CN103833730A - Benzo five-membered nitrogen-containing heterocycle-based piperazine derivative and preparation method as well as application thereof - Google Patents

Benzo five-membered nitrogen-containing heterocycle-based piperazine derivative and preparation method as well as application thereof Download PDF

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CN103833730A
CN103833730A CN201210486619.9A CN201210486619A CN103833730A CN 103833730 A CN103833730 A CN 103833730A CN 201210486619 A CN201210486619 A CN 201210486619A CN 103833730 A CN103833730 A CN 103833730A
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alkyl
group
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piperidine
optionally substituted
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CN103833730B (en
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周延
张丽荣
周杰
周欣
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Original Pharmaceutical Port Life Science Research Liaoning Co ltd
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LIAONING BEILEI BIOLOGICAL PHARMACEUTICAL Co Ltd
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Priority to EP13857383.7A priority patent/EP2924032B1/en
Priority to EP13857563.4A priority patent/EP2924033B1/en
Priority to PCT/CN2013/001442 priority patent/WO2014079155A1/en
Priority to US14/647,378 priority patent/US9802929B2/en
Priority to JP2015543245A priority patent/JP6350535B2/en
Priority to PCT/CN2013/001441 priority patent/WO2014079154A1/en
Priority to JP2015543244A priority patent/JP2016500084A/en
Priority to US14/647,408 priority patent/US9415047B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The invention relates to an application of a benzo five-membered nitrogen-containing heterocycle-based piperazine derivative shown in the specification as well as a pharmaceutically acceptable salt and a preparation method thereof, and further relates to a medicine composition containing the derivative and an application thereof in preparation of a vasodilatation medicine, wherein R1, R2, Y, A and B are defined as the specification.

Description

Benzo five-membered azaheterocyclyl piperidine derivatives, process for their preparation and their use
Technical Field
The invention relates to a benzo five-membered nitrogen heterocyclic piperidine derivative, pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof in preparing vasodilation medicines.
Background
At present, a plurality of drugs capable of relaxing blood vessels exist clinically,e.g. alpha1Receptor 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 invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA00002467304200011
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.
Detailed Description
The invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I) or a pharmaceutically acceptable salt thereof:
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 C, 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 groups, such 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" as used herein, unless otherwise specifically indicated, refers to fluorine, chlorine, bromine or iodine.
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 one embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):
Figure BDA00002467304200041
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, 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; preferably, when the aromatic group is a benzisoxazolyl group, a is N;
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, 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、CH3、OCH3Or COCH3(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, C with alkyl moieties optionally substituted by 1-3 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, CF3、CH3、OCH3、CHO、COCH3Or COOCH3(ii) a 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 is methylene, 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, octyleneEthyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, hexyleneoxy, or heptyleneoxy; particularly preferred is ethylene, propylene, butylene, ethyleneoxy or propyleneoxy.
In another embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):
Figure BDA00002467304200061
wherein:
R1is represented by R3A monosubstituted aromatic radical, wherein
The aromatic group is preferably phenyl or benzisoxazolyl; preferably, when the aromatic group is a benzisoxazolyl group, a is N;
R3is H, F, Cl, CF3、CH3Or OCH3；
A. B independently represents CH or N; preferably, A, B each represent N;
R2represents H, F, Cl, CN, CH3、OCH3Or CHO;
y represents ethylene, propylene, butylene or propyleneoxy.
In yet another embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):
Figure BDA00002467304200062
wherein:
R1representsBy R3A monosubstituted aromatic radical, wherein
The aromatic group is preferably phenyl or benzisoxazolyl; preferably, when the aromatic group is a benzisoxazolyl group, a is N;
R3is H or CF3；
A. B independently represents CH or N; preferably, A, B each represent N;
R2represents H or OCH3；
Y represents propylene or butylene.
In yet another embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):
Figure BDA00002467304200071
wherein: when the A, B are all N, then,
R1a benzisoxazolyl group which is not 6-fluoro substituted;
R2is not H or Cl; and is
Y is not ethyleneoxy or propyleneoxy.
In yet another embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):
Figure BDA00002467304200072
wherein: when the A, B are all C, the device will,
R1a benzisoxazolyl group which is not 6-fluoro substituted;
R2not being H, F, CN, COOCH3Or Cl; and is
Y is not ethylene, propylene, butylene, pentylene, ethyleneoxy, or propyleneoxy.
In yet another embodiment, the present invention provides a benzo five-membered azaheterocyclyl piperidine derivative of formula (I):
Figure BDA00002467304200081
wherein: when only one of A, B is C, the other is N,
R1a benzisoxazolyl group which is not 6-fluoro substituted;
R2is not H, F or CN; and is
Y is not propylene or butylene.
The benzo five-membered nitrogen heterocyclic piperidine compound comprises:
I-1N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-chlorophenyl) piperidine,
I-2N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-chlorphenyl) piperidine,
I-3N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-4N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-5N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-fluorophenyl) piperidine,
I-6N- (4- (1H-benzimidazol-1-yl) butyl) -4- (2-methoxyphenyl) piperidine,
I-7N- (4- (6-fluoro-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-8N- (4- (6-methoxy-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-9N- (4- (6-cyano-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-10N- (4- (1H-benzotriazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine,
I-11N- (4- (1H-benzimidazol-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine,
I-12N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methylbenzisoxazole)) piperidine,
I-13N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methoxy benzisoxazole)) piperidine,
I-14N- (3- (6-fluoro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-15N- (3- (6-chloro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-16N- (3- (6-methyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-17N- (3- (6-methoxy-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-18N- (3- (6-formyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-19N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine,
I-20N- (2- (1-benzotriazolyl) ethyl) -4- (3- (6-fluorobenzisoxazole)) piperidine,
I-21N- (4- (1-benzotriazolyl) butyl) -4- (3- (6-fluorobenzisoxazole)) piperidine,
I-22N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-23N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-methoxybenzoisoxazole)) piperidine,
I-24N- (2- (6-methoxybenzotriazolyl) ethoxy) -4- (3-benzisoxazole) piperidine,
I-25N- (2- (1-benzotriazolyl) ethoxy) -4- (3-fluorobenzisoxazole) piperidine,
I-26N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzoisothiazole)) piperidine,
I-27N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzopyrazole)) piperidine,
I-28N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzofuran)) piperidine,
I-29N- (4- (1H-benzimidazol-1-yl) butyl) -4- (2-furyl) piperidine,
I-30N- (4- (1H-benzimidazol-1-yl) butyl) -4- (4-pyridyl) piperidine,
I-31N- (4- (1H-benzimidazol-1-yl) butyl) -4- (2-pyrimidinyl) piperidine,
I-32N- (4- (1H-benzotriazole-1-yl) butyl) -4-cyclohexyl piperidine,
I-33N- (4- (1H-benzotriazole-1-yl) butyl) -4- (1-naphthyl) piperidine,
I-34N- (4- (1H-benzotriazole-1-yl) butyl) -4- (2-quinoxaline) piperidine.
The specific chemical structural formula is shown in the following table:
Figure BDA00002467304200101
Figure BDA00002467304200111
Figure BDA00002467304200121
Figure BDA00002467304200131
in a particular embodiment of the invention, the following compounds or pharmaceutically acceptable salts thereof are more preferred:
I-1N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-chlorophenyl) piperidine,
I-2N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-chlorphenyl) piperidine,
I-3N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-4N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-7N- (4- (6-fluoro-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-10N- (4- (1H-benzotriazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine,
I-11N- (4- (1H-benzimidazol-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine,
I-12N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methylbenzisoxazole)) piperidine,
I-13N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methoxy benzisoxazole)) piperidine,
I-14N- (3- (6-fluoro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-15N- (3- (6-chloro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-16N- (3- (6-methyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-17N- (3- (6-methoxy-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-18N- (3- (6-formyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-19N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine,
I-20N- (2- (1-benzotriazolyl) ethyl) -4- (3- (6-fluorobenzisoxazole)) piperidine,
I-21N- (4- (1-benzotriazolyl) butyl) -4- (3- (6-fluorobenzisoxazole)) piperidine,
I-22N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine,
I-23N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-methoxybenzoisoxazole)) piperidine.
In a particular embodiment of the invention, the following compounds or pharmaceutically acceptable salts thereof are particularly preferred:
I-3N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-4N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine,
I-19N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine.
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.
The invention also relates to the use of the compounds of formula (I) of the invention and their pharmaceutically acceptable salts for the prevention, alleviation or treatment of diseases or conditions 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 invention also relates to pharmaceutical compositions comprising a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof for oral, parenteral, administration by inhalation spray, rectal, intranasal, sublingual, buccal, transdermal or by implantation, 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 can 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 components. 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.
In another aspect, the invention provides a process for the preparation of a benzo five-membered azaheterocyclyl piperidine compound of formula (I):
scheme I
Comprises that
At a temperature of 10-150 ℃ to react
And compounds
Figure BDA00002467304200172
Reacting in a solvent in the presence of an inorganic base and a phase transfer catalyst to form a compound
Figure BDA00002467304200173
Then under reflux, reacting it with the compound
Figure BDA00002467304200181
In the presence of an organic base in a solvent to form a compound
Figure BDA00002467304200182
Or
Scheme two
Comprises that
At a temperature of 10-150 ℃ to react
Figure BDA00002467304200183
And compounds
Figure BDA00002467304200184
Reacting in a solvent in the presence of an inorganic base and a phase transfer catalyst to form a compound
Figure BDA00002467304200185
Then under reflux, reacting it with the compound
Figure BDA00002467304200186
In the presence of an organic base in a solvent to form a compound
Figure BDA00002467304200187
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, 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; preferably, when the aromatic group is a benzisoxazolyl group, a is N;
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 radicals),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、CH3、OCH3Or COCH3(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, C with alkyl moieties optionally substituted by 1-3 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、CF3、CH3、OCH3、CHO、COCH3Or COOCH3(ii) a 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 is methylene, 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 ethylene, propylene, butylene, ethyleneoxy or propyleneoxy;
the first-step reactions of the scheme (one) and the scheme (two) are each carried out in a solvent in the presence of an inorganic base, preferably sodium hydride, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium bicarbonate, potassium hydride, potassium hydroxide, potassium methoxide, potassium ethoxide, potassium carbonate, or potassium bicarbonate, more preferably sodium hydride or sodium hydroxide, and a phase transfer catalyst; the phase transfer catalyst is preferably tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, or 1, 4, 7, 10, 13, 16-hexaoxacyclooctadecane (i.e., 18 crown 6), etc., more preferably tetrabutylammonium bromide; the solvent used in the first reaction step is a solvent commonly used in the art, preferably water, N-methylpyrrolidone (NMP) or N, N-Dimethylformamide (DMF), and a mixture thereof; the reaction temperature of the first step is 10-150 ℃, preferably 20-130 ℃, more preferably 30-100 ℃;
the second-step reactions of scheme (one) and scheme (two) are each carried out in a solvent in the presence of an organic base, more preferably an organic base and potassium iodide, the organic base preferably being diisopropylethylamine, diethylamine, triethylamine, pyridine, tert-butylamine, cyclopropylamine, di-n-butylamine, diisopropylamine or 1, 2-dimethylpropylamine, more preferably diisopropylethylamine; the solvent used in the second reaction step is a solvent commonly used in the art, preferably acetonitrile, DMF, dimethyl sulfoxide (DMSO), or butanone, and a mixture thereof;
the process of the invention also preferably comprises the step of reacting the product with the corresponding acid to form a pharmaceutically acceptable salt. Wherein the acid used may be hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, trifluoroacetic acid, tartaric acid, malic acid, succinic acid, maleic acid, citric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, fumaric acid, oxaloacetic acid, ethanesulphonic acid, oxalic acid, benzenesulphonic acid or isethionic acid, more preferably hydrochloric acid, hydrobromic acid, sulphuric acid or methanesulphonic acid, most preferably hydrochloric acid. The salt formation step is preferably carried out in a solvent which may be methanol, ethanol, propanol, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or tetramethylene sulfone and the like, preferably ethyl acetate and/or ethanol.
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, n are as defined above; m represents a pharmaceutically acceptable salt thereof, e.g. HCl, HBr, H2SO4、CH3SO3H, and the like.
Substituted benzo five-membered nitrogen heterocycle is used as a raw material, and is subjected to condensation reaction with chloroalkyl bromide in a sodium hydroxide aqueous solution to prepare an N-chloroalkyl-benzo five-membered heterocyclic compound, and is subjected to condensation reaction with 4-substituted piperidine to prepare a compound shown in a formula (I), and optionally, the compound is acidified to form salt to prepare corresponding salt. The compounds I-1 to I-9, I-12 to I-23, I-26 to I-34 and salts thereof can be prepared by the method.
Scheme 2:
Figure BDA00002467304200212
wherein R is1、R2A, B, n are as defined above; m represents a pharmaceutically acceptable salt thereof, e.g. HCl, HBr, 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 reacts with 4-substituted piperidine for condensation to prepare a compound shown in a formula (I), and finally, the compound is optionally acidified to form salt to prepare corresponding salt. The compounds I-10 to I-11, I-24 to I-25 and salts thereof can be prepared by the method.
The general synthesis method I comprises the following steps: preparation of N- (3-chloropropyl) -substituted benzo five-membered nitrogen heterocyclic compound
1H-substituted benzo pentaazacyclo (0.10mol) was dissolved in 100ml of 30% by weight aqueous sodium hydroxide solution, and 3-chlorobromopropane (31.4g, 0.10mol) 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. 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 matter2O3And (3) separating and purifying by chromatography or preparative HPLC to obtain the N- (3-chloropropyl) -substituted benzo five-membered nitrogen heterocyclic compound with the yield of 30.0-85.0%.
A second synthesis method: preparation of N- (3- (substituted benzo penta-nitrogen heterocycle) propyl) -4-substituted piperidine
Dissolving N- (3-chloropropyl) -substituted benzo five-membered nitrogen heterocyclic compound (0.06mol) in 150ml acetonitrile, respectively adding 4-substituted piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol), stirring for 10 minutes at room temperature, and then heating and refluxing for 10-20 hours. Cooling to room temperature, filtering, concentrating the filtrate to obtain oil, and purifying with neutral Al2O3And (3) carrying out chromatographic separation and purification, and eluting with a dichloromethane/methanol mixed solvent to obtain the compound shown in the formula (I), wherein the yield is 65.0-72.0%.
A third synthesis method: preparation of N- (2-chloroethoxy) -substituted benzo five-membered nitrogen heterocyclic compound
The substituted N-hydroxy benzo five-membered nitrogen heterocyclic compound (0.01mol) is dissolved in 10ml NMP, 50 weight percent of solid paraffin mixture of sodium hydrogen (0.01mol) is added in portions, and the mixture is stirred and reacted for 0.5 h. Meanwhile, 3-chlorobromopropane (0.015mol) was dissolved in 5ml of NMP, and the resulting solution was added thereto, followed by reaction with stirring at room temperature for 12 hours. Pouring the reaction solution into 50mL of water, extracting with ethyl acetate (3X 50mL), combining the organic phases, washing with 30mL of water, adding anhydrous magnesium sulfate to dry the organic phase, filtering, evaporating the solvent to dryness, and passing the oily substance through neutral Al2O3And (3) separating and purifying by chromatography or preparative HPLC to obtain the 1- (2-chloroethoxy) -substituted benzo five-membered nitrogen heterocyclic compound with the yield of 75.0-85.0%.
Example 1
Preparation of N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-chlorophenyl) piperidine (I-1)
1H-benzimidazole (11.8g, 0.10mol) was dissolvedTo 200ml of a 20 wt% aqueous solution of sodium hydroxide were added 4-chlorobromobutane (34.3g, 0.20mol) and 1.0g of tetrabutylammonium bromide, followed by stirring for 5 minutes, warming to 60 ℃ and stirring 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-chlorophenylpiperidine (5.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, 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 7.3g of compound (I-1) with yield of 66.4%. ESI-MS [ M + H ]]+：m/z 368.2。
Example 2
Preparation of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-chlorophenyl) piperidine (I-2)
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-chlorophenylpiperidine (5.9g, 0.03mol) and diisopropylethyl piperidine were added thereto, respectivelyAmine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were mixed with stirring 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 to obtain 7.8g of compound (I-2), with a yield of 70.3%. ESI-MS [ M + H ]]+：m/z 369.2。
Compound (I-2) (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 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 5.4g of a compound (II-2) solid, wherein the yield is 88.0%.
Example 3
Preparation of N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-3)
1- (4-chlorobutyl) -1H-benzimidazole was prepared by the method of example 1.
1- (4-chlorobutyl) -1H-benzimidazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperidine (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 N- (4- (1H-benzimidazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-3)11.0g, with the yield of 64.9%. ESI-MS [ M + H ]]+：m/z 402.2。
Compound (I-3) (6.02g, 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 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 5.4g of a compound (II-3) solid, wherein the yield is 89.0%.
Example 4
Preparation of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-4)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 2.
1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (25.8g, 0.2mol), and potassium iodide (0.05mol) were added thereto, respectively, followed by mixing and stirring 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 13.6g of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-4) with the yield of 67.8%. ESI-MS [ M + H ]]+：m/z 403.2。
Example 5
Preparation of N- (4- (1H-benzimidazol-1-yl) butyl) -4- (3-fluorophenyl) piperidine (I-5)
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-fluorophenylpiperidine (5.9g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were added, respectively, 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 7.1g of compound (I-5), with yield of 67.2%. ESI-MS [ M + H ]]+：m/z 352.2。
Example 6
Preparation of N- (4- (1H-benzimidazol-1-yl) butyl) -4- (2-methoxyphenyl) piperidine (I-6)
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 1To 00ml of acetonitrile were added 2-methoxyphenylpiperidine (5.7g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol), 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 6.7g of compound (I-6) with yield of 61.3%. ESI-MS [ M + H ]]+：m/z 364.2。
Example 7
Preparation of N- (4- (6-fluoro-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-7)
6-fluoro-benzotriazole (15.3g, 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 6-fluoro-1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 77.0%.
6-fluoro-1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) is dissolved in 150ml of acetonitrile, 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) are added respectively, and the mixture is mixed and stirred at room temperature for 10 minutes and then heated to reflux for reaction 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 13.5g of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-7) with a yield of 64.1%. ESI-MS [ M + H ]]+：m/z 421.2。
Example 8
Preparation of N- (4- (6-methoxy-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-8)
6-methoxy-benzotriazole (14.9g, 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 matter2O3Carrying out chromatographic separation and purification, eluting by dichloromethane to obtain 17.9g of 6-methoxy-1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 75.0%.
6-methoxy-1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, 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 N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-8)14.0g, with a yield of 64.6%. ESI-MS [ M + H ]]+：m/z 433.2。
Example 9
Preparation of N- (4- (6-cyano-1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-9)
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 17.3g of 6-cyano-1- (4-chlorobutyl) -1H-benzotriazole, wherein the yield is 74.0%.
6-cyano-1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3-trifluoromethylphenyl) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, 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 13.5g of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (3-trifluoromethylphenyl) piperidine (I-9) with a yield of 63.1%. ESI-MS [ M + H ]]+：m/z 427.2。
Example 10
Preparation of N- (4- (1H-benzotriazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine (I-10)
Preparation of N- (2-chloropropoxy) -benzotriazole
1-hydroxybenzotriazole (0.01mol) is dissolved in 10ml NMP, 50 percent of solid paraffin mixture of sodium hydrogen (0.01mol) is added in portions, and the mixture is stirred and reacted for 0.5 h. Meanwhile, 3-chlorobromopropane (0.015mol) was dissolved in 5ml of NMP, and the resulting solution was added thereto, followed by reaction with stirring at room temperature for 12 hours. Pouring the reaction solution into 50mL of water, extracting with ethyl acetate (3X 50mL), combining the organic phases, washing with 30mL of water, adding anhydrous magnesium sulfate to dry the organic phase, filtering, evaporating the solvent to dryness, and passing the oily substance through neutral Al2O3And (3) separating and purifying by chromatography or preparative HPLC to obtain the 1- (3-chloropropoxy) benzotriazole with the yield of 75.0-85.0%.
1- (3-chloropropyloxy) benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluoro-benzisoxazolyl)) piperidine (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 13.2g of N- (4- (1H-benzotriazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine (I-10), with the yield of 65.3%. ESI-MS [ M + H ]]+：m/z 405.2。
Example 11
Preparation of N- (4- (1H-benzimidazol-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine (I-11)
Preparation of N- (2-chloropropyloxy) -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. Meanwhile, 3-chlorobromopropane (0.015mol) was dissolved in 5ml of NMP, and the resulting solution was added thereto, followed by reaction with stirring at room temperature for 12 hours. Pouring the reaction solution into 50mL of water, extracting with ethyl acetate (3X 50mL), combining the organic phases, washing with 30mL of 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) benzimidazole with yield of 75.0%.
1- (3-Chloropropoxy) benzimidazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluorophenylisoxazolyl)) piperidine (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 13.6g of N- (4- (1H-benzimidazole-1-yl) propoxy) -4- (3-trifluoromethylphenyl) piperidine (I-11), with the yield of 67.1%. ESI-MS [ M + H ]]+：m/z 404.2。
Example 12
Preparation of N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methylbenzisoxazole)) piperidine (I-12)
1- (3-chloropropyl) -1H-benzotriazole (11.7)g, 0.06mol) was dissolved in 150ml of acetonitrile, 6-methyl-3- (piperidin-4-yl) benzisoxazole (10.8g, 0.05mol), diisopropylethylamine (25.8g, 0.2mol), and potassium iodide (8.3g, 0.05mol) were added, and mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 15 hours. The work-up was carried out according to general method two to give 12.4g of (I-12) in 66.1% yield. ESI-MS [ M + H ]]+：m/z 376.2。
Example 13
Preparation of N- (3- (1H-benzotriazol-1-yl) propyl) -4- (3- (6-methoxy benzisoxazole)) piperidine (I-13)
1- (3-chloropropyl) -1H-benzotriazole (11.7g, 0.06mol) was dissolved in 150ml of acetonitrile, and 6-methoxy-3- (piperidin-4-yl) benzisoxazole (11.6g, 0.05mol), diisopropylethylamine (25.8g, 0.2mol), and potassium iodide (8.3g, 0.05mol) were added thereto, and mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Working up was carried out according to general method II to give 13.3g of (I-13) in 67.7% yield. ESI-MS [ M + H ]]+：m/z 392.2。
Example 14
Preparation of N- (3- (6-fluoro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-14)
Preparation of 1- (3-chloropropyl) -6-fluoro-1H-benzotriazole
6-fluoro-1H-benzotriazole (13.7g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) 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. Post-treatment operation is carried out according to the general synthesis method I, and 6.9g of 1- (3-chloropropyl) -6-fluoro-1H-benzotriazole is obtained through separation and purification by preparative HPLC, with the yield of 32.3%.
Preparation of N- (3- (6-fluoro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-5)
1- (3-chloropropyl) -6-fluoro-1H-benzotriazole (6.41g,0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 16 hours. The work-up was carried out according to general method two to give 8.3g of (I-14) in 69.6% yield. ESI-MS [ M + H ]]+：m/z 398.2。
Example 15
Preparation of N- (3- (6-chloro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-15)
Preparation of 1- (3-chloropropyl) -6-chloro-1H-benzotriazole
6-chloro-1H-benzotriazole (15.4g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) 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. After-treatment operation is carried out according to the general synthesis method I, and the 1- (3-chloropropyl) -6-chloro-1H-benzotriazole is separated and purified by preparative HPLC to obtain 7.3g of 1- (3-chloropropyl) -6-chloro-1H-benzotriazole with the yield of 31.7 percent.
Preparation of N- (3- (6-chloro-1H-benzotriazol-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-6))
1- (3-chloropropyl) -6-chloro-1H-benzotriazole (6.90g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 16 hours. The work-up was carried out according to general method two to give 8.1g of (I-15) in 65.2% yield. ESI-MS [ M + H ]]+：m/z 414.1。
Example 16
Preparation of N- (3- (6-methyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-16)
Preparation of 1- (3-chloropropyl) -6-methyl-1H-benzotriazole
6-methyl-1H-benzotriazole (13.3g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) 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. After-treatment operation is carried out according to the general synthesis method I, and 7.2g of 1- (3-chloropropyl) -6-methyl-1H-benzotriazole is obtained through separation and purification by preparative HPLC, with the yield of 34.3%.
Preparation of N- (3- (6-methyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-7)
1- (3-chloropropyl) -6-methyl-1H-benzotriazole (6.29g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 16 hours. The work-up was carried out according to general method two to give 8.5g of (I-16) with a yield of 71.9%. ESI-MS [ M + H ]]+：m/z 394.2。
Example 17
Preparation of N- (3- (6-methoxy-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-17)
Preparation of N- (3-chloropropyl) -6-methoxy benzotriazole
6-methoxy-1H-benzotriazole (14.9g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) 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. After-treatment operation is carried out according to the general synthesis method I, and the N- (3-chloropropyl) -6-methoxy benzotriazole is separated and purified by preparative HPLC to obtain 7.7g of N- (3-chloropropyl) -6-methoxy benzotriazole with the yield of 34.1 percent.
Preparation of N- (3- (6-methoxy-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-8)
1- (3-chloropropyl) -6-methoxy-1H-benzotriazole (6.77g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating under reflux for 16 hours. The work-up was carried out according to general method two to give 8.6g of (I-17) in 70% yield. ESI-MS [ M + H ]]+：m/z 410.2。
Example 18
Preparation of N- (3- (6-formyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-18)
Preparation of 1- (3-chloropropyl) -6-formyl-1H-benzotriazole
6-formyl-1H-benzotriazole (16.2g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) 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. After-treatment operation is carried out according to the general synthesis method I, and 7.9g of 1- (3-chloropropyl) -6-formyl-1H-benzotriazole is obtained through separation and purification by preparative HPLC, with the yield of 33.2%.
Preparation of N- (3- (6-formyl-1H-benzotriazole-1-yl) propyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-18)
1- (3-chloropropyl) -6-formyl-1H-benzotriazole (7.13g, 0.03mol) was dissolved in 150ml of acetonitrile, and 6-fluoro-3- (piperidin-4-yl) benzisoxazole (5.5g, 0.025mol), diisopropylethylamine (12.9g, 0.1mol), and potassium iodide (4.15g, 0.025mol) were mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. After-treatment according to general method II to obtain 7.5g of (I-18) with 73.6% yield. ESI-MS [ M + H ]]+：m/z 408.2。
Example 19
Preparation of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine (I-19)
N- (3-chloropropyl) -6-methoxybenzotriazole is prepared as described in example 17.
Dissolving N- (3-chloropropyl) -6-methoxy benzotriazole (0.06mol) in 150ml of acetonitrile, adding 4- (3-benzisoxazole) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) respectively, mixing and stirring for 10 minutes at room temperature, and then 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 13.14g of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3-benzisoxazole) piperidine (I-19) with yield of 67.2%. ESI-MS [ M + H ]]+：m/z 391.2。
Example 20
Preparation of N- (2- (1-benzotriazolyl) ethyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-20)
Benzotriazole (11.9g, 0.10mol) was dissolved in 100ml of a 30 wt% aqueous solution of sodium hydroxide, and 3-chlorobromopropane (31.4g, 0.10mol) 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 for extraction to the water phase, combining the organic phases, washing with 100ml saturated saline solution, separating, and evaporating the organic phase to obtain oil. The oil is subjected to column chromatography (neutral Al)2O3) Separating and purifying, eluting and separating by dichloromethane to obtain 16.0g of 1- (3-chloropropyl) -1H-benzotriazole with the yield of 82.0 percent.
1- (3-chloropropyl) -1H-benzotriazole (0.06mol) is dissolved in 150ml of acetonitrile, 4- (3- (6-fluorobenzoisoxazole)) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) are added respectively, and the mixture is mixed and stirred at room temperature for 10 minutes and then heated to reflux for reaction 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 N- (2- (1-benzotriazolyl) ethyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine(I-20)12.67g, yield 69.4%. ESI-MS [ M + H ]]+：m/z 365.2。
Example 21
Preparation of N- (4- (1-benzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-21)
1- (4-chlorobutyl) -1H-benzotriazole was prepared according to the method in example 2.
1- (4-chlorobutyl) -1H-benzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluorobenzoisoxazole)) piperidine (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 13.96g of N- (4- (1-benzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-21) with the yield of 71.0%. ESI-MS [ M + H ]]+：m/z 393.2。
Example 22
Preparation of N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-22)
Preparation of 1- (3 chlorobutyl) -6-cyano-1H-benzotriazole
6-cyano-1H-benzotriazole (15.9g, 0.10mol) was dissolved in 100ml of a 30% by weight aqueous solution of sodium hydroxide, and 3-chlorobromobutane (32.6g, 0.10mol) 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. After-treatment operation is carried out according to the general synthesis method I, and the 1- (3 chlorobutyl) -6-cyano-1H-benzotriazole is separated and purified by preparative HPLC, so that 9.1g of 1- (3 chlorobutyl) -6-cyano-1H-benzotriazole is obtained with the yield of 32.6%.
1- (3-chlorobutyl) -6-cyanobenzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluorobenzoisoxazole)) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, followed by mixing and stirring at room temperature for 10 minutesAfter that, the temperature is increased and the reflux reaction is carried out for 15 h. 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 15.07g of N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-fluorobenzoisoxazole)) piperidine (I-22) with yield of 72.1%. ESI-MS [ M + H ]]+：m/z 418.2。
Example 23
Preparation of N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-methoxybenzoisoxazole)) piperidine (I-23)
1- (3-chlorobutyl) -6-cyanobenzotriazole was prepared as in example 22.
1- (3-chlorobutyl) -6-cyanobenzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-methoxybenzoisoxazole)) piperidine (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 15.01g of N- (4- (6-cyanobenzotriazolyl) butyl) -4- (3- (6-methoxybenzoisoxazole)) piperidine (I-23) with the yield of 69.8%. ESI-MS [ M + H ]]+：m/z 430.2。
Example 24
Preparation of N- (2- (6-methoxybenzotriazolyl) ethoxy) -4- (3-benzisoxazole) piperidine (I-24)
The N-hydroxy-6-methoxy benzotriazole is prepared by the method in the general method III.
Dissolving N- (2-chloroethoxy-6-methoxy benzotriazole (0.06mol) prepared by a synthesis and post-treatment method in the general method I in 150ml of acetonitrile by using N-hydroxy-6-methoxy benzotriazole as a raw material, respectively adding 4- (3-benzisoxazolyl) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol), mixing and stirring at room temperature for 10 minutes, and then raising the temperature to obtain the productThe reaction was refluxed for 15 h. 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 N- (2- (6-methoxybenzotriazolyl) ethoxy) -4- (3-benzisoxazole) piperidine (I-24)14.21g with 69.1% yield. ESI-MS [ M + H ]]+：m/z 394.2。
Example 25
Preparation of N- (2- (1-benzotriazolyl) ethoxy) -4- (3-fluorobenzoisoxazole) piperidine (I-25)
The N-hydroxybenzotriazole is prepared by the method in the general method III.
Dissolving N- (2-chloroethoxy benzotriazole (0.06mol) prepared by using N-hydroxy benzotriazole as a raw material according to a synthesis and post-treatment method in the general method I in 150ml of acetonitrile, respectively adding 4- (3-benzisoxazole) piperidine (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol), mixing and stirring for 10 minutes at room temperature, then heating up for reflux reaction for 15 hours, cooling to room temperature, filtering, concentrating the filtrate to obtain an oily substance, and performing neutral Al treatment on the oily substance2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain N- (2- (1-benzotriazolyl) ethoxy) -4- (3-fluorobenzoisoxazole) piperidine (I-25)12.88g, with the yield of 67.6%. ESI-MS [ M + H ]]+：m/z 364.2。
Example 26
Preparation of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzoisothiazole)) piperidine (I-26)
N- (3-chloropropyl) -6-methoxybenzotriazole is prepared as described in example 17.
N- (3-chloropropyl) -6-methoxybenzotriazole (0.06mol) was dissolved in 150ml of acetonitrile, and 4- (3- (6-fluorobenzoisothiazole)) piperidine (0.05mol), diisopropylethylamine (0.2mol), and potassium iodide (0.05mol) were added thereto, respectively, and mixed and stirred at room temperature for 10 minutes, followed by heating and refluxing for 15 hours. Cooling to room temperature, filtering, and concentrating the filtrate to obtain oilNeutral Al2O3Separating and purifying by chromatography, eluting with dichloromethane/methanol mixed solvent to obtain 13.17g of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzoisothiazole)) piperidine (I-26), with the yield of 69.1%. ESI-MS [ M + H ]]+：m/z 426.1。
Example 27
Preparation of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzopyrazole)) piperidine (I-27)
N- (3-chloropropyl) -6-methoxybenzotriazole is prepared as described in example 17.
N- (3-chloropropyl) -6-methoxybenzotriazole (0.06mol) is dissolved in 150ml of acetonitrile, 4- (3- (6-fluorobenzoisothiazole)) (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) are added respectively, and the mixture is mixed and 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 12.11g of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzopyrazole)) piperidine (I-27) with the yield of 66.5%. ESI-MS [ M + H ]]+：m/z 409.2。
Example 28
Preparation of N- (3- (6-methoxybenzotriazolyl) propyl) -4- (3- (6-fluorobenzofuran)) piperidine (I-28)
N- (3-chloropropyl) -6-methoxybenzotriazole is prepared as described in example 17.
N- (3-chloropropyl) -6-methoxybenzotriazole (0.06mol) is dissolved in 150ml of acetonitrile, 4- (3- (6-fluorobenzoisothiazole)) (0.05mol), diisopropylethylamine (0.2mol) and potassium iodide (0.05mol) are added respectively, and the mixture is mixed and 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 N- (3- (6-methoxy-6)Benzobenzotriazolyl) propyl) -4- (3- (6-fluorobenzofuran)) piperidine (I-28)12.40g, 68.1% yield. ESI-MS [ M + H ]]+：m/z 409.2。
Example 29
Preparation of N- (4- (1H-benzimidazolyl-1-yl) butyl) -4- (2-furyl) piperidine (I-29)
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) piperidine (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 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 6.0g of compound (I-29) with yield of 61.6%. ESI-MS [ M + H ]]+：m/z 324.2。
Example 30
Preparation of N- (4- (1H-benzimidazolyl-1-yl) butyl) -4- (4-pyridyl) piperidine (I-30)
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- (4-pyridyl) piperidine (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-30) with yield of 62.1%. ESI-MS [ M + H ]]+：m/z 335.2。
Example 31
Preparation of N- (4- (1H-benzimidazolyl-1-yl) butyl) -4- (2-pyrimidinyl) piperidine (I-31)
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) piperidine (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-31) with yield of 60.1%. ESI-MS [ M + H ]]+：m/z 336.2。
Example 32
Preparation of N- (4- (1H-benzotriazole-1-yl) butyl) -4-cyclohexylpiperidine (I-32)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 2.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (1-cyclohexyl) piperidine (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-32) in 63.7% yield. ESI-MS [ M + H ]]+：m/z 341.3。
Example 33
Preparation of N- (4- (1H-benzotriazol-1-yl) butyl) -4- (1-naphthyl) piperidine (I-33)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 2.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (1-naphthyl) was added thereto) Piperidine (6.4g, 0.03mol), diisopropylethylamine (15.5g, 0.12mol), and potassium iodide (5.0g, 0.03mol) were mixed with stirring and then refluxed 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 6.9g of the compound (I-33) with the yield of 60.1%. ESI-MS [ M + H ]]+：m/z 385.3。
Example 34
Preparation of N- (4- (1H-benzotriazole-1-yl) butyl) -4- (2-quinoxaline) piperidine (I-34)
1- (4-chlorobutyl) -1H-benzotriazole was prepared by the method of example 2.
1- (4-chlorobutyl) -1H-benzotriazole (7.55g, 0.036mol) was dissolved in 100ml of acetonitrile, and 4- (2-quinoxalinyl) piperidine (6.4g, 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 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 7.3g of Compound (I-34) in 62.7% yield. ESI-MS [ M + H ]]+：m/z 387.2。
Example 35
Relaxation of isolated vascular smooth muscle of rabbit by Compounds II-1 to II-34
1. Test animals:
the rabbit can be used for both male and female, has the weight of 2.0-3.0 kg and is provided by the experimental animal center of Chinese medical university.
2. Drugs and reagents:
compounds II-1 to II-34, i.e., hydrochloride salts of compounds I-1 to I-34, were prepared using the methods of the examples, and their salts (hydrochloride salts) were prepared according to example 2 (or 3) for the following experiments;
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 Injection (Norepepinephrine Bitartrate Injection) specification 2mg/1ml, Dai medicine (China) Co., Ltd., lot number 120304;
3. an experimental instrument:
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. Preparing a nutrient solution:
Krebs-Henseleit (K-H) physiological solution: NaCl 6.92 (concentration unit), KCl 0.35, MgSO4 0.29、KH2PO4 0.16、CaCl2 0.28，NaHCO3 2.1，Glucose 2.0(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 solutions of Compounds II-1 to II-34: weighing a certain mass of compound II-1-II-34 samples, and diluting the samples to a series of concentrations (10) by using distilled water as a solvent-10～10-3mol/L) for standby.
5. Preparation of 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 with 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 a container containing tension transducerThe change in tension was recorded by a recorder in a bath tube of 20ml of nutrient solution. Keeping the temperature in the bath tube at 37 +/-0.5 ℃, and introducing mixed gas (95% O) 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. Specific test operation and test result
6.1 relaxation of Compounds II-1 to II-34 on vascular smooth muscle in vitro of Epinephrine (AD) contractile rabbits
After the specimen tension was stabilized, a waveform was recorded and epinephrine hydrochloride (AD) (10) was added to the bath tube-5mol/L), fully washing the specimen after the maximum contraction is reached, changing K-H liquid every 20min, balancing for 60min, and inducing the contraction again by using the spasmolytic with the same concentration after the baseline is recovered to be stable. When the maximum contraction reaction of the latter time is basically consistent with that of the former time, the prepared compound II-1-II-34 solution (1X 10) is added in an accumulated way-10～1×10-3mol/L), the waveform is recorded. The relaxation effect of compounds II-1 to II-34 is shown in Table 1.
TABLE 1 relaxation of isolated vascular smooth muscle of AD-contracted rabbits by Compounds (II-1 to II-34)
Compound (I) -logEC50 Compound (I) -logEC50
II-1 5.03±0.02 II-18 5.56±0.04
II-2 5.16±0.03 II-19 6.11±0.07
II-3 6.21±0.04 II-20 5.92±0.05
II-4 6.36±0.03 II-21 5.96±0.04
II-5 4.89±0.02 II-22 5.53±0.07
II-6 4.76±0.03 II-23 5.23±0.06
II-7 5.31±0.04 II-24 4.03±0.05
II-8 4.86±0.03 II-25 4.26±0.04
II-9 4.79±0.02 II-26 4.01±0.03
II-10 5.56±0.05 II-27 4.13±0.05
II-11 5.31±0.06 II-28 4.26±0.06
II-12 5.45±0.04 II-29 4.43±0.05
II-13 5.34±0.03 II-30 4.86±0.04
II-14 5.61±0.05 II-31 4.72±0.03
II-15 5.42±0.04 II-32 4.39±0.05
II-16 5.38±0.03 II-33 4.22±0.06
II-17 5.23±0.05 II-34 4.83±0.05
6.2 relaxation of Noradrenaline (NA) contracting isolated vascular smooth muscle in rabbits with Compounds II-1 to II-34
After the specimen tension was stabilized, a waveform was recorded and epinephrine hydrochloride (AD) (10) was added to the bath tube-5mol/L) inducing contraction, fully washing the specimen after maximum contraction is reached, changing K-H solution every 20min, balancing for 60min, and after baseline is recovered to be stable, Norepinephrine (NA) with bitartrate (10)-5mol/L) induced shrinkage. When the maximum response of the latter contraction is substantially identical to the former one, the prepared solutions of compounds II-1 to II-34 are added cumulatively at 1X 10-10～1×10-3mol/L), the waveform is recorded. The relaxation effect of compounds II-1 to II-34 is shown in Table 2.
TABLE 2 relaxation of NA contracting rabbit Ex vivo vascular smooth muscle by Compounds II-1 to II-34
Compound (I) -logEC50 Compound (I) -logEC50
II-1 5.11±0.02 II-18 5.73±0.04
II-2 5.27±0.03 II-19 6.07±0.04
II-3 6.32±0.04 II-20 5.81±0.03
II-4 6.45±0.03 II-21 5.73±0.04
II-5 4.67±0.02 II-22 5.31±0.06
II-6 4.55±0.03 II-23 5.09±0.04
II-7 5.21±0.04 II-24 4.31±0.05
II-8 4.77±0.03 II-25 4.04±0.07
II-9 4.53±0.02 II-26 4.19±0.03
II-10 5.36±0.05 II-27 4.43±0.04
II-11 5.15±0.06 II-28 4.06±0.06
II-12 5.26±0.04 II-29 4.23±0.03
II-13 5.04±0.03 II-30 4.66±0.02
II-14 5.73±0.05 II-31 4.52±0.04
II-15 5.22±0.04 II-32 4.44±0.05
II-16 5.35±0.03 II-33 4.34±0.04
II-17 5.31±0.05 II-34 4.53±0.05
6.3 relaxation of Compounds II-1 to II-34 on isolated vascular smooth muscle of rabbits contracted with high Potassium solution
After the specimen tension was stabilized, a waveform was recorded and epinephrine hydrochloride (AD) (10) was added to the bath tube-5mol/L), fully washing the specimen after the maximum contraction is reached, changing K-H liquid every 20min, balancing for 60min, and changing the K-H liquid in the bath tube into high-potassium liquid to induce contraction after the baseline is recovered to be stable. When the maximum response of the latter contraction is substantially identical to the former one, the prepared solutions of compounds II-1 to II-34 (1X 10) are added cumulatively-10～1×10-3mol/L), compound II-1 to II-34 relaxation effects are shown in Table 3.
TABLE 3 relaxation of isolated vascular smooth muscle of rabbits by Compounds II-1 to II-34 in high Potassium solution
Compound (I) -logEC50 Compound (I) -logEC50
II-1 4.69±0.02 II-18 5.32±0.04
II-2 4.82±0.03 II-19 5.11±0.03
II-3 6.01±0.04 II-20 3.92±0.02
II-4 6.12±0.03 II-21 3.96±0.03
II-5 4.44±0.02 II-22 3.53±0.02
II-6 4.38±0.03 II-23 4.23±0.04
II-7 5.03±0.04 II-24 3.53±0.03
II-8 4.56±0.03 II-25 4.26±0.04
II-9 4.23±0.02 II-26 3.31±0.03
II-10 5.22±0.05 II-27 3.63±0.04
II-11 5.17±0.06 II-28 3.46±0.03
II-12 5.09±0.04 II-29 4.53±0.03
II-13 5.12±0.03 II-30 4.26±0.04
II-14 5.72±0.05 II-31 4.32±0.02
II-15 5.12±0.04 II-32 4.14±0.05
II-16 5.28±0.03 II-33 4.04±0.03
II-17 5.02±0.05 II-34 4.13±0.04

Claims (10)

1. A benzo five-membered azaheterocyclyl piperidine derivative of formula (I):
Figure FDA00002467304100011
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 moietyOptionally 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.
2. The compound 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 compound of 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, 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; preferably, when the aromatic group is a benzisoxazolyl group, a is N; or
The aliphatic cyclic group is 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; preferably cyclopentyl, cyclohexyl, tetrahydrofuranyl, piperidinyl or piperazinyl; more preferably cyclohexyl, piperidinyl or piperazinyl; cyclohexyl is particularly preferred.
4. The compound of claim 1, wherein 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、CH3、OCH3Or COCH3(ii) a Particularly preferably, H, F, Cl, CF3、CH3Or OCH3(ii) a Most preferably, R3Is H or CF3(ii) a 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 with one or more halogen atoms.
5. The compound of claim 1, wherein R2Is 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, 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, CF3、CH3、OCH3、CHO、COCH3Or COOCH3(ii) a Particularly preferably, R2Is H, F, Cl, CN, CH3、OCH3Or CHO; most preferably, R2Is H or OCH3(ii) a 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 with one or more halogen atoms.
6. A compound according to claim 1, wherein Y is an unsubstituted saturated hydrocarbon radical containing 2 to 8 carbons, or an unsubstituted saturated hydrocarbon radical 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 ethylene, propylene, butylene, ethyleneoxy, or propyleneoxy; particularly preferably, Y is ethylene, propylene, butylene or propyleneoxy; most preferably, Y is propylene or butylene.
7. The compound of claim 1, wherein
R1Is represented by R3A monosubstituted aromatic radical, wherein
The aromatic group is preferably phenyl or benzisoxazolyl; preferably, when the aromatic group is a benzisoxazolyl group, a is N;
R3is H or CF3；
A. B independently represents CH or N; preferably, A, B each represent N;
R2represents H or OCH3；
Y represents propylene or butylene.
8. A process for the preparation of the compounds of claims 1-7:
scheme I
Comprises that
At a temperature of 10-150 ℃ to react
Figure FDA00002467304100031
And compounds
Figure FDA00002467304100041
Reacting in a solvent in the presence of an inorganic base and a phase transfer catalyst to form a compound
Figure FDA00002467304100042
Then under reflux, reacting it with the compound
Figure FDA00002467304100043
In the presence of an organic base in a solvent to form a compound
Figure FDA00002467304100044
Or
Scheme two
Comprises that
At a temperature of 10-150 ℃ to react
Figure FDA00002467304100045
And compounds
Figure FDA00002467304100046
Reacting in a solvent in the presence of an inorganic base and a phase transfer catalyst to form a compound
Then under reflux, reacting it with the compound
Figure FDA00002467304100048
In the presence of an organic base in a solvent to form a compound
Figure FDA00002467304100049
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, 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; preferably, when the aromatic group is a benzisoxazolyl group, a is N;
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, 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、CH3、OCH3Or COCH3(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, C with alkyl moieties optionally substituted by 1-3 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, CF3、CH3、OCH3、CHO、COCH3Or COOCH3(ii) a 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 is methylene, 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 ethylene, propylene, butylene, ethyleneoxy orPropyleneoxy.
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, optionally together with one or more pharmaceutically acceptable excipients or other vascular smooth muscle spasm activity ingredients.
10. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a composition according to claim 9 for the manufacture of a vasodilating medicament, preferably for the manufacture of a medicament for the prevention, alleviation or treatment of a disease or condition associated with persistent hypertension, 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 alpha receptor antagonism (especially selective alpha receptor antagonism)1Receptor antagonism), and Ca2+Use in a medicament for dual action of channel blocking.
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US14/647,408 US9415047B2 (en) 2012-11-26 2013-11-25 Use of benzo five-membered nitrogen heterocyclic piperazine or piperidine derivatives
PCT/CN2013/001442 WO2014079155A1 (en) 2012-11-26 2013-11-25 Use of benzo five-membered nitrogen heterocyclic piperazine or piperidine derivatives
US14/647,378 US9802929B2 (en) 2012-11-26 2013-11-25 Benzo five-membered nitrogen heterocyclic piperidine or piperazine derivatives and preparation methods and pharmaceutical compositions thereof
JP2015543245A JP6350535B2 (en) 2012-11-26 2013-11-25 Nitrogen-containing benzo-hetero 5-membered nitrogen-containing benzo-hetero-5-membered ring piperazine or piperidine derivatives
PCT/CN2013/001441 WO2014079154A1 (en) 2012-11-26 2013-11-25 Benzo five-membered nitrogen heterocyclic piperidine or piperazine derivatives and preparation methods and pharmaceutical compositions thereof
EP13857383.7A EP2924032B1 (en) 2012-11-26 2013-11-25 Benzo five-membered nitrogen heterocyclic piperidine or piperazine derivatives and preparation methods and pharmaceutical compositions thereof
EP13857563.4A EP2924033B1 (en) 2012-11-26 2013-11-25 Use of benzo five-membered nitrogen heterocyclic piperazine or piperidine derivatives
JP2015543244A JP2016500084A (en) 2012-11-26 2013-11-25 Nitrogen-containing benzoheterocyclic 5-membered piperidine or piperazine derivative, method for producing the same, and pharmaceutical composition
JP2018078748A JP6644825B2 (en) 2012-11-26 2018-04-16 Nitrogen-containing 5-membered benzoheterocyclic piperidine or piperazine derivative and pharmaceutical composition

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