HK1047039A1

HK1047039A1 - Method for treating chronic pain using mek inhibitors

Info

Publication number: HK1047039A1
Application number: HK02108607.6A
Authority: HK
Inventors: S‧D‧巴勒特; A‧J‧布利德格斯; H‧泰克; A‧迪克森; K‧利; R‧D‧品诺克; 张鲁岩; R‧D‧品諾克; 張魯岩
Original assignee: 沃尼尔‧朗伯公司
Priority date: 1999-07-16
Filing date: 2000-07-05
Publication date: 2003-02-07
Also published as: PE20010547A1; TR200200204T2; HUP0202381A3; CN1358095A; PL352705A1; WO2001005391A3; WO2001005391A2; CO5190702A1; AU5785900A; CA2377100A1; HUP0202381A2; KR20020015379A; IL147617A0; EP1202732A2; JP2003504399A; ZA200109903B; UY26248A1

Abstract

The invention features a method for treating chronic pain using the diarylamines disclosed in formula (I) of claim 1.

Description

Methods of treating chronic pain using MEK inhibitors

Technical Field

The invention features methods of treating chronic pain using MEK inhibitors. Chronic pain includes neuropathic pain, and chronic inflammatory pain.

Any abnormalities in nerve transmission interfere with nerve signals and are therefore not properly interpreted in the brain, causing neuropathic pain. Neuropathic pain can be, for example, deep pain, burning sensation, or hypersensitivity to the touch. Diseases or symptoms associated with neuropathic pain include, without limitation, diabetic neuropathy, causalgia, plexus aspiration, neuroma, vasculitis, crush injury, viral infection (e.g., herpes virus infection or HIV), constriction injury, tissue injury, nerve injury from the peripheral to central nervous system, amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and vitamin deficiency.

Infections such as herpes zoster can cause neuroinflammation and produce postherpetic neuralgia, a chronic burn located in the area of the viral infection. Hyperalgesia is when an already noxious stimulus becomes more painful, and allodynia, when a previously innocuous stimulus becomes painful (e.g. clothing or breezy contact). Reflex sympathetic dystrophy is accompanied by swelling and sweating or changes in local blood flow, tissue atrophy or osteoporosis. Causalgia, including severe burning pain and swelling, sweating, and changes in the blood flow, in turn, can cause injury or disease to major nerves, such as the sciatic nerve. Some types of chronic lower back pain can have neuropathic components (e.g., sciatica, post-polio, and CPRM). Neuropathic pain can also be induced by cancer or chemotherapy.

Neuropathic pain is now treated with anticonvulsants such as carbamazepine and antidepressants such as amitriptyline. NSAIDS and opioids generally have less of a role (Fields et al, 1994Textbook of Pain, p 991-996 (publication: Churchill Livingstone), James & Page 1994; J.Am.Peditar.Med.Assoc, 8: 439-447, Galer, 1995 Neurology 45S 17-S25. neuropathic conditions that have been treated with gabapentin include postherpetic neuralgia, post-polio, CPRM, HIV-related neuropathy, trigeminal neuralgia, and Reflex Sympathetic Dystrophy (RSD).

The generally poor efficacy of anti-inflammatory agents predicts that the mechanism of chronic pain is less related to hyperalgesia.

Summary of the invention

The invention features a method of treating chronic pain comprising the step of administering to a patient in need of such treatment a pharmaceutical composition comprising a MEK inhibitor. Chronic pain includes neuropathic pain, spontaneous pain, and pain associated with vitamin deficiency, uremia, hypothyroidism, postoperative pain, arthritis, back pain, and chronic alcoholism. The invention also features the disclosed compositions formulated for the treatment of chronic pain. Such compositions may comprise one or more MEK inhibitor compounds having the structure disclosed in patent application PCT/US99/30416 (international application date 1999, 12/21).

Examples of MEK inhibitors include compounds having the following formula (I):w is one of the following formulae (i) - (xiii):

X₁is O, S or NR_F。X₂Is OH, SH or NHR_E。R_EAnd R_FEach is H or C_1-4An alkyl group; r₁And R₂Independently selected from H, F, NO₂Br and Cl; r₁Or may be SO₂NR_GR_HOr R is₁And R₂Together with the phenyl ring to which they are attached form an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzothiazole. R₃Selected from H and F; r_G、R_HAnd R₄Each independently selected from H, Cl and CH₃。R₅Is H or C_1-4An alkyl group. Each of the above hydrocarbyl groups is optionally substituted with 1-3 substituents independently selected from halogen, hydroxy, amino, (amino) sulfonyl, and NO₂. Each of the above heterocyclic groups is optionally substituted with 1-3 substituents independently selected from halogen, C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_3-4Alkenyl radical, C_3-4Alkynyl, phenyl, hydroxy, amino, (amino) sulfonyl, and NO₂Wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally independently selected from halogen, C_1-2Alkyl, hydroxy, amino, and NO₂1-2 substituents of (A). The invention also relates to pharmaceutically acceptable salts or C of the disclosed compounds_1-8And (3) an ester. For example, the disclosed alcohol compounds may form esters having a structure represented by-C (═ O) C_1-7Acyl replacing H of hydroxyl.

Preferred embodiments of the present invention include methods of using one or more of the following compounds:

(a) the MEK inhibitor has a structure selected from: 2, 4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitrobenzoic acid; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; (2, 3-difluoro-6- [1, 3, 4] oxadiazol-2-yl-phenyl) (4-iodo-2-methyl-phenyl) -amine; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-thiol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; and 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; and

(b) the MEK inhibitor has a structure selected from: 2, 4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitrobenzoic acid.

Other aspects of the invention are provided in the following description and examples and the accompanying specification.

Brief description of the drawings

FIG. 1 is a bar graph showing Paw Withdrawal Threshold (PWT) (g) as a function of time (days). Empty, cross-hatched and single-hatched bars are vehicle, PD198306, and pregabalin, respectively. The arrow indicates the time of administration (30mg/kg, p.o.).

Figure 2 is a bar graph of force (grams) required to initiate paw withdrawal using von Frey hair filaments versus time (days). Baseline (BL) measurements were taken prior to treatment. Animals received a single p.o. dose of PD198306(3-30mg/kg) or pregabalin (30mg/kg) and reassessed the withdrawal threshold 1 hour after treatment. This treatment was repeated twice daily for two days. These results are expressed as the median ± first and third quartile.^*P＜0.05，^**P＜0.01，^***P < 0.001 is clearly different from vehicle-treated animals (Mann-Whitney t test; n-7-8).

FIG. 3 is the force (grams) and time (days) required to initiate paw withdrawal using von Frey hair filaments) A bar graph of the relationship of (1). Baseline (BL) measurements were taken prior to treatment. Animals received a single p.o. dose of PD198306(3-30mg/kg) or pregabalin (30mg/kg) and reassessed the withdrawal threshold 1 hour after treatment. This treatment was repeated twice daily for two days. These results are expressed as the median ± first and third quartile.^**P < 0.01 is clearly different from vehicle-treated animals (Mann-Whitney t test; n ═ 6).

Figure 4 is a bar graph of force (grams) required to initiate paw withdrawal using von Frey hair filaments versus time (days). Baseline (BL) measurements were taken prior to treatment. Animals received a single i.t. administration of either PD198306 (1-30. mu.g/10. mu.L) or pregabalin (100. mu.g/10. mu.L), and the withdrawal thresholds were re-assessed at 30 minutes, 1 hour and 2 hours after treatment. These results are expressed as the median ± first and third quartile.^*P＜0.05，^***P < 0.001 is clearly different from vehicle-treated animals (Mann-Whitney t test; n-7-9).

Figure 5 is a bar graph of force (grams) required to initiate paw withdrawal using von Frey hair filaments versus time (days). Baseline (BL) measurements were taken prior to treatment. Animals received a single i.t. administration of PD198306 (1-30. mu.g/10. mu.L) or pregabalin (100. mu.g/10. mu.L) and re-assessed paw withdrawal thresholds 30min, 1h and 2h after treatment. These results are expressed as the median ± first and third quartile.^*P＜0.05，^**P＜0.01，^***P < 0.001 is clearly different from vehicle-treated animals (Mann-Whitney t test; n-6-8).

Figure 6 is a bar graph of force (grams) required to initiate paw withdrawal using von Frey hair filaments versus time (days). Animals received a single intraplantar (i.pl.) administration of PD198306(3 mg/100. mu.L), or intrathecal injection administration of PD198306 (30. mu.g/10. mu.L), and paw withdrawal thresholds were re-assessed 1 hour after treatment. These results are expressed as the median ± first and third quartile.^**P < 0.01 is clearly different from vehicle-treated animals (Mann-Whitney t test, n ═ 6-9).

Figure 7 is a bar graph of force (grams) required to initiate paw withdrawal using von Frey hair filaments versus time (days). Animals received a single intraplantar (i.pl.) administration of PD198306(3 mg/100. mu.L), or intrathecal injection administration of PD198306 (30. mu.g/10. mu.L), and paw withdrawal thresholds were re-assessed 1 hour after treatment. These results are expressed as the median ± first and third quartile.^**P < 0.01 is clearly different from vehicle-treated animals (Mann-Whitney t test; n ═ 6).

FIG. 8 is a bar graph showing the force (grams) required to initiate paw withdrawal using von Frey hair filaments. Baseline (BL) measurements were taken prior to treatment. Animals received a single i.t. administration of PD219622, PD297447, PD184352 or PD254552(30 μ g/10 μ L), or pregabalin (100 μ g/10 μ L), and paw withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. These results are expressed as the median ± first and third quartile.^*P＜0.05，^**P＜0.01，^***P < 0.001 is clearly different from vehicle-treated animals (Mann-Whitney t test; n-7-8).

Detailed Description

The compounds disclosed herein have pharmaceutical activity, e.g., they inhibit MEK. MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation and proliferative diseases such as cancer and restenosis.

Proliferative diseases are caused by defects in the intracellular signaling system, or by the signal transduction mechanisms of certain proteins. These include changes in intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade. The cell may produce growth factors that bind to its own receptors, resulting in an autocrine loop that continues to stimulate proliferation. Variation or overexpression of intracellular signaling proteins can lead to intracellular pseudo-mitogenic signaling. Some of the most common variations occur in the gene encoding a protein, known as Ras, which is a G protein that is activated when bound to GTP and inactivated when bound to GDP. The growth factor receptors mentioned above, and many other mitogenic receptors, but when activated, result in the conversion of Ras from a GDP-bound state to a GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. In these signaling systems, especially in Ras-GTP complex deactivation defects are common in cancer, and lead to Ras below the signaling cascade by chronic activation.

Activated Ras in turn leads to activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require active Ras-GTP for its activation is the Raf family. These in turn activate MEK (e.g., MEK)₁And MEK₂) It then activates MAP kinase, ERK (ERK)₁And ERK₂). Activation of MAP kinase by mitogens appears to be essential for hyperplasia; constitutive activation of this kinase is sufficient to induce transformation of the cell. Blockade of downstream Ras signaling, for example by using a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or oncogenic Ras mutants. Although Ras is not a protein kinase per se, it is involved in the activation of Raf and other kinases, most likely by a phosphorylation mechanism. Once activated, Raf and other kinases bring two serine residues-S into close proximity²¹⁸And S²²²Phosphorylation of MEK (on MEK-1) is a prerequisite for activation of MEK as a kinase. MEK in turn enables tyrosine (Y) to be separated at a single amino acid¹⁸⁵) And threonine residues (T)¹⁸³) MAP kinases on both are phosphorylated.

This bisphosphorylation activates MAP kinase by at least 100-fold. Activated MAP kinases then catalyze the phosphorylation of a number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activated for target proteins such as kinases, transcription factors, or additional cellular proteins. In addition to Raf-1 and MEKK, other kinases activate MEK, which itself appears to be signal-integrating kinases. It is currently understood that MEK is highly specific for phosphorylation of MAP kinase. Indeed, no substrate for MEK other than MAP kinase ERK has been currently validated, and MEK does not phosphorylate peptides, or even denaturant MAP kinases, according to the MAP kinase phosphorylation sequence. MEK also appears to strongly associate with MAP kinase before phosphorylating it, suggesting that MAP kinase phosphorylation with MEK may require a strong interaction between the two proteins before. This need and the unusual specificity of MEK both suggest that there is a sufficient difference in its mechanism of action for other protein kinases to find selective inhibitors of MEK that may operate by allosteric mechanisms rather than by the usual blockade of ATP binding sites.

The effect of the MEK inhibitor PD198306 was investigated in two animal models of neuropathic pain by assessing static allodynia (static allodynia) with von Frey hair.

Oral administration of PD198306(3-30mg/kg) had no effect in the Chronic Constrictive Injury (CCI) model of the sciatic nerve. However, after repeated dosing (3 doses over 2 days), it had a temporary effect in the diabetic neuropathy model (streptozocin). This may be due to a blood brain barrier disorder induced by diabetic symptoms in these animals, thus allowing for a central effect of the compound. Intrathecal administration of PD198306(1-30 μ g) at the lowest effective dose (MED) of 3 and 10 μ g respectively will be dose dependent to block static allodynia in both the streptozocin and CCI models of neuropathic pain. The highest dose used (30 μ g) totally blocked the maintenance of static allodynia for up to 1 hour. Intraplantar administration of PD198306(3 mg/100. mu.l) had no effect on static allodynia in any model of neuropathic pain at a dose 100-fold higher than the dose that showed intrathecal efficacy (30. mu.g/10. mu.l). This finding confirms the lack of effect seen after systemic administration, suggesting a central location for the compound to act.

From this study we can suggest MEK inhibitors as potential new therapeutic tools for chronic pain. Future studies of potential side effects of MEK inhibitors, particularly those associated with memory, as brain penetrants will show therapeutic promise for this new class of compounds in the treatment of pain.

A. Term(s) for

Certain terms are defined below and used throughout this disclosure.

Alkyl groups include aliphatic groups having a free valence (i.e., a hydrocarbon group or hydrocarbon-based structure containing hydrogen and carbon atoms). Alkyl is understood to include both straight-chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2, 3-dimethylpropyl, hexyl, 2, 3-dimethylhexyl, 1, 1-dimethylpentyl, heptyl, and octyl. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The alkyl group can be substituted with 1, 2, 3, or more substituents independently selected from halogen (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkoxy, heterocyclyl, and (heterocyclyl) oxy. Specific examples include fluoromethyl, hydroxyethyl, 2, 3-dihydroxyethyl, (2-or 3-furyl) methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridyl) methyl, (2-or 3-furyl) methyl, (2-thienyl) ethyl, hydroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, N-pyridylethyl, diethylaminoethyl, and cyclobutylmethyl.

Alkenyl groups are similar to alkyl groups, but have at least one double bond (two adjacent sp)²Carbon atom). Depending on the double bond and the position of the substituents, the geometry of the double bond, if any, may be entgegen (E), or zusammen (Z), cis or trans. Similarly, an alkynyl group has at least one triple bond (two adjacent sp carbon atoms). The unsaturated alkenyl or alkynyl group may have one or more double or triple bonds, respectively, or mixtures thereof; like the alkyl radicals, the unsaturated radicals may be straight-chain or branched, and they canCan be substituted as described above for alkyl and throughout the disclosure in the examples. Examples of alkenyl, alkynyl, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3- (2' -fluorophenyl) -2-propynyl, 3-methyl (5-phenyl) -4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2-propenyl, 4-hydroxy-3-butynyl, 3- (3-fluorophenyl) -2-propynyl, and 2-methyl-2-propenyl. In formula (I), the alkenyl and alkynyl groups can be, for example, C_2-4Or C_2-8And is preferably C_3-4Or C_3-8。

More general forms of substituted hydrocarbyl include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and the corresponding forms prefixed with amino-, halogen- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl-, and the like, or mixtures of such substituents. Thus, according to formula (I), substituted alkyl groups include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkyl (branched alkyl, such as methylpentyl), (cycloalkyl) alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, aralkyl, aryloxyalkyl, arylalkoxyalkyl, (heterocyclyl) alkyl, and (heterocyclyl) oxyalkyl. R₁Thus included are hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl) alkyl, (haloaryl) alkyl, (hydroxyaryl) alkynyl, and the like. Similarly, R_AIncluding hydroxyalkyl and aminoaryl, and R_BIncluding hydroxyalkyl, aminoalkyl, and hydroxyalkyl (heterocyclyl) alkyl.

Heterocyclyl, which includes but is not limited to heteroaryl, includes: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1, 3, 4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, and their non-aromatic counterparts. Other examples of heterocyclyl groups include piperidinyl, quinolinyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiophenyl, and octahydrobenzofuranyl.

Selective MEK1 or MEK2 inhibitors are compounds that inhibit the MEK1 or MEK2 enzymes, respectively, but do not significantly inhibit other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinase, and C-src. In general, a selective MEK1 or MEK2 inhibitor has an IC50 for MEK1 or MEK2 that is its IC for one of the other enzymes named above₅₀At least one fiftieth (1/50). Preferably, the selective inhibitor has an IC₅₀Is its IC for one or more of the above named enzymes₅₀At least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less.

B. Compound (I)

One aspect of the invention features the disclosed compounds shown in formula (1) in the summary section.

Examples of the invention include compounds wherein: (a) r₁Is bromine or chlorine; (b) r₂Is fluorine; (c) r₃Is H; (d) r₂And R₃Each of which is H; (e) r₂And R₃Each of which is fluorine; (f) r₁Is bromine; (g) r₁、R₂And R₃Each of which is fluorine; (h) r₂Is a nitro group; (i) r₃Is H; (j) r₄Is chlorine; (k) r₄Is methyl; (1) r₅Is H; (m) R₅Is CH₃；(n)X₁Is O or S; (o) X₁Is NH or NCH₃；(p)X₂Is OH, SH or NH₂；(q)X₂Is OH; (r) X₂Is NHR_E；(s)R₄Is H; (t) R₄Is chloro or methyl; or a combination thereof.

Preferably, when one of the substituents on the heterocyclyl is alkenyl or alkynyl, the double or triple bond, respectively, is not adjacent to the point of attachment of the heteroatom. For example, in such cases, the substituent is preferably prop-2-ynyl, or but-2 or 3-ynyl, and less preferably prop-1-ynyl or but-1-ynyl.

Examples of compounds include: [ 5-fluoro-2- (1H-tetrazol-5-yl) phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [2, 3-difluoro-6- (1H-tetrazol-5-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; (4-iodo-2-methyl-phenyl) - [2, 3, 4-trifluoro-6- (1H-tetrazol-5-yl) -phenyl ] -amine; [ 4-bromo-2, 3-difluoro-6- (1H-tetrazol-5-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [ 5-fluoro-4-nitro-2- (1H-tetrazol-5-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [2- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -5-fluoro-phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [6- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -2, 3-difluoro-phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [6- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -2, 3, 4-trifluorophenyl ] - (4-iodo-2-methyl-phenyl) -amine; [ 4-bromo-6- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -2, 3-difluoro-phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [2- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -5-fluoro-4-nitro-phenyl ] - (4-iodo-2-methyl-phenyl) -amine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ol; and 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -4H- [1, 2, 4] triazol-3-ol.

Other examples include: 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; and 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -4H- [1, 2, 4] triazole-3-thiol.

Additional examples are: 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] -isothiazol-3-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] -isothiazol-3-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] -isothiazol-3-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -isothiazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -isoxazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -1H-pyrazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -isothiazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -isoxazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1-methyl-1H-pyrazol-3-ol; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1-methyl-1H-pyrazol-3-ol; 1-methyl-4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1-methyl-1H-pyrazol-3-ol; and 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -1-methyl-1H-pyrazol-3-ol.

The invention is also characterized by the following compounds, such as: 5- [2- (2-amino-4-iodo-phenylamino) -4-fluoro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [2- (2-amino-4-iodo-phenylamino) -3, 4-difluoro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [2- (2-amino-4-iodo-phenylamino) -3, 4, 5-trifluoro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [2- (2-amino-4-iodo-phenylamino) -5-bromo-3, 4-difluoro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [2- (2-amino-4-iodo-phenylamino) -4-fluoro-5-nitro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -3-methyl-3H- [1, 2, 3] triazol-4-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -3-methyl-3H- [1, 2, 3] triazol-4-ol; 3-methyl-5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -3H- [1, 2, 3] triazol-4-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -3-methyl-3H- [1, 2, 3] triazol-4-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitrophenyl ] -3-methyl-3H- [1, 2, 3] triazol-4-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2-methyl-2H-pyrazol-3-ol; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2-methyl-2H-pyrazol-3-ol; 2-methyl-4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-pyrazol-3-ol; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2-methyl-2H-pyrazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -2-methyl-2H-pyrazol-3-ol; 1- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4-methyl-1, 4-dihydro-tetrazol-5-one; 1- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4-methyl-1, 4-dihydro-tetrazol-5-one; 1-methyl-4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1, 4-dihydro-tetrazol-5-one; 1- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4-methyl-1, 4-dihydro-tetrazol-5-one; 1- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -4-methyl-1, 4-dihydro-tetrazol-5-one; 1- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H- [1, 2, 3] triazol-4-ol; 1- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H- [1, 2, 3] triazol-4-ol; 1- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H- [1, 2, 3] triazol-4-ol; 1- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H- [1, 2, 3] triazol-4-ol; and 1- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -1H- [1, 2, 3] triazol-4-ol.

Other examples of the invention include: 3- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-isoxazol-5-one; 3- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-isoxazol-5-one; 3- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-isoxazol-5-one; 3- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-isoxazol-5-one; 3- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -2H-isoxazol-5-one; [ 5-fluoro-2- (2-oxo-2, 3-dihydro-21 > 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] - (4-iodo-2-methylphenyl) -amine; [2, 3-difluoro-6- (2-oxo-2, 3-dihydro-21 > 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; (4-iodo-2-methyl-phenyl) - [2, 3, 4-trifluoro-6- (2-oxo-2, 3-dihydro-21 > 4_ - [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] -amine; [ 4-bromo-2, 3-difluoro-6- (2-oxo-2, 3-dihydro-21 > 4- [1, 2, 3, 5] oxathiadiazol-4-yl) phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [ 5-fluoro-4-nitro-2- (2-oxo-2, 3-dihydro-21 > 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H-isoxazol-5-one; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H-isoxazol-5-one; 4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H-isoxazol-5-one; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H-isoxazol-5-one; and 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -4H-isoxazol-5-one.

Other compounds, wherein R₁Can also be S0₂NR_GR_HOr R is₁And R₂Together with the phenyl ring to which they are bonded, form an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzothiazole, including the following groups:

group 1

(1) 2-fluoro-5- (5-hydroxy-1, 3, 4-oxadiazol-2-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy-1, 3, 4-oxadiazol-2-yl) -N-methyl-benzenesulfonamide

(3)2, 3-difluoro-5- (5-hydroxy-1, 3, 4-oxadiazol-2-yl) -4- (4-iodo-2-methyl-phenylamino) -N, N-dimethyl-benzenesulfonamide

(4)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (5-hydroxy-1, 3, 4-oxadiazol-2-yl) -N-methyl-N- (3-morpholin-4-yl-propyl) -benzenesulfonamide

(5) 2-fluoro-5- (5-hydroxy-1, 3, 4-oxadiazol-2-yl) -4- (4-iodo-phenylamino) -N- [2- (2-methoxy-ethoxy) -ethyl ] -benzenesulfonamide

(6) N- (2-dimethylamino-ethyl) -2-fluoro-5- (5-hydroxy-1, 3, 4-oxadiazol-2-yl) -4- (4-iodo-phenylamino) -N-methyl-benzenesulfonamide

2 groups of

(1)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide

(3)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-benzenesulfonamide

(5)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(6)4- (5-amino-1, 3, 4-oxadiazol-2-yl) -2-fluoro-5- (4-iodo-phenylamino) -benzenesulfonamide

2b group

(2)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-phenylamino) -N-methyl-N- (3-morpholin-4-yl-propyl) -benzenesulfonamide

(4)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(5)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-N- [3- (4-methyl-piperazin-1-yl) -propyl ] -benzenesulfonamide

(6)5- (5-amino-1, 3, 4-oxadiazol-2-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-N- (3-piperidin-1-yl-propyl) -benzenesulfonamide

Group 3

(1) 2-fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-mercapto-1, 3, 4-oxadiazol-2-yl) -benzenesulfonamide

(2) 2-fluoro-5- (4-iodo-phenylamino) -4- (5-mercapto-1, 3, 4-oxadiazol-2-yl) -benzenesulfonamide

(3)2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-mercapto-1, 3, 4-oxadiazol-2-yl) -benzenesulfonamide

(4) 2-fluoro-4- (4-iodo-phenylamino) -5- (5-mercapto-1, 3, 4-oxadiazol-2-yl) -benzenesulfonamide

(5)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (5-mercapto-1, 3, 4-oxadiazol-2-yl) -benzenesulfonamide

(6)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-mercapto-1, 3, 4-oxadiazol-2-yl) -benzenesulfonamide

4 groups of

(1) 2-fluoro-5- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2) 2-fluoro-4- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide

(3)2, 3-difluoro-5- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4) 2-fluoro-5- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide

(5)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -benzenesulfonamide

(6)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy-1, 3, 4-thiadiazol-2-yl) -benzenesulfonamide

5 groups of

(1)5- (5-amino-1, 3, 4-thiadiazol-2-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)4- (5-amino-1, 3, 4-thiadiazol-2-yl) -5- (4-iodo-phenylamino) -2-mercapto-benzenesulfonamide

(3)5- (5-amino-1, 3, 4-thiadiazol-2-yl) -2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)5- (5-amino-1, 3, 4-thiadiazol-2-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(5)5- (5-amino-1, 3, 4-thiadiazol-2-yl) -4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-benzenesulfonamide

(6)5- (5-amino-1, 3, 4-thiadiazol-2-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide

6 groups of

(1) 2-fluoro-5- (5-hydroxy-4H-1, 2, 4-triazol-3-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2) 2-fluoro-4- (5-hydroxy-4H-1, 2, 4-triazol-3-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide

(3)2, 3-difluoro-5- (5-hydroxy-4H-1, 2, 4-triazol-3-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)5- [4- (2-dimethylamino-ethyl) -5-hydroxy-4H-1, 2, 4-triazol-3-yl ] -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(5)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (5-hydroxy-4H-1, 2, 4-triazol-3-yl) -benzenesulfonamide

(6)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy-4-methyl-4H-1, 2, 4-triazol-3-yl) -benzenesulfonamide

7 groups of

(1)5- (5-amino-4H-1, 2, 4-triazol-3-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)4- (5-amino-4H-1, 2, 4-triazol-3-yl) -2-fluoro-5- (4-iodo-phenylamino) -benzenesulfonamide

(3)5- (5-amino-4-methyl-4H-1, 2, 4-triazol-3-yl) -2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)5- [ 5-amino-4- (3-dimethylamino-propyl) -4H-1, 2, 4-triazol-3-yl ] -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(5)5- (5-amino-4H-1, 2, 4-triazol-3-yl) -4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-benzenesulfonamide

(6)5- (5-amino-4-methyl-4H-1, 2, 4-triazol-3-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide

8 groups of

(1) 2-fluoro-5- (3-hydroxy-isoxazol-5-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2) 2-fluoro-4- (3-hydroxy-isoxazol-5-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide

(3)2, 3-difluoro-5- (3-hydroxy-isoxazol-5-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4) 2-fluoro-5- (3-hydroxy-isoxazol-5-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide

(5)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (3-hydroxy-isoxazol-5-yl) -benzenesulfonamide

(6)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (3-hydroxy-isoxazol-5-yl) -benzenesulfonamide

9 groups of

(1)5- (3-amino-isoxazol-5-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)4- (3-amino-isoxazol-5-yl) -2-bromo-5- (4-iodo-phenylamino) -benzenesulfonamide

(3)5- (3-amino-isoxazol-5-yl) -2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)5- (3-amino-isoxazol-5-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(5)5- (3-amino-isoxazol-5-yl) -4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-benzenesulfonamide

(6)5- (3-amino-isoxazol-5-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide

10 groups of

(1) 2-fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide

(2)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide

(3)2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide

(4)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide

(5) 2-fluoro-4- (4-iodo-phenylamino) -5- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide

(6) 2-bromo-5- (4-iodo-phenylamino) -4- (3-mercapto-isoxazol-5-yl) -benzenesulfonamide

11 groups of

(1) 2-fluoro-5- (3-hydroxy-isoxazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (3-hydroxy-isoxazol-4-yl) -benzenesulfonamide

(3)2, 3-difluoro-5- (3-hydroxy-isoxazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (3-hydroxy-isoxazol-4-yl) -benzenesulfonamide

(5) 2-fluoro-5- (3-hydroxy-isoxazol-4-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide

(6) 2-bromo-4- (3-hydroxy-isoxazol-4-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide

12 groups of

(1)5- (3-amino-isoxazol-4-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)5- (3-amino-isoxazol-4-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide

(3)5- (3-amino-isoxazol-4-yl) -2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)5- (3-amino-isoxazol-4-yl) -4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-benzenesulfonamide

(5)5- (3-amino-isoxazol-4-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(6)4- (3-amino-isoxazol-4-yl) -2-chloro-5- (4-iodo-phenylamino) -benzenesulfonamide

13 groups of

14 groups of

(1)5- (2-amino-5H-pyrrol-3-yl) -2-fluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)5- (2-amino-5H-pyrrol-3-yl) -4- (2-chloro-4-iodo-phenylamino) -2-fluoro-benzenesulfonamide

(3)5- (2-amino-5H-pyrrol-3-yl) -2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)5- (2-amino-5H-pyrrol-3-yl) -4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-benzenesulfonamide

(5)5- (2-amino-5H-pyrrol-3-yl) -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(6)4- (2-amino-5H-pyrrol-3-yl) -2-chloro-5- (4-iodo-phenylamino) -benzenesulfonamide

15 groups of

(1) 2-fluoro-5- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy-1H-pyrazol-4-yl) -benzenesulfonamide

(3)2, 3-difluoro-5- (5-hydroxy-1H-pyrazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (5-hydroxy-1H-pyrazol-4-yl) -benzenesulfonamide

(5) 2-fluoro-5- { 5-hydroxy-1- [3- (4-methyl-piperazin-1-yl) -propyl ] -1H-pyrazol-4-yl } -4- (4-iodo-phenylamino) -benzenesulfonamide

(6) 2-fluoro-4- (5-hydroxy-1H-pyrazol-4-yl) -5- (4-iodo-phenylamino) -benzenesulfonamide

16 groups of

(1) 2-fluoro-5- (5-hydroxy-3-methyl-3H-1, 2, 3-triazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(2)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-hydroxy-3H-1, 2, 3-triazol-4-yl) -benzenesulfonamide

(3)2, 3-difluoro-5- (5-hydroxy-3H-1, 2, 3-triazol-4-yl) -4- (4-iodo-2-methyl-phenylamino) -benzenesulfonamide

(4)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (5-hydroxy-3H-1, 2, 3-triazol-4-yl) -benzenesulfonamide

(5) 2-fluoro-5- (5-hydroxy-3H-1, 2, 3-triazol-4-yl) -4- (4-iodo-phenylamino) -benzenesulfonamide

(6) 2-fluoro-5- { 5-hydroxy-3- [2- (2-methoxy-ethoxy) -ethyl ] -3H-1, 2, 3-triazol-4-yl } -4- (4-iodo-phenylamino) -benzenesulfonamide

17 group of

18 groups of

(1) 2-fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

(2)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

(3)2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

(4)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

(5) 2-fluoro-4- (4-iodo-phenylamino) -5- (5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

(6)2, 6-difluoro-3- (4-iodo-phenylamino) -4- (5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

19 groups of

(1) 2-fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (4-methyl-5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

(2)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (4-methyl-5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

(5)5- [4- (2-dimethylamino-ethyl) -5-oxo-4, 5-dihydro-tetrazol-1-yl ] -2-fluoro-4- (4-iodo-phenylamino) -benzenesulfonamide

(6) 2-fluoro-5- (4-iodo-phenylamino) -4- (4-methyl-5-oxo-4, 5-dihydro-tetrazol-1-yl) -benzenesulfonamide

20 groups of

(1) 2-fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(2)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(3)2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(4)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(5) 2-fluoro-4- (4-iodo-phenylamino) -5- (2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(6) 2-fluoro-5- (4-iodo-phenylamino) -4- (2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

21 groups of

(1) 2-fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (3-methyl-2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(2)2, 6-difluoro-3- (4-iodo-phenylamino) -4- (3-methyl-2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(3)2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (3-methyl-2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(4) 2-fluoro-4- (4-iodo-phenylamino) -5- (3-methyl-2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(5)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (3-methyl-2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

(6)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-N-methyl-5- (3-methyl-2-oxo-2, 3-dihydro-1, 2, 3, 5-oxathiadiazol-4-yl) -benzenesulfonamide

22 groups of

(1) 2-fluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-oxo-2, 5-dihydro-isoxazol-3-yl) -benzenesulfonamide

(2)2, 6-difluoro-3- (4-iodo-phenylamino) -4- (5-oxo-2, 5-dihydro-isoxazol-3-yl) -benzenesulfonamide

(3)2, 3-difluoro-4- (4-iodo-2-methyl-phenylamino) -5- (5-oxo-2, 5-dihydro-isoxazol-3-yl) -benzenesulfonamide

(4) 2-fluoro-4- (4-iodo-phenylamino) -5- (5-oxo-2, 5-dihydro-isoxazol-3-yl) -benzenesulfonamide

(5)4- (2-chloro-4-iodo-phenylamino) -2, 3-difluoro-5- (5-oxo-2, 5-dihydro-isoxazol-3-yl) -benzenesulfonamide

(6)4- (2-chloro-4-iodo-phenylamino) -2-fluoro-5- (5-oxo-2, 5-dihydro-isoxazol-3-yl) -benzenesulfonamide

23 groups of

(1)5- [6- (4-iodo-2-methyl-phenylamino) -1H-benzimidazol-5-yl ] -1, 3, 4-oxadiazol-2-ol

(2)5- [6- (4-iodo-phenylamino) -benzofuran-5-yl ] -1, 3, 4-oxadiazol-2-ol

(3)5- [ 7-fluoro-6- (4-iodo-2-methyl-phenylamino) -benzooxazol-5-yl ] -1, 3, 4-oxadiazol-2-ol

(4)5- [5- (4-iodo-phenylamino) -benzofuran-6-yl ] -1, 3, 4-oxadiazol-2-ol

(5)5- [6- (2-chloro-4-iodo-phenylamino) -7-fluoro-1, 3-dihydro-isobenzofuran-5-yl ] -1, 3, 4-oxadiazol-2-ol

(6)5- [6- (2-chloro-4-iodo-phenylamino) - ] -methyl-1H-benzimidazol-5-yl ] -1, 3, 4-oxadiazol-2-ol

24 groups of

(1)5- [ 2-amino-6- (4-iodo-2-methyl-phenylamino) -1H-benzimidazol-5-yl ] -1, 3, 4-oxadiazol-2-ol

(2)5- [6- (4-iodo-phenylamino) -benzo [ b ] thiophen-5-yl ] -1, 3, 4-oxadiazol-2-ol

(3)5- [ 7-fluoro-6- (4-iodo-2-methyl-phenylamino) -benzothiazol-5-yl ] -1, 3, 4-oxadiazol-2-ol

(4)5- [5- (4-iodo-phenylamino) -benzo [ b ] thiophen-6-yl ] -1, 3, 4-oxadiazol-2-ol

(5)5- [6- (2-chloro-4-iodo-phenylamino) -7-fluoro-1, 3-dihydro-benzo [ c ] thiophen-5-yl ] -1, 3, 4-oxadiazol-2-ol

(6)5- [6- (2-chloro-4-iodo-phenylamino) -2-oxo-2, 3-dihydro-1H-2 $1 > 4-oxa-2, 1, 3-benzothiadiazol-5-yl ] -1, 3, 4-oxadiazol-2-ol

25 groups of

(1)5- [ 2-amino-6- (4-iodo-2-methyl-phenylamino) -benzothiazol-5-yl ] -1, 3, 4-oxadiazol-2-ol

(2)5- [6- (4-iodo-phenylamino) -1H-indol-5-yl ] -1, 3, 4-oxadiazol-2-ol

(4)5- [5- (4-iodo-phenylamino) -1H-indol-6-yl ] -1, 3, 4-oxadiazol-2-ol

(5)5- [6- (2-chloro-4-iodo-phenylamino) -7-fluoro-2, 3-dihydro-1H-isoindol-5-yl ] -1, 3, 4-oxadiazol-2-ol

(6)5- [5- (2-chloro-4-iodo-phenylamino) -1H-indazol-6-yl ] -1, 3, 4-oxadiazol-2-ol

26 groups of

(2)5- [6- (4-iodo-phenylamino) -1H-indol-5-yl ] -1, 3, 4-oxadiazol-2-ol

(4)5- [5- (4-iodo-phenylamino) -benzooxazol-6-yl ] -1, 3, 4-oxadiazol-2-ol

C. Synthesis of

The disclosed compounds can be synthesized according to schemes 1-25 or their analogous variations. These synthetic strategies are further exemplified in examples 1-8 below. The solvent between compounds 4 and 5 in scheme 1 is toluene (PhMe). Reaction scheme 1Reaction scheme 2Reaction scheme 3Reaction scheme 4Reaction scheme 5Reaction scheme 6Reaction scheme 7Reaction scheme 8Reaction scheme 9Reaction scheme 10Reaction scheme 11Reaction scheme 12Reaction scheme 13Reaction scheme 14Reaction scheme 15Reaction scheme 16Reaction scheme 17Reaction scheme 18Reaction scheme 19Reaction sequence 20Reaction scheme 21Reaction sequence 22Alternative synthesis:reaction scheme 23Reaction scheme 24Reaction scheme 25

D. Use of

The disclosed compositions are useful as prophylactic and therapeutic treatments for diseases or conditions associated with chronic pain, including neuropathic pain, as provided in the summary section, as well as diseases or conditions modulated by the MEK cascade. For example, in one embodiment, the disclosed methods relate to post-operative pain, phantom limb pain, causalgia, gout, trigeminal neuralgia, acute post-herpetic and post-herpetic pain, causalgia, diabetic neuropathy, plexus extraction, neuroma, vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritic pain, or amputation.

For example, topical injuries may be treated with topical administration. Chronic pain affects the entire body, as diabetic neuropathy can be treated with systemic administration (injection or oral) of the disclosed compositions. Treatment of chronic pain confined to the lower body (e.g., post-operative pain) can be centrally (e.g., epidural) administered. Formulations and methods of administration can include the use of more than one MEK inhibitor or the combined use of a MEK inhibitor and another agent, such as an anti-inflammatory, analgesic, muscle relaxant, or anti-infective agent. Preferred routes of administration are oral, intrathecal or epidural, subcutaneous, intravenous, intramuscular, and for mammals other than humans intraplantar, and preferably epidural.

1. Dosage form

According to known methods, the person skilled in the art is able to determine the appropriate dosage for a patient by taking into account factors such as age, weight, general health, type of pain to be treated and the presence or absence of other medication. Generally, an effective amount per day is between 0.1 and 1000mg/kg, preferably between 1 and 300mg/kg body weight, and a daily dose for an adult subject of normal body weight is between 10 and 5000 mg. 100mg, 200mg, 300mg, or 400mg of commercially available capsules or other formulations (such as liquids and film coated tablets) can be administered according to the disclosed methods.

2. Formulation of

Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers suitable for dividing into individual doses. Dosage unit forms can also be adapted for various methods of administration, including sustained release formulations, such as subcutaneous implants. Methods of administration include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, topical (drops, powders, ointments, gels, or creams), and administration by inhalation (oral or nasal spray).

Parenteral formulations include pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity is maintained by the use of a coating agent such as lecithin, a surfactant, or by the maintenance of suitable particle size. The carrier of the solid dosage form comprises (a) a filler or bulking agent, (b) a binder, (c) a humectant, (d) a disintegrant, (e) a dissolution retardant, (f) an absorption enhancer, (g) an adsorbent, (h) a lubricant, (i) a buffer, and (6) a propellant.

The compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as sugars or sodium chloride; absorption-extending agents such as aluminum monostearate and gelatin; and an absorption enhancer.

3. Related compounds

The present invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; a masked or protected form; and racemic mixtures, or enantiomers or optically pure forms.

Pharmaceutically acceptable salts, esters, and amides include carboxylic acid ester salts (e.g., C_1-8Alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclyl), amino acid addition salts, esters, and amides that are pharmacologically effective within a reasonable benefit/hazard ratio range, and are suitable for contact with the tissues of patients without excessive toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, cis-maleateButenedioic acid salts, fumaric acid salts, succinic acid esters, tartaric acid salts, naphthoic acid salts, methanesulfonic acid salts, gluconic acid salts, lactobionic acid salts, and dodecyl sulfonic acid salts. These may include alkali metal and alkaline earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethylammonium, methylamine, trimethylamine, and ethylamine. See, e.g., s.m. berge et al, "pharmaceutical salts", j.pharm. sci., 1977, 66: 1-19, incorporated herein by reference. Representative pharmaceutically acceptable amides of the present invention include those derived from ammonia, primary C_1-6Alkylamine and secondary di (C)_1-6Alkyl) amine derived ones. Secondary amines include 5-or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally 1-2 other heteroatoms. Preferred amides are from ammonia, C_1-3Primary alkyl amine, and di (C)_1-2Alkyl) amine derived. Representative pharmaceutically acceptable esters of the invention include C_1-7Alkyl radical, C_5-7Cycloalkyl, phenyl, and phenyl (C)_1-5) An alkyl ester. Preferred esters include methyl esters.

The invention also includes the disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by protecting groups. Some of these masked or protected compounds are pharmaceutically acceptable; others are useful as intermediates. The synthetic intermediates and methods disclosed herein, with minor modifications thereof, are also within the scope of the present invention.

Hydroxy protecting group

Hydroxyl protecting groups include: ethers, esters, and protects 1, 2-and 1, 3-diols. The ether protecting group includes: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers, and silyl ethers are converted to other functional groups.

Substituted methyl ethers

Substituted methyl ethers include: methoxymethyl, methylthiomethyl, tert-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolylmethyl, tert-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2, 2, 2-trichloroethoxymethyl, bis (2-chloro-ethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxygen (dioxidido), 1- [ (2-chloro-4-methyl) phenyl ] -4-methoxypiperidin-4-yl, 1, 4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, and 2, 3, 3a, 4, 5, 6, 7, 7 a-octahydro-7, 8, 8-trimethyl-4, 7-ethanobenzofuran-2-yl.

Substituted ethyl ethers

Substituted ethyl ethers include: 1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, and benzyl.

Substituted benzyl ethers

Substituted benzyl ethers include: p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-and 4-picolyl, 3-methyl-2-picolyl N-oxyalkylene (oxido), diphenylmethyl, p, p ' -dinitrodiphenylmethyl, 5-dibenzosuberyl, trityl, alpha-naphthyldiphenyl-methyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri- (p-methoxyphenyl) methyl, 4- (4 ' -bromobenzoyloxy) phenyldiphenylmethyl, 4, 4 ' -tris (4, 5-dichlorophthalimidophenyl) methyl, 4, 4 ', 4 "-tris (acetylpropionyloxyphenyl) methyl, 4, 4', 4" -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ', 4 "-dimethoxyphenyl) -methyl, 1, 1-bis (4-methoxyphenyl) -1' -pyrenylmethyl, 9-anthracenyl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthracenyl, 1, 3-benzodithiolan-2-yl, and benzisothiazolyl S, S-dioxyene.

Silyl ethers

Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-benzylsilyl, triphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl. Esters as pesticides

Ester protecting groups include: esters, carbonates, cleavage aids, miscellaneous esters, and sulfonates.

Esters as pesticides

Examples of protected esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, P-chlorophenoxyacetate, P-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4, 4- (ethylenedithio) pentanoate, pivalate, adamantanecarboxylate, crotonate, 4-methoxycrotonate, benzoate, P-benzoate, and 2, 4, 6-trimethylbenzoate (m-trimethylbenzoate).

Carbonic acid esters

The carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2, 2, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.

Assisted splitting

Examples of cleavage-assisting protecting groups include: 2-iodobenzoate, 4-azido-butyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzene-sulfonate, 2- (methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2- (methylthiomethoxymethyl) benzoate.

Hybrid esters

In addition to the above types, miscellaneous esters include: 2, 6-dichloro-4-methylphenoxyacetate, 2, 6-dichloro-4- (1, 1, 3, 3-tetramethylbutyl) phenoxyacetate, 2, 4-bis (1, 1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate (tiglate), o- (methoxycarbonyl) benzoate, P-benzoate, α -naphthoate, nitrate, N' -tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2, 4-dinitrophenylsulfenate.

Sulfonic acid ester

The protective sulfates include: sulfate, methane sulfonate (methanesulfonate), benzyl sulfonate, and tosylate. Protection of 1, 2-and 1, 3-diols

Protecting groups for 1, 2 and 1, 3-diol groups include: cyclic acetals and ketals, cyclic orthoesters, and silyl derivatives.

Cyclic acetals and ketals

Cyclic acetals and ketals include: methylene, ethylene, 1-tert-butylethylene, 1-phenylethylene, (4-methoxyphenyl) ethylene, 2, 2, 2-trichloroethylene, acetonide (isopropylidene), cyclopentylene, cyclohexylene, cycloheptylene, benzylene, p-methoxybenzylene, 2, 4-dimethoxybenzylene, 3, 4-dimethoxybenzylene, and 2-nitrobenzylene.

Cyclic ortho esters

Cyclic orthoesters include: methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylene, 1-ethoxyethylene, 1, 2-dimethoxyethylene, α -methoxybenzylidene, 1- (N, N-dimethylamino) ethylidene derivative, α - (N, N-dimethylamino) benzylidene derivative, and 2-oxocyclopentylidene. Protection of carboxyl groups

Esters as pesticides

Ester protecting groups include: esters, substituted methyl esters, 2-substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, hybrid derivatives, and stannyl esters.

Substituted methyl esters

Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, phenacyl, p-bromobenzoylmethyl, α -methylbenzoylmethyl, p-methoxybenzoylmethyl, carboxamidomethyl, and N-phthalimidomethyl.

2-substituted ethyl ester

The 2-substituted ethyl ester comprises: 2, 2, 2-trichloroethyl, 2-haloethyl, 1-chloroalkyl, 2- (trimethylsilyl) ethyl, 2-methylthioethyl, 1, 3-dithianyl-2-methyl, 2- (p-nitrophenylsulfenyl) -ethyl, 2- (p-toluenesulfonyl) ethyl, 2- (2' -pyridyl) ethyl, 2- (diphenylphosphino) ethyl, 1-methyl-1-phenylethyl, tert-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamyl, alpha-methylcinnamyl, phenyl, p- (methylmercapto) -phenyl, and a benzyl group.

Substituted benzyl esters

Substituted benzyl esters include: trityl, benzhydryl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2- (9, 10-dioxo) anthrylmethyl, 5-dibenzo-cycloheptyl, 1-pyrenylmethyl, 2- (trifluoromethyl) -6-chromylmethyl, 2, 4, 6-trimethylbenzyl, P-bromobenzyl, o-nitrobenzyl, P-methoxybenzyl, 2, 6-dimethoxybenzyl, 4- (methylsulfinyl) benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl.

Silyl esters

Silyl esters include: trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl, and di-t-butylmethylsilyl.

Hybrid derivatives

Miscellaneous derivatives include: oxazole, 2-alkyl-1, 3-oxazoline, 4-alkyl-5-oxo-1, 3-oxazolidine, 5-alkyl-4-oxo-1, 3-dioxolane, orthoesters, phenyl, and pentaaminocobalt (III) complex.

Stannyl esters

Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl. Amides and hydrazides

The amide includes: n, N-dimethyl, pyrrolidinyl, piperidinyl, 5, 6-dihydrophenanthridinyl, o-nitroanilide, N-7-nitroindolyl, N-8-nitro-1, 2, 3, 4-tetrahydroquinolinyl, and P-P-benzenesulfonamide. Hydrazides include: n-phenyl, N' -diisopropyl and other dialkyl hydrazides. Protection of amino groups

Carbamates

Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.

Carbamates, their preparation and their use

Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 9- (2, 7-dibromo) fluorenylmethyl, 2, 7-di-tert-butyl- [9- (10, 10-dioxo-10, 10, 10, 10-tetrahydro-thioxanthyl) ] methyl, and 4-methoxybenzoylmethyl.

Substituted ethyl radical

Substituted ethyl protecting groups include: 2, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1, 1-dimethyl-2-haloethyl, 1, 1-dimethyl-2, 2-dibromoethyl, 1, 1-dimethyl-2, 2, 2-trichloroethyl, 1-methyl-1- (4-biphenyl) ethyl, 1- (3, 5-di-tert-butylphenyl) -1-methylethyl, 2- (2 '-and 4' -pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) -ethyl, tert-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, quinolinyl, N-hydroxypiperidinyl, alkyldithiol, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2, 4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and benzhydryl.

Assisted splitting

Protection via assisted fragmentation includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1, 3-dithianyl) ] methyl, 4-methylthiophenyl, 2, 4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1, 1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxyboryl) benzyl, 5-benzisoxazolyl-methyl, and 2- (trifluoromethyl) -6-chromonylmethyl.

Splitting by photolysis

Photolytic cleavage methods use groups such as: m-nitrophenyl, 3, 5-dimethoxybenzyl, o-nitrobenzyl, 3, 4-dimethoxy-6-nitrobenzyl, and phenyl (o-nitrophenyl) methyl.

Urea type derivative

Examples of urea-type derivatives include: phenothiazinyl- (10) -carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl, and N' -phenylaminothiocarbonyl.

Hybrid carbamates

In addition to those mentioned above, hybrid carbamates include: tert-pentyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2, 2-dimethoxycarbonylvinyl, o- (N, N-dimethyl-carboxamido) -benzyl, 1, 1-dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1, 1-dimethyl-propynyl, bis (2-pyridyl) methyl, 2-furylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p (p' -methoxyphenyl-azo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropyl-methyl, 1-methyl- (3, 5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-phenylazophenyl) -ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2, 4, 6-tri-tert-butylphenyl, 4- (trimethylammonium) benzyl, and 2, 4, 6-trimethylbenzyl. Amides of amides

Amides of carboxylic acids

The amide includes: n-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridyl-carboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, and N-p-phenylbenzoyl.

Assisted splitting

The cleavage assisting group includes: n-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N' -dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl, N-3- (o-nitrophenyl) propionyl, N-2-methyl-2- (o-nitrophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o- (benzoyloxymethyl) benzoyl, and 4, 5-diphenyl-3-oxazolin-2-one.

Cyclic imide derivatives

The cyclic imide derivative includes: n-phthalimide, N-dithiasuccinoyl, N-2, 3-diphenyl-maleoyl, N-2, 5-dimethylpyrrolyl, N-1, 1, 4, 4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1, 3-dimethyl-1, 3, 5-triazacyclohexan-2-one, 5-substituted 1, 3-dibenzyl-1, 3, 5-triazacyclohexan-2-one, and 1-substituted 3, 5-dinitro-4-pyridonyl.

Special-NH protective groups

Protecting groups for-NH include: n-alkyl and N-aryl amines, imine derivatives, enamine derivatives, and N-heteroatom derivatives (e.g., N-metal, N-N, N-P, N-Si, and N-S), N-sulfenyl, and N-sulfonyl.

N-alkyl and N-aryl amines

N-alkyl and N-aryl amines include: the alkyl group of N-methyl, N-allyl,

n- [2- (trimethylsilyl) ethoxy ] -methyl, N-3-acetoxypropyl,

n- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salt,

n-benzyl, N-bis (4-methoxyphenyl) methyl, N-5-dibenzocycloheptyl,

n-trityl group, N- (4-methoxyphenyl) diphenylmethyl group, N-9-phenylfluorenyl group,

n-2, 7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine N' -oxide.

Imine derivatives

The imine derivative includes: n-1, 1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N- [ (2-pyridyl)  -yl ] methylene, N- (N ', N ' -dimethylaminomethylene), N, N ' -isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N- (5-chloro-2-hydroxyphenyl) phenyl-methylene, and N-cyclohexylidene.

Enamine derivatives

An example of an enamine derivative is N- (5, 5-dimethyl-3-oxo-1-cyclohexenyl).

N-heteroatom derivatives

N-metal derivatives include: n-borane derivatives, N-diphenylboronic acid derivatives, N- [ phenyl (chromium pentacarbonyl-or-tungsten) ] carbene-based, and N-copper or N-zinc chelates. Examples of N-N derivatives include: n-nitro, N-nitroso, and N-oxide. Examples of N-P derivatives include: n-diphenylphosphinyloxyphosphine, N-dimethylthiophosphinyl, N-diphenylphosphinyloxyphosphine, N-dialkylphosphoryl, N-dibenzylphosphoryl, and N-diphenylphosphoryl. Examples of the N-sulfenyl derivative include: n-benzenesulfenyl, N-o-nitrobenzenesulfonyl, N-2, 4-dinitrobenzenesulfenyl, N-pentachlorophenylsulfenyl, N-2-nitro-4-methoxy-benzenesulfenyl, N-triphenylmethylsulfinylene and N-3-nitropyridinesulfonyl. N-sulfonyl derivatives include: n-p-toluenesulfonyl, N-benzenesulfonyl, N-2, 3, 6-trimethyl-4-methoxybenzenesulfonyl, N-2, 4, 6-trimethoxybenzenesulfonyl, N-2, 6-dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2, 3, 5, 6-tetramethyl-4-methoxybenzenesulfonyl, N-2, 4, 6-trimethylbenzenesulfonyl, N-2, 6-dimethoxy-4-methylbenzenesulfonyl, N-2, 2, 5, 7, 8-pentamethylbenzodihydropyran-6-sulfonyl, N-methanesulfonyl, n-beta-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4- (4 ', 8' -dimethoxynaphthylmethyl) -benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, and N-benzoylmethylsulfonyl.

The disclosed compounds that are masked or protected can be prodrugs, compounds that are metabolized or converted in vivo to the disclosed compounds, e.g., instantaneously during metabolism. This transition may be hydrolysis or oxidation, due to contact with body fluids such as blood, or due to acids, or the action of liver, gastrointestinal or other enzymes.

The features of the present invention are further described in the following examples.

E. Examples of the embodiments

Biological examples

Example 1

Effect of PD198306 on streptozocin-induced static allodynia

Animal(s) production

Male Sprague Dawley rats (250-300g), obtained from Bantin and Kingman (Hull, U.K.), were housed in groups of three. All animals were kept in a 12h light/dark cycle (starting at 07h 00min lighting) with no food and water limitation. All experiments were performed by observers who did not see drug treatment.

Development of diabetes in rats

Diabetes was induced in rats by a single intraperitoneal injection of streptozocin (50mg/kg) as described previously (Courteix et al, 1993).

Assessment of static allodynia

Mechanosensitivity was measured using Semmes-Weinstein von Frey hair (Stoelting, Illinois, u.s.a.). Animals were placed in a cage with a wire bottom, allowing access to the underside of their paws. Animals were habituated to this environment before starting the experiment. Mechanosensitivity was tested by touching the plantar surface of the animal's right hind paw with von frey hair for 6 seconds with increasing sequence of forces (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29 g). Once the flinching reaction has been completed, the paw is re-tested and the test is started with the next decreasing force of von frey hair until there is no response. A force of up to 29g lifts the pawl and causes a response, thus indicating the cut-off point. The minimum amount of force required to elicit a response is recorded as the Paw Withdrawal Threshold (PWT), in g.

Medicament

PD198306 [ N-cyclopropylmethoxy-3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide ] and CI-1008(pregabalin) were synthesized in Parke-Davis (Ann Arbor, Ml, USA). PD198306 was suspended in a polyethylene glycol compound (cremophor) ethanol water (1: 8) vehicle. Pregabalin was dissolved in water. Both compounds are administered orally. Streptozotocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally. The agent is administered in a volume of 1 ml/kg.

Statistics of

This static allodynia data was analyzed using Kruskall-Wallis ANOVA for non-parametric results, followed by a t-test of Mann-Whitney when significant.

Original record of experiment

Static allodynia was assessed with von Frey hair prior to (baseline, BL) and 1 hour after oral administration of PD198306(30 mg/kg, p.o.), vehicle (polyethylene glycol compound: ethanol: water, 1: 8) or pregabalin (30mg/kg, p.o.) (test). These animals were administered the same compound again the next day, in the morning and afternoon. Static allodynia was assessed only prior to administration in the afternoon and 1 hour after administration in order to minimise habituation of the animal to these test conditions. Animals treated with pregabalin receive water at the morning time of administration in order to avoid potential development of tolerance to the repeatedly administered compound.

Day 1 day 2

a.m.：PD 198306

Water (W)

Media

p.m.：BL p.m.：BL

PD 198306 PD 198306

Pregabal in Pregabal in

Media

Test of

Results

Single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1 hour after dosing. In contrast, a single administration of PD198306(30 mg/kg, p.o) had no effect on streptozocin-induced static allodynia 1 hour after dosing (see below). However, after more than two administrations of the compound on the second day, it significantly blocked streptozocin-induced static allodynia after the third administration. The effect has disappeared in the following days (see fig. 1).

Example 2

Materials and methods

Animal(s) production

Male Sprague Dawley rats (250-300g, obtained from Charles River, Margate, U.K.) were housed in 3-6 pens per group. All animals were kept in a 12h light/dark cycle (starting at 07h 00min of lighting) and were given food and water ad libitum. All experiments were performed by observers who did not see drug treatment.

Formation of chronic constrictive lesions in rats

Animals were treated with 2% isoflurane 1: 4O via nose cone during surgical procedures₂/N₂O mixture to perform anesthesia. The sciatic nerve was ligated in the manner previously described by Bennett and Xie, 1988. Animals were placed on the temperature-controlled blankets throughout the procedure. After surgical preparation, the biceps femoris muscle was dissected using blunt instruments, exposing the common sciatic nerve in the midsection of the femur. Adjacent to the ischial trigeminal site, approximately 7mm of the nerve was stripped from the adherent tissue and tied loosely around it with 4 ligatures (4-0 silk) at approximately 1mm intervals. The incision was closed layer by layer and the wound was treated with topical antibiotics.

Intrathecal injection

PD198306 and pregabalin were administered intrathecally in a volume of 10 μ l using a 100 μ l Hamilton syringe by exposing the spinal column of the rat under simple isoflurane anesthesia. A 10mm long 27 gauge needle was injected into the intrathecal space between the waist regions 5-6. If there is a tail roll response, the penetration is judged to be successful. Wounds were closed with an automatic clip and mice appeared to be fully aroused within 2-3 minutes after injection.

Assessment of static allodynia

Mechanosensitivity was measured using Semmes-Weinstein von Frey hair (Stoelting, Illinois, u.s.a.). Animals were placed in a cage with a wire bottom, allowing access to the underside of their paws. Animals were habituated to this environment before starting the experiment. Mechanosensitivity was tested by touching the plantar surface of the animal's right hind paw with von frey hair for 6 seconds with increasing sequence of forces (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29 g). Once the withdrawal response was determined, the paw was retested and the test was started with the next decreasing force of von frey hair until no response was detected. A force of up to 29g lifts the pawl and causes a response, thus indicating the cut-off point. The minimum amount of force required to elicit a response is recorded as the Paw Withdrawal Threshold (PWT), in g. Original record of experiment

Static allodynia was assessed with von Frey hair before (baseline, BL) and at 0.5h, 1h and 2h after intrathecal or intraplantar administration of PD198306(1-30 μ g, i.t.), vehicle (polyethylene glycol compound: ethanol: water, 1: 8) or pregabalin (10 μ g, i.t.). For oral experiments, static allodynia was assessed with von Frey hair before (baseline, BL) and 1 hour after oral PD198306(3-30mg/kg, p.o.), vehicle (polyethylene glycol compound: ethanol: water, 1: 8) or pregabalin (30mg/kg, p.o.). These animals were administered the same compound again the next day, in the morning and afternoon. Static allodynia was analyzed before and 1h after morning dosing. In the afternoon, static allodynia was assessed in streptozotocin treated animals prior to dosing, at 1h, 2h and 3h after dosing. CCI animals were evaluated prior to dosing, at 1h and 2h after dosing. The medicament used

PD198306 and pregabalin were synthesized in Parke-Davis (Ann Arbor, MI, USA). PD198306 was suspended in a polyethylene glycol compound: ethanol: water (1: 8) vehicle. Pregabalin was dissolved in water. The two compounds were administered orally, intrathecally or intraplantarly in volumes of 1ml/kg, 10. mu.l and 100. mu.l, respectively. Streptozotocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally in a volume of 1 ml/kg. Statistics of

This data was analyzed using Kruskall-Wallis ANOVA for nonparametric results, followed by a t-test for Mann-Whitney for the vehicle group when significant. Results

Effect of PD198306 on static allodynia after systemic administration

Effect of PD198306 on streptozocin-induced static allodynia

Single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1 hour after dosing. In contrast, a single administration of PD198306(3-30mg/kg, p.o) had no effect on streptozocin-induced static allodynia 1 hour after dosing (fig. 2). However, after two more administrations of the compound on the second day, PD198306(30 mg/kg) significantly blocked streptozocin-induced static allodynia for 2h after the third administration (fig. 2).

Effect of PD198306 on CCI-induced static allodynia

A single administration of pregabalin (30mg/kg, p.o.) significantly blocked CCI-induced static allodynia 1 hour after dosing. In contrast, single or multiple administrations of PD198306(3-30mg/kg, p.o) had no effect on CCI-induced static allodynia (FIG. 3).

Effect of PD198306 on static allodynia following intrathecal administration

Intrathecally administered doses of PD198306(1-30 μ g) -independently blocked the maintenance of static allodynia in streptozotocin (fig. 4) and CCI animals (fig. 5), with 3 and 10 μ g of MEDs, respectively. This anti-allodynic effect lasted 1 h.

Effect of PD198306 on static allodynia following intraplantar administration

Intrathecal administration of PD198306(30 μ g) significantly blocked static allodynia in both models of neuropathic pain (fig. 6, 7). In contrast, a single direct application of PD198306 to the paw at a dose 100-fold higher (3mg/100 μ l) had no effect on streptozocin (fig. 6) or CCI-induced static allodynia (fig. 7).

Reference to the literature

Bennett GJ, Xie Y-K. Peripheral mononeuropathy in rats, which produces pain disturbances like those seen in humans. Pain (Pain) 1988; 33: 87-107.

Courteix C, escalier a and Lavarenne j. streptozocin-induced rats: evidence of performance for a model of chronic pain. Pain (Pain) 1993; 53: 81-8

Example 3

Summary of the effects of other MEK inhibitors in the neuropathic pain model in rats

The effects of several MEK inhibitors with different binding affinities have been investigated in the CCI model of neuropathic pain in rats by assessing static allodynia with von Frey hair. Intrathecal administration of PD219622 or PD297447(30 μ g) had no significant effect on allodynia. This lack of effect reflects the low affinity or solubility of the compound. However, intrathecal administration of PD254552 or PD184352 (30 μ g) with higher binding affinity blocked the maintenance of static allodynia in CCI animals. This anti-allodynic effect became evident only 30min after injection and therefore was shorter than that observed for pregabalin (100 μ g). The magnitude of the effect was the same for both 30. mu.g PD184352 and 100. mu.g pregabalin. From this study, it was concluded that MEK inhibitors exert an anti-allodynic effect in CCI-induced neuropathic pain rats when administered intrathecally and that this anti-allodynic effect is related to the compound's affinity.

The method of forming chronic constriction injury in animals and rats, injection of test compound and evaluation of static allodynia were all in accordance with example 2 above. PD219622, PD297447, PD184352, PD254552 and pregabalin were all administered intrathecally at a dose of 30 μ g for all PD compounds and at a dose of 100 μ g for pregabalin. Static allodynia was assessed with von Frey hair prior to intrathecal administration of the compound (baseline, BL), at 0.5h, 1h and 2h post administration. The medicament used

PD297447, PD219622, PD254552, PD184352(CI-1040) and pregabal in were synthesized in Parke-Davis (Ann Arbor, MI, USA). PD297447, PD219622, PD254552 and PD184352 are suspended in a polyethylene glycol compound, ethanol, water (1: 8) vehicle. Pregabalin was dissolved in water. All compounds were administered intrathecally in a volume of 10 μ l. Statistics of

Intrathecal administration of PD297447 or PD219622(30 μ g) had no significant effect on allodynia. This lack of effect probably reflects the low affinity of the compound (965 nM and 100nM, respectively). However, intrathecal administration of PD184352 or PD254552(30 μ g) blocked the maintenance of static allodynia in CCI animals (see FIG. 8). These compounds have a high affinity (2 and 5nM, respectively). This anti-allodynic effect became evident only 30min after injection and therefore was shorter than that observed for pregabalin (100 μ g). The magnitude of the effect was similar for 30. mu.g PD184352 and 100. mu.g pregabalin.

The results obtained indicate that MEK inhibitors exert an anti-allodynic effect in rats with neuropathic pain induced by CCI when administered intrathecally and that this anti-allodynic effect is linked to the compound's affinity.

Chemical examples

Example 1

[ 4-chloro-2- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -phenyl]- (4-iodo-2-methylphenyl) -amine (18). (reaction scheme 2, R)₁＝Cl，R₂＝R₃＝H，R₄＝CH₃)

a) 5-chloro-2-methoxybenzoic acid 16(14.8g, 0.0793mol) and SOCl₂(28.31g, 14.97ml, 0.1584mol) was refluxed for 2 hours to remove excess SOCl₂Leaving a white residue. Dissolving the solid in CH₂Cl₂Then added to 2-amino-2-methyl-1-propanol (13.98g, 14.97ml, 0.1584mol) in CH which had been cooled with an ice bath₂Cl₂In the solution of (1). The ice bath was removed and after stirring at room temperature for 3 hours, a white solid precipitated.The precipitate was separated by filtration and discarded. The filtrate was concentrated to leave a thick colorless oil. Adding SOCl₂(17.4ml) was added dropwise to the oil. An exothermic reaction takes place and a free flowing solution is obtained. After stirring for 30min, the reaction mixture was poured into Et₂O (200 ml). An oil was isolated. Et was removed by decantation₂Layer O and discarded. The oily residue was dissolved in a minimum amount of water, basified with 20% aqueous NaOH, and Et₂And (4) extracting. Et was obtained₂The O layer is dried (K)₂CO₃) And concentrated to give product 17 as a brown oil. Yield 14.63g (77%).

b) LDA (5ml of a 2.0M solution in THF) was added to a solution of 4-iodo-2-methylaniline (2.33g, 0.O10mol) in THF (15ml) at-78 ℃. The mixture was stirred at-78 ℃ for 30 minutes. To this was added a solution of compound 17(1.199g, 0.005mol) in THF (15 ml). The mixture was stirred for 16 hours while it was warmed to room temperature. NH for the reaction mixture₄Quenching with aqueous Cl solution and Et₂And (4) extracting. Et was obtained₂The O layer was dried (MgSO)₄) And concentrated to give crude product 18 as a brown oil. The oil was purified by silica column chromatography. By CH₂Cl₂Elution gave pure 1.7g (77%) of 18 as a brown oil. Dissolve 409mg of oil in Et₂In O, with Et₂O-HCl treatment gave the HCl salt as a pale yellow solid precipitate. Yield 356.4mg (81%); mp 324-330 ℃; c₁₈H₁₈N₂OCl I·HCl.0.5H₂Analytical calcd/found for O: c, 44.47/44.32; h, 4.15/3.94; n, 5.76/5.66.

Example 2

[2, 3-difluoro-6- (1H-tetrazol-5-yl) -phenyl]- (4-iodo-2-methyl-phenyl) -amines

[2, 3-difluoro-6-cyano-phenyl ] - (4-iodo-2-methyl-phenyl) -amine (1.11g, 3mmol) and sodium azide (0.255g, 3.9mmol) and triethylamine hydrochloride (0.537g, 3.9mmol) were all suspended in 10ml of toluene and stirred at 100 ℃ for 12 hours. The mixture was concentrated and the residue was purified by column chromatography with ethyl acetate/methanol (10/1) to give the product as a foamy solid. Yield: about 50%.

m.p：83.4-88.7℃

¹H NMR(CDCl₃400 Hz): delta/ppm 7.69(1H, m, phenyl-H); 7.42(1H, s, phenyl-H); 7.27(1H, m, phenyl-H); 6.91(1H, dd, J ═ 16.2Hz, 8.3Hz, phenyl-H); 6.40(1H, dd, phenyl-H); 2.28(3H, s, CH)₃)

Example 3

[6- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -2, 3-difluoro-phenyl]- (4-iodo-2-methyl-phenyl) -amines

A solution of 3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (1.17g, 3mmol), oxalyl chloride (0.457g, 3.6mmol) in 30ml of dichloromethane was treated with 2 drops of dimethylformamide, stirred at room temperature for 3 hours, and then concentrated. The residue was dissolved in 25ml dichloromethane and the solution was added dropwise to a solution of 2-amino-2-methyl-1-propanol (0.623g, 7mmol) in 25ml dichloromethane at 0 ℃, stirred at room temperature for 12h, the precipitate was filtered off, the filtrate was washed with water, 5% aqueous sodium bicarbonate, 1N HCl, brine and dried over sodium sulfate. After concentration the crude product is obtained, which is then resuspended in 25ml of chloroform, thionyl chloride is then added at 0 ℃ and stirred at room temperature for 15 hours, then concentrated and the residue is dissolved in 30ml of dichloromethane, 1N HCl is added to adjust the pH to 11, separated and extracted with chloroform and dried over sodium sulfate. Concentration followed by column chromatography with hexane/dichloromethane (20/1) gave the compound as white crystals. Yield: 65 percent of

m.p.：103.7-104.4℃

¹H NMR(CDCl₃400 Hz): delta/ppm 10.2(1H, s, NH), 7.48-7.58(1H, m, phenyl-H); 7.48(1H, s, phenyl-H); 7.38(1H, d, J ═ 8.5Hz, phenyl-H), 6.66-6.72(1H, m, phenyl-H); 6.58(1H, t, J ═ 8.0Hz, phenyl-H); 4.01(2H, s, -CH)₂-) according to the formula (I); 2.31(3H, s, phenyl-CH)₃)；1.32(6H，s，-C(CH₃)₂-)。

Example 4

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid methyl ester

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (5g) was dissolved in 100ml of methanol, 5 drops of concentrated sulfuric acid were added, and refluxing was carried out for 4 days. Column chromatography with hexane/dichloromethane afforded the product as a white solid, yield: 50 percent.

m.p.：90.1-90.4℃

¹H NMR(CDCl₃400 Hz): delta/ppm 8.92(1H, s, NH), 7.75-7.78(1H, m, phenyl-H); 7.49(1H, s, phenyl-H); 7.38(1H, dd, J ═ 8.5Hz, 2.0Hz, phenyl-H), 6.66-6.73(1H, m, phenyl-H); 6.56-6.60(1H, m, phenyl-H); 3.88(3H, s, -OCH)₃) (ii) a 2.30(3H, s, phenyl-CH)₃)

Example 5

5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl]-4H-[1，2，4]Triazol-3-ylamines

Aminoguanidine nitrate (1.65g, 12mmol) was added to a solution of sodium methoxide (0.648g, 12mmol) in methanol (12ml) at 0 ℃ and then 3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid methyl ester was added as a solution of methanol and refluxed for 20 hours, concentrated and column chromatographed with hexane/ethyl acetate to give the product as white crystals. Yield: 60 percent of

m.p.：191.7-192.0℃

¹H NMR (DMSO, 400 Hz): delta/ppm 9.45(1H, s, -NH-); 7.79(1H, t, J ═ 7.3Hz, phenyl-H); 7.51(1H, s, phenyl-H); 7.35(1H, d, J ═ 10.1Hz, phenyl-H); 7.05-7.11(1H, m, phenyl-H); 6.44-6.48(1H, m, phenyl-H); 6.32(2H, s, -NH)₂)，2.32(3H，s，CH₃)

Example 6

5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl]-[1，3，4]Oxadiazol-2-ylamines

To a solution of 3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid hydrazide (0.806g, 2mmol) in 5ml of dioxane was added cyanogen bromide (0.212g, 2mmol), followed by a solution of sodium bicarbonate (0.17g, 2mmol) in 5ml of water. The obtained mixture was stirred at room temperature for 18 hours, the solution was concentrated, and the residue was subjected to column chromatography using hexane/ethyl acetate (3/1) to give a product, which was recrystallized from ethyl acetate/hexane to give pale yellow crystals. Yield: 58%, m.p.: 183.7-184.0 deg.C.

¹H NMR(CDCl₃400 Hz): delta/ppm 8.87(1H, s, -NH-); 7.52(1H, s, phenyl-H); 7.45-7.49(1H, m, phenyl-H); 7.40(1H, d, J ═ 8.3Hz, phenyl-H); 6.77-6.83(1H, m, phenyl-H); 6.60-6.63(1H, m, phenyl-H); 5.02(2H, s, -NH)₂)，2.36(3H，s，CH₃)

Example 7

2- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) benzoyl]Hydrazine thioamides

A solution of 3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (3.9g, 0.01mol), oxalyl chloride (1.90g, 0.015mol) in 40ml dichloromethane was treated with 2 drops of dimethylformamide and stirred at room temperature for 3 hours before concentration. The residue was dissolved in 10ml of tetrahydrofuran, added to a solution of thiosemicarbazide (2.0g, 0.022mol) in 50ml of tetrahydrofuran at 0 ℃ and stirred at room temperature for 14 hours. Concentration and column chromatography with hexane/ethyl acetate (1/1) gave the product as a yellow solid. 2.91 g. Yield: 63% m.p.: 159.5 to 160.0 ℃.

¹H NMR (DMSO, 400 Hz): delta/ppm 10.58(1H, s, -NH-); 9.28(1H, s, -NH-); 8.83(1H, s, -NH-); 7.95(1H, s, phenyl-H); 7.12-7.75(2H, m, NH)₂) (ii) a 7.51(1H, s, phenyl-H); 7.37(1H, dd, J ═ 8.6Hz, 1.7Hz, phenyl-H); 7.16(1H, dd, J ═ 17Hz, 9.0Hz, phenyl-H); 6.40-6.50(1H, m, phenyl-H); 5.02(2H, s, -NH)₂)，2.00(3H，s，CH₃)

Example 8

5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl]-4H-[1，2，4]Triazole-3-thiols

2- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) benzoyl ] hydrazine thioamide (1.386g, 3mmol) was dissolved in 15ml of anhydrous methanol, and 2.5ml of sodium methoxide (25% by weight in methanol) were added in one portion at 0 ℃. The mixture obtained was heated at reflux for 17 hours before concentration. Column chromatography with hexane/ethyl acetate gave the product as needle-like white crystals. Yield: 40 percent of

m.p.: 196.5 (decomposition)

¹H NMR(DMSO，400Hz)：δ/ppm 13.87(1H, s, -NH-); 13.80(1H, s, -NH-); 8.16(1H, s, -NH-); 7.61-7.65(1H, m, phenyl-H); 7.48(1H, s, phenyl-H); 7.32(1H, dd, J ═ 8.6Hz, 2.2Hz, phenyl-H); 7.24(1H, dd, J ═ 16.4Hz, 9.5Hz, phenyl-H); 6.42-6.46(1H, m, phenyl-H); 5.02(2H, s, -NH)₂)，2.20(3H，s，CH₃)。

Example 9

(2, 3-difluoro-6- [1, 3, 4]]Oxadiazol-2-yl-phenyl) - (4-iodo-2-methyl-phenyl) -amines

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid hydrazide (146mg, 0.36mmol) was suspended in 7ml absolute EtOH, 2ml HC (OEt)₃Added with about 3mg of pTsOH. The reaction was heated to reflux for 3h, cooled and concentrated on a rotary evaporator. The reaction mixture is purified (SiO)₂4: 1 Hexane/EtOAc) to yield 117mg (79%) of (2, 3-difluoro-6- [1, 3, 4]]Oxadiazol-2-yl-phenyl) - (4-iodo-2-methyl-phenyl) -amine as a yellow powder. M.p. 144.4-145.5 ℃.¹H NMR(400MHz，CDCl₃)δ8.89(s，1 H)，8.44(s，IH)，7.66(m，1H)，7.52(d，J＝1.7Hz，1H)，7.38(dd，J＝8.5，1.9Hz，1H)，6.83(m，1H)，6.14(dd，J＝8.5，5.9Hz，1H)，2.37(s，3H)。

Example 10

5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl]-[1，3，4]Oxadiazole-2-thiols

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid hydrazide (170mg, 0.42mmol) was suspended in 7ml absolute EtOH and cooled to 0 ℃. Carbon disulfide (74mg, O.97mmol) was added followed by 24mg (0.42mmol) of powdered KOH. The reaction was stirred at 0 ℃ for 1 hour, at room temperature for 1 hour, andflow 3 hours, a homogeneous reaction mixture was obtained. The reaction mixture was cooled to room temperature, at which point ppt was formed. Water was added and the reaction product was diluted with 5mL EtOAc. 1N HCl was added to acidify the aqueous layer (pH 2). The aqueous layer was extracted with EtOAc (3 ×). The combined organic layers were washed with Na₂SO₄Dried and concentrated to give 96mg (51%) of 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl][1，3，4]Oxadiazole-2-thiol as a yellow powder. M.p. 231.8-232.8 ℃.¹H NMR(400MHz，CDCl₃) δ 7.62(m, 2H), 7.47(s, 1H), 7.30 (complex m, 2H), 6.44(dd, J ═ 8.0, 4.5Hz, 1H), 2.19(s, 3H).

F. Other embodiments

The essential features of the invention are readily understood from the above disclosure and examples and from the appended claims. The scope of the present invention also includes various changes and modifications within the knowledge of one of ordinary skill. Examples include disclosed compounds modified by addition or removal of a protecting group, or an ester, pharmaceutically acceptable salt, hydrate, acid, or amide of a disclosed compound. The publications cited herein are incorporated by reference in their entirety.

Claims

1. A method of treating chronic pain, the method comprising administering to a subject in need thereof a composition comprising a MEK inhibitor selected from: a compound of the general formula (I):w is one of the following structural formulae (i) - (xiii):X₁is O, S or NR_F；

X₂Is OH, SH or NHR_E；

R_EAnd R_FEach of which is H or C_1-4An alkyl group;

R₁and R₂Each independently selected from H, F, NO₂Br and Cl; r₁Or may be SO₂NR_GR_HOr R is₁And R₂Together with the phenyl ring to which they are attached form an indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, or benzothiazole;

R₃is H or F;

R_G、R_Hand R₄Each independently selected from H, Cl and CH₃；

R₅Is H or C_3-4An alkyl group; and

wherein each of the above hydrocarbyl groups is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxy, amino, (amino) sulfonyl, and NO₂(ii) a And

wherein each of the above heterocyclic groups is optionally substituted with 1-3 substituents independently selected from halogen, C_3-4Alkyl radical, C_3-6Cycloalkyl radical, C_3-4Alkenyl radical, C_3-4Alkynyl, phenyl, hydroxy, amino, (amino) sulfonyl, and NO₂Wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally independently selected from halogen, C_1-2Alkyl, hydroxy, amino and NO₂Substituted by 1 to 2 substituents of (1);

or their pharmaceutically acceptable salts or C_1-8And (3) an ester.

2. The method of claim 1, wherein the chronic pain is selected from neuropathic pain, spontaneous pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

3. The method of claim 2, wherein the chronic pain is of the type neuropathic pain.

4. The method of claim 3, wherein the neuropathic pain is associated with one of: inflammation, post-operative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and post-herpes zoster pain, causalgia, diabetic neuropathy, plexus extraction, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, amputation, post-operative pain, arthritic pain, and any other nerve injury between and including the peripheral and central nervous systems.

5. The method of claim 2, wherein the chronic pain is associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

6. The method of claim 2, wherein the chronic pain is associated with spontaneous pain.

7. The method of claim 1, wherein the chronic pain is associated with inflammation.

8. The method of claim 1, wherein the chronic pain is associated with arthritis.

9. The method of claim 1, wherein the chronic pain is associated with post-operative pain.

10. The method of claim 1, wherein R₁Is bromine or chlorine.

11. The method of claim 1, wherein R₂Is fluorine.

12. The method of claim 1, wherein R₃Is H.

13. The method of claim 12, wherein R₂And R₃Each is H.

14. The method of claim 1, wherein R₂And R₃Each being fluorine.

15. The method of claim 14, wherein R₁Is bromine.

16. The method of claim 14, wherein R₁Is fluorine.

17. The method of claim 1, wherein R₂Is a nitro group.

18. The method of claim 16, wherein R₃Is H.

19. The method of claim 1, wherein R₄Is chlorine.

20. The method of claim 1, wherein R₄Is methyl.

21. The method of claim 1, wherein R₅Is H.

22. The method of claim 1, wherein R₅Is CH₃。

23. The method of claim 1, wherein X₁Is O or S.

24. The method of claim 1, wherein X₁Is NH or NCH₃。

25. The method of claim 1, wherein X₃Is OH, SH, or NH₂

26. The method of claim 1, wherein X₂Is NHCH₃Or OH.

27. The method of claim 1, wherein the MEK inhibitor has a structure selected from: [ 5-fluoro-2- (1H-tetrazol-5-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [2, 3-difluoro-6- (1H-tetrazol-5-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; (4-iodo-2-methyl-phenyl) - [2, 3, 4-trifluoro-6- (1H-tetrazol-5-yl) -phenyl ] -amine; [ 4-bromo-2, 3-difluoro-6- (1H-tetrazol-5-yl) -phenyl ] - (4-iodo-2-methylphenyl) -amine; [ 5-fluoro-4-nitro-2- (1H-tetrazol-5-yl) -phenyl ] - (4-iodo-2-methylphenyl) -amine; [2- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -5-fluoro-phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [6- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -2, 3-difluoro-phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [6- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -2, 3, 4-trifluoro-phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [ 4-bromo-6- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -2, 3-difluoro-phenyl ] - (4-iodo-2-methylphenyl) -amine; [2- (4, 4-dimethyl-4, 5-dihydro-oxazol-2-yl) -5-fluoro-4-nitrophenyl ] - (4-iodo-2-methyl-phenyl) -amine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] thiadiazol-2-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] oxadiazol-2-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ol; and 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -4H- [1, 2, 4] triazol-3-ol.

28. The method of claim 1, wherein the MEK inhibitor has a structure selected from: 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] thiadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitrophenyl ] -4H- [1, 2, 4] triazol-3-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] thiadiazole-2-thiol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] - [1, 3, 4] oxadiazole-2-thiol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol; and 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitrophenyl ] -4H- [1, 2, 4] triazole-3-thiol.

29. The method of claim 1, wherein the MEK inhibitor has a structure selected from: 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -isothiazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -isoxazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl) -1H-pyrazol-3-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -1H-pyrazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isothiazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -isothiazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -isoxazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -isoxazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1-methyl-1H-pyrazol-3-ol; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1-methyl-1H-pyrazol-3-ol; 1-methyl-4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H-pyrazol-3-ol; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1-methyl-1H-pyrazol-3-ol; and 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -1-methyl-1H-pyrazol-3-ol.

30. The method of claim 1, wherein the MEK inhibitor has a structure selected from: 5- [2- (2-amino-4-iodo-phenylamino) -4-fluoro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [2- (2-amino-4-iodo-phenylamino) -3, 4-difluoro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [2- (2-amino-4-iodo-phenylamino) -3, 4, 5-trifluoro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [2- (2-amino-4-iodo-phenylamino) -5-bromo-3, 4-difluoro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [2- (2-amino-4-iodo-phenylamino) -4-fluoro-5-nitro-phenyl ] -1-methyl-1H- [1, 2, 3] triazol-4-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -3-methyl-3H- [1, 2, 3] triazol-4-ol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] -3-methyl-3H- [1, 2, 3] triazol-4-ol; 3-methyl-5- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -3H- [1, 2, 3] triazol-4-ol; 5- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -3-methyl-3H- [1, 2, 3] triazol-4-ol; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -3-methyl-3H- [1, 2, 3] triazol-4-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2-methyl-2H-pyrazol-3-ol; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] -2-methyl-2H-pyrazol-3-ol; 2-methyl-4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-pyrazol-3-ol; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2-methyl-2H-pyrazol-3-ol; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -2-methyl-2H-pyrazol-3-ol; 1- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4-methyl-1, 4-dihydro-tetrazol-5-one; 1- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4-methyl-1, 4-dihydro-tetrazol-5-one; 1-methyl-4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1, 4-dihydro-tetrazol-5-one; 1- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4-methyl-1, 4-dihydro-tetrazol-5-one; 1- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -4-methyl-1, 4-dihydro-tetrazol-5-one; 1- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H- [1, 2, 3] triazol-4-ol; 1- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H- [1, 2, 3] triazol-4-ol; 1- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] -1H- [1, 2, 3] triazol-4-ol; 1- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -1H- [1, 2, 3] triazol-4-ol; and 1- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -1H- [1, 2, 3] triazol-4-ol.

31. The method of claim 1, wherein the MEK inhibitor has a structure selected from: 3- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-isoxazol-5-one; 3- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-isoxazol-5-one; 3- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -2H-isoxazol-5-one; 3- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) phenyl ] -2H-isoxazol-5-one; 3- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -2H-isoxazol-5-one; [ 5-fluoro-2- (2-oxo-2, 3-dihydro-21 > 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [2, 3-difluoro-6- (2-oxo-2, 3-dihydro-21 > 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; (4-iodo-2-methyl-phenyl) - [2, 3, 4-trifluoro-6- (2-oxo-2, 3-dihydro-21 > 4_ - [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] -amine; [ 4-bromo-2, 3-difluoro-6- (2-oxo-2, 3-dihydro-21 > 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; [ 5-fluoro-4-nitro-2- (2-oxo-2, 3-dihydro-21 > 4- [1, 2, 3, 5] oxathiadiazol-4-yl) -phenyl ] - (4-iodo-2-methyl-phenyl) -amine; 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H-isoxazol-5-one; 4- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H-isoxazol-5-one; 4- [3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H-isoxazol-5-one; 4- [ 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H-isoxazol-5-one; and 4- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -4H-isoxazol-5-one.

32. The method of claim 1, wherein the MEK inhibitor has a structure selected from: 2, 4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ylamine; 5- [ 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-ol; (2, 3-difluoro-6- [1, 3, 4] oxadiazol-2-yl-phenyl) (4-iodo-2-methyl-phenyl) -amine; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [1, 3, 4] oxadiazol-2-thiol; 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazol-3-ylamine; and 5- [3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -4H- [1, 2, 4] triazole-3-thiol.

33. The method of claim 1, wherein the MEK inhibitor has the structure: 2, 4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid.