CN1946732A - Adenosine receptor agonists - Google Patents

Abstract

Use of compounds of general formula (A) as medicaments is described, in particular for the treatment of pain or inflammation; wherein: (I) when X = OH, R2 = NH2, R5 = CH2OH, R6 = H , R1 is C5-C6 alkoxy, OCH2Cyclopropyl, O-(2,2,3,3-tetrafluoro-cycloButyl), phenoxy, substituted phenoxy, OCH2CH2OH, or OCH2CHF2, (5-indanyl)oxy, C1, C2, C5, or C6 alkylamino, (R) or (S)-sec-Butylamino, C5 or C6 cycloalkylamino, exo-norbornane amino, (N-methyl, N-isoamylamino), phenylamino, phenylamino with either rnethoxy or fluoro substituents, a C2 sulfone group, a C2 alkyl group, a cyano group, a CONH2 group, or 3,5-dimethylphenyl; or when X = H, R2 = NH2, R5 = CH2OH , R6 = H, R1 is n-hexyloxy; or (II) when X = OH , R1 = H, R5 = CH2OH, R6 = H, R2 is NMe2, N-(2-isopentenyl), piperazinyl, (N-Me, N-benzyl), (N-Me, N-CH2Ph(3-Br)), (N-Me, N-CH2Ph(3-CF3)), or (N-Me, N-(2-rnethoxyethyl)), or OCH2Cyclopentyl; or (III) when X = OH, R5 = CONHR3, R6 = H: R1 is H, R3 is an isopropyl group, and R2 is either NH2 or a methylamino group (NHMe) or an isoamyl group (CH2CH2CHMe2); or R1 is H, R3 is H, and R2 is NH2; or R1 is OMe, R3 is Ph, and R2 is NH2; or R1 is NHCH2CH2CH2CH2CH2Me, R3 is CH2CH2CH2Me, and R2 is NH2; or (IV) when X = OH, R1 = H, R2 = NH2, R5 = CH2NHCOR.4, R6 = H, R4 is n-propyl or NHCH2CH3; or (V) when X = OH, R5 = CH2OH, R6 = H: R1 is NHCyclohexyl when R2 is NMe2; or R1 is OMe when R2 is NHBenzyl; or (VI) when X = OH , R2 = NH2, R5 = CH2OH, R6 = Me, R1 is NHCyclohexyl or NHCyclopentyl.

Description

Adenosine receptor agonist

The present invention relates to compound as adenosine receptor agonist, and as the treatment compound, particularly as pain relieving or anti-inflammatory compound or the purposes of regulating the moist medicine of wind resistance (DMARD) of disease, and the method for using this compounds prevention, treatment or alleviating pain or inflammation.

Adenosine is as ubiquitous autacoid/neurotransmitter, and it acts on four kinds of known receptor: adenosine A 1, A2A, A2B and A3 acceptor.Adenosine has the effect of the supply and demand of equilibrium energy usually in tissue.For example, the adenosine that discharges in the heart is by the mediation of A1 acceptor in tubercle and atrium slow down heartbeat (Belardinelli, L ﹠amp; I senberg, G Am.J.Physiol.224 H734-H737), makes coronary artery expansion and energization (being glucose, fat and oxygen) supplies with that (people such as Knabb, Circ.Res. (1983) 53,33-41) simultaneously.Similarly, in inflammatory process, adenosine has the active effect of inflammation-inhibiting, and in neural activity over-drastic illness (as epilepsy), and adenosine suppresses neural and provides (firing) (people such as Klitgaard, Eur J.Pharmacol. (1993) 242,221-228).Above-mentioned system or its modification be present in the institute in a organized way in.

Adenosine self can be used for diagnosis and treatment supraventricular tachycardia.Known adenosine a1 receptor agonists can be used as potent anodyne, and (1-11), simultaneously known adenosine A 2 A receptor agonist has anti-inflammatory activity (referring to for example US5,877,180 and WO 99/34804) for Sawynok, J.Eur J Pharmacol. (1998) 347.In experimental animal, the A2A receptor stimulant can effectively resist various illnesss according to the show, comprises septicemia, sacroiliitis and by kidney, crown or ischemia/reperfusion injury that cerebral artery occlusion causes.The common factor of these symptoms is the inflammatory response reduction that the restraining effect of most of (even not being whole) inflammatory cell caused by above-mentioned acceptor.

Yet the ubiquitous distribution means of Adenosine Receptors and is used adenosine receptor agonist and will cause disadvantageous side effect.This has hindered the therapeutic development based on adenosine usually.Selectivity A1 receptor stimulant can cause bradyrhythmia.The A2A receptor stimulant can cause vasorelaxation widely, and the result causes ypotension and tachycardia.First selectivity A2A receptor stimulant (2-[4-(2-propyloic) phenyl ethylamino]-5 '-N-ethyl-formamide adenosine or title CGS21680) in the 2A clinical trial phase, accepted test as the potential antihypertensive drug.Yet, use this compound and cause that blood pressure declines to a great extent, cause cardiac output to increase then.This has hindered the application of CGS21680 as medicine.People such as Webb (J.Pharmacol Exp Ther (1991) 259,1203-1212), people such as Casati (J Pharmacol Exp Ther (1995) 275 (2): 914-919) and people such as Bonnizone (Hypertension. (1995) 25, point out that 564-9) selectivity A2A adenosine receptor agonist can cause ypotension and tachycardia.The tachycardic degree of inducing is enough to hinder its application as medicine.People such as Alberti (JCardiovasc Pharmacol.1997 September; 30 (3): 320-4) disclose selectivity A2A adenosine receptor agonist as strong vasodilator, it can bring high blood pressure down and induce heart rate and plasma renin activity to significantly improve.These side effects have hindered its application as medicine.

US 5,877, and 180 relate to and claimed the A2A adenosine receptor agonist that can effectively treat inflammatory diseases.Preferred agonist WRC0090 and SHA 211 (WRC0474) are disclosed that for example CGS21680 and CV1808 are more effective and have a selectivity than the previous neplanocin of reporting.Using SHA 211 or WRC0090 has been considered to reduce and occurs being combined with other Adenosine Receptors and the possibility of the side effect that mediates by this analogue.Yet, wherein only comprise relating to SHA 211 active vitro datas.Do not have evidence to prove that all compounds all are that treatment is effective in vivo, and can not cause severe side effect.Although expection is by using above-mentioned agonist can reduce by making effective as selective adenosine A 2 A receptor agonist combine the side effect that mediates with other Adenosine Receptors, but the Adenosine Receptors of ubiquitous distribution means these compounds and still may activate the adenosine A 2 A receptor in the healthy tissues, thereby causes severe side effect (for example ypotension and reflex tachycardia).

US 3,936, and 439 disclose 2, and 6-diamino nebularine derivative is as the purposes that is used for crown expansion of Mammals and/or anticoagulant.Comprising data in the body in dog, it proves N ²-phenyl-2,6-diamino nebularine, N ²-cyclohexyl-2,6-diamino nebularine, N ²-(p-methoxyphenyl)-2,6-diamino nebularine and N ²-ethyl-2,6-diamino nebularine has crown expansion effect, and vitro data proves, N ²-phenyl-2,6-diamino nebularine, N ²-cyclohexyl-2,6-diamino nebularine, 2,6-diamino nebularine and N ²-ethyl-2,6-diamino nebularine have the poly-restraining effect of thrombocyte.(Takeda Chemical Industries Ltd) discloses adenosine derivative (comprising the 2-alkoxyl group adenosine derivative that contains the low alkyl group that is no less than two carbon atoms) and has had hypotensive and the coronary vasodilation activity FR 2162128.Digital proof in the body in the dog, 2-n-pentyloxy adenosine, 2-(beta-hydroxy oxyethyl group)-adenosine and 2-phenoxy group adenosine have the coronary vasodilation activity.Yet US 3,936,439 or FR 2162128 do not confirm that described whole compound can be used for administration and do not cause severe side effect.

People such as Ribeiro (Progress in Neurobiology 68 (2003) 377-392) summarize the various Adenosine Receptorss in the neural system.Ending at this paper is commented on (the 387th page, right hurdle, the 8th section 4-10 is capable) in point out, " as pointing out a long time ago, the activation of periphery Adenosine Receptors is relevant with ypotension, bradyrhythmia and hypothermy ... these side effects have seriously limited the clinical application of adenosine receptor agonist all the time ".

Therefore, still need to provide have minimum side effect can administration adenosine receptor agonist.

Some aspect of the present invention relates to treatment of pain.Pain has two key elements, and they all relate to the activation to Sensory neurone.The first element is the phase of sending out in early days or promptly, and this moment, Sensory neurone was stimulated owing to the cause of for example skin heating or pressurized.Second key element is the susceptibility enhanced results to the sensing mechanism of before impaired nerve innervate tissue.Second key element is known as hyperpathia, and it relates to the chronic pain of the arbitrary form that is caused by tissue injury, rather than the phase of sending out in early days or promptly of pain perception.

Therefore, hyperpathia is the pain perception enhanced illness that is caused by tissue injury.This symptom is as neural natural response, and its purpose obviously is in order to encourage injured individual protection damaged tissue, thereby obtains to carry out the time of tissue repair.Why two known basic reasons of above-mentioned illness existence appear: the active neurone process appearance variation that increases and occur in the sensation injury information in the spinal cord of Sensory neurone.In chronic inflammatory diseases (for example rheumatoid arthritis) illness, and when sensory nerve damage (being neuropathic pain) occurring, hyperpathia may weaken to some extent.

Known have a main anodyne of two classes: (i) nonsteroidal anti-inflammatory agent (NSAID) and relevant cox 2 inhibitor; (ii) based on the opiate of morphine.This two classes anodyne can be controlled general pain, the i.e. property sent out pain or nociceptive pain effectively.Yet, they for the hyperpathia of some type for example neuropathic pain but be not effectively same.Most of medical science practitioners are reluctant to leave the opiate prescription according to the required high dosage of affecting the nerves property pain, this is to have various side effects (for example be on tenterhooks, feel sick and vomiting) because use these compounds, and the patient also may be to its habituation.Therefore even also may need more this compound of high dosage because the effectiveness of NSAID is far away not as good as opiate.Yet,, thereby so also be not suitable for because these compounds can cause the GI irritation effect.

Equally still, need the anodyne (particularly anti-hyperalgesic) that provides such, this class medicine is enough to control effectively the pain perception in nervosa and other hyperpathia syndrome, and can not produce severe side effect or cause the patient to its habituation.

Spongosine (spongosine) was separated (Bergmann and Feeney in 1945 at first from tropical sponge Cryptotethia cstypta, J.Org.Chem. (1951) 16,981, the same (1956) 21,226), and be the methoxyl group purine the earliest that nature is found.It also is known as 2-methoxy adenosine or 9H-purine-6-amine, 9-α-D-ARA-A-2-methoxyl group.People such as Bartlett have described the initial biological activity of spongosine, and (J.Med.Chem. (1981) 24,947-954).After oral, tested the skeletal muscle of spongosine (and other compound) in rodent and relaxed, reduced body temperature, cardiovascular and anti-inflammatory activity (anti-inflammatory activity is by inducing the restraining effect of oedema to estimate to rat pawl carrageeman).Oral 20mg/kg spongosine makes carrageeman inductive inflammation be subjected to 25% inhibition in the rat.Yet, after using this compound, also observe mean blood pressure (41%) and heart rate (25%) decreases with above-mentioned dosage.

Spongosine is measured the avidity of rat adenosine A 1 and A2A acceptor.Resulting Kd value (in rat) is 340nM to the A1 acceptor, is 1.4 μ M to the A2A acceptor, and is that (people such as Daly, Pharmacol. (1993) 46,91-100) for 3 μ M according to the show for the EC50 value of stimulation in rats A2A acceptor.In the isolated heart goods of cavy, measured the effectiveness of spongosine, for adenosine A 1 and A2A acceptor, resulting EC50 value be respectively 10 μ M and 0.7 μ M (people such as Ueeda, J Med Chem (1991) 34,1334-1339).Because this compound renders a service low and receptor-selective is poor, therefore when seeking more effective receptor-selective adenosine receptor agonist, it is often out in the cold.

Unexpectedly find now, than based on this compound to the desired dosage of known avidity of Adenosine Receptors low reaching under 100 times the dosage, spongosine is a kind of effective anodyne.Under above-mentioned dosage, spongosine can not cause with this compound of high dosage more or other adenosine receptor agonist relevant significance side effect.Therefore, result of treatment and its side effect of spongosine can be separated.Spongosine has constituted the theme of international patent application no PCT/GB03/05379 as the activity of anodyne, and the compound that relates to spongosine has constituted the theme of international patent application no PCT/GB04/00935 as the activity of anodyne.The purposes of spongosine and related compound treatment inflammation and other disease has constituted the theme of international patent application no PCT/GB04/000952.

The applicant finds, spongosine of describing among PCT/GB04/00935 and the PCT/GB04/000952 and related compound thereof have the avidity that has improved for Adenosine Receptors under the pH that is lower than pH 7.4.It is believed that this character can be used for explaining why these compounds have beat all activity under low dosage.Which the applicant can identify other compound has the avidity that has improved to Adenosine Receptors under the low pH equally.It is believed that these compound useful as drug, also can not cause severe side effect simultaneously.

The invention provides adenosine receptor agonist or its pharmacologically acceptable salt of following formula:

Wherein:

When X=OH, R ₁Be C ₁Or C ₄-C ₆Alkoxyl group (preferred C ₅-C ₆Alkoxyl group), OCH ₂Cyclopropyl, OCH ₂Cyclopentyl, O-(2,2,3,3-ptfe ring butyl), phenoxy group, substituted phenoxy group are (preferably by nitrile (preferred 4-nitrile), 4-methyl, phenyl (preferred 3-phenyl), 3-bromine, 3-sec.-propyl, 2-methyl, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 2,3,5-trifluoro or (3-methyl, 4-fluorine) replace), OCH ₂CH ₂OH, OCH ₂CHF ₂, (5-indanyl) oxygen base, C ₁, C ₂, C ₅Or C ₆Alkylamino, (R) or (S)-Zhong Ding amino, C ₅Or C ₆Naphthene amino, exonorborn alkylamino, (N-methyl, N-isoamylamino), phenylamino, phenylamino, C with methoxyl group or fluoro substituents ₂Sulfuryl (sulfone group), C ₇Alkyl, cyano group, CONH ₂Group or 3, the 5-3,5-dimethylphenyl; Perhaps

When X=H, R ₁It is positive hexyloxy;

R wherein ₂Be NMe ₂, N-(2-isopentene group), piperazinyl, (N-Me, N-benzyl), (N-Me, N-CH ₂Ph (3-Br)), (N-Me, N-CH ₂Ph (3-CF ₃)) or (N-Me, N-(2-methoxyethyl)) or OCH ₂Cyclopentyl;

Wherein:

Work as R ₁During=H, R ₃Be sec.-propyl, and R ₂Be NH ₂, methylamino-(NHMe) or isopentyl (CH ₂CH ₂CHMe ₂); Perhaps

Work as R ₁During=H, R ₃Be H, and R ₂Be NH ₂Perhaps

Work as R ₁When being OMe, R ₃Be Ph, and R ₂Be NH ₂Perhaps

Work as R ₁Be NHCH ₂CH ₂CH ₂CH ₂CH ₂During Me, R ₃Be CH ₂CH ₂CH ₂Me, and R ₂Be NH ₂

R wherein ₄Be n-propyl or NHCH ₂CH ₃

Wherein:

Work as R ₂Be NMe ₂The time, R ₁It is the NH cyclohexyl; Perhaps

Work as R ₂When being the NH benzyl, R ₁Be OMe;

R wherein ₁Be that NH cyclohexyl, NH cyclopentyl or NH are just own.

Term as used herein " alkyl " is meant unsubstituted straight or branched alkyl.Described alkyl is preferably straight chain.

Term as used herein " alkoxyl group " is meant unsubstituted straight or branched alkoxyl group.Described alkoxyl group is preferably the straight chain alkoxyl group.

Term as used herein " C ₁, C ₂, C ₅Or C ₆Alkylamino " be meant group-NR ^XR ^Y, R wherein ^XBe hydrogen, and R ^YBe C ₁, C ₂, C ₅Or C ₆Alkyl, perhaps R wherein ^XAnd R ^YBe C independently of one another ₁, C ₂, C ₅Or C ₆Alkyl.Preferred R ^XAnd R ^YEach is C naturally ₁Alkyl.

Preferred formula (I) compound is (a) or (I) (b) compound of formula (I):

Wherein:

When X=OH, R ₁Be C ₅-C ₆Alkoxyl group, the phenoxy group, (5-indanyl) oxygen base, the C that are replaced by nitrile (preferred 4-nitrile), phenyl (preferred 3-phenyl) or 3-sec.-propyl ₅Or C ₆Alkylamino, (N-methyl, N-isoamylamino), C ₂Sulfuryl or C ₇Alkyl; Perhaps

When X=H, R ₁It is positive hexyloxy;

Or its pharmacologically acceptable salt;

Wherein:

When X=OH, R ₁Be phenoxy group, substituted phenoxy group, C ₁Or C ₂Alkylamino, phenylamino or OCH with methoxyl group or fluoro substituents ₂CH ₂OH; Perhaps

When X=H, R ₁It is positive hexyloxy;

Or its pharmacologically acceptable salt.

The preferred compound of the present invention is the numbering 2,3 described in the following embodiment 1-6,7-18,22-25,31-33,35,37,40,44,45,47,48 or the compound of 51-61, perhaps its pharmacologically acceptable salt.The synthetic of these compounds is described among the following examples 14-30.

The present invention also provides the numbering 2,3 described in the claims of back, 7-18,22-25,31-33,35,37,40,44,45,47,48 or the synthetic method of 51-61 compound.In some cases, the precursor of these compounds comprises one or more blocking groups.It should be understood that if necessary other hydroxy-protective group based on carboxyl also can be used for substituting the pointed group of this paper.

It is believed that compound of the present invention has the avidity of raising to Adenosine Receptors under the pH that is lower than pH 7.4.In the normal mammalian tissue, external pH is strictly controlled between the pH7.35-7.45.Has lower pH value in some tissue, particularly stomach inner chamber (pH is between 2-3) and some surface epithelial cell (for example lung surface p H is about 6.8).For example be in inflammation, ischemic and other type injured tissues at pathological tissue, reducing can appear in pH.

Because The compounds of this invention has the avidity of raising to Adenosine Receptors under low pH, thereby think that these compounds may be the zone of targeting in low pH, for example pathological tissue.Therefore, make these compounds give play to the required dosage of result of treatment well below according to the desired dosage of its avidity that outside normal cell, under the physiological pH Adenosine Receptors is had.Owing to only need the compound of low dosage, therefore just avoid or got rid of the serious side effects relevant with using adenosine receptor agonist.This will bring amazing result (with respect to this area US5 for example, 877, instruction in 180): some adenosine receptor agonist and/or non-selective agonist (for example spongosine) that has low-affinity under physiological pH will be effectively in treatment, also can not cause severe side effect simultaneously.

Some compound that falls in formula (I)-(VI) scope before was disclosed as adenosine receptor agonist.Yet, can not expect thus think the effect of these compounds can targeting in various pathological tissues, or think that in view of the above their result of treatment can separate with its side effect.According to instruction of the present invention, it is believed that formula (I)-(VI) compound can use at the much lower dosage of the desired dosage of avidity that pH has Adenosine Receptors for 7.4 times according to it according to beguine, under this dosage, can obtain result of treatment and can not cause severe side effect.

Therefore, according to the The compounds of this invention that the invention provides as medicine.

Therefore it is believed that formula (I)-(VI) compound has pain relieving and/or anti-inflammatory activity, for other adenosine receptor agonist, using possibility and the severity that side effect appears in above-claimed cpd will be lower.

According to the invention provides formula (I), (II), (III), (IV), (V) or (VI) compound be used to prepare the purposes of prevention, treatment or alleviating pain, particularly hyperalgesic medicine.

The method of prevention, treatment or alleviating pain (particularly hyperpathia) also is provided according to the present invention, and described method comprises to needs accepts this prevention, treatment or the object alleviated is used formula (I), (II), (III), (IV), (V) or (VI) compound.

Describe preferred formula (I), (II), (III), (IV), (V) or (VI) compound among the embodiment in detail.

It is believed that formula (I)-(VI) compound can effectively suppress just to suffer from the mammiferous pain perception of pain, particularly nervosa or inflammatory pain, even when also effective when the known dosage that can activate the plasma concentration of Adenosine Receptors is used according to the plasma concentration that obtained of expection.Therefore, it is believed that formula (I)-(VI) compound can treat pain (particularly nervosa and inflammatory pain), can not cause the apparent side effect relevant simultaneously with using other adenosine receptor agonist.

As mentioned above, hyperpathia is the result of tissue injury in most of situations, or is directly to damage sensory nerve, or is the tissue that the sensory nerve domination is specified in infringement.Therefore, in a lot of symptoms, pain perception comprises this key element of hyperpathia.

According to the invention provides formula (I), (II), (III), (IV), (V) or (VI) compound is as being used for prevention, the purposes of the pain killer (particularly anti-hyperalgesic agent) of treatment or alleviating pain (particularly hyperpathia), described pain (particularly hyperpathia) is by comprising that following neuropathy causes: diabetic neuropathy, polyneuropathy, cancer pain, fibromyalgia, myofascial pain syndrome, osteoarthritis, pancrealgia, pelvic/perineal pain, postherpetic neuralgia, rheumatoid arthritis, sciatica/lumbar nerve root disease, spinal stenosis, temporomandibular joint disorder, HIV pain, trigeminal neuralgia, chronic neuropathic pain, low back pain, back surgery failure pain, backache, postoperative pain, pain (comprises shooting behind the physical trauma, road traffic accident, burn), pained, pectoralgia, pelvic pain/PID, arthrodynia (tendonitis, bursitis, acute arthritis), cervicodynia, enterodynia, phantom limb pain, obstetrics' pain (childbirth/C-part), renal colic, acute herpes zoster pain, acute pancreatitis (Breakthrough) pain (cancer) of breaking, dysmenorrhoea/endometriosis.

According to the invention provides formula (I), (II), (III), (IV), (V) or (VI) compound is as being used for prevention, the purposes of the pain killer (particularly anti-hyperalgesic agent) of treatment or alleviating pain (particularly hyperpathia), described pain (particularly hyperpathia) is by inflammatory diseases, the perhaps inflammatory of He Binging, autoimmunity and nervosa tissue injury result cause, comprising rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, urarthritis and other arhritis conditions, cancer, HIV, chronic pulmonary inflammation disease, silicosis, the lung sarcosis, bone resorption disease, reperfusion injury (comprises by ischemic stroke myocardial infarction for example, the organ damage that perfusion again after the apoplexy causes), the autoimmunization damage (comprises multiple sclerosis, Guillam Barre syndrome, myasthenia gravis), graft is to host's repulsion, allograft rejection, heating that infection causes and myalgia, the complication relevant (ARC) with AIDS, keloid forms, scar tissue forms, Crohn disease, ulcerative colitis and heating, irritable bowel syndrome, osteoporosis, cerebral malaria and bacterial meningitis, enterodynia, cancer pain, backache, fibromyalgia, postoperative pain.

Expect also that in addition spongosine can effectively prevent, treats or alleviate avascular pain.It is believed that those compounds relevant with spongosine also can effectively resist avascular pain.

According to the invention provides the purposes that formula (VII) compound or pharmaceutically acceptable salt thereof is used to prepare the medicine of prevention, treatment or alleviating pain, particularly avascular pain:

Wherein R is C _1-4Alkoxyl group, and X is H or OH.

Preferred R is C _1-4Alkoxyl group, and X is OH, or its pharmacologically acceptable salt.Formula (VII) compound can be got rid of 2-methoxy adenosine (spongosine).

The method of prevention, treatment or alleviating pain, particularly avascular pain also is provided according to the present invention, and described method comprises to needs accepts this prevention, treatment or the object alleviated is used formula (VII) compound.

Expect also that in addition formula (I)-(VI) compound can effectively prevent, treats or alleviate avascular pain.

Term as used herein " avascular pain " is meant and reduces relevant pain to the blood supply of health part.Blood supply reduces to have limited to this part of health supplies with oxygen (anoxic) and energy.Ischemic is by organizing the blood hypoperfusion to cause, so avascular pain causes by coronary artery disease, peripheral arterial disease, and those features show as the insufficient illness of blood flow, and to tend to secondary be atherosclerosis.Other vascular disease also may cause avascular pain.They comprise: left ventricular hypertrophy, coronary artery disease, essential hypertension, the acute hypertension acute disease, myocardosis, the heart body deficiency, exercise tolerance, chronic heart failure, irregular pulse, arrhythmia, syncopy, arteriosclerosis, slight chronic heart failure, stenocardia, Prinzmetal ' s (modification) stenocardia, stable angina pectoris and exercise induced stenocardia, heart bypass is closed again, intermittent claudication (arteriosclerosis oblitterens), arteritis, diastolic dysfunction and systole dysfunction, atherosclerosis, behind the ischemic/reperfusion injury, diabetes (I type and II type), thromboembolism.Bleeding episode also may cause avascular pain.In addition, hypoperfusion also may cause nervosa that the neural cell injury owing to hypoxia inducible causes and inflammatory pain (for example heartbeat stop or shunt operation in, diabetes or post-partum pain).

It is believed that formula (I)-(VII) compound can effectively prevent, treats or alleviate avascular pain, even when also effective when the known dosage that can activate the plasma concentration of Adenosine Receptors is used according to the plasma concentration that obtained of expection.Under this dosage, it is believed that described compound can not cause and uses more high dosage spongosine or the relevant apparent side effect of other adenosine receptor agonist.

Be used for preventing, treat or the purposes of the medicine of amelioration of inflammation in preparation according to having the present invention further provides The compounds of this invention (be formula (I), (II), (III), (IV), (V), (VI) or (VII) compound).

According to the method that the present invention further provides prevention, treatment or amelioration of inflammation, described method comprises to needs accepts this prevention, treatment or the object alleviated is used compound of the present invention.

Especially, it is believed that The compounds of this invention (be formula (I), (II), (III), (IV), (V), (VI) or (VII) compound) can be used for prevention, treatment or alleviate being caused or relative inflammation by following disease: cancer (for example leukocytosis, lymphoma, cancer, colorectal carcinoma, mammary cancer, lung cancer, carcinoma of the pancreas, hepatocellular carcinoma, kidney, melanoma, liver cancer, lung cancer, mammary cancer and prostate cancer etc.); Autoimmune disease (for example organ-graft refection, lupus erythematosus, graft comprise that to host's repulsion, allograft rejection, multiple sclerosis, rheumatoid arthritis, type i diabetes pancreas islet destroys the diabetes that cause and the inflammation result of diabetes); Autoimmunization damage (comprising multiple sclerosis, Guillam Barre syndrome, myasthenia gravis); Fat; With the not enough cardiovascular disorder relevant of perfused tissue (cardiovascular complications of for example vasospasm that causes of congee sample spot, atherosclerosis, apoplexy, ischemia reperfusion injury, limping, Spinal injury, congestive heart failure, vasculitis, hemorrhagic shock, subarachnoid hemorrhage, vasospasm that cerebrovascular accident causes, pleuritis, pericarditis, diabetes) with inflammation; The restenosis that ischemia reperfusion injury, ischemic and occurring together property inflammation, angioplasty and inflammatory aneurysma cause; Epilepsy, neurodegeneration (comprising Alzheimer), muscle fatigue or muscle cramp (particularly sportsmen's cramp), sacroiliitis (rheumatoid arthritis for example, osteoarthritis, rheumatoid spondylitis, urarthritis), fibrosis (lung for example, skin and hepatic fibrosis), multiple sclerosis, septicemia, septic shock, encephalitis, infective arthritis, jarisch-Herxheimer reaction, zoster, toxic shock, cerebral malaria, Lyme ' s disease, interior toxicogenic shock, gram-negative shock, hemorrhagic shock, hepatitis (causing) by tissue injury or virus infection, dvt forms, gout; The disease (for example chronic retardancy tuberculosis, air flue retardance and obstruction, bronchoconstriction, lung vasoconstriction, dyspnoea, chronic pulmonary inflammation disease, silicosis, lung sarcosis, cystic fibrosis, pulmonary hypertension, lung vasoconstriction, pulmonary emphysema, broncho-allergic reaction and/or inflammation, asthma, ragweed fever, rhinitis, vernal conjunctivitis and adult respiratory distress syndrome) relevant with expiratory dyspnea; The illness relevant (comprising psoriatic, eczema, ulcer, contact dermatitis) with chafing; The illness relevant (comprising Crohn disease, ulcerative colitis and heating, irritable bowel syndrome, inflammatory bowel) with the intestines inflammation; HIV (particularly HIV infects), cerebral malaria, bacterial meningitis, TNF-enhanced HIV duplicates, the active TNF of AZT and DDI suppresses, osteoporosis and other bone resorption disease, osteoarthritis, rheumatoid arthritis, it is sterile that endometriosis causes, heating that infection causes and myalgia, be secondary to the emaciation of cancer, be secondary to the emaciation of infection or malignant tumour, be secondary to the emaciation of acquired immune deficiency syndrome (AIDS) (AIDS), the complication relevant (ARC) with AIDS, keloid forms, scar tissue forms, the undesirable action that the amphotericin B treatment causes, the undesirable action that the interleukin-2 treatment causes, the undesirable action that the OKT3 treatment causes, perhaps GM-CSF treats the undesirable action that causes, and other (comprises neutrophilic granulocyte by excessive anti-inflammatory cell, eosinocyte, hugely have a liking for cell and T-cell) illness of active mediation.

Known lasting low-level inflammation and fat relevant (existing and not existing in insulin resistance and the type ii diabetes) (people (2004) Metabolism 53 such as Browning, 899-903, Inflammatory markers elevated in blood of obese women; People such as Mangge (2004) Exp Clin Endocrinol diabetes 112,378-382, Juvenileobesity correlates with serum inflammatory marker C-reactiveprotein; People Int J Obes Relat Metab Disord.2004 28 such as Maachi, 993-997, Systemic low grade inflammation in obese people).Wherein possible reason is that adipocyte secreted TNF-α and interleukin-11 and 6 of proinflammatory.

Especially preferred The compounds of this invention is the selective agonist of adenosine A 2 A and/or A3 acceptor, and this is because it is believed that this compounds has strong anti-inflammatory activity.The selective agonist of adenosine A 2 A and/or A3 acceptor is meant the agonist that can activate adenosine A 2 A and/or A3 acceptor under the concentration that is lower than (preferred thousandth to five/one) activation adenosine A 1 receptor desired concn.In addition, because the A1 acceptor has short inflammatory activity, therefore expection can be reduced to minimum with A2A and/or A3 acceptor being had optionally the above-mentioned activity of compound like this.

It should be understood that all can be prevented or the illness improved can utilize formula (I)-(VII) compound to prevent, treat or alleviate by exciting adenosine A 2 A and/or A3 acceptor.

Be used to prepare prevention, treatment or alleviate and to improve or the purposes of the medicine of the illness of preventing by exciting adenosine A 2 A and/or A3 acceptor according to the invention provides formula (I)-(VII) compound.

According to the present invention, prevention, treatment also are provided or have alleviated and can improve or the method for the illness of preventing by exciting adenosine A 2 A and/or A3 acceptor, described method comprises to the object of this prevention of needs, treatment or alleviation uses formula (I)-(VII) compound.

Whether those of ordinary skills can measure the illness that use formula (I)-(VII) compound prevents, treats or alleviate easily and play a role by adenosine A 2 A and/or A3 acceptor.For example,, the effect of compound in suffering from the animal model of above-mentioned illness contrasted, can realize above-mentioned purpose by under the situation that is with or without adenosine A 2 A and/or A3 receptor-selective antagonist.If compound exists effect under the situation of antagonist to decrease or lacking, can think that then this compound is by adenosine A 2 A and/or A3 acceptor performance curative effect for the effect of compound under the situation that does not have antagonist.The antagonist of adenosine A 2 A and A3 acceptor is that those of ordinary skills are known (referring to people such as for example Ongini, the Farmaco.2001 1-2 month; 56 (1-2): 87-90; Muller, Curr Top Med Chem.2003; 3 (4): 445-62).

Perhaps, also can use by the adenosine A 2 A receptor knock-out mice (Ohta A and Sitkovsky M, Nature 2001; 414:916-20).For example, compound is contrasted for the effect of the mouse with above-mentioned illness and its effect to adenosine A 2 A knock-out mice with corresponding symptom.If this compound only be in having the mouse of adenosine A 2 A receptor effectively, can think that then this compound brings into play curative effect by adenosine A 2 A receptor.

The compounds of this invention (be formula (I), (II), (III), (IV), (V), (VI) or (VII) compound) it is believed that under low dosage more effective more than other adenosine receptor agonist.Therefore, the expection The compounds of this invention dosed administration that can be effectively be lowered or do not observe side effect according to the possibility and the severity of appearance side effect.For other adenosine receptor agonist of the major part that only has anti-inflammatory activity, The compounds of this invention has clear superiority observing under the same concentrations of serious side effects.

Alternatively or additionally, for other adenosine receptor agonist, possibility and severity that side effect appears in The compounds of this invention all decrease.

It is believed that also that in addition The compounds of this invention (be formula (I), (II), (III), (IV), (V), (VI) or (VII) compound) can also be effectively as the antirheumatic (DMARD) that improves disease, especially for prevention, treatment or rheumatoid arthritis and possible other joint disease osteoarthritis for example.

The medicine that is used for the treatment of rheumatoid arthritis (RA) can be divided into two classes: the medicine that helps to alleviate the RA symptom; Help to improve the medicine of disease.The medicine that helps to alleviate the RA symptom is included in influenced joint alleviating pain and the non-steroidal anti-inflammatory drug (NSAIDs) that reduces inflammation, alleviating pain but does not delay joint injury or the pain killer (for example Paracetamol and narcoticness pain medication) that reduces inflammation and as the cortin of anti-inflammatory medicaments.

DMARD helps to improve RA symptom (for example arthroncus and tenderness), also helps to delay the progress of the joint injury that caused by RA.Therefore, although can not cure RA, DMARD helps to delay the progress of RA.Past DMARD is normally used for treating the RA that uses after the NSAID treatment is failed.Yet DMARD begins to use in early days in the RA stage now, and this is can obtain considerable advantage because of studies show that early stage use DMARD intervenes.DMARDs and NSAID unite use usually mutually.

The clinical study result shows that existing DMARDs has delayed the progress of RA.After the treatment beginning 6 months, the ratio of bone and cartilage injury begins to slow down in the patient joint.After 1 year, the patient shows as joint injury and extremely slight progress occurs, and after 2 years, the X-ray shows that the joint of new damage appearred in the patient who accepts research at 1 year that treats.

The example of known DMARD comprises sulfasalazine, Trolovol, chloroquine, Oxychloroquine, gold (with auranofin form intramuscularly or oral), methotrexate, S-Neoral, azathioprine, endoxan, leflunomide.Developed the biology DMARD that can suppress tumor necrosis factor alpha (TNF-α) recently.One of example is Humira , and this medicine is pointed out can be used for to reduce sign and symptom, and suppresses to have the structural damage among the slight adult to the active RA of severe (it responds insufficient to one or more DMARD).Humira  is a kind of anti-TNF-Alpha antibodies.

Most of known DMARD can cause severe side effect.Therefore wish the new DMARD that acquisition has minimal side effect.

The following examples 13 show spongosine and reduce the ability that phorbol inductive TNF-α discharges in the U937 human macrophages.On this basis, it is believed that spongosine and formula (I), (II), (III), (IV), (V), (VI) or related compound (VII) also have the DMARD activity.

According to the invention provides formula (I), (II), (III), (IV), (V), (VI) or (VII) compound be used to prepare the purposes of the medicine that delays the joint disease progress.

The method that delays the joint disease progress also is provided in addition according to the present invention, and described method comprises to the object that these needs are arranged uses formula (I), (II), (III), (IV), (V), (VI) or (VII) compound.

The progress of preferred RA is delayed, and particularly the progress of the joint injury that is caused by RA is delayed.

The compounds of this invention can be used in any stage during RA.The compounds of this invention can with one or more NSAID or other DMARD Combined Preparation.

The compounds of this invention it is believed that and can be used as DMARD effectively, in addition when the plasma concentration that is obtained according to expection also effective when the known dosage that can activate the plasma concentration of Adenosine Receptors is used.Under this dosage, it is believed that described compound can not cause and uses more high dosage spongosine or the relevant apparent side effect of other adenosine receptor agonist.

Use The compounds of this invention to be that as the peculiar advantage of DMARD it is oral effectively, on the contrary, anti-TNF-Alpha antibodies must drug administration by injection.

Should also be understood that the blood vessel injury that formula (I)-(VII) compound can effectively prevent, treats or alleviate the great vessels of 1 type or diabetes B and microvascular complication (comprising retinopathy, ephrosis, autonomic neuropathy) or be caused by ischemic (diabetes or other) or atherosclerosis (diabetes or other) in addition.

According to the invention provides formula (I), (II), (III), (IV), (V), (VI) or (VII) compound be used to the great vessels for preparing prevention, treatment or alleviate 1 type or diabetes B or microvascular complication, retinopathy, ephrosis, autonomic neuropathy or the purposes of the medicine of the blood vessel injury that causes by ischemic or atherosclerosis.

Prevention, treatment also are provided according to the present invention or have alleviated the great vessels of 1 type or diabetes B or the method for microvascular complication, retinopathy, ephrosis, autonomic neuropathy or the blood vessel injury that caused by ischemic or atherosclerosis, described method comprises to the object that these needs are arranged uses formula (I), (II), (III), (IV), (V), (VI) or (VII) compound.

Preferred formula (VII) compound is 2-methoxy adenosine (being spongosine), 2-oxyethyl group adenosine and 2-butoxy adenosine.

Formula (I)-(VII) compound it is believed that the great vessels and the microvascular complication that can effectively prevent, treat or alleviate 1 type or diabetes B, comprise retinopathy, ephrosis, autonomic neuropathy, the perhaps blood vessel injury that causes by ischemic or atherosclerosis (diabetes or other), in addition when the plasma concentration that is obtained according to expection also effective when the known dosage that can activate the plasma concentration of Adenosine Receptors is used.Under this dosage, it is believed that described compound can not cause and uses more high dosage spongosine or the relevant apparent side effect of other adenosine receptor agonist.

Formula (I)-(VII) compound it is believed that and can promote wound healing effectively.According to the present invention, provide formula (I), (II), (III), (IV), (V), (VI) or (VII) compound be used to prepare the purposes of the medicine that promotes wound healing.The method that promotes wound healing in the object also is provided according to the present invention, and described method comprises to this object uses formula (I), (II), (III), (IV), (V), (VI) or (VII) compound.

Consumption from formula (I)-(VII) compound to object that use can guarantee that preferably resulting peak plasma concentration is lower than this compound to the EC50 value of Adenosine Receptors (preferably pH 7.4 times).

The EC50 value that it should be understood that compound may be different for different Adenosine Receptorss (being A1, A2A, A2B, A3 Adenosine Receptors).The consumption of institute's administered compound should calculate the minimum EC50 value of isoacceptor not with respect to this compound.

Therefore, the consumption to the object administered compound should guarantee that resulting peak plasma concentration is lower than the minimum EC50 value of this compound to different Adenosine Receptorss.

The peak plasma concentration of preferred compound be minimum EC50 value thousandth to two/one (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/3rd, or 1/50th to 1/2nd, or 1/50th to 1/5th, or 1/10th to 1/2nd, perhaps 1/10th to 1/5th).

The resulting plasma concentration of consumption of preferred institute administered compound surpass remain in 1 hour time period this compound to thousandth to two/one of the minimum EC50 value of Adenosine Receptors (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/2nd, or 1/50th to 1/5th, or 1/10th to 1/2nd, perhaps 1/10th to 1/5th).

The preferred resulting plasma concentration of being used of consumption surpass remain in 1 hour time period this compound pH 7.4 times to thousandth to two/one of the EC50 value of Adenosine Receptors or thousandth to five/one or one of thousandth to two 1/10th or percentage to 1/2nd or one of percentage to 1/5th or 1/50th to 1/2nd or 1/50th to 1/5th between.

For fear of query, being acceptor response that compound excited herein with the EC50 value defined of compound is the concentration (for example using, dose-response curve records) of the response of baseline acceptor and the maximum acceptor intermediate value between responding.

Described EC50 value should be measured down in standard conditions (being buffered to the balanced salt solution of pH 7.4).About using stripped film, cell and tissue to carry out the measurement of EC50, this can carry out in pH is 7.4 buffer salt solution (for example cell culture medium), people such as Daly for example, (Pharmacol. (1993) 46,91-100) or people such as preferred Tilburg (J.Med.Chem. (2002) 45,91-100) buffer salt solution in.By in the animal of normal health or even measure down response the normal health animal in the dabbling tissue at normal condition (be vadose solution matchmakers such as oxygenated blood or oxygenate, be buffered to pH 7.4 equally) by the Adenosine Receptors mediation, also can record EC50.

Perhaps, the consumption of the The compounds of this invention of using can be lower than the consumption of this compound to the minimum or the highest Kd value (promptly being lower than the minimum or the highest Kd value of this compound to A1, A2A, A2B and A3 Adenosine Receptors) of Adenosine Receptors for the peak plasma concentration that is caused.

The peak plasma concentration of preferred this compound be ten thousand of minimum or the highest Kd value/to 1/2nd (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to three/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/2nd, or 1/50th to 1/5th, or 1/10th to 1/2nd, or 1/10th to 1/5th).

The resulting plasma concentration of consumption of preferred institute administered compound remains at least 1 hour time period between thousandth to two/one or thousandth to five/one of this compound to the Kd value of Adenosine Receptors, more preferably one of thousandth to two 1/10th or percentage to 1/2nd or one of percentage to 1/5th or 1/50th to 1/2nd or 1/50th to 1/5th between.

The resulting plasma concentration of consumption of preferred institute administered compound surpass remain in 1 hour time period this compound to ten thousand of the minimum or the highest Kd value of Adenosine Receptors/to 1/2nd (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/2nd, or 1/50th to 1/5th, or 1/50th to 1/3rd, or 1/10th to 1/2nd, or 1/10th to 1/5th).

Compound should record under standard conditions the Kd value of each acceptor, uses the Adenosine Receptors of the cell of tissue or cell that is derived from these acceptors of endogenous expression or the dna vector that coding adenosine acceptor gene is arranged from transfection to originate as plasma membrane.Perhaps, also can use expression that the full cell product of Adenosine Receptors is arranged.Should in buffering (pH 7.4) salts solution, use at isoacceptor mark selected part (for example radiolabeled) not (referring to people such as for example Tilburg, J.Med.Chem. (2002) 45,420-429), thus record binding affinity and the Kd of compound to each acceptor.

Perhaps, the consumption of the The compounds of this invention of using for infraspecific animal as this compound administration object in cause bradyrhythmia, ten thousand of the described compound minimum amount (or dosage) of ypotension or tachycardia side effect/to 1/2nd (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/2nd, or 1/50th to 1/3rd, or 1/50th to 1/5th, or 1/10th to 1/2nd, or 1/10th to 1/5th).The preferred resulting plasma concentration of dosage surpass remain in 1 hour time period ten thousand of the described compound minimum amount that causes above-mentioned side effect/to 1/2nd (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/2nd, or 1/50th to 1/5th, or 1/10th to 1/2nd, or 1/10th to 1/5th).

The preferred resulting plasma concentration of dosage is surpassing thousandth to two/one that remains on the lowest dose level that causes above-mentioned side effect in 1 hour time period or one of thousandth to two 1/10th or percentage or 1/50th to 1/2nd or one of percentage or between 1/50th to 1/5th.

Perhaps, the consumption of the The compounds of this invention of using for infraspecific animal as this compound administration object in cause bradyrhythmia, ten thousand of the minimum plasma concentration of described compound of ypotension or tachycardia side effect/to 1/2nd (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/2nd, or 1/50th to 1/3rd, or 1/50th to 1/5th, or 1/10th to 1/2nd, or 1/10th to 1/5th).The resulting plasma concentration of preferred used consumption surpass remain in 1 hour time period ten thousand of the minimum plasma concentration of compound that causes above-mentioned side effect/to 1/2nd (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/2nd, or 1/50th to 1/5th, or 1/10th to 1/2nd, or 1/10th to 1/5th).

The resulting plasma concentration of preferred used consumption is surpassing thousandth to two/one that remains on the minimum plasma concentration that causes above-mentioned side effect in 1 hour time period or one of thousandth to two 1/10th or percentage or 1/50th to 1/2nd or one of percentage or between 1/50th to 1/5th.

The optimal dose of The compounds of this invention will depend on age, sex, body weight and the situation of object to be treated, the effectiveness of compound (for example it is for the EC50 value of Adenosine Receptors), transformation period, body absorbing state and route of administration etc.Certainly, those skilled in the art can determine appropriate dosage easily.

A kind of proper method of determining optimal dose is to estimate its cardiovascular variation for Adenosine Receptors (acceptor that preferably it is had maximum avidity) (for example by electrocardiogram(ECG and monitoring of blood pressure) in the EC50 of compound value or about it, thereby determines maximum tolerated dose.Then expection treatment effective dose be ten thousand of this maximum tolerated dose/to 1/2nd (perhaps ten thousand/to 1/5th, or ten thousand/to 1/20th, or ten thousand/to one of percentage, or ten thousand/to thousandth, or thousandth to two/one, or thousandth to five/one, or thousandth to two 1/10th, or 1/50th to 1/10th, or one of percentage is to 1/2nd, or one of percentage is to 1/5th, or 1/50th to 1/2nd, or 1/50th to 1/3rd, or 1/50th to 1/5th, or 1/10th to 1/2nd, or 1/10th to 1/5th).

The following examples 31 show for spongosine, and its dosage should be less than 28mg in human body.The resulting plasma concentration of this dosage (approaches 7.4 times Kd to adenosine A 2 A receptor at pH, sees below) between 0.5-0.9 μ M.According to The above results, the preferred dose scope of spongosine is 0.03-0.3mg/kg.

Spongosine has the minimum plasma concentration that maximum pain relieving alleviates effect in suffering from arthritic rat assistant agent model be 0.06 μ M, and this is well below the EC50 of spongosine to adenosine A 2 A receptor, and the latter is about 1 μ M.The preferred dose scope that obtains maximal plasma concentration in the people is 0.005-0.5 μ M, and this is starkly lower than by acting on the dosage that this receptor expection obtains pain relieving or anti-inflammatory activity.

Perhaps, the suitable treatment concentration of The compounds of this invention be contemplated to the Ki of Adenosine Receptors (this compound has the acceptor of maximum avidity to it) under pH 5.5 about 10-20 doubly.Therefore, for spongosine, requiring it is 15-30nM, and uses the Ki under the pH 7.4, and this concentration expection requires to be 20-30 μ M.

The consumption of the expection The compounds of this invention of using should be 0.001-15mg/kg.Described consumption can be lower than 6mg/kg.This consumption can be at least 0.001,0.01,0.1 or 0.2mg/kg.Described consumption can be lower than 0.1 or 0.01mg/kg.Preferable range is 0.001-10,0.001-5,0.001-2,0.001-1,0.001-0.1,0.001-0.01,0.01-15,0.01-10,0.01-5,0.01-2,0.01-1,0.1-10,0.1-5,0.1-2,0.1-1,0.1-0.5,0.1-0.4,0.2-15,0.2-10,0.2-5,0.2-2,0.2-1.2,0.2-1,0.6-1.2mg/kg.

For people's (for example object of 70kg), preferred dose is lower than 420mg, preferably is lower than 28mg, more preferably less than 21mg, is preferably at least 0.07,0.1,0.7 or 0.8mg, and more preferably at least 3.5 or 7mg.More preferably 7-70mg, 14-70mg or 3.5-21mg.

It is believed that above-mentioned concrete dosage significantly is lower than (low about 1000 times at the most) and according to this compound the EC50 value expection based on adenosine A 2 A receptor is had pain relieving or the needed dosage of anti-inflammatory activity.

Above-mentioned preferred dosage scope target be to make the plasma concentration that is generated reach this compound for one of percentage of the EC50 value of the Adenosine Receptors that it is had maximum avidity to about 1/2nd.

The compounds of this invention can be with can not using with other therapeutical agent yet, and other therapeutical agent is pain killer or anti-inflammatory agent (as opiates, steroid class, NSAID, Cannabinoids, tachykinin modulators or bradykinin modulators) or anti-hyperalgesic (as gabapentin, Pregabalin, Cannabinoids, calcium sodium or calcium channel modulators, antiepileptic drug or antidepressive) or DMARD for example.

In general, The compounds of this invention can be according to known way with any appropriate dosage form, by suitable administration.The compounds of this invention preferably by oral, non-enteron aisle, hypogloeeis, in skin, sheath or mucosal.Other suitable route comprises intravenously, intramuscular, subcutaneous, suction and topical.The consumption of institute's drug administration when oral is usually above the consumption when the intravenous administration.

It should be understood that The compounds of this invention can acceptable carrier, excipient or thinner administration on physiology.

In order to treat the time that effective plasma concentration maintenance prolongs, The compounds of this invention can be mixed in the sustained release preparation.

The suitable composition that for example is used for oral administration comprises and wherein contains for example solid unit formulation of injection liquid of liquid, for example tablet, capsule, bottle and ampoule, wherein promoting agent is passed through known way, utilize acceptable excipient on the physiology, diluent or carrier preparation.Suitable thinner and carrier are known, for example comprise and suitable tackiness agent blended lactose and talcum.

The dosage unit of The compounds of this invention (be formula (I), (II), (III), (IV), (V), (VI) or (VII) compound) contains 500mg (for example 1-500mg or (preferably) 5-500mg) promoting agent at the most usually.Preferred promoting agent is to contain the pharmaceutical composition that can accept carrier, excipient or thinner on promoting agent and the physiology.Preferred dosage scope (being the preferred content of activeconstituents in dosage unit) is 0.001-10,0.001-5,0.001-2,0.001-1,0.001-0.1,0.001-0.01,0.01-15,0.01-10,0.01-5,0.01-2,0.01-1,0.1-10,0.1-5,0.1-2,0.1-1,0.1-0.5,0.1-0.4,0.2-15,0.2-10,0.2-5,0.2-2,0.2-1.2,0.2-1,0.5-1,0.6-1.2, is typically about 0.2 or 0.6mg promoting agent/kg object (people).The preferable amount of promoting agent is less than 420mg, preferably less than 28mg, is more preferably less than 21mg, is preferably at least 0.07,0.1,0.7 or 0.8mg, more preferably at least 3.5 or 7mg.Most preferably be 7-70mg or 14-70mg, 3.5-21mg, 0.07-0.7mg or 0.7-7mg.In above-mentioned scope, it is believed that basically to obtain effective treatment, can not cause occurring together property blood pressure to reduce (for example being no more than 10%) and/or the raising of compensatory heart rate simultaneously.

The unit dosage form of The compounds of this invention further can contain one or more other therapeutical agents, for example pain killer, anti-inflammatory agent, anti-hyperalgesic agent or DMARD.

Preferred The compounds of this invention is according to the frequency administration of every day 2 or 3 times.

The compounds of this invention can also be as being used to identify more efficient drug or having the basis of the medicine of the further side effect that has reduced.

The example of pharmacologically acceptable salt is and forms the organic additive salt that can accept anionic acid formation on the physiology, for example tosylate, mesylate, malate, acetate, Citrate trianion, malonate, tartrate, succinate, benzoate, ascorbate salt, alpha-ketoglutarate and α-glycerophosphate.Suitable inorganic salt be can also form, hydrochloride, vitriol, nitrate, supercarbonate and carbonate comprised.

Pharmacologically acceptable salt can utilize standard step well known in the art to make, and for example by with the compound of total alkali for example amine and suitable acid-respons, obtains acceptable negatively charged ion on the physiology.Can also make the basic metal (for example sodium, potassium or lithium) or alkaline-earth metal (for example calcium) salt of carboxylic acid.

According to formula of the present invention (VII) compound be used to prepare prevention, treatment or alleviate avascular pain medicine purposes or got rid of prevention, treatment or alleviated by the method for using the prevention of formula (I) compound, treatment or alleviating avascular pain because the ischemic stroke pain that causes of the organ damage that causes of the perfusion again after myocardial infarction, the apoplexy for example.

Use 2-propoxy-adenosine, 2-isopropoxy adenosine, 3 ' deoxidation, 2 methoxy adenosines or 3 ' deoxidation, 2 oxyethyl group adenosines have been got rid of according to the purposes that formula of the present invention (VII) compound is used to prepare prevention, treatment or alleviate the medicine of avascular pain.

According to having got rid of use 2-propoxy-adenosine, 2-isopropoxy adenosine, 3 ' deoxidation, 2 methoxy adenosines or 3 ' deoxidation, 2 oxyethyl group adenosines by the method for using the prevention of formula (I) compound, treatment or alleviation avascular pain.

Formula (I) compound has been got rid of 2-phenylamino adenosine (numbering 26 compounds), 2-ethylamino adenosine (numbering 20 compounds), the amino adenosine (numbering 30 compounds) of 2-cyclohexyl, 2-(4-anisole amino) adenosine (numbering 27 compounds), 2-phenoxy group adenosine (numbering 6 compounds) or 2-(β-hydroxy ethoxy)-adenosine (numbering 34 compounds)

With reference to accompanying drawing embodiment of the present invention is described in the following embodiments, wherein:

Fig. 1 shows spongosine (0.6mg/kg p.o.) to A: the blood pressure of normal rat; B: the influence of heart rate;

Fig. 2 shows the variation of plasma concentration versus time after the administration of spongosine;

Fig. 3 shows spongosine (0.6mg/kg p.o.) for by the hyperalgesic anti-hyperpathia effect of carrageenin inductive.A: time course (* p＜0.05, and * * p＜0.01 couple solvent (Sidak ' s), p＞0.05 couple BL, 5 hours, spongosine and IND (Dunnett ' s)); B: the dose-dependently of anti-hyperalgesic effect;

Fig. 4 shows the anti-hyperpathia effect of spongosine (0.6mg/kg p.o.) in the chronic systolic damage model of neuropathic pain (* p＜0.05, * * p＜0.01 couple solvent (ANOVASidak ' s));

Fig. 5 shows the effectiveness of spongosine (0.6mg/kg p.o.) in the chronic systolic damage model of the neuropathic pain that has and do not exist naloxone;

Fig. 6 shows spongosine and the additive effect of gabapentin in the chronic systolic damage model of neuropathic pain;

It is for the influence that is discharged by LPS inductive TNF-α in the U937 cell at human macrophage that Fig. 7 shows spongosine; And

Fig. 8 shows spongosine (62.4 and 624 μ g/kgi.p.) under the concentration that does not influence blood pressure can be suppressed by carrageenin (CGN) inductive inflammation, and its render a service with indomethacin (3mg/kg, po) suitable.

Provided the result of preferred The compounds of this invention in the following embodiments.The Ki value of each compound provides for 7.4 times at pH 5.5 and pH.In order to calculate above-mentioned value, under 22 ℃, have a 2nM[3H]-CGS21680,1 unit/ml adenosine deaminase and cumulative the waiting of concentration study under the situation of compound, and the rat striatum film was cultivated 90 minutes, filter then and carry out liquid scintillation counting(LSC).

Embodiment 1

When X=OH

Compound number No.	Structure R 1	(Ki)nM (pH5.5)	(Ki)nM (pH7.4)
				1	OCH 3	1.5	1300
2	OCH 2CHF 2	17	780
				3	OCH 2Cyclopropyl	39	670
4	OCH 2CH 2CH 2CH 3	11	280
				5	OCH 2CH 2CH 2CH 2CH 2CH 3	3	1500
6	OPh	71	2500
				7	O-(4-cyano group) Ph	4	1300
8	O-(3-Ph)Ph	0.7	620
				9	O-(2，5-F 2)Ph	16	2500
10	O-(2，4-F 2)Ph	16	6400
				11	O-(3，4-F 2)Ph	63	3300
12	O-(2，3，5-F 3)Ph	46	5900
				13	O-(3-Me，4-F)Ph	43	3100
14	O-(2-Me)Ph	24	22000
				15	O-(3-Br)Ph	35	590
16	O-(4-Me)Ph	3.4	720
				17	5-indanyl oxygen base	12	760
18	O-(3-CH(CH 3) 2)Ph	16	560
				19	NHCH 3	24	1356
20	NHCH 2CH 3	130	1200
				21	N(CH 3) 2	24	13350
22	NH-(R)-sec-butyl	33	510
				23	NH-(S)-sec-butyl	29	1400
24	NHCH 2CH 2CH 2CH 2CH 2CH 3	0.7	290
				25	Outside the NH--norbornane	5.5	120
26	NHPh	5	160
				27	NH-(4-MeO)Ph	3	55
28	NH-(4-F)Ph	10	200
				29	The NH-cyclopentyl	2.0	420
30	The NH-cyclohexyl	0.4	1000

31	N-CH 3，N-CH 2CH 2CH(CH 3) 2	26	4000
				32	OCH 2Cyclopentyl	0.2	200
33	SO 2CH 2CH 3	100	39000
				34	OCH 2CH 2OH	4	203
35	O-(2,2,3,3-tetrafluoro-cyclobutyl)	11	220
				36	CH 2CH 2CH 2CH 2CH 2CH 2CH 3	15	800
37	3, the 5-Me2-phenyl	24	5500
				38	CN	25	175
39	CONH 2	23	610

When X=H

Compound number	Structure R 1	(Ki)nM (pH5.5)	(Ki)nM (pH7.4)
				40	OCH 2CH 2CH 2CH 2CH 2CH 3	13	2990

Embodiment 2

Compound number No.	Structure R 2	(Ki)nM (pH5.5)	(Ki)nM (pH7.4)
				41	N(CH 3) 2	42	450000
42	NHCH 2CHC(CH 3) 2	91.5	8600
				43	N-CH 3，N-CH 2Ph	7	18500
44	N-CH 3，N-CH 2Ph(3-Br)	29	7500
				45	N-CH 3，N-CH 2Ph(3-CF 3)	3.8	20000
46	Piperazinyl	38	5000
				47	N-Me，N-(CH 2CH 2OCH 3)	13	13000
48	OCH 2Cyclopentyl	140	21000

Embodiment 3

Compound number	R 1	R 2	R 3	(Ki)nM (pH5.5)	(Ki)nM (pH7.4)
						49	H	NH 2	CH(CH 3) 2	5	1930
50	H	NH 2	H	9	270
						51	H	NHCH 3	CH(CH 3) 2	188	2440
52	H	NH(CH 2) 2CHMe 2	CH(CH 3) 2	39	1300
						53	OCH 3	NH 2	Ph	230	26100
54	NH(CH 2) 5Me	NH 2	(CH 2) 3Me	0.3	540

Embodiment 4

Compound number	Structure R 4	(Ki)nM (pH5.5)	(Ki)nM (pH7.4)
				55	CH 2CH 2CH 3	145	16900
56	NHCH 2CH 3	40	6570

Embodiment 5

Compound number	R 1	R 2	(Ki)nM (pH5.5)	(Ki)nM (pH7.4)
					57	The NH cyclohexyl	NMe 2	2.6	18000
58	OMe	The NH benzyl	4.5	6100

Embodiment 6

Compound number	R 1	(Ki)nM (pH5.5)	(Ki)nM (pH7.4)
				59	The NH cyclohexyl	31	3900
60	The NH cyclopentyl	49	2400
				61	The NH-n-hexyl	130	4800

Embodiment 7

Fig. 1: spongosine (0.624mg/kg p.o.) is to blood pressure or not obviously effect of heart rate.Implantable biotelemetry device is placed the abdominal cavity of every group of 6 rats.The catheter pressure of device inserts in the aorta abdominalis, and two electrodes are imbedded in (abdominal cavity left side shoulder) under the skin that is in leading (lead) II position.Each rat places to be arranged in and is used for the cage separately of radioreceptor (DSI) top of image data.A: blood pressure; B: heart rate.

Embodiment 8

Spongosine is 900ng/ml (3 μ M) to the EC50 value (measuring under pH7.4) of Adenosine Receptors.Fig. 2 shows the variation with 0.6mg/kg plasma concentration versus time after the rat administration of spongosine.Therefrom as can be seen, lasting more than 2% of EC50 value that remained on above 3 hours of plasma concentration.When peak plasma concentration is between the 1%-30% of external measured EC50 value, observe anti-hyperalgesic effect (no blood pressure).If peak plasma concentration reaches the EC50 value, find that then significantly reducing appears in blood pressure, and continue 4 hours.

Embodiment 9

Fig. 3: A. spongosine (0.624mg/kg p.o.) has suppressed by carrageenin (CGN) inductive thermal hyperalgesia (CITH), and its render a service with indomethacin (3mg/kg, po) suitable.B. administration after 3 hours to the concentration-response of spongosine relation.Rear solid end carrageenan administration (2%, 10 microlitre) to the right.At the rear solid end placed around thermal source of receiving treatment and not receiving treatment, the pawl of removing that demonstrates them there are differences latent period.According to the time administration of spongosine identical with carrageenin.

Embodiment 10

Fig. 4: spongosine (0.624mg/kg p.o.) has suppressed to damage the thermal hyperalgesia that causes by the rat sciatic nerve chronic systolic.Under anesthetic action, sciatic nerve is presented in the right leg, and four loose silk threads are wrapped in around the nerve tract.After about 2 weeks, remove the difference of pawl between latent period by left and right sides pawl and judge in rat leg whether formed thermal hyperalgesia through operation.Discovery is removed the difference of pawl between latent period and is reduced to some extent, and this shows that administration of spongosine has alleviated hyperpathia.Spongosine and Carbamzepine (CBZ, 100mg/kg s.c.) are the same or more effective.

Embodiment 11

Fig. 5: having and do not having in the presence of the naloxone (1mg/kg s.c.), spongosine (1.2mg/kg p.o.) has suppressed to damage the Static allodni that causes by the rat sciatic nerve chronic systolic.Under anesthetic action, sciatic nerve is presented in the right leg, and four loose silk threads are wrapped in around the nerve tract.After about 2 weeks, judge in rat leg whether formed Static allodni through treatment by the difference that left and right sides pawl is removed between the pawl threshold value.Discovery is removed pawl threshold value (PWT) and is all increased in the presence of the naloxone having and do not have, and this shows that administration of spongosine has alleviated hyperpathia.Veh: solvent.

Embodiment 12

Fig. 6: spongosine and gabapentin have suppressed to damage the Static allodni that causes by the rat sciatic nerve chronic systolic.Use as shown in the figure spongosine that is divided into different piece and gabapentin (p.o.).The total dose of being used is presented on the transverse axis, removes pawl threshold value (PWT) and is presented on the longitudinal axis.If the activity of two kinds of compounds is synergetic words (*), then show the anti-hyperpathia activity (dose response curve that is obtained by each medicament of independent employing obtains) of expection.Viewed active with (■) expression.There is not significant difference between obvious viewed activity and the activity that obtains by stack expection.

Embodiment 13

With human macrophage is that the U937 cell is grown in the suspension with 500,000 cells/ml, and titration is handled the back with 20ng/ml PMA and cultivated 8 hours in 48 orifice plates then.Cell adhesion is at the bottom of the hole, and recovered 36 hours before using the washing back.Orifice plate is cultivated in advance with the spongosine enriched material, adds 100ng/ml LPS after 10 minutes and generates to stimulate TNF.After 3 hours, use the TNF-α in the fluorescently-labeled ELISA test kit analysis of cells supernatant liquor.The figure of display result (antagonism spongosine enriched material suppresses TNF-α and discharges) as shown in Figure 7.The result shows that spongosine has suppressed LPS inductive TNF and discharged, and this restraining effect is to Adenosine Receptors inhibitor sensitivity.

Embodiment 14

Compound 2 and 32 preparation

Schema 1

Add Benzoyl chloride (7eq) in the pyridine solution of adenosine (1eq), resulting solution refluxed 4 hours down at 80 ℃.Solvent removed in vacuo, resistates are dissolved among the EtOAc, use NaHCO ₃The aqueous solution, salt solution and water washing, organic phase MgSO ₄Dry.Obtain pentaphene formyl radical adenosine by methylene dichloride (DCM)/EtOH crystallization into white solid.

Add trifluoroacetic anhydride (TFAA) (1.5eq) in tetramethyl-ammonium nitrate (TMAN) DCM solution (1.5eq), resulting solution at room temperature stirred 1 hour.Mixture is cooled to 0 ℃, adds the DCM solution of pentaphene formyl radical adenosine (1eq).Resulting solution was warmed to room temperature in 4 hours.Solution NaHCO then ₃The aqueous solution, salt solution and water washing (x3), organic phase MgSO ₄Dry.By the DCM/EtOH crystallization, obtain pentaphene formyl radical-2-nitro-adenosine into light yellow solid.

To alcohol roh (R=CH ₂CHF ₂(2) or CH ₂Cyclopentyl (32)) add NaH (1.5eq) in the THF solution (1.5eq), resulting suspension stirred 1 hour.Resulting solution is added in the THF solution of pentaphene formyl radical-2-nitro-adenosine (1eq), continues to stir 16 hours.Solvent removed in vacuo then, resistates is dissolved among the MeOH.Add NaOMe (4eq) then, resulting suspension stirred after 4 hours, used the aqueous citric acid solution quencher.Solvent removed in vacuo, resistates obtains the 2-alkoxy derivative by reversed-phase column chromatography method purifying.

Embodiment 15

Compound 3 and 35 preparation

Schema 2

In the MeCN suspension of inosine (1eq) and DMAP (0.1eq), add Et ₃N (3.8eq) and diacetyl oxide (3.5eq), resulting mixture stirred 1 hour.Add MeOH then, continue to stir 15 minutes.Solvent removed in vacuo subsequently, product is developed with Virahol.Behind the resulting solid filtering, obtain triacetyl oxygen base inosine with washed with isopropyl alcohol.

CHCl to triacetyl oxygen base inosine (1eq) ₃Add DMF (3eq) and thionyl chloride (3eq) in the solution, resulting solution refluxed 16 hours.Solvent removed in vacuo then, resistates is dissolved among the DCM, uses NaHCO ₃With the salt water washing, organic phase MgSO ₄Drying obtains triacetyl oxygen base-6-chlorine adenosine.

Add trifluoroacetic anhydride (TFAA) (1.5eq) in tetramethyl-ammonium nitrate (TMAN) DCM solution (1.5eq), resulting solution at room temperature stirred 1 hour.Mixture is cooled to 0 ℃, adds the DCM solution of triacetyl oxygen base-6-chloro-adenosine (1eq).Resulting solution was warmed to room temperature in 2.5 hours.Solution is used NaHCO subsequently ₃The aqueous solution, salt solution and water washing (x 3), organic phase MgSO ₄Dry.By the DCM/EtOH crystallization, obtain triacetyl oxygen base-6-chloro-2-nitro-adenosine, with its water and EtOH washing into light yellow solid.

To alcohol roh (R=CH ₂Cyclopropyl (3) or 2,2,3,3-ptfe ring butane (35)) add NaH (1.5eq) in the THF solution (1.5eq), resulting suspension stirred 15 minutes.Resulting solution is added in the THF solution of triacetyl oxygen base-6-chloro-2-nitro-adenosine (1eq) then, continues to stir 2-6 hour.Solvent removed in vacuo adds EtOH and NH subsequently ₃The aqueous solution, resulting solution heated 16 hours in 80 ℃ airtight test tube.After the mixture cooling, solvent removed in vacuo, resistates obtains the 2-alkoxy derivative by reversed-phase column chromatography method purifying.

Embodiment 16

The preparation of compound 7-18

Schema 3

To phenol ArOH (Ar=4-cyano-phenyl (7) or 3-phenyl-phenyl (8) or 2,5-difluorophenyl (9) or 2,4-difluorophenyl (10) or 3,4-difluorophenyl (11) or 2,3,5-trifluorophenyl (12) or 3-methyl, 4-fluorophenyl (13) or 2-aminomethyl phenyl (14) or 3-bromophenyl (15) or 4-aminomethyl phenyl (16) or 5-indanyl (17) or 3-isopropyl phenyl (18)) add KOtBu (1.5eq) in (1.5eq) the THF solution, resulting suspension stirred 30 minutes.Resulting solution is added in pentaphene formyl radical-2-nitro-adenosine (referring to schema 1) THF solution (1eq), continues to stir 16 hours.Solvent removed in vacuo then, resistates is dissolved among the MeOH.Add NaOMe (4eq) subsequently, resulting suspension stirred after 4 hours, used the aqueous citric acid solution quencher.Solvent removed in vacuo, resistates obtains 2-aryloxy derivative by reversed-phase column chromatography method purifying.

Embodiment 17

Compound 22-25 and 31 preparation

Schema 4

With the solution of 2-chlorine adenosine in pure amine RR ' NH (outside RR ' N=NH-(R)-sec-butyl (22) or NH-(S)-sec-butyl (23) or NH-n-hexyl (24) or the NH--norbornane (25) or N (Me) isopentyl (31)) 190 ℃ of following microwave heatings 30 minutes or 40-100 ℃ of heating 16 hours down.Solvent removed in vacuo then, resistates obtains 2-aminoalkyl group derivative by reversed-phase column chromatography method purifying.

Embodiment 18

The preparation of compound 33

Schema 5

Add NaSEt (1.3eq) in the DMSO solution of 2-chloro-adenosine (1eq), resulting solution heated 20 hours down at 80 ℃.Solvent removed in vacuo then, resistates obtains 2-ethylmercapto group-adenosine by reversed-phase column chromatography method purifying.

MeCN/H to 2-ethylmercapto group-adenosine ₂Add metachloroperbenzoic acid (mCPBA) (3eq) in O (1: the 1) solution, continue to stir 16 hours.Solvent removed in vacuo then, resistates obtains 33 by reversed-phase column chromatography method purifying.

Embodiment 19

The preparation of compound 37

Schema 6

With 2-iodo-adenosine (1eq), ArB (OH) ₂(Ar=3,5-3,5-dimethylphenyl) (1eq), Pd (PPh ₃) ₄(0.1eq), Cs ₂CO ₃(2.2eq) and Et ₃The solution of N (2.2eq) in PhMe/EtOH (2: 1) heated 16 hours down at 110 ℃.Suspension filters subsequently, behind the filtrate vacuum concentration, by reversed-phase column chromatography method purifying, obtains 37.

Embodiment 20

The preparation of compound 40

Schema 7

To 3 '-adding Benzoyl chloride (6eq) in the pyridine solution of deoxidation-adenosine (1eq), resulting solution refluxed 4 hours down at 65 ℃.Solvent removed in vacuo, resistates are dissolved among the EtOAc, water (x3) and salt water washing, organic phase MgSO ₄Dry.Use the silica gel chromatography purifying, obtain 3 '-deoxidation-four benzoyl adenosine.

Add TFAA (1.5eq) in the DCM solution of TMAN (1.5eq), resulting solution at room temperature stirred 1 hour.Mixture is cooled to 0 ℃, add 3 '-the DCM solution of deoxidation four benzoyl adenosines (1eq).Resulting solution was warmed to room temperature in 16 hours.Solution is water (x3) and salt water washing subsequently, organic phase MgSO ₄Drying, obtain 3 '-deoxidation-four benzoyls-2-nitro-adenosine.

Add NaH (2.1eq) in the THF solution of n-hexyl alcohol (2eq), resulting suspension stirred 30 minutes.Resulting solution is added to 3 '-the THF solution of deoxidation-four benzoyls-2-nitro-adenosine (1eq) in, continue to stir for 1 week.Solvent removed in vacuo then, resistates is by the silica gel column chromatography purifying.In the THF of above-mentioned substance solution, add NH ₃The aqueous solution, resulting suspension stirred 12 hours.Solvent removed in vacuo, resistates obtains 40 by reversed-phase column chromatography method purifying.

Embodiment 21

Compound 44,45 and 47 preparation

Schema 8

In the MeOH of 6-chlorine adenosine (1eq) or DMSO solution, add amine RR ' NH (RR ' N=N (Me) CH ₂(3-bromophenyl) (44) or N (Me) CH ₂(3-trifluoromethyl) (45) or N (Me) CH ₂CH ₂OMe (47)) (3-5eq), resulting solution stirring is 16 hours.Solvent removed in vacuo then, resistates obtains 6-dialkylamino derivative by reversed-phase column chromatography method purifying.

Embodiment 22

The preparation of compound 48

Schema 9

Add NaH (1.5eq) in the THF solution of cyclopentyl-methyl alcohol (1.5eq), resulting suspension stirred 1 hour.Resulting solution is added in triacetyl oxygen base-6-chloro-adenosine (referring to schema 2) THF solution (1eq), continues to stir 16 hours.Solvent removed in vacuo then, resistates is dissolved among the MeOH.Add NaOMe (4eq) subsequently, resulting suspension stirred after 4 hours, used the aqueous citric acid solution quencher.Solvent removed in vacuo, resistates obtains the 6-alkoxy derivative by reversed-phase column chromatography method purifying.

Embodiment 23

Compound 51 and 52 preparation

Flow process Figure 10

Under 0 ℃, in the acetone suspension of 6-chloro-adenosine, add HClO ₄, continue to stir 2 hours.Add NH then ₃The aqueous solution, solution for vacuum concentration.Solution is cooled to-20 ℃, collects resulting white precipitate 2 ', 3 '-isopropylidene-6-chloro-adenosine, uses washing with acetone then.

With KOH (2.5eq) and KMnO ₄(2.5eq) be added in the aqueous suspension of 2 ', 3 '-isopropylidene-6-chloro-adenosine (1eq), continue to stir 4 hours.Reaction mixture is used the hydrogen peroxide quencher then, concentrates and is cooled to-20 ℃.Resulting precipitation washes with water and obtains 2 ', 3 '-O-isopropylidene-6-chloro-adenosine-5 '-carboxylic acid after collecting.

To 2 ', add RNH in the DMSO solution of 3 '-O-isopropylidene-6-chloro-adenosine-5 '-carboxylic acid (1eq) ₂(R=Me (51) or isopentyl (52)) (2eq), resulting solution stirring 16 hours.Solvent removed in vacuo then, resistates obtains corresponding 2 ', 3 '-O-isopropylidene-6-alkylamino-adenosine-5 '-carboxylic acid by reversed-phase column chromatography method purifying.

With 2 ', 3 '-O-isopropylidene-6-alkylamino-adenosine-5 '-carboxylic acid (1eq), Mukiyama ' s reagent (1.2eq), Isopropylamine (1.5eq) and Et ₃The solution stirring of N (2.5eq) in DMF 6 hours.Solvent removed in vacuo then, resistates is by reversed-phase column chromatography method purifying.Handled 2 hours with trifluoroacetic acid (TFA)/water (2: 1), solvent removed in vacuo by reversed-phase column chromatography method purifying, obtains title product then.

Embodiment 24

The preparation of compound 53

Flow process Figure 11

Under 0 ℃, in the acetone suspension of 2-methoxyl group-adenosine, add HClO ₄, continue to stir 2 hours.Add NH then ₃The aqueous solution, solvent removed in vacuo, resistates obtains 2 ', 3 '-O-isopropylidene-2-methoxyl group-adenosine by reversed-phase column chromatography method purifying.

With KOH (2.5eq) and KMnO ₄(2.5eq) be added in the aqueous suspension of 2 ', 3 '-O-isopropylidene-2-methoxyl group-adenosine (1eq), continue to stir 2 hours.Add KOH (0.2eq) and KMnO again ₄(0.2eq), and continue to stir 4 hours.Reaction mixture is used the hydrogen peroxide quencher then, concentrates and is cooled to-20 ℃.Resulting precipitation washes with water after collecting, and obtains 2 ', 3 '-O-isopropylidene-2-methoxyl group-adenosine-5 '-carboxylic acid.

With 2 ', 3 '-O-isopropylidene-2-methoxyl group-adenosine-5 '-carboxylic acid (1eq), Mukiyama ' s reagent (1.2eq), aniline (1.5eq) and Et ₃The solution stirring of N (2.5eq) in DMF 6 hours.Add DMSO/ water (1: 1) then, resulting white solid filters.This solid is dissolved in the TFA/ water (2: 1), continues to stir 5 hours.Solvent removed in vacuo then, resistates obtains 53 by reversed-phase column chromatography method purifying.

Embodiment 25

The preparation of compound 54

Flow process Figure 12

Under 0 ℃, in the acetone soln of 2-chloro-adenosine, add HClO ₄, continue to stir 2 hours.Add NH then ₃The aqueous solution, solution for vacuum concentration.Solution is cooled to-20 ℃, collects resulting white precipitate 2 ', 3 '-O-isopropylidene-2-chloro-adenosine, uses washing with acetone.

With KOH (2.5eq) and KMnO ₄(2.5eq) be added in the aqueous suspension of 2 ', 3 '-O-isopropylidene-2-chloro-adenosine (1eq), continue to stir 4 hours.Reaction mixture is used the hydrogen peroxide quencher then, concentrates and is cooled to-20 ℃.Resulting precipitation washes with water after collecting, and obtains 2 ', 3 '-O-isopropylidene-2-chloro-adenosine-5 '-carboxylic acid.

The airtight test tube of the solution of 2 ', 3 '-O-isopropylidene-2-chloro-adenosine-5 '-carboxylic acid (1eq) in clean normal hexyl Amine at 100 ℃ heated 24 hours.After the solvent removed in vacuo,, obtain light brown solid (1eq), it is dissolved among 0 ℃ the DMF by reversed-phase column chromatography method purifying.In this solution, add n-Butyl Amine 99 (4eq), DIPEA (2.1eq) and HBTU (1eq), continue to stir 4 hours down at 0 ℃.Solvent removed in vacuo then, resistates is dissolved among the EtOAc, with 0.2N HCl, NaHCO ₃The aqueous solution and salt water washing, MgSO ₄Drying obtains yellow oil.

This oily matter is dissolved in the TFA/ water (2: 1), continues to stir 2 hours.Solvent removed in vacuo then, resistates obtains 54 by reversed-phase column chromatography method purifying.

Embodiment 26

The preparation of compound 55

Flow process Figure 13

Under 0 ℃, in the acetone suspension of adenosine, add HClO ₄, continue to stir 2 hours.Add NH then ₃The aqueous solution, solution for vacuum concentration.After solution is cooled to-20 ℃, collect resulting white precipitate 2 ', 3 '-O-isopropylidene-adenosine, use washing with acetone.

Under argon shield, to 2 ', add azo-2-carboxylic acid's diethyl ester (1eq) in 3 '-O-isopropylidene-adenosine (1eq) and triphenylphosphine (1eq) and the solution of phthalic imidine (1.03eq) in THF, mixture stirred 10 hours.Resulting precipitation is washed with diethyl ether after collecting.Add hydrazine (15eq) in the EtOH solution of this solid (1eq), solution refluxed 2 hours, was cooled to room temperature then.Behind the resulting sedimentation and filtration, be dissolved in the water, regulate pH to 4.Behind the sedimentation and filtration, filtrate is adjusted to pH 10, uses chloroform extraction, MgSO ₄Drying obtains 2 ', 3 '-O-isopropylidene-5 '-amino adenosine.

Under 0 ℃, in the DMF solution of butyric acid (1eq), add DIPEA (1.2eq) and TBTU (1eq), continue to stir 5 minutes.Solution form with DMF adds 2 ', 3 '-O-isopropylidene-5 '-amino adenosine (1eq), resultant solution stirring 3 hours then.With the DCM extraction, water (x3) washs crude product, MgSO subsequently ₄Dry.

After 2 hours, then solvent removed in vacuo by reversed-phase column chromatography method purifying, obtains 55 with TFA/ water (2: 1) processing.

Embodiment 27

The preparation of compound 56

Flow process Figure 14

To 2 ', add ethyl isocyanate (1.2eq) in 3 '-O-isopropylidene-5 '-amino-adenosine (referring to flow process Figure 13) DCM solution (1eq), continue to stir 16 hours.Add versamid 900 then, filter the rear filtrate vacuum concentration.By reversed-phase column chromatography method purifying.

Resulting solid is dissolved in the TFA/ water (2: 1), continues to stir 3 hours.Solvent removed in vacuo then, resistates obtains 56 by reversed-phase column chromatography method purifying.

Embodiment 28

The preparation of compound 57

Flow process Figure 15

In triacetyl oxygen base-6-chloro-2-nitro-adenosine (referring to schema 2) THF solution (1eq), add dimethylamine (2eq), continue to stir 4 hours.Add hexahydroaniline (1eq) then, resulting solution heated 2 days down at 85 ℃.Solvent removed in vacuo then, resistates is dissolved among the MeOH.Add NaOMe (1eq) then, resulting suspension stirred 16 hours.After the solvent removed in vacuo, resistates obtains 57 by reversed-phase column chromatography method purifying.

Embodiment 29

The preparation of compound 58

Flow process Figure 16

In triacetyl oxygen base-6-chloro-2-nitro-adenosine (referring to schema 2) DMF solution (1eq), add benzylamine (1eq) and Et ₃N (1.5eq) continues to stir 10 minutes.Solvent removed in vacuo then, resistates is dissolved among the MeOH then by reversed-phase column chromatography method purifying.Add NaOMe (2eq) subsequently, resulting solution stirring 4 hours.After the solvent removed in vacuo, resistates obtains 58 by reversed-phase column chromatography method purifying.

Embodiment 30

The preparation of compound 59-61

Flow process Figure 17

Add bromine (1.2eq) in the solution of 2-chlorine adenosine (1eq) in the 1M NaOAc aqueous solution (being buffered to pH 4), resulting solution at room temperature stirred 16 hours.Reaction mixture is used NaHSO then ₃Aqueous solution quencher is adjusted to pH 7 and is cooled to 4 ℃.After resulting precipitation 2-chloro-8-bromo-adenosine is collected, wash with water and drying.

The solution of 2-chloro-8-bromo-adenosine (1eq) in HMDS and two  alkane was refluxed 8 hours down at 110 ℃.Solvent removed in vacuo then, add toluene after, solvent removed in vacuo once more.Resistates is dissolved in the N-Methyl pyrrolidone (NMP), adds Pd (PPh ₃) ₄(0.04eq) and SnMe ₄(2eq), resulting suspension heated 16 hours down at 110 ℃.After the solution cooling, solvent removed in vacuo.Resistates is dissolved among the EtOAc, washes organic phase MgSO with water ₄Dry.In the MeOH of resulting oily matter solution, add K ₂CO ₃, resulting suspension stirred 4 hours.Solvent removed in vacuo then, resistates obtains 2-chloro-8-methyladenosine by reversed-phase column chromatography method purifying.

Clean amine RNH with 2-chloro-8-methyladenosine ₂(R=cyclohexyl (59) or cyclopentyl (60) or n-hexyl (61)) solution was 190 ℃ of following microwave heatings 30 minutes.Solvent removed in vacuo then, resistates obtains 8-methyl-2-aminoalkyl group derivative by reversed-phase column chromatography method purifying.

Embodiment 31

Measure the plasma concentration of spongosine among 5 or 6 people volunteers behind independent oral administration.Use 12 ECG that lead to measure tachycardia.Minimum effective pain relieving plasma concentration in the rat is 0.025 μ M, and the subliminal dose among this prompter should be about 0.8mg, and this dosage can obtain approximately to continue 1.5 hours plasma concentrations above 0.025 μ M.

Dosage	Plasma C max (μ M)	The tachycardia side effect
			0.2mg 0.8mg 3.5mg 10.5mg 21mg 28mg	0.01±0.005 0.04±0.02 0.13±0.04 0.3±0.04 0.5±0.1 0.6±0.1	Not having has

Embodiment 32

Under the concentration that does not influence blood pressure, spongosine (62.4 and 624 μ g/kg i.p.) has suppressed carrageenin (CGN) inductive inflammation, and has and indomethacin (3mg/kg, po) suitable effectiveness.To the right back pawl carrageenan administration (2%, 10 microlitre) of rat, by plethysomometry measuring claw volume.According to the time administration of spongosine identical with carrageenin.The result as shown in Figure 8.(Indo, 3mg/kg p.o.) is equally effective for spongosine and indomethacin.

Claims (76)

1. be used as following general formula compound or its pharmacologically acceptable salt of medicine:

Wherein:

(I) work as X=OH, R ₂=NH ₂, R ₅=CH ₂OH, R ₆During=H, R ₁Be C ₅-C ₆Alkoxyl group, OCH ₂Cyclopropyl, OCH ₂Cyclopentyl, O-(2,2,3,3-tetrafluoro-cyclobutyl), phenoxy group, substituted phenoxy group, OCH ₂CH ₂OH or OCH ₂CHF ₂, (5-indanyl) oxygen base, C ₁, C ₂, C ₅Or C ₆Alkylamino, (R) or (S)-Zhong Ding amino, C ₅Or C ₆Naphthene amino, exonorborn alkylamino, (N-methyl, N-isoamylamino), phenylamino, phenylamino, C with methoxyl group or fluoro substituents ₂Sulfuryl, C ₇Alkyl, cyano group, CONH ₂Group or 3, the 5-3,5-dimethylphenyl; Or

Work as X=H, R ₂=NH ₂, R ₅=CH ₂OH, R ₆During=H, R ₁It is positive hexyloxy; Or

(II) work as X=OH, R ₁=H, R ₅=CH ₂OH, R ₆During=H, R ₂Be NMe ₂, N-(2-isopentene group), piperazinyl, (N-Me, N-benzyl), (N-Me, N-CH ₂Ph (3-Br)), (N-Me, N-CH ₂Ph (3-CF ₃)) or (N-Me, N-(2-methoxy ethyl)) or OCH ₂Cyclopentyl; Or

(III) work as X=OH, R ₅=CONHR ₃, R ₆During=H:

R ₁Be H, R ₃Be sec.-propyl, and R ₂Be NH ₂Or methylamino (NHMe) or isopentyl (CH ₂CH ₂CHMe ₂); Or

R ₁Be H, R ₃Be H, and R ₂Be NH ₂Or

R ₁Be OMe, R ₃Be Ph, and R ₂Be NH ₂Perhaps

R ₁Be NHCH ₂CH ₂CH ₂CH ₂CH ₂Me, R ₃Be CH ₂CH ₂CH ₂Me, and R ₂Be NH ₂Or

(IV) work as X=OH, R ₁=H, R ₂=NH ₂, R ₅=CH ₂NHCOR ₄, R ₆During=H, R ₄Be n-propyl or NHCH ₂CH ₃Or

(V) work as X=OH, R ₅=CH ₂OH, R ₆=H:

R ₂Be NMe ₂The time, R ₁It is the NH cyclohexyl; Or

R ₂When being the NH benzyl, R ₁Be OMe; Perhaps

(VI) work as X=OH, R ₂=NH ₂, R ₅=CH ₂OH, R ₆During=Me, R ₁Be NH cyclohexyl, NH cyclopentyl or NH n-hexyl.

2. as (I) compound of the formula according to claim 1 or its pharmacologically acceptable salt of medicine, wherein working as X is OH, R ₂Be NH ₂, R ₅Be CH ₂OH, and R ₆When being H, R ₁By 4-nitrile, 4-methyl, 3-phenyl, 3-bromine, 3-sec.-propyl, 2-methyl, 2,4-difluoro, 2,5-difluoro, 3,4-difluoro, 2,3, the phenoxy group that 5-trifluoro or (3-methyl, 4-fluorine) replace.

3. as the compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 of medicine, described compound has as any one described structure among the embodiment 1-6.

4. as the compound or pharmaceutically acceptable salt thereof according to claim 3 of medicine, described compound has corresponding to any one structure in the numbering described in embodiment 1-6 2,3,7-19,22-25,28,31-33 or the 35-60 compound.

5. as the compound or pharmaceutically acceptable salt thereof according to claim 3 of medicine, described compound have corresponding to the numbering described in embodiment 1-6 2,3,7-18,22-25,31-33,35,37,40,44,45,47,48 or the 51-60 compound in any one structure.

As described above in the claim pharmacologically acceptable salt of any described compound or formula (VII) compound be used to prepare prevention, treatment or alleviate and can improve or the purposes of the medicine of the pathologic conditions of preventing by exciting adenosine A 2 A receptor:

Wherein: R is C _1-4Alkoxyl group, and X is H or OH.

7. formula as claimed in claim 6 (VII) compound is used to prepare prevention, treatment or alleviates and can improve or the purposes of the medicine of the pathologic conditions of preventing by exciting adenosine A 2 A receptor, and described illness is got rid of pain, cancer, inflammation, autoimmune disease, ischemia reperfusion injury, epilepsy, septicemia, septic shock, neurodegeneration (comprising Alzheimer), muscle fatigue and muscle cramp.

8. be used to prepare the purposes of prevention, treatment or lenitive medicine as the pharmacologically acceptable salt of any described compound among the claim 1-5 or formula as claimed in claim 6 (VII) compound.

9. purposes according to Claim 8, wherein said pain is hyperpathia.

10. according to the purposes of claim 9, wherein said hyperpathia is neuropathic pain.

11. any one purposes according to Claim 8-10, be used for prevention, treatment or alleviation: the pain relevant with cancer, pancrealgia, pelvic/perineal pain, infect relevant pain with HIV, chronic neuropathic pain, low back pain, back surgery failure pain, backache, postoperative pain, pain behind the physical trauma, pained, pectoralgia, pelvic pain/PID, arthrodynia, cervicodynia, enterodynia, phantom limb pain, obstetrics' pain, acute herpes zoster pain, the acute pancreatitis pain of breaking perhaps is used for prevention, treatment or alleviation are by diabetic neuropathy, polyneuropathy, fibromyalgia, myofascial pain syndrome, osteoarthritis, postherpetic neuralgia, rheumatoid arthritis, sciatica/lumbar nerve root disease, spinal stenosis, temporomandibular joint disorder, trigeminal neuralgia, renal colic, dysmenorrhoea/endometriosis causes or relative nervosa or other pain.

12. according to the purposes of claim 9, wherein said hyperpathia is inflammatory pain.

13. according to Claim 8, any one purposes in 9 or 12, wherein said pain causes by inflammation or Immunological diseases or is relevant with it, perhaps is the result of the inflammatory, autoimmunity and the neuropathic tissue injury that merge.

14. according to Claim 8,9, any one purposes in 12 or 13, be used for prevention, treatment or alleviation enterodynia, the pain relevant with cancer, backache, postoperative pain perhaps is used for prevention, treatment or alleviation are by rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, urarthritis, cancer, HIV, chronic pulmonary inflammation disease, silicosis, the lung sarcosis, bone resorption disease, reperfusion injury, the autoimmunization damage, graft is to host's repulsion, allograft rejection, heating that infection causes and myalgia, fibromyalgia, the complication relevant (ARC) with AIDS, keloid forms, scar tissue forms, Crohn disease, ulcerative colitis and heating, irritable bowel syndrome, osteoporosis, cerebral malaria and bacterial meningitis cause or relative inflammatory or other pain.

15. the purposes of purposes according to Claim 8 or formula as claimed in claim 6 (VII) compound, the medicine that is used to prepare prevention, treatment or alleviates avascular pain.

16. according to Claim 8 or 15 purposes, be used for the preparation prevention, treatment or alleviation and coronary artery disease, peripheral arterial disease, left ventricular hypertrophy, essential hypertension, the acute hypertension acute disease, myocardosis, the heart body deficiency, exercise tolerance, chronic heart failure, irregular pulse, arrhythmia, syncopy, arteriosclerosis, slight chronic heart failure, stenocardia, Prinzmetal ' s (mutation) angina, stable angina pectoris, exercise induced stenocardia, heart bypass is closed again, intermittent claudication (arteriosclerosis oblitterens), arteritis, diastolic dysfunction, the systole dysfunction, atherosclerosis, behind the ischemic/reperfusion injury, diabetes (I type or II type), thromboembolism, bleeding episode, the perhaps medicine of the pain that nervosa that is caused by the neural cell injury of hypoxia inducible or inflammatory pain are relevant.

17. be used to prepare prevention, treat or alleviate the great vessels of 1 type and diabetes B or microvascular complication, retinopathy, ephrosis, autonomic neuropathy or the purposes of the medicine of the blood vessel injury that causes by ischemic or atherosclerosis as any described compound among the claim 1-5 or formula as claimed in claim 6 (VII) compound or pharmaceutically acceptable salt thereof.

18. as any described compound among the claim 1-5 or be used to prepare the purposes of the medicine of prevention, treatment or amelioration of inflammation as the pharmacologically acceptable salt of formula (VII) compound as described in the claim 6.

19., be used for prevention, treatment or alleviate causing or relative inflammation: cancer (for example leukocytosis, lymphoma, cancer, colorectal carcinoma, mammary cancer, lung cancer, carcinoma of the pancreas, hepatocellular carcinoma, kidney, melanoma, liver cancer, lung cancer, mammary cancer and prostate gland metastatic carcinoma etc.) by following disease according to the purposes of claim 18; Autoimmune disease (for example organ-graft refection, lupus erythematosus, graft comprise that to host's repulsion, allograft rejection, multiple sclerosis, rheumatoid arthritis, type i diabetes pancreas islet destroys the diabetes that cause and the inflammation result of diabetes); Autoimmunization damage (comprising multiple sclerosis, Guillam Barre syndrome, myasthenia gravis); Fat; With the not enough cardiovascular disorder relevant of perfused tissue (cardiovascular complications of for example vasospasm that causes of congee sample spot, atherosclerosis, apoplexy, ischemia reperfusion injury, limping, congestive heart failure, vasculitis, hemorrhagic shock, subarachnoid hemorrhage, vasospasm that cerebrovascular accident causes, pleuritis, pericarditis, diabetes) with inflammation; The restenosis that ischemia reperfusion injury, ischemic and occurring together property inflammation, angioplasty and inflammatory aneurysma cause; Epilepsy, neurodegeneration (comprising Alzheimer), muscle fatigue or muscle cramp (particularly sportsmen's cramp), sacroiliitis (rheumatoid arthritis for example, osteoarthritis, rheumatoid spondylitis, urarthritis), fibrosis (lung for example, skin and hepatic fibrosis), septicemia, septic shock, encephalitis, infective arthritis, jarisch-Herxheimer reaction, zoster, toxic shock, cerebral malaria, Lyme ' s disease, interior toxicogenic shock, gram-negative shock, hemorrhagic shock, hepatitis (causing) by tissue injury or virus infection, dvt forms, gout; The disease (for example chronic retardancy tuberculosis, air flue retardance and obstruction, bronchoconstriction, lung vasoconstriction, dyspnoea, chronic pulmonary inflammation disease, silicosis, lung sarcosis, cystic fibrosis, pulmonary hypertension, lung vasoconstriction, pulmonary emphysema, broncho-allergic reaction and/or inflammation, asthma, ragweed fever, rhinitis, vernal conjunctivitis and adult respiratory distress syndrome) relevant with expiratory dyspnea; The illness relevant (comprising psoriatic, eczema, ulcer, contact dermatitis) with chafing; The illness relevant (comprising Crohn disease, ulcerative colitis and heating, irritable bowel syndrome, inflammatory bowel) with the intestines inflammation; HIV (particularly HIV infects), bacterial meningitis, TNF-enhanced HIV duplicates, the active TNF of AZT and DDI suppresses, osteoporosis and other bone resorption disease, osteoarthritis, rheumatoid arthritis, it is sterile that endometriosis causes, heating that infection causes and myalgia, be secondary to the emaciation of cancer, be secondary to the emaciation of infection or malignant tumour, be secondary to the emaciation of acquired immune deficiency syndrome (AIDS) (AIDS), relevant with AIDS and freeze (ARC), keloid forms, scar tissue forms, the undesirable action that the amphotericin B treatment causes, the undesirable action that the interleukin-2 treatment causes, the undesirable action that the OKT3 treatment causes, perhaps GM-CSF treats the undesirable action that causes, and other (comprises neutrophilic granulocyte by excessive anti-inflammatory cell, eosinocyte, hugely have a liking for cell and T-cell) illness of active mediation.

20. be used to prepare the purposes of the moist medicine of wind resistance (DMARD) of the adjusting disease that delays the joint disease progress as any described compound among the claim 1-5 or formula as claimed in claim 6 (VII) compound or pharmaceutically acceptable salt thereof.

21. 20 purposes according to claim is used to prepare the DMARD that delays rheumatoid arthritis.

22. according to any described purposes in the aforementioned claim, wherein after the object administration, the compound peak plasma concentration that used dosage obtains is lower than this compound in 7.4 times EC50 values to Adenosine Receptors of pH.

23. according to any described purposes in the aforementioned claim, wherein used dosage for infraspecific animal as described compound administration object in cause the described compound lowest dose level of bradyrhythmia, ypotension or tachycardia side effect thousandth to five/one.

24. according to the purposes of claim 23, wherein said dosage is to cause that one of the percentage of lowest dose level of described side effect is to 1/5th.

25. according to any described purposes in the aforementioned claim, wherein after the object administration, the compound plasma concentration that used dosage obtains surpassed in 1 hour time period, as with the infraspecific animal of described compound administration object in, remain between thousandth to two/one of the described compound lowest dose level that causes bradyrhythmia, ypotension or tachycardia side effect.

26. according to any described purposes in the aforementioned claim, wherein used dosage is less than 0.4mg/kg.

27. according to any described purposes in the aforementioned claim, wherein used dosage is 0.003mg/kg at least.

28. according to any described purposes in the aforementioned claim, wherein used dosage is 0.01-0.1mg/kg.

29. have corresponding to the compound number described in embodiment 1-6 2,3,7-18,22-25,31-33,35,37,40,44,45,47,48 or 51-60 in the compound of any one structure, or its pharmacy acceptable salt.

30. prevention, treatment or alleviate and can be prevented or the method for the pathologic conditions improved by exciting adenosine A 2 A receptor, described method comprise in the object of this prevention of needs, treatment or alleviation is used as claim 1-5 any described compound or as the pharmacologically acceptable salt of formula (VII) compound as described in the claim 6.

31. prevention, treatment or alleviate and to be prevented or the method for the pathologic conditions improved by exciting adenosine A 2 A receptor, described illness is got rid of pain, cancer, inflammation, autoimmune disease, ischemia reperfusion injury, epilepsy, septicemia, septic shock, neurodegeneration (comprising Alzheimer), muscle fatigue and muscle cramp, and described method comprises to the object of this prevention of needs, treatment or alleviation uses formula as claimed in claim 6 (VII) compound.

32. prevention, treatment or lenitive method, described method comprise in this prevention of needs, treatment or the object alleviated are used as claim 1-5 any described compound or as the pharmacologically acceptable salt of formula (VII) compound as described in the claim 6.

33. the method for prevention, treatment or alleviation avascular pain, described method comprises any described compound or formula as claimed in claim 6 (VII) compound or pharmaceutically acceptable salt thereof in the object of this prevention of needs, treatment or alleviation is used as claim 1-5.

34. according to the method for claim 33, it is used for prevention, treatment or alleviation and coronary artery disease, peripheral arterial disease, left ventricular hypertrophy, essential hypertension, the acute hypertension acute disease, myocardosis, the heart body deficiency, exercise tolerance, chronic heart failure, irregular pulse, arrhythmia, syncopy, arteriosclerosis, slight chronic heart failure, stenocardia, Prinzmetal ' s (mutation) angina, stable angina pectoris, exercise induced stenocardia, heart bypass is closed again, intermittent claudication (arteriosclerosis oblitterens), arteritis, diastolic dysfunction, the systole dysfunction, atherosclerosis, behind the ischemic/reperfusion injury, diabetes (I type or II type), thromboembolism, bleeding episode or the nervosa or the relevant avascular pain of inflammatory pain that cause by the neural cell injury of hypoxia inducible.

35. the method for prevention, treatment or amelioration of inflammation, described method comprise in this prevention of needs, treatment or the object alleviated are used as claim 1-5 any described compound or as the pharmacologically acceptable salt of formula (VII) compound as described in the claim 6.

36. according to the method for claim 35, it is used for prevention, treatment or alleviates being caused or relative inflammation by following disease: cancer (for example leukocytosis, lymphoma, cancer, colorectal carcinoma, mammary cancer, lung cancer, carcinoma of the pancreas, hepatocellular carcinoma, kidney, melanoma, liver cancer, lung cancer, mammary cancer and prostate gland metastatic carcinoma etc.); Autoimmune disease (for example organ-graft refection, lupus erythematosus, graft comprise that to host's repulsion, allograft rejection, multiple sclerosis, rheumatoid arthritis, type i diabetes pancreas islet destroys the diabetes that cause and the inflammation result of diabetes); Autoimmunization damage (comprising multiple sclerosis, Guillam Barre syndrome, myasthenia gravis); Fat; With the not enough cardiovascular disorder relevant of perfused tissue (cardiovascular complications of for example vasospasm that causes of congee sample spot, atherosclerosis, apoplexy, ischemia reperfusion injury, limping, congestive heart failure, vasculitis, hemorrhagic shock, subarachnoid hemorrhage, vasospasm that cerebrovascular accident causes, pleuritis, pericarditis, diabetes) with inflammation; The restenosis that ischemia reperfusion injury, ischemic and occurring together property inflammation, angioplasty and inflammatory aneurysma cause; Epilepsy, neurodegeneration (comprising Alzheimer), muscle fatigue or muscle cramp (particularly sportsmen's cramp), sacroiliitis (rheumatoid arthritis for example, osteoarthritis, rheumatoid spondylitis, urarthritis), fibrosis (lung for example, skin and hepatic fibrosis), septicemia, septic shock, encephalitis, infective arthritis, jarisch-Herxheimer reaction, zoster, toxic shock, cerebral malaria, Lyme ' s disease, interior toxicogenic shock, gram-negative shock, hemorrhagic shock, hepatitis (causing) by tissue injury or virus infection, dvt forms, gout; The disease (for example chronic retardancy tuberculosis, air flue retardance and obstruction, bronchoconstriction, lung vasoconstriction, dyspnoea, chronic pulmonary inflammation disease, silicosis, lung sarcosis, cystic fibrosis, pulmonary hypertension, lung vasoconstriction, pulmonary emphysema, broncho-allergic reaction and/or inflammation, asthma, ragweed fever, rhinitis, vernal conjunctivitis and adult respiratory distress syndrome) relevant with expiratory dyspnea; The illness relevant (comprising psoriatic, eczema, ulcer, contact dermatitis) with chafing; The illness relevant (comprising Crohn disease, ulcerative colitis and heating, irritable bowel syndrome, inflammatory bowel) with the intestines inflammation; HIV (particularly HIV infects), bacterial meningitis, TNF-enhanced HIV duplicates, the active TNF of AZT and DDI suppresses, osteoporosis and other bone resorption disease, osteoarthritis, rheumatoid arthritis, it is sterile that endometriosis causes, heating that infection causes and myalgia, be secondary to the emaciation of cancer, be secondary to the emaciation of infection or malignant tumour, be secondary to the emaciation of acquired immune deficiency syndrome (AIDS) (AIDS), the complication relevant (ARC) with AIDS, keloid forms, scar tissue forms, the undesirable action that the amphotericin B treatment causes, the undesirable action that the interleukin-2 treatment causes, the undesirable action that the OKT3 treatment causes, perhaps GM-CSF treats the undesirable action that causes, and other (comprises neutrophilic granulocyte by excessive anti-inflammatory cell, eosinocyte, hugely have a liking for cell and T-cell) illness of active mediation.

37. prevention, treat or alleviate the great vessels of 1 type and diabetes B or microvascular complication, retinopathy, ephrosis, autonomic neuropathy or the method for the blood vessel injury that caused by ischemic or atherosclerosis, described method comprises any described compound or formula as claimed in claim 6 (VII) compound or pharmaceutically acceptable salt thereof in the object of this prevention of needs, treatment or alleviation is used as claim 1-5.

38. delay the method for joint disease progress, described method comprises in the object that these needs are arranged is used as claim 1-5 any described compound or formula as claimed in claim 6 (VII) the compound or pharmaceutically acceptable salt thereof moist medicine of wind resistance (DMARD) as the adjusting disease.

39. according to the method for claim 38, described method is used to delay the progress of rheumatoid arthritis.

40. according to method any among the claim 30-39, wherein the compound peak plasma concentration that obtains of the dosage of institute's administered compound is lower than this compound in 7.4 times EC50 values to Adenosine Receptors of pH.

41. according to method any among the claim 30-40, wherein to the compound amount that this object is used make the peak plasma concentration of this compound in described object for this compound to ten thousand of the minimum EC50 value of Adenosine Receptors/to 1/2nd.

42. according to method any among the claim 30-41, wherein make this compound surpass in 1 hour time period to the compound amount that this object is used, the plasma concentration in described object remains on this compound between ten thousand of the minimum EC50 value of Adenosine Receptors/to 1/2nd.

43. according to method any among the claim 30-42, wherein to the compound amount that this object is used make the peak plasma concentration of this compound in described object for this compound to ten thousand of the minimum Kd value of Adenosine Receptors/to 1/2nd.

44. according to method any among the claim 30-43, wherein make this compound surpass in 1 hour time period to the compound amount that this object is used, the plasma concentration in described object remains on this compound between ten thousand of the minimum Kd value of Adenosine Receptors/to 1/2nd.

45. according to method any among the claim 30-44, wherein to compound amount that this object is used for infraspecific animal as described compound administration object in cause bradyrhythmia, ypotension or tachycardia side effect described compound minimum amount ten thousand/to 1/2nd.

46. according to method any among the claim 30-45, the dosage of wherein using this compound for infraspecific animal as described compound administration object in cause the described compound lowest dose level of bradyrhythmia, ypotension or tachycardia side effect thousandth to two/one.

47. according to the method for claim 46, wherein said dosage is to cause that one of the percentage of lowest dose level of described side effect is to 1/2nd.

48. according to method any among the claim 30-47, wherein surpassing in 1 hour time period to the compound plasma concentration that the compound amount that this object is used obtains, with infraspecific animal as described compound administration object in, remain on ten thousand of the minimum plasma concentration of described compound that causes bradyrhythmia, ypotension or tachycardia side effect/between 1/2nd.

49. according to method any among the claim 30-48, the compound plasma concentration that the compound dosage of wherein using obtains surpassed in 1 hour time period, in the infraspecific animal as described compound administration object, one of the percentage that remains on the described compound lowest dose level that causes bradyrhythmia, ypotension or tachycardia side effect is between 1/2nd.

50. according to method any among the claim 30-49, the compound dosage of wherein using is less than 0.4mg/kg.

51. according to method any among the claim 30-50, the compound dosage of wherein using is 0.001-0.4mg/kg.

52. according to method any among the claim 30-51, the compound dosage of wherein using is 0.003mg/kg at least.

53. according to method any among the claim 30-52, the compound dosage of wherein using is 0.01-0.1mg/kg.

54. according to method any among the claim 30-53, wherein said compound is by oral, non-enteron aisle, hypogloeeis, in skin, sheath, through mucous membrane, intravenously, intramuscular, subcutaneous, part or inhalation.

55. according to method any among the claim 30-54, wherein said compound is according to the frequency administration of every day 2 or 3 times.

56. it is, wherein said to liking the people according to method any among the claim 30-55.

57. according to the purposes of claim 20 or 21 or according to the method for claim 38 or 39, wherein said compound is spongosine or its pharmacologically acceptable salt.

58. pharmaceutical composition in unit dose form wherein contains at the most among 500mg such as the claim 1-5 acceptable carrier, excipient or thinner on any described compound and the physiology.

59. pharmaceutical composition in unit dose form wherein contains at the most among 500mg such as the claim 1-5 acceptable carrier, excipient or thinner on any described compound or formula as claimed in claim 6 (VII) compound or pharmaceutically acceptable salt thereof, NSAID or DMARD and the physiology.

60. preparation is as the method for numbering 2 as described in the embodiment 1 or 32 compounds, described method comprises reacts pentaphene formyl radical-2-nitro-adenosine with ROH, make this reaction product deprotection obtain numbering 2 or 32 compound, wherein R=CH then ₂CHF ₂Or CH ₂Cyclopentyl.

61. preparation is as the method for numbering 3 as described in the embodiment 1 or 35 compounds, described method comprises reacts triacetyl oxygen base-6-chloro-2-nitro-adenosine with ROH, make this reaction product deprotection obtain numbering 3 or 35 compound, wherein R=CH then ₂Cyclopropyl or 2,2,3,3-ptfe ring butane.

62. preparation is as any one method in the numbering 7-18 compound as described in the embodiment 1; described method comprises pentaphene formyl radical-2-nitro-adenosine and ArOH reaction; make this reaction product deprotection obtain numbering in the 7-18 compound any one then; wherein Ar=4-cyano-phenyl, 3-phenyl-phenyl, 2; 5-difluorophenyl, 2; 4-difluorophenyl, 3; 4-difluorophenyl, 2; 3; 5-trifluorophenyl, 3-methyl, 4-fluorophenyl, 2-aminomethyl phenyl, 3-bromophenyl, 4-aminomethyl phenyl, 5-indanyl or 3-isopropyl phenyl.

63. preparation is as any one method in numbering 22-25 or 31 compounds as described in the embodiment 1, described method comprises 2-chlorine adenosine and RR ' NH reaction, obtain numbering any one in 22-25 or 31 compounds, wherein RR ' N=NH-(R)-sec-butyl, NH-(S)-sec-butyl, NH-n-hexyl, NH-outer-norborneol alkyl or N (Me) isopentyl.

64. preparation is as the method for compound number 33 as described in the embodiment 1, described method comprises reacts 2-chloro-adenosine with NaSEt, obtain 2-ethylmercapto group-adenosine, obtains numbering 33 compounds by 2-ethylmercapto group-adenosine then.

65. preparation is as the method for numbering 37 compounds as described in the embodiment 1, described method comprises 2-iodo-adenosine and ArB (OH) ₂Reaction, Ar=3 wherein, 5-3,5-dimethylphenyl.

66. preparation is as the method for numbering 40 compounds as described in the embodiment 1, and described method comprises 3 '-deoxidation-four benzoyls-2-nitro-adenosine reacts with n-hexyl alcohol, makes this reaction product deprotection obtain numbering 40 compounds then.

67. preparation is as the method for numbering 44,45 as described in the embodiment 2 or 47 compounds, described method comprises reacts 6-chloro-adenosine with RR ' NH, wherein RR ' N=N (Me) CH ₂(3-bromophenyl), N (Me) CH ₂(3-trifluoromethyl) or N (Me) CH ₂CH ₂OMe.

68. preparation is as the method for numbering 48 compounds as described in the embodiment 2, described method comprises reacts triacetyl oxygen base-6-chloro-adenosine and cyclopentyl-methyl alcohol, makes this reaction product deprotection obtain numbering 48 compounds then.

69. preparation is as the method for numbering 51 as described in the embodiment 3 or 52 compounds, described method comprise with 2 of following formula ', 3 '-O-isopropylidene-6-alkylamino-adenosine-5 '-carboxylic acid:

Wherein R=Me or isopentyl;

With the Isopropylamine reaction, make the ketal group deprotection of this reaction product obtain numbering 51 or 52 compounds then.

70. preparation is as the method for numbering 53 compounds as described in the embodiment 3, and described method comprises 2 ', 3 '-O-isopropylidene-2-methoxyl group-adenosine-5 '-carboxylic acid and aniline reaction, make the ketal group deprotection of this reaction product obtain numbering 53 compounds then.

71. preparation is as the method for numbering 54 compounds as described in the embodiment 3; described method comprises 2 '; 3 '-O-isopropylidene-2-chloro-adenosine-5 '-carboxylic acid and normal hexyl Amine reaction; gained reaction product and n-Butyl Amine 99 reaction make the ketal group deprotection of this reaction product obtain numbering 54 compounds with n-Butyl Amine 99 then.

72. preparation is as the method for numbering 55 compounds as described in the embodiment 4, and described method comprises 2 ', 3 '-O-isopropylidene-5 '-amino-adenosine reacts with butyric acid, makes the ketal group deprotection of this reaction product obtain numbering 55 compounds then.

73. preparation is as the method for numbering 56 compounds as described in the embodiment 4, and described method comprises 2 ', 3 '-O-isopropylidene-5 '-amino-adenosine reacts with ethyl isocyanate, makes the ketal group deprotection of this reaction product obtain numbering 56 compounds then.

74. preparation is as the method for numbering 57 compounds as described in the embodiment 5; described method comprises triacetyl oxygen base-6-chloro-2-nitro-adenosine and dimethylamine reaction; gained reaction product and hexahydroaniline reaction make this reaction product deprotection obtain compound 57 with hexahydroaniline then.

75. preparation is as the method for numbering 58 compounds as described in the embodiment 5, described method comprises reacts triacetyl oxygen base-6-chloro-2-nitro-adenosine and benzylamine, and gained reaction product and methylate anionic reactive make the blocking group deprotection obtain compound 58 then.

76. preparation is as any one method in the numbering 59-61 compound as described in the embodiment 6, described method comprises 2-chloro-8-methyl-adenosine and RNH ₂Reaction, wherein R is cyclohexyl, cyclopentyl or n-hexyl, obtains numbering 59,60 or 61 compounds.

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