CN1358094A

CN1358094A - Method for treating chronic pain using MEK inhibitors

Info

Publication number: CN1358094A
Application number: CN00809478A
Authority: CN
Inventors: S·D·巴瑞特; A·J·布里德格斯; H·泰克; A·迪克森; K·利; R·D·皮诺可
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1999-07-16
Filing date: 2000-07-05
Publication date: 2002-07-10
Also published as: PE20010546A1; EP1202731A2; HUP0202319A3; KR20020015376A; HUP0202319A2; IL147150A0; WO2001005390A3; AU6068600A; PL352835A1; CO5190704A1; CA2377092A1; WO2001005390A2; JP2003504398A; ZA200109906B

Abstract

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

Description

Method with mek inhibitor treatment chronic pain

Background technology

The present invention relates to method with mek inhibitor treatment chronic pain.Chronic pain comprises neuropathic pain and chronic inflammatory pain.

Anywhere the nerve signal that unusually all can make interrupts in nervous pathway, thereby makes brain interrupt signal aborted, causes neuropathic pain.Neuropathic pain can be for example deep pain, burning sensation or to hyperpselaphesia.Comprise with neuropathic pain diseases associated or disease, but be not limited to: diabetic neuropathy, causalgia, panizza's plexuses avulsion (plexus avulsion), neuroma, nodular vasculitis, crush injury, viral infection (for example herpesvirus infection or HIV), constriction injury, tissue injury, nerve injury by outer thoughtful central nervous system, amputation, hypothyroidism, uremia, chronic alcoholism, postoperative pain, arthritis, backache and vitamin deficiency.

For example infect that herpes zoster (shingles) can cause neural inflammation, and produce postherpetic neuralgia, this is a kind of chronic calcination at the viral infection position.Hyperpathia is the existing destructive stimulus pain more that becomes, and allodynia to be previous innocuousness stimulate the pain (for example contacting clothes or coal dust) that becomes.Reflex sympathetic dystrophhy is with swelling and perspiration or regional flow's variation, Telatrophy or osteoporosis.For example causalgia occurs after the sciatic nerve disease in damage or main nerve, comprise that serious calcination pain and swelling, perspiration and blood flow change.The low back pain of some type may have neuropathic composition (for example sciatica, back poliomyelitis (postpoliomyelitis) and CPRM).Neuropathic pain can also be caused by cancer or chemotherapy.

Neuropathic pain is with for example carbamazepine and for example amitriptyline (amitryptaline) treatment of antidepressants of anticonvulsant at present.NSAIDS and opioid be very little (Fields etc., 1994 Textbook of Pain p 991-996 (pub:Churchill Livingstone), James﹠amp of effect usually; Page 1994 J.Am.Pediatr.Med.Assoc, 8:439-447, Galer, 1995Neurology 45 S17-S25.Used the neuropathy symptom of gabapentin treatment to comprise: postherpetic neuralgia, back poliomyelitis, CPRM, neuropathy, trigeminal neuralgia and the reflex sympathetic dystrophhy (RSD) relevant with HIV.Usually the weak effect of antiinflammatory shows that the substrate of chronic pain is different with hyperpathia.

Summary of the invention

The present invention relates to the Therapeutic Method of chronic pain, this method comprises that the patient to this treatment of needs uses the compositions that comprises mek inhibitor.Chronic pain comprise neuropathic pain, special send out property pain with vitamin deficiency, uremia, hypothyroidism postoperative pain, arthritis, the backache pain relevant with chronic alcoholism.The invention still further relates to disclosed compositions, said composition is used for the treatment of chronic pain.Said composition can comprise one or more mek inhibitor chemical compounds, described chemical compound has the disclosed structure of International Application PCT/US99/30483 of U.S. Patent application USSN December in 60/115,873,1999 submission of submitting on January 13rd, 1999 on the 21st.

The example of mek inhibitor comprises following formula (I) chemical compound:

In formula (I), W is OR ₁, NR ₂OR ₁, NR _AR _B, NR ₂NR _AR _B, O (CH ₂) _2-4NR _AR _B, or NR ₂(CH ₂) _2-4NR _AR _BR ₁Be H, C _1-8Alkyl, C _3-8Alkenyl, C _3-8Alkynyl group, C _3-8Cycloalkyl, phenyl, (phenyl) C _1-4Alkyl, (phenyl) C _3-4Alkenyl, (phenyl) C _3-4Alkynyl group, (C _3-8Cycloalkyl) C _1-4Alkyl, (C _3-8Cycloalkyl) C _3-4Alkenyl, (C _3-8Cycloalkyl) C _3-4Alkynyl group, C _3-8Heterocyclic radical, (C _3-8Heterocyclic radical) C _1-4Alkyl, (C _3-8Heterocyclic radical) C _3-4Alkenyl, (C _3-8Heterocyclic radical) C _3-4Alkynyl group or (CH ₂) _2-4NR _CR _DR ₂Be H, C _1-4Alkyl, phenyl, C _3-6Cycloalkyl, C _3-6Heterocyclic radical or (C _3-6Cycloalkyl) methyl.R _ABe H, C _1-6Alkyl, C _3-8Alkenyl, C _3-8Alkynyl group, C _3-8Cycloalkyl, phenyl, (C _3-8Cycloalkyl) C _1-4Alkyl, (C _3-8Cycloalkyl) C _3-4Alkenyl, (C _3-8Cycloalkyl) C _3-4Alkynyl group, C _3-8Heterocyclic radical, (C _3-8Heterocyclic radical) C _1-4Alkyl, (amino-sulfonyl) phenyl, [(amino-sulfonyl) phenyl] C _1-4Alkyl, (amino-sulfonyl) C _1-6Alkyl, (amino-sulfonyl) C _3-6Cycloalkyl, [(amino-sulfonyl) C _3-6Cycloalkyl] C _1-4Alkyl or (CH ₂) _2-4NR _CR _DR _BBe H, C _1-8Alkyl, C _3-8Thiazolinyl, C _3-8Alkynyl group, C _3-8Cycloalkyl or phenyl.

Q is one of following formula (i)-(iii):

R ₃Be H or F; R ₄Be halogen, NO ₂, SO ₂NR _O(CH ₂) _2-4NR _ER _F, SO ₂NR _ER _FOr (CO) T.T is C _1-8Alkyl, C _3-8Cycloalkyl, (NR _ER _F) C _1-4Alkyl, OR _F,-NR _O(CH ₂) _2-4NR _ER _FOr NR _ER _FZ be following formula (iv)-(one of viii):

R ₅And R ₆In one be H or methyl, and R ₅And R ₆In another be H, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl group, phenyl, benzyl or-M-E-G.M is O, CO, SO ₂, NR _J, (CO) NR _H, NR _H(CO), NR _H(SO ₂), (SO ₂) NR _HOr CH ₂E is (CH ₂) _1-4Or (CH ₂) _mO (CH ₂) _p, 1≤(each m and p)≤3 and 2≤(m+p)≤4 wherein; Perhaps E does not exist.G is R _K, OR ₁Or NR _JR _JR _K, condition is if p=1, then G is H.R ₇Be H, C _1-4Alkyl, C _2-4Alkenyl, C _2-4Alkynyl group, C _3-6Cycloalkyl, phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, (CH ₂) _1-2Ar, wherein Ar is phenyl, 2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals, SO ₂NR _H(CH ₂) _2-4NR _JR _K, (CO) (CH ₂) _2-4NR _JR _KOr (CO) NR _H(CH ₂) _2-4NR _JR _KX ₁Be O, S, NR ₈Or CHR ₉X ₂Be O, S or CHR ₉And X ₃Be O or S.In a specific embodiments, if X ₁Or X ₂Be CHR ₉, then disclosed chemical compound can also be tautomeric indole.R ₈Be H, C _1-4Alkyl, phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, (CH ₂) _1-2Ar, wherein Ar is phenyl, 2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals, C _2-4Alkenyl, C _2-4Alkynyl group, C _3-6Cycloalkyl or (C _2-4Alkyl) NR _LR _M, condition is R ₇And R ₈Be no more than 14 carbon atoms together, except R _L, R _M, R _JAnd R _KOutside.R _GBe C _1-4Alkyl, phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, C _3-4Alkenyl, C _3-4Alkynyl group, C _3-6Cycloalkyl, (CO) OR _P, (C _2-4Alkyl) NR _LR _M, (CO) NR _N(CH ₂) _2-4NR _LR _M, (CO) NR _LR _M, (CO) (CH ₂) _2-4-NR _LR _MOr (CH ₂) _1-2Ar, wherein Ar is phenyl, 2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals.R ₉Be C _1-4Alkyl, phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, C _2-4Alkenyl, C _2-4Alkynyl group, C _3-6Cycloalkyl, (CO) OR _P, (C _2-4Alkyl) NR _LR _M, (CO) NR _N(CH ₂) _2-4NR _LR _M, (CO) NR _LR _M, (CO) (CH ₂) _2-4-NR _LR _M, or (CH ₂) _1-2Ar ', wherein Ar ' is phenyl, 2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals.R _pBe H, C _1-6Alkyl, phenyl, C _3-4Alkenyl, C _3-4Alkynyl group, C _3-6Cycloalkyl or (CH ₂) _2-4NR _LR _MR ₁₀Be H, methyl, halogen or NO ₂R ₁₁Be H, methyl, halogen or NO ₂R _C, R _D, R _E, R _F, R _I, R _J, R _K, R _LAnd R _MIn each be independently selected from H, C _1-4Alkyl, C _3-4Alkenyl, C _3-4Alkynyl group, C _3-6Cycloalkyl and phenyl; NR _CR _D, NR _ER _F, NR _JR _KAnd NR _LR _MIn each be morpholinyl, piperazinyl, pyrrolidinyl or piperidyl independently.R _H, R _NAnd R _OIn each be H, methyl or ethyl independently.At last, above-mentioned each alkyl or heterocyclic radical randomly are independently selected from following substituent group replacement by 1-3: halogen, C _1-4Alkyl, C _3-6Cycloalkyl, C _2-4Alkenyl, C _2-4Alkynyl group, phenyl, hydroxyl, amino, (amino) sulfonyl and NO ₂, wherein each substituent group alkyl, cycloalkyl, alkenyl, alkynyl group or phenyl randomly are independently selected from following substituent group replacement by 1-3 successively: halogen, C _1-2Alkyl, hydroxyl, amino and NO ₂Except above-claimed cpd, the present invention also provides their officinal salt or C _1-7Ester.

Preferred specific embodiments of the present invention comprise the using method of one or more following compounds: (a) described MEKK inhibitor has and is selected from following structure: 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-6,7-dihydro-1H-benzimidazole-5-formic acid (hydrochlorate); 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-5-formic acid (2-hydroxyl-ethyoxyl)-amide; 6-(2-chloro-4-iodo-phenyl amino)-7-fluoro-1H-benzimidazole-5-formic acid; With 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid pentafluorophenyl group ester; (b) described mek inhibitor has and is selected from following structure: 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide; With 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-5-formic acid (2-hydroxyl-ethyoxyl)-amide.

The invention still further relates to pharmaceutical composition, wherein contain (a) benzheterocycle (for example heterocycle of formula I) and (b) pharmaceutically suitable carrier.

Brief description of drawings

Fig. 1 is that expression is shunk back threshold (PWT) as the bar in the time function in sky in the pawl of gram.Oblique line hollow, left and right oblique line rod are respectively excipient, PD 198306 and pregabalin.Arrow is represented administration time (30mg/kg, oral).

Fig. 2 is that the pawl required masterpiece of shrinking back that causes in gram that expression uses that von Frey hair carries out is the bar in the time function in sky.Before treatment, measure baseline (BL).Give animal single oral PD 198306 (3-30mg/kg) or pregabalin (30mg/kg), and measured the threshold of shrinking back in back 1 hour again in treatment.Every day, repetitive therapy twice, carried out altogether two days.The result represents with the quartile of meansigma methods ± 1st and the 3rd time.* p＜0.05, * * P＜0.01, * * * P＜0.001 significantly are different from animal (the Mann-Whitney t test of excipient treatment; N=7-8).

Fig. 3 is that the pawl required masterpiece of shrinking back that causes in gram that expression uses that von Frey hair carries out is the bar in the time function in sky.Before treatment, measure baseline (BL).Give animal single oral PD 198306 (3-30mg/kg) or pregabalin (30mg/kg), and measured the threshold of shrinking back in back 1 hour again in treatment.Every day, repetitive therapy twice, carried out altogether two days.The result represents with the quartile of meansigma methods ± 1st and the 3rd time.* P＜0.01 significantly is different from animal (the Mann-Whitney t test of excipient treatment; N=6).

Fig. 4 is that the pawl required masterpiece of shrinking back that causes in gram that expression uses that von Frey hair carries out is the bar in the time function in sky.Before treatment, measure baseline (BL).Use PD 198306 (1-30 μ g/10 μ l) or pregabalin (100 μ g/10 μ l) for animal single sheath interior (i.t.), and measured the threshold of shrinking back in back 30 minutes, 1 hour and 2 hours again in treatment.The result represents with the quartile of meansigma methods ± 1st and the 3rd time.* P＜0.05, * * * P＜0.001 significantly are different from animal (the Mann-Whitney t test of excipient treatment; N=7-9).

Fig. 5 is that the pawl required masterpiece of shrinking back that causes in gram that expression uses that von Frey hair carries out is the bar in the time function in sky.Before treatment, measure baseline (BL).Use PD 198306 (1-30 μ g/10 μ l) or pregabalin (100 μ g/10 μ l) for animal single sheath interior (i.t.), and measured the threshold of shrinking back in back 30 minutes, 1 hour and 2 hours again in treatment.The result represents with the quartile of meansigma methods ± 1st and the 3rd time.* P＜0.05, * * P＜0.01, * * * P＜0.001 significantly are different from animal (the Mann-Whitney t test of excipient treatment; N=6-8).

Fig. 6 is that the pawl required masterpiece of shrinking back that causes in gram that expression uses that von Frey hair carries out is the bar in the time function in sky.Use PD198306 (3mg/100 μ l) or intrathecal injection PD 198306 (30 μ g/10 μ l) to (i.pl.) in the animal single vola, and measured the threshold of shrinking back in back 1 hour again in treatment.The result represents with the quartile of meansigma methods ± 1st and the 3rd time.* P＜0.01 significantly is different from animal (the Mann-Whitney t test of excipient treatment; N=6-9).

Fig. 7 is that the pawl required masterpiece of shrinking back that causes in gram that expression uses that von Frey hair carries out is the bar in the time function in sky.Use PD198306 (3mg/100 μ l) or intrathecal injection PD 198306 (30 μ g/10 μ l) to (i.pl.) in the animal single vola, and measured the threshold of shrinking back in back 1 hour again in treatment.The result represents with the quartile of meansigma methods ± 1st and the 3rd time.*＜0.01 significantly is different from animal (the Mann-Whitney t test of excipient treatment; N=6).

Fig. 8 be expression use that von Frey hair carries out cause the shrink back bar of required power of pawl in gram.Before treatment, measure baseline (BL).Use PD219622, PD 297447, PD 184352 or PD 254552 (30 μ g/10 μ l) or pregabalin (100 μ g/10 μ l) for animal single sheath interior (i.t.), and measured the threshold of shrinking back in back 30 minutes, 1 hour and 2 hours again in treatment.The result represents with the quartile of meansigma methods ± 1st and the 3rd time.* P＜0.05, * * P＜0.01, * * * P＜0.001 significantly are different from animal (the Mann-Whitney t test of excipient treatment; N=7-8).

Detailed Description Of The Invention

Compound disclosed herein is pharmaceutically active, and for example, they suppress MEK. The MEK enzyme is dual The specificity kinases relates to for example immunological regulation, inflammatory and hyperplasia for example cancer and ISR.

Hyperplasia is that the signal conduction mechanism by signal system defective or some albumen in the cell causes . Defective comprises intrinsic activity or the cell concentration of one or more signal proteins in the signal cascade Change. Cell can produce the growth factor with himself receptors bind, produces autocrine loop, Growth factor continued stimulus propagation. The sudden change of signal protein or undue expression can cause cell in the cell Middle false mitogenesis signal. Some modal sudden change occurs in the known Ras's of being called of coding In the gene of albumen, Ras albumen is a kind of G-albumen, when it is activated when GTP is combined, and When its then deactivation when GDP is combined. When having caused silk, above-mentioned growth factor receptors and many other divide When splitting acceptor and being activated, cause Ras to be converted into the GTP bonding state by the GDP-bonding state. This letter Number be indispensable for most cell types propagation. In this signal system, particularly exist Defective in the deactivation of Ras-GTP compound is common in cancer, and cause signal cascade be lower than by The Ras that slowly activates.

The Ras of activation causes serine/threonine kinase cascade activation successively. The known needs activates Ras-GTP is so that one group of kinases of himself activation is Raf family. They (for example activate MEK successively MEK₁And MEK₂), activate then map kinase, ERK (ERK₁And ERK₂). Mitogen draws It seems that the activation of the map kinase that rises be that propagation is essential; This kinase whose basic activation is enough to cause carefully Dysuria with lower abdominal colic. The retardance of downstream Ras signal for example uses the dominant negative Raf-1 albumen can be complete Suppress mitogenesis, no matter caused or by giving birth to knurl Ras by cell surface receptor Mutant causes. Although Ras itself is not protein kinase, it participates in Raf and other swashs The activation of enzyme, majority may be by phosphorylation mechanism. For ME-1, in case quilt Activation, Raf and other kinases make MEK phosphorus at two next-door neighbours' serine residue S218 and S222 Acidifying, this is that MEK is as the prerequisite of kinase activation. MEK is being separated by monamino acid successively Make the map kinase phosphorylation on tyrosine y185 and the threonine residues T183.

This bis phosphoric acid turns into making 100 times of map kinase activation at least. Then, the map kinase of activation Can a large amount of albumen of catalysis, comprise several transcription factors and other kinase whose phosphorylation. For Target protein, for example kinases, transcription factor or other cell protein, many these map kinases Phosphorylation is that mitogenesis activates. Except Raf-1 and MEKK, other kinase activation MEK, and it seems that MEK self be signal integrating kinase. Current understanding is that MEK is to map kinase The phosphorylation height single-minded. In fact, up to now, verified only have map kinase, and ERK is The substrate of MEK, and the phosphorylation that MEK is not based on map kinase makes the peptide phosphorylation in proper order, perhaps, It in addition can make the map kinase phosphorylation of sex change. MEK before the map kinase phosphorylation just and MAP Kinases has close relationship, and this shows that map kinase may need these two kinds by the phosphorylation of MEK Strong preferential interaction is arranged between the albumen. The uncommon specificity of this demand and MEK is all pointed out it The mechanism of action and other protein kinase have enough differences, can find the MEK selective depressant May be by allosteric mechanism but not work by common blockade ATP-binding site.

In two kinds of neuropathic pain animal models, static unusual by estimating with von Frey hair Property pain is studied the effect of mek inhibitor PD 198306.

Oral PD 198306 (3-30mg/kg) is at the chronic constriction injury of sciatic nerve (CCI) model In not impact. But behind repeat administration (administration is 3 times in 2 days), it is at diabetic neuropathy Has of short duration effect in the model (streptozotocin). This may be since in these animals because of diabetes The blood-brain barrier disorder that causes, thus make compound produce central action. Chain in neuropathic pain In assistant star and the CCI model, use PD 198306 (1-30 μ g) in the sheath all in dose-dependent mode Block static allodynia, minimum effective dose (MED) is respectively 3 and 10g. The highest use agent Amount (30 μ g) blocks the static allodynia that continues fully and reaches 1 hour. To exceed in effective sheath Use PD 198306 (3mg/100 μ l) in the dosage vola that dosage (30 μ g/10 μ l) is 100 times to appointing The static allodynia of what a kind of neuropathic pain model is all less than effect. This discovery has confirmed After being administered systemically, lack visible effect, and pointed out the central action site of this compound.

By this research, we can propose the application of mek inhibitor as the potential new treatment tool of chronic pain.To the possible side effect of following brain penetrant m EK inhibitor, particularly indicated the treatment window of such noval chemical compound in treatment pain with the research that the relevant side effect of memory is carried out.A. term

Below some term is defined, and they will be used in full.

Alkyl comprises aliphatic group with free valency (be alkyl or contain hydrogen and the alkyl radical structure of carbon atom).Alkyl can be understood as and comprises straight chain and branched structure.The example comprises methyl, ethyl, propyl group, isopropyl, butyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group, isopentyl, 2,3-dimethyl propyl, hexyl, 2,3-dimethyl hexyl, 1,1-dimethyl amyl group, heptyl and octyl group.Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl group.

Alkyl can by 1,2,3 or a plurality of substituent group that is independently selected from following groups replace: halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, alkoxyl, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy group, aralkoxy, heterocyclic radical and (heterocyclic radical) oxygen base.Concrete example comprises methyl fluoride, ethoxy, 2,3-dihydroxy ethyl, (2-or 3-furyl) methyl, cyclopropyl methyl, benzyloxy ethyl, (3-pyridine radicals) methyl, (2-or 3-furyl) methyl, (2-thienyl) ethyl, hydroxypropyl, aminocyclohexyl, 2-dimethylamino butyl, methoxy, N-pyridine radicals ethyl, diethylamino ethyl and cyclobutylmethyl.

Alkenyl and alkyls seemingly, different is has at least one two key (two adjacent sp ²Carbon atom).According to the position and the substituent group of two keys, if possible, the geometric configuration of two keys can be E or Z, cis or trans.Similarly, alkynyl group has at least one triple bond (two adjacent sp carbon atoms).Unsaturated chain thiazolinyl or alkynyl group can have one or more pairs of keys or triple bond or its mixture respectively; The same with alkyl, unsaturated group can be a straight or branched, and they can be as above to alkyl described and as give an example in the text those be substituted.Alkenyl, alkynyl group and its example that replaces form comprise suitable-crotyl, anti--crotyl, 3-butynyl, 3-phenyl-2-propynyl, 3-(2 '-fluorophenyl)-2-propynyl, 3-methyl-(5-phenyl)-4-pentynyl, 2-hydroxyl-2-propynyl, 2-methyl-2-propynyl, 2-acrylic, 4-hydroxyl-3-butynyl, 3-(3-fluorophenyl)-2-propynyl and 2-methyl-2-acrylic.In formula (I), alkenyl and alkynyl group can be C for example _2-4Or C _2-8, preferred C _3-4Or C _3-8

Substituted hydrocarbon radical form more generally comprise hydroxy alkyl, hydroxyl alkenyl, hydroxyl alkynyl group, hydroxyl cycloalkyl, hydroxyaryl and have amino-, halo-(for example fluoro-, chloro-or bromo-), nitro-, alkyl-, phenyl-and cycloalkyl-etc. the corresponding group of prefix, perhaps substituent combining form.Therefore, according to formula (I), the alkyl of replacement comprises hydroxy alkyl, aminoalkyl, 4-nitro alkyl, haloalkyl, alkyl-alkyl (branched alkyl, for example methyl amyl), (cycloalkyl) alkyl, phenylalkyl, alkoxyl, alkyl amino alkyl, dialkyl aminoalkyl, aryl alkyl, aryloxyalkyl group, sweet-smelling alkoxy alkyl, (heterocyclic radical) alkyl and (heterocyclic radical) oxyalkyl.So R ₁Comprise hydroxy alkyl, hydroxyl alkenyl, hydroxyl alkynyl group, hydroxyl cycloalkyl, hydroxyaryl, aminoalkyl, amino alkenyl, amino alkynyl group, amino cycloalkyl, aminoaryl, alkyl chain thiazolinyl, (alkylaryl) alkyl, (halogenated aryl) alkyl and (hydroxyaryl) alkynyl group etc.Similarly, R _AComprise hydroxy alkyl and aminoaryl, and R _BComprise hydroxy alkyl, aminoalkyl and hydroxy alkyl (heterocyclic radical) alkyl.

Heterocyclic radical comprises furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, pyrrole radicals, imidazole radicals, 1,3 including, but not limited to heteroaryl, 4-triazolyl, tetrazole radical, pyridine radicals, pyrimidine radicals, pyridazinyl, indyl and non-aromatics homologue thereof.Other examples of heterocyclic radical comprise that piperidyl, quinolyl, isothiazolyl, piperidyl, morpholinyl, piperazinyl, tetrahydrofuran base, nafoxidine base, pyrrolidinyl, octahydro indyl, octahydro benzimidazole thiophanate are for furyl and octahydro benzofuranyl.

Selectivity MEK 1 or MEK inhibitor 2 are to suppress MEK 1 or MEK 2 enzymes respectively and do not suppress for example chemical compound of MKK3, PKC, Cdk2A, phosphorylase kinase, EGF and pdgf receptor kinase and C-src of other enzymes basically.Usually, selectivity MEK 1 or MEK inhibitor 2 are to the IC of MEK 1 or MEK 2 ₅₀Value is the IC to above-mentioned a kind of other enzymes ₅₀At least 1/50 of value.Preferably, the IC of selective depressant ₅₀Value is the IC of one or more above-mentioned enzymes ₅₀At least 1/100, more preferably 1/500 of value, even more preferably 1/1000,1/5000 is perhaps less than the IC of one or more above-mentioned enzymes ₅₀Value.B. chemical compound

One aspect of the present invention provides the purposes of general introduction one joint Chinese style (I) chemical compound.The specific embodiment of the present invention comprises formula (I) chemical compound, and wherein: (a) Q is formula (i); (b) R ₃Be H or fluorine (c) R ₄Be fluorine, chlorine or bromine; (d) R ₁₀Be H, methyl, fluorine or chlorine; (e) R ₁₁Be methyl, chlorine, fluorine, nitro or hydrogen; (f) R ₁₁Be H; (g) R ₁₁It is fluorine; (h) R ₁₀And R ₁₁In each be fluorine; (i) R ₁Be H, methyl, ethyl, propyl group, isopropyl, isobutyl group, benzyl, phenethyl, pi-allyl, C _3-5Alkenyl, C _3-6Cycloalkyl, (C _3-5Cycloalkyl) C _1-2Alkyl, (C _3-5Heterocyclic radical) C _1-2Alkyl or (CH ₂) _2-4NR _CR _D(j) R ₁Be H or (C _3-4Cycloalkyl) C _1-2Alkyl; (k) R ₂Be H or methyl; (1) R _AHas at least one hydroxyl substituent; (m) R _ABe H, methyl, ethyl, isobutyl group, hydroxyethyl, phenyl, 2-piperidines-1-base-ethyl, 2,3-dihydroxy-propyl group, 3-[4-(2-hydroxyethyl)-piperazine-1-yl]-propyl group, 2-pyrrolidine-1-base-ethyl or 2-diethylamino-ethyl; And R _RBe H; Perhaps R wherein _BBe methyl and R _AIt is phenyl; (n) W is NR _AR _BOr NR ₂NR _AR _B(o) W is NR ₂(CH ₂) _2-4NR _AR _BOr O (CH ₂) _2-3NR _AR _B(P) W is NR ₂OR ₁(q) W is OR ₁(r) Z be formula (v); Perhaps (s) X ₁Be NR ₈, and R ₇Be H; Perhaps (t) its combination.In formula (I), the value of Z represents that from left to right perhaps the benzyl ring around Q counterclockwise calculates.

According to one aspect of the present invention, formula (I) chemical compound has following structure, and wherein: Q is a formula (i) or (ii); R ₃Be H or fluorine; R ₄Be fluorine, chlorine or bromine; R ₁₀Be H, methyl or chlorine; R ₁₁Be chlorine, fluorine or hydrogen; R ₁Be H, methyl, ethyl, propyl group, isopropyl, isobutyl group, benzyl, phenethyl, pi-allyl, C _3-5Alkenyl, C _3-6Cycloalkyl, (C _3-5Cycloalkyl) C _1-2Alkyl, (C _3-5Heterocyclic radical) C _1-2Alkyl or (CH ₂) _2-4NR _CR _DR ₁Be H or (C _3-4Cycloalkyl) C _1-2Alkyl; R ₂Be H or methyl; And Z be formula (v) or (vi).A specific embodiments of this aspect is X ₁Be NR ₈An example is 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1-[(2 ＇-morpholinyl)-ethyl] 2-(phenyl)-benzimidazole-5-formic acid cyclo propyl methoxy-amide.

A specific embodiments of the present invention also comprises wherein R ₁₀Be H; R ₁₀Be methyl or chlorine; And R wherein ₁₀It is the chemical compound of chlorine.In some specific embodiments, R ₇And R ₈Be no more than 14 carbon atoms together,-+except R _L, R _M, R _JAnd R _KOutside.The example comprises wherein R ₇And R ₈Have together and be no more than 13 carbon atoms; Be no more than 7,8 or 10 carbon atoms; 4-8 carbon atom; 1-10 carbon atom; 1-8 carbon atom and be no more than the chemical compound of 6 carbon atoms.

Preferably, R wherein ₁, R ₂, R _A, R _B, R _C, R _D, R _E, R _F, R _I, X _J, R _K, R _L, R _M, R _G, R _H, R _N, R _OAnd R _PIn one be alkenyl or alkynyl group, its pair key or triple bond are not adjacent with junction point separately.For example, wherein W is NR ₂OR ₁, R ₂Be preferably Propargyl or fourth-2 or 3-thiazolinyl, and not preferred third-1-alkynyl or but-1-ene base.

List some below and can utilize

reaction scheme

1,2,10 and 11 synthetic preferred construction.Free acid, free hydroxamic acid and hydroxamic acid cyclopropyl methyl ester are divided into same group.For example, chemical compound 1,11 with 21 only be " W " different (such as in claims definition); Chemical compound 2,12 and 22 is similar relevant.Preferred chemical compound also comprises 2-chlorine (the replacing the 2-methyl) analog of listed chemical compound.

Examples for compounds comprises: 7-fluoro-6-(4-iodo-2-aminomethyl phenyl amino)-1H-benzimidazole-5-formic acid (APK IC ₅₀=47 ± 17nM); 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzothiazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] oxadiazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-2-(2-hydroxyethyl)-1H-benzimidazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-2-(2-dimethylamino-ethyl)-1H-benzimidazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1-acetyl group-benzimidazole-5-formic acid; 8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-5-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzothiazole-5-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino) benzo [1,2,5] oxadiazoles-5-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-2-(2-hydroxyethyl)-1H-benzimidazole-5-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-2-(2-dimethylamino-ethyl)-1H-benzimidazole-5-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1-acetyl group-benzimidazole-5-formic acid hydroxy amide; 8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid hydroxy amide; 7-fluoro-6-(4-iodo-2-aminomethyl phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-5-formic acid cyclo propyl methoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzothiazole-5-formic acid cyclo propyl methoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid cyclo propyl methoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] oxadiazoles-5-formic acid cyclo propyl methoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-2-(2-hydroxyethyl)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-2-(2-dimethylamino-ethyl)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1-acetyl group-benzimidazole-5-formic acid cyclo propyl methoxy amide; 8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid cyclo propyl methoxy-amide; With 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid cyclo propyl methoxy-amide.

Listed the embodiment that represents reaction scheme 3-9 below.As mentioned above, free acid, free hydroxamic acid and hydroxamic acid cyclopropyl methyl ester are divided into same group.For example, chemical compound 31,45 with 59 only be " W " different (such as in claims definition); Chemical compound 32,46 and 60 is similar relevant.Preferred chemical compound also comprises 2-chlorine (the replacing the 2-methyl) analog of listed chemical compound.

Reaction scheme 3-9 examples for compounds comprises: 4-fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzothiazole-6-formic acid; 4-fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-6-formic acid; 5-(2-chloro-4-iodo-phenyl amino)-6,7-two fluoro-3H-benzimidazole-4-formic acid; 6,7-two fluoro-2-(2-hydroxyl-ethyl)-5-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-4-formic acid; 6,7-two fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzoxazole-4-formic acid; 6,7-two fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzothiazole-4-formic acid; 7,8-two fluoro-6-(4-iodo-2-methyl-phenyl amino)-quinoxaline-5-formic acid; 6-(4-iodo-2-aminomethyl phenyl amino)-8-nitro-quinoxaline-5-formic acid; 5-(4-iodo-2-methyl-phenyl amino)-8-nitro-quinoxaline-6-formic acid; 8-chloro-5-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid; 3-cyclopropyl-7-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-4,6-dioctyl phthalate 4-dimethylformamide; 7-bromo-4-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-5-formic acid; 7-(2-chloro-4-iodo-phenyl amino)-4-fluoro-benzothiazole-6-formic acid; 7-(4-iodo-2-methyl-phenyl amino)-4-nitro-benzoxazoles-6-formic acid; 4-fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzothiazole-6-formic acid hydroxy amide; 4-fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-6-formic acid hydroxy amide; 5-(2-chloro-4-iodophenyl amino)-6,7-two fluoro-3H-benzimidazoles-4-formic acid hydroxy amide; 6,7-two fluoro-2-(2-hydroxyl-ethyl)-5-(4-iodo-2-aminomethyl phenyl amino)-3H-benzimidazole-4-formic acid hydroxy amide; 6,7-two fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzoxazole-4-formic acid hydroxy amide; 6,7-two fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzothiazole-4-formic acid hydroxy amide; 7,8-two fluoro-6-(4-iodo-2-methyl-phenyl amino) quinoxaline-5-formic acid hydroxy amide; 6-(4-iodo-2-aminomethyl phenyl amino)-8-nitro-quinoxaline-5-formic acid hydroxy amide; 5-(4-iodo-2-methyl-phenyl amino)-8-nitro-quinoxaline-6-formic acid hydroxy amide; 8-chloro-5-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid hydroxy amide; 3-cyclopropyl-7-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-4,6-dioctyl phthalate 4-dimethylformamide 6-hydroxy amide; 7-bromo-4-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-5-formic acid hydroxy amide; 7-(2-chloro-4-iodo-phenyl amino)-4-fluoro-benzothiazole-6-formic acid hydroxy amide; 7-(4-iodo-2-methyl-phenyl amino)-4-nitro-benzoxazoles-6-formic acid hydroxy amide; 4-fluoro-5-(4-iodo-2-aminomethyl phenyl amino)-benzothiazole-6-formic acid cyclo propyl methoxy-amide; 4-fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-6-formic acid cyclo propyl methoxy-amide; 5-(2-chloro-4-iodo-phenyl amino)-6,7-two fluoro-3H-benzimidazoles-4-formic acid cyclo propyl methoxy-amide; 6,7-two fluoro-2-(2-hydroxyl-ethyl)-5-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-4-formic acid cyclo propyl methoxy-amide; 6,7-two fluoro-5-(4-iodo-2-aminomethyl phenyl amino)-benzoxazole-4-formic acid cyclo propyl methoxy-amide; 6,7-two fluoro-5-(4-iodo-2-methyl-phenyl amino)-benzothiazole-4-formic acid cyclo propyl methoxy-amide; 7,8-two fluoro-6-(4-iodo-2-methyl-phenyl amino) quinoxaline-5-formic acid cyclo propyl methoxy-amide; 6-(4-iodo-2-methyl-phenyl amino)-8-nitro-quinoxaline-5-formic acid cyclo propyl methoxy amide; 5-(4-iodo-2-methyl-phenyl amino)-8-nitro-quinoxaline-6-formic acid cyclo propyl methoxy-amide; 8-chloro-5-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid cyclo propyl methoxy-amide; 3-cyclopropyl-7-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-4,6-dioctyl phthalate 4-dimethylformamide cyclo propyl methoxy-amide; 7-bromo-4-(4-iodo-2-aminomethyl phenyl amino)-benzoxazoles-5-formic acid cyclo propyl methoxy-amide; 7-(2-chloro-4-iodo-phenyl amino)-4-fluoro-benzothiazole-6-formic acid cyclo propyl methoxy-amide; And 7-(4-iodo-2-methyl-phenyl amino)-4-nitro-benzoxazoles-6-formic acid cyclo propyl methoxy-amide.C. synthetic

Can be according to the synthetic disclosed chemical compound of the form of following 7 kinds of reaction scheme or its variation.To further illustrate among these synthesis strategies embodiment 1-22 below.

Reaction scheme 1

Reaction scheme 2

Reaction scheme 3

Reaction scheme 4

Reaction scheme 5

Reaction scheme 6

Reaction scheme 7

Reaction scheme 8

Reaction scheme 9

Reaction scheme 10

Reaction scheme 11 D. purposes

As summarize described in the joint, disclosed compositions is applicable to and comprises neuropathic pain diseases associated or disease with chronic pain and by the disease of MEK cascade control or the prevention and the therapeutic treatment of disease.For example, in a specific embodiments, disclosed method relates to postoperative pain, phantom limb pain, causalgia, gout, trigeminal neuralgia, acute herpes and herpes zoster and infects back pain, diabetic neuropathy, blood vessel, neural from avulsion, neuroma, nodular vasculitis, crush injury, constriction injury, tissue injury, postoperative pain, arthritis ache or amputation.

For example, local damage can pass through topical treatment.Chronic pain influences whole health, and for example diabetic neuropathy can be treated by (injection or oral) the disclosed compositions that is administered systemically.Can be to the treatment of lower body part chronic pain (for example postoperative pain) through central administration, epidural administration for example.Preparation and medication can comprise the mek inhibitor that uses more than one, and perhaps for example anti-inflammatory agent, analgesic, muscle relaxant or anti-infective are used in combination with mek inhibitor and other drug.Preferred route of administration is in per os, the sheath or epidural, subcutaneous, intravenous, intramuscular administration, and for administration in the non-human mammal vola, preferred epidural administration.

1. dosage

According to known method, consider the factors such as existence of age for example, body weight, health status, the types of pain that needs treatment and other drug treatment, this area professional can determine the suitable dosage used to the patient.Usually, effective dose is 0.1-1000mg/kg/ days, preferred 1-300mg/kg body weight, and for the adult patients of normal type, daily dose is 10-5000mg.According to disclosed method, can use commercially available capsule or other preparations (for example liquid and film-coated tablets) of 100mg, 200mg, 300mg or 400mg.

2. preparation

Unit dosage forms comprises tablet, capsule, piller, powder, granule, water and non-mouth of a river clothes solution and suspension and non-intestinal solution, and they are packaged in the container that can be further divided into single dosage.Unit dosage forms also can be used for various medications, comprises for example hypodermic implant of controlled release preparation.That medication comprises is oral, in the rectum, non-intestinal (intravenous, intramuscular, subcutaneous), brain pond, intravaginal, intraperitoneal, intravesical, part (drop, powder, ointment, gel or emulsifiable paste) and suck (cheek or nose spraying).

Parenteral formulation comprises the sterilized powder of pharmaceutically acceptable water or non-aqueous solution, dispersion, suspension, emulsion and these preparations of preparation.The example of carrier comprises for example ethyl oleate of water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol), vegetable oil and injectable organic ester.Can use coating for example lecithin, surfactant maintenance flowability, perhaps keep suitable granularity.The carrier of solid dosage forms comprises (a) filler or extender, (b) binding agent, (c) wetting agent, (d) disintegrating agent, (e) solution blocker, (f) absorption enhancer, (g) adsorbent (adsorbants), (h) lubricant, (i) buffer agent and (j) propellant.

Compositions can also contain adjuvant for example antiseptic, wetting agent, emulsifying agent and dispersant; Antibacterial is p-Hydroxybenzoate, methaform, phenol and sorbic acid for example; Isotonic agent is sugar or sodium chloride for example; The absorption delay agent is aluminum monostearate and gelatin for example; And absorption enhancer.

3. relevant chemical compound

The invention provides disclosed chemical compound and with the closely-related pharmaceutically acceptable form of disclosed chemical compound, for example salt, ester, amide, hydrate or its solvate; That shelter or protect form; And racemic mixture, or enantiomer-pure or optically pure form.

Officinal salt, ester and amide comprise carboxylate (C for example _1-8Alkyl, cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclic), amino acid addition salt, ester and amide, they have reasonably useful/dangerous than, drug effectiveness, and be suitable for contacting and do not have unsuitable toxicity, zest or an atopic reaction with patient tissue.Typical salt comprises hydrobromate, hydrochlorate, sulfate, disulfate, nitrate, acetate, oxalates, valerate, oleate, palmitate, stearate, laruate, borate, benzoate, lactate, phosphate, toluene fulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, gluceptate, lactiobionate and lauryl sulfonate.These salt comprise alkali metal and alkaline earth metal cation for example sodium, potassium, calcium and magnesium, and nontoxic ammonium, quaternary ammonium and amine cation for example tetramethyl-ammonium, methylamine, trimethylamine and ethamine.Referring to for example S.M.Berge etc., " Pharmaceutical Salts, " J.Pharm.Sci., 1977,66:1-19, the document is combined in herein as a reference.The typical pharmaceutically acceptable amide of the present invention comprises derived from ammonia, uncle C _1-6Alkylamine and secondary two (C _1-6Alkyl) amide of amine.Secondary amine comprises that containing at least one nitrogen-atoms comprises 1-2 other heteroatomic 5-or 6-unit's heterocycle or hetero-aromatic ring part with choosing wantonly.Preferred amide is derived from ammonia, C _1-3Kiber alkyl amine and two (C _1-2Alkyl) amine.Typical pharmaceutically acceptable ester of the present invention comprises C _1-7Alkyl, C _5-7Cycloalkyl, phenyl and phenyl (C _1-6) Arrcostab.Preferred ester comprises methyl ester.

The present invention also comprises the disclosed chemical compound of the functional group's (for example hydroxyl, amino or carboxyl) that has one or more protected bases and shelter.Some of them chemical compound masked or protection is pharmaceutically useful; To be suitable for of other as intermediate.Synthetic intermediate disclosed herein and method and less change thereof are also included within the scope of the invention.Hydroxyl protecting group

Hydroxyl protecting group comprises: ether, ester are used to protect 1,2-and 1, the group of 3-glycol.The ether protecting group comprises: the benzylic ether of the methyl ether of methyl, replacement, the ethylether of replacement, replacement, silyl ether and silyl ether is converted into other functional groups.

The methyl ether that replaces

The methyl ether that replaces comprises: methoxy, methylthiomethyl, uncle's butylthio methyl, (phenyl dimetylsilyl) methoxy, benzyloxymethyl, to ethyoxyl benzyloxy ylmethyl, (4-methoxyl group phenoxy group) methyl, the guaiacol methyl, the tert-butoxy methyl, 4-amylene oxygen ylmethyl, the siloxy methyl, 2-methoxy ethoxy methyl, 2,2,2-trichlorine ethoxyl methyl, two (2-chloro-ethyoxyl) methyl, 2-(trimethyl silyl) ethoxyl methyl, THP trtrahydropyranyl, 3-bromine tetrahydrochysene-pyranose, tetrahydro thiapyran base, 1-methoxyl group cyclohexyl, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, 4-methoxyl group tetrahydro thiapyran base, S, S-dioxy base, 1-[(2-chloro-4-methyl) phenyl]-4-methoxyl group piperidin-4-yl, 1,4-dioxane-2-base, tetrahydrofuran base, tetrahydro-thienyl (thiofuranyl) and 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4, the 7-ethanobenzofuran-2-base.

The ethylether that replaces

The ethylether that replaces comprises: 1-ethoxyethyl group, 1-(2-chloroethoxy) ethyl, 1-methyl isophthalic acid-methoxy ethyl, 1-methyl isophthalic acid-benzyloxy ethyl, 1-methyl isophthalic acid-benzyloxy-2-fluoro ethyl, 2,2,2-three chloroethyls, 2-trimethyl silyl ethyl, 2-(phenyl selenyl) ethyl, the tert-butyl group, pi-allyl, rubigan, p-methoxyphenyl, 2,4-dinitrophenyl and benzyl.

The benzylic ether that replaces

The benzylic ether that replaces comprises: to methoxy-benzyl, 3, the 4-dimethoxy-benzyl, adjacent nitrobenzyl, to nitrobenzyl, to halogeno-benzyl, 2, the 6-dichloro benzyl, to the cyano group benzyl, to phenylbenzyl, 2-and 4-picolyl, 3-methyl-2-picolyl N oxygen, diphenyl methyl, p, p '-dinitro benzhydryl, 5-dibenzo suberyl, trityl group, Alpha-Naphthyl diphenyl-methyl, the p-methoxyphenyl diphenyl methyl, two (p-methoxyphenyl) phenyl methyl, three-(p-methoxyphenyl) methyl, 4-(4 '-bromobenzene acetoxyl group) phenyl diphenyl methyl, 4,4 ', 4 " three (4; 5-dichloro phthalimido phenyl) methyl; 4; 4 '; 4 "-three (levulinic acyl-oxygen phenyl) methyl, 4,4 ', 4 " three (benzoyl oxygen phenyl) methyl; 3-imidazoles-1-ylmethyl) two (4 '; 4 "-Dimethoxyphenyl)-methyl, 1,1-two (4-methoxyphenyl)-1 '-pyrenyl methyl, the 9-anthryl, 9-(9-phenyl) xanthyl, 9-(9-phenyl-10-oxo) anthryl, 1,3-benzo dithiolane-2-base and benzisothiazole base S, S-dioxy base.

Silyl ether

Silyl ether comprises: trimethyl silyl, triethylsilyl, triisopropyl silicyl, dimethyl isopropyl silicyl, diethyl isopropyl silicyl, dimethyl hexyl silicyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzyl silicyl, three xylol base silicyls, triphenyl silicyl, diphenyl methyl silicyl and tert-butyl group methoxyphenyl silicyl.Ester

The ester protecting group comprises: ester, carbonic ester help cracked ester, mixed ester and sulphonic acid ester.

Ester

The example of the ester of protection comprises: fumarate; the benzoyl fumarate; acetas; chloracetate; the dichloroacetic acid ester; trichloroacetic esters; trifluoro-acetate; the 2-Methoxyacetic acid ester; triphenyl 2-Methoxyacetic acid ester; the phenoxyacetic acid ester; acid tomatotone ester; to P-phenylacetic acid ester; 3-phenylpropionic acid ester; 4-oxopentanoie acid salt (levulinate); 4; 4-(ethylene sulfur) valerate; pivalate; adamantate; crotonates; 4-methoxyl group crotonates; benzoate; to phenylbenzoate and 2; 4,6-trimethylbenzoic acid ester (a trimethylbenzoic acid ester).

Carbonic ester

Carbonic ester comprises: methyl, 9-fluorenyl methyl, ethyl, 2; 2; 2-three chloroethyls; 2-(trimethyl silyl) ethyl, 2-(phenyl sulfonyl) ethyl, 2-(triphenyl phosphorio) ethyl, isobutyl group, vinyl, pi-allyl, p-nitrophenyl, benzyl, to methoxy-benzyl, 3,4-dimethoxy-benzyl, adjacent nitrobenzyl, to nitrobenzyl, S-benzyl sulfocarbonate, 4-ethyoxyl-1-naphthyl and methyl dithiocarbonates.

Help cracked ester

Help the example of cracked protecting group to comprise: 2-iodo-benzoic acid ester, 4-azido-butyrate, 4-nitro-4-methyl valerate, neighbour-(two bromomethyls) benzoate, 2-formoxyl benzene sulfonate, 2-(methyl mercapto methoxyl group) ethyl carbonate ester, 4-(methyl mercapto methoxy) benzoate and 2-(methyl mercapto methoxy) benzoate.

Mixed ester

Except above-mentioned all kinds of esters, mixed ester comprises: 2,6-two chloro-4-methylenedioxy phenoxy yl acetates, 2,6-two chloro-4-(1,1,3, the 3-tetramethyl butyl) phenoxyacetic acid ester, 2,4-two (1, the 1-dimethyl propyl) phenoxyacetic acid ester, the chlorodiphenyl yl acetate, isobutyrate, the monosuccinic acid ester, (E)-2-methyl-2-butene acid esters (methyl butene acid esters), neighbour-(methoxycarbonyl group) benzoate, right-the P-benzoate, the α-Nai Jiasuan ester, nitrate, N, N, N ', N '-tetramethyl phosphorodiamidate, the N-carbanilate, borate, dimethyl disulfide phosphino-ester and 2,4-dinitrophenyl sulfenic acids ester.

Sulphonic acid ester

The sulfuric ester of protection comprises: sulfuric ester, methanesulfonates, benzyl sulphonic acid ester and tosylate.The group of protection 1.2-and 1.3-glycol

Protection 1,2-and 1, the group of 3-glycol comprises: ring acetal and ketal, cyclic orthoesters and silicyl derivant.

Ring acetal and ketal

Ring acetal and ketal comprise: methylene, ethylidene, 1-tert-butyl group ethylidene, 1-phenyl ethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-three chlorethylidenes, acetonide (isopropylidene), ring pentylidene, cyclohexylene, the inferior heptyl of ring, benzal, to methoxyl group benzal, 2,4-dimethoxybenzylidenegroup group, 3,4-dimethoxybenzylidenegroup group and 2-nitro benzal.

Cyclic orthoesters

Cyclic orthoesters comprises: methoxyl group methylene, ethyoxyl methylene, dimethoxy methylene, 1-methoxyl group ethylidene, 1-ethyoxyl ethylidene, 1,2-dimethoxy ethylidene, α-methoxyl group benzal, 1-(N, the N-dimethylamino) ethidene derivant, α-(N, N-dimethylamino) benzylidene derivatives and 2-oxa-ring pentylidene.Carboxyl-protecting group

Ester

The ester protecting group comprises: the ethyl ester that the methyl ester of ester, replacement, 2-replace, benzyl ester, silyl ester, Acibenzolar, mixed derivative and the stannyl ester of replacement.

The methyl ester that replaces

The methyl ester that replaces comprises: 9-fluorenyl methyl, methoxy, methylthiomethyl, THP trtrahydropyranyl, tetrahydrofuran base, methoxy ethoxy methyl, 2-(trimethyl silyl) ethyoxyl-methyl, benzyloxymethyl, phenacyl, to bromobenzene formyl methyl, Alpha-Methyl phenacyl, to methoxybenzoyl methyl, formamido group methyl and N-phthalimido methyl.

The ethyl ester that 2-replaces

The ethyl ester that 2-replaces comprises: 2,2,2-three chloroethyls, the 2-halogenated ethyl, the alpha-chloro alkyl, 2-(trimethyl silyl) ethyl, 2-methylmercaptoethyl, 1,3-dithiane base-2-methyl, 2-(p-nitrophenyl sulfenyl)-ethyl, 2-(tolysulfonyl) ethyl, 2-(2 '-pyridine radicals) ethyl, 2-(diphenylphosphino) ethyl, 1-methyl isophthalic acid-phenylethyl, the tert-butyl group, cyclopenta, cyclohexyl, pi-allyl, 3-butene-1-Ji, 4-(trimethyl silyl)-2-butyl-1-base, cinnamyl, the Alpha-Methyl cinnamyl, phenyl, to (methyl mercapto)-phenyl and benzyl.

The benzyl ester that replaces

The benzyl ester that replaces comprises: trityl group, diphenyl methyl, two (ortho-nitrophenyl base) methyl, 9-anthryl methyl, 2-(9; the 10-dioxo) anthryl methyl, 5-dibenzo suberyl, 1-pyrenyl methyl, 2-(the trifluoromethyl)-chromyl methyl of 6-, 2; 4; the 6-trimethyl benzyl, to bromobenzyl, adjacent nitrobenzyl, to nitrobenzyl, to methoxy-benzyl, 2,6-dimethoxy-benzyl, 4-(methylsulfinyl) benzyl, 4-sulfur benzyl, piperonyl and 4-P-benzyl.

Silyl ester

Silyl ester comprises: trimethyl silyl, triethylsilyl, t-butyldimethylsilyl, isopropyl dimetylsilyl, phenyl dimetylsilyl and di-t-butyl methyl silicane base.

Mixed derivative

Mixed derivative comprises: oxazole, 2-alkyl-1,3-oxazoline, 4-alkyl-5-oxo-1,3-oxazolidine, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl and pentaamino cobalt (III) coordination compound.

The stannyl ester

The example of stannyl ester comprises: triethyl group stannyl and three normal-butyl stannyls.Amide and hydrazides

Amide comprises: N, N-dimethyl, pyrrolidinyl, piperidyl, 5,6-dihydro phenanthridinyl, adjacent nitro N-anilide, N-7-nitroindoline base, N-8-nitro-1,2,3,4-tetrahydric quinoline group and right-P-benzsulfamide.Hydrazides comprises: N-phenyl, N, N '-diisopropyl and other two-alkyl hydrazides.The amino protecting group carbamate

Carbamate comprises: the ethyl of carbamate, replacement, help cracked group, photodestruciton group, carbamide derivative and mixed amino formic acid esters.

Carbamate

Carbamate comprises: methyl and ethyl, 9-fluorenyl methyl, 9-(2-sulfur) fluorenyl methyl, 9-(2, the 7-dibromo) fluorenyl methyl, 2, the 7-di-t-butyl-[9-(10,10-dioxy-10,10,10,10-tetrahydrochysene-thioxanthene base (thioxanthyl))] methyl and 4-methoxybenzoyl methyl.

The ethyl that replaces

The ethyl protecting group that replaces comprises: 2; 2; 2-three chloroethyls; 2-trimethyl silyl ethyl; the 2-phenylethyl; 1-(1-adamantyl)-1-Methylethyl; 1; 1-dimethyl-2-halogenated ethyl; 1; 1-dimethyl-2; 2-two bromoethyls; 2-three chloroethyls; 1-methyl isophthalic acid-(4-xenyl) ethyl; 1-(3; the 5-di-tert-butyl-phenyl)-the 1-Methylethyl; 2-(2 '-and 4 '-pyridine radicals) ethyl; 2-(N; N-ring (icyclo) hexyl formamido group)-ethyl; the tert-butyl group; the 1-adamantyl; vinyl; pi-allyl; 1-isopropyl pi-allyl; cinnamyl (connamyl); 4-nitro cinnamyl; quinolyl; N-hydroxy piperidine base; the alkyl disulfide group; benzyl; to methoxy-benzyl; to nitrobenzyl; to bromobenzyl; p-chlorobenzyl; 2,4 dichloro benzyls; 4-methyl sulfinyl benzyl; 9-anthryl methyl and diphenyl methyl.

Help cracked group

Comprise by the group that helps the cracking protection: 2-methylmercaptoethyl, 2-methyl sulphonyl ethyl, 2-(p-toluenesulfonyl) ethyl, [2-(1; 3-dithiane base)] methyl, 4-methylthiophene base, 2; 4-dimethyl-thienyl, 2-phosphorio ethyl, 2-triphenyl phosphorio isopropyl, 1,1-dimethyl-2 cyano ethyl, a chloro-be right-acyloxy benzyl, to (dihydroxy boryl) benzyl, 5-benzoisoxazole base-methyl and 2-(trifluoromethyl)-6-chromone ylmethyl.

Photodestruciton

The group that the photodestruciton method is used for example is: m-nitro base, 3,5-dimethoxy-benzyl, adjacent nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl and phenyl (ortho-nitrophenyl base) methyl.

Carbamide derivative

The example of carbamide derivative comprises: phenothiazinyl-(10)-carbonyl derivative, N '-tolysulfonyl amino carbonyl and N '-phenyl amino thiocarbonyl.

The mixed amino formic acid esters

Except that above-mentioned group, the mixed amino formic acid esters comprises: tertiary pentyl, S-benzyl thiocarbamate, to the cyano group benzyl, cyclobutyl, cyclohexyl, cyclopenta, the cyclopropyl methyl, to oxygen base-benzyl in the last of the ten Heavenly stems, the diisopropyl methyl, 2,2-dimethoxy carbonyl ethenyl, neighbour-(N, N-dimethyl-formamido group)-benzyl, 1,1-dimethyl-3-(N, N-dimethylformamide base) propyl group, 1,1-dimethyl-propinyl, two (2-pyridine radicals) methyl, the 2-furyl methyl, 2-iodine ethyl, isobornyl, isobutyl group, different nicotinoyl (isonicotinyl), right-(p '-methoxyphenyl-azo) benzyl, 1-methyl cyclobutyl, the 1-methylcyclohexyl, 1-methyl isophthalic acid-cyclopropyl-methyl, 1-methyl-(3, the 5-Dimethoxyphenyl) ethyl, 1-methyl isophthalic acid-(right-the henyl azobenzene)-ethyl, 1-methyl isophthalic acid-phenylethyl, 1-methyl isophthalic acid-(4-pyridine radicals) ethyl, phenyl, to (phenylazo) benzyl, 2,4,6-tri-tert phenyl, 4-(trimethyl ammonium) benzyl and 2,4, the 6-trimethyl benzyl.Amide

Amide

Amide comprises: N-formoxyl, N-acetyl group, N-chloracetyl, N-tribromo-acetyl base, N-TFA base, N-phenyl acetyl, N-3-phenyl propiono, N-pyridine formoxyl (picolinoyl), N-pyridine radicals-Methanamide, N-benzoyl phenyl alanyl derivant, N-benzoyl and N-are to the phenyl benzoyl.

Help cracked group

Help cracked group to comprise: N-ortho-nitrophenyl base acetyl group; N-ortho-nitrophenyl oxygen base acetyl group; the N-acetoacetyl; (N '-two sulfur benzyloxycarbonyl amino) acetyl group; N-3-(p-hydroxybenzene) propiono; N-3-(ortho-nitrophenyl base) propiono; N-2-methyl-2-(ortho-nitrophenyl oxygen base) propiono; N-2-methyl-2-(adjacent phenylazo phenoxy group) propiono; the N-4-chlorobutyryl; N-3-methyl-3-nitro bytyry; the adjacent nitro cinnamoyl of N-; N-acetyl group methionine derivant; the N-o-nitrobenzoyl; N-neighbour's (benzoyloxy methyl) benzoyl and 4,5-diphenyl-3-oxazoline-2-ketone.

The epimino derivant

The epimino derivant comprises: N phlhalimide, N-dithia succinyl group, N-2; 3-diphenyl-maleoyl, N-2,5-dimethyl pyrrole, N-1,1,4; 1 of 4-tetramethyl dimethyl silanyl aza-cyclopentane adduct, 5-replacement; 3-dimethyl-1,3,1 of 5-Trianacyclohexane-2-ketone, 5-replacement; 3-dibenzyl-1; 3,3 of 5-Trianacyclohexane-2-ketone and 1-replacement, 5-dinitro-4-hydroxy-pyridyl.Special-the NH protecting group

-NH protecting group comprises: N-alkyl and N-arylamine, imine derivative, enamine derivates and N-hetero atom derivant (for example N-metal, N-N, N-P, N-Si and N-S), N-sulfinyl and N-sulfonyl.

N-alkyl and N-arylamine

N-alkyl and N-arylamine comprise: N-methyl, N-pi-allyl, N-[2-(trimethyl silyl) ethyoxyl]-methyl, N-3-acetoxyl group propyl group, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salt, N-benzyl, N-two (4-methoxyphenyl) methyl, N-5-dibenzo suberyl, N-trityl group, N-(4-methoxyphenyl) diphenyl methyl, N-9-phenyl fluorenyl, N-2,7-two chloro-9-fluorenyl methylene, N-ferrocenyl methyl and N-2-picolyl amine N '-oxide.

Imine derivative

Imine derivative comprises: N-1,1-dimethyl sulfide methylene, N-benzal, N-are to methoxyl group benzal, N-diphenyl methylene, N-[(2-pyridine radicals) base] methylene, N-(N ', N '-dimethylamino methylene), N, N '-isopropylidene, N-are to nitro benzal, N-salicylidene, N-5-chlorine salicylidene, N-(5-chloro-2-hydroxy phenyl) phenylmethylene and N-cyclohexylene.

Enamine derivates

The example of enamine derivates is N-(5,5-dimethyl-3-oxo-1-cyclohexenyl group).

N-hetero atom derivant

The N-metal derivative comprises: N-borane derivative, N-diphenyl boric acid (borinic acid) derivant, N-[phenyl (pentacarbonyl chromium-or-tungsten)] and N-copper or N-chelates of zinc.The example of N-N derivant comprises: N-nitro, N-nitroso-group and N-oxide.The example of N-P derivant comprises: N-two phenenyl phosphinyl, N-diformazan sulfenyl phosphinyl, N-diphenyl sulfur phosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl and N-diphenylphosphine acyl group.The example of N-sulfinyl derivant comprises: N-benzenesulfinyl, N-ortho-nitrophenyl sulfinyl, N-2,4-dinitro benzene sulfinyl, N-pentachlorobenzene sulfinyl, N-2-nitro-4-methoxyl group-benzenesulfinyl, N-trityl group sulfinyl and N-3-nifedipine sulfinyl.The N-sulfonyl-derivatives comprises: the N-p-toluenesulfonyl; the N-benzenesulfonyl; N-2; 3; 6-trimethyl-4-methoxybenzene sulfonyl; N-2; 4; 6-trimethoxy benzenesulfonyl; N-2; 6-dimethyl-4-methoxybenzene sulfonyl; N-pentamethylbenzene sulfonyl; N-2; 3; 5; 6-tetramethyl-4-methoxybenzene sulfonyl; N-4-methoxybenzene sulfonyl; N-2,4,6-trimethylbenzene sulfonyl; N-2; 6-dimethoxy-4 '-Methyl benzenesulfonyl base; N-2; 2,5,7; 8-pentamethyl benzo dihydropyran-6-sulfonyl; the N-mesyl; N-trimethyl silyl ethylsulfonyl; N-9-anthracene sulfonyl; N-4-(4 ', 8 '-dimethoxy naphthyl methyl)-benzenesulfonyl; N-benzyl sulfonyl; N-trifluoromethyl sulfonyl and N-phenacyl sulfonyl.

Disclosed chemical compound that shelter or protection can be prodrug, in vivo through metabolism or transform to produce the chemical compound of disclosed chemical compound, the chemical compound of transition in metabolic process for example.This conversion can be since with body fluid for example blood contact, perhaps because sour effect, perhaps hydrolysis or the oxidation that causes owing to the effect of liver, the intestines and stomach or other enzymes.

To be further described other features of the present invention in the following embodiments.E. embodiment

Biology embodiment

The static allodynia that 198306 pairs of streptozocin of embodiment 1PD cause influence animal

(Hull, male Sprague Dawley rat (250-300g) U.K.) is divided into per 3 one group raising will to derive from Bantin and Kingman.All animals all are in bright/dark circulation (7:00 begins illumination in the morning) in 12 hours, freely get food and drinking-water.All tests are all carried out under the unwitting situation Drug therapy the observer.In rat, produce diabetes

(Courteix etc., 1993) as mentioned above, (50mg/kg) causes diabetes by the peritoneal injection streptozocin.Estimate static allodynia

(Stoelting, Illinois U.S.A.) measure mechanical hypersensitivity to use Semmes-Weinstein von Frey hair.Place the bottom to be the cage of tinsel mesh animal, make below its claw can touch.Beginning to make animal get used to this environment before the test.By touching maximum 6 seconds of the plantar surface of the right back pawl of animal with the power that makes progress (0.7,1.2,1.5,2,3.6,5.5,8.5,11.8,15.1 and 29g), measure mechanical hypersensitivity with von Frey hair.In case the generation withdrawing reaction then begins this pawl is tested with next downward von Frey hair, until no longer reacting.The high-tensile strength of 29g makes pawl raise and induce reaction, and therefore shows point of cut-off (point).With pawl the induce reaction minimum flow of required power of threshold (PWT) record of shrinking back, with the gram expression.Medicine

PD 198306[N-cyclo propyl methoxy-3,4,5-three fluoro-2-(4-iodo-2-methyl-phenyl amino)-Benzoylamide] and CI-1008 (pregabalin) by Parke-Davis (Ann Arbor, MI, USA) synthetic.PD 198306 is suspended in cremophor: ethanol: in water (1: 1: the 8) carrier.Pregabalin is dissolved in the water.Two kinds of chemical compounds all pass through oral administration.(Aldrich UK) is dissolved among the 0.9%w/v NaCl also by the peritoneal injection administration with streptozocin.The dosage of medicine is 1ml/kg.Statistics

For the nonparametric result, when Mann-Whitney ' s t check has significance, use Kruskall-Wallis ANOVA that static allodynia data are analyzed.Testing program

At oral PD 198306 (30mg/kg, p.o.), excipient (cremophor: ethanol: water, 1: 1: 8) or pregabalin (30mg/kg, p.o.) (test) (baseline before, BL) and 1 hour afterwards, use von Frey hair that static allodynia is estimated.At second day in the morning with give the oral same chemical compound of animal afternoon again.Only estimated static allodynia in 1 hour before the administration and after the administration in the afternoon, so that animal minimizes the habituation of experimental condition.Drink water during administration in the morning with the animal of pregabalin treatment, to avoid that this chemical compound repetitively administered is produced possible drug resistance.The 1st day: the 2nd day:

Morning: PD 198306

Water

Excipient afternoon: BL afternoon: BL

PD?198306 PD?198306

Pregabalin Pregabalin

The excipient excipient

The test result of the test

(30mg/kg p.o.) significantly blocked the static allodynia that streptozocin causes in 1 hour to single oral pregabalin after administration.On the contrary, single oral PD 198306 (30mg/kg, p.o) not influence (as follows) of the static allodynia that after administration, streptozocin was caused in 1 hour.But behind the 2nd day oral again twice this chemical compound, it obviously blocked the static allodynia that streptozocin causes in 1 hour after the 3rd administration.This effect (see figure 1) that promptly disappeared in second day.

Embodiment 2 materials and methods animals

(Margate, male Sprague Dawley rat (250-300g) U.K.) is divided into only one group of raising of every 3-6 will to derive from Charles River.All animals all are in bright/dark circulation (7:00 begins illumination in the morning) in 12 hours, freely get food and drinking-water.All tests are all carried out under the unwitting situation Drug therapy the observer.

(Courteix etc., 1993) as mentioned above, (50mg/kg) causes diabetes by the peritoneal injection streptozocin.In rat, produce chronic constriction injury

In operation process,, use 2% isoflurane (1: 4 O by nose-cone ₂/ N ₂The O mixture) make animal keep anesthesia.As described in front Bennett and the Xie (1988) with the sciatic nerve ligation.In this operating process, animal is placed on the homothermic blanket.Perform the operation ready after, by passing the blunt dissection of biceps brachii m., in the middle of common sciatic nerve is exposed to strand.Near three branched portions of ischium,, and 4 root knot bindings (4-0 silk thread) are tied up to around it loosely with the interval of about 1mm from adherent tissue about 7mm nerve that dissociates.Successively close otch, and with antibiotics topical therapeutic wound.Intrathecal injection

Under simple isoflurane anesthesia, expose the spinal column of rat, with 100 μ l Hamilton syringes through intrathecal injection 10 μ l PD 198306 and pregabalin.Use No. 27 long pins of 10mm to be expelled in the sheath crack in 5-6 joint lumbar portion.If having the reaction of flicking, afterbody can judge that penetration is successful.With automatic clip (autoclip) wound is sealed, and 2-3 minute rat waken up fully after injection.Estimate static allodynia

(Stoelting, Illinois U.S.A.) measure mechanical hypersensitivity to use Semmes-Weinstein von Frey hair.Place the bottom to be the cage of tinsel mesh animal, make below its claw can touch.Beginning to make animal get used to this environment before the test.By touching maximum 6 seconds of the plantar surface of the right back pawl of animal with the power that makes progress (0.7,1.2,1.5,2,3.6,5.5,8.5,11.8,15.1 and 29g), measure mechanical hypersensitivity with von Frey hair.In case the generation withdrawing reaction then begins this pawl is tested with next downward von Frey hair, until no longer reacting.The high-tensile strength of 29g makes pawl raise and induce reaction, and therefore shows point of cut-off (point).With pawl the induce reaction minimum flow of required power of threshold (PWT) record of shrinking back, with the gram expression.Testing program

Injection PD 198306 (1-30 μ g in sheath or in the vola, i.t.), excipient (cremophor: ethanol: water, 1: 1: 8) or pregabalin (10 μ g, i.t.) (baseline before, BL) and 0.5 hour afterwards, 1 hour and 2 hours, use von Frey hair that static allodynia is estimated.For oral test, and oral PD 198306 (3-30mg/kg, p.o.), excipient (cremophor: ethanol: water, 1: 1: 8) or pregabalin (30mg/kg, p.o.) before (baseline BL) with 1 hour afterwards, uses von Frey hair that static allodynia is estimated.Used same chemical compound to animal again with afternoon in the morning at second day.Estimated static allodynia in the morning before the administration and after the administration in 1 hour.For streptozocin treatment animal, in the afternoon before the administration, estimated static allodynia after the administration in 1 hour, 2 hours and 3 hours.CCI treatment animal then before administration, estimated static allodynia after the administration in 1 hour and 2 hours.The medicine that uses

(Ann Arbor, MI USA) synthesize by Parke-Davis for PD 198306 and pregabalin.PD 198306 is suspended in cremophor: ethanol: in water (1: 1: the 8) carrier.Pregabalin is dissolved in the water.Two kinds of chemical compounds are all by in oral, the sheath or in the vola, respectively with the amount administration of 1mg/kg, 10 μ l and 100 μ l.(Aldrich UK) is dissolved among the 0.9%w/v NaCl and by the peritoneal injection administration, the dosage of medicine is 1ml/kg with streptozocin.Statistics

For the nonparametric result, when Mann-Whitney ' s t check has significance to vehicle group, use Kruskall-Wallis ANOVA that data are analyzed.1. influences that influence the static allodynia that 1.1. PD198306 causes streptozocin that are administered systemically back PD 198306 pairs of static allodynias as a result

(30mg/kg p.o.) significantly blocked the static allodynia that streptozocin causes in 1 hour to single administration pregabalin after administration.On the contrary, single oral PD 198306 (3-30mg/kg, p.o) not influence (as follows) of the static allodynia that after administration, streptozocin was caused in 1 hour.But at the 2nd day again behind this chemical compound of administered twice, PD 198306 (30mg/kg) obviously blocked the static allodynia (Fig. 2) that streptozocin causes in 2 hours after the 3rd administration.1.2. the influence of the static allodynia that PD198306 causes CCI

(30mg/kg p.o.) significantly blocked the static allodynia that CCI causes in 1 hour to single administration pregabalin after administration.On the contrary, single or multiple is used PD 198306 (3-30mg/kg, p.o) the static allodynia that CCI is caused is all less than effect (Fig. 3).2. the influence of 198306 pairs of static allodynias of PD behind the intrathecal drug delivery

No matter intrathecal injection PD198306 (1-30 μ g) is to streptozocin (Fig. 4) or CCI animal (Fig. 5), has all blocked the static allodynia that continues in dose-dependent mode, and its med value is respectively 3 and 10 μ g.The effect of this anti-allodynia continues 1 hour.3. the influence of 198306 pairs of static allodynias of PD after the administration in the vola

In two kinds of neuropathic pain models, use PD 198306 (30 μ g) in the sheath and all obviously blocked static allodynia (Fig. 6 and 7).On the contrary, the static allodynia (Fig. 7) that directly 198306 pairs of streptozocin of pawl single administration PD (Fig. 6) or CCI is caused with 100 times of high dosage (3mg/100 μ l) is all less than effect.Reference literature Bennett GJ, Xie Y-K.A peripheral mononeuropathy in rat thatproduces disorders of pain sensation like those seen in man.Pain1988; 33:87-107.Courteix C, Eschalier A and Lavarenne J.Streptozocin-induced rats:behavioural evidence for a model of chronic pain .Pain 1993; 53:81-8.

Embodiment 3

The effect general introduction of other mek inhibitors in rat neuropathic pain model

In rat CCI neuropathic pain model, estimate static allodynia by using von Frey hair, several effects with mek inhibitor of different binding affinities are studied.Using PD219622 or PD297447 (30 μ g) in the sheath has no significant effect allodynia.The shortage of this effect reflects the low-affinity or the dissolubility of chemical compound.But, use the PD 254552 or the PD 184352 (30 μ g) that may have high affinity more in the sheath and blocked the static allodynia that the CCI animal continues.Therefore the effect of this anti-allodynia only back 30 minutes of injection obviously is shorter than the action time of pregabalin (100 μ g).The size of its effect is similar to 30 μ g PD184352 and 100 μ g pregabalin.Research can be inferred thus, when intrathecal drug delivery, and the effect that mek inhibitor produces anti-allodynia to the inductive neuropathy rat of CCI, and the effect of this anti-allodynia is relevant with the affinity of chemical compound.

Animal and in rat, produce the test compound of method, injection of chronic constriction injury and as above described to embodiment 2 to the evaluation of static allodynia.The equal intrathecal drug delivery of PD219622, PD297447, PD184352, PD254552 and pregabalin, the dosage of all PD chemical compounds are 30 μ g, and the dosage of pregabalin is 100 μ g.(baseline BL) with 0.5 hour afterwards, 1 hour and 2 hours, is estimated static allodynia with von Frey hair before the administered compound in sheath.The medicine that uses

(Ann Arbor, MI USA) synthesize by Parke-Davis for PD297447, PD219622, PD254552, PD 184352 (CI-1040) and pregabalin.PD297447, PD219622, PD254552 and PD184352 are suspended in cremophor: ethanol: in water (1: 1: the 8) carrier.Pregabalin is dissolved in the water.All chemical compounds all with the amount of 10 μ l through intrathecal drug delivery.Statistics

For the nonparametric result, when Mann-Whitney ' s t check has significance to vehicle group, use Kruskall-Wallis ANOVA that static allodynia data are analyzed.The result

Using PD297447 or PD219622 (30 μ g) in the sheath has no significant effect allodynia.The shortage of this effect reflects the low-affinity (being respectively 965nM and 100nM) of chemical compound.But, use PD 184352 or PD 254552 (30 μ g) in the sheath and blocked the static allodynia (see figure 8) that the CCI animal continues.These chemical compounds have higher affinity (be respectively 2 and 5nM).Therefore the effect of this anti-allodynia only back 30 minutes of injection obviously is shorter than the action time of pregabalin (100 μ g).The size of its effect is similar to 30 μ g PD 184352 and 100 μ gpregabalin.

This result shows, when intrathecal drug delivery, and the effect that mek inhibitor produces anti-allodynia to the inductive neuropathy rat of CCI, and the effect of this anti-allodynia is relevant with the affinity of chemical compound.

Chemistry embodiment

Preparation (the APK IC of embodiment 17-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid (PD 205293) ₅₀=14nM; Colon 26 cells, IC ₅₀=＞10 micromoles) step a:5-nitro-2,3, the preparation of 4-trifluoro-benzoic acid

Concentrated sulphuric acid (50ml) the adding fuming nitric aicd of past gentle agitation (3.4ml, 0.076mol).Directly add solid 2,3, and the 4-trifluoro-benzoic acid (10.00g, 0.05565mol).Stir after 45 minutes, this reactant mixture becomes orange homogeneous solution, then in the impouring cold water (400ml).Extracted with diethyl ether three times (3 * 200ml) of gained water slurry.The extract that merges obtains the dark light yellow solid of 12.30g with anhydrous magnesium sulfate drying and vacuum concentration.Recrystallization in chloroform (50ml) obtains the light yellow crystallite product of 9.54g; Productive rate 78%; M.p.; ¹H-NMR (400MHz; DMSO) δ 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); ¹³C-NMR (100MHz; DMSO) δ 162.41,154.24 (dd, J _C-F=270.1,10.7Hz), 148.35 (dd, J _C-F=267.0,9.2Hz), 141.23 (dt, J _C-F=253.4Hz), 133.95,123.30 (d, J _C-F=2.2Hz), 116.92 (dd, J _C-F=18.2,3.8Hz); ¹⁹F-NMR (376MHz; DMSO) δ-120.50 to-120.63 (m) ,-131.133 to-131.27 (m) ,-153.63 to-153.74 (m). step b:4-amino-2,3-two fluoro-5-nitrobenzoic acids

With solid 5-nitro-2,3, (0.75g 0.00339mol) is dissolved in the dense ammonium hydroxide (25ml) and obtains yellow solution immediately-trifluoro-benzoic acid.Begin in five minutes to form precipitation, with concentrated hydrochloric acid aqueous solution this mixture is acidified to pH 0 afterwards.Form yellow mercury oxide fast.This mixture heated is extremely seethed with excitement and filtered while hot.This yellow solid washs with 10% aqueous hydrochloric acid solution, and suction dried obtains the 0.47g yellow powder; Productive rate 64%; ¹H-NMR (400MHz; DMSO) δ 13.32 (s, 1H), 8.36 (d, 1H, J=7.6Hz), 7.98 (s, 2H); ¹⁹F-NMR (376MHz; DMSO) δ-128.69 to-128.76 (m) ,-153.60 (d). step c:4-amino-2, the preparation of 3-two fluoro-5-nitrobenzoic acid methyl ester

Be dissolved in the absolute methanol (30ml) hydrogen chloride gas warm until solution.With solid 4-amino-2,3-two fluoro-5-nitrobenzoic acid (0.47g; 0.00215mol) be dissolved in this solution, under blanket of nitrogen and under the vigorous stirring, make this reaction mixture refluxed 23 hours.Placement is slowly cooled off reactant mixture.Form yellow mercury oxide, vacuum filtration is collected and suction dried, obtains the yellow microfilament shape of 0.35g product; Productive rate 70%; M.p.183.5-184 ℃;

¹H-NMR (400MHz; DMSO) δ 8.36 (dd, 1H, J=7.3,1.7Hz), 8.06 (s, 2H), 3.78 (s, 3H); ¹⁹F-NMR (376MHz; DMSO) δ-128.85 to-128.92 (m) ,-153.29 (d); MS (APCI-) 231 (M-1,100); IR (KBr) 3433,3322,1700,1650,1549,1343,1285cm ^-1Analyze. value of calculation/measured value: C ₈H ₆F ₂N ₂O ₄C, 41.39/41.40; H.2.61/2.50; N.12 steps d: the preparation of 4-amino-3-fluoro-2-(2-methyl-phenyl amino)-5-nitrobenzoic acid methyl ester

With solid 4-amino-2,3-two fluoro-5-nitrobenzoic acid methyl ester (0.087g, 3.7 * 10 ^-4Mol) be dissolved in ortho-aminotoluene (3ml, 0.028mol) in.Under blanket of nitrogen, this reactant mixture was stirred 35 minutes down at 200 ℃.This mixture is assigned in ether (150ml) and 10% aqueous hydrochloric acid solution (150ml) then.Ether is a solid crude product with anhydrous magnesium sulfate drying and vacuum concentration.This crude product is dissolved in the 5ml dichloromethane and filters quick silica gel short column.Use the dichloromethane eluting, obtain the 0.0953g yellow solid; Productive rate 81%; M.p.164-168 ℃; ¹H-NMR (400MHz; DMSO) δ 9.20 (s, 1H), 8.52 (d, 1H, J=1.7Hz), 7.57 (s, 2H), 7.19 (d, 1H, J=7.3Hz), 7.12-7.08 (m, 1H), 7.02-6.98 (m, 1H), 6.95-6.91 (m, 1H), 3.78 (s, 3H), 2.21 (s, 3H); ¹⁹F-NMR (376 MHz; DMSO) δ-141.13 (s); MS (APCI+) 320 (M+1,100); (APCI-) 318 (M-1,100); IR (KBr) 3467,3346,1690,1305cm ^-1C ₁₅H ₁₄FN ₃O ₄0.21H ₂Elementary analysis calculating/the measured value of O: C, 55.77/55.97; H, 4.50/4.55; N, 13.01/12.61; F, 5.88/5.95.Step e:4,5-diaminourea-3-fluoro-2-(2-aminomethyl phenyl amino) essence of Niobe

Under 30.2 ℃, toward 4-amino-3-fluoro-2-(2-methyl-phenyl amino)-5-nitrobenzoic acid methyl ester of vibration in the container (2.52g, 0.00789mol), apply 4 hours 48 minutes 48.6psi hydrogen in the mixture of oxolane (50ml), methanol (50ml) and washed Raney nickel (0.5g) composition.This mixture is filtered, and the filtrate vacuum concentration obtains 2.20g salmon color amorphous solid; Productive rate 96%; ¹H-NMR (400MHz; DMSO) δ 7.84 (s, 1H), 7.04 (d, 1H, J=7.1Hz), 6.98 (d, 1H, J=1.2Hz), 6.95-6.91 (m, 1H), 6.68-6.64 (m, 1H), 6.40-6.36 (m, 1H), 5.39 (s, 2H), 4.73 (s, 2H), 3.66 (s, 3H), 2.21 (s, 3H); ¹⁹F-NMR (376MHz; DMSO) δ-139.66 (s). step f:7-fluoro-6-(2-methyl-phenyl amino)-1H-benzimidazole-5-methyl formate

With 4,5-diaminourea-3-fluoro-2-(2-methyl-phenyl amino)-essence of Niobe (1.78g, and formic acid 0.00615mol) (Aldrich, 95-97%, 100ml, 2.5mol) solution refluxed 3 hours, and vacuum concentration obtains the brown solid crude product then.This crude product chloroform (40ml), vacuum filtration is collected then.With this solid suction dried, obtain 1.09g lavender powder.The filtrate vacuum concentration is a solid crude product, and it is developed with 10ml chloroform-dichloromethane.Vacuum filtration is collected these solids and suction dried, and (total obtains: 1.64g) to obtain other 0.55 lavender powder; Productive rate 87%; Fusing point: 259-262 ℃; ¹H-NMR (400MHz; DMSO) δ 8.42 (s, 1H), 8.03 (s, 1H), 7.93 (broad s, 1H), 7.12 (d, 1H, J=7.0Hz), 6.99-6.95 (m, 1H), 6.75-6.71 (m, 1H), 6.48-6.44 (m, 1H), 3.81 (s, 3H), 2.30 (s, 3H); ¹⁹F-NMR (376MHz; DMSO) δ-132.84 (s); MS (APCI+) 300 (M+1,100); (APCI-) 298 (M-1,100); IR (KBr) 3322,1689,1437,1326,1218cm ^-1C ₁₆H ₁₄N ₃O ₂0.32 H ₂Elementary analysis calculating/the measured value of O: C, 62.99/63.01; H, 4.84/4.61; N, 13.77/13.70.Step g: the preparation of 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-methyl formate

Under agitation, with 7-fluoro-6-(2-aminomethyl phenyl amino)-1H-benzimidazole-5-methyl formate (0.2492g, 8.326 * 10-4mol), benzyl trimethyl dichloro ammonium iodide (Aldrich, 95%, 0.3934g, 0.00113mol) and zinc chloride (0.1899g, 0.00139mol) mixture in glacial acetic acid (20ml) refluxed 15 minutes.This suspension filtered while hot is isolated precipitation, and dry (90 ℃, about 10mm Hg) spend the night in vacuum oven, obtain the 0.2392g green powder; Productive rate 68%; M.p.219-220 ℃ of decomposition;

¹H-NMR (400MHz; DMSO) δ 8.71 (s, 1H), 8.02 (s, 1H), 7.85 (broads, 1H), 7.43 (d, 1H, J=1.7Hz), 7.24 (dd, 1H, J=8.5,2.2Hz), 6.24 (dd, 1H, J=8.5,5.4Hz), 3.76 (s, 3H), 2.22 (s, 3H); ¹⁹F-NMR (376MHz; DMSO) δ-132.86 (s); MS (APCI+) 426 (M+1,48), 169 (100); (APCI-) 424 (M-1,100); IR (KBr) 1704,1508,1227cm ^-1. the preparation of step h:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1 H-benzimidazole-5-formic acid

7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-methyl formate (0.2035g, 4.786 * 10 under past the stirring ^-4Adding solid front three potassium silanolate in oxolane mol) (20ml) solution (0.315g, 0.00246mol).This reactant mixture was stirred 16 hours under room temperature and argon atmospher.Add other 0.082g (6.39 * 10 ^-4Mol) the front three potassium silanolate also stirs this mixture 30 minutes.Behind reactant mixture vacuum concentration to 1/3 volume, handle with ether (50ml).Vacuum filtration is collected the near-white precipitation that forms, and obtains the hygroscopicity solid.In the solid that should wet is dissolved in 4: 1 (v/v) ethyl acetate-methanol solution (500ml).This solution washs with 0.84M aqueous citric acid solution (50ml), dry (MgSO ₄), and vacuum concentration, obtain yellow liquid.This liquid is dissolved in fresh ethyl acetate-methanol again.The salt water washing of this solution, dry (MgSO ₄), and vacuum concentration.Residue is dissolved in the chloroform again and concentrates once more, obtains the heavy-gravity yellow residue of 1.55g, and it mainly contains citric acid; MS (APCI-) 191 (M-1,100).In residue water-soluble (50ml).In insoluble substance is extracted into 1: 1 (v/v) ethyl acetate-ether (250ml).After the separation, water is still highly acid (pH 0).Organic facies is washed with some fresh waters (150ml).After the separation, these washings only are faintly acid (pH 4.5).Organic facies drying (MgSO ₄), vacuum concentration and with chloroform washing obtains the yellowish-brown semisolid.This product is developed with hexane.Vacuum filtration and suction dried obtain 0.0839g yellowish-brown powder.Portion of product (0.050g) is recrystallization in ebullient ethanol (1ml).In refrigerative scraping simultaneously, form the near-white solid.Through the isolated by vacuum filtration product and under fine vacuum dry (23 ℃), obtain 0.018g near-white powder, productive rate 9%; M.p.247-248 ℃ of DEC;

¹⁹F-NMR(376MHz；DMSO)δ-132.87(s)；MS(APCI+)412(M+1，100)；(APCI-)410(M-1，100)；IR(KBr)3322，1689，1437，1326，1218cm ^-1；Anal.calcd/found?for：C ₁₅H ₁₁FIN ₃O ₂·0.61?C ₂H ₆O·0.59?H ₂O(91.4％parent)C，43.30/43.30；H，3.55/3.34；N，9.34/9.15.

Preparation (the APK IC of embodiment 27-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide (PD 254552) ₅₀＜10nM (n=2); Colon 26 cells, infiltration in 1 hour, IC ₅₀=20nM) preparation (the APK IC of step a:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid pentafluorophenyl group ester (PD 254551) ₅₀=120nM (n=2))

7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid (0.844g, 2.05 * 10 under past the stirring ^-3Mol) add Pentafluorophenol (0.375g, 2.04 * 10 in the suspension in ethyl acetate (4ml) ^-3Mol) N, dinethylformamide (10ml) solution.Add solid dicyclohexylcarbodiimide (0.415g, 1.99 * 10 then ^-3Mol), and with reactant mixture stirred 22 hours.The vacuum filtration reactant mixture is removed the precipitation of formation.Filtrate is diluted with ethyl acetate (400ml), and this solution with water washing (3 * 400ml), dry (MgSO ₄), and vacuum concentration, obtain the yellow foam thing of 1.7g.This crude product is through quick silica column chromatogram purification.With eluent (CHCl ₃～0.5% methanol CHCl ₃) eluting, obtain the yellow amorphous product of 0.69g; Productive rate 60%; ¹H-NMR (400MHz; CDCl ₃) δ 8.54 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.49 (d, 1H, J=1.7Hz), 7.36 (dd, 1H, J=8.2,1.7Hz), 6.57 (dd, 1H, J=8.4,6.5Hz), 2.31 (s, 3H); ¹⁹F-NMR (376MHz; CDCl ₃) δ-132.02 (s) ,-152.35 (d, J=18.3Hz) ,-157.26 (t, J=21.4Hz) ,-161.96 (dd, J=21.3,18.3Hz); MS (APCI+) 578 (M+1,57), 394 (100); (APCI-) 576 (M-1,44), 409 (100), 393 (95), 392 (82), 378 (55), 183 (97), 165 (68), 127 (53); IR (KBr) 1731 cm ^-1The preparation of (C=O stretching, extension) step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide

7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid pentafluorophenyl group ester (0.63g, 1.09 * 10 under past the stirring ^-3Mol) add solid cyclo propyl methoxy amine hydrochlorate (0.14g, 1.13 * 10 in anhydrous tetrahydro furan (5ml) solution ^-3Mol) and diisopropyl ethyl amine (0.6ml, 3.4 * 10 ^-3Mol).This reactant mixture is stirred a week.Except that desolvating and, extracting with ether (200ml) with 10% aqueous hydrochloric acid solution (200ml) evaporation process.Obtain biphase suspension, precipitate by isolated by vacuum filtration.Crude product dehydrated alcohol recrystallization obtains 0.18g yellow green powder, productive rate 35%; Mp 168-172 ℃; ¹H-NMR (400MHz; DMSO) δ 11.48 (s, 1H), 8.37 (s, 1H), 7.50 (broad s, 1H), 7.45 (s, 1H), 7.24 (s, 1H), 7.07 (d, 1H, J=8.4Hz), 6.03-5.97 (m, 1H), 3.38 (d, 2H, J=6.5Hz), 2.04 (s, 3H), 0.85-0.75 (m, 1H), 0.30-0.22 (m, 2H), 0.00 (s, 2H); ¹⁹F-NMR (376MHz; DMSO) δ-133.23 (s); MS (APCI+) 481 (M+1,77), 409 (100); (APCI-) 480 (M, 22), 407 (100); IR (KBr) 1659,1632,1493cm ^-1C ₁₉H ₁₈FIN ₄O ₂0.50 the elementary analysis calculating/measured value of HCl (9.63% parent): C, 45.78/45.74; H, 3.74/3.84; N, 11.23/10.88.

The preparation of the preparation process a:7-fluoro-6-(4-iodo-2-methyl-phenyl amino) of embodiment 37-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid hydroxy amide-1H-benzimidazole-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide

With 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid, O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (1.25 equivalent), benzotriazole-1-base-oxygen-three-pyrrolidinyl phosphine hexafluorophosphate (1.25 equivalent) and diisopropyl ethyl amine (3 equivalent) are 1: the solution stirring in 1v/v oxolane-dichloromethane 30 minutes.With the reactant mixture vacuum concentration, residue is through purification by flash chromatography; Use the dichloromethane eluting, obtain expecting product.Be further purified if desired, with this product The suitable solvent, as recrystallizing methanol.The preparation of step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid hydroxy amide

Chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1 H benzimidazole-5-formic acid 0-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide is dissolved in the suitable saturated solvent of usefulness hydrogen chloride, in methanol or ethanol.In case form uniform solution,, obtain expecting product with its vacuum concentration.Be further purified if desired, with this product The suitable solvent, as chloroform or dichloromethane development.

The preparation process i:2-cyclo propyl methoxy-iso-indoles-1 of the preparation process a:O-cyclopropyl methyl hydroxylamine hydrochlorate of embodiment 47-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide, the preparation of 3-diketone

Under blanket of nitrogen, toward be cooled to ice-water bath under the stirring of 6 ℃ (mixture internal temperatures) N-hydroxyl phthalic amide (Aldrich, 57.15g, 339.8mmol), cyclopropane methanol (Aldrich, 25.10g, 341.1mmol) and triphenylphosphine (" DEAD, " Aldrich, 91.0g, 344mmol) in the solution/suspension in the 1.00L oxolane, with 20 minutes by charging hopper drip diethyl azodiformate (Aldrich, 56ml, 356mmol).During adding, make the temperature of reactant mixture keep below 20 ℃.Add after the DEAD, remove cooling bath, reactant mixture was stirred 15 minutes.With this mixture simmer down to pastel under reduced pressure.Add chloroform (about 300ml) and this mixture that turns round and round, make solid loose.Vacuum filtration is removed insoluble matter.Equally filtrate is filtered, remove the white precipitate of formation, obtain clear and bright filtrate.Concentrating under reduced pressure obtains clear and bright grease.Make it filter silica gel (100% chloroform) fast, obtain containing the not filtrate of separated product.Filtrate is merged and concentrating under reduced pressure, obtain the clear and bright grease of 127.4g.This oil is dissolved in the dehydrated alcohol (40ml) and made this solution freezing 2 hours.Be settled out white crystalline solid, vacuum filtration is collected this solid subsequently.This product is dry in vacuum oven (60%), obtains 42.66g (58%) expection product; M.p.71-77 ℃;

¹H-NMR (400MHz; CDCl ₃Signal offset to δ 6.96) δ 7.54-7.43 (m, 4H), 3.74 (d, 2H, J=7.6Hz), 1.02-0.95 (m, 1H), 0.34-0.30 (m, 1H), 0.04-0.00 (m, 1H). the preparation of step I i:O-cyclopropyl methyl hydroxylamine hydrochlorate

At room temperature, toward stirring 2-cyclo propyl methoxy-iso-indoles-1 down, the 3-diketone (42.64g, 196.3mmol) careful adding methyl hydrazine in the solution in the 150ml dichloromethane (Aldrich, 10.7ml, 197mmol).Almost begin to form white precipitate immediately.After the vigorous stirring 15 minutes, with this suspension vacuum filtration.Equally, filter filtrate to remove other precipitation.The clear and bright filtrate of gained is under reduced pressure carefully concentrated (volatile products), obtain clear and bright liquid/solid mixtures.Ether (200ml) solution and the vacuum filtration that prepare this product are removed white solid.Filtrate is used the hydrogen chloride gas acidify, obtains white precipitate immediately.Vacuum filtration is collected solid and with vacuum oven drying (55 ℃), is obtained 18.7g (77%) white powder product; M.p.165-168 ℃; ¹H-NMR (400MHz; DMSO) δ 10.77 (broad s, 2H), 3.57 (d, 2H, J=7.3Hz), 0.84-0.74 (m, 1H), 0.31-0.25 (m, 2H), 0.04-0.00 (m, 1H); ¹³C-NMR (100MHz; DMSO) δ 75.39,5.52,0.00. step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide

With 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1 H benzimidazole-5-formic acid, O-cyclopropyl methyl hydroxylamine hydrochlorate (1.25 equivalent), benzotriazole-1-base-oxygen-three-pyrrolidinyl-phosphine hexafluorophosphate (1.25 equivalent) and diisopropyl ethyl amine (3 equivalent) solution stirring in 1: 1 v/v oxolane-dichloromethane 30 minutes.With this reactant mixture vacuum concentration, residue is added in the ether.Ether is used diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and salt water washing mutually, dry (MgSO ₄), and vacuum concentration obtains expecting product.Be further purified if desired, this product The suitable solvent is as methanol or chloroform recrystallization.

The preparation process a:5-nitro-2,3 of embodiment 57-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-formic acid, the preparation of 4-trifluoro-benzoic acid

Identical with the step a of embodiment 1.Step b:2, the preparation of 3-two fluoro-4-hydroxyl-5-nitrobenzoic acids

With solid 5-nitro-2,3, (1.00g 0.00452mol) is dissolved in the 10wt.% sodium hydrate aqueous solution 4-trifluoro-benzoic acid.This mixture is clear and bright darkorange.After at room temperature placing several minutes, this mixture is handled until reaching highly acid (pH 0) with concentrated hydrochloric acid aqueous solution.To obtain 0.40g near-white solid through the white solid precipitation suction dried of isolated by vacuum filtration.This solid obtains 0.22g near-white crystalline powder with chloroform (20ml) recrystallization; Productive rate 22%; MS (APCI-) 218 (M-1,100).Step c:2, the preparation of 3-two fluoro-4-hydroxyls-5-nitrobenzoic acid methyl ester

Be dissolved in the absolute methanol (50ml) exsiccant hydrogen chloride gas warm until solution.With microcrystalline solids 2, (0.22g 0.00100mol) is dissolved in the methanol solution of hydrogen chloride 3-two fluoro-4-hydroxyl-5-nitrobenzoic acids.Under blanket of nitrogen, with this reactant mixture stirring and refluxing 16 hours.This mixture vacuum concentration obtains white solid.Product is dry under fine vacuum, obtains the 0.213g white powder, productive rate 91%; M.p.108-109.5 ℃; ¹H-NMR (400MHz; DMSO) δ 8.25 (dd, 1H, J=7.7,2.2Hz), 3.83 (s, 3H); (CDCl ₃) δ 10.83 (s, 1H), 8.66 (dd, 1H, J=7.0,2.2Hz), 3.98 (s, 3H); ¹⁹F-NMR (376MHz; DMSO) δ-127.85 (s) ,-154.32 (d, J=19.8Hz); (CDCl ₃) δ-118.31 to-118.37 (m) ,-152.38 (d, J=18.3Hz); MS (APCI-) 232 (M-1,100); IR (KBr) 3264,1731,1640,1546,1307,1286,1160cm ^-1Steps d: 1-gold steel alkyl 4-carboxymethyl-2,3-two fluoro-6-nitrophenyl carbonate

In room temperature with under stirring, in 1-gold steel alkyl fluoride formic acid esters (2.0M) and the solution of pyridine (2.0M) in oxolane, add 2,3-two fluoro-4-hydroxyls-5-nitrobenzoic acid methyl ester (0.96 equivalent, tetrahydrofuran solution 0.384M).This reactant mixture stirred after 6 hours, solvent removed in vacuo.Residue is dissolved in the dichloromethane.This organic solution diluted hydrochloric acid aqueous solution, dilute sodium carbonate aqueous solution and water washing, dry (MgSO ₄), and vacuum concentration obtains expecting product.Step e:1-gold steel alkyl 4-carboxymethyl-2-fluoro-3-(2-methyl-phenyl amino)-6-nitrophenyl carbonate

With chemical compound 1-gold steel alkyl 4-carboxymethyl-2,3-two fluoro-6-nitrophenyl carbonate are dissolved in excessive ortho-aminotoluene.Reactant mixture stirred 6 hours at 200 ℃.Make the cooling of this mixture and be dissolved in the ether.Organic facies diluted hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and salt water washing, dry (MgSO ₄), and vacuum concentration obtains expecting product.If desired, product is through purification by flash chromatography.The preparation of step f:3-fluoro-4-hydroxyl-2-(2-methyl-phenyl amino)-5-nitrobenzoic acid methyl ester

At room temperature, chemical compound 1-gold steel alkyl 4-carboxymethyl-2-fluoro-3-(2-methyl-phenyl amino)-6-nitrophenyl carbonate is dissolved in the excessive trifluoroacetic acid.This mixture stirred 20 minutes.TFA is removed in decompression.Residue is removed golden steel alkane-1-alcohol by vacuum pump suction, obtains expecting product.Step g: the preparation of 5-amino-3-fluoro-4-hydroxyl-2-(2-methyl-phenyl amino)-essence of Niobe

Step e as embodiment 1 handles 3-fluoro-4-hydroxyl-2-(2-methyl-phenyl amino)-5-nitrobenzoic acid methyl ester.The preparation of step h:7-fluoro-6-(2-methyl-phenyl amino)-1H-benzoxazole-5-methyl formate

Step f as embodiment 1 handles 5-amino-3-fluoro-4-hydroxyl-2-(2-methyl-phenyl amino) essence of Niobe.If desired, the product The suitable solvent is as chloroform or ethyl alcohol recrystallization.Step I: the preparation of 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-methyl formate

With 7-fluoro-6-(2-methyl-phenyl amino)-1H-benzoxazole-5-methyl formate (0.042M), benzyl trimethyl dichloro ammonium iodide (Aldrich, 95%, 0.057M, 1.36 equivalent) and the mixture agitating heating of zinc chloride (0.070M, 1.67 equivalents) in glacial acetic acid 15 minutes.This mixture vacuum concentration, residue is added in the ether.This diethyl ether solution diluted hydrochloric acid aqueous solution, water and salt water washing, dry (MgSO ₄), and vacuum concentration obtains expecting product.Product is through using suitable solvent, as the ethyl alcohol recrystallization purification.The preparation of step j:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-formic acid

In the tetrahydrofuran solution of 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-methyl formate (0.024M) that stirs, add solid front three potassium silanolate (5.14 equivalent).Under argon atmospher, reactant mixture was at room temperature stirred 16 hours.Adding other equivalent front three potassium silanolate more also stirs this mixture 30 minutes.With the reactant mixture vacuum concentration, obtain residue, this residue is added in 1: 1 (v/v) ethyl acetate-ether.Organic facies diluted hydrochloric acid aqueous solution, water and salt water washing, dry (MgSO ₄), vacuum concentration and with chloroform washing obtains crude product.In The suitable solvent, as recrystallization purifying expection product in the ethanol.

The preparation of the preparation process a:7-fluoro-6-(4-iodo-2-methyl-phenyl amino) of embodiment 67-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-formic acid hydroxy amide-1H-benzoxazole-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide

Step a as embodiment 2 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-formic acid.The preparation of step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-formic acid hydroxy amide

Step b as embodiment 2 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide.

The preparation of embodiment 77-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-formic acid cyclo propyl methoxy-amide

Step b as embodiment 3 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzoxazole-5-formic acid.

The preparation process a:5-nitro-2,3 of embodiment 87-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-formic acid, the preparation of 4-trifluoro-benzoic acid

Identical with the step b of embodiment 4.Step c:2, the preparation of 3-two fluoro-4-hydroxyls-5-nitrobenzoic acid methyl ester

Identical with the step c of embodiment 4.Steps d: the 4-dimethyl disulfide is for carbamoyloxy-2, the preparation of 3-two fluoro-5-nitrobenzoic acid methyl ester

With 2, the N of 3-two fluoro-4-hydroxyls-5-nitrobenzoic acid methyl ester, dinethylformamide solution is handled in order to the cesium carbonate of molar equivalent and is warming to 85 ℃, keeps 30 minutes.Drip excessive N slightly fast in the chemical compound of this stirring, the N-dimethyl disulfide is for the N of carbamyl chloride, the solution of dinethylformamide.With this reactant mixture stirring at room 1 hour, perhaps can be on steam bath warm 1 hour.With in this mixture impouring water and use ethyl acetate extraction.Organic facies is used desiccant with 5% sodium hydrate aqueous solution, water and salt water washing, as magnesium sulfate or dried over sodium sulfate.Solvent removed in vacuo obtains crude product.This chemical compound is through conventional method, for example chromatograph or in suitable solvent crystallization purifying.Step e:4-dimethyl disulfide is for the preparation of carbamoyloxy-3-fluoro-5-nitro-2-o-tolyl amino-essence of Niobe

For carbamoyloxy-2,3-two fluoro-5-nitro-essence of Niobe are dissolved in the excessive ortho-aminotoluene with chemical compound 4-dimethyl disulfide.The gained mixture was heated 1 hour at 200 ℃.Then in impouring 5% aqueous hydrochloric acid solution.This mixture aqueous solution extracted with diethyl ether.Organic facies water and salt water washing, through dried over mgso, and vacuum concentration.Crude product is through conventional method, for example chromatograph or in suitable solvent crystallization purifying.The preparation of step f:7-fluoro-6-(2-methyl-phenyl amino)-1H benzothiazole-5-methyl formate

Step h as embodiment 4 handles 5-amino-3-fluoro-4-sulfydryl-2-(2-aminomethyl phenyl amino)-essence of Niobe.Step g: the preparation of 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-methyl formate

Step I as embodiment 4 is handled chemical compound 7-fluoro-6-(2-methyl-phenyl amino)-1H-benzothiazole-5-methyl formate.The preparation of step h:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-formic acid

Step j as embodiment 4 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-methyl formate.

The preparation of the preparation process a:7-fluoro-6-(4-iodo-2-methyl-phenyl amino) of embodiment 97-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-formic acid hydroxy amide-1H-benzothiazole-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide

Step a as embodiment 2 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-formic acid.The preparation of step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-formic acid hydroxy amide

Step b as embodiment 2 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide.

The preparation of embodiment 107-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzothiazole-5-formic acid cyclo propyl methoxy-amide

Step b as embodiment 3 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H benzothiazole-5-formic acid.

The preparation of preparation process a:8-fluoro-7-(2-methyl-phenyl amino)-quinoxaline-6-formic acid of embodiment 118-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid

With 4,5-diaminourea-3-fluoro-2-(2-methyl-phenyl amino) essence of Niobe (by embodiment 1 step e preparation) is dissolved in 2: 1: 1.2 v/v/v 2.0M acetic acid-4.0M sodium acetate-methanol.This suspension is warming to 65 ℃ (perhaps until evenly), this clear and bright solution impouring is warming in 70 ℃ 0.078M Biformyl sodium sulfite (Aldrich, monohydrate, the 1.05 equivalents) aqueous solution.This reactant mixture was stirred under 55-75 ℃ 1 hour gently, be cooled to 12 ℃ with ice-water bath then.The sodium hydroxide ball of pulverizing (27 equivalent) is added to this to be cooled in the solution.Stirred 45 minutes after making this mixture gently be warming to 30 ℃.Make temperature rise to 70 ℃ and kept 15 minutes.Make the cooling of this mixture and handle with ethyl acetate.This two-phase mixture is handled with concentrated hydrochloric acid aqueous solution, so that water pH is 0.Separate organic facies, dry (MgSO ₄), and vacuum concentration obtains expecting product.If desired, this product The suitable solvent is as the dichloromethane development or at solvent, as the ethyl alcohol recrystallization purification.The preparation of step b:8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid

Step I as embodiment 4 is handled chemical compound 8-fluoro-7-(2-methyl-phenyl amino)-quinoxaline-6-formic acid.

The preparation of the preparation process a:8-fluoro-7-(4-iodo-2-methyl-phenyl amino) of embodiment 128-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid hydroxy amide-quinoxaline-6-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide

Step a as embodiment 2 handles chemical compound 8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid.The preparation of step b:8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid hydroxy amide

Step b as embodiment 2 handles chemical compound 8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide.

The preparation of embodiment 138-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid cyclo propyl methoxy-amide

Step b as embodiment 2 handles chemical compound 8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid.

The preparation of the preparation process a:7-fluoro-6-(2-methyl-phenyl amino) of embodiment 147-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid-benzo [1,2,5] thiadiazoles-5-methyl formate

Under past stirring the 4,5-diaminourea-3-fluoro-2-(2-aminomethyl phenyl amino)-essence of Niobe (by the step e preparation of embodiment 1) and diisopropyl ethyl amine (2 equivalent) are in suitable solvent, as adding reagent in the solution in ether or the toluene, as N-thioaniline or thionyl chloride (1.35 equivalent).Made reaction mixture refluxed 1 hour.This mixture is handled with diluted hydrochloric acid aqueous solution.Organic facies saturated sodium bicarbonate aqueous solution and salt water washing, dry (MgSO ₄), and vacuum concentration obtains expecting product.Be further purified if desired, this product suitable solvent is as chloroform or ethyl alcohol recrystallization.Another kind method: with chemical compound 4,5-diaminourea-3-fluoro-2-(2-aminomethyl phenyl amino)-essence of Niobe is added to the N of the sulfur monochloride (6 equivalent) of stirring, and dinethylformamide solution also slowly is heated to 75-80 ℃.After 5 hours, make this mixture be cooled to 10 ℃ after, add entry lentamente.This mixture solvent, for example ether or dichloromethane extraction.Organic extract liquid drying (MgSO ₄) and vacuum concentration, obtain expecting product.Be further purified if desired, the product The suitable solvent is as chloroform or ethyl alcohol recrystallization.The preparation of step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-methyl formate

Step I as embodiment 4 is handled chemical compound 7-fluoro-6-(2-methyl-phenyl amino) benzo [1,2,5] thiadiazoles-5-methyl formate.The preparation of step c:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid

Step j as embodiment 4 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino) benzo [1,2,5] thiadiazoles-5-methyl formate.

Embodiment 157-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] preparation of the preparation process a:7-fluoro-6-of thiadiazoles-5-formic acid hydroxy amide (4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide

Step a as embodiment 2 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid.The preparation of step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid hydroxy amide

Step b as embodiment 2 handles 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide.

The preparation of embodiment 167-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid cyclo propyl methoxy-amide

Step b as embodiment 3 handles 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid.

The preparation of the preparation process a:7-fluoro-6-(2-methyl-phenyl amino) of embodiment 177-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid-benzo [1,2,5] thiadiazoles-5-formic acid 2-oxide

Referring to Takakis, I.M.; Hadjimihalakis, P.M., J.HeterocyclicChem., 27,177 (1990).

4-amino-3-fluoro-2-(2-methyl-phenyl amino)-5-nitrobenzoic acid methyl ester (by the steps d preparation of embodiment 1) and the mixture of iodosobenzene diacetate esters (iodosobenzenediacetate) (1.76 equivalent) in benzene were at room temperature stirred 5 hours.With this mixture vacuum concentration, residue is through the column chromatography purification, obtains expecting product.Another kind method: with the tetrahydrofuran solution diazotising of 4-amino-3-fluoro-2-(2-methyl-phenyl amino)-5-nitrobenzoic acid methyl ester (0.86M), this diazol on the spot with Hydrazoic acid,sodium salt handle (as Smith, P.A.S.; Boyer, J.H., Org.Synth., 31,14 (1951) is described) and the list of

references

4 and 8 of citation wherein.This intermediate in 110-120 ℃ of following thermal decomposition 1 hour, obtains expecting product in ethylene glycol.The preparation of step b:7-fluoro-6-(2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-methyl formate

[ethylene glycol solution of 1,2,5] oxadiazoles-5-methyl formate 2-oxide and Hydrazoic acid,sodium salt (1.38 equivalent) after column chromatography, obtains expecting product 140-150 ℃ of heating 30 minutes with 7-fluoro-6-(2-methyl-phenyl amino)-benzo.Step c:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-methyl formate

Step I as embodiment 4 is handled chemical compound 7-fluoro-6-(2-methyl-phenyl amino)-benzo [1,2,5] oxadiazole-5-methyl formate.Steps d: the preparation of 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid

Step j as embodiment 4 handles 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] oxadiazole-5-methyl formate.

Embodiment 187-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] preparation of the preparation process a:7-fluoro-6-of thiadiazoles-5-formic acid hydroxy amide (4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide

Step a as embodiment 2 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] oxadiazole-5-formic acid.The preparation of step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid hydroxy amide

Step b as embodiment 2 handles chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] oxadiazole-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide.

The preparation of embodiment 197-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid cyclo propyl methoxy-amide

Handle 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] oxadiazole-5-formic acid as embodiment 3 step b.

The preparation of preparation process a:7-fluoro-6-(2-methyl-phenyl amino)-1H benzotriazole-5-methyl formate of embodiment 207-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid

By conventional method diazotising 4,5-diaminourea-3-fluoro-2-(2-methyl-phenyl amino) essence of Niobe (by the step e preparation of embodiment 1).Obtain expecting product through post processing.The preparation of step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-methyl formate

Step I as embodiment 4 is handled 7-fluoro-6-(2-methyl-phenyl amino)-1H-benzotriazole-5-methyl formate.The preparation of step c:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid

Step j as embodiment 4 handles 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-methyl formate.

The preparation of the preparation process a:7-fluoro-6-(4-iodo-2-methyl-phenyl amino) of embodiment 217-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid hydroxy amide-1H-benzotriazole-5-carboxylic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide

Handle chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H benzotriazole-5-formic acid as embodiment 2 step a.The preparation of step b:7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid hydroxy amide

Handle chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H benzotriazole-5-formic acid O-(tetrahydrochysene-2H-pyrans-2-yl)-oxygen base amide as embodiment 2 step b.

The preparation of embodiment 227-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid cyclo propyl methoxy-amide

Handle chemical compound 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H benzotriazole-5-formic acid as embodiment 3 step b.F. other embodiment

Essential characteristics of the present invention is easy to by above-mentioned disclosure and embodiment, and following claim is clearly known.Scope of the present invention also comprises interior various modifications and the variation of the ken that those of ordinary skill is grasped.Example comprises by interpolation or removes the compound of coming into the open that protecting group is modified, or its ester, officinal salt, hydrate, acid or amide.The document that this paper quotes is all introduced for your guidance in full.

Claims

1. the Therapeutic Method of chronic pain, described method comprises that the patient to this treatment of needs uses the compositions that comprises mek inhibitor, described mek inhibitor is selected from following formula (I) compound or pharmaceutically acceptable salt thereof or C _1-7Ester:

Wherein W is OR ₁, NR ₂OR ₁, NR _AR _B, NR ₂NR _AR _B, O (CH ₂) _2-4NR _AR _BOr NR ₂(CH ₂) _2-4NR _AR _BR ₁Be H, C _1-8Alkyl, C _3-8Alkenyl, C _3-8Alkynyl group, C _3-8Cycloalkyl, phenyl, (phenyl) C _1-4Alkyl, (phenyl) C _3-4Alkenyl, (phenyl) C _3-4Alkynyl group, (C _3-8Cycloalkyl) C _1-4Alkyl, (C _3-8Cycloalkyl) C _3-4Alkenyl, (C _3-8Cycloalkyl) C _3-4Alkynyl group, C _3-8Heterocyclic radical, (C _3-8Heterocyclic radical) C _1-4Alkyl, (C _3-8Heterocyclic radical) C _3-4Alkenyl, (C _3-8Heterocyclic radical) C _3-4Alkynyl group or (CH ₂) _2-4NR _CR _DR ₂Be H, C _1-4Alkyl, phenyl, C _3-6Cycloalkyl, C _3-6Heterocyclic radical or (C _3-6Cycloalkyl) methyl; R _ABe H, C _1-6Alkyl, C _3-8Alkenyl, C _3-8Alkynyl group, C _3-8Cycloalkyl, phenyl, (C _3-8Cycloalkyl) C _1-4Alkyl, (C _3-8Cycloalkyl) C _3-4Alkenyl, (C _3-8Cycloalkyl) C _3-4Alkynyl group, C _3-8Heterocyclic radical, (C _3-8Heterocyclic radical) C _1-4Alkyl, (amino-sulfonyl) phenyl, [(amino-sulfonyl) phenyl] C _1-4Alkyl, (amino-sulfonyl) C _1-6Alkyl, (amino-sulfonyl) C _3-6Cycloalkyl, [(amino-sulfonyl) C _3-6Cycloalkyl] C _1-4Alkyl or (CH ₂) _2-4NR _CR _DR _BBe H, C _1-8Alkyl, C _3-8Alkenyl, C _3-8Alkynyl group, C _3-8Cycloalkyl or phenyl; Q is one of following formula (i)-(iii):

R ₃Be H or F; R ₄Be halogen, NO ₂, SO ₂NNR ₀(CH ₂) _2-4NR _ER _F, SO ₂NR _ER _FOr (CO) T; T is C _1-8Alkyl, C _3-8Cycloalkyl, (NR _ER _F) C _1-4Alkyl, OR _F,-NR _O(CH ₂) _2-4NR _ER _FOr NR _ER _FZ be following formula (iv)-(one of viii):

R ₅And R ₆In one be H or methyl, and R ₅And R ₆In another be H, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl group, phenyl, benzyl or-M-E-G;

M is O, CO, SO ₂, NR _J, (CO) NR _H, NR _H(CO), NR _H(SO ₂), (SO ₂) NR _HOr CH ₂

E is (CH ₂) _1-4Or (CH ₂) _mO (CH ₂) _p, 1≤(each m and p)≤3 and 2≤(m+p)≤4 wherein; Perhaps E does not exist;

G is R _K, OR ₁Or NR _JR _K, condition is if p=1, then G is H; R ₇Be H, C _1-4Alkyl, C _2-4Alkenyl, C _2-4Alkynyl group, C _3-6Cycloalkyl, phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, (CH ₂) _1-2Ar, wherein Ar is phenyl, 2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals, SO ₂NR _H(CH ₂) _2-4NR _JR _K, (CO) (CH ₂) _2-4NR _JR _KOr (CO) NR _H(CH ₂) _2-4NR _JR _KX ₁Be O, S, NR ₈Or CHR ₉X ₂Be O, S or CHR ₉And X ₃Be O or S; If X ₁Or X ₂Be CHR ₉, then disclosed chemical compound can also be tautomeric indole; R ₈Be H, C _1-4Alkyl, phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, (CH ₂) _1-2Ar, wherein Ar is phenyl, 2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals, C _2-4Alkenyl, C _2-4Alkynyl group, C _3-6Cycloalkyl or (C _2-4Alkyl) NR _LR _M, condition is R ₇And R ₈Be no more than 14 carbon atoms together, except R _L, R _M, R _JAnd R _KOutside; R _GBe C _1-4Alkyl, phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, C _3-4Alkenyl, C _3-4Alkynyl group, C _3-6Cycloalkyl, (CO) OR _P, (C _2-4Alkyl) NR _LR _M, (CO) NR _N(CH ₂) _2-4NR _LR _M, (CO) NR _LR _M, (CO) (CH ₂) _2-4-NR _LR _MOr (CH ₂) _1-2Ar, wherein Ar is phenyl, 2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals; R ₉Be C _1-4Alkyl, phenyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, C _2-4Alkenyl, C _2-4Alkynyl group, C _3-6Cycloalkyl, (CO) OR _P, (C _2-4Alkyl) NR _LR _M, (CO) NR _N(CH ₂) _2-4NR _LR _M, (CO) NR _LR _M, (CO) (CH ₂) _2-4-NR _LR _M, or (CH ₂) _1-2Ar ', wherein Ar ' is phenyl, 2-pyridine radicals, 3-pyridine radicals or 4-pyridine radicals; R _PBe H, C _1-6Alkyl, phenyl, C _3-4Alkenyl, C _3-4Alkynyl group, C _3-6Cycloalkyl or (CH ₂) _2-4NR _LR _MR ₁₀Be H, methyl, halogen or NO ₂R ₁₁Be H, methyl, halogen or NO ₂R _C, R _D, R _E, R _F, R _I, R _J, R _K, R _LAnd R _MIn each be independently selected from C _1-4Alkyl, C _3-4Alkenyl, C _3-4Alkynyl group, C _3-6Cycloalkyl and phenyl; NR _CR _D, NR _ER _F, NR _JR _KAnd NR _LR _MIn each be morpholinyl, piperazinyl, pyrrolidinyl or piperidyl independently; R _H, R _NAnd R _OIn each be H, methyl or ethyl independently; Wherein, each alkyl or heterocyclic radical randomly are independently selected from following substituent group replacement by 1-3: halogen, C _1-4Alkyl, C _3-6Cycloalkyl, C _3-4Alkenyl, C _3-4Alkynyl group, phenyl, hydroxyl, amino, (amino) sulfonyl and NO ₂, wherein each substituent group alkyl, cycloalkyl, alkenyl, alkynyl group or phenyl randomly are independently selected from following substituent group replacement by 1-3 successively: halogen, C _1-2Alkyl, hydroxyl, amino and NO ₂

2. the process of claim 1 wherein that described chronic pain is selected from neuropathic pain, the special property sent out pain and the pain relevant with chronic alcoholism, vitamin deficiency, uremia or hypothyroidism.

3. the method for claim 2, wherein said chronic pain is a neuropathic pain.

4. the method for claim 3, wherein said neuropathic pain is with following at least a kind of relevant: inflammation, postoperative pain, phantom limb pain, Burning Pain, gout, trigeminal neuralgia, acute herpes and herpes zoster infect back pain, causalgia, diabetic neuropathy, panizza's plexuses avulsion, neuroma, nodular vasculitis, viral infection, crush injury, constriction injury, tissue injury, amputation, postoperative pain, arthritis ache and any other and are included in nerve injury among peripheral nervous and the central nervous system.

5. the method for claim 2, wherein said chronic pain is relevant with alcoholism, vitamin deficiency, uremia or hypothyroidism.

6. the method for claim 2, wherein said chronic pain is relevant with spy's property sent out pain.

7. the process of claim 1 wherein described chronic pain and inflammation-related.

8. the process of claim 1 wherein that described chronic pain is relevant with arthritis.

9. the process of claim 1 wherein that described chronic pain is relevant with postoperative pain.

10. the process of claim 1 wherein that Q is formula (i).

11. the method for claim 10, wherein R ₃Be H or fluorine.

12. the method for claim 11, wherein R ₄Be fluorine, chlorine or bromine.

13. the process of claim 1 wherein R ₁₀Be hydrogen, methyl, fluorine or chlorine.

14. the process of claim 1 wherein R ₁₁Be methyl, chlorine, fluorine, nitro or hydrogen.

15. the method for claim 14, wherein R ₁₁Be H.

16. the method for claim 14, wherein R ₁₁It is fluorine.

17. the method for claim 13, wherein R ₁₀And R ₁₁In each all are fluorine.

18. the process of claim 1 wherein R ₁Be H, methyl, ethyl, propyl group, isopropyl, isobutyl group, benzyl, phenethyl, pi-allyl, C _3-5Alkenyl, C _3-6Cycloalkyl, (C _3-5Cycloalkyl) C _1-2Alkyl, (C _3-5Heterocyclic radical) C _1-2Alkyl or (CH ₂) _2-4NR _CR _D

19. the method for claim 18, wherein R ₁Be H or (C _3-4Cycloalkyl) C _1-2Alkyl.

20. the process of claim 1 wherein R ₂Be H or methyl.

21. the process of claim 1 wherein R _AHas at least one hydroxyl substituent.

22. the process of claim 1 wherein R _ABe H, methyl, ethyl, isobutyl group, 2-piperidines-1 base-ethyl, hydroxyethyl, phenyl, 2,3-dihydroxypropyl, 3-[4-(2 hydroxyethyl)-piperidines-1 base]-propyl group, 2-pyrrolidine-1-base-ethyl or 2-diethylamino ethyl; And R _BBe H; Perhaps R wherein _BBe methyl, and R _AIt is phenyl.

23. the process of claim 1 wherein that W is NR _AR _BOr NR ₂NR _AR _B

24. the process of claim 1 wherein that W is NR ₂(CH ₂) _2-4NR _AR _BOr O (CH ₂) _2-3NR _AR _B

25. the process of claim 1 wherein that W is NR ₂OR ₁

26. the process of claim 1 wherein that W is OR ₁

27. the process of claim 1 wherein Z be formula (v).

28. the method for claim 27, wherein X ₁Be NR ₈, and R ₇Be H.

29. the process of claim 1 wherein that described mek inhibitor has the structure that is selected from 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid.

30. the process of claim 1 wherein that described mek inhibitor has is selected from following structure: 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzoxazoles-5-formic acid; 7-fluoro-6-4-iodo-2-methyl-phenyl amino)-benzothiazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] thiadiazoles-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-benzo [1,2,5] oxadiazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-2-(2-hydroxyethyl)-1H-benzimidazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-2-(2-dimethylamino-ethyl)-1H benzimidazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1-acetyl group-benzimidazole-5-formic acid; 8-fluoro-7-(4-iodo-2-methyl-phenyl amino)-quinoxaline-6-formic acid and 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzotriazole-5-formic acid; And corresponding hydroxamic acid and cyclopropyl methyl Hydroxamates.

31. the process of claim 1 wherein that described mek inhibitor has is selected from following structure: 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-6,7-dihydro-1H-benzimidazole-5-formic acid (hydrochlorate); 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid; 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-5-formic acid (2-hydroxyl-ethyoxyl)-amide; 6-(2-chloro-4-iodo-phenyl amino)-7-fluoro-1H-benzimidazole-5-formic acid and 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid pentafluorophenyl group ester.

32. the process of claim 1 wherein that described mek inhibitor has is selected from following structure: 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-1H-benzimidazole-5-formic acid cyclo propyl methoxy-amide; With 7-fluoro-6-(4-iodo-2-methyl-phenyl amino)-3H-benzimidazole-5-formic acid (2-hydroxyl-ethyoxyl)-amide.