CN103804309B - A kind of chlorine oxime compound and preparation method thereof and the application in pharmacy - Google Patents

A kind of chlorine oxime compound and preparation method thereof and the application in pharmacy Download PDF

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CN103804309B
CN103804309B CN201210447383.8A CN201210447383A CN103804309B CN 103804309 B CN103804309 B CN 103804309B CN 201210447383 A CN201210447383 A CN 201210447383A CN 103804309 B CN103804309 B CN 103804309B
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disease
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CN103804309A (en
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王玉强
姚辉
吴传斌
陶亮
孙业伟
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GUANGZHOU XIQUE MEDICINE Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
    • C07D241/52—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Application the present invention relates to a kind of chlorine oxime compound and preparation method thereof and in pharmacy.The chlorine oxime compound has the structure of following general formula I:Such compound has the very strong active effect of synergic adjustment heat shock protein, can be used to treat rat because injecting A β1‑42Caused neurodegenerative disease, in order to treat the neurodegenerative disease of the mankind.Such compound also have the function of significantly resist stress, can be used for preparing treatment due to protein Misfolding and/or the new drug of aggregation, oxidative stress diseases caused.

Description

A kind of chlorine oxime compound and preparation method thereof and the application in pharmacy
Technical field
The present invention relates to a kind of chlorine oxime compound, and preparation method thereof and in preparation for treating and preventing due to albumen Neurodegenerative disease caused by matter folds mistake or assembles, metabolic system disease, the heart, cerebrovascular system disease and inflammation Application in drug.
Background technique
Protein is all extremely important to the life of human and animal, is one of three major nutrient of human body, is life Material base, without protein just without life.Therefore, it is closely connected with life and with various forms of vital movements Substance together.In the cell, most of native protein mass-energy spontaneously form more stable natural structure, or by ligand and generation It thanks to the factor to stablize.But it was found that about 10%~20% newly synthesized polypeptide chain need to be in conjunction with molecular chaperones, just by molecular chaperones It can correctly fold.It cannot form correct three-dimensional structure there are also about 20% newly synthesized polypeptide chain and be degraded by protease.It turns over Quality control after translating mainly guarantees the normal function of protein by molecular chaperones and this two systems of protease.Molecule companion The effect of companion be to aid in cannot spontaneous folding protein folding and assembling, so that its is restored normal structure, protease system Effect be remove false folding protein.
And when cell is in stress situation such as infection, heat shock and oxidative damage, it can lead to protein stability drop Low, certain protein cannot be folded by correct mode.In the case of oxidative stress, Mitochondrial DNA Mutation or reactive oxygen species The amount of having a net increase of of (reactive oxygen species, ROS), which increases, can all greatly improve Parkinson's disease, the nerves such as senile dementia The disease incidence of degenerative disease.In animal and external model, Antioxidation Treatment can protect neuron to a certain extent (Simpson,Lancet Neurol.4:266,2005;Neymotin et al.,Free Radic Biol Med.51:88- 96,2011)。
It is usually that carbon containing amino acid one end abundant is exposed on surface when protein folding mistake, rather than it is wrapped in The inside, and carbon containing such group abundant can combine closely the similar group in other oroteins, constitute polymer macromolecule.This A little polymer are lethals for cell (neuron).In fact, almost all of neurodegenerative disease all involves The abnormal process of neuronal protein.Abnormal process can lead to a kind of false folding of protein, cause newly synthesized after translating Protein cannot be normally modified, and protein cleavage is abnormal, abnormal gene splicing, misrepresentation, or remove the energy of paraprotein Power reduces.The protein of false folding is often accumulated by.Many neurodegenerative diseases, feature most outstanding is in brain cell, Outer cell occur the fibrous structure of amyloid protein protein aggregate (Muchowski, Neuron.35:9-12, 2002).Cell, which deals with these protein improperly, causes different neural tuples to break down, and clinically will appear as various Different neurodegenerative diseases (Prusiner, N Engl J Med.344:1516-1526,2001).
There are two types of protein aggregations to precipitate in senile dementia (AD).It is extracellular around brain parenchym and cerebrovascular wall There is amyloid plaque deposition, main component is that the polypeptide of the composition of 40-42 amino acid residue is known as beta amyloid egg
In Parkinson's disease (PD) patient in the endochylema of brain substantia nigra neuron, it may be observed that Lewy body aggregation, these The main component of aggregation is protein fragments (Spillantini the et al., Nature.388:839- of α-synuclein 840,1997)。
Copper-zinc Sudismase (copper-zinc of 20% typical Familial Occurrence lateral sclerosis of spinal cord (ALS) Superoxide dismutase, SOD1) gene coding have mutation, the mutant apparent error of SOD1 is folded, cause height Aggregationization.And always along with ubiquitin-dyeing inclusion body aggregation, (Kiernan et as shown in Figure 1A in sporadic ALS al.,Lancet.377:942-955,2011).Therefore protein Misfolding and being gathered in the pathogenesis of ALS rises emphatically Act on (Cudkowicz et al., Muscle Nerve.38:837-844,2008).
Deposited in the nucleus of Huntingdon (HD) patient a large amount of Huntington protein (Huntingtin protein, Htt poly glumine (polyglutamine, polyQ) aggregation), this is the typical brain feature of this patient (DiFiglia et al.,Science.277:1990-1993,1997).This mutain accumulates in the cell, is formed with Malicious oligomer and polymer.Immunohistochemistry and electron microscopy, either in HD patient or experimental model, all tables The autophagy approach that cell is illustrated is changed.Largely increase in the autophagic vacuole of many HD models and patient earliest source of evidence Observation result (Davies et al., Cell.90:537-548,1997;Sapp et al.,Ann Neurol.42:604- 612,1997;Kim et al.,J Neurosci.19:964-973,1999;Kegel et al.,J Neurosci.20: 7268-7278,2000;Nagata et al.,Neuroreport.15:1325-1328,2004;Heng et al.,Hum MolGenet.19:3702-3720,2010)。
When cell is in stress situation (such as oxidative stress ROS increases), cause protein folding mistake or aggregation, finally Lead to the generation of neurodegenerative disease, therefore repairing this protein Misfolding or degradation aggregation may be exactly to prevent disease The effective way that feelings further develop.
One importance for the treatment of albumen matter misfolding diseases is exactly the quantity for increasing molecular chaperones, improves heat shock The activity of albumen, the correct folding of auxilin, promotes the degradation of misfolded protein.Heat shock protein (heat shock Protein, HSP) stress protein that is otherwise known as (stress proteins, SP) is as a member in molecular chaperones, with numerous eggs White active function play it is related, be capable of auxiliary adjustment false folding albumen restore normal configuration (Hartl et al., Nature.475:324-332,2011).When stress reaction (heat shock response) occurs for cell, heat shock protein can big scale It reaches, then identifies the protein and its aggregation of false folding or unfolding, and mark them for proteasome degradation.Example Such as, heat shock protein HSP27 and HSP90 is very early it is verified that can be improved Ubiquitin-proteasome system (ubiquitin- Proteasome system, UPS) activity.There are also a kind of heat shock protein HSP70 can be with the protein that carrys out autofolding mistake Surface hydrophobicity area combines, and then guides a kind of ligase (such as CHIP, carboxy terminus of HSC70- of E3 ubiquitin Interacting protein) upper ubiquitin is marked on the protein and its aggregation for folding mistake, hereafter proteasome is just It can combine and degrade them.But high-intensitive oxidative damage can reinforce degree interconnected between protein fragments, Proteasome is difficult to degrade the protein polymer of such high stability.More heat shock protein expressions may be needed to mention at this time The degradation capability of high Ubiquitin-proteasome system.
Heat shock protein activity is also related to many diseases, almost with it is all stress caused by disease maintain close ties with.Such as Heat shock protein can prevent inflammation, such as Hsp60, Hsp70 as molecular chaperones with prophylactic treatment disease of immune system, Hsp90 and gp96 can in conjunction with bacterial exotoxin LPS (Tsan et al., J Leukoc Biol.85:905-910,2009), It is closely bound up (Di Cesare et al., Immunology.76:341-343,1992) with immunologic deficiency disease AIDS, also with Cardiovascular and cerebrovascular disease is closely coupled (Pockley, Circulation.105:1012-1017,2002).
Chlorine 9 oxime derivate is that one kind of Biorex company, Hungary discovery can selectively amplify the expression chemical combination of HSPs first Object, clinical test for the comprehensive disease of anti-glycosuria (Biro et al., Brain Res Bull.44:259-263,1997;Nanasi et al.,Cardiovasc Drug Rev.19:133-151,2001).Biorex company in 2004 is received by CytRx company, the U.S. Purchase, and new chlorine 9 oxime derivate is developed as prodrug, it is further used for treating various and heat shock protein (molecule companion Companion) the relevant disease neurodegenerative disease of activity.Numerous studies confirm that chlorine oxime compound is living with good molecular chaperones Property adjustment effect, can improve the activity of heat shock protein, can be used for the treatment of neurodegenerative disease.In normal cell, chlorine oxime Derivative does not activate HSF1 or induces the expression of HSPs.Chlorine oxime compound only amplifies companion's egg in stress situation or diseased cells White activity (Soti et al., Br J Pharmacol.146:769-780,2005).Such special molecular mechanism of action, it is special Targeting to act on stress cell, than those indiscriminate molecular chaperones regulators for acting on all cells have more potentiality, Safer (Soti et al., Br J Pharmacol.146:769-780,2005).
Chlorine 9 oxime derivate activity has been affirmed.Compound Bimoclomol and arimoclomol (Figure 1B) are two Representative chlorine 9 oxime derivate, all coming into the clinical II/III phase studies.Just it was applied to before Bimoclomol more years The treatment of diabetes and diabetic nephropathy, Abbott's infusion of financial resources in 1997 are closed with bimoclomol finder Biorex company Make the second stage of clinical research (Kalman.1997) of progress bimoclomol diabetic syndrome.Bimoclomol can selectively be put The activity of big a variety of heat shock proteins and heat shock factor, such as Hsp60, Hsp70, Hsp90, Grp94(glucose Regulated protein94kDa, grape regulatory protein 94) etc. (Nat Med.3:1150-1154,1997), and this kind of molecule Companion's mechanism of action is related to a variety of diseases, it is not only proved that the diabetes rat and multiple complications of STZ modeling can be treated (Biro et al.,Brain Res Bull.44:259-263,1997;Biro et al.,Neuroreport.9:2029- 2033,1998), and cardiac dysfunction, cerebrovascular exception various diseases (Erdo et al., Brain Res can be treated Bull.45:163-166,1998;Lubbers et al.,Eur J Pharmacol.435:79-83,2002;Polakowski et al.,Eur JPharmacol.435:73-77,2002)。
Arimoclomol shows activity outstanding, clinical test on treating a variety of neurodegenerative diseases (NCT00706147) it can at least delay the process of ALS illness 30% as the result is shown.Early-stage study report also demonstrates Arimoclomol is HSPs inducer (amplifier), can significantly improve HSF1 in stress situation cell, HSP70's, HSP90 etc. Expression quantity, and unobvious (Polakowski et al., Eur are influenced on the expression of HSPs in normal condition cell JPharmacol.435:73-77,2002;Hargitai et al.,Biochem Biophys Res Commun.307:689- 695,2003;Kieran et al.,Nat Med.10:402-405,2004)。
Arimoclomol is equally originally developed for treating diabetes also like bimoclomol, is found in later dynamic ALS significant effect is treated in object model.Arimoclomol is considered as the sound molecular chaperones regulator of function, can usually be lured The heat shock protein activity in all cells of human body is led, to improve the natural repair ability of cell, treats many diseases, including The impaired protein of ALS is abnormal.Another is applied to the chlorine 9 oxime derivate Iroxanadine of clinical test, is applied to heart and brain blood The treatment of pipe disease.(http://www.cytrx.com/molecular_chaperone_regulation.html,2010).
Ligustrazine (Tetramethylpyrazine, TMP) is the main active extracted in chuanxiong, tool There is extensive pharmacological action, the treatment for a variety of cardiovascular and cerebrovascular diseases.The Ca2+ overloading that ligustrazine is also shown in vascular tissue Agent effect (Pang et al., Planta Med.62:431-435,1996), this mechanism may be applied to nervus retrogression disease Disease.As ROS inhibitor, it can remove superoxide anion (O2 -), hydroxyl radical negative ion (OH-), lipid peroxy anion (lipid peroxyl, LOO-) etc. free radicals (Zhang et al., Zhongguo Yao Li Xue Bao.15:229-231, 1994;Zhang et al.,Life Sci.72:2465-2472,2003).In central nervous system, TMP can significantly inhibit iron The nerve cell oxidative damage of mediation and mitigate nerve cell death caused by glutamate toxicity (Shih et al., Neuroreport.13:515-519,2002;Zhang et al.,Eur J Pharmacol.467:41-47,2003;Liao et al.,Neurosci Lett.372:40-45,2004).Ligustrazine systemic administration protects the ischemic or brain to mouse and rabbit The nerve cell of wound or spinal cord injury, can promote its functional rehabilitation (Fan et al., BMC Neurosci.7:48,2006; Kao et al.,Neurochem Int.48:166-176,2006).It is interesting that Formulations for systemic administration ligustrazine can mitigate D- gala Rodent learning and memory impairment (Ni et al., Jpn J caused by sugar or ischemic brain damage Pharmacol.67:137-141,1995;Zhang et al.,Chin Med Sci J.19:180-184,2004).Significantly change The cognitive function of kind dementia model mice and brain amyloid protein amount (Tan, J Ocul Biol Dis Infor.2: 57-64,2009)。
But the antioxidation of ligustrazine is faint, bioavilability is low, clinically multiple dosing is needed to have can be only achieved Imitate concentration.The treatment of neurodegenerative disease at present is there are no specific drug, and the drugs few in number listed are all because treat Bad or toxic side effect is imitated to be difficult to meet the requirements greatly.Induction heat shock protein expression repairs the protein of false folding or removes it The emphasis that the effect of aggregation protection nerve cell is always studied both at home and abroad.
Summary of the invention
The present invention is intended to provide a kind of chlorine oxime compound and its pharmaceutically acceptable salt, such compound can induce heat The expression of shock protein, antioxidant stress injury have very strong cytoprotection ability；And provide the chlorine oxime compound Preparation method；The chlorine oxime compound and its pharmaceutically acceptable salt are also provided in treatment due to protein Misfolding Or it is abnormal fold the method for forming aggregation or the disease caused by oxidative stress and the chlorine oxime compound and its Pharmaceutically acceptable salt is preparing the application in relative medicine.
On the one hand, the present invention provides a kind of chlorine oxime compound and its pharmaceutically acceptable salt, the chlorine oximes Compound has the structure of following general formula I:
A kind of chlorine oxime compound and its pharmaceutically acceptable salt, the chlorine oxime compound is with following general formula I's Structure:
Wherein:
R1,R2,R3,R4Identical or different, independent is H, OH, NH2, COOH, linear or branched alkyl group, replace or not Substituted monocycle or multi-ring alkyl, aryl, heterocyclic base (O, S), nitrogenous heterocyclic base and its N → O group, acyl group, ester group or amine Base；R2With R3Also substituted or unsubstituted 4-8 member ring can be formed with N atom；
Work as R4When for H, R1It is not H, substituted or unsubstituted phenyl, naphthalene, pyridyl group or thienyl；
N is 0,1,2 or 3.
According to general formula I, preferred chlorine oxime compound has the structure of following general formula II:
Wherein: R2,R3,R4Identical or different, independent is H, OH, NH2, COOH, linear or branched alkyl group, substitution Or unsubstituted monocycle or multi-ring alkyl, aryl, heterocyclic base (O, S), nitrogenous heterocyclic base and its N → O group, acyl group, ester group, or Amido；R2With R3Also substituted or unsubstituted 4-8 member ring can be formed with N atom；
R5,R6,R7Identical or different, independent is H, F, Cl, Br, I, OH, NH2, COOH, linear or branched alkyl group, Aryl, heterocyclic base (O, N, S), acyl group, ester group or amido；
At least one is N atom to X and Y, and when X and Y only one are N atomic time, R4It is not H；Be connected on N atom oxygen or Person does not connect oxygen；
N is 0,1,2 or 3.
According to general formula II, preferred chlorine oxime compound has the structure of general formula III:
According to general formula III, preferred chlorine oxime compound is it is characterized in that R2Selected from methyl, ethyl, n-propyl, isopropyl Base, R3Selected from 3- methyl adamantane base, 3,5- dimethyladamantane bases, isopropyl or R2, R3Hexatomic ring is connected into N atom； Further preferred chlorine oxime compound is it is characterized in that R5,R6,R7For methyl, R2,R3Hexatomic ring is connected into N atom, it is described Chlorine oxime compound has the structure of following general formula IV:
R4For H, OH, NH2, COOH, linear or branched alkyl group, substituted or unsubstituted monocycle or multi-ring alkyl, aryl are fragrant Miscellaneous base (O, S), nitrogenous heterocyclic base and its N → O group, acyl group, ester group, amido.R8Selected from H, the linear chain or branched chain alkane of C1-C4 Base；
Oxygen is connected with above pyridine ring N atom or does not connect oxygen；
N is 0,1,2 or 3.
According to general formula IV, preferred chlorine oxime compound has the structure of general formula V:
R4For H, OH, NH2, COOH, linear or branched alkyl group, substituted or unsubstituted monocycle or multi-ring alkyl, aryl are fragrant Miscellaneous base (O, S), nitrogenous heterocyclic base and its N → O group, acyl group, ester group or amido；
Oxygen is connected with above pyridine ring N atom or does not connect oxygen；
N is 0,1,2 or 3.
According to general formula V, preferred chlorine oxime compound has the structure of general formula VI:
Wherein: being connected with oxygen on pyridine ring N atom or do not connect oxygen；N is 0,1,2 or 3.
According to general formula VI, preferred chlorine oxime compound has the structure of following TCO-1 and TCO-2, but is not limited only to this Two compounds.
On the other hand, the present invention also provides the preparation methods of the chlorine oxime compound.The described method includes: will rise Amino is made with substituted 2- hydroxyl -4- azepine -4- reactant salt again after reacting with hydroxylamine hydrochloride in the itrile group derivative of beginning raw material Substituted amino oxime compound, last amino oxime is reacted with hydrochloric acid is made chlorine oxime compound.
The present invention also provides any of the above-described compound comprising pharmaceutical effective dose or its pharmaceutically-acceptable salts Pharmaceutical composition.The effective dose is 1mg-10g.
Invention further provides any of the above-described compound of pharmaceutical effective dose or its pharmaceutically-acceptable salts, with And the pharmaceutical composition of any of the above-described compound or its pharmaceutically-acceptable salts comprising pharmaceutical effective dose treatment due to Protein Misfolding or abnormal folding form the method for aggregation or the disease caused by oxidative stress and in preparation phases Answer the application in drug.
Compared with prior art, the present invention having following innovative:
1) clinical test drug is replaced using active Chinese drug component molecule TMP ring and its derivative or pyridine ring for the first time The pyridine ring of bimoclomol and arimoclomol chlorine 9 oxime derivate has synthesized serial new chlorine 9 oxime derivate.
2) for the first time in the pyridine of TMP ring replacement clinical test drug bimoclomol and arimoclomol chlorine 9 oxime derivate Spread out on the basis of ring using the new chlorine oxime of the piperidines synthesis series of alkane or branched paraffin, adamantane and its derivative replacement right side Biology；The activity of newly synthesized compound TCO-1, TCO-2 are significantly higher than bimoclomol and arimoclomol.
3) for the first time in the pyridine of TMP ring replacement clinical test drug bimoclomol and arimoclomol chlorine 9 oxime derivate Active small molecular danshensu is used on the basis of ring, cinnamic acid, lipoic acid, biotin, TMP and its derivative replace intermediate hydroxyl The new chlorine 9 oxime derivate of hydrogen synthesis series.
4) a set of practicable chemical synthesis route (method) Lai Hecheng chlorine oxime-ligustrazine derivant is had found.
Detailed description of the invention
Figure 1A is document report diagram, wherein describing in sporadic ALS always along with ubiquitin-dyeing inclusion body Aggregation is (referring to Cellular and molecular processes mediating neurodegeneration in ALS, Kiernan et al., Lancet.377:942-955,2011)；
Figure 1B shows the chemical structure in relation to chlorine oxime compound；
Fig. 1 C. shows the chemical structure of TMP, TCO-1 and TCO-2；
Fig. 2 shows a kind of synthetic route of compound TCO-1；
Fig. 3 shows another synthetic route of compound TCO-1；
Fig. 4 shows a kind of synthetic route of compound TCO-2；
Fig. 5 shows another synthetic route of compound TCO-2；
Fig. 6 describes the protection of compound TCO-1, TCO-2, PCO-1 and BCO-1 to the cell of MG-132 induced damage Effect；
Fig. 7 describes compound TCO-1, TCO-2, PCO-1 and BCO-1 to the inhibiting effect of ROS；
Fig. 8 describes the protective effect of compound TCO-1, TCO-2 and PCO-1 to the cell of MPP+ induced damage；
Fig. 9 is to show that compound TCO-1/TCO-2 removes the picture of the aggregation of ubiquitin protein；
Figure 10 is to show that TCO-1 reduces the datagram that AD rat model reaches plateau time；
Figure 11 is to show that TCO-1 increases the datagram that AD rat model passes through platform number.
Specific embodiment
Definition:
Meaning and range defined below to illustrate and define various terms used in the invention.
The term as used herein " alkyl " refers to up to 15 of unsubstituted or substituted straight chain, branch or annular The alkyl carbon chain of carbon atom.Straight chained alkyl include as methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl and N-octyl.Branched alkyl includes such as isopropyl, sec-butyl, isobutyl group, tert-butyl, neopentyl.Monocycle alkyl include as cyclopropyl, Cyclobutyl, cyclopenta, cyclohexyl and suberyl.Alkyl can be substituted by one or more substituents.Above-mentioned substituent group it is non-limiting Property example includes OH, F, Cl, Br, I, NH2, NO2, ONO2.Term " multi-ring alkyl " also refers to unsubstituted or substituted two member ring, three Member ring, the Non-limiting examples of substituent group include OH, F, Cl, Br, I, NH2, NO2, ONO2。
The term as used herein " aryl " refers to unsubstituted or substituted aromatic, carbon ring group and heteroaryl Base.Aryl monocycle either fused polycyclic compounds.For example, phenyl is monocyclic aryl.Naphthalene is that have polycyclic condense Aryl example.Aryl can be substituted by one or more substituents, and the unrestricted example of substituent group includes OH, F, Cl, Br, I, NH2, NO2, ONO2.That term " heteroaryl " is related to replacing or non-substituted monocycle or polycyclic group, in ring extremely It less include a hetero atom, for example nitrogen, oxygen and sulphur.For example, typical heterocyclic group includes one or more nitrogen-atoms For example tetrazole radical, pyrrole radicals, pyridyl group (such as 4- pyridyl group, 3- pyridyl group, 2- pyridyl group etc.), pyridazinyl, indyl, quinolyl (such as 2- quinolyl, 3- quinolyl etc.), imidazole radicals, isoquinolyl, pyrazolyl, pyrazinyl, pyrimidine radicals, pyriconyl or pyridazine Base；Typically the heterocyclic group containing an oxygen atom includes 2- furyl, 3- furyl or benzofuranyl；Typical thia is former Subbase group includes thienyl, benzothienyl；Typical mixing heteroatom group includes furan a word used for translation base, oxazolyl, isoxazolyl, thiophene Oxazolyl and phenoxthine base.Heterocyclic group can be substituted by one or more substituents.These substituent groups include NH2、NO2, O- alkyl, NH- alkyl, N (alkyl)2, NHC (O)-alkyl, ONO2、F、Cl、Br、I、OH、OCF3、OSO2CH3、CO2H、CO2Alkyl, CN with And low alkyl group, aryl and polyaryl.These situations include simultaneously in ring hetero atom be oxidized, for example formed N- oxide, ketone Or sulfone.
Nitrogenous heteroaryl N → O compound is related to N → O compound containing 1 or 2 N atom aromatic heterocycle.
Terms used herein " pharmaceutically acceptable " refer to not having unacceptable poison in compound such as salt Property.Pharmaceutically acceptable salt includes inorganic anion, for example, chloride ion, sulfate radical, inferior sulfate radical, nitrate anion, nitrite anions, Phosphate radical, hydrogen phosphate etc..Organic anion includes acetate, propionate, cinnamate, benzene methanesulfonic acid root, citrate, cream Acid group, glucose acid group etc..
It includes following excellent for having the noval chemical compound of logical formula (I) structure provided by a specific embodiment of the invention Select compound: (TCO-1), (TCO-2), (PCO-1), (PCO-2), (ACO-1a), (ACO-1b), (ACO-2a), (ACO-- 2b),(GCO-1c-7c),(GCO-1d-7d),(FCO-1a-6a),(FCO-1b-6b),(LCO-1),(LCO-2)。
Compound (TCO-1) with logical formula (I) structure, (TCO-2), (PCO-1), (PCO-2), (ACO-1a), (ACO- 1b),(ACO-2a),(ACO--2b),(GCO-1c-7c),(GCO-1d-7d),(FCO-1a-6a),(FCO-1b-6b),(LCO- 1), chlorine oxime and oxime TMP involved in (LCO-2) or its N → Oization derivative are all the energy with induction heat shock protein expression Power, on the one hand they can induce the heat shock protein expression under stress situation, and on the other hand can repair stress cause to fold The protein of mistake removes its aggregation, and therefore, they can be used for preventing and treating protein folding mistake or abnormal aggregation Disease caused by being formed.These diseases include but is not limited to the nervous system disease, outside ischemic-hypoxic brain injury, apoplexy, brain Wound, senile dementia, epilepsy, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, it is aids dementia disease, multiple Sclerosis, chronic ache, priapism, cystic fibrosis, schizophrenia, depression, premenstrual syndrome, anxiety, Habituation and migraine etc.；It further include cardiovascular disease, such as heart effluent, ischemia reperfusion injury, ischemia-reperfusion, Poisoning Shock syndrome, adult respiratory distress wait group, cachexia, myocarditis, atherosclerosis, coronary heart disease heart disease and heart Onste etc.；It further include inflammation infection disease, as inflammatory intestines problem, diabetes, rheumatoid arthritis, asthma, liver are hard Change, allosome rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, Glomerulonephritis, systemic loupus erythematosus, gastrointestinal motility function disorder, obesity, hyperalimentation, hepatitis and renal failure；Also Including ophthalmology disease, such as diabetic retinopathy, uveitis, glaucoma, blepharitis, chalazion, allergic ophthalmopathy, cornea Ulcer, keratitis, cataract, age-related macular degeneration and optic neuritis.
Chlorine oxime compound of the present invention can a kind of pharmaceutically acceptable salt or pharmaceutical composition form to trouble Person's administration.Some compound need to be mixed to form pharmaceutical composition with suitable carrier or excipient to guarantee to reach effective therapeutic agent Amount." dose therapeutically effective " refers to that chlorine oxime compound reaches therapeutic effect and (repairs protein folding mistake, remove abnormal aggregation Protein, reduce because of cellular damage caused by neurodegenerative disease, metabolic disease or cardiovascular and cerebrovascular disease etc.) must The dosage of palpus.
A variety of dosage forms, including solid dosage forms can be made in chlorine oxime compound and its composition containing such compound, Semisolid dosage form, liquid preparation and aerosol (Remington ' s Pharmaceutical Sciences, Mack Publishing Company(1995),Philadelphia,PA,19thEd).Specific dosage form in this few class dosage form includes piece Agent, pill, dragee, granule, gelling agent, paste, solution, suppository, injection, inhalant and spray.These agent Type can be used to locally or systemically be administered but also be used for quick-release or slow continuous administration, and there are many kinds of the administration modes of such drug, removes Aforesaid way there are also oral administration, buccal administration, rectally, peritoneal administration, Intraperitoneal medication, epidermis administration, is subcutaneously given Medicine and intrarterial etc..
When chlorine oxime compound and its composition drug administration by injection containing these compounds, water-soluble or liposoluble can be used Such compound is configured to solution, suspension and emulsion by the solvent of property.Fat-soluble solvent specifically includes vegetable oil and similar Oils, synthctic fat acid glyceride, high-grade aliphatic ester and glycol ester (proylene glycol).This kind of compound is more It is soluble in ethanol solution, micro DMSO solution.
When chlorine oxime compound and its composition oral containing these compounds are administered, it can use common technology will Compound is made with pharmaceutically acceptable excipient in it.These excipient these compounds can be made it is a variety of can be by patient Dosage form, such as tablet, pill, suspension, gelling agent.There are many methods for the preparation of oral preparation, such as first compound and solid Excipient mixes, and is fully ground mixture, adds auxiliary material appropriate, working process is at particle.Can be used for that peroral dosage form is made Auxiliary material include: carbohydrate such as lactose, sucrose, mannitol or sorbierite；Cellulose family such as cornstarch, wheaten starch, potato Starch, gelatin, western twelve month yam glue, methylcellulose, hydroxymethyl cellulose (hydroxyproylmethyl-cellulose), carboxylic first Ji Xianweisuna, polyvinyl pyrrolidone etc..
Spray can also be made in chlorine oxime compound of the present invention and its composition containing these compounds, this Kind dosage form is realized by a pressurizer and a sprayer or a powder inhaler.It may be used as injector In suitable stock solution such as dicholorodifluoromethane, fluoro trichloromethane, dichlorotetra-fluoroethane, carbon dioxide and dimethyl ether etc..Aerosol The dosage of agent administration can be adjusted by the valve of injector.
Various dosage forms of the present invention are all related to chlorine oxime compound and its composition containing these compounds Dose therapeutically effective.The dose therapeutically effective of such compound depends on patient receiving treatment.When determining suitable dosage, Weight, the state of an illness, medicining mode and the subjective judgement of the prescriber factor of patient will account for.Chlorine oxime compound and The therapeutically effective amount of its composition for containing these compounds should be determined by having the ability with the prescriber of rich experiences.
Although the dose therapeutically effective of chlorine oxime compound and its composition containing these compounds can be according to patient's feelings Condition changes, but usually dosage range appropriate is 10mg-10g.
Compared with the prior art, the invention has the following advantages: the present invention provides a kind of compounds of brand new, together When there is double action mechanism (repair protein folding mistake & remove its abnormal aggregation object or/and cytoprotection), can pass through Blood-brain barrier and safely and effectively compound.These compounds are to be worth the treatment and prevention of exploitation due to protein folding mistake Mistake or abnormal aggregation or the neurodegenerative disease due to caused by oxidative stress, metabolic system disease, the heart, cerebrovascular system disease The drug of disease, infectious diseases and ageing disorders etc..
The following examples are used to be illustrated for implementation of the invention, can be by but be not construed as the present invention To the limitation of these embodiments.
The synthesis (Fig. 2) of embodiment one, compound TCO-1
It weighs Tetramethylpyrazine 10g (73.5mmol) to be dissolved in 20ml acetic acid, 30% hydrogen peroxide 8ml is added.70 °C of conditions Lower oil bath adds 8.3ml30% (73.5mmol) hydrogen peroxide after reacting 5 hours, and the reaction was continued 5 hours, and TLC monitors reaction interval Degree stops reaction.It is cooled to room temperature, sodium hydroxide saturated solution adjusts pH to 10.Methylene chloride extracts (50ml*5 times), takes organic Layer does to obtain white solid (1a-1) with Rotary Evaporators vacuum distillation.20ml acetic anhydride (212mmol) 125 °C of oil are added thereto Bath reaction 2.5 hours, TLC detects fully reacting.Vacuum distillation removes acetic anhydride, obtains acetylation crude product (1a-2).Then, hydrogen Sodium oxide molybdena saturated solution is adjusted to pH to 12, is stirred at room temperature, and hydrolysis is overnight.Ethyl acetate extracts reaction solution (50ml*5 times), Vacuum distillation is dry, and wet process loading column chromatography, mobile phase EA:PE (1:1), TLC detect fraction, collects TMP-OH fraction.Merge institute Identical fraction is needed, vacuum distillation is dry, obtains Off-white solid powder 7.5g (1a-3, TMP-OH, 49.3mmol), [M+Na]+=175, Yield 67%.
By gained 7.5g TMP-OH (49.3mmol) be dissolved in 50ml dehydrated alcohol be added activated manganese dioxide (6.4g, It 73.6mmol) aoxidizes, 2h is reacted in 84 °C of oil baths, after TLC detects fully reacting, carefully filters reaction using five layers of filter paper while hot Liquid removes manganese dioxide powder.Clear filtrate is obtained after filter, Rotary Evaporators vacuum distillation is dry.Wet process loading column chromatography: flowing Phase EA:PE (1:5) is isolated and purified, and TLC monitors fraction.Compound 1a-4 fraction is collected, merges identical fraction distillation and does to obtain crystal Shape white solid 5.5g (36.7mmol), [M+H]+=151 i.e. 1a-4 (TMP-CHO), yield 75%.
5.5g (36.7mmol) compound 1a-4 sample 30ml formic acid is dissolved, 3.2g (45.9mmol) hydrochloric acid hydroxyl is weighed Amine is added, and 3.13g (45.9mmol) sodium formate is then added, miscible, and 120 °C of oil bath reactions are refluxed overnight.It is saturated sodium hydroxide Solution adjusts reaction solution pH to 10, and methylene chloride extracts (30ml*5 times), takes organic layer vacuum distillation dry.100-200 mesh silica gel Mix sample, dry method loading column chromatography: mobile phase EA:PE(1:5), TLC monitoring outflow fraction compositions collect compound 1a-5 fraction. It is dry to merge identical fraction distillation, obtains white solid i.e. compound 1a-5, yield 65%.
It takes compound 1a-5 (3.5g, 23.9mmol) to be dissolved in 30ml dehydrated alcohol, hydroxylamine hydrochloride 2.1g is added (29.9mmol), takes sodium bicarbonate 2.6g(30.9mmol) it is dissolved by heating in 20ml distilled water, miscible, 105 °C of oil bath reactions 3 Hour.TLC monitors the extent of reaction, stops reaction.Vacuum distillation is dry, dry method loading column chromatography, mobile phase EA:PE:Et3N(60: 40:0.5), fraction is collected, TLC monitors fraction compositions.It is dry to merge identical fraction vacuum distillation, obtains white solid i.e. compound 1a- 6, yield 95%.
It takes compound 1a-6 (4.1g, 22.7mmol) to be dissolved in 30ml ethyl alcohol, sodium hydroxide (1.4g, 35mmol) is taken to be dissolved in In 30ml distilled water, rear be added quaternary ammonium salt 1a-75.1g (28.8mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, TLC detection reaction Degree.Ethyl acetate extracts reaction solution (30ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, mobile phase EA:PE:Et3N (70:30:0.5) elution, collects fraction, and TLC detects fraction compositions.Merge the vacuum distillation of compound fraction to do Transparent oil 1a-8 (4.4g, 13.7mmol), yield 60%.
It weighs sodium nitrite (1.2g, 17.4mmol) to be dissolved in 4ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 1a-8 (4.4g, 13.7mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 20ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath item in salt ice bath stirring thereto PH to 10 is adjusted with the NaOH solution (7M) cooled under part.It is extracted with dichloromethane reaction solution (15ml*5 times), receives finally, adopting Take organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N (17:83:0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless and transparent oily object That is TCO-1 (2.2g, 6.8mol), yield 50%.1H-NMR(CDCl3,300MHz)(ppm)δ:1.37-1.60(m,6H,3CH2), 2.30-2.40(m,6H,3NCH2),2.52(s,6H,2CH3),2.60(s,3H,CH3),4.04(m,1H,CH),4.28(m,2H, NOCH2).13C-NMR(CDCl3,75.47MHz)(ppm)δ:21.57(CH3);21.97(CH3);22.40(CH3);24.29, 26.16(3C,piperidine,3CH2);55.78,55.41(2C,piperidine,2NCH2);61.09(CHOH);65.34 (CH2N);78.31(NOCH2);135.89(2-pyrazine);141.98(C(Cl)=N);148.96(5-pyrazine); 149.24(3-pyrazine);152.20(6-pyrazine).MS(ESI)[M+H]+m/z341;Analysis calculated for(C16H25ClN4O2):C,56.38;H,7.39;N,16.44.Found:C,56.14;H,7.58;N,16.19.
Embodiment two, another synthetic method (Fig. 3) of compound TCO-1
Take the 1a-6 (2.1g, 11.6mmol) prepared to be dissolved in 20mlNaOH solution, take epoxychloropropane (2.05ml, It 21.5mmol) is dissolved in a small amount of DMSO, miscible, ice bath stirring is overnight, and TLC monitors the extent of reaction, stops reaction.Methylene chloride extraction It extracts reaction solution (50ml*5 times), column chromatographic purifying obtains compound 1a-9 (1.64g, 6.96mmol), yield 60%.By gained 1a- 9 are dissolved in 10ml DMF, are added 80 °C of piperidines (1.04ml, 10.3mmol), react 3h, and TLC monitors the extent of reaction, stop anti- It answers.Ethyl acetate extracts (30ml*5 times), and column chromatographic purifying obtains compound 1a-8(2.12g, 6.6mmol), yield 95%.Claim Sodium nitrite (0.57g, 8.3mmol) is taken to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and it is spare that sub- acid sodium solution is made.It will Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 1a-8 (2.12g, 6.6mmol) is taken to be dissolved in the cold hydrochloric acid of 13ml In solution, then sodium nitrite solution reaction 1h is slowly added dropwise, then with cooling under condition of ice bath in salt ice bath stirring thereto NaOH solution (7M) adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, collects organic layer. Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N (17:83:0.5), TLC monitoring evaporate It is divided into point, merges that identical fraction vacuum distillation is dry, and oil pump decompression abstraction residual solvent obtains the colorless and transparent i.e. TCO-1 of oily object (1.1g, 3.4mol), yield 51.5%.Detection data is identical as a upper method.
The synthesis (Fig. 4) of embodiment three, compound TCO-2
The intermediate 1a-5 (3g, 20.4mmol) prepared is taken, the dissolution of 30ml methylene chloride is added, m-chloro mistake is then added For 24 hours, TLC monitors the extent of reaction, stops reaction for oxybenzoic acid (MCPBA, 3.5g, 20.4mmol) (20-24 °C) of room temperature stirring.Subtract Methylene chloride, dry method loading column chromatography is distilled off in pressure.Mobile phase EA:PE (1:2) collects fraction, and TLC monitors fraction compositions, Merge identical fraction.Vacuum distillation is dry, obtains white solid 1b-1 (2.8g, 17.2mmol).Yield 84%.
Resulting 1b-1 (2.8g, 17.2mmol) is dissolved in 30ml dehydrated alcohol, hydroxylamine hydrochloride 1.5g is added (21.7mmol) takes sodium bicarbonate 1.9g (22.6mmol) to dissolve in 20ml distilled water, miscible, and reaction 24 hours is stirred at room temperature. TLC monitors the extent of reaction, stops reaction.Vacuum distillation is dry, dry method loading column chromatography, mobile phase EA:PE:Et3N(80:20: 0.5) fraction, is collected, TLC monitors fraction compositions.It is dry to merge identical fraction vacuum distillation, obtains white solid i.e. compound 1b-2, Yield 95%.
It takes compound 1b-2 (3.2g, 16.3mmol) to be dissolved in 30ml ethyl alcohol, sodium hydroxide (0.8g, 20mmol) is taken to be dissolved in In 20ml distilled water, rear be added quaternary ammonium salt 1a-7 (3.5g, 19.7mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (30ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (85:15:0.5) elution, collects fraction, and TLC detects fraction compositions.Merge the decompression of compound 1b-2 fraction to steam Evaporate dry transparent oil (3.3g, 9.8mmol), yield 60%.
It weighs sodium nitrite (1.06g, 12.25mmol) to be dissolved in 3.5ml distilled water, salt ice bath is down to -5 °C, and Asia is made Acid sodium solution is spare.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Take compound 1b-3 (3.3g, 9.8mmol) molten In the cold hydrochloric acid solution of 20ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath in salt ice bath stirring thereto Under the conditions of with the NaOH solution (7M) that cools adjust pH to 10.Reaction solution (15ml*5 times) is extracted with dichloromethane finally, adopting, Collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(20:80: 0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless transparent oil White solid i.e. TCO-2 (1.8g, 4.9mmol), yield 50% can be obtained after shape object multigelation.1H-NMR(CDCl3,300MHz) (ppm)δ:1.23-1.60(m,6H,3CH2),2.04-2.41(m,6H,3NCH2),2.51(s,3H,CH3),2.56(s,3H, CH3),2.59(s,3H,CH3),4.01-4.35(m,3H,CH and NOCH2).13C-NMR(CDCl3,75.47MHz)(ppm)δ: 13.81(CH3);14.23(CH3);22.57(CH3);24.33,26.22(3C,piperidine,3CH2);54.78,54.81, 60.97(3C,3NCH2);65.29(CHOH);78.58(NOCH2);134.22(C(Cl)=N);141.48(2-pyrazine); 143.11(6-pyrazine); 144.96(3-pyrazine);152.27(5-pyrazine).ESI-MS[M+H]+m/z357; Analysis calculated for (C16H25ClN4O3):C,53.85;H,7.06;N,15.70.Found:C,53.91;H, 6.91;N,16.04.
Example IV, another synthetic method (Fig. 5) of compound TCO-2
Take the 1b-2 (1.6g, 8.2mmol) prepared to be dissolved in 10ml NaOH solution, take epoxychloropropane (1.2ml, It 12.6mmol) is dissolved in a small amount of DMSO, miscible, ice bath stirring is overnight, and TLC monitors the extent of reaction, stops reaction.Methylene chloride extraction It extracts reaction solution (10ml*5 times), column chromatographic purifying obtains compound 1b-4 (1.23g, 4.9mmol), yield 60%.By gained 1b-4 It is dissolved in 10ml DMF, is added 80 °C of piperidines (0.74ml, 7.3mmol), react 3h, TLC monitors the extent of reaction, stops reaction. Ethyl acetate extracts (10ml*5 times), and column chromatographic purifying obtains compound 1b-3(1.57g, 4.65mmol), yield 95%.It weighs Sodium nitrite (0.4g, 5.8mmol) is dissolved in 4ml distilled water, and salt ice bath is down to -5 °C, and it is spare that sub- acid sodium solution is made.It will be dense Hydrochloric acid be 1M solution, be cooled to -5 °C it is spare.Take compound 1b-3(1.57g, 4.66mmol) to be dissolved in the cold hydrochloric acid of 10ml molten In liquid, then sodium nitrite solution reaction 1h is slowly added dropwise, then under condition of ice bath with cooling in salt ice bath stirring thereto NaOH solution (7M) adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, collects organic layer.Subtract Press the resulting sample liquid of distillation extraction, wet process loading column chromatography, mobile phase EA:PE:Et3N (20:80:0.5), TLC monitor fraction Ingredient merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains the colorless and transparent i.e. TCO-2 of oily object (0.86g, 2.3mol), yield 51.7%.Detection data is identical as a upper method.
Embodiment five, a kind of synthetic method of compound BCO-1
The midbody compound 1a-3 (TMP-OH, 4g, 26.3mmol) synthesized is taken, 79ml ammonium hydroxide is added thereto (30%) it dissolves, elemental iodine 0.67g (2.63mmol), tert-butyl hydroperoxide (TBHP) 8.3ml (57.86mmol) is then added Oil bath is reacted under the conditions of being miscible in 60 °C, and TLC monitors the extent of reaction after 15h, stops reaction.Ethyl acetate extracts (30ml*5 It is secondary), collected organic layer vacuum distillation is dry.100-200 mesh silica gel mixed sample, dry method loading column chromatography.Mobile phase: Acetone:PE: Et3N (20:80:0.5) elution, TLC monitoring outflow fraction compositions merge identical fraction vacuum distillation and do, obtain faint yellow solid powder Last 2a-1 (0.45g, 3.06mmol), yield 11.6%.
It takes the 2a-1 (0.45g, 3.06mmol) synthesized to be dissolved in 10ml dehydrated alcohol, hydroxylamine hydrochloride is then added (0.27g, 3.88mmol) in addition weighs sodium bicarbonate (0.33g, 3.93mmol) and is dissolved in miscible in 5ml distilled water, 105 °C of oil Bath reaction 3 hours, TLC detects the extent of reaction, stops reaction.Vacuum distillation is dry, silica gel mixed sample dry method loading column chromatography, mobile phase EA:PE:Et3N (80:20:0.5) elution, TLC monitoring outflow fraction compositions, merges identical component, vacuum distillation is white admittedly dry Body 2a-2 (0.53g, 2.93mmol), yield 95.7%.
It takes compound 2a-2 (0.53g, 2.93mmol) to be dissolved in 15ml ethyl alcohol, takes sodium hydroxide (0.18g, 4.5mmol) molten In 5ml distilled water, rear be added quaternary ammonium salt 1a-70.65g (3.66mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (10ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (80:20:0.5) elution, collects fraction, and TLC detects fraction compositions.Merge the decompression of compound 2a-3 fraction to steam Evaporate dry transparent oil 2a-3 (0.28g, 0.87mmol), yield 30%.
It weighs sodium nitrite (0.075g, 1.09mmol) to be dissolved in 0.5ml distilled water, salt ice bath is down to -5 °C, and Asia is made Acid sodium solution is spare.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Take compound 2a-3 (0.28g, 0.87mmol) It is dissolved in the cold hydrochloric acid solution of 1.3ml, salt ice bath stirring, sodium nitrite solution is then slowly added dropwise thereto, react 1h.Then exist PH to 10 is adjusted with the NaOH solution (7M) cooled under condition of ice bath.Reaction solution (2ml*5 is extracted with dichloromethane finally, adopting It is secondary), collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(15: 85:0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colourless Bright grease, that is, 2a, BCO-1 (0.063g, 0.0017mol), yield 20%.1H-NMR(CDCl3,300MHz)(ppm)δ:1.42- 1.62(m,6H,3CH2),2.24-2.66(m,12H,3NCH2,2CH3),4.02-4.37(m,3H,CH,NOCH2).13C-NMR (CDCl3,75.47MHz)(ppm)δ:21.75(CH3);22.52(CH3);24.32,26.20(3C,piperidine,3CH2); 54.79,54.86(2C,piperidine,2NCH2);60.96(CHOH);65.26(CH2N);78.60(NOCH2);135.17 (2-pyrazine,CCl);142.85(5-pyrazine);147.81(C(Cl)=N);149.61(3-pyrazine);150.45 (6-pyrazine).ESI-MS[M+H]+m/z361;Analysis calculated for(C15H22Cl2N4O2):C,49.87; H,6.14;N,15.51.Found:C,50.27;H,6.18;N,15.40.
Embodiment six, a kind of synthetic method of compound PCO-1
It takes compound 2- itrile group pyrazine (3g, 28.6mmol) to be dissolved in 35ml dehydrated alcohol, hydroxylamine hydrochloride 2.5g is added (36.2mmol) takes sodium bicarbonate 3.1g (36.9mmol) to dissolve by heating in 25ml distilled water, miscible, and 105 °C of oil bath reactions 3 are small When.TLC monitors the extent of reaction, stops reaction.Vacuum distillation is dry, dry method loading column chromatography, mobile phase EA:PE:Et3N(70:30: 0.5) fraction, is collected, TLC monitors fraction compositions.It is dry to merge identical fraction vacuum distillation, obtains white solid i.e. compound 3a-1 (3.75g, 27.2mmol, yield 95%).
It takes compound 3a-1 (3.75g, 27.2mmol) to be dissolved in 30ml ethyl alcohol, sodium hydroxide (1.4g, 35mmol) is taken to be dissolved in In 30ml distilled water, rear be added quaternary ammonium salt 1a-75.1g (28.8mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, TLC detection reaction Degree.Ethyl acetate extracts reaction solution (30ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, mobile phase EA:PE:Et3N (85:15:0.5) elution, collects fraction, and TLC detects fraction compositions.Merge the vacuum distillation of compound 3a-2 fraction Do to obtain transparent oil (4.5g, 16.1mmol), yield 59%.
It weighs sodium nitrite (1.4g, 20.3mmol) to be dissolved in 4ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Take compound 3a-2 (4.5g, 16.1mmol It 13.7mmol) is dissolved in the cold hydrochloric acid solution of 25ml, salt ice bath stirring, sodium nitrite solution reaction is then slowly added dropwise thereto Then 1h adjusts pH to 10 with the NaOH solution (7M) cooled under condition of ice bath.Reaction is extracted with dichloromethane finally, adopting Liquid (15ml*5 times), collects organic layer.Vacuum distillation extracts resulting sample liquid, and wet process loading column chromatographs, mobile phase EA:PE: Et3N (20:80:0.5), TLC monitor fraction compositions, merge identical fraction vacuum distillation and do, oil pump decompression abstraction residual solvent, Obtain colorless and transparent oily object, that is, 3a, PCO-1 (2.2g, 6.8mol), yield 50%.1H-NMR(CDCl3,300MHz)(ppm)δ: 1.35-1.51(m,6H,3CH2),2.25-2.38(m,6H,3NCH2),3.96-4.40(m,3H,CH,NH2).13C-NMR (CDCl3,75.47MHz)(ppm)δ:23.99,25.67(3C,piperidine,3CH2);58.40(2C,piperidine, 2NCH2);61.71(CH2N),66.09(CHOH);79.36(NOCH2);135.09(5-pyrazine);143.75(3- pyrazine);144.30(6-pyrazine);145.11(2-pyrazine);145.76(C(Cl)=N).ESI-MS[M+H]+ m/z299;Analysis calculated for (C13H19ClN4O2):C,52.26;H,6.41;N,18.75.Found:C, 52.19;H,6.53;N,18.62.
Embodiment seven, a kind of synthetic method of compound FCO-1a
2,6- lupetidine (10ml, about 8.23g) is taken to be dissolved in 25ml methanol, and addition epoxychloropropane (9ml, about 10g), 80 °C of oil baths are reacted 10 hours, are evaporated under reduced pressure out methanol, and 25ml water is added, washs (15ml*3 times) with methylene chloride and removes Surplus stock is removed, water phase evaporated under reduced pressure is collected and obtains light red solid 5a-1(8.6g, 41.9nmol), yield 60%.
It takes compound 1a-6 (1.0g, 5.6mmol) to be dissolved in 20ml ethyl alcohol, sodium hydroxide (0.6g, 15mmol) is taken to be dissolved in In 10ml distilled water, rear be added quaternary ammonium salt 5a-12.28g (11.1mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (20ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (80:20:0.5) elution, collects fraction, and TLC detects fraction compositions.It is dry to merge the vacuum distillation of compound fraction It obtains transparent oil 5a-2 (1.1g, 3.2mmol), yield 59%.
It weighs sodium nitrite (0.43g, 6.3mmol) to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 5a-2 (1.1g, 3.2mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 10ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath item in salt ice bath stirring thereto PH to 10 is adjusted with the NaOH solution (7M) cooled under part.It is extracted with dichloromethane reaction solution (10ml*5 times), receives finally, adopting Take organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N (20:80:0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless and transparent oily object That is FCO-1 (0.57g, 1.5mmol), yield 50%.ESI-MS[M+H]+m/z369,ESI-MS[M+Na]+m/z391。
Embodiment eight, a kind of synthetic method of compound FCO-1b
It takes compound 1b-2 (1.0g, 5.1mmol) to be dissolved in 20ml ethyl alcohol, sodium hydroxide (0.43g, 10.7mmol) is taken to be dissolved in In 10ml distilled water, rear be added quaternary ammonium salt 5a-1 (2.00g, 9.75mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (20ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (80:20:0.5) elution, collects fraction, and TLC detects fraction compositions.It is dry to merge the vacuum distillation of compound fraction It obtains transparent oil 5b-1 (1.12g, 3.07mmol), yield 60%.
It weighs sodium nitrite (0.42g, 6.1mmol) to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 5b-1 (1.12g, 3.07mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 9.2ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath in salt ice bath stirring thereto Under the conditions of with the NaOH solution (7M) that cools adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, Collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(20:80: 0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless transparent oil Shape object, that is, FCO-2 (0.58g, 1.5mmol), yield 50%, ESI-MS [M+H]+m/z385,ESI-MS[M+Na]+m/z407。
Embodiment nine, a kind of synthetic method of compound FCO-2a
3,5- lupetidine (10ml, about 8.23g) is taken to be dissolved in 25ml methanol, and addition epoxychloropropane (9ml, about 10g), 80 °C of oil baths are reacted 10 hours, are evaporated under reduced pressure out methanol, and 30ml water is added, washs (15ml*3 times) with methylene chloride and removes Surplus stock is removed, water phase evaporated under reduced pressure is collected and obtains white solid 6a-1(9.7g, 47.3nmol), yield 65%.
It takes compound 1a-6 (1.0g, 5.6mmol) to be dissolved in 20ml ethyl alcohol, sodium hydroxide (0.6g, 15mmol) is taken to be dissolved in In 10ml distilled water, rear be added quaternary ammonium salt 6a-12.3g (11.2mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, TLC detection reaction Degree.Ethyl acetate extracts reaction solution (20ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, mobile phase EA:PE:Et3N (80:20:0.5) elution, collects fraction, and TLC detects fraction compositions.Merge the vacuum distillation of compound fraction to do Transparent oil 6a-2 (1.04g, 2.97mmol), yield 54%.
It weighs sodium nitrite (0.41g, 6.0mmol) to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 6a-2 (1.04g, 2.97mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 8.9ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath in salt ice bath stirring thereto Under the conditions of with the NaOH solution (7M) that cools adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, Collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(20:80: 0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless transparent oil Shape object, that is, FCO-2a (0.58g, 1.5mmol), yield 51%, ESI-MS [M+H]+m/z369,ESI-MS[M+Na]+m/z391。
Embodiment ten, a kind of synthetic method of compound FCO-2b
It takes compound 1b-2 (1.0g, 5.1mmol) to be dissolved in 20ml ethyl alcohol, sodium hydroxide (0.49g, 12.3mmol) is taken to be dissolved in In 10ml distilled water, rear be added quaternary ammonium salt 6a-1 (2.1g, 10.0mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (20ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (80:20:0.5) elution, collects fraction, and TLC detects fraction compositions.It is dry to merge the vacuum distillation of compound fraction It obtains transparent oil 6b-1 (0.93g, 2.5mmol), yield 50%.
It weighs sodium nitrite (0.35g, 5.1mmol) to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 6b-1 (0.93g, 2.5mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 7.6ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath in salt ice bath stirring thereto Under the conditions of with the NaOH solution (7M) that cools adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, Collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(20:80: 0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless transparent oil Shape object, that is, FCO-2b (0.58g, 1.5mmol), yield 50%, ESI-MS [M+H]+m/z385,ESI-MS[M+Na]+m/z407。
Embodiment 11, a kind of synthetic method of compound FCO-3a
It takes diisopropylamine (10ml, about 7g) to be dissolved in 25ml methanol, is added epoxychloropropane (10ml, about 11.7g), 80 ° C oil bath is reacted 10 hours, and methanol is evaporated under reduced pressure out, and 30ml water is added, and it is remaining former to wash (20ml*3 times) removing with methylene chloride Material collects water phase evaporated under reduced pressure and obtains white solid 7a-1(7.4g, 38.3nmol), yield 56%.
It takes compound 1a-6 (1.0g, 5.6mmol) to be dissolved in 20ml ethyl alcohol, sodium hydroxide (0.6g, 15mmol) is taken to be dissolved in In 10ml distilled water, rear be added quaternary ammonium salt 5a-12.14g (11.1mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (20ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (80:20:0.5) elution, collects fraction, and TLC detects fraction compositions.It is dry to merge the vacuum distillation of compound fraction It obtains transparent oil 7a-2 (1.04g, 3.08mmol), yield 60%.
It weighs sodium nitrite (0.43g, 6.3mmol) to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 7a-2 (1.04g, 3.08mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 9.2ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath in salt ice bath stirring thereto Under the conditions of with the NaOH solution (7M) that cools adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, Collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(20:80: 0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless transparent oil Shape object, that is, FCO-3a (0.42g, 1.2mmol), yield 38%.ESI-MS[M+H]+m/z357,ESI-MS[M+Na]+m/z379。
Embodiment 12, a kind of synthetic method of compound FCO-3b
It takes compound 1b-2 (1.0g, 5.1mmol) to be dissolved in 20ml ethyl alcohol, sodium hydroxide (0.43g, 10.7mmol) is taken to be dissolved in In 10ml distilled water, rear be added quaternary ammonium salt 7a-1 (1.97g, 10.2mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (20ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (80:20:0.5) elution, collects fraction, and TLC detects fraction compositions.It is dry to merge the vacuum distillation of compound fraction It obtains transparent oil 7b-1 (0.83g, 2.35mmol), yield 46%.
It weighs sodium nitrite (0.32g, 4.7mmol) to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 7b-1 (0.83g, 2.35mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 7.1ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath in salt ice bath stirring thereto Under the conditions of with the NaOH solution (7M) that cools adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, Collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(20:80: 0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless transparent oil Shape object, that is, FCO-6 (0.304g, 0.8mmol), yield 34.7%, ESI-MS [M+H]+m/z373,ESI-MS[M+Na]+m/z395。
Embodiment 13, a kind of synthetic method of compound ACO-1a
It takes adamantane 10g (73.5mmol), is added dropwise bromine 23.5g (147.0mmol), is slowly warming up to 70 °C within 1 hour, instead It answers 6 hours, stands overnight, saturation bisulfite is added dropwise and receives, until solution becomes colorless, ethyl acetate extracts (30ml*3), takes Organic phase is concentrated under reduced pressure, and vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, and mobile phase is petroleum ether, TLC monitoring Fraction compositions merge identical fraction vacuum distillation and do, and oil pump decompression abstraction residual solvent obtains colourless transparent oil liquid i.e. 8a-1 (11.0g, 51.4mmol), yield 70%.
Take compound 8a-1(11.0g, 51.4mmol), it is added N-METHYLFORMAMIDE (10g, 169.4mmol), 170 °C are returned Stream 2 hours is cooled to 100 °C, 10% hydrochloric acid 30ml is added, 100 °C are stirred 2 hours, and cooling, toluene washs (20ml*3), water phase Middle addition active carbon 1g, 70 °C are stirred 30 minutes, cooling, filtering, and saturation sodium hydroxide adjusts pH to 12, anhydrous ether extraction (30ml*3) is evaporated to obtain white solid 8a-2(6.6g, 40mmol), yield 78%.
Take 8a-2(6.6g, 40mmol) it is dissolved in 50ml methanol, it is added epoxychloropropane (4.6g, 80mmol), 80 °C of oil Bath reaction 10 hours, is evaporated under reduced pressure out methanol, and 50ml water is added, washs (25ml*3 times) removing surplus stock with methylene chloride, Collect water phase evaporated under reduced pressure and obtain white solid 8a-3(4.4g, 17.2mmol), yield 43%.
It takes compound 1a-6 (1.0g, 5.6mmol) to be dissolved in 20ml ethyl alcohol, sodium hydroxide (0.6g, 15mmol) is taken to be dissolved in In 10ml distilled water, rear be added quaternary ammonium salt 8a-3 (2.85g, 11.1mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (20ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (67:33:0.5) elution, collects fraction, and TLC detects fraction compositions.It is dry to merge the vacuum distillation of compound fraction It obtains transparent oil 8a-4 (1.1g, 2.7mmol), yield 50%.
It weighs sodium nitrite (0.37g, 5.4mmol) to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 8a-4 (1.1g, 2.7mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 8.5ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath in salt ice bath stirring thereto Under the conditions of with the NaOH solution (7M) that cools adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, Collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(20:80: 0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless transparent oil Shape object, that is, ACO-1a (0.44g, 1.1mmol), yield 38%, ESI-MS [M+H]+m/z421,ESI-MS[M+Na]+m/z443。1H- NMR(CDCl3,300MHz)(ppm)δ:1.49-1.68(m,12H,CH2),1.98(s,3H,CH),2.27(s,3H,NCH3), 2.47(s,6H,2CH3),2.56(s,3H,CH3),2.14-2.18,2.63-2.73(m,2H,OCH2),3.84-3.92(m,1H, OCH),4.21-4.26(m,2H,OCH2).1C-NMR(CDCl3,300MHz)(ppm)δ:21.47(CH3),21.87(CH3), 22.30(CH3),29.69 (3CH),34.25(3CH2),36.68(3NCH2),38.96(NCH3),51.46(OCH2),56.44 (NCH2),65.44(HOCH),78.26(NOCH2),135.67(2-pyrazine);141.91(C(Cl)=N);148.86(5- pyrazine);149.11(3-pyrazine);152.35(6-pyrazine).
Embodiment 14, a kind of synthetic method of compound ACO-1b
It takes compound 1b-2 (1.0g, 5.1mmol) to be dissolved in 20ml ethyl alcohol, sodium hydroxide (0.43g, 10.7mmol) is taken to be dissolved in In 10ml distilled water, rear be added quaternary ammonium salt 8a-3 (2.6g, 10.2mmol) is miscible, and 80 °C of oil baths are reacted 3 hours, and TLC detection is anti- Answer degree.Ethyl acetate extracts reaction solution (20ml*5 times), collects organic layer vacuum distillation and does, wet process loading column chromatography, flowing Phase EA:PE:Et3N (80:20:0.5) elution, collects fraction, and TLC detects fraction compositions.It is dry to merge the vacuum distillation of compound fraction It obtains transparent oil 8b-1 (0.95g, 2.29mmol), yield 45%.
It weighs sodium nitrite (0.31g, 4.58mmol) to be dissolved in 2ml distilled water, salt ice bath is down to -5 °C, and sub- sour sodium is made Solution for standby.Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 °C it is spare.Compound 8b-1 (0.95g, 2.29mmol) is taken to be dissolved in In the cold hydrochloric acid solution of 7.0ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath in salt ice bath stirring thereto Under the conditions of with the NaOH solution (7M) that cools adjust pH to 10.Reaction solution (10ml*5 times) is extracted with dichloromethane finally, adopting, Collect organic layer.Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, mobile phase EA:PE:Et3N(20:80: 0.5), TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless transparent oil Shape object, that is, ACO-1b (0.8g, 1.8mmol), yield 36%, ESI-MS [M+H]+m/z437,ESI-MS[M+Na]+m/z459。1H- NMR(CDCl3,300MHz)(ppm)δ:1.61-1.76(m,12H,6CH2),2.09(s,3H,3CH),2.23(s,3H,CH3), 2.26-2.34,2.73-2.81(m,2H,CH2),2.52(s,3H,CH3),2.57(s,3H,CH3),2.70(s,3H,CH3), 3.09-3.98(m,1H,CHOH),4.33-4.34(d,2H,OCH2).1C-NMR(CDCl3,300MHz)(ppm)δ:13.64 (CH3),14.04(CH3),22.39(CH3),29.48(3CH),33.57(3CH2),36.66(3NCH2),38.95(NCH3), 50.93(OCH2),54.10(NCH2),65.40(HOCH),82.17(NOCH2),133.83(2-pyrazine);141.66(C (Cl)=N);142.91(5-pyrazine);144.79(3-pyrazine);152.08(6-pyrazine).
The protection of embodiment 15, compound TCO-1, TCO-2, PCO-1, BCO-1 to the cell of MG-132 induced damage It acts on (Fig. 6)
10000, every hole SY5Y cell first protects 1h, the MG-132 that final concentration of 15 μ Μ is then added to incubate with compound It educates for 24 hours.Using bimoclomol, arimoclomol and TMP as positive control, DMSO is as Vehicle controls, mtt assay inspection Survey cell activity.
The compound TCO-1, TCO-2 that we synthesize as the result is shown can protect to dose-dependant neural cellular stress to damage, The bioactivity of TCO-1 is suitable with the activity of the bimoclomol of CytRx company and arimoclomol；And the activity of TCO-2 is bright It is aobvious to be better than bimoclomol and arimoclomol.#P<0.01versus control group.*P<0.05versus MG- 132group.**P<0.01versus MG-132group.Ctrl:control,Ari:arimoclomol,Bim: bimoclomol.
Embodiment 16, compound TCO-1, TCO-2, PCO-1, BCO-1 are to the inhibiting effect (Fig. 7) of ROS
Oxidation stimulation will lead to cell and be in stress situation, and protein expression is abnormal, it is possible to create the folding of mistake is poly- Collection, leads to the generation of neurodegenerative disease.We are damaged by tert-butyl hydroperoxide induced oxidation first, then with difference The compound protection of concentration gradient detects each compound with oxidation resistance ability.10000, every hole SY5Y cell, is first protected with compound 1h, the TBHP that final concentration of 150 μ Μ is then added are incubated for 4h.Using bimoclomol, arimoclomol and TMP conduct Positive control, DMSO detect cell activity as Vehicle controls, mtt assay.Experimental result is shown: positive reference substance Bimoclomol, arimoclomol, TMP are without antioxidation, and newly synthesized compound TCO-1, TCO-2 have obvious resist Oxidation.#P<0.01versus control group.*P<0.05versus t-BHP group.
Embodiment 17, compound TCO-1, TCO-2, PCO-1 is to MPP+The protective effect (Fig. 8) of the cell of induced damage
10000, every hole SY5Y cell first protects 1h with compound, and the MPP of final concentration 2m Μ is then added+It is incubated for for 24 hours. Using bimoclomol, arimoclomol, and clinical antiparkinsonism drugs selegiline (MAO-B) inhibitor is as sun Property control, DMSO be used as Vehicle controls, mtt assay detection cell activity.Preliminary experimental results are shown: positive reference substance Bimoclomol, arimoclomol, selegiline are other than 10 μM of arimoclomol without nonreactive MPP+Induction Cells apoptosis, and newly synthesized compound TCO-1, TCO-2, at 1 μM, 10 μM have apparent Anti-G value.#P< 0.01versus control group.*P<0.05versus MPP+group.Sel:Selegiline.
Embodiment 18, compound TCO-1, TCO-2 inhibit the aggregation (Fig. 9) of ubiquitin protein
TCO-1, TCO-2 are adjustable HSPs protein expression under heat shock state；And MG-132 stress in cell model, 100 μM of TCO-1 and TCO-2 can obviously remove the aggregation of ubiquitin protein.
Embodiment 19, compound TCO-1 are to A β1-42The protective effect of the AD rat model of induction
Inject A β1-42Rat Senlie dementia model is manufactured, then with the chlorine 9 oxime derivate TCO-1 treatment of synthesis, investigationization Close protective effect of the object to rat.Using clinical anti senile dementia drug donepezil (donepezil, DPH) as positive right According to physiological saline group is Normal group.Morris water maze system detection behavioral indexes observe new synthesis compound Protective effect size.Firstly, lateral ventricle of rat brain injects A β1-42After (10 μ g/ are only), observation each group rats'swimming speed is not obvious Statistical difference illustrates that the state of rat is identical.
Lateral ventricle of rat brain injects A β1-42After (10 μ g/ are only), the time (incubation period) for reaching platform for the first time significantly extends, * P < 0.01versus A β group.Positive control drug donepezil (3mg/kg) can fight A β1-42Effect, hence it is evident that shorten for the first time Reach the time of platform, * P < 0.01versus A β group.The TCO-1 tested can significantly shorten rat and reach platform for the first time Time (incubation period), * P < 0.01versus A β group (Figure 10).
Lateral ventricle of rat brain injects A β1-42After (10 μ g/ are only), the number of spanning platform is significantly reduced, * P < 0.01versusA β Group.DPH (3mg/kg) can fight A β1-42Effect, hence it is evident that increase the number of spanning platform, * P < 0.01versus A β group.Newly The chlorine 9 oxime derivate TCO-1 of synthesis can dramatically increase the number of spanning platform, * P < 0.01versus A β group (Figure 11).
It is above-mentioned clearly to illustrate this noval chemical compound to protein folding mistake or abnormal aggregation specific descriptions of the invention The disease of formation such as neurodegenerative disease, the treatment or prevention of Cardial or cerebral vascular diseases, metabolic disease and inflammation provide uniqueness Method.The above-mentioned detailed description about specific embodiment, only as the example explanation to technical solution of the present invention, without limiting The range of the claims in the present invention.It particularly points out, inventor considers by scrupulous, the present invention different substitution, change and modification All without departing from the connotation and extension defined in the claims in the present invention.

Claims (8)

1. a kind of chlorine oxime compound and its pharmaceutically acceptable salt, the chlorine oxime compound has the knot of following general formula VI Structure:
Wherein: being connected with oxygen on pyridine ring N atom；N is 0,1,2 or 3.
2. chlorine oxime compound and its pharmaceutically acceptable salt according to claim 1, it is characterised in that n is in general formula VI 0, oxygen is connected on pyridine ring N atom, the chlorine oxime compound has the structure such as following formula TCO-2:
3. a kind of preparation method of chlorine oxime compound, wherein the chlorine oxime compound is TCO-2:
The described method includes:
It weighs Tetramethylpyrazine 10g to be dissolved in 20ml acetic acid, 30% hydrogen peroxide 8ml is added；Oil bath reaction 5 is small under the conditions of 70 DEG C When after add 8.3ml30% hydrogen peroxide, the reaction was continued 5 hours, TLC monitor the extent of reaction, stop reaction；It is cooled to room temperature, hydrogen Sodium oxide molybdena saturated solution adjusts pH to 10；Methylene chloride extracts 50ml*5 times, takes the vacuum distillation of organic layer Rotary Evaporators dry Obtain white solid 1a-1；20ml acetic anhydride is added thereto, 125 DEG C of oil baths are reacted 2.5 hours, and TLC detects fully reacting；Decompression Acetic anhydride is distilled off, obtains acetylation crude product 1a-2；Then, sodium hydroxide saturated solution is adjusted to pH to 12, is stirred at room temperature, water Solution reaction is overnight；Ethyl acetate extracts reaction solution 50ml*5 times, and vacuum distillation is dry, and wet process loading column chromatography, mobile phase is 1:1's EA:PE, TLC detect fraction, collect TMP-OH fraction；Identical fraction needed for merging, vacuum distillation is dry, obtains Off-white solid powder 7.5g1a-3, i.e. TMP-OH, [M+Na]+=175, yield 67%；
1a-3, that is, TMP-OH of gained 7.5g is dissolved in 50ml dehydrated alcohol, activated manganese dioxide 6.4g oxidation, 84 DEG C of oil baths are added 2h is reacted, after TLC detects fully reacting, reaction solution is carefully filtered using five layers of filter paper while hot, removes manganese dioxide powder；After filter Clear filtrate is obtained, Rotary Evaporators vacuum distillation is dry；Wet process loading column chromatography: mobile phase is that the EA:PE of 1:5 is isolated and purified, TLC monitors fraction；Compound 1a-4 fraction is collected, merges identical fraction distillation and does to obtain lenticular white solid 5.5g, 1a-4, i.e., TMP-CHO, [M+H]+=151, yield 75%；
5.5g compound 1a-4 sample 30ml formic acid is dissolved, the addition of 3.2g hydroxylamine hydrochloride is weighed, 3.13g formic acid is then added Sodium, miscible, 120 DEG C of oil bath reactions are refluxed overnight；It is saturated sodium hydroxide solution and adjusts reaction solution pH to 10, methylene chloride extraction 30ml*5 times, take organic layer vacuum distillation dry；100-200 mesh silica gel mixed sample, dry method loading column chromatography: mobile phase is the EA of 1:5: PE, TLC monitoring outflow fraction compositions, collect compound 1a-5 fraction；It is dry to merge identical fraction distillation, obtains white solid i.e. chemical combination Object 1a-5, yield 65%；
The intermediate 1a-5 3g prepared is taken, the dissolution of 30ml methylene chloride is added, metachloroperbenzoic acid, which is then added, is MCPBA 3.5g is stirred at room temperature for 24 hours, and TLC monitors the extent of reaction, stops reaction；Vacuum distillation removes methylene chloride, dry method loading Column chromatography；Mobile phase is the EA:PE of 1:2, collects fraction, and TLC monitors fraction compositions, merges identical fraction；Vacuum distillation is dry, obtains White solid 1b-1 2.8g, yield 84%；
Resulting 1b-1 2.8g is dissolved in 30ml dehydrated alcohol, hydroxylamine hydrochloride 1.5g is added, takes sodium bicarbonate 1.9g in 20ml Distilled water dissolution, it is miscible, reaction 24 hours is stirred at room temperature；TLC monitors the extent of reaction, stops reaction；Vacuum distillation is dry, in dry method Sample column chromatography, mobile phase are the EA:PE:Et of 80:20:0.53N, collects fraction, and TLC monitors fraction compositions；Merge identical fraction Vacuum distillation is dry, obtains white solid i.e. compound 1b-2, yield 95%；
Then, the method still further comprises step (C) or (D):
Step (C): taking compound 1b-2 3.2g to be dissolved in 30ml ethyl alcohol, sodium hydroxide 0.8g taken to be dissolved in 20ml distilled water, rear to add It is miscible to enter quaternary ammonium salt 1a-7 3.5g, 80 DEG C of oil baths are reacted 3 hours, and TLC detects the extent of reaction；Ethyl acetate extracts reaction solution It 30ml*5 times, collects organic layer vacuum distillation and does, wet process loading column chromatography, mobile phase is the EA:PE:Et of 85:15:0.53N is washed It is de-, fraction is collected, TLC detects fraction compositions；Merge the vacuum distillation of compound 1b-3 fraction and does to obtain transparent oil 3.3g, yield 60%；
It weighs sodium nitrite 1.06g to be dissolved in 3.5ml distilled water, salt ice bath is down to -5 DEG C, and it is spare that sub- acid sodium solution is made；It will be dense Hydrochloric acid be 1M solution, be cooled to -5 DEG C it is spare；Compound 1b-3 3.3g is taken to be dissolved in the cold hydrochloric acid solution of 20ml, salt ice bath Then sodium nitrite solution reaction 1h is slowly added dropwise in stirring thereto, then molten with the 7M NaOH cooled under condition of ice bath Liquid adjusts pH to 10；Reaction solution is extracted with dichloromethane 15ml*5 times finally, adopting, collects organic layer；Vacuum distillation extraction gained Sample liquid, wet process loading column chromatography, mobile phase be 20:80:0.5 EA:PE:Et3N, TLC monitor fraction compositions, merge phase Dry with fraction vacuum distillation, oil pump decompression abstraction residual solvent can obtain white solid after obtaining colorless and transparent oily object multigelation That is TCO-2 1.8g, yield 50%；
Step (D): it takes the 1b-2 1.6g prepared to be dissolved in 10ml NaOH solution, epoxychloropropane 1.2ml is taken to be dissolved on a small quantity Miscible in DMSO, ice bath stirring is overnight, and TLC monitors the extent of reaction, stops reaction；Methylene chloride extracts reaction solution 10ml*5 times, Column chromatographic purifying obtains compound 1b-4 1.23g, yield 60%；Gained 1b-4 is dissolved in 10ml DMF, piperidines is added 0.74ml, reacts 3h by 80 DEG C, and TLC monitors the extent of reaction, stops reaction；Ethyl acetate extracts 10ml*5 times, and column chromatographic purifying obtains To compound 1b-3 1.57g, yield 95%；It weighs sodium nitrite 0.4g to be dissolved in 4ml distilled water, salt ice bath is down to -5 DEG C, system It is spare at sub- acid sodium solution；Concentrated hydrochloric acid is diluted to the solution of 1M, be cooled to -5 DEG C it is spare；Compound 1b-3 1.57g is taken to be dissolved in In the cold hydrochloric acid solution of 10ml, then sodium nitrite solution reaction 1h is slowly added dropwise, then in ice bath item in salt ice bath stirring thereto PH to 10 is adjusted with the 7M NaOH solution cooled under part；Reaction solution is extracted with dichloromethane 10ml*5 times finally, adopting, collects Organic layer；Vacuum distillation extracts resulting sample liquid, wet process loading column chromatography, and mobile phase is the EA:PE:Et of 20:80:0.53N, TLC monitors fraction compositions, merges identical fraction vacuum distillation and does, and oil pump decompression abstraction residual solvent obtains colorless and transparent oily object That is TCO-2 0.86g, yield 51.7%；
Wherein, compound 1a-1,1a-2,1a-3,1a-4,1a-5,1a-7,1b-1,1b-2,1b-3,1b-4 is respectively as follows:
4. chlorine oxime compound according to claim 1 and pharmaceutical composition containing the compound are in medicine preparation Purposes, it is cranial nerve or cranial vascular disease, cardiovascular disease, inflammation infection that the drug, which is used to the disease preventing or treat, Disease or ophthalmology disease.
5. purposes according to claim 4, wherein the cranial nerve or cranial vascular disease are alzheimer's disease, pa gold Gloomy disease, Huntington's disease, prion disease, cerebromalacia disease, lethal familial insomnia, the mankind striatal-spinal degeneration disease, Scrapie, it is rabid ox disease, amyotrophic lateral sclerosis, dementia, multiple sclerosis, chronic pain class encephalopathy, cerebral trauma, insane Epilepsy, apoplexy or brain of neonatal rat on ischemia hypoxia.
6. purposes according to claim 4, wherein the cardiovascular disease be cardiopulmonary effluent, heart ischemia or Reperfu- sion, Myocarditis, atherosclerosis, coronary heart disease and sudden heart disease class heart or vascular conditions.
7. purposes according to claim 4, wherein the inflammation infection disease is inflammatory bowel disease, rheumatoid joint Inflammation, asthma, encephalomyelitis, encephalomyelitis, pancreatitis, peritonitis, vasculitides, Choriomeningitis, glomerulonephritis, whole body Property lupus erythematosus or hepatitis.
8. purposes according to claim 4, wherein the ophthalmology disease be diabetic retinopathy, uveitis, Glaucoma, blepharitis, chalazion, allergic ophthalmopathy, ulcer of the cornea, keratitis, cataract, Age related macular degenerative change Or optic neuritis.
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WO1998043948A1 (en) * 1997-04-03 1998-10-08 Biorex Kutató És Fejleszto^' Rt. Process for preparing o-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides
WO2003045387A1 (en) * 2001-11-29 2003-06-05 Biorex Kutató És Fejlesztö Rt. Pharmaceutical composition with combined active agents containing metformin and a hydroxylamine derivative
CN1901913A (en) * 2003-10-30 2007-01-24 塞特雷克斯公司 Use of a hydroximic acid halide derivative in the treatment of neurodegenerative diseases
WO2008137149A1 (en) * 2007-05-04 2008-11-13 Cytrx Corporation Diabetic wound healing
CN101600434A (en) * 2006-12-01 2009-12-09 塞特雷克斯公司 The hydroxylamine derivative of treatment apoplexy
CN102215842A (en) * 2008-11-18 2011-10-12 参天制药株式会社 Therapeutic agent for chorioretinal degenerative diseases comprising pyridine-3-carbaldehyde o-(piperidin-1-yl-propyl)-oxime derivative as active ingredient

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998043948A1 (en) * 1997-04-03 1998-10-08 Biorex Kutató És Fejleszto^' Rt. Process for preparing o-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides
WO2003045387A1 (en) * 2001-11-29 2003-06-05 Biorex Kutató És Fejlesztö Rt. Pharmaceutical composition with combined active agents containing metformin and a hydroxylamine derivative
CN1901913A (en) * 2003-10-30 2007-01-24 塞特雷克斯公司 Use of a hydroximic acid halide derivative in the treatment of neurodegenerative diseases
CN101600434A (en) * 2006-12-01 2009-12-09 塞特雷克斯公司 The hydroxylamine derivative of treatment apoplexy
WO2008137149A1 (en) * 2007-05-04 2008-11-13 Cytrx Corporation Diabetic wound healing
CN102215842A (en) * 2008-11-18 2011-10-12 参天制药株式会社 Therapeutic agent for chorioretinal degenerative diseases comprising pyridine-3-carbaldehyde o-(piperidin-1-yl-propyl)-oxime derivative as active ingredient

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