WO2004007464A1 - Derive d'imidazole - Google Patents

Derive d'imidazole Download PDF

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Publication number
WO2004007464A1
WO2004007464A1 PCT/JP2003/008682 JP0308682W WO2004007464A1 WO 2004007464 A1 WO2004007464 A1 WO 2004007464A1 JP 0308682 W JP0308682 W JP 0308682W WO 2004007464 A1 WO2004007464 A1 WO 2004007464A1
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WIPO (PCT)
Prior art keywords
group
methyl
formula
saturated
imidazole
Prior art date
Application number
PCT/JP2003/008682
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English (en)
Japanese (ja)
Inventor
Masafumi Kitano
Hiroki Yamaguchi
Original Assignee
Sumitomo Pharmaceuticals Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumitomo Pharmaceuticals Co., Ltd. filed Critical Sumitomo Pharmaceuticals Co., Ltd.
Priority to JP2004521157A priority Critical patent/JPWO2004007464A1/ja
Priority to AU2003281039A priority patent/AU2003281039A1/en
Publication of WO2004007464A1 publication Critical patent/WO2004007464A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D233/84—Sulfur atoms

Definitions

  • Chymase is one of the in vivo enzymes found in mast cell secretory granules and one of the subfamilies of chymotrypsin-like serine proteases. Chymase, when released extracellularly, rapidly binds to the surrounding extracellular matrix, cleaves the extracellular matrix of type IV collagen fibronectin, enhances vascular permeability together with histamine, and enhances histamine action.
  • ACE angiotensin-converting enzyme
  • bathoactive intestinal polypeptide VIP
  • apoprotein B apoprotein B
  • VIP bathoactive intestinal polypeptide
  • apoprotein B apoprotein B
  • chymase also uses ApoA-I as a substrate, it has been revealed that chymase has an effect of inhibiting the reverse phase system of cholesterol. Looking at the distribution of chymase, it has been confirmed that mast cells exist outside the blood vessels of the heart, and that chymase activity exists in mast cells and interstitium in association with extracellular matrix. In addition to the heart, there are many distributions in the skin, lung, liver, and renal cortex.
  • chymase having such various physiological activities is involved in various disease states, for example, myocardial infarction, heart failure, restenosis after PTCA (Percutaneous Transluminal Coronary Angioplasty), Involved in hypertension, diabetic complications, allergic diseases, asthma, etc. Is known to be.
  • PTCA Percutaneous Transluminal Coronary Angioplasty
  • an activity inhibitor for chymase is considered to be useful as a therapeutic agent for cardiovascular disorders, a therapeutic agent for arteriosclerosis, an anti-inflammatory agent, an anti-allergic agent and the like.
  • a compound having a chymase inhibitory action is a compound that is considered to improve its condition based on this action, for example, hypertension mediated by angiotensin II, endothelin, etc., heart failure, ischemia Peripheral circulatory disorder, myocardial ischemia, venous insufficiency, progression of heart failure after myocardial infarction, diabetic nephropathy, nephritis, arteriosclerosis, hyperaldosteronism, scleroderma, glomerulosclerosis, renal failure, central nervous system Disorders, Alzheimer's disease, memory deficiency, depression, sensory dysfunction including amnesia and senile dementia, anxiety and tension symptoms, discomfort, glaucoma, ocular hypertension, restenosis or asthma after
  • Compounds having a chymase inhibitory action include, for example, benzimidazole derivatives (International Publication WOOOZO 3997). These compounds are structurally different from the compounds of the present invention. .
  • An object of the present invention is to provide a compound having chymase inhibitory activity and useful as a therapeutic agent for the above-mentioned diseases.
  • the present inventors have conducted intensive studies to achieve the above object, and as a result, have found that a compound represented by the general formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof (hereinafter referred to as the compound of the present invention as necessary) (Sometimes abbreviated) has an excellent chymase inhibitory action. That is, the present invention relates to the following.
  • Y 1 is a saturated or unsaturated monocyclic hydrocarbon ring, a saturated or unsaturated polycyclic hydrocarbon ring, a saturated or unsaturated monocyclic heterocyclic ring, or a saturated or unsaturated polycyclic complex ring (These rings may be unsubstituted or have a substituent.)
  • Y 2 is a saturated or unsaturated monocyclic hydrocarbon ring group, a saturated or unsaturated polycyclic carbon Hydride ring group, saturated or unsaturated monocyclic heterocyclic group, or saturated or unsaturated polycyclic heterocyclic group (these groups may be unsubstituted or have a substituent ).
  • R 7 one S (O) 2 N (R 6 ) R 7 , one N (R 4 ) S (O) 2 R 8 , or a tetrazolyl group
  • M is a hydrogen atom There may be.
  • R lb is a saturated or unsaturated monocyclic hydrocarbon ring, a saturated or unsaturated polycyclic hydrocarbon ring, a saturated or unsaturated monocyclic heterocyclic ring, or a saturated or unsaturated polycyclic heterocyclic ring (These rings may be unsubstituted or may have a substituent.)
  • R lc is a hydrogen atom, a substituted or unsubstituted alkoxycarboyl group, or a substituted Alternatively, it represents an unsubstituted alkyl group.
  • n and n each independently represent 0, 1 or 2.
  • R 3 , R 4 , R 4a , R 6 , R 7 , R 9 , R 10 , and R 11 are the same or different, and when there are a plurality of them, each is independently a saturated or unsaturated monocyclic A hydrocarbon ring group, a saturated or unsaturated polycyclic hydrocarbon ring group, a saturated or unsaturated monocyclic heterocyclic group, or a saturated or unsaturated polycyclic heterocyclic group (these groups are unsubstituted Or a substituted or unsubstituted alkyl group, a substituted or unsubstituted acyl group, or a substituted or unsubstituted alkoxy group. Represents a hydroxyl group.
  • R 6 and R 7 , and R 10 and R 11 may contain another heteroatom in the ring together with the nitrogen atom to which they are bonded.
  • a saturated 3- to 8-membered cyclic amino group wherein the cyclic amino group is at least one substituted or unsubstituted alkyl group, or a compound represented by the formula: 1 S (O) m R 12 or 1 OR 9a (where R 9a is Which represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted acyl group).
  • R 5 , R 8 , and R 12 are the same or different, and if there is more than one, each is independently a saturated or unsaturated monocyclic hydrocarbon ring group, a saturated or unsaturated polycyclic hydrocarbon ring.
  • R lb is saturated
  • the compound according to [1] a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is a monocyclic heterocycle of
  • [8] A drug containing the compound according to any one of [1] to [7], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • a chymase inhibitor comprising the compound according to any one of [1] to [7], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • Y 1, R 1 b 2 monovalent definition of saturation are used or unsaturated monocyclic carbon hydrocarbon ring group such as a polycyclic hydrocarbon rings saturated or unsaturated, single saturated or unsaturated
  • the cyclic complex ring and the saturated or unsaturated polycyclic heterocycle mean those in which two hydrogen atoms of each ring described below are replaced by a bond.
  • the heterocyclic group includes a monocyclic heterocyclic group and a polycyclic heterocyclic group
  • the hydrocarbon ring group includes a monocyclic hydrocarbon ring group and a polycyclic hydrocarbon ring group.
  • the groups are each a saturated or unsaturated monocyclic hydrocarbon ring, a saturated or unsaturated polycyclic hydrocarbon ring, a saturated or unsaturated monocyclic heterocyclic ring, and a saturated or unsaturated Means that one hydrogen atom of the polycyclic heterocycle has been replaced by a bond.
  • saturated or unsaturated monocyclic hydrocarbon ring examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cycloheptene , Cyclooctene, benzene and the like, and a 3- to 8-membered hydrocarbon ring.
  • cycloalkane ring examples include a 3- to 8-membered cycloalkane ring such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane and the like.
  • saturated or unsaturated polycyclic hydrocarbon ring examples include, for example, indene, naphthalene, azulene, fulsylene, phenalene, phenanthrene, anthracene, acephenanthrylene, 1,2-dihydronaphthalene, 6,7-dihydro-5H— Benzocycloheptene, benzocyclooctene, 1,2,3,4-tetrahydronaphthalene, decahydronaphthalene, octahydro-iH-Indene, and other polycyclic rings with up to 16 carbon atoms Adamantane, bicyclo [2,2,2] octane, bicyclo [3,3,3] ndecane, bicyclo [2,2,2] octa-1-ene, bicyclo [ [3,3,3] Indeca-2-ene and the like, and a crosslinked polycyclic hydrocarbon ring having 12 or less carbon atoms.
  • saturated or unsaturated monocyclic heterocyclic ring examples include, for example, a 3- to 8-membered unsaturated monocyclic heterocyclic ring containing 1 to 4 nitrogen atoms, and a 3- to 4-membered monocyclic heterocyclic ring containing 1 to 4 nitrogen atoms.
  • Examples of the 3- to 8-membered unsaturated monocyclic heterocyclic ring containing 1 to 4 nitrogen atoms include pyrrole, pyrroline, pyridine, dihydropyridine, imidazole, pyrazole, imidazoline, pyrazine, pyrimidine, pyridazine, pyrazo / Re, triazole, tetrazole and the like.
  • Examples of the 3- to 8-membered saturated monocyclic heterocyclic ring containing 1 to 4 nitrogen atoms include pyrrolidine, piperidine, imidazolidine, virazolidine, piperazine and the like.
  • Examples of the 3- to 8-membered unsaturated monocyclic heterocyclic ring containing one oxygen atom include furan and pyran.
  • Examples of the 3- to 8-membered unsaturated monocyclic heterocyclic ring containing 1 to 2 sulfur atoms include thiophene, dihydrodithioin, and dihydrodithione.
  • Examples of the 3- to 8-membered unsaturated monocyclic complex containing 1 to 3 nitrogen atoms and 1 to 2 oxygen atoms include oxazole, oxazidazole, isoxazole and the like.
  • Examples of the 3- to 8-membered saturated monocyclic heterocyclic ring containing 1 to 3 nitrogen atoms and 1 to 2 oxygen atoms include morpholine and oxazolidin.
  • Examples of the 3- to 8-membered unsaturated monocyclic complex containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms include thiazole, isothiazole, thiadiazonol and the like.
  • Examples of the 3- to 8-membered saturated monocyclic heterocyclic ring containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms include thiazolidine.
  • Examples of the 3- to 8-membered unsaturated monocyclic heterocyclic ring containing one oxygen atom and one or two sulfur atoms include dihydrooxathiin.
  • saturated or unsaturated polycyclic heterocyclic ring examples include a saturated or unsaturated condensed heterocyclic ring containing 1 to 4 nitrogen atoms, and containing 1 to 3 nitrogen atoms and 1 to 2 oxygen atoms.
  • Unsaturated condensed heterocycles containing an oxygen atom and one or two sulfur atoms, and unsaturated condensed heterocycles containing one or two sulfur atoms are included.
  • indole isoindole, indoline, quinoline, isoquinoline, quinolizine, indazole, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, and rubazonole
  • Examples of unsaturated condensed heterocycles containing 1 to 3 nitrogen atoms and 1 to 2 oxygen atoms include, for example, benzoxazonole, benzoxadiazonole, phenoxazine, and pyrrole [1, 2,3—de] [1,4] Benzoxazine, Pyro mouth [2,1—c] [1,4] Benzoxazine, Pyro mouth [3,2,11 k1] Benz [e] [4,1 Oxazosin, etc., and preferably benzoxazole, pyro [1,2,3-de] [1,4] benzoxazine, pyro [2,1-1c] [1,4] benzoxazine, pyro [3 , 2, 1— k 1] benz [e] [4, 1] oxazosin.
  • Examples of the unsaturated condensed heterocyclic ring containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms include benzothiazole, benzothiadiazole, 1,4-benzothiazine, phenothiazine and the like, and preferably benzothiazole , 1,4 Benzothiazine.
  • Examples of the unsaturated condensed heterocycle containing one or two oxygen atoms include benzofuran, dihydrobenzofuran, chromene, isobenzofuran, xanthene, isochroman, chroman, and benz [b] oxepin. Benzofuran, benz [b] oxepin and the like.
  • Examples of the unsaturated condensed heterocyclic ring containing one oxygen atom and one or two sulfur atoms include 1,4-benzoxathiin, phenoxathiin and the like.
  • Examples of the unsaturated condensed heterocyclic ring containing one or two sulfur atoms include benzothiophene, benzothiin, benzothiopyran, thiochroman, and thiantrene, and preferably benzothiophene, benzothiopyran and thiochroman.
  • a naphthyl group, a heterocyclic group, an arylo group, a saturated heterocyclic-carbonyl group, and a heteroaromatic acyl group may be one or more, and may be the same or different; for example, a hydrogen atom, a substituted or Unsubstituted alkyl group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubsti
  • A'-CH NR 19 (A, represents an oxygen atom, one S (O) r or one N (R 21 ) —, r represents an integer of 0, 1 or 2;
  • R 19 and R 21 each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloanolealkyl group, a fuel group, a naphthyl group, a saturated or unsaturated heterocyclic group, or an acyl group; Represents a saturated complex ring consisting of one to eight-membered nitrogen atom and carbon atom).
  • R 13 and R 13a independently represent a hydroxy group, an alkyl group, a cycloalkyl group, a phenyl group, a naphthyl group, or a saturated or unsaturated heterocyclic group.
  • R 15 , R 16 , R 17 , and R 18 each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a phenyl group, a naphthyl group, a saturated or heterocyclic group unsaturated alkoxycarbonyl El group of the formula: a S (O) n group represented by R 13 or represents a Ashiru group, or R 15 and R 16 or R 17 and R 18, mutually A saturated 3- to 8-membered cyclic amino group which may contain another heteroatom in the ring together with the nitrogen atom to which they are attached (the cyclic amino group may be one or more).
  • a substituted or unsubstituted alkyl group of one S (O) n R 13, - represents a n (R 14) R 14a, with water acid groups or single oR 14b may be substituted).
  • R 14 , R 14a , or R 14b independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a fuel group, a naphthyl group, or a saturated or unsaturated heterocyclic group.
  • Examples of the group represented by R 34 include the same groups as the groups represented by R 9 .
  • alkyl group for example, straight-chain or branched such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butylinole, 2-methylpropyl, 1,1-dimethylinoleethyl, pentyl, hexyl, heptyl, otatyl and the like
  • alkyl groups with 8 or less carbon atoms are mentioned.
  • Examples of the cycloalkyl group include 3- to 8-membered cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Examples of the cycloalkenyl group include 3- to 8-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl and 3-cyclohexenyl.
  • a cyclized alkenyl group having one membered double bond is exemplified.
  • alkenyl group examples include a linear or branched alkenyl group having 6 or less carbon atoms such as butyl, aryl, propyl, 2-propenyl, butyr, pentyl, hexenyl and the like.
  • alkienole group examples include straight-chain or branched alkynyl groups having 6 or less carbon atoms, such as ethel, propargyl, butchur, and pentul.
  • halogen atom examples include iodine, fluorine, chlorine, and bromine atoms.
  • acyl group examples include a formyl group, for example, an anorecanoyl group having 2 to 6 carbon atoms such as acetyl and propanoyl, for example, propanecarbonole, cyclobutanecanoleponyl, cyclopentanecanoleponyl, and hexahexanecarbonyl.
  • a cycloanolecancanoleponinole group having 4 to 7 carbon atoms such as, for example, ⁇ cyclopentene carbonyl, a cycloalkene carbonyl group having 3 to 6 carbon atoms such as cyclohexene carbole, for example, benzoinole, Toluoyl, naphthoyl and other aromatic atoms having 6 to 10 carbon atoms, such as 2-piperidinecarbonate, 3-morpholinecarbonyl and other nitrogen atoms, oxygen atoms and sulfur atoms.
  • Heterocycles having a 5- or 6-membered saturated heterocycle including -canoleponyl groups, such as Freonole
  • Examples thereof include a heteroaromatic acyl group having a 5- or 6-membered heteroaromatic ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur, such as tenyl, nicotinol, and isonicotinoyl.
  • R 19 has the same meaning as described above, and the ring represents a saturated heterocyclic group comprising one 3- to 8-membered nitrogen atom and a carbon atom.
  • the phenyl group, the naphthyl group , An arylsulfonyloxy group, a saturated or unsaturated heterocyclic group may be substituted with one or more, the same or different, substituents. Examples of such a substituent include an alkyl group and an alkoxy group. Groups, halogen atoms).
  • R 33 , R 35 , and R 36 include the same groups as R 13 , R 15 , and R 16 , respectively.
  • Examples of such a substituted alkyl group include an alkyl group having 1 to 5 carbon atoms substituted with a cycloalkyl having 3 to 6 carbon atoms, a polyhaloalkyl group having 1 to 5 carbon atoms, and a carbon atom having 1 to 5 carbon atoms.
  • Typical substituted alkyl groups include polyhaloalkyl groups having 1 to 3 carbon atoms, such as trifluoromethyl, trifluoroethyl, and trichloromethyl, and carbon atoms such as hydroxymethyl, hydroxyethyl, and 1-hydroxyethyl.
  • C1-C6 alkoxyalkyl such as hydroxyalkyl group, aminomethyl, aminoethyl, 1-aminoethyl, etc., having 1-5 carbon atoms; C1-C6 alkoxy such as methoxyl, ethoxyl, methoxypropyl, etc.
  • Alkyl group carboxyethyl, carboxypropyl Which C2 -C6 carboxyalkynole group, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, etc., C3 -C7 alkoxy quinoleponinoleanolequinole group, benzylinole, Phenyl or naphthyl mono-Cl to C 5 alkyl groups (such as C 1 to C 3 alkyl groups in the phenyl or naphthyl portion, One nitrogen atom such as a halogen atom, a nitro group, an amino group, a hydroxyl group, a C1-C3 alkoxy group, etc.), rubamoylmethyl, levamoylethyl, dimethylcarbamoylmethyl, etc.
  • two C1-C3 alkyl groups may be substituted with a rubamoyl mono-C1-C3 alkyl group
  • Nitrogen atoms are substituted with one or two C1-C3 alkyl or C7-C11 aralkyl such as aminopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminoethyl, N-methyl-N-benzylaminoethyl, etc. an amino _C1 ⁇ C5 alkyl group, 1 one pyrrolidin Ruechiru, etc. saturated 3 to 8-membered cyclic amino C.
  • R 3 alkyl groups such as piperidines Rijinoechiru can be mentioned
  • R 3, RRRR 10, Rn , R 15, R 16, R 17, R 18, R 35, and in R 36 can be mentioned phenylene Lou C1 ⁇ C5 alkyl groups such Fueniruechiru.
  • Examples of the substituent in the substituted alkenyl group, the substituted alkynyl group, the substituted alkoxycarbonyl group, or the substituted alkanoyl group include the same groups as the above-mentioned substituted alkyl group.
  • the substituents of these groups may be substituted one or more times, the same or different.
  • Examples of the aralkyl group include an alkyl group substituted with a phenyl group or a polycyclic hydrocarbon ring group.
  • R 6 and R 7 , R 10 and R 11 R 15 and R 16 , R 17 and R 18 , or R 35 and R 36 combine with each other to form together with the nitrogen atom to which they are attached,
  • the heteroatom of a saturated 3- to 8-membered cyclic amino group which may contain a heteroatom includes an oxygen atom, a nitrogen atom and a sulfur atom.
  • Specific examples of such a saturated 3- to 8-membered cyclic amino group include a 3- to 8-membered ring group containing 1 to 3 nitrogen atoms or a 3- to 8-membered ring group containing 1 nitrogen atom and 1 oxygen atom.
  • Examples thereof include an 8-membered ring group, and more specifically, 1-pyrrolidinyl, 11-piperidino, 1-piperazinyl, morpholino, 1- (4-methyl) pidazul and the like.
  • Examples of the group represented by the formula: one S (O) 2 R 12 , one S (O) 2 R 13 , or one S (O) 2 R 13a include, for example, a methylsulfonyl group, an ethylsulfonyl group, and a pulpyl a sulfonyl group, an alkylsulfonyl group having a carbon number of 8 or less, such as isopropylsulfonyl group include et al are of the formula: the group represented by a S (O) n R 12, in addition the corresponding alkyl sulfinyl group of the above group Or an alkylthio group or a sulfo group.
  • the substituent of the lower alkylene group, alkenylene group and alkylene group may be one or more, the same or different, for example, an alkyl group, a substituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkyl group.
  • R 45 and R 46 include the same groups as R 15 and R 16 described above.
  • Examples of the lower alkylene group include alkylene groups having 10 or less carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.
  • the compounds represented by the formula (1) include those having an optically asymmetric center, and therefore, they may be in a racemic form or in an optically active form when an optically active starting material is used. Obtainable. If necessary, the racemates obtained can be physically or chemically resolved into their optical antipodes by methods known per se. Preferably, diastereomers are formed from the racemate by reaction with an optically active resolving agent. The diastereomers in different forms can be separated by methods known per se, for example by fractional crystallization.
  • Examples of the “prodrug” include those that are easily hydrolyzed in vivo and regenerate the compound represented by the formula (1).
  • the carboxyl group is converted to an alkoxycarbonyl group.
  • the compound include a compound that has become a group, a compound that has become an alkylthiocarbinole group, and a compound that has become an alkylaminocarboyl group.
  • a compound having an amino group a compound in which the amino group is substituted with an alkanoyl group to form an alkanol group
  • a compound in which the alkoxy group is substituted with an alkoxycarbonyl group to form an alkoxycarbonylamino group, acyloxy
  • Examples include a compound having a methylamino group or a compound having a hydroxylamine.
  • a compound having a hydroxyl group a compound in which the hydroxyl group has been substituted with the above-mentioned acyl group to be an acyloxy group, a compound which has become a phosphoric ester, or a compound which has become an acyloxymethyloxy group can be mentioned.
  • a compound having a phosphono group a compound in which the phosphono group is substituted with one or two alkyl groups to form a phosphonate monoester or a phosphonate ester can be mentioned.
  • alkyl moiety of the group used in these prodrugs include the above-mentioned alkyl groups, and the alkyl group may be substituted (for example, with an alkoxy group having 1 to 6 carbon atoms).
  • Preferred examples include the following.
  • Examples of compounds in which a carbonyl group is an alkoxyl group include lower alkoxy (for example, having 1 to 6 carbon atoms) such as methoxycarbonyl and ethoxycarbonyl, methoxymethoxycarbonyl, ethoxymethoxy. Toxicarbo And lower (for example, having 1 to 6 carbon atoms) alkoxycarbonyl substituted by an alkoxy group such as benzyl, 2-methoxyethoxycarbol, 2-methoxyethoxymethoxycarbyl, and pivaloyloxymethoxycarbonyl.
  • lower alkoxy for example, having 1 to 6 carbon atoms
  • Toxicarbo And lower alkoxycarbonyl substituted by an alkoxy group such as benzyl, 2-methoxyethoxycarbol, 2-methoxyethoxymethoxycarbyl, and pivaloyloxymethoxycarbonyl.
  • Examples of compounds in which a sulfo group is an alkoxysulfonyl group include lower (e.g., 1 to 6 carbon atoms) alcoholoxynorhonolene, methoxysulfonyl, methoxysulfonyl, ethoxysulfonyl and the like. Lower (for example, having 1 to 6 carbon atoms) alkoxysulfonyl substituted by an alkoxy group such as honinole, ethoxymethoxinolehoninore, 2-methoxyethoxysulfonyl, 2-methoxyethoxymethoxysulfonyl, pivaloyloxymethoxysulfonyl, etc. Is mentioned. ⁇
  • Examples of compounds in which a phosphono group is an alkoxyphosphoryl group include lower (for example, C 1 -C 1) such as methoxy (hydroxy) phosphorinole, ethoxy (hydroxy) phosphorinole, dimethoxyphosphoryl, and diethoxyphosphoryl.
  • alkoxyphosphoryl methoxymethoxy (hydroxy) phosphoryl, ethoxymethoxy (hydroxy) phosphoryl, 2-methoxyethoxy (hydroxy) phosphoryl, 2-methoxyethoxymethoxy (hydroxy) Phosphoryl, Vivaloy mouth xymethoxy (hydroxy) phosphoryl, Bis (methoxymethoxy) phosphoryl, Bis (ethoxymethoxy) phosphoryl, Bis (2-methoxyethoxy) phosphoryl, Bis (pivaloyloxime) Shi) phosphoryl, lower substituted by alkoxy groups, such as (for example 1 to 6 carbon atoms) (mono one or di- I) alkoxy phosphoryl and the like.
  • alkoxy groups such as (for example 1 to 6 carbon atoms) (mono one or di- I) alkoxy phosphoryl and the like.
  • the compound represented by the formula (1) or a prodrug thereof can be converted into a pharmaceutically acceptable salt as required.
  • salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, and aspartic acid.
  • a salt with an organic carboxylic acid such as glutamic acid
  • a salt with a sulfonic acid such as methanesnolephonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzene sulfonic acid, dihydroxybenzene sulfonic acid;
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • ammonium salt triethylamine salt
  • pyridine Salts picoline salts
  • ethanolanol salts dihexylhexylamine salts, salts with N, N'-dibenzylethylenediamine, and the like.
  • the compound represented by the formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof may be an anhydride, hydrate or solvate thereof.
  • the compounds of the present invention can be administered orally or parenterally when using them as medicaments. That is, it can be orally administered in a commonly used dosage form, such as a powder, granule, tablet, capsule, syrup, suspension or the like, or, for example, a solution, emulsion, or suspension thereof. Can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories.
  • the above-mentioned suitable dosage form can be produced, for example, by mixing the compound of the present invention with an acceptable usual carrier, excipient, binder, stabilizer, or diluent.
  • an acceptable buffer, solubilizing agent, or isotonic agent can be added.
  • the dosage and number of administrations vary depending on, for example, the target disease, symptoms, age, body weight, and dosage form, but are usually 0.1 to 2000 mg, preferably 1 to 200 mg per day for an adult once or several times. (For example, 2 to 4 times).
  • the compound represented by the formula (1) can be synthesized from a known compound by combining known synthesis methods, and for example, can be synthesized by the following method.
  • L represents a substituted or unsubstituted halogen atom such as a chlorine atom or a bromine atom, or a methanesulfonyloxy group.
  • arylsulfonyloxy group such as an alkylsulfonyloxy group, a benzenesulfonyloxy group, and a monotoluenesulfonyloxy group.
  • Imidazole derivatives of the formula represented by the formula (2) L one X 2 - to the reaction a compound represented by Y 2 inert solvent (e.g., N, N- dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, etc.) in The compound represented by the formula (1) can be produced by reacting at 0 ° C. to the boiling point of the solvent in the presence of a base.
  • a compound represented by Y 2 inert solvent e.g., N, N- dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, etc.
  • an inorganic base eg, lithium carbonate, sodium carbonate, etc.
  • an organic base eg, triethylamine, pyridine, etc.
  • an alkali metal hydride eg, hydrogen hydride Sodium and the like.
  • the imidazole derivative represented by the formula (2) used in the above reaction can be synthesized from a known compound by combining known synthesis methods, and for example, can be synthesized by the following method.
  • X 1 in the formula (2) has the formula:
  • a S- X la - is a group represented by a compound represented by the formula (2 a)
  • X la Among X 1, as _S- this case Represents a part other than the part specified by a specific group), for example, can be produced by the following synthesis method (A1) or (A2).
  • a compound represented by the formula (2a) can be produced according to the method described in 2, 226). That is, for example, a thioimidazole derivative represented by the formula (4) is synthesized by reacting a compound represented by the formula (3) or a salt thereof with a thiocyanate force rim in an aqueous solvent under heating conditions. can do.
  • the compound represented by the formula (4) and the compound represented by the formula: L_X la —Y 1 —Q—M are converted into a solvent inert to the reaction (for example, N, N-dimethylformamide, dimethyl sulfoxide,
  • the compound represented by the formula (2a) can be produced by reacting in tetrahydrofuran, toluene, acetone or the like) in the presence of a base at 0 ° C to the boiling point of the solvent.
  • the reaction between the compound represented by the formula (4) and the compound represented by the formula: L-X ⁇ —Y 1 —Q—M can be carried out according to ordinary S-alkylation conditions.
  • examples include inorganic bases (eg, potassium carbonate, sodium carbonate, etc.), organic bases (eg, triethylamine, pyridine, etc.), metal hydrides (eg, potassium hydride, sodium hydride, etc.) Is mentioned.
  • R 1 R 2 , YL, Q, M, and X la represent the same meaning as described above, and B represents a hydrogen atom or a protecting group for an imidazo / nitro ring nitrogen atom (eg, a tert-butoxycarbonyl group) Etc.).
  • a compound represented by the formula (6) is prepared according to the method described in a literature (for example, J. Org. Chem., 1995, 6296, Syn 1 ett, 1995, 239). Can be produced. That is, the compound represented by the formula (5) is heated in a mixed solvent of a reaction inert solvent and an aqueous alkaline solution or in a mixed solvent of a solvent inert to water and water in the presence of an organic base.
  • the compound represented by the formula (6) can be synthesized by reacting with phenyl chlorothioformate below.
  • the resulting compound represented by the formula (6) is reacted with the compound represented by the formula: L—X la —Y 1 —Q—M in the same manner as in the above-mentioned synthesis method (A1), and then the imidazole ring is obtained.
  • the compound represented by the formula (2a) can be produced by performing the deprotection reaction of the protecting group B for the nitrogen atom.
  • B in the formula is a hydrogen atom
  • the compound represented by the formula (5) is reacted with a thiol formate as described above, followed by an alcoholic solvent (eg, methanol, ethanol, 2-propanol).
  • the compound represented by the formula (6) can be synthesized by reacting at room temperature to the boiling point of the solvent in the presence of an organic base.
  • the compound represented by the formula (2a) can be similarly obtained by reacting with the compound represented by the formula: L_X la —Y 1 —Q—M.
  • Examples of the solvent used in the reaction with phenyl chlorothioformate include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ether solvents such as tetrahydrofuran and 1,4-dioxane; dichloromethane; Examples include halogenated hydrocarbon solvents such as 2-dichloroethane.
  • Examples of the alkaline aqueous solution include aqueous solutions of sodium hydrogencarbonate, carbonated sodium carbonate, sodium hydroxide, and the like.
  • Examples of the organic base include triethylamine, pyridine, and the like.
  • a method for removing the protecting group B for the nitrogen atom of the imidazole ring for example, a method using an aqueous alkali solution such as sodium hydroxide, or an acid such as hydrochloric acid or trifluoroacetic acid can be used.
  • an aqueous alkali solution such as sodium hydroxide, or an acid such as hydrochloric acid or trifluoroacetic acid
  • the compound represented by the formula (1a) (X la has the same meaning as described above) may be prepared, for example, by the synthesis method (A3), (A4), or (A5 ). Synthesis method (A3)
  • the compound represented by the formula (1a) can be synthesized according to a method described in a literature (for example, J. Heterocycl. Chem., 1345 (1956)). That is, the expression
  • An alcoholic solvent eg, methanol, ethanol or butyl alcohol
  • an acidic aqueous solution eg, hydrochloric acid solution
  • the thioimidazole derivative represented by (8) can be synthesized. Further, the compound represented by the formula (8) and the compound represented by the formula: L-X la —Y 1 —Q—M are reacted in the same manner as in the above-mentioned synthesis method (A1) to obtain the compound represented by the formula (8). The compound represented by (1a) can be produced. Synthesis method (A 4)
  • RR 2 , X la , Y ⁇ XY 2 , L, Q, and M represent the same meaning as described above, and B 1 represents a protecting group for a nitrogen atom of an imidazole ring (for example, triphenylmethyl group, tert- Butoxycarbyl group or N, N-dimethylaminocarbol group).
  • B 1 represents a protecting group for a nitrogen atom of an imidazole ring (for example, triphenylmethyl group, tert- Butoxycarbyl group or N, N-dimethylaminocarbol group).
  • the compound represented by the formula (10) can be produced by the following steps (Bl), (B2) or (B3).
  • a compound represented by the formula (5a) and a compound represented by the formula: L-X 2 — Y 2 are converted into a solvent inert to the reaction (for example, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,
  • the substituted imidazole derivative represented by the formula (10) can be produced by reacting in the presence of a base in a solvent such as toluene or acetonitrile at 0 ° C to the boiling point of the solvent.
  • the compound represented by the formula (10) is obtained by reacting at room temperature or under heating conditions in a solvent inert to the reaction (for example, ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, 1,4-dioxane, dichloromethane, etc.).
  • a solvent inert for example, ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, 1,4-dioxane, dichloromethane, etc.
  • reaction-inert solvent e.g., New, Nyu- dimethylformamidine de, dimethyl sulfoxide, Tet Rahidorofuran, toluene , Acetonitrile, etc.
  • a compound represented by the formula (11) is synthesized by reacting the compound represented by the formula (10) with phenyl chlorothioformate in the same manner as in the above-mentioned synthesis method (A2). be able to. Further, the compound represented by the obtained formula (1 1) and the formula: L one X la one Y 1 - the aforementioned synthetic method of a compound represented by Q_M by reacting in the same manner as (A1), the formula (la) Can be produced.
  • Examples of the base used in the steps (B1) and (B3) include, for example, an inorganic base (for example, sodium hydrogencarbonate, carbonated carbonate, sodium hydroxide, etc.) or an aqueous solution thereof, and an organic base (for example, triethylamine or pyridine). Etc.) and alkali metal hydrides (eg, hydrogenation power, hydrogenation sodium, etc.).
  • a phase transfer catalyst eg, n-tetrabutylammonium hydrogen sulfate, n-tetrabutylammonium bromide, etc.
  • the removal of the protecting group B 1 of Imidazonore ring nitrogen atom include hydrochloric, formic acid, a method using an acid, such as Torifuruoro acetate or aralkyl Chikarari aqueous solution of hydroxide Natoriumu or unloading Monia solution method using, and .
  • L 1 represents a halogen atom such as a chlorine atom or a bromine atom, or methanesulfonyloxy.
  • a compound represented by the formula (12) and an amine represented by the formula: H 2 N—X 2 —Y 2 are converted into a solvent inert to the reaction (for example, N, N-dimethylformamide, tetrahydrofuran, ethanol, isopropyl alcohol).
  • the reaction is carried out in the presence or absence of a base in the presence or absence of a base at 0 ° C. to the boiling point of the solvent.
  • the amino acid ketone derivative represented by or a hydrochloride thereof can be synthesized.
  • the resulting compound represented by the formula (13) or a hydrochloride thereof is reacted with potassium thiocyanide in the same manner as in the above-mentioned synthesis method (A1) to obtain a thiol represented by the formula (11).
  • An imidazole derivative can be synthesized.
  • the compounds described above wherein a synthetic method (A1) and similar conditions: L-X la - by reacting with Y 1 compound represented by one Q-M, represented by the formula (1 a) Can be prepared.
  • Examples of the base used for the synthesis of the ⁇ -aminoketone derivative include, for example, an inorganic base (for example, sodium hydrogen carbonate, carbonated carbonate, sodium hydroxide and the like) or an aqueous solution thereof.
  • Organic bases for example, triethylamine, pyridine and the like
  • Equation (1) and (2) X 1 in the formula: A N (W) -X la - is a group represented by the formula (1 b) and the compound represented by (16) (X la is the And W represents a group represented by the formula: (CH) q—W 1.
  • W 1 represents a hydrogen atom or a substituted or unsubstituted lower alkyl group
  • q represents 0
  • C1 synthesis method (C1), (C2), (C3), or (C4).
  • a 2-inaminoimidazole derivative represented by the formula (14) and a compound represented by the formula: L—X 2 —Y 2 are reacted with an inert solvent (for example, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide). , Tetrahydrofuran, dichloromethane, etc.) in the presence of a base at 0 ° C. to the boiling point of the solvent to produce the compound represented by the general formula (15). Further, a compound of formula represented by the obtained formula (15): L - X 1 a - Y 1 - Q- inert solvent a compound represented by M, the presence of a base, The compound represented by the formula (1b) can be produced by reacting at 0 ° C.
  • an inert solvent for example, ⁇ , ⁇ -dimethylformamide, dimethyl sulfoxide. , Tetrahydrofuran, dichloromethane, etc.
  • an inorganic base eg, sodium hydrogen carbonate, carbonated carbonate, sodium hydroxide, etc.
  • an organic base eg, triethylamine, pyridine, etc.
  • an alkali metal hydrogen Eg, lithium hydride / sodium hydride
  • a phase transfer catalyst for example, n-tetrabutylammonium hydrogen sulfate, n-tetrabutylammonium bromide, etc.
  • the synthesis of the compounds represented by the formulas (17) and (18) in which X la in the formulas (lb) and (16) is a group represented by the formula: C ( 0) —X lb—
  • the compounds represented by the formulas (17) and (18) can be produced by reacting in an active solvent at room temperature or under heating conditions.
  • Examples of the condensing agent used in the above reaction include dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DI PC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WS C), benzotriazole-1-yl tris (dimethylamino) phosphonium hexafluorophosphoride (BOP), diphenylphosphonyl diamide (DPPA), N, N-carboerdiimidazolone (Ange w. Chem. Int. Ed.
  • N-hydroxysuccinimide HOS u
  • 1-hydroxyl Additives such as benzotriazonole (HOBt) and 3-hydroxy-14-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt)
  • the solvent include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ether solvents such as tetrahydrofuran and 1,4-dioxane; and halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane.
  • Examples thereof include hydrocarbon solvents, amide solvents such as dimethylformamide and dimethylacetamide, basic solvents such as pyridine, and mixed solvents thereof.
  • Examples of the base include inorganic bases such as sodium hydroxide, hydroxylated lime, sodium carbonate, carbonated lime, and sodium hydrogencarbonate, and organic bases such as triethylamine and pyridine. Acid halides include acid chloride or acid bromide. Synthesis method (C 3)
  • R 1 R 2 , W, YXY 2 , Q, M, and X lb represent the same meaning as described above.
  • the reaction can be carried out by reacting with the compound represented by M.
  • Examples of the reducing agent used in the reductive alkylation reaction of the aminoimidazole derivative include complex hydrogen compounds such as sodium triacetoxyborohydride, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and the like. No. Also, reduction with sodium, sodium amalgam or zinc monoacid Alternatively, electrical reduction using lead or platinum as a cathode is also possible.
  • Examples of the reducing agent for the amide after condensation include complex hydrogen compounds such as lithium hydride / remidium, diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride or zirconium borohydride.
  • Examples include boron-based reducing agents such as diborane, and metal reduction using sodium, sodium amalgam, zinc, or the like is also possible.
  • the solvent used in the above reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, and halogenated carbons such as dichloromethane, chloropho / REM, and 1,2-dichloroethane. Examples thereof include a hydrogen solvent, an acidic solvent such as sulfuric acid, or a mixed solvent thereof.
  • R 1 R 2 , W, X lb , X 2 , Y ⁇ Y 2 , Q, and M represent the same meaning as described above, and Ar represents a phenole group or a ditrophene such as p-ditrophenine. Represents a nore group.
  • the compound represented by (21b) is treated in an inert solvent (for example, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, etc.) at 0 ° C in the presence or absence of a base.
  • an inert solvent for example, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, etc.
  • an inorganic base eg, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, etc.
  • an organic base eg, triethylamine, pyridine, etc.
  • an alkali metal hydride eg, hydride Potassium and hydrogen
  • compound W is substituted or is unsubstituted lower alkyl group, W is a hydrogen atom
  • the compound represented by the formula (15a) or (14a) can be produced by a synthesis method shown below, respectively, as a starting material.
  • the 2-aminoimidazole derivative represented by the formula (15a) or (14a) used in the above reaction can be synthesized from known compounds by combining known synthesis methods. For example, the following synthesis method (Dl ), (D2), (D3), (D4), (D5), or (D6). Synthesis method (D 1)
  • RR ⁇ and L 1 represent the same meaning as described above, and X 4 represents a hydrogen atom or a protecting group for a nitrogen atom of guanidine (eg, an acetyl group and the like). ]
  • the compound represented by the formula (14a) can be synthesized according to a method described in a literature (for example, J. Org. Chem., 1994, 7299 or Pol. J. Chem., 1994, 1317). can do. That is, the compound represented by the formula (12) and the compound represented by the formula (23) or a salt thereof are mixed in an inert solvent in the presence or absence of a base at 0 ° C to the boiling point of the solvent.
  • the compound represented by the formula (14a) can be produced by the reaction described above.
  • X 4 is a protecting group for the nitrogen atom of guanidine
  • the compound represented by the formula (14a) can be produced by performing a deprotection reaction.
  • an inorganic base eg, potassium carbonate, sodium carbonate, sodium hydroxide, etc.
  • an alkali metal alkoxide eg, sodium methoxide ⁇ sodium ethoxide, etc.
  • an organic base for example, triethylamine, pyridine, etc.
  • metal hydrides of alkali metal eg, hydrogen hydride / sodium hydride
  • the solvent include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, toluene, pyridine, and a mixed solvent thereof.
  • the compound represented by the formula (14a) can be prepared by using cyamide in the literature (for example, Eur. J. Med. Chem., 1999, 225, J. Med. Chem., 1985, 1628, J. Med. Chem., 1969, 775). Further, it can be carried out according to a method described in a literature (for example, TetrahedronLett., 1997, 3581) using S-alkylisothiourea such as S-ethylisothiourea.
  • the compound represented by the formula (3) or a salt thereof and S_alkylisothioprea such as cyanamide or S-ethylisothioprea are reacted in a solvent inert to the reaction in the presence of a base.
  • the compound represented by the formula (14a) can be produced by reacting at 0 ° C. to the boiling point of the solvent in the absence of the solvent.
  • Examples of the base used in the above reaction include an inorganic base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, etc.) or an aqueous solution thereof, an alkali metal alkoxide (for example, sodium methoxide-sodium ethoxide, etc.), an organic base (For example, triethylamine and pyridine) and metal hydrides of alkali metal (for example, hydrogen hydride and sodium hydride).
  • Examples of the solvent include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, toluene, pyridine, and a mixed solvent thereof.
  • R 1 has the same meaning as described above.
  • R 1 and R 2 have the same meaning as described above, B represents a protecting group for an imidazole ring nitrogen atom (for example, a triphenylmethyl group, etc.), and TMS represents a trimethylsilyl group. ]
  • the compound represented by the formula (25) can be separately synthesized according to the method described in a literature (for example, Heterocycles, 199 6, 1375). That is, the compound represented by the formula (5) is reacted with a brominating agent (eg, bromine or N-promosuccinide) at 0 ° C. to the boiling point of the solvent, and the resulting bromide and trimethylsilyl azide are converted into palladium. It can be synthesized by reacting at 0 ° C. to the boiling point of the solvent in the presence of a catalyst. Further, the resulting compound represented by the formula (25) is subjected to hydrogenation reaction conditions, preferably after deprotection of the protecting group B, to produce the compound represented by the formula (14a). be able to. Synthesis method (D6)
  • a brominating agent eg, bromine or N-promosuccinide
  • Examples of the base used in the above reaction include an inorganic base (eg, sodium hydrogen carbonate, carbonated carbonate, sodium hydroxide, etc.) or an aqueous solution thereof, an organic base (eg, triethylamine, pyridine, etc.), an alkali metal hydrogen (Eg, hydrogen hydride, sodium hydride, etc.).
  • an alkaline aqueous solution e.g, a phase transfer catalyst (eg, n-tetrabutylammonium hydrogen sulfate, n-tetrabutylammonium bromide) can be used in combination.
  • a palladium catalyst for example,?
  • a platinum catalyst for example, Pt-CPtO2, etc.
  • a nickel catalyst for example, Raney-Ni
  • rhodium or A method of reacting with a hydrogen source such as hydrogen, ammonium formate or sodium borohydride in the presence of a catalyst such as ruthenium, etc.
  • a metal such as iron, zinc, tin dichloride, or hydrosulfite sodium
  • solvent to be used include methanol, ethanol, N, N-dimethylformamide, ethyl acetate, tetrahydrofuran, 1,4-dioxane, acetic acid, and a mixed solvent thereof.
  • a compound represented by the formula (lc) wherein X 1 in the formula (1) is a group represented by the formula: CH 2 —X la — (X la has the same meaning as described above) is, for example, It can be produced by the synthesis method shown in (1).
  • Table inert solvent e.g., N, N- dimethylformamide, di-methyl sulfoxide , Tetrahydrofuran, dichloromethane, etc.
  • Examples of the base used in the above reaction include an inorganic base (eg, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, etc.) or an aqueous solution thereof, an organic base (eg, triethylamine, pyridine, etc.), an alkali metal hydride (eg, Potassium hydride and sodium hydride).
  • an inorganic base eg, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, etc.
  • an organic base eg, triethylamine, pyridine, etc.
  • an alkali metal hydride eg, Potassium hydride and sodium hydride
  • a phase transfer catalyst for example, n-tetrabutylammonium hydrogen sulfate, n-tetrabutylammonium bromide, etc.
  • the 2-anolequinoleimidazole derivative represented by the formula (2c) can be synthesized from a known compound by combining known synthesis methods.
  • Rc represents a lower alkyl group such as a methyl group or an ethyl group
  • R d represents a hydrogen atom or an acetyl group
  • the compound represented by the formula (28) or a salt thereof and the compound represented by the formula (29) are subjected to pressure or pressure in a solvent inert to the reaction in the presence of aqueous ammonia.
  • the compound represented by the formula (2c) can also be produced by reacting at 0 ° C to the boiling point of the solvent under normal pressure.
  • an inorganic base for example, carbonated sodium, sodium carbonate, sodium hydroxide or the like
  • an alkali metal alkoxide for example, sodium methoxide or sodium methoxide
  • Organic bases eg, triethylamine and pyridine
  • metal hydrides eg, lithium hydride / sodium hydride
  • the solvent include N, N-dimethylhonolemamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane
  • examples thereof include sun, water, methanol, ethanol, toluene, pyridine, and a mixed solvent thereof.
  • the compound represented by the formula (2c) can be prepared by a method described in literature (for example, Synth. Commun., 19993, 2623, J. Org. Chem., 1997, 8449). It can be synthesized according to That is, a compound represented by the formula (30) or a salt thereof and a compound represented by the formula (12) are reacted in a solvent inert to the reaction in the presence or absence of a base at 0 ° C.
  • the compound represented by the formula (2c) can be produced by reacting under the boiling point conditions.
  • the compound represented by the formula (30) or a salt thereof and the compound represented by the formula (7) are mixed in a solvent inert to the reaction in the presence of aqueous ammonia, under pressure or normal pressure, at 0 ° C.
  • the compound represented by the formula (2c) can also be produced by reacting under the conditions of the boiling point of the solvent.
  • an inorganic base eg, potassium carbonate, sodium carbonate, sodium hydroxide, etc.
  • an aqueous solution thereof an alkali metal alkoxide (eg, sodium methoxide-sodium ethoxide, etc.)
  • an organic base eg, , Triethylamine, pyridine, etc.
  • metal hydrides eg, hydrogen hydride, sodium hydride, etc.
  • the solvent include N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane.
  • phase transfer catalyst eg, n-tetrabutylammonium hydrogen sulfate, n-tetrabutylammonium bromide, etc.
  • RR 2 , X la , YQ and M have the same meanings as described above, and G represents a hydrogen atom or a hydroxyl-protecting group (for example, tert-butyldiphenylsilyl group or benzyl group)]
  • the acid chloride or acid anhydride of the carboxylic acid represented by the formula (31) and the compound represented by the formula (3) or a salt thereof are reacted in a solvent inert to the reaction in the presence or absence of a base.
  • the compound represented by the formula (34) can be produced.
  • an acid chloride or an acid anhydride of a carboxylic acid represented by the formula (31) and an azide derivative represented by the formula (32) are reacted with a phosphine reagent (for example, trimethylphosphine or trimethylphosphine) in a solvent inert to the reaction.
  • a phosphine reagent for example, trimethylphosphine or trimethylphosphine
  • the compound represented by the formula (34) can also be produced by reacting under the conditions of the boiling point of the solvent. Further, the compound represented by the formula (34) is obtained by combining the compound represented by the formula (33) with the acid chloride or acid anhydride of the carboxylic acid represented by the formula (31). After reacting under the same conditions as in the reaction using the compound represented by the formula, the compound can also be synthesized by using a route that involves deprotection of the protective group G for the hydroxyl group and subsequent oxidation of the hydroxyl group.
  • the obtained compound represented by the formula (34) was converted to a compound (for example, Syn 1 ett, 201, 2 18 and J. Am. Chem., 1992,
  • the compound represented by the formula (2c) can be synthesized by reacting according to the method described in 1495). That is, the compound represented by the formula (2c) is reacted by reacting the compound represented by the formula (34) with ammonium acetate or ammonia in a solvent inert to the reaction at 0 ° C. to the boiling point of the solvent. Can be produced.
  • Examples of the base used in the amide bond forming reaction include an inorganic base (for example, potassium carbonate, sodium carbonate, sodium hydroxide, etc.) or an aqueous solution thereof, and an alkali metal alkoxide (for example, sodium methoxide-sodium ethoxide). And organic bases (for example, triethylamine and pyridine).
  • Examples of the solvent used in all the above reactions include, for example, N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, acetonitrile, water, methanol, ethanol, ethanol, tonolen, pyridine, and dichloromethane. And chlorophonolem or a mixed solvent thereof.
  • L 2 represents a halogen atom, a substituted or unsubstituted alkylsulfonoxy group such as a methanesulfonyloxy group, or a benzenesulfonyloxy group or a -toluenesulfonyloxy group. And a substituted or unsubstituted arylsulfonyloxy group.
  • the compound represented by the formula (2c) is described in the literature (for example, J. Med. Chem., 1995, 2925, Te trahedron Lett "1 996, 5503, J. Heterocycl. Chem.,
  • the compound can be synthesized according to the method described in 1994, 857. That is, the imidazole derivative represented by the formula (5) is prepared in a solvent inert to the reaction at -78 ° C to the boiling point of the solvent. After reacting with a strong base, for example, n_butyllithium, the compound represented by the formula (36) can be reacted with a compound represented by the formula (35) to produce a compound represented by the formula (36).
  • a strong base for example, n_butyllithium
  • the compound represented by the formula (2c) By removing the protecting group B on the nitrogen atom of the imidazole ring, the compound represented by the formula (2c) can be produced, or the compound represented by the formula (5) can be reacted with a strong base. Then, by reacting with an aldehyde derivative represented by the formula (37), the alcohol derivative represented by the formula (38) is synthesized. Then, the compound represented by the formula (2c) can be produced through the deprotection of the protecting group B of the imidazole ring nitrogen atom and the reductive removal of the hydroxyl group, and the compound represented by the formula (5) Is reacted with a strong base and then with a compound represented by formula (39). To synthesize the compound represented by the formula (40), followed by the deprotection of the protecting group B, the reduction of the carbonyl group to the hydroxyl group, and the reductive removal of the hydroxyl group. Can be produced.
  • Examples of the reducing agent used in the above-mentioned reduction reaction from the carbonyl group to the hydroxyl group include lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride, and borohydride.
  • Complex hydrides such as zirconium; and boron-based reducing agents such as diborane.
  • metal reduction using sodium, sodium amalgam, or zinc is also possible.
  • a palladium catalyst e.g., P d_c
  • platinum catalysts e.g., P t0 2, etc.
  • the method of reacting with hydrogen in the presence of a catalyst such as or rhodium and ruthenium.
  • the solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, chlorophonolem and 1,2-dichloroethane, and acidic solvents such as acetic acid.
  • the solvent include a solvent and a mixed solvent thereof.
  • a method for removing the protecting group B for the imidazole ring nitrogen atom a method using an acid such as hydrochloric acid, formic acid, or trifluoroacetic acid, a method using an alkaline aqueous solution such as sodium hydroxide, or a method using an ammonia solution is used. Can be used. Further, depending on the type of RR 2 , X la , YX 2 , ⁇ 2 , and ⁇ , the compound represented by the formula (lc) can be obtained by, for example, the following synthesis methods (Fl), (F2), (F 3) or (F4).
  • a compound represented by the formula (28) or a salt thereof and a compound represented by the formula (13) or a salt thereof are reacted in a solvent inert to a reaction in the presence of a base.
  • the compound represented by the formula (1c) can be produced by reacting in the absence of a solvent at 0 ° C. to the boiling point of the solvent.
  • the compound represented by the formula (1c) is a compound represented by the formula (28) or a salt thereof, a compound represented by the formula (29), and a compound represented by the formula: H 2 N—X 2 —Y 2 It can be produced by reacting the represented amine derivative in a solvent inert to the reaction in the presence of a base at 0 ° C. to the boiling point of the solvent.
  • the compound represented by the formula (1c) is reacted with the compound represented by the formula (35) according to the above-mentioned synthesis method (E4) using the imidazole derivative represented by the formula (10) as a starting material. It can be manufactured by making In addition, the imidazole derivative represented by the formula (10) is reacted with the compound represented by the formula (37) or (39) by the same method as the above-mentioned synthesis method (E4), and the reduction-reduction reaction is performed. By doing so, it is possible to produce the compound represented by the formula (1c). Synthesis method (F4)
  • X la in the formula (lc) is represented by the formula: one NH—X lb —
  • the compound represented by the formula (45), which is a group represented by the formula (45), can be synthesized as follows.
  • Y 2 inert solvent e.g., N, N- dimethylformamide
  • the compound represented by the formula (44) can be produced by reacting in dimethyl sulfoxide, tetrahydrofuran, dichloromethane, or the like) in the presence of a base at 0 ° C to the boiling point of the solvent. Furthermore, the resulting 2-formylimidazole derivative represented by the formula (44) is obtained.
  • the compound represented by the formula (45) is obtained by reacting an amine represented by H 2 N—X ⁇ —Y 1 —Q—M in the presence of a reducing agent according to the synthesis method (C 3). Can be produced.
  • the formyl group of the 2-honoleminoleimidazole derivative represented by the formula (44) is oxidized to a carboxylic acid, and the resulting 2-hydroxycanolepoerimidazonole derivative represented by the formula (46) and the formula: H
  • the compound represented by the formula (1d) can be produced by condensing an amine represented by 2 N_X lb — Y 1 — Q—M in the same manner as in the synthesis method (C 2).
  • Examples of the above oxidation reaction include a reaction using sodium chlorite (for example, in the presence of 2-methyl 2-butene and sodium dihydrogen phosphate), a reaction using permanganate (for example, potassium permanganate), Reactions using chromic acid or chromate (eg, Jone's reagent), reactions using silver salts (eg, silver nitrate, silver oxide, etc.), or t Reactions using ert-butyl hydroperoxide are mentioned.
  • sodium chlorite for example, in the presence of 2-methyl 2-butene and sodium dihydrogen phosphate
  • permanganate for example, potassium permanganate
  • Reactions using chromic acid or chromate eg, Jone's reagent
  • reactions using silver salts eg, silver nitrate, silver oxide, etc.
  • t Reactions using ert-butyl hydroperoxide are mentioned.
  • a compound represented by the formula (2e), wherein X 1 in the formula (2) is a group represented by the formula: 0_X la — (X la is a substituted or unsubstituted lower alkylene chain similar to X 1 Can be produced, for example, by the following synthesis methods (G1) and (G2). Constitution (G1)
  • RRX la , YLQ, and M have the same meanings as described above, and B is a protecting group for the imidazole ring nitrogen atom (for example, methoxymethyl group, ethoxymethyl group, benzyloxymethyl group, triphenylmethyl group, or t-methyl group). Etc.).
  • an inorganic base eg, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, etc.
  • an aqueous solution thereof or alkali metal hydrogen (Eg, hydrogen hydride, sodium hydride, etc.).
  • alkali metal hydrogen e.g., hydrogen hydride, sodium hydride, etc.
  • Li aqueous solution phase transfer catalyst e.g., hydrogen sulfate n- tetra Petit Ruan mode - ⁇ beam bromide n - such as tetra Petit Ruan Moe ⁇ beam
  • Li aqueous solution phase transfer catalyst e.g., hydrogen sulfate n- tetra Petit Ruan mode - ⁇ beam bromide n - such as tetra Petit Ruan Moe ⁇ beam
  • the removal of the protecting group B for the imidazole ring nitrogen atom includes, for example, a method using an aqueous solution of sodium hydroxide such as sodium hydroxide or an acid such as hydrochloric acid or trifluoroacetic acid.
  • the compound represented by the formula (49) can be synthesized by reacting the imidazole derivative represented by the formula (5a) with nitric acid in acetic acid at 0 ° C. to room temperature. Further, the resulting compound represented by the formula (49) and the compound represented by the formula: HO—X—Y 1 —Q—M are converted into a solvent inert to the reaction (eg, N, N-dimethylformamide, dimethyl).
  • a solvent inert eg, N, N-dimethylformamide, dimethyl
  • the compound represented by the formula (2e) can be produced by reacting in a sulfoxide, tetrahydrofuran or the like) in the presence of a base at 0 ° C to the boiling point of the solvent.
  • Examples of the base used in the above reaction include, for example, an inorganic base (eg, potassium carbonate, sodium carbonate, sodium hydroxide, etc.) or an aqueous solution thereof, an alkali metal alkoxide (eg, sodium methoxide ⁇ sodium ethoxide, etc.), and an organic base (eg, , Triethylamine, pyridine, etc.), metal hydrides (eg, hydrogen hydrides) Sodium hydride).
  • a phase transfer catalyst for example, n-tetrabutynoleammonium hydrogen sulfate, n-tetrabutylammonium bromide, etc.
  • the compound represented by the formula (1e) can be produced by the synthesis method (HI). Synthesis method (HI)
  • a compound represented by the formula (43a) and a compound represented by the formula: L-X 2 — Y 2 are dissolved in a solvent inert to the reaction (eg, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, etc.)
  • the compound represented by the formula (50) can be synthesized by reacting at 0 ° C. to the boiling point of the solvent in the presence of a base. Subsequently, according to the case Naruho (G1), the presence of a base, a compound of formula represented by the formula (50): HO- X 1 a - Yi- by reacting a compound represented by Q-M, The compound represented by the formula (le) can be produced.
  • an inorganic base eg, carbonated sodium, sodium carbonate, sodium hydroxide, etc.
  • an alkali metal alkoxide for example, sodium methoxide and sodium ethoxide
  • organic bases for example, triethylamine and pyridine
  • alkali metal hydrides for example, lithium hydride and sodium hydride.
  • a phase transfer catalyst eg, n-tetrabutylammonium hydrogen sulfate, n-tetrabutylammonium bromide, etc.
  • phase transfer catalyst eg, n-tetrabutylammonium hydrogen sulfate, n-tetrabutylammonium bromide, etc.
  • each starting compound has a group active in the reaction such as a carboxyl group, a hydroxyl group, or an amino group
  • the target compound can be produced by previously protecting with an appropriate protecting group and removing the protecting group after performing this reaction.
  • the method of protection and deprotection depends on the type of each protecting group. For example, literatures (eg, Green, TW and Wuts, PGM, Protrusive Grousin Organic Synthesis, John Wiley & Sons, I n c. (1999)).
  • the distribution of mobile phases A and B at each time is as follows.
  • Triethylamine (6.06 g, 59.9 mmo 1) was added to the (50 ml) solution, and the mixture was stirred at 80 ° C for 3 hours. After the reaction, the mixture was cooled to 0 ° C, saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate.
  • Triethylamine (0.64 mL, 4.6 mm 01) and di-tert-dicarbonate
  • a solution of butyl (274 mg, 12.6 mmo 1) in tetrahydrofuran (3 ml) was caloried and stirred at 60 ° C. for 2 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
  • Methyl benzoate (810 mg, 1 To a solution of 56 mm o 1) in dichloromethane (10 ml) Oroacetic acid (1 ml) was added and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
  • tert-putinole 4-[[ ⁇ 2 -— ⁇ [2- ⁇ Toxicarbol) benzyl] thio ⁇ 1-1_ (1-naphthylmethinole) -1H-imidazole-14-inole] methyl ⁇ amino) carboyl] piperidine-1 lipoxylate was hydrolyzed to give the title compound.
  • Lithium aluminum hydride (737 mg) was added to a solution of tert-butynole 4- (ethoxycarbonyl) piperidine-one-force norreboxilate (5.00 g, 19.4 mmo 1) in tetrahydrofuran (30 ml) at 0 ° C at 0 ° C. , 19.4 mmol) and stirred for 1 hour. After the reaction, water (0.8 ml), 1 M aqueous sodium hydroxide solution (2.0 ml) and water (3.0 ml) were added to the reaction solution, and the purified precipitate was filtered.
  • a saturated aqueous sodium hydrogen carbonate solution was poured into the reaction solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated saline, and then dried over anhydrous magnesium sulfate.
  • the residue obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran, and di-tert-butyl dicarbonate (104 mg, 0.477 mmol) and triethynoleamine (0.009 ml, 0.636) were added thereto.
  • mmo 1 was added and the mixture was stirred at room temperature for 2 hours. After the reaction, saturated saline was added, and the mixture was extracted with ethyl acetate.
  • the solvent was distilled off under reduced pressure, and 2 M aqueous hydrochloric acid was added to the obtained residue at 0 ° C to adjust the pH of the solution to about 5, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was added to a solution of acetic acid (2 ml) in 4 M hydrochloric acid / 1,4-dioxane (0.500 ml, 2.0 Ommo 1), and the mixture was stirred at room temperature for 2 hours.
  • the obtained oily substance was dissolved in methanol (3 ml), 4 M aqueous sodium hydroxide solution (1 ml) was added thereto at room temperature, and the mixture was stirred at 60 ° C for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was added with 2 M aqueous hydrochloric acid at 0 ° C to adjust the pH of the solution to about 5, and the solution was extracted with chloroform. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate.
  • Example 2 7 (a) Synthesis of N- (tert-butyl) 1-2-methinolebenzenesnolehonamide A solution of 2-methinole-benzenesnolehoninole chloride (6.00 g, 31.5 mmol) in tetrahydrofuran (2 Om 1) To the mixture were added tert-butylamine (3.64 ml, 34.6 mmol) and triethynoleamine (6.6 ml, 47.2 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction, the mixture was cooled to 0 ° C, saturated saline was added, and the mixture was extracted with ethyl acetate.
  • N- (tert-butyl) -12-methylbenzenesulfonamide is reacted with N-bromosuccinimide to give 2- (bromomethyl) -1-N- (tert-butyl).
  • Benzenesulfonamide was synthesized.
  • a solution of the above compound (2.88 g) in tetrahydrofuran (10 ml) was added at 0 ° C. to a 2 M aqueous solution of 2-mercaptoimidazole (45 Omg, 4.49 mmo 1) in sodium hydroxide (6. 7 ml) and stirred at room temperature for 2 hours.
  • Example 1 (c) the hydrolysis reaction of 2-( ⁇ [1- (1-naphthinolemethyl) -4-1vinyl-1H-imidazole-2-yl] thio ⁇ methyl) methyl benzoate was carried out. This was performed to synthesize the title compound.
  • tert-butyl 4- (Nitroacetinol) piperidine-one-pot oleboxylate (3.45 g, 12.7 mmo 1) was added to acetic acid (2 Om 1), methanol (15 ml) and 2 M aqueous hydrochloric acid (12 ml). The mixture was dissolved, 10% Pd-C (50% wet., 2.6 g) was added thereto, and the mixture was stirred under a hydrogen atmosphere (8 hours at normal pressure and 8 hours at 5 atm). After the reaction vessel was set to a nitrogen atmosphere, the reaction solution was filtered, and the solvent of the obtained filtrate was distilled off under reduced pressure to obtain 2-amino-1-piperidine-14-ylethanone dihydrochloride.
  • Example 4 the obtained compound (crude product: 2.73 g) was reacted with a thiocyanate-forming rim, and the secondary amine on the obtained compound was further reacted.
  • the title compound (869 mg, 24.1% over 3 steps) was synthesized by protection with a tert-butylcarpoel group.
  • 1 H-NMR (DMS0-d 6 ) ll.92 (brs, 1H), 11.68 (brs, 1H), 6.53 (s, 1H), 3.94 (br, 2H), 2.71 (br, 2H), 1.78 (br, 2H), 1.38 (s, 911), 1.26-1.42 (ra, 2H).
  • tert-butyl 4 -— [2 -— [[2- (methoxycanolepoel) benzinole] thio ⁇ 1 1 _ (11-naphthinolemethinole) 1 1 H—imidazonole 1 4 [Yl] piperidine-11-carboxylate was hydrolyzed to give the title compound. ; - NMR (CDC1 3) 7 .60-7.90 (m, 4H), 7.25-7.56 (ra, 6H), 6.92 (.
  • Example 1 (c) the hydrolysis reaction of methyl 2-( ⁇ [4-methinoly 11- (1 _naphthylmethyl) -11J-imidazole-2-yl] thio ⁇ methyl) methyl benzoate was carried out.
  • Example 1 (a) 1- (1-naphthylmethyl) -4,5,6,7-tetrahydro-1H-benzimidazo-l-lu 2-thiol and 2- (promomethyl) benzo
  • the reaction with ethyl ethyl was carried out, and the obtained 2-(( ⁇ [1- (1-naphthylmethyl) -4,5,6,7-tetrahydro-1H) was obtained according to the method of Example 1 (c).
  • the title compound was synthesized by hydrolysis of methyl benzoate.
  • Example 6 According to the method of Example 6 (a), a condensation reaction of 11- (11-naphthylmethinole) -11H-imidazole-2-amine and phthalic acid-mono (tert-butyl) ester was carried out to give the title compound.
  • LC / MS M + l, retention time
  • Example 41 (b) According to the method of Example 41 (b), the reduction reaction of the 2-nitro group of 4- (2-nitrobenzoyl) morpholine was carried out, and the obtained 4- (2-aminobenzoyl) morpholine (2.3 g, 11.15mmo 1) in THF (50ml) was added with phenyl phenyl carbonate (3.49g, 22.3Ommo 1), and the mixture was stirred at 40 to 50 ° C for 1 hour and at room temperature for 12 hours. . The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the organic layer was washed with water and saturated saline, dried over magnesium sulfate, The solvent was distilled off under reduced pressure.
  • the residue was dissolved in ethanol (5 ml), to which was added a 2 M aqueous sodium hydroxide solution (lml), and the mixture was stirred at 40 to 50 ° C for 1 hour.
  • the solvent was evaporated under reduced pressure, and the obtained residue was adjusted to pH around 7 with 2M aqueous hydrochloric acid and extracted with ethyl acetate.
  • the organic layer was washed with water and saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure to give the title compound (280 mg, 75.7%).
  • Example 6 According to the method of Example 6 (a), a condensation reaction of 1- (1-naphthylmethinole) -1H-imidazole 2-amine and ⁇ 2-[(benzyloxy) caprolponyl] phenoxy ⁇ acetic acid was carried out to give the title compound. Synthesized. ; - ⁇ R (CDC1 3) 7.80-7.92 (rn , 4H), 7.23-7.55 (m, 7H), 6.93-7.01 (m, 2 ⁇ ) ', 6.52 (br, IH), 5.48 (s, 2H), 5.21 (s, 2H), 4.81 (s, 2H). LC / MS (M + l, retention time): 492.2, 4.28 minutes
  • Chymase inhibitory activity (in-vitro test)
  • the chymase inhibitory activity of the compound of Example No. 1 is IC 5 .
  • the compound of the present invention has a chymase inhibitory action, and based on this action, a disease whose condition is considered to be improved, for example, hypertension mediated by angiotensin II, endothelin, etc., heart failure, ischemic peripheral circulatory disorder, Myocardial ischemia, venous dysfunction, progression of heart failure after myocardial infarction, diabetic nephropathy, nephritis, arteriosclerosis, hyperaldosteronism, scleroderma, glomerulosclerosis, renal failure, central nervous system disease, Alzheimer's disease , Memory deficiency, depression, amnesia, sensory dysfunction including senile dementia, anxiety and tension symptoms, discomfort mental state, glaucoma, ocular hypertension, restenosis after PTCA, asthma, rhinitis, atopic dermatitis It is useful as a therapeutic drug for allergic diseases such as.

Abstract

L'invention concerne un composé représenté par la formule (1), dans laquelle X1 représente alkylène inférieur (non) substitué, X2 et Q représentent chacun une liaison simple ou alkylène inférieur (non) substitué, Y1 représente un noyau hydrocarbure monocyclique (non) saturé, etc., M représente un groupe représenté par la formule C(=O)OR5, etc., R1 et R2 représentent chacun hydrogène, alkyle (non) substitué, etc., et R5 représente hydrogène, alkyle (non) substitué, etc. L'invention concerne également un promédicament dudit composé ou un sel pharmaceutiquement acceptable de l'un ou l'autre desdits composés, lesquels présentent une activité inhibitrice de chymase et sont utiles comme agent thérapeutique destiné à l'hypertension, à l'insuffisance cardiaque, etc.
PCT/JP2003/008682 2002-07-10 2003-07-08 Derive d'imidazole WO2004007464A1 (fr)

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WO2006046593A1 (fr) * 2004-10-27 2006-05-04 Daiichi Sankyo Company, Limited Composé du benzène ayant deux ou plus de deux substituants
JP2007039425A (ja) * 2004-10-27 2007-02-15 Sankyo Co Ltd ２以上の置換基を有するベンゼン化合物
WO2007139230A1 (fr) 2006-05-31 2007-12-06 Asubio Pharma Co., Ltd. Anneau hétérocycliques à 7 éléments, son procédé de production et ses utilisations pharmaceutiques
US7888348B2 (en) 2004-12-02 2011-02-15 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
US8106070B2 (en) 2006-10-20 2012-01-31 Merck Sharp & Dohme Corp. Substituted imidazoles as bombesin receptor subtype-3 modulators
US8153626B2 (en) 2006-12-11 2012-04-10 Merck Sharp & Dohme Corp. Substituted diazepine sulfonamides as bombesin receptor subtype-3 modulators
US8183275B2 (en) 2006-10-20 2012-05-22 Merck Sharp & Dohme Corp. Substituted imidazoles as bombesin receptor subtype-3 modulators
US8193228B2 (en) 2006-10-20 2012-06-05 Merck Sharp & Dohme Corp. Substituted imidazole as bombesin receptor subtype-3 modulators
US8846660B2 (en) 2009-12-25 2014-09-30 Daiichi Sankyo Company, Ltd. Seven-membered ring compound and pharmaceutical use therefor
WO2016132483A1 (fr) * 2015-02-18 2016-08-25 学校法人福岡大学 Inhibiteur de chymase humaine et médicament pour prévenir et traiter une maladie associée à une activité de chymase humaine
US10144731B2 (en) 2013-12-18 2018-12-04 Glaxosmithkline Intellectual Property Development Limited Nrf2 regulators
US10272095B2 (en) 2015-06-15 2019-04-30 GlaxoSmithKline Intellectual Propert Development Limited NRF2 regulators
US10364256B2 (en) 2015-10-06 2019-07-30 Glaxosmithkline Intellectual Property Development Limited Biaryl pyrazoles as NRF2 regulators
US10604509B2 (en) 2015-06-15 2020-03-31 Glaxosmithkline Intellectual Property Development Limited Nrf2 regulators

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006046593A1 (fr) * 2004-10-27 2006-05-04 Daiichi Sankyo Company, Limited Composé du benzène ayant deux ou plus de deux substituants
JP2007039425A (ja) * 2004-10-27 2007-02-15 Sankyo Co Ltd ２以上の置換基を有するベンゼン化合物
KR101021828B1 (ko) 2004-10-27 2011-03-17 다이이찌 산쿄 가부시키가이샤 2 이상의 치환기를 갖는 벤젠 화합물
US7888348B2 (en) 2004-12-02 2011-02-15 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
US8507714B2 (en) 2004-12-02 2013-08-13 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
EP2463268A1 (fr) 2004-12-02 2012-06-13 Daiichi Sankyo Company, Limited Acides aromatiques aminométhyl-substitués comme intermédiaires pour la préparation de composés 1,4-diazépan-2,5-dione inhibant la chymase
WO2007139230A1 (fr) 2006-05-31 2007-12-06 Asubio Pharma Co., Ltd. Anneau hétérocycliques à 7 éléments, son procédé de production et ses utilisations pharmaceutiques
US8049006B2 (en) 2006-05-31 2011-11-01 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
US8183275B2 (en) 2006-10-20 2012-05-22 Merck Sharp & Dohme Corp. Substituted imidazoles as bombesin receptor subtype-3 modulators
US8193228B2 (en) 2006-10-20 2012-06-05 Merck Sharp & Dohme Corp. Substituted imidazole as bombesin receptor subtype-3 modulators
US8106070B2 (en) 2006-10-20 2012-01-31 Merck Sharp & Dohme Corp. Substituted imidazoles as bombesin receptor subtype-3 modulators
US8153626B2 (en) 2006-12-11 2012-04-10 Merck Sharp & Dohme Corp. Substituted diazepine sulfonamides as bombesin receptor subtype-3 modulators
US8846660B2 (en) 2009-12-25 2014-09-30 Daiichi Sankyo Company, Ltd. Seven-membered ring compound and pharmaceutical use therefor
US10144731B2 (en) 2013-12-18 2018-12-04 Glaxosmithkline Intellectual Property Development Limited Nrf2 regulators
WO2016132483A1 (fr) * 2015-02-18 2016-08-25 学校法人福岡大学 Inhibiteur de chymase humaine et médicament pour prévenir et traiter une maladie associée à une activité de chymase humaine
US10272095B2 (en) 2015-06-15 2019-04-30 GlaxoSmithKline Intellectual Propert Development Limited NRF2 regulators
US10485806B2 (en) 2015-06-15 2019-11-26 Glaxosmithkline Intellectual Property Development Limited Nrf2 regulators
US10604509B2 (en) 2015-06-15 2020-03-31 Glaxosmithkline Intellectual Property Development Limited Nrf2 regulators
US10364256B2 (en) 2015-10-06 2019-07-30 Glaxosmithkline Intellectual Property Development Limited Biaryl pyrazoles as NRF2 regulators

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