MXPA06009224A

MXPA06009224A - 2-substituted and 4-substituted aryl nitrone compouds

Info

Publication number: MXPA06009224A
Application number: MXPA/A/2006/009224A
Authority: MX
Inventors: G Kelly Michael; Janagani Satyanarayana; Kincaid John
Original assignee: Janagani Satyanarayana; G Kelly Michael; Kincaid John
Priority date: 2000-02-17
Filing date: 2006-08-11
Publication date: 2007-04-10

Abstract

The present invention provides aryl nitrones, compositions comprising the same and methods of their use for the treatment or prevention of oxidative, ischemic, ischemia/reperfusion-related and chemokine mediated conditions.

Description

COMPOUNDS OF ARIL NITRONA 2-SUSTAINED AND 4-SUBSTITUTE This application claims the benefit of the provisional applications of E.U.A. Nos. 60 / 544,764, 60 / 544,766, 60 / 545,616 and 60 / 562,509, the contents of which are incorporated herein by reference e? your totalities. 1. FIELD OF THE INVENTION The present invention provides orally active nitrona compounds useful for the treatment and prevention of conditions mediated by free radical, ischemic conditions and conditions related to ischemia / reperfusion, and with conditions mediated by chemokine. 2. BACKGROUND OF THE INVENTION Numerous conditions that afflict human subjects are mediated by oxidative and / or free radical mechanisms. These conditions include, but are not limited to, neurological, neurodegenerative, inflammatory, autoimmune and pain conditions. Prominent examples include stroke, arteriosclerosis and other cardiovascular diseases, myocardial infarction and dysfunction, multiple sclerosis, head trauma and traumatic brain damage, nerve damage and neuropathies, pain (acute and chronic or neuropathic), arthritis and other autoimmune disorders , and asthma and allergic reactions.

There is a constant need for the development of compounds, pharmaceutical compositions and methods of treatment for these conditions. Nitrons constitute a class of compounds that are believed to have antioxidant properties due to their ability to form stable adducts (ie, spin traps) with free radicals. Since the oxidizing species and / or free radicals can cause oxidative damage to cellular constituents (eg, proteins and lipids), which can lead to pathological consequences, it has been reported that the antioxidant properties of nitrones are at least partially under their control. therapeutic potential. Therefore, diseases that have been reported to be susceptible to antioxidant therapy and that involve the generation of free radicals may be susceptible to treatment with nitrone based on the antioxidant activity of nitrones. Aromatic nitrone compounds such as C- (phenyl) -N- (tert-butyl) nitrone (PBN) and derivatives thereof have been reported as potential therapeutics for the treatment of a wide variety of disease conditions that arise from or it is characterized by oxidative damage or oxidant stress. Nitron compounds that exhibit improved antioxidant activity compared to PBN may have better therapeutic potential than PBN. The products of interruption, metabolism or degradation of aromatic nitrone, such as hydroxylamines of N-alkyl, hydroxynitroxides of N-alkyl or nitric oxide can also contribute to the antioxidant properties of aromatic nitrones, and contribute to their interruption of inflammatory signaling pathways . A nitrone, C- (2,4-disulfo-phenyl) -N- (per-butyl) nitrone, disodium salt (Cerovi e < R)) is currently being evaluated in phase III clinical trials for the treatment of ischemic attack acute. See Patent of E.U.A. No. 5,475,032. There is a need for new classes of aromatic nitrone derivatives that have improved properties such as low toxicity, increased solubility, enhanced cellular and blood brain barrier permeability, and improved oral bioavailability. 3. COMPENDIUM OF THE INVENTION The present invention provides 2-substituted and 4-substituted aryl nitrones that exhibit surprisingly high oral bioavailability and surprisingly low toxicity. The aryl nitrones of the invention, as described in the examples below, may exhibit elevated oral bioavailability and high in vivo half-life. With such surprising bioavailability, the compounds of the present invention are useful as oral therapeutics for the treatment and prevention of diseases, such as oxidative, ischemic, ischemia-reperfusion-related and chemokine-mediated diseases., in a subject. In a first aspect, the present invention provides 2-substituted aryl nitrones which, in certain embodiments, exhibit high oral bioavailability. The compounds comprise an aryl group or a heteroaryl group linked to the carbon atom of a nitrone group. The nitrona carbon may be additionally linked to hydrogen, lower alkyl or alkyl, and the nitrona nitrogen may be bonded to lower alkyl, alkyl, aryl, alkylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or cycloheteroalkyl. The aryl group or heteroaryl group may be any aryl or heteroaryl known to those of skill in the art. Preferably the aryl or heteroaryl groups comprise a six-membered ring bonded to the nitrone. Significantly, in these aryl nitrones of the invention, the aryl or heteroaryl groups are substituted with one or more substituents selected from the group consisting of sulfone, carboxyl, aminocarbonyl and tetrazole, when at least one of these substituents is in an ortho or 2-position. - of the ring of aryl in relation to the group of nitrona. In preferred embodiments, the compound is not one of compounds 201-204, described below.

In certain embodiments, the present invention provides 2-substituted aryl nitrones in accordance with formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or cycloheteroalkyl; at least one of A and B is C-R3, and the other is selected from C-R3 and N; At least one R3 is S02R5, C02R5, CONR5R6 or tetrazole, and any other R3 is independently selected from R4, H, lower alkyl, alkenyl, halogen alkyl, aryl, S02R5, S02NR5Rs, C02H, CONR5R6 and tetrazole; Z, Y and Z are each independently selected from C-R4 and N; each R4 is independently selected from hydrogen, alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, arylalkyloxy substituted, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroaryloxy, substituted teroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or tio; and R5 and Re are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl and wherein they can feasibly be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more heteroatoms selected from the list NR1, 0 or S. In additional embodiments, the present invention provides compounds according to formula (I), wherein the compounds do not encompass any of compounds 201 to 204, below. In a second aspect, the present invention provides aryl nitrones which, in certain embodiments, show high oral bodisopportunity. The compounds comprise an aryl group or a heteroaryl group linked to the carbon atom of a nitrone group. The nitrona carbon may be further linked to hydrogen, lower alkyl or alkyl, and the nitrona nitrogen may be linked to lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylaluyl or cycloheteroalkyl. The aryl group or heteroaryl group can be any aryl or heteroaryl known to those skilled in the art. Preferred aryl or heteroaryl groups comprise a six-membered ring bonded to the nitrone. Significantly, in these aryl nitrones of the invention, the aryl or heteroaryl groups are substituted with one or more sulfonamides, and at least one of these sulfonamides is in the ortho or 2- position of the aryl ring relative to the nitrona group. In certain embodiments, the present invention provides 2-sulfonamidyl aryl nitrones according to formula (II): (II) or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; at least one of A and B is C-R3, and the other is selected from C-R3 and N; at least one R3 is S02NR5R6, and any other R3 that independently selects from R4, H, lower alkyl, alkenyl, alkyl, halogen, aryl, S02NR5R6, S02R5, C02H, C0NR5R6 and tetrazole; X, Y and Z are each independently selected from C-R4 and N; each R 4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamine, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or tio; and R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, and when feasible they can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more heteroatoms selected from the NR1, O or S list. In a third aspect, the present invention provides 4-substituted aryl nitrones which, in certain embodiments, exhibit elevated oral bioavailability. The compounds comprise an aryl group or a heteroaryl group linked to the carbon atom of a nitrona group. The nitrone carbon may be further linked to hydrogen, lower alkyl or alkyl, and the nitrona nitrogen may be linked to lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl or cycloheteroalkyl. The aryl group or heteroaryl group can be any aryl or heteroaryl known to those skilled in the art. Preferred aryl or heteroaryl groups comprise a six-membered ring bonded to the nitrone. Significantly, in these aryl nitrones of the invention, the aryl or heteroaryl group is substituted with one or more substituents selected from the group consisting of sulfonamide, sulfone, carboxyl, aminocarbonyl and tetrazole, and at least one of these substituents is in position to or 4- of the aryl ring relative to the nitrona group. In preferred embodiments, the compound is not one of compounds 401-426, described below. Preferred compounds include substituted 4-sulfonamide compounds and 4-sulfonyl compounds. In another aspect, the present invention provides 4-substituted aryl nitrones according to formula III: (III) or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; Y is C-R9, and R9 is selected from S02NR5R6, S02R5, C0NR5R6 and tetrazole; A, B, X and Z are each independently selected from C-R4 and N; Each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ether, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azide, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, cycloalkyl. substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio; and Rs and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, and when feasible can be linked together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more heteroatoms selected from the list NR1, O or S. In another aspect, the present invention provides pharmaceutical compositions comprising an aryl nitrone of the invention. The pharmaceutical compositions of the invention comprise an amount of the aryl nitrona effective to treat or prevent an oxidative, ischemic, ischemia / reperfusion or chemokine-mediated condition in a subject. The compositions can be administered by a variety of routes, including, for example, orally and parenterally. In advantageous embodiments, the compounds are formulated for oral administration. In a further aspect, the present invention provides unit dosage forms of an aryl nitrone of the invention for treating or preventing an ischemic, reperfusion-related or ischemic, or chemokine-mediated oxidative, ischemic condition in a subject. In certain embodiments, the unit dosage forms comprise a pharmaceutical composition of an aryl nitrone in an amount effective to treat or prevent oxidative, ischemic, ischemia / reprefusion-related or chemokine-mediated condition in a subject. In a method of treatment or aspects of prophylaxis, this invention provides a method for treating or prophylacting a mammal susceptible or affected with an ischemic, ischemic, or ischaemia / reperfusion related condition. Exemplary conditions include, but are not limited to, neurological, cardiovascular and organ transplantation related conditions. The method comprises administering an effective amount of one or more of the aryl nitrones or pharmaceutical compositions described above. The compounds can be administered in accordance with any technique known to those skilled in the art. In advantageous embodiments, the compounds are administered orally. In a further method of prophylaxis treatment aspect, the present invention provides a method of treating or prophylacting a susceptible or afflicted mammal with a condition modulated by a chemokine function or activity. Such conditions include, but are not limited to, neurodegenerative disease, peripheral neuropathies, infections, sequelae of infections and autoimmune diseases. The method comprises administering an effective amount of one or more of the aryl nitrones or pharmaceutical compositions described above. In additional aspects, this invention provides methods for synthesizing the aryl nitrones of the invention. 4. BRIEF DESCRIPTION OF THE FIGURES Figure 1 provides the inversion of mechanical hyperalgesia by Compound 62 in rat; Figure 2 provides the reversal of ailodynia by Compound 62 in the rat; Figure 3 provides anti-allodynic effects of Compound 62 in the rat; Figure 4 provides total infarct volume at 48 hours for animals treated with compounds 62, 60 and 63; Figure 5 provides a total infarct volume at 48 hours for animals treated with Compound 62; and Figure 6 provide total infarct volume at 48 hours for animals treated with Compound 63. 5. DETAILED DESCRIPTION OF THE INVENTION The present invention is based, in part, on the discovery that the aryl nitrones of the invention which, in certain modalities present surprising oral bioavailability and surprisingly low toxicity. Accordingly, the present invention provides the aryl nitrones, compositions comprising aryl nitrones and methods of their use to treat or prevent oxidative, ischemic, ischemia / reperfusion-related or chemokine-mediated disorders. 5.1 Definitions When describing the aryl nitrones, pharmaceutical compositions and methods of this invention, the following terms have the following meanings unless otherwise specified. "Acyl" refers to the group -C (0) R wherein R is hydrogen, alkyl, aryl or cycloalkyl. "Acylamino" refers to the group -NRC (0) R wherein each R is independently hydrogen, alkyl, aryl or cycloalkyl. "Acyloxy" refers to the group -OC (0) R wherein R is hydrogen, alkyl, aryl or cycloalkyl. "Alkenyl" refers to a branched or unbranched, unsaturated hydrocarbon group preferably having 2 to 10 carbon atoms and more preferably 2 to 8 carbon atoms and having at least 1 and preferably 1-2 sites of carbon-carbon double bond unsaturation. Preferred alkenyl groups include ethyl (-CH = CH2), n-propenyl (-CH2CH = CH2), isopropenyl (-C (CH3) = CH2), and the like. "Substituted alkenyl" refers to an alkenyl group having 1 or more substituents, for example 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy , alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, indocarbonyloxy, aryl, aryloxy, azide, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (O) -, alkyl-S (O) 2- and aryl-S (0) 2-. "Alkoxy" refers to the group -OR where R is alkyl. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like . "Alkoxy substituted" refers to an alkoxy group having 1 or more substituents, for example 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamine, acyloxy, alkoxy, substituted alkoxy alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl- (S) O) -, aryl-S (O) -, alkyl-S (O) 2- and aryl-S (LO) 2-. "Alkoxycarbonyl" refers to the group -NRC (0) OR 'wherein R is hydrogen, alkyl, aryl or cycloalkyl, and R' is alkyl or cycloalkyl. "Alkyl" refers to a saturated, branched or unbranched, monovalent hydrocarbon group, preferably having from 1 to about 11 carbon atoms, more preferably from 1 to 8 carbon atoms and still more preferably from 1 to 6. carbon atoms. This term is exemplified by groups such as methyl, ethyl, n- > -propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like. The term "lower alkyl" refers to an alkyl group having 1 to 11 carbon atoms. "Substituted alkyl" refers to an alkyl group having 1 or more substituents, for example from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (0) 2- and aryl-S (0) 2-. "Alkylene" refers to a divalent, branched or unbranched saturated hydrocarbon group preferably having 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., CH2CH2CH2- and -CH (CH3) CH2-) and the like. "Substituted alkylene" refers to an alkylene group having 1 or more substituents, for example 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S ( ) -, aryl-S (O) -, alkyl-S (0) 2- and aryl-S (0) 2-. "Alkynyl" refers to a monovalent, branched or unbranched, unsaturated hydrocarbon group, preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1 - 2 sites of carbon-carbon triple bond unsaturation. Preferred alkyl groups include ethynyl (-C = CH), propargyl (-CH2 = CH), propargyl (-CH2C ^ CH) and the like. "Substituted alkynyl" refers to an alkynyl group having 1 or more substituents, for example 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (0) 2- and aryl-S (0) 2-. "Amino refers to the group -NH2." "Substituted amino" refers to the group -N (R) 2 wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl substituted, aryl, cycloalkyl, substituted cycloalkyl, and wherein both R groups are linked to form an alkylene group When both R groups are hydrogen, -N (R) 2 is an amino group. "Alkylamino" refers to the alkyl group. NR '-, where R' is selected from hydrogen and allyl "Arylamino" refers to the group aryl-NR'-, wherein R 'is selected from hydrogen, aryl and heteroaryl. "Alcoxyamino" refers to a radical - N (R) 0R ', wherein R is selected from hydrogen, alkyl and aryl; and R represents an alkyl or cycloalkyl group as defined herein. "Alkylarylamino" refers to a radical -NRR ', wherein R represents an alkyl or cycloalkyl group and R' is an aryl as defined herein. "Aminocarbonyl" refers to the group -C (0) NRR, wherein each R is independently hydrogen, alkyl, aryl and cycloalkyl, or wherein the R groups are joined to form an alkylene group. "Aminocarbonylamino2" refers to the group -NRC (0) NRR, wherein each R is independently hydrogen, alkyl, aryl or cycloalkyl, or wherein two R groups are attached to form an alkylene group. "Aminocarbonyloxy" refers to the group -0C (0) NRR wherein each R is independently hydrogen, alkyl, aryl or cycloalkyl, or wherein the R groups are linked to form an alkylene group "Aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl) Preferred aryls include phenyl, biphenyl, naphthyl and the like, unless otherwise restricted by the definition for the individual substituent, said aryl groups may be optionally substituted with 1 or more substituents, for example from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyl oxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, k alkynyl-S (O) -, aryl- (S (0) -, alkyl-S (0) 2- or aryl-S (0) 2- . "Aralkyl" or "arylalkyl" refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. "Aryloxy" refers to the group -OH where R is aryl. "Cycloalkyl" refers to a cyclic alkyl group of 3 to 10 carbon atoms having a single cyclic ring or multiple fused or bridged rings that may be optionally substituted with 1 to 3 alkyl groups. These cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as adamantanyl and the like. The term "lower cycloalkyl" refers to a cycloalkyl group having from 3 to 6 carbon atoms. "Substituted cycloalkyl" refers to a cycloalkyl group having 1 or more substituents, for example 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carbonyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl -S (0) -, aryl-S (O) -, alkyl-S (0) 2- and aryl-S (0) 2-. "Cycloalkoxy" refers to the group -OR where R is cycloalkyl. Said cycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxy and the like. "Cycloalkenyl" refers to a cyclic alkenyl group of 4 to 10 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which may be optionally substituted with 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for example, cyclopent-3-enyl, cyclohex-2-enyl, cyclooct-3-enyl and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group having 1 or more substituents, for example 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy , alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro keto, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl -S (0) -, aryl-S (O) -, alkyl-S (0) 2 and aryl-S (0) 2- As used herein, the term "cycloheteroalkyl" refers to a non-aromatic ring stable heterocyclic and fused rings containing one or more heteroatoms independently selected from N, 0 and S. A fused heterocyclic ring system may include carbocyclic rings and need only include a heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl, and are shown in the following illustrative examples: Optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, acyloxy, azido, carboxyl, cyano, cycloalkyl , substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, thiol, alkyl-S (0) -, aryl-S (O) -, alkyl-S (0) 2 or aro )2-. Substitution groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives. In the examples, M is CR7, NR2, 0, or S; Q is 0, NR2 or S. R7 and R8 are independently selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido , carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioke, triol, alkyl-S (0) -, aryl-S (O) -, alkyl-S (0) ) 2-, and aril-S (0) 2-. As used herein, the term "heteroaryl" refers to an aryl ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, where the rest of the atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur and nitrogen. Preferably, the heterocyclic ring system is monocyclic or bicyclic. Non-limiting examples include the following, which can be substituted with one or more R7: wherein R7 and R8 are each independently selected from hydrogen, lower alkyl, alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR1: LCOR12, NR11SOmR12, wherein m = lo 2 , COOalkyl, COOaryl, CONR ^ R12, CONRUR12, SOa P ^ R12, S (O) n-alkyl or S (O) n-aryl, where n is 0, 1 or 2; R7 and R8 can be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S; and R11, R12, and R12 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; "Halo" or "halogen" refers to fluorine, chlorine, bromine and me. Preferred halo groups are either fluorine or chlorine. "Hydroxyl" refers to the group -OH. "Ceto" or "oxo" refers to the group = 0. "Nitro" refers to the group -N02. "Thioalkoxy" refers to the group -SR wherein R is alkyl "Substituted thioalkoxy" refers to a thioalkoxy group having 1 or more substituents, for example from 1 to 5 substituents, and preferably from 1 to 3 substituents, selected of the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl-S (O) 2-, and aryl-S (0) 2-. "Sulfanyl" refers to the radical HS- "Substituted sulfanyl" refers to a radical such as RS- wherein R is any substituent described herein In certain embodiments "substituted sulfanyl" refers to a radical -SR wherein r is an alkyl or cycloalkyl group as defined herein which optionally substituted as defined herein. Illustrative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like. "Sulfinyl" refers to the radical -S (0) H. "Substituted sulfinyl" refers to a radical such as S (0) -R, wherein R is any substituent described herein. "Sulfonyl" refers to the divalent radical -S (02) -. "Substituted sulfonyl" refers to a radical such as -S (02) -R wherein R is any substituent described herein. "Aminosulfonyl" or "Sulfonamide" refers to the radical H2N (02) S-, and "substituted aminosulfonyl" "substituted sulfonamide" refers to a radical such as R2N (02) S- wherein each R is independently any substituent described in the present. In certain embodiments, R is selected from H, lower alkyl, alkyl, aryl and heteroaryl. "Thioaryloxy" refers to the group -SR wherein R is aryl. "Tioceto" refers to the group = S. "Tiol" refers to the group -SH. The term "subject" refers to an animal such as a mammal, including, but not limited to primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse and so on. similar. In the preferred embodiments, the subject is a human. The terms "treat", "treating" or "treatment", as used herein, refer to a method for alleviating or abrogating a disorder and / or its inherent symptoms. The terms "prevent", "preventing" or "prevention", as used herein, refer to a method for reducing the risk of acquiring a disorder and / or its inherent symptoms. "Pharmaceutically acceptable salt" refers to any salt of a compound of this invention that retains its biological properties and that is not biologically undesirable or otherwise. These salts can be derived from a variety of organic and inorganic counterions well known in the art and include, by way of example illustration, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to a pharmaceutically acceptable cationic counterion of a functional acid group. These cations are exemplified by cations of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like. "Solvate" refers to a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces.

When the solvent is water, the solvate is a hydrate. The therapeutic methods and pharmaceutical compositions of the invention employ one or more aryl nitrones as the active agent. For the purposes of this invention, the nitrones of the formula I are named using conventional nitrile nomenclature, that is, the carbon atom of the carbon-nitrogen double bond (C = N =) is designated the a- position and substituents in the nitrogen atom of the carbon-nitrogen double bond receives the prefix N-. In some cases, the aryl nitrones of this invention may contain one or more chiral centers. Typically, these compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as enriched mixtures of stereoisomers. All of these stereoisomers (and enriched mixtures) of the aryl nitrones of the formula I are included within the scope of this invention. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of said compounds can be separated using, for example, chiral column chromatography, chiral resolution agents and the like. Additionally, all geometric isomers in the nitrona compounds of the formula I are included within the scope of this invention including, for example, all isomers (ie, E and Z isomers) of the carbon-nitrogen double bond of the functionality of nitrona. As used herein, the term "around" refers to a tolerance scale higher or lower than a quantitative amount known as acceptable to those of experience in the field. For example, a dose of about 1000 mg indicates a dose typically administered under the guidance of a practitioner when a dose of 1000 mg is indicated. In certain modalities, the term "around" refers to + 10% or + Jo • 5.2 2-Substituted Aryl Nitrones of the Invention The present invention provides 2-substituted aryl nitrones useful for preventing and / or treating diseases and disorders related to oxidative conditions, ischemic conditions and conditions related to ischemia / reperfusion or chemokine-mediated mammals In certain embodiments, the present invention provides aryl nitrones according to formula (2.1): (2.1) or a pharmaceutically acceptable salt or solvate thereof. In the formula (2.1), R1 is selected from hydrogen, lower alkyl and alkyl. For example R1 can be hydrogen, methyl, ethyl, propyl, butyl and the like. In certain embodiments, R1 is hydrogen. R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl. In certain embodiments R2 is selected from alkyl, aryl, arylalkyl and heteroaryl. In further embodiments, R2 is selected from phenyl, benzyl or tert-butyl. Preferred compounds include tert-butyl and benzyl compounds. At least one of A and B is C-R3, and the other is selected from C-R3 and N. At least one R3 is S02R5, C02R5, CONR5R6, C02H, CONR5R6 and tetrazole. In certain embodiments, each of A and B is independently C-R3. In certain modalities, at least one of A and B is C-S02R5. In additional modalities, at least one of A and B is C-C02R5. In particular embodiments, at least one of A and B is C-C02H. In additional embodiments, at least one of A and B is C-C0NR5R6. In additional embodiments at least one of A and B is C-tetrazole. X, Y and Z are each independently selected from C-R4 and N. In certain embodiments, none of A, B, X, Y and Z are N. In additional embodiments, one of A, B, X, Y and Z is N. In additional embodiments two of A, B, X, Y and Z are N. In still further embodiments, three of A, B, X, Y and Z are N. In still further embodiments, four of A, B, X, Y and Z are N. Each R4 is independently selected from hydrogen, alkyl, alkyl substituted, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulphanil, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminodihydrophosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, carbamoyl substituted, carboxyl, cyano, cycloalkyl, cycloalkyl subst cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio. In certain embodiments, each R4 is independently selected from H, lower alkyl, alkyl, alkenyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, C02H, CONR5R6 and tetrazole. R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more selected heteroatoms of NR1, 0 and S. In preferred embodiments, when R3 or R4 is S02R5, R5 is not hydrogen. In a further aspect of the present invention, R3 can be linked with an adjacent R4 to form a saturated or unsaturated cyclic ring containing from four to eight atoms, optionally containing one or more heteroatoms selected from the list of N, 0 or S. this way, in this embodiment, the compounds of the formula (2.2) - (2.4) are provided: (2.3! (2.3) (3.-J5 In which the terms R1, R2, R3, R4, R5, R6, A, B, X, Y and Z are as defined above. aryl nitrona is a compound according to formula (2.4) wherein the A in the aromatic ring containing the nitrona group is S02R5, C02R5, CONR5R6 or tetrazole In a further aspect of the present invention, a subset of compounds is provided wherein the adjacent R4 groups can be joined to form a saturated or unsaturated cyclic ring containing from four to eight atoms, optionally containing one or more heteroatoms selected from the list N, 0 or S. Thus, in this embodiment, the compounds of the formula (2.5) - (2.6) are provided: Where the terms R1, R2, R3, R4, R5, R6, A, B, X, Y and Z are as defined above. In certain embodiments, the aryl nitrona compound is a compound according to formula (2.6) wherein the A in the aromatic ring bearing the nitrone group is S02R5. CP2R5, CONR5R6 or tetrazole. In preferred embodiments, the present invention provides compounds according to formula (2.1) wherein the compounds do not include compounds 201 -204 below: 201. β-2-carboxy-phenyl-Nt-butyl-nitrona 202. -2- carboxy-phenyl-N-phenyl-nitrona 203. a-2-carboxy-phenyl-N-3, 4-dimethyl-phenyl-nitrona 204. ß-2-carboxy-3,4-dimethoxy-phenyl-N-methyl- nitrone In certain embodiments, the present invention provides a compound according to any of formulas (2-1) - (2.6) that is not any or all of compounds 201-204, any or all of compounds 210-2.210, below, and / or any or all compounds 1-81 (eg, any or all of compounds 1-12, 14-16, 62-66, 68, 69 and 72-79) below. In particular embodiments, the present invention provides compounds according to any of formulas (2.1) - (2.6) which are none of compounds 201-204, or 14 or 15, below. In additional embodiments, the present invention provides individual compounds 201-204, 2.10-2.210 and compounds 1-81 (eg, compounds 1-12, 14-16, 62-66, 68, 69 and 72-79), salts or pharmaceutically acceptable solvates of these compounds, pharmaceutical compositions comprising these compounds, methods using these compounds and methods for making these compounds as described in detail in sections below. In a preferred embodiment of compounds of the formula (2.1) to (2.6): R1 is selected from H and alkyl, R2 is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heteroarylalkyl, A, B and R3 are as described above. X, Y and Z are independently selected from CR4 or N, Each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, C02H, CONR5R6, tetrazole, R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, which optionally has one or more heteroatoms selected from the list NR1, 0 or S. In an even more preferred embodiment, the compounds of the formula (2.1) to (2.6): R1 is selected from H and alkyl, R2 is selected from alkyl, aryl, arylalkyl, heteroaryl, A, B and R3 are as described above, X, Y and Z are independently selected from CR4 or N. Each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02NR5F6 , S02R5, CONR5R6, tetrazole, R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more heteroatoms selected from the list NR1, O or S. In certain embodiments of compounds of the formula (2.1) to (2.6): R2 is H; R2 is selected from alkyl, aryl, arylalkyl, heteroaryl; at least one R3 is S02R5, C02R5, CONR5R6 or tetrazole; X, Y and Z are independently selected from CR4 or N; each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02MNR5R6, S02R5, CONR5R6, tetrazole; R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more heteroatoms selected from the list NR1, 0 or S. In certain embodiments according to this paragraph, R2 is selected from alkyl and arylalkyl. In additional modalities in accordance with this paragraph, at least one R3 is C02R5. In additional modalities in accordance with this paragraph, at least one R3 is C0NR5R6. In additional embodiments in accordance with this paragraph, at least one R3 is tetrazole. In certain embodiments, R5 and R6 are each independently H or alkyl, or more particularly, H or lower alkyl. In certain exemplary embodiments, the present invention provides a compound selected from the compounds provided in the examples below and from the following: . 3 2-Sulfonamidyl Aryl Nitrones of the Invention The present invention provides 1-sulfonamidinyl aryl nitrones useful for preventing and / or treating diseases and disorders related to oxidative conditions ischemic conditions and related to ischemia / reperfusion or related chemokine conditions in mammals. In certain embodiments, the present invention provides aryl nitrones according to the formula (3.1 í * ny ¿o- (3.1) or a pharmaceutically acceptable salt or solvate thereof. In the formula (3.1 R1 is selected from hydrogen, lower alkyl and alkyl For example, R1 can be hydrogen, methyl, ethyl, propyl, butyl and the like.

In certain embodiments, R1 is hydrogen. R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl. In certain embodiments, R 2 is selected from alkyl, aryl, arylalkyl and heteroaryl. In further embodiments, R2 is selected from phenyl, benzyl or tert-butyl. Preferred compounds include tert-butyl and benzyl compounds. At least one of A and B is C-R3, and the other is selected from C-R3 and N. At least one R3 is S02NR5R6, and any other R3 is independently selected from R4, H, lower alkyl, alkenyl, alkyl, halogen, aryl, S02NR5R6, S02R5, C02H, C0NR5R6 and tetrazole. In certain embodiments, each of A and B is independently C-R3. In particular embodiments, each of A and B is independently C-R3, and each R3 is independently S02NRsR6. X, Y and Z are each independently selected from C-R4 and N. In certain embodiments, none of A, B, X, Y and Z are N. In other embodiments, one of A, B, X, Y and Z is N. In additional embodiments, two of A, B, X, Y and Z are N. In still further embodiments, three of A, B, X, Y and Z are N, In still further embodiments, four of A, B , X, Y and Z are N. Each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, acyl substituted acylamino, acylamino substituted alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonyl substituted aluilarilamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, dimethyl sulfoxide substituted sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, alkylaminosulfonyl substituted arylsulfonyl, arylsulfonyl substit acid, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio. In certain embodiments, each R4 is independently selected from H, lower alkyl, alkyl, alkenyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, C02H ', C0NR5R6 and tetrazole. R5 and R6 each independently selected from H, lower alkyl, aryl, and heteroaryl, and where feasible can be joined together to form a ring saturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more selected heteroatoms of NR1, 0 and S. In preferred embodiments, wherein R3 or R4 is S02R5, R5 is not hydrogen. In a further aspect of the present invention, R3 may be attached with an adjacent R4 to form a saturated or unsaturated cyclic ring containing four to eight atoms, optionally containing one or more heteroatoms selected from N list, C or S. Thus in this embodiment, the compounds of the formula (3.2) - (3,4) are provided: C3.2) (3.3) (3.4) Where the terms R1, R2, R3, R4, R5, R6, A, B, X, Y and Z are as defined above. In certain embodiments, the aryl nitrona compound is a compound according to formula (3,4) wherein the A in the aromatic ring containing the nitrona group is C-S02NR5R6. In a further aspect of the present invention, a subset of compounds is provided in which two adjacent R4 groups can be joined to form a saturated or unsaturated cyclic ring of four to eight atoms, optionally containing one or more heteroatoms selected from the list N, O or S. In this way, in this embodiment, the compounds of the formula (3.5) - (3.6) are provided.

Where the terms R1, R2, R3, R4, R5, R6, Z, B, X, Y and Z are as defined above. In certain embodiments the aryl nitrona compound is a compound according to the formula (3.6) wherein the A in the aromatic ring containing the nitrona group is C-SO-NR5R6. In certain embodiments, the present invention provides compounds in accordance with any of formulas (3.1) - (3.6) which are none or all of compounds 3.10-3.200, below, and / or any or all compounds 1-81 (by example any or all of the compounds 13, 18-26, 38-29, 50-61, 63-65, 67, 70, 71, 80 and 81) below. In additional embodiments, the present invention provides individual compounds 3.10-3.200 and compounds 1-81 (for example compounds 13, 18-26, 28-29, 50-61, 63-65, 67, 70, 71, 80 and 81). ), pharmaceutically acceptable salts and solvates of these compounds, pharmaceutical compositions comprising these compounds, methods using these compounds and methods for making these compounds and described in detail in the sections below. In a preferred embodiment, the compounds of the formula (3.1) to (3.6): R1 is selected from H and alkyl, R2 is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heteroarylalkyl, A, B and R3 are as described above, X, Y and Z are independently selected from CR4 or N, Each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, C02H, CONR5R6, tetrazole, R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having optionally one or more heteroatoms selected from the list NR1, 0 or S. In an even more preferred embodiment of compounds of the formula (3.1) to (3.6): R1 is selected from H and alkyl, R2 is selected from alkyl, aryl, arylalkyl, heteroaryl, A, B and R3 are as described above, X, Y and Z are independently selected from CR4 or N Each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, CONR5R6, tetrazole, R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having optionally one or more heteroatoms selected from the list NR1, O or S. In certain embodiments the compounds of the formula (3.1) to (3.6): R1 is H; R2 is selected from alkyl, aryl, arylalkyl, heteroaryl; when at least one R3 is S02NR5R6, X, Y and Z are independently selected from CR4 or N; each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, CONR5R6, tetrazole; R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible, can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more heteroatoms selected from the list NR1, O or S. In certain embodiments according to this paragraph, R2 is selected from alkyl and arylalkyl. In certain embodiments, Rs and R6 are each independently H or alkyl, or more particularly H or lower alkyl. In certain exemplary embodiments, the present invention provides a compound selected from the following: 3.10 3.2B 3.01 3.40 3, sa 3.60 3.79 3.88 3M 3.100 3.110 3.3120 3.130 3.140 3.170 3.X80 . 4-Substituted Aryl Nitrones of the Invention The present invention provides aryl nitrones 4-substituted to prevent and / or treat diseases and disorders related to oxidative conditions, ischemic conditions, and conditions related to ischemid / reperfusion or mediated by chemokine in mammals. In certain embodiments, the present invention provides aryl nitrones according to the formula (4.1): (4.1) or a pharmaceutically acceptable salt or solvate thereof. In the formula (4.1) R1 is selected from hydrogen, lower alkyl and alkyl. For example, R1 can be hydrogen, methyl, ethyl, propyl, butyl and the like. In certain embodiments, R1 is hydrogen. R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl. In certain embodiments, R 2 is selected from alkyl, aryl, arylalkyl and heteroaryl. In further embodiments, R2 is selected from phenyl, benzyl or tert-butyl. Preferred compounds include tert-butyl and benzyl compounds. Y is C-R9, and R9 is selected from S02NR5R6, S02R5, C02R5, C0NR5R6, and tetrazole. In certain modalities, Y is C-S02R5. In additional modalities, Y is C-C02R5. In particular modalities, Y is C-C02H. In additional modalities Y is C-C0NR5R6. In additional embodiments, Y is C-tetrazole. In preferred embodiments, Y is C-S02NR5R6. A, B, X and Z are each independently selected from C-R4 and N. In certain embodiments, none of A, B, X, Y and Z are N. In additional embodiments, one of A, B, X, Y and Z is N. In additional embodiments, two of A, B, X, Y and Z are N. In still further embodiments, three of A, B, X, Y and Z are N. In still further embodiments, four of A , B, X, Y and Z are N. Each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl , substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, arylsulfonyl substituted, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio. In certain embodiments each R4 is independently selected from H, lower alkyl, alkyl, alkenyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, C02H, C0NR5R6 and tetrazole. R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more selected heteroatoms of NR1, 0 and S. In preferred embodiments, wherein R3 or R4 is S02R5, R5 is hydrogen. In a further aspect of the present invention, R3 can be linked with an adjacent R4 to form a saturated or unsaturated cyclic ring containing from four to eight atoms, optionally containing one or more heteroatoms selected from the N, 0 or S list. Thus, in this embodiment, the compounds of the formula (4.2) - (4.4) are provided: (4.2) (4.4) (4.3) where the terms R1, R1, R3, R4, R5, R6, A, B, X, Y and Z are as defined above. In a further aspect of the present invention, a subset of compounds is provided in which two R4 groups can be joined to form a saturated or unsaturated cyclic ring containing from four to eight atoms, optionally containing one or more heteroatoms selected from the group list N, 0 or S. In this way, in this embodiment, compounds of the formula (4.5) - (4.6) are provided: 4.55 ¡4 is wherein the terms R1, R2, R3, R4, R5, R6, A, B, X, Y and Z are as defined above. In preferred embodiments, the present invention provides compounds according to any of the formulas (4.1) - (4.6) wherein the compounds do not include the compounds 401-426 below: 401. benzenane N-oxide, N- [[4 - (Methylsulfo-nil) phenyl] methylene] - 402. N-Oxide of benzenamine, 4-bromo-N- [[4- (ethylsulfonyl) phenyl] methylene] - 403. N-oxide of benzenamine, 4-chloro-N - [[4- (methylsulfonyl) phenyl] methylene] -404. Benzenamine N-oxide, - [[4- (methylsulfo-nyl) phenyl] methylene] -4-nitro-405. Benzenamine N-oxide, N- [[4- (Methylsulfo-nyl) phenyl] methylene] -4- (phenylthio) -406.N-oxide of benzenamine, N- [[4- (methylsulfo-nyl) phenyl] methylene] -2- (phenyltium) - 407. Benzenamine N-oxide, 4-methoxy-N- [[4- (methylsulfonyl) phenyl] methylene] -408. 4- [[[4- (methylsulfonyl) phenyl] methylene] oxidoamino] - of phenol 409. N - [4- [[[4- (Methylsulfonyl) phenyl] methylene-oxidoamino] phenyl] -acetamide 410. N-oxide benzenamine, 4-methyl-N- [[4- (methylsulfonyl) phenyl] met ileno] - 411. Benzoic acid, 4- [[(1,1-dimethylethyl) oxidoimino] methyl] - (oCi) 412. Benzoic acid, 4- [[[(1,1-dimethylethyl) -2- (octylthio)] ethyl] oxidoimino] methyl] -413. Benzoic acid, 4- [(oxidophenylimino) methyl]; wherein the phenyl group may be para-substituted with alkyl, alkoxy or acyloxy groups containing up to 18 carbon atoms. 414. Benzoic acid, 4- [[oxido (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) imino] methyl] 415. Benzoic acid, 4- [[ (4-ethoxyphenyl) oxidoimino] methyl] 416. Benzoic acid, 4- [[(1,1-dimethylethyl) oxidoimino] methyl] -2-hydroxy-417. Benzoic acid, 4- [[oxido (pentamethylphenyl) -imino] methyl] -; wherein the ortho and para methyls of the pentamethylphenyl group can be substituted with alkyl or hydrogen 418. N- (1-methylethyl) -4- [[(phenylmethylene) -amino] methyl] -benzamide 419. 4- [[[[ 4- [[bis (2,2,6,6-tetramethyl-4-pi? Eri-dinyl) amino] carbonyl] phenyl] methylene] oxidoamino] methyl] -N, N-bis (2,2,6,6) -tetramethyl-4-piperidinyl) -benzamide 420. 4- [[(1,1-dimethylethyl) oxidoiminod] methyl] -benzenesulfonamide 421. N-methyl-4- [[oxido (3,4,4-trimethyl-2- thioxo-5-thiazolidinyl) iminod] methyl] -benzenesulfonamide 422. 4- [[(5,5-dimethyl-3-phenyl-2-thioxo-4-thiazo-lidinyl) oxidoimino] methyl] -N-methyl-benzenesulfonamide 423 N-methyl-4- [[oxido (3,5,5-trimethyl-2-thioxo-5-thiazolidinyl) imino] ethyl] benzenesulfonamide 424. 4- [[(3-butyl-5,5-dimethyl-2 -thioxo-4-thiazole-dinyl) oxidoimino] methyl] N-methyl-benzenesulfonamide 425. 4- [[(3-propyl-5,5-dimethyl-2-thioxo-4-thiazo-lidinyl) oxidoimino] ethyl] - N-methyl-benzenesulfonamide 426. 4- [[(3-phenylmethyl-5,5-dimethyl-2-thioxo-4-thiazolidinyl) oxide] imino] methyl] -N-methyl-benzenesulfonamide In certain embodiments, the present invention provides compounds according to any of the formulas (4.1- (4.6) which are not any or all of the compounds 401-426, any or all of the compounds 4.30 -4.280 below, and / or any or all of the compounds 1-81 (e.g., any or all of the compounds 27 and 30-49) below. In particular embodiments, the present invention provides compounds according to any of formulas (4.1) - (4.6) which are not any of compounds 401-426 or 4,240-4,280 or 13, 18, 19, 20, 21 or 62, down. In further embodiments, the present invention provides individual compounds 401-426, 4.30-4.280 and compounds 1-81 (eg, compounds 27 and 30-49), pharmaceutically acceptable salts or solvates of these compounds, pharmaceutical compositions comprising these compounds, methods using these compounds and methods for making these compounds as described in detail in the sections below. In a preferred embodiment of the compounds of formula (4.1) to (4.6): R1 is selected from H and alkyl, R2 is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl and heteroarylalkyl, Y, A, B and R3 are as described above, X and Z are independently selected from CR4 or N, Each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, C02H, C0NR5R6, tetrazole, R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more heteroatoms selected from the list Nrq, 0 or S. In an even more preferred embodiment of compounds of the formula (4.1) to (4.6): R1 is selected from H and alkyl, R2 is selected from alkyl, aryl, arylalkyl, heteroaryl, Y, A, B and R3 are as defined above, X and Z are independently selected from CR4 or N Each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, CONR5R6, tetrazole, R5 and R6 are selected each one independently of H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, optionally having one or more heteroatoms selected from the NR1 list , O or S. In certain embodiments of compounds of the formula (4.1) to 84.6): R2 is H; R2 is selected from alkyl, aryl, arylalkyl, heteroaryl; R9 is selected from S02NR5R6, S02R5, C02R5, CONR5R6, tetrazole, X, Y and Z are independently selected from CR4 or N; each R4 is independently selected from H, lower alkyl, alkyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, CONR5R6, tetrazole; R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl, heteroaryl, and when feasible can be joined together to form a saturated or unsaturated cycloheteroalkyl ring containing from 4 to 8 atoms, optionally having one or more heteroatoms selected from the list NR1, O or S. In certain embodiments, according to this paragraph, R2 is selected from alkyl and arylalkyl. In additional modalities in accordance with this paragraph, R9 is S02NR5R6. In additional modalities in accordance with this paragraph, R9 is S02R5. In additional modalities in accordance with this paragraph, R9 is S02R5. In additional modalities in accordance with this paragraph, R9 is C02R5. In additional modalities in accordance with this paragraph, R9 is CONR5R6. In additional embodiments according to this paragraph, R9 is tetrazole. In certain embodiments, R5 and R6 are each independently H or alkyl or, more particularly H or lower alkyl. In additional embodiments of this section, at least one of A and B is independently C-R9. In other words, at least one of A and B is replaced with a selected group of S02NR5R6, S02R5, C02R5, CONR5R6 and tetrazole. In particular modalities, at least one of A and B is substituted with S02NR5R6. In particular additional embodiments, at least one of A and B is replaced with S02NR5R6. In additional particular embodiments, at least one of A and B is substituted with S02R5. In further embodiments of this paragraph, at least one of A and B is C-R9 wherein R9 is identical to R9 in Y. In certain exemplary embodiments, the present invention provides a compound selected from the following or from the compounds provided in the examples below. -30 . Substitutes of the Nitrona Compounds While not intended to be limited to any particular theory of operation, the present invention is based, in part, on the discovery that particular substituents in A, B and / or Y provide aryl nitrona compounds with advantageous pharmaceutical properties as illustrated in the examples below. In some embodiments according to (2.1) - (2.6) or (3.1) - (3.6), or (4.1) - (4.6), A or B is C-R3 or Y is C-R9 is -S02R5, -S02NR5R6 -, C02R5, -CONR5R6 or tetrazole. In certain modalities,. R3 or R9 can be selected from -S02R5 and -SOP2NR5R6. In further embodiments, R3 or R9 is -S02R6. In further embodiments, R3 or R9 is -S02NR7R8. In certain embodiments, the additional substituents of the preceding paragraph are selected from the substituents described for R4 in the preceding paragraph. In particular embodiments, the additional substituents are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, amino, substituted amino, sulfonyl, substituted sulfonyl, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl , carboxy, substituted carboxy (i.e., ester), carbamoyl, substituted carbamoyl, halo, hydroxyl and tetrazole. In more particular embodiments, the additional substituents (including R4) are selected from the group consisting of hydrogen, lower alkyl, alkyl, alkenyl, halogen, aryl, aryloxy, -S02NR7R8, -S03R9, -C02H, -CQ2R9, -CONR7R8 and tetrazole . In formulas (2.1) - (2.6) or (3.1) - (3.6) or (4.1- (4.6), R2 is selected from substituted or unsubstituted aliphatic alkyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, aryl substituted or unsubstituted, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaralkyl In particular embodiments, R 2 is alkyl, aryl, arylalkyl cycloalkyl, heteroaryl and heteroarylalkyl In more particular embodiments, R 2 is alkyl or In the formulas (2.1) - (2.6) or (3.1) - (3.6) or (4.1) - (4.6), R1 is selected from hydrogen, substituted or unsubstituted C6-C6 alkyl, cycloalkyl (d-) C6) substituted or unsubstituted, aryl, substituted or unsubstituted, and substituted or unsubstituted aralkyl.In particular embodiments, R1 is hydrogen or lower alkyl. ticular, R1 is hydrogen.

In the formulas (2.1) - (2.6), or (3.1) - (3.6) or (4.1) - (.46), each R5 and R6 is independently selected from hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted hetertoaliphatic , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, and any adjacent Rs and R6 may be joined together to form a substituted or unsubstituted heteroaryl ring or a saturated or unsaturated, substituted or unsubstituted cycloheteroalkyl ring of 4 7 atoms. In particular embodiments, each R5 and R6 is independently selected from substituted or unsubstituted aliphatic hydrogen, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl and, together, a cycloalkyl ring of from 4 to 7 atoms. In certain embodiments, each R 5 and R 6 is independently selected from hydrogen, alkyl and, together, a cycloheteroalkyl ring of 4 to 7 atoms. In certain embodiments, R5 and R6 are each independently H or alkyl, or more particularly H or lower alkyl. In preferred embodiments of the invention, R2 is a substituted carbon. For example, in certain embodiments, R2 is: R11 I -C-R12 I R13 wherein each R11, R12 and R13 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, substituted amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfonyl, substituted sulfonyl, sulfanyl, substituted sulphanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, amido, carboxy, carbamoyl, substituted carbamoyl, carboxyl cyano, cycloalkyl, cycloalkyl subs substituted, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro, and thio. In certain embodiments, at least two of R11, R12 and R13 are other than hydrogen. In further embodiments, all three of R11, R12 and R13 are other than hydrogen. In certain embodiments, each R 11, R 12 and R 13 is independently selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl. In further embodiments, each R 11, R 12 and R 13 is independently alkyl or substituted alkyl. In still further embodiments, each R 11, R 12 and R 13 is independently unsubstituted alkyl. In still further embodiments, each R 11, R 12 and R 13 is independently unsubstituted lower alkyl. For example, in certain embodiments, one of R11, R12 and R13 is methyl. In further embodiments, two of R11, R12 and R13 are methyl. In still further embodiments each of R11, R12 and R13 is methyl. In particular embodiments, R 2 is methyl, ethyl, propyl or butyl. For example, in certain embodiments, R 2 is isopropyl or tert-butyl. The present invention also provides compounds in accordance with any combination of the embodiments, preferred embodiments and particular embodiments described above. Other derivatives of the aryl nitrona compounds of this invention have activity in both their acid and acid derivative forms. An acid sensitive form often offers advantages of solubility, tissue compatibility or delayed release in the mammalian organism (See H. Bundgard, 1985, Design of Prodrugs, Elsevier, Amsterdam, pp. 7-9, 21-24). The prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reaction of the original acid with an appropriate alcohol, amides prepared by reaction of the original acidic compound or with a substituted or unsubstituted amine, anhydrides of acid and mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from pendant acid groups in the compounds of this invention are preferred prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl) oxy) alkyl esters. Preferred are C 1 -Ca alkyl, C 2 -C 3 alkenyl, aryl, CC 2 substituted aryl, and C 7 -C 2 arylalkyl esters of the compounds of the invention 5.6 Pharmaceutical Compositions When used as pharmaceuticals, the aryl nitrones of this invention are typically administered in the form of a pharmaceutical composition. Said compositions can be prepared in a manner well known in the pharmaceutical field and comprise at least one active compound. In preferred embodiments, the active compound is in purified form. As usual, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a doctor, in light of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and patient response. individual, the severity of the patient's symptoms, and the like. The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal,. transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the intended route of delivery, the compounds of this invention are preferably formulated as either injectable or oral compositions or as plasters, as lotions or as patches all for transdermal administration. Compositions for oral administration may take the form of liquid solutions or suspensions by volume, or powders by volume. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with an appropriate pharmaceutical excipient. Typical unit dosage forms include prefilled fillings or syringes, previously measured from liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the active agent is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various carriers or carriers and aids of processing that help to form the desired dosage form. Liquid forms suitable for oral administration can include an appropriate aqueous or non-aqueous carrier with buffers, suspending or dispensing agents, colorants, flavors and the like. The solid forms may include, for example, any of the following ingredients, or compounds of a similar nature, a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Promogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide, a sweetening agent such as sucrose or saccharin, or a flavoring agent such as peppermint, methyl salicate or orange flavor. Injectable compositions are typically based on sterile injectable saline or phosphate buffered saline or other injectable carriers known in the art. As before, the active compound in said compositions is typically a minor component, frequently being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like. The transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulating an ointment, the active ingredients will typically be combined with an ointment base either paraffinic or water-miscible. Alternatively, the active ingredients can be formulated in a cream with, for example, an oil-in-water cream base. These transdermal formulations are well known in the art and generally include additional ingredients to improve dermal penetration of stability of the active ingredients or formulation. All of these transdermal formulations and known ingredients are included within the scope of this invention. The compounds of this invention can also be administered by a transdermal device. Accordingly, transdermal administration can be achieved using a patch either of the reservoir or porous membrane type or of a solid matrix variety. The components described above for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. The compounds of this invention can also be administered in sustained release forms or sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences. In another embodiment, the pharmaceutical compositions may be in unit dose or unit of use forms or packets. As is known to those of experience in the field, a unit dose form or package is a convenient prescription size, patient-ready unit labeled for direct distribution by health care providers. A unit of use form contains a pharmaceutical composition in an amount necessary for a typical treatment interval and duration for a given indication. A unit dosage form contains a pharmaceutical composition in an amount required for administration of a single dose of the composition. The present invention provides unit dosage forms of pharmaceutical compositions in an amount for delivery of a dose of about 0.1 to 125 mg / kg of the aryl nitrona to a subject. The subject can be, for example, a human subject with an average weight of about 80 kg. In certain embodiments, the present invention provides a unit dosage form comprising about 10, 25, 50, 100, 500, 1000, 2000 or 2500 mg of the nitrile aryl. In certain embodiments, the unit dosage form consists essentially of these amounts of the aryl nitrona; in other words, the unit dosage form may additionally comprise other ingredients for administration of the aryl nitrona such as pharmaceutically acceptable carrier, excipient or diluent, vial, syringe, or part or other ingredients known to those of experience in the art to administer the aryl nitrona. Typical dosage forms include pre-filled ampoules or syringes, previously measured, of the injectable compositions or tablets or capsules wrapped in unit dose in the case of oral, solid compositions. The unit dosage form can be, for example, a single-use vial, a pre-filled syringe, a single transdermal patch and the like. As is known to those of experience in the field, a unit of use form or package is convenient, patient-ready, prescription-sized unit labeled for direct distribution by health care providers. A unit of use form contains a pharmaceutical composition in an amount necessary for a typical treatment interval and duration for a given indication. The methods of the invention provide a unit package of use of a pharmaceutical composition comprising, for example, an aryl nitrone in an amount sufficient to treat a male or female adult of average size with about 10, 25, 50, 109, 500, 1000, 2000 or 2500 mg orally or 10, 25, 50, 500, 1000, 2000 or 2500 mg subcutaneously three times a week for one month. In this way a package unit of use as described above would have twelve (injections three times per week for four weeks) of pre-filled syringes, each containing 10, k 25, 50, 500, 1000, 2000 or 2500 mg of composition pharmaceutical of aril nitrona. The pharmaceutical compositions may be labeled and have accompanying labeling to identify the composition contained therein and other information useful to health care providers and subjects in the treatment of the diseases and / or disorders described above, including, but not limited to , instructions for use, dosage, dosage interval, duration, indication, contraindications, warnings, precautions, handling and storage instructions and the like. The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention, however, is not limited to the following pharmaceutical compositions. Formulation 1 - Tablets A compound of the formula I, II or III is mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1: 2. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 240-270 mg (80-90 mg of active amide compound per tablet) in a tablet press. Formulation 2 - Capsules A compound of the formula I, II or III is mixed as a dry powder with a starch diluent in an approximate weight ratio of 1: 1. The mixture is filled into 250 mg capsules (125 mg of active amide compound per capsule). Formulation 3 - Liquid A compound of formula I, II or III (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are mixed, passed through a No. 10 US mesh screen, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 g), flavor and color are diluted with water and added with agitation. Then enough water is added to produce a total volume of 5 ml.

Formulation 4 - Tablets The compound of the formula I, II or III is mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1: 2. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 450-900 mg (150-300 mg of active amide compound) in a tablet press. Formulation 5 - Injection The compound of the formula I, II or III is dissolved or suspended in an aqueous sterile injectable medium buffered saline at a concentration of about 5 mg / ml. Formulation 6 - Topical Stearyl alcohol (250 g) and white petrolatum (250 g) are melted at about 75 ° C and then a mixture of a compound of formula I, II or III (50 mg) methylparaben (0.25 g) , propylparaben (0.15 g), sodium lauryl sulphate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) are added and the resulting mixture is stirred until frozen. 5.7 Methods of Treatment and Prevention The aryl nitrones present are used as therapeutic agents for the treatment of conditions in mammals. Accordingly, the compound and pharmaceutical compositions of this invention find use as therapeutics for preventing and / or treating oxidative, ischemic, and ischemia / reperfusion-related and chemokine-mediated conditions in mammals including humans. The ischemia and ischemia / reperfusion related conditions include neurological conditions and cardiovascular conditions as described below. In a method of treatment or aspect of prophylaxis, this invention provides a method for treating or prophylacting a mammal susceptible to or afflicted with a neurological condition such as attack, multiple infarction, dementia, traumatic brain damage, spinal cord damage, diabetic neuropathy. or neurological sequelae of surgical procedures, which method comprises administering an effective amount of one or more just described pharmaceutical compositions. The neurological sequelae of surgical procedures include those sequelae of surgical procedures known to those of experience in the art such as neurological sequelae after procedures using a heart or a lung machine. In particular embodiments, the present invention provides methods for treating or preventing attack with any compound of the invention. In yet another method of treatment or aspect of prophylaxis, this invention provides a method of treating or prophylacting a mammal susceptible to or afflicted with a cardiovascular condition such as myocardial infarction, angina or a non-neurological organ or tissue damage following ischemia, which method comprises administering an effective amount of one or more of the just described pharmaceutical compositions. Non-neurological organ damage or tissue after ischemic include those conditions known to those skilled in the art to follow decreased blood flow or reperfusion after ischemia, such as kidney ischemia, muscle ischemia, and the like. In a treatment method or aspect of further prophylaxis, this invention provides a method of treating or prophylacting a mammal susceptible to or afflicted with a condition related to chemokine function such as a neurodegenerative disease, a peripheral neuropathy, an infection, a sequela of a infection, or an autoimmune disease, which method comprises administering an effective amount of one or more of the just described pharmaceutical compositions. Compounds that inhibit chemokine activity or function can be used for the treatment of diseases that are associated with inflammation, including but not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity of lung diseases, hypersensitivity pneumonitis. , eosinophilic pneumonias, delayed-type hypersensitivity, interstitial lung disease (ILD) (eg, idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosis, ankylosing spondylitis, sysdemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies, insect picket allergies, autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythomatosis, myasthenia gravis, beginning of jubenil diabetes, glomerulonephritis, autoimmune troiditis, Alopecia Areata, Spondylitis Ankylosing, Antiphospholipid Syndrome, Autoimmune Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Behcet's Disease, Pemphigoid Bullous, Cardiomyopathy, Celia Sprue Cermatitis, Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic Inflammatory Demyelinating Polyneuropathy, Scar Pemphigoid , CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease, Discoid Lupus, Essential Mixed Cryoglobulinemia, Fibromyalgia-Fibromyalgia, Graves' Disease, Guillain-Barré, Hashimoto's Thyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura, IgA Nephropathy, Insulin Dependent Diabetes, Juvenile Arthritis, Lichen Planus, Lupus, Ménière's Disease, Mixed Connective Tissue Disease, Multiple Sclerosis, Grave Myasthenia, Pangigus Vulgaris, Pernicious Anemia, Nodosa Polyarteritis, Polychondritis, Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjögren Syndrome, Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis / Giant Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo, Wegener's Granulomatosis, Churg-Strauss Syndrome, Atopic Allergy, Autoimmune Atrophic Gastritis , Autoimmune Aclorhydra, Cush Syndrome Ings, Dermatomyositis, Erythematosis, Goodpasture Syndrome, Idiopathic Adrenal Atrophy, Lambert-Eaton Syndrome, Hepatitis Lupode, Lymphopenia, Phacogenic Uveitis, Primary Sclerosis Cholangitis, Schmídt Syndrome, Sympathetic Ophthalmia, Systemic Lupus Erythematosis, Thyrotoxicosis, Insulin Resistance Type B, autoimmune ureitis, co-morbidity or autoimmune orchitis, Determatitis herpetiformis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis), and inflammatory dermatosis such as determatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous and hypersensitivity vasculitis); Eosinophilic myotis, eosinophilic fsciitis; and cancers. In addition, compounds that activate or promote chemokine receptor function can be used for the treatment of diseases that are associated with immunosuppression such as individuals undergoing chemotherapy, radiation therapy, improved wound healing and treatment taking, therapy for autoimmune disease or another drug therapy (e.g., corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft / transplant rejection, which causes immunosuppression; immunosuppression due to congenital deficiency in receptor function or other causes; and infectious diseases, such as parasitic diseases, including but not limited to helminth infections, such as nematodes (roundworms); Trichuriasis, enterobiasis, Ascariasis, Hookworm, Stronguloidiasis, Trichinosis, filariasis; trematodes; visceral worms, visceral larva migrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp, Phocanema ssp.), cutaneous larval migrans (Ancylostona brisilena, Ancuylostoma canina); the protozoa that cause Plasmodium vivax malar, Human cytomegalovirus, Saimiri Herpesvirus, and Kaposi's sarcoma herpesvirus, also known as human herpesvirus 8, and Mollusc poxyirus contagious. In certain embodiments, the present invention provides any compound of the invention for use in the manufacture of a medicament. In further embodiments, the present invention provides any compound of the invention for use in the manufacture of a medicament for the treatment or prevention of any condition identified herein. For example, the present invention provides any compound of the invention for use in the manufacture of a medicament for the treatment and / or prevention of oxidative, ischemic, and ischemia / reperfusion related, and chemokine-mediated conditions in mammals including humans. These conditions are described in detail herein. The compounds of the present invention can be used in combination with any other active agents or pharmaceutical compositions wherein said combination therapy is useful for modulating chemokine receptor activity and thus preventing and treating inflammatory and immune regulatory diseases. Injection dose levels vary from 0.1 mg / kg / hour or at least 15 mg / kg / hour, everything from around 1 to around 120 hours and especially 24 to 96 hours. A pre-loading bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 25 g / day for a human patient of 40 to 80 kg. The present invention provides doses of about 0.1 mg to about 25 g per day for an 80 kg human patient. In particular embodiments, the present invention provides doses of from about 0.1 mg to about 20 g per day, from about 0.1 mg to about 10 g per day, from about 0.1 mg to about 5 g per day, from about 0.1 mg to about 1 g per day, and from about 0.1 mg to about 05. G per day. Preferred doses for ischemic conditions include from about 0.1 mg to about 10 g per day, from about 50 mg to about 10 g per day, from about 100 mg to about 10 g per day, and from about 100 mg to about 1 g per day. Preferred doses for chemokine-mediated disorders include from about 0.1 mg to about 10 g per day, from about 10 mg to about 1000 mg per day, and from about 100 mg to about 1000 mg per day. For the prevention and / or treatment of prolonged term conditions, such as neurodegenerative and autoimmune conditions, the regimen for treatment usually lasts for many months or years so that oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 65 mg / kg of aryl nitrone, with preferred doses each providing from about 0.1 to about 20 mg / kg, about 0.1 to about 10. mg / kg and especially around 1 to about 5 mg / kg. Transdermal doses are generally selected to provide blood levels similar or lower than those achieved using injection doses. When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the aryl nitrones of this invention will be administered to a patient at risk of developing the condition, typically with the warning and under the supervision of a physician, at the levels of dosage described above. Patients at risk for developing a particular condition generally include those who have a family history of the condition, or those who have been identified by screening or genetic screening that is particularly susceptible to developing the condition. The compounds of this invention can be administered as the sole active agent or can be administered in combination with other agents, including other active aryl nitrones. 5.8 Methods for Making Aryl Nitrones The aryl nitrones of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that when typical or preferred process conditions (ie, reaction temperatures, times, reactant molar ratios, solvents, pressures, etc.) are provided, other process conditions may also be used unless it manifests itself another way. The optimum reaction conditions may vary with the particular reagents or solvent used, but such conditions can be determined by a person skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protection groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. The selection of an appropriate protecting group for a particular functional group as well as appropriate conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein. The aryl nitrones of the invention can be prepared, for example, by reaction of an appropriately substituted carboxaldehyde derivative with an appropriately substituted hydroxylamine and the product isolated and purified by known conventional procedures. These methods include, but are not limited to, recrystallization, column chromatography and HPLC. Useful starting materials can either be obtained from commercial sources or prepared from conventional synthetic protocols reported in the literature. For example, 2-formylphenyl sulfones can be prepared by initiating with appropriately substituted 2-halo aromatic aldehyde by substitution of the halogen with a sodium sulfide, followed by alkylation of the resulting thiol to provide the intermediate thioethers. The controlled oxidation of thioethers can provide the desired sulfones.

Alternatively, the sulfones are accessible starting from substituted 2-halo aromatic aldehydes by nucleophilic substitution by appropriately substituted sodium thiolate followed by oxidation The 2-formyl carboxamides can be prepared by initiating with appropriately substituted 2-formyl carboxylic acids by activation of the acid group with either thionyl chloride or POCL3 followed by reaction with appropriately substituted amine.

The reaction of an aromatic aldehyde derivative with a substituted hydroxylamine in an organic solvent such as methanol, dichloromethane, benzene, toluene or tetrahydrofuran can be used to produce an aromatic nitrone derivative, such as an aryl nitrone of the invention. The reaction can proceed with heating (reflux) and can proceed with or without an organic or inorganic acid as a catalyst. The condensation reaction can also be achieved using microwave-mediated synthesis, and typically employs conditions such as heating at 160 ° C for 5 minutes in a sealed tube.

The aryl nitrones of the formula (2.1) can also be prepared by well documented alternative methods such as oxidation of amines, imines, hydroxylamines and N-alkylation of oximes as is known to those of experience in the art and illustrated in the schemes continuation.

In addition, 2-formylsulfonamides may be prepared starting from appropriately substituted 2-formylsulfonic acids by activation of the sulfonic acid group with either thionyl chloride or P0CL3 followed by reaction with appropriately substituted amine.

The reaction of an aromatic aldehyde derivative with a substituted hydroxylamine in an organic solvent such as methanol, dichloromethane, benzene, toluene or tetrahydrofuran can be used to produce an aromatic nitrone derivative, such as an aryl nitrone of the invention. The reaction may proceed with heating (reflux), and may proceed with or without an organic or inorganic acid as a catalyst. The condensation reaction can also be achieved using microwave-mediated synthesis, and typically employs conditions such as heating at 160 degrees for 5 minutes in a sealed tube.

The aryl nitrones of the formula (3.1) can also be prepared by well documented alternative methods such as oxidation of amines, imines, hydroxylamine and N-alkylation of amines as is known to those skilled in the art and illustrated in the example schemes down.

In addition, 4-formylsulfonamides can be prepared from appropriately substituted 4-formulphonyl chloride and reacted with appropriately substituted amines.

The 4-formylphenylsulfones can be prepared by initiating 4-halo aromatic aldehydes appropriately substituted by substitution of the halogen by sodium sulfide followed by alkylation of the resulting thiol to provide the intermediate thioether. The controlled oxidation of the thioethers provides the desired sulfones.

Alternatively, starting sulfones of 4-halo substituted aromatic aldehydes can be prepared by nucleophilic substitution by appropriately substituted sodium thiolates followed by oxidation --r XA ' The 4-formyl carboxamides can be prepared by initiating appropriately substituted carboxylic acids of 4-formyl by activation of the acid group with either thionyl chloride or POC13 followed by reaction with appropriately substituted amine.

The reaction of an aromatic aldehyde derivative with a substituted hydroxylamine in an organic solvent such as methanol, dichloromethane, benzene, toluene or tetrahydrofuran can be used to produce an aromatic nitrone derivative, such as an aryl nitrona of the invention. The reaction may proceed with heating (reflux), and may proceed with or without an organic or inorganic acid as a catalyst. The condensation reaction can also be achieved using microwave-mediated synthesis, and typically employs conditions such as heating at 160 degrees for 5 minutes in a sealed tube.

The aryl nitrones of the formula (4.1) can also be prepared by well-documented alternative methods such as oxidation of amines, imines, hydroxylamines and N-alkylation of oximes as are known to those skilled in the art and illustrated in the aba or .

The following synthetic and biological examples are offered to illustrate this invention and should not be construed in any way as limiting the scope of this invention. 6. EMPLOYMENTS In the examples below, all temperatures are in degrees Celsius unless otherwise indicated. way. Examples 1-8 describe the synthesis of various aryl, heteroaromatic and bicyclic aryl nitrones of this invention that have been or could be carried out.

The graphic illustrations of all the nitrone compounds illustrated herein are not intended to indicate the (E) - or (Z) -real stereochemistry of the double bond C = N of the nitrone group. The present invention provides each stereoisomer of the compounds below. The NMR spectra are recorded at 400 Mhz on a JEOL ECS-400 spectrometer using either deuterated chloroform or DMSO as a solvent and using TMS as an internal standard. Chemical shift values are quoted in parts per million (ppm) and coupling constants (J) in hertz (Hz). The FID was transferred to a PC and processed using NMR processing software NUTSÍR) of Acorn NMR, Inc. 6.1 Example 1: N- (tert-butyl) -C- [2- (methoxy-carbonyl) phenyl] nitrone ( 1) A mixture of commercially available 2-formylbenzoic acid methyl ester (100 mg, 0.61 mmol) and N- (tert-butyl) hydroxylamine hydrochloride (109 mg, 0.732 mmol) in methanol (5 mL) was stirred at room temperature for 24 hours. h. The mixture was then concentrated in vacuo and the crude product was dissolved in ethyl acetate (15 ml) and extracted with water (2 x 20 ml). After the combined organic layers were dried over Na2SO4 and concentrated in vacuo, chromatography on silica gel yielded compound 1 (10 mg, 20%). MS: m / 2 236 (MH +). Following the procedure described in the Example 1, or with slight modifications thereof, and procedures familiar to one of ordinary skill in the art, the compounds of Examples 2-15 were prepared by condensation of appropriate aromatic aldehydes with appropriate hydroxylamines or salts thereof. 6.2: N-Cyclohexyl-C- [2- (methoxy-trbonyl) phenyl] nitrona (2) Compound 2 was prepared according to the procedure described in Example 1, starting with N-cyclohexylhydroxylamine hydrochloride and methyl. -2-formylbenzoate. MS: m / 2 262 (MH +). 6.3 Example 3: N-Benzyl-C- [2-methoxycarbonyl) -phenyl] nitrona (3) Compound 3 was prepared according to the procedures described in Example 1, starting with N-benzylhydroxylamine hydrochloride and methyl 2-formylbenzoate. MS: m / s 270 (MH +) - 6.4 Example 4: N- (tert-butyl) -C- [2-methoxy-carbonyl) -3,5-dimethoxyphenyl] -nitrona (4) Compound 4 was prepared according to the procedure described in Example 1, starting with N- (tert-butyl) hydroxylamine hydrochloride and methyl 2-formyl-4,6-dimethoxybenzoate. MS: m / z 296 (MH +) 6.5 Example 5: N-cyclohexyl-C- [2-methoxy-carbonyl) -3,5-dimethoxyphenyl] -nitrona (5) Compound 5 was prepared according to the procedure described in Example 1, starting with N-cyclohexylhydroxylamine hydrochloride and methyl 2-formyl-4,6-dimethoxybenzoate. MS: m / z 322 (MH +). 6.6 Example 6: N-benzyl-C- [2 (methoxycarbonyl) -3,5-dimethoxyphenyl] -nitrona (6) Compound 6 was prepared according to the procedure described in Example 1, starting with N-benzylhydroxylamine hydrochloride and methyl 2-formyl-4,6-dimethoxybenzoate. MS: m / z 330 (MH +). 6.7 Example 7: N- (/ tert-butyl) -C- (2-carboxy-phenyl) nitrone (7) Compound 7 was prepared according to the procedure described in Example 1, starting with N- (tert-butyl) hydroxylamine hydrochloride and 2-formylbernzoic acid. MS: m / z 222 (MH +). 6. 8 Example 8: N-Cyclohexyl-C- (2-carboxyphenyl) -nitrona (8) Compound 8 was prepared according to the procedure described in Example 1, starting with N-cyclohexylhydroxylamine hydrochloride and 1-formylbenzoic acid. MS: m / z 248 (MH +). 6.9 Example 9: N-Benzyl-C- (2-carboxyphenyl) -nitrona (9) Compound 9 was prepared according to the procedure described in Example 1, starting with N-benzylhydroxylamine hydrochloride and 2-formylbenzoic acid. MS: m / z 256 (MH +). 6.10 Example 10: N- (tert-butyl) -C- (2-carboxy-3,5-dimethoxyphenyl) nitrone (10) Compound 10 was prepared according to the procedure described in Example 1, starting with N- (tert-butyl) hydroxylamine hydrochloride and 2-formyl-4,6-dimethoxybenzoic acid. MS: m / z 282 (MH +). 6.11 Example 11: N-cyclohexyl-C- (2-carboxy-3,5-dimethoxyphenyl) nitrone (11) Compound 11 was prepared according to the procedure described in Example 1, starting with N-cyclohexylhydroxylamine hydrochloride and 2-formyl-4,6-dimethoxybenzoic acid. MS: m / z 308 (MH +). 6.12. N-benzyl-C- (2-carboxy-3,5-dimethoxyphenyl) -nitrona (12) Component 12 was prepared according to the procedure described in Example 1, starting with N-benzylhydroxylamine hydrochloride and 2-formyl-4,6-dimethoxybenzoic acid. MS: m / z 316 (MH +). 6.13 Example 13: N-tert-butyl-C- (4-carboxy-phenyl) nitrone (13) Compound 13 was prepared according to the procedure described in Example 1, starting with N-tert-butylhydroxylamine hydrochloride and 4-formylbenzoic acid. MS: m / z 222 (MH +). 6.14 Example 14: N-tert-butyl-C- (2-carboxy-phenyl) nitrone (14) Compound 14 was prepared according to the procedure described in Example 1, starting with N-tert-butylhydroxylamine hydrochloride and 2-formylbenzoic acid, MS: m / z 222 (MH +). 6. Example 15: N-tert-butyl-C (2-carboxy-3,5-dimethoxyphenyl) nitrone (15) Compound 15 was prepared according to the procedure described in Example 1, starting with N-tert-butylhydroxylamino hydrochloride and 6-formyl-2,3-dimethoxybenzoic acid. MS: m / z 282 (MH +). 6.16 Example 16: N- (tert-butyl) -C- [2- (N, N-dimethylcarbamoyl) phenyl] nitrone (16) (a) 2-formyl-N, N-dimethylbenzamide To a suspension of 2-carboxybenzaldehyde (500 mg, 3.33 mmol) in CH 2 CH 2 (25 ml) was added thionyl chloride (1.98 g, 16.65 mmol) and the mixture was subjected to reflux for 1 h. The resulting solution was then concentrated in vacuo, dissolved in THF, and treated with N, N-dimethylamine (3.9 ml of a 1 m solution in THF, 180 mg, 4.0 mmol) at ice cold temperature. The mixture was slowly warmed to room temperature and stirred at room temperature for 2 h. The mixture was then concentrated in vacuo and the crude product was subjected to flash chromatography on silica gel to provide 2-formyl-N, N-dimethylbenzamide (100 mg, 15%). MS: m / z 178 (MH +). (b) N- (tert-butyl) -C- [2- (N, N-dimethylcarbamoyl) phenyl] nitrone (16) Compound 16 was prepared by condensing 2-formyl-N, N-dimethylbenzamide with N- hydrochloride. tert-butyl) -hydroxylamine in accordance with the procedure described in Example 1. MS: m / z 249 (MH +). 6.18 Example 18: N- (tert-butyl) -C- [4-tert-butylcarbamoyl) phenyl] nitrone (18) Compound 18 was prepared according to the procedure described in Example 16, starting with N-tert-butylhydroxylamine hydrochloride and 4-formylbenzoic acid. MS: m / z 277 (MH +). 6.19 Example 19: N- (tert-butyl) -C- [4-amino-carbamoyl) phenyl] nitrona (19) Compound 19 was prepared according to the procedure described in Example 16, starting with N-tert-butylhydroxylamine hydrochloride and 4-formylbenzoic acid. MS: m / z 221 (MH +). 6.20 Example 20: N- (tert-Butyl) -C- [4- (sulfanoyl) phenyl] nitrona (20) A suspension of sodium salt of 4-formylbenzenesulfonic acid (1.Og, 4.78 mM) in excess of thionyl chloride (15 ml) was heated to reflux for 30 minutes. The mixture was then concentrated to dryness, was dissolved in anhydrous THF (20 ml). The mixture was cooled (ice bath) to which excess ammonia (5 mL, l.OM solution in THF) was added and the suspension was stirred for 3 hours at room temperature. The reaction was cooled rapidly with ice cold water where the amide was precipitated out. It was filtered, washed with water and dried under vacuum overnight. No efforts were made to purify the amide and it was used as such in the subsequent reaction. The crude amide was dissolved in methanol (10 ml) and subjected to condensation with n-tert-butylhydroxylamine hydrochloride (0.72 g, 5.74 mM) and reflux temperature for 6 hours. Concentration of the mixture followed by silica gel column chromatography afforded the title compound as a white solid. MS: m / z 257 (MH +). X? NMR d 1.5 (s, 9H); 7.39 (brs, 2H); K 7.83 (d, J = 8.8Hz, 2H); 7.99 (s, 1H); 8.49 (d, J = 8.i8Hz, 2H). Following the procedure described in the Example , or with slight modifications thereof, and procedures familiar to one of ordinary skill in the art, the compounds of Examples 21-61 were prepared by condensation of appropriate aromatic aldehydes with appropriate hydroxylamines or salts thereof. 6.21 Example 21: N- (tert-butyl) -C- [4- (3-methoxy-phenylsulfamoyl) phenyl] itrona (21) The title compound was prepared according to the procedure described in Example 20, starting with N-tert-butylhydroxylamine hydrochloride and 4- (3-methoxy-phenylsulfamoyl) enzaldehyde. MS: m / z 363 (MH +). 6.22 Example 22: N- (tert-butyl) -C- [4- (4-methyl-piperazin-1-sulfonyl) phenyl] nitrona (22) The title compound was prepared according to the procedure described in Example 20, starting with N-tert-butylhydroxylamine hydrochloride and 4- (4-methyl-piperazin-1-sulfonyl) benzaldehyde. MS: m / z 340 (MH +). 6.23 Example 23: N- (tert-butyl) -C- [4-morpholino-4-sulfonyl) phenyl] nitrona a) 4- (Morpholino-4-sulfonyl) -benzaldehyde: Morpholine (8.94 g, 102.62 mM, 2.1 eq.), dripped slowly in a cooled solution (0 ° C) of 4-formylbenzenesulfonyl chloride (10.0 g, 48.87 mM; 1.0 eq.), and the mixture was slowly heated to room temperature. TLC indicated complete disappearance of the starting sulfonyl chloride. The mixture was then poured into ice-cold water, the solid was filtered, washed with water and dried under vacuum to obtain the title sulfonamide as a white solid (11.5 g, 92%). Purity read 98% by LC / MS. b) N- (tert-butyl) -C- [4- (morpholino-4-sulfonyl) -phenyl] itrona (23) A mixture of 4- (morpholino-4-sulfonyl) -benzaldehyde (11.5 g, 45.05 mM; 1.0 eq.), And tert-butylhydroxylamine acetate (8.07 g, 54.06 mM, 1.2 eq.), In methanol was refluxed for several hours (supervised by TLC for the disappearance of the starting aldehyde). The mixture was then concentrated, dissolved in EtOAc, washed with water (to remove hydroxylamine acetate), dried and concentrated. The crude product was crystallized from EtOAc / hexane to obtain the title nitrona (11.0 g, 75%) as a white solid. MS: m / z 327 (MH-A). XE NMR d 1.52 (s, 9H); 2.86 (t, J = 4.6Hz, 4H); 3.62 (t, J = 4.6 Hz, 4H); 7.76 (d, J = 8.8 Hz, 2H); 8.08 (s, 1H); 8.59 (d, J = 8Hz, 2H). 6.24 Example 24: N- (tert-butyl) -C- [4-ethylsulfamoyl) phenyl] nitrone (24) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 4- (ethylsulphonyl) benzaldehyde MS: m / z 285 (MH +). 6.25 Example 25: N- (tert-butyl) -C- [4-4-fluoro-phenylsulfamoyl) phenyl] nitrone (25) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 4- (4-fluoro-phenylsulfamoyl) benzaldehyde MS: m / z 351 (MH +) 6.26 Example 26: N- (tert-butyl) -C. [4- (pyridin-3-ylsulfamoyl) phenyl] nitrona (26) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 4- (pyridin-3-ylsulfamoyl) enzaldehyde MS: m / z 334 (MH +). 6.27 Example 27: N- (tert-butyl) -C. [4-morpholine-4-sulfonyl) phenyl] nitrona (27) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 2- (morpholin-4-sulfonyl) benzaldehyde MS: m / z 327 (MH +). 6.28 Example 28: N- (tert-butyl) -C- [4-piperidin-1-sulfonyl) phenylInitrona (28) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 4- (piperidin-1-sulfonyl) benzaldehyde MS: m / z 325 (MH +). 6.29 Example 29: N- (tert-butyl) -C- [4-pyrrolidin-1-sulfonyl) phenyl] nitrona (29) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 4- (pyrrolidin-1-sulfonyl) enzaldehyde MS: m / z 311 (MH +). 6.30 Example 30: N-tert-butyl-C- (2-diethylsulfa-moylphenyl) nitrone (30) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 2- (diethylsulfamoyl) benzaldehyde MS: m / z 313 (MH +). 6.31 Example 31: N-cyclohexyl-C- (2-diethylsulfamoylphenyl) nitrone (31) The title compound was prepared according to the procedure described in Example 23, starting with N-cyclohexylhydroxylamine hydrochloride and 2- (diethylsulfamoyl) benzaldehyde MS: m / z 339 (MH +). Example 32: N-Benzyl-C- (2-diethylsulfamoylphenyl) -nitrona (32) The title compound was prepared according to the procedure described in Example 23, starting with N-benzylhydroxylamine hydrochloride and 2- (diethylsulfa-olyl) benzaldehyde MS: m / z 347 (MH +) 6.33 Example 33: N-ter butyl-C- [2-piperidin-l-sulfonyl) phenyl] nitrona (33) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 2- (piperidin-1-sulfonyl) enzaldehyde MS: m / z 325 (MH +) 6.34 Example 34: N-cyclohexyl-C- [2-piperidin-1-sulfonyl) phenyl] nitrone (34) The title compound was prepared according to the procedure described in Example 23, starting with N-cyclohexylhydroxylamine hydrochloride and 2- (piperidin-1-sulfonyl) benzaldehyde MS: m / z 351 (MH +). 6.35 Example 35: N-benzyl-C- [2-piperidin-1-sulfonyl) phenyl] nitrona (35) The title compound was prepared according to the procedure described in Example 23, starting with N-benzylhydroxylamine hydrochloride and 2- (piperidin-1-sulfonyl) enzaldehyde MS: m / z 359 (MH +). 6.36 Example 36: N-cyclohexyl-C- [2-morpholin-4-sulfonyl)) phenyl] nitrona (36) The title compound was prepared according to the procedure described in Example 23, starting with N-cyclohexylhydroxylamine hydrochloride and 2- (morpholine-4-sulfonyl) enzaldehyde MS: m / z 353 (MH +). 6.37 Example 37: N-benzyl-C- [2 (morpholin-4-sulfonyl)) phenyl] nitrona (37) The title compound was prepared according to the procedure described in Example 23, starting from N-benzylhydroxylamine hydrochloride and 2- (morpholin-4-sulfonyl) benzaldehyde MS: m / z 361 (MH +). 6.38 Example 38: N-tert-butyl-C- [2- (4-methyl-piperazin-1-sulfonyl) phenyl] nitrona (38) The title compound was prepared according to the procedure described in Example 23, starting from N-tert-butylhydroxylamine hydrochloride and 2- (4-methyl-piperazine-1-sulfonyl) benzaldehyde MS: m / z 340 (MH +). XI NMR d 1.51 (2, 9H); 2.13 (3, 3H); 2.32 (t, J = 4.7Hz, 4H); 2.94 (t, J = 4.7Hz, 4H); 7.63 (dt, J = 7.7Hz, 1.4Hz, 1H); 7. 76 (dt, J = 7.7Hz, 1.0Hz, 1H); 8.20 (dd, J = 7.9Hz, 1.4Hz, 1H); 8. 46 (s, 1H); 9.16 (dd, J = 7.9Hz, 1.0Hz, 1H). 6.39 Example 39: N-cyclohexyl-C- [2- (4-methyl-piperazin-1-sulfonyl) phenyl] nitrona (39) The title compound was prepared according to the procedure described in Example 23, starting from N-cyclohexylhydroxylamine hydrochloride and 2- (4-methyl-piperazin-1-sulfonyl) benzaldehyde MS: m / z 366 MH +). 6. Example 40: N-benzyl-C- [2- (4-methyl-piperazin-1-sulfonyl) phenyl] nitrona (40) The title compound was prepared in accordance with the procedure described in Example 23, starting with N-benzylhydroxylamine hydrochloride and 2- (4-methyl-piperazin-1-sulfonyl) benzaldehyde MS: m / z 374 (MH +). XH NMR d 1.23 (s.9H); 3.12 (s, 3H); 7.10-7.14 (m, 2H); 7.29-7.40 (m, 3H); 7.61 (dt; J = 7.8Hz, 1.4Hz, 1H); 7.75 (dt, 10 J = 7.8Hz, 1.4Hz, 1H); 7 -.91 (dd, J = 8.1Hz, 1.4Hz, 1H); 9.39 (dd, J = 8.1Hz, 1H). 6.41 Example 41: N-tert-butyl-C- [4- (2-methyl-phenyl-sulfamoyl) phenyl] nitrone (41) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 2- (2-methyl-phenyl-sulfamoyl) benzaldehyde MS: m / z 347 (MH +). 6.42 Example 42: N-cyclohexyl-C- [4- (2-methyl-phenyl-sulfamoyl) phenyl] nitrona (42) The title compound was prepared according to the procedure described in Example 23, starting with N-cyclohexylhydroxylamine hydrochloride and 2- (2-methyl-phenyl-sulfamoyl) benzaldehyde MS: m / z 373 (MH +). 6.43 Example 43: N-benzyl-C- [4- (2-methyl-phenyl-sulfamoyl) phenyl] nitrona (43) The title compound was prepared according to the procedure described in Example 23, starting with N-benzylhydroxylamine hydrochloride and 2- (2-methyl-phenyl-sulfamoyl) enzaldehyde MS: m / z 381 (MH +) 6.44 Example 44: N-tert-butyl-C- [2- (3,4-dihydro-2 H -quinolin-l-sulfonyl) phenyl] nitrone (44) The title compound was prepared according to the procedure described in Example 23, starting with N-benzylhydroxylamine hydrochloride and 2- (3,4-dihydro-2H-quinolin-1-sulfonyl) benzaldehyde MS: m / z 373 ( MH +). 6.45 Example 45: N-cyclohexyl-C- [2- (3, 4-dihydro-2H-quinolin-1-sulfonyl) phenyl] nitrone (45) The title compound was prepared according to the procedure described in Example 23, starting with N-cyclohexylhydroxylamine hydrochloride and 2- (3,4-dihydro-2H-quinolin-1-sulfonyl) benzaldehyde MS: m / z 399 ( MH +). 6.46 Example 46: N-benzyl-C- [2- (3, 4-dihydro-2H-quinolin-1-sulfonyl) phenyl] nitrona (46) The title compound was prepared according to the procedure described in Example 23, starting with N-benzylhydroxylamine hydrochloride and 2- (3,4-dihydro-2H-quinolin-1-sulfonyl) benzaldehyde MS: m / z 407 ( MH +). 6.47 Example 47: N-tert-butyl-C- (2-methyl-sulfamoyl-phenyl) nitrone (47) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 2- (2-methyl-sulfamoyl) benzaldehyde MS: m / z 271 (MH +). 6.48 Example 48: N-tert-butyl-C- (2-tert-butyl-sulfamoyl-phenyl) nitrone (48) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 2- (2-tert-butylsulfamoyl) enzaldehyde MS: m / z 313 (MH +). 6.49 Example 49: N-tert-butyl-C- (2-benzyl-sulfamoyl-phenyl) -nitrone (49) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 2- (2-benzyl-sulfamoyl) benzaldehyde MS: m / z 347 (MH +). 6.50 Example 50: N-tert-butyl-C- (4-diethylsulfamoylphenyl) nitrone (50) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-hydroxyhydroxylamine hydrochloride and 4- (diethylsulfamoyl) enzaldehyde MS: m / z 313 (MH +). 6.51 Example 51: N-Isopropyl-C- (4-diethyl-sulfamoylphenyl) nitrone (51) The title compound was prepared according to the procedure described in Example 23, starting with N-isopropylhydroxylamine hydrochloride and 4- (diethylsulfamoyl) benzaldehyde MS: m / z 299 (MH +). 6.52 Example 52: N-cyclohexyl-C- (4-diethyl-sulfamoylphenyl) nitrone (52) The title compound was prepared according to the procedure described in Example 23, starting with N-cyclohexylhydroxylamine hydrochloride and 4- (diethylsulfamoyl) enzaldehyde MS: m / z 339 (MH +). 6.53 Example 53: N-benzyl-C- (4-diethylsulfamoyl-phenyl) nitrone (53) The title compound was prepared according to the procedure described in Example 23, starting from N-benzylhydroxylamine hydrochloride and 4- (diethylsulfamoyl) benzaldehyde MS: m / z 347 (MH +). 6.54 Example 54: N-tert-butyl-C- [4- (methyl-phenyl-sulfamoyl) phenyl] itrona (54) The title compound was prepared according to the procedure described in Example 23, starting with N-hydrochloride. -tert-butylhydroxylamine and 4- (methyl-phenyl-sulfamoyl) benzaldehyde MS: m / z 347 (MH +). 1 H NMR d 1.51 (s, 9H); 3.14 (s, 3H); 7.06-7.12 (, 2H); 7.26-7.36 (m, 3H); 7.51 (d, J = 8.8Hz, 2H); 8.03 (s, 1H); 8.49 (d, J = 8Hz, 2H). 6.55 Example 55: N-isopropyl-C- [4-methyl-phenyl-sulfamoyl) phenyl) nitrona (55) The title compound was prepared according to the procedure described in Example 23, starting with N-isopropylhydroxylamine hydrochloride and 4- (methyl-phenyl-sulfamoyl) benzaldehyde MS: m / z 333 (MH +). 6.56 Example 56: N-cyclohexyl-C- [4- (methyl-phenyl-sulfamoyl) phenyl] nitrona (56) The title compound was prepared according to the procedure described in Example 23, starting with N-cyclohexylhydroxylamine hydrochloride and 4- (methyl-phenyl-sulfamoyl) benzaldehyde MS: m / z 373 (MH +). 6.57 Example 57: N-benzyl-C- [4-methyl-phenyl-sulfamoyl) phenyl] nitrona (57) The title compound was prepared according to the procedure described in Example 23, starting from N-benzylhydroxylamine hydrochloride and 4- (methyl-phenyl-sulfamoyl) benzaldehyde MS: m / z 381 (MH +). 6.58 Example 58: N- (tert-btul-C- [4-tert-butyl-sulfamoyl) phenyl] nitrone (58) The title compound was prepared according to the procedure described in Example 23, starting with N-tert-butylhydroxylamine hydrochloride and 4- (tert-butyl-sulfamoyl) benzaldehyde MS: m / z 313 (MH +). XI NMR d 1.08 (s, 9H); 1.56 (s, 9H); 7.56 (s, 1H); 7.83 (d, J = 8.8Hz, 2H); 8.0 (s, 1H); 8.49 (d, J = 8.8Hz, 2H). 6.59 Example 59: N-isopropyl-C- [4-tert-butyl-sulfa oil) phenyl] nitrona (59) The title compound was prepared according to the procedure described in Example 23, starting from N-isopropylhydroxylamine hydrochloride and 4- (tert-butyl-sulfamoyl) benzaldehyde MS: m / z 299 (MH +). 6.60 Example 60: N-cyclohexyl-C- [4-tert-butyl-sulfamoyl) phenyl] nitrone (60) The title compound was prepared according to the procedure described in Example 23, starting with N-cyclohexylhydroxylamine hydrochloride and 4- (tert-butyl-sulfamoyl) benzaldehyde MS: m / z 339 (MH +), 6.61 Example 61: N -benzyl-C- [4-tert-butyl-sulfamoyl) phenyl] itrona (61) The title compound was prepared according to the procedure described in Example 23, starting with N-benzylhydroxylamine hydrochloride and 4- (tert-butyl-sulfamoyl) benzaldehyde. MS: m / z 347 (MH +). 6.62 Example 62: N-tert-Butyl-C- [4-methanesulfonyl) phenyl] nitrona (62) a) N-tert-butyl-C- [4- (methanesulfanyl) phenyl] -nitrona A mixture of 4-methylsulfanyl benzaldehyde (47.0 g, 0.315 M) and tert-butylhydroxylamine acetate (40.0 g, 0.263 M) in methanol ( 300 ml) was refluxed overnight. After all of the starting aldehyde has disappeared (monitored by TLC), the mixture was concentrated to dryness. The crude product was dissolved in EtOAc, washed with saturated NaHCO 3 solution followed by water, the organic layer was dried and concentrated to obtain the title product as an oil (51.0 g, 87%). The purity reading > 905% and was subjected to oxidation without further purification. b) N-tert-butyl-C- [4- (methanesulfonyl) phenyl] -nitrona (62) Oxone solution (160.0 g, 0.26 M in EDTA (4 x 10 -4 in 400 ml) of water) was added slowly for 15 minutes at 0 ° C to the suspension of the nitrone (51.0 g, 0.228 M) and NaHCO3 (110.0 g, 1.31 M) in a mixture of acetone (150 ml) and water (150 ml). The mixture was stirred at the same temperature for an additional 2 hours before being partitioned between EtOAc and water. The organic layer was separated, washed with water, dried and concentrated. The crude product was chromatographed on silica gel to obtain the title product (25.0 g, 43%) as a white solid. MS: m / z 256 (MH +). Xl NMR d 1.52 (s, 9H); 3.22 (s, 3H); 7.95 (d, J = 8.8Hz, 2H); 8.06 (s, 1H); 8.57 (d, J = 8.8Hz, 2H). Following the procedure described in Example 62, or with slight modifications thereof, and procedures familiar to one of ordinary skill in the art, the compounds of Examples 63-76 were prepared by condensation of appropriate aromatic aldehydes with appropriate idroxylamines or salts of the same. 6.63 Example 63: N-tert-butyl-C- (2,4-bis-methanesulfonylphenyl) nitrone (63) a) 2,4-bis-methylsulfanyl-benzaldehyde Sodium thiomethoxide (12 g, 171 mmol) was suspended in DMF (80 mL). To the mixture was added dropwise a solution of 2,4-diflorobenzaldehyde (8.9 mL, 82 mmol) in DMF at 0 ° C. The mixture was then stirred at room temperature for ~ 3 hours. The yellow crystals were precipitated from the solution while H20 was added. The crystals were collected by filtration and washed with H20 and dried in vacuo to obtain the title compound. (Yield: 13.9 g, yellow crystals). b) N-tert-butyl-C- (2,4-bis-methanesulfanylphenyl) -nitrona A mixture of 2,4-bis-methylsulfanyl benzaldehyde (18.0 q, 90.31 mM) and tert-butylhydroxylamine acetate (16.25 g), 108.92 mM) in methanol (200 ml) was refluxed overnight. After all the aldehyde match disappeared (monitored by TLC), the mixture was concentrated to dryness. The crude product was dissolved in EtOAc, washed with saturated NaHCO 3 solution followed by water, the organic layer was dried and concentrated and chromatographed on silica gel to obtain the title product (24.0 g) as an oil. c) N-tert-butyl-C- (2,4-bis-methanesulfonylphenyl) -nitrona (63) Oxone (149.0 g, 142 mM; 5.4 eq.), In EDTA (4 x 10"4 in 200 ml of water,) the solution was added slowly for 15 minutes at 0 ° C to a suspension of the above sulfanilitronate (12.07 g, 44.8 mM, 1.0 eq,) , Y NaHCO3 (90.3 g, 1.08 M, 22.5 eq.), In a mixture of acetone (100 ml) and water (100 ml). The mixture was stirred at the same temperature for an additional 2 hours before being partitioned between EtOAe and water. The organic layer was separated, washed with water, dried and concentrated. The crude product was crystallized from EtOAC / hexane to obtain the title sulfonyl product (10.0 g, 68%) as a white solid. MS: m / z 334 (MH +). XH NMR d 1.55 (s, 9H); 3.33 (s, 6H); 8.33 (dd, J = 8.5Hz, 1.8Hz, 1H); 8.45 (d, J = 1.8 Hz, 1H); 8.67 (s, 1H); 9.46 (d, J = 8.5 Hz, 1H). 6. 64 Example 64: N-tert-butyl-C- (2,4-bis-ethanesulfonylphenyl) nitrone (64) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 2-4- (bis-ethansulfanyl) benzaldehyde and subsequent oxidation with oxone. MS: m / z 362 (MH +). 6.65 Example 65: N-tert-butyl-C- (2, -bis-2-propanesulfonylphenyl) nitrone (65) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 2,4- (bis-2-propansulfanyl) benzaldehyde and subsequent oxidation with oxone. MS: m / z 390 (MH +). 6.66 Example 66: N-tert-butyl-C- (2-methanesulfonyl phenyl) nitrone (66) a) 2-Methansulfanyl benzaldehyde The title compound was prepared following the procedure described in Example 63a. b) N-tert-butyl-C- (2-methanesulfanylphenyl) nitrone The title compound was prepared following the procedure described in Example 63b. c) N-tert-butyl-C- (2-methanesulfonylphenyl) nitrone (66) Oxone (7.45 g, 12.1 mM, 2.7 eq.), in EDTA (4 x 10 -4 in 20 ml of water,) the solution added slowly for 15 minutes at 0 ° C to a suspension of the above sulfanyl nitrone (1.0 g, 4.48 M, 1.0 eq.), and NaHCO3 (3.01 g, 35.84 mM, 8.0 eq.), in a mixture of acetone (10 ml) and water (10 ml). The mixture was stirred at the same temperature for an additional 2 hours before being partitioned between EtOAc and water. The organic layer was separated, washed with water, dried and concentrated. The crude product was chromatographed on silica gel to obtain the title product (900 mg, 87%) as an oil that solidified during prolonged standing. MS: m / z 256 (MH +). 2 H NMR d 1.53 (s, 9 H); 3.28 (s, 3H); 7.66 (dt, J = 7.6Hz, 1.4Hz, 1H); 7.79 (dt, J = 7.6Hz, 1.4 Hz, 1H); 8.04 (dd, J = 8.0Hz, 1.4Hz, 1H); 8.67 (s, 1H); 9.23 (dd, J = 8.0Hz, 1.4Hz, 1H). 6.67 Example 67: N-tert-butyl-C- (4-ethanesulfonyl) nitrone (67) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 4- (ethansulfanyl) benzaldehyde and subsequent oxidation with oxone. MS: m / z 270 (MH +). XH NMR d 1.08 (t, J = 7.4Hz, 3H); 1.52 (s, 9H); 3.29 (q, J = 7.4Hz, 2H); 7.90 (d, J = 8.6Hz, 2H); 8.07 (s, 1H); 8.58 (d, J = 8.6Hz, 2H). 6.68 Example 68: N-tert-butyl-C- (2-ethanesulfonyl-phenyl) nitrone (68) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 2- (ethanesulfanyl) benzaldehyde and subsequent oxidation with oxone. MS: m / z 270 (MH +). XH NMR d 1.09 (t, J = 7.2Hz, 3H); 1.52 (s, 9H); 3.38 (q, J = 7.2Hz, 2H); 7.66 (dt, J = 7.8Hz, 1.4Hz, 1H); 7.80 (dt, J = 7.8Hz, 1.4Hz, 1H); 8.0 (dd, J = 7.8Hz, 1.4Hz, 1H); 8.58 (s, 1H); 9.25 (dd, J = 8.0Hz, 1.4Hz, 1H). 6.69 Example 69: N-tert-butyl-C [2- (2-propan-sulfonyl) phenyl] nitrona (69) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhiroxylamine hydrochloride with 2- (2-propansulfanyl) benzaldehyde and subsequent oxidation with oxone. MS: m / z 284 (MH +). XI NMR d 1.15 (d, J = 6.8Hz, 6H); 1.52 (s, 9H); 3.43 (quintet, J = 6.8Hz, 1H); 7.66 (dt, J = 7.8Hz, 1.4Hz, 1H), 7.81 (dt, J = 7.8Hz, 1.4Hz, 1H); 7.98 (dd, J = 7.8Hz, 1.4Hz, 1H); 8.59 (s, 1H); 9.26 (dd, J = 8.0Hz, 1.4Hz, 1H). 6.70 Example 70: N-tert-butyl-C- [4- (2-propan-sulfonyl) phenyl] nitrone (70) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 4- (2-propanesulfanyl) enzaldehyde and subsequent oxidation with oxone. MS: m / z 284 (MH +). XH NMR d 1.14 (d, 6.8Hz, 6H); 1.52 (s, 9H); 3.41 (quintet, 6.8Hz, 1H); 7.87 (d, 8.6Hz, 2H); 8.08 (s, 1H); 8.58 (d, J = 8.6Hz, 2H). 6.71 Example 71: N-tert-butyl-C- [4-cyclo? Entan-sulfonyl) phenyl] nitrone (71) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 4- (cyclopentanesulfanyl) benzaldehyde and subsequent oxidation with oxone. MS: m / z 310 (MH +). 6.72 Example 72: N-tert-butyl-C- [2-methanesulfonyl-4-trifluoromethylphenyl] nitrone (72) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 2-methanesulfanyl-4-trifluoromethylbenzaldehyde and subsequent oxidation with oxone. MS: m / z 324 (MH +). 1 H NMR d 1.55 (s, 9H); 3.40 (s, 3H); 8.16-8.26 (m, 2H); 8.64 (s, 1H); 9.43 (d, J = 8.4Hz, 1H). 6.73 Example 73: N-tert-butyl-C- (2-methanesulfonyl-pyridin-3-yl) nitrone (73) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 2-methanesulfanyl-pyridine-3-aldehyde and subsequent oxidation with oxone. MS: m / z 257 (MH +). XH NMR d 1.52 (s, 9H); 3.46 (s, 3H); 7.79 (dd, J = 8.2Hz, 4.6Hz, 1H); 8.65 (dd, J = 4.6Hz, 1.62Hz, 1H); 8.67 (s, 1H); 9.65 (dd, J = 8.2Hz, 1.6Hz, 1H). 6.74 Example 74: N-tert-butyl-C- (2-methanesulphonyl-quinolin-3-yl) nitrone (74) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 2-methanesulfanyl-quinolin-3-aldehyde and subsequent oxidation with oxone. MS: m / z 307 (MH +). XH NMR d 1.39 (s, 9H); 2.34 (s, 3H); 7.25-7.33 (m, 1H); 7.43 (d, J = 8.3Hz, 1H); 7.61-7.67 (, 1H); 7.91 (d, 7.8Hz, 1H); 8.8 (s, 1H); 9.80 (s, 1H), 6.75 Example 75: N-benzyl-C- (2-methanesulfonyl-pyridin-3-yl) nitrone (75) The title compound was prepared according to the procedure described in Example 63, by condensation of N-benzylhydroxylamine hydrochloride with 2-methanesulfanyl-pyridine-3-aldehyde and subsequent oxidation with oxone. MS: m / z 291 (MH +). 6.76 Example 76: N-cyclohexyl-C- (2-methansulfo-nyl-pyridin-3-yl) itrona (76) The title compound was prepared according to the procedure described in Example 63, by condensation of N-cyclohexylhydroxylamine hydrochloride with 2-methanesulfanyl-pyridine-3-aldehyde and subsequent oxidation with oxone. MS: m / z 283 (MH +). 6.77 Example 77: N- (tert-butyl-C- [2-methoxy-carbonyl) -lH-indol-3-yl] itrona (77) Compound 77 was prepared according to the procedure described in Example 1, starting with N- (tert-butyl) idroxylamine hydrochloride and 3-formyl-2- (methoxycarbonyl) indole. MS: m / z 275 (MH +). 6.78 Example 78: N-cyclohexyl-C- [2-methoxy-carbonyl) -lH-indol-3-yl] nitrona (78) Compound 78 was prepared according to the procedure described in Example 1, starting with N-cyclohexylhydroxylamine hydrochloride and 3-formyl-2- (methoxycarbonyl) indole. MS: m / z 301 (MH +). 6.79 Example 79: N-benzyl-C- [2- (methoxixarbonyl) -lH-indol-3-yl] nitrona (79) Compound 79 was prepared according to the procedure described in Example 1, starting with N-benzylhydroxylamine hydrochloride and 3-formyl-2- (methoxycarbonyl) indole. MS: m / z 309 (MH +). 6.80 Example .80: N-tert-butyl-C- (6-methanesulfonyl) -pyridin-3-yl) nitrone (80) The title compound was prepared according to the procedure described in Example 63, by condensation of N-tert-butylhydroxylamine hydrochloride with 6-methanesulfanyl-pyridine-3-aldehyde and subsequent oxidation with oxone. MS: m / z 257 (MH +). XH NMR d 1.54 (s, 9H); 3. 28 (s, 3H); 8.10 (d, J = 8.4Hz, 1H); 8.21 (s, 1H); 9.22 (dd, J = 8.4Hz, 1.8Hz, 1H); 9.42 (d, J = 1.8Hz, 1H). 6.82 Example 81: N-benzyl-C- (6-methansulfonyl-pyridin-3-yl) itrona (81) The title compound was prepared according to the procedure described in Example 63, by condensation of N-benzylhydroxylamine hydrochloride with 6-methanesulfanyl-pyridin-3-aldehyde and subsequent oxidation with oxone. MS: m / z 291 (MH +). 6.82 Example 82: Cleaning Test / Radical Antioxidant Free of Nitrona Compounds Nitrons are a chemical class of compounds that have antioxidant properties due to their ability to form stable adducts (ie, traps of revolution) with free radicals (See, e.g., Janzen, EG, et al., 1992, Stabilities of Hydroxyl Radical Spin Adducts of PBN-Type Spin Traps, Free Radical Biol. Med., 12 (2): 169-73). Because free radicals can cause oxidative damage to cellular constituents (eg, proteins and lipids), which can lead to pathological consequences, it has been reported that the antioxidant properties of nitrone compounds remain at least partially under their therapeutic potential. , as reported in studies using a canonical member of this chemical class, C- (phenyl) -N- (tert-butyl) nitrone (PBN) (See, e.g., JM Carney and RA Floyd, 1991, Protection against Oxidative Damage to CNS by alpha-phenyl-tert-butylnitrone (PBN) and Other Spin-Trapping Agents: a Novel Series of Nonlipid Free Radical Scavengers, J. Mol. Neurosci., 3 (1): 47-57, and Thomas , CE., Et al., 1994, Multiple Mechanisms for Inhibition of Low Density Lipoprotein Oxidation by Novel Cyclic Nitrone Spin Traps, J. Biol. Chem., 269 (45: 28055-61). that have improved antioxidant activity compared to PBN may have better therapeutic potential than PBN More generally, diseases and conditions that have been reported to be susceptible to antioxidant therapy or that involve the generation of free radicals may be susceptible to nitronate treatment based on the antioxidant activity of nitrones. Diseases or conditions that arise from or are characterized by oxidative damage or oxidant current include, but are not limited to neurodegenerative, autoimmune and inflammatory diseases or conditions. The nitrona compounds of the present invention were tested for their cleaning / antioxidant activity. of free radical in an in vitro assay that is accepted by those skilled in the art as a model for conditions involving the generation of free radicals. The assay is based on a reaction between a free radical donor, 2,2-diphenyl-1-picrylhydrazyl (DPPH), and a radical scavenger / antioxidant to be tested for free radical scavenging activity. After the donation of the free radical electron to the proposed radical cleanser, the visible peak absorption of DPPH (515-520 nm) decreases so that the optical density readings in this part of the visual spectrum reflect the progression of the following reaction: DPPH- + AH - > DPPH-H + A- Where AH is a hypothetical radical scavenger / antioxidant. The assay is based on an originally detailed protocol in Brand-Williams, W., et al., 1995, Use of a Free Radical Method to Evaluate Antioxidant Activity, Lebensm. Wiss. Technol., 28: 25-30, with additional modifications described in L.R. Fukamoto and G. Mazza, 2000, Assessing Antioxidant and Prooxidant Activities of Phenolic Compounds, J. Agrie. Food Chem,., 48: 3597-3604. The antioxidant assay was performed using black wall, Perkin-Elmer 96-well clear bottom plates, (ordered from E &K. Scientific Products) and a Tecan Safire absorbency plate reader. Positive controls were Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, Sigma-Aldrich), BHA monomethyl ether (2 (3) -ter-butylhydroquinone, Sigma Aldrich), PBN (C- (phenyl) -N- (tert-butyl) nitrone, Sigma-Aldrich) and S-PBN (Sodium salt of (C- (2-sulfophenyl) -N- (tert-butyl) nitrone, prepared in accordance with EG Janzen and RV Shetty, 1979, Tetrahedron Lett., 35: 3229-32), and negative control ( Briefly, 2 uL of 100X DMSO material of the desired final concentration of each control or nitrone compound to be tested in the same batch was added to a separate well. 198 uL of 50 uM DPPH recently made (Sigma-Aldrich in 80% methanol using a multichannel pipette.) Absorption was read immediately in the plate reader at 520 nm and subsequently read periodically to determine the kinetics until all reactions reached completion (ie, constant state.) Since the constant state point was 24 hours, the test results are shown from the time point of 24 h.The absorption at 520 nm (OD) was plotted against the concentrations of the controls and nitrona compounds to determine the dose response and interpolate the EC5o values of the controls and test compounds In this antioxidant assay, the example compounds of the invention exhibited EC5o values as shown in Table 1.

TABLE 1: DPPH Test Data Compound PM EC50 (um) roZo: < 2? 1 ' 3 2 7", Q S - • 55 2" 1C 231 1"11 10 / 3'-12 1 -. 2ri ? 32- 4t ? , 11 13 ; •; - < 4 o Z "0 43 380 .47 44 372 - 43 45 333.52 47 270.35 48 X2. 3-15.45 b O 312.43 . ';?. 2S3.40 56 372 .'-. 9 333.47 58 312. ' 3 293.40 SO 333.47 3-15. ? 255.34 0 333.43 S4 361.43 3B3.53 255.34. 269.26 269.35 283.39 70 B3.33 30.9.43 7 323.33 2hS.32 3C5.38 290.34 232.35 Composite PM ECSO (uM) 78 324.38 + 79 308.34 + * EC5o is the concentration at which a compound reduces by 50% the peak absorption of DPPH at 520 nm. +++++ EC50 < 10 uM ++++ 100 uM > EC5o > 10 uM +++ 500 uM > EC50 > 100 uM ++ 1000 um > EC50 > 500 uM + EC50 > 1000 uM As can be seen from Table 1, the nitrona compounds of the present invention possess significant and potent free radical scavenging / antioxidant activity. In fact, many of the nitrona compounds of the invention exhibit antioxidant activity comparable or even greater than PBN. Accordingly, the aryl, heteroaromatic and bicyclic aryl nitrona compounds of the invention with potential therapeutic agents useful for the treatment and / or prevention of diseases or conditions that have been reported that can be brought to antioxidant therapy or involve generation of free radical. These diseases and conditions include, but are not limited to, pain conditions, diseases or autoimmune conditions, inflammatory diseases or conditions, and neurological or neurodegenerative conditions or diseases. Non-limiting examples of pain conditions that arise from or are characterized by oxidative damage or oxidative stress are: migraine (See, e.g., Ciancarellí, I., et al., 2003, Urinary Nitric Oxide Metabolites and Lipid Peroxidation By-Products in Migraine, Cephalalgia, 23 (1) (: 39-42), syndromes of acute, chronic and neuropathic pain and neuralgia (See, e.g., De las Heras Castaño G., et al., 2000, Use of Antioxidants to Treat Pain in Chronic Pancreatitis, Rev. Esp. Enfer Dig., 92 (6): 375-85), irritable bowel syndrome, and nerve damage and neuropathies including diabetic neuropathy (See, e.g. , gray, C, et al., 2003, Neuroprotective Effects of Nitrone Radical Scavenger S.PBN on Reperfusion Nerve Injury in Rats, Brain Res., 982 (2): 179-85, and Strokov, LA, et al., 2000 , The Function of Endogenous Protective Systems in Patients with Insulin-Dependent Diabetes Mellitus and Polyneuropathy: Effect of Antioxidnt Therapy, Bull, Exp. Biol. Med., 130 (10): 986-90). Non-limiting examples of diseases or autoimmune conditions that arise from or are characterized by oxidative damage or oxidative stress are multiple sclerosis (See, e.g., Liu, Y., et al., 2003, Bílírubin as a Potent Antioxidant Suppresses Experimental Autoimmune Encephalomyelitis: Implications for the Role of Oxidative Stress in the Development of Multiple Sclerosis, J, Neuroimmunol. , 139 (1-2): 27-35); arthritis; diabetes and related complications (See, e.g., Tabatabaie, T., et al., 1997, Spin Trapping Agent Phenyl-N-tert-butylnitrone Protects against the Onset of Drug-induced Insulin-Dependent Diabetes Mellitus, FEBS Lett. , 407 (2): 148-52); and Graves 'disease and other thyroid disorders (See, e.g., Vrca, VB, et al., 2004, supplementation with Antioxidant in the Treatment of Graves' Disease: the Effect on Glutathione Peroxidase Activity and Concentration of Selenium, Clin Chim. Acta, 341 (1-2): 55-63). Non-limiting examples of diseases or inflammatory conditions that arise from or are characterized by oxidative damage or oxidative stress are: myocardial infarction and dysfunction (See, e.g., Vergely, C, et al., 2003, Effect of Two New PBN-Derived Phosphorylated Nitrones against Postischaemjc Ventricular Dysrhythmias, Funda.Clin.Pharmacol., 17 (4): 433-42); arteriosclerosis and other vascular diseases (See, e.g., Micheletta, F., et al., 2004, Vitamin E Supplementation in Patients with Carotid Atherosclerosis: Reversal of Altered Oxidative Stress Status in Plasma but Not in Plaque, Arterioscler, Thromb. Vasc. Biol., 24 (1): 136-40); asthma, reactive pathway diseases and allergies (See, e.g., Nadeem, A. et al., 2003, Increased Oxidative Stress and Altered Levéis of Antioxidants in Asthma, J. Allergy Clin. Immunol., 111 (1): 72-8); failure or rejection of transplantation and grafting (See, e.g., Connor, HD, et al., 1992, Evidence that free Radicáis Are Involved in Graft Failure following Orthotopic Liver Transplantation in the Rat - an Electron Paramagnetic Resonance Spin Trapping Study, Transplantation, 52 (2): 199-204); lung damage (See, e.g., Muprhy, PG., et al., 1991, Direct Detection of Free Radical Generation in anh in vivo Model of Acute Lung Injury, Radical Res. Commun., 15 (3): 167 -76); hepatitis and liver disorders induced by jaundice (See, e.g., Yamashita, T., et al., 1996, The Effects of alpha-Phenil-tert-butylnitrone (PBN) on Copper-Induced Rat Fulminant Hepatitis with Jaundice , Free Radical Biol. Med., 21 (6): 755-61); pancreatitis and other pancreatic disorders (See, e.g., Koiwai, T., et al., 1989, The Role of Oxygen Free Radicals in Experimental Acute Pancreatitis in the Rat, Int. J. Pancreatol., 5 (2): 135-43); inflammatory bowel disease including Crohn's disease and other disorders of the digestive tract (See, e.g., Reimund, JM, et al., 1998, Antioxidants Inhibit the in vitro Production of Inflammatory Cytokines in Crohn's Disease and Ulcerative Colitis, Eur, J. Clin.Inest., 28 (2): 145-50); retinal ischemia and damage including macular degeneration and other degenerative or inflammatory disorders of the retina and eye (See, e.g., F. Block and M.

Schwarz, 1997, Effects of Antioxidants on Ischemic Retinal Dysfunction, Exp. Eye Res., 6484): 559-64); disorders of kidney and kidney ischemia (See, e.g., Kadkhodaee, M., et al., 1996, Detection of Hydroxy and Carbon-Centered Radicáis by EPR Spectroscopy after Ischaemia and Reperfusion of Rat Kidney, Free Radical Res. , 25 (1): 31-42); and endotoxemia (See, e.g., Harkins, JD, et al., 1997, Effect of alpha-Phenyl-tert-butylnitrone on endotoxin Toxemia in horses, Vet. Hum. Toxicol., 39 (5): 268- 71). Non-limiting examples of diseases or neurological or neurodegenerative conditions arising from or characterized by oxidative damage or oxidative stress are: attack (See, e.g., Marshall, JW, et al., 2001, NXY-059, a free Radical -Trapping Agent, Substantially Lessens the Functional Disability Resulting from Cerebral Ischemia in a Primate Species, Stroke, 32 (1): 190-98, and Ginsberg, MD, et al., 2003, Stilbazulenyl Nitrone, to Novel Antioxidant, Is < highly Neuroprotective in Focal Ischemia, Ann. Neurol., 5483): 330-42), schizophrenia and other knowledge disorders (See, e.g., Dakhale, G, et al., 2004, Oxidative Damage and Schizophrenia: the Potential Benefit of Atypical Antipsychotics, Neurophsychoibiol., 49 (4): 205-09), character disorder, and other disorders of affection (See, e.g., Ranjckar, PK et al., 2003, Decreased Antioxidant Enzymes and membrane Essential Polyunsaturated Fatty Acids in Schizophrenic and bipolar Mood Disorder Patients, Psychiatry Res., 121 ( 2): 109-22); epilepsy (See, e.g., Gupta, M., et al., 2004, Add-on Melatonin Improves quality of Life in Epileptic Children on Valproate Mkonotherapy: a Randomized, Double-Blint, Placebo-Controlled Tiral, Epilepsy Behav. , 5 (3): 316-21); Aging and Senescence (See, eg, Carney, JM, et al., 1991, Reversal of Age-Related Increase in Brain Protein Oxidation, Decrease in Enzyme Activity, and Loss in Temporal and Spatial Memoryby Chronic Administration of the Spin -Trapping Compound N-tert-Butyl-alpha-phenylnitrone, Proc. Nati, Acad. Sci. USA, 88 (9): 3633-6); Parkinson's disease (See, e.g., Fredriksson, A, et al., 1997, MPTP-Induced Deficits in Motor Activity: Neuroprotective Effects of the Spin-Trapping Agent, alpha-Phenyl-tert-butylnitrone (PBN), J. Neural, Transm., K 104 (6-7): 579-92); Alzheimer's disease (See, e.g., butterfield, DA et al., 1996, A (25-35) Peptide displays H202Like Reactivity towards Aqueous Fe2 +, Nitroxide Spin Probes, and Synaptosomal Membrane Proteins, Life Sci., 58 (3 ): 217-28); Huntington's disease (See, e.g., Nakao, N., et al., 1996, Antioxidant Trestment protects Striatal neurons against Excitotoxic Insults, neuroscience, 73 (1): 185-200); Amyotrophic lateral sclerosis (See, e.g., Desnuelle, C, et al., 2001, A. Double-Blind, Placebo-Controlled Randomized Clinical Trial of Alpha-Tocopherol (Vitamin E) in the Treatment of Amyotrophic Lateral Sclerosis, Amyotrophic Lated Scler, Other Motro Neuron Disorders, 2 (1): 9-18); and traumatic brain damage and head trauma (See, e.g., Sen. S., et al., 1994, alpha-Phenyl-ter-butylnitrone Inhibits Free radical Releave in Brain Concussion, Free Radical Biol. Med., 16 (6): 685-91, and Marklund, N., et al., 2001, Effects of the Nitrone Radical Scavengers PBN and S-PBN on in vivo Trapping of Reactive Oxygen Species after Traumatic Brain Injury in Rats, J. Cereb Blood Flow Metab., 21 (11); 1259-67). 6.83. Example 83: Pharmacokinetic Evaluation of Aryl Nitrona Compounds of the Invention after Intravenous and Oral Administration in Rats Male Sprague-Dawley rats received at least 24 hours of acclimatization before the start of the experiment. During the feeding period, all animals received food and water ad libitum. However, the feed (not water) was removed from the animal cages until 12 hours before the start of the experiment. During the first 4 hours of experimentation, the animals received only water ad libitum. Two to three iv animals and three animals for oral administration were tested. For iv formulation nitrona compounds of this invention were dissolved (1 mg / mL) in a mixture of % dimethylacetamide (v / v), 0 to 4% Tween 80 (v / v), 10 to 405 PEG 400 (v / v) and the remaining percentage of water (v / v). For oral formulation nitrone compounds of this invention were dissolved (2 mg / mL) in a mixture of 4% 10% Tween in water and 96% 0.5% carboxymethylcellulose (medium viscosity) in water, or 4% % Tween in water, 48% 0.5% Carboxymethylcellulose (medium viscosity) in water, and 48% 0.5% Hydroxypropylmethylcellulose / 0.2% Sodium Lauryl Sulfate in water. These formulations were stored at 5 ° C until the experimental formulations were then mixed with agitation at least half an hour before dosing. Exactly 200 uL of each left formulation was diluted with CH3CN / H20 for concentration analysis. The animals were weighed before dosing. The bodily one was used to calculate the true dose for each animal IV dose: Volume of dose (mL) = 1.0 mL / kg The intravenous dose was administered through the jugular vein catheter or tail vein in less than 1 minute . Dosage of PO Volume of dose (mL) = 2.5 mL / kg The oral dose was administered by oral forced feeding.

For IV dosing, blood samples were collected (using a previously heparinized syringe) through the carotid artery or jugular vein catheter at = 2, 5, 15, 30, 60, 120, 180, 360, and 480 minutes after dosage. For PO dosing, blood samples were collected (using a previously heparinized syringe) through the carotid artery or jugular vein catheter before dosing yat = 5, 15, 30, 60, 120, 180, 360, and 480 minutes after of the dosage. For some nitrona compounds, a sample of 1440 minutes (24 hours) was also taken in both IV and PO administrations. About 250 uL of blood were obtained at each point of the animals. Volumes equal to 0.9% normal saline were replaced to prevent dehydration. Whole blood samples were kept on ice until centrifuged. The blood samples were then centrifuged at 14,000 rpm for 10 minutes at 4 ° C and the upper plasma layer was transferred to a clean vial and stored at 80 ° C. The resulting plasma samples were then analyzed by mass spectroscopy using conventional methods. 6.84 Example 84: LC / MS / MS Method for the Analysis of Aryl Nitrona Compounds of the Invention in Rat Plasma All the samples from the above assays were analyzed in a Pe-Sci8ex Triple 3000 quadrupole API with a source of Ion Spray Turbo. The nitrone compounds of this invention were separated from the matrix through linear gradient reverse phase chromatography using a C18 column, such as Thermo BDS Hypersil C18 (100x4.6 mm, 5 micron particle, pore size 120A) . The mobile phases were: A: 200 mL CH3CN, 1800 mL H20, 1.54 g NH40Ac, and 2 mL formic acid B: 1800 mL CH3CN, 200 mL H20, 1.54 g NH4OAc, and 2 mL formic acid. The nitrone compounds were detected by the mass spectrometer in the multiple positive ion reaction (MRM) monitoring mode. For "quantitative analysis, a conventional curve was prepared by nibbling a solution of nitrone compound material to the appropriate matrix to achieve a quantification curve scale and analyzed the standards in the same way as the samples. The aryl nitrona compound was determined by a non-compartmental analysis using WinNonlin-Pro (Version 4.1, Pharsight Corporation) The average and conventional deviation of the parameters were calculated using conventional formulas in Microsoft Excel parameters.

Pharmakokinetic are presented in Table 2, TABLE 2: Pharmacokinetic Data for Nitron Comp Compounds. PM F (%) T1 / 2 Cl Vd C «(PO) Tmax (PO) (hr) (L / h / kg) (L / Kg) (ng / mL) (hr) 55S0 - s i -J - - 'u «, = - > * ar r " - '/ ..' / & • iJd.H ', - «- 0 -'i' PM: Molecular weight of the nitrona compound F (%): Oral bioavailability, calculated by dividing the plasma exposure of oral dose with that of the intravenous dose, normalized to its respective doses, T? / 2: Average elimination half life of the nitrona compound Cl: Cleaning of the nitrone compound obtained from intravenous administration Vd: Distribution volume of the nitrone compound obtained by intravenous administration. Cmax: Maximum plasma concentration of the nitrone compound detected after oral administration. Tmax: Time taken to reach the maximum plasma concentration of the nitrone compound after oral administration. The aryl nitrona compounds of this invention have favorable pharmacokinetic properties. The majority of the compounds exhibited low to moderate cleaning. While a distribution volume scale (from low to high) was observed, more than half of the compounds showed volume distribution greater than the body water volume of rat, suggesting tissue distribution. When administered orally, the nitrona compounds were rapidly absorbed, as demonstrated by the Tma-, short (< 0.5 hours for most compounds). Oral exposure was generally elevated and more than 60% of the compounds showed oral bioavailability > 30% 6.85 Example 85: Plasma Protein Linkage of Aryl Nitrona Compounds of the Invention The nitrona compounds of this invention were dissolved individually in DMSO to make a material solution of 1 mg / mL. The compound was voided to plasma to achieve a final concentration of 1 ug / mL. The voided plasma and phosphate buffer (0.1M, pH 7.4), 200 ul of each, were added to the opposite sides of the membrane in a 96-well equilibrium dialyzer. The dialyzer plate was then converted and equilibrated overnight at 37 ° C in an orbital shaker. Aliquots of the plasma and buffer compartments were taken and prepared by adding model plasma to samples of the drug-free phosphate buffer and buffer compartments to samples of the plasma compartments to eliminate matrix effects. Samples were extracted using protein precipitation procedure by adding CH3CN. The samples were analyzed using an LC / MS / MS method. The percentage of free and bound nitrona compound were calculated according to the following formula:% Free = [Free Drug / Total Drug] * 100 = [(Crest Area) tmpdn / (Crest Area) serum] * 100% Sound = 100 -% Free. TABLE 3: Plasma Protein Link of Nitron Compounds PM Compound Plasma Protein Link% Link Rat% Link Human 20 256.32 2.41 333. 41 vs. n: S5.34 o. a = 1? . -? 333.42 2S.9 3.3 'S-? "2-57." 3 3a. s 3t > 3 369.35 13 5 • ss;: t > 3.3S? .- •. > 21.D 233.35 3? .S 4S.S ^ S3.39 -5 «.3 2C. 309.13 YES s • = s.s 323.34 sp- "; 53.3 The aryl nitrona compounds of this invention showed low plasma-protein binding. The majority of the compounds (10 of 13) had less than 30% binding values. Consequently, aryl nitrona compounds have the potential to achieve in vivo targets and exert their pharmacological effects. 6.86 Example 86: Brain Penetration of Aryl Nitron Compounds of the Invention The nitrone compounds of this invention were formulated individually as suspensions and administered as a single dose to Sprague-Dawley rats through oral forced feed (compound 26 to 5). mg / kg, compound 62 to 15 mg / kg, compounds 20, 63 and 66 to 50 mg / kg). Plasma samples were obtained at or near the projected Tmax at the dose provided for each compound and the animals were sacrificed using carbon dioxide. Immediately after sacrifice, cerebrospinal fluid (CSF) was obtained by puncture of the atlanto-occipital membrane and removed from the cisterna magnum. The brain was first perfused intracardially with -150 mL of 0.1 M ice cold phosphate buffered saline (PBS) at pH7.4. After the removal of the dura, the brain was weighed. The brain was then dissected into smaller pieces and rinsed twice with -10 mL of PBS. The brain, CSF, and samples plasma was frozen in dry ice and stored at -80 ° C before analysis. Samples of CSF and plasma were subjected to a protein precipitation method before LC / MS / MS analysis. The rat plasma model and CSF were used consistently to dilute the samples when needed. Conventional bioanalytical curves were prepared by drawing a material solution of the nitrone compound to model rat plasma or CSF to achieve a quantification curve scale and the standards were analyzed in the same manner as the samples. The brain samples were subjected to homogenization in 2 mL of water and liquid-liquid extraction with ethyl acetate three times. The combined organic phase for each sample was evaporated under a nitrogen stream at 40 ° C and the residues were reconstituted with an appropriate amount of mobile phase B (referring to LC / MS / MS method section)A conventional bioanalotic curve for brain analysis was prepared by tracing 100 mL of material solution directly to the sliced mold of rat brain purchased from Pelfreez. The chopped brains were then subjected to the same processing procedures for the dosed samples. The reconstituted samples were vortexed and incubated to completely dissolve the analytes. The samples were centrifuged, and then further diluted with Mobile phase B if necessary before LC / MS / MS analysis. The levels of nitrone compound in the brain were calculated based on the measured concentration, the volume of reconstitution and brain weight to provide a unit of ng (of compound) per g of brain. To calculate the brain / plasma ratio (w / v) it was assumed that 1 g of brain tissue takes approximately 1 mL of volume. As shown in Table 4, a majority of the nitrone compounds had good brain penetration properties with 3 out of 5 compounds that have a brain / plasma ratio of >;twenty%. TABLE 4: Brain Penetration of Nitron Compounds PM Compound of Brain (Rat) CSF / Plasma (%) Brain / Plasma (%) 20 256.32 14.4 22.9 26 333.41 0.12 0.56 62 255.34 78.6 62.5 63 333.43 33.6 18.9 66 255.34 93.6 22.4 6.87 Example 87: Solubility Measurements of Nitrona Compounds at pH 7.4 The nitrona compounds (> 3 mg) of this invention were mixed with a phosphate buffer at pH 7.4 to make a mixture of > 0.3 mg / mL. The mixture was vortexed for more than 2 hours and equilibrated for 12 hours at room temperature. The balanced mixture was used to saturate a Tuffryn syringe filter of 0.45 um. After saturating, the remainder of the mixture was filtered through the saturated filter. The filtrate was diluted by 1, 10, 100 and 1000 times and analyzed using a LC / MS / MS method with a conventional curve ranging from 1 to 1000 ng / mL.

TABLE 5: Solubility of Nitron Compounds PM Compound Solubility @ pH 7.4 Solubility @ pH (ug / mL) 7.4 (uM) 13 221.26 3QQ0 3039 275.38 3 '.' 136 s 1S 220.2 ') 3130 14310 791 2332 ji. 338.47 973 23S < 33 324.44 > -.030 > 23? .S: < 4 350.48 ORBO 142!) 35 3iß.45 38.4 0 i * ÍS 352-45 SOS 534 38 339.46; • 632 > :H.H? 33 355.5 > S52 > 2632 40 373-47 > 351 s237S í. 345.45 M? 443 42 3? Í.49 35.0 í'3.7. I 320. I7 66? 72 U 372.45 58.1 156 4'j 338.57. 1.42 3.5 44 4UÍ.? 2.14 a.H n 256.3 ?. > 29GI > > 1 314 74 305.33 2S.Í 9; 75 2S3.35; • lli > Í? 7 As shown in Table 5, the aryl nitrona compounds of this invention showed high aqueous solubility at pH 74. 38 of the 42 tester compounds had solubility greater than 10Oug / mL. 26 compounds had solubility greater than 100 ug / mL, and 6 compounds had more than 1 mg / mL of solubility. The favorable aqueous solubility contributes to the high oral bioavailability of these compounds. 6.88 Example 88: Microsomal Stability of Aryl Nitrona Compounds of the Invention Frozen Sprague-Dawley rat liver (RLM) microsomes were thawed on ice and mixed gently before use. The final reaction mixture consisted of a nitrona compound of this invention (at -500 ng / ml), 1 mM of NDPH, and 0.5 mg / ml of RLM protein in 0.1 M PBS (pH7.4), with a concentration of organic solvent that does not exceed 1% (v / v). By incubation set, a positive control compound was included. The mixture was first incubated 3 to 5 minutes previously at 37 ° C without NADPH, and the reaction was then initiated by the addition of NADPH and incubated at 37 ° C for up to 30 minutes. An aliquot of the reaction mixture was sampled at the start of the reaction and at the designated time after the reaction was started. The samples taken were rapidly quenched with acetonitrile, diluted with mobile phase to ensure detection of the test article on the linear scale, and analyzed by LC / MS / MS. The half-life or percentage of the remaining nitrone compound was calculated using conventional methods. A similar method, or a slight variation thereof, was used to test the stability of nitrones in human liver microsomes (HLM). TABLE 6: Stability of Nitrona Compounds PM Compound% Nitrona Remaining at% Nitrona 30 min (Human) Remaining at 30 min (Rat) li 221-25: i "100 iS 275.3í> 1IT 100 30 317 '-3 st 7.4 -' '- 333, ^ 7 at' - V JS .--- E:? t 2 ¡3 324, ^ UT l? - 34 JbC -.8 MT. "• 5 3" 'B.4S or 3a or 3i "35 24 2« • _ • Vi 360 Ai 6I>. £ -, t 7. 39 3S5.50 41.3? Go 40 373.47 2 .3 HT 4. 3 345.45 -3 S! 3 i ?. 372.43 2 .T 43 332.4?; j?;? < % > l 372.49 0 ¿G 43 39S.52 r, K? 4C 405, SO 0: 47 270.35 ET 4íí 33.2.43 103 yr • 1.-J 3 £ .45 3?; T 50 313.43 36 K? 51 1? 33.40 34? J? 52 333.47 5- X: 53 34S.Í5 65 K? 54 34S.45 62 3? 55 332.42 82 ET 55 372.43 3 317 S7 3 SO, 47 14 HT 58 315.43 100 TT 5S 293. 3 100 ílT eo 338.47 300 M? 63 345.45 Sl5 «r 62? 'h .ii ".30 3.3» 63 333.43 39 sv G4 351. í 3 300 100 is 38 ') S3 54 7: 5 7. 1 256.3.2 1GJ ET 74. 30C.3G 757 ax 75 230.34 1) 5.1 XT 3. 3Ó 80 256, 33 94. 5 NT 81 290.34 90. 5 NT The nitrona compounds of this invention are generally stable in human or rat liver microsomes. Among the 45 compounds tested, 23 compounds showed more than 75% compound remaining after 30 minutes of incubation with either rat or human liver microsomes with the addition of NADPE. The high stability indicates the slow rate of oxidative metabolism of these compounds by the liver, which in turn resulted in a low space and a high oral bioavailability. The microsomal stability data are consistent with the pharmacokinetic results. 6.89. Example 89: Compound 62 is Effective In Vivo Against Diabetic Neuropathy (Mechanical Hyperalgesia) In this example, the ability of Compound 62 to produce beneficial effects by protecting against and / or reversing the pathology of neuropathy in a rat model induced by streptozotocin ( STZ) of diabetes. To assess whether chronic treatment of Compound 62 protects diabetic animals from developing neuropathy, were examined for mechanical hyperalgesia responses. Adult male Sprague Dawley rats (SD) weighing 250-300 gr. (Charles River Laboratories, San Diego, CA) were used. The animal's room was artificially illuminated at a 12-light-dark cycle (from 7:00 a.m. to 7:00 p.m.) with water supply and food ad libitum. The animals were randomized into groups. Forty-nine (49) days before the behavioral tests, the rats received a bolus injection of STZ (75 mg / kg, i.v.). STZ was dissolved in 0.1 M sodium citrate buffer, pH 4.5, at the concentration of 75 mg / ml. To ensure the development of hyperglycemia, their non-fasting levels of white blood glucose, obtained through tail veins, were evaluated, using a glochometer (Accucheck <RX Roche Diagnostics, Palo Alto, CA), once a week. Animals that fail to show hyperglycemic conditions (ie, whole blood glucose> 120 mg / dL) were separated from the study. The diabetic rats were orally treated with Compound 62 (5 mg / kg or 25 mg / kg, both bid) or vehicle (1 ml / kg, bid), starting on the date of STZ injection. Compound 62 was dissolved in vehicle, which is composed of 96% of 0.5% CMC and 4% of 10% Tween 80, As a control, a group of innocuous rats received Compound 62 oral (25 mg / kg, bid) ) or vehicle (1 ml / kg, bid) as a treatment. Each group had > 12 rats The time effect curves of the STZ diabetic rats (Compound 62 versus Vehicle) were compared with each other, while the cures of the innocuous rats (Compound 62 against Vehicle) were compared with each other. The comparisons were conducted, using repeated measures analysis of two-way (group x time) of variation (ANOVA) followed by Post-hoc Fishers test. A probability value of p < 0.05 was considered as statistically significant. Prior to the experiments, these rats were trained in the paw withdrawal reflex test, using a Basile Analgesimeter (Ugo Basile, Biological Research Apparatus, Comerio, VA, Italy), which applies linearly increasing mechanical force to the back of the hind paw of rats. Mechanical nociceptive flexion reflex training in response was performed in slightly restrained rats, at 5 minute intervals for 1 hour each day for a period of 5 days. On the day of the experiment, the paw withdrawal thresholds (P T) (ie mechanical force that causes the animal to remove its paw from the stimulus) were measured at 5 minute intervals for 1 hour. The average was obtained from the average of the last 6 readings of PWT. The data is presented as means = SEM (Conventional Error of the Medium); One-way ANOVA was used to determine the significant difference between multiple pairs of media. A probability value of p > 0.05 was considered as statistically significant. As shown in Figure 1 and Table 7 below, High dose Compound 62 (25 mg / kg, po, bid, x 49d [STZ + compound 62L, dashed bar) significantly reversed mechanical hyperalgesia in STZ diabetic rats. , compared to STZ diabetic rats treated with vehicle (STZ * vehicle, open bar). There was no mechanical hyperalgesia in harmless rats (innocuous * Vehicle, black solid bar). TABLE 7: Mechanical Hyperalgesia Investment by Compound 62. GRAMS PWT GROUP) STZ-VEHICLE 72.19 ± 3.09 STZ-COMPOUND 62L 70.29 + 3.18 STZ + COMPOUND 62H 86.86 ± 4.79 INOCUOUS + VEHICLE 114.00 ± 2.34 6.90 Example 90: Compound 62 is Effective In Vivo against Diabetic Neuropathy (Mechanical Allodynia) In this example, the ability of Compound 62 to produce beneficial effects by protecting against and / or reversing the pathology of neuropathy in a model of rat diabetes induced by streptozotocin (STZ). To assess whether chronic treatment with Compound 62 protects diabetic animals from developing neuropathy, they were examined for mechanical allodynia responses (i.e., amplified response to non-painful tactile stimulation).

In this experiment, each rat was placed on a metal mesh floor, covered with a plastic box (10 x 10 x 18 cm), and allowed 1-2 hours to habituate. Tactile stimulation (i.e., non-painful mechanical stimulation) was induced by a set of calibrated von Frey filaments (North Coast Medical Inc., Morgan Hill, CA), which was applied to the plant surface of each rat hind paw . The mechanical stimulus was qualified by the strength of bending force in a von Frey filament that causes the animal to remove its paw to avoid pain. Each test consisted of 4 applications of a von Frey filament provided every 4 seconds. Live leg withdrawals (ie, PWT) at least twice from 4 applications, in response to the von Frey filament stimulus, were considered positive. Depending on the initial response, subsequent filaments were applied in the order of either descending or ascending force to determine threshold strength (Tal, M. &Bennett, GJ: Extra-territorial pain in rats with a mononeuropathy a: mechano- hyperalgesia and mechano-allodynia in the territory of an unijured nerve Pain, 57: 275-382, 1994, Mao, J., Price, D, D., Zhu, J., Lu, J. &Mayer, DJ: The inhibition of nitric oxide-activated poly (ADP-ribose) synthetase attenuates transynpatic alteration of spinal cord dorsal horn neurons and neuropathic pain in the rat.

Pain, 72: 355-366, 1997: The data presented as means + SEM. The results obtained from several groups of animals were compared, using an unpaired Students t test, of two tails. A probability value of p < 0.05 was considered as statistically significant. As shown in Figure 2 and Table 8 below, Compound 62 provided at 25 mg / kg, p.o., bid, x 49d (cross-hatched bar), but not its vehicle (open bar), significantly improved the PWT. An increase in PWT represents an inversion of allodynia. TABLE 8: Improvement of PWT by Compound 62 PWT GROUP (GRAMS) STZ + VEHICLE 3.30 + 0.56 STZ + COMPOUND 62 6.08 + 0.94 Example 91: Effect of Aryl Nitrona Compounds of the Invention on Mechanical Allodynia in a Rat Model of Mononeuropathic Pain. In this example, the ability of the compounds of the invention to produce beneficial effects by protecting against and / or reversing neuropathic pain pathology, the compounds were tested in a mononeuropathic pain model. Adult male SD rats weighing 250-300 gr (Charles River Laboratories, San Diego, CA) were used. The animal's room was artificially illuminated by a 12-hour light-dark cycle (7:00 A.M. to 7.00 P.M.), with water supply and food ad libitum. The animals were randomized into groups. Seven days before establishing the mononeuropathic pain disease model, the rats were trained on a metal mesh floor, covered with a plastic box (10 x 10 x 18 cm) 1 - 2 hours a day for habituation. During the habituation phase, non-painful tactile stimulation on the plant surface of each hind paw was induced by a set of calibrated von Frey filaments through the mesh floor, as described in example 2. After the phase of After 7 days of training, the animals were anesthetized by ip injection of sodium pentobarbital (65 mg / kg, Abbott Lab, Chicago, IL). Under aseptic procedures, the skin of the left thigh opened with a cut in -2 cm. The mid-thigh level of the common sciatic nerve was exposed after the separation of the muscles. Two 4-9 silk sutures and one 4-0 chromic gut suture (both from Ethicon, Somerville, NJ) were loosely tied around the nerve, with an interval of 1-1.5 mm between each. The wound on the skin was then closed with wound staples. The right side (that is, the contralateral side) was not surgically damaged. After recovery from surgery, rats showing neurological deficits after surgery or under care were excluded from the experiments. This surgical procedure (ie, chronic constrictive damage, CCI, or Bennett model) to establish mononeuropathic pain disease was described elsewhere (Bennett, GJ, and Xie, YK: A mononeuropathy Ane in which that causes disordered pain sensation like those seen in man. , 33: 87-107, 1988). On days 1, 3, 4, 7, 9, 11 and 14 after surgery, the animals were tested for mechanical allodynia with von Frey filaments as described above. On or about day 14 after surgery, the ipsilateral hind paw felt at 5 grams, an indication that allodynia began to manifest mechanical allodynia (ie, amplified response to non-painful tactile stimulation by von Frey filaments), Legs contralateral hindquarters remained above the level of 5 grams (ie, no allodynia). After the manifestation of this allodynia, Compound 62 (50 mg / kg, po), Compound 63 (50 mg / kg, po), Compound 66 (50 mg / kg, po), Compound 23 (50 mg / kg, po), 4-hydroxy-tempol (TEMPOL, 50 mg / kg, po), or piroxicam (a COX1 inhibitor, 50 mg / kg, po), were administered to randomly assigned animals. Changes in mechanical allodynia in the ipsilateral hind paw were recorded at various time points over the course of up to 24 hours. A single dose of piroxicam induced a long lasting anti-allodynic effect (data not shown). As shown in Figure 3 and Table 9 below, a single dose of Compound 62 (full circles), but not its vehicle (open circles), produced a fast but short-lived anti-allodynic effect by moving the dramatically higher PWT , far from the allodynia level of 5 grams. The data is presented as means + SEM. The difference between the levels of allodynia during the time in the ipsilateral hind legs of the CCI rats (Compound 62 versus Vehicle) were found to be significant per day pathways (group x time) analysis of repeated measures of variation (ANOVA), followed by Fishers test post-hoc. A probability value of p <0.05 is considered as statistically significant. TABLE 9 Anti-allodynic effect of Compound 62 in the rat Time After Compound Vehicle 62 Dosage (min) -15 3.20 + 0.68 gr 3.17 + 1.10 gr 5 3.59 + 1.85 gr 2.86 + 0.94 gr 120 6.00 + 0.44 gr 16.71 + 3.44 gr 240 4.86 + 1.22 gr 15.14 ± 3.90 gr 360 5.34 + 0.79 gr 5.46 + 1.46 gr 1440 4.51 + 1.22 gr 3.43 + 1.02 gr As shown in Table 10, a single dose of Compound 63, but not its vehicle, produced anti-allodynic effects on ipsilateral hind legs, in a pattern similar to that of Compound 63 (it is say, fast in principle but short in duration). The data is presented as means + SEM. The difference between the levels of allodynia during the time in the ipsilateral hind legs of the CCI rats (group of Compound 63 against Vehicle group) was found to be significant by the same analysis performed for Compound 62. TABLE 10 Anti-allodynic effect of Compound 63 in the rat Time after Compound Vehicle 63 Dosage (min -15 3.20 + 0.97 gr 3.88 + 0.97 gr 2.68 + 0.84 gr 18.4 + 10.42 gr 60 3.80 + 0.80 gr 18.8 + 11.29 gr 300 4.52 + 1.23 gr 5.20 + 1.63 gr 1400 4.28 + 1.23 gr 3.60 + 1.30 gr As shown in Table 11, a single dose of Compound 66 did not produce significant anti-allodynic effect compared to its vehicle- Data are presented as means + SEM. Statistical analyzes were performed as for the compounds above. TABLE 11 Lack of anti-allodynic effect of Compound 66 in the rat Time after Compound Vehicle 66 Dosage (min) -15 3.20 + 0.97 gr 1.97 + 0.84 gr 2.68 + 0.84 gr 5.33 + 0.42 gr 60 3.80 + 0.80 gr 4.12 + 0.91 gr 300 4.52 + 1.23 gr 5.33 + 1.12 gr 1440 4.28 + 1.23 gr 1.57 + 0.23 gr As shown in Table 12, a single dose of Compound 23, but not its vehicle, produces statistically significant anti-allodynic effects on ipsilateral hind legs. The data is presented as means + SEM. Statistical analyzes were performed as for the compounds above, TABLE 12 Anti-allodynic effect of Compound 23 in the rat Time after Compound Vehicle 23 Dosing (min) -15 3.20 + 0.97 gr 2.43 + 0.54 gr 2.68 + 0.84 gr 7.67 + 0.80 gr 60 3.80 + 0.80 gr 8.17 + 1.52 gr 300 4.52 ± 1.23 gr 4.43 + 1.35 gr 1440 4.28 + 1.23 gr 4.67 + 0.84 gr As shown in Table 13, a single dose of TEMPOL compound did not produce significant anti-allodynic effect compared to its vehicle. The data is presented as means + SEM. The statistical analyzes were performed as for the previous compounds. TABLE 13 Lack of anti-allodynic effect of TEMPOL in the rat Time after vehicle TEMPOL Dosage (min) -15 3.20 + 0.97 gr 4.00 + 0.89 gr 2.68 + 0.84 gr 4.80 + 0.49 gr 60 3.80 + 0.80 gr 4.80 + 0.49 gr 300 4.52 + 1.23 gr 5.48 + 1.09 gr 1440 4.28 + 1.23 gr 4.80 + 1.02 gr 6.92 Example 92: The Aril Nitrone Compound of the Invention Decreases Thermal Hyperalgesia in Acute Inflammation Produced by Carrageenan in Rats In this example, the ability of the compounds of the invention to decrease low thermal hyperalgesia Acute inflammatory conditions is demonstrated. An inflammatory model sensitized with rat carrageenan was used and the compounds were tested for their effects in response to thermal pain using the Hargreaves test. In this experiment, the animals were habituated to the test environment for 2 days. Each rat was placed individually on a transparent perplex glass floor, covered with a plastic box (10 x 10 x 18 cm), and left 0.5 - 1 hour to habituate. After the acclimation period, the basal thermal withdrawal latency (PXL, time interval between heat stimulation and paw withdrawal) was measured by exposing the plant surface of a hind leg of rats on a beam of radiant heat generated from a bulb of focused projection through a transparent perplex glass surface (Hargreaves test; Hargreaves, KR, Dubner, R., Borwn, F., Flores, C. &Joris, J.: A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia., 32: 77-88, 1988). The PWL averages at least two tests separated by a 2 minute interval. A stopwatch was used to measure withdrawal latency and a time cut of 20 seconds was used to prevent tissue damage. Prior to the test in diabetic rats by STZ, the intensity of the radiant heat was adjusted to the level that caused the safe animal to remove its paw for about 10 seconds. After a stable basal PWL was located, animals were briefly anaesthetized with isoflurane (2-5% effect). One side of its hind legs received an intraplant injection of lambda carrageenan (2 mg in 100 microliters of sterile saline, Sigma, St. Louis, MO). The contralateral side did not receive injection and served as an intra-subject control. The animals were then returned to home cages and transferred to individual test beds for thermal hyperalgesic heat test, 2.5 hours after carrageenan injection, 3 hours after injection of carrageenan, the PWLs of both hind legs ( that is, ipsilateral and contralateral) were measured at various time points after injection of carrageenan (15-min at 24-hr). Without any anti-hyperalgesic intervention, PWL of the ipsilateral hind legs was significantly lower than the contralateral hind legs not injected until spontaneous recovery at the 24-hour time point (data not shown). To test the compound, rats were randomly enrolled in groups which, immediately after 3 hours after carrageenan PWL was obtained, received oral dosing of Compound 62 (50 mg / kg), Compound 63 (50 mg / kg), vehicle (1 ml / kg), or indomethacin (30 mg / kg), Compound 62 and Compound 63 were prepared as a vehicle suspension (96% 0.5% CMC and 4% 10% Tween 80), while indomethacin was prepared as 30 mg / ml in normal saline. Orally administered indomethacin significantly reversed the thermal hyperalgesia sensitized by carrageenan (data not shown). As shown in Table 14, compound 62 produced a statistically significant effect compared to the carrageenan leg treated with vehicle. In Table 14, the data is presented as means + _ SEM. The statistical comparison method used in this study was one of repeated measures of two-way ANOVA followed by Fishers' post-hoc test. A probability value of p <0.05 was considered as statistically significant. TABLE 14 Inversion of thermal hyperalgesia sensitized by carrageenan to Compound 62 in the rat Time after dosing (min) Group 0 14 120 240 1400 PWL for Vehicle (sec) 3.29 + 0.70 3.15 + 0.77 3.08 + 0.81 3.61 + 0.90 5.60 ± 0.70 PWL for Compound 62 (sec) 4.65 + 0.63 7.33 + 1.43 7.55 + 1.08 5.38 + 1.11 5.33 + 1.09 As shown in Table 15, Compound 63 also produced a statistically significant effect compared to carrageenan treated leg with vehicle. In Table 15, the data are presented as means + SEM. The statistical methods used were the same as above. TABLE 15 Inversion of thermal hyperalgesia sensitized with carrageenan by Compound 63 in the rat Time after Dosing (min) Group 0 15 60 180 240 1400 PWL for Vehicle (sec) 3.29 ± 0.70 3.15 + 0.77 not re 2.43 + 0.51 2.61+ 0.90 5.60 + 0.70 taken PWL for Compound 63 (sec) 4-98 + 0-85 4.93 + 1.22 4.15 + 1.04 3.65 + 0.64 not re 5.70 + 0.71 taken 6.93 Example 93: Compound 62 Relieves Kidney Dysfunction in a Model of Ischemia Damage-Kidney Reperfusion In this example, the ability of Compound 62 to protect or reverse the damage caused by ischemia-reperfusion (I / R) damage of the kidney is demonstrated. An I / R model of a kidney staple (i.e. 1K1C) was used. The rats were housed individually in a modified cage that was equipped with a raised mesh bottom to separate the fecal product from the urine. Before the test, all animals were removed from food and water during the night. On the morning of the test, normal saline (ie, 0.9% sodium chloride) was provided via oral obligate feed at 50 mg / kg (Lipachitz, WL, Hadidian, Z. &Kerpear, A .: Bioassay of diuretics , J. Pharmacol, Exp. Ther., 79: 97-100, 1943). The blood and urine samples were collected (conventional procedures) at time points (1 and / or 5 hours after fluid admission) of the animals, centrifuged and maintained at 4 degrees until analysis by factors that they reflect renal functions. Sodium and creatinine levels were determined by Quality Clinical Labs., Inc. (Mountain View, CA). Sodium concentrations were determined by ion selective electrode (conventional procedures). Cretinine levels were determined by the alkaline picrate reaction (Jaffe) as described (Liobat-Estelles, M., Sevillano-Cabe a, A. &Campines-Falco, P .: Kinetic chemometric studies of the determination of creatinine using the Jaffe reaction, Part 1: kinetics of the reaction; analytical conclusion. 11: 597-602, 1989). Fractional sodium excretion (FENa +), a parameter to manage ion by the kidney, was calculated, using the following equation: = A x or / Pna x UCG? e where Una is the concentration of sodium in urine; Por is the plasma concentration of creatinine; Pna is the concentration of sodium in urine; and Uor is the concentration of creatinine in the urine. After the data for the calculation of baseline levels of FENa + were obtained (Table 16), the rats were anesthetized with pentobarbital (65 mg / kg, i.p.). The abdominal region was shaved with a safety razor and sterilized with povidone iodine solution. A midline incision was made and the right kidney was exposed. The right renal pedicle and right ureter were ligated both twice with 4-0 sutures and cut between the ligaments. The right kidney was then removed. 7 days later, these rats, after another night of feed-water deprivation, were randomly assigned into 3 groups and orally provided either Compound 62 (50 mg / kg, volume 1 ml / kg, po) , or his vehicle (ie, 96% CMC 0.5% and 4 Tween 80 20%, volume 1 ml / kg, po), 1 hour before kidney ischemia occurred. Positive controls were performed using quercetin (30 mg / kg, ip), provided 2 hours before ischemia (Kahraman, A., Erkasap, N., Serteser, M. &Koken, T .: Protective effect of quercetin on renal ischemia / reperfusion injury in rats, J. Nephrol., 16: 219-234, 2003). Then the animals were anesthetized and left their left kidney exposed after the opening of their abdominal cavities. A non-traumatic vascular fixation was applied to the left renal pedicle (the ischemia phase), which was released 45 minutes later (the reperfusion phase). The Lipschitz test was then conducted to measure ion handling capabilities. Normal saline was administered orally at 50 mg / kg as soon as the vascular staple was released. 60- and 300 min after reperfusion, plasma and orchid samples were obtained.

Compared with the vehicle treatment group, the acutely dosed Compound 62 significantly improved FENa + 5 hours after reperfusion and the level in this group (i.e., 1K1C rats treated with Compound 62) was significantly higher than the levels obtained from the same animals. before the 1K1C modeling (Table 17). The effects of Compound 62 were similar to that of Quecetin, even when less than the latter. The data are presented as means ¿SEM. The data was processed by repeated two-way ANOVA measurements followed by a Fishers post-hoc test. A probability of value of p < 0.05 is considered as statistically significant. TABLE 16. Lack of effect of Compound C in levels before surgery of FENa + in rats Group FENa + (%) Vehicle 1.45 + 0.10 Compound 62 1.71 + 0.36 Quercetin 1.60 + 0.15 TABLE 17. Effect of Compound 62 on levels of FENa + in ischemic rats after Kidney Group 1 hour after 5 hours after Isquemica FENa +. { %) ischemic FENa + (%) Vehicle 0.30 + 0.10 1.20 + 0.22 Compound 62 0.52 + 0.29 2.52 + 0.5 Querocetin 0.54 + 0.02 * 5.23 + 4.43 6.94 Example 94: Effects of Compound on Rat Attack Damage Relief In this example, The ability of the compounds of the invention to reduce the infarct volume in an in vivo attack model is demonstrated. A rat model of focal ischemia, medial transient cerebral artery occlusion (tMCAO), was used. The MCA occlusion was induced by the intraluminal filament technique described by Deberson et al. (Rat Middle Cerebral Artery occlusion: evaluation of the model and deveopment of a neurological examination Stroke Vol 17 (3) (1986) p.472-476)]. Male Sprague-Dawley rats (270-300 g) were anesthetized with 2.5% isoflurane. During the procedure, the core leather temperature was maintained around 37 ° C with a heating pad fixed to a rectal thermometer and a temperature controller. The animal's neck was shaved and prepared with betadine and alcohol. An incision was made just below the jaws, which extends approximately 1-2 cm caudally. The blunt dissection was performed to expose the trachea and retract the muscles to locate the right carotid artery. Similarly, the bifurcation of the external common carotid artery (ACE) and the internal common carotid artery (ICA) were exposed. A silk suture was placed rostrally around the ECA, followed by a second suture next to the first. Both sutures were then tied tightly and the artery was cut between the sutures. The simulated operated animals did not receive additional surgery. His incision was sutured and allowed to recover as described below before returning to his home cage. In animals that undergo MCAO of 120 minutes, the suture in the proximal portion of the ECA was pulled caudally so that the ACE and ICA formed a straight line at the bifurcation. Another temporary mooring was placed on the ECA just above the bifurcation to retain the monofilament in place. Blood flow through the common carotid artery (CCA) and ICA was temporarily stopped using a curved vascular staple. A small hole was made using iridectomy scissors above the temporary mooring and just below the permanent mooring at the end of the external carotid artery. A 3-0 monofilament nylon suture, previously treated with a cauterizer to flare the tip, was placed on the ECA end beyond the temporary tie, which was then lightly tightened to prevent blood loss. The vascular staple was then released and the suture was advanced into the lumen of the ICA. The temporary staple at the CCA / ECA / ICA bifurcation was separated and the monofilament was advanced to the ICA until the appropriate resistance was found. At this point, MCAO was assumed and the filament was left in this position for the duration of the ischemic insult (120 minutes). The suture was held in place by squeezing the suture into the ECA and cutting the loose ends. The entire region was irrigated with saline, and the incision was closed using surgical staples. At the end of the occlusion period, the animal was placed under isoflurane anesthesia, the surgical staples were removed and the monofilament was removed from the carotid artery. The temporary suture in the ECA was permanently ligated to prevent blood loss. The reflux was established again towards the ICA., The area was irrigated with saline and the incision of the animal was closed with Ethilon No. 5 or equivalent. Two days after MCAO, the rats were sacrificed and the degree of brain damage was determined using tetrazolium spotting (TTC) in two 2 mm thick sections prepared using conventional methods followed by computer image analysis to quantify infarct volumes. (that is, the regions of dead tissue). A Wilcoxan Rank Sum test (as previously specified to follow in a one way analysis) was used to compare specific groups of compound treatment with the control treated with Vehicle. Three studies were conducted. All the studies used in the tMCAO model of 2 hours and each followed the same dosing regimen whereby the drug was dosed BID (bi-daily), every 12 hours, beginning 48 hours before the occlusion and through to the sacrifice at 48 hours after occlusion. The animals received a total of 8 doses of drug and MCAO was performed 1 hour after the fifth dose. The first study compared the effects of Compound 62 (50 mg / kg), Compound 63 (50 mg / kg), and Compound 20 (50 mg / kg) to vehicle-treated controls. Phenyl-N-butyl-nitrona (PBN, 100 mg / kg) administered intraperitoneally (i.p.), once 15 minutes before occlusion and then BID (every 12 hours) until sacrifice at 48 hours, was used as a positive control. There were approximately 15 rats in each experimental group. In Figure 4, the data with bars representing average values for each group are plotted. The results of statistical analyzes showed statistically significant effects for some compounds for the group treated with Compound 62 compared to vehicle, (p = 0.01); for the group treated with Compound 63 compared to vehicle, (p = (0.05) for the group treated with Compound 20 compared with vehicle, p = 1.54, and for the group treated with PBN compared with vehicle, p = 0.28. saw for a dose response relationship of treatment with Compound 62 in infarct volume.There were three doses used in this experiment: 3, 10 and 30 mg / kg administered through forced oral BID feeding starting 48 hours before MCAO and continuing until the end of the study, 48 hours after MCAO, the data with bars representing mean values for each group are plotted in Figure 5. The results of statistical analyzes showed statistically significant effects for Compound 62: p = 0.03 for the group of 30 mg / kg dose compared to vehicle The third study looked at a dose response response of Compound 63 in infarct volume There were three doses of Compound 63 used in this experiment : 15, 50 and 100 mg / kg administered with obligatory oral BID food starting 48 hours before MCAO and continuing until the end of the study: 48 hours after MCAO. 4-Hydroxy-TEMPO (100 mg / kg) was used as a positive control and was administered using the same dosing regimen. In Figure 6, the data is graphed with bars that represent average values for each group. The results of the statistical analyzes showed possible effects for Compound 63 (50 mg / kg), p = 0.07 for the 50 mg / kg dose group compared to vehicle. All publications, patents and patent applications cited in this specification are incorporated herein by reference as if each individual patent application or publication is specifically and individually indicated to be incorporated by reference. Although the above invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary experience in the art in light of the teachings of this invention that certain changes and modifications they can be made to it without abandoning the spirit or scope of the appended claims. All these changes and modifications are included in this.

Claims

CLAIMS 1.- A compound of the formula (1) or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; at least one of A and B is C-R3, and the other is selected from C-R3 and N; when less than R3 is S02R5, C02R5, CONRsR6 or tetrazole, and any other R3 is independently selected from R4, H, lower alkyl, alkenyl, alkyl, halogen, aryl, S03R5, S02NR5R6, C02H, CONR4R6 and tetrazole; X, Y and Z are each independently selected from C-R4 and N; each R 4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyl, substituted arylalkyloxy, amino, acyl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azide, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio; and R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, or are joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected of NR1, O and S, wherein the compound is not a-2-carboxy-phenyl-Nt-butyl-nitrona, a-2-carboxy-phenyl-N-phenyl-nitrona, a-2-carboxy-phenyl-N 3, 4-dimethyl-phenyl-nitrona, nor a-2-carboxy-3,4-dimethoxy-phenyl-N-methyl-nitrona. 2. - A compound according to formula (2), (3) or (4): . { --o. { - =) or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; A and B are independently selected from C-R3 and N; each R3 is independently selected from R4, H, lower alkyl, alkenyl, alkyl, halogen, aryl, S02NR5R5, S02R5, C02H, CONR5R6 and tetrazole; X, Y and Z are each independently selected from C-R4 and N; each R 4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted or, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio; and R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, or are joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected from NR1, O and S; wherein the adjacent A the nitrona group is S02R5, C02R5, CONR5R6 or tetrazole. 3. A compound according to formula (5) or (6): or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; A and B are independently selected from C-R3 and N; each R3 is independently selected from R4, H, lower alkyl, alkenyl, alkyl, halogen, aryl, S02NR5R6, S02R5, C02H, CONR5R6 and tetrazole; X, Y and Z are each independently selected from C-R4 and N; each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, acyl substituted, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonyl substituted ^ alkylarylamino, alkylarylamino substituted arylalkyloxy , aryl substituted amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, dimethyl sulfoxide substituted sulfone, substituted sulfone, sulfanyl, I sulfanyl substituted aminosulfonyl, aminosulfonyl substituted arylsulfonyl, arylsulfonyl substituted, sulfuric acid, sulfuric acid ester, dihidroxifosforilo , dihidroxifosforilo substituted aminohidroxifosforilo, aminohidroxifosforilo substituted, azido, carboxy, carbamoyl, substituted, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino , halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, -nitro or thio; and R5 and R6 are each independently selected from H, lower alkyl, aryl, and heteroaryl, or joined together to form a ring saturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected of NR1, O and S; Where the A adjacent to the nitrona group is S02R5, C02R5, C0NR5Rs or tetrazole. 4. The compound according to any of claims 1-3, each R4 is independently selected from H, lower alkyl, alkyl, alkenyl, halogen, aryl, aryloxy, S02NR5R6, S02R5, C0H, C0NR5R6 and tetrazole. 5. The compound according to any of claims 1-3, wherein at least one A or B adjacent to a nitrone is C-SO2R5. 6. The compound according to any of claims 1-3, wherein at least one of A or B adjacent to a nitrone is C-C02R5. 7. The compound according to any of claims 1-3, wherein at least one of A or B adjacent to a nitrone is C-C02H. 8. The compound according to any of claims 1-3, wherein at least one of A or B adjacent to a nitrone is C-CONR5R6. 9. The compound according to any of claims l-3n wherein at least one of A or B adjacent to a nitrone is C-tetrazole. 10. The compound according to any of claims 1-9, wherein R2 is: Rll I -C-R12 I R13 wherein each R 11, R 12 and R 13 is independently selected from hydrogen, lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl. 11. The compound according to claim 10, wherein each R11, R12 and R13 is independently alkyl or substituted alkyl. 12. The compound according to claim 10, wherein each R11, R12 and R13 is independently unsubstituted alkyl. 13. The compound according to claim 10, wherein each R11, R12 and R13 is independently unsubstituted lower alkyl. 14. The compound according to claim 10 wherein one of R11, R12 and R13 is methyl. 15. The compound according to claim 10, wherein two of R11, R12 and R13 is methyl. 16. The compound according to claim 10, wherein each of R11, R12 and R13 is methyl. 17. A pharmaceutical composition comprising a compound according to any of claims 1-3., and a pharmaceutically acceptable carrier, excipient or diluent. 18. A unit dosage form of the composition according to claim 17, comprising about 10, 25, 50, 100, 500, 1000, 2000 or 2500 mg of the compound. 19. A method for treating or preventing an ischemic or reperfusion-related ischemic or ischemic condition comprising the step of administering an effective amount of the compound according to any of claims 1-3 to a subject in need of said treatment or prevention. 20. A method for treating or preventing a chemokine-mediated condition comprising the step of administering an effective amount of the compound according to any of claims 1-3 to a subject in need of said treatment or prevention. 21. The method according to claim 19, wherein the subject is a mammal. 22. The method according to claim 19, wherein the subject is a human. 23. The method according to claim 19, wherein the compound is administered orally. 24. A device for treating or preventing an ischemic or ischaemia / reperfusion-related condition or a chemokine-mediated condition in a subject in need thereof, comprising an effective amount of a pharmaceutical composition, the composition comprising compound in accordance with any of claims 1-3, and a label or labeling with instructions for using the composition to treat or prevent the condition. 25. A method for making an aryl nitrona according to claim 1, comprising the step of reacting an aldehyde according to formula (7): with a hydroxylamine in accordance with formula 8: i, ("to provide the aryl nitrona according to the formula (1)." 26.- A compound of the formula (11), -:or; or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; at least one of A and B is C-R3, and the other is selected from C-R3 and N; At least one R3 is S02NR5R6, and the other R3 is independently selected from R4, H, lower alkyl, alkenyl, alkyl, halogen, aryl, S02NR5R6, S02Rs, C03H, C0NR5R6 and tetrazole; X, Y and Z are each independently selected from C-R4 and N; each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfanyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, substituted cycloalkyl cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl dialkylamino, substituted dialkylamino, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio; and Rs and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, or are joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected of NR1, O and S. 27.- A compound according to formula (12), (13) or (14): 12! i-i) i-t ' or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; A and B are independently selected from C-R3 and N; each R3 is independently selected from R4, H, lower alkyl, alkenyl, alkyl, halogen, aryl, S02NR5R6, S02R5, C02H, CONR5R6 and tetrazole; X, Y and Z are each independently selected from C-R4 and N; each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyl, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio; and R5 and Re are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, or are joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected of NR1, O and S; wherein the A adjacent to the nitrone group is C-S02NR5R6. 28.- A compound according to formula (15) or (16): V-S: or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; A and B are independently selected from C-R3 and N; each R3 is independently selected from R4, H, lower alkyl, alkenyl, alkyl, halogen, aryl, S02NR5R6, S02R5, C02H, CONR5R6 and tetrazole; X, Y and Z are each independently selected from C-R4 and N; each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheterosyl, dialkylamino, dialkylamino substituted, allo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio; and R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, or are joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected of NR1, 0 and S; wherein the A adjacent to the nitrone group is C-S02NR5R6. 29. A compound according to any of claims 26-28, wherein R4 is selected from H, lower alkyl, alkyl, alkenyl, halogen, aryl, aryloxy, S02NR5R6, C03H, CONR5R6 and tetrazole. 30. The pharmaceutical composition according to any of claims 26-29, wherein R2 is R11 I -C-R12 I R13 wherein each R11, R12 and R13 is independently selected from hydrogen, lower alkyl, alkyl, aryl, Arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl. 31. The compound according to claim 30, wherein each R11, R12 and R13 is independently alkyl or substituted alkyl. 32. The compound according to claim 30, wherein each R11, R12 and R13 is independently unsubstituted alkyl. 33. The compound according to claim 30, wherein each R11, R12 and R13 is independently unsubstituted lower alkyl. 34. The compound according to claim 30, wherein one of R11, R12 and R13 is methyl. 35. The compound according to claim 30, wherein two of R11, R12 and R13 are methyl. 36. The compound according to claim 30, wherein each of R11, R12 and R13 is methyl. 37.- A pharmaceutical composition comprising a compound according to any of claims 26-28, and a pharmaceutically acceptable carrier, excipient or diluent. 38.- A unit dosage form of the composition according to claim 37, comprises about 10, 25, 50, 100, 500, 1000, 2000 or 2500 mg of the compound 39.- A method to treat or prevent a condition ischemic or ischaemia / reperfusion related, comprising the step of administering an effective amount of the compound according to any of claims 26-28 to a subject in need of said treatment or prevention. A method for treating or preventing a chemokine-mediated condition comprising the step of administering an effective amount of a compound according to any of claims 26-28 to a subject in need of said treatment or prevention. 41. The method according to claim 39, wherein the subject is a mammal. 42. The method according to claim 39, wherein the subject is a human. 43. - The method according to claim 39, wherein the compound is administered orally. 44.- A device for treating or preventing an ischemic or reperfusion-related or ischemia-related or chemokine-mediated condition in a subject in need thereof comprising an effective amount of a pharmaceutical composition, the composition comprising a compound in accordance with any of claims 26-28, and a label or labeling with instructions for using the composition to treat or prevent the condition. 45. A method for making an aryl nitrone according to claim 26, comprising the step of reacting an aldehyde according to formula (17): With a hydroxylamine according to formula (18): To provide the aryl nitrone according to the formula (11). 46. - A compound of the formula (21 or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl or alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; Y is C-R9, and R9 is selected from S02NRsR6, S02R5, C02R5, CONR5R6 and tetrazole; A, B, X and Z are each independently selected from C-R4 and N; each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyl, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl dihydroxyphosphoryl substituted, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, substituted carbamoyl carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted, halo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, substituted heteroalkyl heteroalkyl, hydroxyl, nitro or thio; and R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, or are joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected of NR1, O and S, wherein the compound is none of the compounds 401-426. 47.- A compound according to formula (22), (23) or (24): (31 X- ^ v24 ' Or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R 2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl; Y is C-R9, and R9 is selected from S02NR5R6, S02R5, C02R5, CONR5R6 and tetrazole; A, B, X and Z are each independently selected from C-R4 and N; each R 4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamine, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulphanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, aminohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azide, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted , hyalo, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio; and R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, or are joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected of NR1, O and S. 48.- A compound according to formula (25) or (26); (35) or a pharmaceutically acceptable salt or solvate thereof, wherein: R1 is selected from H, lower alkyl and alkyl; R2 is selected from lower alkyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl, Y is C-R9, and R9 is selected from S02NR5R6, S02R5, C02R5, CONR5R6 and tetrazole; A, B, X and Z are each independently selected from C-R4 and N; each R4 is independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamine, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamine, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfanyl, substituted sulfanyl, aminosulfonyl, substituted aminosulfonyl, arylsulfonyl, substituted arylsulfonyl, sulfuric acid, sulfuric acid ester, dihydroxyphosphoryl, substituted dihydroxyphosphoryl, arainohydroxyphosphoryl, substituted aminohydroxyphosphoryl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cyclohetersalkyl, substituted cycloheteroalkyl, dialkylamino, dialkylamino substituted do, heteroaryloxy halo, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl, hydroxyl, nitro or thio; and R5 and R6 are each independently selected from H, lower alkyl, alkyl, aryl and heteroaryl, or are joined together to form a saturated or unsaturated cycloheteroalkyl ring containing 4 to 8 atoms, having zero, one or more heteroatoms selected of NR1, 0 and S. 49. The compound according to any of claims 46-48, wherein Y is C-S02NR5Rs. 50.- The compound according to any of claims 46-48, wherein Y is C-S02R5. 51. The compound according to any of claims 46-48, wherein Y is C-C02R5. 52. The compound according to any of claims 46-48, wherein Y is C-C02H. 53. The compound according to any of claims 46-48, wherein Y is C-CONR5R6. 54. The compound according to any of claims 46-48, wherein Y is C-tetrazole. The compound according to any of claims 46-54, wherein R2 is R11 I -C-R12 I R13 wherein each R11, R12 and R13 is independently selected from hydrogen, lower alkyl, alkyl, aryl, arylalkyl , cycloalkyl, heteroaryl, heteroarylalkyl and cycloheteroalkyl. 56. The compound according to claim 55, wherein each R11, R12 and R13 is independently alkyl or substituted alkyl. 57. The compound according to claim 55, wherein each R11, R12 and R13 is independently unsubstituted alkyl. 58. The compound according to claim 55, wherein each R11, R12 and R13 is independently unsubstituted lower alkyl. 59. The compound according to claim 55, wherein one of R11, R12 and R13 is methyl. 60.- The compound according to claim 55, wherein two of R11, R12 and R13 are methyl. 61. The compound according to claim 55, wherein each of R11, R12 and R13 is methyl. 62. A pharmaceutical composition comprising a compound according to any of claims 46-48, and a pharmaceutically acceptable carrier, excipient or diluent. 63.- A unit dosage form of the composition according to claim 62, comprising about 10, 256, 50, 100, 500, 1000, 2000 or 2500 mg of the compound. 64.- A method for treating or preventing an ischemic or ischaemia / reperfusion-related condition comprising the step of administering an effective amount of the compound according to any of claims 46-48 in a subject in need of said treatment or prevention. 65.- A method for treating or preventing a chemokine-mediated condition comprising the step of administering an effective amount of the compound according to any of claims 46-48 to a subject in need of said treatment or prevention. 66.- The method according to claim 64, where the subject is a mammal. 67.- The method according to claim 64, wherein the subject is a human. 68.- The method according to claim 64, wherein the compound is administered orally. 69.- A device for treating or preventing an ischemic or reperfusion-related or chemokine-mediated ischemic or ischemic condition in a subject in need thereof comprising an effective amount of a pharmaceutical composition, the composition comprising a compound in accordance with any of the claims 46-48, and a label or labeling with instructions for using the composition to treat or prevent the condition. 70. A method for making an aryl nitrone according to claim 46, comprising the step of reacting an aldehyde according to formula (27): With a hydroxylamine according to the formula (28) i '? and '011 (235 To provide aryl nitrone according to formula (21). 71. A compound selected from the group consisting of compounds 1-81, or a pharmaceutically acceptable salt or solvate thereof. 72.- A pharmaceutical composition comprising a compound according to claim 71, and a pharmaceutically acceptable carrier, excipient or diluent. 73. - A unit dosage form of the composition according to claim 72, comprising about 10, 25, 50, 100, 500, 1000, 2000 or 2500 mg of the compound. 74.- A method for treating or preventing an ischemic or reperfusion-related ischemic or ischemic condition comprising the step of administering an effective amount of the compound according to claim 71 to a subject in need of treatment or prevention. A method for treating or preventing a chemokine-mediated condition comprising the step of administering an effective amount of the compound according to claim 71 to a subject in need of said treatment or prevention. 76.- The method according to claim 74, wherein the subject is a mammal. 77.- The method according to claim 74, wherein the subject is a human. 78. The method according to claim 74, wherein the compound is administered orally. 79.- A device for treating or preventing an ischemic or reperfusion-related or ischemic or chemokine-mediated condition in a subject in need thereof comprising an effective amount of a pharmaceutical composition, a composition comprising the compound in accordance with the claim 71, and a label or labeling with instructions for using the composition to treat or prevent the condition.