JPH10147568A - Naphthalene derivative and medicine containing the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a treatment and/or prophylax is action for pathologies such as inflammation caused by autoimmune diseases, e.g. rheumatics, nephritis and asthma, and various kinds of circulatory diseases, e.g. arteriosclerosis and restenosis after PTCA, and useful as a highly safe medicine. SOLUTION: A naphthalene derivative of the formula (the semidouble bond is a single bond or a double bond; R1 -R3 are each H, a 1-4C alkyl, a halogen, hydroxyl, etc.; R4 is carboxyl, a 1-4C alkylthiocarbonyl, etc.) and its pharmacologically aceptable salt. For example, (Z)-3-(2-naphthyl)-2-(phenylthio) propenoic acid. The compound of the formula is obtained e.g. by reacting a naphthalene aldehyde derivative with a phenylthioacetic acid derivative (preferably in an equivalent ratio of 1:1) in the presence of acetic anhydride and triethylamine preferably at 80-160 deg.C with stirring.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel naphthalene derivative and its application to the field of medicine. More specifically, it has a cell adhesion inhibitory effect, inflammation caused by autoimmune diseases such as rheumatism, nephritis, asthma, allergy, dermatitis, colitis, diabetes, and atherosclerosis, restenosis after PTCA, cardiovascular disorder, The present invention relates to a novel naphthalene derivative having a therapeutic and / or prophylactic action on various circulatory disorders such as cerebrovascular disorder and peripheral vascular disorder, and further on metastasis and growth of cancer.

[0002]

2. Description of the Related Art Living organisms are composed of a large number of cells that are highly differentiated structurally and functionally. Living organisms are maintained by these cells that correspond to and adapt to the surrounding environment while communicating with each other. This interaction between cells is regulated by humoral regulators such as various cytokines and hormones, as well as by direct contact between cells. In particular, T cells and antigen presenting cells in the immune system, and cytotoxic T cells Cell-cell interactions between anti-neutrophils and platelets and vascular endothelial cells at target cells and inflammation sites are involved in the expression of functions or the establishment of pathological conditions by direct contact of cells via cell adhesion factors or binding of molecules. Has recently been revealed. Furthermore, in addition to the regulation of the immune system as well as the metastasis of cancer cells, it has been found that the interaction between cells and the extracellular matrix plays an important role in addition to direct contact between cells.

As described above, in recent years, many adhesion factors (molecules) relating to cell-cell adhesion or cell-extracellular matrix adhesion have been identified, and it has been revealed that they are involved in the pathology of various diseases. In particular, among these cells, anti-neutrophils, which are greatly involved in the inflammatory response, have a large trigger of their action by adhesion to vascular endothelial cells, and Mac-1 (CD-11) is used as an adhesion factor (molecule).
b / CD18), LFA-1 (CD-11a / CD1)
8), LECAM-1 and the like,
CAM-1, ICAM-2, VCAM-1, PECA
M, ELAM-1, GMP-140 and the like have been identified.

[0004] Some attempts have been made to treat and / or prevent a wide range of anti-inflammatory effects, various anti-cardiovascular effects, and cancer metastasis-suppressing effects by inhibiting the action of this adhesion factor. For example, the so-called Leum
Various amino acid derivatives having a fluorene skeleton called edin (Proc. Natl. Acad. Sci. US
A 88 355 (1991), Immunopharm
acol. 23 139 (1992), J. Med. Ch.
em. 38 1650 (1995), Tokuhyo Hei 4-506
No. 350 gazette. Other) benzothiophene derivatives (J. Med. Chem. 37 717 (1994);
J. Med. Chem. 38 4597 (1995),
JP-T-7-504199, etc.), thiazole derivatives (J. Med. Chem. 38 1057 (1995))
Etc. However, all of these compounds have many problems to be developed as pharmaceuticals, such as insufficient activity, poor physical properties such as water solubility, poor oral absorption, and side effects such as hemolysis, and are still in clinical use. No drugs applied. That is, development of a drug having higher activity and less side effects is desired.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to inhibit rheumatism, nephritis, asthma, allergy, dermatitis, colitis, diabetes, etc. by strongly inhibiting cell adhesion which is deeply involved in many disease states. Inflammation due to autoimmune disease,
A highly safe drug having a therapeutic and / or prophylactic action for various circulatory disorders such as arteriosclerosis, restenosis after PTCA, cardiovascular disorders, cerebrovascular disorders, peripheral vascular disorders, and also metastasis and proliferation of cancer. Is to find useful compounds.

[0006]

Means for Solving the Problems The present inventors have focused on neutrophils and vascular endothelial cells in order to solve the above-mentioned problems, and have found substances that inhibit the adhesion of these substances from many compound groups. I've been working hard. Among them, the naphthalene derivative represented by the general formula (1) was found to have a very strong cell adhesion inhibitory activity, low toxicity and useful as a medicine, and completed the present invention. That is, the present invention relates to [1] the general formula (1)

[0007]

Embedded image In the formula, R ₁ and R ₂ may each independently be any position on the naphthalene ring, and may be a hydrogen atom, a carbon atom having 1 to 4 carbon atoms.
Lower alkyl group, a halogen atom, a hydroxyl group, an alkyloxy group having 1 to 8 carbon atoms, a nitro group, an amino group,
A lower alkylamino group having 1 to 4 carbon atoms or a cyano group; R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a hydroxyl group or a 1 to 4 carbon atoms;
Represents a lower alkyloxy group, R ₄ is a carboxyl group, a lower alkyloxycarbonyl group having 1 to 4 carbon atoms,
A hydrazinocarboxy group or at least one nitrogen atom
It represents a 5-membered heterocyclic ring containing two or more. However, when R ₁ and R ₂ are alkyloxy groups, R ₁ and R ₂ may combine to form a methylenedioxy group. ) And a pharmacologically acceptable salt thereof,
[2] General formula (2)

[0008]

Embedded image A naphthalene derivative and a pharmacologically acceptable salt contained in claim 1 represented by the formula:
A cell adhesion factor expression inhibitor containing, as an active ingredient, a naphthalene derivative represented by the general formula (1) of [1],
[4] A pharmaceutical composition containing a naphthalene derivative represented by the general formula (1) of [1] as an active ingredient.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail.

[0010] The lower alkyl group having 1 to 4 carbon atoms means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and the like.

The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The alkyloxy group having 1 to 8 carbon atoms means a methoxy group, an ethoxy group, a propoxy group, a butyloxy group, a pentyloxy group, a hexyloxy group, a heptyloxy group, an octyloxy group and the like.

The lower alkylamino group having 1 to 4 carbon atoms means a methylamino group, an ethylamino group, a propylamino group, a butylamino group, a dimethylamino group, a diethylamino group and the like.

The lower alkyloxycarbonyl group having 1 to 4 carbon atoms includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butyloxycarbonyl group and the like.

The 5-membered heterocyclic ring containing at least one nitrogen atom includes pyrrole, imidazole, triazole, tetrazole, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, imidazoline, imidazolidin, pyrazole, 5-membered nitrogen-containing heterocyclic ring such as pyrazoline and pyrazolidine (the heterocyclic ring may be substituted with an alkyl group such as a methyl group or an ethyl group and a hydroxyl group, a thiol group, a carbonyl group or a thiocarbonyl group) Is shown.

The pharmacologically acceptable salt is not particularly limited, and includes both acidic salts and basic salts. Here, as the inorganic acid salt, hydrochloride, bromate, sulfate, nitrate,
Shows phosphates and the like, organic salts include acetate, tosylate, oxalate, tartrate, fumarate, malonate, maleate, etc., and inorganic base salts such as ammonium salt, sodium salt, Potassium salts, calcium salts, magnesium salts and the like, and organic base salts include pyridine salts, triethylamine salts, piperazine salts and the like.

The pharmaceutical composition according to the present invention includes inflammation due to autoimmune diseases such as rheumatism, nephritis, asthma, allergy, dermatitis, colitis, diabetes, arteriosclerosis, restenosis after PTCA, cardiovascular disorders, It refers to those used for the treatment and / or prevention of various circulatory disorders such as cerebrovascular disorder and peripheral vascular disorder, and furthermore, for the metastasis and proliferation of cancer.

A method for producing the compound of the general formula (1) will be described. [Synthesis Method 1] In many cases, the naphthalene aldehyde derivative represented by the general formula (3) can be converted into the carboxylic acid derivative represented by the general formula (5) by various commonly known condensation reactions. For example, one example is shown in Reaction formula (1) [Chemical formula 5].

[0018]

Embedded image (Wherein R ₁ , R ₂ and R ₃ are as defined above) The aldehyde compound of the general formula (3) and the phenylthioacetic acid derivative represented by the general formula (4) are heated and stirred in the presence of acetic anhydride and triethylamine. It can be obtained by: The reaction proceeds under any conditions of 0.5 to 5 equivalents of the phenylthioacetic acid derivative with respect to the aldehyde compound, but the equivalent is desirable. The reaction temperature is acceptable in the range from room temperature to the boiling point of the solvent, and is preferably from 80 to 160 ° C. As a solvent, acetic anhydride and triethylamine can be used also as a solvent, but a solvent that does not participate in the reaction, such as toluene, chloroform, dimethylformamide, etc., can also be used. The amounts of acetic anhydride and triethylamine are not particularly limited, but it is desirable to use any of them in excess with respect to the aldehyde compound or the phenylthioacetic acid derivative. The naphthalene derivative of the general formula (5) produced under such conditions can be purified by recrystallization or column chromatography. Various biological evaluations were performed using this purified product.

[Synthesis Method 2] As another synthesis method, a method of reacting a halogen compound represented by the general formula (6) with a phenylthioacetic acid derivative represented by the general formula (7) in the presence of a base as shown below is used. Formula (2) is shown in [Formula 6].

[0020]

Embedded image (In the formula, R ₁ , R ₂ , and R ₃ have the same meanings as described above. R ₅ represents an alkyl group having 1 to 4 carbon atoms and X represents a halogen atom.) In this case, the phenylthioacetic acid derivative is 0.
The reaction proceeds in any range of 5 to 5 equivalents, but preferably is equivalent. Further, the reaction temperature is in the range of -78 ° C to the boiling point of the solvent, and is preferably -78 to 50 ° C. The solvent to be used is not particularly limited, and examples thereof include a protic solvent such as water, methanol and ethanol, and an aprotic solvent such as tetrahydrofuran, ethyl ether and dimethylformamide. As the base, sodium hydroxide, potassium hydroxide, sodium hydride, butyllithium, lithium diisobutylamide, triethylamine and the like can be used.

[Synthesis Method 3] A method for synthesizing a derivative having a 5-membered heterocyclic ring containing at least one nitrogen atom in the general formula (1) will be described. This can be synthesized by using a cyano compound represented by the general formula (9) or an acid hydrazide represented by the general formula (11) described in [Synthesis Method 4].

For example, an example of a method for synthesizing a tetrazole compound having a nitrogen-containing 5-membered heterocyclic ring is shown in Reaction formula (3).

[0023]

Embedded image By treating the cyano compound of the general formula (9) with an azide compound, a tetrazole compound represented by the general formula (10) can be obtained. As the azide compound, sodium azide, lithium azide, ammonium azide (which can also be generated in the system from an alkali metal azide and ammonium halide, etc.), hydrogen azide and the like can be used. There is no particular limitation on the solvent used, but water, methanol,
Protic solvents such as ethanol, tetrahydrofuran,
Examples include aprotic solvents such as dimethylformamide and dimethylsulfoxide. The reaction is possible in a temperature range from room temperature to the boiling point of the solvent.

[Synthesis Method 4] Another synthesis method of the derivative having a 5-membered heterocyclic ring according to claim 1 is to use an acid hydrazide represented by the general formula (11) as shown below. Can be synthesized by Hereinafter, 1,3,4-oxadiazol-2 (3H) -one, 1,3,4-oxadiazole-2 (3H) -thione and 4-alkyl-
An example of a method for synthesizing 1,2,4-triazole-3 (3H) -thione is shown in Reaction formula (4).

[0025]

Embedded image

Example 1 1,3,4-oxadiazole
The 2 (3H) -one derivative can be synthesized by reacting the acid hydrazide represented by the general formula (11) with 1 ′, 1′-carbonylbisimidazole under basic conditions. The reaction of 1 ', 1'-carbonylbisimidazole proceeds under any condition of 0.5 to 5 equivalents to acid hydrazide. Triethylamine as the base,
Any of amines such as 1,8-diazabicycloundecene and inorganic bases such as sodium hydroxide, potassium carbonate and sodium hydrogen carbonate can be used. The reaction is -20 ° C ~
Although it is possible within the range of the boiling point of the solvent, it is preferably 0 ° C to 5 ° C.
0 ° C. The solvent to be used is not particularly limited, and examples thereof include a protic solvent such as water, methanol, and ethanol, and an aprotic solvent such as tetrahydrofuran, ethyl ether, and dimethylformamide.

Example 2 1,3,4-oxadiazole-
This is a synthesis example of a 2 (3H) -thione derivative, and can be obtained by using an acid hydrazide represented by the general formula (11) under basic conditions using carbon disulfide. The carbon disulfide used is 0.5 to 5 with respect to acid hydrazide.
The reaction proceeds within the range of the equivalent amount. As the base, any of amines such as triethylamine and 1,8-diazabicycloundecene and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium hydrogencarbonate can be used. The reaction can be carried out at a temperature in the range of -20 ° C to the boiling point of the solvent, preferably 0 ° C to 100 ° C. The solvent to be used is not particularly limited, and examples thereof include a protic solvent such as water, methanol and ethanol, and an aprotic solvent such as tetrahydrofuran, ethyl ether and dimethylformamide.

Example 3 This is a synthesis example of 4-alkyl-1,2,4-triazole-3 (3H) -thione. In this case, the acid hydrazide represented by the general formula (11) is first converted to an alkyl isocyanate or It can be obtained by reacting with an alkyl isothiocyanate, leading to semicarbazide or thiosemicarbazide, and subsequently cyclizing them under basic conditions.

As conditions for the semicarbazide or thiosemicarbazide, the reaction proceeds if the alkyl isocyanate or the alkyl isothiocyanate is in the range of 0.5 to 5 equivalents to the acid hydrazide. A base is not particularly required, but any base may be used if necessary. The solvent to be used is not particularly limited, and examples thereof include a protic solvent such as water, methanol and ethanol, and an aprotic solvent such as tetrahydrofuran, ethyl ether and dimethylformamide. The reaction can be carried out at a temperature in the range of from -20 ° C to the boiling point of the solvent, preferably from 0 to 50 ° C.

Subsequently, the cyclization reaction is carried out. Examples of the base include amines such as triethylamine and 1,8-diazabicycloundecene; and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium hydrogen carbonate. Either may be used. The reaction can be carried out at a temperature in the range of 0 ° C to the boiling point of the solvent, but is preferably 0 ° C to 100 ° C. The solvent to be used is not particularly limited, and examples thereof include a protic solvent such as water, methanol and ethanol, and an aprotic solvent such as tetrahydrofuran, ethyl ether and dimethylformamide.

The compounds included in the general formula (1) are exemplified below. However, the present invention is not limited by this. (1) (Z) -3- (2-naphthyl) -2- (phenylthio) propenoic acid (2) (Z) -3- (1-bromo-2-naphthyl) -2
-(Phenylthio) propenoic acid (3) (Z) -3- (6-methoxy-2-naphthyl)-
2- (phenylthio) propenoic acid (4) (Z) -3- (6,7-methylenedioxy-2-
Naphthyl) -2- (phenylthio) propenoic acid (5) (Z) -3- (5,6,7-trimethoxy-2-
Naphthyl) -2- (phenylthio) propenoic acid

(6) (Z) -3- (6-hydroxy-2)
-Naphthyl) -2- (phenylthio) propenoic acid (7) (Z) -3- (6,7-dimethoxy-2-naphthyl) -2- (phenylthio) propenoic acid (8) (Z) -3- [6 -(2-Dimethylaminoethoxy) -2-naphthyl] -2- (phenylthio) propenoic acid (9) (Z) -3- (6-isopropoxy-2-naphthyl) -2- (phenylthio) propenoic acid (10 ) (Z) -3- (6-Octyloxy-2-naphthyl) -2- (phenylthio) propenoic acid

(11) (Z) -3- (3-methoxy-2)
-Naphthyl) -2- (phenylthio) propenoic acid (12) (Z) -3- (1-methoxy-2-naphthyl)
-2- (Phenylthio) propenoic acid (13) (Z) -3- (6-methyl-2-naphthyl)-
2- (phenylthio) propenoic acid (14) (Z) -3- (1,4-dimethyl-2-naphthyl) -2- (phenylthio) propenoic acid (15) (Z) -3- (2-naphthyl)- 2- (3-methoxyphenylthio) propenoic acid

(16) (Z) -3- (2-naphthyl)-
2- (2-chlorophenylthio) propenoic acid (17) (Z) -3- (2-naphthyl) -2- (3-chlorophenylthio) propenoic acid (18) (Z) -3- (2-naphthyl)- 2- (4-chlorophenylthio) propenoic acid (19) DL-3- (2-naphthyl) -2- (phenylthio) propionic acid methyl ester (20) DL-3- (2-naphthyl) -2- (phenylthio) Propionic acid

(21) DL-5- [2- (2-naphthyl) -1- (phenylthio) ethyl] -1H-tetrazole (22) DL-3- (2-naphthyl) -2- (phenylthio) propionic acid Hydrazide (23) DL-5- [2- (2-naphthyl) -1- (phenylthio) ethyl] -1,3,4-oxadiazol-2 (3H) -one (24) DL-5- [2 -(2-Naphthyl) -1- (phenylthio) ethyl] -1,3,4-oxadiazole-2 (3H) -thione (25) DL-5- [2- (2-naphthyl) -1- ( Phenylthio) ethyl] -2,4-dihydro-4-methyl-1,2,4-triazole-3 (3H) -thione

When the compound of the present invention is used as a therapeutic and / or prophylactic agent, it can be administered orally or parenterally. The dosage varies depending on the condition, age, sex, etc. of the patient to be administered.
g is administered once or in several divided doses. When administered orally, tablets, granules, powders, suspensions, capsules,
Forms such as syrups are possible.

For example, in the case of tablets, crystalline cellulose, light anhydrous silicic acid and the like are used as adsorbents, corn starch, lactose, calcium phosphate, magnesium stearate and the like are used as excipients, and if necessary, Agent,
Moisturizers, lubricants and the like can be used.

Parenterally, intravenous injections, subcutaneous injections,
Forms such as intramuscular injections, suppositories, transdermals and the like are possible. For example, in the case of an injection, an isotonic, sterilized aqueous solution or a suspension solution of cottonseed oil, corn oil, olive oil or the like, or a surfactant such as HCO-60 was used. Used as an emulsion.

As will be described in more detail in the following Examples and Test Examples, the compounds of the present invention strongly inhibit the adhesion between neutrophils and vascular endothelial cells. Furthermore, in an acute toxicity test using rats, all compounds have low LD50 (50% lethal dose) of 500 mg / kg or more. Therefore, inflammation caused by autoimmune diseases such as rheumatism, nephritis, asthma, allergy, dermatitis, colitis, diabetes, and various types of arteriosclerosis, restenosis after PTCA, cardiovascular disorders, cerebrovascular disorders, peripheral vascular disorders, etc. It is highly useful as a therapeutic and / or prophylactic agent for cardiovascular injuries, and also for pathological conditions such as cancer metastasis and proliferation.

[0040]

The present invention will be described in more detail with reference to examples and test examples below, but the present invention is not limited to these examples. Example 1 (Z) -3- (2-naphthyl) -2- (phenylthio)
Synthesis of propenoic acid [Chemical formula 9]: Exemplified compound (1)

[0041]

Embedded image Acetic anhydride (7.5 g) and triethylamine (2.5 g) were added to 2-naphthaldehyde (3.9 g, 25 mmol) and phenylthioacetic acid (4.2 g, 25 mmol).
Was added and stirred at 110 ° C. for 9 hours. Subsequently, water (6 ml) was added to the reaction solution, and the mixture was stirred at 60 ° C. for 1 hour. After allowing the reaction solution to cool, it was poured into ice water, extracted with ethyl ether, and washed with water. The desired product was extracted into an aqueous layer using a 5% aqueous sodium carbonate solution, and the obtained aqueous layer was acidified with 4N hydrochloric acid to precipitate crystals. The obtained crude crystals were recrystallized from water-methanol to give the title compound (3.7 g, 48%) as pale-yellow crystals.

Melting point = 180-181.5 ° C. ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ =
8.35 and 8.26 (2s, each 1H),
8.02 (d, 1H, J = 8.8 Hz), 7.88−
7.80 (m, 3H), 7.33-7.11 (m, 5
Calcd H) Elemental Analysis _{C 19 H 14 O 2 S (} 306.39) C: 74.48; H: 6.18 analysis C: 74.52; H: 6.12

Example 2 Synthesis of (Z) -3- (1-bromo-2-naphthyl) -2- (phenylthio) propenoic acid [formula 10]: Exemplified compound (2)

[0044]

Embedded image 1-bromo-2-naphthaldehyde (1.0 g, 4.3
mmol) and phenylthioacetic acid (716 mg, 4.25).
mmol) to give the title compound (613 mg, 37%) as pale yellow crystals. Melting point = 179-181 ° C ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 13.30 (bs, 1H), 8.31 (s, 1H),
8.24 (d, 1H, J = 8.1 Hz), 8.00-
7.96 (m, 2H), 7.74-7.66 (m, 3
H), 7.31-7.13 (m, 5H ) calcd elemental analysis _{C 19 H 13 3BrO 2 S (} 385.28) C: 59.23; H: 3.40 analysis C: 59.33 H: 3.51

Example 3 (Z) -3- (6-Methoxy-2-naphthyl) -2-
Synthesis of (phenylthio) propenoic acid: Exemplified compound (3) [Reaction 1] 6-methoxy-2-naphthaldehyde
Synthesis of 1]

[0046]

Embedded image 6-methoxy-2-naphthonitrile (5.0 g, 27.
3 mmol) was dissolved in tetrahydrofuran (120 ml), and a 1.0 M solution of diisopropylaluminum hydride in toluene (49 ml) was added dropwise at -78 ° C. −
After stirring at 78 ° C for 30 minutes, the mixture was heated to 0 ° C and stirred for 3 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes, and then the desired product was extracted with ethyl ether. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained white solid was latched with n-hexane to give the title compound (4.5 g, 89%). Melting point = 77-79 ° C ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ = 1
0.09 (s, 1H), 8.25 (bs, 1H), 7.
95-7.84 (m, 3H), 7.30-7.18
(M, 2H), 3.96 (s, 3H) [Reaction 2] Synthesis of (Z) -3- (6-methoxy-2-naphthyl) -2- (phenylthio) propenoic acid

[0047]

Embedded image 6-methoxynaphthaldehyde (1.0 g, 5.4 mm
ol) and phenylthioacetic acid (900 mg, 5.4 mmol)
l) was treated as in Example 1 and the title compound (896 m
g, 49%) as pale yellow crystals. Melting point = 191-193 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 8.31 and 8.29 (2s, each 1H),
8.65 (dd, 1H, J = 1.5, 8.8 Hz),
7.87 (d, 1H, J = 8.8 Hz), 7.83
(D, 1H, J = 8.8 Hz), 7.35-7.14
(M, 7H), 3.89 ( s, 3H) calcd elemental analysis _{C 20 H 16 O 3 S (} 336.41) C: 71.41; H: 4.79 analysis C: 71.45; H: 4.85

Example 4 Synthesis of (Z) -3- (6,7-methylenedioxy-2-naphthyl) -2- (phenylthio) propenoic acid: Exemplified compound (4) [Reaction 1] 6,7 Synthesis of methylenedioxy-2-naphthonitrile

[0049]

Embedded image Piperanal (1.5 g, 10 mmol) and 3-cyanopropanaldehyde diethyl acetal (1.57 g,
10 mmol) using SynthesisCommu
The title compound (1.5 g, 76%) was obtained according to the method described in Nation 427-429 (1986). Melting point = 142-143 ° C ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ =
8.00 (s, 1H), 7.70 and 7.47 (2
d, each 1H, J = 8.4 Hz), 7.14
(S, 2H), 6.11 (s, 2H) [Reaction 2] Synthesis of 6,7-methylenedioxy-2-naphthaldehyde [Formula 14]

[0050]

Embedded image 6,7-methylenedioxy-2-naphthonitrile (80
(0 mg, 4.1 mmol) was treated in the same manner as in Reaction 1 of Example 3 to obtain the title compound (809 mg, 100%) as milky white crystals. Melting point = 137-139 ° C ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ = 1
0, 08 (s, 1H), 8.15 (s, 1H), 7.8
1 and 7.74 (2s, each 1H, J = 8.8)
Hz), 7.26 and 7.17 (2s, each 1
H), 6.11 (s, 2H) [Reaction 3] (Z) -3- (6,7-methylenedioxy-
Synthesis of 2-naphthyl) -2- (phenylthio) propenoic acid

[0051]

Embedded image 6,7-methylenedioxy-2-naphthaldehyde (6
30 mg, 3.2 mmol) and phenylthioacetic acid (53
(8 mg, 3.2 mmol) to give the title compound (460 mg, 41%) as milky white crystals. Melting point = 199-201 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 12.96 (bs, 1H), 8.24 (s, 1H),
8.18 (d, 1H, J = 1.5 Hz), 7.90 (d
d, 1H, J = 1.5, 8.8 Hz), 7.74 (d,
1H, J = 8.8 Hz), 7.35-7.14 (m, 7
H), 6.16 (s, 2H ) calcd elemental analysis _{C 20 H 14 O 4 S (} 350.40) C: 68.56; H: 4.03 analysis C: 68,58; H: 4 .15

Example 5 Synthesis of (Z) -3- (5,6,7-trimethoxy-2-naphthyl) -2- (phenylthio) propenoic acid: Exemplified compound (5) [Reaction 1] 5,6 Of 7,7-Trimethoxy-2-naphthonitrile

[0053]

Embedded image 3,4,5-trimethoxybenzaldehyde (2.94
g, 15 mmol) and 3-cyanopropanaldehyde
Diethyl acetal (2.52 g, 15 mmol) was treated in the same manner as in Reaction 1 of Example 4 to give the title compound (2.21).
g, 61%). Melting point = 90-91 ° C ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ =
8.12 and 7.48 (d, each 1H, J =
8.8 Hz), 8.05 (s, 1H), 6.97 (s,
1H), 4.05, 4.01 and 4.00 (3s, e
ach 3H) [Reaction 2] Synthesis of 5,6,7-trimethoxy-2-naphthaldehyde [Formula 17]

[0054]

Embedded image 5,6,7-Trimethoxy-2-naphthonitrile (1.
(22 g, 5 mmol) was treated in the same manner as in Reaction 1 of Example 3 to obtain the title compound (1.09 g, 89%). Melting point = 98-99 ° C ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ = 1
0.11 (s, 1H), 8.19 (s, 1H), 8.1
5 and 7.82 (2d, each 1H, J = 8.8)
Hz), 7.10 (s, 1H), 4.05, 4.02a
nd4.01 (3s, each 3H) [Reaction 3] (Z) -3- (5,6,7-trimethoxy-
Synthesis of 2-naphthyl) -2- (phenylthio) propenoic acid

[0055]

Embedded image5,6,7-trimethoxy-2-naphthaldehyde
(1.0 g, 4.06 mmol) and phenylthioacetic acid
(841 mg, 5 mmol) as in Example 1
To give the title compound (692 mg, 43%) in amorphous
Obtained as a yellow solid. ¹ HN. M. R. (CDCl_Three, 270 MHz) δ =
8.44 and 8.23 (s, each 1H), 8.
03 (d, 1H, J = 8.8 Hz), 7.93 (dd,
1H, J = 2.2, 8.8 Hz), 7.35-7.17
(M, 5H), 6.97 (s, 1H), 4.03, 3.
99 and 3.98 (3s, each 3H) Elemental analysis C_{twenty two}H₂₀O_FiveCalculated as S (396.47) C: 66.65; H: 5.08 Analytical value C: 66.49; H: 5.15

Example 6 (Z) -3- (6-hydroxy-2-naphthyl) -2-
Synthesis of (phenylthio) propenoic acid: Exemplified compound (6) [Reaction 1] 6-hydroxy-naphthonitrile
Synthesis of

[0057]

Embedded image 6-Methoxy-2-naphthonitrile (950 mg, 5.
19 mmol) was dissolved in acetonitrile (20 ml), and trimethylsilyl chloride (786 μl, 6.2) was dissolved.
mmol) and sodium iodide (932 mg, 6.
2 mmol) and heated under reflux for 6 hours. The reaction solution was diluted with ethyl acetate and washed sequentially with a 5% aqueous solution of sodium thiosulfate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
Crystallized from n-hexane, the title compound (600 mg,
68%) as white crystals.

Melting point = 159-162 ° C. ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ =
8.15 (s, 1H), 7.81 and 7, 74 (2
d, each 1H, J = 8.8 Hz), 7.55 (d
d, 1H, J = 1.5, 8.8 Hz), 7.25-7.
16 (m, 2H), 5.54 (bs, 1H) [Reaction 2] Synthesis of 6-hydroxy-2-naphthaldehyde [formula 20]

[0059]

Embedded image 6-hydroxy-2-naphthonitrile (1.7 g, 10
mmol) as in Reaction 1 of Example 3 to give the title compound (1.5 g, 88%) as white crystals. Melting point = 145-149 ° C ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 10.36 (bs, 1H), 10.04 (s, 1
H), 8.43 (s, 1H), 8.02 (d, 1H, J
= 9.5 Hz), 7.84-7.79 and 7.25-
7.20 (m, 4H) [Reaction 3] Synthesis of (Z) -3- (6-hydroxy-2-naphthyl) -2- (phenylthio) propenoic acid [Chemical Formula 21]

[0060]

Embedded image 6-hydroxy-2-naphthaldehyde (861 mg,
5 mmol) and phenylthioacetic acid (1.01 g, 6 mm
ol) and treated in the same manner as in Example 1 to obtain (Z) -3-
(6-Acetoxy-2-naphthyl) -2- (phenylthio) propenoic acid (350 mg) was obtained as a brown solid. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 8.37 and 8.30 (2s, each 1H),
8.06 (dd, 1H, J = 1.4, 8.8 Hz),
7.93 (d, 1H, J = 8.8 Hz), 7.69
(D, 1H, J = 1.4 Hz), 7.38-7.16
(M, 6H), 2.33 (s, 3H)

The obtained brown solid was dissolved in methanol-tetrahydrofuran (10 ml: 5 ml), 2N aqueous sodium hydroxide solution (1.2 ml) was added, and the mixture was added at room temperature for 30 minutes.
Stirred for minutes. The reaction solution was acidified with 1N hydrochloric acid and water (50 m
After l) was added, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-n-hexane to give the title compound (308 mg, 19%).
Was obtained as pale yellow crystals. Melting point = 202-203 ° C

¹ HN. M. R. (DMSO-d _6, 27
0 MHz) δ = 12.92 (bs, 1H), 10.07
(S, 1H), 8.29 and 8.26 (2s, eac
h 1H), 8.01 (dd, 1H, J = 1.5, 8.
8 Hz), 7.81 (d, 1H, J = 9.5 Hz),
7.69 (d, 1H, J = 8.8 Hz), 7.33-
7.10 (m, 7H) calcd elemental analysis _{C 19 H 14 O 3 S (} 322.39) C: 70.79; H: 4.38 analysis C: 70.72; H: 4.51

Example 7 (Z) -3- (6,7-Dimethoxy-2-naphthyl)-
Synthesis of 2- (phenylthio) propenoic acid: Exemplified compound (7) [Reaction 1] Synthesis of 6,7-dimethoxy-2-naphthonitrile

[0064]

Embedded image 3,4-dimethoxybenzaldehyde (2.49 mg,
15 mmol) and 3-cyanopropanaldehyde diethyl acetal (2.52 g, 15 mmol) were treated in the same manner as in Reaction 1 of Example 4 to give the title compound (2.20 g,
69%). Melting point = 121-123 ° C ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ =
8.01 (s, 1H), 7.69 and 7.45 (2
d, each 1H, J = 8.5 Hz), 7.16
(S, 2H), 3.97 and 3.96 (2s, eac
h 3H) [Reaction 2] Synthesis of 6,7-dimethoxy-2-naphthaldehyde [Formula 23]

[0065]

Embedded image 6,7-dimethoxy-2-naphthonitrile (1.5 g,
7.03 mmol) was treated in the same manner as in Reaction 1 of Example 3 to give the title compound (1.5 g, 92%) as milky white crystals. Melting point = 95-99 ° C ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 10.70 (s, 1H), 8.37 (s, 1H),
7.89 and 7.74 (2d, each 1H),
7.54 and 7.44 (2s, each 1H),
3.96 and 3.93 (2s, each 3H) [Reaction 3] (Z) -3- (6,7-dimethoxy-2-naphthyl) -2- (phenylthio) propenoic acid
Synthesis of

[0066]

Embedded image 6,7-dimethoxy-2-naphthaldehyde (1.0
g, 4.62 mmol) and phenylthioacetic acid (778 m
g, 4.62 mmol) was treated in the same manner as in Example 1 to obtain the title compound (762 mg, 45%) as pale yellow crystals. Melting point = 195-197 ° C ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 12.92 (bs, 1H), 8.25 (s, 2H),
7.88 and 7.76 (2d, each 1H, J =
8.5 Hz), 7.34 and 7.15 (m, 7H),
3.90and3.89 (2s, each 3H) Calculated elemental analysis _{C 21 H 18 O 4 S (} 366.44) C: 68.83; H: 4.95 analysis C: 68.87; H: 5 .09

Example 8 (Z) -3- [6- (2-dimethylamino) ethoxy-
Synthesis of 2-naphthyl] -2- (phenylthio) propenoic acid: Exemplified compound (8) [Reaction 1] (Z) -3- (6-hydroxy-2-naphthyl) -2- (phenylthio) propenoic acid ethyl ester [ Embedded image

[0068]

Embedded image (Z) -3- (6-acetoxy-2-naphthyl) -2-
(Phenylthio) propenoic acid (200 mg, 0.55 m
mol) dissolved in ethanol (5 ml) and concentrated sulfuric acid (0.1
ml) and heated to reflux for 3 hours. After most of the ethanol was distilled off under reduced pressure, water was added and the mixture was weakly acidified with sodium hydrogen carbonate. The desired product was extracted with ethyl acetate, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the title compound (160 mg) was obtained as a pale brown syrup.

¹ HN. M. R. (CDCl ₃ , 270M
Hz) δ = 8.23 (s, 2H), 8.02, 7.78
and 7.66 (3d, each 1H, J = 8.8H
z), 7.33-7.09 (m, 7H), 5.25 (b
s, 1H), 4.14 (q, 2H, J = 7.3 Hz),
1.08 (t, 3H, J = 7.3 Hz) [Reaction 2] (Z) -3- [6- (2-dimethylamino)
Synthesis of ethoxy-2-naphthyl] -2- (phenylthio) propenoic acid ethyl ester

[0070]

Embedded image (Z) -3- (6-hydroxy-2-naphthyl) -2-
(Phenylthio) propenoic acid ethyl ester (160
mg) in methylene chloride (4 ml), triphenylphosphine (240 mg, 0.91 mmol), diethylazodicarboxylate (141 μl, 0.91 m).
mol) and 2-dimethylaminoethanol (92μ)
1, 0.91 mmol) and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, and then the organic layer was dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to give the title compound (120 mg) as a pale brown syrup.

¹ H-N. M. R. (CDCl ₃ , 270M
Hz) δ = 8.24 and 8.23 (2s, each
1H), 8.03 (dd, 1H, J = 1.5, 8.8H
z), 7.76 and 7.70 (2d, each 1
H, J = 8.8 Hz), 7.31-7.12 (m, 7
H), 4.19 and 2.80 (2t, each 2
H, J = 6.9 Hz), 4.13 (q, 2H, J = 7.
3 Hz), 2.37 (s, 6H), 1.08 (t, 3
H, J = 7.3H) [Reaction 3] (Z) -3- [6- (2-dimethylamino)
Synthesis of ethoxy-2-naphthyl] -2- (phenylthio) propenoic acid

[0072]

Embedded image (Z) -3- [6- (2-dimethylamino) ethoxy-
2-Naphthyl] -2- (phenylthio) propenoic acid ethyl ester was dissolved in methanol (3 ml) and 2N-
An aqueous sodium hydroxide solution (0.1 ml) was added,
For 4 hours. The methanol is distilled off under reduced pressure and water (10 m
After adding l), the mixture was neutralized with 1N hydrochloric acid to precipitate light yellow crystals. The precipitated crystals were collected by filtration, and were latched with water and ethyl ether to give the title compound (86 mg,
(40%) as pale yellow crystals.

Melting point = 191-193 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 8.27and8.25 (2s, each 1H),
8.02 (dd, 1H, J = 1.5, 8.8 Hz),
7.86 and 7.80 (2d, each 1H, J =
8.8 Hz), 7.36 (d, 1H, J = 1.5H)
z), 7.36-7.15 (m, 6H), 4.21an
d2.78 (2t, each 2H, J = 6.9H
z), 2.30 (s, 6H ) calcd elemental analysis _{C 23 H 23 NO 3 S (} 393.51) C: 70.20; H: 5.89; N: 3.56 Analytical values C: 70 .03; H: 6.11; N: 3.58

Example 9 (Z) -3- (6-Isopropoxy-2-naphthyl)-
Synthesis of 2- (phenylthio) propenoic acid [Formula 28]: Exemplified compound (9)

[0075]

Embedded image (Z) -3- (6-acetoxy-2-naphthyl) -2-
(Phenylthio) propenoic acid (1.0 g, 2.78 mm
ol) was treated in the same manner as in Example 8 to give the title compound (36
(4 mg, 36%) as pale yellow crystals. Melting point = 144-145 ° C ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 12.95 (bs, 1H), 8.29 (s, 2H),
8.03, 7.85 and 7.79 (3d, each
1H, J = 8.8 Hz), 7.34-7.14 (m, 7
H), 4.79 (quintet, 1H, J = 5.9H)
z), 1.35 and 1.33 (2s, each 3
Calcd H) Elemental Analysis _{C 22 H 20 O 3 S (} 364.47) C: 72.50; H: 5.53 analysis C: 72.25; H: 5.81

Example 10 Synthesis of (Z) -3- (6-octyloxy-2-naphthyl) -2- (phenylthio) propenoic acid [Formula 29]: Exemplified compound (10)

[0077]

Embedded image (Z) -3- (6-acetoxy-2-naphthyl) -2-
(Phenylthio) propenoic acid (470 mg, 1.29 m
mol) was treated in the same manner as in Example 8 to give the title compound (2
52 mg, 45%) as pale brown crystals.

Melting point = 118-120 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 12.98 (bs, 1H), 8.28 (s, 2
H), 8.04 (dd, 1H, J = 1.5, 8.8H)
z), 7.85 and 7.80 (2d, each 1
H, J = 8.8 Hz), 7.33-7.14 (m, 7
H), 4.09 (t, 2H, J = 6.6 Hz), 1.8
0 (quintet, 2H, J = 6.6 Hz), 1.5
0-1.25 (m, 10H), 1.27 (t, 3H, J
= Calculated 6.6 Hz) Elemental Analysis _{C 27 H 30 O 3 S (} 434.60) C: 74.61; H: 6.96 analysis C: 74.30; H: 7.31

Example 11 (Z) -3- (3-Methoxy-2-naphthyl) -2-
Synthesis of (phenylthio) propenoic acid: Exemplified compound (1
1) [Reaction 1] Synthesis of ethyl 3-methoxy-2-naphthoate [Formula 30]

[0080]

Embedded image 3-hydroxy-2-naphthoic acid (15 g, 80 mmol
l) was dissolved in ethanol (200 ml) and concentrated sulfuric acid (2
ml) and heated under reflux for 8 hours. Ethanol was distilled off under reduced pressure to about 50 ml, weakly acidified with sodium hydrogen carbonate, and water was added. Then, the desired product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained light brown syrup-like residue was dissolved in acetone (250 ml) without purification, methyl iodide (5.2 ml, 84 mmol) and potassium carbonate (19.3 g, 84 mmol) were added, and the mixture was heated under reflux for 12 hours. Was. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane 1: 9) to give the title compound (14.2 g, 7
7%) as a light brown syrup.

¹ HN. M. R. (CDCl ₃ , 270M
Hz) δ = 8.36 (s, 1H), 7.89 and 7.
75 (2d, each 1H, J = 8.8 Hz);
54 and 7.38 (2t, each 1H, J = 8.
8 Hz), 7.20 (s, 1H), 4.45 (q, 2
H, J = 7.3 Hz), 4.07 (s, 3H), 1.4
5 (t, 3H, J = 7.3 Hz) [Reaction 2] 3-methoxy-naphthaldehyde
Synthesis of

[0082]

Embedded image 3-methoxy-2-naphthoic acid ethyl ester (9.
4 g, 50 mmol) in pentane (50 ml) and diethylamine (10.3 ml, 100 mmol)
And cooled to 0 ° C. To this solution was added a 1 M lithium aluminum hydride-tetrahydrofuran solution (50
ml) was added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes, and then stirred for 1 hour while warming to room temperature. After adding 2N hydrochloric acid to the reaction solution and stirring at room temperature for 6 hours, sodium chloride was added. The desired product was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, ethanol was added to the obtained residue for crystallization, and the title compound (6.7 g, 72
%).

Melting point = 80-82 ° C. ¹ HN. M. R. (CDCl ₃ , 270 MHz) δ = 1
0.58 (s, 1H), 8.36 (s, 1H), 7.8
9 and 7.75 (2s, each 1H, J = 8.8)
Hz), 7.74 and 7.38 (2t, each 1
H, J = 8.8 Hz), 7.20 (s, 1H), 4.0
3 (s, 3H) [Reaction 3] (Z) -3- (3-methoxy-2-naphthyl) -2-
Synthesis of (phenylthio) propenoic acid

[0084]

Embedded image 3-methoxy-naphthaldehyde (931 mg, 5 mm
ol) and phenylthioacetic acid (841 mg, 5 mmol)
Was treated in the same manner as in Example 1 to give the title compound (807 mg,
48%) as pale yellow crystals.

Melting point = 190-191 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 13.05 (bs, 1H), 8.34 and 8.1.
8 (2s, each 1H), 7.83 (d, 2H, J
= 8.8 Hz), 7.50 and 7.35 (2t, ea
ch 1H, J = 8.8 Hz), 7.41 (s, 1
H), 7.30-7.15 (m, 5H), 3.97.
(S, 3H) calcd elemental analysis _{C 20 H 16 O 3 S (} 336.410) C: 71.41; H: 4.79 analysis C: 71.45; H: 4.95

Example 12 (Z) -3- (1-Methoxy-2-naphthyl) -2-
Synthesis of (phenylthio) propenoic acid [Formula 33]: Exemplified compound (12)

[0087]

Embedded image Using 1-hydroxy-2-naphthoic acid as a starting material, the same procedures as in Example 11 were carried out to give the title compound (24%, 3 steps)
Was obtained as pale yellow crystals.

Melting point = 165-166 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 13.10 (bs, 1H), 8.45 (s, 1
H), 8.12-7.90 (m, 2H), 7.94an
d 7.70 (2d, each 1H, J = 8.8H
z), 7.63-7.59 (m, 2H), 7.33-
7.15 (m, 5H), 3.93 (s, 3H) calcd elemental analysis _{C 20 H 16 O 3 S (} 336.410) C: 71.41; H: 4.79 analysis C: 71 .75; H: 4.92

Example 13 Synthesis of (Z) -3- (6-methyl-2-naphthyl) -2- (phenylthio) propenoic acid: Exemplified compound (13) [Reaction-1] 6-methyl-2- Naphthaldehyde [Chemical Formula 3
Synthesis of 4]

[0090]

Embedded image 2.6-Dimethylnaphthalene (940 mg, 6 mmol
l), a 50% aqueous acetic acid solution (150 ml) was added,
To make a heated suspension state. In this reaction solution, CAN (cerium ammonium nitrate) (13.2 g, 24
(mmol) in a 50% aqueous acetic acid solution (200 ml) was slowly added dropwise over 50 minutes. Further 80
The mixture was stirred with heating at 30 ° C. for 30 minutes, allowed to cool, and then extracted with chloroform. The organic layer was washed sequentially with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure,
The obtained residue is subjected to silica gel column chromatography (ethyl acetate: chloroform: n-hexane = 1: 1: 1).
Purification was performed in 3) to give the title compound (800 mg, 78%). ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ = 1
0.18 (s, 1H), 8.30 (s, 1H), 7.9
2-7.80 (m, 3H), 7.67 (s, 1H),
7.40 (d, 1H, J = 8.0 Hz) [Reaction 2] Synthesis of (Z) -3- (6-methyl-2-naphthyl) -2- (phenylthio) propenoic acid [Formula 35]

[0091]

Embedded image 6-methyl-2-naphthaldehyde (1.16 g, 6.
82 mmol) and phenylthioacetic acid (1.15 g, 6.
82 mmol) was treated in the same manner as in Example 1 to obtain the title compound (210 mg, 10%) as pale brown crystals.

Melting point = 169-171 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 8.12 and 8.08 (2s, each 1
H), 7.86 (dd, 1H, J = 1.5, 8.8H)
z), 7.77, 7.73 and 7.34 (3d, e
ach 1H, J = 8.8 Hz), 7.63 (s, 1
H), 7.26-7.03 (m, 5H), 2.46.
(S, 3H)

Example 14 (Z) -3- (1,4-Dimethyl-2-naphthyl) -2
Synthesis of-(phenylthio) propenoic acid: Exemplified compound (1
4) [Reaction 1] Synthesis of 1,4-dimethyl-2-naphthaldehyde [Formula 36]

[0094]

Embedded image 1,4-dimethylnaphthalene (5.14 g, 32.9 m
mol) was dissolved in methylene chloride (45 ml), and titanium tetrachloride (10.9 g, 57.6 mmol) and 1,1-dichlorodimethyl ether (3.9 g, 33.
5 mmol) -methylene chloride (1.5 ml) solution
It was added dropwise over a period of minutes. After the dropwise addition, the reaction solution was heated to reflux for 2 hours. After allowing the reaction solution to cool, it was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to obtain the title compound (5.38 g, 88%).

¹ H-N. M. R. (CDCl ₃ , 270M
Hz) δ = 10, 64 (s, 1H), 8.28 and
8.11 (2d, each 1H, J = 8.8Hz)
7.76 (s, 1H), 7.70-7.57 (m, 2
H), 3.01 and 2.69 (2s, each 3
H) [Reaction 2] Synthesis of (Z) -3- (1,4-dimethyl-2-naphthyl) -2- (phenylthio) propenoic acid

[0096]

Embedded image 1,4-dimethyl-2-naphthaldehyde (3.14
g, 18.7 mmol) and phenylthioacetic acid (3.14).
g, 18.7 mmol) in the same manner as in Example 1 to obtain the title compound (310 mg, 5%) as pale brown crystals.

Melting point = 176 to 176.5 ° C ¹ H-N. M. R. (CDCl ₃ , 270 MHz) δ =
8.64 and 7.42 (2s, each 3H),
8.10-7.95 (m, 2H), 7.58-7.55
(M, 2H), 7.30-7.10 (m, 5H), 2.
64 and 2.62 (2s, each 3H)

Example 15 Synthesis of (Z) -3- (2-naphthyl) -2- (3-methoxyphenylthio) propenoic acid: Exemplified compound (15) [Reaction 1] 3-methoxyphenylthioacetic acid [ 38)

[0099]

Embedded image 3-methoxythiophenol (2.0 g, 14.3 mm
ol) and ethyl bromoacetate (2.87 g, 17.2).
mmol) with N, N-dimethylformamide (20 m
l) and dissolved in potassium carbonate (6.96 g, 21.5 m
mol) and stirred at room temperature for 5 hours. The reaction solution was washed with water (2
00 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The colorless transparent oil obtained after concentration under reduced pressure was dissolved in methanol (40 ml), a 2N aqueous sodium hydroxide solution (8.4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with 2N hydrochloric acid, and then the desired product was extracted with ethyl ether and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (2.5
2 g, 91%) as a clear, colorless syrup.

¹ H-N. M. R. (CDCl ₃ , 270M
Hz) δ = 7.72 (t, 1H, J = 8.1 Hz),
6.98 and 6.78 (2dd, each 1H, J
= 1.5, 8.1 Hz), 6.96 (bs, 1H),
3.79 (s, 3H), 3.68 (s, 2H) [Reaction 2] (Z) -3- (2-naphthyl) -2- (3-
Synthesis of methoxyphenylthio) propenoic acid

[0101]

Embedded image 3-methoxyphenylthioacetic acid (990 mg, 5 mmol
l) and 2-naphthaldehyde (780 mg, 5 mmol)
l) was treated as in Example 1 and the title compound (875m
g, 52%) as pale yellow crystals.

Melting point = 157-159 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 13.05 (s, 1H), 8.33 and 8.31
(2s, each 1H), 8.03 (dd, 1H, J
= 2.2,8.8 Hz) 7.98-7.91 (m, 3
H), 7.61-7.55 (m, 2H), 7.23.
(T, 1H, J = 8.1 Hz), 6.81-6.74
(M, 3H), 3.71 ( s, 3H) calcd elemental analysis _{C 20 H 16 O 3 S (} 336.41) C: 71.41; H: 4.79 analysis C: 71.22; H: 4.91

Example 16 Synthesis of (Z) -3- (2-naphthyl) -2- (2-chlorophenylthio) propenoic acid [Formula 40]: Exemplified compound (16)

[0104]

Embedded image The same treatment as in Example 15 was performed using 2-chlorothiophenol as a starting material, to give the title compound (35%) as pale-yellow crystals.

Melting point = 182-184 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 13.19 (s, 1H), 8.48 and 8.34
(2s, each 1H), 8.03-7.90 (m,
4H), 7.62-7.53 (m, 2H), 7.48.
(Dd, 1H, J = 1.5, 7.4 Hz), 7.27a
nd 7.19 (2dt, each 1H, J = 1.5,
7.4, 7.4 Hz), 7.13 (dd, 1H, J =
1.5, 7.4 Hz) Elemental analysis Calculated for C ₁₉ H ₁₃ ClO ₂ S (340.83) Calculated C: 66.96; H: 3.82 Analytical value C: 67.21; H: 4.02

Example 17 Synthesis of (Z) -3- (2-naphthyl) -2- (3-chlorophenylthio) propenoic acid [Formula 41]: Exemplified compound (17)

[0107]

Embedded image Example 15 using 3-chlorothiophenol as a starting material
The title compound (33%) was obtained as pale yellow crystals. Melting point = 160-161 ° C ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 13.19 (s, 1H), 8.39 and 8.34
(2s, each 1H), 8.03 (dd, 1H, J
= 1.5, 8.2 Hz), 7.98-7.92 (m, 3
H), 7.62-7.53 (m, 2H), 7.34.
(T, 1H, J = 8.1 Hz), 7.25-7.20
(M, 3H) Elemental analysis Calculated for C ₁₉ H ₁₃ ClO ₂ S (340.83) Calculated C: 66.96; H: 3.82 Analytical value C: 66.72; H: 3.92

Example 18 Synthesis of (Z) -3- (2-naphthyl) -2- (4-chlorophenylthio) propenoic acid [Formula 42]: Exemplified compound (18)

[0109]

Embedded image Example 15 using 4-chlorothiophenol as a starting material
The title compound (22%) was obtained as pale yellow crystals.

Melting point = 161-162 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 13.13 (s, 1H), 8.34 (s, 2H),
8.04-7.92 (m, 4H), 7.62-7.53
(M, 2H), 7.38 and 7.26 (2d, eac
h 2H, J = 8.1Hz) Calculated elemental analysis _{C 19 H 13 ClO 2 S (} 340.83) C: 66.96; H: 3.82 analysis C: 66.75; H: 3.99

Example 19 Synthesis of DL-3- (2-naphthyl) -2- (phenylthio) propionic acid methyl ester [Formula 43]: Exemplified compound (19)

[0112]

Embedded image Diisopropylamine (1.77 ml, 13.5 mmol
l) in tetrahydrofuran (10 ml),
At 8 ° C, a 1.6 M n-butyllithium hexane solution (8.5 ml, 13.5 mmol) was added dropwise. After heating to 0 ° C and stirring for 30 minutes, the mixture was cooled again to -78 ° C, and methyl phenylthioacetate (2.05 g, 11.3 mmol) dissolved in tetrahydrofuran (10 ml) was added dropwise.

After stirring for 1 hour, 2-bromonaphthalene (2.49 g, 11.3 mmol) dissolved in tetrahydrofuran (10 ml) was added dropwise. Thereafter, the temperature was raised to 0 ° C., and after stirring for 1 hour, water was added. The desired product was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane =
1:15) to give the title compound (2.43 g, 67).
%) As a clear, colorless syrup.

¹ H-N. M. R. (CDCl ₃ , 270M
Hz) δ = 7.81-7.75 (m, 3H), 7.64
(S, 1H), 7.48-7.43 (m, 4H), 7.
34-7.29 (m, 4H), 4.00 (dd, 1H,
J = 5.8, 9.3 Hz), 3.56 (s, 3H),
3.36 (dd, 1H, J = 9.3, 14.0 Hz),
3.22 (dd, 1H, J = 5.8, 14.0 Hz)

Example 20 Synthesis of DL-3- (2-naphthyl) -2- (phenylthio) propionic acid [Formula 44]: Exemplified compound (20)

[0116]

Embedded image DL-3- (2-naphthyl) -2- (phenylthio) propionic acid methyl ester (1.2 g, 3.6 mmol)
1) was dissolved in methanol (24 ml), a 2N aqueous sodium hydroxide solution (2.7 ml) was added, and the mixture was stirred at room temperature for 3 hours. Most of methanol was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl ether. The aqueous layer was neutralized with 1N hydrochloric acid, and the desired product was extracted with ethyl ether.
It was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was crystallized from water-methanol to give the title compound (1.08 g, 97%) as white crystals.

Melting point = 94-96 ° C ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 7.88-7.27 (m, 3H), 7.75 (s, 1
H), 7.51-7.28 (m, 8H), 4.16 (d
d, 1H, J = 6.5, 8.8 Hz), 3.26 (d
d, 1H, J = 8.8, 13.5 Hz), 3.15 (d
d, 1H, J = 6.6, 13.5 Hz) Elemental analysis: calculated as C ₁₉ H ₁₆ O ₂ S (308.40). C: 74.00; H: 5.23. Analytical value: 73.82; H: 5.35

Example 21 Synthesis of DL-5- [2- (2-naphthyl) -1- (phenylthio) ethyl] -1H-tetrazole: Exemplified compound (21) [Reaction 1] 2- [2-cyano -2- (Phenylthio) ethyl] Synthesis of naphthalene [Formula 45]

[0119]

Embedded image 2-bromonaphthalene (1.1 g, 5 mmol) and phenylthioacetonitrile (750 mg, 5 mmol)
l) was treated as in Example 19 to give the title compound (1.1
4 g, 79%) as a colorless transparent syrup. ¹ H-N. M. R. (CDCl ₃ , 90 MHz) δ = 7.
85-7.20 (m, 12H), 4.02 (dd, 1
H, J = 6.5, 8.8 Hz), 3.40-3.05
(M, 2H) [Reaction 2] DL-5- [2- (2-naphthyl) -1-
(Phenylthio) ethyl] -1H-tetrazole
Synthesis of 6]

[0120]

Embedded image 2- [2-cyano-2- (phenylthio) ethyl] naphthalene (720 mg, 2.5 mmol) was dissolved in N, N-dimethylformamide (20 ml), and sodium azide (810 mg, 12.5 mmol) and ammonium chloride ( 665 mg, 12.5 mmol)
The mixture was heated and stirred at 140 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with ethyl ether.
When the aqueous layer was acidified with 1N hydrochloric acid, a white solid precipitated.
This was recrystallized from water-methanol to give the title compound (5
(40 mg, 65%) as white crystals.

Melting point = 131-134 ° C ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 7.75-7.66 (m, 4H), 7.56 (s, 1
H), 7.43-7.37 (m, 2H), 7.24-
7.14 (m, 5H), 5.03 (t, 1H, J = 7.
3Hz), 3.63 and 3.52 (2dd, each)
1H, J = 7.3,14.0Hz) Calculated elemental analysis _{C 19 H 16 N 4 S (} 332.43) C: 68.64; H: 4.85; N: 16.8
5 Analytical value C: 68.45; H: 5.02; N: 16.7
5

Example 22 Synthesis of DL-3- (2-naphthyl) -2- (phenylthio) propionic acid hydrazide [Formula 47]: Exemplified compound (22)

[0123]

Embedded image DL-3- (2-naphthyl) -2- (phenylthio) propionic acid methyl ester (1.48 g, 4.6 mm)
ol) was dissolved in methanol (30 ml), hydrazine monohydrate (2.5 ml) was added, and the mixture was stirred at 60 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained white crystals were recrystallized from ethanol to give the title compound (1.26).
g, 86%).

Melting point = 112-115 ° C. ¹ HN. M. R. (DMSO-d ₆ , 270 MHz) δ
= 9.17 (bs, 1H), 7.87-7.80 (m,
3H), 7.66 (s, 1H), 7.51-7.24.
(M, 8H), 4.20 (s, 2H), 4.05 (d
d, 1H, J = 5.9, 9.5 Hz), 3.31 (d
d, 1H, J = 9.5, 13.9 Hz), 3.06 (d
d, 1H, J = 5.9,13.9Hz) Calculated elemental analysis _{C 19 H 18 N 4 OS (} 322.43) C: 70.78; H: 5.63; N: 8.69 Analytical values C: 70.68; H: 5.76; N: 8.60

Example 23 DL-5- [2- (2-naphthyl) -1- (phenylthio) ethyl] -1,3,4-oxadiazole-2 (3
Synthesis of H) -one [Formula 48]: Exemplified compound (23)

[0126]

Embedded image DL-3- (2-Naphthyl) -2- (phenylthio) propionic acid hydrazide (322 mg, 1 mmol) was dissolved in tetrahydrofuran (10 ml), and 1 ′, 1′-carbonylbisimidazole (325 m) was added at 0 ° C.
g, 2 mmol) and triethylamine (210 μm).
1,1.5 mmol) and stirred for 1 hour. Subsequently, the reaction solution was heated to room temperature, stirred for 4 hours, and then poured into water.
The precipitated white crystals were collected by filtration and recrystallized from ethanol to give the title compound (247 mg, 71%).

Melting point = 143-145 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 12.10 (bs, 1H), 7.89-7.80
(M, 4H), 7.52-7.34 (m, 8H), 4.
79 (dd, 1H, J = 7.3, 8.8 Hz), 3.4
1-3.32 (m, 2H) calcd elemental analysis _{C 20 H 16 N 2 O 2} S (348.43) C: 68.94; H: 4.63; N: 8.04 Analytical values C: 68.94; H: 4.83; N: 7.98

Example 24 DL-5- [2- (2-naphthyl) -1- (phenylthio) ethyl] -1,3,4-oxadiazole-2 (3
Synthesis of H) -thione [Formula 49]: Exemplified compound (24)

[0129]

Embedded image DL-3- (2-naphthyl) -2- (phenylthio) propionic hydrazide (300 mg, 0.93 mmol
l) was dissolved in methanol (10 ml) and potassium hydroxide (63 mg, 1.12 mmol) and carbon disulfide (1
(0 μl, 2.33 mmol) was added at 0 ° C. and stirred for 30 minutes, and then heated to reflux for 1 hour. Methanol was concentrated under reduced pressure, and the obtained residue was dissolved in water and washed with ethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and the desired product was extracted with ethyl acetate, and then the organic layer was washed with water. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 20) to give the title compound (246 m
g, 78%) as a clear, colorless syrup.

¹ H-N. M. R. (DMSO-d _6, 27
0 MHz) δ = 7.81-7.76 (m, 3H), 7.
64 (s, 1H), 7.49-7.23 (m, 8H),
4.46 (t, 1H, J = 7.3 Hz), 3.45
(D, 2H, J = 7.3 Hz)

Example 25 DL-5- [2- (2-naphthyl) -1- (phenylthio) ethyl] -2,4-dihydro-4-methyl-1,
2,4-triazole-3 (3H) -thione
Synthesis of Exemplified Compound (25)

[0132]

Embedded image DL-3- (2-naphthyl) -2- (phenylthio) propionic hydrazide (300 mg, 0.93 mmol
l) was dissolved in tetrahydrofuran (6 ml), and methyl isothiocyanate (90 mg, 1.12 mm) was added at room temperature.
ol) and stirred for 8 hours. The white solid residue obtained by concentration under reduced pressure was suspended in water (3 ml), 1N sodium hydroxide (2.3 mmol) was added, and the mixture was heated and stirred for 2 hours. The reaction solution was allowed to cool, acidified with 1N hydrochloric acid, and the desired product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: chloroform: n-hexane = 1: 1: 3) to give the title compound (253m2).
g, 72%) as white crystals.

Melting point = 154-156 ° C. ¹ H-N. M. R. (DMSO-d ₆ , 270 MHz) δ
= 11.29 (bs, 1H), 7.80-7.73
(M, 3H), 7.62 (s, 1H), 7.48-7.
41 and 7.36-7.24 (m, 8H), 4.32
(Dd ,, 1H, J = 5.9, 8.8 Hz), 3.58
(Dd, 1H, J = 8.8, 13.7 Hz), 3.49
(S, 3H), 3.43 (dd, 2H, J = 5.9, 1
3.7Hz)

[Test Example] The usefulness of the compound of the present invention as a leukocyte cell adhesion inhibitor is shown by a cell adhesion inhibition test. [Test Example 1 Cell Adhesion Inhibition Test Using Human Neutrophils] (Separation of neutrophils / plasma from human peripheral blood) Heparin-added peripheral blood was collected from a healthy human and a monopoly separated solution (Dainippon Pharmaceutical Co., Ltd.) , Cat No. 16-980-49DN), and neutrophils / plasma were separated by specific gravity centrifugation. (Measurement of cell adhesion ability) Neutrophils isolated from human peripheral blood
The test was suspended in HANKS solution containing 10 mM HEPES (HHBSS) or 10% human plasma and HANKS solution containing 10 mM HEPES (10% plasma / HHBSS), and dissolved in dimethyl sulfoxide (DMSO, Wako Pure Chemical Industries, Ltd.) at a concentration of 10 mM. Add an appropriate amount of medicine, 37
It was left at ℃ for 10 minutes. N-formyl-Met-Leu-Phe (fMLP, SIGMA, F-350) was added to this reaction solution to a final concentration of 10 μM.
6) and allowed to stand at room temperature for 5 minutes. 200 μl was added to each well of a 48-well multiwell plate (flat bottom, costar, Cat No. 3524) coated with 0.1 mg / ml human fibrinogen (SIGMA, F-4883). The mixture was dispensed at 37 ° C. for 15 minutes. Each well was washed twice with HHBSS to remove non-adherent cells.

0.5% hexadecyl was added to the wells to which the cells had adhered.
An aqueous solution of trimethylammonium bromide (HTAB, Junsei Kagaku) (100 μl) was added, and the mixture was allowed to stand for 30 minutes to be solubilized. Solubilized solution
Transfer 50 μl each to a 96-well multiwell plate, 0.2 mg / ml
250 μl of PBS (−) containing o-dianisidine (SIGMA, D-9154) and 0.4 mM H ₂ O ₂ was added, and after 5 minutes, the absorbance at 450 nm was measured with an immunoreader. All experiments were performed in triplicate,
The average value of the absorbance was determined. Table 1 [Table 1] shows the results of a biological activity test on the cell adhesion inhibitory effect using neutrophils from human peripheral blood. As the test drug, each of the compounds shown in the examples was used. As the biological activity value, the neutrophil adhesion inhibition rate at the test drug concentration of 30 μM or the test drug concentration at which neutrophil adhesion was inhibited by 50% (IC ₅₀ Value).

[0136]

[Table 1] Each compound strongly inhibited the neutrophil adhesion reaction at the test drug concentration of 30 μM. In particular, the compounds of Example 1 and Example 7 were found to have extremely excellent cell adhesion factor expression inhibitory action.

[Test Example 2 Adhesion Inhibition Test Using Differentiation-Inducing HL-60 Cells] (Cells) Human leukemia cell line HL-60 (purchased from Dainippon Pharmaceutical Co., Ltd.) was obtained from RPMI1640 medium containing 10% fetal bovine serum. Was used. Induction of differentiation into neutrophil-like cells
0.5 mM final concentration of dibutyryl cyclic AMP (dbcAMP, SIGMA,
D-0627) was added to 10% fetal bovine serum-containing RPMI1640 medium, and HL-60 was suspended at 1 × 10 ⁶ cells / ml.
Cultivation was performed for 3 days at 5 ° C. and 5% CO ₂ . The differentiation into neutrophil-like cells was confirmed to be 70% or more due to NBT reducing ability.

(Measurement of Cell Adhesion Ability)
× 10 ⁶ cells / ml and made as 10 mM HEPES containing HANKS solution (H
HBSS), an appropriate amount of a test drug dissolved at 10 mM in Dimethyl Sulfoxide (DMSO, Wako Pure Chemical Industries, Ltd.) was added, and the mixture was allowed to stand at 37 ° C. for 10 minutes. Add a final concentration of 10μ
N-formyl-Met-Leu-Phe (fMLP, SIGMA, F-
3506) and add 0.1mg / ml human fibrinogen (SIGM
(A, F-4883), 200 μl was dispensed into each well of a 96-well multiwell plate (flat bottom, cornering 25880-96) coated with the mixture, and allowed to stand at room temperature for 60 minutes. Each well was filled with HHBSS, sealed with a plate seal, and inverted at room temperature for 60 minutes to remove non-adherent cells.

0.5% hexadecyl was added to the wells to which the cells had adhered.
A 50 μl aqueous solution of -trimethylammoniumbromide (HTAB, Junsei Chemical) was added, and the mixture was allowed to stand for 30 minutes to be solubilized. 0.2mg / mlo-dianisi
dine (SIGMA, D-9154) PBS containing and 0.4mM H ₂ O ₂ (-)
Was added, and after 5 minutes, the absorbance at 450 nm was measured with an immunoreader. All experiments were performed in triplicate, and the average value of absorbance was determined. Table 2 [Table 2] shows differentiation-inducing HL-60.
The results of the biological activity test for cell adhesion inhibitory action using cells were shown. As the test drug, using each compound shown in the examples,
As the biological activity value, the concentration of the test drug (IC ₅₀ value) when inhibiting the adhesion of the differentiation-inducing HL-60 cells by 50% was shown.

[0140]

[Table 2] Each compound strongly inhibited the adhesion reaction to differentiation-induced HL-60 cells. In particular, it was found that the compounds of Examples 1, 3 and 6 have extremely excellent cell adhesion factor expression inhibitory effects.

[0141]

The compound of the present invention is a novel substance and, as shown in Examples and Test Examples, has a strong inhibitory effect on the adhesion of neutrophils to vascular endothelial cells which is greatly involved in the inflammatory response. . Rheumatism because of low toxicity,
It is expected to be useful as a therapeutic and / or prophylactic agent for pathological conditions such as nephritis, asthma, allergy, dermatitis, colitis, diabetes, arteriosclerosis, restenosis after PTCA, cardiovascular disorders, peripheral vascular disorders or metastasis of cancer. .

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/275 ADS A61K 31/275 ADS 31/34 ABN 31/34 ABN ADU ADU ADU 31/41 ACV 31/41 ACV C07D 249/12 509 C07D 249/12 509 257/04 257/04 E 271/10 271/10 317/70 317/70 (72) Inventor Ayako Watanabe 1900 Togo, Togo, Mobara City, Chiba Pref.

Claims (4)

[Claims] 1. A compound of the general formula (1) In the formula, R ₁ and R ₂ may each independently be any position on the naphthalene ring, and may be a hydrogen atom, a carbon atom having 1 to 4 carbon atoms.
Lower alkyl group, a halogen atom, a hydroxyl group, an alkyloxy group having 1 to 8 carbon atoms, a nitro group, an amino group,
A lower alkylamino group having 1 to 4 carbon atoms or a cyano group; R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a hydroxyl group or a 1 to 4 carbon atoms;
Represents a lower alkyloxy group, R ₄ is a carboxyl group, a lower alkyloxycarbonyl group having 1 to 4 carbon atoms,
A hydrazinocarboxy group or at least one nitrogen atom
It represents a 5-membered heterocyclic ring containing two or more. However, when R ₁ and R ₂ are alkyloxy groups, R ₁ and R ₂ may combine to form a methylenedioxy group. And a pharmacologically acceptable salt thereof. 2. A compound of the general formula (2) The naphthalene derivative and the pharmacologically acceptable salt according to claim 1, which is represented by the formula: 3. A cell adhesion factor expression inhibitor comprising the naphthalene derivative represented by the general formula (1) of claim 1 as an active ingredient. 4. A pharmaceutical composition comprising the naphthalene derivative represented by the general formula (1) according to claim 1 as an active ingredient.