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CN110386881B - Diarylethene compound, pharmaceutical composition and application thereof - Google Patents

Diarylethene compound, pharmaceutical composition and application thereof Download PDF

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CN110386881B
CN110386881B CN201811600348.9A CN201811600348A CN110386881B CN 110386881 B CN110386881 B CN 110386881B CN 201811600348 A CN201811600348 A CN 201811600348A CN 110386881 B CN110386881 B CN 110386881B
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diarylethene
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CN110386881A (en
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左之利
孙威
孔德信
彭佳乐
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Kunming Institute of Botany of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/35—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

The invention relates to a diarylethene compound, a pharmaceutical composition thereof and application thereof, and relates to the technical field of medicines. The invention provides a diarylethene compound; the structural general formula of the diarylethene compound is shown as the formula (I):
Figure DDA0001922329370000011
the diarylethene compound provided by the invention has obvious monoamine oxidase B (MAO-B) inhibition effect, and can be used for preparing monoamine oxidase inhibitor B and anti-Parkinson's disease drugs. The present invention also provides a pharmaceutical composition comprising the diarylethene compounds as an active ingredient, which can be used as monoamine oxidase B (MAO-B)Inhibitor, and Parkinson's Disease (PD) therapeutic agent. In addition, the diarylethene compounds provided by the invention have novel structures, easy chemical synthesis, low cost and small side effects.

Description

Diarylethene compound, pharmaceutical composition and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to diarylethene compounds, a pharmaceutical composition taking the diarylethene compounds as active ingredients, and applications of the diarylethene compounds and the pharmaceutical composition in preparation of Monoamine Oxidase B (MAO-B) inhibitors and medicines for treating Parkinson's Disease (PD).
Background
Parkinson's Disease (PD) is a common degenerative disease of the nervous system, the average age of onset is about 60 years, the health of the old is seriously endangered, and the Parkinson's disease has great influence on the society and the economy. The most prominent pathological change in parkinson's disease is the degenerative death of the Dopaminergic (DA) neurons of the basal ganglia, which in turn causes a marked reduction in the striatal DA content and causes disease.
Monoamine Oxidase (MAO) is an enzyme that catalyzes the oxidative deamination of monoamines in humans, with the products of oxidative deamination being the corresponding aldehydes, amines and hydrogen peroxide. Monoamine oxidases are classified into two types, MAO-A and MAO-B, depending on the substrate. MAO-B is abundantly distributed in the basal ganglia of brain tissue and increases in activity with age. DA depletion in the relevant part of the brain of PD patients is exacerbated by the capacity of MAO-B to metabolize DA. In addition, aldehyde and hydrogen peroxide generated by MAO-B catalyzed reaction have neurocytotoxicity, and the aldehyde dehydrogenase deficiency of the substantia nigra part of PD patients strengthens the neurotoxicity caused by MAO-B catalyzed reaction. Thus, inhibition of MAO-B can treat PD by both increasing monoamino neurotransmitters such as DA in the brain and reducing neurotoxicity.
The primary reason why MAO inhibitors have been implicated in the early days is that patients who use irreversible and non-selective MAO inhibitors need to follow strict low-cheese diet guidelines to prevent fatal hypertension from being triggered by tyramine intake. However, as the proportion and distribution of MAO-B in humans has been extensively studied, both reversible and selective MAO-B inhibitors are now generally considered safe and acceptable for the treatment of PD. At present, the MAO-B inhibitor with high safety is not approved to be applied to clinical treatment in China. Therefore, there is a need to develop a new structural backbone compound that meets the above criteria and has the potential to be a highly selective MAO-B inhibitor.
Disclosure of Invention
In view of the above, the present invention provides a diarylethene compound, a pharmaceutical composition thereof and an application thereof, and mainly aims to provide an application of a diarylethene compound inhibitor molecule in resisting parkinson's disease, and develop a lead compound with a similar skeleton. The invention provides application of diarylethene compounds in preparation of monoamine oxidase inhibitor B and medicines for resisting Parkinson's disease.
In order to achieve the purpose, the invention mainly provides the following technical scheme:
in one aspect, an embodiment of the present invention provides a diarylethene compound, which is characterized in that the structural general formula of the diarylethene compound is as shown in formula (I):
Figure BDA0001922329350000021
in formula (I), W is one of the following groups:
Figure BDA0001922329350000022
wherein R is1. R2, R3, R4, R5, R6 and R7 are independently selected from one of the following groups: -H, -CH3、-CH2CH3、-Ph、-p-Me-Ph；
In the formula (I), Ar1 and Ar2 are independent from each other and are selected from one of the following groups:
Figure BDA0001922329350000023
wherein R8 and R9 are mutually independent and are selected from one of the following groups: -H, -CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2OH、-CH2NH2、-CH(CH3)NH2、-OH、-OCH3、-OCH2CH3、-OCH(CH3)2、-CF3、-CHF2、-CN、-F、-Cl、-Br、-I、-NO2、-N(CH3)2、-NH2、-NHCH3、-NHAc、-NHSO2CH3、-NHCOCF3；
Wherein X, Y, Z are independently selected from one of the following groups:
Figure BDA0001922329350000031
wherein R10 is one of the following groups: -H, -CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2OH、-CH2NH2、-CH(CH3)NH2、-OH、-OCH3、-OCH2CH3、-OCH(CH3)2、-CF3、-CHF2、-CN、-F、-Cl、-Br、-I、-NO2、-N(CH3)2、-NH2、-NHCH3、-NHAc、-NHSO2CH3、-NHCOCF3、
Figure BDA0001922329350000032
Wherein R11 is one of the following groups:
-H、-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2OH、-CH2NH2、-CH(CH3)NH2、-CH2CH2NH2、-CH2CH2OH。
preferably, the diarylethene compound is one of the following compounds:
Figure BDA0001922329350000033
Figure BDA0001922329350000041
Figure BDA0001922329350000051
in another aspect, embodiments of the present invention provide a pharmaceutical composition, wherein the pharmaceutical composition comprises: the diarylethene compounds and at least one pharmaceutically acceptable auxiliary material.
Preferably, the pharmaceutical composition contains 0.1-99% of diarylethene compounds.
Preferably, the pharmaceutical composition contains 0.5-90% of diarylethene compounds.
In another aspect, the diarylethene compounds are used for preparing monoamine oxidase B inhibitor. The diarylethene compounds are applied to the preparation of medicines for treating Parkinson's disease.
In still another aspect, a process for the preparation of diarylethene compounds 8, wherein,
the preparation equations of the diarylethenes 83, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161 are as follows:
Figure BDA0001922329350000052
wherein E1 is one of the following groups:
Figure BDA0001922329350000053
wherein E2 is one of the following groups:
Figure BDA0001922329350000061
and/or
The preparation equations of the diarylethene compounds 162, 163, 164, 165 are as follows:
Figure BDA0001922329350000062
wherein E3 is one of the following groups:
Figure BDA0001922329350000063
e4 is one of the following groups:
Figure BDA0001922329350000064
preferably, the preparation steps of the diarylethenes 83, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161 are as follows:
adding into methanol or ethanol
Figure BDA0001922329350000065
Sodium ethoxide is stirred for a set time and is filtered to obtain a solid product;
washing the solid product with ethanol, and drying to obtain the diarylethene compound.
The preferred preparation steps of the diarylethenes 162, 163, 164, 165 are as follows:
adding into methanol or ethanol
Figure BDA0001922329350000071
Stirring for a set time after the sodium ethoxide is added, and purifying (such as silica gel column chromatography separation and purification) to obtain a solid product;
and (4) carrying out Boc protecting group removal reaction on the solid product to obtain the diarylethene compound.
By means of the technical scheme, the diarylethene compound, the pharmaceutical composition thereof and the application thereof at least have the following beneficial effects:
the diarylethene compounds in the formula (I) provided by the embodiment of the invention are discovered for the first time through long-term research and are verified to have the inhibitory activity of the single ammonia oxidase B (MAO-B) through an activity test; and the compound of formula (I) of the present invention has the potential to be a highly selective MAO-B inhibitor (this is the first time the present invention has been proposed, and the prior art has never been reported). The diarylethene compounds in the formula (I) are novel in structure, easy to synthesize chemically, low in cost and small in side effect. Meanwhile, the invention also provides a new application of the diarylethene compound in the formula (I) as a target inhibitor of the single ammonia oxidase B (MAO-B) and a Parkinson disease medicament.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.
Drawings
FIG. 1 is a graph showing the in vitro inhibition of monoamine oxidase B (MAO-B) by diarylethene compounds 83, according to an embodiment of the present invention;
FIG. 2 is a graph showing the in vitro inhibition of monoamine oxidase B (MAO-B) by diarylethene compounds 144 according to the present invention;
FIG. 3 is a graph showing the in vitro inhibition of monoamine oxidase B (MAO-B) by a diarylethene compounds 145 according to an embodiment of the present invention;
FIG. 4 is a graph showing the in vitro inhibition of monoamine oxidase B (MAO-B) by a diarylethene compounds 146, according to an embodiment of the present invention.
Detailed Description
To further explain the technical means and effects of the present invention adopted to achieve the predetermined object, the following detailed description of the embodiments, structures, features and effects according to the present invention will be made with reference to the accompanying drawings and preferred embodiments. In the following description, different "one embodiment" or "an embodiment" refers to not necessarily the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
Example 1
A portion of the diarylethenes of the present invention is available from specs, Netherlands (website: http:// www.specs.com), and the corresponding numbers of the diarylethenes of this portion in the library are shown in Table 1:
table 1 shows the corresponding numbering of some diarylethenes in the library
Compound (I) Numbering Compound (I) Numbering Compound (I) Numbering
66 AO-289/25117029 75 AB-131/06806028 93 AJ-291/34003011
67 AM-814/41094729 76 AA-516/12432405 94 AG-777/36178018
68 AB-131/42301429 78 AG-690/37079203 103 AA-504/06813049
69 AB-131/42300921 80 AN-970/40920809 107 AT-051/43422454
70 AB-131/42300746 82 AB-131/42302837 108 AE-641/02580034
71 AB-131/40897212 84 AI-211/09901015 114 AG-664/02670043
72 AB-131/40897213 85 AG-690/11665343 116 AE-641/01920053
73 AB-131/40897214 88 AG-690/12135048 117 AE-641/02517058
74 AB-131/40897238 92 AB-016/30007056 120 AP-406/42800673
Example 2
This example mainly provides a method for producing compound 83 and data on the structure measurement of compound 83.
Compound 83 is given the english name:
(Z)-2-(4-chlorophenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-enenitrile
compound 83 was prepared as follows:
Figure BDA0001922329350000091
the preparation method comprises the following specific steps: 455mg of p-chlorobenzonitrile, 0.41mL of p-trifluoromethylbenzaldehyde and 21mg of sodium ethoxide were added to 10mL of methanol, and stirred at room temperature for 2 hours, and filtered to obtain a white solid, which was washed with 2mL of low-temperature ethanol 2 times and dried to obtain 349mg of compound 83 (yield: 38%).
The structural determination data for compound 83 is as follows:
1H NMR(400MHz,CDCl3)δ7.97(d,J＝8.0Hz,2H),7.74(d,J＝8.0Hz,2H),7.63(d,J＝8.8Hz,2H),7.55(s,1H),7.45(d,J＝8.8Hz,2H)。
example 3
This example mainly provides a method for producing compound 144 and data on the structure measurement of compound 144.
Compound 144 is given the english name:
(Z)-2-(4-chlorophenyl)-3-[6-(trifluoromethyl)-3-pyridyl]prop-2-enenitrile
compound 144 was prepared as follows:
Figure BDA0001922329350000092
the preparation method comprises the following specific steps: only the reaction starting materials in the preparation step of compound 83: replacing 6- (trifluoromethyl) pyridine-3-carbaldehyde with p-trifluoromethylbenzaldehyde.
The structure determination data for compound 144 is as follows:
1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.62(d,J＝8.4Hz,1H),7.82(d,J＝8.4Hz,1H),7.66(d,J＝8.8Hz,2H),7.56(s,1H),7.48(d,J＝8.8Hz,2H)。
example 4
This example mainly provides a method for producing compound 145 and data on the structure measurement of compound 145.
Figure BDA0001922329350000101
Compound 145 is given the english name:
(Z)-2-(5-chloro-2-pyridyl)-3-[4-(trifluoromethyl)phenyl]prop-2-enenitrile
preparation procedure of compound 145: starting materials for the reaction in the preparation step of compound 83: replacing the p-chlorobenzonitrile with 2- (5-chloro-2-pyridine) acetonitril, and performing other steps in a consistent manner.
Wherein the structural formula of the 2- (5-chloro-2-pyridine) acetonitrile is as follows:
Figure BDA0001922329350000102
the structure determination data for compound 145 is as follows:
1H NMR(400MHz,CDCl3)δ8.60(d,J＝2.0Hz,1H),8.50(s,1H),8.07(d,J＝8.4Hz,2H),7.73-7.82(m,4H)。
example 5
This example mainly provides a method for producing compound 146 and data on the structure measurement of compound 146.
Figure BDA0001922329350000103
Compound 146 is given the english name:
(Z)-2-(5-chloro-2-pyridyl)-3-[6-(trifluoromethyl)-3-pyridyl]prop-2-enenitrile
the preparation of compound 146 was as follows: starting materials for the reaction in the preparation step of compound 83: the method can be replaced by 2- (5-chloro-2-pyridine) acetonitrile (the specific structure is shown in example 4) and 6- (trifluoromethyl) pyridine-3-carbaldehyde (the specific structure is shown in example 3), and other steps are consistent.
The structural determination data for compound 146 is:
1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.67(d,J＝8.4Hz,1H),8.62(d,J＝2.0Hz,1H),8.53(s,1H),7.83(d,J＝7.6Hz,2H),7.75(d,J＝8.4Hz,1H)。
example 6
This example mainly provides a method for producing compound 147 and data on the structure measurement of compound 147.
Figure BDA0001922329350000111
Compound 147 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(4-methoxyphenyl)acrylonitrile
preparation procedure for compound 147: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridol) acetonitrile (see example 4 for specific structure), and p-methoxybenzaldehyde.
The structure determination data for compound 147 is as follows:
1H NMR(400MHz,CDCl3)δ8.56(d,J＝2.0Hz,1H),8.38(s,1H),8.00(d,J＝8.8Hz,2H),7.74(dd,J＝8.4,2.4Hz,1H),7.67(d,J＝8.8Hz,1H),7.00(d,J＝8.8Hz,2H),3.89(s,3H)。
example 7
This example mainly provides a method for producing compound 148 and data on the structure measurement of compound 148.
Figure BDA0001922329350000121
The english name for compound 148 is as follows:
(Z)-2-(5-chloropyridin-2-yl)-3-phenylacrylonitrile
preparation of compound 148: starting materials for the reaction in the preparation step of compound 83: the p-chlorobenzonitrile and the p-trifluoromethylbenzaldehyde are replaced by: 2- (5-chloro-2-pyridol) acetonitrile (see example 4 for specific structure), and benzaldehyde.
The structure determination data for compound 148 is as follows:
1H NMR(400MHz,CDCl3)δ8.59(d,J＝2.0Hz,1H),8.46(s,1H),7.99(dd,J＝7.6,4.0Hz,2H),7.77(dd,J＝8.4,2.4Hz,1H),7.71(d,J＝8.4Hz,1H),7.49(dd,J＝4.8,1.2Hz,3H)。
example 8
This example mainly provides a method for producing compound 149 and data on the structure measurement of compound 149.
Figure BDA0001922329350000122
Compound 149 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(thiophen-3-yl)acrylonitrile
preparation procedure for compound 149: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridoxal) acetonitrile (see example 4 for a specific structure) and thiophene-3-carbaldehyde (3-thiophenecarboxaldehyde).
The structural determination data for compound 149 is as follows:
1H NMR(400MHz,CDCl3)δ8.58(s,1H),8.55(d,J＝2.4Hz,1H),7.81–7.72(m,2H),7.67–7.62(m,2H),7.19(dd,J＝4.8,4.0Hz,1H)。
example 9
This example mainly provides a method for producing compound 150 and data on the structure measurement of compound 150.
Figure BDA0001922329350000131
Compound 150 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(p-tolyl)acrylonitrile
preparation procedure for compound 150: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridoyl) acetonitrile (see example 4 for specific structure), p-tolualdehyde.
Structural characterization data for compound 150 is as follows:
1H NMR(400MHz,CDCl3)δ8.57(d,J＝2.0Hz,1H),8.42(s,1H),7.90(d,J＝8.0Hz,2H),7.76(dd,J＝8.8,2.4Hz,1H),7.69(d,J＝8.4Hz,1H),7.30(d,J＝8.0Hz,2H),2.43(s,3H)。
example 10
This example mainly provides a method for producing compound 151 and data on the structure measurement of compound 151.
Figure BDA0001922329350000141
Compound 151 is given the english name:
(Z)-3-(4-bromophenyl)-2-(5-chloropyridin-2-yl)acrylonitrile
preparation procedure for compound 151: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridoyl) acetonitrile (see example 4 for specific structure) and p-bromobenzaldehyde.
The structure determination data for compound 151 is as follows:
1H NMR(400MHz,CDCl3)δ8.58(d,J＝2.1Hz,1H),8.39(s,1H),7.85(d,J＝8.5Hz,2H),7.78(dd,J＝8.5,2.4Hz,1H),7.71(d,J＝8.4Hz,1H),7.63(d,J＝8.5Hz,2H)。
example 11
This example mainly provides a method for producing compound 152 and data on the structure measurement of compound 152.
Figure BDA0001922329350000142
Compound 152 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(4-fluorophenyl)acrylonitrile
preparation procedure for compound 152: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridoyl) acetonitrile (see example 4 for specific structure) and p-fluorobenzaldehyde.
The structure determination data for compound 152 is as follows:
1H NMR(400MHz,CDCl3)δ8.58(d,J＝2.0Hz,1H),8.43(s,1H),8.01(dd,J＝8.8,5.6Hz,2H),7.77(dd,J＝8.4,2.4Hz,1H),7.70(d,J＝8.4Hz,1H),7.18(t，J＝8.6Hz，2H)。
example 12
This example mainly provides a method for producing compound 153 and data on the structure measurement of compound 153.
Figure BDA0001922329350000151
Compound 153 is given by the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(pyridin-4-yl)acrylonitrile
preparation procedure for compound 153: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridine) acetonitrile (see example 4 for the specific structure) and pyridine-4-carbaldehyde.
Wherein the pyridine-4-carbaldehyde has the structure as follows:
Figure BDA0001922329350000152
the structure determination data for compound 153 is as follows:
1H NMR(400MHz,CDCl3)δ8.78(d，J＝5.6Hz，2H)，8.61(d，J＝2.0Hz，1H)，8.41(s，1H)，7.82(dd，J＝8.4，2.4Hz,1H)，7.77(dd，J＝11.2，6.0Hz，3H)。
example 13
This example mainly provides a method for producing compound 154, and data on the structure measurement of compound 154.
Figure BDA0001922329350000161
Compound 154 is given the english name:
(Z)-4-(2-(5-chloropyridin-2-yl)-2-cyanovinyl)benzonitrile
preparation procedure for compound 154: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridol) acetonitrile (see example 4 for specific structure), and p-cyanobenzaldehyde.
The structure determination data for compound 154 is as follows:
1H NMR(400MHz,CDCl3)δ8.60(d,J＝2.0Hz,1H),8.48(s,1H),8.05(d,J＝8.4Hz,2H),7.81(dd,J＝8.4,2.4Hz,1H),7.76(dd,J＝14.4,8.4Hz,3H)。
example 14
This example mainly provides a method for producing compound 155 and data on the structure measurement of compound 155.
Figure BDA0001922329350000162
Compound 155 is given the english name:
(Z)-3-(2-bromophenyl)-2-(5-chloropyridin-2-yl)acrylonitrile)
preparation procedure of compound 155: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridoyl) acetonitrile (see example 4 for specific structure) and o-bromobenzaldehyde.
The structure determination data for compound 155 is as follows:
1H NMR(400MHz,CDCl3)δ8.72(s,1H),8.63(d,J＝2.0Hz,1H),8.11(d,J＝8.0Hz,1H),7.79(dd,J＝8.4,2.4Hz,1H),7.74–7.69(m,2H),7.46(t,J＝7.6Hz,1H),7.36–7.30(m,1H)。
example 15
This example mainly provides a method for producing compound 156 and data on the structure measurement of compound 156.
Figure BDA0001922329350000171
Compound 156 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(6-chloropyridin-2-yl)acrylonitrile
preparation procedure of compound 156: starting materials for the reaction in the preparation step of compound 83: the p-chlorobenzonitrile and the p-trifluoromethylbenzaldehyde are replaced by: 2- (5-chloro-2-pyridine) acetonitrile (see example 4 for a specific structure) and 6-chloropyridine-2-carbaldehyde (6-chloro-2-pyridinecarbaldehyde).
Wherein the structural formula of the 6-chloropyridine-2-carbaldehyde is as follows:
Figure BDA0001922329350000172
the structure determination data for compound 156 is as follows:
1H NMR(400MHz,CDCl3)δ8.75(d,J＝1.6Hz,1H),8.60(d,J＝1.2Hz,1H),8.45(s,1H),7.83-7.80(m,2H),7.78-7.75(m,2H)。
example 16
This example mainly provides a method for producing compound 157, and data on the structure measurement of compound 157.
Figure BDA0001922329350000181
Compound 157 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(furan-2-yl)acrylonitrile
preparation procedure for compound 157: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridine) acetonitrile (see example 4 for specific structure) and furan-2-carbaldehyde.
Wherein the structural formula of the furan-2-carbaldehyde is as follows:
Figure BDA0001922329350000182
the structural determination data for compound 157 is:
1H NMR(400MHz,CDCl3)δ8.54(d，J＝2.0Hz，1H)，8.25(s，1H)，7.74(dd，J＝8.4,2.4Hz,1H),7.66(d,J＝8.8Hz,2H),7.22(d,J＝3.6Hz,1H),6.61(dd,J＝3.2,1.6Hz，1H)。
example 17
This example mainly provides a method for producing compound 158 and data on the structure measurement of compound 158.
Figure BDA0001922329350000183
Compound 158 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(furan-3-yl)acrylonitrile
preparation procedure for compound 158: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridine) acetonitrile (see example 4 for specific structure) and furan-3-carbaldehyde.
Wherein, the structure of the furan-3-carbaldehyde is as follows:
Figure BDA0001922329350000191
the structural determination data for compound 158 was:
1H NMR(400MHz，CDCl3)δ8.54(d，J＝2.4Hz，1H)，8.31(s，1H)，8.01(s,1H)，7.74(dd,J＝8.4,2.4Hz,1H),7.62(d,J＝8.4Hz,1H),7.54(s,1H),7.28(s,1H)。
example 18
This example mainly provides a method for producing compound 159 and data on the structure measurement of compound 159.
Figure BDA0001922329350000192
Compound 159 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(2-fluorophenyl)acrylonitrile
preparation procedure of compound 159: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridoyl) acetonitrile (see example 4 for the structure) and o-fluorobenzaldehyde.
The structure determination data for compound 159 is:
1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.61(d,J＝2.0Hz,1H),8.33(t,J＝7.2Hz,1H),7.78(dd,J＝8.4,2.4Hz,1H),7.72(d,J＝8.4Hz,1H),7.48(td,J＝7.6,1.6Hz,1H),7.29(t,J＝7.6Hz,1H),7.20–7.15(t,J＝9.2Hz,1H)。
example 19
This example mainly provides a method for producing compound 160 and data on the structure measurement of compound 160.
Figure BDA0001922329350000201
Compound 160 is given the english name:
(Z)-2-(5-chloropyridin-2-yl)-3-(2-(trifluoromethyl)phenyl)acrylonitrile
preparation procedure for compound 160: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridoyl) acetonitrile (see example 4 for a specific structure) and o-trifluoromethylbenzaldehyde.
The structure determination data for compound 160 is as follows:
1H NMR(400MHz,CDCl3)δ8.78(d,J＝2.0Hz,1H),8.63(d,J＝2.4Hz,1H),8.08(d,J＝7.6Hz,1H),7.79(dd,J＝8.4,2.8Hz,2H),7.75–7.65(m,2H),7.58(t,J＝7.6Hz,1H)。
example 20
This example mainly provides a method for producing compound 161, and data on the structure measurement of compound 161.
Figure BDA0001922329350000202
Compound 161 is given the english name:
(Z)-3-(4-chlorophenyl)-2-(5-chloro-2-pyridyl)prop-2-enenitrile
preparation procedure for compound 161: starting materials for the reaction in the preparation step of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: 2- (5-chloro-2-pyridoyl) acetonitrile (see example 4 for specific structure) and p-chlorobenzaldehyde.
The structure determination data for compound 161 is:
1H NMR(400MHz,CDCl3)δ8.54(d,J＝2.0Hz,1H),8.37(s,1H),7.89(d,J＝8.5Hz,2H),7.74(dd,J＝8.4,2.4Hz,1H),7.66(d,J＝8.4Hz,1H),7.43(d,J＝8.4Hz,2H),7.22(s,1H)。
example 21
This example mainly provides a method for producing compound 162 and data on the structure measurement of compound 162.
Figure BDA0001922329350000211
Compound 162 is given the english name:
(Z)-3-(6-(aminomethyl)pyridin-3-yl)-2-(4-chlorophenyl)acrylonitrile
the procedure for the preparation of compound 162 is similar to that of compound 83, except that: (1) starting from the reaction of compound 83: p-trifluoromethylbenzaldehyde, substituted by: tert-butyl N- [ (5-formamyl-2-pyridyl) methyl ] carbamate; (2) and after the reaction is finished, removing the Boc protecting group to obtain a compound 162.
Wherein the structural formula of tert-butyl N- [ (5-formamyl-2-pyridyl) methyl ] carbamate is as follows:
Figure BDA0001922329350000212
the structure determination data for compound 162 is as follows:
1H NMR(400MHz,CD3OD)δ9.02(s,1H),8.44(q,J＝3.45Hz,1H)，7.91(s，1H)，7.75(d，J＝8.64Hz,2H)，7.57(d，J＝8.24Hz，1H)，7.50(d，J＝8.64Hz，2H)，4.23(d,J＝3.52Hz,2H)。
example 22
This example mainly provides a method for producing compound 163, and data on the structure measurement of compound 163.
Figure BDA0001922329350000221
The english name of compound 163 is as follows:
(Z)-3-(6-(difluoromethyl)pyridin-3-yl)-2-(4-(piperidin-4-yl)phenyl)acryloni trile
the procedure for the preparation of compound 163 is similar to that of compound 83, except that: (1) starting from the reaction of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components:
tert-butyl4- [4- (cyanomethyl) phenyl ] piperidine-1-carboxylate and 6- (difluoromethyl) pyridine-3-carbaldehyde; (2) after the reaction is finished, the Boc protecting group needs to be removed, and the compound 163 can be obtained.
Wherein the structural formula of the 4- [4- (cyanomethyl) phenyl ] piperidine-1-carboxylate is as follows:
Figure BDA0001922329350000222
wherein the structural formula of the 6- (difluoromethyl) pyridine-3-carbaldehyde is as follows:
Figure BDA0001922329350000231
the structural determination data for compound 163 is as follows:
1H NMR(400MHz,CD3OD)δ8.93(s,1H),8.48(q,J＝3.33Hz,1H),7.84(s,1H),7.73(d,J＝8.28Hz,1H),7.69(d,J＝8.32Hz,2H),7.34(d,J＝8.28Hz,2H),6.68(t,J＝55.10Hz，1H)，3.43(d，J＝12.64Hz，2H),3.07(m,J＝6.41Hz,2H),2.90(m，J＝4.05Hz，1H),2.01(d，J＝13.88Hz，2H)，1.84(m，J＝6.21Hz，2H)。
example 23
This example mainly provides a method for producing compound 164 and data on the structure measurement of compound 164.
Figure BDA0001922329350000232
Compound 164 is given the english name:
(Z)-2-(4-(piperidin-4-yl)phenyl)-3-(6-(trifluoromethyl)pyridin-3-yl)acrylon itrile
the procedure for the preparation of compound 164 is analogous to that of compound 83, except that: (1) starting from the reaction of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: tert-butyl4- [4- (cyanomethyl) phenyl ] piperidine-1-carboxylate (formula shown in example 22) and 6- (trifluoromethylphenyl) pyridine-3-carbaldehyde (formula shown in example 3); (2) and after the reaction is finished, removing the Boc protecting group to obtain the compound 164.
The structure determination data for compound 164 is as follows:
1H NMR(400MHz,CD3OD)δ9.02(s,1H),8.56(q,J＝3.17Hz,1H),7.91(s,1H),7.89(d,J＝8.40Hz,1H),7.74(d,J＝8.36Hz,2H),7.38(d,J＝8.36Hz,2H),3.46(d,J＝12.36Hz,2H),3.10(q,J＝7.83Hz,2H),2.94(m,J＝3.86Hz,1H),2.06(d,J＝14.00Hz,2H),1.88(m,J＝6.23Hz,2H)。
example 24
This example mainly provides a method for producing compound 165 and data on the structure measurement of compound 165.
Figure BDA0001922329350000241
The english name for compound 165 is as follows:
(Z)-3-(6-methylpyridin-3-yl)-2-(4-(piperidin-4-yl)phenyl)acrylonitrile
the procedure for the preparation of compound 165 is similar to that of compound 83, except that: (1) starting from the reaction of compound 83: p-chlorobenzonitrile, p-trifluoromethylbenzaldehyde, and replacing the raw materials by the following components: tert-butyl4- [4- (cyanomethyl) phenyl ] piperidine-1-carboxylate (see example 22) and 6-methylpyridine-3-carbaldehyde; (2) and after the reaction is finished, removing the Boc protecting group to obtain the compound 165.
Wherein the structural formula of the 6-methylpyridine-3-carbaldehyde is as follows:
Figure BDA0001922329350000242
the structural characterization data for compound 165 is:
1H NMR(400MHz,CD3OD)δ8.95(d,J＝1.44Hz,1H),8.77(q,J＝3.45Hz,1H),7.84(s,1H),7.82(d,J＝8.64Hz,1H),7.67(d,J＝8.32Hz,2H),7.33(d,J＝8.32Hz,2H),3.40(d,J＝12.72Hz,2H),3.04(q,J＝7.87Hz,2H),2.88(m,J＝3.93Hz,1H),2.69(s,3H),1.98(d,J＝13.88Hz,2H),1.83(m,J＝6.21Hz,2H)。
from example 2 to example 24 it can be seen that: the diarylethene compounds in the formula (I) are novel in structure, easy to synthesize chemically, low in cost and small in side effect.
Example 25
Inhibition of monoamine oxidase B (MAO-B) by the compounds of the invention at a concentration of 500 nM:
1. principle of experiment
Monoamine oxidase B can catalyze the degradation of its substrate analog kynuramine to produce 4-quinoline alcohol. The 4-quinolinol formed by the reaction can be detected by 320nM excitation wavelength/400 nM emission wavelength. The compound and the mixed solution of monoamine oxidase B react at 37 ℃, if the compound has inhibition effect on monoamine oxidase B, the degradation amount of the monoamine oxidase B catalytic substrate analogue kynuramine is reduced, and the corresponding reaction product 4-quinanol is reduced, namely the signal value at 320nM excitation wavelength/400 nM emission wavelength is reduced, so as to screen the compound with inhibition activity.
2. Procedure of experiment
1) Prepare 1 × buffer solution: prepare 1x reaction phosphate buffer.
2) Dilution compound: compound solutions were prepared at 100x DMSO dilution, and 500nL were taken into each well of 384-well plates. The final DMSO concentration was 1%.
3) Preparing an enzyme solution: monoamine oxidase B was added to the 1x reaction buffer to give a 2x enzyme solution.
4) Preparing a substrate solution: substrate was added to 1x reaction buffer to give a 2x substrate solution.
5) Transfer 25 μ Ι _ of enzyme solution to each well of 384-well plate; add 25. mu.L of 1 Xreaction buffer to the blank in air.
6) Incubate at room temperature for 15 minutes.
7) Enzyme reactions were initiated by adding 25. mu.L of substrate solution to each well of a 384-well plate.
8) The reaction was carried out at 37 ℃ for 30 minutes.
9) The reaction was stopped by adding 20. mu.L of 2M NaOH solution.
10) Data were read at 320nM excitation/400 nM emission wavelength.
3. Data processing:
the inhibition rate of the compound on monoamine oxidase B is calculated in Excel according to the following formula. The calculation formula is as follows:
inhibition ratio [% ] (maximum value-experimental value)/(maximum value-blank value) × 100 formula (1)
4. Results of the experiment
The results of the experiment are shown in table 2:
table 2 shows the inhibition rate of the compound of the present invention on monoamine oxidase B (MAO-B) at a concentration of 500nM
Compound (I) Inhibition ratio% Compound (I) Inhibition ratio% Compound (I) Inhibition ratio%
66 88 88 94 116 53
69 20 92 28 117 12
75 98 97 50 119 15
76 25 98 97 120 79
78 25 103 23 162 81
80 44 104 39 163 87
82 5 110 53 164 82
83 98 111 37 165 60
84 82 114 2 152 45
144 97 148 95 153 67
145 72 149 74 154 78
146 75 150 66 155 64
147 86 151 42 156 53
157 78 158 25 159 50
160 45 161 66
As can be seen from table 2: the compound of the invention has an inhibiting effect on monoamine oxidase B, and some compounds have stronger inhibiting effect on monoamine oxidase B.
Example 26:
compounds of the present invention have monoamine oxidase B (MAO-B) inhibitory activity IC50The determination of (1):
1. principle of experiment (same as example 25).
2. Procedure of experiment (same as example 25).
3. Data processing: the inhibition rate of the compound on monoamine oxidase B was calculated in Excel according to the following formula (1).
Inhibition [% ] (maximum value-experimental value)/(maximum value-blank value) [% 100 equation (1)
The IC of the compound on monoamine oxidase B inhibition was calculated in GraphPad Prism 5 according to the following formula (2)50The value is obtained.
Y＝Bottom+(Top-Bottom)/(1+10∧((LogIC50-X)' Hill Slope)) formula (2)
In equation (2): y is the inhibition rate and X is the compound concentration.
4. Results of the experiment
The experimental results of this example are shown in table 3:
table 3 shows the monoamine oxidase B (MAO-B) inhibitory activity IC50 of the compounds of the present invention
Figure BDA0001922329350000271
As can be seen from table 3: compared with the control (Resveratrol Resveratrol), the compound has better inhibition activity on monoamine oxidase B (MAO-B). In addition, the inhibitory activity of partial compounds is better than that of clinical drug selegiline (selegiline is clinically used MAO-B inhibitor approved by FDA, first generation irreversible inhibitor)
As can be seen from fig. 1 to 4: the compounds 83, 144, 145 and 146 of the present invention have a good inhibitory activity.
Example 27:
compounds of the present invention have monoamine oxidase A (MAO-A) inhibitory activity IC50The determination of (1):
1. principle of experiment (same as example 25).
2. Procedure of experiment (same as example 25).
3. Data processing (same as example 26).
4. Results of the experiment
The experimental results of this example are shown in table 4:
table 4 shows the monoamine oxidase A (MAO-A) inhibitory activity IC50 of the compounds of the invention
Figure BDA0001922329350000281
As can be seen from table 4: the compounds of the invention have a poor monoamine oxidase a (MAO-B) inhibitory activity compared to the control (Resveratrol).
In summary, the diarylethene compounds in formula (I) provided by the invention have the activity of inhibiting the single ammonia oxidase B (MAO-B) and have the potential of being high-selectivity MAO-B inhibitors (the invention is firstly provided, and the prior art has not been reported). Therefore, the invention also provides that the diarylethene compounds in the formula (I) can be used as a target inhibitor of the single ammonia oxidase B (MAO-B) and a Parkinson disease medicament.
In addition, when the diarylethene compounds provided by the invention are used as medicines, the diarylethene compounds can be directly used, and also can be used in the form of a pharmaceutical composition. When used as a pharmaceutical composition, the pharmaceutical composition contains 0.1 to 99 percent, preferably 0.5 to 90 percent of diarylethene compounds, and the balance of pharmaceutically acceptable excipients (such as carriers or excipients) which are nontoxic and inert to human and animals. Herein, a pharmaceutically acceptable adjuvant (carrier or excipient) is one or more adjuvants selected from solid, semi-solid and liquid diluents, super-fillers and pharmaceutical preparations. The effective extract or the effective part is used in the form of unit weight dosage. The medicament of the invention can be administered in both oral and oral spray forms. The oral preparation can be made into solid or liquid preparation, such as powder, tablet, coated tablet, capsule, tincture, syrup, dripping pill, etc. The oral spray may be in solid or liquid form. The medicine can be used for treating Parkinson's disease.
Formulation examples:
formulation example 1:
the compound purchased in example 1 or the compound of the invention prepared according to examples 2-24 is taken, added with excipients in a weight ratio of 1:1 to the excipients, granulated and tabletted.
Formulation example 2:
the compound purchased in example 1 or prepared according to examples 2-24 is taken, added with excipient according to the weight ratio of 1:2 of the compound to the excipient, granulated and tabletted.
Formulation example 3:
the compound purchased in example 1 or prepared according to examples 2 to 24 was taken and encapsulated according to the conventional capsule preparation method.
Formulation example 4:
the compound purchased in example 1, or prepared according to examples 2-24, was then tableted as follows:
Figure BDA0001922329350000291
formulation example 5:
and (3) capsule preparation: the compound purchased in example 1, or prepared as per examples 2-24, was taken: 100mg, starch: proper amount, magnesium stearate: proper amount of
The preparation method comprises the following steps: mixing the compound with adjuvants, sieving, mixing in suitable container, and encapsulating the obtained mixture into hard gelatin capsule.
Formulation example 6:
nasal spray: the compound purchased in example 1, or prepared as per examples 2-24, was taken: 80mg of
Figure BDA0001922329350000301
The preparation method comprises the following steps: adding one component into double distilled water with stirring until completely deeply decomposing, and adding the other component. After adding water to 2ml, the solution was filtered on a sterile filter, bottled and partitioned according to the appropriate dose.
Formulation example 7:
dripping pills: the compound purchased in example 1, or prepared as per examples 2-24, was taken: 1g, polyethylene glycol 6000: 9g of
The preparation method comprises the following steps: preparation of compound and polyethylene glycol 6000 melt: weighing the compound according to the formula amount, adding a proper amount of absolute ethyl alcohol, slightly heating for dissolving, adding the mixture into polyethylene glycol melt according to the formula amount (keeping the temperature of 60 ℃ water bath), stirring and mixing uniformly until the ethyl alcohol is volatilized completely, standing in the water bath at 60 ℃ for heat preservation for 30 minutes until bubbles are removed completely, then transferring the uniformly mixed melt with the bubbles removed completely into a liquid storage cylinder, controlling the dropping speed under the condition of keeping the temperature at 80-85 ℃, dropping the uniformly mixed melt into condensate drop by drop until the condensation is complete, pouring off the condensate, collecting dropping pills, draining, removing the condensate on the pills by using filter paper, and placing in a silica gel dryer or naturally drying.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are still within the scope of the technical solution of the present invention.

Claims (6)

1. A diarylethene compound, wherein the diarylethene compound is one of the following compounds:
Figure FDA0002887501100000011
Figure FDA0002887501100000021
2. a pharmaceutical composition, comprising: the diarylethene compounds according to claim 1 and at least one pharmaceutically acceptable excipient.
3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition comprises 0.1-99% of the diarylethenes.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition comprises 0.5-90% of the diarylethenes.
5. Use of the diarylethene compounds according to claim 1 for the preparation of a medicament for the treatment of parkinson's disease.
6. Use of a diarylethene compounds according to claim 1 for the preparation of monoamine oxidase B inhibitors.
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