Classifications

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  • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to a medicament, particularly a novel benzamide derivative or a salt thereof, which is useful as a capsaicin receptor VR1 (Vanilloid Receptor 1) activation inhibitor, and a medicament thereof.
• a medicament particularly a novel benzamide derivative or a salt thereof, which is useful as a capsaicin receptor VR1 (Vanilloid Receptor 1) activation inhibitor, and a medicament thereof.
• Capsaicin the main component of the chili, is a stimulant, causing pain by activating the capsaicin receptor VR1, which is present on the primary afferent sensory nerves (primarily C fibers).
• VR 1 was clawed [Nature 389: 816-824 (1997)] and revealed to be a non-selective cation channel with high Ca 2+ permeability.
• VR 1 is activated not only by force psycin but also by heat stimulus and acid (proton) stimulus.
• Inflammation-related substances such as ATP and bradykinin act on metabolic receptors to regulate VR1 activity through activation of phospholipase C (PLC) and protein kinase C (PKC) It became clear that they did.
• cabsaicin induces pain by activating VR1, but desensitizes afferent nerves by sustained activation and suppresses subsequent activation, thereby exhibiting an analgesic effect.
• cabsaicin cream is used to treat neuropathic pain, such as postherpetic neuralgia and diabetic neuropathic pain, and inflammatory pain, such as rheumatic joint pain.
• bladder dysfunction which is observed in patients with spinal cord injury, is alleviated by intravesical infusion of capsaicin and an analog, residifuratoxin (RTX), as well as analgesic effects in afferent nerve desensitization. It is believed to be based.
• VR1 antagonists In addition to desensitization by VR1 agonists, VR1 antagonists also exhibit analgesic effects. Psazepine, a long-known VR1 antagonist, has been shown to be effective in neuropathic and inflammatory pain in animal models [J. Pharmacol. EXD. Ther. 304: 56-62 (2003)]. Although the endogenous ligand of VR1 is not clear, several candidate substances have been reported, and antagonists suppress VR1 activation by antagonizing these substances, and are considered to exhibit 'analgesic effects'. Can be Inhibition of VR1 activation in this way is expected to lead not only to analgesia but also to prevention or treatment of symptoms and diseases related to VR1 activation.
• compounds having an inhibitory effect on VR1 activation include various types of pain including neuropathic pain and inflammatory pain, headaches such as migraine and cluster headache, pruritus, overactive bladder and interstitial cystitis, etc. It is considered useful for bladder disease.
• Patent Document 1 discloses that a piperazine derivative represented by the following general formula is used as a ligand of a capsaicin receptor receptor for chronic and acute pain, psoriasis, urinary incontinence. And the like can be used for such treatments.
• R 3 and R 4 are independently hydrogen Atom, halogen atom, hydroxy, amino, cyano, etc.
• R 5 represents cyano, hydroxy, amino, etc.
• R 9 represents halogen atom, cyano, nitro, etc.
• Patent Document 2 discloses that an amamine derivative represented by the following general formula is used as an antagonist of VR1 for urinary incontinence, overactive kinetic bladder, chronic pain, neuropathic pain, and surgery. It is described that it can be used for treatment of post-pain and the like.
• Q represents ⁇ or N
• ⁇ represents substituted naphthalene
• R 6 represents a hydrogen atom or methyl
• R 7 represents a hydrogen atom or methyl
• X represents substituted benzene, substituted naphthalene, or the like.
• Patent Document 3 describes that an amide derivative represented by the following general formula can be used as a VR1 antagonist for the treatment and prevention of various pains and the like. Have been.
• ⁇ is phenyl or heteroaryl, etc.
• R 1 and R 2 are halogen, alkyl, alkoxy or NR 4 R 5 etc.
• R 3 is substituted with R 2 is optionally alkyl, alkoxy or Fuweniru etc.
• q, r and ⁇ Pi s are each 0 to 3
• R 4 ⁇ Pi R 5 is a hydrogen atom, an alkyl or R 4 and R 5 together such connexion nitrogen source
• a heterocyclic ring is formed by including a child.
• the application discloses a compound in which the combination of P and R 3 is biphenyl.
• each of those substituents is a low molecular weight compound such as a lower alkyl group, a halogen, or a substituted alkoxy group.
• WO 98/41508 pamphlet (Patent Document 6) and International Patent Publication WO 97 48683 pamphlet (Patent Document 7) describe tetrahydroisoquinoline derivatives each having an anticonvulsant effect. I have. However, all compounds are limited to those having no or low-molecular-weight substituents on the bi-ale ring, and furthermore, inhibiting the activation of the VR1 receptor. No effect is disclosed or suggested.
• inhibitors of capsaicin receptor VR1 activation are used for various types of pain including inflammatory pain, neuropathic pain, migraine, cluster headache, and bladder diseases including overactive bladder Can be expected as a therapeutic agent.
• a capsaicin receptor VR1 activation inhibitor that has a different chemical structure from the above-mentioned known compounds and has a better effect. Disclosure of the invention
• the present inventors have conducted intensive studies on compounds having an inhibitory effect on activation of the capsaicin receptor VR1 receptor.
• the benzene ring is linked to the D ring (monocyclic or bicyclic hydrocarbon ring) via an amide bond. Or a monocyclic or bicyclic heteroaromatic ring), and the benzene ring is directly bonded to the E ring (monocyclic or bicyclic hydrocarbon ring, or monocyclic or bicyclic heteroaromatic ring).
• the benzene ring is further bonded to A (an amino moiety, a monocyclic or bicyclic heterocyclic ring) via L (lower alkylene), and is represented by the following general formula (I).
• the present invention relates to a compound represented by the following general formula (I) and a salt thereof, and a medicament containing these as an active ingredient.
• the present invention includes nitrogen-containing bicyclic heterocycles such as quinoline and tetrahydroisoquinoline as the ring group represented by D.
• a benzamide derivative represented by the following general formula (I) or a salt thereof [1] A benzamide derivative represented by the following general formula (I) or a salt thereof.
• Ring D and ring E the same or different, a monocyclic or bicyclic hydrocarbon ring, or one or more heteroatoms selected from the group consisting of N, S and O having 1 to 4
• G ring one or two or more hetero atoms selected from the group consisting of N, S and O ⁇ 1 to 4 monocyclic or bicyclic heterocyclic rings having 4 to 12 ring members,
• R 10 hydrogen atom or lower alkyl
• the monocyclic or bicyclic hetero ring may be substituted with a halogen atom, lower alkyl, -O-lower alkyl or -OH, respectively.
• a halogen atom lower alkyl, -O-lower alkyl or -OH, respectively.
• D in the formula (I) E, compounds according to the the symbols have the following meanings represented by scale 1 to 1 9 and 1 11 ⁇ 13 ⁇ 4 15 [1].
• D-ring and E-ring same or different, containing 1 to 4 heteroatoms selected from the group consisting of benzene ring, naphthalene ring, or N, S, and O
• a preferred embodiment of the present invention is a compound described in the following [3], a more preferred embodiment is a compound described in the following [4] to [9], and a particularly preferred embodiment is a compound described in the following [10].
• the ring represented by G in the formula (I) is a nitrogen-containing saturated hetero ring, more preferably tetrahydropyridine, tetrahydroquinoline, tetrahydroisoquinoline, piperidine, pyrrolidine, morpholine, Hazepan and The compound according to [4], which is a ring selected from 1,4-oxazepane, wherein a ring nitrogen atom is bonded to L.
• the ring represented by G in the formula (I) is a ring selected from morpholine, piperidine and pyrrolidine, wherein a ring nitrogen atom is bonded to L.
• the ring represented by D in the above formula (I) is benzothiazole, quinoline, isoquinoline, indoline, tetrahydroquinoline, tetrahydridoisoquinoline, 3,4-dihydro-2J-1,4 -The compound according to the above [4], which is a ring selected from benzoxazine, dihydroquinoline and dihydroisoquinoline.
• R 6a and R 6b same or different, hydrogen atom, lower alkyl or halogen-substituted lower alkyl,
• R 7a , R 8a , R 7b and R 8b are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl or a halogen-substituted lower alkyl.
• R 7 R 8 R 7d and R 8d identical or different, a hydrogen atom, a halogen atom, a lower alkyl or a halogen-substituted lower alkyl.
• the compound according to the above [4] which is a group selected from the group consisting of: the compound according to the above [4a], more preferably the compound according to the above [4b].
• the monocyclic or bicyclic heterocyclic ring may be substituted with a halogen atom, lower alkyl, -O-lower alkyl or -OH, respectively.
• a R 11 a is lower alkyl
• the ring represented by D in the formula (I) is benzothiazole, quinoline, isoquinoline, indoline, tetrahydroquinoline, tetrahydridoisoquinoline, 3,4-dihydro-2iJ-l, 4-benzoxazine
• the compound according to [5] which is a ring selected from dihydroquinoline and dihydroisoquinoline.
• R 7a , R 8a , R 7b and R 8b are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl or a halogen-substituted lower alkyl.
• the lengths 1 to! ⁇ are the same or different and each represents a hydrogen atom, halogen, halogen-substituted lower alkyl, lower alkyl, -N (lower alkyl) 2 or -0-lower alkyl.
• R 6 to R 8 are the same or different and each are a hydrogen atom, a halogen atom, a lower alkyl or a halogen-substituted lower alkyl, and 19 is 0.
• the benzamide derivative represented by the above formula (I) is a compound of the formula: N-1,3-benzothiazomono-5-inole_2-2- ⁇ [[cyclohexyl (isopropyl) amino] methyl ⁇ biphenyl-4 -Carboxamide, V- (1-Methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl) -2- (piperidine-1-ylmethyl) biphenyl-4-carboxamide , V— (3,3-dimethinole-2-oxo-1,2,3-dihydro-1 ⁇ -indole / le 6-inole) -12- (piperidine-1-ylmethyl) biphenyl-4-carboxamide, 2- ⁇ [Ethyl (2-hydroxy-2-methylpropyl) amino] methyl ⁇ -V- (2-methyl-3-oxo-3,4-dihydro-2 // _ 1,4-benzoxazine-6-yl
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a benzamide derivative represented by the above formula (I) or a salt thereof, and a pharmaceutically acceptable carrier.
• the pharmaceutical composition is a VR1 activation inhibitor, and more preferably, the pharmaceutical composition is a prophylactic or therapeutic agent for pain.
• Another embodiment is the use of a benzamide derivative represented by the general formula (I) or a salt thereof according to any one of (1) to (10) for the manufacture of a prophylactic or therapeutic agent for pain,
• a method for preventing or treating pain which comprises administering to a mammal an effective amount of a benzamide derivative represented by the general formula (I) or a salt thereof according to any one of [1] to [10].
• VR1 activation inhibitor J is a compound that binds to VR1 receptor and suppresses VR1 activation by antagonizing an endogenous ligand (VR1 antagonist) , And a compound (VR1 agonist) that desensitizes the nerve in which the receptor is present by the persistent activation of the receptor and suppresses subsequent activation.
• the "activation inhibitor” is a VR1 antagonist.
• lower means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Therefore, “lower alkyl” Preferably, it is alkyl having 1 to 5 carbon atoms, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl and 1,2-dimethylpropyl are particularly preferred.
• the “lower alkylene” is preferably a straight-chain alkylene such as methylene, ethylene, propylene, butylene and the like, and a branched alkylene such as methylmethylene. Methylene and ethylene are particularly preferred.
• Halogen atom includes fluorine, chlorine, bromine, and iodine atoms. Particularly, a fluorine atom and a chlorine atom are preferable.
• Halogen-substituted lower alkyl means the same as or different from the above-mentioned lower alkyl substituted with 1 to 3 halogen atoms. Trifluoromethyl is particularly preferred.
• Examples of the “monocyclic or bicyclic hydrocarbon ring” include benzene, naphthalene, a cycloalkyl ring having 3 to 8 ring members, a cycloalkyl ring having 4 to 8 ring members, and a cycloalkyl ring or a cycloalkyl ring or a cycloalkyl ring with benzene. And a condensed saturated hydrocarbon ring aryl ring. Preferred are benzene, naphthalene, indane and tetrahydronaphthalene.
• aryl is preferably an aryl having 6 to 14 carbon atoms, more preferably phenyl and naphthyl.
• cycloalkyl is preferably a cycloalkyl group having 3 to 10 carbon atoms, which may have a bridge, and more preferably cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and It is an adamantyl group.
• a "nitrogen-containing saturated heterocycle” is a 5- to 8-membered saturated or partially unsaturated monocyclic ring containing one N atom and may further contain one heteroatom consisting of N, S and 0. It is a hetero ring, and preferably a pyrrolidine, piperidine, piperazine, azepan, azepan, morpholine, thiomorpholine and tetrahydropyridine ring.
• the ring atom contains an N atom or an S atom, an oxide or a dioxide may be formed.
• the 5- to 6-membered monocyclic heteroaromatic ring includes pyridine, pyrimidine, pyrazine, Pyridazine, triazine, pyrrole, furan, thiophene, thiazole, imidazole, oxazole, isothiazole, pyrazole, isoxazole, thiadiazole, triazole and tetrazole rings are preferred, and bicyclic heterocycles are benzothiazonole and benzoiso.
• a monocyclic or bicyclic heterocyclic ring having 4 to 12 ring members containing 1 to 4 heteroatoms selected from the group consisting of N, S and O In addition to the monocyclic or bicyclic aromatic ring described above, a 4- to 8-membered saturated or partially unsaturated monocyclic hetero ring, and a cycloalkyl ring, a cycloalkenyl ring or a saturated or It is a bicyclic heterocycle fused to a partially unsaturated monocyclic heterocycle.
• the substituent indicates that may be attached to a carbon atom of the left or right ring.
• the compound of the present invention may have a geometric isomer, a tautomer, an optical isomer, or the like depending on the type of the substituent, and the present invention relates to a mixture of these isomers or an isolated isomer. Things.
• the compound of the present invention may form an acid addition salt. It may also form a salt with a base.
• Specific examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Acid addition salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric ⁇ , citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc. And inorganic salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, or-tin, and ammonium salts.
• the present invention also includes hydrates of the compound of the present invention, various pharmaceutically acceptable solvates and polymorphic compounds.
• the compounds of the present invention also include so-called prodrugs, which are metabolized in vivo and converted into the compound represented by the above general formula (I) or a salt thereof.
• prodrugs which are metabolized in vivo and converted into the compound represented by the above general formula (I) or a salt thereof.
• Examples of the group that forms a prodrug of the compound of the present invention include those described in Prog. Med. 5: 2157-2161 (1985), and Hirokawa Shoten, 1990, “Development of Drugs”.
• the groups described on page 198 can be mentioned.
• the functional group should be replaced with an appropriate protecting group at the stage of the raw material or intermediate, that is, a group that can be easily converted to the functional group. May be effective in manufacturing technology. Then, if necessary, The protecting group can be removed to give the desired compound.
• a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like.
• protecting group include Protective Groups in Organic Synthesis, 3rd edition (T. Green and PGM Wuts , JOHN WILLY & SONS, IN), and these may be appropriately used depending on the reaction conditions.
• the method described in this reference can be applied as appropriate.
• the first production method is a reaction for synthesizing a compound (I) by a condensation reaction between a carboxyl and an amine using the compound (II) and the compound (III).
• This reaction may be carried out according to a conventional method in the presence of a condensing agent using the compound ( ⁇ ) and the amine derivative (III) in an equal amount or one of them in an excess amount.
• a condensing agent examples include V, N-dicyclohexylcarpoimide (DCC), 1-ethyl-3- [3-N, dimethylamino.
• Athenole dichloroethane, dichloromethane, chlorohonolem, carbon tetrachloride, dimethoxymethane, dimethoxetane, ethyl acetate, benzene, ⁇ Tonitrile, dimethyl sulfoxide—a mixed solvent of these, etc.
• a base such as 4-dimethylaminopyridine, or by reacting these bases as a solvent. May progress smoothly.
• the reaction is carried out under cooling to room temperature, but depending on the kind of acylation reaction, it may be preferable to carry out the reaction under heating.
• Compound (I) can also be produced by a method in which a carboxylic acid is converted to an active derivative and then condensed with an amine.
• the reaction is carried out using the compound (II) and the amine derivative (III) in an equal amount or one of them in an excess amount.
• the active derivative of the carboxylic acid include an active ester obtained by reacting with a phenolic compound such as P-nitrophenol; n-nor, or a ⁇ -hydroxyamine compound such as 1-hydroxysuccinimide or 1-hydroxybenzotriazole.
• Monoalkyl carbonates Monoalkyl carbonates, mixed acid anhydrides obtained by reacting with organic acids, mixed acid anhydrides obtained by reacting difluorophosphoryl chloride and -methylmorpholine, mixed esters of hydrazine and nitrous acid Acid halides such as acid azide, acid chloride or acid promide obtained by successive reaction with alkyl, and symmetric acid anhydrides.
• the activating reagent for synthesizing the carboxylic acid activity derivative is used in an amount equivalent to or an excess of the compound (II).
• the reaction conditions in this case are the same as those when the condensing agent is used.
• any reaction other than the reaction described here can be used as long as it is a reaction that forms an amide bond.
• X represents a leaving group such as -Cl, -Br, -1, methanesulfonyloxy, or toluenesulfo-loxy group. The same applies hereinafter.
• the second production method is a reaction for synthesizing compound (I) by nucleophilic substitution reaction using compound (IV) and amine compound AH.
• compound (IV) and AH are used in an equal amount or one of them in an excess amount, and a base (preferably potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium-erer-butoxide, triethylamine, pyridine, ⁇ ) is used.
• a base preferably potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium-erer-butoxide, triethylamine, pyridine, ⁇
• -Methylmorpholine, sodium hydride and using the solvent described in the first process as a solvent, under ice-cooling to heating. Will be implemented. 1 '
• the compound (I) of the present invention has various side chains and functional groups
• these compounds may be obtained by using a reaction which is obvious to those skilled in the art, using the compound of the present invention or an intermediate for producing the compound, or a modified method thereof. In this way, it can be easily synthesized.
• Examples of such conversion include conversion of any one of R 1 to R 1 of the compound (I) obtained by the first production method, or conversion of newly introducing R 1 to R 1 , and for example, the following reaction can be applied.
• 1 ⁇ is any substituent of ⁇ - S 0 2 - NH 2, or CO- NH 2 der Ru compound, each corresponding 1 ⁇ ⁇ is -.!
• S_ ⁇ 3 H, or C_ ⁇ may be prepared using a compound that is 2 H. This reaction, under the same conditions as the first production method, 1 ⁇ Bruno - is effected by S0 3 H, or condensed C0 2 H and ammonia!.
• a compound in which the ring D is a saturated ring and any of R 6 to R 9 is —OH is a compound in which the present substituent is a carboxyl group. It can be produced by applying a conventional method of reduction reaction. For example, it can be carried out with reference to the method described in Tetrahedron, 35, 567-607 (1979). '
• the ring D or the ring E when the ring D or the ring E is a hetero ring, and the hetero atom in the ring is oxygenated to an oxide, the ring may be converted to the oxide using a conventional oxidation reaction. It can be synthesized by oxidizing atoms. This reaction is carried out with reference to the method described in J. Hetrocycl. Chem. 19, 237-240, (1982) and J. Chem. Soc. Perkin Trans. 1, 1949-1955, (1984). be able to. '
• the first to eleventh steps show the steps for producing the raw material compound (II) in the first production method.
• V (V) (VII) (Wherein, U and Q are either one - B r, - C l, - I or - CF 3, the other is - - O- S 0 2 B ( OH) 2 or - B (O- Lower alkyl) 2.
• P 1 represents a carboxyl protecting group such as methyl, ethyl, benzyl or tert-butyl, XiCl, -Br or -I. Similarly.)
• the first step is a step of producing compound (VII) by cross-coupling reaction using compound (V) and aldehyde compound (VI). This reaction is described in Synth. Coimun., 11, 513-519 (1981), Synlett 2000, No. 6, 829-831, and 3 ⁇ 4eyz ?.
• the second step is a step of producing (VIII) by treating compound (VII) with a halogenating agent.
• This reaction is carried out in a solvent such as carbon tetrachloride, chloroform, benzene, etc., using ⁇ / "-promosquen imide (NBS), bromine, stuffed sulfuryl or copper bromide as a halogenating agent.
• NBS ⁇ / "-promosquen imide
• bromine bromine
• stuffed sulfuryl or copper bromide as a halogenating agent.
• the third step is to remove the protecting group P 1 of the compound (VIII), by hydrolysis of the group X 1, is a step for preparing a compound (IXa).
• This reaction may be carried out according to a conventional method of basic hydrolysis of a halide, but in the case of a protecting group which is not deprotected by hydrolysis with a base, after hydrolyzing X 1 group of compound (VIII), Depending on the protecting group of the carboxylic acid, the deprotection reaction may be carried out by hydrolysis with an acid such as hydrochloric acid or trifluoroacetic acid, or reduction such as catalytic hydrogenation. Reaction conditions and the like may be used a method described in "Prot eC ti ve Groups in Organic Synthesis, supra.
• the fourth step is a step of subjecting compound (VIII) to an oxidation reaction to produce compound (X).
• This reaction is carried out by the reaction of -methylmorpholine- -oxide, trimethylamine-V-oxide, sodium salt of 2-nitropropane described in J. Am. Chem. Soc., 71, 1767-1769, (1949), or silver nitrate.
• the reaction is carried out in a solvent such as acetonitrile or ethanol under ice-cooling to reflux under heating.
• the fifth step is a step of producing compound (XI) from compound (X).
• This reaction can be carried out using (methoxymethyl) triphenylphosphonium chloride or (Xymethyl) trifluorophosphonium bromide, etc., in the presence of bases such as butyllithium, sec-butyllithium, sodium hydride, potassium er-butoxyside, tetrahydrofuran, getyl ether or cyclopentyl methyl ether, etc.
• bases such as butyllithium, sec-butyllithium, sodium hydride, potassium er-butoxyside, tetrahydrofuran, getyl ether or cyclopentyl methyl ether, etc.
• the reaction is carried out at a temperature of 178 ° C. in a solvent.
• the sixth step is a step of producing a compound (Xlla) by condensing the compound (XI) and A-H by a reductive amination reaction.
• a reaction triacetoxy sodium borohydride or sodium borohydride is used as a reducing agent, and an organic acid is used if necessary.
• acetic acid formic acid or / ⁇ toluenesulfonic acid
• a metal salt preferably tetraisopropoxytitanium
• the reaction is carried out under ice-cooling to warming using dichloromethane, dichloroethane, chloroform, carbon tetrachloride or tetrahydrofuran as a solvent.
• the seventh step and the eighth step are steps for reducing the formyl group of the compounds (X) and (XI) to produce the compounds (Xllla) and (Xlllb), respectively.
• This reaction can be carried out with reference to the method described in Tetrahedron, 35, 567-607 (1979).
• the ninth step is a step of producing a compound (XIVa) by converting a hydroxyl group of the compound (Xlllb) into a halogenated or sulfonic acid ester.
• the halogenation is carried out using an acid halide (preferably thiol chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or phosphorus tribromide), or triphenylphosphine and carbon tetrachloride, or triphenyl.
• Phosphine and carbon tetrabromide can be used.
• the conversion to the sulfonate is carried out by treating with methanesulfonyl chloride or p-toluenesulfuryl chloride in the presence of a base (preferably, triethylamine, pyridine, potassium carbonate).
• a base preferably, triethylamine, pyridine, potassium carbonate.
• the reaction is carried out by using dichloroethane, methylene chloride, chloroform, dioxane or hexane as a solvent, and refluxing by heating from ice-cooling.
• an iodide can also be obtained by allowing sodium iodide, potassium iodide, or the like to act on the obtained chloride, bromide, or sulfonic ester. In this case, acetone, 2.-butanone, ethanol or the like is used as the solvent.
• the ability to convert the hydroxyl group of the compound (Xllla) into a halogenated or sulfonic ester can be obtained.
• the tenth step is a step of reacting compound (XIV) with AH to produce compound (XII). This reaction may be performed under the same conditions as in the second production method.
• the compound (XII) protecting group P 1 is removed in a step of producing the compound (II).
• the deprotection reaction it is preferable to use the method described in the above-mentioned “Protective Groups in Organic Synthesis” depending on the protecting group of the carboxylic acid.
• the twelfth to fifteenth steps show the steps of producing the starting compound (IV) in the second production method.
• compound (IV) can be produced by sequentially performing the twelfth step and the fifteenth step.
• the hydroxyl group of compound (XV) obtained is halogenated or converted to a sulfonic acid ester in the same manner as in the ninth step.
• a compound in which X is limited to X 1 in the formula (IV), that is, the compound (IVa) can also be produced through the thirteenth step and the fourteenth step. That is, the compound By treating (IX) under the conditions for the halogenation reaction described in the ninth step, the halogenation of the hydroxyl group and the conversion of the carboxyl group to the acid halide were simultaneously carried out, and the resulting acid halide (XVI) was obtained.
• An amide bond may be formed by reacting with an amide derivative (III) prepared separately.
• the reaction is carried out from cooling to room temperature in the presence of a base (pyridine, triethylamine, potassium carbonate or sodium hydrogencarbonate, etc.) using dichloroethane, methylene chloride or the like as a solvent, but it is carried out under heating depending on the type of the acylyl reaction. .
• a base pyridine, triethylamine, potassium carbonate or sodium hydrogencarbonate, etc.
• the compound (IV) is allowed also be synthesized by condensing a protecting group P 1-carboxylic acid to be obtained was removed and Ryo amine compound (III) under the same conditions as the first production method of the compound (XIV) Noh.
• the compound of the present invention thus produced can be isolated as free or as a salt thereof by a conventional chemical operation in the art, such as extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization and the like. It can be purified.
• the salt of the compound can be produced by subjecting the free compound of the present invention to a usual salt formation reaction.
• optical isomers exist. These optical isomers can be converted into diastereomeric salts with an optically active acid or base and then separated by ordinary methods such as fractional crystallization, column chromatography, etc., or by using optically active starting compounds. It can be manufactured by a technique of synthesizing.
• Reference Examples 4 to 16 ′ The compounds of Reference Examples 4 to 16 shown in the following Table were obtained in the same manner as in Reference Example 3.
• the reaction solution was distilled off, and ethyl acetate and water were added to the residue, and the organic layer was separated.
• the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel gel column chromatography (hexane: ethyl acetate) to obtain 1.66 g of a colorless oily substance.
• This substance was dissolved in 50 ml of 1,2-dichloroethane, 25 ml of formic acid was added at room temperature, and the mixture was stirred for 51 hours. Water and ethyl acetate were added to the reaction solution, liquid separation was performed, and the obtained organic layer was dried over anhydrous magnesium sulfate.
• reaction solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate) to give yellow foamy V-1,3-benzothiazol-5-yl-2. 11.23 g of-(chloromethyl) biphenyl-4-carboxamide were obtained.
• 2,2,2-Trifluoroacetamide was hydrolyzed with sodium hydroxide to obtain 6_amino-8-chloro-2H-1,4-benzoxazin-3 (4H) -one.
• Reference Example 180 After sealing methyl 2,6-dic-mouth-5-fluoronicotinate and reacting with dimethylamine to obtain methyl 2-chloro-mouth 6- (dimethylamino) -5-fluoronicotinate, hydrogen The reaction was carried out in an atmosphere in the presence of palladium carbon to obtain methyl 6- (dimethylamino) -5-fluoronicotinate.
• Methyl 4-[(1E)-3-ethoxy-2-methyl-3-oxoprono-1-ene-1-yl] -3-nitrobenzoate and palladium carbon are added to ethanol, and the mixture is treated under a hydrogen atmosphere. The mixture was stirred to obtain methyl 3-methynole-2-oxo-1,2,3,4-tetrahydroquinoline-7-potoxyloxylate. .
• Methyl 2-[(2,4-dinitrophenyl). (Hydroxy) methyl] acrylate is reacted in ethanol in the presence of palladium carbon under a hydrogen atmosphere to give 7-amino-3-methylquinoline-2 ( 1H)-got on.
• Reference Example 204 The compounds of Reference Examples 201 to 203 shown below were obtained in the same manner as in Reference Example 201.
• Reference Example 204 The compounds of Reference Examples 201 to 203 shown below were obtained in the same manner as in Reference Example 201.
• Reference Example 204
• Cinnamic acid chloride is allowed to act on ⁇ - (3-aminophenyl) acetamide in the presence of a base, and the resulting ⁇ - [3- (acetylano) phenyl] _3-phenylacrylamide is converted into chloride.
• Treatment with aluminum gave ⁇ (2-oxo-1,2-dihydroquinoline-7-yl) acetamide. .
• ⁇ - (3-Aminophenyl) acetamide is reacted with 2-etrophenylsulfoyl chloride in the presence of triethylamine, and the resulting compound is treated with iodomethane and potassium carbonate, and then thioglycolic acid is removed.
• ⁇ - [3- (methylamino) phenyl] acetamide is reacted with 2-etrophenylsulfoyl chloride in the presence of triethylamine, and the resulting compound is treated with iodomethane and potassium carbonate, and then thioglycolic acid is removed.
• Echinole 5,6-dichloronicotinate, (2,4-dimethoxybenzyl) amine hydrochloride, and triethylamine are added to the clonor honolem, and the mixture is stirred at room temperature and stirred at room temperature for ethyl 5-chloro-6-[(2,4-dimethyl). To-xybenzyl) amino] nicotinate was obtained.
• Trifluoroacetic anhydride is added to a mixed solution of 6-amino-2H-1,4-benzoxazin-3 (4H) -one and clomouth formite tetrahydrofuran, and 2,2,2-trifluoro- (3-oxo-3, 4-Dihydro-2H-1,4-benzoxazine-6-yl) acetamide was obtained.
• Ethylamine was allowed to act on 1-chloro-2-methylpropan-2-ol to obtain 1- (ethylamino) _2-methylprono-2-ol.
• (2R, 6S) -2,6-dimethylbiperazine is reacted with di-t-butylcarbonyl in dioxane to obtain 4-butoxycarbonyl-2,6-dimethylbiperazine.
• acetyl chloride By reacting acetyl chloride with chloroethane in the presence of triethylamine, 1-acetyl-4-butoxycarbol-2,6-dimethylbiperazine was obtained. Then, this compound was treated with hydrochloric acid to obtain (2R, 6S) -1-acetyl-2,6-dimethylbiperazine.
• a suspension of 500 mg of a mixture of 2- (piperidine_1-ylmethyl) biphenyl-4-carboxylic acid and 1.5 equivalents of sodium chloride was suspended in 20 ml of 1,2-dichloroethane, and the suspension was added to 2 ml of 1,2-dichloroethane.
• Example 100 In the same manner as in Example 10, the compounds of Examples 44 to 99 shown in the table below were obtained.
• Example 100 In the same manner as in Example 10, the compounds of Examples 44 to 99 shown in the table below were obtained.
• Example 10 In the same manner as in Example 10, the compound of Example 113 shown in the table below was obtained.
• N- (3-oxo-2,3-dihydro-1-indene-5-yl) -2- (piberidin-1-ylmethyl) biphenyl-4-carboxamide 250 mg is suspended in methanol (15 ml) and hydrogenated at room temperature. 40 mg of sodium borohydride were added. After the reaction solution was stirred at room temperature for 1 hour, 5 ml of water was added. The reaction solution was distilled off under reduced pressure, and the obtained residue was dissolved in a mixed solution of chloroform and water, followed by extraction with chloroform. The organic layer was dried over sodium sulfate, filtered, and the solution was distilled off under reduced pressure.
• Example 1 In the same manner as in Example 1, the compounds of Examples 115 to 121 shown in the table below were obtained. In the same manner as in Example 2, the compounds of Examples 122 and 123 shown in the table below were obtained. In the same manner as in Example 10, the compounds of Examples 124 to 181 shown in the table below were obtained.
• Tables 1 to 38 below show the structural formulas and physicochemical properties of the reference example compounds and the example compounds.
• the compounds described in Tables 39 and 40 described below are substantially the same as the methods described in the above Reference Examples, Examples, and Production Methods, or some modifications thereof obvious to those skilled in the art are applied to those methods. Thereby, it can be easily manufactured.
• the symbols in the table have the following meanings.
• R f Reference example number
• EX Example number, No: Compound number, Structure: Structural formula
• salt Salt (2HC1: Dihydrochloride, those not described indicate a free form)
• Me Methyl group
• E t ethyl group
• Ac acetyl group
• iPr isopropyl group
• nPr normal pill group
• tBu t-butyl group
• Boc t-butoxycarbonyl group
• Ph phenyl group
• T s p-toluenesulfonyl group
• Ms methanesulfonyl group
• DATA physical property data
• NMR nuclear magnetic resonance spectrum (TMS internal standard ': @NMR:
• the compound of the present invention has an excellent inhibitory action on activation of VR1 of capsaicin receptor, it can be used as a medicine, especially for various pains including neuropathic pain and inflammatory pain, headaches such as migraine and cluster headache, It is useful as a treatment for bladder diseases such as pruritus, overactive bladder and interstitial cystitis.
• the full-length cDNA encoding human VR1 was obtained by the following method. First, human brain mRNA was reverse transcribed using reverse transcriptase to synthesize first strand cDNA. Next, this first strand cDNA was made into type II, and hot-started using Taq. DNA polymerase.
• PCR was performed.
• an oligonucleotide oligonucleotide consisting of the nucleotide sequence of nucleotides 424 to 443 of the known human VR1 cDNA sequence (Genbank AJ277028.1) was used as a sense primer, and an oligonucleotide No. 3082 to nucleotide 3100 was used as an antisense primer.
• pcDNA3.1-VR1 was introduced into HEK293 cells or CH0-K1 cells.
• VR1 / HEK293 cells were transformed into 10% VR1 / CH0 cells using DMEM medium (Invitrogen, USA) containing 10% FBS, 100 ⁇ g / ml streptomycin, 100 l / ml penicillin and 400 ⁇ g / ml G418.
• DMEM medium Invitrogen, USA
• FBS 100 ⁇ g / ml streptomycin
• 100 l / ml penicillin 100 ⁇ g / ml G418
• HumF12 medium containing FBS
• 100 ⁇ g / l streptomycin 100 U / ml penicillin and ⁇ 400 / ig / ml G418, respectively
• cell lines expressing stable receptors were prepared. .
• Each of the cells stably expressing the receptor was subcultured in the above medium. '
• the operation of centrifugation was repeated twice.
• the obtained sediment was suspended in 25 mM Tris-HCl, pH 7.4, and the protein concentration was determined using a protein assay stain (Bio'Rad, USA).
• the prepared membrane sample was stored at -80 ° C.
• Atsushi buffer 25 mM Tris-HC1, 0.025% BSA, pH 7.4
• test compound 3 ⁇ l test compound 3 ⁇ l
• RTX 50 ⁇ approximately 50,000 dpm; PerkinElmer Life
• 100 ⁇ l of the above membrane preparation protein amount: about 25 ⁇ g was mixed, incubated at 37 ° C for 60 minutes, and then incubated on ice for 10 minutes. Ice-cooled acid protein. (AGP; Sigma) was added at 200 ⁇ g / 50 ⁇ , and the mixture was further incubated for 5 minutes.
• the compound of 1995 has an IC 5 of 1 ⁇ or less. The value was shown. This test confirmed that the compound of the present invention has VR1 receptor affinity.
• VR1 / CH0 cells were seeded at a density of 30,000 cells per well in a 96-well white plate. After culturing for 24 hours in the above medium, replace the medium with 25 ⁇ of Atsushi's buffer (I-BS, 0.1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 10 raM glucose, 0.025% BSA, pH 7.4) And incubated at 37 ° C for 10 minutes. A mixed solution 251 of cabsaicin (Sigma, USA) and test compound adjusted to about 4 kBq. Of 45 Ca and a final concentration of 300 nM was added to the wells, and the mixture was incubated at 37 ° C. for 10 minutes.
• Atsushi's buffer I-BS, 0.1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 10 raM glucose, 0.025% BSA, pH 7.4
• the mixture is washed three times with a washing buffer (PBS, 0.1 mM CaCl 2 , 1 mM MgCl 2 ), and 0.1 ⁇ N NaOH 17 ⁇ and ⁇ 100 ⁇ liquid scintillator (Micro-Scinti-PS; PerkinElmer-Life) (Science, USA) was added, and the radioactivity was measured with a scintillation counter for microplates (Top Count; Norkin Elmer Life Sciences, USA).
• aicin-induced VR 1 receptor-specific 45 Ca uptake was reduced by the antagonist 10 ⁇ -force psazepine (Sigma, USA) out of the total intracellular 45 Ca uptake upon stimulation with 300 nM capsaicin.
• test compound was calculated as a relative value when the amount of decrease in specific uptake at the time of addition of forcepsazepine was defined as 100%.
• IC 5 Values were calculated by Logistic regression.
• the compounds of the present invention exhibited a strong inhibitory effect on 4 5 C a uptake via VR 1.
• mice (ddY, male, 4-5 weeks old) induces limb licking behavior.
• the pain-suppressing action was evaluated by measuring the onset time of ⁇ -licking action for 5 minutes after administration.
• the test compound was administered intraperitoneally 30 minutes before cabsaicin administration or orally 45 minutes before administration. Evaluation of the test compound was performed by obtaining each inhibition rate of the test compound administration group when the time of onset of licking action in the solvent administration group was defined as 100%.
• the compound of the present invention showed a strong inhibitory action on pain behavior both in intraperitoneal administration and oral administration.
• Table 41 shows the inhibition rates of the representative example compounds in the oral administration group (30 mg / kg). '
• ⁇ Patent Document 3 Compound of examplell5. 2) Values at 100 mg / kg oral administration. ⁇
• compositions containing one or more of the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a commonly used carrier for pharmaceutical preparations. It is prepared into tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches, etc. using excipients and other additives. Administered orally.
• the one or more active substances include at least one inert diluent, such as lactose, mannitol, pudose, hydroxypropylcellulose, microcrystalline cellulose, starch, polybutyl. Pyrrolidone, mixed with magnesium aluminate metasilicate.
• the composition may be formulated in accordance with conventional practice with additives other than inert diluents, for example, lubricating agents such as magnesium stearate, disintegrating agents such as calcium cellulose glycolate, stabilizing agents, solubilizing agents, or It may contain a solubilizer.
• compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents, such as Contains purified water and ethyl alcohol.
• the composition may contain, in addition to the inert diluent, solubilisers, solubilizing agents, wetting agents, auxiliary agents such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. '
• Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• diluents for aqueous solutions and suspensions include distilled water for injections and physiological saline.
• diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 '(trade name).
• Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers or dissolution aids.
• These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.
• the clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which the compound is applied, and is usually 0.1 to 500 mg orally per adult per day, parenteral.
• the dose is 0.01 to 100 mg, which is administered once or in several divided doses. Since the dose varies under various conditions, a dose smaller than the above dose range may be sufficient. (table 1)

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