JP2005097196A - N-type calcium channel inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a compound having N-type calcium channel-inhibiting activities. <P>SOLUTION: This N-type calcium channel inhibitor contains a compound represented by formula (I) or a salt thereof, and a prodrug thereof. The compound of this invention has the N-type calcium channel-inhibiting activities, and therefor is useful as a prophylactic and/or therapeutic agent of a disease associated with the N-type calcium channel, e.g. cerebral infarction, transient ischemic attack, encephalomyelopathy after operation of the heart, vascular disease of spinal cord, stress hypertension, neurosis, epilepsy, asthma, pollakiuria and eye diseases. The compound is also useful as a prophylactic and/or therapeutic agent of pain (e.g. acute pain, chronic pain, postoperative pain, cancer pain, neuralgia and infectious pain). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an N-type calcium channel inhibitor.

  Calcium ions are known as one of intracellular signaling substances, and it is suggested that various physiological functions are expressed by triggering changes in the calcium ion concentration in the cells. A factor that increases the intracellular calcium ion concentration is the inflow of calcium ions from the outside of the cell. One of the inflow entrances is a voltage-gated calcium channel. The voltage-gated calcium channel opens by depolarization of the cell membrane potential and selectively allows extracellular calcium ions to flow according to the electrochemical gradient. Voltage-gated calcium channels are currently classified into N-type, L-type, P / Q-type, R-type, and T-type. Although L-type and T-type calcium channels are present in a wide variety of tissues, it is known that L-type is particularly abundant in smooth muscle and cardiomyocytes. On the other hand, N-type, P / Q-type and R-type calcium channels are mainly present in the nervous system and are involved in the release of various neurotransmitters. This neurotransmitter is normally stored in synaptic vesicles at nerve endings, but when the action potential of nerves is transmitted through presynaptic fibers through information transmission and reaches nerve endings, voltage-dependent calcium channels are activated, Calcium ions flow into the nerve endings. Thereby, synaptic vesicles fuse with the presynaptic membrane and neurotransmitters are released. The released neurotransmitters act on receptors on the postsynaptic membrane and participate in synaptic transmission. From the above, since N-type calcium channel inhibitors are useful for various diseases caused by a large release of neurotransmitters, for example, cerebral infarction (J. Cereb. Blood Flow Metab., 17, 421-429, 1997), transient ischemic attack, cerebrospinal disorder after heart surgery, spinal vascular disorder, stress hypertension (Science, 239, 57-61, 1988), neurosis, epilepsy, asthma (Neuroscience, 34, 1 , 243-250, 1990), frequent urination (Jpn. J. Pharmacol., 71, 161-166, 1996), prevention of eye diseases (glaucoma, diabetic retinopathy, macular degeneration, retinal vascular occlusion, etc.) And / or treatment, or a preventive and / or therapeutic agent for pain (for example, acute pain, chronic pain, postoperative pain, cancer pain, neuralgia, infectious pain, etc.) (Pain, 60, 83-90, 1995 ) Is also considered useful.

  As N-type calcium channel inhibitors, ω-conotoxin GVIIA and ω-conotoxin MVIIA isolated from mussel poison are known.

  However, since these ω-conotoxins are peptide compounds, various problems such as migration into a living body are expected. For this reason, it is desired to make these inhibitors non-peptide, in other words, to reduce the molecular weight.

  Non-patent document 1 discloses a formula (A) known as a cholesterol biosynthesis inhibitor.

It is described that the compound represented by (triparanol) has high affinity for the sigma 1 receptor.

British Journal of Pharmacology, (UK), 1997, 121, p. 1-6

  The development of N-type calcium channel inhibitors with low molecular weight compounds is eagerly desired.

  In view of the above problems, the present inventors have intensively studied. As a result, they found that the compound represented by the general formula (I) achieves the object, and completed the present invention.

That is, the present invention provides (1) general formula (I)

(In the formula, ring A represents an optionally substituted cyclic group, W represents an oxygen atom, an optionally oxidized sulfur atom, or a —NR ⁴ — group, R ⁴ represents a hydrogen atom, Or an alkyl group which may have a substituent, wherein X represents a spacer having 1 to 10 atoms in the main chain, or one of the spacer atoms represented by X is combined with the substituent of ring A; A ring which may have a substituent may be formed, V represents a bond or a spacer having 1 to 3 atoms in the main chain, and Q has a hydrogen atom or a protecting group. Represents an optionally substituted hydroxyl group, a mercapto group optionally having a protecting group, or an amino group optionally having a protecting group, wherein R ¹ represents —OR ⁵ group, —SR ⁵ group, or —NR ⁵ R; represents ^{six, R 5} and ^{R 6} each independently represent a hydrogen atom or a substituent Which may have an alkyl group, or represents a cyclic group which may have a substituent, or R ⁵ and R ⁶ together with the adjacent nitrogen atom, which may have a substituent May form a good nitrogen-containing heterocycle, R ² represents a hydrogen atom or —Y ¹ —Z ¹ group, R ³ represents a hydrogen atom or —Y ² —Z ² group, and Y ¹ and Y ² each independently represents a bond or a spacer having 1 to 10 atoms in the main chain, and Z ¹ and Z ² each independently represent a cyclic group which may have a substituent. , R ² and R ³ are not hydrogen atoms at the same time), a calcium channel inhibitor comprising a compound thereof, a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof,
(2) The agent according to item (1), wherein the calcium channel is N-type,
(3) The agent according to (2) above, which is a preventive and / or therapeutic agent for an N-type calcium channel mediated disease,
(4) The agent according to the above item (2), which is a preventive and / or therapeutic agent for pain,
(5) The agent according to the above item (4), wherein the pain is acute pain, chronic pain, postoperative pain, cancer pain, neuralgia, or infectious pain,
(6) The agent according to the above item (2), wherein the ring A is a monocyclic carbocycle optionally having a substituent,
(7) The agent according to item (6), wherein the monocyclic carbocycle is a benzene ring,
(8) General formula (IA)

(Wherein Q ¹ represents a hydroxyl group which may have a protecting group, ring A ¹ represents a monocyclic carbocycle which may have a substituent, and other symbols are as defined in claim 1. The same meaning)), the agent according to item (2),
(9) The agent according to the above item (2), further comprising one or more selected from opioid receptor agonists and non-steroidal anti-inflammatory drugs,
(10) A method for preventing and / or treating a calcium channel-mediated disease in a mammal, which comprises administering an effective amount of the compound or a salt thereof, or a prodrug thereof according to (1) above to the mammal,
(11) Use of the compound of the preceding item (1) or a salt thereof, or a prodrug thereof for producing a preventive and / or therapeutic agent for a calcium channel-mediated disease, and (12) General formula (I)

(In the formula, ring A represents an optionally substituted cyclic group, W represents an oxygen atom, an optionally oxidized sulfur atom, or a —NR ⁴ — group, R ⁴ represents a hydrogen atom, Or an alkyl group which may have a substituent, wherein X represents a spacer having 1 to 10 atoms in the main chain, or one of the spacer atoms represented by X is combined with the substituent of ring A; A ring which may have a substituent may be formed, V represents a bond or a spacer having 1 to 3 atoms in the main chain, and Q has a hydrogen atom or a protecting group. Represents an optionally substituted hydroxyl group, a mercapto group optionally having a protecting group, or an amino group optionally having a protecting group, wherein R ¹ represents —OR ⁵ group, —SR ⁵ group, or —NR ⁵ R; represents ^{six, R 5} and ^{R 6} each independently represent a hydrogen atom or a substituent Which may have an alkyl group, or represents a cyclic group which may have a substituent, or R ⁵ and R ⁶ together with the adjacent nitrogen atom, which may have a substituent May form a good nitrogen-containing heterocycle, R ² represents a hydrogen atom or —Y ¹ —Z ¹ group, R ³ represents a hydrogen atom or —Y ² —Z ² group, and Y ¹ and Y ² each independently represents a bond or a spacer having 1 to 10 atoms in the main chain, and Z ¹ and Z ² each independently represent a cyclic group which may have a substituent. , R ² and R ³ are not simultaneously hydrogen atoms and not 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol. ), Its salts, N- oxide thereof or a solvate thereof, or prodrugs thereof.

  Examples of the cyclic group in the “cyclic group optionally having substituent (s)” represented by ring A include carbocycle and heterocycle.

  The carbocycle includes, for example, a C3-15 monocyclic, bicyclic or tricyclic aromatic carbocyclic ring, a carbocyclic ring partially or wholly saturated, a spiro-bonded bicyclic carbocyclic ring, and Examples thereof include a bridged bicyclic carbocycle. Examples of the C3-15 monocyclic, bicyclic or tricyclic aromatic carbocyclic ring, and a carbocyclic ring partially or completely saturated include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclo Octane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridodecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, par Hydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, hepta Emissions, perhydro hept, biphenylene, as-indacene, s- indacene, acenaphthylene, acenaphthene, fluorene, phenalene, phenanthrene, anthracene ring, and the like. Examples of the spiro-bonded bicyclic carbocycle and the bridged bicyclic carbocycle include, for example, spiro [4.4] nonane, spiro [4.5] decane, spiro [5.5] undecane, and bicyclo [2. 2.1] heptane, bicyclo [2.2.1] hept-2-ene, bicyclo [3.1.1] heptane, bicyclo [3.1.1] hept-2-ene, bicyclo [2.2. 2] Octane, bicyclo [2.2.2] oct-2-ene, adamantane, noradamantane ring and the like.

  As the heterocyclic ring, for example, a 3 to 15 membered monocyclic ring containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and / or a sulfur atom, which may be partially or fully saturated, Bicyclic or tricyclic aromatic heterocycles, spiro-bonded bicyclic heterocycles, bridged bicyclic heterocycles and the like can be mentioned. 3 to 15-membered monocyclic, bicyclic or tricyclic aromatic, which contains 1 to 5 heteroatoms selected from the oxygen atom, nitrogen atom and sulfur atom, and may be partially or fully saturated Examples of the heterocyclic ring and the spiro-linked bicyclic heterocyclic ring and the bridged bicyclic heterocyclic ring include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, Pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoin , Indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, pyrrolopyridine, benzoxazole, Benzothiazole, thieno [3,2-c] pyridine, benzimidazole, chromene, benzoxepin, benzoxazepine, benzoxiazepine, benzothiepine, benzothiazepine, benzothiazepine, benzoazepine, benzodiazepine, benzofurazan, benzothiadiazole , Benzotriazole, carbazole, β-carboline, acridine, phenazine, dibenzofuran, xanthene, dibenzothiophene Phenothiazine, phenoxazine, phenoxathiin, thianthrene, phenanthridine, phenanthroline, perimidine, pyridonaphthyridine, pyrazoloisoquinoline, pyrazolonaphthyridine, pyrimidoindole, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, Triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, Tetrahydroazepine, perhydroazepine, dihydro Azepine, tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, thiirane, thietane, dihydrothiophene, tetrahydro Thiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole ( Thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), di Drofurazan, Tetrahydrofurazan, Dihydrooxadiazole, Tetrahydrooxadiazole (oxadiazolidine), Dihydrooxazine, Tetrahydrooxazine, Dihydrooxadiazine, Tetrahydrooxadiazine, Dihydrooxazepine, Tetrahydrooxazepine, Perhydrooxase Pin, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine , Tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiazepine , Morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, Dihydroindazole, Perhydroindazole, Dihydroquinoline, Tetrahydroquinoline, Octahydroquinoline, Perhydroquinoline, Dihydroisoquinoline, Tetrahydroisoquinoline, Octahydroisoquinoline, Perhydroisoquinoline, Dihydrophthalazine, Tetrahydrophthalazine, Perhydrophthalazine, Dihydronaphthyridine , Tetrahydronaphthyridine, perhydronaphthyridine, dihydroquino Sarin, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, tetrahydropyrrolopyridine, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyra Dinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, 4,5,6,7-tetrahydrothieno [3,2-c] pyridine, dihydrobenzimidazole, perhydrobenzimidazole, dihydro Benzoazepine, tetrahydrobenzoazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, benzodioxepane, Hydrobenzoxazepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, Perhydrodibenzothiophene, tetrapyridonaphthyridine, tetrahydro-β-carboline, dihydroazepinoindole, hexahydroazepinoindole, tetrahydropyrazoloisoquinoline, tetrahydropyrazolonaphthyridine, dihydroazepinoindazole, hexahydroazepinoindazole, dihydropyra Zolopyridazepine, hexahydropyrazolopi Adoazepine, tetrahydropyrimidoindole, dihydrothiazinoindole, tetrahydrothiazinoindole, dihydrooxazinoindole, tetrahydrooxazinoindole, 2,3-dihydro-1H-benzo [de] isoquinoline, dioxolane, dioxane, dithiolane, dithiane, dioxaindane , Benzodioxane, chroman, benzodithiolane, benzodithiane, azaspiro [4.4] nonane, oxazaspiro [4.4] nonane, oxaazaspiro [2.5] octane, dioxaspiro [4.4] nonane, azaspiro [4.5] decane , Thiaspiro [4.5] decane, dithiaspiro [4.5] decane, dioxaspiro [4.5] decane, oxazaspiro [4.5] decane, azaspiro [5.5] undecane, oxaspiro [5.5 Undecane, dioxaspiro [5.5] undecane, 1,4-dioxa-8-azaspiro [4.5] decane, 1,3,8-triazaspiro [4.5] decane, azabicyclo [2.2.1] heptane, Oxabicyclo [2.2.1] heptane, azabicyclo [3.1.1] heptane, azabicyclo [3.2.1] octane, oxabicyclo [3.2.1] octane, azabicyclo [2.2.2] Examples include octane, diazabicyclo [2.2.2] octane, and 2,5-diazabicyclo [2.2.1] heptane ring.

In this specification, examples of the substituent in the “optionally substituted cyclic group” represented by ring A include (1) an optionally substituted alkyl group, and (2) a substituent. An alkenyl group optionally having (3) an alkynyl group optionally having a substituent, (4) a carbocyclic group optionally having a substituent, and (5) a substituent. An optionally substituted heterocyclic group, (6) a hydroxyl group optionally having a protecting group, (7) a mercapto group optionally having a protecting group, and (8) an amino group optionally having a protecting group. (9) an optionally substituted carbamoyl group, (10) an optionally substituted sulfamoyl group, (11) a carboxyl group, (12) an alkoxycarbonyl group (for example, methoxycarbonyl, ethoxy C1-6 alkyl such as carbonyl, tert-butoxycarbonyl and the like Alkoxycarbonyl group, etc.), (13) a sulfo group _(-SO 3 H), (14) sulfino group, (15) phosphono group, (16) a nitro group, (17) cyano group, (18) amidino group, (19 ) Imino group, (20) -B (OH) ₂ group, (21) halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (22) alkylsulfinyl group (for example, C1 such as methylsulfinyl, ethylsulfinyl, etc.) -6 alkylsulfinyl groups, etc.), (23) aromatic sulfinyl groups (eg, C6-10 aromatic ring sulfinyl groups such as phenylsulfinyl), (24) alkylsulfonyl groups (eg, C1- 6 alkylsulfonyl group, etc.), (25) aromatic ring sulfonyl group (for example, C6-10 aromatic ring sulfo group such as phenylsulfonyl) Nyl group etc.), (26) oxo group, (27) thioxo group, (28) (C1-6 alkoxyimino) methyl group (eg (methoxyimino) methyl group etc.), (29) acyl group, (30) formyl A group, (31) an alkyl group substituted with a hydroxyl group optionally having a protecting group, (32) an alkyl group substituted with a mercapto group optionally having a protecting group, and (33) having a protecting group. And an alkyl group substituted with an amino group which may optionally be substituted, (34) (alkyl which may have a substituent) oxycarbonyl group and the like. Or 5 may be substituted.

  Examples of the alkyl group in “(1) an optionally substituted alkyl group” as a substituent include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. And linear or branched C1-6 alkyl groups such as pentyl and hexyl groups. Here, examples of the substituent of the alkyl group include a hydroxyl group, a mercapto group, an amino group, a carboxyl group, a nitro group, a cyano group, a mono- or di-C1-6 alkylamino group (for example, methylamino, ethylamino, propylamino, Dimethylamino, diethylamino, etc.), N-aromatic ring amino group (eg, N-phenylamino group), N-aromatic ring-N-alkylamino group (eg, N-phenyl-N-methylamino group, N-phenyl-N) -Ethylamino group, N-phenyl-N-propylamino group, N-phenyl-N-butylamino group, N-phenyl-N-pentylamino group, N-phenyl-N-hexylamino group, etc.), acylamino group, N-acyl-N-alkylamino group, C1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy Hexyloxy etc.), C3-7 cycloalkyl-C1-6 alkoxy group (eg cyclohexylmethyloxy group, cyclopentylethyloxy group etc.), C3-7 cycloalkyloxy group (eg cyclohexyloxy group etc.), C7-15 aralkyloxy. Groups (for example, benzyloxy, phenethyloxy, phenylpropyloxy, naphthylmethyloxy, naphthylethyloxy, etc.), phenoxy groups, C1-6 alkoxycarbonyl groups (for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), C1- 6 alkylcarbonyloxy groups (eg acetoxy, ethylcarbonyloxy etc.), C 1-6 alkylthio groups (eg methylthio, ethylthio, propylthio, butylthio etc.), halogen atoms (eg fluorine , Chlorine, bromine, iodine, etc.), alkylsulfonyl groups (eg, C1-4 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, etc.), aromatic ring sulfonyl groups (eg, C6-10 aromatic ring sulfonyl groups such as phenylsulfonyl, etc.) ), An optionally substituted carbamoyl group (for example, unsubstituted carbamoyl group, N-mono-C 1-6 alkylcarbamoyl (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N- Isopropylcarbamoyl, N-butylcarbamoyl, etc.), N, N-diC1-6 alkylcarbamoyl (for example, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibuty) Rucarbamoyl, etc.), piperidin-1-ylcarbonyl Group), an acyl group, a carbocyclic group which may have a substituent, a heterocyclic group which may have a substituent, and the like. 1 to 4 may be substituted. Here, as the alkyl group in the N-acyl-N-alkylamino group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl groups, etc. Examples thereof include a linear or branched C1-6 alkyl group. The acyl group in the acylamino group and the N-acyl-N-alkylamino group has the same meaning as “(29) acyl group” as a substituent described later. Further, the carbocyclic group which may have a substituent and the heterocyclic group which may have a substituent are described later in “(4) carbocyclic group which may have a substituent”, And “(5) heterocyclic group optionally having substituent (s)”.

  Examples of the alkenyl group in the “(2) optionally substituted alkenyl group” as a substituent include linear or branched C 2-6 alkenyl such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like. Groups and the like. Here, the substituent of the alkenyl group has the same meaning as the substituent in “(1) an alkyl group which may have a substituent” as the substituent.

  Examples of the alkynyl group in the “(3) optionally substituted alkynyl group” as a substituent include linear or branched C 2-6 alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Groups and the like. Here, the substituent of the alkynyl group has the same meaning as the substituent in “(1) an alkyl group which may have a substituent” as the substituent.

  The carbocyclic group in “(4) optionally substituted carbocyclic group” as the substituent is the “cyclic group” in the “optionally substituted cyclic group” represented by ring A above. The same meaning as the carbocyclic ring in Here, as the substituent of the carbocyclic group, for example, a linear or branched C1-6 alkyl group optionally substituted with a hydroxyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl, pentyl, hexyl group, etc.), linear or branched C2-6 alkenyl group (eg ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc.), linear or branched chain C2-6 alkynyl group (for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.), hydroxyl group, linear or branched C1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, Isobutyloxy, tert-butoxy, pentyloxy, hexyloxy, etc.), mercapto A linear or branched C1-6 alkylthio group (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, hexylthio, etc.), amino group, mono- or di-C1 -6 alkylamino groups (eg methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, N-methyl-N -Ethylamino etc.), halogen atom (eg fluorine, chlorine, bromine, iodine etc.), cyano group, nitro group, carboxyl group, linear or branched C1-6 alkoxycarbonyl group (eg methoxycarbonyl, ethoxy) Carbonyl, tert-butoxycarbonyl etc.), trihalomethyl group (eg trifluoromethyl etc.), trihalomethoxy group (eg trifluoromethoxy etc.), trihalomethylthio group (eg trifluoromethylthio etc.), dihalomethylthio group (eg difluoromethylthio) Etc.), a cyano group, a nitro group, an oxo group, a carbocyclic ring (which has the same meaning as the carbocyclic ring in the “cyclic group” in the “cyclic group optionally having substituents” represented by the ring A), A heterocyclic ring (having the same meaning as the heterocyclic ring in the “cyclic group” in the “cyclic group optionally having substituents” represented by the ring A), etc., and these optional substituents are substituted 1 to 4 may be substituted at possible positions.

  The heterocyclic group in “(5) optionally substituted heterocyclic group” as a substituent is the “cyclic group” in the “optionally substituted cyclic group” represented by ring A above. The same meaning as the heterocyclic ring in Here, the substituent of the heterocyclic group has the same meaning as the substituent in the “(4) optionally substituted carbocyclic group”.

  “(6) hydroxyl group optionally having protecting group”, “(7) mercapto group optionally having protecting group” and “(8) protecting group as a substituent” Examples of the protecting group in the “amino group” include an alkyl group which may have a substituent (having the same meaning as the above-mentioned “(1) alkyl group which may have a substituent”), a substituent. An alkenyl group which may have (which has the same meaning as the above-mentioned “(2) alkenyl group which may have a substituent”), an alkynyl group which may have a substituent (the above “(3 ) Represents the same meaning as “optionally substituted alkynyl group”), optionally substituted carbocyclic group (the above-mentioned “(4) optionally substituted carbocyclic ring”). The same meaning as “group”), a heterocyclic group optionally having a substituent (the above-mentioned “(5) substitution”). And a heterocyclic group optionally having an alkyl group), an alkylsulfonyl group (for example, a C1-4 alkylsulfonyl group such as methylsulfonyl or ethylsulfonyl), an aromatic ring sulfonyl group (for example, phenylsulfonyl). C6-10 aromatic ring sulfonyl group and the like), acyl group (which has the same meaning as “(29) acyl group” described later), and (optionally substituted alkyl) oxycarbonyl group (described later). “(34) (which may have a substituent, an alkyl) oxycarbonyl group” has the same meaning).

  Examples of the “(9) optionally substituted carbamoyl group” as a substituent include an unsubstituted carbamoyl group, N-mono-C 1-6 alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethyl). Carbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, etc.), N, N-diC1-6 alkylcarbamoyl (for example, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N- Dipropylcarbamoyl, N, N-dibutylcarbamoyl, etc.), piperidin-1-ylcarbonyl group and the like.

  Examples of the “(10) optionally substituted sulfamoyl group” as the substituent include an unsubstituted sulfamoyl group, N-mono-C 1-6 alkylsulfamoyl (for example, N-methylsulfamoyl). N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), N, N-diC1-6 alkylsulfamoyl (for example, N, N- Dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.).

  As the “(29) acyl group” as a substituent, for example, an alkylcarbonyl group which may have a substituent (in the group, an alkyl which may have a substituent represents the above-mentioned “(1) substituent”. The same meaning as “optionally substituted alkyl group” represents an alkenylcarbonyl group which may have a substituent (in the group, the alkenyl which may have a substituent is the above-mentioned “(2) substitution”). The same meaning as “optionally substituted alkenyl group” and an optionally substituted alkynylcarbonyl group (in which the optionally substituted alkynyl is the above-mentioned “(3 ) Represents an alkynyl group optionally having substituent (s)), and a carbocyclic carbonyl group optionally having substituent (s). “(4) optionally substituted carbocyclic group” and A heterocyclic carbonyl group which may have a substituent (in the group, the heterocyclic ring which may have a substituent may have the above-mentioned (5) substituent). And the same meaning as “heterocyclic group”.

  The hydroxyl group optionally having a protecting group in the “(31) alkyl group substituted with a hydroxyl group optionally having a protecting group” as a substituent has the above-mentioned “(6) protecting group”. The mercapto group optionally having a protecting group in “(32) an alkyl group substituted with a mercapto group optionally having a protecting group” has the same meaning as “may be a hydroxyl group”. ) Represents a mercapto group optionally having a protecting group ", and may have a protecting group in" (33) an alkyl group substituted with an amino group optionally having a protecting group ". A good amino group has the same meaning as the above “(8) amino group optionally having a protecting group”. Further, “(31) an alkyl group substituted with a hydroxyl group optionally having a protecting group”, “(32) an alkyl group substituted with a mercapto group optionally having a protecting group” and “(33 Examples of the alkyl group in “) an alkyl group substituted with an amino group optionally having a protecting group” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Examples thereof include linear or branched C1-6 alkyl groups such as pentyl and hexyl groups.

  The alkyl which may have a substituent in “(34) (alkyl which may have a substituent) oxycarbonyl group” as a substituent may have the above-mentioned “(1) substituent”. It represents the same meaning as “good alkyl group”.

The optionally oxidized sulfur atom represented by W, for example -S -, - SO- and -SO 2 _- group, and the like.

The alkyl group which may have a substituent represented by R ⁴ is the “(1) substituent as a substituent in the“ cyclic group which may have a substituent ”represented by the ring A. It represents the same meaning as the “alkyl group which may be present”.

  The “spacer having 1 to 10 main chain atoms” represented by X means an interval in which 1 to 10 main chain atoms are connected. Here, the “number of atoms in the main chain” is counted so that the number of atoms in the main chain is minimized. Examples of the “spacer having 1 to 10 atoms in the main chain” represented by X include a linear or branched C1-10 alkylene group which may have a substituent, and a substituent. And a linear or branched C2-10 alkenylene group, a linear or branched C2-10 alkynylene group which may have a substituent, and the like. Examples of the linear or branched C1-10 alkylene group include methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene and decylene. Examples of the linear or branched C2-10 alkenylene group include ethenylene, propenylene, butenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, heptenylene, heptadienylene, octenylene, octadenylene, nonenylene, nonadenylene, nonadenylene, Is mentioned. Examples of the linear or branched C2-10 alkynylene group include ethynylene, propynylene, butynylene, butadiynylene, pentynylene, pentadiinylene, hexynylene, hexadiinylene, heptynylene, heptadinylene, octynylene, octadiynylene, nonidylene, nonenidylene, Is mentioned. Moreover, the linear or branched C1-10 alkylene group which may have a substituent, the linear or branched C2-10 alkenylene group which may have a substituent, a substituent The substituent of the linear or branched C2-10 alkynylene group optionally having the same meaning as the substituent in the “cyclic group optionally having substituent (s)” represented by ring A above These optional substituents may be substituted at 1 to 5 substitutable positions.

  The “optionally substituted ring” represented by one spacer atom represented by X together with the substituent of ring A is one spacer atom, one of the substituents of ring A, and W is a “heterocycle optionally having substituent (s)” represented by W together. The heterocyclic ring has the same meaning as the above “(5) heterocyclic group optionally having substituent (s)”.

  The “spacer having 1 to 3 main chain atoms” represented by V means an interval in which 1 to 3 main chain atoms are connected. Here, the “number of atoms in the main chain” is counted so that the number of atoms in the main chain is minimized. Examples of the “spacer having 1 to 3 atoms in the main chain” represented by X include a linear or branched C1-3 alkylene group which may have a substituent, and a substituent. And a linear or branched C2-3 alkenylene group, a linear or branched C2-3 alkynylene group which may have a substituent, and the like. Examples of the linear or branched C1-3 alkylene group include methylene, ethylene, and propylene groups. Examples of the linear or branched C2-10 alkenylene group include ethenylene and propenylene groups. Examples of the linear or branched C2-10 alkynylene group include ethynylene and propynylene groups. Moreover, the linear or branched C1-3 alkylene group which may have a substituent, the linear or branched C2-3 alkenylene group which may have a substituent, a substituent The substituent of the linear or branched C2-3 alkynylene group optionally having the same meaning as the substituent in the “cyclic group optionally having substituent (s)” represented by ring A above 1 to 2 of these optional substituents may be substituted at substitutable positions.

The “alkyl group optionally having substituent (s)” represented by R ⁵ and R ⁶ has the same meaning as the above “(1) alkyl group optionally having substituent (s)”.

The “cyclic group optionally having substituent (s)” represented by R ⁵ and R ⁶ has the same meaning as the “cyclic group optionally having substituent (s)” represented by the ring A.

Examples of the “nitrogen-containing heterocycle” represented by R ⁵ and R ⁶ together with the adjacent nitrogen atom include, for example, 0 containing at least one nitrogen atom and further selected from an oxygen atom, a nitrogen atom and a sulfur atom Or 3 to 15-membered monocyclic, bicyclic or tricyclic aromatic heterocycles containing 1 to 4 heteroatoms, which may be partially or fully saturated. 3 to 15 members which are partially or fully saturated, containing at least one nitrogen atom and further containing 0 or 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms Examples of the monocyclic, bicyclic or tricyclic aromatic heterocycle include pyrrole, imidazole, triazole, tetrazole, pyrazole, indole, isoindole, indazole, purine, pyrrolopyridine, benzimidazole, benzoazepine, benzodiazepine, benzo Triazole, carbazole, β-carboline, phenothiazine, phenoxazine, perimidine, pyrazoloisoquinoline, pyrazolonaphthyridine, pyrimidoindole, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolyl , Tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine Perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, tetrahydrooxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), Dihydrofurazan, tetrahydrofuran Zan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, perhydrooxazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, Tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, perhydrothiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, indoline, isoindoline, dihydroindazole Perhydroindazole, dihydroquinoline, tetrahydroquinoline, octahydroquinoline, perhydroquinoline, dihydroisoquinoline, Trahydroisoquinoline, octahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline , Perhydroquinazoline, tetrahydropyrrolopyridine, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydro Benzothiazole, 4,5,6,7-tetrahydrothieno "3 2-c "pyridine, dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzazepine, tetrahydrobenzoazepine, dihydrobenzodiazepine, tetrahydrobenzodiazepine, tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, perhydro Acridine, tetrapyridonaphthyridine, tetrahydro-β-carboline, dihydroazepinoindole, hexahydroazepinoindole, tetrahydropyrazoloisoquinoline, tetrahydropyrazolonaphthyridine, dihydroazepinoindazole, hexahydroazepinoindazole, dihydropyrazolopyrido Azepine, hexahydropyrazolopyridazepine, tetrahydropyrimido Ndole, dihydrothiazinoindole, tetrahydrothiazinoindole, dihydrooxazinoindole, tetrahydrooxazinoindole, 2,3-dihydro-1H-benzo [de] isoquinoline, azaspiro [4.4] nonane, oxazaspiro [4.4] Nonane, oxaazaspiro [2.5] octane, azaspiro [4.5] decane, oxazaspiro [4.5] decane, azaspiro [5.5] undecane, 1,4-dioxa-8-azaspiro [4.5] decane, 1,3,8-triazaspiro “4.5” decane, azabicyclo [2.2.1] heptane, azabicyclo [3.1.1] heptane, azabicyclo [3.2.1] octane, 2,5-diazabicyclo [ 2.2.1] heptane ring and the like.

  The “hydroxyl group optionally having a protecting group” represented by Q represents the same meaning as the above “(6) hydroxyl group optionally having a protecting group”.

  The “mercapto group optionally having a protecting group” represented by Q represents the same meaning as the “(7) mercapto group optionally having a protecting group”.

  The “amino group optionally having a protecting group” represented by Q represents the same meaning as the “(8) amino group optionally having a protecting group”.

The “spacer having 1 to 10 atoms in the main chain” represented by Y ¹ and Y ² has the same meaning as the “spacer having 1 to 10 atoms in the main chain” represented by X.

The “cyclic group optionally having substituent (s)” represented by Z ¹ and Z ² has the same meaning as the “cyclic group optionally having substituent (s)” represented by the ring A.

Examples of the monocyclic carbocyclic ring represented by ring A ^1, for example, monocyclic aromatic carbocyclic ring of C3-15, partially or entirely and carbon ring, which is saturated. Examples of the carbocycle include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridodecane, cyclotetradecane, cyclopentadecane, cyclopentene, cyclohexene, cycloheptene, cyclohexane Examples include octene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, and a benzene ring.

  In the present invention, all isomers are included unless otherwise specified. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene, alkynylene include straight chain and branched chain. Furthermore, isomers (E, Z, cis, trans isomers) in double bonds, rings, condensed rings, isomers due to the presence of asymmetric carbon, etc. (R, S isomers, α, β configuration, enantiomers, diastereomers) , Optically active substances having optical activity (D, L, d, l form), polar bodies (high polar bodies, low polar bodies) by chromatographic separation, equilibrium compounds, rotamers, mixtures of these in any proportions, All racemic mixtures are included in the present invention.

  In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

Indicates that it is connected to the other side of the page (ie α configuration),

Indicates that it is connected to the front side of the paper (that is, β arrangement),

Represents α configuration, β configuration or a mixture thereof,

Represents a mixture of α configuration and β configuration.

  Salts of the compounds represented by the general formula (I) include all pharmacologically acceptable salts. The pharmacologically acceptable salt is preferably non-toxic and water-soluble. Examples of suitable salts of the compound represented by the general formula (I) include salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts (tetramethylammonium salts, Tetrabutylammonium salts, etc.), organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl- Salt of D-glucamine, etc., acid adduct salt (inorganic acid salt (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salt (acetate, Trifluoroacetate, lactate, tartrate, oxalate, fumaric acid Maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate, etc.)) It is done. The salt of the compound of the present invention includes a solvate or a solvate of an alkali (earth) metal salt, ammonium salt, organic amine salt or acid adduct salt of the compound of the present invention. The solvate is preferably non-toxic and water-soluble. Examples of suitable solvates include solvates such as water and alcohol solvents (ethanol and the like). The compound of the present invention is converted into a pharmacologically acceptable salt by a known method.

Further, the salt includes a quaternary ammonium salt. The quaternary ammonium salts, nitrogen atoms of the compound represented by formula (I), R ⁰ group (R ⁰ group represents a C1~8 alkyl group substituted C1~8 alkyl group, by a phenyl group. ) Represents a quaternized product.

  The salt also includes N-oxide. The compound of the present invention can be converted to N-oxide by any method. N-oxide represents an oxidized nitrogen atom of the compound represented by formula (I).

The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body. As a prodrug of the compound represented by the general formula (I), for example, when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example, The amino group of the compound represented by the general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated. , Pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated compounds, etc.); when the compound represented by the general formula (I) has a hydroxyl group, the hydroxyl group is acylated and alkylated , Phosphorylated and borated compounds (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoyl , Propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylated compound, etc.); when the compound represented by the general formula (I) has a carboxy group, the carboxy group is esterified, Amidated compounds (for example, the carboxy group of the compound represented by the general formula (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyl Oxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.) It is done. These compounds can be produced by a method known per se. The prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate. In addition, the prodrug of the compound represented by the general formula (I) has a general formula under physiological conditions as described in Yodogawa Shoten 1990, “Drug Development”, Vol. 7, “Molecular Design”, pages 163-198. It may be changed to the compound represented by (I). Furthermore, the compound represented by the general formula (I) may be labeled with an isotope (for example, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I and the like).

In the general formula (I) of the present invention, each of the definitions represented by the rings A, W, X, V, Q, R ¹ , R ² , R ^{3 and the} like is preferable. Preferred groups and preferred rings are listed below, but all symbols used herein have the same meaning as described above.

  The “cyclic group” in the “cyclic group optionally having substituent (s)” represented by ring A is preferably, for example, a carbocycle, a heterocycle, etc., more preferably a C3-15 monocyclic, bicyclic or A tricyclic aromatic carbocycle, or a carbocycle in which part or all thereof is saturated, containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and / or a sulfur atom, or A 3- to 15-membered monocyclic, bicyclic or tricyclic aromatic heterocyclic ring which may be all saturated, particularly preferably a C3-10 monocyclic or bicyclic aromatic carbocyclic ring, Or a part or all of which includes one or two heteroatoms selected from a carbocycle, oxygen atom, nitrogen atom and / or sulfur atom, which is partially or fully saturated, may be saturated 3 10-membered monocyclic or bicyclic aromatic heterocycle It is equal, especially preferably benzene, a pyridine ring or the like.

W is preferably, for example, an oxygen atom, a sulfur atom that may be oxidized, a —NR ⁴ — group, or the like, and more preferably, for example, an oxygen atom.

  X is preferably a spacer of 1 to 8 atoms in the main chain, more preferably a spacer of 2 to 6, particularly preferably a spacer of 2 to 4, particularly preferably, for example, ethylene or propylene , Butylene and the like.

  The ring represented by one of the main chain atoms of the spacer represented by X together with the substituent of ring A preferably contains 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom and / or a sulfur atom A 3 to 10-membered monocyclic aromatic heterocyclic ring which may be partially or fully saturated. Particularly preferred are compounds represented by the following general formula (IB) and general formula (IC).

In the above formula, the wavy line represents a bond or a single bond, and X ¹ represents the same meaning as X, but a spacer having one less main chain atom, that is, a main chain atom number 1 to 9 spacer. And other symbols have the same meaning as described above.

  V is preferably a bond or a spacer having 1 to 3 atoms in the main chain, and more preferably a bond or 1 spacer in the main chain.

R ¹ is preferably an —OR ⁵ group, an —SR ⁵ group, an —NR ⁵ R ⁶ group or the like, and more preferably an —NR ⁵ R ⁶ group or the like.

  Q is preferably, for example, a hydrogen atom, a hydroxyl group optionally having a protecting group, and more preferably a hydroxyl group optionally having a protecting group.

R ² is preferably a —Y ¹ —Z ¹ group or the like.

R ³ is preferably a —Y ² —Z ² group or the like.

Y ¹ and Y ² are preferably, for example, a bond or a spacer having 1 to 10 atoms in the main chain, more preferably a bond or a spacer having 1 to 5 atoms in the main chain, and particularly preferably a bond. Or a spacer having 1 to 3 atoms in the main chain.

The “cyclic group” in the “cyclic group optionally having substituent (s)” represented by Z ¹ and Z ² is preferably, for example, a carbocycle, a heterocycle, etc., more preferably a C3-15 monocycle, Containing 1 to 5 heteroatoms selected from a bicyclic or tricyclic aromatic carbocycle, or a carbocycle in which part or all thereof is saturated, an oxygen atom, a nitrogen atom and / or a sulfur atom, 3 to 15-membered monocyclic, bicyclic or tricyclic aromatic heterocycles which may be partially or fully saturated, particularly preferably C3-10 monocyclic or bicyclic aromatic A carbocycle, or a carbocycle in which part or all of it is saturated, including one or two heteroatoms selected from an oxygen atom, a nitrogen atom and / or a sulfur atom; 3-10 membered monocyclic or bicyclic An aromatic heterocyclic ring such as, especially preferably benzene, a pyridine ring or the like.

  In the present invention, the compounds of the general formula (I) containing the preferred groups and preferred ring combinations listed above are preferred.

Specific preferred compounds of the present invention include, for example, the compounds shown in the following (1) to (205), the compounds described in the examples or salts thereof.
(1) 2- (4-Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, (2) 2- (4-chlorophenyl) -1- {4- [3- (diethylamino) propoxy] phenyl} -1- (4-methylphenyl) ethanol, (3) 2- (4-chlorophenyl) -1- {4- [4- (diethylamino) butoxy] phenyl} -1- (4-methylphenyl) ethanol, (4) 2- (4-chlorophenyl) -1- {4- [2- (ethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, ( 5) 2- (4-Chlorophenyl) -1- [4- (2-methoxyethoxy) phenyl] -1- (4-methylphenyl) ethanol, (6) 2- (4-Chlorophenyl) -1 (4-methylphenyl) -1- {4- [2- (methylsulfanyl) ethoxy] phenyl} ethanol, (7) 1- [4- (2-anilinoethoxy) phenyl] -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (8) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- [4- (2-piperidin-1-ylethoxy) phenyl] ethanol, ( 9) 2- (4-Chlorophenyl) -1- (4- {2- [4- (2-hydroxyethyl) piperazin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (10 ) 1- [4- (2-Azepan-1-ylethoxy) phenyl] -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (11) 2- (4-chloropheny) ) -1- {4- [2- (4-Ethylpiperazin-1-yl) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, (12) 2- (4-chlorophenyl) -1- (4 -Methylphenyl) -1- [4- (2-morpholin-4-ylethoxy) phenyl] ethanol, (13) 1- {4- [2- (4-benzylpiperazin-1-yl) ethoxy] phenyl} -2 -(4-Chlorophenyl) -1- (4-methylphenyl) ethanol, (14) 1- {4- [2- (4-Benzhydrylpiperazin-1-yl) ethoxy] phenyl} -2- (4- Chlorophenyl) -1- (4-methylphenyl) ethanol, (15) 2- (4-chlorophenyl) -1- {4- [2- (3,4-dihydroquinolin-1 (2H) -yl) ethoxy] phenyl } -1- (4-methylphenyl) ethanol, (16) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- {4- [2- (4-phenylpiperazin-1-yl) ethoxy ] Phenyl} ethanol, (17) 2- (4-chlorophenyl) -1- {4- [2- (3,4-dihydroisoquinolin-2 (1H) -yl) ethoxy] phenyl} -1- (4-methyl Phenyl) ethanol, (18) 2- (4-chlorophenyl) -1- {4- [2- (4-methyl-1,4-diazepan-1-yl) ethoxy] phenyl} -1- (4-methylphenyl) ) Ethanol, (19) 2- (4-chlorophenyl) -1- {4- [2- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) ethoxy] phenyl} -1- (4-methylphenyl) Tanol, (20) 2- (4-Chlorophenyl) -1- (4-methylphenyl) -1- (4- {2- [4- (2-morpholin-4-ylethyl) piperazin-1-yl] ethoxy} Phenyl) ethanol, (21) 2- (4-chlorophenyl) -1- [4- (2- {4- [2- (2-hydroxyethoxy) ethyl] piperazin-1-yl} ethoxy) phenyl] -1- (4-methylphenyl) ethanol, (22) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- {4- [2- (4-pyrazin-2-ylpiperazin-1-yl) Ethoxy] phenyl} ethanol, (23) 2- (4-chlorophenyl) -1- (4- {2- [4- (2-methoxyethyl) piperazin-1-yl] ethoxy} phenyl) -1- (4- Methylph Nyl) ethanol, (24) 1- (4- {2- [4- (1,3-benzodioxol-5-ylmethyl) piperazin-1-yl] ethoxy} phenyl) -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (25) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- [4- (2-thiomorpholin-4-ylethoxy) phenyl] ethanol, (26) 2- (4-Chlorophenyl) -1- (4- {2- [4- (2-ethoxyethyl) piperazin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, ( 27) 1- [4- (2-Azocan-1-ylethoxy) phenyl] -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (28) 2- (4-chlorophenyl) -1- {4- [2- (2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, (29) 1- [4- (2- {4- [Bis (4-fluorophenyl) methyl] piperazin-1-yl} ethoxy) phenyl] -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (30 ) 1- (2- {4- [2- (4-Chlorophenyl) -1-hydroxy-1- (4-methylphenyl) ethyl] phenoxy} ethyl) -D-prolinamide, (31) 2- (4- Chlorophenyl) -1- [4- (2- {4- [2- (2,5-dimethyl-1H-pyrrol-1-yl) ethyl] piperazin-1-yl} ethoxy) phenyl] -1- (4- Methylphenyl) ethanol, 32) 2- (4-Chlorophenyl) -1- {4- [2- (2,5-dihydro-1H-pyrrol-1-yl) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, (33 ) 1- {4- [2- (1H-benzo [de] isoquinolin-2 (3H) -yl) ethoxy] phenyl} -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (34 ) 2- (4-Chlorophenyl) -1- (4- {2- [4- (4-fluorobenzyl) -1,4-diazepan-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) Ethanol, (35) 2- (4-chlorophenyl) -1- (4- {2- [4- (2-hydroxyethyl) -1,4-diazepan-1-yl] ethoxy} phenyl) -1- (4 -Methylphenyl) ethano (36) 2- (4-Chlorophenyl) -1- {4- [2- (1,3-dihydro-2H-isoindol-2-yl) ethoxy] phenyl} -1- (4-methylphenyl) Ethanol, (37) tert-butyl (1S, 4S) -5- (2- {4- [2- (4-chlorophenyl) -1-hydroxy-1- (4-methylphenyl) ethyl] phenoxy} ethyl)- 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate, (38) 8- (2- {4- [2- (4-chlorophenyl) -1-hydroxy-1- (4-methylphenyl) ) Ethyl] phenoxy} ethyl) -1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one, (39) 4- (2- {4- [2- (4-chlorophenyl)- 1-hydroxy-1- ( -Methylphenyl) ethyl] phenoxy} ethyl) piperazin-2-one, (40) {4- [2- (diethylamino) ethoxy] phenyl} (diphenyl) methanol, (41) (4-chlorophenyl) {4- [2 -(Diethylamino) ethoxy] phenyl} phenylmethanol, (42) {4- [2- (diethylamino) ethoxy] phenyl} (4-methylphenyl) phenylmethanol, (43) {4- [2- (diethylamino) ethoxy] Phenyl} (4-fluorophenyl) phenylmethanol, (44) {4- [2- (diethylamino) ethoxy] phenyl} (phenyl) [4- (trifluoromethyl) phenyl] methanol, (45) {4- [2 -(Diethylamino) ethoxy] phenyl} (4-methoxyphenyl) phenyl Tanol, (46) 1,1′-biphenyl-4-yl {4- [2- (diethylamino) ethoxy] phenyl} phenylmethanol, (47) {4- [2- (diethylamino) ethoxy] phenyl} (6- Methyl-2-naphthyl) phenylmethanol, (48) 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1-phenylethanol, (49) 1- {4- [ 2- (diethylamino) ethoxy] phenyl} -2- (4-methylphenyl) -1-phenylethanol, (50) 3- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1-phenylpropan-1-ol, (51) 1- {4- [2- (diethylamino) ethoxy] phenyl} -3- (4-methylpheny ) -1-phenylpropan-1-ol, (52) 4- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1-phenylbutan-1-ol, (53 ) 1- {4- [2- (diethylamino) ethoxy] phenyl} -4- (4-methylphenyl) -1-phenylbutan-1-ol, (54) bis (4-chlorophenyl) {4- [2- (Diethylamino) ethoxy] phenyl} methanol, (55) (4-chlorophenyl) {4- [2- (diethylamino) ethoxy] phenyl} (4-methylphenyl) methanol, (56) (4-chlorophenyl) {4- [ 2- (diethylamino) ethoxy] phenyl} (4-fluorophenyl) methanol, (57) (4-chlorophenyl) {4- [2- (diethyl) Mino) ethoxy] phenyl} [4- (trifluoromethyl) phenyl] methanol, (58) (4-chlorophenyl) {4- [2- (diethylamino) ethoxy] phenyl} (4-methoxyphenyl) methanol, (59) 1,1′-biphenyl-4-yl (4-chlorophenyl) {4- [2- (diethylamino) ethoxy] phenyl} methanol, (60) (4-chlorophenyl) {4- [2- (diethylamino) ethoxy] phenyl } (6-methyl-2-naphthyl) methanol, (61) 1,2-bis (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} ethanol, (62) 1- (4 -Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -2- (4-methylphenyl) ethane (63) 1,3-bis (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} propan-1-ol, (64) 1- (4-chlorophenyl) -1 -{4- [2- (diethylamino) ethoxy] phenyl} -3- (4-methylphenyl) propan-1-ol, (65) 1,4-bis (4-chlorophenyl) -1- {4- [2 -(Diethylamino) ethoxy] phenyl} butan-1-ol, (66) 1- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -4- (4-methylphenyl) butane -1-ol, (67) {4- [2- (diethylamino) ethoxy] phenyl} [bis (4-methylphenyl)] methanol, (68) {4- [2- (diethylamino) eth Si] phenyl} (4-fluorophenyl) (4-methylphenyl) methanol, (69) {4- [2- (diethylamino) ethoxy] phenyl} (4-methylphenyl) [4- (trifluoromethyl) phenyl] Methanol, (70) {4- [2- (diethylamino) ethoxy] phenyl} (4-methoxyphenyl) (4-methylphenyl) methanol, (71) 1,1′-biphenyl-4-yl {4- [2 -(Diethylamino) ethoxy] phenyl} (4-methylphenyl) methanol, (72) {4- [2- (diethylamino) ethoxy] phenyl} (6-methyl-2-naphthyl) (4-methylphenyl) methanol, ( 73) 1- {4- [2- (Diethylamino) ethoxy] phenyl} -1,2-bis (4-methylphenyl) ethanol (74) 3- (4-Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) propan-1-ol, (75) 1- {4- [2- (Diethylamino) ethoxy] phenyl} -1,3-bis (4-methylpheny
) Propan-1-ol, (76) 4- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) butan-1-ol, 77) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1,4-bis (4-methylphenyl) butan-1-ol, (78) {4- [2- (diethylamino) ethoxy] phenyl } [Bis (4-fluorophenyl)] methanol, (79) {4- [2- (diethylamino) ethoxy] phenyl} (4-fluorophenyl) [4- (trifluoromethyl) phenyl] methanol, (80) { 4- [2- (diethylamino) ethoxy] phenyl} (4-fluorophenyl) (4-methoxyphenyl) methanol, (81) 1,1′-biphenyl-4- Yl {4- [2- (diethylamino) ethoxy] phenyl} (4-fluorophenyl) methanol, (82) {4- [2- (diethylamino) ethoxy] phenyl} (4-fluorophenyl) (6-methyl-2 -Naphthyl) methanol, (83) 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-fluorophenyl) ethanol, (84) 1- {4- [2- (Diethylamino) ethoxy] phenyl} -1- (4-fluorophenyl) -2- (4-methylphenyl) ethanol, (85) 3- (4-chlorophenyl) -1- {4- [2- ( Diethylamino) ethoxy] phenyl} -1- (4-fluorophenyl) propan-1-ol, (86) 1- {4- [2- (diethylamino) ethoxy ] Phenyl} -1- (4-fluorophenyl) -3- (4-methylphenyl) propan-1-ol, (87) 4- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy ] Phenyl} -1- (4-fluorophenyl) butan-1-ol, (88) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-fluorophenyl) -4- (4 -Methylphenyl) butan-1-ol, (89) {4- [2- (diethylamino) ethoxy] phenyl} {bis [4- (trifluoromethyl) phenyl]} methanol, (90) {4- [2- (Diethylamino) ethoxy] phenyl} (4-methoxyphenyl) [4- (trifluoromethyl) phenyl] methanol, (91) 1,1′-biphenyl-4-yl {4- [ -(Diethylamino) ethoxy] phenyl} [4- (trifluoromethyl) phenyl] methanol, (92) {4- [2- (diethylamino) ethoxy] phenyl} (6-methyl-2-naphthyl) [4- (tri Fluoromethyl) phenyl] methanol, (93) 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- [4- (trifluoromethyl) phenyl] ethanol, (94 ) 1- {4- [2- (Diethylamino) ethoxy] phenyl} -2- (4-methylphenyl) -1- [4- (trifluoromethyl) phenyl] ethanol, (95) 3- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- [4- (trifluoromethyl) phenyl] propane-1 All, (96) 1- {4- [2- (diethylamino) ethoxy] phenyl} -3- (4-methylphenyl) -1- [4- (trifluoromethyl) phenyl] propan-1-ol, (97 ) 4- (4-Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- [4- (trifluoromethyl) phenyl] butan-1-ol, (98) 1- {4 -[2- (diethylamino) ethoxy] phenyl} -4- (4-methylphenyl) -1- [4- (trifluoromethyl) phenyl] butan-1-ol, (99) {4- [2- (diethylamino) ) Ethoxy] phenyl} [bis (4-methoxyphenyl)] methanol, (100) 1,1′-biphenyl-4-yl {4- [2- (diethylamino) ethoxy] phenyl} ( -Methoxyphenyl) methanol, (101) {4- [2- (diethylamino) ethoxy] phenyl} (4-methoxyphenyl) (6-methyl-2-naphthyl) methanol, (102) 2- (4-chlorophenyl)- 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methoxyphenyl) ethanol, (103) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4- Methoxyphenyl) -2- (4-methylphenyl) ethanol, (104) 3- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methoxyphenyl) propane -1-ol, (105) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methoxyphenyl) -3 -(4-methylphenyl) propan-1-ol, (106) 4- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methoxyphenyl) butane- 1-ol, (107) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methoxyphenyl) -4- (4-methylphenyl) butan-1-ol, (108) di (1,1′-biphenyl-4-yl) {4- [2- (diethylamino) ethoxy] phenyl} methanol, (109) 1,1′-biphenyl-4-yl {4- [2- (diethylamino) ethoxy ] Phenyl} (6-methyl-2-naphthyl) methanol, (110) 1- (1,1′-biphenyl-4-yl) -2- (4-chlorophenyl) -1- {4- [2- (diethyl) Amino) ethoxy] phenyl} ethanol, (111) 1- (1,1′-biphenyl-4-yl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -2- (4-methylphenyl) Ethanol, (112) 1- (1,1′-biphenyl-4-yl) -3- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} propan-1-ol, 113) 1- (1,1′-biphenyl-4-yl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -3- (4-methylphenyl) propan-1-ol, (114) 1- (1,1′-biphenyl-4-yl) -4- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} butan-1-ol, (115) 1- ( 1,1'-bi Phenyl-4-yl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -4- (4-methylphenyl) butan-1-ol, (116) 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (6-methyl-2-naphthyl) ethanol, (117) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (6 -Methyl-2-naphthyl) -2- (4-methylphenyl) ethanol, (118) 3- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (6- Methyl-2-naphthyl) propan-1-ol, (119) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (6-methyl-2-naphthyl) -3- (4-methylphenyl) Nyl) propan-1-ol, (120) 4- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (6-methyl-2-naphthyl) butane-1- All, (121) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (6-methyl-2-naphthyl) -4- (4-methylphenyl) butan-1-ol, (122) 1,3-bis (4-chlorophenyl) -2- {4- [2- (diethylamino) ethoxy] phenyl} propan-2-ol, (123) 1- (4-chlorophenyl) -2- {4- [2 -(Diethylamino) ethoxy] phenyl} -3- (4-methylphenyl) propan-2-ol, (124) 1,4-bis (4-chlorophenyl) -2- {4- [2- (diethylamino) Toxi] phenyl} butan-2-ol, (125) 1- (4-chlorophenyl) -2- {4- [2- (diethylamino) ethoxy] phenyl} -4- (4-methylphenyl) butan-2-ol (126) 1,5-bis (4-chlorophenyl) -2- {4- [2- (diethylamino) ethoxy] phenyl} pentan-2-ol, (127) 1- (4-chlorophenyl) -2- { 4- [2- (diethylamino) ethoxy] phenyl} -5- (4-methylphenyl) pentan-2-ol, (128) 2- {4- [2- (diethylamino) ethoxy] phenyl} -1,3- Bis (4-methylphenyl) propan-2-ol, (129) 4- (4-chlorophenyl) -2- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4 -Methylphenyl) butan-2-ol, (130) 2- {4- [2- (diethylamino) ethoxy] phenyl} -1,4-bis (4-methylphenyl) butan-2-ol, (131) 5 -(4-Chlorophenyl) -2- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) pentan-2-ol, (132) 2- {4- [2- (diethylamino) ) Ethoxy] phenyl} -1,5-bis (4-methylphenyl) pentan-2-ol, (133) 1,5-bis (4-chlorophenyl) -3- {4- [2- (diethylamino) ethoxy] Phenyl} pentan-3-ol, (134) 1- (4-chlorophenyl) -3- {4- [2- (diethylamino) ethoxy] phenyl} -5- (4-methylphenyl) pe Tan-3-ol, (135) 1,6-bis (4-chlorophenyl) -3- {4- [2- (diethylamino) ethoxy] phenyl} hexane-3-ol, (136) 1- (4-chlorophenyl) ) -3- {4- [2- (diethylamino) ethoxy] phenyl} -6- (4-methylphenyl) hexane-3-ol, (137) 3- {4- [2- (diethylamino) ethoxy] phenyl} -1,5-bis (4-methylphenyl) pentan-3-ol, (138) 6- (4-chlorophenyl) -3- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4- Methylphenyl) hexane-3-ol, (139) 3- {4- [2- (diethylamino) ethoxy] phenyl} -1,6-bis (4-methylphenyl) hexane-3-o (140) 1,7-bis (4-chlorophenyl) -4- {4- [2- (diethylamino) ethoxy] phenyl} heptan-4-ol, (141) 1- (4-chlorophenyl) -4- { 4- [2- (diethylamino) ethoxy] phenyl} -7- (4-methylphenyl) heptan-4-ol, (142) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- [ 4- (2-pyrrolidin-1-ylethoxy) phenyl] ethanol, (143) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- {4- [2- (4-methylpiperidine-1 -Yl) ethoxy] phenyl} ethanol, (144) 2- (4-chlorophenyl) -1- {4- [2- (2,6-dimethylpiperidin-1-yl) ethoxy] phenyl} -1 -(4-methylphenyl) ethanol, (145) 1- (2- {4- [2- (4-chlorophenyl) -1-hydroxy-1- (4-methylphenyl) ethyl] phenoxy} ethyl) piperidine-4 -Ol, (146) 2- (4-chlorophenyl) -1- (4- {2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] ethoxy} phenyl) -1- (4-methyl Phenyl) ethanol, (147) 2- (4-chlorophenyl) -1- (4- {2- [4- (2-hydroxyethyl) piperidin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ) Ethanol, (148) 1- {4- [2- (1,4′-bipiperidin-1′-yl) ethoxy] phenyl} -2- (4-chlorophenyl) -1- (4-methylphenyl) ethane (149) 2- (4-Chlorophenyl) -1- (4-methylphenyl) -1- {4- [2- (1,3-thiazolidin-3-yl) ethoxy] phenyl} ethanol, (150 ) 2- (4-Chlorophenyl) -1- (4-methylphenyl) -1-
{4- [2- (4-Pyridin-4-ylpiperazin-1-yl) ethoxy] phenyl} ethanol, (151) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- {4 -[2- (4-Pyrimidin-2-ylpiperazin-1-yl) ethoxy] phenyl} ethanol, (152) 1- {4- [2- (4-benzylpiperidin-1-yl) ethoxy] phenyl}- 2- (4-Chlorophenyl) -1- (4-methylphenyl) ethanol, (153) 2- (4-Chlorophenyl) -1- (4-methylphenyl) -1- {4- [2- (4-pyrrolidine) -1-ylpiperidin-1-yl) ethoxy] phenyl} ethanol, (154) 2- (4-chlorophenyl) -1- (4- {2-[(2R) -2- (hydroxymethyl) pyrrolidine- -Yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (155) (3R) -1- (2- {4- [2- (4-chlorophenyl) -1-hydroxy-1- (4 -Methylphenyl) ethyl] phenoxy} ethyl) pyrrolidin-3-ol, (156) 2- (4-chlorophenyl) -1- [4- (2-{(2S) -2- [hydroxy (diphenyl) methyl] pyrrolidine -1-yl} ethoxy) phenyl] -1- (4-methylphenyl) ethanol, (157) 2- (4-chlorophenyl) -1- [4- (2- {4- [hydroxy (diphenyl) methyl] piperidine -1-yl} ethoxy) phenyl] -1- (4-methylphenyl) ethanol, (158) 2- (4-chlorophenyl) -1- [4- (2-{(2R) -2- [H Roxy (diphenyl) methyl] pyrrolidin-1-yl} ethoxy) phenyl] -1- (4-methylphenyl) ethanol, (159) 2- (4-chlorophenyl) -1- (4- {2- [4- ( Hydroxymethyl) piperidin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (160) 2- (4-chlorophenyl) -1- (4- {2-[(2R) -2- (Methoxymethyl) pyrrolidin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (161) 1- (4- {2-[(2S) -2-benzhydrylpyrrolidine-1- Yl] ethoxy} phenyl) -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (162) 4- (4-bromophenyl) -1- (2- {4- [2 -(4-Chlorophenyl) -1-hydroxy-1- (4-methylphenyl) ethyl] phenoxy} ethyl) piperidin-4-ol, (163) 2- (4-Chlorophenyl) -1- (4- {2- [3- (Diethylamino) pyrrolidin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (164) 2- (4-chlorophenyl) -1- {4- [2- (3,6 -Dihydropyridin-1 (2H) -yl) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, (165) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- (4- {2-[(2S) -2- (pyrrolidin-1-ylmethyl) pyrrolidin-1-yl] ethoxy} phenyl) ethanol, (166) 2- (4-chlorophenyl) -1- ( -Methylphenyl) -1- {4- [2- (4-phenylpiperidin-1-yl) ethoxy] phenyl} ethanol, (167) 2- (4-chlorophenyl) -1- (4- {2-[( 3R) -3- (dimethylamino) pyrrolidin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (168) 2- (4-chlorophenyl) -1- (4- {2- [ (3S) -3- (Dimethylamino) pyrrolidin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (169) (3S) -1- (2- {4- [2- ( 4-chlorophenyl) -1-hydroxy-1- (4-methylphenyl) ethyl] phenoxy} ethyl) pyrrolidin-3-ol, (170) 2- (4-chlorophenyl) -1- (4- {2-[( 2 ) -2- (methoxymethyl) pyrrolidin-1-yl] ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (171) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1 -{4- [2- (2-{[(2S) -1-methylpyrrolidin-2-yl] methyl} piperidin-1-yl) ethoxy] phenyl} ethanol, (172) 2- (4-chlorophenyl)- 1- (4-methylphenyl) -1- (4- {2- [4- (trifluoromethyl) piperidin-1-yl] ethoxy} phenyl) ethanol, (173) 1- [4- (2-azetidine- 1-ylethoxy) phenyl] -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (174) 2- (4-chlorophenyl) -1- (4-methylphenyl) -1- {4- [2- (1,3,4,9-tetrahydro-2H-β-carbolin-2-yl) ethoxy] phenyl} ethanol, (175) 2- (4-chlorophenyl) -1- { 6- [2- (Diethylamino) ethoxy] pyridin-3-yl} -1- (4-methylphenyl) ethanol, (176) 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy ] -1-naphthyl} -1- (4-methylphenyl) ethanol, (177) 2- (4-chlorophenyl) -1- {3- [2- (diethylamino) ethoxy] cyclopentyl} -1- (4-methyl Phenyl) ethanol, (178) 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] -3-methylphenyl} -1- (4-methylphenyl) Nord, (179) 1- {3-Chloro-4- [2- (diethylamino) ethoxy] phenyl} -2- (4-chlorophenyl) -1- (4-methylphenyl) ethanol, (180) 2- (4 -Chlorophenyl) -1- (4-{[2- (diethylamino) ethyl] amino} phenyl) -1- (4-methylphenyl) ethanol, (181) 2- (4-chlorophenyl) -1- {4- [ [2- (Diethylamino) ethyl] (methyl) amino] phenyl} -1- (4-methylphenyl) ethanol, (182) 2- (4-chlorophenyl) -1- (4-{[2- (diethylamino) ethyl ] Sulfanyl} phenyl) -1- (4-methylphenyl) ethanol, (183) 1- (4-chlorophenyl) -2- {4- [2- (diethylamino) ethoxy Si] phenyl} -2- (4-methylphenyl) ethanol, (184) 1- (4-chlorophenyl) -2- {4- [2- (diethylamino) ethoxy] phenyl} -2- (4-methylphenyl) Ethaneone, (185) 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} ethanol, (186) {4- [2- (diethylamino) ethoxy] phenyl} (4-methyl Phenyl) methanol, (187) N- (2- {4- [2- (4-chlorophenyl) -1- (4-methylphenyl) ethyl] phenoxy} ethyl) -N, N-diethylamine, (188) 1- (4-Chlorophenyl) -2- {4- [2- (diethylamino) ethoxy] phenyl} -3-phenylpropan-2-ol, (189) 1- {4 [2- (Diethylamino) ethoxy] phenyl} -1,2-diphenylethanol, (190) 2- (4-chlorophenyl) -1- {2-[(diethylamino) methyl] -1-benzofuran-5-yl}- 1- (4-methylphenyl) ethanol, (191) 2- (4-chlorophenyl) -1- {2-[(diethylamino) methyl] -3,4-dihydro-2H-chromen-6-yl} -1- (4-Methylphenyl) ethanol, (192) N- (2- {4- [1-amino-2- (4-chlorophenyl) -1- (4-methylphenyl) ethyl] phenoxy} ethyl) -N, N -Diethylamine, (193) N- (2- {4- [3- (4-chlorophenyl) -2- (4-methylphenyl) propyl] phenoxy} ethyl) -N, N-diethyla (194) N- (2- {4- [2- (4-chlorophenyl) -1-methoxy-1- (4-methylphenyl) ethyl] phenoxy} ethyl) -N, N-diethylamine, (195) N- [2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethyl] -N-methylamine, (196) N- [2 -(4-Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethyl] -N, N-dimethylamine, (197) 2- (4-chloro -2-methylphenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, (198) 2- (4-chlorophenyl) -1- {4- [ 2- (Diethylamino) ethoxy] phenyl} -1- (2-methoxy-4-methylphenyl) ethanol, (199) 2- (4-chlorophenyl) -1- (4- {2- [ethyl (2-methoxyethyl) amino ] Ethoxy} phenyl) -1- (4-methylphenyl) ethanol, (200) 1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) -2- (2-naphthyl) ) Ethanol, (201) 2- (1,1′-biphenyl-4-yl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, (202) 1- (4-chlorophenyl) -3- {4- [2- (diethylamino) ethoxy] phenyl} -2- (4-methylphenyl) propan-2-ol, (203) 2 -(4-Chlorophenyl) -1- {4- [2- (1H-indol-1-yl) ethoxy] phenyl} -1- (4-methylphenyl) ethanol, (204) 2- (4-Chlorophenyl)- 1- (4-Methylphenyl) -1- [4- (pyridin-2-ylmethoxy) phenyl] ethanol, (205) 1- (2- {4- [2- (4-chlorophenyl) -1-hydroxy-1 -(4-Methylphenyl) ethyl] phenoxy} ethyl) -4-phenylpiperidin-4-ol.
[Method for producing compound of the present invention]
The compounds of the present invention represented by the general formula (I) can be prepared by known methods, for example, the methods described below, the methods described in the Examples, or Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock , John Wiley & Sons Inc, 1999) can be used in combination. In each of the following production methods, the raw material compound may be used as a salt. As such a salt, those described as the salt of the general formula (I) are used.
(1) Among the compounds of the present invention represented by the general formula (I), V represents a bond, Q represents a hydroxyl group, R ² -Y ¹ -Z ¹ Represents the group R ³ -Y ² -Z ² A compound representing a group, ie a compound of the general formula (IA)

(Wherein all symbols have the same meanings as described above) can be produced by the following method.

  The compound represented by the general formula (IA) is represented by the general formula (II)

(Wherein all symbols have the same meaning as described above), and a compound represented by the general formula (III)

(In the formula, halo represents a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc., and other symbols have the same meanings as described above).) It can manufacture by attaching | subjecting to.

  The compound represented by the general formula (II) and the compound represented by the general formula (III) are publicly known, and are performed, for example, by reacting in an organic solvent (for example, tetrahydrofuran, ether, etc.) at -30 ° C. to reflux temperature. .

  A compound in which at least one group in general formula (IA) represents a group containing a carboxyl group, a hydroxyl group, an amino group, or a mercapto group is subjected to a deprotection reaction in which each group is protected by a protecting group. Can be manufactured.

  Examples of the protecting group for the carboxyl group include a methyl group, an ethyl group, an allyl group, a tert-butyl group, a trichloroethyl group, a benzyl (Bn) group, and a phenacyl group.

  Examples of hydroxyl protecting groups include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), and trimethylsilyl. (TMS) group, triethylsilyl (TES) group, tert-butyldimethylsilyl (TBDMS) group, tert-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, pivaloyl group, benzoyl group, benzyl (Bn) group, Examples thereof include a p-methoxybenzyl group, an allyloxycarbonyl (Alloc) group, and a 2,2,2-trichloroethoxycarbonyl (Troc) group.

  Examples of the protecting group for the amino group include benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1- (4-biphenyl) ethoxycarbonyl (Bpoc) group, trifluoroacetyl group. Group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, 2- (trimethylsilyl) ethoxymethyl (SEM) group and the like.

  Examples of the mercapto group-protecting group include a benzyl group, a methoxybenzyl group, a methoxymethyl (MOM) group, a 2-tetrahydropyranyl (THP) group, a diphenylmethyl group, and an acetyl (Ac) group.

  The protecting group for a carboxyl group, a hydroxyl group, an amino group or a mercapto group is not particularly limited as long as it is a group that can be easily and selectively eliminated other than those described above. For example, those described in Protective Groups in Organic Synthesis (T. W. Greene, John Wiley & Sons Inc, 1999) are used.

The deprotection reaction of a protecting group of a carboxyl group, a hydroxyl group, an amino group or a mercapto group is well known, for example,
(1) alkaline hydrolysis,
(2) Deprotection reaction under acidic conditions,
(3) Deprotection reaction by hydrogenolysis,
(4) Deprotection reaction of silyl group,
(5) Deprotection reaction using metal,
(6) Deprotection reaction using an organic metal and the like.

To explain these methods in detail,
(1) The deprotection reaction by alkali hydrolysis is, for example, an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.) in an organic solvent (methanol, tetrahydrofuran, 1,4-dioxane, etc.). , Using an alkaline earth metal hydroxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of 0 to 40 ° C. .

  (2) The deprotection reaction under acidic conditions can be carried out, for example, in an organic solvent (methylene chloride, chloroform, 1,4-dioxane, ethyl acetate, anisole, etc.) in an organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or the like), inorganic acid (hydrochloric acid, sulfuric acid or the like) or a mixture thereof (hydrogen bromide / acetic acid or the like) at a temperature of 0 to 100 ° C.

  (3) Deprotection reaction by hydrogenolysis includes, for example, a solvent (ether type (tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, etc.), alcohol type (methanol, ethanol, etc.), benzene type. (Benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (N, N-dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixed solvent of two or more thereof ), In the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), in a hydrogen atmosphere at normal pressure or under pressure, or in the presence of ammonium formate, at a temperature of 0 to 200 ° C. .

  (4) Deprotection reaction of silyl group is, for example, fluoride (tetrabutylammonium fluoride, hydrogen fluoride aqueous solution, hydrogen fluoride-pyridine complex, etc.) in an organic solvent miscible with water (tetrahydrofuran, acetonitrile, etc.) Is carried out at a temperature of -20 to 40 ° C.

  (5) The deprotection reaction using a metal is, for example, the presence of powdered zinc in an acidic solvent (acetic acid, a buffer solution of pH 4.2 to 7.2 or a mixed solution of such a solution and an organic solvent such as tetrahydrofuran). Below, it is carried out at a temperature of 0 to 40 ° C. with or without applying ultrasonic waves.

  (6) The deprotection reaction using a metal complex is, for example, an organic solvent (methylene chloride, N, N-dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, 1,4-dioxane, ethanol, etc.), water or a mixed solvent thereof. Among them, trap reagents (tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine etc.), organic acids (acetic acid, formic acid, 2-ethylhexanoic acid etc.) and / or organic acid salts (sodium 2-ethylhexanoate, Metal complexes (tetrakistriphenylphosphine palladium (0), bis (triphenylphosphine) palladium dichloride) in the presence or absence of phosphine reagents (triphenylphosphine, etc.) in the presence of potassium 2-ethylhexanoate, etc. (II), palladium acetate (II) With tris (triphenylphosphine) rhodium (I) etc.), at a temperature of 0 to 40 ° C..

  In addition to the above, the deprotection reaction can be performed, for example, by the method described in Protective Groups in Organic Synthesis (T. W. Greene, John Wiley & Sons Inc, 1999).

  As can be easily understood by those skilled in the art, the intended compound of the present invention can be easily produced by properly using these deprotection reactions.

If necessary, this reaction may be followed by an operation for conversion to the target salt by a known method.
(2) Among the compounds of the present invention represented by formula (I), V represents a bond, Q represents a hydroxyl group, R ² represents a —Y ¹ —Z ¹ group, and R ³ represents a hydrogen atom. Compound, ie, general formula (IB)

(Wherein all symbols have the same meanings as described above) can be produced by the following method.

  The compound represented by the general formula (IB) is represented by the general formula (II)

(Wherein all symbols have the same meanings as described above) can be produced by subjecting the compound to a reduction reaction and, if desired, a deprotection reaction.

  The above reduction reaction is publicly known. For example, in an organic solvent (eg, methanol, ethanol, 2-propanol, tetrahydrofuran, etc.), a reducing agent (eg, sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, trihydride hydride). This is carried out by reacting with acetoxy boron sodium or the like) at -80 ° C to 40 ° C.

The deprotection reaction of the protecting group can be carried out by the same method as described above.
(3) Among the compounds of the present invention represented by the general formula (I), V represents a bond, Q represents a hydrogen atom, R ² represents a —Y ¹ —Z ¹ group, and R ³ represents —Y ^2. A compound representing —Z ² group, ie, a compound represented by the general formula (IC)

(Wherein all symbols have the same meanings as described above) can be produced by the following method.

  The compound represented by the general formula (IC) can be produced by sequentially subjecting the compound represented by the general formula (IA) to a dehydration reaction and a hydrogenation reaction and, if desired, a deprotection reaction. .

  The above dehydration reaction is known, for example, in an organic solvent (for example, benzene, toluene, acetonitrile, etc.) and in the presence of an acid (for example, hydrochloric acid, p-toluenesulfonic acid, etc.) at -60 ° C. to reflux temperature. It is done by.

  Further, the above hydrogenation reaction is known, and examples thereof include solvents (ether-based (tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethyl ether, etc.), alcohol-based (methanol, ethanol, etc.), benzene-based ( Benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (N, N-dimethylformamide, etc.), water, ethyl acetate, acetic acid or a mixture of two or more thereof) In the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), the reaction is carried out at a temperature of 0 to 200 ° C. in a hydrogen atmosphere at normal pressure or under pressure or in the presence of ammonium formate.

  The deprotection reaction of the protecting group can be carried out by the same method as described above.

  The compounds represented by the general formulas (II) to (III) used as other starting materials or reagents are known per se or known methods such as Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition. (Richard C. Larock, John Wiley & Sons Inc, 1999).

  Among the compounds of the present invention represented by the general formula (I), compounds other than those shown above can be used in the examples described in the present specification or known methods such as “Comprehensive Organic Transformations: A Guide to Functional”. Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) "can be used in combination.

In each reaction in the present specification, the reaction product is obtained by a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, It can be purified by scavenger resin, column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.
[toxicity]
The toxicity of the compound of the present invention represented by the general formula (I) is very low, and is sufficiently safe for use as a medicine.
[Application to pharmaceutical products]
Since the compound of the present invention represented by the general formula (I) has an inhibitory action on N-type calcium channel, for example, cerebral infarction, transient ischemic attack, cerebrospinal injury after cardiac surgery, spinal vascular disorder, stress property It is useful as a preventive and / or therapeutic agent for hypertension, neurosis, epilepsy, asthma, pollakiuria, eye diseases (eg glaucoma, diabetic retinopathy, macular degeneration, retinal vascular occlusion, etc.) and the like. The compound of the present invention represented by the general formula (I) is also useful as a preventive and / or therapeutic agent for pain (for example, acute pain, chronic pain, postoperative pain, cancer pain, neuralgia, infectious pain, etc.). is there.

  The compound of the present invention is 1) complementation and / or enhancement of the preventive and / or therapeutic effect of the compound of the present invention, 2) kinetics / absorption improvement of the compound of the present invention, reduction of dosage, and / or 3) In order to reduce the side effects of the compound, it may be administered in combination with other drugs as a concomitant drug.

  The concomitant drug of the compound of the present invention and another drug may be administered in the form of a combination drug containing both components in one preparation, or may be administered in separate preparations. When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, administration by time difference may be such that the compound of the present invention is administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later. The administration method may be the same or different.

  The other drug may be a low molecular weight compound, and may be a high molecular protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine. Also good. The dosage of other drugs can be appropriately selected based on the clinically used dose. In addition, the compounding ratio of the compound of the present invention and other drugs can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time, target disease, symptom, combination and the like. For example, 0.01 to 100 parts by weight of another drug may be used with respect to 1 part by weight of the compound of the present invention. The other drugs may be administered by combining one or two or more kinds arbitrarily selected from the following homogeneous groups and heterogeneous groups in an appropriate ratio.

  The disease that exerts the preventive and / or therapeutic effect by the above-mentioned concomitant drug is not particularly limited as long as it is a disease that complements and / or enhances the preventive and / or therapeutic effect of the compound of the present invention.

  For example, other drugs for complementing and / or enhancing the effect of the compound represented by the general formula (I) on pain include, for example, opioid receptor agonists, nonsteroidal anti-inflammatory drugs, antipyretic analgesics, Antiepileptic drugs, antiarrhythmic drugs, antidepressants, anxiolytics, antipsychotics, corticosteroids, antihistamines, local anesthetics, NMDA antagonists, migraine drugs, painful diabetic neuropathy drugs Etc.

  Opioid receptor agonists include, for example, opium, opium tocon powder, opium alkaloid hydrochloride, opium alkaloid atropine, opium alkaloid scopolamine, morphine hydrochloride, morphine atropine, ethyl morphine hydrochloride, compound oxycodone, compound oxycodone / atropine, phosphorus Examples include acid codeine, dihydrocodeine phosphate, oxymethanol, cocaine hydrochloride, pethidine hydrochloride, fentanyl citrate, pentazocine, pentazocine hydrochloride, tramadol hydrochloride, butorphanol tartrate, buprenorphine hydrochloride, and eptazocine hydrobromide.

  Non-steroidal anti-inflammatory drugs include, for example, Sazapyrine, sodium salicylate, aspirin, aspirin dialuminate, diflunisal, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, tolmetin sodium, clinolyl, napmeton, ibuprofen piconol, keto Phenylbutazone, oxyphenbutazone, napagel ointment, sulpyrine, migrenin, salidone, cedes G, amidopiro-N, sorbon, pilin-type common cold drug, acetaminophen, phenacetin, dimethothiazine mesylate, cimetride combination drug, non-pyrine common cold drug Salicylamide, flufenamic acid, flufenamic acid aluminum, mefenamic acid, aluminum mefenamic acid, fructaphenine, tolfenamic acid, Clofenac, diclofenac sodium, sulindac, fenbufen, ampenac sodium, indomethacin, indomethacin farnesyl, progouracacine maleate, acemethacin, nabumetone, etodolac, mofezolac, ibuprofen, ketoprofen, flurbiprofen, flurbiprofen axetenophen, oxaprozin Profen calcium, thiaprofenic acid, naproxen, pranoprofen, loxoprofen sodium, aluminoprofen, zaltoprofen, bucolome, piroxicam, ampiroxicam, tenoxicam, epirizole, thiaramide hydrochloride, emorphazone and the like.

  Examples of antipyretic analgesics include sulpyrine, acetaminophen, dimethothiazine mesylate and the like.

  Examples of antiepileptic drugs include phenytoin, ethotoin, phenobarbital, phenobarbital sodium, mehobarbital, metalbital, trimethadione, ethosuximide, acetylphenetride, primidone, sodium valproate, carbamazepine, zonisamide, acetazolamide, diazepam and the like.

  Antiarrhythmic drugs include, for example, aprindine hydrochloride, amiodarone hydrochloride, 1-isoprenalin, quinidine sulfate, dizopyramide, disopyramide phosphate, cibenzoline succinate, pyrmenol hydrochloride, flecainide acetate, pilcainide hydrochloride, procainamide hydrochloride, provafenone hydrochloride, mexiletine hydrochloride, Lidocaine etc. are mentioned.

  Examples of the antidepressant include desipramine hydrochloride, nortriptyline hydrochloride, amoxapine, maprotiline hydrochloride, imipramine hydrochloride, amitriptyline hydrochloride, clomipramine hydrochloride, trimipramine maleate, lofepramine hydrochloride, dosrepine hydrochloride, trazodone hydrochloride, fluvoxamine maleate, paroxetine hydrochloride hydrate, Examples include milnacipran hydrochloride and mianserin.

  Anti-anxiety drugs include, for example, alprazolam, etizolam, oxazolam, cloxazolam, clothiazepam, chlordiazepoxide, diazepam, fludiazepam, bromazepam, medazepam, ethyl loflazepate, lorazepam, hydroxyzine hydrochloride, hydroxyzine hydrochloride, tofisopam, etc. .

  Antipsychotics include, for example, chlorpromazine hydrochloride, thioridazine hydrochloride, propericazine, perphenazine, fluphenazine decanoate, levomepromazine maleate, spiperone, timiperone, haloperidol, haloperidol decanoate, bromperidol, crofectone, sulpiride, zotepine, pimozide Mosapramine hydrochloride, risperidone, perospirone hydrochloride hydrate, quetiapine fumarate, olanzapine and the like.

  Examples of corticosteroids include dexamethasone, dexamethasone palmitate, triamcinolone acetonide, hydrocortisone, fludrocortisone acetate, prednisolone betamethasone, methylprednisolone, and the like.

  Examples of the antihistamine include clemastine fumarate, chlorpheniramine d-maleate, cyproheptadine hydrochloride, promethazine hydrochloride, homochlorcyclidine hydrochloride, mequitazine, diphenhydramine hydrochloride, ebastine, cetirizine hydrochloride, olopatadine hydrochloride, fexofenadine hydrochloride, etc. Can be mentioned.

  Examples of the local anesthetic include cocaine hydrochloride, bupivacaine hydrochloride, procaine hydrochloride, mepivacaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, lidocaine hydrochloride, sotalol hydrochloride and the like.

  Examples of the NMDA antagonist include ketamine and dextromedorphan.

  Examples of the migraine treatment drug include dihydroergotamine mesylate, lomerizine hydrochloride, sumatriptan succinate and the like.

  Examples of the therapeutic agent for painful diabetic neuropathy include mexiletine hydrochloride and the like.

  In addition, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present invention include not only those that have been found so far, but also those that will be found in the future based on the above-mentioned mechanism. It is.

  In order to use the compound of the present invention or a combination agent of the compound of the present invention and another drug for the above-mentioned purpose, it is usually administered systemically or locally in an oral or parenteral form.

  The dose varies depending on age, weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once or several times a day in the range of 100 μg to 1000 mg per adult. Or it is administered parenterally once or several times a day in the range of 50 μg to 500 mg per adult, or continuously administered intravenously in the range of 1 to 24 hours per day.

  Of course, as described above, since the dosage varies depending on various conditions, an amount smaller than the above dosage may be sufficient, or administration may be necessary beyond the range.

  When administering the compound of the present invention or a combination agent of the compound of the present invention and another drug, for example, a solid preparation for internal use for oral administration, a liquid preparation for internal use, and an injection, a preparation for external use, a sitting for oral administration. It is used as an agent, eye drops, inhalant and the like.

  Examples of the solid preparation for internal use for oral administration include tablets, pills, capsules, powders, granules and the like. Examples of capsules include hard capsules and soft capsules.

  In such solid preparations for internal use, for example, one or more active substances are left as they are, or excipients (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (for example, hydroxypropyl) Cellulose, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant (eg, calcium calcium glycolate), lubricant (eg, magnesium stearate), stabilizer, solubilizer (eg, glutamic acid, asparagine) Acid) and the like, and formulated into a conventional method. Moreover, you may coat | cover with a coating agent (For example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.) as needed, and you may coat | cover with two or more layers. Also included are capsules of absorbable substances such as gelatin.

  Examples of liquids for internal use for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like. In such a solution, one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). Furthermore, this liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.

  Examples of external dosage forms for parenteral administration include ointments, gels, creams, poultices, patches, liniments, sprays, inhalants, sprays, aerosols, eye drops, and spots. Includes nasal preparations. These contain one or more active substances and are prepared by known methods or commonly used formulations.

  The ointment is produced by a known or commonly used formulation. For example, it is prepared by mixing or melting one or more active substances in a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (E.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., Dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (eg, ethylene glycol, diethylene glycol, propylene glycol, polyethylene) Recalls, macrogol, etc.), vegetable oils (castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (eg mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, anti-rash agents It is used alone or in combination of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like may be included.

  The gel is produced by a known or commonly used formulation. For example, it is prepared by melting one or more active substances in a base. The gel base is selected from known or commonly used ones. For example, lower alcohol (eg, ethanol, isopropyl alcohol, etc.), gelling agent (eg, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agent (eg, triethanolamine, diisopropanolamine, etc.), One selected from surfactants (for example, polyethylene glycol monostearate), gums, water, absorption enhancers, and anti-rash agents, or a mixture of two or more types may be used. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The cream is produced by a known or commonly used formulation. For example, it is prepared by melting or emulsifying one or more active substances in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (eg, 2-hexyldecanol, cetanol, etc.), emulsifiers (eg, polyoxy (Ethylene alkyl ethers, fatty acid esters, etc.), water, absorption accelerators, anti-rash agents, or a mixture of two or more thereof. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, and applying it as a kneaded product on a support. The poultice base is selected from known or commonly used ones. For example, thickeners (eg, polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin, methyl cellulose, etc.), wetting agents (eg, urea, glycerin, propylene glycol, etc.), fillers (eg, kaolin, zinc oxide, Talc, calcium, magnesium, etc.), water, a solubilizing agent, a tackifier, and a rash prevention agent may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base and spreading and coating them on a support. The base for patch is selected from known or commonly used ones. For example, those selected from a polymer base, fats and oils, higher fatty acids, tackifiers and anti-rash agents may be used alone or in admixture of two or more. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  The liniment is produced by a known or commonly used formulation. For example, one or more active substances are dissolved or suspended in one or more selected from water, alcohol (eg, ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifier, suspending agent and the like. Prepared by turbidity or emulsification. Furthermore, a preservative, an antioxidant, a flavoring agent and the like may be included.

  Sprays, inhalants, and sprays are commonly used diluents such as sodium bicarbonate, sodium citrate or citric acid to provide isotonicity with stabilizers such as sodium bisulfite. Such an isotonic agent may be contained. A method for producing a spray is described in detail in, for example, US Pat. Nos. 2,868,691 and 3,095,355.

  Examples of the injection for parenteral administration include solutions, suspensions, emulsions, and solid injections used by dissolving or suspending in a solvent at the time of use. An injection is used by dissolving, suspending or emulsifying one or more active substances in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof are used. Furthermore, this injection contains a stabilizer, a solubilizing agent (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifying agent, a soothing agent, a buffering agent, a preservative and the like. Also good. These are sterilized in the final process or manufactured by aseptic manipulation. In addition, a sterile solid preparation, for example, a lyophilized product, can be produced and used by dissolving it in sterilized or sterile distilled water for injection or other solvent before use.

  Eye drops for parenteral administration include ophthalmic solutions, suspension type ophthalmic solutions, emulsion type ophthalmic solutions, pre-dissolving type ophthalmic solutions, and eye ointments.

  These eye drops are produced according to known methods. For example, one or more active substances are used by dissolving, suspending or emulsifying them in a solvent. As the solvent for the eye drops, for example, sterilized purified water, physiological saline, other aqueous solvents or non-aqueous preparations for injection (for example, vegetable oil) and the like, and combinations thereof are used. Eye drops include isotonic agents (eg, sodium chloride, concentrated glycerin, etc.), buffering agents (eg, sodium phosphate, sodium acetate, etc.), surfactants (eg, polysorbate 80 (trade name), stearic acid) Polyoxyl 40, polyoxyethylene hydrogenated castor oil, etc.), stabilizers (eg, sodium citrate, sodium edetate, etc.), preservatives (eg, benzalkonium chloride, parabens, etc.), etc. are selected as necessary. May be included. These are sterilized in the final step or prepared by aseptic manipulation. In addition, an aseptic solid preparation, for example, a freeze-dried product, can be produced and dissolved before use in a sterilized or aseptically sterilized purified water or other solvent.

  Inhalants for parenteral administration include aerosols, inhalable powders or inhalable solutions, which are used by dissolving or suspending them in water or other suitable media at the time of use. It may be.

  These inhalants are produced according to known methods.

  For example, in the case of inhalation solutions, preservatives (eg, benzalkonium chloride, parabens, etc.), colorants, buffering agents (eg, sodium phosphate, sodium acetate, etc.), isotonic agents (eg, chloride) Sodium, concentrated glycerin, etc.), thickeners (for example, cariboxyvinyl polymer, etc.), absorption enhancers and the like are appropriately selected as necessary.

  In the case of powders for inhalation, lubricants (for example, stearic acid and its salts), binders (for example, starch, dextrin, etc.), excipients (for example, lactose, cellulose, etc.), colorants, antiseptics An agent (for example, benzalkonium chloride, paraben, etc.), an absorption accelerator and the like are appropriately selected as necessary.

  When administering a liquid for inhalation, a nebulizer (for example, an atomizer, a nebulizer, etc.) is usually used, and when administering a powder for inhalation, an inhaler for powder medicine is usually used.

  Other compositions for parenteral administration include suppositories for rectal administration and pessaries for intravaginal administration, which contain one or more active substances and are prescribed by conventional methods.

  The compounds of the present invention represented by the general formula (I) have an inhibitory action on N-type calcium channels, for example, and are therefore useful as preventive and / or therapeutic agents for N-type calcium channel-mediated diseases.

  EXAMPLES Hereinafter, although a reference example and an Example demonstrate this invention in detail, this invention is not limited to these.

  The location of separation by chromatography and the solvent in parentheses shown in TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

NMR is a measured value of ¹ HNMR at 300 MHz, and the solvent in parentheses shown in the NMR part indicates the solvent used for the measurement.

The nomenclature of the compound of the present invention is shown below. The nomenclature used herein is a method in accordance with IUPAC rules or a computerized system that generally generates IUPAC rule nomenclature, ACD / Name ^™ (version 6.00, manufactured by Advanced Chemistry Development Inc.) ).
Example 1
1- {4- [2- (Diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) -2-phenylethanol hydrochloride

10% palladium-carbon (4.5 mg) was suspended in methanol (1 mL), and then 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4- Methylphenyl) ethanol (5.0 mg) in methanol (1 mL) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. Palladium-carbon was filtered off from the reaction mixture. The filtrate was concentrated under reduced pressure to give the title compound (3.0 mg) having the following physical data.
TLC: Rf 0.36 (methanol: methylene chloride = 1: 9);
NMR (CDCl ₃ ): δ 7.30, 7.28, 7.20-7.13, 7.10, 6.94-6.87, 6.81, 4.26-4.06, 3.58, 3.14-2.93, 2.92-2.73, 2.32, 1.25-1.06.
Example 2
N, N-diethyl-2- {4- [1- (4-methylphenyl) -2-phenylethyl] phenoxy} ethanamine hydrochloride

A solution of 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol (4.5 mg) in anhydrous acetonitrile (1 mL) under an argon gas atmosphere Was cooled to −40 ° C., triethylsilane (1 drop) and boron trifluoride etherate (1 drop) were added, and the mixture was stirred for 2.5 hours while raising the temperature to 0 ° C. The reaction mixture was diluted with saturated aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After 10% palladium-carbon (5.0 mg) was suspended in methanol (1 mL), a solution of the residue obtained earlier in methanol (1 mL) was added, and the mixture was stirred at room temperature for 9 hours in a hydrogen atmosphere. Palladium-carbon was filtered off from the reaction mixture. The filtrate was concentrated under reduced pressure to give the title compound (5.7 mg) having the following physical data.
TLC: Rf 0.40 (methanol: methylene chloride = 1: 9);
NMR (CDCl ₃ ): δ 12.43, 7.22-6.96, 6.75, 4.45, 4.16, 3.41, 3.31, 3.29, 3.30-3.12, 2.29, 1.45.
Example 3
4-hydroxy-N-methoxy-N-methylbenzamide N, O-dimethylhydroxylamine hydrochloride (5.30 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (9.72 g) and argon gas atmosphere After stirring a solution of triethylamine (7.57 mL) in acetonitrile (100 mL), the mixture was cooled in a water bath, 4-hydroxybenzoic acid (5.0 g) was added, and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate and 2N hydrochloric acid were added to the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (6.02 g) having the following physical data. The obtained residue was used for the next reaction without purification.
TLC: Rf 0.72 (chloroform: methanol = 9: 1).
Example 4
4- [2- (Diethylamino) ethoxy] -N-methoxy-N-methylbenzamide In an argon gas atmosphere, the compound prepared in Example 3 (6.0 g) was dissolved in acetone (60 mL), and (2-chloroethyl) Diethylamine hydrochloride (6.28 g), potassium carbonate (10.5 g) and sodium iodide (500 mg) were added, and the mixture was stirred at 75 ° C. for 1 hr, dimethylformamide (50 mL) was added, and the mixture was stirred at 100 ° C. for 6 hr. After cooling the reaction mixture, ethyl acetate and water were added. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 19: 1) to obtain the title compound (4.62 g) having the following physical property values.
TLC: Rf 0.26 (chloroform: methanol = 9: 1).
Example 5
2- (4-Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} ethaneone

Under argon gas atmosphere, magnesium (729 mg) was stirred in anhydrous tetrahydrofuran (5 mL), 1,2-dibromoethane (0.043 mL) was added, and the mixture was cooled with cold brine and then 1-chloro-4- (chloromethyl). ) A solution of benzene (1.61 g) in tetrahydrofuran (15 mL) was slowly added dropwise and stirred at −10 to 0 ° C. for 30 minutes to prepare chloro (4-chlorobenzyl) magnesium (Grignard reagent). . In a separate flask, the compound (1.2 g) produced in Example 4 was dissolved in tetrahydrofuran (8.6 mL) under an argon gas atmosphere, cooled with cold brine, and the previously prepared Grignard reagent (10.3 mL) was added dropwise. And stirred at 0 ° C. for 30 minutes. The reaction mixture was poured into hydrochloric acid and ice water, and extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane to give the title compound (572 mg) having the following physical data.
TLC: Rf 0.23 (chloroform: methanol = 9: 1).
Example 6
2- (4-Chlorophenyl) -1- (4- {2- [ethyl (methyl) amino] ethoxy} phenyl) ethanol

Under an argon gas atmosphere, a solution of the compound prepared in Example 5 (60 mg) in methanol (0.3 mL) was cooled, sodium borohydride (3.9 mg) was added, and the mixture was stirred at 0 to 20 ° C. for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane to give the title compound (31 mg) having the following physical data.
TLC: Rf 0.58 (chloroform: methanol = 4: 1);
_{NMR (CDCl 3): δ 1.07} , 2.64, 2.87, 2.98, 4.04, 4.81, 6.87, 7.07, 7.24.
Example 6 (1)
{4- [2- (diethylamino) ethoxy] phenyl} (4-methylphenyl) methanol Example 5 → Example 6 with chloro (4-chlorophenyl) magnesium instead of chloro (4-chlorobenzyl) magnesium By subjecting to the same operation, the title compound having the following physical property values was obtained.
TLC: Rf 0.58 (chloroform: methanol = 4: 1);
NMR (CDCl ₃ ): δ 1.06, 2.33, 2.62, 2.85, 4.02, 5.77, 6.86, 7.14, 7.26.
Example 7
2- (4-Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1-phenylethanol

In an argon gas atmosphere, the compound (50 mg) prepared in Example 6 was dissolved in tetrahydrofuran (0.3 mL), cooled with ice water, and bromo (phenyl) magnesium (0.174 mL, 1.0 mol / L THF solution) was added dropwise. And stirred at 50 ° C. for 2 hours. The reaction mixture was cooled, poured into a saturated aqueous ammonium chloride solution and ice water, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 2 → ethyl acetate) to give the title compound (9.8 mg) having the following physical data.
TLC: Rf 0.28 (ethyl acetate: methanol = 4: 1);
_{NMR (CDCl 3): δ 1.06} , 2.14, 2.63, 2.86, 3.55, 4.03, 6.83, 7.11, 7.30.
Example 7 (1)
1- (4-Chlorophenyl) -2- {4- [2- (diethylamino) ethoxy] phenyl} -3- (4-methylphenyl) propan-2-ol Bromo (4-methyl) instead of bromo (phenyl) magnesium The title compound having the following physical data was obtained by the same procedure as in Example 7 using benzyl) magnesium.
TLC: Rf 0.39 (ethyl acetate: methanol = 4: 1);
NMR (CDCl ₃ ): δ 1.08, 1.80, 2.26, 2.65, 2.87, 3.03, 3.21, 4.02, 6.82, 6.98, 7.11.
[Biological Example]
It was proved by the following experiment that the compound of the present invention represented by the general formula (I) has N-type calcium channel inhibitory activity.
N-type calcium channel inhibitory activity
Cells were induced to differentiate according to the method described in FEBS Letters (1988) 235 178-182, and the N-type calcium channel current was measured using the whole cell patch clamp method. The composition of the extracellular fluid was as follows. 123 (mmol / L) TEA-Cl, 5 KCl, 10 BaCl ₂ , 1 MgCl ₂ , 10 HEPES-Tris, 5.6 glucose, 0.3 μmol / L TTX, pH 7.4. Measurement electrodes 3 to 6 M.OMEGA. Glass electrode (electrode in solution composition: 126 (mmol / L) CsCl , 11 NaCl, 3 MgCl 2, 10 EGTA, 10 HEPES-Tris, 2 ATP-Mg, 1 GTP-Tris, pH 7.3) was used. L-type calcium channel current was suppressed by adding nifedipine to the extracellular fluid.

  When depolarizing stimulation was performed with a rectangular wave (stimulation pulse) for 50 milliseconds from a holding potential of -100 mV, an inward current was recorded. Since this current was suppressed by the N-type calcium channel inhibitor ω-conotoxin MVIIA, it was considered to be a current passing through the N-type calcium channel. After the compound of the present invention was added to the extracellular fluid for 60 seconds, the stimulation pulse was applied 20 times at 10 Hz, and the peak value of the inward current was measured. The percent inhibition of N-type calcium channel current that occurs when the 20th stimulation pulse is applied was calculated from the following equation.

Invention compound (3 μM) N-type calcium channel current inhibition% (inhibition%) = (1-inward current peak value when compound of the invention is added / inward current peak value when compound is not added) × 100
As a result, 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol showed 81% N-type calcium channel current suppression effect. .
[Formulation example]
Formulation examples that can be used in the practice of the present invention are shown below.
Formulation Example 1 :
The following components were mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 10 mg of the active ingredient.
2- (4-Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol (100 g);
Carboxymethylcellulose calcium (disintegrant) (20.0 g);
Magnesium stearate (lubricant) (10.0 g);
-Microcrystalline cellulose (870 g).
Formulation Example 2 :
The following components were mixed by a conventional method, filtered through a dust removal filter, filled in 5 ml aliquots, and sterilized by heating in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient per ampoule.
2- (4-Chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol (200 g);
・ Mannitol (2 kg);
-Distilled water (50 L).

Since the compound of the present invention represented by the general formula (I) has an N-type calcium channel inhibitory action, it is useful as a preventive and / or therapeutic agent for N-type calcium channel-mediated diseases. Therefore, this invention compound can be utilized as a pharmaceutical.

Claims (12)

Formula (I)

(In the formula, ring A represents an optionally substituted cyclic group, W represents an oxygen atom, an optionally oxidized sulfur atom, or a —NR ⁴ — group, R ⁴ represents a hydrogen atom, Or an alkyl group which may have a substituent, wherein X represents a spacer having 1 to 10 atoms in the main chain, or one of the spacer atoms represented by X is combined with the substituent of ring A; A ring which may have a substituent may be formed, V represents a bond or a spacer having 1 to 3 atoms in the main chain, and Q has a hydrogen atom or a protecting group. Represents an optionally substituted hydroxyl group, a mercapto group optionally having a protecting group, or an amino group optionally having a protecting group, wherein R ¹ represents —OR ⁵ group, —SR ⁵ group, or —NR ⁵ R; represents ^{six, R 5} and ^{R 6} each independently represent a hydrogen atom or a substituent Which may have an alkyl group, or represents a cyclic group which may have a substituent, or R ⁵ and R ⁶ together with the adjacent nitrogen atom, which may have a substituent May form a good nitrogen-containing heterocycle, R ² represents a hydrogen atom or —Y ¹ —Z ¹ group, R ³ represents a hydrogen atom or —Y ² —Z ² group, and Y ¹ and Y ² each independently represents a bond or a spacer having 1 to 10 atoms in the main chain, and Z ¹ and Z ² each independently represent a cyclic group which may have a substituent. , R ² and R ³ are not hydrogen atoms at the same time.) A calcium channel inhibitor comprising a compound, a salt thereof, an N-oxide or a solvate thereof, or a prodrug thereof. The agent according to claim 1, wherein the calcium channel is N-type. The agent according to claim 2, which is a preventive and / or therapeutic agent for an N-type calcium channel-mediated disease. The agent according to claim 2, which is a preventive and / or therapeutic agent for pain. The agent according to claim 4, wherein the pain is acute pain, chronic pain, postoperative pain, cancer pain, neuralgia, or infectious pain. The agent according to claim 2, wherein ring A is a monocyclic carbocycle which may have a substituent. The agent according to claim 6, wherein the monocyclic carbocycle is a benzene ring. Formula (IA)

(Wherein Q ¹ represents a hydroxyl group which may have a protecting group, ring A ¹ represents a monocyclic carbocycle which may have a substituent, and other symbols are as defined in claim 1. The agent according to claim 2, which represents the same meaning. The agent according to claim 2, further comprising one or more selected from opioid receptor agonists and non-steroidal anti-inflammatory drugs. A method for preventing and / or treating a calcium channel-mediated disease in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof, or a prodrug thereof to the mammal. Use of the compound according to claim 1 or a salt thereof, or a prodrug thereof for producing a preventive and / or therapeutic agent for a calcium channel-mediated disease. Formula (I)

(In the formula, ring A represents an optionally substituted cyclic group, W represents an oxygen atom, an optionally oxidized sulfur atom, or a —NR ⁴ — group, R ⁴ represents a hydrogen atom, Or an alkyl group which may have a substituent, wherein X represents a spacer having 1 to 10 atoms in the main chain, or one of the spacer atoms represented by X is combined with the substituent of ring A; A ring which may have a substituent may be formed, V represents a bond or a spacer having 1 to 3 atoms in the main chain, and Q has a hydrogen atom or a protecting group. Represents an optionally substituted hydroxyl group, a mercapto group optionally having a protecting group, or an amino group optionally having a protecting group, wherein R ¹ represents —OR ⁵ group, —SR ⁵ group, or —NR ⁵ R; represents ^{six, R 5} and ^{R 6} each independently represent a hydrogen atom or a substituent Which may have an alkyl group, or represents a cyclic group which may have a substituent, or R ⁵ and R ⁶ together with the adjacent nitrogen atom, which may have a substituent May form a good nitrogen-containing heterocycle, R ² represents a hydrogen atom or —Y ¹ —Z ¹ group, R ³ represents a hydrogen atom or —Y ² —Z ² group, and Y ¹ and Y ² each independently represents a bond or a spacer having 1 to 10 atoms in the main chain, and Z ¹ and Z ² each independently represent a cyclic group which may have a substituent. , R ² and R ³ are not simultaneously hydrogen atoms and not 2- (4-chlorophenyl) -1- {4- [2- (diethylamino) ethoxy] phenyl} -1- (4-methylphenyl) ethanol. ), Its salts, N- oxide thereof or a solvate thereof, or a prodrug thereof.