TW200904414A - Method for treating CB2 receptor mediated pain - Google Patents

Abstract

The present invention is directed to a pharmaceutical composition for treating, ameliorating or preventing CB2 receptor mediated pain in a subject in need thereof comprising an effective amount of a compound of formula (I): or a form thereof, wherein X1R1, X2R2, X3R3, X4R4 and X5R5 are as defined herein.

Description

200904414 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a pharmaceutical composition for treating, ameliorating or preventing pain of a CB2 receptor vector in a subject in need thereof. More particularly, the pharmaceutical composition comprises an effective amount of a hexahydro-cyclooctylpyrazole CB2 promoter compound of the invention. [Prior Art] PCT application WO2006/030124 describes pyrazole derivatives as CB1 or CB2 receptor promoters. CB2-selective enhancers have been shown to be effective in the carrageenan model of inflammatory pain, and are therefore effective for the treatment of acute and chronic inflammatory pain (Gutierrez T, Farthing JN, Zvonok AM, Makriyannis A and Hohmann) AG, activation of surrounding cannabinoid CB1 and CB2 receptors inhibits the persistence of inflammatory pain perception: a comparative analysis, "妫Journal of Pharmacology, (2007), 150(2), 153-163; QuartilhoA, Mata HP, Ibrahim MM, Vanderah TW, Porreca F, Makriyannis A and MalanTP, Jr., inhibit inflammatory hyperalgesia by activating surrounding CB2 cannabinoid receptors, (2〇〇3), 99(4), 955-960; And Nackley AG, Makriyannis A and Hohmann AG, selective activation of the cannabinoid CB2 receptor in a rat model of inflammation inhibits spinal Fos protein expression and pain behavior, yVfei/rosc/e/zce (Oxford, UK) (2〇〇3), 119 (3), 747-757). CB 2 -selective enhancers have also been shown to be potent inhibitors of thermal pain perception in gene-transferred mice, and potentially effective in the treatment of acute pain 200904414 (Ibrahim MM, Rude ML, Stagg NJ, Mata HP, Lai J, Vanderah TW, Porreca F, Buckley NE, Makriyannis A and Malan TP, Jr., CB2 Analgesic Effects of Cannabinoid Receptor Vectors, PaiT?, (2006), 122(1-2), 36-42). Activation of the CB2 receptor produces an analgesic effect after surgical incision, suggesting that selective cannabinoid CB2 receptor enhancers are effective for postoperative pain management (LaBudaCJ, KoblishM and LittlePJ, canine CB2 in hind foot incision Live, also, European Journal of Pharmacology, (2005), 527 (1-3), 172-174). Activation of the surrounding cannabinoid CB2 receptor is sufficient to normalize the pain threshold and analgesia in persistent pain (Hohmann AG, Farthing JN, Zvonok AM and Makriyannis A, selective activated cannabinoid CB2 receptor inhibits dermis Pain allergy caused by capsaicin, Journal of pharmacology and Experimental Therapeutics, (2004), 308(2), 446-453). Selective CB2 receptor enhancers inhibit acute, chronic, inflammatory, and neuropathic pain responses in animal models, and thus predict hopes for the treatment of acute and chronic pain (MalanTP, jr., Ibrahim MM, Lai J,

Vanderah TW, Makriyannis A and PorrecaF, CB2 Cannabis receptor enhancer: relieve pain without psychoactive activity? , 仏rre/?i in Pharmacology, (2003), 3(1), 62-67; Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderah TW,

Lai J, Porreca F, Makriyannis A and Malan TP, Jr., Activated CB2 cannabinoid receptors with AM1241 inhibited experimental neuropathic pain: inhibition of pain by receptors present in the CNS by non-20090414, / § 〇 /

National Academy of Sciences of the United States of (2003), 100 (18), 10529-10533; and, Burns TL and Ineck JR, cannabis analgesia as a potential new treatment option for the treatment of chronic pain, Annals of Pharnmcotherapy, {2(10) Milk {2\ 251-260). The CB2 receptor-selectivity promoter AM1241 has an analgesic effect on thermal stimulation (MalanTP, Jr., Ibrahim MM, Deng H, Liu Q, Mata HP, Vanderah T, Porreca F and Makriyannis A, CB2 cannabinoid receptor-mediated The analgesic effect around (2〇〇1), 93(3), 239-245). SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical composition for treating, ameliorating or preventing pain of a CB2 receptor vector in a subject in need thereof, which comprises an effective amount of a compound of the formula (I):

(I) or a salt, isomer, prodrug, metabolite or polymorph thereof, wherein the dotted line between position 2-3 and position 3a-9a in formula (I) represents each of the The position of the two double keys; , the dotted line between the position 3_3a and the position 9a_i in (Shi I) represents the position of each of the two double bonds existing at the time; the dotted line between the position 9 and the LR4 in the formula (I) Represents the position of the double bond; 200904414 Χι is a non-existent or low-carbon stretching group; X2 is a non-existent or low-carbon stretching group; wherein only one of XA! and LR2 exists; X3 is a non-existent, low-carbon alkylene group , lower alkylene or -NH-; although the dotted line between position 9 and XA4 does not exist, the alkyl group; 'heart does not exist or is low carbon when the dotted line between position 9 and LR4 exists, &;non-existent; X5 is non-existent or low-resistance; 1 is selected from hydrogen, stimuli (optionally or at multiple positions via (4), trans-base or 23⁄4 calcination, base substitution), low-carbon alkyl group _ continued Mercapto, aryl, cyclocalcin or heterocyclic group wherein aryl, C3_C12 cyclodyl or heterocyclic group are optionally halogenated, amine-based thiol, or low-carbon burned at or a monoamine group, a silk (replacement by self-priming, subtraction or low carbon, a gas-based group as needed), a trans- or a low-carbon alkoxy group (optional in one or more positions via a halogen) Or hydroxy substituted) substituted; 1 is selected from hydrogen, alkyl (depending on - or multiple positions via halogen, trans- or di-, calcined, substituted), low-carbon alkyl _ continuation, aryl, CrCi2 Ring-burned soil III, hetero-basic group 'where aryl, C3-Ci2 cycloalkyl or heterocyclic group, as needed, or at the same position, dentate, amino acid group, low carbon syl-amino sulfonate = , silk (as needed - ❹ position _ prime, recorded or low carbon

^Substituted), mithyloxy (substituted at one or more positions by a carboxylic or hydroxy group); W C(9)-Z1 (R0, _s〇2_NR74(R8M_c(8)._Z3(3).), · "at position 9 and m In the absence of N, X, if present or low carbon extension 200904414, is a gas, a mercapto group, a low-carbyl group, a low-carbon aerobic *, a halogen, an aryl group, a 3 C12^alkyl group or a heterocyclic group, wherein Ere. The cycloalkyl or heterocyclic group is required to be - or a plurality of positions - a group, a fluorenyl group, a low hetero group (optionally in the case of + = a position (tetra), a substituted oxy group), a low oxy group (depending on - or excess, _indolyl substitution) or 4-priming; placing 9, when the dotted line between R4 is present, X4 is absent and R4 is CH_ heterocyclyl 'where aryl or heterocyclic Each is optionally substituted with one or more bases, low-wei groups, low-carbon green groups or self-reagents; required for recording, time, amine group, silk, or dialysis (as needed; bit/dihalogen, thiol or Low carbon institute oxy-substituted), alkoxy rolling base, amine methine, amine methionyl chlorophyll oxy or heterocyclic; * aryloxy, ke group, aryl, (: heart Cyclohexyl or heterocyclic or heterocyclic Depending on the need - or more _ base groups, you can base the base, burn (based on - or a plurality of soil '^,, ', prime, amine, amine alkoxy substituted), alkoxy (optional, secret or low-carbon substitution), silk, county alkoxy, (d) = position of the element / elemental or aryloxy group, silk pure or heterocyclic / substituted amine A "burning base, aromatic Is hydrogen or a low-resistance base; R8 is an aryl group, (: 3-(:12cyclodecyl or heterocyclic group, or a heterocyclic group, each optionally requires an alkyl group, G3-. a cycloalkyl group) , locks need to be - or more;;, (d), amine, amine gas group substituted), alkoxy (optional in -, recorded or low-break, or multiple positions replaced by halogen or hydroxyl 9 200904414) a fluorenyl group, a carbonyl alkoxy group, a aryl group, an aramidyl group, an amine fluorenyl group, an aryl hydrazine is a hydrogen or a lower alkyl group; a substituent, a 3 fluorene 12 ring cyclyl or a heterocyclic group, wherein an aryl group , (10) cyclodextrin η needs to pass one or more thiol, keto, sulphate, amine, carbon 2: as needed - or multiple positions via halogen, hydroxy or oxime, alkoxy (as appropriate - Or multiple locations via halogen or by ^, county, recorded Oxyl group, amine f fluorenyl group, amine f aryl group, sulfhydryl group, low carbon alkyl group-amino group thiol group, aryl alkoxy group or heterocyclic group substituted; cubic earth based square 匕 and △ Each is non-existent or alkyl; and Z3 is absent, _NH_, _s〇2_ or alkyl (wherein the alkyl group is required to be in one or more positions via i, cheng, low carbon, low wei, County or thiol alkoxy substituted). This example is a compound of formula (I) or a salt, isomer, prodrug, generation or polymorph thereof, wherein X1 is absent or low carbon And the oxime is selected from the group consisting of hydrogen, alkyl (optionally substituted with halogen, hydroxy or lower alkoxy at one or more positions), aryl, C3-匕2 cycloalkyl or heterocyclic, wherein a C3_Cl2 cycloalkyl or heterocyclyl group, optionally at one or more positions, via a carboxylic acid, an alkyl group (optionally substituted at one or more positions via one or more positions via a dentate, a hydroxy or a lower alkoxy group), a hydroxy group or The alkyl group is substituted (optionally substituted at one or more positions with a halogen or a hydroxy group). The present invention is exemplified by a compound of the formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof, wherein X1 is absent; and the lanthanide is selected from the group consisting of aryl or C3 〇200904414 Cyclone, The quinone is the compound of the formula (1) or a salt thereof, the isomeric quinone metabolite or the phenotype, wherein Χι is the material; An example of the invention is a compound of formula (1) or a salt, isomer, pre-hua, metabolite or polymorph thereof, wherein H-7 core-(10)-. 3 is C(0) rotten, genus-saki) or an example of the present invention is a compound of the formula (1) or a salt thereof, an isomer, a ruthenium, a metabolite f crystal form, wherein the R side is on a paper: low is an aryl group, (10) a cycloalkyl or heterocyclic group, wherein the aryl group has a wei- or poly-based group, _, _, which is required to be taken at one or more positions via a dentate or a hydroxyl group - Substituted by alkoxy groups, amines, amines, aryl, octylene, aryloxy or heterocyclic groups. (iv) ΐΓ - examples of the compound of formula (1) or its salts, isomers, former a drug, a crystalline form, wherein R3 is absent in the presence of Χ3; Zl is absent, and R8 is a heterocyclic group. u The present invention - an example of a compound of the formula (1) or a salt, isomer thereof, prodrug thereof, Crystal form 'wherein R3 is -S〇2,7-Z2 (R〇; X3 is absent or h is hydrogen or lower sulfhydryl; Z2 is absent or a base; and t is at - or a plurality of positions (4)^ Γ—Examples are compounds of the formula CO or salts, isomers, prodrugs thereof, wherein the ruthenium is -S〇2_NH-Z2 (R8); X3 is absent or 11 200904414 lower alkylene; hydrazine is absent or alkyl; and Rs is aryl Needed to be substituted with an alkoxy group at one or more positions. An example of the invention is a compound of formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof wherein R3 is -C(0)- NR9-Z3(R1()); X3 is absent, lower alkylalkylene, lower alkylene or -NH-; R9 is hydrogen or lower alkyl; Z3 is absent, -NH---S 〇2- or alkyl (wherein the alkyl group is optionally substituted at one or more positions via a halogen, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxyl group or a carbonyl alkoxy group), and Ri is an aryl group. , C3_Ci2cyclohexyl or heterocyclyl, each optionally having one or more via groups, groups, halogens, amine groups, amine groups, or alkyl groups (optionally halogen, hydroxyl or low carbon in one or more positions as desired) Alkoxy substituted), alkoxy (optionally substituted with halogen or hydroxy at one or more positions), carboxyl group, carbonyl alkoxy group, amine mercapto group, amine alkylalkyl group, aminosulfonyl group, Substituted with a lower alkyl-aminosulfonyl, aryl, aryloxy, arylalkoxy or heterocyclic group. An example of the invention is a compound of formula (I) or a salt, isomer or prodrug thereof , metabolite or polymorphic' Wherein R3 is _C(0)_NH-Z3(RlD); X3 is absent; Z3 is absent, _NH_ or alkyl (wherein the alkyl group is required to be at one or more positions via ii, hydroxy, low) a carbon alkyl group, a lower alkoxy group, a carboxyl group or a carbonyl alkoxy group); and a private one, an aryl group, a GC! 2 cycloalkyl group or a heterocyclic group, optionally having one or more hydroxyl groups, a ketone group, or a halogen , an amine group, an aminoalkyl group, an alkyl group (optionally at position, i.e., or a low carbon filament), a substituted alkyl group, a carboxyl group, a carbonyl alkoxy group, an aryl group or a heterocyclic group. 200904414 z3 is absent or burned; and Rl. The G_G2 cyclodyl group is optionally subjected to one or more transradical, sulfhydryl, arginyl, amine, amine alkyl, alkyl (halogen, hydroxy or lower alkoxy at one or more positions as needed). Substituted by a), alkoxy, carboxy, carbonylalkoxy, aryl or heterocyclic group. An example of the invention is a compound of formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof, wherein W-c(8) is Z3(f); X3 is absent; Z3 is absent or alkyl, and R1 . The C3_Ciz cycloalkyl group is optionally substituted with - or a plurality of alkyl or carbonyl alkoxy groups. An example of the invention is a compound of formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof, wherein R3 is -C(〇)_nh_Z3(Riq); X3 is absent; Z3 is Occurs, _NH- or alkyl (wherein the alkyl group is required to be in one or more positions,, two, four, perme, low; 5 charcoal, low carbon alkoxy, dike or a few Oxygen substituted); and R,. The aryl group is optionally substituted with one or more of a hydroxy group, a aryl group, a halogen, an amine group, an aminoalkyl group, an alkyl group (substituted at one or more positions by a south, a hydroxy or a lower alkoxy group) , alkoxy, carboxy, carbonyl alkoxy, aryl 2 or heterocyclyl substituted. An example of the invention is a compound of formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof, wherein R3 is -C(〇)-NH_Z3(RlQ); X3 is absent; Z3 is no The presence or the alkyl group (wherein the alkyl group is optionally substituted at one or more positions with a halogen, a hydroxyl group or a lower alkoxy group); and Rlf1 is an aryl group which is optionally substituted with one or more halogens. An example of the invention is a compound of formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof, wherein Rs is -C(〇)-nH-Z3(Rh>); X3 is absent; Z3 is absent or alkyl (wherein the alkyl group is optionally substituted at one or more positions via a halogen 13 200904414, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxyl group or a carbonyl alkoxy group); . The heterocyclic group is optionally substituted with one or more alkyl groups. An example of the invention is a compound of formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof wherein the dotted line between position 9 and between is absent 'X4 is absent or low carbon stretched An alkyl group; and the hydrazine is hydrogen or an aryl group which is optionally substituted at one or more positions. An example of the invention is a compound of formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof wherein the dotted line between positions 9 and (10) is present, X4 is absent and R4 is CH The aryl group is optionally substituted with one element at one or more positions on the aryl group. An example of the invention is a compound of formula (I) or a salt, isomer, prodrug, metabolite or polymorph thereof wherein X5 is absent and Rs is absent. An example of the invention is a compound of formula (la):

X3r3 (la) or a salt, isomer, prodrug, metabolite or polymorph thereof wherein X1 is absent; X3 is absent or lower alkylene; when the dotted line between position 9 and X4R4 is not When present, 'X4 is an aryl group which is absent or has a low carbon alkyl group and is deuterated to hydrogen or is optionally substituted with a halogen at one or more positions; when a dotted line at position 9 and is present, X4 is absent and R4 is a CH-aryl group, wherein the aryl group is optionally substituted by halogen at - or a plurality of positions; R is selected from hydrogen, aryl or G-Cl2 ring-fired 14 200904414 base 'where the aryl group is required Or a plurality of positions substituted by halogen; 匕 is -C(〇)-Zl(R6), -S〇2-NH-Z2(R8) or -C(0)-NH-Z3〇M; R6 is a heterocyclic group Rs is an aryl group which is optionally substituted by an alkoxy group at one or more positions, and Rio is an aryl group, a GC!2 cycloalkyl group or a heterocyclic group, wherein the aryl group or the G_Ci2 cycloalkyl group is optionally one or more Substituted halo, alkyl or carbonylalkoxy; Z1 is absent; Δ is alkyl; and deuterium is absent, -NH- or alkyl (wherein alkyl is required to be in one or more positions, Hydroxy or lower alkoxy substituted)An example of the present month is a compound of the formula (la) or a salt, isomer, prodrug, metabolite or polymorph thereof, wherein X1 is absent; χ3 is absent or low carbon alkylene; When the dotted line between a and a is not present, χ4 is a non-existent or low-carbon extension group and R4 is a wind or an aryl group which is substituted by dentate at one or more positions as a dotted line between positions 9 and a When present, L is absent and hydrazine is CH-aryl' wherein aryl is optionally substituted by dentate at one or more positions; R1 is selected from hydrogen, silk or 2 ring filaments, Substituted at _ or at multiple positions; R3 is genus Z2 (R8) or

b) -NH-Z3(RlQ); R8 is an aryl group as desired - or a plurality of positions through a female, said base 'wherein aryl or C3-. Ring-burning A =::=(=-based oxy-oxyl substituted "(tetra)-, thiol-carbon-based, Hilt-based, as needed, at - or multiple positions. An example of the invention includes the formula (1), which is: And its trading company accepts the shape----name%___ 1 1-cyclohexyl-4, 5, 6 7 8 " /, 虱~1Η_cyclooctylpyrazole_3_carboxylic acid 15 200904414 (1,3, 3-dimercapto-double soil [2·2·1]hept-2-yl)-acid amine 2 hexyl group 5, 6, 7, 8, 9-hexahydro-1H-cyclooctyl η ratio 嗤3- Oreic acid (adamantan-1-ylindenyl)-decylamine, 3 1 -cyclopentyl-4, 5, 6, 7, 8, 9-hexahydro-1Η~cyclooctazole-3-carboxylic acid ( Adamantan-1-ylmethyl)-decylamine, 4 1-% hexyl-4, 5, 6, 7, 8, 9-hexahydro-1 Η-cyclooctyl tau Adamantane-1 -yl-ethyl)-guanamine, 5 (2Ε)-[9-(3-chloro-benzyl)-4, 5, 6, 7, 8, 9-hexahydro-1Η-cyclo Octazol-3-yl]-ethyl acetate [(1S)-1-phenyl-ethyl]-decylamine, 6 (9S*)-(3-gas-benzyl)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctane α-pyrazole-3-carboxylic acid [(lR)-2-hydroxy-1-phenyl-ethyldoxime, 7 (服*)-(3- Gas-benzyl)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctane "Bizozole-3-carboxylic acid [(lR)-2-hydroxy-1-phenyl-ethyl] —醯Amine, 8 (9R*)-(3- gas-benzyl)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctazole-3-carboxylic acid [(lS)-2- Benzyl-1-phenyl-ethyl]-decylamine, 9 (9S*)-(3- gas-benzyl)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctane Oxazole-3-Resin [[1S)-2-yl-1-phenyl-ethyl]-decylamine, 10 (9S*)-(3-chloro-benzyl)-4, 5, 6, 7 , 8, 9-hexahydro-1H-cyclooctazoleazole-3-carboxylic acid [(lR)-2-decyloxy-1-phenyl-ethyl]-decylamine, 11 (9R*)-(3 - gas group)-4, 5, 6, 7, 8, 9-hexanitro-1H-cyclooctane ratio. sit-3-carboxylic acid [(lR)-2-methoxy-1-phenyl-B ]], guanamine, 12 (9E)-(3-milk-subunit)_4, 5, 6, 7, 8, 9-hexahydro-cyclooctane^ than sal-3-carboxylic acid [(1R)- 1-phenyl-ethyl]-decylamine, 13(9£)-(3-gas-subunit)-4,5,6,7,8,9_hexa-1^-cyclooctane ratio Squat 16 200904414-3-carboxylic acid [(IS)-1-phenyl-ethyl]-decylamine, 14 (9E)-(3-chloro-indenyl)-4, 5, 6, 7, 8 , 9~ hexahydro-1H-cyclooctine than saliva-3-carboxylic acid [(lS)-2-hydroxy-1-phenyl-ethyl]-decylamine, or 15 (9E)-(3-chloro- Benzylene)-4, 5, 6, 7, 8, 9-hexahydro-lH-cycloxin'1 than saliva-3-acid [(ir)-2-heptyl-1-phenyl-ethyl ]_ Brewing amine. As used herein, the following terms have the following meanings: The term "alkyl" refers to a saturated or straight-chain monovalent hydrocarbon radical of up to 10 carbon atoms. Alkyl groups typically include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, and the like. The term "lower alkyl" refers to an alkyl group of up to 4 carbon atoms. The point of attachment "T is on any of the alkyl or low sulphonic carbon atoms, and when further substituted, the 'substituent variable' can be on any carbon atom. The term "hypergamma" refers to a saturated branched or straight-chain monovalent hydrocarbon linking group of up to one carbon atom, wherein the linking group is derived by removing one hydrogen from each of the two carbon atoms. Typical alkylene groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, decyl, heptyl and Similar base. The term "low-carbon alkylene" is an extended alkyl linking group of two to four carbon atoms. The point of attachment can be on any carbon atom of the extended, meta or low rabbit extension, and when further substituted, the radical can be located on any carbon atom.小二术 2 "Alkylene" means a radical linking group having from 1 to 2 carbon atoms formed between two adjacent carbon atoms to two double bonds, wherein the double bond is derived from Each carbon atom is removed - derived from a money atom. Atomic 17 200904414 The compliant double bond is in the cis (E) or trans (z) configuration. Alkylene groups typically include, but are not limited to, methylene, vinylidene, propylene, isopropylidene, methallyl, allenyl (2-propenylene), crotonyl (2-extenyl), pentenyl (3-methyl-2-exenbutyl); and the like. The term "lower alkylene" refers to a radical of 1 to 4 carbon atoms or a linking ring. The point of attachment can be on the carbon atom of any alkylene or lower alkylene group, and when further substituted, the substituent number can be on any carbon atom. The term "alkoxy" refers to a alkyl, alkyl or alkylene group attached to up to 10 carbon atoms via an oxygen atom, wherein the point of attachment is from the hydroxide substituent on the parent group. The formation of hydrogen atoms is removed. The term "low carbon, dairy based" refers to a pyrolyzed, extended or sub-alkyl group of up to 4 carbon atoms. Low carbon, oxy groups typically include, but are not limited to, methoxy, ethoxy, propoxy, butyl, and the like. When substituted with a frequency, the substituent variable can be on the carbon atom of any alkoxy group. , W δα %, 兀"" you are saturated or partially unsaturated monocyclic, polycyclic 戋 bridge ring system f or linkage 圏. (4) A ring of broken atoms can be == Two rings of It12 carbon atoms can be represented by C3-12 ring-burning groups, and 3 to 8 anisotropy: the ring of the ring can be represented by a group of bases and the like. The m 裱 alkyl group typically includes, but is not limited to, cyclopropyl, zedingmei, & cyclohexyl, cyclohexyl, valproate, decyl-hexenyl-5-heptyl,裱 octyl, hydroquinone, benzyl, i 2 3 tetrahydro-naphthyl, 5,6,7,8-tetrahydro-laugh 47" 卩泰乂 3,4~ 庵抡萁, c. 0 Λ虱,6,7,8,9~tetrahydro-5Η-benzo ring 5, 6, 7, 8, 9, 10-hexahydro-benzocyclooctyl [2. 2. 1] heptyl, Bicyclo[2. 2. 1]heptene, 雔„土裱裱[UU-heptyl, bicyclo 3 ·2.2] octyl, double 芊 裱 裱 [2· 2. 2] octenyl, 200904414 = [3:2:;] octenyl, dimethyl octadecyl, octahydro-4,7-methylene, 茚ί美; bisindolyl-lacquer base (also known as hexahydro-2) , 5-indenyl-maolin. When the feed is skipped, the amount of money can be located in the h. The term "heterocyclyl" refers to a saturated, partially unsaturated or unsaturated monocyclic ring, a bridged hydrocarbon ring system or a linker. a group in which at least one ring carbon atom is substituted with: or two:: a hetero atom selected from N, hydrazine or S. The heterocyclic ring system includes: (10) having a ring member having a maximum of 4 slit atoms or having a enthalpy to 3 Nitrogen atom ring member One oxygen or sulfur atom is ringed into a ring system of M. When the available valences permit, two adjacent ring members may be heteroatoms, one of which is nitrogen and the other is selected from N, 0sts. Heterocyclic groups are derived by the removal of one hydrogen atom from a single carbon or =. The heterocyclyl linking group is derived by removing two hydrogen atoms from each of the carbon or nitrogen ring atoms. Heterocyclyl typically includes, but is not limited to, furyl, thienyl, Ipyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyrrolidinyl, pyrrolyl, oxopentyl, decyl , thiazolyl, imidazolyl, 2-imidazolinyl (also known as 4, 5-dihydro-1H♦ sylylene), imidazinyl, 2_β than salinyl, 吼 money base " Hetero-line, hetero-radio"? Diphtho, tri-, oxadiazolyl, tetrazolyl, 2H-pyran, 4H-pyran, pyridyl, piperidinyl: bisaki, morphine, 1,4-Diweiyl, 嗔like, heart well base, 'sneeze base, base base, base, ah base, ah base, 昱 base, 3Η-10 bases" (4) Linji, benzo [b]吱, benzo[b] phenyl, 1H-carbazolyl, benzene Imidazolyl, benzothiazolyl, fluorenyl, 4h quinuclidyl, fluorene, isoindole, stalk, spur, sputum, sin 19 200904414 porphyrin, 1'8-acridinyl , acridinyl, aziridyl, hexahydro-1>4-diazahryl, 1,3-benzo-oxapentenyl (also known as hydrazine, methyl 2-oxophenyl), 2 , 3-dihydro-1'4-benzodioxanyl (also known as anthracene, 4-ethylidene), benzo-dihydro-furanyl, benzo-tetrahydro-pyran Benzo, benzodihydro-thienyl, 5, 6, 7, 8-tetrahydro" fluorene-cycloheptyl (b) thienyl, 5, 6, 7-tris~4H-cyclohexyl (b) thienyl , 5,6-dihydro-4H-cyclopenta(b)thienyl, 2-aza-bicyclo[2.2.1]heptyl, aza-bicyclo[2. 2. 2]octyl, 8 _ aza-bicyclo[3.2.1]octyl, 7-oxa-bicyclo[2.indolyl]heptyl and the like. The term "aryl" refers to an unsaturation of 6, g, 1 or 14 carbon atoms, a conjugated 7 fluorene electron monocyclic or polycyclic hydrocarbon ring system or a linking group. An aryl group is derived by removing a hydrogen atom from a mono-carbon ring atom. An extended aryl linking group is derived by removing two hydrogen atoms from each of two carbon ring atoms. Aryl groups typically include, but are not limited to, phenyl, naphthyl, county, fluorenyl and the like. The term "amino" refers to the radical of the formula -ΝΗ2. The term "aminoalkyl" refers to a radical of the formula _ΝΗ-alkyl or oxime (alkyl)2. The term "aminosulfonyl" refers to the radical of the formula -S〇2NH2. The term "arylalkoxy" refers to a radical of the formula _ 〇-alkyl-aryl. The term "aryloxy" refers to the radical of the formula aryl. The term "amine sulfhydryl" refers to the radical of the formula _C(〇)NH2. The term "amine mercaptoalkyl" refers to a radical of the formula -C(O)NH-alkyl or ~c(〇)N(alkyl)2. The term "carbonylalkoxy" refers to a radical of the formula -C(〇)〇-alkyl. The term "carboxy" refers to the radical of the formula __c〇〇H or gas (10). The term "halo" or "halogen" means fluoro, chloro, bromo or iodo. 20 200904414 The term "lower alkyl-amino" refers to a radical of the formula __NH-alkyl or _N(alkyl)2. The term "lower alkyl-aminosulfonyl" refers to a radical of the formula _s〇2NH-alkyl or -S〇2N (alkyl). The term "lower alkyl-sulfonyl" refers to a radical of the formula _S02_alkyl or _C(0)N(alkyl)2. The term "substituted" means that one or more nitrogen atoms on the core molecule are substituted with one or more groups or linking groups, wherein the linking group may be further substituted by definition. The specific ability of a particular group or a contiguous hydride is best suited to be determined by a skilled artisan to produce a chemically stable core molecule. The term "independently selected" refers to the presence of one or more substituents in a particular combination (e.g., a substituent group typically found in the list). The nomenclature used in the present disclosure is derived using naming conventions well known to those skilled in the art (e.g., IUpac). Pharmaceutical Forms The compounds of the invention may exist in the form of pharmaceutically acceptable salts. As used in the medical treatment, "pharmaceutically acceptable salts" of the compounds of the present invention means non-toxic acidic/anionic or basic/cationic salt forms. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may be, for example, by solution of a compound of the invention with a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid A solution of benzoic acid, #citric acid, tartaric acid, carbonic acid or phosphoric acid is mixed to form. Furthermore, when the compound of the present invention has an acidic group, a suitable pharmaceutically acceptable salt thereof may include an alkali metal salt such as a sodium salt or a salt of a salt, and a salt such as a calcium salt or a magnesium salt; and a reduced form with a suitable organic ligand, such as a quaternary amine salt. Thus, representative pharmaceutically acceptable salts include the following: acetate, besylate, benzoate, bicarbonate, diacid salt, hydrogen tartrate, borate, bromide, calcium salt, Camphoric acid (camsylate or camposulphonate), carbonate, chloride, clavulanate, citrate, dihydrochloride, edentate, fumarate, gluconate , glutamate, hydrabaidne, hydrobromide, hydrochloride, iodide, isosulfur & salt, lactate, malate, maleate, mandelate, methanesulfonate Acid, oleate, pamoate, palmate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tartrate, toluene Acid salt. The prodrugs and metabolites of the compounds of the invention are included within the scope of the invention. In general, this drug and daisy are functional derivatives of the compound which can be rapidly converted into active compounds in vivo. The term "prodrug" means a pharmaceutically acceptable work = derivative form of a compound of the invention (or a salt thereof), wherein the prodrug can be: 丨) a relatively activated precursor that is converted to an active component in a living body; 2) a relatively non-activated precursor that converts active money into an active prodrug component; 3) a relatively low active compound component that provides therapeutic biological activity (ie, as a metabolite) after the living tissue becomes useful. . Conventional processes for selecting and preparing suitable prodrug derivatives are, for example, ""

Elsevier, 1985. By "metabolite" is meant a pharmaceutically acceptable form of a compound of the invention (or a salt thereof) 22 200904414, wherein the derivative is a relatively less active compound component which becomes useful in vivo It provides therapeutic biological activity. , 'The invention encompasses compounds of various isomers and mixtures thereof. The term "isomer" refers to a compound having the same composition and molecular weight' but having different physical properties and/or chemical properties. These materials have the same number and type of atoms but differ in structure. This structural difference can be in the construction (regional isomers) or in the ability to rotate the polar plane (stereoisomers). The term "stereoisomer" refers to an isomer of the same composition having a different arrangement of atoms in space. The mirror image isomers and diastereomers are stereoisomers in which the asymmetrically substituted carbon atom system acts as the center of the palm. The term "a molecule that does not overlap with its lining" refers to the lack of a plane or center of the dragon. The term "mirror isomer" means that the molecular species are mirror images of each other and are not superimposable. The term "diastereomer" refers to a stereoisomer that is not a mirror image. The symbol "R" & "s" represents the configuration of a substituent around the palm carbon atom. The symbols "R*" and "S*" refer to the configuration of substituents around the carbon atom. The term "racemate" or "racemic mixture" refers to a molar amount of a compound of two mirrored isomers wherein the compound lacks optical activity. Arthroplasty "Optical activity" refers to the angle of the (4) racemic mixture of the palm of the palm of the hand. The term "regioisomer" refers to an isomer of a different atomic orientation of a substituent associated with a carbon-carbon double bond, a cycloalkyl ring or a bridged bicyclic ring. The substituent atom (other than Η) on each side of the carbon-carbon double bond may be in the ruthenium or osmium configuration. In the "Ε" (phase 23 200904414 reverse side) or "chair shape" structure, replace the opposite side. In the "z" (same side) or "ship ten =, the carbon-carbon double bond associated with the phase of the slave bond", the substituent is oriented outward) can be cis; the substitution of the carbocyclic phase connection _ In the related ring-plane "form" configuration, the substituent-related ring plane is on the opposite side. A compound having a "substrate-based compound is called "shun," type), and is a (four) trans-type. It can be an "inward" or "outward" configuration when connected to a bridged double-ring system. In the "inner (D non-substituting) substituting system, the bridge (non-bridge head) point of the larger bridge in the "way" direction; in the "outward" configuration, the smaller of the remaining bridges The bridge points are linked to one. It should be understood that the various substituent stereoisomers, regioisomers and mixtures thereof used to prepare the compounds of the present invention are commercially available or can be obtained from commercially available starting materials. 4 can be prepared by the method of synthesizing the isomers by the techniques well known to those skilled in the art, and the isomers are described by the symbols "r", "s", "s*", "r". *", "e" and "z", "cis", "trans", "extrovert" and "introvert" are used in the text "reporting" to refer to the liver of the heart molecule. The definition of the basic stereochemistry (E part), external / ^ J is /. calendar., 1976, 45: 13-30). ' · Furthermore, the compound of the invention may have one or more polycrystals Type or form, and such forms are intended to be included in the scope of the invention. In addition, certain compounds may be soluble in water (i.e., hydrates) or common organic solvents. Solvates are formed and such solvates are also intended to be encompassed within the scope of the invention. 24 200904414 Therapeutic uses The CB2 receptor system belongs to the G-protein-coupled receptor (GCPR) family and appears to be predominantly expressed in peripheral lymphoid tissues (cellular mediators). And innate immunity), surrounding, peripheral (peripheral nervous system), spleen immune cells (immune system regulation) arsenic retina (intraocular pressure). CB2 mRNA is found in CNS cerebellar granule cells (coordinated visual function). A CB2 receptor vector that is activated by a promoter compound in the model is a pain response. / / The present invention relates to a pharmaceutical composition for treating, ameliorating or preventing pain of a CB2 receptor vector in a subject in need thereof, which comprises - effective Amount of IU) or a compound of formula (la) or a form thereof. $ The term "CB2 receptor media pain" as used herein refers to chronic or acute pain symptoms resulting from postoperative, inflammatory or neurological or injury or aging, and is not limited to the central and peripheral pathways. The painful symptoms of the media are difficult to characterize and can be treated by a CB 2 receptor enhancer. The scope of the method of the present invention is intended to include inflammatory-related pain symptoms selected from the group consisting of: bone and joint Inflammation, rheumatoid arthritis, headache, migraine, toothache, labor pain, menstrual pain, interstitial cystitis, peripheral neuritis, mucositis, surgical pain, sports injury pain, trauma, cancer pain, fibromyalgia, pancreas Dampitis, enteritis, cellulitis, fracture, postoperative intestinal obstruction, intestinal irritability #, pain of inflammatory bowel disease, Crohn's disease, ulcerative colitis, cholestasis, burns, sunburn, toxic The pain of a snake, a spider bite, or an insect bite in a painful room with a snake, a spider bite, or an insect bite. Further, the scope of the method of the present invention is intended to include a neurologically relevant pain symptom in the group consisting of: chemotherapy neuropathy, s-related neuropathy, diabetic neuropathy, and post-herpetic neuralgia. An example of the invention includes the use of a compound of formula (丨) or formula (Ia) or a form thereof for the manufacture of a medicament for the treatment of a subject in need thereof for the treatment, amelioration or prevention of pain in a CB2 receptor vector. An embodiment of the invention includes a method of treating, ameliorating or preventing pain in a CB2 receptor vector in a subject in need thereof, which comprises administering a compound of formula (I) or formula (ia) a combination of its form and a therapeutic agent and/or treatment. Or a compound of the formula (la) is a CB2 promoter which is useful in the method of the present invention, which has a singularity of from about 50 ιαΜ to about 〇. 〇1 nM; from about 25 μΜ to about 0.01 ηΜ; 15 μΜ to about 〇. 〇1 •, between about 1〇μΜ to about 〇. 01 ηΜ; between about 1 μΜ to about 〇. 〇1 ηΜ; between about 800 ηΜ to about 〇· 01 ηΜ; Μ 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ Μ 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 The activity ICso value is between about 1 〇ηΜ to about 〇·1 ηΜ; or about 〇. 1 pool of CB2 promoter. The term "subject" as used herein refers to a patient, which may be an animal, preferably a mammal, preferably a human, which has been the subject of treatment, observation or experimentation and has the symptoms of developing a CB receptor vector, The risk of a condition or disease (easy to suffer). The term "administering" is explained in accordance with the method of the invention. Such methods comprise administering a therapeutically or prophylactically administered/effective amount of a compound of formula (1) or formula (Ia) at a different time or simultaneously in a therapeutic time course. Because 26 200904414 =, in the method of treatment of the present invention, the term should include treating, ameliorating or preventing the cB2 receptor-induced pain of the cB2 described herein with a specifically disclosed hydration or prodrug or metabolite thereof. It is intended that the specific sigma of the present invention is not specifically disclosed but is obviously included in the scope of the present invention. Prophylactic administration can be manifested by the characteristic of the pain symptoms of the CB2 receptor vector, thereby treating, ameliorating, preventing or otherwise delaying the deterioration. The method of the present invention further includes all of the therapeutic or prophylactic therapies used by those skilled in the art. σ 词汇 ” ” refers to the amount of the compound of the invention sought by a researcher, veterinarian, physician or other medical practitioner, which may cause a biological or medical response in a group age, animal or person; Treated in the form of a heart, disease or disease. An effective amount of the compound for use in the present invention is from about 笔1 gram/kg/day to about 300 mg/kg/day. The term "pharmaceutical" refers to a product used to treat, ameliorate or prevent the symptoms, conditions or diseases of the cannabis-mediated vector. The term "combination product and/or treatment" refers to a pharmaceutical composition comprising a combination of formula (1) or formula (10) in combination with one or more therapeutic agents. A dosage system of formula (ι) or formula G, chemotherapy, or a plurality of therapeutic agents. In the case of combination, it is adjusted to achieve the second government. Among them, Lin Ming’s term “effective amount” refers to the amount of music used in the combination, so that the combination effect is as good as possible. The skilled artisan will appreciate that the components comprising the combination product can be independently optimized and combined to achieve synergistic results, thereby reducing the pathology to ^ 27 200904414 when using the components of the product alone. Insofar as the present invention relates to administration of a combination product and/or treatment, the compound of the present invention and the agent can be administered simultaneously, continuously, at intervals or in a separate form at the same or different times during the course of treatment by any suitable method. ', ', when the compound of the present invention and the pharmaceutical component are administered separately, the number of doses of the compound of the present invention is not necessarily the same every day, for example, when the substance has a large activity duration, it should be administered. Less times Suitable examples of oral administration methods are oral, intravenous (iv), intramuscular (v), subcutaneous (sc), transdermal and topical. Compounds may also be administered with or without internal or internal needles and/or catheters. Delivery under the sputum, directly into the oracle system, which includes (but is not limited to) the administration path within the cerebellum, intraventricular, intracerebral ventricle, intracranial, intraspinal, and/or spinal cord. The optimum dosage for administration can be readily determined by those skilled in the art and will vary depending upon the particular compound employed, the mode of administration, the effectiveness of the preparation, and the condition of the disease. In addition, the specific condition to be treated A factor that includes the sex, age, weight, diet, time of administration, and concomitant disease of the patient will require a dose adjustment. / / The present invention comprises administering a mixture comprising a compound of the invention and, if desired, a pharmaceutically acceptable carrier Pharmaceutical composition or pharmaceutical. 'Pharmaceutical composition' The term "composition" means a product containing a specific amount of a specific component, and any combination of specific components directly or indirectly derived from such specific amounts. 28 200904414 The pharmaceutical composition of the present invention may comprise, in addition to or in addition to a compound of formula (1) or formula (Ia), a pharmaceutically acceptable salt of a compound of formula (I) or formula (Ia) or a compound or salt thereof The drug or pharmaceutically active metabolite is mixed with a pharmaceutically acceptable carrier. W acceptable carrier is meant to be of sufficient purity and quality for formulating the compositions of the invention and when suitably administered to an animal or human Molecular entities and compositions which can cause harmful, allergic or other unpleasant reactions. Because clinical and veterinary uses are also included in the scope of the present invention, pharmaceutically acceptable formulations should include pharmaceutical formulations for clinical or veterinary use. Depending on the method of administration, the composition or pharmaceutical product can be administered in a wide range of dosage forms; including, but not limited to, oral, sublingual, (sucking or insufflation), transdermal, rectal, vaginal, Local (with or without occlusion), intravenous (bottle or infusion) or injection (intraperitoneal, subcutaneous, intramuscular,

Or parenteral) ❹ 投 ❹ ❹ ❹ ❹ ❹ ❹ ❹ 2 2 2 2 2 2 2 2 2 2 Therefore, the terms "unit dose" or "dosage form" may additionally be limited to fines, pills, capsules, solutions, (d), _, heart, sputum, suppositories, powders, granules or sterile solutions, emulsions or, for example, or The syringe is filled with m or used as an aerosol, and the female bottle can be adapted to the "week" or "four" service y (for example, suitable for intramuscular injection of the library preparation = to dissolve salts (such as citrate )). The compound includes, in non-monthly, a group of the present invention or a prodrug thereof which is present in a therapeutically effective amount or in a therapeutically effective amount. 29 200904414 Prophylactic or therapeutically effective amount of the prodrug may be in accordance with the method and suitable for the subject Within the scope and can be constructed to form any form suitable for administration. According to ", the person who wants to treat the paralyzed person, the daily prevention of the disease ^ for the average weight of about 70 kg kg to about 300 g / eight - kg effective amount can be from about 0._ mg / g /kg. From ^ ^ from (four) · 〇 1 mg / kg to about 200 mg A kg 'from about 〇 · 05 亳 / kg to about 100 mg / kg; or from about ο. 1 mg / kg to (four) gram The optimal preventive or therapeutically effective amount and administration method and therapy within the range of kg/kg can be easily determined by those skilled in the art, and the patient-related factors (age, weight, diet and The time of administration), the severity of the symptoms to be treated, the compound used and the unit dosage, the mode of administration, and the potency of the formulation vary. The unit dose can be prevented from about 5 times a day to about 5 times a day. Or a therapeutically effective amount. The preferred unit dosage for oral administration is 0. 01, 0. 05, 0. 〇. 5, 1. 〇, 2. 5, 5. 0, 10. 〇, 15 0, 25. 0, 50. 0, 100, 150, 200, 250 or 500 mg of the active ingredient. [Embodiment] Biological example The column examples illustrate that the compounds of the invention are useful in a method for treating, ameliorating or preventing pain in a CB2 receptor vector for a subject in need thereof. Example 1 Carrageenan Model of Inflammatory Pain 30 200904414 Intravenous injection of carrageenan (Cg) produced a significant allergic effect on both thermal and mechanical stimuli. The efficacy of carrageenan was minimal after administration. ', Process in male Sprague-Dawley rats (250-350 g) Before the injection of carrageenan _λ (2〇〇) in the foot, the baseline response latency was obtained on the radiant heat stimulation to evaluate the ability of the test compound to eliminate thermal hyperalgesia. The retraction response of the rapid hind foot movement (with or without the hind foot). The movement of the foot related to the movement or weight change is not considered to be a contraction reaction. The weight of each animal is recorded on the day of the experiment. Each animal is placed in a warm (= about body temperature, 30. 〇 glass surface and make it adapt to the test room about 1〇15^2 and then concentrate the radiant heat stimulus (beam) on the sole of each hind foot and record each The initial (baseline) response time of the thermal stimulus. Use the stimulus intensity of the baseline withdrawal latency of 10-15 seconds (radiation heat set at 5 f) and add the maximum cutoff time of 20 seconds. When the foot moves or when the truncation is reached When the interval is limited, the light stimulation will be automatically stopped by the photorelay. The treatment group (8 animals each) is injected intraperitoneally (/.) with a vehicle (5% and 5/e Tween-80 sterile saline solution). Other treatment groups (each 8 were intraperitoneally injected with 3 or 30 mg/kg of compound 2. - Xiao shouting, recording the withdrawal period of the side money. After the evaluation, some animals were given subcutaneously. After the % angle and vegetable gum _uL timeless salt solution), the soles of the feet are under the tissue to stimulate an acute inflammatory response. The three-hour &lt; </ RTI> estimate of the reaction time v of the stimulating of the different animals is shown in Table 1 below as SEM SEM 31 200904414 SEM. Table 1 Baseline administration of Cg after administration of Cg 1 hour _3 hours vehicle 12.13 ± 0. 84 12. 74 ± 0. 77 6. 66 ± 0. 72 3 mg / kg 5. 11 ± 0.84 10 mg / kg 6.18 ± 0. 91 30 mg / kg 14.41 ± 1. 75 After three hours of carrageenan (Cg) administration, the average incubation period of the animals treated with the vehicle was significantly reduced, indicating a thermal pain. sensitive. Example 2 The experiment of Example 1 was repeated, but the animals were first subcutaneously administered with 1% carrageenan (200 uL of sterile saline solution) to the plantar tissue of the left hind foot to stimulate an acute inflammatory response. After two and a half hours, the withdrawal latency (after 'Cg') was assessed. A treatment group was then injected intraperitoneally with vehicle (5% DMSO and 5% Tween-80 in sterile saline solution). The other treatment groups were injected intraperitoneally with 3, 10 or 30 mg/kg of Compound 2. Thirty minutes after administration of the test compound, the withdrawal latency was recorded. The results are shown in Table 2 below in seconds ± SEM. Table 2 Baseline administration of Cg after Cg administration 2. 5 hours 3 hours 5. 92 ± 1. 15 Vehicle 11. 82 ± 0. 34 6. 56 ± 1. 16 3 mg / kg 32 200904414 10 mg / kg 6.88 ± 0.44 30 mg/kg 8. 52 ± 1. 08 After two and a half hours of carrageenan (Cg) administration, the average incubation period of the animals treated with the vehicle was significantly reduced, indicating a thermal hyperalgesia. Example 3 The hot plate pain sensation test was slightly corrected using a hot plate test originally described by Eddy and Leimbach (J Ching Co/. Wan Ye. 107:385-393, 1953) (eg 0'Callaghan and Holtzman, Hall J ct ?/. 77^ Plant 192: 497-505, 1975) to determine the analgesic potential of the compounds evaluated. The hot plate pain testers used in these studies were produced by Columbus Instruments International (Columbus, Ohio). Procedure Male CD-1 mice (30-35 g) were weighed, placed in a plastic box with wood chips and allowed to acclimate prior to testing. An individual mouse was placed on a heated surface and forced to move on the plate with a glass cylinder. Record the time interval between placing and shaking, licking or rolling up any hind foot (painful feeling) as the measurement baseline. Immediately after the reaction or up to 40 seconds, the animals were removed from the hot plate immediately to avoid tissue damage. Each mouse was tested only once. A treatment group was then injected intraperitoneally with vehicle (5% MS® and 5% Tween 80 in sterile saline solution). The other treatment groups evaluated the response of each animal with J 3 〇 0 ^ and the maximum cut-off time of 90 seconds. The reaction time of the animals treated with the vehicle or test compound was compared to the individual baseline reaction times for each of the mobilized 33 200904414. The post-treatment response time was deducted from the baseline reaction time and the result was divided by the wear-off time (90 seconds) minus the baseline time difference to get the maximum efficacy percentage (%MPE). Example 4 Visceral Hyperalgesia Model This method was used to assess the efficacy and utility of test compounds in the treatment of visceral hyperalgesia using constant pressure device control, isobaric colorectal dilatation (CRD). Procedure Rats (male Sprague Dawley (275-350 g; CD (SD); Charles River Laboratory) were housed in 2 and 4 animals per cage in a temperature and humidity control room at 12 hours/12 hours light/dark cycle Feel free to give food and water. After one day of release from the isolation, the animal is gradually adapted to the plexiglass device (G_3, rat ECU 'Braintree Scientific; Branco, MA) (30 minutes and 4 hours later, A single incarceration period of 45 minutes. Return the animal to its original cage until overnight. Allow it to acclimate for 60 minutes in the morning in the morning. After 4 hours, take 70% C〇2:30% 〇2 The animals were slightly anesthetized. Then a high-scoring, 4 cm long polyethylene balloon lubricated with KY jelly was inserted through the anus into the rectum and the end of the large intestine. The balloon was placed 1 cm from the anus at the end of the mouth and the balloon was placed The catheter is placed on the base of the tail and is placed in position. The catheter is connected to a computerized pressure device that controls balloon inflation and causes colorectal expansion. Continuous recording of balloon pressure (representing intrarectal pressure). CRD causes in conscious animals Reflex visceral motor response including anterior abdominal wall contraction (Ness TJ and Gebhart GF, colorectal dilation as a harmful visceral stimulus: physiological and pharmacological properties of rat pseudo-emotional reflexes, 34 200904414 (1988), 450: 153 -169) These muscle contractions increase intra-abdominal pressure and subsequently increase intracolonic pressure. The intra-colon pressure changes are converted by the same balloon that delivers the CRD. This pressure-measuring endpoint has recently been raised from the rat's anterior abdominal wall muscle. Recorded simulated EMG response (Tammpere A,

Brusberg M, Axenborg J, Hirsch I, Larsson Η and Lindstrom E, assessing the rat's pseudo-emotional response to harmful colorectal dilatation by manometry, 7/(2005), 116: 220-226). Stimulation response data was obtained by delivering two consecutive 2 sec differentials (15, 30, 45, 60, 75 mm Hg) in a four minute interval and the pressure response was recorded as follows. The intracolonic pressure signal passed through a digit. A 1 Hz high-pass waver was modified and the integral of the 15 second CRD was used as the baseline impairment (seconds before balloon expansion); the expansion pressure responses were averaged to obtain a control stimulation/response curve for each animal. The colorectal balloon was then removed and the animals were returned to their original cages: On the following morning, a treatment group was intraperitoneally injected with 1 mM of test compound (dissolved in 5% DMS0 and 5% TWeen-80 sterile salt). In the water). One hour later 'by 5% by weight (by weight/volume) of zymosan ( (from Saccharomyces cerevisiae; Sigma Chemical Company, St. Louis). A 30% ethanol solution caused acute colitis in all treatment groups (under a slight 70% C〇2:30% 〇2 anesthesia). Four small days of Feng De, Yu Xin here on the wrong Me m ^ animals slightly anesthetized and will be straightforward to know the ball as the day - the day of the human silk control expansion. The pressure response and U sputum/release as analyzed as described in the experimental control phase were recorded and recorded. The animals in the -treated group were then administered subcutaneously in 丨^/dosage. At 4 hours after the start of colitis and 3 minutes before (10), another '35 200904414 group of animals was given subcutaneous (s. c.) at a dose of 3 mg/kg as a comparison value for the analgesic response. Data of animals (6 animals) in the vehicle treatment group in which no hyperalgesia reaction was administered after administration of zymosan was excluded from the experiment. Data are expressed as a percentage of initial (control) pressure response (% ± SEM) and each animal is used as its own control. It will be appreciated that the foregoing description of the invention and its various examples have been presented in particular. However, many other equivalents, which are not specifically described or discussed in detail, may fall within the spirit and scope of the invention or the scope of the following claims. 36

Claims (1)

200904414 X. Patent Application Range: 1. A pharmaceutical composition for treating, ameliorating or preventing pain of cB2 receptor mediators in a subject in need thereof, comprising an effective amount of a compound of formula (1): Or a salt, isomer, prodrug, metabolite or polymorph thereof, wherein the dotted line between the position 2_3 and the position 3a-9a in the formula (I) represents each of the two double bonds present when the sense is also present Position; the dotted line between position 3-3a and position 9a- in formula U) represents the position of each two double bonds existing when χ2β2 exists; the dotted line between position 9 and LR4 in formula (I) represents double X1 is a non-existent or low-carbon alkylene group; X2 is a non-existent or low-carbon exudyl group; wherein only one of XiRi and X2R2 is present; X3 is absent, low-carbon alkylene, low-carbon Alkyl or -NH-; when the dotted line between position 9 and LR4 is absent, I is absent or is a low carbon alkyl group; ' _ X4 does not exist when the dotted line between position 9 and XA4 exists X5 is a non-existent or low-carbon stretching group; R! is selected from hydrogen, alkyl (substituted at one or more positions by halogen, hydroxy or lower alkoxy), low-carbon alkyl-acid Alkyl, aryl, c3_c12 ring 37 200904414 alkyl or heterocyclic group wherein the aryl, cardo- 2 ring alkyl or heterocyclic group is optionally required in one or more positions By _, an amino group, a decyl group, a lower alkyl-amino group, a decyl group, an alkyl group (optionally substituted at a position or a plurality of positions via a _, a trans or a lower alkoxy group), a hydroxyl group or a low a carbon alkoxy group (optionally substituted at one or more positions with a halogen or a hydroxy group); selected from hydrogen, alkyl (optionally substituted at one or more positions with a halogen, hydroxy or lower alkoxy group), a lower alkyl-sulfonyl group, an aryl group, a Cr_Cl2 cycloalkyl group or a heterocyclic group wherein the aryl group, the C3_Ci2 cycloalkyl group or the heterocyclic group are each required to be an electron or an amino group. , a low-wei-amino group which is optionally substituted at—or a plurality of positions—lower than an oxy group, and (iv) a hydroxy group (substituted as a halogen or a hydroxy group at the m-mole position); , 'R^ZV :(R〇' ~S〇2-NR-Z2(R8)^-«〇)-NR9-z3(R10); When the two dotted lines are not present, Μ does not exist or low carbon 、, low carbon wire , a low-carbon alkoxy group, a hydroxyl group, a C3 C-pyringyl group or a heterocyclic group, wherein the ruthenium, fluorene-fluorene-heterocyclic heterocyclic group is required to be in a soil of 3 Cl2 or Need to be in - or multiple bits ♦ secret, shout Low-carbon alkyl-carbon alkoxy group (optional = di-based / alkoxy-substituted), low-n-substituent substitution; 4 more positions (four) perforation-based substitution) or 2-fragmented dotted line, the heart is non-existent A plurality of positions of a ketone group, a keto group, and a low heterocyclic group are each required to be one or a generation; a low anaerobic group, a lower alkoxy group or a sulphin is taken as a 38, 200904414 base, (d), an amine group, a silk, and a burnt Base (optional η-solid position by (iv), trans- or low-carbon alkoxy substituted), succinct or multiple positions via functional or mesogenic), fluorenyl, amine called carbamoyl, aryl, aromatic Alkoxy or aryl group: a aryl or heterocyclic group; a C:Cl 2 cycloalkyl group or an anthracene, wherein an aryl group, a (tetra) daisty == need, a mono- or poly- face group, a keto group, an amine group, tt , meta-soil (optionally halogen, hydroxy or substituted at one or more positions), alkoxy (optional at - or multiple positions via a halogen): its dicarboxy J carbonyl alkoxy, amine A Mercapto, amine-mercapto- yl yl-based base-aryl substituted with aryl or heterocyclic; heart is hydrazine or lower carbon; hydrazine is aryl, (: cardinyl or heterocyclic, Wherein &amp; base ^cycloalkyl as desired - or more _ group, _ base soil, halogen, 1 amine f yl, alkyl (optionally substituted at one or more positions via halogen, hydroxy "di = oxy"), oxygenated Base (optional at one or more positions via ^== base =), ", alkoxy, amine (10), amine A _ private hydrogen or low carbon filament; cancer substitution, Rl 〇 is aryl, OC, a 2 cycloalkyl or heterocyclic group, wherein the aryl group and the heterocyclic group are each required to pass one or more transbasic groups; ==: an amine group filament, a calcination group (optionally - or a plurality of positions (tetra), via j Low carbon filament substituted), leuco oxy (substituted by one or more positions via one or more positions via a dentate or a trans group), an enantiomer, a carbonyl alkoxy group, an amine carbaryl group, an amine group 39 200904414 decylalkyl group, Aminosulfonyl, lower alkyl-aminosulfonyl, aryl, aryloxy, aryl alkoxy or heterocyclic; Z2 is absent or alkyl; and Z3 is absent And -MS〇2~ or an alkyl group (wherein the alkyl group is optionally substituted at - or at a plurality of positions via a halogen, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxyl group or a carbonyl alkoxy group). The pharmaceutical composition of claim 1, wherein Χι is absent or low-carbon alkylene; and the lanthanide is selected from the group consisting of hydrogen and alkyl (optionally halogen or hydroxy at one or more positions) Or a lower alkoxy group), an aryl group, a cycloalkyl group or a heterocyclic group, wherein the aryl group, the C3_Ci2 cycloalkyl group or the heterocyclic group are each optionally contained in the halogen or a plurality of positions (optional if necessary) - or multiple positions substituted by dentate, hydroxy or lower alkoxy), hydroxy or alkoxy (optionally substituted with one or more positions via halogen or hydroxy). 3. If the pharmaceutical composition for the third item is applied, the towel is not present and the FM is selected from an aryl group or a C3-C12 cycloalkyl group, wherein the aryl group is replaced by dentate depending on the desired position. , wood more (such as the pharmaceutical composition of the scope of the patent application, ! is and R! is hydrogen. π a cray in 5. pharmaceutical application of the scope of the first paragraph of the pharmaceutical composition, against -C (0)- Zl(R6) . -S〇2-NH-Z2(R8)^-C(〇)^NH_Z3(r;〇) 〇,: . such as c (= the pharmaceutical composition of the range 1 item, its...彳A, is a non-existent, low-carbon extended-burning base, low-carbon alkylene group up to a heterocyclic or a burnt base; and R6 is an aryl group, (5) 2-ring-burning "''s earthworm base, 〇-(: 12 ring yard The base or heterocyclic group may be subjected to a plurality of hydroxyl groups, fluorenyl groups, and south to one or more positions, a base group, an amine base wire, or a hospital base as needed (if necessary, the fluorination of the halogen, hydroxyl or Lower alkoxy substituted), alkoxy i alkoxy sulphate or warp), silk, alkoxy or hetero: carbenyl, aryl, aryloxy, ^ t R3 ^ 8. If the patent application is not in use; and &amp; is a heterocyclic group. -SD, a pharmaceutical composition of the diver, wherein R3 is stone ^7 7 2 inflammation 8, X3 is absent or low carbon Sub-alkyl; hydrazine is hydrogen or low is absent or burned; and R8 is aryl as needed. The position is replaced by an alkoxy group. 9. The pharmaceutical composition of claim i, wherein; X3 is absent or low carbon alkylene; Z2 is absent or in 'and R8 is aryl as needed - a position is substituted by a silk base. The pharmaceutical composition of claim 1 wherein R3 is C (〇), a Z3 (Rl.); 乂3 is non-existent, low carbon stretch base: low Carbanetidine or ~NH-; R9 is hydrogen or lower alkyl; &amp; is absent, _nh_, _s〇2_ or alkyl (wherein the alkyl group is required to be dentate at one or more positions, _ Substituted, low-carbon alkyl, low-carbon alkoxy, carboxy or decyl alkoxy substituted) and are aryl, C3-G2 cycloalkyl or heterocyclic groups, respectively, depending on one or more bases, shouting, i, silk, silk, 妓 (optional or at multiple positions via halogen, county or low oxyfluoride), alkoxy oxime to be substituted at one or more positions by halogen or vial), rebel , carbonyl, methoxy, carboxylic acid, amine sulfhydryl, amine fluorenyl, low 41 200904414 alkyl-aminosulfonyl, aryl, aryloxy, arylalkoxy Base or miscellaneous Substituting. 11. A pharmaceutical composition according to the scope of the patent application, wherein -C(0)-NH-Z3(Rlt)); X3 is absent; Zs is absent, _NH_ or alkane The base is optionally substituted at one or more positions with a halogen, hydroxy, oligo, valeryl, decyl or carbonylalkoxy group; and 'is aryl, GC! 2 cycloalkyl or The heterocyclic group is optionally substituted by one or more of a hydroxyl group, a keto group, a halogen, an amine group, an aminoalkyl group, an alkyl group (optionally substituted at one or more positions via a dentate, a hydroxyl group or a lower alkoxy group) , alkoxy, fluorenyl, carbonylalkoxy, aryl or heterocyclic group substituted. 12. The pharmaceutical composition of claim i, wherein hydrazine is -C(0)-NH-Z3(R1Q); X3 is absent; Z3 is absent or alkyl; and is GC, 2 naphthenic Base view requires one or more hydroxyl, keto, halogen, amine, aminoalkyl, alkyl (optionally substituted at one or more positions via halogen, hydroxy or lower alkoxy), alkoxy Substituted by a carboxyl group, a carbonyl alkoxy group, an aryl group or a heterocyclic group. 13. The pharmaceutical composition of claim i, wherein R3 is -C(0)-NH-Z3(Rh)); X3 is absent; Z3 is absent or alkyl; and is GC! 2 ring The alkyl group is optionally substituted with one or more alkyl or carbonyl alkoxy groups. 14. The pharmaceutical composition according to claim 1, wherein 匕 is -c(o)-nh-z3(Ri〇) 'Yes 3 is absent; Z3 is absent, _NH_ or alkyl (wherein The alkyl group is optionally substituted by halogen, hydroxy, lower alkyl, lower alkoxy, carboxy or carbonyl alkoxy at one or more positions; and Ri〇42 200904414 is aryl as needed ~ or more a base group, a burnt group (optionally substituted with a halogen, an amine group, an amine carbocarbonate alkoxy group), a tr sterically immobilized position substituted by a dentate, a mercapto group or a low ring group. &quot;^ base, fluorenyl, alkoxy group, aryl or hetero 15.. ## Patent scope of the pharmaceutical composition of the 'th which is sweet; χ3 is non-existent; Z3 is non-existent, I or 2 The middle silk is required to be substituted at one or more positions via an i-, silyl or low-stone anti-azepine; and Ri. The aryl group is replaced by one or more halogens as needed. 16. The pharmaceutical composition of claim 1, wherein r3 is -C(0):NH-Z3(R1()); X3 is absent; Zs is absent or alkyl (wherein Requires substitution at - or multiple positions via a halogen, hydroxy, lower alkyl, lower carbon alkoxy, carboxy or carbonyl alkoxy group; and R1. The heterocyclic group is optionally substituted with one or more alkyl groups. 17. The pharmaceutical composition of claim 1, wherein the dotted line between position 9 and LR4 is absent, Χ4 is absent or low carbon alkyl; and R4 is hydrogen or optionally An aryl group substituted with a halogen at a plurality of positions. 18♦ The pharmaceutical composition according to claim 1, wherein the dotted line between the positions 9 and LR4 is absent, the Χ4 is absent and the ((3)-aryl group is required to be on the aryl group one or more The positions are replaced by halogen. 19. The pharmaceutical composition of claim 1, wherein Xs is absent and Rs is absent. 20. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of compounds of formula (la): 43 200904414 X3R3 (la) IS two prodrugs, metabolites or polymorphs, where Xl is a dotted line 3 = or a low carbon alkylene group; when at position 9 and ^ or gaze; to sub-L is not present Or a lower alkylalkyl group and R4 is an aryl group substituted by a hydroxyl group at the hydrogen position; when the dotted line between the positions f Μ, 'Χ4 is absent and 匕 is C&quot;. From, 1 = see the need to - or a plurality of positions by halogen substitution 4 or Wei group, wherein the aryl group is required to be replaced by dentate at the -= solid position; __c (9) rotten, period ^,, νη-ζ3〇μ '·匕 is a heterocyclic group; Rs is an aryl group as needed; one is substituted with an oxy group; R4 aryl, ^12 cycloalkyl or heterotunan, /, aryl or G-Ci2 cycloalkyl, as needed By one or more of the prime, sulfhydryl or county oxygenated silk; Zl is broken; Z2 is alkyl; △ is absent, -NH_ or alkyl (wherein alkyl is required to be in one or more positions) A pharmaceutical composition according to claim 2, wherein l is absent. X3 is absent or low-carbon alkylene; when in position 9 and When the dotted line between LR4 is absent, &amp; is absent or low carbon alkyl and hydrazine is hydrogen or aryl substituted at one or more positions; when at position 9 = X4R4 In the presence of a dotted line, X4 is absent and h is a CH-aryl group, wherein 44 200904414 aryl is optionally substituted by dentate at one or more positions; Ri is selected from hydrogen, aryl or CtC! 2 cycloalkyl , where aryl Substituting halogen at one or more positions as needed; r3 is a s〇2_NH_Z2(R8) or -C(0)-NH-Z3(Rlfl); Re is an aryl group which needs to be alkoxy at one or more positions. Substituted, Ri8 is aryl or G-Ci2 cycloalkyl, wherein aryl or c3_c12 cycloalkyl is optionally substituted by one or more halo, alkyl or carbonyl alkoxy groups, Z2 is alkyl; and & Is a non-existent or alkyl group (wherein the alkyl group is optionally substituted at one or more positions by an imine, a hydroxy group or a lower alkoxy group). 22. The pharmaceutical composition according to claim 1, wherein the compound is Selected from: ', 1% hexyl-4, 5,6,7, 8, 9-hexachloro-1H-cyclooctane α than β-sodium decanoic acid (1,3,3-trimethyl-bicyclo[ 2· 2. 1]hept-2-yl)-nonylamine, 1-cyclohexyl-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctylpyrazine-salt-3-carboxylic acid (King Kong Sodium-1-ylmethyl)-decylamine, 1-cyclopentyl-4, 5, 6, 7, 8,9-hexahydro-1 fluorene-cyclooctazole-3-carboxylic acid (Astragalus -1- Benthyl)-nonylamine, 1-cyclohexyl-4, 5, 6, 7, 8, 9-hexahydro-111-cyclooctane than saliva-3-carboxylic acid (1_ diamond just-1 -yl-B Base)-nonylamine, (2Ε)-[9-(3-chloro-benzyl)-4, 5, 6, 7, 8, 9-Hexahydro-1 Η-cyclooctyl η-biazole-3-yl]-ethlyronic acid [(1S)-1-phenyl-ethyl]-decylamine, (9S*)-(3-chloro-benzyl Base)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctane. Bis-azole-3-carboxylic acid [(lR)-2-hydroxy-1-phenyl-ethyl]-decylamine, (9P〇-(3-chloro-benzyl)-4, 5, 6, 7, 8 , 9-Hexahydro-1H-cyclooctaπ-pyrazole-3-carboxylic acid [(lR)-2-hydroxy-1-phenyl-ethyl]-decylamine, 45 200904414 (9R*)-(3-chloro -benzyl)-4, 5, 6, 7, 8, 9_ hexahydro-1H-cyclooctaπ-pyrazole-3-carboxylic acid [(lS)-2-hydroxy-1-phenyl-ethyl]-oxime Amine, (9S*)-(3-chloro-benzyl)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctylazole-3-carboxylic acid [(lS)-2-hydroxyl -1-phenyl-ethyl]-decylamine, (9S*)-(3-chloro-benzyl)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctane 0-azole- 3-carboxylic acid [(lR)-2-decyloxy_i-phenylethyl]-decylamine, (9R*)-(3-gas-benzyl)-4, 5, 6, 7, 8 , 9-Hexahydro-1H-cyclooctane 0-pyridyl-3-carboxylic acid [(lR)-2-decyloxy-1-phenylethyl]-decylamine, (9EM3-chloro-benzylidene) —4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctyl 11-pyridyl-3-carboxylic acid [(1R)-;!-phenyl-ethyl; decylamine, (9EM3-gas- Benzylene)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctyl 11 azole-3-carboxylic acid [(is)-l-phenyl-ethyl]-decylamine, ( 9E)-(3-Gas-benzylidene)-4, 5, 6, 7, 8, 9-hexahydro-1H-cyclooctyl-s-zine- 3-decanoic acid [(is)-2-hydroxy-1 - -ethyl]-decylamine, or (9E)-(3-gas-benzylidene)-4, 5, 6, 7, 8, 9-hexahydro-iH-cyclooctyl. Acid [(lR)-2-hydroxy-indole-phenyl-ethyl]- decylamine. The pharmaceutical composition of claim 1, wherein the pain of the CB2 receptor vector is Chronic or acute. The pharmaceutical composition of claim 23, wherein the pain of the cb2 receptor vector is caused by postoperative, inflammatory or neurological or injury or aging. The pharmaceutical composition, wherein the pain of the cβ 2 by the media is a pain symptom of the towel pivot and the path (4), which is characterized by another description and can be treated by (10) a receptor enhancer = 46 200904414 26. The pain of the medium of patent application No. 24 is composed of the following receptor arthritis, rheumatoid arthritis, first two pains: bone pain, menstrual pain, interstitial cystitis, shaw, toothache, labor pain, exercise Injury pain, trauma =, visceral inflammation, surgical viscera, enteritis, bee-like tissue inflammation, 'painful fibromyalgia, snoring, inflammatory bowel disease Pain: jinlong =, sputum, intestinal inflammation, cholecystitis, burns, sunburn, right main disease, seven ulcers, large intestine bites, pain and non-toxic snakes, insects, two, two, cockroaches, spider bites or insects 27. For example, the pain of ^^叮/ in the 24th section of the patent application. The pain of the vector is caused by the following young &amp;, less f, sigma, wherein the CB 2 receptor u is selected from the group of sacral neuropathy, AIDS-related neuropathy (4) she/sexual pain Post-herpetic neuralgia. &lt;, diabetic neuropathy and 28. If the compound of the scope of item 1 of the scope of the patent application is 1 &quot;, if the application for patents is up to about milligrams per kilogram / kg / the scope of patent application i The effective amount of the compound of the pharmaceutical composition ^ item 13 is from about days to about 300 mg / kg / day.厶 / / 3〇.^: The pharmaceutical composition of claim 1 of the patent scope, wherein the effective amount of the compound of the 14th item of the Shenjing special thorn range is from about 〇.〇, to about 300 mg/kg/day. . Brother a kg / patent application scope! The pharmaceutical composition of the item is in the form of an effective amount of the compound of the first application of the patent scope and the combination of the treatment and treatment of 47 47044044 and/or treatment. 32.M please patent scope! The use of a compound of the formula is for the treatment of a subject in need of treatment, amelioration or prevention of pain in the CB2 receptor vector. 33. The use of claim 32, wherein the pain is chronic or acute. ^ The team uses the scope of claim 32, wherein the (10) receptor mediator = is produced after surgery, inflammatory or neurological or injury or aging.疚, 广Ϊ ί 范 ( 四 四 四 四 该 该 该 该 该 该 该 该 该 GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB GB Profit. The use of the scope of claim 34, wherein the (10) receptor y 甬糸 is selected from the group consisting of inflammatory pain: bone joints, rheumatoid arthritis, Gu, migraine, toothache, and pain. , =, interstitial cystitis, peripheral neuritis, mucositis, surgical pain, pain, pain, trauma, cancer (4), fibromyalgia, visceral inflammation, =, cellulitis, fracture, postoperative intestinal obstruction, bowel Stimulation, pain in sexual bowel disease, Crohn's disease, ulcerative colitis, gallbladder, burns, sunburn, poisonous snakes, spider bites or insect bites, painful and non-toxic snakes, spider bites or insects The pain of biting. The use of the scope of claim 34, wherein the CB2 receptor vector has two neuropathic pains selected from the group consisting of: chemotherapy nerve 2, AIDS-related neuropathy, diabetic neuropathy, and bandage repair Post neuralgia. 48 200904414 VII. Designated representative map: (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: None 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: Formula (1) 4