CN101600434A

CN101600434A - The hydroxylamine derivative of treatment apoplexy

Info

Publication number: CN101600434A
Application number: CNA2007800505945A
Authority: CN
Inventors: J·R·巴伯
Original assignee: CytRx Corp
Current assignee: LadRx Corp
Priority date: 2006-12-01
Filing date: 2007-11-30
Publication date: 2009-12-09

Abstract

The invention provides the method for treatment apoplexy, described method comprises one or more some hydroxylamine derivative that the patient of needs effective dose is arranged.The present invention also provides some hydroxylamine derivative that comprises optional and one or more other therapeutic agents combinations or the Pharmaceutical composition of its pharmaceutically acceptable salt.In some compositions, described other therapeutic agent is second hydroxylamine derivative or its pharmaceutically acceptable salt.

Description

The hydroxylamine derivative of treatment apoplexy

Background of invention

[0001] apoplexy is the medical science emergency case, only about 700,000 people of the annual invasion and attack of the U.S..Apoplexy loses blood supply suddenly by the part of brain, usually causes succeeded by perfusion again nature or medical intervention subsequently.Owing to lose that the anoxia of blood supply and dabbling again reoxygenation all can cause death and/or to being attacked regional brain tissue injury, usually cause half permanent and temporary paralysis or unable of health, cause and look thing or parathria, thinking, consciousness, attention, study, judgement and memory problems appear, emotional problem and rarely not dead.

[0002] apoplexy is divided into two kinds of main types: cerebral infarction, it accounts for more than 85% of all apoplexy incidents, and the hemorrhagic apoplexy that accounts for remaining incident.In the middle of cerebral infarction, to the blood vessel of a part of cerebral oxygen supply because of the following former thereby obstruction that becomes: perhaps because the grumeleuse (thrombotic apoplexy) that is produced in the locking part of tremulous pulse, perhaps owing to move to the locked position of coupler of tremulous pulse and reside in the grumeleuse or the speckle (embolic stroke) of there: perhaps because the venous locking (phlebothrombosis) that causes perfusion to descend, stop blood fresh, oxygen enrichment to enter affected zone.In hemorrhagic apoplexy, angiorrhexis or bleed causes fresh blood can not arrive damaged region in front.In addition, be accompanied by hemorrhagic apoplexy, blood damages the cerebral tissue and the rising intracranial pressure of its contact, if when particularly perfusion is inaccessible.Preferred treatment for cerebral infarction and hemorrhagic apoplexy can be different, particularly consider the use of antithrombotic agent, because when patient suffers from the cerebral infarction incident, can be benefited from the blood clotting molten and the suitable blood flow of removal obstruction that disappears, and such medicine can cause further hemorrhage and damage in the patient who suffers from the hemorrhagic apoplexy incident.

[0003] ischemia injury in the brain causes the heat shock protein (HSP) in cerebral tissue to express increase.HSPs is a molecular chaperoning, and it is the class protein by the suitable protein folding of help that play an important role, main in the various kinds of cell process.For example, molecular chaperoning is incorporated into new raw albumen (nascent proteins) and partially folded intermediate in non-covalent mode, and guides them to carry out correct folding path, thereby the irreversibility that prevents them is assembled and false folding.Molecular chaperoning also makes the protein unfolding, so that their migrations enter organelle by the cell inner membrance.In addition, molecular chaperones makes the protein of false folding be easy to degraded.

[0004] when cellular exposure during in the temperature that raises or other cellular stress, the expression of HSP increases.HSPs is also referred to as " stress protein ", and their rise is described usually as " stress " a part of the time sometimes more.Show, to suffering from inferior lethal ischemia (sublethal ischemia) but animal carry out the pretreatment inducing molecule and accompany hsp70 to express and the protection brain avoids more serious follow-up ischemic injury; Referring to Simon etc., Neurosci.Lett., 163:135-137 (1993), and the outburst that avoids the oxygen-derived free radicals that produces when perfusion recovers again fast at blood flow.

[0005] therefore, the increase of companion's expression is considered to that ischemic and reperfusion injury are had protection and beneficial effect.

[0006] recent, there is three types intervention that apoplexy is reversed: to treat immediately so that damage is restored after reducing to minimum and apoplexy after the prevention of apoplexy, incident take place.So that reducing to the effectiveness of the therapy of minimum, damage after the ischemic incident, sharply descends in 1 hour.Because it is little to reach the probability of such treatment in the so short time, unless the victim of apoplexy has been under the medical monitoring, the application of the present therapy of the type is limited.

[0007] therefore, the urgent new method of being badly in need of the treatment apoplexy.Particularly, be intended to find new Therapeutic Method,, make after apoplexy has been taken place damage reduce to minimum and promote the functional rehabilitation of the cerebral tissue of damage even after apoplexy, just began to treat in one or more hours.

The invention summary

[0008] this paper provides the method for treatment apoplexy, described method comprises in some hydroxylamine derivative that the patient of needs effective dose is arranged one or more, described patient as, be diagnosed as suffer from apoplexy, symptom or alternative index (surrogate markers) that proof is relevant with apoplexy, and/or the patient who is easy to suffer from apoplexy.Some useful hydroxylamine derivative in implementing this method comprises, but is not to be limited to those that describe in patent documentation before: U.S. Patent number 5,147,879; U.S. Patent number 6,143,741; U.S. Patent number 6,653,326; U.S. Patent number 6,649,628; U.S. Patent number 6,384,029; U.S. Patent number 5,328,906; U.S. Patent number 5,296,606; U.S. Patent number 5,919,796; U.S. Patent number 6,002,002; U.S. Patent number 6,180,787; U.S. Patent number 6,384,029; With U.S. Patent Publication number 2005/0043295, these documents are incorporated into this paper by reference.

[0009] useful exemplary compounds comprises in implementing this method: N-[2-hydroxyl-3-(piperidino) propoxyl group]-3 pyridines-first imido acyl (carboximidoyl)-chlorine (chloropyridine alcohol),

[0010] N-[2-hydroxyl-3-(piperidino) propoxyl group]-pyridine-1-oxide-3-first imido acyl chloride (Ah not 's chloropharin),

[0011] 5,6-dihydro-5 (piperidino)-methyl-3-(3-pyridine radicals)-4H-1,2,4-oxadiazine (oxadiazine) is (Ai Shanading).

[0012] another exemplary compounds that is used to implement this method is N-[3-(1, a 1-dimethyl ethyl) amino] 2-hydroxyl propoxyl group]-3-trifluoromethylbenzene-first imido acyl chloride (chemical compound 2)

[0013] for the structural formula of any above chemical compound, plan to comprise all stereochemical forms of described chemical compound, comprise geometric isomer (that is, and E, Z) and optical isomer (that is, and R, S).The single three-dimensional chemical isomer of this chemical compound and the mixture of enantiomorph and diastereomer are included within the category of the present invention.Unless otherwise stated, each structural formula described herein is also intended to comprise only with the atom performance of one or more isotope enrichments different chemical compound and all aforesaid salt.

[0014] above any chemical compound can use separately or use is united in optional and one or more other be used for the treatment of disease, disorder or treatment of conditions agent of involving molecular chaperoning.This paper provides preferred other therapeutic agent.

[0015] more generally be, also available Pharmaceutical composition is implemented the embodiment of the inventive method, described Pharmaceutical composition comprises the tautomer chemical compound of formula (I) chemical compound or its formula (II):

And pharmaceutically acceptable salt, wherein, in each formula (I) with (II) in the chemical compound:

A is the alkyl, aralkyl of alkyl, replacement, at the heteroaryl of aryl, heteroaryl or the replacement of aryl and/or the aralkyl that in moieties, replaces, aryl, replacement;

Z is covalent bond, oxygen or N (R ³);

R ³Be selected from the aryl, aralkyl of alkyl, aryl, the replacement of hydrogen, alkyl, replacement or at aryl and/or the aralkyl that in moieties, replaces;

R is the alkyl of alkyl or replacement,

X in formula (I) chemical compound, is hydroxyl or amino, mono-substituted amino or dibasic amino of halogen or replacement, and in formula (II) chemical compound, is the imino group of oxygen, imino group or replacement;

R ' is the acyl group of aralkyl, acyl group or replacement of alkyl, aryl, aryl, the aralkyl of replacement, the aryl with replacement and/or the moieties of hydrogen, alkyl, replacement;

[0016] in one embodiment, this method comprises patient's hydroxylamine derivative of suffering from apoplexy after the apoplexy immediately.In another embodiment, this method comprises at least 0.25,0.5,1,2,6,24,48 or 72 hour or longer time after the apoplexy, gives first dose of hydroxylamine derivative.

[0017] in another embodiment, this method comprises that the one or more hydroxylamine derivatives of associating give one or more other therapeutic agents.In preferred embodiments, this method comprises uniting and gives Ah not 's chloropharin and Ai Shanading.In another embodiment, other therapeutic agent is the related indication medicine of known alleviation apoplexy.In special embodiment, other therapeutic agent is selected from antiinflammatory, oxygen free radical scavenger, antipyretic, antithrombotic agents (anti-platelet agents and anticoagulant), thrombolytic agent and neuroprotective.

[0018] according to embodiment preferred, the administration of this Pharmaceutical composition oral administration.

[0019] the present invention also provides the Pharmaceutical composition that is used for the treatment of apoplexy that comprises one or more hydroxylamine derivatives.

The accompanying drawing summary

[0020] Fig. 1 demonstration gives the functional rehabilitation of permanent occlusion's rat with hydroxylamine derivative, described at this paper embodiment 1, is presented at forelimb and places the improvement of testing in (forelimbplacing test).

[0021] Fig. 2 gives the functional rehabilitation of permanent occlusion's rat with hydroxylamine derivative, described at this paper embodiment 1, is presented at hind leg and places the improvement of testing in (hindlimb placingtest).

[0022] Fig. 3 demonstration gives the functional rehabilitation of permanent occlusion's rat with hydroxylamine derivative, described at this paper embodiment 1, is presented at the improvement in the body swing test (body swingtest).

[0023] Fig. 4 shows the body weight of the laboratory animal in the experiment of describing among the embodiment 1.

[0024] Fig. 5 shows the infraction size as the therapeutic process of the experiment described in this paper embodiment 1.

[0025] Fig. 6 shows the rat that gives the permanent occlusion with Ah not 's chloropharin, and a kind of functional rehabilitation of hydroxylamine derivative described at embodiment 4, is presented at the improvement in the forelimb placement test.

[0026] Fig. 7 demonstration gives the functional rehabilitation of permanent occlusion's rat with Ah not 's chloropharin, described at this paper embodiment 4, is presented at the improvement in the hind leg placement test.

[0027] Fig. 8 demonstration gives the functional rehabilitation of permanent occlusion's rat with Ah not 's chloropharin, described at this paper embodiment 4, is presented at the improvement in the body swing test.

[0028] Fig. 9 is presented at the body weight of the laboratory animal of describing among the embodiment 4.

[0029] Figure 10 shows the dose-response effect with the functional rehabilitation of Ah not 's chloropharin of the rat that gives the permanent occlusion, described at embodiment 2, is presented at forelimb and places improvement in the test.

[0030] Figure 11 shows the dose-response effect with the functional rehabilitation of Ah not 's chloropharin of the rat that gives the permanent occlusion, described at embodiment 2, is presented at hind leg and places improvement in the test.

[0031] Figure 12 shows the dose-response effect with the functional rehabilitation of Ah not 's chloropharin of the rat that gives the permanent occlusion, described at embodiment 2, is presented at the improvement in the body swing test.

[0032] Figure 13 is presented at the body weight of the laboratory animal of describing among the embodiment 2.

[0033] Figure 14 shows as the percentage cell death after the oxygen/glucose deprivation described in the embodiment 10.

[0034] Figure 15 shows the relative pharmacokinetics drug exposure of the oral Ah not 's chloropharin of people and rat.

[0035] Figure 16 is presented at orally give 3 hours and 6 hours the cerebrospinal fluid that time point reached (CSF) level behind Ah not 's chloropharin of increment gradually.

Detailed Description Of The Invention

1. definition

[0036] for simplicity, collected in this specification, embodiment and attached reality herein Execute some term of using in the scheme. Unless otherwise defined, all technology used herein and Scientific terminology has the identical meanings of usually understanding with one skilled in the art of the present invention.

[0037] article used herein " " and " one " refer to one or more than one (that is, at least One) the phraseological object of article. Illustrate, " a kind of element " mean a kind of element or More than a kind of element.

[0038] term used herein " comprises " and means and " include, but are not limited to " hand over phrase Use mutually.

[0039] term "or" used herein mean and with term " and/or " the mutual use, unless Context has clear and definite indication in addition.

[0040] term used herein " for example " mean and with phrase " such as, but not limited to " hand over Use mutually.

[0041] term " disorder " and " disease " are used interiorly, and refer to any part of health, Deviating from of any normal configuration of organ or system (or its any combination) or function. Specified disease By distinctive sings and symptoms performance, described sings and symptoms comprises biological, chemical With physical variation, and usually relevant with multiple other factors, described factor comprises, but not Be limited to demographic, environment, employ situation, heredity and medical history factor. Some Distinctive sign, symptom and correlative factor can be carried out quantitative analysis to draw by several different methods Important diagnostic message.

[0042] term " preventative " or " therapeutic " treatment is showed and is given one or more groups of patient Compound. If harmful illness (as, the disease of host animal or other harmful state) Administration before the clinical manifestation, then this treatment is preventative, namely it helps the host is protected Protect to avoid developing into harmful illness, otherwise, if administration after harmful illness performance, Then this treatment be curative (that is, plan to reduce, improve or the process of the illness that prevention is harmful or Their side effect).

[0043] term " therapeutic effect " refers to animal, particularly mammal and more specifically Among the people, by part or the systemic effect of one or more pharmacological active substances generations. Cause And this term means any being easy to for diagnosis, alleviation, treatment or prophylactic material, Or the health that enhancing is wanted in the animal or human or the material of Mental development and condition. Phrase " effectively Therapeutic dose " mean being applicable under the rational interests/risk-ratio of any treatment, produce Such amount of substance of the part of wanting or systemic effect. In certain embodiments, change Effective therapeutic dose of compound will depend on its therapeutic index, dissolubility etc. For example, can be sufficient Amount give to be applicable to closing of such treatment for some compound of implementing this method with generation Interests/the risk-ratio of reason.

[0044] term " effective dose " refers to when giving the patient by suitable dosage and dosage regimen Therapeutic agent is to produce the amount of results needed.

[0045] " curee " or " patient " that treated by this method can finger or people or non--people animal, preferred mammal.

[0046] term " need treatment disorderly patient " be diagnosed as suffer from disorder, proof has disorderly Disorderly relevant symptom or Substitute Indexes or suspection are suffered from disorderly patient.

[0047] run through this specification, word " comprises " or changes, such as " comprising " or " containing " Be construed as hint and comprise integer or the array integer of statement, but do not get rid of other integer or The integer group.

[0048] term " alkyl " refer to contain 1-21 carbon atom, straight or branched, saturated fat Family's hydrocarbon. " short-chain alkyl " refers to contain the alkyl of 1-8 carbon atom. The example of short-chain alkyl comprises, But be not limited to methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the second month in a season-butyl, amyl group, Uncle-amyl group, hexyl, heptyl and octyl group. Preferably, short-chain alkyl contains 1-6 carbon atom and choosing From methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the second month in a season-butyl, amyl group, uncle-Amyl group and hexyl. " chain alkyl " refers to contain the alkyl of 9-21 carbon atom. The example of chain alkyl Include, but are not limited to nonyl, decyl, hendecyl, dodecyl, tritriacontyl, tetradecyl, ten Five bases, palmityl, heptadecyl, octadecyl, nonadecyl, eicosyl and heneicosyl. Preferably, chain alkyl contains 9-17 carbon atom and is selected from nonyl, decyl, hendecyl, ten Two bases, tritriacontyl, tetradecyl, pentadecyl, palmityl and heptadecyl.

[0049] term " cycloalkyl " refers to contain the monocycle of 3-8 carbon atom, non-aromatic hydrocarbon ring system System. " becate alkyl chain " refers to contain the cycloalkyl of 3-8 carbon atom. Example includes, but are not limited to Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl group. Preferably, cycloalkanes Base contains 3-7 carbon atom and is selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.

[0050] term " aryl " refers to contain the list of 6,10,12 or 14 carbon atoms-or polycyclic system The system, wherein at least one ring of loop systems is aromatics. The example of aromatic ring system comprises, but not Be limited to phenyl, naphthyl, pentalene base, anthryl. Preferably, aryl is phenyl or naphthyl.

[0051] term " aralkyl " one or more hydrogen atoms of referring to alkyl wherein by one or The alkyl that a plurality of aryl replace. The example of aralkyl include, but are not limited to benzyl, benzhydryl, Trityl, 1-phenyl-ethyl, 2-phenylethyl, 2-benzhydryl-ethyl, 3-phenyl propyl, 1-methyl-2-phenyl-ethyl, 1-phenyl butyl, 4-trityl butyl, 1,1-dimethyl-2-benzene Base ethyl, 4-phenyl butyl, 5-phenylpentyl and 6-phenyl hexyl-group. Preferably, aralkyl Base is to contain 1-4 carbon atom and by the low alkyl group of phenyl substituted. Preferably aralkyl comprises, But be not limited to benzyl, 1-phenylethyl, 2-phenylethyl and 1-methyl-2-phenylethyl.

[0052] term " heterocycle " refers to contain 1-15 carbon atom and 1-4 heteroatomic monocycle system System, wherein loop systems can be chosen wantonly and contain undersaturated key, but is not aromatics. Hetero atom independently is Sulphur, nitrogen or oxygen. Example include, but are not limited to the aziridine base-, azetidinyl-, Oxaza propyl (oxaziranyl)-, pyrrolidinyl-, imidazolidinyl-, pyrazolidinyl-, complete Hydrogenation-thiazolyl (tiazolyl)-, the perhydro--carotene isoxazolyl-, piperidyl-, piperazinyl-, perhydro Change-pyrimidine radicals-, the perhydro--carotene pyridazinyl-, morpholinyl-, perhydro--carotene 1H-azepineJi, oxazolyl He isoxazolyl, oxadiazolyl (as, 1,2,4-oxadiazolyl-and other). Preferably, described Heterocycle is 3-8 unit loop systems. More preferably, described heterocycle is 5-8 unit loop systems. More preferably Ground, described heterocycle are the 5-6 unit rings that contains 1-2 oxygen atom and 1-3 N-atom.

[0053] term " heteroaryl " refer to contain the individual heteroatomic list of 1-15 carbon atom and 1-4-Or multi-loop system, and wherein at least one ring in the loop systems is aromatics. Hetero atom be sulphur, Nitrogen or oxygen. Preferably, described heteroaryl is the first ring of undersaturated 3-8. More preferably, described Heteroaryl be 5-6 unit, 1-4 contain N undersaturated assorted-the monocycle base. Example comprises, but does not limit In pyrrole radicals, pyrrolinyl, imidazole radicals, pyrazolyl, pyridine radicals and its N-oxide, Pirimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazole radical and dihydrogen triazine base. Preferably Ground, described heteroaryl is the many rings that contain 1-5 N-atom. Example includes, but are not limited to indoles Base, isoindolyl, indolizine base, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, BTA base, tetrazolo pyridine radicals, tetrazolo pyridazinyl and dihydro-Triazolopyridazines base. Excellent Selection of land, described heteroaryl contain undersaturated ring, a 1-2 oxygen atom and 1-3 N-atom Many rings. Example includes, but are not limited to benzoxazolyl and Ben Bing oxadiazolyl. Preferably, institute Stating heteroaryl is 3-8 unit monocycle, more preferably is to contain 1-2 sulphur atom and 1-3 N-atom 5-6 unit ring. Example includes, but are not limited to thiazolyl, 1,2-thiazolyl, thiazolinyl and thiophene Di azoly. Preferably, described heteroaryl is 3-8 unit monocycle, more preferably is that to contain 1 sulphur former The 5-6 unit ring of son or 1 oxygen atom. Example includes, but are not limited to thienyl and furyl. Preferably, described heteroaryl is the dicyclo that contains 1-2 sulphur atom and 1-3 nitrogen-atoms. Example Include, but are not limited to benzothiazolyl and diazosulfide base.

[0054] term " acyl group " refers to can be following acyl group: the short chain alkanoyl (as, formoxyl, Acetyl group, propiono, bytyry etc.), short chain alkoxyl-carbonyl (as, methoxyl group-carbonyl, second Oxygen base-carbonyl, propoxyl group-carbonyl, butoxy-carbonyl, uncle-butoxy-carbonyl etc.), short chain alkane Base-sulfonyl (as, methyl-sulfonyl, ethyl-sulfonyl etc.), aryl-sulfonyl is (such as, phenyl-sulfonyl etc.), aroyl (as, benzoyl, naphthoyl etc.), aryl-(short chain alkane acyl The base) and (as, phenyl-acetyl group, phenyl-propiono etc.), ring-(short-chain alkyl)-(short chain alkane acyl Base) (such as, cyclohexyl-acetyl group etc.), aryl-(short chain alkoxyl)-carbonyl are (such as, benzyloxy-carbonyl Deng), aryl-carbamoyl (as, phenyl-carbamoyl, naphthyl carbamoyl etc.), Cycloalkyl-carbamoyl (such as, cyclohexyl-carbamoyl etc.), assorted-the monocycle sulfonyl (as, Thienyl-sulfonyl, furyl-sulfonyl etc.). Acyl group can be by as described above 1-3 replacement Base is optional to be replaced.

[0055] term " omega-amino--alkyl " refers to that ω-position at alkyl chain contains the N-atom of replacement Short-chain alkyl, alkyl chain wherein be by one or more substituting groups, preferably one or two halogen (as, chlorine, bromine, fluorine, iodine), optional replacement of hydroxyl of hydroxyl or acidylate. Preferably, one Or two short-chain alkyls and " alkyl " definition as above write. In the ω of alkyl chain-position The N-atom can be by one or two short-chain alkyl substituting group, preferable methyl-, ethyl-, tert-butyl-etc., by the cycloalkyl amino formoxyl-(as, cyclohexyl-carbamoyl-etc.) replace. Preferably, Described N-atom can be the part of the saturated heterocycle that contains 1-4 nitrogen-atoms, and is described saturated Heterocycle be selected from aziridine base, azetidinyl, oxaza propyl, pyrrolidinyl, Imidazolidinyl, pyrazolidinyl, perhydro--carotene thiazolyl, perhydro--carotene isoxazolyl, piperidyl, Piperazinyl, perhydro--carotene pyrimidine radicals, perhydro--carotene pyridazinyl, morpholinyl and perhydro--carotene 1H-azepine

Base. The N-of described ω-position is former to give and can be replaced by aryl (such as, phenyl etc.) and can be by short-chain alkyl Substituting group season (quatemarized) or also can be oxidized.

[0056] term " halogen " refers to F, Cl, Br or I.

[0057] term " optional replacement " aryl or alkyl refer to have one or more substituting groups Aryl-or alkyl. Substituent example includes, but are not limited to cyano group, hydroxyl, short-chain alkyl (as, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the second month in a season-butyl, amyl group, Uncle-amyl group, hexyl, heptyl, octyl group etc.), the short chain alkoxyl (as, methoxyl group, ethyoxyl, Propoxyl group, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy, uncle-butoxy, penta Base oxygen base, uncle-amyl group oxygen base, hexyl oxygen base etc.), aryl (as, phenyl, naphthyl, etc.), nitre The amino of base, amino, single-(short-chain alkyl)-replacement (as, methyl, ethyl, propyl group, isopropyl Base, tert-butyl)-amino of amino etc., two-(short-chain alkyl)-replace (as, dimethylamino, Diethylamino, dipropyl amino, diisopropylaminoethyl, dibutylamino, diamyl amino, Dihexyl amino etc.), single halogen, two halogens or three halogens (short chain)-alkyl (as, chloro methyl, 2,2-Dichloroethyl, trifluoromethyl etc.) or halogen atom (as, fluoro-, chloro-, bromo-and iodine atom).

[0058] term " but biological utilisation " the specific compound that means at least one tittle is deposited Be in the systemic circulation. The formal calculating of oral administration biaavailability carried out according to the description to the F value (" the basic principle of Clinical pharmacokinetics (Fundamentals of Clinical Parmacokinetics) ", " John G.Wegner, Drug Intelligence Publications; Hamilton, I11.1975). The F value by intravenously administrable after parent's medicine in systemic circulation (such as, blood Slurry) concentration in by the non-vein approach (as, oral) after the administration parent drug in systemic circulation The ratio of the concentration in (such as, blood plasma) is derived. Therefore, include the oral biology of category of the present invention in Detectable parent drug in the blood plasma behind availability expection and the intravenously administrable oral administration relatively This ratio or the F value of amount.

[0059] term " treatment " or " processing " mean and alleviate or releasing mammal, such as the symptom of people's disease, or with the improvement of the confirmable detected value of disease association.

[0060] term " patient " refers to comprise the mammal animal of (as, people).

[0061] term " pharmaceutically acceptable derivates " refers to any pharmaceutically acceptable salt, ester of The compounds of this invention or the salt of such ester, or any other chemical compound, (directly or indirectly) The compounds of this invention or its metabolite or residue can be provided when giving the receiver.

2. embodiment

[0062] the present invention relates to treat the method for apoplexy, described method comprises one or more some hydroxylamine derivative that the patient of needs effective dose is arranged, described have the patient who needs to be to be diagnosed as suffer from apoplexy, show the patient that symptom relevant with apoplexy or alternative index and/or suspection are suffered from apoplexy.Those that describe at following patent documentation before the hydroxylamine derivative that is used for implementing this method comprises:

U.S. Patent number 5,147,879; U.S. Patent number 6,143,741; U.S. Patent number 6,653,326;

U.S. Patent number 6,649,628; U.S. Patent number 6,384,029; U.S. Patent number 5,328,906;

U.S. Patent number 5,296,606; U.S. Patent number 5,919,796; U.S. Patent number 6,002,002

U.S. Patent number 6,180,787; U.S. Patent number 6,384,029; With U.S. Patent Publication number 2005/0043295, all these documents are incorporated into this paper by reference.

[0063] in one embodiment, this method comprise give N-[2-hydroxyl-3-(piperidino) propoxyl group]-step of 3 pyridines-first imido acyl chloride (chloropyridine alcohol):

[0064] at U.S. Patent number 5,147, in 879 (being incorporated into this paper by reference) chloropyridine alcohol has been described, it can be by method preparation well known by persons skilled in the art, as to be used for similar compound.Particularly, referring to U.S. Patent number 6,180,787, it is incorporated into this paper by reference.

[0065] in another embodiment, the inventive method comprise give N-[2-hydroxyl-3-(piperidino) propoxyl group]-step of pyridine-1-oxide-3-first imido acyl chloride (Ah not 's chloropharin),

[0066] as describing elsewhere, Ah not 's chloropharin can be used for treating suffers from disease, disease or the disorderly patient who involves molecular chaperoning.Such disease includes, but are not limited to neurodegenerative diseases.In some embodiments, nerve retrograde affection is arranged in central nervous system (CNS).In some embodiments, described disease is selected from apoplexy, amyotrophic lateral sclerosis (ALS), parkinson (PD), Alzheimer (AD), Huntington's disease and cystic fibrosis.

[0067] can being used for of being familiar with prepare Ah not 's chloropharin by those skilled in the art to the method for similar compound.Referring to, as U.S. Patent number 6,649,628 and PCT publication No. WO01/79174, both are incorporated into this paper by reference.

[0068] another embodiment of the present invention utilizes 5,6-dihydro-5 (piperidino)-methyl-3-(3-pyridine radicals)-4H-1,2,4-oxadiazine (Ai Shanading).

[0069] is described in PCT publication No. WO98/06400 and U.S. Patent number 6 before Ai Shanading and the related compound, 384, in 029 (all being incorporated into this paper by reference), and can be equipped with by the system method that is used for similar compound that those skilled in the art are familiar with, described at these publications.

[0070] another chemical compound that is used to implement the inventive method is N-[3-(1, the 1-dimethyl ethyl) amino-2-hydroxyl propoxyl group]-3-trifluoromethylbenzene-first imido acyl chloride (chemical compound 2)

[0071] can prepare chemical compound 2 by the method that is used for similar compound that those skilled in the art are familiar with.Referring to, as U.S. Patent number 6,649,628 and PCT publication No. WO01/79174, both are incorporated into this paper by reference.Can for example use in above document, to be used to describe the method for preparing Ah not 's chloropharin, as by using CF ₃The initial alternative CN-pyrido tert-butylamine substituted piperidine of-cyanopyridine, preparation chemical compound 2.

[0072] in specific embodiment, find Ah not 's chloropharin, Ai Shanading and chemical compound 2, unite separately or mutually or unite with other therapeutic agent, effective in the treatment of apoplexy.

[0073] more generally, can adopt the Pharmaceutical composition that contains formula (I) chemical compound or its formula (II) tautomer chemical compound and pharmaceutically acceptable salt thereof to implement certain embodiments of the present invention:

Wherein, in formula (I) and chemical compound separately (II):

Z is covalent bond, oxygen or N (R ³);

R is the alkyl of alkyl or replacement,

X in formula (I) chemical compound, is hydroxyl or amino, mono-substituted amino or dibasic amino of halogen or replacement, and in formula (II) chemical compound, is the imino group of oxygen, imino group or replacement; With

[0074] structural formula that is used for any above chemical compound is intended to comprise all stereochemical forms of chemical compound, comprise geometric isomer (that is, and E, Z) and optical isomer (that is, and R, S).The single three-dimensional chemical isomer of this chemical compound and the mixture of enantiomorph and diastereomer are included within the category of the present invention.Unless otherwise stated, each structural formula described herein only is also intended to comprise the different chemical compound with the atom performance of one or more isotope enrichments.For example, have the chemical compound of this structural formula, except with deuterium or tritium displacement hydrogen, or use ¹³C-or ¹⁴Outside the carbon displacement carbon of C-enrichment, all be included within the category of the present invention.

[0075] in some embodiments, formula (I) or (II) chemical compound on the carbon of hydroxyl, have " R " configuration.In some embodiments, formula (I) or (II) chemical compound on the carbon of hydroxyl, have " S " configuration.

[0076] in some embodiments, formula (I) or (II) chemical compound on the two keys of carbon-nitrogen, have " E " configuration.In some embodiments, formula (I) or (II) chemical compound on the two keys of carbon-nitrogen, have " Z " configuration.

[0077] in one embodiment, in formula (I) chemical compound, Z is that covalent bond and X are halogens.Aspect some of this embodiment, X is chloro or bromo.Aspect some of this embodiment, A is selected from (i) aralkyl or has the aralkyl of the aryl moiety of replacement; The (ii) aryl of aryl or replacement; (iii) naphthyl; (iv) contain the N heteroaryl, comprise can with condensed those groups of phenyl ring; (v) contain the S heteroaryl and (vi) contain the O heteroaryl.Aspect some of this embodiment, A is phenylalkyl or has one or more substituent groups, the phenylalkyl of preferred alkoxyl.In the others of this embodiment, A is the phenyl of phenyl or replacement.Aspect some of this embodiment, A is the phenyl that contains the one or more substituent replacements that are selected from alkyl, halo, haloalkyl, alkoxyl and nitro.Aspect some of the present embodiment, A is a pyridine radicals.Aspect other of the present embodiment, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, ω-nitrilo-alkyl is the moieties of 3-8 carbon atom.

[0078] at U.S. Patent number 5,147, disclose wherein in 879,5,328,906 and 5,296,606 that Z is that covalent bond and X are formula (I) chemical compounds of halogen, all these documents are incorporated into this paper by reference.Can be by the method for in the United States Patent (USP) of quoting, describing, preferably, by in the presence of suitable hydrohalide, making corresponding X=NH ₂Derivant diazotising prepares these chemical compounds.Can be by known method, as, methods that those are described in hungarian patent numbers 177,578 (1976), promptly the amidoxim by making formula (1) (R '=R ²=H):

Formula (1)

Reactive derivatives with for example formula (2):

R-L

Formula (2)

Coupling in the presence of alkali, and can be through diazotising does not need isolated or purified usually and obtains initial compounds.If desired, can make end group A and the further amidatioon of R or the derivatization of chemical compound.

[0079] in another embodiment, in formula (I) chemical compound, Z is that covalent bond and X are the hydroxyl O-Q that replaces, and wherein Q is alkyl or an aralkyl unsubstituted or that replace.Aspect of this embodiment, Q is the straight or branched alkyl.Aspect of this embodiment, A is aryl or heteroaryl; Be selected from (i) omega-amino--alkyl with R, (ii) have the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, A contains the N heteroaryl.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, omega-amino--alkyl is the moieties of 3-8 carbon atom.

[0080] in another embodiment, in formula (I) chemical compound, Z is a covalent bond, and X is O-Q, and Z is that covalent bond and R are-CH ₂-CH (OH)-R ".Make chemical compound pass through the hydroxyl cyclisation and represent with formula (I '):

R " is selected from the straight or branched alkyl of straight or branched alkyl and replacement.Aspect some of this embodiment, R " is to take up an official post at its amino to choose the omega-amino--alkyl in generation.Aspect some of this embodiment, R " is by C on amino _1-5Omega-amino--alkyl that the straight or branched alkyl chain replaces.In some aspects, R " be single on amino-or dibasic omega-amino--alkyl, amino-substituent group wherein independently can be one or two straight or branched alkyl or cycloalkyl separately; or two amino-substituent groups, form the 3-7 heterocycle with their adjacent N-atoms.In some aspects, this ring is a 5-7 unit heterocycle, chooses wantonly to contain extra hetero atom.In some aspects, A be selected from phenyl, replacement phenyl, contain N heteroaryl, replacement contain the N heteroaryl, contain S heteroaryl and replacement contain the S heteroaryl.

[0081] disclosing wherein in Hungarian patent application number 2385/1992 (being incorporated into this paper by reference), Z is that covalent bond and X are formula (I ') chemical compounds of O-Q.Can be that covalent bond and X are formula (I) chemical compounds of halogen from Z wherein, by describing method in Hungarian patent application number 2385/1992, for example by with pure reactant salt, or the alkali ring closure of through type (I ') cyclic compound prepares these chemical compounds.

[0082] in another embodiment, in formula (I) chemical compound, Z is that covalent bond and X are NR ₁R ₂, R wherein ₁And R ₂Independently be selected from H, straight or branched alkyl, the straight or branched alkyl of replacement, cycloalkyl, or R ₁And R ₂The nitrogen-atoms that connects with their forms and contains the saturated ring of 3-7 unit.Aspect some of this embodiment, R ₁And R ₂Form saturated 5-7 unit ring.Aspect some of this embodiment, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, omega-amino--alkyl is the moieties of 3-8 carbon atom.Aspect some of this embodiment, A is selected from (i) aralkyl or has the aralkyl of the aryl moiety of replacement; The (ii) aryl of aryl or replacement; (iii) naphthyl; (iv) contain the N heteroaryl, comprise that those can be condensed with phenyl ring; (v) contain the S heteroaryl and (vi) contain the O heteroaryl.Aspect some of this embodiment, A is phenylalkyl or the phenylalkyl with one or more substituent replacements.Aspect some of this embodiment, the phenylalkyl that A is replaced by one or more alkoxyls.Aspect some of this embodiment, A is the phenyl of phenyl or replacement.Aspect some of this embodiment, A contains to be selected from the phenyl that the one or more substituent groups in alkyl, halogen, haloalkyl, alkoxyl, nitro and the acyl amino replace.In the others of this embodiment, A is a pyridine radicals.

[0083] disclosing wherein in hungarian patent numbers 177578 (1976) and U.S. Patent number 6,653,326 (both are incorporated into this paper by reference), Z is that covalent bond and X are NR ¹R ²Formula (I) chemical compound.Can be by in the presence of alkali, make formula (I) chemical compound (formula (I), wherein R with the reactive derivatives of formula (II) chemical compound ¹=R ²=H) unsubstituted amidoxim derivant alkylation, synthetic these chemical compounds.

[0084] in another embodiment, in formula (I) chemical compound, Z is a covalent bond, and X is NR ₁R ₂With R be-CH ₂-CH (OH)-R ".Pass through NR ₁R ₂Group makes the chemical compound cyclisation, and with formula (I ") expression:

Wherein R " is selected from the straight or branched alkyl of straight or branched alkyl or replacement.R ¹Be selected from hydrogen, the unsubstituted or straight or branched alkyl that replaces, cycloalkyl, unsubstituted aralkyl and at aryl-and aralkyl of replacing of moieties.Aspect some of this embodiment, A is selected from the aryl of (i) aryl or replacement; (ii) naphthyl; (iii) contain the N heteroaryl, comprise that those can be condensed with phenyl ring; (iv) contain the S heteroaryl; (v) contain the O heteroaryl.In some aspects, A is the phenyl of phenyl or replacement.In some aspects, A is the phenyl that contains the one or more replacement in alkyl, halogen, haloalkyl, alkoxyl, amino or the nitro." being selected from (i) has the omega-amino--alkyl of single or dibasic amino part or (ii) has single or dibasic amino part and also have the omega-amino-alkyl of the moieties that replaces for aspect other, R.Aspect some of this embodiment, this omega-amino--alkyl is the moieties of 3-8 carbon atom.In some aspects, this omega-amino--alkyl has dibasic amino part, and the nitrogen-atoms that wherein said substituent group connects with them forms saturated 3-7 unit heterocycle.In some aspects, this ring be 5-7 unit and optional contain extra hetero atom.In some aspects, this omega-amino--alkyl, amino-substituent group is the straight or branched alkyl or cycloalkyl.

[0085] can be by adopting fisher's formula (I) chemical compound, wherein Z is a covalent bond, X is=NR ¹R ², R wherein ¹As with following formula (the relevant definition of I ") chemical compound, R ²Be H, R is-CH ₂-CHY ⁵-R ", Y herein ⁵Be leaving group, as, halogen atom makes at atom N (4)-C and carries out closed loop between (5), preparation formula (I ") chemical compound.Can be from corresponding Y ⁵=OH chemical compound and inorganic halogenating agent, as, thionyl chloride or phosphorus pentachloride obtain such derivant.Available or without atent solvent, as, benzene, chloroform, oxolane etc. usually by boiling, are implemented halogenation.After removing too much reactant, as, by the evaporation thionyl chloride, can make thick halogen derivatives cyclisation-or afterwards or need not isolated or purified-by using highly basic, handle as the butanols potassium in the tert-butyl alcohol, (I ") chemical compound, it finally separates and purification by standard method (extraction, recrystallize etc.) to obtain formula.

[0086] according to an embodiment, in formula (I) chemical compound, Z is that oxygen and X are O-Q, and wherein Q is selected from alkyl, the aralkyl of alkyl, replacement and has the aryl of replacement or the aralkyl of the replacement of the moieties of replacement.Aspect some of this embodiment, when A was the alkyl of alkyl or replacement, it contained 1-4 carbon atom.In some aspects, A is selected from C _1-4The alkyl of alkyl or replacement, aralkyl and have the aryl of replacement or the aralkyl of the replacement of the moieties of replacement.Aspect some of this embodiment, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, this alkyl is replaced by hydroxyl or acyloxy.

[0087] azanol that can replace by the O-that makes formula (6) (referring to, as, Ger.Off.2,651,083 (1976)) and formula (7) ortho esters react, preparing wherein, Z is that oxygen and X are formula (I) chemical compounds of O-Q:

H ₂N-O-R C(OQ) ₄

Formula (6) formula (7)

[0088] can in reactant self,, implement condensation reaction preferably by boiling as solvent.After the evaporation, can product be separated into the form (if there is amine functional group in side chain R) of acid-addition salts by crystallization.

[0089] according to an embodiment, in formula (I) chemical compound, Z is an oxygen, and X is NR ¹R ², and R ¹And R ²Independently be selected from straight or branched alkyl, cycloalkyl, the aryl of H, straight or branched alkyl, replacement and the aryl that replaces, or R ¹And R ²The nitrogen-atoms that connects with their forms and contains the saturated ring of 3-7 unit.In some aspects, R ¹And R ²Form the saturated ring of 5-7 unit.Aspect some of this embodiment, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, this omega-amino--alkyl is the moieties of 3-8 carbon atom.Aspect some of this embodiment, A is selected from the alkyl of (i) alkyl or replacement; (iii) aralkyl or have the aryl of replacement and/or the aralkyl of the moieties of replacement; The (iv) aryl of aryl or replacement.Aspect some of this embodiment, A is the phenyl of phenyl or replacement.

[0090] can be as this paper preparation formula described below (I) chemical compound, wherein said method depends on the character of X, no matter promptly X is unsubstituted amino (NH ₂) or the amido functional group that replaces.

[0091] can be added to organic cyanate of formula A-O-CN by the azanol with formula (6), preparing wherein, X is NH ₂Formula (I) chemical compound (referring to, as, Chem.Ber.98,144 (1965)).Can preferably in inert organic solvents, usually at room temperature, implement this reaction.Separating usually needs chromatography purification.

[0092] can be from the halo first imino-ester (haloformimidate) of known formula (9):

Formula (9)

(referring to, as, Houben-Weil, " Methoden der Organischen Chemie, " Band E/4, p.544 (1983) and formula (6) chemical compound, organic base (as, triethylamine) or inorganic base, under sodium carbonates' presence, at atent solvent, in benzene, oxolane etc., carry out the post processing and the purge process of standard subsequently, prepare wherein X and be mono-substituted amino (as, NHR ¹) formula (I) chemical compound.

[0093] can be that oxygen and X are that formula (I) chemical compound (its can by method preparation described above) of O-Q reacts by making formula 5 secondary amine and Z wherein, preparing wherein, X be formula (I) chemical compound of dibasic amino:

HNR ¹R ²

Formula (5)

At polar organic solvent, in ethanol,,, implement these aminating reactions by refluxing if essential.

[0094] according to another embodiment, in formula (I) chemical compound, Z is N (R ³), R wherein ³Be selected from hydrogen, alkyl, replacement alkyl, aryl, replacement aryl, aralkyl and have the aryl of replacement or the aralkyl of the moieties of replacement; With X be NR ¹R ², R wherein ¹And R ²Independently be selected from aryl, the cycloalkyl of straight or branched alkyl, aryl or the replacement of H, straight or branched alkyl, replacement, and R ¹And R ²The nitrogen-atoms that connects with them forms the saturated ring of 3-7 unit.

[0095] aspect some of this embodiment, A is selected from aralkyl, the aryl of the moieties of alkyl, the aralkyl of alkyl, replacement, the aryl with replacement or replacement and the aryl that replaces.In some aspects, R ¹And R ²Form the saturated ring of 5-7 unit.In the others of this embodiment, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, this omega-amino--alkyl is the moieties of 3-8 carbon atom.

[0096] can (promptly wherein Z be that oxygen and X are NR to belonging to chemical compound group described above by adopting ammonia or uncle or secondary amine ¹R ²Formula (I) chemical compound) the ammonolysis process of corresponding isourea derivatives, preparing wherein, Z is NR ³With X be NR ¹R ²Formula (I) chemical compound.Preferably at polar solvent, as, in water or the ethanol, use excessive amine, implement this reaction.Perhaps, also can in the presence of organic or inorganic alkali, make formula (10) halo Methanamide (Houben-Weil " Methodender Organischen Chemie, " Band E/4, page 553 (1983)) react with chemical compound with formula (6), also can obtain this group chemical compound:

Formula (10)

[0097] can in inert organic solvents, usually at room temperature, implement this reaction.

[0098] wherein R is formula (I) chemical compound of formula (b) group:

Formula (b)

Wherein R is an acyl group, can be corresponding hydrogeneous as R by making ⁷Chemical compound esterification preparation.By using acyl chlorides or anhydride, in the presence of tertiary amine or inorganic base, preferably in atent solvent, can obtain the alkyl or aryl ester.

[0099] it should be understood, however, that chemical compound group described above does not comprise the hydroxylamine derivative of array structure down:

R ³-A-C(NH ₂)＝N-O-CH ₂-CH(OH)-CH ₂-N(R ¹)(R ²)

Wherein

R ¹Be H or C _1-5Alkyl,

R ²The C that is H, can be replaced by OH or phenyl _1-5Alkyl, C _3-8Cycloalkyl or phenyl, R ¹And R ²When combining with the nitrogen-atoms of their adjacency, form the saturated or unsaturated ring of 5-8 unit, it is optional to contain one or more extra N, O or S atom, and can condense with phenyl ring,

R ³Be H or by one or more halos or C _1-4Optional phenyl, naphthyl or the pyridine radicals that replaces of alkoxyl,

A is the group of formula (a),

Wherein

R ⁴Be H or phenyl,

R ⁵Be H or phenyl,

M be 0,1 or 2 and

N is 0,1 or 2.

[0100], the invention provides formula (II) chemical compound of the tautomeric form of representative formula (I) chemical compound according to another embodiment.Aspect of this embodiment, in formula (II) chemical compound, Z is that covalent bond and X are oxygen.Aspect this embodiment other, A is selected from (i) alkyl, aralkyl or has the aryl of replacement or the aralkyl of moieties; The (ii) aryl of aryl or replacement; (iii) contain the N heteroaryl; (iv) contain the S heteroaryl.Aspect some of this embodiment, A is phenyl or the phenyl with one or more substituent replacements.Aspect some of this embodiment, A contains the phenyl that is selected from the one or more substituent replacements in alkyl, haloalkyl and the alkoxyl.In the others of this embodiment, A is a pyridine radicals.

[0101] aspect more, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, this omega-amino--alkyl is the moieties of 3-8 carbon atom.

[0102] aspect more, R ' be selected from hydrogen, alkyl, replacement alkyl, aryl, replacement aryl, aralkyl and have the aryl of replacement or the aralkyl of moieties.

[0103] in Hungarian patent application number 2385/1992 (being incorporated into this paper by reference) chemical compound that belongs to this group is disclosed.Can prepare these chemical compounds according to describing method there, most preferably, can be by with acyl chlorides with formula (11):

Formula (11)

The hydroxylamine derivative acidylate that the have formula O-of (6) is replaced obtain they (also referring to, as, Ger.Off.2,651,083 (1976))

[0104] this path can be applicable to also prepare wherein that R ' is not the chemical compound of hydrogen, and use formula (12) chemical compound replaces formula (6) as initiation material:

R ¹HN-O-R

Formula (12)

[0105] according to another embodiment, in formula (II) chemical compound, Z is a chemical bond; X is=NR ⁴, R wherein ⁴Be selected from aralkyl, the cycloalkyl of alkyl of alkyl, aryl, aryl, the aralkyl of replacement, aryl or the replacement of H, alkyl, replacement with replacement; And R ⁴Be selected from alkyl, replacement alkyl, aryl, replacement aryl, aralkyl and have the aryl of replacement or the aralkyl of the moieties of replacement.Aspect some of this embodiment, A is (i) aralkyl or the aralkyl with aryl moiety of replacement; The (ii) aryl of aryl or replacement; (iii) naphthyl; (iv) contain the N heteroaryl; (v) contain the S heteroaryl.Aspect some of this embodiment, A is phenylalkyl or has one or more substituent phenylalkyls.Aspect some of this embodiment, the phenylalkyl that A is replaced by one or more alkoxyls.Aspect some of this embodiment, A is the phenyl of phenyl or replacement.Aspect some of this embodiment, A contains to be selected from the phenyl that the one or more substituent groups in alkyl, haloalkyl and the nitro replace.In the others of this embodiment, A is a pyridine radicals.

[0106] in some embodiments, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, this omega-amino--alkyl is the moieties of 3-8 carbon atom.

[0107] can or by making the N of formula (13) with formula (2) chemical compound, (its reaction condition is that covalent bond and X are NR referring to Z wherein to N '-dibasic amidoxim O-alkylation ¹R ²The preparation of formula (I) chemical compound):

Formula (13)

Perhaps by or with imido acyl (imidoyl) halogenide of formula (16):

Formula (16)

Make the N of formula (12), the dibasic azanol O-of O-acyl groupization prepares these chemical compounds.

[0108] can in atent solvent, preferably in the presence of the organic or inorganic acid scavenger, implement this reaction.

[0109] can be corresponding hydrogeneous as R by making ⁷The chemical compound esterification prepare wherein that R is the chemical compound of formula (b) group (wherein R is an acyl group).Can in the presence of tertiary amine or inorganic base, preferably in atent solvent, obtain the alkyl or aryl ester by using acyl chlorides or anhydride.

[0110] according to an embodiment, in formula (II) chemical compound, Z is that oxygen and X are oxygen.Aspect some of this embodiment, A is selected from alkyl, the aralkyl of alkyl, replacement and has the aryl of replacement or the aralkyl of moieties.In some aspects, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; (iv) have single or dibasic amino part A) and the omega-amino-alkyl of the moieties that also have to replace.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, this omega-amino--alkyl is the moieties of 3-8 carbon atom.Aspect some of this embodiment, R ' be selected from hydrogen, alkyl, replacement alkyl, aryl, replacement aryl, aralkyl and have the aryl of replacement or the aralkyl of moieties.

[0111] according to this embodiment, Hungarian patent application number 1756/95 (submit to January 15 nineteen ninety-five, is incorporated into this paper by reference) discloses this chemical compound.Can use simple acyl chlorides by to be used for synthetic wherein Z as description be that covalent bond and X are the modes of formula (II) chemical compound of oxygen to be similar to, the chloro-formate that usefulness has a formula (14) makes the azanol acyl groupization of have formula (6) or formula (12), prepares these chemical compounds.The existence of the inorganic or organic base of this reaction needed, and can be in atent solvent, as in chloroform, implementing.For example, remove by-product salt, and this product is separated in organic solution by using water extraction.

[0112] in going back an embodiment, in formula (II) chemical compound, Z is an oxygen; X is=NR ⁴, R wherein ⁴Be selected from the heteroaryl of aryl, heteroaryl and replacement of aralkyl, aryl, replacement of replacement of the alkyl of alkyl, the aralkyl of alkyl, replacement, aryl or replacement with replacement.Aspect some of this embodiment, A be selected from alkyl, replacement alkyl, aryl, replacement aryl, aralkyl and have the aryl of replacement or the aralkyl of moieties.Aspect some of this embodiment, A is a phenyl unsubstituted or that replace.

[0113] aspect some of this embodiment, R is the omega-amino-alkyl, its suit in alkyl chain hydroxyl or acyloxy and take up an official post at amine nitrogen and to choose generation, and wherein the alkyl chain of omega-amino-alkyl preferably contains 3-8 former the giving of carbon.Aspect some of this embodiment, R ' is selected from and can be alkyl, aryl or aralkyl unsubstituted or that replace.

[0114] according to this embodiment, can be similarly from halo first imino-ester (haloformimidates) with formula (9) and chemical compound with formula (12), organic base (as, triethylamine) or inorganic base, under sodium carbonates' presence, at atent solvent, in benzene, oxolane etc., post processing and purification step by standard subsequently, prepare these wherein Z be that oxygen and X are NR ¹R ²Formula (I) chemical compound.

[0115] in another embodiment, in formula (II) chemical compound, Z is N (R ³), R wherein ³Be selected from hydrogen, alkyl, replacement alkyl, aryl, replacement aryl, aralkyl and have the aryl of replacement or the aralkyl of the moieties of replacement; With X be oxygen.Aspect some of this embodiment, A is selected from (i) aralkyl or has the aralkyl of the alkyl or aryl part of replacement; (ii) the aryl of aryl or replacement (iii) contains the N heteroaryl; The (iv) alkyl of alkyl or replacement, straight or branched; (v) cycloalkyl.Aspect some of this embodiment, A is phenylalkyl or has one or more substituent phenylalkyls.Aspect some of this embodiment, A is the phenyl of phenyl or replacement.Aspect some of this embodiment, A contains the phenyl that is selected from the one or more substituent replacements in alkyl, alkoxyl, halogen, haloalkyl and the nitro.In the others of this embodiment, when a is (iv) the time, alkyl contains 4-12 carbon atom.

[0116] aspect some of this embodiment, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, this omega-amino--alkyl is the moieties of 3-8 carbon atom.In some aspects, R ' is selected from the acyl group of aryl, acyl group and replacement of aralkyl, aryl, the replacement of alkyl, the aralkyl of hydrogen, alkyl, replacement, the aryl with replacement or moieties.

[0117] according to this embodiment, these chemical compounds are open in Hungarian patent application number 1756/95 (being incorporated into this paper by reference), and can be by in atent solvent, usually by mixture being stirred 2-24 hour simply, makes the hydroxylamine compound and isocyanate reaction preparation of have formula (6) or formula (12) with formula (15):

A-N＝C＝O

Formula (15)

At last, separable this product, then evaporating solvent.In some aspects, can be through this product of Crystallization Separation.

[0118] in another embodiment, in formula (II) chemical compound, Z is N (R ³), R wherein ³Be selected from hydrogen, alkyl, replacement alkyl, aryl, replacement aryl, aralkyl and have the aryl of replacement or the aralkyl of the moieties of replacement; X is=NR ⁴, R wherein ⁴Be selected from the aralkyl of alkyl of alkyl, aryl, aryl, the aralkyl of replacement, aryl or the replacement of H, alkyl, replacement with replacement, and cycloalkyl; Be selected from the aryl of aralkyl, aryl and replacement of replacement of the moieties of alkyl, the aralkyl of alkyl, replacement, aryl or replacement with R with replacement.Aspect some of this embodiment, R ³Be selected from the alkyl of hydrogen, alkyl and replacement; R ⁴Be hydrogen or aryl; Be selected from alkyl, the aryl of alkyl, replacement, the aryl of replacement with A, or can be at the aryl or aralkyl of aryl and/or the substituted replacement of moieties.Aspect more, R is selected from (i) omega-amino--alkyl, (ii) has the omega-amino--alkyl of single or dibasic amino part; The omega-amino-alkyl that (iii) has the moieties of replacement; The omega-amino-alkyl of the moieties that (iv) has single or dibasic amino part and replace in addition.Aspect some of this embodiment, when R is (iv) the time, alkyl is replaced by hydroxyl or acyloxy.Aspect some of this embodiment, this omega-amino--alkyl is the moieties of 3-8 carbon atom.

[0119] according to this embodiment, can be by (wherein Z is that oxygen and X are NR to corresponding isourea derivatives with uncle or secondary amine or ammonia ⁴Formula (II) chemical compound) ammonolysis process, prepare this chemical compound.Can in water or ethanol, use excessive amine preferably at polar solvent, implement this reaction.Perhaps, can in atent solvent, under their boiling point, make halo carbonamidine and this chemical compound of formula (12) chemical compound prepared in reaction of formula (10) usually by in the presence of organic or inorganic alkali.

[0120] according to an embodiment, the invention provides formula (I) chemical compound, wherein X is a halogen; Z is that chemical bond and A are formula (a) group, wherein Y ¹Be selected from halo, alkoxyl, nitro and haloalkyl; Be selected from 1,2 and 3 with n; Or can be with the condensed O of the containing heteroaryl of phenyl ring, contain the S heteroaryl or contain the N heteroaryl; With R be the group with formula (b), wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl and cycloalkyl separately, or R ⁵And R ⁶When the nitrogen-atoms that is connected with them combines, form 3-7 unit ring; Y ⁶Be-OR ⁷, R wherein ⁷Be H or acyl group; K is 1,2 or 3; With m be 1,2 or 3, condition is, when A is pyridine radicals or naphthyl or formula (a) group, Y wherein ¹Be halo or alkoxyl, then R ⁷Not H.These chemical compounds can be chosen the C with season N-that contains as A wantonly _1-4The oxide and/or the R that contain N heteroaryl or the described N of containing heteroaryl of alkyl are wherein by end group R ⁶And R ⁷The ring that forms is saturated heterocycle N-seasonization or the N-oxidation.

[0121] aspect some of this embodiment, X is chloro or bromo.Aspect some of this embodiment, Y ¹It is the haloalkyl that contains 1-4 carbon atom.In others, Y ¹Be selected from furyl, thienyl, pyridine radicals (piridyl), quinolyl and isoquinolyl.Aspect some of this embodiment, R ⁵And R ⁶Independent separately straight or branched alkyl for replacing.In some aspects, R ⁵And R ⁶Be C _1-4Alkyl.In others, work as R ⁵And R ⁶The nitrogen-atoms that connects with them forms 3-7 unit ring, and the ring of formation is the saturated heterocycle of 5-7 unit.In some aspects, R ⁷Be selected from the aryl carbonyl of alkyl-carbonyl, aryl carbonyl or replacement of alkyl-carbonyl, replacement and the aminoacyl of aminoacyl or replacement.

[0122] aspect some of this embodiment, A is formula (a) group, wherein Y ¹It is trifluoromethyl.Aspect some of this embodiment, X is a halo, and A is a pyridine radicals, and Z is that chemical bond and R are formula (b) group, wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl and cycloalkyl separately, or R ⁵And R ⁶Form 3-7 unit ring, Y with adjacent N atom ⁶Be-OR ⁷, R wherein ⁷Be aminoacyl, k be 1,2 or 3 and m be 1,2 or 3.In some aspects, R ⁵And R ⁶Independent separately is C _1-4Alkyl or cycloalkyl.In others, R ⁵And R ⁶Form 5-7 unit heterocycle with adjacent N atom.According to the each side of this embodiment, this chemical compound can be optically active.

[0123], can adopt to be similar in U.S. Patent number 5,147,879 according to this embodiment; 5,398,906; With 5,996, the method for describing in 606 (all these are incorporated into this paper by reference) prepares these chemical compounds.For example, can be by being similar in U.S. Patent number 5,147,879; The method of describing in 5,328,906 and 5,296,606 is in the presence of suitable hydrogen halides, with corresponding N H ₂(that is, wherein Z is that covalent bond and X are NH to derivant ₂Formula (I) chemical compound) diazotising, prepare wherein R ⁵And R ⁶It all not the chemical compound of hydrogen.Also can be by known method, as those methods of describing in hungarian patent number 177578 (being incorporated into this paper by reference), promptly by making the have formula amidoxim of (1), the R of its Chinese style (1) ¹And R ²Be H, with the reactive derivatives that for example has formula (2), but in the presence of alkali coupling and diazotization, isolated or purified not obtains initial compounds usually.

[0124] or, for R wherein ⁷Be that H and m are 1 chemical compounds, can prepare this chemical compound by making formula (3) oxirane (oxyrane) and the reaction of formula (4) amine.The method also can be used to prepare wherein R ⁵It is the chemical compound of H.

[0125] or, be by formula (b) expression and R for R wherein ⁷Be acylated compound, can be by making accordingly wherein R ⁷The chemical compound esterification that is H prepares this chemical compound.Can use acyl chlorides or anhydride, in the presence of tertiary amine or inorganic base, preferably in atent solvent, perhaps, in some cases,, adopt the inorganic base aqueous solution in binary system, obtain the alkyl or aryl ester by the Schotten-Bauman method.In order to prepare the aminoacyl ester, in known basically method from chemistry of peptides, the amino acid derivativges of carboxyl-activatory N-protected (as, active ester) can be used as reactant.This coupling also needs the alkali existence of (as, triethylamine).Can implement the separation and the purification of product by adopting standard fabrication technique; Final prepared product can usually adopt suitable the form inorganic or salt that organic acid became to present.Initial from chiral amino acid, product can be a diastereomer often, has second chiral centre in the R group.In separation process, these diastereomers usually can be separated and can be obtained the product of three-dimensional pure form.

[0126] in another embodiment of formula (I) chemical compound, Z is a chemical bond, and X is a halo; A is that formula (c) group and R are formula (d) groups:

Formula (c) formula (d)

Y ²And Y ³In at least one must be present in the molecule, one of them or two are oxygen or have the alkyl of 1-4 carbon atom or the alkyl of replacement that k is 1,2 or 3; With m be 1,2 or 3.Y ²And Y ³Connect by a dotted line.Aspect some of this embodiment, X is chloro or bromo.When this chemical compound be one-or during bivalent cation, then its anion is one or two halogenation ion.Aspect some of this embodiment, this anion is the iodate ion.

[0127], can as by N-oxidation or seasonization (quatemerization), prepare this chemical compound by the terminal pyridine and/or the piperidines group of their unsubstituted precursor of chemical modification according to this embodiment.Aspect some of this embodiment, can prepare this chemical compound by with the acid oxidase of crossing in the atent solvent.In the others of this embodiment, this peracid is the benzylhydroperoxide that replaces.In the others of this embodiment, atent solvent is chloroform or dichloromethane.When if two oxidable groups all exist, then can form single-or dioxide according to the amount of used reagent.When oxidation reaction finished, unnecessary reagent was decomposed and passes through the evaporation separated product.In the others of the present embodiment, can be by this chemical compound of season preparation.Aspect some of this embodiment, can be by with this chemical compound of alkyl halide season preparation.Aspect some of this embodiment, alkyl halide is a methyl iodide.In the others of this embodiment, can prepare this chemical compound in the middle backflow of suitable solvent by making reagent.In some aspects, solvent is an acetone.Aspect some of this embodiment, this chemical compound be insoluble in the medium and can separate by simple filtering.

[0128] in another embodiment of formula (I) chemical compound, Z is a chemical bond, A be selected from aralkyl, replacement aralkyl, phenyl, have one or more substituent replacements phenyl, can with the condensed N of containing heteroaryl of phenyl ring and sulfur-bearing heteroaryl; X is-NR ¹R ², R wherein ¹And R ²Independently be selected from H, straight or branched alkyl, the straight or branched alkyl of replacement, cycloalkyl separately, and R ¹And R ²The nitrogen-atoms that is connected with them combines and can form 3-7 unit ring; R is the group of formula (e),

Formula (e)

R wherein ⁵And R ⁶Independently be selected from the straight or branched alkyl or cycloalkyl of H, straight or branched alkyl or replacement separately, or R ⁵And R ⁶The nitrogen-atoms that connects with them forms 3-7 unit ring, and it can contain extra hetero atom and substituent group; Y ⁴Be selected from H, alkyl and have the alkyl of the replacement of 1-4 carbon atom; Y ⁵Be selected from the alkyl of H, alkyl and replacement; Have 1-4 carbon atom, or OR ⁷, R wherein ⁷Be H or acyl group; K is 1,2 or 3; With m be 1,2 or 3, condition is, when A is a phenyl unsubstituted or that replaced by halogen or alkoxyl, or the phenylalkyl that replaces of alkoxy, or pyridine radicals, with R ⁷When being H, R then ¹And R ²In at least one be not H, or when A be phenyl unsubstituted or that replaced by halogen or alkoxyl, the phenylalkyl that alkoxy replaces, or pyridine radicals and R ¹And R ²When respectively being H, R then ⁷Not H.

[0129] aspect some of this embodiment, A is phenylalkyl or phenyl.In some aspects, when A was phenylalkyl, phenyl can be replaced by one or more alkoxyls.In some aspects, this alkoxyl has 1-4 carbon atom.In others, A is the phenyl with one or more substituent replacements.In some aspects, this substituent group is selected from alkyl, preferably has alkyl or haloalkyl, halo, acyl amino or the nitro of 1-4 carbon atom.In others, A is selected from pyrrole radicals, pyridine radicals, isoquinolyl, quinolyl and thienyl.In some aspects, when A was heteroaryl, they can be by one or more alkyl, and the alkyl that preferably has 1-4 carbon atom replaces.

[0130] aspect some of this embodiment, R ¹And R ²Separate for having the individual carbon atom alkyl of 1-6.In others, work as R ¹And R ²When the nitrogen-atoms that connects with their formed ring, this ring was the saturated heterocycle of 5-7 unit.

[0131] aspect some of this embodiment, R ⁵And R ⁶Separate for having the alkyl of 1-4 carbon atom.In others, work as R ⁵And R ⁶When the nitrogen-atoms that connects with their formed ring, this ring was to contain the saturated heterocycle of extra hetero atom and substituent 5-7 unit.In this regard, substituent group can be the alkyl with 1-4 carbon atom.

[0132], can be similar to above-mentioned method, by making the R of corresponding its Chinese style (1) according to this embodiment ¹And R ²Be formula (1) chemical compound and the reaction of formula 2 chemical compounds of H, preparing wherein, X is NH ₂Chemical compound.But the alkylating agent hydroxyl of formula 2 and/or amino substituent group.The existence of the inorganic or organic base of this reaction needed with optimal way, uses alcoholates solution as medium and alkali.Available suitable organic or inorganic acid separates the chemical compound as salt.

[0133], can prepare wherein R by two kinds of methods according to this embodiment ¹And R ²In one or two be not the chemical compound of H.In first method, be similar to the method for in paragraph before, describing, can have the substituent R that needs ¹And/or R ²Formula (1) amidoxim and reactive formula (2) chemical compound reaction.From document, learn the amidoxim of the replacement of the formula (1) that is used as initiation material.Referring to, as, Chem.Rev.62,155-183 (1962), it is incorporated into this paper by reference.

[0134] in second method, replacing Z wherein with formula (5) amine is that covalent bond and X are the halogen atoms in formula (I) chemical compound of halogen, also can produce similar compounds.At R group (Y ⁴=have under the situation of the substituent derivant of OH in OH), must before substitution reaction, protect this hydroxyl and after reaction, make it protection, otherwise help the cyclic derivatives of the formula that forms (I ').For protection, proved the blocking group of acetyl group type, be the most satisfied as THP trtrahydropyranyl.Can be by making the reaction of unprotected chemical compound and dihydropyran, with after halogen/amine displacement, it need as reflux in alcohol in solvent usually, implements protection.At last, can as in the presence of for example right-toluenesulfonic acid, making the alcoholic solution boiling, finish the protection of going by using acid treatment to product.

[0135] according to another embodiment, formula (I) chemical compound comprises those wherein Y ⁵It is the chemical compound of acyloxy.Can be by making accordingly wherein Y ⁵Be OH the preparation of chemical compound acyl group they, itself or from document (as, hungarian patent numbers 177578), know or in the present invention, describe.Can be used for wherein R ⁷This reaction is finished in the description that is the similar halo derivatives of acyl group the samely.

[0136] according to another embodiment, formula (I) chemical compound also comprises those following chemical compounds, and wherein Z is oxygen or N (R ³) group, wherein R ³It is alkyl unsubstituted or that replace; X is-NR ¹R ², R wherein ¹And R ²Independently be selected from hydrogen, the unsubstituted or straight or branched alkyl that replaces, unsubstituted or the aryl and the aralkyl unsubstituted or that replace that replace separately, or R ¹And R ²The nitrogen-atoms that connects with them forms optional one or more heteroatomic, first saturated heterocycles of 3-7 that contain.According to this embodiment, A is selected from the unsubstituted or alkyl that replaces, unsubstituted or the aryl and the aralkyl unsubstituted or that replace that replace.According to this embodiment, R is formula (b) group, wherein R again ⁵And R ⁶Independently be selected from H, straight or branched alkyl separately, and cycloalkyl, or R ⁵And R ⁶The N-atom that connects with them forms the saturated heterocycle of 3-7 unit.According to this embodiment, Y ⁶Be H or-OR ⁷, R wherein ⁷Be H or acyl group, k be 1,2 or 3 and m be 1,2 or 3.

[0137] aspect of this embodiment, R ¹And R ²Independent separately is phenyl.In others, work as R ¹And R ²When the nitrogen-atoms that connects with their formed ring, this ring was the optional saturated heterocycle of one or more heteroatomic 5-7 units that contains.According to some aspects, A is the phenyl of phenyl or replacement.According to some aspects, R ⁵And R ⁶Independent separately is C _1-4Alkyl.Perhaps, according to some aspects, R ⁵And R ⁶With the N-atom that they connect, form 3-7 unit ring, this ring is the saturated heterocycle of 5-7 unit.According to some aspects, R ⁷Be alkyl-carbonyl or aryl carbonyl unsubstituted or that replace.

[0138] according to another embodiment, formula (I) chemical compound also comprises those following chemical compounds, wherein Z is that oxygen and X are-OR, wherein Q is unsubstituted or the alkyl of replacement or aralkyl unsubstituted or that replace, A is unsubstituted or the alkoxyl or aralkyl and the R unsubstituted or that replace that replace are formula (b) group, wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl and cycloalkyl separately, or R ⁵And R ⁶With the N-atom that they connect, form the saturated heterocycle of 3-7 unit, Y ⁶Be H or-OR ⁷, R wherein ⁷Be H or acyl group, k be 1,2 or 3 and m be 1,2 or 3.

[0139] aspect some of this embodiment, R ⁵And R ⁶Independent separately is C _1-4Alkyl.In others, R ⁵And R ⁶When N atom one time-out that is connected with them formed 3-7 unit ring, this ring was a 5-7 unit heterocycle.In some aspects, R ⁷Be alkyl-carbonyl or aryl carbonyl unsubstituted or that replace.

[0140] according to another embodiment, formula (I) chemical compound also comprises those following chemical compounds, and wherein A is selected from unsubstituted or the aryl that replaces, contains the N heteroaryl and contain the S heteroaryl, and Z is a chemical bond, and X is-OQ that wherein Q is C _1-4Alkyl and R are formula (b) group, wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl and cycloalkyl separately, or R ⁵And R ⁶When combining, the N atom that is connected with them forms 3-7 unit heterocycle, Y ⁶Be H, k be 1,2 or 3 and m be 1,2 or 3.

[0141] aspect some of this embodiment, A is a phenyl.In others, A is a pyridine radicals.Aspect some of this embodiment, R ⁵And R ⁶Independent separately is C _1-4Alkyl.In others, R ⁵And R ⁶The N atom that is connected with them is combined together to form 5-7 unit heterocycle.

[0142] according to this embodiment, can be halogenated formula (I) chemical compound and corresponding alcoholates by making accordingly wherein X, preferably the corresponding alcoholates reaction in ethanol preferably by refluxing, prepares these chemical compounds.Available methods known in the art reaction mixture, and can pass through chromatography or salification process separated product.

[0143] according to another embodiment, formula (II) chemical compound comprises those following chemical compounds, and wherein X is an oxygen, and A is selected from C _1-20Straight or branched alkyl, the unsubstituted or aryl that replaces, unsubstituted or the aralkyl, the naphthyl that replace and contain the N heteroaryl, Z is a chemical bond, R ' is selected from H, C _1-4Alkyl and aralkyl, Z are formula (b) group, wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl and cycloalkyl separately, or R ⁵And R ⁶The N atom that connects with them forms 3-7 unit heterocycle, Y ⁶Be H or-OR ⁷, R ⁷Be H, k be 1,2 or 3 and m be 1,2 or 3, condition is, when A is not alkyl and R ¹When being H, Y ⁶Be H.

[0144] aspect some of this embodiment, A is phenyl or halogenophenyl.In others, A is a pyridine radicals.Aspect some of this embodiment, R ' is a phenylalkyl.Aspect some of this embodiment, R ⁵And R ⁶Independent separately is C _1-4Alkyl.In others, R ⁵And R ⁶The N atom that connects with them forms 5-7 unit heterocycle.

[0145] according to another embodiment, formula (II) chemical compound also comprises those following chemical compounds, and wherein Z is selected from covalent bond, oxygen and N (R ³) group, wherein R ³Be hydrogen or alkyl unsubstituted or that replace, X is=NR ⁴, R wherein ⁴Be selected from hydrogen, the unsubstituted or alkyl that replaces, unsubstituted or the aryl and replacement or the unsubstituted aralkyl that replace.According to this embodiment, A is selected from the unsubstituted or alkyl that replaces, the unsubstituted or aryl that replaces, unsubstituted or the aralkyl and the cycloalkyl that replace, R ' is selected from the unsubstituted or alkyl that replaces, the unsubstituted or aryl that replaces, with aralkyl, R unsubstituted or that replace be formula (b) group, wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl separately, or R ⁵And R ⁶The N atom that connects with them forms 3-7 unit heterocycle, Y ⁶Be H or-OR ⁷, R ⁷Be H or acyl group, k be 1,2 or 3 and m be 1,2 or 3.

[0146] aspect some of this embodiment, R ⁴Be phenyl or phenylalkyl.Aspect some of this embodiment, A is selected from the phenyl of phenyl, replacement, and phenylalkyl.Aspect some of this embodiment, R ' is phenyl or phenylalkyl, aspect some of this embodiment, and R ⁵And R ⁶Independently be selected from C separately _1-4Alkyl.In others, R ⁵And R ⁶The N atom that connects with them forms 5-7 unit heterocycle.Aspect some of this embodiment, R ⁷Be alkyl-carbonyl or aryl carbonyl unsubstituted or that replace.

[0147] according to another embodiment, formula (II) chemical compound also comprises those following chemical compounds, and wherein X is an oxygen, A is unsubstituted or the alkyl that replaces, the unsubstituted or aralkyl that replaces, and Z is an oxygen, and R ' is alkyl or aralkyl, preferred phenylalkyl, R is formula (b) group, wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl and cycloalkyl separately, or R ⁵And R ⁶When the N atom that is connected with them combines, form 3-7 unit, Y ⁶Be H or-OR ⁷, R ⁷Be H or acyl group, k be 1,2 or 3 and m be 1,2 or 3.In some aspects, R ⁵And R ⁶Independent separately is C _1-4Alkyl.In others, R ⁵And R ⁶The N atom that connects with them forms 5-7 unit heterocycle.In some aspects, R ⁷Be alkyl-carbonyl or aryl carbonyl unsubstituted or that replace.

[0148] aspect some of this embodiment, A is a phenylalkyl.In some aspects, R ' is a phenylalkyl.

[0149] according to another embodiment, formula (II) chemical compound also comprise those wherein X be that oxygen and Z are=chemical compound of NH.

[0150] according to an embodiment, formula (II) chemical compound comprises those following chemical compounds, and wherein A is selected from alkyl, cycloalkyl and aralkyl unsubstituted or that replace unsubstituted or that replace, and R is one group of formula (b) group, wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl and cycloalkyl separately, or R ⁵And R ⁶The N atom that connects with them forms 3-7 unit heterocycle, Y ⁶Be H or-OH, k be 1,2 or 3 and m be 1,2 or 3.

[0151] aspect some of this embodiment, A is phenylalkyl, unsubstituted phenyl or the phenyl that replaced by halo, alkyl, haloalkyl, alkoxyl or nitro.In others, R ⁵And R ⁶, independent separately is C _1-4Alkyl.In others, R ⁵And R ⁶The N atom that connects with them forms 5-7 unit heterocycle.

[0152] according to an embodiment, formula (II) chemical compound comprises that wherein A is those chemical compounds of formula (a) group:

Y wherein ¹Be haloalkyl, n is 1,2 or 3, and R ' is that H and R are formula (b) group, wherein R ⁵And R ⁶Independently be selected from H, straight or branched alkyl and cycloalkyl separately, or R ⁵And R ⁶The N atom that connects with them forms 3-7 unit heterocycle, Y ⁶Be H or-OH, k be 1,2 or 3 and m be 1,2 or 3.

[0153] aspect some of this embodiment, Y ¹It is trifluoromethyl.In others, R ⁵And R ⁶Independent separately is C _1-4Alkyl.In others, R ⁵And R ⁶The N atom that connects with them forms 3-7 unit heterocycle.

[0154] according to an embodiment, formula (II) chemical compound also comprise formula (cyclic compound of I "), wherein A be selected from unsubstituted phenyl, the phenyl that replaced by halo or nitro and contain N heteroaryl, R ¹Be H and R " be single on amino-or dibasic omega-amino--alkyl; have the alkyl chain of 1-5 carbon atom; and amino substituent group; it is separate; can be one or two straight or branched alkyl or cycloalkyl; or two amino-substituent groups form 3-7 unit ring, the first saturated heterocycle of preferred 5-7, or C with the N atom of their adjacency _1-4The derivant of alkyl N-seasonization, condition are that when A was 3-pyridine radicals (piridyl), R " was different from the l-piperidino methyl.

[0155] above any chemical compound can singly be used or coupling, and optional and one or more other therapeutic agents are united, and are used for wherein involving disease, disorder or the treatment of conditions of molecular chaperoning.Such disease includes, but are not limited to neurodegenerative diseases, gets rid of diabetic peripheral nervous pathological changes.In some embodiments, nerve retrograde affection is in central nervous system (CNS).In some embodiments, described disease is selected from apoplexy, neurodegenerative diseases and cystic fibrosis.In some embodiments, described disease is an apoplexy.

[0156] in certain embodiments, this method comprises patient's hydroxylamine derivative of suffering from apoplexy after the apoplexy immediately.In other embodiment, this method comprises at least 0.25,0.5,1,2,6,24,48 or 72 hour or longer time after the apoplexy, gives first dose of hydroxylamine derivative.In other embodiment, perhaps while or priority give the patient more than one hydroxylamine derivative sequential the associating.In preferred embodiments, this method comprises and gives Ah not 's chloropharin and Ai Shanading.

[0157] in other embodiment, this method comprises the one or more hydroxylamine derivatives of patient and the one or more other therapeutic agent that gives to suffer from apoplexy.In another embodiment, other therapeutic agent is selected from antiinflammatory, oxygen free radical scavenger, antipyretic, antithrombotic agents (anti-platelet agents and anticoagulant), thrombolytic agent, neuroprotective and EGFR inhibitor.

[0158] anti-inflammatory agent and/or antipyretic can be: NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), such aminoaryl carboxylic acid derivates is such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid (mefanamic acid), niflumic acid, talniflumate, terofenamate and tolfenamic acid; The Arylacetic acids derivant is such as acemetacin, alclofenac, amfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac, Isoxepac, lonazolac, metiazinic acid, oxametacin, proglumetacin, sulindac, tiaramide, tolmetin and zomepirac; Arylbutyric acid derivatives is such as bumadizon, butibufen (butibufen), fenbufen and xenbucin (xenbucin); The aryl carboxylic acid class is such as clidanac, ketorolac and tinoridine; Aryl propionic acid derivatives is such as alminoprofen, benoxaprofen, bucloxic acid; Carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, miroprofen, naproxen, Evil promazine, piketoprofen, pirprofen, pranoprofen, protizinic acid, suprofen and tiaprofenic acid; Pyrazoles is such as diphenylimidazol (difenamizole) and epirizole; The pyrazoline ketone is such as azapropazone, benzpiperilone (benzpiperylon), feprazone, mofebutazone, morazone, oxyphenbutazone, Phenylbutazone, pipebuzone, isopropylantipyrine, ramifenazone, suxibuzone and thiazolinobutazone (thiazolinobutazone); Salicyclic acid derivatives is such as acetaminosalol, aspirin, benorylate, 5-bromosaligenin, tylcalsin, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, aspisol (lysineacetylsalicylate), mesalazine, Morpholine Salicylate, salicylic acid l-naphthyl ester, olsalazine, parsalmide, acetylphenyl salicylate, phenyl salicytate, salacetamide, salicylamine o-acetic acid, salicylsulfuric acid, salsalate (salsalate) and sulfasalazine; The thiazine benzamide type is such as drogelor, isoxicam, piroxicam and tenoxicam; Other, such as

-acetamidohexanoic acid, s-S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine (amixetrine), bendazac, benzydamine, bucolome, difenpiramide, ditazole (ditazol), emorfazone, guaiene (guaiazulene), nabumetone, nimesulide (nimesulide), orgotein, oxaceprol, paranyline (paranyline), perisoxal, pifoxime, proquazone, proxazole and tenidap; With its pharmaceutically acceptable salt; Steroidal anti-inflammatory drugs is such as adrenal gland's glucocorticoid; With other analog, such as acetaminophen and opiates.

[0159] steroidal class anti-inflammatory therapeutics class (glucocorticoids) comprises, but be not limited to 21-prebediolone acetate (acetoxyprefnenolone), alclometasone, algestone, amicinonide, beclometasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, Fluazacort, flucloronide (flucloronide), flumehtasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, FLUTICASONE PROPIONATE, formocortal, halcinonide, halobetasol propionate, halometasone, the halopredone acetas, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, momestasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethyl amino yl acetate, the prednisone sodium phosphate, prednisone, W-4869, prednylidene, rimexolone, tixocortol (tixocortal), triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and pharmaceutically acceptable salt.

[0160] oxygen free radical scavenger can be: N-(2-mercapto radical propionyl group) glycine (MPG), Edaravone (edaravone), 2-(4-carboxyl phenyl)-4; 4; 5,5-tetramethyl imidazoline-1-oxygen base-3-oxide (carboxyl-PTIO), superoxide dismutase or its analogies or CAPE (CAPE).

[0161] antiplatelet drug can be: aspirin, clopidogrel or ticlopidine; It can be the medicine of another combination, such as aspirin and delayed release dipyridamole formulations (Aggrenox);

[0162] anticoagulant can be: warfarin, heparin, reach heparin (Fragmin), Enoxaparin (Lovenox) or booth is pricked heparin (Innohep).

[0163] thrombolytic agent example is that tissue plasminogen activator (t-PA) or sulphur reach heparin (Arixtra).

[0164] other appropriate drug of the sequela after the treatment apoplexy comprises that the acetic acid lattice draw for thunder (glatiramer acetate), interferon beta 1A, interferon beta 1B, estradiol, progesterone and composition thereof.

[0165] Shi Yi neuroprotective includes, but are not limited to donepezil (donepezil), memantine (memanine), nimodipine, riluzole (riluzole), sharp this bright, tacrine, TAK147, xaliproden (xaliproden and composition thereof.

[0166] Shi Yi EGFR inhibitor comprises, but be not limited to gefitinib, Erlotinib, Lapatinib, card knob for Buddhist nun, Sorafenib (sorafenib), ZD6474, Cetuximab, handkerchief wood monoclonal antibody, Qu Sizhu monoclonal antibody, its pharmaceutical salts and its mixture.

[0167] can offer patient's hydroxylamine derivative by any suitable mode, preferably directly (as, part, as by being injected to the nervous tissue site) or the whole body administration of described mode (as, through parenteral or oral).When the chemical compound parenteral is provided, such as by in vein, subcutaneous, intramuscular, the eye socket, in the ophthalmic, ventricle, in the intracranial, capsule, in the spinal column, in the cartilage, intraperitoneal, mouthful cheek, rectum, vagina, intranasal or pass through aerosol drug delivery.According to embodiment preferred, orally give Pharmaceutical composition of the present invention.

[0168] can with the amount of this chemical compound of the single dosage form of carrier mass combination results and other therapeutic agent, will be according to object to be treated and concrete mode of administration different and different.Preferably, prepare compositions of the present invention, so that the dosage that can give is the 0.1-1g/kg body weight/day, preferred 0.1-300mg/kg body weight.The dosage of chemical compound can be depending on patient's the disease and dosage every day of disease and needs.In human therapy, oral every day, dosage was preferably 10-300mg.In some case, in oral medication, these dosage give with unit dosage forms especially, it can be divided into 2-3 littler dosage every day.

[0169] in compositions of the present invention, this chemical compound can play mutual synergic effect in combination, and further plays synergic effect in the presence of other therapeutic agent.Therefore, the amount of this chemical compound in such compositions and other therapeutic agent can be less than needed amount in the monotherapy that uses this therapeutic agent separately.In such compositions, can give the other therapeutic agent of 0.1-1g/kg body weight/day.

[0170] it should be understood that, given dose and therapeutic scheme for any concrete patient can be depending on a plurality of factors, comprise employed specific compound activity, age, body weight, general health, sex, diet, administration number of times, discharge rate, drug combination situation and attending doctor judgement and by the order of severity of the disease specific of being treated.It is that the dosage of chemical compound can be depending in compositions for which kind of concrete chemical compound.Perhaps, effective dose can based on, in other factors, the biological activity of the size of chemical compound, the biodegradability of chemical compound, chemical compound and the bioavailability of chemical compound.If this chemical compound is not degraded fast, be biological available and high activity, then need littler amount to reach effectiveness.Be suitable for the dosage of patient's reality, can be used as conventional practice, be easy to by the those skilled in the art that provide general starting point, for example, doctor or veterinary determine.

[0171] can with chemical compound with per hour, every day, weekly, every month, annual (as, with delayed version) transmit or as disposable transmission.This transmission can be transmitted in a period of time continuously, as the vein transmission.In an embodiment of method described herein, give therapeutic composition at least once a day.In one embodiment, give therapeutic composition every day.In one embodiment, every other day give therapeutic composition.In one embodiment, every 6-8 days or more particularly give therapeutic composition weekly.

[0172] in one embodiment, give therapeutic compound described herein or compositions with the form that continues to discharge.Such method comprises implants capsule or the implantable medical treatment device that continues release, to such an extent as to the hydroxylamine derivative of effective therapeutic dose is passed to the patient of this method continuously.Can be via the capsule transmission hydroxylamine derivative that allows in a period of time, to continue to discharge medicine or peptide.Controlled release or slow releasing composition comprise be encapsulated in the lipotropy bank (as, fatty acid, wax, oil) in preparation.Also by the present invention be understood that with polymer (as, poloxamer or poloxamines) the micronized compositions of encapsulation.

[0173] another aspect of the present invention provides the Pharmaceutical composition that comprises the hydroxylamine derivative that is used for the treatment of apoplexy.Such compositions comprises hydroxylamine derivative and suitable pharmaceutical carrier.

[0174] with the route of administration of preparation of raw material to be suitable for wanting.Preparation can comprise the excipient that comprises the familiar pharmaceutically acceptable buffer agent in this area, stabilizing agent, local anesthetic etc.For parenteral, can be sterile solution agent or suspensoid as the preparation of illustration; For oral administration, syrup, tablet, capsule, capsule lozenge (gelcap) or good to eat solution are arranged; For passing through inhalation, microcrystalline powder or solution are suitable for atomizing; For intravaginal or drop rectum with drug, with vaginal suppository (pessaries), suppository, ointment or foam.Preferred preparation is the preparation that is suitable for oral administration.

[0175] the suitable pharmaceutically acceptable carrier that can be used for these Pharmaceutical compositions comprises, but be not limited to ion-exchanger, aluminium oxide, aluminium stearate, magnesium stearate, lecithin, serum albumin, such as the human serum albumin, buffer substance, such as phosphate, glycine, sorbic acid, potassium sorbate, the mixture of the partial glyceride of saturated vegetablefats acid, water, salt or electrolyte are such as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, Polyethylene Glycol, sodium carboxy methyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block copolymer, Polyethylene Glycol and lanoline.In some embodiments, pharmaceutically acceptable carrier is a magnesium stearate.Usually acceptable and employed other pharmaceutical excipient exists, for example, Lei Shi pharmacy complete works (Remington ' s Pharmaceutical Sciences) (Gennaro, A. writes), Mack publishing house finds in 1990 (being incorporated into this paper by reference).

[0176] as describing in detail in following examples, the chemical compound that will be used for this method gives the cerebral infarction animal model.The result shows that Ai Shanading and especially Ah not 's chloropharin quicken the rehabilitation of cerebral infarction, does not influence the infraction size.This phenomenon was met before using other chemical compound, but just known to the author, did not certainly meet this phenomenon with oral available medicine.Ah not 's chloropharin also has this effect or is better than best positive control, and it is injected directly into brain with bFGF.

[0177] following examples are intended for illustrative.Embodiment is nonrestrictive, and skilled technician will recognize that the disclosure is conceived other embodiment.

Embodiment

Embodiment 1. intraluminal middle cerebral artery occlusion in rats obturations (Middle Cerebral Artery Occlusion (MCAO)) the functional rehabilitation in back

[0178] purpose of this research is, estimates Ah not 's chloropharin and Ai Shana and fixes on usefulness in the neural rehabilitation in the model that strengthens permanent intraluminal middle cerebral artery occlusion in rats obturation (MCAO).Permanent MCAO is fully received and is considered to study the standard animal model of apoplexy clinicing aspect.(Stroke.1999；30：2752-2758.)

[0179] with 40 male Sprague Dawley rat, every heavy 300-400g, before operation, for the adaptability purpose, raise in cages and handle 7 days to be used for behavior rating, according to the Tamura model of revision, these rats are implemented operation under anesthesia, by making near-end right middle cerebral artery (MCA) permanent occlusion to cause local cerebrum block.In brief, be used in N ₂O: O ₂2-3% halothane anesthesia rat in (2: 1) mixture also is used in N ₂O: O ₂1-1.5% halothane in (2: 1) mixture is kept anesthesia.With temporalis in two and turn back by by the otch of being made on the way between the E ﹠ E film auditory meatus.Not removing zygomatic arch and not crosscut face nerve by craniectomy under the temporo exposes near-end MCA.Then, arterial occlusion and crosscut is disconnected by the urgent contiguous tractus olfactorius of little bipolarity concretion to inferior cerebral vein.In whole surgery, make body temperature maintain 37.5 ℃ ± 0.5 ℃.Before MCAO and and then i.p. gives cefazolin sodium (40mg/kg behind the MCAO; Baxter, Lot 06014.1, Exp.Jan 2009) one day with prevention infection.

[0180] rat is divided into 4 groups at random, every group of 10 animals.One group of p.o. gives Ah not chloropharin, beginning in inaccessible back 1 hour, and with the 200mg/kg/d administration, totally 3 days once a day, then with the 50mg/kg/d administration, totally 29 days once a day.Second group is adopted and the same relieve pain Ai Shanading of Ah not 's chloropharin.The 3rd group is positive controls, and inaccessible posterior vein gives β-fibroblast growth factor (bFGF) a hour and a day (i.e. twice administration) of 1 μ g (with 20 μ g/ml, also containing the bSA of 100 μ g/ml).The 4th group of negative matched group only gives solvent.

[0181] place test and body swing test by forelimb and hind leg, before operation (day-1), operation back (7,14,21 and 28 days) evaluation in per 7 days animal then, described test as well accepted apoplexy model after the functional rehabilitation code test of indicating.

[0182] place test for forelimb, the experimenter keeps rat to be close on the table, and the ability that forelimb is placed on desktop is scored in rat reply beard, vision, sense of touch or proprioceptive stimulation.Similarly, place test for hind leg, the experimenter assesses rat reply sense of touch and proprioceptive stimulation and hind leg is placed on the ability of desktop.Acquisition is for the little branch that separates (least bit (halfpoint) indication probability) of the sensation of every kind of pattern input, and they are added up obtains total points (place test for forelimb: 0=is normal, and 12=is maximum to be weakened; Place test for hind leg: 0=is normal, and 6=is maximum to be weakened).

[0183] for the body swing test, rat is being controlled from the about 1 inch place of its tail root.It is increased to from 1 inch of desktop then.Rat is controlled with vertical axis, about all be no more than 10 °.The record rat head moves away the swing on any one side of vertical axis.The upright position must be got back to and the swing next time of rat could be counted.Count 30 (30) inferior total swings.Typically, normal rat equates to the number of times of both sides swing.After the ischemia, rat tends to be rocked to offside (left side).

[0184] estimate behavior by the score value scope in bracket that obtains after each test:

Forelimb is placed test (0-12), places (0-2) by the beard sense of touch; Vision is placed (forward, sideways) (0-4); Sense of touch is placed (back, lateral) (0-4); Form with proprioceptive placement (0-2);

Hind leg is placed test (0-6), places (back, lateral) (0-4) by sense of touch; Form with proprioceptive placement (0-2).

[0185] behind MCAO the 28th day, with the rat deep anaesthesia in matched group and the maximal dose group, and (contains heparin 2 units/ml) and pass heart perfusion with normal saline with chloral hydrate.The excision brain also is stored in it in 10% formalin.Then, fixed brain is cut into the crown section of 5 μ m with paraffin embedding and use microtome.Then, with hematoxylin and eosin (H﹠amp; E) with section statining.With digital camera to from each brain, take out 7 sections (+4.7 ,+2.7 ,+0.7 ,-1.3 ,-3.3 ,-5.3 and-7.3, compare with anterior fontanelle respectively) take a picture, by adopting NIH image (Image J), use " round-about way " (area of [right side] hemisphere of the homonymy of the area-health of complete offside [left side] hemisphere) to proofread and correct cerebral edema (Jiang etc., 1996), determine the infarct size of every section.Then, add up to the infarct size in the every section and multiply by slice thickness, obtain total infarct volume, it is expressed as the percent of complete offside hemisphere volume.

[0186] by not knowing which group is that the researcher of Ah not 's chloropharin, Ai Shanading and negative control group is implemented this experiment.Because the dosage regimen difference, the bFGF group may not be ignorant.All data are represented with meansigma methods ± S.E.M.By repeated measure ANOVA (handling X time) analysis behavior and weight data.For the positive F-value of the whole ANOVAs that comprise all groups, make that ANOVAs becomes possibility between paired group.Analyze the infarct volume data by single factor ANOVA.In figure below: *=different, p＜0.05 with solvent-processed group; *=different with solvent-processed group, p＜0.01; * *=different with solvent-processed group, p＜0.001.Ah not 's chloropharin the results are shown in Fig. 1,2 and 3.

[0187] Fig. 1 shows the result of forelimb placement test.As expected, the rehabilitation in the positive control bFGF group is higher than solvent group (p＜0.01).Rehabilitation in Ah not 's chloropharin group all is higher than solvent group (p＜0.05) at all time points.Compare with the solvent group, the enhanced rehabilitation trend of Ai Shanading group is not remarkable.Be higher than the scoring of solvent group in the rehabilitation scoring of early time point (promptly the 1st, 3 and 7 day), the rehabilitation that expression Ai Shana fixes on apoplexy has effect in early days probably, but improve slowly and after inaccessible incident longer time point effect lasting.

[0188] Fig. 2 shows the result of hind leg placement test.Rehabilitation in the positive control bFGF group is higher than solvent group (p＜0.001).The result who places test with forelimb is similar, and the rehabilitation in Ah not 's chloropharin group all is higher than solvent group (p＜0.001) at all time points, and the enhancing of expression Ah not chloropharin has seriality from the effect of the rehabilitation of apoplexy.The rehabilitation of Ai Shanading group is higher than solvent group (p＜0.01).The rehabilitation scoring of Ai Shanading group improves continuously, but after inaccessible incident, the speed ratio Ah not chloropharin group of raising or the low several times of positive controls.

[0189] Fig. 3 shows the result of body swing test.Rehabilitation in the bFGF group is higher than solvent group (p＜0.05).Rehabilitation in Ah not 's chloropharin group is higher than solvent group (p＜0.01).Compare with the solvent group, the enhanced rehabilitation trend in Ah not 's chloropharin group is not remarkable.

[0190] Fig. 4 shows that the body weight between each group does not have significant difference, and Fig. 5 shows that the infraction size does not change.

[0191] body weight of experimental animal does not have significance to change, and the infarct volume of experimental animal brain does not have significance to change.See Table I:

Table I: infarct volume (%)

Ah not 's chloropharin 21.6 ± 3.6

Ai Shanading 21.8 ± 2.1

Solvent 21.0 ± 3.5

bFGF 23.1±1.7

[0192] conclusion, the visible significant difference of neural rehabilitation in four groups.In all behavior tests (forelimb is placed test, hind leg is placed test and body swing test), Ah not 's chloropharin group and bFGF group show that the rehabilitation significance than solvent strengthens.

Ai Shanading treatment group is placed at hind leg and is shown significance rehabilitation potentiation in the test, and places in test and the body swing test at forelimb and to tend to the rehabilitation enhancing.There is not significant difference in body weight between group or the infarct volume.These results show, Ah not 's chloropharin-and the animal of Ai Shanading-treatment in the enhancing of sensorimotor rehabilitation.Forelimb and hind leg are placed the functional rehabilitation of test reflection sensorimotor cortex, and the striatal functional rehabilitation of body swing test reflection.In a word, these results represent, Ah not 's chloropharin and Ai Shanading, and the chemical compound of shared common structure member, with with these hydroxylamine derivatives in the structurally relevant and function of arbitrary chemical compound on the chemical compound that is equal to, be useful as the medicine that strengthens the rehabilitation of apoplexy aftersensation sporting functionality.The time-histories of rehabilitation is represented, shows Ah not 's chloropharin of improved rehabilitation scoring and tends at all test period points and can bring into play its effect separately in the different time points after the inaccessible incident at the Ai Shanading that strengthens rehabilitation than test period point early.Therefore, likely is to use the conjoint therapy of these two chemical compounds can have addition or synergism, Ai Shana fixes on the time point early after the obturation, helped rehabilitation in 7 days as many as, and Ah not 's chloropharin provides behind 7 days after the obturation and improves continuously, until 28 days or slower.

Embodiment 2. gives functional rehabilitation--the dose study after the MCA obturation of Ah not 's chloropharin in rat.

[0193] 50 male Sprague Dawley rat, every heavy 300-400g as implementing operation described in this paper embodiment 1 under anesthesia, causing the MCA obturation, and is divided into 5 groups with rat, every group of 10 animals.Every group of p.o. gives Ah not chloropharin, and obturation begins one day after, with 25mg/kg/d, 50mg/kg/d, 100mg/kg/d or 200mg/kg/d administration, and totally 35 days once a day.One group is matched group, only gives solvent.

[0194] place test and body swing test by forelimb and hind leg, before operation (day-1), per 7 days (7,14,21 and 28 days) evaluation animal after the operation then is as the scoring that provides described at this paper embodiment 1.

[0195] rat in matched group and the maximum dose level group is put to death, as estimate their brain among the embodiment 1 in the 35th day behind MCAO.Put to death the rat in other group and excise their brain, quick freezing is to be used for further analysis.

[0196] forelimb that shows in Figure 10,11 and 12 is placed, hind leg is placed and the body swing result of the test is illustrated, start from 50,100 and significance dosage correlation with behavior scoring of Ah not 's chloropharin of 200mg/kg/ days dosage improve.Show between solvent matched group and the 25mg/kg/ days dosage groups and do not have significant difference.The result of these three tests independently confirms the result in

embodiment

1 and 3, shows Ah not 's chloropharin in the stroke rehabilitation model, is effectively under the dosage of 50-200mg/kg/ days scopes, and under study for action 200mg/kg/ days be ceiling effect dosage.In addition, do not observe the variation of body weight or infarct volume.This is similar with the result in 4 to embodiment 1.

Embodiment 3. gives functional rehabilitation--dose study after the MCA obturation of Ai Shanading in rat.

[0197] also adopts Ai Shana tailor-made, different be to use higher dosage 50mg/kg/d, 100mg/kg/d, 200mg/kg/d or 400mg/kg/d, once a day, counted 35 days for therapeutic agent carries out the experiment of embodiment 2.The result of embodiment 1 shows, in the animal of the Ai Shanading that gives given dosage, do not have-the significance trend of improved rehabilitation.The clearer and more definite indication of this embodiment expectation, Ai Shanading effectively strengthens the rehabilitation after the apoplexy.

Embodiment 4. gives functional rehabilitation--treatment window after the MCA obturation of Ah not 's chloropharin in rat

[0198] to 50 male Sprague Dawlcy rats, every heavy 300-400g as implementing operation described in this paper embodiment 1 under anesthesia, causing the MCA obturation, and is divided into 5 groups with rat, every group of 10 animals.Every group of p.o. gives Ah not chloropharin, 6 beginnings after obturation, and 12,24 and 48 hours, with the 200mg/kg/d administration, totally 35 days once a day.One group is matched group, only gives solvent in the time of 6 hours.As the evaluation animal described at embodiment 2.

[0199] Fig. 6 shows that the forelimb give behind the rat Ah not chloropharin places result of the test.Consistent with the result of experiment of describing in embodiment 1, the rehabilitation in all groups discloses, and a plurality of time points of Ah not 's chloropharin after obturation are higher than the solvent group.The rehabilitation time-histories result of every treatment group is higher than solvent group (ANOVA, p＜0.06).Rehabilitation be the tool significance and continue, even to give Ah not 's chloropharin also be like this 48 hours first time after inaccessible; Yet in these experiments, under these conditions, the group rehabilitation outcome that gave Ah not 's chloropharin after the apoplexy in 6 hours is than higher.This results suggest, the treatment mechanism of Ah not 's chloropharin can and all work at the early stage of stroke rehabilitation process late period.

[0200] Fig. 7 shows that the hind leg give behind Ah not 's chloropharin places the result of test.The result who places test to forelimb is similar, and the time-histories of the rehabilitation in each Ah not 's chloropharin-treatment group is longer than solvent group (ANOVA, p＜0.001), shows that Ah not 's chloropharin strengthens the continuous effect of the rehabilitation after the apoplexy.Whether no difference of science of statistics between the treatment group is inaccessible back 6,12,24 or 48 hours no matter give for the first time Ah not 's chloropharin, and it is efficient to show that Ah not 's chloropharin has in promoting rehabilitation, even after administration occurs in obturation over a long time, grow to 48 hours at least.

[0201] Fig. 8 shows the result give the body swing test behind Ah not 's chloropharin.Rehabilitation in all Ah not 's chloropharin groups is higher than solvent group (ANOVA, p＜0.03) in the rehabilitation time-histories.The as many as of the rehabilitation of the inaccessible back group of accepting Ah not 's chloropharin in 48 hours and those inaccessible back batch total time points of accepting Ah not 's chloropharin in 6 hours and comprise that the back 21 days rehabilitation of obturation is as broad as long.In these experiments, under these conditions, after the inaccessible back group of accepting Ah not 's chloropharin in 6 hours shows the performance to 21 that improves continuously day, and other group reduces gradually.The treatment mechanism of this results suggest Ah not chloropharin can and work at the early stage of stroke rehabilitation process late period, and the early effect of Ah not 's chloropharin can have positive-effect continuously, even in rehabilitation course late period.

[0202] Fig. 9 is presented at the body weight there was no significant difference between different groups.

Embodiment 5. gives functional rehabilitation--time-histories after the MCA obturation of Ai Shanading in rat.

[0203] adopts also that Ai Shana is tailor-made to carry out the experiment of embodiment 4 for therapeutic agent.Outcome expectancy shows that Ai Shana fixes on the effect of the time that is later than current available therapeutic agent.

Embodiment 6. unites functional rehabilitation after the MCA obturation that gives Ah not 's chloropharin and Ai Shanading in rat

[0204] gives Ai Shanading and A Mo chloropharin and carry out the experiment in embodiment 2-5, described.Outcome expectancy shows does not have conflict between the chemical compound, and two therapeutic compounds have addition and possible synergism at least.

Embodiment 7. gives the neuroprotective because of the damage of transience global brain ischemia of gerbil jird chemical compound 2.

[0205] before operation, gives the chemical compound 2 of 50mg/kg to the bull mongolian gerbil intraperitoneal of heavy 60-80g, to bring out the transience global brain ischemia.Be used in 70%N ₂O and 30%O ₂Admixture of gas in 2% halothane anesthesia under gerbil jird is implemented operation, under 1% halothane maintenance condition, surgical exposure and clamp carotid artery 5 minutes are in case hemostasis flows to brain subsequently.After 5 minutes, remove clamp and perfusion again takes place.As at Gupta and Sharma, describe among Biol.Pharm.Bull.29 (5) 957-961 (2006), estimate the mobility of gerbil jird in Y-type maze test and spontaneous change, and gerbil jird beheaded to carry out Histological evaluation in back 4 days pouring into again, be used for the neuronal survival in Hippocampus CA-1 zone.

[0206] in two experiments, chemical compound 2 shows neuroprotective, compares with the matched group of only giving carrier, allows the gerbil jird in the test group to show improved result.

The protective effect of the chemical compound 2 of embodiment 8. in standing experimental heart ischemia/dabbling again rat.

[0207] when before standard heart ischemia/re-perfusion model well known by persons skilled in the art, giving chemical compound 2, the ventricular arrhythmia persistent period that rat experience significance reduces and whole survival rates of increase.

The protective effect of the chemical compound 2 in the mice under the embodiment 9. cytotoxicity histanoxias.

[0208] mice that gives chemical compound 2 stress have the life span that significance increases under (cytotoxicity histanoxia) condition inductive by hydrogen cyanide poisoning.Cytotoxicity histanoxia is induced by standard scheme.Chemical compound 2 be not have significantly toxic, the LD in mice ₅₀Be about 1000mg/kg.Respectively, test compounds 2 and find that it is not the material of inducing mutant organism in the contrary mutation analysis of standard antibacterial.

Embodiment 10. saves the rat cortical neuron after oxygen/glucose deprivation

[0209] 10.1 cell culture

Mix the cortex culture from E18Wistar rat embryo (national animal center, Kuopio, Finland) preparation.Cut cortex and tissue is cut into pieces.By hatching 15 minutes isolated cells with deoxyribonuclease (DNase) and papain.By centrifugal (1500rpm, 5min) collecting cell.With pipette tissue abrasion and with cell (300,000 cells/cm ²) place the MEM (2g/L glucose) the 48-orifice plate, that replenished 2rmM glutamine, 0.1 μ g/mL gentamycin, 10% heat-inactivated hyclone (FSB-HI) and 10% heat-inactivated horse serum (HS-HI) of poly-L-Lysine coating.After 3-4 hour, it is that MEM (2g/L glucose) also replenishes 2mM glutamine, 0.1 μ g/mL gentamycin, 5%HS-HI that culture medium is changed.After external 3 days, cell transfer glutamine, gentamycin and 5% have been replenished separately in the culture medium of the MEM (2g/L glucose) of FSB-HI and HS-HI serum to containing.At external the 6th day, suppressed undesired cell division in 24 hours by adding cytosine arabinoside (10 μ M final concentration).Before implementing further experiment, culture is shifted among the MEM (2g/L glucose) that has filled glutamine, gentamycin and 5%HS-HI that nourishes.

[0210] 10.2 oxygen glucose deprivation (OGD)

Selected to contain hole at external the 10th day and be used for experiment with healthy cell that shows.Ah not 's chloropharin is diluted in the balanced salt solution.As the contrast of total neuronal death, 300 μ M NMDA are used for 24 hours, from culture, remove oxygen and glucose 5 hours to induce about 30-60% cell death.The hole of only handling with culture medium and hatching under normoxic condition is as zero contrast.Behind the beginning OGD one hour, add Ah not 's chloropharin to the hole with 0.1,0.2,0.5,1,2,5,10,20 and 50 μ M concentration.Wash cell again, and after 4 hours, remove culture medium, the normal culture medium that will contain chemical compound with pipette moves in the hole, and places normoxic incubator to cultivate 20 hours plate again.

The assessment of [0211] 10.3 cell death that discharges by LDH

After 24 hours, (13,000rpm 3min.) removes the cell debris that may exist by centrifugal.Move in the titer plate with the culture medium of pipette, and move in the hole with the LDH reagent of pipette with equivalent with two parts of 100mL equivalent.Adopt 3min. kinetic measurement scheme, (Labsystems is detected on the absorptance of 340nm on Finland) immediately to read the plate device at Multiskan ELISA.Measure the variation of absorptance/min, it is directly proportional with relevant LDH (=cell death).

[0212] Figure 14 is presented in the oxygen glucose deprivation (OGD); when starting oxygen and glucose deprivation and give cell after one hour; detected as discharging by LDH, Ah not 's chloropharin of all concentration (except 0.2 μ M) all has the cytoprotection of antagonism OGD.

Pharmacokinetic data in embodiment 11. rats

[0213] pharmacokinetic comprises a matched group and three administration groups (200mg/kg/ days, 400mg/kg/ days and 900mg/kg/ days), administration six months.Matched group and three administration groups (n=96 animal/sex/group) use Ah not 's chloropharin of solvent and debita spissitudo through the oral processing of tube feed six months.From 8 time points of three animals the 0th, 27,89 and 180 day (male) and the 0th, 27,89 and 181 day (female)--taked blood sample after 0 (before the administration), the administration in 0.5,1,2,4,8,12 and 24 hour.Detect the serum-concentration of Ah not 's chloropharin by HPLC.With WinNonlin v5.0.1 pharmacokinetics software evaluation pharmacokinetic parameter (AUC and Cmax).Figure 15 shows behind the oral 200mg/kg/ days dosage 27 days average A UC and cmax value.

The pharmacokinetics clinical research of embodiment 12. philtrums

[0214] in the clinical research of double blinding and placebo, gives 400mg t.i.d. dosage (1200mg/ days) to seven healthy people volunteer orals.Do not observe ECGs, vital sign, clinical chemistry or comprise physical examination clinical unusual of body weight or change.Figure 15 shows that the P of Rats K research level that exposed can reach people volunteer's level safely in 200mg/kg/ days.

[0215] Figure 16 shows, by 3 and 6 hours detection cerebrospinal fluid (CSF) levels behind the Ah not 's chloropharin that increases dosage at orally give, learns Ah not 's chloropharin infiltration people blood-brain barrier.

[0216] any patent, patent application, patent publications or the scientific literature of the application's the reference of institute Anywhere all are incorporated into this paper by quoting in full.

Claims

1. method for the treatment of apoplexy, described method comprises the chemical compound that the patient of needs effective dose is arranged, wherein said chemical compound is the one or more hydroxylamine derivatives by formula (I), (II) or (I ') expression,

Or its salt or its any optical activity stereoisomer, wherein

A is the alkyl, aralkyl of alkyl, replacement, at the heteroaryl of aryl, heteroaryl or the replacement of aryl and/or the aralkyl that in moieties, replaces, aryl, replacement,

Z be covalent bond, oxygen or=NR ³, R wherein ³Be selected from the aryl, aralkyl of alkyl, aryl, the replacement of hydrogen, alkyl, replacement and at aryl and/or the aralkyl that in moieties, replaces,

R is the alkyl of alkyl or replacement,

X in the tautomer of formula (I) be the hydroxyl of halo or replacement or amino, mono-substituted amino or dibasic amino and

X in the tautomer of formula (II) be oxygen, imino group or replacement imino group and

R ' is the acyl group of aralkyl, acyl group or replacement of alkyl, aryl, aryl, the aralkyl of replacement, the aryl with replacement or the moieties of hydrogen, alkyl, replacement,

And formula (I) chemical compound optional contain formula (the intramolecularly ring structure of I "),

Alleviate by this or symptom that prevention is relevant with apoplexy.

2. according to the process of claim 1 wherein that described chemical compound is by formula (I) expression, wherein

R be alkyl or replacement alkyl and

(a) Z is that covalent bond and X are halogens; Or

(b) Z is that covalent bond and X are the hydroxyl-OQ that replaces, and wherein Q is a hydrocarbon; Or

(c) Z is that covalent bond and X are NR ¹R ², wherein

R ¹And R ²Independent is H, straight or branched alkyl, the straight or branched alkyl of replacement, cycloalkyl, or

R ¹And R ²The nitrogen-atoms that connects with their form contain 3-7 member saturated rings.

3. according to the method for claim 2, wherein R takes up an official post at one or more amino or alkyl to choose the omega-amino--alkyl in generation, and contains 3-8 carbon atom and can be replaced by hydroxyl or acyloxy for the alkyl chain of straight or branched.

4. according to the method for claim 2 or 3, wherein R is single on amino-or dibasic omega-amino--alkyl, amino substituent group wherein, independently of one another from one or two straight or branched alkyl or cycloalkyl, or two amino substituent groups, the nitrogen-atoms that connects with their forms and can contain extra heteroatomic 3-7 unit saturated heterocyclic.

5. according to the method for claim 2, wherein

Z be chemical bond and

X be halo and

A is the aryl or the heteroaryl of aralkyl, the aralkyl that replaces in one or more aryl or moieties, aryl, replacement.

6. according to the method for claim 5, wherein A is:

(a) unsubstituted phenylalkyl maybe can have the phenylalkyl of the replacement of one or more alkoxy substituents,

(b) phenyl,

(c) phenyl that is replaced by one or more halos, alkyl, alkoxyl, haloalkyl or nitro,

(d) naphthyl,

(e) can with the condensed N heteroaryl that contains of phenyl ring, or

(f) contain S or contain the O heteroaryl.

7. according to the method for claim 2, wherein

Z be chemical bond and

X is the hydroxyl of formula-OQ of replacing, wherein Q be straight or branched and wherein Q be unsubstituted or the alkyl, unsubstituted aralkyl or the aralkyl that in one or more aryl or moieties, replaces that replace and

A is a heteroaryl.

8. according to the method for claim 2, wherein

Z is a chemical bond,

X is-NR ¹R ², wherein

R ¹And R ²Independent is the straight or branched alkyl of H, unsubstituted straight or branched alkyl, replacement, or cycloalkyl, or

R ¹And R ²With their adjacent N-atoms form the saturated ring of 3-7 unit and

A is aralkyl, the aralkyl that replaces on one or two of aryl or moieties, unsubstituted or the aryl or the heteroaryl that replace.

9. according to the method for claim 8, wherein A is

(a) phenylalkyl,

(b) optional in phenyl moiety have one or more substituent phenylalkyls,

(c) phenyl,

(d) phenyl that is replaced by one or more alkyl, halo, alkoxyl, haloalkyl, nitro or acyl amino,

(e) naphthyl,

(f) can with the condensed N heteroaryl that contains of phenyl ring, or

(g) contain S or contain the heteroaryl of O.

10. foundation the process of claim 1 wherein described chemical compound by formula (I) expression,

Wherein

A) X is a halo, Z be chemical bond and

A1) A is formula (a) group,

Y wherein ¹Be that halo, alkoxyl, haloalkyl or nitro and n are 1,2 or 3, or contain the O heteroaryl, contain the S heteroaryl or can with the condensed N of the containing heteroaryl of phenyl ring, or N-C _1-4Alkyl quaternary derivant or its N-oxide,

R is formula (b) group,

R wherein ⁵And R ⁶Independent is H, straight or branched alkyl, or cycloalkyl, or R ⁵And R ⁶When the N-atom that is adjacent combines, form 3-7 unit saturated heterocyclic,

Y ⁶Be-OR ⁷, R wherein ⁷Be H or alkyl-carbonyl, aryl carbonyl or aminoacyl unsubstituted or that replace, k be 1,2 or 3 and m be 1,2 or 3, or N-C _1-4Alkyl-Jiization derivant or its N-oxide,

Condition is, when A is pyridine radicals or formula (a) group, and Y wherein ¹Be halo or alkoxyl, R ⁷Not H, or

A2) A is formula (c) group,

R is formula (d) group,

And optional substituent group Y ²And Y ³, one of them must exist with molecule, is oxygen or C _1-4Alkyl,

K be 1,2 or 3 and m be 1,2 or 3 and

When chemical compound be single-or during bivalent cation, anion is one or two halogen ion, or

B) A is an aryl unsubstituted or that replace, or contains the N heteroaryl or contain the S heteroaryl,

Z is a chemical bond, and X is OQ, and wherein Q is C _1-4Alkyl and R are the group of formula (b), wherein R ⁵And R ⁶Independent is H, straight or branched alkyl or cycloalkyl, or R ⁵And R ⁶When the N-atom that is adjacent combines, form 3-7 unit saturated heterocyclic,

Y ⁶Be H,

K be 1,2 or 3 and m be 1,2 or 3.

11. according to the method for claim 10, compd A wherein is the group and the Y of formula (a) ¹Be C _1-4Haloalkyl.

12. according to the method for claim 10, chemical compound wherein is the optical activity stereoisomer of hydroxylamine derivative, wherein

X is a halo,

Z be chemical bond and

R is the group of formula (b), wherein R ⁵And R ⁶Independent is H, straight or branched alkyl or cycloalkyl, or R ⁵And R ⁶When the N-atom that is adjacent combines, form 3-7 unit saturated heterocyclic,

Y ⁶Be-OR ⁷, R wherein ⁷Be aminoacyl,

K be 1,2 or 3 and m be 1,2 or 3.

13. foundation the process of claim 1 wherein described chemical compound by formula (I) expression,

Wherein X is NR ¹R ², R wherein ¹And R ²Independent is H or straight or branched alkyl unsubstituted or that replace, or cycloalkyl, or R ¹And R ²When connected N-atom combines, form 3-7 unit heterocycle,

The phenyl that A is unsubstituted phenylalkyl or the phenylalkyl that is replaced by one or more alkoxyls, phenyl, replaced by one or more halos, alkyl or haloalkyl or acyl amino or nitro; perhaps can with phenyl ring condensed unsubstituted or replace contain the N heteroaryl; or contain the S heteroaryl; wherein said hetero atom can have one or more alkyl substituents

Z be chemical bond and

R is the group of formula (e),

R wherein ⁵And R ⁶Independent is H, straight or branched alkyl or cycloalkyl, or

R ⁵And R ⁶When the N-atom that is adjacent combines, form 3-7 unit saturated heterocyclic, it can have extra hetero atom and optional C _1-4Alkyl substituent,

Y ⁴Be H or C unsubstituted or that replace _1-4Alkyl,

Y ⁵Be H or C unsubstituted or that replace _1-4Alkyl or-OR ⁷, R wherein ⁷Be H or acyl group,

K be 1,2 or 3 and m be 1,2 or 3,

Condition is to work as R ⁷When being H, R ¹And R ²In at least one be not H, and work as R ¹And R ²When respectively being H, R ⁷Not H.

14. according to the method for claim 10, wherein in segment (a), A is furyl, thienyl, pyridine radicals, quinolyl or isoquinolyl.

15. according to the method for claim 10, wherein in segment (b), A is phenyl or pyridine radicals.

16. according to the method for claim 13, wherein A is pyrrole radicals, pyridine radicals, isoquinolyl, quinolyl or thienyl.

17. method according to claim 1, wherein said chemical compound is selected from: N-[2-hydroxyl-3-(piperidino) propoxyl group]-3 pyridines-first imido acyl chloride (chloropyridine alcohol), N-[2-hydroxyl-3-(piperidino) propoxyl group]-pyridine-1-oxide-3-first imido acyl chloride (Ah not 's chloropharin), N-[3-(1, the 1-dimethyl ethyl) amino] 2-hydroxyl propoxyl group]-3-trifluoromethylbenzene-first imido acyl chloride and 5,6-dihydro-5 (piperidino)-methyl-3-(3-pyridine radicals)-4H-1,2,4-oxadiazine (Ai Shanading) or its pharmaceutically acceptable salt or its any optical activity stereoisomer.

18. according to the method for claim 17, chemical compound wherein is N-[2-hydroxyl-3-(piperidino) propoxyl group]-pyridine-1-oxide-3-first imido acyl chloride (Ah not 's chloropharin) or its pharmaceutically acceptable salt or its any optical activity stereoisomer.

19. according to the method for claim 17 or 18, chemical compound wherein gave after apoplexy takes place at least 1 hour.

20. according to the method for claim 19, chemical compound wherein gave after apoplexy takes place at least 6 hours.

21. according to the method for claim 20, chemical compound wherein gave after apoplexy takes place at least 24 hours.

22. according to the method for claim 21, chemical compound wherein gave after apoplexy takes place at least 72 hours.

23. according to the method for claim 17, it also comprises and gives other therapeutic agent.

24. according to the method for claim 17, it also comprises and gives second hydroxylamine derivative.

25. according to the method for claim 24, hydroxylamine derivative wherein is Ah not 's chloropharin and second hydroxylamine derivative is Ai Shanading.

26. according to the method for claim 23, wherein other therapeutic agent is selected from antiinflammatory, oxygen free radical scavenger, antipyretic, antithrombotic agents (anti-platelet agents and anticoagulant), thrombolytic agent and neuroprotective.