JPH0616643A - Biphenyl derivative - Google Patents

Abstract

PURPOSE:To obtain a new biphenyl derivative, having vasopressin antagonistic action and useful as a water diuretic, an anticardiac failure and an antihypertensive agents. CONSTITUTION:The compound of formula I [either of R<1> and R<2> is H and the other is H, amino or mono- or di-lower alkylamino or R<1> and R<2> together form carbonyl; R<3> is H, OH, lower alkyl, lower alkoxy or lower alkanoyloxy; X is CH2 or NR<4> (R<4> is H, lower alkyl or lower alkanoyl)], e.g. 1-(biphenyl-4- ylcarbonyl)-2,3,4,5-tetrahydro-1H-benzazepine. This compound is obtained by reacting a compound of formula II with a compound of formula III (Y is carboxyl or its reactive derivative) according to usual reaction for forming amide bond.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel biphenyl derivative useful as a drug, especially as an arginine vasopressin antagonist.

[0002]

2. Description of the Related Art Arginine vasopressin (AVP) is
It is a peptide consisting of 9 amino acids that is biosynthesized and secreted in the hypothalamus-pituitary system. Conventionally, as this arginine vasopressin antagonist, a peptide vasopressin antagonist (see, for example, JP-A-2-32098) and a non-peptide vasopressin antagonist (for example, JP-A-3-1738)
70, International Publication No. 91/05549 pamphlet (1991)), but the compounds of the present invention are novel compounds having different structures from these compounds.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have completed the present invention as a result of earnest research on a compound having an arginine vasopressin antagonistic action.

[0004]

That is, the present invention relates to a novel biphenyl derivative represented by the following general formula 2.

[0005]

[Chemical 3] (In the formula, ^one of R ¹ and R ² is a hydrogen atom and the other is a hydrogen atom, an amino group, a mono- or di-lower alkylamino group, or R ¹ and R ² are combined to form a carbonyl group, ³ represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group, and X represents a methylene group or a group represented by Chemical formula 2.

[0006]

[Chemical 4]

(In the formula, R ⁴ represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group. The same applies hereinafter.)

In the definition of the general formulas herein, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, as the "lower alkyl group", specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group Group, neopentyl group, t
ert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group,
Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethyl Butyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1 −
Examples thereof include an ethyl-1-methylpropyl group and a 1-ethyl-2-methylpropyl group. Of these groups, a methyl group, an ethyl group and an isopropyl group are preferable, and a methyl group and an ethyl group are more preferable. It is a base.

The "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, te.
rt-butoxy group, pentyloxy (amyloxy)
Group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group,
1,2-Dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group and the like can be mentioned. Of these groups, methoxy group, ethoxy group, propoxy group and isopropoxy group are preferable, and methoxy group is more preferable. , Ethoxy group.

Specific examples of the "mono- or di-lower alkylamino group" include methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group. Group, tert-butylamino group, pentyl (amyl) amino group, isopentylamino group, neopentylamino group, tert-pentylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group , A diisobutylamino group and the like. Of these groups, a methylamino group, an ethylamino group, a dimethylamino group and a diethylamino group are preferable, and a dimethylamino group is more preferable.

The "lower alkanoyl group" includes acetyl group, propionyl group, butyryl group, isobutyryl group,
Valeryl group, isovaleryl group, etc., preferably acetyl group, "lower alkanoyloxy group" includes acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, etc. Among these groups,
An acetyloxy group and a propionyloxy group are preferable, and an acetyloxy group is more preferable.

The substituent R ³ may be bonded to any position of the benzene ring. The compound of the present invention represented by the general formula (I) may contain an asymmetric carbon atom depending on the kind of the substituent, and in this case, various optical isomers are included. The compound of the present invention also includes hydrates, solvates and the like of compound (I). Among the compounds of the present invention, particularly preferable compounds are as follows. 1- (biphenyl-4-ylcarbonyl) -2,3
4,5-Tetrahydro-1H-benzazepine 1- (2 'or 3'or 4'-methylbiphenyl-4-
Ilcarbonyl) -2,3,4,5-tetrahydro-1
H-benzazepine 1- (2 'or 3'or 4'-methoxybiphenyl-4
-Ylcarbonyl) -2,3,4,5-tetrahydro-
1H-benzazepine

(Production Method) The compound represented by the general formula (I) can be synthesized by various methods, and representative production methods are shown below. (First manufacturing method)

[0014]

[Chemical 5]

(In the formula, Y means a carboxyl group or a reactive derivative thereof. The same applies hereinafter) The object compound of the present invention represented by the general formula (I) is a compound represented by the general formula (II) The compound represented by the formula (III) can be reacted in a usual amide bond formation reaction. Here, as an ordinary amide bond formation reaction, for example, a mixed acid anhydride method, that is, a method in which an alkylhalocarboxylic acid is reacted with a carboxylic acid compound (III) to form a mixed acid anhydride and the compound (II) is reacted therewith , An active ester method, that is, a method in which a carboxylic acid compound (III) is used as an active ester such as p-nitrophenyl ester N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, and the compound (II) is reacted therewith, Carbodiimide method, that is, compound (II) is bound to carboxylic acid (III) in the presence of an activator such as dicyclooxylcarbodiimide or carbonyldiimidazole, compound (II) is added to halide of carboxylic acid (III) And the like. The reaction solvent in this case can be appropriately selected depending on the reaction conditions, and for example, chloroform, dichloromethane,
Halogenated hydrocarbons such as dichloroethane, benzene,
Examples thereof include aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether and tetrahydrofuran, esters such as ethyl acetate, dimethylformamide and dimethylsulfoxide. (Second manufacturing method)

[0016]

[Chemical 6] (In the formula, R ⁵ means a lower alkanoyl group. The same applies hereinafter.) The second production method of the present invention is represented by the general formula (Ib) by hydrolyzing the compound of the present invention represented by the general formula (Ia). It is a method of converting into a compound. The hydrolysis is preferably alkaline hydrolysis, and is carried out by treating with sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or the like.

The thus-produced compound of the present invention is isolated and purified by subjecting it to commonly used separation operations such as extraction, concentration, distillation, crystallization, recrystallization, filtration and various chromatographies. It

[0018]

INDUSTRIAL APPLICABILITY The vasopressin antagonist of the present invention has a water diuretic action, a urea excretion promoting action, a factor VIII secretion inhibiting action,
Vasodilatory effect, cardiac hyperactivity effect, mesangial cell contraction inhibitory effect, mesangial cell proliferation inhibitory effect, hepatic gluconeogenesis inhibitory effect, platelet aggregation inhibitory effect, aldosterone secretion inhibitory effect, endothelin production inhibitory effect, central blood pressure control effect, renin secretion It has regulatory action, memory control action, body temperature control action, prostaglandin production control action, etc., and is a water diuretic, urea excretion enhancer, vasodilator, antihypertensive agent, anti-heart failure agent, anti-renal failure agent, blood coagulation suppression Useful as an agent,
Heart failure, hyponatremia, pasopressin secretion abnormality syndrome (SIADH), hypertension, renal failure, edema, ascites, cirrhosis, hypokalemia, water metabolism disorder, diabetes, various ischemic diseases, circulatory insufficiency, renal dysfunction, etc. Effective for prevention and treatment. The usefulness of the compound of the present invention was confirmed below by the following test methods.

[0019] V ₁ receptor binding assay (V ₁ receptor binding assay) Nakamura et al. Method (J.Biol.Chem., 258,9283 (1983) ) using a rat liver membrane preparation prepared in accordance with, [H] ^3-
Arg-vasopressin (2
nM, specific activity = 75.8
Ci / mmol)) and 70 ng of membrane preparation and test drug (10
^-8 to 10 ^-4 M), 5 mM MgCl ₂ , 1 mM ED
Incubation was carried out for 30 minutes at 25 ° C. in a total volume of 250 μl of 100 mM Tris-hydrochloric acid buffer solution (pH = 8.0) containing TA and 0.1% BSA. Then, the incubation solution was aspirated using a cell harvester and passed through a glass filter (GF / B) to remove free ligand and excess buffer solution, and the labeled ligand bound to the receptor was trapped on the glass filter. The glass filter was taken out, sufficiently dried and then mixed with a liquid scintillation cocktail, and the amount of [H] ³ -vasopressin bound to the membrane was measured with a liquid scintillation counter, and the inhibition rate was calculated by the following formula.

[0020]

[Equation 1]

C ₁ ; known amount of reagent and [H] ³ −
Amount of [H] ³ -vasopressin bound to the membrane in the presence of vasopressin C ₀ ; amount of [H] ³ -vasopressin bound to the membrane when the reagent was removed B ₁ ; excess vasopressin (10 ⁻⁶ M ) Amount of [H] ³ -vasopressin bound to the membrane in the presence of the IC ₅₀ value was determined from the concentration of the reagent agent at which the inhibition rate calculated above was 50%. The dissociation constant (Ki) was calculated from the following formula.

[0022]

[Equation 2]

[L]; Radioligand concentration KD; Dissociation constant determined by Scatchard blot. The negative logarithm of Ki calculated above was taken as pKi value. V ₂ receptor binding assay (V ₂ recepto
r binding assay) Campbell et al. method (J. Biol. Chem., 247, 6167 (1972))
Was prepared according to. Using a rabbit kidney meningeal membrane specimen,
[H] ³ -Arg-vasopressin (2 nM, specific a
ctivity = 75.8 Ci / mmol) and membrane sample 100
ng and a test drug (10 ⁻⁸ to 10 ⁻⁴ M) were added to the above-mentioned V ₁
The assay was performed in the same manner as the receptor binding assay, and the pKi value was similarly determined.

A preparation containing one or more kinds of the compound (I) of the present invention as an active ingredient is prepared by using a carrier, an excipient and other additives usually used for preparation.
The carrier or excipient for the preparation may be solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol, etc. Examples include regular ones.

For administration, tablets, pills, capsules, granules,
It may be in any form of oral administration such as powder or liquid, or parenteral administration such as injection such as intravenous injection or intramuscular injection, suppository, and transdermal. The dose is appropriately determined according to each case in consideration of symptoms, age of the subject, sex, etc., but usually, in the case of oral administration, 1 to 500 mg is administered once a day or in divided doses. .

[0026]

EXAMPLES The compound of the present invention and the method for producing the same have been described above, but the present invention will be described in more detail below.
The invention is in no way limited by these examples.

Reference Example 1

[0028]

[Chemical 7]

A: Under an argon atmosphere, 6.00 mol (50 mmol) of o-bromotoluene was dissolved in 60 ml of tetrahydrofuran, and 30.9 ml of n-butyllithium (1.62M n-hexane solution) was added at -78 ° C.
(50 mmol) was added dropwise and the mixture was stirred for 30 minutes as it was.
At the same temperature, further zinc chloride (1.0 M ether solution) 50
ml (50 mmol) was added dropwise and the mixture was stirred for 30 minutes as it was. B: NiCl ₂ (PPh ₃ ) ₂ under an argon atmosphere ₂ .
27 (0.1 eq.5 mmol) was suspended in 50 ml of tetrahydrofuran, and 4.9 ml of diisobutylaluminum hydride (0.93M n-hexane solution) under ice cooling.
(0.09 eq.4.5 mmol) was added dropwise and the mixture was stirred for 15 minutes as it was. At the same temperature, tetrahydrofuran p-iodobenzoate 8.4 ml (50 mmol) 50
The ml solution was added dropwise and the mixture was stirred as it was for 15 minutes. here,
Solution A was added dropwise to solution B cooled to -78 ° C, and the mixture was stirred at room temperature overnight. After distilling off the solvent, chloroform and saturated saline were added, and the precipitated catalyst was filtered through a GFPfilter. After extraction, the chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was subjected to silica gel column chromatography (n-hexane: acetic acid ethyl ester = 30:
Purified in 1), 7.76 g (32.4 m) of an oily substance, ethyl 2'-methylbiphenyl-4-ylcarboxylate.
mol, yield 65%) was obtained.

Physicochemical properties ¹ H-NMR (δ ppm, in CDCl ₃ , TMS internal standard): 1.41 (3 H, t), 2.20 (3 H,
s), 4.40 (2H, q), 7.15-7.45 (total 6H), 8.10 (2H, d) Reference example 2

[0031]

[Chemical 8]

M-Bromotoluene 3.64 ml (30 m
was used as a starting material, and ethyl 3′-methylbiphenyl-4-ylcarboxylate was used as an oil to give 3.86 g (16.1 mmo).
1, yield 53%) was obtained.

Physicochemical properties ¹ H-NMR (δ ppm, in CDCl ₃ , TMS internal standard): 1.40 (3 H, t), 2.42 (3 H,
s), 4.39 (2H, q), 7.17-7.40 (total 4H), 7.65 (2H, d), 8.09 (2H, d) MS (FAB): 241 (M ⁺ +1) Reference example 3

[0034]

[Chemical 9]

3.69 ml of p-bromotoluene (30 m
was used as a starting material, and ethyl 4′-methylbiphenyl-4-ylcarboxylate was used as an oil to give 3.24 g (13.5 mmo).
1, yield 45%) was obtained.

Physicochemical properties ¹ H-NMR (δ ppm, in CDCl ₃ , TMS internal standard): 1.41 (3 H, t), 2.40 (3 H,
s), 4.40 (2H, q), 7.22-7.77 (total 6H), 8.09 (2H, d) MS (FAB): 241 (M + 1) Reference Example 4

[0037]

[Chemical 10]

O-Bromoanisole 3.74 ml (30
mmol) as a starting material and a method similar to that in Reference Example 1 was used, and 5.76 g (22.5 mm) of ethyl 2′-methoxybiphenyl-4-ylcarboxylate as an oily substance.
ol, yield 75%) was obtained.

Physicochemical properties ¹ H-NMR (δ ppm, in CDCl ₃ , TMS internal standard): 1.39 (3 H, t), 3.78 (3 H,
s), 4.38 (2H, q), 6.91-7.44 (total 4H), 7.59 (2H, d), 8.09 (2H, d) Reference Example 5

[0040]

[Chemical 11]

3.77 ml of m-bromoanisole (30
mmol) as a starting material and using the same method as in Reference Example 1, 3.46 g (13.5 mmol, yield 4) of ethyl 3′-methoxybiphenyl-4-ylcarboxylate.
5%) was obtained.

Physicochemical properties ¹ H-NMR (δ ppm, in CDCl ₃ , TMS internal standard): 1.41 (3 H, t), 3.87 (3 H,
t), 4.40 (2H, q), 6.87-7.48 (total 4H), 7.66 (2H, d), 8.13 (2H, d) MS (GC): 256 (M ⁺ ). ) Reference example 6

[0043]

[Chemical 12]

3.74 ml of p-bromoanisole (30
mmol) as a starting material and using the same method as in Reference Example 1, 3.87 g (15.1 mmol, yield 5) of ethyl 4′-methoxybiphenyl-4-ylcarboxylate.
0%).

Physicochemical properties ¹ H-NMR (δ ppm, in CDCl ₃ , TMS internal standard): 1.40 (3H, t), 3.86 (3H,
t), 4.39 (2H, q), 6.99 (2H, d),
7.55 (2H, d), 7.62 (2H, d), 8.0
8 (2H, d) MS (FAB): 257 (M ⁺⁺ 1) Reference Example 7

[0046]

[Chemical 13]

Ethyl 2'-methylbiphenyl-4-ylcarboxylate 0.972 g (4.04 mmol)
20 ml of 1N-sodium hydroxide aqueous solution (5 eq.
0 mmol) and 20 ml methanol 1
Reflux for hours. The solvent was distilled off, and 1N-HCl was cooled with ice.
aq. Was added to adjust pH = 1. The reaction solution was filtered, the filtrate was saturated with sodium chloride, and then extracted three times with ethyl acetate. The residue was dissolved in warm ethyl acetate and combined with the extracted ethyl acetate layer. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Recrystallization from ethyl acetate gave 0.51 g (240 mmol, yield 60%) of 2'-methylbiphenyl-4-ylcarboxylic acid.

Physicochemical properties ¹ H-NMR (δ ppm, in DMSO-d ₆ , TM
S internal standard): 2.23 (3H, s), 7.23-8.
05 (total 8H) MS (FAB): 213 (M ⁺ +1) The following compounds were also synthesized in the same manner as in Reference Example 7. Reference example 8

[0049]

[Chemical 14]

3'-Methylbiphenyl-4-ylcarboxylic acid

Physicochemical properties ¹ H-NMR (δ ppm, in DMSO-d ₆ , TM
S internal standard) δ: 2.39 (3H, s), 7.19-8.08 (total 8)
H) MS (FAB): 213 (M ⁺ +1) Reference example 9

[0052]

[Chemical 15]

4'-methylbiphenyl-4-ylcarboxylic acid

Physicochemical properties ¹ H-NMR (δ ppm, in DMSO-d ₆ , TM
S internal standard) δ: 2.36 (3H, s), 7.26-8.06 (total 8)
H) MS (FAB): 213 (M ⁺ +1) Reference example 10

[0055]

[Chemical 16]

2'-methoxybiphenyl-4-ylcarboxylic acid

Physicochemical properties ¹ H-NMR (δ ppm, in DMSO-d ₆ , TM
S internal standard) δ: 3.78 (3H, s), 6.96-8.03 (total 8)
H) MS (FAB): 229 (M ⁺ +1) Reference Example 11

[0058]

[Chemical 17]

3'-methoxybiphenyl-4-ylcarboxylic acid

Physicochemical properties ¹ H-NMR (δ ppm in DMSO-d ₆ , TM
S internal standard) δ: 3.84 (3H, s), 6.90-7.99 (total 8)
H) MS (FAB): 229 (M ⁺ +1) Reference Example 12

[0061]

[Chemical 18]

4'-methoxybiphenyl-4-ylcarboxylic acid

Physicochemical properties ¹ H-NMR (δ ppm in DMSO-d ₆ , TM
S internal standard) δ: 3.82 (3H, s), 7.05 (2H, d),
7.67 (2H, d), 7.72 (2H, d), 8.0
1 (2H, d) MS (FAB): 229 (M ⁺ +1) Example 1

[0064]

[Chemical 19]

0.74 g of 2,3,4,5-tetrahydro-1H-benzazepine was dissolved in 10 ml of dichloromethane and 0.91 ml of triethylamine. below freezing,
A solution of 1.30 g of p-phenylbenzoyl chloride in 10 ml of dichloromethane was added dropwise, and the mixture was stirred as it was at room temperature overnight. The reaction solution was extracted, the dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (CHCl ₃ : MeOH = 200:
Purified in 1) and recrystallized from chloroform-n-hexane system to give 1- (biphenyl-4-ylcarbonyl)-
0.99 g of 2,3,4,5-tetrahydro-1H-benzazepine was obtained.

Physicochemical properties Melting point 178-180 ° C ¹ H-NMR (δppm in CDCl ₃ , TMS internal standard) δ: 1.80-2.30 (total 3H), 2.60-3.2
0 (total 4H), 4.90-5.20 (1H, br),
6.64-7.57 (total 13H) MS (FAB): 328 (M ⁺⁺ 1) Example 2

[0067]

[Chemical 20]

1.06 g of 2'-methylbiphenyl-4-ylcarboxylic acid were suspended in 25 ml of benzene, 0.87 ml of oxalyl chloride and 1 drop of pyridine.
After refluxing for 2 hours under an argon stream, the solvent was distilled off. Dichloromethane (20 ml) and triethylamine (0.91 ml) were added to the residue, and the mixture was cooled on ice with 2,3,4,5-
A solution of 0.74 g of tetrahydro-1Hbenzazepine in 20 ml of dichloromethane was added dropwise. After stirring overnight at room temperature, extraction was performed, the dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane: AcOEt = 5: 1) and recrystallized from a chloroform-n-hexane system.
1- (2'-methylbiphenyl-4-ylcarbonyl)
0.54 g of -2,3,4,5-tetrahydro-1H-benzazepine was obtained.

Physicochemical properties Melting point 127-128 ° C. ¹ H-NMR (δppm in CDCl ₃ , TMS internal standard) δ: 1.80-2.30 (4H, m), 2.21 (3
H, s), 2.80-3.30 (total 4H), 6.60-
7.50 (total 12H) MS (FAB): 342 (M ⁺ +1) Example 3

[0070]

[Chemical 21]

0.530 g of 3'-methylbiphenyl-4-ylcarboxylic acid were suspended in 10 ml of dichloromethane and 1 drop of dimethylformamide. Oxalyl chloride 0.44m at -40 ° C under argon flow
1 was added, and the mixture was stirred for 2 hours at room temperature. The solvent was distilled off and the residue was dissolved in 10 ml of dichloromethane. Under ice cooling 2,
3,4,5-Tetrahydro-1H-benzazepine and triethylamine 0.45 ml dichloromethane 10
The ml solution was added dropwise. After stirring overnight at room temperature, extraction was performed, the dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is subjected to silica gel column chromatography (nh
exane: AcOEt = 5: 1) and recrystallized from chloroform-n-hexane to give 1- (3'-methylbiphenyl-4-ylcarbonyl) -2,3,4,4.
0.65 g of 5-tetrahydro-1H-benzazepine
Obtained.

Physicochemical properties Melting point 150.5-151.5 ° C. Elemental analysis value (as C ₂₄ H ₂₃ NO) C (%) H (%) N (%) Calculated value 84.42 6.79 4.10 Actual measurement The value ^{84.60 6.87 4.07 1 H-NMR (} δppm, in CDCl 3, TMS internal standard): 1.80-2.30 (4H, m) , 2.37
(3H, s), 2.60-3.10 (3H, m), 4.
90-5.20 (1H, br), 6.60-7.50
(Total 12H) MS (FAB): 342 (M ⁺⁺ 1) Example 4

[0073]

[Chemical formula 22]

Starting from 0.530 g of 4'-methylbiphenyl-4-ylcarboxylic acid as starting material, 1- (4'-methylbiphenyl-4-ylcarbonyl) -2,3,3 was prepared in the same manner as in Example 3. 4,5-Tetrahydro-1H
-0.55 g of benzazepine was obtained.

Physicochemical properties Melting point 136.5-137.5 ° C. Elemental analysis value (as C ₂₄ H ₂₃ NO) C (%) H (%) N (%) Calculated value 84.42 6.79 4.10 Actual measurement Value 84.64 6.88 4.11 ¹ H-NMR (δ ppm, in CDCl ₃ , TMS internal standard): 1.80-2.20 (total 4H), 2.36 (3
H, s), 2.60-3.10 (total 3H), 4.90-
5.20 (1H, br), 6.60-7.46 (total 12
H) MS (FAB): 342 (M ⁺⁺ 1) Example 5

[0076]

[Chemical formula 23]

Starting from 1.63 g of 4'-acetoxybiphenyl-4-ylcarboxylic acid, 1- (4'-acetoxybiphenyl-4 was prepared in the same manner as in Example 3.
0.87 g of -yl carbonyl) -2,3,4,5-tetrahydro-1H-benzazepine was obtained.

Physicochemical properties Melting point 155-156 ° C. Elemental analysis value (as C ₂₅ H ₂₃ NO ₃ ) C (%) H (%) N (%) Calculated value 77.90 6.01 3.63 Measured value 77. ^{74 6.11 3.66 1 H-NMR (} δppm, in CDCl 3, TMS internal standard): 2.30 (3H, s) , 4.9-5.2 (1
H, m), 6.6-7.6 (total 12H) MS (GC): 385 (M ⁺ ) Example 6

[0079]

[Chemical formula 24] 1- (4'-acetoxybiphenyl-4-ylcarbonyl) -2,3,4,5-tetrahydro-1H-benzazepine 350 mg of methanol in 10 ml suspension was added with 1N sodium hydroxide aqueous solution 2.72 ml under ice cooling. In addition, after stirring at room temperature for 1 hour, 1N hydrochloric acid 2.72 was obtained by cooling with ice.
ml was added. Chloroform and water were added thereto, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure and crystallized from chloroform-n-hexane to give 1-
(4'-hydroxybiphenyl-4-ylcarbonyl)
310 mg of -2,3,4,5-tetrahydro-1H-benzazepine was obtained.

Physicochemical properties Melting point 250 ° C. or higher Elemental analysis value (as C ₂₃ H ₂₁ NO ₂ · 3 / 4H ₂ O) C (%) H (%) N (%) Calculated value 77.40 6.35 3. 92 measured value 77.40 6.05 3.90 ¹ H-NMR (δ ppm, in DMSO-d ₆ , TMS
Internal standard): 4.7-5.1 (1H, m), 6.7-
7.6 (total 12H), 9.57 (1H, s) MS (EI): 343 (M ⁺ ) Example 7

[0081]

[Chemical 25]

1 '(2'-Methoxybiphenyl-4-ylcarbonyl) -2,3,4, using 2'-methoxybiphenyl-4-ylcarboxylic acid as a starting material and the same procedure as in Example 3. 0.76 g of 5-tetrahydro-1H-benzazepine was obtained as a foamy substance.

Physicochemical properties ¹ H-NMR (δ ppm, in CDCl ₃ , TMS internal standard): 1.80-2.20 (total 4H), 2.60-
3.10 (3H in total), 3.71 (3H, s), 4.90
-5.20 (1H-br), 6.60-7.35 (total 1
2H) MS (FAB): 358 (M ⁺⁺ 1) Example 8

[0084]

[Chemical formula 26]

Using 0.571 g of 3'-methoxybiphenyl-4-ylcarboxylic acid as a starting material and the same procedure as in Example 3, 1- (3'-methoxybiphenyl-4-) was prepared.
Ilcarbonyl) -2,3,4,5-tetrahydro-1
0.46 g of H-benzazepine was obtained.

Physicochemical properties Melting point 129-130 ° C. Elemental analysis value (as C ₂₄ H ₂₃ NO ₂ ) C (%) H (%) N (%) Calculated value 80.64 6.49 3.92 Measured value 80. ^{24 6.32 3.86 1 H-NMR (} δppm, in CDCl 3, TMS internal standard): 1.70-2.30 (total 4H), 2.50-
3.10 (3H in total), 3.82 (3H, s), 4.90
-5.20 (1H-br), 6.60-7.50 (total 1
2H) MS (EI): 357 (M ⁺⁺ 1) Example 9

[0087]

[Chemical 27]

4'-methoxyphenylbiphenyl-4-
Example 3 Using 0.571 g of carboxylic acid as a starting material
A similar method was used to obtain 0.376 g of 1- (4′-methoxybiphenyl-4-ylcarbonyl) -2,3,4,5-tetrahydro-1H-benzazepine.

Physicochemical properties Melting point 169-170 ° C. Elemental analysis value (as C ₂₄ H ₂₃ NO ₂ ) C (%) H (%) N (%) Calculated value 80.64 6.49 3.92 Measured value 80. ^{57 6.57 3.83 1 H-NMR (} δppm, in CDCl 3, TMS internal standard): 1.80-2.30 (total 4H), 2.60-
3.10 (3H in total), 3.82 (3H, s), 4.90
-5.20 (1H, br), 6.60-7.60 (total 1
2H) MS (EI): 357 (M ⁺ ) Example 10.

[0090]

[Chemical 28]

5-oxo-2,3,4,5-tetrahydro-1H-benzazepine (0.54 g) and p-phenylbenzoyl chloride (0.8 g) were used in the same manner as in Example 1 to prepare 1- (biphenyl-4-). Ilcarbonyl)-
0.82 g of 5-oxo-2,3,4,5-tetrahydro-1H-benzazepine was obtained.

Physicochemical properties Melting point 185-187 ° C. Elemental analysis value (as C ₂₃ H ₁₉ NO ₂ ) C (%) H (%) N (%) Calculated value 80.91 5.61 4.10 Measured value 80. 87 5.46 4.05 ¹ H-NMR (δppm, in CDCl ₃ , TMS internal standard): 2.0-2.4 (total 2H), 2.8-3.05
(Total 3H), 4.1 (1H, m), 6.8 (1H,
m), 7.1-7.6 (total 11H), 7.9 (1H,
m) MS (FAB): 342 (M ⁺⁺ 1) Example 11

[0093]

[Chemical 29]

0.26 g of 2'-methoxybiphenyl-4-ylcarboxylic acid and 5-dimethylamino-2,3
4,5-Tetrahydro-1H-benzazepine 0.18
Using g as a starting material and using the same method as in Example 3, 5
-Dimethylamino-1- [4- (2-methoxyphenyl) benzoyl] -2,3,4,5-tetrahydro-1
0.38 g of H-benzazepine was obtained. 20 ml of this
Dissolve in isopropyl alcohol of 0.24 ml of 4
After adding N hydrochloric acid-dioxane, isopropyl ether was added to give a precipitate. After filtration and drying, 0.34 g of 5-dimethylamino-1- [4- (2-methoxyphenyl) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine hydrochloride was obtained.

Physicochemical properties Elemental analysis value (as C ₂₆ H ₂₈ N ₂ O ₂ .HCl.2-PrOH) C (%) H (%) N (%) Cl (%) Calculated value 70.07 7.50 5.64 7.13 Found 70.05 7.16 5.83 7.51 ¹ H-NMR (δppm, in CDCl ₃ , TMS internal standard): 0.98 (1H, m), 1.70 (1H). ，
m), 1.93 (1H, m), 2.34 (1H, m),
2.95 (total 3H), 3.04 (total 3H), 3.48
(1H, d), 3.72 (1H, s), 3.87 (1
H, t), 5.07 (1H, m), 6.85 (1H,
d), 7.00 (1H, t), 7.09 (1H, d),
7.96 (1H, t), 11.70 (1H, br.s) MS (FAB): 401 (M ⁺ +1) Example 12

[0096]

[Chemical 30] 1.06 g of 2'-mebiphenyl-4-ylcarboxylic acid and 4-methyl-2,3,4,5-tetrahydro-1H
Using 0.811 g of -1,4-benzodiazepine as a starting material and using the same method as in Example 2, 4-methyl-1-
(2'-Methylbiphenyl-4-ylcarbonyl)-
1.55 g of 2,3,4,5-tetrahydro-1H-benzodiazepine was obtained.

Physicochemical properties Melting point 128-129 ° C. Elemental analysis value (as C ₂₄ H ₂₄ N ₂ O) C (%) H (%) N (%) Calculated value 80.87 6.79 7.86 Measured value 80 .32 6.82 7.83 ¹ H-NMR (δppm, in CDCl ₃ , TMS internal standard): 2.15 (3H, s), 2.44 (3H,
s), 3.08 (total 3H), 3.93 (total 2H), 4.
80-5.20 (1H, br), 6.60-7.34
(Total 12H) MS (FAB): 357 (M ⁺⁺ 1) Example 13

[0098]

[Chemical 31] 2'-Methylbiphenyl-4-ylcarboxylic acid 0.53
g and 4-acetyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (0.476 g) as starting materials, and 4-acetyl-1- (2 ′ -Methylbiphenyl-4-ylcarbonyl) -2,3,4,5-tetrahydro-1H-1,4-
0.881 g of benzodiazepine was obtained.

Physicochemical properties Melting point 169-170 ° C. Elemental analysis value (as C ₂₅ H ₂₄ N ₂ O ₂ .1 / 4H ₂ O) C (%) H (%) N (%) Calculated value 77.19 6. 35 7.20 Found 77.32 6.31 7.11 ¹ H-NMR (δppm, in CDCl ₃ , TMS internal standard): 2.14 (3H, s), 3.70-4.00.
(Total 2H), 4.66 (2H, s), 4.90-5.4.
0 (1H, br), 6.60-7.60 (total 12H) MS (FAB): 385 (M ⁺ +1)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Akira Matsuhisa 2-5-9 Ninomiya, Tsukuba, Ibaraki Prefecture Rumi Tsukuba 302 (72) Inventor Yuzo Matsumoto 6 (72) invention at 9 Kuwahara, Toride City, Ibaraki Prefecture Yutani Yatsu 2-11-7 Hiradai, Ryugasaki-shi, Ibaraki (72) Inventor Isao Yanagisawa 2-22-8 Shakujidai, Nerima-ku, Tokyo

Claims (2)

[Claims] 1. A biphenyl derivative represented by the following chemical formula 1. (In the formula, ^one of R ¹ and R ² is a hydrogen atom and the other is a hydrogen atom, an amino group, a mono- or di-lower alkylamino group, or R ¹ and R ² are combined to form a carbonyl group, ³ represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group, and X represents a methylene group or a group represented by Chemical formula 2. (In the formula, R ⁴ represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group.) 2. R ¹ and R ² are both hydrogen atoms, and R ³
Is a lower alkoxy group and X is a methylene group.