TWI334415B - Novel substituted 4-phenyl-4-(1h-imidazol-2-yl)-piperidine derivatives and their use as selective non-peptide delta-opioid agonists - Google Patents

Description

1334415 V. INSTRUCTION DESCRIPTION (I) The present invention relates to novel 4-phenyl-4-[1 oxime-imidazol-2-yl]-hexahydropyridine derivatives, processes for their preparation and their use in medicine, in particular As a selective non-peptide, it is an opioid agent. The existence of at least three types of opioid emergents (commonly referred to as 缪(μ), dextran (6), and 5 gram (κ) receptors is currently well established and proven, and all three categories are shown to exist in humans. The central and peripheral nervous systems of many species (Lord JAH et al., 1977, 267, 495). 'Changes in one or more of these opioid receptor subtypes can lead to the observation of multiple effects in animal models, enhancing the unique pharmacological profile of each receptor, such as 10 dextran agents in mice, rats, salivary, primate and Even humans have different analgesic effects (including the spine and the spine) (Moulin et al. 1985, Q, 213), increasing the release of growth hormone and inhibiting dopamine release, while the German antagonist has no analgesic effect and reduces release. Growth hormone (Goodman and Gilman, 772e 15 Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill, 1996, 525). Some experiments have also suggested that de-antagonists also lack the general side effects associated with sputum- and keba-receptor activation (Galligan et al., J. Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs)

Exp_ Ther. 229, 641) 0 20 The animal model also demonstrates that the opiate receptor agent also has a direct effect on the gastrointestinal tract (such as the stagnation effect) and the respiratory tract (such as the stimulating effect of beer smoking activity), and It shows that the opiate receptor agent also plays a synergistic role in a variety of pharmacological effects. In fact, it positively regulates the central anti-nociceptive and antitussive activity of the sputum-acting agent, resulting in the reduction of the paper size to the Chinese national standard (CNS). A4 size (2丨0X297 public 3⁄4) 1334415 A7 B7 V. INSTRUCTIONS (2) The dose delay is associated with the adverse side effects associated with these anesthetics. Interestingly, the immunostimulatory activity of some of its opioid receptor agents is Developing medical strategies has value in human immunodeficiency diseases (Dondio et al. Review: Non-peptide ttU〇pi〇id agonists and antagonists, 5 Exp. Opin. Ther. Patents, 1997, l〇^, 1075) ° Its important pharmacological value, for its role as an agent (showing weak or no antagonistic activity) and for its receptors (for weak or no for sputum- or kba-opioid receptor subtypes) Preference) is selective. Its opioid receptor is required as a keratogen, and it is necessary that this opioid receptor agent is not a peptide peptide because it is not stable for systemic administration. The Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, publishes the currently known non-peptides and opioids containing oxime-and benzofuran morphine (Searle & Co US-5354863 (1994), WO of Astra AB -9531464 (1995)), octahydroisoindole (for example, TAN-67 of Toray Inc. 15, Smithkline Beecham SPA, published in JP-4275288 (1992) and WO-9710216 (I997)), hexahydropyridinium derivatives (eg, BW373U86 and SNC 80 of The Welcome Foundation, published in WO-9315062 (1993)), pyrrole hexahydroisoindole (WO-9504734 (1995) by Smithkline Beecham SPA), and ethylamine derivative 20 (Nippon Shinyaku Co) WO-9622276 (1996) of Ltd., triazaspiroquinone (WO 0146192 (2001) by Meiji Seika Kaisha Ltd.) and substituted amino-derivatives (Gruenenthal Gmbh EP-864559 (1998) )).

WO-9828270 (1998) and WO-9828275 of Astra AB -4- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) A7 1334415 B7 V. Invention description (3) (1 99 8) An analgesic effect of a hexahydropyridine derivative having a structure which is not related to the compound of the present invention.

EP 1 038 872 A1 (2000) to Pfizer Products Inc. discloses a 4-phenyl-4-heteroarylhexafluoropyridine derivative as an opioid receptor ligand, 5 which has a structure different from that of the present application. Wherein in the nature of the hexahydropyridyl nitrogen substitution, the divalent 7C-bonder substitution is absent.

Janssen Pharmaceutica NV, in WO 00/37470 (2000), generally discloses a route for the use of a portion of a compound of the invention to synthesize an antihistamine spiro compound, but this compound has not been exemplified in prior art application 10 and no suggestion It has the properties of an opioid receptor agent. It is an object of the present invention to provide a novel class of highly selective opiate receptor agents based on a hexahydropyridine moiety, and another object of the present invention is to provide an opioid receptor which can be used as an analgesic having reduced side effects. Further, it is a further object of the present invention to provide an opioid receptor agent for use in a disease in which the opium is affected by 15 intermediaries. The present invention relates to a novel substituted 4-phenyl-4-[1H-imidazol-2-yl]-hexahydropyridine derivative according to the general formula (1).

:A1\ R

X

R This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1334415 A7 V. Invention description (4) 10 15 Ministry of Economic Affairs Intellectual Property Bureau Η Consumer Cooperative Print 20 Pharmaceutically acceptable acid or test a salt, a stereochemically isomeric form, a tautomeric form thereof and an N-oxide form thereof, wherein: A = B is a divalent π-bond; X is a covalent bond, -CH2-CCH2CH2- ; Rl is hydrogen, alkoxy, alkoxycarbonyl, Ar-oxy, Het-oxy, Ar-carbonyloxy, Het-carbonyloxy, Ar-alkoxy, Het-alkoxy, alkyl , poly-alkyl, alkoxyalkyl, Ar-alkyl, Het-alkyl, kr, Het, thio, alkylthio, Ar-thio, Het-thio or » NR9R1G, wherein R9 and R10 Each independently is hydrogen, alkyl, Ar, Ar-alkyl, Het, Het-alkyl, Ar-carbonyl, Het-carbonyl or alkyl ester alkyl; or A=B and R1 together form as desired Half _ aromatic or aromatic carbocyclic or heterocyclic group Het2 or Het3; R2 is hydroxy, alkoxy, alkylcarbonyloxy, phenoxy, phenylcarbonyloxy, halo, cyano, poly-alkane Base, alkoxyalkyl group, methyl carboxy group, burning Base, calcined SI group, amino group, mono- or di-alkylaminocarbonyl, phenyl, nitro, amine, mono or dialkylamine, thio or thio; R3 is alkyl, Ar, Ar.alkyl, Ar-alkenyl, Ar-carbonyl, Het, Het-homo, Het-dilute or Het-yl; r4, r5 are each independently hydrogen, alkyl, carboxy, aminocarbonyl, alkane An ester group, a halogen group or a hydroxyalkyl group; P is an integer equal to 0, 1, 2 or 3. In the organization of the present application, an alkyl group is a linear or branched saturated hydrocarbon group having from 〗 〖6 carbon atoms; or a cyclic saturated -6-sheet containing from 3 to 7 carbon atoms. Finance@国标准(CNS)A4 Specification (2 hearts 297 gong - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1334415 V. Invention description (5) and hydrocarbon group (cycloalkyl); or from 3 to 7 a cyclic saturated hydrocarbon group of one carbon atom is bonded to a linear or branched saturated hydrocarbon group having from 1 to 6 carbon atoms; wherein each carbon atom may optionally have an amine group, a nitro group, a thio group, a hydroxyl group, an oxy group or a cyano group. Substituted, fluorenyl or m-substituted, preferred alkyl is methyl, ethyl 5, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl Indenyl and cyclohexylethyl. In the organization of the present application, an alkenyl group is an alkyl group having one or more double bonds according to the above definition, and a preferred alkenyl group is a vinyl group and a propenyl group. In the structure, Ar is selected from the group consisting of a 10-carbon ring including a phenyl group and a naphthyl group, each of which is optionally substituted with one or more substituents, each of which is independently Selected from the group consisting of hydroxy, alkoxy, alkoxycarbonyl, phenoxy, phenylcarbonyloxy, 1,4-carbonyl, cyano, alkyl, polyhalo, alkoxyalkyl, fluorenyl, hydrazine Base, carboxyl, alkylcarbonyl, alkyl ester, aminocarbonyl, mono or dialkylaminocarbonyl, streptoalkyl, phenyl, nitro, amine, mono 15 or dialkylamino, thio, alkane Or S02-CH3, preferably Ar is a naphthyl group or a phenyl group, each optionally having a hydroxyl group, a methoxy group, an ethoxy group, a phenoxy group, a trihalomethoxy group, a halogen group, a methyl group, a trifluoromethyl group. , chloromethyl hydrazino, carboxy-, decyl ester, ethyl ester, diethylaminocarbonyl, phenyl, nitro, pseudothio, trifluoromethoxy or so2-cv3 alkyl. 20 In the present application In the structure, the halogen group is selected from a substituent including fluorine, gas, bromine and iodine and the polyhaloalkyl group is a linear or branched saturated hydrocarbon group having from 1 to 6 carbon atoms or contains from 3 to 7 A cyclic saturated hydrocarbon group of a carbon atom in which one or more carbon atoms are substituted by one or more halogen atoms, a preferred halogen group is bromine, fluorine or gas, and a preferred polyhaloalkyl group is a trifluoromethyl group.

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x 297 mm). 1334415 A7 B7 V. Inventive Note (6) In the organization of the present application, Het is selected from heterocyclic groups including Het1, Het2 and Het3. Het1 is selected from the group consisting of pyrrolidinyl, dimercapto, and imides. sit. Base, σ ratio. Sedentary, hexahydroindole, dioxy, ruthenium, di-sigma, thiofuran, hexahydro-D argon and tetrahydrofuranyl 5 aliphatic monocyclic a cyclic group, Het2 is a semi-aromatic monocyclic heterocyclic group selected from the group consisting of 2H-pyrrolyl, pyrrolidinyl, imidazolium and pyrazolyl, and Het3 is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, Furanyl, thiol, . boast. Sitting base, different π sitting base, σ plug. An aromatic monocyclic heterocyclic group of a sitting group, an isomeric D-based group, a p-biting base, a densely occluded base, a D-flavor base, a tower D well base or a tris-sigma well base; or喳11林基, fluorenyl, benzopyridinium, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl and benzothiophene An aromatic bicyclic heterocyclic group; each monocyclic and bicyclic heterocyclic group may be optionally bonded to a carbon and/or hetero atom via a halo, hydroxy, alkoxy, alkyl, Ar, Ar-alkyl or Pyridyl substitution. 15 Valuable compounds are acid or base addition salts, their stereochemically isomeric forms, and their tautomerism, which are printed according to the compound of formula (I) and its Pharmacological Economics Intellectual Property Office employee consumption cooperative. And its N-oxide form, wherein A = B is selected from the group consisting of C = 0, C = N - R6 wherein R6 is hydrogen or cyano, C = S, S = 0, Lu 02 and C = CR7R8 R7 and R8 are each independently hydrogen, nitro or alkyl. 20 Other valuable compounds are compounds according to formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemically isomeric forms thereof, tautomeric forms thereof and their N-oxide forms Wherein R1 is selected from the group consisting of alkoxy groups, Ar-alkoxy groups, alkyl groups, polydentate groups, leuco-based thio groups, Ar-alkyl groups, Het-hospital groups, Ar, hexahydro-α ratio π wells Base, 0 ratio <7 base, sputum paper size applicable to China National Standard (CNS) A4 specification (2 ΙΟ X 297 mm) A7 1334415 V. Description of invention (7) Azolyl, pyrrolidinyl and NR9R1g Wherein R9 and Rl() are each independently hydrogen, a deuterium, an Ar group, an Ar-alkyl group, an alpha-bite group or a calcinyl group. Other valuable compounds are those according to formula (1), their pharmaceutically acceptable acid or base addition and subtraction salts, their stereochemically isomeric forms, their tautomeric forms and their indole-oxide forms, of which = Β and R1 are formed to form a group selected from the group consisting of Het2 and Het3, and more preferably Β=Β and R1 are formed to be selected from the group consisting of benzoxazolyl, thiazolyl, benzothiazolyl, and benzopyrimidine. Sitting base and 11 dense bite base. Further valuable compounds are compounds according to formula (I), their chemically acceptable acid or base addition salts, their stereochemically isomeric forms, their tautomeric forms and their oxime- An oxide form, wherein X is a covalent bond or a -CH2- group, and preferably X is a covalent bond. Still other valuable compounds are compounds according to formula (I), pharmaceutically acceptable acid or base addition salts thereof, stereochemically isomeric forms thereof, tautomeric forms thereof and N-oxides thereof Form wherein R2 is alkoxy or halo. Other valuable compounds printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs are compounds according to formula (I), their pharmaceutically-acceptable acid or base addition salts, their stereochemically isomeric forms, a tautomeric form thereof and an N-oxide form thereof, wherein R3 is selected from the group consisting of phenylalkyl and tea groups, each independently selected from at least one selected from the group consisting of halo, alkyl, hydroxy, alkoxy Substituted with a substituent of a dialkylaminocarbonyl group. When R3 is an alkyl group, the preferred alkyl group is a cyclohexylmethyl group. Other valuable compounds are based on the compound of formula (1), its drug -9- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm). Description of the invention (〇5, a scientifically acceptable acid or base) An addition salt, a stereochemically isomeric form thereof, a tautomeric form thereof, and a ruthenium-oxide form thereof, wherein α=Β is C=〇 or S02, and R1 is an alkoxy group, an alkoxyalkyl group, Ar or NR9R10 wherein R and R10 are each independently "I or Ar; or A = B and R1 - form a benzene 5-oxazolyl group; P is hydrazine, and R3 is optionally substituted with a hydroxy group, an alkyl group or an alkyl ester group. The benzyl group and R4 and R5 are each hydrogen. More specifically, the following compounds are the most preferred compounds: 1-ethylacetate-4-phenyl-4-[1-(phenylmethyl)-indole-_ Sodium-2-yl]-hexahydro. is more specific; 10 1-propyl ketone_4_phenyl-4-[1-(phenylmethylmita-2-yl)-hexahydro. 1-. Ethyl 4-phenyl-4-[1-[(4-hydroxyphenyl)methyl]-1Η-imidazol-2-yl]-hexahydro. Specific bite; 1-ethyl ester base 4-phenyl-4-[1-(1-phenylethyl)-1Η-imidazol-2-yl]-hexahydro-15 0-pyridinium; 1-isopropyl ester-4-phenyl-4- [1-(phenylmethyl)-1Η-imidazole-2 -yl]-hexahydropyridine; 1-ethyl ester-4-phenyl-4-[1-[[4-(decyl)phenyl]methyl]-1Η-imidazole - Ministry of Economic Affairs Intellectual Property Office Employee-consumer cooperative printed 2-yl]-hexahydroindole; 20 1-benzylidene-4-phenyl-4-[1-(phenylmethyl)-1Η-imidazol-2-yl]-hexa Hydrogen hydrazide; W mercapto)-4-phenyl-4-[ 1-(1-phenylethyl)-1 Η-imidazol-2-yl]-six mouse 0 bite; 4- [[2-(1-Benzyl-4-phenyl-4-hexahydropyridyl)-1Η-imidazol-1-yl]-10- This paper size applies to China National Standard (CNS) A4 specification (210x297 )) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1334415 V. Description of invention (9) Methyl]-methyl benzoate; 4-[[2-[1-(2- benzoxazolyl) -4-phenyl-4-hexahydropyridyl)-1Η-imidazol-1-yl]methyl]-indolyl benzoate; 1-benzoinyl_4_phenyl-4+-(1 -phenylethyl)-1Η-imidazol-2-yl]-hexa-5 hydrogen ratio bite; 1-ethyl ester-4-phenyl-4-[1-[1-[4-(ethyl ester) Phenyl]ethyl]-1H-mi. Sodium-2-yl]-hexahydro-β ratio bite; and hydrazine, 4-diphenyl-4-[1-(phenylidenyl)-1Η-imidazol-2-yl]-1-hexahydropyridine amine. 10 A pharmaceutically acceptable acid addition salt is a medically active non-toxic acid addition salt form which may be formed by the inclusion of a compound of formula (I), which may be obtained from a base form according to a compound of formula (I) Suitable acid treatment, such as inorganic acids such as hydrohalic acid, especially hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, glycolic acid, propionic acid, lactic acid 15, pyruvic acid, oxalic acid, and propylene Acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, mandelic acid, pseudosulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylamine sulfonic acid, water Acid, p-aminosalicylic acid and balmoic acid. The acid-containing protons can also be converted into their medically active non-toxic base addition salt forms by treatment with a suitable organic and 20 inorganic base. Suitable salt forms include, for example, salt, alkali metal and test. Soil metal salts, especially lithium, sodium, potassium, magnesium and calcium salts, with organic bases such as ethylenedibenzylamine, hydrazine-methyl-D-reducing glucosamine salts, hyalamine salts and amines Base acids such as salts of arginine and lysine. This paper scale applies to the Chinese National Standard (CNS) A4 specification (2|〇x 297 mm)

A7 1334415 V. INSTRUCTIONS (10) Conversely, the acid or base addition salt form can be converted to the free form by treatment with a suitable base or acid. The noun addition salt used in the organization of the present application also includes a solvate formed according to the compound of the formula (I) and a salt thereof, such as a hydrate and an alcoholate. The term "stereochemically isomeric form" as used herein, defines a compound of formula (I) which may have all possible isomeric forms, unless otherwise mentioned or indicated, the chemical name of the compound represents all possible stereochemistry. a mixture of true structural forms containing all of the non-parent isomers and palmar isomers of the basic molecular structure 10, more specifically, the stereocenter may have an R- or S-configuration, in the bivalent ring The substituent on the (partial) saturated group may have a cis- or trans-configuration, and the stereochemically isomeric form of the compound of formula (I) is obviously included in the scope of the present invention. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing According to the CAS-naming convention, when two stereo 15 centers of absolute configuration are known to exist in the numerator, the R or S description is specified (based on the Cahn-Ingold-Prelog order principle) to The configuration of the smallest number to the palm center, the reference center, and the second stereo center is to use the relative description [R*, R*] or [R'S*], where R* is always specified as the reference center and [R*, R *] indicates the same center of palmity and [R*, S*] indicates the center of the different palms, for example 20, if the smallest number in the numerator has the S configuration for the center of the palm and the second center is the R, stereo The description will be specific to S-[R*, S*], and if "α" and "stone" are used, the position of the highest order substituent on the asymmetric carbon atom in the ring system with the least number of rings is arbitrary forever. The "α" position of the plane determined by the ring system, relative to the highest order substituent on the reference atom -12 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1334415 V. Description of the invention ( 11) The highest asymmetry on other asymmetric carbon atoms in the position loop system The position of the substituent group, if it is on the same side of the plane determined by the ring system is named "if it is in the plane of the other side is determined by the ring system is named" β ,,. — 5 We note that the substituted carbon atom at the 4-position of the hexahydropyridyl moiety is not a palm atom, therefore, the compound of formula (1) is via the para-substituent R1, R2, R3, R4 or R5 There can be at least one stereo center in the structure. The tautomeric form of the compound of the formula (ί) is meant to include the formula (1) wherein, for example, the enol group is converted to a keto group (keto-enolyl tautomer). The ruthenium-oxide form of the compound according to formula (I) is meant to include the compound of formula (I) wherein one or more nitrogen atoms are oxidized to the so-called cerium-oxide, especially the cerium-oxide wherein hexahydrogen The nitrogen of the pyridyl moiety and/or the imidazolyl 15 moiety is oxidized. The Intellectual Property Office of the Ministry of Economy, the Intellectual Property Office, the Consumer Cooperative, which produces the compound of formula (I) prepared according to the following method, can be synthesized as a racemic mixture of the palmo isomers, which can be subjected to dissociation methods known in the art. Separated from each other, the racemic compound of formula (1) can be converted to the corresponding non-palphalinic salt form by reaction with a suitable palmitic acid, followed by separation of the non-palphalinic salt form, for example via Selective or stepwise crystallization and release of the palmo isomers therefrom with a base, the alternative method of isolating the palmomeric form of the compound of formula (1) involves the use of a liquid chromatography of the palmitic stationary phase, the pure stereochemistry The conformational form can also be derived from the appropriate starting material in the form of the corresponding pure stereochemical isomer, Condition - 13 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x 297 mil) 1334415 V. Description of the invention ( 12) The reaction is stereospecific, and it is preferred that if a specific stereoisomer is required, the compound will be synthesized by stereospecific preparation methods, which are suitable for use in the palm of the hand. Pure starting materials. The present invention also encompasses a derivatized 5-compound (generally referred to as a "precursor") of a pharmacologically active compound according to the present invention, which is decomposed in vivo to give a compound according to the present invention, and the effect of the prodrug at the target receptor is usually (but Not all) lower than the original decomposition of the compound, the precursor drug is particularly useful when the chemical or physical properties of the desired compound make it difficult or ineffective, for example, the compound of the household may have only poor solubility, which may Not well transported through the mucosal epithelium, or it may have unwanted transient plasma half-lives. Other discussion of prodrugs can be found in Stella, VJW, "Prbdrugs' Drwg De/z.very/Sysiews, 1985, ρρ· 112-176 and Drw Furnace, 1985, 29, ρρ. 455-473. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed According to the present invention, the pharmacologically active compound pre-drug form is usually root 15 according to formula (I), which is pharmaceutically acceptable Acid or base addition salt, stereochemically isomeric form thereof, tautomeric form thereof and its bismuth-oxide form, acid group may be esterified or amided Esterification of the acid included in this group is the group of formula -COORx, where Rx is (: μ6 alkyl, phenyl, benzyl or one of the following groups:

20

-CH2 amide group includes the formula -CONRyRz group, where 1^ is 14, C, _6 alkane-14- This paper scale applies to China National Standard (CNS) A4 specification (2丨Οχ 297 mm) 1334415 A7 A7 B7 The invention according to the invention may be derived from a ketone or an aldehyde, for example, by a ketone or an aldehyde, for example, a phenyl or benzyl group and a Rz*-〇H, H, CN6 alkyl, phenyl or benzyl hydrazine-containing amine group. The Mannich test is formed, which can be hydrolyzed in the aqueous solution in the fifth-order kinetics. The compounds according to the invention show surprising use in medicine, in particular for the treatment of a variety of pain conditions, such as, in particular, the pain of the central nervous system, the pain of peripheral nerves, the pain of structural or soft tissue injuries, Progressive disease-related pain, neuropathy 10 pain and acute pain such as acute injury, trauma or surgery and conditions such as neuropathy, diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, post-stroke pain syndrome and clusters Chronic pain caused by a headache or migraine. The compounds according to the invention are also useful in the treatment of arthritis, psoriasis 15, asthma, inflammatory bowel disease, respiratory dysfunction, functional diarrhea, non-ulcer dyspepsia and incontinence, and such use is also disclosed in WO/9852929 (Pfizer Ltd). , 1998) ° Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed in the presence of its opioid receptor in human colon can also be demonstrated by radioligand binding and automated radioactive spectroscopy studies, combined with a maximum density of 20 (80-90%) In the myenteric plexus neurons between the annular and longitudinal smooth muscle layers, the low-density receptor is located on the smooth muscle layer. In functional studies, the opiate agent can inhibit the cholinergic energy in the human colon. Cholinergic excitatory nerve transmission, according to these findings, it is expected to inhibit human colonic peristalsis and also show peripheral nerve action -15- This paper scale applies Chinese National Standard (CNS) A4 specification (210x297 mm) 1334415 A7 B7 V. INSTRUCTIONS (14) The selectivity of its opioid agent UK-321 130 appears to be effective, dose-related in preclinical models. Knot peristalsis system, therefore, compounds of the present invention may also be useful in treating irritable bowel syndrome (IB S). The invention therefore also relates to a compound of formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a tautomeric form thereof and an N-oxide form thereof, according to the above definition Use as a Pharmacy According to the following description of the present application, in vitro receptor and neurotransmitter signal transfection studies can also be used to evaluate the activity of dexame, guanidine and kappa opium. The invention also relates to a composition comprising a pharmaceutically acceptable carrier and an effective therapeutic amount of a compound according to the invention as an active ingredient, the compound according to the invention being modulatable For the purpose of administering medicines in different medical forms, a suitable composition which is generally used for systemic use of 15 pharmaceutical agents, is an effective amount of a specific compound which is an active ingredient when preparing the pharmaceutical composition of the present invention. If necessary, the addition salt form is used, and is intimately mixed with a pharmaceutically acceptable carrier. The carrier may be in various forms depending on the preparation form of the drug to be administered. These pharmaceutical compositions are preferably in the form of unit administration, especially For parenteral injection or infusion, for example, when preparing a composition, any conventional medical medium may be used. For parenteral compositions, the carrier usually includes sterile water, at least for the most part, although Including other ingredients such as to help solubility, for example, an injection solution can be prepared in which the carrier contains a saline solution , glucose solution or a mixture of saline and glucose solution, can also be prepared -16- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) A7 B7 1334415 V. Invention description (15 injection suspension can use liquid Carriers, suspending agents, etc., also include solid form preparations which are converted into a liquid form shortly before use. Depending on the mode of administration, the pharmaceutical composition preferably contains from 0.05 to 99 weight percent, preferably more than 5%. 0.〗 to 7〇% by weight of the active ingredient, and from the plexus to 99.95 heavy stem%, more preferably from 3〇 to 999% by weight of the pharmaceutically acceptable carrier, all percentages are based on the total composition The pharmaceutical composition may additionally contain various other ingredients known in the art such as stabilizers, buffers, emulsifiers, viscosity modifiers, '10 surfactants or preservatives. Co-operatively, the present invention also relates to a compound of the formula (1), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, a tautomer thereof, and a N-oxidation thereof Forms and any of the above-described pharmaceutical compositions for the manufacture of a medicament for the treatment of a variety of pain conditions, such as, in particular, pain in the mid-intermediate 15 nerves, pain in the peripheral nerves, pain associated with structural or soft tissue injuries, progressive disease Related pain', ° neuropathic pain and acute pain such as acute injury, trauma or surgery and conditions such as neuropathy, diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, post-stroke pain syndrome, clustering 20 Chronic pain, arthritis, psoriasis, asthma caused by headache or migraine: inflammatory bowel disease, respiratory dysfunction, functional diarrhea, non-ulcerative dyspepsia, incontinence, and irritable bowel syndrome (IBS). In another aspect, the present invention provides a method of treating a patient suffering from any of the above circumstances, comprising applying an effective medical amount according to the invention -17 - the paper size is applicable to the Chinese National Standard (CNS) A4 specification (2Ι〇χ 297 PCT 1334415 A7 B7 V. INSTRUCTIONS (16) Compositions or pharmaceutical compositions are needed for this treatment People. Isotopically labeled compounds of the invention can be used as diagnostic agents, and the invention therefore also relates to compounds labeled with such isotopes, as well as methods for the diagnosis of each compound using isotopes according to the invention. 5 The compounds according to the invention can generally be prepared via a series of steps, each step being known to those skilled in the art, in particular, the compound according to formula (Ia) can be via formula (II) according to reaction scheme (1) The reaction of the intermediate is prepared. The reaction is carried out in a suitable reaction solvent such as toluene in the presence of a suitable base i triethylamine. In the reaction scheme (1), all 10 variables are as in the formula (I). The definition of W1 and the portion to which it is attached is equal to R1; the W1 example is alkyl, Ar or Het, and the WhCpCOCl example is a gas formate. · Figure 1

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Co., Ltd. 20 Compounds according to formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ig) may also be reacted according to the reaction. Any reaction shown in the formula (2) is prepared via the reaction of the intermediate of the formula (III), in which all the variables are as defined in the formula (I) and the portion to which W1 and the moiety are attached is equal to R1; Examples of W1 are alkyl, Ar or Het. -18- This paper scale applies to national standard (CNS) A4 specification (210x297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1334415 A7 B7 V. Invention description (17) Reaction (a) is in a suitable solvent For example, in dioxane and using BOC20, the reaction is conveniently carried out under reflux for several hours. The reaction (b) is carried out in a suitable solvent such as THF, and the reaction is conveniently carried out at room temperature for 1 to several *4 hours. 5 Reaction (c) is carried out in a suitable solvent such as dioxane at room temperature for 1 hour in the presence of a suitable base such as Et3N. Reaction (d) is carried out in a suitable solvent such as THF or DMF without the need for a base and "at room temperature for several hours. The reaction (e) is carried out in refluxing acetone or in a suitable assay such as DMF in the presence of potassium carbonate 10 and can conveniently be carried out at 80 °C. The reaction (f) is carried out in a suitable solvent such as dichlorosilane in the presence of a suitable base such as triethylamine at room temperature for about 30 to 120 minutes. The reaction (g) is carried out in a suitable solvent such as acetonitrile under reflux for 24 hours. 15 Reaction (h) is carried out according to R1 under different conditions, for example, when R1:=CF3, the reaction is carried out in dichloromethane in the presence of triethylamine at -78 ° C for 1 hour, for R1 = NH 2, the reaction is At the reflux temperature at two. The reaction was carried out for 12 hours for Ι^=(:Η3, the reaction was carried out in dioxane methane at room temperature in the presence of triethylamine for 3 hours. 20 reaction (i) was in a suitable solvent such as isopropanol The reaction is carried out at reflux temperature for 12 to 36 hours. The reaction (j) is carried out in a suitable solvent such as acetonitrile at reflux temperature for 24 hours.

This paper scale applies to the Chinese National Standard (CNS) A4 specification (2丨Ox 297 mm) 1334415 A7 B7

V. Description of the invention (I

Figure 2 Ο A人A Ό 0—W' R3 (a) (R")p (III) (b) (c) (e) (0 (g) (h)

Wl—N=C=B

B = 0. S O O , Ren R1 o W1— 0-a) β W1— H (l-b) Λ (»-C) (H3C)Si—N=C=0 or H2N X—Cl R1—2—Cl

°W° R〆, W2 d*d) X^o H2N X d-e) (l-c) N Person (l-f) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative (i) (1)

Q

W2=r\ Cl. nh2 Het-Hal Hal=CI, Br.l, F R〆Q d-g) R7,

He(~Q (l-h) R7, /R8

(M) —. This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1334415 A 7 B7 V. Description of invention (I9) The compound according to formula (Ic) can also pass through the middle of formula (IV) Preparation of the reaction with a halide in which all the variables are as defined for formula (I), the reaction being carried out with a base such as NaH (60% in mineral oil) and in a reaction inert solvent such as DMF minus THF .

10 (IV) (K) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, printing of starting substances and intermediate compounds according to formula (II), (III) and (IV) are commercially available compounds or may be used according to this technique. It is generally known to be prepared by a conventional reaction method. The intermediate of the formula (II) can be produced according to the following reaction scheme (4), wherein all the variables are as defined in the formula (I). This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1334415 A? ____________________ B7 V. Invention description (20) (R2) p M type 4

(a)

CV 10 15

R4 SOCI2

H2N

R4

Q (R2)P — (c)

(Π) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing 20, Reaction Scheme 4 includes the steps (4) of the hydrazine-based gas and substituted amines, and amines such as the lower amine in the presence of a suitable test such as E13 N. In a suitable di-inert solvent such as a gas chamber, the reaction is conveniently carried out in the next step (b) of the adduct and the α2 reflux... and then the resulting product is The appropriately substituted 2,2-dimethoxyethylamine is reacted in anti-riding solution (iv) such as DM F towel, for example, at room temperature (step c), and in step (d), the adduct obtained in step (4) is龄里-22- This paper scale applies to national standard (CNS) A4 specification (2Ι0χ297 mm) 4415 A7 B7 V. Description of invention (2 〇 而 而 。 。 。 。 。 。 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐The intermediate compound can be prepared by selectively reducing the alkyl ester moiety of the hexahydropyridyl moiety from the hydrazine '纟k according to formula (Ic) according to the following reaction: 10 Λ R5 Η4 η〇Λ^ R5 R* ( Ic) (ΠΙ) The reaction is carried out in the presence of a suitable base such as K〇H in a suitable reaction inert solvent such as 2-propanol And under reflux. The intermediate compound of the formula (IV) can be produced by hydrogenating a compound according to the formula (I-c) according to the following reaction: 15 Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printing 20

Λ All of the variables are as defined in formula (1), and the reaction is carried out in methanol in the presence of a catalyst such as Pd/C (10%) at moderate temperature. Obviously in the foregoing and the following reactions, the reaction product can be separated from the reaction medium, and if necessary, can be applied to the Chinese National Standard (CNS) A4 specification (210x297 publicity) according to the general -23-paper scale of the art. 1334415 A7 B7 V. INSTRUCTIONS (22) Known methods for further purification, such as extraction, crystallization and chromatography, the presence of more than one reaction product in the form of palmomere is also apparently known from known techniques. The mixture is separated, in particular preparative chromatography, such as preparative HPLC. The following examples illustrate the invention without limiting it. In the experimental part of the compound, the absolute stereochemical configuration of the stereoscopic carbon atom was not determined experimentally. In these cases, the first separated stereochemical isomer form was "A" and the second was called "B". "There is no further indication of the stereochemistry of the real 10, but the "Α" and "Β" isomer forms can be used by those skilled in the art using fractional methods known in the art such as X-ray diffraction. The method is clearly identified, and the separation method is described in detail below. Hereinafter, "DMF" is defined as hydrazine, Ν-dimethylformamide, ''THF'' is defined as tetrahydrofuran and ''DIPE'' is defined as diisopropyl ether. 15 Α. Preparation of Intermediate Compounds Α1 Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, printing 1 - mercapto-4-phenyl-4-hexahydropyridine carbon ruthenium chloride (0.49 mol) added at room temperature Stirring mixture of benzylamine (0.49 mol) and hydrazine, hydrazine-diethylethylamine (1.223 mol) in CH2C12 (2500 ml), and mixing mixture 20 at room temperature for 1 hour, adding K2C03 (150 g And H20, the mixture is stirred and the liquid layer is separated, the aqueous layer is extracted with CH2C12, the combined organic layers are dried (MgS 〇 4), filtered and the solvent is evaporated, yield: 144 g (95%) of 1-A 4--4-phenyl-N-(phenylindenyl)-4-hexahydropyridiniumamine (Intermediate 1). -24- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1334415 A7 B7 V. Description of invention (23) Example A2 Mixing intermediate 1 (0.47 mol) in S0C12 (750 ml) And refluxing for 1 hour, the solvent was evaporated, toluene was added twice and evaporated again. Yield: 190 g (100^6) of N-[gas (1-methyl-4-phenyl-4-hexahydro-5 pyridyl) Amidoxime] benzoguanamine hydrochloride (Intermediate 2). Example A3 A mixture of Intermediate 2 (0.47 mol) in DMF (750 mL) was cooled in an ice bath, and 2,2-dimethoxyethylamine (0.54 Mofeng) dissolved in DMF was added dropwise. The mixture was stirred at room temperature overnight, the solvent was evaporated, 10 yield: 210 g (100%) of N-(2,2-dimethoxyethyl)-1-methyl-4-phenyl-indole- Phenyl indenyl)-4-hexahydropyridine decylamine dihydrochloride (Intermediate 3). Example A4 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Mixture of intermediate 3 (0.47 mol) in 6 equivalents of HC1 (1500 ml) into a turbid solution, then rinse with CH2C12 (900 ml) at 80°. When stirring, cool, basify with NaOH 50% solution and extract with Η2 (:12, separate the organic layer, dry (MgS04), filter and evaporate the solvent, crystallize the residue from CH3CN, filter the precipitate and dry Yield: 38_3 g (25%) of 1-mercapto-4-phenyl-4-[1-(phenyl 20 decyl)-1 oxime-imidazol-2-yl]hexahydropyridine (Intermediate 4). Example A5 A mixture of compound 1 (0.089 mol) in methanol (250 ml) was hydrogenated with Pd/C 10% (3 g) as a catalyst at 50 ° C. After hydrogen (1 eq.) was consumed, the catalyst was filtered. Evaporate the filtrate to make the residue from the -25- paper scale applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1334415 A7

The CHsCN crystallized, the precipitate was filtered and dried, yield: 23 g (e.g., %) of 4-phenyl_4_(1H--.s.s.). Example A6-5 A mixture of Intermediate 5 (0.026 mol) and hydrazine (0.26 mol) in 2-propanol (150 ml) was stirred and refluxed for a few hours, the solvent was evaporated and residue The material was dissolved in hydrazine and the mixture was extracted with cj^ci2. The organic layer was separated, dried, filtered and evaporated. The yield: 94 g of 4-phenyl- 4-[1-l-phenylphenyl)-1 2-yl]hexahydropyridine (intermediate 6). 10 Example A7 was reacted under A pressure, and a mixture of Intermediate 5 (0 0033 mol) in DMF (5 mL) and THF (5 mL) was added dropwise to 60% NaH (0.004 m) in mineral oil. The solution was stirred in THF (10 mL) at room temperature and the mixture was stirred at room temperature for 1 hour, then a solution of 4-(15-ethoxyethoxy)benzophenone (0.004 mol) in THF was added dropwise. The obtained reaction mixture was extracted with CH2C12, the separated organic layer was dried (Na2SO4), filtered, and the solvent was evaporated, and the residue was purified on silica gel via short open-column column chromatography (flow washing: Ministry of Economics Intellectual Property) Bureau employee consumption cooperative printed CH2Cl2/(CH3OH/NH3)95/5), collected pure stream washing and evaporated solvent 20, yield: 1.33 g of 4-phenyl-4-[l-((4-mercapto) Ethyl carboxy)phenyl indenyl)-1 -imidazol-2-yl]-1-hexahydropyridinecarboxylate (Intermediate 7). B. Preparation of final compound Example B1 Intermediate 4 (0.05 mol) and N,N-diethylethylamine (0.15 mol) -26- This paper scale applies to China National Standard (CNS) A4 specification (210x297 PCT) 1334415 V. INSTRUCTIONS (25) In the case of a stupid (750 ml) compound at 1 〇〇t: mixing, adding ethyl citrate (0 · 2.5 m) and reacting The mixture was stirred and refluxed for 1 hour, then cooled, and the mixture was poured into aq. K 2 C 3 aqueous solution (35 g of K 2 C 3 ), the liquid layer was separated, the aqueous layer was extracted with CH 2 C 12 , and the separated organic layer was dried (MgS 〇 4) 5, Filtration and evaporation of the solvent, the residue was filtered on a glass filter via gelatin (flow washing: collecting the desired stream washings and evaporating the solvent, crystallizing the residue from CEUCN, filtering and drying, 'yield:克(10) Red phenyl phenyl hydrazide)]!^ Imidazol-2-yl]-1-hexahydropyridinecarboxylate (Compound 1). 10 Example B2 Preparation of Compound 2

The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed a clumsy gas (0.0023 mol) added to the intermediate 6 (〇〇〇19 mol) and ν,ν-diethylethylamine (0_0024 mol) at ( :1^(: 丨2 (15 ml) and stirred at room temperature, the reaction mixture was stirred at room temperature for 3 hrs, water was added, the liquid layer was separated, and the aqueous layer was extracted with C^C丨2 The combined organic layers were dried (Na2S 〇 4), filtered and the solvent was evaporated. The residue was purified on silica gel eluting with short open-column chromatography (flow washing: CH2Cl2/(CH3〇H/NH3) 98 /2), the pure stream fraction was collected and the solvent was evaporated, the residue was crystallized from n-hexane, filtered and dried, yield: 〇·42 g (52%) of compound 2, melting point 122.71. -27- Applicable to China National Standard (CNS) A4 specification (210x297 mm;)

Description of the invention (26 A7 B7 Preparation of Compound 3 5

5 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed at Ν2 atmosphere, add intermediate 5 (0.0054 mol) in DMF (10 ml) and THF (10 ml) dropwise to THF (30 ml) Naii (0.00624 mol) and the mixture was stirred at room temperature for 1 hour, then methyl 4-(bromomethyl)benzoate (0.00624 mol) in THF (5 mL) was added dropwise and the mixture The mixture was stirred at 6 ° C for 3 hours, and the mixture was extracted with chkI2. The combined organic layers were dried (Na.sub.2.sub.4), filtered and evaporated. Purification (flow washing: CH2Cl2/(CH3OH/NH3) 98/2), the desired fractions were collected, and the solvent was evaporated, the residue was crystallized from DIPE, filtered and dried, yield: 1.7 g (70%) Compound 3, m.p. 149.1 〇C. Example B4 Preparation of Compound 4 20

-28- This paper scale applies to national standard (CNS) A4 specification (210x297 public hair) 丄幻4415 A7 B7 V. Invention description (27) Intermediate 6 (0.0059 m) and (0.0059 m) in CHfN The mixture was stirred and refluxed for 24 hours, the solvent was evaporated, water was added, and the mixture was extracted with CH.sub.2 C.sub.2, and the separated organic layer was dried (Na2SO4), filtered and evaporated. Filtration and crystallization from ch3CN, filtration and drying, yield: 0-33 g of compound 4, mp. f Example B5 Preparation of Compound 5

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Intermediate 4 (0.0001 mol) in a mixture of 6 equivalents of HCi (22.8 ml) 15 and refluxed for 4 hours. The reaction mixture was basified and then extracted with CH2C12. The separated organic layer was dried (anhyd. Na.sub.2.sub.4), filtered and evaporated. Example B6 20 Preparation of Compound 6

This paper scale applies to China National Standard (CNS) A4 specification (21〇-29- x 297 mm) 1334415 A7 B7 V. Inventive Note (28) Add isocyanatobenzene (0.0094 mol) dropwise to THF (50 ml) of intermediate 6 (0.0094 mol) and the reaction mixture was stirred at room temperature for 30 min, water was added and the mixture was extracted with CH.sub.2 C. The solid residue was washed with 2-propanum, filtered and dried, yield: 2.7 g (68%) Compound 6. Example Β7 Preparation of Compound 7

10 Add isocyanooxybenzene (0.0007 mol) to intermediate 6 (0.0007 mol) in THF (10 ml) and stir the reaction mixture at room temperature for 3 h 15 , then add water and extract the mixture with CH2C12 The separated organic layer was dried (Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. , Production: 0.2 g (66%) of the Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperatives, printing 20, example B8 a) Preparation of compound 8

-30- This paper scale applies to China National Standard (CNS) A4 specification (210x 297 mm) 1334415 A7 B7 V. Invention description (29) Compound 3 (〇.〇02 Moer) and Li0H (0·〇2 Mo The mixture was stirred at room temperature for 24 hours, Η20 was added, the mixture was adjusted to ΡΗ6 and extracted with CH.sub.2Cl.sub.2, and the organic layer was separated, dried, filtered and evaporated. The residue was washed with CH.sub.2Cl.sub.5, yield: yield: 0.72 g (83%) Compound 8. (: b) Preparation of compound 9

10 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed under N2 pressure, a solution of NaH60% (0_000642 mol) in DMF (2 ml) was stirred at room temperature, and intermediate 6 (0.000642 mol) was added dropwise. A solution of DMF (8 ml) was added and the mixture was stirred at room temperature for 1 hour, CHd (0.001 284 m) was added, and the reaction mixture was stirred at 6 ° C for 2 hours in a Parr pressure vessel, and the solvent was evaporated. The residue was purified by flash chromatography on EtOAc (EtOAc:EtOAc:EtOAc: c) Preparation of compound 10

Add 1 molar concentration of THF to LiAlH4 (0.000444 mol) dropwise -31- 1334415 A7 B7 5. Inventive Note (30) Add to Intermediate 7 (0.000404 mol) in THF (5 mL) at 0 ° The solution was stirred and the mixture was stirred at EtOAc for 30 min. EtOAc (EtOAc) 5 Purification by GC-TLC on Chromatotron (flow wash: CH2C12/CH30H 96/4). The desired fractions were collected and evaporated. The residue was crystallised from ch3oh/h2, filtered and dried, yield: 0.020 g 10%) of compound 10. d) Preparation of compound &

The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed LiOH (0.001423 mol) was added dropwise to the intermediate 7 15 (0.0006469 mol) in dioxane / H20 1 / 1 (6 ml) solution, the resulting suspension The mixture was stirred at room temperature for 18 hrs. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 51%) of compound 11. Example B9 Adding LiOH (0.01 8 mole) to Intermediate 7 (0_0018 Mo) at -32- This paper scale applies Chinese National Standard (CNS) A4 specification (210x297 mm) 1334415 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printing A7 B7 V. Inventive Note (3l) Mixture of THF (10 ml) and H20 (10 ml), stir the reaction mixture at room temperature for 3 hours, add water, add CH2CI2, extract the reaction mixture, organic The layers were separated, dried (Na2SO4), filtered and evaporated, and the residue was evaporated, and the residue of white solid was washed with decyl alcohol and CH2C12, and then dried, and the yield was 0.54 g of 4-phenyl-4-[1-(4- Phenylmethyl)-1Η·flavor. Sodium-2-yl]-1-hexahydro-α is σ-determined by the acid (Scheme 12). This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1334415 A7 B7 V. INSTRUCTIONS (32) The following compounds listed in Table 1-5 are prepared: Table 1: 〇

Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Compound No. Experiment No. R1... Physical Properties 110 B2 » —Η Or'- 13 B1 - - · - - - . . . . . . . _ , 0*··* CT 14 B3 — A/ CT&quot; mp =137 1 B1 A/· σ' 12 B9 /V —HQXT' 15 B3 /,0· Ί. 16 B3 /V Fxr mp= l 17 17 133 A/ XT' mp =127 18 B3 A /. &quot;XT' mp= 125 8 B6 〇ΓΓ&quot;- mp=252 —一一· · · - -.......-............ OH -34- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1334415 A7 B7 V. Description of invention (34) 〇

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Compound No. Experiment No. R^— RJ—Physical Properties 27 B1 cr. mp=80 2Ϊ — &quot;B1 &quot; cr σ' mp=215 29 .B2 \〇产.·- Cr mp =111 '30 ~ B3 Υ····· &quot;3Ϊ&quot;- B3 rV', 32 ΒΪ 〇τ°·- 〇τ- 33 B2 ch3— CT. mp= 183 34' B2 CH3CHr- CT. Mp = 133 35 B2 isopropyl... ζΤ. mp II 107 36 B2 t&gt;...·· cr. mp= l 11 &quot;....1T—one ¥2 — third butyl-or-- (mp= 165 - 36- This paper scale applies to the National Standards (CNS) A4 specification (2丨0x297 mm) 1334415 A7 B7 V. Invention Description (35

0II

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Compound No. Experiment No. R1— R, --- Physical Properties. 2 B2 〇r... mp=123 38 B3 σ 39 B3 〇····· 0^. 〇 Γσ&quot;&quot;&quot; ......40 ' ....B3—... —σ.— O '-41一—百三——... _&quot;σ a1··. ------------ -----------------...... .....-42---B2 or-· mp= 151 Tf3 43 B2 ▼ cr mp =79 44&quot; B2 Λ —cr mp = 149 45...—&quot; B2 cr· -37- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1334415 A7 B7 V. Invention description (36) 0

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed compound number, experiment number R1 — R\- physical plate 46 B2 nh2— cr. mp=208 47 B2 /V Η Cf&quot; mp=144 48 B2 Α人ΝΗ' cr· ... 49 B2 yL.... CT: — 50 B2 H cr 51 B2 a:- 6 B6 σ'··· cr:. 52 B3 σ'..· ojCT&quot;&quot; 〇53 B3 σ'... 0 〇r 54 B3 a&quot;· σ···· -38- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1334415

A B V. Description of invention (39 ) 0

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Compound No. Experiment No. RJ... : Physical Properties 73 B2 cr 74... One B2 » 10 B6 cr- 75 B2. rV. 〇r_ 76 B2 _『 -....... -......... 77 B2 f3c, 9 cr 11 B6 cr 78 B2 or' -41- This paper scale applies to National Standard (CNS) A4 (210x297 mm) 1334415 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (4〇) R1 I - compound number experiment number RJ-- RJ - physical properties 79 B2 〇r_. 9 B6 σ1· cr 80 B2 cn..·. cr 8.1 B2 〇/.·· 〇r' 113 B2 HN··· 〇6 〇r· 82 B2 σ' 83 B2 广〇···' σ' mp=74 &quot;84 B2 cr. 85 B2 ό.... Cr_ mp =165 8—6 B2 σ, cr:... -42- This paper scale applies to China National Standard (CNS) A4 specification (2丨0 X 297 mm) 1334415 A7 B7 V. Invention description (41) 〇

Compound number Actual number RJ~ Physical properties. 87 B2 cr·· Table 2 ·· ,

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

This paper scale applies to China National Standard (CNS) A4 specification (210x 297 public) 1334415 A7 B7 V. Description of invention (42) Table 3 ·

B

Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Compound Number ί实骀i No. A=B R1... Physical Data • 5 B5 ONH H 91 B5 C=NH . 4 B4 C=N-CN H w mp=84 92 B4 ON-CN σ'- 93 B4 C=C-N02 a&quot;- 95 B2 C=SH VN··· mp=172 96 B2 C=S 94 B2 S02 —ch3 mp =167 97 B2 S02 --nh2 mp=2 \2 111 B2 S02 —CF3 mp= 104 98 B2 S〇2 -44- This paper scale applies to China National Standard (CNS) A4 specification (210x 297 mm) 1334415 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V , invention description (44) Table 5:

Compound experiment. Editing number R1—·· Physical data.107 B3 —OH 108 B2 —··-......—..... mp =105 &quot;Ϊ 09 B2 ...NH2 mp=136 B. Pharmacological Examples In the Radioligand Binding and GTPrS Binding Assays, a review of the pharmacological properties of 15 selected compounds for replication of human dextromethorphan, keba and opioid receptors expressed in mammalian cell lines was stimulated via [35s]GTPtS The second messenger signal of the film preparation is measured, and in this functional test method, the action and antagonistic properties of the compound are studied. DPDPE ((D-Pen2,5) enkephalin) was used as a reference agent and naltrindole as a reference antagonist for malaria receptors (Malatynska E., Wang K, Knapp RJ, Santoro) G., Li X., Waite S., Roeske WRt Yamamura HI: Human δ opioid receptor: a stable cell line for functional studies of opioids· NeuroReport 6,613-616, 1995)^L(Portoghese -46- paper scale Applicable to Chinese national standards (CNS> A4 specifications (2丨Ox297 mm)

1334415 A7 B7 V. INSTRUCTIONS (45) PS, Sultana M., Takemori AE: Naltrindole, a highly selective and potent non-peptide δ opioid receptor antagonist. Eur. J. Pharmacol· 146, 185-186, 1988) U69593 and No-Binadora Sf (nor-BNI) were used as reference agents and antagonists in Kappa opioid receptors, respectively. For opioid receptors, morphine was used as a reference agent and naloxone as a reference antagonist. Ii, Mansour A., Akil H., Medzihradsky F., Traynor JR,

Woods JH: Stimulation of guanosine-5 ^0-(3-[35S]thio)triphosphate binding by endogenous opioids 10 acting at a cloned Mu receptor. J. Pharmacol. Exp. Ther. 286, 282-288, 1998) and Smart D·, Hirst RA·, Hirota K·, Grandy DK, Lambert DG: The effects of recombinant rat μ-opioid receptor activation in CHO cells on phospholipase C, [Ca2+]I and adenylyl cylase. Br. J. \5 Pharmacol 120, 1165-1171, 1997). Materials and Methods Cell Culture Fluid Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed CHO cells permanently transfected with Kappa or Oscar Receptor in supplemented with 10% heat-deactivated burdock serum and containing 100 IU/ml penicillin G, 100 μm Dulbecco's Modified Eagle's Medium (DMEM)/Nutrition Mixture Ham 2 F12 (Proportion 1) 2 g/ml streptomycin sulfate, 110 μg/ml pyruvate and 300 μg/ml L-proline antibiotic solution :1) Medium culture, C6 glioma cells that will be permanently transfected with opiate receptors in DMEM medium supplemented with the above 1%% heat-activated burdock serum and antibiotic solution-47- This paper scale applies to Chinese national standards ( CNS) A4 specification (210x297 mm) 1334415 A7 B7 V. Inventive description (46) Medium culture. Membrane Preparation The membrane was prepared as a total particulate matter component. All cell lines were cultured in a 14 5 mm Petri dish to 9 θ·% pool. Add 5 mM 5 mM sodium butyrate 24 hours before collection to remove the medium. The cells were washed with ice-cold phosphate-buffered saline (PBS w/o Ca2+ and Mg2+), scraped from the culture dish to 50 mM Tris-HCl buffer pH 7.4, and centrifuged (16,0O0 RPM). Collected at 4 ° C for 1 ) minutes, the cell pellet was resuspended in hypotonic '5 mM Tris-HCl buffer pH 7.4 and re-homogenized with an Ultra 10 Turrax homogenizer to give a homogeneous solution at 18000 1 ^]^ At 4&lt;\: centrifugation for 20 minutes, the final pellet was resuspended at 50 mM Tris-HCl buffer pH 7.4 and aliquoted at -70 °C using the Biorad protein assay ( Bradford) Protein assay using burdock serum albumin (BSA) as a standard MM. J 15 method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochem. 72: 248-254, 1976). Radioligand Binding Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, conducted preliminary radioligand binding experiments to show the best test conditions for these opiums in the corresponding mammalian cell membrane. Competitive inhibition of compound [3H]DPDPE at different single-line concentration compounds with a radioligand concentration of 2 nanomolar (Kd = 1.7 nanomolar) and at least three orders in the vicinity of pIC5〇 For competitive binding of keba and guanidine receptors, [3H]U69539 (Kd=〇.4 nano Mo-48- This paper scale applies Chinese National Standard (CNS) A4 specification (2丨0x297 mm) 1334415 A7 B7 V. Inventive Note (47) Ear Concentration) and [3H]DAMGO (Kd=0.6 nanomolar Concentration) were used at a concentration of 1 nanomolar, respectively, and the membrane was thawed on ice and diluted at 50 mils. Moer concentration Tris-HCl buffer pH 7.4, for the opiate receptor, in this culture buffer to make a supplement, 2 millimolar concentration MgCl2, 1 millimolar concentration 5 degrees EGTA and 0.1% BSA, non-specific combination Is defined for the Dessert, Keba and Osmium receptors in the presence of 1 micromolar Natto, Spiradoline and dextromoramide, found at 25 ° C A competitive 4-integration test method suitable for all three receptor subtypes for 1 hour. The test method is the final body at 500 μl. 10 rows, using Filtermate 196 (Packard) to quickly pass under reduced pressure

UniFilterTM-96, GF/BTM was filtered, and the reaction was terminated, and the amount of bound radioactivity was measured on a filter paper unit by liquid flash counting after paper drying and addition of scintillator (Microscint-O; Packard). [35s]GTPr s in combination 15 Using the modified Lazareno method S·: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed of agonist-stimulated[35S]GTP ^ S binding to cell membranes. Meth: Moiec. Biol. 106,231- 243, 1999), the determination of [35S]GTPT S binding to G-protein, in the initial [35S] GTP TS binding experiment, the optimization of the test conditions led to the selection of the following buffer 20 liquid: 20 millimolar concentration Hepes and 100 Mille molar concentration of NaCl, containing 3 micromolar GDP and 1 millimolar concentration of MgCl2 for the opioid receptor CHO membrane, containing 10 micromolar GDP and 1 millimolar concentration of MgCl2ffl in the opiate receptor C6 Glia tumor cell membrane, and 10 micromolar GDP and 0.3 millimolar concentration of MgCl2 for Kappa opioid receptor CHO membrane, test mixed -49- This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1334415 A7 B7 V. INSTRUCTION DESCRIPTION (48) The compound contains 10 μg of membrane protein, and 1 μg/ml of soap is added to the diluted membrane as a cleaning agent to maximize the [35S]GTPr s penetrating membrane. For the test activity, 175 microliters of the diluted membrane was incubated with 25 microliters of 25 microliters of hair and 25 microliters of compound 5 at a total volume of 225 microliters in the above buffer for antagonistic activity. 25 μl of buffer was added to the reference agent to stimulate the basal value. For all three cell lines, DPDPE, U69593 and morphine at a concentration of 300 nanomolar were used for their corresponding receptor subtypes, at 37 After incubation at 20 °C for 20 minutes, 25 μl of [35S]GTPt S was added to a final concentration of 0.25 10 nanomolar and the test mixture was incubated for an additional 20 minutes at 37 °C using Filtermate 196 (Packard). Pressing quickly

UniFilterTM-96, GF/BTM transition will be combined with free state [35s] 〇TPr S, and the binding will be determined on a filter paper unit after drying on filter paper by liquid scintillation counting and adding a flashing agent (Microscint-O; Packard). Radiation 15 activity amount. The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed the substrate [35S]GTP γ S binding in the absence of compounds, and the stimulation by the agent was calculated by increasing the percentage above the substrate value, using the GraphPad Prism program via nonlinear regression analysis. The S-shaped agent concentration response curve and the inhibition reference effect of the [35s] GTPr s binding antagonist inhibition curve in the [35s]GTp r S binding. All of the compounds according to the present invention show a transposition value of at least 6 for the opiate receptor and a mouth 1 (:5 () value for the ruthenium or keba receptor 6 or lower. The compounds listed in Table 6 Shows the pICw value between 7 and 8 for the opiate receptor and the plc5 for the 缪 or keba receptor 6 or lower. - 50 - This paper size applies the Chinese National Standard (CNS) A4 specification. (2丨0 X 297 mm) 1334415

A

7 B V. INSTRUCTIONS (51) Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Compound No. Chemical Agent Receptor Binding (pic5〇) Agent Receptor Binding (pIC5〇 Value) De Tuckerbad Acting Agent It is an antagonist 38 0 8.7 6 ndndnd 20 ό 8.6 6 nd 7 5 102 • 8.5 1 6 ndndnd 25 1 0 Everyone C c ) 3⁄4 8.4 6 nd 6.9 5 2 (/c ( )3⁄4 8.3 6 nd 6.8 5 41 o ^cc |A] 8.3 6 ndndnd -53- . 装装, .线 · This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 1334415

AB Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (52) Compound No. Chemical Agent Receptor Binding (pic5〇) Agent Receptor Binding (pIC5〇 Value) De Tuckerbad Acting Agent Its antagonist 98 H k/ ( j^O 8.2 5.6 5.8 6.1 5 19 0 8.2 6 nd 6.5 5 24 • 0 Λ 5 DO 8.2 6 nd 6.9 5 1 0 ^人^ υ C )3⁄4 8.1 5 6.3 nd 5 31 0 Entry A (also) ) 3⁄4 8.1 6 ndndnd 12 0 υ 8.0 6 nd 7 5 -54- This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm)

Claims (1)

1334415 A8 B8 C8 D8 8a 5.21 VI. Patent Application Patent Application No. 1123531 ROC Patent Appln. No. 91123531 Amendment of the scope of the patent application - Annex (II) Amended Claims in Chinese - Encl, (in (Republic of China 99) Submitted on May 21, 2011) (Submitted on May 21, 2010) 1. A compound according to formula (i) 0 10 R1 B II -A Formulate its pharmaceutically acceptable acid or base addition salts and their N-oxide forms, of which: 15 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 20 A = B is selected from the following base: 00, C =N-R6, wherein R6 is hydrogen or cyano, C=S, S02 and C=CR7R8, wherein R7 and R8 are each independently hydrogen or nitro; X is a covalent bond or -CHr·; 〇1.6 炫乳, phenyl-〇1_6 saponin, ^11_6 alkyl, 〇3-7 cycloalkoxy, (: 3_7 cycloalkyl, CF3, Cw alkoxy CN6 alkyl, phenyl- Cu alkyl, optionally substituted by CF3 or substituted C, -6 alkyl, hydroxy, hexahydropyranin substituted by C -6 alkyl, pyrrolidinyl substituted by c3-7 cycloalkyl CN 6 alkyl Pyridyl substituted thiazolyl, Ci-6 alkyl or CF3 substituted pyrrolyl, or NR9R1G, where R9 and -55 are of the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1334415 A8 B8 C8 _____D8____ A. Patent application scope R10 is independently hydrogen, Cu alkyl, Cw alkoxycarbonyl Cw alkyl, C3.7 cycloalkyl, optionally halo, Cl-6 alkoxy, Cw alkyl, ^.6 alkoxycarbonyl, nitro Phenyl, hydroxy Cw alkyl, phenoxy, Cw alkylthio, trifluoromethoxy or carboxy substituted stupyl, 5 naphthyl, phenyl C!-6 alkyl, or n ratio. Alkyl; or A= B and R1—Starting up W Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed benzoxazolyl, thiazolyl, benzothiazolyl, pyrimidinyl or benzopyrazole substituted by CV6 alkyl; R2 is alkoxy Or a halogen group; R3 is a c3_7 cycloalkyl Cw alkyl group; a phenyl cN6 alkyl group, wherein the phenyl moiety 10 is optionally a hydroxyl group, a Cm alkoxy group, a halogen group, a carboxyl group, a CK6 alkoxycarbonyl group, a di-Cw alkane. Amine carbonyl or S02-CH3 substituted, and the alkyl moiety is optionally substituted by oxy, Cai Ci-6, phenyl C2-6, 11 secant, 6 alkyl or CN6 alkyl The carbazolyl Cw alkyl group is substituted; 15 r4, R5 are each independently hydrogen; P is an integer equal to 0 or 1; the dentate group is selected from the group consisting of fluorine, gas and bromine. A compound of the formula characterized in that Ri is selected from the group consisting of CU6 alkoxy, phenyl-Cl-6 alkoxy, Cy alkyl, CF3, 20 Ci-6 alkoxy CV6 alkyl, phenyl-Cw alkyl , phenyl, and NR9Ri〇 Wherein R 9 and R 10 are each independently hydrogen, CN 6 alkyl, stupid, stupid _ Cl 6 or a C 6 alkoxycarbonyl (^-6 alkyl. 3. According to claim 1 or 2 Compound, characterized by X being a covalent bond -56 - This paper scale applies to China National Standard (CNS) A4 娆 (210 X 297 mm) 1334415 Α8 Β8 C8 D8 VI. Patent application scope 4. Patent application The compound of claim 1 or 2, wherein R3 is selected from the group consisting of phenyl Cu alkyl and naphthyl Ci-6 alkyl, each independently selected from at least one selected from the group consisting of a benzyl group, a Cw alkoxycarbonyl group, and a Cw alkoxy group. Substituted with a substituent of a di-Cu alkylaminocarbonyl group. 5. The compound according to claim 1, wherein A = B is C = 0 or S02, R1 is CN6 alkoxy, Cm alkoxy Cw alkyl, phenyl or NR9R1G wherein R9 and R1Q are each independently Is hydrogen, phenyl or naphthyl; or A = B and R1 together form a benzoxazolyl group; p is 0, R3 is a benzyl group optionally substituted by a Cm alkoxycarbonyl group, and R4 and R5 are each hydrogen. 10. A compound according to claim 1 which is selected from the group consisting of 1-ethylsulfonyl-4-phenyl-4-[1-(phenylmethyl)-1H-flavor. Sodium-2-yl]-hexanitrogen π ratio bite; 1 -propane S-yl-4-phenyl-4-[ 1 -(phenylmethyl)-111-°°°-2-yl]-six Nitrogen 0 is determined by the ratio; 15 1-ethyl ester-4-phenyl-4-[1-[(4-hydroxyphenyl)methyl]-1Η-imidazol-2-yl]-hexahydro 11 ratio. 1-ethyl ester-4-phenyl-4-[1-(1-phenylethyl)-1Η-imidazol-2-yl]-hexahydrogen ratio. Printing; 1-isopropyl ester-4-phenyl-4-[1-(phenylindenyl)-1Η-imidazol-2-yl]-hexahydro 20 pyridine; Ethyl 4-phenyl-4-[1-[[4-(carbomethoxy)phenyl]methyl]-1 Η-imidazole-2-yl]-hexanitropurine bite, 1-benzonitrile 4-phenyl-4-[1-(phenylmethyl)-1Η-imidazol-2-yl]-hexahydro-n-specific bite; -57 - This paper scale applies to China National Standard (CNS) A4 specification ( 210x297 mm) 1334415 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A8 B8 C8 D8 VI. Patent Application Scope 1-(Methoxyethyl)-4-phenyl-4-[l-(l-phenyl) Ethyl)-1 Η-imidazol-2-yl]-hexahydron ratio bite; 4-[[2-(1- 曱 基 -4- -4- 4- 4- 4- 4- 4- 4- 4- σ米零坐-1-yl]methyl]-methylbenzoate; 5 4-[[2-[ 1 -(2-benzoxyl)-4-phenyl-4-hexahydropyridyl Tertiary)-1Η-imidazol-1-yl]methyl]-methylbenzoate; 1-benzylidene-4-phenyl-4-[l-(l-phenylethyl)-1Η -imidazol-2-yl]-hexahydropyridine; 1-ethyl ester-4-phenyl-4-[1-[1-[4-(ethyl)phenyl]ethyl]-1]-mi 10 β sit-2-yl]-hexanitrogen 0 ratio And Ν, 4- diphenyl-4- [1- (phenylmethyl) -1Η- imidazol-2-yl] -1-piperidine continued Amides. 7. A compound according to any one of claims 1-6, which is for use as a medicament. 15 8. A pharmaceutical composition for use as a selective non-peptide d-opioid agent, comprising a pharmaceutically acceptable carrier and an effective medical amount as an active ingredient, according to claims 1-7 a compound of one. 9. A compound according to claim 1 of the patent application for the manufacture of a variety of pain conditions, progressive disease related pain, neuropathic pain 20 pain and acute pain and chronic pain, arthritis, psoriasis, asthma, inflammatory Enteric disease, respiratory dysfunction, functional diarrhea, non-ulcerative dyspepsia, incontinence, and agents of the irritable bowel syndrome (IBS). -58 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed 1334415 i〇. A compound according to claim 9 of the scope of the patent application, wherein the pain is selected from the group consisting of central nervous system intervening pain, peripheral nerve intervening pain, structure and soft tissue injury related pain composition Group of. 11. A compound according to claim 9 in which the acute pain is caused by 5 acute scars, (4) or surgery. 12. A compound according to claim 9 wherein the chronic pain is caused by a neuropathy condition, diabetic peripheral neuropathy, post-herpetic neuropathy, trigeminal neuralgia, post-stroke pain syndrome, and cluster headache or migraine. 10 I3. A pharmaceutical composition according to item 8 of the scope of the patent application for the treatment of various pain conditions, progressive disease-related pain, neuropathic pain and acute pain and chronic pain, arthritis, psoriasis, asthma, inflammatory Enteric disease, respiratory dysfunction, functional diarrhea, non-ulcerative dyspepsia, incontinence, and irritable bowel syndrome (IBS). 15. The pharmaceutical composition according to claim 13 wherein the pain condition is selected from the group consisting of pain affected by the central nervous system, pain associated with the peripheral nerve intervening, and pain and tissue associated with soft tissue injury. 15. A pharmaceutical composition according to item n of the scope of the patent application, wherein the acute pain is caused by acute injury, trauma or surgery. 16. The pharmaceutical composition according to claim 13 of the scope of patent application, wherein the chronic pain is caused by a neuropathy condition, a diabetic peripheral neuropathy, a neuralgia after a trace treatment, a tri-neural pain, a post-stroke pain syndrome, and a cluster headache or partial Caused by headache.