MXPA00009438A - Amide derivatives and nociceptin antagonists - Google Patents

Abstract

Compounds represented by general formula (1') and nociceptin antagonists containing the compounds [1']as the active ingredient wherein R2 represents optionally hydroxylated lower alkyl, amino, etc.;the ring B represents phenyl, thienyl, etc.;E represents a single bond, -O-, -S-, etc.;the ring G represents aryl, a heterocycle, etc.;R5 represents halogeno, hydroxy, lower alkyl optionally substituted by, for example, halogeno, etc.;t is 0 or an integer of from 1 to 5, provided that when t is 2 to 5, then R5s may be the same or different;m is 0 or an integer of from 1 to 8;and n is 0 or an integer of from 1 to 4. The compounds [1']exert an analgetic effect on serious pains such as postoperative pain via a nociceptin inhibitory action. Utilization of specific amide derivatives including the compounds [1']as nociceptin antagonists or analgetic agents.

Description

AMID DERIVATIVE AND NOCICEPTINE ANTAGONIST TECHNICAL FIELD The present invention relates to a nociceptin antagonist containing a new amide derivative or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to an analgesic containing, as an active ingredient, a new amide derivative or a pharmaceutically acceptable salt thereof, which exhibits an analgesic effect such as the nociceptin antagonist by selectively acting on an opioid receptor. similar to receptor 1 and which are useful for the treatment of pain, particularly acute pains or pains caused by a nervous-sensory abnormality, such as a hyperalgesia and allodynia. The present invention is further related to the novel use of a certain class of amide derivative as an antagonist of nociceptin and analgesic.

ANTECEDENTS OF THE TECHNIQUE Pain is a sensation felt by anyone and is an important vital sign or an alarm signal. The pain caused by wounds, surgeries, inflammations and the like, as well as the chronic pain that arises from wounds, dysfunctions and nerves after the recovery of a wound, is one of the biggest clinical problems. Chronic pain sometimes causes autonomic disorder, disquiecy or mental disorder where pain itself is the cause of a different disease. It is also known that there are pains due to nervous-sensory abnormality, such as hyperalgesia associated with the promotion of reaction in response to an ordinary painful stimulus, or allodynia wherein the pain is felt in response to a stimulus that normally does not cause pain and the like. . Analgesics are divided into central analgesics and peripheral analgesics according to their main place of action. Since the cause of pain is a complicated increase in autonomic reactions of the nerves, sensations and the like, sedatives, antianxiety, antidepressants, hypnotics, antispasmodics, vasodilators and the like are used as analgesic agents. Central analgesics are grossly divided into narcotics, anarcotics and antipyretics. Narcotic and anarcotic opioids are used for the treatment of acute pain such as postoperative pain and myocardial infarction, burns and the like. These analgesics show remarkable effects resulting from a strong analgesic action combined with an action to remove the fear of pain. On the other hand, narcotic analgesics accompany physical dependence and mental dependence and express syndromes for dependence on drugs. Other side effects such as respiratory suppression, nausea, emesis, constipation, dysuria and the like restrict its use. Antipyretic analgesics are effective for superficial pains such as toothache, myalgia and the like, but are considered ineffective for visceralgia. Its antipyretic action is considered focused in the thermoregulation center of the hypothalamus, and its analgesic action is exerted mainly through the peripheral nerves. However, many parts of this central mechanism of action are unknown. Its analgesic effect is generally weaker than that offered by narcotic and anarcotic opioids. Consequently, acute pain is carefully treated with narcotic and anarcotic opioids in clinical situations to the extent that it causes fewer side effects. Although more than 20 years have passed since the analgesic effect of morphine was confirmed by intrathecal administration to humans and morphine was applied for the first time in clinical situations, no pharmaceutical agent exceeding morphine has been found in terms of effects. various collaterals, histotoxicity to the spinal cord and the like, which enjoy the same analgesic effect of morphine. Certain pain caused by wounds and functional disorders of nerves and the like is resistant to analgesics currently in clinical use such as antipyretic analgesics and narcotic analgesics and does not exhibit significant analgesic effect.

Thus, there remains a demand for a safe and effective analgesic, particularly a strong pain-free analgesic and an analgesic for treating pain caused by nervous-sensory abnormality such as hyperalgesia, allodynia and the like. The pain is caused when an alginate substance, which is released when a tissue disorder occurs due to nociceptive stimuli (chemical, mechanical, thermal stimuli), excites the nociceptor (free nerve terminal) in the nerve end and the information of the Pain sensation reaches the cerebral cortex and is recognized as pain. In addition, it is considered that the visceralgia is caused by the contraction of the visceral smooth muscles that extend mechanically and excite the sensory nerve. The sensation of pain is transmitted mainly by two classes of thin nerve fibers A delta and C, where the acute mechanical stimuli are driven by the A delta myelinated fibers and the pains are driven by demyelinated fibers C. Typical algic substances include bradykinin , serotonin, histamine and the like acting on the nociceptor in the nerve terminal. There is a substance that drives the action of an alginate substance such as the prostaglandin synthesized at the site of inflammation in the peripheral tissue. Such a pain afferent fiber (primary afferent fiber) forms a synapse on the superficial layer of the dorsi. The primary afferent fiber excites nociceptive neurons through neurotransmitters, such as excitatory amino acids, substance P, and the like, and information is transmitted from the dorsi-mal to the medulla oblongata, the thalamus, and the cerebral cortex. The sensations of pressure and touch are transmitted mainly by the thicker A beta fiber, which transmits information from the sensory nerve terminal to the dorsifix, the medulla oblongata, the thalamus and the cerebral cortex, as does the afferent fiber of the brain. pain. The opioid receptors involved in algesia exist in various parts of these spinothalamic tracts. The suppressive respiratory action, the generating action of nausea and the like result from the action of the opioid receptor in the medulla oblongata. While the opioid acts on the spinal cord the medulla oblongata, the thalamus and the cerebral cortex, exhibiting strong analgesic defect, the suppression of the thalamus and the cerebral cortex is not its main action. Direct suppression of the opioid receptor in dorsi-nerve neurons and suppression of dorsi-nerve neurons through a descending depression through the midbrain and the medulla oblongata are considered the main action. The tactile sensation tends to be slow by the sustained application of stimuli of the same intensity. This adaptation is impossible in case of pain, but the sustained release of the neurotransmitter by prolonged stimulation of the sensory nerve is considered to induce chronic pain by changing the efficiency of the transmission of information or the excitatory efficiency of the nerve cell. In addition inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA), glycine and the like, suppress excitation of the nerves by activation of each receptor. While allodynia is considered to be partially induced by the slow suppression of neurotransmission due to stimuli repeatedly applied to the sensory nerve, the mechanism of establishing chronic pain, hyperalgesia and allodynia is known only to a limited degree. As described, the transmission by the sensory nerves is controlled by the excitatory nerve fiber and by the inhibitory nerve fiber in a complicated relationship with each other, and it has been found that there are many involved neurotransmitters. Therefore many targets are used to find a pharmaceutical agent that exhibits an effective analgesic action. After the discovery of the brain receptor of morphine in 1973, enkephalin, which is an endogenous pentapeptide with analgesic effect, was found and isolated for the first time in 1975. There are 20 classes of morphinomimetic peptides under the category of opioid peptides, which inhibit the transmission of algesic information. These opioids, including morphine, act on the opioid receptor. It is known that the opioid receptor includes subtypes, while morphine shows high affinity for a μ receptor, enkephalin shows a high affinity for the K receptor, which is the basis thereof. It is a well-known fact that the participation of the μ receptor among these is important for the analgesic effect and its mechanism has been almost elucidated. The study of the induction capacity of the retraction syndrome and the like of each subtype by the use of opioid antagonists has revealed that addiction to morphine is mainly attributable to action through the μ receptor. An opioid receptor type 1 (ORL-1) has high homology with an opioid receptor but does not bind opioid ligands. This receptor was cloned in 1993. * 1 * 2 In 1995, a peptide consisting of 17 amino acids was isolated with endogenous ligand of the ORL-1 receptor, structurally characterized and called nociceptin or orphanin FQ * 3 * 4 (* 1; FEBS Lett., 341, 33-38, 1994) (2 *; FEBS Lett., 347, 284-288, 1994) (* 3; Nature, 377, 532-535, 1995) (4 *; Science, 270, 792-794, 1995). The amino acid sequence of nociceptin to that of dynorphin A which is an endogenous opioid peptide. Dynorphin A is a K agonist receptor with an analgesic effect but weakly binds to the ORL-1 receptor and is said to have no activity. Nociceptin binds extremely weakly with an * 6-opioid receptor and the * 7 algesia tests including the warm plate test with mice, scraping the lower abdomen, the hindquarters of the mouse (SBL), biting behaviors of both hindquarters and similar * 8 induction studies revealed their promoter action in the transmission of pain information. These reports show that nociceptin and the ORL-1 receptor had specific affinity to each other and that nociceptin was a peptide that induced or amplified pain, inversely to the case of the opioid peptide. The study of this mechanism is ongoing. (* 5; Eur. J. Pharmacol., 321, 97, 1997) (* 6; J.

Biol. Chem., 271, 23642, 1996) (* 7; Anesthesia, 45, 1060-1066, 1996) (* 8; 18th Analgesic • Opioid Peptide Symposium Abstract, 11-14, 1997). The ORL-1 receptor has been reported as expressing more in the central nervous system such as the cerebral cortex, the hypothalamus, the spinal cord and the like * 9, and nociceptin has been shown to be more distributed in the superficial layer of the dorsi where the afferent fibers of pain end, and the algesia of transmission of nociceptin is mainly considered through the central nervous system (* 9; J. Neuochemistry, 64,34-40, 1995) (* 10; Neuro Report 7, 3021 -3025, 1996). It has also been reported that the administration of nociceptin induces nociceptive hypersensitivity (hyperalgesia * 3 * 4, allodynia * 11) and that it amplifies excitatory stimuli by heat and touch (* 11; Molecular Brain Research, 43, 96-104 , nineteen ninety six). Under the circumstances, the substances which are reported to exhibit an antagonistic action to nociceptin are only polypeptides similar to nociceptin and naloxon benzoylhydrazone which is a K antagonist receptor that has a structure similar to morphine, having the two affinities for the ORL-1 receptor and pharmaceutical agent that has specific antagonist action on the ORL-1 receptor has not been developed. Known analgesics having a quinoline skeleton include analgesic anesthetic antagonists or opioids [Japanese Unexamined Patent Publication No. 63-264460 (EP 277794; BOC Inc.)], analgesics with different mechanisms of action [Japanese Patent Publication Not Examined No 62-503030 (EU 5104884; Alkaloida Vegyeszeti Gyar, antial action), WO96 / 13485 (EP 807105; Fujisawa Pharmaceutical Industries, Ltd., bradykinin antagonist) WO96 / 11930 (Smithkline beecham PLC, serotonin receptor antagonist), publication Unexamined Japanese Patent No. 59-210084 (US 4839366; Chiesu Farmaceutici SpA, Prostaglandin Synthesis Inhibition), Japanese Unexamined Patent Publication No. 54-73784 (EUA 4293549; Leo Pharmaceutical Products Limited A / S), FR 1557928 and FR 1543405 (M. Robert ARIES)] and the like. They do not include a compound with the structure of the compound of the invention nor do they describe an action on nociceptin or on the ORL-1 receptor as it is done in the present invention. Compounds having a quinoline skeleton structurally similar to that of the compound of the invention and which can be used for effects other than the analgesic effect are shown in DE 831100 and DE 947552 (antiparasitic agent in the blood), WO97 / 14681 (therapeutic agent of abnormalities in bone metabolism), Japanese Unexamined Patent Publication No. 63-99069 (EUA 4753951; antisychotic agent), Japanese Unexamined Patent Publication No. 2-167265 (EUA 5019574, psychoneurotic enhancing agent) Journal of American Chemistry Society (76,3703-3708, 1956) (antibacterial agent), HU 34479 (description of the quinoline skeleton as a synthetic intermediate for the imdiazo [4,5-c] derivative (analgesic) and the like, although none of which describes its effectiveness as an analgesic.

DESCRIPTION OF THE INVENTION Based on the above findings, a pharmaceutical agent having antagonistic action to nociceptin can be an effective pain agent, particularly acute pain such as post-surgery pain and the like or pain caused by nervous-sensory abnormality, such as hyperalgesia, allodynia and similar, and a safe pharmaceutical agent that shows selective action on the receptor OLR-1 and free of marked collateral effects. It is therefore an object of the present invention to provide a pharmaceutical agent having a mechanism of action different from that of known analgesics, through the action antagonist to nociceptin. It is also an object of the present invention to provide a novel compound having an antagonistic action to nociceptin which is useful as an analgesic. As a result of the intense study of the present inventors in an attempt to solve the aforementioned problems, the present invention now provides a new compound having an analgesic effect. The present invention specifically provides the following (1) to (20). (1) A nociceptin antagonist containing an amide derivative of the formula [1] wherein R1 and R2 are the same or different and each is a hydrogen atom, a lower alkyl optionally substituted by hydroxy, amino, lower alkylamino or dialkylamino lower; R3 and R4 are the same or deferent and each is a hydrogen atom, a halogen atom or a lower alkyl; Ring A is an aryl or heterocyclic group; ring B is phenyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl or cyclohexenyl; and X is a hydrogen atom, a halogen atom, a lower alkyl optionally substituted by a lower alkoxy, lower alkenyl, amino, cyano or a group of the formula wherein E is a single bond, carbonyl, sulfinyl, -O-, -S-, -NHCO-, -CH = CR6- wherein R6 = is a hydrogen or aryl atom or -NR7 wherein R7 is a hydrogen atom hydrogen, a lower alkyl or a lower alkoxycarbonyl; ring G is aryl, heterocyclic group, cycloalkyl or fused aryl; R5 is a halogen atom, hydroxy, lower alkyl optionally substituted by a halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by lower alkoxy, lower alkoxy optionally substituted by lower alkoxy, amino, lower alkylamino, lower dialkylamino, nitro, cyano , lower alkanoyloxy, carboxy, lower alkoxycarbonyl, lower alkylsulfonyl or phenyl; t is O or an integer from 1 to 5, which indicates the number of substituent on ring G, where t is an integer from 2 to 5, each R5 may be the same or different; m is O or an integer from 1 to 8; and n is an integer from 1 to 4, or a pharmaceutically acceptable salt thereof as an active ingredient. (2) A nociceptin antagonist containing the amide derivative of (1), wherein ring A is quinolyl or a pharmaceutically acceptable salt thereof as an active ingredient. (3) A nociceptin antagonist containing the amide derivative of (1) wherein ring B is phenyl and X is a group of the formula wherein e, the ring G, R5, t, m, and n are as defined in (1) or a pharmaceutically acceptable salt thereof as the active ingredient. (4) A nociceptin antagonist containing the amide derivative of (3), wherein ring A is wherein R8 is a lower alkylthio or a pharmaceutically acceptable salt thereof as the active ingredient. (5) An amide derivative of the formula [1T wherein R2, ring B, E, ring G, R3, t, m and n are defined as in (1), or a pharmaceutically acceptable salt thereof. (6) The amide derivative of (5), wherein ring b is phenyl and R is a lower alkyl, or a pharmaceutically acceptable salt thereof. (7) The amide derivative of (6), wherein the amino replaces in the 4- position on a quinoline skeleton, R2 is methyl substituting at the 2- position of the quinoline skeleton, E is -O- and the ring B of phenyl has a substituent of the formula - (CH2) mE- (CH2) fH- G "HR5) t wherein the ring G, R5, t, myn are as defined in (1), in the 2- position, or a pharmaceutically acceptable salt of the (8) the amine derivative of (7) or a pharmaceutically acceptable salt thereof, which are selected from the group consisting of N- (4-amino-2-methyl-6-quinolyl 2 - [( 4-ethylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl 2 - [(2,4-dichlorophenoxy) methyl] benzamide, N- (4-amino-2- methyl-6-quinoli • 2- (dimethylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-2 - [(4-dimethoxyphenoxy) methyl] benzamide, N- (4-amino-2 -metl-6-quinolyl 2 - [(3,5-dimethylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl - [(3,4-dimethoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) 2 - [(4-nitrophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinol) • 2 - [(2,3-dimethoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinol-2 - [( 3-methylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl 2 - [(3,5-dimethoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinol 2 - [(4-chlorophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl 2 - [(4-acetylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2- 4-hydroxyphenoxy) methyl ]benzamide, N- (4-amino-2-methyl-6-quinolyl) -2- 4-methoxymethoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2- 3-methoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-2-4-cyanophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-2- (4-methoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-2-4-trifluoromethylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-3-nitrophenoxy) methyl] benzamide, N - (4-amino-2-methyl-6-quinolyl 2- 2- 2-nitrophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-2-4-acetoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2- 2-methoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-2-4-aminophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinol-2-3-chlorophenoxy) methyl ]benzamide, N- (4-amino-2-methyl-6-quinolyl-2-4-fluorophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-3,4-dichlorophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl-2-dimethylammonophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinol-4-tert-butylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinol) -2 - [( 4-bephenedioxymethyl) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-isopropylphenoxy) methyl] benzamide, N- (4-amino-2-methyl) -6-quinoli) -2 - [(4-nitrophenoxy) methyl] benzamida, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-bromophenoxy) methy1] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-propylfenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-florofenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-trifluoromethylphenoxy) methyl] benzamide, methyl-4- [2-. { N- (4-amino-2-methyl-6-quinolyl) carbamoyl hydrochloride} benzyloxy] benzoate, N- (4-amino-2-methyl-2-6-quinolyl) -2 - [(4-iodophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-2-hydrochloride -6-quinolyl) -2 - [(3-pyridyloxymethyl) methyl] benzamide, N- (4-amino-2-methyl-2-6-quinolyl) -2- [(benzyloxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-2-6-quinolyl) -2 - [(3-cyano-phenoxy) -methyl] -benzamide hydrochloride, N- (4-amino-2-methyl-2-6-quinol hydrochloride ) -2 - [(4-mesylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-2-6-quiol) -2 - [(2-chloro-4-ethylphenoxy) methyl hydrochloride ] benzamide, N- (4-amino-2-methyl-2-6-quinolyl) -2 - [(4-chloro-3-methylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-hydrochloride methyl-2-6-quinolyl) -2 - [(2-chloro-4-methylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-2-6-quinolyl) -2 - [(4-ethylphenoxy) hydrochloride ) methyl] benzamide, N- (4-amino-2-methyl-2-6-quinolyl) -2 - [(4-chloro-3-methylphenoxy) methy1] benzamide hydrochloride, 4- [2-. { (4-amino-2-methyl-6-quinolyl) carbamoyl hydrochloride} benzyl] benzoacetate, N- (4-amino-2-methyl-2-6-quinolyl) -2 - [(4-hydroxymethylphenoxy) methyl] benzamide hydrochloride and N- (4-amino- 2-methyl-2-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide. (9) An amide derivative of the formula [1"] wherein ring A, R2, R5 and t are as defined in (1), or a pharmaceutically acceptable salt thereof. (10) A pharmaceutical composition comprising the amide derivative of any of (5) to (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. (11) A nociceptin antagonist containing the amide derivative of any of (5) to (9) or a pharmaceutically acceptable salt thereof as the active ingredient. (12) An analgesic containing the amide derivative of any one of (1) to (9) or a pharmaceutically acceptable salt thereof as an active ingredient. (13) A method for expressing an antagonist action to nociceptin, comprising administering the amide derivative of any one of (1) to (9) or a pharmaceutically acceptable salt thereof. (14) A method for treating pain, comprising administering the amide derivative of any one of (1) to (9) or a pharmaceutically acceptable salt thereof. (15) The use of the amide derivative of any one of (1) to (9) or a pharmaceutically acceptable salt thereof for the production of a nociceptin antagonist. (16) The use of the amide derivative of any one of (1) to (9) or a pharmaceutically acceptable salt thereof for the production of an analgesic. (17) A pharmaceutical composition for antagonizing nociceptin, comprising the amide derivative of any of (1) a (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. (18) A commercial package comprising the pharmaceutical composition of (17) and a written material associated with it establishing said written material that the pharmaceutical composition can or should be used to antagonize nociceptin. (19) A pharmaceutical composition for analgesic use, comprising the amide derivative of any one of (1) to (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. (20) A commercial package comprising the pharmaceutical composition of (19) and a written material associated therewith establishing said written material that the pharmaceutical composition can or should be used for analgesia. Each substituent and structural unit used in the present specification is defined as follows: The halogen atom is a fluorine, chlorine, bromine or iodine atom. In R3, R4, R5 and R5"is preferably chlorine.

The lower alkyl has straight or branched chains and from 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like. It is preferably a linear or branched alkyl having from 1 to 4 carbon atoms. In R3, R4, R7, R9, R10, R11 and R2 'is more preferably methyl in R5? Is more preferably methyl or ethyl. The lower alkoxy has an alkyl unit defined above as lower alkyl. Specific examples include methoxy, ethoxy, propoxy, isopropyloxy, tert-butoxy and the like. The lower alkylthio has an alkyl unit defined above as lower alkyl. Specific examples include methyl, ethylthio, propiitio, isopropylthio, tert-butylthio and the like. Preferably its alkyl unit is a linear or branched alkyl with 1 to 4 carbon atoms. In R8 it is more preferably methylthio. The lower alkanoyl has an alkyl unit defined above as lower alkyl. Specific examples include acetyl, propionyl, butynyl, isobutyryl pivaloyl and the like. Preferably its unit is linear or branched alkyl with 1 to 4 carbon atoms. In R5 it is more preferably acetyl.

The lower alkyl sulfonyl has an alkyl unit defined above as lower alkyl. Specific examples include mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl and the like. Preferably its unit is a linear or branched alkyl with 1 to 4 carbon atoms. In R5 it is more preferably mesil. The lower alkanoyloxy has a lower alkyl unit. Specific examples include acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, and the like. Preferably its alkyl unit is a linear or branched alkyl with 1 to 4 carbon atoms. In R5 it is more preferably acetoxy. The lower alkoxycarbonyl has an alkyl unit defined above as lower alkyl. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyloxycarbonyl, tert-butoxycarbonyl and the like. Preferably its alkyl unit is a linear or branched alkyl with 1 to 4 carbon atoms. In R5 it is more preferably methoxycarbonyl and in R7 it is more preferably tert-butoxycarbonyl. A lower alkyl optionally substituted by hydroxy means that the lower alkyl can be unsubstituted. Specific examples initiate methyl, ethyl, propyl, isopropyl, hydroxymethyl, 1,2-dihydroxyethyl, 2- (hydroxymethyl) butyl and the like.

R1 and R2 are preferably methyl, ethyl, propyl, isopropyl or hydroxymethyl, and more preferably ethyl or methyl. A lower alkyl optionally substituted by lower alkoxy means the lower alkyl defined above optionally substituted by the lower alkoxy defined above including unsubstituted alkyl. Specific examples include methylethyl, methoxymethyl, ethoxymethyl, 2- (methoxymethyl) butyl and the like. Preferably its basic alkyl unit is a linear alkyl with 1 to 4 carbon atoms. In X it is more preferably methoxymethyl. A lower alkoxy optionally substituted by lower alkoxy means the lower alkoxy defined above optionally substituted by the lower alkoxy defined above including unsubstituted alkoxy. Specific examples include methoxy, ethoxy, methoxymethoxy, methoxyethoxy, 2- (methoxymethyl) butyloxy and the like. Preferably its basic alkyl unit is a linear or branched alkyl with 1 to 4 carbon atoms. In R5 it is more preferably methoxy or methoxymethoxy. A lower alkyl optionally substituted by a halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by 1 or more of the halogen atoms defined above, hydroxy, the lower alkanoyloxy defined above and the lower lower alkoxy defined optionally substituted by the alkoxy each of which may be the same or different, and the lower alkyl may be unsubstituted. Specific examples include methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, acetoxymethyl, pivaloyloxymethyl, bromomethyl, trifluoromethyl, methoxymethoxymethyl, methoxyethoxyethyl, and the like. Preferably its basic alkyl unit is a linear or branched alkyl with 1 to 4 carbon atoms. In R5 it is more preferably methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl, acetoxymethyl, trifluoromethyl or methoxymethoxymethyl and more preferably ethyl. A lower alkylamino is a monoalkylamino group wherein the alkyl unit is defined as lower alkyl. Specific examples include methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino and the like. Preferably its linear or branched alkyl unit with 1 to 4 carbon atoms. In R1 and 2 is more preferably methylamino. A lower dialkylamino is an alkylamino group wherein the alkyl unit is the same or different and is defined as a lower alkyl. Specific examples include dimethylamino, diethylamino, methylethylamino, N-isopropyl-N-isobutylamino hydrochloride and the like. Preferably its alkyl unit is a linear or branched alkyl with 1 to 4 carbon atoms. In R1 R2 and R5 it is more preferably dimethylamino. A lower alkenyl is a linear alkenyl chain with 1 to 6 carbon atoms.

Examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 1,3-butadienyl, 2,4-butadiene, 1-pentenyl, 1,3-pentadienyl and 1, 3,5-hexatrienyl and the like. X is preferably vinyl. Aryl is an aromatic hydrocarbon group with 6 to 18 carbon atoms. Examples thereof include phenyl, naphthyl, n-nyl, azulenyl, fluoremyl, phenethyl, pyrenyl and the like. Ring A is preferably phenyl and naphthyl, more preferably phenyl. Ring G and R6 are preferably phenyl. When the ring G is phenyl, the substituent R5 is preferably in the phenyl position. The heterocyclic ring is a group of cyclic compound with 1 or more oxygen, nitrogen and sulfur atoms as heteroatoms, while it may contain plural heteroatoms and the numbers of atoms constituting the ring is from 5 to 20. Specific examples thereof include pyridyl as pyrazinyl, pyrimidinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, benzimidazolyl, imidazolidinyl, indolinyl, pyrrolidinyl, pyrolinyl, piperidylino, piperazinyl, cramalino, morpholinyl, phthalazinyl, naphthyridyl , quinazolinino, quinoxalilo, cinolinilo, pteridilino, 4H-quinolicinilo, carbazolilo, 1, 3,5-triazinilo, 5,6,7,8-tetrahidroacrivinilo, 2,3-dihidro-1H-ciclopentaquinoiilo and similars.

Ring G is preferably pyridyl, benzufuranyl or 2,3-dihydrobenzoduranyl, more preferably 2,3-dihydrobenzofuranyl. Ring A is preferably a cyclic compound group containing 1 or more nitrogen atoms as heteroatoms and the number of atoms constituting the ring is from 9 to 14. More preferably quinolyl, isoquinolyl, quinoxalyl, benzimidazolyl, 5,6,7,8 -tetrahydroquinolyl, 5,6,7,8-tetrahydrocridinyl or 2,3-dihydro-1H-cyclopentaquinolyl, more preferably quinolyl, 5,6,7,8-tetrahydroacridinyl or 2,3-dihydro-1 H-cyclopentaquinolyl. When ring A is quinolyl it is preferred that R1 is an amino group substituting at the 4-position, that R2 is a lower alkyl substituting at the 2-position and that -NHCO- is substituted at the 6-position. A cycloalkyl is a cycloalkyl saturated with 3 to 8 carbon atoms, exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The ring G is preferably cyclooxy. A condensed aryl is the aryl defined above wherein the cycloalkyl groups defined above are condensed being a cyclic group in which the number of atoms constituting the ring is from 5 to 18. Specific examples include indanyl, 5,6,7,8- tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro-3-naphthyl, 1, 2,3,4-tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro-2-anthryl, 1,2,3-trihydroazinyl and the like The ring G is preferably 5,6,7,8-tetrahydro-2-naphthyl.

A protected amino is an amino group protected by an amino protecting group used in a typical chemical synthesis. Specific examples of the amino protecting group include formyl, acetyl, benzoyl, benzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, phthaloyl, tosyl benzyl and the like. A carboxy protecting group is a carboxy protecting group used in a typical chemical synthesis. Specific examples include methyl, methoxyethoxymethyl, phenacyl, phthalimidomethyl, ethyl, 2,2,2, -trichloroethyl, 2-methylthioethyl tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, tert-butyldimethylsilyl and the like. A hydroxy protecting group is a hydroxy protecting group used in a typical chemical synthesis. Specific examples include trimethylsilyl, tert-butyldimethylsilyl, methyl, benzyl, p-methoxybenzyl, tert-butyl, trityl, tetrahydropyranyl, methoxymethyl, methoxyethy- oxyethyl, acetyl, bezoyl and the like. In the formulas defined above [1], [1x] and [1"] each symbol preferably means the following: Ring G is preferably aryl R 5 is preferably halogen, lower alkyl optionally substituted by halogen, hydroxy, lower alkanoyloxy or alkoxy lower optionally substituted by lower alkoxy; nitro; cyano; or lower alkanoyl and more preferably lower alkyl optionally substituted by lower alkoxy.

The T is preferably O or an integer of 1 to 2, more preferably 1. The E is preferably a single bond or -O-, more preferably -O-. When E is -O-, m is preferably an integer from 1 to 7, more preferably 1, and n is preferably o. When E is a single bond m + n is preferably 2. The compound of the formula [1] includes several isomers. For example, there are geometric isomers E and Z. When there are asymmetric carbon atoms, there are stereoisomers (enantiomers and diastereomers). Depending on the case, tautomers may exist in the present invention. Therefore, the present invention covers all these isomers and mixtures thereof. The pharmaceutically acceptable salt thereof can be any salt as long as it forms a toxic salt with the above described compound of formula [1]. [1 *] or [1"] Examples include salts with inorganic acids such as hydrochloric, sulfuric, phosphoric and hydrobromic and the like, salts with organic acids such as oxalic, citric, fumaric, malic, succinic, tartaric, acetic, gluconic, ascorbic, methylsulfonic and the like, salts with inorganic bases, such as sodium, potassium, calcium, magnesium, ammonium hydroxides, and the like, salts with organic bases such as methyl amine, diethyl amine, triethylamine, triethanolamine, ethylenmine, tris) h hydroxymethyl) methylamine, guanidine, choline, cinchonine and the like, or salts with amino acids such as lysine, arginine, alanine and the like The present invention also covers compounds with water content as well as hydrates and solvates of each compound. present invention also covers prodrugs and metabolites of each compound A prodrug is a derivative of the compound of the present invention having a group that can be decomposed chemically or metabolically and exhibiting efficacy after being restored to its original form after being administered to an organism when a complex without a covalent bond or salts is included. When the compound of the present invention is used in a pharmaceutical preparation, it is generally mixed with a known pharmaceutically acceptable carrier as well as with excipients, diluents, extenders, disintegrants, stabilizers, preservatives, emulsifying regulators, flavorings, colorants, sweeteners, thickeners, flavorings. , solubilizers and other additives, specifically water, vegetable oil, alcohol (for example benzyl ethanol and the like), polyethylene glycol, glycerol triacetate, gelatin, carbohydrates (for example lactose, starch and the like), magnesium stearate, talc, lanolin, petrolatum and the like, and formulated into tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, tablets, aerosols, elixirs, suspensions, emulsions, syrups and the like by a conventional method, which can be administered systemically or locally by oral or parenteral administration. While the dose depending on age, body weight, symptoms, therapeutic effect, route of administration and others, is generally given from 0.01 mg to 1 g per dose several times a day for an adult. An example of the production method of the compound for practicing the present invention is explained below, to which the production method of the compound of the present invention is not limited. At each step the treatment of the reaction may be conventional, such as isolation and purification, crystallization, recrystallization, silica gel column chromatography, preparative HPLC and the like, which may be appropriately selected and combined. When necessary, a protective group can be introduced into a functional group and unprotected for production.

Production method 1 A synthetic method of the following formula [I] is shown below where ring A, R 1, R D 2"and D R 3 are as defined.

When ring A is quinoline, the method of Camps, Combes, Friedlander, Knorr, Niementowski and the like can be used for the synthesis. A part of the compound can be obtained as a commercially available reagent. The methods of producing the quinoline ring with substituents are shown below.

Production method 1-1 In this production method the ester of a beta-catoacid and an aniline compound, react to produce a 4-hydroxyquinoline compound. 0-1] [I-2] [I-3] Where R3 is as defined above, R2 'is a lower alkyl and Y is nitro or a protected amino. Step 1 Compound [1-1] and [I-2] are condensed in an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol and the like at room temperature p under heating to produce the compound [I-3] .

Step 2 The compound [I-3] obtained in the production method 1-1 step 1 is added in portions to a heated solvent and cyclized to give the compound [I-4]. The preferred solvent is diphenylether or a mixture of dinephylether and diphenyl such as Dowtherm A (trademark Fluka). This production method can be applied to the compound [1-1] when the alpha position of the beta-zero acid ester is substituted by a lower alkyl.

Production method 1-2 According to this production method, the quinoline compound is obtained from a satin compound.

[I-5] [I-6] [I-7] Where R3 and Y are as defined above. Step 1 Compound [1-5], acetone and aqueous ammonia react under pressurization and heating to give compound [1-6].

Step 2 Compound I-6 obtained in the production method 1-2 step 1 reacts in the presence of an oxidizing agent such as sodium hypochlorite, sodium hypobromite and the like, under cooling, and the reaction mixture obtained is poured drop to drop over hot water and heat additionally to give the compound [I-7]. The following production method can be used to introduce a specific substituent into a specific substitution site.

Production method 1-3 According to this production method, the compound 4-hydroxy-2-methoxycarbonylquinoline is obtained. The methoxycarbonyl group of this compound can be converted to hydroxymethyl group by reduction in a subsequent step. [μß] D-9] [HO] r 11] Where R3 and Y are as defined above. Step 1 Compound [1-8], and [1-9] are condensed in the same way as in the production method 1-1 step 1 to give the compound [1-10].

Step 2 The compound [1-10] obtained in the production method 1-3 step 1 is cyclized in the same way as in the production method 1-1 step 2 to give the compound [1-11]. Production method 1-4 According to this production method the 4,6-diaminoquinoline compound is obtained from the compound 4-nitroquinoline N-oxide [M2] [3] [M4] Step 1 The compound [1-12] and metallic iron react in an acidic solvent, such as hydrochloric acid, acetic acid and the like, under heating and the resulting solution is made alkaline to produce the compound [1-13]. Alternatively, a typical reduction can be used using tin or tin chloride [II] and concentrated hydrochloric acid; or an alkali metal sulfide such as aqueous sodium sulfide solution, or catalytic reduction.

Step 2 Compound 1-13 obtained in the production method 1-4 step 1 is treated with bromine in acetic acid under cooling to room temperature to halogenate and obtain compound [1-14]. Alternatively halogenating people such as a hypohalite (for example hypochlorite and the like) or N-bromosuccinimide can be used for halogenation instead of bromine.

Step 3 The compound [1-14] obtained in the production method 1-4 step 2 is subjected to nitration in a sulfuric acid solvent under cooling by adding concentrated nitric acid to give the compound [I-15]. Nitric acid or nitrated sulfuric acid can be used instead of the nitric-sulfuric acid mixture for nitration.

Step 4 Compound [1-15] obtained in the production method 1-4 step 3 is subjected to catalytic reduction using a hydrogenation catalyst in an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol and the like by adding hydrochloric acid or a solution of hydrogen bromide in acetic acid at room temperature or under heating under normal pressure or at high pressure to produce the compound [1-16]. Examples of the hydrogenation catalyst include palladium carbide, palladium hydroxide, black palladium, nickel, Raney, platinum oxide and the like. The following are examples of synthesis in which ring A is an isoquinoline ring.

Production method 1-5 According to this production method, 1-halogen-7-nitroisoquinoline is obtained from tetrahydroisoquinoline.

Step 1 Step 2 [M7] [1-18] [1-19] Step 3 Step 4 [I-20] [1-21] Step 1 The compound [1-17] is subjected to nitration in the same manner as in the production method 1-4 step 3 to give the compound [1-18] ] Step 2 The compound [1-18] obtained in the production method 1-5 step 1 is subjected to dehydrogenation for a few days using the Fremy salt in 4% aqueous sodium carbonate solution at room temperature to produce the compound [ 1-19].

Step 3 Compound [1-19] obtained in the production method 1-5 step 2 reacts with m-chloroperbenzoic acid in a halogen solvent such as dichloromethane, chloroform, carbon tetrachloride and the like, at room temperature for an N-oxidation to give the compound [I-20].

Step 4 The compound [I-20] obtained in the production method 1-5 step 3 reacts with phosphorous oxychloride in a hydrocarbon solvent such as toluene, xylene and the like under heating to give the compound [I-21].

Production method 1-6 According to this production method a quinoline compound condensed with a cycloalkyl is obtained by condensation of saturated cyclic ketone and the anthranilonitrile compound.

Where Y is as defined above and p is 0 or an integer of 1. An acid catalyst such as Lewis acid (for example zinc chloride) is added to a mixture of the compound [I-22] and the compound [I-23] under heating to condense and give the compound [I-24].

Production method 1-7 According to this production method a substituent of a compound is substituted by an amino group or by a substituted amino group.

Where the ring A, R2, R3 and Y are as defined above, R9 is a hydrogen atom or a lower alkyl and R10 is a lower alkyl.

Step 1 The compound [I-25] obtained in the production method 1-1 or a commercially available reagent reacts with chlorosulfonyl isocyanate in acetonitrile or dichloroethane under heating to give the compound [I-26].

Step 2 The compound [I-25] obtained in the production method 1-1 or a commercially available reagent reacts with an alkylating agent in a solvent under heating or at room temperature to give the compound [I-27]. As the alkylating agent dimethylsulfate or methyl p-toluenesulfonate is used to introduce the methoxy group into the scheme. Examples of preferred solvents include hydrocarbons such as benzene, toluene, hexane, xylene and the like; and ethereal solvents such as 1,4-dioxane, diethylether, 1,2-dimethoxyethane, tetrahydrofuvane and the like.

Step 3 The compound [I-25] obtained in the production method 1-1 or commercially available reagent reacts with a halogenating agent such as phosphorous oxychloride, phosphorous pentachloride and the like, under heating and the reaction mixture is made alkaline to give the compound [I-28] Step 4 The compound [I-28] obtained in the production method 1-5 or in the production method 1-7 step 3 or a commercially available reagent reacts with a metal alkoxide in an alcoholic solvent such as methanol, ethanol, propanol , butanol and the like under heating to give the compound [1-27]. As the metal alkoxide, sodium methoxide is used and as a solvent methanol is used as the corresponding alcohol solvent to introduce the methoxy shown in the scheme.

Step 5 The compound [I-27] obtained in the production method 1-7 step 2 or in the production method 1-7 step 4 or the commercially available reagent reacts with an aminating agent such as ammonium acetate and the like under heating to give the compound [I-26].

Step 6 The compound [I-28] obtained in the production method 1-7 step 3 or the commercially available reagent reacts in the compound [I-29] in the presence of a base, such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, under heating to give the compound [I-30]. The compound [I-25] in this production method 1-7 can also be the compound [1-11] obtained in the production method 1-3.

Production method 1-8 According to this production method the amino protecting group of a compound is eliminated or the nitro group of a compound is reduced.

Where ring A, R1, R2, R3 and Y are as defined above. When Y is a protected amino, a typical deprotection method corresponding to the protecting group is used. For example, when the protecting group is acetyl, concentrated hydrochloric acid is added to the compound 1-31 obtained in the production method 1-7 or a commercially available reagent and the mixture is heated for deacetylation to give the compound [I]. Instead of the concentrated hydrochloric acid treatment, heating in concentrated ammonia, potassium hydroxide and the like can be used. When Y is nitro, a typical method of conversion to amine is used for nitro reduction. For example, the compound [1-31] obtained in the production method 1-7 or the commercially available reagent is subjected to catalytic reaction in a solvent at room temperature or under heating, at normal pressure or at high pressure using a hydrogenating catalyst to give the compound [I]. Examples of the solvent include ethereal solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as dimethylformamide, dimethisulfoxide, acetonitrile, acetone and the like: alcohol solvents such as methanol, ethanol, propanol, butanol and the like; esters such as ethyl formate, ethyl acetate, butyl acetate and the like; Water; or a mixture of solvents. The hydrogenating catalyst is exemplified with palladium carbide, palladium hydroxide, black palladium, Raney nickel, platinum oxide and the like.

Production method 2 The synthetic method of the compound of the formula [II] is shown below. 00 Where ring B, R4 and X are as defined above. When X is a group of the formula Where ring G, R5 and t are as defined above, the following production method is exemplified.

Production method 2-1 According to this production method, the methyl of a methyl substituted carboxylic acid is converted into an ether.

R4 R4 ZO2C + - B - -Me ZO2C + - B H-CH2Br Step 1 [p-1] [II-2] [IM] Where ring B, the ring G, R 4, R 5 and t are as defined above, and Z is a carboxy protecting group.

Step 1 The compound [11-1] reacts with a radical initiator such as benzoyl peroxide, azobisisobutyronitrile and the like and N-bromosuccinimide to give the compound [II-2].

Step 2 The compound [II-2] obtained in the production method 2-1 step 1 reacts with the compound II-3 in a solvent in the presence of a base, such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like, under heating to give the compound [II-4]. Examples of the solvents include hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; ethereal solvents such as 1,4-dioxane, diethylether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as dimethylformamide, dimethisulfoxide, acetonitrile, acetone and the like, and alcohol solvents such as methanol, ethanol, propanol, butanol and the like. Most of the compound [II-3] can be easily obtained as a commercially available reagent but a difficult-to-obtain compound can be synthesized by the following production methods. Production method 2-2 According to this production method, a cyclic compound having a substituent can be substituted by a halogen atom.

[II-5] m Where the ring G is as defined above, R5 'is a lower alkyl and R5"is a halogen atom, in the same way as in the production method 1-4 step 2 the compound [ II-5] is halogen to give the compound [II-6]. By using sulfuryl chloride as the halogenating agent, the compound is halogen in a halogen solvent, such as dichloromethane, chloroform, carbon tetrachloride, tetrachlorethylene and the like, to replace the Chlorine atom in the ortho position of the phenol 4 substituted alkyl.

Production method 2-3 According to this production method, a cyclic compound is replaced by alkyl sulfonyl.

Where the ring G is as defined above Q is a hydroxy protecting group and R 11 is a lower alkyl Step 1 The compound [II-7] reacts with alkyl sulfonic anhydride for example methane sulfonic anhydride in a halogen solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrachlorethylene and the like under heating to give the compound [11-8].

Step 2 The compound [II-8] obtained in the production method 2-3 step 1 is deprotected by a conventional method to give the compound [II-9]. For example when R 11 is methyl, aqueous hydrogen bromide is added and heated or heated with sodium cyanide in dimethyl sulfoxide to allow deprotection.

Production method 2-4 According to this production method, the benzofuran or 2,3-dihydrobenzofuran compounds are synthesized from a phenolic compound. [11-10] [IM 1] [11-12] [11-13] [11-14] [11-15] Where Q is as it is defined above.

Step 1 E Compound [11-10] is condensed with the compound [11-11] in a polar solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, acetone and the like, in the presence of a base such as potassium carbonate, carbonate sodium, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like under heating to give the compound [11-12].

Step 2 The compound [11-12] obtained in the production method 2-4 step 1 is cyclized using a condensing agent such as polyphosphoric acid and the like in a hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like under heating to give the compound [11-13]. The compound [11-13] obtained in the production method 2-4 step 2 is subjected to catalytic reduction in the same way as in the production method 1-4 step 4 to give the compounds [11-14] and [11] -fifteen]. Examples of the solvent include, in addition to the alcohol solvents, ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like or a mixed solvent thereof and the like.

Production method 2-5 According to this production method, a carboxy protecting group is removed from a compound.

[I 6] DO Where the ring B, R, X and Z is defined as above defined. The carboxy protecting group can be removed by a conventional deprotection method depending on the kind of protecting group. For example when Z is the compound [11-16] reacts in an alcohol solvent, such as methane, ethanol, n-propanol hydrochloride, isopropanol and the like, in the presence of a base such as potassium carbonate, sodium carbonate, hydroxide of lithium, sodium hydroxide, potassium hydroxide and the like under heating to exert the deprotection and the resulting solution is acidified to produce the compound [II].

Production method 3 According to this production method an amine compound and a carboxylic acid are condensed to form an amine.

[O [10 Where ring A ring B, R1, R2, R3, R4 and X are as defined above. The compound [I] obtained in the production method 1 or a commercially available reagent and the compound [II] obtained in the production method 2 or a commercially available reagent are condensed by a conventional method of forming amide by condensation. For example, the compound [II] is treated with a halogenating agent such as oxalyl chloride, thionyl chloride, phosphorous oxychloride, phosphorous pentachloride and the like in a solvent at room temperature to give the corresponding acid chloride. Then the compound is condensed with compound I in the presence of a tertiary amine, such as triethylamine and the like, or with pyridine at room temperature under cooling to give compound [1]. Examples of preferable solvents include halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like: ether solvents such as 1,4-dioxane, diethyl ether. 1,2-dimethoxyethane, tetrahydrofuran and the like. Alternatively, the compound [I] and the compound [II] react in a solvent in the presence of a condensing agent at room temperature to give the compound [1]. For a softer reaction, use a reinforcer. Examples of the condensing agent include N, N'-carbonyldiimidazole, N.N'-dicycloxycarbodiimidae, N, N'-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and the like and examples of the enhancer include hydroxysuccinimide, 1-hydroxybenzotriazole and the like. Examples of the preferable solvents include a hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like; a halogen solvent such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloromethane and the like; an ether solvent such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; a polar solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile and the like; and a mixture of said solvents. To improve performance, cost reduction and other benefits leading to higher efficiency in production, reduction, deprotection and the like, can be carried out after the formation of the amide by condensation.

For example, when the compound [I] or the compound [II] has a nitro group, the nitro group can be reduced after the formation of the amide by condensation or when the compound [I] and the compound [II] have a group functional such as hydroxy and the like the deprotection can be carried out after the formation of the amide by condensation. Alternatively, the methoxycarbonyl substituted compound obtained in the production method 1-3 and in the production method 3 is added to an ether solvent, such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like and lithium tetrahydroborate is added in portions in an argon stream under cooling to reduce and produce the substituted hydroxymethyl compound.

EXAMPLES The compound of the formula [1] of the present invention and the production method thereof are specifically explained below by means of examples. It is unnecessary to say that the present invention is not limited to these examples.

EXAMPLE OF PREPARATION 1-1 Synthesis of 4,6-diamino-2-methylquinoline The synthesis was carried out according to a reference publication (Journal oh the American Chemical Society, 70, 4065, 1948).

Step 1 4-Aminoacetonilide (150.2g, 1 mol) was added to a solution of methyl acetoacetate (136.8 g 1.1 mol) in methanol (450ml) the mixture was refluxed under heating for 17 hours. The reaction vessel was cooled to 0 ° C and the resulting white precipitate was collected by filtration to yield methyl-beta- (p-acetamidophenylamino) crotonate (231.5g 93%, white crystals).

Step 2 The methyl-beta- (p-acetamidophenylamino) crotonate (231.5g 0.93 mol) obtained in the preparation example 1-1 step 1 was added in small portions Dowtherm a (trademark 600ml) and refluxed under heating. The mixture was refluxed under heating for 10 minutes and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with ethyl acetate. The crude crystals obtained were suspended in methanol and collected by filtration to give N- (4-hydroxy-2-methyl-6-quinolyl) acetamine (178.3 g 88%, deep yellow crystals).

Step 3 To a suspension of N- (4-hydroxy-2-methyl-6-quinolyl) acetamide (100g 0.46 moles), obtained in Preparation Example 1-1 step 2 toluene (490ml) was added dimethyl sulfate (75ml, 0.79 moles) and the mixture was refluxed under heating for 8 hours. The resulting precipitate was collected by filtration, dissolved in water (1350 ml) and heated to 70 ° C. The solution was filtered and 35% aqueous sodium hydroxide (100 ml) was added to the filtrate. The resulting precipitate was collected by filtration to give N- (4-methoxy-2-methyl-6-quinolinyl) acetamide (55.3 g, 52% pale brown crystals).

Step 4 N- (4-methoxy-2-methyl-6-quinoyl) acetamide (55.6 g, 0.24 mole), obtained in the preparation example 1-1 step 3 was mixed with ammonium acetate (279.4 g 3.62 mole) and the The mixture was stirred under heating at 135 ° C for 4 hours. To the reaction mixture was added water (280 ml) and concentrated hydrochloric acid (450 ml) the mixture was stirred under heating at 90 ° for 5 hours. The reaction mixture was cooled to 0 ° C and the resulting precipitate was collected by filtration. The obtained crystals were dissolved in hot water and treated with activated charcoal and filtered. To the filtrate was added 35% aqueous sodium hydroxide solution under ice cooling. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure at 100 ° C to give the title compound (28.4g, 68% pale yellow crystals).

EXAMPLE OF PREPARATION 1-2 Synthesis of 4,6-diamino-methylquinoline Step 1 To the 5-nitroisatin (19.21 g, 0.1 mole) was added acetone (36.7 g, 0. 5 moles) and aqueous ammonia (100 ml) and the mixture was heated in a autocalve at 100 ° C for 12 hours. The reaction mixture was cooled to room temperature and the resulting crystals were collected by filtration and washed with water. The crystals obtained were dried by heating under reduced pressure to give 2-methyl-6-nitroquinoline-4-carboxamide (18.30 g, 79%).

Step 2 To the 2-methyl-6-nitroquinoline-4-carboxamide (231 mg, 1 mmol) obtained in Preparation Example 1-2 step 1 was added aqueous sodium hypochlorite solution (0.851 mL, 1.2 mmol) and the mixture was stirred at 0 ° C for 2.5 hours. The reaction mixture was added dropwise to hot water (10 ml) under reflux with heating and the mixture was refluxed under heating for 20 minutes. The reaction was cooled to room temperature and the resulting crystals were collected by filtration and dried by heating under reduced pressure to give 4-amino-2-methyl-6-nitroquinoline (177 mg, 87%).

Step 3: The 4-amino-2-methyl-6-nitroquinoline (377 mg 1.7 mmol) obtained in the preparation example 1-2 step 2 was dissolved in methanol (15 ml) and 10% of palladium carbon was added ( 200 mg) and the mixture was stirred at room temperature at 3 atm under a hydrogen atmosphere for 15 hours. The reaction mixture was filtered through celite by suction and the filtrate was concentrated under reduced pressure to give the title compound (200 mg, 70%).

EXAMPLE OF PREPARATION 1-3 Synthesis of 6-amino-2-methyl-4-methylaminoquinoline Step 1 The N- (4-hydroxy-2-methyl-6-quinoyl) acetamide (4.32 g, 20 mmol) and phosphorous oxychloride (9.32 mL, 100 mmol) were heated at 100 ° C for 15 minutes. The reaction mixture was cooled to room temperature and poured into ice water. There, 28% aqueous ammonia was added to make the alkaline solution. The resulting insoluble material was collected by filtration, washed with ether and water, dried under reduced pressure at 80 ° C to give N- (4-hydroxy-2-methyl-6-quinol) acetamide (6.85 g). solid crude, yellow).

Step 2 A suspension of N (4-hydroxy-2-methyl-6-quinoline) acetamidate (4.0 g, crude) obtained in the preparation example 1-3 step 1 and 85% potassium hydroxide (6.6 g 100 mmol) in N-methylformamide (100 ml) were heated at 170 ° C for 3 hours 20 minutes. The reaction mixture was cooled to room temperature and diluted with chloroform and water. The chloroform layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The oil obtained was purified by silica gel column chromatography (chloroform: methanol = 85: 15-chloroform: methanol: 28% aqueous ammonia = 85: 15: 0.1) to give N (2-methyl-4-methylamino-6-). quinoyl) acetamide (255mg 9.5%) as a pale brown solid.

Step 3: The N- (2-methyl-4-methylamino-6-quinoyl) acetamide (248 mg 1.08 mmol) obtained in the preparation example 1-3 step 2 was refluxed under heating for 2 hours in 6N hydrochloric acid (10 ml). The reaction mixture was cooled to room temperature and 4N sodium hydroxide solution was added to make the pH not less than 13, followed by cooling with ice. The resulting insoluble matter was collected by filtration and dried under reduced pressure at 60 ° C to give the title compound (202 mg, 99.7% pale yellow solid).

EXAMPLE OF PREPARATION 1-4 Synthesis of 4,6-diaminoquinoline dibromhydrate The synthesis of steps 2 to 4 followed the method of a reference publication (Yakigaku Zasshi, 72,665,1952).

Step 1 A suspension of 4-nitroquinoline N-oxide (10g, 52.5 mmol) and metallic iron (26.4 g, 0.47 mol) in acetic acid (500 ml) was stirred under heat at 110 ° C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added an aqueous solution of sodium hydroxide to make the alkaline solution, which was followed by extraction with chloroform (50ml x 6). The organic layer was washed with water and saturated brine was dried over sodium sulfate and concentrated under reduced pressure to give 4-aminoquinoline (6.0g, 79% brown crystals).

Step 2 To a solution of 4-aminoquinoline (2.28g, 15.8mmol) obtained in Preparation Example 1-4 Step 1 in acetic acid (30ml) was added bromine (2.78g, 17.4mmol) with stirring under ice cooling and the mixture was stirred at room temperature for 30 minutes. Diethylether was added and the resulting precipitate was collected by filtration to give 4-amino-3-bromoquinoline bromohydrate (4.39 g, 91%). The obtained crystals were dissolved in water and 1N aqueous solution of sodium hydroxide was added to make the alkaline solution. The resulting precipitate was collected by filtration washed with water and dried under reduced pressure to give 4-amino-3-bromoquinoline (2.91 g, 82%, pale gray crystals).

Step 3 To a solution of 4-amino-3-bromoquinoline (2.90 g, 13 mmol) obtained in the preparation example 1-4 step 2 in concentrated sulfuric acid (25 ml) was added 60% nitric acid (1.5 ml, 20 mmole) with stirring under ice cooling and the mixture was stirred for 1 hour. Sodium hydroxide (40g) was added to the reaction mixture under cooling with ice and the resulting precipitate was collected by filtration. The obtained crystals were dissolved in acetone, treated with activated charcoal and recrystallized to give 4-amino-3-bromo-6-nitroquinoline (1.65 g, 47% yellow crystals).

Step 4 To a solution of giving 4-amino-3-bromo-6-nitroquinoline (0.82g, 3.05 mmol) obtained in Preparation Example 1.4 step 3 in ethanol (30 mL) was added 25% hydrogen bromide solution in acetic acid (0.7m !, 3.05mmol) and 10% palladium carbide catalyst and the mixture was subjected to catalytic reduction at room temperature for 6 hours. The catalyst was filtered and washed with water. The filtrate was concentrated under reduced pressure. The residue obtained was recrystallized from water-ethanol-ethyl acetate to give the title compound (0.92 g, 94%, greenish-brown crystals).

EXAMPLE OF PREPARATION 1.5 Synthesis of 1.7, diaminoisoquinoline Step 1 Concentrated sulfuric acid (80 ml) was added in small portions to tetrahydroisoquinoline (24.4 g, 183 mmol) under cooling with ice for dissolution. 60% nitric acid (18 ml) was then added dropwise from a funnel and the mixture was stirred under ice-cooling for 3 hours. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water under ice cooling and 35% aqueous sodium hydroxide solution was added to adjust the solution to pH12. After extraction with chloroform the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (180 ml) and concentrated hydrochloric acid (20 ml) was added under cooling with ice. The precipitated brown crystals were collected by suction filtration to give 7-nitrotetrahydroisoquinoline hydrochloride (7.18 g, 22%).

Step 2 To the 7-nitrotetrahydroisoquinoline hydrochloride (7.18 g, 33 mmol) obtained in Preparation Example 1-5 was added Fremy's salt (100 g, 280 mmol) in 4% aqueous sodium carbonate solution (1.5 L) . The mixture was stirred at room temperature for 7 days and the reaction mixture was extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by neutral alumina column chromatography (hexane: ethyl acetate = 3: 2) to give 7-nitroisoquinoline (3.21 g, 55%).

Step 3 To a solution of 7-nitroisoquinoline (2.38 g, 14 mmol) obtained in Preparation Example 1-5 step 2 in chloroform (68 mL) was added m-chloroperbenzoic acid (3.54 g, 21 mmol). The mixture was stirred at room temperature for 21 hours. The insoluble material in chloroform was filtered with suction and washed with chloroform. The filtrate was washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 7-nitroisoquinoline N-oxide. The obtained compound was used in the next reaction without purification.

Step 4 To a suspension of 7-nitroisoquinoline N-oxide obtained in Preparation Example 1-5 step 3 in toluene (185 mL) was added phosphorous oxychloride (3.5 mL, 37 mmol) and the mixture was stirred under heating at 90 ° C. for 2 hours. The reaction mixture was cooled to room temperature and poured into an aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 30: 1) to give 1-chloro-7-nitroisoquinoline (540 mg, 14%).

Step 5 To a suspension of 1-chloro-7-nitroisoquinoline (670 mg, 3.21 mmol) obtained in Preparation Example 1-5 step 4 in methanol (100 mL) was added a 1 M solution (6.5 mL, 6.5 mmol) of sodium methoxide. The mixture was refluxed under heating for 3 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 30: 1) to give 1-methoxy-7-nitroisoquinoline (530 mg, 81%).

Step 16 A mixture of 1-methoxy-7-nitroisoquinoline (530 mg, 2.60 mmol) obtained in Preparation Example 1-5 step 5 and ammonium acetate (3 g, 39.0 mmol) was stirred under heating at 135 ° C for 4 hours. hours. The reaction mixture was added aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3) to give 1-ammonium-7-nitroisoquinoline (246 mg, 50%).

Step 7 A mixture of 1-amino-7-nitroisoquinoline (246 mg, 1.3 mmol) obtained in Preparation Example 1-5 step 6 and 5% palladium carbide (100 mL) in methanol (100 mL) was stirred at room temperature and normal pressure under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through celite by suction and the filtrate was concentrated under reduced pressure to give the title compound (203 mg, 99%).

EXAMPLE OF PREPARATION 1-6 Synthesis of 7,9-diamino-1,2,3,4-tetrahydroacridna Step 1 To a mixture of 5-nitroisoquinoline (1.63 g 10 mmol) and cyclohexanone (10.3 ml 100 mmol) was added zinc chloride (1.36 g, 10 mmol) and the mixture was refluxed under heat for 20 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and the insoluble matter was filtered. The filtrate was concentrated under reduced pressure and chloroform was added to the brown oil obtained. The resulting yellow precipitate was collected by filtration and dried under reduced pressure at 80 ° C. This solid (1.56 g) was diluted with ethyl acetate and 1N aqueous sodium hydroxide solution, and ether was added. The insoluble material was collected by filtration and dried under reduced pressure at 80 ° C to give 9-amino-7-nitro-1, 2,3,4-tetrahydroacridine (810 mg, 33%) as a yellow solid.

Step 2 9-amino-7-nitro-1,2,3,4-tetrahydroacridine (773 mg, 3.18 mmol) obtained in the preparation example 1-6 step 1 was dissolved in a mixed solvent of tetrahydrofuran (5 ml) and Ethanol (5 ml) and 5% palladium carbide (500 mg) was added, which was followed by hydrogenation at room temperature and under normal pressure. After 7 hours, the reaction mixture was passed through celite and the filtrate was concentrated to give the title compound (665 mg, 98%) as a yellow oil.

EXAMPLE OF PREPARATION 2-1 Synthesis of 2 - [(4-ethylphenoxy) methybenzoic acid Step 1 To a solution of methyl o-toluate (15.0 g 0.1 mmol) in carbon tetrachloride (200 ml) was added N-bromosucinimide (18.7 g, 0.1 mole) and benzoyl peroxide (catalytic amount) and the mixture was subjected to at reflux under heating for 2 hours. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered. The filtrate was concentrated under reduced pressure to give methyl alpha-bromo-o-toluate (yellow oil). The obtained oil was used in the next reaction without purification.

Step 2 To a solution of methyl alpha-bromo-o-toluate (2.29 g, 10 mmol) obtained in Preparation Example 2-1, Step 1 and 4-ethylphenol (1.28 g, 10.5 mmol) in dimethylformamide (50 mL) ) potassium carbonate (4.15 g, 30 mmol) was added and the mixture was stirred under heat at 100 ° C for 1 hour. The reaction mixture was added to ethyl acetate (100 ml) and washed with water and saturated brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel crude was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 5) to give 2 - [(4-ethylphenoxy) methyl] benzoate benzoate (1.96 g, 73%).

Step 3 To a solution of 2 - [(4-ethylphenoxy) methyl] benzoate benzoate (1.96 g, 7.3 mmol) obtained in Preparation Example 2-1, Step 2 in Ethanol (20 mL) was added aqueous hydroxide solution of potassium 2N (11 ml, 21.8 mmol) and the mixture was stirred under reflux with heat for 2 hours. To the reaction mixture was added water (70 ml) and 6N hydrochloric acid (5 ml) and the resulting precipitate was collected by filtration and washed with water. The solid obtained was dried under reduced pressure to give the title compound (1.75 g, 94% white crystals).

EXAMPLES OF PREPARATION 2-2 Synthesis of 2-chloro-4-ethylphenol A solution of 4-ethylphenol (25.4 g, 0.21 mol) and sulfuryl chloride (18.5 ml, 0.23 mol) in carbon tetrachloride (40 ml) was stirred under heat at 70 ° C for 3 hours. The reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give 2-chloro-4-ethylphenol (25.1 g, 77%).

EXAMPLES OF PREPARATION 2-3 Synthesis of 4-methylsulfonylphenol Step 1 To an anisole solution (3.3 ml, 30 mmol) in tetrachlorethylene (30 ml) was added anhydridomethanesulfonic acid (5.75 g, 33 mmol) and the mixture was stirred under heat at 145 ° C for 18 hours. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and the obtained crystals were recrystallized twice from hexane-ethyl acetate to give 4-methylsulfonylanisole (505 mg, 9%, colorless crystals ).

Step 2 To the 4-methylsulfoilanisol (505 mg, 2.7 mmol) obtained in Preparation Example 2-3 step 1 was added aqueous hydrogen bromide at 48% (3 ml) and the mixture was refluxed under heat for 10 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (256 mg, 55% colorless crystals). The obtained compound was used in the next reaction without purification.

EXAMPLES OF PREPARATION 2-4 Synthesis of 2-((5-benzofuranloxy) m9tHH-benzoate and methyl 2-1? 2.3- dihydrobenzofuran-5-yloxy) benzoate Step 1 To a solution of 4- (benzyloxy) phenol (10.01 g, 50 mmol) and bromoacetaldehyde diethyl acetal (7.52 mL, 50 mmol) in dimethyl formamide (100 mL) was added potassium carbonate (10.37 g, 75 mmol) and the mixture was heated to 170 ° C. After 2.5 hours, the reaction mixture was cooled to room temperature. The mixture was diluted with water and ethyl acetate and the aqueous layer was removed. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give 2- [4- (benzyloxy) phenoxy] acetaldehyde diethyl acetal (11.902 g, 75% pale brown oil).

Step 2 The 2- [4- (benzyloxy) phenoxy] acetaldehyde diethyl acetal (3.16 g, 10 mmol) obtained in the preparation example 2-4 step 1 and polyphosphoric acid (3.16 g) were heated in toluene (30 ml) to 100 ° C. After 40 minutes the mixture was cooled to room temperature. The reaction mixture was diluted with ether and the supernatant was separated by decantation. The supernatant was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 5- (benzyloxy) benzofuran (1.032 g, 46% pale yellow oil).

Step 3 The 5- (benzyloxy) benzofuran (1.02 g, 4.55 mmol) obtained in the preparation example 2-4 step 2 was dissolved in a mixed solvent of ethanol (5 ml) and ethyl acetate (5 ml) and added 5% palladium carbide (500 mg), followed by hydrogenation at room temperature under normal pressure. After 2 hours, the reaction mixture was passed through celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethyl formamide (20 ml) and methyl alpha-bromo-o-toluate (1.042 g, 4.55 mmol) and potassium carbonate (1.26 g, 9.10 mmol). The mixture was heated at 100 ° C for 1.25 hours and cooled to room temperature. The reaction mixture was diluted with water and ethyl acetate to separate the layers. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give methyl 2 - [(5-benzofuranyloxy) methyl] benzoate (352 mg, 27% white crystals) and 2- [ (Methyl 2,3-dihydrobenzofuran-5-yloxy) methyl] benzoate (220 mg, 17% pale yellow oil).

EXAMPLE 1 Synthesis of N- (4-amino-2-methyl-6-quinolyl) -2-r (4-ethylphenoxy) methybenzamide hydrochloride A solution of (2 - [(4-ethylphenoxy) methyl] benzoic acid (1.13 g, 4.4 mmol) obtained in the preparation example 2-1 in chloroform (20 ml) was added oxalyl chloride (0.6 ml, 6.8 mmol) and the mixture was stirred at room temperature for 1 hour, then the reaction mixture was concentrated under reduced pressure and the acid chloride obtained was mixed with pyridine (20 ml) and 4,6-diamino-2-methylene quinoline ( 623 mg, 4 mmol) obtained in Preparation Example 1-1 and the mixture was stirred at room temperature for 10 hours.To the reaction mixture was added aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate The organic layer was washed with water and saturated brine and dried over sodium sulfate and the solvent was evaporated.The crude product obtained was dissolved in ethanol and treated with activated carbon and the solvent was evaporated.The residue obtained was dissolved in acetate of ethyl and hydrochloric acid solution was added 1 N-ether The resulting precipitate was collected by filtration. The solid obtained was heated and dried under reduced pressure to give the title compound (1.06 g, 59% pale yellow crystals). Elemental analysis for C26 H25 N3O2 • Calculated HCl: C: 69.71% H: 5.85%, N: 9.38% Found: C: 69.77%, H: 5.78%, N: 9.41% Melting point: 235 ° C EXAMPLE 131 Synthesis of N- (4-amino-2-hydroxymethyl-6-quinolyl) -2-r (4-methylphenoxy-methyl-benzamide hydrochloride Step 1 A solution of 4-nitroaniline (6.91 g, 50 mmol) and dimethyl acetylenedicarboxylate (7.82 g, 55 mmol) in methanol (100 ml) was refluxed with heat for 24.5 hours. The reaction vessel was cooled to room temperature and left to stand for one day. The resulting crystals were collected by filtration to give dimethyl 2 - [(4-nitrophenyl) amino] -2-butenedioate (6.43 g, 46% yellow crystals) Step 2 To the Dowtherm A (trade mark, 30 ml) under reflux under heat was added dimethyl 2 - [(4-nitrophenyl) amino] -2-butenedioate (6.32 g, 22.6 mmol) obtained in example 131, step 1 for 5 minutes in small portions. The mixture under reflux with heat for 25 minutes was then cooled to room temperature. The reaction mixture was diluted with ether and the resulting precipitate was filtered. The crude crystals obtained were suspended in methanol and collected by filtration to give methyl 1,4-dihydro-6-nitro-4-oxo-2-quinolinecarboxylate (4.75 g, 85% dark brown crystals).

Step 3 To a suspension of methyl 1,4-dihydro-6-nitro-4-oxo-2-quinolinocarboxylate (3.72 g, 15 mmol) obtained in example 131, step 2 in acetonitrile (50 ml) was added: socianate of chlorosulfonyl (1.30 ml, 15 mmol) and the mixture was refluxed with heat for 1 hour. The reaction mixture was cooled to room temperature and methanol was added followed by concentration under reduced pressure. To the residue, 2 mol / l aqueous sodium carbonate solution was added to allow the suspension and the insoluble material was collected by filtration. The insoluble material was dried under reduced pressure at 80 ° C to give methyl 4-amino-6-nitro-2-quinolino carboxylate as brown crude crystals (3.23 g). This compound was used in the next reaction without purification.

Step 4 To a suspension of crude crystals (494 mg) of methyl 4-amino-6-nitro-2-quinoline carboxylate obtained in example 131 step 3 and 5% palladium carbide (500 mg) in ethanol (10 ml ) was hydrogenated at room temperature under normal pressure. After 2.5 hours the reaction mixture was passed through celite. The filtrate was concentrated under reduced pressure to give a crude product of methyl 4,6-diamino-2-quinoline carboxylate (275 mg yellow foamy solid). This compound was used in the next reaction without purification.

Step 5 The crude product (270 mg) of methyl 4,6-diamino-2-quinoline carboxylate obtained in example 131, step 4 and 2 - [(4-methylphenoxy) methyl] benzoic acid (363 mg, 1.5 mmol ) obtained in the same manner as preparation example 2-1 were condensed to amide in the same manner as example 1 to give N- (4-amino-2-methoxycarbonyl-6-quinolyl) -2 - [(4- methylphenoxy) methyl] benzamide (175 mg, 17%) from 1,4-dihydro-6-nitro-4-oxo-2-quinolinecarboxylate dimethyl as a yellow solid.

Step 6 To a solution of N- (4-amino-2-methoxycarbonyl-6-quinolyl) -2 - [(4-methyxycarbonyl) methyl] benzamide (170 mg, 0.385 mmol) obtained in example 131, step 5 in tetrahydrofuran (10 ml) Lithium tetrahydroborate (42 mg, 1927 mmol) was added in small portions under ice cooling under an argon stream. After 10 minutes, the mixture was warmed to room temperature and the mixture was stirred for 2 hours. The reaction mixture was diluted with saturated brine and with ethyl acetate to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The yellow residue obtained was dissolved in ethyl acetate and 4N-dioxane hydrochloric acid solution (0.5 ml) which was added to precipitate the hydrochloride. This salt was collected by filtration and dried under reduced pressure at 80 ° C to give the title compound (116 mg, 67% pale yellow crystals). A substituted amino compound obtained in the same manner as in Preparation Examples 1-1 to 1-6 or a commercially available substituted amino compound and the carboxylic acid derivative obtained in the same manner as in Preparation Examples 2-1 to 2-4 or the commercially available carboxylic acid derivative were treated in the same manner as in Examples 1 or 131 to give the compounds of Example 2 to Example 130 and Example 132. The values of their properties are shown in Tables 1 to 44.

EXAMPLE 133 Synthesis of N- (4-amino-2-methyl-6-quinolyl) -2 - [(ethylphenoxy) methylenebenzamide hydrochloride monohydrate The crude crystals of N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethyl phenoxy) methyl] benzamide hydrochloride (24.0 g, 53.7 mmoles) obtained in the same manner as example 1 they were mixed with ethanol (120 ml) and the mixture was heated to 55-60 ° C for its dissolution. This solution was filtered and to the filtrate water (120 ml) was added dropwise with stirring under heating at 55-60 ° C. This reaction mixture was cooled to room temperature and the resulting precipitate was filtered. The solid obtained was dried at 1 mm Hg at 60 ° C for 3 days to give the title compound (22.6 g, 94% colorless crystals). Elemental analysis for C2ß H25 N3O2 • HC1 • H2O Calculated: C: 67.02%, H: 6.06%, N: 9.02% Found: C: 66.64%, H: 6.06%, N: 8.99% Melting point: 130 ° C TABLE 1 TABLE 2 MS TABLE 3 TABLE 4 TABLE 5 TABLE 6 TABLE 7 TABLE 8 TABLE 9 TABLE 10 Exp. No. FORMULA ESTRUCTURAL P.F. 1HNMR (d) ppm MS SOLVENT CHARACTER DMSO-d6,300MHz 28 233 ° C DMSO-d6,300MHz 29 268 ° C DMSO-d6,300MHz 268 ° C TABLE 11 TABLE 12 TABLE 13 TABLE 14 TABLE 15 TABLE 16 9 TABLE 17 TABLE 18 TABLE 19 TABLE 20 TABLE 21 TABLE 22 TABLE 23 TABLE 24 TABLE 25 TABLE 26 TABLE 27 1 2 TABLE 28 TABLE 29 TABLE 30 TABLE 31 TABLE 32 TABLE 33 TABLE 34 TABLE 35 1 0 TABLE 36 TABLE 37 TABLE 38 TABLE 39 14 TABLE 40 TABLE 41 TABLE 42 TABLE 43 TABLE 44 The method for evaluating the analgesic effect of the compound of the present invention is explained below. For an in vitro evaluation, the ORL-1 receptor binding assay was performed, and the μ receptor binding assay was performed for the selectivity evaluation. For an in vivo evaluation, the hot plate test and the tail whip test known for a long time as a test method for the analgesic effect to be carried out, and the tactile sensation stimulation test was performed using a model of allodynia for the evaluation of allodynia.

EXPERIMENTAL EXAMPLE (1) ORL-1 receptor binding assay The cell membrane suspension obtained from human ORL-1 expression cells was adjusted with a Tris pH regulator [50 mM Tris, 2 mM EDTA, 0.1 mM (p-amidinophenyl) methanesulfonyl fluoride hydrochloride (p-APMSF), 2 mg / ml BSA] for a membrane protein amount of almost 25 μg / ml (2.5 μg / well). This was mixed with [3 H] nociceptin (diluted with a Tris pH regulator to a final concentration of 0.5 nM) and a test compound (diluted with a Tris pH regulator to a final concentration of 10 nM-10 μM), and The mixture was incubated at room temperature for 60 minutes. The membrane was recovered on a G / F-B filter (Packard, Unifilter 96GF / B) using a cell cultivator and the reaction was stopped. After washing it three times, the filter was dried at 42 ° C for 1 hour. A scintillation solution (Packard, microscint-20) was added and the radioactivity (Packard, Top count A9912V) was tested. The non-specific binding was the binding in the presence of 1 μM nociceptin and the difference between the total binding and the non-specific binding was taken as the specific binding. An IC5n of specific binding inhibition was calculated at each concentration of the compound and a Ki value of the test compound was calculated from this value and the Kd value of nociceptin [3H].

EXPERIMENTAL EXAMPLE (2) Receptor binding assays u The standard sample of the brain membrane of the rat (with a final concentration of 0.755 mg • protein / ml), [3H] DAMGO (Try-D-Ala-Gly-NMe-Phe-Gly-ol) [diluted with a pH regulator Tris (50 mM Tris-HCl, 0.1 mM p-APMSF, 2 mg / ml BSA (pH = 7.4)) at a final concentration of 1 nM] and a test compound (diluted with a pH regulator Tris a a final concentration of 10 nM-10 μM) were mixed, and the mixture was incubated at room temperature for 90 minutes. The membrane was recovered on a G / F-B filter (the same as the previous one) using a cell cultivator and the reaction was stopped. After washing it three times, the filter was dried at 42 ° C for 1 hour. A scintillation solution (the same as the previous one) was added and the reactivity (the same as the previous one) was tested. The non-specific binding was the binding in the presence of 10 μM naloxen and the difference between the total binding and the non-specific binding was taken as the specific binding. An IC50 of specific binding inhibition was calculated at each concentration of the compound, and a Ki value of the test compound was calculated from this value and the Kd value of [3 H] DAMGO.

EXPERIMENTAL EXAMPLE (3) Hot plate test Mice (Crj, ICR, 4 weeks, males) were placed on a hot plate (at a temperature of 55.5 ± 0.5 ° C) and the time was recorded until the mice jumped and tried to escape. The mice were grouped according to time and body weight because the groups were uniformly integrated. The test compound was suspended in a 0.5% methylcellulose (MC) solution and orally administered to the mice. After 60 minutes, the mice were placed back on a hot plate and time was recorded until they licked their hind limbs or jumped and tried to escape. The remarkable difference of the group administered with solvent was analyzed with ANOVA followed by Dunnett's two-tailed test.

EXPERIMENTAL EXAMPLE (4) Tail whip test The rats (Crj, SD, 7 or 8 weeks, males) were irradiated with a thermal beam around the base of the tail from below and the time until the rats moved the tail and escaped was measured using a measuring device of the analgesic effect of the tail whip (manufactured by UGO BASILE). Before administration of the test compound, the measurement was repeated 3 times and the rats were grouped according to time and body weight because the groups were uniformly integrated. The test compound was suspended in a 0.5% MC solution and administered orally to the rats. After 30,60,90,120 and 180 minutes of administration, the same measurement was repeated. The remarkable difference of the group administered with solvent was analyzed with ANOVA followed by Dunnett's two-tailed test.

EXPERIMENTAL EXAMPLE (5) Allodynia test Mice (Crj-ICR, 4 weeks, males) were intrathecally administered with nociceptin (50 pg / 5 μl) without anesthesia. During 20 minutes after administration and at 5 minute intervals, an area of the lateral region in the tail of the mice was rubbed with a brush and the response of the mice was observed. The evaluation follows the criteria of 0; without change, 1; run or scream before tactile stimulation, and 2; scream loudly or run away from tactile stimulation. The test compound was suspended in a 0.5% MC solution and administered orally 60 minutes before the administration of nociceptin. With the Mann-Whitny U-test, the remarkable difference in the score of each administration group was analyzed 20 minutes after the administration of nociceptin from a group administered with solvents. The results of the experimental examples from [1] to [5] are shown in tables 45 to 47.

TABLE 45 D.M.E. MINIMUM EFFECTIVE DOSE TABLE 46 D.M.E. MINIMUM EFFECTIVE DOSE TABLE 47 D.M.E. MINIMUM EFFECTIVE DOSE EFFECTS OF THE INVENTION As is evident in the results of the above tests, the compound of the present invention shows a strong analgesic effect due to the antagonistic action of nociceptin, and a part of it shows a selective action at the ORL-1 receptors. as compared to opioid receptors (μ,?, d receptors) including a μ receptor. Therefore, the compound of the invention can create an effect of a pharmaceutical agent against pain, particularly with strong pain such as post-operative pain and the like or pain caused by an abnormality of the sensory nerve such as hyperalgesia, allodynia and the like. . In addition, because the compound shows a selective action in the ORL-1 receptor, it can be a safe pharmaceutical agent without marked side effects. This application is based on application number 100029/1998 filed in Japan, the content of which is incorporated herein by reference.

Claims (18)

NOVELTY OF THE INVENTION CLAIMS

1. - A nociceptin antagonist containing an amide derivative of the formula (I) [1] wherein R1 and R2 are the same or different and each is a hydrogen atom, a lower alkyl optionally substituted by hydroxy, amino, lower alkylamino or dialkylamino lower; R3 and R4 are the same or different and each is a hydrogen atom, a halogen atom or lower alkyl; Ring A is an aryl or heterocyclic group; Ring B is phenyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl or cyclohexenyl; and X is a hydrogen atom, a halogen atom, a lower alkyl optionally substituted by a lower alkoxy, lower alkenyl, amino, cyano or a group of the formula wherein E is a single bond, carbonyl, sulfinyl, -O-. -S-, -NHCO-, CH = CR6- wherein R6 is a hydrogen atom or aryl or -NR7 wherein R7 is a hydrogen atom, a lower alkyl or a lower akoxycarbonyl; ring G is aryl, heterocyclic group; cycloalkyl or fused aryl: R 5 is a halogen atom, hydroxy, lower alkyl optionally substituted by a halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by lower alkoxy, lower alkoxy optionally substituted by lower alkoxy, amino, lower alkylamino, dialkylamino lower, nitro, cyano, lower alkanoyl, lower alkanoyloxy carboxy, lower alkoxycarbonyl, lower alkylsulfonyl or phenyl; t is O or an integer from 1 to 5, which indicates the number of substituents on ring G, where t is an integer from 2 to 5, each R 5 can be the same or different: m is O or an integer of 1 to 8; and n is O or an integer from 1 to 4, or a pharmaceutically acceptable salt thereof as an active ingredient.

2. An antagonist of the nociceptin containing the amide derivative of claim 1, wherein ring A is quinolyl or a pharmaceutically acceptable salt thereof as an active ingredient.

3. An antagonist of the nociceptin containing the amide derivative of claim 1, wherein ring B is phenyl and X is a group of the formula 0 where E, the ring G, R5 t, m, and n are as defined in claim 1 or a pharmaceutically acceptable salt thereof as the active ingredient.

4. A nociceptin antagonist containing the derivative of claim 3, wherein ring A is wherein R8 is a lower alkylthio or a pharmaceutically acceptable salt thereof as the active ingredient.

5. An amide derivative of the formula [1 '] [11 wherein R2, ring, B, E, ring G R3, t, m and n are defined as in claim 1, or a pharmaceutically acceptable salt thereof.

6. The amide derivative of claim 5, wherein ring B is phenyl and R2 is a lower alkyl, or a pharmaceutically acceptable salt thereof.

7. - The amide derivative of claim 6, wherein the amino replaces at position 4 on a backbone that quinoline, R2 is methyl substituting at the 2-position of the quinoxy skeleton, E is -O- and ring B of the phenyl has a substituent of the formula wherein the ring G, R5, t, m and n are as defined in claim 1, in the 2- position, or a pharmaceutically acceptable salt thereof.

8. The amine derivative of claim 7, or a pharmaceutically acceptable salt thereof, which are selected from the group consisting of N- (4-amino-2-methyl-6-quinolyl) -2 - [( 4-ethylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2,4-dichlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-chlorohydrate) 2-methyl-6-quinolyl) -2- (phenoxy-methyl) benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 [(4-methoxyphenoxy) methyl] benzamide hydrochloride, N-hydrochloride - (4-amino-2-methyl-6-quinolyl) -2 - [(3,5-dimethylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) hydrochloride -2 - [(3,4-dimethoxy-phenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-nitrophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2,3-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-methylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3,5-dimethylphenoxy) methyl] benzamide hydrochloride, N- hydrochloride (4-amino-2-methyl-6-quinolyl) -2 - [(4-chlorophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [( 4-acetylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinoyl) -2 - [(4-hydroxy-phenoxy) methyl] benzamide hydrochloride, hydrochloride of N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-methoxymethoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2- [ (3-methoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-cyanophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2- hydrochloride methyl-6-quinolyl) -2 - [(4-methylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-trifluoromethylphenoxy) methyl] benzamide hydrochloride , N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-nitrophenoxy) methyl] benzamide hydrochloride, c N- (4-amino-2-methyl-6-quinolyl) -2 - [(2-nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) hydrochloride -2 - [(4-acetoxyphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2-methoxyphenoxy) methyl] benzamide hydrochloride, N- (4- hydrochloride) amino-2-methyl-6-quinolyl) -2 - [(4-aminophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-chlorophenoxy) methyl hydrochloride ] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-fluorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) hydrochloride -2 - [(3,4-Dichlorophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2-chlorophenoxy) methyl] benzamide hydrochloride, N- hydrochloride 4-amino-2-methy-6-quinolyl) -2 - [(4-dimethylamino-phenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) hydrochloride -2 - [(4-tert-Butylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-benzopyloxymethyl) methyl] benzamide hydrochloride, hydrochloride of N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-isopropylphenoxy) methyl] b Enzyme, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) hydrochloride -2 - [(4-Bromophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-propylfenoxy) methyl] benzamide hydrochloride, hydrochloride of N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-fluorophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2- [ (3-trifluoromethylphenoxy) methyl] benzamide, methyl-4- [2-] hydrochloride. { N- (4-amino-2-methyl-6-quinolyl) carbamonyl} benzyloxy] benzoate, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-iodophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl hydrochloride ) -2 - [(3-pyridyloxymethyl) benzamide, hydrochloride of 4- [2-. { (4-amino-2-methyl-6-quinolinyl) carbamoyl} benzyloxy] benzoate, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-cyano-phenoxy) -methyl] -benzamide hydrochloride, N- (4-amino-2-methyl-6-hydrochloride) -quinol1) -2 - [(4-mesophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2-chloro-4-hydrochloride ethylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-chloro-3-methylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-hydrochloride -methyl-6-quinolyl) -2 - [(2-chloro-4-methylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4- ethylphenoxy) methylene] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-chloro-3-methylphenoxy) methyl] benzamide hydrochloride, 4- [2-hydrochloride] -. { (4-amino-2-methyl-6-quinolyl) carbamonyl} benzylloxy] benzyl acetate, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-hydroxylmethylphenoxy) methyl] benzamide hydrochloride and N- hydrochloride 4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide monohydrate.

9. An amide derivative of the formula [1"'] [V] wherein ring A, R2, R5 and t are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the amide derivative of any of claims 5 to 9, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

11. An antagonist of the nociceptin containing the amide derivative of any of claims 5 to 9, or a pharmaceutically acceptable salt thereof as an active ingredient.

12. An analgesic containing the amide derivative of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof as an active ingredient.

13. The use of the amide derivative as claimed in any of claims 1 to 9, or a pharmaceutically acceptable salt thereof for the production of a medicament for expressing an antagonistic action of nociceptin.

14. The use of the amide derivative as claimed in any of claims 1 to 9, or a pharmaceutically acceptable salt thereof for the production of an analgesic medicament for the treatment of pain.

15. A pharmaceutical composition for antagonizing nociceptin, comprising the amide derivative of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. A commercial package comprising the pharmaceutical composition of claim 15 and a written material associated therewith establishing said written material that the pharmaceutical composition can or should be used to antagonize nociceptin.

17. A pharmaceutical composition for analgesic use, comprising the amide derivative of any of claims 1 to 9, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

18. A commercial package comprising the pharmaceutical composition of claim 17, and a written material associated therewith establishing said written material that the pharmaceutical composition can or should be used for analgesia.