WO2005007644A1 - ヘテロアリールオキシ含窒素飽和へテロ環誘導体 - Google Patents
ヘテロアリールオキシ含窒素飽和へテロ環誘導体 Download PDFInfo
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- WO2005007644A1 WO2005007644A1 PCT/JP2004/009272 JP2004009272W WO2005007644A1 WO 2005007644 A1 WO2005007644 A1 WO 2005007644A1 JP 2004009272 W JP2004009272 W JP 2004009272W WO 2005007644 A1 WO2005007644 A1 WO 2005007644A1
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Definitions
- the present invention relates to saturated heteroaryl derivatives containing heteroaryloxy nitrogen which are useful in the field of medicine.
- This compound acts as a histamine receptor H3 antagonist and is useful as a preventive or therapeutic agent for various cardiovascular, nervous, and metabolic diseases, etc.
- histamine In mammals and other organisms, histamine, a physiologically active endogenous factor, has been shown to function as a neurotransmitter and have a wide range of pharmacological activities [see, for example, Life Sciences]. (Life Science), vol. 17, 1975, p503]. Immunohistochemical studies have revealed that histaminergic (producing) cell bodies are present in the papillary nucleus of the nodule in the posterior hypothalamus, and that histamine is projected over a very wide area in the brain. And support the diverse pharmacological effects of histamine [see, for example, Journal ⁇ of'Compliance Neurology ⁇ , 273, 283].
- histaminergic nerves in the papillary nucleus of the nodule in the posterior hypothalamus is related to histamine in brain function, especially for hypothalamic functions (sleep, arousal rhythm, endocrine, eating, drinking behavior, sexual behavior, etc.) Suggests that they play an important role in the regulation of physiological functions [eg, Progress * in * Neurobiology (Prog ressin N eurobio 1 ogy), 63, 637 (200: [year], .
- Histamine 4 also exerts its pharmacological action by acting on a specific macromolecule called a receptor on the cell membrane surface or in target cells when released from producer cells, and regulates various bodily functions. ing. To date, four histamine receptors have not been found. In particular, various pharmacological and physiological studies have shown the existence of the histamine H 3 receptor as a receptor involved in central and peripheral nervous functions of histamine.
- Pharmaceutical Sciences (Trend sin Pharmaeo1ogica1Science), Vol. 8, 24: pp. (-1 986-years)], recently,-Human and rodent histamine H3 receptors Somatic genes have been identified and their presence has been revealed [eg-Molecular Pharma:? Mouth—Gini — (Molecu lar Phrmac o l ogy), Vol. 55, pp. 11-11 (1999)].
- the histamine ⁇ 3 receptor is located in the presynaptic membrane of central or peripheral neurons and functions as an autoreceptor, controlling the release of histamine and also controlling the release of other neurotransmitters.
- the histamine ⁇ 3 receptor agonist, antagonist or inverse agonist regulates release of histamine, noradrenaline, serotonin, acetylcholine or dopamine from nerve endings.
- agonists such as (R)-( ⁇ ) -methylhistamine inhibit the release of these neurotransmitters, and antagonists such as thioperamide (Thiope ramide) or inverse agonists.
- histamine H3 receptors are highly constitutively active in receptor-expressing cells, tissues or expressing cells, tissue-derived membrane fractions, and even in vivo (endogenous agonists such as histamine).
- histamine histamine
- These constitutive activities have been reported to be suppressed by inverse agonists. For example, thioperamide or ciproxyphan suppresses homeostatic receptor activity, resulting in the release of neurotransmitters from nerve endings, eg For example, histamine release and release are promoted.
- thioperamide or GT-2331 a histamine H3 receptor antagonist or inverse agonist, reduces dysarthria and sleep in narcolepsy dogs [for example, Sleep (S1eep), Volume 24, Abstracts] A23 page (2001)
- H3 receptors are involved in coordination between wakeful sleep and sleep disorders, and that selective H3 agonists or antagonists, or inverse agonists, And various disorders associated with sleep disorders (eg, idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, periodic limb movement disorder during sleep, sleep apnea syndrome group, circadian rhythm disorder, Chronic fatigue syndrome, REM sleep disorder, elderly insomnia, night shift
- insomnia idiopathic insomnia
- repetitive insomnia idiopathic insomnia
- intrinsic insomnia idiopathic insomnia
- depression idiopathic insomnia
- schizophrenia idiopathic insomnia
- Histamine is suggested to be involved in regulating eating behavior [see, for example, Brain Research, 793, 279-page (19-98) Year) see].
- Thioperamide a histamine H3 receptor antagonist or inverse agonist, suppresses eating behavior in a dose-dependent manner.
- Thioperamide also promotes the release of histamine in the brain [see, for example, Life Sciences (Life Sciences), 69, 469 (2001)].
- H3 receptor is involved in the regulation of eating behavior, and that H3 antagonists or inverse agonists are associated with metabolic pathways such as eating disorders, obesity, diabetes, leanness, and hyperlipidemia. It suggests that it may be useful for prevention or treatment of the disease.
- administration of the histamine H.3 receptor agonist (R)-(a) -methylhistamine dose-dependently reduces basal diastolic blood pressure.
- histamine H3 receptor antagonists or the inverse agonist thioperamide [see, for example, Journal of Physiology and Pharmacology (Journal of Phy siology and P). harma co 1 o gy), 49, 191 (1998)].
- histamine H3 receptors are involved in regulating blood pressure, heart rate, and cardiovascular output, and that histamine H3 receptor agonists or antagonists or inverse agonists This suggests that the drug may be useful for preventing or treating cardiovascular diseases such as hypertension and various heart diseases.
- histamine H3 receptor agonist R-() -methylhistamine
- thioperamide a histamine H3 receptor antagonist or inverse agonist
- amnesia caused by the drug in a scopolamine-induced amnesia test in a dose-dependent manner
- histamine H3 receptor antagonists or inverse agonists can be used to prevent or treat various diseases associated with memory and learning disorders, such as Alzheimer's disease, Parkinson's disease or attention deficit / hyperactivity disorder.
- histamine an antagonist of the H3 receptor or thioperamide, an inverse agonist, induced seizures induced by lightning stimuli or epileptiform seizures induced by pentylenetetrazol (PTZ). It has been shown to inhibit in a dose-dependent manner (e.g., Europian Journal of Phorma cology, Vol. 234, p. 29 (1993) and Pharmacology, biochemistry and 'beheihi / (Pharrt aco 1 ogy, Biochemistry and Behavo.r), 68, 735 (2001)].
- PTZ pentylenetetrazol
- Examples of the compound having histamine H 3 receptor antagonism or inverse agonism include, in addition to the above-mentioned thioperamide or cycloxyphan, for example, the following formula (A)
- the compound represented by the formula (A) has a propylene group between the pyrrolidinyl group and the oxygen atom, whereas the compound (I) according to the present invention has an oxygen atom and a pyrrolidinyl group.
- the group differs from the group in that they are directly bonded.
- the phenyl group is bonded to the oxygen atom, whereas the compound of the present invention has the following formula (I-11)
- the compound represented by the formula (B) has a 4-acetylphenoxy group and a pyrrolidinyl group, which are a part of the constituents of the compound according to the present invention, and the compound represented by the formula (B) has a 4-acetylphenoxy group and a pyrrolidinyl group.
- the compound represented by the formula (B) has a 4-acetylphenoxy group and a pyrrolidinyl group.
- the position of the nitrogen atom in the pyrrolidinyl group of the formula (B) is also different from the compound according to the present invention.
- the compound represented by (C) is described [for example, JP-A-2003-064081].
- the compound represented by the above formula (C) has a octahydropyrido [1,2-a] pyrazidyl group, but the compound according to the present invention has a Y moiety in the formula (I)
- a monocyclic or bicyclic group having one nitrogen atom in the ring such as a pyrrolidinyl group or an octahydroquinolidinyl group.
- the octahydropyridine [1,2-a] birazinyl group and the oxygen atom are bonded via a propylene group
- the compound according to the present invention is directly bonded without using an alkylene group.
- the structure is essentially different.
- a compound having an N_isopropyl-piperidine-4-yl group represented by the following formula is described as a compound that binds strongly and selectively to the histamine H 3 receptor [for example, see WO 03X024929]. .
- the compound represented by the formula (D) is common to the compound according to the present invention in that it has an N-isopropylpiperidine-4-yl group, but the compound represented by the formula (I)
- the compound according to the present invention does not have a biphenyl group, and in the compound represented by the formula (D), the biphenyl group and the N-isopropylpiperidine-14-yl group are a carbamoylmethyl group.
- the substituted piperidinyl group of the formula (I) is bonded to the above-mentioned formula (1-1) via an oxygen atom.
- the compound represented by (E) is described [for example, WO01 / 19817].
- the position of N in homopiperidine is determined according to the present invention. It differs from the N position of the compound.
- the compound represented by the above formula (E) has a property as a dicotin acetylcholine receptor ligand, whereas the compound according to the present invention has a histamine H3 receptor antagonist or It has the properties of an inverse agonist.
- WO 01 Z 198 17 does not disclose that the compound represented by the formula (E) acts as a histamine H 3 receptor antagonist or an inverse agonist. There is no description suggesting.
- the compound represented by the above formula (F) is structurally different from the compound according to the present invention in having a methyl group at the 3- and 6-positions of the pyrazine ring in the formula (F).
- the use of this compound is as a CRF receptor ligand, and the above WO 01/80608 publication does not describe a histamine H3 receptor antagonist or inverse agonist. There is no description suggesting these.
- the present invention provides a heteroaryloxy nitrogen-containing saturated heterocyclic derivative having an activity of antagonizing the binding of histamine to the histamine H3 receptor or an activity of suppressing the homeostatic activity of the histamine H3 receptor, Metabolic diseases such as hypertension, diabetes, hormonal secretion, hyperlipidemia, gout, fatty liver, etc.
- angina pectoris acute, congestive heart failure, myocardial infarction, atherosclerosis, hypertension , Kidney disease, sleep disorders and various disorders accompanied by sleep disorders, such as idiopathic hypersomnia, repetitive hypersomnia, intrinsic hypersomnia, narcolepsy, sleep periodic limb movement disorder, sleep apnea syndrome, Cardiovascular disorders such as daily rhythm disorders, chronic fatigue syndrome, REM sleep disorders, insomnia for the elderly, sleep insanity for night-shift workers, idiopathic insomnia, repetitive insomnia, intrinsic insomnia, electrolyte abnormalities, etc.
- Illnesses such as binge eating, emotional disorders, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, Attention deficitHyperactivity disorder, memory disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, cognitive disorder, movement disorder, paresthesia, olfactory disorder, epilepsy, morphine tolerance, drug addiction, alcohol dependence, etc. It is intended to provide a prophylactic or therapeutic agent for peripheral nervous system diseases.
- the present inventors have conducted intensive studies to develop a compound that inhibits the binding of histamine to the histamine H3 receptor, and the compound according to the present invention is a histamine H3 receptor antagonist and Z or an inverse agonist.
- a heteroaryloxycycloalkylamine derivative characterized by having an action is a novel substance not described in the literature, and a specific compound containing the compound is effective as a histamine H3 receptor antagonist or inverse agonist.
- the present inventors have found that the present invention has been completed based on such findings.
- X i, X 2 or X 3 each independently represent N or CH (however, not all of X i, X 2 and X 3 may be CH at the same time); (II)
- R is a cyano group, a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group)),
- a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a lower alkylsulfonyl group, a cyclo-lower alkylsulfonyl group, a halogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyl Oxy group, mono-lower alkylcarbamo Linear or branched lower alkyl, which may be substituted with a group selected from the group consisting of benzyl group, di-lower alkyl group rubamoyl group, rubamoyl group, cycloalkyliminocarbonyl group and trifluoromethyl group.
- R o represents a lower alkyl group having 1 to 4 carbon atoms, and represents a cyano group, a hydroxy group, or a lower alkyl group (the lower alkyl group is a hydroxy group, a halogen group, Atom or amino group), lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), lower alkylsulfonyl group, cyclo-lower alkylsulfonyl group, halogen atom Mono-lower alkyl rubamoyl group, di-lower alkyl rubamoyl group, rubamoyl group, cycloalkyliminocarbamoyl group, lactam ring, trifluoromethyl group, mono-lower alkylamino group, di-lower alkylamino group, alkanoyl group, An alkoxycarbonylamino group (a nitrogen atom in the group may be substituted with a lower alkyl group), an alk
- R 1 and R 2 are the same or different and each represents a lower alkyl group or a mono- or di-lower alkyl group rubamoyl group, or R i and R 2 are taken together with an adjacent nitrogen atom.
- each symbol is the same as defined above, is a C! -4 lower alkylene group, a carbonyl group, — C (0) 101, one C 1.4 lower alkylene one C (0 ) One, one C 1-4 lower alkylene one C ( ⁇ ) one, -C! -4 lower alkylene — C ( ⁇ ) one N
- Q 1 is a cyano group, a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the A lower alkoxy group may be substituted with a halogen atom), a lower alkylsulfonyl group, a cycloalkyl lower alkylsulfonyl group, an octogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyloxy group, Mono-lower alkyl rubamoyl group, di-lower alkyl rubamoyl group, rubamoyl group, cycloalky
- R 10 and R 20 are combined with a nitrogen atom adjacent to each other to form a 3 to 9-membered lactam ring, a heterocyclic ring having 3 to 8 carbon atoms (R 10 and R 20 May have, in addition to the nitrogen atom adjacent to each other, one or two nitrogen atoms or oxygen atoms in the ring as a constituent atom of the heterocyclic group), and one to four nitrogen atoms in the ring.
- one Y is a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the lower alkoxy group)
- one Y is a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the lower alkoxy group) Group may be substituted with a halogen atom), lower alkylsulfonyl group, cycloalkyl lower alkylsulfonyl group, halogen atom, mono-lower alkylaminoaminopropyl group, di-lower alkylaminocarbonyloxy group, mono-lower alkyl Carbamoyl group, di-lower alkyl rubamoyl group, cycloalkyliminocarbamoyl group, lactam ring, mono-lower-alkylamino group, di-lower-alkylamino group, alkanoyl group, alkoxyl-propionylamino group (the nitrogen atom in the group is lower al
- one Y is a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the lower alkoxy group)
- a furyl group which may have 1 to 2, a furyl group, a chenyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, an isothiazolyl group, an oxazolyl group, a isoxazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, or A compound according to the above (1), which is a pyrazinyl group, or a pharmaceutically acceptable salt thereof;
- -Y is a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the lower alkoxy group)
- the group may be substituted with a halogen atom), a halogen atom, a mono-lower alkylamino carbonyl group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkyl rubamoyl group, a di-lower alkyl rubamoyl group, cyclo Alkylimino carbamoyl group, lactam ring, mono-lower alkylamino group, di-lower alkylamino group, alkanoyl group, alkoxycarbonylamino group (the nitrogen atom in the group may be substituted with a lower alkyl group), alkano Ilamino group (The nitrogen atom in the group may be substituted with
- a compound according to the above (1) which is an oxesynyl group, a tetrahydrofuranyl group, a tetrahydrovinylil group, a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, a morpholinyl group, a homomorpholinyl group, or a pharmaceutically acceptable compound thereof. salt,
- the compound represented by the formula (I) is 2- (1-cyclopentylpiberidin-4-yloxy) -5- (4-cyanophenyl) pyrimidine, 2- (1-sopropylpiperidine-1-4-yloxy) )-5-(4-Cyanophenyl) pyrimidine, 2- (1-cyclopentylpyrrolidine-3-yloxy)-5--(4 -l-rubamoylphenyl) pyrimidine, 2--(1-Cyclopentylpyrrolidine-1 -3-yloxy)- 5- (4-Cyanophenyl) pyrimidine, 2-1 (1-cyclopentylpiperidine-1-4-yloxy)-5- ⁇ (3-Methyl-1 2,4,1-oxodiazol-5-yl) phenyl ⁇ Pyrimidine, 2 -(1-cyclopentylpyridine-1 4-yloxy)-5-(4-cyanophenyl) pyridine, 2 (1-cyclopen
- a histamine receptor H3 antagonist or inverse agonist comprising a compound according to any of the above formulas (1) to (12) as an active ingredient;
- a histamine receptor H3 antagonist comprising the compound according to any one of the formulas (1) to (12) as an active ingredient
- a histamine receptor Yuichi H3 inverse agonist comprising a compound according to any of the above formulas (1) to (12) as an active ingredient;
- a metabolic disease such as obesity, diabetes, abnormal hormonal secretion, hyperlipidemia, gout, and fatty liver, comprising a compound according to any one of the formulas (1) to (7) as an active ingredient.
- R 1 is a cyano group, a hydroxy group, or a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom, or an amino group)
- a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a halogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkylcarbamoyl group, A straight-chain or branched lower alkyl group which may be substituted with a group selected from the group consisting of lower alkyl groups such as rubamoyl group, rubamoyl group, cycloalkyliminocarbonyl group, and trifluoromethyl group; Group), C3-C9 alkyl group, aralkyl group or C3-C8 A telocyclic group
- L 1 represents a lower alkylene group having 1 to 4 carbon atoms or a single bond
- M represents an oxygen atom or a formula (V)
- Q 1 represents a cyano group, a hydroxy group, or a lower alkyl group (the lower alkyl group is a hydroxy group, a halogen group, Atom or an amino group), a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a lower alkylsulfonyl group, a cyclo-lower alkylsulfonyl group, a halogen atom, Mono-lower-alkylaminocarbonyloxy group, di-lower-alkylaminocarbonyloxy group, mono-lower-alkyl rubamoyl group, di-lower-alkyl rubamoyl group, dylvamoyl group, cycloalkyliminocarbamoyl group, lactam ring, trifluoromethyl group, Mono-lower alkylamino group, di-low
- a branched lower alkyl group a cycloalkyl group having 3 to 9 carbon atoms, a phenyl group, a 5 to 6-membered heteroaryl group, a heterocyclic group having 3 to 8 carbon atoms (a nitrogen atom or Having one or two oxygen atoms), a naphthyl group or a condensed heteroaryl group, or If necessary, a group corresponding to Q 1 in which a protecting group has been introduced, or a group represented by the formula (V-11)
- R 1 and R 2 are the same or different and each represents a lower alkyl group or a mono- or di-lower alkyl group rubamoyl group, or R 1 and R 2 together with an adjacent nitrogen atom A 3- to 9-membered lactam ring, a heterocyclic group having 3 to 8 carbon atoms (having one or two nitrogen or oxygen atoms in the heterocyclic group), a 5-membered heteroaryl group or Or a condensed heteroaryl group) or a group corresponding to -Y in which a protecting group is introduced, if necessary, into a substituent of 1Y.
- VIII a compound represented by the general formula (VIII)
- Wi is the following formula (I 1— 1)
- R 1 represents a cyano group, a hydroxy group, or a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom, or an amino group)
- a lower alkoxy group (the lower alkoxy group may be substituted with an octane atom), a halogen atom, a mono-lower alkylamino group Substituted with a group selected from the group consisting of a luponyloxy group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkylcarbamoyl group, a di-lower alkyl group, a rubamoyl group, a dirubamoyl group, a cycloalkylimino group, and a trifluoromethyl group.
- a straight-chain or branched lower alkyl group (excluding a methyl group), a cycloalkyl group having 3 to 9 carbon atoms, an aralkyl group or a heterocyclic group having 3 to 8 carbon atoms, which may be A nitrogen atom or an oxygen atom in the ring group) or a group in which a protecting group is appropriately introduced into the substituent of R, or
- Q i represents a cyano group, a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (a narrow lower alkoxy group) May be substituted with a halogen atom), a lower alkylsulfonyl group, a cyclo-lower alkylsulfonyl group, a halogen atom, a mono-lower alkylaminoaminocarbonyl group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkyl group Rubamoyl group, di-lower alkyl group lubamoyl group, di-rubamoyl group, cycloalkyliminocarbamoyl group, lactam ring, trifluoromethyl group, mono-lower alkylamino group, di-lower alkylamino group, alkan
- a lower alkyl group May be substituted with a lower alkyl group), which may be substituted with a group selected from the group consisting of: a straight-chain or branched lower alkyl group, a cycloalkyl group having 3 to 9 carbon atoms, To a phenyl group, a 5- to 6-membered heteroaryl group, a C3-C8 heterocyclic group (having one or two nitrogen or oxygen atoms in the heterocyclic group), a naphthyl group or a condensed ring If necessary, a group corresponding to Q 1 in which a protecting group has been introduced, or a group represented by the formula (V-1)
- [ ⁇ ⁇ , 2 or 3 each independently represent ⁇ or CH (however, X i,
- L 1 represents a lower alkylene group having 1 to 4 carbon atoms or a single bond
- M represents an oxygen atom or a formula (V)
- R 0 represents a lower alkyl group having 1 to 4 carbon atoms
- Q 1 represents a cyano group, a hydroxy group, or a lower alkyl group
- the lower alkyl group is a hydroxy group
- a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a lower alkylsulfonyl group, a cyclo-lower alkylsulfonyl group, Halogen atom, mono-lower alkylaminoaminocarpoxyloxy group, di-lower alkylaminocarboxyloxyl group, mono-lower alkyl alkyl group, di-lower alkyl carpamoyl group, alkyl group, cycloalkyl iminocarbamoyl group, lactam ring, tri Fluoromethyl group, mono-lower alkylamino group, di-lower alkylamino group, al A noyl group, an alkoxy
- branched lower alkyl group carbon A cycloalkyl group of the formulas 3 to 9, a phenyl group, a 5- or 6-membered heterocyclic group, a heterocyclic group having a carbon number of 3 to 8 (in the heterocyclic group, a nitrogen atom or an oxygen atom is 1 or 2 ), A naphthyl group or a condensed heteroaryl group, or a group corresponding to Q 1 in which a protecting group has been introduced, if necessary, or a compound represented by the formula (V-1)
- R 1 and R 2 are the same or different and each represents a lower alkyl group or a lower alkyl group rubamoyl group having 1 to 6 carbon atoms, or R 1 and R 2 together with an adjacent nitrogen atom
- a 5-membered heteroaryl L represents a group or a condensed heteroaryl group) or a group corresponding to 1 Y in which a protecting group has been introduced, if necessary, for a substituent of -Y. 2 represents a leaving group.
- XV a compound represented by the general formula (XV)
- the “aryl group” includes, for example, a hydrocarbon ring aryl group having 6 to 14 carbon atoms such as a phenyl group, a naphthyl group, a biphenyl group, an anthryl group and the like.
- lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec_butyl.
- alkylene group means a linear or branched alkylene group having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, and a pentamethylene group.
- cycloalkyl group having 3 to 9 carbon atoms includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a cyclononyl group.
- Alkoxy group means a group in which a hydrogen atom of a hydroxy group is substituted by the above-mentioned lower alkyl group. Examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group and a tert- Butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, and isohexyloxy group.
- alkylsulfonyl group means a group in which the alkyl group and the sulfonyl group are bonded, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, and a butylsulfonyl group.
- Alkylsulfonylamino group means a group in which one of the hydrogen atoms of the amino group is substituted with the above-mentioned alkylsulfonyl group, for example, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino Amino group, isopropylsulfonylamino group, butylsulfonylamino group, sec—butylsulfonylamino group, tert—butylsulfonylamino group, N-methyl-methylsulfonylamino group, N-methylethylsulfonylamino group, N-methyl-propylsulfonylamino group, N-methyl-isopropylsulfonylamino group, N-methyl-butylsulfonylamino group, N-methyl-sec-butyls
- cyclo lower alkylsulfonyl group means a group in which the above “cycloalkyl group having 3 to 9 carbon atoms” ′ and a sulfonyl group are bonded, for example, a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group And cyclohexylsulfonyl, cycloheptylsulfonyl, cyclooctylsulfonyl, and cyclononylsulfonyl.
- Alkyl group means the lower alkyl group having the aryl group, for example, benzyl group, 1-1phenylethyl group, 2-phenylethyl group, 1-naphthylmethyl group, 21-naphthylmethyl group, etc. Is mentioned.
- Heteroaryl group means a 5- to 7-membered monocyclic ring having 1 to 3 hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, or Means a bicyclic heteroaryl group in which a heteroaryl group and a benzene ring or a pyridine ring are condensed.
- Halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
- alkoxyl ponylamino group means a group in which one of the hydrogen atoms of the amino group is substituted with the above-mentioned alkoxycarbonyl group. Isopropoxyl-ponylamino group, butoxycarpylamino group, sec-butoxyl-ponylamino group, tert-butoxyl-ponylamino group, pentyloxycarbonylamino group, (N-methyl) methoxycarbonylamino group, (N-methyl) X 2
- Toxicarbonylamino group (N-methyl) propoxyl-ponylamino group, (N-methyl) isopropoxycarbonylamino group, (N-methyl) butoxycarbonylamino group, (N-methyl) secbutoxycarbonylamino group , (N-methyl) tert-butoxyl ponylamino group, (N-ethyl) methoxycarbonylamino group, (N-ethyl) ethoxycarbonylamino group, (N-ethyl) propoxyl ponylamino group, (N-ethyl) iso A propoxycarbonylamino group, a (N-ethyl) butoxycarponylamino group, a (N-ethyl) sec-butoxylaminolamino group, and a (N-ethyl) tert-butoxycarbonylamino group.
- Hydroalkyl group means a group in which one of the hydrogen atoms in the lower alkyl group is substituted with a hydroxy group, such as a hydroxymethyl group, a hydroxyethyl group, a 1-hydroxypropyl group, and a 1-hydroxyethyl group. Examples thereof include a tyl group, a 2-hydroxypropyl group, and a 2-hydroxy-1-methylethyl group.
- the “mono-lower alkylcarbamoyl group” means a carbamoyl group mono-substituted with the lower alkyl group, for example, a methylcarbamoyl group, an ethylcarbamoyl group, a propyl-l-bamoyl group, an isopropyl-l-l-bamoyl group, and a butyl-l-carbamoyl group. , Sec-butyl carbamoyl group, tert-butyl carbamoyl group and the like.
- di-lower alkyl group rubamoyl group means a rubamoyl group di-substituted with the same or different lower alkyl group.
- examples of the “di-lower alkyl group rubamoyl group” include dimethylcarbamoyl group and Examples thereof include a rucarbamoyl group, an ethylmethylcarbamoyl group, a dipropylcarbamoyl group, a methylpropyl-based rubamoyl group, and a disopropyl-based rubamoyl group.
- a nitrogen atom constituting the group and a same or different lower alkyl group bonded to the nitrogen atom are combined to form a 5- to 8-membered monocyclic ring.
- a case where the monocyclic ring and a benzene ring or pyr are condensed to form a bicyclic ring are condensed to form a bicyclic ring.
- Alkylamino group means an amino group mono-substituted by the lower alkyl group, for example, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, sec-butylamino group or tert-butylamino group. And a lumino group.
- Dialkylamino group means an amino group di-substituted by the same or different lower alkyl group, for example, dimethylamino group, ethylamino group, dibutylamino group, methylpropylamino group or diisopropylamino group. And the like.
- Aminoalkyl group means a group in which one of the hydrogen atoms constituting the above-mentioned alkyl group is substituted with an amino group, and examples thereof include an aminomethyl group, an aminoethyl group and an aminopropyl group.
- alkanoyl group means a group in which the above-mentioned alkyl group and carbonyl group are bonded, and examples thereof include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, and an isopropyl group.
- alkanoylamino group means a group in which the above-mentioned alkanoyl group and amino group are bonded, such as acetylamino, propanoylamino, butanoylamino, pentanoylamino, N-methylamino.
- Cetylamino group, N-methylpropanoylamino group, N-methyl-butanoylamino group, N-methyl-pentano Examples include an ilamino group, an N-ethyl-acetylamino group, an N-ethylloopanoylamino group, an N-ethyllooptanylamino group, and an N-ethylethylpentanoylamino group.
- mono-lower alkylamino propyloxy group refers to a monoalkyl-substituted oxypropyl group such as a methylamino carboxy group, an ethylamino carboxy group, and a propyl group.
- Examples include an aminocarbonyloxy group and an isopropylaminocarbonyloxy group.
- di-lower alkylaminocarboxy group means a di-substituted alkoxy group di-substituted with the above-mentioned lower alkyl group, for example, dimethylamino-aminopropyl group, dimethylaminocarbonyl group, diethylaminocarbonyl group, di-amino group. Examples thereof include a isopropylaminocarbonyloxy group and an ethylmethylaminocarbonyloxy group.
- XI, 2 or 3 each independently represents nitrogen atom or CH and (although, X i, all X 2 and X 3 do not become CH simultaneously) compounds you express in Is shown.
- M in the formula (II) represents an integer of 0 to 3.
- R represents a cyano group, a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the lower alkoxy group May be substituted with a halogen atom), a halogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkyl force rubamoyl group, a di-lower alkyl force rubamoyl group, a force rubamoyl A linear or linear group, which may be substituted with a group selected from the group consisting of a cycloalkylimino propyl group and a trifluoromethyl group.
- ⁇ Is a branched lower alkyl group (excluding a methyl group), a C 3-9 cycloalkyl group, an aralkyl group or a C 3-8 heterocyclic group (in which a nitrogen atom or oxygen Has 1 or 2 atoms).
- the “linear or branched lower alkyl group” represented by R in the formula (II) has the same meaning as the above-defined lower alkyl group (excluding the methyl group), for example, ethyl group, propyl group, butyl Group, isopropyl group, isobutyl group, tert-butyl group pentyl group, isoamyl group, neopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, hexyl group, isohexyl group, 1 And a methylpentyl group and a 1,1-dimethylbutyl group.
- the substituent which the lower alkyl group may have is, among the substituents described above, a cyano group, a hydroxy group, a lower alkoxy group, Groups (the lower alkoxy group may be substituted with a halogen atom), a halogen atom, a di-lower alkylaminocarbonyloxy group, a di-lower alkyl group rubamoyl group, and a trifluoromethyl group, and a hydroxy group And a lower alkoxy group (the lower alkoxy group may be substituted with an octogen atom) or a trifluoromethyl group.
- the "lower alkyl group substituted with a cyano group" represented by R includes, for example, 1-cyanoethyl group, 2-cyanoethyl group, 2-cyano-1,1,1-dimethylethyl group, and 5-cyanopentyl group , 4-cyanopentyl group, 3-cyanopentyl group, 2-cyanopentyl group, 2-cyanopentyl group, 1-cyanopentyl group, 3-cyano 1-methylpropyl group, 2-cyano_1-methylethyl group, 1-cyanomethylpropyl And the like.
- lower alkyl group substituted with a hydroxy group for R, more specifically, for example, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 5-hydroxypentyl group, 4-hydroxypentyl group, 3-hydroxypentyl group, 2-hydroxypentyl group, 1-hydroxypentyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-hydroxy-11 Examples include a methylethyl group, a 2-hydroxy-1-methylethyl group, a 3-hydroxy-1-methylpropyl group, a 1-hydroxymethylpropyl group, and a 1,1-dimethyl-2-hydroxyethyl group.
- R As the “lower alkyl group substituted by an alkoxy group (the alkoxy group may be substituted by a halogen atom)” represented by R, more specifically, for example, 2 1- (2-chloroethoxy) ethyl group, 2- (chloromethoxy) ethyl group, 1-methoxethyl group, 2-methoxyethyl group, 2-methoxy-1-methylethyl group, 1-chloromethoxy-1-methylethyl group, 3 —Methoxy-1-methylpropyl, 1- (methoxymethyl) propyl, 3- (chloromethoxy) 1-1-methylpropyl, 1- (chloromethoxymethyl) propyl, 1,1-dimethyl-2-methoxyethyl, 2 — (Chloromethoxy)-a 1,1-dimethylethyl group, a 5-methoxypentyl group, a 4-methoxypentyl group, a 3-methoxyp
- the “lower alkyl group substituted by a halogen atom” represented by R includes, for example, 1-fluoroethyl group, 2-fluoroethyl group, 2-fluoro-1-methylethyl group, 31-fluoro-1-methyl methyl group Pyr group, 2,2-difluoroethyl group, 2,2,2-Trifluoroethyl group, 1-Fluoromethyl group Pill group, 3,3-Difluoropropyl group, 3,3,3-Trifluor O-propyl, 2-fluoro-1,1-dimethylethyl, 1-chloroethyl, 2-chloroethyl, 2-chloro-1-methylethyl, 3-chloro-1-methylpropyl, 1-chloro Examples include a methylpropyl group and a 2-chloro-1,1-dimethylethyl group.
- Examples of the “lower alkyl group substituted by a mono-lower alkylaminocarbonyloxy group” represented by R include 2- (ethylaminopropyloxy) ethyl group, 2- (pyruaminocarbonyloxy) ethyl group, (Isopropylaminocarboxy) ethyl group and the like.
- Examples of the “lower alkyl group substituted by a dialkylaminocarponyloxy group” represented by R include, for example, an 11- (dimethylaminoaminopropyl) ethyl group, a 2- (dimethylaminoaminopropyl) ethyl group, — (Getylaminocarbonyloxy) ethyl group, 2— (Getylaminocarbonyloxy) ethyl group, 1- (Diisopropylaminocarbonyloxy) ethyl group, 2- (Dimethylaminocarbonyloxy) -1- 1-methylethyl And 2- (diethylaminocarbonyloxy) -11-methylethyl group and the like.
- Examples of the “lower alkyl group substituted with a dialkyl rubamoyl group” represented by R include, for example, a 2- (methylcarbamoyl) ethyl group and an 11- (methyl rubamoyl) ethyl group.
- Examples of the “lower alkyl group substituted with a sorbamoyl group” represented by R include, more specifically, 2- 2- rubamoyl ethyl group, 3- 3- rubamoyl propyl group, 2- 2- rubamoyl-1-methylethyl group and the like. No.
- the “lower alkyl group substituted by a trifluoromethyl group” represented by R is, for example, a 3,3,3-trifluoropropyl group, a 2,2,2-trifluoro-1 Examples include a monomethylethyl group, a 4,4,4-trifluorobutyl group, and a 3,3,3-trifluoro-1-methylpropyl group.
- Examples of the “lower alkyl group substituted by a lower alkylsulfonyl group” represented by R include, more specifically, for example, a 2-methanesulfonylethyl group, a 1-methanesulfonylethyl group, a 2-ethanesulfonylethyl group, 2-methanesulfonyl-1-methylethyl group and the like.
- lower alkyl group substituted by a cycloalkyl lower alkylsulfonyl group represented by R, more specifically, for example, a 2-cyclopropanesulfonylethyl group, a 1-cyclopropanesulfonylethyl group, a 3-cyclobutane Examples thereof include a sulfonylpropyl group and a 2-cyclobutanesulfonylpropyl group.
- R is “a cycloalkyl group having 3 to 9 carbon atoms”
- the “cycloalkyl group having 3 to 9 carbon atoms” represented by R in the formula (II) has the same meaning as the above definition, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclohexyl group. Examples thereof include a butyl group, a cyclooctyl group, and the like.
- a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group are preferable, and a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group are more preferable.
- C3-C9 cycloalkyl group when the C3-C9 cycloalkyl group may have a substituent, among the substituents described above, a cyano group A hydroxy group, a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a lower alkyl group (the lower alkoxy group is A halogen atom, a halogen atom, a di-lower alkylaminocarbonyloxy group, a di-lower alkylcarbamoyl group or a trifluoromethyl group, preferably a cyano group, a hydroxy group, a lower alkoxy group (the lower The alkoxy group may be substituted with a halogen atom), and a halogen atom or a trifluoromethyl group is more preferable.
- the cycloalkyl group having 3 to 9 carbon atoms may have the same or different 1 or 2 at the position where these substituents can be bonded.
- cycloalkyl group substituted with a lower alkyl group represented by R, more specifically, for example, 1-methylcyclopropyl group, 1-ethylcyclopropyl group, 1-methylcyclobutyl group, 1-methylcyclopentyl group, 1-methylcyclopentyl group, 1-methylcyclohexyl group, 1-ethylcyclohexyl group, 1-methylcycloheptyl group, 1-ethylcycloheptyl group, 1-methylcyclopentyl group Examples thereof include a methylcyclooctyl group and a 1-ethylcyclooctyl group.
- the “cycloalkyl group substituted by a cyano group” represented by R includes, for example, a 2-cyanocyclopropyl group, a 3-cyanocyclobutyl group, a 2-cyanocyclobutyl group, —Cyanocyclopentyl group, 3-cyanocyclopentyl group, 2-cyanocyclohexyl group, 3-cyanocyclohexyl group, 4-cyanocyclohexyl group, 2-cyanocycloheptyl group, 3-cyanocycloheptyl group, 4 —Cyanocyclyl heptyl group, 2-cyanocyclooctyl group, 3-cyanocyclooctyl group, 4-cyanocyclooctyl group, 5-cyanocyclooctyl group and the like.
- cycloalkyl group substituted with a hydroxy group represented by R includes, for example, 2-hydroxycyclopropyl, 3-hydroxycyclobutyl, 2-hydroxycyclobutyl, 2-hydroxy Cyclopentyl, 3-hydroxycyclopentyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2-hydroxycyclo, 2-hydroxycyclooctyl, 3-hydroxy Cyclooctyl group, 41
- cycloalkyl group substituted by an alkoxy group (the alkoxy group may be substituted with a halogen atom)” represented by R, more specifically, for example, a 2-chloromethoxycyclopropyl group, 2 —Methoxycyclopropyl group, 2-ethoxycyclopropyl group, 2- (chloromethoxy) cyclobutyl group, 3-methoxycyclobutyl group, 2- (chloromethoxy) cyclopentyl group, 2-methoxycyclopentyl group, 3-methoxycyclopentyl group, 2- (chloromethoxy) cyclo mouth hexyl group, 2-methoxycyclohexyl group, 3-methoxycyclohexyl group,
- cycloalkyl group substituted by a halogen atom represented by R, more specifically, for example, a 2-fluorocyclopropyl group, a 3-fluorocyclobutyl group, a 2-fluorocyclobutyl group Group, 2-fluorocyclopentyl group, 3-fluorocyclopentyl group, 2-fluorocyclohexyl group, 3-fluorocyclohexyl group, 4-fluorocyclohexyl group, 2-fluorocycloheptyl group, 3-fluorocycloheptyl Group, 4-fluorocycloheptyl group, 2-fluorocyclooctyl group, 3-fluorocyclooctyl group, 4-fluorocyclooctyl group, 5-fluorocyclooctyl group, 2-chlorocyclopropyl group , 3-chlorocyclobutyl, 2-chlorocyclobutyl, 2-chlorocyclopent
- cycloalkyl group substituted by a mono-lower alkylaminocarboxy group represented by R, more specifically, for example, 2- (methylcarbamoyloxy) cyclopropyl group, 3— (methylcarbamoyloxy) Xy) cyclobutyl group, 2 1- (Methylcarbamoyloxy) cyclobutyl group, 2- (methylcarbamoyloxy) cyclopentyl group, 3- (methylcarbamoyloxy) cyclopentyl group, 2- (methylcarbamoyloxy) cyclohexyl group, 3- (methylcarbamoyloxy) cyclopentyl group (Moyloxy) cyclohexyl group, 4- (methylcarbamoyloxy) cyclohexyl group, 2- (methylcarbamoyloxy) cycloheptyl group, 3- (methylcarbamoyloxy) cycloheptyl group
- Examples of the “cycloalkyl group substituted with a di-lower alkylaminocarbonyloxy group” represented by R include, for example, 2- (dimethylcarbamoyloxy) cyclopropyl group and 3- (dimethylcarbamoyloxy) cyclopropyl group.
- cycloalkyl group substituted with a dialkyl rubamoyl group represented by R, more specifically, for example, 2- (dimethylcarbamoyl) cyclopropyl group, 31- (dimethylcarbamoyl) cyclobutyl group, 2- (dimethyl Carbamoyl) cyclobutyl group, 2- (dimethylcarbamoyl) cyclopentyl group, 3- (dimethylcarbamoyl) cyclopentyl group, 2- (dimethylcarbamoyl) cyclohexyl group, 31- (dimethylcarbamoyl) cyclohexyl group, 4- (dimethylcarboxyl) Rubamoyl) cyclohexyl group, 2- (dimethylcarbamoyl) cycloheptyl group, 3- (dimethylcarbamoyl) cycloheptyl group,-(dimethylcarbamoyl group
- the “cycloalkyl group substituted with an alkylcarbamoyl group” represented by R includes 21- (methylcarbamoyl) cyclopropyl, 31- (methylcarbamoyl) cyclobutyl, and 21-methylcarbamoyl ) Cyclobutyl group, 2- (methylcarbamoyl) cyclopentyl group, 3- (methylcarbamoyl) cyclopentyl group, 2- (methylcarbamoyl) cyclohexyl group, 3- (methylcarbamoyl) cyclohexyl group, 4- (methyl (Carbamoyl) cyclohexyl group, 2- (methylcarbamoyl) cycloheptyl group, 31- (methylcarbamoyl) cycloheptyl group, 41- (methylcarbamoyl) cycloheptyl group, 21- (methylcarbamoyl) cyclooct
- the “cycloalkyl group substituted with a l-rubamoyl group” represented by R includes, for example, 2 lrubamoylcyclopropyl group, 3 lrubamoylcyclobutyl group, 2 lrubamoylcyclobutyl group Group, 2 rubamoyl cyclopentyl group, 3 rubamoyl cyclopentyl group, 2 rubamoyl cyclohexyl group, 3 rubamoyl cyclohexyl group, 4 rubamoyl cyclohexyl group, 2 lbamoyl cycloheptyl group Group, 3 rubamoyl cycloheptyl group, 4 carbamoyl cycloheptyl group, 2 lbamoyl cyclooctyl group, 3 lbamoyl cyclooctyl group, 4 rubamoyl cyclooctyl group, 5 And
- cycloalkyl group substituted by a trifluoromethyl group represented by R, more specifically, for example, a 2- (trifluoromethyl) cyclopropyl group, a 2- (trifluoromethyl) cyclobutyl group , 3-1- (trifluoromethyl) cyclobut Tyl group, 2- (trifluoromethyl) cyclopentyl group, 3- (trifluoromethyl) cyclopentyl group, 2- (trifluoromethyl) cyclohexyl group, 3- (trifluoromethyl) cyclohexyl group, 4 — (Trifluoromethyl) cyclohexyl group, 2— (trifluoromethyl) cycloheptyl group, 3— (trifluoromethyl) cycloheptyl group, 41- (trifluoromethyl) cycloheptyl group, 2 — (Trifluoromethyl) cyclooctyl group, 3- (trifluoromethyl) cyclomethyl
- Examples of the “lower alkylsulfonyl-substituted cycloalkyl group” represented by R include, for example, 2-methanesulfonylcyclopropyl group, 2-methanesulfonylcyclobutyl group, 3-methanesulfonylcyclobutyl group Group, 2-methanesulfonylcyclopentyl group, 3-methanesulfonylcyclopentyl group, 2-methanesulfonylcyclohexyl group, 3-methanesulfonylcyclohexyl group, 4-methanesulfonylcyclohexyl group, 2-methanesulfonyl group Rucycloheptyl group, 3-methanesulfonylcycloheptyl group, 4-methansulfonylcycloheptyl group, 2-methanesulfonylcyclooctyl group, 31-me
- the “cyclo lower alkylsulfonyl-substituted cycloalkyl group” represented by R is, for example, 2-cyclopropanesulfonylcyclopropyl group, 2-cyclopropanesulfonylcyclobutyl group, 3 —Cyclopropanesulfonylcyclobutyl group, 2-cyclopropanesulfonylcyclopentyl group, 3-cyclopropanesulfonylcyclopentyl group, 2-cyclopropanesulfonylcyclohexyl group, 3-cyclopropanesulfonylcyclohexyl group, 4-cyclopropanesulfonylcyclohexyl group, 2-cyclopropanesulfonylcycloheptyl group, 3-cyclopropanesulfonylcycloheptyl group, 4-cyclopropanesulfonylcycloheptyl group, 2-cyclopropanesulfonyl
- the “aralkyl group” represented by R in the formula (II) refers to the lower alkyl group having a hydrocarbon ring aryl group having 6 to 14 carbon atoms such as a phenyl group, a naphthyl group and a biphenyl group. It means, for example, benzyl group, 2-phenylethyl group, 1-phenylethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1-naphthalene-1-ethyl group, and 1-naphthalene-12-ylethyl group.
- a benzyl group, a 2-phenylethyl group, a 1-phenylethyl group, a 1-naphthylmethyl group or a 2-naphthylmethyl group is preferable, and a benzyl group, a 2-phenylethyl group, a 1-phenylethyl group or a 1-naphthyl group is preferable.
- a methyl group is more preferred.
- the substituents that the aralkyl group may have include, among the substituents described above, a cyano group, a hydroxy group, a lower alkoxy group (the lower alkoxy group).
- the group may be substituted with a halogen atom), a halogen atom, a di-lower alkylaminocarbonyloxy group, a di-lower alkylcarbamoyl group or a trifluoromethyl group, preferably a cyano group, a hydroxy group,
- a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a halogen atom or a trifluoromethyl group is more preferable.
- the aralkyl group may have the same or different 1 or 2 at the position where these substituents can be bonded.
- Examples of the “aralkyl group substituted by a cyano group” represented by R include, more specifically, a 4-cyanobenzyl group, an 1-1 (4-cyanophenyl) ethyl group, a 2- (4-cyanophenyl) ethyl group, and the like. No.
- Examples of the “aralkyl group substituted by a hydroxy group” for R include, more specifically, for example, a 4-hydroxybenzyl group, an 11- (4-hydroxyphenyl) ethyl group, and a 2- (4-hydroxy Phenyl) ethyl and the like.
- aralkyl group substituted by an alkoxy group (the alkoxy group may be substituted with a halogen atom)” represented by R, more specifically, for example, 2-methoxybenzyl group, 3-methoxybenzyl Group, 4-methoxybenzyl group, 2-
- Examples of the “aralkyl group substituted with a halogen atom” represented by R include, more specifically, a 4-chlorobenzyl group, a 1- (4-chlorophenyl) ethyl group, a 2- (4-cyclophenyl) ) Ethyl group and the like.
- the “aralkyl group substituted with an alkylaminocarbonyloxy group” represented by R is more specifically, for example, a 4- (methylcarbamoyloxy) benzyl group or a 4- (ethylcarbamoyloxy) Benzyl group, 4- (cyclopropylcarbamoyloxy) benzyl group and the like.
- Examples of the “aralkyl group substituted with a dialkylaminocarbonyloxy group” represented by R include, for example, 4- (dimethylaminocarbonyloxy) benzyl group and 4- (ethylmethylcarbamoyloxy) ) Benzyl group and 41- (ethyl carbamoyloxy) benzyl group.
- Examples of the “aralkyl group substituted by a dialkyl rubamoyl group” represented by R include, for example, a 4-dimethylcarbamoylpentyl group, a 4- (ethylmethylcarbamoyl) benzyl group, and a 2- (3-dimethyl Carbamoylphenyl) ethyl group and the like.
- the “aralkyl group substituted by an alkyl group” represented by R is, for example, a 4- (methylcarbamoyl) benzyl group, a 3- (methyl group rubamoyl) benzyl group, a 2- (methyl Carbamoyl) benzyl group, 2- (3-ethylcarbamoylphenyl) ethyl group, 2- (4-methylcarbamoylphenyl) ethyl group and the like.
- the “aralkyl group substituted with a sorbamoyl group” represented by R includes, for example, 4-force rubamoyl pendyl group, 3-force rubamoyl pendyl group, 2 Groups, 2- (3-force rubamoyl> refenyl) ethyl group and 2- (4 force rubamoylphenyl) ethyl group.
- the “aralkyl group substituted with a trifluoromethyl group” represented by R includes, for example, a 4- (trifluoromethyl) benzyl group and a 3- (trifluoromethyl) benzyl group.
- Examples of the “aralkyl group substituted by a lower alkylsulfonyl group” represented by R include, for example, 4-methansulfonylbenzyl group, 3-methanesulfonylbenzyl group, 2-methanesulfonylbenzyl group, Ethanesulfonylbenzyl, 3-ethanesulfonylbenzyl, 2-ethanesulfonylbenzyl, 2- (3-methanesulfonylphenyl) ethyl, 2- (3-methanesulfonylphenyl) ethyl, 2--( (4) methanesulfonylphenyl) ethyl group and the like.
- Examples of the “aralkyl group substituted with a cyclo-lower alkylsulfonyl group” represented by R include, for example, 4-cyclopropanemethanesulfonylbenzyl group, 3-cyclopropanemethanesulfonylbenzyl group, 2- A cyclopropanemethanesulfonylbenzyl group, a 2- (3-cyclopropanesulfonylphenyl) ethyl group, a 2- (3-cyclopropanesulfonylphenyl) ethyl group, a 2- (4-cyclopropanesulfonylphenyl) ethyl group, and the like. No. Next, the case where is a “3- to 8-membered heterocycle” will be described.
- the “3- to 8-membered heterocyclic group” represented by R in the formula (II) means a 3- to 8-membered heterocyclic ring having one or two nitrogen atoms or oxygen atoms in the ring. I do. When the hetero ring has two oxygen atoms or nitrogen atoms in the hetero ring, these hetero atoms may be the same or different.
- Examples of the 3- to 8-membered heterocyclic group include an oxenyl group, a tetrahydrofuran group, a tetrahydropyranyl group, a azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, a morpholinyl group, a homomorphonyl group, ⁇ Lül group or homopiperazinyl group, among which oxenyl group, tetrahydrofuranyl group, tetrahydropyrael group, pyrrolidinyl group, pyridinyl group, homopiperidinyl group, morpholinyl group, and homomorphonyl group are preferred, and oxoxenyl group is preferred. Evenyl group, tetrahydrofurel group, tetrahydropyranyl group, A peridinyl group and a homopiperidinyl group are
- the substituent which the hetero ring may have includes, among the substituents described above, a cyano group, a hydroxy group, a lower alkoxy group, Group (the lower alkoxy group may be substituted with a halogen atom), a lower alkyl group (the lower alkoxy group may be substituted with a halogen atom), a halogen atom, di-lower alkylaminocarponyloxy Group, a di-lower alkylcarbamoyl group or a trifluoromethyl group, preferably a cyano group, a hydroxy group, a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a lower alkyl group (the The lower alkoxy group may be substituted with a halogen atom), a halogen atom or a trifluoromethyl group is more preferable.
- the 3 to 8 hetero rings may have one or two different positions in the same sentence at positions where these substituents can be bonded.
- the “3- to 8-membered heterocyclic ring substituted with a cyano group” represented by R is more specifically, for example, a 4-cyanoxetane-2-yl group, 4-cyanotetrahydrofuran-13-y And 3-cyanopiperidine-1-yl, 6-cyanoazepan-4-yl and the like.
- the “3- to 8-membered heterocyclic ring substituted with a lower alkyl group” represented by R is more specifically, for example, a 2-methyloxetane-13-yl group, a 2-chloromethyloxetane 1-3-yl, 4-methyloxetane-12-yl, 5-methyltetrahydrofuran-13-yl, 5-chloromethyltetrahydrofuran-13-yl, 4-methyltetrahydrofuran-12- 2-methyltetrahydropyran-1-yl, 5-methylpyrrolidine-3-yl, 4-methylpyrrolidine-3-yl, 2-methylpiperidine-1-4-yl, 3-methylpiperidine 4-yl group, 7-methylazepan-4-yl group and the like.
- Examples of the “3- to 8-membered heterocyclic ring substituted with a hydroxy group” represented by R include, for example, a 4-hydroxyoxetane-1-yl group and a 4-hydroxytetrahydrofuran-1-yl group. Examples thereof include a 3-yl group, a 3-hydroxypiperidine-4-yl group, and a 6-hydroxyazepanyl 4-yl group.
- R As the “3- to 8-membered heterocycle substituted with a halogen atom” represented by R, Specifically, for example, a 4-fluorooxetane-2-yl group, a 3-fluorooxetane-12-yl group, a 2-fluorooxetane-1-3-yl group, a 4-fluorotetrahydrofuran 1 3-yl group, 3-fluoropiperidine-4-yl group, 6-fluoroazepan-1-yl group, 4-fluorooxetane 1-2-yl group, 3-fluoroxyxetane 1-2 —Yl group, 21-chloro-oxetane-13-yl group, 4-chlorotetrahydrofuran-13-yl group, 3-chloropiperidine-4-yl group, 6-chloroazepan-4-yl group and the like.
- R Specifically, for example, a 4-fluorooxetane-2-yl
- R As the “3- to 8-membered heterocyclic ring substituted with an alkylaminocarbonyloxy group” represented by R, more specifically, for example, 4- (methylcarbamoyloxy) oxetane-1-yl group, 3 — (Methylcarbamoyloxy) oxetane— 2-yl group, 21- (ethylcarbamoyloxy) oxetane-3-yl group, 4- (methylcarbamoyloxy) tetrahydrofuran-3-yl group, 3 — (Methylcarbamoyloxy) piperidine— 4-yl group and 61- (methylcarbamoyloxy) azepan-4-yl group.
- 4- (methylcarbamoyloxy) oxetane-1-yl group 3 — (Methylcarbamoyloxy) oxetane— 2-yl group, 21- (e
- the “3- to 8-membered heterocyclic ring substituted with a dialkylaminocarbonyloxy group” represented by R is more specifically, for example, 4- (dimethylcarbamoyloxy) oxetane-1-2-f 1- (dimethylcarbamoyloxy) oxetane-12-yl group, 21- (getylcarbamoyloxy) oxetane-1-3-yl group, 4- (ethylmethylcarbamoyloxy) tetrahydrofuran-3-yl Group, 3- (dimethylcarbamoyloxy) piperidine-4-yl group, 6- (dimethylcarbamoyloxy) azepan-4-yl group and the like.
- Examples of the “3- to 8-membered heterocyclic ring substituted with an alkylrubumoyl group” represented by R include, for example, 4- (methylcarbamoyl) oxetane-2-yl group, 31- ( Methylcarbamoyl) oxetane-1-2-yl group, 4- (ethylcarbamoyl) tetrahydrofuran-3-yl group, 3- (methylcarbamoyl) piperidine-4-yl group, 61-1 (dimethylcarbamoyl) azepan-1 4-yl And the like.
- Examples of the “3- to 8-membered heterocyclic ring substituted with a carbamoyl group” represented by R include, for example, a 4-hydroxy group and a 3-hydroxy group.
- R As the “3- to 8-membered heterocyclic ring substituted with a trifluoromethyl group” represented by R, more specifically, for example, a 4- (trifluoromethyl) oxetane-12-yl group, 3 — (Trifluoromethyl) oxetane — 2-yl, 4- (trifluoromethyl) tetrahydrofuran-3-yl, 3- (trifluoromethyl) pyridin — 4-yl, 61- (trifluoro L-methyl) azepane-a 4-yl group and the like.
- a 4- (trifluoromethyl) oxetane-12-yl group 3 — (Trifluoromethyl) oxetane — 2-yl, 4- (trifluoromethyl) tetrahydrofuran-3-yl, 3- (trifluoromethyl) pyridin — 4-yl, 61- (trifluoro L-methyl) azepane
- R represents a “4- (methylsulfonyl) oxetane-2-yl group substituted with a lower alkylsulfonyl group, a 3- (ethylsilulfonyl) oxetane-2-yl group, a 4- (ethylsulfonyl) Trihydrofuran-1-yl group, 3- (methylsulfonyl) piperidine-4-yl group, 61- (methylsulfonyl) azepanyl-4-yl group and the like.
- the “3- to 8-membered heterocyclic ring substituted with a cycloalkyl lower alkylsulfonyl group” represented by R is, for example, more specifically, for example, a 4- (cyclopropylsulfonyl) oxetane-21-diphenyl group 3- (cyclopropylsulfonyl) oxetane-12-yl group, 4- (cyclopropylsulfonyl) tetrahydrofuran-13-yl group, 3- (cyclopropyl) piperidine-4-yl group, 6- (cyclopropylsulfonyl) ) Azepan-4 -yl group and the like.
- a group represented by (111-3) is more preferable in the above formula (II) or (III), when m or n of one (CH 2 ) m — or one (CH 2 ) n — is 0, one (CH 2 ) m —, one (CH 2 ) n — Means a single bond.
- one (O) j— means a single bond.
- L I represents a lower alkyl group having 1 to 4 carbon atoms or a single bond.
- L! I preferably a lower alkyl group having 1 to 3 carbon atoms or a single bond, and more preferably a lower alkyl group having 1 to 2 carbon atoms or a single bond.
- M is an oxygen atom or formula (V)
- Ro in the formula (V) represents a lower alkyl group having 1 to 4 carbon atoms.
- the Ro group include a methyl group, an ethyl group, a propyl group, an n-butyl group, an isopropyl group, an isobutyl group and a tert-butyl group.
- a methyl group, an ethyl group and a propyl group are exemplified.
- N-butyl group and isopropyl group are preferable
- methyl group, ethyl group, propyl group and isopropyl group are more preferable.
- -C! -4 Lower alkylene-1 C (0) 100_, -C 1-4 Lower alkylene-1 C (O) -N (R 0) ⁇ , — C (O) 1 N (R) ⁇ , 1 O — C 4 lower alkylene—or a single bond is preferable, and C! -4 lower alkylene group, 1 C (O) 1 O—, -C! -4 lower alkylene 1 C (0) C 1-4 lower alkylene—C (O) —N (0) —, —C ( ⁇ ) —N (R o) —, one O—C ⁇ 4 lower alkylene— or a single bond is more preferred.
- Ro has the same meaning as described above.
- Qi is a cyano group, a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the lower alkoxy group is a halogen atom , A halogen atom, a mono-lower alkylamino carboxy group, a di-lower alkylamino carboxy group, a mono-lower alkyl rubamoyl group, a di-lower alkyl rubamoyl group, a carpamoyl group, a cycloalkylimino A carbamoyl group, a lactam ring, a trifluoromethyl group, a mono-lower alkylamino group, a di-lower alkylamino group, an alkanol group, an alkoxycarbonylamino group (the nitrogen atom in the group is substituted with a lower alkyl group;
- R i and R 2 are the same or different and each represents a lower alkyl group or a mono- or di-lower alkyl group rubamoyl group, or R i and R 2 together with an adjacent nitrogen atom A 3- to 9-membered lactam ring, a heterocyclic group having 3 to 8 carbon atoms (having one or two nitrogen or oxygen atoms as constituent atoms of the group), a 5-membered heteroaryl Or a condensed heteroaryl group).
- the “linear or branched lower alkyl group” represented by Q i includes the same groups as the lower alkyl groups defined above, and among them, methyl group, ethyl group, propyl group, isopropyl group, and butyl group , Isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, isopentyl, 1,1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethyl Propyl, hexyl and isohexyl are preferred, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl More preferred are an isopentyl group, a 1,1-dimethylpropyl group, a hexyl group and an
- the “linear or branched lower alkyl group” represented by the —Y more specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Isobutyl, sec-butyl, tert-butyl, ⁇ Methyl, isoamyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonanyl, decanyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.
- examples of the substituent which the lower alkyl group may have include, among the substituents which Q i may have, Ano group, hydroxy group, lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), halogen atom, di-lower alkylaminocarbonyloxy group, di-lower alkyl group rubamoyl group, and trifluoro group A lomethyl group is preferred, and a hydroxy group, a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom) or a trifluoromethyl group is more preferred.
- Y include, for example, a 3-cyanopropyl group, a 4-cyanobutyl group, and a 2-cyanobutyl Group, 5-cyanopentyl group, 4-cyanopentyl group, 6-cyanohexyl group, 5-cyanohexyl group, 4-cyanohexyl group, 7-cyanoheptyl group, 6-cyanoheptyl group, 5-cyanoheptyl group, 8 —Cyanyl octyl group, 7—Cyanoctyl group, 6—Cyanoctyl group, 5—Cyanoctyl group, 3 _Cyanopropoxy group, 4-Cyanobutoxy group, 3-Cyanobutoxy group, 5-Cyanopentyloxy group, 4—Cyanopentyloxy group Nopentyloxy, 6-cyanohexyloxy
- —Y is more specifically, for example, a 3-hydroxypropyl group, a 4-hydroxybutyl group, 2-hydroxybutyl, 5-hydroxypentyl, 4-hydroxypentyl, 6-hydroxyhexyl, 5-hydroxyhexyl, 4-hydroxyhexyl, 7-hydroxyheptyl, 6-hydroxyheptyl Group, 5-hydroxyheptyl group, 8-hydroxyoctyl group, 7-hydroxyl oxyoctyl group, 6-hydroxyoctyl group, 5-hydroxyoctyl group, 3-hydroxypropoxy group, 4-hydroxybutoxy group, 3- Hydroxybutoxy, 5-hydroxypentyloxy, 4-hydroxypentyloxy, 6-hydroxyhexyloxy , 5-hydroxy into Kishiruokishi group, 4 Kishiruokishi group to Hidoro alkoxy, 7-hydroxy-heptyl O alkoxy group, 6-hydroxy heptene
- Y is, for example, a 3-fluoropropyl group, a 4-fluorobutyl group, or a 2-fluorobutyl group.
- Q i is a “linear or branched lower alkyl group substituted with a mono-lower alkylaminocarbonyloxy group”, more specifically, as Y, for example, 3- (methylcarbamoylo) Xy) propyl, 4- (methylcarbamoyloxy) butyl, 3- (methylcarbamoyloxy) butyl, 5- (methylcarboxy Bamoyloxy) pentyl group, 4- (methylcarbamoyloxy) pentyl group,
- the Y represented by the formula (IV) is more specifically Is, for example, 3- (dimethylcarbamoyloxy) propyl group, 4- (dimethylcarbamoyloxy) butyl group, 3- (dimethylcarbamoyloxy) butyl group, 5- (dimethylcarbamoyloxy) pentyl group, 4 1- (dimethylcarbamoyloxy) pentyl group, 61- (dimethylcarbamoyloxy) hexyl group, 5- (dimethylcarbamoyloxy) hexyl group, 4- (dimethylcarbamoyloxy) hexyl group, 2- (dimethyl Carbamoyloxy) cycloheptyl group, 7— (dimethylcarbamoyloxy) hept
- Q 1 is “a linear or branched lower alkyl group substituted with a dialkyl group rubamoyl group”, as the Y represented by the formula (IV), more specifically, for example, To 3-dimethylcarbamoylpropyl, 4-dimethylcarbamoylbutyl, 3-dimethylcarbamoylbutyl, 5-dimethylcarbamoylpentyl, 4-dimethylcarbamoylpentyl, 6-dimethylcarbamoylhexyl, 7-dimethylcarbamoyl Butyl group, 6—
- Q i is a “linear or branched lower alkyl group substituted with a trifluoromethyl group”, as the Y represented by the formula (IV), more specifically, for example, , 3- (trifluoromethyl) propyl, 4- (trifluoromethyl) butyl, 2- (trifluoromethyl) butyl, 5- (trifluoromethyl) pentyl, 4- (trifluoromethyl) 6- (Trifluoromethyl) hexyl group, 5- (Trifluoromethyl) hexyl group, 4- (Trifluoromethyl) hexyl group, 7- (Trifluoromethyl) heptyl group , 6- (trifluoromethyl) heptyl group, 5- (trifluoromethyl) heptyl group, 8- (trifluoromethyl) octyl group, 7— (trifluoromethyl) octyl group, 6- (trifluoromethyl) octyl group, 5-(Trifle (
- Examples of the ⁇ C3-C9 cycloalkyl group '' represented by Q i include the same groups as the above-mentioned C3-C9 cycloalkyl groups, and more specifically, for example, a cyclopropyl group, Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, Cyclobutylpropyl, cyclobutylbutyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclohexylmethyl, cyclohexylethyl Group, cyclohexylpropyl group, cyclo
- a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopentyl group, and the like are preferable. preferable.
- examples of the substituent that the cycloalkyl group may have include substituents that Q i may have. That is, for example, a cyano group, a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the lower alkoxy group is A halogen atom, a halogen atom, a mono-lower alkylamino propyloxy group, a di-lower alkylaminocarponyloxy group, a mono-lower alkyl rubamoyl group, a di-lower alkyl carbamoyl group, and a carbamoyl group A lactam ring, a trifluoromethyl group, a mono-lower alkylamino group, a di-lower alkylamino group or an al
- the cycloalkyl group may have one or two of these substituents at a bondable position, and when it has two of these substituents, they may be the same or different.
- Q i is a “cycloalkyl group having 3 to 9 carbon atoms” substituted with these substituents
- one Y represented by the formula (IV) is more specifically, for example,
- the phenyl group may have, among the substituents that may have, a cyano group, a hydroxy group, a lower alkyl group ( The lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group, a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a halogen atom, a mono-lower group.
- the xy group may be substituted with a halogen atom), a halogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyloxy group, a 'mono-lower alkyl group rubamoyl group, a di-lower alkyl group rubamoyl group Group, cycloalkyliminocarbamoyl group, lactam ring, mono-lower alkylamino group, di-lower radical A killamino group and an alkanoyl group are more preferred.
- the phenyl group may have one or two of these substituents at a position capable of binding.
- —Y represented by the above formula (IV) is more specifically, for example, a phenyl group, 4- Cyanophenyl group, 3-cyanophenyl group, 2-cyanophenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, 4- (dimethylcarbamoyl) phenyl group, 3- (dimethylcarbamoyl) group ) Phenyl, 2- (dimethylcarbamoyl) phenyl, 4- (methylcarbamoyl) phenyl, 3- (methylcarbamoyl) phenyl, 2- (methylcarbamoyl) phenyl, 4 , 3-carbamoylphenyl group, 3-force rubamoylphenyl group, 21-strength rubamoylphenyl group, 41- (cyclopropyl-stre
- the “5- to 6-membered heteroaryl group” represented by Q i is a 5- to 6-membered ring having 1 to 3 hetero atoms in the ring selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. And includes, for example, a furyl group, a chenyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, and a pyrazinyl group.
- a furyl group, a cyenyl group, a pyrrolyl group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, and a pyrazinyl group are exemplified.
- pyrazolyl Preference is given to pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, An oxazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, and a pyrazinyl group are more preferred.
- the substituent that the heteroaryl group may have is, among the substituents that Q 1 may have, A cyano group, a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkyl group, a lower alkoxy group (the lower alkoxy group is a halogen atom ), A halogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkyl force rubamoyl group, a di-lower alkyl force rubamoyl group, a lubamoyl group, a lactam ring And a trifluoromethyl group, a mono-lower alkylamino group, a di-lower alkylamino group and an alken
- lower alkyl group lower alkoxy
- a lower alkoxy group may be substituted with a halogen atom), a halogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkylamino group, More preferred are lower alkyl rubamoyl groups, cycloalkylimino rubamoyl groups, lactam rings, mono-lower alkylamino groups, di-lower alkylamino groups, and alkanoyl groups.
- the heteroaryl group may have one or two of these substituents at a bondable position.
- Q i is a ⁇ 5- or 6-membered heteroaryl group '' which may be substituted with these substituents, as the Y represented by the formula (IV), more specifically,
- heterocyclic group having 3 to 8 carbon atoms represented by Q i means a 3- to 8-membered monocyclic ring having 1 to 2 nitrogen atoms or oxygen atoms in the ring, and the heterocyclic group is Or a group similar to the heterocyclic group having 3 to 8 carbon atoms represented by R, or the following formula (Q—l)
- R 7 represents a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a halo-lower alkyl group or an aralkyl group].
- the substituent which the hetero ring may have is, among the substituents which may have, a cyano group A hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a cyclo lower alkyl group, a lower alkoxy group (the lower alkoxy group is a halogen atom Optionally substituted), halogen atom, mono-lower alkylaminocarbonyloxy group, di-lower alkylaminocarbonyloxy group, mono-lower alkyl carbamoyl group, di-lower alkylcarbamoyl group, carpamoyl group, lactam ring, Trifluoromethyl, mono-lower alkylamino, di-lower alkylamino and alkanoyl are preferred.
- a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group), a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), Halogen atom, mono-lower alkylaminocarbonyloxy group, di-lower alkylaminocarbonyloxy group, mono Lower alkyl rubamoyl, di-lower alkyl rubamoyl, cycloalkyliminocarbamoyl, lactam ring, mono-lower alkylamino, di-lower alkylamino and alkanoyl are more preferred.
- the heterocyclic group may have one or two of these substituents at a position capable of binding.
- Q 1 is optionally substituted with these groups, and is a ⁇ heterocyclic group having 3 to 8 carbon atoms '', as the Y represented by the formula (IV), more specifically,
- 1H-pyridine-2-one-4-yl group 1H-pyridine-12-one-14-yl group, 1-methyl-1H-pyridine-12-one-4-yl group, 1-ethyl-1 H_pyridine-1-one-1-yl group, 1-isopropyl-1H-pyridine-12-one-4-yl group, 1-difluoromethyl-1H-pyridine-12-one-4-yl group, 1- (2-fluoroethyl) -1-H-pyridine-1-one-4-yl group, 1- (2,2-difluoroethyl) -1-H-pyridine-2-one-1-yl group, 1- (2,2,2-triflule) 1) LH—Pyridine 1-2-one 4-yl group, 1- (2-Fluoroethoxy) — 1H—
- the substituents that the naphthyl group may have include, among the substituents that Q 1 may have, a cyano group, a hydroxy group, and a lower alkyl group.
- the lower alkyl group may be substituted with a hydroxy group, an octogen atom or an amino group
- a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a halogen atom
- the naphthyl group may have 1 or 2 at a position where these substituents can be bonded, and Q i may be substituted with these substituents.
- 1 Y is more specifically, for example, 5 -cyana naphthalene-1-yl group, 6-cyana naphthalene-11-yl group, 7-cyana naphthalene 1 1-yl group, 5-cyanonaphthalene 1-2-yl group, 6-cyanonaphthalene 1-2-yl group, 7 _cyanonaphthylene 1-2-yl group, 5-fluoronaphthalene-1-yl group, 6 -Fluoronaphthalene-1-yl group, 7-Fluoronaphthalene-1-yl group, 5-Fluoronaphthalene-12-yl group, 6-Fluoronaphthalene-12-yl group, 7-Fur Olonaphthalene-1-yl group, 5-methoxyn
- 5-trifluoromethylnaphthalene-1-yl group 6-trifluoromethylnaphthalene-1-yl group, 7-trifluoromethylnaphthyl-1-yl group, 5-trifluoromethylnaphthyl Len-2-yl group, 6-trifluoromethylnaphthalene-12-yl group, 7-trifluoromethylnaphthalene-12-yl group and the like.
- condensed heteroaryl group means a benzene ring or a pyridine ring, a 5- to 7-membered ring having 1 to 3 hetero atoms in the ring selected from the group consisting of oxygen, sulfur and nitrogen. It means a bicyclic group fused to a monocyclic ring, or a tricyclic group in which the bicyclic group is further bonded to a benzene ring or a pyridine ring.
- Examples of the "fused heteroaryl group" represented by Q 1 include a benzfuranyl group, an indolyl group, a quinolinyl group, an isoquinolinyl group, a benzoxazolyl group, a benzimidazolyl group, a phthalazinyl group, a naphthyridinyl group, and a quinoxalinyl group Quinazolinyl group, cinnolinyl group, imidazopyridinyl group, triazolopyridine group and the like.
- benzfurael group, indolyl group, quinolinyl group, isoquinolinyl group, benzoxazolyl group, benzimidazolyl group, Phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, imidazopyridinyl group and triazolopyridine group are preferred, and quinolinyl group, isoquinolinyl group, benzoxazolyl group, benzimidazolyl group, and phthalazinyl Group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, imidazopyridinyl group and triazolopyridine group are more preferred.
- the fused heteroaryl group is examples of the substituent that may be present include, among the above substituents, a cyano group, a hydroxy group, and a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom, or an amino group); A lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a halogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkylcarbamoyl group, a di-lower group Alkyl rubamoyl groups, alkamoyl groups, lactam rings, trifluoromethyl groups, mono-lower alkylamino groups, di-lower alkylamino groups and alkynyl groups are preferred, and hydroxy groups, lower alkyl
- Q 1 is a “naphthyl group” which may be substituted by these substituents, more specifically, as Y represented by the formula (IV), for example, quinoline-3-y Group, quinoline_2-yl group, 1H-indole-6-yl group, 1H-indole-17-yl group, indoline-2-one-1-yl group, indoline-12-one 1-7-yl group, 1-methylindoline 1-2-one-6-yl group, 1-methylindoline_2-one-7-yl group, 1-ethylindoline-21-one-6-yl group , 1-Ethylindoline-2-one-1-7-yl group, 1- (difluoromethyl) indoline1-2-one-6-yl group, 1- (difluoromethyl) indoline1-2-one-1-7-yl group , Quinoline-8-yl group, quinoline-1 7-yl group, dibenzofuran-13-yl group, di
- Q 1 represents a linear or branched lower alkyl group, a phenyl group, a 5- or 6-membered heteroaryl group, or a heterocyclic group having 3 to 8 carbon atoms (a nitrogen atom or an oxygen atom 1 or 2), a naphthyl group or a fused heteroaryl group
- the lactam ring when the substituent is a “lactam ring” is represented by —N (R 3) —C ( ⁇ ) — in the ring.
- R 3 represents a hydrogen atom or a lower alkyl group.
- the lactam ring may have one or two oxygen atoms or nitrogen atoms in the ring in addition to the nitrogen atom constituting —N—C (O) 1.
- the bonding position of the lactam ring bonded to is not particularly limited as long as it is a bondable position.
- T Qi which is a group represented by the formula (V-1), is a group represented by the formula (V-10) 8
- Q! Is an alkyl group having 1 to 6 carbon atoms represented by R 1 and R 2 when is a group represented by the formula (V 1), and the same linear or branched lower alkyl group as defined above.
- the lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, and hexyl.
- isohexyl groups are preferred, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isoamyl, neopentyl and hexyl are more preferred.
- -Y represented by, for example, an N, N-getylamino group, an N, N-dipropylamino group, an N, N-diisopropylamino group, an N, N-dibutylamino Group, N, N-dipentylamino group, N, N-dihexylamino group, N, N-diheptylamino group, N-methyl-N-ethylamino group, N-methyl-N-propylamino group, N-methyl-N- ⁇ propylamino group, N-methyl-N-butylamino group, N-methyl-N-pentylamino group, N-methyl-N-hexylamino group, N-methyl-N-heptylamino group, N -Ethy
- the “mono-lower alkyl group” represented by R 1 and R 2 is the “mono-lower alkyl group” defined above. It has the same meaning, and among these, methylcarbamoyl group, ethylcarbamo Butyl, propyl carbamoyl, isopropyl carbamoyl, butyl carbamoyl, sec-butyl carbamoyl, tert-butyl carbamoyl, methyl carbamoyl, ethyl carbamoyl, propyl carbamoyl, isopropyl rubamoyl, isopropyl rubamoyl
- the group tert-butylcarbamoyl is more preferred.
- the ⁇ di-lower alkyl group rubamoyl group '' represented by R 1 and R 2 is di-substituted by the same or different lower alkyl groups.
- di-lower alkyl group refers to, for example, a dimethylcarbamoyl group, a acetylcarbamoyl group, an ethylmethylcarbamoyl group, a dipropyl group, a methylpropyl group, a methylpropyl group, a dipropyl group. And the like.
- di-lower alkyl group includes a nitrogen atom constituting the group and an identical or different lower alkyl group bonded to the nitrogen atom.
- the “lower alkyl group or mono- or di-lower alkyl group rubamoyl group” represented by R 1 and R 2 may be the same or different.
- a lower alkyl group or a mono- or di-lower alkylcarbamoyl group More specifically, as one Y in the formula (IV), for example, an N-methyl-N- (dimethylcarbamoylmethyl) amino group, an N-methyl-N- (dimethylcarbamoylethyl) amino group, —Methyl-N— (Getyl carbamoylmethyl) amino group, N-methyl-N— (Getylcarbamoylethyl) amino group, N-methyl-1-N— (dimethylcarbamoylmethyl) aminomethyl group, N-methyl—N— ( Dimethylcarbam
- Q 1 is a group represented by the above formula (V-1), and R i and R 2 together with an adjacent nitrogen atom form a 3- to 9-membered lactam ring
- the “3- to 9-membered lactam ring” refers to a 3- to 9-membered group containing a group represented by —N—C (0) — in the ring, and One N—C ( ⁇ )
- the nitrogen atom that constitutes one one or two oxygen atoms or nitrogen atoms may be present in the ring.
- the lactam ring for example, the following formula (Q i-2) And a group represented by the following formula (Q i — 20) The group represented by is preferred.
- Y is, for example, a 1H-pyridin-2-one-1-yl group, a pyrrolidine-12-one-1-yl group, a pyridin-12-one-1-yl group, a homopyridinyl group.
- Q 1 is a group represented by the above formula (V-1), and R 1 and R 2 together with a nitrogen atom adjacent to each other form a heterocyclic ring having 3 to 8 carbon atoms
- heterocycle having 3 to 8 carbon atoms in the case of forming a heterocyclic ring means a 3- to 8-membered heterocycle having 1 or 2 nitrogen atoms or oxygen atoms as constituent atoms of the heterocycle.
- —Y in the above formula (IV) is more specifically, for example, morpholine-1-y Group, homomorpholine-1-yl group, morpholine-1-ylmethyl group, homomorpholine-1-ylmethyl group, 2- (morpholine-11-yl) ethyl group, 2- (homomorpholine-11-yl) ethyl group, 3- And a 3- (homomorpholine-11-yl) propyl group.
- L is a group represented by the above formula (V-1), and; and i together with nitrogen atoms adjacent to each other form a 5-membered heteroaryl group
- the “5-membered heteroaryl group” is a group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
- a 5-membered monocyclic ring having 1 to 4 hetero atoms in the ring which are the same or different and selected from the group consisting of, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl And pyrazole, triazole, tetrazole, oxazole, thiazol, and thiadiazole.
- pyrazole, triazole, oxazole, thiazole, and thiadiazole are more preferable.
- one Y in the above formula (IV) is more specifically, for example, a pyrazole-1-yl group, a 3-phenylpyrazole-1-yl group, or a 4-phenylpyrazol-1-yl group , 5-phenylvirazole-1-yl group, triazole-1-yl group, tetrazole-1-yl group, pyrazole-1-ylmethyl group, triazole-1-ylmethyl group, tetrazole-1-ylmethyl group, 21- (birazol-1-ylmethyl group) An ethyl group, a 2- (triazole-11-yl) ethyl group, and a 2- (tedrazol-11-yl) ethyl group.
- Q 1 is represented by the above formula (V-1), and R 1 and R 2 are a condensed heteroaryl group together with a nitrogen atom adjacent to each other; More specifically, as one Y in the above formula (IV), for example, benzimidazo
- 2-ylmethyl group imidazo [1,2, a] pyridine-6-ylmethyl group, 2- (benzimidazole-11-yl) ethyl group, 2- (benzotriazole-11-yl) ethyl group, 2- (benzotriazole-2-yl) ethyl group; and 2- (imidazo [1,2, a] pyridine-16-yl) ethyl group.
- the compound (I) according to the present invention for example, 2- (1-cyclopentylpiperidine-4-1yloxy) -5- (4-cyanophenyl) pyrimidine, 21- (1-isopropyl) Pyridine-1 4 1 ⁇ -peroxy) -5- (4-Cyanophenyl) pyrimidine, 2- (1-cyclopentylpyrrolidine-3-yloxy) 1 5- (4-Lubamoylphenyl) pyrimidine, 2- (1-cyclopentylpyrrolidine—3-yloxy) -5- (4-cyanophenyl) pyrimidine, 2- (1-cyclopentylpiperidine—4-yloxy) 1 5— ⁇ (3-methyl-1,1,2,4-oxaziazio) 5- (yl) phenyl ⁇ pyrimidine, 2- (1-cyclopentylbiperidine-1-41 ⁇ f-roxy) -5- (4-cyanophenyl) pyridine,
- the compound (I) according to the present invention is a histamine H 3 receptor antagonist or an insulin gonist. It acts as a bar sagonist.
- histamine receptor H3 inverse agonist is a receptor-binding substrate having a completely or partially opposite action to histamine receptor H3 agonist. It means a ligand that suppresses constitutive activity.
- the compound (I) according to the present invention can be easily produced using a known reaction means or according to a method known per se.
- the compound (I) according to the present invention can be produced not only by a general synthesis method in a liquid phase but also by a method using a solid phase such as a combinatorial synthesis method or a parallel synthesis method which has been remarkably developed in recent years. Can be.
- the compound according to the present invention can be produced, for example, by the following method.
- m represents an integer of 0 to 3, 1 is a cyano group, a hydroxy group, a lower alkyl group (the lower alkyl group may be substituted with a hydroxy group, a halogen atom or an amino group)),
- a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a halogen atom, a mono-lower alkylaminocarbonyloxy group, a di-lower alkylaminocarbonyloxy group, a mono-lower alkylcarbamoyl group, a di-lower group Selected from the group consisting of alkyl rubamoyl, carbamoyl, cycloalkylimino propylonyl, and trifluoromethyl
- a linear or branched lower alkyl group (excluding a methyl group), a cycloalkyl group having 3 to 9 carbon atoms, an aralkyl group, or a heterocyclic group having
- L i represents a lower alkylene group having 1 to 4 carbon atoms or a single bond
- M represents an oxygen atom or a formula (V)
- RQ represents a lower alkyl group having 1 to 4 carbon atoms
- Q i represents a cyano group, a hydroxy group, or a lower alkyl group
- the lower alkyl group is a hydroxy group
- a lower alkoxy group (which may be substituted with a halogen atom), a lower alkylsulfonyl group, a cyclo-lower alkylsulfonyl group, a halogen atom, , Mono-lower alkylaminocarbonyloxy group, di-lower alkylaminocarbonyloxy group, mono-lower alkyl force rubamoyl group, di-lower alkyl force rubamoyl group, force rubamoyl group, cycloalkyliminocarbamoyl group, lactam ring, tri A linear or branched lower alkyl group which may be substituted with a group selected from the group consisting of a fluoromethyl group, a mono-
- R i and R 2 are the same or different and each represents a lower alkyl group or a mono- or di-lower alkyl group rubamoyl group, or R 1 and R 2 are taken together with an adjacent nitrogen atom.
- the general organometallic atom of Met means an organometallic atom generally used in a cross-coupling reaction, for example, lithium, boron, silicon, magnesium, aluminum, zinc, tin, etc., more preferably boron, Specific examples of usage include boron as boric acid or borate ester, zinc as zinc chloride, zinc bromide or zinc iodide, and tin as tri-lower alkyltin. Are mentioned.
- any leaving group may be used as long as it has a function of leaving in the reaction between the above formulas (VI) and (VI I).
- any leaving group may be used as long as it has a function of leaving in the reaction between the above formulas (VI) and (VI I).
- chlorine atom, bromine atom or iodine atom, etc. octalogen atom, methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, etc.
- examples thereof include organic sulfonyl groups, organic sulfonyloxy groups, trifluoromethanesulfonyloxy groups, and organic sulfonyloxy groups such as P-toluenesulfonyloxy group.
- the compound (VII) is usually used in an amount of 0.5 mol to 5 mol per 1 mol of the compound (X). And preferably from 0.7 mol to 3 mol.
- the catalyst used in the reaction examples include transition metals generally used in a cross-coupling reaction such as copper, nickel, and palladium, and more specifically, tetrakis (triphenylphosphine) palladium (0), palladium ( II) Acetate, bis (triphenylphosphine) palladium (II) chloride, [1,1,1-bis (diphenylphosphino) phenyl] palladium (II) dichloride and the like are preferable.
- transition metals generally used in a cross-coupling reaction such as copper, nickel, and palladium
- tetrakis (triphenylphosphine) palladium (0), palladium ( II) Acetate, bis (triphenylphosphine) palladium (II) chloride, [1,1,1-bis (diphenylphosphino) phenyl] palladium (II) dichloride and the like are preferable.
- the reaction is usually performed in an inert solvent.
- inert solvent examples include water, benzene, toluene, xylene, methylene chloride, chloroform, dimethoxyethane, tetrahydrofuran, dioxane, dimethylformamide and the like or a mixture thereof. Solvents and the like are preferred.
- the reaction temperature is usually from room temperature to the boiling point of the solvent used in the reaction, preferably from 20 ° C to 200 ° C.
- the reaction time is generally 30 minutes to 7 days, preferably 3 hours to 2 days.
- the above reaction is preferably carried out in the presence of a base.
- the base include inorganic bases such as sodium hydroxide, ⁇ potassium oxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like, triethylamine, diisopropylamine And the like.
- the amount of the base to be used is generally 0.5 to 5 mol, preferably 0.7 to 3 mol, per 1 mol of the compound represented by the general formula (VI). .
- the compound of the present invention (1- 2) or the compound of (1-3) can be produced.
- the compound (1-2) or (I-13) according to the present invention thus obtained can be obtained by a known separation and purification means, for example, concentration, concentration under reduced pressure, recrystallization, reprecipitation, solvent extraction, and chromatography. Can be isolated and purified.
- the compound represented by the formula (VI), (VII), (IX) 'or (X) may be, for example, a commercially available product, a known method or a method analogous thereto, or described in Examples and Reference Examples. It can be manufactured by appropriately combining the methods described above as needed.
- the “protecting group for an amino or imino group” is not particularly limited as long as it has the function thereof. Examples thereof include a benzyl group, a P-methoxybenzyl group, a 3,4-dimethoxybenzyl group, and an o-nitrobenzyl group.
- Aralkyl groups such as p-nitrobenzene group, benzylhydryl group, and trityl group; lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group and piperoyl group; benzoyl group; Arylalkanol groups such as enoxyacetyl group; lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, tert-butoxycarbonyl group; and benzyloxycarbonyl group; Nitrobenziloxy carbonyl group, phenene Aralkyloxypropyl groups such as a tyloxypropyl group; lower alkylsilyl groups such as a trimethylsilyl group and tert-butyldimethylsilyl group; a tetrahydroviranyl group; a trimethylsilylethoxymethyl group; a methylsulf
- the “protecting group for the hydroxy group” is not particularly limited as long as it has the function thereof.
- a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group; a trimethylsilyl group; a lower alkylsilyl group such as a tert-butyldimethylsilyl group; a lower alkoxymethyl group such as a methoxymethyl group or a 21-methoxyethoxymethyl group; a tetrahydropyrael group; such as a trimethylsilylethoxymethyl group;
- Aralkyl groups such as P-methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, and trityl group; for example, acyl groups such as formyl group and acetyl group In particular, methyl
- the “protecting group for the carboxyl group” is not particularly limited as long as it has the function.
- a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a tert-butyl group; Halo-lower alkyl groups such as 2,2-trichloromethyl group; lower alkenyl groups such as 2-propenyl group; benzyl group, p -methoxybenzyl group, p -nitrobenzyl group, benzhydryl group, trityl group And the like, and particularly preferred are a methyl group, an ethyl group, a tert-butyl group, a 2-propenyl group, a benzyl group, a p-methoxybenzyl group, a benzylhydryl group and the like.
- the “protecting group for an oxo group or a carbonyl group” is not particularly limited as long as it has the function, and examples thereof include acetal such as ethylene ketal, trimethylene ketal, and dimethyl ketal, and ketal.
- the compound according to the present invention can also be produced, for example, by the following method. Manufacturing method 2
- Xi, ⁇ 2, X 3, ml, ⁇ and ⁇ are as defined above] can be produced represented by reduction compounds with.
- the compound (X) is usually used in an amount of 0.5 mol to 5 mol based on 1 mol of the compound (IX). It is preferably carried out using 0.7 mol to 3 mol.
- Examples of the catalyst used in the reaction include transition metals generally used in cross-coupling reactions such as copper, nickel, and palladium. More specifically, tetrakis (triphenylphosphine) palladium (0), palladium ( II) Acetate, bis (triphenylphosphine) palladium (II) chloride, [1,1, —bis (diphenylphosphino) phenacene] palladium (II) dichloride and the like are preferable.
- transition metals generally used in cross-coupling reactions such as copper, nickel, and palladium. More specifically, tetrakis (triphenylphosphine) palladium (0), palladium ( II) Acetate, bis (triphenylphosphine) palladium (II) chloride, [1,1, —bis (diphenylphosphino) phenacene] palladium (II) dichloride and the like are preferable.
- the reaction is usually carried out in an inert solvent.
- the inert solvent include water, benzene, toluene, xylene, methylene chloride, chloroform, dimethoxyethane, tetrahydrofuran, dioxane, dimethylformamide and the like.
- the mixed solvent is suitable.
- the reaction temperature is usually from room temperature to the boiling point of the solvent used in the reaction, preferably from 20 ° C to 200 ° C.
- the reaction time is generally 30 minutes to 7 days, preferably 3 hours to 2 days.
- the above reaction is preferably performed in the presence of a base.
- the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; triethylamine; diisopropylethylamine. And the like.
- the amount of the base to be used is generally 0.5 to 5 mol, preferably 0.7 to 3 mol, per 1 mol of the compound represented by the general formula (IX). .
- the compound is subjected to a usual treatment to produce the compound of the present invention.
- Removal of the protecting group, post-treatment, and the like can be performed according to the method described in the above-mentioned Production Method 1.
- the compound represented by formula (X) can be produced by a known method or a method analogous thereto, or by appropriately combining the methods described in Examples and Reference Examples as needed.
- the compound according to the present invention can also be produced by the following method. Manufacturing method 3
- R ii represents R i or an amino-protecting group, and other symbols have the same meanings as described above), or a group represented by the formula (III)
- the compound of the general formula (I), (I-12) or (I_3), which is a compound according to the present invention, can be easily isolated and purified by ordinary separation means.
- Such means include, for example, solvent extraction, recrystallization, reprecipitation, column chromatography, preparative thin layers: One example can be exemplified.
- the heteroaryloxy nitrogen-containing saturated heterocyclic derivative according to the present invention can exist as a pharmaceutically acceptable salt, and the compound represented by the formula (I) can be produced by a conventional method. can do.
- the acid addition salt include hydrooctylates such as hydrochloride, hydrofluoride, hydrobromide, and hydroiodide; nitrates, perchlorates, sulfates, phosphates, and the like.
- Inorganic acid salts such as carbonate; lower alkylsulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt and ethanesulfonic acid salt; arylsulfonic acids such as benzenesulfonic acid salt and p-toluenesulfonic acid salt Salts; organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate and maleate; and acid addition salts such as amino acids such as glutamate and aspartate. Can be mentioned.
- the base addition salt examples include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, salts with organic bases such as guanidine, triethylamine, and dicyclohexylamine.
- the compounds of the present invention may exist as any hydrates or solvates of the free compounds or salts thereof.
- the cDNA sequence encoding the human histamine 3 receptor [see International Patent Application WO00 / 39164] was added to the expression vectors PCR2.1, EF1x (manufactured by Invitrogen) and (31_1160 (manufactured by Promega)).
- the resulting expression vector was cloned into a cationic lipid method [Proceeding of the National Academy of Sciences, Ob, The United, Steadov, USA] (Proceeding soft he nati on alac ad e my ofscie nc esoft he un itedsta tesof America), Vol. 84, p. 7413 (1987)], and transfected into host cells, HEK293 and CHO-K1 (American 'type' culture 'collection), and cells expressing histamine 3 receptor were transfected. Obtained.
- a membrane sample prepared from cells expressing the histamine 3 receptor was combined with a test compound and 20,000 cpm of H] N-a-methhylhistamine (NEN) together with an Atssey buffer ( After incubation in 5 OmM Tris buffer, pH 7.4) at 25 ° C for 2 hours, the mixture was filtered through a glass filter GFZC. After washing with 5 OmM Tris buffer and H7.4, the radioactivity on the glass filter was determined. Non-specific binding was measured in the presence of 10 / M thioperamide (manufactured by SI GAM), and the 50% inhibitory concentration (IC 50 value) of the test compound against specific N- ⁇ -methyhistamine binding was determined. (See Molecular Pharmacology, 55, 1101 (1999)). As a result, the IC so value of the compound of Example 1 was 15 nM.
- a membrane preparation prepared from cells expressing the histamine 3 receptor was treated with a test compound, 20 nM R-methy 1 histamine (histamine analog, manufactured by Sigma), 10 M GDP (guanine nucleotide diphosphate, Sigma), 200 pM
- [5S] GTPr S (guanine nucleotide triphosphate analog, manufactured by Amersham), S PA resin (W heatge rm agg lutinin SPA beads, manufactured by Amersham), and Atzey buffer (5 OmM Tris buffer, 100m) M NaCl, 5 mM MgCl 2 , pH 7.4 25) at 96 ⁇ Eroptiplate (Packard). C, incubated for 3 hours, centrifuged at 300 rpm, and the activity was determined by TopCount (Packard).
- the compounds of the present invention potently inhibited the binding of N-methyhistamine (histamine analog) to the hisminamine 3 receptor.
- Pharmacological Test Example 3 Antagonism test on drinking behavior induced by R- ⁇ -methhy 1 histamine, a histamine 3 receptor selective agonist
- Under ketamine / xylazine anesthesia (74 and 1 lmgZkg single intraperitoneal injection)
- a male SD rat (7-10 weeks old, 200-300 g) was inserted into the third ventricle using a stereotaxic device to insert a chronic guide force neura (26 gauge, 11 mm long). And fixed with resin.
- the position of the tip of the guide cannula was 2.2 mm behind the bregma, on the midline, and 8 mm deep from the skull surface.
- R-a-methylhistamine 0.3 g / 1 L / head, 30% propyleneglycol solution
- the test compound suspended in 0.5% methylcellulose aqueous solution was orally administered 2 hours before the administration of R—Q! —Methhy 1 histamine, and the R— ⁇ —methy 1 histamine was administered. One hour later, the amount of drinking water was measured.
- the compound of the present invention significantly suppressed the increase in water consumption due to R-1 methy1 istamine administered into the third ventricle at 1 OmgZkg.
- Pharmacological test example 4 (Pharmacokinetic test) ⁇ ⁇ The test compound is orally or intravenously administered to fasted male SD rats (7 to 10 weeks old, 200 to 400 g), and at predetermined time, using tailored caviali via the tail vein. About 100 L of blood was collected. Blood was centrifuged (4 ° C, 6000 rpm, 10 minutes) to obtain plasma. Three times the amount of ethanol (including the internal standard substance) was added to the plasma, stirred, left at 20 ° C for 20 minutes, and centrifuged (4C, 10,000 rotations, 10 minutes). The supernatant was analyzed by LC / MS / MS, and the plasma concentration was quantified by the relative calibration curve method.
- Example 1 had a bioavailability of 53% and a half-life in blood of 5.3 hours.
- Pharmacological test example 5 (brain / cerebrospinal fluid migration test)
- test compound was orally or intravenously administered to male SD rats (7-10 weeks old, 200-400 g), and whole blood was collected from the abdominal aorta using a heparin-treated syringe under ether anesthesia at a predetermined time. did. After that, the skin of the head was incised, 30 G ⁇ for dental use was inserted into the cervical vertebra, and further inserted into the subarachnoid space. The cerebrospinal fluid of 50-10 O L was collected through a tube connected to a dental 30G needle into an lmL syringe, and the brain was removed.
- the blood sample was centrifuged (4 ° C, 6000 rpm, 10 minutes), and three times the amount of ethanol (including the internal standard) was added to the plasma and stirred.
- the brain sample was homogenized by adding 2 mL of water, a portion was taken, and three times the amount of ethanol (including the internal standard) was added and stirred.
- the cerebrospinal fluid was mixed with 3 volumes of ethanol (including the internal standard) and stirred.
- the above sample was left at -20 ° C for 20 minutes, centrifuged (4 ° C, 12,000 g, 10 minutes), and the supernatant was analyzed by LCZMSZMS. The concentrations in the brain and cerebrospinal fluid were quantified.
- the compound of Example 1 showed a brain concentration of 6.18 nmolZg, a cerebrospinal fluid concentration of 0.128 ⁇ M, and a plasma concentration of 0.54 two hours after oral administration (10 mg / kg). .
- the compound represented by the general formula (I) can be administered orally or parenterally, and when formulated into a form suitable for such administration, it can be used for obesity, diabetes, and hormone secretion. Abnormalities, hyperlipidemia, gout, metabolic diseases such as fatty liver, etc.
- Angina pectoris acute and depressive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease, various disorders with sleep disorders and sleep disorders, such as idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia Syndrome, narcolepsy, periodic limb movement disorder during sleep, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, elderly insomnia, night shift sleep insanity, idiopathic insomnia, repetitive Cardiovascular diseases such as insomnia, intrinsic insomnia, and electrolyte abnormalities, such as bulimia, affective disorder, depression, anxiety, epilepsy, delirium, dementia, schizophrenia, attention deficit * hyperactivity disorder, memory disorder, and Alzheimer's Preventive or therapeutic agent for central and peripheral nervous system diseases such as Parkinson's disease, Parkinson's disease, sleep disorder, cognitive disorder, movement disorder, paresthesia, olfactory disorder, epilepsy, morphine resistance, drug dependence, and alcohol dependence For the purpose that you provide.
- the compound of the present invention When used clinically, it can be administered after formulating various preparations by adding pharmaceutically acceptable additives according to the dosage form.
- Various additives usually used in the field of pharmaceutical preparations can be used in this case, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, propyloxymethylcellulose, and corn starch.
- Microcrystalline wax white petrolatum, magnesium metasilicate aluminate, calcium phosphate anhydrous, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitan], sorbitan fatty acid ester, polysorbate, sucrose Fatty acid esters, polyoxyethylene, hydrogenated castor oil, polipinylpyrrolidone, magnesium stearate, light caffeic anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol , It includes the polyalkyl down, and the like.
- Dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders and suppositories; or liquids such as syrups, elixirs and injections Preparations and the like can be mentioned, and these can be prepared according to a usual method in the field of preparations.
- a liquid preparation it may be in the form of being dissolved or suspended in water or another appropriate medium before use.
- injections they can be dissolved or suspended in physiological saline or dextrose as necessary.
- a buffer and a preservative may be added.
- formulations may contain the compounds of the present invention in a proportion of from 1.0 to 100% by weight, preferably from 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.
- the compounds of the present invention can be used in combination with other agents useful for treating metabolic disorders and Z or eating disorders.
- the individual components of such combinations can be administered in divided or single dosage forms during the treatment, at different times or simultaneously.
- the present invention should be construed to include all administrations, either simultaneously or at different times, and administrations in the present invention should be construed accordingly.
- the range of the combination of the compound of the present invention and another drug useful for treating a metabolic disorder and / or an eating disorder is, in principle, a combination with a metabolic disorder and Z or any pharmaceutical preparation useful for treating an eating disorder. Are also included.
- the compound of the present invention is a drug effective for hypertension, hypertension related to obesity, hypertension-related disease, cardiac hypertrophy, left ventricular hypertrophy, metabolic disease, obesity, obesity-related disease and the like (hereinafter referred to as “combination drug”). ) Can be used in combination. Such drugs can be administered simultaneously, separately or sequentially in the prevention or treatment of the aforementioned diseases. When the compound of the present invention is used contemporaneously with one or more concomitant drugs, it can be made into a pharmaceutical composition as a single dosage form. However, in combination therapy, the composition containing the compound of the present invention and the concomitant drug may be administered to the subject in different packages, simultaneously, separately or sequentially. They may be administered at staggered times.
- the dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration target, administration route, disease, combination and the like.
- the administration form of the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
- Such administration forms include, for example, 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) separate administration of the compound of the present invention and the concomitant drug.
- concomitant drug used in the present invention examples include a "diabetic drug”, a “hyperlipidemic drug”, a “hypertensive drug”, an “antiobesity drug” and the like. Two or more of these concomitant drugs may be used in combination at an appropriate ratio.
- anti-diabetic agent examples include: 1) glidazones (g 1 it az on es) [for example, cigli dazone (cig 1 itazone), dalgli dazone (darg 1 itaz on e), enclitazone, eng lit az one), isa Daridazon (is ag litaz one) (MC C-555) etc.), piodari evening (piog 1 itaz one), mouth siglidazone (rosig 1 itazone), troglitazone (tro 1 itaz one), BRL 49653, C LX-0921, 5—P PAR agonists such as BTZD, GW-0207, LG-100641, LY—300512; 2) Biguanides such as metformin (metformin), buformin, phenformin; 3) Protein tyrosine phosphatase -1B inhibitor; 4) acetohexamide,
- repaglinide rep ag lini de
- meglitinides such as nateglinide (nateg 1 inide); 6) acarbose, adiposin (ad iposi ne), force miglipose (cami 1 ibose), emiglitate (em ig 1 itate), Miglito (Mig 1 ito 1), poglipois (vog 1 ib), pradimicin-Q (pradimicin-Q), sarpostatin (sa 1 ostatin), CKD-711, MDL- 25, 673, MDL-73, 945, M ⁇ R 14 etc.
- Linodalide 1 inog 1 iride
- an insulin secretagogue such as A-4166
- chromoxyl c 1 omo Xir
- etomoxil et omox ir
- other fatty acid oxidation inhibitors 10) midaglizole (midag 1 izo 1) e), A2 angst gonists such as isagridol (isag 1 ido 1 e), deliglidol (de rigli do le), idazoxan, idolaxan, earoxan, flupar ox an; 1 1) Biota, LP-100, Novalapid, insulindet emir, insulin 1 ispr o> insu 1 ingl argine, insulin zinc, Lys_Pro—insulin
- hypolipidemic agent examples include: 1) cholesterylamine, colesevelem, colestipol, colestipol, dialkylaminoalkyl derivatives of cross-dextran, Co 1 estid registered trademark, L o C Bile acid absorption enhancers such as ho 1 est registered trademark and Questran registered trademark; 2) atorvastatin (itavastatin), fluvastatin (fl uv astatin), lovastatin (l) ov astatin), pravastatin, rivastatin, rosuvastatin, simvastatin, ZD-4522, etc.
- MG—Co A reductase inhibitor 3) HMG—CoA synthesis inhibitor; 4) Sunitol ester, cholesterol absorption inhibitor such as) 3-sitosterol, sterol darcoside, ezetimibe; 5) Avasimibe (Av as imi be), eflucimibe, KY-505, SMP-709, etc., and isolcoenzyme A cholesterol-acyltransferase inhibitors; 6) JTT 705, torcetrapib, CP .532632, BAY-63-2149, SC-591, SC-795, etc .; CETP inhibitors; 7) Squalene synthesis inhibitors, 8) Antioxidants, such as propol, 9) Beclofibrate, Benzafibrate, Ciprofibrate, Clofibrate, Etofibrate, Fuenofibrate, Gen emb abene, Genfib brozil (Gemf ibrozi 1), GW-7647, BM-170744
- hypotensive agent examples include: 1) thiazides such as clothiariadone, chlorothiazide, dichlorophenamide, hydrofluorothiazide, indapamide (indapamide), hydroclochia thiazide; bumetanide (b time tanide), ethacrynic acid ⁇ loop system such as furosemid, torsemide, etc., sodium system such as amicolide, triamterene, etc., diuresis such as spironolactone, eposterone, etc. aldosterone angiogonist system.
- thiazides such as clothiariadone, chlorothiazide, dichlorophenamide, hydrofluorothiazide, indapamide (indapamide), hydroclochia thiazide
- bumetanide b time tanide
- ethacrynic acid ⁇ loop system such as furosemid, torsemide, etc.
- Indropri Ripanipril (quanipri 1), Subirapril (spirapri 1), Tenocaprinole (tenocapril), Trandolapril (tr ando lapri 1), Zofenopril (zof enop ri) 1) angiotensin converting enzyme inhibitors such as 5) omapatrilat (oma patri 1 at), dexoxatril (cadoxatri 1), ecadotril, fosidotril (fosi do tril), sampatrilat (samp atri 1 at), AVE 7688 ER4030, neutral endopeptidase inhibitors; 6) tezosentan, A308165, YM62899, etc.
- endothelin antagonist 7) hydralazine, clonidine, minoxidil, nicochel alcohol, etc.
- Vasodilators candesartan, eprosartan, irbesartan, oral sultan, pratosartan, tasosartan, telmisartan (e1) misart an), palsartan, EXP-3137, angiotensin II antagonists such as FI 6828 RNH6270; 9) ⁇ / 3 adrenaline blockers such as nipradilol, arotinolol, and amoslarol; 10) terazosin, ⁇ rapidil (urapidi 1), brazosin ⁇ 1 blockers such as bunazosin, trimazosin, doxazosin, naftopidil, indolamine, WHI P164, XEN010;
- ⁇ 2agonist such as oral fexidine (lofexidine), thiamenidine (tiaminedine), moxonidine (moxonidine), hydrogen chloride (ri1menidine), guanoben (guanobenz);
- antiobesity drug examples include 1) paroxetine (par ox etine;), fluoxetine (fl uoxe tine), fenfluramine en f 1 ur ami ne, flupoxamine (fl uvoxami ne), sertraline (sertra 1) ine), 5HT (serotonin) transporter inhibitor such as imipramine; 2) norepinephrine transporter inhibitor such as GW320659, desibramine, evening spram, nomifensin; 3) rimonabant ( S ano ii Syn t he l abo), SR-147778 (S ano fi Syn tel abo), BAY— 65-2520 (Bayer), S LV-319 (Solvey), other USP 5,532,237, USP 4,973,587, USP 5,0 13,837, USP 5,081,122, US P 5,1 12, 820, USP 5, 292, 736, USP
- CB-1 cannabinide 1 receptor 1
- Dareline antagonists such as compounds disclosed in WO 01/87355, WO 02/08250, etc .
- NPY 5 antagonists such as the compounds disclosed in (2000); 10) Human recombinant leptin (PEG-OB, Hoffman La Roche), recombinant methionyl leptin ( 11) USP 5,552, 524, USP 5, 552, 523, USP 5, 552, 522, USP 5, 521, 283, WO 96/23513, WO 96/2 3514, WO 96/23515, WO 96/23516, WO 96/2351 7, WO 96/23518, WO 96/23519 and WO 96/23520, lebutin derivatives such as the compounds disclosed therein; 12) nalmefene (Re vex®), 3-methoxynaltrexone, naloxone, naltrexone, opioid antagonists such as the compounds disclosed in WO00 / 21509; 13) SB_334867A, others WO 01/96302, WO 01
- Serotonin receptor 2 C agonist such as compounds disclosed in WO 02/44152, WO 02/5 1844, WOO 2/40456 and WO 02/40457; 20) Melanocortin 3 receptor Agonist; 21) CH IR 86036 (Chiron), ME-10142, ME-10145 (Me1acure), other W ⁇ 99 / 64002, WO00 / 74679, WO01 / 991752, WOO1 / 74844, WOO 1/7
- valine pyrrolidide such as the compounds disclosed in 003/000181; 39) Tetrahydroributin (registered trademark of orlistat / Xenical), Triton WR 1339, HC 80267, Libstatin, teas aponin ), Detyl hyn umbe l 1 ife ry l pho
- the combination drug can be obtained by using one or more of the compound of the present invention and the combination drug in combination.
- the combination drug is useful for preventing or treating a metabolic disease by combining it with one or more drugs selected from the group consisting of a drug for treating diabetes and a drug for treating hyperlipidemia.
- a combination containing a therapeutic agent for hypertension and an antiobesity agent is useful for the prevention or treatment of metabolic diseases with a synergistic effect by adding a therapeutic agent for diabetes and a therapeutic agent for Z or hyperlipidemia.
- the dosage and frequency of administration vary depending on the patient's sex, age, body weight, degree of symptoms, and the type and range of the intended treatment effect.
- a routine physician, veterinarian, or clinician may be able to stop, inhibit, or arrest the progress of the condition.
- the required effective drug amount can be easily determined and processed.
- the thin-layer chromatograph of the example used Si1cage160F245 (Merck) as a plate and a UV detector as a detection method.
- Wakogel C-300 (Wako Pure Chemical Industries) is used as the silica gel for the column, and LC-SORB S PB-ODS (Chemco) or YMC—GEL ODS-AQ 120 -S 50 ( Yamamura Chemical Laboratory) was used.
- the mass vector is Quat tro ll (Micromass).
- n-Pr n-propyl group
- the title compound was obtained by performing the same reaction as in Example 11-1) using 2-chloro-5-bromopyrimidine and 4-hydroxy-1-cyclopentyl piperidine.
- the title compound was obtained in the same manner as in Example 1 except for using 5-indolylporonic acid instead of 4-cyanophenylporonic acid.
- the title compound was obtained in the same manner as in Example 17 by using 2- (1-cyclopentylbiperidine-14-yloxy) -15-bromopyrimidine and piperidin-2-one.
- the title compound was obtained in the same manner as in Example 1, except that 4- (trifluoromethyl) phenylporonic acid was used in place of 4-cyanophenylporic acid.
- the title compound was obtained in the same manner as in Example 1 except for using 4-methoxyphenylporonic acid instead of 4-cyanophenylporonic acid.
- the title compound was obtained in the same manner as in Example 1 except for using 4- (methylsulfonyl) phenylporonic acid instead of 4-cyanophenylporonic acid.
- the title compound was obtained in the same manner as in Example 1 except for using 4-acetylphenylporonic acid instead of 4-cyanophenylporonic acid.
- Example 62-1 The synthetic intermediate obtained in Example 62-1) and 3-chloro-5-odo-1-methyl
- the title compound was obtained in the same manner as in Examples 48-2) and 3) using 1-1H-pyridin-2-one.
- the heteroaryloxy-nitrogen-containing saturated heterocyclic derivative or a pharmaceutically acceptable salt thereof according to the present invention represented by the above formula (I) has a strong histamine receptor H3 agonist or inverse agonist activity.
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CA002529790A CA2529790A1 (en) | 2003-06-27 | 2004-06-24 | Heteroaryloxy nitrogenous saturated heterocyclic derivative |
JP2005511807A JP4735261B2 (ja) | 2003-06-27 | 2004-06-24 | ヘテロアリールオキシ含窒素飽和ヘテロ環誘導体 |
EP04746741A EP1642898B1 (en) | 2003-06-27 | 2004-06-24 | Heteroaryloxy nitrogenous saturated heterocyclic derivative |
US10/561,115 US7595316B2 (en) | 2003-06-27 | 2004-06-24 | Heteroaryloxy nitrogenous saturated heterocyclic derivative |
AU2004257025A AU2004257025B9 (en) | 2003-06-27 | 2004-06-24 | Heteroaryloxy nitrogenous saturated heterocyclic derivative |
US12/540,534 US8044070B2 (en) | 2003-06-27 | 2009-08-13 | Heteroaryloxy nitrogenous saturated heterocyclic derivative |
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Also Published As
Publication number | Publication date |
---|---|
US20060178375A1 (en) | 2006-08-10 |
CA2529790A1 (en) | 2005-01-27 |
US8044070B2 (en) | 2011-10-25 |
EP1642898A4 (en) | 2009-03-18 |
EP1642898B1 (en) | 2013-03-27 |
JP4735261B2 (ja) | 2011-07-27 |
AU2004257025B9 (en) | 2010-05-27 |
US20100210637A1 (en) | 2010-08-19 |
US7595316B2 (en) | 2009-09-29 |
CN1812981A (zh) | 2006-08-02 |
JPWO2005007644A1 (ja) | 2006-08-31 |
EP1642898A1 (en) | 2006-04-05 |
AU2004257025B2 (en) | 2010-01-28 |
AU2004257025A1 (en) | 2005-01-27 |
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