WO2001058880A1 - Novel triazole derivatives - Google Patents

Abstract

Triazole derivatives represented by the general formula (I) or pharmaceutically acceptable salts thereof; and arginine vasopressin V1A receptor antagonists containing both as the active ingredient wherein A is an optionally substituted benzene or thiophene ring; Y is N or CH; R1 is hydrogen or alkyl; and R?2 and R3¿ are each hydrogen, halogeno, amino, or other substituent.

Description

 Specification

 New triazole derivatives

The present invention relates to a medicament, particularly a novel triazole derivative or a pharmaceutically acceptable salt thereof, and an arginine vasopressin A receptor antagonist containing the same as an active ingredient. Background art

 Diabetic nephropathy is one of the three major complications of diabetes, clinically showing signs of microalbuminuria, proteinuria, renal dysfunction, hypertension and edema, and eventually renal failure There are many. It is said that this diabetic nephropathy progresses relatively slowly in the early stage, and that the lesion is also reversible.However, in the overt period when proteinuria is positive, the disease becomes irreversible and rapidly It is said that severe renal function decline causes end-stage renal failure. At present, pathological diagnosis can be made before proteinuria becomes positive by measurement of microalbuminuria, etc.Aggressive treatment should be implemented as early as possible with reversible lesions as a measure to prevent progression of nephropathy It is believed that.

It has been reported that plasma arginine vasopressin (hereinafter referred to as AVP) levels increase in diabetic patients and diabetic model animals (Diabetes, 38 (1989), 54-57). _1A the physiological actions in the kidney through the receptor, direct contractile effects of export fibrillation pulse (Am. J. Physiol. 256 ( 1989), F274-F278) and prosulfuron evening synthesis Aran Jin E ₂ class It has an effect of increasing renal glomerular pressure by expansion of imported arterioles via the enhancement effect (J. Hypertens. 11 (1993), 127-134), renal mesangial cell proliferation, hypertrophy and extracellular matrix accumulation (Am. J Physiol. (1988), F898-F906), suggesting a close correlation with the onset and progression of diabetic nephropathy. Moreover, clinical reports and improved the OPC-21268 (Compound of EP three hundred eighty-two thousand one hundred and eighty-five JP Example 141) actually in NIDDM patients albuminuria is V _1A receptor selective antagonists have also been made (Arzneim. Forsch. 46 (1996), 875-878). Based on the above, V _1A receptor antagonist Is expected to be an effective prophylactic and therapeutic agent for diabetic nephropathy. Recently, AVP is a vascular permeability enhancer via _V1A receptor expressed in vascular smooth muscle.

(Eur. J Pharmacol. 368 (1999), 89-94) has been shown to strongly promote the production of (also known as vascular endothelial growth factor) diabetic retinopathy ゃ nephropathy, arteriosclerosis Involvement in the process of formation of vascular lesions has been pointed out in various diseases (Biochimica et Biophysica Acta 1243 (1995), 195-202). Therefore, _V1A receptor antagonists are useful for preventing and treating vascular diseases in various diseases.

On the other hand, V ₂ receptor antagonists are known to have a water diuretic, preferably compounds having antagonistic activity against V _1A and v ₂ both receptors on renal diseases involving edema, as this For example, benzazepine derivatives described in International Publications WO95 / 03305 and WO95 / 06035 are known. However, diseases without edema or the like, in such as diabetic nephropathy with symptoms such as mouth thirst Ya polyuria, considered more preferable selective V _1A receptor antagonist.

 In addition, the amino acid sequence is very similar to AVP, and also in the hypothalamus-pituitary system

It is known that AVP receptor antagonists also antagonize this oxytocin receptor and cause inhibition of physiological actions such as uterine contraction and milking.

Thus, blood vessel diseases such as in diabetic nephropathy or various diseases, for edema accompanied such have diseases, V _1A receptor selective for v ₂ receptor and Okishitoshin receptors, and more powerful Compounds having significant antagonistic activity are expected to be good therapeutic agents.

Against this background, the inventors of the present invention have proceeded with screening of compounds having selective and high affinity for the _V1A receptor, and as a result, have found that certain specific triazole derivatives Found that the above conditions were satisfied, and completed the present invention.

Disclosure of the invention

The present invention is a pharmaceutical composition comprising a triazole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, Relates to vasopressin V _{1 A} receptor antagonists.

 (The symbols in the formula have the following meanings.

Ring A: a) a benzene ring which may be substituted with 1 to 3 substituents selected from halogen, nitro, amino, lower alkyl group or a group represented by —X—R ⁴ , or

 b) a thiophene ring optionally substituted with an aryl group,

R ^{1 is a} hydrogen atom or a lower alkyl group,

R ² : a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, an optionally substituted lower alkynyl group, or an optionally substituted amino Base ''

R ³ : hydrogen atom, halogen atom, amino, nitro, cyano, trifluoromethyl, lower alkyl, —0-lower alkyl group,

Or may form a cycloalkyl ring together with the R ² group

 Y: CH or N

X: single bond, —NH—CO—, one CO—NH—, —NH—CO—NH—, —NH—CS—NH—,-(CH ₂ ) _k one—, or —O— (CH ₂ ) _k — group

R ⁴ : aryl group optionally substituted with lower alkyl or aryl group; 5- or 6-membered heteroaryl group optionally substituted with lower alkyl group; optionally substituted with lower alkyl group 3 to 8 membered saturated heterocyclic group;

 m: Integer from 1 to 3

 k: integer from 0 to 5)

The present invention also relates to a triazole derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof. (In)

 (The symbols in the formula have the following meanings.

Ring A: a) a benzene ring which may be substituted with 1 to 3 substituents selected from halogen, nitro, amino, lower alkyl group or a group represented by —X—R ⁴ , or

 b) a thiophene ring optionally substituted with an aryl group,

R ^{1 is a} hydrogen atom or a lower alkyl group,

R ² : a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, an optionally substituted lower alkynyl group, or an optionally substituted amino Base

R ³ : hydrogen atom, halogen atom, amino, nitro, cyano, trifluoromethyl, lower alkyl, lower alkyl group,

Or may form a cycloalkyl ring together with the R ² group

 Y: CH or N

X: single bond, — NH—CO—, — CO—NH—, — NH—CO—NH—, one NH—CS—NH—, one (CH ₂ ) _k — 0—, or one-one (CH ₂ ) _k — group 4: aryl group optionally substituted by lower alkyl or aryl group; 5- or 6-membered heteroaryl group optionally substituted by lower alkyl group; optionally substituted by lower alkyl group Good 3-8 membered saturated heterocyclic groups;

 m: Integer from 1 to 3

 k: integer from 0 to 5

And伹, R ¹ groups are methyl groups in ring A Bifue two Le group, Y is CH, m is 1, R ³ groups are water atom, and, except for the compound R ² groups are methoxy groups. )

 The triazole derivative according to the present invention will be further described.

Preferred compounds in the present invention are those represented by the above general formulas (I) and (1). R ² is

1) Formula 1 R ⁵ , 100 (CH ₂ ) _P _R ⁵ , -NH- (CH ₂ ) _p — R ⁵ , -CO- (CH ₂ ) _P — R ⁵ , -CO-O- (CH ₂ ) an alkoxy, lower alkyl or lower alkynyl group having a substituent selected from the group represented by _p —R ⁵ and —CO—NH— (CH ₂ ) _p— R ⁵ ;

[Wherein, R ⁵ represents i) a hydrogen atom, or ii) an aryl, a 5- to 6-membered heteroaryl or a 3- to 8-membered saturated heterocyclic group (these ring groups may further be a halogen atom, amino, nitro , Cyano, lower alkyl, —0—lower alkyl, one COO—lower alkyl, one CO—3- to 8-membered saturated heterocycle, one CO—3- to 8-membered saturated heterocycle, one- to three- to 8-membered saturated heterocycle 1-CO--3- to 8-membered saturated heterocyclic ring-lower alkyl, aryl, 5- or 6-membered heteroaryl, or 3- to 8-membered saturated heterocyclic group which may be substituted with a lower alkyl group And p is an integer of 0 to 4];

产 Η ₂ ). \

 -N X

 \ /

2) a group ^{represented by the} formula ( ^eH2 ) ";

(Where X is CH—R ⁶ , N—R ⁶ , O or S, where R ⁶ is lower alkyl, 1 O—lower alkyl, 1 COO—lower alkyl, —CO—3 to 8 member saturated Ring-lower alkyl, aryl, 5- to 6-membered heteroaryl or 3- to 8-membered saturated heterocyclic group, and Q and r are integers of 1 to 3);

Is a triazole derivative or a pharmaceutically acceptable salt thereof,

Also, the A ring has the formula

(Where X and R ⁴ are as described above, and R ⁷ is a hydrogen atom, a halogen atom, a nitroamino or a lower alkyl group)

A triazole derivative or a pharmaceutically acceptable salt thereof, which is a group represented by the formula: In a further preferred compound of the present invention, Y is CH and the R ² group is represented by the following formula: And a pharmaceutically acceptable salt thereof.

One 0 (CH ₂ ) n— R ⁵

1 0-(CH ₂ ) _n -0- (CH ₂ ) _P -R ⁵

One O— (CH ₂ ) _n -NH- (CH ₂ ) _P -R ⁵

— O-(CH ₂ ) _n — CO— (CH ₂ ) _P - ⁵

One O-(CH ₂ ) _n — CO— O-(CH ₂ ) _P - ⁵

— O-(CH ₂ ) _n -CO-NH- (CH ₂ ) _P -R ⁵

(Where R ⁵ and p are as described above, and n is an integer of 1 to 12)

The most preferred compound in the present invention is a triazole derivative or a pharmaceutical thereof, wherein the A ring is a 4-biphenyl ring, R ¹ is a methyl group, and ² is a group represented by —0— (CH ₂ ) _n —R ^5. It is a chemically acceptable salt, and specific examples include the following compounds. 8. 4- (2-benzyloxyphenyl) -1-3- (4, -biphenyl) -1-5-methyl-1,2,4-triazole, 4- {2-[5-(4-methylbiperazine-1) 1-yl) pentyloxy] phenyl}-3-(4, -biphenyl) -1-5-methyl-1,2,4-triazole, 4- {2- [6- (4-methylpyrazine-1) 1 ^ f) hexyloxy] phenyl} 1-3- (4,1-biphenyl) 1 5-methyl-1,2,4-triazolyl, 4- {2-[7- (4-methylpiperazine-1 1-yl) Heptyloxy] phenyl} —3- (4, -biphenyl) -1-5-methyl-1,2,4-triazolyl, 4- {2-[8— (4-methylpiperazine—11) Yl) octyloxy] phenyl} 1-3- (4, -biphenyl) 1-5-methyl-1,2,4-triazole, 4-1 {2- [6-(4-methylpiperazine-1-11yl)] Hexyloxy] 6-Methylphenyl} 1 3- (4, -biphenyl) — 5 —Methyl-1,2,4-triazole, 4- {2-[6-(4-Methylhomopyrazine-11-yl)] Xyloxy] — 6 _methylphenyl} 1 3 — (4, -biphenyl) _ 5 —methyl_1,2,4-triazolyl, 4 — [2 — (6-piberidinohexyloxy) phenyl] 1 3 — (4, -biphenyl) -1-5-methyl-1,2,4-triazole, 4- {2- [6- (4-piperidinopiperidine-1-11yl) Hexyloxy] phenyl} 1- (4-biphenyl) 5-methyl-1,2,4-triazole, 4- {2-1- [4- (4-piperidinopiperidine-1-yl)] Hexyloxy] — 6-methylphenyl} 1 3- (4, -biphenyl) — 5-methyl-1,2,4-triazole, 4- {2— [4- (4-piperidyl) butoxy] phenyl} -3-(4, -biphenyl) — 5-methyl-1,2,4-triazole, 4- {2- [4- (4-methylpiperazine-1 1-yl) carbonylphenyl] methoxy-6-methylphenyl Nyl} — 3 -— (4-,-Piphenyl) — 5-Methyl-1,2,4-triazole, 4- {2- [4- (4-Piperidinopiperidin-1 1-yl) carbonylphenyl] methoxy— 6-methylphenyl}-3-(4'-biphenyl) — 5-methyl-1,2,4-triazole, 4- {2-[4- Razine-1 -yl) carboxyphenyl] methoxyphenyl} 1-3-(4'-biphenyl) 1-5-methyl-1, 2, 4-triazole or 4- {2-[3- (3 -Pyridyl) propyl] phenyl} 3- (4, -biphenyl) -5-methyl-1,2,4 triazole.

 In addition, in the definition of the group of the general formula in this specification, "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

 Accordingly, a “lower alkyl group” is an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methyl, ethyl, propyl, butyl, pentyl, hexyl group, or an isopropyl group, or the like. And is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl or ethyl group.

 “Lower alkynyl group” is an alkynyl group having 2 to 6 carbon atoms, specifically, ethynyl group, 1-propenyl group, 1-l-pentynyl group, 1-l-pentynyl group, 1-l-hexynyl group Or a structural isomer such as a 1-methyl-2-propynyl group, preferably an ethenyl group.

The “alkoxyl group” is an alkoxyl group having 1 to 12 carbon atoms. Specifically, it is a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, a heptanoxy group, an octanoxy group. Group, nonanoxy group, decanoxy group, pendecanoxy group, dodecanoloxy group, or the same carbon number Having a branched alkoxyl group.

 Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and a fluoride atom.

 “Aryl” is an aromatic ring having 6 to 14 carbon atoms and may have a substituent, and specific examples thereof include benzene, naphthalene, anthracene, and phenanthrene group, and preferably benzene. .

 "5- to 6-membered heteroaryl" refers to a 5- or 6-membered aromatic ring having 1 to 4 N, 0 or S atoms, which may have a substituent, specifically, furan, Examples include pyrrol, thiophene, imidazole, pyrazole, oxazole, thiazole, triazole, pyridine, pyrazine, pyrimidine, tetrazole and the like.

 The “3- to 8-membered saturated heterocycle” is a 3- to 8-membered saturated monocyclic ring having 1 to 3 N atoms which may contain 0 or S atoms, specifically, for example, azepine, Examples include piperidine, piperidine, piperazine, and morpholine.

Examples of the substituent of the “optionally substituted alkoxyl group”, the “optionally substituted alkyl group” and the “optionally substituted alkynyl group” of R ² include aryl and 5 to 6 members. Terroaryl or a 3- to 8-membered saturated heterocyclic group, or these ring groups are —O— (CH ₂ ) _p —, —NH— (CH ₂ ) _p —, —CO— (CH ₂ ) _p —, —CO — O— (CH ₂ ) _p —, —CO-NH— (CH ₂ ) _p — group (p is an integer of 0 to 4), and other substituents, such as halogen atom, amino, cyano, and nitrite Mouth, — OH, 1 O—lower alkyl, 1 NH—lower alkyl, 1 N—di—lower alkyl, — CO—lower alkyl, — COOH, 1 COO—lower alkyl, 1 C〇NH ₂ , 1 CO NH— And lower alkyl groups. Here, the aryl, the 5- or 6-membered heteroaryl, and the 3- or 8-membered saturated heterocyclic group may further have a substituent. Any substituent can be used as the substituent for these ring groups, as long as it is a commonly used substituent. For example, lower alkyl (the lower alkyl is a halogen atom, 10-lower alkyl, one COOH, amino, one NH-lower alkyl) And may be substituted with 1 to 4 substituents selected from the group consisting of N-di-lower alkyl group), halogen atom, amino, nitro, cyano, 10H, —〇lower alkyl , One C〇〇H, one COO—lower alkyl, one CO—3NO To 8-membered saturated heterocyclic ring, _C〇3 to 8 membered saturated heterocyclic ring 1 to 3 to 8 membered saturated heterocyclic ring, 1 CO-3 to 8 membered saturated heterocyclic ring, lower alkyl, —NH-lower alkyl, - N- Gee lower alkyl, one S- lower alkyl, -SO- lower alkyl, -S0 ₂ - lower alkyl, one C_〇_NH ₂ one CONH - lower alkyl, Ariru, Teroari Ichiru or lower to 5 or 6-membered Examples thereof include a 3- to 8-membered saturated heterocyclic group which may be substituted with an alkyl group, which may have 1 to 3 substituents.

Preferred substituents for the “optionally substituted alkoxyl group”, the “optionally substituted alkyl group J” and the “optionally substituted alkynyl group” are those represented by the formula —R ⁵ , 10— (CH ₂ ) _p — R ⁵ , — NH— (CH ₂ ) _p — R ⁵ , —CO— (CH ₂ ) _P — R ⁵ , — CO— O— (CH ₂ ) _p — R ⁵ or one CO—NH— (CH ₂ ) _p — is a group represented by R ⁵ . (Where R ⁵ is i) a hydrogen atom, or ii) an aryl, a 5- to 6-membered heteroaryl or a 3- to 8-membered saturated heterocyclic group (these ring groups are further halogen atoms, amino, nitro, cyano , Lower alkyl, —O—lower alkyl, —COO—lower alkyl, —CO—3- to 8-membered saturated heterocycle, 1-CO—3- to 8-membered saturated heterocycle, _3- to 8-membered saturated heterocycle, _CO — 3- to 8-membered saturated heterocyclic ring-lower alkyl, aryl, 5- or 6-membered heteroaryl, or 3- to 8-membered saturated heterocyclic group which may be substituted by lower alkyl group Good) and p is an integer from 0 to 4)

Specific examples of such an “optionally substituted alkoxyl group” include the following. Phenylalkoxy group, (4-alkylpiperazin-1-ylcarbonyl) phenylalkoxy group, (4-piperidinopiperidinocarbonyl) phenylalkoxy group, (piperidinocarbonyl) phenylalkoxy group, (4-alkylpyridinyl) Razine-1-ylcarbonyl) alkoxy group, (4-piperidinopiperidinocarbonyl) alkoxy group, (piperidinocarbonyl) alkoxy group, (morpholino-capillon) alkoxy group, (alkoxy-caprolponyl) alkoxy group, ( (Hydroxycarbonyl) alkoxy group, [(4-alkylpyrazine-111-Tyl) alkylaminocarbonyl] alkoxy group, [4- (pyrimidin-2-yl) pyrazine-1-1yl] alkoxy Group, [4— (2—pyri (Jil) piperazine-11-yl] alkoxy group, (4-alkylpiperazine-11-yl) alkoxy group, (4-alkylhomopirazine-1-yl) alkoxy group, (4-piperidino Piperidino) alkoxy group, [(piveridinyl 11-yl) alkylamino] alkoxy group, piperidinoalkoxy group, piperidylalkoxy group, morpholinoalkoxy group, pyridylalkoxy group, imidazolylalkoxy group, (2-aminophenoxy) And an alkoxy group, a hydroxyalkoxy group, and the like.

The “optionally substituted amino group” of R ² may be an amino group substituted with a lower alkyl group, or may form a saturated heterocycle containing an N atom together with the substituent. Preferably,

—

で示される基である。 ここで、 Xは C H— R ⁶、 N— R ⁶、 0又はformula

Is a group represented by Where X is CH—R ⁶ , N—R ⁶ , 0 or

S is R, and R ⁶ is lower alkyl, lower alkyl-1 O—, lower alkyl 1-1 CO 1, lower alkyl 1- to 8-membered saturated heterocycle CO—, aryl, 5- to 6-membered heteroaryl or 3 to It is an 8-membered saturated heterocyclic group, and Q and r are integers of 1 to 3.

Specific examples of the cycloalkyl group formed by combining the R ² group and the R ³ group include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

Specific examples when the ring A is a phenyl group substituted with the group represented by X—R ⁴ include the following.

Phenoxyphenyl group, phenylalkoxyphenyl group, (2-biphenyl) carbonylaminophenyl group, biphenyl group optionally substituted by lower alkyl group, furylcarbonyl optionally substituted by lower alkyl group Aminophenyl group, biphenyl group, piperidinophenyl group, (piberidinoalkoxy) phenyl group, pyrrolidinylphenyl group optionally having substituent (s), imidazolyl group optionally having substituent (s) A phenyl group, a thiazolylphenyl group which may have a substituent, A ruphorinophenyl group, a (morpholinoalkoxy) phenyl group, a phenyl-perylene phenyl group optionally substituted with a lower alkyl group, a phenylthio-perylene phenyl group optionally substituted with a lower alkyl group, Examples thereof include a phenyloxyphenyl group and a phenylthiophenyl group.

 In some cases, the compound of the present invention can form a salt with an inorganic acid or an organic acid, and these salts also have an action inhibiting effect. Suitable salts include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid Salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, carbonic acid, glutamic acid, aspartic acid, methanesulfonic acid, ethanesulfonic acid, sodium, potassium, magnesium, calcium, aluminum And the like, salts with organic bases such as methylamine, ethylamine and ethanolamine, and salts with basic amino acids such as lysine and orditin. Also, a quaternary ammonium salt can be formed by reaction with a lower alkyl halide, lower alkyl triflate, lower alkyl tosylate, benzyl halide, or the like, but quaternary ammonium salts include methyl iodide or benzyl chloride. Are preferred.

 The compound of the present invention may have an optical isomer based on an asymmetric carbon atom and a geometric isomer based on a double bond ゃ cyclohexan ring, and when the compound has two or more asymmetric carbon atoms, In addition, diastereoisomers exist. The present invention includes isolated ones of these various isomers and a mixture of these isomers. The compounds of the present invention also include hydrates, various solvates, tautomers and the like. Further, some of the compounds of the present invention have a crystalline polymorph, and the compounds of the present invention include all such crystalline forms.

The compound which is an active ingredient of the medicament according to the present invention is a compound represented by the formula (I), wherein the A ring group is a 4-biphenyl group, R ¹ is a methyl group, Y is CH, m is 1, R ³ is a hydrogen atom. And R ² is new except for those having a methoxy group. In the above formula (I), a compound in which the A ring group is a 4-biphenyl group, R ¹ is a methyl group, Y is CH, m is 1, R ³ is a hydrogen atom, and R ² is a methoxy group. The Labtest GmbH (Freiberg, Germany) This product is available on request from Rabotest.

 (Manufacturing method)

 Hereinafter, the method for producing the compound according to the present invention will be described.

 The 3,4-diaryl-substituted-5-substituted-1,2,4-triazole derivative (7), which is the basic skeleton, can be usually produced by the following two methods. First, as a first method, as shown in the following formula, an aromatic carboxylic acid (1) is condensed in an inert solvent such as tetrahydrofuran diacetonitrile as an aromatic sulfonic acid chloride activated with thionyl chloride or the like. Or the reaction of an acid hydrazide (4), obtained by reacting an aromatic sulfonic acid ester with 10 equivalents of hydrazine in an alcohol, in the presence of an acylating agent such as acetic anhydride and an organic base such as pyridine. Condensation, or by reacting the aromatic carboxylic acid chloride (2) directly with the acid hydrazide to obtain diacylhydrazine (5), and the diacylhydrazine (5) thus obtained is converted to phosphorus pentoxide or the like. The cyclization reaction is carried out in the presence of a dehydrating agent to give 1,3,4-oxazole (6), which is heated with an aniline derivative without solvent, or acid-catalyzed with tosylic acid or the like. 1 can be obtained the target by the presence of heating to reflux in a solvent such as toluene, 2, 4 one Toriazo Ichiru derivative (7).

The method for producing 1,3,4-oxadiazole (6) is described below. Refer to E. Klinsberg, J. Am. Chem. Soc., 1958, 80, 5786-5789 as necessary.

 In addition, as the acid catalyst used for the heating and refluxing, besides tosylic acid, mesylic acid, sulfonic acid and the like can be used, and as the solvent, xylene, mono or dichlorobenzene other than toluene can be used.

 As a second method, as shown in the following formula, an aniline derivative (8) is condensed with an acylating agent such as acetic anhydride in an organic solvent such as tetrahydrofuran to obtain anilide (9), which is then dissolved in toluene or the like. Thioamide (10) is obtained by thioamidation using phosphorus pentasulfide in an organic solvent, and the thioamide (10) thus obtained is converted to S-methylthioimidate (11) with methyl iodide, and this is converted to acid hydrazide (4). With dimethylformaldehyde (hereinafter sometimes referred to as DMF) at 120 ° C to obtain the 1,2,4-triazole derivative (7), or by heating the compound (8) with an orthoester to obtain —Alkylimidate (12), which can be reacted with acid hydrazide (4) in the same manner as above to give 1,2,4-triazole derivative (7). In the reaction with the acid hydrazide (4), dimethylacetoamide, DMSO, 1-methyl-2-pyrrolidone and the like are suitably used as a solvent in addition to DMF.

Next, a method for converting a side chain such as an R ² group will be described.

Examples of the method for converting the side chain include the method shown in the following formula. That is, benzyloxy PT / JP00 / 00668 De-benzylation of the derivative (7) by catalytic reduction to obtain the phenol derivative compound (13), which is then subjected to a Mitsunobu reaction with an alkyl halide, alkyl sulfonate or alcohol to form an alkyl group To obtain an alkoxyphenyltriazole derivative (14). Further, an alkylenedihalide is reacted with a phenol derivative compound (13) to obtain an octogenoalkoxyphenyltriazole derivative, which is subjected to a substitution reaction with an amine to obtain an aminoalkoxyphenyltriazole derivative. Further, the iodine element (1 5), subjected to Sonogashira reaction _{(P dC 1 2 (PPh 3} ) 2, Cu I, PPh 3, acetylene / E t ₃ N-pyridine), alkylene induction body (16) , And subjected to catalytic reduction to obtain an alkylphenyltriazole derivative (17).

 In the compound of the present invention, in particular, isomers such as a racemate, an optically active substance, and a diastereomer may exist alone or as a mixture. The racemic compound is stereochemically prepared by using an appropriate starting compound or by a general racemic resolution method (for example, a method of optically resolving a diastereomeric salt with a general optically active acid (tartaric acid, etc.)). Can lead to a pure isomer. The mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.

Industrial applicability

The compounds of the present invention, as compared to the V ₂ receptor and Okishitoshin receptors AVP, V _IA receptor Has selective antagonistic activity in the body, such as vasodilatory, hypotensive, cardiac hypertrophy, cardiomyocyte hypertrophy, vascular smooth muscle cell contraction / proliferation / hypertrophy, kidney mesangial cell contraction It has an inhibitory action on growth / hypertrophy, an inhibitory action on extracellular matrix accumulation in the kidney, an inhibitory action on platelet aggregation, and an inhibitory action on vascular permeability factor (vascular endothelial growth factor) production.

Moreover, since action on AVP receptor of the present invention compounds are V _1A receptor selective, without the effect of such Motozukuko temple shrinkage in water diuretic based on V ₂ receptor antagonist, or Okishitoshin receptor antagonist may V _1A receptors AVP is present use in the treatment of various diseases involving, for example, vasodilators, antihypertensive agents, anti-heart failure agent, an anti-renal failure agent, anti-platelet aggregation inhibitor, a useful Yes, high blood pressure, heart failure, renal disease, cerebrovascular disease, diabetes, diabetic nephropathy, diabetic retinopathy, various ischemic diseases, circulatory failure, arteriosclerosis, dysmenorrhea, gastric ulcer, nausea, vomiting, fainting, It is effective for the prevention and treatment of malignant tumors, cancer, renal dysfunction, etc. In particular, it is useful for the prevention and treatment of diabetic nephropathy.

 Further, the compound of the present invention has excellent oral absorbability, is hardly metabolized in vivo, and has good sustainability.

 Hereinafter, the pharmacological action of the compound of the present invention will be described with reference to experimental examples.

(1) Receptor binding test using human _V1A receptor-expressing cell membrane preparation

Preparation of human V _1A receptor expressing cells Thibomiier et al method (J. Biol. Chem. 269 ( 1994), 3304-3310) was carried out in accordance with. [ ³ H] AVP (0.5 nM) and a cell membrane preparation expressing human _V1A receptor were mixed with various concentrations of the test agent and incubated. The assay was performed in a total volume of 2501, the assay buffer was 50 mM Tris-HCl buffer (pH = 7.4) containing 10 mM magnesium chloride and 0.1% serum albumin, and the incubation time was 25 ° C. Went in one hour. After the incubation, the cells are subjected to suction filtration using a cell harvester and passed through a glass filter (GF / B) to remove the free ligand and excess buffer, and the labeled ligand bound to the membrane sample is removed from the glass filter. Trapped. After the glass filter was sufficiently dried, it was mixed with a liquid scintillation cocktail, and the radioactivity was measured with a liquid scintillation counter. 50% inhibition of specific binding of [ ³ H] AVP to membrane preparation of test drug Concentration (IC ₅ o value) was determined from regression analysis of the displacement curve of the test drug. Inhibition constants (Ki values) were calculated from the _{Ki = IC 50 / (l +} [L] / Kd) ([L] is [IH] concentration of AVP, Kd was determined from saturation binding experiments or found Scatchard plot analysis values ). The negative logarithm of the Ki value calculated above was taken as the pKi value.

As a result, the example compounds of the invention showed good affinity for the human V _1A receptor in the range of pKi values from 6.0 to 9.1.

(2) _V1A receptor binding test using rat liver membrane preparation

Preparation of rat liver membrane preparation was performed according to the method of Nakamura et al. (J. Biol. Cem. 258 (1983), 9283-9289). [ ³ H] AVP (0.5 nM) and rat liver membrane specimens were mixed with various concentrations of the test drugs and incubated. Atssay was performed in a total volume of 250 d, and Atsushi buffer was used with 50 mM Tris-HCl buffer (pH = 7.4) containing 10 mM magnesium chloride and 0.1% serum albumin, incubation time was 1 hour at 25 ° C. . After the incubation, the cells were subjected to suction filtration using a cell harvester, and free ligand and excess buffer were removed by passing through a glass filter (GF / B) to bind to the membrane sample at the glass filter. Labeled ligand was trapped. After the glass filter was sufficiently dried, it was mixed with a cocktail for liquid scintillation, and the radioactivity was measured with a liquid scintillation counter. The concentration (IC ₅₀ value) that inhibits the specific binding of [ ³ H] AVP by 50% to the membrane preparation of the test drug was determined by regression analysis of the displacement curve of the test drug. Inhibition constant (Ki value) was calculated from Ki = ICso I (1 + [L] I Kd) ([L] is the concentration of [1H] AVP, and Kd is the value obtained from the saturation binding experiment by Scatchard plot) . The negative logarithm of the Ki value calculated above was taken as the pKi value. As a result, the example compounds of the present invention showed good affinity for rat _V1A receptor.

(3) V _1A receptor antagonism in conscious rats (oral administration)

Male Wistar rats were anesthetized with pentobarbital sodium (60 mg / kg intraperitoneally), and a polyethylene tube for blood pressure measurement was introduced into the left common carotid artery. Rats were housed in individual cages and used for experiments after a 1-2 day recovery period. Blood pressure was measured from an arterial tube via a pressure transducer under anesthesia and unrestrained. To rats AVP (30 mU / kg) was administered intravenously, and the increase in blood pressure at that time was measured. The test drug was suspended orally in a 0.5% methylcellulose solution, and the pressor response due to AVP was measured. The pressor response by AVP before administration of the test drug was defined as 100%, and the suppression rate of the pressor response by AVP after administration of the test drug was observed over time to determine the _V1A receptor antagonism.

As a result, the compound of the present invention exhibited potent and sustained V _1A receptor antagonistic activity. Pharmaceutical compositions containing one or more of the compounds represented by the general formulas (I) and (1) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient are commonly used. Tablets, powders, granules, granules, capsules, pills, liquids, injections, suppositories, ointments, patches with the use of carriers, excipients and other additives Etc. and administered orally or parenterally.

 The clinical dose of the compound of the present invention for humans is appropriately determined depending on the individual case in consideration of the symptoms, age, sex, weight, etc. of the patient to which the compound is applied. 5500 mg, which is administered once or in several divided doses. Since the dose varies under various conditions, a dose smaller than the above range may be sufficient.

 Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicone. It is mixed with magnesium acid aluminate.

In accordance with the usual methods, the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, glutamic acid. Alternatively, a solubilizing or solubilizing agent such as aspartic acid may be contained. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as Contains purified water and ethyl alcohol. The composition may contain, in addition to the inert diluent, solubilizing or solubilizing agents, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

 Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of aqueous diluents and suspension diluents include distilled water for injections and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and surfactants such as polysorbate 80 (trade name). Agents. Such compositions may further include isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing or solubilizing agents (eg, glutamic acid, aspartic acid). May contain various additives. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They can also be used in the preparation of a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use.

BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples. It goes without saying that the present invention is not limited to only the compounds of the examples. Further, when the raw materials used in the present invention are new, they will be described as reference examples.

Example 1

 4- (2-Methoxyphenyl) -1-3- (4'-biphenyl) -1,2,4-triazole (Compound No. 22)

 3— (4'—Biphenyl) — 1,3,4-oxaziazol (538mg) and o-anisidine (6ml) are insoluble! Then, it was heated at 150 ° C for 12 hours. The reaction mixture was purified by silica gel column chromatography to give the title compound (95 mg, 12%) as a brown solid. The NMR data of the obtained compound are as follows.

3.63 (3H, s), 7.11 (1H, t, 1 = 1.5Hz), 7.25 (1H, d, J = 8.4Hz), 7.35-7.57 (7H, m), 7.67-7.69 (4g, ffl), 8.72 (1H, s) Reference example 1

 N- (2-benzyloxyphenyl) acetamide

 Acetic anhydride (20 ml) was added to a solution of 2-aminophenol (10.91 g) in ethyl acetate (100 ml) at room temperature, and the mixture was stirred for 30 minutes. After concentrating the reaction solution, ethyl acetate was added to the residue, and the crystals were collected by filtration. A mixture of the crystals, benzyl bromide (18.8 g), and potassium carbonate (30.0 g) in acetonitrile (300 ml) was stirred at 70 ° C. overnight. After filtering the reaction solution, ethyl acetate was added to the residue, which was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography 1 to give 22.64 g (94%) of the title compound as a white solid. Its physical properties are as follows.

FAB-MS m / z: 242 (M + + H).

'Η -Recommended R (CDCI ₃ ) δ: 2.15 (3H, s), 5.12 (2, s), 6.92-7.05 (3 m, m), 7.35-7.48 (5H, m), 7.76 (1H, br s) , 8.30-8.40 (1H, m).

Reference example 2

 N- (2-benzyloxyphenyl) -S-methylacetothioimidate N- (2-benzyloxyphenyl) acetamide (22.5 5 g), phosphorus pentasulfide (23.0 g )) (300 ml) was stirred at 70 ° C. for 2 hours. The supernatant of the reaction solution was separated and concentrated, and the residue was purified by silica gel column chromatography to obtain 11.51 g of N- (2-benzyloxyphenyl) thioacetamide as a brown liquid. . This and a mixed solution of methyl iodide (20.0 g) and potassium carbonate (30.0 g) in acetonitrile (300 ml) were stirred at 50 ° C. for 3 hours. After filtration of the reaction solution, ethyl acetate was added to the residue, which was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography to give 16.23 g (64%) of the title compound as a red liquid. Its physical properties are as follows.

FAB-MS m / z: 272 (M + + H).

'Η-丽 R (CDC1 ₃ ) δ: 1.97 (3Η, s), 2.46 (3Η, s), 4.99 (2H, s), 6.65 (1H, d, J = 10Hz), 6.90- 7.08 (3H, m ), 7.28-7.49 (5H, m). oz garden ^^ l ^ 齄 驟 驟 I w w w I I I I 園 園 ^

• 0) Mine ^ —Ma 4 ^. , /% 0 and 8 Z), Γι4— 'Ζ Ί -Λ (ΐ ^-g-(nyaet 3—') one ε- nie ^:, ψ κ く ^ 一 z) one

 (ε ^ violent 导 [^ one

— — /, Γ — ^C Z 'X -Λ (^^-S-(("^^ 7 \-') — ε]-ζ

(ui 'Η ΐ) 09' ί-ΟΖ 'I' (ui 'Η)

9ΐ Ά-96 · 9 '(ΖΗ81-ί' Ρ 'ΗΙ) 90' 9 '(ΖΗ8ϊ = ί' Ρ 'ΗΙ) 96' (s 'Η8) 18 Ύ' 9 (

、丽 驟¾ え^ ^ ° つ^ ¾¾ 翻 つ。 o sて ¾逖缀 ( ΐ 'd co マ 「QS〇 土 ^ 一 ^ WN))) ¾ ° ¾ (% 99) ZS 呦 ^ ίΐϋ ^ 齄

¾, 丽 ¾ ¾ ^ ¾ つ. os ¾ ¾ 缀 缀 (¾ 'd co Ma'

^ ΊΓ ^^^ Ο) (Suig I z) Piku Nyeoto —, (Sino 0

(6 S ^ violence — ^l Z Ί-(ichi (ni ェ oto 3 —,) — ε — (r nier ^ 4 ψ κ, ku ^ ζ)-

 z m

'(s Jq' HI) 88 "6 '(ω'ΗΖ)

00 -8-06 ・ ί '(ui' cold 6 '-09 · ί' (in 'Η2) 09' Z-08 'ί' (s Jq 'ΗΖ) Ζ 1- Q 13 (D)

• (H + ₊ i¾) SIZ: z / ui SK-aVd

° ¾¾ ^ 0! 歷 0) 丄 ^ ¾ 呦 0) 0) Co § 6 S-T Tsuma Garden ^ Halla

'^ η ίΐί ^ ^^ ο ί I ^ ^ ^ m ^ (ι o τ) ir- ^ x> (o ■ s) I · ¹ (S 92 -z) 鏹 ^^: — One Ni ^ :: λ

89900 / 00df / X3d 0888S / T0 OAV (2.05 g) was obtained as a form. The NMR data of this is as follows. Ή—Awake R (DMS0- d ₆ ) 6: 2.17 (3H, s), 6.95 (IH, t, J = 8Hz), 7.07 (IH, t, J = 8Hz), 7.30-7.53 (7H, m), 7.60-7.65 (4H, m), 10.33 (IH, s)

Reference example 4

 4- [2- (6-Promohexyloxy) phenyl] -1-3- (4'-biphenyl) —5-methyl-1,2,4-triazolyl

 2- [3- (4'-biphenyl) -1-5-methyl-1,2,4-triazo-1-yl-4-phenol] phenol (1.04 g), 1,6-dibumohexane (3.90 g) ) And potassium carbonate (3.0 g) in acetonitrile (50 ml) were stirred at 50 ° C for 30 minutes. After the reaction solution was filtered, ethyl acetate was added to the residue, which was washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography to obtain 1.22 g (77%) of the title compound as amorphous.

 Its physical properties are as follows.

FAB-MS m / z: 492 (M ++ H).

 (H-NMRCCDCla) δ: 1.15-1.35 (4Η, m), 1.50-1.65 (2H, m), 1.68-1.90 (2H, m), 2.29 (3H, s), 3.31 (2H, t, J = 7Hz ), 3.75-3.99 (2H, m), 7.06 (2H, t, J = 8Hz), 7.15—

7.60 (13H, m).

Example 4

4- {2 -— [6 (4-Methylpiperazine-1-11-yl) hexyloxy] phenyl} — 3 -— (4 ^: biphenyl) —5-methyl-1--1,2,4-triazole Compound number 54)

4- [2- (6-Promohexyloxy) phenyl] — 3- (4′-Biphenyl) — 5-Methyl 1,2,4-triazole (0.60 g), 1-Methylpirazine (20 Omg ) And potassium carbonate (2.0 g) in a mixture of acetonitrile (2 Om 1) were stirred at 70 ° C. for 2 hours. After the reaction solution was filtered, the residue was mixed with formaldehyde-methanol (10: 1), washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography, and crystallized from hexane monoethyl acetate to give 42 Omg (69%) of the title compound as a white solid. This one

m), 6. "95-7.60 (15H, m), 8, 30 (1H, s), 8.39 (1H, d, J = 5Hz)

Example 7

 4- (2- {2- [4- (4-Methylpiperazine-1-11-yl) caprolpophenyl) ethynyl} phenyl) -1-3- (4'-biphenyl) -1-5-methyl-1,2,4-triazole (Compound No. 41)

 4- (2-phenyl) iodide 3- (4'-biphenyl) -5-methyl-1-

2,4-triazole (1.30 g), triethylamine (10 ml), pyridin (4 ml), copper iodide (56 mg), dichlorobis (triphenylphosphine) palladium (104 mg) and triphenylphosphine (780 mg) ) Was stirred at 70 ° C overnight. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography and crystallized from hexane monoethyl acetate to obtain 1.22 g (68%) of the title compound as beige powder. The NMR data of this is as follows.

H-NMR (DMS0-d ₆ ) δ: 2.25-2.47 (4Η, m), 2.33 (3H, s), 2.38 (3H, s), 3.42 (2H, brs),

3.79 (2H, brs), 7.30-7.58 (17H, m)

Example 8

 4- (2- {2- [4- (4-Methylpiperazine-1-1-yl) carbonylphenyl] ethyl} phenyl) 1 3- (4'-biphenyl) -1-5-methyl-1,2,4-triazol ( (Compound No. 42)

 4- (2- {2- [4- (4-Methylpiperazine-1-11-yl) carbonylphenyl] ethynyl} phenyl) — 3 -— (4′-biphenyl) -1-5-methyl-1,2,4-triazole ( 1.09 g) was subjected to catalytic reduction for 3 days in methanol (30 ml) using 10% palladium carbon (700 mg) as a catalyst. After filtering the reaction solution, the residue was purified by silica gel column chromatography, and crystallized from hexane monoacetate to give 175 Omg (67%) of the title compound as a white powder. The NMR data for this is as follows.

'H-NMR (DMSO-d ₆ ) δ: 2.20-2.65 (8Η, m), 2.23 (3H, s), 2.30 (3H, s), 3.41 (2H, brs), 3.75 (2H, brs), 6.93 (2H, d, J = 7.8Hz), 7.17-7.56 (15H, m) Tables 1 to 8 below show the structural formulas of typical compounds of the novel triazole compounds according to the present invention, including the compounds obtained in the above Examples, together with their physical properties. Further, among the compounds other than the compounds described in the examples, the NMR data of the compounds whose physical properties are indicated as amorphous crystals are also shown in Tables 9 to 11. Compounds other than those described in the examples can be easily prepared by substantially the same methods as those described in the above-mentioned production methods and examples, or by applying slight modifications obvious to those skilled in the art. _c Note can be, symbols in the tables have the following meanings.

 No: Compound number

 NMR: nuclear magnetic resonance spectrum,

 m.p .: melting point, Amorph .: amorphous crystal,

 Me: methyl, Et: ethyl, Pr: propyl,

 iPr: isopropyl, Bn: benzyl,

In addition, “4-”, “5-” and “6-” attached to the substituents in the table represent “4”, “5” added to the structural formula in the table regardless of the chemical name. , "6" means that a substituent is bonded.

表 2

表 3

表 4

表 5

表 7

表 8

化合物 ^l H - NMR δ ( p p m)

Table 2

Table 3

Table 4

Table 5

Table 7

Table 8

Compound ^l H-NMR δ (ppm)

3 2.14C3H, s), 2.3K3H, s), 2.46C2H, br s), 3.42C2H, br s), 3.79 (2H, br s), 4.93-5.06 (2H , m), 7.00-7.05 (3H, m), 7.10 (1H, dt, J = 7.8, 1.0 Hz), 7.2K1H, dd, J = 7.8, 1 . 9Hz), 7. 3K3H, t , J = 8. 8Hz), 7. 39 (2H, dd, J = fi. 9, 1. 9Hz), 7. 48 (111, m) / CDCl 3

4 2.33C6H, s), 2.9C2H, br s), 3.41 (2H, br s), 3.79 (2H, br s), 4.93-5.06C2H, m), 7.06C2H , d, J = 8.3 Hz), 7.11-7.17C2H, m), 7.23C1H, m), 732H, d.J = 10.3Hz) .7.52 (1H, m), 7.60-7.63C2H, m), 8.11 (2H, d, J = 9.3Hz) / CDCl ₃

5 2.27C3H, s), 2.32C3H, s), 2.47 (2H, br s), 3.4K2H, br s), 3.79 (4H, br s), 4.94-5. 06C2H , m), 6.50-6. 52 (2H, m), 7.00-7. 07C4H, i), 7.18 / ϋΛύΠ »11, 1 · tj, il, U, J-0 · Ϋ́ίΐώ ノ · f · ¾ύ 、 丄 Π 、 JI1 ノ / し L <レ 3

8 1.66C3H, s), 2.25C3H, s), 2.32 (3H, s), 2.45C2H, br s), 3.39C2H, br s), 3.75C2H, br s), 4. 93-5. 03C2H, m), 7.00-7. 19C4H, m), 7.22 (1H, m), 7.26-7. 37C7H, i), 7.48C1H, m), 7.8K1H , br s), 7.9K1H, br s) /

9 1.64 (3H, s), 2.23C3H, s), 2.28C3H, s), 2.32 (2H, br s), 2.4 (2H, br s), 3.37C1H, br s ), 3.77C1H, br s), 4.90-4. 98C2H, m), 7.00-7. 09C5H, m Πυ ヽ, 71 · 1111— "7 C ^ QU m ヽ l

i. ώΟ, ΰΠ) nU, 7 "OR Ri itl, m ίΙΙ _{ヽ" A 0 n ^ 1i0l, m} mヽdi, / <^ G Ri fl U

 丄 n, Dr-r S ο ノ, 71.7 <11

(1H, d, J = 7.6Hz), 8.62 (1H, br s) / CDCl ₃

1 2 1.30-1.70C6H, i), 1.90-2.05C2H, m), 2.12C3H, s), 2.40-2.80C6H, m), fumarate 3.70C3H, s), 8.90-4. 05 (2H, m), 6.54 (2H, s), 6.75-7.55 (8H, m) /

 DMSO-de

1 7 1.95C3H, s), 2.26 (3H, s), 2.31 (3H, s), 2.48 (3H, s), 3.38C2H, br s), 3.76C2H, br s ), 5.03 (2H, m), 6.89C1H, d, J = 0.9Hz), 6.92-7.00C2H, m), 7.10 (2H, d, J = 6.9Hz), 7.26-7.44C3H, i), 7.5 belly m), 7.82C2H, dd, J = 6.9, 2.0Hz) / CDCl ₃

1 8 1.95 (3H, s), 2.26C3H, s), 2.3K3H, s), 2.45C2H, br s), 2.74C3H, s), 3.38C2H, br s), 3. 76C2H, br s), 4.98-5.08C2H, m), 6.91-7.00C2H, m), 7.04C2H, d, J = 8.3Hz), 7.28-7.37C4H, m ), 7. 48C2H. dd, J = 6. 9, 1. 9Hz), 7. 77C2H, dd, J = 6. 9, 1. 9Hz) / CDCl 3 Table 1 o Compound ^l H-NMR δ (ppm)

 I 2 0 1.2 C3H, t, J = 7.Hz), 2.31 (3H, s), 2.62 (2H, q, J = 7.8 Hz), 4.97-5.10

 (2H, m), 6.96C1H, d, J = 0.9Hz), 7.00-7.29 (8H, in), 7.33-7.38C3H, m), 7 47-7 HC¾H m CDC

2 1 2.05C3H, s), 2.27 (3H, s), 2.32 (3H, s), 2.43C2H, br s), 3.36C2H, br s), 3.75C2H, br s) , 5.05C2H, m), 6.80 (IH, d, J = 3.9 Hz), 6.88 (1H, d, J = 7 QH7 *) 7 ri J = 7 D 7 (1R-7 1 1 CE m 7 9R-7 ii / 'RH m ") 7.50-7. 53C2H, m) / CDCl _a

4 8 1.25-1.90C10H, m), 2.24C3H, s), 2.45-3.00C5H, m), 3.65-3.80C2H, m) fumarate.4 30-4.40C2H.m), 4.92C1H, d, J = 15Hz), 5.04 (1H, d, J = 15Hz), 6.56

(2H, s), 7.00-7.70C13H, m) / D S0-d ₆

5 1 1.01-1.12 (2H, m), 1.16-1.29C2H, m), 1.37-1.48 (2H, m), 2.04-2.21 (10H, m), 2. 10 (3H, s), 2.16C3H, s), 3.81-4.0K2H, m), 7.12C1H, t, J = 7.7Hz), 7.27C1H, d, J = 8.1Hz) , 7.34-7.56 (7H, m), 7.63-7.67C4H, m)

5 5 1.20C6H, brs), 1.36-1.44 (2H, m), 1.50-1.57C2H, m), 2.24-2.30C4H, m), 2.28 (3H, s ), 2.29C3H, s), 2.43C6H, brs), 3.80-3.87 (1H, m), 3.90- 3.98C1H, m), 7.02-7.06C2H, m), 7.16C1H, dd, J = l.8Hz, 8.1Hz), 7.31-

5 8 1.15-1.20C6H, m), 1.47-1.67C4H, m), 1.91-2.00C2H, m), 1.99C3H, s), 2.25C3H, s), 2.83 (3H, s), 3.03C1H, brs), .3. 40-3. 70 (4H, m), 3.98- 4.07C3H, nO, 7.06 (1H, d, J = 7.8Hz ), 7.19C1H, d, J = 8.7Hz), 7.37-7.54

5 9 1.13-1.18C4H, m), 1, 51-1.60 (4H, m), 1.96C3H, s), 2.14C2H, brs), 2.26C3H, s), 2.77C3H , s), 2.98 (2H, brs), 3.18-3.77 (8H, ra), 7.06C1H, d, J = 7.5Hz), 7.18C1H, d, J = 8.4Hz) , 7.36-7.53C13H, m), 11.0-11.

6 0 1.53C2H, quint, J = 7.0 Hz), 2.19 (2H, t, J = 7.0 OHz), 2. 24-2.2.42C8H, m), 2.25 (3H, s), 2.33 (3H, s), 3.12C2H, quart, J = 7.OHz), 4.25 (IH, d, J = 14.6Hz), 4.37C1H, d, J = 14.6Hz), 5.80 (1H, t, J = 7.OHz), 6.99C1H, brd, J = 8.Hz), 7.23C1H, brd, J = 7.8Hz), 7.321-7.58C11H, ra ) / CDCl ₃

m 1

Claims

The scope of the claims 1. A pharmaceutical composition comprising a triazole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (.)

 (The symbols in the formula have the following meanings. A ring: a) a benzene ring which may be substituted with 1 to 3 substituents selected from halogen, nitro, amino, lower alkyl group or group represented by —X—R ⁴ , or  b) a thiophene ring optionally substituted with an aryl group, R ^{1 is a} hydrogen atom or a lower alkyl group, R ² : hydrogen atom, halogen atom, hydroxyl group, optionally substituted alkoxy group, optionally substituted lower alkyl group, optionally substituted lower alkynyl group, optionally substituted amino group R ³ : hydrogen atom, halogen atom, amino, nitro, cyano, trifluoromethyl, lower alkyl, 10-lower alkyl group, Or may form a cycloalkyl ring together with the R ² group  Y: CH or N X: single bond, one NH—CO—, one CO—NH—, — NH—CO—NH—, -NH—CS—NH—,-(CH ₂ ) _k — O—, or — O— (CH ₂ ) _k -group. R ⁴ : an aryl group optionally substituted with a lower alkyl group or an aryl group; a 5- or 6-membered heteroaryl group optionally substituted with a lower alkyl group; 3 to an aryl group optionally substituted with a lower alkyl group 8-membered saturated heterocyclic group; m: Integer from 1 to 3  k: integer from 0 to 5) 2. The pharmaceutical composition according to claim 1, which is a vasopressin V _1A receptor antagonist. 3. A triazole derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof. (. ')

 (The symbols in the formula have the following meanings. Ring A: a) a benzene ring which may be substituted with 1 to 3 substituents selected from halogen, nitro, amino, lower alkyl group or group represented by —X—R ⁴ , or  b) a thiophene ring optionally substituted with an aryl group, R ^{1 is a} hydrogen atom or a lower alkyl group, R ² : a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted lower alkyl group, an optionally substituted lower alkynyl group, an optionally substituted amino group R ³ : hydrogen atom, halogen atom, amino, nitro, cyano, trifluoromethyl, lower alkyl, 10-lower alkyl group, Or may form a cycloalkyl ring together with the R ² group  Y: CH or N X: single bond, one NH—CO—, —CO—NH—, —NH—CO—NH—, one NH—CS—NH—, — (CH ₂ ) _k —〇_, or — O— (CH ₂ ) _k units R ⁴ : an aryl group optionally substituted with a lower alkyl or aryl group; a 5- or 6-membered heteroaryl group optionally substituted with a lower alkyl group; optionally substituted with a lower alkyl group Good 3 to 8 membered saturated heterocycle; m: Integer from 1 to 3  k: integer from 0 to 5 However, compounds in which ring A is a biphenyl group, R ¹ is a methyl group, Y is CH, m is 1, R ³ is a hydrogen atom, and R ² is a methoxy group are excluded. ) 4. R ² group is 1) Formula — R ⁵ , -0- (CH ₂ ) _p — R ⁵ , -NH- (CH ₂ ) _P — R ⁵ , one CO— (CH ₂ ) _p —R ⁵ , —CO—O— (CH ₂ ) _p —R ⁵ and —C〇—NH— (CH ₂ ) _p — having a substituent selected from the group represented by R ⁵ , An alkoxy, lower alkyl or lower alkynyl group; [Where R ⁵ is i) a hydrogen atom, or ii) an aryl, a 5- to 6-membered heteroaryl or a 3- to 8-membered saturated heterocyclic group (these ring groups are further halogen atoms, amino, nitro , Cyano, lower alkyl, —0—lower alkyl, one COO—lower alkyl, —CO—3 to 8 membered saturated heterocycle, one CO—3 to 8 membered saturated heterocycle, 1 to 3 membered saturated heterocycle Ring, —CO—3- to 8-membered saturated heterocycle—lower alkyl, aryl, 5- to 6-membered heteroaryl, or 3- to 8-membered saturated heterocyclic group which may be substituted by a lower alkyl group, And p is an integer of 0 to 4]; / CH ₂ ) q,  — X  \ / 2) a group ^{represented by the} formula ( ^{eH2) I} "; (Where X is CH—R ⁶ , N_R ⁶ , O or S, R ⁶ is lower alkyl, 10-lower alkyl, 1 C〇〇lower alkyl, 1 CO—lower to 3-8 members saturated A telocyclic monoalkyl, aryl, 5- or 6-membered heteroaryl or 3- to 8-membered saturated heterocyclic group, and Q and r are integers of 1 to 3); A triazole derivative or a pharmaceutically acceptable salt thereof. 5. Ring A is a formula

 5. The triazole derivative or a pharmaceutically acceptable salt thereof according to claim 4, which is a group represented by the formula: (Where X and R ⁴ are as described above, and R ⁷ is a hydrogen atom, a halogen atom, nitro, amino or lower alkyl group) 6. The triazole derivative or a pharmaceutically acceptable salt thereof according to claim 5, wherein Y is CH and the R ² group is a group selected from the group represented by the following formula. — O-(CH ₂ ) _n — R ⁵ — 0-(CH ₂ ) _n -0- (CH ₂ ) _p -R ⁵ One O— (CH ₂ ) _n -NH- (CH ₂ ) _P -R ⁵ One O-(CH ₂ ) _n — CO-(CH ₂ ) _P - ⁵ _〇— (CH ₂ ) _n — CO— O— (CH ₂ ) _P -R ⁵ -O- (CH ₂ ) _n -CO-NH- (CH ₂ ) _P -R ⁵ (Where R ⁵ and p are as described above, and n is an integer of 1 to 12) 7. Ring A is a 4-biphenyl ring, R ¹ is a methyl group, and R ² is —0— (CH _{2) n} - Toriazoru derivative or a pharmaceutically acceptable salt thereof in the range 6 claim of claim is a group represented by R ^5. 8. 4- (2-benzyloxyphenyl) -1-3- (4'-biphenyl) -5-methyl-1,2,4-triazolyl,  4- {2- [5— (4-Methylpiperazine-11-yl) pentyloxy] phenyl} —3- (4, -biphenyl) —5-methyl-1,2,4-triazole,  4- {2- [6- (4-Methylpiperazine-11-yl) hexyloxy] phenyl} —3-((4-biphenyl) -1-5-methyl-1,2,4-triazole; 4- {2- [7- (4-Methylbiperazine_1-yl) heptyloxy] phenyl} -1-3- (4'-biphenyl) -5-methyl-1,2,4_triazo ,  4— {2- [8— (4-Methylpiperazine—1-yl) octyloxy] phenyl} -3- (4, —Biphenyl) —5-Methyl-1,2,4-triazole,  4- {2- [6- (4-Methylpiperazine-1-1yl) hexyloxy] -1-6-methylphenyl} -3- (4-biphenyl) -5-methyl-1,2,4-triazole,  4- 1 {2— [6 -— (4-Methylhomopirazine—1—yl) hexyloxy] 1—6—methylphenyl} 1—3— (4, -biphenyl) -5-methyl—1,2,4-triazo One,  4- [2- (6- (piberidinohexyloxy) phenyl] -1-3- (4, -biphenyl) -1-5-methyl-1,2,4-triazole,  4- {2- [6-(4-piperidinopiperidine-1-1yl) hexyloxy] phenyl} -1-3- (4, -biphenyl) -5-methyl-1,2,4-triazole ,  4-{2- [6- (4-piperidinopiperidine-1 r-l) hexyloxy] 1-61-methylphenyl]-3--(4, -biphenyl) 1-5-methyl-1, 2,2 4-triazole,  4- {2- [4- (4-piperidyl) but, xy] phenyl} -1-3- (4'-biphenyl) —5-methyl-1,2,4-triazole, 4- {2- [4- (4-Methylpiperazine-11-yl) carbonylphenyl] methoxy-6-methylphenyl} 1-3- (4, -biphenyl) -5-methyl-1,2,4-triazole ,  4-{{2- [4- (4-piperidinopiperidin-1-yl) carbonylphenyl] methoxy-6-methylphenyl} -3- (4-biphenyl) — 5-methyl-1,2,4 —Triazole, 4- {2- [4- (4-Methylpiperazine-1 11-yl) carbonylphenyl] methoxyphenyl} 1-3- (4, -biphenyl) 1 5-Methyl-1,2,4- Triazole,  4- {2- [3- (3-pyridyl) propyl] phenyl} 13- (4, -biphenyl) -5-methyl_1,2,4-triazole, or a pharmaceutically acceptable product thereof Salt.