CN108864033A - The hydrazide derivatives and application thereof that phenyl replaces - Google Patents

The hydrazide derivatives and application thereof that phenyl replaces Download PDF

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Publication number
CN108864033A
CN108864033A CN201710333749.1A CN201710333749A CN108864033A CN 108864033 A CN108864033 A CN 108864033A CN 201710333749 A CN201710333749 A CN 201710333749A CN 108864033 A CN108864033 A CN 108864033A
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alkyl
disease
compound
alkoxy
halogenated
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陈康智
金传飞
李世玺
张英俊
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses the hydrazide derivatives and application thereof that phenyl replaces, in particular it relates to the hydrazide derivatives that a kind of novel phenyl replaces 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 treat disease related with glutamate excitotoxicity, oxidativestress damage or free radical in preparation, or the purposes in the drug of neurodegenerative disease, especially Alzheimer disease.

Description

The hydrazide derivatives and application thereof that phenyl replaces
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to 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 that phenyl replaces.
Background technique
Currently, about treatment acute nerve injury (such as apoplexy, spinal injury) and chronic neurodegenerative disease (Ru Aer Ci Haimo disease, 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, mind 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 administration property and penetrates the energy of blood-brain barrier Power, thus, begin one's study about Apoptosis micromolecular inhibitor (Huang, Chem&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 seriously affecting the progress sexual development of 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 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, disease 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 the increase with the age and increases.Wherein, in more than 60 years old crowds, more than 70 years old crowds and more than 80 years old crowds 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 crowds, 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, the concentration by increasing acetylcholine improves the symptom of Alzheimer disease；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, can treat A Er Ci Haimo disease；Third can prevent A Erci by using estrogen, antioxidant, radical scavenger or anti-inflammatory agent indirectly The further deterioration of the silent disease in sea；4th, A Erci gradually is treated with irreversible degeneration by prevent cynapse and neuron The silent disease in sea.
At present clinically there are no can effectively reversing cognitive defect improve treatment Alzheimer disease drug.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 has always been considered as being the new way got a good chance of 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 damage) 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), G- albumen coupling in it and film.These receptors be activated after by G- albumen effect 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- isoxazole receptor (AMPAR) With kainate receptor (KAR).They and ion channel are coupled, and 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 cynapse transmitting but also had maintained the normal physiological function of nerve cell.Under normal circumstances, Release, intake and the reabsorption of glutamic acid maintain dynamic equilibrium.However, glutamic acid exists when it excessively discharges or absorbs obstacle Intracerebral is largely gathered, and concentration sharply increases, receptor excessive activation can lead to 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 that body when being stimulated, 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, easily generation lipid peroxidation, 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), it is transferred to electronics 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 has 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 damage of the A β to neuron, improve cognitive disorder.
Summary of the invention
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 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 that a kind of novel phenyl replaces, the HT22 cellular oxidation 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 of neurodegenerative disease is treated, the drug for the treatment of Alzheimer disease is especially used to prepare.
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, the present invention relates to a kind of compounds, are compound shown in formula (I) compound represented or formula (I) Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
Each R1、R2、R3、R4、R5And R6With meaning as described in the present invention, condition is R1、R2、R3、R4And R5At least two A is not H.
In one embodiment, R1For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-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-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C6Alkyl, C1-C6Halogenated alkyl, C2-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C6Alkyl, C1-C6Halogenated alkyl, C2-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R3For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R3、R23-6 former molecular carbocyclic ring or heterocycle, institute are constituted with coupled carbon atom State 3-6 former molecular carbocyclic ring and heterocycle it is individually optional by one or more selected from D, F, Cl, Br, I, C1-C4Alkyl, C1- C4Halogenated alkyl, C1-C4Alkoxy and C1-C4Replaced the substituent group of halogenated alkoxy.
In one embodiment, R3、R43-6 former molecular carbocyclic ring or heterocycle, institute are constituted with coupled carbon atom State 3-6 former molecular carbocyclic ring and heterocycle it is individually optional by one or more selected from D, F, Cl, Br, I, C1-C4Alkyl, C1- C4Halogenated alkyl, C1-C4Alkoxy and C1-C4Replaced the substituent group of halogenated alkoxy.
In one embodiment, R6For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
In one embodiment, R1For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-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-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In one embodiment, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C1-C4Halogenated alkyl, C2-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C1-C4Halogenated alkyl, C2-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In one embodiment, R3For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In one embodiment, R3、R25-6 former molecular carbocyclic ring or heterocycle, institute are constituted with coupled carbon atom State 5-6 former molecular carbocyclic ring and heterocycle it is individually optional by one or more selected from D, F, Cl, Br, I, C1-C4Alkyl, C1- C4Halogenated alkyl, C1-C4Alkoxy and C1-C4Replaced the substituent group of halogenated alkoxy.
In one embodiment, R3、R45-6 former molecular carbocyclic ring or heterocycle, institute are constituted with coupled carbon atom State 5-6 former molecular carbocyclic ring and heterocycle it is individually optional by one or more selected from D, F, Cl, Br, I, C1-C4Alkyl, C1- C4Halogenated alkyl, C1-C4Alkoxy and C1-C4Replaced the substituent group of halogenated alkoxy.
In one embodiment, R6For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1- C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl.
In one embodiment, R1For 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, 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, R2For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R4For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, first Base, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup.
In one embodiment, R3For 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, R3、R2Constituting with coupled carbon atom has one of following structure：
Wherein each subformula shown in Formulas I-a to I-v individually optionally by one or more selected from D, F, Cl, Br, I, Methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygen Replaced the substituent group of base and trifluoromethoxy.
In one embodiment, R3、R4Constituting with coupled carbon atom has one of following structure：
Wherein each subformula shown in Formulas I-a to I-v individually optionally by one or more selected from D, F, Cl, Br, I, Methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygen Replaced the substituent group of base and trifluoromethoxy.
In one embodiment, R6For 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, compound of the present invention for the compound with one of following structure or has 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 any 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, the drug or their combination for treating 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 any 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 mind Through degenerative disease.
In one embodiment, the disease related with glutamate excitotoxicity is Alzheimer disease, Huntingdon Chorea, Parkinson's disease, myasthenia gravis, amyotrophic lateral sclerosis, senile dementia, glaucoma, bronchial asthma, first Shape gland hyperfunction, IV type 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 caused by cataract, acute pancreatitis, alcohol, kidney damage or cancer.
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 disease, 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 damage of glutamate induction Protective effect, and can be used as preferable neuroprotective agent.
Any embodiment in either present invention face can be combined with other embodiments, as long as they are not It will appear contradiction.In addition, any technical characteristic can be adapted for other realities in any embodiment of either side of the present invention 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 where (including 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 invention, be it is clearly visible, carry out in a number of independent embodiments Description, but can also provide in combination in a single embodiment.Conversely, various features of the invention, for brevity, It is described in a single embodiment, but can also be individually or with the offer of any suitable sub-portfolio.
Unless otherwise stated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element With the 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, the 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 " at least n " refers to n or n or more.For example, referring to two or more there are two at least.
Term " stereoisomer " refers to identical chemical constitution, but spatially arrangement mode is different for atom or group Compound.Stereoisomer includes that enantiomter, diastereoisomer, conformer (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 achieve 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 compounds some in this way, raw material, composition and/or dosage form, they are cured rationally Learn judgement in the range of, be suitable for contacted with patient tissue and without excessive toxicity, irritation, allergy or with reasonable benefit The symmetrical other problems of benefit/Hazard ratio and complication, and effective for given application.
Term " optionally by ... replaced " can be used interchangeably, i.e., with term " unsubstituted or by ... replaced .. " 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, term it is " substituted " indicate specifically replaced to one or more hydrogen atoms in structure or group Replaced base.Unless otherwise indicated, a substituent group can be replaced in each substitutive reasonable position of group. Replaced the specific substituent group of one or more that more than one position can be selected from given structural formula, then substituent group It can each reasonable position be replaced in structural formula identical or differently.
Term "comprising" is open language, that is, includes content specified by the present invention, but be not precluded otherwise Content.
It is disclosed in the substituent group of each section of this specification, disclosed compound of present invention according to radical species or range.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 the methyl being individually disclosed, 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)。
Term " hetero atom " refers to O, S, N, P and Si, the form including any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole base N), NH (as the NH in pyrrolidinyl) or NR (NR in pyrrolidinyl replaced as N-).
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 Replace.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), tert-butyl (t-Bu ,-C (CH3)3), etc..
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 Replaced the substituent group that the present invention describes.
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 " alkyl that hydroxyl replaces " indicates alkyl group replaced 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- hydroxyethyl, 2- hydroxyl -1- third Base, 3- hydroxyl -1- propyl, 2,3- dihydroxypropyl etc..
Term " halogenated alkyl " indicates alkyl group replaced 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 " indicate alkoxy base replaced 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.
Term " carbocylic radical " or " carbocyclic ring " are used interchangeably here, indicate containing 3-12 ring carbon atom, it is monovalent or The monocycle of multivalence, bicyclic or three-ring system, middle ring can be it is fully saturated or comprising one or more degrees of unsaturation, but One armaticity ring cannot all have.Carbon bicyclic group includes spiral shell carbon bicyclic group and condensed carbon bicyclic group, suitable carbocylic radical group packet It includes, but is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.In one embodiment, carbocylic radical includes 3-8 ring carbon atom；? In another embodiment, carbocylic radical includes 3-6 ring carbon atom.The example of carbocylic radical group includes, but are not limited to：Cyclopropyl, Cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- hexamethylene Base -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- cyclohexyl -3- alkenyl, cyclohexadienyl, etc..The carbocylic radical group can be with It is independently unsubstituted or replaced one or more substituent groups described in the invention.
Term " heterocycle " and " heterocycle " are used interchangeably here, indicate to include 3-12 annular atom, unit price or more The monocyclic, bicyclic or tricyclic system of valence, one or more atoms are independently replaced by hetero atom in middle ring, the hetero atom With meaning as described in the present invention, ring can be fully saturated or comprising one or more degrees of unsaturation, a but fragrance Property ring cannot all have.Unless otherwise stated, heterocycle can be carbon-based or nitrogen base, and-CH2Group can optionally by-C (= O)-substitution.The sulphur atom of ring can optionally be oxidized to S- oxide.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen Compound.The example of heterocycle includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, Pyrrolidinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran Base, dihydrofuryl, tetrahydro-thienyl, dihydrothiophene, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro Pyranose, 2H- pyranose, 4H- pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, etc..It is miscellaneous - CH in ring group2Group includes, but are not limited to 2- oxo-pyrrolidine base, oxo -1,3-thiazoles by-C (=the O)-example substituted Alkyl, 2- piperidone base, 3,5- dioxy piperazine piperidinyl and hybar X base.The example that sulphur atom is oxidized in heterocycle includes, But it is not limited to, sulfolane base, 1,1- dioxothiomorpholinyl.The heterocyclyl groups can be optionally one or more Replaced substituent group described in the invention.
Term " naphthenic base " indicates containing 3-12 ring carbon atom, monovalent or multivalence saturation monocyclic, bicyclic or tricyclic System.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used 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, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, 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. documented.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 acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- naphthalene sulphur 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-C8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association 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 that improving disease or illness (slows down in some of these embodiments 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 in terms of (such as stablizing perceptible symptom) on body or physiologically (such as parameter of stable 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 that phenyl of the present invention replaces, 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 by an elevated temperature using normal 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 in suitable solvent with peracid, such as is reacted in methylene chloride, ethyl acetate or methyl acetate with peracetic acid, or It is reacted in chloroform or methylene chloride with 3- chloroperoxybenzoic acid, prepares the nitrogen oxides of the compounds of this invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to and 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 and be used to prepare and/or purify compound shown in formula (I) and/or for separating compound shown in this formula (I) Enantiomer intermediate.
Officinal salt of the 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 reaction of metered amount is to be prepared.Such reaction usually carries out in the mixture of water or organic solvent or both. Generally, in appropriate cases, it needs using 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 that other is 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 Isotope including 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 of compound shown in preparation 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 their combination.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 shown in formula (I) or its individual stereoisomer, 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.
It further comprise carrying out other to patient to resist comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered The administration of Alzheimer disease drug (combination therapy), wherein the drug of other anti-Alzheimer diseases is 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 any 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.Every kind of excipient mixing when must with pharmaceutical composition it is other at Split-phase is held, and interaction the effect of to avoid will be greatly reduced disclosed compound of present invention when administering to a patient and will lead to not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of 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.Facilitate to carry or transport the compounds of this invention when may be selected to administer to a patient from an organ of body or partially 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, Disintegrating agent, 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 for the suitable of appropriate amount of the 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 Well-known technique, the respective content of these documents are incorporated by reference into the present invention.Except any such as because generating any undesirable life Object effect, 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 of preparation pharmaceutical composition, described pharmaceutical composition includes the present invention Open compound and pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination, the technique include that mixing is each Kind ingredient.Pharmaceutical composition comprising disclosed compound of present invention can mix 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 those dosage forms for being 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 invention can exist for treating in a free form, or if 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 gastric acid 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 fatty acid, rouge 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 preparing 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 describe with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrating agent, 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, and 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 by being added glycerol, sorbierite or the plasticizing of similar polyalcohol.It is raw that soft gelatin shell may include the pre- preventing microorganism of preservative It is long.Suitable preservative be as described in the present invention those, including methylparaben 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 and suspension in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；It is prepared 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 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, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；And have one or 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 be suitable for dry powder doses to the dosage form of 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 Include 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 cream 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.
The pharmaceutical composition for being suitable for cutaneous penetration can be prepared into discontinuous patch agent, it is intended that keep 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 in conjunction with the soluble polymer as target medicine carrier.Such polymer packet Include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, polyhydroxyethylaspart or The oxide polylysine that palmitoyl residues replace.In addition, compound disclosed in this invention can with realizing drug Control release used in one kind Biodegradable polymeric combination, for example, polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, Polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel crosslinking or amphiphilic block copolymer.
Pharmaceutical composition provided by the invention can be by injection, infusion or implantation parenteral administration, for part or entirely Body administration.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 be prepared according to conventional method known to the technical staff in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, ibid).
Be intended for parenteral administration pharmaceutical composition 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 dissolution discharges drug.Due to individual difference, bigger variation can be presented in the severity of symptom, and every kind of medicine has Its unique treatment characteristic, therefore, for the accurate administration mode of each individual, dosage form and therapeutic scheme all should be by operation Doctor determines.
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 each active component for being enough to show 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, the disease including treatment, the severity of disease, the certain drug used Activity, administration 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 in need of consideration 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 individual and provides the drug of therapeutically effective amount, and administration mode includes oral, sublingual, vein, skin Under, it is percutaneously, intramuscular, it is intradermal, it is intrathecal, on dura mater, intraocularly, and 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 weight of compound when the compound of per unit dose refers to each administration 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 comprising it is antibacterial or fungistatic concentrations resist it is 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 It prepares, or the substance co-formulation with the expected effect of supplement.
In one embodiment, treatment method 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 administration, parenteral, Cutaneous penetration and rectally.Typical parenteral refers to through 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 administration.Another In embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be inhalation.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 administration.
In one embodiment, the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can disposably give 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, the duration including implementing the program are treated disease depending on treated disease The severity of disease, the age of patient under consideration and physical condition, the medical history of patient under consideration while the property of therapy are thought 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 to change as time goes by it may require that adjust it is suitable to Prescription case.
The compounds of this invention can be administered simultaneously, or before it or later with one or more other therapeutic agents.This hair Bright compound can be administered with other therapeutic agents by identical or different administration route respectively, or therewith with same pharmaceutical composition Form administration.
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, one of implementable following manner of those skilled in the art or more：(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 compound are changed；(d) modification Close the internal solubility of object；And the side effect or other difficult points for (e) overcoming compound to be faced.It is used to prepare the typical of prodrug Functional derivatives, comprising in vivo chemically or the variant of compound that cracks of the mode of enzyme.Comprising 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 provided by the invention and pharmaceutical composition can be used for preparing for protecting neuron, promoting nerve regneration And/or memory formed drug, can be used for preparation 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 composition of the invention Member, term " protection neuron ", which refers to, prevents 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 composition of the invention Regeneration, term " regeneration " refer to that neuron regrows and carry out repairing nerve damage.
Specifically, the amount of compound effectively can detectably selectively promote memory in composition of the invention It is formed.
Specifically, the amount of compound effectively detectably can selectively inhibit paddy ammonia in composition of the invention Sour excitatory toxicity, the compound of the present invention can be used as the drug for the treatment of disease related with glutamate excitotoxicity, institute 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 type 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 answer in composition of the invention Swash, the compound of the present invention can be used as the drug for the treatment of disease related with oxidativestress damage or free radical, described and oxygen Change stress damage or the related disease of free radical is cerebral injury, headstroke, brain of neonatal rat on ischemia hypoxia, cerebral hemorrhage, Parkinson's disease, henry 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 disease, 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 Method of the invention is practiced in offer.
Generally, 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：Chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing 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 purchase is in quotient Product supplier such as Aldrich Chemical 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 development 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 It with chloroform 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 flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
1H H NMR spectroscopy is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.1H H NMR spectroscopy is with CDC13、 DMSO-d6、CD3OD or acetone-d6For solvent (as unit of ppm), use TMS (0ppm) or chloroform (7.26ppm) as referring to mark It is quasi-.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 (triplet of doublets, three Doublet).Coupling constant is indicated with hertz (Hz).
The determination condition of low resolution mass spectrometry (MS) data is：6120 level four bars HPLC-M (column model 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) in (H containing 0.1% formic acid2O the ratio in), using electrospray ionisation (ESI), at 210nm/254nm, It is detected with UV.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type Number：NOVASEP 50/80mm DAC), it is detected in 210nm/254nm with UV.
The use of logogram word below is through the present invention：
CH2Cl2, DCM methylene chloride
CDC13Deuterated chloroform
DMF N,N-dimethylformamide
EtOAc, EA ethyl acetate
(CF3CO)2O trifluoroacetic anhydride
CH3COCl chloroacetic chloride
Et3N triethylamine
G grams
H hours
NaHCO3Sodium bicarbonate
ML, ml milliliters
PE petroleum ether (60-90 DEG C)
RT, rt, r.t. room temperature
Following synthetic schemes describes the step of preparation disclosed compound of present invention, unless otherwise stated, wherein each R1、R2、 R3、R4、R5And R6With definition of the present invention.
Synthetic schemes 1
Compound (3) can be prepared by following process：Containing different substituents formula (1) compound represented with 2,4- dimethyl hydrazinobenzene hydrochloride salt obtain formula (2) compound represented.Formula (2) compound represented and trifluoroacetic anhydride or acetyl Chlorine react in the presence of alkali the formula that obtains (3) compound represented.
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment
Embodiment 1 (E)-N'- (phendioxin, 3- bis- dislike pentamethylene -5- methylene)-N- (2,4- xylyl) -2,2,2- The synthesis of trifluoroacetyl hydrazine
The synthesis of step 1) (E) -1- (phendioxin, 3- bis- dislike pentamethylene -5- methylene) -2- (2,4- xylyl) hydrazine
By phendioxin, 3- bis- dislikes pentamethylene -5- formaldehyde (0.59g, 3.93mmol), 2,4- dimethyl hydrazinobenzene hydrochloride salts (0.68g, 3.93mmol) and DMF (10mL) are added sequentially in 100mL single necked round bottom flask, react 2h at room temperature, add 4mL full Then plus water (70mL) in sodium bicarbonate solution and hydrochloride, there is yellow solid precipitation, the solid was filtered, washing (30mL × 2), with methylene chloride (30mL) dissolve, liquid separation, collect organic phase, be concentrated to get title compound be yellow solid (1.00g, 94.8%).
MS(ESI,pos.ion)m/z:269.2[M+H]+.
Step 2) (E)-N'- (phendioxin, 3- bis- dislike pentamethylene -5- methylene)-N- (2,4- xylyl) -2,2,2- three The synthesis of acetyl fluoride hydrazine
By (E) -1- (phendioxin, 3- bis- dislike pentamethylene -5- methylene) -2- (2,4- xylyl) hydrazine (1.00g, 3.73mmol), triethylamine (1.04mL, 7.46mmol) and methylene chloride (10mL) are added sequentially to 100mL single necked round bottom flask In, it is transferred to 0 DEG C, trifluoroacetic anhydride (0.62mL, 4.48mmol) slowly is added dropwise, room temperature reaction 20.5h is transferred to after dripping, Then it is brown oil compound that direct column chromatographic purifying (petrol ether/ethyl acetate (v/v)=100/1), which obtains title compound, (0.63g, 46%).
MS(ESI,pos.ion)m/z:365.2[M+H]+；
1H NMR(400MHz,DMSO)δ(ppm):7.33 (s, 2H), 7.24-7.21 (m, 3H), 7.16 (d, J=7.8Hz, 1H), 6.95 (d, J=7.9Hz, 1H), 6.08 (s, 2H), 2.38 (s, 3H), 1.99 (s, 3H)；
13C NMR(151MHz,DMSO)δ(ppm):156.4,150.2,148.5,144.9,140.9,136.1,132.7, 129.8,129.2,129.1,127.8,124.8,109.0,106.1,102.2,21.3,16.9.
Embodiment 2 (E)-N'- (2,4 dichloro benzene methylene)-N- (2,4- xylyl) -2,2,2- trifluoroacetyl hydrazine Synthesis
The synthesis of step 1) (E) -1- (2,4 dichloro benzene methylene) -2- (2,4- xylyl) hydrazine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by 2,4- dichloro-benzenes first Aldehyde (1g, 5.71mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salt (0.986g, 5.71mmol) are dissolved in DMF (10mL) reaction and are prepared into It is yellow solid (1.64g, 98%) to title compound.
MS(ESI,pos.ion)m/z:293.1[M+H]+.
The conjunction of step 2) (E)-N'- (2,4 dichloro benzene methylene)-N- (2,4- xylyl) -2,2,2- trifluoroacetyl hydrazine At
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e., by (E) -1- (2,4- Dichloro benzylidene) -2- (2,4- xylyl) hydrazine (1.6g, 5.46mmol), triethylamine (1.5mL, 10.92mmol) and trifluoro Prepared by acetic anhydride (0.9mL, 6.55mmol) reaction in methylene chloride (20mL), then direct column chromatographic purifying (petroleum ether/second Acetoacetic ester (v/v)=40/1) title compound is obtained as brown oil compound (1.25g, 59%).
MS(ESI,pos.ion)m/z:389.0[M+H]+；
1H NMR(400MHz,CDCl3)δ(ppm):7.99 (d, J=8.5Hz, 1H), 7.67 (s, 1H), 7.35 (s, 1H), 7.31 (d, J=8.5Hz, 1H), 7.26 (s, 1H), 7.22 (d, J=7.8Hz, 1H), 7.06 (d, J=7.9Hz, 1H), 2.42 (s,3H),2.09(s,3H)；
13C NMR(101MHz,CDCl3)δ(ppm):157.2 (q, J=37.0Hz), 141.1,140.0,136.9, 135.9,135.2,132.6,129.5,129.3,128.8,128.51,128.2,127.8,1 16.8 (q, J=288.4Hz), 21.2,16.9.
Embodiment 3 (E)-N'- (phendioxin, 3- bis- dislike pentamethylene -5- methylene)-N- (2,4- xylyl) acethydrazide Synthesis
The synthesis of step 1) (E) -1- (phendioxin, 3- bis- dislike pentamethylene -5- methylene) -2- (2,4- xylyl) hydrazine
This step title compound method referring to described in 1 step 1 of embodiment is prepared, i.e., by phendioxin, 3- bis- It dislikes pentamethylene -5- formaldehyde (0.59g, 3.93mmol) and 2,4- dimethyl hydrazinobenzene hydrochloride salt (0.68g, 3.93mmol) is dissolved in DMF It is yellow solid (1.00g, 94.8%) that title compound, which is prepared, in reaction in (10mL).
MS(ESI,pos.ion)m/z:269.2[M+H]+.
Step 2) (E)-N'- (phendioxin, 3- bis- dislike pentamethylene -5- methylene)-N- (2,4- xylyl) acethydrazide Synthesis
This step title compound method referring to described in 1 step 2 of embodiment is prepared, i.e. (E) -1- (phendioxin, 3- bis- dislikes pentamethylene -5- methylene) -2- (2,4- xylyl) hydrazine (1g, 3.73mmol), triethylamine (1.0mL, 7.46mmol) The reaction preparation in the methylene chloride (10mL) with chloroacetic chloride (0.3mL, 4.48mmol), then direct column chromatographic purifying (petroleum ether/ Ethyl acetate (v/v)=5/1) title compound is obtained as brown solid (0.81g, 70%).
MS(ESI,pos.ion)m/z:311.2[M+H]+；
1H NMR(600MHz,CDCl3)δ(ppm):7.29 (s, 1H), 7.18 (s, 1H), 7.14 (d, J=7.7Hz, 1H), 7.02 (s, 1H), 6.95 (d, J=7.8Hz, 1H), 6.85 (d, J=7.9Hz, 1H), 6.74 (d, J=8.0Hz, 1H), 5.96 (s,2H),2.60(s,3H),2.38(s,3H),2.03(s,3H)；
13C NMR(151MHz,CDCl3)δ(ppm):172.3,149.0,148.1,140.3,139.4,136.2,132.0, 131.9,128.9,128.8,128.3,123.2,108.0,105.3,101.3,21.8,21.1,17.1.
Biologic test
Embodiment A：Evaluate protective effect of the compound to the HT22 cellular oxidation stress damage of glutamate induction
Experimental method
Recovery HT22 cell (mouse hippocampal neuron cell), by the cell of logarithmic growth phase according to 4 × 104A/mL is close Degree is seeded to 96 orifice plates (100 μ L), and 37 DEG C, 5%CO2Incubator, culture is for 24 hours.Experimental day discards culture medium in hole, according to reality Test requirement, every 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 Concentration is 0.25%.), 37 DEG C, 5%CO2Incubator is protected from light incubation 24 hours.Terminate after being incubated for, according to lactic dehydrogenase cell Toxicity detection kit operation instruction carries out the detection of lactic dehydrogenase enzyme r e lease.Cell viability is calculated according to result.% Viability=[1- (Compound treated LDH activity-Spontaneous LDH activity)/ (Maximum LDH activity-Spontaneous LDH activity)] × 100%
Standard curve is obtained by the experiment test of series of concentrations, 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 damage of glutamate induction
Example No. EC50(μM)
Embodiment 1 0.13
Embodiment 2 0.13
Embodiment 3 4.12
Experimental result shows that the compounds of this invention has preferable guarantor to the HT22 cellular oxidation stress damage of glutamate induction Shield effect.
In the description of this specification, reference term " one embodiment ", " embodiment ", " some embodiments ", " show The description of example ", specific examples or " some examples " etc. means to combine the specific spy of the embodiment, embodiment or example description 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, modifies, replacement and variant.

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、R5It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl；
R2、R4It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Halogenated alkyl, C2-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl；
R3For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl；Alternatively,
R3、R23-6 former molecular carbocyclic ring or heterocycle, described 3-6 former molecular carbon are constituted with coupled carbon atom Ring and heterocycle it is individually optional by one or more be selected from D, F, Cl, Br, I, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alcoxyl Base and C1-C4Replaced the substituent group of halogenated alkoxy；Alternatively,
R3、R43-6 former molecular carbocyclic ring or heterocycle, described 3-6 former molecular carbon are constituted with coupled carbon atom Ring and heterocycle it is individually optional by one or more be selected from D, F, Cl, Br, I, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alcoxyl Base and C1-C4Replaced the substituent group of halogenated alkoxy；
Condition is R1、R2、R3、R4And R5At least there are two be not H；With
R6For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Alkoxy, C1-C6The C that halogenated alkoxy or hydroxyl replace1-C6Alkyl.
2. compound according to claim 1, wherein R1、R5It is each independently 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 hydroxyl The C that base replaces1-C4Alkyl；
R2、R4It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C4Alkyl, C1-C4Halogenated alkyl, C2-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl；
R3For H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2、C1-C4Alkyl, C1-C4Alkyl halide Base, C1-C4Alkoxy, C1-C4The C that halogenated alkoxy or hydroxyl replace1-C4Alkyl；Alternatively,
R3、R25-6 former molecular carbocyclic ring or heterocycle, described 5-6 former molecular carbon are constituted with coupled carbon atom Ring and heterocycle it is individually optional by one or more be selected from D, F, Cl, Br, I, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alcoxyl Base and C1-C4Replaced the substituent group of halogenated alkoxy；Alternatively,
R3、R45-6 former molecular carbocyclic ring or heterocycle, described 5-6 former molecular carbon are constituted with coupled carbon atom Ring and heterocycle it is individually optional by one or more be selected from D, F, Cl, Br, I, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alcoxyl Base and C1-C4Replaced the substituent group of halogenated alkoxy；
Condition is R1、R2、R3、R4And R5At least there are two be not H.
3. compound according to claim 1, wherein R6For 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.
4. compound according to claim 1 or 2, wherein R1、R5Be each independently H, D, F, Cl, Br, I ,-CN ,- NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, ethyl, n-propyl, isopropyl ,-CF3、-CH2CF3, methoxyl group, ethoxy Base, n-propyl oxygroup or isopropyl oxygroup；
R2、R4It is each independently H, D, F, Cl, Br, I ,-CN ,-NO2、-NH2,-OH ,-COOH ,-C (=O) NH2, methyl, second Base, n-propyl, isopropyl ,-CF3、-CH2CF3, ethyoxyl, n-propyl oxygroup or isopropyl oxygroup；
R3For 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；Alternatively,
R3、R2Constituting with coupled carbon atom has one of following structure： Each sub- knot shown in the Formulas I-a to I-e, I-o to I-r Structure formula is selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl ,-CF by one or more individually optionally3、- CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup and trifluoromethoxy substituent group replaced； Alternatively,
R3、R4Constituting with coupled carbon atom has one of following structure： Each sub- knot shown in the Formulas I-a to I-e, I-o to I-r Structure formula is selected from D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl ,-CF by one or more individually optionally3、- CH2CF3、-CF2CF3, methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup and trifluoromethoxy substituent group replaced；
Condition is R1、R2、R3、R4And R5At least there are two be not H.
5. compound according to claim 1 or 3, wherein R6For 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.
6. compound according to claim 1 for the compound with one of following structure or has one of following knot Stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, the pharmaceutically acceptable salt of the compound of structure Or its prodrug：
7. a kind of pharmaceutical composition includes compound as claimed in any one of claims 1 to 6；With
Described pharmaceutical composition optionally further includes pharmaceutically acceptable excipient, carrier, adjuvant or theirs is any 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 their combination of nervous disorders；
Wherein the 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 any combination.
9. pharmaceutical composition described in compound as claimed in any one of claims 1 to 6 or claim 7-8 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 type 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 disease, ataxia telangiectasia, cerebral atrophy, myeloid flesh Atrophy, primary lateral sclerosis or multiple sclerosis.
CN201710333749.1A 2017-05-12 2017-05-12 The hydrazide derivatives and application thereof that phenyl replaces Pending CN108864033A (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
KR20170017173A (en) * 2015-08-05 2017-02-15 건국대학교 산학협력단 A novel anti-Alzheimer agent inhibiting oligomerization and fibriliation of beta-amyloid protects neuronal cell from A-induced cytotoxicity

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
KR20170017173A (en) * 2015-08-05 2017-02-15 건국대학교 산학협력단 A novel anti-Alzheimer agent inhibiting oligomerization and fibriliation of beta-amyloid protects neuronal cell from A-induced cytotoxicity

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
[美]R.B.西尔弗曼 编，郭宗儒 主译: "《有机药物化学[原著第二版]》", vol. 2008, 31 January 2008, 化学工业出版社, pages: 19 *
CHANDRAMOULI CHIRUTA ET AL.: "Metabolism of a potent neuroprotective hydrazide", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 21, no. 10, 24 March 2013 (2013-03-24), pages 2733 - 2741, XP028583444, DOI: 10.1016/j.bmc.2013.03.020 *
许军 主编: "《药物化学选论》", vol. 2012, 31 October 2012, 华中科技大学出版社, pages: 101 - 103 *

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