0.03 II-16 4.26±0.06
II-4 5.41±0.03 II-17 3.88±0.04
II-5 4.39±0.04 II-18 3.83±0.05
II-6 8.07±0.06 II-19 4.05±0.03
II-7 4.89±0.05 II-20 4.52±0.03
II-8 5.31±0.04 II-21 5.21±0.04
II-9 5.56±0.03 II-22 4.01±0.04
II-10 5.72±0.05 II-23 4.26±0.03
II-11 5.47±0.04 II-24 4.88±0.04
II-12 4.51±0.05 II-25 4.28±0.05
II-13 4.39±0.04 ? ?
6.2 compounds (II-1)-(II-25) cause the diastole effect of shrinking rabbit myocardium vessel unstriated muscle to causing convulsion agent High potassium solution
After sample tension stability, record one section of waveform, add and cause convulsion agent adrenalin hydrochloride (AD) (10 to bathing in pipe -5mol/L) induction is shunk, and when reaching after maximum collapse, fully rinses sample, within every 20 minutes, changes one time K-H liquid, and balance 60 minutes, after baseline restorer is steady, is shunk with causing the high potassium liquid induction of convulsion agent.When after once shrink maximum reaction with front when once basically identical, accumulation adds (II-1)-(II-25) solution (1 × 10 preparing -8-1 × 10 -3mol/L), wave recording.Taking the diastole percentage ratio of (II-1)-(II-25) as ordinate zou, maximum stretching reaction is 100% to make effect curve.Wherein the diastole effect of (II-3) is more obvious, and the negative logarithm of its each concentration is that X-coordinate is drawn amount effect curve, sees Fig. 4; Wherein (II-1) also has obvious diastole effect, and its amount effect curve is shown in Fig. 5.
As can be seen from Figure 4, compound (II-3) causes to high potassium liquid sample that convulsion agent causes and shrinks and have diastole effect, it presents certain dose-dependently to the diastole effect of high potassium liquid, shrink-logEC of the Rabbit Aorta that the high potassium liquid of compound (II-3) diastole causes 50value is 5.55 ± 0.03; Same, visible in Fig. 5, compound (II-1) also presents certain dose-dependently to the diastole effect of high potassium liquid, shrink-logEC of the Rabbit Aorta that the high potassium liquid of its diastole causes 50value is 5.64 ± 0.01; Visible in Fig. 6, shrink-logEC of the Rabbit Aorta that the high potassium liquid of compound (II-6) diastole causes 50value is 4.77 ± 0.06.
Compound (II-1)-(II-25) cause that to causing convulsion agent High potassium solution the diastole effect of contraction rabbit myocardium vessel unstriated muscle is as shown in table 2:
Table 2 compound (II-1)-(II-25) diastole effect to High potassium solution contraction rabbit myocardium vessel unstriated muscle
Compound -logEC 50 Compound -logEC 50
II-1 5.64±0.01 II-14 3.85±0.04
II-2 5.13±0.03 II-15 3.73±0.03
II-3 5.55±0.03 II-16 3.92±0.02
II-4 4.61±0.03 II-17 3.54±0.03
II-5 3.94±0.04 II-18 3.43±0.04
II-6 4.77±0.06 II-19 3.85±0.03
II-7 4.49±0.05 II-20 4.46±0.03
II-8 5.31±0.04 II-21 4.91±0.04
II-9 5.43±0.03 II-22 4.31±0.03
II-10 5.33±0.04 II-23 4.11±0.02
II-11 5.22±0.04 II-24 4.58±0.04
II-12 4.61±0.05 II-25 3.88±0.02
II-13 3.93±0.04 ? ?
Embodiment 27
The diastole study on mechanism of compound (II-3) to rabbit myocardium vessel unstriated 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-3) adopts embodiment 3 method self-controls;
Sodium-chlor (NaCl): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120413;
Repone K (KCl): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20111123;
Anhydrous magnesium sulfate (MgSO 4): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20101029;
Calcium Chloride Powder Anhydrous (CaCl 2): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20110314;
Sodium bicarbonate (NaHCO 3): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120507;
Glucose (Glucose): be purchased from Tianjin great Mao chemical reagent factory, lot number: 20120512;
Potassium primary phosphate (KH 2pO 4): be purchased from Tianjin great Mao chemical reagent factory product, lot number: 20110928;
Sodium chloride injection (NaC1): be purchased from Zhiying Pharmaceutical Factory, Shenyang, lot number: 12021001;
Adrenalin hydrochloride injection liquid (Epinephrine Hydrochloride Injection) specification: 1mg/1ml, 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;
Doxazosin mesylate (Doxazosin Mesylate): be purchased from Suizhou Jia Ke medication chemistry company limited, lot number: 20110305;
Amlodipine besylate tablets (Amlodipine Besylate Tablets): be purchased from pfizer inc, specification: 5mg/ sheet lot number: 1205018; Adrenalin hydrochloride injection liquid (Epinephrine Hydrochloride Injection) specification: 1mg/1ml, is purchased from Grandpharma (China) Co., Ltd., lot number 120105;
(R)-phenylephrine hydrochloride ((R)-Phenylephrine Hydrochloride), ladder is uncommon likes that (Shanghai) changes into industrial development company limited, 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 unit, lot number: 101115;
Ethylurethanm (Urethane): China Medicine (Group) Shanghai Chemical Reagent Co.,, lot number: C30191228;
Ethylenediamine tetraacetic acid (EDTA) (EDTA), Tianjin great Mao chemical reagent factory product, lot number: 20050809.
3 laboratory apparatuss
HSS-1 (B) type thermostatic bath: Chengdu Instruement Factory;
RM6240B type multi-path physiology signal acquiring processing system: Chengdu Instruement Factory;
JZJ01 type muscle tone transverter: Chengdu Instruement Factory;
YPJ01 type pressure transducer: Chengdu Instruement Factory;
TG-328A photoelectric analytical balance: Shanghai balance equipment factory;
T-500 type electronic balance: Changshu Shuan Jie testing tool factory;
Micropipet: Shanghai Rong Tai biochemical engineering company limited;
Electric-heated thermostatic water bath: Tianjin Stettlen Instrument Ltd..
The preparation of 4 nutritive mediums
Krebs-Henseleit (K-H) physiological solution: NaCl6.92 (concentration unit), KCl0.35, MgSO 40.29, KH 2pO 40.16, CaCl 20.28, NaHCO 32.1, Glucose2.0 (g/L), pH7.2.
High potassium solution: will add KCl to be mixed with containing K after the NaCl of the mole numbers such as removal in K-H liquid +the improvement K-H liquid of 60mmol/L.
Without calcium K-H liquid: by the CaCl in K-H liquid 2remove, the KCl of mole number such as add, and add EDTA -2na +0.1mmol/L, other components unchanged.
Without the high potassium liquid of calcium: by the CaCl in high potassium liquid 2remove, the KCl of mole number such as add, and add EDTA -2na +0.1mmol/L, other components unchanged.
The preparation of compound (II-3) solution: take the sample of certain mass compound (II-3), taking distilled water as solvent cut to series concentration (10 -10-10 -4mol/L), for subsequent use.
The preparation of 5 rabbit myocardium vessel unstriated muscle samples
Rabbit, animal is hit after dizzy and cuts rapidly thoracic cavity open, separate descending aorta, (if carry out Serotonin receptor antagonistic experiment, also should use smooth stainless steel rod iron remove endotheliocyte) by reticular tissue and after fatty tissue is removed around, be cut into 3-5mm vascular circle, then steel wire hook is through vascular circle, and one end is fixed on ventilation hook, and the other end is connected on tonotransducer, be placed in the bath pipe that fills 20ml nutritive medium, record tension variation by registering instrument.Bathe 37 ± 0.5 DEG C of the interior maintenance of pipe temperature, and pass into mixed gas (95%O with the speed of a 1-2 per second bubble 2+ 5%CO 2).Sample initial load 1.5g, changes one time of nutrition liquid for every 20 minutes, and balance 2 hours starts experiment after baseline stability.
6 experimental implementation and test-results
The antagonistic action of 6.1 compounds (II-3) to rabbit vascular smooth muscle α receptor stimulant
6.1.1 compound (II-3) impact that amount effect curve is shunk in accumulation on norepinephrine
After sample tension stability, record one section of waveform, add norepinephrine (NA) (3 × 10 to bathing accumulation in pipe -7-6 × 10 -5mol/L) until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, after balance 1h, add compound (II-3) (3 × 10 -6mol/L), after 20 minutes, add NA (3 × 10 with same method again -7-3 × 10 -4mol/L).Taking maximum reaction as 100%, NA percentage of contraction is for ordinate zou, the negative logarithm of the each concentration of NA is that X-coordinate is drawn amount effect curve, adds compound (II-3) (3 × 10 -6mol/L) after, as Fig. 7, NA amount effect curve is parallel moving to right obviously, and maximum reaction is almost constant, and each concentration-response percentage ratio is carried out after statistics t inspection, and most P value < 0.01, exist significant difference.Compound (II-3) antagonism NA shrinks the pA of Rabbit Aorta 2value is 6.02 ± 0.13.
6.1.2 the positive control drug Doxazosin impact that amount effect curve is shunk in accumulation on norepinephrine
On the basis of upper step, repeatedly rinse sample with K-H liquid, after balance 1h, add Doxazosin (10 -7mol/L), after 15 minutes, add NA with same method again.Taking maximum reaction as 100%, NA percentage of contraction is for ordinate zou, NA (3 × 10 -7-3 × 10 -4mol/L) the negative logarithm of each concentration is that X-coordinate is drawn amount effect curve, adds medicine Doxazosin (10 -7mol/L) after, as Fig. 7, NA amount effect curve is parallel moving to right obviously, and maximum reaction is almost constant, and each concentration-response percentage ratio is carried out after statistics t inspection, and most P value < 0.01, exist significant difference.Medicine Doxazosin antagonism NA shrinks the pA of Rabbit Aorta 2value is 7.16 ± 0.24.
Learn by statistics t inspection, compound (II-3) and the pA of positive control drug Doxazosin to NA 2between value, relatively,, there is the difference of highly significant between the two in P < 0.01, illustrate compound (II-3) to the antagonistic action of α receptor stimulant than Doxazosin a little less than.
6.2 compounds (II-3) are to rabbit vascular smooth muscle calcium channel (Ca 2+) antagonistic action
6.2.1 compound (II-3) is to CaCl 2the impact of rabbit blood vessel concentration-response curve is shunk in accumulation
After sample tension stability, use without calcium K-H liquid sample is rinsed 3 times, and use without calcium K-H liquid and hatch 40 minutes, add without the high potassium liquid of calcium and make sample depolarize 20 minutes, then add CaCl to bathing accumulation in pipe 2(10 -5-3 × 10 -2mol/L), until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, within every 20 minutes, change one time K-H liquid, balance 60 minutes, after baseline restorer is steady, again use without calcium K-H liquid sample is rinsed 3 times, and use without calcium K-H liquid and hatch 40 minutes, add without the high potassium liquid of calcium and make sample depolarize 20 minutes, add compound (II-3) (10 to bathing in pipe simultaneously -5mol/L), hatch after 20 minutes and add CaCl with same method accumulation again 2(10 -5-3 × 10 -1mol/L), until reach maximum reaction, wave recording.Taking maximum reaction as 100%, CaCl 2percentage of contraction when each concentration is ordinate zou, CaCl 2the negative logarithm of each concentration is that X-coordinate is drawn amount effect curve, adds compound (II-3) (10 -5mol/L) after, as Fig. 8, CaCl 2amount effect curve is parallel moving to right obviously, and maximum reaction is almost constant, and each concentration-response percentage ratio is carried out after statistical test, and most P value < 0.01, exist significant difference.Compound (II-3) antagonism CaCl 2shrink the pA of Rabbit Aorta 2value is 6.56 ± 0.032.
6.2.2 positive control drug amlodipine is to CaCl 2the impact of amount effect curve is shunk in accumulation
On basis based on upper step, then repeatedly rinse sample with K-H liquid, within every 20 minutes, change one time K-H liquid, balance 60 minutes, until baseline restorer steadily after, again use without calcium K-H liquid sample rinsed 3 times, and use without calcium K-H liquid and hatch 40 minutes, add without the high potassium liquid of calcium and make sample depolarize 20 minutes, add amlodipine (10 to bathing in pipe simultaneously -7mol/L), hatch after 15 minutes and add CaCl with same method accumulation again 2(10 -5-3 × 10 -2mol/L), until reach maximum reaction, wave recording.Taking maximum reaction as 100%, CaCl 2percentage of contraction when each concentration is ordinate zou, CaCl 2the negative logarithm of each concentration is that X-coordinate is drawn amount effect curve, adds amlodipine (10 -7mol/L) after, as Fig. 8, CaCl 2amount effect curve is parallel moving to right obviously, and maximum reaction is almost constant, and each concentration-response percentage ratio is carried out after statistical test, and most P value < 0.01, exist significant difference.Amlodipine antagonism CaCl 2shrink the pA of Rabbit Aorta 2value is 7.15 ± 0.288.
The antagonistic action of 6.3 compounds (II-3) to rabbit vascular smooth muscle serotonin (5-HT) receptor stimulant
After sample tension stability, record one section of waveform, add 5-HT (10 to bathing accumulation in pipe -8-3 × 10 -4mol/L) until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, after balance 1.5h, add compound (II-3) (3 × 10 -6mol/L), after 20 minutes, add 5-HT with same method again.Taking maximum reaction as 100%, 5-HT percentage of contraction is for ordinate zou, the negative logarithm of the each concentration of 5-HT is that X-coordinate is drawn amount effect curve, adds compound (II-3) (3 × 10 -6mol/L) after, as Fig. 9,5-HT amount effect curve is parallel moving to right obviously, and maximum reaction is almost constant, and each concentration-response percentage ratio is carried out after statistical test, and P value < 0.01, exists significant difference.Compound (II-3) antagonism 5-HT shrinks the pA of Rabbit Aorta 2value 6.726 ± 0.089.
Embodiment 28
The diastole study on mechanism of compound (II-6) to rabbit myocardium vessel unstriated muscle
The preparation of the present embodiment experimental animal used, medicine and reagent, laboratory apparatus, nutritive medium, and the preparation method of rabbit myocardium vessel unstriated muscle sample is identical with embodiment 27, concrete test operation and test-results are as follows.
The antagonistic action of 1 compound (II-6) to rabbit vascular smooth muscle α receptor stimulant
1.1 compounds (II-6) impact that amount effect curve is shunk in accumulation on phyenlephrinium
After sample tension stability, record one section of waveform, add phyenlephrinium (10 to bathing accumulation in pipe -6-6 × 10 -3mol/L) until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, after balance 1h, add compound (II-6) (3 × 10 -8mol/L), after 20 minutes, add phyenlephrinium with same method again.Taking maximum reaction as 100%, phyenlephrinium percentage of contraction is ordinate zou, and the negative logarithm of the each concentration of phyenlephrinium is that X-coordinate is drawn amount effect curve, adds compound (II-6) (3 × 10 -8mol/L) after, as Figure 10, phyenlephrinium amount effect curve is parallel moving to right obviously, and maximum reaction is almost constant, and each concentration-response percentage ratio is carried out after statistics t inspection, and most P value < 0.01, exist significant difference.Compound (II-6) antagonism phyenlephrinium shrinks the PA of Rabbit Aorta 2value is 8.45 ± 0.03;
2 compounds (II-6) are to rabbit vascular smooth muscle calcium channel (Ca 2+) antagonistic action
2.1 compounds (II-6) are to CaCl 2the impact of rabbit blood vessel concentration-response curve is shunk in accumulation
After sample tension stability, use without calcium K-H liquid sample is rinsed 3 times, and use without calcium K-H liquid and hatch 40 minutes, add without the high potassium liquid of calcium and make sample depolarize 20 minutes, then add CaCl to bathing accumulation in pipe 2(10 -5-10 -2mol/L), until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, within every 20 minutes, change one time K-H liquid, balance 60 minutes, after baseline restorer is steady, again use without calcium K-H liquid sample is rinsed 3 times, and use without calcium K-H liquid and hatch 40 minutes, add without the high potassium liquid of calcium and make sample depolarize 20 minutes, add compound (II-6) (10 to bathing in pipe simultaneously -5mol/L), hatch after 20 minutes and add CaCl with same method accumulation again 2(10 -5-10 -2mol/L), until reach maximum reaction, wave recording.Taking maximum reaction as 100%, CaCl 2percentage of contraction when each concentration is ordinate zou, CaCl 2the negative logarithm of each concentration is that X-coordinate is drawn amount effect curve, adds compound (II-6) (10 -5mol/L) after, as Figure 11, CaCl 2amount effect curve is parallel moving to right obviously, and maximum reaction is almost constant, and each concentration-response percentage ratio is carried out after statistical test, and most P value < 0.01, exist significant difference.Compound (II-6) antagonism CaCl 2shrink the PA of Rabbit Aorta 2value is 5.36 ± 0.26.
The antagonistic action of 3 compounds (II-6) to rabbit vascular smooth muscle serotonin (5-HT) receptor stimulant
After sample tension stability, record one section of waveform, add 5-HT (10 to bathing accumulation in pipe -8-3 × 10 -4mol/L) until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, after balance 1.5h, add compound (II-6) (10 -7mol/L), after 20 minutes, add 5-HT with same method again.Taking maximum reaction as 100%, 5-HT percentage of contraction is for ordinate zou, the negative logarithm of the each concentration of 5-HT is that X-coordinate is drawn amount effect curve, adds compound (II-6) (10 -7mol/L) after, as Figure 12,5-HT amount effect curve is parallel moving to right obviously, and maximum reaction is almost constant, and each concentration-response percentage ratio is carried out after statistical test, and P value < 0.01, exists significant difference.Compound (II-6) antagonism 5-HT shrinks the PA of Rabbit Aorta 2value 8.86 ± 0.14.
Comprehensive above-mentioned test-results: in vitro animal experiment, compound (II-1), (II-3), (II-6) all have significant to relax the VSM effect.Wherein, compound (II-3) has stronger antagonistic action to α acceptor, the PA of its antagonism NA 2value is 6.02 ± 0.13, the PA of Doxazosin antagonism NA 2value is 7.16 ± 0.24, compound (II-3) antagonism CaCl 2pA 2value is 6.56 ± 0.032, amlodipine antagonism CaCl 2pA 2value is 7.15 ± 0.288, and compound (II-3) is to 5-HT 2Aacceptor has stronger antagonistic action, the PA of its antagonism 5-HT 2value is 6.726 ± 0.089; The PA of compound (II-6) antagonism phyenlephrinium 2value is 8.45 ± 0.03, antagonism CaCl 2pA 2value is 5.36 ± 0.26, the PA of antagonism 5-HT 2value 8.86 ± 0.14.Test-results illustrates compound (II-3) and (II-6) belongs to the vasodilator activity molecule of novel many target spots mechanism, can be used for preparing vasodilator drug, is especially applied to Novel blood pressure-reducing class medicine.

Claims (10)

1. benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of formula (I),
Figure FDA0000379885240000011
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
R is by R 5when monosubstituted, R 5represent H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R is by R 5when polysubstituted, R 5represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R 1, R 2, R 3, R 4represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
Q represents CH 2or oxygen;
Y represents the straight or branched alkyl of the saturated or undersaturated 1-8 of the containing carbon atom optionally being replaced by one or more halogen atoms, and the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes;
Condition is
Described heteroaryl is not pyrimidyl, benzopyrazoles base, Thienopyrimidine Ji, oxazole pyrimidyl or purine radicals;
When R is when being represented methylene radical or ethylidene by the mono-substituted aryl of Cl and Y, R 1-R 4be not H entirely;
When R is by CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
In the time that Y represents methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
2. benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of the formula of claim 1 (I),
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
Described cyclic hydrocarbon radical is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group;
Described aryl or heteroaryl are phenyl, naphthyl, furyl, pyridyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzofuryl, benzo pyrimidyl, benzo pyridyl Huo quinoxalinyl;
R is by R 5when monosubstituted, R 5represent H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
R is by R 5when polysubstituted, R 5represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
R 1, R 2, R 3, R 4represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
Q represents CH 2or oxygen;
Y represents the straight or branched alkyl of the saturated or undersaturated 1-8 of the containing carbon atom optionally being replaced by one or more halogen atoms, and the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes;
Condition is
When R is when being represented methylene radical or ethylidene by the mono-substituted aryl of Cl and Y, R 1-R 4be not H entirely;
When R is by CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
In the time that Y represents methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
3. benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of the formula of claim 1 (I),
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
Described cyclic hydrocarbon radical is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
Described aryl or heteroaryl are phenyl, naphthyl, furyl, pyridyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzofuryl Huo quinoxalinyl;
R is by R 5when monosubstituted, R 5represent H, halogen, CN, C 1-C 4alkyl, C 2-C 4alkoxyl group, CHO, CO (C 1-C 4alkyl), COOH, COO (C 1-C 4alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
R is by R 5when polysubstituted, R 5represent independently of one another H, halogen, CN, C 1-C 4alkyl, C 2-C 4alkoxyl group, CHO, CO (C 1-C 4alkyl), COOH, COO (C 1-C 4alkyl), in above-mentioned group, moieties is optionally replaced by 1-3 halogen atom;
R 1, R 2, R 3, R 4represent independently of one another H, F, Cl, Br, I, CN, CH 3, OCH 3, COCH 3or COOCH 3;
Q represents CH 2or oxygen;
Y represents ethylidene, propylidene, butylidene, pentylidene or hexylidene, and wherein said group is optionally replaced by one or more halogen atoms;
Condition is
When R is by Cl or CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
4. benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of the formula of claim 1 (I),
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
Described cyclic hydrocarbon radical is cyclohexyl;
Described aryl or heteroaryl are phenyl, naphthyl, furyl, pyridyl, benzisothiazole base, benzoisoxazole base, benzofuryl Huo quinoxalinyl;
R is by R 5when monosubstituted, R 5represent H, F, Cl, CN, CH 3or CF 3;
R is by R 5when polysubstituted, R 5represent independently of one another H, F, Cl, CN, CH 3or CF 3;
R 1, R 4represent independently of one another H;
R 2, R 3represent independently of one another H, F, Cl, CN, CH 3or COOCH 3;
Q represents CH 2or oxygen;
Y represents ethylidene, propylidene or butylidene;
Condition is
When R is by Cl or CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely.
5. benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of the formula of claim 1 (I),
Wherein
R represents optionally by R 5monosubstituted or polysubstituted aryl or heteroaryl;
Described aryl or heteroaryl are phenyl, benzisothiazole base, benzoisoxazole base or benzofuryl;
R is by R 5when monosubstituted, R 5represent H, F, Cl, CN, CH 3or CF 3;
R is by R 5when polysubstituted, R 5represent independently of one another H, F, Cl, CN, CH 3or CF 3;
R 1, R 4represent independently of one another H;
R 2, R 3represent independently of one another H, F or Cl;
Q represents CH 2or oxygen;
Y represents ethylidene or propylidene;
Condition is
When R is by Cl or CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely.
6. benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of the formula of claim 1 (I),
Wherein
R represents optionally by R 5monosubstituted or polysubstituted aryl or heteroaryl;
Described aryl or heteroaryl are phenyl, benzoisoxazole base or benzisothiazole base;
R is by R 5when monosubstituted, R 5represent H, F, Cl or CF 3;
R is by R 5when polysubstituted, R 5represent independently of one another H, F, Cl or CF 3;
R 1, R 2, R 3, R 4represent independently of one another H;
Y represents ethylidene or propylidene,
Condition is
When R is by Cl or CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely.
7. benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of the formula of claim 1 (I),
Wherein
R represents optionally by R 5monosubstituted or polysubstituted phenyl or benzisothiazole base;
R is by R 5when monosubstituted, R 5represent H, Cl or CF 3;
R is by R 5when polysubstituted, R 5represent independently of one another H, Cl or CF 3;
R 1, R 2, R 3, R 4represent independently of one another H;
Y represents propylidene;
Comprise 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole, 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole or 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole and pharmacy acceptable salt thereof.
8. benzotriazole base piperazine compounds and the pharmacy acceptable salt thereof of the formula of claim 1 (I), described pharmacy acceptable salt is hydrochloride, hydrogen bromide salt, vitriol, mesylate, trifluoroacetate, tartrate, malate, succinate, maleate, Citrate trianion, phosphoric acid salt, lactic acid salt, pyruvate salt, acetate, fumarate, oxaloacetate, esilate, oxalate, benzene sulfonate or isethionate; Pharmacy acceptable salt of the present invention, preferably containing crystal water, more preferably contains the crystal water of 0.5-3 molecule; Described pharmacy acceptable salt is more preferably hydrochloride, hydrogen bromide salt, vitriol or mesylate; Described pharmacy acceptable salt optimum is preferably hydrochloride.
9. the benzotriazole base piperazine compounds of the formula (I) of preparation claim 1-8 and the preparation method of pharmacy acceptable salt thereof:
(scheme one)
Be included at the temperature of 10-150 DEG C, make benzotriazole (A)
Figure FDA0000379885240000061
With chloro alkyl bromide (B)
Figure FDA0000379885240000062
Under the existence of mineral alkali and phase-transfer catalyst, in solvent, reaction generates N-chloro alkyl benzotriazole derivatives (C)
Figure FDA0000379885240000063
Then under refluxing, make N-chloro alkyl benzotriazole derivatives (C)
Figure FDA0000379885240000064
With N-substituted-piperazinyl (D)
Under the existence of organic bases in solvent reacting generating compound (I-a)
Figure FDA0000379885240000071
Or
Scheme (two)
Be included at the temperature of 10-150 DEG C the benzotriazole (E) that N-hydroxyl is replaced
Figure FDA0000379885240000072
With chloro alkyl bromide (F)
Cl-Y-Br(F)
Under the existence of mineral alkali, in solvent, reaction generates N-chlorinated alkoxy benzotriazole derivatives (G)
Figure FDA0000379885240000073
Then under refluxing, make N-chlorinated alkoxy benzotriazole derivatives (G)
Figure FDA0000379885240000074
With N-substituted-piperazinyl (D)
Figure FDA0000379885240000075
Under the existence of organic bases, in solvent, react, generate compound (I-b)
Wherein
R represents optionally by R 5monosubstituted or polysubstituted cyclic hydrocarbon radical, aryl or heteroaryl;
R is by R 5when monosubstituted, R 5represent H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R is by R 5when polysubstituted, R 5represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 2-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
R 1, R 2, R 3, R 4represent independently of one another H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COOH, COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), N (C 1-C 6alkyl) 2, SH, S (C 1-C 6alkyl), S (O) (C 1-C 6alkyl), S (O) 2h or S (O) 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
Y represents the straight or branched alkyl of the saturated or undersaturated 1-8 of the containing carbon atom optionally being replaced by one or more halogen atoms, and the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes;
Condition is
Described heteroaryl is not pyrimidyl, benzopyrazoles base, Thienopyrimidine Ji, oxazole pyrimidyl or purine radicals;
When R is when being represented methylene radical or ethylidene by the mono-substituted aryl of Cl and Y, R 1-R 4be not H entirely;
When R is by CF 3when mono-substituted aryl and Y represent methylene radical, R 1-R 4be not H entirely;
In the time that Y represents methylene radical, R 1-R 4be not H entirely;
Work as R 2and R 3be OCH 3time, R 5be not H.
10. comprise the benzotriazole base piperazine compounds of formula (I) of claim 1-8 and/or the pharmaceutical composition of its pharmacy acceptable salt.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114075186A (en) * 2020-08-18 2022-02-22 沈阳海王生物技术有限公司 Crystal of compound X7 hydrochloride, preparation method and application thereof

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
ALESSANDRO BOIDO,ET AL.: "Synthesis and pharmacological evaluation of aryl/heteroaryl piperazinyl alkyl benzotriazoles as ligands for some serotonin and dopamine receptor subtypes", 《IL FARMACO》 *
ALESSANDRO BOIDO,ET AL.: "α1-and α2-Adrenoreceptor Antagonist Profiles of 1-and 2-[ω-(4-Arylpiperazin-1-yl)alkyl]-1,2,3-benzotriazoles", 《CHEMISTRY & BIODIVERSITY》 *
ANDREAS EVERS,ET AL.: "Virtual Screening of Biogenic Amine-Binding G-protein Coupled Receptors:Comparative Evaluation of Protein-and Ligand-Based Virtual Screening Protocols", 《JOURNAL OF MEDICINAL CHEMISTY》 *
ANNA SPARATORE,ET AL.: "2-{4-[3-(4-Aryl/heteroaryl-1-piperazinyl)propoxy]phenyl}-2H-benzotriazoles and their N-oxides as ligands for serotonin and dopamine receptors", 《IL FARMACO》 *
G CALIENDO, ET AL.: "Synthesis and biological activity of benzotriazole derivatives structurally related to trazodone", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
G CALIENDO, ET AL.: "Synthesis and trazodone-like pharmacological profile of 1-and 2-[3-[4-(X)-1-piperazinyl]-propyl]-benzotriazoles", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
JERZY L,ET AL.: "Structure-Activity Relationship Studies of Central Nervous System Agents.13.4-[3-(Benzotriazol-1-yl)propyl]-1-(2-methoxyphenyl)piperazine, a New Putative 5-HT1A Receptor Antagonist, and Its Analogs", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
MARIA H. PALUCHOWSKA,ET AL.: "Conformational Restriction in Novel NAN-190 and MP3022 Analogs and Their 5-HT1A Receptor Activity", 《ARCHIV DER PHARMZIE-CHEMISTRY IN LIFE SCIENCE》 *
MARIA H.PALUCHOWSKA,ET AL: "On the Bioactive Conformation of NAN-190(1) and MP3022(2),5-HT1A Receptor Antagonists", 《JOUNAL OF MEDICINAL CHEMISTRY》 *
THOMAS KLABUNDE,ET AL.: "GPCR Antitarget Modeling:Pharmacophore Models for Biogenic Amine Binding GPCRs to Avoid GPCR-Mediated Side Effects", 《CHEMBIOCHEM》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114075186A (en) * 2020-08-18 2022-02-22 沈阳海王生物技术有限公司 Crystal of compound X7 hydrochloride, preparation method and application thereof
WO2022037580A1 (en) * 2020-08-18 2022-02-24 沈阳海王生物技术有限公司 Crystal of compound x7 hydrochloride, preparation method therefor and use thereof

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