WO2005077953A1 - 含窒素縮合へテロ芳香環誘導体 - Google Patents
含窒素縮合へテロ芳香環誘導体 Download PDFInfo
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Definitions
- the present invention relates to a nitrogen-containing fused heteroaromatic ring derivative.
- Histamine a physiologically active endogenous factor in mammals and other organisms, is known to function as a neurotransmitter and have a wide range of pharmacological activities (eg, (See Life Sciences, Vol. 17, pp. 53 (1975)).
- histaminergic nerves in the papillary nucleus of the posterior hypothalamus indicates that histamine is particularly associated with hypothalamic functions (sleep, arousal rhythm, endocrine, eating and drinking behavior, sexual behavior, etc.) in brain function (Eg Progress in Neurobiology, Volume 63, pp. 637 (2001) ) See).
- Histaminergic projections of neurons in areas of the brain involved in maintaining wakefulness suggest a role for histamine in regulating the wakefulness or wake-sleep cycle .
- the projection of histaminergic nerve fibers on many marginal structures, such as the hippocampus or tonsillar complex is associated with regulation of autonomic nervous system, control of emotions and motivated behaviors, and learning. ⁇ Suggest a role for histamine in the memory process.
- histamine When histamine is released from a producing cell, histamine exerts its pharmacological action by acting on a specific macromolecule called a receptor on the surface of a cell membrane or in a target cell, and regulates various bodily functions.
- histamine is a receptor involved in central and peripheral nerve functions of histamine.
- the presence of the H3 receptor has been demonstrated by various pharmacology and physiological studies (eg, Trends in PharroLacological Science, 8, 24 ( 1 9 8 6))).
- human and rodent histamine H3 receptor genes have been identified and their presence has been clarified (for example, Molecular Pharmacology; 55, 1101). (See 199 9).
- histamine H3 receptor exists in the central or ft: presynaptic membrane of peripheral nerve cells and functions as an autoreceptor, controlling not only histamine O release but also other neurotransmitter proteins. That is, histamine 3 receptor agonist (agonist), antago 3st (antagonist) or inverse: r gonist (inverse agonist) is used for histamine, noradrenaline, serotonin, acetylcholine, dozmin, etc. from nerve endings. Regulate release.
- histamine H3 receptor gonists such as (R)-(a) -methinolehistamine, and His: ⁇ min H3 receptor such as Thioperamide Facilitated by antagonists or inverse agonists (eg Trends in Pharn Lacological Science, Vol. 19, pp. 177)
- the present invention provides a histamine H 3 receptor antagonistic action (an action of inhibiting the binding of histamine to the histamine H 3 receptor) or a reverse-acting action (for suppressing the homeostatic activity of the histamine H 3 receptor) It is an object of the present invention to provide a novel substance having the following, ie, a novel substance that acts as a histamine H 3 receptor agonist or antagonist in vivo.
- the present inventors have found that a specific nitrogen-containing fused heteroaromatic ring derivative acts as a histamine H 3 receptor antagonist or inverse agonist, and have completed the present invention.
- the present invention provides the following compounds or salts (1) to (20) in order to achieve the above object.
- a 2 represents the same group as described above, and when k is 0, a group represented by the formula (II 1-2) in the formula (I)
- the same or different heteroatoms selected from the group consisting of 1 or 2 or more, preferably 1 to 3 and representing a 5-membered or 6-membered monocyclic aromatic heterocyclic group, or A condensed aromatic heterocyclic group formed by combining the cyclic aromatic heterocyclic group and the aryl group, and W is a group represented by the formula (I1-1)
- a lower alkyl group (said lower Al Le group may be further substituted with halogen atom) or a cycloalkyl group; ⁇ or to, or G 2 and the G 2 : a 5- to 8-membered aliphatic heterocyclic ring formed by joining a nitrogen atom adjacent to S (the heterocyclic ring may be substituted with a halogen atom) / Represents a lower alkyl group or a halogen atom in the ring which may have 1 or 2) or a bicyclo ring), and ml represents a number of 2 to 4; And m3 represents an integer of 1 to 3, and (CH 2 ) ml in the formula (I1-1) may be further substituted with a lower alkyl group of 1 to 3 carbon atoms.
- Substituent group ⁇ amino group, nitro group, cyano group, hydroxy group, halogen atom, lower alkylsulfonyl group, lower alkyl group (the lower alkyl group may be substituted with a halogen atom), lower cycloalkyl Group (the lower cycloalkyl group may be substituted with a halogen atom), a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a lower cycloalkoxy group (the lower cycloalkoxy group).
- the group may be substituted with a halogen atom), an aryl / reoxy group, an araryloxy group, an aryl group, a heteroaryl group, a mono-lower alkyl group rubamoyl group, a di-lower alkyl group rubamoyl group, a lower alkyl carboxamide group, Aryl carboxamide group, heteroaryl carboxamide group, Rukanoi group, an alkylthio group,
- Substituent groups an amino group, a lower alkylsulfonyl group, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower cycloalkoxy group, and the lower alkyl / re group may be substituted with a halogen atom),
- a lower cycloalkyl group (the cycloalkyl group may be substituted with a halogen atom), a lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom), a lower cycloalkoxy group (the lower The cycloalkoxy group may be substituted with a halogen atom,), a carbamoyl group, a mono- or di-lower alkyl lvamoyl group
- Substituent group ⁇ amino group, nitro group, cyano group, hydroxy group, lower alkylsulfonyl group, halogen atom, lower alkyl group (the lower alkyl group may be substituted with a halogen atom), lower cyclo group Alkyl group (the lower alkyl group may be substituted with a genogen atom), lower alkoxy group (the lower alkoxy group may be substituted with a halogen atom or a hydroxy group), lower cycloalkoxy group Groups (the lower alkyl group may be substituted with a halogen atom), aryloxy group, arylaloxy group, aryl group, heteroaryl group, mono-lower ⁇ / alkyl carbamoyl group, di-lower alkyl group rubamoyl group, lower alkyl carboxy group Sumid group, aryl carboxamide group, heteroaryl carboxamide Group, Al force Roh I group, an alkylthio group,
- A is a hydrogen atom, a lower alkyl group (the lower alkyl group may be substituted with a halogen atom), a lower alkoxy group, a phenyl group, a pyridyl group, a carbamoyl group, a mono- or di-lower alkyl group.
- a 2 , A 3 and A 4 are each independently a hydrogen atom or a lower alkyl group, or a pharmaceutically acceptable salt thereof.
- Equation (I) is the following equation (1-0)
- Equation (I) is the following equation (1-1)
- Equation (I) is the following equation (1-2)
- Equation (I) is the following equation (I-1 3)
- Equation (I) is the following equation (1-4)
- the ring A is a benzene ring or a heteroaryl ring having one or two nitrogen atoms in the ring (the benzene ring and the heteroaryl ring are a nitro group, a hydroxy group, a lower alkyl group, a halo-lower alkyl group).
- a histamine receptor H3 antagonist comprising the compound according to any one of (1) to (14) as an active ingredient.
- the metabolic disease is at least one selected from the group consisting of obesity, diabetes, hormonal abnormalities, hyperlipidemia, gout, and fatty liver (17). .
- the circulatory system disease is at least one selected from the group consisting of angina pectoris, acute / congestive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease and electrolyte abnormality.
- the nervous system disorder is a sleep disorder, a disorder associated with sleep disorder, bulimia, information disorder, epilepsy, delirium, dementia, attention deficit hyperactivity disorder, memory disorder, Alzheimer's disease, Parkinson's disease, cognition
- the nervous system disorder is idiopathic hypersomnia, repetitive hypersomnia, intrinsic hypersomnia, narcolepsy, periodic limb movement disorder during sleep, sleep apnea syndrome, circadian rhythm disorder, chronic At least one selected from the group consisting of fatigue syndrome, REM sleep disorder, insomnia for the elderly, sleep insanity for night shift workers, idiopathic 'knee insomnia, repetitive insomnia, intrinsic insomnia, depression, anxiety and schizophrenia (17)
- the compounds or salts according to the above (1) to (14) act as histamine-3 receptor antagonists or inverse agonists in vivo. That is, the present invention also relates to the compound described in the above (1) to (14) or a pharmaceutically acceptable pentasalt thereof.
- a histamine H3 receptor antagonist or inverse agonist comprising:
- histamine H3 receptor has a very high homeostatic activity in receptor-expressing cells / tissues or in membrane fractions derived from expressing cells / tissues and also in vivo (endogenous agonists such as histamine ) Have been shown to have an activity observed in the absence of the enzyme (see, for example, Nature, Vol. 408, p. 860). It has been reported that it is suppressed by parsagonists. For example, thioperamide or ciproxyphan suppresses the constitutive autoreceptor activity of the histamine H3 receptor, thereby promoting the release and release of nerve conduction proteins (eg, histamine) from nerve endings.
- nerve conduction proteins eg, histamine
- histamine is involved in the regulation of behavioral arousal, as highly selective inhibitors of histamine synthase (histidine decarboxylase) inhibit its arousal.
- histamine H3 receptor agonist R-( ⁇ ) -methylhistamine also increases deep slow-wave sleep (eg, Brain's Research, 52). Vol. 3, page 325 (see 1991)).
- thioperamide increases wakefulness in a dose-dependent manner, and thioperamide reduces slow waves and REM sleep (eg, Life's Science, See Vol. 48, pp. 2397 (1991)).
- the histamine H3 receptor antagonist or inverse agonist, thioperamide or GT-2331 reduces emotional weakness and sleep in narcolepsy dogs (eg, Brain 'Research). Research), Vol. 793, pp. 279 (1998)).
- H3 receptors are involved in the regulation of wakeful sleep and sleep disorders, and that selective histamine H3 agonists, antagonists, or inverse agonists have various sleep disorders and sleep disorders.
- Diseases eg, idiopathic hypersomnia, repetitive hypersomnia, intrinsic hypersomnia, narcolepsy, sleep limb movement disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, Elderly insomnia, night work workers sleep insomnia, idiopathic insomnia, repetitive insomnia, true insomnia, depression, anxiety, Schizophrenia). Therefore, histamine
- the compounds or salts according to the above (1) to (14), which act as H3 receptor antagonists or inverse agonists, are considered to be effective for prevention or treatment of sleep disorders and various diseases associated therewith.
- histamine H3 receptor antagonist or inverse agonist thioperamide or GT-2331 improves learning disorder (LD), attention-deficit / hyperactivity disorder (ADHD) -like symptoms (eg, , Life Science, Vol. 69, pp. 469 (2010). Furthermore, in rats, the histamine H3 receptor agonist (R)-(a) monomethylhistamisi reduces objective recognition and learning effects in objective recognition tests and passive evacuation tests.
- LD learning disorder
- ADHD attention-deficit / hyperactivity disorder
- thioperamide which is a histamine H3 receptor antagonist or inverse agonist, reduces the amnesia caused by the drug in a dose-dependent manner (for example, pharmacology 'biochemistry' ant. Behavior (.Pharmacology, Biochemistry and Behavior), 68; pp. 7-5 (2001)).
- histamine 3 receptor antagonists or inverse agonists may be useful in preventing or treating memory and learning disorders and associated disorders (eg, Alzheimer's disease, Parkinson's disease, attention deficit / hyperactivity disorder). Suggest useful. Therefore, the compounds or salts described in the above (1) to (14) are considered to be effective also for the prevention or treatment of such memory / learning disorders and various diseases accompanying them.
- histamine H3 receptor antagoist or impergodist, thioperamide suppresses eating behavior in a dose-dependent manner, while promoting histamine release in the brain (e.g., Behavioral 'Plain Research ( Behavioral Brain Research), vol. 104, p. 147 (1999)).
- histamine H3 receptor is involved in the regulation of eating behavior, and that histamine H3 antagonists or inverse agonists are eating disorders ⁇ S Tomahane 'diabetes' • thinness ⁇ hyperlipidemia, etc. It is suggested that it is useful for the prevention or treatment of metabolic (metabolic) diseases. Therefore, the compounds or salts described in the above (1) to (14) are considered to be also effective in preventing or treating such diseases.
- the histamine H3 receptor agonist (R)-( ⁇ ) -methylhistamine dose-dependently reduces basal diastolic blood pressure.
- These effects are antagonized by the histamine ⁇ 3 receptor antagonist or thioperamide, which is an inverse agonist (see, for example, European Journal of Pharmacology, 234 vol. , P. 29 (1993)).
- mice histoperamide, a histamine H3 receptor antagonist or inverse agonist, dose-dependently suppressed seizures induced by electric shock or epileptiform seizures induced by pentylenetetrazole (PTZ).
- PTZ pentylenetetrazole
- histamine H3 receptor antagonists or inverse agonists are useful for preventing or treating epilepsy or central convulsions. Therefore, the compounds or salts described in (1) to (14) above are also considered to be effective in preventing or treating such epilepsy or central convulsions.
- the present invention further provides a method according to any one of the above (1) to (14).
- a prophylactic or therapeutic agent for a metabolic disease, a circulatory disease or a nervous system disease comprising a compound or a pharmaceutically acceptable salt thereof as an active ingredient.
- Examples of the above metabolic system disease include at least one selected from the group consisting of S Manga, diabetes, hormonal secretion abnormality, hyperlipidemia, gout and fatty liver.
- the circulatory system disease includes at least one selected from the group consisting of angina pectoris, acute depressive heart failure, myocardial infarction, atherosclerosis, hypertension, kidney disease and electrolyte abnormality.
- the above nervous system diseases include sleep disorders, diseases accompanied by sleep disorders, bulimia, affective disorders, epilepsy, delirium, dementia, attention deficit / hyperactivity disorder, memory disorders, Alzheimer's disease, Parkinson's disease, cognitive disorders, and movement disorders At least one selected from the group consisting of paresthesia, olfactory disturbance, morphine tolerance, drug dependence, alcohol dependence and tremor.
- the above-mentioned nervous system diseases also include idiopathic hypersomnia, repetitive hypersomnia, intrinsic hypersomnia, narcolepsi, sleep periodic movement disorder, sleep apnea syndrome, circadian rhythm disorder, At least one selected from the group consisting of chronic fatigue syndrome, REM sleep disorder, insomnia for the elderly, sleep insanity for night workers, idiopathic insomnia, repetitive insomnia, intrinsic insomnia, depression, anxiety and schizophrenia No.
- the compounds described in (1) to (14) or a pharmaceutically acceptable salt thereof can be used together with a concomitant drug. That is, the present invention further provides a metabolic disease, a circulatory disease, or a neurological disease comprising, as active ingredients, the compound according to (1) to (14) or a pharmaceutically acceptable salt thereof, and a concomitant drug.
- a concomitant drug include a drug for treating diabetes, a drug for treating hyperlipidemia, a drug for treating hypertension, and an antiobesity drug. These concomitant drugs may be used in combination of two or more.
- a prophylactic or therapeutic agent for a metabolic disease, a circulatory disease or a nervous system disease comprising the following (i), (ii) and (iiii) is further provided.
- 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, and an anthryl group.
- “Lower alkyl group” means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group.
- “Hydroxy lower alkyl group” means the lower alkyl group substituted with a hydroxy group, for example, a hydroxymethyl group, a 2-hydroxyl group, an 11-hydroxyl group, or a 2-hydroxyl group. And a methyl-ethyl group.
- “Lower cycloalkyl group” means a cycloalkyl group having 3 to 9 carbon atoms, Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a cyclononyl group.
- lower alkoxy group means a group in which the lower alkyl group is bonded to an oxygen atom, such as a cyclopropyloxy group, a cyclobutyloxy group, a pentyloxy group, and a Xyloxy, cyclohexyloxy, cyclooctyloxy, cyclononyloxy and the like.
- Alkoxy group means a group in which a hydrogen atom of a hydroxy group is substituted by the above-mentioned lower alkyl group, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, tert-group. — A butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, an isohexyloxy group and the like.
- 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, propylsulfonyl.
- Amino group isopropyls olephoninoleamino group, butylsulfonylamino group, sec-butylsulfonylamino group, tert-butylsulfonylamino group, N-methyl-methylsnolehoninoleamino group, N-methyl Ruetylsulfonylamino group, N-methyl-pyrpyrusulfonylamino group, N-methyl-1-isopropylsulfonylamino group, N_methyl-l-butylenolesnolehoninoleamino group, N-methyl-sec-butynolesphonyl Amino group, N-methyl-tert-butynoles-le-honinole-amino group, N-ethyl-methyls-no-le-honyla Group, N-ethyl-ethylsulfonylamino group, N-
- cycloalkyl lower alkylsulfonyl group means a group in which the above “cycloalkyl group having 3 to 9 carbon atoms” and a sulfonyl group are bonded, and examples thereof include cyclopropylsulfonyl group.
- Nolephonyl group, cyclobutylsnolephonyl group, cyclopentinolesnolephonyl group, cyclohexinolesnolephonyl group, cycloheptylslenonylonyl group, cyclobutynolesnorlephonyl group, cyclotinolslenonylonyl group, and cyclononylsulfonyl group Can be
- the “aralkyl group” means the lower alkyl group having the aryl group, and examples thereof include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 11-naphthylmethyl group, and a 2-naphthylmethyl group. .
- 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 A bicyclic heteroaryl group in which a ring heteroaryl group and a benzene or pyridine ring are condensed, such as a furyl group, a phenyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a thiadiazolyl group, and an isothiazolyl group.
- Oxazolyl group isoxazolyl group, pyridyl group, pyrimidyl group, pyridazinyl group, pyrazolyl group, virazinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinolizinyl group, quinoxalinyl group, cinnolinidyl group, benzimidazolyl group Group, benzofuranyl group, naphthyridinyl group, 1,2 Benzosoxazolyl group, benzoxazolyl group, benzothiazolyl group, oxazoporidyl pyridyl group, pyridothiazolyl group, isotizazolopyridyl group, benzothienyl group and the like.
- Halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
- Halo-lower alkyl group means a lower anoalkyl group substituted with 1 to 3 halogen atoms, for example, chloromethyl group, 2-chloroethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group. And a methyl group.
- alkoxycarbonylamino group means a group in which one of the hydrogen atoms of the amino group is substituted with the above-mentioned alkoxycarbyl group. Examples thereof include a methoxycarbonylamino group, an ethoxycarbonylamino group, and a propoxy group.
- Luponylamino group isopropoxycarbonylamino group, butoxycarbonylamino group, sec-butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbo-amino group, N-methyl-methoxycarbonylamino group, N —Methyl monoethoxy Cicarbonylamino group, N-methylpropoxycarbonylamino group, N-methylisopropoxycarbonylamino group, N-methyl-1-butoxycarbonylamino group, N-methyl-1-sec-butoxycarbonyl group Amino group, N-methyl-1-tert-butoxycarbonylamino group, N-ethyl-1-methoxycarbonylamino group, N-ethyl-1-ethoxycarbonylamino group, N-ethylloop-opening oxycarbonylamino group, N— Examples thereof include an ethyl-isopropoxycarbonylamino group, an N-
- Hydroalkyl group means a group in which one of the hydrogen atoms in the lower alkyl group has been substituted with a hydroxy group, for example, a hydroxymethyl group, a hydroxyethyl group, a 1-hydroxypropyl group. , 1-hydroxyl, 2-hydroxypropyl, 2-hydroxy-1-methyl-ethyl, and the like.
- mono-lower alkyl rubamoyl group means a carbamoyl group mono-substituted with the lower alkyl group, for example, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, and a butylcarbamoyl group.
- a methylcarbamoyl group an ethylcarbamoyl group
- a propylcarbamoyl group an isopropylcarbamoyl group
- a butylcarbamoyl group for example, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, and a butylcarbamoyl group.
- the “di-lower alkyl group rubamoyl group” means a carpamoyl group di-substituted with the same or different lower alkyl group.
- Examples of the “di-lower alkyl group rubamoyl group” include dimethylcarbamoyl group and getylcarbamoyl group.
- a nitrogen atom constituting the group and an identical or different lower alkyl group bonded to the nitrogen atom together form a 5- to 8-membered monocyclic ring.
- the monocyclic ring and a benzene ring or a pyridine ring are condensed to form a bicyclic ring.
- Alkylamino group means an amino group mono-substituted by the lower alkyl group, for example, a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a sec-butylamino group or a tert-butylamino group. And the like.
- Dialkylamino group means an amino group di-substituted by the same or different lower alkyl group, for example, dimethylamino group, ethylamino group, dipyramino group, methylpropylamino group or diisopropylamine. And a mino group.
- 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.
- alkanol group means a group in which the alkyl group and the carbonyl group are bonded, and examples thereof include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, and an isopropylcarbonyl 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-methylpronoylamino group, N-methyl-butanoylamino group, N-methyl-pentanoylamino group, N-ethylethylacetylamino group, N-ethylloopanoylamino group , N-ethyluptanoylamino group, N-ethyl-pentanoylamino group and the like.
- the “mono-lower alkylaminocarbonyloxy group” means a carboxy group mono-substituted by the lower alkyl group, for example, a methylaminocarbonyloxy group, an ethylaminocarbonylcarbonyl group, a propyloxy group. Examples include a minocarbonyloxy group and an isopropylaminocarboxy group.
- the “di-lower alkylaminocarbonyloxy group” means a carboxy group di-substituted by the lower alkyl group, for example, a dimethylaminocarbonyloxy group, a getylaminocarbonyloxy group, Examples thereof include a diisopropylpropylaminocarbonyl group and an ethylmethylaminocarbonyloxy group.
- Alkylthio group means a group in which the alkyl group and a sulfur atom are bonded, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, and an isopropylthio group.
- Cycloalkyl group means a cycloalkyl group having 3 to 9 carbon atoms, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclohexyl group, cyclooctyl group, cyclooctyl group Groups.
- “Cycloalkoxy group” means a group in which the alkyl group of the alkoxy group is substituted with a cycloalkyl group having 3 to 9 carbon atoms. And a cyclohexoxy group, a cyclopentoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cyclohexyloxy group.
- aryloxy group means a group in which an oxygen atom is bonded to the aryl group, and examples thereof include a phenoxy group, a naphthalene_1-yloxy group, and a naphthalene-12-yloxy group.
- heteroaryloxy group means a group in which the above-defined “heteroaryl group” is bonded to an oxy group, and examples thereof include a furan-2-yloxy group, a furan-3-yloxy group, and a thiophen-2-ene group.
- heteroarylalkyl group means a group in which the heteroaryl group and the alkyl group are bonded, for example, a furan-3-ylmethyl group, a furan-2-ylmethyl group, a furan-3-ylethyl group, Furan-2-ylethyl, furan-3-ylpropyl, furan-2-ylpropyl, thiophen-3-ylmethyl, thiophen-2-ylmethyl, thiophen-13-ylethyl, thiophen-12-ylethyl Group, thiophen-1-ylpropynole group, thiophen-12-propyl group, 1H-pyrrole-3-ylmethyl group, 1H-pyrrole-12-ylmethyl group, 1H-pyrroyl-3-ylethyl group, 1H-pyrroyl group Lou 2-Illechinole group, 1H-Pyro-monopropyl-3-ylpropyl group, 1H-
- the “monoaryl carbamoyl group” means a carbamoyl group mono-substituted by the aryl group, and includes, for example, a phenylcarbamoyl group.
- substituent group examples include those described above, and among these, for example, a cyano group, a halogen atom, a lower alkyl group, a lower alkoxy group, and a lower cycloalkoxy group are preferable.
- substituent group jS examples include those described above, and among these, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, and a lower cycloalkyl group are preferable.
- Examples of the “substituent group optionally having one or two groups selected from substituent group a; group selected from 3” represented by A 1 include, for example, a methyl group, an ethyl group, a trifluoro group A methyl group and a tert-butyl group are preferred.
- substituent group T examples include those described above. Among them, for example, a cyano group, a halogen atom, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower cycloalkoxy group, Preferred are lower alkyl rubamoyl groups, di-lower alkyl rubamoyl groups, lower alkyl carboxamide groups, aryl carboxamide groups, and heteroaryl carboxamide groups.
- heteroaryl group represented by (1) represents the following (1) or (2).
- a furyl group for example, a furyl group, a chelyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, a thiazolyl group, a thiadiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group Groups, a pyrazolyl group, a virazinyl group, a tetrazolyl group, an oxaziazolyl group and the like.
- a phenyl group a disoxazolyl group
- ⁇ formula aromatic heterocyclic group '' means that a 5-membered or 6-membered monocyclic aromatic heterocyclic group represented by the formula (1) is fused to a hydrocarbon ring aryl group having 6 to 14 carbon atoms as defined above.
- a condensed cyclic aromatic heterocyclic group in which the same or different monocyclic aromatic heterocyclic groups represented by the above (1) are fused to each other and more specifically, for example, Quinolyl group, isoquinolyl group, quinazolinyl group, quinolizinyl group, quino Xalinyl group, cinnolinyl group, benzimidazolyl group, imidazopyridyl group, benzofuranyl group, naphthyridinyl group, 1,2-benzisoxazolyl group, benzozoxazolyl group, benzothiazolyl group, oxazopyridyl group, pyridothiazolyl group, Examples thereof include an isothiazolopyridyl group, a benzochenyl group, an indolyl group, a benzothienyl group, a benzoisothiazolyl group, an indazolyl group, a prenyl group, a
- Examples thereof include a hydrogen atom, a methyl group, a trifluoromethyl group, an ethyl group, a pyridyl group, a phenyl group, a mono-lower alkyl group rubamoyl group, a di-lower alkylcarbamoyl group, and a piperidine-1-yl-carbonyl group.
- a hydrogen atom a methyl group, a trifluoromethyl group, an ethyl group, a pyridyl group, a phenyl group, a mono-lower alkyl group rubamoyl group, a di-lower alkylcarbamoyl group, and a piperidine-1-yl-carbonyl group.
- Examples of A 2 include the same groups as those described above for A. Of these, a hydrogen atom and a lower alkyl group are preferable, and a hydrogen atom is more preferable!
- a 3 the A E and may be mentioned the same groups, among these, a hydrogen atom, a lower alkyl group is preferred.
- a 4 the A E and may be mentioned the same groups, among these, a hydrogen atom, preferably a lower alkyl group, more preferably a hydrogen atom.
- E may have 1 to 3 groups selected from the substituent group ⁇ , the same or different from a phenyl group or a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;
- ⁇ (the ⁇ may have from 1 to 3 groups selected from the group consisting of the substituent group ⁇ ) is more specifically, for example, a phenyl group, a pyrimidyl group, a pyridyl group or A pyridazyl group, that is, a divalent group obtained by removing two hydrogen atoms from benzene, pyrimidine, pyridine, or pyridazine, and among these, a phenyl group or a pyrimidyl group, that is, two groups from benzene or pyrimidine And a divalent group obtained by removing two hydrogen atoms from benzene, and more preferably a phenyl group, that is, a divalent group obtained by removing two hydrogen atoms from benzene.
- a halogen atom for example, a lower alkoxy group and a hydroxy lower alkyl group are preferred.
- the halogen atom include a fluorine atom, a bromine atom and a chlorine atom.
- the lower alkoxy group include a methoxy group and an ethoxy group. These lower alkoxy groups may be further substituted with a halogen atom.
- the lower alkyl group include a methyl group and an ethyl group.
- W is the formula (I 1-1)
- W is the formula (I I— 1)
- ni 3 or 4
- ni 3 or 4
- Examples of the “lower alkyl group” represented by 2 include the same groups as the above-mentioned lower alkyl group, that is, a methyl group, an ethyl group, a propyl group, an isopropyl group and the like.
- the lower alkyl groups may be the same or different.
- the lower alkyl may be further substituted with a halogen atom.
- cycloalkyl group Ri said cycloalkyl group as defined der, cyclopropyl group, cyclobutyl group.
- G 2 and the nitrogen atom in the above formula (I1-1) are taken together to form a 5- to 8-membered aliphatic heterocyclic ring (the heterocyclic ring may be substituted with a halogen atom.
- a lower alkyl group or one or more halogen atoms may be present in the ring) or a bicyclic ring.
- Examples of the 5- to 8-membered aliphatic hetero ring include a pyrrolidine ring, a piperidine ring, a homopyridine ring, a heptamethyleneimine ring, a piperazine ring, a morpholine ring, and a homomorpholine ring.
- G 1 G 2 and the nitrogen atom in the above formula (I1-1) are an azani cyclic ring as a bicyclo ring formed together, and are the only heteroatoms constituting the ring.
- G 2 in the above formula (II-11) is a non-aromatic ring containing nitrogen atoms adjacent to each other.
- the bicyclo ring preferably has 6 to 10 ring-constituting atoms, and more preferably 7 to 9-membered ring-constituting atoms.
- Examples of the bicyclo ring include a group represented by the formula (II-1).
- CH 2 in the above formula (I 1-1) may be substituted with a lower alkyl group having 1 to 3 carbon atoms.
- the lower alkyl group include a methyl group, an ethyl group, an n-propyl group and an isopropyl group.
- W is a group represented by the above formula (I1-1)
- ml is 3 or 4
- G 2 and a nitrogen atom are joined together to form a 5- to 8-membered aliphatic heterocyclic ring (the heterocyclic ring contains a lower alkyl group optionally substituted with a halogen atom or a halogen atom in the ring).
- Ru to form a bicyclo ring of 1 or 2 may have) or 6 to 1 0-membered, ml is 3, and 5 to 8 G 2 and the nitrogen atom together Membered heterocyclic ring (the hetero ring may have a lower alkyl group which may be substituted with a halogen atom or one or two halogen atoms in the ring, or a bicyclic ring) Is more preferable.
- W is the formula (I 1-2)
- m2 represents an integer of 1 to 3, and among them, 2 or 3 is preferable.
- W is a is a group represented by the formula (II one 2) two carbon atoms different ones of the carbon atoms constituting the W (carbon atoms in the G i and G 2 are excluded) is a single bond
- a bicyclo ring may be formed by bonding via 1 (CH 2 ) ml — (m 11 represents an integer of 1 to 3). Examples of the bicyclo ring include a group represented by the formula (III-2).
- W is a bicyclo ring represented by the above formula (II 1 -2), and preferred examples of G 2 are the same as those described above.
- W is the formula (I 1-3)
- m 3 represents an integer of 1 to 3, and among them, 2 or 3 is preferable.
- W is represented by the formula (I 1-3)
- two different carbon atoms among the carbon atoms constituting W are one (CH 2 ) mll- (ml 1 is an integer of 1 to 3) )
- ml 1 is an integer of 1 to 3
- Examples of the bicyclo ring include a group represented by the formula (II 1-3). !
- W is, for example, 2-dimethylaminoethyl group, 2-ethylaminoethyl group, 2-di-n-propylaminoethyl group, 2-diisopropinoleaminoethyl group, 3-dimethylaminopropyl group, 3-dimethylaminopropyl group, Jethylaminopropyl, 3-di-n-propylamino-propyl, 3-diisopropyl Monoaminopropyl group, 4-dimethylaminobutyl group, 4-butylethylaminobutyl group, 4-diaminopropylaminobutyl group, 4-diisopropylaminobutyl group, 2- (ethylmethylamino) ethyl group, 2 _ (Ethylpropylamino) ethyl group, 2- (ethylisopropylamino) ethyl group,
- Cyclobutyl-cyclopropyl-amino) butyl group 4- (cyclobutyl-1-cyclopentylamino) butyl group, 4-1 (cyclohexylcyclopentylamino) butyl group, 2- (cyclopropyl-methylamino) Ethyl group, 2- (cyclopropyl-1-ethylamino) ethyl group, 2- (cyclopropyl-1-n-propylamino) ethyl group, 2- (cyclopropyl-1-isopropylamino) ethyl group, 2- (cyclobutyl-methylamino) ) Ethyl group, 2- (cyclobutyl-ethyl-amino) ethyl group, 2- (cyclopropyl Lou n- propyl one amino) Echiru group, 2- (cyclobutyl over isopropyl over ⁇ amino) Echiru group, 2- (Cyclopentyl-
- 2-Homopiperidine 1-1-a Norecyclopeptinole 3-Homopiperidine-1-1-yl-cyclopentyl / re, 2-Homopiperidine-1-1-inole-1-cyclopentinole, 4-Homopiperidine-1-1-Pinolecin , 3-Homopiperidine-1-yl-hexyl group, 2-Homopiperidine-1-yl-1-hexyl group, 3-heptamethyleneimine-1-1-cyclobutyl group, 2-heptamethylene Min-1-yl cyclobutyl group, 3-heptamethyleneimine-1-yl pentyl group, 21-heptamethyleneimine 1-yluc pentyl group, 4-heptamethyleneimine-1-yl hexyl Group, 3-heptamethyleneimine 1-hexanol group, 21-heptamethyleneimine 1-1-hexanol group, hexyl group, 2-monorephorin-41-ino Lacecycl
- the compound of formula (I-14) represented by the above formula (1-0) is obtained by combining A 2 and W 2 to form an A ring.
- the compound represented by is also included.
- Ring A represents a benzene ring or a 5- or 6-membered heteroaryl ring having 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in the ring.
- the ring A is preferably a heteroaryl ring having 1 or 2 nitrogen atoms as a benzene ring or a hetero ring-constituting atom.
- a benzene ring, a pyridine ring, a thiophene ring, a furan ring, a pyrazine ring and the like are preferable, and among these, a benzene ring, a pyridine ring or a pyrimidine ring is more preferable, and a benzene ring or a pyridine ring is more preferable. preferable.
- the compound (I) according to the present invention can be 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 conventional synthesis method in a liquid phase but also by a wake-up method recently used, for example, a method using a solid phase such as a combinatorial synthesis method or a parallel synthesis method. You can do it.
- Compound (1-11) according to the present invention can be produced, for example, by the following method.
- Y 2 is a linear or branched I ⁇ alkyl group, a Shikuroarukinore group or haa aralkyl group
- gamma 3 is a lower Anorekiru group or Ararukiru group
- Upsilon 4 Ha port Gen atom or methane Represents an organic sulfonyloxy group such as a sulfonyloxy group, an ethanesulfonyloxy group, a ⁇ -toluenes / lephonyloxy group, or a trifluoromethanesulfonyloxy group, and other symbols have the same meanings as above.
- This step is a method for producing the compound (3) by reacting the compound (1) with the oxalate derivative (2) in the presence of a base.
- Y 3 in the compound (1) means a lower alkyl group or an aranoalkyl group as defined above, and more specifically, for example, a methyl group, an ethyl group, a benzyl group and the like. It is.
- Y 2 in the compound (2) represents a linear or branched lower alkyl group, cycloalkyl group or aralkyl group.
- Upsilon 2 is "lower alkyl group linear" shown, more specifically, if Reimen, methylation group, Echiru group, .eta. propyl, .eta. butyl group and the like.
- Upsilon 2 indicates "branched lower alkyl group", more specifically, for example, tert one butyl group, a 2-methylpropyl group.
- cycloalkyl group represented by Y 2 , more specifically, for example, a cyclohexyl group and the like can be mentioned.
- the amount of compound (2) used in this step is usually 1 equivalent to excess equivalent to 1 equivalent of compound (1).
- Examples of the base used in this step include sodium hydride, sodium methoxide, sodium methoxide, lithium hexamethyldisilazane, and the like. Of these, sodium hydride is preferable.
- the amount of the base used in this step is usually 1 equivalent to excess equivalent based on 1 equivalent of compound (1).
- the reaction temperature is usually from ⁇ 50 ° C. to 100 ° C., preferably from 120 ° C. to 50 ° C.
- the reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours.
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and specific examples thereof include toluene, benzene, xylene, getyl ether, dioxane, hexane, and tetrahydrofuran.
- the compound (3) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc. Without purification or isolation and purification.
- This step is a method for producing a compound (4) by reacting the compound (3) obtained in the above step 1 with hydrazine.
- the amount of hydrazine used in this step is usually 1 equivalent to an excess equivalent to 1 equivalent of compound (3).
- the reaction temperature is usually from 0 ° C. to 200 ° C., and preferably from room temperature to the boiling point of the solvent used for the reaction.
- the reaction time is usually 30 minutes to 7 days, preferably 1 hour to 24 hours.
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and specific examples thereof include, for example, ethanol, methanol, and acetic acid.
- the compound (4) thus obtained may be isolated or purified by publicly known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, or chromatography. This can be applied to the next step without separation and purification.
- This step is a method for producing a compound (5) by reducing the ester group of the compound (4) obtained in the above step 2.
- reducing agent used in this step include lithium aluminum hydride and lithium borohydride.
- the amount of the reducing agent used in this step is generally 1 equivalent to an excess equivalent, preferably 1 equivalent to 1.5 equivalents, per 1 equivalent of the compound (4).
- the reaction temperature is usually from 150 to 100 ° C., preferably from 120 to 50 ° C.
- the reaction time is generally from 5 minutes to 24 hours, preferably from 30 minutes to 24 hours. .
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction. Specifically, for example, trahydrofuran, One tel and the like.
- the compound (5) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography or the like. It can be applied to the next step.
- This step is a method for producing an aldehyde compound (6) by oxidizing the compound (5) obtained in the above step 3.
- acid reagent used in this step include manganese dioxide, manganese oxide, pyridinium dichromate, pyridinium dichromate, selenium diacid, dimethyl sulfoxide and the like.
- the amount of the acid reagent used in this step is usually 1 equivalent to excess equivalent, preferably 5 equivalent to 20 equivalent, relative to 1 equivalent of compound (4).
- the reaction temperature is usually from 0 ° C. to 200 ° C., preferably from 50 ° C. to the boiling point of the solvent used for the reaction.
- the reaction time is generally 5 minutes to 7 days, preferably 30 minutes to 24 hours.
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction. Specifically, for example, tetrahydrofuran, dimethyl ether, dichloromethane, chlorophonolem, acetone, benzene, toluene, xylene, etc. Is mentioned.
- the compound (6) thus obtained may be isolated or purified or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. And can be used in the next step.
- a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. And can be used in the next step.
- This step in the presence of a base, by reacting the obtained compound (6) and human hydrazide derivative conductor (O) NH NH 2 in the above Step 4, a way to produce a compound (8). .
- the base used in this step include triethylamine and the like.
- the amount of the base used in this step is usually 1 equivalent to excess equivalent, and preferably 1 equivalent to 1.5 equivalent, relative to 1 equivalent of compound (6).
- Examples of the hydrazide derivative (7) used in this step include the groups defined above, and more specifically, for example, a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, n-butyl group, isopropyl group, tert-butyl group, phenyl group, pyridine-12-yl group, pyridine-13-yl group, pyridin-14-inole group, furan-12-inole group, thiophene1-2- Examples include an inole group, an indole-1-yl group, and a 5-methylisoxazole-13-yl group.
- hydrazide derivative (7) a commercially available product may be used, or an ester derivative represented by AC (O) 2 O 5 (where 5 represents a lower alkyl group such as a methyl group or an ethyl group) may be used.
- a product obtained by reacting hydrazine with a reaction solvent such as ether using a method usually used in the field of organic chemistry can also be used in the present invention.
- the amount of the hydrazide derivative (7) used in this step is usually 1 equivalent to an excess equivalent, and preferably 1 equivalent to 1.5 equivalents, relative to 1 equivalent of the compound (6).
- the reaction temperature is usually from 0 ° C. to 200 ° C., preferably from 50 ° C. to the boiling point of the solvent used for the reaction.
- the reaction time is generally 5 minutes to 7 days, preferably 1 hour to 24 hours.
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction. Specifically, for example, xylene, toluene, dioxane, tetrahydrofuran, dimethylformamide, ⁇ -methylpyrrolidone, Quinoline and the like.
- the compound (8) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography or the like. It can be applied to the next step.
- This step removes the Upsilon 3 with the resultant compound (8) in the above step 5, compound
- a method for removing Y 3 specifically, for example, a method using borax tribromide or trimethylsilyl roside can be mentioned.
- the amount of boron tribromide used in this step is usually from 1 equivalent to excess equivalent, preferably from 1.5 to 2 equivalents, per 1 equivalent of the compound (8> 1 equivalent).
- the reaction temperature is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to room temperature.
- the reaction time is generally 5 minutes to 7 days, preferably 1 hour to 24 hours.
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and specific examples thereof include chlorophonolem, methylene chloride, and carbon tetrachloride.
- the compound (9) thus obtained is isolated or purified or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be applied to the next step without the need.
- a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be applied to the next step without the need.
- This step is
- Step 7-1) in the presence of a base by reacting the compound (9) with the compound (10) W-Y 4, compounds according to the present invention (1 1 1) or to produce,
- Step 7 2 in the presence of a base, compound (9) with the compound (1 0 - 1) Wp- Y 4 (wherein, [rho, the formula (II _1), (II one 2) or (I 1 —3) represents a protecting group for an amino group in), and then removing the protecting group for an amino group to produce the compound (1-2) of the present invention.
- the amount of the compound (10) or (10-1) used in this step is determined based on the amount of the compound (10) or (10-1) used in this step.
- the method for removing the protecting group for the amino group may be the method described in the literature (for example, the Protective Group S. Organic Synthesis (Organic Synthesis), by TL. W. Green, 2nd edition. John Wiley & Sons, 1991, etc.) It can be performed by combining with a conventional method.
- the base used in this step- includes, for example, inorganic bases such as sodium hydroxide, hydroxylated lime, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like, and organic bases such as triethylamine and diisopropylamine. .
- the amount of the base to be used is generally 1 equivalent to excess equivalent, preferably 1 equivalent to excess equivalent, relative to 1 equivalent of compound (9).
- the skin temperature is usually from 0 ° C. to 200 ° C., preferably from room temperature to the boiling point of the solvent used for the reaction.
- the reaction time is generally 5 minutes to 7 days, preferably 1 hour to 24 hours.
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and specific examples include tetrahydrofuran, dioxane, dimethylformamide, and the like.
- the compound (1-2) of the present invention thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like. Can be.
- the compound (1-2) according to the present invention can also be produced by the following method.
- Step 8 This step is a method for producing a compound (13) by reacting the compound (1) with the compound (12) in the presence of a base.
- reaction in this step can be carried out by the same method as in the above step 1, a method analogous thereto, or a combination thereof with a conventional method.
- the compound (13) thus obtained can be isolated or purified by a known separation and purification method, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be applied to the next step without the need.
- Step 9 This step is a method for producing a compound (14) by reacting the compound (13) with hydrazine.
- reaction in this step is performed in the same manner as in the step 2, the It can be performed by combining these methods with conventional methods.
- the compound (14) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, without isolation or purification.
- separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, without isolation or purification.
- the next step can be performed.
- Step I 0 This step converts the hydroxy group of the compound (14) into a leaving group Y 7, is a step for preparing a compound (15).
- Examples of Y 7 include a leaving group such as a halogen atom such as a chlorine atom.
- a leaving group such as a halogen atom such as a chlorine atom.
- Y 7 is a chlorine atom
- the hydroxy group of the compound (14) can be converted to a chlorine atom by reacting the compound (14) with oxysalt.
- the amount of the oxysalt used in this step is usually 1 equivalent to an excess equivalent, preferably 10 to 20 equivalents, per 1 equivalent of the compound (14).
- the reaction temperature is usually from 0 to 200 degrees, preferably from 50 degrees to the boiling point of the solvent used in the reaction.
- the reaction time is generally 5 minutes to 7 days, preferably 1 hour to 24 hours.
- the reaction can be carried out without a solvent in the case where an oxysalt ichryline is used.
- the reaction may be carried out using a reaction solvent.
- the reaction solvent used is not particularly limited as long as it does not hinder the reaction, and specific examples include, for example, black form and shiridani methylene. And carbon tetrachloride.
- the compound (26) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, without isolation or purification.
- separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, without isolation or purification.
- the next step can be performed.
- Step 1 1 This step is a method for producing a compound (16) by reacting the compound (15) with a hydrazide derivative (7) A X C (O ) NHNH 2.
- the hydrazide derivative (7) is a commercially available product, or AC (O) OY
- hydrazide derivative (7) is usually 1 to an excess equivalent, preferably 1.5 to 2.0 equivalents, per 1 equivalent of the compound (15).
- the reaction temperature is usually from 0 ° C. to 200 ° C., preferably from 100 ° C. to the boiling point of the solvent used for the reaction.
- the reaction time is generally 5 minutes to 24 hours, preferably 5 hours to 14 hours.
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and specific examples include xylene, toluene, and dioxane.
- the compound (16) obtained as above is isolated and purified by known means for separation and purification, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, or the like. The next step can be carried out without performing.
- Step 12 This step is a method for producing a compound (17) by removing Y 3 of the compound (16).
- reaction in this step can be carried out by the same method as in the above step 6, a method analogous thereto, or a combination thereof with a conventional method.
- the compound (17) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.
- separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.
- the next step can be performed.
- Step 13-1 reacting compound (17) with compound (10) W_Y 4 in the presence of a base to produce compound (1-2) according to the present invention
- Step 13-2) In the presence of a base, compound (17) and compound (10_1) Wp—Y 4 (where ⁇ is the above formula (11-1), (II-2) or (I 1) — 3) represents the protecting group for the amino group in), and then removing the protecting group for the amino group of the compound (10-1) to produce the compound (1-2) of the present invention.
- ⁇ is the above formula (11-1), (II-2) or (I 1) — 3
- the compound (1-2) according to the present invention thus obtained can be isolated and purified by a known separation and purification method, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. it can.
- the compound (1-3) according to the present invention can be produced, for example, by the following method.
- Step 14 In this step, compound (la) is reacted with dalioxylic acid (18). This is a method for producing compound (19).
- Specific examples of the compound (la) used in this step include 4-methoxyphenylaceton and the like.
- the amount of dalioxylic acid (18) used in this step is usually 1 equivalent to excess equivalent, preferably 1.2 to 1.5 equivalent, relative to 1 equivalent of compound (la).
- the reaction temperature is generally from 0 to 200 degrees, preferably from 10 degrees to the boiling point of the solvent used in the reaction.
- the reaction time is generally 1 hour to 24 hours, preferably 5 hours to 15 hours.
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include water, toluene, tetrahydrofuran, dioxane, and dimethylformamide.
- the compound (19) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography or the like. It can be applied to the next step.
- Step 15 This step is a method for producing a compound (20) by reacting the compound (19) with hydrazine.
- reaction in this step can be carried out by the same method as in the above step 2, a method analogous thereto, or a combination thereof with a conventional method.
- the compound (20) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.
- separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.
- the next step can be performed.
- Step 1 6) This step converts the hydroxy group of the compound (20) into a leaving group Y 7, is a step for preparing Compound (2 1).
- reaction in this step can be carried out by the same method as in the above step 10, a method analogous thereto, or a combination thereof with a conventional method.
- the compound (21) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. Or can be subjected to the next step without isolation or purification.
- a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. Or can be subjected to the next step without isolation or purification.
- Step 17 This step is a method for producing a compound (22) by reacting the compound (21) with a hydrazide derivative (7) A′C (O) NHNH 2 .
- the reaction in this step can be carried out by the same method as in the above step 11, a method analogous thereto, or a combination thereof with a conventional method.
- the compound (22) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.
- separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.
- the next step can be performed.
- Step 18 This step is a method for producing a compound (23) ′ by removing Y 3 of the compound (22).
- reaction in this step can be carried out by the same method as in the above step 6, a method analogous thereto, or a combination thereof with a conventional method.
- the compound (23) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, without isolation or purification.
- separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, without isolation or purification.
- the next step can be performed.
- Step 1 9 one 1) the presence of a base, compound (23) with the compound (10) W- Upsilon 4 (W and Upsilon 4 are as defined above) and reacting the compound of the present invention (1-3) the ability to manufacture,
- Step 19 2 in the presence of a base, after a compound (23) with the compound (10- 1) Wp- Y 4 ( W, p ⁇ Pi ⁇ 4 has the same meaning shows the above) obtained by reacting a,
- This is a method for producing the compound (1-2) of the present invention by removing the protecting group of the amino group.
- the reaction in step 19-11 can be performed in the same manner as in step 7-1, a method analogous thereto, or a combination thereof with a conventional method. It can be carried out by the same method as in the above step 7-2, a method analogous thereto, or a combination of these methods with a conventional method.
- the compound (1-3) according to the present invention thus obtained can be obtained by a known separation and purification method, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. Can be isolated and purified.
- Compound (1-4) according to the present invention can be produced, for example, by the following method.
- Y 8 represents a halogen atom such as a bromine atom, and the other symbols have the same meanings as described above]
- Step 20 This step is a method of reacting compound (24) with compound (25) to produce compound (26).
- the compound (25) used in this step is a so-called Grignard reagent, and may be any compound as long as it produces the compound (26) in the reaction with the compound (24). , 4-methoxyphenylmagnesium bromide, 4-methoxyphenylmagnesium chloride, 4-methoxyphenylmagnesium chloride, and the like.
- the amount of (25) used in this step is based on 1 equivalent of compound (24). It is usually 1 equivalent to excess equivalent, preferably 1.0 to 1.5 equivalent.
- the reaction temperature is usually from 150 to 200 degrees, preferably from 0 to the boiling point of the solvent used in the reaction.
- the reaction time is generally 5 minutes to 7 days, preferably 1 hour to 24 hours. ⁇
- the reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include getyl ether and tetrahydrofuran.
- the compound (24) used in this step for example, a compound represented by the formula (24)
- the compound (26) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. Or can be subjected to the next step without isolation or purification.
- a known separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. Or can be subjected to the next step without isolation or purification.
- Step 21 This step is a method for producing a compound (27) by reacting the compound (26) with hydrazine.
- reaction in this step can be carried out by the same method as in the above step 2, a method analogous thereto, or a combination thereof with a conventional method.
- the compound (27) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, without isolation or purification.
- separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, without isolation or purification.
- the next step can be performed.
- Step 22 This step is a converts Okiso group of the compound (27) into a leaving group Y 7, is a step for preparing a compound (28).
- reaction in this step can be carried out in the same manner as in the above step 10, a method analogous thereto, or a combination thereof with a conventional method.
- oxychloride phosphorus or the like can be used.
- reaction conditions such as the amount of the oxysalt used in the reaction can be determined by the same method as in the above step 1 °, a method analogous thereto, or a compound which can be produced by using these and a conventional method ( 28) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc., or subjected to the next step without isolation and purification. Can be.
- Step 23 is a method for producing a compound (29) by reacting the compound (28) with a hydrazide derivative (7) A X C (O ) NHNH 2.
- the reaction in this step can be carried out by the same method as in the above step 11, a method analogous thereto, or a combination thereof with a conventional method.
- the compound (29) thus obtained is isolated and purified or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography and the like. It can be applied to the next step without the need.
- a known separation and purification means for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography and the like. It can be applied to the next step without the need.
- Step 24 This step is a step of producing compound (30) by removing Y 3 in step (29).
- the reaction in this step can be isolated and purified by the same method as in the above step 6, a method analogous thereto, or a combination thereof with a conventional method, or can be subjected to the next step without isolation and purification. .
- the compound (30) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.
- separation and purification means for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like.
- the next step can be performed.
- Step 25_1 Compound (30) is reacted with compound (10) W—Y 4 in the presence of a base to produce the compound (1-4) according to the present invention, or
- Step 25-1 can be carried out in the same manner as in Step 7_1, a method analogous thereto, or a combination thereof with a conventional method. It can be carried out by the same method as in the above step 7-2, a method analogous thereto, or a combination of these methods with a conventional method.
- the compound (1-4) according to the present invention thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. it can.
- the compound of the present invention represented by the formula (I) can be easily isolated and purified by ordinary separation and purification means.
- Such means include, for example, solvent extraction, recrystallization, reprecipitation, column chromatography, preparative thin-layer chromatography, and the like.
- the nitrogen-containing condensed heteroaromatic ring derivative according to the present invention can exist as a pharmaceutically acceptable salt, and such a salt is produced by a conventional method using the compound represented by the formula (I). can do.
- acid addition salts include, for example, halogenated Hydrochloride (hydrochloride, hydrofluoride, hydrobromide, hydroiodide, etc.), inorganic acid salt (nitrate, perchlorate, sulfate, phosphate, carbonate, etc.), lower grade Alkyl sulfonates (methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.), arylsulfonates (benzenesulfonate, p-toluenesulfonate, etc.), organic acid salts ( Fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.) or amino acid salts (glutamate, aspartate,
- base addition salts include, for example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salt, and organic bases (guanidine, Triethylamine, dicyclohexylamine, etc.).
- the compounds of the present invention may exist as any hydrate or solvate of the free compound or a salt thereof.
- the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally.
- the compound of the present invention When used clinically, it may be formulated with pharmaceutically acceptable additives according to the mode of administration.
- Various additives that are commonly used in the pharmaceutical field can be used as additives in this case. Examples of such additives include gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methinoresenolerose, and canolepo '.
- Ximethinoresenorelose corn starch, microcrystalline wax, white petrolatum, magnesium metaoleate magnesium magnesium, anhydrous calcium phosphate, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sho Sugar Fatty acid ester, polyoxyethylene, hydrogenated castor oil, polybierpyrrolidone, magnesium stearate, light caustic anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, Examples include propylene glycol, polyalkylene glycol, cyclodextrin, and hydroxypropyl cyclodextrin.
- the mixture of the compound of the present invention and the above-mentioned additives may be used as a solid preparation (tablets, capsules, granules, powders, suppositories, etc.) or a liquid preparation (syrup, elixir, injection, etc.).
- Can be These preparations follow the usual procedures in the pharmaceutical field.
- the liquid preparation may be one that is dissolved or suspended in water or another appropriate medium before use.
- it may be dissolved or suspended in a physiological saline solution or a budou sugar solution, and a buffer or a preservative may be added.
- the compounds of the present invention 1.0 to 1 0 0 wt%, the good Mashiku can be contained in an amount of I. 0 to 6 0 wt 0/0.
- Formulation of the compound of the present invention can be performed, for example, according to the following formulation examples. (Formulation Example 1)
- compositions may also contain other therapeutically effective drugs as described below.
- the compounds of the present invention can be used in combination with other drugs useful for the treatment (prevention or treatment) of metabolic disorders or eating disorders.
- the individual components in such combinations can be administered in divided or single formulations during the treatment, at different times or simultaneously.
- Compounds of the invention are useful for treating metabolic or eating disorders
- Combinations with other drugs also include those in principle that are not useful for the treatment of metabolic disorders or eating disorders.
- the compound of the present invention may also be a drug effective for hypertension, hypertension related to obesity, hypertension-related disease, cardiac hypertrophy, left ventricular hypertrophy, metabolic disease, obesity, obesity-related disease, etc. (hereinafter referred to as “concomitant drug”).
- concomitant drug a drug effective for hypertension, hypertension related to obesity, hypertension-related disease, cardiac hypertrophy, left ventricular hypertrophy, metabolic disease, obesity, obesity-related disease, etc.
- concomitant drug can be used in combination with Such drugs can be administered simultaneously, separately or sequentially with the compound of the present invention in the prevention or treatment of the above-mentioned diseases.
- a compound of the present invention When a 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.
- the composition containing the compound of the present invention and the concomitant drug may be administered to the four subjects simultaneously, separately or sequentially. At that time, the composition and the
- the dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, 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 the concomitant drug, and 2) separately preparing the compound of the present invention and the concomitant drug. Simultaneous administration of the two obtained preparations by the same administration route; 3) Administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug at the same administration route with a time lag.
- glidazones eg, glidazones
- glidazones eg, ciglitazone, dar glitazone (darglitazone), englitazone (englitazone), isagridazone (isaglitazone) (MCC-555), pioglitazone (pioglitazone), lip gliglizone (rosiglidazone) troglitazone), BRL 49 653, CLX-0921, 5-BTZD, etc.
- GW-0207 LG-100 641, LY-300512, etc.
- PPAR peroxisome proliferator-activated receptor
- acarbose akanosebose
- adiposine adiposine
- mimiglibose emiglitate
- miglitone miglitone
- hodaribosu voglibose
- pradimicin-Q pradimicin-Q
- pradimicin-Q pradimicin-Q , CKD-711, MDL-25, 673, MDL-73, 945, MOR 14, etc.
- ⁇ -amylase inhibitors such as tendamistat, trestatin ⁇ A13688, etc.
- insulin secretagogues such as linogliride, A-4166,
- Fatty acid oxidation inhibitors such as clomoxir and etomoxir.
- midaglizole isaglidole (isaglidole), deridari d'onore (deriglidole), idazoxan (idazoxan), elaroxan (earoxan) ), A2 antagosto such as fluparoxan,
- LP-1 (73-7), GLP 1 (7-36) — Insulin or insulin mimetic status such as NH 2 ,
- Non-thiazolidinedione such as JT-501, farglitazar,
- PPAR ⁇ dual agonist such as CLX-0940, GW-1536, GW-1929, GW_2433, KRP-297, L-1796449, LR-90 and SB219994
- VPAC 2 receptor agonist 1 5) VPAC 2 receptor agonist.
- Examples of the above-mentioned drug for treating hyperlipidemia include:
- atorvastatin itavastatin, itavastatin, fluvastatin, fluvastatin, oral pastatin (lovastatin), pravastatin (pr avastatin), linokustatin (rivastatin), rosuvastatin (simvastatin), simpastatin (simvastatin) HMG—CoA reductase inhibitor such as ZD—4522,
- cholesterol absorption inhibitors such as snathonoreestenole, ⁇ -sitostellone monole, steronoregnolecoside, ezetimibe,
- ACAT acyl mono-CoA ⁇ cholesterol acyltransferase inhibitors such as avasimibe, eflucimibe, KY-505, SMP-709, etc.
- antioxidants such as probucol
- FXR receptor antagonists such as GW-4064, SR-103912, 1
- LXR receptor agonists such as GW3965, T9013137, XTC C-179628,
- lipoprotein synthesis inhibitors such as niacin
- Bile acid reabsorption inhibitors such as BARA1453, SC435, PHA 384640, S-435, AZD 7706,
- P PAR ⁇ agonists such as GW501 516, GW 590735, etc.
- MTTP microsomal triglyceride transport inhibitors
- inplitapide LAB 687 CP 346086
- hypertension drug examples include, for example,
- Black mouth thiaridone, black mouth thiazide, dichlorofuethimide, hydrophnoleo mouth Thiazide compounds such as thiazide dapamide (indapamide) and hydrochloride thiazide, bumetanide (bumetanide), ethacrynic acid (ethacrynic acid), loop systems such as flosemid and torsemide; Diuretics such as aldosterone antagonists such as sodium, spironolatone, and epilenone;
- Bepantololone (bevantolol), Bisoprolol (bisoprolol), Bopindolonele (bopindolol), Power-note-teoronore (carteolol), Power-note-vejironore (carvedilo 1), Serif.
- Loro-nore celiprolol
- Esmolorno Esmolorno
- Indenolow-nore '(indenolol) Metaprolonore
- Nadronole nadolol
- Nebivololole Nebivolol
- Pembbutronole Pinbutololone, Pinbutololol, Pinbutololol jS-adrenaline blocker, such as tertatolol), tili solol, timo mouth
- neutral endopeptidase inhibitors such as omapatrilat, cadoxatril, ecadotril, fosidotril, sambatrilat, AVE7-688, ER4030, etc.
- Endothelin antagonists such as tezosentan, A308816, YM62889, etc.
- Vasodilators such as hydralazine, clonidine, minoxidil, -cotinyl alcohol, etc.
- a beta-adrenergic blocker such as Nipradilol, Arotinolol, Amosula
- ⁇ 1 blockers such as terazosin, perapidil (urapidil), prazosin, bunazosin, trimazosin, doxazosin, naphthovidil, indolamine, WHIP 164, XEN 010, etc.
- antiobesity drugs examples include, for example,
- 5HT (serotonin) transporter inhibitors such as paroxetine, paroxetine, fluoxetine, fenfunoramine, fenfluramine, fluvoxamine, sertraline, imipramine, etc.
- Ghrelin antagonists such as the compounds disclosed in WO 01/87355, WO 02/08250, etc.
- T-1 2 2 6 2 9 6 (Takeda), SNP- 791 (Synaptic), others WO 0 1 8 2 9 25, WO 0 1/8 78 34, WO 02/0 5 1 809, WO 0 2/06 245, WO 02/0 76 9 29, WO 02/0 76 947, WO 02 no 0443 3, WO 02/5 1 809, WOO 2/08 3 1 34, WO 02/0 94 79 9, WO 03/004027 and MCH-1 R (melanin-concentrating hormone receptor 1) antagonists such as the compounds disclosed in JP-A-2001-226269, 7) MCH-2 R (melanin Aggregating hormone receptor 2) agonist / antagonis K
- NP Y 1 Neuropeptide Y ⁇ 1 such as compounds disclosed in Z89 528
- Leptins such as human recombinant leptin (PEG-OB, Hoffman La Roche), recombinant methionyl leptin (Amgen),
- Ovioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone, naloxone, nanoretrexone, compounds disclosed in WO 00/21509,
- Olexin antagonists such as the compounds disclosed in 1,
- G I— 1 8 1 771 (Glaxo-SmithKline), SR146131 (Sanof i Synthelabo), Butabindide (butabindide), PD 170, 292, PDTF 149164 (Fuisa Ichi) and other CNTF (ciliary neurotrophic factors),
- axokine (Regeneron), other CN 94 derivatives such as the compounds disclosed in WO 94/091 34, WO 98/22 128, WO 99/4381 3,
- Mc 3 r (melanocortin 3 receptor) agonist
- Sibutramine (Meridia® ZReductil®) and its salts, other USP 4,746,680, USP4,806,570, USP5,436,272, Monoamine reuptake inhibitors such as the derivatives disclosed in U.S. Patent Application Publication No. 2002/0006 964, WO 01/27068 and WO 01/62341;
- GLP 1 (glucagon-like peptide 1) agonist
- DGAT1 diacylglycerolacyltransferase 1 inhibitor
- DGAT 2 diacylglycerolacyltransferase 2
- FAS fatty acid synthase inhibitors such as calrenin (Cerulenen) and C75,
- B VT 3498 B VT 2733, others 11/1/3 HSD 1 such as compounds disclosed in WO 01/90091, WO 01 Z 90090, WO 01/90092, etc. (11-J3 hydroxysteride dehydrogenase type 1) inhibitor, 38) SCD1 (stearoyl-CoA desaturase 1) inhibitor,
- the compound of the present invention can be combined with one or more of the above concomitant drugs.
- the combination of the compound of the present invention and one or more drugs selected from the group consisting of a therapeutic drug for diabetes and a therapeutic drug for hyperlipidemia is useful for the prevention or treatment of metabolic diseases.
- a therapeutic agent for diabetes or a therapeutic agent for hyperlipidemia with the compound of the present invention in addition to the antihypertensive agent and the antiobesity agent, synergistic synergistic effects of preventing or treating metabolic diseases can be achieved. Become.
- the dose and frequency of administration differ depending on the sex, age, body weight, degree of symptoms, type and range of the intended treatment effect, etc. of the patient.
- 0.01 to 10 mg / kg preferably 0.03 to 1 mg / kg per day for adults is administered in one or several divided doses.
- 0.001 to: L OmgZkg preferably 0.001 to 0.1 mg / kg, is administered in 1 to several divided doses.
- a physician, veterinarian or clinician will readily be able to determine the effective amount of drug required to prevent, counter or arrest the progress of the condition.
- the thin-layer chromatography in the examples was performed using Si1icage160F245 (Merck) as a plate and a UV detector as a detector. Wakoge 1 TM C-300 (Wako Pure Chemical Industries) as the silica gel for the column, and LC—SORBTM S PB-ODS (Chem co) or YMC—GE LTM OD S-AQ 120—S 50 ( Yamamura Chemical Laboratory) was used. Mass spectrometry was measured by Electrospray ionization (ESI) using Quattro II (manufactured by Micromass).
- ESI Electrospray ionization
- CDgOD heavy methanol
- Lithium hydride was added to a solution of 2.31 g (9.4 mm o 1) of 5- (4-methoxyphenyl) -2H-pyrazole-3-carboxylic acid ethyl ester obtained in 30 ml of tetrahydrofuran under ice-cooling.
- 89 Omg (18.8 mmo 1) of aluminum was added, and the reaction solution was stirred for 1 hour under ice cooling. After adding 2N aqueous sodium hydroxide solution to the reaction solution and extracting with ethyl acetate, the organic layer was washed with saturated saline solution. It was.
- Example 3 The compound of Example 3 was obtained by using 4,1-methoxypropiophenone in place of 4,1-methoxyacetophenone, using the same method as in Example 1, a method analogous thereto, or a conventional method. Can be produced by combining
- Example 4 The compound of Example 4 was prepared in the same manner as in Example 1, using the same method as in Example 1, using the same method as in Example 1, or using the same method as in Example 1, except for using 4-methoxyethoxyphenone instead of 4-methoxyethoxyphenone. This was obtained as a colorless oil by combining the above method.
- Example 5 The compound of Example 5 was obtained in the same manner as in Example 1, except that 5-acethydrazide was used instead of 5- (4-methoxyphenyl) -12H-pyrazole-13-carpoanolaldehyde and formylhydrazide obtained in Example 1. It can be produced by a method according to the above, a method according to the method, or a combination of these methods with a conventional method.
- Example 6 The compound of Example 6 was obtained by substituting 5- (4-methoxyethoxy) 1-2H-viazol-3-caprolbuorelehide and 5-formylhydrazide obtained in Example 1 for 5-methylisoxazoluru-3-carbohydrazide.
- Example 1 The compound of Example 6 was obtained by substituting 5- (4-methoxyethoxy) 1-2H-viazol-3-caprolbuorelehide and 5-formylhydrazide obtained in Example 1 for 5-methylisoxazoluru-3-carbohydrazide.
- Example 1 was obtained as a white solid by the same method as in Example 1, a method analogous thereto, or a combination thereof with a conventional method.
- Example 7 The compound of Example 7 was prepared in the same manner as in Example 1 except that benzyl (hydrazide) was used instead of 5- (4-methoxyphenyl) -2H-pyrazole-3-carboanolaldehyde and formylhydrazide obtained in Example 1.
- a white solid was obtained by a method according to this method or a combination of these methods with a conventional method.
- Example 8 3-Methyl- 7 _ phenyl-2-1- [4- (3-piperidine-1 1-ylpropoxy) B) 1-Fe2Lu 3 aH-pyrazo mouth “1, 5-d] [1, 2, 4] triazine
- the compound of Example 8 is 4′-methoxypropionofenone instead of 4, -methoxyacetophenone.
- Example 9 The compound of Example 9 was prepared in the same manner as in Example 1, except that 4′-methoxypropiophenone was used instead of 4, -methoxyacetophenone and nicotinic acid hydrazide was used instead of formyl hydrazide. A white solid was obtained by a method according to this method or a combination of these methods with a conventional method.
- Example 11 The compound of Example 11 was prepared in the same manner as in Example 10 by using 4, -methoxypropiophenone in place of 4, -methoxyacetophenone, a method analogous thereto, or a usual method. This was obtained as a white solid by combining the above method.
- Example 12 The compound of Example 12 was prepared in the same manner as in Example 10, except that 3_chloro-6- (4-methoxyphenyl) -pyridazine and forminolehydrazide obtained in Example 10 were replaced with acetohydrazide.
- a white solid was obtained by a method according to the above or a combination thereof with a conventional method.
- Example 13 The compound of Example 13 was prepared in the same manner as in Example 10 except that trifluorochlorohydrazide was used instead of 3-chloro-6- (4-methoxyphenyl) -pyridazine and forminolehydrazide obtained in Example 10.
- a white solid was obtained by a method according to this method or a combination of these methods with a conventional method.
- Example 14 The compound of Example 14 was prepared by using pinocholic acid hydrazide instead of 3-chloro-1- (4-methoxyenyl) -pyridazine and forminolehydrazide obtained in Example 10. It was obtained as a colorless oil by the same method as in 10, a method according to this method, or a combination of these methods with a conventional method.
- Example 15 The compound of Example 15 was prepared by substituting 3-chloro-6- (4-methoxyphenyl) -pyridazine obtained in Example 10 and benzhydrazide in place of formylhydrazide.
- the compound was obtained as a white solid by the same method as described above, a method analogous thereto, or a combination of these methods with a conventional method.
- Example 16 The compound of Example 16 was prepared by using 2-picolinic acid hydrazide instead of 3-chloro-1- (4-methoxyphenyl) -pyridazine and formylhydrazide obtained in Example 10. It was obtained as a yellow solid by a method similar to 0, a method analogous thereto, or a combination of these methods with a conventional method.
- Example 17 The compound of Example 17 was prepared in the same manner as in Example 10 except that nicotinic acid hydrazide was used instead of 3-chloro-6- (4-methoxyphenyl) monopyridazine and formyl hydrazide obtained in Example 10.
- the compound was obtained as a white solid by the method of, a method analogous thereto, or a combination of these methods with a conventional method.
- Example 18 The compound of Example 18 was obtained by substituting 4,1-methoxypropiophenone in place of 4,1-methoxyacetofonone with 3_chloro-6- (4-methoxyphenyl) obtained in Example 10.
- a yellow oil was obtained by the same method as in Example 10, a method analogous thereto, or a combination thereof with a conventional method using benzhydrazide instead of monopyridazine and formylhydrazide.
- Example 20 The compound of Example 20 was prepared by using acetohydrazide in place of 6-chloro-4- (4-methoxyphenyl) -13-methyl-pyridazine and formylhydrazide obtained in Example 19. It was obtained as a white solid by the same method as described above, a method according to this method, or a combination of these methods with a conventional method.
- Example 21 The compound of Example 21 was obtained by replacing the 6-chloro-4- (4-methoxyphenyl) -13-methyl-pyridazine and formylhydrazide obtained in Example 19 with benzyl Using hydrazide, a method was obtained as a pale yellow solid by a method similar to that of Example 19, a method analogous thereto, or a combination of these methods with a conventional method.
- Example 23 The compound of Example 23 was obtained by replacing the 8-chloro-5- (4-methoxyphenyl) -pyrido [2,3-d] pyridazine and formylhydrazide obtained in Example 22 with Benz A method similar to that of Example 22 using hydrazide, a method similar thereto, or Was obtained as a white individual by combining these with a conventional method.
- Phthalic anhydride 1 In a solution of 4.81 g (0.1 Omo 1) in tetrahydrofuran (200 ml) at 1 78 ° C, 1 M methyl ether solution of 4-methoxyphenylmagnesium bromide 1 0 ml (0.11 mo 1) was added dropwise, and the mixture was stirred at room temperature for one hour. To the reaction solution was added a 1N aqueous hydrochloric acid solution, and the mixture was extracted with a form of ethyl acetate. Then, the organic layer was washed with a saturated aqueous saline solution.
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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US10/589,832 US7645756B2 (en) | 2004-02-18 | 2005-02-17 | Nitrogenous fused heteroaromatic ring derivative |
CA002556404A CA2556404A1 (en) | 2004-02-18 | 2005-02-17 | Nitrogenous fused heteroaromatic ring derivative |
EP05710600A EP1719756A4 (en) | 2004-02-18 | 2005-02-17 | DERIVATIVE NITROGEN OF HETEROAROMATIC CORE FUSIONED |
JP2005518077A JPWO2005077953A1 (ja) | 2004-02-18 | 2005-02-17 | 含窒素縮合ヘテロ芳香環誘導体 |
CN2005800054176A CN1922183B (zh) | 2004-02-18 | 2005-02-17 | 含氮的稠合杂芳环衍生物 |
AU2005212096A AU2005212096B2 (en) | 2004-02-18 | 2005-02-17 | Nitrogenous fused heteroaromatic ring derivative |
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JP2004-042171 | 2004-02-18 | ||
JP2004042171 | 2004-02-18 |
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WO2005077953A1 true WO2005077953A1 (ja) | 2005-08-25 |
Family
ID=34857965
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PCT/JP2005/002948 WO2005077953A1 (ja) | 2004-02-18 | 2005-02-17 | 含窒素縮合へテロ芳香環誘導体 |
Country Status (7)
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US (1) | US7645756B2 (ja) |
EP (1) | EP1719756A4 (ja) |
JP (2) | JPWO2005077953A1 (ja) |
CN (1) | CN1922183B (ja) |
AU (1) | AU2005212096B2 (ja) |
CA (1) | CA2556404A1 (ja) |
WO (1) | WO2005077953A1 (ja) |
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US8198448B2 (en) | 2006-07-14 | 2012-06-12 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
US8212041B2 (en) | 2006-07-14 | 2012-07-03 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
US8217177B2 (en) | 2006-07-14 | 2012-07-10 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
US8324241B2 (en) | 2008-04-11 | 2012-12-04 | Bristol-Myers Squibb Company | Triazolo compounds useful as DGAT1 inhibitors |
US8394823B2 (en) | 2008-04-11 | 2013-03-12 | Bristol-Myers Squibb Company | Triazolopyridine compounds useful as DGAT1 inhibitors |
US8420645B2 (en) | 2008-05-21 | 2013-04-16 | Incyte Corporation | Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
US8487096B2 (en) | 2010-02-03 | 2013-07-16 | Incyte Corporation | Imidazo[1,2-B][1,2,4]triazines as C-MET inhibitors |
WO2017192930A1 (en) * | 2016-05-05 | 2017-11-09 | Lysosomal Therapeutics Inc. | SUBSTITUTED IMIDAZO[1,2-b]PYRIDAZINES, SUBSTITUTED IMIDAZO[1,5-b]PYRIDAZINES, RELATED COMPOUNDS, AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS |
US10570135B2 (en) | 2014-11-06 | 2020-02-25 | Lysosomal Therapeutics Inc. | Substituted pyrazolo[1,5-A]pyrimidines and their use in the treatment of medical disorders |
US10751341B2 (en) | 2014-11-06 | 2020-08-25 | Lysosomal Therapeutics Inc. | Substituted pyrrolo[1,2-a]pyrimidines and their use in the treatment of medical disorders |
US10786508B2 (en) | 2014-11-06 | 2020-09-29 | Lysosomal Therapeutics Inc. | Substituted imidazo[1,5-A]-pyrimidines and their use in the treatment of medical disorders |
US10787454B2 (en) | 2016-04-06 | 2020-09-29 | BIAL—BioTech Investments, Inc. | Imidazo[1,5-a]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders |
US10934298B2 (en) | 2016-04-06 | 2021-03-02 | BIAL—BioTech Investments, Inc. | Substituted pyrazolo[1,5-a]pyrimidines for the treatment of medical disorders |
US11124516B2 (en) | 2016-04-06 | 2021-09-21 | BIAL-BioTech Investments, Inc. | Pyrrolo[1,2-A]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders |
US11345698B2 (en) | 2016-05-05 | 2022-05-31 | Bial—R&D Investments, S.A. | Substituted imidazo[1,2-a]pyridines, substituted imidazo[1,2-a]pyrazines, related compounds, and their use in the treatment of medical disorders |
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US8546394B2 (en) | 2007-04-17 | 2013-10-01 | Bristol-Myers Squibb Company | Substituted [1,2,4]triazolo[4,3-A]pyrazine 11-beta-hydroxysteroid dehydrogenase inhibitors |
US8188083B2 (en) | 2007-06-28 | 2012-05-29 | Abbott Laboratories | Triazolopyridazines |
JP2011507894A (ja) * | 2007-12-19 | 2011-03-10 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | プロリルヒドロキシラーゼ阻害剤 |
EP2318391A1 (en) * | 2008-07-23 | 2011-05-11 | Schering Corporation | Tricyclic heterocycle derivatives as histamine h3 antagonists |
KR20120111739A (ko) | 2009-12-31 | 2012-10-10 | 센트로 내셔널 드 인베스티가시오네스 온콜로지카스 (씨엔아이오) | 키나제 억제제로서의 사용을 위한 삼환식 화합물 |
WO2012098387A1 (en) | 2011-01-18 | 2012-07-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors |
WO2013004984A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncologicas (Cnio) | Tricyclic compounds for use as kinase inhibitors |
WO2013005041A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Tricyclic heterocyclic compounds as kinase inhibitors |
WO2013005057A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | New compounds |
JP6186424B2 (ja) * | 2015-12-28 | 2017-08-23 | ユニ・チャーム株式会社 | 吸収性物品、及び、吸収性物品の製造方法 |
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- 2005-02-17 CA CA002556404A patent/CA2556404A1/en not_active Abandoned
- 2005-02-17 JP JP2005518077A patent/JPWO2005077953A1/ja active Pending
- 2005-02-17 AU AU2005212096A patent/AU2005212096B2/en not_active Ceased
- 2005-02-17 CN CN2005800054176A patent/CN1922183B/zh not_active Expired - Fee Related
- 2005-02-17 WO PCT/JP2005/002948 patent/WO2005077953A1/ja not_active Application Discontinuation
- 2005-02-17 US US10/589,832 patent/US7645756B2/en not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
---|---|
AU2005212096B2 (en) | 2010-12-16 |
EP1719756A4 (en) | 2007-09-26 |
US7645756B2 (en) | 2010-01-12 |
JPWO2005077953A1 (ja) | 2007-10-18 |
EP1719756A1 (en) | 2006-11-08 |
CN1922183B (zh) | 2010-05-26 |
US20070167453A1 (en) | 2007-07-19 |
CN1922183A (zh) | 2007-02-28 |
JP2011178806A (ja) | 2011-09-15 |
CA2556404A1 (en) | 2005-08-25 |
AU2005212096A1 (en) | 2005-08-25 |
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