JPH083163A - Condensed pyridine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject derivative shown by a prescribed formula, useful for an immunosuppressive agent and a therapeutic agent for an autoimmune diseases. CONSTITUTION:This derivative is expressed by formula I [R<1> is methyl, styryl or carboxyl; R<2> is H or a lower alkyl; R<3> to R<5> are H, a lower alkoxy, a halogen, nitro, amino or a lower alkylamino; ring A is groups of formula II to formula IV ((n) is 0 or 1), etc.] such as 2-(2'-fluoro-1,1'-biphenyl-4-yl)-4- methyl[1,8]naphythridine. The derivative, for example, is obtained by reacting a compound of formula V (t-Bu is tert-butyl) with an equivalent amount of a compound of formula VI in a lower fatty acid such as propionic acid in the presence of a concentrated sulfuric acid at 100-150 deg.C for 2-48 hours.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fused pyridine derivative useful as an immunosuppressant and a therapeutic agent for autoimmune diseases.

[0002]

2- (2'-Fluoro-1,1'-biphenyl-4-yl) -6-fluoro-3-methyl-4-
Quinolinecarboxylic acid sodium salt (Dup785)
It is disclosed as a use of an immunosuppressive agent in JP-A-1-313428.

[0003]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a fused pyridine derivative useful as an immunosuppressive agent and a therapeutic agent for autoimmune diseases.

[0004]

According to the invention, the formula (I)

[0005]

Embedded image

[Wherein R ¹ represents methyl, styryl or carboxyl, R ² represents hydrogen or lower alkyl, R ³ , R ⁴ and R ⁵ are the same or different and are hydrogen, lower alkoxy, halogen, nitro, Amino and lower alkylamino are represented, and ring A is represented by formulas (a), (b), (c),
(D) or (e)

[0007]

[Chemical 4]

[Wherein n represents 0 or 1]]
A fused pyridine derivative represented by or a pharmaceutically acceptable salt thereof is provided. In the definition of each group of formula (I),
The lower alkyl part of lower alkyl, lower alkoxy and lower alkylamino includes, for example, linear or branched C 1-6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Examples include pentyl, neopentyl, hexyl and the like. Halogen represents each atom of fluorine, chlorine, bromine and iodine.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. The pharmacologically acceptable acid addition salt of compound (I) includes a hydrochloride salt,
Inorganic acid salts such as sulfates and phosphates, acetates, organic acid salts such as maleates, fumarates, tartrates and citrates, and metal salts such as alkali salts such as sodium salts and potassium salts. Examples thereof include alkaline earth metal salts such as metal salts, magnesium salts, calcium salts, aluminum salts, zinc salts, etc., examples of ammonium salts include salts of ammonium, tetramethylammonium, etc., and pharmacologically acceptable organic amine additions. Examples of salts include addition salts such as morpholine and piperidine, and examples of pharmacologically acceptable amino acid addition salts include addition salts such as lysine, glycine and phenylalanine.

Next, a method for producing the compound of the present invention will be described. Production method 1: In compound (I), ring A is (a ¹ ),
Compounds (Ia) and (I- which are (b ¹ ) or (c ¹ ).
b) and (Ic) can be obtained according to the following reaction steps.

[0011]

Embedded image

[Wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above, t-Bu represents tert-butyl, Me represents methyl, Ph represents phenyl and ring A ¹ Is the formula (a ¹ ),
(B ¹ ) or (c ¹ )

[0013]

[Chemical 6]

Step 1; Compound (II) and an equivalent amount of Compound (III) in a lower fatty acid such as acetic acid or propionic acid in the presence of concentrated sulfuric acid,
Compound (Ia) can be usually obtained by reacting at 100 to 150 ° C. for 2 to 48 hours.

Compound (II) can be prepared by a known method [J. Heterocy
clic Chem. (Journal Heterocyclic Chemistry), 26 , 105 (1989)] or in accordance therewith. Compound (III) is Friedel-
It can be easily obtained by a craft acylation reaction. Step 2; 1 to compound (Ia) in benzaldehyde
In the presence of 3 equivalents of a dehydrating agent such as zinc chloride, usually 150 to 20
By reacting at 0 ° C. for 2 to 10 hours, the compound (I
-B) can be obtained. Step 3; Compound (Ib) in acetone with 2-3 equivalents of potassium permanganate, usually at 0 ° C to room temperature for 10 minutes to 2
Compound (Ic) can be obtained by reacting for a time. Production method 2: In compound (I), ring A is (a ² ),
The compound (Ie) which is (b ² ) or (c ² ) can be obtained according to the following reaction step.

[0016]

[Chemical 7]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and ring A ¹ have the same meanings as defined above, and ring A ² is represented by formula (a ² ), (b ² ) or (c ² )

[0018]

Embedded image

Step 4; Compound (Id) in dichloromethane at 1-5
By reacting with an equivalent amount of peracid such as metachloroperbenzoic acid at 0 ° C. to room temperature for 1 to 7 days, the compound (I-
e) can be obtained. Production Method 3: Compounds (If), (Ig) and (I) wherein Ring A in Compound (I) is (d) or (e).
-H) can be obtained according to the following reaction steps.

[0020]

[Chemical 9]

[Wherein R ² , R ³ , R ⁴ and R ⁵ have the same meanings as defined above, R ⁶ represents hydrogen or acetyl, Me represents methyl, Ph represents phenyl, and ring A ³ represents Formula (d) or (e)

[0022]

[Chemical 10]

Step 5; Compound (IV) and an equivalent amount of Compound (III) are reacted in the absence of a solvent in the presence of 1 to 3 equivalents of a dehydrating agent such as zinc chloride, usually at 150 to 200 ° C. for 2 to 10 hours. The compound (If) can be obtained by the reaction.

Compound (IV) is a commercially available product (manufactured by Maybridge) or a known method [Bull. Chem. Soc. Jpn. (Bulletin Chemistry Society Japan), 48 , 14].
7 (1975)] or according to it. Step 6; Compound (Ig) can be obtained from compound (If) by the same method as in Step 2 above. Step 7: Compound (I-h) can be obtained from compound (I-g) by the same method as in Step 3 above.

The intermediates and target compounds in the above-mentioned production method are isolated and purified by purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization and various chromatographies. can do. In addition, the intermediate may be subjected to the next reaction without being particularly purified. When you want to obtain the salt of compound (I),
When compound (I) is obtained in the form of a salt, it may be purified as it is. When it is obtained in a free form, it may be dissolved or suspended in a suitable solvent and added with an acid or a base to form a salt. Should be formed.

The compound (I) and its pharmacologically acceptable salt may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Specific examples of compound (I) obtained by each production method are shown in Table 1.

[0027]

[Table 1]

[0028]

[Table 2]

(In the table, Me represents methyl and Ph represents phenyl) Next, the pharmacological action of compound (I) will be described in Test Examples. Test Example. Effect on antibody production The spleen of a Balb / c male mouse (7 to 10 weeks old, Charles River) was removed, made into a cell suspension in Hanks' solution (Nissui Pharmaceutical), and filtered through a nylon mesh. It was centrifuged at 1200 rpm for 5 minutes. After centrifugation, discard the supernatant and discard Tris ・ N
Red blood cells were hemolyzed and removed with H ₄ Cl solution, and washed with Hanks' solution three times. After washing, wash the cells with 10% fetal bovine serum (Gibco),
Streptomycin (Meiji Seika) 50 μg / ml, Penicillin (Meiji Seika) 50 μU / ml, 2-mercaptoethanol (5x10
^{ー 5} M) (Tokyo Kasei) in RPMI-1640 (Meiji Seika) medium, and culture in micro culture plate (Nunc, 96
Per 1well the holes), 1x10 ⁶ cells by the number of viable cells, dimethylsulfoxide test compound dissolved in de stock ^{(10-2 2} M) of the above-mentioned RPMI-1640 as was diluted 10 ^{@ 5} M in medium and Jacobs Method [Journ of Immunology (Journ
al of Immunology), 114 , 360 (1975)], and combined TNP-LPS (0.5 μg / ml) to make a total volume of 200 μl.
It was cultured at 7 ° C for 4 days. After the completion of the culture for 4 days, the plate was centrifuged, the supernatant was removed, and the above-mentioned culture solution containing no TNP-LPS and the drug was added, and the culture was further continued for 24 hours, and then the culture supernatant was collected.

The anti-TNP antibody titer in the supernatant was measured by enzyme-linked immunosorbent assay (ELISA method). 96-well ELISA microtiter plate (Nunc) Schmidt Bellhorst et al. [Journal of Experimental Medicine, 147 , 352 (197)
8)], TNP-BSA prepared in accordance with the procedure above was added and coated, and after completion of the coating, the culture supernatant was added and reacted. Peroxidase-labeled anti-mouse IgM (American Corelex) was bound to the anti-TNP antibody in the culture supernatant bound to the plate.
After adding ortho-phenylenediamine (Wako Pure Chemical Industries) solution containing hydrogen peroxide (Wako Pure Chemical Industries) to cause reaction and allowing sufficient color development, 10% sulfuric acid (Wako Pure Chemical Industries) was used to stop the reaction.
The absorbance at the wavelength of nm was measured using an immuno reader (NJ-2000, manufactured by Nippon Intermed Co., Ltd.).

The inhibition rate of antibody production by the test compound was determined by the following formula.

[0032]

[Equation 1]

The results are shown in Table 2.

[0034]

[Table 3]

Chronic diseases involved in the immune response include rheumatoid arthritis and other autoimmune diseases (systemic lupus erythematosus, psoriatic arthritis, atopic dermatitis, ankylosing myelitis), and these diseases include bacteria and viruses. Alternatively, self-antigens induce various immune abnormalities including a decrease in T cell function and an increase in B cell function. Therefore, immunosuppressive agents are useful drugs against these diseases.

According to the test results, it showed an inhibitory effect on T cell-dependent antibody production. This suggests the possibility of suppressing T cell abnormalities and autoantibody production, and means that it is effective for diseases that cause immune abnormalities. That is,
It was suggested that the compound of the present invention exhibits an excellent immunosuppressive action and is useful as an immunosuppressive agent and a therapeutic agent for autoimmune diseases.

The compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms for administration purposes depending on its pharmacological action. The pharmaceutical composition of the present invention can be produced by uniformly mixing, as an active ingredient, an effective amount of compound (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unit dose form suitable for oral or injection administration.

In preparing the composition in the oral dosage form, any useful pharmacologically acceptable carrier can be used. Oral liquid preparations such as suspensions and syrups include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil,
It can be produced by using oils such as soybean oil, preservatives such as alkyl p-hydroxybenzoate, flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets include excipients such as lactose, glucose, sucrose, mannitol,
Using starch, disintegrators such as sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, surfactants such as fatty acid esters, plasticizers such as glycerin, etc. Can be manufactured. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. Solid pharmaceutical carriers are used in the production of tablets and capsules.

Injectable solutions can also be prepared using carriers which consist of distilled water, salt solutions, glucose solutions or mixtures of saline and glucose solutions. Compound (I)
Alternatively, a pharmacologically acceptable salt thereof can be administered orally or parenterally by injection, and the effective dose and the number of administrations vary depending on the administration form, age, weight, symptoms of the patient, etc. Usually 1 to 50 mg / kg per day
Is preferably administered in 3 to 4 divided doses.

The embodiments of the present invention will be described below with reference to Examples and Formulation Examples.

[0041]

【Example】

Example 1: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) -4-methyl [1,8] naphthyridine (Compound 1) 3-Acetyl-2-pivaloylaminopyridine 7. 40
g (32.6 mmol) and 4- (2-fluorophenyl) acetophenone 6.98 g (32.6 mmol)
Was dissolved in 70 ml of propionic acid, 7 ml of concentrated sulfuric acid and 18 ml of water, and heated under reflux for 48 hours. The reaction solution was poured into aqueous ammonia and ice, extracted with chloroform, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent,
Separation and purification by silica gel column chromatography [eluting solvent: hexane-ethyl acetate (2: 1)] gave 2.84 g (yield 28%) of the title compound.

Melting point: 164.3 to 165.1 ° C. Elemental analysis (%): C ₂₁ H ₁₅ FN ₂ calculated: C 80.24, H 4.81, N 8.91 Found: C 80.05, H 4.69, N 8.77

IR (KBr) cm ^-1 : 1602, 1594, 1485 NMR (CDCl ₃ ) δ (ppm): 9.12 (1H, dd, J = 2,4Hz), 8.44-8.35
(3H, m), 7.88 (1H, s), 7.74-7.70 (2H, m), 7.56-7.14 (5H,
m), 2.78 (3H, s) MS (m / e): 314 (M ⁺ ), 229

Example 2: 3,4-Dimethyl-2- (2'-fluoro-1,1'-
Biphenyl-4-yl) [1,8] naphthyridine (Compound 2) 3-acetyl-2-pivaloylaminopyridine 8.5 g
(38.6 mmol) and 4- (2-fluorophenyl) propiophenone (8.8 g, 38.6 mmol) were dissolved in propionic acid (90 ml), concentrated sulfuric acid (9 ml) and water (21 ml), and the mixture was heated under reflux for 48 hours. The reaction solution was poured into aqueous ammonia and ice, extracted with chloroform, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was separated and purified by silica gel column chromatography [eluting solvent: hexane-ethyl acetate (2: 1)] to obtain 3.92 g of the title compound (yield 31%).

Melting point: 167.0 to 168.8 ° C. Elemental analysis (%): C ₂₂ H ₁₇ FN ₂ calculated value: C 80.47, H 5.22, N 8.53 Actual value: C 80.22, H 5.30, N 8.36

IR (KBr) cm ^-1 : 1579, 1483, 1341 NMR (CDCl ₃ ) δ (ppm): 9.04 (1H, dd, J = 2,4Hz), 8.38 (1H, d
d, J = 2,8Hz), 7.67-7.37 (4H, m), 7.65-7.15 (5H, m), 2.66
(3H, s), 2.49 (3H, s) MS (m / e): 328 (M ⁺ ), 233

Example 3: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) -4-styryl [1,8] naphthyridine (Compound 3) 2 of the compound 1 obtained in Example 1 To 0.2 g (7.0 mmol), 10 ml of benzaldehyde and 0.95 g (7.0 mmol) of zinc chloride were added under an argon stream to give 18
The mixture was stirred at 0 ° C for 6 hours. Dilute sodium hydroxide solution and ethyl acetate were added to the reaction solution, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, silica gel column chromatography
Separation and purification with [eluting solvent: hexane-ethyl acetate (2: 1)] gave 2.05 g (yield 73%) of the title compound.

Melting point: 200.2 to 201.1 ° C. Elemental analysis (%): C ₂₈ H ₁₉ FN ₂ Calculated value: C 83.56, H 4.76, N 6.96 Measured value: C 83.22, H 4.74, N 6.75

IR (KBr) cm ⁻¹ : 1599, 1541, 1485 NMR (CDCl ₃ ) δ (ppm): 9.15 (1H, dd, J = 2,4Hz), 8.58 (1H, d
d, J = 2,8Hz), 8.47-8.44 (2H, m), 8.23 (1H, s), 7.81-7.18
(14H, m) MS (m / e): 402 (M ⁺ ), 325

Example 4: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) [1,8] naphthyridine-4-carboxylic acid (Compound 4) Of the compound 3 obtained in Example 3 2.36 g (5.86 mmol) was suspended in 120 ml of acetone, 2.32 g (14.7 mmol) of potassium permanganate was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was further heated under reflux for 1 hour, cooled, filtered, and the filtered material was suspended in hot water. After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration.
After washing with water and ethanol and drying, the title compound 1.
74 g (yield 86%) was obtained.

Melting point:> 300 ° C. Elemental analysis (%): C ₂₁ H ₁₃ FN ₂ O ₂ Calculated value: C 73.25, H 3.81, N 8.14 Measured value: C 73.28, H 3.71, N 8.13

IR (KBr) cm ^-1 : 1602, 1485, 1257, 1218 NMR (DMSO-d ₆ ) δ (ppm): 14.2 (1H, brs), 9.19-9.13 (2H,
m), 8.66 (1H, s), 8.48 (2H, d, J = 7Hz), 7.82-7.34 (7H, m) MS (m / e): 344 (M ⁺ ), 300

Example 5: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) -3-methyl [1,8] naphthyridine-4-carboxylic acid (Compound 5) Obtained in Example 2. 15 ml of benzaldehyde was added to 1.85 g (5.63 mmol) of the obtained compound 2 under an argon stream.
And 0.77 g (5.6 mmol) of zinc chloride,
The mixture was stirred at 180 ° C for 6 hours. Dilute sodium hydroxide solution and ethyl acetate were added to the reaction solution, and the mixture was extracted under neutral conditions.
The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was separated by silica gel column chromatography (eluting solvent: ethyl acetate) to obtain 1.40 g of a crude styryl product. This was suspended in 100 ml of acetone, and under ice cooling, 1.33 g of potassium permanganate
(8.4 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was further heated under reflux for 1 hour, cooled, filtered, and the filtered material was suspended in hot water. After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration. After washing with water and methanol and drying, 0.9 g of the title compound (yield 45% from compound 2)
I got

Melting point: 292 ° C. (decomposition) Elemental analysis (%): C ₂₂ H ₁₅ FN ₂ O ₂ .0.1H ₂ O Calculated value: C 73.37, H 4.25, N 7.78 Measured value: C 73.20, H 4.23, N 7.72

IR (KBr) cm ⁻¹ : 1717, 1579, 1486, 1401 NMR (DMSO-d ₆ ) δ (ppm): 9.12 (1H, dd, J = 2,4Hz), 8.31 (1
H, dd, J = 2,8Hz), 7.82-7.33 (9H, m), 2.50 (3H, s) MS (m / e): 358 (M ⁺ ), 313

Example 6: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) -4-methyl [1,7] naphthyridine (Compound 6) 4-Acetyl-3-pivaloylamino Pyridine 3.0g
(13.6 mmol) and 4- (2-fluorophenyl) acetophenone (2.92 g, 13.6 mmol) were dissolved in 90 ml of propionic acid, 9 ml of concentrated sulfuric acid and 9 ml of water, and the mixture was heated under reflux for 12 hours. The reaction solution was poured into aqueous ammonia and ice, extracted with chloroform, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was separated and purified by silica gel column chromatography [eluting solvent: hexane-ethyl acetate (2: 1)] to obtain 2.15 g (yield 50%) of the title compound.

Melting point: 125.5-125.9 ° C. Elemental analysis (%): C ₂₁ H ₁₅ FN ₂ Calculated value: C 80.24, H 4.81, N 8.91 Actual value: C 79.98, H 4.64, N 8.91

IR (KBr) cm ^-1 : 1604, 1485, 1452, 1417 NMR (CDCl ₃ ) δ (ppm): 9.54 (1H, s), 8.58 (1H, d, J = 6Hz),
8.21 (2H, d, J = 9Hz), 7.87 (1H, s), 7.71-7.69 (3H, m), 7.
52-7.13 (4H, m), 2.71 (3H, s) MS (m / e): 314 (M ⁺ ), 299

Example 7: 3,4-Dimethyl-2- (2'-fluoro-1,1'-
Biphenyl-4-yl) [1,7] naphthyridine (Compound 7) 4-acetyl-3-pivaloylaminopyridine 4.9 g
(22.2 mmol) and 4- (2-fluorophenyl) propiophenone 5.07 g (22.2 mmol)
120 ml of propionic acid, 12 ml of concentrated sulfuric acid and 12 m of water
It was dissolved in 1 and heated under reflux for 12 hours. The reaction solution was poured into aqueous ammonia and ice, extracted with chloroform, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, silica gel column chromatography [elution solvent;
Separation and purification with hexane-ethyl acetate (2: 1)] gave 4.5 g of the title compound (yield 62%).

Melting point: 136.4 to 136.9 ° C. Elemental analysis (%): C ₂₂ H ₁₇ FN ₂ Calculated value: C 80.47, H 5.22, N 8.53 Measured value: C 80.24, H 5.09, N 8.52

IR (KBr) cm ^-1 : 1483, 1446, 1378, 1203 NMR (CDCl ₃ ) δ (ppm): 9.50 (1H, s), 8.60 (1H, d, J = 6Hz),
7.79 (1H, d, J = 6Hz), 7.68-7.14 (8H, m), 2.68 (3H, s), 2.5
0 (3H, s) MS (m / e): 328 (M ⁺ ), 233

Example 8: (2'-Fluoro-1,1'-biphenyl-4-yl)
-4-styryl [1,7] naphthyridine (Compound 8) To 3.5 g (11.1 mmol) of the compound 6 obtained in Example 6 under an argon stream, 10 ml of benzaldehyde and 1.51 g (11.1 mmol) of zinc chloride. ),
The mixture was stirred at 180 ° C for 6 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography [eluting solvent: hexane-ethyl acetate (4: 1)] to obtain 4.1 g of the title compound (yield 92%).

Melting point: 197.3 to 198.2 ° C. Elemental analysis (%): C ₂₈ H ₁₉ FN ₂ calculated: C 83.56, H 4.76, N 6.96 Found: C 83.34, H 4.70, N 6.84

IR (KBr) cm ^-1 : 1584, 1484, 1452, 1416 NMR (CDCl ₃ ) δ (ppm): 9.57 (1H, s), 8.61 (1H, d, J = 6Hz),
8.28-8.14 (3H, m), 7.94-7.92 (1H, m), 7.75-7.63 (4H, m),
7.56-7.14 (9H, m) MS (m / e): 402 (M ⁺ ), 325

Example 9: (2'-Fluoro-1,1'-biphenyl-4-yl)
-3-Methyl-4-styryl [1,7] naphthyridine (Compound 9) 5.17 g (15.7 mmol) of the compound 7 obtained in Example 7 was added to 25 ml of benzaldehyde under an argon stream.
And 2.14 g (15.7 mmol) of zinc chloride were added, and the mixture was stirred at 180 ° C. for 6 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, silica gel column chromatography
Separation and purification with [eluting solvent: hexane-ethyl acetate (4: 1)] gave 3.14 g (yield 48%) of the title compound.

Melting point: 193.8 to 194.2 ° C. Elemental analysis (%): C ₂₉ H ₂₁ FN ₂ calculated: C 83.63, H 5.08, N 6.73 Found: C 83.51, H 5.13, N 6.64

IR (KBr) cm ^-1 : 1482, 1477, 1451, 1377 NMR (CDCl ₃ ) δ (ppm): 9.53 (1H, s), 8.57 (1H, d, J = 6Hz),
7.93 (1H, d, J = 6Hz), 7.69-7.11 (14H, m), 6.94 (1H, d, J = 16
Hz), 2.55 (3H, s) MS (m / e): 416 (M ⁺ ), 339

Example 10: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) [1,7] naphthyridine-4-carboxylic acid (Compound 10) Of compound 8 obtained in Example 8 3.0 g (5.86 mmol) was suspended in 150 ml of acetone, 2.94 g (18.7 mmol) of potassium permanganate was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Heat to reflux for another hour,
After cooling, it was filtered, and the filtered material was suspended in hot water. After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration. After washing with water and methanol and drying, the title compound (1.5 g)
(Yield 59%) was obtained.

Melting point: 291.6 to 297.7 ° C. Elemental analysis (%): C ₂₁ H ₁₃ FN ₂ O ₂ .0.3H ₂ O Calculated value: C 72.11, H 3.92, N 8.01 Measured value: C 72.13, H 3.59, N 7.90

IR (KBr) cm ^-1 : 1594, 1253, 1202, 1042 NMR (DMSO-d ₆ ) δ (ppm): 9.55 (1H, s), 8.80 (1H, s), 8.71
(1H, d, J = 6Hz), 8.59 (1H, d, J = 6Hz), 8.47-8.44 (2H, m), 7.
82-7.34 (6H, m) MS (m / e): 344 (M ⁺ ), 299

Example 11: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) -3-methyl [1,7] naphthyridine-4-carboxylic acid (Compound 11) Obtained in Example 9. 2.6 g (6.2 mmol) of the obtained compound 9 was suspended in 130 ml of acetone, 2.55 g (16.1 mmol) of potassium permanganate was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Heat to reflux for another hour,
After cooling, it was filtered, and the filtered material was suspended in hot water. After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration. After washing with water and methanol and drying, the title compound was 1.75.
g (yield 78%) was obtained.

Melting point: 287.6 to 293.4 ° C. Elemental analysis (%): C ₂₂ H ₁₅ FN ₂ O ₂ .0.2H ₂ O Calculated value: C 73.00, H 4.29, N 7.74 Measured value: C 73.02, H 4.13, N 7.84

IR (KBr) cm ⁻¹ : 1486, 1388, 1213 NMR (DMSO-d ₆ ) δ (ppm): 9.44 (1H, s), 8.68 (1H, d, J = 6H
z), 7.84-7.33 (9H, m), 2.52 (3H, s) MS (m / e): 358 (M ⁺ ), 263

Example 12: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) -3-methyl [1,7] naphthyridine-7-oxide-4-carboxylic acid (Compound 12) Implementation 0.65 g (1.8 g) of the compound 11 obtained in Example 11
150 mmol) was suspended in 150 ml of methylene chloride, and 1.56 g (9 mmol) of metachloroperbenzoic acid was added under ice cooling. After stirring at room temperature for 7 days, the mixture was filtered, washed well with methylene chloride, and dried to give 0.63 g of the title compound (yield 93
%) Was obtained.

Melting point: 264 ° C. (decomposition) Elemental analysis (%): C ₂₂ H ₁₅ FN ₂ O ₃ .0.3H ₂ O Calculated value: C 69.57, H 4.14, N 7.38 Measured value: C 69.41, H 3.85, N 7.27

IR (KBr) cm ^-1 : 1705, 1578, 1484, 1346 NMR (DMSO-d ₆ ) δ (ppm): 8.94 (1H, d, J = 1Hz), 8.29 (1H, d
d, J = 1,7Hz), 7.81-7.33 (9H, m), 2.46 (3H, s) MS (m / e): 374 (M ⁺ ), 358

Example 13: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) -4-methyl [1,6] naphthyridine (Compound 1
3) 3-acetyl-4-pivaloylaminopyridine 3.0 g
(13.6 mmol) and 4- (2-fluorophenyl) acetophenone (2.92 g, 13.6 mmol) were dissolved in 90 ml of propionic acid, 9 ml of concentrated sulfuric acid and 9 ml of water, and the mixture was heated under reflux for 12 hours. The reaction solution was poured into aqueous ammonia and ice, extracted with chloroform, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was separated and purified by silica gel column chromatography [eluting solvent: hexane-ethyl acetate (2: 1)] to obtain 2.15 g (yield 50%) of the title compound.

Melting point: 191.6 to 192.7 ° C. Elemental analysis (%): C ₂₁ H ₁₅ FN ₂ Calculated value: C 80.24, H 4.81, N 8.91 Actual value: C 80.10, H 4.73, N 8.54

IR (KBr) cm ⁻¹ : 1605, 1486, 1452, 1414 NMR (CDCl ₃ ) δ (ppm): 9.46 (1H, s), 8.76 (1H, d, J = 5Hz),
8.26-8.23 (2H, m), 7.95 (1H, d, J = 5Hz), 8.82 (1H, s), 7.7
4-7.71 (2H, m), 7.39-7.12 (4H, m), 2.86 (3H, s) MS (m / e): 314 (M ⁺ ), 299

Example 14: 3,4-Dimethyl-2- (2'-fluoro-1,1'-
Biphenyl-4-yl) [1,6] naphthyridine (Compound 14) 3-Acetyl-4-pivaloylaminopyridine 4.9 g
(22.2 mmol) and 4- (2-fluorophenyl) propiophenone 5.07 g (22.2 mmol)
120 ml of propionic acid, 12 ml of concentrated sulfuric acid and 12 m of water
It was dissolved in 1 and heated under reflux for 12 hours. The reaction solution was poured into aqueous ammonia and ice, extracted with chloroform, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, silica gel column chromatography [elution solvent;
Separation and purification with hexane-ethyl acetate (2: 1)] gave 4.5 g of the title compound (yield 62%).

Melting point: 181.7 to 182.3 ° C. Elemental analysis (%): C ₂₂ H ₁₇ FN ₂ .0.1H ₂ O Calculated value: C 79.59, H 5.28, N 8.44 Measured value: C 79.80, H 5.26 , N 8.41

IR (KBr) cm ⁻¹ : 1601, 1486, 1382, 1246 NMR (CDCl ₃ ) δ (ppm): 9.55 (1H, s), 8.72 (1H, d, J = 6Hz),
7.91 (1H, d, J = 6Hz), 7.71-7.15 (8H, m), 2.81 (3H, s), 2.4
9 (3H, s) MS (m / e): 328 (M ⁺ ), 233

Example 15: (2'-Fluoro-1,1'-biphenyl-4-yl)
-4-styryl [1,6] naphthyridine (Compound 15) 2.66 g (8.5 of Compound 13 obtained in Example 13
Benzaldehyde 20m under argon flow
1 and 1.16 g (8.5 mmol) of zinc chloride were added to 1
The mixture was stirred at 80 ° C for 3 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was separated and purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (4: 1)] to obtain 2.26 g (yield 66%) of the title compound.

Melting point: 184.7-184.9 ° C. Elemental analysis (%): C ₂₈ H ₁₉ FN ₂ .0.1 H ₂ O Calculated value: C 83.19, H 4.79, N 6.93 Measured value: C 83.08, H 4.76 , N 6.59

IR (KBr) cm ^-1 : 1581, 1488, 1423, 1362 NMR (CDCl ₃ ) δ (ppm): 9.68 (1H, s), 8.79 (1H, d, J = 6Hz),
8.32-8.29 (2H, m), 8.18 (1H, s), 8.00-7.16 (14H, m) MS (m / e): 402 (M ⁺ ), 325

Example 16: (2'-Fluoro-1,1'-biphenyl-4-yl)
-3-Methyl-4-styryl [1,6] naphthyridine (Compound 16) 20 g of benzaldehyde was added to 2.8 g (8.5 mmol) of the compound 14 obtained in Example 14 under an argon stream.
And 1.16 g (8.5 mmol) of zinc chloride were added,
The mixture was stirred at 180 ° C for 4 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was separated and purified by silica gel column chromatography [eluting solvent: hexane-ethyl acetate (4: 1)] to obtain 1.0 g of the title compound (yield 28%).

Melting point: 180.1-180.3 ° C. Elemental analysis (%): C ₂₉ H ₂₁ FN ₂ calculated: C 83.63, H 5.08, N 6.73 Actual value: C 83.35, H 5.16, N 6.63

IR (KBr) cm ⁻¹ : 1598, 1562, 1486, 1010 NMR (CDCl ₃ ) δ (ppm): 9.61 (1H, s), 8.73 (1H, d, J = 6Hz),
7.94 (1H, d, J = 6Hz), 7.74-7.16 (14H, m), 7.01 (1H, d, J = 17
Hz), 2.55 (3H, s) MS (m / e): 416 (M ⁺ ), 339

Example 17: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) [1,6] naphthyridine-4-carboxylic acid (Compound 17) Of the compound 15 obtained in Example 15 2.15 g (5.3
(4 mmol) was suspended in 110 ml of acetone, 2.11 g (13.4 mmol) of potassium permanganate was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was further heated under reflux for 1 hour, cooled, filtered, and the filtered material was suspended in hot water.
After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration. After washing with water and methanol and drying, 1.3 g (yield 71%) of the title compound was obtained.

Melting point:> 300 ° C. Elemental analysis (%): C ₂₁ H ₁₃ FN ₂ O ₂ .0.1H ₂ O Calculated value: C 72.87, H 3.84, N 8.09 Measured value: C 72.73, H 3.61, N 8.09

IR (KBr) cm ⁻¹ : 1619, 1592, 1487, 1243 NMR (DMSO-d ₆ ) δ (ppm): 10.03 (1H, s), 8.83 (1H, d, J = 6H
z), 8.65 (1H, s), 8.48-8.45 (2H, m), 8.06 (1H, dd, J = 1,6H
z), 7.82-7.34 (6H, m) MS (m / e): 344 (M ⁺ ), 299

Example 18: 2- (2'-Fluoro-1,1'-biphenyl-4-yl) -3-methyl [1,6] naphthyridine-4-carboxylic acid (Compound 18) Obtained in Example 16. Compound 16 of 0.40 g (0.9
6 mmol) was suspended in 130 ml of acetone, 0.38 g (2.4 mmol) of potassium permanganate was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was further heated under reflux for 1 hour, cooled, filtered, and the filtered material was suspended in hot water.
After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration. After washing with water and methanol and drying, 0.29 g (yield 84%) of the title compound was obtained.

Melting point: 279 ° C. (decomposition) Elemental analysis (%): C ₂₂ H ₁₅ FN ₂ O ₂ .0.1H ₂ O Calculated value: C 70.21, H 4.55, N 7.44 Measured value: C 70.18, H 4.50, N 7.35

IR (KBr) cm ⁻¹ : 3500, 1559, 1486, 1380 NMR (DMSO-d ₆ ) δ (ppm): 9.27 (1H, s), 8.79 (1H, d, J = 6H
z), 7.98 (1H, d, J = 6Hz), 7.81-7.33 (8H, m), 2.50 (3H, s) MS (m / e): 358 (M ⁺ ), 313

Example 19: 5- (2'-Fluoro-1,1'-biphenyl-4-yl) -7-methylthieno [3,2-b] pyridine (Compound 19) 2-Acetyl-3-aminothiophene 5.6 g (40 mmol) and 4- (2-fluorophenyl) acetophenone 9.35 g (44 mmol) were added to an argon stream,
3.46 g (25.4 mmol) of zinc chloride was added, and 16
The mixture was stirred at 0 ° C for 4 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography [elution solvent: hexane-ethyl acetate (10: 1)] to obtain 6.75 g (yield 53%) of the title compound.

Melting point: 155.1 to 156.3 ° C. Elemental analysis (%): C ₂₀ H ₁₄ FNS Calculated value: C 75.21, H 4.42, N 4.39 Measured value: C 75.23, H 4.43, N 7.23

IR (KBr) cm ^-1 : 1570, 1484, 1451, 1364 NMR (CDCl ₃ ) δ (ppm): 8.15-8.12 (2H, m), 7.76-7.14 (9
H, m), 2.67 (3H, s) MS (m / e): 319 (M ⁺ ), 304

Example 20: 6,7-Dimethyl-5- (2'-fluoro-1,1'-
Biphenyl-4-yl) thieno [3,2-b] pyridine (Compound 20) 4-Acetyl-3-aminothiophene 4.96 g (3
5.1 mmol) and 4- (2-fluorophenyl)
4.73 g (34.7 mmol) of zinc chloride was added to 8.83 g (38.6 mmol) of propiophenone under an argon stream, and the mixture was stirred at 160 ° C. for 6 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, silica gel column chromatography [eluting solvent: hexane-ethyl acetate (10:
1)] and separated and purified to give 5.04 g of the title compound (yield 4
3%).

Melting point: 151.2 to 151.8 ° C. Elemental analysis (%): C ₂₁ H ₁₆ FNS Calculated value: C 75.65, H 4.84, N 4.20 Measured value: C 75.82, H 4.86, N 4.14

IR (KBr) cm ^-1 : 1578, 1484, 1346, 1211 NMR (CDCl ₃ ) δ (ppm): 7.68-7.46 (7H, m), 7.35-7.14 (3
H, m), 2.61 (3H, s), 2.41 (3H, s) MS (m / e): 333 (M ⁺ ), 317

Example 21: 5- (2'-Fluoro-1,1'-biphenyl-4-yl) -7-styrylthieno [3,2-b] pyridine (Compound 21) Compound 19 obtained in Example 19 5.4 g (16.9
Benzaldehyde 25m under argon flow
1, and 2.30 g (16.9 mmol) of zinc chloride were added, and the mixture was stirred at 180 ° C. for 5 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, silica gel column chromatography
Separation and purification with [elution solvent: hexane-ethyl acetate (10: 1)] gave 5.13 g (yield 75%) of the title compound.

Melting point: 175.8 to 177.9 ° C. Elemental analysis (%): C ₂₇ H ₁₈ FNS Calculated value: C 79.58, H 4.45, N 3.44 Actual value: C 79.38, H 4.40, N 3.32

IR (KBr) cm ⁻¹ : 1564, 1486, 1369, 1253 NMR (CDCl ₃ ) δ (ppm): 8.21-8.18 (2H, m), 7.88 (1H, s),
7.82-7.15 (15H, m) MS (m / e): 407 (M ⁺ ),

Example 22: 5- (2'-Fluoro-1,1'-biphenyl-4-yl) thieno [3,2-b] pyridine-7-carboxylic acid (Compound 22) Obtained in Example 21. 3.2 g of compound 21 (7.85)
Millimolar) in 100 ml of acetone, and under ice cooling,
3.1 g (19.6 mmol) of potassium permanganate was added, and the mixture was stirred at room temperature for 1 hour. The mixture was further heated under reflux for 1 hour, cooled, filtered, and the filtered material was suspended in hot water. After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration.
After washing with water and methanol and drying, the title compound 2.
3 g (yield 84%) was obtained.

Melting point:> 300 ° C. Elemental analysis (%): C ₂₀ H ₁₂ FNO ₂ S Calculated value: C 68.76, H 3.46, N 4.01 Measured value: C 69.01, H 3.45, N 3.89

IR (KBr) cm ⁻¹ : 1703, 1579, 1486, 1400 NMR (DMSO-d ₆ ) δ (ppm): 14.4 (1H, brs), 8.41 (1H, s),
8.35-8.31 (3H, m), 7.76-7.33 (6H, m) MS (m / e): 349 (M ⁺ ), 138

Example 23: 5- (2'-Fluoro-1,1'-biphenyl-4-yl) -6-methylthieno [3,2-b] pyridine-7-
Carboxylic Acid (Compound 23) 2.0 g (6.0 mmol) of the compound 20 obtained in Example 20 was added to 10 ml of benzaldehyde under an argon stream.
And 0.82 g (6.0 mmol) of zinc chloride,
The mixture was stirred at 180 ° C for 8 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was separated by silica gel column chromatography [elution solvent: hexane-ethyl acetate (10: 1)],
1.5 g of crude styryl product was obtained. This was suspended in 100 ml of acetone, 1.5 g (9.5 mmol) of potassium permanganate was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The mixture was further heated under reflux for 1 hour, cooled, filtered, and the filtered material was suspended in hot water. After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration. After washing with water and methanol and drying, 0.36 g of the title compound (yield 17% from compound 20) was obtained.

Melting point: 290 ° C. (decomposition) Elemental analysis (%): C ₂₁ H ₁₄ FNO ₂ S Calculated value: C 69.41, H 3.88, N 3.85 Measured value: C 69.48, H 3.76, N 3.68

IR (KBr) cm ⁻¹ : 1699, 1486, 1346, 1291 NMR (DMSO-d ₆ ) δ (ppm): 8.15 (1H, d, J = 6Hz), 7.72-7.30
(9H, m), 2.60 (3H, s) MS (m / e): 363 (M ⁺ ), 343

Example 24: 5- (2'-Fluoro-1,1'-biphenyl-4-yl) -7-methylthieno [2,3-b] pyridine (Compound 24) 3-Acetyl-2-acetylamino Thiophene 7.79
g (42.5 mmol) and 4- (2-fluorophenyl) acetophenone 9.71 g (42.5 mmol)
5.8 g (42.6 mmol) of zinc chloride was added to the mixture under argon, and the mixture was stirred at 160 ° C. for 4 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, silica gel column chromatography [eluting solvent: hexane-ethyl acetate (50:
1)] and separated and purified to give 3.95 g of the title compound (yield 2
9%) was obtained.

Melting point: 148.4 to 148.8 ° C. Elemental analysis (%): C ₂₀ H ₁₄ FNS Calculated value: C 75.21, H 4.42, N 4.39 Measured value: C 75.06, H 4.71, N 4.00

IR (KBr) cm ⁻¹ : 1563, 1470, 1249, 843 NMR (CDCl ₃ ) δ (ppm): 8.18-8.14 (2H, m), 7.71-7.14 (9
H, m), 2.69 (3H, s) MS (m / e): 319 (M ⁺ ), 304

Example 25: 5- (2'-Fluoro-1,1'-biphenyl-4-yl) thieno [2,3-b] pyridine-7-carboxylic acid (Compound 25) Obtained in Example 24. 2.20 g of compound 24 (6.8)
Benzaldehyde 10 to 9 mmol) under an argon stream.
ml and 0.94 g (6.89 mmol) of zinc chloride were added, and the mixture was stirred at 180 ° C. for 8 hours. Dilute sodium hydroxide solution and ethyl acetate were added, and the mixture was extracted under neutral conditions. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, silica gel column chromatography
Separation with [elution solvent: hexane-ethyl acetate (10: 1)] gave 2.4 g of a crude styryl product. This was suspended in 150 ml of acetone, 2.4 g (15.2 mmol) of potassium permanganate was added under ice cooling, and the mixture was stirred at room temperature for 1 hour.
Stirred for hours. The mixture was further heated under reflux for 1 hour, cooled, filtered, and the filtered material was suspended in hot water. After filtering again, acetic acid was added to the filtrate, and the precipitated crystals were collected by filtration. After washing with water and methanol and drying, 0.54 g of the title compound (compound 2
(22% yield from 4) was obtained.

Melting point: 249 ° C. (decomposition) Elemental analysis (%): C ₂₀ H ₁₂ FNO ₂ S.0.4H ₂ O Calculated value: C 67.37, H 3.62, N 3.93 Measured value: C 67.17, H 3.26, N 3.73

IR (KBr) cm ⁻¹ : 1719, 1578, 1485, 1405 NMR (DMSO-d ₆ ) δ (ppm): 8.45 (1H, s), 8.33-8.29 (2H,
m), 8.11 (1H, d, J = 6Hz), 8.01 (1H, d, J = 6Hz), 7.76-7.32 (6
H, m) MS (m / e): 349 (M ⁺ ), 304

Formulation Example 1. Tablet A tablet having the following composition is prepared by a conventional method. Prescription Compound 1 10 mg Lactose 30 mg Potato starch 15 mg Polyvinyl alcohol 1.5 mg Magnesium stearate 0.5 mg

Formulation Example 2. Capsule A capsule having the following composition is prepared by a conventional method. Formulation Compound 1 10 mg Lactose 100 mg Magnesium stearate 2.5 mg These are mixed and filled in a gelatin capsule.

Formulation Example 3. Injection Preparation An injection preparation having the following composition is prepared by a conventional method. Formulation Compound 1 10 mg Sodium chloride 20 mg To this, distilled water for injection is added to make a total volume of 5 ml (1 ampoule portion).

[0119]

Industrial Applicability According to the present invention, a condensed pyridine derivative useful as an immunosuppressant can be provided.

Claims (1)

[Claims] 1. Formula (I): [Wherein R ¹ represents methyl, styryl or carboxyl, R ² represents hydrogen or lower alkyl, R ³ , R ⁴ and R ⁵ are the same or different and are hydrogen, lower alkoxy,
Represents halogen, nitro, amino, lower alkylamino, ring A is of formula (a), (b), (c), (d) or (e) (Wherein, n represents 0 or 1)] or a pharmaceutically acceptable salt thereof.