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CN108689906A - The hydrazide derivatives and application thereof of indoles substitution - Google Patents

The hydrazide derivatives and application thereof of indoles substitution Download PDF

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Publication number
CN108689906A
CN108689906A CN201710233211.3A CN201710233211A CN108689906A CN 108689906 A CN108689906 A CN 108689906A CN 201710233211 A CN201710233211 A CN 201710233211A CN 108689906 A CN108689906 A CN 108689906A
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alkyl
disease
compound
methyl
alkoxy
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Inventor
金传飞
陈康智
钟文和
罗明
张英俊
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses the hydrazide derivatives and application thereof of indoles substitution, in particular it relates to the hydrazide derivatives of a kind of novel indoles substitution and the pharmaceutical composition comprising such compound, they have preferable protective effect to nerve cell.The invention further relates to the methods for preparing this kind of compound and pharmaceutical composition, and they are preparing treatment disease related with glutamate excitotoxicity, oxidativestress damage or free radical, or the purposes in the drug of neurodegenerative disease, especially Alzheimer disease.

Description

The hydrazide derivatives and application thereof of indoles substitution
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to be used for the compound and composition of neuroprotection, and its use Method and purposes.Particularly, of the present invention is related with glutamate excitotoxicity, oxidativestress damage or free radical The hydrazide derivatives of indoles substitution.
Background technology
Currently, about treatment acute nerve injury (such as apoplexy, spinal injury) and chronic neurodegenerative disease (Ru Aer Ci Haimo diseases, Parkinson's disease, Huntington chorea, amyotrophic lateral sclerosis, retinosis etc.) active drug It is considerably less.Therefore, being badly in need of exploitation has protection neuron, promotes nerve regneration and/or remembers the drug of formation effect to treat These destructive damages or disease.
In the past few decades, neurotrophic growth factor (such as nerve growth factor, neurotrophic factor derived from brain, god Through trophic factors -3 etc.) acute or chronic neurodegenerative disease is treated as very promising drug candidate.These Protein neurotrophic growth factor plays very important effect in nervous function maintenance.However, clinical research shows:Egg For white matter neurotrophic factor since pharmacokinetic property is poor, biocompatibility is low, brain Barrier penetrability difference and multiple-effect, Therapeutic effect is simultaneously bad.Thus, a large amount of positive researchs have been carried out to the small molecule neurotrophic factor of non-peptides.
The nerve cell death of neurodegenerative disease (such as Alzheimer disease, Parkinson's disease) and unusual Apoptosis Rate is relevant (Thompson, Science, 1995,267:1456-1462).Apoptosis inhibitor or nerve cell Death inhibitor can promote nerve cell to regenerate, wherein the Caspase inhibitors of peptides as neurotrophic factor, It is difficult to across blood-brain barrier.But small molecule neurotrophic factor has potential oral medication property and penetrates the energy of blood-brain barrier Power, thus, micromolecular inhibitor (Huang, the Chem&amp to begin one's study about Apoptosis;Biol.,2002,9:1059- 1072)。
Alzheimer disease (Alzheimer ' s disease, AD) is the main Types of senile dementia, is that the elderly recognizes Know the Etiological with mental deterioration, is the Neuro-degenerative disease for the progress sexual development for seriously affecting life of elderly person quality Disease.Clinically with memory disorders, aphasia, appraxia, agnosia, the damage of visual space technical ability, execution dysfunction and personality and behavior The performance of the generalized dementias such as change is characterized.Alzheimer disease not only deteriorates personal and quality of social life, can also make patient It agonizes with other people of surrounding.Alzheimer disease is that the 4th height after being located at cancer, heart disease and cerebral hemorrhage is dead Die reason.
According to the multiple epidemiological surveys in China as a result, the illness rate of AD is about 5% in over-65s crowd, incidence Generally increase with the increase at age.The Research statistics of developed country are shown with the number of the patient with Alzheimer disease Amount ratio is also to increase with the increase at age.Wherein, in more than 60 years old crowd, more than 70 years old crowd and more than 80 years old crowd Illness rate is respectively 15-20%, 30-40% and 60%.It can be seen that the case where suffering from AD in more than 80 years old crowd, is very serious, often Alzheimer disease is just suffered to a people in spouse.
There are many causes of disease for leading to Alzheimer disease, presently mainly treats Alzheimer disease according to the cause of disease.It is first First, according to existing research, the patient with Alzheimer disease has the acetylcholine of low concentration, when acetylcholinesterase quilt When inhibition, improve the symptom of Alzheimer disease by increasing the concentration of acetylcholine;Second, by studying Alzheimer The inherent cause of disease postpones the progress of Alzheimer disease, the inherent cause be related to A β (beta-amyloid protein) synthesis, Carry out, the accumulation of neuron and in cortex beta-amyloid protein deposition.Similarly, beta-amyloid protein is reduced by discovery Extracellular concentration governing factor, and the beta-amyloid protein deposit in intracerebral is selectively removed, A Er can be treated Ci Haimo diseases;Third can prevent A Erci indirectly by using estrogen, antioxidant, radical scavenger or anti-inflammatory agent The further deterioration of the silent disease in sea;4th, treat A Erci by preventing the gradual and irreversible degeneration of cynapse and neuron The silent disease in sea.
Clinically there are no effectively reversing cognitive defect can improve the drug for the treatment of Alzheimer disease at present.Acetylcholine Esterase inhibitor (donepezil, Rivastigmine, huperzine, galanthamine), which treats light-moderate AD patients, certain curative effect, But also it is temporary relief of symptoms, can not further prevents the decaying of nerve cell, and be accompanied by serious adverse reaction.Combine and answers Has certain curative effect in terms of improving memory with brain blood flow and cerebral metabolism such as Oxiracetam (oxiracetam), still It is more often to exist as intelligence development agent.Therefore, it is necessary to develop the drug that can improve treatment Alzheimer disease.For paddy ammonia The drug development of sour excitatory toxicity, oxidativestress damage or free radical is considered as a new way got a good chance of always Diameter.
Glutamic acid is most important excitatory neurotransmitter in mammalian central nervous system, it is passed in excitatory synapse It passs and plays vital effect in the adjusting with synaptic plasticity.But content of glutamic acid is excessively increased (paddy in neuron Propylhomoserin damages) serious toxic effect can be generated to neuron, cause a large amount of Neuron Apoptosis.Glutamate receptor is divided into two classes: One kind is metabotropic receptor (mGluRs), it with film in G- albumen couplings.These receptors be activated after by G- albumen effects enzyme, The signal transduction system of the compositions such as intracerebral second messenger works, and generates more slow physiological reaction;It is another kind of be ionic by Body, including N-methyl-D-aspartate receptor (NMDAR), alpha-amido -3- hydroxy-5-methyl base -4- isoxazoles receptors (AMPAR) With kainate receptor (KAR).They are coupled with ion channel, form receptor channel complex, and fast signal is mediated to transmit (Wang S J,Yang T T,et al.Drug News Perspect,2005,18(9):561-566).Glutamic acid is central nervous system The most abundant most important amino acid of system had not only participated in the normal physiological function that cynapse transmits but also maintains nerve cell.Under normal circumstances, Release, intake and the reabsorption of glutamic acid maintain dynamic equilibrium.However, when it excessively discharges or absorbs obstacle, glutamic acid exists Intracerebral is largely gathered, and concentration drastically increases, receptor excessive activation can cause the damage of extensive histopathology (Kumar A, Zou L,Yuan X,et al.Journal of neuroscience research,2002,67(6):781-786).Paddy ammonia Generation, the development of sour this Excitotoxicity and a variety of neurodegenerative diseases have close ties, are that nerve is caused to move back One of the important mechanisms of nerve cell death in row disease.
Oxidative stress refers to body when being stimulated, and generates a large amount of oxide intermediates in vivo, makes active oxygen and antioxygen Change the physiology course of system imbalance.It is this it is unbalance be partial to generate a large amount of free radical make the reduced activity of antioxidant system, from And lead to body oxidative damage.These free radicals include active nitrogen free radical (Reactive nitrogen species, RNS) With active oxygen radical (Reactive oxygen species, ROS).The generation link of free radical and a variety of Physiology and biochemistry mistakes Journey is closely related, sufficiently complex (Conrad et al.Neurochem Int.2013,62 (5):738-749).Due to neuron Phospholipid bilayer in contain a large amount of polybasic unsaturated fatty acid, lipid peroxidation easily occurs, thus, neuronal cell More more sensitive to oxidative stress than other cells (Facecchia K, et al.Journal of toxicology, 2011, 2011.).The oxygen metabolism damage of central nervous system can generate more serious oxidative stress effect, cause to nervous system Further damage (Mohsenzadegan et al.Iran J Allergy Asthma Immunol.2012Sep, 11 (3): 203-216).When normal physiological condition, internal excessive free radical, hydrogen peroxide (H2O2), ozone (O3) and singlet oxygen etc. it is living Property oxygen can quickly be removed by antioxidant system, but under pathological conditions, this Scavenging activity is damaged.Active oxygen tires out Product can cause nucleic acid break, lipid peroxidation, polysaccharide depolymerization, enzymatic inactivation to eventually lead to neuronal death (Yan et al.Free Radic Biol Med.2013,62:90-101).Cause many because being known as of oxidative stress, A β, mitochondria and Metal ion etc. is considered to play an important role during oxidative stress.A β can change ion channel permeability, activation Nadph oxidase II (NOX2), so that electronics is transferred on oxygen by NADPH, improves the generating rate of ROS.The content of soluble A β Generation rate with hydrogen peroxide is in good linear relationship.A β have the metal ion with redox active very strong simultaneously Affinity (Pigmental et al.Oxid Med Cell Longev.2012,2012:132-146).It and these activity Metal ion can generate hydrogen peroxide after combining.Studies have shown that prooxidant can promote the generation of A β, and antioxidant, such as Vitamin E and some other free radical scavenger can then prevent damages of the A β to neuron, improve cognitive disorder.
Invention content
The present invention provides a kind of new chemical combination related with glutamate excitotoxicity, oxidativestress damage or free radical Object has preferable potential applicability in clinical practice.Only summarize some aspects of the present invention below, it is not limited to this.These sides Face and other parts have more complete explanation later.All bibliography in this specification are incorporated in this by whole.When When the disclosure of the specification and citation are variant, it is subject to the disclosure of the specification.
The present invention relates to the hydrazide derivatives of a kind of novel indoles substitution, the HT22 cellular oxidations to glutamate induction Stress damage has preferable protective effect, can inhibit glutamate excitotoxicity or anti-oxidation stress, so as to be used to prepare The drug for treating neurodegenerative disease is especially used to prepare the drug for the treatment of Alzheimer disease.
The compounds of this invention property is stablized, good security, has good pharmacodynamics and pharmacokinetic property, such as Good brain/blood plasma ratio (brain plasma ratio), good bioavilability or good metabolic stability etc., therefore Has preferable potential applicability in clinical practice.
Pharmaceutical composition the present invention also provides the method for preparing this kind of compound and containing such compound.
On the one hand, it is compound shown in formula (I) compound represented or formula (I) the present invention relates to a kind of compound Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
Each R1,R2,R3,R4,R5,R6And R7With meaning as described in the present invention.
In one embodiment, R1,R4And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,- SH,-COOH,-CONH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkane Oxygroup), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1- C6Alkylthio group, C1-C6Alkylamino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,-SH,-COOH,-CONH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkane Amino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R3For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,-SH,-COOH,-CONH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkane Amino or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R5For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2,C1- C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R7For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2,C1- C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy or the C of hydroxyl substitution1-C6Alkyl.
In one embodiment, R1,R4And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,- SH,-COOH,-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or hydroxyl Substituted C1-C4Alkyl.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,-SH,-COOH,-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkyl.
In one embodiment, R3For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,-SH,-COOH,-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1-C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkyl.
In one embodiment, R5For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2,C1- C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy or the C of hydroxyl substitution1-C4Alkyl.
In one embodiment, R7For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2,C1- C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy or the C of hydroxyl substitution1-C4Alkyl.
In one embodiment, R1,R4And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,- SH,-COOH,-CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH(CH3)2, methyl, ethyl, n-propyl, isopropyl ,-CF3,-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl Oxygroup.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,-SH,-COOH,-CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH (CH3)2, methyl, second Base, n-propyl, isopropyl ,-CF3,-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R3For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,-SH,-COOH,-CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH (CH3)2, methyl, second Base, n-propyl, isopropyl ,-CF3,-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R5For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-propyl, isopropyl ,-CF3,-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R7For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-propyl, isopropyl ,-CF3,-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
Each R of the present invention1,R2,R3,R4,R5,R6And R7Individually optionally by one or more RwReplaced;With
Each RwIt independently is H, D, F, Cl, Br, I ,-NO2,-CN,-N3,-NH2,-OH ,-SH, oxo (=O), C1-C4Alkane Base, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylamino, C1-C4 Alkylthio group, NH2-(C1-C4Alkylidene)-, HO- (C1-C4Alkylidene)-, HS- (C1-C4Alkylidene)-, (C1-C4Alkoxy)-(C1- C4Alkylidene)-, (C1-C4Alkylamino)-(C1-C4Alkylidene)-, (C1-C4Alkylthio group)-(C1-C4Alkylidene)-, C3-C6Naphthenic base, (C3-C6Naphthenic base)-(C1-C4Alkylidene)-, the heterocycle of 3-7 annular atom composition, (heterocycle that 3-7 annular atom forms Base)-(C1-C4Alkylidene)-, phenyl, phenyl-(C1-C4Alkylidene)-, the heteroaryl or (5-6 ring of 5-6 annular atom composition Former molecular heteroaryl)-(C1-C4Alkylidene)-.
In one embodiment, compound of the present invention, for one of following structure compound or have The stereoisomer of the compound of one of following structure, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes chemical combination disclosed by the invention Object.
In one embodiment, pharmaceutical composition of the present invention, further include pharmaceutically acceptable excipient, Carrier, adjuvant or their arbitrary combination.
In one embodiment, pharmaceutical composition of the present invention, further includes additional therapeutic agent, wherein described Additional therapeutic agent is the drug for treating Alzheimer's disease, treats the drug or combination thereof of nervous disorders.
In another embodiment, pharmaceutical composition of the present invention, wherein the additional therapeutic agent be donepezil, Nalmefene, Risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, idalopirdine, Tacrine, Rivastigmine, galanthamine, Memantine, rice Ta Zhaping, Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, oneself Ketone theobromine or their arbitrary combination.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for protecting neuron, nerve regneration and/or memory being promoted to be formed.
On the other hand, the purposes the present invention relates to compound or composition disclosed by the invention in medicine preparation, it is described Drug is for preventing, treating or mitigating disease related with glutamate excitotoxicity, oxidativestress damage or free radical, or god Through degenerative disease.
In one embodiment, the disease related with glutamate excitotoxicity is Alzheimer disease, the prosperous court of a feudal ruler Chorea, Parkinson's disease, myasthenia gravis, amyotrophic lateral sclerosis, senile dementia, glaucoma, bronchial asthma, Hyperthyroidism, IV types hyperlipoprotememia, hypertension or renal failure.
In another embodiment, the disease related with oxidativestress damage or free radical be cerebral injury, headstroke, Brain of neonatal rat on ischemia hypoxia, cerebral hemorrhage, Parkinson's disease, Huntington chorea, epilepsy, amyotrophic lateral sclerosis, A Erci The silent disease in sea, dementia, ischemic heart disease, blood vessel embolism, hypercholesterolemia, atherosclerosis, diabetes, pulmonary emphysema, Liver diseases, kidney damage or cancer caused by cataract, acute pancreatitis, alcohol.
In yet another embodiment, the neurodegenerative disease is Parkinson's disease, cerebral ischemia, Alzheimer disease, flesh Meat atrophic lateral schlerosis, bovine spongiform encephalopathy, Huntington chorea, gram refined Er Shi diseases, ataxia-telangiectasia Disease, cerebral atrophy, spinal muscular atrophy, primary lateral sclerosis or multiple sclerosis.
On the other hand, the present invention relates to the methods of preparation, separation and the purifying of compound shown in formula (I).
Biological results show that the compounds of this invention has preferably the HT22 cellular oxidation stress damages of glutamate induction Protective effect, and can be used as preferable neuroprotective agent.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its Content in terms of him will make more specific complete description below.All bibliography in this specification pass through whole reference In this.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In range.Those skilled in the art will appreciate that many can be used in similar or equivalent method and material of the present invention The practice present invention.The present invention is not limited to method of the present invention and material.In document, patent and the similar material combined One or more or contradict in the case of (include but not limited to defined in term, term application, institutes different from the application Technology of description, etc.), it is subject to the application.
It will further be appreciated that certain features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also in combination be provided in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With periodic table of elements CAS editions, and"Handbook of Chemistry and Physics", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can With reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito: 1999, and " March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:Description in 2007, entire contents are incorporated by reference into the present invention.
There is apparent conflict unless otherwise indicated or in context, article " one " used in the present invention, " one (kind) " and " described " are intended to include "at least one" or " one or more ".Therefore, these articles used in the present invention refer to The article of one or more than one (i.e. at least one) object.For example, " component " refers to one or more components, it is possible to have more It uses or uses in the embodiment that one component is taken into account in the embodiment.
Term " stereoisomer " refers to having identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, rotamer (rotational isomer), geometry are different Structure body (cis/trans) isomers, atropisomer, etc..
Term " tautomer " or " tautomeric form " refer to that with different energy can be by low energy barrier (low Energy barrier) mutually inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical balance of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer)) include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Imine-enamine isomerizations.
" pharmaceutically acceptable " refers to some such compounds, raw material, composition and/or dosage form, they are cured rationally Learn judge in the range of, be suitable for patient tissue contacts and without excessive toxicity, irritation, allergy or with rational profit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " optionally by ... replaces " can exchange use, i.e., with term " unsubstituted or by ... .. replaces " The structure is unsubstituted or is replaced by one or more substituent groups of the present invention, substituent group packet of the present invention It includes, but is not limited to D, F, Cl, N3,-CN ,-OH ,-SH ,-NH2, alkyl, alkoxy, alkylthio group, alkylamino, naphthenic base, heterocycle, Aryl, heteroaryl etc..
In general, " substituted " expression of term is specifically replaced to one or more of structure or group hydrogen atom Base is replaced.Unless otherwise indicated, a substituent group can be replaced in each commutable rational position of group. When in given structural formula more than one position can by selected from the specific substituent groups of one or more replace, then substituent group It can each rational position be replaced in structural formula identical or differently.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded otherwise Content.
It is disclosed according to radical species or range in the substituent group of each section of this specification, disclosed compound of present invention.It is special It does not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and range.For example, term "C1-C6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
Term " D " indicates single D-atom.
Term " halogen " and " halogenated " are used interchangeably in the present invention, refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I)。
Terminology used in the present invention " alkyl " or " alkyl group ", indicate contain 1-20 carbon atom, the straight chain of saturation or Branch univalent hydrocarbyl group, wherein the substituent group institute that the alkyl group can be described optionally by one or more present invention Substitution.In one embodiment, alkyl group contains 1-6 carbon atom;In another embodiment, alkyl group contains 1-4 A carbon atom;Also in one embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group includes, but and unlimited In methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tertiary butyl (t-Bu ,-C (CH3)3), etc..
Term " alkenyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one carbon-to-carbon sp2Double bond, wherein the alkenyl group can be retouched optionally by one or more present invention The substituent group stated is replaced comprising the positioning of " cis " and " trans ", or " E " and " Z " positioning.
Term " alkynyl " indicates the linear chain or branched chain monovalent hydrocarbon containing 2-12 carbon atom, wherein at least one insatiable hunger And site, i.e., there are one tri- keys of carbon-to-carbon sp, wherein the alkynyl group can be retouched optionally by one or more present invention The substituent group stated is replaced.
Term " alkoxy " indicates that alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In an embodiment party In case, alkoxy base contains 1-6 carbon atom;In another embodiment, alkoxy base contains 1-4 carbon atom; In another embodiment, alkoxy base contains 1-3 carbon atom.The alkoxy base can be optionally one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), etc..
Term " alkylthio group " indicates that alkyl group is connected by sulphur atom with molecule rest part, and wherein alkyl group has Meaning as described in the present invention.Unless otherwise detailed instructions, the alkylthio radicals contain 1-12 carbon atom.In an embodiment party In case, alkylthio radicals contain 1-6 carbon atom;In another embodiment, alkylthio radicals contain 1-4 carbon atom; In another embodiment, alkylthio radicals contain 1-3 carbon atom.The alkylthio radicals can be optionally one or more The substituent group that the present invention describes is replaced.
The example of alkylthio radicals includes, but is not limited to, methyl mercapto (MeS ,-SCH3), ethylmercapto group (EtS ,- SCH2CH3), 1- rosickyite base (n-PrS, n- rosickyite base ,-SCH2CH2CH3), 2- rosickyite base (i-PrS, i- rosickyite base ,-SCH (CH3)2), 1- butylthios (n-BuS, n- butylthio ,-SCH2CH2CH2CH3), 2- methyl-l- rosickyite base (i-BuS, i- fourth sulphur Base ,-SCH2CH(CH3)2), 2- butylthios (s-BuS, s- butylthio ,-SCH (CH3)CH2CH3), 2- methyl -2- rosickyite bases (t- BuS, t- butylthio ,-SC (CH3)3), etc..
Term " alkylamino " or " alkyl amino " include " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group, and wherein alkyl group has meaning as described in the present invention.It closes Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- first ammonia Base, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..The alkylamino radicals are optionally by one or more sheets The described substituent group of invention is replaced.
Term " alkyl of hydroxyl substitution " indicates that alkyl group is replaced by one or more hydroxyls, and wherein alkyl group has There is meaning as described in the present invention;Such example includes, but is not limited to, methylol, 2- hydroxyethyls, 2- hydroxyls -1- third Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyls etc..
Term " halogenated alkyl " indicates that alkyl group is replaced by one or more halogen atoms, and wherein alkyl group has Meaning as described in the present invention, such example includes, but is not limited to ,-CF3,-CH2CF3,-CHFCH3,-CH2CH2F,- CF2CH3Deng.In one embodiment, C1-C6Halogenated alkyl includes fluorine-substituted C1-C6Alkyl;In another embodiment, C1- C4Halogenated alkyl includes fluorine-substituted C1-C4Alkyl;In yet another embodiment, C1-C2Halogenated alkyl includes fluorine-substituted C1-C2 Alkyl.
Term " halogenated alkoxy " indicates that alkoxy base is replaced by one or more halogen atoms, wherein alkoxy base Group has meaning as described in the present invention, and such example includes, but is not limited to ,-OCF3,-OCH2CF3,-OCHFCH3,- OCH2CH2F,-OCF2CH3Deng.In one embodiment, C1-C6Halogenated alkoxy includes fluorine-substituted C1-C6Alkoxy;Another In embodiment, C1-C4Halogenated alkoxy includes fluorine-substituted C1-C4Alkoxy;In yet another embodiment, C1-C2Alkyl halide Oxygroup includes fluorine-substituted C1-C2Alkoxy.
When term " blocking group " or " PG " refer to a substituent group and other reacted with functional groups, commonly used to resistance It is disconnected or protect special functionality.It is connected with amino group to block for example, " blocking group of amino " refers to a substituent group Or the functionality of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group be used for blocking or protecting the functionality of hydroxyl, suitable blocking group includes trialkylsilkl, acetyl group, benzene Formoxyl and benzyl." carboxy protective group " refers to that the substituent group of carboxyl is used for blocking or protecting the functionality of carboxyl, general Carboxyl-protecting group includes-CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy Ylmethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro second Base, etc..Document can refer to for the general description of blocking group:Greene et al.,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991and Kocienski et al., Protecting Groups,Thieme,Stuttgart,2005。
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change Closing the metabolite of object can be identified by technology well-known in the art, and activity can be retouched by such as the present invention It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, being restored, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document:S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. recorded.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by recorded in books, literature Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphurs Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that alkali appropriate obtains includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any The compound of the group of included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be turned by quaternary ammonium With obtaining.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises fitting When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C1-C8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to that one or more solvent molecules are formed by association with the compound of the present invention Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Or mixtures thereof acid, ethanol amine.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When the solvent is water, term " hydrate " can be used.In one embodiment, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate;In another embodiment, a compounds of this invention molecule It can be combined with more than one hydrone, such as dihydrate;In yet another embodiment, a compounds of this invention point Son can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remain with it is non- The biological effectiveness of the compound of hydrated form.
Any disease of term " treatment " or illness, refer to improvement disease in some of these embodiments or illness (slows down Or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments, " treatment " refer to mitigation or Improve at least one body parameter, including the body parameter that may not be discovered by patient.In other embodiments, it " controls Treat " refer to from (such as stablizing perceptible symptom) on body or physiologically in terms of (such as stablizing parameter of body) or above-mentioned two Adjust disease or illness.In other embodiments, " treatment " refers to the breaking-out, generation or evil for preventing or delaying disease or illness Change.
Term " preventing " or " prevention " refer to the reduction for the risk for obtaining disease or obstacle (i.e.:Make at least one clinical condition of disease Shape stops development in main body, which may face or be inclined in advance in face of this disease, but without undergoing or show The symptom of disease).
The hydrazide derivatives of indoles substitution of the present invention, pharmaceutically acceptable salt, pharmaceutical preparation and combinations thereof Object can inhibit glutamate excitotoxicity or anti-oxidation stress, to neurodegenerative disease, especially Alzheimer disease Treatment has potential purposes.
Unless otherwise mentioned, all suitable isotope variations of the compound of the present invention, stereoisomer, tautomerism Body, solvate, metabolite, salt and pharmaceutically acceptable prodrug are intended to be included within the scope of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and be included in the invention as disclosed compound of present invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body is with regard to this clear and definition.
The nitrogen oxides of the compounds of this invention is also contained within the scope of the present invention.It can be normal by using at an elevated temperature Corresponding nitrogen-containing basic substance is aoxidized, or pass through in the presence of the acid of such as acetic acid with oxidant (such as hydrogen peroxide) It reacts with peracid in suitable solvent, such as is reacted with peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or It is reacted with 3- chloroperoxybenzoic acids in chloroform or dichloromethane, prepares the nitrogen oxides of the compounds of this invention.
Compound can exist in a salt form shown in formula (I).In one embodiment, the salt refers to that can pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refer to substance or composition must with other ingredients comprising preparation and/or use it The mammal for the treatment of is compatible chemically and/or in toxicology.In another embodiment, the salt, which is not necessarily, pharmaceutically may be used The salt of receiving can be used to prepare and/or purify compound shown in formula (I) and/or for detaching compound shown in this formula (I) Enantiomer intermediate.
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalinity or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, Hydroxide, carbonate, bicarbonate of Mg or K etc.) reaction, or free alkali form and chemistry by making these compounds The suitable acid of metered amount reacts to be prepared.Such reaction usually carries out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it needs to use non-aqueous medium such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile. Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton,Pa.,(1985);" pharmaceutical salts handbook:Property, selection and application (Handbook of Pharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the other suitable for salt can be found in.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
On the other hand, the present invention relates to the intermediates for preparing compound shown in formula (I).
On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes the compounds of this invention.One In embodiment, pharmaceutical composition of the present invention further includes pharmaceutically acceptable carrier, excipient, adjuvant, molten Matchmaker or combination thereof.In another embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray Type.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, including compound or its individual stereoisomer shown in formula (I), isomery The racemic or non-racemic mixture of body or its pharmaceutically acceptable salt or solvate.In one embodiment of the present invention In formula, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally Ground, others treatment and/or prevention ingredient.
It is that suitable carrier, adjuvant and excipient are well known to those skilled in the art and be described in detail in for example Ansel H.C.et al.,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems(2004)Lippincott,Williams&Wilkins,Philadelphia;Gennaro A.R.et al., Remington:The Science and Practice of Pharmacy(2000)Lippincott,Williams& Wilkins,Philadelphia;With Rowe R.C., Handbook of Pharmaceutical Excipients (2005) In Pharmaceutical Press, Chicago.
Including the compounds of this invention or the therapy of pharmaceutical composition administration, further comprise that carrying out other to patient resists The administration of Alzheimer disease drug (combination therapy), the wherein drug of other anti-Alzheimer diseases are donepezil, Na Mei Sweet smell, Risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX- 8066, SB-742457, naluzaton, idalopirdine, Tacrine, Rivastigmine, galanthamine, Memantine, meter Ta Zha Flat, Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, hexanone can Theobromine or their arbitrary combination.
" pharmaceutically acceptable excipient " used in the present invention means related to form of administration or pharmaceutical composition consistency Pharmaceutically acceptable material, mixture or solvent.Each excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid that can substantially reduce disclosed compound of present invention when administering to a patient and can cause not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, each excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific dosage form.In addition, can be according to them in group The specific function in object is closed to select pharmaceutically acceptable excipient.For example, may be selected to can help to produce equal one dosage type low temperature Certain pharmaceutically acceptable excipient.The certain pharmaceutically acceptable figurations that can help to produce stabilizer type may be selected Agent.Contribute to carry or transport the compounds of this invention when may be selected to administer to a patient from an organ of body or partly to body Another organ or partial certain pharmaceutically acceptable excipient.May be selected enhancing patient compliance it is certain pharmaceutically Acceptable excipient.
Suitable pharmaceutically acceptable excipient includes following kind of excipient:Diluent, filler, adhesive, Disintegrant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifier, sweetener, is rectified lubricant Taste agent, odor mask, colorant, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that certain pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which other Excipient.
Technical staff grasps the knowledge and skills of this field, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are resources obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press)。
In Remington:The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object acts on, or with interaction occurs for any other ingredient in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of compound, pays close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology and methods well known by persons skilled in the art.This field The description of some common methods can be found in Remington's Pharmaceutical Sciences(Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to the technique for preparing pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combination thereof, the technique include that mixing is each Kind ingredient.Include the pharmaceutical composition of disclosed compound of present invention, can be mixed under such as environment temperature and atmospheric pressure to make It is standby.
Compound disclosed by the invention is usually formulated as the dosage form for being suitable for administering to a patient by required approach.Example Such as, dosage form includes the dosage form that those are suitable for following administration route:(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent contains tablet, pulvis, syrup, elixir, suspension, solution, emulsion, sachet agent and cachet;(2) parenteral, example Such as sterile solution agent, suspension and redissolution powder;(3) cutaneous penetration, such as transdermal patch tablet;(4) rectally, such as bolt Agent;(5) it sucks, such as aerosol, solution and dry powder doses;(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
It will also be appreciated that certain compounds of the present invention can exist for treating in a free form, or if it is appropriate Can exist in the form of its pharmaceutically acceptable derivates.Some unrestricted implementations of pharmaceutically acceptable derivative Scheme includes pharmaceutically acceptable prodrug, salt, ester, the salt of these esters, or when patient in need is administered can directly or Any other adduct or derivative of compound of the present invention or its metabolite or residue are provided indirectly.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention can be with It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable pastille, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the substance packet for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, to prevent the acidic environment of active ingredient contacts stomach.Enteric coating includes, but are not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece can be conducive to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of substance.Film coating includes, but are not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses general characteristic identical with sweet tablet.It is multiple Tabletting is the compressed tablets by being prepared more than a press cycles, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active constituent are individual or are described with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colorant.Fumet and sweetener are particularly useful when forming chewable tablets and pastille.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard capsule, can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section It fills in another section, therefore encloses active constituent completely.Soft elastic capsules (SEC) are soft, spherical shell, such as gelatin shell, It is plasticized by the way that glycerine, sorbierite or similar polyalcohol is added.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative be as described in the present invention those, including methyl hydroxybenzoate and propylben and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution in propene carbonate, vegetable oil or triglycerides and suspension.Including the capsule of such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245;Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active constituent.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in pellet form in another liquid, It can be oil-in-water type or water-in-oil type.Emulsion may include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifier and Preservative.Suspension may include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions may include pharmaceutically may be used The acetal of receiving, for example, low alkyl group aldehyde two (low alkyl group) acetals, such as acetaldehyde diethyl acetal;With tool there are one or it is more The water-soluble solvent of a hydroxyl, such as propylene glycol and ethyl alcohol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and can also include preservative.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Pharmaceutical composition provided by the invention can be configured to be suitable for any dosage form to patient's inhalation, such as dry powder Agent, aerosol, suspension or liquid composite.In one embodiment, pharmaceutical composition disclosed in this invention can be prepared At suitable for the dosage form with dry powder doses to patient's inhalation.In yet another embodiment, pharmaceutical composition disclosed in this invention It can be configured to be suitable for the dosage form by sprayer to patient's inhalation.Dry powder composite by inhalation delivery to lung is usual Including fine powdered compound disclosed in this invention and one or more fine powdered pharmaceutically acceptable taxes Shape agent.Pharmaceutically acceptable excipient dawn known to those skilled in the art be especially suitable for dry powder doses comprising breast Sugar, starch, mannitol and mono-, two- and polysaccharide.Fine powder can be for example, by being micronized and grinding is prepared.It is general next It says, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value with laser diffractometry (for example, surveyed Amount) it defines.
Discontinuous patch agent can be prepared by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for local administration pharmaceutical composition can be formulated into ointment, cream, suspension, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix may include water, and/or oily example Such as atoleine and vegetable oil (such as peanut oil or castor oil) or solvent such as polyethylene glycol.It is used according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and Cellulose derivative and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
The compounds of this invention can also be combined with the soluble polymer as target medicine carrier.Such polymer packet Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or The oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can with realizing drug A kind of Biodegradable polymeric for using combines in control release, for example, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, Crosslinking or the amphiphilic block copolymer of polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body is administered.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any dosage form suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such dosage form can according to conventional method known to the technical staff in pharmaceutical science field come prepare (referring to Remington:The Science and Practice of Pharmacy, ibid).
The pharmaceutical composition for being intended for parenteral administration may include one or more pharmaceutically acceptable carriers and Excipient includes, but are not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and the dispersion of object growth Agent, wetting agent or emulsifier, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Pharmaceutical composition provided by the invention can be administered by rectal suppository, by by drug with it is suitable nonirritant Excipient (such as cupu oil, the glyceride of polyethylene glycol synthesis) mixing, be solid under room temperature, then in rectum intraluminal fluid Change or dissolving discharges drug.Due to individual difference, the severity of symptom will present bigger variation, and each medicine has Its unique treatment characteristic, therefore, for the accurate administering mode of each individual, dosage form and therapeutic scheme all should be by operation Doctor judges.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Term as used herein " therapeutically effective amount " refers to being enough to show each active component of beneficial therapeutic effect Total amount.For example, being administered or making the amount for the symptom for being enough to treat, curing or mitigating disease for reaching balance in vivo.Special controls Effective quantity needed for treatment scheme depends on many factors, includes the disease for the treatment of, the severity of disease, the certain drug used Activity, administering mode, the clearance rate of certain drug, duration for the treatment of, drug combination, the age, weight, gender, diet and The health etc. of patient.This field description as described in " therapeutically effective amount " other factors needed to be considered can be found in Gilman et al.,eds.,Goodman And Gilman's:The Pharmacological Bases of Therapeutics,8th ed.,Pergamon Press,1990;Remington's Pharmaceutical Sciences,17th ed.,Mack Publishing Company,Easton,Pa.,1990.The therapeutically effective amount of the compounds of this invention, typical total daily dose are 0.001-100mg/kg, preferably 0.05-10mg/kg.
Term " administration " shows the drug that individual provides therapeutically effective amount, and administering mode includes oral, sublingual, vein, skin Under, it is percutaneously, intramuscular, it is intradermal, it is intrathecal, on dura mater, intraocular, encephalic, sucking, rectum, vagina etc..Form of administration includes paste, is washed Agent, tablet, capsule, pill, dustability powder agent, granule, suppository, sublimed preparation, pastille, injection, sterile solution or non-aqueous Solution, suspending agent, emulsion, patch agent etc..Active component and nontoxic pharmaceutically acceptable carrier (such as glucose, lactose, Gum arabic, gelatin, mannitol, gelatinized corn starch, magnesium trisilicate, talcum powder, cornstarch, keratin, silica gel, potato starch, Urea, dextran etc.) it is compound.
Preferred administration route can change with Clinical symptoms, and the variation of dosage is necessarily dependent upon patient being treated The case where, doctor can determine suitable dosage according to individual patient.The therapeutically effective amount of per unit dose depends on weight, raw Manage the vaccination regimen of function and selection.The compound of per unit dose refers to the weight of compound when being administered every time, does not include carrying The weight (containing carrier in drug) of body.
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multi-dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art and practice.
Pharmaceutical composition provided by the invention can be common with the other active constituents that will not damage expected therapeutic effect Prepare, or with the substance co-formulation that is acted on expected from supplement.
In one embodiment, therapy of the invention includes that this hair of safe and effective amount is given to patient in need Bright compound or pharmaceutical composition comprising the compounds of this invention.Each embodiment of the present invention includes by patient in need It gives the compounds of this invention of safe and effective amount or the pharmaceutical composition comprising the compounds of this invention, is referred to treat the present invention Disease.
In one embodiment, the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be by any Suitable administration route is administered, including Formulations for systemic administration and local administration.Formulations for systemic administration include oral medication, parenteral, Cutaneous penetration and rectally.Typical parenteral refers to by injection or administered by infusion, including intravenous, intramuscular and skin Lower injection or administered by infusion.Local administration includes being applied to skin and intraocular, ear, intravaginal, sucking and intranasal administration.One In a embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be oral medications.Another In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalations.It is also real one It applies in scheme, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be intranasal administrations.
In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably be given Medicine, or according to dosage regimen, at the appointed time in section, doses at intervals is several times in different times.For example, daily administration one It is secondary, twice, three times or four times.In one embodiment, it is administered once a day.In yet another embodiment, it is taken twice daily. It can be administered until reaching desired therapeutic effect or indefinitely maintaining desired therapeutic effect.The compounds of this invention or comprising The appropriate dosage regimen of the pharmaceutical composition of the compounds of this invention depends on the pharmacokinetic property of the compound, such as inhales Receipts, distribution and half-life period, these can be by determination of technical staff.In addition, the compounds of this invention or including the compounds of this invention The appropriate dosage regimen of pharmaceutical composition, including implement the duration of the program, treated disease is depended on, disease is treated The severity of disease, the age of patient under consideration and physical condition, are thought the property of the medical history of patient under consideration while therapy The factor within the scope of technical staff's knowledge and experience such as therapeutic effect wanted.Such technical staff should also be understood that for Reaction of the individual patient to dosage regimen, or when individual patient needs variation as time goes by it may require that adjust it is suitable to Prescription case.
The compounds of this invention can simultaneously, or before it or later be administered with one or more other therapeutic agents.This hair Bright compound can be respectively administered with other therapeutic agents by identical or different administration route, or therewith with same pharmaceutical composition Form is administered.
In addition, the compounds of this invention can be administered with prodrug forms.In the present invention, " prodrug " of the compounds of this invention is When administering to a patient, the functional derivatives of the compounds of this invention can be finally released in vivo.This hair is given with prodrug forms When bright compound, those skilled in the art can implement one kind or more in following manner:(a) the internal action of compound is changed Time;(b) the internal acting duration of compound is changed;(c) the internal conveying or distribution of change compound;(d) modification Close the internal solubility of object;And the side effect for (e) overcoming compound to be faced or other difficult points.It is used to prepare the typical of prodrug Functional derivatives, including in vivo chemically or the variant of compound that cracks of the mode of enzyme.Including prepare phosphate, Amide, ester, monothioester, carbonate and carbaminate these variants be well-known to those skilled in the art.
The purposes of the compounds of this invention and composition
Compound and pharmaceutical composition provided by the invention can be used for preparing for protecting neuron, promoting nerve regneration And/or memory formed drug, can be used for prepare for treat with glutamate excitotoxicity, oxidativestress damage or from By the drug of the related disease of base or neurodegenerative disease.
Specifically, the amount of compound effectively detectably can selectively protect nerve in the composition of the present invention Member, term " protection neuron " refers to preventing neurotrosis, nerve degeneration and/or neuronal death (no matter reason or pathogen What is).
Specifically, the amount of compound effectively can detectably selectively promote nerve in the composition of the present invention Regeneration, term " regeneration " refer to that neuron regrows and carrys out repairing nerve damage.
Specifically, the amount of compound effectively can detectably selectively promote memory in the composition of the present invention It is formed.
Specifically, the amount of compound effectively detectably can selectively inhibit paddy ammonia in the composition of the present invention Sour excitatory toxicity, the compound of the present invention can be as the drug for treating disease related with glutamate excitotoxicity, institutes State disease related with glutamate excitotoxicity be Alzheimer disease, Huntington chorea, Parkinson's disease, severe flesh without Power, amyotrophic lateral sclerosis, senile dementia, glaucoma, bronchial asthma, hyperthyroidism, IV types egg high in fat White mass formed by blood stasis, hypertension or renal failure.
Specifically, the amount of compound effectively detectably selectively anti-oxidant can be answered in the composition of the present invention Swash, the compound of the present invention can be as the drug for treating disease related with oxidativestress damage or free radical, described and oxygen It is cerebral injury, headstroke, brain of neonatal rat on ischemia hypoxia, cerebral hemorrhage, Parkinson's disease, henry to change stress damage or the related disease of free radical The court of a feudal ruler chorea, epilepsy, amyotrophic lateral sclerosis, Alzheimer disease, dementia, ischemic heart disease, blood vessel bolt Liver disease caused by plug, hypercholesterolemia, atherosclerosis, diabetes, pulmonary emphysema, cataract, acute pancreatitis, alcohol Disease, kidney damage or cancer.
The compound of the present invention can be applied to, but be not limited to, and use the effective of the compound of the present invention or composition Amount administers to a patient to prevent, treat or mitigate neurodegenerative disease.The neurodegenerative disease, further comprises but simultaneously It is not limited to, hearing disability caused by Parkinson's disease, cerebral ischemia, Alzheimer disease, amyotrophic lateral sclerosis, aging, Dementia, retinosis, macular degeneration, glaucoma, bovine spongiform encephalopathy, Huntington chorea, gram refined Er Shi diseases, incoordination Telangiectasia, cerebral atrophy, spinal muscular atrophy, primary lateral sclerosis or multiple sclerosis.
The compound of the present invention and pharmaceutical composition to human treatment in addition to beneficial to other than, applying also for veterinary treatment and doting on Mammal in the animal of object, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat. This, the compound of the present invention includes its pharmaceutically acceptable derivates.
General synthesis step
For the description present invention, it is listed below embodiment.But it is to be understood that the present invention is not limited to these Examples, only The method that the practice present invention is provided.
Usually, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment is for being further illustrated this The content of invention.
The professional of fields will be recognized that:Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and other methods for the preparation of the compounds of the present invention are considered as the model in the present invention Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention It is completed by method of modifying, such as protection interference group appropriate, by using other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in quotient Product supplier such as AldrichChemical Company, Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Tenglong Chemical Reagent Co., Ltd. and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by sodium metal reflux.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopies are recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometers.1H H NMR spectroscopies are with CDC13, DMSO-d6,CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as with reference to mark It is accurate.When there is multiplet, following abbreviation will be used:S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, double doublet), dt (doublet of triplets, double triplets), td (tripletof doublets, three Doublet).Coupling constant is indicated with hertz (Hz).
The determination condition of Algorithm (MS) data is:6120 level four bars HPLC-M (column models of Agilent: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase:5%-95% (contains 0.1% The CH of formic acid3CN) (containing the H of 0.1% formic acid2O the ratio in), using electron spray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar types Number:NOVASEP 50/80mm DAC), it is detected with UV in 210nm/254nm.
The use of brief word below is through the present invention:
CH2Cl2, DCM dichloromethane;CDC13Deuterochloroform;DMF N,N-dimethylformamides;EtOAc, EA acetic acid second Ester;1,4-dioxane 1,4- dioxane;THF tetrahydrofurans;MeI, CH3I iodomethane;CH3COCl chloroacetic chlorides;Et3Tri- second of N Amine;DMAP 4-dimethylaminopyridine;Boc2O di-tert-butyl dicarbonates, Boc acid anhydrides;G grams;H hours;NaHCO3Sodium bicarbonate; NaH sodium hydrides;ML, ml milliliters;PE petroleum ethers (60-90 DEG C);RT, rt, r.t. room temperature;Rt retention times.
Following synthetic schemes describes the step of preparing disclosed compound of present invention, unless otherwise stated, wherein each R1,R2, R3,R4,R6With
R7With definition of the present invention.
Synthetic schemes 1
Compound (5) can be prepared by following process:Containing different substituents formula (1) compound represented with Boc acid anhydrides obtain formula (2) compound represented.Formula (2) compound represented and 2,4- dimethyl hydrazinobenzene hydrochloride salts obtain formula (3) Compound represented.Formula (3) compound represented and the acyl chlorides containing different substituents be obtained by the reaction in the presence of alkali formula (4) Compound represented.Formula (4) compound represented slough Boc obtain formula (5) compound represented.
Synthetic schemes 2
Compound (8) can be prepared by following process:Formula (1) compound represented containing different substituents with MeI obtains formula (6) compound represented.Formula (6) compound represented is obtained with 2,4- dimethyl hydrazinobenzene hydrochloride salts shown in formula (7) Compound.Formula (7) compound represented is obtained by the reaction with the acyl chlorides containing different substituents shown in formula (8) in the presence of alkali Compound.
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1 (E)-N'The conjunction of ((the fluoro- 1H- indol-3-yls of 5-) methylene)-N- (2,4- xylyls) acethydrazide At
The synthesis of the fluoro- 3- formyl indoles -1- carboxylic acid tert-butyl esters of step 1) 5-
By 5- fluoro indole -3- formaldehyde (0.5g, 3.07mmol), triethylamine (0.85mL, 6.14mmol), DMAP (0.036g, 0.3mmol) with dichloromethane (10mL), it is added sequentially in 100mL single necked round bottom flask, adds Boc2O(0.7mL, 3.07mmol), it then reacts 10 hours at room temperature, stops reaction, then direct column chromatography purifies (petrol ether/ethyl acetate (v/ V) it is white solid (0.77g, 95.5%)=10/1) to obtain title compound.
MS(ESI,pos.ion)m/z:286.2[M+Na]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.93 (s, 1H), 7.98 (dd, J=9.2,2.5Hz, 1H), 7.85 (d, J =3.1Hz, 1H), 7.41 (dd, J=8.8,4.1Hz, 1H), 7.10 (td, J=9.0,2.5Hz, 1H), 1.63 (s, 9H)
The conjunction of the fluoro- 3- of step 2) (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters At
By the fluoro- 3- formyl indoles -1- carboxylic acid tert-butyl esters (0.64g, 2.43mmol) of 5-, 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.42g, 2.43mmol) and DMF (10mL) are added sequentially in 100mL single necked round bottom flask, are reacted 1 hour at room temperature, are stopped Reaction, adds in 6mL saturated sodium bicarbonate solutions and hydrochloride, adds water (40mL), is precipitated without solid, is dissolved with ethyl acetate And (50mL × 2) are extracted, it washes (50mL × 2), collects ethyl acetate layer, it is yellow solid to be concentrated to give title compound (0.92g, 99%).
MS(ESI,pos.ion)m/z:382.2[M+H]+.
Step 3) (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) fluoro- indoles -1- carboxylic acids of -5- The synthesis of the tert-butyl ester
By the fluoro- 3- of (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters (0.92g, 2.41mmol), triethylamine (0.3mL, 2.41mmol) and dioxane (10mL) are added sequentially to 100mL single necked round bottom flask In, it is cooled to 0 DEG C, chloroacetic chloride (0.2mL, 2.89mmol) is slowly added dropwise, room temperature reaction 15h is transferred to after dripping, is stopped anti- It answers, it is white solid that then direct column chromatography purifying (petrol ether/ethyl acetate (v/v)=2/1), which obtains title compound, (0.66g, 65%).
MS(ESI,pos.ion)m/z:424.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.50 (s, 1H), 8.12 (s, 1H), 7.58 (s, 1H), 7.48 (dd, J= 8.7,1.7Hz, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 7.13 (d, J=7.8Hz, 1H), 6.93 (d, J=7.9Hz, 1H), 2.53(s,3H),2.42(s,3H),2.10(s,3H),1.63(s,9H).
Step 4) (E)-N'The synthesis of ((the fluoro- 1H- indol-3-yls of 5-) methylene)-N- (2,4- xylyls) acethydrazide
By (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) the fluoro- tertiary fourths of indoles -1- carboxylic acids of -5- Ester (0.65g, 0.86mmol) is added to 100mL single necked round bottom flask, then adds dioxane (10mL) and water (5mL) dissolving, 100 DEG C of reaction 7h are heated to, reaction is stopped, it is cooling, dioxane is concentrated, add methylene chloride (20mL) dissolving, and liquid separation is collected Dichloromethane layer, it is white solid (0.47g, 95%) to be concentrated to give title compound.
MS(ESI,pos.ion)m/z:324.1[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)9.22(s,1H),8.50(s,1H),7.35(s,1H),7.20-7.12 (m,3H),7.09(s,1H),6.99(s,1H),2.72(s,3H),2.30(s,3H),2.04(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)171.5,140.6,138.4,137.5,135.6,133.2,131.5, 130.6,129.1,128.5,127.0,125.4,124.6,118.6,114.0,112.6,22.3,21.8,17.8.
Embodiment 2 (E)-N'The conjunction of ((the chloro- 1H- indol-3-yls of 5-) methylene)-N- (2,4- xylyls) acethydrazide At
The synthesis of the chloro- 3- formyl indoles -1- carboxylic acid tert-butyl esters of step 1) 5-
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 5- chloro-indoles -3- Formaldehyde (0.5g, 2.79mmol), triethylamine (0.78mL, 5.58mmol), DMAP (0.034g, 0.28mmol) and Boc2O (0.64mL, 2.79mmol) is added to reaction in dichloromethane (10mL) and prepares, crude on silica gel column chromatography (petroleum ether/second Acetoacetic ester (v/v)=10/1), it is gray solid (0.73g, 94%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:302.2[M+Na]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.89 (s, 1H), 8.40 (s, 1H), 8.07 (d, J=2.0Hz, 1H), 7.56 (d, J=8.6Hz, 1H), 7.38 (dd, J=8.6,2.1Hz, 1H), 1.64 (s, 9H)
The conjunction of the chloro- 3- of step 2) (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters At
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by the chloro- 3- formyls of 5- Base indoles -1- carboxylic acid tert-butyl esters (0.7g, 2.51mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.42g, 2.51mmol) are added It is yellow solid (0.93g, 93%) that title compound, which is prepared, to reaction in DMF (10mL).
MS(ESI,pos.ion)m/z:398.1[M+H]+.
Step 3) (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) chloro- indoles -1- carboxylic acids of -5- The synthesis of the tert-butyl ester
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by the chloro- 3- formyls of 5- Base indoles -1- carboxylic acid tert-butyl esters (0.926g, 2.33mmol), triethylamine (0.32mL, 2.33mmol) and chloroacetic chloride (0.2mL, It 2.80mmol) is added to reaction in dioxane (5mL) to prepare, then direct column chromatography purifies (petrol ether/ethyl acetate (v/ V) it is white solid (0.635g, 62%)=2/1) to obtain title compound.
MS(ESI,pos.ion)m/z:440.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.55 (s, 1H), 8.20 (s, 1H), 7.62 (s, 1H), 7.54 (dd, J= 8.8,1.9Hz, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 7.14 (d, J=7.8Hz, 1H), 6.95 (d, J=7.9Hz, 1H), 2.52(s,3H),2.44(s,3H),2.12(s,3H),1.63(s,9H).
Step 4) (E)-N'The synthesis of ((the chloro- 1H- indol-3-yls of 5-) methylene)-N- (2,4- xylyls) acethydrazide
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e., by (E) -3- ((2- second Acyl group -2- (2,4- xylyls) hydrazono-) methyl) the chloro- indoles -1- carboxylic acid tert-butyl esters (0.62g, 1.41mmol) of -5- are dissolved in In dioxane (10mL) and water (5mL) prepared by reaction, has concentrated dioxane, and add methylene chloride (20mL) dissolving, and liquid separation is received Collect dichloromethane layer, it is white solid (0.44g, 93%) to be concentrated to give title compound.
MS(ESI,pos.ion)m/z:340.1[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)9.20(s,1H),8.51(s,1H),7.35(s,1H),7.15-7.09 (m,4H),7.02(s,1H),2.72(s,3H),2.43(s,3H),2.12(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)172.0,139.1,137.6,136.2,135.0,132.1,131.5, 129.4,129.1,128.5,127.1,126.0,125.0,115.4,114.0,113.2,22.2,21.5,17.0.
Embodiment 3 (E)-N'The conjunction of ((the bromo- 1H- indol-3-yls of 5-) methylene)-N- (2,4- xylyls) acethydrazide At
The synthesis of the bromo- 3- formyl indoles -1- carboxylic acid tert-butyl esters of step 1) 5-
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 5- bromo indoles -3- Formaldehyde (0.5g, 2.23mmol), triethylamine (0.63mL, 4.46mmol), DMAP (0.027g, 0.22mmol) and Boc2O (0.51mL, 2.23mmol) is added sequentially to reaction in dichloromethane (10mL) and prepares, crude on silica gel column chromatography (oil Ether/ethyl acetate (v/v)=10/1), it is gray solid (0.67g, 92.9%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:345.9[M+Na]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.92 (s, 1H), 8.34 (d, J=3.2Hz, 1H), 8.22 (d, J= 1.9Hz, 1H), 7.49 (d, J=8.6Hz, 1H), 7.39 (dd, J=8.6,2.0Hz, 1H), 1.64 (s, 9H)
The conjunction of the bromo- 3- of step 2) (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters At
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by the bromo- 3- formyls of 5- Base indoles -1- carboxylic acid tert-butyl esters (0.64g, 1.97mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.34g, 1.97mmol) are added It is yellow solid (0.87g, 99%) that title compound, which is prepared, to reaction in DMF (10mL).
MS(ESI,pos.ion)m/z:443.1[M+H]+.
Step 3) (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) bromo- indoles -1- carboxylic acids of -5- The synthesis of the tert-butyl ester
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by the bromo- 3- of (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters (0.626g, 1.42mmol), triethylamine (0.2mL, 1.42mmol) and chloroacetic chloride (0.12mL, 1.70mmol) are added sequentially to reaction in dioxane (5mL) and prepare, so Afterwards direct column chromatography purifying (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound be white solid (0.43g, 62%).
1H NMR(400MHz,CDCl3) δ (ppm) 8.52 (d, J=1.8Hz, 1H), 8.05 (d, J=8.7Hz, 1H), 7.60 (s, 1H), 7.50 (dd, J=8.8,1.9Hz, 1H), 7.25 (s, 1H), 7.22 (s, 1H), 7.18 (d, J=7.9Hz, 1H), 6.99 (d, J=7.9Hz, 1H), 2.72 (s, 3H), 2.40 (s, 3H), 2.06 (s, 3H), 1.64 (s, 9H)
Step 4) (E)-N'The synthesis of ((the bromo- 1H- indol-3-yls of 5-) methylene)-N- (2,4- xylyls) acethydrazide
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e., by (E) -3- ((2- second Acyl group -2- (2,4- xylyls) hydrazono-) methyl) the bromo- indoles -1- carboxylic acid tert-butyl esters (0.417g, 0.86mmol) of -5- are dissolved in In dioxane (7mL) and water (5mL) prepared by reaction, has concentrated dioxane, and add methylene chloride (20mL) dissolving, and liquid separation is received Collect dichloromethane layer, it is white solid (0.31g, 94%) to be concentrated to give title compound.
MS(ESI,pos.ion)m/z:384.1[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)9.25(s,1H),8.46(s,1H),7.31(s,1H),7.14-7.08 (m,4H),7.00(s,1H),2.74(s,3H),2.32(s,3H),2.05(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)172.6,139.6,137.4,136.7,135.5,132.2,131.9, 129.6,129.2,128.4,126.1,125.8,124.8,114.5,113.0,112.3,22.4,21.2,17.4.
Embodiment 4 (E)-N- (2,4- xylyls)-N'((5- Methyl-1H-indole -3- bases) methylene) acethydrazide Synthesis
The synthesis of step 1) 5- methyl -3- formyl indole -1- carboxylic acid tert-butyl esters
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 5- methyl indols- 3- formaldehyde (0.5g, 3.14mmol), triethylamine (0.87mL, 6.28mmol), DMAP (0.038g, 0.31mmol) and Boc2O (0.72mL, 3.14mmol) is added sequentially to reaction in dichloromethane (10mL) and prepares, crude on silica gel column chromatography (oil Ether/ethyl acetate (v/v)=10/1), it is white solid (0.77g, 95%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:260.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.71 (s, 1H), 8.65 (s, 1H), 8.00 (d, J=2.1Hz, 1H), 7.55 (d, J=8.5Hz, 1H), 7.36 (s, 1H), 2.33 (s, 3H), 1.64 (s, 9H)
Step 2) (E) -3- ((2- (2,4- xylyls) hydrazono-) methyl) tertiary fourth of -5- Methyl-1H-indole -1- carboxylic acids The synthesis of ester
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by 5- methyl -3- first Acyl indol -1- carboxylic acid tert-butyl esters (0.76g, 2.01mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.348g, 2.01mmol) It is yellow solid (1.08g, 98%) to be added to reaction in DMF (10mL) and title compound is prepared.
MS(ESI,pos.ion)m/z:378.2[M+H]+.
Step 3) (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) -5- Methyl-1H-indoles -1- The synthesis of carboxylic acid tert-butyl ester
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by (E) -3- ((2- (2,4- xylyls) hydrazono-) methyl) -5- Methyl-1H-indole -1- carboxylic acid tert-butyl esters (1g, 2.65mmol), triethylamine (0.37mL, 2.65mmol) and chloroacetic chloride (0.23mL, 3.18mmol) are added sequentially to reaction in dioxane (10mL) and prepare, Then direct column chromatography purifying (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound be white solid (0.64g, 58%).
MS(ESI,pos.ion)m/z:420.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.75 (s, 1H), 8.19 (s, 1H), 7.85 (d, J=8.6Hz, 1H), 7.55 (s, 1H), 7.47 (dd, J=8.7,1.8Hz, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 6.94 (s, 1H), 2.67 (s, 3H),2.40(s,3H),2.06(s,3H),2.04(s,3H),1.64(s,9H).
Step 4) (E)-N- (2,4- xylyls)-N'The conjunction of ((5- Methyl-1H-indole -3- bases) methylene) acethydrazide At
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e., by (E) -3- ((2- second Acyl group -2- (2,4- xylyls) hydrazono-) methyl) -5- Methyl-1H-indole -1- carboxylic acid tert-butyl esters (0.63g, 1.50mmol) It is dissolved in reaction in dioxane (10mL) and water (5mL) to prepare, has concentrated dioxane, add methylene chloride (20mL) dissolving, point Liquid collects dichloromethane layer, and it is white solid (0.45g, 94%) to be concentrated to give title compound.
MS(ESI,pos.ion)m/z:320.1[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)8.70(s,1H),8.05(s,1H),7.58(s,1H),7.25-7.14 (m,3H),7.16(s,1H),7.05(s,1H),2.68(s,3H),2.41(s,3H),2.05(s,3H),2.03(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)166.6,141.6,139.4,137.6,136.5,134.2,133.4, 130.6,129.6,127.7,126.9,126.8,125.7,115.4,114.2,113.3,22.4,21.9,21.0,17.3.
Embodiment 5 (E)-N- (2,4- xylyls)-N'The conjunction of ((the fluoro- 1H- indol-3-yls of 6-) methylene) acethydrazide At
The synthesis of the fluoro- 3- formyl indoles -1- carboxylic acid tert-butyl esters of step 1) 6-
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 6- fluoro indoles -3- Formaldehyde (0.5g, 3.07mmol), triethylamine (0.85mL, 6.14mmol), DMAP (0.038g, 0.31mmol) and Boc2O Prepared by (0.7mL, 3.07mmol) reaction in dichloromethane (10mL), crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1 it is white solid (0.77g, 95%)), to be concentrated and dried and obtain title compound.
MS(ESI,pos.ion)m/z:286.2[M+Na]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.74 (s, 1H), 8.51 (s, 1H), 8.15 (d, J=2.2Hz, 1H), 7.66 (d, J=8.8Hz, 1H), 7.42 (dd, J=8.6,2.2Hz, 1H), 1.64 (s, 9H)
The conjunction of the fluoro- 3- of step 2) (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters At
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by the fluoro- 3- formyls of 6- Base indoles -1- carboxylic acid tert-butyl esters (0.75g, 2.85mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.492g, 2.85mmol) exist In DMF (10mL) prepared by reaction, and it is yellow solid (1.02g, 94%) to obtain title compound.
MS(ESI,pos.ion)m/z:382.1[M+H]+.
Step 3) (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) fluoro- indoles -1- carboxylic acids of -6- The synthesis of the tert-butyl ester
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by the fluoro- 3- of (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters (1.00g, 2.62mmol), triethylamine (0.36mL, 2.62mmol) and chloroacetic chloride (0.22mL, 3.14mmol) are reacted in dioxane (10mL) to be prepared, then direct column It is white solid (0.78g, 70%) that chromatographic purifying (petrol ether/ethyl acetate (v/v)=2/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:424.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.45 (s, 1H), 8.23 (d, J=8.3Hz, 1H), 7.62 (s, 1H), 7.54 (d, J=8.3Hz, 1H), 7.34 (s, 1H), 7.26 (s, 1H), 7.19 (d, J=8.0Hz, 1H), 7.10 (d, J= 7.8Hz,1H),2.70(s,3H),2.41(s,3H),2.09(s,3H),1.64(s,9H).
Step 4) (E)-N- (2,4- xylyls)-N'The synthesis of ((the fluoro- 1H- indol-3-yls of 6-) methylene) acethydrazide
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e., by (E) -3- ((2- second Acyl group -2- (2,4- xylyls) hydrazono-) methyl) the fluoro- indoles -1- carboxylic acid tert-butyl esters (0.75g, 1.77mmol) of -6- are two Prepared by six ring of oxygen (10mL) and water (6mL) reaction, concentrated dioxane, and add methylene chloride (20mL) dissolving, and liquid separation collects two Chloromethanes layer, it is white solid (0.52g, 90%) to be concentrated to give title compound.
MS(ESI,pos.ion)m/z:324.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.46 (s, 1H), 8.24 (d, J=8.2Hz, 1H), 7.63 (s, 1H), 7.52 (d, J=7.9Hz, 1H), 7.32 (s, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 2.71 (s, 3H), 2.40(s,3H),2.06(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)167.4,141.5,139.6,137.4,136.8,134.2,133.8, 131.3,129.8,128.6,125.7,124.4,123.2,118.9,115.4,114.4,22.3,21.6,17.3.
Embodiment 6 (E)-N'The conjunction of ((the chloro- 1H- indol-3-yls of 6-) methylene)-N- (2,4- xylyls) acethydrazide At
The synthesis of the chloro- 3- formyl indoles -1- carboxylic acid tert-butyl esters of step 1) 6-
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 6- chloro-indoles -3- Formaldehyde (0.5g, 2.79mmol), triethylamine (0.78mL, 5.58mmol), DMAP (0.034g, 0.28mmol) and Boc2O Prepared by (0.64mL, 2.79mmol) reaction in dichloromethane (10mL), crude on silica gel column chromatography (petroleum ether/acetic acid second Ester (v/v)=10/1), it is white solid (0.76g, 97%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:302.1[M+Na]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.75 (s, 1H), 8.50 (s, 1H), 8.12 (d, J=1.9Hz, 1H), 7.66 (d, J=8.8Hz, 1H), 7.42 (dd, J=8.7,2.1Hz, 1H), 1.64 (s, 9H)
The conjunction of the chloro- 3- of step 2) (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters At
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by the chloro- 3- formyls of 6- Base indoles -1- carboxylic acid tert-butyl esters (0.75g, 2.69mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.464g, 2.69mmol) exist In DMF (10mL) prepared by reaction, and it is yellow solid (1.04g, 98%) to obtain title compound.
MS(ESI,pos.ion)m/z:398.2[M+H]+.
Step 3) (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) chloro- indoles -1- carboxylic acids of -6- The synthesis of the tert-butyl ester
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by the chloro- 3- of (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters (1g, 2.52mmol), triethylamine (0.35mL, It 2.52mmol) reacts and prepares in dioxane (10mL) with chloroacetic chloride (0.2mL, 3.02mmol), then direct column chromatography purifying It is white solid (0.77g, 70%) that (petrol ether/ethyl acetate (v/v)=2/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:440.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.47 (s, 1H), 8.28 (d, J=8.2Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=8.3Hz, 1H), 7.30 (s, 1H), 7.25 (s, 1H), 7.23 (d, J=7.8Hz, 1H), 7.05 (d, J= 7.9Hz,1H),2.68(s,3H),2.40(s,3H),2.07(s,3H),1.65(s,9H).
Step 4) (E)-N'The synthesis of ((the chloro- 1H- indol-3-yls of 6-) methylene)-N- (2,4- xylyls) acethydrazide
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e., by (E) -3- ((2- second Acyl group -2- (2,4- xylyls) hydrazono-) methyl) the chloro- indoles -1- carboxylic acid tert-butyl esters (0.75g, 1.71mmol) of -6- are two Prepared by six ring of oxygen (10mL) and water (6mL) reaction, concentrated dioxane, and add methylene chloride (20mL) dissolving, and liquid separation collects two Chloromethanes layer, it is white solid (0.56g, 97%) to be concentrated to give title compound.
MS(ESI,pos.ion)m/z:340.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.48 (s, 1H), 8.27 (d, J=7.8Hz, 1H), 7.62 (s, 1H), 7.56 (d, J=6.9Hz, 1H), 7.32 (s, 1H), 7.20 (s, 1H), 7.17 (d, J=7.8Hz, 1H), 7.11 (s, 1H), 2.70 (s,3H),2.38(s,3H),2.06(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)170.4,147.5,139.6,138.1,136.9,134.1,133.1, 131.3,129.4,128.5,126.8,125.4,124.1,117.8,115.4,113.6,22.0,21.1,18.4.
Embodiment 7 (E)-N'The conjunction of ((the bromo- 1H- indol-3-yls of 6-) methylene)-N- (2,4- xylyls) acethydrazide At
The synthesis of the bromo- 3- formyl indoles -1- carboxylic acid tert-butyl esters of step 1) 6-
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 6- bromo indoles -3- Formaldehyde (0.5g, 2.23mmol), triethylamine (0.63mL, 4.46mmol), DMAP (0.027g, 0.22mmol) and Boc2O Prepared by (0.51mL, 2.23mmol) reaction in dichloromethane (10mL), crude on silica gel column chromatography (petroleum ether/acetic acid second Ester (v/v)=10/1), it is white solid (0.67g, 92.0%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:346.0[M+Na]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.78 (s, 1H), 8.45 (s, 1H), 8.10 (d, J=2.0Hz, 1H), 7.65 (d, J=8.7Hz, 1H), 7.40 (dd, J=8.6,2.2Hz, 1H), 1.63 (s, 9H)
The conjunction of the bromo- 3- of step 2) (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters At
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by the bromo- 3- formyls of 6- Base indoles -1- carboxylic acid tert-butyl esters (0.66g, 2.04mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.35g, 2.04mmol) exist In DMF (10mL) prepared by reaction, and it is yellow solid (0.85g, 94.4%) to obtain title compound.
MS(ESI,pos.ion)m/z:443.1[M+H]+.
Step 3) (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) bromo- indoles -1- carboxylic acids of -6- The synthesis of the tert-butyl ester
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by the bromo- 3- of (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) indoles -1- carboxylic acid tert-butyl esters (0.85g, 1.92mmol), triethylamine Prepared by the reaction in dioxane (10mL) of (0.27mL, 1.92mmol) and chloroacetic chloride (0.16mL, 2.30mmol), then directly It is white solid (0.61g, 65%) that column chromatography purifying (petrol ether/ethyl acetate (v/v)=2/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:484.0[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.42 (s, 1H), 8.22 (d, J=8.4Hz, 1H), 7.59 (s, 1H), 7.51 (d, J=8.4Hz, 1H), 7.29 (s, 1H), 7.24 (s, 1H), 7.20 (d, J=7.9Hz, 1H), 7.02 (d, J= 7.8Hz,1H),2.72(s,3H),2.42(s,3H),2.08(s,3H),1.66(s,9H).
Step 4) (E)-N'The synthesis of ((the bromo- 1H- indol-3-yls of 6-) methylene)-N- (2,4- xylyls) acethydrazide
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e., by (E) -3- ((2- second Acyl group -2- (2,4- xylyls) hydrazono-) methyl) the bromo- indoles -1- carboxylic acid tert-butyl esters (0.5g, 1.03mmol) of -6- are in dioxy In six rings (10mL) and water (6mL) prepared by reaction, has concentrated dioxane, and add methylene chloride (20mL) dissolving, and liquid separation collects two Chloromethanes layer, it is white solid (0.35g, 87%) to be concentrated to give title compound.
MS(ESI,pos.ion)m/z:384.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.64 (s, 1H), 8.19 (d, J=7.7Hz, 1H), 7.50 (s, 1H), 7.37 (d, J=6.9Hz, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 7.15 (s, 1H), 7.01-7.00 (m, 1H), 2.71 (s, 3H),2.36(s,3H),2.06(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)172.4,139.5,137.6,137.1,136.7,132.2,131.9, 129.3,128.8,128.4,124.7,123.4,123.1,116.9,114.4,113.3,22.5,21.2,17.4.
Embodiment 8 (E)-N- (2,4- xylyls)-N'((6- Methyl-1H-indole -3- bases) methylene) acethydrazide Synthesis
The synthesis of step 1) 6- methyl -3- formyl indole -1- carboxylic acid tert-butyl esters
This step title compound method with reference to described in 1 step 1 of embodiment is prepared, i.e., by 6- methyl indols- 3- formaldehyde (0.5g, 3.14mmol), triethylamine (0.87mL, 6.28mmol), DMAP (0.038g, 0.31mmol) and Boc2O (0.72mL, 3.14mmol) is added sequentially to reaction in dichloromethane (10mL) and prepares, crude on silica gel column chromatography (oil Ether/ethyl acetate (v/v)=10/1), it is white solid (0.79g, 97%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:260.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.70 (s, 1H), 8.66 (s, 1H), 8.13 (d, J=2.2Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 7.40 (s, 1H), 2.35 (s, 3H), 1.63 (s, 9H)
Step 2) (E) -3- ((2- (2,4- xylyls) hydrazono-) methyl) tertiary fourth of -6- Methyl-1H-indole -1- carboxylic acids The synthesis of ester
This step title compound method with reference to described in 1 step 2 of embodiment is prepared, i.e., by 6- methyl -3- first Acyl indol -1- carboxylic acid tert-butyl esters (0.77g, 2.97mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.513g, 2.97mmol) It is yellow solid (1.09g, 97%) to be added to reaction in DMF (10mL) and title compound is prepared.
MS(ESI,pos.ion)m/z:378.2[M+H]+.
Step 3) (E) -3- ((2- acetyl group -2- (2,4- xylyls) hydrazono-) methyl) -6- Methyl-1H-indoles -1- The synthesis of carboxylic acid tert-butyl ester
This step title compound method with reference to described in 1 step 3 of embodiment is prepared, i.e., by (E) -3- ((2- (2,4- xylyls) hydrazono-) methyl) -6- Methyl-1H-indole -1- carboxylic acid tert-butyl esters (1.09g, 2.89mmol), triethylamine (0.4mL, 2.89mmol) and chloroacetic chloride (0.25mL, 3.47mmol) are added to reaction in dioxane (20mL) and prepare, then Direct column chromatography purifying (petrol ether/ethyl acetate (v/v)=2/1) obtain title compound be white solid (0.75g, 62%).
MS(ESI,pos.ion)m/z:420.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.74 (s, 1H), 8.20 (s, 1H), 7.87 (d, J=8.7Hz, 1H), 7.56 (s, 1H), 7.48 (dd, J=8.7,1.7Hz, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 6.97 (s, 1H), 2.68 (s, 3H),2.42(s,3H),2.07(s,3H),2.05(s,3H),1.63(s,9H).
Step 4) (E)-N- (2,4- xylyls)-N'The conjunction of ((6- Methyl-1H-indole -3- bases) methylene) acethydrazide At
This step title compound method with reference to described in 1 step 4 of embodiment is prepared, i.e., by (E) -3- ((2- second Acyl group -2- (2,4- xylyls) hydrazono-) methyl) -6- Methyl-1H-indole -1- carboxylic acid tert-butyl esters (0.74g, 1.77mmol) It is dissolved in reaction in dioxane (10mL) and water (5mL) to prepare, has concentrated dioxane, add methylene chloride (20mL) dissolving, point Liquid collects dichloromethane layer, and it is white solid (0.54g, 96%) to be concentrated to give title compound.
MS(ESI,pos.ion)m/z:320.2[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)8.73(s,1H),8.11(s,1H),7.60(s,1H),7.27-7.17 (m,3H),7.15(s,1H),7.07(s,1H),2.68(s,3H),2.42(s,3H),2.07(s,3H),2.05(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)165.6,142.7,139.7,138.4,136.4,134.6,133.2, 131.6,129.5,127.8,126.7,126.5,125.6,115.4,114.3,113.2,22.3,21.7,21.2,17.1.
Embodiment 9 (E)-N'((the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
The synthesis of the fluoro- 1- methyl indols -3- formaldehyde of step 1) 5-
5- fluoro indole -3- formaldehyde (0.5g, 3.07mmol) and tetrahydrofuran (10mL) are added sequentially to 100mL single port circle In the flask of bottom, it is cooled to 0 DEG C, is slowly added into NaH (60%, 196mg, 4.91mmol), after reacting 10min, is transferred at room temperature 1h is reacted, then adds MeI (0.38mL, 6.14mmol), 15.5h is reacted at room temperature, adds water (5mL) to be quenched, concentrated tetrahydrofuran, Add ethyl acetate (40mL × 1) extract, wash (20mL × 3), collect ethyl acetate, then mix sample column chromatography purifying (petroleum ether/ Ethyl acetate (v/v)=5/1) title compound is obtained as white solid (0.50g, 92%).
MS(ESI,pos.ion)m/z:178.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.85 (s, 1H), 8.40 (d, J=3.3Hz, 1H), 8.15 (d, J= 2.0Hz, 1H), 7.55 (d, J=8.5Hz, 1H), 7.42 (s, 1H), 3.68 (s, 3H)
The synthesis of the fluoro- 3- of step 2) (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles
By the fluoro- 1- methyl indols -3- formaldehyde (0.49g, 2.77mmol) of 5-, 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.478g, It 2.77mmol) is added sequentially in 100mL single necked round bottom flask with DMF (10mL), reacts 1 hour at room temperature, stop reaction, add In 6mL saturated sodium bicarbonate solutions and hydrochloride, (40mL) is added water, is precipitated without solid, ethyl acetate is added to dissolve and extract (40mL × 2), wash (30mL × 3), collect ethyl acetate layer, be concentrated to give title compound be yellow solid (0.82g, 90%).
MS(ESI,pos.ion)m/z:296.2[M+H]+.
Step 3) (E)-N'((the fluoro- 1- Methyl-1H-indoles -3- bases of 5-) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
By the fluoro- 3- of (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles (0.81g, 2.74mmol), triethylamine (0.38mL, 2.74mmol) and dioxane (10mL) are successively in 100mL single necked round bottom flask, drop Chloroacetic chloride (0.23mL, 3.29mmol) is slowly added dropwise to 0 DEG C in temperature, and room temperature reaction 12h is transferred to after dripping, stops reaction, so Afterwards direct column chromatography purifying (petrol ether/ethyl acetate (v/v)=3/1) obtain title compound be white solid (0.52g, 56%).
MS(ESI,pos.ion)m/z:338.0[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.50 (s, 1H), 7.42 (d, J=8.3Hz, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 7.18-7.16 (m, 2H), 7.11 (s, 1H), 7.05 (d, J=7.8Hz, 1H), 3.69 (s, 3H), 2.70 (s, 3H),2.38(s,3H),2.10(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)171.1,140.3,137.7,136.5,136.2,134.1,133.2, 132.4,129.6,128.7,126.6,125.8,125.2,115.1,112.3,111.0,33.0,22.5,21.3,17.4.
Embodiment 10 (E)-N'((the chloro- 1- Methyl-1H-indoles -3- bases of 5-) methylene)-N- (2,4- xylyls) second Hydrazides
The synthesis of the chloro- 1- methyl indols -3- formaldehyde of step 1) 5-
This step title compound method with reference to described in 9 step 1 of embodiment is prepared, i.e., by 5- chloro-indoles -3- Formaldehyde (0.5g, 2.79mmol), NaH (60%, 178mg, 4.47mmol) and MeI (0.35mL, 5.58mmol) sequentially add four In hydrogen furans (10mL) prepared by reaction, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1), is concentrated and dried It is gray solid (0.51g, 94%) to obtain title compound.
MS(ESI,pos.ion)m/z:194.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.83 (s, 1H), 8.39 (d, J=3.5Hz, 1H), 8.17 (d, J= 2.1Hz, 1H), 7.56 (d, J=8.6Hz, 1H), 7.43 (s, 1H), 3.68 (s, 3H)
The synthesis of the chloro- 3- of step 2) (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles
This step title compound method with reference to described in 9 step 2 of embodiment is prepared, i.e., by the chloro- 1- methyl of 5- Indole -3-formaldehyde (0.5g, 2.59mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.447g, 2.59mmol) are added to DMF It is yellow solid (0.76g, 94%) that title compound, which is prepared, in reaction in (10mL).
MS(ESI,pos.ion)m/z:312.1[M+H]+.
Step 3) (E)-N'((the chloro- 1- Methyl-1H-indoles -3- bases of 5-) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
This step title compound method with reference to described in 9 step 3 of embodiment is prepared, i.e., by the chloro- 3- of (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles (0.757g, 2.43mmol), triethylamine (0.34mL, It 2.43mmol) is added to reaction in dioxane (10mL) with chloroacetic chloride (0.21mL, 2.92mmol) and prepares, then direct column layer It is white solid (0.52g, 60%) that analysis purifying (petrol ether/ethyl acetate (v/v)=2/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:354.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.60 (s, 1H), 8.35 (s, 1H), 7.65 (s, 1H), 7.56 (dd, J= 8.7,1.8Hz, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 7.16 (d, J=7.7Hz, 1H), 7.02 (d, J=7.8Hz, 1H), 3.68(s,3H),2.46(s,3H),2.15(s,3H),2.09(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)167.1,140.3,137.7,136.5,136.1,134.2,133.1, 132.5,129.7,128.5,126.7,126.2,125.5,116.5,113.3,112.9,33.1,22.1,21.2,17.0.
Embodiment 11 (E)-N'((the bromo- 1- Methyl-1H-indoles -3- bases of 5-) methylene)-N- (2,4- xylyls) second The synthesis of hydrazides
The synthesis of the bromo- 1- methyl indols -3- formaldehyde of step 1) 5-
This step title compound method with reference to described in 9 step 1 of embodiment is prepared, i.e., by 5- bromo indoles -3- Formaldehyde (0.5g, 2.23mmol), NaH (60%, 143mg, 3.57mmol) and MeI (0.28mL, 4.46mmol) are dissolved in tetrahydrochysene furan Prepared by (10mL) middle reaction of muttering, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1), concentrate drying obtains Title compound is white solid (0.48g, 90.1%).
MS(ESI,pos.ion)m/z:238.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.89 (s, 1H), 8.32 (d, J=3.2Hz, 1H), 8.12 (d, J= 1.9Hz, 1H), 7.50 (d, J=8.6Hz, 1H), 7.40 (dd, J=8.6,2.0Hz, 1H), 3.70 (s, 3H)
The synthesis of the bromo- 3- of step 2) (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles
This step title compound method with reference to described in 9 step 2 of embodiment is prepared, i.e., by the bromo- 1- methyl of 5- Indole -3-formaldehyde (0.47g, 1.97mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.34g, 1.97mmol) are added to DMF It is yellow solid (0.60g, 85.3%) that title compound, which is prepared, in reaction in (10mL).
MS(ESI,pos.ion)m/z:356.1[M+H]+.
Step 3) (E)-N'((the bromo- 1- Methyl-1H-indoles -3- bases of 5-) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
This step title compound method with reference to described in 9 step 3 of embodiment is prepared, i.e., by the bromo- 3- of (E) -5- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles (0.6g, 1.68mmol), triethylamine (0.24mL, It 1.68mmol) is added to reaction in dioxane (10mL) with chloroacetic chloride (0.14mL, 2.0mmol) and prepares, then direct column layer It is white solid (0.30g, 67%) that analysis purifying (petrol ether/ethyl acetate (v/v)=3/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:398.0[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.47 (s, 1H), 7.40 (d, J=8.4Hz, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 7.17-7.15 (m, 2H), 7.09 (s, 1H), 7.00 (d, J=7.7Hz, 1H), 3.73 (s, 3H), 2.72 (s, 3H),2.39(s,3H),2.06(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)172.1,139.3,136.7,136.4,136.3,133.2,132.1, 132.0,129.3,128.3,126.4,125.9,125.0,114.6,111.3,110.9,33.2,22.3,21.2,17.3.
Embodiment 12 (E)-N'((1,5- dimethyl -1H- indol-3-yls) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
The synthesis of step 1) 1,5- dimethyl -1H- indole -3-formaldehydes
This step title compound method with reference to described in 9 step 1 of embodiment is prepared, i.e., by 5- methyl indols- 3- formaldehyde (0.5g, 3.14mmol), NaH (60%, 200mg, 5.02mmol) and MeI (0.39mL, 6.28mmol) are dissolved in tetrahydrochysene In furans (10mL) prepared by reaction, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), is concentrated and dried It is white solid (0.51g, 93%) to obtain title compound.MS(ESI,pos.ion)m/z:174.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.72 (s, 1H), 8.64 (s, 1H), 8.02 (d, J=2.0Hz, 1H), 7.56 (d, J=8.6Hz, 1H), 7.35 (s, 1H), 3.69 (s, 3H), 2.34 (s, 3H)
The synthesis of step 2) (E) -3- ((2- (2,4- xylyls) hydrazono-) methyl) -1,5- dimethyl -1H- indoles
This step title compound method with reference to described in 9 step 2 of embodiment is prepared, i.e., by 1,5- dimethyl- 1H- indole -3-formaldehydes (0.5g, 2.89mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.499g, 2.89mmol) are added to DMF It is yellow solid (0.76g, 90%) that title compound, which is prepared, in reaction in (10mL).
MS(ESI,pos.ion)m/z:292.2[M+H]+.
Step 3) (E)-N'((1,5- dimethyl -1H- indol-3-yls) methylene)-N- (2,4- xylyls) acethydrazide Synthesis
This step title compound method with reference to described in 9 step 3 of embodiment is prepared, i.e., by (E) -3- ((2- (2,4- xylyls) hydrazono-) methyl) -1,5- dimethyl -1H- indoles (0.757g, 2.60mmol), triethylamine (0.36mL, It 2.60mmol) is added to reaction in dioxane (10mL) with chloroacetic chloride (0.22mL, 3.12mmol) and prepares, then direct column layer It is white solid (0.53g, 61%) that analysis purifying (petrol ether/ethyl acetate (v/v)=3/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:334.1[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)8.69(s,1H),8.10(s,1H),7.60(s,1H),7.24-7.18 (m,3H),7.20(s,1H),7.08(s,1H),3.68(s,3H),2.36(s,3H),2.34(s,3H),2.10(s,3H),2.05 (s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)167.4,142.3,139.5,137.8,136.7,135.2,134.1, 132.6,129.5,127.8,127.1,126.5,125.6,115.3,114.4,112.9,33.8,22.5,21.8,21.1, 17.5.
Embodiment 13 (E)-N'((the fluoro- 1- Methyl-1H-indoles -3- bases of 6-) methylene)-N- (2,4- xylyls) second The synthesis of hydrazides
The synthesis of the fluoro- 1- methyl indols -3- formaldehyde of step 1) 6-
This step title compound method with reference to described in 9 step 1 of embodiment is prepared, i.e., by 6- fluoro indoles -3- Formaldehyde (0.5g, 3.07mmol), NaH (60%, 196mg, 4.91mmol) and MeI (0.38mL, 6.14mmol) are dissolved in tetrahydrochysene furan Prepared by (10mL) middle reaction of muttering, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1), concentrate drying obtains Title compound is white solid (0.51g, 94%).MS(ESI,pos.ion)m/z:178.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.84 (s, 1H), 8.41 (d, J=3.3Hz, 1H), 8.16 (d, J= 2.0Hz, 1H), 7.56 (d, J=8.5Hz, 1H), 7.42 (s, 1H), 3.69 (s, 3H)
The synthesis of the fluoro- 3- of step 2) (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles
This step title compound method with reference to described in 9 step 2 of embodiment is prepared, i.e., by the fluoro- 1- methyl of 6- Indole -3-formaldehyde (0.5g, 2.82mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.488g, 2.82mmol) are added to DMF It is yellow solid (0.79g, 95%) that title compound, which is prepared, in reaction in (10mL).
MS(ESI,pos.ion)m/z:296.2[M+H]+.
Step 3) (E)-N'((the fluoro- 1- Methyl-1H-indoles -3- bases of 6-) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
This step title compound method with reference to described in 9 step 3 of embodiment is prepared, i.e., by the fluoro- 3- of (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles (0.79g, 2.68mmol), triethylamine (0.37mL, It 2.68mmol) is added to reaction in dioxane (10mL) with chloroacetic chloride (0.23mL, 3.21mmol) and prepares, then direct column layer It is white solid (0.50g, 55%) that analysis purifying (petrol ether/ethyl acetate (v/v)=3/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:338.0[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.51 (s, 1H), 7.44 (d, J=8.4Hz, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 7.17-7.15 (m, 2H), 7.12 (s, 1H), 7.07 (d, J=7.8Hz, 1H), 3.68 (s, 3H), 2.71 (s, 3H),2.37(s,3H),2.09(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)169.0,141.2,138.1,137.6,136.1,135.0,133.4, 132.1,130.1,129.7,127.6,125.4,125.1,115.3,112.6,112.0,33.2,22.3,21.2,17.1.
Embodiment 14 (E)-N'((the chloro- 1- Methyl-1H-indoles -3- bases of 6-) methylene)-N- (2,4- xylyls) second The synthesis of hydrazides
The synthesis of the chloro- 1- methyl indols -3- formaldehyde of step 1) 6-
This step title compound method with reference to described in 9 step 1 of embodiment is prepared, i.e., by 6- chloro-indoles -3- Tetrahydrochysene furan is added in formaldehyde (0.5g, 2.79mmol), NaH (60%, 178mg, 4.47mmol) and MeI (0.35mL, 5.58mmol) Prepared by (10mL) middle reaction of muttering, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1), concentrate drying obtains Title compound is gray solid (0.52g, 97%).MS(ESI,pos.ion)m/z:194.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 9.84 (s, 1H), 8.40 (d, J=3.5Hz, 1H), 8.15 (d, J= 2.1Hz, 1H), 7.57 (d, J=8.6Hz, 1H), 7.41 (s, 1H), 3.68 (s, 3H)
The synthesis of the chloro- 3- of step 2) (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles
This step title compound method with reference to described in 9 step 2 of embodiment is prepared, i.e., by the chloro- 1- methyl of 6- Indole -3-formaldehyde (0.5g, 2.59mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.447g, 2.59mmol) are added to DMF It is yellow solid (0.79g, 98%) that title compound, which is prepared, in reaction in (10mL).
MS(ESI,pos.ion)m/z:312.1[M+H]+.
Step 3) (E)-N'((the chloro- 1- Methyl-1H-indoles -3- bases of 6-) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
This step title compound method with reference to described in 9 step 3 of embodiment is prepared, i.e., by the chloro- 3- of (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles (0.789g, 2.54mmol), triethylamine (0.35mL, It 2.54mmol) is added to reaction in dioxane (10mL) with chloroacetic chloride (0.21mL, 3.05mmol) and prepares, then direct column layer It is white solid (0.48g, 54%) that analysis purifying (petrol ether/ethyl acetate (v/v)=2/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:354.1[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.60 (s, 1H), 8.36 (s, 1H), 7.64 (s, 1H), 7.57 (dd, J= 8.7,1.1Hz, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 7.12 (d, J=7.8Hz, 1H), 7.04 (d, J=7.7Hz, 1H), 3.69(s,3H),2.45(s,3H),2.12(s,3H),2.08(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)167.0,141.3,138.7,136.7,136.0,134.1,133.4, 132.2,129.6,128.4,126.6,126.1,125.4,116.3,114.3,113.9,33.0,21.9,21.3,17.1.
Embodiment 15 (E)-N'((the bromo- 1- Methyl-1H-indoles -3- bases of 6-) methylene)-N- (2,4- xylyls) second The synthesis of hydrazides
The synthesis of the bromo- 1- methyl indols -3- formaldehyde of step 1) 6-
This step title compound method with reference to described in 9 step 1 of embodiment is prepared, i.e., by 6- bromo indoles -3- Tetrahydrofuran is added in formaldehyde (0.5g, 2.23mmol), NaH (60%, 143mg, 3.57mmol) and MeI (0.28mL, 4.5mmol) In (10mL) prepared by reaction, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=5/1), and concentrate drying is marked Topic compound is white solid (0.53g, 99.7%).MS(ESI,pos.ion)m/z:238.1[M+H]+;
1H NMR(400MHz,DMSO-d6) δ (ppm) 9.80 (s, 1H), 8.50 (s, 1H), 8.09 (d, J=8.2Hz, 1H), 7.77 (s, 1H), 7.46 (d, J=8.1Hz, 1H), 3.65 (s, 3H)
The synthesis of the bromo- 3- of step 2) (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles
This step title compound method with reference to described in 9 step 2 of embodiment is prepared, i.e., by the bromo- 1- methyl of 6- Indole -3-formaldehyde (0.5g, 2.11mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.364g, 2.11mmol) are added to DMF It is yellow solid (0.64g, 86.0%) that title compound, which is prepared, in reaction in (10mL).
MS(ESI,pos.ion)m/z:356.1[M+H]+.
Step 3) (E)-N'((the bromo- 1- Methyl-1H-indoles -3- bases of 6-) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
This step title compound method with reference to described in 9 step 3 of embodiment is prepared, i.e., by the bromo- 3- of (E) -6- ((2- (2,4- xylyls) hydrazono-) methyl) -1- Methyl-1H-indoles (0.63g, 1.77mmol), triethylamine (0.25mL, It 1.77mmol) is added to reaction in dioxane (10mL) with chloroacetic chloride (0.15mL, 2.12mmol) and prepares, then direct column layer It is white solid (0.47g, 70%) that analysis purifying (petrol ether/ethyl acetate (v/v)=3/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:398.2[M+H]+;
1H NMR(400MHz,CDCl3) δ (ppm) 8.20 (d, J=8.4Hz, 1H), 7.44 (s, 1H), 7.37 (d, J= 8.3Hz, 1H), 7.31 (s, 1H), 7.19 (s, 1H), 7.15 (d, J=7.7Hz, 1H), 7.01 (d, J=8.3Hz, 1H), 6.99 (s,1H),3.63(s,3H),2.71(s,3H),2.38(s,3H),2.08(s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)171.8,139.1,138.3,136.6,136.5,132.9,131.9, 131.8,129.1,128.1,124.0,123.4,123.3,116.5,112.4,111.6,32.8,22.2,21.0,17.2.
Embodiment 16 (E)-N'((1,6- dimethyl -1H- indol-3-yls) methylene)-N- (2,4- xylyls) acetyl The synthesis of hydrazine
The synthesis of step 1) 1,6- dimethyl -1H- indole -3-formaldehydes
This step title compound method with reference to described in 9 step 1 of embodiment is prepared, i.e., by 6- methyl indols- 3- formaldehyde (0.5g, 3.14mmol), NaH (60%, 200mg, 5.02mmol) and MeI (0.39mL, 6.28mmol) are dissolved in tetrahydrochysene In furans (10mL) prepared by reaction, crude on silica gel column chromatography (petrol ether/ethyl acetate (v/v)=10/1), is concentrated and dried It is white solid (0.50g, 91%) to obtain title compound.MS(ESI,pos.ion)m/z:174.1[M+H]+;
1H NMR(400MHz,CDCl3) δ 9.70 (s, 1H), 8.64 (s, 1H), 8.01 (d, J=2.0Hz, 1H), 7.55 (d, J=8.5Hz, 1H), 7.34 (s, 1H), 3.68 (s, 3H), 2.33 (s, 3H)
The synthesis of step 2) (E) -3- ((2- (2,4- xylyls) hydrazono-) methyl) -1,6- dimethyl -1H- indoles
This step title compound method with reference to described in 9 step 2 of embodiment is prepared, i.e., by 1,6- dimethyl- 1H- indole -3-formaldehydes (0.495g, 2.86mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.494g, 2.86mmol) are added to It is yellow solid (0.77g, 92%) that title compound, which is prepared, in reaction in DMF (10mL).
MS(ESI,pos.ion)m/z:292.2[M+H]+.
Step 3) (E)-N'((1,6- dimethyl -1H- indol-3-yls) methylene)-N- (2,4- xylyls) acethydrazide Synthesis
This step title compound method with reference to described in 9 step 3 of embodiment is prepared, i.e., by (E) -3- ((2- (2,4- xylyls) hydrazono-) methyl) -1,6- dimethyl -1H- indoles (0.766g, 2.63mmol), triethylamine (0.36mL, It 2.63mmol) is added to reaction in dioxane (10mL) with chloroacetic chloride (0.22mL, 3.15mmol) and prepares, then direct column layer It is white solid (0.45g, 51%) that analysis purifying (petrol ether/ethyl acetate (v/v)=3/1), which obtains title compound,.
MS(ESI,pos.ion)m/z:334.1[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)8.70(s,1H),8.11(s,1H),7.62(s,1H),7.27-7.20 (m,3H),7.14(s,1H),7.10(s,1H),3.67(s,3H),2.40(s,3H),2.35(s,3H),2.11(s,3H),2.06 (s,3H);
13C NMR(151MHz,CDCl3)δ(ppm)167.3,145.3,139.6,138.1,136.4,135.1,134.2, 132.2,129.1,127.4,127.0,126.2,125.1,116.3,114.5,113.9,33.1,22.4,21.7,21.2, 17.1.
Biologic test
Embodiment A:Evaluate protective effect of the compound to the HT22 cellular oxidation stress damages of glutamate induction
Experimental method
Recovery HT22 cells (mouse hippocampal neuron cell), by the cell of exponential phase according to 4 × 104A/mL is close It spends and is seeded to 96 orifice plates (100 μ L), 37 DEG C, 5%CO2Incubator, culture is for 24 hours.Experimental day discards culture medium in hole, according to reality Test requirement, per hole be added 150 μ L compound working solutions (untested compound is subjected to gradient dilution with 100%DMSO, totally 10 it is dense Gradient is spent, is then diluted to working concentration with the culture medium (DMEM+10%FBS+1%PS) containing 15mM glutamic acid.DMSO is whole A concentration of 0.25%.), 37 DEG C, 5%CO2Incubator is protected from light incubation 24 hours.Terminate after being incubated, according to lactic dehydrogenase cell Toxicity detection kit operation instruction carries out lactic dehydrogenase enzyme r e lease detection.Cell viability is calculated according to result.% Viability=[1-(Compound treated LDH activity-Spontaneous LDHactivity)/ (Maximum LDH activity-Spontaneous LDH activity)]× 100%
Standard curve is obtained by the experiment test of series concentration, to calculate EC50.It the results are shown in Table A.
Protective effect test result of the Table A the compounds of this invention to the HT22 cellular oxidation stress damages of glutamate induction
Example No. EC50(μM) Example No. EC50(μM)
Embodiment 1 4.22 Embodiment 6 4.30
Embodiment 2 4.20 Embodiment 7 4.07
Embodiment 3 4.25 Embodiment 8 4.15
Embodiment 4 4.13 Embodiment 11 4.17
Embodiment 5 4.23 --- ---
Experimental result shows that the compounds of this invention has preferable guarantor to the HT22 cellular oxidation stress damages of glutamate induction Shield acts on.
In the description of this specification, reference term " one embodiment ", " embodiment ", " some embodiments ", " show The description of example ", " specific example " or " some examples " etc. means the specific spy for combining the embodiment, embodiment or example to describe Sign, structure, material or feature are contained at least one embodiment of the present invention, embodiment or example.In this specification In, schematic expression of the above terms are necessarily directed to identical embodiment, embodiment or example.Moreover, description Particular features, structures, materials, or characteristics can be in any one or more embodiments, embodiment or example with suitable Mode combines.In addition, without conflicting with each other, those skilled in the art can be by difference described in this specification Embodiment, embodiment or example and different embodiments, embodiment or exemplary feature are combined.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, changes, replacing and modification.

Claims (10)

1. a kind of compound is stereoisomer, the tautomerism of compound shown in formula (I) compound represented or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
R1,R2,R3,R4And R6It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,-SH,-COOH,- CONH2,-C (=O) NHCH3,-C (=O) N (CH3)2,-C (=O)-(C1-C6Alkyl) ,-C (=O)-(C1-C6Alkoxy), C1- C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6Halogenated alkoxy, C1-C6Alkylthio group, C1-C6Alkylamino or the C of hydroxyl substitution1-C6Alkyl;
R5For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2,C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Alkoxy, C1-C6Halogenated alkoxy or the C of hydroxyl substitution1-C6Alkyl;With
R7For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2,C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Alkoxy, C1-C6Halogenated alkoxy or the C of hydroxyl substitution1-C6Alkyl.
2. compound according to claim 1, wherein R1,R2,R3,R4And R6Be each independently H, D, F, Cl, Br, I ,- CN,-NO2,-NH2,-OH,-SH,-COOH,-CONH2,-C (=O)-(C1-C4Alkyl) ,-C (=O)-(C1-C4Alkoxy), C1- C4Alkyl, C2-C4Alkenyl, C2-C4Alkynyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkylthio group, C1-C4Alkylamino or the C of hydroxyl substitution1-C4Alkyl.
3. compound according to claim 1, wherein R5For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,- COOH ,-C (=O) NH2,C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4What halogenated alkoxy or hydroxyl replaced C1-C4Alkyl;
R7For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2,C1-C4Alkyl, C1-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4Halogenated alkoxy or the C of hydroxyl substitution1-C4Alkyl.
4. compound according to claim 1 or 2, wherein R1,R2,R3,R4And R6Be each independently H, D, F, Cl, Br, I,-CN,-NO2,-NH2,-OH,-SH,-COOH,-CONH2,-C (=O) CH3,-C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OCH2CH2CH3,-C (=O) OCH (CH3)2, methyl, ethyl, n-propyl, isopropyl ,-CF3,-CH2CF3, methoxyl group, second Oxygroup, n-propyl oxygroup or isopropyl oxygroup.
5. compound according to claim 1 or 3, wherein R5For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH,- COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3,-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup Or isopropyl oxygroup;
R7For H, D, F, Cl, Br, I ,-CN ,-NO2,-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl Base ,-CF3,-CH2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
6. compound according to claim 1, for one of following structure compound or tie with one of following Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt of the compound of structure Or its prodrug:
7. a kind of pharmaceutical composition, including the compound described in claim 1-6 any one;With
Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is arbitrary Combination.
8. pharmaceutical composition according to claim 7, further includes additional therapeutic agent, wherein the additional therapeutic agent To treat the drug of Alzheimer's disease, treating the drug or combination thereof of nervous disorders;
The wherein described additional therapeutic agent is donepezil, nalmefene, Risperidone, vitamin e, SAM-760, AVN-211, AVN- 101, RP-5063, tozadenant, PRX-3140, PRX-8066, SB-742457, naluzaton, idalopirdine, he Crin, Rivastigmine, galanthamine, Memantine, mitzapine, Venlafaxine, desipramine, nortriptyline, zolpidem, assistant gram Grand, Nicergoline, Piracetam, selegiline, pentoxifylline or their arbitrary combination.
9. the pharmaceutical composition described in compound or claim 7-8 any one described in claim 1-6 any one exists The purposes in drug is prepared, the drug is for protecting neuron, nerve regneration and/or memory being promoted to be formed.
10. purposes according to claim 9, the drug for prevent, treat or mitigate with glutamate excitotoxicity, Oxidativestress damage or the related disease of free radical or neurodegenerative disease;
Wherein, the disease related with glutamate excitotoxicity is Alzheimer disease, Huntington chorea, Parkinson Disease, myasthenia gravis, amyotrophic lateral sclerosis, senile dementia, glaucoma, bronchial asthma, hyperthyroidism, IV types hyperlipoprotememia, hypertension or renal failure;
The disease related with oxidativestress damage or free radical is cerebral injury, headstroke, brain of neonatal rat on ischemia hypoxia, brain overflow Blood, Parkinson's disease, Huntington chorea, epilepsy, amyotrophic lateral sclerosis, Alzheimer disease, dementia, ischemic Heart disease, blood vessel embolism, hypercholesterolemia, atherosclerosis, diabetes, pulmonary emphysema, cataract, acute pancreatitis, wine Liver diseases caused by essence, kidney damage or cancer;
The neurodegenerative disease is Parkinson's disease, cerebral ischemia, Alzheimer disease, amyotrophic lateral sclerosis, ox Spongiform encephalopathy, Huntington chorea, gram refined Er Shi diseases, ataxia telangiectasia, cerebral atrophy, myeloid flesh Atrophy, primary lateral sclerosis or multiple sclerosis.
CN201710233211.3A 2017-04-11 2017-04-11 The hydrazide derivatives and application thereof of indoles substitution Pending CN108689906A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009052116A1 (en) * 2007-10-15 2009-04-23 The Salk Institute For Biological Studies Methods for treating a variety of diseases and conditions, and compounds useful therefor
WO2016106760A1 (en) * 2014-12-31 2016-07-07 广州喜鹊医药有限公司 Trifluoroacethydrazide compound as well as preparation method therefor and application thereof in preparing medicament

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009052116A1 (en) * 2007-10-15 2009-04-23 The Salk Institute For Biological Studies Methods for treating a variety of diseases and conditions, and compounds useful therefor
WO2016106760A1 (en) * 2014-12-31 2016-07-07 广州喜鹊医药有限公司 Trifluoroacethydrazide compound as well as preparation method therefor and application thereof in preparing medicament

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