WO2000031036A1 - Novel naphthalene derivatives - Google Patents

Abstract

Novel naphthalene derivatives represented by general formula (1), which exhibit an excellent fibrinolysis accelerating effect and are useful as orally administrable antithrombotic or thrombolytic agents.

Description

 Handbook, New Naphthalene Induction Technology

 The present invention relates to a naphthalene derivative having a fibrinolysis-promoting action and useful as a thrombolytic agent and an antithrombotic agent.

Background art

 In the living body, when the blood vessel wall is damaged, the blood coagulation system acts as a defense mechanism to prevent bleeding, and forms a hemostatic thrombus at the damaged site. On the other hand, there is also a fibrinolytic system that dissolves thrombus formed in the blood vessels and maintains blood flow. When a blood clot is formed in a blood vessel, the vascular endothelial cells are transformed into tissue plasminogen activator by the stimulation of ischemia.

Produce and secrete (t-PA). t-PA converts the inactive form of plasminogen present in the blood to the active form of plasmin on the thrombus. The resulting plasmin exerts an enzymatic action and degrades fibrin, a component of the thrombus, thereby promoting thrombolysis. This series of reactions is called fibrinolysis. In addition, as a plasminogen activator (PA) other than t-PA, a perokinase-type plasminogen activator (u-PA) is known to be present in blood vessels. Dissolution of this thrombus must occur at the appropriate time. If the thrombus dissolves too early, it causes bleeding, and if it is too late, the thrombus increases, resulting in narrowing or occlusion of blood vessels. Normally, the homeostasis of the living body is maintained by this delicate balance between the coagulation system and the fibrinolysis system. This subtle balance breaks down, and when leaning toward the coagulation system, it becomes thrombotic and produces thrombi. In addition, if a blood vessel becomes narrowed or obstructed by this thrombus, the tissue under the control of the blood vessel may become severely ischemic, such as myocardial infarction, stroke, angina, pulmonary embolism, disseminated intravascular coagulation (DIC) And so on.

Currently, therapies to administer PAs to dissolve thrombus, namely thrombolytic therapy (fibrinolytic therapy) 1 are widely practiced. The thrombolytic agents used in this fibrinolytic therapy include biological substances such as perokinase (UK) and t-PA, and bacterial cell producing substances such as streptokinase (SK) and staphylokinase (SAK). Genetically modified products and the like are known.

 However, since these existing thrombolytic drugs are all protein preparations, they have a short half-life in blood, are rapidly metabolized in the liver, and have thrombi due to the presence of inhibitors in vivo. Large-dose administration is required to exert a thrombolytic effect locally. In clinical practice, it has been reported that the higher the dose, the higher the reperfusion rate. However, such a transient large-volume administration of a thrombolytic agent significantly enhances the thrombolytic activity systemically, resulting in thromboembolic sites. Is expected to be opened, but serious side effects of bleeding are observed. Further, even if the embolization site is temporarily opened by administration of these thrombolytic agents, reocclusion tends to occur easily, which is a major problem. Furthermore, the method of administration used for treatment is intravenous systemic administration or intracoronary administration, and since it is directly administered into blood vessels, there is a problem that long-term administration requires a large burden on patients. . Therefore, development of orally administrable thrombolytic agents based on a new mechanism of action is desired.

Disclosure of the invention

 An object of the present invention is to provide an antithrombotic agent and a thrombolytic agent which have a fibrinolysis promoting action and can be orally administered.

 The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that the following novel naphthalene derivatives have excellent fibrinolysis-promoting activity and are extremely useful as antithrombotic agents and thrombolytic agents. That is, the present invention provides the following formula (1)

Equation (1)

(In the formula, R 1 represents a hydrogen atom, R 2 -carbonyl lower alkyl group or R 3 -lower alkyl group, and R 2 represents a hydroxyl group, a lower alkoxy group, a lower alkylamino group having a substituent, or a lower alkyl group. R 3 represents a phenyl group having a substituent, an amino group having a substituent or a hydroxyl group,

A is

Represents

 R 4 represents a hydrogen atom or a lower acyl group,

 X represents an oxygen atom or a sulfur atom,

 R5 represents a halogen, a hydroxyl group, a mercapto group, one OR6 or one S R6, R6 represents a lower alkyl group or R7-carbonyl lower alkyl group, R7 represents a hydroxyl group or a lower alkoxy group,

 R 8 represents a hydrogen atom or a lower alkyl group,

 Y represents one (CH2) n- (n = 2 or 3) or one C H = C H—, and P represents —NH—, an oxygen atom or a sulfur atom. )

(However, when R 1 represents a hydrogen atom, A

(Y is — (CH2) n—, n = 2 and P represents an oxygen atom or 1 NH—). )

And a salt compound and solvate thereof, and an antithrombotic agent and a thrombolytic agent containing them as an active ingredient. Further, the formula (2) of the present invention

(Where B is

Represents )

The compound represented by is useful as a synthetic intermediate for the compound represented by the formula (1).

In the present invention, the lower alkyl group as a part of the lower alkyl group and the lower alkoxy group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methyl group, an ethyl group Propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, and hexyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The compound represented by the above formula (1) of the present invention can be converted into a pharmacologically acceptable salt as required, or the resulting salt can be converted into a free base or a free acid. Further, those compounds may be solvates. Salts include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine salts, and amino acid addition salts. Specifically, examples of the acid addition salts include inorganic acid salts such as hydrochloride, phosphate, and sulfate, and organic acid salts such as acetate, citrate, and methanesulfonate, and sodium as the metal salt. Alkali metal salts such as salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; aluminum salts; etc.Ammonium salts include salts such as ammonium, and organic amine salt addition salts Include addition salts such as morpholine and piperidine, and amino acid addition salts include addition salts such as glycine and lysine. Examples of the solvates include hydrates.

 Any of the compounds represented by the above formula (1) of the present invention can be synthesized by a known method. Scheme A

 In the formula (4), the formula (1) [In the formulas (3) and (7), R 9 represents a halogen atom or a trifluoromethanesulfonyloxy group, and in the formulas (4) and (6), Bu represents butyl. Represents a group. In the formula (3) and the formula (4), R1 is as described above, and the formula (5) and the formula

In (6) and formula (7), A is as defined above.

Process 1

The compound represented by the formula (1) can be obtained by using the compound represented by the formula (3) and the compound represented by the formula (5) by the method of Somma i Pivsa-Art et al. [Bull. Chem. Soc. Jpn., 71, 467 (1998).]. For example, the compound represented by the formula (3) is a 6-promo-2-naphthol derivative, and the compound represented by the formula (5) is a heterocyclic compound. When a compound such as N-methylbenzimidazole, benzothiophene, benzoxazole or benzothiazole is used, the corresponding compound represented by the formula (1) is converted to the corresponding 6- (1-methylbenzimidazole). 12-naphthol derivative, 6- (benzothiophene-12-yl) 1-2-naphthol derivative, 6- (benzoxazol-2-yl) -12-naphthol derivative or 6- (Nzothiazole-12-yl) -12-naphthol derivative can be obtained. In the formula (3), when R 1 is a hydrogen atom, it can be protected with an appropriate protecting group in advance, and after the reaction, deprotected and converted into a desired functional group. The obtained compound represented by the formula (1) can be converted into a desired compound by converting a functional group as necessary. In the present invention, the base refers to an inorganic base such as sodium, an alkoxyalkali metal (for example, sodium methoxide), potassium carbonate, sodium carbonate, or sodium hydroxide, or an organic base such as triethylamine or pyridine. Methods for introducing and removing protecting groups commonly used in organic synthetic chemistry include, for example, TW Green, "Protective Group Organic Synthesis, 2nd Ed., John Wiley & Sons, 19 9 There is a method described in 1. As a conversion reaction to the target functional group, for example, in the case of a hydroxyl group, a reaction with a substituted or unsubstituted lower alkyl halide in the presence of a base in a suitable solvent is given. There is a reaction to form a substituted or unsubstituted lower alkoxy group by other methods.Other known methods include, for example, RC Larock,

 C omp r e h e n s i v e O r g a n i c

 198. 9. The method described in Transforamoisns., VHCPublishers, Inc. The above method is an example, and other known methods can be used.

Process 2

The compound represented by the formula (1) can be obtained by using a compound represented by the formula (3) and a compound represented by the formula (6) by Sti 11 e et al. [TN Mitche 11, Synthesis, 803 (1) 9 9 2).] Can also be manufactured. For example, a compound represented by the formula (3) has a 6-bromo-2-naphthol derivative, and a compound represented by the formula (6) has a triptylstannyl group. By using various heterocyclic derivatives, for example, 2-triptylstannylfuran or 2-trib, tilstanylthiophene, etc., the corresponding compound represented by the formula (1) is converted into the corresponding 6- (2-furyl) -12-naphthol A derivative or a 6-phenyl-1-naphthol derivative can be obtained. In the formula (3), the desired compound represented by the formula (1) can be produced by subjecting the shaku 1 to the same reaction as in the step 1 above. The above method is an example, and other known methods may be used.

Process 3-1

 Production of intermediate (6-triptylstannyl-2-naphthol derivative) [Formula (4)]

The compound represented by the formula (4) can be produced by heating the compound represented by the formula (3) and bis (tributyltin) in a suitable solvent in the presence of tetrakis (triphenyl) phosphine palladium. For example, methyl (6-bromo-2-naphthyloxyacetate) is used as the compound represented by the formula (3), bis (tributyltin) is added to a dioxane solution of tetrakis (triphenyl) phosphinepalladium, and the mixture is heated under reflux. The reaction mixture is concentrated under reduced pressure, and purified by a silica gel column (ethyl hexane monoacetate) to obtain methyl 6-tributylstannyl-2-naphthyloxy, a compound represented by the formula (4). You can get an asset. In the formula (3), R 1 can perform the same reaction as in Step 1.

Process 3-2

The compound represented by the formula (1) can also be produced from the compound represented by the formula (4) and the compound represented by the formula (7) according to the method of Stille et al. For example, as the compound represented by the formula (4), methyl 6-tributylstanyl-2-naphthyloxyacetate, and as the compound represented by the formula (7), various heterocyclic derivatives, for example, 2-bromopyridine, 3-bromopyridine , 4-bromopyridine, 3-bromofuran, 3-bromothiophene, 5-bromopyrimidine, 2-bromo-1,3-thiazonoline, 3-bromoquinoline, 4-bromoisoquinoline, N-acetinolate 4-bromopyrazonole, 5 —Bromo-2—Metinorebenzo By using thiazole or 4-bromoantipyrine etc., the corresponding methyl 6- (2-pyridyl) -12-naphthyloxyacetate, methyl 6- (3-pyridyl) -12-naphthyloxyacetate Methyl 6- (4-pyridyl) -1-2-naphthyloxyacetate, Methyl 6- (3-furyl) -12-Naphthyloxyacetate, Methyl 6- (3-Chenyl) —2— Naphthyloxycetate, methyl 6- (5-pyrimidinyl) 1-2-naphthyloxyacetate, Methyl 6- (1,3-thiazol-2-l) 1-2-Naphthyloxyacetate, Methyl 6- (3-quinolyl) 1-2-naphthyloxyacetate, Methyl 6- (4-isoquinolyl) 1-2-naphthyloxyacetate, Methyl 6- (N-acetyl-4-pyrazolyl) 1-2_ Naphthyloxy Settate, methyl 6- [5- (2-methyl-1,3-benzothiazolyl)]-1-2-naphthyloxyacetate or methyl 6- (2,3_dimethyl-1-Fe-Ru 3-Vilazolin-1 5 —On 1 4 1 ^ f 1) 2-naphthyl oxyacetate can be obtained. The obtained compound represented by the formula (1) can be converted to a functional group by the method described in Step 1 as necessary to obtain the desired compound. The above method is an example, and other known methods can be used.

Scheme B

Process 5—

(In the formulas (8), (9), (10), (11), (12), (13) and (14), R1 is as defined above, (In (13), R 5 is as described above.)

Process 4

 The method of Paul C. Unangst et al. [J. Med Chem., 35, 3691 (1992)] was carried out using the compound represented by the formula (8) and carbonyl sulferyl chloride. ], The compound represented by the formula (9) can be produced. For example, if 6-hydroxyxaphthalene-12-carboxamide is used as the compound represented by the formula (8), 5- (6-hydroxy-2-naphthyl) 1-2-oxo-1 is used as the compound represented by the formula (9). 1,3,4 Monooxathiazole is obtained. The obtained compound represented by the formula (9) can be converted to a desired compound by converting a functional group according to the method described in Step 1 as necessary. The above method is an example, and other known methods can be used.

Process 5-1

 Intermediate (2-hydroxyamidino 2-naphthol derivative) For the compound represented by the formula (10) in the formula (11), the compound represented by the formula (8) is treated with a salt such as ichthionyl. Is obtained by Alternatively, it can be derived from 2-cyano 6-naphthol by the functional group conversion reaction described in Step 1. For example, when 2-cyano 6-naphthol is reacted with methyl bromide acetate in an appropriate solvent in the presence of a carbonate group such as carbonated sodium carbonate or sodium carbonate, the compound represented by the formula (10) is converted into methyl 6-cyano-naphthol. _ 2--Naphthoxy acetate is obtained. Formula obtained

Using the compound represented by (10) and hydroxylamine, the compound represented by the formula (11) can be produced in accordance with the method of Pau1C. Unangst et al. Described above. For example, when methyl 6-cyano 2-naphthyl oxyacetate is used as the compound represented by the formula (10), methyl 6-hydroxyamidino 2 is used as the compound represented by the formula (11). —Naphthyloxy acetate is obtained.

Process 5-2 Using the compound represented by the formula (11), thionyl chloride and pyridine, the method of Y. Kohara et al. [J. Med. Chem., 39, 52, 28 (1996). ], The compound represented by the formula (12) can be produced. For example, when the methyl 6-hydroxyamidino-2-naphthyloxyacetate described in the above step 5-1 is used as the compound represented by the formula (11), the compound is represented by the formula (12) As a compound, methyl 6- (2-oxo-13H-1,2,3,5-oxaxiadiazol-4-yl) -2-naphthyloxyacetate is obtained. The above method is an example, and other known methods can be used.

Process 5-3

 Using the compound represented by the formula (11) and ethyl ethyl chloroformate, the above Y.

According to the method of Kohara et al., The compound represented by the formula (13) can be produced. For example, in the formula (11), when a compound in which a 2-methoxyethoxymethyl group or a methoxycarbonylmethyl group is introduced into R 1 is used, the compound represented by the formula (13) corresponds to 3- (2-Methoxy ethoxy methoxy-6-naphthyl) 1,1,2,4-oxaziazol-l 5-ol or methyl 6- (5-hydroxyl 1,2,4-l-oxaziazol-l 3-inole) 1 2—Naphthoxy acetate is obtained. The resulting 3- (2-methoxyethoxyethoxy 6-naphthyl) -1-1,2,4-oxaziazol-1-yl 5-ol can be treated with an acid, for example, hydrochloric acid, or trifluoroacetic acid. [2— (6—Hydroxynaphthyl)] — 1,2,4-oxaziazol-l-5-ol is obtained, and methyl 6- (5-hydroxyl 1,2,4l-oxaziazol-13f) 1 2 —Naphthoxyacetate can be treated with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent to give 6- (5-hydroxy-1,1,2,4-oxaziazol-13-yl). 1) 2-Naphthyloxyacetic acid is obtained. The obtained 6- (5-hydroxy-1,2,4,1-oxaziazol-1-yl) -12-naphthol derivative [Formula (13)] is represented by 6- (4H-1,2,4 —Oxaziazol-1-5-one-3-yl) It has a tautomeric relationship with a 12-naphthol derivative, and both compounds are equivalent. The 5-hydroxy-1,2,4-oxadiazole derivative described in the present invention shows both tautomers unless otherwise specified. The different isomers are also included in the scope of the present invention. In the formula (13), R 1 and R 5 can be converted into the desired functional group by the method described in step 1 and the method of Pau 1 C. Unangst described above. The obtained 6- (5-mercapto-1,2,4-oxoxadiazol-3-yl) -1 2-naphthol derivative is 6- (5-thioxo-4H-1,2,4, oxaziazol-1). 3 f) Tautomeric relationship with 12-naphthol derivatives, and both compounds are equivalent. The 5-mercapto-1,1,2,4-oxadizazole derivative described in the present invention shows both tautomeric isomers unless otherwise specified, and both isomers are included in the scope of the present invention. The above method is an example, and other known methods can be used.

Process 6

 The compound represented by the formula (14) can be produced by using the compound represented by the formula (10), sodium azide and ammonium chloride. For example, when methyl 6-cyano 2-naphthyl oxyacetate is used as the compound represented by the formula (10), methyl 6- (5-tetrazolyl) 12-naphthyl oxyacetate is used as the compound represented by the formula (14). Is obtained. The obtained compound represented by the formula (14) can be converted into a desired compound by converting a functional group according to the method described in Step 1 as necessary. The above method is an example, and other known methods can also be used.

Production of Intermediate (2_Amidino 6-naphthol derivative) [Formula (15)]

Scheme c

[In the formulas (15), (16) and (17), R 1 is as described above]

 Using the compound represented by the formula (8) and a trialkyloxodinotetrafluoroborate, Meerwein et al. [R.F. Borch,

The compound of formula (15) is produced by converting a rubamoyl group into an alkoxycarboximidyl group by the method of Te trahedron Lett., 61 (1968).] And then reacting with ammonia. or _c can, using the compound represented by the formula (1 0), P inner et al [R.

Roger, D. Neilson, Chem. Rev., 61, 179 (1961)] to produce a compound represented by the formula (15). In the formulas (8) and (10), R1 can perform the same reaction as in the step 1. Process 7

Compound represented by formula (15), acetoamide, and 1,1-dimethoxytriol The compound represented by the formula (16) can be produced by dissolving methylamine in dioxane and heating in the presence of a base using, for example, potassium t-butoxide. For example, when 2-amidino-6-naphthol'methanesulfonate is used as the compound represented by the formula (15), 6- (1,3,5-triazine) is obtained as the compound represented by the formula (16). 1 2-^ f) 1 2-naphthol is obtained. The obtained compound represented by the formula (16) can be converted into a desired compound by converting a functional group according to the method described in Step 1 as necessary. The above method is an example, and other known methods can be used.

Process 8

 Using the compound represented by the formula (15) and acetoaldehyde dimethyl acetate, the method of JW Cornforth et al. [J. Chem. Soc., 1960 (1948).] The compound represented by (17) can be produced. For example, when ethyl-6-amidino-2-naphthyloxyacetate'acetate is used as the compound represented by the formula (15), the compound represented by the formula (17) becomes ethyl-6- ^ midazolyl2- Naphthoxy acetate is obtained. The obtained compound represented by the formula (17) can be converted into a functional group by the method described in Step 1 as necessary to obtain a target compound. The above method is an example, and other known methods can be used.

Step 9 Scheme D

 Equation (1 8) Equation (1 9)

[In the formula (18) and the formula (19), R 1 is as described above]

Using a compound represented by the formula (18), nitromethane and sodium azide, the method of NS Zefirov et al. [Chem. Commun., 1001 (1971).] Is used. The compound represented by (19) can be produced. For example, by performing a reaction using t-butyl 6-formyl-12-naphthyloxyacetate as a compound represented by the formula (18), t-butyl is converted to a compound represented by the formula (19). 6- (1,2,3-triazole-4-yl) 1-2-naphthyloxyacetate is obtained. In the formula (18), R 1 can perform the same reaction as in step 1. In the formula (19), R 1 can be converted to a functional compound by the method described in Step 1 to obtain a target compound. The above method is an example, and other known methods can be used.

Process 10

 Preparation of intermediate (2-naphthoic acid derivative) [Formula (21)] Scheme E

 Equation (23) Equation (22) Equation (24) Step 14

 Equation (25)

[In the formula (21), R 10 represents lower alkyl or arylalkyl; and in the formula (22), R 11 represents a substituted lower alkyl. In equation (23), Y represents — (CH2) n_ (n = 2 to 3), and in equation (24), P and Q are the same. Or differently represents a nitrogen, NH or sulfur atom. In the formulas (20),, (21), (22), (23), (24) and (25), R 1 is as described above.

After using 6-hydroxy-2-naphthoic acid as the compound represented by the formula (20) and dissolving in a suitable solvent, a substituted or unsubstituted lower alkyl or arylalkyl halide is substituted in the presence of a suitable base. By reacting, the formula (2

The compound represented by 1) can be produced. For example, if chloroiodide is used as the lower alkyl halide and benzyl bromide is used as the arylalkyl halide, the corresponding compound represented by the formula (21) will be ethyl 6-hydroxy-12-naphthate. Benzyl 6-hydroxy-2-naphthate is obtained. When an excess amount of the base and the halide used is used, a compound represented by the formula (21) in which both 11 and 1-10 are substituted by an alkyl group or an arylalkyl group can be produced. The above method is an example, and other known methods can be used.

Process 1 1

 Production of Intermediate (2-Naphthalenecarboxamide derivative) [Formula (22)] The compound represented by the formula (21) and a lower alkylamine having a substituent are heated in a solvent or without solvent to obtain a compound represented by the formula The compound represented by (22) can be produced. For example, when ethyl-6-hydroxy-12-naphthate is used as the compound represented by the formula (21) and 2-aminoethanol or 3-amino-1-propanol is used as the lower alkylamine having a substituent, the formula (2)

As the compounds represented by 2), 6-hydroxy-1-N- (2-hydroxyxethyl) -1-2-naphthalenecarboxamide or 6-hydroxy-N- (3-hydroxypropyl) -1-2-naphthalene Carboxamide can be manufactured.

Process 1 2

Using the compound represented by the formula (22) and thionyl chloride, the compound represented by the formula (23) is obtained by the method of Guy D. Diana et al. [J. Med. Chem., 30, 383 (187)]. Can be produced. For example, the expression (2 As the compound represented by 2), 6-hydroxy N— (2.—hydroxyxetyl) obtained in step 11-1-naphthalenecarboxamide or 6-hydroxy-N- (3-hydroxypropyl) When using 2-naphthalenecarboxamide, the corresponding compound represented by the formula (23) is 6- (4,5-dihydro-1,3-oxazolyl-2-yl). Naphthol or 6- (5,6-dihydro-4H-1,3-oxazine-12- ^ f) -12_naphthol can be produced. In the formula (23), R 1 can be converted into a functional group by the method described in Step 1 to obtain a target compound. The above method is an example, and other known methods can be used.

Process 1 3

 Using a compound represented by the formula (21), a lower alkylamine having a substituent and a trialkylanolamine, the method of Car 1 A. Busacca et al.

 [T etrahedron Lett., 37, 2935 (1996).] Or the method of Gunter Neef et al. [J. Org. Chem., 46, 2824 (198) 1).], The compound represented by the formula (24) can be produced. For example, if benzyl 6-benzyloxy-1-naphthate is used as the compound represented by the formula (21) and ethylenediamine or 2-aminoethanethiol is used as the lower alkylamine having a substituent, the compound is represented by the formula (24) The corresponding compounds are 2-benzyloxy-6- (2-imidazolinyl) naphthalene or 2-benzyl / reoxy-1-6- (4,5-dihydro-1,1,3-thiazoline-12-yl) naphthalene, respectively. Can be manufactured. In formula (24), 11 can be converted into a target compound by converting a functional group by the method described in step 1. The above method is an example, and other known methods can be used.

Process 1 4

 Using a compound represented by the formula (22), sodium azide and trifluoromethanesulfonic anhydride, the method of EdwardW.Thomas

According to [Synthesis, 767 (1993).], The compound represented by the formula (25) can be produced. For example, when a compound represented by the formula (22) is a compound in which R 11 is a methyl group, the compound represented by the formula (25) can be produced. Wear. In the formula (25), R 1 can be converted to a functional compound by the method described in Step 1 to obtain a target compound. The above method is an example, and other known methods can be used.

 Pharmaceuticals containing as an active ingredient the novel naphthalene derivative represented by the general formula (1) and its salt compound or a solvate thereof, which are produced as described above, are usually used in mammals (including human patients). On the other hand, it can be administered as an oral preparation such as tablets, capsules, powders, fine granules and syrups, a rectal preparation or an injection. Further, the compound of the present invention can be administered as one therapeutic agent or as a mixture with another therapeutic agent. Although they may be administered alone, they are generally administered in the form of a pharmaceutical composition. These preparations can be manufactured by a conventional method by adding pharmacologically and pharmaceutically acceptable additives. That is, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, and coating agents can be used for oral administration. Oral liquids may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, or provided as dry syrups in water or other suitable solvent before use. Is also good. Said solutions may contain usual additives such as suspending agents, fragrances, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. Suppositories are based on suitable substances such as cocoa butter, lauric fat, macrogol, glycemic gelatin, witetbsol, sodium stearate or a mixture thereof, and are emulsifiers, suspending agents, and preservatives as necessary. Etc. can be added. Injectables are dissolving or dissolution aids such as distilled water for injection, physiological saline, 5% glucose solution, propylene glycol, etc., which can constitute aqueous or ready-to-use dosage forms, pH adjusters, isotonic Pharmaceutical ingredients such as a stabilizing agent and a stabilizing agent are used.

 Specific examples of excipients and the like used in the above composition are shown below.

Excipients: calcium hydrogen phosphate, synthetic aluminum silicate, magnesium aluminate metasilicate, aluminum hydroxide 'magnesium hydroxide, magnesium silicate, calcium carbonate, magnesium carbonate, light silicic anhydride, silicate anhydride, Avicel, various types Starch, dextrin, carboxymethyl starch (CMS), lactose, etc. Binders: Ethyl cellulose (EC), carboxymethyl cellulose Na (CMC) -Na), low-substituted hydroxypropylcellulose (L-HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), hydroxypropylcellulose (HPC), various starches, dextrin, sodium alginate, Gelatin, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), etc.

Disintegrators: synthetic aluminum silicate, magnesium aluminate metasilicate, CMC-Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CMS, hydroxypropyl starch (HPS), etc.

Anti-solidification agent: Light caustic anhydride, synthetic aluminum silicate, etc.

Lubricants: synthetic aluminum silicate, carboxylic anhydride, talc, Avicel, etc.

Flavoring agents: mannitol, cunic acid, cunic acid Na, sugar, etc.

Emulsifiers: gelatin, cunic acid, sodium citrate, polyoxyethylene hydrogenated castor oil, macrogol (PEG), propylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, propylene glycol, sodium lauryl sulfate, phospholipids, etc.

Stabilizers: sodium bisulfite, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, phospholipids etc.

Absorption promoter: polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, medium-chain fatty acid triglycerides, etc.

Dissolution aids: ethanol, polyoxyethylene hydrogenated castor oil, PEG, propylene glycol fatty acid esters, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodextrins, etc.

Suspending agent: CMC_Na, HPMC, MC, HPC, sodium alginate, gelatin, propylene glycol, lauryl sulfate Na, etc. Coating agent: EC, magnesium silicate, talc, titanium oxide, calcium carbonate, triacetin, carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), HPMC, hydroxypropylmethylcellulose phthalate ( HPMCP), MC, HPC, sodium alginate, polyvinylacetate rugethylaminoacetate, polyacrylic acid Na, copolymers of various acrylic acid methacrylic acid derivatives, polyglycolic acid Na, and the like.

Colorant: titanium oxide, tar dye, caramel, etc.

 When the compound of the present invention is administered to humans, the dose varies depending on the age, symptoms, etc. of the patient.In general, for adults, 1 mg to 100 mg / day for oral or rectal administration, about 100 mg / day, injection In 0.1 ~ 50 OmgZ people Z days is about. However, these numerical values are merely examples, and the dose may be appropriately adjusted according to various conditions such as the patient's symptoms.

BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the present invention will be described specifically with reference to examples and test examples, but the present invention is not limited to these examples.

Reference example 1

 Preparation of methyl 6-bromo-2-naphthyloxyacetate

 To a suspension of 6-bromo-2-naphthol (22.3 g) and anhydrous potassium carbonate (17.9 g) in DMF (200 ml) was added methyl bromide acetate (11.4 ml) for 1 hour. Stir. After the reaction solution was concentrated under reduced pressure, purified water was added to the residue, and the precipitated solid was collected by filtration to obtain methyl 6-bromo-2-naphthyloxyacetate. Reference example 2

Preparation of Methyl 6_triptyl styrene 2-naphthyloxyacetate Methyl 6_bromo-2-naphthyloxyacetate (5.9 g) and tetrakis (triphenylphosphine) palladium (461 mg) Bis (tributyltin) (13.lml) was added to the dioxane (5Oml) solution, and the mixture was heated under reflux for 10 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by a silica gel column (hexane-ethyl acetate) to obtain methyl 6-tributylstannyl-2-naphthyloxy acetate. Reference Example 3, Production of methyl 6-cyano-1-naphthyloxyacetate

 To a suspension of 2_cyano-6-naphthol (5 g) and anhydrous potassium carbonate (12.3 g) in DMF (30 ml) was added methyl bromide acetate (3.3 ml), and the mixture was stirred for 2 hours. After the reaction solution was concentrated under reduced pressure, methanol was added to the residue, and the precipitated solid was collected by filtration to obtain methyl 6-cyano-12-naphthyloxyacetate.

Example 1

 Production of 6- (2-furyl) 1-2-naphthyloxyacetic acid

 A solution of methyl 6-bromo_2-naphthyloxyacetate (294mg) and tetrax (triphenylphosphine) palladium (58mg) in dioxane (1Oml) was used to prepare 2- (triptylstanyl) furan (0.94m l) was added and the mixture was heated under reflux for 2 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by a silica gel column (hexane-ethyl acetate) to obtain methyl 6- (2-furyl) -12-naphthyloxacetate. The obtained methyl 6_ (2-furyl) -2-naphthyloxyacetate was suspended in ethanol (9 ml), 2N aqueous sodium hydroxide solution (1. Oml) was added, and the mixture was stirred for 20 minutes. The reaction solution was neutralized with dilute hydrochloric acid and then concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with purified water to obtain Compound 1.

 lH-NMR (DMS0-d6 / TMS):

 δ = 4.60 (2Η, s) 6.62 (1H, dd, J = 1.7, 3.3Hz), 6.99 (1H, d, J = 3.3Hz),

7.17-7.20 (2H, m), 7.77 (3H, s), 7.86 (1H, d, J = 9.6Hz), 8.12 (1H, s) ₀

FABMS (m / z): 269 (M + l) +.

Example 2

 Preparation of 6- (2-Chenyl) -1-2-naphthyloxyacetic acid (Compound 2)

Example using methyl 6-bromo-1-naphthyloxyacetate (588 mg), tetrakis (triphenylphosphine) palladium (116 mg), and 2- (tributylstannyl) thiophene (1.5 ml) By performing the same operation as in 1, methyl 6_ (2-Chenyl) -1-2-naphthyloxyacetate was obtained. The obtained methyl 6- (2-Chenyl) -12-naphthyloxyacetate (15 Omg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 1. Compound 2 was obtained as a white solid. lH-NMR (DMS0-d6 / TMS):

 6 = 4.69 (2H, s), 7.14-7.23 (3H, m), 7.53-7.59 (2H, m),

 7.74-7.83 (2H, m), 7.88 (1H, d, J = 8.9Hz), 8.09 (lH, s).

 FABMS (m / z): 283 (M-1)-.

Example 3

 Preparation of 6- (2-pyridyl) _2-naphthyloxyacetic acid (Compound 3)

 Methinole 6-tributylstannyl-2-naphthyloxyacetate (505 mg) and tetrakis (triphenylphosphine) palladium (58 mg) in dioxane (1 Om 1) solution were mixed with 2-pyridinepyridine (0.29 ml). ) Was added and the mixture was heated under reflux for 48 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by a silica gel column (hexane-ethyl acetate) to obtain methyl 6- (2-pyridyl) -12-naphthyloxacetate. The obtained methyl 6- (2-pyridyl) 1-2-naphthyl oxyacetate (120 mg) was suspended in ethanol (9 ml), and a 2N aqueous sodium hydroxide solution (1.0 ml) was added, followed by stirring for 20 minutes. did. The reaction solution was neutralized with dilute hydrochloric acid and then concentrated under reduced pressure. Purified water was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 3.

 lH-NMR (DMS0-d6 / TMS):

 δ = 4.82 (2Η, s), 7.23-7.38 (3Η, m), 7.88-8.00 (3H, m),

 8.09 (1H, d, 8 · 21 (1H, d, J = 8.6Hz), 8.60 (lH, s),

8.69 (1H, d,

13.1 (1H, br) ₀

FABMS (m / z): 280 (M + l) + ₀

Example 4

 Preparation of 6- (3-Chenyl) -1-2-naphthyloxyacetic acid (Compound 4)

Example 3 using methyl 6-tributylstannyl-2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium (58 mg), and 3-thiophenobromide (0.28 ml) The same operation as described above was performed to obtain methyl 6- (3-Chenyl) -12-naphthyloxyacetate. The resulting methyl 6- (3-Chenyl) -12-naphthyloxyacetate (150 mg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to obtain Compound 4.

 1H-NMR (DMS0-d6 / TMS):

 δ = 4.42 (2Η, s), 7.13-7.16 (2H, m), 7.65-7.66 (2H, m), 7.74-7.91 (3H, m),

8.13 (1H, s) _D

 FABMS (ra / z): 283 (M-1)-.

Example 5

 Preparation of 6- (5-pyrimidinyl) -1-2-naphthyloxyacetic acid (compound 5) Methyl 6-triptylstanyl-2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium (58 mg), The same operation as in Example 3 was carried out using 5-pyrimidine bromide (0.48 ml) to obtain methyl 6- (5-pyrimidyl) -12-naphthyloxyacetate. The obtained methyl 6- (5-pyrimidinyl) -12-naphthyloxyacetate (18 Omg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to give Compound 5 I got

 1H-NMR (DMS0-d6 / TMS):

 0 = 4.21 (2H, s), 7.14-7.21 (2H, m), 7.86-7.89 (3H, m), 8.30 (1H, s), 9.17 (lH, s), 9.26 (2H, s).

 FABMS (m / z): 281 (M + l) +.

Example 6

 Preparation of 6- (3-quinolyl) -1-naphthyloxy acid (compound 6)

 Example using methyl 6-tributylstanninole-2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium (58 mg), and 3-quinoline bromide (0.41 ml) The same operation as in 3 was performed to obtain methyl 6- (3-quinolyl) -12-naphthyloxyacetate. The obtained methyl 6- (3-quinolyl) -12-naphthyloxyacetate (14 Omg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to give Compound 6. Obtained as a solid.

lH-NMR (DMS0-d6 / TMS): 6 = 4.84 (2Η, s), 7.29 (1Η, dd, J = 2.6, 8.9Hz), 7.36 (1H, d, J = 2.3Hz), 7.67 (lH, m), 7.78 (1H, m), 7.96 —8.01 (3H, m), 8.04—8.10 (2H, m), 8.43 (1H, s), 8.77 (1H, d, J = 2.3Hz), 9.40 (1H, d, J = 2.3Hz), 13.07 ( lH, br).

 FABMS (m / z): 330 (M + l) +.

Example 7

 Preparation of 6- (4-isoquinolyl) _2-naphthyloxyacetic acid (compound 7) Methyl 6-triptylstannyl-2-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium (58 mg), The same operation as in Example 3 was performed using isoquinoline 4-monobromide (624 mg) to obtain methyl 6- (4-isoquinolyl) -12-naphthyloxyacetate. The obtained methyl 6- (4- ^ f soquinolyl) _2-naphthyloxyacetate (11 Omg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3. Compound 7 was obtained as a solid.

 lH-NMR (DMS0-d6 / TMS):

 6 = 4.84 (2H, s), 7.29 (1H, dd, J = 2.3,8.9Hz), 7.40 (1H, d, J = 2.3Hz),

 7.64 (1H, dd, J = l.7, 8.3Hz), 7.72-7.83 (2H, m), 7.89-7.99 (3H, m), 8.04 (lH, s), 8.25 (1H, dd, J = 2.0 , 9.2Hz), 8.53 (1H, s), 9.37 (1H, s). FABMS (m / z): 330 (M + l) +.

Example 8

 Preparation of 6- (2,3-dimethyl-1-phenylenolate 3-pyrazolin-5-one-4-yl) -1-naphthyloxyacetic acid (compound 8)

Similar to Example 3 using methyl 6-tributylstannyl-1-naphthyloxyacetate (505 mg), tetrakis (triphenylphosphine) palladium (58 mg), and 4-bromoantipyrine (801 mg). The operation was carried out to obtain methyl 6- (2,3-dimethyl-1-phenyl-2-pyrazolin-15-one-4-yl) _2-naphthyloxyacetate. To the obtained methyl 6_ (2,3-dimethyl-11-phenyl-3-pyrazolin-15-one-14-yl) -12-naphthyloxyacetate (8 Omg), Same as 2N water Reaction with an aqueous solution of sodium oxide was carried out to obtain Compound 8 as a solid. , LH-NMR (DMS0-d6 / TMS):

 δ = 2.44 (3H, s), 3.18 (3H, s), 4.77 (2Η, s), 7.18-7.29 (2Η, m),

 7.35 (1Η, πι), 7.41-7.44 (2Η, m), 7.50-7.53 (2Η, m), 7.63 (lH, m), 7.78-7.86 (2H, m), 7.96 (lH, m).

 FABMSCm / z): 389 (M + l) +.

Example 9

 Preparation of 6- (4-Pyrazolyl) -12-naphthyloxy Acid (Compound 9) 4Pyrazole monobromide (1.5 g) was dissolved in pyridine (20 ml), and acetic anhydride (4.7 ml) was added. And stirred at room temperature for 30 minutes. After the reaction mixture was partitioned with a form-form monosaturated aqueous sodium hydrogen carbonate solution, the form-form layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with hexane to obtain N-acetyl-4-bromopyrazole. Using the obtained N-acetyl-4 monobromide pyrazo monophosphate (567 mg), methinole 6-tryptinoresta / 2 / le 2-naphthy / reoxyacetate (505 mg), and tetrakis (triphenylphosphine) paradigm (58 mg). The same operation as in Example 3 was performed to obtain methyl 6- (N-acetyl-4-pyrazolyl) _2-naphthyloxyacetate. The obtained methyl 6- (N-acetyl-4-pyrazolyl) -12-naphthyloxyacetate (II Omg) was reacted with a 2N aqueous sodium hydroxide solution in the same manner as in Example 3 to give the compound 9 was obtained as a solid.

 1H-Marauder R (DMS0-d6 / TMS):

 δ = 4.77 (2Η, s), 7.18 (1H, dd, J = 2.6, 8.9Hz), 7.23 (1H, d, J = 2.6Hz), 7.75-7.81 (3H, m), 8.05 (1H, s) 8.14 (2H, s), 13.00 (lH, br). FABMS (ra / z): 269 (M + l) +.

Example 10

 Preparation of methyl 6_ (5-tetrazolyl) -1-2-naphthyloxyacetate (Compound 10)

Sodium azide (650 mg) and ammonium chloride were added to a solution of methyl 6-cyano 2-naphthyloxyacetate (1. Og) in DMF (20 ml). (535 mg), and the mixture was stirred at 100 ° C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Then, the residue was purified by a silica gel column (form-form-methanol) to obtain Compound 10 as a solid.

 1H-band R (DMS0-d6 / TMS):

 δ = 3.76 (3Η, s), 4.99 (2H, s), 7.35 (1H, dd, J = 2.3, 8.9Hz),

 7.43 (lH, d, J = 2.3Hz), 8.00-8.11 (3H, m), 8.60 (lH, s).

 FABMS (m / z): 285 (M + l) +.

Example 1 1

 Preparation of methyl 6- (5-hydroxy-1,2,4-oxaziazol-13-yl) -12-naphthyloxyacetate (Compound 11)

 To a solution of hydroxylamine hydrochloride (1.2 g) in water (50 ml) was added sodium carbonate (880 mg), and the mixture was stirred at room temperature for 5 minutes, and then methyl 6-cyano 2-naphthyloxyacetate ( A solution of 2.0 g) in ethanol (50 ml) was added, and the mixture was refluxed for 5 hours. The reaction solution was cooled on ice, and the precipitated solid was collected by filtration and washed with purified water to obtain methyl 6-hydroxyamidino-12-naphthyloxyacetate as a white solid. The obtained methyl 6-hydroxyamidino 2-naphthyloxyacetate (800 mg) was dissolved in pyridine (5 ml), and ethyl chloride formate (0.34 ml) was added. The mixture was heated and refluxed for one day. . After the reaction solution was concentrated under reduced pressure, the residue was dissolved in a small amount of chloroform, ether was added, and the precipitated solid was collected by filtration to obtain Compound 11.

 1H-NMR (DMS0-d6 / TMS):

 6 = 3.75 (3H, s), 4.99 (2H, s), 7.35 (1H, dd, J = 2.6, 8.9Hz),

 7.43 (lH, d, J = 2.3Hz), 7.83 (1H, dd, J = l.7, 8.6Hz), 7.95-7.98 (2H, m), 8.35 (1H, d, J = 1.0Hz), 13.03 (lH, br).

 FABMS (m / z): 301 (M + l) +.

Example 1 2

 6- (5-Hydroxy-1,2,4-oxadiazol-3-yl) Preparation of 12-naphthyloxyacetic acid (Compound 12)

Methyl 6— (5-hydroxy-1,2-, 4-oxaziazol-3-yl) 12-Naphthoxyacetate (190 mg) was dissolved in methanol (5 ml), 1N aqueous sodium hydroxide solution (1.6 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with citric acid, and the precipitated solid was collected by filtration to obtain Compound 12.

 1H-NMR (DMS0-d6 / TMS):

 δ = 4.85 (2H, s), 7.32 (1H, dd, J = 2.6, 8.9Hz), 7.39 (1H, d, J = 2.3Hz), 7.81 (1H, dd, J = 2.0, 8.9Hz), 7.94 -7.98 (2H, m), 8.34 (1H, s), 13.04 (1H, br).

 FABMS (m / z): 285 (M_l)-.

Example 13

 4- [6-(5-Hydroxy-1,2,4-oxodazol-13- ^ fur)-2-naphthyloxymethylcarbonylamino] of methylbenzoic acid (Compound 13)

6- (5-Hydroxy_1,2,4_oxaziazol-13-yl) To a solution of 12-naphthyloxyacetic acid (80 mg) and methyl 4-aminomethylbenzoate (79 mg) in DMF (2 ml) was added N —Hydroxybenzotriazole-hydrate (43 mg), triethylamine (0.04 ml), and 1- (3-dimethylaminopropyl) -1-ethylcarposimid 'hydrochloride (54 mg) were added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-5% aqueous citric acid solution. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a white solid. The obtained white solid was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration to obtain Compound 13.

 lH-NMR (DMS0-d6 / TMS):

 δ = 4.44 (2H, d, J = 6.0Hz), 4.76 (2H, s), 7.31-7.42 (4H, m),

 7.81-7.86 (3H, m), 7.91-8.00 (2H, m), 8.35 (lH, s),

8.84 (1H, t, J = 6.0Hz), 12.88 (1H, br) ₀

FABMS (m / z): 420 (M + l) + ₀ Example 14

 Production of N-2-N ', N, 1-dimethylaminoethyl-1- [6- (5-hydroxy-1,2,4-oxadiazol-3f) 1-2-naphthyloxy] acetamide (Compound 14)

 6- (5-Hydroxy-1,2,4-oxaziazol-1-yl) -12-naphthyloxyacetic acid (80 mg) and 1-amino-12-dimethylaminoethane (28 mg) in DMF (1.5 ml) In water, add N-hydroxybenzotriazo monoluohydrate (43 mg) and 1_ (3-dimethylaminopropyl) -13-ethylcarboimide 'hydrochloride (54 mg), and add at room temperature. Stirred. After the reaction solution was concentrated under reduced pressure, the residue was purified by reverse phase column chromatography (C18, water-acetonitrile) to obtain Compound 14 as a solid.

 1H-Marauder R (DMS0-d6 / TMS):

 δ = 3.05 (6H, s), 3.08-3.17 (2H, m), 3.58-3.62 (2H, m), 4.95 (2Hs),

 7.22 (1H, dd, J = 2.3, 8.9Hz), 7.33 (1H, d, J = 2.3Hz), 7.75-7.91 (3H, m), 8.25 (lH, s).

 FABMS (m / z): 357 (M + l) +.

Example 15

 Preparation of 6- (1,3,5-triazine-2-yl) -12-naphthyloxyacetic acid (Compound 15)

Acetamide (236 mg) and 1,1-dimethoxytrimethylamine (0.64 ml) were stirred at 80 ° C. for 1 hour, concentrated under reduced pressure, and dried to prepare a reaction reagent. Dissolve 2-amidino 6-naphthyl methanesulfonate (282 mg) and potassium t-butoxide (112 mg) in dioxane (5 ml), add the reagent prepared above, and heat to reflux for 2 hours. did. The reaction mixture was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (form-form-ethanol). 3,5-Triazine-2 ^^) 1 2-naphthol was obtained. The resulting 6- (1,3,5-triazine-12- ^ f) -12-naphthol (25 mg) and anhydrous potassium carbonate (46 mg) were suspended in DMF (2 ml), and methyl bromide acetate was added. (0.01 ml) was added and stirred for 1 hour. After partitioning the reaction solution with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was washed with hexane and ethanol. The obtained methyl 6- (1,3,5-triazine-12-yl) -12-naphthyloxycetate (23 mg) was suspended in ethanol (5 ml), and a 2N aqueous sodium hydroxide solution ( 0.2 ml) was added and stirred for 20 minutes. The reaction solution was neutralized with dilute hydrochloric acid and concentrated under reduced pressure. Purified water was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 15.

 lH-NMR (DMS0-d6 / TMS):

 δ = 4.87 (2Η, s), 7.31 (1H, dd, J = 2.3, 8.9Hz), 7.39 (1H, d, J = 2.3Hz),

7.97 (1H, d, J = 8.9Hz), 8.13 (1H, d, J = 9.2Hz),

 8.45 (1H, dd, J = 1.7, 8.6 Hz), 9.06 (lH, s), 9.38 (2H, s).

 FABMS (m / z): 282 (M + l) +.

Example 16

 Preparation of 6- (1-Methyltetrazole-5- ^ f1) -2-naphthyloxyacetic acid (Compound 16)

Dissolve 6-acetoxy-1-naphthoic acid (2.3 g) in DMF (20 ml) and add methylamine hydrochloride (743 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodi. Imide 'hydrochloride (2.1 g), N-hydroxybenzotriazole hydrate (1.5 g), and triethylamine (1.5 ml) were added, and the mixture was stirred at room temperature. The reaction solution was distributed between ethyl acetate and a saturated aqueous solution of ammonium chloride, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained 6-N-methylcarbamoyl-2-naphthyl acetate (730 mg) was dissolved in methanol (10 ml), anhydrous potassium carbonate (415 mg) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction solution was neutralized with dilute hydrochloric acid, purified water was added, and the precipitated solid was collected by filtration to obtain N-methyl-16-hydroxynaphthoic acid amide. The obtained N-methyl-6-hydroxynaphthoic acid amide (201 mg) was dissolved in DMF (4 ml), and t-butylchlorodimethylsilane (196 mg) and imidazole (204 mg) were added. It was stirred. Concentrate the reaction under reduced pressure Thereafter, purified water was added to the residue, and the precipitated solid was collected by filtration to obtain N-methyl-6- (t-butyldimethylsilyl) oxy-12-naphthoic acid amide. The obtained N-methyl-6- (t-butyldimethylsilyl) oxy-1-naphthoic acid amide (145 mg) and sodium azide (90 mg) were dissolved in acetonitrile (5 ml), and trifluoromethanesulfonic anhydride was added. (0.23 ml) and Molecular Sieve 4A (20 Omg) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-form-ethanol). 1-methyltetrazole-5-yl) -2-naphthol was obtained. The obtained 6- (1-methyltetrazole-5-yl) -2-naphthol (25mg) and anhydrous potassium carbonate (46mg) were added to DMF.

(2 ml), added with methyl bromide acetate (0.02 ml), and stirred for 1 hour. The reaction mixture was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was washed with hexane and ethanol to give methyl 6- (1- Methyltetrazole-15-yl) 1-2-naphthoxyacetate was obtained. The obtained methyl 6_ (1-methyltetrazole-1-yl) -12-naphthyloxyacetate was suspended in ethanol (5 ml), and a 2N aqueous sodium hydroxide solution (0.2 ml) was added. Was added and stirred for 20 minutes. The reaction solution was neutralized with dilute hydrochloric acid, concentrated under reduced pressure, purified water was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 16.

 1H-NMR (DMS0-d6 / TMS):

 δ = 4.26 (3H, s), 4.87 (2H, s), 7.35 (1H, dd, J = 2.6, 8.9Hz),

 7.42 (lH, d, J = 2.6Hz), 7.90 (1H, dd, J = 2.0, 8.6Hz), 8.01-8.04 (2H, m), 8.43 (lH, d, J = 1.3Hz), 13.11 (lH , Br).

 FABMS (m / z): 285 (M + l) +.

Example 17

Preparation of 6- (2-imidazolinyl) -12-naphthyloxyacetic acid (compound 17) According to the method of T. Nakayama, et al. [Chem.Pharm.Bull., 41, 117 (1993).] Synthesized, 6— (2-imidazolinyl) — Dissolve 2-naphthyl methanesulfonate (1.1 g) in DMF (5 ml), add triethylamine (1. Om 1) and di-t-butyl dicarbonate (0.86 ml), Stirred. After concentrating the reaction mixture under reduced pressure, the residue was purified by a silica gel column (form-form-methanol), and 6- (1-t-butoxycarbonyl-12-imidazolinyl) -2-naphthol (300 mg) was obtained as a light brown solid. Obtained. The obtained 6- (1-t-butoxycarbonyl-12-imidazolinyl) -12-naphthol (26 Omg) and anhydrous potassium carbonate (115 mg) were suspended in acetone (4 ml), and acetic acid bromide was added. t-Butyl (0.12 ml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified by a silica gel column (hexane monoethyl acetate) to obtain a white solid. The obtained white solid was dissolved in 4N hydrochloric acid-dioxane solution (3.3 ml) and stirred at room temperature for 5 hours. Ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 17.

 1H-Awake R (DMS0-d6 / TMS):

 δ = 4.04 (4Η, s), 4.88 (2H, s), 7.37-7.45 (2H, m), 7.97-8.01 (3H, m), 8.69 (lH, s), 10.80 (2H, s).

FABMS (m / z): 271 (M + l) + ₀

Example 18

 3 -— [2— (6-Hydroxynaphthyl)]-1,2,4

6-Cyanol 2- (2-methoxetoxymethyl) naphthol (3.5 g) was dissolved in ethanol (120 ml), and hydroxylamine hydrochloride (2.8 g) and sodium carbonate (4 g) were dissolved in ethanol (120 ml). A solution of 3 g) in water (80 ml) was added, and the mixture was heated under reflux for 5 hours. After the reaction solution was concentrated under reduced pressure, the solution was extracted with chloroform. After drying the extract from the mouth with anhydrous magnesium sulfate and concentrating under reduced pressure, the residue was purified on a silica gel column (ethyl hexane monoacetate) to give 6_ (2-methoxyethoxymethoxy) naphthalene-1-carboxy. Amidoxime was obtained. The obtained 6- (2-methoxyethoxymethoxy) naphthalene-1-carboxyamidoxime (1.5 g) was dissolved in pyridine (10 ml), and ethyl ethyl formate (0.74 ml) was added. The mixture was heated under reflux for 8 hours. The reaction solution is concentrated under reduced pressure, and is then applied to a silica gel column. Purification with methylene chloride gave 3- (2-methoxyethoxymethoxy-16-naphthyl) -1,2,4-oxadiazol-1-ol 5-ol. The obtained 3- (2-methoxethoxymethoxy-6-naphthyl) -1,1,2,4-oxaziazol-5-ol (1.Og) and 4N hydrochloric acid-dioxane solution (9.5 ml) ) Was added and the mixture was stirred at room temperature for 2 hours. Purified water (500 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes, and the precipitated solid was collected by filtration to obtain Compound 18.

 1H-NMR (DMS0-d6 / TMS):

 6 = 7.17-7.21 (2H, m), 7.74 (1H, dd, J = 1.7, 8.6Hz), 7.80-7.89 (2H, m), 8.27 (1H, d, J = 1.3Hz), 10.16 ( lH, br), 12.93 (lH, br).

 FABMS (m / z): 229 (M + l) +.

Example 19

 Preparation of 6- (5-chloro-1,2,4-oxaziazol-13-yl) -12-naphthyl acetate (compound 19)

 3— [2— (6-Hydroxynaphthyl)] _ 1,2,4-oxoxadiazo-l-uol (26 Omg) is dissolved in pyridine (2 ml) and acetic anhydride (0.1 ml) is added at room temperature. 3 ml) and stirred for 1 hour. Purified water was added to the reaction solution, and the precipitated solid was collected by filtration to obtain 6- (5-hydroxy-11,2,4-oxaziazol-13- ^ fur) -12-naphthyl acetate. 6- (5-Hydroxy-l, 2,4-l-oxaziazol-l- 3-yl) -l-naphthyl acetate (25 Omg) was added to oxyphosphorus chloride (1 ml) and pyridine (0.2 ml). ) And stirred at 80 ° C. for 12 hours. Ice was added to the reaction solution, and the mixture was stirred under ice cooling for 2 hours, and the precipitated solid was collected by filtration to obtain Compound 19.

 1H-Marauder R (DMS0-d6 / TMS):

 δ = 2.36 (3Η, s), 7.44 (1H, dd,] = 2.3, 8.9Hz), 7.79 (1H, d, J = 2.0Hz), 8.02-8.11 (2H, m), 8.20 (1H, d, J = 8.9Hz), 8.66 (1H, s).

 FABMS (m / z): 289 (M + l) +.

Example 20

Preparation of 6- (5-Thioxo-1,2,4,1-oxadiazo-3_yl) -12-naphthol (Compound 20) 6— (5—Mouth — 1,2,4,3-oxaziazolu-3-yl) Dissolve 2-naphthyl acetate (200 mg) in ethanol (20 ml), add thiourea (126 mg) The mixture was refluxed for 6 hours. To the reaction solution was added a 1N aqueous sodium hydroxide solution (4.8 ml), and the mixture was stirred at room temperature for 1 hour. Purified water (100 ml) was added to the reaction solution, neutralized with a 1N aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration to obtain Compound 20.

 lH-NMR (DMS0-d6 / TMS):

 6 = 7.19-7.22 (2H, m), 7.78-7.90 (3H, m), 8.40 (lH, s), 10.19 (lH, br). FABMS (m / z): 245 (M + l) +.

Example 21

 Preparation of 6- (5-carboxymethylthio-1,2,4-oxaziazol-13-yl) -12-naphthyloxyacetic acid (Compound 21)

 6- (5-Thioxo-1,2,4-oxaziazol-1-yl) _2-naphthol (10 Omg) and anhydrous potassium carbonate (141 mg) are suspended in DMF (3 ml), and the suspension is kept at room temperature. Then, t-butyl bromide acetate (0.12 ml) was added thereto, and the mixture was stirred with stirring. The reaction solution was partitioned between ethyl acetate and purified water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (hexane monoethyl acetate) to give t-butyl 6- (5-t-butoxycarbonylmethylthio-1,2). , 4-Oxadiazole-13-yl-2-naphthyloxyacetate was obtained as a yellow oily substance.The obtained t-butyl 6- (5-t-butoxycarbylmethylthio-1,1,2,41) Oxadizazole (13 fl) -12-naphthyloxyacetate (14 Omg) was dissolved in 4N hydrochloric acid-dioxane solution (3.9 ml), and the mixture was stirred at room temperature for 4 hours. )), And the precipitated solid was collected by filtration to obtain Compound 21.

 lH-NMR (DMS0-d6 / TMS):

 δ = 4.32 (2Η, s), 4.83 (2H, s), 7.27-7.36 (2H, m), 7.95 (2H, s) ヽ

 8.04 (1H, d, J = 8.9Hz), 8.51 (1H, s), 13.15 (2H, br).

 FABMS (m / z): 365 (M + l) +.

Example 22 Production of N, N-dimethyl 2- [6- (5-hydroxy-1,2,4-oxaziazol.l-3-yl) -12-naphthyloxy] ethylamine (Compound 22)

3- [2- (6-Hydroxynaphthyl)]-1,2,4-Ioxaziazol-15-ol (15 Omg) and anhydrous potassium carbonate (228 mg) are suspended in DMF (4 ml), and the mixture is suspended at room temperature. 2-Chloro-N, N-dimethylethylamine 'hydrochloride (95 mg) was added thereto, and the mixture was stirred at 80 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and then purified by reversed-phase column chromatography (C18, water-methanol). The obtained product was dissolved in a small amount of methanol, acidified with dilute hydrochloric acid, and ether was added. The precipitated brown solid was collected by filtration to obtain Compound 22.

 lH-NMR (DMS0-d6 / TMS):

 6 = 2.86 (6Η, s), 3.57 (2H, t, J = 5. OHz), 4.51 (2H, t, J = 5.0Hz),

 7.34 (1H, dd, J = 2.3,8.9Hz) 7.52 (1H, d, J = 2.3Hz),

 7.85 (1H, dd, J = 1.6, 8.9Hz), 7.97-8.01 (2H, m), 8.38 (1H, s). FABMS (ra / z): 300 (M + l) +.

Example 23

 4 -— [6— (5-Hydroxy-1,2,4-oxoxadiazo-nor-3-3-inole) -1-2-naphthyloxy] butanoic acid (Compound 23)

 3- [2- (6-Hydroxynaphthyl)]-1,2,4-oxaziazol-l-monool (20 mg) and anhydrous potassium carbonate (182 mg) are suspended in DMF (4 ml), and the suspension is carried out at room temperature. Then, ethyl 4-bromobutanoate (0.13 ml) was added thereto, and the mixture was stirred at 80 for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% aqueous solution of citric acid. The ethyl acetate layer was washed with purified water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-form-methanol) to obtain a colorless oil. The obtained colorless oil was dissolved in methanol (1 ml), 4N aqueous sodium hydroxide solution (1.5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with dilute hydrochloric acid, concentrated under reduced pressure, and then purified by a silica gel column (form-form-methanol-acetic acid) to obtain Compound 23 as a solid.

lH-NMR (DMS0-d6 / TMS): δ = 1.98-2.13 (2H, m), 2.44 (2Η, t, J = 7.3Hz), 4.15 (2H, t, J = 6.6Hz), .7.28 (lH, dd, J = 2.3, 8.9Hz), 7.43 (1H, d, J = 2.3Hz),

 7.81 (1H, d, J = 8.6Hz), 7.91-7.98 (2H, m), 8.32 (1H, s),

 12.14 (lH, br), 12.97 (lH, br).

 FABMS (m / z): 315 (M + l) +.

Example 24

 Preparation of 5- (6-hydroxy-1-naphthyl) -12-oxo_1,3,4-oxathiazole (Compound 24)

 6-Hydroxy-2-naphthamide (300 mg) is suspended in a mixed solvent (30 ml) of toluene-tetrahydrofuran (2: 1), and carbonyl sulfenyl chloride (0.27 ml) is added thereto. Heated to reflux for an hour. After the reaction solution was concentrated under reduced pressure, the residue was suspended in methanol (10 ml) and the insoluble matter was removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was purified by a silica gel column (chloroform-form-methanol) to obtain Compound 24 as a solid.

 111-band 1 (0¾ ^ 0_016, 020 ^ ¥ 8):

 δ = 7.20-7.29 (2H, m), 7.80-8.01 (3H, m), 8.37 (1H, s).

 FABMS (m / z): 246 (M + l) +.

Example 25

 Preparation of 6- (2-oxo-1,3,4_oxathiazol-15-yl) -12-naphthyloxyacetic acid (Compound 25)

5- (6-Hydroxy-2-naphthyl) _2-oxo-1,3,4-oxathiazole (175 mg) and triethylamine (0.59 ml) in DMF (3 ml) solution t-Butyl (0.63 ml) was added, and the mixture was stirred at room temperature for 6 hours. After concentrating the reaction mixture under reduced pressure, purify it on a silica gel column (hexane monoacetate) to obtain t-butyl 6- (2_oxo-1,3,4, oxoxathiazole-1-yl). One 2-naphthyloxyacetate was obtained as a pale yellow solid. The obtained t_butyl 6_ (2-oxo-1,3,4, -oxathiazol-1-yl) -12-naphthyloxyacetate (50 mg) was dissolved in a 4N hydrochloric acid-dioxane solution (50 mg). 4.2 ml) and stirred at room temperature. Hexane in the reaction solution A mixed solution (100 ml) of (1: 1) was added, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration to obtain Compound 25.

 lH-NMR (DMS0-d6 / TMS):

 δ = 4.86 (2Η, s), 7.32 (1H, dd, J = 2.3, 8.9Hz), 7.39 (1H, d, J = 2.3Hz),

 7.95 (2H, s), 8.10 (1H, d, J = 8.9Hz), 8.49 (lH, s), 13.09 (lH, br).

FABMS (m / z): 302 (M_l) _.

Example 26

 Preparation of 6- (4,5-dihydro-1,3-thiazono-1-yl) -12-naphthonone (compound 26)

Dissolve 6-hydroxy-1-naphthoic acid (1.9 g) in ethanol (2 Om 1), add a solution of cesium carbonate (2.4 g) in water (5 ml), and stir at room temperature for 30 minutes. Stirred. After the reaction solution was concentrated under reduced pressure and dried, the residue was suspended in DMF (30 ml), iodinated chill (1. Oml) was added, and the mixture was stirred at 60 ° C for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by a silica gel column (black-mouthed form) to obtain ethyl 6-hydroxy-2-naphthate. The obtained ethyl 6-hydroxy-2-naphthoate (700 mg) and anhydrous potassium carbonate (1.3 g) were suspended in DMF (4 ml), and benzyl dibromide (0.77 ml) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was distributed between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain ethyl 6-benzyloxy-12-naphthoate as a white solid. 2-Aminoethanethiol 'hydrochloride (168 mg) is dissolved in toluene (14 ml), and a 15% triisobutyl phenolic hexane solution (7.4 ml) is added dropwise under a nitrogen stream, and the solution is added for 30 minutes. After heating under reflux, a toluene (15 ml) solution of ethyl 6-benzyloxy12-naphthate (500 mg) obtained above was added dropwise. The reaction solution was heated under reflux for 2 hours, and partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified on a silica gel column (ethyl hexane monoacetate) to give 6- (4,5-dihydro-11,31-thiazol-2-yl) -12-benzyloxynaphthalene as a white solid. . The obtained 6- (4,5-dihydro 1,3 _thiazole-2 f) 1 2 To a mixture of 1-benzyloxynaphthalene (180 mg) and a mixture of trifluoromethanesulfonic acid and thioanisole lute trifluoroacetic acid (1:12:40) (13.3 ml) was added under ice-cooling. Stirred for 50 minutes. The reaction solution was concentrated under reduced pressure, ether was added to the residue, and the precipitated solid was collected by filtration to obtain Compound 26.

 1H-NMR (Acetone-d6 / TMS):

 δ = 3.51 (2H, t, J = 8.6Hz), 4.41 (2H, t, J = 8.6Hz), 7.10-7.15 (2H, m),

7.64 (1H, d, J = 8.6Hz), 7.80-7.84 (2H, m), 8.20 (1H, d, J = 1.7Hz) ₀ FABMS (m / z): 230 (M + l) +.

Example 27

 Preparation of 6- (4,5-dihydro-1,3-thiazo-1-yl-2-yl) -1-naphthyloxyacetic acid (Compound 27)

 6- (4,5-Dihydro-1,3-thiazol-2-yl) -12-naphthyl (12 Omg) and anhydrous potassium carbonate (199 mg) are suspended in DMF (4 ml), and room temperature. Under the atmosphere, methyl bromide acetate (0.09 ml) was added and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% aqueous solution of citric acid. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and methyl 6- (4,5-dihydro-1,3-thiazol-12-yl) -12-naphthinoleoxyacetate (116 mg) ) Was obtained as a yellow solid. The obtained methyl 6- (4,5-dihydro-1,3-thiazonole_2-yl) -12-naphthinoleoxyacetate (10 Omg) was dissolved in methanol (2 ml). A normal aqueous sodium hydroxide solution (1.7 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration to obtain Compound 27.

 1H-NMR (DMS0-d6 / TMS):

 δ = 3.46 (2H, t, J = 8.3Hz), 4.27 (2H, s), 4.42 (2H, t, J = 8.3Hz),

7.15 (lH, s), 7.18-7.23 (2H, m), 7.75 (1H, d, J = 8.9Hz) _N

 7.84-7.94 (2H, m), 8.14 (1H, s).

 FABMS (m / z): 288 (M + l) +.

Example 28

6— (5,6-dihidrogen 4H—1,3-oxazine-1-2-yl) 1-2-naph Preparation of Toll Hydrochloride (Compound 28) To the ethyl 6-hydroxy-12-naphthate (1.Og) synthesized in Example 26 was added 3_amino-11-propanol (695 mg), and the mixture was heated at 120 ° The mixture was stirred at C for 6 hours. The reaction solution was purified by a silica gel column (form-form-methanol in a mouth) to obtain 6-hydroxy N- (3-hydroxypropyl) naphthamide as a pale red solid. 6-Hydroxy-N- (3-hydroxypropyl) naphthoamide (300 mg) was dissolved in isopropyl acetate (10 ml), and thionyl chloride (0.34 ml) was added dropwise thereto. Stirred. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate to obtain Compound 28 as a solid.

 1H-Awake R (DMS0-d6 / TMS):

 δ = 2.26 (2Η, t, J = 5.0Hz), 3.68 (2H, t, J = 5.6Hz), 4.82 (2H, t, J = 5.0Hz),

 7.23-7.26 (2H, m), 7.90 (2H, s) 7.99 (lH, m), 8.57 (lH, s), 10.49 (1H, s), 12.43 (lH, br).

 FABMS (m / z): 228 (M + l) +.

Example 29

 Preparation of 6- (5,6-dihydro-4H-1,3-oxazine-12-yl) -12-naphthyloxyacetic acid hydrochloride (Compound 29)

 6- (5,6-Dihydro-4H-1,3-oxazine-12-yl) -12-naphthol hydrochloride (15 Omg) and anhydrous potassium carbonate (235 mg) were converted to DMF (3 ml). The mixture was suspended, and methyl bromide acetate (0.11 ml) was added thereto at room temperature, and the mixture was stirred under reduced pressure. After the reaction solution was concentrated under reduced pressure, the residue was partitioned with ethyl acetate-5% aqueous solution of citric acid, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (1.7 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified by dropwise addition of a 1N aqueous hydrochloric acid solution, concentrated under reduced pressure, and then purified by a silica gel column (chloroform / methanol / monoacetic acid) to obtain Compound 29 as a solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.24 (2Η, t, J2 5.0Hz), 3.67 (2Η, t, J = 5.9Hz), 4.80 (2H, t, J = 5.OHz),

4.88 (2H, s), 7.36 (1H, dd, J = 2.0, 8.9Hz), 7.42 (lH, s), 8.00 (2H, s), 8.07 (1H, d, J = 8.9Hz), 8.64 (lH, s). -FABMS (m / z): 286 (M + l) + ₀

Example 30

 Preparation of 6- (4,5-dihydro-1,3-oxazole_2-2-yl) -1-naphthinoleoxyacetic acid hydrochloride (Compound 30)

 Using ethyl 6-hydroxynaphthoate (216 mg), 2-aminoethanol (122 mg), and thionyl chloride (0.19 ml), 6- (4,5- Dihydro-1,3-oxazol-13 f) -12-naphthol was obtained as a white solid. The obtained 6- (4,5-dihydro-1,3-oxazol-3-yl) -12-naphthol (45 mg) and anhydrous potassium carbonate (1 16 mg) were added to DMF (2 ml). The suspension was suspended, and methyl bromide acetate (0.06 ml) was added at room temperature, followed by stirring at room temperature. After the reaction solution was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and a 5% aqueous solution of citric acid, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (2.1 ml) was added, and the mixture was stirred at room temperature for 2 hours. A 1N aqueous hydrochloric acid solution was added dropwise to the reaction solution to make it acidic, and the precipitated solid was collected by filtration to obtain Compound 30.

 1H-NMR (DMS0-d6 / TMS):

 δ = 3.99 (2H, t, J = 9.6Hz), 4.44 (2H, t, J = 9.6Hz) 4.82 (2H, s),

7.26 (1H, dd, J = 2.3,8.9Hz) _Λ 7.33 (1H, d, J = 2.3Hz), 7.83-8.01 (3H, m),

8.35 (1H, s), 13.03 (lH, br).

 FABMS (m / z): 272 (M + l) +.

Example 3 1

 Preparation of Methyl 6_ (2-oxo-1H-3,1,2,3,5-oxaxiadiazoyl 4-^^)-1-2-naphthyloxyacetate (Compound 31)

A solution of methyl 6-hydroxyamidino-1-naphthoxyacetate (274 mg) and pyridine (0.32 ml) in tetrahydrofuran (5 ml) was added to a solution of thionyl chloride (0.29 ml) in methylene chloride (3 ml). l) The solution was added dropwise under ice cooling. After stirring the reaction solution at 0 ° C for 30 minutes, ethyl acetate-saturated sodium hydrogen carbonate The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by a silica gel column (ethyl acetate) to obtain Compound 31 as a solid.

 1H-NMR (DMS0-d6 / TMS):

 δ = 3.74 (3H, s), 4.97 (2H, s), 7.31-7.42 (2H, m), 7.84-8.00 (3H, m),

8.38 (1H, s), 12.22 (lH, br).

 FABMS (m / z): 321 (M + l) +.

Example 32

Preparation of 6- (2-imidazolyl) -1-2-naphthyloxyacetic acid (Compound 32) N-Pendinoleoxycarbonyl-6-hydroxynaphthalene-1-carboxyamidine (2.7 g) and anhydrous potassium carbonate (3.5 g) was suspended in DMF (40 ml), and ethyl bromide acetate (1.2 ml) was added, followed by stirring at room temperature. The reaction mixture was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was solidified from ethanol in the form of ethanol to form ethyl 6_ (N —Benzyloxycarboninolea midino) One 2-naphthyloxyacetate was obtained. The obtained 6- (N-benzyloxycarbonylamidino) -12-naphthyloxyacetate (1.5 g) was dissolved in ethanol (30 ml), and 10% palladium on activated carbon (300 mg) was dissolved. Acetic acid (0.21 ml) was added, and the mixture was stirred for 2 hours under a hydrogen stream. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration to obtain ethyl 6-amidino 2-naphthyloxyacetate acetate. The obtained ethyl 6-amidino 2-naphthyloxyacetate 'sulfate (40 Omg) was dissolved in dioxane (1 Oml), and acetoaldehyde getylacetal bromide (3.6 ml) and Triethylamine (0.33 ml) was added, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure and purified with a silica gel column (form-form-ethanol) to obtain ethyl 6- (21 / f midazolyl) -12-naphthyloxyacetate. The obtained ethyl 6- (2-imidazolyl) -12-naphthyloxyacetate (10 Omg) was suspended in ethanol (9 ml), and a 2N aqueous sodium hydroxide solution (1. Oml) was added. And stirred for 20 minutes. After neutralization with dilute hydrochloric acid, add ethanol to the reaction mixture. Then, the precipitated solid was collected by filtration to obtain Compound 32. , LH-NMR (DMS0-d6 / TMS):

 6 = 4.64 (2H, s) ヽ 7.18-7.22 (4H, m), 7.80-7.85 (2H, m),

 8.04 (1H, dd, J = l.7,8.6Hz), 8.36 (1H, d, J = l.0Hz).

 FABMS (m / z): 267 (M-1)-.

Example 3 3

 Preparation of 6- (1,2,3-triazo-1-yl) _2-naphthyloxyacetic acid

6-Hydroxy-2-naphthaldehyde (172 mg) and anhydrous carbon dioxide (415 mg) are suspended in DMF (10 ml), and t-butyl bromide acetate (0.19 ml) is added. Stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, it was partitioned with ethyl acetate-purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane monoacetate) to obtain t-butyl 6-formyl-12-naphthyloxyacetate. The obtained t-butyl 6-formyl-12-naphthyloxyacetate (lO Omg) was dissolved in methanol (5 ml), and nitromethane (5 ml) and ammonium acetate (27 Omg) were added. And stirred at room temperature for 3 hours. After partitioning the reaction solution with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified with a silica gel column (ethyl hexane monoacetate). After the obtained product was dried, it was dissolved in DMF (5 ml), sodium azide (22 mg) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was partitioned with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified on a silica gel column (ethyl hexane monoacetate) to give t-butyl 6 — (1,2,3-triazol-1-yl) 1-2-naphthyloxyacetate was obtained. The obtained t-butyl 6- (1,2,3-triazole-4) -l-naphthyloxyacetate (22 mg) was dissolved in ethanol (2 ml), and a 4N hydrochloric acid-dioxane solution was added. (0.17 ml) was added and stirred for a while. The reaction solution was concentrated under reduced pressure, and the precipitated solid was collected by filtration and washed with ethanol to obtain Compound 33.

. 1

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Compound No R1 A

 H

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 33 CH2COOH

 V \ II

Formulation example 1 (tablets)

 Compound of the present invention 10.0 g

 Lactose 9.0 g

 Hydroxypropinole cellulose 2.O g

 Microcrystalline cellulose 7.7 g

 0.3 g of magnesium stearate

 Tanorek 1.0 g

Formulation Example 2 of a _c- Formulation as a Tablet Containing 10 Omg of the Compound of the Present Invention According to the Conventional Method (Injection)

 1 mg of the compound of the present invention

 5ml glucose injection 2ml

 The above is taken as an injection by a conventional method.

Formulation example 3 (suppository)

 Compound of the present invention 10 mg

 Cocoa butter

 The above is used as a suppository in a conventional manner.

Since the compound of the present invention has a fibrinolytic promoting action and exhibits an excellent thrombolytic action, it is effective for diseases caused by thrombus. Various types of thrombosis, including venous thrombosis, myocardial infarction, pulmonary embolism, cerebral infarction, atrial thrombus in atrial fibrillation, disseminated intravascular coagulation (DIC), diabetic complications, and slowly progressing cerebral thrombosis Treatment of thromboembolism associated with vascular surgery and extravasation and improvement of blood flow, prevention or treatment of restenosis or reocclusion after percutaneous transluminal coronary angioplasty (PTCA), chronic arterial occlusion Treatment of thrombosis and embolism associated with ischemic cerebrovascular disease, as a therapeutic agent for thromboembolism in general, as a thrombolytic agent, antithrombotic agent alone, or as a thrombolytic agent It can be used in combination with a therapeutic agent for thrombosis.

 The following experimental examples proved that the compound of the present invention has a fibrinolysis-promoting action and exhibits an excellent thrombolytic action, and is effective for diseases caused by thrombus.

 (1) Plasmin formation promoting activity

The present compound, 1 X 1 0- ² was dissolved in dimethyl sulfoxide (DMS O) such that M, 2 Omm phosphate buffer solution containing the prepared solution 0. 1 5 M sodium chloride (p H 7. 1. 2 X 1 0 4) - diluted ³ M, to prepare the present compound solution. Glutamate-type human plasminogen (final concentration: 0.1 μΜ), human recombinant t-PA (final concentration: 50 / M) and the compound solution of the present invention (final concentration: 300 μΜ) were each added to a 96-well microplate. Add 50/1 to the titer plate and incubate at 37 ° C for 1 hour. Then, a synthetic substrate solution (S-2251, 2 mM), which is a plasmin substrate, is added to each well at a ratio of 50/1, and immediately after the addition, the absorbance (A1) at 405 nm is measured. Then, incubate again at 37 ° C for 15 minutes, and measure the absorbance (A 2) at 405 nm. The difference between the obtained absorbances (A1 and A2) and the ratio to the control (control) can be determined to determine the plasmin formation promoting activity. As a result, it was revealed that the compound of the present invention has an excellent plasmin formation promoting action. Table 2 shows the results.

Table 2

(2) Effect of oral administration on improving lethality in mouse lung thrombosis lethal model

The experiments were performed using 15 to 20 dd Y male mice, 6 weeks old, per group. The compound of the present invention was suspended in distilled water to give lmgZkg (lOml) and orally administered to a mouse that had been fasted for 4 hours. Distilled water was orally administered to the disease control group. Six hours after the administration, thrombin (1 OUZm 1) was administered at a dose of 1 ml from the tail vein to induce thrombus. The next day, death and death were confirmed, and the survival rate was determined. Table 3 shows the results. Table 3

(3) Effect of intravenous administration on the lethality of mouse pulmonary thrombotic lethal model The experiment was carried out using 15-20 dd Y male mice 6 weeks old in one group. The compound of the present invention was dissolved in a 5% glucose solution to a concentration of 0.1 mgZkg (10 ml), and administered through the left tail vein of a mouse fasted for 4 hours. The disease control group was similarly administered a 5% Darcos solution. Fifteen minutes after the administration, thrombin (10 UZm 1) was administered at a dose of 1 ml from the right tail vein to induce thrombosis. The next day, survival and death were confirmed, and the survival rate was determined. Table 4 shows the results.

 Table 4

Industrial applicability

 According to the present invention, there are provided an antithrombotic agent and a thrombolytic agent which have a fibrinolysis promoting action and can be orally administered.

Claims

The scope of the claims

1. Equation (1)

(In the formula, R 1 represents a hydrogen atom, an R 2 -carbonyl lower alkyl group or an R 3 -lower alkyl group, and R 2 represents a hydroxyl group, a lower alkoxy group, a lower alkylamino group having a substituent, or a lower alkyl group. R 3 represents a phenyl group having a substituent, an amino group having a substituent or a hydroxyl group,

 A is

Represents

 R 4 represents a hydrogen atom or a lower acyl group,

 X represents an oxygen atom or a sulfur atom,

 R 5 represents a halogen, a hydroxyl group, a mercapto group, one OR 6 or one SR 6,

R 6 represents a lower alkyl group or R 7 -carbonyl lower alkyl group, R 7 represents a hydroxyl group or a lower alkoxy group, R 8 represents a hydrogen atom or a lower alkyl group,

 Y represents one (CH2) n-(n = 2 or 3) or one CH = CH-, and P represents _NH-, an oxygen atom or a sulfur atom. )

(However, when R 1 represents a hydrogen atom, A

(Y does not represent — (CH2) n_, n = 2 and P represents an oxygen atom or —NH—). )

And salts thereof and solvates thereof.

2. 6— (2-Chenyl) -1-2-naphthyloxyacetic acid, 6— (2-pyridyl) —2-naphthyloxyacetic acid, 6— (5-pyrimidinyl) 1-2-naphthyloxyacetic acid, 6— (3-quinolyl) 1- 2-naphthyloxyacetic acid, 6_ (4- ^ f soquinolyl) 1- 2-naphthyloxyacetic acid, 6- (2,3-dimethyl- 1-phenyl-13-pyrazoline-15-one-1 4-f) 1-2-naphthyloxy Acetic acid, 6- (4-pyrazolyl) -1-2-naphthyloxyacetic acid, methyl 6- (5-tetrazolyl) 1-2-naphthyloxyacetate, methyl 6- (5-hydroxy-1-1,2,4-) 1-Naphthyloxyacetate, 6- (5-Hydroxy-1,2,4,1-xylaziryl 3-yl) _2-Naphthyloxyacetic acid, 4- [6— (5—Hydroxy-1,2,4-oxoxadiazole-3 12-naphthyloxymethylcarbonylamino] methylbenzoic acid, N-2-N ', N'-dimethylaminoethyl [6- (5-hydroxy-1,2,4-oxoxadizole-13) —Yl) —2—naphthyloxy] acetamide, 6— (1,3,5—triazine-1-yl) -12-naphthyloxyacetic acid, 6— (1-methyltetrazole-5-yl) -2— Naphthyloxyacetic acid, 6- (2-imidazolinyl) -1-2-naphthyloxyacetic acid, 3- [2- (6-hydroxynaphthyl)]-1,2,4-oxadiazol-5-ol, 6- ( 1,2-naphthyl acetate, 6- (5-thioxa 1,2,4-oxadiazol-3-yl) 1-2-naphthol , 6— (5—Carboxyme Tylthio-1,2,4-oxaziazol-3-yl) -2-naphthyloxycarboxylic acid, N, N-dimethyl-1-2- [6- (5-hydroxy1,2,4-oxaziazol-1) 3- (yl) 1-2-naphthyloxy] ethylamine, 4- [6- (5-hydroxy1,2,4,1-oxaziazo-l 3-yl) 1-2-naphthyloxy] butanoic acid, 6- (4,5 —Dihydro 1,3—thiazol-2-yl) 1—2-naphthone, 6— (4,5-dihydro 1,3 _thiazono 1—2—yl) 1-2—naphthyloxyacetic acid, 6— (5,6-dihydro-4H-1,3-oxazine-12-yl) 1-2-naphthyloxyacetic acid'hydrochloride, 6- (4,5-dihydro-1,3-oxazole-2-yl ) — 2-naphthyloxyacetic acid 'hydrochloride, methyl 6- (2-oxo- 1 3H- 1,2,3,5-oxoxathiazol-1-41 ^) f)) 2-Naphthyloxyacetate, 6- (2 ^ f midazolyl) 1-2-Naphthyloxyacetic acid, 6- (1,2,3-Triazole-4-yl) — 2-Naphthyloxyacetic acid.

 3. A pharmaceutical composition comprising the compound according to any one of claims 1 or 2.

 4. The thrombolytic agent according to any one of claims 1 to 3.

 5. The fibrinolysis promoter according to any one of claims 1 to 3.

 6. The antithrombotic agent according to any one of claims 1 to 3.

 7. Equation (2)

(Where B is

Represents )

Compound represented by