CN103833642A - Application of benzo five-membered nitrogen-containing heterocycle-based piperazine derivative - Google Patents

Application of benzo five-membered nitrogen-containing heterocycle-based piperazine derivative Download PDF

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CN103833642A
CN103833642A CN201210486967.6A CN201210486967A CN103833642A CN 103833642 A CN103833642 A CN 103833642A CN 201210486967 A CN201210486967 A CN 201210486967A CN 103833642 A CN103833642 A CN 103833642A
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piperazine
butyl
benzotriazole
benzoglyoxaline
phenyl
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周延
张丽荣
周杰
周欣
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LIAONING BEILEI BIOLOGICAL PHARMACEUTICAL Co Ltd
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LIAONING BEILEI BIOLOGICAL PHARMACEUTICAL Co Ltd
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Priority to CN201610828410.4A priority Critical patent/CN106420754B/en
Priority to CN201210486967.6A priority patent/CN103833642A/en
Priority to PCT/CN2013/001442 priority patent/WO2014079155A1/en
Priority to JP2015543245A priority patent/JP6350535B2/en
Priority to EP13857563.4A priority patent/EP2924033B1/en
Priority to US14/647,408 priority patent/US9415047B2/en
Publication of CN103833642A publication Critical patent/CN103833642A/en
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    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • 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
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    • 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 an application of a benzo five-membered nitrogen-containing heterocycle-based piperazine derivative shown as a formula (I) in the specification in preparation of a vasodilatation medicine, wherein R1, R2, Y, A and B are defined as the specification.

Description

The purposes of benzo five-membered Azacyclyl bridged piperazine derivatives
Technical field
The present invention relates to benzo five-membered Azacyclyl bridged piperazine derivatives in the purposes of preparing in vasodilator drug.
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, reduce resistance or make its toxic side effect less, to meet different patients' needs clinically as far as possible.
Summary of the invention
The invention provides formula (I) compound and pharmacy acceptable salt thereof in the purposes of preparing in vasodilator drug:
Figure BDA00002469067800011
Wherein:
R 1representative is by R 3monosubstituted or polysubstituted aromatic group or aliphatics cyclic group, wherein
R 3for H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Work as R 3during for polysubstituted group, R 3independently selected from H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
A, B independently represent respectively CH or N;
R 2represent H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Work as R 2during for polysubstituted group, R 2independently selected from H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
Saturated or the undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom that Y representative is optionally replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes.
Accompanying drawing explanation:
Fig. 1 is Compound I I-2 (10 -8-10 -4molL -1) to suprarenin (10 -5molL -1) shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect.
Fig. 2 is Compound I I-2 (10 -8-10 -4molL -1) to high potassium liquid (60mmolL -1) shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect.
Fig. 3 is Compound I I-2 (3 × 10 -7mol/L) antagonism norepinephrine NA (10 -8-10 -4mol/L) the cumulative concentration effect curve of contraction rabbit myocardium vessel.
The positive contrast Doxazosin (10 of Fig. 4 -7mol/L) antagonism norepinephrine NA (10 -8-6 × 10 -5mol/L) the cumulative concentration effect curve of contraction rabbit myocardium vessel.
Fig. 5 is Compound I I-2 (10 -6mol/L) antagonism CaCl 2(10 -6-10 -2mol/L) the cumulative concentration effect curve of contraction rabbit myocardium vessel.
Fig. 6 is amlodipine (10 -7mol/L) antagonism CaCl 2(10 -6-10 -2mol/L) the cumulative concentration effect curve of contraction rabbit myocardium vessel.
Fig. 7 is Compound I I-2 (3 × 10 -6mol/L) antagonism serotonin (10 -7-3 × 10 -4mol/L) the cumulative concentration effect curve of contraction rabbit myocardium vessel.
Fig. 8 is Compound I I-3 (10 -8-3 × 10 -5molL -1) to suprarenin (10 -5molL -1) shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect.
Fig. 9 is Compound I I-3 (10 -8-3 × 10 -5molL -1) to high potassium liquid (60mmolL -1) shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect.
Figure 10 is Compound I I-31 (10 -8-10 -5molL -1) to suprarenin AD (10 -5molL -1) shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect.
Figure 11 is Compound I I-31 (3 × 10 -7-3 × 10 -5molL -1) to high potassium liquid (60mmolL -1) shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect.
Figure 12 is Compound I I-31 (3 × 10 -6mol/L), positive control Doxazosin (10 -7mol/L) antagonism norepinephrine NA (3 × 10 -7-10 -4mol/L) the cumulative concentration effect curve of contraction rabbit myocardium vessel.
Figure 13 is Compound I I-31 (10 -5mol/L), amlodipine (10 -7mol/L) antagonism CaCl 2(10 -5-3 × 10 -1mol/L) the cumulative concentration effect curve of contraction rabbit myocardium vessel.
Figure 14 is Compound I I-31 (3 × 10 -6mol/L) antagonism serotonin (10 -8-3 × 10 -4mol/L) the cumulative concentration effect curve of contraction rabbit myocardium vessel.
Figure 15 is Compound I I-29 (10 -8-3 × 10 -5molL -1) to suprarenin AD (10 -5molL -1) shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect.
Figure 16 is Compound I I-29 (10 -7-3 × 10 -5molL -1) to high potassium liquid (60mmolL -1) shrink the cumulative concentration effect curve of rabbit myocardium vessel diastole effect.
Embodiment
The invention provides formula (I) compound and pharmacy acceptable salt thereof in the purposes of preparing in vasodilator drug:
Figure BDA00002469067800031
Wherein:
R 1representative is by R 3monosubstituted or polysubstituted aromatic group or aliphatics cyclic group, wherein
R 3for H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Work as R 3during for polysubstituted group, R 3independently selected from H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
A, B independently represent respectively CH or N;
R 2represent H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Work as R 2during for polysubstituted group, R 2independently selected from H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
Saturated or the undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom that Y representative is optionally replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes.
Preferably, the R in formula of the present invention (I) 2for example, for monosubstituted or polysubstituted group, R on described benzo five-membered nitrogen heterocyclic 2for monosubstituted, two replacements, three substituted radicals etc.; R 2the group connecting on any carbon atom for benzo five-membered nitrogen heterocyclic, for example, when A (or B) is C atomic time, R 2also can be coupled.
The implication of term used herein " aromatic group " is interpreted as the C that wherein at least one ring is aromatic nucleus 5-12monocyclic hydrocarbon ring or dicyclic hydrocarbon ring, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes.The example of aromatic group comprises aryl and heteroaryl, for example phenyl, naphthyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzopyrazoles base, benzofuryl, benzo pyrimidyl, benzo pyridyl, quinoxalinyl, furyl, pyridyl or pyrimidyl.
The implication of term used herein " aliphatics cyclic group " is interpreted as C 4-12monocycle saturated cyclic or dicyclo saturated cyclic, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes.The example of aliphatics cyclic group comprises cyclobutyl, cyclopentyl, cyclohexyl, suberyl, tetrahydrofuran base, piperidyl or piperazinyl etc.
Unless specifically noted in addition, term as used herein " halogen " refers to fluorine, chlorine, bromine or iodine.
Term used herein " alkyl " comprises straight or branched alkyl.Described " C 1-C 6alkyl " example of group comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl etc.
Refer to-O-of term used herein " 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.
In a specific embodiments, the invention provides formula (I) compound and pharmacy acceptable salt thereof in the purposes of preparing in vasodilator drug:
Figure BDA00002469067800051
Wherein:
R 1representative is by R 3monosubstituted or polysubstituted aromatic group or aliphatics cyclic group, wherein
Described aromatic group is preferably phenyl, naphthyl, heteroatoms and is selected from benzo five-membered heterocycle or the hexa-member heterocycle of N, S, O, or five yuan or hexa-atomic unsaturated heterocycle; More preferably phenyl, naphthyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzopyrazoles base, benzofuryl, benzo pyrimidyl, benzo pyridyl, quinoxalinyl, furyl, pyridyl or pyrimidyl; More preferably phenyl, benzoisoxazole base, benzisothiazole base, benzopyrazoles base, benzofuryl, naphthyl, furyl, pyridyl, pyrimidyl Huo quinoxalinyl again; Be particularly preferably phenyl, benzoisoxazole base, benzisothiazole base, benzofuryl, quinoxalinyl or pyrimidyl; Most preferably be phenyl;
Described aliphatics cyclic group is preferably five yuan or hexa-atomic saturated cyclic, or heteroatoms is selected from five yuan or the hexa-atomic saturated heterocyclyl of N, S, O; More preferably cyclopentyl, cyclohexyl, tetrahydrofuran base, piperidyl or piperazinyl; More preferably cyclohexyl, piperidyl or piperazinyl again; Be particularly preferably cyclohexyl;
R 3for H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Preferably, R 3for H, F, Cl, Br, CN, moieties are optionally by the C of 1-3 halogen atom replacement 1-C 6alkyl or C 1-C 6alkoxyl group, CHO, COCH 3or COOCH 3; More preferably, R 3for H, F, Cl, COCH 3, the C that optionally replaced by 1-3 halogen atom of moieties 1-C 4alkyl or C 1-C 4alkoxyl group; Again more preferably, R 3for H, F, Cl, CN, CF 3, CH 3or OCH 3; Most preferably be R 3for H, F, Cl or OCH 3; Work as R 3during for polysubstituted group, R 3independently selected from the above group;
A, B independently represent respectively CH or N; Preferably, A, B all represent N;
R 2represent H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Preferably, R 2for H, F, Cl, Br, CN, NO 2, the C that optionally replaced by 1-3 halogen atom of moieties 1-C 6alkyl or C 1-C 6alkoxyl group, CHO, COCH 3or COOCH 3; More preferably, R 2for H, F, Cl, CN, CHO, COCH 3, COOCH 3or the C that moieties is optionally replaced by 1-3 halogen atom 1-C 4alkyl or C 1-C 4alkoxyl group; Again more preferably, R 2for H, F, Cl, CN, CH 3or COOCH 3; Particularly preferably, R 2for H, F, Cl or CH 3; Most preferably, R 2for H; Work as R 2during for polysubstituted group, R 2independently selected from the above group;
Saturated or the undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom that Y representative is optionally replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes; Preferably, Y is the unsubstituted saturated hydrocarbyl containing 2-8 carbon, or wherein 1 carbon atom for example, by oxygen or the alternative unsubstituted saturated hydrocarbyl containing 2-8 carbon of sulphur ,-C 1-7alkylidene group-O-; More preferably Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, oxygen methylene, oxygen base ethylidene, oxygen base propylidene, oxygen base butylidene, oxygen base pentylidene, oxygen base hexylidene, the sub-heptyl of oxygen base, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Again more preferably, Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Particularly preferably, Y is propylidene, butylidene or propylidene oxygen base; Most preferably, Y is butylidene.
In another embodiment, the invention provides formula (I) compound and pharmacy acceptable salt thereof in the purposes of preparing in vasodilator drug:
Figure BDA00002469067800071
Wherein:
R 1representative is by R 3monosubstituted or disubstituted aromatic group or aliphatics cyclic group, wherein
Described aromatic group is preferably phenyl, benzoisoxazole base, benzofuryl, benzisothiazole base, benzopyranyl or pyrimidyl;
Described aliphatics cyclic group is preferably cyclohexyl;
R 3for H, F, Cl, CF 3, CN, CH 3or OCH 3; Work as R 3during for polysubstituted group, R 3independently selected from the above group;
A, B independently represent respectively CH or N; Preferably, A, B all represent N;
R 2represent H, F, Cl or CH 3; Work as R 2during for polysubstituted group, R 2independently selected from the above group;
Y represents propylidene, butylidene or propylidene oxygen base.
In another embodiment, the invention provides formula (I) compound and pharmacy acceptable salt thereof in the purposes of preparing in vasodilator drug:
Wherein:
R 1representative is by R 3monosubstituted or disubstituted aromatic group, wherein
Described aromatic group is preferably phenyl, benzoisoxazole base or benzisothiazole base;
R 3for H, F, Cl, CF 3, CN, CH 3or OCH 3; Work as R 3during for polysubstituted group, R 3independently selected from the above group;
A, B independently represent respectively CH or N; Preferably, A, B all represent N;
R 2represent H;
Y represents propylidene or butylidene.
In another specific embodiments, the invention provides formula (I) compound and pharmacy acceptable salt thereof in the purposes of preparing in vasodilator drug:
Figure BDA00002469067800082
Wherein:
R 1representative is by R 3monosubstituted or disubstituted aromatic group, wherein
Described aromatic group is preferably phenyl or benzisothiazole base;
R 3for H, Cl or CF 3; Work as R 3during for polysubstituted group, R 3independently selected from the above group;
A, B independently represent respectively CH or N; Preferably, A, B all represent N;
R 2represent H;
Y represents butylidene.
In another specific embodiments, the invention provides formula (I) compound and pharmacy acceptable salt thereof in the purposes of preparing in vasodilator drug:
Figure BDA00002469067800091
Wherein, in the time that A, B are N,
R 1be not by H or OCH 3mono-substituted phenyl, and
R 2be not H or OCH 3, wherein OCH 3two replacement on described benzo five-membered nitrogen heterocyclic; And
Y is not ethylidene, propylidene, butylidene or pentylidene.
In another specific embodiments, formula of the present invention (I) compound and pharmacy acceptable salt thereof
Figure BDA00002469067800092
Wherein,
R 1representative is by R 3monosubstituted or disubstituted phenyl or benzothiazolyl, wherein
R 3for H or Cl; Work as R 3during for polysubstituted group, R 3independently selected from the above group;
A, B independently represent respectively C;
R 2represent H or CN;
Y represents butylidene.
Described benzo five-membered Azacyclyl piperazine compounds comprises:
I-11-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-21-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-31-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-41-(4-(4-(2-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-52-methyl isophthalic acid-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The fluoro-1-of I-66-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-71-(3-(4-phenylpiperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-81-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-92-methyl isophthalic acid-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-101-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-111-(4-(4-(4-aminomethyl phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-121-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-131-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-141-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-151-(4-(4-(1-cyclohexyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-161-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-171-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-181-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-191-(4-(4-(3-(6-fluorobenzene isothiazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-201-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-211-(4-(4-(3-(6-fluorine benzofuryl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-221-(3-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
I-231-(4-(4-(3-trifluoromethyl) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
I-241-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
The chloro-1-of I-256-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-266-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-276-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The chloro-1-of I-282-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzoglyoxaline,
I-291-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-301-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-311-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
The fluoro-1-of I-326-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-335,6-dimethyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-343-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
I-353-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-366-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-376-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole,
I-381-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-391-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-401-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-411-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-421-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzotriazole,
I-431-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-441-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-451-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-461-(4-(4-cyclohexyl piperazine-1-yl) butyl)-1H-benzotriazole,
I-471-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-481-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-491-(4-(4-(3-(the fluoro-benzisothiazole base of 6-)) piperazine-1-yl) butyl)-1H-benzotriazole,
I-501-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzotriazole,
I-511-(3-(4-(3-(the fluoro-benzofuryl of 6-)) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-521-(4-(4-(3-(the fluoro-benzoisoxazole base of 6-)) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The fluoro-1-of I-536-(4-(4-(3-(the fluoro-benzisothiazole base of 6-)) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The chloro-1-of I-546-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-556-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-566-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-571-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-indoles,
I-586-cyano group-1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-indoles,
I-591-(3-(4-(3-trifluoromethyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles,
I-606-cyano group-1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles,
I-611-[4-(4-(4-fluorine) phenyl) piperazine] butyl-1H-indoles,
I-621-[4-cyclohexyl piperazine] butyl-1H-indoles,
I-631-[4-(4-(4-fluorine) phenyl) piperazine] butyl-5-ethanoyl-1H-indoles,
I-641-[4-cyclohexyl piperazine] butyl-5-ethanoyl-1H-indoles,
I-651-[3-(4-(2,4-difluoro) phenyl) piperazine] butyl-5-ethanoyl-1H-indoles,
I-661-[3-(4-(4-methyl) phenyl) piperazine] propyl group-1H-indoles,
I-671-[4-(4-(4-chlorine) phenyl) piperazine] butyl-1H-indoles,
I-681-[4-(4-(2-methyl) phenyl) piperazine] butyl-1H-indoles,
I-691-[4-(4-(3-trifluoromethyl) phenyl) piperazine] butyl-1H-indoles,
I-701-[3-(4-(4-methyl) phenyl) piperazine] propyl group-5-methoxyl group-1H-indoles,
I-711-[4-(4-(4-trifluoromethoxy) phenyl) piperazine] butyl-5-methoxyl group-1H-indoles,
I-721-[4-(4-(3-trifluoromethyl) phenyl) piperazine] butyl-5-methoxyl group-1H-indoles,
I-731-[3-(4-(2-methyl) phenyl) piperazine] butyl-5-methoxyl group-1H-indoles,
I-741-[3-(4-(2,4-difluoro) phenyl) piperazine] propyl group-5-nitro-1H-indoles,
I-751-[4-(4-(4-chlorine) phenyl) piperazine] butyl-5-nitro-1H-indoles,
I-761-[4-(4-(3-trifluoromethyl) phenyl) piperazine] butyl-5-nitro-1H-indoles,
I-771-[4-(4-(2-methoxyl group) phenyl) piperazine] butyl-5-nitro-1H-indoles,
I-781-[4-(4-(2-methoxyl group) phenyl) piperazine] the chloro-1H-indoles of butyl-5-,
I-791-[4-(4-(3-trifluoromethyl) phenyl) piperazine] the chloro-1H-indoles of butyl-5-,
I-801-[4-(4-(2,4-difluoro) phenyl) piperazine] the chloro-1H-indoles of butyl-5-,
I-811-[2-(4-(2,4-, bis-trifluoromethoxies) phenyl) piperazine] the chloro-1H-indoles of ethyl-5-,
I-821-[2-(4-(2,4-dimethoxy) phenyl) piperazine] ethyl-6-nitro-1H-indoles,
I-831-[2-(4-(2,4-dichloro) phenyl) piperazine] ethyl-6-methoxyl group-1H-indoles.
Particular chemical formula is as shown in the table:
Figure BDA00002469067800131
Figure BDA00002469067800151
Figure BDA00002469067800161
Figure BDA00002469067800171
Figure BDA00002469067800181
Figure BDA00002469067800191
Figure BDA00002469067800201
Figure BDA00002469067800211
In specific embodiment of the invention scheme, more preferably following compound or its pharmacy acceptable salt:
I-11-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-21-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-31-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-41-(4-(4-(2-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-52-methyl isophthalic acid-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The fluoro-1-of I-66-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-71-(3-(4-phenylpiperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-81-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-92-methyl isophthalic acid-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-101-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-111-(4-(4-(4-aminomethyl phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-121-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-131-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-141-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-151-(4-(4-(1-cyclohexyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-161-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-171-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-181-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-191-(4-(4-(3-(6-fluorobenzene isothiazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-201-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-211-(4-(4-(3-(6-fluorine benzofuryl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-221-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-231-(4-(4-(3-trifluoromethyl) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
I-241-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
The chloro-1-of I-256-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-266-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-276-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The chloro-1-of I-282-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzoglyoxaline,
I-291-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-301-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-311-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
The fluoro-1-of I-326-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-335,6-dimethyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-343-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
I-353-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-366-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-376-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole,
I-381-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-391-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-401-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-411-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-421-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzotriazole,
I-431-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-441-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-451-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-461-(4-(4-cyclohexyl piperazine-1-yl) butyl)-1H-benzotriazole,
I-471-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-481-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-491-(4-(4-(3-(the fluoro-benzisothiazole base of 6-)) piperazine-1-yl) butyl)-1H-benzotriazole,
I-501-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzotriazole,
I-511-(3-(4-(3-(the fluoro-benzofuryl of 6-) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-521-(4-(4-(3-(the fluoro-benzoisoxazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The fluoro-1-of I-536-(4-(4-(3-(the fluoro-benzisothiazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The chloro-1-of I-546-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-556-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-566-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-571-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-indoles,
I-586-cyano group-1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-indoles,
I-591-(3-(4-(3-trifluoromethyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles,
I-606-cyano group-1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles.
In specific embodiment of the invention scheme, more more preferably following compound or its pharmacy acceptable salt:
I-11-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-21-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-31-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-41-(4-(4-(2-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-52-methyl isophthalic acid-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The fluoro-1-of I-66-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-81-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-131-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-151-(4-(4-(1-cyclohexyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-171-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-181-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-221-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-231-(4-(4-(3-trifluoromethyl) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
I-241-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
The chloro-1-of I-256-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-291-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-301-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-311-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
The fluoro-1-of I-326-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-343-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
I-353-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-366-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-376-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole,
I-381-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-391-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-401-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-411-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-511-(3-(4-(3-(the fluoro-benzofuryl of 6-) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-521-(4-(4-(3-(the fluoro-benzoisoxazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The chloro-1-of I-546-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-591-(3-(4-(3-trifluoromethyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles.
In specific embodiment of the invention scheme, particularly preferably following compound or its pharmacy acceptable salt:
I-11-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-21-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-31-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-291-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-301-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-311-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-343-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
The fluoro-3-of I-366-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-376-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole,
I-381-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-391-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-401-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole.
In specific embodiment of the invention scheme, particularly preferably following compound or its pharmacy acceptable salt:
I-31-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-291-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-311-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-343-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole.
The pharmacy acceptable salt of formula of the present invention (I) compound is preferably hydrochloride, hydrogen bromide salt, vitriol, trifluoroacetate, mesylate, 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.
In the specific embodiments of purposes of the present invention, especially preferred compound I-2 or its pharmacy acceptable salt, for example its hydrochloride, i.e. Compound I I-2, chemical structure is as shown in II-2.
Figure BDA00002469067800271
The preferred salt in Compound I-3 is hydrochloride, i.e. Compound I I-3, and chemical structure is as under II-3 institute.
Figure BDA00002469067800272
Wherein, the preferred salt in Compound I-29 is hydrochloride, i.e. Compound I I-29, and chemical structure is as shown in II-29.
The preferred salt in Compound I-31 is hydrochloride, i.e. Compound I I-31, and chemical structure is as shown in II-31.
Figure BDA00002469067800274
The preferred salt in Compound I-34 is hydrochloride, i.e. Compound I I-34, and chemical structure is as shown in II-34.
Figure BDA00002469067800275
Animal isolated test proves: Compound I I-2, and the vascular smooth muscle can diastole being shunk by suprarenin and high potassium liquid, its diastole-logEC 50value was respectively for 5.73 ± 0.03 and 5.34 ± 0.02 (as shown in Figure 1 and Figure 2); Compound I I-3, the vascular smooth muscle that diastole is shunk by suprarenin and high potassium liquid-logEC 50value was respectively for 6.01 ± 0.05 and 5.49 ± 0.05 (as shown in Figure 8, Figure 9).
The research of the to relax the VSM mechanism of action of Compound I I-2 shows, this compound contestable antagonism norepinephrine, calcium ion and the contraction of serotonin to blood vessel, can make parallel the moving to right of amount effect curve of above-mentioned agonist, do not reduce its maximum reaction, explanation is competitive antagonism, the PA of its antagonism norepinephrine (NA), calcium ion and the contraction of serotonin (5-HT) to blood vessel 2value is respectively 7.37 ± 0.08 (Doxazosin is 7.52 ± 0.04), 5.61 ± 0.04 (amlodipine is 6.99 ± 0.05) and 5.71 ± 0.08 (as shown in Fig. 3, Fig. 4, Fig. 5, Fig. 6 and Fig. 7).Result shows, Compound I I-2 is by blocking-up α 1acceptor, Ca 2+ionic channel and blood vessel 5-HT 2Aacceptor is brought into play its vasorelaxation action.
Animal isolated test proves: Compound I I-29, and the vascular smooth muscle can diastole being shunk by suprarenin and high potassium liquid, its diastole-logEC 50value is respectively 6.01 ± 0.02 and 5.64 ± 0.01 (as shown in Figure 15, Figure 16).The vascular smooth muscle that Compound I I-31 diastole is shunk by suprarenin and high potassium liquid-logEC 50value was respectively for 6.19 ± 0.03 and 5.55 ± 0.03 (as shown in Figure 10, Figure 11).
The research of the to relax the VSM mechanism of action of Compound I I-31 shows, this compound contestable antagonism norepinephrine, calcium ion and the contraction of serotonin to blood vessel, can make parallel the moving to right of amount effect curve of above-mentioned agonist, do not reduce its maximum reaction, explanation is competitive antagonism, the PA of its antagonism norepinephrine, calcium ion and the contraction of serotonin to blood vessel 2value is respectively 6.02 ± 0.13 (Doxazosin is 7.76 ± 0.24), 6.56 ± 0.032 (amlodipine is 7.51 ± 0.288) and 6.726 ± 0.089 (as shown in Figure 12, Figure 13 and Figure 14).These results show, Compound I I-31 is also by blocking-up α 1 acceptor, Ca 2+ionic channel and blood vessel 5-HT 2Aacceptor, brings into play its vasorelaxation action.
Compound I I-2 in bulk testing, shows obvious hypotensive effect in rat body, and its oral absorption is good, and toxicity is little, and therapeutic index is large, and Teratogenic effects is negative, and has the potential value as novel many target spots vasodilator drug exploitation.
Inventor's discovery, formula of the present invention (I) compound and pharmacy acceptable salt thereof have the effect of significant experimenter's to relax the VSM.Formula of the present invention (I) compound and pharmacy acceptable salt thereof can pass through for example α receptor antagonism (particularly α 1receptor antagonism) realize to relax the VSM effect.In addition, formula of the present invention (I) compound and pharmacy acceptable salt thereof also may act on other target spots or approach and realize to relax the VSM effect, for example Ca 2+carrier frequency channel break or antagonism 5-HT 2Areceptor antagonism.Particularly preferably there is the compounds of this invention of multiple target spot effect, for example Compound I-2 or Compound I I-2.This multiple target spot effect makes the compounds of this invention be effective to especially the contraction of continuous vessel pathologic or the relevant disease of vascular smooth muscle spasm, it is with respect to single single target drug or multiple single target drug coupling during for described disease, can realize more high-drug-effect, or effectively reduce resistance or reduce undesired side effect, making security higher.Specifically, for example make can be at the incomplete α of blocking-up vascular smooth muscle in the effect of multiple target spot 1when acceptor, by blocking-up Ca 2+passage and/or 5-HT 2Athe synergy of acceptor produces good step-down drug effect, and this makes remaining α 1acceptor still can participate in pressor reflex, can prevent from reducing the generation of postural hypotension; And/or by blocking-up Ca 2+channeling, in collaborative step-down, produce resisting cardiac hypertrophy, protection vascular endothelial cell, atherosclerosis, inhibition vascular smooth muscle hyperplasia, improve the effects such as cerebral circulation, and pass through reducing heart rate, effectively prevent the generation of tachycardia and palpitaition, prevent the generation of first-dose response; And/or by blocking-up 5-HT 2Areceptor acting, when producing collaborative step-down, can effectively improve occlusion vascular disease patient's supply of blood flow, and it is applicable to atherosclerosis, with the hyperpietic of endothelial injury.
Thus, formula of the present invention (I) compound and pharmacy acceptable salt thereof can be used for prevention, alleviate or treat disease or the illness that experimenter is relevant to the contraction of continuous vessel pathologic or vasospasm.Described formula (I) compound and pharmacy acceptable salt thereof can be used in particular for prevention, alleviate or treatment hypertension heart failure, stenocardia, coronary heart disease etc.; For the cerebral ischemia diseases being caused by vasospasm, myocardial ischemia disease, shock etc.; The poor kidney and the periperal vascular spasm that be used for renal ischaemia, are caused by kidney vasospasm.
Experimenter's preferred mammal described herein, particularly preferably people.
The invention provides formula (I) compound or its pharmacy acceptable salt and be particularly preferred for prevention, alleviate or for example treat, hypertension, stenocardia, heart failure, coronary heart disease, cerebral ischemia and periperal vascular spasm are as thromboangiitis obliterans, Raynaud disease etc.
Formula of the present invention (I) compound or its pharmacy acceptable salt can be prepared into suitable pharmaceutical compositions for oral administration, administered parenterally, by sucking administration in spray delivery, rectal administration, intranasal administration, sublingual administration, cheek, transdermal administration or through drug delivery implant, that described administered parenterally comprises is subcutaneous, in intracutaneous, intravenously, intramuscular, intraarticular, synovial membrane, in breastbone, in sheath, intralesional and intracranial injection administration or drip infusion technique.Formula of the present invention (I) compound or its pharmacy acceptable salt preferred oral administration, sublingual administration, intravenously, intramuscular, subcutaneous injection administration.Described pharmaceutical composition can comprise one or more conventional pharmaceutically acceptable carrier, auxiliary agent or medium, for example: thinner, vehicle are as water etc.; Tackiness agent is 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.; And other auxiliarys are as flavouring agent and sweeting agent.
The described pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can be the form of aseptic injection, for example, as sterile aqueous or oil suspension.This suspension can for example, according to the suitable dispersion agent of utilization known in the art or wetting agent (Tween 80) and suspension agent preparation.Aseptic injection also can be aseptic injectable solution or the suspension in the nontoxic thinner or the solvent that can be used for administered parenterally, for example, as the solution in 1,3 butylene glycol.Spendable usable medium and solvent are N.F,USP MANNITOL, water, Ringer ' s solution and isotonic sodium chlorrde solution.In addition, aseptic expressed oil routine can be used as solvent or suspension medium.For this purpose, the expressed oil of any gentleness be can use, synthetic monoglyceride or triglyceride comprised.Lipid acid, for example oleic acid and glyceride derivative thereof can be used in injectable formulation, and natural pharmaceutically useful oil also can be used for wherein, for example sweet oil or Viscotrol C, especially its polyoxyethylene form.Described oil solution or suspension also can comprise long-chain alcohol thinner or dispersion agent (be for example described in Ph.Helv those) or similar alcohol.
The pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can any formulation oral administration that can be oral, described formulation includes but not limited to, capsule, tablet, pulvis, granule and aqueous suspension agent and solution.Described formulation is to make according to known technology in field of pharmaceutical preparations.For the tablet orally using, normally used carrier comprises lactose and W-Gum.Also conventionally add lubricant (for example Magnesium Stearate).To the oral administration of capsule form, available thinner comprises lactose and dry W-Gum.When aqueous suspension agent is during by oral administration, active ingredient can be combined with emulsifying agent and suspension agent.If need, can add some sweeting agent and/or seasonings and/or tinting material.
The pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can be by nose gaseous solvents or inhalation.This based composition can be according to known technology preparation in field of pharmaceutical preparations, and absorption enhancer, fluorocarbon and/or other solubilizing agent known in the art or the dispersion agent that can use phenylcarbinol or other suitable sanitass, raising bioavailability, be prepared as the solution in salt solution.
The pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can also be used for the suppository form administration of rectal administration.Described composition can be by the compounds of this invention and suitable non-stimulated mixed with excipients are made, and described vehicle is at room temperature solid but is liquid under rectal temperature, therefore in rectum, will dissolve to discharge active ingredient.This class material includes but not limited to, theobroma oil, beeswax and polyoxyethylene glycol.
Infer according to anesthetized rat test-results, dosage every day of formula of the present invention (I) compound should be less than dosage every day of amlodipine.Dosage every day for vasodilator or hypertensive amlodipine is known in the art, for example 10mg/ day.The concrete dosage of formula of the present invention (I) compound can be determined by doctor according to clinical experiment result and patient's the state of an illness, age etc.
The pharmaceutical composition that comprises formula of the present invention (I) compound or its pharmacy acceptable salt can adopt the method for medical field routine to be prepared, wherein the content of activeconstituents is 0.1 % by weight-99.5 % by weight, the characteristic that this depends on the illness of to be treated or prevention and gives the experimenter of described compound.Dosage for given compound can utilize content disclosed herein easily to determine by those skilled in the art.
In a specific embodiments, compound formula (I) compound of the present invention or its pharmacy acceptable salt can with one or more other active medicine component couplings.This coupling medicine can be the form of the single composition that comprises the compounds of this invention or its pharmacy acceptable salt and one or more other active medicine components, or, this coupling medicine can be the cooperative programs of two or more independent compositions, wherein compound of the present invention is included in a kind of composition, and one or more other active medicine components are included in one or more independent compositions.Can to formula of the present invention (I) compound or its pharmacy acceptable salt coupling take prevention, alleviate or other active medicine components for the treatment of experimenter and the contraction of continuous vessel pathologic or the relevant disease of vasospasm or illness for example as other anti-smooth muscle spasm medicines, preferably from Sertraline, captopril, benazepril, valsartan, Proprasylyte, hydragog(ue).
Each embodiment that the application addresses, or other scheme of different priority except as otherwise noted all can arbitrary combination.
Compound of the present invention can adopt following method to synthesize:
Synthetic route 1:
Figure BDA00002469067800321
Wherein, R 1, R 2, A, B as above definition; N=2-7; X represents its pharmaceutically useful salt, for example HCl, 2HCl, HBr, 2HBr, H 2sO 4, CH 3sO 3h etc.
To replace the benzo five-membered nitrogen heterocyclic of 1H-as raw material, in aqueous sodium hydroxide solution, carry out condensation reaction with chlorine alkyl bromide, preparation N-chlorine alkyl-replacement benzo penta azacyclo compound, carry out condensation reaction with substituted aryl piperazine again, compound shown in preparation formula (I), prepares corresponding salt finally by acidifying salify, obtains formula (II) compound.Adopt aforesaid method can prepare Compound I-1-I-21, I-25-I-51 and I-54-I-60 and salt thereof.
Synthetic route 2:
Figure BDA00002469067800322
Wherein, R 1, R 2, A, B as above definition; N=2-7; X represents its pharmaceutically useful salt, for example HCl, 2HCl, HBr, 2HBr, H 2sO 4, CH 3sO 3h etc.
Replacing benzo penta azacyclo-1 alcohol is raw material, obtain corresponding sodium salt with sodium hydride exchange reactive hydrogen, obtain corresponding muriate with chloro alkyl bromine reaction again, carry out condensation reaction with substituted-piperazinyl again, compound shown in preparation formula (I), prepare corresponding salt finally by acidifying salify, obtain formula (II) compound.Adopt aforesaid method can prepare Compound I-22-24, I-52-53 and salt thereof.
The preparation of synthetic logical method: N-(4-chlorobutyl)-replacement benzo penta azacyclo compound
1H-is replaced to benzo penta azacyclo (0.10mol) and be dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, add 4-chlorine n-butyl bromide (34.0g, 0.10mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, 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 N-(4-chlorobutyl)-replacement benzo penta azacyclo compound, yield 30.0-85.0%.
Embodiment 1
The preparation of 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-1)
1H-benzoglyoxaline (11.8g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 1-(4-chlorobutyl)-1H-benzoglyoxaline 12.5g, yield 60.0%.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trichlorophenyl piperazine (5.9g, 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 15 hours.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 compound (I-1) 6.8g, yield 61.4%.ESI-MS[M+H] +：m/z 369.2。
Embodiment 2
The preparation of 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-2) and 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline hydrochloride (II-2)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.91g, 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 compound (I-2) 7.6g, yield 62.8%.
Compound (I-2) (6.04g, 0.015mol) is dissolved in 80ml ethyl acetate and 8ml ethanol.Under ice-water bath cooling conditions, drip hydrogenchloride/ethyl acetate solution of 3mol/L, adjust pH value of solution=3, be warming up to 50 ℃ and stir 20min, cooling crystallization, filters, dry, obtains compound (II-2) solid 5.9g, yield 89.7%.ESI-MS[M+H] +：m/z 403.2。
Embodiment 3
1-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl) preparation of-1H-benzoglyoxaline (I-3) and 1-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline hydrochloride (II-3)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 2,3-dichlorophenyl piperazine (6.93g, 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 compound (I-3) 7.5g, yield 62.0%.
Compound (I-3) (6.05g, 0.015mol) is dissolved in 80ml ethyl acetate and 8ml ethanol.Under ice-water bath cooling conditions, drip hydrogenchloride/ethyl acetate solution of 3mol/L, adjust pH value of solution=3, be warming up to 50 ℃ and stir 20min, cooling crystallization, filters, dry, obtains compound (II-3) solid 6.0g, yield 90.9%.ESI-MS[M+H] +：m/z 403.1。
Embodiment 4
The preparation of 1-(4-(4-(2-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-4)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 2-methoxyphenylpiperazderivatives (5.77g, 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 15 hours.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 compound (I-4) 7.7g, yield 70.6%.ESI-MS[M+H] +：m/z 365.2。
Embodiment 5
The preparation of 2-methyl isophthalic acid-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-5)
2-methyl isophthalic acid H-benzoglyoxaline (13.2g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 1-(4-chlorobutyl)-2-methyl isophthalic acid H-benzoglyoxaline 13.7g, yield 61.5%.
By 1-(4-chlorobutyl)-2-methyl isophthalic acid H-benzoglyoxaline (8.02g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.91g, 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 15 hours.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 compound (I-5) 8.1g, yield 64.9%.ESI-MS[M+H] +：m/z417.2。
Embodiment 6
The preparation of the fluoro-1-of 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-6)
Fluoro-6-1H-benzoglyoxaline (13.2g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, stirring reaction 2 hours.Carry out post-processing operation by logical method, through neutral Al 2o 3chromatographic separation purifying, obtains the fluoro-1H-benzoglyoxaline of 1-(4-chlorobutyl)-6-14.2g, yield 62.6%.
By the fluoro-1H-benzoglyoxaline of 1-(4-chlorobutyl)-6-(8.16g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.91g, 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 15 hours.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 compound (I-6) 8.5g, yield 67.4%.ESI-MS[M+H] +：m/z 421.2。
Embodiment 7
The preparation of 1-(3-(4-phenylpiperazine-1-yl) propyl group)-1H-benzoglyoxaline (I-7)
1H-benzoglyoxaline (11.8g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 3-chlorobromopropane (31.4g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 1-(3-chloropropyl)-1H-benzoglyoxaline 12.0g, yield 62.0%.
By 1-(3-chloropropyl)-1H-benzoglyoxaline (6.98g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively phenylpiperazine (4.9g, 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 15 hours.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 compound (I-7) 6.1g, yield 63.2%.ESI-MS[M+H] +：m/z 321.2。
Embodiment 8
The preparation of 1-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline (I-8)
Adopt the method in embodiment 7 to prepare 1-(3-chloropropyl)-1H-benzoglyoxaline.
By 1-(3-chloropropyl)-1H-benzoglyoxaline (6.98g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-fluorophenyl piperazine (6.91g, 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 15 hours.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 compound (I-8) 6.4g, yield 63.1%.ESI-MS[M+H] +：m/z 339.2。
Embodiment 9
The preparation of 2-methyl isophthalic acid-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline (I-9)
2-methyl isophthalic acid H-benzoglyoxaline (13.2g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200mL, adds 3-chlorobromopropane (31.4g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 1-(3-chloropropyl)-2-methyl isophthalic acid H-benzoglyoxaline 12.9g, yield 62.1%.
By 1-(3-chloropropyl)-2-methyl isophthalic acid H-benzoglyoxaline (7.49g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluorophenyl piperazine (4.9g, 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 15 hours.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 compound (I-9) 6.67g, yield 63.1%.ESI-MS[M+H] +：m/z 353.2。
Embodiment 10
The preparation of 1-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-10)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.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 compound (I-10) 6.7g, yield 62.4%.ESI-MS[M+H] +：m/z 360.2。
Embodiment 11
The preparation of 1-(4-(4-(4-aminomethyl phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-11)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-aminomethyl phenyl piperazine (5.3g, 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 15 hours.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 compound (I-11) 6.4g, yield 60.7%.ESI-MS[M+H] +：m/z 349.2。
Embodiment 12
The preparation of 1-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-12)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.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 compound (I-12) 6.0g, yield 61.5%.ESI-MS[M+H] +：m/z 325.2。
Embodiment 13
The preparation of 1-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-13)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.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 compound (I-13) 6.3g, yield 62.1%.ESI-MS[M+H] +：m/z 336.2。
Embodiment 14
The preparation of 1-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-14)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 4-(2-pyrimidyl) piperazine (4.9g, 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 20 hours.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 compound (I-14) 6.1g, yield 60.1%.ESI-MS[M+H] +：m/z 337.2。
Embodiment 15
The preparation of 1-(4-(4-(1-cyclohexyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-15)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.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 compound (I-15) 6.4g, yield 62.9%.ESI-MS[M+H] +：m/z 341.3。
Embodiment 16
The preparation of 1-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-16)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.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 compound (I-16) 6.8g, yield 59.1%.ESI-MS[M+H] +：m/z 385.2。
Embodiment 17
The preparation of 1-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-17)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 20 hours.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 compound (I-16) 6.9g, yield 59.6%.ESI-MS[M+H] +：m/z 387.2。
Embodiment 18
The preparation of 1-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-18)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100mL acetonitrile, add respectively the fluoro-3-of 6-(piperazine-4-yl) benzoisoxazole (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 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through column chromatography (neutral Al 2o 3) chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-18) 7.7g, yield 65.6%.ESI-MS[M+H] +：m/z 394.2。
Embodiment 19
The preparation of 1-(4-(4-(3-(6-fluorobenzene isothiazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-19)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100mL acetonitrile, add respectively the fluoro-3-of 6-(piperazine-4-yl) benzisothiazole (7.1g, 0.05mol), 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 column chromatography (neutral Al 2o 3) chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-19) 7.9g, yield 64.6%.ESI-MS[M+H] +：m/z 410.2。
Embodiment 20
The preparation of 1-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-20)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 0.036mol) be dissolved in 100mL acetonitrile, add respectively 3-(piperazine-4-yl) benzopyrazoles (6.1g, 0.05mol), 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 column chromatography (neutral Al 2o 3) chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-20) 6.9g, yield 61.5%.ESI-MS[M+H] +：m/z 375.2。
Embodiment 21
The preparation of 1-(4-(4-(3-(6-fluorine benzofuryl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-21)
Adopt the method in embodiment 1 to prepare 1-(4-chlorobutyl)-1H-benzoglyoxaline.
By 1-(4-chlorobutyl)-1H-benzoglyoxaline (7.51g, 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 15h.Be cooled to room temperature, filter, concentrating filter liquor obtains oily matter, through column chromatography (neutral Al 2o 3) chromatographic separation purifying, methylene dichloride wash-out, obtains compound (I-21) 7.5g, yield 63.6%.ESI-MS[M+H] +：m/z 393.2。
Embodiment 22
The preparation of 1-(3-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline (I-22)
The preparation of 1-(3-chlorine propoxy-) benzoglyoxaline
1-hydroxy benzo imidazoles (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 5mlNMP, 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-) benzoglyoxaline, yield 75.0%.
1-(3-chlorine propoxy-) benzoglyoxaline (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-(6-fluorobenzene Bing isoxazolyl)) 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-(3-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline (I-22) 13.7g, yield 69.1%.ESI-MS[M+H] +：m/z 396.2。
Embodiment 23
The preparation of 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline (I-23)
Adopt the method in embodiment 22 to prepare 1-(3-chlorine propoxy-) benzoglyoxaline.
1-(3-chlorine propoxy-) benzoglyoxaline (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-trifluoromethyl) 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, obtains 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline (I-23) 13.7g, yield 67.9%.ESI-MS[M+H] +：m/z 405.2。
Embodiment 24
The preparation of 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline (I-24)
Adopt the method in embodiment 22 to prepare 1-(3-chlorine propoxy-) benzoglyoxaline.
1-(3-chlorine propoxy-) benzoglyoxaline (0.06mol) is dissolved in 150ml acetonitrile, add respectively 4-(3-chloro-phenyl-) 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, obtains 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline (I-24) 12.2g, yield 66.1%.ESI-MS[M+H] +：m/z371.2。
Embodiment 25
The preparation of the chloro-1-of 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-25)
Chloro-6-1H-benzoglyoxaline (15.2g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, stirring reaction 2 hours.Carry out post-processing operation by logical method, through neutral Al 2o 3chromatographic separation purifying, obtains the chloro-1H-benzoglyoxaline of 1-(4-chlorobutyl)-6-15.1g, yield 62.3%.
By the chloro-1H-benzoglyoxaline of 1-(4-chlorobutyl)-6-(8.71g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.91g, 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 15 hours.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 compound (I-25) 8.6g, yield 65.8%.ESI-MS[M+H] +：m/z 437.2。
Embodiment 26
The preparation of 6-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-26)
6-cyano group-1H-benzoglyoxaline (14.3g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, stirring reaction 2 hours.Carry out post-processing operation by logical method, through neutral Al 2o 3chromatographic separation purifying, obtains 1-(4-chlorobutyl)-6-cyano group-1H-benzoglyoxaline 14.7g, yield 63.1%.
By 1-(4-chlorobutyl)-6-cyano group-1H-benzoglyoxaline (8.39g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.91g, 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 15 hours.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 compound (I-26) 8.6g, yield 66.9%.ESI-MS[M+H] +：m/z428.2。
Embodiment 27
The preparation of 6-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline (I-27)
By 6-methoxycarbonyl-1H-benzoglyoxaline (17.6g, 0.10mol) be dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, add 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, be warming up to 60 ℃, stirring reaction 2 hours.Carry out post-processing operation by logical method, through neutral Al 2o 3chromatographic separation purifying, obtains 1-(4-chlorobutyl)-6-methoxycarbonyl-1H-benzoglyoxaline 16.9g, yield 63.4%.
By 1-(4-chlorobutyl)-6-methoxycarbonyl-1H-benzoglyoxaline (9.58g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.91g, 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 15 hours.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 compound (I-27) 8.8g, yield 63.7%.ESI-MS[M+H] +：m/z461.2。
Embodiment 28
The preparation of the chloro-1-of 2-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzoglyoxaline (I-28)
Chloro-2-1H-benzoglyoxaline (15.2g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 5-chlorine bromo pentane silane (36.8g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 1-(5-chlorine amyl group) the chloro-1H-benzoglyoxaline of-2-16.0g, yield 62.5%.
By 1-(5-chlorine amyl group) the chloro-1H-benzoglyoxaline of-2-(9.22g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trifluoromethylphenypiperazine piperazine (6.91g, 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 15 hours.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 compound (I-5) 8.8g, yield 65.2%.ESI-MS[M+H] +：m/z 451.2。
Embodiment 29
The preparation of 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole (I-29)
Benzotriazole (11.9g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, 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-29) 7.8g, yield 70.3%.
Compound (I-29) (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 10min, filter, dry, obtain compound (II-29) solid 5.4g, yield 88.0%.ESI-MS[M+H] +：m/z 370.1。
Embodiment 30
The preparation of 1-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-30)
Adopt the method in embodiment 29 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-30) 7.3g, yield 68.9%.ESI-MS[M+H] +：m/z 354.2。
Embodiment 31
The preparation of 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-31) and 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole hydrochloride (II-31)
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-31) 7.8g, yield 64.5%.
Compound (I-31) (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 10min, filter, dry, obtain compound (II-31) solid 5.6g, yield 84.8%.ESI-MS[M+H] +：m/z 404.2。
Embodiment 32
The preparation of the fluoro-1-of 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-32)
Fluoro-6-1H-benzotriazole (13.7g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, stirring reaction 2 hours.Carry out aftertreatment by the method in synthetic logical method, 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-32) 8.3g, yield 65.7%.ESI-MS[M+H] +：m/z 422.2。
Embodiment 33
The preparation of 5,6-dimethyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-33)
5,6-dimethyl-1H-benzotriazole (14.7g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, stirring reaction 2 hours.Carry out aftertreatment by the method in synthetic logical method, 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-33) 9.1g, yield 70.3%.ESI-MS[M+H] +：m/z 432.2。
Embodiment 34
The preparation of 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole (I-34)
Adopt the method in embodiment 29 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-34) 8.2g, yield 69.6%.
Compound (I-34) (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 10min, filter, dry, obtain compound (II-34) solid 5.5g, yield 85.5%.ESI-MS[M+H] +：m/z 393.2。
Embodiment 35
The preparation of 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole (I-35)
Adopt the method in embodiment 29 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-35) 8.0g, yield 70.9%.ESI-MS[M+H] +：m/z 377.2。
Embodiment 36
The preparation of the fluoro-3-of 6-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole (I-36)
Adopt the method in embodiment 29 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-36) 8.3g, yield 70.0%.ESI-MS[M+H] +：m/z 395.2。
Embodiment 37
The preparation of the fluoro-3-of 6-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole (I-37)
Benzotriazole (11.9g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 3-chlorobromopropane (30.2g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, 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-37) 7.9g, yield 69.3%.ESI-MS[M+H] +：m/z 380.2。
Embodiment 38
The preparation of 1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole (I-38)
Adopt the method in embodiment 37 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-38) 8.2g, yield 70.2%.ESI-MS[M+H] +：m/z 389.1。
Embodiment 39
The preparation of 1-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole (I-39)
Adopt the method in embodiment 37 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-39) 7.5g, yield 74.6%.ESI-MS[M+H] +：m/z 335.2。
Embodiment 40
The preparation of 1-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-40)
Adopt the method in embodiment 29 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-methoxyphenylpiperazderivatives (5.8g, 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-40) 7.6g, yield 69.4%.ESI-MS[M+H] +：m/z 365.2。
Embodiment 41
The preparation of 1-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-41)
Adopt the method in embodiment 29 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-41) 7.6g, yield 70.5%.ESI-MS[M+H] +：m/z 360.2。
Embodiment 42
The preparation of 1-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzotriazole (I-42)
Benzotriazole (11.9g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 5-chlorine bromo pentane silane (36.8g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, 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-42) 7.7g, yield 61.5%.ESI-MS[M+H] +：m/z 417.2。
Embodiment 43
The preparation of 1-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-43)
Adopt the method in embodiment 29 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-43) 7.0g, yield 71.3%.ESI-MS[M+H] +：m/z 325.2。
Embodiment 44
The preparation of 1-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-44)
Adopt the method in embodiment 29 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-44) 6.6g, yield 65.3%.ESI-MS[M+H] +：m/z 336.2。
Embodiment 45
The preparation of 1-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-45)
Adopt the method in embodiment 29 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-pyrimidyl) 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-45) 6.8g, yield 67.1%.ESI-MS[M+H] +：m/z 337.2。
Embodiment 46
The preparation of 1-(4-(4-cyclohexyl piperazine-1-yl) butyl)-1H-benzotriazole (I-46)
Adopt the method in embodiment 29 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-46) 6.5g, yield 63.7%.ESI-MS[M+H] +：m/z 341.2。
Embodiment 47
The preparation of 1-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-47)
Adopt the method in embodiment 29 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-47) 6.9g, yield 60.1%.ESI-MS[M+H] +：m/z 385.2。
Embodiment 48
The preparation of 1-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-48)
Adopt the method in embodiment 29 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-48) 7.3g, yield 62.7%.ESI-MS[M+H] +：m/z 387.2。
Embodiment 49
The preparation of 1-(4-(4-(3-(the fluoro-benzisothiazole base of 6-)) piperazine-1-yl) butyl)-1H-benzotriazole (I-49)
Adopt the method in embodiment 29 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-49) 8.2g, yield 66.5%.ESI-MS[M+H] +：m/z 410.2。
Embodiment 50
The preparation of 1-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzotriazole (I-50)
Adopt the method in embodiment 29 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-4-yl) benzopyrazoles (6.1g, 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-50) 7.7g, yield 68.2%.ESI-MS[M+H] +：m/z 375.2。
Embodiment 51
1-(the preparation of 3-(4-(3-(the fluoro-benzofuryl of 6-) piperazine-1-yl) propyl group)-1H-benzotriazole (I-51)
Adopt the method in embodiment 37 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-51) 7.9g, yield 69.1%.ESI-MS[M+H] +：m/z 379.2。
Embodiment 52
1-(the preparation of 4-(4-(3-(the fluoro-benzoisoxazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole (I-52)
The preparation of 1-(3-chlorine propoxy-) benzotriazole
1-hydroxy benzo triazole (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 5mlNMP, 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-52) 13.4g, yield 67.6%.ESI-MS[M+H] +：m/z 396.2。
Embodiment 53
The fluoro-1-of the 6-(preparation of 4-(4-(3-(the fluoro-benzisothiazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole (I-53)
The preparation of the fluoro-1-of 6-(2-chlorine propoxy-)-benzotriazole
Fluoro-6-1-hydroxy benzo triazole (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 5mlNMP, 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-53) 14.1g, yield 65.6%.ESI-MS[M+H] +：m/z 430.1。
Embodiment 54
The preparation of the chloro-1-of 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-54)
Chloro-6-benzotriazole (15.3g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, 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-54) 8.5g, yield 64.7%.ESI-MS[M+H] +：m/z 437.2。
Embodiment 55
The preparation of 6-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-55)
6-cyano group-benzotriazole (14.4g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, 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-55) 8.5g, yield 66.4%.ESI-MS[M+H] +：m/z 428.2。
Embodiment 56
The preparation of 6-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole (I-56)
6-methoxycarbonyl-benzotriazole (17.7g, 0.10mol) is dissolved in 30 % by weight aqueous sodium hydroxide solution 100ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 0.8g, mix and blend 5 minutes.Reaction solution is slowly warming up to 60 ℃, 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-56) 8.8g, yield 63.4%.ESI-MS[M+H] +：m/z 461.2。
Embodiment 57
The preparation of 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-indoles (I-57)
1H-indoles (11.7g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 1-(4-chlorobutyl)-1H-indoles 12.5g, yield 60.1%.
By 1-(4-chlorobutyl)-1H-indoles (7.45g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.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 compound (I-57) 7.3g, yield 60.6%.ESI-MS[M+H] +：m/z 402.2。
Embodiment 58
The preparation of 6-cyano group-1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-indoles (I-58)
6-cyano-1 H-indol-(14.2g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 4-chlorine n-butyl bromide (34.3g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 6-cyano group-1-(4-chlorobutyl)-1H-indoles 13.9g, yield 60.3%.
By 6-cyano group-1-(4-chlorobutyl)-1H-indoles (8.35g, 0.036mol) be dissolved in 100ml acetonitrile, add respectively 3-trichlorophenyl piperazine (5.9g, 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 15 hours.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 compound (I-58) 6.9g, yield 62.3%.ESI-MS[M+H] +：m/z 393.2。
Embodiment 59
The preparation of 1-(3-(4-(3-trifluoromethyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles (I-59)
1H-benzopyrazoles (11.8g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 3-chlorobromopropane (31.2g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 1-(3-chloropropyl)-1H-benzopyrazoles 11.5g, yield 59.3%.
To obtain 1-(3-chloropropyl)-1H-benzopyrazoles (6.98g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.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 compound (I-59) 7.6g, yield 63.1%.ESI-MS[M+H] +：m/z 389.2。
Embodiment 60
The preparation of 6-cyano group-1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles (I-60)
6-cyano group-1H-benzopyrazoles (14.3g, 0.10mol) is dissolved in 20 % by weight aqueous sodium hydroxide solution 200ml, adds 3-chlorobromopropane (31.2g, 0.20mol), Tetrabutyl amonium bromide 1.0g, mix and blend 5 minutes, is warming up to 60 ℃, 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 3chromatographic separation purifying, obtains 6-cyano group-1-(3-chloropropyl)-1H-benzopyrazoles 13.9g, yield 63.8%.
By 6-cyano group-1-(3-chloropropyl)-1H-benzopyrazoles (7.88g, 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), stirring at room temperature 10 minutes, then temperature rising reflux reaction 15 hours.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 compound (I-60) 7.6g, yield 61.1%.ESI-MS[M+H] +：m/z 414.1。
Embodiment 61
According to the method described in patent application US20100329978A1, prepare compound of the present invention (I-61 to I-65).
Embodiment 62
According to the method described in Chinese patent application 200610097269.1, prepare compound of the present invention (I-66 to I-84).
Embodiment 63
Compound I I-1 to II-60 causes 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 I I-1-II-60, i.e. the hydrochloride of Compound I-1-I-60, can prepare according to embodiment 2 (or 3 or 31 or 34) their salt (hydrochloride), adopts the self-control of embodiment method;
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 long-range medicine (China) company limited, lot number 120105;
Noradrenaline bitartrate (Norepinephrine Bitartrate Injection) specification 2mg/1ml, long-range medicine (China) company limited, 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: NaCl 6.92 (concentration units), KCl0.35, MgSO 40.29, KH 2pO 40.16, CaCl 20.28, NaHCO 32.1, Glucose2.0 (g/L), pH 7.2.
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 I I-1-II-60 solution: take certain mass compound sample, take 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 ℃ of the interior maintenance of pipe temperature, and pass into mixed gas (95%O2+5%CO with the speed of a 1-2 per second bubble 2).Sample initial load 1.5g, every 20min changes one time of nutrition liquid, and balance 2 hours starts experiment after baseline stability.
6 concrete test operation and test-results
6.1 Compound I I-1 to II-60 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, and every 20min changes K-H liquid one time, and balance 60min, after baseline restorer is steady, again uses same concentration to cause convulsion agent induction and shrinks.When after once shrink maximum reaction with front when once basically identical, accumulation adds the Compound I I-1-II-60 solution (1 × 10 preparing -8-1 × 10 -3mol/L), wave recording.Take the diastole percentage ratio of Compound I I-1-II-60 as ordinate zou, maximum stretching reaction is 100% to make effect curve, and wherein the diastole effect of II-2, II-3 is the most obvious, and the negative logarithm of its each concentration is that X-coordinate is drawn amount effect curve and seen Fig. 1 and Fig. 8.
From Fig. 1 and 8, Compound I I-2, II-3 cause to AD sample that convulsion agent causes and shrink and have diastole effect, and it presents certain dose-dependently to adrenergic diastole effect, shrink-logEC of the Rabbit Aorta that wherein Compound I I-2 diastole AD causes 50value is 5.73 ± 0.03, shrink-logEC of the Rabbit Aorta that Compound I I-3 diastole AD causes 50value is 6.01 ± 0.05.
Compound I I-31 also shows more obvious diastole effect, and the negative logarithm of its each concentration is that X-coordinate is drawn amount effect curve, sees Figure 10; Wherein II-29 also has obvious diastole effect, and its amount effect curve is shown in Figure 15.As can be seen from Figure 10, Compound I I-31 causes to AD sample that convulsion agent causes and shrinks and have diastole effect, and it presents certain dose-dependently to adrenergic diastole effect, shrink-logEC of the Rabbit Aorta that Compound I I-31 diastole AD causes 50value is 6.19 ± 0.03; Similarly, Compound I I-29 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.
The diastole effect that Compound I I-1 to II-60 shrinks rabbit myocardium vessel unstriated muscle to AD is as shown in table 1:
Table 1 Compound I I-1-II-60 shrinks the diastole effect of rabbit myocardium vessel unstriated muscle to AD
Compound -logEC 50 Compound -logEC 50
II-1 5.03±0.04 II-31 6.19±0.03
[0631]
II-2 5.73±0.03 II-32 5.41±0.03
II-3 6.01±0.05 II-33 4.39±0.04
II-4 4.96±0.03 II-34 8.07±0.06
II-5 4.78±0.04 II-35 4.89±0.05
II-6 4.63±0.06 II-36 5.31±0.04
II-7 4.29±0.05 II-37 5.56±0.03
II-8 4.71±0.04 II-38 5.72±0.05
II-9 4.37±0.03 II-39 5.47±0.04
II-10 4.26±0.05 II-40 5.35±0.06
II-11 4.05±0.04 II-41 4.51±0.05
II-12 4.35±0.06 II-42 4.39±0.04
II-13 4.41±0.05 II-43 4.45±0.04
II-14 4.22±0.04 II-44 4.15±0.03
II-15 4.47±0.04 II-45 4.33±0.03
II-16 4.29±0.03 II-46 4.26±0.06
II-17 4.53±0.03 II-47 3.88±0.04
II-18 4.86±0.06 II-48 3.83±0.05
II-19 4.18±0.04 II-49 4.05±0.03
II-20 4.23±0.05 II-50 4.35±0.04
II-21 4.05±0.03 II-51 4.52±0.03
II-22 4.55±0.04 II-52 4.88±0.04
II-23 4.72±0.03 II-53 4.28±0.05
II-24 4.52±0.04 II-54 5.21±0.04
II-25 4.79±0.05 II-55 4.01±0.03
II-26 4.19±0.04 II-56 4.26±0.05
II-27 4.31±0.04 II-57 4.21±0.03
II-28 3.99±0.03 II-58 4.17±0.04
II-29 6.01±0.02 II-59 4.53±0.05
II-30 5.52±0.03 II-60 4.05±0.04
6.2 Compound I I-1 to II-60 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, and every 20min changes K-H liquid one time, and balance 60min, after baseline restorer is steady, changes K-H liquid in bath pipe into high potassium liquid induction and shrinks.When after once shrink maximum reaction with front when once basically identical, accumulation adds the Compound I I-1-II-60 solution (1 × 10 preparing -8-1 × 10 -3mol/L), wave recording.Take the diastole percentage ratio of Compound I I-1-II-60 as ordinate zou, maximum stretching reaction is 100% to make effect curve.Wherein the diastole effect of II-2, II-3 is the most obvious, and the negative logarithm of its each concentration is that X-coordinate drafting amount effect curve is shown in Fig. 2 and Fig. 9.
From Fig. 2 and 9, the sample that Compound I I-2 and II-3 cause high potassium liquid shrinks obvious diastole effect, and it presents certain dose-dependently to adrenergic diastole effect, shrink-logEC of the Rabbit Aorta that the high potassium liquid of Compound I I-2 diastole causes 50value is 5.34 ± 0.02, shrink-logEC of the Rabbit Aorta that the high potassium liquid of Compound I I-3 diastole causes 50value is 5.49 ± 0.05.Wherein Compound I I-31 shows obvious diastole effect, and the negative logarithm of its each concentration is that X-coordinate is drawn amount effect curve, sees Figure 11; Wherein II-29 also has obvious diastole effect, and its amount effect curve is shown in Figure 16.As can be seen from Figure 11, Compound I I-31 causes to high potassium liquid sample that convulsion agent causes and shrinks and have diastole effect, and 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 I I-31 diastole causes 50value is 5.55 ± 0.03; Similarly, Compound I I-29 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.
Compound I I-1 to II-60 causes 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 I I-1-II-60 shrinks the diastole effect of rabbit myocardium vessel unstriated muscle to High potassium solution
Compound -logEC 50 Compound -logEC 50
II-1 5.05±0.03 II-31 5.55±0.03
II-2 5.34±0.02 II-32 4.61±0.03
II-3 5.49±0.05 II-33 3.94±0.04
II-4 4.79±0.05 II-34 4.77±0.02
II-5 4.53±0.03 II-35 4.49±0.05
II-6 4.41±0.04 II-36 5.31±0.04
II-7 3.79±0.03 II-37 5.43±0.03
II-8 4.41±0.05 II-38 5.33±0.04
II-9 4.28±0.03 II-39 5.22±0.04
II-10 3.96±0.05 II-40 5.29±0.04
II-11 3.85±0.04 II-41 4.61±0.05
II-12 4.15±0.06 II-42 3.93±0.04
II-13 4.52±0.05 II-43 3.85±0.04
II-14 4.05±0.04 II-44 3.73±0.03
II-15 4.52±0.05 II-45 4.09±0.03
II-16 4.19±0.03 II-46 3.92±0.02
[0638]
II-17 4.31±0.04 II-47 3.54±0.03
II-18 4.74±0.06 II-48 3.43±0.04
II-19 4.06±0.03 II-49 3.85±0.03
II-20 3.93±0.02 II-50 3.79±0.04
II-21 3.75±0.03 II-51 4.46±0.03
II-22 4.64±0.04 II-52 4.58±0.04
II-23 4.42±0.05 II-53 3.88±0.02
II-24 4.52±0.04 II-54 4.91±0.04
II-25 4.53±0.03 II-55 3.71±0.03
II-26 3.99±0.05 II-56 3.51±0.02
II-27 4.06±0.04 II-57 3.58±0.02
II-28 3.85±0.04 II-58 3.75±0.04
II-29 5.64±0.01 II-59 4.21±0.03
II-30 5.13±0.03 II-60 3.81±0.02
Embodiment 64
The diastole study on mechanism of Compound I I-2 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 I I-2 adopts embodiment 2 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 (NaCl): be purchased from Zhiying Pharmaceutical Factory, Shenyang, lot number: 12021001;
Adrenalin hydrochloride injection liquid (Epinephrine Hydrochloride Injection) specification: 1mg/1ml, is purchased from long-range medicine (China) company limited, lot number 120105;
Noradrenaline bitartrate (Norepinephrine Bitartrate Injection) specification 2mg/1ml, long-range medicine (China) company limited, 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 long-range medicine (China) company limited, 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: NaCl 6.92 (concentration units), KCl0.35, MgSO 40.29, KH 2pO 40.16, CaCl 20.28, NaHCO 32.1, glucose 2.0 (g/L), pH 7.2.
High potassium solution: will add KCl to be mixed with the improvement K-H liquid containing K+60mmol/L after the NaCl of the mole numbers such as removal in K-H liquid.
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 I I-2 solution: take-Ding the sample of quality compound II-2, take 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 ℃ 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, every 20min changes one time of nutrition liquid, and balance 2 hours starts experiment after baseline stability.
6 experimental implementation and test-results
The antagonistic action of 6.1 Compound I I-2 to rabbit vascular smooth muscle α receptor stimulant
6.1.1 the Compound I I-2 impact that amount effect curve is shunk in accumulation on norepinephrine
After sample tension stability, record one section of waveform, add norepinephrine (NA) (10 to bathing accumulation in pipe -8-10 -4mol/L) until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, after balance 1h, add Compound I I-2 (3 × 10 -7mol/L), after 20min, add NA with same method again.Take 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 I I-2 (3 × 10 -7mol/L) after, as shown in Figure 3.
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 check, and most P value < 0.01, exist significant difference.Compound I I-2 antagonism NA shrinks the PA of Rabbit Aorta 2value is 7.37 ± 0.08;
6.1.2 the positive control drug Doxazosin impact that amount effect curve is shunk in accumulation on norepinephrine
After sample tension stability, record one section of waveform, add norepinephrine (NA) (10 to bathing in pipe -8-10 -4mol/L) (10 -8-3 × 10 -3mol/L) until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, every 20min changes K-H liquid one time, and balance 60min, after baseline restorer is steady, adds Doxazosin (10 -7mol/L), after 15min, add norepinephrine (NA) (10 with same method again -8-6 × 10 -5mol/L).Take 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 Doxazosin (10 -7mol/L) after, as shown in Figure 4, 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 statistical test, and most P value < 0.01, exist significant difference.Positive drug Doxazosin antagonism NA shrinks the PA of Rabbit Aorta 2value is 7.52 ± 0.04.
Learn by statistics t check, Compound I I-2 and the PA of positive control drug Doxazosin to NA 2between value, compare, P > 0.05, there was no significant difference between the two, illustrates that antagonistic action and the Doxazosin of Compound I I-2 to α receptor stimulant is close.
6.2 Compound I I-2 are to rabbit vascular smooth muscle calcium channel (Ca 2+) antagonistic action
6.2.1 Compound I I-2 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 40min, add without the high potassium liquid of calcium and make sample depolarize 20min, then add CaCl to bathing accumulation in pipe 2(10 -6-10 -2mol/L), until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, every 20min changes K-H liquid one time, balance 60min, 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 40min, add without the high potassium liquid of calcium and make sample depolarize 20min, add Compound I I-2 (3 × 10 to bathing in pipe simultaneously -6mol/L), hatch after 20min and add CaCl with same method accumulation again 2(10 -6-10 -2mol/L), until reach maximum reaction, wave recording.Take 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 I I-2 (3 × 10 -6mol/L) after, as shown in Figure 5, 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 I I-2 antagonism CaCl 2shrink the PA of Rabbit Aorta 2value is 5.61 ± 0.04.
6.2.2 positive control drug amlodipine is to CaCl 2the impact of amount effect 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 40min, add without the high potassium liquid of calcium and make sample depolarize 20min, then add CaCl to bathing accumulation in pipe 2(10 -6-10 -2mol/L), until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, every 20min changes K-H liquid one time, balance 60min, 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 40min, add without the high potassium liquid of calcium and make sample depolarize 20min, add amlodipine (10 to bathing in pipe simultaneously -7mol/L), hatch after 15min and add CaCl with same method accumulation again 2(10 -6-10 -2mol/L), until reach maximum reaction, wave recording.Take 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 (3 × 10 -6mol/L) after, as shown in Figure 6, 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 6.99 ± 0.05.
The antagonistic action of 6.3 Compound I I-2 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 -7-3 × 10 -4mol/L) until reach maximum reaction, wave recording.Then repeatedly rinse sample with K-H liquid, after balance 1.5h, add Compound I I-2 (3 × 10 -6mol/L), after 20min, add 5-HT with same method again.Take 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 I I-2 (3 × 10 -6mol/L) after, as shown in Figure 7,5-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 I I-2 antagonism 5-HT shrinks the PA of Rabbit Aorta 2value 5.71 ± 0.08.
Embodiment 65
The diastole study on mechanism of Compound I I-31 to rabbit myocardium vessel unstriated muscle
The antagonistic action of 1.1 Compound I I-31 to rabbit vascular smooth muscle α receptor stimulant
1.1.1 the Compound I I-31 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 I I-31 (3 × 10 -6mol/L), after 20min, add NA (3 × 10 with same method again -7-3 × 10 -4mol/L).Take 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 I I-31 (3 × 10 -6mol/L) after, as shown in figure 10, 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 check, and most P value < 0.01, exist significant difference.Compound I I-31 antagonism NA shrinks the PA of Rabbit Aorta 2value is 6.02 ± 0.13.
1.1.2 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 15min, add NA with same method again.Take 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 shown in figure 12, 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 check, and most P value < 0.01, exist significant difference.Medicine Doxazosin antagonism NA shrinks the PA of Rabbit Aorta 2value is 7.76 ± 0.24.
Learn by statistics t check, Compound I I-31 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 I I-31 to the antagonistic action of α receptor stimulant than Doxazosin a little less than.
1.2 Compound I I-31 are to rabbit vascular smooth muscle calcium channel (Ca 2+) antagonistic action
1.2.1 Compound I I-31 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 40min, add without the high potassium liquid of calcium and make sample depolarize 20min, 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, every 20min changes K-H liquid one time, balance 60min, 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 40min, add without the high potassium liquid of calcium and make sample depolarize 20min, add Compound I I-31 (10 to bathing in pipe simultaneously -5mol/L), hatch after 20min and add CaCl with same method accumulation again 2(10 -5-3 × 10 -1mol/L), until reach maximum reaction, wave recording.Take 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 I I-31 (10 -5mol/L) after, as shown in figure 13, 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 I I-31 antagonism CaCl 2shrink the PA of Rabbit Aorta 2value is 6.56 ± 0.032.
1.2.2. 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, every 20min changes K-H liquid one time, balance 60min, 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 40min, add without the high potassium liquid of calcium and make sample depolarize 20min, add amlodipine (10 to bathing in pipe simultaneously -7mol/L), hatch after 15min and add CaCl with same method accumulation again 2(10 -5-3 × 10 -2mol/L), until reach maximum reaction, wave recording.Take 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 -5mol/L) after, as shown in figure 13, 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 7.51 ± 0.288.
The antagonistic action of 1.3 Compound I I-31 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 I I-31 (3 × 10 -6mol/L), after 20min, add 5-HT with same method again.Take 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 I I-31 (3 × 10 -6mol/L) after, as shown in figure 14,5-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 I I-31 antagonism 5-HT shrinks the PA of Rabbit Aorta 2value 6.726 ± 0.089.
Embodiment 66
The acute toxicity test of Compound I I-2
Kunming mouse (being provided by Chinese Medical Sciences University's experimental animal center) is provided, male and female half and half, body weight 18-22g, carries out Compound I I-2 and simplifies probit method acute toxicity test, gastric infusion LD 50for 361.88mg/kg (95% fiducial limit interval is 302.96-420.80mg/kg).
Embodiment 67
The Teratogenic effects of the mouse of Compound I I-2
10 of Kunming mouses (being provided by Chinese Medical Sciences University's experimental animal center) are provided, and male and female half and half, by 120mg/kg/ days body weight gastric infusion Compound I I-2.Continue medication 4 days, within the 5th day, carry out Micronuclei In The Mouse Bone Marrow test.
Positive controls, gives endoxan 60mg/kg/ days; Negative control group, gives physiological saline 0.1ml/10g/ days.Continue medication 4 days, within the 5th day, carry out Micronuclei In The Mouse Bone Marrow test.
Disconnected mouse neck is put to death, separate rapidly femur and breastbone, remove blood stains and muscle, deduct epiphysis, breastbone with mosquito forceps, marrow is squeezed on dripping in advance the clean slide glass that has calf serum or with calf serum directly by the marrow punching in femur to clean slide glass, mix rear push jack; Put by pushing away the marrow sheet drying the staining jar that fills methyl alcohol into subsequently, fixing 15min, taking-up is dried, after marrow sheet dries, with freshly prepared Giemsa application liquid (Giemsa storing solution portion adds 9 parts of the phosphate buffered saline buffers of pH 6.8), dyeing 10min, thread water washes out slide staining fluid, after drying, examines under a microscope.
Experimental result shows: the polychromatic erythrocyte that contains micronucleus in 1000 polychromatic erythrocytes of Compound I I-2 group accounts for 2.0 ± 0.333 ‰, the polychromatic erythrocyte that contains micronucleus in 1000 polychromatic erythrocytes of blank group accounts for 1 ‰, and the polychromatic erythrocyte that contains micronucleus in 1000 polychromatic erythrocytes of endoxan group accounts for 12 ‰.The bone marrow micronucleus test result that shows Compound I I-2 is negative.
Embodiment 68
The impact of Compound I I-2 on SD rat blood pressure
Through urethane (1.25mg/kg) anesthesia, after rat vital sign is steady, adopt arteria carotis communis intubation procedure to measure blood pressure 4 SD rats.Until blood pressure steadily after, compound (II-2) is pressed to 4.0mg/kg body weight gastric infusion, observe and record blood pressure temporal evolution situation after administration,
Experimental result is in table 3, table 4 and table 5 data.
The impact (n=4) of table 3 Compound I I-2 to urethane anesthetized rat diastolic pressure (DBP, mmHg)
Figure BDA00002469067800691
Note: * represents P value < 0.05, and * * represents P value < 0.01
The impact (n=4) of the systolic pressure (SBP, mmHg) of table 4 Compound I I-2 to urethane anesthetized rat
Figure BDA00002469067800692
Figure BDA00002469067800701
Note: * represents P value < 0.05, and * * represents P value < 0.01
The impact (n=4) of the mean arterial pressure (MAP, mmHg) of table 5 Compound I I-2 to urethane anesthetized rat
Note: * represents P value < 0.05, and * * represents P value < 0.01
Experimental result shows: Compound I I-2 has obvious hypotensive effect to urethane (1.25mg/kg) anesthesia SD rat, and administration can return to the front level of administration after 3.5 hours.
Comprehensive the above results shows: in vitro animal experiment, Compound I I-2 has significant to relax the VSM effect.Antagonistic action and the Doxazosin of Compound I I-2 to α-adrenoceptor is suitable, the PA of its antagonism norepinephrine NA 2value is 7.37 ± 0.08, the PA of Doxazosin antagonism NA 2value is 7.52 ± 0.04, Compound I I-2 antagonism CaCl 2pA 2value is 5.61 ± 0.04, the PA of its antagonism 5-HT 2value is 5.71 ± 0.08.In rat body, in bulk testing, Compound I I-2 shows obvious hypotensive effect, and its oral absorption is good, toxicity is little, and therapeutic index is large, and Teratogenic effects is negative, there is as novel many target spots vasodilator drug the potential value of especially developing as Novel blood pressure-reducing medicine.
Reference
1.[internal medicine] Ye Rengao Lu Zaiying chief editor, people's health is published, April in 2007 the 6th edition.
2.[pharmacology] Li Duan chief editor, people's health is published, August in 2007 the 6th edition.
3.Sanders-Bush E，MayerSE.5-Hydroxytryptamine(serotonin)：Receptor agonists and antagonists.
In：Brunton LL.Lazo JS，Parker KL(eds).Goodman & Gilman’sThe Pharmacological Basis of Therapeutics(11th ed)，Philadelphia：The McGraw-Hill Companies，2006：158
4.Hoyer D，Clarke DE，Fozard JR，et al.Pharmacol Rev，1994，46(2)：158
5.Martin GR.5-Hydroxytryptamine receptors.In：The IUPHARCommittee on Receptor Nomenclature and Drug Classification(ed)，The IUPHAR Compendium of Receptor Characterization and Classification-，London：IUPHAR Media，1998：p167。

Claims (10)

1. formula (I) compound or its pharmacy acceptable salt are in the purposes of preparing in vasodilator drug:
Figure FDA00002469067700011
Wherein:
R 1representative is by R 3monosubstituted or polysubstituted aromatic group or aliphatics cyclic group, wherein
R 3for H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Work as R 3during for polysubstituted group, R 3independently selected from H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
A, B independently represent respectively CH or N;
R 2represent H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Work as R 2during for polysubstituted group, R 2independently selected from H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms;
Saturated or the undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom that Y representative is optionally replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes.
2. the purposes of claim 1, wherein said pharmacy acceptable salt is hydrochloride, hydrogen bromide salt, vitriol, trifluoroacetate, mesylate, tartrate, malate, succinate, maleate, Citrate trianion, phosphoric acid salt, lactic acid salt, pyruvate salt, acetate, fumarate, oxaloacetate, esilate, oxalate, benzene sulfonate or isethionate; Preferably, described salt contains crystal water, is preferably the crystal water of 0.5-3 molecule.
3. the purposes of claim 1, wherein said aromatic group is selected from benzo five-membered heterocycle or the hexa-member heterocycle of N, S, O or five yuan or hexa-atomic unsaturated heterocycle for phenyl, naphthyl, heteroatoms; Be preferably phenyl, naphthyl, benzothiazolyl, benzisothiazole base, benzoxazolyl, benzoisoxazole base, benzimidazolyl-, benzopyrazoles base, benzofuryl, benzo pyrimidyl, benzo pyridyl, quinoxalinyl, furyl, pyridyl or pyrimidyl; More preferably phenyl, benzoisoxazole base, benzisothiazole base, benzopyrazoles base, benzofuryl, naphthyl, furyl, pyridyl, pyrimidyl Huo quinoxalinyl; Be particularly preferably phenyl, benzoisoxazole base, benzisothiazole base, benzofuryl, quinoxalinyl or pyrimidyl; Most preferably be phenyl;
Described aliphatics cyclic group is preferably five yuan or hexa-atomic saturated cyclic, or heteroatoms is selected from five yuan or the hexa-atomic saturated heterocyclyl of N, S, O; More preferably cyclopentyl, cyclohexyl, tetrahydrofuran base, piperidyl or piperazinyl; More preferably cyclohexyl, piperidyl or piperazinyl again; Be particularly preferably cyclohexyl.
4. the purposes of claim 1, wherein R 3for H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Preferably, R 3for H, F, Cl, Br, CN, moieties are optionally by the C of 1-3 halogen atom replacement 1-C 6alkyl or C 1-C 6alkoxyl group, CHO, COCH 3or COOCH 3; More preferably, R 3for H, F, Cl, COCH 3, the C that optionally replaced by 1-3 halogen atom of moieties 1-C 4alkyl or C 1-C 4alkoxyl group; Again more preferably, R 3for H, F, Cl, CN, CF 3, CH 3or OCH 3; Most preferably be R 3for H, F, Cl or OCH 3; Work as R 3during for polysubstituted group, R 3independently selected from the above group.
5. the purposes of claim 1, wherein R 2for H, halogen, CN, C 1-C 6alkyl, C 1-C 6alkoxyl group, CHO, CO (C 1-C 6alkyl), COO (C 1-C 6alkyl), NO 2, NH 2, NH (C 1-C 6alkyl), SH, S (C 1-C 6alkyl) ,-SO (C 1-C 6alkyl) or-SO 2(C 1-C 6alkyl), in above-mentioned group, moieties is optionally replaced by one or more halogen atoms; Preferably, R 2for H, F, Cl, Br, CN, NO 2, the C that optionally replaced by 1-3 halogen atom of moieties 1-C 6alkyl or C 1-C 6alkoxyl group, CHO, COCH 3or COOCH 3; More preferably, R 2for H, F, Cl, CN, CHO, COCH 3, COOCH 3or the C that moieties is optionally replaced by 1-3 halogen atom 1-C 4alkyl or C 1-C 4alkoxyl group; Again more preferably, R 2for H, F, Cl, CN, CH 3or COOCH 3; Particularly preferably, R 2for H, F, Cl or CH 3; Most preferably, R 2for H; Work as R 2during for polysubstituted group, R 2independently selected from the above group.
6. the purposes of claim 1, wherein Y is the saturated or undersaturated straight or branched hydrocarbyl chain that contains 2-8 carbon atom optionally being replaced by 1-3 halogen atom, the heteroatoms that wherein one or more carbon are optionally selected from oxygen, sulphur and nitrogen substitutes; Preferably, Y is the unsubstituted saturated hydrocarbyl containing 2-8 carbon, or wherein 1 carbon atom for example, by oxygen or the alternative unsubstituted saturated hydrocarbyl containing 2-8 carbon of sulphur ,-C 1-7alkyl-O-; Preferably Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, oxygen methylene, oxygen base ethylidene, oxygen base propylidene, oxygen base butylidene, oxygen base pentylidene, oxygen base hexylidene, the sub-heptyl of oxygen base, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; More preferably, Y is methylene radical, ethylidene, propylidene, butylidene, pentylidene, hexylidene, sub-heptyl, octylene, methylene radical oxygen base, ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, hexylidene oxygen base or sub-heptyl oxygen base; Again more preferably, Y is propylidene, butylidene, propylidene oxygen base or pentylidene; Particularly preferably, Y is propylidene, butylidene or propylidene oxygen base; Most preferably, Y is butylidene.
7. the purposes of claim 1, wherein
In the time that A, B are N,
R 1be not by H or OCH 3mono-substituted phenyl, and
R 2be not H or OCH 3, wherein OCH 3two replacement on described benzo five-membered nitrogen heterocyclic; And
Y is not ethylidene, propylidene, butylidene or pentylidene.
8. the purposes of claim 1, wherein
R 1representative is by R 3monosubstituted or disubstituted aromatic group, wherein
Described aromatic group is preferably phenyl or benzisothiazole base;
R 3for H, Cl or CF 3; Work as R 3during for polysubstituted group, R 3independently selected from the above group;
A, B independently represent respectively CH or N;
R 2represent H;
Y represents butylidene.
9. the purposes of claim 1, wherein said compound comprises:
I-1 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-2 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-3 1-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-4 1-(4-(4-(2-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-5 2-methyl isophthalic acid-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The fluoro-1-of I-6 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-7 1-(3-(4-phenylpiperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-8 1-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-9 2-methyl isophthalic acid-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-10 1-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-11 1-(4-(4-(4-aminomethyl phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-12 1-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-13 1-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-14 1-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-15 1-(4-(4-(1-cyclohexyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-16 1-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-17 1-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-18 1-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-19 1-(4-(4-(3-(6-fluorobenzene isothiazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-20 1-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-21 1-(4-(4-(3-(6-fluorine benzofuryl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-22 1-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-23 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
I-24 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
The chloro-1-of I-25 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-26 6-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-27 6-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The chloro-1-of I-28 2-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzoglyoxaline,
I-29 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-30 1-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-31 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
The fluoro-1-of I-32 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-33 5,6-dimethyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-34 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
I-35 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-36 6-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-37 6-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole,
I-38 1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-39 1-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-40 1-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-41 1-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-42 1-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzotriazole,
I-43 1-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-44 1-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-45 1-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-46 1-(4-(4-cyclohexyl piperazine-1-yl) butyl)-1H-benzotriazole,
I-47 1-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-48 1-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-49 1-(4-(4-(3-(the fluoro-benzisothiazole base of 6-)) piperazine-1-yl) butyl)-1H-benzotriazole,
I-50 1-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzotriazole,
I-51 1-(3-(4-(3-(the fluoro-benzofuryl of 6-) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-52 1-(4-(4-(3-(the fluoro-benzoisoxazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The fluoro-1-of I-53 6-(4-(4-(3-(the fluoro-benzisothiazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The chloro-1-of I-54 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-55 6-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-56 6-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-57 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-indoles,
I-58 6-cyano group-1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-indoles,
I-59 1-(3-(4-(3-trifluoromethyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles,
I-60 6-cyano group-1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles,
I-61 1-[4-(4-(4-fluorine) phenyl) piperazine] butyl-1H-indoles,
I-62 1-[4-cyclohexyl piperazine] butyl-1H-indoles,
I-63 1-[4-(4-(4-fluorine) phenyl) piperazine] butyl-5-ethanoyl-1H-indoles,
I-64 1-[4-cyclohexyl piperazine] butyl-5-ethanoyl-1H-indoles,
I-65 1-[3-(4-(2,4-difluoro) phenyl) piperazine] butyl-5-ethanoyl-1H-indoles,
I-66 1-[3-(4-(4-methyl) phenyl) piperazine] propyl group-1H-indoles,
I-67 1-[4-(4-(4-chlorine) phenyl) piperazine] butyl-1H-indoles,
I-68 1-[4-(4-(2-methyl) phenyl) piperazine] butyl-1H-indoles,
I-69 1-[4-(4-(3-trifluoromethyl) phenyl) piperazine] butyl-1H-indoles,
I-70 1-[3-(4-(4-methyl) phenyl) piperazine] propyl group-5-methoxyl group-1H-indoles,
I-71 1-[4-(4-(4-trifluoromethoxy) phenyl) piperazine] butyl-5-methoxyl group-1H-indoles,
I-72 1-[4-(4-(3-trifluoromethyl) phenyl) piperazine] butyl-5-methoxyl group-1H-indoles,
I-73 1-[3-(4-(2-methyl) phenyl) piperazine] butyl-5-methoxyl group-1H-indoles,
I-74 1-[3-(4-(2,4-difluoro) phenyl) piperazine] propyl group-5-nitro-1H-indoles,
I-75 1-[4-(4-(4-chlorine) phenyl) piperazine] butyl-5-nitro-1H-indoles,
I-76 1-[4-(4-(3-trifluoromethyl) phenyl) piperazine] butyl-5-nitro-1H-indoles,
I-77 1-[4-(4-(2-methoxyl group) phenyl) piperazine] butyl-5-nitro-1H-indoles,
I-78 1-[4-(4-(2-methoxyl group) phenyl) piperazine] the chloro-1H-indoles of butyl-5-,
I-79 1-[4-(4-(3-trifluoromethyl) phenyl) piperazine] the chloro-1H-indoles of butyl-5-,
I-80 1-[4-(4-(2,4-difluoro) phenyl) piperazine] the chloro-1H-indoles of butyl-5-,
I-81 1-[2-(4-(2,4-, bis-trifluoromethoxies) phenyl) piperazine] the chloro-1H-indoles of ethyl-5-,
I-82 1-[2-(4-(2,4-dimethoxy) phenyl) piperazine] ethyl-6-nitro-1H-indoles,
I-83 1-[2-(4-(2,4-dichloro) phenyl) piperazine] ethyl-6-methoxyl group-1H-indoles;
Preferably,
I-1 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-2 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-3 1-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-4 1-(4-(4-(2-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-5 2-methyl isophthalic acid-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The fluoro-1-of I-6 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-7 1-(3-(4-phenylpiperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-8 1-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-9 2-methyl isophthalic acid-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-10 1-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-11 1-(4-(4-(4-aminomethyl phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-12 1-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-13 1-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-14 1-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-15 1-(4-(4-(1-cyclohexyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-16 1-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-17 1-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-18 1-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-19 1-(4-(4-(3-(6-fluorobenzene isothiazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-20 1-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-21 1-(4-(4-(3-(6-fluorine benzofuryl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-22 1-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-23 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
I-24 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
The chloro-1-of I-25 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-26 6-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-27 6-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The chloro-1-of I-28 2-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzoglyoxaline,
I-29 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-30 1-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-31 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
The fluoro-1-of I-32 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-33 5,6-dimethyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-34 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
I-35 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-36 6-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-37 6-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole,
I-38 1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-39 1-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-40 1-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-41 1-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-42 1-(5-(4-(3-trifluoromethyl) piperazine-1-yl) amyl group)-1H-benzotriazole,
I-43 1-(4-(4-(2-furyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-44 1-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-45 1-(4-(4-(2-pyrimidyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-46 1-(4-(4-cyclohexyl piperazine-1-yl) butyl)-1H-benzotriazole,
I-47 1-(4-(4-(1-naphthyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-48 1-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-49 1-(4-(4-(3-(the fluoro-benzisothiazole base of 6-)) piperazine-1-yl) butyl)-1H-benzotriazole,
I-50 1-(4-(4-(3-benzopyrazoles base) piperazine-1-yl) butyl)-1H-benzotriazole,
I-51 1-(3-(4-(3-(the fluoro-benzofuryl of 6-) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-52 1-(4-(4-(3-(the fluoro-benzoisoxazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The fluoro-1-of I-53 6-(4-(4-(3-(the fluoro-benzisothiazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The chloro-1-of I-54 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-55 6-cyano group-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-56 6-methoxycarbonyl-1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-57 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-indoles,
I-58 6-cyano group-1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-indoles,
I-59 1-(3-(4-(3-trifluoromethyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles,
I-60 6-cyano group-1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles.
More preferably,
I-1 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-2 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-3 1-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-4 1-(4-(4-(2-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-5 2-methyl isophthalic acid-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
The fluoro-1-of I-6 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-8 1-(3-(4-(3-fluorophenyl) piperazine-1-yl) propyl group)-1H-benzoglyoxaline,
I-13 1-(4-(4-(4-pyridyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-15 1-(4-(4-(1-cyclohexyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-17 1-(4-(4-(2-quinoxalinyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-18 1-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-22 1-(4-(4-(3-(6-fluorobenzene Bing isoxazolyl)) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-23 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
I-24 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) propoxy-)-1H-benzoglyoxaline,
The chloro-1-of I-25 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-29 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-30 1-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-31 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
The fluoro-1-of I-32 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-34 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
I-35 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-36 6-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-37 6-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole,
I-38 1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-39 1-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-40 1-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-41 1-(4-(4-(3-cyano-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-51 1-(3-(4-(3-(the fluoro-benzofuryl of 6-) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-52 1-(4-(4-(3-(the fluoro-benzoisoxazole base of 6-) piperazine-1-yl) propoxy-)-1H-benzotriazole,
The chloro-1-of I-54 6-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-59 1-(3-(4-(3-trifluoromethyl) piperazine-1-yl) propyl group)-1H-benzopyrazoles;
Particularly preferably,
I-1 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-2 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-3 1-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-29 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-30 1-(4-(4-(3-fluorophenyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-31 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-34 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
The fluoro-3-of I-36 6-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzoisoxazole,
The fluoro-3-of I-37 6-(4-(3-(1H-benzotriazole-1-yl) propyl group) piperazine-1-yl) benzoisoxazole,
I-38 1-(3-(4-(2,3-dichlorophenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-39 1-(3-(4-(3-aminomethyl phenyl) piperazine-1-yl) propyl group)-1H-benzotriazole,
I-40 1-(4-(4-(3-p-methoxy-phenyl) piperazine-1-yl) butyl)-1H-benzotriazole;
Most preferably,
I-3 1-(4-(4-(2,3-dichlorophenyl) piperazine-1-yl) butyl)-1H-benzoglyoxaline,
I-29 1-(4-(4-(3-chloro-phenyl-) piperazine-1-yl) butyl)-1H-benzotriazole,
I-31 1-(4-(4-(3-trifluoromethyl) piperazine-1-yl) butyl)-1H-benzotriazole,
I-34 3-(4-(4-(1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole.
10. the purposes of claim 1, wherein said formula (I) compound or its pharmacy acceptable salt, optional and one or more pharmaceutically acceptable vehicle, and optionally together with other resisting vascular smooth muscle spasm active ingredients, in the purposes of preparing in vasodilator drug, preferably in preparation prevention, purposes in the disease that alleviation or treatment experimenter are relevant to the contraction of continuous vessel pathologic or vasospasm or the medicine of illness, more preferably in preparation treatment hypertension, in heart failure, stenocardia, coronary heart disease, the cerebral ischemia diseases being caused by vasospasm, myocardial ischemia disease, shock, renal ischaemia, purposes in the poor kidney being caused by kidney vasospasm and the medicine of periperal vascular spasm, more preferably there is α receptor antagonist (particularly selectivity α in preparation one 1receptor antagonist), Ca 2+carrier frequency channel break, 5-HT 2Athe purposes of the medicine of receptor antagonist triple role.
CN201210486967.6A 2012-11-26 2012-11-26 Application of benzo five-membered nitrogen-containing heterocycle-based piperazine derivative Pending CN103833642A (en)

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