CN101437513A

CN101437513A - Use of imidazo[2,1-b)]-1,3,4-thiadiazole-2-sulfonamide compounds to treat neuropathic pain

Info

Publication number: CN101437513A
Application number: CNA2007800162926A
Authority: CN
Inventors: 容·德金; 金伯利·休伊特; 彼得·威诺库尔
Original assignee: Aegera Therapeutics Inc
Current assignee: Aegera Therapeutics Inc
Priority date: 2006-04-13
Filing date: 2007-04-13
Publication date: 2009-05-20

Abstract

Disclosed herein are methods and compositions for treating and/or prophylaxis of neuropathic pain in a subject. The methods comprise administering to the subject suffering from neuropathic pain, a therapeutically effective amount of a compound, according to Formula (I): or a salt thereof, wherein A, R<5> and R<6> are defined herein.

Description

Imidazo [2,1-b]-1,3,4-thiadiazoles-2-sulfonamide compounds is used for the treatment of the purposes of neuropathic pain

Technical field

The present invention relates to imidazo [2,1-b]-1,3,4-thiadiazoles-2-sulfonamide compounds is used for the treatment of the purposes of mammal, particularly people's neuropathic pain as medicament.

Background of invention

Neuropathic pain be around or the damage or the result of malfunction among the central nervous system.The neuropathic pain disease is characterised in that hyperesthesia (for the enhancing sensitivity of natural stimulation), hyperpathia (for the unusual sensitivity of pain), allodynia (from the pain that stimulates, described stimulation does not normally make pain) and/or spontaneous causalgia.In the mankind, it is chronic that neuropathic pain trends towards.Described pain is often triggered by damage, but this damage may or may not relate to for neural actual damage.Nerve can be by tumor-infiltrated or extruding, by the scar tissue strangulation, or by infecting or as the host of viral infection and inflammation described virus such as herpesvirus or HIV (human immunodeficiency virus).Described pain often has the character of burning, isolate or shock by electricity.Persistent allodynia from the pain that the contact of non-nociceptive stimulus such as light produces, also is the universal feature of neuropathic pain.After the healing of the surface of any damaged tissue, this pain can continue several months or several years.In this case, pain signal is no longer represented the alarm of ongoing or upcoming damage, but described warning system itself is a malfunction.Example comprises (or behind herpes zoster) neuralgia after the herpes, reflex sympathetic dystrophy/causalgia (nerve injury), cancerous pain composition, phantom limb pain, compressive neuropathy (for example, carpal tunnel syndrome), and peripheral polyneuropathy (general nerve injury).In many reasons of neuropathic pain, diabetes are the most general, but described disease can also be used, is exposed to other toxin (comprising many chemotherapies), vitamin deficiency and diversified other medical conditions by long term alcohol and caused-can not make a definite diagnosis that the reason of this disease is common.

Utilized the analgesia medicine to treat neuropathic pain traditionally such as opiates.The using of various opiates derivants such as morphine can provide alleviating to a certain degree, but it is unpractiaca for lifelong treatment aspect dosage.(Bennett, hospitalization put into practice (Hosp.Practice) the 33rd volume, the 95th to 114 page, 1998).Ratified pregabalin recently and be used for the treatment of neuropathic pain and the postherpetic neuralgia relevant, yet its shows limited clinical efficacy and needs dosed administration every day repeatedly with diabetic peripheral neuropathy (DN).Other medicament that is used for the treatment of neuropathic pain comprises antidepressants, anticonvulsant, and local anesthetic.Though many these reagent provide pain symptom to alleviate, their life-time service is owing to limited clinical efficacy, short acting duration and incoherent model of action are complicated; Has the characteristic side effect, such as dizzy, somnolence, ataxia, Bewu, abnormal thinking, blurred vision, incoordination and dependency or addicted development.Generally, the reagent of these classifications has had limited clinical success, make to need the alternative therapy of exploitation, is used for the treatment of, prevents or cure neuropathic pain.

We before disclosed also [2,1-b]-1,3 of imidazole, and 4-thiadiazoles-2-sulfonamide is in the external neuroprotective that proved, it is characterized in that protecting standing superior cervical ganglion (SCG) neuron that NGF stops using and avoiding apoptosis.These chemical compounds prevent that also the neuron of cultivating from avoiding multiple neurotoxic injury, and it comprises with cell toxicant reagent such as paclitaxel, platinum derivatives and catharanthus alkaloid handles.These chemical compounds selected and their N-acyl group prodrug derivant have proved the effect in the neuropathic around animal model, produce the enhanced functional rehabilitation from deleterious peripheral stimulation, such as those of the neuropathy that causes chemotherapy-induced (CTIN).Functional rehabilitation is to measure according to the gait motility of nerve conduction velocity of recovering and improvement.Described chemical compound shows that in the nerve injury model enhanced axon regeneration is long, and shows the electroretinograph function of improving after retinal ischemia.Because the neuron that their protections are cultivated avoids the character of neurotoxic injury, described neurotoxic injury such as the neure growth factor (NGF) is stopped using, and believes that these compound effects are on neurotrophin existence signal transduction pathway.The NGF replacement therapy has proved the clinical associated treatment of diabetic peripheral neuropathy and the inductive peripheral neuropathy of HIV-, yet it shows induces hyperpathia relevant with injection site local pain level with unacceptable.Obviously, identify and to attempt to treat potential neuropathy and do not induce or the chemical compound that worsens neuropathic pain states is useful.

The present invention relates to beat all discovery, described discovery is that chemical compound of the present invention can be treated neuropathic pain states, such as by diabetes and inflammatory mediators inductive those, cause working rapidly, permanent pain relief.As if in addition, this compounds is nerve injury in prevention or the reverting diabetes neuropathy model, indicated as the assessment of the reverse by motion and sensory nerve conduction velocity (NCV) measurement and axon diameter and loss of morphology.

Study on mechanism has shown that recently the common molecule association in many peripheral nerve poisoning injuries is the inducing of JNK phosphorylation in the dorsal horn neuron in neuron, for example cell culture, and it causes inducing of Neuron Apoptosis (apoptotic) state.Chemical compound of the present invention can be in extracorporeal blocking neuronal cell culture the inducing of JNK phosphorylation.

Recently increasing document shows, also observes JNK phosphorylation and activity (Daulhac etc., 2006 of rise in vivo in the neuron of the PNS in diabetic neuropathy (DN) preclinical models and the model at neuropathic pain; Zhuang etc., 2006; Middlemas, Agthong ， ﹠amp; Tomlinson, 2006).Similarly, neurocyte JNK phosphorylation (Doya etc., 2005 in the model of inflammatory pain, have been observed recently; Liu etc., 2007).The spinal cord of jnk inhibitor is used and is presented in the animal is being effective aspect the reverse pain status.(Zhuang etc., 2006; Liu etc., 2007).Abnormal J NK phosphorylation is also observed in the nerve biopsy sample from diabetics.(Purves etc., 2001).The related observation of supporting that the inventor alleviates for neuropathic pain in the disease model of this mechanism, and expect that further disclosed this compounds is will be in treatment people disease useful in the various states of neuropathic pain here.

Summary of the invention

The invention provides the compositions and the method for the neuropathic pain that is used for the treatment of the above-mentioned type.Described compositions and method adopt acidylate and imidazo on-acylated [2,1-b]-1,3, and 4-thiadiazoles-2-sulfonamide compounds is as their activating agent.Chemical compound lot has been disclosed in u.s. patent application serial number 10/498,548 and disclosed PCT application PCT CA02/01942 and the u.s. patent application serial number of owning together 10/599,675, among the disclosed PCT application PCT/CA2004/000873.

When using by drug systemic administration route, imidazo of the present invention [2,1-b]-1,3,4-thiadiazoles-2-sulfonamide show beat all effect beginning and acting duration in the body inner model of several diabetes nerve pain and inflammatory neuropathic pain.In addition, when oral providing, oral is the preferred routes that is used for long-term treatment, and the subclass of these chemical compounds has shown effect.

Unexpectedly, these chemical compounds work unlike typical analgesic such as NSAIDS, opiates or gabapentin, described typical analgesic after single administration only 2-6 hour be active.Be presented at after the single dose chemical compound, the pain relief that provides by chemical compound of the present invention continues nearly 24 hours.

In addition, nerve injury is prevented or reversed to such other compound exhibits in the model of DN, as measure by motion and sensation conduction velocity (NCV) and the two evaluation of aixs cylinder morphology as shown in.

According to one embodiment of the invention; the method that treats and/or prevents neuropathic pain is provided; described method comprises: the imidazo [2 one or more acidylates or on-acylated that will treat effective dose; 1-b]-1; 3,4-thiadiazoles-2-sulfonamide compounds is applied to the experimenter who suffers neuropathic pain.

According to another embodiment of the invention, the method that treats and/or prevents neuropathic pain is provided, described method comprises that the compound or its salt according to formula I with the treatment effective dose is administered to the experimenter who suffers neuropathic pain:

Wherein:

N is 1 or 2;

M is 0 to 22 integer;

S is 0 to 6 integer;

P is 0 to 1 integer;

Y is NH, O or S;

A is-S (O) ₂NR ¹R ²

R ¹And R ²Be independently selected from:

1)H，

2) C ₁-C ₆Alkyl, or

3)C(O)R ⁴；

R ⁴Be

1) C ₁-C ₁₈Alkyl,

2) aryl,

3) heteroaryl,

4) (CH ₂) _s-(C (O)) _p-(OCH ₂CH ₂) _mOR ¹⁰Or

5) C ₁-C ₆Alkyl-NR ¹¹R ¹²,

Wherein alkyl is chosen wantonly and is used one or more R ¹⁵Substituent group replaces; And aryl and heteroaryl are chosen wantonly and are used one or more R ²⁰Substituent group replaces;

R ⁵Be:

1)H，

2) halogen,

3) C ₁-C ₆Alkyl,

4) phenyl,

5) S-aryl, or

6) S-heteroaryl,

Wherein said aryl and described heteroaryl are chosen wantonly and are used one or more R ²⁰Substituent group replaces; R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

Wherein said aryl and described heteroaryl are optional with one or more R that are independently selected from ²⁰Substituent group replace;

R ¹⁰Be

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) C ₂-C ₆Alkenyl;

5) C ₂-C ₆Alkynyl;

6) C ₅-C ₇Cycloalkenyl group,

7) aryl,

8) heteroaryl, or

9) heterocyclic radical,

Wherein said alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl group are chosen wantonly and are used one or more R ¹⁵Substituent group replaces, and described aryl, and heteroaryl, heterocyclic radical and xenyl are chosen wantonly and used one or more R ²⁰Substituent group replaces;

R ¹¹And R ¹²Be independently selected from:

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) aryl,

5) heteroaryl,

6) heterocyclic radical,

7) CO-C ₁-C ₆Alkyl

8) CO-C ₃-C ₇Cycloalkyl

9) CO-aryl,

10) CO-heteroaryl,

11) CO-heterocyclic radical,

12) C (O) Y-C ₁-C ₆Alkyl

13) C (O) Y-C ₃-C ₇Cycloalkyl

14) C (O) Y-aryl,

15) C (O) Y-heteroaryl, or

16) C (O) Y-heterocyclic radical,

Wherein said alkyl and described cycloalkyl are chosen wantonly and are used one or more R ¹⁵Substituent group replaces, and described aryl, and heteroaryl, heterocyclic radical and xenyl are chosen wantonly and used one or more R ²⁰Substituent group replaces; Or R ¹¹And R ¹²Nitrogen-atoms with their bondings forms optional one or more R that use ²⁰Five, six or seven membered heterocyclic that substituent group replaces;

R ¹⁵Be

1)NO ₂，

2)CN，

3) halogen,

4) C ₁-C ₆Alkyl,

5) C ₃-C ₇Cycloalkyl,

6) alkylhalide group,

7) aryl,

8) heteroaryl,

9) heterocyclic radical,

10)OR ¹⁰，

11)S(O) _nR ¹⁰，

12)NR ¹¹R ¹²，

13)COR ¹⁰，

14)CO ₂R ¹⁴，

15) CONR ¹¹R ¹², or

16)S(O)nNR ¹¹R ¹²，

Wherein said aryl and heteroaryl are chosen wantonly and are used one or more R ¹⁰Substituent group replaces;

R ²⁰Be

1)NO ₂，

2)CN，

3)N ₃，

4)B(OH) ₂，

5) adamantyl,

6) halogen,

7) C ₁-C ₆Alkyl,

8) C ₃-C ₇Cycloalkyl,

9) aryl,

10) heteroaryl,

11) heterocyclic radical,

12) fused phenyl heterocyclic radical,

13) alkylhalide group,

14)OR ¹⁰，

15)SR ¹⁰，

16)S(O) _nR ¹⁰，

17)NR ¹¹R ¹²，

18)COR ¹⁰，

Wherein said alkyl, described aryl, described heteroaryl, described heterocyclic radical and described cycloalkyl are chosen wantonly and are used one or more R ¹⁵Substituent group replaces.

According to another embodiment of the invention, be provided for treating and/or preventing the pharmaceutical composition of neuropathic pain, described compositions comprises: the compound or its salt according to formula I of pharmaceutical carrier and treatment effective dose:

R wherein ⁵And R ⁶As defined above.

Therefore in another embodiment, the method that treats and/or prevents neuropathic pain is provided, and described method comprises: with the chemical compound of formula I and another kind of reagent to be enough to the causing treatment effective dose administering drug combinations of pain relief to the experimenter who suffers neuropathic pain.

Therefore in another embodiment, the method that treats and/or prevents neuropathic pain is provided, and described method comprises: with aforesaid compositions and another kind of reagent to be enough to the causing treatment effective dose administering drug combinations of pain relief to the experimenter who suffers neuropathic pain.

According to another embodiment of the invention, provide aforesaid formula I chemical compound or pharmaceutical composition in the experimenter, to treat and/or prevent the purposes of neuropathic pain.

According to another embodiment of the invention, aforesaid formula I chemical compound or the pharmaceutical composition purposes in the preparation medicine is provided, described medicine is used for treating and/or preventing neuropathic pain the experimenter.

According to another embodiment of the invention, provide aforesaid formula I chemical compound or pharmaceutical composition and another kind of combination of agents in the experimenter, to treat and/or prevent the purposes of neuropathic pain.

Therefore, in another embodiment, provide aforesaid formula I chemical compound or pharmaceutical composition and another kind of combination of agents in the purposes of preparation in the medicine, described medicine is used for the treatment of and/or prevents neuropathic pain.

The accompanying drawing summary

Combine with following accompanying drawing, with reference to description, many-sided and advantage of the present invention will become better understood, wherein:

Fig. 1 is illustrated in after the bimestrial treatment, and chemical compound 150 is for the chart of the influence of sensory nerve conduction velocity in the diabetes rat (SNCV), and treatment has been significantly to start later in the conduction velocity defective;

Fig. 2 is illustrated in after the bimestrial treatment, and chemical compound 150 is for the chart of the influence of motor nerve conduction velocity in the diabetes rat (MNCV), and treatment has been significantly to start later in the conduction velocity defective;

Fig. 3 is the form metric analysis that the diagram sural nerve has the marrow aixs cylinder.Notice that D refers to the animal of vehicle treatment, B refers to the animal of chemical compound 150 treatments, and DI indication rats with diabetes and C indicate ND age-matched contrast; The average aixs cylinder area of Fig. 3 a diagram; Fig. 3 b diagram size-frequency histogram;

Fig. 4 is the form metric analysis of the medullated aixs cylinder of sural nerve of diagram large-size (greater than 9 square microns).Fig. 4 A: average aixs cylinder area and Fig. 4 B: by the frequency histogram of size classes.Notice that D refers to the animal of vehicle treatment, B refers to the animal of chemical compound 150 treatments, and DI indication rats with diabetes and C indicate ND age-coupling to contrast;

Fig. 5 is the influence of diagram chemical compound 150 for tactile allodynia in the later diabetes rat of 1,5 and 10 treatment;

Fig. 6 is that diagram chemical compound 157 is for treating the figure of the influence of the tactile allodynia in the later diabetes rat every day before the treatment and at 1,13 and 14 time;

Fig. 7 is that diagram chemical compound 158 is for treating the figure of the influence of the tactile allodynia in the later diabetes rat every day before the treatment and at 1,13 and 14 time;

Fig. 8 is diagram chemical compound 155 6 hours figure for the influence of the tactile allodynia in the diabetes rat after the single subcutaneous administration;

Fig. 9 is a diagram chemical compound 157 for the figure of the influence of the tactile allodynia in 6 hours the diabetes rat after the subcutaneous administration;

Figure 10 is a diagram chemical compound 157 for the figure of the influence of the tactile allodynia in 6 hours the diabetes rat behind the oral administration;

Figure 11 is a diagram chemical compound 154 for the figure of the influence of the tactile allodynia in 6 hours the diabetes rat after the subcutaneous administration;

Figure 12 is a diagram chemical compound 158 for the figure of the influence of the tactile allodynia in 6 hours the diabetes rat after the subcutaneous administration;

Figure 13 diagram chemical compound 160 is for the influence of the tactile allodynia in 6 hours the diabetes rat after the subcutaneous administration;

Figure 14 is the chart of diagram chemical compound 157 for the influence of the tactile allodynia in 6 hours later on diabetes rat of the 5th oral drugs, and described medicine is oral once a day, continuous 5 days;

Figure 15 is the chart of diagram chemical compound 158 for the influence of the tactile allodynia in 6 hours later on diabetes rat of the 5th oral drugs, and described medicine is oral once a day, continuous 5 days;

Figure 16 is diagram chemical compound 150 figure for the hyperalgesic influence of sense of touch in the CFA pain model after subcutaneous administration;

Figure 17 is diagram chemical compound 155 figure for the hyperalgesic influence of sense of touch in the CFA pain model after subcutaneous administration;

Figure 18 is diagram chemical compound 157 figure for the hyperalgesic influence of sense of touch in the CFA pain model after subcutaneous administration;

Figure 19 is diagram chemical compound 158 figure for the hyperalgesic influence of sense of touch in the CFA pain model after subcutaneous administration;

Figure 20 is diagram chemical compound 157 figure for the hyperalgesic influence of sense of touch in the CFA pain model after oral; With

Figure 21 is diagram chemical compound 157 6 hours charts for the hyperalgesic influence of sense of touch in the diabetes rat after the 5th drug oral, and described medicine is oral once a day, continuous 5 days.

Detailed Description Of The Invention

Definition

Unless except as otherwise noted, be suitable for following definition:

＂ of singulative ＂, ＂＂ and the described ＂ of ＂ comprise that corresponding plural number refers to object, unless on Hereinafter clearly stipulate in addition.

As used herein, described term ＂ comprises ＂ and is intended to refer at word and " comprises " afterwards key element tabulation Be that need or compulsory, but other key element is optional and can exist or not exist.

As used herein, term " by ... form " be intended to refer to and comprise and be limited at phrase " by ... institute Form " afterwards anything. Thus described term " by ... form " the listed key element of expression is needs Or compulsory, and do not have other key element to exist.

As used herein, term ＂ alkyl ＂ is intended to comprise side chain and the saturated aliphatic hydrocarbon groups of straight chain, and it has the carbon atom of specified quantity, for example, and at C₁-C ₆C in the-alkyl₁-C ₆Be defined as and comprise having 1,2, the group with the arrangement of straight or branched form of 3,4,5 or 6 carbon, and C₁-C ₄C in the alkyl₁-C ₄Be defined as and comprise having 1,2,3, or 4 carbon with the straight or branched form The group of arranging. C as defined above₁-C ₆-alkyl and C₁-C ₄The example of alkyl comprises, but does not limit In, methyl, ethyl, just-and propyl group, different-propyl group, just-and butyl, tert-butyl, different-butyl, amyl group And hexyl. Be also included within this definition is C_1-18C in the alkyl_1-18, with its be defined as comprise lower The row group, described group has 1,2,3,4,5,6,7,8,9,10,11,12,13, 14,15,16,17, or 18 carbon atoms, arrange with the straight or branched form.

As used herein, term ＂ alkenyl ＂ is intended to refer to unsaturated straight or branched alkyl, at it Described in alkyl have the carbon atom of specified quantity, and wherein at least two described carbon atoms by two The mutual bonding of key, and have E or Z regional chemistry and combination thereof. For example, C₂-C ₆C in the alkenyl₂-C ₆Be defined as and comprise having arranging with the straight or branched form of 2,3,4,5 or 6 carbon Group, at least two carbon atoms are bonded together by two keys. C₂-C ₆The example of alkenyl comprises Vinyl (vinyl), 1-acrylic, 2-acrylic, 1-cyclobutenyl etc.

As used herein, term ＂ alkynyl ＂ be intended to refer to have therein specified quantity carbon atom also And the alkyl of undersaturated, the straight chain that is bonded together by triple bond of at least two carbon atoms wherein. Example Such as C₂-C ₄C in the alkynyl₂-C ₄Be defined as to be included in and have 2,3 in the chain, or the base of 4 carbon atoms Group, at least two carbon atoms are bonded together by triple bond. The example of such alkynyl comprise acetenyl, 1-propinyl, 2-propynyl etc.

As used herein, term ＂ cycloalkyl ＂ is intended to refer to the monocycle representative examples of saturated aliphatic alkyl that has therein the specified quantity carbon atom, for example, and C₃-C ₇C in the cycloalkyl₃-C ₇Be defined as comprise have 3, 4, the group with single loop arrangement of 5,6 or 7 carbon. C as defined above₃-C ₇The reality of cycloalkyl Example includes, but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.

As used herein, term ＂ cycloalkenyl group ＂ is intended to refer to the monocycle representative examples of saturated aliphatic alkyl that has therein the specified quantity carbon atom, for example, and C₃-C ₇C in the cycloalkenyl group₃-C ₇Be defined as comprise have 3, 4, the group with the arrangement of monocycle form of 5,6 or 7 carbon. C as defined above₃-C ₇Cycloalkenyl group Example include, but not limited to cyclopentenyl, and cyclohexenyl group.

As used herein, term ＂ halogen ＂ or ＂ halogen ＂ are intended to refer to fluorine, chlorine, bromine and iodine.

As used herein, term ＂ alkylhalide group ＂ is intended to refer to as defined above alkyl, wherein each Hydrogen atom can be used the halogen atom sequential replacement. The example of alkylhalide group includes, but not limited to CH₂F， CHF ₂And CF₃。

As used herein, term ＂ aryl ＂ is intended to refer to and contains any stable of 6 or 10 carbon atoms Monocycle or bicyclic aromatic carbocyclic ring. The example of such aryl substituent includes, but not limited to phenyl And naphthyl.

As used herein, term ＂ xenyl ＂ is intended to refer to any one of available site on phenyl ring Two phenyl that are bonded together on individual. For example:

As used herein, term ＂ fused-aryl-C₃-C ₇Cycloalkyl ＂ is intended to refer to and defines here Cycloalkylfused defined aryl here. Aryl-the C that condenses₃-C ₇Cycloalkyl can be at cycloalkanes Be connected to another group on the suitable position on basic ring or the aromatic ring. For example:

The arrow line of pulling out from member ring systems represents that described key can be incorporated into the annular atoms that is fit to arbitrarily.

When using in this article, term ＂ condensed heteroaryl-C₃-C ₇Cycloalkyl ＂ is intended to refer to heteroaryl, When here using, it is with as herein defined Cycloalkylfused. Condensed heteroaryl-C₃-C ₇Cycloalkyl can be connected to another group in the suitable position on cycloalkyl ring or heteroaromatic rings.

When using in this article, term ＂ fused-aryl-heterocyclic radical ＂ is intended to refer to the heterocycle of this paper definition Base, its be with limit here aryl-fused. Fused-aryl-heterocyclic radical can be on aromatic ring or heterocycle Suitable position be connected to another group. The example of fused-aryl-heterocyclic radical includes, but not limited to Benzo [d] [1,3] dioxole, 2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxine and 3,4-dihydro-2H-benzene And [b] [Isosorbide-5-Nitrae] dioxane heptene (dioxepine).

When using in this article, term ＂ condensed heteroaryl-heterocyclic radical ＂ is intended to refer to as defined herein Heteroaryl, it condenses with heterocyclic radical as herein defined. Condensed heteroaryl-heterocyclic radical can Suitable position on hetero-aromatic ring or heterocycle is connected to another group.

As used herein, term ＂ heteroaryl ＂ be intended to refer to ten atoms at the most monocycle or dicyclo Ring system, wherein at least one ring is aromatics, and contain 1 to 4 be selected from by O, N, The hetero atom of the group that forms with S. Described heteroaryl substituting group can be assorted former via ring carbon atom or one Sub-connection. The example of heteroaryl includes, but are not limited to thienyl, benzimidazolyl, benzo [b] thiophene Base, furyl, benzofuranyl, pyranose, isobenzofuran-base, benzopyranyl, xanthyl, The 2H-pyrrole radicals, pyrrole radicals, imidazole radicals, pyrazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazine Base, indolizine base, isoindolyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-The quinolizine base, isoquinolyl, quinolyl, phthalazinyl, 1,5-phthalazinyl, quinoxalinyl, quinoline azoles The quinoline base, the cinnolines base, pteridyl, isothiazolyl, the isochroman base, chromanyl, Isoxazolyl, furazan base, indolinyl, and iso-dihydro-indole-group.

As used herein, term ＂ heterocycle ＂, the ＂ of ＂ heterocycle or ＂ heterocyclic radical ＂ are intended to refer to and contain 1 to 4 Individual heteroatomic 5, the 6 or 7 yuan of non-aromatic loop systems that are selected from the group that is formed by O, N and S. Assorted The example of ring includes, but are not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, pyrrolinyl, piperazine The piperazine base, imidazolinyl, morpholinyl, imidazolinyl, pyrazolidinyl, and pyrazolinyl.

When using in this article, term ＂ neuropathic pain ＂ is intended to refer to by following caused pain: Peripheral nerve trauma, compressive neuropathy, nerve block (transaction), comprise operation, burn Bitterly, amputation and deformed limb pain, neuroma and cut open chest postoperative (post-choracotomy) pain, single Neuropathy is such as the diabetes mononeuropathy, and pernicious nerve/neuropile is invaded, the local hemorrhage irradiation (ischemic irradiation), connective tissue disease, rheumatoid arthritis, systemic loupus erythematosus, PAN; Polyneuropathy is such as the diabetes polyneuropathy, Alcoholic polyneuropathy, nutrition The property polyneuropathy, amyloidosis polyneuropathy, glycosphingolipidosis, chemistry (for example, chemotherapeutics), congenital Property and AIDS neuropathy; Root and DRGs, prolapsus dish/compressing, postherpetic neuralgia or trident Neuralgia, archnoiditis, root avulsion, oncothlipsis and surgery rhizotomy; Spinal cord injury Such as wound, block, hemisection, agile tractotomy in distress, fistula, multiple sclerosis, oncothlipsis, Arteriovenous malformation, dysraphism (Dyscraphism), vitamin B12 deficiency, hematomyelia, syphilis Property myelitis, and commissural; Brain-stem injury is such as Wallenberg syndrome, multiple sclerosis Disease, tuberculoma, tumour, and fistula; Thalamic lesions, such as infarct, tumour, the surgery of main nuclear, sensory nucleus Damage and hemorrhage; Damage under cortex/cortex, such as infarct, wound, tumour, and arteriovenous malformation, Such as the pain management (Pain Management) at Rochelle Wagner and Robert R.Myers Middle definition. The painful diabetic peripheral neuropathy of other type, postherpetic neuralgia, trident god Dysmenorrhoea, pain after the apoplexy, the pain that multiple sclerosis is relevant, the pain that neuropathy is relevant, such as After the congenital or wound in neuropathy and the mononeuritis, the neuropathic pain that HIV-is relevant, cancer is relevant Neuropathic pain, the neuropathic pain that canalis carpi is relevant, the pain that spinal cord injury is relevant, complexity district The territory pain syndrome, the neuropathic pain that fibromyalgia is relevant, waist and cervical pain reflect sympathetic The property malnutrition, phantom limb syndrome and the relevant pain syndrome of other chronic and weak illness.

As used herein, term ＂ hetero atom ＂ is intended to refer to O, S or N.

As used herein, term " replaces arbitrarily with one or more substituting groups " or its equivalent terms " is used At least one substituting group replaces arbitrarily " be intended to refer to subsequently that the situation event of describing may take place or can Can not take place, and described description comprises the situation that event wherein or situation take place and wherein it does not take place Situation. This definition is intended to refer to 0-5 substituting group.

As used herein, term " treatment effective dose " is intended to refer to by treating and/or preventing effectively Alleviate or eliminate the amount of the compound of the present invention of neuropathic pain.

As used herein, term ＂ experimenter ＂ is intended to refer to the mankind and non-human mammal, such as Primate, cat, dog, pig, ox, sheep, goat, horse, rabbit, rat, mouse etc.

As used herein, term ＂ pharmaceutical carrier, diluent or excipient ＂ are intended to refer to without limitation Any adjuvant, carrier, excipient, glidant, sweetener, diluent, anticorrisive agent, dyestuff/ Colouring agent, flavour enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizing agent, Isotonic agent, solvent, emulsifying agent, or encapsulation agent, such as liposome, cyclodextrin is sealed polymerization and is sent System or polyethylene glycol matrix, it is the experimenter, preferably the use among the mankind is acceptable.

As used herein, term ＂ pharmaceutical salts ＂ is intended to refer to the bronsted lowry acids and bases bronsted lowry addition salts.

As used herein, term ＂ medicinal acid addition salt ＂ is intended to refer to the biology effect that keeps free alkali Those salt of power and character, it is not biologically or otherwise undesirable, its be with Inorganic acid and organic acid form, all example hydrochloric acids of described inorganic acid, hydrobromic acid, sulfuric acid, nitric acid, phosphorus Acid etc., described organic acid are such as acetic acid, trifluoroacetic acid, and propionic acid, glycolic, pyruvic acid, oxalic acid, Maleic acid, malonic acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, Mandelic acid, methanesulfonic acid, ethyl sulfonic acid, right-toluenesulfonic acid, salicylic acid, etc.

As used herein, term ＂ medicinal basic addition salts ＂ is intended to refer to the biology effect that keeps free acid Those salt of power and character, it is not biology or otherwise undesirable. These salt are Prepare from the addition of inorganic base or organic base and free acid. The salt that is obtained by inorganic base comprises, but Be not limited to sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salt etc. By organic base The salt that obtains includes, but not limited to following salt: primary amine, secondary amine, and tertiary amine, replacement Amine comprises the amine of naturally occurring replacement, cyclic amine and deacidite, and such as isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA), monoethanolamine, DMAE, 2-diethyl Ethylaminoethanol, dicyclohexyl amine, lysine, arginine, histidine, caffeine, procaine, sea Ba Mingqing, choline, betaine, 1,2-ethylenediamine, aminoglucose, methylglucosamine, dimethyl yellow is fast Purine, purine, piperazine, piperidines, N-ethylpiperidine, polyamines resin etc.

Compound of the present invention, or their pharmaceutical salts can contain one or more asymmetric centers, Chiral axis and chirality plane, and thereby can produce enantiomter, diastereoisomer and Its stereoisomeric forms in any ratio, and can be chemically defined according to absolute stereo, such as (R)-or (S)-, such as For amino acid whose (D)-or (L)-. This invention is intended to comprise all so possible isomers, and, Their racemic and optically pure form. Can utilize chiral synthon (synthon) or chiral reagent Prepare optically active (+) and (-), (R)-and (S)-or (D)-and (L)-isomers, or utilize routine side Method splits such as reversed-phase HPLC. Can and be separated into subsequently independent revolving with the racemic mixture preparation Photoisomer, or these optical isomers can be by the synthetic preparation of chirality. Described enantiomter can To split by method known to those skilled in the art, for example by forming diastereo-isomerism salt, right After can be with it by crystallization, gas-liquid or liquid chromatogram, a kind of enantiomter and mapping is different Structure body specific reagent selective reaction and separating. It will be appreciated by those skilled in the art that wherein with institute Need enantiomter to change into by isolation technics in the situation of another kind of chemical entities, then need to add Step is to form required enantiomeric forms. Alternatively, can be by utilizing optically-active reagent, the end The asymmetric syntheses of thing, catalyst or solvent or a kind of enantiomter is turned to by asymmetric conversion Change into another kind of enantiomter and synthetic specific enantiomter.

Some compound of the present invention can exist with zwitterionic form, and the present invention includes these Zwitterionic form of compound and composition thereof.

I. compound

Compound of the present invention can be represented by formula I. Compound of the present invention can utilize WO03/051,890A1; And WO2004/111, disclosed chemistry or its reorganization among the 061A and synthesize, Its content is incorporated into this by reference in its entirety.

One subset of the compound of formula I comprises the compound or its salt of formula Ia:

R wherein¹，R ²，R ⁵And R⁶As defined above.

In the subset of formula Ia, R¹And R²Be independently selected from by H, methyl, ethyl, propyl group, Group with the butyl composition. In one embodiment, R¹And R²All be H.

In the alternative subset of formula Ia, R²H and R¹C (O) R⁴, R wherein⁴As above Define in the literary composition.

In the subset of formula Ia, R⁵H, C₁-C ₆Alkyl or phenyl. In one embodiment, R⁵H.

In the subset of formula Ia, R⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) the optional fused phenyl-heterocyclic radical that replaces with cycloalkyl, wherein said aryl and described heteroaryl are optional with one or more R that are independently selected from²⁰Substituting group replace.

The above R in sight⁶A subset in, R⁶Optional one or more R that use²⁰Substituting group is got The phenyl in generation. In one embodiment, R⁶Be selected from the group that is formed by following:

In the alternative subset of formula Ia, R⁶Heteroaryl, with two or more methyl substituted thick Close phenyl-cycloalkyl, or the fused phenyl-heterocyclic radical that replaces with cyclohexane. In one embodiment, R⁶Be selected from the group that is formed by following:

With

The instantiation of the compound of formula Ia comprises:

Other instantiation comprises the compound of formula Ia:

R ¹	R ²	R ⁵	R ⁶
R ¹	R ²	R ⁵	R ⁶

Can in implementing method of the present invention, comprise by other useful imidazo thiadiazole compound:

2. composition

Compound of the present invention or their pharmaceutical salts or their prodrug, can with pure form or with Suitable pharmaceutical compositions is used, and can be via Gai Lun (Galenic) medicine of any acceptance Practice mode carries out.

Pharmaceutical composition of the present invention and suitable pharmaceutical carrier, diluent or excipient can pass through The following manner preparation: with compound of the present invention, with described carrier, diluent or mixed with excipients, Can be mixed with then the preparation of following form: solid, half-solid, liquid or gas form, such as Tablet, capsule, powder, granule, ointment, solution, suppository, injection, inhalant, solidifying Glue, microsphere, and aerosol. The typical method of administration of such pharmaceutical composition is wrapped without limitation Draw together, oral, local, transdermal, suck parenteral (hypodermic injection, intravenous, flesh In, intrasternal injection or infusion techniques), the hypogloeeis, eye, rectum, vagina, and nose In. Prepare pharmaceutical composition of the present invention in order to allow that the active component that is included in wherein is with described It is bioavailable when composition is applied to the experimenter. Will be applied to experimenter or patient's combination Thing is taked the form of one or more dosage units, and wherein for example, tablet can be single dosage list The position, and the container of the The compounds of this invention of aerosol form can hold a plurality of dosage units. For Those skilled in the art, the practical methods for preparing such formulation is known, maybe will be apparent ; For example, see Lei Mingdun pharmaceutical science (Remington ' s Pharmaceutical Sciences), the 18th Version, (Mack publishing company (Mack Publishing Company), Easton, Pa., 1990). Any In the situation, the composition that use contains the The compounds of this invention for the treatment of effective dose, or its pharmaceutical salts, Be used for the treatment of aforesaid neuropathic pain.

Pharmaceutical composition of the present invention can be the form of solid or liquid. In one aspect, described Carrier is particulate, so that described composition is, for example, with tablet or powder form. Described a kind of or Variety carrier can be liquid, and described composition is, for example, and oral syrup agent, injectable liquid Or aerosol, it is useful in inhalation for example.

For oral, described pharmaceutical composition is typically with solid or liquid form, wherein semi-solid, Semiliquid, suspension and gel form are included in here within the form of considering as solid or liquid.

As being used for oral solid composite, described pharmaceutical composition can be mixed with powder, particle Agent, compressed tablets, pill, capsule, chewing gum, the forms such as wafer. So a kind of solid Composition will typically contain one or more inert diluents or edible carrier. In addition, can Have following one or more: adhesive is such as carboxymethyl cellulose, ethyl cellulose, crystallite fibre Dimension is plain, bassora gum or gelatin; Excipient is such as starch, and lactose or dextrin, disintegrant be such as alginic acid, Sodium alginate, sodium carboxymethyl starch (Primogel), cornstarch etc.; Lubricant such as dolomol or Hydrogenated vegetable oil; Glidant is such as colloidal silica; Sweetener is such as sucrose or asccharin; Fumet Such as peppermint, gaultherolin or orange flavor flavor enhancement; And colouring agent.

When described pharmaceutical composition was capsule form, for example, gelatine capsule was except above class section bar Outside the material, it can also contain liquid-carrier such as polyethylene glycol or oil, such as soybean or vegetable oil.

Described pharmaceutical composition can be the form of liquid, for example, and elixir, syrup, solution, breast Liquid or supensoid agent. As two examples, described liquid can be used for oral or be used for passing through injected delivery. When being oral design, except this compound, composition can contain sweetener, anticorrisive agent, In dyestuff/colouring agent and the flavour enhancer one or more. At the composition that is intended to use by injection In, can comprise surfactant, anticorrisive agent, wetting agent, dispersant, suspending agent, buffer solution, In stabilizing agent and the isotonic agent one or more.

Composition of liquid medicine of the present invention, no matter they are solution, supensoid agent or other form can To comprise in the following adjuvant one or more: sterile diluent is such as water for injection, saline solution, Physiological saline typically, Ringer solution, isotonic sodium chloride, fixed oil is such as serving as Synthetic list or the diglyceride of solvent or suspension media, polyethylene glycol, glycerine, propane diols or its Its solvent; Antiseptic is such as phenmethylol or methyl hydroxybenzoate; Antioxidant such as ascorbic acid or Sodium hydrogensulfite; Chelating agent is such as 1,2-ethylenediamine tetra-acetic acid; Buffer solution is such as acetate, citric acid Salt or phosphate and be used for the reagent of tension adjustment are such as sodium chloride or dextrose. Parenteral administration Can be enclosed in ampoule, disposable syringe or the multiple dose phial of being made by glass or plastics. Can The pharmaceutical composition of injection is typically aseptic.

Being used for parenteral administration or oral composition of liquid medicine of the present invention should contain an amount of Therefore The compounds of this invention will obtain the dosage that is fit to. Typically, this amount is in described composition At least 0.01% The compounds of this invention. When being oral design, this amount can be heavy at described composition Amount 0.1 and about 70% between change. Use for parenteral, preparation is according to composition of the present invention With preparation so that parenteral dosage unit contains the The compounds of this invention of at least 0.01 % by weight.

Pharmaceutical composition of the present invention can be used for local application, and in described situation, described carrier can Compatibly to comprise solution, emulsion, ointment or gel-type vehicle. Described matrix for example, can be wrapped Contain following one or more: vaseline, lanolin, polyethylene glycol, beeswax, mineral oil, diluent Such as water and alcohol and emulsifying agent and stabilizing agent. Thickener may reside in the medicine for local application In the composition. If for transdermal administration designs, then described composition can comprise percutaneous plaster or Iontophoretic device. The concentration that topical formulations can contain The compounds of this invention is at least 0.1 weight Amount/volume % (weight/unit volume).

Pharmaceutical composition of the present invention can be used for rectal administration with for example suppository form, and it will be at rectum The middle thawing and the release medicine. The composition that is used for rectal administration can contain oleaginous base as being fit to Non-irritating excipient. This matrix comprises lanolin without limitation, cocoa butter and polyethylene glycol.

Pharmaceutical composition of the present invention can comprise multiple material, and it changes solid or liquid dosage unit Physical form. For example, described composition can comprise the material that forms around the dressing shell of active component Material. The material that forms the dressing shell is inertia typically, and can be selected from, for example, sugar, lac, And other enteric coating reagent. Alternatively, described active component can be encapsulated in the gelatine capsule.

The pharmaceutical composition of the present invention of solid or liquid form can comprise and is attached to chemical combination of the present invention The reagent that thing and therefore auxiliary described compound are sent. The reagent that is fit to that in this ability, works Include, but not limited to monoclonal or polyclonal antibody, protein or liposome.

Pharmaceutical composition of the present invention can be made up of the dosage unit of using as aerosol. Term gas The mist agent be used for expression from have a colloidal state attribute those in the system scope that is formed by pressurized package Multiple systems. Can be by gas liquefaction or compression or by distributing being fit to of described active component Pumping system is sent. The aerosol of The compounds of this invention can be in single-phase, two-phase or three-phase system Send, in order to send one or more active components. Sending of aerosol comprises necessary container, and be sharp Agent alive, valve, inferior container etc., it can form external member together. Those skilled in the art were not having Can determine concrete aerosol in the situation of degree experiment.

Can prepare pharmaceutical composition of the present invention by the well-known technology of drug world. Example As, being intended to the pharmaceutical composition used by injection can be by with The compounds of this invention and aseptic steaming Heating up in a steamer the water mixing prepares in order to form solution. Can add surfactant to promote homogeneous phase solution or outstanding The formation of supernatant liquid. Surfactant is in order to promote described with the The compounds of this invention noncovalent interaction The compound that compound dissolves in the aqueous delivery system or homogeneous phase suspends.

Compound of the present invention, or their pharmaceutical salts are used described controlling to treat effective dose Treat effective dose and will depend on that many factors changes, described factor comprises the work of the particular compound of employing The property; The metabolic stability of described compound and action length; Patient's age, body weight, general health, Sex, and diet; Method of application and time; Secreting rate; Drug regimen; Neuropathic pain tight The treatment that principal characteristic and experimenter stand.

3. effectiveness

Have been found that at present acidylate and imidazo on-acylated [2,1-b]-1,3,4-thiadiazoles-2-sulfonamide Compound provides treating and/or preventing of neuropathic pain. Thus, compound as described herein and medicine Compositions is found to have as treating and/or preventing mammal, particularly human neuropathic pain The purposes of therapeutic agent.

As mentioned above, compound as described herein is suitable in the multi-medicament delivery system. Be used for The dosage level that passes through the intravenous route injection for the treatment of pain associated conditions can be at about 0.1mg/kg To the scope of about 10mg/kg. The intramuscular injection scheme can be sent described amount with 1 to 3 daily dose. Also can use about 0.1mg/kg to the pill of about 10mg/kg or above preloaded to realize enough Steady-state level. Human patients for 40 to 80kg, the maximum accumulated dose of expection is no more than about 2 G/ days.

For the treatment of long-term illness such as chronic neuropathic pain, therapeutic scheme can continue the several months or Several years is so the oral dose administration is typical for patient's convenience and tolerance. In oral agents In the situation of amount administration, typical scenario can be every day 1 to 5 time, and particularly 2 to 4 times also And usually be 3 times oral dose. Utilize these dosage regimens, each dosage can provide About 0.1 to about 100mg/kg described compound, exemplary dosage provide about 0.1 separately to about 50mg/kg.

Described compound can be used as that independent activating agent is used or they can with active analgestic connection Close and use, described analgestic comprises morphine such as opioid analgesic, C16H25NO2, and buprenorphine, Dolantin, Oxycodone, hydrocodone and diacetylmorphine, paracetamol, Gabapentin, A Si Woods and that NSAIDs.

Also with the The compounds of this invention therapeutic alliance in effectively reagent be from the antidepressants classification, all As, amitriptyline, desipramine, maprotiline, Paxil, nortriptyline and Venlafaxine; Anticonvulsive drug is such as carbamazepine, valproate, Gabapentin and Clonazepam; And local anesthetic Such as mexiletine and lidocaine.

In order to prevent neuropathic pain, also above-mentioned composition can be applied to described experimenter.

Embodiment

The following example only is used for the illustrative purpose and is intended that nonrestrictive.

Synthesizing of chemical compound 1:

The 6-phenylimidazole is [2,1-b]-1,3 also, 4-thiadiazoles-2-sulfonamide

(4.00g, 20.0mmol) with 2-amino-1,3, (3.60g's 4-thiadiazoles-5-sulfonamide 20.0mmol) refluxed 60 hours in ethanol (150mL) with the 2-bromoacetophenone.The solution that obtains is collected by filtering in the cooled on ice and the precipitation that will obtain, and with washing with alcohol so that the chemical compound 1 as white crystalline solid (2.50g, 44%) to be provided. ¹H?NMR(200MHz，DMSO-d ⁶)δ?8.89(s，1H)，8.72(brs，2H)，7.90(d，J＝7.3Hz，2H)，7.43(t，J＝7.3Hz，2H)，7.32(t，J＝7.3Hz，1H)。

Synthesizing of chemical compound 148:

The 6-phenylimidazole is [2,1-b]-1,3 also, 4-thiadiazoles-2-sulfonamide list sodium salt

(200mg 0.71mmol) adds 4:1MeOH/H to chemical compound 1 ₂Sodium hydroxide solution among the O (5mL) (28mg, 0.71mmol) in.With this solution in stirred overnight at room temperature.Under reduced pressure remove volatile matter so that the chemical compound 148 as white solid (235mg, 99%) to be provided. ¹H?NMR(200MHz，DMSO-d ⁶)δ?8.59(s，1H)，7.85(d，J＝8.2Hz，2H)，7.32(m，3H)。

Pharmacokinetics

Can send chemical compound by number of ways, for example comprise, IV, SC, intramuscular or oral.Multiple delivery routes and dosage form are possible.For example, a kind of solubility aqueous dosage form relates to the dissolving of single sodium salt in 20%HPCD of the chemical compound among the present invention, and it often is with sodium bicarbonate buffer liquid buffering.This dissolvable dosage forms is suitable for SC, IV, and IM and Orally administered described medicine provide the acceptable plasma concentration of medicine.

Alternatively, chemical compound of the present invention can be used with their form of parent/nonionicization, perhaps as solid or be dissolved in appropriate solvent or excipient mixture in.

In arbitrary situation, it is as the free alkali of active substance and is quantitative in vivo.For example, chemical compound 1 described free alkali of expression or parent form, and chemical compound 148 is single sodium salts of chemical compound 1.Chemical compound 148 can be formulated among the 20%HPCD and SC is delivered to animal, in case but chemical compound 148 dissociates from described 20%HPCD, and then it is neutralized in blood plasma, and circulates in vivo as free alkali compound 1.Similarly, the oral delivery of the chemical compound 148 among the 20%HPCD will cause chemical compound 148 to be neutralized by gastric acid, so chemical compound 1 is absorbed by the experimenter.

For chemical compound 148 described similar approach, following free alkali is changed into their corresponding single sodium salt by above.

Free alkali (compound number) Na salt (compound number)

1 148

12 154

21 155

24 156

30 157

49 158

52 159

53 160

81 150

When using by number of ways, chemical compound of the present invention has shown acceptable pharmacokinetics.

Chemical compound of the present invention reverses the conduction velocity defective, weakens axonal atrophy, improves the neuropathic pain in the diabetes rat of STZ treatment, and prevents the hyperpathia of CFA-mediation.

The inventor pro-has shown that the external improvement of The compounds of this invention stops using from NGF or be exposed to the neuronal cell death of chemotherapeutic agent.Described in vivo chemical compound can weaken chemotherapy-inductive neuropathy, and described neuropathy is inductive by cisplatin, paclitaxel and oxaliplatin.Here the data that provide show, chemical compound 150 can improve for the treatment of diabetes rat that neuropathy in the nerve conduction velocity (NCV) changes and the axonal atrophy of chronic treatment (2 months).And, when providing by subcutaneous and/or oral delivery routes, chemical compound 155,157,154,158 and 160 neuropathic pains in can the reverting diabetes rat.The specific characteristic of this analgesic activity is that the drug action of described chemical compound needs about 3-6 hour to show, and can continue later on nearly 24 hours in single administration (illustrating) by chemical compound 150 and 158, and under the situation of repetitive administration, these effects can continue 24-48 hour.This is the characteristic (profile) that is different from conventional therapy fully, is complementary with the blood plasma pharmacokinetics usually at the drug activity of conventional therapy Chinese medicine, causes lacking effect and the frequent dosed administration of needs of persistent period.

In order to expand and verify the analgesic activity of this compounds, also will test in their hyperalgesic complete Freund adjuvant (CFA) models in rat.After subcutaneous and/or oral delivery, chemical compound 150,155,157 and 158 is activated, in rat pain sensitivity is effectively returned to normally.

These results are summarized in the following table.

These chemical compounds suppress the JNK approach and weaken its a kind of new mechanism that is used for solving in neuropathic conditions unusual pain reaction of activated ability representative.The chemical compound of a kind of uniqueness of chemical compound 150 representatives, the underlying diseases state (conduction velocity defective and axonal atrophy) of its influence experiment diabetic neuropathy, and this classification is represented a kind of new method for the treatment of nerve or inflammatory pain state generally.

The effect of chemical compound 150 in diabetic neuropathy-nerve conduction velocity is degenerated

In diabetes rat, checked the influence of chemical compound 150 for nerve conduction (motion and sensation) and axonal atrophy.Interfere example to be used for estimating two kinds of relevant micromolecule on the experimental rat diabetic peripheral neuropathy of the foundation of 2 months persistent period blind reverse, it provided in continuous 2 months, estimated motion and sensation conduction and sura aixs cylinder size particularly.

Method:

(200-300g) is used for this experiment with male Sprague-Dawley rat, and described rat is raised and feeds with standard rat food in having the plastics cage that the indoor sawdust of normal light when calculating mentally cover.Described scheme is estimated and approval by animal care committee of University of Calgary (University of CalgaryAnimal Care Committee), follows the criterion of Canadian animal care council (Canadian Council on Animal Care (CCAC)).Diabetes are by the streptozotocin (STZ) in the single peritoneal injection citrate buffer (65mg/kg) and inductive, have the age-matched contrast of the buffer that no STZ is provided.Animal is used for described research, and condition is the fasting glucose level 〉=16.0mmol/L (promptly touch soon and get (One Touch FasTake) bar, Johson ﹠ Johnson (Johnson and Johnson)) after 5-7 days.

In the later persistent period of treatment being used 2 months of 2 months hyperglycemias.Before getting involved, carry out movement conduction later on and two months of diabetes then and write down (1-3).Sensation conduction utilizes the method for Parry and Kozu, relates to that sciatic toe branch stimulates and neural temperature remains on 37 ℃ of (4) Xia Zai popliteal nest horizontal recording sciatic nerves nearby.

In terminal point (4 months diabetes, 2 months treatment), make described rat euthanasia and obtain sural nerve to be used for MORPHOMETRIC STUDY.Sural nerve is fixed in the buffered glutaraldehyde of cacodylate, uses dehydration of alcohols, be fixed on the section that is embedded in then in the Osmic acid. in the epoxy resin to produce a micron, in work the preceding (5,6).To cut into slices and not take a picture (1000X) down with the whole sural nerve of taking a sample in oil immersion.Utilize the Scion graphical analysis image of off-line to measure the aixs cylinder area with 100 medullated aixs cylinders for each sural nerve bundle.Data are by forming less than 9 square microns (" little aixs cylinder ") greater than aixs cylinder (" big aixs cylinder ") and 20 areas of 9 square microns with 80 areas selecting at random arbitrarily.The surface area that Scion image analysis technology by calibration produces is represented actual aixs cylinder area and is without the circle that is corrected into supposition, as taking place in some programs.Changing average sura aixs cylinder area by the program that generates the estimation of circular aixs cylinder area from the aixs cylinder girth, is to produce bigger average sura Method for Area (1,7,8).For more than a branch of sural nerve, with each Shu Jinhang separate analysis, and for calculate average aixs cylinder area from the rat of described bundle.Do not know the experimenter under the situation of processed group and all measure.

For statistical analysis, the inventor has studied the meansigma methods with meansigma methods standard error, and has compared the value in the intervention group of using one way ANOVA or repeated measurement ANOVA, and Si Shi after this (Student ' s) the t-check.

The result

(i) SNCV: within comparison (the only group of diabetes): the diabetic groups of carrier (excipient) treatment month has the remarkable minimizing (p=0.005) of SNCV later on from baseline to 2.Chemical compound 150 treatment groups do not have significant change from baseline.Thus, though diabetic animal worsens, the animal of Drug therapy has stable SNCV in phase in the same time.

Comparison between the group (diabetics is for normal group) is after 2 months treatment, the diabetic animal of chemical compound 150 (5 days weekly) treatment significantly is not different from the normal group of chemical compound 150 treatments (p〉0.05), show

chemical compound

150,5 days dosed administrations weekly, reverting diabetes is for the influence of the SNCV in the diabetes

rat.Chemical compound

150,2 days dosed administrations do not have similar protection weekly, because diabetes rat significantly is different from the intact animal with carrier or chemical compound 150 the two treatments.

Comparison between the group (only diabetic groups): at baseline: all diabetic groups equate.At 2 months: the animal of accepting chemical compound 150 (5 days/week) significantly was better than the diabetic groups (p=0.04) of vehicle treatment.Supply with twice chemical compound 150 weekly similar protection is not provided.

The result is illustrated among Fig. 1.

(ii) MNCV: in (only diabetic groups) within the comparison: in the diabetes matched group, do not change in time.Chemical compound 150 (5 days weekly) month causes MNCV from baseline to 2 diabetic animal remarkable improvement the (p=0.007).

Chemical compound 150 (2 days weekly) has same function (p=0.005﹠amp respectively, with the medicine that provided in 5 days weekly in diabetes rat; 0.001).

Comparison between the group (diabetic groups is to normal group): in diabetes rat, chemical compound 150 (5 days weekly) does not return to MNCV normally (with comparing with the normal group of chemical compound 150 similar treatments).Chemical compound 150 (2 days weekly) does not return to MNCV normally (comparing with the normal group for the treatment of with chemical compound 150 in 5 days weekly with the normal group of vehicle treatment).

Comparison between the group (only diabetic groups): baseline: all diabetic groups equates.2 months: the diabetic groups that the animal of accepting chemical compound 150 (weekly 5 days and 2X/ week) is better than vehicle treatment significantly (respectively; P=0.007﹠amp; 0.002).The result is illustrated among Fig. 2.

(III) the medullated aixs cylinder morphology metering of sural nerve:MORPHOMETRIC STUDY is limited to the non-diabetic group of supplying compound 150 (in 7 days 5 days) or carrier and diabetic groups so that analyze the change that has in these that forceful electric power physiology more changes.Average area for the aixs cylinder of all measurements in whole 4 groups, ANOVA is inapparent, but more only supply with the diabetic groups of carrier the separate analysis (two tail Si Shi t-verification) of the group of supplying compound 150 is determined that the average aixs cylinder area with activating agent increases (p=0.016).When the non-diabetic group of relatively supplying with carrier and diabetic groups, only observe the inapparent trend that is tending towards less average area.Then only carry out the comparison of the average aixs cylinder area in the medullated aixs cylinder of " big " (greater than 9 square micron areas).ANOVA is inapparent in four groups.Yet in above-mentioned analysis, the diabetic groups of accepting carrier has the remarkable increase (p=0.012) of the average aixs cylinder area of activating agent to the independent comparison between the diabetic groups of accepting chemical compound 150 (two tail Si Shi t-verification) indication.As above, when the non-diabetic group of relatively supplying with carrier and diabetic groups, the inapparent trend for less average area is only arranged.

The result is provided in Fig. 3 and 4.

Discuss

Use the experimental model of the type i diabetes neuropathy in the rat.The experiment diabetes that are exposed to 2 months are compared with independent with vehicle treatment those with the rat of chemical compound 150 treatment 2 months (5/7 day weekly) subsequently, are presented to move and the benefit of sensory nerve conduction velocity aspect.Have than those that only supply with carrier with the medullated aixs cylinder of sura in the rat of chemical compound 150 treatment (5/7 day) and to have bigger area.The influence of chemical compound 150 for three indexs of experiment diabetes determined in described discovery.

The human diabetes polyneuropathy (DPN) relevant with the foot amputation risk of sensory deprivation, pain and rising is general (diabetic subjects 50%) and permanent disability.Do not stop or reverse the available treatment of described disease.Confused be in the described human diseases the earliest, and be the most outstanding form, but it is weak also can to develop motion subsequently.Have of the treatment of several experimental models with the test new model, but the most general research and report be with rat in the relevant experimental model of streptozotocin (STZ).STZ is the β cytotoxin, its with 3-5 days in hyperglycemia break out relevant, and as the model of I type human diseases.The rat of supply STZ was through survival in 12 months and do not need insulin in addition.Do not having under the situation of insulin, described model is the development of express analysis DPN more, and does not have the potential problem of upsetting the neurotrophy character of insulin.About in the exploitation human therapeutic agent, utilizing the interventional method of this model to have many documents.Several in utilizing described model, occur and warned, can improve its value in the following human treatment of precognition.Though many movement conduction that studies show that slow down, a kind of electrophysiologic characteristics of described disease, such slowing down occurs in the described model very in early days and is malleable for many reported method.It also may not reflect direct confused in the diabetes.Tighter interventional method is emphasized: (i) record motion and sensation (tail nerve, or nearer ischium toe nerve) conduction under near the neural temperature control strictness; (ii) ＂ reverses the ＂ example, and described example is to exist the diabetes set up and DPN feature with after-applied intervention; (iii) fully the model of persistent period (the final persistent period is greater than 8 weeks) is with the translation of better reflection model information to human diseases, and wherein DPN is through the many decades development; (iv) increase the terminal point (for example sural nerve norphometry, epidermin innervation, tactile allodynia) of other DPN index as research.Though the STZ rat model of diabetes does not prove in sciatic nerve or the sural nerve that tangible aixs cylinder comes off or neuroganglion in the loss of sensory neuron, but there are the atrophy (if the persistent period of diabetes is 2-3 month at least) of sural nerve aixs cylinder and the loss of epiderm skin aixs cylinder.It is valuable in the model of the early sign that makes up people DPN that the inventor has proposed described on the whole rat STZ model, and the early sign of described people DPN does not comprise serious neurone loss.Thereby described model is for example understood unique pathophysiological process: at first be the shrinking back of terminal fiber in the target organ (for example skin), has the degeneration axonal atrophy, change in the time of irritability (conduction velocity), be doomed to be used for downward modulation (some survivals and molecular injury raise) and the only neuron or finally the coming off of aixs cylinder much late of axon structure and other proteinic gene expression in the sensory neuron.In the STZ rat, the diabetes for 12 months do not come off.

By 2 months motions and sensation conduct velocity, hyperglycemia is relevant with the forceful electric power physiologic character of DPN.As mentioned above, sural nerve attenuation and significantly the aixs cylinder feature of taking off this model that gets blamed.Yet, utilize this model, can in some researchs of this persistent period, observe axonal atrophy, but generally be slight.The minimizing of average aixs cylinder area or diameter is represented in atrophy.In this research and ND contrast, with in the diabetics of vehicle treatment, sura aixs cylinder area trends towards lower value, but described difference does not obtain significance,statistical.

Chemical compound 150 started in the time of the DPN2 that sets up month, reversed slowing down of motion and sensation conduction velocity.After one month treatment only, do not observe to get involved and normalizedly slow down and do not observe the trend that is tending towards improving.Described reagent does not show neurovirulent evidence.Chemical compound 150 shows strong improvement and selects it to be used for norphometry work.Accept the aixs cylinder area that increases in the diabetics of chemical compound 150 with directly relatively showing of the diabetics of carrier vs. reagent treatment.

Be intended for transforming in adult's the potential noval chemical compound of DPN research in evaluation, nearest clinical trial has depended on preclinical nerve conduction data.The intervention in the STZ rat model that existing many definite motor conduction velocity raise.Yet when estimating the experiment diabetes of unusual short-term, numeral may be criticized, because begin to intervene or only rely on the movement conduction result from hyperglycemia (prevention example).In work at present, described method reverses the unusual and existence change simultaneously in motion and sensation neurite of the electrophysiology of setting up.At determining of increasing with the aixs cylinder size in the cohort of chemical compound 150 groups treatment, even slight (and only having in diabetic groups under the situation for the trend of atrophy) is important, because can in this model of similar persistent period, prove slight atrophy, and the also parallel electrophysiological improvement of reverse of other method of its usefulness (for example insulin in the sheath).The synthetic damage of the similar reflection neuron of atrophy, the output of neurofilament and be inserted in aixs cylinder part (5).Though axonal atrophy can produce slowing down of conducting in the aixs cylinder, its development in diabetes is represented aspect the different structure of described disease probably.Delayed conduction is fast-developing in the STZ diabetes, can identify the atrophy or the decline of neurofilament output afterwards.Be more possibly, the change of its reflection aixs cylinder irritability aspect metabolic induction, such as by Sima and colleague description (12).Thereby The above results is determined three the independent influences of described chemical compound for experiment DPN: movement conduction, sensation conduction and aixs cylinder size.

Treat the neuropathic pain relevant with diabetic neuropathy

Chemical compound 150,155,157 and 158 effects for the neuropathic pain reaction characterize by the tactile allodynia in the check diabetes rat.Use blind reverse and get involved example, know when unusual pain status to start treatment when setting up to estimate described chemical compound.As described, estimate single or repetition (5 days or 2 days weekly) dosage regimen.

Method:

Make rat (female Sprague Dawley with commercially available reagent streptozotocin; 250-270g) suffer from diabetes, and, it is compared with the age-matched contrast of vehicle treatment, keep nearly 6 weeks or more than.Before the research of the metabolism state of estimating animal, during and later record standard physiological parameter (body weight and blood-glucose).

Research 1: will be normal and diabetic groups all be divided into two 12 organize and accept carrier among the 20%HPCD or chemical compound 150 (10mg/kg, sc), 5 days weekly, totally two weeks.At baseline, before Drug therapy, after the 5th dosed administration 48 hours, and putting to death (after the 10th dosed administration) before once more, measure the standard index (haptic response threshold value) of sensory nerve function, and the standard physiological parameters of body weight and plasma glucose.

Research 2: according to research 1, difference is that (10mg/kg is sc) with 14 Consecutive Days of treatment of animals with the chemical compound 157 or 158 among the 20%HPCD.

Research 3: after diabetes rat is treated 1 month with the single subcutaneous administration of 150,155,157,154,158 or 160 among the 20%HPCD, as indicated; Treat by oral gavage single administration with 157, or treated continuous 5 days by oral gavage, estimate cumulative effect with 157 and 158.After single or final administration, estimated the effect of described chemical compound in 6 hours.

The detailed method that is used for implementing described operation element can be in following discovery: neuroscience method magazine (Journal of Neuroscience Methods) (1994), method in 53:55-63 and the molecular medicine (Methods in Molecular Medicine), the 99th volume: pain research: method and rules (PainResearch:methods and protocols), compiled by Z.D.Luo, Humana publishing company, Totowa, New Jersey (NJ).

The result:

Research 1:

Before with carrier or chemical compound 150 1,5 and 10 time injection and the later tactile allodynia of test animal.The result is presented among Fig. 5.At baseline, diabetic animal shows tangible allodynia, has lower response lag for the von Frey filament of the toe face that is applied to rear solid end.Beginning back six hours with chemical compound 150 treatments, tactile allodynia reverses in diabetic animal.This effect continues in all remaining is tested (Fig. 5).

Conclusion: chemical compound 150 has tangible effect for the neuropathic pain of diabetes-induced, as indicated in the reverse in the allodynia.Than typical analgesic, described medicine has very different character, and has the very unique mechanism that is used to influence pain probably.The most direct analgesic has initial rapidly and short effect period.After the initial injection for diabetes rat, chemical compound 150 needs 4 to 6 hours pain to be worked, and this continues at least 24 hours.The multidose administration makes diabetic animal as one man respond in normal range tactual stimulation.

Research 2:

Chemical compound 157 (Fig. 6) and 158 (Fig. 7) prove the rapid effect for the tactile allodynia in the diabetes rat, beginning in 3-6 hour after initial therapy, and 157 effect continues 24 hours after single administration.Chemical compound 150 in the similar research 1, under the situation of dosed administration repeatedly, after 157 and 158 both dosed administrations (the last time point of estimating in described research), this acts at least 24 hours was significantly (Fig. 6-7).

Conclusion: chemical compound 157 and 158 boths reverse the neuropathic pain states of setting up in diabetes rat.As if these chemical compounds provide and surpass the advantage of reporting for gabapentin, because under multiple dosed administration situation, have long continuous action for neuropathic pain, its prompting is better effect under the situation that requires more not frequent dosed administration.

Research 3:

When in single administration to the diabetes rat during check in 6 hours, for chemical compound 150,155,157 (all sc and po provide), and 154,158 and 160 effects (seeing Fig. 8-13 respectively) of observing single administration.When 157 and 158 by oral route are taken medicine 5 Consecutive Days, observe effect (Figure 14-15) of equal value, confirm Orally active for described chemical compound.Notice that though 157 with 10-20mg/kg, po is effectively as single dose, under the situation of dosed administration repeatedly, be reduced to 5-10mg/kg, po for the needed dosage range of effect.

Conclusion: the common trait of this classification chemical compound is the ability that they reverse neuropathic pain, as measured by the tactile allodynia in the diabetes rat.They are Orally actives, and have the anti-tactile allodynia effect of prolongation later at cumulative dosed administration.

Chemical compound is for the effect of the pain of CFA-mediation

Freund adjuvant (CFA) is used to induce inflammatory reaction completely, produces hyperpathia.Select this model as second experiment example to obtain following positive evidence: this evidence shows as if described chemical compound gets in touch the activity of the anti-pain status that produces and prove that this signal cascade mediates the pain reaction (Doya etc. 2005) in this model at least in part owing to it and the inductive of abnormal J NK phosphorylation.

Method:

Pain test (chemical compound 150,155,157 and 158 is dissolved among the 20%HPCD with 1-10mg/mL) 6 hours before, for female Sprague Dawley rat supply with carrier or chemical compound 150 (10mg/kg, sc), 155 (1-10mg/kg, sc), 157 (1-10mg/kg, sc; 10-40mg/kg, po) or 158 (10mg/kg, sc).Chemical compound 157 is also tested under the condition of repeated doses administration, wherein with it with 5-20mg/kg, po supplies with five Consecutive Days.Under whole treatment conditions, before the pain test 1 hour (that is, after finally the using of chemical compound 5 hours), the single injection (50 μ L) of CFA is supplied to the toe face of right back pawl.After the CFA injection, immediately animal is placed in the test cabinet with metal gauze bottom so that custom.Standard von Frey filament is used to estimate the haptic response threshold value.The pawl that the left side is not injected is with comparing.In the utilization-following method, the mode described with Dixon (1980) use fiber.Determine 50% withdrawal threshold (withdrawal threshold) (with the gram expression) for each pawl

The result:

When with the subcutaneous supply of dosage of≤10mg/kg, chemical compound 150,155,157 and 158 all weakens the inductive sense of touch hyperpathia of CFA-(Figure 16-19).Also oral test in this model of chemical compound 157, and be effectively in the dosage range of 20-40mg/kg, Orally active (Figure 20) proved once more.Yet, if the repeated doses example application when accepting that every day, dosed administration reached the animal of 5 Consecutive Days, the dosage range that needs reduces to 5-10mg/kg, po (Figure 21)

。Conclusion: such other chemical compound shows firm effect in second pain model, described second pain model utilizes CFA to induce sense of touch hyperpathia.Be similar to the STZ model, the repetition medicine is sent and is caused lower dosed administration needs

Total general introduction:

Here illustrational chemical compound can influence the neuropathic many aspects of diabetes-induced.In the animal of setting up conduction velocity defective and neuropathic pain, these chemical compounds can prevent further to fail (SNCV), or actual (MNCV) conduction defect that reverses, and alleviate tactile allodynia simultaneously.And neuronatrophy is also treated advantageously influence, shows that these chemical compounds not only shelter neuropathic disease, and can advantageously promote neurological health and function.The analgesic activity of chemical compound is transferred to the second inflammatory pain model, shows that they have influence for the common mechanism that drives different pain statuses probably.The inventor believes that this is a kind of new mechanism, and described mechanism is that the reduction from the abnormal level of drug-induced phosphorylation JNK produces.At last, these chemical compounds are in effect another advantage aspect the permanence, have to seem nearly 24 hours effect, and are later on 48 hours at dosed administration repeatedly in some cases.This can point out, and the dosed administration frequency may be as few as once a day, or even every other day once.This provides and surpasses current medicine such as the opiates and the obvious advantage of channel modulators, and described current medicine needs multidose administration every day and has pronounced side effects for many patients.

List of references

(1) Zochodne DW, Verge VMK, Cheng C, Sun H, whether Johnston J. diabetes targeting neuroganglion neuron? gradual sensory neuron confusion in the diabetes of long-term experiment.(Does diabetes target ganglion neurons? Progressive sensory neuroninvolvement in long term experimental diabetes. brain (Brain) 2001; 124:2319-2334).

(2) Brussee V, Cunningham A, Zochodne DW. double is used 15203 directed neuronic insulin signaling reverting diabetes neuropathy.(Duplicate Use 15203 Directinsulin signalling of neurons revereses diabetic neuropathy.) diabetes (Diabetes) 2004; 53 (7): 1824-1830.

(3) Zochodne DW, Ho LT. indomethacin and guanethidine are for the influence of the streptozotocin diabetic neuropathy of experiment.(The influence of indomethacin and guanethidine onexperimental streptozotocin diabetic neuropathy.) Canadian Journal of Neuroscience (CanJ Neurol Sci) 1992; 19 (4): 433-441.

(4) Parry GJ, Kozu H. piroxicam can reduce experiment diabetic neuropathy carry out speed.(Piroxicam may reduce the rate of progression of experimentaldiabetic neuropathy.) neurological (Neurology) 1990; 40:1446-1449.

(5) Scott JN, Clark AW, the neurofilament in the gradual experiment diabetes of Zochodne DW. and the gene expression of tubulin: the output of synthetic inefficacy and sensory neuron.(Neurofilament and tubulin gene expression in progressive experimentaldiabetes:failure of synthesis and export by sensory neurons.) brain (Brain) 1999; 122:2109-2118.

(6) Brussee V, Cunningham FA, the direct neuron insulin signaling of Zochodne DW. reverting diabetes neuropathy.(Neurofilament and tubulin gene expression inprogressive experimental diabetes:failure of synthesis and export by sensoryneurons.) diabetes (Diabetes) 2004; 53 (7): 1824-1830.

(7) Auer RN. utilizes based on the automatic nerve fiber size of the digital image analysis of microcomputer and the measurement of myelin sheath: theory, method and result.(Automated nerve fibre size andmyelin sheath measurement using microcomputer-based digital image analysis:theory, method and results.) neuroscience method magazine (J Neurosci Methods) 1994; 51:229-238.

(8) Singhal A, Cheng C, near the delayed conduction the Sun H, Zochodne DW. in the neural local insulin prevention experiment diabetes.(Near nerve local insulin prevents conductionslowing in experimental diabetes.) brain research (Brain Res) 1997; 763 (2): 209-214.

(9) O ' Brien PC, Shampo MA. carry out the statistics of a plurality of tests in the single experiment and consider.(Statistical?considerations?for?performing?multiple?tests?in?a?singleexperiment.)Mayo?Clin?Proc?1988；63：813-820。

(10) nerve in the Zochodne DW. diabetes and neuroganglion blood flow: estimate.(Nerveand ganglion blood flow in diabetes:an appraisal.) is in following: Tomlinson D, ed. the neurobiology of diabetic neuropathy (Neurobiology of diabetic neuropathy.) Santiago: academic press (Academic Press), 2002:161-202.

(11) Zochodne DW, Ho LT. sulindac is for the influence of the inductive diabetic neuropathy of streptozotocin of experiment.(The influence of sulindac on experimental streptozotocin-induced diabetic neuropathy.) Canadian Journal of Neuroscience (Can J Neurol Sci) 1994; 21 (3): 194-202.

(12) Sima AAF, Brismar T, the neuropathy that Yagihashi S. faces in the BB of spontaneous diabetes Wistar rat.(Neuropathies encountered in the spontaneously diabeticBB Wistar rat.) is in following: Dyck PJ, Thomas PK, Asbury AK, Winegrad Al, Porte D, Jr., compile. diabetic neuropathy (diabetic neuropathy) .Toronto:W.B.Saunders, 1987.

Other embodiment

From foregoing description, can change and revise the present invention described herein so that its adapts to multiple use and condition to it will be evident to one of ordinary skill in the art that.Such embodiment also within the scope of the invention.

Whole publications of mentioning in this description are incorporated into this by reference.

Claims

1. method that treats and/or prevents neuropathic pain, described method comprises: the compound or its salt according to formula I that will treat effective dose is administered to the experimenter who suffers neuropathic pain,

Wherein:

N is 1 or 2;

M is 0 to 22 integer;

S is 0 to 6 integer;

P is 0 to 1 integer;

Y is NH, O or S;

A is-S (O) ₂NR ¹R ²

R ¹And R ²Be independently selected from:

1)H，

2) C ₁-C ₆Alkyl, or

3)C(O)R ⁴；

R ⁴Be

1) C ₁-C ₁₈Alkyl,

2) aryl,

3) heteroaryl,

4) (CH ₂) _s-(C (O)) _p-(OCH ₂CH ₂) _mOR ¹⁰Or

5) C ₁-C ₆Alkyl-NR ¹¹R ¹²,

R ⁵Be:

1)H，

2) halogen,

3) C ₁-C ₆Alkyl,

4) phenyl,

5) S-aryl, or

6) S-heteroaryl,

Wherein said aryl and described heteroaryl are chosen wantonly and are used one or more R ²⁰Substituent group replaces;

R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

R ¹⁰Be

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) C ₂-C ₆Alkenyl;

5) C ₂-C ₆Alkynyl;

6) C ₅-C ₇Cycloalkenyl group,

7) aryl,

8) heteroaryl, or

9) heterocyclic radical,

R ¹¹And R ¹²Be independently selected from:

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) aryl,

5) heteroaryl,

6) heterocyclic radical,

7) CO-C ₁-C ₆Alkyl

8) CO-C ₃-C ₇Cycloalkyl

9) CO-aryl,

10) CO-heteroaryl,

11) CO-heterocyclic radical,

12) C (O) Y-C ₁-C ₆Alkyl

13) C (O) Y-C ₃-C ₇Cycloalkyl

14) C (O) Y-aryl,

15) C (O) Y-heteroaryl, or

16) C (O) Y-heterocyclic radical,

Wherein said alkyl and described cycloalkyl are chosen wantonly and are used one or more R ¹⁵Substituent group replaces, and described aryl, and heteroaryl, heterocyclic radical and xenyl are chosen wantonly and used one or more R ²⁰Substituent group replaces;

Or R ¹¹And R ¹²Nitrogen-atoms with their bondings forms optional one or more R that use ²⁰Five, six or seven membered heterocyclic that substituent group replaces;

R ¹⁵Be

1)NO ₂，

2)CN，

3) halogen,

4) C ₁-C ₆Alkyl,

5) C ₃-C ₇Cycloalkyl,

6) alkylhalide group,

7) aryl,

8) heteroaryl,

9) heterocyclic radical,

10)OR ¹⁰，

11)S(O) _nR ¹⁰，

12)NR ¹¹R ¹²，

13)COR ¹⁰，

14)CO ₂R ¹⁴，

15) CONR ¹¹R ¹², or

16)S(O) _nNR ¹¹R ¹²，

R ²⁰Be

1)NO ₂，

2)CN，

3)N ₃，

4)B(OH) ₂，

5) adamantyl,

6) halogen,

7) C ₁-C ₆Alkyl,

8) C ₃-C ₇Cycloalkyl,

9) aryl,

10) heteroaryl,

11) heterocyclic radical,

12) fused phenyl heterocyclic radical,

13) alkylhalide group,

14)OR ¹⁰，

15)SR ¹⁰，

16)S(O) _nR ¹⁰，

17) NR ¹¹R ¹², or

18)COR ¹⁰

2. according to the process of claim 1 wherein that described chemical compound is a pharmaceutical salts.

3. according to the process of claim 1 wherein that the chemical compound of described formula I comprises the compound or its salt of formula Ia:

R wherein ¹, R ², R ⁵And R ⁶As defined in claim 1.

4. according to the method for claim 3, R wherein ¹And R ²Be independently selected from the group of forming by H, methyl, ethyl, propyl group and butyl.

5. according to the method for claim 4, R wherein ¹And R ²All be H.

6. according to the method for claim 3, R wherein ²Be H and R ¹Be C (O) R ⁴

7. according to the method for claim 3, R wherein ⁵Be H, C ₁-C ₆Alkyl or phenyl.

8. according to the method for claim 7, R wherein ⁵Be H.

9. according to the method for claim 3, R wherein ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

Wherein said aryl and described heteroaryl are optional with one or more R that are independently selected from ²⁰Substituent group replace.

10. according to the method for claim 9, R wherein ⁶Be optional one or more R that use ²⁰The phenyl that substituent group replaces.

11. according to the method for claim 10, wherein R ⁶Be selected from the group of forming by following:

12. according to the method for claim 9, wherein R ⁶Be heteroaryl, with two or more methyl substituted fused phenyl-cycloalkyl, or the fused phenyl-heterocyclic radical that replaces with cyclohexane extraction.

13. according to the method for claim 12, wherein R ⁶Be selected from the group of forming by following:

With

14. according to the process of claim 1 wherein that described chemical compound is selected from the group of being made up of following: compound number 12,154,21,155,24,156,30,157,49,158,52,159,53,160,81 and 150.

15. according to the process of claim 1 wherein that described chemical compound is subcutaneous administration, intramuscular administration, that intravenous is used or Orally administered.

16. according to the process of claim 1 wherein that described experimenter is the people.

17. according to the process of claim 1 wherein that described neuropathic pain is by following caused: peripheral nerve wound, compressive neuropathy, nerve blocks, and comprises surgical operation, causalgia, amputation and deformed limb pain, neuroma and cut open the breast postoperative pain, mononeuropathy is such as the diabetes mononeuropathy, and pernicious nerve/plexus nervorum is invaded, the local hemorrhage irradiation, connective tissue disease, rheumatoid arthritis, systemic lupus erythematosus (sle), polyarteritis nodosa; Polyneuropathy is such as the diabetes polyneuropathy, ethanol polyneuropathy, trophism polyneuropathy, amyloidosis polyneuropathy, glycosphingolipidosis, chemical (for example, chemotherapeutics), congenital and AIDS neuropathy; Root and dorsal root ganglion, prolapsus dish/compressing, postherpetic neuralgia or trigeminal neuralgia, arachnoiditis, root avulsion, oncothlipsis and surgery rhizotomy; Spinal cord injury is blocked such as wound, hemisection, agile tractotomy in distress, fistula, multiple sclerosis, oncothlipsis, arteriovenous malformotion, dysraphism, vitamin B12 deficiency, hematomyelia, syphilitic myelitis, and commissural; Brain stem injury is such as Wallenberg syndrome, multiple sclerosis, tuberculoma, tumor, and fistula; Thalamic lesions, such as infarction, tumor, the surgery damage of main nuclear, sensory nucleus and hemorrhage; Damage under cortex/cortex, such as infarction, wound, tumor, and arteriovenous malformotion, painful diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, pain after the apoplexy, the pain that multiple sclerosis is relevant, the pain that neuropathy is relevant, in neuropathy and mononeuritis after congenital or wound, the neuropathic pain that HIV-is relevant, the neuropathic pain that cancer is relevant, the neuropathic pain that canalis carpi is relevant, the pain that spinal cord injury is relevant, complexity zone pain syndrome, the neuropathic pain that fibromyalgia is relevant, waist and cervical pain, reflex sympathetic dystrophy, phantom limb syndrome and the relevant pain syndrome of other chronic and weak disease.

18. according to the method for claim 17, wherein said neuropathic pain is caused by diabetic neuropathy.

19. according to the process of claim 1 wherein the compounds for reducing tactile allodynia of described formula I.

20. according to the process of claim 1 wherein the compounds for reducing neuronatrophy of described formula I.

21. a pharmaceutical composition that is used for the treatment of and/or prevents neuropathic pain, described compositions comprises: the compound or its salt according to formula I of pharmaceutical carrier and treatment effective dose:

Wherein:

N is 1 or 2;

M is 0 to 22 integer;

S is 0 to 6 integer;

P is 0 to 1 integer;

Y is NH, O or S;

A is-S (O) ₂NR ¹R ²

R ¹And R ²Be independently selected from:

1)H，

2) C ₁-C ₆Alkyl, or

3)C(O)R ⁴；

R ⁴Be

1) C ₁-C ₁₈Alkyl,

2) aryl,

3) heteroaryl,

4) (CH ₂) _s-(C (O)) _p-(OCH ₂CH ₂) _mOR ¹⁰Or

5) C ₁-C ₆Alkyl-NR ¹¹R ¹²,

R ⁵Be:

1)H，

2) halogen,

3) C ₁-C ₆Alkyl,

4) phenyl,

5) S-aryl, or

6) S-heteroaryl,

R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

R ¹⁰Be

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) C ₂-C ₆Alkenyl;

5) C ₂-C ₆Alkynyl;

6) C ₅-C ₇Cycloalkenyl group,

7) aryl,

8) heteroaryl, or

9) heterocyclic radical,

R ¹¹And R ¹²Be independently selected from:

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) aryl,

5) heteroaryl,

6) heterocyclic radical,

7) CO-C ₁-C ₆Alkyl

8) CO-C ₃-C ₇Cycloalkyl

9) CO-aryl,

10) CO-heteroaryl,

11) CO-heterocyclic radical,

12) C (O) Y-C ₁-C ₆Alkyl

13) C (O) Y-C ₃-C ₇Cycloalkyl

14) C (O) Y-aryl,

15) C (O) Y-heteroaryl, or

16) C (O) Y-heterocyclic radical,

R ¹⁵Be

1)NO ₂，

2)CN，

3) halogen,

4) C ₁-C ₆Alkyl,

5) C ₃-C ₇Cycloalkyl,

6) alkylhalide group,

7) aryl,

8) heteroaryl,

9) heterocyclic radical,

10)OR ¹⁰，

11)S(O) _nR ¹⁰，

12)NR ¹¹R ¹²，

13)COR ¹⁰，

14)CO ₂R ¹⁴，

15) CONR ¹¹R ¹², or

16)S(O) _nNR ¹¹R ¹²，

R ²⁰Be

1)NO ₂，

2)CN，

3)N ₃，

4)B(OH) ₂，

5) adamantyl,

6) halogen,

7) C ₁-C ₆Alkyl,

8) C ₃-C ₇Cycloalkyl,

9) aryl,

10) heteroaryl,

11) heterocyclic radical,

12) fused phenyl heterocyclic radical,

13) alkylhalide group,

14)OR ¹⁰，

15)SR ¹⁰，

16)S(O) _nR ¹⁰，

17) NR ¹¹R ¹², or

18)COR ¹⁰，

22. a method that treats and/or prevents neuropathic pain, described method comprises:

With the compound or its salt of formula I and another kind of reagent being enough to causing that the treatment effective dose of described pain relief is co-administered to the experimenter who suffers neuropathic pain,

Wherein:

N is 1 or 2;

M is 0 to 22 integer;

S is 0 to 6 integer;

P is 0 to 1 integer;

Y is NH, O or S;

A is-S (O) ₂NR ¹R ²

R ¹And R ²Be independently selected from:

1)H，

2) C ₁-C ₆Alkyl, or

3)C(O)R ⁴；

R ⁴Be

1) C ₁-C ₁₈Alkyl,

2) aryl,

3) heteroaryl,

4) (CH ₂) _s-(C (O)) _p-(OCH ₂CH ₂) _mOR ¹⁰Or

5) C ₁-C ₆Alkyl-NR ¹¹R ¹²,

R ⁵Be:

1)H，

2) halogen,

3) C ₁-C ₆Alkyl,

4) phenyl,

5) S-aryl, or

6) S-heteroaryl,

R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

R ¹⁰Be

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) C ₂-C ₆Alkenyl;

5) C ₂-C ₆Alkynyl;

6) C ₅-C ₇Cycloalkenyl group,

7) aryl,

8) heteroaryl, or

9) heterocyclic radical,

R ¹¹And R ¹²Be independently selected from:

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) aryl,

5) heteroaryl,

6) heterocyclic radical,

7) CO-C ₁-C ₆Alkyl

8) CO-C ₃-C ₇Cycloalkyl

9) CO-aryl,

10) CO-heteroaryl,

11) CO-heterocyclic radical,

12) C (O) Y-C ₁-C ₆Alkyl

13) C (O) Y-C ₃-C ₇Cycloalkyl

14) C (O) Y-aryl,

15) C (O) Y-heteroaryl, or

16) C (O) Y-heterocyclic radical,

R ¹⁵Be

1)NO ₂，

2)CN，

3) halogen,

4) C ₁-C ₆Alkyl,

5) C ₃-C ₇Cycloalkyl,

6) alkylhalide group,

7) aryl,

8) heteroaryl,

9) heterocyclic radical,

10)OR ¹⁰，

11)S(O) _nR ¹⁰，

12)NR ¹¹R ¹²，

13)COR ¹⁰，

14)CO ₂R ¹⁴，

15) CONR ¹¹R ¹², or

16)S(O) _nNR ¹¹R ¹²，

R ²⁰Be

1)NO ₂，

2)CN，

3)N ₃，

4)B(OH) ₂，

5) adamantyl,

6) halogen,

7) C ₁-C ₆Alkyl,

8) C ₃-C ₇Cycloalkyl,

9) aryl,

10) heteroaryl,

11) heterocyclic radical,

12) fused phenyl heterocyclic radical,

13) alkylhalide group,

14)OR ¹⁰，

15)SR ¹⁰，

16)S(O) _nR ¹⁰，

17) NR ¹¹R ¹², or

18)COR ¹⁰，

23. a method that treats and/or prevents neuropathic pain, described method comprises: will be according to the compositions of claim 21 and another kind of reagent to be enough to causing that the treatment effective dose of described pain relief is co-administered to the experimenter who suffers neuropathic pain.

24. according to the method for claim 22 and 23, wherein said another kind of reagent is active analgesic.

25. according to the method for claim 24, wherein said analgesic is an opioid analgesic agent, acetaminophen, aspirin or NSAIDs.

26. according to the method for claim 22 and 23, wherein said another kind of reagent is antidepressant, anticonvulsant or local anesthetic.

27. method that treats and/or prevents neuropathic pain; described method comprises: the imidazo [2 that will treat the formula I one or more acidylates or on-acylated of effective dose; 1-b]-1,3,4-thiadiazoles-2-sulfonamide compounds is administered to the experimenter who suffers neuropathic pain.

28. the compound or its salt of formula I treats and/or prevents the purposes of neuropathic pain in the experimenter:

Wherein:

N is 1 or 2;

M is 0 to 22 integer;

S is 0 to 6 integer;

P is 0 to 1 integer;

Y is NH, O or S;

A is-S (O) ₂NR ¹R ²

R ¹And R ²Be independently selected from:

1)H，

2) C ₁-C ₆Alkyl, or

3)C(O)R ⁴；

R ⁴Be

1) C ₁-C ₁₈Alkyl,

2) aryl,

3) heteroaryl,

4) (CH ₂) _s-(C (O)) _p-(OCH ₂CH ₂) _mOR ¹⁰Or

5) C ₁-C ₆Alkyl-NR ¹¹R ¹²,

R ⁵Be:

1)H，

2) halogen,

3) C ₁-C ₆Alkyl,

4) phenyl,

5) S-aryl, or

6) S-heteroaryl,

R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

R ¹⁰Be

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) C ₂-C ₆Alkenyl;

5) C ₂-C ₆Alkynyl;

6) C ₅-C ₇Cycloalkenyl group,

7) aryl,

8) heteroaryl, or

9) heterocyclic radical,

R ¹¹And R ¹²Be independently selected from:

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) aryl,

5) heteroaryl,

6) heterocyclic radical,

7) CO-C ₁-C ₆Alkyl

8) CO-C ₃-C ₇Cycloalkyl

9) CO-aryl,

10) CO-heteroaryl,

11) CO-heterocyclic radical,

12) C (O) Y-C ₁-C ₆Alkyl

13) C (O) Y-C ₃-C ₇Cycloalkyl

14) C (O) Y-aryl,

15) C (O) Y-heteroaryl, or

16) C (O) Y-heterocyclic radical,

R ¹⁵Be

1)NO ₂，

2)CN，

3) halogen,

4) C ₁-C ₆Alkyl,

5) C ₃-C ₇Cycloalkyl,

6) alkylhalide group,

7) aryl,

8) heteroaryl,

9) heterocyclic radical,

10)OR ¹⁰，

11)S(O) _nR ¹⁰，

12)NR ¹¹R ¹²，

13)COR ¹⁰，

14)CO ₂R ¹⁴，

15) CONR ¹¹R ¹², or

16)S(O) _nNR ¹¹R ¹²，

R ²⁰Be

1)NO ₂，

2)CN，

3)N ₃，

4)B(OH) ₂，

5) adamantyl,

6) halogen,

7) C ₁-C ₆Alkyl,

8) C ₃-C ₇Cycloalkyl,

9) aryl,

10) heteroaryl,

11) heterocyclic radical,

12) fused phenyl heterocyclic radical,

13) alkylhalide group,

14)OR ¹⁰，

15)SR ¹⁰，

16)S(O) _nR ¹⁰，

17) NR ¹¹R ¹², or

18)COR ¹⁰，

29. formula I compound or its salt is used for treating and/or preventing purposes in the medicine of neuropathic pain the experimenter in preparation:

Wherein:

N is 1 or 2;

M is 0 to 22 integer;

S is 0 to 6 integer;

P is 0 to 1 integer;

Y is NH, O or S;

A is-S (O) ₂NR ¹R ²

R ¹And R ²Be independently selected from:

1)H，

2) C ₁-C ₆Alkyl, or

3)C(O)R ⁴；

R ⁴Be

1) C ₁-C ₁₈Alkyl,

2) aryl,

3) heteroaryl,

4) (CH ₂) _s-(C (O)) _p-(OCH ₂CH ₂) _mOR ¹⁰Or

5) C ₁-C ₆Alkyl-NR ¹¹R ¹²,

R ⁵Be:

1)H，

2) halogen,

3) C ₁-C ₆Alkyl,

4) phenyl,

5) S-aryl, or

6) S-heteroaryl,

R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

R ¹⁰Be

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) C ₂-C ₆Alkenyl;

5) C ₂-C ₆Alkynyl;

6) C ₅-C ₇Cycloalkenyl group,

7) aryl,

8) heteroaryl, or

9) heterocyclic radical,

R ¹¹And R ¹²Be independently selected from:

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) aryl,

5) heteroaryl,

6) heterocyclic radical,

7) CO-C ₁-C ₆Alkyl

8) CO-C ₃-C ₇Cycloalkyl

9) CO-aryl,

10) CO-heteroaryl,

11) CO-heterocyclic radical,

12) C (O) Y-C ₁-C ₆Alkyl

13) C (O) Y-C ₃-C ₇Cycloalkyl

14) C (O) Y-aryl,

15) C (O) Y-heteroaryl, or

16) C (O) Y-heterocyclic radical,

R ¹⁵Be

1)NO ₂，

2)CN，

3) halogen,

4) C ₁-C ₆Alkyl,

5) C ₃-C ₇Cycloalkyl,

6) alkylhalide group,

7) aryl,

8) heteroaryl,

9) heterocyclic radical,

10)OR ¹⁰，

11)S(O) _nR ¹⁰，

12)NR ¹¹R ¹²，

13)COR ¹⁰，

14)CO ₂R ¹⁴，

15) CONR ¹¹R ¹², or

16)S(O) _nNR ¹¹R ¹²，

R ²⁰Be

1)NO ₂，

2)CN，

3)N ₃，

4)B(OH) ₂，

5) adamantyl,

6) halogen,

7) C ₁-C ₆Alkyl,

8) C ₃-C ₇Cycloalkyl,

9) aryl,

10) heteroaryl,

11) heterocyclic radical,

12) fused phenyl heterocyclic radical,

13) alkylhalide group,

14)OR ¹⁰，

15)SR ¹⁰，

16)S(O) _nR ¹⁰，

17) NR ¹¹R ¹², or

18)COR ¹⁰，

30. formula I compound or its salt and another kind of combination of agents treat and/or prevent the purposes of neuropathic pain in the experimenter:

Wherein:

N is 1 or 2;

M is 0 to 22 integer;

S is 0 to 6 integer;

P is 0 to 1 integer;

Y is NH, O or S;

A is-S (O) ₂NR ¹R ²

R ¹And R ²Be independently selected from:

1)H，

2) C ₁-C ₆Alkyl, or

3)C(O)R ⁴；

R ⁴Be

1) C ₁-C ₁₈Alkyl,

2) aryl,

3) heteroaryl,

4) (CH ₂) _s-(C (O)) _p-(OCH ₂CH ₂) _mOR ¹⁰Or

5) C ₁-C ₆Alkyl-NR ¹¹R ¹²,

R ⁵Be:

1)H，

2) halogen,

3) C ₁-C ₆Alkyl,

4) phenyl,

5) S-aryl, or

6) S-heteroaryl,

R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

R ¹⁰Be

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) C ₂-C ₆Alkenyl;

5) C ₂-C ₆Alkynyl;

6) C ₅-C ₇Cycloalkenyl group,

7) aryl,

8) heteroaryl, or

9) heterocyclic radical,

R ¹¹And R ¹²Be independently selected from:

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) aryl,

5) heteroaryl,

6) heterocyclic radical,

7) CO-C ₁-C ₆Alkyl

8) CO-C ₃-C ₇Cycloalkyl

9) CO-aryl,

10) CO-heteroaryl,

11) CO-heterocyclic radical,

12) C (O) Y-C ₁-C ₆Alkyl

13) C (O) Y-C ₃-C ₇Cycloalkyl

14) C (O) Y-aryl,

15) C (O) Y-heteroaryl, or

16) C (O) Y-heterocyclic radical,

R ¹⁵Be

1)NO ₂，

2)CN，

3) halogen,

4) C ₁-C ₆Alkyl,

5) C ₃-C ₇Cycloalkyl,

6) alkylhalide group,

7) aryl,

8) heteroaryl,

9) heterocyclic radical,

10)OR ¹⁰，

11)S(O) _nR ¹⁰，

12)NR ¹¹R ¹²，

13)COR ¹⁰，

14)CO ₂R ¹⁴，

15) CONR ¹¹R ¹², or

16)S(O) _nNR ¹¹R ¹²，

R ²⁰Be

1)NO ₂，

2)CN，

3)N ₃，

4)B(OH) ₂，

5) adamantyl,

6) halogen,

7) C ₁-C ₆Alkyl,

8) C ₃-C ₇Cycloalkyl,

9) aryl,

10) heteroaryl,

11) heterocyclic radical,

12) fused phenyl heterocyclic radical,

13) alkylhalide group,

14)OR ¹⁰，

15)SR ¹⁰，

16)S(O) _nR ¹⁰，

17) NR ¹¹R ¹², or

18)COR ¹⁰，

31. formula I compound or its salt and another kind of combination of agents are used for preparing the purposes that treats and/or prevents the medicine that neuropathic pain uses the experimenter,

Wherein:

N is 1 or 2;

M is 0 to 22 integer;

S is 0 to 6 integer;

P is 0 to 1 integer;

Y is NH, O or S;

A is-S (O) ₂NR ¹R ²

R ¹And R ²Be independently selected from:

1)H，

2) C ₁-C ₆Alkyl, or

3)C(O)R ⁴；

R ⁴Be

1) C ₁-C ₁₈Alkyl,

2) aryl,

3) heteroaryl,

4) (CH ₂) _s-(C (O)) _p-(OCH ₂CH ₂) _mOR ¹⁰Or

5) C ₁-C ₆Alkyl-NR ¹¹R ¹²,

R ⁵Be:

1)H，

2) halogen,

3) C ₁-C ₆Alkyl,

4) phenyl,

5) S-aryl, or

6) S-heteroaryl,

R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

R ¹⁰Be

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) C ₂-C ₆Alkenyl;

5) C ₂-C ₆Alkynyl;

6) C ₅-C ₇Cycloalkenyl group,

7) aryl,

8) heteroaryl, or

9) heterocyclic radical,

R ¹¹And R ¹²Be independently selected from:

1) C ₁-C ₆Alkyl,

2) C ₃-C ₇Cycloalkyl,

3) alkylhalide group,

4) aryl,

5) heteroaryl,

6) heterocyclic radical,

7) CO-C ₁-C ₆Alkyl

8) CO-C ₃-C ₇Cycloalkyl

9) CO-aryl,

10) CO-heteroaryl,

11) CO-heterocyclic radical,

12) C (O) Y-C ₁-C ₆Alkyl

13) C (O) Y-C ₃-C ₇Cycloalkyl

14) C (O) Y-aryl,

15) C (O) Y-heteroaryl, or

16) C (O) Y-heterocyclic radical,

R ¹⁵Be

1)NO ₂，

2)CN，

3) halogen,

4) C ₁-C ₆Alkyl,

5) C ₃-C ₇Cycloalkyl,

6) alkylhalide group,

7) aryl,

8) heteroaryl,

9) heterocyclic radical,

10)OR ¹⁰，

11)S(O) _nR ¹⁰，

12)NR ¹¹R ¹²，

13)COR ¹⁰，

14)CO ₂R ¹⁴，

15) CONR ¹¹R ¹², or

16)S(O) _nNR ¹¹R ¹²，

R ²⁰Be

1)NO ₂，

2)CN，

3)N ₃，

4)B(OH) ₂，

5) adamantyl,

6) halogen,

7) C ₁-C ₆Alkyl,

8) C ₃-C ₇Cycloalkyl,

9) aryl,

10) heteroaryl,

11) heterocyclic radical,

12) fused phenyl heterocyclic radical,

13) alkylhalide group,

14)OR ¹⁰，

15)SR ¹⁰，

16)S(O) _nR ¹⁰，

17) NR ¹¹R ¹², or

18)COR ¹⁰，

32. according to claim 28,29,30 or 31 purposes, wherein said chemical compound is a pharmaceutical salts.

33. according to claim 28,29,30 or 31 purposes, the chemical compound of wherein said formula I comprises the compound or its salt of formula Ia:

R wherein ¹, R ², R ⁵And R ⁶As defined in claim 1.

34. according to the purposes of claim 33, wherein R ¹And R ²Be independently selected from the group of forming by H, methyl, ethyl, propyl group and butyl.

35. according to the purposes of claim 34, wherein R ¹And R ²All be H.

36. according to the purposes of claim 33, wherein R ²Be H and R ¹Be C (O) R ⁴

37. according to the purposes of claim 33, wherein R ⁵Be H, C ₁-C ₆Alkyl or phenyl.

38. according to the purposes of claim 37, wherein R ⁵Be H.

39. according to the purposes of claim 33, wherein R ⁶Be

1) alkylhalide group,

2) adamantyl,

3) aryl,

4) heteroaryl,

5) fused phenyl-cycloalkyl that replaces with alkyl, or

6) optional fused phenyl-heterocyclic radical with cycloalkyl substituted,

40. according to the purposes of claim 39, wherein R ⁶Be optional one or more R that use ²⁰The phenyl that substituent group replaces.

41. according to the purposes of claim 40, wherein R ⁶Be selected from the group of forming by following:

42. according to the purposes of claim 39, wherein R ⁶Be heteroaryl, with two or more methyl substituted fused phenyl-cycloalkyl, or the fused phenyl-heterocyclic radical that replaces with cyclohexane extraction.

43. according to the purposes of claim 42, wherein R ⁶Be selected from the group of forming by following:

With

44. according to claim 28,29,30 or 31 purposes, wherein said chemical compound is selected from the group of being made up of following: compound number 12,154,21,155,24,156,30,157,49,158,52,159,53,160,81 and 150.

45. according to claim 28,29,30 or 31 purposes, wherein said chemical compound is subcutaneous administration, intramuscular administration, that intravenous is used or Orally administered.

46. according to claim 28,29,30 or 31 purposes, wherein said experimenter is the people.

47. according to claim 28,29,30 or 31 method, wherein said neuropathic pain is by following caused: the peripheral nerve wound, and compressive neuropathy, nerve blocks, comprise surgical operation, causalgia, amputation and deformed limb pain, neuroma and cut open the breast postoperative pain, mononeuropathy is such as the diabetes mononeuropathy, pernicious nerve/plexus nervorum is invaded, local hemorrhage irradiation, connective tissue disease, rheumatoid arthritis, systemic lupus erythematosus (sle), polyarteritis nodosa; Polyneuropathy is such as the diabetes polyneuropathy, ethanol polyneuropathy, trophism polyneuropathy, amyloidosis polyneuropathy, glycosphingolipidosis, chemical (for example, chemotherapeutics), congenital and AIDS neuropathy; Root and dorsal root ganglion, prolapsus dish/compressing, postherpetic neuralgia or trigeminal neuralgia, arachnoiditis, root avulsion, oncothlipsis and surgery rhizotomy; Spinal cord injury is blocked such as wound, hemisection, agile tractotomy in distress, fistula, multiple sclerosis, oncothlipsis, arteriovenous malformotion, dysraphism, vitamin B12 deficiency, hematomyelia, syphilitic myelitis, and commissural; Brain stem injury is such as Wallenberg syndrome, multiple sclerosis, tuberculoma, tumor, and fistula; Thalamic lesions, such as infarction, tumor, the surgery damage of main nuclear, sensory nucleus and hemorrhage; Damage under cortex/cortex, such as infarction, wound, tumor, and arteriovenous malformotion, painful diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, pain after the apoplexy, the pain that multiple sclerosis is relevant, the pain that neuropathy is relevant, in neuropathy and mononeuritis after congenital or wound, the neuropathic pain that HIV-is relevant, the neuropathic pain that cancer is relevant, the neuropathic pain that canalis carpi is relevant, the pain that spinal cord injury is relevant, complexity zone pain syndrome, the neuropathic pain that fibromyalgia is relevant, waist and cervical pain, reflex sympathetic dystrophy, phantom limb syndrome and the relevant pain syndrome of other chronic and weak disease.

48. according to the purposes of claim 47, wherein said neuropathic pain is caused by diabetic neuropathy.

49. according to claim 28,29,30 or 31 purposes, the compounds for reducing tactile allodynia of wherein said formula I.

50. according to claim 28,29,30 or 31 purposes, the compounds for reducing neuronatrophy of wherein said formula I.

51. according to the purposes of claim 30 and 31, wherein said another kind of reagent is active analgesic.

52. according to the purposes of claim 51, wherein said analgesic is opioid analgesic agent, acetaminophen, aspirin or NSAIDs.

53. according to the purposes of claim 30 and 31, wherein said another kind of reagent is antidepressant, anticonvulsant or local anesthetic.