CN103172587B - The amides compound of 3 ketone of benzisothiazole 2 with the inhibitory activity of Caspase 3 - Google Patents
The amides compound of 3 ketone of benzisothiazole 2 with the inhibitory activity of Caspase 3 Download PDFInfo
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- CN103172587B CN103172587B CN201210537265.6A CN201210537265A CN103172587B CN 103172587 B CN103172587 B CN 103172587B CN 201210537265 A CN201210537265 A CN 201210537265A CN 103172587 B CN103172587 B CN 103172587B
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- benzisothiazole
- ketone
- acid amides
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- BROAXDYDIICLES-UHFFFAOYSA-N C/[O]=C1\N(C(NCCc2ccccc2)=O)Sc2ccccc12 Chemical compound C/[O]=C1\N(C(NCCc2ccccc2)=O)Sc2ccccc12 BROAXDYDIICLES-UHFFFAOYSA-N 0.000 description 1
- UIBSLLYDPMQGGE-UHFFFAOYSA-N COc(cccc1)c1NC(N1Sc2ccccc2C1=O)=O Chemical compound COc(cccc1)c1NC(N1Sc2ccccc2C1=O)=O UIBSLLYDPMQGGE-UHFFFAOYSA-N 0.000 description 1
- VISABOZDZJMUJA-UHFFFAOYSA-N O=C(Nc1cccc(Br)c1)N1[SH-]c2ccccc2C1=O Chemical compound O=C(Nc1cccc(Br)c1)N1[SH-]c2ccccc2C1=O VISABOZDZJMUJA-UHFFFAOYSA-N 0.000 description 1
Abstract
The amides compound of 3 ketone of benzisothiazole 2 with the inhibitory activity of Caspase 3.The present invention provides the amides compound of 3 ketone of a class benzisothiazole 2, the compound has the inhibitory activity of Caspase 3, it can be used in the disease that treatment is mediated by Caspase 3, belong to medicinal chemistry art, the compound has structure shown below formula (I).
Description
Technical field
The present invention relates to the benzisothiazole-3-ketone -2- amides compounds that a class has Caspase-3 inhibitory activity,
Belong to medicinal chemistry art.
Background technology
Apoptosis (apoptosis) is that the cell controlled by specific gene is autonomous, order death, or due to outer
The cell suicide process come factor to trigger intracellular intrinsic death program and triggered, also known as apoptosis
(Programmed Cell Death, PCD).One of essential characteristic as life, Apoptosis is common accurate with cell propagation
Body normal growth and development and homeostasis are adjusted, accurate regulatory mechanism is related to complex proteinase cascade reaction process, wrapped
A variety of regulatory factors are included, wherein Caspase (the aspartic acid proteolytic enzyme containing cysteine) is most important regulation enzyme.
Caspase belongs to the cysteine proteinase family of aspartic acid specific, cysteine proteinase cut its substrate specificity and
1 asparagicacid residue is left, is served in the startup of Apoptosis and implementation procedure key.
Under normal circumstances, Caspase enzymes exist in inactive proenzyme (proenzymes) form, it is necessary to by line grain
It can just be played a role after the activation such as body approach, death receptor pathway *, endoplasmic reticulum-induced.When being stimulated by apoptotic signal,
The Caspase of upstream can in turn activate the Caspase in downstream, form cascade reaction, and apoptotic signal one-level level is passed into apoptosis
Substrate.Caspase-3 can inactivate ICAD (inhibitor CAD) as main downstream effect Caspase, after being activated,
The DNA enzymatic (Capase-activated Dnase, CAD) that the active Caspase that dissociates is activated, so that hydrolyzing DNA causes cell
Apoptosis.Caspase-3 can cut most of apoptotic cell substrates and crack many apoptosis program cascade albumen enzymic catalytic reactions
In albumen, be also the key enzyme of apoptosis and to hold so Caspase-3 is the only way which must be passed of apoptotic protease cascade reaction
Passerby.The key protein of kytoplasm, karyon and cytoskeleton, drops in the signal activation Caspase-3 that a variety of stimulus start
Solution inactivation.Various gene knockout experiments and animal model are shown in recent years, suppress Caspase-3 activity will significantly block it is external and
Internal Apoptosis, this is for research tumour, autoimmune disease, viral infection and various nerve degenerative diseases
Develop, explore therapeutic scheme, and exploitation novel agrochemical, veterinary drug suffer from particularly important value.
Representative in existing Caspase-3 inhibitor is quinolines Caspase-3 inhibitor.Quinolines
Caspase-3 inhibitor is main based on quinolines, quinoline derivatives and iloquinoline derivative.With 1,3- dioxos -2,3- bis-
Hydrogen -1H- pyrroles-[3,4-c] quinoline (structural formula is as follows) is that main body synthesizes a series of compounds, in core skeleton the 4th
Substituted derivative is stronger to Caspase-3 inhibitory activity, and wherein methyl replaces the 4th and phenyl replaces the derivative of the 4th
IC of the thing to Caspase-350Respectively 23nM and 27nM：
Core skeleton 1,3- dioxo -2,3- dihydro -1H- pyrroles-[3,4-c] quinoline.
The compound come out by optimizing high flux screening obtains a series of isoquinolin -1,3,4- triketone analogs, wherein
6-N- acyl groups substituted compound (structural formula is as follows) has the inhibitory activity of nanomole level, IC50=40nM：
Isoquinolin -1,3 of 6-N- acyl groups substitution, 4- triketone analogs.
Except quinolines, many isatin sulfamido Caspase-3 inhibitor also have developed.These compounds
Common feature be with Michael acceptors, wherein many compounds Caspase-3 inhibitory activity is reached nanomole level
Not, found by technical research such as NMR, the action target of such compound I (structural formula is as follows) is Caspase-3 activity
The benzyl mercaptan for the cysteine that site is 285, compound interacts to suppress its activity with mercaptan.Then research is found
Benzyl isatin sulfanilamide (SN) analog (structural formula is as follows) also has the inhibitory activity of nanomole level to Caspase-3：
Compound I benzyl isatin sulfanilamide (SN) analogs in isatin sulfanilamide (SN) analog.
Although some Caspase-3 inhibitor have been developed at present, it is contemplated that Caspase-3 inhibitor demands
Greatly, have a extensive future, and current Caspase-3 inhibitor species is less, there is also certain limitation in use.Cause
This, develops inhibitor new and with good Caspase-3 inhibitory action, is still the target of pharmacy worker.
The content of the invention
Inventor carries out high flux screening to small molecule segment storehouse, obtains the parent nucleus bone with Caspase-3 inhibitory action
Frame, structural formula is as follows：
This is to find that the skeleton has Caspase-3 inhibitory action first, based on this, develops a series of benzisoxas
Thiazole ketones derivant, and its Caspase-3 inhibitory action is studied, determine that they all have preferable Caspase-
3 inhibitory activity, can be used for preparing Caspase-3 inhibitor, for treating the disease mediated by Caspase-3.In above-mentioned work
On the basis of work, the present invention is proposed.
Technical scheme is as follows：
One class benzisothiazole-3-ketone -2- amides compounds, with structure shown below formula (I)：
Wherein, R1The following group replaced selected from unsubstituted or substituted base：Aryl；Aryl alkyl；Or azepine virtue
Base, wherein, the substituent is selected from one or more of halogen, alkyl, haloalkyl, alkoxy and nitro.
Currently preferred technical scheme is：
One class benzisothiazole-3-ketone -2- amides compounds, with structure formula (I) illustrated above, wherein：
R1The following group replaced selected from unsubstituted or substituted base：C6-14Aryl；C6-14Aryl-C1-8Alkyl；Or
5-10 member azepine aryl, wherein, one or many in halogen, alkyl, haloalkyl, alkoxy and nitro of the substituent
It is individual.
The further preferred technical scheme of the present invention is：
One class benzisothiazole-3-ketone -2- amides compounds, with structure formula (I) illustrated above, wherein：
R1Selected from the C being substituted with a substituent6-14Aryl；Unsubstituted C10-14Aryl；Unsubstituted C6-10Aralkyl-
C2-8Alkyl；The C being substituted with a substituent6-10Aralkyl-C1-8Alkyl, wherein the substituent is selected from halogen, C1-8Alkyl, halo
C1-8Alkyl, C1-8One or more of alkoxy and nitro.
The further preferred technical scheme of the present invention is：
One class benzisothiazole-3-ketone -2- amides compounds, with structure formula (I) illustrated above, wherein：
R1Selected from the C being substituted with a substituent6-10Aryl；Unsubstituted C10-14Aryl；Unsubstituted C6-10Aryl-C2-6
Alkyl；The C being substituted with a substituent6-10Aryl-C1-6Alkyl, wherein the substituent is selected from halogen, C1-6Alkyl, halo C1-6Alkane
Base, C1-6One or more of alkoxy and nitro.
Present invention technical scheme still more preferably is：
One class benzisothiazole-3-ketone -2- amides compounds, with structure formula (I) illustrated above, wherein：
R1Selected from the phenyl or naphthyl being substituted with a substituent；Unsubstituted naphthyl；Unsubstituted phenyl-C2-4Alkyl；
Phenyl-the C being substituted with a substituent1-4Alkyl, wherein the substituent is selected from halogen, C1-4Alkyl, halo C1-4Alkyl, C1-4Alcoxyl
One or more of base and nitro.
Most preferably technical scheme of the invention is：
One class benzisothiazole-3-ketone -2- amides compounds, selected from following compound：
N- (1- naphthyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- naphthyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- bromophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- bromophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- bromophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- nitrobenzophenones)-benzisothiazole-3-ketone -2- acid amides；
N- (3- nitrobenzophenones)-benzisothiazole-3-ketone -2- acid amides；
N- (2- nitrobenzophenones)-benzisothiazole-3-ketone -2- acid amides；
N- (4- iodophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- [4- chloro- 3- (trifluoromethyl) phenyl] benzisothiazole-3-ketone -2- acid amides；
N- (α-methylbenzyl)-benzisothiazole-3-ketone -2- acid amides；
N- (4- methoxy-benzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- methoxy-benzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- methoxy-benzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- luorobenzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- luorobenzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- luorobenzyls)-benzisothiazole-3-ketone -2- acid amides；With
N- (phenethyl)-benzisothiazole-3-ketone -2- acid amides.
The present invention further provides following technical scheme：
Benzisothiazole-3-ketone -2- amides compounds of the present invention are used for the use for preparing Caspase-3 enzyme inhibitors
On the way.Benzisothiazole-3-ketone -2- the amides compounds are preferably particular compound above-mentioned.
Benzisothiazole-3-ketone -2- amides compounds of the present invention are used to treat in preparation to be mediated by Caspase-3
Disease medicine in purposes.Benzisothiazole-3-ketone -2- the amides compounds are preferably materialization above-mentioned
Compound, and the disease are tumour, autoimmune disease, viral infection and various nerve degenerative diseases.
A kind of Caspase-3 inhibitor, comprising in benzisothiazole-3-ketone -2- amides compounds of the present invention
At least one is used as active component, and pharmaceutically acceptable excipient and carrier.Benzisothiazole-3-ketone -2- the acyls
Aminated compounds is preferably particular compound above-mentioned.
It is a kind of to be used to treat the pharmaceutical composition by the Caspase-3 diseases mediated, include benzisothia of the present invention
At least one of azoles -3- ketone -2- amides compounds are used as active component, and pharmaceutically acceptable excipient and load
Body.Benzisothiazole-3-ketone -2- the amides compounds are preferably particular compound above-mentioned；And the disease
It is tumour, autoimmune disease, viral infection and various nerve degenerative diseases.
Present invention firstly discovers that benzisothiazole-3-ketone -2- amide backbones have the effect for suppressing Caspase-3 activity,
A series of noval chemical compounds developed based on this have good inhibitory activity, and some of compounds are even more to have reached Na Mo
That rank, therefore, benzisothiazole-3-ketone -2- amides compounds of the present invention can be used for preparing treatment
The medicine of the disease of Caspase-3 mediations, so as to enrich the species of Caspase-3 inhibitor.
In the present invention：
Caspase represents the aspartic acid proteolytic enzyme containing cysteine；
HEPES represents hydroxyethyl piperazine second thiosulfonic acid；
Glycerol represents glycerine；
CHAPS represents 3- (3- cholamidopropyls) dimethylamino -1- propane sulfonic acid；
DMEDA represents N, N '-dimethyl-ethylenediamine；
C6-14Aryl refers to the aromatic hydrocarbyl containing 6-14 carbon atom, and (such as 2- joins for such as phenyl, naphthyl, xenyl
Phenyl, 3- xenyls, 4- xenyls etc.), anthryl etc.；
C1-8Alkyl refers to the straight or branched alkyl with 1-8 carbon atom, for example, methyl, ethyl, propyl group, isopropyl
Base, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, neopentyl, tertiary pentyl, 1- ethyl propyls, hexyl, 2- ethyls
Butyl, 3,3- dimethylbutyls, heptyl, 1- butyls, 3- ethyl pentyl groups, octyl group etc.；
C6-14Aryl-C1-8Alkyl refers to C6-14Aryl passes through C1-8Alkyl is connected with parent nucleus, for example benzyl, phenethyl, phenylpropyl alcohol
Base, propyloxy phenyl base, 2- phenyl butyls, 2- phenyl isobutyls base, 3- phenylpentyls, 2- Phenylhexyls, phenylheptyl, 3- phenyl heptan
Base, phenyl octyl group, naphthyl methyl, naphtylethyl group etc.；
5-10 member azepine aryl refers to the 5-10 member heteroaryl ring groups containing at least one nitrogen-atoms, and it can also optionally contain
One or more hetero atoms selected from oxygen or sulphur, such as pyrrole radicals, imidazole radicals, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
Isoxazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, 1,2,4- oxadiazoles, 1,3,4- oxadiazoles, 1,2,4- thiadiazoles,
1,3,4- thiadiazoles etc.；
Halogen refers to halogen atom, i.e. fluorine, chlorine, bromine and iodine；
Halo C1-8Alkyl refers to the C replaced by one or more halogen atoms1-8Alkyl, example includes chloromethyl, fluorine first
Base, difluoromethyl, trifluoromethyl, bromomethyl, 1,2- dichloromethyls, 2,2- dichloromethyls, Chloroethyl, 2- chloros propyl group, 2,
2,2- trifluoroethyls, chlorobutyl, perfluoropentyl, bromine hexyl, chlorine heptyl, fluorine octyl group etc.；
C1-8Alkoxy is the C that connection is closed by oxygen key1-C8Alkyl, the example include but is not limited to methoxyl group, ethyoxyl,
Propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, amoxy, isoamoxy, tertiary amoxy, the oxygen of 1- ethyls third
Base, hexyloxy, epoxide in heptan, octyloxy etc.；
C6-10Aryl refers to the aromatic hydrocarbyl containing 6-10 carbon atom, such as phenyl, naphthyl；
C10-14Aryl refers to the aromatic hydrocarbyl containing 10-14 carbon atom, including but not limited to naphthyl, xenyl, anthryl,
Phenanthryl etc.；
C6-10Aryl-C2-8Alkyl refers to C6-10Aryl passes through C2-8Alkyl is connected with parent nucleus, for example phenethyl, phenylpropyl, benzene
Isopropyl, 2- phenyl butyls, 2- phenyl isobutyls base, 3- phenylpentyls, 2- Phenylhexyls, phenylheptyl, 3- phenylheptyls, phenyl
Octyl group etc.；
C6-10Aryl-C1-8Alkyl refers to C6-10Aryl passes through C1-8Alkyl is connected with parent nucleus, for example benzyl, phenethyl, phenylpropyl alcohol
Base, benzene isopropyl, 2- phenyl butyls, 2- phenyl isobutyls base, 3- phenylpentyls, 2- Phenylhexyls, phenylheptyl, 3- phenyl heptan
Base, phenyl octyl group etc.；
C1-6Alkyl refers to the direct-connected or branched alkyl with 1-6 carbon atom, for example, methyl, ethyl, propyl group, isopropyl
Base, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, isopentyl, neopentyl, tertiary pentyl, 1- ethyl propyls, hexyl, 2- ethyls
Butyl, 3,3- dimethylbutyls etc.；
C6-10Aryl-C1-6Alkyl refers to C6-10Aryl passes through C1-6Alkyl is connected with parent nucleus, for example benzyl, phenethyl, phenylpropyl alcohol
Base, benzene isopropyl, 2- phenyl butyls, 2- phenyl isobutyls base, 3- phenylpentyls, 2- Phenylhexyls etc.；
C6-10Aryl-C2-6Alkyl refers to C6-10Aryl passes through C1-6Alkyl is connected with parent nucleus, for example phenethyl, phenylpropyl, benzene
Isopropyl, 2- phenyl butyls, 2- phenyl isobutyls base, 3- phenylpentyls, 2- Phenylhexyls etc.；
Halo C1-6Alkyl refers to the C replaced by one or more halogen atoms1-6Alkyl, example includes chloromethyl, fluorine first
Base, difluoromethyl, trifluoromethyl, bromomethyl, 1,2- dichloromethyls, 2,2- dichloromethyls, Chloroethyl, 2- chloros propyl group, 2,
2,2- trifluoroethyls, chlorobutyl, perfluoropentyl, bromine hexyl etc.；
C1-6Alkoxy is the C that connection is closed by oxygen key1-6Alkyl, the example includes but is not limited to methoxyl group, ethyoxyl, third
Epoxide, isopropoxy, butoxy, isobutoxy, tert-butoxy, amoxy, isoamoxy, tertiary amoxy, 1- ethylpropoxies,
Hexyloxy etc.；
Phenyl-C2-4Alkyl refers to that phenyl passes through C2-4Alkyl is connected with parent nucleus, for example phenethyl, phenylpropyl, benzene isopropyl,
2- phenyl butyls, 2- phenyl isobutyl bases etc.；
Phenyl-C1-4Alkyl refers to that phenyl passes through C1-4Alkyl is connected with parent nucleus, and for example benzyl, phenethyl, phenylpropyl, benzene are different
Propyl group, 2- phenyl butyls, 2- phenyl isobutyl bases etc.；
C1-4Alkyl refers to the alkyl containing 1-4 carbon atom of straight chain or side chain, including methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl group etc.；
C1-4Alkoxy is the C that connection is closed by oxygen key1-C4Alkyl, the example include but is not limited to methoxyl group, ethyoxyl,
Propoxyl group, isopropoxy, butoxy etc.；
Halo C1-4Alkyl refers to the C replaced by one or more halogen atoms1-4Alkyl, example includes chloromethyl, trifluoro
Methyl, Chloroethyl, 2- chloros propyl group, 2,2,2- trifluoroethyls etc..
Tumour, autoimmune disease, viral infection and various are included by the example of the Caspase-3 diseases mediated
Nerve degenerative diseases etc..
Brief description of the drawings
Fig. 1 shows the amino acid sequence figure of artificial synthesized Caspase-3 natural substrate in the prior art.
Embodiment
It is further described to various aspects of the present invention with feature below.
The wood various terms that use of invention and phrase have well known to a person skilled in the art general sense, nonetheless,
The present invention remains desirable to that these terms and phrase are described in more detail and explained at this, the term and phrase referred to if any
It is inconsistent with common art-recognized meanings, it is defined by the implication that the present invention is stated.Abbreviation used herein is usually art technology
Known to personnel, or can be understandable according to rudimentary knowledge.
The preparation of compound
Initiation material employed in the preparation of the compounds of this invention is known, can prepared according to known method
Or it is commercially available.
In the present invention, the following surface current journey institute of the synthetic route of the benzisothiazole-3-ketone -2- amides compounds
Show：
It is by aminated compounds (i) and triphosgene ((CCl first3)2CO) synthesize different in the presence of organic base such as triethylamine
Cyanate compound (ii), then makes (ii) and 1,2- benzisothiazole-3-ketones (iii) back flow reaction, generates institute of the present invention
State formula (I) compound, wherein, it is various in R1As to defined in structure formula (I).
Intermediate and end-product can according to conventional methods be post-processed and/or purified, and the conventional method includes
Adjust pH, extraction, filtering, drying, concentration, chromatography, grinding, crystallization etc..
In addition, the compounds of this invention can also be by the accommodations of various methods or methods described herein known in the art
It is prepared by method.
The following example is only used for illustrating the present invention, does not limit the invention in any way.
Embodiment 1：The preparation of N- (3- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides
Step 1：In 100ml round-bottomed flasks, m-anisidine (1.23g, 10mmol) is dissolved in 20ml dichloromethane
In, 0 DEG C is slowly dropped into the triphosgene (2.96g, 10mmol) for being dissolved in 20ml dichloromethane, adds and is dissolved in 10ml dichloromethane
Triethylamine (3ml), be then warmed to room temperature, stir 15min.Solvent is evaporated off, isocyanic acid meta-methoxy phenyl ester crude product is obtained
1.32g。
Step 2：Isocyanic acid meta-methoxy phenyl ester crude product 1.32g obtained above is directly dissolved in 20ml dichloromethane
In, it is slowly added to 1, the 2- benzisothiazole-3-ketones (1.51g, 10mmol) being dissolved in 20ml dichloromethane, back flow reaction
30min.Solvent is evaporated off, solid crude product is obtained, successively with 30ml acetone and 30ml water washings, then with acetone-water (1: Isosorbide-5-Nitrae
× 5ml) washing, filter, obtain 2.65g title compounds N- (3- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides, receive
Rate is 88%.
The compound is white powder, and its appraising datum is as follows：m.p.：165.7-169.3℃；ESI-MS：m/z
301.40([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.09 (s, 1H), 8.10 (d, J=8.0Hz, 1H), 7.76
(t, J=1.2Hz, 1H), 7.70 (m, 1H), 7.48 (m, 1H), 7.30 (m, 2H), 7.14 (m, 1H), 6.74 (m, 1H), 3.86
(s, 3H).
Embodiment 2：The preparation of N- (2- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in o-aminoanisole alternative embodiment 1, using method same as Example 1, system
The standby compound, obtains 2.71g products, yield is 90%.The compound is white powder, and its appraising datum is as follows：
ESI-MS：m/z 301.40([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.20 (s, 1H), 8.31 (d, J=
8.0Hz, 1H), 8.12 (d, J=8.0Hz, 1H), 7.75 (t, J=8.0Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.48 (t,
J=8.0Hz, 2H), 7.14 (t, J=8.0Hz, 1H), 7.04-6.96 (m, 1H), 4.02 (s, 3H).
Embodiment 3：The preparation of N- (4- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in P-nethoxyaniline alternative embodiment 1, using method same as Example 1, system
The standby compound, obtains 2.71g products, yield is 90%.The compound is white powder, and its appraising datum is as follows：
ESI-MS：m/z 301.40([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：10.90 (s, 1H), 8.09 (d, J=
8.0Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.54 (d, J=8.0Hz, 2H), 7.48
(t, J=8.0Hz, 1H), 6.93 (d, J=8.0Hz, 2H), 3.84 (s, 3H).
Embodiment 4：The preparation of N- (4- bromophenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in para-bromoaniline alternative embodiment 1, using method same as Example 1, preparing should
Compound, yield is 87%.The compound is white powder, and its appraising datum is as follows：m.p.：232.6-234.8℃；
ESI-MS：m/z 350.25([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.09 (s, 1H), 8.07 (d, J=
8.0Hz, 1H), 7.75 (t, J=8.0Hz, 1H), 7.62 (d, J=8.4Hz, 1H), 7.49 (m, 5H).
Embodiment 5：The preparation of N- (3- bromophenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 3- bromanilines alternative embodiment 1, using method same as Example 1, preparing should
Compound, yield is 89%.The compound is white powder, and its appraising datum is as follows：m.p.：217.9-220.5℃；
ESI-MS：m/z 350.20([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.12 (s, 1H), 8.10 (d, J=
8.0Hz, 1H), 7.92 (s, 1H), 7.76 (d, J=7.2Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.51 (dd, J=6.8,
14.4Hz, 2H), 7.30 (m, 2H).
Embodiment 6：The preparation of N- (2- bromophenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 2- bromanilines alternative embodiment 1, using method same as Example 1, preparing should
Compound, yield is 85%.The compound is white powder, and its appraising datum is as follows：m.p.：197.3-197.8℃；
ESI-MS：m/z 350.22([M+H+])；1H NMR (400MHz, DMSO-d6, δ ppm)：11.43 (s, 1H), 8.26 (d, J=
1.6Hz, 1H), 8.09 (m, 2H), 7.84 (m, 1H), 7.74 (dd, J=1.2,8.0Hz, 1H), 7.53 (m, 1H), 7.44 (d, J
=1.2Hz, 1H), 7.15 (dd, J=1.2,8.0Hz, 1H).
Embodiment 7：The preparation of N- (4- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 4- fluoroanilines alternative embodiment 1, using method same as Example 1, preparing should
Compound, obtains 2.30g products, and yield is 80%.The compound is white powder, and its appraising datum is as follows：ESI-MS：
m/z 289.22([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.03 (s, 1H), 8.09 (d, J=8.0Hz, 1H),
7.74 (s, 1H), 7.65-7.57 (m, 3H), 7.50 (d, J=8.0Hz, 1H), 7.09 (t, J=8.0Hz, 2H).
Embodiment 8：The preparation of N- (3- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 3- fluoroanilines alternative embodiment 1, using method same as Example 1, preparing should
Compound, obtains 2.36g products, and yield is 82%.The compound is white powder, and its appraising datum is as follows：ESI-MS：
m/z 289.20([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.16 (s, 1H), 8.10 (d, J=8.0Hz, 1H),
7.77 (t, J=8.0Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.58 (d, J=10.8Hz, 1H), 7.50 (t, J=8.0Hz,
1H), 7.35-7.30 (m, 2H), 6.89 (t, J=1.6Hz, 1H).
Embodiment 9：The preparation of N- (2- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 2- fluoroanilines alternative embodiment 1, using method same as Example 1, preparing should
Compound, obtains 2.30g products, and yield is 80%.The compound is white powder, and its appraising datum is as follows：ESI-MS：
m/z 289.20([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.35 (s, 1H), 8.28 (s, 1H), 8.12 (d, J
=8.0Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.50 (d, J=8.0Hz, 1H), 7.20-
7.14 (m, 3H).
Embodiment 10：The preparation of N- (4- iodophenyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 4- Iodoanilines alternative embodiment 1, using method same as Example 1, preparing should
Compound, yield is 85%.The compound is lavender powder, and its appraising datum is as follows：m.p.：222.9-225.1℃；
ESI-MS：m/z 397.22([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.10 (s, 1H), 8.09 (d, J=
8.0Hz, 1H), 7.77 (s, 1H), 7.70 (d, J=8.4Hz, 2H), 7.64 (d, J=8.0Hz, 1H), 7.49 (s, 1H), 7.42
(d, J=8.4Hz, 2H).
Embodiment 11：The preparation of N- [4- chloro- 3- (trifluoromethyl) phenyl]-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 4- chloro- 3- (trifluoromethyl) aniline alternative embodiment 1, using same as Example 1
Method, prepare the compound, yield is 90%.The compound is white powder, and its appraising datum is as follows：m.p.：
189.5-190.5℃；ESI-MS：m/z 373.80([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：11.29 (s,
1H), 8.11 (d, J=8.0Hz, 1H), 8.01 (s, 1H), 7.78 (m, 2H), 7.65 (d, J=8.0Hz, 1H), 7.52 (m, 2H).
Embodiment 12：The preparation of N- (2- nitrobenzophenones)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 2- nitroanilines alternative embodiment 1, using method same as Example 1, prepare
The compound, obtains 2.31g products, and yield is 81%.The compound is white powder, and its appraising datum is as follows：ESI-
MS：m/z 316.20([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：12.86 (s, 1H), 8.67 (d, J=8.0Hz,
1H), 8.26 (d, J=8.0Hz, 1H), 8.17 (d, J=8.0Hz, 1H), 7.77 (t, J=8.0Hz, 1H), 7.71 (t, J=
8.0Hz, 1H), 7.63 (d, J=8.0Hz, 1H), 7.49 (t, J=8.0Hz, 1H), 7.30 (t, J=8.0Hz, 1H).
Embodiment 13：The preparation of N- (1- naphthyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in naphthalidine alternative embodiment 1, using method same as Example 1, the change is prepared
Compound, obtains 2.72g products, and yield is 85%.The compound is white powder, and its appraising datum is as follows：ESI-MS：m/
z321.22([M+H+])；1H NMR (400MHz, DMSO-d6, δ, ppm)：11.04 (s, 1H), 8.10 (d, J=8.0Hz, 1H),
7.76 (t, J=8.0Hz, 1H), 7.64 (d, J=8.0Hz, 3H), 7.49 (t, J=8.0Hz, 1H), 7.40 (t, J=8.0Hz,
2H), 7.19 (t, d=8.0Hz, 1H).
Embodiment 14：The preparation of N- (α-methylbenzyl)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in Alpha-Methyl benzylamine alternative embodiment 1, using method same as Example 1, prepare
The compound, yield is 87%.The compound is white powder, and its appraising datum is as follows：ESI-MS：m/z 298.22
([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：9.32 (s, 1H), 8.02 (d, J=8.0Hz, 1H), 7.70 (t, J=
8.0Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 7.45-7.36 (m, 5H), 7.30 (d, J=8.0Hz, 1H), 5.23-5.16
(m, 1H), 1.65 (d, J=8.0Hz, 3H)；13C NMR (100MHz, CDCl3, δ ppm)：165.21,150.26,142.78,
140.85,133.83,128.80,127.55,127.16,126.06,125.83,125.05,120.51,50.68,22.75.
Embodiment 15：The preparation of N- (4- methoxy-benzyls)-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in 4-Methoxybenzylamine alternative embodiment 1, using method same as Example 1, system
The standby compound, yield is 88%.The compound is white powder, and its appraising datum is as follows：ESI-MS：m/z 315.80
([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：9.20 (s, 1H), 8.02 (d, J=8.0Hz, 1H), 7.71 (t, J=
8.0Hz, 1H), 7.60 (d, J=8.0Hz, 1H), 7.44 (t, J=8.0Hz, 1H), 7.32 (d, J=8.0Hz, 2H), 6.91 (d,
J=8.0Hz, 2H), 4.59 (d, J=5.6Hz, 2H), 3.82 (s, 3H).
Embodiment 16：The preparation of N- phenethyls-benzisothiazole-3-ketone -2- acid amides
With the m-anisidine in phenyl ethylamine alternative embodiment 1, using method same as Example 1, the change is prepared
Compound, yield is 83%.The compound is white powder, and its appraising datum is as follows：ESI-MS：m/z 299.22([M+H+])；1H NMR (400MHz, CDCl3, δ, ppm)：8.95 (s, 1H), 8.03 (d, J=8.0Hz, 1H), 7.71 (t, J=8.0Hz,
1H), 7.59 (d, J=8.0Hz, 1H), 7.44 (t, J=8.0Hz, 1H), 7.35 (t, J=8.0Hz, 2H), 7.29-7.24 (m,
3H), 3.75-3.70 (m, 2H), 2.80 (t, J=8.0Hz, 2H).
Pharmacological activity is tested
A series of compounds to synthesis carry out Activity determination, and live body system is as follows：
Live body system：Buffer solution：50mM HEPES (pH 7.5), 100mM NaCl, 1mM EDTA, 10%glycerol,
0.1%CHAPS；Substrate：Ac-LDEVD-AMC (purchased from the biochemical Co., Ltd of Shanghai gill).
Instrument for fluorescent strength determining is Fluoraskan Ascent luminoscopes (Thermo Scientific), is swashed
Luminous and transmitting light wavelength is respectively 355nm and 460nm.
Screening model is as follows：Amino acid sequence (the Ac- of artificial synthesized Caspase-3 natural substrate as shown in Figure 1
Leu-Asp-Glu-Veu-Asp-AMC AMC fluorophors), and in sequence one end are added, AMC is connected on polypeptide as derivative
Unstressed configuration, after Caspase-3 is added, substrate is cut open, and fluorophor AMC dissociates, glimmering using Fluoroskan Ascent
Light analyzer detects its fluorescent value.Add after compound, if compound has inhibitory action to Caspase-3 activity, show
Fluorescence intensity weakens, and may determine that whether compound is inhibited to Caspase-3 with this, so as to play screening compounds
Effect.
Activity determination concrete operation step：
1. primary dcreening operation
In cushioning liquid (50mM HEPES (pH 7.5), 100mM NaCl, 1mM EDTA, 10%glycerol, 0.1%
CHAPS Caspase-3 protease is added in) and (purifies what is obtained for this laboratory, purification process sees reference document：Hyo Jin
Kang, Young-mi Lee, Yu-Jin Jeong, Kyoungsook Park, Mi Jang, Sung Goo Park, Kwang-
Hee Bae, Moonil Kim and Sang J Chung.Large-scale preparation of active
caspase-3in E.coli by designing its thrombin-activatable precursors.BMC
Biotechnology 2008,8：92), make its final concentration of 25nM, add the DMSO dissolved matters of compound candidate, make it dense eventually
Spend for 0.5mM, after 298K is placed 5 minutes, be rapidly added fluorescence labeling substrate (Ac-LDEVD-AMC, 20 μM of final concentration).Setting
Negative control：Alternative sample is added without, remaining condition is identical.Excitation wavelength and launch wavelength are respectively 355nm and 460nm, temperature
Degree keeps 298K, and every 3 seconds record first order fluorescence readings determine 50 points altogether.Using the time as X-axis, fluorescent value is that Y-axis is mapped just
It can obtain enzyme activity kinetic curve.Gone forward the initial velocity V that the numerical computations slope of 6 points just can be reacted by figure, by the moon
Property control initial velocity of reaction be defined as V0, add compound initial velocity of reaction be defined as Vi, so as to calculate addition correspondingization
Residual activity (the V of Caspase-3 protease after compoundi/V0), the inhibiting rate of respective compound is then (1-Vi/V0).Can be right
The alternative sample that residual activity was less than for 20% (or inhibiting rate is more than 80%) carries out further IC50Value is determined.
2. compound IC50The measure of value
Reaction system be the μ L substrates of 96 μ L Caspase-3+2 μ L compounds+2, the final concentration of 25nM of wherein Caspase-3,
Final substrate concentrations are 25 μM, to each 18 concentration gradient of setting in embodiment 1-16 compounds, make its final concentration successively
For 200 μM, 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, 0.7812 μM, 0.3906 μM,
0.1952μM、0.0977μM、0.0488μM、0.0244μM、0.0122μM、0.0061μM、0.0031μM、0.0015μM.Using
Assay method same as above, determines the residual activity of the Caspase-3 in the presence of various concentrations compound, then with change
The logarithm value of compound concentration is abscissa, and Caspase-3 residual activity is ordinate, is mapped with GraphPad Prism 5,
Calculate IC50, the IC of embodiment 1-16 compounds50Value is shown in Table 1.
IC of the embodiment 1-16 compounds of table 1 to Caspase-3 inhibitory action50Value
| Compound | IC50It is worth (nM) | Compound | IC50It is worth (nM) |
| Embodiment 1 | 1167±115 | Embodiment 9 | 16270±2460 |
| Embodiment 2 | 4167±483.88 | Embodiment 10 | 77.74%* |
| Embodiment 3 | 10710±1085.77 | Embodiment 11 | 22050±1880 |
| Embodiment 4 | 3071±314 | Embodiment 12 | 9823±1204.51 |
| Embodiment 5 | 9628±1049 | Embodiment 13 | Itself has fluorescent absorption |
| Embodiment 6 | 8093±925 | Embodiment 14 | 85.11±9.54 |
| Embodiment 7 | 593.5±49.13 | Embodiment 15 | 40.40±1.84 |
| Embodiment 8 | 438.5±111.7 | Embodiment 16 | 31.64±4.74 |
*：IC is not surveyed50Value, show inhibiting rate.
In summary, benzisothiazole-3-ketone -2- amides compounds of the present invention, which have, suppresses Caspase-3 work
The effect of property, can be prepared into Caspase-3 inhibitor, for preventing or treating the disease mediated by Caspase-3, especially
Tumour, autoimmune disease, viral infection and the various nerve degenerative diseases mediated by Caspase-3.
Although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of changes, modification can be carried out to these embodiments, replace without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (2)
1. benzisothiazole-3-ketone -2- amides compounds are being prepared for treating the medicine by the Caspase-3 diseases mediated
In purposes, the benzisothiazole-3-ketone -2- amides compounds have structure shown below formula (I)：
Wherein, R1Selected from the phenyl or naphthyl being substituted with a substituent；Unsubstituted naphthyl；Unsubstituted phenyl-C2-4Alkyl；
Phenyl-the C being substituted with a substituent1-4Alkyl, wherein the substituent is selected from halogen, C1-4Alkyl, halo C1-4Alkyl, C1-4Alcoxyl
One or more of base and nitro；
The disease is autoimmune disease, viral infection or nerve degenerative diseases.
2. purposes according to claim 1, it is characterised in that be following compound：
N- (1- naphthyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- naphthyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- methoxyphenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- bromophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- bromophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- bromophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- fluorophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- nitrobenzophenones)-benzisothiazole-3-ketone -2- acid amides；
N- (3- nitrobenzophenones)-benzisothiazole-3-ketone -2- acid amides；
N- (2- nitrobenzophenones)-benzisothiazole-3-ketone -2- acid amides；
N- (4- iodophenyls)-benzisothiazole-3-ketone -2- acid amides；
N- [4- chloro- 3- (trifluoromethyl) phenyl]-benzisothiazole-3-ketone -2- acid amides；
N- (α-methylbenzyl)-benzisothiazole-3-ketone -2- acid amides；
N- (4- methoxy-benzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- methoxy-benzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- methoxy-benzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (4- luorobenzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (3- luorobenzyls)-benzisothiazole-3-ketone -2- acid amides；
N- (2- luorobenzyls)-benzisothiazole-3-ketone -2- acid amides；With
N- phenethyls-benzisothiazole-3-ketone -2- acid amides.
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| CN105368855B (en) * | 2015-09-22 | 2019-03-29 | 广西大学 | The regulatory factor peanut class caspase-3 gene and coded sequence of Translation of Programmed Cell Death in Plants |
| CN110128369A (en) * | 2019-05-27 | 2019-08-16 | 东南大学 | Benzo [d] isothiazole -3 (2H) -one derivative and its preparation method and application |
| CN113105409B (en) * | 2021-04-06 | 2023-06-02 | 四川大学 | 2- (hydroxybenzyl) benzo [ d ] isothiazolone compound, preparation method and application thereof |
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