CN101522181A - Use of hypothermia inducing drugs to treat ischemia - Google Patents

Use of hypothermia inducing drugs to treat ischemia Download PDF

Info

Publication number
CN101522181A
CN101522181A CNA200780037326XA CN200780037326A CN101522181A CN 101522181 A CN101522181 A CN 101522181A CN A200780037326X A CNA200780037326X A CN A200780037326XA CN 200780037326 A CN200780037326 A CN 200780037326A CN 101522181 A CN101522181 A CN 101522181A
Authority
CN
China
Prior art keywords
alkyl
group
thiazolinyl
replace
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA200780037326XA
Other languages
Chinese (zh)
Inventor
尤诺·雅格布·韦伯
雅各布·高特弗瑞德森
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NEUROKEY AS
Original Assignee
NEUROKEY AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NEUROKEY AS filed Critical NEUROKEY AS
Publication of CN101522181A publication Critical patent/CN101522181A/en
Pending legal-status Critical Current

Links

Abstract

The present invention relates to the induction of hypothermia in humans in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising a vanilloid receptor agonists, capsaicinoid or capsaicinoid-like agonist capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by tissue anoxia.

Description

Induce the hypothermia medicine in the ischemic application of treatment
Technical field
The present invention relates to be used to induce the application of hypothermic chemical compound on prevention and treatment ischemia.Ischemia is meant various body parts shortage oxygenate blood flows and can is stopped and suffocating causing by apoplexy, heart beating.
Background technology
Ischemia is meant that various body parts and organ lack the oxygenate blood flow.Cerebral ischemia is that the part of brain or brain can not receive enough blood flows so that keep the ischemia situation of normal neurological function.Cerebral ischemia can be the result that various serious diseases such as apoplexy or heart beating stop, or the result of obstruction of artery such as strangulation.Serious or long cerebral ischemia will cause loss of consciousness, cerebral lesion or death.
After cerebral ischemia or inducing hypothermic neuroprotective during the cerebral ischemia is obvious [1-11] in the experimental animal apoplexy model.In the mankind, two tests that stop to carry out among the patient in heart beating have shown the neurological result [12 who induces hypothermic improvement; 13].The therapeutic hypothermia can not increase complication rate in these two tests, and induces the application of hypothermia in the stupor survivor that heart beating stops to obtain recommendation [14] at present in the world.
Hypothermia is offset the ischemic cerebral lesion by several mechanism:
1. as if ischemia is induced the opening of blood-brain barrier, and this is a kind of to the highstrung process of brain temperature [15].According to tracer and their research through the blood-brain barrier migration, this is significantly, and wherein hypothermia alleviates exosmosing [16] of a few hours after the ischemia and prevents angioedema [17].
2. the perfusion again after the cerebral ischaemia causes the generation of free radical, and this causes the peroxidating and the damage [18] of film fat.Hypothermia prevents to produce between flush phase free radical such as hydroxyl and nitrogen oxide [19 again after cerebral ischaemia; 20; 24].
3. aminoacid such as glutamic acid, aspartic acid and glycine serve as the excitatory toxicity neurotransmitter by near the neuron of the overstimulation ischemia infringement, and this causes further damage.Hypothermia reduces release and even can cause these mediators reuptake [21-23] more rapidly.The release of excitatory toxicity neurotransmitter also can cause the carrying out property neuronal death (progressive neuronal death) [22] in the penumbra region in the paralytic, and the hypothermia after the cerebral ischemia can weaken this process.
4. during ischemia, the cellular metabolism experience in the penumbra changes significantly.Along with the neuron persistent fever, potassium ion pours in ECS, and calcium ionic current is gone in the neuron, causes the degraded of cytoskeleton, and along with energy expenditure continues, ATP lowering of concentration [25].Stream and born of the same parents' inner structure are subsequently destroyed [26] in the hypothermia minimizing calcium, improve potassium ion stable state [27], and help the recovery [28 of the protein kinase activity of metabolic function such as calcium or calmodulin, CaM dependence; 29].
5. by the neutrophil cell after the reduction ischemia and the activation of microgliacyte, hypothermia also has antiinflammatory action [30; 31].
6. programmed cell death and DNA variation is the critical stage [32] in the delayed neuronal death after transient cerebral ischemia.Hypothermia directly suppresses programmed cell death [33] and can increase the endogenous generation [34] of anti-apoptotic protein B cl-2.Hypothermia even can have effect: slightly reduce the brain temperature and cause less dna break [35] and less programmed cell death [36] at dna level.
The conduit that is placed in the bulk container by a lot of mechanical chillers such as surface cooling and utilization cools off, and has attempted inducing by the hypothermia that reduction body center temperature is carried out.Yet these hypothermia mechanical induction things have shown to have the side effect of not expecting in a large number.These side effect comprise tremble, serious infection and lung puncture.The heart fatigue degree that causes the patient of trembling increases, and this will cause heart ischemia and therefore cause M ﹠ M to increase in some cases.
By comprising that the pharmaceutical composition that can induce hypothermic chemical compound regulates body center's temperature and not only will solve and reduce or the problem of the ischemia effect of prevention such as histologic lesion effect, and will be related to safer and more cheap alternative method as present used mechanical means.
Summary of the invention
The present invention relates to comprise that by utilization the pharmaceutical composition that can induce hypothermic chemical compound to induce hypothermia with measurable and dose response mode in human body that to suffer from histanoxia be the patient of the disease of feature thereby be of value to.The inventor has been found that in the mankind this type of hypothermia effect can be by realizing such as Rhizoma et radix valerianae element (vanilloid) receptor stimulating agent, arrival and with the chemical compound of bonded capsaicin of novel vanilloid receptor or Capsaicinoid agonist.
Therefore, the invention discloses and be used for inducing hypothermic chemical compound to be used for the treatment of application in the ischemic medicine of individuality in preparation.
Be similarly providing of aspect of the present invention and comprise the medicine that to induce individual hypothermic chemical compound.
Comprise that the test kit of the component of medicine is another aspect of the present invention as disclosed herein.
In addition, correspondingly to be used for preparing the purposes in order to the inductive medicine of hypothermia of eliminating individuality be an aspect of of the present present invention to chemical compound.
The specific embodiment
Definition
Agonist: the novel vanilloid receptor agonist is the plain chemical compound of Rhizoma et radix valerianae.
Antagonist: vanilloid receptor antagonist is the material that can suppress the effect of novel vanilloid receptor agonist.
Alcohol: a class organic compound that contains one or more hydroxyls (OH).In this context, be meant as substituent group to be positioned at than saturated or unsaturated, side chain on the macromole or non-branched hydrocarbyl.
Alicyclic group: term " alcyl " is meant to have the cyclic hydrocarbon group that is similar to aliphatic group character.
Aliphatic group: in the context of the present invention, term " aliphatic group " is meant saturated or undersaturated straight or branched alkyl.This term is used to comprise for example alkyl, thiazolinyl and alkynyl group.
Alkoxy base: term alkoxy base or alkoxyl are contained the alkyl that is connected with major part by oxygen.
Alkyl group: term " alkyl group " is meant saturated straight chain or branched hydrocarbyl, and it comprises for example methyl, ethyl, isopropyl, the tert-butyl group, heptyl, dodecyl, octadecyl, amyl group, 2-ethylhexyl etc.
Alkenyl group: term " alkenyl group " is meant the unsaturated straight or branched alkyl with one or more carbon-to-carbon double bonds, such as vinyl.
Alkynyl group: term " alkynyl group " is meant the unsaturated straight or branched alkyl with one or more carbon-to-carbon triple bonds.
Amphiphile: contain polarity, water soluble group and material nonpolar, these two kinds of groups of water-insoluble group.
Aromatic group: term " aromatic group " or " aryl " are meant monocycle or polycyclic aromatic group.
Capsaicin: can also separate certainly or be equal in conjunction with capsaicin receptor/novel vanilloid receptor from organism isolated compound such as plant or animal.In the context of the invention, being meant can be in conjunction with any chemical compound of capsaicin receptor/novel vanilloid receptor.Capsaicin also can be called as the novel vanilloid receptor agonist.
Capsaicinoid: can produce or the chemical compound of chemosynthesis in conjunction with capsaicin receptor/novel vanilloid receptor and by standard technique known in the art.In the context of the invention, being meant can be in conjunction with any chemical compound of capsaicin receptor/novel vanilloid receptor.The Capsaicinoid chemical compound also can be called as the novel vanilloid receptor agonist.
Chemical compound: the chemical substance that the fixed proportion of being made up of with decision two or more elements that lump together by chemical bonded refractory forms.Each element is lost its chemical characteristic and this chemical compound separately and is had new characteristic.Following all substances contained in this term in this article: capsaicin, Capsaicinoid and novel vanilloid receptor agonist.
Cyclic group: term " cyclic group " is meant the closed loop alkyl, and it is divided into alcyl, aryl or heterocyclic radical.
Cycloalkenyl group: be meant by one; the monovalence unsaturated carbon cyclic group that two or three rings are formed; each ring has three to eight carbon, and it can be chosen wantonly and be selected from following substituent group with one or two and replace or do not replace: hydroxyl; cyano group; the low-carbon (LC) thiazolinyl; low-carbon alkoxy; the low-carbon (LC) halogenated alkoxy; alkenylthio group; halogen; haloalkenyl group; the hydroxyl thiazolinyl; nitro; alkoxy carbonyl group (alkoxycarbonenyl); amino; alkenyl amino; the thiazolinyl sulfonyl; aryl sulfonyl; the alkenyl amino sulfonyl; n-aryl sulfonyl; alkyl sulfonyl amino; Arenesulfonyl amino; the thiazolinyl aminocarbonyl; the aryl aminocarbonyl; alkenyl carbonyl amino and aryl-amino-carbonyl.
Cycloalkyl: be meant by one; the monovalence saturated carbon cyclic group that two or three rings are formed; each ring has three to eight carbon, and it can be chosen wantonly and be selected from following substituent group with one or two and replace or do not replace: hydroxyl; cyano group; low-carbon alkyl; low-carbon alkoxy; the low-carbon (LC) halogenated alkoxy; alkylthio group; halogen; haloalkyl; hydroxy alkyl; nitro; alkoxy carbonyl group; amino; alkyl amino; alkyl sulphonyl; aryl sulfonyl; alkyl amino sulfonyl; n-aryl sulfonyl; alkyl sulfonyl amino; Arenesulfonyl amino; alkyl amino carbonyl; the aryl aminocarbonyl; alkyl-carbonyl-amino and aryl-amino-carbonyl.
Cation group: when the compound dissolution that comprises chemical group was in solvent, when particularly being dissolved in the water, this chemical group can serve as proton donor.
Form ring: be meant that related atom connects by key when forming ring structure.
Group: (partly/replace)Fully understand that as the present technique field big replacement degree is not only admissible, and often be desirable.Replacement on the material of the present invention is expected.Run through the discussion of some used terms of the application and the means of description as simplification, term " group " and " part " are used to distinguish and allow replace or can substituted chemical species and those chemical species that does not allow or can not be so substituted.Therefore, when term " group " when being used to describe chemical substituent group, described chemical substance comprises not substituted radical and have for example O, N or S atom and carbonyl or other conventional this groups that replaces on chain.When term " part " is used to describe chemical compound or substituent group, only be intended to comprise unsubstituted chemical substance.For example; word " alkyl group " is intended to not only comprise simple open chain saturated hydrocarbon alkyl substituent; such as methyl, ethyl, propyl group, the tert-butyl group etc.; but also comprise and further contain substituent alkyl substituent known in the art, such as hydroxyl, alkoxyl, alkyl sulphonyl, halogen atom, cyano group, nitro, amino, carboxyl etc.Therefore, " alkyl group " comprises ether group, haloalkyl, 4-nitro alkyl, carboxyalkyl, hydroxy alkyl, sulfo group alkyl etc.On the other hand, word " moieties " is limited to and comprises only simple open chain saturated hydrocarbon alkyl substituent, such as methyl, ethyl, propyl group, the tert-butyl group etc.Identical definition is suitable for " alkenyl group " and " alkenyl part "; Be suitable for " alkynyl group " and " alkynyl part "; Be suitable for " cyclic group " and " annulus "; Be suitable for " alicyclic group " and " alicyclic moiety "; Be suitable for " aromatic group " and " aromatic yl group " and " aromatics part " or " aryl moiety "; And suitable " heterocyclic group " and " heterocyclic moiety ".
Heterocyclic group: term " heterocyclic group " is meant closed-ring hydrocarbons, and the one or more atoms on its medium ring are the elements (for example, nitrogen, oxygen, sulfur etc.) beyond the carbon.
Heterocyclic radicalBe meant the monovalence saturated cyclic base of being made up of one to two ring, each ring has three to eight atoms, introduces one or two ring hetero atom and (is selected from N, O or S (O) 0-2), and it can be chosen wantonly and is selected from following substituent group with one or two and replaces or do not replace: hydroxyl, oxo, cyano group, low-carbon alkyl, low-carbon alkoxy, low-carbon (LC) halogenated alkoxy, alkylthio group, halogen, haloalkyl, hydroxy alkyl, nitro, alkoxy carbonyl group, amino, alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl amino, Arenesulfonyl amino, alkyl amino carbonyl, aryl aminocarbonyl, alkyl-carbonyl-amino or aryl-amino-carbonyl.
Heteroaryl: be meant to have a monovalence aromatic ring yl to three rings; each ring has four to eight atoms; in ring, introduce one or two hetero atom and (be selected from nitrogen; oxygen or sulfur), and this ring can be chosen wantonly and is selected from following substituent group with one or two and replaces or do not replace: hydroxyl; cyano group; low-carbon alkyl; low-carbon alkoxy; the low-carbon (LC) halogenated alkoxy; alkylthio group; halogen; haloalkyl; hydroxy alkyl; nitro; alkoxy carbonyl group; amino; alkyl amino; alkyl sulphonyl; aryl sulfonyl; alkyl amino sulfonyl; n-aryl sulfonyl; alkyl sulfonyl amino; Arenesulfonyl amino; alkyl amino carbonyl; the aryl aminocarbonyl; alkyl-carbonyl-amino (alkylcarbonlamino) and aryl-amino-carbonyl.
Hypothermia: body temperature is reduced under the normal level.
Ischemia: blood supply is limited, and the result who follows organizes malfunction or infringement.
Particular compound PartThe group (one or more) or the part (one or more) that comprise described particular compound.
Pharmaceutical composition: or medicine, medicine or medicament are meant any chemistry or biomaterial, chemical compound or the compositions of the therapeutic effect that can induce expectation when suitably being applied to the patient.Some medicines are to sell with the form of non-activity, and it is converted into the metabolite with pharmaceutically active in vivo.For the purposes of the present invention, term " pharmaceutical composition " and " medicine " comprise the medicine and the active metabolite of non-activity.
The low-carbon alkyl that replacesBe meant to have one to three substituent low-carbon alkyl, described substituent group is selected from hydroxyl, alkoxyl, amino, amide groups, carboxyl, acyl group, halogen, cyano group, nitro and thiol.
The novel vanilloid receptor agonist: can be in conjunction with the capsaicin or the Capsaicinoid chemical compound of novel vanilloid receptor/capsaicin receptor.
Principle of the present invention is to use novel vanilloid receptor agonist induction hypothermia, to alleviate ischemic influence, such as the effect of ischemic histologic lesion.
Ischemia
Ischemia is to the blood supply reduction of tissue or disappears.Oxygen of being followed and nutrient can not cause completely the getting involved cell death (necrosis) of tissue regions.Lack the infringement that causes by oxygenated blood in the brain and occur in two stages.At first because the deficiency of oxigen cellular metabolism is stopped, and as it some cells and tissue will be dead in several minutes as a result.The second, cascade process such as programmed cell death is initiated and can continue until 12 hours after the incident of inducing the ischemia state has at first stopped.Tissue by second cascade infringement can be conclusive, and compares with the primary lesion that ischemia takes place in several minutes at first, and individuality is caused bigger injury.
The present invention is intended to correct the ischemia of brain, thereby minimizes the infringement to the central nervous system.The present invention carries out with the hypothermia of inducing the patient by giving medicine.The hypothermia effect is speculated as by several mechanism in brain weakens the ischemia infringement: prevent the blood-brain barrier disruption of ischemia outbreak very fast generation afterwards, the ischemia outbreak makes because the formation edema of exosmosing; Reduce the generation of oxygen base free radical; Reduce stimulation oversaturation and adjoin neuronic excititoxic neurotransmitter release; Reduce metabolic rate and energy expenditure subsequently; And antiinflammatory action.Induce hypothermia to have neuroprotective.
The purpose of this invention is to provide and in individuality, to induce hypothermic chemical compound, and further provide described chemical compound to be used for the treatment of purposes aspect the individual ischemic medicine in production.
Ischemia can take place in all cases; Relevant especially with the present invention is with cardiovascular disease, suffocate and situation that traumatic brain injury is relevant.
Therefore, ischemia be by cardiovascular disease for example, suffocate and situation that traumatic brain injury causes under, provide and reduce the individual ischemic method of ischemia risk and treatment within the scope of the invention.
One aspect of the present invention is the effect of the ischemic histologic lesion of treatment.
Cardiovascular disease
Cardiovascular disease is the modal cause of death of developed world and health and moral damage reason.Along with other parts of the world its fatty diet, do not get enough athletic exercise and the average life increase aspect just catching up with the life style in the Western Hemisphere, observe similar development in other regions of the world.
Main cause dead and disabled in cardiovascular disease is myocardial infarction, acute coronary syndrome, heart beating stops and apoplexy, but much more uncommon cardiovascular disease is individual same harmful to getting involved.These more uncommon diseases comprise aneurysm, subarachnoid hemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, arrhythmia, megalocardia, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
Above-mentioned each disease causes and causes ischemic a series of incident, and therefore becomes place whole interested related to the present invention.Myocardial infarction (heart attack) is atheromatous plaque slowly accumulation in inner membrance coronarius, and it breaks suddenly then, partly or entirely occluded artery and stop the result of blood flow.It is to stop suddenly owing to heart can not effectively shrink the normal circulation that causes blood that heart beating stops.Under the situation that does not have medical treatment to get involved, unless under hypothermic situation, brain injury might take place after 3-4 minute.Apoplexy is continue to surpass 24 hours acute nerve injury, and the blood supply that wherein arrives the part brain is interrupted, itself or since the grumeleuse in the tremulous pulse cause or under the situation of arteriorrhexis, cause.Aneurysm is that 50% the local balloon sample of tremulous pulse that surpasses blood vessel diameter expands.Aneurysm is the most common to be occurred in the tremulous pulse of brain bases and in the aorta.This expansion in tremulous pulse brings disruptive risk and causes internal hemorrhage.It is big more that aneurysm becomes, and it might break more.Subarachnoid hemorrhage (SAH) is that blood flows in the brain subarachnoid space on every side, i.e. zone between arachnoidea and pia mater encephali.It can be owing to wound causes or spontaneous appearance, and is the medical science emergency case, though in early days the stage be identified and treat, it can cause death or serious deformity.Arteriosclerosis is because formation collagen or calcium deposition cause arterial wall through several years or the hardened disease of many decades.Hyperpiesia or hypertension are the medical conditions of the chronic rising of blood pressure wherein.Hypercholesterolemia is to have high-caliber cholesterol in blood.It is a kind of disorder of facilitating the disease of a lot of forms, and the most significant is cardiovascular disease.Arrhythmia is that the flesh of heart shrinks irregular or than normal one group of fast or slow disease.Some arrhythmias are life-threatening medical science emergency cases, and it can cause that heart beating stops and dying suddenly.Megalocardia are medical conditions of cardiac enlargement.It can be often relevant with other serious medical conditions.Cardiomyopathy is cardiac muscle (that is Shi Ji cardiac muscle) functional deterioration.Suffers from the danger that myocardiac people has arrhythmia and/or sudden cardiac death.Heart valve regurgitation is also referred to as heart valve insufficiency, is the unusual seepage through the blood of cardiac valve.The cardiac conditions that the incomplete opening that heart valve stenosis is by cardiac valve---being generally aortic valve or Bicuspid valve---causes, it weakens the blood flow through heart.
Each cardiovascular disease of being mentioned and other cardiovascular disease of not mentioning can cause the ischemia of organ.No matter this ischemia is the ischemia of brain, heart or other organs, if treat rapidly, can cause death or damage.
The purpose of this invention is to provide chemical compound, it is used for production for treating or prevention suffers from the ischemia that cardiovascular disease causes or is in the medicine of suffering from the individuality under the ischemic risk that cardiovascular disease causes, described cardiovascular disease such as, but not limited to: myocardial infarction, heart beating stop, apoplexy, aneurysm, subarachnoid hemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, arrhythmia, megalocardia, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
Preferably, this medicine is used for the treatment of or prevents ischemia by heart beating stops, myocardial infarction, apoplexy, aneurysm, subarachnoid hemorrhage or angina pectoris cause.
All above-mentioned cardiovascular disease need special diagnostic detection and treatment.These detections and treatment are used for the detection and the treatment of sudden cardiac arrest, apoplexy and heart attack as following appointment, can combine with the treatment of defined novel vanilloid receptor agonist in this patent and carry out.
The sudden cardiac arrest patient can carry out early stage CPR, early stage defibrillation and early stage Advanced Nursing.Further detect and treat and to comprise cardiac catheterization, electrophysiology detection, coronary bypass, balloon angioplasty or PTCA, arrhythmia medicine, implantable cardiac conversion device/defibrillator, implantable cardiac pacemaker and heart transplantation.
Depend on whether the patient suffers from Ischemic Stroke or hemorrhagic apoplexy, acute treatment can comprise thrombolytic (for example, tPA) or surgery get involved gripping (for example, aneurysm clamp and such as operation in the blood vessel that inserts " coil ").Prophylactic treatment comprises and gives anticoagulant/anti-platelet agents.It can comprise carotid endarterectomy and angioplasty and/or support in addition.
The patient of outbreak (myocardial infarction) of having a heart disease can carry out one or more treatments and operation with the survival and the diagnosis state of an illness: these treatments and operation comprise recovery (early stage CPR, early stage defibrillation, early stage Advanced Nursing), thrombolytic, coronary angioplasty (being also referred to as percutaneous tranluminal coronary angioplasty [PTCA], percutaneous coronary intervention [PCI], balloon angioplasty and coronary artery air bag expansion) and coronary artery bypass graft surgery (CABG).
Suffocate
Suffocating, (suffocating, suffocation) is the common cause of death and the health and the moral damage reason of adult of neonate, child and institute's has age.
Suffocate and can be divided into perinatal asphyxia and non-perinatal asphyxia: perinatal asphyxia is to be lacked the sufficiently long time of oxygen and caused the medical conditions that obvious damage produces by ewborn infant.It the most normally is because parent blood pressure drops or interference farrowing interval blood flow cause to baby's brain.This can be owing to inadequate circulation or perfusion, impaired respiratory effort or inadequate ventilation take place.The limit degree of suffocating can cause that heart beating stops and death.The anoxia infringement can betide most of organs of baby, but cerebral lesion merits attention most, and may rapid and probability minimum that fully cure.Under serious situation, the baby may be survived, but follows the brain damage that shows as hypoevolutism and spasticity; Non-perinatal asphyxia is the disease that arrives the oxygen supply wretched insufficiency of health, and it results from can not eupnea.Its common cause comprises that drowning, strand hang and be exposed to toxic gas.Suffocating causes the whole body anoxia, and this at first main influence tissue and organ the most responsive to anoxia such as brain, therefore causes cerebral anoxia.Lack effective treatment and will very rapidly cause loss of consciousness, brain injury and death.
Mentioned every kind suffocates and the suffocate ischemia that can cause organ and be purpose of the present invention therefore of NM other.
An aspect of of the present present invention provides and is used for the treatment of the chemical compound of suffering from the ischemic individuality that causes by suffocating, described suffocating such as perinatal asphyxia and/or non-perinatal asphyxia.
Treatment by the novel vanilloid receptor agonist that gives to define in this patent can be carried out with the detection and the treatment combination that comprise the disease of suffocating and accident (perinatal asphyxia with include but not limited to drowning, strand hang and the non-perinatal asphyxia that contact toxic gas).These diseases and damage can need early stage CPR, early stage defibrillation, early stage and lasting Advanced Nursing, and other NM detection and treatments.
Traumatic brain injury
Traumatic brain injury (TBI) is the reason of common death and health and moral damage all over the world.TBI can by since violence or self-inflicted accident cause.
Traumatic brain injury is also referred to as the intracranial damage, perhaps simply is called head injury, takes place when sudden trauma causes cerebral lesion.TBI can result from closure head injury or break-through head injury.Can comprise cerebral hemisphere, cerebellum and brain stem by damaged brain branch.The symptom of TBI can be slight, medium or serious, and this depends on the degree to brain damage.The result can be any result, from returning to permanent disability or death fully.Ischemia is the key factor that causes suffering from nervous lesion common among the patient of TBI.
An aspect of of the present present invention provides and is used for the treatment of the chemical compound of suffering from the ischemic individuality that is caused by traumatic brain injury.
Treatment by the novel vanilloid receptor agonist that gives in this patent, to define also can be relevant with traumatic head damage (closed head injury or break-through head injury) detection and treatment in conjunction with carrying out.These damages can need early stage CPR, early stage defibrillation, early stage and lasting Advanced Nursing, and unaccounted other detections and treatment.
Hypothermia
Hypothermia is that body center's temperature is reduced to the temperature under the normal level.The adult's who measures in the per rectum 24 hours normal body temperature be 37 degrees centigrade (℃)+/-0.6 ℃, and therefore between individuality and in the individuality, can change in time.When being generally defined as central temperature and dropping under 35 ℃ as the hypothermia of medical conditions on body viewed effect.If body temperature drops to below 32 ℃, it may become critical.In the present invention, hypothermia is defined as central body temperature and is reduced to temperature under the normal level.This means, the given time in a day or given during, any temperature that is lower than under the normal central body temperature with its particular individual that changes naturally is defined as hypothermia in this article.Particularly, hypothermia is the temperature below 35.5 ℃, under 35 ℃, under 34.5 ℃, under 34.0 ℃.
Body temperature can utilize several different methods to measure at zones of different such as forehead, mouth, axillary fossa, ear or the rectum of health by hydrargyrum, electronics or plastic strip thermometer.Should be appreciated that at present the temperature of indication is a central body temperature in this application, and more above-mentioned measuring methods are different from demonstration the temperature of central temperature.
Importantly, hypothermic inducing can be followed the process that can estimate in individuality, and in response to inducing hypothermic chemical compound by the dosage of administration.Inducing of state of hypothermia can be rapidly or slowly, and this depends on the patient's of needs treatment situation.The severity that also depends on ischemic conditions, interested providing is used to make the individual medicine that keeps different time length at state of hypothermia.Can use the unification compound, this depends on the dosage in the temperature range or is used to induce hypothermia to reach the dosage of specified temp.Can use combination of compounds in addition, reduce rapidly, and keep the temperature that reached subsequently for a long time so that central body temperature is initial.If state of hypothermia can reverse in a controlled manner, depend on that individual state is slow or fast, it is further useful.
Therefore the purpose of this invention is to provide chemical compound, this chemical compound is used for producing suffering from ischemic patient induces hypothermic medicine, wherein this chemical compound can be induced any temperature range between hypothermia to 37 ℃ and 31 ℃, between 36.5 ℃ and 31.5 ℃, between 36 ℃ and 32 ℃, between 35.5 ℃ and 32.5 ℃, between 35 ℃ and 33 ℃, between 34.5 ℃ and 33.5 ℃.This scope can be further between 37 ℃ and 34 ℃, between 36.5 ℃ and 34.5 ℃, between 36 ℃ and 35 ℃, alternatively between 34 ℃ and 31 ℃, between 33.5 ℃ and 31.5 ℃, between 33 ℃ and 32 ℃, alternatively between 36 ℃ and 33 ℃ or between 35 ℃ and 32 ℃.Preferably, chemical compound of the present invention can induce in 36 ℃ to the 32 ℃ scopes, the more preferably hypothermia between 35 ℃ to 33 ℃, and most preferably between 34 ℃ and 32 ℃.
Be similarly providing of the object of the invention and can induce the hypothermic chemical compound that reaches specified temp, described specified temp is such as 37 ℃, 36.5 ℃, 36 ℃, 35.5 ℃, 35 ℃, 34.5 ℃, 34 ℃, 33.5 ℃, 33 ℃, 32.5 ℃, 32 ℃, 31.5 ℃ or 31 ℃, perhaps more preferably, chemical compound of the present invention can be induced the hypothermia that reaches in ℃ scope of any above-mentioned specified temp+/-0.5, this scope therefore+/-0.4 ℃ between, such as+/-0.3 ℃ between, such as+/-0.2 ℃ or such as+/-0.1 ℃ between.Given chemical compound can inductive temperature range or specified temp in this drug targets temperature that is also referred to as this chemical compound and/or comprises this chemical compound.
The novel vanilloid receptor agonist
The novel vanilloid receptor agonist be one group can be in conjunction with the chemicals of vallinoid rece tor trpvl (VR1), VR1 is also referred to as the transient receptor potential cationic channel, subfamily V (TRPV1).Term novel vanilloid receptor agonist is contained the array chemical compound, comprises capsaicin and Capsaicinoid chemical compound such as resinoid (resiniferanoids) and unsaturated full gear.Before discovery or synthetic other types, the term capsaicin is called as one group by the secondary metabolite that plant produced that belongs to Capsicum such as Fructus Capsici.These chemical compounds are active component of Fructus Capsici, produce the sensation of burning when it is ingested in mouth.The novel vanilloid receptor agonist can be divided into two types based on source and chemical composition:
1. classical novel vanilloid receptor agonist, this group comprise native compound and other Rhizoma et radix valerianae amide (vanillamide) derivants of Fructus Capsici.
2. non-classical novel vanilloid receptor agonist, the member in this group does not comprise the vanilloyl amine moiety usually.
The novel vanilloid receptor agonist is irritating for mammal, but to not effect of birds, shows that these chemical compounds may be evolved to be the repellant (deterrent) to herbivore.Various novel vanilloid receptor agonist have the different zests according to Shi Gaoweier index (Scoville scale) measurement, and capsaicin and dihydrocapsaicin are the most effective classical novel vanilloid receptor agonist.
Anecdote anecdote and science be the application of known capsaicin all, and today, it was widely used as treating or alleviating the medicine of various diseases.The main clinical practice of capsaicin is successfully to treat such as by herpes zoster (shingles) infection, diabetic neuropathy, rheumatism, fibromyalgia, such as the caused neuralgic pain of all kinds arthritis of osteoarthritis or rheumatoid arthritis with the external ointment form, and other forms of chronic pain.Capsaicin is neural to the pain desensitization by making through the unwanted neurocyte of the dead elimination of gangrenosum acne, and comes the arthritic helpful by decapeptide Substance P (DSP) level that reduces in the knuckle synovia.Capsaicin destroys DSP, and DSP can destroy cartilage and also can amplify the pain sensation.The capsaicin that studies have shown that in recent years is an effective anticancer agent.Capsaicin is induced the apoptosis of cancer of pancreas and prostate gland cancer cell, and to not significantly infringement of healthy cell on every side.Known capsaicin influences NF-kB, and believes and pass through this albumen just, and capsaicin activation apoptotic proteins causes cell death.In another cancer related application, the confection that contains capsaicin can alleviate the pain of recurrent oral ulcer in patients undergoing chemotherapy significantly.Capsaicin paste and ointment are used for the treatment of muscle and arthralgia, and when chemicals caused vasodilation, the medicine that contains the novel vanilloid receptor agonist was as antiinflammatory.Capsaicin is referred as the rem that reduces serum cholesterol level, alleviation psoriasis and treatment headache, migraine and chronic sinus infection in addition.The novel vanilloid receptor agonist has caused concern as the neuroprotective material of inferring in addition.As described below, this neuroprotective to small part is by inducing hypothermia to mediate.
Can be defined as the novel vanilloid receptor agonist, all fall within the scope of the invention for the capsaicin of classical or non-classical novel vanilloid receptor agonist or Capsaicinoid chemical compound or in conjunction with any chemical compound of the chemical compound of novel vanilloid receptor.Term novel vanilloid receptor agonist, capsaicin or Capsaicinoid are exchanged in this article and are used.
Receptor
The causalgia sense that is caused by the novel vanilloid receptor agonist occurs by optionally activating sensory neuron, and sensory neuron will be about the information transmission of noxious stimulation to the central nervous system.Mainly based on the existence of VR1/TRPV1 receptor, this receptor is a kind of nonselective cationic channel to this selectivity, and novel vanilloid receptor agonist, capsaicin and Capsaicinoid chemical compound combine with it as agonist.TRPV1 also can be activated by the temperature in extracellular proton and the harmful scope, shows that its effect is the pick off as pain thermostimulation in the body.By with the TRPV1 receptors bind, the novel vanilloid receptor agonist causes and the identical effect of effect overheated or that the scratch infringement will cause, thus explained capsaicin why pungently be described to produce burn feeling and do not cause the chemical burn of reality.
Propose many different mechanism and explained the various effects of novel vanilloid receptor agonist.Novel vanilloid receptor may be striden many subunits, the non-selective cationic channel of forming in the film district by 6, and it induces Ca when activation 2+Enter, and except somatostatin, also discharge sensory neuropeptide sample calcitonin-gene-related peptide (CGRP) and tachykinin (for example, P material) subsequently.This induces many effects successively, and these effects can change according to types of organization, and comprises vasodilation, plasma protein extravasation and immunocyte gathering and whole body antiinflammatory and analgesic effect in the innervation zone.Can't know definitely that up to now which kind of mechanism can explain the hypothermia effect of novel vanilloid receptor agonist, but above-mentioned by inference reaction may there be certain relation with it.
The TRPV1 receptor is named as vallinoid rece tor trpvl (VR1) at first, because the plain part of Rhizoma et radix valerianae constitutes the main component of classical novel vanilloid receptor agonist, but because the homology of this receptor is extended other TRP family members, therefore henceforth is renamed as TRPV1.TRPV1 is the subfamily member of TRPV receptor, comprises TRPV1-6.In these receptors several can make the cell of expressing them with heat, mechanical pressure and multiple chemical compound such as novel vanilloid receptor agonist, Camphora and other chemical compound sensitivities to different interval.The hypotype of novel vanilloid receptor and the soluble receptor of the combination of multiple oligomer viewed physiology result's after being activated variation by different novel vanilloid receptor agonist.The oligomerization structure of receptor has increased finds that some organ that contains the novel vanilloid receptor agonist in many organs is had specific active substance, thereby only activates the part of vanilloid receptor system.
Novel vanilloid receptor is very abundant in many organs of body, and these organs comprise the neuronal tissue of looking proparea, locus coeruleus, medial hypothalamus, network structure and ventral thalamus.Tissue (for example at non-neuronal " immigration port " in addition, skin, digestive tract, air flue, conjunctiva), the various cell types of these tissues of liner (promptly, horn cell, epithelial cell, endotheliocyte etc.) find novel vanilloid receptor, also in the Rodents and the mankind's multiple periphery non-neuron tissue (for example, kidney, lung, testis, pancreas, spleen, liver, stomach, skin, vascular smooth muscle, Placenta Hominis, cornea, uterus and bladder), found novel vanilloid receptor.Hypothalamus is rich in novel vanilloid receptor, and it is that the present invention is interested especially: it may be the part in the hypothermia of novel vanilloid receptor mediation, because it contains the thermoregulation maincenter of CNS.
Receptor except that TRPV1 relates to and cause hypothermia when combining with agonist.Although some data show that capsaicin passes through Cannabined receptor (CB1 and CB2) dependent/non-dependent mechanism and causes hypothermia, have and to induce hypothermic novel vanilloid receptor agonist with TRPV1, especially CB2 are interactional.Except the top TRPV3 as the active regulator of TRPV1 that mentions, kinetins (prokineticin) receptor 1 and 2 (PKR1 and PKR2) have shown with the TRPV1 interaction and have regulated its activity.Novel vanilloid receptor agonist of the present invention, capsaicin and the combinative receptor of Capsaicinoid chemical compound, except TRPV1 and other TRPV subfamilies member TRPV2 ,-3 ,-4 ,-5 and-6, also comprise CB1, CB2 and the 3rd CB receptor (this paper is called CB3), PKR1 and PKR2, GABA (γ-An Jidingsuan) receptor, NMDA (N-methyl-D-aspartate) receptor, 5-HT (1A) receptor (also being known as 5-hydroxytryptamine receptor), delta opiate receptor (DOR).In addition within the scope of the invention be: chemical compound of the present invention can be in conjunction with the TRPV1 co-receptor.Can therefore fall within the scope of the invention in conjunction with the chemical compound of any above-mentioned receptor.
Preferably, chemical compound of the present invention is in conjunction with TRPV1 and/or TRPV1 associated receptor.The TRPV1 receptor is the significant hypothermic response that the whole body administration by capsaicin is caused for inducing the hypothermic importance of mammal, and this is reflected in the mice that lacks the TRPV1 gene is non-existent.
Structure
The application's novel vanilloid receptor agonist mostly based on their structure by following classification: classical novel vanilloid receptor agonist and non-classical novel vanilloid receptor agonist.The chemical compound that belongs to these any classes falls within the scope of the invention.
Chemical compound of the present invention can induce hypothermia within the scope of the invention in individuality.
Chemical compound of the present invention can be in conjunction with TRPV1 receptor and/or relative receptor further within the scope of the invention.
Therefore, aspect the most generalized, the application of compound of the structure of one of general formula shown in below the present invention relates to comprise.In these sketch maps, R is chemical bond or the chemical part as defining in the above.R can be the arbitrary portion that is substituted arbitrary number of times according to the detail description list, R is thus: C, H, S, N, O, it is optional by C, H, S, N, O, B, P, OH, CHO, hydrogen, alkoxyl, alkyl, thiazolinyl, alkynyl, phenyl, xenyl, benzyl, amine (NH), halogen, the low-carbon alkyl of replacement, thiazolinyl, aryl, heterocyclic group, Heterocyclylalkyl, heteroaryl, aryl-(C 1-4)-alkyl, heteroaryl-(C 1-4)-alkyl, heterocyclic radical-(C 1-4)-alkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkenyl group or phosphate replace one or many or do not replace, optional further by the low-carbon alkyl of C, S, N, O, P, OH, H, phenyl, amine (NH), halogen, alkoxyl, replacement or alkyl, such as (C 1-C v) alkenyl or alkynyl, acetyl group, sulfonyl, phenyl, cycloalkyl, cycloalkenyl group, heterocyclic radical or heterocyclic group replace one or many, any in them can or can not be branching or further by C, O, P, methyl, dimethyl, such as (C 1-C v) alkyl or alkenyl, alkoxyl, phenyl, sulfate radical, phosphate, halogen replace one or many, perhaps further by fluoride, sulfate radical, phosphate, methyl, dimethyl, aryl, heterocyclic radical, heteroaryl, aryl-(C 1-4)-alkyl, heteroaryl-(C 1-4)-alkyl, heterocyclic radical-(C 1-4)-alkyl, cycloalkyl-alkyl, bicyclic alkyl, tricyclic alkyl, cycloalkenyl group, alkoxyl, carboxyl, halogen, trifluoromethyl, cyano group, amino, nitro, halogen or alcohol further replace, and the phenyl by O, OH, methyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, dimethyl or further usefulness alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, heterocyclic radical replacement further replaces once at least, wherein v is from 1 to 30 integer, and wherein any its above-mentioned substituent group can form ring with another R.R can be a chemical bond in addition, or any one pharmaceutically acceptable addition salt or hydrate in above-mentioned.
For each general formula, enumerated with preferred and the tabulation of more preferred substituents group for substituent more specifically selection of given R.
The present invention relates to comprise the purposes of the chemical compound of general formula (I) such as classical or non-classical novel vanilloid receptor agonist:
Figure A200780037326D00241
-wherein R1 is selected from group: C, S, N, O, its optional C that uses, S, N, O, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, sulfonyl or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And be preferably C, and it uses C, O, P, H, OH, phosphate, alkyl, thiazolinyl, alkynyl substituted, and any in them can be (C 1-C v), or be phenyl, in them any can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace, and any in them can further use methyl, ethyl or phenyl to replace; C more preferably, it is with alkyl, alkenyl substituted, and any in them can be (C 4-C W), any in them can further be used O, OH, methoxyl group, ethyoxyl or methyl substituted, and any in them can further use methyl, ethyl or phenyl to replace, wherein VBe 1 to 30 integer, and WBe 5 to 18 integer, and;
-wherein R2 is selected from group: C, S, N, O, it is optional with C, S, N, O, P, OH, hydrogen, alkoxyl, alkyl, thiazolinyl, alkynyl, phenyl, xenyl, benzyl, amine (NH), halogen, the low-carbon alkyl of replacement, thiazolinyl, aryl, Heterocyclylalkyl, heteroaryl, aryl-(C 1-4)-alkyl, heteroaryl-(C 1-4)-alkyl, heterocyclic radical-(C 1-4)-alkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkenyl group or phosphate replace one or many or do not replace, and optionally further replace one or many with following radicals or do not replace: the low-carbon alkyl of C, S, N, O, P, OH, H, COOH, phenyl, amine (NH), halogen, alkoxyl, replacement, such as (C 1-C v) alkyl or alkenyl, cycloalkenyl group, sulfate, phosphate, aryl, heterocyclic radical, heteroaryl, aryl-(C 1-4)-alkyl, heteroaryl-(C 1-4)-alkyl, heterocyclic radical-(C 1-4)-alkyl, cycloalkyl-alkyl, bicyclic alkyl, tricyclic alkyl, cycloalkenyl group, alkoxyl, carboxyl, halogen, cyano group, amino, nitro or alcohol, any in them can further replace one or many with following radicals: OH, methyl, dimethyl, such as (C 1-C v) alkyl or alkenyl, alkoxyl, phenyl, sulfate, phosphate, aryl, heteroaryl, carboxyl, amino, nitro, alcohol or halogen; And be preferably C, it replaces one or many with following radicals: low-carbon alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group or the phosphate of C, N, O, P, OH, hydrogen, alkoxyl, alkyl, thiazolinyl, amine (NH), halogen, replacement optional further replace one or many with following radicals or do not replace: C, N, O, OH, COOH, hydrogen, amine (NH), halogen, alkoxyl, replacement such as (C 1-C x) low-carbon alkyl or thiazolinyl, phosphate, cycloalkenyl group, alkoxyl, carboxyl or halogen, they any can further replace one or many with following radicals: OH, methyl, dimethyl, such as (C 1-C x) alkyl or alkenyl, alkoxyl, phenyl, sulfate, phosphate, carboxyl or halogen; And C more preferably, it replaces once at least with following radicals: further replace twice cycloalkenyl group at least with in OH or the methoxyl group any, or such as (C 1-C 2) low-carbon alkyl, and further replace one or many with OH, COOH, chloride, methyl or cycloalkenyl group, randomly further replace one or many or do not replace, and wherein with OH or methoxyl group VBe 1 to 30 integer, and XIt is 1 to 5 integer.
Preferably, the present invention relates to comprise the application of compound of general formula (I), wherein R1 is C, and it uses C, O, P, H, OH, phosphate, alkyl, thiazolinyl, alkynyl substituted, and any in them can be (C 1-C v); or phenyl; in them any can further replace one or many with following radicals: O; OH; methyl; dimethyl; alkyl; thiazolinyl; cycloalkyl; Heterocyclylalkyl; cycloalkenyl group; acetyl group; phenyl; methoxyl group; ethyoxyl; alkoxyl or phosphate; in them any can further be used methyl; ethyl or phenyl replace; and R2 is C; it replaces one or many with following radicals: C; N; O; P; OH; hydrogen; alkoxyl; alkyl; thiazolinyl; amine (NH); halogen; the low-carbon alkyl that replaces; thiazolinyl; aryl; cycloalkyl; cycloalkenyl group or phosphate optional further replace one or many with following radicals or do not replace: C; N; O; OH; COOH; hydrogen; amine (NH); halogen; alkoxyl; replace such as (C 1-C x) low-carbon alkyl or thiazolinyl, phosphate, cycloalkenyl group, alkoxyl, carboxyl or halogen, any in them can further use OH, methyl, dimethyl, such as (C 1-C x) alkyl or alkenyl, alkoxyl, phenyl, sulfate, phosphate, carboxyl or halogen replace one or many, and wherein VBe 1 to 30 integer, wherein XIt is 1 to 5 integer.
More preferably, the present invention relates to comprise the application of compound of general formula (I), wherein R1 is C, and it uses alkyl, alkenyl substituted, and any in them can be (C 4-C W), any in them can further be used O, OH, acetyl group, methoxyl group, ethyoxyl or methyl substituted one or many, and any in them can further use methyl, ethyl, cycloalkenyl group or phenyl to replace one or many, and WBe from 5 to 18 integer, and R2 is C, it replaces once at least with following radicals: further replace twice cycloalkenyl group at least with in OH or the methoxyl group any, or such as (C 1-C 2) low-carbon alkyl, and further replace one or many with OH, COOH, chloride, methyl or cycloalkenyl group, optionally further replace one or many or do not replace with OH or methoxyl group.
The present invention relates to the application of compound such as the non-classical novel vanilloid receptor agonist that comprises general formula (II) in addition:
Figure A200780037326D00261
-wherein R1 is selected from group: C, S, N, O, its optional C that uses, S, N, O, B, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted, they any can be or can not be branching or comprise such as phosphate, cycloalkyl, heterocyclic radical, heterocyclic group, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, sulfonyl or phenyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, heterocyclic group, in them any can be or can not be branching or comprise such as C, O, H, OH, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, the substituent group of phosphate, further use O, OH, methyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, further use alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, dimethyl or phenyl that heterocyclic radical replaces replace once at least, and be preferably C, it uses C, N, O, B, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, heterocyclic radical, heterocyclic group, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, heterocyclic group, in them any can be or can not be branching or comprise such as C, O, H, OH, methyl, ethyl, alkyl, thiazolinyl, alkoxyl, the substituent group of phosphate, further use O, OH, methyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group replaces once at least, further uses alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, heterocyclic radical replaces; And C more preferably, by (C4-C W) alkyl or alkenyl, B or form ring and comprise that thus the heterocyclic radical of pyrrolidine replaces with R6, further replace one or many with O, methyl, alicyclic group connected to one another, they are saturated or unsaturated, or comprise the heterocyclic group of described B, N and O, and further replace at least once with O, methyl, or for further replacing once C at least with cycloalkenyl group, cycloalkyl, heterocyclic radical, further replace at least once, further replace with low-carbon alkyl and cycloalkenyl group with O, OH, methyl, thiazolinyl; Wherein above-mentioned any can with R2, R3, R4, R5 and/or R6 in any form at least one key, and WBe from 5 to 18 integer, and;
-wherein R2 is selected from group: C, S, N, O, its optional C that uses, S, N, O, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted or do not replace, they any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And being preferably the C that uses C, O, P, H, OH, phosphate, alkyl, thiazolinyl, alkynyl substituted, any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; And C more preferably, it replaces once at least with OH or hydrogen, and wherein above-mentioned any can with R1 and/or R3 in any form at least one key, and wherein VIt is 1 to 30 integer; And
-wherein R3 is selected from group: C, S, N, O, its optional C that uses, S, N, O, B, P, OH, hydrogen, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And being preferably the C that uses C, O, P, H, OH, phosphate, acetyl group, alkoxyl, alkyl, alkenyl substituted, any in them can be (C 1-C v), or be phenyl, randomly replace or do not replace with O, OH, methyl, dimethyl, alkyl, thiazolinyl, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate; And more preferably use OH, methoxyl group, low-carbon alkyl (C1-C Y) C that replaces, and can form ring in the arbitrfary point with R4, and wherein above-mentioned any can with R2 and/or R4 in any form at least one key, and wherein VBe 1 to 30 integer, and YIt is 2 or 3 integer; And
-wherein R4 is selected from group: C, S, N, O, its optional C that uses, S, N, O, B, P, OH, hydrogen, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And being preferably the C that uses C, O, P, H, OH, phosphate, acetyl group, alkoxyl, alkyl, alkenyl substituted, any in them can be (C1-C v), or be phenyl, randomly replace or do not replace with O, OH, methyl, dimethyl, alkyl, thiazolinyl, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate; And more preferably use OH, methoxyl group, low-carbon alkyl (C1-C Y) C that replaces, and can form ring in the arbitrfary point with R4, and wherein above-mentioned any can with R2 and/or R4 in any form at least one key, and wherein XIt is 1 to 30 integer; And YIt is 2 or 3 integer; And
-wherein R5 is selected from group: C, S, N, O, its optional C that uses, S, N, O, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, CHO, hydrogen, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, sulfonyl or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And be preferably with C, O, P, H, OH, CHO, phosphate, alkyl, thiazolinyl and replace once C at least, any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; And the C that more preferably uses hydrogen, OH, CHO or methyl substituted one or many, it can form ring with R6, wherein VBe 1 to 30 integer, and;
-wherein R6 is selected from group: C, S, N, O, its optional C that uses, S, N, O, B, P, OH, CHO, hydrogen, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, the substituent group of dimethyl or phenyl; And being preferably the C that uses C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl substituted, any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; And more preferably use hydrogen, CHO, low-carbon alkyl (C1-C Y) or the C of methyl substituted one or many, it can form at least one key with R5, or forms at least one key of ring with R1, and wherein described at least one key between any among R1, R2, R3, R4 and/or the R5 can be singly-bound or two key, and wherein VIt is 1 to 30 integer; And YIt is 2 or 3 integer.
Preferably; the present invention relates to comprise the application of compound of general formula (I); wherein R1 is C; it uses C; N; O; B; P; OH; hydrogen; alkyl; thiazolinyl; alkynyl substituted; in them any can be or can not be branching or comprise such as phosphate; cycloalkyl; Heterocyclylalkyl; heterocyclic group; cycloalkenyl group; methyl; ethyl; dimethylated substituent group; perhaps can further replace one or many: C with following radicals; N; O; P; OH; methoxyl group; ethyoxyl; acetyl group; alkoxyl; alkyl; thiazolinyl; cycloalkyl; cycloalkenyl group; heterocyclic radical; heterocyclic group; in them any can be or can not be branching or comprise such as C; O; H; OH; methyl; ethyl; alkyl; thiazolinyl; alkoxyl; the substituent group of phosphate; further use O; OH; methyl; thiazolinyl; cycloalkyl; Heterocyclylalkyl; cycloalkenyl group replaces at least once; further use alkyl; thiazolinyl; cycloalkyl; cycloalkenyl group; heterocyclic radical replaces; above-mentioned any can with R2; and/or R6 forms key; and R2 is preferably and uses C; O; P; H; OH; phosphate; alkyl; thiazolinyl; the C of alkynyl substituted, any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; And R3 is preferably the C with C, O, P, H, OH, phosphate, acetyl group, alkoxyl, alkyl, alkenyl substituted, and any in them can be (C 1-C v); or be phenyl; in them any can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; and R4 is preferably the C with C, O, P, H, OH, phosphate, acetyl group, alkoxyl, alkyl, alkenyl substituted, and any in them can be (C 1-C v), or be phenyl, choose wantonly with O, OH, methyl, dimethyl, alkyl, thiazolinyl, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate and replace or do not replace, and R5 is preferably with C, O, P, H, OH, CHO, phosphate, alkyl, thiazolinyl and replaces once C at least, and any in them can be (C 1-C v), or be phenyl, in them any can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace, and R6 is preferably the C with C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl substituted, and any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace, and wherein VIt is 1 to 30 integer.
More preferably, the present invention relates to comprise the application of compound of general formula (I), wherein R1 is can be (C4-C Z) the C that replaces with alkyl or alkenyl, boron or form ring with R6 and comprise the heterocyclic radical of pyrrolidine thus, further replace one or many with O, methyl, alicyclic group connected to one another, they are saturated or unsaturated, or comprise the heterocyclic group of described boron, N and O, and further replace at least once with O, methyl, or for further replacing once C at least with cycloalkenyl group, cycloalkyl, heterocyclic radical, further replace at least once, further replace with low-carbon alkyl and cycloalkenyl group with O, OH, methyl, thiazolinyl; R2 is the C that replaces with OH or hydrogen; R3 is with OH, methoxyl group, low-carbon alkyl (C1-C Z) C that replaces, and can on any point, form ring with R4; R4 is with OH, methoxyl group, low-carbon alkyl (C1-C Z) C that replaces, and can on any point, form ring with R3; R5 is the C with hydrogen, OH, CHO or methyl substituted one or many, and it can form ring with R6; And R6 is for using hydrogen, CHO, low-carbon alkyl (C1-C Z) or the C of methyl substituted one or many, it can form at least one key with R5, or forms ring with R1, and wherein described at least one key between any among R1, R2, R3, R4, R5 and/or the R6 can be singly-bound or two key, and YBe 2 or 3 integer, and ZIt is 5 or 12 integer.
Especially as if for classical novel vanilloid receptor agonist compound, specific molecular modification is preferred, because they can guarantee the novel vanilloid receptor activation of preferable degree.These modifications comprise the non-branching alkyl side chain of specific minimum length, because reduce effect and therefore hypothermia can not be induced to satisfied degree than the short chain analog.Therefore preferred chemical compound of the present invention has long relatively alkyl or alkenyl chain (R1 from following formula begins to calculate), such as the chain greater than 6 carbon atoms.The length of preferred alkyl/alkenylene chain is between 6 and 25 carbon atoms, most preferably between 7 and 18 carbon atoms, even more preferably between 8 and 9 carbon atoms.
Opposite with it, the replacement in aromatic ring seems complete elimination activity, and trends towards producing effective antagonist by the halogenation of aromatic ring being modified many TRPV1 capsaicin and Capsaicinoid agonist.
Examples for compounds
The examples for compounds relevant especially with the present invention includes but not limited to classical novel vanilloid receptor agonist, such as (in the bracket name be called alternative title): capsaicin (C; 8-methyl-N-vanillyl-6-nonene amide); dihydrocapsaicin (DHC); nor-dihydrocapsaicin (NDHC); Homodihydrocapsaicin (HDHC); homocapsaicin (HC); olvanil (olvanil) (N-9-Z-oleoyl-Rhizoma et radix valerianae amide); Rinvanil (the Rhizoma et radix valerianae amide of castor oil acid); Arvanil (N-vanillyl arachidonic amide (vanillylarachidonamide)); PhAR (phenylacetylrinvanil); Nuvanil; Farvanil (the Rhizoma et radix valerianae amide of method acid); Ac-Rinvanil; Retvanil (the Rhizoma et radix valerianae amide of tretinoin); Vanillyl pelargonic amide; and Ervanil (the Rhizoma et radix valerianae amide of erucic acid).
The example of the non-classical novel vanilloid receptor agonist compound relevant especially with the present invention includes but not limited to such as following chemical compound (name in the bracket is called alternative name): resin toxin (resiniferatoxin) (RTX); the arachidonic acid ethanolamine (the arachidonic acyl ethanol amine, arachidonylethanolamine); N-arachidonic acyl dopamine (arachidonoyldopamine) (NADA); N-arachidonic acyl-L-serine (ARA-S); arachidonic acyl-2-chloroethyl amine; 2-amino ethoxy biphenyl borate (2-APB); evodiamine; propofol; different floss Virgin's milk mushroom aldehyde (isovelleral); Scutigeral; 12-hydrogen peroxide eicosatetraenoic acid; α-sanshool; β-sanshool; γ-sanshool; δ-sanshool; Alpha-hydroxy-sanshool; beta-hydroxy-sanshool; piperine; (4-hydroxy-3-methoxyphenyl)ethyl methyl ketone and Bv8.
Preferred chemical compound
Chemical compound of the present invention can be induced second order effect or have other features except that being induced hypothermia.These may be relevant with the capsaicin character of chemical compound, and may more or less be desired therefore.Preferably, chemical compound of the present invention is not induced the effect of any change blood pressure or is induced particularly hyperpathia, pain (nocifensive), plasma extravasation, peripheral vasodilation, bronchoconstriction, bradycardia or apneic effect.Potential analgesic effect can not be considered untoward reaction, and depends on application possibility of the present invention or even desired.In addition, chemical compound of the present invention can be hydrophilic or hydrophobic.For ease of the administration according to chemical compound of the present invention, preferred compound is hydrophilic.Preferred chemical compound and be metabolic stability.
Therefore the preferred chemical compound of the present invention is can be in conjunction with the TRPV1 receptor and induce the chemical compound of individual hypothermia to the 36 ℃ temperature in 32 ℃ of scopes, and wherein said chemical compound is hydrophilic.
Preferably or especially relevant examples for compounds comprises: capsaicin and with the closely-related chemical compound of capsaicin such as dihydrocapsaicin (DHC), nor-dihydrocapsaicin (NDHC), Homodihydrocapsaicin (HDHC) and homocapsaicin.Other relevant especially chemical compounds comprise resin toxin and chemical compound closely-related with it.
Antagonist
The purpose of this invention is to provide the chemical compound that to eliminate the effect of inducing hypothermic chemical compound.These chemical compounds are referred to herein as antagonist, and it brings into play their antagonism by the ability of blocking any novel vanilloid receptor agonist as herein described, capsaicin or Capsaicinoid chemical compound and its receptors bind.The purpose of this type of antagonist provides other security mechanism, can stop decline, the stable individual central body temperature of central body temperature whereby and/or improve individual central body temperature.
Therefore embodiments of the present invention comprise the purposes that is used for resisting the individual inductive medicine of hypothermia according to above-mentioned arbitrarily chemical compound in preparation.
The example of antagonist includes but not limited to: 5-iodo resin toxin (5-iodoresiniferatoxin), amido quinazoline (amido quinazoline 70), the nor-dihydrocapsaicin of 6-iodo-, IBTU (N-(4-benzyl chloride base)-N '-(4-hydroxyl-3-iodo-5-methoxybenzyl) thiourea), KJM429 and JYL1421, A-425619, AMG9810, SB 366791, adenosine and Fructus Capsici are put down (Capsazepine).
Novel application of compound
Novel vanilloid receptor agonist, capsaicin and Capsaicinoid chemical compound have been used to multiple purpose for a long time.The purpose of this invention is to provide these chemical compounds and be used to induce hypothermic new purposes, especially for inducing the hypothermic purposes of suffering from ischemia or being in the individuality of suffering under the ischemia risk.
Medicine
It is by preparation that the hypothermia of being undertaken by any chemical compound described herein is induced, produce and therefore provide the medicine or the pharmaceutical composition that comprise at least a described chemical compound to implement.Therefore medicine of the present invention is used for individual hypothermia induces, with the ischemia of treatment and/or described individuality.
Pharmaceutical composition
Although it is possible using with feed chemicals for chemical compound of the present invention or salt,, preferably the form with pharmaceutical preparation presents them.Therefore, the present invention further provides the pharmaceutical preparation that is used for medicinal application, it comprises chemical compound of the present invention or its pharmaceutically acceptable salt as defined herein and the pharmaceutically acceptable carrier that is used for it.
Chemical compound of the present invention can be prepared with a variety of peroral dosage forms.Pharmaceutical composition and dosage form can comprise that chemical compound of the present invention or its pharmaceutically acceptable salt or its crystal habit are as active component.Pharmaceutically acceptable carrier can be solid or liquid.But the preparation of solid form comprises powder, tablet, pill, capsule, cachet, suppository and discrete particles.Solid carrier can be one or more materials, and described material also can serve as diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, bonding agent, antiseptic, wetting agent, tablet disintegrant or encapsulation material.
Chemical compound of the present invention can (for example be used for parenteral administration by preparation, by injection, for example bolus injection or continuous infusion), and can be present in ampoule, prefilled syringe, the low capacity transfusion device with unit dosage form, perhaps be present in containing the multi-dose container that adds antiseptic.Compositions can adopt the form such as suspension, solution or Emulsion in oil or water vehicle, for example solution in aqueous Polyethylene Glycol.Oil or nonaqueous carrier, diluent, solvent or vectorial example (for example comprise propylene glycol, Polyethylene Glycol, vegetable oil, olive oil) and injectable organic ester (for example ethyl oleate), and can contain preparaton (formulatory agents), such as antiseptic, wetting agent, emulsifying agent or suspending agent, stabilizing agent and/or dispersant.Alternatively, active component can be a powder form, and it obtained by the solid aseptic separation of sterilizing before, apirogen water for example aseptic with suitable carriers are used, perhaps by obtaining from the solution lyophilizing that is used for forming.
The oil that is used for parenteral administration comprises oil, animal oil, vegetable oil or artificial oil.The instantiation that is used for the oil of this type of preparation comprises Oleum Arachidis hypogaeae semen, soybean oil, Oleum sesami, Oleum Gossypii semen, Semen Maydis oil, olive oil, vaseline and mineral oil.The suitable fatty acids that is used for parenteral administration comprises oleic acid, stearic acid and isostearic acid.Ethyl oleate and isopropyl myristate are the examples of suitable fatty acids ester.
The suitable soap class that is used for parenteral administration comprises fatty acid alkali metal, ammonium and triethanolamine salt, and suitable detergent comprises: (a) cationic detegent, such as dimethyl dialkyl ammonium halide (dimethyl dialkylammonium halides) and halogenated alkyl pyridine (alkyl pyridinium halides); (b) anionic detergent, such as alkylsulfonate, arylsulphonate and sulfonic acid alkene ester, alkyl sulfate, olefin sulfate, ether sulfate and sulphuric acid monoglyceride salt, and alkyl sulfo succinate, alkene sulfosuccinate, ether sulfosuccinic hydrochlorate and 2-Sulfosuccinic acid monoglyceride, (c) nonionic detergent, such as, fatty amine oxide, Marlamid and polyoxyethylene polypropylene copolymer, (d) ampholytic detergent, such as, alkyl-Beta-alanine salt and 2-alkyl-imidazoline quaternary ammonium salt and (e) their mixture.
Parenteral administration contains about active component of 0.5 to about 25wt% usually in solution.Can use antiseptic and buffer agent.In order to minimize or eliminate the stimulation in the injection site, this based composition can contain one or more hydrophile-lipophile balance values (HLB) and be about 12 to about 17 non-ionic surface active agent.The amount of the surfactant in this type of preparation will change to about 15wt% scope about 5 usually.Suitable surfactant comprises the polyethylene sorbitan fatty ester, such as dehydrating sorbitol monooleate, and the high molecular weight adducts of oxirane and hydrophobic alkali, by the condensation formation of expoxy propane and propylene glycol.Parenteral administration can provide in container such as the ampoule of unit dose or multiple dose sealing and bottle, and can be stored under lyophilization (freeze dried) environment, only needs just to add before using sterile liquid excipient, for example water for injection.Interim injection solution and suspension can be from sterile powder, granule and the preparation tablets of aforementioned type.
Pharmaceutically acceptable salt
The pharmaceutically acceptable salt of this chemical compound---when they can be produced---is also intended to be covered by the present invention.These salt will be acceptable those salt when it is applied to medicinal usage.This means that described salt will keep the biological activity of parent compound, and described salt will can not have in its treatment application of disease and purposes or deleterious effects bad.
Pharmaceutically acceptable salt prepares with standard mode.If parent compound is an alkali, it is handled in suitable solvent with excessive organic or inorganic acid.If parent compound is acid, it is handled in suitable solvent with inorganic or organic base.
Chemical compound of the present invention can be common with pharmaceutically acceptable carrier or excipient with the form of its alkali metal or alkali salt with effective dose, simultaneously or use, no matter use with the form of its pharmaceutical composition especially and preferably, be by oral, rectum or by parenteral (comprising subcutaneous) approach.
Pharmaceutically acceptable salt is meant any salt of described chemical compound.Particularly, it is meant pharmaceutically-acceptable acid addition.The pharmaceutically-acceptable acid addition of chemical compound comprises the salt from nontoxic mineral acid---all example hydrochloric acids of described nontoxic mineral acid, nitric acid, phosphoric acid, sulphuric acid, hydrobromic acid, hydroiodic acid, Fluohydric acid., phosphorous acid etc., and the deutero-salt of non-toxic organic acid, alkanoic acid, hydroxyl alkane acid, alkanedioic acid, aromatic acid, aliphatic series and aromatic sulfonic acid etc. that described non-toxic organic acid such as aliphatic monocarboxylic acid or dicarboxylic acids, phenyl replace.Therefore this type of salt comprise sulfate, pyrosulfate, disulfate, sulphite, bisulfites, nitrate, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chloro benzoate, ar-Toluic acid salt, dinitro-benzoate, phthalate, benzene sulfonate, toluene fulfonate, phenylacetic acid salt, citrate, lactate, maleate, tartrate, mesylate etc.
pH
An aspect of of the present present invention is about the pH of medicine.The pH of medicine depends on form of medication, because the pH of medicine preferably is fit to selected route of administration.Embodiments of the present invention comprise the medicine of pH between pH5 and pH9 of compositions, such as between pH5.5 and 8.5, such as between pH6 and 8, such as between pH6.5 and 7.5.Most preferably, the pH of medicine will select according to the tissue that route of administration and this medicine are used.
Indication
The invention provides the chemical compound of the ischemic medicine that is used for the production for treating individuality.Ischemia can occur owing to various environment, and therefore treating the ischemia that is caused by multiple medical indications is purpose of the present invention.
These indications include but not limited to: cardiovascular disease, such as myocardial infarction, heart beating stop, apoplexy, aneurysm, subarachnoid hemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, arrhythmia, megalocardia, cardiomyopathy, heart valve regurgitation and heart valve stenosis, perinatal asphyxia and non-perinatal asphyxia and traumatic brain injury.
Target temperature and peak effect
The target temperature of medicine is a central body temperature, its can use opened according to drug effect, dosage etc. according to medicine of the present invention after reach.Dropping on various scopes in the scope of the invention and concrete low temperature central body temperature equals as can inductive temperature at the cited chemical compound of hypothermia part itself.
Therefore an embodiment of the invention are to comprise in the scope that hypothermia can be induced between 36 to 31 ℃, and the more preferably medicine of the chemical compound of the present invention in the scope between 34 and 32 ℃.
Chemical compound of the present invention showed the peak value of hypothermia inductive effect in 30 minutes to 120 minutes after the administration of being everlasting, but might be than reach peak value thus at interval earlier described or more lately.The hypothermia inductive effect will usually continue 1 hour to 12 hours, but might continue the shorter or longer time than described at interval thus.
An object of the present invention is to provide the medicine that is suitable for to induce the hypothermic medicine of long or weak point persistent period apace and is suitable for slowly reducing body length or the central temperature of short persistent period.
Therefore embodiments of the present invention are hypothermia can be induced under 36 ℃, under 35.5 ℃, under 35 ℃, under 34.5 ℃, under 34.0 ℃, in its scope between 36 ℃ to 32 ℃, the more preferably medicine between 35 ℃ and 33 ℃.
Administration
In Therapeutic Method, the main path of drug conveying be intravenous, per os with partial, as described in will be below.Also consider the other drug application process, such as subcutaneous injection or by sucking, it is introduced drug conveying in the blood flow to target site or with medicine effectively.
The mucosa that pharmaceutical preparation of the present invention is used can be any mucosa that will use the individuality of bioactive substance, for example, at the mucosa of nose, vagina, eye, mouth, reproductive tract, lung, gastrointestinal tract or rectum, the mucosa of preferred nose, mouth or rectum.
Chemical compound of the present invention can be by parenteral administration, just by in intravenous, intramuscular, the spinal column, subcutaneous, intranasal, internal rectum, intravaginal or intraperitoneal use.Being used for this type of dosage forms of using can prepare by routine techniques.Chemical compound also can be used by sucking, and promptly sucks by intranasal and per os and uses.Being used for this type of dosage forms of using such as aerosol preparations or dosing inhalant can prepare by routine techniques.
Can use with at least a other chemical compounds according to chemical compound of the present invention.Chemical compound can or be combined in the unit dosage form with independent preparation and be used simultaneously, is perhaps used in proper order.
Preferred implementation of the present invention is by injection, suppository, oral, Sublingual tablet or spraying, percutaneous drug delivery or sucks the medicine of using.More preferably, administration form is by injection, wherein this injection be in the intravenous, intramuscular, spinal column, intraperitoneal, subcutaneous, bullet or continuous administration.
Some novel vanilloid receptor agonist can be used as stimulant under specific environment.Therefore, depend on the given activity material, chemical compound of the present invention can be preferably as capsule rather than tablet or suppository administration, and preferably as intravenous injection liquid rather than subcutaneous or intramuscular injection administration.
Individual
The individuality of using that can have benefited from medicine as described herein can be to suffer from ischemia or be in the individuality of suffering under the ischemia risk.Suffer under the ischemic risk if described individuality is in, the preferred form of medication of medicine can be suppository, oral or suction.Preferably, described individuality is to suffer from ischemic individuality.For suffering from ischemic individuality, preferred form of medication is injection, such as in intravenous, intramuscular, the spinal column, intraperitoneal or subcutaneous injection.
Individuality can be human, sex, baby or old people.Whether the ischemic conditions of waiting to be treated in individuality or preventing can have disease of taking a disease or disease with age of individuality, individual general health and individuality, and the history of past illness of---it can or induce ischemic conditions in individuality---is relevant.
Dosage
Dosage according to chemical compound of the present invention depends on described chemical compound; Yet the amount of chemical compound is also formed with the medicine of medicine, any second active component of any second chemical compound of medicine or medicine is closely related.
For all application processes at this disclosed chemical compound, a day oral administration scheme will be preferably from about 0.01 to about 80mg/kg TBW.Day parenteral scheme will be to about 80mg/kg TBW from about 0.001.
For all application processes at this disclosed chemical compound, a day oral administration scheme will be preferably from about 0.01 to about 80mg/kg TBW.Day parenteral scheme will be from about 0.01 to about 2, the 400mg/kg TBW, preferably, according to the dosage of medicine of the present invention between 10 μ g to 10mg/kg TBWs, between 100 μ g to 1mg/kg TBWs, this depends on selected chemical compound.Have been found that the Rhizoma et radix valerianae element changes at the effectiveness of receptor and affinity and at molecular weight.
For any other receptor agonist compounds according to the present invention, accurate dose can be calculated based on the pig study model described in the embodiment 14.
Term " unit dosage form " is meant the unit of the physical separation of the single dose that is suitable as the humans and animals individuality as used herein, per unit contain independent or with the chemical compound of the scheduled volume of other combinations of substances, its amount is calculated to be enough to producing desired effects, and in conjunction with pharmaceutically acceptable diluent, carrier or excipient.The specification of unit dosage form of the present invention depend on the particular compound that adopted or multiple chemical compound and the effect that will realize and with the host in the relevant pharmacodynamics of each chemical compound.The dosage of being used should be " effective dose " or reach " effect level " required amount in individual patient.
Because " effect level (effective level) " is used as the preferred terminal point of administration, therefore actual dosage and scheme can change, and this depends between the individuality in pharmacokinetics, drug distribution and metabolic difference." effect level " for example for example can be defined as corresponding to according to the blood of expecting in individuality of one or more compound concentrations of the present invention or organize level.Effect level also can be defined as the required consumption of every kg body weight, in other words, need reach the concentration of peak effect for certain drug.In addition, effect level depends on the severity of ischemic conditions, such as experience hypoxia or the anoxybiotic persistent period of organizing total amount, ischemic conditions, no matter its be individual first or the outbreak of ischemia subsequently or the like.
More preferably, according to the dosage of medicine of the present invention between 10 μ g to 80mg/kg TBWs, between 100 μ g to 1mg/kg TBWs.
Dosage and treatment time
According to the speed of the effectiveness of chemical compound/medicine, the target temperature that will reach, compound effects, the metabolic stability of chemical compound, the persistent period of treatment and the optimum frequency that medicine is given, medicine can be used with any proper dosage scheme.
Provide within the scope of the invention, such as 1 to 47 hour, 2 to 45 hours, 3 to 43 hours, 4 to 41 hours, 5 to 39 hours, 6 to 37 hours, 7 to 35 hours, 8 to 33 hours, 9 to 31 hours, 10 to 29 hours, 11 to 27 hours, 12 to 25 hours, 13 to 23 hours, 14 to 21 hours, 15 to 19 hours, 16 to 18 hours with the medicine used at interval in 30 minutes to 48 hours.Provide also within the scope of the invention, such as the interval of 1 to 23 hour, 2 to 22 hours, 3 to 20 hours, 4 to 18 hours, 5 to 16 hours, 6 to 14 hours, 7 to 12 hours or 8 to 10 hours with the medicine used at interval in 30 minutes to 24 hours.Preferably, with 1 to 6 hour interval administration, such as 2 to 5 hours, 3 to 4 hours.
Best dosing interval depends on the persistent period of hypothermia treatment.The persistent period of treatment is depended on severity and other factors of ischemic conditions.Provide and induce hypothermic medicine within the scope of the invention, wherein Zhi Liao persistent period is 6 to 72 hours, such as 7 to 69 hours, such as 8 to 66 hours, 9 to 63 hours, 10 to 60 hours, 11 to 57 hours, 12 to 54 hours, 13 to 51 hours, 14 to 48 hours, 15 to 45 hours, 16 to 42 hours, 17 to 39 hours, 18 to 36 hours, 1 to 35 hour, 20 to 32 hours, 21 to 29 hours, 22 to 26 hours, 23 to 25 hours.Preferably, the persistent period of treatment is between 6 and 48 hours, more preferably between 6 and 24 hours.
Polyvoltine compound medicine
Target of the present invention provides can induce hypothermic chemical compound in individuality.The hypothermic feature that depends on chemical compound of inducing---and these features can be the target temperature that reaches different or different target temperature ranges, reach target temperature (different peak effect times) with various speed, the inductive hypothermic persistent period, the life-span of reactive compound etc.Therefore, target of the present invention provides and comprises more than one chemical compounds as described herein, such as the medicine of at least two kinds, at least three kinds or at least four kinds chemical compounds.
Therefore described medicine can comprise chemical compound of the present invention, and wherein at least a chemical compound is induced hypothermia rapidly, or wherein at least a alternatively chemical compound is induced hypothermia at a slow speed.Medicine can comprise at least a hypothermic chemical compound of inducing in cycle long period in addition, and optionally wherein at least a chemical compound is induced the hypothermia of short time.
Second active component
An embodiment of the invention are to comprise chemical compound as described herein and the pharmaceutical composition that further comprises second active component.Second active component can increase the hypothermia effect of The compounds of this invention, perhaps can have optional medical function, alleviates or vasodilation such as induction pain.
Therefore second active component can be selected from the indefiniteness group: cannabinoid, neurotensin, analgesic, opioid, GABAs and 1 adrenergic antagonists.
These example includes but not limited to: (the arachidonic acid ethanolamine is the agonist of Cannabined receptor CB1 and novel vanilloid receptor VR1 to cannabinoid such as arachidonic acid ethanolamine, therefore and be called as cannabinoid and capsaicin/novel vanilloid receptor agonist), δ-9-THC, δ-8-THC, cannabidiol, HU210, BAY38-7271, WIN 55,212 and CP55940, phosphate derivative and neurotensin peptide analogues KK13 and KK14 with these chemical compounds.
The component test kit
Another embodiment of the present invention comprises the component test kit, wherein said test kit comprise at least a according to above-mentioned pharmaceutical composition, be used to use the instrument of described vaccine and the description how to use.Comprise the same combination of multiple dose or several different compositions within the scope of the invention.One preferred embodiment in, the component test kit further comprises second active component.
Embodiment
Embodiment 1-heart beating stops
Women of 57 years old no sign collapse (collapsed) ventricular fibrillation took place in about afterwards 5 minutes, find that her rescue personnel nurses her.Patient's quilt is defibrillation immediately, and occurs from major cycle and ventilation.When arriving hospital, collapsed back 21 minutes, the patient has had palp pulse.The medical worker of emergency room awaits orders in advance.The patient is estimated, and the attending doctor determines the patient should accept hypothermia treatment at once, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (AHA (American Heart Association) suggestion at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 2-heart beating stops
A sportsman of 22 years old collapses when motion.The medical worker finds about 6 minutes generation ventricular fibrillation/ventricular tachycardias after collapse.He is delivered to hospital rapidly by defibrillation successfully and this patient, and in ambulance, the doctor in the ambulance corps determines the patient should accept the hypothermia treatment at once, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 3-heart beating stops
A man of 66 years old operation on heart of selecting a time.Arrhythmia has taken place in him during operation technique, and causes heart beating to stop, and circulates impaired nearly 6 minutes, and surgical team manages to recover circulation afterwards.After recovering circulation, the surgeon determines the patient should accept the hypothermia treatment at once immediately, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 4-heart beating stops
An electrician unexpectedly has been subjected to impacting with high pressure and has also fallen into a coma immediately.The doctor of company manages the patient that heart beating stops to be recovered after 7 minutes.The patient is by the anxious hospital that delivers to, and the doctor in charge there determines the patient should accept the hypothermia treatment at once, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 5-perinatal asphyxia
Because of its cervical region of cord entanglement, a neonate is suffered from cerebral ischemia in birth process.10 minutes APGAR scoring is 6 after the childbirth.The doctor in charge estimates the patient, and the decision patient should accept the hypothermia treatment at once, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 6-suffocates
9 years old boy is in the stupor when being saved out from incendiary house.Begin CRP then and there, but when ambulance travelled back arrival hospital at 15 minutes, he did not revive.The patient is estimated, and the doctor in charge determines the patient should accept the hypothermia treatment at once, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 7-apoplexy
Left arm and the stiff and difficulty speaking of left lower limb appear suddenly in 78 years old woman, are admitted to hospital after 50 minutes.Whole right side of body is sent to hospital when occurring numb and weak 1 hour 30 minutes afterwards.The patient is diagnosed as apoplexy.The patient is estimated, and the doctor in charge determines the patient should accept the hypothermia treatment at once, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 8-apoplexy
Constant pain takes place at its head rear portion and collapses suddenly and fall into a coma after two weeks in 29 years old man.This patient is diagnosed as apoplexy.The patient is estimated, and the doctor in charge determines the patient should accept the hypothermia treatment at once, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 9-myocardial infarction
55 years old man is being taken place to feel sick, had been admitted to hospital in 18 minutes after rapid breathing and the serious chest pain.This patient suffers from myocardial infarction, and the doctor in charge estimates this patient, and the decision patient should accept the hypothermia treatment at once, to minimize the risk that heart and its hetero-organization is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 10-traumatic brain injury
41 years old man's head be subjected to on-site the falling serious bump of fragment of brick.When this patient remains loss of consciousness when wound was brought into emergency room in back 24 minutes.The patient is estimated, and the doctor in charge determines the patient should accept the hypothermia treatment at once, to minimize the risk that brain is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
Embodiment 11-pulmonary infarction
60 years old woman felt good after major operation in 2 days, but she precepitates into stupor.This causes by pulmonary infarction, after emergency operation, and stable disease.The patient is estimated, and the doctor in charge determines the patient should accept the hypothermia treatment at once, to minimize the risk that brain and its hetero-organization is caused damage.Give subcutaneous or vein bolus injection chemical compound of the present invention.Dosage is probably in the interval of 0.01mg/kg to 80mg/kg.
The purpose of hypothermia treatment is to reduce patient's central body temperature to 32-34 degree centigrade, keeps 12 to 24 hours (suggestion of AHA at present).Depend on individual reaction, may need additional bolus injection 1-8 time Drug therapy.
The treatment of carrying out simultaneously in hospital and check the influence of not used the hypothermia induced drug.Do not interrupt carrying out these other treatment and inspection.
The rabbit pyrogenicity test of embodiment 12-improvement
Various active substances with low, in and high dose on 3 rabbits, initially screen.After giving active substance, measured temperature, blood pressure, pulse 72 hours.These parameters are with following record:
Continuous record (time=0-3h),
Per 30 minutes (time=3-6h),
Per 1 hour (time=6-12h),
Per 2 hours (time=12-24h),
Per 6 hours (time=24-48h),
Per 12 hours (time=48-72h)
These are details of initial screening:
Rabbit kind: New Zealand white rabbit, Charles River
Weight:〉1.5kg
Sex: female
Room temperature: 21 ℃ (+/-1 ℃)
Relative humidity: 55% (+/-5%)
Temperature probe type: the thermal source detection system of PC base, Ellab APT 91
Cage type: Pro Plast Noryl, 2475cm2
The quantity of rabbit in one cage: 1
Water and food intake: ad libitum access and drinking-water in the cage.
12-hour illumination period: be
The research of embodiment 13-receptor
Use FLIPR and the HEK293 cell (being respectively hTRPV1-HEK293 and rTRPV1-HEK293) of stably express recombined human and rat TRPV1 to come in the active adjusting of in-vitro evaluation TRPV1 by the Ca2+ flow of measuring the novel vanilloid receptor agonist induction.To measure Ca2+ level in the cell in the TRPV1-express cell with the chemical compound period of contact.The interior stream of Ca2+ that end user and rat cell system all can observe concentration dependent increases.By with its with by the inductive maximum effect of relatively estimating agonist of reacting of capsaicin institute.
Embodiment 14-pig study model
In order to estimate effective hypothermia dosage, can in the pig study model, test this chemical compound according to receptor agonist compounds of the present invention.Use pig model to be because body weight of pig and people's body weight is suitable.The effect of the chemical compound of testing in pig model can be associated with the effect of the plain chemical compound of the Rhizoma et radix valerianae of testing in identical pig study model.
Object of study
In body weight is " Denmark head white (dansk landrace) " enterprising evaluation row of pig of 70-90 kilogram.Pig does not give tranquilizer; They one day by twice of feeding; And make their experience by seeing light 12 hours dark day-night cycle of forming then in 12 hours.
Medicament administration
The plain chemical compound of the Rhizoma et radix valerianae of being studied is used with the bolus injection intravenous, and can be made up of single injection, carries out 2-4 duplicate injection in initial injection in 24 hours time alternatively.
Usually, 4 various dose that produce low-temp reaction are in various degree added that carrier tests.
The hypothermia effect
The main effects of being estimated is a hypothermia.Utilize temperature probe to measure temperature, be placed in the femoral artery by surgical operation at this temperature probe of the last fortnight of studying beginning.Probe links to each other with remote-measuring equipment (for example, from the telemeter of the implantation of Data Sciences International), guarantees the data read that needs.
Before giving from medicine 1 hour after medicine gives 12 hours, per 15 minutes take temperatures, and 24 hours per 30 minutes take temperatures after medicine gives subsequently.Temperature survey will be undertaken by fixed femoral artery temperature probe (telemetry).
For the Rhizoma et radix valerianae plain record minimum temperature of every kind of dosage and the temperature chart of each measurement point.
Other effects
Before the drug administration 1 hour after drug administration 12 hours, per 15 minutes recording blood pressures, heart rate and ECG, and after drug administration 24 hours subsequently, per 30 minutes recording blood pressures, heart rate and ECG.
List of references
(1)Busto?R，Dietrich?WD，Globus?MY，Valdes?I，Scheinberg?P，Ginsberg?MD：Smalldifferences?in?intraischemic?brain?temperature?critically?determine?the?extent?ofischemic?neuronal?injury.J?Cereb?Blood?Flow?Metab?1987；7(6)：729-738.
(2)Barone?FC，Feuerstein?GZ，White?RF：Brain?cooling?during?transient?focalischemia?provides?complete?neuroprotection.Neurosci?Biobehav?Rev?1997；21(1)：31-44.
(3)Onesti?ST，Baker?CJ，Sun?PP，Solomon?RA：Transient?hypothermia?reduces?focalischemic?brain?injury?in?the?rat.Neurosurgery?1991；29(3)：369-373.
(4)Coimbra?C，Wieloch?T：Moderate?hypothermia?mitigates?neuronal?damage?in?therat?brain?when?initiated?several?hours?following?transient?cerebral?ischemia.ActaNeuropathol(Berl)1994；87(4)：325-331.
(5)Zhang?Y，Wong?KC，Zhang?Z：The?effect?of?intraischemic?mild?hypothermia?onfocal?cerebral?ischemia/reperfusion?injury.Acta?Anaesthesiol?Sin?2001；39(2)：65-69.
(6)Yamashita?K，Eguchi?Y，Kajiwara?K，Ito?H：Mild?hypothermia?amelioratesubiquitin?synthesis?and?prevents?delayed?neuronal?death?in?the?gerbil?hippocampus.Stroke?1991；22(12)：1574-1581.
(7)Ooboshi?H，Ibayashi?S，Takano?K，Sadoshima?S，Kondo?A，Uchimura?H，Fujishima?M：Hypothermia?inhibits?ischemia-induced?efflux?of?amino?acids?andneuronal?damage?in?the?hippocampus?of?aged?rats.Brain?Res?2000；884(1--2)：23-30.
(8)Colbourne?F，Corbett?D，Zhao?Z，Yang?J，Buchan?AM：Prolonged?but?delayedpostischemic?hypothermia：a?long-term?outcome?study?in?the?rat?middle?cerebralartery?occlusion?model.J?Cereb?Blood?Flow?Metab?2000；20(12)：1702-1708.
(9)Kawai?N，Okauchi?M，Morisaki?K，Nagao?S：Effects?of?delayed?intraischemic?andpostischemic?hypothermia?on?a?focal?model?of?transient?cerebral?ischemia?in?rats.Stroke?2000；31(8)：1982-1989.
(10)Maier?CM，Sun?GH，Kunis?D，Yenari?MA，Steinberg?GK：Delayed?induction?andlong-term?effects?of?mild?hypothermia?in?a?focal?model?of?transient?cerebral?ischemia：neurological?outcome?and?infarct?size.J?Neurosurg?2001；94(1)：90-96.
(11)Maier?CM，Ahern?K，Cheng?ML，Lee?JE，Yenari?MA，Steinberg?GK：Optimaldepth?and?duration?of?mild?hypothermia?in?a?focal?model?of?transient?cerebralischemia：effects?on?neurologic?outcome，infarct?size，apoptosis，and?inflammation.Stroke?1998；29(10)：2171-2180.
(12)Mild?therapeutic?hypothermia?to?improve?the?neurologic?outcome?after?cardiacarrest：N?Engl?J?Med?2002；346(8)：549-556.
(13)Bernard?SA，Gray?TW，Buist?MD，Jones?BM，Silvester?W，Gutteridge?G，SmithK：Treatment?of?comatose?survivors?of?out-of-hospital?cardiac?arrest?with?inducedhypothermia.N?Engl?J?Med?2002；346(8)：557-563.
(14)Bernard?S：Therapeutic?hypothermia?after?cardiac?arrest：now?a?standard?of?care.Crit?Care?Med?2006；34(3)：923-924.
(15)Dietrich?WD，Halley?M，Valdes?I，Busto?R：Interrelationships?between?increasedvascular?permeability?and?acute?neuronal?damage?following?temperature-controlledbrain?ischemia?in?rats.Acta?Neuropathol(Berl)1991；81(6)：615-625.
(16)Karibe?H，Zarow?GJ，Graham?SH，Weinstein?PR：Mild?intraischemichypothermia?reduces?postischemic?hyperperfusion，delayed?postischemichypoperfusion，blood-brain?barrier?disruption，brain?edema，and?neuronal?damagevolume?after?temporary?focal?cerebral?ischemia?in?rats.J?Cereb?Blood?Flow?Metab1994；14(4)：620-627.
(17)Huang?ZG，Xue?D，Preston?E，Karbalai?H，Buchan?AM：Biphasic?opening?of?theblood-brain?barrier?following?transient?focal?ischemia：effects?of?hypothermia.Can?JNeurol?Sci?1999；26(4)：298-304.
(18)Bagenholm?R，Nilsson?UA，Kjellmer?I：Formation?offree?radicals?in?hypoxicischemic?brain?damage?in?the?neonatal?rat，assessed?by?an?endogenous?spin?trap?andlipid?peroxidation.Brain?Res?1997；773(1-2)：132-138.
(19)Kil?HY，Zhang?J，Piantadosi?CA：Brain?temperature?alters?hydroxyl?radicalproduction?during?cerebral?ischemia/reperfusion?in?rats.J?Cereb?Blood?Flow?Metab1996；16(1)：100-106.
(20)Kumura?E，Yoshimine?T，Takaoka?M，Hayakawa?T，Shiga?T，Kosaka?H：Hypothermia?suppresses?nitric?oxide?elevation?during?reperfusion?after?focal?cerebralischemia?in?rats.Neurosci?Lett?1996；220(1)：45-48.
(21)Baker?AJ，Zornow?MH，Grafe?MR，Scheller?MS，Skilling?SR，Smullin?DH，Larson?AA：Hypothermia?prevents?ischemia-induced?increases?in?hippocampalglycine?concentrations?in?rabbits.Stroke?1991；22(5)：666-673.
(22)Takagi?K，Ginsberg?MD，Globus?MY，Dietrich?WD，Martinez?E，Kraydieh?S，Busto?R：Changes?in?amino?acid?neurotransmitters?and?cerebral?blood?flow?in?theischemic?penumbral?region?following?middle?cerebral?artery?occlusion?in?the?rat：correlation?with?histopathology.J?Cereb?Blood?Flow?Metab?1993；13(4)：575-585.
(23)Nakashima?K，Todd?MM：Effects?of?hypothermia?on?the?rate?of?excitatory?aminoacid?release?after?ischemic?depolarization.Stroke?1996；27(5)：913-918.
(24)Maier?CM，Sun?GH，Cheng?D，Yenari?MA，Chan?PH，Steinberg?GK：Effects?ofmild?hypothermia?on?superoxide?anion?production，superoxide?dismutase?expression，and?activity?following?transient?focal?cerebral?ischemia.Neurobiol?Dis?2002；11(1)：28-42.
(25)Pulsinelli?W：Pathophysiology?of?acute?ischaemic?stroke.Lancet?1992；339(8792)：533-536.
(26)Eguchi?Y，Yamashita?K，Iwamoto?T，Ito?H：Effects?of?brain?temperature?oncalmodulin?and?microtubule-associated?protein?2?immunoreactivity?in?the?gerbilhippocampus?following?transient?forebrain?ischemia.J?Neurotrauma?1997；14(2)：109-118.
(27)Sick?TJ，Tang?R，Perez-Pinzon?MA：Cerebral?blood?flow?does?not?mediate?theeffect?of?brain?temperature?on?recovery?of?extracellular?potassium?ion?activity?aftertransient?focal?ischemia?in?the?rat.Brain?Res?1999；821(2)：400-406.
(28)Hu?BR，Kamme?F，Wieloch?T：Alterations?of?Ca2+/calmodulin-dependentprotein?kinase?II?and?its?messenger?RNA?in?the?rat?hippocampus?following?normo-and?hypothermic?ischemia.Neuroscience?1995；68(4)：1003-1016.
(29)Busto?R，Globus?MY，Neary?JT，Ginsberg?MD：Regional?alterations?of?proteinkinase?C?activity?following?transient?cerebral?ischemia：effects?of?intraischemic?braintemperature?modulation.J?Neurochem?1994；63(3)：1095-1103.
(30)Ishikawa?M，Sekizuka?E，Sato?S，Yamaguchi?N，Inamasu?J，Bertalanffy?H，Kawase?T，Iadecola?C：Effects?of?moderate?hypothermia?on?leukocyte-endotheliuminteraction?in?the?rat?pial?microvasculature?after?transient?middle?cerebral?arteryocclusion.Stroke?1999；30(8)：1679-1686.
(31)Inamasu?J，Suga?S，Sato?S，Horiguchi?T，Akaji?K，Mayanagi?K，Kawase?T：Post-ischemic?hypothermia?delayed?neutrophil?accumulation?and?microglialactivation?following?transient?focal?ischemia?in?rats.J?Neuroimmunol?2000；109(2)：66-74.
(32)Hara?A，Niwa?M，Iwai?T，Yano?H，Bunai?Y，Uematsu?T，Yoshimi?N，Mori?H：Increase?of?fragmented?DNA?transport?in?apical?dendrites?of?gerbil?CA1?pyramidalneurons?following?transient?forebrain?ischemia?by?mild?hypothermia.Neurosci?Lett2000；280(1)：73-77.
(33)Xu?L，Yenari?MA，Steinberg?GK，Giffard?RG：Mild?hypothermia?redueesapoptosis?of?mouse?neurons?in?vitro?early?in?the?cascade.J?Cereb?Blood?Flow?Metab2002；22(1)：21-28.
(34)Zhang?Z，Sobel?RA，Cheng?D，Steinberg?GK，Yenari?MA：Mild?hypothermiaincreases?Bcl-2?protein?expression?following?global?cerebral?ischemia.Brain?Res?MolBram?Res?2001；95(1-2)：75-85.
(35)Niwa?M，Hara?A，Iwai?T，Nakashima?M，Yano?H，Yoshimi?N，Mori?H，Uematsu?T：Relationship?between?magnitude?of?hypothermia?during?ischemia?and?preventiveeffect?against?post-ischemic?DNA?fragmentation?in?the?gerbil?hippocampus.BrainRes?1998；794(2)：338-342.
(36)Inamasu?J，Suga?S，Sato?S，Horiguchi?T，Akaji?K，Mayanagi?K，Kawase?T：Postischemic?hypothermia?attenuates?apoptotic?cell?death?in?transient?focal?ischemiain?rats.Acta?Neurochir?Suppl?2000；76：525-527.
(37)Silva?C，Silva?J，Ribeiro?MJ，Avelino?A，Cruz?F：Urodynamic?effect?ofintravesi-cal?resiniferatoxin?in?patients?with?neurogenic?detrusor?overactivity?of?spinalorigin：results?of?a?double-blind?randomized?placebo-controlled?trial.Eur?Urol?2005；48(4)：650-655.
(38)Payne?CK，Mosbaugh?PG，Forrest?JB，Evans?RJ，Whitmore?KE，Antoci?JP，Perez-Marrero?R，Jacoby?K，Diokno?AC，O′Reilly?KJ，Griebling?TL，Vasavada?SP，YuAS，Frumkin?LR：Intravesical?resiniferatoxin?for?the?treatment?ofinterstitial?cystitis：arandomized，double-blind，placebo?controlled?trial.J?Urol?2005；173(5)：1590-1594.
(39)Kim?JH，Rivas?DA，Shenot?PJ，Green?B，Kennelly?M，Erickson?JR，O′Leary?M，Yoshimura?N，Chancellor?MB：Intravesical?resiniferatoxin?for?refractory?detrusorhy-perreflexia：a?multicenter，blinded，randomized，placebo-controlled?trial.J?SpinalCord?Med?2003；26(4)：358-363.
(40)Hayes?AG，Oxford?A，Reynolds?M，Shingler?AH，Skingle?M，Smith?C，Tyers?MB：The?effects?of?a?series?of?capsaicin?analogues?on?nociception?and?body?temperature?inthe?rat.Life?Sci?1984；34(13)：1241-1248.
(41)Woods?AJ，Stock?MJ，Gupta?AN，Wong?TT，Andrews?PL：Thermoregulatoryeffects?of?resiniferatoxin?in?the?rat.Eur?J?Pharmacol?1994；264(2)：125-133.
(42)Miller?MS，Brendel?K，Buck?SH，Burks?TF：Dihydrocapsaicin-inducedhypother-mia?and?substance?P?depletion.Eur?J?Pharmacol?1982；83(3-4)：289-292.
(43)Ding?Z，Cowan?A，Rawls?SM：Capsaicin?evokes?hypothermia?independent?ofcannabinoid?CB1?and?CB2?receptors.Brain?Res?2005；1065(1-2)：147-151.
(44)Jakab?B，Helyes?Z，Varga?A，Bolcskei?K，Szabo?A，Sandor?K，Elekes?K，BorzseiR，Keszthelyi?D，Pinter?E，Petho?G，Nemeth?J，Szolcsanyi?J：Pharmacologicalchar-acterization?of?the?TRPV1?receptor?antagonist?JYL1421(SC0030)in?vitro?andin?vivo?in?the?rat.Eur?J?Pharmacol?2005；517(1-2)：35-44.
(45)Swanson?DM，Dubin?AE，Shah?C，Nasser?N，Chang?L，Dax?SL，Jetter?M，Bre-itenbucher?JG，Liu?C，Mazur?C，Lord?B，Gonzales?L，Hoey?K，Rizzolio?M，Bogen-staetter?M，Codd?EE，Lee?DH，Zhang?SP，Chaplan?SR，Carruthers?NI：Identification?and?biological?evaluation?of4-(3-trifluoromethylpyridin-2-yl)piperazine-l-carboxylic?acid(5-trifluoromethylpyridin-2-yl)amide，a?high?affinity?TRPV1(VR1)vanilloidre-ceptor?antagonist.J?Med?Chem?2005；48(6)：1857-1872.

Claims (44)

1. a novel vanilloid receptor agonist is by inducing hypothermia to treat application in the ischemia of described individuality in individuality.
2. application of compound according to claim 1, wherein said chemical compound can be in conjunction with novel vanilloid receptor.
3. according to the application of compound of claim 1 and 2 described in each, wherein said chemical compound is the novel vanilloid receptor agonist that is selected from the group of classical novel vanilloid receptor agonist, non-classical novel vanilloid receptor agonist and other novel vanilloid receptor binding compounds.
4. according to the application of compound of claim 1 to 3 described in each, wherein said chemical compound is the classical or non-classical novel vanilloid receptor agonist with general formula (I):
Figure A200780037326C00021
Wherein R1 and R2 are chemical part or chemical bond.
5. as the defined application of compound of claim 4, wherein R1 is selected from group: C, S, N, O, its optional C that uses, S, N, O, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, sulfonyl or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And be preferably C, and it uses C, O, P, H, OH, phosphate, alkyl, thiazolinyl, alkynyl substituted, and any in them can be (C 1-C v), or be phenyl, in them any can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace, and any in them can further use methyl, ethyl or phenyl to replace; C more preferably, it is with alkyl, alkenyl substituted, and any in them can be (C 4-C W), any in them can further be used O, OH, methoxyl group, ethyoxyl or methyl substituted, and any in them can further use methyl, ethyl or phenyl to replace, and wherein V is 1 to 30 integer, and W is 5 to 18 integer.
6. as the defined application of compound of claim 4, wherein R2 is selected from group: C, S, N, O, it is optional with C, S, N, O, P, OH, hydrogen, alkoxyl, alkyl, thiazolinyl, alkynyl, phenyl, xenyl, benzyl, amine (NH), halogen, the low-carbon alkyl of replacement, thiazolinyl, aryl, Heterocyclylalkyl, heteroaryl, aryl-(C 1-4)-alkyl, heteroaryl-(C 1-4)-alkyl, heterocyclic radical-(C 1-4)-alkyl, cycloalkyl-alkyl, cycloalkyl, cycloalkenyl group or phosphate replace one or many or do not replace, and optionally further replace one or many with following radicals or do not replace: the low-carbon alkyl of C, S, N, O, P, OH, H, COOH, phenyl, amine (NH), halogen, alkoxyl, replacement, such as (C 1-C v) alkyl or alkenyl, cycloalkenyl group, sulfate, phosphate, aryl, heterocyclic radical, heteroaryl, aryl-(C 1-4)-alkyl, heteroaryl-(C 1-4)-alkyl, heterocyclic radical-(C 1-4)-alkyl, cycloalkyl-alkyl, bicyclic alkyl, tricyclic alkyl, cycloalkenyl group, alkoxyl, carboxyl, halogen, cyano group, amino, nitro or alcohol, any in them can further replace one or many with following radicals: OH, methyl, dimethyl, such as (C 1-C v) alkyl or alkenyl, alkoxyl, phenyl, sulfate, phosphate, aryl, heteroaryl, carboxyl, amino, nitro, alcohol or halogen; And be preferably C, it replaces one or many with following radicals: low-carbon alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group or the phosphate of C, N, O, P, OH, hydrogen, alkoxyl, alkyl, thiazolinyl, amine (NH), halogen, replacement optional further replace one or many with following radicals or do not replace: C, N, O, OH, COOH, hydrogen, amine (NH), halogen, alkoxyl, replacement such as (C 1-C x) low-carbon alkyl or thiazolinyl, phosphate, cycloalkenyl group, alkoxyl, carboxyl or halogen, they any can further replace one or many with following radicals: OH, methyl, dimethyl, such as (C 1-C x) alkyl or alkenyl, alkoxyl, phenyl, sulfate, phosphate, carboxyl or halogen; And C more preferably, it replaces once at least with following radicals: further replace twice cycloalkenyl group at least with in OH or the methoxyl group any, or such as (C 1-C 2) low-carbon alkyl, and further replace one or many with OH, COOH, chloride, methyl or cycloalkenyl group, randomly further replace one or many or do not replace, and wherein V is 1 to 30 integer, and X is 1 to 5 integer with OH or methoxyl group.
7. as the defined application of compound of claim 4, wherein R1 is C, and it uses C, O, P, H, OH, phosphate, alkyl, thiazolinyl, alkynyl substituted, and any in them can be (C 1-C v); or phenyl; in them any can further replace one or many with following radicals: O; OH; methyl; dimethyl; alkyl; thiazolinyl; cycloalkyl; Heterocyclylalkyl; cycloalkenyl group; acetyl group; phenyl; methoxyl group; ethyoxyl; alkoxyl or phosphate; in them any can further be used methyl; ethyl or phenyl replace; and R2 is C; it replaces one or many with following radicals: C; N; O; P; OH; hydrogen; alkoxyl; alkyl; thiazolinyl; amine (NH); halogen; the low-carbon alkyl that replaces; thiazolinyl; aryl; cycloalkyl; cycloalkenyl group or phosphate optional further replace one or many with following radicals or do not replace: C; N; O; OH; COOH; hydrogen; amine (NH); halogen; alkoxyl; replace such as (C 1-C x) low-carbon alkyl or thiazolinyl, phosphate, cycloalkenyl group, alkoxyl, carboxyl or halogen, any in them can further use OH, methyl, dimethyl, such as (C 1-C x) alkyl or alkenyl, alkoxyl, phenyl, sulfate, phosphate, carboxyl or halogen replace one or many, and wherein V is 1 to 30 integer, wherein X is 1 to 5 integer.
8. as the defined application of compound of claim 4, wherein R1 is C, and it uses alkyl, alkenyl substituted, and any in them can be (C 4-C W); in them any can further be used O, OH, acetyl group, methoxyl group, ethyoxyl or methyl substituted one or many; in them any can further use methyl, ethyl, cycloalkenyl group or phenyl to replace one or many; and W is from 5 to 18 integer; and R2 is C; it replaces once at least with following radicals: further replace twice cycloalkenyl group at least with in OH or the methoxyl group any, or such as (C 1-C 2) low-carbon alkyl, and further replace one or many with OH, COOH, chloride, methyl or cycloalkenyl group, optionally further replace one or many or do not replace with OH or methoxyl group.
9. according to the application of compound of claim 1 to 3 described in each, wherein said chemical compound is the non-classical novel vanilloid receptor agonist with general formula (II):
Figure A200780037326C00041
Wherein R1, R2, R3, R4, R5 and R6 are chemical part or chemical bond.
10. as the defined application of compound of claim 9, wherein R1 is selected from group: C, S, N, O, its optional C that uses, S, N, O, B, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted, they any can be or can not be branching or comprise such as phosphate, cycloalkyl, heterocyclic radical, heterocyclic group, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, sulfonyl or phenyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, heterocyclic group, in them any can be or can not be branching or comprise such as C, O, H, OH, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, the substituent group of phosphate, further use O, OH, methyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, further use alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, dimethyl or phenyl that heterocyclic radical replaces replace once at least, and be preferably C, it uses C, N, O, B, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, heterocyclic radical, heterocyclic group, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, heterocyclic group, in them any can be or can not be branching or comprise such as C, O, H, OH, methyl, ethyl, alkyl, thiazolinyl, alkoxyl, the substituent group of phosphate, further use O, OH, methyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group replaces once at least, further uses alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, heterocyclic radical replaces; And C more preferably, it can be (C4-C W) alkyl or alkenyl, B or form ring and comprise that thus the heterocyclic radical of pyrrolidine replaces with R6, further replace one or many with O, methyl, alicyclic group connected to one another, they are saturated or unsaturated, or comprise the heterocyclic group of described B, N and O, and further replace at least once with O, methyl or C, further replace at least once with cycloalkenyl group, cycloalkyl, heterocyclic radical, further replace at least once, further replace with low-carbon alkyl and cycloalkenyl group with O, OH, methyl, thiazolinyl; Wherein above-mentioned any can with R2, R3, R4, R5 and/or R6 in any form at least one key, and W is from 5 to 18 integer.
11. application of compound according to claim 9, wherein R2 is selected from group: C, S, N, O, its optional C that uses, S, N, O, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted or do not replace, they any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And being preferably the C that uses C, O, P, H, OH, phosphate, alkyl, thiazolinyl, alkynyl substituted, any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; And C more preferably, it replaces once at least with OH or hydrogen, and wherein above-mentioned any can with R1 and/or R3 in any form at least one key, and wherein V is 1 to 30 integer.
12. application of compound according to claim 9, wherein R3 is selected from group: C, S, N, O, its optional C that uses, S, N, O, B, P, OH, hydrogen, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And being preferably the C that uses C, O, P, H, OH, phosphate, acetyl group, alkoxyl, alkyl, alkenyl substituted, any in them can be (C 1-C v), or be phenyl, randomly replace or do not replace with O, OH, methyl, dimethyl, alkyl, thiazolinyl, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate; And more preferably use OH, methoxyl group, low-carbon alkyl (C1-C Y) C that replaces, and can form ring in the arbitrfary point with R4, and wherein above-mentioned any can with R2 and/or R4 in any form at least one key, and wherein V is 1 to 30 integer, and Y is 2 or 3 integer.
13. application of compound according to claim 9, wherein R4 is selected from group: C, S, N, O, its optional C that uses, S, N, O, B, P, OH, hydrogen, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And being preferably the C that uses C, O, P, H, OH, phosphate, acetyl group, alkoxyl, alkyl, alkenyl substituted, any in them can be (C 1-C V), or be phenyl, randomly replace or do not replace with O, OH, methyl, dimethyl, alkyl, thiazolinyl, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate; And more preferably use OH, methoxyl group, low-carbon alkyl (C1-C Y) C that replaces, and can form ring in the arbitrfary point with R4, and wherein above-mentioned any can with R2 and/or R4 in any form at least one key, and wherein X is 1 to 30 integer; And Y is 2 or 3 integer.
14. application of compound according to claim 9, wherein R5 is selected from group: C, S, N, O, its optional C that uses, S, N, O, P, OH, hydrogen, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, S, N, O, P, OH, CHO, hydrogen, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, sulfonyl or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, the substituent group of dimethyl or phenyl; And be preferably with C, O, P, H, OH, CHO, phosphate, alkyl, thiazolinyl and replace once C at least, any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; And the C that more preferably uses hydrogen, OH, CHO or methyl substituted one or many, it can form ring with R6, and wherein V is 1 to 30 integer.
15. application of compound according to claim 9, wherein R6 is selected from group: C, S, N, O, its optional C that uses, S, N, O, B, P, OH, CHO, hydrogen, alkyl, thiazolinyl, alkynyl substituted or do not replace, in them any can be or can not be branching or comprise such as phosphate, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, methyl, ethyl, dimethylated substituent group, perhaps can further replace one or many: C with following radicals, N, O, P, OH, methoxyl group, ethyoxyl, acetyl group, alkoxyl, alkyl, thiazolinyl, alkynyl, or phenyl, any in them can be or can not be branching or comprise such as hydrogen, methyl, ethyl, alkyl, thiazolinyl, alkynyl, alkoxyl, phosphate, the substituent group of dimethyl or phenyl; And being preferably the C that uses C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl substituted, any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; And more preferably use hydrogen, CHO, low-carbon alkyl (C1-C Y) or the C of methyl substituted one or many, it can form at least one key with R5, or form at least one key of ring with R1, wherein described at least one key between any among R1, R2, R3, R4 and/or the R5 can be singly-bound or two key, and wherein V is 1 to 30 integer; And Y is 2 or 3 integer.
16. application of compound according to claim 9; wherein R1 is C; it uses C; N; O; B; P; OH; hydrogen; alkyl; thiazolinyl; alkynyl substituted; in them any can be or can not be branching or comprise such as phosphate; cycloalkyl; Heterocyclylalkyl; heterocyclic radical; heterocyclic group; cycloalkenyl group; methyl; ethyl; dimethylated substituent group; perhaps can further replace one or many: C with following radicals; N; O; P; OH; methoxyl group; ethyoxyl; acetyl group; alkoxyl; alkyl; thiazolinyl; cycloalkyl; cycloalkenyl group; heterocyclic radical; heterocyclic group; in them any can be or can not be branching or comprise such as C; O; H; OH; methyl; ethyl; alkyl; thiazolinyl; alkoxyl; the substituent group of phosphate; further use O; OH; methyl; thiazolinyl; cycloalkyl; Heterocyclylalkyl; cycloalkenyl group replaces at least once; further use alkyl; thiazolinyl; cycloalkyl; cycloalkenyl group; heterocyclic radical replaces; above-mentioned any can with R2; and/or R6 forms key; and R2 is preferably and uses C; O; P; H; OH; phosphate; alkyl; thiazolinyl; the C of alkynyl substituted, any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; And R3 is preferably the C with C, O, P, H, OH, phosphate, acetyl group, alkoxyl, alkyl, alkenyl substituted, and any in them can be (C 1-C v); or be phenyl; in them any can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace; and R4 is preferably the C with C, O, P, H, OH, phosphate, acetyl group, alkoxyl, alkyl, alkenyl substituted, and any in them can be (C 1-C v), or be phenyl, choose wantonly with O, OH, methyl, dimethyl, alkyl, thiazolinyl, phenyl, methoxyl group, ethyoxyl, alkoxyl or phosphate and replace or do not replace, and R5 is preferably with C, O, P, H, OH, CHO, phosphate, alkyl, thiazolinyl and replaces once C at least, and any in them can be (C 1-C v), or be phenyl, in them any can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace, and R6 is preferably the C with C, O, P, H, OH, CHO, phosphate, alkyl, alkenyl substituted, and any in them can be (C 1-C v), or be phenyl, any in them can use O, OH, methyl, dimethyl, alkyl, thiazolinyl, methoxyl group, ethyoxyl, alkoxyl or phosphate to replace, and wherein V is 1 to 30 integer.
17. application of compound according to claim 9, wherein R1 is can be with (C4-C Z) the C that replaces of alkyl or alkenyl, boron or form ring with R6 and comprise the heterocyclic radical of pyrrolidine thus, further replace one or many with O, methyl, alicyclic group connected to one another, they are saturated or unsaturated, or comprise the heterocyclic group of described boron, N and O, and further replace at least once with O, methyl or C, or further replace at least once with cycloalkenyl group, cycloalkyl, heterocyclic radical, further replace at least once, further replace with low-carbon alkyl and cycloalkenyl group with O, OH, methyl, thiazolinyl; R2 is the C that replaces with OH or hydrogen; R3 is with OH, methoxyl group, low-carbon alkyl (C1-C Z) C that replaces, and can on any point, form ring with R4; R4 is with OH, methoxyl group, low-carbon alkyl (C1-C Z) C that replaces, and can on any point, form ring with R3; R5 is the C with hydrogen, OH, CHO or methyl substituted one or many, and it can form ring with R6; And R6 is the C with hydrogen, CHO, low-carbon alkyl (C1-Cz) or methyl substituted one or many, it can form at least one key with R5, or form ring with R1, wherein described at least one key between any among R1, R2, R3, R4, R5 and/or the R6 can be singly-bound or two key, and Y is 2 or 3 integer, and Z is 5 or 12 integer.
18. application according to claim 1, wherein said novel vanilloid receptor are TRPV1-6 and/or the receptor relevant with it.
19. application according to claim 1, wherein said novel vanilloid receptor is TRPV1.
20. according to the application of compound of claim 1 to 17 described in each, it is hydrophilic.
21. according to claim 4,9 and/or 20 described medicines according to the application of claim 1 to 3 described in each, described medicine is used for inducing hypothermia at the individuality of suffering from ischemia or being in ischemia danger.
22. according to the medicine of claim 4 to 21 described in each according to the application of claim 1 to 3 described in each, described medicine is used to prevent and/or treat with cardiovascular disease, suffocates and/or ischemia that traumatic brain injury is relevant.
23. according to claim 1 to 3 and/or 22 described application, wherein said ischemia causes by cardiovascular disease, described cardiovascular disease such as: myocardial infarction, heart beating stop, apoplexy, aneurysm, subarachnoid hemorrhage, arteriosclerosis, angina pectoris, hypertension, hypercholesterolemia, arrhythmia, megalocardia, cardiomyopathy, heart valve regurgitation and heart valve stenosis.
24. according to claim 1 to 3 and/or 22 described application, wherein said ischemia is by causing such as suffocating of perinatal asphyxia and/or non-perinatal asphyxia.
25. one kind comprises the medicine according to the chemical compound of claim 4 to 24 described in each, described chemical compound can be as claim 1 to 3 defined hypothermia of inducing in individuality in each.
26. medicine according to claim 25, it is used for preventative and/or therapeutic is used.
27. according to the medicine of claim 25 or 26 described in each, its being used for the treatment of property application.
28. according to the medicine of claim 25 to 27 described in each, the hypothermia between wherein said drug-induced 32-36 ℃.
29. according to the medicine of claim 25 to 28 described in each, it comprises at least two kinds according to the chemical compound of claim 4 to 24 described in each.
30. medicine according to claim 29, wherein at least a chemical compound is promptly induced hypothermia.
31. according to the medicine of claim 29 and 30 described in each, wherein at least a chemical compound is induced hypothermia lentamente.
32. according to the medicine of claim 25 to 31 described in each, it comprises second active component.
33. medicine according to claim 32, wherein said second active component is selected from group: cannabinoid, neurotensin, analgesic, opioid, GABA and 1 adrenergic antagonists.
34. according to the medicine of claim 25 to 33 described in each, it comprises pharmaceutically acceptable carrier.
35. according to the medicine of claim 25 to 34 described in each, the pH of wherein said compositions is between pH5 and pH9.
36. according to the medicine of claim 25 to 35 described in each, it is used for by injection, suppository, oral, sublingual tablet or spray, percutaneous drug delivery or sucks carrying out administration.
37. medicine according to claim 36, wherein said injection are in the intravenous, intramuscular, spinal column, intraperitoneal, subcutaneous, bullet or successive administration.
38. according to the medicine of claim 25 to 37 described in each, wherein dosing interval is 30 minutes to 48 hours.
39. according to the medicine of claim 25 to 38 described in each, wherein dosing interval is 1 to 6 hour.
40. according to the medicine of claim 25 to 39 described in each, the wherein said treatment persistent period is 6 to 72 hours.
41. according to the medicine of claim 25 to 40 described in each, the dosage of wherein said medicine is 10 μ g-80mg/ kg body weight.
42. a component test kit, it comprises as claim 25 to 41 defined medicine in each.
43. according to the chemical compound of claim 4 to 17 described in each in the application that is used for preparing the medicine of eliminating application according to claim 1.
44. an ischemic method for the treatment of the individuality that needs described treatment, it comprises and gives described individuality with the hypothermic novel vanilloid receptor agonist of can inducing of effective dose, described chemical compound such as claim 1 to 17 in each definition.
CNA200780037326XA 2006-10-04 2007-10-04 Use of hypothermia inducing drugs to treat ischemia Pending CN101522181A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DKPA200601289 2006-10-04
DKPA200601289 2006-10-04
DKPA200700335 2007-03-06

Publications (1)

Publication Number Publication Date
CN101522181A true CN101522181A (en) 2009-09-02

Family

ID=41082329

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA200780037326XA Pending CN101522181A (en) 2006-10-04 2007-10-04 Use of hypothermia inducing drugs to treat ischemia

Country Status (1)

Country Link
CN (1) CN101522181A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109562096A (en) * 2016-04-13 2019-04-02 内布拉斯加大学董事会 Apply the method for resin toxin and the method with resin toxin treatment cardiovascular disease

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109562096A (en) * 2016-04-13 2019-04-02 内布拉斯加大学董事会 Apply the method for resin toxin and the method with resin toxin treatment cardiovascular disease
AU2017248665B2 (en) * 2016-04-13 2023-01-05 Board Of Regents Of The University Of Nebraska Methods for administration and methods for treating cardiovascular diseases with resiniferatoxin

Similar Documents

Publication Publication Date Title
KR20090064435A (en) Use of hypothermia inducing drugs to treat ischemia
Sikiric et al. Brain-gut axis and pentadecapeptide BPC 157: Theoretical and practical implications
KR20090027689A (en) Use of cannabinoid receptor agonists as hypothermia inducing drugs for the treatment of ischemia
CN100448439C (en) Pharmaceutical compositions for headache, migraine, nausea and emesis
CN107427477A (en) 1,2,4 oxadiazoles and thiadiazole compound as immunomodulator
US20100029739A1 (en) Use of a combination of hypothermia inducing drugs
CN101589026A (en) Method of treatment of glioma brain tumour
WO2010015260A2 (en) Administration by infusion for the treatment of ischemic effects
CN104684901A (en) Cystathionine-y-gamma-lyase (cse) inhibitors
WO2009124552A2 (en) Use of a combination of hypothermia inducing drugs
CN109966293A (en) For inhibiting the NHE3 binding compounds and method of phosphate cotransporter
CN109152780A (en) For treating the CXCR-2 inhibitor of Crystal Arthropathy disease
Liu et al. Edaravone Ameliorates Cerebral Ischemia–Reperfusion Injury by Downregulating Ferroptosis via the Nrf2/FPN Pathway in Rats
WO2009071095A2 (en) Prevention of hyperthermia subsequent to hypothermia treatment of ischemia
KR20060013547A (en) Tissue protective cytokines for the protection, restoration, and enhancement of responsive cells, tissues and organs with an extended therapeutic window
WO2009071094A2 (en) Combination treatment of ischemic effects
CN101522181A (en) Use of hypothermia inducing drugs to treat ischemia
RU2536270C1 (en) Combination for correction of neurologic and psychoemotional status in case of organic cns disorders
CN101489548A (en) Use of cannabinoid receptor agonists as hypothermia inducing drugs for the treatment of ischemia
KR20150119439A (en) Inhibitors of na(v) 1.9 channel activity and uses thereof for treating pain
JP6475733B2 (en) Method for reducing neuronal cell death using haloalkylamine
JP6153838B2 (en) Vascular permeability inhibitor
US20190040101A1 (en) Compound for treating sequelae of ischemic cerebral stroke
WO2009124551A2 (en) Use of hypothermia inducing drugs
US20190201376A1 (en) Method for Treating or Preventing Fatty Acid Binding Protein 3 Induced B-amyloid Aggregation Diseases

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20090902