CN101123959A

CN101123959A - Aryl, heteroaromatic and bicyclic aryl nitrone compounds, prodrugs and pharmaceutical compositions of the same to treat human disorders

Info

Publication number: CN101123959A
Application number: CNA2004800266902A
Authority: CN
Inventors: 迈克尔·G·凯利; 萨加纳雷亚纳·加纳哥尼; 雷温德拉·B·阿帕萨尼
Original assignee: Renovis Inc
Current assignee: Renovis Inc
Priority date: 2003-08-04
Filing date: 2004-08-04
Publication date: 2008-02-13

Abstract

Disclosed are aryl, heteroaromatic and bicyclic aryl nitrone compounds and pharmaceutical compositions containing such derivatives. The disclosed compositions are useful for preventing and/or treating pain, neurodegenerative, autoimmune and inflammatory diseases or conditions in mammals.

Description

The aryl, heteroaryl and the aryl bicyclic nitrone compound that are used for the treatment of human diseases, its prodrug and pharmaceutical composition

The application requires the U.S. Provisional Application No.60/492 of submission on August 4th, 2003,488,60/492,489 and 60/492,490 priority, and the full content of these applications is included into this paper as a reference.

1. invention field

The present invention relates to aryl, heteroaryl and aryl bicyclic nitrone compound and they as therapeutic agent with the related indication purposes of treatment inflammation in mammals, described symptom includes but not limited to: arthritis, neurodegenerative disease such as (but being not limited to) parkinson disease and Alzheimer, apoplexy, uveitis, asthma, myocardial infarction, the treatment of pain syndrome and prevention (acute and chronic or neuropathic pain), traumatic brain injury, acute spinal cord injury, alopecia (shaving one's head), inflammatory bowel and autoimmune disease.

2. background of invention

Arthritis and related inflammatory disease symptoms have kind more than 100 multi-form, comprising rheumatoid arthritis (RA), osteoarthritis (OA), ankylosing spondylitis and systemic lupus erythematosus (sle) (SLE).The arthritis of most of forms is feature with the chronic inflammatory disease of some types.For example, RA is usually directed to joint lining and/or internal's chronic inflammatory disease.This chronic inflammatory disease makes those affected arthralgias and swelling usually and may cause damage to cartilage, bone, tendon, ligament etc., finally causes deformity and maimed person.

Known very early prostaglandins (PG) is relevant with inflammatory process.Therefore, developed the synthetic inhibitor of many PG with treatment of arthritis and relevant inflammatory diseases symptom.This NSAID (non-steroidal anti-inflammatory drug) (NSAID) stops manufacturing PG by the enzyme that suppresses such as cyclo-oxygenase (COX) and lipoxidase usually.Known COX enzyme exists with two kinds of forms.COX-1 is the composition form of finding in great majority tissue and organ.In other characteristic, COX-1 makes and keeps the necessary PG of GI road integrity on a small quantity.COX-2 is the induce form relevant with PG production increase in the inflammatory symptom.Because many NSAID suppress the COX of two kinds of forms, so they can be interfered and the irrelevant PG regulation process of inflammatory process.Consequently, many NSAID have caused the serious side effects such as gastric ulcer and injury of kidney, and this has limited their curative effect.

Therefore, need and to cross effective treatment of arthritis and other inflammation related symptoms but can not produce the novel therapeutic chemical compound of undesirable side effect.

Nitrone is the chemical compound that a class has anti-oxidation characteristics, and this is because they can form stable adduct (being spin trapping) with free radical.Cause oxidative damage because but the free radical pair cell is formed (for example protein and lipid), this can cause pathological state, it is reported, the anti-oxidation characteristics of nitrone is the part basis of its treatment potential at least.Therefore, based on the antioxidant activity of nitrone, may treat sensitivity to nitrone to the disease of antioxidation therapy sensitivity or with the generation diseases associated of free radical in the report before.

It is reported that armaticity nitrone compound such as C-(phenyl)-N-(tert-butyl) nitrone (PBN) and derivant thereof may be able to be treated many that caused by oxidative damage or oxidative stress or as the disease of feature.Compare with PBN, the treatment potential with nitrone compound of improved antioxidant activity may be better than PBN.The decomposition of armaticity nitrone, metabolism or catabolite, also may have the anti-oxidation characteristics of armaticity nitrone as N-alkyl azanol, N-alkyl hydrogen nitrogen oxide (N-alkyl hydronitroxide) or nitrogen oxide, and have the effect of interrupting the inflammatory signal pathway.That maybe stress cause by oxidative damage or comprise as the disease of feature, for example, such as the CNS of apoplexy, parkinson disease, nervous lesion etc. and the disease of PNS, and such as the peripheral organ's of atherosclerosis, cardiac infarction, ulcerative colitis etc. disease.

Also need the new armaticity nitrone derivative of a class with improvement performance such as hypotoxicity, the stability of increase, improved cell and blood brain barrier permeability and improved oral administration biaavailability.

3. summary of the invention

This paper has described and has compared the armaticity nitrone compound that PBN has improved antioxidant activity.These chemical compounds of the present invention are potential therapeutic agents of some indications, these indications it is reported and be suitable for antioxidant therapy or relevant with the generation of free radical, comprising but be not limited to: apoplexy, myocardial infarction and dysfunction, comprise the retinal ischemia and the damage of degeneration of macula and other progression of retinal degenerative disorders, renal ischaemia, arteriosclerosis and other cardiovascular disease, amyotrophic lateral sclerosis, parkinson disease, Alzheimer, Huntington Chorea, multiple sclerosis, head trauma and traumatic brain injury, nerve injury and neuropathy, migraine, schizophrenia and other cognitive disorders, mood disorders and other affective disorder, pancreatitis and other pancreatic diseases, the treatment of diabetes and related complications, epilepsy, transplanting and graft failure or repulsion, the hepatopathy that hepatitis and jaundice are brought out, pulmonary lesion and infringement, gastric ulcer, endotoxemia, aging and old and feeble, because the fetal damage that the uterus ischemia causes, pain (acute or chronic or nerve) syndromic treatment and prevention, arthritis and other autoimmune disease, asthma and anaphylaxis, inflammatory bowel, irritable bowel syndrome, uveitis, cancer, complication and treatment of conditions and alopecia (shaving one's head) that treatment of cancer causes.

The invention provides the armaticity nitrone compound that to modify mammiferous pathways of inflammation, the nitrone that the aryl, heteroaryl or the aryl bicyclic that contain replacement be provided as the pharmaceutical composition of active component and they in treatment, prevent or improve application in the multiple mammal disease, described disease such as, but be not limited to, the pain of a variety of causes or the cause of disease, as acute, chronic, inflammatory and neuropathic pain, toothache and headache (as migraine, cluster headache and tension headache).Chemical compound of the present invention also can be used as the anti-inflammatory agent of treatment of arthritis and is used as the reagent of the following disease of treatment: parkinson disease, Alzheimer, apoplexy, uveitis, asthma, myocardial infarction, traumatic brain injury, spinal cord injury, neurodegenerative disease, alopecia (shaving one's head), inflammatory bowel, autoimmune disease, nephropathy, obesity, eating disorders, cancer, schizophrenia, epilepsy, sleep disorder, cognitive disorders, depression, anxiety neurosis, hypertension, lipid disorders and atherosclerosis.

On the one hand, the invention provides the aryl nitrone chemical compound that contains 5-8 unit's cycloalkenyl group or aryl rings.First carbon atom of this ring in conjunction with the nitrone group.This carbon atom of nitrone is further combined with arriving hydrogen, replacement or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl.The nitrogen-atoms of nitrone group is attached to and replaces or unsubstituted aliphatic series, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.This ring is near above-mentioned first or connect second group at its adjacent second by direct key or methylene bonding base.Optional methylene bonding base can be substituted or not be substituted.Described second group is selected from the carboxyl (being ester) of hydroxy amino phosphoryl, carboxyl and replacement of dihydroxy phosphoryl, hydroxy amino phosphoryl, the replacement of amino, hydroxyl, dihydroxy phosphoryl, the replacement of carbamyl, amino, the replacement of amino-sulfonyl, sulfonic acid, sulphonic acid ester (being sulfonate), carbamyl, the replacement of sulfane base (sulfanyl), the sulfane base that replaces, amino-sulfonyl, replacement.In some embodiments, this ring is further replaced, and in other embodiments, this ring only is substituted at first and second.In preferred embodiments, chemical compound of the present invention does not comprise the described chemical compound 1-50 of 5.3 parts.

In a specific embodiments of the present invention, the ring of this chemical compound is a phenyl ring.Described phenyl ring can only be replaced (at first and second) by above-mentioned first with second group, and perhaps described phenyl ring can further be replaced.When this phenyl ring was further replaced, in some embodiments, described phenyl ring was replaced by the 3rd group in the para-position of nitrone group.In specific embodiment, the substituent group of ortho position and para-position, promptly second and the 3rd group are identical.

On the other hand, the invention provides the pharmaceutical composition that contains aryl nitrone chemical compound and pharmaceutical carrier, excipient or diluent.In this one side of the present invention, described pharmaceutical composition can contain above-mentioned aryl nitrone chemical compound.In addition, described pharmaceutical composition can contain one or more among the described chemical compound 1,8,9,11 of 5.3 parts, 16-22,25-27,37-43 and the 45-50.

On the other hand, the invention provides the heteroaryl nitrone compound that contains assorted thiazolinyl of 5-8 unit ring or heteroaryl ring.In specific embodiment of the present invention, the ring of this chemical compound is furan, thiophene or pyrimidine ring.First carbon atom of this ring in conjunction with the nitrone group.The carbon atom of this nitrone is further combined with arriving hydrogen, replacement or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl.The nitrogen-atoms of nitrone group is attached to and replaces or unsubstituted aliphatic series, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.This ring is near above-mentioned first or connect second group at its adjacent second by direct key or methylene bonding base.Described methylene bonding base can be substituted or not be substituted.Described second group is selected from the carboxyl (being ester) of hydroxy amino phosphoryl, carboxyl and replacement of dihydroxy phosphoryl, hydroxy amino phosphoryl, the replacement of amino, hydroxyl, dihydroxy phosphoryl, the replacement of carbamyl, amino, the replacement of amino-sulfonyl, sulfonic acid, sulphonic acid ester (being sulfonate), carbamyl, the replacement of sulfane base, amino-sulfonyl, the replacement of sulfane base, replacement.In some embodiments, this ring is further replaced, and in other embodiments, this ring only is substituted at first and second.In preferred embodiments, chemical compound of the present invention does not comprise the described chemical compound 51-69 of 5.4 parts.

Described ring can only be replaced (at first and second) by above-mentioned first with second group, and perhaps described ring can further be replaced.When this ring was further replaced, in some embodiments, described ring was replaced by the 3rd group on the position of two positions, position of leaving the nitrone group on the direction opposite with second group.For example, in hexatomic ring, second group is adjacent with nitrone, and then the 3rd group is in the para-position of second group.In specific embodiment, described second is identical with the 3rd group.

On the other hand, the invention provides the pharmaceutical composition that contains heteroaryl nitrone compound and pharmaceutical carrier, excipient or diluent.In this one side of the present invention, described pharmaceutical composition can contain above-mentioned heteroaryl nitrone compound.In addition, described pharmaceutical composition also can contain one or more among described chemical compound 51 of 5.4 parts and the 53-69.

Again on the other hand, the invention provides the aryl bicyclic nitrone compound, it contains 8-11 unit bicycloenyl, bicyclo-assorted thiazolinyl, aryl bicyclic or bicyclic heteroaryl ring.First carbon atom that is attached to the nitrone group of this ring.The carbon atom of nitrone is also in conjunction with hydrogen, replacement or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl.The nitrogen-atoms of nitrone group is in conjunction with replacing or unsubstituted aliphatic series, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.This ring passes through direct key or second group of methylene bonding base connection near above-mentioned primary second.Described methylene bonding base can be substituted or not be substituted.Second group is selected from the carboxyl (being ester) of hydroxy amino phosphoryl, carboxyl and replacement of dihydroxy phosphoryl, hydroxy amino phosphoryl, the replacement of amino, hydroxyl, dihydroxy phosphoryl, the replacement of carbamyl, amino, the replacement of amino-sulfonyl, sulfonic acid, sulphonic acid ester (being sulfonate), carbamyl, the replacement of sulfane base, amino-sulfonyl, the replacement of hydrogen, sulfane base, replacement.In preferred embodiments, chemical compound of the present invention does not comprise any one among the chemical compound 70-78 of 5.5 parts.

On the other hand, the invention provides the pharmaceutical composition that contains aryl bicyclic nitrone compound and pharmaceutical carrier, excipient or diluent.In this one side of the present invention, described pharmaceutical composition can contain above-mentioned aryl bicyclic nitrone compound.In addition, described pharmaceutical composition also can contain one or more among the described chemical compound 70-78 of 5.5 parts.

Aspect Therapeutic Method, the invention provides treatment and easily suffer from or suffer from the mammiferous method of certain disease, described disease is relevant with arthritis, uveitis, asthma, myocardial infarction, traumatic brain injury, acute spinal cord injury, alopecia (shaving one's head), inflammatory bowel or autoimmune disease, and this method comprises one or more aforementioned pharmaceutical compositions that give effective dose.

Aspect another Therapeutic Method, the invention provides the mammiferous method that certain disease is easily suffered from or suffered from treatment, described disease can cause pain reaction or relevant with the imbalance of keeping the sensory nerve primary activity.Nitrone compound is used as the pain of analgesic with the treatment a variety of causes and the cause of disease, for example, acute inflammation pain (as the pain relevant) with osteoarthritis and rheumatoid arthritis; Various neuropathic pain syndromes (neuropathy that the neuropathy that causes as postherpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Green's barye syndrome, fibromyalgia, phantom limb pain, mastectomy postoperative pain, peripheral neurophaty, HIV neuropathy and chemotherapy and other reason cause); Visceral pain (as reflecting disease, irritable bowel syndrome, inflammatory bowel, pancreatitis and gynaecopathia and the relevant pain of urological diseases) with the stomach esophagus; Toothache; And headache (as migraine, cluster headache and tension headache).

Aspect another Therapeutic Method, the invention provides the mammiferous method that neurodegenerative disease and disease are easily suffered from or suffered from treatment, described disease and disease for example: parkinson disease, Alzheimer and multiple sclerosis; Mediate or cause neuritic disease and obstacle by neuritis's (neuroinidia), as traumatic brain injury, apoplexy and encephalitis; The neuropsychiatric disease and the obstacle of maincenter mediation, such as, depression for example, manic disorder, two-phase disease, anxiety neurosis and schizophrenia; Eating disorders, sleep disorder and cognitive disorder; Epilepsy and seizure of disease; Prostate, bladder and bowel dysfunction, such as, for example, urinary incontinence, hesitancy in urination, rectum allergy, fecal incontinence, benign prostatauxe and inflammatory bowel; Respiratory tract and airway disorders and obstacle, such as, for example, allergic rhinitis, asthma, RAD and chronic obstructive pulmonary disease; By inflammation mediated or cause the disease and the obstacle of inflammation, such as, for example, rheumatoid arthritis, osteoarthritis, myocardial infarction, various autoimmune diseasees and obstacle, uveitis and atherosclerosis; Itch/scratch where it itches, such as, for example, psoriasis; Alopecia (shaving one's head); Obesity; Lipid disorders; Cancer; Hypertension; Spinal cord injury; And nephropathy.Described method comprises one or more aforementioned pharmaceutical compositions that give effectively to treat symptom or prevention symptom amount.

In others, the invention provides the method for synthetic aryl of the present invention, assorted virtue and aryl bicyclic nitrone compound.

4. accompanying drawing summary

Fig. 1 has exemplified the representative oxidation route of synthesis of aryl nitrone chemical compound of the present invention.

Fig. 2 has exemplified the representative oxidation route of synthesis of heteroaryl nitrone compound of the present invention.

Fig. 3 has exemplified the representative oxidation route of synthesis of aryl bicyclic nitrone compound of the present invention.

5. detailed Description Of The Invention

5.1 definition

When explanation compound of the present invention, when comprising the pharmaceutical composition of this compound and using the method for this compound and composition, except as otherwise noted, following term has the following meaning:

" acyl group " refers to group-C (O) R, and in the formula, R is defined as hydrogen, alkyl, cycloalkyl, the assorted alkyl of ring, aryl, aryl alkyl, assorted alkyl, heteroaryl or heteroaryl alkyl in this article. Representational example includes but not limited to formoxyl, acetyl group, cyclohexyl-carbonyl, cyclohexyl methyl carbonyl, benzoyl, benzyloxycarbonyl group etc.

" acylamino-" refers to group-NR ' C (O) R, in the formula, R ' is defined as hydrogen, alkyl, cycloalkyl, the assorted alkyl of ring, aryl, aryl alkyl, assorted alkyl, heteroaryl or heteroaryl alkyl in this article, R is hydrogen, alkyl, alkoxyl, cycloalkyl, the assorted alkyl of ring, aryl, aryl alkyl, assorted alkyl, heteroaryl or heteroaryl alkyl. Representational example includes but not limited to formamido group, acetylamino, cyclohexyl-carbonyl amino, cyclohexyl methyl carbonylamino, benzamido, benzyloxycarbonyl group amino etc.

" aliphatic series " refers to form carbon atom straight line, branch or annular arrangement is feature and alkyl organic compound or the group that does not contain the armaticity unsaturation. Aliphatic series includes but not limited to alkyl, alkylidene, thiazolinyl, alkenylene, alkynyl and alkynylene. Aliphatic group contains 1 or 2 to 12 carbon atom usually.

" alkyl " refers to preferably contain 1 to about 11 carbon atoms, more preferably contains 1-8 carbon atom, and preferably contains the unit price radical of saturated aliphatic alkyl group of 1-6 carbon atom again. Its hydrocarbon chain can be straight line or branch. The example of this term comprises the group such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-hexyl, n-octyl, uncle's octyl group etc. Term " low alkyl group " refers to contain the alkyl group of 1-6 carbon atom. Term " alkyl " also comprises " cycloalkyl " that defines below.

" alkylidene " refers to preferably contain 1-11 carbon atom, more preferably contains the straight or branched divalence radical of saturated aliphatic alkyl group of 1-6 carbon atom. The example of this term comprises such as methylene (CH₂-), ethylidene (CH₂CH ₂-), the isomer of propylidene (for example-CH₂CH ₂CH ₂-and-CH (CH₃)CH ₂-) etc. group.

" thiazolinyl " refers to preferably contain 2-11 carbon atom, more preferably contains the unit price alkene unsaturated alkyl group of 2-6 carbon atom, it can be straight or branched and have at least one, preferred 1-2 unsaturated position of alkene. Preferred alkenyl group comprises vinyl (CH=CH₂), positive acrylic (CH₂CH＝CH ₂), isopropenyl (C (CH₃)＝CH ₂) etc.

" alkenylene " refers to preferably contain 2-11 carbon atom, more preferably contains the divalence alkene unsaturated alkyl group of 2-6 carbon atom, it can be straight or branched and have at least one, preferred 1-2 unsaturated position of alkene. The example of this term comprise such as ethenylidene (CH=CH-), the isomer of allylidene (for example-CH=CHCH₂-and-C (CH₃)=CH-and-CH=C (CH₃)-) etc.

" alkynyl " refers to preferably to contain 2-11 carbon atom, more preferably contains the alkynes unsaturated alkyl of 2-6 carbon atom, it can be straight or branched and at least 1, preferred 1-2 unsaturated position of alkynyl arranged. Preferred alkynyl group comprises acetenyl acetenyl (C ≡ CH), propargyl (CH₂C ≡ CH) etc.

" alkoxyl " refers to group " O-alkyl ", in the formula, and alkyl such as top definition. Preferably alkoxy base comprises, for example, and methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, just own oxygen base, 1,2-dimethyl butoxy etc.

In the literary composition, " alkanoyl " refers to group-C (O)-R, and in the formula, R is alkyl defined above.

" aryl " refers to by removing the monovalent aromatic alkyl that a hydrogen atom is derived from a carbon atom of existing aromatic ring system. Typical aromatic yl group includes but not limited to derived from aceanthrylene, acenaphthene, the luxuriant and rich with fragrance alkene of vinegar, anthracene, Azulene, benzene, bends, the group of coronene, fluoranthene, fluorenes, hexacene, hexaphene, hexalene, asymmetric indacene (as-indacene), symmetrical indacene (s-indacene), indane, indenes, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentalene, pentaphene, perylene, non-that alkene, Fei, Pi, pleiadiene, pyrene, pyranthrene, rubicene, benzophenanthrene, trinaphthylene etc. Aryl preferably contains 6-14 carbon atom.

" fused-aryl " refers to two ring carbon atoms and second aromatic ring or the aryl public with alicyclic ring.

" alkaryl " refers to by the as mentioned aryl of definition of one or more alkyl replacements defined above.

" aralkyl " or " aryl alkyl " is meant the alkyl of definition as mentioned that is replaced by one or more aryl defined above.

" aryloxy group " is meant-the O-aromatic yl group, and " aryl " wherein defines as mentioned.

" alkyl amino " is meant group-NRR ', wherein, has at least one to be alkyl defined above among R and the R '.

" arylamino " is meant group-NRR ', wherein, has at least one to be aryl defined above among R and the R '.

" alkoxy amino " is meant group-N (R) OR ', and wherein, R can be a hydrogen or alkyl, the alkyl or cycloalkyl that R ' expression is defined herein.

" alkoxy carbonyl " is meant group-C (O) alkoxyl, alkoxyl wherein such as the definition of this paper.

" alkyl aryl amino " is meant group-NRR ', and wherein, R represents alkyl or cycloalkyl, and R ' is defined as aryl in this article.

" alkyl sulphonyl " is meant group-S (O) ₂R, wherein, R is defined as alkyl or cycloalkyl in this article.Its representational example includes but not limited to methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, butyl sulfonyl etc.

" alkyl sulphinyl " is meant group-S (O) R, and wherein, R is the alkyl or cycloalkyl that this paper defines.Its representational example includes but not limited to methylsulfinyl, ethyl sulfinyl, propyl group sulfinyl, butyl sulfinyl etc.

" alkylthio group " is meant group-SR, and wherein, R is the alkyl or cycloalkyl as defined herein that can be optionally substituted.Representational example includes but not limited to methyl mercapto, ethylmercapto group, rosickyite base, butylthio etc.

" amino " is meant group-NH ₂

" alkoxy aryl " is meant group-O-aryl alkyl, aryl alkyl wherein such as the definition in the literary composition.

" aryloxycarbonyl " is meant group-C (O)-O-aryl, aryl wherein such as the definition in the literary composition.

" aryl sulfonyl " is meant group-S (O) ₂R, R wherein is defined as aryl in this article.

" azido " is meant group-N ₃

" carbamyl " is meant group-C (O) N (R) ₂, as the definition in the literary composition, each R group independently is hydrogen, alkyl, cycloalkyl or aryl, it can be chosen wantonly and be substituted as the definition in the literary composition.

" carboxyl " is meant group-C (O) OH.

" carboxyamino " is meant group-N (R) C (O) OH, and as the definition in the literary composition, R wherein can be a hydrogen or alkyl.

" cycloalkyl " is meant the cyclic hydrocarbon group that contains 3-10 carbon atom and contain a monocycle or a plurality of condensed ring, comprises condensed ring or bridge ring systems, and it can be chosen wantonly by 1-3 alkyl and replace.This cycloalkyl comprises, for example, and such as the single ring architecture of cyclopropyl, cyclobutyl, cyclopenta, ring octyl group, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc. and such as the multiring structure of adamantyl etc.

" cycloalkenyl group " is meant the single ring that contains 3-10 carbon atom or the cyclic hydrocarbon group of a plurality of condensed ring, comprises condensed ring and bridge ring systems, and at least 1, preferred 1-2 unsaturated position of alkene are arranged.This cycloalkenyl group comprises, for example, and such as the single ring architecture of cyclohexenyl group, cyclopentenyl, cyclopropanyl etc.

" fused rings thiazolinyl " is meant two ring carbon atoms and second alicyclic ring or the shared cycloalkenyl group of aromatic ring.The cycloalkenyl group armaticity can be given in the undersaturated position of its alkene.

" cyanato-" is meant group-OCN.

" cyano group " is meant group-CN.

" dialkyl amido " is meant group-NRR ', wherein, the heteroaryl of ring assorted alkyl, heteroaryl or the replacement of the aryl of the alkyl of the alkyl that defines in the independent respectively expression literary composition of R and R ', replacement, aryl, replacement, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring, replacement.

" halo " or " halogen " is meant fluorine, chlorine, bromine and iodine.Preferred halo group is a fluorine or chlorine.

" hydroxyl " is meant group-OH.

" nitro " is meant group-NO ₂

" replacing " the one or more hydrogen atoms that are meant in the group is substituted by identical or different substituent group independently of one another.Typical substituent group includes but not limited to :-X ,-R ¹⁴,-OH ,=O ,-OR ¹⁴,-SR ¹⁴,-SH ,=S ,-NR ¹⁴R ¹⁵,=NR ¹⁴,-CX ₃,-CF ₃,-CN ,-OCN ,-SCN ,-NO ,-NO ₂,=N ₂,-N ₃,-S (O) ₂OH ,-S (O) ₂OR ¹⁴,-S (O) ₂R ¹⁴,-OS (O ₂) OH ,-OS (O) ₂OR ¹⁴,-P (O) (OH) ₂,-P (O) (OR ¹⁴) (OH) ,-OP (O) (OR ¹⁴) (OR ¹⁵) ,-C (O) R ¹⁴,-C (S) R ¹⁴,-C (O) OR ¹⁴,-C (O) NR ¹⁴R ¹⁵,-C (O) OH ,-C (S) OR ¹⁴,-NR ¹⁶C (O) NR ¹⁴R ¹⁵,-NR ¹⁶C (S) NR ¹⁴R ¹⁵,-NR ¹⁷C (NR ¹⁶) NR ¹⁴R ¹⁵With-C (NR ¹⁶) NR ¹⁴R ¹⁵, wherein, each X independently is a hydrogen; R ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Independent separately be heteroaryl, heteroaryl alkyl, the replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, mix alkyl, replacement heteroaryl alkyl ,-NR ¹⁸R ¹⁹,-C (O) R ¹⁸Or-S (O) ₂R ¹⁸, wherein, R ¹⁸And R ¹⁹Can choose the assorted alkyl ring of ring that forms assorted alkyl of ring or replacement wantonly with their all bonded atoms; And R ¹⁸And R ¹⁹Independent separately be the heteroaryl alkyl of heteroaryl, heteroaryl alkyl or replacement of assorted alkyl, heteroaryl, the replacement of aryl alkyl, cycloalkyl, the cycloalkyl of replacement, the assorted alkyl of ring of aryl, aryl alkyl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, the assorted alkyl of ring of replacement, mix alkyl, replacement.

The example of the aryl of representational replacement comprise following these:

In the formula, R ⁶And R ⁷One of can be hydrogen, and R ⁶And R ⁷In at least one independently be selected from the assorted alkyl of alkyl, thiazolinyl, alkynyl, ring, acyl group, alkoxyl, aryloxy group, heteroaryloxy, alkyl amino, arylamino, heteroaryl amino ,-NR ¹⁰C (O) R ¹¹,-NR ¹⁰S (O) R ¹¹,-NR ¹⁰SO ₂R ¹¹,-C (O) O alkyl ,-C (O) O aryl ,-C (O) NR ¹⁰R ¹¹,-C (O) NR ¹⁰OR ¹¹,-NR ¹OR ¹¹,-SO ₂NR ^1OR ¹¹,-S-alkyl ,-S (O) alkyl ,-SO ₂Alkyl ,-the S-aryl ,-S (O) aryl and SO ₂Aryl, perhaps R ⁶And R ⁷The ring (saturated or unsaturated) that can contain 5-8 atom in conjunction with formation, the wherein optional hetero atom that contains one or more N of being selected from, O or S.R ¹⁰And R ¹¹Independent separately be hydrogen, alkyl, thiazolinyl, alkynyl, perfluoroalkyl, cycloalkyl, ring mix aryl, the heteroaryl of alkyl, aryl, replacement, the heteroaryl of replacement etc.

When being used for describing group on chemical compound or the chemical compound, " mixing " represent to have in this chemical compound or the group one or more carbon atoms to be replaced by nitrogen, oxygen or sulfur heteroatom.Mixing can be used for above-mentioned any alkyl, and as alkyl (promptly assorted alkyl), cycloalkyl (promptly encircling assorted alkyl), aryl (being heteroaryl), cycloalkenyl group (promptly encircling the thiazolinyl of mixing) etc., this group contains 1-5 and also preferably contains 1-3 hetero atom.

" heteroaryl " or " assorted virtue " is meant by removing a hydrogen atom and deutero-unit price heteroaryl from an atom of female heteroaromatic ring system.Typical heteroaryl groups includes but not limited to derived from acridine, arsindole, carbazole, B-carboline, color alkane, chromene, cinnolines, furan, imidazoles, indazole, indole, indoline, indolizine, isobenzofuran, heterochromatic alkene, iso-indoles, isoindoline, isoquinolin, isothiazole isoxazole, benzodiazine oxadiazole oxazole, perimidine, phenanthridines, phenanthroline, azophenlyene, phthalazines, pteridine, purine, pyrans, pyrazine, pyrazoles, pyridazine, pyridine, pyrimidine, the pyrroles, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazolium, thiadiazole, thiazole, thiophene, triazole, the group of xanthene etc.Described heteroaryl is preferably 5-to 20-unit heteroaryl, more preferably 5-to 10-unit heteroaryl.Preferred heteroaryl is the heteroaryl derived from thiophene, pyrroles, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazoles, oxazole and pyrazine.

The example of representational heteroaryl comprises:

In the formula, Y is selected from NH, NR ⁴, O and S.

The example of the assorted alkyl of representational ring comprises:

In the formula, X is selected from CR ³R ⁴, NR ⁴, O and S, Y is selected from NH, NR ⁴, O and S.

The example of the assorted thiazolinyl of representational ring comprises:

Wherein, each X is selected from CR ³R ⁴, CR ⁴, N, NR ⁴, O and S, Y is selected from NH, NR ⁴, O and S.

The representational example that closes hetero atom and substituent aryl comprises:

Wherein, X is selected from CR ³R ⁴, NR ⁴, O and S, Y is selected from NH, NR ⁴, O and S.

" assorted substituent group " is meant the degree of functionality that contains halogen, O, S or N atom, and they can be used as R ⁴Appear at C-R ⁴In the group, this group directly appears among compd A of the present invention, Q, W, X, Y or the Z as substituent group again.This degree of functionality also can be used as substituent group and appears in " replacement " aryl and aliphatic group of chemical compound.Assorted substituent example comprises:

-halogen ,-CN;

-OH、-OR、-SR；

-NO ₂、-NH ₂、-NHR、-NRR′；

-NRC(O)R′、-NRS(O)R′、-NRSO ₂R′；

-CO ₂H ,-CO ₂R ,-C (O) NRR ' ,-C (O) N (R) OR '; With

-SO ₃H ,-SO ₃R ,-SO ₂R ,-S (O) R and-SO ₂NRR ',

Wherein, R and R ' are independent separately is aryl or aliphatic series and the optional substituent group that contains.In containing the assorted substituent group of R and/or R ', preferably contain the aryl that defines in the literary composition or the substituent group of alkyl R or R ' group.Preferred assorted substituent group is those that list above.

The those skilled in the art in organic synthesis field will know, can determine heteroatomic maximum number in stable, a chemically feasible armaticity or the non-armaticity heterocycle by the size of ring, the degree of unsaturation and the heteroatomic valence mumber of ring.Heterocycle contains 1-4 hetero atom usually, and is feasible and be stable as long as this aromatic ring is a chemical formula.

" pharmaceutically acceptable " be meant the approval of federation management mechanism or state government or American Pharmacopeia or other generally acknowledged pharmacopeia in list to be used for animal especially human.

" pharmaceutically acceptable salt " is meant pharmaceutically acceptable and has the salt of the The compounds of this invention of the required pharmacologically active of parent compound.This salt comprises:

(1) acid-addition salts that forms by following acids

(a) mineral acid, example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc., or

(b) organic acid, as acetic acid, propanoic acid, caproic acid, cyclopentanepropanoiacid acid, glycolic, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, Fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxy benzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1,2-ethane-disulfonic acid, the 2-ethylenehydrinsulfonic acid, benzenesulfonic acid, the 4-chlorobenzenesulfonic acid, the 2-LOMAR PWA EINECS 246-676-2, the 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl bicyclic [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, the 3-phenylpropionic acid, trimethylace tonitric, tert-butyl acetic acid, lauryl sulphate acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid etc.; Or

(2) salt that when having acidic moiety in the parent compound, forms one of in the following manner

(a) use the metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion to replace, or

(b) with such as the organic base coordination of ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine etc.

Only by way of example, salt also comprises sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, tetraalkylammonium salt etc., and, when chemical compound contains alkaline degree of functionality, the salt that also comprises non-toxic organic or mineral acid, example hydrochloric acid salt, hydrobromate, tartrate, mesylate, acetate, maleate, oxalates etc.Term " pharmaceutically acceptable cation " is meant cation counterbalancing ion nontoxic, pharmaceutically acceptable acid functional groups.This cationic example has sodium, potassium, calcium, magnesium, ammonium and tetraalkylammonium cation, or the like.

" dihydroxy phosphoryl " or " phosphono " are meant group-PO (OH) ₂

" the dihydroxy phosphoryl that replaces " is meant dihydroxy phosphoryl group, and one of them or two hydroxyls can be substituted.Suitable substituents is in above-detailed.

" hydroxy amino phosphoryl " is meant group-PO (OH) NH ₂

" the hydroxy amino phosphoryl that replaces " is meant hydroxy amino phosphoryl group, and amino wherein can be replaced by one or two substituent group.Suitable substituents is in above-detailed.In some embodiments, hydroxyl also can be substituted.

" pharmaceutically acceptable carrier " is meant diluent, adjuvant, excipient or the carrier that can be used to give chemical compound of the present invention.

" prevent " or " prevention " be meant the risk that reduce to obtain disease or disease (that is, the clinical symptoms of at least a disease is not occurred in object, this object may contact or susceptibility to disease but the symptom of this disease does not also appear or shows).

" object " comprises the people.Term " people ", " patient " and " object " can exchange use here.

" sulfane base " or " sulfydryl " are meant group-SH." the sulfane base that replaces " or " thioether " are meant group-SR, and R wherein states what substituent group of appointing in the literary composition.

" sulfonyl " is meant divalent group-S (O) ₂-." sulfonyl that replaces " is meant group-S (O) ₂R, R wherein are any substituent groups described in the literary composition." amino-sulfonyl " or " sulfonamides " is meant group-S (O) ₂NH ₂, " amino-sulfonyl that replaces " or " sulfonamides that replaces " is meant group-S (O) ₂NR ², wherein each R independently is any substituent group described in the literary composition.

" treatment effective dose " is meant the amount of chemical compound, when giving object with the treatment disease, is enough to effectively treat this type of disease." treatment effective dose " can change according to chemical compound, disease and the order of severity thereof and by the age of treatment target, body weight etc.

" treatment " or " processing " is meant and alleviates this disease or disease (promptly stoping or slow down the development of this disease or at least a its clinical symptoms) in one embodiment, to any disease or disease.In another embodiment, " treatment " or " " be meant and alleviate at least a physical parameter, this parameter can be that object can not be distinguished in processing.Again in another embodiment, " treatment " or " processing " is meant in health (for example, stable can debate symptom) or physiology (for example, stablizing physical parameter) adjusted disease or disease, or regulates the two simultaneously.Treatment more in another embodiment, " " or " processing " is meant the outbreak that delays disease or disease.

" prodrug " is the derivant of The compounds of this invention, and it has the purgeable group of metabolism therefore can be by solvolysis, and perhaps chemical compound of the present invention has the drug disposition activity under physiological condition.Its example includes but not limited to cholinester derivant etc. and N-alkyl morpholine ester etc.

Other derivant of the present invention has activity under its acid and acid derivative form.That acid-sensitive sense form has in mammalian organism usually is solvable, the advantage of tissue compatible or slow release (see H.Bundgard, 1985, Design of Prodrugs, Elsevier, Amsterdam, 7-9,21-24 page or leaf).Prodrug comprises acid derivant well-known to those having ordinary skill in the art, such as, for example the esters by the reaction of parent acid and suitable alcohol is made makes parent acid compound and replacement or unsubstituted amine react amide, anhydride and the mixed acid anhydride that makes.Simple aliphatic series or aromatic ester, amide and anhydride derived from acidic-group on the The compounds of this invention are preferred prodrugs.Under the certain situation, need the prodrug of preparation diester types, as (acyloxy) Arrcostab or ((alkoxy carbonyl) oxygen base) Arrcostab.The C of preferred The compounds of this invention ₁-C ₈Alkyl, C ₂-C ₈Thiazolinyl, aryl, C ₇-C ₁₂The aryl and the C that replace ₇-C ₁₂Alkyl aryl.

Should be understood that and have the same molecular formula but the one-tenth key character of its atom or order or its atoms in space are arranged different chemical compounds and be called as " isomers ".Atoms in space is arranged different isomerss and is called " three-dimensional isomers ".

Do not become the three-dimensional isomers of mirror image to be called " diastereomer " mutually, and those being called of non-superimposable mirror image " enantiomer " each other mutually.When chemical compound has asymmetric center, for example, when it during in conjunction with four different groups, and have a pair of enantiomer.Can characterize enantiomer according to the absolute configuration of its asymmetric center, and can be shown (R) or (S) according to the rule list of Cahn and Prelog, perhaps can characterize, and be expressed as dextrorotation and left-handed (promptly be respectively (+)-or (-)-isomers) according to molecule rotation and polarized light flat.Chipal compounds can exist with independent enantiomer or with its mixture.The mixture that contains the equal proportion enantiomer is called as " racemic mixture ".

Chemical compound of the present invention can have one or more asymmetric centers; Therefore this chemical compound can be made into independent (R)-or (S)-enantiomer, perhaps as its mixture.Except as otherwise noted, description or the name to particular compound will comprise two kinds of independent enantiomer and composition thereof, racemate or other form in this description and claims.Determine that spatial chemistry is well known in the art with the method for separating three-dimensional isomers.

5.2 aryl, heteroaryl and aryl bicyclic nitrone compound

The invention provides the aryl, heteroaryl and the aryl bicyclic nitrone compound that are used to prevent and/or treat mammal arthritis, parkinson disease, Alzheimer, apoplexy, uveitis, asthma, myocardial infarction, pain syndrome (acute and chronic or nerve), traumatic brain injury, acute spinal cord injury, neurodegenerative disease, alopecia (shaving one's head), inflammatory bowel and autoimmune disease or symptom.

In some embodiments, the invention provides the aryl shown in the formula (I), heteroaryl and aryl bicyclic nitrone compound:

In the formula:

For aryl nitrone, W and Z be in conjunction with the cycloalkenyl group or the aryl rings that form 5-8 atom, described ring only by formula (I)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces, or described ring can further be replaced;

For the heteroaryl nitrone, W and Z be in conjunction with forming assorted thiazolinyl of 5-8 unit ring or heteroaryl ring, described ring only by formula (I)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces or described ring is further replaced;

For the aryl bicyclic nitrone, W and Z be in conjunction with forming 8-11 unit bicycloenyl, bicyclo-assorted thiazolinyl, aryl bicyclic or bicyclic heteroaryl ring, and described ring only by formula (I)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces or described ring is further replaced;

L is C (R ²) ₂

R ¹Be selected from and replace or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted ring assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl and replacement or unsubstituted heteroarylalkyl;

Each R ²Independently be selected from hydrogen, replacement or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl;

For aryl nitrone, R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

For heteroaryl and aryl bicyclic nitrone, R ³Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

R ⁷And R ⁸Independently be selected from respectively hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl, replacement or unsubstituted heteroarylalkyl ,-CO ₂R ⁹With-CON (R ⁹) ₂, and can replace or unsubstituted hetero-aromatic ring or saturated or undersaturated replacement or the assorted alkyl ring of unsubstituted 4-7 unit ring in conjunction with forming;

Each R ⁹Independently be selected from hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl and replacement or unsubstituted heteroarylalkyl; With

N is the integer of 0-1; Or

Its pharmaceutically acceptable salt or prodrug.

In other embodiment of the assorted virtue of formula (I) and aryl bicyclic nitrone, R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In the aryl nitrone of above-mentioned formula (I), W in this chemical compound and Z are in conjunction with forming 6-unit aryl rings usually.

In the assorted fragrant nitrone of above-mentioned formula (I), W in this chemical compound and Z are in conjunction with forming 6-unit hetero-aromatic ring usually.Yet this hetero-aromatic ring can be to be proficient in the first hetero-aromatic ring of any 5-to 8-known to those skilled in the art, comprises the exemplary hetero-aromatic ring (5.1 part) that above-mentioned definitional part is described.In some embodiments, this hetero-aromatic ring is pyridine, pyrimidine, furan, thiophene or pyrrole ring.

In the aryl bicyclic nitrone of formula (I), in some embodiments, R ¹Replaced by the group outside the phenyl of phenyl, replacement or the methyl.In other embodiments, R ¹Replaced by the group outside the phenyl of phenyl, replacement or the low alkyl group.For example, R ¹Can be to replace or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

Again in the aryl bicyclic nitrone of formula (I), in some embodiments, R ²Can be replaced by the group outside the hydrogen.For example, R ²Can be to replace or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl.

In other embodiment of the aryl bicyclic nitrone of formula (I), R ³Can by-OH ,-SMe or-S (C ₆H ₅) outside group replace.For example, R ³Can be selected from-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In the aryl bicyclic nitrone of formula (I), in some embodiments, W and Z are fused to the hexatomic ring of second ring in conjunction with formation.Described second ring can be that for example, 5-or 6-unit ring also can contain hetero atom.Described second ring can be fused in first ring on any adjacent a pair of atom.

In the aryl bicyclic nitrone of formula (I), in some embodiments, W and Z are fused to the heptatomic ring of second ring in conjunction with formation again.Described second ring can be that for example, 5-unit ring also contains hetero atom.Described second ring can be fused in first ring on any adjacent a pair of atom.For example, described bicyclo-aromatic ring can be an azulene.

In another embodiment, the invention provides the aryl and the heteroaryl nitrone compound of formula (II):

In the formula:

For aryl nitrone, W, X, Y and Z independently are C-R separately ⁴

For assorted fragrant nitrone, having m among W, X, Y and the Z is N, and remaining independently is C-R separately ⁴

L is C (R ²) ₂

For assorted virtue and aryl bicyclic nitrone, R ³Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

Each R ⁴Independent is hydrogen; alkyl; the alkyl that replaces; acyl group; the acyl group that replaces; acylamino-; the acylamino-that replaces; alkyl amino; the alkyl amino that replaces; alkylthio group; the alkylthio group that replaces; alkoxyl; the alkoxyl that replaces; alkoxy carbonyl; the alkoxy carbonyl that replaces; alkyl aryl amino; the alkyl aryl amino that replaces; alkoxy aryl; the alkoxy aryl that replaces; amino; aryl; the aryl that replaces; aryl alkyl; the aryl alkyl that replaces; sulfoxide; the sulfoxide that replaces; sulfone; the sulfone that replaces; the sulfane base; the sulfane base that replaces; amino-sulfonyl; the amino-sulfonyl that replaces; aryl sulfonyl; the aryl sulfonyl that replaces; sulfonic acid; sulphonic acid ester (being sufonate); the dihydroxy phosphoryl; the dihydroxy phosphoryl that replaces; the hydroxy amino phosphoryl; the hydroxy amino phosphoryl that replaces; azido; carboxyl; the carboxyl (being ester) that replaces; carbamyl; the carbamyl that replaces; cyano group; cycloalkyl; the cycloalkyl that replaces; the assorted alkyl of ring; the assorted alkyl of the ring that replaces; dialkyl amido; the dialkyl amido that replaces; halo; heteroaryloxy; the heteroaryloxy that replaces; heteroaryl; the heteroaryl that replaces; assorted alkyl; the assorted alkyl that replaces; hydroxyl; nitro or sulfo-.

R ⁷And R ⁸Independently be selected from respectively hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl, replacement or unsubstituted heteroarylalkyl ,-CO ₂R ⁹With-CON (R ⁹) ₂, and can replace or unsubstituted hetero-aromatic ring or saturated or undersaturated replacement or the unsubstituted assorted alkyl ring of ring that contains 4-7 atom in conjunction with forming;

N is the integer of 0-1;

For assorted fragrant nitrone, m is the integer of 1-3; Or

Its pharmaceutically acceptable salt or prodrug.

In other embodiment of the assorted fragrant nitrone of formula (II), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In some embodiment of the assorted fragrant nitrone of formula (II), X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹And R ³And R ⁵On substituent group can independently change, in some embodiments, R ³And R ⁵Be identical.In specific embodiment, n is 0, R ³And R ⁵Be identical.

5.3 aryl nitrone chemical compound

In other embodiments, the invention provides the aryl nitrone chemical compound of formula (III):

In the formula:

W, Y and Z independently are C-R separately ⁴

L is C (R ²) ₂

R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

Each R ⁴Independent is hydrogen, alkyl, the alkyl that replaces, acyl group, the acyl group that replaces, acylamino-, the acylamino-that replaces, alkyl amino, the alkyl amino that replaces, alkylthio group, the alkylthio group that replaces, alkoxyl, the alkoxyl that replaces, alkoxy carbonyl, the alkoxy carbonyl that replaces, alkyl aryl amino, the alkyl aryl amino that replaces, alkoxy aryl, the alkoxy aryl that replaces, amino, aryl, the aryl that replaces, aryl alkyl, the aryl alkyl that replaces, sulfoxide, the sulfoxide that replaces, sulfone, the sulfone that replaces, the sulfane base, the sulfane base that replaces, amino-sulfonyl, the amino-sulfonyl that replaces, aryl sulfonyl, the aryl sulfonyl that replaces, sulfonic acid, sulphonic acid ester (being sulfonate), the dihydroxy phosphoryl, the dihydroxy phosphoryl that replaces, the hydroxy amino phosphoryl, the hydroxy amino phosphoryl that replaces, azido, carboxyl, the carboxyl (being ester) that replaces, carbamyl, the carbamyl that replaces, carboxyl l, cyano group, cycloalkyl, the cycloalkyl that replaces, the assorted alkyl of ring, the assorted alkyl of the ring that replaces, dialkyl amido, the dialkyl amido that replaces, halo, heteroaryloxy, the heteroaryloxy that replaces, heteroaryl, the heteroaryl that replaces, assorted alkyl, the assorted alkyl that replaces, hydroxyl, nitro or sulfo-; With

R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

R ⁷And R ⁸Independently be selected from respectively hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl, replacement or the heteroarylalkyl that replaces ,-CO ₂R ⁹With-CON (R ⁹) ₂, and can replace or unsubstituted hetero-aromatic ring or saturated or undersaturated replacement or the unsubstituted assorted alkyl ring of ring that contains 4-7 atom in conjunction with forming;

N is the integer of 0-1;

Or its pharmaceutically acceptable salt or prodrug.

Because R ³And R ⁵On substituent group can change independently, in some embodiments, R ³And R ⁵Be identical.In specific embodiment, n is 0, R ³And R ⁵Be identical.

In preferred embodiments, the aryl nitrone chemical compound of formula (I), formula (II) or formula (III) does not comprise chemical compound 1-50.(the chemical compound 1-78 in the 5.3-5.5 part is different from the chemical compound among the embodiment 1-92.) in specific embodiment, the aryl nitrone chemical compound of formula (I), formula (II) or formula (III) does not comprise chemical compound 1-50.In another embodiment, the aryl nitrone chemical compound of formula (I), formula (II) or formula (III) does not comprise isomers, diastereomer or the enantiomer of chemical compound 1-50.Chemical compound 1-50 is as follows:

1.1,3-benzenedisulfonic acid, 4-[[(1-Methylethyl) and the epoxy imino group] methyl]-, disodium salt or N-isopropyl-C-(2,4-two sulfur phenenyls) nitrone, disodium salt };

2.1,3-benzenedisulfonic acid, 4-[[(1,1-dimethyl ethyl) and the epoxy imino group] methyl]-or N-(tert-butyl)-C-(2,4-two sulfur phenenyls) nitrone;

3.1,3-benzenedisulfonic acid, 4-[[(1-hydroxyl-1,1-dimethyl ethyl) and the epoxy imino group] methyl]-, disodium salt or N (2-hydroxyl-1,1-dimethyl ethyl)-C-(2,4-two sulfur phenenyls) nitrone, disodium salt };

4.1,3-benzenedisulfonic acid, 4-[[(1,1-dimethyl ethyl) and the epoxy imido] methyl]-, disodium salt or N-(tert-butyl)-C-(2,4-two sulfur phenenyls) nitrone, disodium salt };

5. benzenesulfonic acid, 2-[[(1,1-dimethyl ethyl) the epoxy imido] methyl]-, ion (1-) or N-(tert-butyl)-C-(2-sulfur phenenyl) nitrone, ion (1) };

6.1,3-benzenedisulfonic acid, 4-[[(1,1-dimethyl ethyl) and the epoxy imino group] methyl]-, di-ammonium salts or N-(tert-butyl)-C-(2,4-two sulfur phenenyls) nitrone, di-ammonium salts };

7.1,3-benzenedisulfonic acid, 4-[[(1,1-dimethyl ethyl) and the epoxy imino group] methyl]-, magnesium salt (1: 1) or N-(tert-butyl)-C-(2,4-two sulfur phenenyls) nitrone, magnesium salt (1: 1) };

8.1,3-benzenedisulfonic acid, 4-[(ethyl epoxy imino group) and methyl]-, disodium salt or N-ethyl-C-(2,4-two sulfur phenenyls) nitrone, disodium salt };

9.1,3-benzenedisulfonic acid, 4-[(butyl epoxy imino group) and methyl]-, disodium salt or N-butyl-C-(2,4-two sulfur phenenyls) nitrone, disodium salt };

10.1,3-benzenedisulfonic acid, 4-[[(1,1-dimethyl ethyl) and the epoxy imino group] methyl]-, ion (2-) or N-(tert-butyl)-C-(2,4-two sulfur phenenyls) nitrone, ion (2) };

11.1,3-benzenedisulfonic acid, 4-[[(1,1-dimethyl propyl) and the epoxy imino group] methyl]-, disodium salt or N (1, the 1-dimethyl propyl)-C-(2,4-two sulfur phenenyls) nitrone, disodium salt };

12.1,3-benzenedisulfonic acid, 4-[[(1,1-dimethyl ethyl) and the epoxy imido] methyl]-, di-potassium or N-(tert-butyl)-C-(2,4-two sulfur phenenyls) nitrone, di-potassium };

13. benzenesulfonic acid, 2-[[(1,1-dimethyl ethyl) the epoxy imido] methyl]-or N-(tert-butyl)-C-(2-sulfur phenenyl) nitrone;

14. benzenesulfonic acid, 2-[[(1,1-dimethyl ethyl) the epoxy imino group] methyl]-, sodium salt or N-(tert-butyl)-C-(2-sulfur phenenyl) nitrone, sodium salt };

15.1,3-benzenedisulfonic acid, 4-[[(1,1-dimethyl ethyl) and the epoxy imino group] methyl]-, calcium salt (1: 1) or N-(tert-butyl)-C-(2,4-two sulfur phenenyls) nitrone, calcium salt (1: 1) };

16. benzenesulfonic acid, 2-[[epoxy (pentamethyl phenyl) imino group] methyl]-, sodium salt or N (pentamethyl phenyl)-C-(2-sulfur phenenyl) nitrone, sodium salt };

17. phenethylamine, N-[[2-(thiophenyl) phenyl] methylene]-, the N-oxide, (E)-or (E)-N-(2-phenylethyl)-C-[2-(thiophenyl) phenyl] nitrone };

18. cyclohexylamine, 2-nitro-N-[[2-(thiophenyl) phenyl] methylene]-, the N-oxide or N-(2-nitrocyclohex base)-C-[2-(thiophenyl) phenyl] nitrone };

19. aniline, 4-(thiophenyl)-N-[[2-(thiophenyl) phenyl] methylene]-, the N-oxide, (Z)-or (Z)-N-[4-(thiophenyl) phenyl]-C-[2-(thiophenyl) phenyl] nitrone };

20. phenethylamine, N-[[2-(thiophenyl) phenyl] methylene]-, the N-oxide, (Z)-or (Z)-N-(2-phenylethyl)-C-[2-(thiophenyl) phenyl] nitrone };

21. nitrone, α-carboxy-N-methyl-α-[2-(methyl mercapto) phenyl]-, methyl ester or N-methyl-C-[2-(methyl mercapto) phenyl]-C '-(methoxycarbonyl group) nitrone };

22. glycine, the N-[(2-methoxyphenyl) methylene]-, with the anhydride of diphenyl boric acid (borinic acid), the N-oxide or N-[2-(diphenyl boron) oxygen base-2-oxoethyl]-C-(2-methoxyphenyl) nitrone };

23.2-propylamine, N-(2-ethoxyl phenenyl) methylene]-the 2-methyl-, N-oxide or N-(tert-butyl)-C-(2-ethoxyl phenenyl) nitrone;

24. phenol, 2-[[(1,1-dimethyl ethyl) the epoxy imino group] methyl]-the 6-ethyoxyl-or N-(tert-butyl)-C-(3-ethyoxyl-2-hydroxy phenyl) nitrone;

25.2-the Thiazolidine thioketone, the 4-[[(2-methoxyphenyl) methylene] epoxy amino]-3,5,5-trimethyl-N-(3,5,5-trimethyl-2-sulfo-Thiazolidine-4-yl)-C-(2-methoxyphenyl) nitrone };

26. acetic acid, [the 2-[[(4-chlorphenyl) the epoxy imino group] methyl] phenoxy group]-or N-(4-chlorphenyl)-C-[2-(carboxyl methoxyl group) phenyl] nitrone };

27. aniline, N-[[2-(2-furyl methoxyl group) phenyl] methylene]-, the N-oxide or N-phenyl-C-[2-(2-furyl methoxyl group) phenyl] nitrone };

28. nitrone, α-(2, the 3-dihydroxy phenyl)-N-phenyl-or N-phenyl-C-(2, the 3-dihydroxy phenyl) nitrone;

29. phenol, 2-[(epoxy-phenyl imino group) methyl]-, radical ion (1-) or N-phenyl-C-(2-hydroxy phenyl) nitrone, radical ion (1) };

30. phenol, 2-[[epoxy [2-(thiophenyl) phenyl] imino group] methyl]-or N-[2-(thiophenyl) phenyl]-C-(2-hydroxy phenyl) nitrone };

31. phenol, 2-[[epoxy [2-(thiophenyl) phenyl] imino group] methyl]-;

32. nitrone, α-(2, the 3-dihydroxy phenyl)-N-phenyl-;

33. phenol, the 2-[[[(2-hydroxy phenyl) methylene] epoxy amino] methyl]-or N-[(2-hydroxy phenyl) methyl]-C-(2-hydroxy phenyl) nitrone };

34. phenol, 2-[[(1,1-dimethyl ethyl) the epoxy imino group] methyl]-6-fluoro-or N-(tert-butyl)-C-(3-fluoro-2-hydroxy phenyl) nitrone;

35. phenol, 2-[(epoxy-phenyl imino group) methyl]-, radical ion (1-);

36. phenol, 2-[[(1,1-dimethyl ethyl) the epoxy imino group] methyl]-the 6-ethyoxyl-or N-(tert-butyl)-C-(3-ethyoxyl-2-hydroxy phenyl) nitrone;

37. acetamide, N-[2-[[(1,1-dimethyl ethyl) the epoxy imino group] methyl] phenyl]-or N-(tert-butyl)-C-[2-(acetylamino) phenyl] nitrone };

38.2-crotonamide, 4,4,4-three fluoro-N[2-[[epoxy (phenyl methyl) imino groups] methyl] phenyl]-3-(trifluoromethyl)-(or N-benzyl-C-{2-[3,3-two (trifluoromethyl)-2-acrylamido] phenyl } nitrone);

39. glycine, N (2-acetylaminohydroxyphenylarsonic acid 5-chloro-α-phenyl benzylidene)-, methyl ester, the N-oxide or N-(2-methoxyl group-2-oxoethyl)-C-[2-(acetylamino)-5-chlorphenyl]-C '-phenyl nitrone 3;

40.2-crotonamide, 4,4,4-three fluoro-3-methyl-N-[2-[[epoxy (phenyl methyl) imino group] methyl] phenyl]-(or N-benzyl-C-{2-[3-methyl-3-(trifluoromethyl)-2-acrylamido] phenyl } nitrone);

41. Benzoylamide, N-[5-chloro-2-[[[4-(dimethylamino) phenyl] the epoxy imino group] methyl] phenyl]-or N-[4-(N, N-dimethylamino) phenyl]-C-[2-(benzamido)-4-chlorphenyl] nitrone };

42. nitrone, α-(2-acetylaminohydroxyphenylarsonic acid 5-chlorphenyl)-N-(carboxyl methyl)-α-phenyl or N-(carboxyl methyl)-C-[2-(acetylamino)-5-chlorphenyl]-C '-phenyl nitrone };

43. nitrone, N-(carboxyl methyl)-α-[5-chloro-2-(methylamino) phenyl]-α-phenyl or N (carboxyl methyl)-C-[2-(methylamino)-5-chlorobenzene basis]-C '-phenyl nitrone };

44. benzoic acid, 2-[[(1,1-dimethyl ethyl) the epoxy imino group] methyl]-or N-(tert-butyl)-C-(2-carboxyl phenyl) nitrone;

45. nitrone, α-(O-carboxyl phenyl)-N-3, the 4-xylyl-or N-(3, the 4-3,5-dimethylphenyl)-C-(2-carboxyl phenyl) nitrone;

46.o-veratric acid, 6-(N-methylene imine methyl)-, the N-oxide, sodium salt or N-methyl-C-(2-carboxyl-3,4-Dimethoxyphenyl) nitrone, sodium salt };

47.o-veratric acid, 6-(N-methylene imine methyl)-, the N-oxide, methyl ester or N-methyl-C-[2-(methoxycarbonyl)-3, the 4-Dimethoxyphenyl] nitrone };

48.o-veratric acid, 6-(N-methylene imine methyl)-, N-oxide or N-methyl-C-(2-carboxyl-3,4-Dimethoxyphenyl) nitrone;

49. benzoic acid, 2-[(epoxy-phenyl imino group) methyl]-, methyl ester or N-phenyl-C-[2-(methoxycarbonyl) phenyl] nitrone }; With

50. benzoic acid, 2-[(epoxy-phenyl imino group) methyl-, N-oxide or N-phenyl-C-(2-carboxyl phenyl) nitrone.

In the aryl nitrone chemical compound of formula (I)-(III), this ring can only be replaced by the group described in the general formula, and perhaps they can further be replaced.For example, in formula (I), contain the ring of W and Z can be only by described-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces.Perhaps, the ring that contains W and Z can comprise other substituent group on any position of this ring.In formula (II) with (III), described hexatomic ring can contain described two or three substituent groups respectively, and perhaps this ring can contain other substituent group.

In some embodiments of the aryl nitrone chemical compound of formula (I)-(III), R ³It is the substituent group that contains sulphur atom or phosphorus atoms.For example, R ³Can be selected from-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂

In some embodiments, R ³Be-SO ₃H and R ¹It or not the phenyl of low alkyl group, acetylation low alkyl group, hydroxylating low alkyl group, phenyl or replacement.In another embodiment, R ³Be-SR ⁹, and R ⁹Not phenyl or methyl.

In other embodiments, R ³Be-SR ⁹, and R ¹Be not-CH ₂(C ₆H ₅), replace-CH ₂(C ₆H ₅), the phenyl of cyclohexyl, methyl, phenyl or the replacement of cyclohexyl, replacement.In another embodiment, R ³Be-SR ⁹, R ⁹Not phenyl or methyl.

In other embodiments, R ³It is hydroxyl.For example, work as R ¹Be not-CH ₂(C ₆H ₅), replace-CH ₂(C ₆H ₅), the R during phenyl of low alkyl group, phenyl or replacement ³Can be-OH.

In another embodiment, R ³Can comprise nitrogen-atoms.For example, R ³Can be amino.In some embodiments, R ³Can comprise nitrogen-atoms, at this moment R ³Be-NR ⁷R ⁸And R ⁷And R ⁸Not hydrogen.In another embodiment, R ³Can comprise nitrogen-atoms, at this moment R ³Be-NR ⁷R ⁸And R ¹Be not-CH ₂CO ₂Me ,-CH ₂CO ₂H ,-CH ₂(C ₆H ₅), replace-CH ₂(C ₆H ₅), the phenyl of low alkyl group, phenyl or replacement.

In addition, in some embodiments, R ³It is the carboxyl (being ester) of carboxyl or replacement.In specific embodiment, R ³Be-CO ₂R ⁹, this moment R ⁹Not hydrogen or methyl.In other specific embodiments, work as R ¹R when not being the phenyl of low alkyl group, phenyl or replacement ³Be-CO ₂R ⁹

In the aryl nitrone chemical compound of formula (I)-(III), usually preferred R ¹Be alkyl, cycloalkyl, aryl or aralkyl, preferred alkyl and especially low alkyl group.The low alkyl group that on the carbon atom of 1-position, has side chain, for example cyclopropyl, isopropyl, sec-butyl, the tert-butyl group, cyclobutyl, 1-methyl ring third-1-base, sec-amyl, tertiary pentyl, cyclopenta, 1-methyl ring fourth-1-base etc., it is preferred comparing the not ramose equivalent form of value.

Preferred R ²Be hydrogen, alkyl, assorted alkyl, aralkyl or aryl, can be substituted or be further replaced.Hydrogen is most preferred R ²Group.

Preferred R ³Be-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH and-CO ₂R ⁹Preferred R ³Group is-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸With-CO ₂R ⁹

Preferably have one or more R ⁴Group is a hydrogen.

Preferred R ⁵Be hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH or-CO ₂R ⁹Preferred R ⁵Group be hydrogen ,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸With-CO ₂R ⁹

5.4 heteroaryl nitrone compound

In other embodiments, the invention provides the heteroaryl nitrone compound of formula (IV):

In the formula:

W, X and Z independently are selected from CR respectively ⁴, C (R ⁴) ₂, N, NR ⁴, O and S, and only form by formula (IV)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Assorted thiazolinyl of the ring that part replaces or further replaced or heteroaryl ring;

L is C (R ²) ₂

R ³Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

Dotted line is represented single or two key; With

N is the integer of 0-1; Or

Its pharmaceutically acceptable salt or prodrug.

In other embodiment of the assorted fragrant nitrone of formula (IV), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In some embodiments of the heteroaryl nitrone compound of formula (IV), one of W, X and Z are N.In other embodiments, one of W, X and Z are O.In another embodiment, one of W, X and Z are S.

In other embodiment of the nitrone compound of formula (IV), X, Y become a hetero-aromatic ring with Z-shaped, and one of W, X and Z are NR ⁴, O or S, and remaining independently is C-R ⁴In another embodiment, one of W and Z are NR ⁴, O or S, another is C-R ⁴, and X is C-R ⁵, R wherein ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹In some embodiments, R ³And R ⁵Inequality, and in other embodiments, R ³And R ⁵Identical.

In preferred embodiments, the heteroaryl nitrone compound of formula (I), formula (II) or formula (IV) any among the inclusion compound 51-69 not.In specific embodiment, the heteroaryl nitrone compound of formula (I), formula (II) or formula (IV) is any salt of inclusion compound 51-69 not.In another embodiment, not any isomers, diastereomer or the enantiomer of inclusion compound 51-69 of the heteroaryl nitrone compound of formula (I), formula (II) or formula (IV).Chemical compound 51-69 is as follows:

51. nitrone, α-(the 3-carboxyl-2-furyl)-N-[4-(dimethylamino) phenyl]-, methyl ester or N-[4-(dimethylamino) phenyl]-C-[3-(methoxycarbonyl) furan-2-yl] nitrone };

52.2,4-furan disulfonic acid, 5-[[(1-Methylethyl) and the epoxy imido] methyl]-, disodium salt or N-isopropyl-C-(3,5-two sulfur furan-2-yl) nitrone, disodium salt };

53.1H-pyrroles-2,4-dicarboxylic acids, 5-[[[4-(dimethylamino) phenyl] the epoxy imido] methyl]-the 3-methyl-, diethylester or N[4-(dimethylamino) phenyl]-C-[4-methyl-3,5-two (ethoxy carbonyl)-1H-pyrroles-2-yl] nitrone };

54.3-the thiophene carboxylic acid, 2-[[[4-(dimethylamino) phenyl] the epoxy imino group] methyl]-, methyl ester or N[4-(dimethylamino) phenyl]-C-[3-(methoxycarbonyl) thiophene-2-yl] nitrone };

55.5-pyrimidine carboxylic, 4-[(epoxy-phenyl imino group) methyl]-the 2-phenyl-, ethyl ester or N-phenyl-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

56.5-pyrimidine carboxylic, the 4-[[(4-chlorphenyl) the epoxy imino group] methyl]-the 2-phenyl-, ethyl ester or N-(4-chlorphenyl)-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

57.5-pyrimidine carboxylic, the 4-[[(2-aminomethyl phenyl) the epoxy imino group] methyl]-the 2-phenyl-, ethyl ester or N-(2-aminomethyl phenyl)-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

58.5-pyrimidine carboxylic, 4-[[epoxy (phenyl methyl) imino group] methyl]-the 2-phenyl-, ethyl ester or N-benzyl-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

59.5-pyrimidine carboxylic, the 4-[[(2-hydroxyethyl) the epoxy imino group] methyl]-the 2-phenyl-, ethyl ester or N-(2-hydroxyethyl)-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

60.5-pyrimidine carboxylic, 4-[(butyl epoxy imino group) methyl]-the 2-phenyl-, ethyl ester or N-butyl-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

61.5-pyrimidine carboxylic, 4-[(glycidyl imino group) methyl]-the 2-phenyl-, ethyl ester or N-propyl group-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

62.5-pyrimidine carboxylic, 4-[(ethyl epoxy imino group) methyl]-the 2-phenyl-, ethyl ester or N-ethyl-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

63.5-pyrimidine carboxylic, 4-[[[4-(dimethylamino) phenyl] the epoxy imino group] methyl]-the 2-phenyl-, ethyl ester or N[4-(dimethylamino) phenyl]-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

64.5-pyrimidine carboxylic, 4-[N-[p-(dimethylamino) phenyl] formimino group]-2-(methyl mercapto)-, ethyl ester, the N-oxide or N-[4-(dimethylamino) phenyl]-C-[5-(ethoxy carbonyl)-2-(methyl mercapto) pyrimidine-4-yl] nitrone };

65.5-pyrimidine carboxylic, 4-[(epoxy-phenyl imino group) methyl]-the 2-phenyl-, ethyl ester;

66.5-pyrimidine carboxylic, 4-[[[4-(methyl sulphonyl) phenyl] the epoxy imino group] methyl]-the 2-phenyl-, ethyl ester or N-(4-(methyl sulphonyl) phenyl]-C-[5-(ethoxy carbonyl)-2-phenyl pyrimidine-4-yl] nitrone };

67.1H-pyrazoles-5-amine, 1-[2,6-two-chloro-4-(trifluoromethyl) phenyl]-3-[1-(methyl epoxy imino group) ethyl]-4-(methyl mercapto)-or N-methyl-C-{5-amino-4-(methyl mercapto)-1-[4-(trifluoromethyl)-2, the 6-Dichlorobenzene base]-the 1H-pyrazole-3-yl }-C '-(methyl) nitrone };

68.1H-pyrroles-3-carboxylic acid, 1-[2-(3, the 4-Dimethoxyphenyl) ethyl]-4,5-dihydro-2-methyl-4-[(methyl epoxy imino group) methyl]-the 5-oxo-, { or N-methyl-C-[4-(methoxycarbonyl)-5-methyl isophthalic acid-[2-(3 for methyl ester, the 4-Dimethoxyphenyl) ethyl]-2-oxo-2,3-dihydro-1H-pyrroles-3-yl] nitrone }; With

69.3-furancarboxylic acid, the 2-[[[4-dimethylamino) phenyl] the epoxy imino group] methyl]-5-(hydroxymethyl)-, methyl ester or N[4-(dimethylamino) phenyl]-C-[5-(hydroxymethyl)-3-(methoxycarbonyl) furan-2-yl] nitrone }.

In formula (I), (II) and heteroaryl nitrone compound (IV), this ring can only be replaced by the group described in the general formula, and perhaps they can further be replaced.For example, in formula (I), contain the ring of W and Z can be only by described-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces.Perhaps, the ring that contains W and Z can comprise other substituent group on any position of this ring.In formula (II) with (IV), this ring can contain described two substituent groups, and perhaps this ring can contain other substituent group.

In some embodiments, R ³It is the substituent group that contains sulphur atom or phosphorus atoms.For example, R ³Can be selected from-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂

In formula (I), (II) and heteroaryl nitrone compound (IV), usually preferred R ¹Be alkyl, cycloalkyl, aryl or aralkyl, preferred alkyl, and low alkyl group especially.The low alkyl group that on the carbon atom of 1-position, has side chain, for example cyclopropyl, isopropyl, sec-butyl, the tert-butyl group, cyclobutyl, 1-methyl ring third-1-base, sec-amyl, tertiary pentyl, cyclopenta, 1-methyl ring fourth-1-base etc., it is preferred comparing the not ramose equivalent form of value.Tert-butyl is most preferred R ¹Group.

Preferred R ²Be hydrogen, alkyl, assorted alkyl, aralkyl or aryl, they contain or do not contain other substituent group.Hydrogen is most preferred R ²Group.

Preferred R ³Be-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH or-CO ₂R ⁹Preferred R ³Group is-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸With-CO ₂R ⁹

Preferred one or more R ⁴Group is a hydrogen.

In heteroaryl nitrone compound of the present invention, the atom of representing with X can be substituted or not be substituted, and in chemical compound, X is carbon or the hetero atom for having free valency especially.In some embodiments, X can be replaced by any group outside the hydrogen.For example, X can be by-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂Or-CO ₂R ⁹Replace.

In the heteroaryl nitrone compound of formula (II), in some embodiments, this 6-unit hetero-aromatic ring contains a nitrogen-atoms, and in other embodiments, this hetero-aromatic ring contains two nitrogen-atoms.In another embodiment, this ring contains three nitrogen-atoms.

When the hetero-aromatic ring of formula (II) contained two nitrogen-atoms, these two nitrogen-atoms can be in W, X, Y and Z on any one.For example, these two nitrogen-atoms can be on W and X, on W and Y, and on W and Z, on X and Y, on X and Z, or on Y and Z.

At X and Z all is in the embodiment of N, and other group of formula (II) can be represented specific group.For example, Y can be by the carbon of any group replacement outside the phenyl of phenyl, replacement or the methyl sulfane base.In other embodiments, Y can be replaced by the group outside the aryl of sulfane base, aryl or the replacement of sulfane base, replacement.In specific embodiment, Y by hydrogen ,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂Or-CO ₂R ⁹Replace.In other embodiments, Y quilt-SO ²NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂Or-CO ₂R ⁹Replace.

At other X and Z all is in the embodiment of N, R ²Be selected from and replace or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.In some embodiments, be connected to the R of nitrone group ²Group is selected from and replaces or unsubstituted (C-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.

At other X and Z all is in the embodiment of N, R ³Be not-CO ₂Et.In another embodiment, R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹).In specific embodiment, R ³Be-CO ₂R ⁹, and R ⁹It or not ethyl.In other embodiments, R ³Be-CO ₂R ⁹, and R ⁹It or not low alkyl group.

In another W, X, Y and Z, there are two to be in the embodiment of N, R ¹Not the phenyl or the low alkyl group of phenyl, replacement.For example, R ¹Can be to replace or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

Again in other embodiments of the present invention, W and Z are in conjunction with forming 5 yuan of hetero-aromatic rings.In some embodiments, this 5-unit ring can comprise nitrogen-atoms, oxygen atom or sulphur atom.In specific embodiment, available formula (IV) expression that contains group W, X and Z of this ring.

When described hetero-aromatic ring contained oxygen atom, oxygen atom can be on W, X or Z.In some embodiments, oxygen atom is on W or X.In other embodiments, oxygen atom is on Z.In some embodiments, Z is an oxygen when n is 1.

In some embodiments, one of W, X and Z are O, and remaining independently is C-R separately ⁴In some embodiments, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

In another embodiment, Z is O when n is 0.In such embodiments, R ²Optional from replacing or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.In some embodiments, be connected to the R of nitrone group ²Group is selected from and replaces or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.

In other embodiments, Z is O when n is 0, and R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ₈) ₂With-PO (OR ⁹) ₂In specific embodiment, R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂In other embodiments, R ³Be-CO ₂R ⁹, and R ⁹It or not methyl.In specific embodiment, R ⁹It or not low alkyl group.

In other embodiments, Z is O when n is 0, and R ¹Not the phenyl or the isopropyl of phenyl, replacement.In specific embodiment, R ¹It or not low alkyl group.For example, R ¹Can be to replace or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

In another embodiment, the hetero-aromatic ring in the formula (IV) can comprise nitrogen-atoms.Described nitrogen-atoms can be positioned at W, X or Z.In some embodiments, nitrogen-atoms is on W or X.In other embodiments, nitrogen-atoms is on Z.In some embodiments, Z is a nitrogen when n is 1.Again in other embodiments, Z is NR ⁴

In some embodiments, one of W, X and Z are N or NR ⁴, and remaining is selected from C-R independently of one another ⁴, O, S and N.In some embodiments, Z is C-R ⁴, O or S.

In another embodiment, Z is N when n is 0.In such embodiments, R ²Optional from replacing or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.In some embodiments, be connected to the R of nitrone group ²Group is selected from and replaces or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.

In other embodiments, Z is N when n is 0, and R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂In other embodiments, R ³Be-CO ₂R ⁹, R wherein ⁹It or not ethyl.In specific embodiment, R ⁹It or not low alkyl group.

In other embodiments, Z is N when n is 0, and R ¹It or not the phenyl of phenyl or replacement.For example, R ¹Can be to replace or unsubstituted aliphatic series, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

In another embodiment, Z is N when n is 0, and X is C-R ⁴In these embodiments, R ⁴Can not methyl, perhaps R ⁴Can not low alkyl group.For example, R ⁴Can be hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂Or-CO ₂R ⁹

In other embodiments, the hetero-aromatic ring in the formula (IV) can comprise sulphur atom.Described sulphur atom can be on W, X or Z.In some embodiments, sulphur atom is on W or X.In other embodiments, sulphur atom is on Z.In some embodiments, Z is a sulfur when n is 1.

In some embodiments, one of W, X and Z are S, and remaining independently is selected from C-R separately ⁴And N.In some embodiments, Z is C-R ⁴Or N.

In another embodiment, Z is S when n is 0.In such embodiments, R ²Optional from replacing or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.In-a little embodiments, be connected to the R of nitrone group ²Group is selected from and replaces or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.

In other embodiments, Z is S when n is 0, and R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂In other embodiments, R ³Be-CO ₂R ⁹, R wherein ⁹It or not methyl.In specific embodiment, R ⁹It or not low alkyl group.

In other embodiments, Z is S when n is 0, and R ¹It or not the phenyl of phenyl or replacement.For example, R ¹Can be to replace or unsubstituted aliphatic series, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

In another embodiment, Z is S when n is 0, and X is C-R ⁴In some embodiments, R ⁴Can not hydrogen.In other embodiments, R ⁴Can be hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂Or-CO ₂R ⁹

5.5 aryl bicyclic nitrone compound

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula V:

In the formula:

W, X and Z independently are C-R separately ⁴Or C (R ⁴) ₂

Y is C-R ⁴Or carbonyl;

L is C (R ²) ₂

A is selected from NR ⁴, O and S;

R ¹Be selected from the aliphatic series that replaces or replace, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted ring assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl and replacement or unsubstituted heteroarylalkyl;

Each R ⁹The heteroarylalkyl that independently is selected from hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl and replacement or replaces; With

Dotted line is represented single or two key;

Or its pharmaceutically acceptable salt or prodrug.

In other embodiment of the aryl bicyclic nitrone of formula V, R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In some embodiments, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹In other embodiments, R ⁵Not hydrogen.

In other embodiment of the aryl bicyclic nitrone compound of formula V, Y and Z independently are selected from C-R respectively again ⁴, C (R ⁴) ₂, NR ⁴, O, S and carbonyl.In such embodiments, formula V can comprise heteroatomic any arrangement on A, Y and Z, as long as the stable and chemically feasible heterocycle that the technical staff in organic synthesis field generally acknowledges is proficient in its formation.Its example comprises and condenses De oxazole, imidazoles and triazole.

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (VI):

In the formula:

X and Z independently are C-R separately ⁴Or C (R ⁴) ₂

Y is C-R ⁴Or carbonyl;

L is C (R ²) ₂

A is selected from NR ⁴, O and S;

Dotted line is represented single or two key; Or

Its pharmaceutical salts or prodrug.

In other embodiment of the aryl bicyclic nitrone of formula (VI), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In other embodiment of the aryl bicyclic nitrone compound of formula (VI), Y and Z independently are selected from C-R respectively ⁴, C (R ⁴) ₂, NR ⁴, O, S and carbonyl.In such embodiments, formula (VI) can comprise heteroatomic any arrangement on A, Y and Z, as long as the stable and chemically feasible heterocycle that the technical staff in organic synthesis field generally acknowledges is proficient in its formation.Its example comprises and condenses De oxazole, imidazoles and triazole.

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (VII):

In the formula:

W, X and Z independently are C-R separately ⁴Or C (R ⁴) ₂

Y is C-R ⁴Or carbonyl;

L is C (R ²) ₂

A is selected from NR ⁴, O and S;

Dotted line is represented single or two key;

Or its pharmaceutically acceptable salt or prodrug.

In other embodiment of the aryl bicyclic nitrone of formula (VII), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In other embodiment of the aryl bicyclic nitrone compound of formula (VII), Y and Z independently are selected from C-R respectively again ⁴, C (R ⁴) ₂, NR ⁴, O, S and carbonyl.In such embodiments, formula (VII) can comprise heteroatomic any arrangement on A, Y and Z, as long as the stable and chemically feasible heterocycle that the technical staff in organic synthesis field generally acknowledges is proficient in its formation.Its example comprises and condenses De oxazole, imidazoles and triazole.

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (VIII):

In the formula:

X and Z independently are C-R separately ⁴Or C (R ⁴) ₂

Y is C-R ⁴Or carbonyl;

L is C (R ²) ₂

A is selected from NR ⁴, O and S;

Dotted line is represented single or two key;

Or its pharmaceutically acceptable salt or prodrug.

In other embodiment of the aryl bicyclic nitrone of formula (VIII), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ₉) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In other embodiment of the aryl bicyclic nitrone compound of formula (VIII), Y and Z independently are selected from C-R respectively ⁴, C (R ⁴) ₂, NR ⁴, O, S and carbonyl.In such embodiments, formula (VIII) can comprise heteroatomic any arrangement on A, Y and Z, as long as the stable and chemically feasible heterocycle that the technical staff in organic synthesis field generally acknowledges is proficient in its formation.Its example comprises and condenses De oxazole, imidazoles and triazole.

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (IX):

In the formula:

W and X independently are N or C-R separately ⁴

Y and Z independently are carbonyl, C-R separately ⁴Or C (R ⁴) ₂

L is C (R ²) ₂

A and Q independently are selected from carbonyl, NR respectively ⁴, O, S and C-R ⁴

Dotted line is represented single or two key;

Or its pharmaceutically acceptable salt or prodrug.

In some embodiments of the aryl bicyclic nitrone compound of formula (IX), one of W and X are N at least.

In other embodiment of the aryl bicyclic nitrone of formula (IX), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸, PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (X):

In the formula:

W, X, Y, Z, A and Q independently are selected from N and C-R respectively ⁴

L is C (R ²) ₂

R ⁷And R ⁸Independently be selected from respectively hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl, replacement or unsubstituted heteroarylalkyl ,-CO ₂R ⁹With-CON (R ⁹) ₂, and can replace or unsubstituted hetero-aromatic ring or saturated or undersaturated replacement or the unsubstituted assorted alkyl ring of ring that contains 4-7 atom in conjunction with forming; With

Each R ⁹Independently be selected from hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl and replacement or unsubstituted heteroarylalkyl; Or

Its pharmaceutically acceptable salt or prodrug.

In other embodiment of the aryl bicyclic nitrone of formula (X), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In the aryl bicyclic nitrone compound of formula (X), in some embodiments, group W, X, Y and the Z C-R that respectively does for oneself ⁴As W, X, Y and the Z C-R that respectively does for oneself ⁴The time, in some embodiments, R is not a hydrogen.In another embodiment, as W, X, Y and the Z C-R that respectively does for oneself ⁴The time, R ¹Not the phenyl or the methyl of phenyl, replacement.In another embodiment, as W, X, Y and the Z C-R that respectively does for oneself ⁴The time, R ¹Not the phenyl or the low alkyl group of phenyl, replacement.For example, R ¹Can be to replace or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

In another embodiment, as W, X, Y and the Z C-R that respectively does for oneself ⁴The time, R ³Be not-OH or-SMe.For example, R ³Can be selected from-SO ²NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹In another embodiment, as W, X, Y and the Z C-R that respectively does for oneself ⁴The time, A and Q also independently are C-R ⁴, and X can by hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ₉) NR ⁷R ⁸,-PO (OR ⁹) ₂Or-CO ₂R ⁹Replace.In other embodiments, X is replaced by the substituent group outside the hydrogen.

In other embodiments, one of W, X, A, Y, Z and Q are N, and remaining independently is C-R separately ⁴In another embodiment, one of A, Y, Z and Q are N, and remaining group and W and X independently are C-R separately ⁴In specific embodiment, A is N, and W, X, Y, Z and Q independently are C-R separately ⁴In other specific embodiments, Q is N, and W, X, A, Y and Z independently are C-R separately ⁴Again in other embodiments, two among W, X, A, Y, Z and the Q is N, and remaining independently is C-R separately ⁴In another embodiment, two among A, Y, Z and the Q is N, and remaining group and W and X independently are C-R separately ⁴Again in other embodiments, three among W, X, A, Y, Z and the Q is N, and remaining independently is C-R separately ⁴

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (XI):

In the formula:

W and X independently are selected from N and C-R respectively ⁴

Y and Z independently are carbonyl, C-R separately ⁴Or C (R ⁴) ₂

A and Q independently are selected from carbonyl, NR respectively ⁴, O and S;

L is C (R ²) ₂

Dotted line is represented single or two key;

Or its pharmaceutically acceptable salt or prodrug.

In other embodiment of the aryl bicyclic nitrone of formula (XI), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (XII):

In the formula:

W and X independently are selected from N and C-R respectively ⁴

Q is NR ⁴, carbonyl or C (R ⁴) ₂

Y and Z independently are C (R separately ⁴) ₂Or carbonyl;

L is C (R ²) ₂

Each R ⁹Independently be selected from hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl and replacement or unsubstituted heteroarylalkyl;

Or its pharmaceutically acceptable salt or prodrug.

In other embodiment of the aryl bicyclic nitrone of formula (XIII), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (XIII):

In the formula:

W and X independently are selected from N and C-R respectively ⁴

A is NR ⁴, carbonyl or C (R ⁴) ₂

Y and Z independently are C (R separately ⁴) ₂Or carbonyl;

L is C (R ²) ₂

Or its pharmaceutically acceptable salt or prodrug.

In another embodiment, the invention provides the aryl bicyclic nitrone compound of formula (XIV):

In the formula:

W and X independently are selected from N and C-R respectively ⁴,

Y and Z independently are C (R separately ⁴) ₂Or carbonyl;

L is C (R ²) ₂

Each R2 independently is selected from hydrogen, replacement or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl;

R ⁷And R ⁸Independently be selected from respectively hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl, replacement or unsubstituted heteroarylalkyl ,-CO ₂ ⁹R and-CON (R ⁹) ₂, and can replace or unsubstituted hetero-aromatic ring or saturated or undersaturated replacement or the unsubstituted assorted alkyl ring of ring that contains 4-7 atom in conjunction with forming; With

Or its pharmaceutically acceptable salt or prodrug.

In other embodiment of the aryl bicyclic nitrone of formula (XIV), R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

In other embodiment of formula (IX) and aryl bicyclic nitrone compound (XI)-(XIV), A, Y, Z and Q independently are selected from carbonyl, C-R respectively ⁴, C (R ⁴) ₂, N, NR ⁴, O and S.Such embodiment comprises that those have the chemical compound of heteroatomic any arrangement on A, Y, Z and Q, as long as the stable and chemically feasible heterocycle that the technical staff in organic synthesis field generally acknowledges is proficient in its formation.

In other embodiment of the aryl bicyclic nitrone compound of formula V-(XIV), X is C-R again ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹Again in other embodiments, R ⁵Not hydrogen.

In preferred embodiments, above-mentioned various aryl bicyclic nitrone compound does not comprise any one among the chemical compound 70-78.In specific embodiment, above-mentioned various aryl bicyclic nitrone compound does not comprise any salt of chemical compound 70-78.In another embodiment, above-mentioned various aryl bicyclic nitrone compound does not comprise any isomers, diastereomer or the enantiomer of chemical compound 70-78.Chemical compound 70-78 is as follows:

70. benzoic acid, 4-[[(2-hydroxyl-1-naphthyl) methylene] epoxy amino]-, ethyl ester, (Z)-or (Z)-N-[4-(ethoxy carbonyl) phenyl]-C-(2 hydroxy naphthalene-1-yl) nitrone };

71.1, the 4-phenylenediamine, N, N-dimethyl-N '-[[3-(thiophenyl)-2-quinoxalinyl] methylene]-, N '-oxide or N[4-(dimethylamino) phenyl]-C-[3-(thiophenyl) quinoxaline-2-yl] nitrone };

72. hexamethylenetetramine, N-[[2-(methyl mercapto)-1-naphthyl] methylene]-, the N-oxide or N-methyl-C-[2-(methyl mercapto) naphthalene-1-yl] nitrone };

73. aniline, N-[[2-(methyl mercapto)-1-naphthyl] methylene]-, the N-oxide or N-phenyl-C-[2-(methyl mercapto) naphthalene-1-yl] nitrone };

74. aniline, 3-methyl-N-[[2-(methyl mercapto)-1-naphthyl] methylene], the N-oxide or N-(3-aminomethyl phenyl)-C-[2-(methyl mercapto) naphthalene-1-yl] nitrone };

75. aniline, 4-methyl-N-[[2-(methyl mercapto)-1-naphthyl] methylene]-, the N-oxide or N-(4-aminomethyl phenyl)-C-[2-(methyl mercapto) naphthalene-1-yl] nitrone };

76. aniline, 3-chloro-N-[[2-(methyl mercapto)-1-naphthyl] methylene]-, the N7-oxide or N-(3-chlorphenyl)-C-[2-(methyl mercapto) naphthalene-1-yl] nitrone };

77. aniline, 4-chloro-N-[[2-(methyl mercapto)-1-base naphthalene] methylene]-, the N-oxide or N-(4-chlorphenyl)-C-[2-(methyl mercapto) naphthalene-1-yl] nitrone }; With

78.2-naphthols (naphthalenol), the 1-[[(4-nitrobenzophenone) the epoxy imino group] methyl]-or N-(4-nitrobenzophenone)-C-(2 hydroxy naphthalene-1-yl) nitrone.

In above-mentioned various aryl bicyclic nitrone compound, ring can only be replaced by the group described in the general formula, and perhaps they can further be replaced.For example, in formula (I), contain the ring of W and Z can be only by described-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces, and perhaps, the ring that contains W and Z can comprise other substituent group on any position of this ring.In above-mentioned formula, this ring can contain described two substituent groups, and perhaps this ring can contain other substituent group.

In the aryl bicyclic nitrone compound of formula (I), W in this chemical compound and Z are in conjunction with formation and 5-or 6-unit cycloalkyl, the assorted alkyl of ring, aryl or condensed 6-unit's aryl of heteroaryl ring or heteroaryl ring usually.

Also in above-mentioned various aryl bicyclic nitrone compound, usually preferred R ¹Be alkyl, cycloalkyl, aryl or aralkyl, preferred alkyl, and low alkyl group especially.The low alkyl group that on the carbon atom of 1-position, has side chain, for example cyclopropyl, isopropyl, sec-butyl, the tert-butyl group, cyclobutyl, 1-methyl ring third-1-base, sec-amyl, tertiary pentyl, cyclopenta, 1-methyl ring fourth-1-base etc., it is preferred comparing the not ramose equivalent form of value.Tert-butyl is most preferred R ¹Group.

Preferred one or more R ⁴Group is a hydrogen.

Preferred R ⁵Be hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) ₂Or-CO ₂R ⁹Preferred R ⁵Group be hydrogen ,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸With-CO ₂R ⁹

In aryl bicyclic nitrone compound of the present invention, the atom of representing with X can be substituted or not be substituted, and in chemical compound, X is carbon or assorted former the giving for having free valency especially.In some embodiments, X can be replaced by any group outside the hydrogen.For example, X can by hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂Or-CO ₂R ⁹Replace.

5.6 the derivant of aryl, heteroaryl and aryl bicyclic nitrone compound

In some aspects, the invention provides the prodrug and the derivant of following material: the aryl nitrone chemical compound of formula (I)-(III); Formula (I), (II) and heteroaryl nitrone compound (IV); And formula (I) and aryl bicyclic nitrone compound (V)-(XIV).Prodrug is the derivant of The compounds of this invention, and it contains the purgeable group of metabolism and can decompose by solvolysis or under physiological condition and forms the chemical compound of the present invention that has pharmaceutically active in vivo.Its example includes but not limited to cholinester derivant etc. and N-alkyl morpholine ester etc.

Other derivant of aryl of the present invention, heteroaryl and aryl bicyclic nitrone compound has activity in its acidity or acid derivant form.That acid-sensitive sense form has in mammalian organism usually is solvable, the advantage of tissue compatible or slow release (see H.Bundgard, 1985, Design of Prodrugs, Elsevier, Amsterdam, 7-9,21-24 page or leaf).Prodrug comprises acid derivant well-known to those having ordinary skill in the art, such as, the esters by making with parent acid and the reaction of suitable alcohol for example, reacts amide, anhydride and the mixed acid anhydride that makes with parent acid compound and replacement or unsubstituted amine.Simple aliphatic series or aromatic ester, amide and anhydride derived from acidic-group on the The compounds of this invention are preferred prodrugs.Under the certain situation, need the prodrug of preparation diester types, as (acyloxy) Arrcostab or ((alkoxy carbonyl) oxygen) Arrcostab.The C of preferred The compounds of this invention ₁-C ₈Alkyl, C ₂-C ₈Thiazolinyl, aryl, C ₇-C ₁₂The aryl and the C that replace ₇-C ₁₂Alkyl aryl.

5.7 pharmaceutical composition

When as drug use, aryl of the present invention, heteroaryl and aryl bicyclic nitrone compound give with the form of pharmaceutical composition usually.The present invention also provides the pharmaceutical composition that contains following one or more chemical compounds: chemical compound 1,8,9,11,16-22,25-27,37-43 and the 45-50 of 5.3 parts; 5.4 the chemical compound 51 and the 53-69 of part; And the chemical compound 70-78 of 5.5 parts.This compositions can prepare with the method that pharmaceutical field is known, and contains at least a reactive compound of pharmaceutically acceptable carrier and medicine effective quantity usually.

Usually, aryl of the present invention, heteroaryl and aryl bicyclic nitrone compound give with medicine effective quantity.The actual amount of described chemical compound determines according to relevant situation by the doctor usually, and these situations comprise that the seriousness of disease to be treated, patient's symptom, the route of administration of selection, the actual chemical compound of using, age, body weight and patient are to reaction of treatment or the like.

Pharmaceutical composition of the present invention can give by all means, gives comprising oral, rectum, transdermal, subcutaneous, intravenous, intramuscular and intranasal.According to the route of administration that is adopted, chemical compound of the present invention preferably is made into Injectable composition or Orally administered composition, perhaps makes ointment, lotion or patch for transdermal administration.

Liquid preparations for oral administration can be the form of a large amount of powder or a large amount of liquid solution or suspension.Yet under the more susceptible condition, described compositions exists with unit dosage forms so that dosed administration exactly.Term " unit dosage forms " is meant the physically discontinuous unit that is suitable as administration of human class object or other mammiferous single dose, each unit contains the chemical substance of the scheduled volume that passes through calculating to produce required therapeutic effect, contains suitable drug excipient simultaneously.Typical unit dosage forms comprises, the bottle or the needle tubing of the prefill of fluid composition, pre-metering, the pill of solid composite, tablet, capsule etc.In this compositions, active nitrone compound of the present invention is time amount composition (account for 0.1-50 weight %, preferably account for about 1-40 weight %) normally, and remainder is various carriers or carrier, and processes with the method that produces required dosage form.

The liquid form that is fit to oral administration can contain suitable aqueous or non-aqueous carrier and buffer agent, suspending agent and dispersant, coloring agent, flavoring agent etc.Solid form can comprise, for example, and any following composition or chemical compound: such as the binding agent of microcrystalline Cellulose, tragakanta or gelatin with similarity; Excipient such as starch or lactose; Disintegrating agent such as alginic acid, Primogel or corn starch; Lubricant such as magnesium stearate; Fluidizer such as silica sol; Sweeting agent such as sucrose or glucide; And such as the flavoring agent of Herba Menthae, methyl salicylate or flavoring orange essence.

Injectable compositions is usually based on injectable Sterile Saline known in the art or phosphate-buffered saline or other injectable carrier.Before, the reactive compound in this compositions is time amount composition normally, accounts for about 0.05-10 weight % usually, and remainder is an injectable carrier etc.

Transdermal composition is made into local ointment or the cream that uses usually, contains the 0.01-20 weight % that has an appointment, preferably about 0.1-20 weight %, more preferably from about 0.1-10 weight %, the active component of preferably about 0.5-15 weight % more usually.When being made into ointment, described active component usually with can mix with the miscible ointment base material of paraffin or water.Perhaps, described active component can be made cream with for example oil-in-water type cream base material.This preparation capable of permeating skin is well known in the art and comprises other composition usually to strengthen percutaneous permeability or active component or stability of formulation.All this known preparation capable of permeating skin and composition all are included within the scope of the invention.

Aryl of the present invention, heteroaryl and aryl bicyclic nitrone compound also can pass through the transdermal device administration.Therefore, transdermal administration can adopt the patch of apotheca (reservoir) or perforated membrane type or various solid substrates to realize.

But the composition of above-mentioned Orally-administrable, injectable or topical drug delivery composition only is representational.Other material and manufacturing technology etc. are listed in the 8th part of " Lei Mingdun pharmaceutical science " (Remington ' s PharmaceuticalSciences), the 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, its content is included in this paper as a reference by complete.

Aryl of the present invention, heteroaryl and aryl bicyclic nitrone compound can also the slow release forms or are given by the slow releasing pharmaceutical delivery system." Lei Mingdun pharmaceutical science " seen in the description of typical case's slow-release material.

Following formulation examples is for example understood the representational pharmaceutical composition of the present invention.Yet the invention is not restricted to following pharmaceutical composition.

Preparation 1-tablet

Aryl, heteroaryl or aryl bicyclic nitrone compound and the exsiccant gelatin adhesive of formula (I) are mixed into dry powder with about 1: 2 weight ratio.Add a small amount of magnesium stearate as lubricant.This mixture is made the tablet (the every active nitrone compound of 80-90 milligram) of 240-270 milligram in tablet machine.

Preparation 2-tablet

Aryl, heteroaryl or aryl bicyclic nitrone compound and the exsiccant gelatin adhesive of formula (I) are mixed into dry powder with about 1: 2 weight ratio.Add a small amount of magnesium stearate as lubricant.This mixture is made the tablet (the every active nitrone compound of 150-300 milligram) of 450-900 milligram in tablet machine.

Preparation 3-capsule

Aryl, heteroaryl or aryl bicyclic nitrone compound and the starch diluent of formula (I) are mixed into dry powder with about 1: 1 weight ratio.This mixture is filled into 250 milligrams capsule (125 milligrams of active nitrone compounds of every capsule).

Preparation 4-liquid

The aryl of hybrid (I), heteroaryl or aryl bicyclic nitrone compound (125 milligrams), sucrose (1.75 gram) and xanthan gum (4 milligrams), by No.10 order U.S. sieve, then with the aqueous solution of ready-formed microcrystalline Cellulose and sodium carboxymethyl cellulose (11: 89,50 milligrams).Dilute with water sodium benzoate (10 milligrams), flavoring agent and coloring agent also add while stirring.It is 5 milliliters that the water that adds capacity then makes cumulative volume.

Preparation 5-injection

Aryl, heteroaryl or the aryl bicyclic nitrone compound of formula (I) is dissolved in or is suspended in injectable aseptic buffer saline medium, make its concentration be about 5 mg/ml.

Preparation 6-topical formulations

Melt hard ester alcohol (250 gram) and white petrolatum (250 gram) down at about 75 ℃, add aryl, heteroaryl or aryl bicyclic nitrone compound (50 gram), methyl parahydroxybenzoate (0.25 gram), propyl p-hydroxybenzoate (0.15 gram), sodium lauryl sulphate (10 gram) and the propylene glycol (120 gram) of the formula (I) of water-soluble (about 370 grams) then.Stir the gained mixture until condensing.

5.8 Therapeutic Method

Aryl of the present invention, heteroaryl and aryl bicyclic nitrone compound can be used as the therapeutic agent of treatment mammal disease.Therefore, chemical compound of the present invention and pharmaceutical composition can be used as therapeutic agent to prevent and/or treat mammiferous pain, nerve and neural degeneration, autoimmunity and inflammatory diseases or the symptom that comprises the people.

Aspect another Therapeutic Method, the invention provides the mammiferous method that certain disease is easily suffered from or suffered from treatment, described disease can cause pain reaction or relevant with the imbalance of keeping the sensory nerve primary activity.Nitrone compound can be used as the pain of analgesic with the treatment a variety of causes and the cause of disease, for example, and acute inflammation pain (as the pain relevant) with osteoarthritis and rheumatoid arthritis; Various neuropathic pain syndromes (neuropathy that the neuropathy that causes as postherpetic neuralgia, trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, Green's barye syndrome, fibromyalgia, phantom limb pain, mastectomy postoperative pain, peripheral neurophaty, HIV neuropathy and chemotherapy and other reason cause); Visceral pain (as reflecting disease, irritable bowel syndrome, inflammatory bowel, pancreatitis and gynaecopathia and the relevant pain of urological diseases) with the stomach esophagus; Toothache; And headache (as migraine, cluster headache and tension headache).

Aspect another Therapeutic Method, the invention provides the mammiferous method that following disease is easily suffered from or suffered from treatment: neurodegenerative disease and obstacle, as parkinson disease, Alzheimer and multiple sclerosis; By neuritis mediation or the disease and the obstacle that cause, as traumatic brain injury, apoplexy and encephalitis; The neural psychotic disorder and the obstacle of maincenter mediation, such as, depression for example, manic disorder, two-phase disease, anxiety neurosis and schizophrenia; Eating disorders, sleep disorder and cognitive disorder; Epilepsy and seizure of disease; Prostate, bladder and bowel dysfunction, such as, for example, urinary incontinence, hesitancy in urination, rectum allergy, fecal incontinence, benign prostatauxe and inflammatory bowel; Respiratory tract and airway disorders and obstacle, such as, for example, allergic rhinitis, asthma, RAD and chronic obstructive pulmonary disease; By inflammation mediated or cause the disease and the obstacle of inflammation, such as, for example, rheumatoid arthritis, osteoarthritis, myocardial infarction, various autoimmune diseasees and obstacle, uveitis and atherosclerosis; Itch/scratch where it itches, such as, for example, psoriasis; Alopecia (shaving one's head); Obesity; Lipid disorders; Cancer; Hypertension; Spinal cord injury; And nephropathy.Described method comprises one or more aforementioned pharmaceutical compositions that give effectively to treat symptom or prevention symptom amount.

The injected dose level be about 0.1 mg/kg/hour at least 10 mg/kg/hour, all dosage about 1-120 hour, especially in about 24-96 hour, finish.Also can give about 0.1 mg/kg to about 10 mg/kg or the more pre-loading amount of volume realize enough steady-state level.For the human patients of 40-80, maximum accumulated dose should not surpass about 2 gram/skies.

Therefore for preventing and/or treating the long-term symptom such as neural degeneration and autoimmune disease, therapeutic scheme reaches several months or several years usually, takes medicine convenient for the patient and the patience oral administration is preferred.During oral administration, representational scheme is every day 1-5 time, especially 2-4 time, and 3 oral doses normally.When using these dose modes, each dosage provides about 0.01-20 mg/kg active nitrone compound, and preferred dosage is for provide about 0.1-10 mg/kg, especially about 1-5 mg/kg at every turn.

Usually select transdermal administration that the blood levels similar or lower with drug administration by injection is provided.

When being used for preventing the generation of neural degeneration, autoimmune or inflammatory symptoms, nitrone compound of the present invention will be given the patient with ill risk, and administration is carried out under doctor's suggestion and supervision usually, and its dosage level is as indicated above.Have the patient who suffers from concrete disease risk and generally include the people that those have this disease family history, or those have been proved the people who especially easily suffers from this disease by Genetic Detection or genetic screening.

Aryl of the present invention, heteroaryl and aryl bicyclic nitrone compound can be used as independent activating agent and give, and perhaps they can give with other active nitrone compound of other medicament-comprise-unite.

5.9 the general process of synthesizing aryl, heteroaryl and aryl bicyclic nitrone compound

Aryl of the present invention, heteroaryl and aryl bicyclic nitrone can be with following conventional method and step from existing feedstock production.Being appreciated that given herein is typical or preferred reaction condition (being mol ratio, solvent, pressure of reaction temperature, time, reactant etc.), also can use other reaction condition except as otherwise noted.Can change optimum reaction condition according to used concrete reactant or solvent, but this condition can be determined by being proficient in those skilled in the art by the optimization routine process.

In addition, the protecting group that may need to use always prevents that some functional group from unnecessary reaction taking place, and this is obvious for being proficient in those skilled in the art.For the selection of particular functional group's protecting group and for appropriate protection with to go the selection of protective condition be well known in the art.For example, the condition of various protecting groups and introducing thereof and removal is described in T.W.Greene and P.G.M.Wuts, 1991; " protecting group of organic synthesis " (Protecting Groups in Organic Synthesis), second edition, Wiley; among the New York, and quilt at this as a reference.

A kind of method of known manufacturing nitrone is with formaldehyde (carboxaldehyde) derivant and azanol (or its acid-addition salts) reaction that suitably replaces, and with known standard method separation and purified product.This method includes but not limited to recrystallization, column chromatography and HPLC.

Required aryl, heteroaryl or aryl bicyclic nitrone are made in known azanol (or its acid-addition salts) reaction that can make armaticity aldehydes or ketones and replacement in the organic solvent such as methanol, oxolane, dichloromethane, benzene or toluene.This reaction can be carried out at ambient temperature, perhaps can need heating (for example, reflux), and can carry out when the organic or inorganic acid that is with or without as catalyst.When being aromatic ketone, reactant may need high temperature.Also the system of available microwave mediation finishes condensation reaction, and this reaction is usually adopted such as be in 120 ℃ of conditions that heat 5-10 minute in tube sealing.

A synthetic example of above-mentioned aryl nitrone is:

A synthetic example of above-mentioned assorted fragrant nitrone is:

A synthetic example of above-mentioned aryl bicyclic nitrone is:

Aryl of the present invention, heteroaryl and aryl bicyclic nitrone can be with the preparations of other known method, these methods such as, for example with amine, imines or azanol oxidation.Fig. 1-3 has exemplified the example that aryl, heteroaryl and aryl bicyclic nitrone oxygen are combined to approach respectively.

The general process of pyridine/pyrimidine/quinoline aldehyde derivatives that sulfonation replaces

In the pyridine/pyrimidine/quinoline that replaces, add pure 30% oleum at 50-150 ℃, and by such as TLC, LC/MS or ¹The chromatography of H NMR and so on or spectral technique monitoring reaction course.But may need higher temperature when needing repeatedly sulfonation.In case reaction is finished, and mixture is cooled to ambient temperature, handle with trash ice, and carefully alkalize with the sodium hydroxide solution of 1M.Enriched mixture under vacuum, and with the water/acetonitrile that contains 1%TFA as eluent by the reversed phase chromatography purifying crude product.

The general process of pyridine/pyrimidine/quinoline sulfonic acid that amidatioon replaces

Under 0 ℃, dropwise add oxalyl chloride (1.1 equivalent) in the mixture of the sulfonated derivant in dichloromethane and DMF (1: 1) at leisure and mixture was stirred 4 hours.Mixture is cooled to 0 ℃ again, adds suitable amine aqueous solution, mixture is stirred at ambient temperature spend the night.Under vacuum, remove dichloromethane solvent, obtain precipitating the product of shape then with the cold HCl aqueous solution cancellation of 1N, it is leached, wash with water, and drying obtains product under vacuum.

The general process of protection/esterification sulfonic acid

Under the ambient temperature,, handle with suitable alkyl halide then with the excessive Anhydrous potassium carbonate processing sulfonic acid and the mixture of acetone.Mixture was stirred 12 hours at ambient temperature, it is concentrated into dried under vacuum, and handle residue, thereby have product to be settled out with icy water.Nonesterified raw material is stayed in the solution.Sedimentary product is filtered, washes with water and vacuum drying.

The general process of synthesizing aryl, heteroaryl and aryl bicyclic nitrone

Suitable aldehydes or ketones, suitable azanol or its acid-addition salts (1.5 equivalent) and methanol mixture were stirred 6-24 hour down in ambient temperature or higher temperature (for example, refluxing).When ketone is that reactant may need higher temperature.By such as TLC, LC/MS or ¹The chromatography of H NMR and so on or spectral technique monitoring reaction course.Excessive azanol or its acid-addition salts have been added under the certain situation so that react completely.After reaction is finished, enriched mixture and thick product is dissolved in ethyl acetate under vacuum, the water extraction is also carried out silica gel column chromatography to obtain product.

The sodium salt of sulfonic acid then uses following process if desired.The methanol reactant mixture is about 9 as for handling under the ambient temperature and with the methanol solution of Feldalat NM up to the pH of solution.Under vacuum, remove methanol, obtain required sulfonate sodium derivant with the ether precipitation then.

It is in order to set forth the present invention that following synthetic and biology embodiment is provided, and in no case can be interpreted as and limit the scope of the present invention.

6. embodiment

In following examples, except as otherwise noted, all temperature all are expressed as degree centigrade.Embodiment 1-92 has described the synthetic of various aryl of the present invention, heteroaryl and aryl bicyclic nitrone, and they have been implemented or can have implemented.The structure of all nitrone compounds that exemplified in the literary composition is not represented the reality (E) of the two keys of C=N in the nitrone group-or (Z)-spatial chemistry.

Embodiment 1

N-(tert-butyl)-C-[2-(methoxycarbonyl) phenyl] nitrone (1)

(100mg is 0.61mmol) with hydrochloric acid N-(tert-butyl) azanol (109mg, the mixture of methanol 0.732mmol) (5 milliliters) solution 24 hours to stir commercially available 2-acyl radical methyl benzoate at ambient temperature.Then, described mixture is concentrated in a vacuum, the gained raw product is dissolved in the ethyl acetate (15ml), and water (2 * 20ml) extractions.Using Na ₂SO ₄Dry described blended organic layer at the enterprising circumstances in which people get things ready for a trip spectrometry of silica gel, makes chemical compound 1 (10mg, 20%) after also concentrating in a vacuum.MS：m/z236(MH+)。

According to the step that embodiment 1 described step (perhaps doing a little modification) and those skilled in the art are familiar with, carry out condensation reaction by making suitable aldehydes and suitable azanol or its salt, make the described chemical compound of embodiment 2-13 and 38-40.

Embodiment 2

N-cyclohexyl-C-[2-(methoxycarbonyl) phenyl] nitrone (2)

As raw material, prepare chemical compound 2 with hydrochloric acid N-cyclohexyl azanol and 2-acyl radical methyl benzoate according to embodiment 1 described step.MS：m/z 262(MH+)。

Embodiment 3

N-benzyl-C-[2-(methoxycarbonyl) phenyl] nitrone (3)

As raw material, prepare chemical compound 3 with hydrochloric acid N-benzyl hydroxylamine and 2-acyl radical methyl benzoate according to embodiment 1 described step.MS：m/z 270(MH+)。

Embodiment 4

N-(tert-butyl)-C-[2-(methoxycarbonyl)-3, the 5-Dimethoxyphenyl] nitrone (4)

With hydrochloric acid N-(tert-butyl) azanol and 2-formoxyl-4, the 6-dimethoxy p-methyl prepares chemical compound 4 as raw material according to embodiment 1 described step.MS：m/z 296(MH+)。

Embodiment 5

N-cyclohexyl-C-[2-(methoxycarbonyl)-3, the 5-Dimethoxyphenyl] nitrone (5)

With hydrochloric acid N-cyclohexyl azanol and 2-formoxyl-4, the 6-dimethoxy p-methyl prepares chemical compound 5 as raw material according to embodiment 1 described step.MS：m/z 322(MH+)。

Embodiment 6

N-benzyl-C-[2-(methoxycarbonyl)-3, the 5-Dimethoxyphenyl] nitrone (6)

With hydrochloric acid N-benzyl hydroxylamine and 2-formoxyl-4, the 6-dimethoxy p-methyl prepares chemical compound 6 as raw material according to embodiment 1 described step.MS：m/z 330(MH+)。

Embodiment 7

N-(tert-butyl-C-(2-carboxyl phenyl) nitrone (7)

As raw material, prepare chemical compound 7 with hydrochloric acid N-(tert-butyl) azanol and 2-formoxyl benzoic acid according to embodiment 1 described step.MS：m/z 222(MH+)。

Embodiment 8

N-cyclohexyl-C-(2-carboxyl phenyl) nitrone (8)

As raw material, prepare chemical compound 8 with hydrochloric acid N-cyclohexyl azanol and 2-formoxyl benzoic acid according to embodiment 1 described step.MS：m/z 248(MH+)。

Embodiment 9

N-benzyl-C-(2-carboxyl phenyl) nitrone (9)

As raw material, prepare chemical compound 9 with hydrochloric acid N-benzyl hydroxylamine and 2-formoxyl benzoic acid according to embodiment 1 described step.MS：M/z 256(MH+)。

Embodiment 10

N-(tert-butyl)-C-(2-carboxyl-3,5-Dimethoxyphenyl) nitrone (10)

With hydrochloric acid N-(tert-butyl) azanol and 2-formoxyl-4, the 6-dimethoxybenzoic acid prepares chemical compound 10 as raw material according to embodiment 1 described step.MS：m/z 282(MH+)。

Embodiment 11

N-cyclohexyl-C-(2-carboxyl-3,5-Dimethoxyphenyl) nitrone (11)

With hydrochloric acid N-cyclohexyl azanol and 2-formoxyl-4, the 6-dimethoxybenzoic acid prepares chemical compound 11 as raw material according to embodiment 1 described step.MS：m/z 308(MH+)。

Embodiment 12

N-benzyl-C-(2-carboxyl-3,5-Dimethoxyphenyl) nitrone (12)

With hydrochloric acid N-benzyl hydroxylamine and 2-formoxyl-4, the 6-dimethoxybenzoic acid prepares chemical compound 12 as raw material according to embodiment 1 described step.MS：m/z 316(MH+)。

Embodiment 13

N-(tert-butyl)-C-[2-(N, N-dimethylamino formoxyl) phenyl] nitrone (13)

(a) 2-formoxyl-N, the N-dimethyl benzamide

Toward 2-carboxyl benzaldehyde (500mg, CH 3.33mmol) ₂Cl ₂(1.98g 16.65mmol), and refluxes described mixture 1 hour (25ml) to add thionyl chloride in the suspension.Then, gained solution concentrates in a vacuum, is dissolved among the THF, and uses N under ice-cooled temperature, and (180mg 4.0mmol) handles N dimethylamine for 3.9ml, the THF solution of 1M.Described mixture slowly is warming up to ambient temperature, and stirs at ambient temperature 2 hours.Then, described mixture concentrates in a vacuum, and described thick product is carried out flash chromatography handle on silica gel, makes 2-formoxyl-N, N-dimethyl benzamide (100mg, 15%).MS：m/z 178(MH+)。

(b) N-(tert-butyl)-C-[2-(N, N-dimethylamino formoxyl) phenyl] nitrone (13)

According to embodiment 1 described step, with 2-formoxyl-N, N-dimethyl benzamide and the condensation of hydrochloric acid N-(tert-butyl) hydroxylamine compound, preparation chemical compound 13.MS：m/z 249(MH+)。

Embodiment 14

N-(tert-butyl)-C-[2-(imidazoles-1-yl) phenyl] nitrone (14)

Under microwave condition, (355mg is 2.03mmol) with hydrochloric acid N-(tert-butyl) azanol (364mg, methanol solution 2.44mmol) 10 minutes to shine 2-(imidazoles-1-yl) benzaldehyde down at 120 ℃.Then, under vacuum condition, concentrate described solution, and thick product is dissolved in the ethyl acetate (20ml), use water extraction.At Na ₂SO ₄The described blended organic layer of last drying, and concentrate in a vacuum, handle in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, form chemical compound 14 (290mg, 59%).MS：m/z 244(MH+)。

According to the step that embodiment 14 described steps (perhaps doing a little modification) and those skilled in the art are familiar with, carry out condensation reaction by making suitable aromatic aldehyde class and suitable azanol or its salt, make the described chemical compound of embodiment 15-37 and 43-53.

Embodiment 15

N-cyclohexyl-C-[2-(imidazoles-1-yl) phenyl] nitrone (15)

As raw material, prepare chemical compound 15 with hydrochloric acid N-cyclohexyl azanol and 2-(imidazoles-1-yl) benzaldehyde according to embodiment 14 described steps.MS：m/z 270(MH+)。

Embodiment 16

N-benzyl-C-[2-(imidazoles-1-yl) phenyl] nitrone (16)

As raw material, prepare chemical compound 16 with hydrochloric acid N-benzyl hydroxylamine and 2-(imidazoles-1-yl) benzaldehyde according to embodiment 14 described steps.MS：m/z 278(MH+)。

Embodiment 17

N-(tert-butyl)-C-[2-(pyrazol-1-yl) phenyl] nitrone (17)

As raw material, prepare chemical compound 17 with hydrochloric acid N-(tert-butyl) azanol and 2-(pyrazol-1-yl) benzaldehyde according to embodiment 14 described steps.MS：m/z 244(MH+)。

Embodiment 18

N-cyclohexyl-C-[2-(pyrazol-1-yl) phenyl] nitrone (18)

As raw material, prepare chemical compound 18 with hydrochloric acid N-cyclohexyl azanol and 2-(pyrazol-1-yl) benzaldehyde according to embodiment 14 described steps.MS：m/z 270(MH+)。

Embodiment 19

N-benzyl-C-[2-(pyrazol-1-yl) phenyl] nitrone (19)

As raw material, prepare chemical compound 19 with hydrochloric acid N-benzyl hydroxylamine and 2-(pyrazol-1-yl) benzaldehyde according to embodiment 14 described steps.MS：m/z 278(MH+)。

Embodiment 20

N-(tert-butyl)-C-[2-(1-morpholino) phenyl] nitrone (20)

As raw material, prepare chemical compound 20 with hydrochloric acid N-(tert-butyl) azanol and 2-(1-morpholino) benzaldehyde according to embodiment 14 described steps.MS：m/z 263(MH+)。

Embodiment 21

N-cyclohexyl-C-[2-(1-morpholino) phenyl] nitrone (21)

As raw material, prepare chemical compound 21 with hydrochloric acid N-cyclohexyl azanol and 2-(1-morpholino) benzaldehyde according to embodiment 14 described steps.MS：m/z 289(MH+)。

Embodiment 22

N-benzyl-C-[2-(1-morpholino) phenyl] nitrone (22)

As raw material, prepare chemical compound 22 with hydrochloric acid N-benzyl hydroxylamine and 2-(1-morpholino) benzaldehyde according to embodiment 14 described steps.MS：m/z 297(MH+)。

Embodiment 23

N-(tert-butyl)-C-{2-[4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl] phenyl } nitrone (23)

With hydrochloric acid N-(tert-butyl) azanol and 2-[4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl] benzaldehyde is as raw material, prepares chemical compound 23 according to embodiment 14 described steps.MS：m/z 407(MH+)。

Embodiment 24

N-cyclohexyl-C-{2-[4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl] phenyl } nitrone (24)

With hydrochloric acid N-cyclohexyl azanol and 2-[4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl] benzaldehyde is as raw material, prepares chemical compound 24 according to embodiment 14 described steps.MS：m/z 433(MH+)。

Embodiment 25

N-benzyl-C-{2-[4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl] phenyl } nitrone (25)

With hydrochloric acid N-benzyl hydroxylamine and 2-[4-(5-(trifluoromethyl) pyridine-2-yl) piperazine-1-yl] benzaldehyde is as raw material, prepares chemical compound 25 according to embodiment 14 described steps.MS：m/z 441(MH+)。

Embodiment 26

N-(tert-butyl)-C-[2-(4-chlorobenzene sulfenyl) phenyl] nitrone (26)

As raw material, prepare chemical compound 26 with hydrochloric acid N-(tert-butyl) azanol and 2-(4-chlorobenzene sulfenyl) benzaldehyde according to embodiment 14 described steps.MS：m/z 321(MH+)。

Embodiment 27

N-cyclohexyl-C-[2-(4-chlorobenzene sulfenyl) phenyl] nitrone (27)

As raw material, prepare chemical compound 27 with hydrochloric acid N-cyclohexyl azanol and 2-(4-chlorobenzene sulfenyl) benzaldehyde according to embodiment 14 described steps.MS：m/z 347(MH+)。

Embodiment 28

N-benzyl-C-[2-(4-chlorobenzene sulfenyl) phenyl] nitrone (28)

As raw material, prepare chemical compound 28 with hydrochloric acid N-benzyl hydroxylamine and 2-(4-chlorobenzene sulfenyl) benzaldehyde according to embodiment 14 described steps.MS：m/z 355(MH+)。

Embodiment 29

N-(tert-butyl)-C-[2-(encircling penta sulfenyl)-5-nitrobenzophenone] nitrone (29)

As raw material, prepare chemical compound 29 with hydrochloric acid N-(tert-butyl) azanol and 2-(encircling penta sulfenyl)-5-nitrobenzaldehyde according to embodiment 14 described steps.MS：m/z 323(MH+)。

Embodiment 30

N-cyclohexyl-C-[2-(encircling penta sulfenyl)-5-nitrobenzophenone] nitrone (30)

As raw material, prepare chemical compound 30 with hydrochloric acid N-cyclohexyl azanol and 2-(encircling penta sulfenyl)-5-nitrobenzaldehyde according to embodiment 14 described steps.MS：m/z 349(MH+)。

Embodiment 31

N-benzyl-C-[2-(encircling penta sulfenyl)-5-nitrobenzophenone] nitrone (31)

As raw material, prepare chemical compound 31 with hydrochloric acid N-benzyl hydroxylamine and 2-(encircling penta sulfenyl)-5-nitrobenzaldehyde according to embodiment 14 described steps.MS：m/z 357(MH+)。

Embodiment 32

N-(tert-butyl)-C-[2,4-two (methyl mercapto) phenyl] nitrone (32)

With hydrochloric acid N-(tert-butyl) azanol and 2,4-two (methyl mercapto) benzaldehyde prepares chemical compound 32 as raw material according to embodiment 14 described steps.MS：m/z 270(MH+)； ¹H NMR：(DMSO-d ₆)δ1.5(s，9H)，2.53(s，6H)，7.10(d，J＝6Hz，1H)，7.90(s，1H)，9.11(d，J＝6Hz，1H)。

Embodiment 33

N-(tert-butyl)-C-[2-(ethylmercapto group) phenyl] nitrone (33)

As raw material, prepare chemical compound 33 with hydrochloric acid N-(tert-butyl) azanol and 2-(ethylmercapto group) benzaldehyde according to embodiment 14 described steps.MS：m/z 238(MH+)； ¹H NMR：(DMSO-d ₆)δ1.7(t，J＝6.0Hz，3H)，1.5(s，9H)，2.9(q，J＝6.0Hz，2H)，7.30(t，J＝6.0Hz，1H)，7.37(t，J＝6.0Hz，1H)，7.52(d，J＝6.0Hz，1H)，8.16(s，1H)，9.13(d，J＝6.0Hz，1H)。

Embodiment 34

N-(tert-butyl)-C-[2-(iprotiazem base) phenyl] nitrone (34)

As raw material, prepare chemical compound 34 with hydrochloric acid N-(tert-butyl) azanol and 2-(iprotiazem base) benzaldehyde according to embodiment 14 described steps.MS：m/z 252(MH+)； ¹H NMR：(DMSO-d ₆)δ1.21(d，J＝6.0Hz，6H)，1.51(s，9H)，3.32(br s，1H)，7.39(m，2H)，7.54(m，1H)，8.31(s，1H)，9.20(m，1H)。

Embodiment 35

N-(tert-butyl)-C-[2-(methyl mercapto)-4-(trifluoromethyl) phenyl] nitrone (35)

As raw material, prepare chemical compound 35 with hydrochloric acid N-(tert-butyl) azanol and 2-(methyl mercapto)-4-(trifluoromethyl) benzaldehyde according to embodiment 14 described steps.MS：m/z 292(MH+)； ¹HNMR：(DMSO-d ₆)δ1.5(s，9H)，2.6(s，3H)，7.58(d，J＝6.0Hz，1H)，7.62(s，1H)，8.05(s，1H)，9.18(d，J＝6.0Hz，1H)。

Embodiment 36

N-(tert-butyl)-C-[5-nitro-2-(pyridine-2-base sulfenyl) phenyl] nitrone (36)

Prepare chemical compound 36 as raw material according to embodiment 14 described steps with hydrochloric acid N-(tert-butyl) azanol and 5-nitro-2-(pyridine-2-base sulfenyl) benzaldehyde.MS：m/z 332(MH+)。

Embodiment 37

N-cyclohexyl-C-[5-nitro-2-(pyridine-2-base sulfenyl) phenyl] nitrone (37)

Hydrochloric acid N-cyclohexyl azanol and 5-nitro-2-(pyridine-2-base sulfenyl) benzaldehyde prepares chemical compound 37 as raw material according to embodiment 14 described steps.MS：m/z 358(MH+)。

Embodiment 38

N-(tert-butyl)-C-[2-(methoxycarbonyl)-1H-indol-3-yl] nitrone (38)

As raw material, prepare chemical compound 38 with hydrochloric acid N-(tert-butyl) azanol and 3-formoxyl-2-(methoxycarbonyl) indole according to embodiment 1 described step.MS：m/z 275(MH+)。

Embodiment 39

N-cyclohexyl-C-[2-(methoxycarbonyl)-1H-indol-3-yl] nitrone (39)

As raw material, prepare chemical compound 39 with hydrochloric acid N-cyclohexyl azanol and 3-formoxyl-2-(methoxycarbonyl) indole according to embodiment 1 described step.MS：m/z 315(MH+)。

Embodiment 40

N-benzyl-C-[2-(methoxycarbonyl)-1H-indol-3-yl] nitrone (40)

As raw material, prepare chemical compound 40 with hydrochloric acid N-benzyl hydroxylamine and 3-formoxyl-2-(methoxycarbonyl) indole according to embodiment 1 described step.MS：m/z 309(MH+)。

Embodiment 41

N-(tert-butyl)-C-(3-carboxy thiophene-2-yl) nitrone (41)

Under 120 ℃, (100mg is 0.64mmol) with hydrochloric acid N-(tert-butyl) azanol (97.0mg, methanol solution 0.77mmol) 10 minutes for irradiation 2-formoxyl thiophene-3-carboxylic acid under microwave condition.Then, described solution is concentrated into drying in a vacuum.The crystallization from methanol and ethyl acetate mixture of described thick product makes chemical compound 41 (23mg, 16%).MS：m/z 228(MH+)。

Embodiment 42

N-cyclohexyl-C-(3-carboxy thiophene-2-yl) nitrone (42)

With hydrochloric acid N-cyclohexyl azanol and 2-formoxyl thiophene-3-carboxylic acid is raw material, and the step of being familiar with according to embodiment 41 described those of ordinary skills (or making an amendment slightly) prepares chemical compound 42.MS：m/z254(MH+)。

Embodiment 43

N-(tert-butyl)-C-[2-(4-methylbenzene sulfenyl) pyridin-3-yl] nitrone (43)

As raw material, prepare chemical compound 43 with hydrochloric acid N-(tert-butyl) azanol and 2-(4-methylbenzene sulfenyl) pyridine-3-formaldehyde according to embodiment 14 described steps.MS：m/z 301(MH+)。

Embodiment 44

N-cyclohexyl-C-[2-(4-methylbenzene sulfenyl) pyridin-3-yl] nitrone (44)

As raw material, prepare chemical compound 44 with hydrochloric acid N-cyclohexyl azanol and 2-(4-methylbenzene sulfenyl) pyridine-3-formaldehyde according to embodiment 14 described steps.MS：m/z 327(MH+)。

Embodiment 45

N-benzyl-C-[2-(4-methylbenzene sulfenyl) pyridin-3-yl] nitrone (45)

As raw material, prepare chemical compound 45 with hydrochloric acid N-benzyl hydroxylamine and 2-(4-methylbenzene sulfenyl) pyridine-3-formaldehyde according to embodiment 14 described steps.MS：m/z 335(MH+)。

Embodiment 46

N-(tert-butyl)-C-[2-(1-morpholino) pyridin-3-yl] nitrone (46)

As raw material, prepare chemical compound 46 with hydrochloric acid N-(tert-butyl) azanol and 2-(1-morpholino) pyridine-3-formaldehyde according to embodiment 14 described steps.MS：m/z 264(MH+)。

Embodiment 47

N-cyclohexyl-C-[2-(1-morpholino) pyridin-3-yl] nitrone (47)

As raw material, prepare chemical compound 47 with hydrochloric acid N-cyclohexyl azanol and 2-(1-morpholino) pyridine-3-formaldehyde according to embodiment 14 described steps.MS：m/z 290(MH+)。

Embodiment 48

N-benzyl-C-[2-(1-morpholino) pyridin-3-yl] nitrone (48)

As raw material, prepare chemical compound 48 with hydrochloric acid N-benzyl hydroxylamine and 2-(1-morpholino) pyridine-3-formaldehyde according to embodiment 14 described steps.MS：m/z 298(MH+)。

Embodiment 49

N-(tert-butyl)-C-[2-(methyl mercapto) quinoline-3-yl] nitrone (49)

As raw material, prepare chemical compound 49 with hydrochloric acid N-(tert-butyl) azanol and 3-formoxyl-2-(methyl mercapto) quinoline according to embodiment 14 described steps.MS：m/z 275(MH+)。

Embodiment 50

N-benzyl-C-[2-(methyl mercapto) quinoline-3-yl] nitrone (50)

As raw material, prepare chemical compound 50 with hydrochloric acid N-benzyl hydroxylamine and 3-formoxyl-2-(methyl mercapto) quinoline according to embodiment 14 described steps.MS：m/z 309(MH+)。

Embodiment 51

N-(tert-butyl)-C-[6-(2,2-dimethyl propylene acylamino-) pyridine-2-yl] nitrone (51)

Prepare chemical compound 51 as raw material according to embodiment 14 described steps with hydrochloric acid N-(tert-butyl) azanol and 6-(2,2-dimethyl propylene acylamino-) pyridine-2-formaldehyde.MS：m/z 278(MH+)。

Embodiment 52

N-cyclohexyl-C-[6-(2,2-dimethyl propylene acylamino-) pyridine-2-yl] nitrone (52)

Prepare chemical compound 52 as raw material according to embodiment 14 described steps with hydrochloric acid N-cyclohexyl azanol and 6-(2,2-dimethyl propylene acylamino-) pyridine-2-formaldehyde.MS：m/z 304(MH+)。

Embodiment 53

N-benzyl-C-[6-(2,2-dimethyl propylene acylamino-) pyridine-2-yl] nitrone (53)

Prepare chemical compound 53 as raw material according to embodiment 14 described steps with hydrochloric acid N-benzyl hydroxylamine and 6-(2,2-dimethyl propylene acylamino-) pyridine-2-formaldehyde.MS：m/z 312(MH+)。

Embodiment 54

N-(tert-butyl)-C-[3-hydroxyl-5-(hydroxymethyl)-2-picoline-4-yl] nitrone (54)

Use Dean-Stark equipment with 3-hydroxyl-5-(hydroxymethyl)-2-picoline-4-formaldehyde (9.9g, 49.1mmol) and hydrochloric acid N-(tert-butyl) azanol (9.81g, 110.0mmol) suspension in toluene its boiled 22 hours.Then, concentrate described mixture under vacuum condition, make yellow deposit, it makes chemical compound 54 (3.84g, 33%) from methanol crystallization. ¹H NMR：(CDCl ₃)δ1.65(s，9H)，2.5(s，3H)，4.56(br s，2H)，7.55(s，1H)，8.56(s，1H)，11.45(br s，1H)。

Embodiment 55

N-ethyl-C-(2-carboxyl-6-methyl-4-sulfur phenenyl) nitrone

As raw material, prepare described title compound with hydrochloric acid N-ethyl azanol and 2-formoxyl-3-methyl-5-sulfosalicylic acid according to above-mentioned general step.

Embodiment 56

N-(oxolane-3-yl)-C-(5,6-two chloro-2,4-two sulfur phenenyls) nitrone

With hydrochloric acid N-(oxolane-3-yl) azanol and 5,6-two chloro-2,4-two sulfur benzaldehydes prepare described title compound as raw material according to above-mentioned general step.

Embodiment 57

N-(1, the 1-dimethyl propyl)-C-(6-fluoro-2,4-two sulfur phenenyls) nitrone

With hydrochloric acid N-(1, the 1-dimethyl propyl) azanol and 6-fluoro-2,4-two sulfur benzaldehydes prepare described title compound as raw material according to above-mentioned general step.

Embodiment 58

N-(1-methyl cyclopropyl)-C-(2,4-two sulfur phenenyls) nitrone

With hydrochloric acid N-(1-methyl cyclopropyl) azanol and 2,4-two sulfur benzaldehydes prepare described title compound as raw material according to above-mentioned general step.

Embodiment 59

N-(2-hydroxyethyl)-C-(2,4-two sulfur phenenyls) nitrone

With hydrochloric acid N-(2-hydroxyethyl) azanol and 2,4-two sulfur benzaldehydes prepare described title compound as raw material according to above-mentioned general step.

Embodiment 60

N-(2-hydroxyl-1,1-dimethyl ethyl)-C-[2,4-two (N-methyl sulfonamides) phenyl] nitrone

With hydrochloric acid N-(2-hydroxyl-1,1-dimethyl ethyl) azanol and 2,4-two (N-methyl sulfonamides) benzaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 61

N-cyclopenta-C-(2,4-two sulfur phenenyls) nitrone

With hydrochloric acid N-cyclopenta azanol and 2,4-two sulfur benzaldehydes prepare described title compound as raw material according to above-mentioned general step.

Embodiment 62

N-cyclohexyl-C-[2-(O-first sulfo group) phenyl] nitrone

Prepare described title compound as raw material according to above-mentioned general step with hydrochloric acid N-cyclohexyl azanol and 2-(O-first sulfo group) benzaldehyde.

Embodiment 63

N-phenyl-C-(2,4-two sulfur phenenyls) nitrone

With hydrochloric acid N-Phenylhydroxylamine and 2,4-two sulfur benzaldehydes prepare described title compound as raw material according to above-mentioned general step.

Embodiment 64

N-benzyl-C (2,4-diacyl phenyl) nitrone

With hydrochloric acid N-benzyl hydroxylamine and 2,4-two phosphono benzaldehydes prepare described title compound as raw material according to above-mentioned general step.

Embodiment 65

The N-[(pyridin-3-yl) methyl]-C-[2,4-two (phosphinylidyne amino) phenyl] nitrone

With hydrochloric acid N-[(pyridin-3-yl) methyl] azanol and 2,4-two (phosphinylidyne amino) benzaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 66

N-(tert-butyl)-C-[2-(dimethyl phosphoric acid (phospono)) phenyl] nitrone

Prepare described title compound as raw material according to above-mentioned general step with hydrochloric acid N-(tert-butyl) azanol and 2-(dimethyl phosphoric acid) benzaldehyde.

Embodiment 67

N-ethyl-C-6-methyl-2,4-two sulfur phenenyls) nitrone

With hydrochloric acid N-ethyl azanol and 6-methyl-2,4-two sulfur benzaldehydes prepare described title compound as raw material according to above-mentioned general step.

Embodiment 68

N-(tert-butyl)-C-(2,6-two thiopyridines-3-yl) nitrone

With hydrochloric acid N-(tert-butyl) azanol and 2,6-two thiopyridines-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 69

N-(tert-butyl)-C-[4,6-two (O-first sulfo group) pyridin-3-yl] nitrone

With hydrochloric acid N-(tert-butyl) azanol and 4,6-two (O-first sulfo group) pyridine-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 70

N-(tert-butyl)-C-[4,6-two (N-methyl sulfonamides) pyridin-3-yl] nitrone

With hydrochloric acid N-(tert-butyl) azanol and 4,6-two (N-methyl sulfonamides) pyridine-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 71

N-(tert-butyl)-C-(2,5-two thiopyridines-3-yl) nitrone

With hydrochloric acid N-(tert-butyl) azanol and 2,5-two thiopyridines-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 72

N-(tert-butyl)-C-[4,5-two (O-first sulfo group) pyridin-3-yl] nitrone

With hydrochloric acid N-(tert-butyl) azanol and 4,5-two (O-first sulfo group) pyridine-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 73

N-(tert-butyl)-C-[2,4-two (N-methyl sulfonamides) pyridin-3-yl] nitrone

With hydrochloric acid N-(tert-butyl) azanol and 2,4-two (N-methyl sulfonamides) pyridine-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 74

N-(tert-butyl)-C-[2,6-two (O-methoxy methyl sulfo group) pyridin-3-yl] nitrone

With hydrochloric acid N-(tert-butyl) azanol and 2,6-two (O-methoxy methyl sulfo group) pyridine-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 75

N-(tert-butyl)-C-[4,6-two (O-methoxy methyl sulfo group) pyridin-3-yl] nitrone

With hydrochloric acid N-(tert-butyl) azanol and 4,6-two (O-methoxy methyl sulfo group) pyridine-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 76

N-(tert-butyl)-C (2-carboxyl-6-sulfo group pyridin-3-yl)-C '-methyl nitrone

Prepare described title compound as raw material according to above-mentioned general step with hydrochloric acid N-(tert-butyl) azanol and 1-(2-carboxyl-6-sulfo group pyridin-3-yl) ethyl ketone.

Embodiment 77

N-(tert-butyl)-C-(3-carboxyl-5-sulfo group pyridine-2-yl) nitrone

As raw material, prepare described title compound with hydrochloric acid N-(tert-butyl) azanol and 2-formoxyl-5-sulfo group pyridine-3-carboxylic acid according to above-mentioned general step.

Embodiment 78

N-(tert-butyl)-C-[6-(N, N-dimethylamino sulphonyl)-4-fluoro-2-sulfo group pyrrole is decided-the 3-yl] nitrone

As raw material, prepare described title compound with hydrochloric acid N-(tert-butyl) azanol and 6-(N, N-dimethylamino sulphonyl)-4-fluoro-2-sulfo group pyridine-3-formaldehyde according to above-mentioned general step.

Embodiment 79

N-(pyridin-4-yl)-C-[4-chloro-2-(N-methyl sulfonamides)-6-(O-first sulfo group) pyridin-3-yl] nitrone

Prepare described title compound as raw material according to above-mentioned general step with hydrochloric acid N-(pyridin-4-yl) azanol and 4-chloro-2-(N-methyl sulfonamides)-6-(O-first sulfo group) pyridine-3-formaldehyde.

Embodiment 80

N-(piperidin-4-yl)-C-[2,4-two (O-ethyl sulfo group)-6-(trifluoromethyl) pyrimidine-5-yl] nitrone

With hydrochloric acid N-(piperidin-4-yl) azanol and 2,4-two (O-ethyl sulfo group)-6-(trifluoromethyl) pyrimidine-5-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 81

N-ethyl-C-(2-carboxyl-4-methyl-6-sulfo group pyridin-3-yl) nitrone

As raw material, prepare described title compound with hydrochloric acid N-ethyl azanol and 3-formoxyl-4-methyl-6-sulfo group pyridine-2-carboxylic acids according to above-mentioned general step.

Embodiment 82

N-(oxolane-3-yl)-C-(4,5-two chloro-2,6-two thiopyridines-3-yl) nitrone

With hydrochloric acid N-(oxolane-3-yl) azanol and 4,5-two chloro-2,6-two thiopyridines-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 83

N-(tert-butyl)-C-(4-fluoro-2,6-two thiopyridines-3-yl) nitrone

With hydrochloric acid N-(tert-butyl) azanol and 4-fluoro-2,6-two thiopyridines-3-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 84

N-(tert-butyl)-C-(6,8-two sulfur-1,7-diaza how-the 5-yl) nitrone

With hydrochloric acid N-(tert-butyl) azanol and 6,8-two sulfur-1,7-benzodiazine-5-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 85

N-(tert-butyl)-C-(5,7-two sulfur-1H-pyrrolo-[2,3-c] pyridin-4-yl) nitrone

With hydrochloric acid N-(tert-butyl) azanol and 5,7-two sulfur-1H-pyrrolo-[2,3-c] Pyridine-4-Carboxaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 86

N-(tert-butyl)-C-(2,3-dihydro-6,8-two sulfur benzo [b] [1,4] dioxin-5-yls) nitrone, disodium salt

With hydrochloric acid N-(tert-butyl) azanol and 8-formoxyl-2,3-dihydro-benzo [b] [1,4] dioxin-5, the 7-disulfonic acid prepares described title compound as raw material according to above-mentioned general step.

Embodiment 87

N-(tert-butyl)-C-(5-carboxyl-7-sulfo group benzofuran-4-yl) nitrone

As raw material, prepare described title compound with hydrochloric acid N-(tert-butyl) azanol and 4-formoxyl-7-sulfo group benzofuran-5-carboxylic acid according to above-mentioned general step.

Embodiment 88

N-(tert-butyl)-C-{5-(methylamino)-7-(methyl carbamyl)-3,4-dihydro-2H-pyrans is [3,2-c] pyridine-8-yl also } nitrone

With hydrochloric acid N-(tert-butyl) azanol and 5-(methylamino)-7-(methyl carbamyl)-3,4-dihydro-2H-pyrans also [3,2-c] pyridine-8-formaldehyde prepares described title compound as raw material according to above-mentioned general step.

Embodiment 89

N-(tert-butyl)-C-{7-(N-phenyl sulfamoyl)-5-sulfo group-1H-pyrrolo-[2,3-c] pyridin-4-yl } nitrone

Prepare described title compound as raw material according to above-mentioned general step with hydrochloric acid N-(tert-butyl) azanol and 7-(N-phenyl sulfamoyl)-5-sulfo group-1H-pyrrolo-[2,3-c] Pyridine-4-Carboxaldehyde.

Embodiment 90

N-(tetrahydropyran-4-base)-C-(2,4-two sulfur how-the 1-yl) nitrone

With hydrochloric acid N-(tetrahydropyran-4-base) azanol and 4-formoxyl naphthalene-1, the 3-disulfonic acid prepares described title compound as raw material according to above-mentioned general step.

Embodiment 91

N-(furan-3-yl)-C-(3-carboxyl-1-sulfo group isoquinolin-4-yl) nitrone

As raw material, prepare described title compound with hydrochloric acid N-(furan-3-yl) azanol and 4-formoxyl-1-sulfo group isoquinolin-3-carboxylic acid according to above-mentioned general step.

Embodiment 92

N-(tert-butyl)-C-(1,3-two sulfur isoquinolin-4-yl) nitrone

With hydrochloric acid N-(tert-butyl) azanol and 4-formoxyl isoquinolin-1, the 3-disulfonic acid prepares described title compound as raw material according to above-mentioned general step.

Embodiment 93

Measure the free radical-removing/antioxidant activity of nitrone compound

Because nitrone has with free radical and forms the ability (trap promptly spins) of stablizing adduct, therefore they constituted the chemical compound that a class has anti-oxidation characteristics (referring to, for example, Janzen, E.G etc., 1992, Stabilities of Hydroxyl Radical Spin Adducts of PBN-Type Spin Traps, FreeRadical Biol.Med., 12 (2): 169-73).Because free radical can cause the oxidative damage of cellular component (for example protein and lipid), this damage can cause pathological examination, therefore according to a typical member in this compounds, C-(phenyl)-N-(tert-butyl) nitrone (PBN), that carries out studies show that, the anti-oxidation characteristics of nitrone be at least in part its treatment potential basis (referring to, for example, J.M.Carney and R.A.Floyd, 1991, Protection against Oxidative Damage to CNS bya-Phenyl-tert-butylnitrone (PBN) and Other Spin-Trapping Agents:a Novel Seriesof Nonlipid Free Radical Scavengers, J.Mol.Neurosci., 3 (1): 47-57, and Thomas, C.E. etc., 1994, Multiple Mechanisms for Inhibition of Low Density LipoproteinOxidation by Novel Cyclic Nitrone Spin Traps, J.Biol.Chem., 269 (45): 28055-61).

Therefore, compare with PBN, the treatment potential with nitrone compound of improved antioxidant activity may be better than PBN.More generally speaking, based on the antioxidant activity of nitrone, it is reported and to treat sensitivity to nitrone to antioxidation therapy sensitivity or with the generation diseases associated or the symptom of free radical.Cause or include but not limited to neural degeneration, autoimmune and inflammatory diseases or symptom by oxidative damage or oxidative stress as the disease of feature.

That those skilled in the art accepts by being proficient in, as with the in vitro tests of the model of the relevant symptom of free-radical generating in detected nitrone compound of the present invention and removed free radical/antioxidant activity.This test is based on free radical donor-2, and the reaction between 2-diphenyl-1-picrylhydrazyl (DPPH) and the free radical scavenger/antioxidant is to test its free radical scavenging activity.Owing to contributed the free radical electronics for above-mentioned free radical scavenger, the visible absorbance peak (515-520nm) of DPPH can reduce, so the optical density of reading on the visible spectrum has in this section reflected the process of following reaction:

DPPH·+AH→DPPH-H+A·

In the formula, AH is the free radical scavenger/antioxidant of hypothesis.This test is based at first by Brand-Williams, W. etc., 1995, Use of a Free Radical Method to EvaluateAntioxidant Activity, Lebensm.Wiss.Technol., the method that 28:25-30 describes, and according to L.R.Fukumoto and G.Mazza, 2000, Assessing Antioxidant and ProoxidantActivities of Phenolic Compounds, J.Agric.Food Claim., the description of 48:3597-3604 is done further to revise.

Described antioxidation test is (available from E ﹠amp with the black wall flat board of Perkin-Elmer 96 hole clear bottom; KScientific Products) and Tecan Safire extinction flat bed reader carry out.Positive control is a Trolox (6-hydroxyl-2,5,7,8-tetramethyl primary colours alkane-2-carboxylic acid, Sigma-Aldrich), BHA (2 (3)-tert-butyl Hydroquinone monomethylethers, Sigma-Aldrich), PBN (C-(phenyl)-N-(tert-butyl) nitrone, Sigma-Aldrich) and S-PBN (C-(2-sulfur phenenyl)-N-(tert-butyl) nitrone, sodium salt, (according to for example Janzen and R.V.Shetty, 1979, Tetrahedron Lett., the method manufacturing of 35:3229-32), negative control (being carrier) is DMSO.In brief, add in each hole that 2 microlitres contain every kind of contrast of required final concentration or with 100 * DMSO storage liquid of a collection of nitrone compound to be measured.In each hole, add DPPH (Sigma-Aldrich) solution of 198 microlitres with the multiple tracks liquid-transfering gun then with 50 μ M of 80% methanol prepared fresh.On flat bed reader, read the absorbance at 520nm place immediately, periodically read then so that kinetics is assessed, up to respond and finish (being stable state).Because steady state point is 24 hours, so result of the test is presented on 24 hours the time point.With the concentration mapping of the absorbance (OD) of 520nm and contrast and nitrone compound with the dose response of assessment contrast and test compounds and calculate EC ₅₀Value.In this antioxidation test, exemplary compounds of the present invention has EC as shown in table 1 ₅₀Value.

Table 1. free radical-removing/antioxidant activity

Chemical compound (title or embodiment numbering)	EC ₅₀ ^*
Chemical compound (title or embodiment numbering)	EC ₅₀ ^*	Trolox	+++++
BHA	+++++	Trolox	+++++
BHA	+++++	PBN	+
S-PBN	+	PBN	+
S-PBN	+	1	++
3	++	1	++
3	++	4	+++
5	+++	4	+++
5	+++	6	+++
7	+++	6	+++
7	+++	8	++++
9	++++	8	++++
9	++++	10	++
11	++++	10	++
11	++++	12	++++
13	+++	12	++++
13	+++	14	+
15	+	14	+
15	+	16	+
17	+	16	+
17	+	18	+
19	+	18	+
19	+	20	+++

21	+++
21	+++	22	+
23	+++	22	+
23	+++	24	++++
25	+++++	24	++++
25	+++++	27	+
28	+++	27	+
28	+++	30	+
31	++	30	+
31	++	32	+
33	+	32	+
33	+	34	+
35	+	34	+
35	+	36	+++
37	++++	36	+++
37	++++	38	+
39	+	38	+
39	+	40	+
41	++++	40	+
41	++++	42	+++
43	+	42	+++
43	+	46	+
47	+	46	+
47	+	48	+
49	++	48	+
49	++	51	+

52	++
52	++	53	++++

^*EC ₅₀Be to make the peak absorption value of the DPPH of 520nm place reduce by 50% compound concentration

+++++EC ₅₀＜10μM

++++100μM＞EC ₅₀＞10μM

+++500μM＞EC ₅₀＞100μM

++1000μM＞EC ₅₀＞500μM

+EC ₅₀＞1000μM

As known from Table 1, nitrone compound of the present invention has significant or effective free radical scavenging/antioxidant activity.In fact, the antioxidant activity of many nitrone compounds of the present invention is better than PBN.Therefore, aryl of the present invention, heteroaryl and aryl bicyclic nitrone compound are the potential therapeutic agents that treats and/or prevents some diseases or symptom, it is reported that these diseases or symptom can be with antioxidant therapies or relevant with the generation of free radical.This disease or symptom include but not limited to pain symptom, autoimmune disease or symptom, inflammatory diseases or symptom and nerve or neurodegenerative disease or symptom.

Cause or have by oxidative damage or oxidative stress as the non-limitative example of the pain symptom of feature:

Migraine (referring to, for example, Ciancareli, I. etc., 2003, Urinary Nitric Oxide Metabolitesand Lipid Peroxidation By-Products in Migraine, Cephalalgia, 23 (1): 39-42);

Acute, chronic and neuropathic pain syndrome and neuralgia (referring to, for example, De las HerasCastano, G. etc., 2000, Use of Antioxidants to Treat Pain in Chronic Pancreatitis, Rev.Esp.Enferm.Dig., 92 (6): 375-85);

Irritable bowel syndrome; With

Nerve injury and neuropathy, comprise diabetic neuropathy (referring to, for example, Gray, C. etc., 2003, Neuroprotective Effects of Nitrone Radical Scavenger S-PBN onReperfusion Nerve Injury in Rats, Brain Res., 982 (2): 179-85, and Strokov, I.A. etc., 2000, The Function of Endogenous Protective Systems in Patients withInsulin-Dependent Diabetes Mellitus and Polyneuropathy:Effect of AntioxidantTherapy, Bull.Exp.Biol.Med., 130 (10): 986-90).

[00349] cause by oxidative damage or oxidative stress or have as the autoimmune disease of feature or the non-limitative example of symptom:

Multiple sclerosis (referring to, for example, Liu, Y. etc., 2003, Bilirubin as a Potent AntioxidantSuppresses Experimental Autoimmune Encephalomyelitis:Implications for theRole of Oxidative Stress in the Development of Multiple Sclerosis, J.Neuroimmunol., 139 (1-2): 27-35);

Arthritis;

Diabetes and related complications (referring to, for example, Tabatabaie, T. etc., 1997, Spin TrappingAgent Phenyl-N-tert-butylnitrone Protects against the Onset of Drug-InducedInsulin-Dependent Diabetes Mellims, FEBS Lett., 407 (2): 148-52); With

Graves disease and other thyroid disease (referring to, for example, Vrca, V.B. etc., 2004, Supplementation with Antioxidants in the Treatment of Graves ' Disease:the Effecton Glutathione Peroxidase Activity and Concentration of Selenium, Clin.Chim.Acta., 341 (1-2): 55-63).

Cause or have by oxidative damage or oxidative stress as the inflammatory diseases of feature or the non-limitative example of symptom:

Myocardial infarction and dysfunction (referring to, for example, Vergely, C. etc., 2003, Effect of TwoNew PBN-Derived Phosphorylated Nitrones against Postischaemic VentricularDysrhythmias, Fundam.Clin.Pharmacol., 17 (4): 433-42);

Arteriosclerosis and other angiopathy (referring to, for example, Micheletta, F. etc., 2004, VitaminE Supplementation in Patients with Carotid Atherosclerosis:Reversal of AlteredOxidative Stress Status in Plasma But Not in Plaque, Arterioscler.Throrzb.Vasc.Biol., 24 (1): 136-40);

Asthma, RAD and allergy (referring to, for example, Nadeem, A. etc., 2003, Increased Oxidative Stress and Altered Levels of Antioxidants in Asthma, J.AllergyClin.Immunol., 111 (1): 72-8);

Transplanting and graft failure or repulsion (referring to, for example, Connor, H.D. etc., 1992, Evidencethat Free Radical Are Involved in Graft Failure following Orthotopic LiverTransplantation in the Rat-an Electron Paramagneric Resonance Spin TrappingStudy, Transplantation, 54 (2): 199-204);

Pulmonary lesion and infringement (referring to, for example, Murphy, P.G. etc., 1991, Direct Detectionof Free Radical Generation in an in vivo Model of Acute Lung Injury, RadicalRes.Commun., 15 (3): 167-76);

The hepatopathy that hepatitis and jaundice are brought out (referring to, for example, Yamashita, T. etc., 1996, The Effectsof α-Phenyyl-tert-butylnitron (PBN) on Copper-Induced Rat Fulminant Hepatitiswith Jaundice, Free Radical Biol Med., 21 (6): 755-61);

Pancreatitis and other pancreatic diseases (referring to, for example, Koiwai, T. etc., 1989, The Role ofOxygen Free Radical in Experimental Acute Pancreatitis in the Rat, Int.J.Pancreatol., 5 (2): 135-43);

Comprise the inflammatory bowel of Crohn disease and gastral other disease (referring to, for example, Reimund, J.M. etc., 1998, Antioxidants Inhibit the in vitro Production ofInflammatory Cytokines in Crohn ' s Disease and Ulcerative Colitis, Eur.J.Clin.Invest., 28 (2): 145-50);

Comprise the retinal ischemia of degeneration of macula and other retinal degeneration or inflammatory disease and damage (referring to, for example, F.Block and M.Schwarz, 1997, Effects of Antioxidants on IschemicRetinal Dysfunction, Exp.Eye Res., 64 (4): 559-64);

Renal ischaemia and kidney disorder (referring to, for example, Kadkhodaee, M. etc., 1996, Detectionof Hydroxyl and Carbon-Centered Radicals by EPR Spectroso Opy after Ischaemiaand Reperfusion of the Rat Kidney, Free Radical Res., 25 (1): 31-42); With

Endotoxemia (referring to, for example, Harkins, J.D. etc., 1997, Effect of α-Phenyyl-tert-butylnitron on Endotoxin Toxemia in Horses, Vet.Hum.Toxicol., 39 (5): 268-71).

Cause or have by oxidative damage or oxidative stress as the nerve of feature or the non-limitative example of neurodegenerative disease or symptom:

Apoplexy (referring to, for example, Marshal, J.W. etc., 2001, NXY-059, a Free Radical-TrappingAgent, Substanually Lessens the Functional Disability Resulting from CerebralIschemia in a Primate Species, Stroke, 32 (1): 190-98, and Ginsberg, M.D. etc., 2003, Stilbazulenyl Nitrone, a Novel Antioxidant, Is Highly Neuroprotective inFocal Ischemia, Ann.Neurol., 54 (3): 330-42);

Schizophrenia and other cognitive disorders (referring to, for example, Dakhale, G. etc., 2004, Oxidative Damage and Schizophrenia:the Potential Benefit by AtypicalAntipsychotics, Neuropsychobiol., 49 (4): 205-09);

Mood disorders and other affective disorder (referring to, for example, Ranjekar, P.K. etc., 2003, DecreasedAntioxidant Enzymes and Membrane Essential Polyunsaturated Fatty Acids inSchizophrenic and Bipolar Mood Disorder Patients, Psychiatry Res., 121 (2): 109-22);

Epilepsy (referring to, for example, Gupta, M. etc., 2004, Add-on Melatonin Improves Qualityof Life in Epileptic Children on Valproate Monotherapy:a Randomized, Double-Blind, Placebo-Controlled Trial, Epilepsy Behav., 5 (3): 316-21);

Aging and old and feeble (referring to, for example, Carney, J.M. etc., 1991, Reversal of Age-RelatedIncrease in Brain Protein Oxidation, Decrease in Enzyme Activity, and Loss inTemporal and Spatial Memory by Chronic Administration of the Spin-TrappingCompound N-tert-Butyl-α-phenylnitrone, Proc.Natl.Acad.Sci.USA, 88 (9): 3633-6);

Parkinson disease (referring to, for example, FredriksSOn, A. etc., 1997, MPTP-Induced Deficitsin Motor Activity:Neuroprotective Effects of the Spin-Trapping Agent, α-Phenyyl-tert-butylnitron (PBN), J.Neural.Transm., 104 (6-7): 579-92);

Alzheimer (referring to, for example, Butterfield, D.A. etc., 1996, A β (25-35) PeptideDisplays H ₂02-Like Reactivity towards Aqueous Fe ²⁺, Nitroxide Spin Probes, andSynaptosomal Membrane Proteins, Life Sci., 58 (3): 217-28);

Huntington Chorea (referring to, for example, Nakao, N. etc., 1996, Antioxidant Treatment ProtectsStriatal Neurons against Excitotoxic Insults, Neuroscience, 73 (1): 185-200);

Amyotrophic lateral sclerosis (referring to, for example, Desnuelle, C. etc., 2001, A Double-Blind, Placebo-Controlled Randomized Clinical Trial of a-Tocopherol (Vitamin E) in theTreatment of Amyotrophic Lateral Sclerosis, Amyotrophic Lateral Scler.OtherMotor Neuron Disorders, 2 (1): 9-18); With

Head trauma and traumatic brain injury (referring to, for example, Sen, S. etc., 1994, α-Phenyyl-tert-butylnitron Inhibits Free Radical Release in Brain Concussion, FreeRadical Biol.Med, 16 (6): 685-91, and Marklund, N. etc., 2001, Effects of NitroneRadical Scavengers PBN and S-PBN in vivo Trapping of Reactive OxygenSpecies after Traumatic Brain Injury in Rats, J.Cereb.Blood Flow Metab., 21 (11); 1259-67).

All publications, patent and patent application that this description is quoted are included into this paper as a reference, and this is just included in this paper as a reference one by one and separately as each publication or patent application.Although described foregoing invention in greater detail with the embodiment ratio by way of example for the purpose of being convenient to understand, but one of ordinary skill in the art obviously should be appreciated that, under the prerequisite of the spirit and scope that do not deviate from claims, technology disclosed according to the present invention can be carried out some changes and improvements to it.

Claims

1. the nitrone compound of formula (I):

In the formula:

W and Z be in conjunction with forming 5-8 unit's cycloalkenyl group or aryl rings, described ring only by formula (I)-(I) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces, or described ring can further be replaced;

L is C (R ²) ₂

Each R ²Be independently selected from hydrogen, replacement or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl;

N is the integer of 0-1;

Or its pharmaceutically acceptable salt or prodrug;

Condition is that described chemical compound is not selected from the chemical compound 1-50 in 5.3 parts.

2. chemical compound as claimed in claim 1, it is the aryl nitrone chemical compound of formula (II):

In the formula:

W, X, Y and Z are C-R independently of one another ⁴With

3. chemical compound as claimed in claim 1, it is the aryl nitrone chemical compound of formula (III):

In the formula:

W, Y and Z are C-R independently of one another ⁴

Each R ⁴Be hydrogen independently, alkyl, the alkyl that replaces, acyl group, the acyl group that replaces, acylamino-, the acylamino-that replaces, alkyl amino, the alkyl amino that replaces, alkylthio group, the alkylthio group that replaces, alkoxyl, the alkoxyl that replaces, alkoxy carbonyl, the alkoxy carbonyl that replaces, alkyl aryl amino, the alkyl aryl amino that replaces, alkoxy aryl, the alkoxy aryl that replaces, amino, aryl, the aryl that replaces, aryl alkyl, the aryl alkyl that replaces, sulfoxide, the sulfoxide that replaces, sulfone, the sulfone that replaces, the sulfane base, the sulfane base that replaces, amino-sulfonyl, the amino-sulfonyl that replaces, aryl sulfonyl, the aryl sulfonyl that replaces, sulfonic acid, sulphonic acid ester (being sufonate), the dihydroxy phosphoryl, the dihydroxy phosphoryl that replaces, the hydroxy amino phosphoryl, the hydroxy amino phosphoryl that replaces, azido, carboxyl, the carboxyl (being ester) that replaces, carbamyl, the carbamyl that replaces, carboxyl, cyano group, cycloalkyl, the cycloalkyl that replaces, the assorted alkyl of ring, the assorted alkyl of the ring that replaces, dialkyl amido, the dialkyl amido that replaces, halo, heteroaryloxy, the heteroaryloxy that replaces, heteroaryl, the heteroaryl that replaces, assorted alkyl, the assorted alkyl that replaces, hydroxyl, nitro or sulfo-; With

4. chemical compound as claimed in claim 1, wherein, described ring only by formula (I)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces.

5. chemical compound as claimed in claim 1, wherein, described ring is further replaced.

6. chemical compound as claimed in claim 3, wherein, R ³And R ⁵Identical.

7. as claim 1,2 or 3 described chemical compounds, wherein, n is 1.

8. as claim 1,2 or 3 described chemical compounds, wherein, n is 0.

9. chemical compound as claimed in claim 8, wherein, R ³Be selected from-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂

10. chemical compound as claimed in claim 8, wherein, R ³Be-SO ₃H, and R ¹It or not the phenyl of low alkyl group, acetylation low alkyl group, hydroxylating low alkyl group, phenyl or replacement.

11. chemical compound as claimed in claim 8, wherein, R ³Be-SR ⁹, and R ⁹Not phenyl or methyl.

12. chemical compound as claimed in claim 8, wherein, R ³Be-SR ⁹, and R ¹Be not-CH ₂(C ₆H ₅), replace-CH ₂(C ₆H ₅), the phenyl of cyclohexyl, methyl, phenyl or the replacement of cyclohexyl, replacement.

13. chemical compound as claimed in claim 8, wherein, R ³Be-OH, and R ¹Be not-CH ₂(C ₆H ₅), replace-CH ₂(C ₆H ₅), the phenyl of low alkyl group, phenyl or replacement.

14. chemical compound as claimed in claim 8, wherein, R ³Be-NR ⁷R ⁸, and R ⁷And R ⁸Not hydrogen.

15. chemical compound as claimed in claim 8, wherein, R ³Be-NR ⁷R ⁸, and R ¹Be not-CH ₂CO ₂Me ,-CH ₂CO ₂H ,-CH ₂(C ₆H ₅), replace-CH ₂(C ₆H ₅), the phenyl of low alkyl group, phenyl or replacement.

16. chemical compound as claimed in claim 8, wherein, R ³Be-CO ₂R ⁹, and R ⁹Not hydrogen or methyl.

17. chemical compound as claimed in claim 8, wherein, R ³Be-CO ₂R ⁹, and R ¹It or not the phenyl of low alkyl group, phenyl or replacement.

18. the nitrone compound of formula (I):

In the formula:

W and Z be in conjunction with forming assorted thiazolinyl of 5-8 unit ring or heteroaryl ring, and described ring only by formula (I)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces or described ring is further replaced; Or

L is C (R ²) ₂

N is the integer of 0-1; Or

Its pharmaceutically acceptable salt or prodrug;

Condition is that described chemical compound is not selected from the chemical compound 51-66 of 5.4 parts.

19. chemical compound as claimed in claim 18, it is the aryl nitrone chemical compound of formula (II):

In the formula:

Having m among W, X, Y and the Z is N, and remaining is C-R independently of one another ⁴

Each R ⁴Be hydrogen independently, alkyl, the alkyl that replaces, acyl group, the acyl group that replaces, acylamino-, the acylamino-that replaces, alkyl amino, the alkyl amino that replaces, alkylthio group, the alkylthio group that replaces, alkoxyl, the alkoxyl that replaces, alkoxy carbonyl, the alkoxy carbonyl that replaces, alkyl aryl amino, the alkyl aryl amino that replaces, alkoxy aryl, the alkoxy aryl that replaces, amino, aryl, the aryl that replaces, aryl alkyl, the aryl alkyl that replaces, sulfoxide, the sulfoxide that replaces, sulfone, the sulfone that replaces, the sulfane base, the sulfane base that replaces, amino-sulfonyl, the amino-sulfonyl that replaces, aryl sulfonyl, the aryl sulfonyl that replaces, sulfonic acid, sulphonic acid ester (being sufonate), the dihydroxy phosphoryl, the dihydroxy phosphoryl that replaces, the hydroxy amino phosphoryl, the hydroxy amino phosphoryl that replaces, azido, carboxyl, the carboxyl (being ester) that replaces, carbamyl, the carbamyl that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, the assorted alkyl of ring, the assorted alkyl of the ring that replaces, dialkyl amido, the dialkyl amido that replaces, halo, heteroaryloxy, the heteroaryloxy that replaces, heteroaryl, the heteroaryl that replaces, assorted alkyl, the assorted alkyl that replaces, hydroxyl, nitro or sulfo-; With

M is the integer of 1-3.

20. aryl nitrone chemical compound as claimed in claim 19, wherein, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

21. aryl nitrone chemical compound as claimed in claim 19, wherein, one of W, X, Y and Z are N, and remaining is C-R independently of one another ⁴

22. aryl nitrone chemical compound as claimed in claim 21, wherein, X is N.

23. aryl nitrone chemical compound as claimed in claim 21, wherein, W is N.

24. aryl nitrone chemical compound as claimed in claim 21, wherein, Y is N.

25. aryl nitrone chemical compound as claimed in claim 21, wherein, Z is N.

26. as claim 23,24 or 25 described basic nitrone compounds, wherein, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

27. aryl nitrone chemical compound as claimed in claim 26, wherein, R ³And R ⁵Identical.

28. aryl nitrone chemical compound as claimed in claim 19, wherein, two among W, X, Y and the Z is N.

29. heteroaryl nitrone compound as claimed in claim 28, wherein, W and the X N that respectively does for oneself.

30. aryl nitrone chemical compound as claimed in claim 28, wherein, X and the Y N that respectively does for oneself.

31. aryl nitrone chemical compound as claimed in claim 28, wherein, X and the Z N that respectively does for oneself.

32. aryl nitrone chemical compound as claimed in claim 28, wherein, W and the Y N that respectively does for oneself.

33. aryl nitrone chemical compound as claimed in claim 28, wherein, W and the Z N that respectively does for oneself.

34. aryl nitrone chemical compound as claimed in claim 28, wherein, Y and the Z N that respectively does for oneself.

35. as claim 32,33 or 34 described aryl nitrone chemical compounds, wherein, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

36. aryl nitrone chemical compound as claimed in claim 35, wherein, R ³And R ⁵Identical.

37. as claim 19 or 31 described aryl nitrone chemical compounds, wherein, Y is C-R ⁶, and R ⁶Be: hydrogen; alkyl; the alkyl that replaces; acyl group; the acyl group that replaces; acylamino-; the acylamino-that replaces; alkyl amino; the alkyl amino that replaces; alkylthio group; the alkylthio group that replaces; alkoxyl; the alkoxyl that replaces; alkoxy carbonyl; the alkoxy carbonyl that replaces; alkyl aryl amino; the alkyl aryl amino that replaces; alkoxy aryl; the alkoxy aryl that replaces; amino; aryl; the aryl that replaces; aryl alkyl; the aryl alkyl that replaces; sulfoxide; the sulfoxide that replaces; sulfone; the sulfone that replaces; the sulfane base; the sulfane base that replaces; amino-sulfonyl; the amino-sulfonyl that replaces; aryl sulfonyl; the aryl sulfonyl that replaces; sulfonic acid; sulphonic acid ester (being sulfonate); the dihydroxy phosphoryl; the dihydroxy phosphoryl that replaces; the hydroxy amino phosphoryl; the hydroxy amino phosphoryl that replaces; azido; carboxyl; the carboxyl (being ester) that replaces; carbamyl; the carbamyl that replaces; cyano group; cycloalkyl; the cycloalkyl that replaces; the assorted alkyl of ring; the assorted alkyl of the ring that replaces; dialkyl amido; the dialkyl amido that replaces; halo; heteroaryloxy; the heteroaryloxy that replaces; heteroaryl; the heteroaryl that replaces; assorted alkyl; the assorted alkyl that replaces; hydroxyl; nitro or sulfo-, but be not phenyl; the phenyl that replaces or-SMe.

38. aryl nitrone chemical compound as claimed in claim 37, wherein, R ²Be selected from and replace or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.

39. aryl nitrone chemical compound as claimed in claim 37, wherein, R ⁶It or not alkylthio group.

40. aryl nitrone chemical compound as claimed in claim 37, wherein, R ⁶It or not the sulfane base of sulfane base or replacement.

41. aryl nitrone chemical compound as claimed in claim 37, wherein, R ⁶It or not aryl.

42. aryl nitrone chemical compound as claimed in claim 37, wherein, R ⁶It or not the aryl of aryl or replacement.

43. aryl nitrone chemical compound as claimed in claim 37, wherein, R ⁶Be selected from hydrogen ,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

44. aryl nitrone chemical compound as claimed in claim 43, wherein, R ⁶Be selected from-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

45. aryl nitrone chemical compound as claimed in claim 37, wherein, R ³Be not-CO ₂Et.

46. aryl nitrone chemical compound as claimed in claim 37, wherein, R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂

47. aryl nitrone chemical compound as claimed in claim 37, wherein, R ³Be-CO ₂R ⁹, and R ⁹It or not ethyl.

48. aryl nitrone chemical compound as claimed in claim 37, wherein, R ³Be-CO ₂R ⁹, and R ⁹It or not low alkyl group.

49. aryl nitrone chemical compound as claimed in claim 37, wherein, R ¹Not the phenyl or the low alkyl group of phenyl, replacement.

50. aryl nitrone chemical compound as claimed in claim 37, wherein, R ¹Be to replace or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

51. aryl nitrone chemical compound as claimed in claim 19, wherein, m=3.

52. chemical compound as claimed in claim 18, wherein, W and Z be in conjunction with form replacing or unsubstituted 5 yuan of hetero-aromatic rings, and described ring only by formula (I)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces or described ring is further replaced.

53. chemical compound as claimed in claim 18, it is the assorted thiazolinyl of ring or the heteroaryl nitrone compound of formula (IV):

In the formula:

W, X and Z are independently selected from CR respectively ⁴, C (R ⁴) ₂, N, NR ⁴, O and S, and only form by formula (IV)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Assorted thiazolinyl of the ring that part replaces or further replaced or heteroaryl ring;

Each R ⁴Independent is hydrogen, alkyl, the alkyl that replaces, acyl group, the acyl group that replaces, acylamino-, the acylamino-that replaces, alkyl amino, the alkyl amino that replaces, alkylthio group, the alkylthio group that replaces, alkoxyl, the alkoxyl that replaces, alkoxy carbonyl, the alkoxy carbonyl that replaces, alkyl aryl amino, the alkyl aryl amino that replaces, alkoxy aryl, the alkoxy aryl that replaces, amino, aryl, the aryl that replaces, aryl alkyl, the aryl alkyl that replaces, sulfoxide, the sulfoxide that replaces, sulfone, the sulfone that replaces, the sulfane base, the sulfane base that replaces, amino-sulfonyl, the amino-sulfonyl that replaces, aryl sulfonyl, the aryl sulfonyl that replaces, sulfonic acid, sulphonic acid ester (being sulfonate), the dihydroxy phosphoryl, the dihydroxy phosphoryl that replaces, the hydroxy amino phosphoryl, the hydroxy amino phosphoryl that replaces, azido, carboxyl, the carboxyl (being ester) that replaces, carbamyl, the carbamyl that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, the assorted alkyl of ring, the assorted alkyl of the ring that replaces, dialkyl amido, the dialkyl amido that replaces, halo, heteroaryloxy, the heteroaryloxy that replaces, heteroaryl, the heteroaryl that replaces, assorted alkyl, the assorted alkyl that replaces, hydroxyl, nitro or sulfo-; With

Dotted line is represented singly-bound or two key.

54. heteroaryl nitrone compound as claimed in claim 53, wherein, one of W, X and Z are O, and remaining is C-R independently of one another ⁴

55. heteroaryl nitrone compound as claimed in claim 54, wherein, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

56. heteroaryl nitrone compound as claimed in claim 55, wherein, R ³And R ⁵Identical.

57. heteroaryl nitrone compound as claimed in claim 54, wherein, W or X are O.

58. heteroaryl nitrone compound as claimed in claim 54, wherein, Z is O, and n=1.

59. heteroaryl nitrone compound as claimed in claim 54, wherein, Z is O, and R ²Be selected from and replace or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.

60. heteroaryl nitrone compound as claimed in claim 54, wherein, Z is O, and R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂

61. heteroaryl nitrone compound as claimed in claim 54, wherein, Z is O, and R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂

62. heteroaryl nitrone compound as claimed in claim 54, wherein, Z is O, R ³Be-CO ₂R ⁹, and R ⁹It or not methyl.

63. heteroaryl nitrone compound as claimed in claim 62, wherein, R ⁹It or not low alkyl group.

64. heteroaryl nitrone compound as claimed in claim 54, wherein, Z is O, and R ¹Not the phenyl or the isopropyl of phenyl, replacement.

65. as the described heteroaryl nitrone compound of claim 64, wherein, R ¹It or not low alkyl group.

66. heteroaryl nitrone compound as claimed in claim 54, wherein, Z is O, and R ¹Be to replace or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

67. heteroaryl nitrone compound as claimed in claim 54, wherein, Z is O, and X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH, PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

68. heteroaryl nitrone compound as claimed in claim 53, wherein, one of W, X and Z are N or NR ⁴, and remaining is selected from C-R independently of one another ⁴, O, S and N.

69. as the described heteroaryl nitrone compound of claim 68, wherein, W or X are N.

70. as the described heteroaryl nitrone compound of claim 68, wherein, Z is C-R ⁴, O or S.

71. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, and n=1.

72. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, and R ²Be selected from and replace or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.

73. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, and R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂

74. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, R ³Be-CO ₂R ⁹, and R ⁹It or not ethyl.

75. as the described heteroaryl nitrone compound of claim 74, wherein, R ⁹It or not low alkyl group.

76. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, and R ¹It or not the phenyl of phenyl or replacement.

77. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, and R ¹Be to replace or unsubstituted aliphatic series, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

78. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, X is C-R ⁴, and the R of X ⁴It or not methyl.

79. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, X is C-R ⁴, and the R of X ⁴It or not low alkyl group.

80. as the described heteroaryl nitrone compound of claim 68, wherein, Z is N, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

81. heteroaryl nitrone compound as claimed in claim 53, wherein, one of W, X and Z are S, and remaining is selected from C-R independently of one another ⁴And N.

82. as the described heteroaryl nitrone compound of claim 81, wherein, W or X are S.

83. as the described heteroaryl nitrone compound of claim 81, wherein, Z is C-R ⁴Or N.

84. as the described heteroaryl nitrone compound of claim 81, wherein, Z is S, and n=1.

85. as the described heteroaryl nitrone compound of claim 81, wherein, Z is S, and R ²Be selected from and replace or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl and replacement or unsubstituted aralkyl.

86. as the described heteroaryl nitrone compound of claim 81, wherein, Z is S, and R ³Be selected from-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂With-PO (OR ⁹) ₂

87. as the described heteroaryl nitrone compound of claim 81, wherein, Z is S, R ³Be-CO ₂R ⁹, and R ⁹It or not methyl.

88. as the described heteroaryl nitrone compound of claim 87, wherein, R ⁹It or not low alkyl group.

89. as the described heteroaryl nitrone compound of claim 81, wherein, Z is S, and R ¹It or not the phenyl of phenyl or replacement.

90. as the described heteroaryl nitrone compound of claim 81, wherein, Z is S, and R ¹Be to replace or unsubstituted aliphatic series, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

91. as the described heteroaryl nitrone compound of claim 81, wherein, Z is S, X is C-R ⁴, and the R of X ⁴Not hydrogen.

92. as the described heteroaryl nitrone compound of claim 81, wherein, Z is S, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

93. the nitrone compound of formula (I):

In the formula:

W and Z be in conjunction with forming 8-11 unit bicycloenyl, bicyclo-assorted thiazolinyl, aryl bicyclic or bicyclic heteroaryl ring, and described ring only by formula (I)-(L) _n-R ³With-C (R ²)=N (O)-R ¹Part replaces or described ring is further replaced;

L is C (R ²) ₂

Each R ⁹Independently be selected from hydrogen, replacement or unsubstituted aliphatic series, replacement or unsubstituted heterolipid family, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl and replacement or unsubstituted assorted alkyl; With

N is the integer of 0-1;

Or its pharmaceutically acceptable salt or prodrug;

Condition is that described chemical compound is not selected from the chemical compound 67-75 of 5.5 parts.

94. as the described chemical compound of claim 93, wherein, R ¹Not the phenyl or the methyl of phenyl, replacement.

95. as the described chemical compound of claim 93, wherein, R ¹It or not low alkyl group.

96. as the described chemical compound of claim 93, wherein, R ¹Be to replace or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

97. as the described chemical compound of claim 93, wherein, R ²Not hydrogen.

98. as the described chemical compound of claim 93, wherein, R ²Be to replace or unsubstituted (C ₁-C ₆) alkyl, replacement or unsubstituted (C ₁-C ₆) cycloalkyl, replacement or unsubstituted aryl or replacement or unsubstituted aralkyl.

99. as the described chemical compound of claim 93, wherein, R ³Be not-OH ,-SMe or-S (C ₆H ₅).

100. as the described chemical compound of claim 93, wherein, R ³Be selected from-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

101. as the described chemical compound of claim 93, wherein, described chemical compound has following formula:

In the formula:

W, X, Y and Z are selected from cycloalkenyl group, ring assorted thiazolinyl, aryl or heteroaryl ring; With

Any adjacent a pair of can further combining with the cycloalkenyl group that contains W, X, Y and Z, the assorted thiazolinyl of ring, aryl or heteroaryl ring forms bicycloenyl, bicyclo-assorted thiazolinyl, aryl bicyclic or bicyclic heteroaryl ring among W, X, Y and the Z.

102. as the described chemical compound of claim 101, wherein, W and X can further be combined to form bicycloenyl, bicyclo-assorted thiazolinyl, aryl bicyclic or bicyclic heteroaryl ring.

103. as the described chemical compound of claim 101, wherein, X and Y can further be combined to form bicycloenyl, bicyclo-assorted thiazolinyl, aryl bicyclic or bicyclic heteroaryl ring.

104. as the described chemical compound of claim 101, wherein, Y and Z can further be combined to form bicycloenyl, bicyclo-assorted thiazolinyl, aryl bicyclic or bicyclic heteroaryl ring.

105. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula V:

In the formula:

W, X and Z ' are C-R independently of one another ⁴Or C (R ⁴) ₂

Y is C-R ⁴Or carbonyl;

A is selected from NR ⁴, O and S;

Dotted line is represented single or two key.

106. as the described aryl nitrone chemical compound of claim 105, wherein, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

107. as the described aryl nitrone chemical compound of claim 106, wherein, R ⁵Not hydrogen.

108. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (VI):

In the formula:

X and Z ' are C-R independently of one another ⁴Or C (R ⁴) ₂

Y is C-R ⁴Or carbonyl;

A is selected from NR ⁴, O and S;

Each R ⁴Be hydrogen independently, alkyl, the alkyl that replaces, acyl group, the acyl group that replaces, acylamino-, the acylamino-that replaces, alkyl amino, the alkyl amino that replaces, alkylthio group, the alkylthio group that replaces, alkoxyl, the alkoxyl that replaces, alkoxy carbonyl, the alkoxy carbonyl that replaces, alkyl aryl amino, the alkyl aryl amino that replaces, alkoxy aryl, the alkoxy aryl that replaces, amino, aryl, the aryl that replaces, aryl alkyl, the aryl alkyl that replaces, sulfoxide, the sulfoxide that replaces, sulfone, the sulfone that replaces, the sulfane base, the sulfane base that replaces, amino-sulfonyl, the amino-sulfonyl that replaces, aryl sulfonyl, the aryl sulfonyl that replaces, sulfonic acid, sulphonic acid ester (being sulfonate), the dihydroxy phosphoryl, the dihydroxy phosphoryl that replaces, the hydroxy amino phosphoryl, the hydroxy amino phosphoryl that replaces, azido, carboxyl, the carboxyl (being ester) that replaces, carbamyl, the carbamyl that replaces, cyano group, cycloalkyl, the cycloalkyl that replaces, the assorted alkyl of ring, the assorted alkyl of the ring that replaces, dialkyl amido, the dialkyl amido that replaces, halo, heteroaryloxy, the heteroaryloxy that replaces, heteroaryl, the heteroaryl that replaces, assorted alkyl, the assorted alkyl that replaces, hydroxyl, nitro or sulfo-; With

Dotted line is represented single or two key.

109. as the described aryl nitrone chemical compound of claim 108, wherein, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

110. as the described aryl nitrone chemical compound of claim 109, wherein, R ⁵Not hydrogen.

111. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (VII):

In the formula:

W, X and Z ' are independent separately to be C-R ⁴Or C (R ⁴) ₂

Y is C-R ⁴Or carbonyl;

A is selected from NR ⁴, O and S;

Dotted line is represented single or two key.

112. as the described aryl nitrone chemical compound of claim 111, wherein, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH, PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ²R ⁹

113. as the described aryl nitrone chemical compound of claim 112, wherein, R ⁵Not hydrogen.

114. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (VIII):

In the formula:

X and Z ' are independent separately to be C-R ⁴Or C (R ⁴) ₂

Y is C-R ⁴Or carbonyl;

A is selected from NR ⁴, O and S;

Dotted line is represented single or two key.

115. as the described aryl nitrone chemical compound of claim 114, wherein, X is C-R ⁵, and R ⁵Be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (OR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

116. as the described aryl nitrone chemical compound of claim 115, wherein, R ⁵Not hydrogen.

117. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (IX):

In the formula:

W and X independently are N or C-R separately ⁴

Y and Z ' are independent separately to be carbonyl, C-R ⁴Or C (R ⁴) ₂

Dotted line is represented single or two key.

118. as the described aryl nitrone chemical compound of claim 117, wherein, one of W and X are N at least.

119. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (X):

In the formula:

W, X, Y, Z ', A and Q are independently selected from N and C-R respectively ⁴With

Each R ⁴Be hydrogen independently; alkyl; the alkyl that replaces; acyl group; the acyl group that replaces; acylamino-; the acylamino-that replaces; alkyl amino; the alkyl amino that replaces; alkylthio group; the alkylthio group that replaces; alkoxyl; the alkoxyl that replaces; alkoxy carbonyl; the alkoxy carbonyl that replaces; alkyl aryl amino; the alkyl aryl amino that replaces; alkoxy aryl; the alkoxy aryl that replaces; amino; aryl; the aryl that replaces; aryl alkyl; the aryl alkyl that replaces; sulfoxide; the sulfoxide that replaces; sulfone; the sulfone that replaces; the sulfane base; the sulfane base that replaces; amino-sulfonyl; the amino-sulfonyl that replaces; aryl sulfonyl; the aryl sulfonyl that replaces; sulfonic acid; sulphonic acid ester (being sulfonate); the dihydroxy phosphoryl; the dihydroxy phosphoryl that replaces; the hydroxy amino phosphoryl; the hydroxy amino phosphoryl that replaces; azido; carboxyl; the carboxyl (being ester) that replaces; carbamyl; the carbamyl that replaces; cyano group; cycloalkyl; the cycloalkyl that replaces; the assorted alkyl of ring; the assorted alkyl of the ring that replaces; dialkyl amido; the dialkyl amido that replaces; halo; heteroaryloxy; the heteroaryloxy that replaces; heteroaryl; the heteroaryl that replaces; assorted alkyl; the assorted alkyl that replaces; hydroxyl; nitro or sulfo-.

120. as the described aryl nitrone chemical compound of claim 119, wherein, W, X, Y and Z ' are C-R independently of one another ⁴, and R ²Not hydrogen.

121. as the described aryl nitrone chemical compound of claim 119, wherein, W, X, Y and Z ' are C-R independently of one another ⁴, and R ¹It or not the phenyl of methyl, phenyl or replacement.

122. as the described aryl nitrone chemical compound of claim 119, wherein, W, X, Y and Z ' are C-R independently of one another ⁴, and R ¹It or not the phenyl of low alkyl group, phenyl or replacement.

123. as the described aryl nitrone chemical compound of claim 119, wherein, W, X, Y and Z ' are C-R independently of one another ⁴, and R ¹Be to replace or unsubstituted assorted alkyl, replacement or unsubstituted acyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted aralkyl or replacement or unsubstituted heteroarylalkyl.

124. as the described aryl nitrone chemical compound of claim 119, wherein, W, X, Y and Z ' are independent separately to be C-R ⁴, and R ³Be not-OH or-SMe.

125. as the described aryl nitrone chemical compound of claim 119, wherein, R ³Be selected from-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-PO (OR ⁹) NR ⁷R ⁸,-PO (NR ⁷R ⁸) ₂,-PO (OR ⁹) ₂With-CO ₂R ⁹

126. as the described aryl nitrone chemical compound of claim 119, wherein, W, X, Y, Z ', A and Q are C-R independently of one another ⁴

127. as the described aryl nitrone chemical compound of claim 119, wherein, W, X, Y, Z ', A and Q are C-R independently of one another ⁴, X is C-R ⁵, and W be selected from hydrogen ,-SR ⁹,-SO ₂NR ⁷R ⁸,-SO ₃R ⁹,-CONR ⁷R ⁸,-NR ⁷R ⁸,-OH ,-PO (ORR ⁹) NR ⁷R ⁸,-PO (OR ⁹) ₂With-CO ₂R ⁹

128. as the described aryl nitrone chemical compound of claim 127, wherein, R ⁵Not hydrogen.

129. as the described aryl nitrone chemical compound of claim 119, wherein, W and X independently are C-R separately ⁴And one of Y, Z ', A and Q are N, and remaining is C-R independently of one another ⁴

130. as the described aryl nitrone chemical compound of claim 119, wherein, A is N, and W, X, Y, Z ' and Q are C-R independently of one another ⁴

131. as the described aryl nitrone chemical compound of claim 119, wherein, W and X independently are C-R separately ⁴And two among Y, Z ', A and the Q is N, and remaining is C-R independently of one another ⁴

132. as the described aryl nitrone chemical compound of claim 119, wherein, W is N, and X, Y, Z ', A and Q are C-R independently of one another ⁴

133. as the described aryl nitrone chemical compound of claim 119, wherein, W is N; X is C-R ⁴And one of Y, Z ', A and Q are N, and remaining is C-R independently of one another ⁴

134. as the described aryl nitrone chemical compound of claim 119, wherein, W and the A N that respectively does for oneself, and X, Y, Z ' and Q are C-R independently of one another ⁴

135. as the described aryl nitrone chemical compound of claim 119, wherein, W is N; X is C-R ⁴And two among Y, Z ', A and the Q is N, and remaining independently is C-R separately ⁴

136. as the described aryl nitrone chemical compound of claim 119, wherein, X is N, and W, Y, Z ', A and Q are C-R independently of one another ⁴

137. as the described aryl nitrone chemical compound of claim 119, wherein, X is N; W is C-R ⁴And one of Y, Z ', A and Q are N, and remaining independently is C-R separately ⁴

138. as the described aryl nitrone chemical compound of claim 119, wherein, X and the A N that respectively does for oneself, and W, Y, Z ' and Q are C-R independently of one another ⁴

139. as the described aryl nitrone chemical compound of claim 119, wherein, X is N; W is C-R ⁴And two among Y, Z ', A and the Q is N, and remaining is C-R independently of one another ⁴

140. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (XI):

In the formula:

W and X are independently selected from N and C-R respectively ⁴

Y and Z ' are carbonyl, C-R independently of one another ⁴Or C (R ⁴) ₂

A and Q are independently selected from carbonyl, NR respectively ⁴, O and S;

Dotted line is represented single or two key.

141. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (XII):

In the formula:

W and X independently are selected from N and C-R respectively ⁴

Q is NR ⁴, carbonyl or C (R ⁴) ₂

Y and Z ' are C (R independently of one another ⁴) ₂Or carbonyl; With

Each R ⁴Independent is hydrogen; alkyl; the alkyl that replaces; acyl group; the acyl group that replaces; acylamino-; the acylamino-that replaces; alkyl amino; the alkyl amino that replaces; alkylthio group; the alkylthio group that replaces; alkoxyl; the alkoxyl that replaces; alkoxy carbonyl; the alkoxy carbonyl that replaces; alkyl aryl amino; the alkyl aryl amino that replaces; alkoxy aryl; the alkoxy aryl that replaces; amino; aryl; the aryl that replaces; aryl alkyl; the aryl alkyl that replaces; sulfoxide; the sulfoxide that replaces; sulfone; the sulfone that replaces; the sulfane base; the sulfane base that replaces; amino-sulfonyl; the amino-sulfonyl that replaces; aryl sulfonyl; the aryl sulfonyl that replaces; sulfonic acid; sulphonic acid ester (being sulfonate); the dihydroxy phosphoryl; the dihydroxy phosphoryl that replaces; the hydroxy amino phosphoryl; the hydroxy amino phosphoryl that replaces; azido; carboxyl; the carboxyl (being ester) that replaces; carbamyl; the carbamyl that replaces; cyano group; cycloalkyl; the cycloalkyl that replaces; the assorted alkyl of ring; the assorted alkyl of the ring that replaces; dialkyl amido; the dialkyl amido that replaces; halo; heteroaryloxy; the heteroaryloxy that replaces; heteroaryl; the heteroaryl that replaces; assorted alkyl; the assorted alkyl that replaces; hydroxyl; nitro or sulfo-.

142. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (XIII):

In the formula:

W and X are independently selected from N and C-R respectively ⁴

A is NR ⁴, carbonyl or C (R ⁴) ₂

Y and Z ' are independent separately to be C (R ⁴) ₂Or carbonyl; With

143. as the described chemical compound of claim 93, it is the aryl nitrone chemical compound of formula (XIV):

In the formula:

W and X are independently selected from N and C-R respectively ⁴

Y and Z ' are independent separately to be C (R ⁴) ₂Or carbonyl; With

144. a pharmaceutical composition, described pharmaceutical composition contain the aforesaid right of pharmaceutically acceptable carrier and medicine effective quantity require in each described chemical compound.

145. as the described pharmaceutical composition of claim 144, wherein, described carrier is the parenteral carrier.

146. as the described pharmaceutical composition of claim 144, wherein, described carrier is an oral carrier.

147. as the described pharmaceutical composition of claim 144, wherein, described carrier is a topical carrier.

148. a pharmaceutical composition, described pharmaceutical composition contain following one or more chemical compounds of pharmaceutically acceptable carrier and medicine effective quantity: chemical compound 1,8,9,11,16-22,25-27,37-43 and 45-50 in 5.3 parts; 5.4 chemical compound 51 and 53-69 in the part; And 5.5 chemical compound 70-78 in the part.

149. as the described pharmaceutical composition of claim 148, wherein, described carrier is the parenteral carrier.

150. as the described pharmaceutical composition of claim 148, wherein, described carrier is an oral carrier.

151. as the described pharmaceutical composition of claim 148, wherein, described carrier is a topical carrier.

152.。A kind of prevention, treatment or improve the method for certain disease of mammal or symptom, described method comprise give described mammal effectively prevent, treat or improve disease or symptom amount as claim 144 or 148 described pharmaceutical compositions.

153. as the described method of claim 152, wherein, described disease or symptom are pain symptoms.

154. as the described method of claim 152, wherein, described disease or symptom are autoimmune disease or symptom.

155. as the described method of claim 152, wherein, described disease or symptom are inflammatory diseases or symptom.

156. as the described method of claim 152, wherein, described disease or symptom are nerve or neurodegenerative disease or symptom.

157. a prevention, treat or improve the method for following disease of mammal or symptom:

Pain comprises acute, inflammatory and neuropathic pain, chronic pain, toothache, and the headache that comprises migraine, cluster headache and tension headache; Parkinson disease, Alzheimer and multiple sclerosis; By neuritis mediation or cause neuritic disease and obstacle, traumatic brain injury, apoplexy and encephalitis; The neuropsychiatric disease and the obstacle of maincenter mediation, depression, manic disorder, two-phase disease, anxiety neurosis and schizophrenia; Eating disorders, sleep disorder and cognitive disorder; Epilepsy and seizure of disease; Prostate, bladder and bowel dysfunction, urinary incontinence, hesitancy in urination, rectum allergy, fecal incontinence, benign prostatauxe and inflammatory bowel; Respiratory tract and airway disorders and obstacle, allergic rhinitis, asthma, RAD and chronic obstructive pulmonary disease; By inflammation mediated or cause the disease and the obstacle of inflammation, arthritis, rheumatoid arthritis, osteoarthritis, myocardial infarction, various autoimmune diseasees and obstacle, uveitis and atherosclerosis; Itch/scratch where it itches and psoriasis; Alopecia (shaving one's head); Obesity; Lipid disorders; Cancer; Hypertension; Spinal cord injury; And nephropathy,

Described method comprise give described mammal effectively prevent, treat or improve disease or symptom amount as claim 144 or 148 described pharmaceutical compositions.

158. as the described method of claim 157, wherein, described disease or symptom are parkinson disease.

159. as the described method of claim 157, wherein, described disease or symptom are Alzheimer.

160. as the described method of claim 157, wherein, described disease or symptom are traumatic brain injuries.

161. as the described method of claim 157, wherein, described disease or symptom are apoplexy.

162. a method for preparing as claim 1,18 or 93 nitrone compound, described method comprises the aldehydes or ketones chemical compound that makes following formula:

With R ¹NHOH or its salt react under the condition that is fit to preparation claim 1,18 or 93 chemical compound.