CN106420754A - Use of benzo five-membered nitrogen-containing heterocyclic piperazine derivative - Google Patents

Use of benzo five-membered nitrogen-containing heterocyclic piperazine derivative Download PDF

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CN106420754A
CN106420754A CN201610828410.4A CN201610828410A CN106420754A CN 106420754 A CN106420754 A CN 106420754A CN 201610828410 A CN201610828410 A CN 201610828410A CN 106420754 A CN106420754 A CN 106420754A
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butyl
piperazin
benzimidazole
benzotriazole
piperazine
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CN106420754B (en
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周延
张丽荣
周杰
周欣
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Original Pharmaceutical Port Life Science Research Liaoning Co ltd
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Liaoning Emmy Biopharmaceutical Industry Co Ltd
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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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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Abstract

The invention relates to use of a benzo five-membered nitrogen-containing heterocyclic piperazine derivative represented by formula (1) in vasodilatation drug preparation. In the formula (I), R1, R2, Y, A, and B are defined in the description.

Description

Use of benzo five-membered azaheterocyclyl piperazine derivatives
The application is a divisional application of Chinese patent application with the application number of 201210486967.6 and the invention name of 'application of benzo five-membered azacyclo piperazine derivative' filed on 26.11.2012.
Technical Field
The invention relates to an application of benzo five-membered nitrogen heterocyclic piperazine derivatives in preparing vasodilation medicines.
Background
There are currently clinically available classes of vasodilating drugs, e.g., α1Receptor blocker drugs, including prazosin, doxazosin, terazosin and the like, have obvious first dose effect or orthostatic hypotension, thereby limiting the wide application of the drugs in clinic; ca2+The channel blocker comprises the existing drugs of amlodipine, nifedipine, felodipine and the like, and the drugs are widely applied clinically at present, but the drugs also have the risk of inhibiting the heart.
Therefore, there is still a need to develop new vasodilating drugs to improve the efficacy, reduce drug resistance or minimize toxic side effects to meet the needs of different patients in clinical practice.
Disclosure of Invention
The present invention provides the use of a compound of formula (I) and pharmaceutically acceptable salts thereof in the preparation of a vasodilator medicament:
wherein:
R1is represented by R3A mono-or poly-substituted aromatic or aliphatic cyclic group, wherein
R3Is H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; when R is3When it is a polysubstituent group, R3Independently selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms;
A. b independently represents CH or N;
R2represents H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; when R is2When it is a polysubstituent group, R2Independently selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl group) of the aboveThe alkyl moiety of the group is optionally substituted with one or more halogen atoms;
y represents a saturated or unsaturated, linear or branched, hydrocarbyl chain containing 2 to 8 carbon atoms, optionally substituted with 1 to 3 halogen atoms, in which one or more carbons are optionally replaced by heteroatoms selected from oxygen, sulphur and nitrogen.
Description of the drawings:
FIG. 1 shows Compound II-2 (10)-8-10-4mol·L-1) For adrenalin (10)-5mol·L-1) Cumulative concentration response curve for isolated vasodilation of rabbit.
FIG. 2 shows Compound II-2 (10)-8-10-4mol·L-1) For high potassium solution (60 mmol. L)-1) Cumulative concentration response curve for isolated vasodilation of rabbit.
FIG. 3 shows Compound II-2(3 × 10)-7mol/L) antagonizes noradrenaline NA (10)-8-10-4mol/L) cumulative concentration response curve of isolated blood vessel of rabbit.
FIG. 4 is a positive control doxazosin (10)-7mol/L) antagonizes noradrenaline NA (10)-8-6×10-5mol/L) cumulative concentration response curve of isolated blood vessel of rabbit.
FIG. 5 shows Compound II-2 (10)-6mol/L) antagonism of CaCl2(10-6-10-2mol/L) cumulative concentration response curve of isolated blood vessel of rabbit.
FIG. 6 is amlodipine (10)-7mol/L) antagonism of CaCl2(10-6-10-2mol/L) cumulative concentration response curve of isolated blood vessel of rabbit.
FIG. 7 shows Compound II-2(3 × 10)-6mol/L) antagonism of 5-hydroxytryptamine (10)-7-3×10-4mol/L) cumulative concentration response curve of isolated blood vessel of rabbit.
FIG. 8 shows Compound II-3 (10)-8-3×10-5mol·L-1) For adrenalin (10)-5mol·L-1) Cumulative concentration response curve for isolated vasodilation of rabbit.
FIG. 9 shows Compound II-3 (10)-8-3×10-5mol·L-1) For high potassium solution (60 mmol. L)-1) Cumulative concentration response curve for isolated vasodilation of rabbit.
FIG. 10 shows Compound II-31 (10)-8-10-5mol·L-1) For epinephrine AD (10)-5mol·L-1) Cumulative concentration response curve for isolated vasodilation of rabbit.
FIG. 11 shows Compound II-31(3 × 10)-7-3×10-5mol·L-1) For high potassium solution (60 mmol. L)-1) Cumulative concentration response curve for isolated vasodilation of rabbit.
FIG. 12 shows Compound II-31(3 × 10)-6mol/L), positive control doxazosin (10)-7mol/L) antagonizes noradrenaline NA (3 × 10)-7-10-4mol/L) cumulative concentration response curve of isolated blood vessel of rabbit.
FIG. 13 shows Compound II-31 (10)-5mol/L), amlodipine (10)-7mol/L) antagonism of CaCl2(10-5-3×10- 1mol/L) cumulative concentration response curve of isolated blood vessel of rabbit.
FIG. 14 shows Compound II-31(3 × 10)-6mol/L) antagonism of 5-hydroxytryptamine (10)-8-3×10-4mol/L) cumulative concentration response curve of isolated blood vessel of rabbit.
FIG. 15 is Compound II-29 (10)-8-3×10-5mol·L-1) For epinephrine AD (10)-5mol·L-1) Cumulative concentration response curve for isolated vasodilation of rabbit.
FIG. 16 is Compound II-29 (10)-7-3×10-5mol·L-1) For high potassium solution (60 mmol. L)-1) Cumulative concentration response curve for isolated vasodilation of rabbit.
Detailed Description
The present invention provides the use of a compound of formula (I) and pharmaceutically acceptable salts thereof in the preparation of a vasodilator medicament:
wherein:
R1is represented by R3A mono-or poly-substituted aromatic or aliphatic cyclic group, wherein
R3Is H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; when R is3When it is a polysubstituent group, R3Independently selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms;
A. b independently represents CH or N;
R2represents H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; when R is2When it is a polysubstituent group, R2Independently selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms;
y represents a saturated or unsaturated, linear or branched, hydrocarbyl chain containing 2 to 8 carbon atoms, optionally substituted with 1 to 3 halogen atoms, in which one or more carbons are optionally replaced by heteroatoms selected from oxygen, sulphur and nitrogen.
Preferably, R in formula (I) according to the invention2Is a mono-or polysubstituent group on the benzo five-membered nitrogen heterocycle, e.g. R2Is a mono-substituted, di-substituted, tri-substituted group, etc.; r2Is a radical attached to any carbon atom of a benzo-penta-nitrogen heterocycle, e.g. when A (or B) is a C atom, then R2Or may be connected thereto.
The term "aromatic group" as used herein is understood to mean C wherein at least one ring is aromatic5-12A monocyclic hydrocarbon ring or a bicyclic hydrocarbon ring, wherein one or more carbons are optionally replaced by a heteroatom selected from oxygen, sulfur and nitrogen. Examples of aromatic groups include aryl and heteroaryl, for exampleSuch as phenyl, naphthyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzopyrazolyl, benzofuranyl, benzopyrimidinyl, benzopyridyl, quinoxalinyl, furanyl, pyridinyl, or pyrimidinyl.
The term "aliphatic cyclic group" as used herein is understood to mean C4-12Monocyclic saturated cycloalkyl or bicyclic saturated cycloalkyl wherein one or more carbons are optionally replaced by a heteroatom selected from oxygen, sulfur and nitrogen. Examples of aliphatic cyclic groups include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuryl, piperidinyl, or piperazinyl, and the like.
The term "halogen clock" as used herein refers to fluorine, chlorine, bromine or iodine unless otherwise specifically indicated.
The term "alkyl" as used herein includes straight or branched chain alkyl groups. Said "C1-C6Examples of alkyl "groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, isohexyl, and the like.
The term "alkoxy" as used herein refers to an-O-alkyl group, wherein alkyl includes straight or branched chain alkyl groups. Said "C1-C6Examples of alkoxy "groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
In a particular embodiment, the present invention provides the use of a compound of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a vasodilator medicament:
wherein:
R1is represented by R3A mono-or poly-substituted aromatic or aliphatic cyclic group, wherein
The aromatic group is preferably phenyl, naphthyl, benzo five-membered heterocycle or six-membered heterocycle with heteroatom selected from N, S, O, or five-membered or six-membered unsaturated heterocycle; more preferably phenyl, naphthyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzpyrazolyl, benzofuranyl, benzopyrimidinyl, benzopyridyl, quinoxalinyl, furanyl, pyridinyl, or pyrimidinyl; even more preferably phenyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzofuranyl, naphthyl, furanyl, pyridinyl, pyrimidinyl, or quinoxalinyl; particularly preferably phenyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, quinoxalinyl or pyrimidinyl; most preferred is phenyl;
the aliphatic cyclic group is preferably a five-membered or six-membered saturated cyclic hydrocarbon group, or a five-membered or six-membered saturated heterocyclic group with a heteroatom selected from N, S, O; more preferably cyclopentyl, cyclohexyl, tetrahydrofuryl, piperidinyl or piperazinyl; even more preferably cyclohexyl, piperidinyl or piperazinyl; particularly preferably cyclohexyl;
R3is H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; preferably, R3Is H, F, Cl, Br, CN, C with alkyl moieties optionally substituted by 1-3 halogen atoms1-C6Alkyl or C1-C6Alkoxy, CHO, COCH3Or COOCH3(ii) a More preferably, R3 is H, F, Cl, COCH3C the alkyl part of which is optionally substituted by 1 to 3 halogen atoms1-C4Alkyl or C1-C4An alkoxy group; even more preferably, R3H, F, Cl is,CN、CF3、CH3Or OCH3(ii) a Most preferably, R3Is H, F, Cl or OCH3(ii) a When R is3When it is a polysubstituent group, R3Independently selected from the groups described above;
A. b independently represents CH or N; preferably, A, B each represent N;
R2represents H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; preferably, R2Is H, F, Cl, Br, CN, NO2C the alkyl part of which is optionally substituted by 1 to 3 halogen atoms1-C6Alkyl or C1-C6Alkoxy, CHO, COCH3Or COOCH3(ii) a More preferably, R2Is H, F, Cl, CN, CHO, COCH3、COOCH3Or C with alkyl moieties optionally substituted by 1 to 3 halogen atoms1-C4Alkyl or C1-C4An alkoxy group; even more preferably, R2Is H, F, Cl, CN, CH3Or COOCH3(ii) a Particularly preferably, R2Is H, F, Cl or CH3(ii) a Most preferably, R2Is H; when R is2When it is a polysubstituent group, R2Independently selected from the groups described above;
y represents a saturated or unsaturated, linear or branched, hydrocarbyl chain containing 2 to 8 carbon atoms, optionally substituted with 1 to 3 halogen atoms, in which one or more carbons are optionally replaced by heteroatoms selected from oxygen, sulphur and nitrogen; preferably, Y is an unsubstituted saturated hydrocarbon group containing 2 to 8 carbons, or an unsubstituted saturated hydrocarbon group containing 2 to 8 carbons in which 1 carbon atom is replaced by oxygen or sulfur, such as-C1-7alkylene-O-; more preferably Y isMethyl, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, oxymethylene, oxyethylene, oxypropylene, oxybutylene, oxypentylene, oxyhexylene, oxyheptylene, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentylene-oxy, hexylene-oxy or heptyleneoxy; even more preferably, Y is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentylene-oxy, hexylene-oxy, or heptyleneoxy; particularly preferably, Y is propylene, butylene or propyleneoxy; most preferably, Y is butylene.
In another embodiment, the present invention provides the use of a compound of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a vasodilator medicament:
wherein:
R1is represented by R3Mono-or di-substituted aromatic or aliphatic cyclic group, wherein
The aromatic group is preferably phenyl, benzisoxazolyl, benzofuranyl, benzisothiazolyl, benzopyranyl or pyrimidinyl;
the aliphatic cyclic group is preferably cyclohexyl;
R3is H, F, Cl, CF3、CN、CH3Or OCH3(ii) a When R is3When it is a polysubstituent group, R3Independently selected from the groups described above;
A. b independently represents CH or N; preferably, A, B each represent N;
R2represents H, F, Cl, or CH3(ii) a When R is2When it is a polysubstituent group, R2Independently selected from the groups described above;
y represents propylene, butylene or propyleneoxy.
In another embodiment, the present invention provides the use of a compound of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a vasodilator medicament:
wherein:
R1is represented by R3Mono-or di-substituted aromatic radicals in which
The aromatic group is preferably phenyl, benzisoxazolyl or benzisothiazolyl;
R3is H, F, Cl, CF3、CN、CH3Or OCH3(ii) a When R is3When it is a polysubstituent group, R3Independently selected from the groups described above;
A. b independently represents CH or N; preferably, A, B each represent N;
R2represents H;
y represents propylene or butylene.
In a further embodiment, the present invention provides the use of a compound of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a vasodilator medicament:
wherein:
R1is represented by R3Mono-or disubstituted aromaticGroup of (i) wherein
The aromatic group is preferably phenyl or benzisothiazolyl;
R3is H, Cl or CF3(ii) a When R is3When it is a polysubstituent group, R3Independently selected from the groups described above;
A. b independently represents CH or N; preferably, A, B each represent N;
R2represents H;
y represents butylene.
In a further embodiment, the present invention provides the use of a compound of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a vasodilator medicament:
wherein, when A, B are both N,
R1is not substituted by H or OCH3Monosubstituted phenyl, and
R2is not H or OCH3In which OCH3Disubstituted on the benzo five-membered azacycle; and is
Y is not ethylene, propylene, butylene or pentylene.
In yet another embodiment, the compounds of formula (I) and pharmaceutically acceptable salts thereof of the present invention
Wherein,
R1is represented by R3Mono-or disubstituted phenyl or benzothiazolyl, wherein
R3Is H or Cl; when R is3When it is a polysubstituent group, R3Independently selected from the groups described above;
A. b independently represents C;
R2represents H or CN;
y represents butylene.
The benzo five-membered nitrogen heterocyclic piperazine compound comprises:
i-11- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-21- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-41- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-52-methyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-66-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-71- (3- (4-phenylpiperazin-1-yl) propyl) -1H-benzimidazole,
I-81- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-92-methyl-1- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-101- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-111- (4- (4- (4-methylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-121- (4- (4- (2-furyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-131- (4- (4- (4-pyridyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-141- (4- (4- (2-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-151- (4- (4- (1-cyclohexyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-161- (4- (4- (1-naphthyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-171- (4- (4- (2-quinoxalinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-181- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-191- (4- (4- (3- (6-fluorobenzoisothiazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-201- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzimidazole,
I-211- (4- (4- (3- (6-fluorophenylfuranyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-221- (3- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-231- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-241- (4- (4- (3-chlorophenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-256-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -IH-benzimidazole,
I-266-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-276-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-282-chloro-1- (5- (4- (3-trifluoromethylphenyl) piperazin-1-yl) pentyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-301- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-326-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-335, 6-dimethyl-1- (4- (4- (3-trifluoromethylphenyl) 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) benzisoxazole,
I-366-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole,
I-376-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazin-1-yl) benzisoxazole,
I-381- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-391- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-401- (4- (4- (3-methoxyphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-411- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-421- (5- (4- (3-trifluoromethylphenyl) piperazine-1-yl) amyl) -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-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-461- (4- (4-cyclohexylpiperazine-1-yl) butyl) -1H-benzotriazole,
I-471- (4- (4- (1-naphthyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-481- (4- (4- (2-quinoxaline) piperazine-1-yl) butyl) -1H-benzotriazole,
I-491- (4- (4- (3- (6-fluoro-benzisothiazolyl)) piperazin-1-yl) butyl) -1H-benzotriazole,
I-501- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-511- (3- (4- (3- (6-fluoro-benzofuranyl)) piperazin-1-yl) propyl) -1H-benzotriazole,
I-521- (4- (4- (3- (6-fluoro-benzisoxazolyl)) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-536-fluoro-1- (4- (4- (3- (6-fluoro-benzisothiazolyl)) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-546-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-556-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-566-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-571- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-indole,
I-586-cyano-1- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-indole,
I-591- (3- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propyl) -1H-benzopyrazole,
I-606-cyano-1- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propyl) -1H-benzopyrazol,
I-611- [4- (4- (4-fluoro) phenyl) piperazine ] butyl-1H-indole,
1-621- [ 4-cyclohexylpiperazine ] butyl-1H-indole,
I-631- [4- (4- (4-fluoro) phenyl) piperazine ] butyl-5-acetyl-1H-indole,
I-641- [ 4-cyclohexylpiperazine ] butyl-5-acetyl-1H-indole,
I-651- [3- (4- (2, 4-difluoro) phenyl) piperazine ] butyl-5-acetyl-1H-indole,
I-661- [3- (4- (4-methyl) phenyl) piperazine ] propyl-1H-indole,
I-671- [4- (4- (4-chloro) phenyl) piperazine ] butyl-1H-indole,
I-681- [4- (4- (2-methyl) phenyl) piperazine ] butyl-1H-indole,
I-691- [4- (4- (3-trifluoromethyl) phenyl) piperazine ] butyl-1H-indole,
I-701- [3- (4- (4-methyl) phenyl) piperazine ] propyl-5-methoxy-1H-indole,
I-711- [4- (4- (4-trifluoromethoxy) phenyl) piperazine ] butyl-5-methoxy-1H-indole,
I-721- [4- (4- (3-trifluoromethyl) phenyl) piperazine ] butyl-5-methoxy-1H-indole,
I-731- [3- (4- (2-methyl) phenyl) piperazine ] butyl-5-methoxy-1H-indole,
I-741- [3- (4- (2, 4-difluoro) phenyl) piperazine ] propyl-5-nitro-1H-indole,
I-751- [4- (4- (4-chloro) phenyl) piperazine ] butyl-5-nitro-1H-indole,
I-761- [4- (4- (3-trifluoromethyl) phenyl) piperazine ] butyl-5-nitro-1H-indole,
I-771- [4- (4- (2-methoxy) phenyl) piperazine ] butyl-5-nitro-1H-indole,
I-781- [4- (4- (2-methoxy) phenyl) piperazine ] butyl-5-chloro-1H-indole,
I-791- [4- (4- (3-trifluoromethyl) phenyl) piperazine ] butyl-5-chloro-1H-indole,
I-801- [4- (4- (2, 4-difluoro) phenyl) piperazine ] butyl-5-chloro-1H-indole,
I-811- [2- (4- (2, 4-bistrifluoromethoxy) phenyl) piperazine ] ethyl-5-chloro-1H-indole,
I-821- [2- (4- (2, 4-dimethoxy) phenyl) piperazine ] ethyl-6-nitro-1H-indole,
I-831- [2- (4- (2, 4-dichloro) phenyl) piperazine ] ethyl-6-methoxy-1H-indole.
The specific chemical structural formula is shown in the following table:
in a particular embodiment of the invention, the following compounds or pharmaceutically acceptable salts thereof are more preferred:
i-11- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-21- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-41- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-52-methyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-66-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-71- (3- (4-phenylpiperazin-1-yl) propyl) -1H-benzimidazole,
I-81- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-92-methyl-1- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-101- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-111- (4- (4- (4-methylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-121- (4- (4- (2-furyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-131- (4- (4- (4-pyridyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-141- (4- (4- (2-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-151- (4- (4- (1-cyclohexyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-161- (4- (4- (1-naphthyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-171- (4- (4- (2-quinoxalinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-181- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-191- (4- (4- (3- (6-fluorobenzoisothiazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-201- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzimidazole,
I-211- (4- (4- (3- (6-fluorophenylfuranyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-221- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-231- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-241- (4- (4- (3-chlorophenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-256-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-266-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-276-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-282-chloro-1- (5- (4- (3-trifluoromethylphenyl) piperazin-1-yl) pentyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-301- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-326-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-335, 6-dimethyl-1- (4- (4- (3-trifluoromethylphenyl) 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) benzisoxazole,
I-366-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole,
I-376-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazin-1-yl) benzisoxazole,
I-381- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-391- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-401- (4- (4- (3-methoxyphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-411- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-421- (5- (4- (3-trifluoromethylphenyl) piperazine-1-yl) amyl) -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-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-461- (4- (4-cyclohexylpiperazine-1-yl) butyl) -1H-benzotriazole,
I-471- (4- (4- (1-naphthyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-481- (4- (4- (2-quinoxaline) piperazine-1-yl) butyl) -1H-benzotriazole,
I-491- (4- (4- (3- (6-fluoro-benzisothiazolyl)) piperazin-1-yl) butyl) -1H-benzotriazole,
I-501- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-511- (3- (4- (3- (6-fluoro-benzofuranyl) piperazin-1-yl) propyl) -1H-benzotriazol,
I-521- (4- (4- (3- (6-fluoro-benzisoxazolyl) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-536-fluoro-1- (4- (4- (3- (6-fluoro-benzisothiazolyl) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-546-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-556-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-566-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-571- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-indole,
I-586-cyano-1- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-indole,
I-591- (3- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propyl) -1H-benzopyrazole,
I-606-cyano-1- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propyl) -1H-benzopyrazol e.
In a particular embodiment of the invention, even more preferred are the following compounds or pharmaceutically acceptable salts thereof:
i-11- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-21- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-41- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-52-methyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-66-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-81- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-131- (4- (4- (4-pyridyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-151- (4- (4- (1-cyclohexyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-171- (4- (4- (2-quinoxalinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-181- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-221- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-231- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-241- (4- (4- (3-chlorophenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-256-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-301- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-326-fluoro-1- (4- (4- (3-trifluoromethylphenyl) 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) benzisoxazole,
I-366-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole,
I-376-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazin-1-yl) benzisoxazole,
I-381- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-391- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-401- (4- (4- (3-methoxyphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-411- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-511- (3- (4- (3- (6-fluoro-benzofuranyl) piperazin-1-yl) propyl) -1H-benzotriazole,
I-521- (4- (4- (3- (6-fluoro-benzisoxazolyl) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-546-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -IH-benzotriazole,
I-591- (3- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propyl) -IH-benzopyrazole.
In a particular embodiment of the invention, the following compounds or pharmaceutically acceptable salts thereof are particularly preferred:
i-11- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-21- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-301- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-343- (4- (4- (1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
I-366-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole,
I-376-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazin-1-yl) benzisoxazole,
I-381- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-391- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-401- (4- (4- (3-methoxyphenyl) piperazine-1-yl) butyl) -1H-benzotriazole.
In a particular embodiment of the invention, the following compounds or pharmaceutically acceptable salts thereof are particularly preferred:
i-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-343- (4- (4- (IH-benzotriazole-I-yl) butyl) piperazine-1-yl) benzisothiazole.
The pharmaceutically acceptable salts of the compounds of formula (I) according to the invention are preferably the hydrochloride, hydrobromide, sulphate, trifluoroacetate, methanesulphonate, tartrate, malate, succinate, maleate, citrate, phosphate, lactate, pyruvate, acetate, fumarate, oxaloacetate, ethanesulphonate, oxalate, benzenesulphonate or isethionate salts. The pharmaceutically acceptable salt of the present invention preferably contains water of crystallization, more preferably 0.5 to 3 molecules of water of crystallization.
In a particular embodiment of the use according to the invention, particular preference is given to compound I-2 or a pharmaceutically acceptable salt thereof, for example the hydrochloride salt thereof, i.e. compound II-2, the chemical structure of which is shown in II-2.
The compound I-3 is preferably hydrochloride, i.e. the compound II-3, and the chemical structure is shown as II-3.
Wherein, the preferable salt of the compound I-29 is hydrochloride, namely the compound II-29, and the chemical structure is shown as II-29.
A preferred salt of compound I-31 is the hydrochloride salt, i.e., compound II-31, having the chemical structure shown in II-31.
A preferred salt of compound I-34 is the hydrochloride salt, i.e., compound II-34, having the chemical structure shown in II-34.
The animal in vitro test proves that: compound II-2, capable of relaxing vascular smooth muscle contracted by adrenaline and high potassium, its diastolic-logEC50The values are 5.73 + -0.03 and 5.34 + -0.02 (as shown in FIG. 1 and FIG. 2), respectively; compound II-3, a logEC that relaxes vascular smooth muscle contracted by epinephrine and hyperkalium50The values were 6.01. + -. 0.05 and 5.49. + -. 0.05 (as shown in FIGS. 8 and 9), respectively.
The research on the vasodilation action mechanism of the compound II-2 shows that the compound can competitively antagonize norepinephrine and calcium ionThe vasoconstrictive effects of the subunit and serotonin can shift the dose-response curve of the agonist to the right and parallel without reducing the maximal response, indicating a competitive antagonism which antagonizes the vasoconstrictive effects of Norepinephrine (NA), calcium ion and serotonin (5-HT) PA2The values were 7.37. + -. 0.08 (doxazosin 7.52. + -. 0.04), 5.61. + -. 0.04 (amlodipine 6.99. + -. 0.05) and 5.71. + -. 0.08 (as shown in FIGS. 3, 4, 5, 6 and 7), respectively, the results show that Compound II-2 is blocked α1Acceptor, Ca2+Ion channels and vascular 5-HT2AThe receptor exerts its vasodilatory action.
The animal in vitro test proves that: compound II-29, capable of relaxing vascular smooth muscle contracted by adrenaline and hyperkalium fluid, its relaxed-logEC50The values were 6.01. + -. 0.02 and 5.64. + -. 0.01 (as shown in FIGS. 15 and 16), respectively. Compound II-31-logEC which relaxes vascular smooth muscle contracted by epinephrine and hyperkalium50The values were 6.19. + -. 0.03 and 5.55. + -. 0.03 (as shown in FIGS. 10 and 11), respectively.
The research on the vasodilatation action mechanism of the vascular smooth muscle of the compound II-31 shows that the compound can competitively antagonize the vasoconstriction action of noradrenaline, calcium ions and serotonin, can enable the dose-response curve of the agonist to be parallelly shifted to the right without reducing the maximum response, and indicates that the compound is competitive antagonism which antagonizes PA of the vasoconstriction action of noradrenaline, calcium ions and serotonin2These results showed that Compound II-31 was also obtained by blocking α 1 receptor, Ca, and Ca, as shown in FIGS. 12, 13, and 14, with values of 6.02. + -. 0.13 (doxazosin 7.76. + -. 0.24), 6.56. + -. 0.032 (amlodipine 7.51. + -. 0.288), and 6.726. + -. 0.089, respectively2+Ion channels and vascular 5-HT2AReceptors to exert their vasodilatory action.
The compound II-2 shows obvious antihypertensive effect in an in vivo whole test of rats, has good oral absorption, low toxicity, large therapeutic index and negative micronucleus experiment of bone marrow, and has potential value for developing novel multi-target vasodilating drugs.
The compound of formula (I) and the pharmaceutically acceptable salt thereof can realize the antagonism of α receptor (especially α)1Receptor antagonism) to achieve vascular smooth muscle relaxation. In addition, the compounds of formula (I) and pharmaceutically acceptable salts thereof of the present invention may also act on other targets or pathways to achieve vascular smooth muscle relaxation, e.g., Ca2+Channel blockade or antagonism of 5-HT2AThe multiple target effect makes the compound of the invention especially effective for the disease related to the persistent pathological constriction of blood vessels or the spasm of blood vessel smooth muscles, compared with a single target drug or a combination of multiple single target drugs, the compound of the invention can achieve higher drug effect, or effectively reduce drug resistance, or reduce unwanted side effects, so that the safety is higher1At the same time as the receptor, by blocking Ca2+Channels and/or 5-HT2AThe synergistic effect of the receptors produces good antihypertensive effect, which results in residual α1The receptor can still participate in the pressure-rising reflex, and the occurrence of orthostatic hypotension can be prevented from being reduced; and/or by blocking Ca2+The channel function, which can generate the functions of resisting cardiac hypertrophy, protecting vascular endothelial cells, resisting atherosclerosis, inhibiting vascular smooth muscle proliferation, improving cerebral circulation and the like while synergistically reducing blood pressure, effectively prevent tachycardia and palpitation and prevent the first dose effect by slowing down heart rate; and/or by blocking 5-HT2AThe receptor has the effects of synergistically lowering blood pressure and effectively improving blood flow supply of patients with obstructive vascular diseases, so that the antihypertensive drug is suitable for patients with hypertension accompanied with atherosclerosis and endothelial injury.
Thus, the compounds of formula (I) and pharmaceutically acceptable salts thereof of the present invention are useful for preventing, alleviating or treating a disease or condition associated with persistent pathological constriction or vasospasm of blood vessels in a subject. The compound of formula (I) and pharmaceutically acceptable salts thereof can be particularly used for preventing, alleviating or treating hypertension, heart failure, angina pectoris, coronary heart disease and the like; used for cerebral ischemic diseases, myocardial ischemic diseases, shock and the like caused by vasospasm; can be used for treating renal ischemia, renal hypofunction caused by renal vasospasm, and peripheral vasospastic diseases.
The subject described herein is preferably a mammal, particularly preferably a human.
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, particularly preferably for use in the prevention, alleviation or treatment of, for example, hypertension, angina pectoris, heart failure, coronary heart disease, cerebral ischemia and peripheral vasospastic diseases such as thromboangiitis obliterans, raynaud's disease and the like.
The compounds of formula (I) or pharmaceutically acceptable salts thereof according to the invention may be prepared in the form of suitable pharmaceutical compositions for oral, parenteral, by inhalation spray, rectal, intranasal, sublingual, buccal, transdermal or by implantation techniques including subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention is preferably administered orally, sublingually, intravenously, intramuscularly or subcutaneously. The pharmaceutical compositions may comprise one or more conventional pharmaceutically acceptable carriers, adjuvants or vehicles, such as: diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch and the like; disintegrating agents such as calcium carbonate, sodium bicarbonate; lubricants such as calcium stearate or magnesium stearate, etc.; and other adjuvants such as flavoring agents and sweetening agents.
The pharmaceutical compositions comprising a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof may be in the form of sterile injectable preparations, for example as sterile aqueous or oleaginous suspensions. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic diluent or solvent which may be employed for parenteral administration, for example as a solution in 1, 3-butanediol. Usable media and solvents which can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. The oil solution or suspension may also contain a long chain alcohol diluent or dispersant (such as those described in ph. helv) or similar alcohols.
Pharmaceutical compositions comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. The dosage forms are prepared according to techniques well known in the art of pharmaceutical formulation. For tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents (e.g., magnesium stearate) are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient may be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
Pharmaceutical compositions comprising a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention may also be administered in the form of suppositories for rectal administration of the drug. The compositions may be prepared by mixing a compound of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredients. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
As concluded from the results of the anesthetized rat test, the daily dose of the compound of formula (I) of the present invention should be smaller than the daily dose of amlodipine. The daily dose of amlodipine for vasodilation or hypertension is known in the art, e.g., 10 mg/day. The specific dosage of the compound of formula (I) according to the present invention can be determined by a physician according to the results of clinical trials and the condition, age, etc. of the patient.
Pharmaceutical compositions comprising a compound of formula (I) of the invention or a pharmaceutically acceptable salt thereof may be prepared by methods conventional in the medical arts, wherein the active ingredient is present in an amount of 0.1% to 99.5% by weight, depending on the condition to be treated or prevented and the nature of the subject to whom the compound is administered. Dosage regimens for a given compound can be readily determined by those skilled in the art using the disclosure herein.
In one embodiment, the compounds of the invention, compounds of formula (I) or pharmaceutically acceptable salts thereof, may be used in combination with one or more other active pharmaceutical ingredients. The combination may be in the form of a single composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more other active pharmaceutical ingredients, or the combination may be in the form of a combination of two or more separate compositions, wherein a compound of the invention is included in one composition and one or more other active pharmaceutical ingredients are included in one or more separate compositions. Other active pharmaceutical ingredients which can be used in combination with a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof for the prevention, alleviation or treatment of a disease or condition associated with persistent pathological constriction of blood vessels or vasospasm in a subject are for example other anti-smooth muscle spasm agents, preferably selected from sertraline, captopril, benazepril, valsartan, propranolol, diuretics.
The embodiments described herein, or different preferred grades, can be combined in any combination, unless otherwise indicated.
The compounds of the present invention can be synthesized by the following methods:
scheme 1:
wherein R is1、R2A, B are as defined above; n is 2-7; x represents a pharmaceutically acceptable salt thereof, e.g. HCl, 2HCl, HBr, 2HBr, H2SO4，CH3SO3H, and the like.
Taking substituted 1H-benzo five-membered nitrogen heterocycle as a raw material, carrying out condensation reaction with chloroalkyl bromide in a sodium hydroxide aqueous solution to prepare an N-chloroalkyl-substituted benzo five-membered nitrogen heterocycle compound, carrying out condensation reaction with substituted aryl piperazine to prepare a compound shown in a formula (I), and finally acidifying to form salt to prepare corresponding salt to obtain a compound shown in a formula (II). Compounds I-1-I-21, I-25-I-51 and 1-54-I-60 and salts thereof can be prepared using the above-described methods.
Scheme 2:
wherein R is1、R2A, B are as defined above; n is 2-7; x represents a pharmaceutically acceptable salt thereof, e.g. HCl, 2HCl, HBr, 2HBr, H2SO4，CH3SO3H, and the like.
Substituted benzo five-membered nitrogen heterocycle-1 alcohol is used as a raw material, exchanges active hydrogen with sodium hydride to obtain corresponding sodium salt, reacts with chloroalkyl bromide to obtain corresponding chloride, and then carries out condensation reaction with substituted piperazine to prepare a compound shown in a formula (I), and finally prepares corresponding salt through acidification and salt formation to obtain a compound shown in a formula (II). Compounds I-22-24, I-52-53 and salts thereof can be prepared using the above-described process.
The general synthesis method comprises the following steps: preparation of N- (4-chlorobutyl) -substituted benzo five-membered nitrogen heterocyclic compound
1H-substituted benzo pentaazacyclo (0.10mol) was dissolved in 100ml of 30 wt% aqueous sodium hydroxide solution, 4-chlorobromobutane (34.0g, 0.10mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter2O3Separating and purifying by chromatography or preparative HPLC to obtain N- (4-chlorobutyl) -substituted benzo five-membered nitrogen heterocyclic compound with the yield of 30.0-85.0%.
Example 1
Preparation of 1- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-1)
1H-benzimidazole (11.8g, 0.10mol) was dissolved in 200ml of 20 wt% aqueous sodium hydroxide solution, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes, warmed to 60 ℃ and stirred for reaction for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter2O3Chromatographic separation and purification to obtain 12.5g of 1- (4-chlorobutyl) -1H-benzimidazole with the yield of 60.0 percent.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trichlorophenylpiperazine (5.9g, 0.03mol), diisopropylethyl, and the like were added theretoAmine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were stirred at room temperature for 10 minutes, and then the reaction was refluxed at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.8g of compound (I-1) with yield of 61.4%. ESI-MS [ M + H ]]+：m/z 369.2。
Example 2
Preparation of 1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-2) and 1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole hydrochloride (II-2)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, 3-trifluoromethylphenylpiperazine (6.91g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 10 to 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 7.6g of compound (I-2) with yield of 62.8%.
Compound (I-2) (6.04g, 0.015mol) was dissolved in 80ml of ethyl acetate and 8ml of ethanol. Under the cooling condition of an ice-water bath, 3mol/L of hydrogen chloride/ethyl acetate solution is dropwise added, the pH value of the solution is adjusted to be 3, the solution is heated to 50 ℃ and stirred for 20min, and the solid compound (II-2) is obtained by cooling, crystallization, filtration and drying, wherein the solid compound (II-2) is 5.9g, and the yield is 89.7%. ESI-MS [ M + H ]]+：m/z 403.2。
Example 3
Preparation of 1- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-3) and 1- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole hydrochloride (II-3)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 2, 3-dichlorophenylpiperazine (6.93g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 10 to 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 7.5g of compound (I-3), with yield of 62.0%.
Compound (I-3) (6.05g, 0.015mol) was dissolved in 80ml of ethyl acetate and 8ml of ethanol. Under the cooling condition of an ice-water bath, 3mol/L of hydrogen chloride/ethyl acetate solution is dropwise added, the pH value of the solution is adjusted to be 3, the solution is heated to 50 ℃ and stirred for 20min, and the solid compound (II-3) is obtained after cooling crystallization, filtration and drying, wherein the solid compound (II-3) is 6.0g, and the yield is 90.9%. ESI-MS [ M + H ]]+：m/z 403.1。
Example 4
Preparation of 1- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-4)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 2-methoxyphenylpiperazine (5.77g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 7.7g of compound (I-4), with yield of 70.6%. ESI-MS [ M + H ]]+：m/z 365.2。
Example 5
Preparation of 2-methyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-5)
2-methyl-1H-benzimidazole (13.2g, 0.10mol) was dissolved in 200ml of a 20 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes, heated to 60 ℃ and reacted for 2 hours with stirring. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter2O3Chromatography separation and purification are carried out to obtain 13.7g of 1- (4-chlorobutyl) -2-methyl-1H-benzimidazole with the yield of 61.5%.
1- (4-chlorobutyl) -2-methyl-1H-benzimidazole (8.02g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.91g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 8.1g of compound (I-5), with yield of 64.9%. ESI-MS [ M + H ]]+：m/z417.2。
Example 6
Preparation of 6-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-6)
6-fluoro-1H-benzimidazole (13.2g, 0.10mol) was dissolved in 200ml of a 20 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes, heated to 60 ℃ and reacted for 2 hours with stirring. The post-treatment operation is carried out according to the general method and is carried out through neutral Al2O3Chromatographic separation and purification14.2g of 1- (4-chlorobutyl) -6-fluoro-1H-benzimidazole was obtained, and the yield was 62.6%.
1- (4-chlorobutyl) -6-fluoro-1H-benzimidazole (8.16g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.91g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 8.5g of compound (I-6), with yield of 67.4%. ESI-MS [ M + H ]]+：m/z 421.2。
Example 7
Preparation of 1- (3- (4-phenylpiperazin-1-yl) propyl) -1H-benzimidazole (I-7)
1H-benzimidazole (11.8g, 0.10mol) was dissolved in 200ml of 20 wt% aqueous sodium hydroxide solution, and 3-chlorobromopropane (31.4g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added thereto, and the mixture was stirred for 5 minutes, warmed to 60 ℃ and stirred for reaction for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter2O3Separating and purifying by chromatography to obtain 12.0g of 1- (3-chloropropyl) -1H-benzimidazole with the yield of 62.0%.
1- (3-chloropropyl) -1H-benzimidazole (6.98g, 0.036mol) was dissolved in 100ml of acetonitrile, phenylpiperazine (4.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.1g of compound (I-7) with yield of 63.2%. ESI-MS [ M + H ]]+：m/z 321.2。
Example 8
Preparation of 1- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole (I-8)
1- (3-chloropropyl) -1H-benzimidazole was prepared by the method of example 7.
1- (3-chloropropyl) -1H-benzimidazole (6.98g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-fluorophenylpiperazine (6.91g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.4g of compound (I-8), with yield of 63.1%. ESl-MS [ M + H ]]+：m/z 339.2。
Example 9
Preparation of 2-methyl-1- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole (I-9)
2-methyl-1H-benzimidazole (13.2g, 0.10mol) was dissolved in 200mL of a 20 wt% aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added thereto, and the mixture was stirred for 5 minutes, heated to 60 ℃ and reacted for 2 hours with stirring. Cooling to room temperature, adding 100mL of dichloromethane for extraction, separating, adding 100mL of dichloromethane into the aqueous phase for extraction, combining the organic phases, washing by 100mL of saturated saline, separating, and evaporating the organic phase to obtain an oily substance. Neutral Al of oily matter2O3Chromatographic separation and purification to obtain 12.9g of 1- (3-chloropropyl) -2-methyl-1H-benzimidazole with the yield of 62.1 percent.
1- (3-chloropropyl) -2-methyl-1H-benzimidazole (7.49g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluorophenylpiperazine (4.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0 g), respectively, were added0.03mol), stirred at room temperature for 10 minutes, and then heated to reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.67g of compound (I-9) with yield of 63.1%. ESI-MS [ M + H ]]+：m/z 353.2。
Example 10
Preparation of 1- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-10)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, 3-cyanophenylpiperazine (5.6g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.7g of compound (I-10) with yield of 62.4%. ESI-MS [ M + H ]]+：m/z 360.2。
Example 11
Preparation of 1- (4- (4- (4-methylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-11)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, 4-methylphenylpiperazine (5.3g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.4g of compound (I-11) with yield of 60.7%. ESI-MS [ M + H ]]+：m/z 349.2。
Example 12
Preparation of 1- (4- (4- (2-furyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-12)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-furyl) piperazine (4.6g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated to reflux for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.0g of compound (I-12) with yield of 61.5%. ESI-MS [ M + H ]]+：m/z 325.2。
Example 13
Preparation of 1- (4- (4- (4-pyridyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-13)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, 4- (4-pyridyl) piperazine (4.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.3g of compound (I-13), with yield of 62.1%. ESI-MS [ M + H ]]+：m/z 336.2。
Example 14
Preparation of 1- (4- (4- (2-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-14)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-pyrimidinyl) piperazine (4.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.1g of compound (I-14), with yield of 60.1%. ESI-MS [ M + H ]]+：m/z 337.2。
Example 15
Preparation of 1- (4- (4- (1-cyclohexyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-15)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (1-cyclohexyl) piperazine (5.1g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.4g of compound (I-15) with yield of 62.9%. ESI-MS [ M + H ]]+：m/z 341.3。
Example 16
Preparation of 1- (4- (4- (1-naphthyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-16)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (1-naphthyl) piperazine (6.4g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.8g of compound (I-16), with yield of 59.1%. ESI-MS [ M + H ]]+：m/z 385.2。
Example 17
Preparation of 1- (4- (4- (2-quinoxalinyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-17)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100ml of acetonitrile, 4- (2-quinoxalinyl) piperazine (6.4g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated to reflux for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.9g of compound (I-16) with yield of 59.6%. ESI-MS [ M + H ]]+：m/z 387.2。
Example 18
Preparation of 1- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole (I-18)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100mL of acetonitrile, and 6-fluoro-3- (piperazin-4-yl) benzisoxazole (6.6g, 0.05mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added to each solution, followed by stirring, mixing, and refluxing at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and performing column chromatography (neutral Al)2O3) Chromatographic separation and purification, and eluting with dichloromethane to obtain 7.7g of the compound (I-18) with the yield of 65.6%. ESI-MS [ M + H ]]+：m/z 394.2。
Example 19
Preparation of 1- (4- (4- (3- (6-fluorobenzoisothiazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole (I-19)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100mL of acetonitrile, and 6-fluoro-3- (piperazin-4-yl) benzisothiazole (7.1g, 0.05mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and refluxing at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and performing column chromatography (neutral Al)2O3) The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.9g of Compound (I-19) in 64.6% yield. ESI-MS [ M + H ]]+：m/z 410.2。
Example 20
Preparation of 1- (4- (4- (3-benzopyrazolyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-20)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100mL of acetonitrile, and 3- (piperazin-4-yl) benzopyrazole (6.1g, 0.05mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and performing column chromatography (neutral Al)2O3) The product was separated and purified by chromatography, and eluted with methylene chloride to give 6.9g of Compound (I-20) in 61.5% yield. ESI-MS [ M + H ]]+：m/z 375.2。
Example 21
Preparation of 1- (4- (4- (3- (6-fluorophenylfuranyl)) piperazin-1-yl) butyl) -1H-benzimidazole (I-21)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (7.51g, 0.036mol) was dissolved in 100mL of acetonitrile, and 6-fluoro-3- (piperazin-4-yl) benzofuran (6.6g, 0.05mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and refluxing at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and performing column chromatography (neutral Al)2O3) The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.5g of Compound (I-21) in 63.6% yield. ESI-MS [ M + H ]]+：m/z 393.2。
Example 22
Preparation of 1- (3- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) propoxy) -1H-benzimidazole (I-22)
Preparation of 1- (3-chloropropoxy) benzimidazole
1-hydroxybenzimidazole (0.01mol) was dissolved in 10ml of NMP, and a 50% by weight mixture of sodium and hydrogen (0.01mol) in paraffin wax was added in portions and stirred for 0.5 h. Simultaneously, 3-chlorobromopropane(0.015mol) is dissolved in 5mL NMP, added into the solution and stirred at room temperature for reaction for 12h, the reaction solution is poured into 50mL of water, extracted by ethyl acetate (3 × 50mL), the organic phases are combined and washed by 30mL of water, added with anhydrous magnesium sulfate to dry the organic phase, filtered and evaporated to dryness, and the oily substance is treated by neutral Al2O3Separating and purifying by chromatography or preparative HPLC to obtain 1- (3-chloropropoxy) benzimidazole with yield of 75.0%.
1- (3-Chloropropoxy) benzimidazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluorophenylisoxazolyl)) piperazine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.7g of 1- (3- (4- (3- (6-fluorobenzoissoxazolyl)) piperazine-1-yl) propoxy) -1H-benzimidazole (I-22) with the yield of 69.1%. ESI-MS [ M + H ]]+：m/z 396.2。
Example 23
Preparation of 1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propoxy) -1H-benzimidazole (I-23)
1- (3-Chloropropoxy) benzimidazole was prepared by the method of example 22.
1- (3-Chloropropoxy) benzimidazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperazine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.7g of 1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) propoxy) -1H-benzimidazole (I-23) with the yield of 67.9%. ESI-MS [ M + H ]]+：m/z 405.2。
Example 24
Preparation of 1- (4- (4- (3-chlorophenyl) piperazin-1-yl) propoxy) -1H-benzimidazole (I-24)
1- (3-Chloropropoxy) benzimidazole was prepared by the method of example 22.
1- (3-Chloropropoxy) benzimidazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-chlorophenyl) piperazine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 12.2g of 1- (4- (4- (3-chlorphenyl) piperazine-1-yl) propoxy) -1H-benzimidazole (I-24), with the yield of 66.1%. ESI-MS [ M + H ]]+：m/z371.2。
Example 25
Preparation of 6-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-25)
6-chloro-1H-benzimidazole (15.2g, 0.10mol) was dissolved in 200ml of a 20 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes, heated to 60 ℃ and reacted for 2 hours with stirring. The post-treatment operation is carried out according to the general method and is carried out through neutral Al2O3Chromatographic separation and purification to obtain 15.1g of 1- (4-chlorobutyl) -6-chloro-1H-benzimidazole with the yield of 62.3 percent.
1- (4-chlorobutyl) -6-chloro-1H-benzimidazole (8.71g, 0.036m0l) was dissolved in 100ml of acetonitrile, 3-trifluoromethylphenylpiperazine (6.91g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 8.6g of compound (I-25), with yield of 65.8%. ESI-MS [ M + H ]]+：m/z 437.2。
Example 26
Preparation of 6-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-26)
6-cyano-1H-benzimidazole (14.3g, 0.10mol) was dissolved in 200ml of a 20 wt% aqueous sodium hydroxide solution, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes, heated to 60 ℃ and reacted for 2 hours with stirring. The post-treatment operation is carried out according to the general method and is carried out through neutral Al2O3The product is separated and purified by chromatography, 14.7g of 1- (4-chlorobutyl) -6-cyano-1H-benzimidazole is obtained, and the yield is 63.1%.
1- (4-chlorobutyl) -6-cyano-1H-benzimidazole (8.39g, 0.036mol) was dissolved in 100ml of acetonitrile, 3-trifluoromethylphenylpiperazine (6.91g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 8.6g of compound (I-26), with 66.9% yield. ESI-MS [ M + H ]]+：m/z428.2。
Example 27
Preparation of 6-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole (I-27)
6-methoxycarbonyl-1H-benzimidazole (17.6g, 0.10mol) was dissolved in 200ml of a 20 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes, heated to 60 ℃ and reacted for 2 hours with stirring. Post-treatment operations by general methodNeutral Al2O3Chromatographic separation and purification to obtain 16.9g of 1- (4-chlorobutyl) -6-methoxycarbonyl-1H-benzimidazole with the yield of 63.4 percent.
1- (4-chlorobutyl) -6-methoxycarbonyl-1H-benzimidazole (9.58g, 0.036mol) was dissolved in 100ml of acetonitrile, 3-trifluoromethylphenylpiperazine (6.91g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 8.8g of compound (I-27) with yield of 63.7%. ESI-MS [ M + H ]]+：m/z461.2。
Example 28
Preparation of 2-chloro-1- (5- (4- (3-trifluoromethylphenyl) piperazin-1-yl) pentyl) -1H-benzimidazole (I-28)
2-chloro-1H-benzimidazole (15.2g, 0.10mol) was dissolved in 200ml of a 20 wt% aqueous sodium hydroxide solution, and 5-chlorobromopentane (36.8g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added thereto, and the mixture was stirred for 5 minutes, heated to 60 ℃ and reacted for 2 hours with stirring. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter2O3Chromatography separation and purification are carried out to obtain 16.0g of 1- (5-chloropentyl) -2-chloro-1H-benzimidazole with the yield of 62.5 percent.
1- (5-Chloropentyl) -2-chloro-1H-benzimidazole (9.22g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.91g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, and the mixture was stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, dichloromethane/methanol mixtureEluting with a solvent to obtain 8.8g of the compound (I-5), with the yield of 65.2%. ESI-MS [ M + H ]]+：m/z 451.2。
Example 29
Preparation of 1- (4- (4- (3-chlorphenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-29)
Benzotriazole (11.9g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane into the water phase for extraction, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oily substance. Neutral Al of oily matter2O3Carrying out chromatographic separation and purification, eluting with dichloromethane to obtain 17.0g of 1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 81.0%.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-chlorophenylpiperazine (5.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, respectively, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 7.8g of the compound (I-29) with the yield of 70.3%.
Compound (I-29) (5.55g, 0.015mol) was dissolved in 50ml of ethyl acetate. Under the cooling condition of an ice-water bath, a hydrogen chloride/ethyl acetate solution with the concentration of 3mol/L was added dropwise until the pH of the reaction solution became 2, and the reaction solution was stirred for 10min, filtered and dried to obtain 5.4g of a compound (1I-29) as a solid, with the yield of 88.0%. ESI-MS [ M + H ]]+：m/z 370.1。
Example 30
Preparation of 1- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-30)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-fluorophenylpiperazine (5.4g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 7.3g of the compound (I-30) with the yield of 68.9%. ESI-MS [ M + H ]]+：m/z354.2。
Example 31
Preparation of 1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-31) and 1- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole hydrochloride (II-31)
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.8g of Compound (I-31) in 64.5% yield.
Compound (I-31) (6.05g, 0.015mol) was dissolved in 50ml of ethyl acetate. Under the cooling condition of an ice-water bath, a hydrogen chloride/ethyl acetate solution with the concentration of 3mol/L is added dropwise until the pH of the reaction solution is 2, the reaction solution is stirred for 10min, and the mixture is filtered and dried to obtain 5.6g of a compound (II-31) solid, wherein the yield is 84.8%. ESI-MS [ M + H ]]+：m/z 404.2。
Example 32
Preparation of 6-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-32)
6-fluoro-1H-benzotriazole (13.7g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. The post-treatment is carried out according to the method in the general synthesis method, and the 1- (4-chlorobutyl) -6-fluoro-1H-benzotriazole is separated and purified by preparative HPLC, so that 8.9g of the 1- (4-chlorobutyl) -6-fluoro-1H-benzotriazole is obtained with the yield of 39.0 percent.
1- (4-chlorobutyl) -6-fluoro-1H-benzotriazole (8.2g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, eluting with methylene chloride, to give 8.3g of Compound (I-32) in 65.7% yield. ESl-MS [ M + H ]]+：m/z 422.2。
Example 33
Preparation of 5, 6-dimethyl-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-33)
5, 6-dimethyl-1H-benzotriazole (14.7g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. The post-treatment is carried out according to the method in the general synthesis method, and the 1- (4-chlorobutyl) -5, 6-dimethyl-1H-benzotriazole is separated and purified by preparative HPLC, so that 17.4g of the 1- (4-chlorobutyl) -5, 6-dimethyl-1H-benzotriazole is obtained with the yield of 73.2 percent.
1- (4-chlorobutyl) -5, 6-dimethyl-1H-benzotriazole (8.56g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol) and bis (methyl) piperazine were added theretoIsopropyl ethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were mixed with stirring, and the mixture was refluxed at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al203The product was separated and purified by chromatography, and eluted with methylene chloride to give 9.1g of Compound (I-33) in 70.3% yield. ESI-MS [ M + H ]]+：m/z 432.2。
Example 34
Preparation of 3- (4- (4- (1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole (I-34)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3- (piperazin-1-yl) benzisothiazole (6.58g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, and after stirring and mixing, the mixture was refluxed for 15 hours at elevated temperature. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 8.2g of Compound (I-34) in 69.6% yield.
Compound (I-34) (5.89g, 0.015mol) was dissolved in 50ml of ethyl acetate and 5ml of ethanol. Under the cooling condition of an ice-water bath, a hydrogen chloride/ethyl acetate solution with the concentration of 3mol/L is dropwise added until the pH of the reaction solution is 2, the reaction solution is stirred for 10min, and the mixture is filtered and dried to obtain 5.5g of a compound (II-34) solid, wherein the yield is 85.5%. ESI-MS [ M + H ]]+：m/z 393.2。
Example 35
Preparation of 3- (4- (4- (1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisoxazole (I-35)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3- (piperazin-1-yl) benzisoxazole (6.1g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, and after stirring and mixing, the mixture was refluxed for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 8.0g of the compound (I-35) with the yield of 70.9%. ESI-MS [ M + H ]]+：m/z 377.2。
Example 36
Preparation of 6-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole (I-36)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 6-fluoro-3- (piperazin-1-yl) benzisoxazole (6.1g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 8.3g of the compound (I-36) with the yield of 70.0%. ESI-MS [ M + H ]]+：m/z 395.2。
Example 37
Preparation of 6-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazine-1-yl) benzisoxazole (I-37)
Benzotriazole (11.9g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, and 3-chlorobromopropane (30.2g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, and separatingThe aqueous phase was extracted with 100ml of dichloromethane, the organic phases were combined, washed with 100ml of saturated brine, separated, and the organic phase was evaporated to dryness to give an oil. Neutral Al of oily matter2O3Carrying out chromatographic separation and purification, eluting with dichloromethane to obtain 15.6g of 1- (3-chloropropyl) -1H-benzotriazole, wherein the yield is 80.0%.
1- (3-chloropropyl) -1H-benzotriazole (7.02g, 0.036mol) is dissolved in 100ml of acetonitrile, 6-fluoro-3- (piperazin-1-yl) benzisoxazole (6.6g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) are added separately, mixed under stirring, and the mixture is heated under reflux for 15H. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.9g of Compound (I-37) in 69.3% yield. ESI-MS [ M + H ]]+：m/z 380.2。
Example 38
Preparation of 1- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole (I-38)
1- (3-chloropropyl) -1H-benzotriazole was prepared by the method in example 37.
1- (3-chloropropyl) -1H-benzotriazole (7.02g, 0.036mol) was dissolved in 100ml of acetonitrile, and 2, 3-dichlorophenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 8.2g of the compound (I-38) with the yield of 70.2%. ESI-MS [ M + H ]]+：m/z 389.1。
Example 39
Preparation of 1- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole (I-39)
1- (3-chloropropyl) -1H-benzotriazole was prepared by the method in example 37.
1- (3-chloropropyl) -1H-benzotriazole (7.02g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-methylphenylpiperazine (5.3g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.5g of Compound (I-39) in 74.6% yield. ESI-MS [ M + H ]]+：m/z335.2。
Example 40
Preparation of 1- (4- (4- (3-methoxyphenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-40)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-methoxyphenylpiperazine (5.8g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 7.6g of the compound (I-40) with the yield of 69.4%. ESI-MS [ M + H ]]+：m/z 365.2。
EXAMPLE 41
Preparation of 1- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzotriazole (I-41)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0).036mol) was dissolved in 100ml of acetonitrile, and 3-cyanophenylpiperazine (5.6g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, and after stirring and mixing, the mixture was refluxed for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 7.6g of the compound (I-41) with the yield of 70.5%. ESI-MS [ M + H ]]+：m/z360.2。
Example 42
Preparation of 1- (5- (4- (3-trifluoromethylphenyl) piperazine-1-yl) pentyl) -1H-benzotriazole (I-42)
Benzotriazole (11.9g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, and 5-chlorobromopentane (36.8g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added thereto, followed by mixing and stirring for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane into the water phase for extraction, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oily substance. Neutral Al of oily matter2O3And (4) carrying out chromatographic separation and purification, eluting with dichloromethane to obtain 15.8g of 1- (5-chloropentyl) -1H-benzotriazole, wherein the yield is 71.0%.
1- (5-chloropentyl) -1H-benzotriazole (8.0g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.7g of Compound (I-42) in 61.5% yield. ESI-MS [ M + H ]]+：m/z 417.2。
Example 43
Preparation of 1- (4- (4- (2-furyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-43)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-furyl) piperazine (4.6g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.0g of Compound (I-43) in 71.3% yield. ESI-MS [ M + H ]]+：m/z 325.2。
Example 44
Preparation of 1- (4- (4- (4-pyridyl) piperazin-1-yl) butyl) -1H-benzotriazole (I-44)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (4-pyridyl) piperazine (4.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 6.6g of Compound (I-44) in 65.3% yield. ESI-MS [ M + H ]]+：m/z 336.2。
Example 45
Preparation of 1- (4- (4- (2-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzotriazole (I-45)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-pyrimidinyl) piperazine (4.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 6.8g of Compound (I-45) in 67.1% yield. ESI-MS [ M + H ]]+：m/z 337.2。
Example 46
Preparation of 1- (4- (4-cyclohexylpiperazine-1-yl) butyl) -1H-benzotriazole (I-46)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (1-cyclohexyl) piperazine (5.1g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 6.5g of Compound (I-46) in 63.7% yield. ESI-MS [ M + H ]]+：m/z 341.2。
Example 47
Preparation of 1- (4- (4- (1-naphthyl) piperazin-1-yl) butyl) -1H-benzotriazole (I-47)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (1-naphthyl) piperazine (6.4g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and iodine were added thereto, respectivelyPotassium (5.0g, 0.03mol), stirred and mixed, and then heated to reflux for 20 h. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 6.9g of the compound (I-47) with the yield of 60.1%. ESI-MS [ M + H ]]+：m/z385.2。
Example 48
Preparation of 1- (4- (4- (2-quinoxaline) piperazine-1-yl) butyl) -1H-benzotriazole (I-48)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-quinoxalinyl) piperazine (6.4g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 7.3g of the compound (I-48) with the yield of 62.7%. ESI-MS [ M + H ]]+：m/z 387.2。
Example 49
Preparation of 1- (4- (4- (3- (6-fluoro-benzisothiazolyl)) piperazin-1-yl) butyl) -1H-benzotriazole (I-49)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 6-fluoro-3- (piperazin-4-yl) benzisothiazole (6.6g, 0.05mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation of pureThen, the reaction mixture was eluted with methylene chloride to give 8.2g of Compound (I-49) in 66.5% yield. ESI-MS [ M + H ]]+：m/z 410.2。
Example 50
Preparation of 1- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-50)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 29.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3- (piperazin-4-yl) benzopyrazole (6.1g, 0.05mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, respectively, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Chromatographic separation and purification, and eluting with dichloromethane to obtain 7.7g of the compound (I-50) with the yield of 68.2%. ESI-MS [ M + H ]]+：m/z 375.2。
Example 51
Preparation of 1- (3- (4- (3- (6-fluoro-benzofuranyl) piperazin-1-yl) propyl) -1H-benzotriazole (I-51)
1- (3-chloropropyl) -1H-benzotriazole was prepared by the method in example 37.
1- (3-chloropropyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 6-fluoro-3- (piperazin-4-yl) benzofuran (6.6g, 0.05mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 7.9g of Compound (I-51) in 69.1% yield. ESI-MS [ M + H ]]+：m/z 379.2。
Example 52
Preparation of 1- (4- (4- (3- (6-fluoro-benzisoxazolyl) piperazine-1-yl) propoxy) -1H-benzotriazole (I-52)
Preparation of 1- (3-chloropropoxy) benzotriazole
Dissolving 1-hydroxybenzotriazole (0.01mol) in 10mL NMP, adding a solid paraffin mixture of sodium hydrogen (0.01mol) with 50% weight ratio in batches, stirring for reaction for 0. Sh., dissolving 3-chlorobromopropane (0.015mol) in 5mL NMP, adding the solution, stirring for reaction for 12h at room temperature, pouring the reaction solution into 50mL water, extracting with ethyl acetate (3 × 50mL), combining organic phases, washing with 30mL water, adding anhydrous magnesium sulfate to dry the organic phase, filtering, evaporating the solvent to dryness, and passing the oily substance through neutral Al2O3Separating and purifying by chromatography or preparative HPLC to obtain 1- (3-chloropropoxy) benzotriazole with yield of 75.0%.
1- (3-chloropropyloxy) benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluoro-benzisoxazolyl)) piperazine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, respectively, and the mixture was stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.4g of 1- (4- (4- (3- (6-fluoro-benzisoxazolyl) piperazine-1-yl) propoxy) -1H-benzotriazole (I-52), with yield of 67.6%]+：m/z396.2。
Example 53
Preparation of 6-fluoro-1- (4- (4- (3- (6-fluoro-benzisothiazolyl) piperazine-1-yl) propoxy) -1H-benzotriazole (I-53)
Preparation of 6-fluoro-1- (2-chloropropoxy) -benzotriazole
Reacting 6-fluoro-1-hydroxyDissolving benzotriazole (0.01mol) in 10mL of NMP, adding a solid paraffin mixture of sodium hydrogen (0.01mol) with the weight ratio of 50% in batches, stirring for reaction for 0.5h, simultaneously dissolving 3-chlorobromopropane (0.015mol) in 5mL of NMP, adding the solution, stirring for reaction for 12h at room temperature, pouring the reaction solution into 50mL of water, extracting with ethyl acetate (3 × 50mL), combining organic phases, washing with 30mL of water, adding anhydrous magnesium sulfate to dry the organic phase, filtering, evaporating the solvent to dryness, and processing the oily matter by neutral Al2O3Separating and purifying by chromatography or preparative HPLC to obtain 6-fluoro-1- (3-chloropropoxy) benzotriazole with the yield of 75.0%.
6-fluoro-1- (3-chloropropoxy) benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluoro-benzisothiazolyl)) piperazine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, followed by mixing and stirring at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 14.1g of 6-fluoro-1- (4- (4- (3- (6-fluoro-benzisothiazolyl) piperazine-1-yl) propoxy) -1H-benzotriazole (I-53), with yield of 65.6%]+：m/z 430.1。
Example 54
Preparation of 6-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-54)
6-chloro-benzotriazole (15.3g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane into the water phase for extraction, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oily substance. Neutral Al of oily matter2O3Separating and purifying by chromatography, eluting with dichloromethane to obtain 6-chloro-1- (4-chloro)19.2g of butyl) -1H-benzotriazole and the yield is 79.0%.
6-chloro-1- (4-chlorobutyl) -1H-benzotriazole (8.75g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, eluting with methylene chloride, to give 8.5g of Compound (I-54) in 64.7% yield. ESI-MS [ M + H ]]+：m/z 437.2。
Example 55
Preparation of 6-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-55)
6-cyano-benzotriazole (14.4g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane into the water phase for extraction, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oily substance. Neutral Al of oily matter2O3Carrying out chromatographic separation and purification, eluting with dichloromethane to obtain 17.8g of 6-cyano-1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 76.0%.
6-cyano-1- (4-chlorobutyl) -1H-benzotriazole (8.42g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and reflux reaction at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, eluting with methylene chloride, to give 8.5g of Compound (I-55), in 66.4% yield. ESI-MS [ M + H ]]+：m/z 428.2。
Example 56
Preparation of 6-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole (I-56)
6-methoxycarbonyl-benzotriazole (17.7g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, 4-chlorobromobutane (34.3g, 0.20mol) and 0.8g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes. The reaction solution was slowly heated to 60 ℃ and stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane into the water phase for extraction, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oily substance. Neutral Al of oily matter2O3And (3) carrying out chromatographic separation and purification, eluting with dichloromethane to obtain 19.5g of 6-methoxycarbonyl-1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 73.0%.
6-methoxycarbonyl-1- (4-chlorobutyl) -1H-benzotriazole (9.61g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added thereto, followed by stirring, mixing, and refluxing at elevated temperature for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3The product was separated and purified by chromatography, and eluted with methylene chloride to give 8.8g of Compound (I-56) in 63.4% yield. ESI-MS [ M + H ]]+：m/z 461.2。
Example 57
Preparation of 1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-indole (I-57)
1H-indole (11.7g, 0.10mol) was dissolved in 200ml of a 20 wt% aqueous sodium hydroxide solution, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added thereto, and the mixture was stirred for 5 minutes, warmed to 60 ℃ and stirred for reaction for 2 hours. Cooled to room temperature and 100ml of bis (ll) are addedExtracting with chloromethane, separating, adding dichloromethane 100ml into water phase, extracting, combining organic phases, washing with 100ml saturated saline, separating, and evaporating organic phase to obtain oily substance. Neutral Al of oily matter2O3Chromatographic separation and purification to obtain 12.5g of 1- (4-chlorobutyl) -1H-indole with the yield of 60.1 percent.
1- (4-chlorobutyl) -1H-indole (7.45g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 7.3g of compound (I-57) with yield of 60.6%. ESI-MS [ M + H ]]+：m/z 402.2。
Example 58
Preparation of 6-cyano-1- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-indole (I-58)
6-cyano-1H-indole (14.2g, 0.10mol) was dissolved in 200ml of a 20 wt% aqueous sodium hydroxide solution, 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added, and the mixture was stirred for 5 minutes, then heated to 60 ℃ and reacted for 2 hours with stirring. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter2O3Chromatographic separation and purification to obtain 13.9g of 6-cyano-1- (4-chlorobutyl) -1H-indole with the yield of 60.3 percent.
6-cyano-1- (4-chlorobutyl) -1H-indole (8.35g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trichlorophenylpiperazine (5.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, and concentrating the filtrate to obtain oilMaterial, neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 6.9g of compound (I-58) with yield of 62.3%. ESI-MS [ M + H ]]+：m/z 393.2。
Example 59
Preparation of 1- (3- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propyl) -1H-benzopyrazol (I-59)
1H-benzopyrazole (11.8g, 0.10mol) was dissolved in 200ml of a 20% by weight aqueous sodium hydroxide solution, and 3-chlorobromopropane (31.2g, 0.20mol) and 1.0g of tetrabutylammonium bromide were added thereto, and the mixture was stirred for 5 minutes, warmed to 60 ℃ and reacted for 2 hours with stirring. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter2O3Chromatographic separation and purification to obtain 11.5g of 1- (3-chloropropyl) -1H-benzopyrazole with the yield of 59.3 percent.
The resulting 1- (3-chloropropyl) -1H-benzopyrazole (6.98g, 0.036mol) was dissolved in 100ml of acetonitrile, and 3-trifluoromethylphenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, and the mixture was stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 7.6g of compound (I-59), with yield of 63.1%. ESI-MS [ M + H ]]+：m/z 389.2。
Example 60
Preparation of 6-cyano-1- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propyl) -1H-benzopyrazol (I-60)
6-cyano-1H-benzopyrazole (14.3g, 0.10mol) was dissolved in 200ml of a 20% by weight aqueous sodium hydroxide solution, and 3-chlorobromide was addedPropane (31.2g, 0.20mol) and tetrabutylammonium bromide (1.0 g) were mixed and stirred for 5 minutes, the temperature was raised to 60 ℃, and the reaction was stirred for 2 hours. Cooling to room temperature, adding 100ml dichloromethane for extraction, separating, adding 100ml dichloromethane for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline, separating, and evaporating the organic phase to obtain oil. Neutral Al of oily matter2O3Chromatographic separation and purification to obtain 13.9g of 6-cyano-1- (3-chloropropyl) -1H-benzopyrazole with the yield of 63.8 percent.
6-cyano-1- (3-chloropropyl) -1H-benzopyrazole (7.88g, 0.036mol) was dissolved in 100ml of acetonitrile, and 2, 3-dichlorophenylpiperazine (6.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, stirred at room temperature for 10 minutes, and then heated under reflux for 15 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 7.6g of compound (I-60) with yield of 61.1%. ESI-MS [ M + H ]]+：m/z 414.1。
Example 61
The compounds (I-61 to I-65) according to the invention were prepared according to the method described in patent application US20100329978A 1.
Example 62
The compounds (I-66 to I-84) according to the invention were prepared according to the method described in Chinese patent application 200610097269.1.
Example 63
Compounds II-1 to II-60 have a vasodilating effect on isolated vascular smooth muscle of rabbits induced by spasmolytic agents
1 test animal:
the rabbit can be used for male and female, has a weight of 2.0-3.0kg, and is provided by Experimental animals center of Chinese medical university.
2 drugs and reagents
Compound II-1-II-60, i.e., the hydrochloride salt of compound I-1-I-60, can be prepared according to example 2 (or 3 or 31 or 34) and prepared as the salt (hydrochloride salt) by the method of example;
sodium chloride (NaCl): purchased from mao chemical reagents factory, Tianjin, lot number: 20120413, respectively;
potassium chloride (KCl): purchased from mao chemical reagents factory, Tianjin, lot number: 20111123, respectively;
anhydrous magnesium sulfate (MgSO)4): purchased from mao chemical reagents factory, Tianjin, lot number: 20101029, respectively;
anhydrous calcium chloride (CaCl)2): purchased from mao chemical reagents factory, Tianjin, lot number: 20110314, respectively;
sodium bicarbonate (NaHCO)3): purchased from mao chemical reagents factory, Tianjin, lot number: 20120507, respectively;
glucose (Glucose): purchased from mao chemical reagents factory, Tianjin, lot number: 20120512, respectively;
potassium dihydrogen phosphate (KH)2PO4): product purchased from the mao chemical reagent plant, Tianjin, lot number: 20110928, respectively;
sodium chloride injection (NaCl): purchased from Shenyang Zhiying pharmaceutical factory, lot number: 12021001, respectively;
specification of Epinephrine Hydrochloride injection (Epinephrine Hydrochloride Inj): 1mg/1ml, available from Yuanda pharmaceutical (China) Co., Ltd., lot number 120105;
noradrenaline Bitartrate Inj selection with a specification of 2mg/1ml, manufactured by far-reaching medicine (china) limited, lot number 120304;
3 laboratory instruments
HSS-1(B) type constant temperature bath: chengdu instrument factories;
RM6240B multichannel physiological signal acquisition processing system: chengdu instrument factories;
model JZJ01 muscle tension transducer: chengdu instrument factories;
YPJ01 type pressure transducer: chengdu instrument factories;
TG-328A electro-optical analytical balance: shanghai balance instrumentation works;
model T-500 electronic balance: a well-done Shuangjie test instrumentation factory;
a micropipette: shanghai Rongtai Biochemical engineering Co., Ltd;
electric heating constant temperature water bath: tester instruments, Inc., Tianjin.
4 preparation of nutrient solution
Krebs-Henseleit (K-H) physiological solution: NaCl 6.92 (concentration units), KCl0.35, MgSO40.29，KH2PO40.16，CaCl20.28，NaHCO32.1，Glucose2.0(g/L)，pH 7.2。
High potassium solution: removing equimolar NaCl from K-H solution, adding KCl to prepare K-containing solution+60mmol/L modified K-H solution.
Calcium-free K-H solution: adding CaCl in K-H solution2Removing, adding KCl in equal molar number, and adding EDTA-2Na+0.1mmol/L, and the other components were unchanged.
Calcium-free high-potassium solution: adding CaCl in the high potassium solution2Removing, adding KCl in equal molar number, and adding EDTA-2Na+0.1mmol/L, and the other components are unchanged.
Preparation of compound II-1-II-60 solution: weighing a certain mass of compound sample, and diluting with distilled water as solvent to a series of concentrations (10)-10-10-3mol/L) for standby.
Preparation of 5 rabbit isolated blood vessel smooth muscle specimen
The rabbit, after stunning the animal, dissect the thorax rapidly, strip the descending aorta, after removing connective tissue and surrounding adipose tissue (if carrying on the antagonist experiment of serotonin receptor, should also use the smooth stainless steel rod to remove the endothelial cell), cut into the blood vessel ring of 3-5mm, then the steel wire hook crosses the blood vessel ring, one end is fixed on ventilating the hook, another end connects to the tension transducer, put into bath tube containing 20ml nutrient solution, record the change of tension through the recorder. The temperature in the bath tube is kept at 37 +/-0.5 ℃, and mixed gas (95% O) is introduced at the speed of 1-2 bubbles per second2+5％CO2). The initial load of the specimen is 1.5g, the nutrient solution is changed every 20min, the balance is carried out for 2 hours, and the experiment is started after the base line is stable.
6 concrete test operations and test results
6.1 Compounds II-1 to II-60 on the vasodilation of isolated vascular smooth muscle of rabbits induced by the spasmolytic epinephrine hydrochloride (AD)
Recording a section of waveform after the specimen is stable in tension, and adding spasmolytic adrenaline hydrochloride (AD) (10) into the bath tube- 5mol/L), fully washing the specimen after the maximum contraction is reached, changing K-H liquid every 20min, balancing for 60min, inducing contraction again by using spasmolytic with the same concentration after the baseline is recovered to be stable, and cumulatively adding the prepared compound II-1-II-60 solution (1 × 10) when the maximum reaction of the next contraction is basically consistent with that of the previous contraction-8-1×10-3mol/L), the waveform is recorded. The percent relaxation of the compound II-1-II-60 is used as the ordinate, the maximum relaxation response is 100 percent, the effect curve is made, wherein the relaxation of II-2 and II-3 is most obvious, and the negative logarithm of each concentration is used as the abscissa to draw a dose-effect curve as shown in figure 1 and figure 8.
As can be seen from FIGS. 1 and 8, compounds II-2 and II-3 have a relaxation effect on the contraction of specimens induced by AD spasmolytic and show a dose-dependence on the relaxation effect of epinephrine, wherein compound II-2 relaxes-logEC of aortic contraction in rabbits induced by AD50A value of 5.73. + -. 0.03 for compound II-3 relaxation of aorta contraction caused by AD-logEC in rabbits50The value was 6.01. + -. 0.05.
The compound II-31 also shows obvious relaxation effect, and the negative logarithm of each concentration is an abscissa to draw a dose-effect curve, which is shown in figure 10; wherein II-29 also has obvious relaxation effect, and the dose-response curve is shown in figure 15. As can be seen from FIG. 10, compound II-31 has a relaxing effect on the contraction of the specimen caused by AD spasmolytic, and shows a certain dose dependence on the relaxation of epinephrine, and compound II-31 relaxes-logEC of the aorta contraction of rabbit caused by AD5oThe value was 6.19. + -. 0.03; similarly, the relaxation of adrenaline by compound II-29 is dose-dependent and relaxes the-logEC of aortic contraction in rabbits induced by AD5oThe value was 6.01. + -. 0.02.
The vasodilatory effect of compounds II-1 to II-60 on isolated vascular smooth muscle of AD-contracted rabbits is shown in Table 1:
TABLE 1 relaxation of isolated vascular smooth muscle of AD-contracted rabbits by Compound II-1-II-60
6.2 the vasodilation of Compounds II-1 to II-60 in isolated vascular smooth muscle of rabbits induced by high Potassium solution of a spasmolytic
Recording a section of waveform after the specimen is stable in tension, and adding spasmolytic adrenaline hydrochloride (AD) (10) into the bath tube- 5mol/L), fully washing the specimen after the maximum contraction is reached, changing K-H liquid once every 20min, balancing for 60min, changing the K-H liquid in the bath tube into high-potassium liquid to induce contraction after the base line is recovered to be stable, and cumulatively adding the prepared compound II-1-II-60 solution (1 ×) when the maximum reaction of the latter contraction is basically consistent with the former one10-8-1×10-3mol/L), the waveform is recorded. The effect curve was plotted with the percent relaxation of compound II-1-II-60 as the ordinate and the maximum relaxation response of 100%. Wherein II-2 and II-3 have the most obvious relaxation effect, and the negative logarithm of each concentration is an abscissa to draw a dose-effect curve as shown in FIG. 2 and FIG. 9.
As can be seen from FIGS. 2 and 9, compounds II-2 and II-3 have significant relaxation effects on specimen contraction caused by hyperkalium fluid, and show certain dose dependence on the relaxation effect of epinephrine, and compound II-2 relaxes-logEC of rabbit aortic contraction caused by hyperkalium fluid50The value is 5.34 +/-0.02, and the compound II-3 relaxes the-logEC of the rabbit aortic contraction caused by high potassium fluid50The value was 5.49. + -. 0.05. Wherein, the compound II-31 shows more obvious relaxation effect, and the negative logarithm of each concentration is the abscissa to draw a dose-effect curve, which is shown in figure 11; wherein II-29 also has obvious relaxation effect, and the dose-response curve is shown in figure 16. As can be seen from FIG. 11, compound II-31 has a relaxation effect on the contraction of the specimen caused by spasmolytic in high potassium fluid, and shows a certain dose dependence on the relaxation effect on high potassium fluid, and compound II-31 relaxes-logEC of aortic contraction in rabbit caused by high potassium fluid50The value was 5.55. + -. 0.03; similarly, the relaxation of potassium-rich fluid by compound II-29 is dose-dependent and relaxes-logEC of aortic contraction in rabbits induced by potassium-rich fluid50The value was 5.64. + -. 0.01.
The effect of compounds II-1 to II-60 on the relaxation of isolated vascular smooth muscle of rabbits induced by a high potassium solution of a spasmolytic is shown in Table 2:
TABLE 2 relaxation of isolated vascular smooth muscle of rabbits by Compound II-1-II-60 in high Potassium solution
Example 64
Research on relaxation mechanism of compound II-2 on isolated vascular smooth muscle of rabbit
1 test animal:
the rabbit can be used for male and female, has a weight of 2.0-3.0kg, and is provided by Experimental animals center of Chinese medical university.
2 drugs and reagents
The compound II-2 is prepared by the method of example 2;
sodium chloride (NaCl): purchased from mao chemical reagents factory, Tianjin, lot number: 20120413, respectively;
potassium chloride (KCl): purchased from mao chemical reagents factory, Tianjin, lot number: 20111123, respectively;
anhydrous magnesium sulfate (MgSO)4): purchased from mao chemical reagents factory, Tianjin, lot number: 20101029, respectively;
anhydrous calcium chloride (CaCl)2): purchased from mao chemical reagents factory, Tianjin, lot number: 20110314, respectively;
sodium bicarbonate (NaHCO)3): purchased from mao chemical reagents factory, Tianjin, lot number: 20120507, respectively;
glucose (Glucose): purchased from mao chemical reagents factory, Tianjin, lot number: 20120512, respectively;
potassium dihydrogen phosphate (KH)2PO4): product purchased from the mao chemical reagent plant, Tianjin, lot number: 20110928, respectively;
sodium chloride injection (NaCl): purchased from Shenyang Zhiying pharmaceutical factory, lot number: 12021001, respectively;
specification of Epinephrine Hydrochloride Injection (Epinephrine Hydrochloride Injection): 1mg/1ml, available from Yuanda pharmaceutical (China) Co., Ltd., lot number 120105;
noradrenaline Bitartrate Inj selection with a specification of 2mg/1ml, manufactured by far-reaching medicine (china) limited, lot number 120304;
doxazosin Mesylate (Doxazosin Mesylate): purchased from zephyceae pharmaceutical chemicals ltd, lot number: 20110305, respectively;
amlodipine Besylate Tablets (Amlodipine Besylate Tablets): purchased from pfeiri pharmaceutical limited, specifications: 5 mg/tablet batch number: 1205018, respectively; specification of Epinephrine Hydrochloride Injection (Epinephrine Hydrochloride Injection): 1mg/1ml, available from Yuanda pharmaceutical (China) Co., Ltd., lot number 120105;
(R) -Phenylephrine Hydrochloride ((R) -Phenylephrine Hydrochloride), echiei (Shanghai) chemical industry development Limited, batch number: GJ 01-TESP;
serotonin creation Sulfate Monohydrate (5-HT), manufactured by Tokyo Kasei Kogyo, lot No.: AZ 01-TBKD;
heparin sodium injection (Heparin sodium): pharmaceutical specifications of Wanbang: 2ml/12500 units, batch number: 101115, respectively;
black sugar (urea): shanghai chemical reagents company, China medicine (group), lot number: c30191228;
ethylenediaminetetraacetic acid (EDTA), a product of majon chemical reagent plant, tianjin, lot number: 20050809.
3 laboratory instruments
HSS-1(B) type constant temperature bath: chengdu instrument factories;
RM6240B multichannel physiological signal acquisition processing system: chengdu instrument factories;
model JZJ01 muscle tension transducer: chengdu instrument factories;
YPJ01 type pressure transducer: chengdu instrument factories;
TG-328A electro-optical analytical balance: shanghai balance instrumentation works;
model T-500 electronic balance: a well-done Shuangjie test instrumentation factory;
a micropipette: shanghai Rongtai Biochemical engineering Co., Ltd;
electric heating constant temperature water bath: tester instruments, Inc., Tianjin.
4 preparation of nutrient solution
Krebs-Henseleit (K-H) physiological solution: NaCl 6.92 (concentration units), KCl0.35, MgSO40.29，KH2PO40.16，CaCl20.28，NaHCO32.1, glucose 2.0(g/L), pH 7.2.
High potassium solution: removing equimolar NaCl from the K-H solution, and adding KCl to prepare the improved K-H solution containing K +60 mmol/L.
Calcium-free K-H solution: adding CaCl in K-H solution2Removing, adding KCl in equal molar number, and adding EDTA-2Na+0.1mmol/L, and the other components were unchanged.
Calcium-free high-potassium solution: adding CaCl in the high potassium solution2Removing, adding KCl in equal molar number, and adding EDTA-2Na+0.1mmol/L, and the other components are unchanged.
Preparation of compound II-2 solution: weighing a certain mass of compound II-2 sample, and diluting with distilled water as solvent to a series of concentrations (10)-10-10-4mol/L) for standby.
Preparation of 5 rabbit isolated blood vessel smooth muscle specimen
Cutting open thoracic cavity of rabbit, stripping off descending aorta, removing connective tissue and peripheral adipose tissue (if serotonin receptor antagonism experiment is performed, endothelial cells should be removed by smooth stainless steel bar), cutting into 3-5mm blood vessel ring, passing steel wire hook through blood vessel ring, fixing one end on ventilation hook, connecting the other end to tension transducer, placing in bath tube containing 20ml of nutrient solution, and passing through recording instrumentThe change in tension is recorded. The temperature in the bath tube is kept at 37 +/-0.5 ℃, and mixed gas (95% O) is introduced at the speed of 1-2 bubbles per second2+5％CO2). The initial load of the specimen is 1.5g, the nutrient solution is changed every 20min, the balance is carried out for 2 hours, and the experiment is started after the base line is stable.
6 Experimental procedures and results
6.1 antagonistic Effect of Compound II-2 on vascular smooth muscle alpha receptor agonists in rabbits
6.1.1 Effect of Compound II-2 on norepinephrine cumulative contractility curves
After the specimen has stabilized tension, a waveform is recorded and Norepinephrine (NA) (10) is cumulatively added to the bath tube-8-10-4mol/L) until the maximum reaction is reached, recording the waveform, then repeatedly washing the specimen with K-H solution, after balancing for 1H, adding compound II-2(3 × 10)-7mol/L) after 20min, NA. is added in the same way to ensure that the maximum reaction is 100 percent, the shrinkage percentage of NA is ordinate and the negative logarithm of each concentration of NA is abscissa to draw a dose-effect curve, and the compound II-2(3 × 10) is added-7mol/L) as shown in FIG. 3.
The NA dose-effect curve is obviously parallel and right-shifted, the maximum reaction is almost unchanged, most P values are less than 0.01 after the statistical t test is carried out on the reaction percentage of each concentration, and significant difference exists. Compound II-2 antagonizes PA of NA contracting rabbit aorta2The value was 7.37. + -. 0.08;
6.1.2 Effect of Positive control doxazosin on cumulative shrinkage dose-response Curve for norepinephrine
After the specimen is stabilized in tension, a waveform is recorded and Norepinephrine (NA) (10) is added to the tube-8-10-4mol/L)(10-8-3×10-3mol/L) until maximum response is reached and the waveform is recorded. Repeatedly washing the specimen with K-H solution, changing K-H solution every 20min, balancing for 60min, and adding doxazosin (10) after baseline is stable-7mol/L), then Noradrenaline (NA) (10) is added in the same way after 15min-8-6×10-5mol/L). The maximum reaction is 100%, the shrinkage percentage of NA is ordinate, the negative logarithm of each concentration of NA is abscissa to draw a dose-effect curve, and doxazosin (10) is added-7mol/L), as shown in FIG. 4, the NA dose-effect curve is obviously parallel and right-shifted, the maximum reaction is almost unchanged, and after the statistical test of the reaction percentage of each concentration, most P values are less than 0.01, and significant difference exists. Positive drug doxazosin antagonizes NA and contracts PA of rabbit aorta2The value was 7.52. + -. 0.04.
Through statistical t test, the compound II-2 and a positive control drug doxazosin PA to NA2Compared with the values, P is more than 0.05, and the two values have no significant difference, which indicates that the antagonism of the compound 11-2 to α receptor agonist is similar to that of doxazosin.
6.2 Compound II-2 on vascular smooth muscle calcium channel (Ca) in rabbits2+) Antagonism of
6.2.1 Compound II-2 vs. CaCl2Effect of cumulative contractile rabbit vascular concentration Effect Curve
After the tension of the specimen is stabilized, the specimen is washed for 3 times by using calcium-free K-H solution, incubated for 40min by using calcium-free K-H solution, depolarized for 20min by adding calcium-free high potassium solution, and CaCl is cumulatively added into the bath tube2(10-6-10-2mol/L) until the maximum reaction is reached, recording waveforms, repeatedly washing the specimen with K-H solution, changing the K-H solution every 20min, balancing for 60min, after the baseline is recovered to be stable, washing the specimen with calcium-free K-H solution for 3 times, incubating with calcium-free K-H solution for 40min, adding calcium-free high potassium solution to depolarize the specimen for 20min, and simultaneously adding compound II-2(3 × 10) into the bath tube-6mol/L), incubating for 20min, and adding CaCl by the same method2(10-6-10-2mol/L) until the maximum response is reached, and the waveform is recorded. CaCl with the maximum reaction of 100%2The percent shrinkage at each concentration is given by the ordinate, CaCl2Plotting dose-response curves with the negative logarithm of each concentration as the abscissa, Compound II-2(3 × 10) was added-6mol/L), as shown in FIG. 5, CaCl2The dose-effect curve is obviously parallel to the right and has the maximum reaction tableThe reaction percentage of each concentration is statistically tested, most P values are less than 0.01, and significant difference exists. Compounds II-2 antagonize CaCl2PA for contracting rabbit aorta2The value was 5.61. + -. 0.04.
6.2.2 Positive control amlodipine vs. CaCl2Effect of cumulative shrinkage dose-response Curve
After the tension of the specimen is stable, the specimen is washed for 3 times by using calcium-free K-H solution, incubated for 40min by using calcium-free K-H solution, depolarized for 20min by adding calcium-free high potassium solution, and CaCl is added into the bath tube2(10-6-10-2mol/L) until the maximum response is reached, and the waveform is recorded. Repeatedly washing the specimen with K-H solution, changing K-H solution every 20min, balancing for 60min, after the baseline is recovered to be stable, washing the specimen with calcium-free K-H solution for 3 times, incubating with calcium-free K-H solution for 40min, adding calcium-free high potassium solution to depolarize the specimen for 20min, and simultaneously adding amlodipine (10-7mol/L), incubating for 15min, and adding CaCl in the same way2(10-6-10-2mol/L) until the maximum response is reached, and the waveform is recorded. CaCl with the maximum reaction of 100%2The percent shrinkage at each concentration is given by the ordinate, CaCl2The negative logarithm of each concentration is an abscissa to draw a dose-effect curve, and amlodipine (3 × 10-6mol/L), as shown in FIG. 6, CaCl2The dose-effect curve is obviously parallel to the right and is almost unchanged in maximum reaction, and after the statistical test is carried out on the reaction percentage of each concentration, most P values are less than 0.01, and significant difference exists. Amlodipine antagonizes CaCl2PA for contracting rabbit aorta2The value was 6.99. + -. 0.05.
6.3 antagonistic Effect of Compound II-2 on Rabbit vascular smooth muscle serotonin (5-HT) receptor agonists
After the specimen tension stabilized, a waveform was recorded and 5-HT (10) was added cumulatively to the bath tube-7-3×10-4mol/L) until the maximum reaction is reached, recording the waveform, then repeatedly washing the sample by using K-H solution, balancing for 1.5H, adding compound II-2(3 × 10)-6mol/L) for 20minAdding 5-HT. in the same way, drawing a dose-effect curve by taking the maximum reaction as 100%, the shrinkage percentage of 5-HT as ordinate and the negative logarithm of each concentration of 5-HT as abscissa, and adding compound II-2(3 × 10)-6mol/L), as shown in FIG. 7, the 5-HT dose-effect curve is obviously parallel to the right, the maximum reaction is almost unchanged, and after the statistical test of the reaction percentage of each concentration, the P value is less than 0.01, and the significant difference exists. Compound II-2 antagonizes PA of 5-HT contractile rabbit aorta2The value was 5.71. + -. 0.08.
Example 65
Research on relaxation mechanism of compound II-31 on rabbit isolated vascular smooth muscle
1.1 antagonistic Effect of Compound II-31 on rabbit vascular smooth muscle alpha receptor agonists
1.1.1 Effect of Compound II-31 on the cumulative contractility Curve for norepinephrine
After the specimen has stabilized in tension, a waveform is recorded and Norepinephrine (NA) (3 × 10) is added cumulatively to the bath tube-7-6×10-5mol/L) until the maximum reaction is reached, recording the waveform, then repeatedly washing the specimen with K-H solution, after 1H of equilibration, adding compound II-31(3 × 10)-6mol/L), adding NA (3 × 10) in the same way after 20min-7-3×10-4mol/L), drawing a dose-effect curve by taking the maximum reaction as 100%, the shrinkage percentage of NA as ordinate and the negative logarithm of each concentration of NA as abscissa, and adding the compound II-31(3 × 10)-6mol/L), as shown in FIG. 10, the NA dose-effect curve is obviously parallel and right-shifted, the maximum reaction is almost unchanged, and after the statistical t test is carried out on the reaction percentage of each concentration, most P values are less than 0.01, and significant difference exists. Compound II-31 antagonizes PA of NA contracting rabbit aorta2The value was 6.02. + -. 0.13.
1.1.2 Effect of Positive control doxazosin on cumulative shrinkage dose-response Curve for norepinephrine
Repeatedly washing the specimen with K-H solution based on the above stepsAfter 1h of equilibration, doxazosin (10) was added-7mol/L), after 15min NA. is added in the same way to ensure that the maximum reaction is 100 percent, the shrinkage percentage of NA is ordinate, and NA (3 × 10)-7-3×10-4mol/L) is used as the abscissa to draw a dose-effect curve, and the medicine doxazosin (10) is added-7mol/L), as shown in FIG. 12, the NA dose-effect curve is obviously parallel and right-shifted, the maximum reaction is almost unchanged, and after the statistical t test is carried out on the reaction percentage of each concentration, most P values are less than 0.01, and significant difference exists. Drug doxazosin antagonizes NA to contract PA of rabbit aorta2The value was 7.76. + -. 0.24.
Through statistical t test, the compound II-31 and the positive control drug doxazosin PA to NA2The comparison between the values, P < 0.01, shows that there is a very significant difference between the two, indicating that compound II-31 has a weaker antagonistic effect on α receptor agonists than doxazosin.
1.2 Compound II-31 pairs of vascular smooth muscle calcium channels (Ca) in rabbits2+) Antagonism of
1.2.1 Compound II-31 para CaCl2Effect of cumulative contractile rabbit vascular concentration Effect Curve
After the tension of the specimen is stabilized, the specimen is washed for 3 times by using calcium-free K-H solution, incubated for 40min by using calcium-free K-H solution, depolarized for 20min by adding calcium-free high potassium solution, and CaCl is cumulatively added into the bath tube2(10-5-3×10-2mol/L) until the maximum response is reached, and the waveform is recorded. Repeatedly washing the specimen with K-H solution, changing K-H solution every 20min, balancing for 60min, after the baseline is recovered to be stable, washing the specimen with calcium-free K-H solution for 3 times, incubating with calcium-free K-H solution for 40min, adding calcium-free high potassium solution to depolarize the specimen for 20min, and adding compound II-31(10-5mol/L), incubating for 20min, and adding CaCl by the same method2(10-5-3×10-1mol/L) until the maximum response is reached, and the waveform is recorded. CaCl with the maximum reaction of 100%2The percent shrinkage at each concentration is given by the ordinate, CaCl2Plotting the log negative of each concentration as the abscissa, addingCompound II-31 (10)-5mol/L), CaCl as shown in FIG. 132The dose-effect curve is obviously parallel to the right and is almost unchanged in maximum reaction, and after the statistical test is carried out on the reaction percentage of each concentration, most P values are less than 0.01, and significant difference exists. Compound II-31 antagonizes CaCl2PA for contracting rabbit aorta2The value was 6.56. + -. 0.032.
1.2.2. Positive control drug amlodipine to CaCl2Effect of cumulative shrinkage dose-response Curve
Based on the above steps, repeatedly washing the specimen with K-H solution, changing K-H solution every 20min, balancing for 60min, washing the specimen with calcium-free K-H solution for 3 times after the baseline is stable, incubating with calcium-free K-H solution for 40min, adding calcium-free high potassium solution to depolarize the specimen for 20min, and simultaneously adding amlodipine (10) into the bath tube-7mol/L), incubating for 15min, and adding CaCl in the same way2(10-5-3×10-2mol/L) until the maximum response is reached, and the waveform is recorded. CaCl with the maximum reaction of 100%2The percent shrinkage at each concentration is given by the ordinate, CaCl2The negative logarithm of each concentration is an abscissa to draw a dose-effect curve, and amlodipine (10) is added-5mol/L), CaCl as shown in FIG. 132The dose-effect curve is obviously parallel to the right and is almost unchanged in maximum reaction, and after the statistical test is carried out on the reaction percentage of each concentration, most P values are less than 0.01, and significant difference exists. Amlodipine antagonizes CaCl2PA for contracting rabbit aorta2The value was 7.51. + -. 0.288.
1.3 antagonistic Effect of Compound II-31 on Rabbit vascular smooth muscle serotonin (5-HT) receptor agonists
After the specimen tension stabilized, a waveform was recorded and 5-HT (10) was added cumulatively to the bath tube-8-3×10-4mol/L) until the maximum reaction is reached, recording the waveform, then repeatedly washing the specimen with K-H solution, after 1.5H of equilibration, adding compound II-31(3 × 10)-6mol/L) and after 20min, adding 5-HT in the same way. The maximum response is 100%, the percent of 5-HT shrinkage is plotted on the ordinate, and the negative logarithm of each concentration of 5-HT is plotted on the abscissaDose-response curves were plotted and Compound II-31(3 × 10) was added-6mol/L), as shown in FIG. 14, the 5-HT dose-effect curve is obviously parallel to the right, the maximum reaction is almost unchanged, and after the statistical test of the reaction percentage of each concentration, the P value is less than 0.01, and the significant difference exists. Compound II-31 antagonizes PA of 5-HT contractile rabbit aorta2The value was 6.726. + -. 0.089.
Example 66
Acute toxicity test of Compound II-2
Taking Kunming mouse (provided by Experimental animal center of Chinese medical university), male and female half, and body weight 18-22g, performing compound II-2 simplified probability unit method acute toxicity test, and performing intragastric administration LD50361.88mg/kg (95% confidence interval 302.96-420.80 mg/kg).
Example 67
Bone marrow micronucleus assay in mice with Compound II-2
Compound II-2 was administered to Kunming mice (from the Experimental animal center of university of medical science, China) 10, male and female halves, at a dose of 120 mg/kg/day by re-gavage. The administration was continued for 4 days, and the mouse bone marrow micronucleus test was performed on day 5.
The positive control group is given 60 mg/kg/day of cyclophosphamide; the negative control group was administered with 0.1ml/10 g/day of physiological saline. The administration was continued for 4 days, and the mouse bone marrow micronucleus test was performed on day 5.
Killing a mouse after neck breaking, rapidly stripping off a femur and a sternum, removing blood stain and muscle, subtracting epiphysis, extruding bone marrow on a clean glass slide on which calf serum is dripped in advance by using a hemostat for the sternum or directly flushing the bone marrow in the femur onto the clean glass slide by using the calf serum, and uniformly mixing and then pushing the bone marrow; and then putting the pushed and dried bone marrow slices into a staining jar containing methanol, fixing for 15min, taking out and drying in the air, after the bone marrow slices are dried in the air, staining for 10min by using a freshly prepared Giemsa application solution (one part of Giemsa stock solution is added with 9 parts of phosphate buffer solution with pH 6.8), flushing away the slide staining solution by using trickle water, and observing under a microscope after drying in the air.
The experimental results show that: compound II-2 group 1000 had polyblast containing micronucleus in the polyblast accounts for 2.0 + -0.333% o, blank group 1000 had polyblast containing micronucleus in the polyblast accounts for 1% o, cyclophosphamide group 1000 had microkernel in the polyblast accounts for 12% o. The result of the bone marrow micronucleus test of the compound II-2 is negative.
Example 68
Effect of Compound II-2 on blood pressure in SD rats
4 SD rats were anesthetized with urethane (1.25mg/kg) and blood pressure was measured by common carotid artery cannulation after the vital signs of the rats were stabilized. After the blood pressure stabilized, compound (II-2) was administered by gavage at 4.0mg/kg body weight, and the blood pressure changes with time after administration were observed and recorded, and the experimental results are shown in tables 3, 4 and 5.
Table 3 effect of compound II-2 on diastolic blood pressure (DBP, mmHg) in uratan anesthetized rats (n ═ 4)
Note: p is less than 0.05, P is less than 0.01
Table 4 effect of compound II-2 on systolic blood pressure (SBP, mmHg) in uratan anaesthetised rats (n ═ 4)
Note: p is less than 0.05, P is less than 0.01
Table 5 effect of compound II-2 on mean arterial pressure (MAP, mmHg) in uratan anesthetized rats (n ═ 4)
Note: p is less than 0.05, P is less than 0.01
The experimental results show that: the compound II-2 has obvious antihypertensive effect on the uratan (1.25mg/kg) anesthetized SD rats, and can recover to the level before administration after 3.5 hours of administration.
The results show that the compound II-2 has obvious vasodilation effect on vascular smooth muscle in vitro animal experiments, the antagonism of the compound II-2 on adrenaline α receptor is equivalent to that of doxazosin, and the antagonism of PA of norepinephrine NA is realized2The value is 7.37 +/-0.08, and the doxazosin antagonizes PA of NA2The value is 7.52 +/-0.04, and the compound II-2 antagonizes CaCl2PA of (2)2A value of 5.61. + -. 0.04 which antagonizes PA of 5-HT2The value was 5.71. + -. 0.08. In an in vivo whole test of a rat, the compound II-2 shows an obvious blood pressure reducing effect, has good oral absorption, low toxicity, large therapeutic index and negative bone marrow micronucleus test, and has potential value of being used as a novel multi-target vasodilating medicament, especially being used as a novel blood pressure reducing medicament for development.
Reference to the literature
[ internal science ] Ye ren Gao Re Ying Main edition, published by the people's health, 6 th edition of 4 months in 2007.
[ pharmacology ] lie kingdom, published in human health, 8 months, 6 th edition, 2007.
3.Sanders-Bush E，Mayer SE.5-Hydroxytryptamine(serotonin)：Receptoragonists and antagonists.
In：Brunton LL.Lazo JS，Parker KL(eds).Goodman&Gilman’s ThePharmacological Basis of Therapeutics(11th ed)，Philadelphia：The McGraw-HillCompanies，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 IUPHAR Committee onReceptor Nomenclature and Drug Classification(ed)，The IUPHAR Compendium ofReceptor Characterization and Classification-，London：IUPHAR Media，1998：p167。

Claims (10)

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a vasodilator medicament:
wherein:
R1is represented by R3A mono-or poly-substituted aromatic or aliphatic cyclic group, wherein
R3Is H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; when R is3When it is a polysubstituent group, R3Independently selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms;
A. b independently represents CH or N;
R2represents H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; when R is2When it is a polysubstituent group, R2Independently selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or moreSubstituted by one halogen atom;
y represents a saturated or unsaturated, linear or branched, hydrocarbyl chain containing 2 to 8 carbon atoms, optionally substituted with 1 to 3 halogen atoms, in which one or more carbons are optionally replaced by heteroatoms selected from oxygen, sulphur and nitrogen.
2. The use of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, trifluoroacetate, methanesulfonate, tartrate, malate, succinate, maleate, citrate, phosphate, lactate, pyruvate, acetate, fumarate, oxaloacetate, ethanesulfonate, oxalate, benzenesulfonate or isethionate salt; preferably, the salt contains water of crystallization, preferably 0.5 to 3 molecules of water of crystallization.
3. The use according to claim 1, wherein the aromatic group is phenyl, naphthyl, a benzo five-or six-membered heterocycle with a heteroatom selected from N, S, O, or a five-or six-membered unsaturated heterocycle; preferably phenyl, naphthyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzpyrazolyl, benzofuranyl, benzopyrimidinyl, benzopyridyl, quinoxalinyl, furanyl, pyridinyl or pyrimidinyl; more preferably phenyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzofuranyl, naphthyl, furanyl, pyridinyl, pyrimidinyl, or quinoxalinyl; particularly preferably phenyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, quinoxalinyl or pyrimidinyl; most preferred is phenyl;
the aliphatic cyclic group is preferably a five-membered or six-membered saturated cyclic hydrocarbon group, or a five-membered or six-membered saturated heterocyclic group with a heteroatom selected from N, S, O; more preferably cyclopentyl, cyclohexyl, tetrahydrofuryl, piperidinyl or piperazinyl; even more preferably cyclohexyl, piperidinyl or piperazinyl; cyclohexyl is particularly preferred.
4. The use of claim 1, whereinR3Is H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; preferably, R3Is H, F, Cl, Br, CN, C with alkyl moieties optionally substituted by 1-3 halogen atoms1-C6Alkyl or C1-C6Alkoxy, CHO, COCH3Or COOCH3(ii) a More preferably, R3Is H, F, Cl, COCH3C the alkyl part of which is optionally substituted by 1 to 3 halogen atoms1-C4Alkyl or C1-C4An alkoxy group; even more preferably, R3Is H, F, Cl, CN, CF3、CH3Or OCH3(ii) a Most preferably, R3Is H, F, Cl or OCH3(ii) a When R is3When it is a polysubstituent group, R3Independently selected from the groups described above.
5. The use of claim 1, wherein R2Is H, halogen, CN, C1-C6Alkyl radical, C1-C6Alkoxy, CHO, CO (C)1-C6Alkyl), COO (C)1-C6Alkyl), NO2、NH2、NH(C1-C6Alkyl), SH, S (C)1-C6Alkyl), -SO (C)1-C6Alkyl) or-SO2(C1-C6Alkyl) in which the alkyl moiety is optionally substituted by one or more halogen atoms; preferably, R2Is H, F, Cl, Br, CN, NO2C the alkyl part of which is optionally substituted by 1 to 3 halogen atoms1-C6Alkyl or C1-C6Alkoxy, CHO, COCH3Or COOCH3(ii) a More preferably, R2Is H, F, Cl, CN, CHO, COCH3、COOCH3Or C with alkyl moieties optionally substituted by 1 to 3 halogen atoms1-C4Alkyl or C1-C4An alkoxy group; even more preferably, R2Is H, F, Cl, CN, CH3Or COOCH3(ii) a Particularly preferably, R2Is H, F, Cl or CH3(ii) a Most preferably, R2Is H; when R is2When it is a polysubstituent group, R2Independently selected from the groups described above.
6. Use according to claim 1, wherein Y is a saturated or unsaturated, linear or branched hydrocarbyl chain containing 2 to 8 carbon atoms, optionally substituted with 1 to 3 halogen atoms, wherein one or more carbons are optionally replaced by heteroatoms selected from oxygen, sulphur and nitrogen; preferably, Y is an unsubstituted saturated hydrocarbon group containing 2 to 8 carbons, or an unsubstituted saturated hydrocarbon group containing 2 to 8 carbons in which 1 carbon atom is replaced by oxygen or sulfur, such as-C1-7alkyl-O-; preferably Y is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, oxymethylene, oxyethylene, oxypropylene, oxybutylene, oxypentylene, oxyhexylene, oxyheptylene, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, hexyleneoxy or heptyleneoxy; more preferably, Y is methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentylene oxy, hexylene oxy, or heptyleneoxy; even more preferably, Y is propylene, butylene, propyleneoxy or pentylene; particularly preferably, Y is propylene, butylene or propyleneoxy; most preferably, Y is butylene.
7. The use of claim 1, wherein
When the A, B are all N, then,
R1is not substituted by H or OCH3Monosubstituted phenyl, and
R2is not H or OCH3In which OCH3Disubstituted on the benzo five-membered azacycle; and is
Y is not ethylene, propylene, butylene or pentylene.
8. The use of claim 1, wherein
R1Is represented by R3Mono-or di-substituted aromatic radicals in which
The aromatic group is preferably phenyl or benzisothiazolyl;
R3is H, Cl or CF3(ii) a When R is3When it is a polysubstituent group, R3Independently selected from the groups described above;
A. b independently represents CH or N;
R2represents H;
y represents butylene.
9. The use of claim 1, wherein the compound comprises:
i-11- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-21- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-41- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-52-methyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-66-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-71- (3- (4-phenylpiperazin-1-yl) propyl) -1H-benzimidazole,
I-81- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-92-methyl-1- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-101- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-111- (4- (4- (4-methylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-121- (4- (4- (2-furyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-131- (4- (4- (4-pyridyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-141- (4- (4- (2-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-151- (4- (4- (1-cyclohexyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-161- (4- (4- (1-naphthyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-171- (4- (4- (2-quinoxalinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-181- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-191- (4- (4- (3- (6-fluorobenzoisothiazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-201- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzimidazole,
I-211- (4- (4- (3- (6-fluorophenylfuranyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-221- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-231- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-241- (4- (4- (3-chlorophenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-256-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-266-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-276-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-282-chloro-1- (5- (4- (3-trifluoromethylphenyl) piperazin-1-yl) pentyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-301- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-326-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-335, 6-dimethyl-1- (4- (4- (3-trifluoromethylphenyl) 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) benzisoxazole,
I-366-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole,
I-376-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazin-1-yl) benzisoxazole,
I-381- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-391- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-401- (4- (4- (3-methoxyphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-411- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-421- (5- (4- (3-trifluoromethylphenyl) piperazine-1-yl) amyl) -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-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-461- (4- (4-cyclohexylpiperazine-1-yl) butyl) -1H-benzotriazole,
I-471- (4- (4- (1-naphthyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-481- (4- (4- (2-quinoxaline) piperazine-1-yl) butyl) -1H-benzotriazole,
I-491- (4- (4- (3- (6-fluoro-benzisothiazolyl)) piperazin-1-yl) butyl) -1H-benzotriazole,
I-501- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-511- (3- (4- (3- (6-fluoro-benzofuranyl) piperazin-1-yl) propyl) -1H-benzotriazole,
I-521- (4- (4- (3- (6-fluoro-benzisoxazolyl) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-536-fluoro-1- (4- (4- (3- (6-fluoro-benzisothiazolyl) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-546-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-556-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-566-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-571- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-indole,
I-586-cyano-1- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-indole,
I-591- (3- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propyl) -1H-benzopyrazole,
I-606-cyano-1- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propyl) -1H-benzopyrazol,
I-611- [4- (4- (4-fluoro) phenyl) piperazine ] butyl-1H-indole,
I-621- [ 4-cyclohexylpiperazine ] butyl-1H-indole,
I-631- [4- (4- (4-fluoro) phenyl) piperazine ] butyl-5-acetyl-1H-indole,
I-641- [ 4-cyclohexylpiperazine ] butyl-5-acetyl-1H-indole,
I-651- [3- (4- (2, 4-difluoro) phenyl) piperazine ] butyl-5-acetyl-1H-indole,
I-661- [3- (4- (4-methyl) phenyl) piperazine ] propyl-1H-indole,
I-671- [4- (4- (4-chloro) phenyl) piperazine ] butyl-1H-indole,
I-681- [4- (4- (2-methyl) phenyl) piperazine ] butyl-1H-indole,
I-691- [4- (4- (3-trifluoromethyl) phenyl) piperazine ] butyl-1H-indole,
I-701- [3- (4- (4-methyl) phenyl) piperazine ] propyl-5-methoxy-1H-indole,
I-711- [4- (4- (4-trifluoromethoxy) phenyl) piperazine ] butyl-5-methoxy-1H-indole,
I-721- [4- (4- (3-trifluoromethyl) phenyl) piperazine ] butyl-5-methoxy-1H-indole,
I-731- [3- (4- (2-methyl) phenyl) piperazine ] butyl-5-methoxy-1H-indole,
I-741- [3- (4- (2, 4-difluoro) phenyl) piperazine ] propyl-5-nitro-1H-indole,
I-751- [4- (4- (4-chloro) phenyl) piperazine ] butyl-5-nitro-1H-indole,
I-761- [4- (4- (3-trifluoromethyl) phenyl) piperazine ] butyl-5-nitro-1H-indole,
I-771- [4- (4- (2-methoxy) phenyl) piperazine ] butyl-5-nitro-1H-indole,
I-781- [4- (4- (2-methoxy) phenyl) piperazine ] butyl-5-chloro-1H-indole,
I-791- [4- (4- (3-trifluoromethyl) phenyl) piperazine ] butyl-5-chloro-1H-indole,
I-801- [4- (4- (2, 4-difluoro) phenyl) piperazine ] butyl-5-chloro-1H-indole,
I-811- [2- (4- (2, 4-bistrifluoromethoxy) phenyl) piperazine ] ethyl-5-chloro-1H-indole,
I-821- [2- (4- (2, 4-dimethoxy) phenyl) piperazine ] ethyl-6-nitro-1H-indole,
1-831- [2- (4- (2, 4-dichloro) phenyl) piperazine ] ethyl-6-methoxy-1H-indole;
preferably, the first and second electrodes are formed of a metal,
i-11- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-21- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-41- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-52-methyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-66-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-71- (3- (4-phenylpiperazin-1-yl) propyl) -1H-benzimidazole,
I-81- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-92-methyl-1- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-101- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-111- (4- (4- (4-methylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-121- (4- (4- (2-furyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-131- (4- (4- (4-pyridyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-141- (4- (4- (2-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-151- (4- (4- (1-cyclohexyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-161- (4- (4- (1-naphthyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-171- (4- (4- (2-quinoxalinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-181- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-191- (4- (4- (3- (6-fluorobenzoisothiazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-201- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzimidazole,
I-211- (4- (4- (3- (6-fluorophenylfuranyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-221- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-231- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-241- (4- (4- (3-chlorophenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-256-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-266-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-276-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-282-chloro-1- (5- (4- (3-trifluoromethylphenyl) piperazin-1-yl) pentyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-301- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-326-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-335, 6-dimethyl-1- (4- (4- (3-trifluoromethylphenyl) 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) benzisoxazole,
I-366-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole,
I-376-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazin-1-yl) benzisoxazole,
I-381- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-391- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-401- (4- (4- (3-methoxyphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-411- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-421- (5- (4- (3-trifluoromethylphenyl) piperazine-1-yl) amyl) -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-pyrimidinyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-461- (4- (4-cyclohexylpiperazine-1-yl) butyl) -1H-benzotriazole,
I-471- (4- (4- (1-naphthyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-481- (4- (4- (2-quinoxaline) piperazine-1-yl) butyl) -1H-benzotriazole,
I-491- (4- (4- (3- (6-fluoro-benzisothiazolyl)) piperazin-1-yl) butyl) -1H-benzotriazole,
I-501- (4- (4- (3-benzopyrazolyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-511- (3- (4- (3- (6-fluoro-benzofuranyl) piperazin-1-yl) propyl) -1H-benzotriazole,
I-521- (4- (4- (3- (6-fluoro-benzisoxazolyl) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-536-fluoro-1- (4- (4- (3- (6-fluoro-benzisothiazolyl) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-546-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-556-cyano-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-566-methoxycarbonyl-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-571- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-indole,
I-586-cyano-1- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-indole,
I-591- (3- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propyl) -1H-benzopyrazole,
I-606-cyano-1- (3- (4- (2, 3-dichlorophenyl) piperazin-1-yl) propyl) -1H-benzopyrazol e.
More preferably still, the first and second liquid crystal compositions are,
i-11- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-21- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-41- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-52-methyl-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-66-fluoro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-81- (3- (4- (3-fluorophenyl) piperazin-1-yl) propyl) -1H-benzimidazole,
I-131- (4- (4- (4-pyridyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-151- (4- (4- (1-cyclohexyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-171- (4- (4- (2-quinoxalinyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-181- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-221- (4- (4- (3- (6-fluorobenzoisoxazolyl)) piperazin-1-yl) butyl) -1H-benzimidazole,
I-231- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-241- (4- (4- (3-chlorophenyl) piperazin-1-yl) propoxy) -1H-benzimidazole,
I-256-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-301- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-326-fluoro-1- (4- (4- (3-trifluoromethylphenyl) 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) benzisoxazole,
I-366-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole,
I-376-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazin-1-yl) benzisoxazole,
I-381- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-391- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-401- (4- (4- (3-methoxyphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-411- (4- (4- (3-cyanophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-511- (3- (4- (3- (6-fluoro-benzofuranyl) piperazin-1-yl) propyl) -1H-benzotriazole,
I-521- (4- (4- (3- (6-fluoro-benzisoxazolyl) piperazin-1-yl) propoxy) -1H-benzotriazole,
I-546-chloro-1- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
1-591- (3- (4- (3-trifluoromethylphenyl) piperazin-1-yl) propyl) -1H-benzopyrazole;
it is particularly preferred that,
i-11- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-21- (4- (4- (3-trifluoromethylphenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-301- (4- (4- (3-fluorophenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-343- (4- (4- (1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole,
I-366-fluoro-3- (4- (4- (1H-benzotriazol-1-yl) butyl) piperazine-1-yl) benzisoxazole,
I-376-fluoro-3- (4- (3- (1H-benzotriazol-1-yl) propyl) piperazin-1-yl) benzisoxazole,
I-381- (3- (4- (2, 3-dichlorophenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-391- (3- (4- (3-methylphenyl) piperazine-1-yl) propyl) -1H-benzotriazole,
I-401- (4- (4- (3-methoxyphenyl) piperazin-1-yl) butyl) -1H-benzotriazole;
most preferably, the first and second substrates are,
i-31- (4- (4- (2, 3-dichlorophenyl) piperazin-1-yl) butyl) -1H-benzimidazole,
I-291- (4- (4- (3-chlorophenyl) piperazin-1-yl) butyl) -1H-benzotriazole,
I-311- (4- (4- (3-trifluoromethylphenyl) piperazine-1-yl) butyl) -1H-benzotriazole,
I-343- (4- (4- (1H-benzotriazole-1-yl) butyl) piperazine-1-yl) benzisothiazole.
10. Use according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof, optionally together with one or more pharmaceutically acceptable excipients, and optionally together with other anti-vascular smooth muscle spasm active ingredients, is for the manufacture of a vasodilator, preferably for the manufacture of a medicament for the prevention, alleviation or treatment of a disease or condition associated with persistent pathological constriction of blood vessels or vasospasm in a subject, more preferably for the manufacture of a medicament for the treatment of hypertension, heart failure, angina pectoris, coronary heart disease, cerebral ischaemic disorders due to vasospasm, myocardial ischaemic disorders, shock, renal ischaemia, renal hypofunction due to renal vasospasm and peripheral vasospastic disorders, more preferably for the manufacture of a medicament having α receptor antagonism (in particular selective α)1Receptor antagonism), Ca2+Channel blocking, 5-HT2AUse of a receptor antagonizing a triple-acting drug.
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