MX2008007010A - 2-aminobenzamide derivative - Google Patents

Abstract

Disclosed is a novel and excellent therapeutic or prophylactic agent for nociceptive pain, neuropathic pain, cancer pain, headache, bladder dysfunction or the like, which relies on a preventive activity on capsaicin receptor VR1 activation. It is found that a benzamide derivative having a benzene ring fused with a monocyclic ring on a nitrogen atom in the amide group and an amino group substituted by a lower alkylamino or cyclic group at a position adjacent to the amide group has a potent preventive activity on VR1 activation and an excellent pharmacological activity relying on the preventive activity, and therefore the derivative can be used as a good therapeutic or prophylactic agent for a VR1-related disease, such as nociceptive pain, neuropathic pain, cancer pain, headache and bladder dysfunction.

Description

DERIVATIVES OF 2-AM I N O B E NZAM I D A Field of the Invention The present invention relates to a particularly novel 2-aminobenzamide pharmaceutical derivative or salt thereof in the form of an inhibitor of capsaicin receptor activation VR1 (Vanilloid Receptor 1), and a pharmacist thereof. Background of the Invention VR1 is a receptor that exists in the primary afferent sensory nerve (mainly C fiber) and that is involved in pain in various pathological conditions. This receptor is activated by capsaicin, which is the main component of red pepper, and pain is induced in this way. It is well known that pain does not disappear solely by capsaicin in a mouse with VR1 elimination, but hyperalgesia is also attenuated at the time of inflammation [Nature, 405: 183-187 (2000)]. Capsaicin induces pain, activating VR1 as described above, but it is known to show, on the other hand, an analgesic action that desensitizes an afferent nerve through activation and persistent inhibition of subsequent activation [Pharmacol. Rev., 51: 159-211 (1999); Drug Agning, 18: 561-573 (2001)]. In fact, a capsaicin cream is used for the treatment of neuropathic pain, such as post-herpetic neuralgia and diabetic neuropathic pain and nociceptive pain, such as rheumatic pain in joints, which is classified as inflammatory pain. On the other hand, it is known that not only the VR1 agonist, but also the VR1 antagonist, show analgesic action, inhibiting the activation of the VR1 receptor. For example, it has been reported that a conventionally known VR1 antagonist, capsazepin, shows efficacy for neuropathic pain and inflammatory pain in animal models [J. Pharmacol Exp. Ther., 304: 56-62 (2003)]. Since diseases for which an agonist or antagonist of the VR1 receptor can show efficacy, for example, neuropathic pain, such as post-herpetic neuralgia, [Clin. Ter., 15: 510-326 (1993)], diabetic neuropathy, [Arch. Intern. Med., 151: 2225-2229 (1991)] and the like, there may be mentioned pains such as joint pain [Clin. Ther., 13: 383-395 (1991), post-operative pain [J. Pharmacol. Exp. Ther. 314: 410-421 (2005)], back pain [Pain, 106: 59-64 (2003)] and the like, headaches such as migraine [Cephalalgia, 20: 597-602 (2000)], cluster headache [Clin. J. Pain, 5: 49-53 (1989)] and the like, pain from cancer [J. Neurosci., 25: 3126-3131 (2005)] and fibromyalgia [Semin. Arthritis Rheum., 3: 41-47 (1994)]. Inhibitors of the VR1 receptor activation are useful for the treatment of the diseases described above.

Furthermore, it is well known that disorders of bladder function are alleviated by injecting capsaicin or its analogous substance resiniferatoxin (RTX) into the bladder of a patient with spinal cord injury and the like [J. Urol., 162: 3-11 (1999)]. This is considered to be based on afferent nerve sensitization similar to the case of analgesic action. Therefore, in addition to bladder function disorders such as overactive bladder, urinary incontinence, neurogenic bladder, nocturia and the like, an inhibitor for VR1 receptor activation is also useful for a bladder dysfunction that accompanies prostate hypertrophy [Drugs Agnig , 18: 561-573 (2001)]. In addition, a therapeutic effect for painful bladder syndrome [J. Urol., 176: 797-801 (2006)], interstitial cystitis [Can. J. Urol., 6: 737-744 (1999)] and chronic nonbacterial prostatitis [Eur. Urol., 48: 162-167 (2005)] by inhibiting the activation of the VR1 receptor. In recent years, studies have been conducted that have progressed in compounds that have inhibitory action on the activation of VR1. For example, it has been reported that the derivative represented by the following general formula, as a regulating agent of VR1, is useful for the treatment of pain and the like (Reference Patent 1).

(In the formula, Z represents C = O or N, V and U are independently a group selected from the class consisting of O, S, C = O, -CH2- and -NR2- [where R2 is H, C ? -4 alkyl or the like], W is C or N, J is hydrogen or the like, L is -NH-C (O) - (CH2) q-, -C (O) -NH- (CH2) q- or similar [wherein q is 0 to 2], ring A is C3_7 cycloalkyl, phenyl or the like, R is independently d-β alkyl, C 1-6 alkoxy, -halo, -CF 3, -O-CF 3, -NH 2, - NH (C? -4-alkyl) or similar and n is 0 to 5, respectively (For details see official gazette.) It has also been reported that the carboxamide derivative represented by the following general formula (III), in the form of a regulatory agent VR1, is useful for the treatment of pain and the like (Patent Reference 2).

(In the formula, P is aryl, heteroaryl or the like, W, X and Y form an aromatic hetero ring containing 5 membered nitrogen [where W, X and Y are selected from CR1a, NR1b, N; S and O] , CR1a and NR1b are independently -H-alkyl or similar, R2 is independently -H, alkyl or the like, R3 is -H, halo, NR4R5 or the like [R4 and R5 may be the same or different from each other and each represents - H or alkyl, or R4 and R5 can form a hetero ring together with the nitrogen atom to which they are attached], r is 0, 1 or 3, and s is 0, 1, 2, 3, 4, 5, or 6. For details, see the official bulletin. Also, it has been reported that the derivative represented by the following general formula (IV), as a ligand of the VR1 receptor, is useful for the treatment of pain and the like. (Patent References 3 and 4).

(In the formula, J is = O or similar, X's are independently N or C, R1 is C2.6 alkyl, C1-6 alkyl which can be substituted, or the like R2 is a saturated 9 or 10 membered bicyclic ring, partially saturated or unsaturated containing 0, 1, 2, or 3 nitrogen atoms and 0, 1, 2 or 3 atoms selected from O and S [total number of the bicyclic O and S atoms does not exceed 2] and the bicyclic ring contains at least one N, O or S atom (the remainder is omitted) and R3 and R6, C1-4 haloalkyl, halo (that of the medium is omitted), -NRaRa, -NRaC2-6 alkylNRaRa or the like [Ra they are independently H or Rb, and Rb s are independently phenyl, benzyl or similar.] For details see the official bulletin). Although compounds having an arylamide structure are described in all Patent References 1 through 4 described above, there is no illustrative description with respect to a compound having a group. monoalkylamino in the adjustment position of the amido group in the aryl. Furthermore, it has been reported that the quinoline derivative represented by the following general formula (V), as a regulatory agent of the VR1 receptor, is useful for the treatment of pain and the like (Patent Reference 5).

(In the formula, R1 is hydrogen, hydroxy, halogen or the like, m is 0, 1 or 2, R2 is hydrogen or C1-8 alkanyl, L is a direct bond or the like, R3 is pyrrolyl, pyridyl, phenyl or the like, R4 is C1-12 alkanyl, -N (R5) (R6) [R5 is hydrogen or the like and R6 is C4-16 alkyl, alkanylcarbonyl, or C1-3alkyl substituted with a group selected from the class consisting of pyrrolo, pyridyl , furyl, thienyl and phenyl, or arylcarbonyl or similar] or similar, n is 1, 2 or 3 and Z is O or S, respectively For details see the official bulletin). Also, a benzothiazole derivative characterized by having regulatory action of the VR1 receptor and having a hydroxymethyl group in the 2-position, is described in an international publication (Patent Reference 6) which was published after the application according to the bases of the priority of the present application. In addition, a benzamide derivative characterized in that possesses regulatory action of receptor VR1 and by the substitution of a ring structure in position-4, is described in an international publication which was published by the applicant of the present application, etc. (Patent Reference 7). The nociceptin antagonist comprising an amide derivative represented by the following general formula (VI), as the active ingredient, has been reported (Patent Reference 8).

(In the formula, R1 and R2 may be the same or different from each other and each represents a hydrogen atom, (lower alkyl group which may be substituted by a hydroxy group), amino group, lower alkylamino group or di group ( lower alkyl), R3 and R4 may be the same or different from each other and each represents a hydrogen atom, a halogen atom or a lower alkyl group, ring A is an aryl group or a heterocyclic ring group, ring B is a phenyl group or the like, E is a single bond, -NR7- or the like [R7 is a hydrogen atom or the like], the ring G is aryl, a heterocyclic ring group, a cycloalkyl group or the like, R5 is a halogen atom, a hydroxyl group, a di (lower alkyl) amino group or the like, t is 0 or an integer from 1 to 5, m is O or an integer from 1 to 8, and n is 0 or an integer from 1 to 10. For details see the official bulletin). Although the use of the nociceptin antagonist in the official brochure is for pain, there is no description or suggestion in it regarding the VR1 receptor. Although the compounds having an arylamide structure are described in said official gazette, there is no illustrative description, with respect to a compound having a monoalkylamino group in the adjustment position of the amido group in the aryl. It has also been reported, 2-aminobenzamide derivatives having a heterocyclic bicyclic ring on the nitrogen atom of the amide group (Patent References 9 to 12). However, although the inhibitory action of angiogenesis and the like based on the VEGF inhibition is described in all references, there is no description regarding the VR1 receptor or description with respect to the application for pain. In addition, there is no disclosure in any of the official bulletins regarding a compound in which a monocyclic ring is directly linked to the amino group of the 2-position without transmitting an alkylene chain. Patent Reference 1: International Publication No. 2004/108133 Patent Reference 2: International Publication No. 2004/072069 Patent Reference 3: International Publication No. 2005/072681 Patent Reference 4: Publication of US Patent Application No. 2005/0165028 Patent Reference 5: International Publication No. 2004/069792 Patent Reference 6: International Publication No. 2006/038871 Patent Reference 7: International Publication No. 2004/110986 Patent Reference 8: Japanese Patent No. 3013989 Patent Reference 9: International Publication No. 2004/005279 Patent Reference 10: International Publication No. 2004/007457 Patent Reference 11: International Publication No. 2004/007458 Patent Reference 12: International Publication No. 2001/085671. Brief Description of the Invention PROBLEMS TO BE SOLVED THROUGH THE PRESENT INVENTION The problems for the present invention is to provide an excellent and novel agent for treating or preventing nociceptive pain, neuropathic pain, pain from cancer, headache, dysfunction of the bladder and the like, with base in the inhibitory action on the activation of the VR1 receptor of capsaicin. MEANS FOR RESOLVING THE PROBLEMS As a result of the intensive studies regarding the compounds that have the inhibitory action on the activation of VR1, the inventors of the present invention have discovered that a benzamide derivative having a benzene ring in which the The monocyclic ring is condensed on the nitrogen atom of the amido group and has a lower alkylamino or an amino group substituted with a ring group in the surrounding position of the amido group, has a potent inhibitory action on the activation of VR1 and an excellent action pharmacological based on this, and can become an excellent agent to treat or prevent diseases involved with VR1, such as nociceptive pain, neuropathic pain, cancer pain, headache, bladder function disorder and the like, thereby achieving the present invention- The pharmacological action of the compound represented by the general formula (I) in the form of the active ingredient of the present invention, is the analgesic action that regulates the function of the VR1 receptor. Accordingly, its action is different from that of the compound of the aforementioned Patent Reference 8, which is a nociceptive antagonist. Also, the compound in the form of the active ingredient of the present invention is also different from that of the illustrative compounds described in the aforementioned Patent Reference 8, in terms of structural features. That is, there is no illustrative description in the aforementioned Patent Reference 8 regarding a benzamide derivative having a lower alkylamino group or an amino group substituted with a ring group in its surrounding position, and the substituent group characteristic. in ring A is also different. In addition, the pharmacological action of the compound in the form of the active ingredient of the present invention is also different from that of the compounds of the aforementioned Patent References 9 to 12, which have VEGF inhibitory action. That is, the present invention relates to an inhibitor of VR1 activation comprising a 2-aminobenzamide derivative represented by the following general formula (I) or a salt thereof in the form of an active ingredient.

(The symbols in the formula have the following meanings: benzene ring or pyridine ring, R3: the same or different from each other and represents each H; halogen, halogen-lower alkyl, cyano, nitro, lower alkyl. -NR4R5, -lower-alkylene-NR4R5, -lower-alkylene-NR6-CO2-lower alkyl, -O-lower alkyl, -O-halogeno-lower alkyl, phenyl or thienyl, m: 1, 2 or 3, R4 and R5: equal or different from each other and each represents H or lower alkyl, wherein R4 and R5 can be combined with the adjacent nitrogen atom to form a saturated monocyclic nitrogen-containing hetero ring, which can be substituted with a lower alkyl or an alkylene lower-OH, R6: H or lower alkyl, : monocyclic ring, cycloalkene or benzene ring, wherein the ring represented by A can be substituted with 1 to 4 groups selected from -OH, -lower-alkylene-NR4R5, -lower-alkylene-CO-N R4R5, halogen, halogen-lower alkyl , lower alkyl and oxy, R1: lower alkyl, -L-cycloalkyl, -L-cycloalkenyl, saturated hetero ring-L-monocyclic containing oxygen, saturated hetero ring-L-monocyclic containing nitrogen, saturated hetero ring containing nitrogen type L-bridged, -L-phenyl or -L-pyridyl, with the proviso that since the type of ring A when R1 is lower alkyl, it means a ring that form indoline, tetrahydroquinoline or 3,4-dihydro-2H-1,4-benzoxazine together with the benzene ring for which it is condensed, wherein the lower alkyl of R 1 can be substituted with 1 to 3 groups selected from the groups shown in the following group G, and cycloalkyl, cycloalkenyl, saturated monocyclic ring containing oxygen, monocyclic saturated ring heterocyclic nitrogen, phenyl and pyridyl of R 1 can be substituted with from 1 to 5 groups selected from groups shown in the following group G, and lower alkyl which may be substituted by a group shown in group G, group G: -O-lower alkyl, -OH, oxo, -S (O) p-lower alkyl, -NR4R5, -NR6-CO2 -lower alkyl, -NR6-SO2-lower alkyl, -N + (lower alkyl) 3, -CO2-lower alkyl, -CO-NR4R5, halogen, phenyl, cycloalkyl, -O-lower alkylene-phenyl, -NR6-cycloalkyl and heterocyclic saturated monocyclic ring containing oxygen, p: 0, 1 or 2, L: bond or alkylene inf erior, R2: same or different from each other and each represents H, lower alkyl, halogen, halogen-lower alkyl or -OH, and n: 1 or 2. The symbols that will be used in the description of the Production Examples described later, they represent the same meanings). In addition, the present invention also relates to a A novel 2-aminobenzamide derivative represented by the following general formula (I ') or a salt thereof, which has inhibitory action on the activation of VR1 and is useful as an agent for treating or preventing diseases in which the VR1 receptor is involved. such as nociceptive pain, neuropathic pain, pain from cancer, headache, bladder function disorder and the like. Although some of the compounds are generally included in the present invention or in the aforementioned Patent References 1 to 4, there is no illustrative description in such patent references with respect to a benzamide derivative having an alkylamino or a lower amino group substituted with a ring group in the surrounding position of the amido group, which is a characteristic of the compound of the present invention, and there is also no description showing that the substituent group in the surrounding position of the amido group is important. In addition, the structure of the compound of the present invention is different from that of the compound of the aforementioned Patent Reference 5, wherein a hetero ring is directly linked at the nitrogen atom, in terms of a benzene ring condensed by a The monocyclic ring is substituted on said amido nitrogen atom. A compound having a lower alkylamino group at the 2-position of the benzamide is described in the Reference of Patent 6 mentioned above, which was opened to public inspection after an application as the basis of the priority of the present application, although said compound is different from the compound of the present invention in terms of the ring structure condensed in the atom of amido nitrogen. Further, the structure of the compound of the aforementioned Patent Reference 7 differs from the compound of the present invention in terms of the essential groups: a ring structure at the 4-position of the benzamide for Patent Reference 7, while the 2-amino group for the present invention. That is, the present invention relates to a novel 2-aminobenzamide derivative represented by the following general formula (I ') (The symbols in the formula have the following meanings: X and W: one is N and the other is CH, or both are CH, R3a and R3b: equal or different from each other and each represents H, halogen, halogen-alkyl lower, cyano, nitro, lower alkyl -NR4R5, -lower-alkylene-NR4R5, -lower-alkylene-NR6-CO2-lower alkyl, -O-lower alkyl, -O- halogen-lower alkyl, phenyl or thienyl, R4 and R5: same or different from each other and each represents H or lower alkyl, wherein R4 and R5 can be combined with the adjacent nitrogen atom to form a saturated monocyclic hetero ring containing nitrogen, which can be substituted with lower alkyl or lower alkylene-OH, R6: H or lower alkyl, : hetero ring monocyclic, cycloalkene or benzene ring, wherein the ring represented by A can be substituted with 1 to 4 groups selected from -OH, -lower-alkylene-NR4R5, -lower-alkylene-CO-NR4R5, halogen, halogen-alkyl lower, lower alkyl and oxo, R1: lower alkyl, cycloalkyl, cycloalkenyl, monocyclic saturated ring heterocyclic oxygen, monocyclic saturated ring heterocyclic nitrogen, phenyl or pyridyl, with the pro that, in the ring type A when R1 is lower alkyl, it means a ring forming indoline, tetrahydroquinoline or 3,4-dihydro-2H-1,4-benzoxazine together with the benzene ring for which it is condensed, wherein the lower alkyl of R1 can be substituted with 1 to 3 groups selected from the groups shown in the following group G, and cycloalkyl, cycloalkenyl, hetero ring saturated monocyclic oxygen-containing, monocyclic saturated ring containing nitrogen, phenyl and pyridyl of R1 may be substituted with from 1 to 5 groups selected from groups shown in the following group G, and lower alkyl which may be substituted by a group shown in group G, group G: -O-lower alkyl, -OH, oxo, -S (O) p-lower alkyl, -NR4R5, -NR6-CO2-lower alkyl, -NR6-SO2-lower alkyl, -N + (lower alkyl) 3, -CO 2 -lower alkyl, -CO-NR 4 R 5, halogen, phenyl, cycloalkyl, -O-lower alkylene-phenyl, -NR 6 -cycloalkyl and monocyclic saturated ring heterocyclic oxygen, p: 0, 1 or 2, R2: equal or different from each other and each represents H, lower alkyl, halogen, halogen-lower alkyl or -OH, and n: 1 or 2. Also, the present invention relates to a pharmaceutical composition, which comprises a 2-aminobenzamide derivative represented by the above-mentioned general formula (I ') or a salt of the same, and a pharmaceutically acceptable carrier. Preferably, the aforementioned pharmaceutical composition, which is an inhibitor of VR1 activation, more preferably the aforementioned pharmaceutical composition which is an agent for treating or preventing nociceptive pain, neuropathic pain, pain from cancer, headache and bone marrow disorder. bladder function.

In addition, other embodiments of the present invention are the use of a 2-aminobenzamide derivative represented by the above-mentioned general formula (I ') or a salt thereof, and a method for preventing or treating nociceptive pain., neuropathic pain, pain from cancer, headache, and bladder function disorders, which comprises administering an effective amount of 2-aminobenzamide derivative or a salt thereof, to a mammal. EFFECT OF THE PRESENT INVENTION The compound in the form of the active ingredient of the pharmaceutical preparations of the present invention, has the advantage of having a gate of inhibitory action in the activation of the VR1 receptor of capsaicin and a good pharmacological action based on it. . The pharmaceutical composition of the present invention is useful for the treatment or prevention of diseases in which VR1 is involved, particularly for the treatment or prevention of nociceptive pain, neuropathic pain, cancer pain, headache, and functional dysfunction. the bladder. BEST MODE FOR CARRYING OUT THE PRESENT INVENTION. The present invention is described in detail below. In this description, the term "inhibitor of VR1 activation" is a compound that binds to the VR1 receptor, and is in general term for a compound that inhibits VR1 activation, competing with an intrinsic ligand (VR1 antagonist) and a nerve-desensitizing compound, wherein the receptor is present through persistent activation of the VR1 receptor and subsequently inhibits activation ( agonist VR1). Preferred as the "VR1 activation inhibitor" is a VR1 antagonist. With respect to the definition of the formulas in the present description, the term "lower" means a straight or branched carbon chain having from 1 to 6 carbon atoms (which will be referred to as d-6 hereinafter) unless otherwise indicated. Thus, the term "lower alkyl" is a C 1-6 alkyl, preferably straight chain alkyl such as a methyl, ethyl, n-propyl, n-butyl, or the like group or a branched chain alkyl such as a group isopropyl, isobutyl, re-butyl, neopentyl, or the like. A C? -alkyl is more preferred, and a methyl, ethyl, n-propyl, isopropyl and re-butyl group are particularly preferred. The term "lower alkylene" is a C 1-6 lower alkylene, preferably straight chain alkylene, such as a methylene, ethylene, trimethylene, tetramethylene or the like group or branched chain alkylene such as a propylene, ethylethylene, 1, 2- group dimethylethylene, 1, 1, 2,2-tetramethylethylethyl or the like. A C1-4 alkylene is more preferable. A "halogen" means F, Cl, Br and I. In particular, F and Cl are preferable. The "lower alkyl-halogen" means a d. 6 alkyl substituted with 1 or more halogens, which is preferably a d-6 alkyl substituted with one or more F, more preferably a trifluoromethyl group. The term "cycloalkyl" is a saturated hydrocarbon ring group C3_? 0 which may have a bridge. A C3.8 cycloalkyl is preferred, more preferred are the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl groups, particularly preferred are cyclopentyl, cyclohexyl and cyclopentyl. The term "cycloalkenyl" is a ring group having a double bond in a part of the ring of the aforementioned "cycloalkyl", preferably a C3.8 cycloalkenyl, more preferably cyclopentenyl and cyclohexenyl. The "nitrogen-containing monocyclic saturated ring hetero" means a saturated or partially unsaturated 5 to 8 membered monocyclic hetero ring group containing an N atom and may further contain one of the heteroatoms consisting of N, S and O. Preferred pyrrolidinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, azocanyl, morpholinyl, thiomorpholinyl and tetrahydropyridinyl groups. Particularly preferred are the pyrrolidinyl, piperidyl, and morpholinyl groups. The "hetero ring containing bridged type nitrogen" is a group of bridged ring in which two are linked optional carbon atoms in non-adjacent positions in the "nitrogen-containing monocyclic saturated ring heterocycle" through an alkylene chain, which may contain a double bond in the ring. Preferred are quinuclidinyl, 8-azabicyclo [3.2.1] octenyl and 7-azabicyclo [2.2.1] heptanil. In the phrase "nitrogen-containing monocyclic saturated ring hetero", mentioned above, the ring atom S can be oxidized to form an oxide or dioxide or N can be oxidized to form an oxide. The "oxygen-containing monocyclic saturated ring" is a saturated 5- to 7-membered monocyclic hetero ring group containing 1 or 2 O atoms, preferably tetrahydrofuranyl, tetrahydropyranyl, and 1,4-dioxanyl. The "monocyclic hetero ring" of A is a 5 or 6 membered unsaturated monocyclic or unsaturated monocyclic ring group containing 1 to 2 heteroatoms consisting of N, S and O, which is a ring having a double bond in a position where the ring is condensed with a benzene ring. Preferred are rings of 2,3-dihydro-1 H -pyrrole, 2,5-dihydro-1 H -pyrrole, 1, 2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, 2,3- dihydro-1,4-dioxin, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro-2H-1,4-thiazine, 1,2-dihydropyridine, pyrrole, pyran, pyrazole, thiophene, oxazole, thiazole, pyridine, 1,3-dioxazole and 6,7-dihydro-5H-1,4-dioxepine, and are groups of rings wherein the ring groups are fused with the ring of benzene to form rings of indoline, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, 2,3-dihydro-1,4-benzodioxin, 3,4-dihydro-2H-1,4-benzoxazine, 3,4-dihydro-2H-1,4 -benzothiazine, 1,2-dihydroquinoline, 2,3-dihydroisoquinoline, nature, benzopyran, indazole, benzothiophene, benzoxazole, benzothiazole, quinoline, isoquinoline, 1,3-benzodioxole, and 3,4-dihydro-2H-1,5- benzodioxepin. The phrase "hetero ring nitrogen monocyclic ring" of ring A, is a group of rings containing at least one nitrogen atom as the ring atom between "hetero ring monocyclic" mentioned above and those preferred are the rings of 2, 3 -dihydro-1H-pyrrole, 1, 2,3,4-tetrahydropyridine, 3,4-dihydro-2H-1,4-oxazine and 1,2-dihydropyridine, and particularly preferred are rings of 2, 3-dih id ro- 1 H-pyrrole, 1,2,3,4-tetrahydropyridine and 3,4-dihydro-2H-1,4-oxazine. The "cycloalkene" of ring A is a C5-8 hydrocarbon ring, which is a ring having a double bond at a position where the ring is fused with a benzene ring. There may be another double link in the other ring. Preferred are the rings of cyclopentene, cyclopentadiene, cyclohexene, and cycloheptene, and the most preferred is the cyclohexene ring. Preferred as the group represented by R3 are H, halogen, halogen-lower alkyl and nitro, and most preferred are halogen and halogen-lower alkyl. The The substitution position is preferably the 4-position or 5-position, or more preferably the 4-position. When a compound has two or more groups in addition to H as the group represented by R3, the substituent groups may be the same or different from each other. Preferred as the group represented by R1 is the saturated heterocyclic ring L-monocyclic, L-cycloalkyl containing oxygen and the nitrogen-containing L-monocyclic saturated ring heterocycle and the most preferred are the saturated hetero ring L-cycloalkyl and L-monocyclic that contain oxygen. A bond in the L-form is preferred. Said ring group can be substituted with from 1 to 5 groups selected from lower alkyl, the groups shown by the group G and the lower alkyl substituted with the groups shown through group G. Preferred as substituent groups shown by the group G is -NR4R5 or cycloalkyl, more preferred is -NR4R5 and further preferred is a group which is a nitrogen-containing monocyclic saturated ring wherein R4 and R5 combine together with the adjacent nitrogen. The R4, R5 and R6 contained in the groups shown in the group G and the R4, R5 and R6 contained in the group represented by R3 are each independent and may be different from each other. When the group represented by R is -L-cycloalkyl, in where the ring group is substituted with lower alkyl and NR4R5 at the same carbon atom, said lower alkyl and R4 can be linked to form a ring. A preferred embodiment of the 2-aminobenzamide derivative represented by the general formula (1) as the active ingredient of the present invention are the derivatives of the following (A1) to (A3) and the derivatives represented by the general formula (I ') ) mentioned above. (A1) A derivative of A is a monocyclic ring containing nitrogen, wherein the ring group has an oxo group or a hydroxyl group as the substituent group and can be further substituted with 1 or 2 groups selected from -lower alkyl- OH, -lower-lower-NR4R5, lower-alkylene-CO-NR4R5, halogen, halogen-lower alkyl and lower alkyl. (A2) More preferred is a derivative described in paragraph (A1) mentioned above, wherein the type of ring A is one that forms indoline, tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine or 1,2-dihydroquinoline together with the benzene ring for which it is condensed . (A3) More preferred is a derivative described in paragraph (A1) above, wherein the type of ring A is one which forms indoline, tetrahydroquinoline or 3,4-dihydro-2H-1,4-benzoxazine together with the benzene ring for which it is condensed. A preferred embodiment of the 2-aminobenzamide derivative as the compound of the present invention represented by the general formula (I '), are the following derivatives. (B1) A derivative wherein X is N or CH, W is CH and A is a monocyclic hetero ring containing nitrogen, wherein the ring group has an oxo group or a hydroxyl group as the substituent group and can be further substituted with 1 or 2 groups selected from -low alkyl-OH, -lower-alkylene-NR4R5, -lower-alkylene-CO-NR4R5, halogen, halogen-lower alkyl, and lower alkyl. (B2) More preferred is a derivative described in the aforementioned (B1), wherein the type of ring A is one which forms indoline, tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine or 1, 2- dihydroquinoline together with the benzene ring for which it is condensed. (B3) More preferred is a derivative described in the aforementioned (B2), wherein the type of ring A is one which forms indoline, tetrahydroquinoline or 3,4-dihydro-2H-1,4-benzoxazine together with the ring of benzene for which it is condensed. (B4) More preferred is a derivative described in (B3) above, which is a ring group in which R1 is selected from cycloalkyl, cycloalkenyl, a saturated monocyclic oxygen-containing hetero ring, and a saturated monocyclic hetero ring containing nitrogen, which can be substituted with 1 to 5 groups selected from the groups shown through the group G, and lower alkyl which can be substituted with the groups shown in group G. (B5) More preferred is a derivative described in the aforementioned (B4), which is a ring group wherein R1 is selected from cycloalkyl, dioxolanyl and piperidyl, which may be substituted with lower alkyl, -NR4R5 or cycloalkyl. Another preferred embodiment of the 2-aminobenzamide derivative represented by the compound of the present invention (I ') are the following derivatives. (C1) More preferred is a derivative described in the aforementioned (B1), which is a ring group wherein R1 is selected from cycloalkyl, cycloalkenyl, a monocyclic saturated ring heterocyclic containing oxygen, monocyclic saturated ring heterocyclic nitrogen , phenyl and pyridyl, which may be substituted with from 1 to 5 groups selected from groups shown by G, and lower alkyl which may be substituted with the groups shown by group G. (C2) More preferred is a derivative described in ( C1) mentioned above, which is a ring group in which R is selected from cycloalkyl and piperidyl, which can be substituted with lower alkyl, -NR R5 or cycloalkyl. Particularly preferred among the 2-aminobenzamide derivatives represented by the compound of the present invention (T) are derivatives selected from the group consisting of 4-chloro-N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) -2-. { [(1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} benzamide, 2- (cyclohexylamino) -N- (2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -4- (trifluoromethyl) benzamide, 4-chloro-N - [(2R) -2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl] -2-. { [1R, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} benzamide, N- [2-oxo-4- (trifluoromethyl) 2,3-d i hydro-1 H-indol-6-yl] -2-. { [1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} -4- (Trifluoromethyl) benzamide, N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -2- (pyridin-4-ylammon) -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-. { [1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} -4- (trifluoromethyl) benzamide, N - (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-. { [1R, 2R) -2-pyrrolidin-1-ylcyclohexyl] amino} -4- (trifluoromethyl) benzamide, 2-. { [1R, 2R) -2- (dimethylamino) cyclohexyl] amino} -N - [(2R) -2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl] -4- (trifluoromethyl) benzamide, 2-. { [1S, 2S) -2- (dimethylamino) cyclohexyl] amino} -N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -4- (trifluoromethyl) benzamide; N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2 - [(1-isobutylpiperidin-4-yl) amino] -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-. { [(3S) -1-pentylpyrrolidin-3-yl] amino} -4- (trifluoromethyl) benzamide, N- (2-oxo-1,2-dihydroquinolin-7-yl) -2-. { [(1R, 2R) -2-pyrrolidin-1-ylcichlohexyl] amino} -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-. { [3S) -1-pentylpyrrolidin-3-yl] amine} -4- (trifluoromethyl) benzamide, 2 - [(1-butylpiperidin-4-yl) amino] -N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-. { [1S, 2R) -2-pyrrolidin-1-ylcyclohexyl] amino} -4- (trifluoromethyl) benzamide, 2-. { [1 S, 2 S) -2-pyrrolidin-1-ylcyclohexyl] amino} -N-quinolin-7-yl-4- (trifluoromethyl) benzamide, 2-. { [1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} -N-quinolin-7-l-4- (trifluoromethyl) benzamide and N- [2-oxo-4- (trifluoromethyl) -2,3-dihydro-1H-indol-6-yl] -2-. { [1S, 2R) -pyrrolidin-1-ylcyclohexyl] amino} -6- (trifluoromethyl) nicotinamide. Also, depending on the type of the substituent groups, stereoisomers, tautomers, optical isomers and the like are sometimes found in the compound represented by the formula (I) which is the active ingredient of the present invention (it will be referred to as the compound (I), hereinafter), and the mixtures and isolated forms of these isomers, are included in the present invention. In addition, "pharmaceutically acceptable prodrugs" with respect to compound (I) are also included in the present invention. The "pharmaceutically acceptable prodrug" is a compound that can produce the compound (I) by being converted to the group such as CO2H, NH2OH or the like, by solvolysis or under a physiological condition. As the groups that form prodrugs, we can mention the groups described in the Publications Prog. Med., 5, 2157- 2161 (1985) and "lyakuhin no Kaihatsu (Development of Medicines)" (Hirokawa Shoten, 1990) Vol. 7 Bunshi Shekel (Molecular Design) 163-198. As the salts of the compound (I), pharmaceutically acceptable salts exist, and illustratively acid addition salts with inorganic acids (for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) ) with organic acids (for example, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid; or aspartic acid, glutamic acid and the like), and the like can be exemplified. In addition, there are cases of formation of salts with bases depending on the type of substituent groups, and for example salts with inorganic bases including metals (for example sodium, potassium, magnesium, calcium, aluminum, lithium and the like), with organic bases ( example, methylamine, ethylamine, ethanolamine, lysine, ornithine and the like), ammonium salts and the like which may be mentioned. In addition, various hydrates and solvates and polymorphic crystals are included in the compound (I) and salts thereof. (Production Methods) The compound (I) as the active ingredient of the present invention, can be produced by applying various methods synthetics conventionally known, having use of their basal structure or characteristics based on the type of substituent groups. In this case, depending on the type of functional group, there is a case in which the protection of the functional group through a group of adequate protection or replacement of a group that can be easily converted into the functional group, in a material stage for intermediaries, it is effective by virtue of production techniques. Therefore a functional group, includes an amino group, a hydroxyl group, a carboxyl group and the like, as their protecting groups, the protection groups described, for example in the Publication of Protective Groups in Organic Synthesis ", and dictated by TW Green and PGM, Wuts, 3rd edition 1999, can be mentioned and these can be optionally selected and used in response to the reaction conditions.Through said method, a desired compound can be obtained by carrying out the reaction, introducing the protection group and subsequently eliminating the protection group as the situation demands or converting it into a desired group In addition, the prodrug of the compound (I) or a salt thereof can be produced by introducing a specific group in a stage of the materials for intermediates similar to the case of the protection group mentioned above, or carrying out the reaction using the compound (I) obtained.

The reaction can be carried out using general methods that are known to those skilled in the art, such as esterification, amidation, acylation and the like. (First production method) The first production method is a method in which the compound (I) of the present invention is produced by an amido condensation reaction using a compound (1) and a compound (2). This reaction is carried out using the compound (1) and the compound (2) in equivalent amounts, or one of them in an excess amount, and leaving them to pass through the reaction under cooling with ice until under heating for generally 0.1 hours to 5 days in an inert reaction solvent in the presence of a condensing agent. As the condensing agent, the agents described in the "Jikken Kakagu Koza (Experimentation Chemistry Course)" publication, edited by The Chemical Society of Japan, 4th edition, Maruzen, 2005, vol. 16, and "Comprehensive Organic Synthesis", (England), edited by B.M. Trost and I. Fleming, Pergamon Press, 1991, vol, 6, N, N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (N, N- dimethylamino) propyl] carbodiimide, O-benzotriazol-1-yl, N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), N- [(dimethylamine) (3 H-1,2,3-triazolo [4 , 5-b] pyridin-3-yloxy] methylene] - N -methylmethanolammonium hexafluorophosphate (HATU), carbonyldiimidazole, diphen ifosfyl azide (DPPA) and the like, can be used appropriately. they are used in an equivalent amount or an excess amount based on the carboxylic acid The solvent is not particularly limited, and for example, aromatic hydrocarbons (for example, benzene, toluene, xylene and the like), ethers (for example , diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane and the like) halogenated hydrocarbons (for example, dichloromethane, 1,2-dichloroethane, chloroform and the like) alcohols (by example, methanol, ethanol, 2-propanol, butanol and the like), N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), sulfoxide of methyl (DMSO), water, or mixed solvents thereof, and the like. In this relation, the reaction proceeds smoothly in some cases when the reaction is carried out in the presence of a base such as N-methylmorpholine, tritylamine, trimethylamine, pyridine, 4-dimethylaminopyridine or the like, or using these bases in a volume of solvent. In addition, the compound (I) can be produced through a method in which the carboxylic acid compound (1) is converted into an active derivative, and subsequently condensed with the amine compound (2) Also in this case, the reaction can be carried out under the same conditions of the aforesaid reaction, wherein the compound (1) is allowed to pass through the reaction directly using equivalent amounts of the compound (1) and compound (2), or using one of them in an excess amount, In this case, as the active derivative of carboxylic acid can be exemplified an active ester obtained allowing it to react with a phenol system compound (p-nitrophenol or the like) or a system compound of N-hydroxyamine (1-hydroxysuccinimide, 1-hydroxybenzotpazole or the like) or a mixed acid anhydride obtained by reacting with an organic acid, or anhydride of acid of the obtained phosphoric acid system allowing it to react with diphenylphosphoyl chloride, and N-methylmorphohene, and acid azide obtained allowing the ester to react ne with hydrazma and an alkyl nitrite in succession, an acid halide (for example, acid chloride, acid bromide or the like), symmetrical acid anhydride and the like Activation reagents and reaction conditions for converting the active derivatives before of the carboxylic acid compound (1) are described, for example, in the "Jikken Kakagu Koza (Expepmentation Chemistry Course)" publications, edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, vol 22, ibid, 5th edition, Maruzen, 2005, vol. 16, "Compendium of Organic Synthetic Methods"; (E.U.A), edited by I.T. Harrison and S. Harrison, Wily Interscience, 1971, vol. 1, and ibid., 1974, vol. 2, "Compendium of Organic Synthetic Methods", (E.U.A.), edited by L.S. Hegedus and L.G. Wade, Wily Interscience, 1977, vol, and the like, and can be carried out with reference to said methods. (Second production method) The second method is the method in which the compound (I) of the present invention is produced by substituting a compound (4) with a compound (3). This reaction is carried out using the compound (3) and the compound (4) in equivalent amounts or one of them in an excess amount and allowing them to go through the reaction under cooling with ice until heating during generally from 0.1 hours to 5 days in an inert reaction solvent in the presence of a base. As the base, organic bases such as pyridine, diisopropylethylamine, triethylamine, 2,6-lutidine and the like can be used, as well as the other bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride, ter -potassium butoxide and the like. The reaction can be carried out for example, optionally selecting the reaction conditions and the like described in Am. Chem. Soc., 1949, 71, 740-741, J. Org. Chem., 1994, 59 (21), 6194-6199, J. Med. Chem., 47 (19), 4642-4644 and Chem. Pharm. Bull., 1996, 47 (1), 28-36. (Third production method) (In the formula, R1A represents a divalent group formed by removing the hydrogen atom from a group selected from lower alkyl, -L-cycloalkyl, -L-cycloalkenyl, a saturated heterocyclic ring L-monocyclic, -L-cycloalkyl, -L- Oxygen-containing cycloalkenyl, an L-monocyclic saturated hetero ring containing nitrogen and L-phenyl Also, R 4a and R 5a may be the same or different from each other and each represents lower alkyl, or together with the lower alkylene group. same should apply later). The third production method is the method in which the compound (I) or (Ia) of the present invention is produced through a reductive alkylation reaction in a compound (5) with a compound (6) or a compound ( 7) with a compound (8a). This reaction is carried out using the compound (5) and the compound (6) or the compound (7) and the compound (8a) in equivalent amounts, or one of them in an excess amount, and allowing them to go through the reaction under cooling conditions until under heating for generally from 0.1 hours to 5 days in an inert reaction solvent in the presence of a reducing agent and a Lewis acid. As the reducing agent, a catalytic reduction condition can be used, as well as stoichiometry reducing agents such as sodium triacetoxyborohydride, sodium borohydride, diborane, lithium aluminum hydride (LAH), and the like. The compound (Ib) of the present invention can be produced by further allowing the compound (la) produced by this method to react with a compound (8b). For the reductive alkylation reaction, for example, the reaction conditions described in the "Jikken Kakagu Koza (Experimentation Chemistry Course)" publication, edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992 may optionally be selected and used. , vol. 22, ibid., 5th edition, Maruzen, 2005, vol. 16. (Fourth production method) Compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention having various functional groups can also be produced using methods obvious to those skilled in the art, methods of production conventionally known or modified methods thereof. For example, the desired compounds can be produced by further subjecting the compounds obtained through the aforementioned production methods to reactions of modification of substituent groups. Typical reactions are shown below Among the compounds (I), a compound having an amido group or a compound having an ester group can be produced using a compound having an amino group or a hydroxyl group as the material, and allowing it to react with a carboxylic acid or reactive derivative thereof. The reaction can be carried out by reference to the methods described, for example, in the "Jikken Kakagu Koza (Experimentation Chemistry Course)", edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, vol. 22, ibid., 5th edition, Maruzen, 2005, vol. 16, or the publication "Compendium of Organic Synthetic Methods", volume 1 to volume 3 or similar mentioned above. (2) Oxidation Among the compounds (I), a compound having a sulfonyl group or a sulfenyl group can be produced through an oxidation reaction of a compound having a sulfide group. The reaction can be carried out by reference to the methods described, for example, in the "Jikken Kakagu Koza (Experimentation Chemistry Course)", edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, vol. 23, ibid., 5th edition, Maruzen, 2005, vol. 17, or the publication "Compendium of Organic Synthetic Methods", volume 1 to volume 3 or similar mentioned above. (3) Alkylation Among the compounds (I), a compound having a lower alkoxy or lower alkylamino group can be produced by subjecting a compound having a hydroxyl group or an amino group to an alkylation reaction. The reaction can be carried out by reference to the methods described, for example, in the "Jikken Kakagu Koza (Experimentation Chemistry Course)", edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, vol. 20, ibid., 5th edition, Maruzen, 2005, vol. 14, or Publication "Compendium of Organic Synthetic Methods", volume 1 to volume 3 or similar mentioned above. (4) Reactions of amination and alkoxylation by reaction Substitution Among the compounds (I), a compound can also produce a compound having a lower alkoxy group or a lower alkylamino group, substituting an alcohol or amine compound corresponding to a compound having a halogen under a basic condition. The reaction can be carried out by optionally selecting and using the reaction conditions described for example, in the "Jikken Kakagu Koza (Experimentation Chemistry Course)", edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, vol. . 20, ibid., 5th edition, Maruzen, 2005, vol. 14. (Methods of production of material compounds) n (In the formulas, Q represents F or Cl, and R7 a carboxyl group protecting group of alkyl, lower benzyl or the like, respectively. successive). The material compound (I) in the aforementioned first production method can be produced through the reaction path described above. In the reaction path described above, the substitution reaction can be carried out by reference to the method described in the "Jikken Kakagu Koza (Experimentation Chemistry Course)", edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, vol. 23 and the like, and hydrolysis with reference to the method described in the "Jikken Kakagu Koza (Experimentation Chemistry Course)", edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, vol. 22 and the like, and deprotection with reference to the method described in the "Protective Groups in Organic Synthesis" Publication, 3rd edition, 1999. With respect to the compound and material (1), a compound can be produced in which R3 is halogen , allowing a halogenating agent such as N-chlorosuccimide, N-bromosuccinimide, chlorine, iodine or the like to react with each intermediate in the reaction path described above, where R3 is a hydrogen atom.

(In the formulas, Hal represents halogen, the same should apply in the future). The reaction path described above shows methods of producing the compounds of material (1), particularly those having a certain alkylamino group as R in the term, ie a compound (1a) which has a group represented by -R1A-NHR4a , a compound (1b) which has a group represented by -R1A-NR4aR5a and a compound (1c) which has a group represented by R1A-NH2. In the reaction path described above, the substitution reaction can be carried out by reference to the method described in the "Jikken Kakagu Koza (Experiment Chemistry Course)" publication, edited by The Chemical Society of Japan, 4th edition, Maruzen , 1992, vol. 23 and similar. Also, the alkylation can be carried out by reference to the method described in the "Jikken Kakagu Koza (Experimentation Chemistry Course)" publication, edited by The Chemical Society of Japan, 4th edition, Maruzen, 1992, vol. 20 and similar. The hydrolysis can be carried out by referring to the method described in the above-mentioned "Protective Groups in Organic Synthesis" (3rd edition, 1999). With respect to the step to convert the compound (11) into the compound (14) by alkylation in the reaction path described above, it is desirable to allow the compound (11) to react with the alkylating agents (12a) and (12b) to through two steps, in this case, it is desirable to allow the compound (11) to react with the alkylating agent (9), after protecting once an amino group with a protection group and subsequently obtaining the intermediate of the first step ( 13) eliminating the protection group. In addition, when R 4a and R 5a in the compound (14) form a monocyclic saturated nitrogen-containing hetero ring, as a couple together with the adjacent nitrogen atom, it is desirable to obtain the compound (14) through a passage through the treatment of the compound (11) using an alkylating agent wherein the alkylating agents (12a) and (12b) are formed in a body. When the (1a) and (1c) produced through the method of Production described above is used as the materials of the first production method, it is desirable to protect the terminal amino group. In some cases it is desirable to carry out protection at the stage of an intermediary, in the production process described above. The compound (I) produced in this form is isolated and purified directly as its free form or as its salt by applying a salt formation treatment by a usual method. The isolation and purification are carried out using general chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography, and the like. Several types of isomers can be isolated through a general method that makes use of the difference in the physico-chemical properties between the isomers. For example, the optical isomers can be separated and purified respectively through the general method wherein a racemic compound is converted into diastereomeric salts which are with an optically active organic acid (tartaric acid or the like) and subsequently subjected to fractional crystallization, or a chromatography assisted by chiral filler or the like. In addition, an optically active compound can also be produced using an optically suitable compound, such as the material. In relation to this, a mixture of diastereomer can also be separated through fractional crystallization, similar chromatography. EXAMPLES The following describes methods of producing novel compounds that are included in the compound (I) as the active ingredient of the present invention. Also, the methods of production of novel compounds among the compounds used as materials are described in the form of reference examples. In relation to this, the production method of the compound (I) is not limited to the production method of the compounds. illustrative examples shown below, and may also be produced through a combination of these production methods or conventional production methods. In addition, the following abbreviations are used in the reference examples and in the Examples, and in the tables described below. Ex: Example Number, REx: reference number reference, No: compound number, Dat: physicochemical data (F: FAB-MS (M + H) +, FN: FAB-MS (MH) ", ES: ESI- MS (M + H) \ ESN: ESI-MS (MH) ", AP: API-MS (M + H) +, El: EI-MS (M) +, APCI: APCI-MS (M + H) + , AN: APCI-MS (MH) \ NMR d (ppm) characteristic peaks by 1 H NMR in DMSO-d 6, NMRC: d (ppm) characteristic peaks by 1 H NMR in CDCl 3), EA: elemental analysis (Caled: value calculated, Found: value found), Str; structural formula, RSn: reference example production method (the number indicates the reference example number where it was used as a reference in the respective production method), Syn: production method of the Example (the number indicates the number of example where the respective production method was used as a reference), Salt: salt (the compound without description indicates its free form), Fum: fumaric acid, Me: methyl, Et: ethyl, Pr: isopropyl, cPr: cyclopropyl, Bu: isobutyl, tBu: fer-butyl, cPen: cyclopentyl, cHex: cyclohexyl, cHep: cyclopentyl, Ph: phenyl, Boc: fer-butoxycarbonyl, Bn: benzyl, and TBS: tert-butylmethylsilyl. In the following reference examples, a case is found in which a treatment operation is described at the end of a reaction until the purification is described, by bridging in the form of "the reaction liquid was subsequently treated". The treatment is a method generally used in organic synthetic chemistry and means a series of steps where the separation of the layers takes place after adding water to a reaction liquid, the extraction is carried out with a suitable solvent, the organic layers are combined and dried and then the solvent is evaporated, and as occasion warrants, purification is carried out by a usual method such as silica gel column chromatography or the like.

Reference Example 1 Cyclopentylamine and potassium carbonate were added to a DMF solution of 4-chloro-4-fluorobenzonitrile, followed by stirring at a temperature of 100 ° C for 12 hours. By subsequent treatment, the reaction liquid, 4-chloro-2- (cyclopentylamino) benzonitrile, was obtained. Reference Example 2 Cyclopentyl amine and potassium carbonate were added to a DMF solution of 4-bromo-4-fluorobenzonitrile, followed by stirring at a temperature of 60 ° C. By subsequent treatment, the reaction liquid, 4-bromo-2- (cyclopentylamino) benzonitrile, was obtained. By referring to the method described in the Publication of J. Am. Chem. Soc; nineteen ninety six; 118-7215-7216, this was allowed to react with piperidine to obtain 2- (cyclohexylamino) -4-piperidin-1-ylbenzonitrile. Reference Example 3 Sodium carbonate and 1,4-dibromobutane were added to a solution of 2- acetonitrile. { [(1S *, 2S *) - 2-aminocyclohexyl] amino} -4-chlorobenzonitrile, followed by heating under reflux for 2 days. Through the subsequent treatment, the reaction liquid, 4-chloro-2-, was obtained. { [(1 S *, 2 S *) - 2-pyrrolidin-1-ylcyclohexyl] amino} benzonitrile. Reference Example 4 4-Chloro-2 - [(2,2,6,6-tetramethylpiperidin-4-yl) amino] benzonitrile was dissolved in N-methyl-2-pyrrolidinone, added potassium carbonate and iodoethane, followed by stirring at a temperature of 90 ° C. By subsequent treatment, the reaction liquid 4-chloro-2 - [(2, 2,6,6-tetramethylpiperidin-4-yl) amino] benzonitrile was obtained. Reference Example 5 Cyclohexanone and sodium triacetoxyborohydride were added to a solution of 1,2-dichloroethane-acetic acid and methyl 2-amino-5-chlorobenzoate, followed by stirring at room temperature. By means of the subsequent treatment, the reaction liquid 5-chloro-2- (cyclohexylamino) benzoate was obtained. Reference Example 6 Methyl 5- (bromomethyl) -2-nitrobenzoate was added to a DMF suspension of potassium carbonate and piperidine, followed by stirring at room temperature to obtain 2-nitro-5- (piperidin-1-methylmethyl) benzoate of methyl (Dat, ES: 279). This compound was dissolved in acetic acid, iron powder was added, followed by stirring at a temperature of 60 ° C to obtain methyl 2-amino-5- (piperidin-1-methylmethyl) benzoate (Dat, F: 279). Cyclohexanone and sodium triacetoxyborohydride were added to an acetic acid solution of this compound, followed by stirring at room temperature. By subsequent treatment, the reaction liquid was 2- (cyclohexylamino) -5- (piperidin-1-methylmethyl) benzoate methyl. Reference Example 7 4-Chloro-2- (cyclopentylamino) benzonitrile from concentrated sulfuric acid to water, followed by stirring while heating under reflux. The reaction liquid was neutralized by adding sodium hydroxide to the reaction liquid, and the organic layer was extracted with chloroform to obtain 4-chloro-2- (cyclopentylamino) benzoic acid. Reference Example 8 Ethylene glycol and sodium hydroxide were added to 4-chloro-2-. { [(1S *, 2S *) - 2-pyrrolidin-1-ylcyclohexyl] amino} benzonitrile, followed by stirring at a temperature of 190 ° C for 5 hours. After neutralizing the reaction liquid by adding hydrochloric acid, the organic layer was extracted with chloroform and the solvent was evaporated to obtain 4-chloro-2- acid. { [(1S *, 2S *) - 2-pyrrolidin-1-ylcyclohexyl] amino} benzonitrile. Reference Example 9 Methyl 5-chloro-2- (cyclohexylamino) benzoate was dissolved in ethanol, an aqueous solution of 1 M sodium hydroxide was added, followed by stirring at a temperature of 70 ° C. By subsequent treatment, the reaction liquid, 5-chloro-2- (cyclohexylamino) benzoic acid, was obtained. Reference Examples 10 to 132 In the same manner as in the methods of Reference Examples 1 to 9, the compounds of Reference Examples 10 to 132 shown in Tables 1 to 7 were produced which are described below, using materials respectively corresponding.

The structures and physicochemical data of the compounds of Reference Examples 10 to 132 are shown in Tables 1 to 7. Reference Example 133 N-Bromosuccinimide and AIBN were added to a solution of 2-fluoro-4 carbon tetrachloride methylbenzonitrile, followed by heating under reflux to obtain 4- (bromomethyl) -2-fluorobenzonitrile. By allowing this to react with morpholine in DMF in the presence of potassium carbonate, 2-chloro-4- (morpholin-4-ylmethyl) benzonitrile was obtained. In DMF and in the presence of potassium carbonate, this was allowed to react with cyclohexaneamine at a temperature of 160 ° C for 30 minutes, carrying out microwave irradiation. By subsequent treatment, the reaction liquid, 2- (cyclohexylamine) -4- (morpholin-4-ylmethyl) benzonitrile, was obtained. Reference Example 134 1-Chloro-2,5-pyrrolidinedione (NCS) was added at room temperature to a DMF solution of. { (1 R, 2R) -2 - [(5-chloro-2-cyanophenyl) amino] cyclohexyl} fer-butyl carbamate, followed by stirring at a temperature of 80 ° C for 5 hours. Through the subsequent treatment, the reaction liquid was obtained. { (1 R, 2R) -2 - [(4,5-dichloro-2-cyanophenyl) amino] cyclohexyl} fer-butyl carbamate. Reference Example 135 Potassium carbonate and 2,2,6,6- tetramethylpiperidine-4-amine to a DMF solution of 2-fluoro-4- (trifluoromethyl) benzonitrile. After stirring at a temperature of 60 ° C for 12 hours, methyl iodide and potassium carbonate were added, followed by stirring at room temperature for 1 day. By subsequent treatment, the reaction liquid 2 - [(1, 2,2,6,6-pentamethylpiperidin-4-yl) amino] -4- (trifluoromethyl) benzonitrile was obtained. Reference Example 136 Di-fer-butyl bicarbonate was added to a THF solution of 2-. { [(1S, 2S) -2-aminocyclohexyl] amino} -4-chlorobenzonitrile and triethylamine, followed by stirring at room temperature for 12 hours. By subsequent treatment, the reaction liquid was obtained. { (1S, 2S) -2 - [(5-chloro-2-cyanophenyl) amino] cyclohexyl} fer-butyl carbamate. Reference Example 137 N-bromosuccinimide (NBS) was added to a dichloromethane solution of. { (1S, 2S) -2 - [(5-chloro-2-cyanophenyl) amino] cyclohexyl} carbamate, followed by stirring at room temperature for 7 hours. By subsequent treatment, the reaction liquid was obtained. { (1S, 2S) -2 - [(4-bromo-5-chloro-2-cyanophenyl) amino] cyclohexyl} urea-butyl carbamate. Reference Example 138 Suspended. { (1S, 2S) -2 - [(4-bromo-5-chloro-2-cyanophenyl) amino] cyclohexyl} fer-butyl carbamate, boroxine trimethyl and potassium carbonate in a mixed solvent of 1,4-dioxane (16 ml) and water (4 ml), tetrakis (triphenylphosphine) palladium was added thereto, followed by stirring at a temperature of 110 ° C for 1 day. By subsequent treatment, the reaction liquid was obtained. { (1S, 2S) -2 - [(5-chloro-4-cyano-4-methylphenyl) amino] cyclohexyl} fer-butyl carbamate. Reference Example 139 4M Hydrogen chloride / ethyl acetate (20 ml) was added to an ethanol solution of. { (1S, 2S) -2 - [(5-chloro-2-cyano-4-methylphenyl) amino] cyclohexyl} carbamate, followed by stirring at room temperature for 12 hours. By concentrating the reaction liquid under reduced pressure, 2- was obtained. { [(1S, 2S) -2-aminocyclohexyl] amine} -4-chloro-5-methylbenzonitrile. Reference Example 140 Through the methods described in the Patent American No. 4801604 and Publication HETEROCYCLES, vol. 31, no. 10, 1990, 1837-1846, cyclohexaneamide of (1R, 2S) -2-pyrrolidin-1-yl was produced. This and 4-chloro-2-fluorobenzonitrile and potassium carbonate were stirred at a temperature of 100 ° C for 1 hour in acetonitrile under microwave irradiation and subsequently stirred at a temperature of 100 ° C for 100 minutes. Through the subsequent treatment, the reaction liquid, 4-chloro-2-, was obtained. { [(1 R, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} benzonitrile. Reference Example 141 Potassium fer-butoxy was added to a mixture of 2-fluoro-4- (trifluoromethyl) benzonitrile, 3-pyridine amine and THF, followed by stirring at room temperature for 7 days. After neutralizing the reaction liquid by adding 1M hydrochloric acid thereto and subsequent extraction with chloroform, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain 2- (pyridine-3-ylamino) -4- (trifluoromethyl) benzonitrile. Reference Example 142 1- (Dimethylamin-1-ylcarbonyl) cyclohexanamine hydrochloride was added to a THF suspension of lithium aluminum hydride (LAH) under cooling with ice, followed by heating under reflux for 3 hours. An aqueous solution of sodium hydroxide and sodium sulfate was added to the reaction liquid and filtered. The filtrate was concentrated under reduced pressure, 4-chloro-2-fluorobenzonitrile and potassium carbonate were added to the resulting residue, and this was stirred at a temperature of 180 ° C for 1 hour to carry out the reaction while it was irradiated with microwaves . By subsequent treatment, the reaction liquid was obtained 4-chloro-2- (. {1 - [(dimethylamino) methy1] cyclohexyl} amino) benzonitrile. Reference Example 143 Under ice cooling, sodium borohydride was slowly added in small portions to a solution of 2- acetic acid. { [(1 R, 2R) -2-aminocyclohexyl] amino} -4- (trifluoromethyl) benzonitrile, followed by stirring with heating at a temperature of 60 ° C for 6 hours. By means of the subsequent treatment, reaction liquid 2- was obtained. { [(1R, 2R) -2- (diethylamino) cyclohexyl] amino} -4- (trifluoromethyl) benzonitrile. Reference Example 144 Under ice cooling, sodium borohydride was slowly added in small portions to a solution of 2- acetic acid. { [(1 R, 2R) -2-aminocyclohexyl] amino} -4- (trifluoromethyl) benzonitrile, followed by heating at a temperature of 60 ° C for 6 hours. By means of the subsequent treatment, reaction liquid 2- was obtained. { [(1 R, 2R) -2- (ethylamino) cyclohexyl] amino} -4- (Trifluoromethyl) benzonitrile. An aqueous solution of formalin and sodium triacetoxyborohydride was added to a THF solution of this, followed by stirring. By subsequent treatment, the reaction liquid was obtained 2- (. {(1 R, 2R) -2- [ethyl (methyl) amino] cyclohexyl}. Amino) -4- (trifluoromethyl) benzonitrile. Reference Example 145 Methanol and thionyl chloride were added at 2-. { [(1S, 2S) -2-aminocyclohexyl] amine} -4- (trifluoromethyl) benzonitrile, followed by stirring with heating at a temperature of 60 ° C. After neutralizing the reaction liquid by adding an aqueous solution of sodium bicarbonate thereto, the reaction liquid was subsequently treated to obtain 2-. { [(1 S, 2S) -2- aminocyclohexyl] amino} -4- (Trifluoromethyl) benzoate methyl. Reference Example 146 In DMF and in the presence of sodium hydride, 2- (. {(1 S, 2S) -2 - [(tert-butoxycarbonyl) amino] cyclohexyl} amine) was allowed to react. methyl (trifluoromethyl) benzoate with methyl iodide at a temperature of 70 ° C for 1 hour. By subsequent treatment, the reaction liquid was obtained 2- (. {(1 S, 2S) -2 - [(tert-butoxycarbonyl) (methyl) amino] cyclohexyl}. Amine) -4- (trifluoromethyl) benzoate of methyl. Reference Example 147 Under a hydrogen atmosphere (1 atm) and in ethanol, catalytic hydrogenation of 4-nitro-2- was carried out. { [(1 S, 2 S) -2-pyrrolidin-1-ylcyclohexyl] amino} ethyl benzoate at room temperature in the presence of 10% palladium on carbon to obtain 4-amino-2-. { [(1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} ethyl benzoate. Reference Example 148 4-amino-2- was allowed to react. { [(1 S, 2 S) -2-pyrrolidin-1-ylcyclohexyl] amino} ethyl benzoate with sodium nitrite (NaNO2) and trifluoroborane-hydrogen fluoride complex (BF3 HF) in water at a temperature of 10 ° C for 10 minutes. By subsequent treatment, the reaction liquid, 4-fluoro-2-, was obtained. { [(1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} ethyl benzoate.

Reference Example 149 Under cooling with ice, an aqueous solution of formaldehyde (36%) and sodium triacetoxyborohydride was added to a THF solution of 2-. { [(1 R, 2R) -2-aminocyclohexyl] amino} -4- (trifluoromethyl) benzonitrile, followed by stirring at room temperature for 30 minutes. By means of the subsequent treatment, reaction liquid 2- was obtained. { [(1 R, 2R) -2- (dimethylamino) cyclohexyl] amino} -4- (trifluoromethyl) benzonitrile. Ethylene glycol and sodium hydroxide were added thereto. This was stirred at a temperature of 170 ° C for 6 hours and subsequently cooled spontaneously. This was neutralized with 1M hydrochloric acid and subsequently stirred while cooled spontaneously. By collecting the solid precipitated in this manner by filtration, 2- acid was obtained. { [(1R, 2R) -2- (dimethylamino) c.clohexyl] amino} -4- (trifluoromethyl) benzoic. Reference Example 150 An aqueous solution of potassium hydroxide was added to a solution mixed with ethanol-water of 2-. { [(1 S, 2S) -2- (benzyloxy) cyclohexyl] amino} -4- (trifluoromethyl) benzonitrile. This was stirred at a temperature of 100 ° C for 5 hours and subsequently cooled spontaneously. After neutralizing with 1M hydrochloric acid, the organic layer was extracted with chloroform. By concentrating the organic layer under reduced pressure, 2- acid was obtained. { [(1 S, 2S) -2- (benzyloxy) cyclohexyl] amino} -4- (Trifluoromethyl) benzoic acid. Reference Example 151 1-Chloro-2,5-pyrrolidinedione was added at room temperature to 1,2-dichloroethane and a DMF solution of 2 - [(cyclopropylmethyl) amino] nicotinic acid, followed by stirring for 1 day. By subsequent treatment, the reaction liquid, 5-chloro-2 - [(cyclopropylmethyl) amino] nicotinic acid, was obtained. Reference Example 152 A mixture of 2-fluoronicotinic acid and 2,2,2-trifluoroethhenamine was stirred at a temperature of 180 ° C for 30 minutes with microwave irradiation and subsequently cooled spontaneously. Water and 6 ml of an aqueous solution of 1N sodium hydroxide and chloroform were added to the mixture, and the water layer was extracted with chloroform. Upon concentrating the organic layer under reduced pressure, 2 - [(2,2,2-trifluoroethyl) amino] nicotinic acid was obtained. Reference Example 153 Diisopropylethylamine and (1S, 2S) -1,2-cyclohexanediamine were added to 2-chloro-6- (trifluoromethyl) nicotinic acid, followed by stirring at a temperature of 100 ° C for 30 minutes and at a temperature of 140 ° C. ° C for 10 minutes, using a microwave reaction apparatus. The reaction liquid was dissolved in acetonitrile, potassium carbonate and 1,4-dibromobutane were added, followed by stirring at a temperature of 50 ° C for 8 hours. When dissolving the residue extracted with chloroform in methanol and THF, adding an aqueous solution of 1M sodium hydroxide thereto and carrying out the reaction at a temperature of 50 ° C, 2- acid was obtained. { [(1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} -6- (trifluoromethyl) nicotinic. Reference Example 154 A mixture of exo-2-aminonorbornane and 2-chloronicotinic acid was stirred at a temperature of 160 ° C for 1 day and subsequently cooled spontaneously. The reaction liquid was diluted with a 1M aqueous sodium hydroxide solution and subsequently washed with diethyl ether. The water layer was neutralized with 1M hydrochloric acid and then the precipitated crystals were collected by filtration to obtain rel-2 - [(1 R, 2R, 4S) -bicyclo [2.2.1] hept-2-ylamino] -nicotinic acid. Reference Example 155 By allowing the ethyl 2,6-dichloronicotinate and cycloexanamine to pass through the reaction at a temperature of 50 ° C for 1 hour in DMF in the presence of potassium carbonate, 6-chloro-2- ( cyclohexylamino) ethyl nicotinate. Upon carrying out the hydrolysis of an ethanol solution at this temperature of 70 ° C for 18 hours in the presence of 1M sodium hydroxide, 6-chloro-2- (cyclohexylamino) nicotinic acid was obtained. Reference Example 156 In methylene chloride, ethyl 2,6-difluoronicotinate and cyclohexanamine were stirred at a temperature of 0 ° C for 0.5 hours to obtain ethyl 2- (cyclohexylamine) -6-fluoronicotinate (ES: 267). This was added in ethanol by adding sodium hydroxide. By concentrating the reaction liquid under reduced pressure and purifying the resulting residue by silica gel column chromatography, 2- (cyclohexylamino) -6-fluoronotinic acid was obtained. Reference Example 157 By treating ethyl 2- (cyclohexylamino) -6-fluoronicotinate with sodium methoxide at room temperature in methanol, methyl 2- (cyclohexylamino) -6-methoxynicotinate (F: 265) was obtained. To this was added ethanol and 1M sodium hydroxide, followed by stirring at a temperature of 75 ° C. The reaction liquid was neutralized with 1M hydrochloric acid and concentrated under reduced pressure to obtain 2- (cyclohexylamino) -6-methoxynicotinic acid. Reference Example 158 2-Fluoro-4- (trifluoromethyl) benzoyl chloride was added to a pyridine solution of 7-amino-1-methyl-3,4-dihydroquinolin-2 (1H) -one, followed by stirring at room temperature. environment for 12 hours. Water was added to the reaction liquid, followed by stirring for 30 minutes and then the precipitated crystals were collected by filtration to obtain 2-fluoro-N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline- 7- il) -4- (trifluoromethyl) benzamide. Reference Example 159 In DMF, 6-amino-4- (trifluoromethyl) -1,3-dihydro-2H-indol-2-one and 1,3-dioxo-1,3-dihydro-2H-isoindol- Ethyl 2-carboxylate will pass through the reaction at a temperature of 60 ° C for 18 hours in the presence of triethylamine. Water was added to the reaction liquid and the resulting precipitate was collected by filtration to obtain 2- [2-oxo-4- (trifluoromethyl) -2,3-dih id ro-1H -ind ol-6-i I] - 1H-isoin do 1-1, 3- (2H) -dione. Reference Example 160 In DMF, 2- [2-oxo-4- (trifluoromethyl) -2,3-dihydro-1H-indol-6-yl] -1H-isoindole-1,3- (2H) - was allowed to proceed. dione will react with methyl iodide at room temperature for 3 hours in the presence of sodium hydride. By the subsequent treatment, the reaction liquid was obtained 2- [3,3-dimethyl-2-oxo-4- (trifluoromethyl) -2,3-dihydro-1 H-indol-6-yl] -1 H-isoindole -1, 3- (2H) -dione. Reference Example 161 When adding an aqueous solution of hydrazine to a methanol-chloroform solution of 2- [3,3-dimethyl-2-oxo-4- (trifluoromethyl) -2,3-dihydro-1H-indol-6 il] -1 H -soindole-1,3- (2H) -dione and carrying out the reaction at room temperature for 10 hours, 6-amino-3,3-dimethyl-4- (trifluoromethyl) -1 was obtained, 3-dihydro-2H-indol-2-one.

Reference Example 162 HATU was added to a dichloroethane solution of 2- (cyclohexylamino) -6-fluoronicotinic acid and triethylamine. After 30 minutes of stirring at room temperature, 7-amino-1-methyl-3,4-dihydroquinolin-2 (1 H) -one was added thereto. The reaction liquid was stirred overnight at room temperature and then heated under reflux for 3 hours. By the subsequent treatment, the reaction liquid was obtained 2- (cyclohexylamino) -6-fluoro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) nicotinamide. Reference Example 163 Sulfuric acid was added to an ethanol solution of 2,6-dichloronicotinic acid and heated under reflux temperature for 24 hours. After adding an aqueous solution of saturated sodium bicarbonate thereto, the ethanol was evaporated under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. Potassium carbonate was added to a DMF solution of ethyl 2,6-dichloronicotinate, and cyclopentylamine was added thereto, followed by stirring at a temperature of 0 ° C for 1 hour and at room temperature for 6 hours. By the subsequent treatment, the reaction liquid 6-chloro-2 - [(cyclopropylmethyl) amino] ethyl nicotinate was obtained. Reference Example 164 Sodium hydride was added at room temperature to a DMF solution of ethyl 6-chloro-2 - [(cyclopropylmethyl) amino] nicotinate and 2,2,2-trifluoroethanol, followed by stirring at a temperature of 80 ° C for 20 hours. By the subsequent treatment, the reaction liquid was obtained 2 - [/ cyclopropylmethyl) amine] -6- (2,2,2-trifluoroethoxy) ethyl nicotinate. Reference Example 165 Methylene chloride 1 - [(tert-Butoxycarbonyl) amino] cyclohexanecarboxylate, pyrrolidine, 1-ethyl-3- [3- (N, N-dimethylamino) propyl] carbodiimide hydrochloride were allowed to react at room temperature. 1-Hydroxybenzotriazole.

By subsequent treatment, the reaction liquid was [tert- butyl [1- (pyrrolidin-1-ylcarbonyl) cyclohexyl] carbamate. Reference Example 166 1- (Pyrrolidin-1-ylcarbonyl) cyclohexanamine hydrochloride was added under cooling with ice to a THF solution of LAH, followed by heating under reflux for 3 hours. An aqueous solution of sodium hydroxide and sodium sulfate was added to the reaction liquid, followed by filtration. By concentrating the filtrate under reduced pressure, 1- (pyrrolidin-1-ylmethyl) -cyclohexanamine was obtained. Reference Example 167 In dichloromethane, a mixture of 4-chloro-2 - [(2-hydroxyethyl) amino] benzoic acid and 7-amino-1-methyl-3,4- was treated dihydroquinolin-2 (1 H) -one with 1-ethyl-3- [3- (N, N-dimethylamino) propyl] carbodiimide hydrochloride at room temperature to obtain 4-chloro-2 - [(2-hydroxyethyl) amino] - N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) benzamide. Reference Example 168 4-Chloro-2 - [(2-hydroxyethyl) amino] -N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) benzamide was dissolved in tetrahydrofuran, Diisopropylethylamine and methanesulfonyl chloride were added, followed by stirring at room temperature for 3 hours. By means of the subsequent treatment, the methanesulfonate reaction liquid of 2- (. {5-chloro-2 - [(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) carbamoyl) was obtained. ] phenyl} amino) ethyl. Reference Example 169 Palladium carbon and ammonium formate were added to a methanol solution of 2 - [(1-benzylpiperidin-4-yl) amino] -N- (1-methyl-2-oxo-1,2, 3,4-tetrahydroquinolin-7-yl) -4- (trifluoromethyl) benzamide, followed by heating under reflux for 2 hours. After spontaneous heating, the Celite filtration was carried out and subsequently the filtrate was concentrated under reduced pressure. Upon purification of the residue by silica gel column chromatography, N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) -2- (piperidin-4-ylamino) was obtained. -4- (trifluoromethyl) benzamide. Reference Example 170 Under ice cooling, chloroformate 1- was added chloroethyl to a solution of 1,2 - [(1-benzylpiperidin-4-yl) amino] -4-chloro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinoline) 1,2-dichloroethane -7-yl) benzamide. This was carried out under reflux heating and subsequently concentrated under reduced pressure. After dissolving in methanol, this was stirred for 2 hours under heating at reflux temperature. After concentration of the reaction liquid under reduced pressure, the residue was purified by silica gel column chromatography to obtain 4-chloro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin -7-yl) -2- (piperidin-4-ylamino) benzamide. Reference Example 171 2-Chloro-6- (trifluoromethyl) nicotinic acid, (1S, 2S) -1,2-cyclohexanediamine and diisopropylethylamine were mixed, followed by stirring at a temperature of 150 ° C for 30 minutes under microwave irradiation . After spontaneous cooling, the reaction liquid was concentrated under reduced pressure, the residue was dissolved in methanol and sulfuric acid was added thereto. After 6 days of stirring under heating at reflux temperature, this was cooled spontaneously and concentrated under reduced pressure. This was neutralized with an aqueous solution of saturated sodium bicarbonate and subsequently extracted with chloroform. After concentration of the organic layer under reduced pressure, the resulting residue was dissolved in THF, and added in said order triacetoxyborohydride sodium and an aqueous solution of formaldehyde (36%). By means of the subsequent treatment, the reaction liquid was obtained, 2-. { [(1S, 2S) -2- (dimethylamino) cyclohexyl] amino} -6- (trifluoromethyl) methyl nicotinate. Reference Example 172 A solution of ethanol of 1 - (2- {[tert-butyl (dimethyl) silyl] oxy} ethyl) -7-nitro-3,4-dihydroquinoline was stirred at room temperature for 3 hours. -2 (1 H) -one and 10% palladium-carbon under a hydrogen atmosphere (1 atm), the reaction liquid was filtered, and then the filtrate was concentrated under reduced pressure. By purification of the residue by silica gel column chromatography, 7-amino-1- (2- {[[tert-butyl (dimethyl) silyl] oxy} ethyl) -3,4-dihydroquinoline- was obtained. 2 (1H) -one. Reference Example 173 7-Nitro-3,4-dihydroquinolin-2 (1 H) -one, (2-bromoethoxy) (tert-butyl) dimethylsilane, potassium carbonate, potassium iodide and water were added to DMF, followed by stirring at room temperature for 2 days and subsequently stirred at a temperature of 40 ° C for 3 days. By subsequent treatment, the reaction liquid was obtained 1- (2. {[[Tert-butyl (dimethyl) silyl] oxy} ethyl) -7-nitro-3,4-dihydroquinoline-1 (1H) ) -one. Reference Example 174 A methylene chloride solution of 7-amino-1 - (2- [{. butyl (dimethyl) silyl] oxy} ethyl) -3,4-dihydroquinolin-2 (1H) -one, 2- (cyclohexylamino) -4- (trifluoromethyl) benzoic acid, 1-ethyl-3- [3- (N, N-dimethylamino) propyl] hydrochloride] carbodiimide, dimethylaminopyridine and triethylamine. By means of the subsequent treatment, the reaction liquid N- [1 - (2- {[[tert-butyl (dimethyl) silyl] oxy} ethyl) -2-oxo-1,2,3,4-tetrahydroquinoline was obtained. -7-yl] -2- (cyclohexylamino) -4- (trifluoromethyl) benzamide. Reference Example 175 Aluminum chloride and tert-butyl chloride were added under ice cooling to 2-fluorophenol and stirred at room temperature. By adding water to the reaction liquid, concentrating the organic layer under reduced pressure and crystallizing from hexane, 4-tert-butyl-2-fluorophenol was obtained. Reference Example 176 A chloroform solution of 4-tert-butyl-2-fluorophenol, 2-dimethylaminopyridine and 2,6-lutidin, cooled to a temperature of -78 ° C, was treated with trifluoromethanesulfonic acid anhydride to obtain trifluoromethanesulfonate. of 4-tert-butyl-2-fluorophenyl. Under a carbon monoxide atmosphere, a DMSO solution of the resulting sulfonate, methanol, triethylamine, palladium acetate and diphenylphosphinopropane was allowed to react at a temperature of 60 ° C. By subsequent treatment, the reaction liquid, methyl 4-tert-butyl-2-fluorobenzoate, was obtained.

Reference Example 177 Oxalyl chloride was added to a THF solution of acid 4-tert-butyl-2-fluorobenzoic acid and stirred for 1 hour, and aqueous ammonia was added thereto. By subsequent treatment, the reaction liquid 4-tert-butyl-2-fluorobenzamide was obtained. Reference Example 178 Pyridine and trifluoroacetic anhydride were added to a dioxane solution of 4-tert-butyl-2-fluorobenzamide and stirred at room temperature for 3 hours. By subsequent treatment, the reaction liquid, 4-tert-butyl-2-fluorobenzonitrile, was obtained. Reference Example 179 Under a hydrogen atmosphere and in ethanol, the catalytic hydrogenation reaction of 2- (cyclohexylamino) -3- (trifluoromethyl) benzonitrile in the presence of Raney nickel to obtain 2- (aminomethyl) was carried out. -N-cyclohexyl-6- (trifluoromethyl) aniline. Reference Examples 180 to 358 In the same manner as the methods of the Examples of Reference 1 to 9 and Reference Examples 133 to 179, the compounds of Reference Examples 180 to 358 shown in Tables 8 to 18 which are described below, using respectively corresponding materials.

Reference Example 359 Sodium hydride was added under cooling with ice to a DMF solution of malonic acid dimethyl ester, and then 1,2-dichloro-3,5-dinitrobenzene was added and allowed to pass at room temperature overnight. By subsequent treatment, the reaction liquid (dimethyl 2-chloro-4,6-dinitrophenyl) malonate (Dat, FN: 332) was obtained. This was dissolved in DMSO, lithium chloride and water was added, followed by stirring at a temperature of 100 ° C for 2 hours. By subsequent treatment, the reaction liquid, methyl (2-chloro-4,6-dinitrophenyl) acetate, was obtained. Reference Example 360 A mixture of methyl (2-chloro-4,6-dinitrophenyl) acetate, ammonium chloride, iron powder, ethanol and water was stirred at a temperature of 120 ° C for 3 hours. The reaction liquid was filtered, trifluoroacetic acid was added to the filtrate, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, 1M sodium hydroxide was added to the residue, and this was subsequently treated with 6-amino-4-chloro-1,3-dihydro-2H-indol-2-one. In this regard, the amine compounds used as the materials in the amidation reaction described in the aforementioned Reference Examples 158 and 167, can be produced by the method described in WO 2004/110986.

The structures and physicochemical data of the compounds of Reference Examples 133 to 360 are shown in Tables 8 to 18. Example 1 1-Ethyl-3- [3- (N, N-dimethylamino) propyl] carbodiimide hydrochloride was added (250 mg) to a solution of chloroform (15 mL) of 4-chloro-2- (cyclopentylamino) benzoic acid (250 mg) and 7-amino-1-methyl-3,4-dihydroquinolin-2- (1 H) -one (184 mg), followed by stirring at room temperature for 26 hours. The reaction liquid was concentrated under reduced pressure. Upon purification of the residue by silica gel column chromatography (chloroform: methanol, 1: 0 to 9: 1), 4-chloro-2- (cyclopentylamino) -N- (1-methyl-2-oxo-1 was obtained. , 2,3,4-tetrahydroquinolin-7-yl) benzamide. When treating this with a 4M solution of hydrogen chloride / ethyl acetate, it was obtained in the form of a solid 4-chloro-2- (cyclopentylamino) -N- (1-methyl-2-oxo-1, 2 hydrochloride. , 3,4-tetrahydroquinolin-7-yl) benzamide (97 mg). Example 2 1-Ethyl-3- [3- (N, N-dimethylamino) propyl] carbodimide hydrochloride (174 mg) and dimethylaminopyridine (21 mg) were added to a solution of methylene chloride (5 mL) of acid 4-chloro-2-. { [(1S *, 2S *) - 2-pyrrolidin-1-cyclohexyl] amino} benzoic acid (220 mg) and 7-amino-1-methyl-3,4-dihydroquinolyl-2- (1 H) -one (100 mg). After shaking during overnight the reaction liquid at room temperature, the reaction liquid was concentrated under reduced pressure. Upon purification of the residue by silica gel column chromatography (hexane: ethyl acetate, 1: 0 to 1: 1), it was obtained in the form of a pale yellow amorphous solid 4-chloro-N- (1-methyl). -2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) -2-. { [(1 S *, 2 S *) - 2-pyrrolidin-1-cyclohexyl] amino} benzamide. By treating this with a 4M hydrogen chloride / ethyl acetate solution, 4-chloro-N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7 hydrochloride was obtained in an amorphous form. -il) -2-. { [(1 S *, 2 S *) - 2-pyrrolidin-1-ylcyclohexyl] amino} Benzamide (212 mg). Example 3 M-Chloroperbenzoic acid (mCPBA, 235 mg) was added under cooling with ice to a solution of methylene chloride of 4-chloro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin -7-il) -2-. { [(methylsulfanyl) ethyl] amino} benzamide (250 mg), followed by stirring at room temperature for 2 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction liquid, followed by extraction with chloroform. The organic layer was dried with sodium sulfate, and then the solution was concentrated under reduced pressure. Upon purification of the resulting residue by silica gel column chromatography (hexane: ethyl acetate, 1: 0 to 1: 1), it was obtained in the form of a solid 4-chloro-N- (1-methyl-2- oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -2-. { [(methylsulfonyl) ethyl] amino} benzamide (150 mg).

Example 4 A solution of 4M hydrogen chloride / ethyl acetate (5 mL) was added to a solution of ethanol (5 mL) of 2-. { [(5-chloro-2 { [(1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) amino] carbonyl, phenyl) amino] methyl} piperidin-1-tert-butyl carboxylate (540 mg), followed by stirring at room temperature for 2 hours. Upon collecting the resulting precipitate by filtration, it was obtained in the form of a solid 4-chloro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) hydrochloride. [(piperidin-2-ylmethyl) amino] benzamide (470 mg). Example 5 4-Chloro-N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) -2 - [(piperidin-2-ylmethyl) amino] benzamide hydrochloride was dissolved ( 100 mg) in a mixed solution of acetic acid (3 mL) and methanol (2 mL), and 1 mL of an aqueous solution of formaldehyde (36%) was added thereto. Sodium triacetoxyborohydride (252 mg) was added to this solution at a temperature of 0 ° C, followed by stirring at room temperature for 30 minutes. After concentration under reduced pressure, this was made basic by adding an aqueous solution of saturated sodium bicarbonate, followed by extraction with chloroform. After drying the organic layer with magnesium sulfate, the solvent was evaporated under reduced pressure. By purifying the residue by chromatography of silica gel column (chloroform: methanol, 10: 1) and treating the resulting free base with a 4M solution of hydrogen chloride / ethyl acetate, 4-chloro-N- (1-methyl 1-2 hydrochloride was obtained -0X0-1, 2,3,4-tetrahydroquinolin-7-yl) -2-. { [(1-methylpiperidin-2-yl) methyl] amino} Benzamide (45 mg) in the form of a solid. Examples 6 to 94 In the same manner as the methods of Examples 1 to 5, the compounds of Examples 6 to 94 shown in Tables 19 to 25, which are described below, were produced using respectively corresponding materials. The structures and physicochemical data of the compounds of Examples 1 to 94 are shown in Tables 19 to 25. Example 95 3-Fluoropyridine hydrochloride (240 mg) and sodium carbonate (250 mg) were added to a solution of dimethylformamide of 2- (. {5-chloro-2 - [(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) carbamoyl] phenyl} amino) ethyl methanesulfonate (595 mg), followed by stirring at a temperature of 40 ° C for 15 hours. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was dried with magnesium sulfate and then the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gel of basic silica, chloroform: methanol, 1: 0 to 95: 5). By treating the resulting free base with a 4M solution of hydrogen chloride / ethyl acetate, it was obtained in the form of a solid 4-chloro-2-hydrochloride. { [2- (3-fluoropyrrolidin-1-yl) ethyl] amine} -N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) benzamide (156 mg). Example 96 At room temperature, 1M hydrochloric acid (0.38 mL) was added to a solution of ethanol (20 mL) of 2-. { [(1S, 2S) -2- (benzyloxy) cyclohexyl] amino} -N- (1-methy1-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -4- (trifluoromethyl) benzamide (140 mg), 10% palladium-carbon was added (240 mg), followed by stirring for 1 day under a hydrogen atmosphere. After neutralizing with an aqueous solution of saturated sodium bicarbonate by extracting with chloroform, the organic layer was concentrated under reduced pressure. Upon purification of the residue by silica gel column chromatography (hexane: ethyl acetate, 1: 0 to 1: 1), it was obtained in an amorphous form 2-. { [(1S, 2S) -2-hydroxycyclohexyl] amino} -N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -4- (trifluoromethyl) benzamide (66 mg). Example 97 2-Fluoro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -4- (trifluoromethyl) benzamide (250 mg), N-methylpiperidone (0.5 mL) and (2S) -2-aminopropan-1 -ol (800 mg), followed by stirring at a temperature of 180 ° C for 40 minutes. minutes under microwave irradiation. After spontaneous cooling and subsequent purification by silica gel column chromatography (chloroform: methanol, 99: 1 to 95: 5), it was obtained in the form of a 2- solid. { [(1S) -2-hydroxy-1-methylethyl] amino} -N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -4- (trifluoromethyl) benzamide (188 mg). Example 98 HATU (220 mg) and triethylamine (0.08 mL) were added to a solution of dichloroethane (10 mL) of 4-tert-butyl-2- acid. { [(1 S, 2 S) -2-pyrrolidin-1-ylcyclohexyl] amino} benzoic acid (200 mg) and 7-amino-1-methyl-3,4-dihydroquinolin-2 (1 H) -one (102 mg), followed by stirring at room temperature for 12 hours. An aqueous solution of 1M sodium hydroxide was added to the reaction liquid, followed by extraction with chloroform. After drying the organic layer, the solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform: methanol, 95: 5). Upon addition of fumaric acid (22 mg) to an ethyl acetate solution of the resulting free base, it was obtained in the form of a solid 4-tert-butyl-N- (1-methyl-2-oxo-1) fumarate. , 2,3,4-tetrahydroquinolin-7-yl) -2-. { [(1 S, 2 S) -2-pyrrolidin-1-ylcyclohexyl] amino} benzamide. Example 99 HATU (406 mg) was added to a DMF solution of 4-chloro-2- acid. { [(1R, 2R) -2-piperidin-1-ylcyclohexyl] amino} benzoic (300 mg) and 7-amino-1-methyl-3,4-dihydroquinoline-2 (1 H) -one (173 mg), followed by stirring at room temperature for 24 hours. After adding water to the reaction liquid and extracting with ethyl acetate, the organic layer was dried with sodium sulfate, and then the solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane) : ethyl acetate, 2: 1). By treating the resulting free base with 4M hydrogen chloride / ethyl acetate, 4-chloro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7 hydrochloride was obtained in an amorphous form). -il) -2-. { [(1R, 2R) -2-piperidin-1-ylcyclohexyl] amino} benzamida (270 mg). Example 100 After dissolving N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -2- (piperidin-4-ylamino) -4- (trifluoromethyl) benzamide (200 mg ), cyclopropanecarbaldehyde (0.10 mL) and acetic acid (0.026 mL) were added in 1,2-dichloroethane (4 mL), sodium triacetoxyborohydride (285 mg). After stirring at room temperature for 2 hours, an aqueous 1M sodium hydroxide solution was added thereto, followed by extraction with chloroform. After drying the organic layer with sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia, 1: 0: 0 to 90: 9: 1). When treating Resulting free base with 4M hydrogen chloride / ethyl acetate was obtained in an amorphous form of 2- hydrochloride. { [1- (cyclopropylmethyl) picperidin-4-yl] amino} -N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -4- (trifluoromethyl) benzamide (199 mg). Example 101 Triethylamine (0.16 mL) and ethyl iodide (0.068 mL) were added to a DMF solution of N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -2- (piperidin-1-ylamino) -4- (trifluoromethyl) benzamide (250 mg). After 12 hours of stirring at room temperature and subsequent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia, 1: 0: 0 to 90: 9: 1). By treating the resulting free base with 4M hydrogen chloride / ethyl acetate, 2 - [(1-ethylpiperidin-4-yl) amino] -N- (1-methyl-2-oxo-) hydrochloride was obtained in an amorphous form. 1, 2,3,4-tetrahydroquinolin-7-yl) -4- (trifluoromethyl) benzamide (266 mg). Example 102 4-Cyano-2- (cyclohexylamino) -N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) benzamide (500 mg), di-ter dicarbonate were added -butyl (Boc2O, 406 mg) and 10% palladium-carbon (200 mg) to a mixed solution of tert-butanol (40 mL) and DMF (20 mL) and stirred at room temperature for 15 hours under an atmosphere of hydrogen (1 atm). The reaction liquid was filtered and the filtrate was concentrated under pressure reduced. Upon purification of the residue by silica gel column chromatography (hexane: ethyl acetate, 8: 1 to 4: 6), it was obtained in the form of a solid. { 3- (cyclohexylamino) -4 - [(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) carbamoyl] benzyl} tert-butyl carbamate (453 mg). EXAMPLE 103 10% palladium-carbon (50 mg) was added to an ethanol solution (20 mL) of 4-chloro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7). -l) -2-. { [1- (pyrroline-1-ylmethyl) cyclohexyl] amino} benzamide (500 mg), followed by stirring at room temperature for 21 days under a hydrogen atmosphere. The reaction liquid was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane: ethyl acetate, 7: 3 to 1: 1). When treating the resulting free base with an aqueous solution of hydrobromic acid, it was obtained in the form of a solid N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -bibromohydrate. 2-. { [1 - (pyrrolidin-1-methylmethyl) cyclohexyl] amino} benzamide. Example 104 A solution of 4M Hydrogen chloride / ethyl acetate (3 mL) was added to methyl [(1 S, 2S) -2- (. {2 - [(1-methyl-2-oxo-1, 2 3,4-tetrahydroquinolin-7-yl) carbamoyl] -5- (trifluoromethyl) phenyl} amino) cyclohexyl] tert-butyl carbamate (1.17 mg), followed by stirring at room temperature during 24 hours to obtain 2- hydrochloride. { [(1S, 2S) -2- (methylamino) cyclohexyl] amino} -N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -4- (trifluoromethyl) phenyl} benzamide (1.04 g) in an amorphous form. Example 105 1M Hydrochloric acid (0.37 mL) was added to a solution of ethanol (1.5 mL) of N- [1 - (2. {[[Tert-butyl (dimethyl) silyl] oxy] ethyl) -2- oxo-1,2,3,4-tetrahydroquinolin-7-yl] -2- (cyclohexylamino) -4- (trifluoromethyl) benzamide (220 mg), followed by stirring at room temperature for 5 hours. The reaction liquid was concentrated under reduced pressure, and an aqueous solution of sodium bicarbonate was added to the residue, followed by extraction with ethyl acetate. After drying the organic layer with sodium sulfate, the solution was concentrated under reduced pressure. Upon purification of the residue by silica gel column chromatography (hexane: ethyl acetate, 2: 1 to 2: 3), it was obtained in the form of a solid 2- (cyclohexylamino) -N- [1- (2- hydroxyethyl) -2-oxo-1,2,3,4-tetrahydroquinolin-7-yl] -4- (trifluoromethyl) benzamide (148 mg). Example 106 HATU (176 mg) was added to a solution of dichloroethane (5 mL) of 4-chloro-2- acid. { [(1 R, 2S) -2-pyrrolidin-1-ylcyclohexyl] amine} benzoic acid (150 mg) and triethylamine (94 mg). After 30 minutes of stirring at room temperature, (2R) -6-amino-2-methyl-2H-1,4-benzoxazin-3 was added thereto. (4H) -one (91 mg). After stirring overnight at room temperature, this was stirred for 3 hours under heating at reflux temperature. The reaction liquid was concentrated under reduced pressure, an aqueous 1M sodium hydroxide solution was added, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: methanol, 1: 0 to 85:15). By treating the resulting free base with 4M hydrogen chloride / ethyl acetate, 4-chloro-N - [(2R) -2-methyl-3-oxo-3,4-dihydro-2H hydrochloride was obtained as an amorphous form. -benzoxazin-6-yl] -2-. { [(1 R, 2S) -2-pyrrolidin-1-ylcyclohexyl] amine} benzamida (100 mg). Example 107 HATU (343 mg) was added to a solution of DMF (5 mL) of 2- acid. { [(1 S, 2 S) -2-pyrrolidin-1-ylcyclohexyl] amino} -4- (trifluoromethyl) benzoic acid (322 mg). After stirring at room temperature for 30 minutes, 6-amino-4- (trifluoromethyl) -1,3-dihydro-2H-indol-2-one (150 mg) was added. After further stirring at a temperature of 60 ° C for 12 hours, the reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia, 1: 0: 0 to 90: 9: 1) and then again purified by silica gel column chromatography (basic silica gel, hexane: ethyl acetate, 1: 0 to 7: 3). By treating the free base Resulting with a 4M solution of hydrogen chloride / ethyl acetate, N- [2-oxo-4- (trifluoromethyl) -2,3-dihydrogen-1H-n-dol-6 hydrochloride was obtained as an amorphous form. -il] -2-. { [(1S, 2S) -2-pyrroline-1-ylcyclohexyl] amino} -4- (trifluoromethyl) benzamide (179 mg). Example 108 An aqueous solution of formaldehyde (36%, 0.12 mL) and sodium triacetoxyborohydride (236 mg) was added to a THF solution (4 mL) of 2-. { [(1S, 2S) -2-aminocyclohexyl] amino} -N- (2-met-1-1,3-benzothiazol-5-yl) -4- (tpfluorometl) benza mide (200 mg). After stirring at room temperature for 30 minutes, the reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia, 1: 0: 0 to 90: 9: 1). When treating the resulting free base with a 4M solution of hydrogen chloride / ethyl acetate, an amorphous form of 2- was obtained as an amorphous form. { [(1S, 2S) -2- (dimethylamino) cyclohexyl] amino} -N- (2-methyl-1,3-benzothiazol-5-yl) -4- (trifluoromethyl) benzamide (214 mg). Example 109 Sodium triacetoxyborohydride (138 mg) was added to a solution of dichloroethane (20 mL) of 2-. { [(1S, 2S) -2-aminocyclohexyl] amino} -N- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -4- (trifluoromethyl) benzamide (200 mg), cyclopentanone (40 mg) and acid acetic acid (29 mg), followed by stirring at room temperature for 1 day. Acetic acid (260 mg), cyclopentanone (140 mg) and sodium triacetoxyborohydride (140 mg) were added to the reaction liquid, followed by stirring for 1 day. An aqueous solution of 1M sodium hydroxide was added to the reaction liquid, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol, 1: 0 to 85:15). When treating the resulting free base with 4M hydrogen chloride / ethyl acetate, it was obtained in the form of a solid 2- hydrochloride. { [(1S, 2S) -2- (cyclopentylamino) cyclohexyl] amino} -N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -4- (trifluoromethyl) benzamide (53 mg). Example 110 Cyclohexanone (65 mg) was added to an ethanol solution (20 mL) of 2-. { [(1S, 2S) -2-aminocyclohexyl] amino} -N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -4- (trifluoromethyl) benzamide (255 mg), followed by stirring at room temperature for 7 hours. The reaction liquid, sodium borohydride (25 mg) was added, followed by stirring for 1 day, and then sodium borohydride (41 mg) was added, followed by stirring for 2 hours. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: methanol, 1: 0 to 85:15). On treating the resulting free base with 4M hydrogen chloride / ethyl acetate (1.0 ml), it was obtained in the form of a white solid 2- hydrochloride. { [(1S, 2S) -2- (cyclohexylamino) cyclohexyl] amino} -N- (3,3-dimethyl-2-oxo-2,3-dihydro-1 H -indol-6-yl) -4- (trifluoromethyl) benzamide (51 mg). Example 111 A mixture of 2-. { [(1S, 2S) -2-aminocyclohexyl] amino} -N- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -4- (trifluoromethyl) benzamide (207 mg), 2-iodopropane (114 mg), Sodium carbonate (71 mg) and acetonitrile (2 mL) was stirred under microwave irradiation at a temperature of 120 ° C for 30 minutes and further stirred at a temperature of 150 ° C for 30 minutes. Water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol, 1: 0 to 85:15). When treating the resulting free base with 4M hydrogen chloride / ethyl acetate (1.0 ml), N- (3,3-dimethyl-2-oxo-2,3-dihydro hydrochloride was obtained in the form of a white solid. -1H-indol-6-yl) -2-. { [(1S, 2S) -2- (isopropyl) cyclohexyl] amino} -4- (trifluoromethyl) benzamide (140 mg). Example 112 2- Acid was stirred. { [(1 R, 2S) -2-Pyrrolidin-1 - ilcyclohexyl] amino} -4- (trifluoromethyl) benzoic acid (150 mg), quinolin-7-amine (67 mg), 1-ethyl-3- [3- (N, N-dimethylamino) propyl] carbodiimide hydrochloride (121 mg) and 1- Hydroxybenzotriazole (57 mg) at a temperature of 110 ° C for 15 minutes in N-methylpyrrolidone under microwave irradiation. An aqueous solution of potassium carbonate was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane: ethyl acetate, 7: 3 to 1: 1). On treating the resulting free base with 4M hydrogen chloride / ethyl acetate, an amorphous form of 2- dihydrochloride was obtained. { [(1 R, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} -N-quinolin-7-yl-4- (trifluoromethyl) benzamide (66 mg). Example 113 A mixture of 2- (cyclohexylamino) -6-fluoro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) nichotinamide (150 mg), piperidine (64 mg ), potassium carbonate (63 mg) and DMF was stirred at a temperature of 60 ° C for 18 hours. Subsequently, water was added, followed by extraction with ethyl acetate. After drying the organic layer with magnesium sulfate, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane: ethyl acetate, 2: 1 to 1: 1) to obtain 2- (cyclohexylamino) -N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl) -6-piperidin-1-ylnicotinamide 8138 mg) in the form of a solid. Example 114 A mixture of acid [7-. { [2- (cyclohexylamino) -4- (trifluoromethyl) benzoyl] amino} -2-oxo-3,4-dihydroquinoline-1 (2H) -yl] acetic acid (70 mg), N, N'-carbonyldiimidazole (70 mg), aqueous methylamine solution (1 mL) and THF, was stirred at room temperature for 3 hours, it was mixed with methanol and stirred for 20 minutes. 0.5M hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol, 20: 1 to 10: 1) to obtain 2- (cyclohexylamino) -N-. { 1- [2- (methylamino) -2-oxoethyl] -2-oxo-1, 2,3,4-tetrahydroquinolin-7-yl} -4- (trifluoromethyl) benzamide (12 mg) in the form of a solid. Examples 115 to 430 In the same manner as in the methods of Examples 1 to 5 and 95 to 114, the compounds of Examples 115 to 430 shown in Tables 26 to 51, which are described below, were produced using respectively corresponding materials . The structures and physicochemical data of the compounds of Examples 95 to 430 are shown in Tables 26 to 51.

In relation to this, between the amine compounds of material used in the amidation reaction described in the aforementioned Examples 1, 2, 98, 99, 106, 107 and 112 and in the production methods of the compounds of the Example which found in the following tables carried out with reference to their production methods, particularly those not described in the aforementioned Reference Examples, are commercially available or can be easily produced by the method described in the publication WO 2004/110986 and similar. In addition, 6-amino-3,3-dimethyl-1,3-dihydro-2H-indol-2-one was produced by the method described in the publication Eur. Pat. Appl., 161632, Nov. 21, 1985. Likewise, the structures of other compounds of the present invention are shown in Tables 52 to 54. These can be easily synthesized through the aforementioned production methods and methods described. in the examples, and methods that are obvious to those skilled in the art, or modified methods thereof. Next, where a symbol * is attached to the asymmetric carbon atom in the structures of the compounds in the tables, it means that said carbon atom has a simple absolute configuration. In the column "Syn" with respect to the production methods found in the tables that are found then, the compounds having different salt formation steps, ie, salt forms, although they are produced through the same type of reactions, were named with the same example number. The internal conversion between a free compound and its salt is a common technical sense of those skilled in the art.

Table 1 Table 2 Table 3 [Table 4] Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28 Table 29 Table 30 Table 31 Table 32 Table 33 Table 34 Table 35 Table 36 Table 37 Table 38 Table 39 Table 40 Table 41 Table 42 Table 43 Table 44 Table 45 Table 46 Table 47 Table 48 Table 49 Table 50 Table 51 Table 52 Table 53 Table 54 (Test Examples) The pharmacological activities of the compounds of the active ingredients of the pharmaceutical preparations of the present invention were confirmed by the following tests. 1. Receptor binding assay using the cell stably expressing VR1. 1) Human cell construction that stably expresses VR1. A full-length cDNA coding of human VR1 was obtained through the following method. First, a first strand cDNA was synthesized by performing reverse transcription of human brain mRNA using reverse transcriptase. Subsequently, PCR was carried out using the Hot Star method using the first-strand cDNA as the template and using Taq DNA polymerase. In the aforementioned PCR, an oligonucleotide consisting of the nucleotide sequence of 424 ° to 443 ° of a conventionally known human VR1 cDNA sequence (Genbank AJ277028.1) as the sense primer, and an oligonucleotide consisting of a chain sequence complementary to the nucleotide sequence from 3082 ° to 3100 ° as the antisense primer, and thermal denaturation was first carried out at a temperature of 98 ° C (1 minute) and subsequently a cycle that was repeated 35 times was repeated. consists in a temperature of 98 ° C (15 seconds) / 63 ° C (30 seconds) / 72 ° C (3 minutes). The cloning of the DNA fragment amplified in this way was carried out using the pCR-XL-TOPO vector (TOPO XL PCR Cloning Kit, Invitrogen, USA). The human VRI-cDNA was only isolated by digesting the resulting plasmid DNA in an EcoRI restriction enzyme, and subsequently it was integrated into the plasmid pcDNA3.1 (+) (Invitrogen, USA). In this case, the above genetic engineering operations were carried out by conventionally known methods (Sambrook, J. and associates, "Molecular Cloning - A Laboratory Manual", Cold Spring Harbor Laboratory Press, NY, 2001) and in accordance with the instructions attached to the respective reagents. Subsequently, the resulting pcDNA3.1-VR1 was transferred into the HEK 293 cell. When selecting the VR1 / HEK 293 cells using the DMEM medium (Invitrogen, USA) containing 10% FBS, 100 μg / ml streptomycin, 100 U / ml of penicillin and 400 μg / ml of G 418, a strain of the cell stably expressing the receptor was prepared. The cell that stably expresses the receptor was subcultured in the medium described above. 2) Preparation of a membrane sample The VR1 / HEK 293 cell described above was mass produced on a plate, and subsequently, after discarding the medium, it was scraped after adding PBS cooled with ice. Centrifugation was carried out at 1000 rpm and at a temperature of 4 ° C for 10 minutes, and the resulting residue was homogenized by adding a homogenization buffer (25 mM Tris-HCl, 220 mM sucrose, pH 7.4) and centrifuged at 2200 rpm at a temperature of 4 ° C for 10 minutes. The resulting supernatant was centrifuged at 30,000 xg at a temperature of 4 ° C for 20 minutes, and the resulting residue was mixed with 25 mM Tris-HCl, pH 7.4 and centrifuged at 30,000 xg and a temperature of 4 ° C for 20 minutes, and this operation was repeated twice. The resulting residue was suspended in 25 mM Tris-HCl, pH 7.4, and the protein concentration was determined using a protein assay staining solution (Bio-Rad, USA). The membrane sample prepared in this way was stored at a temperature of -80 ° C. 3) Receptor binding assay This was carried out by modifying the method of [Neurosci., 57: 747-757 (1993)]. The assay buffer, 25 mM Tris-HCl, 0.025% BSA, pH 7.4 was used. Each test compound, [3 H] RTX 50 μl (approximately 50,000 dpm; Perkin Elmer Life Science, USA) and the aforementioned membrane sample (protein amount of approximately 25 μg) were suspended in a microplate at a total volume of 300 μl, incubated at a temperature of 37 ° C for 60 minutes and subsequently, it was incubated on ice for 10 minutes. A 200 μg / 50 μl portion of an ice-cold ai glycoprotein (AGP, Sigma) was added and incubated further for 5 minutes. The whole incubation was carried out by rapid filtration of the reaction liquid using a GF / B filter (Perkin Elmer Life Science, USA). After washing 7 times with 25 mM ice-cold Tris-HCl buffer (pH 7.4), the radioactivity of the filter was measured through a liquid scintillation counter. With respect to the specific binding, a substituted part was considered through 1 μM of RTX between the total binding of [3 H] RTX with the fraction of the membrane of the cell that stably expresses the VR1 receptor, as the specific binding originated from the receiver VR1. The evaluation of the test compounds was carried out in the following manner. That is, the reduced amount of the link at the time of the addition of each compound was calculated as a relative value when the reduced amount of the link at the time of RTX addition was considered as 100%. Subsequently, the IC50 value was calculated through the Logistic regression method. The compounds of the present invention proved to have good activity. The inhibition activity of the VR1 receptor binding of the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention is exemplified in the following parentheses. The value is an IC50 value shown by μM. Example number (IC50 value, μM): 1 (0.012), 17 (0.0058), 105 (0.0042), 106 (0.052), 107 (0.013), 108 (0.019), 119 (0.045), 170 (0.0026), 173 (0.0056), 176 (0.0089), 178 (0.062), 248 (0.031), 307 (0.0098), 321 (0.025), 327 (0.0037), 334 (0.023), 335 (0.087), 367 (0.015), 386 (0.018), 400 (0.06). In addition, the compounds of Examples 2, 5 to 12, 15 to 21, 23 and 24, 26 to 34, 36 to 50, 52 to 58, 60 and 61, 63 to 66, 68 to 71 and 73 to 94 showed values IC50 of 5 μM or less. It was confirmed through this assay that the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention have the affinity of the VR1 receptor. 2. Inhibition of inhibitory activity in electric current induced by capsaicin using a cell stably expressing VR1. The HEK 293 cells expressing the VR1 receptor prepared in the aforementioned Test Example 1 were inoculated on a cover glass coated with poly i-D-lysine at a density of 1 to 1.5 x 10 4 cells / cm 2. This was allowed to settle even in a CO2 incubator (37 ° C, 5% CO2) and was used in this test after a lapse of 3 to 15 hours. Upon complete registration the cell patch attachment of the HEK 293 cells that expressed the VR1 receptor under a condition subject to voltage, the current response induced by topical application of capsaicin (1 μM) to the surroundings of the cells. The test compounds were dissolved in an extracellular liquid and applied to a chamber by multiple barrel. The composition (mM) of the extracellular solution adjusted to NaCl 145, CsCl 5, CaCl 2 1, MgCl 2 1, HEPES 10 and glucose 10 [pH = 7.3]. The composition (mM) of the intracellular solution was adjusted to CsCl 120, MgCl 2 2, HEPES 10, BAPTA 10, Na 2 GTP 0.2, Mg ATP 4 and phosphorocreatin Na 2 4 [pH = 7.2]. By defining the capsaicin current response in the absence of the test compound as 100% and continuously applying each test compound starting from the lowest concentration, the range of inhibition of each concentration was measured. The IC50 value was calculated by non-linear programming method from the respective inhibition range. As a result, the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention showed good inhibitory action. For example, the IC50 value of the compound of Example 107 was 8.8 nM. Through this test, it was confirmed that the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention, have the action of inhibiting the activation of the VR1 receptor. 3. Capsaicin test The inhibitory action on the pain behavior of the compounds in the form of the active ingredients was evaluated of the pharmaceutical preparations of the present invention, according to the method described in a reference document [Neuropharmacol., 31: 1279-1285 (1992)]. That is, when 1.6 μg of capsaicin was administered to the plant of a mouse (ddY, male, 4 to 5 weeks of age), this induces a licking behavior of the paw. The action of suppression of pain behavior was evaluated by measuring the time of expression of the licking behavior of the paw during 5 minutes after the administration. Each test compound was administered orally 45 minutes before the administration of capsaicin. The evaluation of the test compounds was carried out by calculating each range of inhibition of the administration group of the test compound, when the time of expression of the licking behavior of the leg of the group with administration of the vehicle, was considered as 100% . As a result, the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention showed a strong inhibitory action of the pain behavior at the moment of their oral administration. The range of inhibition after oral administration of the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention, are exemplified by the following parentheses. Example number (inhibition range): 1 (45%), 17 (54%), 54 (34%), 73 (95%), 107 (53%), 179 (58%), 238 (51%), 261 (56%), 282 (64%), 288 (44%), 321 (67 %), 334 (58%), 335 (49%), 347 (57%). Based on the above results, it was shown that the compounds in the forms of the active ingredients of the pharmaceutical preparations of the present invention have a good inhibitory action on the pain behavior, based on the action to inhibit the activation of the receptor. VR1. 4. Test of spinal nerve ligation model The inhibitory action on the pain behavior of the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention was evaluated, according to the method described in a reference publication [Pain, 50: 355-363 (1992)]. Under pentobarbital anesthesia, an incision was made in the skin and lumbar muscle of a rat (SD, male, 5 to 6 weeks of age) and the lumbar nerve was exposed, eliminating the transverse process of the lumbar vertebra L 6. Spinal nerves L 5 and L 6 were ligated with a seam and then the wound was sutured. The treatment was applied to the left side. The evaluation of the effect of the drug was carried out 7 to 15 days after the operation. The pain threshold value for the mechanical stimulus was reviewed through the Frey hair test (VFH). The minimum strength of Hair's (unit: gram) that shows the evasion reaction when stimulates a plant, was converted with logarithm and used as the pain threshold value for mechanical stimulation. Anticipated individuals who had a decreased pain threshold value were selected through the VFH test the day before the evaluation of the effect of the drug and divided into groups, so that the difference in the average threshold value between the respective groups was small. The test compounds were administered orally 60 minutes before the evaluation of the effect of the drug. The evaluation of the test compounds was carried out by calculating each range of improvement of the administration group of the test compound when the threshold value of the leg of the operation side in the group with vehicle administration was considered 0% , and the threshold value of the leg of the side that did not have the operation in this group was considered as 100%. As a result, it was confirmed that the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention show a strong suppressive action on the pain behavior, also in this test. For example, the compound of Example 107 and the compound of Example 347 completely restored the threshold value of the leg from the operation side to the threshold value range of the leg of the non-operating side after the oral administration. As the result of Test Examples 1 and 2, it was revealed that the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention have a good inhibitory action on the activation of the VR1 receptor. In addition, based on the result of Test Examples 3 and 4, it was revealed that the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention have a remarkable action of pain suppression. Accordingly, the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention are useful as agents for treating or preventing diseases wherein the VR1 receptor is involved, ie neuroic pains (e.g., posterplegic neuralgia, neuroy). diabetic and the like), nociceptive pain (e.g., joint pain, postoperative pain, sword pain and the like), headaches (e.g., migraine, cluster headache and the like), pain from cancer, fibromyalgia, or functional disorders of the bladder (for example, overactive bladder, urinary incontinence, neurogenic bladder, nocturia, painful bladder syndrome, interstitial cystitis, chronic nonbacterial prostatitis and the like), or bladder dysfunction accompanied by prostatic hypertrophy. In addition, these are also useful as agents to treat or prevent itching, toothache, asthma, disease chronic obstructive pulmonary, cough, inflammatory bowel disease and irritable bowel syndrome. The pharmaceutical preparation comprising the compound (I) or a salt thereof in the form of the active ingredient, is prepared using carriers, fillers and other additive agents generally used in the preparation of the pharmaceutical preparations. The administration can be either oral administration by tablets, pills, capsules, granules, powders, solutions and the like or parenteral administration by injections for intravenous injection, intramuscular injection and the like, suppositories, transdermal preparations, transnasal preparations, inhalations and the like. The dose is decided optionally in response to individual cases, taking into consideration the symptoms, age, sex and the like of the objects that will be administered, although in the case of oral administration, it is approximately 0.001 mg / kg to 100 mg / kg per day per adult, and this is administered once a day or dividing 2 to 4 times. Also, when administered intravenously depending on the symptoms, it is administered one to two times or more per day, within a generally range of 0.0001 mg / kg to 10 mg / kg per time, per adult. In addition, in the case of inhalation, it is administered once to twice or more per day within a range generally of 0.0001 mg / kg to 1 mg / kg per time, per adult. The form of the solid composition for oral administration of the present invention is used in tablets, powders, granules and the like. In said solid compositions, one or more active substances are mixed with at least one inert filler, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyinyl pyrrolidone, magnesium aluminum silicate or the like. According to the usual manner, the composition may contain inert additives such as lubricants (e.g., magnesium stearate and the like), disintegrants (e.g., sodium carboxymethylstarch and the like) and solubilizing agents. As the occasion demands, the tablets or pills may be coated with a sugar coating or a gastric or enteric coating agent. In the form of the liquid composition for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like are included, and inert diluents such as purified water, ethanol and the like are generally used. In addition to the inert diluents, this composition may contain auxiliary agents such as solubilizing agents, wetting agents, suspending agents and the like, sweeteners, corrective, aromatic and antiseptic. In the form of injections for administration parenteral, sterile aqueous or non-aqueous solutions, suspensions and emulsions are included. In the form of an aqueous solvent, for example, distilled water for injection and physiological saline is included. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oil (for example, olive oil or the like), ethanol or similar alcohols, polysorbate 80 (name in Pharmacopoeia) and the like. Said composition may further contain antiseptic tonicity agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agents and solubilizing agents. These are sterilized, for example, by filtration through a filter that retains bacteria, bactericidal formulation or irradiation. In addition, these can also be used by producing sterile solid compositions by dissolving or suspending them in sterile water or a sterile solvent for injection before use. Transmucosal preparations such as inhalations, transnasal preparations and the like are used in the form of a solid, liquid or semi-solid, and can be produced according to conventionally known methods. For example, excipients such as lactose, starch and the like can also be added as well as pH adjusting agents, antiseptics, surfactants, lubricants, stabilizers, thickeners and the like. A suitable apparatus for inhalation or blowing can be used for administration.

For example, a compound may be administered as such or in the form of a formulated mixing powder, or as a solution or suspension in combination with a medically acceptable carrier, using a conventionally known apparatus, such as a metered administration inhalation apparatus. or similar, or a sprinkler. The dry powder inhaler or the like may be for use in single or multiple administration, and a dry powder or capsule containing powder may be used. Alternatively, it may be in the form of a pressurized aerosol spray or the like, which utilizes a suitable propellant such as chlorofluoroalkane, hydroxyfluoroalkane, carbon dioxide or a similar suitable gas. In the preparation of suppositories, a low melting point wax, such as a mixture of fatty acid glyceride or cocoa butter, melts, and the active ingredient is added thereto and uniformly dispersed by stirring. Subsequently, this is injected into a suitable mold and cooled to effect solidification. Preparations in the form of liquids include a solution, a suspension, a storage enema and an emulsion, such as water or an aqueous solution of propylene glycol. INDUSTRIAL APPLICABILITY Since the compounds in the form of the active ingredients of the pharmaceutical preparations of the present invention, have a strong action to inhibit the activation of the VR1 receptor of capsaicin and good pharmacological actions based on this, the pharmaceutical compositions of the present invention are useful as agents for treating or preventing diseases wherein VR1 is involved, such as diseases in where VR1 is involved, particularly, nociceptive pain, neuropathic pain, cancer pain, headache, bladder function disorder and the like.

Claims (15)

1. CLAIMS 1. An inhibitor of VR1 activation comprising a 2-aminobenzamide derivative represented by the following general formula (I) or a salt thereof in the form of an active ingredient (The symbols in the formula have the following meanings: benzene ring or pyridine ring, R, 3. : the same or different from each other and each represents H, halogen, halogen-lower alkyl, cyano, nitro, lower alkyl. -NR4R5, -lower-alkylene-NR4R5, -lower-alkylene-NR6-CO2-lower alkyl, -O-lower alkyl, -O-halogeno-lower alkyl, phenyl or thienyl, m: 1, 2 or 3, R4 and R5: equal or different from each other and each represents H or lower alkyl, wherein R4 and R5 can be combined with the adjacent nitrogen atom to form a saturated monocyclic nitrogen-containing hetero ring, which can be substituted with a lower alkyl or an alkylene lower-OH, R6: H or lower alkyl, : monocyclic ring, cycloalkene or benzene ring, wherein the ring represented by A can be substituted with 1 to 4 groups selected from -OH, -lower-alkylene-NR-R5, -lower-alkylene-CO-NR4R5, halogen, lower halogen-alkyl , lower alkyl and oxy, R1: lower alkyl, -L-cycloalkyl, -L-cycloalkenyl, saturated hetero ring-L-monocyclic containing oxygen, saturated hetero ring-L-monocyclic containing nitrogen, saturated hetero ring containing nitrogen type L-bridged, -L-phenyl or -L-pyridyl, with the provision that since the type of ring A when R1 is lower alkyl, it means a ring forming indoline, tetrahydroquinoline or 3,4-dihydro-2H-1 , 4-benzoxazine together with the benzene ring for which it is condensed, wherein the lower alkyl of R1 can be substituted with 1 to 3 groups selected from the groups shown in the following group G, and the cycloalkyl, cycloalkenyl, hetero ring saturated monocyclic Oxygen-containing, monocyclic saturated ring containing nitrogen, phenyl and pyridyl of R1 may be substituted with from 1 to 5 groups selected from groups shown in the following group G, and lower alkyl which may be substituted by a group shown in Group G, Group G: -O-lower alkyl, -OH, oxo, -S (O) p-alkyl lower, -NR4R5, -NR6-CO2-lower alkyl, -NR6-SO2-lower alkyl, -N + (lower alkyl) 3, -CO2-lower alkyl, -CO-NR4R5, halogen, phenyl, cycloalkyl, -O- lower alkylene-phenyl, -NR6-cycloalkyl and saturated monocyclic oxygen-containing hetero ring, p: 0, 1 or 2, L: lower alkylene or bond, R2: same or different from each other and each represents H, lower alkyl, halogen , halogen-lower alkyl or -OH, and n: 1 or 2).
2. 2. The VR1 activation inhibitor comprising a 2-aminobenzamide derivative or salt thereof in the form of the active ingredient as described in claim 1, characterized in that A is a monocyclic hetero ring containing nitrogen, wherein the The ring group has an oxo group or a hydroxyl group as the substituent group and can be further substituted with 1 2 groups selected from lower alkylene-OH, lower alkylene-NR4R5, lower alkylene-CO-NR4R5, halogen, lower alkyl-halogen and lower alkyl.
3. 3. A 2-aminobenzamide derivative represented by the following general formula (I ') or a salt thereof (The symbols in the formula have the following meanings: X and W: one is N and the other is CH, or both are CH, R3a and R3b: equal or different from each other and each represents H, halogen, halogen-alkyl lower, cyano, nitro, lower alkyl, -NR4R5, -lower-alkylene-NR4R5, -alkylene-lower-NR6-CO2-lower alkyl, -O-lower alkyl, -O-halogen-lower alkyl, phenyl or thienyl, R4 and R5: same or different from each other and each represents H or lower alkyl, wherein R4 and R5 can be combined with the adjacent nitrogen atom to form a saturated monocyclic nitrogen-containing hetero ring, which can be substituted with lower alkyl or lower alkylene-OH, R6: H or lower alkyl, hetero ring monocyclic, cycloalkene or benzene ring, wherein the ring represented by A can be substituted with 1 to 4 groups selected from -OH, -lower-alkylene-NR4R5, -lower-alkylene-CO-N R4R5, halogen, halogen- lower alkyl, lower alkyl and oxo, R1: lower alkyl, cycloalkyl, cycloalkenyl, monocyclic saturated ring heterocyclic oxygen, monocyclic saturated ring heterocyclic nitrogen, phenyl or pyridyl, with the proviso that, in the ring type When R1 is lower alkyl, it means a ring forming indoline, tetrahydroquinoline or 3,4-dihydro-2H-1,4-benzoxazine together with the benzene ring for which it is condensed, wherein the lower alkyl of R1 may be substituted with 1 to 3 groups selected from the groups shown in the following group G, and the cycloalkyl, cycloalkenyl, monocyclic saturated ring heterocyclic oxygen containing, monocyclic saturated ring heterocyclic nitrogen, phenyl and pyridyl of R 1 can be substituted with 1 to 5 groups selected from groups shown in the following group G, and lower alkyl which may be substituted by a group shown in group G, group G: -O-alkyl lower, -OH, oxo, -S (O) p-lower alkyl, -NR4R5, -NR6-CO2-lower alkyl, -NR6-SO2-lower alkyl, -N + (lower alkyl) 3, -CO2-lower alkyl , -CO-NR4R5, halogen, phenyl, cycloalkyl, -O-lower alkylene-phenyl, -NR6-cycloalkyl and monocyclic saturated ring heterocyclic containing oxygen, p: 0, 1 or 2, R2: equal or different from each other and each represents H, lower alkyl, halogen, halogen-lower alkyl or -OH, and n 1 or 2) 4 The derivative of a salt thereof as described in claim 3, characterized in that X is N or CH, W is CH, and A is a monocyclic ring containing nitrogen, wherein the ring group it has an oxo group or a hydroxy group as the substituent group and can be further substituted with 1 or 2 groups selected from alkylene-OH-ester, alkylene-nfer-or-NR4R5, alkylene-9-NR4R5, halogen, lower alkyl-halogen and lower alkyl The derivative of a salt thereof as described in claim 4, characterized in that the type of ring A is a ring forming indohna, tetrahydroquinolma or 3,4-d? h? dro-2H-1, 4-benzoxazine together with the benzene ring to which is condensed 6 The derivative of a salt thereof as described in claim 5, characterized in that R 1 is a ring group selected from cycloalkyl, cycloalkenyl, saturated hetero ring monocyclic containing oxygen and hetero ring s nitrogen-containing monocyclic atom, which can be substituted with 1 to 5 groups selected from the groups shown through the group G and lower alkyl, which can be substituted with the groups shown through the group G 7 The derivative of a salt of the same as described in claim 6, characterized in that R1 is a ring group selected from cycloalkyl, dioxolanyl and piperidyl, which can be substituted with lower alkyl, -NR4R5 or cycloalkyl. 8. The salt derivative thereof as described in claim 4, characterized in that R1 is a ring group selected from cycloalkyl, cycloalkenyl, monocyclic saturated ring heterocyclic containing oxygen, monocyclic saturated ring heterocyclic nitrogen, phenyl and pyridyl, which can be substituted with 1 to 5 groups selected from the group shown through the group G and lower alkyl which can be substituted with groups shown in group G. 9. The derivative of a salt thereof as described in claim 8, characterized in that R1 is a ring group selected from cycloalkyl, dioxolanyl and piperidyl, which can be substituted with lower alkyl, -NR4R5 or cycloalkyl. 10. The derivative described in claim 3 or a pharmaceutically acceptable salt thereof is selected from the group consisting of 4-chloro-N- (1-methyl-2-oxo-1, 2,3,4-tetrahydroquinolin-7) il) -2-. { [(1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} benzamide, 2- (cyclohexylamino) -N- (2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl) -4- (trifluoromethyl) benzamide, 4-chloro-N - [(2R) -2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl] -2-. { [(1R, 2S) -2-p¡rrol¡din-1- ilcyclohexyl] amino} benzamide, N- [2-oxo-4- (trifluoromethyl) -2,3-dihydro-1H-indol-6-yl] -2-. { [(1S, 2S) -2-pyrrolidin-1-ylcclohexyl] amino} -4- (trifluoromethyl) benzamide, N- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl) -2- (pyridin-4-ylamino) -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H indol-6-yl) -2-. { [(1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H indol-6-yl) -2-. { [(1 R, 2R) -2-pyrrolidin-1-cyclohexyl] amino} -4- (trifluoromethyl) benzamide, 2-. { [(1 R, 2R) -2 (dimethylamino) cyclohexyl] amino} -N - [(2R) -2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl] -4- (trifluoromethyl) benzamide, 2-. { [(1S, 2S) -2- (dimethylamino) cyclohexyl] amino} -N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2 - [(1-isobutylpiperidin-4-yl) amino] -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3) -hydro-1H-indol-6-yl) -2-. { [(3S) -1-pentylpyrrolidin-3-yl] amino} -4- (trifluoromethyl) benzamide, N- (2-oxo-1,2-dihydroquinolin-7-yl) -2-. { [(1R, 2R) -2-pyrrolidin-1-ylcyclohexyl] amino} -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-. { [(3S) -1-pentylpyrrolidin-3-yl] amino} -4- (trifluoromethyl) benzamide, 2 - [(1-butylpiperidin-4-yl) amino] -N- (3, 3-dimethyl-2-0X0-2, 3-dihydro-1-H-indole-6- il) -4- (trifluoromethyl) benzamide, N- (3,3-dimethyl-2-oxo-2,3-dihydro-1H indol-6-yl) -2-. { [(1S, 2R) -2-pyrrolidin-1-ylcyclohexyl] amino} -4- (trifluoromethyl) benzamide, 2-. { [(1 S, 2 R) -2-pi rrolid in- 1 ilcyclohexyl] amino} -N-quinolin-7-yl-4- (trifluoromethyl) benzamide, 2-. { [(1S, 2S) -2-pyrrolidin-1-ylcyclohexyl] amino} -N-quinolin-7-yl-4- (trifluoromethyl) benzamide, and N- [2-oxo-4- (trifluoromethyl) -2,3-dihydro-1H-indol-6-yl] -2-. { [(1S, 2R) -2-pyrrolidin-1-ylcyclohexyl] amino} -6- (trifluoromethyl) nicotinamide. 11. A pharmaceutical composition comprising the derivative described in claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 12. The pharmaceutical composition as described in claim 11, characterized in that it is an inhibitor of VR1 activation. 13. The pharmaceutical composition as described in claim 11, characterized in that it is an agent for treating or preventing nociceptive pain, neuropathic pain, pain from cancer, headache and bladder function disorder. 14. The use of the derivative as described in claim 3 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for treating or preventing nociceptive pain, neuropathic pain, cancer pain, headache and dysfunction of the bladder. 15. A method for treating or preventing nociceptive pain, neuropathic pain, pain from cancer, headache and bladder function disorder, characterized in that it comprises administering a therapeutically effective amount of the derivative described in claim 2 or a pharmaceutically acceptable salt thereof to the patient.