CN105272975A - Indole alkaloids possessing 1,2,4-oxadiazole fragment, and preparation method and application thereof - Google Patents
Indole alkaloids possessing 1,2,4-oxadiazole fragment, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a kind of indole alkaloids possessing a 1,2,4-oxadiazole fragment, and a preparation method and application thereof. The structure of the indole alkaloids is shown as a formula I, and in the formula I, A, R and n are defined as the specification and the claims. The indole alkaloids are novel in structure, the synthetic route is simple in operation, the yield is high, the safety is good, and the indole alkaloids possess obvious protection effect on beta-amyloid protein, hydrogen peroxide and oxygen-glucose deprivation induced nerve cell damage, and are applicable to prepare medicines for preventing and/or treating nervous system degenerative diseases.
Description
Technical field
The present invention relates to medical art, relate to one and there is indole alkaloid of 1,2,4-oxadiazoles fragment structure and its production and use.
Background technology
Nerve degenerative diseases is one group of chronic, degenerative neural disease based on primary neuronal degeneration, such disease mainly comprise A Ercaimo disease (Alzheimer ' sdisease, AD), Parkinson's disease (Parkinson ' sdisease, PD) etc.At present, the problem of an aging population is on the rise, and the sickness rate of nerve degenerative diseases increases increasingly, and that wherein sickness rate is the highest is AD.Scientist points out, within 2025, the whole world estimates there will be 2,200 ten thousand AD patients, will reach 4,500 ten thousand to the year two thousand fifty patient numbers.AD has become the fourth-largest " killer " after elderly population relaying cardiovascular diseases, cancer, apoplexy.China's dementia incidence and American-European countries close, the gerontal patient of nerve degenerative diseases is more than 5,000,000 examples, and wherein AD accounts for 2/3 more than.This disease has developed into the main burden of medical health system, and brings heavy spirit and economic pressures for society, patient and family members, by one " Public health crisis " becoming the 21 century mankind and will tackle.
Nerve degenerative diseases is the complicated syndromes of multi-pathogenesis, too many levels, all there is larger difference in epidemiology, nosetiology, pathology, pathogenesis and clinical manifestation, molecular mechanism of action definite up to now it be unclear that, and brings very large difficulty for finding desirable protective agents.But, there is obvious general character in the generation of these diseases and development, increasing research prompting, all there is abnormal change in matter and energy metabolism and the relevant signal path thereof of oxidative stress, body, these unusual phenomenoies have played very important effect in the Development process of nerve degenerative diseases.
The excessive generation of active oxygen radical, hydroxy radical qiao, superoxide anion and hydrogen peroxide can be observed in most nerve degenerative diseases.Usually antioxidant system is there is to anti-oxidation stress in body, however very responsive to oxidative stress in the central nervous system of nerve degenerative diseases patient, and it is poor that it compares other tissue to the antioxidase effect of defence oxidative stress.The main component of one of typical pathologic features of AD senile plaque is amyloid-beta (β-amyloidprotein, A β), the result of study prompting A β of a large amount of inside and outside has obvious neurotoxicity, close ties are had with the defect of oxidative stress, material energy metabolism, mitochondrial function, finally cause the accumulation of intracellular reactive oxyradical, neuronal death.And on the other hand, oxidative stress also causes the accumulation of A β further, the final Development process accelerating AD.Confirm in Integral animal experiment, rat intracerebral injection A β can bring out Spatial memory obstacle.Equally, PD patient's intracerebral oxidation stress, mitochondrial function defect and excitatory toxicity may be the inducement that causes PD to fall ill and mediated its pathogenic process.Occur in PD patient's brain that hydrogen peroxide, superoxide anion, hydroxy radical qiao isoreactivity oxygen excess generate, Mitochondrial electron respiratory chain complex enzyme ComplexI activity decrease, and the decline of ComplexI activity causes the rising of body reactive oxygen species, finally cause Neuronal cell death in brain.
Another common causes that development occurs the degenerative disease that affects the nerves is that body substance and energy are under-supply or unbalance, and one of topmost performance is that the oxygen sugar supply that vascular lesions causes lacks and other material energy metabolism unbalance.The morbidity that the generation development of nerve degenerative diseases and the disease occurred frequently of elderly population comprise these periphery Abnormality of Glycolipid Metabolism diseases such as diabetes, obesity, hypercholesterolemia has obvious positive correlation.Clinical study also finds in nerve degenerative diseases morbidity early stage, large cerebrose utilizes and obvious decline all appears in cerebral blood flow, the microcirculation blood flow state at patient critical position is caused to change, limit the compensatory of cerebral blood flow, make the oxygen of supply brain, the deficiencies such as glucose, cause the destruction of the energy system chain in neurone, having a strong impact on intracellular mitochondrial function causes the generation of Triphosaden (ATP) to decline, this brain district energy is under-supply, the need energy signal path in its downstream and biological function impaired, this vicious cycle finally causes neural system material energy metabolism disorderly, cause nerve retrograde affection, in addition, some Notes of Key Data contains that from source mitochondrial function is abnormal, the medicine of adjustment body aberrant glucose metabolism, fat/cholesterol metabolic all serves certain improvement result in the therapeutic process of nerve degenerative diseases, and the energy metabolism of prompting Auto-regulator may be effective Intervention Strategy.
Above-mentioned research shows, and oxidative stress, matter energy lack/and unbalance and A β toxicity played vital role in the pathogenic process of the nerve degenerative diseases such as AD.And in fact, the compound for oxidative stress, oxygen sugar shortage, amyloid toxic also makes encouraging progress at treatment neurological in disease, act on mitochondrial medicine MitoQ comprising targeting and started II phase clinical study.Therefore, from the anti-oxidant of compound and improve the supply of body substance energy lack or unbalance activity start with, likely develop novel, to treat nerve degenerative diseases targetedly medicine or drug candidates.
Natural product has the feature of complex structure and diverse biological activities, plays an important role for a long time in the discovery of new drug and new drug lead compound.Wherein, compared with the natural product originated in marine natural product and land, unique ocean environment (high pressure, high salt, anoxic, lucifuge etc.) result in marine natural product and has larger chemistry and diverse biological activities.In recent years, have in a large number the marine natural product of neuroprotective and synthetic analogues thereof report by people (as Mar.drug, 2014,12,700-718; J.Med.Chem., 2012,55,9312-9330; Bioorg.Med.Chem.Lett., 2012,22,2226-2229, Bioorg.Med.Chem., 2006,14,17-24; J.Nat.Prod., 2004,67,1532-1543 etc.).
We find the phidianidine class indole alkaloid (Org.Lett., 2011,13,2516-2519) with brand-new skeleton from cheek subclass mollusk Phidianamilitaris after South China Sea.The novel part of this compounds is that they are separated from occurring in nature the compound with 1,2,4-oxadiazoles structure fragment obtained first.
This compounds energy highly selective of bibliographical information suppresses Dopamine Receptors, selectivity and highly active partial agonist μ opiate receptors and acellular toxic action, result of study shows that some target spot of such compounds on nerve system has certain pharmacological action, potential using value (ACSChem.Neurosci. may be had in treatment AD, PD and analgesic medicament research and development, 2012,3,658-664).
In view of phidianidine class indole alkaloid has potential using value in treatment nervous system disorders, therefore, still need and carry out structure of modification to this compounds in this area, develops to have the medicine preventing and/or treating nerve degenerative diseases more.
Summary of the invention
The object of the present invention is to provide a kind of indoles alkaloid of novel texture, to nervous system degenerative disease, there is the effect of preventing and/or treating.
A first aspect of the present invention, provides a kind of indoles alkaloid or its pharmacy acceptable salt, and structure is such as formula shown in I:
In formula, A is C6-C10 aryl or C3-C8 heterocyclic radical;
N is the integer of 1-5;
Each R is hydrogen, hydroxyl, nitro, itrile group, halogen, C1-C8 alkyl, C1-C8 alkoxyl group ,-NR independently
1r
2,-C (O) C1-C8 alkoxyl group, C3-C6 cycloalkyl, C3-C8 heterocyclic radical or C6-C10 aryl,
Wherein, R
1, R
2independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group;
Described C1-C8 alkyl, C1-C8 alkoxyl group ,-NR
1r
2,-C (O) C1-C8 alkoxyl group, C3-C6 cycloalkyl, C3-C8 heterocyclic radical or the C6-C10 aryl substituting group that is optionally selected from lower group replaces: hydroxyl, amino, nitro, itrile group, halogen, C1-C6 alkyl, C1-C6 alkoxyl group;
Each described heterocyclic radical comprises one or more the heteroatoms being selected from lower group independently: O, S, P and N.
In another preference, A is phenyl, pyrimidyl or tetrahydro pyridyl.
In another preference, each R is hydrogen independently, hydroxyl, halogen, itrile group, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl replace C1-C6 alkyl ,-C (O) C1-C6 alkoxyl group, C1-C6 alkoxyl group ,-NR
1r
2, the C3-C6 heterocyclic radical that replaces of C3-C6 heterocyclic radical or C1-C4 alkyl,
Wherein, R
1, R
2independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxyl group.
In another preference, each described heterocyclic radical is independently selected from furyl, pyrryl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, quinolyl, isoquinolyl, indyl, pyrimidyl, tetrahydro pyridyl, pyrrolinyl, dihydropyridine base, dihydrofuran base, dihydro-thiophene base, pyranyl.
A second aspect of the present invention, provides the preparation method of the indoles alkaloid described in first aspect, comprises the following steps:
A () formula 1 compound and formula 2 compound carry out condensation and obtain formula 3 compound;
B () formula 3 compound and formula 4 compound obtain formula I through linked reaction,
Wherein, various middle R
1for bromine or iodine;
The definition of A, R and n as claimed in claim 1;
R
3for boronate or boric acid ester group.
In another preference, described step (a) has following one or more feature:
(1) condensing agent used is N, N'-dicyclohexylcarbodiimide (DCC), N, N'-DIC (DIC), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI), diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), 1-hydroxyl-7-azo benzotriazole (HOAT), 1-hydroxy benzo triazole (HOBT), O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N', one or more combination in N'-tetramethyl-urea phosphofluoric acid ester (HBTU),
(2) described step (a) is carried out in organic solvent, described organic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile, 1, one or more combination in 4-dioxane, ethylene dichloride, DIPEA, water;
(3) temperature of reaction is 0 DEG C ~ 130 DEG C;
(4) reaction times is 6 ~ 12 hours.
In another preference, described step (b) has following one or more feature:
(1) described step (b) is carried out in organic solvent, described organic solvent is ethanol, N, one or more combination in dinethylformamide, triethylamine, benzene, DIPEA, toluene, Isosorbide-5-Nitrae-dioxane and water;
(2) described step (b) is carried out in palladium catalyst catalysis, and described palladium catalyst is one or more the combination in tetrakis triphenylphosphine palladium, palladium chloride, two (tricyclohexyl phosphine) palladium chloride, two (triphenylphosphine) palladium chloride (II), palladium;
(3) temperature of reaction is 0 DEG C ~ 120 DEG C;
(4) reaction times is 4 ~ 24 hours.
A third aspect of the present invention, provides a kind of pharmaceutical composition, comprises:
Indoles alkaloid described in first aspect or its pharmacy acceptable salt; And
Pharmaceutically acceptable carrier.
In another preference, described pharmaceutical composition comprises 1wt% to 96wt%, is preferably the indoles alkaloid described in the first aspect of 10wt% to 85wt% or its pharmacy acceptable salt, with the total weight of described pharmaceutical composition.
In another preference, described pharmaceutically acceptable carrier comprises sugar, starch, cellulose and its derivates, gelatin, talcum, solid lubricant, vegetables oil, polyvalent alcohol, emulsifying agent, wetting agent, tinting material, seasonings, stablizer, antioxidant, sanitas and apirogen water.
A fourth aspect of the present invention, provides the purposes of indoles alkaloid described in first aspect or its pharmacy acceptable salt or the pharmaceutical composition described in the third aspect, for the preparation of the medicine preventing and/or treating nervous system degenerative disease.
In another preference, be bring out damage realization by improving oxidative stress, amyloid-beta toxicity and/or oxygen sugar shortage for the described nervous system degenerative disease that prevents and/or treats.
A fifth aspect of the present invention, provides the purposes of indoles alkaloid described in first aspect or its pharmacy acceptable salt or the pharmaceutical composition described in the third aspect, for:
A () preparation prevents and/or treats the medicine of oxidative stress inducing neural cell injury;
B () preparation prevents and/or treats the medicine of amyloid-beta inducing neural cell injury; Or
C () preparation prevents and/or treats the medicine that oxygen sugar lacks inducing neural cell injury.
In another preference, described medicine is tablet, capsule, granule or oral liquid.
In another preference, described indoles alkaloid or its pharmacy acceptable salt or described pharmaceutical composition, as nerve cell-protective agents.
A sixth aspect of the present invention, provides a kind of method of external neuroprotective cell, uses formula I or the pharmaceutical composition of safe and effective amount to required object.Described neurocyte is that oxidative stress brings out, amyloid-beta brings out and/or oxygen sugar lacks the neurocyte bringing out damage.
A seventh aspect of the present invention, provides a kind of method for the treatment of nerve degenerative diseases, comprises step:
Give and need the object for the treatment of to use the indoles alkaloid described in first aspect or the pharmaceutical composition described in the third aspect.
Described object is behaved or non-human mammal, as ox, rat, mouse.
Indoles alkaloid of the present invention; novel structure; synthetic route is easy and simple to handle; yield is high; security is good; amyloid-beta, hydrogen peroxide, oxygen sugar are lacked to inducing neural cell injury and all has significant protective effect, can be used for preparing the medicine preventing and/or treating nervous system degenerative disease.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Accompanying drawing explanation
Fig. 1 is the cell viability curve of embodiment 3.
Fig. 2 is the cell viability curve of embodiment 4.
Fig. 3 is the cell viability curve of embodiment 5.
Embodiment
Present inventor is through extensively and in depth studying; develop a kind of indoles alkaloid of novel structure first; structure is such as formula shown in I; amyloid-beta, hydrogen peroxide, oxygen sugar are lacked to inducing neural cell injury and all has significant protective effect, can be used for preparing the medicine preventing and/or treating nervous system degenerative disease.On this basis, the present invention is completed.
Term
In context of the present invention, term " alkyl " represents saturated linear or branched chain hydrocarbon moiety, such as-CH
3or-CH (CH
3)
2.Term " alkoxyl group " represents-O-(C1-8 alkyl) group.Term " cycloalkyl " represents saturated cyclic hydrocarbyl moiety, such as cyclohexyl.Term " heterocyclic radical " expression comprises at least one ring hetero atom (such as N, O or S) cyclic group, such as furyl, pyrryl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, quinolyl, isoquinolyl, indyl, pyrimidyl, tetrahydro pyridyl, pyrrolinyl, dihydropyridine base, dihydrofuran base, dihydro-thiophene base, pyranyl.Term " aryl " represents the hydrocarbyl portion comprising one or more aromatic ring.The example of aryl comprises phenyl (Ph), naphthyl, pyrenyl, anthryl and phenanthryl.Term " amino " expression-NH
2.Halogen is fluorine, chlorine, bromine or iodine.
Unless otherwise indicated, alkyl as herein described, alkoxyl group, cycloalkyl, heterocyclic radical and aryl comprise replacement with unsubstituted group simultaneously.Alkyl, alkoxyl group, cycloalkyl, on heterocyclic radical and aryl, possible substituting group comprises, but be not limited to: hydroxyl, amino, nitro, itrile group, halogen, C1-C6 alkyl, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl group, C1-C20 Heterocyclylalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxyl group, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkyl amido, arylamino, ammonia diaryl base, C1-C10 alkylsulfamoyl group, ammonia aryl sulfonyl, C1-C10 alkyl imino, C1-C10 alkyl sulfobetaines imino-, aryl sulfo group imino-, sulfydryl, C1-C10 alkylthio, C1-C10 alkyl sulphonyl, aryl sulfonyl, acyl amino, aminoacyl, aminothio acyl group, guanidine radicals, urea groups, cyano group, acyl group, Thioacyl, acyloxy, carboxyl and carboxylic acid ester groups.On the other hand, cycloalkyl, Heterocyclylalkyl, heterocycloalkenyl, aryl and heteroaryl also can condense mutually.
In the present invention, described replacement can be monosubstituted or polysubstituted, as two replacements, three replacements, four replace or five replacements.
Pharmacy acceptable salt of the present invention can be the salt that group positively charged in negatively charged ion and formula I is formed.Suitable negatively charged ion comprises chlorion, bromide anion, iodide ion, sulfate radical, nitrate radical, phosphate radical, citrate, methylsulphonic acid root, trifluoroacetic acid root, acetate moiety, malate, tosylate, tartrate anion, fumaric acid radical, glutamate, glucuronic acid root, lactate, glutarate and maleate.Similarly, salt can be formed by the electronegative group on positively charged ion and formula I.Suitable positively charged ion comprises sodium ion, potassium ion, magnesium ion, calcium ion and ammonium ion, such as tetramethyl ammonium.
In another preference, " pharmacy acceptable salt " refers to the salt with being selected from following acid formation: hydrofluoric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methylsulfonic acid, Whitfield's ointment, trifluoromethanesulfonic acid, naphthene sulfonic acid, toxilic acid, citric acid, acetic acid, tartrate, succsinic acid, Herba Oxalidis Corniculatae acid, oxysuccinic acid, L-glutamic acid.
Formula I
In the present invention, " compound shown in general formula I ", " formula I ", " shown in formula I compound " can exchange use, all refer to the indoles alkaloid with structure shown in formula I:
A (or be expressed as
) be C6-C10 aryl or C3-C8 heterocyclic radical;
N is the integer of 1-5;
Each R is hydrogen, hydroxyl, nitro, itrile group, halogen, C1-C8 alkyl, C1-C8 alkoxyl group ,-NR independently
1r
2,-C (O) C1-C8 alkoxyl group, C3-C6 cycloalkyl, C3-C8 heterocyclic radical or C6-C10 aryl,
Wherein, R
1, R
2independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group;
Described C1-C8 alkyl, C1-C8 alkoxyl group ,-NR
1r
2,-C (O) C1-C8 alkoxyl group, C3-C6 cycloalkyl, C3-C8 heterocyclic radical or the C6-C10 aryl substituting group that is optionally selected from lower group replaces: hydroxyl, amino, nitro, itrile group, halogen, C1-C6 alkyl, C1-C6 alkoxyl group;
Each described heterocyclic radical comprises one or more the heteroatoms being selected from lower group independently: O, S, P and N.
In another preference, A is phenyl.
In another preference, each R is hydrogen independently, hydroxyl, halogen, itrile group, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl replace C1-C6 alkyl ,-C (O) C1-C6 alkoxyl group, C1-C6 alkoxyl group ,-NR
1r
2, the C3-C6 heterocyclic radical that replaces of C3-C6 heterocyclic radical or C1-C4 alkyl,
Wherein, R
1, R
2independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxyl group.
In another preference, n is 1; R is hydrogen, methyl, methoxyl group, ethyl, oxyethyl group, propyl group, propoxy-, sec.-propyl, normal-butyl, the tertiary butyl, hydroxy methylene, hydroxyl, amino, dimethylamino, fluorine, chlorine, bromine, trifluoromethyl, itrile group, methoxycarbonyl, morpholinyl, piperazinyl or methylpiperazine base.
In another preference, each described heterocyclic radical is independently selected from furyl, pyrryl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, quinolyl, isoquinolyl, indyl, pyrimidyl, tetrahydro pyridyl, pyrrolinyl, dihydropyridine base, dihydrofuran base, dihydro-thiophene base, pyranyl.
In another preference, A is the tetrahydro pyridyl of tetrahydro pyridyl or replacement, and described replacement refers to that the substituting group being selected from lower group replaces: hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxyl group ,-NR
1r
2,-C (O) C1-C6 alkoxyl group, wherein, R
1, R
2independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxyl group.Preferably, A is the tetrahydro pyridyl replaced, and substituting group is-C (O) C1-C6 alkoxyl group.
In another preference, A is the pyrimidyl of pyrimidyl or replacement, and described replacement refers to that the substituting group being selected from lower group replaces: hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxyl group ,-NR
1r
2, wherein, R
1, R
2independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxyl group.Preferably, A is the amino pyrimidyl replaced.
Preparation method
The preparation method of formula I of the present invention, comprises the following steps:
A () formula 1 compound and formula 2 compound carry out condensation and obtain formula 3 compound;
B () formula 3 compound and formula 4 compound obtain formula I through linked reaction,
Wherein, various middle R
1for bromine or iodine;
The definition of A, R and n as claimed in claim 1;
R
3for boronate or boric acid ester group.
In another preference, described R
3for-B (OH)
2or
Condensing agent used in described step (a) is N, N'-dicyclohexylcarbodiimide (DCC), N, N'-DIC (DIC), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI), diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), 1-hydroxyl-7-azo benzotriazole (HOAT), 1-hydroxy benzo triazole (HOBT), O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N', one or more combination in N'-tetramethyl-urea phosphofluoric acid ester (HBTU).
Described step (a) is carried out in organic solvent, and described organic solvent is one or more the combination in methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile, Isosorbide-5-Nitrae-dioxane, ethylene dichloride, DIPEA, water;
Described step (a) temperature of reaction is 0 DEG C ~ 130 DEG C;
Described step (a) reaction times is 6 ~ 12 hours.
Described step (b) is carried out in organic solvent, and described organic solvent is one or more the combination in ethanol, DMF, triethylamine, benzene, DIPEA, toluene, Isosorbide-5-Nitrae-dioxane and water;
Described step (b) is carried out in palladium catalyst catalysis, and described palladium catalyst is one or more the combination in tetrakis triphenylphosphine palladium, palladium chloride, two (tricyclohexyl phosphine) palladium chloride, two (triphenylphosphine) palladium chloride (II), palladium;
Described step (b) temperature of reaction is 0 DEG C ~ 120 DEG C;
Described step (b) reaction times is 4 ~ 24 hours.
Purposes
Test proves that formula I of the present invention lacks inducing neural cell injury all have significant protective effect to amyloid-beta, hydrogen peroxide, oxygen sugar, has to nervous system degenerative disease the effect of preventing and/or treating.
Described nervous system degenerative disease is selected from: Parkinson's disease, Alzheimer, Huntington Chorea, amyotrophic lateral sclerosis are sick, and spinal muscular atrophy is sick, primary lateral sclerosis is sick, spinocerebellar ataxia.
Pharmaceutical composition
Present invention also offers a kind of pharmaceutical composition, it comprises the activeconstituents in safe and effective weight range, and pharmaceutically acceptable carrier.
" activeconstituents " of the present invention refers to formula I of the present invention.
" activeconstituents " of the present invention and pharmaceutical composition can be used for preparing the medicine preventing and/or treating nervous system degenerative disease.
" safe and effective amount " refers to: the amount of activeconstituents is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-2000mg activeconstituents/agent, more preferably, containing 10-200mg activeconstituents/agent.Preferably, described " potion " is a tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use, and must have enough purity and enough low toxicity." consistency " to referred to herein as in composition each component energy and activeconstituents of the present invention and they between mutually admix, and the drug effect of not obvious reduction activeconstituents.Pharmaceutically acceptable carrier part example has cellulose and its derivates (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as to tell
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
In another preference, formula I can form mixture with macromolecular cpd or polymer by nonbonding effect.In another preference, formula I is also connected with macromolecular cpd or polymer by chemical bond as small molecules.Described macromolecular cpd can be that biomacromolecule is as high glycan, albumen, nucleic acid, polypeptide etc.
The method of application of activeconstituents of the present invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): in oral, knurl, rectum, parenteral (intravenously, intramuscular or subcutaneous) etc.Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, activeconstituents mixes with at least one conventional inert excipients (or carrier), as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mix with following compositions: (a) filler or expanding material, such as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, such as, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, such as, glycerine; (d) disintegrating agent, such as, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, such as paraffin; F () absorbs accelerator, such as, and quaternary ammonium compound; (g) wetting agent, such as hexadecanol and glyceryl monostearate; (h) sorbent material, such as, kaolin; (i) lubricant, such as, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, formulation also can comprise buffer reagent.Described solid dosage also can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and in this composition, the release of activeconstituents can discharge in certain part in a delayed fashion in digestive tube.The example of adoptable embedding component is polymeric material and Wax.Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except activeconstituents, liquid dosage form can comprise the conventional inert diluent adopted in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials.Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.Except activeconstituents, suspension can comprise suspension agent, such as, and the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials.Composition for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
Preferably, the selective dependency of the site of administration of formula I or pharmaceutical composition is in the disease for the treatment of and the symptom for the treatment of.Such as, for those mainly with the retrograde disease of brain, formula I of the present invention or pharmaceutical composition are administered in brain; For those, there is the retrograde disease of focal striatum, formula I or pharmaceutical composition can be administered to striatum, those be had to the disease of general nervus retrogression, can systemic administration.Preferred method of application is the appropriate method of such as injecting.Preferred position formula I of the present invention or pharmaceutical composition being administered to nervus retrogression and occurring, and artery, vein or subcutaneous injection.
Formula I or pharmaceutical composition can be individually dosed, or with other treatment administered in combination.
When making pharmaceutical composition, it is the Mammals (as people) being applicable to the formula I of safe and effective amount or pharmaceutical composition need treatment, when wherein using, dosage is the effective dosage pharmaceutically thought, for the people of 60kg body weight, day dosage is generally 1 ~ 2000mg, preferably 20 ~ 500mg.Certainly, concrete dosage also should consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
The above-mentioned feature that the present invention mentions, or the feature that embodiment is mentioned can arbitrary combination.All features that this case specification sheets discloses can with any composition forms and use, each feature disclosed in specification sheets, anyly can be provided identical, alternative characteristics that is impartial or similar object replaces.Therefore apart from special instruction, the feature disclosed is only general example that is impartial or similar features.
Usefulness of the present invention is:
(1) the invention provides the indoles alkaloid of a class formation novelty.
(2) compounds process for production thereof of the present invention is easy, and yield is high.
(3) compound of the present invention lacks inducing neural cell injury all have significant protective effect to amyloid-beta, hydrogen peroxide, oxygen sugar, can be used for preparing the medicine preventing and/or treating nervous system degenerative disease
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usual conveniently condition is as people such as Sambrook, molecular cloning: laboratory manual (NewYork:ColdSpringHarborLaboratoryPress, 1989) condition described in, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.
Unless otherwise defined, all specialties used in literary composition and scientific words and one skilled in the art the same meaning be familiar with.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The preparation of embodiment 1 formula 3 compound
0.50g formula 1 compound is dissolved in 50mL methyl alcohol, then adds 1.20g2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester and 0.8mLN, N-diisopropylethylamine.Mixture stirring at room temperature, after 0.5 hour, adds 0.59g formula 2 compound, continues stirring at room temperature 1 hour.Afterwards reaction solution is concentrated, ethyl acetate/water extracted organic phase.Organic phase washed with water, saturated common salt water washing, concentrated.Resistates is dissolved in 50mL ethanol, reflux 6 hours.Concentrated, resistates obtains compound as white solid formula 3 after column chromatography purification, productive rate 75%.
1hNMR (300MHz, acetone-d6): δ 7.62 (d, J=9.0Hz, 1H), 7.43 (m, 2H), 7.17 (d, J=6.0Hz, 1H), 7.14 (dd, J=8.0,8.0Hz, 1H), 7.05 (dd, J=6.0,6.0Hz, 1H), 6.74 (d, J=6.0Hz, 1H), 4.51 (s, 2H) .ESI-MS:344.2,346.1 [M+H
+].
The preparation of embodiment 2 formula I
Under Ar protection, 20mg formula 3 compound is dissolved in 3mL1, in 4-dioxane, then adds 4mg tetrakis triphenylphosphine palladium, 0.5mL water, 20mg salt of wormwood and formula 4 compound.Said mixture 90 DEG C heating is after 12 hours, and concentrated, resistates obtains formula I after column chromatography purification.Compound number, concrete structure formula and raw materials used as shown in table 1 below.
Table 1 compound number, concrete structure formula and raw materials used
Compound I-1 productive rate 87%.
1hNMR (300MHz, acetone-d6): δ 7.84 (d, J=90Hz, 2H), 7.65 (d, J=6.0Hz, 1H), 7.50-7.35 (m, 5H), 7.25 (d, J=6.0Hz, 1H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.08 (d, J=6.0Hz, 1H), 7.05 (m, dd, J=6.0,6.0Hz, 1H), 4.53 (s, 2H) .ESI-MS:342.2 [M+H
+], 364.1 [M+Na
+].
Compound I-2 productive rate 85%.
1hNMR (300MHz, acetone-d6): δ 7.77 (m, 1H), 7.67 (d, J=9.0Hz, 1H), 7.4 (m, 2H), 7.29 (m, 4H), 7.15 (dd, J=6.0,6.0Hz, 1H), 7.07 (d, J=6.0Hz, 1H), 6,68 (m, 1H), 4.52 (s, 2H), 2.54 (s, 3H) .ESI-MS:356.2 [M+H
+], 378.1 [M+Na
+].
Compound I-3 productive rate 82%.
1hNMR (300MHz, acetone-d6): δ 7.76-7.62 (m, 3H), 7.45-7.42 (m, 2H), 7.35 (dd, J=6.0,6.0Hz, 1H), (7.24 d, J=6.0Hz, 1H), 7.21-7.04 (m, 4H), 4.53 (s, 2H), 2.39 (s, 3H) .ESI-MS:356.2 [M+H
+], 378.1 [M+Na
+].
Compound I-4 productive rate 80%.
1hNMR (300MHz, acetone-d6): δ 7.72 (d, J=6.0Hz, 2H), 7.64 (d, J=9.0Hz, 1H), 7.44 (m, 2H), 7.28 (m, 2H), 7.22 (d, J=6.0Hz, 1H), 7.13 (dd, J=6.0,6.0Hz, 1H), 7.05 (dd, J=6.0,6.0Hz, 1H), 6.70 (d, J=6.0Hz, 1H), 4.52 (s, 2H), 2.35 (s, 3H) .ESI-MS:356 [M+H
+].
Compound I-5 productive rate 72%.
1hNMR (300MHz, acetone-d6): δ 7.75 (d, J=9.0Hz, 2H), 7.66 (d, J=9.0Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.32 (d, J=9.0Hz, 2H), 7.23 (d, J=3.0Hz, 1H), 7.15 (dd, J=6.0,6.0Hz, 1H), 7.06 (dd, J=6.0,6.0Hz, 1H), 7.02 (d, J=3.0Hz, 1H), 4.52 (s, 2H), 2.67, (q, J=6.0,2H), 1.23 (t, J=6.0,3H) .ESI-MS:370.3 [M+H
+].
Compound I-6 productive rate 75%.
1hNMR (300MHz, acetone-d6): δ 7.75 (d, J=6.0Hz, 2H), 7.66 (d, J=6.0Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.31 (d, J=6.0Hz, 2H), 7.23 (d, J=3.0Hz, 1H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.06 (dd, J=6.0,6.0Hz, 1H), 7.02 (d, J=3.0Hz, 1H), 4.53 (s, 2H), 2.62, (t, J=9.0,2H), 1.64 (m, 2H), 0.93 (t, J=6.0,3H) .ESI-MS:384.3 [M+H
+].
Compound I-7 productive rate 82%.
1hNMR (300MHz, acetone-d6): δ 7.75 (d, J=9.0Hz, 2H), 7.66 (d, J=9.0Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.36 (d, J=9.0Hz, 2H), 7.23 (d, J=3.0Hz, 1H), 7.15 (dd, J=6.0,6.0Hz, 1H), 7.05 (dd, J=6.0,6.0Hz, 1H), 7.01 (d, J=3.0Hz, 1H), 4.53 (s, 2H), (2.94 m, 1H), 1.25, (d, J=6.0,6H) .ESI-MS:384.2 [M+H
+].
Compound I-8 productive rate 70%.
1hNMR (300MHz, acetone-d6): δ 7.75 (d, J=6.0Hz, 2H), 7.66 (d, J=9.0Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.31 (d, J=6.0Hz, 2H), 7.23 (d, J=3.0Hz, 1H), 7.15 (dd, J=6.0, 6.0Hz, 1H), 7.07 (dd, J=6.0, 6.0Hz, 1H), 7.02 (d, J=3.0Hz, 1H), 4.53 (s, 2H), 2.65, (t, J=9.0, 2H), 1.62 (m, 2H), 1.37 (m, 2H), 0.92 (t, J=6.0, 3H) .ESI-MS:398.2 [M+H
+].
Compound I-9 productive rate 80%.
1hNMR (300MHz, acetone-d6): δ 7.76 (d, J=6.0Hz, 2H), 7.65 (d, J=6.0Hz, 1H), 7.52 (d, J=6.0Hz, 2H), 7.44 (s, 1H), 7.43 (d, J=6.0Hz, 1H), 7.24 (d, J=3.0Hz, 2H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.06 (dd, J=6.0,6.0Hz, 1H), 7.02 (d, J=3.0Hz, 1H), 4.52 (s, 2H), (1.33 m, 1H), 1.30, (d, J=15.0,6H) .ESI-MS:398.3 [M+H
+].
Compound I-10 productive rate 65%.
1hNMR (300MHz, acetone-d6): δ 7.95 (m, 1H), (7.66 d, J=9.0Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=6.0Hz, 1H), 7.24 (d, J=3.0Hz, 2H), 7.34 (dd, J=6.0,6.0Hz, 1H), (7.30 d, J=3.0Hz, 1H), 7.15 (dd, J=6.0,6.0Hz, 1H), 7.07-7.03 (m, 2H), 4.54 (s, 2H) .ESI-MS:360.2 [M+H
+], 382.1 [M+Na
+].
Compound I-11 productive rate 72%.
1hNMR (300MHz, acetone-d6): δ 7.90-7.85 (m, 2H), 7.64 (d, J=9.0Hz, 1H), 7.44 (s, 1H), 7.43 (d, J=6.0Hz, 1H), 7.28-7.24 (m, 3H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.08-7.03 (m, 2H), 4.52 (s, 2H) .ESI-MS:360.2 [M+H
+], 382.1 [M+Na
+].
Compound I-12 productive rate 80%.
1hNMR (300MHz, acetone-d6): δ 7.83 (d, J=9.0Hz, 2H), (7.64 d, J=9.0Hz, 1H), (7.50 d, J=9.0Hz, 2H), 7.44 (s, 1H), 7.42 (d, J=6.0Hz, 1H), 7.26 (d, J=3.0Hz, 1H), 7.14 (dd, J=6.0,6.0Hz, 1H), (7.10 d, J=3.0Hz, 1H), 7.06 (dd, J=6.0,6.0Hz, 1H), 4.53 (s, 2H) .ESI-MS:376.1 [M+H
+], 398.1 [M+Na
+].
Compound I-13 productive rate 60%.
1hNMR (300MHz, acetone-d6): δ 7.78 (d, J=9.0Hz, 2H), 7.68-7.64 (m, 3H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.26 (d, J=3.0Hz, 1H), 7.16-7.12 (m, 2H), 7.05 (dd, J=6.0,6.0Hz, 1H), 4.53 (s, 2H) .ESI-MS:420.1,422.1 [M+H
+].
Compound I-14 productive rate 65%.
1hNMR (300MHz, acetone-d6): δ 8.02 (d, J=9.0Hz, 2H), 7.86 (d, J=9.0Hz, 2H), 7.62 (d, J=9.0Hz, 1H), 7.44 (s, 1H), 7.42 (d, J=6.0Hz, 1H), 7.34-7.30 (m, 2H), 7.13 (dd, J=6.0,6.0Hz, 1H), 7.05 (dd, J=6.0,6.0Hz, 1H), 4.54 (s, 2H) .ESI-MS:367.2 [M+H
+], 389.1 [M+Na
+].
Compound I-15 productive rate 82%.
1hNMR (300MHz, acetone-d6): δ 8.05 (d, J=9.0Hz, 2H), 7.82 (d, J=9.0Hz, 2H), 7.64 (d, J=9.0Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.29 (m, 2H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.05 (dd, J=6.0,6.0Hz, 1H), 4.54 (s, 2H) .ESI-MS:410.2 [M+H
+], 432.1 [M+Na
+].
Compound I-16 productive rate 85%.
1hNMR (300MHz, acetone-d6): δ 8.09 (d, J=9.0Hz, 2H), 7.97 (d, J=9.0Hz, 2H), 7.64 (d, J=9.0Hz, 1H), 7.45 (s, 1H), (7.43 d, J=9.0Hz, 1H), 7.29 (m, 2H), 7.13 (dd, J=6.0,6.0Hz, 1H), 7.05 (dd, J=6.0,6.0Hz, 1H), 4.54 (s, 2H), 3.90 (s, 3H) .ESI-MS:400.2 [M+H
+].
Compound I-17 productive rate 61%.
1hNMR (300MHz, acetone-d6): δ 8.80 (s, 1H), 7.69 (d, J=9.0Hz, 2H), 7.65 (d, J=60Hz, 2H), 7.44 (s, 1H), 7.43 (d, J=6.0Hz, 1H), 7.20 (d, J=3.0Hz, 1H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.06 (dd, J=6.0,6.0Hz, 1H), 6.97 (d, J=9.0Hz, 2H), 6.87 (d, J=3.0Hz, 1H), 4.51 (s, 2H) .ESI-MS:358.1 [M+H
+].
Compound I-18 productive rate 85%.
1hNMR (300MHz, acetone-d6): δ 7.76 (d, J=9.0Hz, 2H), 7.65 (d, J=9.0Hz, 1H), 7.44 (s, 1H), 7.43 (d, J=9.0Hz, 1H), (7.22 d, J=3.0Hz, 1H), 7.13 (dd, J=6.0,6.0Hz, 1H), 7.05 (dd, J=6.0,6.0Hz, 1H), 7.03 (d, J=9.0Hz, 2H), 6.93 (d, J=3.0Hz, 1H), 4.51 (s, 2H), 3.84 (s, 3H) .ESI-MS:372.2 [M+H
+].
Compound I-19 productive rate 87%.
1hNMR (300MHz, acetone-d6): δ 7.76 (d, J=9.0Hz, 2H), 7.65 (d, J=9.0Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.21 (d, J=3.0Hz, 1H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.07 (dd, J=6.0,6.0Hz, 1H), 7.02 (d, J=9.0Hz, 2H), 6.92 (d, J=3.0Hz, 1H), 4.52 (s, 2H), (4.09 q, J=9.0Hz, 2H), 1.37 (t, J=9.0Hz, 3H) .ESI-MS:386.2 [M+H
+].
Compound I-20 productive rate 87%.
1hNMR (300MHz, acetone-d6): δ 7.76 (d, J=9.0Hz, 2H), 7.65 (d, J=9.0Hz, 1H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), (7.21 d, J=3.0Hz, 1H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.06 (dd, J=6.0,6.0Hz, 1H), 7.02 (d, J=9.0Hz, 2H), 6.92 (d, J=3.0Hz, 1H), 4.52 (s, 2H), 3.99 (t, J=9.0Hz, 2H), 1.79 (m, 2H), 1.02 (t, J=9.0Hz, 3H) .ESI-MS:400.2 [M+H
+].
Compound I-21 productive rate 82%.
1hNMR (300MHz, acetone-d6): δ 7.80 (d, J=9.0Hz, 2H), 7.65 (d, J=9.0Hz, 1H), 7.48-7.42 (m, 4H), 7.24 (d, J=3.0Hz, 1H), 7.13 (dd, J=6.0,6.0Hz, 1H), 7.08-7.03 (m, 2H), 4.66 (s, 2H), 4.52 (s, 2H) .ESI-MS:372.2 [M+H
+].
Compound I-22 productive rate 85%.
1hNMR (300MHz, acetone-d6): δ 7.64 (d, J=9.0Hz, 1H), 7.54 (d, J=6.0Hz, 2H), 7.43 (d, J=9.0Hz, 1H), 7.41 (s, 1H), (7.17 d, J=3.0Hz, 1H), 7.13 (dd, J=6.0,6.0Hz, 1H), 7.04 (dd, J=6.0,6.0Hz, 1H), 7.03 (d, J=9.0Hz, 2H), 6.75-6.72 (m, 3H), 4.49 (s, 2H) .ESI-MS:357.2 [M+H
+].
Compound I-23 productive rate 85%.
1hNMR (300MHz, acetone-d6): δ 7.67-7.64 (m, 3H), 7.45 (s, 1H), 7.43 (d, J=9.0Hz, 1H), 7.17 (d, J=3.0Hz, 1H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.06 (dd, J=6.0,6.0Hz, 1H), 6.82-6.78 (m, 3H), 4.51 (s, 2H), 3.00 (s, 6H) .ESI-MS:385.2 [M+H
+].
Compound I-24 productive rate 85%.
1hNMR (300MHz, dimethyl sulfoxide (DMSO)-d6): δ 8.67 (s, 2H), (7.53 d, J=6.0Hz, 1H), 7.40 (s, 1H), 7.38 (d, J=6.0Hz, 1H), 7.30 (d, J=3.0Hz, 1H), 7.12-6.99 (m, 5H), 4.50 (s, 2H) .ESI-MS:359.2 [M+H
+].
Compound I-25 productive rate 87%.
1hNMR (300MHz, acetone-d6): δ 7.70 (d, J=9.0Hz, 2H), 7.42 (d, J=6.0Hz, 1H), 7.43-7.41 (m, 2H), 7.20 (d, J=3.0Hz, 1H), 7.14 (dd, J=6.0,6.0Hz, 1H), 7.05 (dd, J=6.0,6.0Hz, 1H), 7.04 (d, J=9.0Hz, 2H), 6.87 (d, J=3.0Hz, 1H), 4.51 (s, 2H), (3.78 d, J=6.0Hz, 4H), 3.21 (d, J=6.0Hz, 4H) .ESI-MS:427 [M+H
+].
Compound I-26 productive rate 80%.
1hNMR (300MHz, dimethyl sulfoxide (DMSO)-d6): δ 7.68 (d, J=9.0Hz, 2H), 7.58 (d, J=6.0Hz, 1H), 7.45 (s, 1H), 7.44 (d, J=6.0Hz, 1H), 7.31 (d, J=3.0Hz, 1H), 7.16 (dd, J=6.0,6.0Hz, 1H), 7.09-7.04 (m, 3H), 7.02 (d, J=3.0Hz, 1H), 4.54 (s, 2H), 3.26 (d, J=6.0Hz, 4H), 2.54 (d, J=6.0Hz, 4H), 2.27 (s, 3H) .ESI-MS:440.4 [M+H
+].
Compound I-27 productive rate 75%.
1hNMR (300MHz, acetone-d6): δ 7.64 (d, J=9.0Hz, 1H), 7.44 (s, 1H), (7.42 d, J=6.0Hz, 1H), 7.16-7.11 (m, 2H), 7.05 (dd, J=6.0,6.0Hz, 1H), 6.59 (s, 1H), 6.39 (s, 1H), 4.50 (s, 2H), 4.09 (s, 2H), 3.60 (d, J=6.0Hz, 2H), 2.44 (s, 2H), 1.46 (s, 9H) .ESI-MS:469.2 [M+Na
+].
Embodiment 3 in-vitro pharmacological experiments
The present embodiment is used for verification expression I to the effect of the beta induced SH-SY5Y cell injury of A.Experimental technique is as follows.
The state-run cell bank of SH-SY5Y purchased from American, adopts MEM:F12 (1:1) mixed culture medium containing 10% foetal calf serum, penicillin 0.05g/L, Streptomycin sulphate 0.06g/L, in 37 DEG C, 5%CO
2cellar culture in the incubator of saturated humidity.With 2 × 10
5the density of individual cell/mL is inoculated in 96 orifice plates, tests after cultivating 24h.
A β
25-35process: change the MEM/F12 with serum-free, compound treatment group adds formula I (10 μMs) prepared by embodiment 2, and EGCG positive controls adds EGCG (tea-polyphenol), and A β group and normal group are not added.After cultivation 2h, except normal group, other each group adds the A β of final concentration 10 μMs
25-35, continue to cultivate 24h, add MTT (final concentration 0.5mg/ml), after cultivating 3h, under 490nm wavelength, detect the change of absorbance.
Can there is redox reaction with MTT and produce Jia Za (bluish voilet crystallization) in the cell of survival, the growing amount of the latter is directly proportional to the quantity of viable cell, and this crystal energy is dissolved by DMSO, detects at wavelength 490nm place.Often group sets up 10 repeating holes.The OD mean value of each group is obtained the cell survival rate of each group divided by the OD mean value of normal group, result as shown in Figure 1, adds A β
25-35the cell survival rate of A β group (the second post) obviously decline, compare with EGCG positive controls with normal group, 18 compounds show good neuroprotective activity.
Embodiment 4 in-vitro pharmacological experiments
The present embodiment is used for verification expression I to H
2o
2the effect of induction SH-SY5Y cell injury.Experimental technique is as follows.
SH-SY5Y (ATCC) cell is placed in 5%CO
237 DEG C of constant incubators in cultivate.Nutrient solution is MEM:F12 (1:1), and adds 10%FBS.Every 3-4 days changes a nutrient solution.When cell density is about 80%, use 0.125% tryptic digestion, go down to posterity in the ratio of 1:2.Get the SH-SY5Y cell of stable growth, with 2 × 10
5individual/ml density is inoculated in 96 orifice plates, and 100 μ l/ holes, in 5%CO
237 DEG C of constant incubators cultivate about 24h.Change fresh nutrient solution, and cell is divided into normal group, H
2o
2damage model group, formula I pretreated group.Formula I pretreated group adds formula I (10 μMs) prepared by embodiment 2, and hydrogen peroxide group and normal group are not added.After cultivating 2h, except normal group, other each group adds H
2o
2(final concentration 100 μMs), continues cultivation 24 hours.Then the cell survival rate often organized is assessed according to mtt assay, namely MTT (final concentration 0.5mg/ml) is added after 24h, 37 DEG C are continued to cultivate 4h, abandon liquid, add DMSO (100%), 100 μ l/ holes, the abundant dissolving crystallized dyestuff of vibration 5min, microplate reader measures absorbancy (measuring wavelength 490nm), calculates cell survival rate, result as shown in Figure 2, only adds H
2o
2h
2o
2damage model group (the 2nd post) cell survival rate declines, and 4 compounds of formula I pretreated group all show good neuroprotective activity.
Embodiment 5 in-vitro pharmacological experiments
The present embodiment is used for verification expression I lacks model induction SH-SY5Y cell injury effect to oxygen sugar.Experimental technique is as follows.
SH-SY5Y (ATCC) cell is placed in 5%CO
237 DEG C of constant incubators in cultivate.Nutrient solution is MEM:F12 (1:1), and adds 10%FBS.Every 3-4 days changes a nutrient solution.When cell density is about 80%, use 0.125% tryptic digestion, go down to posterity in the ratio of 1:2.Get the SH-SY5Y cell of stable growth, with 2 × 10
5individual/ml density is inoculated in 96 orifice plates, and 100 μ l/ holes, in 5%CO
237 DEG C of constant incubators cultivate about 24h.
Normal group, oxygen sugar is divided into by cell to lack model group, test-compound group.Normal group EBSS (sugary) damping fluid washes one time, changes DMEM (low sugar) nutrient solution into; Oxygen sugar lacks model group, test-compound group EBSS (Eagle ' s balanced salt solution, sugar-free) washes one time, changes DMEM (sugar-free) nutrient solution into.
In test-compound group, add test-compound (final concentration 10 μMs), oxygen sugar lacks model group and normal group is not added, and oxygen sugar shortage model group and test-compound group is put into OGD Special-purpose enclosed box, passes into 95%N
2, 5%CO
2mixed gas, in 37 DEG C of constant incubators, Anoxia 1 hour, recovers normal culture condition afterwards and cultivates 24 hours again; Period, normal group cell is cultivated under being still placed in normal culture environment.Then the cell survival rate often organized is assessed according to mtt assay, namely MTT (final concentration 0.5mg/ml) is added after 24h, 37 DEG C are continued to cultivate 4h, abandon liquid, add DMSO (100%), the abundant dissolving crystallized dyestuff of vibration 5min, microplate reader measures absorbancy (measuring wavelength 490nm), calculates cell survival rate.
As shown in Figure 3, result shows that 4 compounds after tested all show good neuroprotective activity to result.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (11)
1. indoles alkaloid or its pharmacy acceptable salt, structure is such as formula shown in I:
In formula, A is C6-C10 aryl or C3-C8 heterocyclic radical;
N is the integer of 1-5;
Each R is hydrogen, hydroxyl, nitro, itrile group, halogen, C1-C8 alkyl, C1-C8 alkoxyl group ,-NR independently
1r
2,-C (O) C1-C8 alkoxyl group, C3-C6 cycloalkyl, C3-C8 heterocyclic radical or C6-C10 aryl,
Wherein, R
1, R
2independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group;
Described C1-C8 alkyl, C1-C8 alkoxyl group ,-NR
1r
2,-C (O) C1-C8 alkoxyl group, C3-C6 cycloalkyl, C3-C8 heterocyclic radical or the C6-C10 aryl substituting group that is optionally selected from lower group replaces: hydroxyl, amino, nitro, itrile group, halogen, C1-C6 alkyl, C1-C6 alkoxyl group;
Each described heterocyclic radical comprises one or more the heteroatoms being selected from lower group independently: O, S, P and N.
2. indole alkaloid as claimed in claim 1, it is characterized in that, A is phenyl, pyrimidyl or tetrahydro pyridyl.
3. indoles alkaloid as claimed in claim 2, it is characterized in that, each R is C1-C6 alkyl ,-C (O) C1-C6 alkoxyl group, C1-C6 the alkoxyl group ,-NR of hydrogen, hydroxyl, halogen, itrile group, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl replacement independently
1r
2, the C3-C6 heterocyclic radical that replaces of C3-C6 heterocyclic radical or C1-C4 alkyl,
Wherein, R
1, R
2independently selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxyl group.
4. indoles alkaloid as claimed in claim 1, it is characterized in that, each described heterocyclic radical is independently selected from furyl, pyrryl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, quinolyl, isoquinolyl, indyl, pyrimidyl, tetrahydro pyridyl, pyrrolinyl, dihydropyridine base, dihydrofuran base, dihydro-thiophene base, pyranyl.
5. the preparation method of indoles alkaloid as claimed in claim 1, it is characterized in that, described preparation method comprises the following steps:
A () formula 1 compound and formula 2 compound carry out condensation and obtain formula 3 compound;
B () formula 3 compound and formula 4 compound obtain formula I through linked reaction,
Wherein, various middle R
1for bromine or iodine;
The definition of A, R and n as claimed in claim 1;
R
3for boronate or boric acid ester group.
6. preparation method as claimed in claim 5, it is characterized in that, described step (a) has following one or more feature:
(1) condensing agent used is N, N'-dicyclohexylcarbodiimide (DCC), N, N'-DIC (DIC), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI), diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD), 1-hydroxyl-7-azo benzotriazole (HOAT), 1-hydroxy benzo triazole (HOBT), O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N', one or more combination in N'-tetramethyl-urea phosphofluoric acid ester (HBTU),
(2) described step (a) is carried out in organic solvent, described organic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, acetonitrile, 1, one or more combination in 4-dioxane, ethylene dichloride, DIPEA, water;
(3) temperature of reaction is 0 DEG C ~ 130 DEG C;
(4) reaction times is 6 ~ 12 hours.
7. preparation method as claimed in claim 5, it is characterized in that, described step (b) has following one or more feature:
(1) described step (b) is carried out in organic solvent, described organic solvent is ethanol, N, one or more combination in dinethylformamide, triethylamine, benzene, DIPEA, toluene, Isosorbide-5-Nitrae-dioxane and water;
(2) described step (b) is carried out in palladium catalyst catalysis, and described palladium catalyst is one or more the combination in tetrakis triphenylphosphine palladium, palladium chloride, two (tricyclohexyl phosphine) palladium chloride, two (triphenylphosphine) palladium chloride (II), palladium;
(3) temperature of reaction is 0 DEG C ~ 120 DEG C;
(4) reaction times is 4 ~ 24 hours.
8. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises:
Indoles alkaloid described in any one of claim 1-4 or its pharmacy acceptable salt; And pharmaceutically acceptable carrier.
9. the purposes of the indoles alkaloid as described in any one of claim 1-4 or its pharmacy acceptable salt or pharmaceutical composition according to claim 8, is characterized in that, for the preparation of the medicine preventing and/or treating nervous system degenerative disease.
10. purposes as claimed in claim 9, it is characterized in that, described nervous system degenerative disease is selected from: Parkinson's disease, Alzheimer, Huntington Chorea, amyotrophic lateral sclerosis are sick, and spinal muscular atrophy is sick, primary lateral sclerosis is sick, spinocerebellar ataxia.
The purposes of 11. indoles alkaloids as described in any one of claim 1-4 or its pharmacy acceptable salt or pharmaceutical composition according to claim 8, is characterized in that, for:
A () preparation prevents and/or treats the medicine of oxidative stress inducing neural cell injury;
B () preparation prevents and/or treats the medicine of amyloid-beta inducing neural cell injury; Or
C () preparation prevents and/or treats the medicine that oxygen sugar lacks inducing neural cell injury.
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| CN110627778A (en) * | 2018-06-25 | 2019-12-31 | 中国科学院上海药物研究所 | Compound containing 1,2, 4-oxadiazole ring, preparation method thereof and application thereof in immunosuppressive drugs |
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| CN106749213A (en) * | 2016-11-25 | 2017-05-31 | 济南大学 | A kind of indole derivatives and preparation method with 1,2,4 oxadiazoles structures and the application in antibacterials are prepared |
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| CN113200971A (en) * | 2021-05-14 | 2021-08-03 | 济南大学 | Synthesis and application of indole oxadiazole derivative with aromatic piperazine structure |
| CN113200971B (en) * | 2021-05-14 | 2022-06-28 | 济南大学 | Synthesis and application of indole oxadiazole derivative with aryl piperazine structure |
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| CN105272975B (en) | 2019-03-26 |
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