HK1048947A

HK1048947A - Method for treating chronic pain using mek inhibitors

Info

Publication number: HK1048947A
Application number: HK03101203.8A
Authority: HK
Inventors: A‧迪克森; K‧李; R‧D‧皮诺克
Original assignee: 沃尼尔‧朗伯公司
Priority date: 1999-07-16
Filing date: 2000-07-05
Publication date: 2003-04-25

Description

Methods of treating chronic pain using MEK inhibitors

Background

The present invention relates to methods of treating chronic pain using MEK inhibitors. Chronic pain includes neuropathic pain and chronic inflammatory pain.

Abnormalities anywhere in the neural pathway disrupt neural signals, which in turn are abnormally reflected in the brain, causing neuropathic pain. Neuropathic pain can be, for example, severe pain, burning sensation, or high sensitivity to touch. Diseases or conditions associated with neuropathic pain include, without limitation, diabetic neuropathy, causalgia, plexus avulsion, neuroma, nodular vasculitis, crush injury, viral infection (e.g., herpes virus infection or HIV), compression injury, tissue injury, nerve injury from the peripheral to the central nervous system, amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and vitamin deficiency.

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

Neuropathic pain is currently treated with anticonvulsants such as carbamazepine and antidepressants such as amitriptyline. NSAIDS and opioids generally have only a minor effect (Fields et al, 1994, Textbook of Pain (Textbook of Pain), pages 991-996 (publication: Churchill Livingstone), James & Page, 1994, journal of the American medical society of pediatrics (J.Am.Peditar.Med.Assoc), 8: 439-447, Galer, 1995, Neurology (Neurology) 45S 17-S25). Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, post-polio, CPRM, HIV-associated neuropathy, trigeminal neuralgia, and Reflex Sympathetic Dystrophy (RSD). The general poor efficacy of anti-inflammatory drugs suggests that the mechanism of chronic pain is distinguished from hyperalgesia.

Summary of The Invention

The present invention relates to a method of treating chronic pain comprising the step of administering to a patient in need of such treatment a composition comprising a MEK inhibitor. Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiency, uremia, hypothyroidism, postoperative pain, arthritis, back pain, and chronic alcoholism. The invention also relates to the disclosed compounds formulated for the treatment of chronic pain. Such a composition may comprise one or more MEK inhibitor compounds having the structure disclosed in patent application PCT/US98/13106, international application date 24, 6/1998 and PCT/US98/13105, international application date 24, 6/1998.

Examples of MEK inhibitors include 4-bromo and 4-iodophenylamino phenoxyhydroxamic acid derivatives, which are kinase inhibitors and are therefore useful in the treatment of proliferative diseases such as cancer, psoriasis and restenosis. These compounds are defined by formula I:

wherein:

R₁is hydrogen, hydroxy, C₁-C₈Alkyl radical, C₁-C₈Alkoxy, halogen, trifluoromethyl or CN;

R₂is hydrogen;

R₃、R₄and R₅Independently hydrogen, hydroxy, halogen, trifluoromethyl, C₁-C₈Alkyl radical, C₁-C₈Alkoxy, nitro, CN or (O or NH)_m-(CH₂)_n-R₉Wherein R is₉Is hydrogen, hydroxy, CO₂H or NR₁₀R₁₁；

n is 0 to 4;

m is 0 or 1;

R₁₀and R₁₁Independently is hydrogen or C₁-C₈Alkyl, or taken together with the nitrogen to which they are attached form a 3-to 10-membered ring, which ring may optionally contain one, two or three members selected from O, S, NH or N-C₁-C₈Other heteroatoms of the alkyl group;

R₆is hydrogen, C₁-C₈Alkyl, aryl, heteroaryl, and heteroaryl,Aryl, aralkyl or C₃-C₁₀A cycloalkyl group;

R₇is hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₁₀(cycloalkyl optionally containing a substituent selected from O, S or NR₉Cycloalkyl of the heteroatom(s); or R₆And R₇Taken together with the N-O to which they are attached to form a 5-to 10-membered ring, optionally containing one, two or three members selected from O, S or NR₁₀R₁₁The other hetero atom of (a);

wherein any of the aforementioned alkyl, alkenyl and alkynyl groups may be unsubstituted or substituted with a cycloalkyl group (or may optionally contain a substituent selected from O, S or NR)₉Cycloalkyl, aryl, aryloxy, heteroaryl or heteroaryloxy.

Preferred compounds have the structure of formula II

Wherein R is₁、R₃、R₄、R₅、R₆And R₇As defined above. Particularly preferred is the compound wherein R₁Is methyl or halogen and R₃、R₄And R₅A compound which is halogen such as fluorine or bromine.

Another group of preferred compounds have the structure of formula III

Wherein R is₁、R₃、R₄、R₅And R₇As defined above.

The most preferred compounds are those wherein R₁Is methyl or halogen, e.g. F, Br, Cl and I, R₃Is hydrogen or halogen, e.g. fluorine, R₄Is halogen, e.g. fluorine, R₅Those compounds which are hydrogen or halogen, such as fluorine or bromine. The compounds have the following structure

Specific compounds provided by the present invention include the following:

3, 4, 5-trifluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

n-hydroxy-2- (4-iodo-2-methyl-phenylamino) -4-nitro-benzamide;

3, 4, 5-trifluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

5-chloro-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-4-nitro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4, 5-trifluoro-N-hydroxy-benzamide;

5-chloro-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

5-bromo-2- (2-bromo-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-hydroxy-4-methyl-benzamide;

2- (2-bromo-4-iodo-phenylamino) -3, 4, 5-trifluoro-N-hydroxy-benzamide;

2- (2-bromo-4-iodo-phenylamino) -5-chloro-3, 4-difluoro-N-hydroxy-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-hydroxy-4-nitro-benzamide;

4-fluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

2- (2-chloro-4-iodo-phenylamino) -4-fluoro-N-hydroxy-benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

2- (2-bromo-4-iodo-phenylamino) -4-fluoro-N-hydroxy-benzamide;

2- (2-bromo-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

n-cyclopropylmethoxy-3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N-cyclopropylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N-cyclopropylmethoxy-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

n-cyclopropylmethoxy-2- (4-iodo-2-methyl-phenylamino) -4-nitro-benzamide;

n-cyclopropylmethoxy-3, 4, 5-trifluoro-2- (2-fluoro-4-iodo-phenylamino) benzamide;

5-chloro-N-cyclopropylmethoxy-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

n-cyclopropylmethoxy-2- (2-fluoro-4-iodo-phenylamino) -4-nitro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4, 5-trifluoro-benzamide;

5-chloro-2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

5-bromo-2- (2-bromo-4-iodo-phenylamino) -N-ethoxy-3, 4-difluoro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-ethoxy-4-nitro-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4, 5-trifluoro-benzamide;

2- (2-bromo-4-iodo-phenylamino) -5-chloro-N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-nitro-benzamide;

n-cyclopropylmethoxy-4-fluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

n-cyclopropylmethoxy-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-fluoro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-fluoro-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -N-isopropyl-benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -N-methyl-benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-hydroxy-4-nitro-benzamide;

3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -4-fluoro-N-hydroxy-benzamide (HCl salt);

2- (2-chloro-4-iodo-phenylamino) -4-fluoro-N- (tetrahydro-pyran-2-yloxy) benzamide;

3, 4-difluoro-2- (2-chloro-4-iodo-phenylamino) -N-cyclobutylmethoxy-benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -N- (2-dimethylamino-ethoxy) -3, 4-difluoro-benzamide monohydrochloride;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

3, 4-difluoro-2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-benzamide;

5-bromo-N-cyclohexylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N-cyclopentylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide; and

5-bromo-N-cyclobutylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide.

Other aspects of the invention are defined in the following description, examples and figures.

Other examples of MEK inhibitors include 4-bromo and 4-iodophenylaminobenzoic acid derivatives, which are selective MEK kinase inhibitors. Such compounds are defined by formula I (a):

wherein:

R₂is hydrogen;

R₃、R₄and R₅Independently hydrogen, hydroxy, halogen, trifluoromethyl, C₁-C₈Alkyl radical, C₁-C₈Alkoxy, nitro, CN or- (O or NH)_m-(CH₂)_n-R₉Wherein R is₉Is hydrogen, hydroxy, CO₂H or NR₁₀R₁₁；

n is 0 to 4;

m is 0 or 1;

z is COOR₇Tetrazolyl, CONR₆R₇、CONHNR₁₀R₁₁Or CH₂OR₇；

R₆And R₇Independently of one another is hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, alkynyl,

O

C-C₁-C₈Alkyl, aryl, heteroaryl, C₃-C₁₀Cycloalkyl or C₃-C₁₀(cycloalkyl optionally containing one, two or three heteroatoms selected from O, S, NH or N alkyl); or R₆And R₇Taken together with the nitrogen to which they are attached to form a 3-10 membered ring, which ring may optionally contain 1, 2 or 3 additional heteroatoms selected from O, S, NH or N alkyl;

wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as well as pharmaceutically acceptable salts thereof.

Preferred compounds have the structure of formula II (A)

When R is₇When hydrogen, the compound of formula II (A) is a carboxylic acid, when R is₇When not hydrogen, the compound of formula II (A) is an ester. Compounds which are similar to acids in terms of physical and biological properties are tetrazolyl derivatives of the formula IIa:

another group of preferred compounds are amides of formula III (A):and a hydrazide of formula IIIa:

the benzyl alcohol of the invention has a structure of formula IV (A)

Of this group of compounds, the preferred compounds are those wherein R is₁Is methyl, R₃Is hydrogen or halogen, e.g. fluorine, R₄Is halogen, e.g. fluorine, R₅Those compounds which are hydrogen or halogen, such as fluorine, bromine or chlorine. Typical compounds have the following structure

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- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

n-cyclopropylmethoxy-3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide, potassium salt;

2- (2-chloro-4-iodo-phenylamino) -N-cyclobutylmethoxy-3, 4-difluoro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-fluoro-benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-methoxy-benzamide;

3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

n-cyclopropylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N-cyclobutylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N-cyclopropylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide, hydrochloride;

5-bromo-3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N- (2-hydroxy-ethoxy) -benzamide;

3, 4-difluoro-N- (2-hydroxy-ethoxy) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N- (3-hydroxy-propoxy) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4, 5-trifluoro-N- (3-hydroxy-propoxy) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4, 5-trifluoro-N- [2- (2-methoxy-ethoxy) -ethoxy ] -benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N- (3-hydroxy-propoxy) -benzamide;

5-bromo-3, 4-difluoro-N- (3-hydroxy-propoxy) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

3, 4, 5-trifluoro-N- (3-hydroxy-propoxy) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

3, 4, 5-trifluoro-N- (2-hydroxy-ethoxy) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N- (2-hydroxy-ethoxy) -benzamide; and

(b) the MEK inhibitor has a structure selected from:

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

(c) the MEK inhibitor has a structure selected from:

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid;

3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid;

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

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-5-nitro-benzoic acid;

2- (2-chloro-4-iodo-phenylamino) -3, 4, 5-trifluoro-benzoic acid;

7-fluoro-6- (4-iodo-2-methyl-phenylamino) 1H-benzimidazole-5-carboxylic acid cyclopropylmethoxy-amide;

5-chloro-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid; and

5-chloro-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid; and

(d) the MEK inhibitor has a structure selected from:

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid; and

7-fluoro-6- (4-iodo-2-methyl-phenylamino) 1H-benzimidazole-5-carboxylic acid cyclopropylmethoxy-amide.

The invention also provides a pharmaceutical formulation suitable for the treatment of chronic pain, said formulation comprising a disclosed compound together with a pharmaceutically acceptable excipient, diluent or carrier. Preferred formulations comprise any one of the aforementioned preferred compounds plus an excipient, diluent or carrier.

The disclosed compounds are potent and selective kinases, particularly MEK₁And MEK₂The inhibitor of (1).

Brief description of the drawings

The bar graph of fig. 1 depicts Paw Withdrawal Threshold (PWT) in grams as a function of time in days. The blank, cross-hatched and single-hatched bars are vehicle, PD198306 and pregabalin, respectively. The arrow indicates the time of administration (30mg/kg, oral).

Figure 2 bar graph depicts the force in grams required to cause paw withdrawal with von Frey hair as a function of time in days. Measurement of Baseline (BL) was performed prior to treatment. Animals received a single oral administration of PD198306(3-30mg/kg) or pregabalin (30mg/kg) and the withdrawal threshold was assessed again 1 hour after treatment. Treatment was repeated twice daily for two days. Results are expressed as median ± first and third quartiles. P < 0.05, P < 0.01, P < 0.001, indicating a significant difference compared to the vehicle-treated animals (Mann-Whitney t test; n-7-8).

Figure 3 bar graph depicts the force in grams required to cause paw withdrawal with von Frey hair as a function of time in days. Measurement of Baseline (BL) was performed prior to treatment. Animals received a single oral administration of PD198306(3-30mg/kg) or pregabalin (30mg/kg) and the withdrawal threshold was assessed again 1 hour after treatment. Treatment was repeated twice daily for two days. Results are expressed as median ± first and third quartiles. P < 0.01 indicates a significant difference compared to vehicle-treated animals (Mann-Whitney t test; n ═ 6).

The bar graph of figure 4 depicts the force in grams required to cause paw withdrawal with yon Frey hair as a function of time in days. Measurement of Baseline (BL) was performed 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 the withdrawal thresholds were assessed again after 30 minutes, 1 hour and 2 hours of treatment. Results are expressed as median ± first and third quartiles. P < 0.05, P < 0.001, indicating a significant difference compared to vehicle-treated animals (Mann-Whitney t test; n ═ 7-9).

Figure 5 bar graph depicts the force in grams required to cause paw withdrawal with von Frey hair as a function of time in days. Measurement of Baseline (BL) was performed 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 the withdrawal thresholds were assessed again after 30 minutes, 1 hour and 2 hours of treatment. Results are expressed as median ± first and third quartiles. P < 0.05, P < 0.01, P < 0.001, indicating a significant difference compared to the vehicle-treated animals (Mann-Whitney t test; n ═ 6-8).

Figure 6 bar graph depicts the force in grams required to cause paw withdrawal with von Frey hair as a function of time in days. Animals received a single intraplantar dose (i.pl.) PD198306(3 mg/100. mu.l) or intrathecal PD198306 (30. mu.g/10. mu.l), and withdrawal thresholds were assessed again 1 hour after treatment. Results are expressed as median ± first and third quartiles. P < 0.01 indicates a significant difference compared to vehicle-treated animals (Mann-Whitney t test; n ═ 6-9).

The bar graph of figure 7 depicts the force in grams required to cause paw withdrawal with von Frey hair as a function of time in days. Animals received a single intraplantar dose (i.pl.) PD198306(3 mg/100. mu.l) or intrathecal PD198306 (30. mu.g/10. mu.l), and withdrawal thresholds were assessed again 1 hour after treatment. Results are expressed as median ± first and third quartiles. P < 0.01 indicates a significant difference compared to vehicle-treated animals (Mann-Whitney t test; n ═ 6).

Figure 8 bar graph depicts the force in grams required to cause paw withdrawal with von Frey hair. Measurement of Baseline (BL) was performed prior to treatment. Animals received a single i.t. administration of PD219622, PD297447, PD184352 or PD254552 (30. mu.g/10. mu.l) or pregabalin (100. mu.g/10. mu.l) and the withdrawal threshold was assessed again after 30 min, 1h and 2h of treatment. Results are expressed as median ± first and third quartiles. P < 0.05, P < 0.01, P < 0.001, indicating a significant difference compared to the vehicle-treated animals (Mann-Whitney t test; n-7-8).

Detailed Description

The compounds disclosed herein are pharmaceutically active, 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, as well as pain.

Proliferative diseases are caused by defects in the intracellular signaling system or the signal transduction mechanisms of certain proteins. Defects include a change in the intrinsic activity or cellular concentration of one or more signaling proteins in the signaling cascade. Cells produce growth factors that bind to their own receptors, resulting in the formation of autocrine loops that continually stimulate proliferation. Mutation or overexpression of intracellular signaling proteins can result in the generation of spurious mitogenic signals within the cell. Some of the most common mutations occur in the gene encoding the protein known as Ras, a G-protein that is activated when bound to GTP and inactivated when bound to GDP. The growth factor receptor, and many other mitogenic receptors, when activated, can cause Ras to transition from a GDP-bound state to a GTP-bound state. This signal is absolutely essential for the proliferation of most cell types. Defects in this signaling system, particularly in the inactivation of the Ras-GTP complex, are common in cancer and result in long-term activation of the signaling cascade under Ras.

Activated Ras in turn causes activation of the serine/threonine kinase cascade. One of the group of kinases known to require active Ras-GTP in its own activation is the Raf family. These kinases in turn activate MEK (e.g., MEK)₁And MEK₂) MEK in turn reactivates the MAP kinase ERK (ERK)₁And ERK₂). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of the kinase is sufficient to result in cellular transformation. Blockade of downstream Ras signaling, for example, by using a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether caused by cell surface receptors or by 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 through a phosphorylation mechanism. Once activated, Raf and other kinases place MEK at two immediately adjacent serine residues (S for MEK-1)²¹⁸And S²²²) Is required for activation of MEK kinase. MEK followed by MAP kinase at tyrosine residue Y separated by only one amino acid¹⁸⁵And threonine residue T¹⁸³And (3) phosphorylation.

This dual phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinases can then catalyze the phosphorylation of a large number of proteins, including a variety of transcription factors and other kinases. Among these MAP kinase phosphorylations are the mitogenic activation of a target protein such as a kinase, a transcription factor or another cellular protein. In addition to Raf-1 and MEKK, other kinases can activate MEK, and MEK itself appears to be a signal-integrating kinase. As is known to date, MEK is highly specific for phosphorylation of MAP kinases. Indeed, no other MEK substrate other than MAP kinase ERK has been found to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to be closely related to MAP kinase prior to its phosphorylation, suggesting that phosphorylation of MAP kinase by MEK may require a strong interaction between these two proteins beforehand. This need and unusual specificity of MEK both suggest a large difference in its mechanism of action from other protein kinases, and it is therefore possible to find selective inhibitors of MEK that may act through allosteric mechanisms rather than through the common blockade of ATP binding sites.

The effects of the MEK inhibitor PD198306 have been studied with two animal models of neuropathic pain by assessing the static allodynia caused by von Frey hairs.

In the Chronic Compressive Injury (CCI) model of the sciatic nerve, oral administration of PD198306(3-30mg/kg) had no effect. However, after repeated administration (3 doses given over 2 days), there was a transient effect in the diabetic neuropathy model (streptozocin). This may be caused by a disturbance of the blood brain barrier due to the diabetic condition of these animals, thus giving rise to a central effect of the compound. Intrathecal administration of PD198306(1-30 μ g) dose-dependently blocked static allodynia in both streptozotocin and CCI models of neuropathic pain, with Minimum Effective Doses (MED) of 3 μ g and 10 μ g, respectively. The highest dose used (30 μ g) completely blocked the maintenance of static allodynia for up to 1 hour. Intraplantar PD198306(3 mg/100. mu.l) at a dose 100-fold higher than the dose that showed efficacy when administered intrathecally (30. mu.g/10. mu.l) did not contribute to static allodynia in both models of neuropathic pain. This finding confirms the lack of action seen following systemic administration and suggests a central site of action for the compound.

The results of this study support the use of MEK inhibitors as a potential new therapeutic tool for chronic pain. The therapeutic window (window) of this novel class of compounds in the treatment of pain will be further supported by future studies of the potential side effects of MEK inhibitors, which are brain penetrating agents, particularly those associated with memory.

A. Term(s) for

Certain terms are defined below and by their use throughout this specification.

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

The alkyl group may be substituted with 1, 2, 3 or more substituents independently selected from halogen (fluorine, chlorine, bromine or iodine), 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 analogous to alkyl groups, but with at least one double bond (two adjacent sp)²Carbon atom). Depending on the position of the double bond and the substituents, if any, the geometry of the double bond may be either the entgegen (E) or zusammen (Z) configuration, 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 a mixture thereof; like alkyl, the unsaturated groups may be straight-chain orBranched, and they may be substituted as described above for alkyl and throughout the specification by the examples. Examples of alkenyl, alkynyl and substituted forms of alkenyl, alkynyl 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), alkenyl and alkynyl may be, for example, C_2-4Or C_2-8Preferably is C_3-4Or C_3-8In (1).

More general forms of substituted hydrocarbyl include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and the corresponding prefix forms: amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl-, and the like, or combinations of these 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, arylalkyl, aryloxyalkyl, arylalkoxyalkyl, (heterocyclyl) alkyl and (heterocyclyl) oxyalkyl. R₁Thus, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, alkylalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl) alkyl, (haloaryl) alkyl, (hydroxyaryl) alkynyl, and the like are included. Similarly, R_AIncluding hydroxyalkyl and aminoaryl, and R_BIncluding hydroxyalkyl, aminoalkyl and hydroxyalkyl (heterocyclyl) alkyl groups.

Heterocyclic groups including, but not limited to, heteroaryl groups include: furyl, oxazolyl, isoxazolyl, thienyl, 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, octahydrobenzothienyl, and octahydrobenzofuranyl.

Selective MEK 1 or MEK 2 inhibitors are those compounds that inhibit the MEK 1 or MEK 2 enzyme, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF and PDGF receptor kinases, and C-src. In general, selective MEK 1 or MEK 2 inhibitors have the IC for MEK 1 or MEK 2₅₀At least its IC for the other enzymes mentioned above₅₀One fiftieth of (1 >₅₀). Preferably, the selective inhibitor has an IC₅₀At least its IC for one or more of the enzymes mentioned above₅₀1/100, more preferably 1/500, even more preferably 1/1000, 1/5000 or less.

B. Compound (I)

The term "aryl" as used herein refers to a monocyclic, bicyclic or tricyclic aromatic ring moiety containing 5 to 12 carbon atoms. Examples of typical aryl groups include phenyl, naphthyl, and fluorenyl. The aryl group may be substituted with one, two or three groups selected from fluorine, chlorine, bromine, iodine, alkyl, hydroxy, alkoxy, nitro or amino. Typical substituted aryl groups include 3-fluorophenyl, 3, 5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl and the like.

The term "aryloxy" refers to an aryl group bonded through an oxygen atom, such as phenoxy, 3-bromophenoxy, naphthoxy, and 4-methyl-1-fluorenyloxy.

"heteroaryl" means a monocyclic, bicyclic or tricyclic aromatic ring moiety containing 4 to 11 carbon atoms and one, two or three heteroatoms selected from O, S or N. Examples thereof include furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, xanthenyl, pyronyl, indolyl, pyrimidinyl, 1, 5-naphthyridinyl, pyridyl and triazinyl. Heteroaryl groups may be unsubstituted or substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro or amino. Examples of substituted heteroaryl groups include chloropyranyl, methylthiophenyl, fluoropyridyl, amino-1, 4-benzisoxazinyl, nitroisoquinolinyl and hydroxyindolyl.

The heteroaryl group may be bonded via an oxygen to form a heteroaryloxy group, such as thiophenoxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.

The term "C₁-C₈Alkyl "refers to a straight or branched chain aliphatic group containing 1 to 8 carbon atoms. Typical C₁-C₈Alkyl groups include methyl, ethyl, isopropyl, t-butyl, 2, 3-dimethylhexyl and 1, 1-dimethylpentyl. The alkyl group may be unsubstituted or substituted by a cycloalkyl group, containing groups selected from O, S or NR₉Cycloalkyl, aryl, aryloxy, heteroaryl or heteroaryloxy as defined above. Examples of aryl-and aryloxy-substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1-dimethyl-3- (2-nitrophenoxy) butyl and 3, 4, 5-trifluoronaphthylmethyl. Examples of the alkyl group substituted with the heteroaryl group or the heteroaryloxy group include thienylmethyl group, 2-furylethyl group, 6-furyloxyoctyl group, 4-methylquinolinyloxymethyl group and 6-isothiazolylhexyl group. Cycloalkyl-substituted alkyl groups include cyclopropylmethyl, 2-cyclopentylethyl, 2-piperidin-1-ylethyl, 3- (tetrahydropyran-2-yl) propyl and cyclobutylmethyl.

“C₂-C₈Alkenyl "means a straight or branched carbon chain containing one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1-dimethyl-hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl and 3-isopropyl-pent-4-enyl. The alkenyl group may be substituted by aryl, aryloxy, heteroaryl or heteroaryloxy groups, such as 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furanyloxy-but-2-enyl and 4-naphthyloxy-hex-2-enyl.

“C₂-C₈Alkynyl "refers to a straight or branched carbon chain containing 2 to 8 carbon atoms and at least one triple bond. Dian (Chinese character)Alkynyl groups of the type include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3, 4-dimethyl-hex-5-ynyl and 2-ethyl-but-3-ynyl. The alkynyl group may be substituted by aryl, aryloxy, heteroaryl or heteroaryloxy groups, such as 4- (2-fluorophenyl) -but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl and 2-furoxy-3-methyl-hex-4-ynyl.

Alkenyl and alkynyl groups may contain one or more double or triple bonds, respectively, or both. For example, typical groups containing both double and triple bonds include hex-2-en-4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl and 3-thiophenoxy-hex-3-en-5-ynyl.

The term "C₃-C₁₀Cycloalkyl "refers to a non-aromatic or fused ring containing 3 to 10 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, bicycloheptyl, adamantyl and cyclohexyl. The ring may optionally contain a substituent selected from O, S or NR₉A heteroatom of (a). Such groups include tetrahydrofuranyl, tetrahydropyrrolyl, octahydrobenzofuranyl, octahydroindolyl and octahydrobenzothienyl.

R₃、R₄And R₅May include a general term (O or NH)_m-(CH₂)_n-R₉A group as defined. Examples of such radicals are aminomethyl, 2-aminoethyl, 2-aminoethylamino, 3-aminopropoxy, N-diethylamino, 3- (N-methyl-N-isopropylamino) -propylamino, 2- (N-acetylamino) -ethoxy, 4- (N-dimethylaminocarbonylamino) -butoxy and 3- (N-cyclopropylamino) -propoxy.

The term "aryl" as used herein refers to a monocyclic, bicyclic or tricyclic aromatic ring moiety containing 5 to 12 carbon atoms. Examples of typical aryl groups include phenyl, naphthyl, and fluorenyl. The aryl group may be substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino or dialkylamino. Typical substituted aryl groups include 3-fluorophenyl, 3, 5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl and the like.

"heteroaryl" means a monocyclic, bicyclic or tricyclic aromatic ring moiety containing 4 to 11 carbon atoms and one, two or three heteroatoms selected from O, S or N. Examples thereof include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthyl, pyronyl, indolyl, pyrimidinyl, 1, 5-naphthyridinyl, pyridyl, benzimidazolyl and triazinyl. Heteroaryl groups may be unsubstituted or substituted with one, two or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino or dialkylamino. Examples of substituted heteroaryl groups include chloropyranyl, methylthiophenyl, fluoropyridyl, amino-1, 4-benzisoxazinyl, nitroisoquinolinyl and hydroxyindolyl.

The term "C₁-C₈Alkyl "refers to straight and branched chain aliphatic groups containing 1 to 8, preferably 1 to 4, carbon atoms. Typical C₁-C₈Alkyl groups include methyl, ethyl, isopropyl, t-butyl, 2, 3-dimethylhexyl and 1, 1-dimethylpentyl. The alkyl group may be unsubstituted or substituted with halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl or heteroaryloxy as defined herein. Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2- (hydroxymethyl) ethyl. Examples of aryl-and aryloxy-substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1-dimethyl-3- (2-nitrophenoxy) butyl and 3, 4, 5-trifluoronaphthylmethyl. Substituted by heteroaryl or heteroaryloxy groupsExamples of alkyl groups include thienylmethyl, 2-furanylethyl, 6-furanyloxyoctyl, 4-methylquinolinyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl-substituted alkyl groups include cyclopropylmethyl, 2-cyclohexylethyl, piperidinyl-2-methyl, 2- (piperidin-1-yl) ethyl, 3- (morpholin-4-yl) propyl.

“C₂-C₈Alkenyl "means a straight or branched carbon chain containing one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1-dimethyl-hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl and 3-isopropyl-pent-4-enyl. The alkenyl group may be substituted by halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl or heteroaryloxy, for example 2-bromovinyl, 3-hydroxy-2-butenyl, 1-aminovinyl, 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl and 4-naphthyloxy-hex-2-enyl.

“C₂-C₈Alkynyl "refers to a straight or branched carbon chain containing 2 to 8 carbon atoms and at least one triple bond. Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3, 4-dimethyl-hex-5-ynyl and 2-ethyl-but-3-ynyl. The alkynyl group may be substituted as for alkyl and alkenyl, for example by aryl, aryloxy, heteroaryl or heteroaryloxy, such as 4- (2-fluorophenyl) -but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl and 2-furanyloxy-3-methyl-hex-4-ynyl.

The term "C₃-C₁₀Cycloalkyl "refers to a non-aromatic or fused ring containing 3 to 10 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, bicycloheptyl, adamantyl and cyclohexyl. The ring may optionally contain one,Two or three selected from O, S or NR₉A heteroatom of (a). Such groups include tetrahydrofuranyl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl and octahydrobenzothienyl. The cycloalkyl group may be substituted with the same substituents as the alkyl group and the alkenyl group, such as halogen, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl and 3-thienylmorpholin-1-yl.

R₆And R₇May be taken together with the nitrogen to which they are attached to form a 3-to 10-membered ring which may contain 1, 2 or 3 further heteroatoms selected from O, S, NH or N-alkyl. Examples of such rings include piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, N-methylpiperazinyl, aziridinyl, and the like. Such rings may be substituted with halogen, hydroxy, alkyl, alkoxy, amino, alkyl and dialkylamino, aryl, aryloxy, heteroaryl and heteroaryloxy. Typical examples include 3-hydroxy-pyrrolidinyl, 2-fluoro-piperidinyl, 4- (2-hydroxyethyl) -piperidinyl and 3-thienylmorpholinyl.

C. Synthesis of

The 4-bromo and 4-iodophenylamino phenoxyhydroxamic acid derivatives of formula I can be prepared from commercially available starting materials using synthetic methods well known to those skilled in the art of organic chemistry. Typical synthesis methods are to react 4-bromo or 4-iodoaniline with benzoic acid bearing a leaving group at the 2-position to give phenylaminobenzoic acid, and then to react the phenylamino derivative of benzoic acid with a hydroxylamine derivative. The process is shown in reaction scheme 1.

Reaction scheme 1Wherein L is a leaving group, for example a halogen such as fluorine, chlorine, bromine or iodine, or an activated hydroxy group such as diethyl phosphate, trimethylsiloxy, p-nitrophenoxy or phenylsulfonyloxy.

The reaction of the aniline derivative with the benzoic acid derivative is usually accomplished by mixing benzoic acid with an equimolar or excess amount of aniline in an inert organic solvent such as tetrahydrofuran or toluene in the presence of a base such as lithium diisopropylamide, n-butyllithium, sodium hydride and sodium amide. The reaction is typically carried out at a temperature of about-78 ℃ to about 25 ℃, and is typically completed in about 2 hours to about 4 days. The product can be isolated by removal of the solvent, for example by evaporation under reduced pressure, and if desired further purified by conventional methods such as chromatography, crystallization or distillation.

Then the phenylaminobenzoic acid is reacted with a hydroxylamine derivative HNR₆OR₇In the presence of a peptide coupling agent. Hydroxylamine derivatives that may be used include methoxyamine, N-ethyl-isopropoxyamine and tetrahydrooxazine. Typical coupling agents include 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), 1, 3-Dicyclohexylcarbodiimide (DCC), bromo-tris (pyrrolidinyl) -phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidinylphosphonium hexafluorophosphate (PyBOP). The phenylaminobenzoic acid and the hydroxyamino derivative are generally mixed in about equimolar amounts in an inert organic solvent such as dichloromethane, tetrahydrofuran, chloroform or xylene, and an equimolar amount of the coupling agent is added. If desired, a base such as triethylamine or diisopropylethylamine may be added as an acid scavenger. The coupling reaction is usually completed after about 10 minutes to 2 hours, and the product is easily isolated by, for example, distilling off the reaction solvent under reduced pressure, and purified by a conventional method such as chromatography or crystallization from a solvent such as acetone, diethyl ether or ethanol.

Another method for preparing the compounds of the present invention involves first converting benzoic acid to a hydroxamic acid derivative and then reacting the hydroxamic acid derivative with aniline. The synthesis is shown in scheme 2.

Reaction scheme 2Wherein L is a leaving group. The general reaction conditions for these two-step reactions in scheme 2 are the same as those described in scheme 1 above。

Yet another method of preparing the compounds of the present invention comprises reacting phenylaminophenoxyhydroxamic acid with an ester-forming group, as shown in scheme 3.

Reaction scheme 3Wherein L is a leaving group such as halogen and the base is triethylamine or diisopropylamine.

The synthesis of the compounds of formula I of the present invention is further illustrated by the following detailed examples 1-102.

The 2- (4-bromo and 4-iodophenylamino) -benzoic acid derivatives of formula I (A) can be prepared from commercially available starting materials using the synthetic procedures well known to those skilled in the art of organic chemistry and illustrated in synthetic examples 1A-224A below. A typical synthesis method is to react 4-bromo or 4-iodoaniline with benzoic acid bearing a leaving group at the 2-position to give 2- (phenylamino) -benzoic acid. The procedure is shown in scheme 1 (A).

Reaction scheme 1(A)Wherein L is a leaving group, for example a halogen such as fluorine.

The reaction of aniline with benzoic acid derivatives is usually accomplished by mixing benzoic acid with an equimolar or excess amount of aniline in an inert organic solvent such as tetrahydrofuran or toluene in the presence of a base such as lithium diisopropylamide, n-butyllithium, sodium hydride, triethylamine and Hunig's base. The reaction is typically carried out at a temperature of from about-78 ℃ to about 100 ℃, and is typically completed in from about 2 hours to about 4 days. The product can be isolated by removal of the solvent, for example by evaporation under reduced pressure, and if desired further purified by conventional methods such as chromatography, crystallization or distillation.

The 2- (phenylamino) -benzoic acid (e.g., of formula IA, wherein R is₇Is hydrogen) may be combined with an organic compoundOr inorganic base such as pyridine, triethylamine, calcium carbonate or sodium hydroxide to obtain pharmaceutically acceptable salt. The free acid may also be reacted with a compound of the formula HOR₇Alcohol of (wherein R₇Other than hydrogen, e.g. methyl) to the corresponding ester. The reaction of benzoic acid with an alcohol may be carried out in the presence of a coupling agent. Typical coupling agents include 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), 1, 3-Dicyclohexylcarbodiimide (DCC), bromo-tris (pyrrolidinyl) -phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidinylphosphonium hexafluorophosphate (PyBOP). The phenylaminobenzoic acid and the alcohol derivative are generally mixed in about equimolar amounts in an inert organic solvent such as dichloromethane, tetrahydrofuran, chloroform or xylene, and an equimolar amount of the coupling agent is added. If desired, a base such as triethylamine or diisopropylethylamine may be added as an acid scavenger. The coupling reaction is usually completed after about 10 minutes to 2 hours, and the product is easily isolated by, for example, distilling off the reaction solvent under reduced pressure, and purified by a conventional method such as chromatography or crystallization from a solvent such as acetone, diethyl ether or ethanol.

Benzamides of the invention wherein Z is CONR₆R₇By reacting the aforementioned benzoic acid with a compound of formula HNR₆R₇By reacting an amine of (a). The reaction is carried out by reacting approximately equimolar amounts of benzoic acid with an amine in an inert organic solvent in the presence of a coupling agent. Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene and xylene. Typical coupling agents include DCC, EEDQ, PyBrOP and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when conducted at a temperature of about 0 ℃ to about 60 ℃. The product amide is readily isolated by, for example, evaporation of the reaction solvent, and further purification can be accomplished by conventional means such as chromatography, crystallization or distillation. Hydrazide (z ═ CONHNR)₁₀R₁₁) Analogously by reacting benzoic acid with formula H₂HNR₁₀R₁₁By coupling with hydrazine.

Benzyl alcohol of the invention wherein Z is CH₂OR₆And R is₆The compounds of formula I (A) which are hydrogen are readily reacted via the corresponding benzoic acidsReduction of the following scheme:

typical reducing agents commonly used include borane in tetrahydrofuran. The reduction is typically carried out in an inert organic solvent such as tetrahydrofuran, and is typically completed in about 2 hours to about 24 hours when carried out at a temperature of about 0 ℃ to about 40 ℃.

The following detailed examples 1A-224A illustrate specific compounds provided by the present invention.

D. Use of

The disclosed compositions are useful for the prevention and treatment of diseases or conditions involving chronic pain, including neuropathic pain, such as those set forth 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, burn pain, gout, trigeminal neuralgia, acute herpes and post-herpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury, compression injury, tissue injury, post-surgical pain, arthritic pain, or amputation.

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

1. Dosage form

According to known methods, the person skilled in the art will be able to determine the appropriate dosage for a patient, taking into account factors such as age, weight, general health, type of pain to be treated and the presence of other medications. In general, for normal weight adult patients, an effective amount will be between 0.1 and 1000 mg/kg/day, preferably between 1 and 300mg/kg body weight, and a daily dose will be between 10-5000 mg. Commercially available 100mg, 200mg, 300mg or 400mg capsules or other formulations (e.g., liquids and coated tablets) may be administered according to the disclosed methods.

2. Preparation

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 administration as divided doses. Dosage unit forms are also suitable for various methods of administration, including controlled 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 can be maintained by the use of a coating such as lecithin, a surfactant or by the maintenance of a suitable particle size. Carriers for solid dosage forms include (a) fillers or bulking agents, (b) binders, (c) humectants, (d) disintegrants, (e) solution inhibitors, (f) absorption enhancers, (g) adsorbents, (h) lubricants, (i) buffering agents, and (j) propellants.

The composition may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing 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 invention provides the disclosed compounds and closely related pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates, or solvates forms thereof; in a masked or protected form; and racemic mixtures, or enantiomerically or optically pure forms.

Pharmaceutically acceptable salts, esters and amides include carboxylates (e.g., C)_1-8Alkyl, cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclic), amino acid addition salts, esters and amides within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue 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, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate and laurylsulfonate. These salts may include alkali and alkaline earth metal 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, "pharmaceutically acceptable salts", journal of pharmaceutical science 1977, 66: 1-19, which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, C_1-6Alkyl primary amines and di (C)_1-6Alkyl) secondary amines. Secondary amines include 5-or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally 1-2 additional heteroatoms. Preferred amides are derived from ammonia, C_1-3Alkyl primary amines and di (C)_1-2Alkyl) amines. Representative pharmaceutically acceptable esters of the invention include C_1-7Alkyl radical, C_5-7Cycloalkyl, phenyl and phenyl (C)_1-6) An alkyl ester. Preferred esters include methyl esters.

The invention also includes disclosed compounds that contain 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 will be useful as intermediates. Synthetic intermediates and methods disclosed herein, as well as minor variations thereof, are also included within the scope of the invention.

Hydroxy protecting group

Hydroxyl protecting groups include: ethers, esters and protection of 1, 2-and 1, 3-diols. Ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers, and the conversion of silyl ethers to other functional groups.

Substituted methyl ethers

Substituted methyl ethers include: methoxymethyl, methylthiomethyl, tert-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, tert-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2, 2, 2-trichloroethoxymethyl, bis (2-chloro-ethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromo-tetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxybridge, 1- [ (2-chloro-4-methyl) phenyl ] -4-methoxypiperidine- 4-yl, 1, 4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiophenyl, 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- (phenylhydrogenselenyl) 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-oxide, diphenylmethyl, p '-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α -naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tris (p-methoxyphenyl) methyl, 4- (4' -bromobenzoylmethoxy) phenyldiphenylmethyl, 4 ', 4 "-tris (4, 5-dichlorophthalimidophenyl) methyl, 4', 4" -tris (tuber sugar acyloxyphenyl) methyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, p-and p-methoxyphenyl, bis (p-methoxyphenyl) phenylme, 4, 4 ', 4 "-tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ', 4" -dimethoxyphenyl) -methyl, 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-dioxy bridge.

Silyl ethers

Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl 1, 1, 2-trimethylpropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Esters

Ester protecting groups include: esters, carbonates, assisted cleavage, heteroates, and sulfonates.

Esters

Examples of protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, P-chlorophenoxyacetate, P-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (tuberonic acid ester), 4- (ethylenedithio) pentanoate, pivalate, adamantane ester, crotonate, 4-methoxycrotonate, benzoate, P-phenylbenzoate, and 2, 4, 6-trimethylbenzoate ( formate).

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-benzylthiocarbonate, 4-ethoxy-1-naphthyl and methyldithiocarbonate.

Assisted lysis

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

Heteroesters

In addition to the above classes, the heteroates 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, alkyl N, N' -tetramethyl-phosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2, 4-dinitrophenylsulfenate.

Sulfonic acid ester

The protective sulfates include: sulfate, methane sulfonate (mesylate), benzyl sulfonate, and tosylate.

Protection of 1, 2-and 1, 3-diols

Protection of the 1, 2-and 1, 3-diol groups includes: 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, (isopropylidene) acetonide, 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

Ester protecting groups include: esters, substituted methyl esters, 2-substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, heteroderivatives, 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, formylaminomethyl and N-phthalimidomethyl.

2-substituted ethyl ester

2-substituted ethyl esters include: 2, 2, 2-trichloroethyl, 2-haloethyl, α -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, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamyl, α -methylcinnamyl, phenyl, p- (methylmercapto) -phenyl and benzyl.

Substituted benzyl esters

Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2- (9, 10-dioxo) anthrylmethyl, 5-dibenzosuberyl, 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.

Heteroderivatives

Hetero 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) complexes.

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-nitro-N-anilide, 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, their preparation and their use

The carbamate includes: carbamate, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and heterocarbamates.

Carbamates, their preparation and their use

The carbamate includes: 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-dimethyl-2-haloethyl, 1-dimethyl-2, 2-dibromoethyl, 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, allyl, benzyl, cinnamyl, 4-nitrocinnamyl, quinolinyl, N-hydroxypiperidinyl, alkyldithiol, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2, 4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted lysis

Protection by assisted cleavage includes: 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1, 3-dithianyl) ] methyl, 4-methylthiophenyl, 2, 4-dimethyl-thienyl, 2-phosphonioethyl, 2-triphenylphosphine-isopropyl, 1-dimethyl-2-cyanoethyl, m-chloro-p-acetoxybenzyl, p- (dihydroxyboryl) benzyl, 5-benzisoxazolylmethyl, and 2- (trifluoromethyl) -6-chromonylmethyl.

Photolytic cleavage

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 derivatives

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

Heterocarbamic acid esters

In addition to the above, heterocarbamates include: tert-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2-dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) benzyl, 1-dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1-dimethyl-propynyl, di (2-pyridyl) methyl, 2-furylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinanyl, p- (p' -methoxyphenyl-azo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 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 carboxylic acids

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

Assisted lysis

The auxiliary cleavage groups include: n-o-nitrophenylacetyl, N-o-nitrophenyloxyacetyl, N-acetoacetyl, (N' -dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl, N-3- (o-nitrophenyl) propionyl, N-2-methyl-2- (o-nitrophenyloxy) propionyl, N-2-methyl-2- (o-phenylphenyloxy) 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-dithiosuccinyl, N-2, 3-diphenyl-maleyl, 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 protecting 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-sulfinyl and N-sulfonyl.

N-alkyl and N-aryl amines

N-alkyl and N-aryl amines include: 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 salts, N-benzyl, N-bis (4-methoxyphenyl) methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N-9-phenylfluorenyl, 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 ' -isopropylidene, N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N- (5-chloro-2-hydroxyphenyl) phenylmethylene, 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-diphenyldihydrocarbylboronic acid derivatives, N- [ phenyl (chromium or tungsten pentacarbonyl) ] carbaenyl 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-diphenylphosphino, N-dimethylphosphino, N-diphenylphosphinophosphino, N-dialkylphosphoryl, N-dibenzylphosphoryl and N-diphenylphosphoryl. Examples of N-sulfinyl derivatives include: n-benzenesulfinyl, N-o-nitrobenzenesulfinyl, N-2, 4-dinitrobenzenesulfinyl, N-pentachlorophenylsulfinyl, N-2-nitro-4-methoxy-benzenesulfinyl, N-triphenylmethylsulfinyl and N-3-nitropyridinylsulfinyl. 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- β -trimethylsilylethanesulfonyl, N-2, 4, 6-methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2, 4, 5, 6-pentamethylb, N-9-anthracenesulfonyl, N-4- (4 ', 8' -dimethoxynaphthylmethyl) -benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl and N-benzoylmethylsulfonyl.

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

Features of the 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 & Kingman (Hull, U.K.) were housed in 3 groups in cages. All animals were kept in a 12 hour light/dark cycle (light started at 7: 00) and were given access to food and water ad libitum. All experiments were performed by observers with unclear status of drug treatment.

Development of diabetes in rats

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

Assessment of static allodynia

Mechano-hypersensitivity was measured with Semmes-Weinstein von Frey hair (Stoelting, Illinois, u.s.a.). Animals were placed in the cage at the bottom of the wire mesh so that the underside of their paws was accessible. Animals were habituated to this environment prior to the start of the experiment. Mechano-hypersensitivity was detected by touching the plantar surface of the animal's right hind paw with von Frey hair with increasing force (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6 seconds. Once the withdrawal response was determined, the paw was then retested with progressively decreasing von Frey hair until no response occurred. The highest force 29g lifting the paw also causes a reaction, thus representing a cut-off point. The lowest force required to elicit a reaction was recorded as Paw Withdrawal Threshold (PWT) in grams.

Medicine

PD198306 [ N-cyclopropylmethoxy-3, 4, 5-trifluoro-2- (4-iodo-2-methylphenylamino) -benzamide ] and CI-1008(pregabalin) were synthesized in Parke-Davis (AnnArbor, MI, USA). PD198306 was suspended in a polyoxyethylated fatty acid ester (cremophor) ethanol water (1: 8) vehicle. Pregabalin is dissolved in water. Both compounds are administered orally. Streptozotocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered by intraperitoneal injection. The drug was administered in a volume of 1 ml/kg.

Statistics of

Static allodynia data was analyzed by Kruskall-Wallis analysis of variance on nonparametric results, after confirmation of significance by Mann-Whitney t test.

Experimental protocol

Static allodynia was assessed using von Frey hair, before (baseline, BL) and 1 hour after PD198306(30mg/kg, oral), vehicle (polyoxyethylated fatty acid ester: ethanol: water, 1: 8) or pregabalin (30mg/kg, oral) (test) administration. The animals were again administered the same compound in the morning and afternoon of the following day. Static allodynia was assessed only before and 1 hour after afternoon dosing to minimize habitual effects on the test conditions in the animals. Animals treated with pregabalin received water at the morning dose to avoid potential compound tolerance due to repeated dosing.

Day 1: day 2:

in the morning: PD198306

Water (W)

Excipient

In the afternoon: BL in the afternoon: BL

PD 198306 PD 198306

Pregabalin Pregabalin

Excipient excipients

Test of

Results

Pregabalin (30mg/kg, oral) administered in a single dose significantly blocked streptozocin-induced static allodynia after 1 hour of administration. In contrast, a single dose of PD198306(30mg/kg, oral) had no effect on streptozocin-induced static allodynia 1 hour after administration (see below). However, when the compound was administered twice more on the second day, it significantly blocked streptozocin-induced static allodynia after the third dose. By the next 3 rd day the effect disappeared (see figure 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 cages of 3-6 groups. All animals were kept in a 12 hour light/dark cycle (light started at 7: 00) and were given access to food and water ad libitum. All experiments were performed by observers with unclear status of drug treatment.

Development of chronic compressive injury in rats

Animals were treated with 2% isoflurane 1: 4O via nose cone during surgery₂/N₂The O-mixture remained anesthetized. As previously Bennett&Sciatic nerve ligation was performed as described by Xie, 1988. During operation the animals were placed on a constant temperature blanket. Following surgical preparation, the medial femoral total sciatic nerve was exposed using blunt dissection through the biceps brachii muscle. Adjacent to the sciatic trigeminal site, approximately 7mm long nerves were separated from the adherent tissue and 4 ligatures (4-0 silk threads) were loosely tied around them at approximately 1mm intervals. The incisions were closed layer by layer and the wounds were treated with topical antibiotics.

Intrathecal injection

PD198306 and pregabalin were administered intrathecally in a volume of 10 μ 1 using a 100 μ l Hamilton syringe by exposing the spinal column of the rat under brief isoflurane anesthesia. A 27 gauge needle 10mm long was injected into the intrathecal space between the 5-6 lumbar regions. If the tail-shaking reaction exists, the success of penetration can be judged. The wound was closed with an automatic clip and the rat appeared to wake up completely within 2-3 minutes after injection.

Assessment of static allodynia

Mechano-hypersensitivity was measured with Semmes-Weinstein von Frey hair (Stoelting, Illinois, u.s.a.). Animals were placed in the cage at the bottom of the wire mesh so that the underside of their paws was accessible. Animals were habituated to this environment prior to the start of the experiment. Mechano-hypersensitivity was detected by touching the plantar surface of the animal's right hind paw with von Frey hair with increasing force (0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6 seconds. Once the withdrawal response was determined, the paw was retested, starting with the next progressively decreasing von Frey hair until no response occurred. The highest force 29g lifting the paw also causes a reaction, thus representing a cut-off point. The lowest force required to elicit a reaction was recorded as Paw Withdrawal Threshold (PWT) in grams.

Experimental protocol

Static allodynia was assessed using von Frey hair, before (baseline, BL) and after 0.5, 1 and 2 hours before intrathecal or intraplantar administration of PD198306(1-30 μ g, i.t.), vehicle (polyoxyethylated fatty acid ester: ethanol: water, 1: 8) or pregabalin (10 μ g, i.t.). For the oral experiments, static allodynia was assessed using von Frey hair, before (baseline, BL) and 1 hour after oral administration of PD198306(3-30mg/kg, oral), vehicle (polyoxyethylated fatty acid ester: ethanol: water, 1: 8) or pregabalin (30mg/kg, oral). The animals were again administered the same compound in the morning and afternoon of the following day. Static allodynia was assessed before and 1 hour after morning dosing. In the afternoon, static allodynia was assessed prior to dosing and 1, 2 and 3 hours after dosing for animals treated with streptozocin. CCI animals were assessed before dosing and 1 and 2 hours after dosing.

The medicine used

PD198306 and pregabalin were synthesized in Parke-Davis (Ann Arbor, MI, USA). PD198306 was suspended in a polyoxyethylated fatty acid ester, ethanol, water (1: 8) vehicle. Pregabalin is 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 by intraperitoneal injection in a volume of 1 ml/kg.

Statistics of

Data were analyzed by Kruskall-Wallis analysis of variance on nonparametric results, after confirmation of significance compared to the vehicle group by Mann-Whitney t test.

Results

1. Effect of PD198306 on static allodynia following systemic administration

Effect of PD198306 on streptozocin-induced static allodynia

Pregabalin (30mg/kg, oral) administered in a single dose significantly blocked streptozocin-induced static allodynia after 1 hour of administration. In contrast, a single dose of PD198306(3-30mg/kg, oral) had no effect on streptozocin-induced static allodynia 1 hour after administration (fig. 2). However, PD198306(30 mg/kg) significantly blocked streptozocin-induced static allodynia 2 hours after the third dose when the compound was administered twice more on the second day (figure 2).

Effect of PD198306 on CCI-induced static allodynia

Pregabalin (30mg/kg, oral) administered in a single dose significantly blocked CCI-induced static allodynia 1 hour after administration. In contrast, single or multiple doses of PD198306(3-30mg/kg, oral) did not have any effect on CCI-induced static allodynia (FIG. 3).

2. Effect of PD198306 on static allodynia following intrathecal administration

Intrathecally administered PD198306(1-30 μ g) dose-dependently blocked the maintenance of static allodynia in streptozotocin (FIG. 4) and CCI animals (FIG. 5), with MEDs of 3 μ g and 10 μ g, respectively. This anti-allodynic effect lasted for 1 hour.

3. Effect of PD198306 on static allodynia following intraplantar administration

Intrathecal administration of PD198306(30 μ g) significantly blocked static allodynia in both neuropathic pain models (fig. 6, 7). In contrast, a single dose of PD198306 administered directly into the paw at a 100-fold higher dose (3mg/100 μ Ι) 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 that produce pain sensory disorders like those seen in humans". Pain (pain) 1988; 33: 87-107.

Courteix C, Eschalier A and Lavarernne J. "streptozotocin-induced rats: behavioral evidence for a model of chronic pain ". "pain" 1993; 53: 81-8.

Example 3

Effect of other MEK inhibitors in the neuropathic pain model in rats

SUMMARY

The effects of several MEK inhibitors with different binding affinities have been studied in the rat CCI model of neuropathic pain by assessing static allodynia with von frey hair. Intrathecally administered PD219622 or PD297447(30 μ g) had no significant effect on allodynia. This lack of effect may reflect a 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 was only evident within 30 minutes after injection and therefore was shorter than that observed with pregabalin (100 μ g). The effect sizes of 30. mu.g PD184352 and 100. mu.g pregabalin are similar. From this study, it can be concluded that: the MEK inhibitor when administered intrathecally produces an anti-allodynic effect in CCI induced neuropathic rats and this anti-allodynic effect correlates with the affinity of the compound.

Animals and methods for developing chronic compression injury in rats, injected test compounds, and assessment of static allodynia were performed as in example 2 above. PD219622, PD297447, PD184352, PD254552 and pregabalin were administered intrathecally, all PD compounds were administered at a dose of 30g and pregabalin was administered at a dose of 100. mu.g. Static allodynia was assessed with von Frey hairs before intrathecal administration of the compound (baseline, BL) and 0.5, 1 and 2 hours after administration.

The medicine used

PD297447, PD219622, PD254552, PD184352 (CI-1040) and pregabalin were synthesized in Parke-Davis (Ann Arbor, MI, USA). PD297447, PD219622, PD254552 and PD184352 were suspended in a polyoxyethylated fatty acid ester, ethanol, water (1: 8) vehicle. Pregabalin is dissolved in water. All compounds were administered intrathecally in a volume of 10 μ l.

Statistics of

Results

Intrathecally administered PD297447 or PD219622 (30 μ g) had no significant effect on allodynia. This lack of effect 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 higher affinities (2 and 5nM, respectively). This anti-allodynic effect was only evident within 30 minutes after injection and therefore was shorter than that observed with pregabalin (100 μ g). The effect sizes of 30. mu.g PD184352 and 100. mu.g pregabalin are similar.

The results show that: the MEK inhibitor when administered intrathecally produces an anti-allodynic effect in CCI induced neuropathic rats and this anti-allodynic effect correlates with the affinity of the compound.

Chemical examples

Example 1

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide

(a) Preparation of 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid

To a stirring solution of 3.16g (0.0133mol) of 2-amino-5-iodotoluene in 5mL of tetrahydrofuran at-78 deg.C was added 10mL (0.020mol) of 2.0M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich). The resulting green suspension was stirred vigorously for 15 minutes, then a solution of 1.00g (0.00632mol)2, 4-difluorobenzoic acid in 10mL tetrahydrofuran was added. The reaction temperature was slowly raised to room temperature, and the mixture was stirred at this temperature for 2 days. The solvent was evaporated under reduced pressure and the reaction mixture was concentrated. To the concentrate was added aqueous HCl (10%) and the solution was extracted with dichloromethane. The organic phase was dried (MgSO)₄) Then concentrated to a small volume (10mL) on a steam bath and cooled to room temperature. The beige fibres formed were collected by vacuum filtration, rinsed with hexane and dried in a vacuum oven (76 ℃ C.; about 10mm Hg) to give 1.10g (47%) of the desired material; mp 224-229.5 ℃;¹H NMR(400MHz，DMSO)：δ9.72(s，1H)，7.97(dd，1H，J＝7.0，8.7Hz)，7.70(d，1H，J＝1.5Hz)，7.57(dd，1H，J＝8.4，1.9Hz)，7.17(d，1H，J＝8.2Hz)，6.61-6.53(m，2H)，2.18(s，3H)；¹³C NMR(100MHz，DMSO)：δ169.87，166.36(d，J_C-F＝249.4Hz)，150.11(d，J_C-F＝11.4Hz)，139.83，138.49，136.07，135.26(d，J_C-F＝11.5Hz)，135.07，125.60，109.32，104.98(d，J_C-F＝21.1Hz)，99.54(d，J_C-F＝26.0Hz)，89.43，17.52；¹⁹f NMR (376MHz, DMSO): δ -104.00 to-104.07 (m); IR (KBr)1670(C ═ O stretch) cm^-1；MS(Cl)M+1＝372.

Elemental analysis, calculation of C₁₄H₁₁FINO₂：

C，45.31；H，2.99；N，3.77。

Measured value: c, 45.21; h, 2.77; and N, 3.64.

(b) Preparation of 4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide

To a stirring solution of 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (0.6495g, 0.001750mol), O- (tetrahydro-2H-pyran-2-yl) -hydroxylamine (0.2590g, 0.002211mol) and diisopropylethylamine (0.40mL, 0.0023mol) in 31mL of an equal volume of tetrahydrofuran-dichloromethane was added directly 1.18g (0.00227mol) of solid PyBOP ([ benzotriazolyloxy-oxy- ] -methylene chloride]Trispyrrolidinylphosphonium hexafluorophosphate, advanced dhetech). The reaction mixture was stirred for 30 minutes and then concentrated in vacuo. The brown oil was treated with 10% aqueous hydrochloric acid. The suspension was extracted with diethyl ether. The organic extracts were washed with 10% sodium hydroxide, then 10% hydrochloric acid and dried (MgSO)₄) And concentrated in vacuo to give 1.0g of a light brown foam. This intermediate was dissolved in 25mL of an ethanol solution of hydrogen chloride, and the solution was left at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo to give a brown oil, which was purified by flash silica gel chromatography. Elution with dichloromethane → dichloromethane-methanol (166: 1) gives 0.2284g of a light brown viscous oil. Scraping with pentane-hexane and drying under high vacuum gave 0.1541g (23%) of beige foam; mp 61-75 ℃;¹H NMR(400MHz，DMSO)：δ11.34(s，1H)，9.68(s，1H)，9.18(s，1H)，7.65(d，1H，J＝1.5Hz)，7.58(dd，1H，J＝8.7，6.8Hz)，7.52(dd，1H，J＝8.4，1.9Hz)，7.15(d，1H，J＝8.4Hz)，6.74(dd，1H，J＝11.8，2.4Hz)，6.62(ddd，1H，J＝8.4，8.4，2.7Hz)，2.18(s，3H)；¹³C NMR(100MHz，DMSO)：δ165.91，164.36(d，J_C-F＝247.1Hz)，146.78，139.18，138.77，135.43，132.64，130.60(d，J_C-F＝11.5Hz)，122.23，112.52，104.72(d，J＝22.1Hz)，100.45(d，J_C-F＝25.2Hz)，86.77，17.03；¹⁹f NMR (376MHz, DMSO): δ -107.20 to-107.27 (m); IR (KBr)3307 (Wide, O-H stretch), 1636(C ═ O stretch) cm^-1；MS(Cl)M+1＝387.

Elemental analysis, calculation of C₁₄H₁₂FIN₂O₂：

C，43.54；H，3.13；N，7.25。

Measured value: c, 43.62; h, 3.24; and N, 6.98.

Example 2

5-bromo-3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide

(a) Preparation of 5-bromo-2, 3, 4-trifluorobenzoic acid

To a stirred solution of 1-bromo-2, 3, 4-trifluorobenzene (Aldrich, 99%; 5.30g, 0.0249mol) in 95mL anhydrous tetrahydrofuran cooled to-78 deg.C was slowly added 12.5mL of a 2.0M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (Aldrich). The mixture was stirred for 1 hour and then transferred through a cannula to 700mL of a saturated carbon dioxide ether solution cooled to-78 ℃ with stirring. The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 hours. To the reaction mixture was poured dilute aqueous hydrochloric acid (10%) (ca. 500mL), and the mixture was then concentrated on a rotary evaporator to give crude solid. The solid product was partitioned between ether (150mL) and aqueous HCl (330mL, pH 0). The aqueous phase was extracted with a second portion of ether (100mL), and the combined ether extracts were washed with 5% aqueous sodium hydroxide (200mL) and water (100mL, pH 12). These combined aqueous alkaline extracts were acidified to pH0 with concentrated aqueous hydrochloric acid. The resulting suspension was extracted with diethyl ether (2X 200 mL). The combined organic extracts were dried (MgSO)₄) Vacuum concentration, then high vacuum until the mass is constant, 5.60g (88% yield) beige powder is obtained; mp139-142.5 ℃;¹h NMR (400MHz, DMSO): δ 13.97 (width s, 1H, 8.00-7.96(m, 1H);¹³C NMR(100MHz，DMSO)：δ162.96，129.34，118.47，104.54(d，J_C-F＝22.9Hz)；¹⁹f NMR (376MHz, DMSO): δ -120.20 to-120.31 (m), -131.75 to-131.86 (m), -154.95 to-155.07 (m); IR (KBr)1696(C ═ O stretch) cm^-1；MS(Cl)M+1＝255.

Elemental analysis, calculation of C₇₄H₂₁BrF₃O₂：

C，32.97；H，0.79；N，0.00；Br，31.34；F，22.35。

Measured value: c, 33.18; h, 0.64; n, 0.01; br, 30.14; f, 22.75.

(b) Preparation of 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid

To a stirred solution of 1.88g (0.00791mol) 2-amino-5-iodotoluene in 10mL tetrahydrofuran at-78 deg.C was added 6mL (0.012mol) of a 2.0M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich). The resulting green suspension is stirred vigorously for 10 minutes, then a solution of 1.00g (0.00392mol) 5-bromo-2, 3, 4-trifluorobenzoic acid in 15mL tetrahydrofuran is added. The cooling bath was then removed and the reaction mixture was stirred for 18 hours. The mixture was concentrated and the concentrate was treated with 100mL of dilute (10%) aqueous hydrochloric acid. The resulting suspension was extracted with diethyl ether (2X 150mL) and the combined organic extracts were dried (MgSO₄) And concentrated in vacuo to give an orange solid. The solid was triturated with boiling dichloromethane, cooled to room temperature, and collected by filtration. The solid was washed with dichloromethane and dried in a vacuum oven (80 ℃) to give 1.39g (76%) of a yellowish green powder; mp 259.5-262 ℃;¹H NMR(400MHz，DMSO)：δ9.03(s，1H)，7.99(dd，1H，J＝7.5，1.9Hz)，7.57(dd，1H，J＝1.5Hz)，7.42(dd，1H，J＝8.4，1.9Hz)，6.70(dd，1H，J＝8.4，6.0Hz)，2.24(s，3H)；¹⁹f NMR (376MHz, DMSO): δ -123.40 to-123.47 (m); -139.00 to-139.14 (m); IR (KBr)1667(C ═ O stretch) cm^-1(ii) a MS (Cl) M +1 ═ 469, elemental analysis, calculated C₁₄H₉BrF₂INO₂：

C, 35.93; h, 1.94; n, 2.99; br, 17.07; f, 8.12; i, 27.11. Measured value: c, 36.15; h, 1.91; n, 2.70; br, 16.40; f, 8.46; and I, 26.05.

(c) Preparation of 5-bromo-3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide

To a stirring solution of 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (0.51g, 0.0011mol), O- (tetrahydro-2H-pyran-2-yl) -hydroxylamine (0.15g, 0.0013mol) and diisopropylethylamine (0.25mL, 0.0014mol) in 20mL of an equal volume of tetrahydrofuran-dichloromethane was added 0.6794g (0.001306mol) directly as a solid PyBOP (Advanced ChemTech). The reaction mixture was stirred at 24 ℃ for 10 minutes and then concentrated to dryness in vacuo. The concentrate was suspended in 100mL of 10% aqueous hydrochloric acid. The suspension was extracted with 125mL of diethyl ether. The ether layer was separated, washed with 75mL of 10% aqueous sodium hydroxide, then with 100mL of dilute acid. The ether solution was dried (MgSO)₄) And concentrated in vacuo to give 0.62g (100%) of a beige foam. The foam was dissolved in about 15mL of hydrogen chloride in methanol. After 5 minutes, the solution was concentrated in vacuo to give an oil which was purified by flash silica gel chromatography. Elution with dichloromethane → dichloromethane-methanol (99: 1) gives 0.2233g (42%) of a yellow powder. The powder was dissolved in diethyl ether and washed with dilute hydrochloric acid. The organic phase was dried (MgSO)₄) And concentrated in vacuo to give 0.200g of foam. The product was triturated with pentane to give 0.1525g of a powder which was repurified by flash silica gel chromatography. Elution with dichloromethane gave 0.0783g (15%) of the analytically pure title compound, mp 80-90 ℃;¹H NMR(400MHz，DMSO)：δ11.53(s，1H)，9.38(s，1H)，8.82(s，1H)，7.70(dd，1H，J＝7.0，1.9Hz)，7.53(s，1H)，7.37(dd，1H，J＝8.4，1.9Hz)，6.55(dd，1H，J＝8.2，6.5Hz)，2.22(s，3H)；¹⁹f NMR (376MHz, DMSO): δ -126.24 to-126.29 (m), -137.71 to-137.77 (m); IR (KBr)3346 (Width, O-H stretch), 1651(C ═ O stretch) cm^-1；MS(Cl)M+1＝484.

Elemental analysis, calculation of C₁₄H₁₀BrF₂IN₂O₂：

C，34.81；H，2.09；N，5.80。

Measured value: c, 34.53; h, 1.73; n, 5.52.

Examples 3-12 and 78-102 in the table below were prepared according to the general method of examples 1 and 2.

Examples 13 to 77

Examples 13-77 appropriately substituted phenylaminobenzoic acids by combinatorial Synthesis

R₆

(iv) reaction of | acids (e.g., as shown in scheme 1) with hydroxylamines (e.g., HN-O-R)₇) And (3) reaction preparation. The general method is given below:

to a 0.8mL autosampler vial in a metal module, 40 μ L of a 0.5M solution of acid in DMF and 40 μ L of hydroxylamine (2M Hunig base and 1M amine solution in DMF) were added. To the autosampler vial was added 50 μ L of 0.5M freshly prepared PyBrop solution. The reaction solution was left to stand for 24 hours.

The reaction mixture was transferred to a 2-inch vial and diluted with 2mL of ethyl acetate. The organic layer was washed with 3mL of distilled water, and the aqueous layer was washed again with 2mL of ethyl acetate. The combined organic layers were evaporated to dryness in an open fume hood.

The residue was dissolved in 2mL of 50% acetonitrile in water and injected onto a semi-preparative reverse column (10mm × 25cm, 5 μ M spherical silica, pore size 115A, derivatized with C-18, sample eluted at 4.7 mL/min, eluent linearly changed to 100% acetonitrile over 8.5 min, elution continued with 100% acetonitrile for 8 min). Fractions were collected by monitoring at 214 nM. The desired fractions were evaporated with Zymark Turbovap. The product was dissolved in chloroform and transferred to a pre-weighed vial, evaporated and weighed again to determine the yield. The structure was confirmed by mass spectrometry.

Examples 3-102 melting points of the CompoundsMS case (. degree. C.) (M-H)⁺) Decomposition of 32- (4-bromo-2-methyl-phenylamino) -4-fluoro-N-hydroxy-benzamide 56-75 52345-chloro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide 65 decomposition of 55-chloro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -N-methyl-benzene 62-67

Carboxamide 65-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (tetrahydropyran-2-yl 105-108

Oxy) benzamide 75-chloro-2- (4-iodo-2-methyl-phenylamino) -N-methoxybenzamide 64-6884-fluoro-N-hydroxy-2- (4-fluoro-2-methyl-phenylamino) -benzamide 119-13594-fluoro-N-hydroxy-2- (2-methyl-phenylamino) -benzamide 101-103104-fluoro-2- (4-fluoro-2-methyl-phenylamino) -N- (tetrahydropyran-2-yl 142-146

Oxy) benzamide 114-fluoro-N-hydroxy-2- (4-chloro (clooro) -2-methyl-phenylamino) -133.5-135

Benzamide 124-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-phenylmethoxy-benzene 107-109.5

Carboxamide 134-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-methoxy-benzoyl 399

Amine 143, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-methoxy-benzene 417

Carboxamide 152- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N-methoxy-benzene 369

Carboxamide 162- (4-bromo-2-methyl-phenylamino) -N-ethoxy-3, 4-difluoro-benzene 342 (M-

Formamide EtO) 175-bromo-N-oxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino 509

Yl) -benzamide 183, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-isopropoxy-445

Benzamide 192- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N-isopropoxy-397

Benzamide 204-fluoro-N- (furan-3-ylmethoxy) -2- (4-iodo-2-methyl-phenylamino 465

Yl) -benzamide 213, 4-difluoro-N- (furan-3-ylmethoxy) -2- (4-iodo-2-methyl-483

Phenylamino) -benzamide 222- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (furan-3-yl 435

Methoxy) -benzamide 235-bromo-3, 4-difluoro-N- (furan-3-ylmethoxy) -2- (4-iodo-2-561

Methyl-phenylamino) -benzamide 245-bromo-N- (but-2-enyloxy) -3, 4-difluoro-2- (4-iodo-2-methyl 536

Yl-phenylamino) -benzamide 254-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (prop-2-ynyloxy 423

Yl) -benzamide 263, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (prop-2-ynyl 441

Oxy) -benzamide 273, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (1-methyl-propane 455

-2-alkynyloxy) -benzamide 282- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (1-methyl-propyl 407

-2-alkynyloxy) -benzamide 29N- (but-3-ynyloxy) -3, 4-difluoro-2- (4-iodo-2-methyl-benzene 455

Amino) -benzamide 302- (4-bromo-2-methyl-phenylamino) -N- (but-3-ynyloxy) -407

3, 4-difluoro-benzamide 315-bromo-N- (but-3-ynyloxy) -3, 4-difluoro-2- (4-iodo-2-methyl 533

Yl-phenylamino) -benzamide 323, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-phenyl-propane 517

-2-alkynyloxy) -benzamide 333, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (3-phenyl-propane 469

-2-alkynyloxy) -benzamide 343, 4-difluoro-N- [3- (3-fluoro-phenyl) -prop-2-ynyloxy ] -2-535

(4-iodo-2-methyl-phenylamino) -benzamide 352- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- [3- (3-fluoro-487)

Phenyl) -prop-2-ynyloxy ] -benzamide 363, 4-difluoro-N- [3- (2-fluoro-phenyl) -prop-2-ynyloxy ] -2-535

(4-iodo-2-methyl-phenylamino) -benzamide 375-bromo-3, 4-difluoro-N- [3- (2-fluoro-phenyl) -prop-2-ynyloxy 613

Yl ] -2- (4-iodo-2-methyl-phenylamino) -benzamide 392- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (3-methyl-5-510

Phenyl-pent-2-en-4-ynyloxy) -benzamide 40N-ethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzene 431

Carboxamide 412- (4-bromo-2-methyl-phenylamino) -N-ethoxy-3, 4-difluoro-benzene 383

Carboxamide 424-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-propoxy-benzoyl 427

Amine 433, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-propoxy-benzene 445

Carboxamide 442- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N-propoxy-benzene 397

Carboxamide 455-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-propoxy 523

Yl-benzamide 464-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-isopropoxy-benzyl 427

Amide 473, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-isopropoxy-445

Benzamide 482- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N-isopropoxy-397

Benzamide 495-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-isopropyl 523

Oxy-benzamide 50N-cyclobutoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -457

Benzamide 512- (4-bromo-2-methyl-phenylamino) -N-cyclobutoxy-3, 4-difluoro-409

Benzamide 52N-cyclopentyloxy-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzyl 453

Amide 53N-cyclopentyloxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -471

Benzamide 542- (4-bromo-2-methyl-phenylamino) -N-cyclopentyloxy-3, 4-difluoro-423

Benzamide 55N-cyclopropylmethoxy-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -439

Benzamide 56N-cyclopropylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino 457

Yl) -benzamide 572- (4-bromo-2-methyl-phenylamino) -N-cyclopropylmethoxy-3, 4-bis 409

Fluoro-benzamide 585-bromo-N-cyclopropylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-435

Phenylamino) 594-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-phenoxy-ethoxy 505

Yl) -benzamide 603, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-phenoxy-523

Ethoxy) -benzamide 612- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-phenoxy-475

Ethoxy) -benzamide 624-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (thiophen-2-ylmethoxy 481

Yl) -benzamide 633, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (thiophen-2-yl 499

Methoxy) -benzamide 642- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (thiophen-2-yl 451

Methoxy) -benzamide 654-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-methyl-allyloxy 439

-benzamide 663, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-methyl-ene 457

Propoxy) -benzamide 672- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-methyl-ene 410

Propoxy) -benzamide 68N- (but-2-enyloxy) -4-fluoro-2- (4-iodo-2-methyl-phenylamine 439

Yl) -benzamide 69N- (but-2-enyloxy) -3, 4-difluoro-2- (4-iodo-2-methyl-benzene 457

Amino) -benzamide 702- (4-bromo-2-methyl-phenylamino) -N- (but-2-enyloxy) -410

3, 4-difluoro-benzamide 713, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (prop-2-ynyl 441

Oxy) -benzamide 72N- (but-3-ynyloxy) -3, 4-difluoro-2- (4-iodo-2-methyl-benzene 455

Amino) -benzamide 732- (4-bromo-2-methyl-phenylamino) -N- (4, 4-dimethyl-pent-2-yne 449

Acyloxy) -3, 4-difluoro-benzamide 74N- (but-2-enyloxy) -3, 4-difluoro-2- (4-iodo-2-methyl-benzene 457

Amino) -benzamide 752- (4-bromo-2-methyl-phenylamino) -N- (but-2-enyloxy) -410

3, 4-difluoro-benzamide 76N- (3-tert-butyl-propyn-2-yl) oxy-4-fluoro-2- (4-iodo-2-methyl 479

Phenyl-phenylamino) -benzamide 774-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-phenylmethoxy-benzene 577

Carboxamide Cl 784-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -N-isopropyl-oil

Benzamide 79N-cyclopropylmethoxy-3, 4, 5-trifluoro-2- (4-iodo-2-methyl-benzene 125-127)

Amino) -benzamide 804-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -N-methyl-benzene 45-55

Carboxamide 814-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzene 208-209

Carboxamide (GLASS) 822- (2-chloro-4-iodo-phenylamino) -N-hydroxy-4-nitro-benzamide 199-200833, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (tetrahydropyran-163-165

2-yloxy) -benzamide 843, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzyl 65-75

Amide 853, 4-difluoro-5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperazine 95

Pyridin-1-yl-ethoxy) -benzamide 865-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino-bis) -N- (tetrahydro 167-169

-pyran-2-yloxy) -benzamide 872- (2-chloro-4-iodo-phenylamino) -4-fluoro-N-hydroxy-benzamide 165-169

(HCl salt) 882- (2-chloro-4-iodo-phenylamino) -4-fluoro-N- (tetrahydropyran-2-yloxy 166-167.5

Yl) -benzamide 893, 4-difluoro-2- (2-chloro-4-iodo-phenylamino) -N-cyclobutylmethoxy 173-174

-benzamide 903, 4-difluoro-2- (2-chloro-4-iodo-phenylamino) -N- (tetrahydropyran-2-121-122

Benzyloxy) -benzamide 915-bromo-2- (2-chloro-4-iodo-phenylamino) -N- (2-dimethylamino-ethoxy 206-211.5

Decomposition of 925-bromo-N- (2-dimethylamino-propoxy) -3, 4-difluoro-2- (4-iodo-95-105) -3, 4-difluoro-benzamide monohydrochloride

-2-methyl-phenylamino) -benzamide 935-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzene 266-280

Formamide decomposition 945-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N- (tetrahydropyridine 167.5-

Pyran-2-yloxy) -benzamide 169.5953, 4-difluoro-2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy 172.5-

-benzamide 173.5965-bromo-2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-171-172.5

3, 4-difluoro-benzamide 975-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-173.5-175

Morpholine-4-yl-ethoxy) -benzamide 985-bromo-N- (2-diethylamino-ethoxy) -3, 4-difluoro- (4-iodo-2-81 decomposition

Methyl-phenylamino) -benzamide 995-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-isobutyl 126-128

Oxy-benzamide 1005-bromo-N-cyclohexylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-139-142

Phenylamino) -benzamide 1015-bromo-N-cyclopentylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-113-115

Phenylamino) -benzamide 1025-bromo-N-cyclobutylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-138-139

Phenylamino) -benzamides

Because the compound of the invention is applied to MEK (dual specificity protein kinase)₁And MEK₂And they are useful in the treatment of chronic pain proliferative disorders. The compounds of the present invention have been evaluated in a number of biological assays commonly used to establish the inhibitory effects of proteins and kinases and to measure mitogenic and metabolic responses to such inhibition.

Example 1A

4-fluoro-2- (4-iodo-2-methylphenylamino) benzoic acid

To a stirred solution of 3.16g (0.0133mol) 2-amino-5-iodotoluene in 5mL tetrahydrofuran at-78 deg.C was added 10mL (0.020mol)2.0M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldr)ich) solution. The resulting green suspension was stirred vigorously for 15 minutes, then a solution of 1.00g (0.00632mol)2, 4-difluorobenzoic acid in 10mL tetrahydrofuran was added. The reaction temperature was slowly raised to room temperature, and the mixture was stirred at this temperature for 2 days. The reaction mixture was concentrated. To the concentrate was added aqueous HCl (10%) and the solution was extracted with dichloromethane. The organic phase was dried (MgSO)₄) Then boiled to small volume on a steam bath and cooled to room temperature. The beige fibres formed were collected by vacuum filtration, rinsed with hexane and dried in a vacuum oven (76 ℃ C.; about 10mmHg) to give 1.10g (47%) of the desired material; mp 224-229.5 ℃;¹H NMR(400MHz；DMSO)：δ9.72(s，1H)，7.97(dd，1H，J＝7.0，8.7Hz)，7.70(d，1H，J＝1.5Hz)，7.57(dd，1H，J＝8.4，1.9Hz)，7.17(d，1H，J＝8.2Hz)，6.61-6.53(m，2H)，2.18(s，3H)；¹³C NMR(100MHz；DMSO)：δ169.87，167.60，165.12，150.17，150.05，139.83，138.49，136.07，135.31，135.20，135.07，125.60，109.32，105.09，

104.87，99.72，99.46，89.43，17.52；

¹⁹f NMR (376 MHz; DMSO): δ -104.00 to-104.07 (m);

IR (KBr)1670(C ═ O stretch) cm^-1；

MS(Cl)M+1＝372.

Elemental analysis, calculation of C₁₄H₁₁FINO₂：

C，45.31；H，2.99；N，3.77。

Measured value: c, 45.21; h, 2.77; and N, 3.64.

Examples 2A to 30A

The following benzoic acids and salts were prepared according to the general method of example 1A: EXAMPLE 2A 3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 206-2103A 3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 240.5-244.54A 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 259.5-2625A 5-chloro-2- (2-chloro-4-iodo-phenylamino) -benzoic acid 255-2606A 5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 234-2387A 5-chloro-2- (4-propanoic acid) at MP deg.C Iodine-2-methyl-phenylamino) -sodium benzoate 310-320

Decomposition of 8 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 239.5-2409 A2- (2-chloro-4-iodo-phenylamino) -5-nitro-benzoic acid 289-29310 A4-fluoro-2- (3-fluoro-4-iodo-2-methyl-phenylamino) -benzoic acid 233-23511 A2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzoic acid 264-26712 A2- (2-fluoro-4-iodo-phenylamino) -5-nitro-benzoic acid 256-25813 A2- (4-bromo-2-methyl-phenylamino) -4-fluoro-benzoic acid -benzoic acid 218.5-22014 A2- (2-bromo-4-iodo-phenylamino) -5-nitro-benzoic acid 285-288

Decomposition of 15 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-benzoic acid 230-23416 A3-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 218-22117 A3, 4-difluoro-2- (4-iodo-2-methoxy-phenylamino) -benzoic acid 230-23318 A4-chloro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 245-255

Decomposition of 19 A2- (4-iodo-2-methyl-phenylamino) -benzoic acid 218-22320 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 243-4621 A5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 241-24526 A2-fluoro-6- (4-iodo-2-methyl-phenylamino) -benzoic acid 179-18227 A4-fluoro-2- (2, 3-dimethyl-4-iodo-2-methyl-phenylamino) -benzoic acid 258-26128 A5-methyl-2- (4-iodo-2-methyl-phenylamino) -benzoic acid Acid 209.5-21129A 2-chloro-6- (4-iodo-2-methyl-phenylamino) -benzoic acid 171-17530A 2- (4-iodo-2-methyl-phenylamino) -4-nitro-benzoic acid 251-263

Example 31A

5-chloro-N- (2-hydroxyethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide

To a stirred solution of 0.1020g (0.2632mmol) 5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid, 0.1mL (1.7mmol) ethanolamine and 0.05mL (0.29mmol) diisopropylethylamine in 5mL 1: 1(v/v) tetrahydrofuran-dichloromethane was added directly 0.15g (0.29mmol) of solid PyBOP powder. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude residue was partitioned between ether (50mL) and 10% aqueous hydrochloric acid (50 mL). The organic phase was washed with 10% aqueous sodium hydroxide (50mL) and dried (MgSO)₄) And concentrated in vacuo to give a brown-yellow oil which crystallises from hexane-ether to give 0.0831g (73%) of a yellow-green powder; mp 120-121 ℃;¹H NMR(400MHz；CDCl₃): δ 9.11(s, 1H), 7.56(d, 1H, J ═ 1.4Hz), 7.46-7.41(m, 2H), 7.20(dd, 1H, J ═ 8.9, 2.4Hz), 7.00(t, 2H, J ═ 9.6Hz), 6.55 (wide t, 1H), 3.86(t, 2H, J ═ 5.0Hz), 3.61(dd, 2H, J ═ 10.1, 5.5Hz), 2.23(s, 3H), 1.56 (wide s, 1H); IR (KBr)3297(O-H stretch), 1627(C ═ O stretch) cm^-1；MS(Cl)M+1＝431.

Elemental analysis, calculation of C₁₆H₁₆ClIN₂O₂：

C，44.62；H，3.74；N，6.50。

Measured value: c, 44.63; h, 3.67; and N, 6.30.

Examples 32 to 48A

The following benzamides were prepared by reacting the corresponding benzoic acid with the corresponding amine following the general procedure of example 31A. EXAMPLE 32A 4-methoxy-N- (4-methoxy-phenyl) -3-nitro-benzamide 153.5-15633A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 15834A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-benzamide 102.5-104.535A N-ethyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 90-9136A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N, n-dimethyl-benzamide oil 37A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (1H-tetrazol-5-yl) -benzyl 285-288

Amidolytic 38A 5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide 180-18239A 5-chloro-2- (4-iodo-2-methyl-phenylamino) -N, N-dimethyl-benzamide 137-13840A [ 5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzoylamino ] -acetic acid 170-17341A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-propyl-benzamide 69-7142A 5-bromo-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) - 132-133.4 portions of benzyl

Amide 43A N, N-diethyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide oil 44A 4-fluoro-N- (3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2-122-124

(4-iodo-2-methyl-phenylamino) -benzamide 45A N, N-diethyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 91-9346A N-butyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 97-9947 A5-chloro-N, N-diethyl-2- (4-iodo-2-methyl-phenylamino) -benzamide 118-12048 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N, N-dimethyl-benzamide 142.5-144.

Example 49

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzyl alcohol 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid (0.50g, 1.35mmol) was dissolved in 6mL (6mmol) of a cold 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran. The reaction mixture was stirred at room temperature under nitrogen overnight. The reaction was stopped with 80mL of methanol. Concentration in vacuo afforded a clear tan oil, which was purified with MPLC. Elution with dichloromethane afforded 0.4285g (89%) of a white solid; mp 99-100.5 ℃;¹h NMR (400 MHz; DMSO): δ 7.57(d, 1H, J ═ 1.7Hz), 7.45(dd, 1H, J ═ 8.4, 1.9Hz), 7.39(s, 1H), 7.29(t, 1H, J ═ 7.5Hz), 6.89(d, 1H, J ═ 8.4Hz), 6.67-6.60(m, 1H), 5.47(t, 1H, J ═ 5.5Hz), 4.49(d, 2H, 5.1Hz), 2.14(s, 3H); IR (KBr)3372(O-H stretch) cm^-1；MS(Cl)M+1＝358.

Elemental analysis, calculation of C₁₄H₁₃FINO：

C，47.08；H，3.67；N，3.92。

Measured value: c, 47.17; h, 3.75; and N, 3.72.

Examples 50A to 52A

The following benzyl alcohols were prepared using the general method of example 49A. EXAMPLE 50A [ 5-chloro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -methanol 82-8551A [2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -methanol 126.5-128.552A [ 5-bromo-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -methanol 60.5-63.5 at MP deg.C

Several compounds of formula I (A) of the present invention are prepared using combinatorial synthesis techniques. The general method is as follows:

to a 0.8mL autosampler vial in a metal module, 40 μ L of a 0.5M solution of acid in DMF and 40 μ L of reagent amine (2M Hunig base and 1M amine solution in DMF) were added. To the autosampler vial was added 50 μ L of 0.5M freshly prepared PyBrop solution. The reaction solution was left to stand for 24 hours.

The residue was dissolved in 2mL of 50% acetonitrile in water and injected onto a semi-preparative reverse column (10mm × 25cm, 5 μ M spherical silica, pore size 115A, derivatized with C-18, sample eluted at 4.7 mL/min, eluent linearly changed to 100% acetonitrile over 8.5 min, elution continued with 100% acetonitrile for 8 min). Fractions were collected by monitoring at 214 nM. The residue was dissolved in chloroform and transferred to a pre-weighed vial, evaporated and weighed again to determine the yield.

Examples 53A to 206A

The following compounds of formula I are prepared using a combinatorial approach: compound No. MS

M-H53A 5-bromo-3, 4-difluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -510

Benzamide 54A N- (2, 3-dihydroxy-propyl) -3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzene 462

Carboxamide 55A 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-577

Ethyl) -benzamide 56 A3, 4-difluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzoyl 432

Amine 57A N- (2, 3-dihydroxy-propyl) -4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoyl 444

Amine 58 A3, 4-difluoro-N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzoyl 446

Amine 59A 5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl 564

-ethyl) -benzamide 60 A5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyridin-4-yl-571

Ethyl) -benzamide 61 A4-fluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 41462 A5-bromo-N- (3-dimethylamino-propyl) -3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino 551

Yl) -benzamide 63 A5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-580

Ethyl) -benzamide 64 A3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -501

Benzamide 65 A3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl 485

Yl) -benzamide 66 A3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyridin-4-yl-ethyl) -493

Benzamide 67A N- (3-dimethylamino-propyl) -3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzene 473

Carboxamide 68A N-benzyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 46069 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-hydroxy-ethyl) -benzoyl 384

Amine 70 A4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzyl 483

Amide 71 A4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzyl 495

Amide 72 A3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -513

Benzamide 73 A4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-thiophen-2-yl-ethyl) -benzyl 480

Amide 74 A4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzene 467

Carboxamide 75 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-morpholin-4-yl-ethyl) -453

Benzamide 76 A5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-pyridin-4-ylmethyl-557

Benzamide 77 A3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-pyridin-4-ylmethyl-benzoyl 479

Amine 78A 2- (4-bromo-2-methyl-phenylamino) -N- (3-dimethylamino-propyl) -3, 4-difluoro-benzene 425

Carboxamide 79A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-pyridin-4-ylmethyl-benzamide 46180A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyridin-4-yl-ethyl) -benzyl 475

Amide 81 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-pyridin-4-yl-ethyl) -445

Benzamide 82 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (3-hydroxy-propyl) -benzoyl 400

Amine 83 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-pyrrolidin-1-yl-ethane 437

Yl) -benzamide 84 A4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-phenethyl-benzamide 47485 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-thiophen-2-yl-ethyl) -450

Benzamide 86 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N-pyridin-4-ylmethyl-benzoyl 431

Amine 87 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N-phenethyl-benzamide 44488 A2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-piperidin-1-yl-ethyl) -451

Benzamide 89 A5-chloro-N- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-557 ×)

2-methyl-phenylamino) -benzamide 90 A5-fluoro-N- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-541 a

2-methyl-phenylamino) -benzamide 91 A2- (4-iodo-2-methyl-phenylamino) -5-nitro-N-pyridin-4-ylmethyl-benzamide 48792 A5-bromo-N- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-601

2-methyl-phenylamino) -benzamide 93 A5-chloro-N- (2-diethylamino-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzoyl 486

Amine 94 A5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-ethyl) -benzyl 497

Amide 95A (3-hydroxy-pyrrolidin-1-yl) - [2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzene 466

-96 A5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzene 484

Carboxamide 97 A5-bromo-N- (2-diethylamino-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzoyl 530

Amine 98A N- {2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl } -5-chloro-2- (4-iodo-2-methyl 518%

-phenylamino) -benzamide 99A N- {2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl } -5-bromo-2- (4-iodo-2-methyl 562 ×)

Yl-phenylamino) -benzamide 100A [ 5-bromo-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - (3-hydroxy-pyrrolidine-1-499

Yl) -101 A2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzoic acid phenethyl ester 501102A N- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-2-methyl 568 x

-phenylamino) -benzamide 103A [ 5-chloro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - (3-hydroxy-pyrrolidine-1-455

Yl) 104 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-pyridin-4-ylmethyl-benzamide 460105 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzene 528

Carboxamide 106 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-ethyl) -benzyl 542

Amide 107 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzene 468

Carboxamide 108 A5-chloro-N- (3-dimethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzoyl 472

Amine 109A N- {2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl } -5-fluoro-2- (4-iodo-2-methyl 502 ×)

Yl-phenylamino) -benzamide 110 A5-chloro-N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 445 a 111 A5-chloro-N- (3-diethylamino-2-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino 516

-benzamide 112 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-ethyl) -benzyl 482

Amide 113 A5-bromo-N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 489 a 114 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzyl 556

Amide 115A N- {2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl } -2- (4-iodo-2-methyl-phenylamino 529

-5-nitro-benzamide 116 A5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzyl 500

Amide 117 A5-chloro-N- (3-diethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzoyl 500

Amine 118 A5-chloro-N- (2-diisopropylamino-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzyl 514

Amide 119 A5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzyl 512

Amide 120 A2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (2-piperidin-1-yl-ethyl) -benzene 509

Carboxamide 121 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperazin-1-yl-ethyl) -benzoic acid methyl 544

Amide 122A N- (2-diethylamino-ethyl) -5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoyl 470

Amine 123 A5-bromo-N- (3-dimethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzoyl 516

Amine 124A N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 456 125 A5-fluoro-N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 429 126A N- (3-diethylamino-propyl) -5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoyl 484

Amine 127A N- (3-diethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenylmethyl 511

Amide 128 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzyl 544

Amide 129 A2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (3-piperidin-1-yl-propyl) -benzene 523

Carboxamide 130A [ 5-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - (3-hydroxy-pyrrolidine-1-439

-131 A5-bromo-N- (2-diisopropylamino-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzyl 558 ×)

Amide 132 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzyl 484

Amide 133 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzyl 496

Amide 134A [ 5-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [4- (2-hydroxy-ethyl) -piperazine 482

oxazine-1-135A N- (3-diethylamino-2-hydroxy-propyl) -5-fluoro-2- (4-iodo-2-methyl-phenylamino 500

Yl) -benzamide 136A [ 5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzoylamino ] -acetic acid 443137 A2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (2-pyrrolidin-1-yl-ethyl) -495 a

Benzamide 138A N- (3-dimethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzyl 483

Amide 139A N- (2-diisopropylamino-ethyl) -5-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenylmethyl 498

Amide 140A 5-fluoro-2- (4-iodo-2-methyl-phenylamino) -thiobenzoic acid S-phenethyl ester 490141A 5-chloro-2- (4-iodo-2-methyl-phenylamino) -thiobenzoic acid S-phenethyl ester 506142A 5-bromo-2- (4-iodo-2-methyl-phenylamino) -thiobenzoic acid S-benzyl ester 536143A 2- (4-iodo-2-methyl-phenylamino) -5-nitro-thiobenzoic acid S-benzyl ester 503144A 5-fluoro-2- (4-iodo-2-methyl-phenylamino) -thiobenzoic acid S-benzyl ester 476145A 5-chloro-2- (4-iodo- 2-methyl-phenylamino) -thiobenzoic acid S-benzyl ester 492146A N-cyclopropyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 409147 A5-chloro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 429148 A5-fluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 413149A N-benzyloxy-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 475150A N-benzyloxy-5-bromo- 2- (4-iodo-2-methyl-phenylamino) -benzamide 593 A2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (4-sulfamoyl-benzyl) -benzoyl 567

Amine 152 A5-bromo-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 473153A N- (2-hydroxy-ethyl) -5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide 521154A N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 440155 A2- (4-iodo-2-methyl-phenylamino) -N-methyl-5-nitro-N-phenyl-benzamide 486156 A5-chloro-N-cyclopropyl-2- (4-hydroxy-ethyl) -benzamide -iodo-2-methyl-phenylamino) -benzamide 425157 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide 459158A N-allyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 409159A N-benzyloxy-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide 583160 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide 538161A N-allyl-5-chloro-2 - (4-iodo-2-methyl-phenylamino) -benzamide 425162A N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 436163 A5-bromo-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -benzamide 469164 A5-chloro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide 475165 A5-iodo-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide 646166 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide 646166 A5 -iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide 598167A N-allyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 436168 A2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (4-sulfamoyl-benzyl) -benzoyl 565

Amine 169A N-allyl-5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide 469170A 5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -benzamide 473171A N-cyclopropyl-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide 517172A 5-bromo-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide 519173A N-benzyloxy-2- (4-iodo-2-methyl-phenylamino) -5-nitro- Benzamide 502174A N-cyclohexyl-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide 559175A N-allyl-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide 517176 A5-iodo-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -benzamide 581177 A2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -5-nitro-benzamide 500178 A5-iodo-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-phenylamino) -N -methyl-N-phenyl-benzamide 567179A N-cyclohexyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 451180 A5-chloro-N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino) -benzamide 467181 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -benzamide 533182 A5-bromo-N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino) -benzamide 511183 A5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -benzamide 489184A N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 478185A N-benzyloxy-5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide 538186A N-benzyloxy-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 477187 A5-chloro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 431188 A5-bromo-N- (2-hydroxy-ethyl) -benzamide 2- (4-iodo-2-methyl-phenylamino) -benzamide 475189 A2- (4-iodo-2-methyl-phenylamino) -N-methyl-5-nitro-N-phenyl-benzamide 488190 A5-chloro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide 477191A N- (2-hydroxy-ethyl) -5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide 523192 A5-chloro-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -benzamide 425193A N-ene Propyl-5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzamide 427194 A5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide 461195A N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 442196 A5-fluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide 415197 A5-bromo-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -benzamide 472198A N-cyclopropyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 411199A 5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide 540200A N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 438201A N-allyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide 411202A N-benzyloxy-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide Benzamide 585203A N-allyl-5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide 472204 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide 601205 A5-bromo-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide 522206A N-allyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide 438M + H

Example 207A

Preparation of [ 4-chloro-2- (1H-tetrazol-5-yl) - (4-iodo-2-methyl-phenyl) -amine step a: preparation of 5-chloro-2-fluoro-benzaldehyde

LDA (2M in THF, 50mL, 0.1mol) was added dropwise to a THF solution (180mL) of 1-chloro-4-fluorobenzene (13.06g, 0.1mol) at-78 ℃. After stirring at-78 ℃ for 1.5 h, DMF (8mL) was added to the reaction mixture and allowed to warm to room temperature overnight. The reaction mixture was taken up in water and Et₂And (4) distributing among the O. Adding Et₂O layer drying (MgSO)₄) And the solvent was removed in vacuo to give 14.95g (94%) of crude aldehyde in yield:

¹H NMR(CDCl₃)：δ10.3(s，-C(＝O)H)。

step b: preparation of 5-chloro-2-fluoro-benzaldoxime

An EtOH solution (100mL) of 5-chloro-2-fluoro-benzaldehyde (10g, 0.0631mol), hydroxylamine hydrochloride (6.57g, 0.0946mol) and pyridine (8.3mL, 0.1010mol) was heated at 75 deg.C (oil bath temperature) for 1 hour and the solvent was removed in vacuo to give an oil. The oil is mixed with water and CH₂Cl₂Are distributed among the devices. Will CH₂Cl₂Layer drying (MgSO)₄) The solvent was removed in vacuo to give the aldoxime crude as a solid. The solid was purified by medium pressure liquid chromatography on silica. By CH₂Cl₂Elution provided 4.87g (28%) of aldoxime as a white solid: mp 95-97 ℃;

elemental analysis, calculation of C₇H₅NOFCl：

C，48.44；H，2.90；N，8.07。

Measured value: c, 48.55; h, 2.69; and N, 7.90.

Step c: preparation of 5-chloro-2-fluoro-benzonitrile

A solution of 5-chloro-2-fluoro-benzaldoxime (3.15g, 0.0182mol) in acetic anhydride (150mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and poured into NaHCO₃Saturated aqueous solution (200 mL). Et used for the mixture₂And (4) extracting. Adding Et₂Drying of the O layer (K)₂CO₃) Removing the solvent to obtain an oily solid product. The product was used in the next step without further purification.

Step d: preparation of 5- (5-chloro-2-fluoro-phenyl) -1H-tetrazole

A mixture of 5-chloro-2-fluoro-benzonitrile (2.84g, 0.01823mol), butanol (15mL), sodium azide (1.543g, 0.0237mol), acetic acid (1.36mL, 0.0237mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, another 1.543g of sodium azide were added and the reaction mixture was refluxed for a further 24 hours. After cooling to room temperature Et was added sequentially₂O (100mL) and 10% aqueous NaOH (200 mL). The mixture was stirred vigorously. The aqueous layer was separated, cooled with an ice-methanol bath (-15 ℃) and acidified to pH1 with concentrated HCl. A grey solid precipitated. The solid was dried under vacuum at 50 ℃ to give 1.76g (49%) of 5- (5-chloro-2-fluoro-phenyl) -1H-tetrazole: mp partially melting at 110 deg.C and completely melting at 124 deg.C;¹H(400Mz，CDCl₃)：δ8.19-8.08(m，1H)，7.77-7.71(m，1H)，7.61-7.52(m，1H)；¹³C(100Mz，CDCl₃)：δ159.00，156.49，140.88，133.02，132.93，130.73，129.23，129.21，129.08，126.05，118.96，118.73，114.50；MS(Cl)M+1＝199(100)，M＝198(6).

step e: preparation of [ 4-chloro-2- (1H-tetrazol-5-yl) - (4-iodo-2-methyl-phenyl) -amine

LDA (2 molar solution in THF, 11.33mL, 0.02267mol) was added dropwise to a THF solution (25mL) of 2-methyl-4-iodoaniline (3.52g, 0.0151mol) at-78 ℃. After stirring for 0.5 h, a solution of 1- (tetrazol-5-yl) -2-fluoro-5-chlorobenzene (1.5g, 0.00756mol) in THF (15mL) was added dropwise. The reaction was stirred for 16 hours and allowed to warm to room temperature. The reaction mixture is treated with concentrated NH₄Aqueous Cl solution to stop the reaction and CH₂Cl₂And (4) extracting. The organic layer was dried (MgSO₄) The solvent was removed to give the crude product as an oil. CH for the oil₂Cl₂→CH₂Cl₂MeOH (9.7: 0.3) gave 1.5g (48%) of the desired product: mp 205-208;¹H(400Mz，DMSO)：δ9.13(s，1H)，8.00-7.99(s，1H)，7.69(s，1H)，7.55-7.52(m，1H)，7.43-7.40(m，1H)，7.12-7.05(m，1H)，2.24(s，3H)；¹³C(100Mz，CDCl₃)：δ141.87，139.28，138.88，135.47，133.71，131.65，128.15，123.69，121.94，116.68，87.79，17.22；MS(Cl)M+2＝413(44)，M+1＝412(85)，M＝411(100).

elemental analysis, calculation of C₁₄H₁₁N₅ClI0.5H₂O：

C，39.97；H，2.87；N，16.65。

Measured value: c, 38.87; h, 2.77; n, 16.47.

The following tetrazole-substituted anilines were prepared according to the general method of example 207A.

Example 208A

(4-iodo-2-methyl-phenyl) - [2- (1H-tetrazol-5-yl) -phenyl ] amine, mp 231 ℃ (decomposition)

Example 209A

[ 4-Nitro-2- (1H-tetrazol-5-yl) - (4-iodo-2-methyl-phenyl) -amine, mp205-208 ℃.

Examples 210A to 224A

Other compounds of the invention prepared according to the above general procedure are: EXAMPLE No. Compound MP deg.C 210A 2- (2-chloro-4-iodo-phenylamino) -3-fluoro-4- (2-morpholin-4-yl-ethylamino 239-241

Radical) -5-Nitro-benzoic acid decomposition 211A 4-amino-2- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid > 270212A 2, 4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid > 265 decomposition 213A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzoic acid 218-225

Decomposition 214 A2- (2, 6-difluoro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid 247-249215 A2- (2-chloro-4-iodo-phenylamino) -4-nitro-benzoic acid 267-269216 A2- (2, 4-diiodo-phenylamino) -4-fluoro-benzoic acid 260-261217 A2- (2-bromo-4-iodo-phenylamino) -4-fluoro-benzoic acid 259-262218 A4-fluoro-2- (2-fluoro-4-iodo-phenylamino) -benzoic acid 215-217219 A2- (2-chloro-4-iodo-phenylamino) -4-fluoro-benzoic acid 242-247220A 5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid 312.5-318221 A2, 3, 5-trifluoro-6- (4-iodo-2-methyl-phenylamino) -4- (4-methyl-piperazine 118-121

-1-yl) -benzoic acid methyl ester dihydrofluoride salt 222 A5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (4-methyl-214-217

Piperazine-1-yl) -benzamide decomposition 223 A5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid 154-175

Decomposition of 224A 4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid hydrazide by N ', N' -dimethyl-hydrazide 153.5-156

F. Other embodiments

The essential features of the invention are apparent from the above disclosure and examples and from the following claims. Various modifications and alterations are also encompassed within the scope of the present invention, which are well within the knowledge of those of ordinary skill in the art. For example, including the disclosed compounds modified by the addition or removal of protecting groups, or esters, pharmaceutically acceptable salts, hydrates, acids, or amides of the disclosed compounds. The disclosures of the publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A method of treating chronic pain, said method comprising administering to a subject in need of such treatment a composition comprising a MEK inhibitor selected from a compound defined by formula I:

wherein:

R₂is hydrogen;

n is 0 to 4;

m is 0 or 1;

R₇is hydrogen, C₁-C₈Alkyl radical, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, C₃-C₁₀(cycloalkyl optionally containing a substituent selected from O, S or NR₉Cycloalkyl of the heteroatom(s);

wherein any of the aforementioned alkyl, alkenyl and alkynyl groups may be unsubstituted or substituted with a cycloalkyl group (or may optionally contain a substituent selected from O, S or NR)₉Cycloalkyl, aryl, aryloxy, heteroaryl or heteroaryloxy of (a); or R₆And R₇Taken together with the N-O to which they are attached to form a 5-to 10-membered ring, optionally containing one, two or three members selected from O, S or NR₁₀R₁₁Other hetero atoms of (a).

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

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

4. The method of claim 3, wherein said neuropathic pain is associated with one of the following conditions: inflammation, post-operative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpes and post-herpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, compression injury, tissue damage, amputation, post-operative pain, arthritic pain, and any other nerve damage between the peripheral and central nervous systems, 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 idiopathic 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 C₁-C₈Alkyl or halogen.

11. The method according to claim 10, wherein,wherein R is₆Is hydrogen.

12. The method according to claim 11, wherein R is₁Is methyl.

13. The method according to claim 12, wherein the MEK inhibitor has the formula

14. The method of claim 13, wherein R₄Is fluorine, and R₃And R₅Is hydrogen.

15. The method of claim 14, wherein the MEK inhibitor has a structure selected from:

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (methoxy) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (prop-2-ynyloxy) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-phenoxyethoxy) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-thienylmethoxy) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (prop-2-enyloxy) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (cyclopropylmethoxy) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (cyclopentyloxy) -benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -N-isopropyl-benzamide; and

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -N-methyl-benzamide.

16. The method of claim 13, wherein R₃And R₄Is fluorine, R₅Is hydrogen.

17. The method of claim 16, wherein the MEK inhibitor has a structure selected from:

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-furanylmethoxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-ethoxy-benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (but-2-enyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (cyclopropylmethoxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (1-methylprop-2-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-phenylprop-2-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-5-phenylpent-2-en-4-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (prop-2-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (propoxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (cyclobutoxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-thienylmethoxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-methyl-prop-2-enyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-phenoxyethoxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (but-2-enyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (but-3-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (cyclopentyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3- (2-fluorophenyl) -prop-2-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (tetrahydropyran-2-yloxy) -benzamide;

3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

3, 4-difluoro-2- (2-chloro-4-iodo-phenylamino) -N-cyclobutylmethoxy-benzamide;

3, 4-difluoro-2- (2-chloro-4-iodo-phenylamino) -N- (tetrahydropyran-2-yloxy) -benzamide; and

3, 4-difluoro-2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-benzamide.

18. The method of claim 13, wherein R₃And R₄Is fluorine, R₅Is bromine.

19. The method according to claim 18, wherein the MEK inhibitor has a structure selected from:

5-bromo-3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (N-propoxy) -benzamide;

5-bromo-3, 4-difluoro-N- (furan-3-ylmethoxy) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N- (but-2-enyloxy) -3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N-butoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-but-2-enyloxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-pent-2-en-4-ynyloxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-benzyl) -N- [5- (3-methoxy-phenyl) -3-methyl-pent-2-en-4-ynyloxy ] -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (prop-2-ynyloxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- [3- (3-methoxy-phenyl) -prop-2-ynyloxy ] -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (thiophen-2-ylmethoxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (pyridin-3-ylmethoxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3- (2-fluorophenyl) -prop-2-ynyloxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (ethoxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (cyclopropylmethoxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (isopropoxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (but-3-ynyloxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-ethoxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (tetrahydropyran-2-yloxy) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethoxy) -benzamide;

5-bromo-N- (2-diethylamino-ethoxy) -3, 4-difluoro- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-isobutoxy-benzamide;

5-bromo-N-cyclopentylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N- (2-dimethylamino-propoxy) -3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N- (tetrahydropyran-2-yloxy) -benzamide; and

5-bromo-2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide.

20. The method of claim 13, wherein R₃And R₄Is hydrogen, R₅Is a halogen.

21. The method according to claim 20, wherein the MEK inhibitor has a structure selected from:

5-chloro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (tetrahydropyran-2-yloxy) -benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N-methoxy-benzamide;

4-bromo-2- (4-iodo-2-methyl-phenylamino) -N-phenylmethoxy-benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-phenylmethoxy-benzamide;

5-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-iodo-2- (4-iodo-2-methyl-phenylamino) -N-phenylmethoxy-benzamide; and

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (tetrahydropyran-2-yloxy) -benzamide.

22. The method of claim 12, comprising formula I (a):

23. the method of claim 22, wherein R₃And R₄Is fluorine, R₅Is hydrogen.

24. The method according to claim 23, wherein the MEK inhibitor has a structure selected from:

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (3-phenylprop-2-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (3-furanylmethoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (2-thienylmethoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (but-3-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (2-methyl-prop-2-enyloxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (but-2-enyloxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (methoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (ethoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (cyclobutoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (isopropoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (2-phenoxyethoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (cyclopropylmethoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (N-propoxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (1-methyl-prop-2-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (3- (3-fluorophenyl) -prop-2-ynyloxy) -benzamide;

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (4, 4-dimethylpent-2-ynyloxy) -benzamide; and

3, 4-difluoro-2- (4-bromo-2-methyl-phenylamino) -N- (cyclopentyloxy) -benzamide.

25. The method according to claim 1, wherein the MEK inhibitor has a structure selected from:

3, 4, 5-trifluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

n-hydroxy-2- (4-iodo-2-methyl-phenylamino) -4-nitro-benzamide;

3, 4, 5-trifluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

5-chloro-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-4-nitro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4, 5-trifluoro-N-hydroxy-benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-hydroxy-4-nitro-benzamide;

5-chloro-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

5-bromo-2- (2-bromo-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-hydroxy-4-methyl-benzamide;

2- (2-bromo-4-iodo-phenylamino) -3, 4, 5-trifluoro-N-hydroxy-benzamide;

2- (2-bromo-4-iodo-phenylamino) -5-chloro-3, 4-difluoro-N-hydroxy-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-hydroxy-4-nitro-benzamide;

4-fluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -N-hydroxy-benzamide;

2- (2-chloro-4-iodo-phenylamino) -4-fluoro-N-hydroxy-benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

2- (2-bromo-4-iodo-phenylamino) -4-fluoro-N-hydroxy-benzamide;

2- (2-bromo-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

n-cyclopropylmethoxy-2- (4-iodo-2-methyl-phenylamino) -4-nitro-benzamide;

n-cyclopropylmethoxy-2- (2-fluoro-4-iodo-phenylamino) -4-nitro-benzamide;

5-bromo-2- (2-bromo-4-iodo-phenylamino) -N-ethoxy-3, 4-difluoro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-ethoxy-4-nitro-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-nitro-benzamide;

n-cyclopropylmethoxy-4-fluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

n-cyclopropylmethoxy-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-fluoro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-fluoro-benzamide;

2- (2-bromo-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-hydroxy-4-nitro-benzamide;

3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -4-fluoro-N-hydroxy-benzamide (HCl salt);

2- (2-chloro-4-iodo-phenylamino) -4-fluoro-N- (tetrahydro-pyran-2-yloxy) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclobutylmethoxy-3, 4-difluoro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N- (tetrahydropyran-2-yloxy) -benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N- (tetrahydropyran-2-yloxy) -benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide; and

26. A method of treating chronic pain, said method comprising administering to a subject in need of such treatment a composition comprising a MEK inhibitor selected from a compound defined by formula I (a):

wherein:

R₂is hydrogen;

n is 0 to 4;

m is 0 or 1;

z is COOR₇Tetrazolyl, CONR₆R₇、CONHNR₁₀R₁₁Or CH₂OR₇；

R₆And R₇Independently of one another is hydrogen, C₁-C₈Alkyl, aryl, heteroaryl, and heteroaryl,C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, alkynyl,

O

27. The method of claim 26, wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

28. The method of claim 27, wherein said chronic pain is a type of neuropathic pain.

29. The method of claim 28, wherein said neuropathic pain is associated with one of the following conditions: inflammation, post-operative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpes and post-herpetic pain, burning pain, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, compression injury, tissue damage, amputation, post-surgical pain, arthritic pain, and any other nerve damage between the peripheral and central nervous systems, including the peripheral and central nervous systems.

30. The method of claim 27, wherein the chronic pain is associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

31. The method of claim 27, wherein the chronic pain is associated with idiopathic pain.

32. The method of claim 26, wherein the chronic pain is associated with inflammation.

33. The method of claim 26, wherein the chronic pain is associated with arthritis.

34. The method of claim 26, wherein the chronic pain is associated with post-operative pain.

35. The method of claim 26, wherein R₁Is CH₃Or a halogen.

36. The process according to claim 35 wherein Z is COOR₇Tetrazolyl or a salt thereof.

37. The method according to claim 36, wherein said MEK inhibitor has a structure selected from:

[ 4-chloro-2- (1H-tetrazol-5-yl) - (4-iodo-2-methyl-phenyl) -amine;

(4-iodo-2-methyl-phenyl) - [2- (1H-tetrazol-5-yl) -phenyl ] amine; and

[ 4-Nitro-2- (1H-tetrazol-5-yl) - (4-iodo-2-methyl-phenyl) -amine.

38. The method according to claim 35, comprising the compound of the formula

39. The method of claim 38, wherein R₃Is hydrogen, fluorine or chlorine; r₄Is hydrogen, fluorine, chlorine or nitro; r₅Is hydrogen, chlorine, fluorine, bromine, nitro or methoxy.

40. The method of claim 39, wherein the MEK inhibitor has a structure selected from the group consisting of:

4-fluoro-2- (4-iodo-2-methyl-phenylamino) benzoic acid;

3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

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

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -sodium benzoate;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzoic acid;

4-chloro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

2, 3, 5-trifluoro-4- (4-iodo-2-methyl-phenylamino) -benzoic acid;

2- (4-iodo-phenylamino) -5-methoxy-benzoic acid;

5-methyl-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

2- (4-iodo-2-methyl-phenylamino) -4-nitro-benzoic acid;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzoic acid;

2, 3, 5-trifluoro-6- (4-iodo-2-methyl-phenylamino) -4- (4-methyl-piperazin-1-yl) -benzoic acid methyl ester dihydrofluoride salt;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (4-methyl-piperazin-1-yl) -benzoic acid;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid N ', N' -dimethyl-hydrazide; and

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid hydrazide.

41. The method of claim 35 comprising the compound of the formula

42. The method of claim 41, wherein R₃Is hydrogen, chlorine or fluorine; r₄Is hydrogen, chlorine, fluorine or nitro; r₅Is hydrogen, chlorine, fluorine, bromine, nitro or methoxy.

43. The method of claim 26, wherein the MEK inhibitor has a structure selected from:

2- (4-bromo-2-methyl-phenylamino) -4-fluoro-benzoic acid;

2- (2-bromo-4-iodo-phenylamino) -5-nitro-benzoic acid;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-benzoic acid;

2- (2-chloro-4-iodo-phenylamino) -3-fluoro-4- (2-morpholin-4-yl-ethylamino) -5-nitro-benzoic acid;

4-amino-2- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid;

2, 4-bis- (2-chloro-4-iodo-phenylamino) -3-fluoro-5-nitro-benzoic acid;

2- (2-chloro-4-iodo-phenylamino) -4-nitro-benzoic acid;

2- (2, 4-diiodo-phenylamino) -4-fluoro-benzoic acid;

2- (2-bromo-4-iodo-phenylamino) -4-fluoro-benzoic acid;

4-fluoro-2- (2-fluoro-4-iodo-phenylamino) -benzoic acid;

2- (2-chloro-4-iodo-phenylamino) -4-fluoro-benzoic acid; and

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid.

44. The process of claim 35, wherein Z is CONR₆R₇。

45. The method of claim 44 comprising the compound of the formula

46. The method of claim 45, wherein R₃Is hydrogen, chlorine or fluorine; r₄Is hydrogen, chlorine, fluorine or nitro; r₅Is hydrogen, chlorine, fluorine, bromine, nitro or methoxy.

47. The method of claim 46, wherein the MEK inhibitor has a structure selected from the group consisting of:

5-chloro-N- (2-hydroxyethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-benzamide;

n-ethyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N, N-dimethyl-benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (1H-tetrazol-5-yl) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N, N-dimethyl-benzamide;

[ 5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzoylamino ] -acetic acid;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-propyl-benzamide;

5-bromo-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n, N-diethyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-N- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n, N-diethyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

n-butyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N, N-diethyl-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N, N-dimethyl-benzamide;

5-bromo-3, 4-difluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- (2, 3-dihydroxy-propyl) -3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-ethyl) -benzamide;

3, 4-difluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- (2, 3-dihydroxy-propyl) -4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

3, 4-difluoro-N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyridin-4-yl-ethyl) -benzamide;

4-fluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N- (3-dimethylamino-propyl) -3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyridin-4-yl-ethyl) -benzamide;

n- (3-dimethylamino-propyl) -3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-benzyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-hydroxy-ethyl) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-thiophen-2-yl-ethyl) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-morpholin-4-yl-ethyl) -benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-pyridin-4-ylmethyl-benzamide;

3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-pyridin-4-ylmethyl-benzamide;

2- (4-bromo-2-methyl-phenylamino) -N- (3-dimethylamino-propyl) -3, 4-difluoro-benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-pyridin-4-ylmethyl-benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyridin-4-yl-ethyl) -benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-pyridin-4-yl-ethyl) -benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (3-hydroxy-propyl) -benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-pyrrolidin-1-yl-ethyl) -benzamide;

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-phenethyl-benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-thiophen-2-yl-ethyl) -benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N-pyridin-4-ylmethyl-benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N-phenethyl-benzamide;

2- (4-bromo-2-methyl-phenylamino) -3, 4-difluoro-N- (2-piperidin-1-yl-ethyl) -benzamide;

5-chloro-N- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-N- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (4-iodo-2-methyl-phenylamino) -5-nitro-N-pyridin-4-ylmethyl-benzamide;

5-bromo-N- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N- (2-diethylamino-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-ethyl) -benzamide;

(3-hydroxy-pyrrolidin-1-yl) - [2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ];

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzamide;

5-bromo-N- (2-diethylamino-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- {2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl } -5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- {2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl } -5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- {3- [4- (2-hydroxy-ethyl) -piperazin-1-yl ] -propyl } -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-pyridin-4-ylmethyl-benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-ethyl) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzamide;

5-chloro-N- (3-dimethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- {2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl } -5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N- (3-diethylamino-2-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperidin-1-yl-ethyl) -benzamide;

5-bromo-N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzamide;

n- {2- [ bis- (2-hydroxy-ethyl) -amino ] -ethyl } -2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzamide;

5-chloro-N- (3-diethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N- (2-diisopropylamino-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzamide;

2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (2-piperidin-1-yl-ethyl) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-piperazin-1-yl-ethyl) -benzamide;

n- (2-diethylamino-ethyl) -5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N- (3-dimethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

5-fluoro-N- (3-hydroxy-propyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- (3-diethylamino-propyl) -5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- (3-diethylamino-propyl) -2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzamide;

2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (3-piperidin-1-yl-propyl) -benzamide;

[ 5-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - (3-hydroxy-pyrrolidin-1-yl) -;

5-bromo-N- (2-diisopropylamino-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (2-morpholin-4-yl-ethyl) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-piperidin-1-yl-propyl) -benzamide;

[ 5-fluoro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] - [4- (2-hydroxy-ethyl) -piperazine-1-;

n- (3-diethylamino-2-hydroxy-propyl) -5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-cyclopropyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-benzyloxy-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-benzyloxy-5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (4-sulfamoyl-benzyl) -benzamide;

5-bromo-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

n- (2-hydroxy-ethyl) -5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

2- (4-iodo-2-methyl-phenylamino) -N-methyl-5-nitro-N-phenyl-benzamide;

5-chloro-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide;

n-allyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-benzyloxy-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide;

n-allyl-5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

5-bromo-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide;

5-iodo-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide;

n-allyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

2- (4-iodo-2-methyl-phenylamino) -5-nitro-N- (4-sulfamoyl-benzyl) -benzamide;

n-allyl-5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -benzamide;

n-cyclopropyl-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide;

n-benzyloxy-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

n-cyclohexyl-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-allyl-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-iodo-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -benzamide;

2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -5-nitro-benzamide;

5-iodo-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide;

n-cyclohexyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -benzamide;

5-bromo-N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N- (3-methyl-benzyl) -benzamide;

n-cyclohexyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

n-benzyloxy-5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-benzyloxy-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

2- (4-iodo-2-methyl-phenylamino) -N-methyl-5-nitro-N-phenyl-benzamide;

5-chloro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide;

n- (2-hydroxy-ethyl) -5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-chloro-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-allyl-5-chloro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide;

2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

5-fluoro-N- (2-hydroxy-ethyl) -2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-cyclopropyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-fluoro-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide;

n-cyclopropyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide;

n-allyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-benzyloxy-5-iodo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

n-allyl-5-bromo-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N- (4-sulfamoyl-benzyl) -benzamide;

5-bromo-2- (4-iodo-2-methyl-phenylamino) -N-methyl-N-phenyl-benzamide; and

n-allyl-2- (4-iodo-2-methyl-phenylamino) -5-nitro-benzamide.

48. The method of claim 35, wherein Z is CH₂OR₇。

49. The method of claim 48 comprising the compound of the formula

50. The method of claim 49, wherein R₃Is hydrogen, chlorine or fluorine; r₄Is hydrogen, chlorine, fluorine or nitro; r₅Is hydrogen, chlorine, fluorine, bromine, nitro or methoxy.

51. The method of claim 50 which is:

4-fluoro-2- (4-iodo-2-methyl-phenylamino) -benzyl alcohol;

[ 5-chloro-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -methanol;

[2- (4-iodo-2-methyl-phenylamino) -5-nitro-phenyl ] -methanol; and

[ 5-bromo-2- (4-iodo-2-methyl-phenylamino) -phenyl ] -methanol.

52. The method of claim 1, wherein the MEK inhibitor has a structure selected from:

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclobutylmethoxy-3, 4-difluoro-benzamide;

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-fluoro-benzamide;

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -N-methoxy-benzamide;

3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-N-hydroxy-benzamide;

n-cyclopropylmethoxy-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

4-fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide, hydrochloride;

5-bromo-3, 4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;

3, 4-difluoro-N- (2-hydroxy-ethoxy) -2- (4-iodo-2-methyl-phenylamino) -benzamide.

53. The method of claim 1, wherein the MEK inhibitor has a structure selected from:

2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-benzamide;

54. The method of claim 26, wherein the MEK inhibitor has a structure selected from:

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid;

3, 4, 5-trifluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

5-bromo-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid;

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

5-bromo-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid;

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-5-nitro-benzoic acid;

2- (2-chloro-4-iodo-phenylamino) -3, 4, 5-trifluoro-benzoic acid;

5-chloro-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid; and

5-chloro-2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid.

55. The method of claim 26, wherein the MEK inhibitor has a structure selected from:

2- (2-chloro-4-iodo-phenylamino) -3, 4-difluoro-benzoic acid; and