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Definitions

• the invention features a method for treating chronic pain, using MEK inhibitors.
• Chronic pain includes neuropathic pain, and chronic inflammatory pain.
• neuropathic pain may be, for example, a deep ache, a burning sensation, or hypersensitivity to touch.
• Diseases or conditions associated with neuropathic pain include, without limitation, diabetic neuropathy, causalgia, plexus avulsion, neuroma, vasculitis, crush injury, viral infections (e.g., herpes virus infection or HIV), constriction injury, tissue injury, nerve injury from the periphery to the central nervous system, limb amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and vitamin deficiencies .
• Infections such as herpes zoster (shingles) can cause nerve inflammation and produce postherpetic neuralgia, a chronic burning localized to the area of viral infection.
• Hyperalgesia is when an already noxious stimulus becomes more painful, and allodynia, when a previously non-noxious stimulus becomes painful (such as contact of clothing or a breeze).
• Reflex sympathetic dystrophy is accompanied by swelling and sweating or changes in local blood flow, tissue atrophy, or osteoporosis.
• Causalgia including severe burning pain and swelling, sweating, and changes in blood flow, may follow an injury or disease of a major nerve such as the sciatic nerve.
• neuropathic pain may also be induced by cancer or chemotherapy.
• Neuropathic pain is currently treated with anticonvulsants such as carbamazepine and antidepressants such as amitryptaline.
• NSAIDS and opioids generally have little effect (Fields et al 1994 Textbook of Pain p 991- 996 (pub: Churchill Livingstone), James & Page 1994 J.Am. Pediatr. Med.Assoc, 8: 439-447, Galer, 1995 Neurology 45 S17-S25.
• Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, postpoliomyelitis, CPRM, HIV-related neuropathy, trigeminal neuralgia, and reflex sympathetic dystrophy (RSD).
• the generally weak efficacy of antiinflammatory agents suggests that the mechanism for chronic pain is separate from hyperalgesia.
• the invention features a method for treating chronic pain, which method includes the step of administering a composition including a MEK inhibitor to a patient in need of such treatment.
• Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiencies, uremia, hypothyroidism post-operative pain, arthritis, back pain, and chronic alcoholism.
• the invention also features compounds as disclosed, formulated for the treatment of chronic pain.
• Such a composition may include one or more MEK inhibitor compounds having a structure disclosed in patent applications PCT/US98/13106, international filing date June 24, 1998, and PCT/US98/13105, international filing date June 24, 1998.
• MEK inhibitors include 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives which are kinase inhibitors and as such are useful for treating proliferative diseases such as cancer, psoriasis, and restenosis.
• the compounds are defined by Formula I
• Rl is hydrogen, hydroxy, Ci-C ⁇ alkyl, C-i-Cs alkoxy, halo, trifluoromethyl, or CN;
• R2 is hydrogen;
• R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl,
• R6 is hydrogen, C-
• R7 is hydrogen, C ⁇ -Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl,
• C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg); or RQ and R7 taken together with the N-O to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NRI QRH ; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by cycloalkyl (or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg), aryl, aryloxy, heteroaryl, or heteroaryloxy.
• Preferred compounds have Formula
• , R3, R4, R5, RQ, and R7 are as defined above.
• is methyl or halo
• R3, R4, and R5 are halo such as fluoro or bromo.
• R wherein R ⁇
• is methyl or halo such as F, Br, Cl, and I
• R3 is hydrogen or halo such as fluoro
• R4 is halo such as fluoro
• R5 is hydrogen or halo such as fluoro or bromo.
• MEK inhibitors include 4-bromo and 4-iodo phenylamino benzoic acid derivatives which are selective MEK kinase inhibitors.
• the compounds are defined by Formula 1(A)
• R-l is hydrogen, hydroxy, C-i-C ⁇ alkyl, Ci-Cs alkoxy, halo, trifluoromethyl, or CN;
• R2 is hydrogen;
• R3 > R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, C-i-C ⁇ alkyl, C ⁇
• 1 independently are hydrogen or C ⁇
• Z is COOR7, tetrazolyl, CONR6R7, CONHNR1 nRl 1 or CH2OR7;
• RQ and R7 independently are hydrogen, C ⁇
• C2-C8 alkynyl C - Ci-Cs alkyl, aryl, heteroaryl, C3-C10 cycloalkyl, or C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or RQ and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1 , 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts thereof.
• Preferred compounds have Formula ll(A)
• , R3, R4, R5, RQ, and R7 are as defined above.
• is methyl or halo
• R3, R4, and R5 are halo such as fluoro or bromo.
• the compounds of Formula 11(A) are carboxylic acids when R7 is hydrogen, and are esters when R7 is other than hydrogen.
• Compounds which are analogous to the acids in physical and biological properties are tetrazolyl derivatives of Formula Ma
• Another preferred group of compounds are amides Formula 111(A)
• the benzyl alcohols of the invention have Formula IV(A)
• the most preferred compounds are those wherein R-l is methyl, R3 is hydrogen or halo such as fluoro, R4 is halo such as fluoro, and R5 is hydrogen or halo such as fluoro, bromo, or chloro.
• Representative compounds have the formulas
• Br or Preferred embodiments for this invention include methods using one or more of the following compounds: (a) said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide, potassium salt;
• said MEK inhibitor has a structure selected from:
• said MEK inhibitor has a structure selected from:
• said MEK inhibitor has a structure selected from:
• This invention also provides pharmaceutical formulations adapted for the treatment of chronic pain, said formalities comprising a disclosed compound together with a pharmaceutically acceptable excipient, diluent, or carrier.
• Preferred formulations include any of the foregoing preferred compounds together with an excipient, diluent, or carrier.
• the disclosed compounds are potent and selective inhibitors of kinase enzymes, particularly MEK-
• FIG. 1 is a bar graph representing the paw withdrawal threshold (PWT) in grams as a function of time in days.
• the empty, cross-hatched, and single- hatched bars are vehicle, PD 198306, and pregabalin, respectively.
• the arrows indicate time of drug administration (30 mg/kg, p.o.).
• FIG 2. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
• FIG. 3. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
• Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin
• FIG. 4. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
• BL Baseline
• FIG. 6 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days .
• FIG. 7. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.
• FIG. 8 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments.
• MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis, as well as pair.
• Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins.
• Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade .
• the cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP.
• Ras leads in turn to the activation of a cascade of serine/threonine kinases.
• One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEKi and MEK2) which then activates MAP kinase, ERK (ERK T and ERK 2 ).
• MEK e.g., MEKi and MEK2
• ERK ERK T and ERK 2
• Blockade of downstream Ras signaling for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants.
• Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism.
• Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, s218 anc
• MEK in turn phosphorylates MAP kinase on both a tyrosine, ⁇ 185 anc
• MAP kinase This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase.
• MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase.
• MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins.
• MEK inhibitor PD 198306 has been investigated in two animal models of neuropathic pain by assessing static allodynia with von Frey hairs.
• PD 198306 had no effect in the model of chronic constriction injury of the sciatic nerve (CCI). However, after repeated administration (3 doses over two days) it had a transient effect in the diabetic neuropathy model (streptozocin). This may be due to disorders of the blood- brain barrier induced by the diabetic condition in these animals, thus allowing central action of the compound.
• Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t- butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1 ,1- dimethylpentyl, heptyl, and octyl. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Alkyl groups can be substituted with 1 , 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
• substituents are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
• alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp 2 carbon atoms).
• alkynyl groups have at least one triple bond (two adjacent sp carbon atoms).
• Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example.
• alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2-propynyl, 2- propenyl, 4-hydroxy-3-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2- propenyl.
• alkenyls and alkynyls can be C 2- or C 2 _ 8 , for example, and are preferably C 3 . 4 or C 3 . 8 - More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents.
• halo- e.g., fluoro-, chloro-, or bromo-
• substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl.
• Ri thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth.
• R A includes hydroxyalkyl and aminoaryl
• R B includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl.
• Heterocyclic radicals which include but are not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1 ,3,4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their nonaromatic counterparts.
• heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl.
• Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinases, and C-src.
• a selective MEK 1 or MEK 2 inhibitor has an IC 50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 5 o for one of the above-named other enzymes.
• a selective inhibitor has an IC 5 o that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its ICso or one or more of the above-named enzymes.
• aryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms.
• typical aryl groups include phenyl, naphthyl, and fluorenyl.
• the aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, 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.
• aryloxy means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1 -fluorenyloxy.
• Heteroaryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, and triazinyl.
• heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, or amino.
• substituted heteroaryl groups include chloropyranyl, methylthienyl, fluoropyridyl, amino-1 ,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.
• heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
• C-i-Cs alkyl means straight and branched chain aliphatic groups having from one to eight carbon atoms.
• -C8 alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, 2,3-dimethylhexyl, and 1 ,1-dimethylpentyl.
• the alkyl groups can be unsubstituted or substituted by cycloalkyl, cycloalkyl containing a heteroatom selected from O, S, or NRg, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined above.
• Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1 ,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.
• Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl.
• Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclopentylethyl, 2-piperidin-1 -ylethyl, 3-(tetrahydropyran-2-yl)propyl, and cyclobutylmethyl.
• C2"C ⁇ Alkenyl means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1 ,1-dimethyl-hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent- 4-enyl.
• alkenyl groups can be substituted with aryl, aryloxy, heteroaryl, or heteroyloxy, for example 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy- but-2-enyl, and 4-naphthyloxy-hex-2-enyl.
• C2-C8 Alkynyl means a straight or branched carbon chain having from two to eight 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 groups can be substituted by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl,
• the alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds.
• typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.
• C3-C-10 cycloalkyl means a non-aromatic ring or fused rings containing from three to ten carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl.
• the ring can optionally contain a heteroatom selected from O, S, or NRg.
• R3, R4, and R5 can include groups defined by the term (O or NH) m -
• aryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms.
• aryl groups examples include phenyl, naphthyl, and fluorenyl.
• the aryl may be substituted by 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.
• aryloxy means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy.
• Heteroaryl means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl.
• heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino.
• substituted heteroaryl groups include chloropyranyl, methy ⁇ thienyl, fluoropyridyl, amino-1 ,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.
• heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
• -C8 alkyl means straight and branched chain aliphatic groups having from one to eight carbon atoms, preferably one to four.
• -C8 alkyl groups include methyl, ethyl, isopropyl, tert.-butyl,
• alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein.
• Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl.
• Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1 ,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.
• Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl.
• Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl-2-methyl, 2-(piperidin-1-yl)- ethyl, 3-(morpholin-4-yl)propyl.
• C2-C8 Alkenyl means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1 ,1-dimethyl-hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent- 4-enyl.
• the alkenyl groups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example 2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoethenyl, 3-phenylprop- 2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl, and 4-naphthyloxy-hex- 2-enyl.
• C2-C8 Alkynyl means a straight or branched carbon chain having from two to eight 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 groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl-hex-4-ynyl.
• the alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds.
• typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.
• C3-C-10 cycloalkyl means a nonaromatic ring or fused rings containing from three to ten carbon atoms.
• Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl.
• the ring can optionally contain one, two, or three heteroatoms selected from O, S, or NRg.
• Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl.
• the cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmorpholine-1-yl.
• Rg and R7 can be taken together with the nitrogen to which they are attached to complete a cyclic ring having from 3 to 10 members, which may contain 1 , 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl.
• cyclic rings examples include piperazinyl, piperidyl, pyrrolidinyl, morpholino, N-methylpiperazinyl, aziridynyl, and the like.
• Such rings can be substituted with halo, hydroxy, alkyl, alkoxy, amino, alkyl, and dialkylamino, aryl, aryloxy, heteroaryl, and heteroaryloxy.
• Typical examples include 3-hydroxy-pyrrolidinyl, 2-fluoro-pipehndyl, 4-(2-hydroxyethyl)-piperidinyl, and 3-thienylmorpholino.
• the 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives of Formula I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a phenylamino benzoic acid, and then reacting the benzoic acid phenylamino derivative with a hydroxylamine derivative. This process is depicted in Scheme 1.
• L is a leaving group, for example halo such as fluoro, chloro, bromo or iodo, or an activated hydroxy group such as a diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.
• halo such as fluoro, chloro, bromo or iodo
• an activated hydroxy group such as a diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.
• the reaction of the aniline derivative and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran, or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, and sodium amide.
• the reaction generally is carried out at a temperature of about -78°C to about 25°C, and normally is complete within about 2 hours to about 4 days.
• the product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
• the phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNR ⁇ OR7 in the presence of a peptide coupling reagent.
• Hydroxylamine derivatives that can be employed include methoxylamine, N-ethyl-isopropoxy amine, and tetrahydro-oxazine.
• Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ), 1 ,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP) and (benzotriazolyloxy)tripyrrolidino phosphonium hexafluorophosphate (PyBOP).
• EEDQ 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline
• DCC 1 ,3-dicyclohexylcarbodiimide
• PyBrOP bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate
• the phenylamino benzoic acid and hydroxylamino derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added.
• a base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired.
• the coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
• An alternative method for making the invention compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the hydroxamic acid derivative with an aniline. This synthetic sequence is depicted in Scheme 2.
• Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 3.
• L is a leaving group such as halo
• a base is triethylamine or diisopropylamine.
• the 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of Formula 1(A) can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry and illustrated in synthetic examples 1A - 224A below.
• a typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a 2-(phenylamino)- benzoic acid. This process is depicted in Scheme 1 (A).
• L is a leaving group, for example halo such as fluoro.
• the reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base.
• a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base.
• the reaction generally is carried out at a temperature of about -78°C to about 100°C, and normally is complete within about 2 hours to about 4 days.
• the product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
• the 2-(phenylamino)-benzoic acid (eg, Formula IA, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt.
• the free acids can also be reacted with an alcohol of the formula HOR7 (where R7 is other than hydrogen, for example methyl) to produce the corresponding ester.
• Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent.
• Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ), 1 ,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidino phosphonium hexafluorophosphate (PyBOP).
• EEDQ 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline
• DCC 1 ,3-dicyclohexylcarbodiimide
• PyBrOP bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate
• PyBOP benzotriazolyloxy tripyrrolidino phosphonium hexafluorophosphate
• the phenylamino benzoic acid and alcohol derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added.
• a base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired.
• the coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
• the benzamides of the invention are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNR6R7.
• the reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent.
• Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene.
• Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP.
• the reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C.
• the product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation.
• benzyl alcohols of the invention compounds of Formula l(A) where Z is CH2 ⁇ R ⁇ and RQ is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following scheme
• Typical reducing agents commonly employed include borane in tetrahydrofuran.
• the reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to about 40°C.
• compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions relating to chronic pain, including neuropathic pain, as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade.
• the disclosed method relates to postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain, or limb amputation
• local injuries can be treated with local or topical administration.
• Chronic pain affecting the entire body such as diabetic neuropathy can be treated with systemic administration (injection or orally) of a disclosed composition.
• Treatment for chronic pain (e.g., post-operative pain) confined to the lower body can be administered centrally, e.g., epidurally.
• Formulations and methods of administration can include the use of more than one MEK inhibitor, or a combination of a MEK inhibitor and another pharmaceutical agent, such as an anti-inflammatory, analgesic, muscle relaxing, or anti-infective agent.
• Preferred routes of administration are oral, intrathecal or epidural, subcutaneous, intravenous, intramuscular, and, for non-human mammals, intraplantar, and are preferably epidural.
• an effective amount will be between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight.
• Commercially available capsules or other formulations such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods.
• Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses.
• Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants.
• Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intrape toneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
• Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof.
• 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 maintaining appropriate particle size.
• Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and 0) propellants.
• Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
• adjuvants such as preserving, wetting, emulsifying, and dispensing agents
• antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid
• isotonic agents such as a sugar or sodium chloride
• absorption-prolonging agents such as aluminum monostearate and gelatin
• absorption-enhancing agents such as aluminum monostearate and gelatin.
• the invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.
• Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C ⁇ -8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are 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, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate.
• alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
• alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium
• non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
• amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
• Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C ⁇ -6 alkyl amines and secondary di (C ⁇ _ 6 alkyl) amines.
• Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms.
• Preferred amides are derived from ammonia, C 1 . 3 alkyl primary amines, and di (C ⁇ -2 alkyl)amines.
• Representative pharmaceutically acceptable esters of the invention include C ⁇ -7 alkyl, C 5 -7 cycloalkyl, phenyl, and phenyl(C .- ⁇ jalkyl esters.
• Preferred esters include methyl esters.
• the invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
• Hydroxyl protecting groups include: ethers, esters, and protection for 1 ,2- and 1 ,3-diols.
• the ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups.
• Substituted Methyl Ethers include: methoxymethyl, methylthiomethyl, t- utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p- ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t- butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiothiothio
• 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-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t- butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
• Substituted Benzyl Ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl ⁇ /-oxido, diphenylmethyl, p, p -dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, ⁇ -naphthyldiphenyl- methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-ths(
• Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, thisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, f-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and f-butylmethoxyphenylsilyl.
• Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.
• esters examples include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate,crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate).
• Carbonates include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlor
• Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, silyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4- ethoxy-1-naphthyl, and methyl dithiocarbonate.
• assisted Cleavage protecting groups include: 2-iodobenzoate, 4- azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2- formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate.
• miscellaneous esters include: 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1 ,1 ,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis(1 ,1-dimethy!propyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (_ ⁇ )-2-methyl-2- butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, ⁇ - naphthoate, nitrate, alkyl N,N,N ' ⁇ / '-tetramethylphosphorodiamidate, N- phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4- dinitrophenylsulfenate.
• Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
• the protection for 1 ,2 and 1 ,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives. Cyclic Acetals and Ketals
• Cyclic acetals and ketals include: methylene, ethylidene, 1-f-butylethylidene,
• Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy- methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1 ,2- dimethoxyethylidene, ⁇ -methoxybenzylidene, 1-(N,N- dimethylamino)ethylidene derivative, ⁇ -( ⁇ /, ⁇ /-dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene.
• Ester protecting groups include: esters, substituted methyl esters, 2- substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters.
• Substituted Methyl Esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, ⁇ -methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N- phthalimidomethyl.
• 2-Substituted Ethyl Esters include: 2,2,2-thchloroethyl, 2-haloethyl, ⁇ - chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1 ,3-dithianyl-2-methyl, 2(p-nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyhdyl)ethyl, 2- (diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, f-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsily)-2-buten-1-yl, cinnamyl, ⁇ - methylcinnamyl, phenyl, p-(methyl
• Substituted Benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5- dibenzo-suberyl, 1 -pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6- trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p- methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl.
• Silyl esters include: trimethylsilyl, triethylsilyl, f-butyldimethylsilyl, / ' - propyldimethylsilyl, phenyldimethylsilyl, and di- .-butylmethylsi ⁇ yl.
• Miscellaneous Derivatives Miscellaneous derivatives includes: oxazoles, 2-alkyl-1 ,3-oxazolines, 4-alkyl- 5-OXO-1 , 3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(lll) complex.
• Stannyl Esters Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl.
• AMIDES AND HYDRAZIDES include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6- dihydrophenanthridinyl, o-nitroanilides, ⁇ /-7-nitroindolyl, ⁇ /-8-nitro-1 , 2,3,4- tetrahydroquinolyl, and p-P-benzenesulfonamides.
• Hydrazides include: N- phenyl, N,N '-diisopropyl and other dialkyl hydrazides.
• Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.
• Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2- sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-_ l -butyl-[9-(1O,10- dioxo-10,10,10,10-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl.
• Substituted Ethyl protective groups include: 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1 ,1-dimethyl- 2-haloethyl, 1 ,1dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1- methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-f-butylphenyl)-1-methylethyl, 2-(2'-and 4'-pyridyl)ethyl, 2-( ⁇ /, ⁇ /-icyclohexylcarboxamido)- ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-
• Protection via assisted cleavage includes: 2-methyithioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1 ,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1 ,1-dimethyl-2cyanoethyl, m-chloro-p- acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyl)-6-chromonylmethyl.
• Photolvtic Cleavage Photolvtic 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 include: phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl, and N '- phenylaminothiocarbonyl.
• miscellaneous carbamates include: f-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-( ⁇ /, ⁇ /-dimethyl-carboxamido)-benzyl, 1 ,1-dimethyl- 3( ⁇ /, ⁇ /-dimethylcarboxamido)propyl, 1 ,1-dimethyl-propynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(p - methoxyphenyl- azo)benzyl, 1-methylcyclo
• Amides includes: ⁇ /-formyl, ⁇ /-acetyl, ⁇ /-chloroacetyl, ⁇ /-trichloroacetyl, ⁇ /-trifluoroacetyl, ⁇ /-phenylacetyl, ⁇ /-3-phenylpropionyl, ⁇ /-picolinoyl, ⁇ /-3- pyridyl-carboxamide, ⁇ /-benzoylphenylalanyl derivative, ⁇ /-benzoyl, and N-p- phenylbenzoyl.
• Assisted Cleavage Assisted cleavage groups include: ⁇ /-o-nitrophenylacetyl, N-o- nitrophenoxyacetyl, ⁇ /-acetoacetyl, ( ⁇ / -dithiobenzyloxycarbonylamino)acetyl, ⁇ /-3-(p-hydroxphenyl) propionyl, ⁇ /-3-(o-nitrophenyl)propionyl, ⁇ /-2-methyl-2- (o-nitrophenoxy)propionyl, ⁇ /-2-methyl-2-(o-phenylazophenoxy)propionyl, ⁇ /-4- chlorobutyryl, ⁇ /-3-methyl-3-nitrobutyryl, ⁇ /-o-nitrocinnamoyl, N- acetylmethionine derivative, ⁇ /-o-nitrobenzoyl, N-o- (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2
• Cyclic imide derivatives include: ⁇ /-phthalimide, ⁇ /-dithiasuccinoyl, ⁇ /-2,3-diphenyl-maleoyl, ⁇ /-2,5-dimethylpyrrolyl, ⁇ /-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.
• Protective groups for - NH include: ⁇ /-alkyl and ⁇ /-aryl amines, imine derivatives, enamine derivatives, and ⁇ /-hetero atom derivatives (such as N- metal, N-N, N-P, N-Si, and N-S), ⁇ /-sulfenyl, and ⁇ /-sulfonyl.
• ⁇ /-Alkyl and ⁇ /-Aryl Amines ⁇ /-alkyl and ⁇ /-aryl amines include: ⁇ /-methyl, ⁇ /-allyl, ⁇ /-[2-(trimethylsilyl)ethoxyl]-methyl, ⁇ /-3-acetoxypropyl,
• quaternary ammonium salts ⁇ /-benzyl, ⁇ /-di(4-methoxyphenyl)methyl, ⁇ /-5-dibenzosuberyl, ⁇ /-triphenylmethyl, ⁇ /-(4-methoxyphenyl)diphenylmethyl, ⁇ /-9-phenylfluorenyl, ⁇ /-2,7-dichloro-9-fluorenylmethylene, ⁇ /-ferrocenylmethyl, and ⁇ /-2-picolylamine N '-oxide.
• Imine derivatives include: ⁇ /-1 ,1-dimethylthiomethylene, ⁇ /-benzylidene, ⁇ /-p-methoxybenzylidene, ⁇ /-diphenylmethylene, ⁇ /-[(2-pyridyl)mesityl]methylene, N-(N ',N '-dimethylaminomethylene), N,N '-isopropylidene, ⁇ /-p-nitrobenzylidene, ⁇ /-salicylidene,
• ⁇ /-5-chlorosalicylidene ⁇ /-(5-chloro-2-hydroxyphenyl)phenyl-methylene, and ⁇ /-cyclohexylidene.
• Enamine Derivative An example of an enamine derivative is N- (5,5-dimethyl-3-oxo-1-cyclohexenyl).
• ⁇ /-Hetero Atom Derivatives ⁇ /-metal derivatives include: ⁇ /-borane derivatives, ⁇ /-diphenylborinic acid derivative, ⁇ /-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and ⁇ /-copper or ⁇ /-zinc chelate.
• Examples of ⁇ /-/V derivatives include: ⁇ /-nitro, ⁇ /-nitroso, and ⁇ /-oxide.
• Examples of ⁇ /-P derivatives include: ⁇ /-diphenylphosphinyl, ⁇ /-dimethylthiophosphinyl, ⁇ /-diphenylthiophosphinyl, ⁇ /-dialkyl phosphoryl, ⁇ /-dibenzyl phosphoryl, and ⁇ /-diphenyl phosphoryl.
• ⁇ /-sulfenyl derivatives include: ⁇ /-benzenesulfenyl, ⁇ /-o-nitrobenzenesulfenyl, ⁇ /-2,4-dinitrobenzenesulfenyl, ⁇ /-pentachlorobenzenesulfenyl, ⁇ /-2-nitro-4-methoxy-benzenesulfenyl, ⁇ /-t phenylmethylsulfenyl, and ⁇ /-3-nitropyridinesulfenyl.
• ⁇ /-sulfonyl derivatives include: ⁇ /-p-toluenesulfonyl, ⁇ /-benzenesulfonyl, ⁇ /-2,3,6-trimethyl- 4-methoxybenzenesulfonyl, ⁇ /-2,4,6-trimethoxybenzenesulfonyl, ⁇ /-2,6-dimethyl-4-methoxy- benzenesulfonyl, ⁇ /-pentamethylbenzenesulfonyl, ⁇ /-2,3,5,6-tetramethyl-4-methoxybenzene- sulfonyl, ⁇ /-4-methoxybenzenesulfonyl, ⁇ /-2,4,6-trimethylbenzenesulfonyl, ⁇ /-2,6-dimethoxy- 4-methylbenzenesulfonyl, ⁇ /-2,2,5,7,8-pentamethylchroman-6-sulfony
• Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism.
• This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.
• mice Male Sprague Dawley rats (250-300g), obtained from Bantin and Kingman, (Hull, U.K.) were housed in groups of 3. All animals were kept under a 12h light/dark cycle (lights on at 07h OOmin) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments.
• PD 198306 [N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide] and CI-1008 (pregabalin) were synthesized at Parke-Davis (Ann Arbor, Ml, USA). PD 198306 was suspended in cremophor:ethanol:water (1 :1 :8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCI and administered intraperitoneally. Drug administrations were made in a volume of 1 ml/kg.
• mice Male Sprague Dawley rats (250-300g), obtained from Charles River, Margate, U.K.) were housed in groups of 3-6. All animals were kept under a 12h light/dark cycle (lights on at 07h OOmin) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments.
• Diabetes was induced in rats by a single i.p. injection of streptozocin (50mg/kg) as described previously (Courteix et al., 1993).
• Intrathecal injections PD 198306 and pregabalin were administered intrathecally in a volume of 10 ⁇ l using a 100 ⁇ l Hamilton syringe by exposing the spine of the rats under brief isoflurane anaesthesia. Injections were made into the intrathecal space between lumbar region 5-6 with a 10 mm long 27 gauge needle. Penetrations were judged successful if there was a tail flick response. The wound was sealed with an autoclip and rats appeared fully awake within 2-3 min following injection.
• Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1h and 2h after intrathecal or intraplantar administration of PD 198306 (1-30 ⁇ g, i.t.), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (10 ⁇ g, i.t).
• static allodynia was assessed with von Frey hairs, before (baseline, BL) and 1h after oral administration of PD 198306 (3-30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1 :1 :8) or pregabalin (30mg/kg, p.o.).
• Static allodynia was assessed before and 1 h after the morning administration. In the afternoon static allodynia was assessed before, 1h, 2h and 3h after administration for streptozocin treated animals. CCI animals were assessed before, 1 h and 2h after administration
• PD 198306 and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA).
• PD 198306 was suspended in cremophor:ethanol:water (1 :1 :8) vehicle.
• Pregabalin was dissolved in water. Both compounds were administered orally, intrathecally or intraplantar in volumes of 1 ml/kg, 10 ⁇ l and 100 ⁇ l respectively.
• Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCI and administered intraperitoneally in a volume of 1 ml/kg.
• the animals and methods for developing chronic constriction injury in the rat, injecting test compounds, and evaluation of static allodynia were according to Example 2 above.
• PD219622, PD297447, PD 184352, PD 254552 and pregabalin were administered intrathecally at doses of 30 g for all PD compounds and 100 ⁇ g for pregabalin.
• Static allodynia was assessed with von Frey hairs, before (baseline, BL) and 0.5h, 1 h and 2h after intrathecal administration of the compounds
• Drugs used PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin were synthesised at Parke-Davis (Ann Arbor, Ml, USA).
• PD297447, PD219622, PD 254552 and PD 184352 were suspended in cremophor:ethanol:water (1 :1 :8) vehicle.
• Pregabalin was dissolved in water. All compounds were administered intrathecally in a 10 ⁇ l volume.
• the antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100 ⁇ g). The magnitude of the effect was similar for 30 ⁇ g of PD 184352 and 100 ⁇ g of pregabalin.
• reaction temperature was allowed to increase slowly to room temperature, at which temperature the mixture was stirred for 2 days.
• the reaction mixture was concentrated by evaporation of the solvent under reduced pressure.
• Aqueous HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane.
• the organic phase was dried (MgS04) and then concentrated over a steambath to low volume (10 mL) and cooled to room temperature.
• the off-white fibers which formed were collected by vacuum filtration, rinsed with hexane, and dried in a vacuum-oven (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;
• reaction mixture was concentrated in vacuo to a brown oil that was purified by flash silica chromatography. Elution with dichloromethane ⁇ dichloromethane-methanol (166:1) afforded 0.2284 g of a light-brown viscous oil.
• aqueous hydrochloric acid (ca. 500 mL) was poured into the reaction mixture, and the mixture was subsequently concentrated on a rotary evaporator to a crude solid.
• the solid product was partitioned between diethyl ether (150 mL) and aq. HCI (330 mL, pH 0).
• the aqueous phase was extracted with a second portion (100 mL) of diethyl ether, and the combined ethereal extracts were washed with 5% aqueous sodium hydroxide (200 mL) and water (100 mL, pH 12). These combined alkaline aqueous extractions were acidified to pH 0 with concentrated aqueous hydrochloric acid.
• the reaction mixture was stirred at 24°C for 10 minutes, and then was concentrated to dryness in vacuo.
• the concentrate was suspended in 100 mL of 10% aqueous hydrochloric acid.
• the suspension was extracted with 125 mL of diethyl ether.
• the ether layer was separated, washed with 75 mL of 10% aqueous sodium hydroxide, and then with 100 mL of dilute acid.
• the ether solution was dried (MgSO4) and concentrated in vacuo to afford 0.62 g (100%) of an off-white foam.
• the foam was dissolved in ca. 15 mL of methanolic hydrogen chloride. After 5 minutes, the solution was concentrated in vacuo to an oil, and the oil was purified by flash silica chromatography.
• Examples 3 to 12 and 78 to 102 in the table below were prepared by the general procedures of Examples 1 and 2.
• Examples 13 to 77 were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids
• the reaction mixture was transferred to a 2 dram vial and diluted with 2 mL of ethyl acetate.
• the organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate.
• the combined organic layers were allowed to evaporate to dryness in an open fume hood.
• the invention compounds are useful in treating chronic pain proliferative diseases by virtue of their selective inhibition of the dual specificity protein kinases MEKi and MEK2.
• the invention compound has been evaluated in a number of biological assays which are normally utilized to establish inhibition of proteins and kinases, and to measure mitogenic and metabolic responses to such inhibition.
• reaction temperature was allowed to increase slowly to room temperature, at which temperature it was stirred for 2 days.
• the reaction mixture was concentrated.
• Aqueous HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane.
• the organic phase was dried (MgSO4) and then boiled over a steambath to low volume and cooled to room temperature.
• the off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca.
• A4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohoW-Fluoro- 2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.50 g, 1.35 mmol) was dissolved in 6 mL (6 mmol) of cold 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran solution. The reaction mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched with 80 mL of methanol. Concentration in vacuo produced a clear tan oil which was purified by MPLC.
• Example 49A The following benzyl alcohols were prepared by the general procedure of Example 49A.
• the reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate.
• the organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate.
• the combined organic layers were allowed to evaporate to dryness in an open fume hood.
• 4-ylmethyl-benzamide 80A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 475 ethyl)-benzamide 81 A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 445
• the E_2 ⁇ layer was dried (K2CO3) and the solvent removed to give the product as an oily solid. The product was used without further purification in the next step.
• Step e Preparation of f4-Chloro-2-(1 H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)- amine

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