WO2000031045A1 - Naphthalene derivatives - Google Patents

Abstract

Naphthalene derivatives represented by general formula (1), which exhibit an excellent fibrinolysis accelerating effect and are useful as orally administrable antithrombotic or thrombolytic agents wherein R1 and R2 are different from each other, and R1 is hydrogen, hydroxyl or the like and R2 is hydrogen, halogeno or the like; and R3 is formula (2) or (3).

Description

 Description Naphtalene Inductor Technical Field

 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 blood vessels and keeps blood flow. When a thrombus is formed in a blood vessel, vascular endothelial cells produce and secrete tissue plasminogen activator (t-PA) due to the stimulation of ischemia. t-PA converts inactive plasmaminogen present in the blood to active 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, 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 that administer PAs to dissolve thrombus, that is, thrombolytic therapy (fibrinolytic therapy) 1) 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). Genetic recombinants and the like are known.

 However, since these existing thrombolytic drugs are all protein preparations, they have a short half-life in the blood, are rapidly metabolized in the liver, and have an inhibitory factor in the living body. In order to achieve thrombolytic effects, large doses are required. In clinical practice, it has been reported that the higher the dose, the higher the rate of recurrent flow. However, such a transient large dose of a thrombolytic agent significantly enhances the thrombolytic activity systemically, resulting in thromboembolism. While the site is expected to open, severe side effects of bleeding are noted. 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 naphthalene derivatives have an excellent fibrinolysis-promoting action and are extremely useful as antithrombotic agents and thrombolytic agents. That is, the present invention provides the following formula (1)

 Equation (1)

(式中、 R 1と R2は異なって、 Rlは水素原子、 水酸基、 置換基を有していて も良い低級アルコキシ基、 低級アルコキシカルボニルォキシ基、 置換基を有する 低級アルキル基、 置換基を有する低級アルケニル基、 一 COOHまたは

(Wherein R 1 and R 2 are different, and Rl represents a hydrogen atom, a hydroxyl group, a lower alkoxy group which may have a substituent, a lower alkoxycarbonyloxy group, a lower alkyl group having a substituent, a substituent Having a lower alkenyl group, one COOH or

-CONH-R12 (R12 is a lower alkyl group having a substituent), R2 is a hydrogen atom, a halogen atom or one CH2 CONH—R13 (R13 is a hydrogen atom or Lower alkyl group having a substituent)

 R3

(R 10 represents an oxygen atom or NH, R 11 represents a lower alkoxycarbonyl lower alkyl group),

 R5 and R6 may be the same or different,

 R5 represents a hydrogen atom, a hydroxyl group, an amino group or a lower alkyl group,

 R6 represents a hydrogen atom, a hydroxyl group, a halogen atom, —OS 03H or a substituted lower alkoxy group;

 R7 represents a hydroxyl group, a lower alkyl group, an amino group or a lower alkoxy group, R8 represents a hydrogen atom, a lower alkoxycarbonyl group, —COOH, a cyano group or an amidino group,

 R9 represents a linear or branched alkyl group having 1 to 7 carbon atoms which may have an amino group as a substituent.

 Or equation (2)

W 0 (2)

W 0

 Four

 (In the formula, R4 represents a hydroxyl group or —〇CH 2 COO—R 14 (R 14 is a hydrogen atom or a lower alkyl group).)

 And salts thereof, solvates thereof, and antithrombotic agents and thrombolytic agents containing them as active ingredients. Furthermore, the present invention provides novel compounds (compounds 21, 29, 38, 86, and 91) useful as intermediates for the synthesis of the compounds represented by formula (1) or (2). ) Is also provided.

In the present invention, a lower alkyl group as a part of a lower alkyl group or a lower alkoxy group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methyl group, Examples include ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butynole group, tert-butyl group, pentyl group and hexyl group. The lower alkenyl group is a linear or branched alkenyl group having 1 to 6 carbon atoms, and specifically includes, for example, a vinyl group, an aryl group, a butenyl group, a pentyl group, and a hexenyl 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) or (2) of the present invention can be converted into a pharmacologically acceptable salt, or the resulting salt can be converted into a free base or a free acid, if necessary. You can also. Further, those compounds may be solvates. Examples of the salt include a pharmacologically acceptable acid addition salt, metal salt, ammonium salt, organic amine salt, and amino acid addition salt. Specifically, acid addition salts include inorganic acid salts such as hydrochloride, phosphate, sulfate, etc., and organic acid salts such as acetate, citrate, methanesulfonate, etc., and sodium salts as metal salts. Alkali metals such as potassium salts, potassium salts, etc., alkaline earth metal salts such as magnesium salts, calcium salts, aluminum salts, etc., and ammonium salts, such as ammonium salts, and organic amine salt addition salts. Addition salts such as morpholine and piperidine are mentioned. Amino acid force [I salts include addition salts such as glycine and lysine. Examples of the solvates include hydrates. There are tautomers of the pyrimidine derivative, and any tautomers are the compounds of the present invention. Further, among the compounds of the present invention, 2- (6-benzyloxy-2-naphthyl) -6-methylpyrimidin-1-ol (compound 26) is disclosed in It is a known compound described in 10-109978, but nothing is known about its pharmaceutical use.

 The novel and known compounds represented by the formula (1) or (2) of the present invention can be synthesized by known methods.

 Hereinafter, typical production methods of the compounds represented by the above formulas (1) and (2) of the present invention will be described.

 Preparation of 2- (6-alkoxy-2-naphthyl) pyrimidine derivative [Formula (5)]

R15

(In the formula (3), R 15 represents a lower alkoxycarbonyl group, a lower acyl group or a cyano group, R16 represents a hydrogen atom, a lower alkoxyalkenyl group or a lower alkyl group which may have a substituent, R17 represents a lower alkyl group; in the formula (5), R18 and R20 may be the same or different; each represents a hydrogen atom, a lower alkyl group, an amino group or a hydroxyl group; and R19 has a hydrogen atom or a substituent. Represents a lower alkyl group, a lower alkoxycarbonyl group or a cyano group which may be

 In the formulas (4) and (5), R1 and R2 are as described above.

 As a general method for synthesizing a pyrimidine derivative, a pyrimidine synthesis method for Pinner [G. W. Kennner, SirA. Todd, "PirimidineanandidItsDe rivatatives", inR.C.

Elderfield, Heterocyclic Compound, Vol. 6, 234. (1957)] is known. That is, a pyrimidine derivative can be produced by carrying out a [3-diketone derivative and a substituted amidine derivative in the presence or absence of an appropriate base in a solvent or without a solvent at room temperature to 150 ° C. The [3-diketones used are] 3-ketoaldehyde,) 3-dialdehyde, β —Keto esters, j3-dicarboxylic acids or their equivalents are used. By selecting the type of the functional group of the 3-diketone substituent, hydrogen, a substituted or unsubstituted alkyl group, a hydroxyl group, an amino group or a cyano group can be introduced at the 4-position (6-position) and 5-position of pyrimidine. A pyrimidine derivative can be produced. According to Scheme A, the 2-amidino 6-naphthol derivative (formula (4)) and its inorganic or organic acid salt are dissolved in a suitable solvent, for example, anhydrous methanol, anhydrous ethanol, or acetonitrile. By reacting with a substituted-diketone equivalent represented by the formula (3) in the presence of a base, a compound represented by the formula (5) can be produced. For example, if 6-amidino-2-naphthol is used as the compound represented by the formula (4) and ethyl acetate acetate is used as the compound represented by the formula (3), the compound represented by the formula (5) is 2- (6 —Hydroxie 2-naphthyl) _ 6-Methylpyrimidin-4-ol. The resulting 2- (6-hydroxy-2-naphthinole) -1-6-methylpyrimidine-14-ol is composed of 2- (6-hydroxy-12-naphthyl) -13--6-methylpyrimidine-14-one. There is a tautomeric relationship, and both compounds are equivalent. The pyrimidine derivative described in the present invention shows both tautomers unless otherwise specified.

 The base referred to herein is an inorganic base such as sodium, alkoxyalkali metal (for example, sodium methoxide), potassium carbonate, sodium carbonate, sodium hydroxide or the like, or an organic base such as triethylamine or pyridine. The base described in the present invention is the same as described above unless otherwise specified.

 Using the protected acetal of malonaldehyde in place of the compound represented by the formula (3), Tiansheng Wang et al., Fe [Synth. Commun., 2521 (1997). A pyrimidine derivative represented by the formula (5) can be synthesized.

In the formula (5), the functional groups represented by Rl, R2, Rl8, Rl9, and R20 can be converted to other functional groups by a known method. For example, the hydroxyl group is reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride or phosphorus trichloride in a suitable solvent or in the absence of a solvent in the presence or absence of a base such as triethylamine or pyridine. Can be converted to a base. Alternatively, in a suitable solvent, In the presence, it can be converted to a substituted or unsubstituted lower alkoxy group by reacting with a substituted or unsubstituted lower alkyl halide. Alternatively, the compound can be converted to a hydroxysulfonyloxy group by reacting with an isopropyl trioxide / N, N-dimethylformamide complex in a suitable solvent. The cyano group is based on the P inner method [R.

Roger, D. Neilson, Chem. Rev. 61, 179 (1961). ] Can be converted to an amidino group. The alkoxycarbonyl group can be converted to a carboxyl group by reacting with an appropriate base such as sodium hydroxide or potassium hydroxide in an appropriate solvent. The carboxyl group can be formed in an appropriate solvent in the presence or absence of additives such as 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole hydrate (HOB t), p-ditrophenol, and triethylamine. , 1- (3-Dimethylaminopropyl)-3-Ethylcarbodimid hydrochloride (WS C · HC 1), N, N '-Dicyclohexylcarbodiimide (DCC), Benzotriazole Condensing agents and amino derivatives such as 1 1 ^^-fluorooxytris- (dimethylamino) phosphonium hexafluorophosphate (BOP reagent), 2-chloro- 1-methyl-pyridinium iodide, diphenylphosphoryl azide By reacting, it can be converted to the corresponding amide compound. The substituted or unsubstituted amino group can be converted to the corresponding amide compound by reacting with a condensing agent and a carboxylic acid derivative in a suitable solvent in the presence or absence of the above-mentioned additive.

 The above conversion can also be performed on a compound represented by the formula (4), which is a precursor of the pyrimidine derivative (formula (5)), in which case, in order to obtain the target compound, Each functional group may be protected with an appropriate protecting group in advance. Methods for introducing and removing protecting groups commonly used in organic synthetic chemistry are described in, for example, T.W.

 reen, Protectivecroupsin Organic Synthesis, 2nd Ed. ", John Wiley & Sons, 199. 1. The above method is an example, and other equivalent known methods are used. Method can also be used.

Preparation of 6-amidino-2-naphthoic acid derivative (formula (8)) and 11-amidino-6-naphthol derivative (formula (11)) Scheme B

 Equation (6) Equation (7) Equation (8)

(In the scheme, R 21 represents a lower alkoxy group, a hydroxyl group or a halogen atom)

 Formula (9) Formula (10) Formula (11) (in the scheme, R4 represents a hydroxyl group or one OCH2COO—R14 (R14 represents a hydrogen atom or a lower alkyl group))

 The compounds represented by the formulas (8) and (11) can be produced by the same synthesis method using naphthoic acid derivatives (compounds represented by the formulas (6) and (9)) as starting materials. That is, a naphthoic acid derivative (compounds represented by the formulas (6) and (9)) is converted to an acid halide with a halogenating agent such as dithithionyl salt in an appropriate solvent or without solvent, and then reacted with ammonia. Naphthoic acid amide derivative (compound represented by formula (7) and formula (10))

Me r we inn method [R.F.Borch, Te t r ah e dron

According to Let et., 61 (1968).], An amidine derivative (represented by the formula (8) and the formula (11)) is obtained by converting a carbamoyl group into an alkoxycarbonimidyl group and then reacting with ammonia. Compound) can be produced. Alternatively, the compounds represented by the formulas (7) and (10) may be converted to a cyano group by using a thionyl chloride or the like, and then the formulas (8) and (8) may be obtained by using the Pinner method described above. The compound represented by the formula (11) can be produced. You. The compound represented by the formula (8) or the formula (11) can be converted into various pyrimidine derivatives by the method shown in Scheme A.

 The above method is an example and other equivalent known methods can be used.

 Preparation of 2-Cyanonaphthalene Derivatives Having a Substituted Alkenyl Group at the 6-Position (Formula (14))

 Scheme D

 R23

R24

 Equation (1 2) Equation (1 4)

(In the formula (12), R22 represents a halogen atom, represents a trifluoromethanesulfonyloxy group or the like, and in the formulas (13) and (14), R23 and R24 are the same or different. , Hydrogen, cyano, substituted or unsubstituted lower alkyl group or lower alkoxycarbonyl group)

 Using the compounds represented by the formulas (1 2) and (1 3), R. F. Heck, al l a d i um R e a g e n t s in n O r g a n i c

 S y n t e s i s., A Ca d em i c P r e s s N e w Y o r k, 1 98 5. Alternatively, J. T s u ji, "P a l a d i um

 R e ag e n t s a n d C a t a ly s t s. ", W i l e y,

The compound represented by the formula (14) can be produced by performing the Heck reaction using the method described in Chichester, 1999.5. For example, when 6-cyano-12-naphthyl trifluoromethansulfonate is used as the compound represented by the formula (12), and methyl acrylate is used as the compound represented by the formula (13), the compound represented by the formula (14) As a result, methyl 3- (6-cyano-1-naphthyl) atalylate is obtained. When an alkyl ester of 3-butenoic acid or an alkyl ester of 4-pentenoic acid is used for the compound represented by the formula (13), the compound represented by the formula (14) has 4 or 5 carbon atoms, respectively. A 6-cyanonaphthalene derivative into which an alkenyl carboxylic acid alkyl ester has been introduced can be produced. The obtained compound represented by the formula (14) can be converted into various pyrimidine derivatives after converting a cyano group into an amidino group by the methods shown in schemes A and B.

 The above method is an example, and other known methods can be used.

 Preparation of 2-naphthol derivative having a substituted alkenyl group at the 6-position (Formula (16)) Scheme E

 R23

R24

(In the formulas (15) and (16), R25 represents a substituted or unsubstituted lower alkyl group, lower acyl group or arylalkyl group, and in the formula (15), R22 is as defined above. Wherein, in the formula (16), R 23 and R 24 are as defined above. Using the compound represented by the formula (15) and the compound represented by the formula (13), the compound represented by the formula (14) The compound represented by the formula (16) can be produced by using the same synthesis method as the compound to be prepared. For example, a 6-bromo-1-naphthol derivative is used as the compound represented by the formula (15), and acrylonitrile is used as the compound represented by the formula (13). 6- (2-cyanoetur) -12-naphthol derivative is obtained. When allylicyanide is used as the compound represented by the formula (13), a 2-naphthol derivative represented by the formula (16) into which a cyanoalkenyl group having 4 carbon atoms is introduced can be produced. When there is no alkenyl nitrile compound corresponding to the desired number of carbon atoms, the alkenyl carboxylic acid can be converted to the corresponding alkenyl nitrile by the method shown in Scheme B. The obtained compound represented by the formula (16) can be converted into various pyrimidine derivatives after converting a cyano group into an amidino group by the methods shown in Schemes A and B. In the formula (15), R 25 is a hydrogen atom In this case, the hydroxyl group is protected with a protecting group described in Scheme A, or in a suitable solvent in the presence of an organic base such as triethylamine or pyridine or in the presence of an inorganic base such as potassium carbonate or sodium carbonate. The Heck reaction can also be used after reacting with a nodogen compound to form an ether compound. The above method is an example, and other equivalent known methods can be used.

 Preparation of naphthylmethylenehydantoin derivative (Formula (20)) Scheme F

式 (1 7) 式 (1 9)

Equation (1 7) Equation (1 9)

 In the formula (20) (in the formula (20), R26 represents a lower alkyl group having a substituent, Ri i is as described above, and in the formulas (18), (19) and (20) , R 10 is as described above)

After dissolving the compounds represented by formulas (17) and (18) in a suitable solvent, for example, a solvent such as DMF, methanol, ethanol, dimethyl sulfoxide, ethyl acetate or a mixed solvent, and then dissolving a suitable base The compound represented by the formula (19) is obtained by heating under the following conditions. For example, when 1-methylhydantoin is used as the compound represented by the formula (18), 5- (6-hydroxy-12-naphthylmethylene) -11-methylhydantoin is used as the compound represented by the formula (19). can get. The obtained compound is present in an organic solvent such as DMF, acetone, etc. in the presence of a suitable base. By reacting with a substituted alkyl halide below, a compound (formula (20)) in which an alkyl group having a substituent at corresponding R 11 and R 26 is introduced can be produced. For example, when methyl bromide is used in the substituted alkyl halide in an equivalent amount, 1-methyl-13-methoxycarbonylmethyl 5- (6-methoxycarbonyl-methoxy-12-naphthylmethylene) hydantoin (Formula (20) )) Is obtained. The above method is an example, and other known methods can be used.

 Pharmaceuticals containing a naphthalene derivative represented by the general formula (1) or (2) and a salt thereof or a solvate thereof as an active ingredient are generally 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 capsules, 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. They may be administered alone, but 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 preparations. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or the like, or provided as dry syrups in water or other suitable solvents before use. Is also good. Said solutions may contain conventional 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, glycerated gelatin, witepsol, sodium stearate or mixtures thereof, and emulsifiers, suspending agents, and preservatives as necessary Agents and the like can be added. Injectables include aqueous or distilled water for injection, which can constitute a ready-to-use dosage form, physiological saline, 5% dextrose solution, propylene glycol, or other solubilizers or solubilizers, pH regulators, isotonic Pharmaceutical components 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 metasilicate, aluminum hydroxide, magnesium hydroxide, magnesium silicate, charcoal Calcium acid, magnesium carbonate, light caffeic anhydride, caffeic anhydride, Avicel, various starches, dextrin, carboxymethyl starch (CMS), lactose, etc. Binders: Ethyl cellulose (EC), carboxymethyl cellulose Na (CMC-Na), low-substituted hydroxypropyl cellulose (L-HPC), hydroxypyl propylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxy Propyl cellulose (HPC), various starches, dextrins, sodium alginate, gelatin, polybutyl alcohol (PVA), polybutylpyrrolidone (PVP), etc.

Disintegrators: synthetic aluminum silicate, magnesium aluminate metasilicate, CMC—Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CMS, hydroxypropyl starch (CPS), 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, sodium kuninate, 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 promoters: 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 ester, polyoxyethylene polyoxypropylene glycol, propylene glycol, lauryl sulfate Na, various natural 'synthetic cyclodex Trin and others.

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, hydroxypropyl methylcellulose phthalate ( HPMCP), MC, HPC, sodium alginate, polyvieraceta rubetylaminoacetate, polyacrylic acid Na, copolymers of various acrylic acid or 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 dosage varies depending on the age, symptoms, etc. of the patient.In general, for adults, about 1 mg to 100 mg / person / day for oral or rectal administration, It is about 0.1 to 50 Omg / person / day for injection. 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, but the present invention is not limited to these examples.

Example 1

 Preparation of 2- (6-hydroxy-2-naphthyl) -1-6-methylpyrimidin-1-ol (Compound 1)

 After dissolving sodium metal (1.8 g) in anhydrous methanol (100 ml) to prepare a methanol solution of sodium methoxide, 2-amidinol 6 _ naphthol 'methanesulfonate (10 g) and acetate acetate Then, ethyl (5 ml) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction solution was neutralized with a 1N aqueous hydrochloric acid solution, ethanol (200 ml) was added, and the mixture was stirred for 10 minutes. The precipitated solid was collected by filtration to obtain Compound 1.

 lH-NMR (DMS0-d6 / TMS):

δ = 2.30 (3H, s), 6.19 (1H, s), 7.16-7.20 (2 to I, m), 7.79 (1H, d, J = 8.6Hz), 7.89 (1H, d, J = 8.9Hz), 8.12 (1H, dd, J = 1.7, 8.9Hz), 8.64 (1H, s)

 F ABMS (m / z): 253 (M + 1) +

Example 2

 Preparation of ethyl 4-hydroxy-2- (6-hydroxy-1-naphthyl) -1,5-pyrimidinecarboxylate (Compound 2)

 After dissolving sodium metal (897 mg) in anhydrous ethanol (50 ml) to prepare a solution of sodium methoxide in ethanol, 2-amidinol 6-naphthol 'methanesulfonate (5 g) and ethoxymethylene malonate getyl ( 3. 9 ml) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction solution was neutralized with a 1N aqueous hydrochloric acid solution, ethanol (200 ml) was added, the mixture was stirred for 10 minutes, and the precipitated solid was collected by filtration to obtain Compound 2.

 lH-NMR (DMS0-d6 / TMS):

 δ = 1.30 (3Η, t, J = 6.9Hz), 4.27 (2H, dd, J = 6.9, 14.2Hz), 7.10-7.33 (2H, m), 7.82 (1H, d, J = 8.9Hz), 7.93 (1H, d, J = 9.9Hz), 8.14 (1H, dd, J = 1.7, 8.9Hz), 8.66 (1H, s), 8.75 (1H, s), 10.23 (1H, s), 13.12 ( 1H, br)

 F ABMS (m / z): 31 1 (M + 1) +.

Example 3

 Preparation of 6-amino-2- (6-hydroxy-2-naphthyl) pyrimidin-4-ol (Compound 3)

After dissolving sodium metal (730 mg) in anhydrous methanol (70 ml) to prepare a methanol solution of sodium methoxide, 2-amidino 6-naphthol 'methanesulfonate (2.8 g) and ethyl ethyl cyanoacetate were prepared. (1.2 g) and stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and then purified by silica gel column (form-methanol-acetic acid) to obtain Compound ₃ .

 lH-NMR (DMS0-d6, D20 / TMS):

 δ = 5.20 (1H, d, J = 1.3Hz), 7.23-7.27 (2H, m), 7.85 (1H, d, J = 8.9Hz), 7.94 (1H, d, J = 8.9Hz), 8.14 ( 1H, dd, J = l.7, 8.9Hz), 8.66 (1H, s)

 F ABMS (m / z): 254 (M + 1) +

Example 4 Preparation of 2- [6- (2-aminoethoxy) -1-naphthyl] -6-methylpyrimidine-14-ol.hydrochloride (compound 4)

 2- (6-hydroxy-1-naphthyl) -1-6-methylpyrimidin-4-ol (4 g) is dissolved in DMF (20 ml), and anhydrous potassium carbonate (2.9 g), potassium iodide ( 133 mg) and N- (t-butoxycarbonyl) 1-2-ethylethylamine (2.8 g) were added, and the mixture was stirred at 80 ° C for 7 hours. After concentrating the reaction mixture under reduced pressure, the residue is purified on a silica gel column (cloth form) to give 2- {6— [2- (Nt-butoxycarbonylamino) ethoxy] —2-naphthyl} —6-methyl L-pyrimidin-1-ol was obtained. The obtained product was dissolved in DMF (6 ml), 4N hydrochloric acid-dioxane solution (30 ml) was added, and the mixture was stirred at room temperature for 4 hours. Ether (300 ml) and acetone (300 ml) were added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 4.

 lH-NMR (DMS0-d6, D20 / TMS):

 δ = 2.57 (3H, s), 3.31-3.35 (2H, m), 4.78 (2H, t, J = 5.3Hz), 6.85 (1H, s),

 7.20 (1H, dd, J = 2.3, 8.9Hz), 7.23 (1H, d, J = 2.0Hz), 7.82 (1H, d, J = 8.9Hz),

7.98 (1H, d, J = 8.6Hz), 8.37 (1H, dd, J = l.7, 8.6Hz), 8.89 (1H, s)

 FABMS (m / z): 296 (M + 1) +

Example 5

 Preparation of 2- [6- (2-N, N-dimethylaminoethoxy) 1-2-naphthyl] -6-methylpyrimidine-1-ol 'hydrochloride (Compound 5)

2- (6-Hydroxy_2-naphthyl) -1-6-methylpyrimidin-14-ol (50 Omg) and anhydrous potassium carbonate (410 mg) are suspended in DMF (10 ml), and the mixture is suspended at room temperature at room temperature. , N-dimethylethylamine hydrochloride (250 mg) and triethylamine (0.25 ml) in DMF (3 ml) were added dropwise, potassium iodide (10 mg) was added, and the mixture was added at 80 ° C for 8 hours. Stirred. The reaction solution was filtered, the filtrate 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 saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was dissolved in a 0.01 N aqueous hydrochloric acid solution and freeze-dried to obtain Compound 5. lH-NMR (DMS0-d6 / TMS):

 δ = 2.28 (6H, s), 2.47 (3H, s), 2.69 (2H, t, J = 5.9Hz), 4.59 (2H, t, J = 5.9Hz),

6.70 (1H, s), 7.11-7.20 (2H, m), 7.77 (1H, d, J = 8.6Hz),

 7.94 (1H, d, J = 8.6Hz), 8.37 (1H, dd, J = 1.7, 8.6Hz), 8.82 (1H, s),

 9.99 (1H, brs)

 F ABMS (m / z): 324 (M + 1) +

Example 6

 2-N, N-dimethyl- {2- [6- (2-N, N-dimethylaminoethoxy) -1-2-naphthyl] -16-methylpyrimigeru 4-ethoxy} ethylamine-dihydrochloride (compound 6) Manufacture

 2- (6-Hydroxy-2-naphthinole) -1-6-methylpyrimidin-14-ol (50 Omg) and anhydrous potassium carbonate (1.4 g) are suspended in DMF (10 ml), and the mixture is suspended in room temperature at room temperature. A DMF (3 ml) solution of N, N-dimethylethylamine hydrochloride (856 mg) and triethylamine (0.83 ml) was added dropwise, and potassium iodide (lOmg) was added. Stir for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-5% aqueous citric acid. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in a 0.01N aqueous hydrochloric acid solution and freeze-dried to obtain Compound 6.

 1H- 丽 R (DMS0-d6, D20 / TMS):

 δ = 2.24 (6Η, s), 2.25 (6H, s), 2.45 (3H, s), 2.67-2.74 (4H, m),

 4.20 (2H, t, J = 5.9Hz), 4.59 (2H, t, J = 5.9Hz), 6.71 (1H, s), 7.21 (1H, dd, J = 2.3, 6.6Hz), 7.40 (1H, d , J = 2.3Hz), 7.90 (1H, d, J = 8.9Hz), 7.97 (1H, d, J = 8.3Hz), 8.44 (1H, dd, J = l.7, 8.3Hz), 8.87 (1H , s)

 F ABMS (m / z): 395 (M + 1) +

Example 7

2- [6- (3-Aminopurobokishi) one 2-naphthyl] one 6- Mechirupiri midges emissions _ ₄ -. Ol preparation of the hydrochloride salt (Compound ₇₎

2- (6-hydroxy-2-naphthyl) -1-6-methylpyrimidine-1-ol (50 Omg) and anhydrous potassium carbonate (410 mg) were suspended in DMF (10 ml), and a solution of N- (t-butoxycarbonyl) -13-propylamine chloride (345 mg) in DMF (3 ml) was added at room temperature. After the dropwise addition, potassium iodide (10 mg) was added, and the mixture was stirred at 80 ° C for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% aqueous solution of taenoic acid. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by a silica gel column (clonal form). To the obtained yellow oil was added a 1N hydrochloric acid-monoacetic acid solution (15 ml), and the mixture was stirred at room temperature for 5 hours. Ether was added to the reaction solution, and the precipitated yellow solid was collected by filtration to obtain Compound 7.

 1H- 丽 R (DMS O— d 6, D20 / TMS):

 δ = 2.12-2.22 (2Η, m), 2.58 (3H, s), 3.00 (2H, t, J = 7.3Hz),

 4.66 (2H, t, J = 6.3Hz), 6.90 (1H, s), 7.19-7 · 25 (2H, m),

 7.83 (1H, d, J = 8.9Hz), 7.99 (1H, d, J = 8.9Hz),

 8.37 (1H, dd, J = l.7, 8.9Hz), 8 · 92 (1H, s)

 FABMS (m / z): 3 10 (M + 1) +

Example 8

 Preparation of 6-methyl-2- [6- (3-N-methylaminopropoxy) -1-naphthyl] pyrimidine-1-ol hydrochloride (Compound 8)

 2- (6-Hydroxy-l-naphthyl) -l- 6-methylpyrimidin-l-ol (50 Omg) and anhydrous potassium carbonate (547 mg) were suspended in DMF (10 ml), and N- (t-l A solution of 1N-methyl-3-propylamine (37 Omg) in DMF (3 ml) was added dropwise, and then potassium iodide (lOmg) was added, followed by stirring at 80 ° C for 8 hours. 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 saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified with a silica gel column (form: form). To the obtained brown oil was added a 4N hydrochloric acid-dioxane solution (3.5 ml), and the mixture was stirred at room temperature for 3 hours. Ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 8.

1H- 丽 R (DMS0-d6, D20 / TMS): δ = 2.14-2.19 (2H, m), 2.55 (3H, s), 2.58 (3H, s), 3.09 (2H, t, J = 7.3Hz), 4.64 (2H, t, J = 6.3Hz), 6.84 (1H, s), 7.17-7.22 (2H, m),

 7.82 (lH, d, J = 8.9Hz), 7.98 (1H, d, J = 8.9Hz),

 8.37 (1H, dd, J = 1.7, 8.9Hz), 8.89 (1H, s).

 F ABMS (m / z): 324 (M + 1) +

Example 9

 Preparation of 2- [6- (6-aminohexyloxy) -1-naphthyl] -6-methylpyrimidine-1-ol hydrochloride (Compound 9)

 2- (6-Hydroxy-2-naphthyl) -1-6-methylpyrimidine-14-ol (1 g) and anhydrous potassium carbonate (828 mg) were suspended in DMF (15 ml), and N- A solution of (t-butoxycarbonyl) -16-hexylamine bromide (1.1 g) in DMF (5 ml) was added dropwise, potassium iodide (20 mg) was added, and the mixture was stirred at 80 ° C for 5 hours. . After the reaction solution was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and a 5% aqueous solution of citric acid. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (hexane-ethyl acetate) to give a colorless oil. To the obtained oil was added 4N hydrochloric acid-dioxane solution (20 ml), and the mixture was stirred at room temperature. Ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 9.

 lH-NMR (DMS0-d6, D20 / TMS):

 δ = 1.43-1.44 (4Η, m), 1.56-1.66 (2H, m), 1.79-1.84 (2H, m), 2.58 (3H, s),

2.79 (2H, t, J = 7.3Hz), 4.57 (2H, t, J = 6.3Hz), 6.91 (1H, s), 7.20-

7.24 (3H, m), 7.85 (1H, d, J = 8.9Hz), 7.98 (1H, d, J = 8.9Hz),

8.32 (1H, dd, J = l.7, 8.6Hz), 8.87 (1H, s)

 F ABMS (m / z): 352 (M + 1) +

Example 10

 Preparation of 2- [6_ (2-N, N-getylaminoethoxy) -1-naphthyl] _6-methylpyrimidine-1-ol hydrochloride (Compound 10)

2- (6-Hydroxy-1-naphthyl) -1-6-methylpyrimidin-14-ol (756 mg) and anhydrous potassium carbonate (621 mg) were added to DMF (10 ml). After suspending and adding dropwise a solution of 2-chloro-N, N-jetylethylamine hydrochloride (464 mg) in DMF (3 ml) at room temperature, add potassium iodide (20 mg) and add 80 ° C For 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified using a silica gel column (form-form-methanol). The obtained pale yellow oily substance was dissolved in acetone, a small amount of hydrochloric acid was added dropwise, and the mixture was solidified from ether to obtain a compound 10.

 1H-Awake (DMS0-d6 / TMS):

 6 = 1.29 (6H, t, J = 6.9Hz), 2.54 (3H, s), 3.21-3.226 (4H, m), 3.57-3.59 (2H, m),

 4.94-4.96 (2H, m), 6.84 (1H, s), 7.18-7.22 (2H, m), 7.80 (1H, d, J = 8.9Hz), 7.97 (1H, d, J = 8.9Hz), 8.39 (1H, d, J = 8.9Hz), 8.91 (1H, s),

11.00 (1H, brs)

 FABMS (m / z): 352 (M + 1) +

Example 1 1

 Preparation of 2- [6- (2-N, N-dibenzylaminoethoxy) 1-2-naphthyl] -1-6-methylbirimidine-1-ol hydrochloride (Compound 11)

 2- (6-Hydroxy-2-naphthyl) -1-6-methylpyrimidin-1-ol (756 mg) and anhydrous potassium carbonate (621 mg) were suspended in DMF (10 ml), and the mixture was suspended at room temperature at room temperature. After a solution of N-dibenzylethylamine 'hydrochloride (799 mg) in DMF (3 ml) was added dropwise, potassium iodide (20 mg) was added, and the mixture was stirred at 80 ° C for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified with a silica gel column (cloth form). The obtained brown oil was dissolved in acetone, and a small amount of hydrochloric acid was added dropwise, and the mixture was solidified from ether to obtain Compound 11.

 1H-丽 R (DMS0-d6 / TMS):

 δ = 2.56 (3Η, s), 3.51 (2Η, m), 4.47 (4Η, s), 4.93 (2Η, m), 6.84 (1H, s),

 7.20-7.25 (2H, m), 7.42-7.45 (6H, m), 7.76-7.82 (5H, m), 7.97 (1H, d, J = 8.6Hz), 8.31 (1H, d, J = 8.6Hz) , 891 (1H, s), 11.93 (1H, brs)

FABMS (m / z): 476 (M + 1) + Example 1 2

 Preparation of methyl 6- (4-hydroxy-1-6-methyl-2-pyrimigel) -12-naphthyloxyacetate (Compound 12)

 2- (6-Hydroxy-l-naphthyl) -l-6-methylpyrimidin-l-l-ol (1.5 g) and anhydrous potassium carbonate (1.2 g) are suspended in DMF (30 ml) and allowed to stand at room temperature. Then, methyl bromide acetate (0.55 ml) was added thereto, and the mixture was stirred for two days. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and purified water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (form: methanol / methanol) to obtain Compound 12.

 1H-Marauder R (DMS0-d6 / TMS):

 δ = 2.51 (3H, s), 3.74 (3H, s), 5.10 (2H, s), 6.84 (1H, s),

 7.15 (1H, dd, J = 2.3, 8.6Hz), 7.18 (1H, s), 7.78 (1H, d, J = 8.6Hz), 7.91 (1H, d, J = 8.6Hz) .8.28 (1H, dd) , J = l.6, 8.6Hz), 8.74 (1H, s), 10.02 (1H, s)

 F ABMS (m / z): 3 25 (M + 1) +

Example 13

 Production of methyl 2_ (6-methoxycarbonylmethoxy-2-naphthyl) -1-6-methyl 4-pyrimidinyl oxyacetate (Compound 13)

 2- (6-Hydroxy-l-naphthyl) -l-6-methylpyrimidin-l-l-ol (1.5 g) and anhydrous potassium carbonate (1.2 g) are suspended in DMF (30 ml), and the mixture is suspended at room temperature. Under the solution, methyl bromide acetate (0.55 ml) was added and the mixture was stirred for two days and night. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and purified water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel gel (form: methanol in methanol) to obtain Compound 13.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.51 (3Η, s), 3.74 (6H, s), 4.97 (2H, s), 5.12 (2H, s), 6.86 (1H, s),

 7.29 (1H, d, J = 8.9Hz), 7.36 (1H, s), 7.90 (1H, d, J = 8.9Hz),

8.01 (1H, d, J = 8.9Hz), 8.35 (1H, d, J = 8.9Hz), 8.80 (1H, s) F ABMS (mZz): 397 (M + 1) + Example 14

 Preparation of 6- (4-hydroxy-6-methyl-1-pyrimidinyl) -12-naphthyloxyacetic acid (compound 14)

 Methyl 6- (4-hydroxy-16-methyl-2-pyrimidinyl) -12-naphthyloxyacetate (2.8 g) was dissolved in methanol (20 ml), and 1N aqueous sodium hydroxide solution (42 ml) was dissolved. ) And stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, neutralized with hydrochloric acid, and the precipitated solid was collected by filtration to obtain Compound 14.

 1H-NMR (DMS0-d6 / TMS):

 δ = 2.55 (3H, s), 5.06 (2H, s), 6.91 (1H, s), 7.18-7.22 (2H, m),

 7.79 (1H, d, J = 8.6Hz), 7.92 (1H, d, J = 8.6Hz), 8.31 (1H, dd, J = l.3, 8.6Hz),

8.84 (1H, s)

 FABMS (m / z): 3 1 1 (M + 1) +

Example 15

 Preparation of sodium 6- (4-hydroxy-16-methyl-1-pyrimidinyl) -12-naphthyloxyacetate (compound 15)

 6- (4-Hydroxy-1-6-methinolay 2-pyrimigel) -12-naphthyloxyacetic acid (12.4 g) was dissolved in a 1N aqueous solution of sodium hydroxide (38 ml) at room temperature. After the reaction solution was filtered, the filtrate was freeze-dried to obtain Compound 15.

 1H- 丽 R (DMS0-d6 / TMS):

 δ = 2.44 (3H, s), 4.68 (2H, s), 6.61 (lH, s), 7.10-7.15 (2H, m),

 7.62 (1H, d, J = 8.9Hz), 7.80 (1H, d, J = 8.9Hz), 8.28 (1H, d, J = 8.6Hz),

8.72 (1H, s), ll.84 (1H, br)

 FABMS (m / z): 3 3 1 (M— 1)

 Example 16

 Preparation of potassium 6- (4-hydroxy-16-methyl-12-pyrimidinyl) -12-naphthyloxyacetate (compound 16)

6- (4-Hydroxy-6-methyl-12-pyrimidinyl) -12-naphthyloxyacetic acid (4 g) is dissolved in ethanol (48 ml) by heating, and then the hydroxylation power (720 mg) is added. )) In water (5 ml) and stirred, and the precipitated solid was collected by filtration. After washing with ethanol (12 ml), compound 16 was obtained.

 lH-NMR (DMS0-d6 / TMS):

 S = 2.44 (3H, s), 4.68 (2H, s), 6.61 (lH, s), 7.11-7.16 (2H, m),

 7.58 (ΙΗ 'd, J = 8.6Hz), 7.76 (1H, d, J = 8.9Hz), 8.26 (1H, dd, J = l.7, 8.9Hz), 8.71 (1H, s), 12.55 (lH , Br)

 F ABMS (m / z): 347 (M-1)-

Example 17

 Preparation of 6- (4-Hydroxysulfonyloxy-1-6-methyl-2-pyrimidinyl) -12-naphthyloxyacetic acid (Compound 17)

 6- (4-Hydroxy-6-methyl-2-pyrimidinyl) 1-2-naphthyloxyacetic acid (5 g) is dissolved in a mixed solvent (60 ml) of DMF-pyridine (1: 1), and the trioxide-DMF complex ( 9.9 g) was added and the mixture was stirred at room temperature for 4 days. After the reaction solution was concentrated under reduced pressure, a 10% aqueous ammonia solution (100 ml) was added thereto under ice-cooling, followed by freeze-drying. Methanol (400 ml) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with ether (400 ml), and further washed four times with methanol (200 ml) and ether (200 ml) to obtain compound 17.

 1H-Marauder R (DMS0-d6 / TMS):

 δ = 2.48 (3Η, s), 4.71 (2H, s), 6.69 (1H, s), 7.40 (1H, dd, J = 2.0, 8.9Hz), 7.71 (1H, d, J = 2.0Hz), 7.89 (1H, d, J = 8.9Hz), 7.98 (1H, d, J = 8.9Hz),

8.40 (1H, dd, J = l.7, 8.6Hz), 8.84 (1H, s)

 F ABMS (m / z): 391 (M + 1) +

 Example 18

 Production of 2- {6 -— [2- (2-imidazolinyl) aminoethoxy] —2-naphthyl} —6-methylpyrimidin-14-ol 'hydrochloride (Compound 18)

Dissolve 2- [6- (2-aminoethoxy) -1-naphthyl] -1-6-methylpyrimidine-4-ol hydrochloride (20 Omg) in pyridine (5 ml) and prepare 2- (2-imidazolinyl) sulfone A solution of acid (117 mg) in water (1 Oml) was added, and the mixture was stirred at room temperature for two days. After concentrating the reaction mixture under reduced pressure, the residue was purified with ice-cooled water. (10 ml) was added and stirred for 1 hour. After the reaction solution was filtered, a saturated aqueous solution of sodium hydrogen carbonate (50 ml) was added to the filtrate, and the mixture was stirred for 1 hour under ice cooling. The precipitated solid was collected by filtration, dissolved in a small amount of methanol, added with hydrochloric acid (0.3 ml) and acetone (70 ml), and stirred overnight. The precipitated yellow solid was collected by filtration and washed with acetone to give Compound 18.

 1H-band R (DMS0-d6 / TMS):

 δ = 2.57 (3Η, s), 3.57 (4H, s), 3.69-3.72 (2H, m), 4.68 (2H, t, J = 5.0Hz),

6.84 (1H, s), 7.19-7.23 (2H, m), 7.81 (1H, d, J = 8.6Hz),

 7.96 (1H, d, J = 8.6Hz), 8.37 (1H, dd, J = l.7, 8.9Hz),

 8.67 (1H, t, J = 5.6Hz), 8.91 (1H, s)

 F ABMS (m / z): 364 (M + 1) +

Example 19

 Preparation of 2- [6- (2-N, N-diallylaminoethoxy) -12-naphthyl] -1-6-methylpyrimidine-4-thiol hydrochloride (Compound 19)

 2- (6-Aminoethoxy) -1-naphthyl] —6-methylpyrimidine-14-ol hydrochloride (33 Omg) in DMF (5 ml) solution of triethylamine (0.28 ml) and odor (0.26 ml) was added, and the mixture was stirred at 60 ° C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-5% aqueous sodium hydrogen carbonate. After the ethyl acetate layer was washed with saturated saline, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified with a silica gel column (chloroform-methanol). The obtained colorless oil was solidified from ether in the presence of a small amount of hydrochloric acid to obtain Compound 19.

 lH-MR (DMS0-d6 / TMS):

 δ: 1.54 (3Η, s), 3.58 (2Η, m), 3.88-3.91 (4H, m), 4.97 (2H, m),

 5.53-5.64 (4H, m), 6.00-6.15 (2H, m), 6.85 (1H, s), 7.16-7.20 (2H, m),

7.80 (1H, d, J = 8.6Hz), 7.96 (1H, d, J = 8.6Hz), 8.83 (1H, d, J = 8.6Hz),

8.88 (1H, s), 11.04 (lH, brs)

 F ABMS (m / z): 376 (M + 1) +

Example 20 2- (6-hydroxy-4-methyl-2-pyrimidinyl) -1-naphthyloxymethyl] — 2-furancarboxylate (Compound 20) Preparation of 2- (6-hydroxy-2-naphthyl) 6-Methyl / repyrimidine-14-onole (50 Omg) and anhydrous potassium carbonate (410 mg) were suspended in DMF (10 ml), and the mixture was stirred at room temperature with ethyl 5-methyl chloride-2-furancarboxylate (36). Omg) in DMF (3 ml) was added dropwise, potassium iodide (10 mg) was added, and the mixture was stirred at 80 ° C for 8 hours. After filtering the reaction solution, the filtrate 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 washed with saturated saline, the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by a silica gel column (form-form methanol). The obtained product was solidified from ether to obtain Compound 20.

 lH-NMR (DMS0-d6, D20 / TMS):

 6 = 1.28 (3H, t, J = 7.3Hz), 2.49 (3H, s), 4.29 (2H, dd, J = 7.3, 14.2Hz),

 5.65 (2H, s), 6.78 (1H, s), 6.85 (1H, d, J-3.3Hz), 7.14-7.20 (2H, m), 7.30 (1H, d, J = 3.3Hz), 7.79 (1H , d, J = 8.9Hz), 7.98 (1H, d, J = 8.9Hz),

8.42 (1H, dd, J = l.7, 8.9Hz), 887 (1H, s)

 F ABMS (m / z): 405 (M + 1) +

Example 21

 Preparation of 2-hydroxy-6- (4-hydroxy-6-methyl-2-pyrimidyl) -11-naphthylacetamide (Compound 21)

 6-Amidino 2-hydroxy-11-naphthyl acetoamide hydrochloride (1.6 g) and ethyl acetoacetate (92 Omg) synthesized according to the method of T. Nakayama et al. Was added to a solution of sodium metal (430 mg) in anhydrous methanol (40 ml), and the mixture was stirred at room temperature for 4 hours. After adding purified water to the reaction solution, the mixture was neutralized with a dilute hydrochloric acid aqueous solution, and the precipitated solid was collected by filtration to obtain Compound 21.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.39 (3Η, s), 3.95 (2H, s), 6.27 (1H, s), 7.10 (1H, br),

7.36 (1H, d, J = 8.6Hz), 7.49 (1H, br), 7.90 (1H, d, J = 8.9Hz), 8.03 (1H, d, J = 8.9Hz), 8.22 (1H, d, J = 8.9Hz), 8.73 (1H, s)

 F ABMS (m / z): 3 10 (M + 1) +

Example 22

 Preparation of 2- (2-N, N-dimethylaminoethoxy) -1-6- (4-hydroxy-6-methyl-2-pyrimidinyl) -11-naphthylacetoamide (Compound 22) Compound 21 (50 mg) was treated with DMF. (25 ml), added with 60% sodium hydride (6 Omg), stirred at room temperature for 30 minutes, and then added 2-chloro-N, N-dimethylethylamine hydrochloride (233 mg). The mixture was stirred at 80 ° C for 8 hours. The reaction solution was distributed between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (form: form-methanol) to obtain Compound 22.

 lH-NMR (DMS0-d6, D20 / TMS):

 δ = 2.26 (6H, s), 2.48 (3H, s), 2.71 (2H, t, J = 5.6Hz), 3.87 (2H, s), 4.59 (2H, t, J = 5.6Hz), 6.69 (1H , S), 7.25 (1H, d, J = 8.9Hz), 7.88 (1H, d, J = 8.9Hz), 7.95 (1H, d, J = 8.9Hz), 8.40 (1H, d, J = 8.9Hz) ),

8.82 (1H, s)

 F ABMS (m / z): 381 (M + 1) +

Example 23

 Preparation of ethyl 1-rubamoylmethyl-1- (4-hydroxy-16-methyl-2-pyrimigel) -1-naphthyloxyacetate (Compound 23)

 2-Hydroxy 6- (4-hydroxy 6-methyl-2-pyrimigel) 11-Naphthyl acetoamide (1.5 g) is dissolved in DMF (40 ml), and anhydrous potassium carbonate (2 g) And ethyl bromide acetate (808 mg) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column (form-form-methanol) to obtain compound 23. Was.

 lH-NMR (DMS0-d6, D20 / TMS):

 δ = 1.19 (3H, t, J = 6.9Hz), 2.51 (3H, s), 3.86 (2H, s),

4.19 (2H, dd, J = 6.9, 14.8Hz), 5.07 (2H, s), 6.84 (1H, s), 7.24 (1H, d, J = 8.9Hz), 7.83 (1H, d, J = 8.9Hz), 7.94 (1H, d, J = 8.9Hz), 8.32 (lH, dd, J = 1.7, 8.9Hz), 8.76 (lH, s), 10.15 (1H, br)

FABMS (m / z): 396 (M + 1) +

Example 24

 1 Production of rubamoylmethyl-1- (4-hydroxy-16-methyl-1-pyrimidinyl) -1-naphthyloxyacetic acid (Compound 24)

 Ethyl 1-forcerubamoylmethyl-6- (4-hydroxy-16-methyl-12-pyrimidinyl) 1-2-naphthyloxyacetate (250 mg) was dissolved in methanol (5 ml) and 1N An aqueous sodium hydroxide solution (1.9 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, the residue was acidified with a 5% aqueous solution of citric acid, and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain Compound 24.

 1H- 丽 R (DMS0-d6, D20 / TMS):

 6 = 2.50 (3Η, s), 3.87 (2Η, s), 5.00 (2H, s), 6.80 (1H, s),

 7.25 (lH, d, J = 8.9Hz), 785 (1H, d, J = 8.9Hz), 7.94 (1H, d, J = 8.9Hz),

8.34 (1H, dd, J = 1.7, 8.9Hz), 8.78 (1H, d, J = 1.7Hz)

 FABMS (m / z): 368 (M + 1) +

Example 25

 Preparation of 2- (6-aryloxy-1-naphthyl) -1-methylpyrimidine-14-ole (Compound 25)

 2-(6-Hydroxy-2-naphthyl) -16-methylpyrimidin-4-ol (2 g) was dissolved in DMF (20 ml), and anhydrous potassium carbonate (3.3 g) and aryl bromide (960 mg) were dissolved. ) And stirred at room temperature for 24 hours. After partitioning the reaction solution with ethyl acetate-purified water, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane monoacetate) to obtain Compound 25.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.48 (3Η, s), 5.05 (2Η, d, J = 5.3Hz), 531 (1H, dd, J = l.7, 10.2Hz),

5.48 (1H, dd, J = 1.7, 17.2Hz), 6.15 (lH, m), 6.72 (1H, s), 7.12-7.16 (2H, m), 7.78 (1H, d, J = 8.9Hz), 7.95 (1H, d, J = 8.6Hz), 8.38 (1H, dd, J = l.7, 8.6Hz), 8.83 (1H, s), 9.99 (1H, br)

 FABMS (m / z): 293 (M + 1) +

Example 26

 Preparation of 2- (6-benzyloxy-2-naphthyl) -16-methylpyrimidine-14-ole (compound 26)

 2- (6-Hydroxy-l-naphthyl) -l-6-methylpyrimidin-l-ol (50 Omg) and anhydrous potassium carbonate (1.4 g) are dissolved in DMF (10 ml) and smelled at room temperature. After benzyl chloride (342 mg) was added dropwise, potassium iodide (1 Omg) was added, and the mixture was stirred at 80 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and a 5% aqueous solution of taenoic acid. The ethyl acetate layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column (form: chloroform) to obtain Compound 26.

 1H-NMR (DMS0-d6 / TMS):

 δ = 2.55 (3H, s), 5.64 (2H, s), 6.90 (1H, s), 7.18-7.22 (2H, m),

 7.36-7.57 (5H, m), 7.82 (1H, d, J = 8.9Hz), 7.97 (1H, d, J = 8.9Hz),

8.38 (1H, dd, J = l.7, 8.9Hz), 8.90 (1H, s)

 FABMS (m / z): 343 (M + 1) +

Example 27

 Preparation of N, N-dimethyl [6- (4-hydroxy-6-methyl-1-pyrimidinyl) -2-naphthyloxy] acetamide (Compound 27)

 2- (6-Hydroxy-l-naphthyl) -l-6-methylpyrimidin-l-ol (50 Omg) and anhydrous potassium carbonate (41 Omg) were suspended in DMF (10 ml), and bromide N, N-Dimethylacetamide (330 mg) was added, and the mixture was stirred at 80 ° C for 4 hours. After the reaction solution was concentrated under reduced pressure, the solution was partitioned between purified form and purified water. After washing the form layer with a 1N aqueous hydrochloric acid solution, the layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was solidified from methanol to obtain Compound 27.

1H—Ran R (DMS0-d6 / TMS): δ = 2.59 (3H, s), 2.89 (3H, s), 3.13 (3H, s), 5.31 (2H, s), 6.98 (1H, s),

 7.20-7.23 (2H, m), 7.82 (1H, d, J = 8.9Hz), 7.92 (1H, d, J = 8.6Hz),

 8.26 (1H, dd, J = l.7, 8.9Hz), 8.81 (1H, s)

 F ABMS (m / z): 3 3 8 (M + 1) +

Example 28

 Production of N, N-dimethyl- [2- (6-N, N-dimethylaminocarbonylmethoxy-12-naphthyl) -16-methyl-4-pyrimidinyloxy] acetoamide (Compound 28)

 The 1N hydrochloric acid washing solution obtained in Example 27 was allowed to stand under ice cooling, and the precipitated solid was collected by filtration to obtain Compound 28.

 1H-band R (DMS0-d6, D20 / TMS):

 δ = 2.49 (3H, s), 3.08 (12H, s), 4.91 (2H, s), 5.18 (2H, s), 6.72 (1H, s),

 7.26 (1H, dd, J = 2.6, 8.9Hz), 7.33 (1H, d, J = 2.6Hz), 7.84 (1H, d, J = 8.6Hz), 7.94 (1H, d, J = 8.9Hz), 8.35 (1H, dd, J = 1.7, 8.9Hz), 8.76 (1H, s)

 F ABMS (m / z): 4 23 (M + 1) +

Example 2 9

 Preparation of 2- (2-t-butoxycarboninoleaminoethoxy) -1-6- (4-hydroxy-6-methyl-2-pyrimidinyl) -11-naphthylacetoamide (Compound 29)

 Compound 21 (2 g) was dissolved in DMF (50 ml), and anhydrous potassium carbonate (2.7 g) and N_ (t-butoxycarbonyl) -12-chloride tylamine (1.4 g) were added. The mixture was stirred at 50 ° C for 3 days. The reaction solution was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (chloroform-form-methanol) to obtain compound 29. -Marauder R (DMS0-d6, D20 / TMS):

 6 = 1.38 (9H, s), 2.48 (3H, s), 3.41-3.43 (2H, m), 3.88 (2H, s),

4.50 (2H, t, J = 5.6Hz), 6.68 (1H, s), 7.25 (1H, d, J = 8.9Hz), 7.93 (2H, t, J = 9.9Hz), 8.41 (1H, d, J = 8.9Hz), 8.85 (1H, s) F ABMS (m / z): 4 5 3 (M + 1) + Example 30

 Preparation of 2- (2-aminoethoxy) -1-6- (4-hydroxy-6-methyl-1-pyrimidinyl) -1-naphthylacetamide hydrochloride (Compound 30)

 To the compound 29 (30 Omg) was added a 1N hydrochloric acid / monoacetic acid solution (4.5 ml), and the mixture was stirred at room temperature for 1.5 hours. Ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 30.

 IH-NMR (DMS0-d6, D20 / TMS):

 δ = 2.61 (3Η, s), 3.34-3.37 (2H, m), 3.89 (2H, s), 4.82 (2H, t, J = 5.OHz),

6.93 (IH, s), 7.36 (1H, d, J = 8.9Hz), 7.93 (IH, d, J = 8.9Hz), 8.00 (1H, d, J = 8.9Hz), 8.39 (IH, dd, J = l.7, 8.9Hz), 8.92 (IH, d, J = l.3Hz)

FABMS (mZz): 353 (M + 1) +

Example 31

 Ethyl 3- {2— [6 -— (4-hydroxy-16-methyl-12-pyrimidinyl) -12-naphthyloxy] ethyl} amino-3-oxopropionate (Compound 31)

 2- [6- (2-Aminoethoxy) 1-2-naphthyl] -6-methylpyrimidine-4-ol hydrochloride (80 Omg) and monoethyl malonate (39 Omg) in pyridine (10 ml) And DCC (60 Omg) were added, and the mixture was stirred at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified by a silica gel column (closed form-methanol). The product was solidified from ether to give compound 31.

 lH-NMR (DMS0-d6 / TMS):

 δ = 1.15 (3H, t, J = 6.9Hz), 2.54 (3H, s), 3.25 (2H, s),

 3.56 (2H, dd, J = 5.9, 10.6Hz), 4.05 (2H, dd, J = 6.9, 14.2Hz), 4.57 (2H, t, J = 5.6Hz), 6.82 (IH, s), 7.16 (IH , d, J = 2.3Hz),

7.20 (IH, d, J = 2.3Hz), 7.81 (IH, d, J = 8.9Hz), 7.97 (IH, d, J = 8.9Hz),

8.37 (IH, dd, J = 1.7, 7.3Hz), 8.45 (IH, t, J = 5.3Hz), 8.90 (IH, s) FABMS (m / z): 410 (M + 1) + Production of N- {2- [6- (4-hydroxy-6-methyl-2-pyrimidinyl) -l-naphthyloxy] ethyl) aminoacetic acid.hydrochloride (Compound 32)

 2 Suspend monochloride tilamine hydrochloride (2.3 g) in chloroform (10 ml), and add triethylamine (3.1 ml) and t-butyl bromoacetate (2.7 ml) under ice-cooling. The mixture was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was partitioned with purified form-water and purified water, and the form-form layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and treated with t-butyl N- (2-ethyl chloride) aminoacetate (2. 4 g) was obtained. After dissolving the obtained compound in chloroform, di-t-butyl dicarbonate (2.4 g) was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with purified water. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and t-butyl N- (t-butoxycarbonyl) -1-N- (2-ethyl chloride) aminoacetate (3.1 g) ). The obtained t-butyl N- (t-butoxycarbonyl) -1-N- (2-ethyl chloride) aminoacetate (1.2 g) was converted to 2- (6-hydroxy-1-2-naphthyl) -16- Methylpyrimidin-4-ol (1. Og) and anhydrous potassium carbonate (883 mg) were added to a suspension of DMF (10 ml) and stirred at 80 for 8 hours. 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 saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, purified on a silica gel column (form: chloroform), and purified using t-butyl N-t-butoxycarbone. — [6— (6-Methinole-1-hydroxy-1-2-pyrimidyl) -12-naphthyloxy] ethylaminoacetate (1. O g) was obtained. Further, the obtained t-butyl N-t-butoxycarboninolate 2- [6- (6-methyl-4-hydroxy-1--2-pyrimidinyl) -12-naphthyloxy] ethylaminoacetate (99 Omg) was added to 4 This was dissolved in a normal dioxane hydrochloride solution (2.4 ml) and stirred at room temperature for 5 hours. The precipitated crude product was collected by filtration, and purified by a silica gel column (chloroform-formanol-acetic acid) to obtain Compound 32.

 1H-NMR (DMS0-d6 / TMS):

 δ = 2.52 (3Η, s), 3.48 (2H, m), 3.96 (2H, m), 4.87 (2H, m), 6.77 (1H, s),

7.18-7.23 (2H, ra), 7.77 (1H, d, J = 8.9Hz), 7.96-7.98 (2H, m), 8.39 (1H, dd, J = 1.7, 8.9 Hz), 8.89 (1H, s), 9.76 (1H, brs) F ABMS (m / z): 354 (M + 1).

Example 33

 Preparation of 2- (6-carboxymethoxy-1-naphthyl) -1-methyl-14-pyrimidinyloxyacetic acid (Compound 33)

 Methyl 2- (6-methoxycarbonylmethoxy-1-naphthyl) 16-methyl-14-pyrimidinyl oxyacetate (51 2 mg) is dissolved in methanol (10 ml) and 1N water An aqueous sodium oxide solution (6.5 ml) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, neutralized with hydrochloric acid, and the precipitated solid was collected by filtration to obtain Compound 33.

 1H-band R (DMS0-d6 / TMS):

 6 = 2.52 (3Η, s), 4.86 (2H, s), 5.04 (2H, s), 6.86 (1H, s),

 7.28 (1H, dd, J = 2.6, 8.9Hz), 7.35 (1H, d, J = 2.3Hz), 7.91 (1H, d, J = 8.6Hz),

8.01 (1H, d, J = 8.9Hz), 8.38 (1H, dd, J = 1.7, 8.6Hz), 8.86 (1H, s)

 F ABMS (m / z): 369 (M + 1) +

Example 34

 Preparation of ethyl 4- [6- (4-hydroxy-6-methyl-2-pyrimidinyl) -1-naphthyloxy] butylate (compound 34)

 2- (6-hydroxy-1-naphthyl) -1-6-methylpyrimidin-1-ol (1.5 g) and anhydrous potassium carbonate (1.2 g) were added to a solution of DMF (10 ml) in DMF (10 ml) at room temperature. Ethyl bromide butanoate (0.86 ml) was added and stirred for two days. The reaction solution was concentrated under reduced pressure, and the residue 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 by a silica gel column (closure form) to obtain Compound 34.

 1H-thigh (DMS0-d6 / TMS):

 δ = 1.17 (3H, t, J = 7.3Hz), 2.01-2.11 (2H, m), 2.42-2.52 (5H, m),

 4.07 (2H, dd, J-7.3, 14.2Hz), 4.52 (2H, t, J = 6.6Hz), 6.67 (1H, s), 7.12-7.18 (2H, m), 7.78 (1H, d, J = 8.6Hz), 7.79 (1H, d, J = 8.6Hz),

8.37 (1H, dd, J = l.7, 8.6Hz), 883 (1H, s), 10.00 (1H, s) F ABMS (m / z): 367 (M + 1) +

Example 35

Echiru 4 one manufacturing of {2 - - [6- (3-ethoxycarbonyl Provo carboxymethyl) one 2-naphthyl] one ^6-methyl-one 4 one-pyrimidinyl O carboxymethyl} Puchirato (Compound 35) 2- (6-human Dorokishi one 2 —Naphthyl) 6-Methylpyrimidin-1-ol (1.5 g) and anhydrous potassium carbonate (1.2 g) in DMF (1 Om 1) solution at room temperature at room temperature. l) was added and stirred for two days. The reaction solution was concentrated under reduced pressure, and the residue 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 by a silica gel column (closure form) to obtain Compound 35.

 1H- 丽 R (DMS0-d6 / TMS):

 δ = 1.12-1.23 (6Η, m), 2.01-2.11 (4H, m), 2.48-2.54 (7H, m),

 4.03—4.18 (6H, m), 4.53 (2H, t, J = 6.3Hz), 6.70 (1H, s),

 7.20 (1H, dd, J = 2.6, 8.9Hz), 7.37 (1H, s),

 7.89 (1H, d, J = 8.9Hz), 8.01 (1H, d, J = 8.9Hz), 8.43 (1H, dd, J = 1.7, 8.9Hz),

8.86 (1H, s)

 F ABMS (m / z): 481 (M + 1) +

Example 36

 Production of 4- [6- (4-hydroxy-6-methyl-1-pyrimidinyl) -12-naphthyloxy] butanoic acid (Compound 36)

 Ethyl 4- [6- (4-hydroxy-16-methyl-12-pyrimidinyl) -1-2-naphthyloxy] butylate (800 mg) was dissolved in methanol (5 ml), and 1N aqueous sodium hydroxide solution (5 ml) was added under ice cooling. 11 ml) was added dropwise. After stirring at room temperature for 24 hours, the mixture was neutralized with a 1N aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration and washed with purified water to obtain Compound 36 as a yellow solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.00-2.10 (2Η, m), 2.45 (2H, t, J = 7.3Hz), 2.59 (3H, s),

 4.59 (2H, t, J = 6.6Hz), 6.91 (1H, s), 719-7.23 (2H, m),

7.83 (1H, d, J = 8.6Hz), 7.97 (1H, d, J = 8.6Hz), 8.35 (1H, dd, J = 1.7, 8.9Hz), 8.93 (1H, s)

 FABMS (m / z): 339 (M + 1) +

Example 37

 Preparation of 4- {2- [6- (3-carboxypropoxy) -12-naphthyl] -6-methyl-4-1-pyrimidinyloxy} butanoic acid (compound 37)

 Ethyl 4- {2- [6- (3-ethoxycanolevonylpropoxy) -12-naphthyl] —6-methyl-14-pyrimidinyloxy} butyrate (365 mg) was dissolved in methanol (5 ml). A 1N aqueous sodium hydroxide solution (7.6 ml) was added, and the mixture was treated in the same manner as in Example 36 to give compound 37.

 lH-NMR (DMS0-d6 / TMS):

 δ = 1.98-2.09 (4H, m), 2.41-2.556 (7H, m), 4.15 (2H, t, J = 6.6Hz),

 4.52 (2H, t, J = 6.6Hz), 6.71 (1H, s), 7.21 (1H, dd, J = 2.3, 8.9Hz),

 7.38 (1H, d, J = 2.3Hz), 7.89 (1H, d, J = 8.9Hz), 8.02 (1H, d, J = 9.2Hz),

8.44 (1H, dd, J = l.7, 8.9Hz), 8.87 (1H, d, J = l.0Hz), 12.19 (2H, s)

 FABMS (m / z): 425 (M + 1) +

Example 38

 Production of 2- (6-hydroxy-2-naphthyl) pyrimidine-1,4,6-diol (compound 38)

 After dissolving sodium metal (1.8 g) in absolute ethanol (50 ml) to prepare ethanol solution of sodium methoxide, 2-amidinol 6-naphthol 'methanesulfonate (10 g) and getyl malonate ( 5.9 ml) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction solution was neutralized with hydrochloric acid, purified water (500 ml) was added, and the precipitated solid was collected by filtration to obtain Compound 38.

 lH-NMR (DMS0-d6 / TMS):

 δ = 5.34 (1H, s), 7.18-7.27 (2H, m), 7.79 (1H, d, J = 8.9Hz),

 7.88 (1H, d, J = 9.2Hz), 8.10 (1H, d, J = 8.9Hz), 8.64 (1H, s), 11.23 (1H, br) FABMS (m / z): 255 (M + 1) +

 Example 39

Methyl 6- (4,6-dihydroxy-2-pyrimidinyl) 1-2-naphthyl Production of xyacetate (compound 39)

 To a solution of 2- (6-hydroxy-2-naphthyl) pyrimidine-1,4,6-diol (1.0 g) and anhydrous potassium carbonate (869 mg) in DMF (5 ml) at room temperature was added methyl bromide acetate (0. 31 ml) was added and the mixture was stirred at 80 ° C for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-0.01 N aqueous hydrochloric acid. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by a silica gel column (chloroform-form-methanol) to obtain Compound 39.

 1H-NMR (DMSO-d6 / TMS):

 δ = 3.73 (3H, s), 5 ・ 01 (2Η, s), 5.72 (1H, brs), 7.16 (1H, d, J = 2.3Hz),

 7.20 (1H, s), 7.80 (1H, d, J = 8.9Hz), 7.86 (1H, d, J = 9.6Hz),

8.08 (1H, d, J = 8.9Hz), 8.65 (1H, s), 10.16 (1H, brs), 12.58 (1H, br) F ABMS (m / z): 327 (M + 1) +

Example 40

Preparation of methyl 6-arsenide Dorokishi one 2- (6-main-butoxycarbonyl main butoxy one 2-naphthyl) Single ₄ one-pyrimidinyl O carboxymethyl § diacetate (Compound 40)

 To a solution of 2- (6-hydroxy-2-naphthyl) pyrimidine-1,4,6-diol (1.0 g) and anhydrous potassium carbonate (869 mg) in DMF (5 ml) at room temperature was added methyl bromide acetate (0. 3 1 ml) and stirred at 80 ° C for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-0.01 N aqueous hydrochloric acid. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified with a silica gel column (form-form-methanol) to obtain Compound 40.

 1H-Marauder R (DMS0-d6 / TMS):

 δ = 3.74 (6Η, s), 5.10 (4H, s), 6.42 (1H, s), 7.15 (1H, d, J = 2.3Hz),

7.18 (1H, s), 7.79 (1H, d, J = 8.6Hz), 7.86 (1H, d, J = 8.6Hz), 8.17 (1H, dd, J = l.7, 8.6Hz), 8.64 (1H , s), 10.08 (1H, s)

 F ABMS (m / z): 399 (M + 1) +

Example 41 Production of 6- (4-chloro-1-6-methyl-2-pyrimidinyl) -12-naphthol (Compound 41)

 2- (6-Hydroxy-1-naphthyl) -16-methylpyrimidin-14-ol (2 g) is dissolved in pyridine (30 ml), acetic anhydride (2.2 ml) is added, and the mixture is heated at room temperature. Stirred for hours. The precipitated solid was collected by filtration and washed with purified water and hexane to obtain 6- (4-hydroxy-16-methylpyrimidinyl) -12-naphthyl acetate. Phosphorus oxychloride (5 ml) was added to the obtained 6- (4-hydroxy-16-methylpyrimidinyl) -12-naphthyl acetate (2.0 g), and the mixture was heated under reflux for 1 hour. After cooling to room temperature, purified water was added to the reaction solution, and the mixture was stirred for 1 hour under ice cooling. The precipitated solid was collected by filtration and dried to obtain 6- (4-chloro-6-methylpyrimidinyl) _2-naphthyl acetate. The obtained 6- (4-chloro-6-methylbilimidinyl) -12-naphthyl acetate (1.5 g) was dissolved in methanol (10 ml), and anhydrous potassium carbonate (2.0 g) was added. For 10 minutes. After the reaction solution was filtered, the filtrate was neutralized by adding a dilute hydrochloric acid aqueous solution, and the precipitated solid was collected by filtration to obtain Compound 41.

 1H- 丽 R (DMS0-d6 / TMS):

 δ = 2.57 (3H, s), 7.13-7 · 18 (2H, m), 7.51 (1H, s), 7.80 (1H, d, J = 8.9Hz),

 8.00 (1H, d, J = 8.9Hz), 8.32 (1H, dd, J = l.7, 8.9Hz), 8.82 (1H, s),

 10.08 (1H, s)

 FABMS (m / z): 271 (M + 1) +

Example 42

 Preparation of 6- (4-methyl-1-pyrimidinyl) -2-naphthol (compound 42)

6- (4-Chloro-6-methinole-1-pyrimidinole) Dissolve 2-naphthonone (1.1 g) in ethanol (20 ml), add 10% palladium on activated carbon (150 mg), and add a stream of hydrogen. Stirred at room temperature for 6 hours. After filtering off the palladium activated carbon, the filtrate was concentrated under reduced pressure. The residue was partitioned with ethyl acetate-purified water, and the ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 42. 1H- 丽 R (DMS0-d6 / TMS):

 δ = 2.57 (3H, s), 7.15 (1H, dd, J = 2.3, 8.6Hz), 7.19 (1H, d, J = l.9Hz),

7.29 (1H, d, J = 5.0Hz), 7.79 (1H, d, J = 8.6Hz), 7.96 (1H, d, J = 8.9Hz),

8.41 (1H, dd, J = l.7, 8.9Hz), 8.75 (1H, d, J = 4.9Hz), 8.87 (1H, s),

 9.98 (1H, s)

 FABMS (m / z): 237 (M + 1) +

Example 43

 Preparation of Methyl 6- (4-Methyl-1-2-Pyrimigel) -12-Naphthyloxyacetate (Compound 43)

 6- (4-Methyl-2-pyrimidinyl) 1-2-naphthol (236 mg) was dissolved in DMF (5 ml), and anhydrous potassium carbonate (415 mg) and methyl bromide acetate (184 mg) were added. Stir for 5 hours. The reaction solution was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with a silica gel column (hexane-ethyl acetate) to obtain Compound 43.

 1H- 丽 R (DMS0-d6 / TMS):

 δ = 2.58 (3H, s), 3.75 (3H, s), 4.98 (2H, s), 7.28 (1H, dd, J = 2.3, 8.9Hz),

 7.31 (1H, d, J = 5.0Hz), 7.37 (1H, d, J = 2.3Hz), 7.91 (1H, d, J = 8.6Hz),

8.06 (1H, d, J = 8.9Hz), 8.48 (1H, dd, J = 1.7, 8.6Hz), 8.77 (1H, d, J = 5.0Hz), 8.93 (lH, s)

 FABMS (m / z): 309 (M + 1) +

Example 44

 Preparation of 6- (4-methyl_2-pyrimidinyl) -2-naphthyloxyacetic acid (compound 44)

Methyl 6- (4-methyl-1-pyrimidinyl) -12-naphthyloxyacetate (240 mg) was dissolved in methanol (5 ml), and 1N aqueous sodium hydroxide solution (2.3 ml) was added. Stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and a 5% aqueous solution of citric acid. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to obtain Compound 44. Was.

 1H-Ran R (DMS0-d6 / TMS):

 δ = 2.57 (3Η, s), 4.85 (2Η, s), 7.26 (1H, dd, J = 2.6, 8.9Hz),

 7.32 (1H, d, J = 5.0Hz), 7.34 (1H, d, J = 2.6Hz), 7.91 (1H, d, J = 8.9Hz), 8.05 (1H, d, J = 9.2Hz), 8.47 ( 1H, dd, J = l.7, 8.6Hz), 8.77 (1H, d, J = 5.OHz),

8.92 (1H, s), 13.11 (1H, br)

 F ABMS (m / z): 295 (M + 1) +

Example 45

 Preparation of 2- (6- (4-Methyl-1-2-pyrimidel) -1-2-naphthyloxy] ethylamine hydrochloride (Compound 45)

 6- (4-Methyl-12-pyrimidinyl) -12-naphthol (236 mg) was dissolved in DMF (5 ml), and anhydrous potassium carbonate (415 mg) and N- (t-butoxycarbonyl) -12_ Chloramine chloride (270 mg) was added, and the mixture was stirred at 80 ° C for 7 hours. The reaction solution was partitioned between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a silica gel column (hexane monoacetate). To the obtained product was added 1N hydrochloric acid / monoacetic acid solution (2 ml), and the mixture was stirred at room temperature for 2 hours, and then solidified by adding ether to obtain Compound 45.

 1H-Awake R (DMS0-d6 / TMS):

 δ = 2.60 (3H, s), 3.30-3.34 (2H, m), 4.38 (2H, d, J = 5.OHz),

 7.31 (1H, dd, J = 2.6, 8.9Hz), 7.38 (1H, d, J = 5.3Hz), 7.46 (1H, d, J = 2.3Hz),

7.97 (1H, d, J = 8.6Hz), 8.08 (1H, d, J = 8.9Hz), 8.47 (1H, dd, J-1.7, 8.6Hz),

8.79 (1H, d, J = 5.3Hz), 8.92 (1H, s)

 F ABMS (m / z): 280 (M + 1) +

 Example 46

 Preparation of Methyl [6- (4-hydroxy-6-methyl-12-pyrimigel) -12-naphthyloxy] carboxylate (Compound 46)

Dissolve 2- (6-hydroxy-2-naphthyl) -1-6-methylpyrimidin-14-ol (1.5 g) in DMF (30 ml), and add anhydrous potassium carbonate (2.9 g) and culoformic acid. Methyl (0.92 ml) was added, and the mixture was stirred at room temperature for 24 hours. Reaction liquid Was concentrated under reduced pressure, and the residue was partitioned between purified form and purified water. The black-mouthed form layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was washed with ethyl acetate-hexane, and the precipitated solid was collected by filtration to obtain Compound 46.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.33 (3Η, s), 3.90 (3Η, s), 6.28 (1H, s), 7.53 (1H, dd, J = 2.3, 8.9Hz),

 7.88 (1H, d, J = 2.3Hz), 8.05 (1H, d, J = 8.9Hz), 8.13 (1H, d, J = 9.2Hz),

8.26 (1H, dd, J = l.7, 8.6Hz), 8.80 (1H, s), 12.64 (1H, br)

 F ABMS (m / z): 3 1 1 (M + 1) +

Example 47

 Preparation of ethinole 6- [6— (4-hydroxy-1-6-methinolay 2-pyrimidinole) -2—naphthyloxy] hexanate (compound 47)

 6-Hexanoic acid bromide in a DMF (5 ml) solution of 2- (6-hydroxy-1-naphthyl) -1-6-methylpyrimidine-l-ol (1 g) and anhydrous potassium carbonate (869 mg) at room temperature After adding ethyl (89 Omg), the mixture was stirred at 80 ° C for 1 hour. After filtration, the reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-0.01 N aqueous hydrochloric acid. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by a silica gel column (chloroform) to obtain Compound 47.

 1H- 丽 R (DMS0-d6 / TMS):

 δ = 1.16 (3H, t, J = 6.9Hz), 1.42-1.57 (2H, m), 1.60-1.68 (2H, m),

 1.75-1.86 (2H, m), 2.33 (2H, t, J = 7.3Hz), 2.52 (3H, s),

 4.04 (2H, dd, J = 6.9, 14.2Hz), 4.52 (2H, t, J = 6.3Hz), 6.80 (1H, s), 7.15 (1H, d, J 2.3Hz), 7.19 (1H, d , J = 2.3Hz), 7.80 (1H, d, J = 8.6Hz), 7.96 (1H, d, J = 8.6Hz), 8.34 (1H, dd, J = l.7, 8, 6Hz), 8.84 ( 1H, s)

 F ABMS (m / z): 395 (M + 1) +

Example 48

Preparation of methyl (2E) — 3 -— [6 -— (4-hydroxy-16-methyl-1-pyrimidinyl) —2-naphthyl] propenate (compound 48) 6-Cyanol 2-naphthol (10 g) was dissolved in pyridine (50 ml), trifluoromethanesulfonic anhydride (11.6 ml) was added at 0 ° C., and the mixture was stirred at room temperature overnight. The reaction mixture was partitioned with ether-purified water, and the ether layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (hexane-ethyl acetate) to give 6-cyano 2-naphthyl trifurate. Methanesulfonate was obtained as a white solid. The obtained 6-cyano-1-naphthyl trifluoromethanesulfonate (3 g) was dissolved in DMF (30 ml), and methyl acrylate (1.3 ml), dichlorobis (triphenylphosphine) palladium (14 Omg), 90 with the addition of triethylamine (6.2 ml). The mixture was stirred at C for 6 hours. The reaction solution was distributed between ethyl acetate and purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried to give methyl (2E) — 3—

(6-cyano 2-naphthyl) Propenate was obtained. The resulting methyl (2E) - 3- (6- Shiano one 2-naphthyl) Puropenato the (2. 0 g) was dissolved in methanol (250 meters l), after the hydrochloric acid gas through 1.5 hours at 0 ^D C The mixture was stoppered and stirred overnight at room temperature. Ether was added to the reaction solution, and the precipitated solid was collected by filtration.The obtained solid was dissolved in methanol (70 ml), and ammonia gas was saturated at 0 ° C until saturated. For 3 days. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol and filtered. After the filtrate was concentrated, it was purified by a silica gel column (form-form-methanol-acetic acid) to obtain methyl (2E) -3- (6-amidino-2-naphthyl) propenate'acetate. Methyl (2E) —3- (6-amidino-2-naphthyl) propenate in a solution of sodium (21 mg) in methanol (50 ml), acetate (97 Omg) and ethyl acetate acetate (0.47 ml) Was added and the mixture was stirred at room temperature. The reaction solution was neutralized with a 1N aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration. The solid thus obtained was purified by a silica gel column (form-form-methanol in chloroform) to obtain Compound 48.

 1H-band R (CDC13 / TMS):

 δ = 2.44 (3Η, s), 3.85 (3H, s), 6.35 (1H, s), 6.60 (1H, d, J = 15.8Hz),

7.74 (1H, d, J = 8.6Hz), 7.86 (1H, d, J = 15.8Hz), 7.96-8.02 (3H, m),

8.28 (1H, dd, J = l.7, 8.6Hz), 8.75 (1H, s) FABMS (m / z): 321 (M + 1) +

Example 49

 Preparation of N-2-aminoethyl- [6- (4-hydroxy-16-methyl-2-pyrimidinyl) -12-naphthyloxy] acetamide.hydrochloride (Compound 49)

 6- (4-Hydroxy-6-methyl-2-pyrimidinyl) -12-naphthyloxyacetic acid (930 mg) was dissolved in DMF, and N- (t-butoxycarbonyl) ethylendiamine (481 mg) and 1- (3 —Dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride (575 mg) and N-hydroxybenzotriazole hydrate (460 mg) were added, and the mixture was stirred at room temperature with stirring. The reaction solution was partitioned with a 5% aqueous solution of ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and purified water, and then concentrated under reduced pressure. The precipitated white solid was collected by filtration, dissolved in DMF (3 ml), added with 4N hydrochloric acid-dioxane solution (12 ml), and stirred at room temperature for 6 hours. Ether was added to the reaction solution, and the resulting yellow oily substance was washed with ether and acetone, and the precipitated yellow solid was collected by filtration to obtain Compound 49.

 1H-Customer R (DMS0- d6 / TMS):

 δ = 2.52 (3Η, s), 2.84-2.90 (2H, m), 3.37-3.44 (2H, m), 4.96 (2H, s),

 6.84 (1H, s), 7.14-7.19 (2H, m), 7.78 (1H, d, J = 8.6Hz),

 7.96 (1H, d, J = 8.9Hz), 8.03 (2H, br), 8.34 (1H, dd, J = 1.7, 8.6Hz), 8.61 (1H, t, J = 5.6Hz), 8.83 (1H , s)

 FABMS (m / z): 353 (M + 1) +

Example 50

 Preparation of 6- [4- (3-Aminopropoxy) -1-6-methyl-1-pyrimidinyl] -2-naphthyloxyacetic acid.hydrochloride (Compound 50)

To a solution of methyl 6_ (4-hydroxy-6-methyl-1-pyrimidinyl) -12-naphthyloxyacetate (324 mg) and anhydrous potassium carbonate (200 mg) in DMF (5 ml) was added N (Butoxycarbonyl) -13-propylamine chloride (250 mg) was added, and the mixture was stirred at 80 ° C for 8 hours. Partition the reaction mixture with ethyl acetate-5% aqueous solution of citric acid. If the ethyl acetate layer is a saturated aqueous sodium hydrogen carbonate solution, And washed with purified water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified with a silica gel column (hexane monoethyl acetate). The obtained white solid was dissolved in methanol (5 ml), 4N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred for 2 hours. The precipitated white solid was collected by filtration, washed with purified water, and subsequently dissolved in 4N hydrochloric acid-dioxane solution (2 ml) and stirred at room temperature for 3 hours. Ether was added to the reaction solution, and the precipitated solid was collected by filtration and washed with ether to obtain Compound 50.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.09-2.19 (2Η, m), 2.53 (3H, s), 2.97-3.01 (2H, m),

 4.22—4.27 (2H, t, J = 5.9Hz), 5.04 (2H, s), 6.86 (1H, s),

 7.25 (1H, dd, J = 2.6, 8.9Hz), 7.41 (1H, d, J = 2.3Hz), 7.91 (1H, d, J = 8.9Hz),

8.00 (1H, d, J = 9.2Hz), 8.24 (2H, br), 8.38 (1H, dd, J = l.7, 8.6Hz), 8.85 (1H, d, J = l.3Hz)

 FABMS (m / z): 368 (M + 1) +

Example 51

6- [A- [N— (2-aminoethyl) aminocarbonylmethoxy] —6-methyl-2-pyrimidinyl} -12-naphthyloxyacetic acid'methyl 6- (4- T-Butyl acetate (0.53 ml) was added to a DMF (7 ml) solution of hydroxy-6-methyl-1-pyrimidinyl (12-naphthyloxyacetate) (972 mg) and anhydrous potassium carbonate (490 mg). ) Was added and stirred at room temperature for 1 hour. The reaction mixture was partitioned with ethyl acetate-5% aqueous citric acid.The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution and purified water, and dissolved in a 4N hydrochloric acid-dioxane solution (12 ml). Stirred for hours. Ether was added to the reaction mixture, and the precipitated pale yellow solid was collected by filtration, dried, dissolved in DMF (7 ml), and N- (t-butoxycarbonyl) ethylenediamine (461 mg), 1- (3-dimethyl (Aminopropyl) -13-ethylcarbodimidamide hydrochloride (552 mg) and N-hydroxybenzotriazole-hydrate (441 mg) were added, and the mixture was stirred at room temperature overnight. Partition the reaction mixture with ethyl acetate-5% aqueous solution of citric acid The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and purified water, and then concentrated under reduced pressure. The residue was dissolved in ethanol (5 ml), 4N aqueous sodium hydroxide solution (14 ml) was added, and the mixture was stirred for 3 hours. Ethanol and purified water were added to the reaction solution, the precipitated solid was collected by filtration, and the obtained solid was dissolved in a 4N dioxane hydrochloride solution (12 ml) and stirred at room temperature for 3 hours. Ether and acetone were added to the reaction solution, and the precipitated yellow solid was washed with acetone to obtain Compound 51.

 1H-NMR (DMS0-d6 / TMS):

 δ = 2.52 (3Η, s), 2.89-2.94 (2H, m), 3.42-3.48 (2H, m), 4.68 (2H, s), 5.04 (2H, s), 6.87 (1H, s), 7.37 ( 1H, dd, J = 2.3, 8.9Hz), 7.42 (1H, s),

7.92 (1H, d, J = 8.6Hz), 8.03 (1H, d, J = 8.9Hz), 8.14 (2H, br),

8.39 (1H, d, J = 9.9Hz), 8.54 (1H, t, J = 5.3Hz), 8.86 (1H, s) FABMS (m / z): 41 1 (M + 1) +

Example 52

 Preparation of 1- [N- (2-aminoethyl) aminocarbonylmethyl] —6- (4-hydroxy_6-methyl-2-pyrimidinyl) —2-naphthyloxyacetic acid hydrochloride (Compound 52)

Methinole 6-amidino 2-hydroxyl-naphthinoleacetate synthesized according to the method of T. Nakayama et al. (WO 9620917). (30 ml), ethyl acetate (351 mg) was added, and the mixture was refluxed for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was neutralized by adding a 10% aqueous solution of citric acid, and the precipitated white solid was collected by filtration. The obtained solid was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (5.4 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with a 10% aqueous solution of citric acid, and the precipitated solid was collected by filtration to obtain 2-hydroxy-6_ (4-hydroxy-16-methyl-2-pyrimidinyl) _1-naphthylacetic acid. . The resulting 2-hydroxy-16- (4-hydroxy-16-methyl-2-pyrimidinyl) -11-naphthylacetic acid (300 mg) and N- (t-butoxycarbonyl) ethylenediamine (171 mg) The DMF (5 ml), and add benzotriazo-1-yl-1-yloxocitris (dimethylamino) phosphonium hexafluorophosphate (469 mg) and N, N-diisopropylethylamine (0.22 ml). The mixture was stirred overnight at room temperature. The reaction mixture was neutralized with a 5% aqueous solution of citric acid, and the precipitated solid was collected by filtration. N- [2- (t-butoxycarbonylamino) ethyl-2-hydroxy-6- (4-hydroxyl 6-Methyl-2-pyrimidinyl) -11-naphthyl] acetamide (274 mg) was obtained as a white solid. The obtained N- [2- (t-butoxycarbonylamino) ethyl-1-hydroxy-6- (4-hydroxy-16-methyl-12-pyrimidinyl) -11-naphthyl] acetoamide (270 mg) and anhydrous Potassium carbonate (81 mg) was suspended in DMF (3 ml), t-butyl bromoacetate (0.09 ml) was added at room temperature, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was partitioned with ethyl acetate-purified water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue was added 4N hydrochloric acid-dioxane solution (4.8 ml), and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 52.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.52 (3H, s), 2.85-2.87 (2H, m), 3.28-3 · 37 (2H, m), 3.93 (2H, s),

5.02 (2H, s), 6.84 (1H, s), 7.29 (1H, d, J = 8.9Hz), 7.84 (1H, d, J = 8.9Hz), 7.95 (1H, d, J = 9.2Hz), 8.33 (1H, dd, J = l.7, 8.9Hz),

 8.78 (1H, d, J = l.7Hz)

 FABMS (m / z): 41 1 (M + 1) +

 Example 53

 Preparation of 6- [5- (6-aminohexyl) -14-hydroxy-1-6-methyl-2-pyrimidinyl] -12-naphthyloxyacetic acid hydrochloride (Compound 53)

Dissolve ethyl acetate (410 mg) in DMF (6 ml), add 60% sodium hydride (400 mg) under ice-cooling, stir for 30 minutes, and add N- (t-butoxycarbol) 16-odor Hexylamine hydrochloride (580 mg) was added, and the mixture was stirred at room temperature with stirring. The reaction mixture was partitioned between ethyl acetate and a 10% aqueous solution of citric acid. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a brown oil (500 mg). W

 45. Dissolve sodium methoxide (324 mg) in methanol (20 ml), add 2-amidino-1-6-naphthol 'methanesulfonate (564 mg) and the oily substance (500 mg) obtained above, and stir at 80 ° C for 25 hours. did. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate-5% aqueous citric acid. The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and purified water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified on a silica gel column (clo-form-methanol). 6-Aminohexyl) 1-2- (6-hydroxy-12-naphthyl) -1-6-methylpyrimidin-14-ol (11 Omg) was obtained as a white solid. The obtained 5- (6-aminohexyl) 1-2- (6-hydroxy-12-naphthyl) -16-methylpyrimidin-14-ol (ll Omg) and potassium carbonate anhydride (33 mg) were added to DMF (2 ml). ), And t-butyl bromide (0.04 ml) was added thereto at room temperature, followed by stirring overnight. The reaction solution was concentrated under reduced pressure, and the residue 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 by a silica gel column (ethyl hexane monoacetate) to obtain t-butyl 6- {5- [6-(N-t-butoxy). Carbonylamino) hexyl 4-hydroxy-1-6-methynole-12-pyrimidinole]} 1-Naphthyloxyacetate was obtained as a colorless oil. To the obtained oil (64 mg) was added a 4N hydrochloric acid-dioxane solution (3 ml), and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound 53.

 lH-NMR (DMS0-d6 / TMS):

 δ = 1.39-1.60 (8Η, m), 2.60-2.77 (7H, m), 5.08 (2H, s), 7.15-7.19 (2H, m), 7.78 (1H, d, J = 8.9Hz), 7.89 ( 1H, d, J = 8.9Hz), 8.08 (2H, br), 8.28 (lH, d, J = 8.9Ηζ), 8.79 (1H, s)

 FABMS (m / z): 410 (M + 1) +

 Example 54

 Preparation of 6- (4-Hydroxy-6-methyl-1-pyrimidel) -11-ode-12-naphthyloxyacetic acid (Compound 54)

Dissolve sodium 6- (4-hydroxy-16-methyl-12-pyrimigel) -12-naphthyloxyacetate (33mg) in acetic acid (2ml) and add iodine (1 03mg) and stirred at 70 ° C for 6 hours. After the reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, the insoluble material was removed by filtration, the filtrate was acidified with a 10% aqueous solution of citric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain Compound 54 as a yellow solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.47 (3H, s), 4.95 (2H, s), 6.75 (1H, s), 7.31 (1H, d, J = 7.6Hz),

 7.91 (1H, d, J = 8.9Hz), 7.98 (1H, d, J = 8.9Hz), 8.40 (1H, d, J = 8.9Hz),

8.74 (1H, s)

 F ABMS (m / z): 437 (M + 1) +

Example 55

 Preparation of benzyl 6- (4-hydroxy-1-6-methyl-2-pyrimidinyl) -12-naphthyloxyacetate (Compound 55)

 6- (4-Hydroxy-1-6-methylinole-2-pyrimidinyl) A solution of cesium carbonate (3.3 g) in methanol (30 Om 1) solution of 1,2-naphthyloxyacetic acid (6.2 g) at room temperature. (300 ml) The solution was added and dissolved, and then the solvent was distilled off under reduced pressure. The residue was dried, and the obtained cesium 6- (4-hydroxy-16-methyl-2-pyrimidyl) was obtained. Benzyl bromide (0.04 ml) was added to a DMF (lm 1) solution of 12-naphthinoleoxyacetate (140 mg), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogencarbonate solution and hexane were added to the reaction solution, and the mixture was stirred, and the precipitated solid was collected by filtration. The obtained solid was washed with purified water and hexane to obtain Compound 55 as a white solid.

 1H-NMR (CDC13 / TMS):

 δ = 2.55 (3H, s), 5.09 (2H, s), 5.24 (2H, s), 6.62 (1H, s),

 7.10 (1H, dd, J = 2.6, 8.9Hz), 7.15 (1H, d, J = 2.6Hz), 7.23-7.32 (6H, m),

7.66 (1H, d, J = 8.6Hz), 7.79 (1H, d, J = 8.6Hz), 8.36 (1H, dd, J = l.7, 8.6Hz),

8.78 (1H, s)

 F ABMS (m / z): 401 (M + 1) +

Example 56 Production of Nonanyl 6- (4-hydroxy-16-methyl-2-pyrimidinyl) -1-naphthyloxyacetate (Compound 56)

 Non-monobromide (0.14 ml) was added to a solution of cesium 6- (4-hydroxy-6-methyl-2-pyrimidinyl) -12-naphthyloxyacetate (300 mg) in DMF (2 ml). In addition, the mixture was stirred at room temperature for 2 hours. 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 purified on a silica gel column (ethyl hexane monoacetate) to give Compound 56 as white Obtained as a solid.

 1H-NMR (CDC13 / TMS):

 δ2 0.86 (3Η, t, J = 6.9Hz), 1.16 (12H, m), 1 58-1.64 (2H, ra), 2.56 (3H, s),

 4.19 (2H, t, J = 6.6Hz), 5.03 (2H, s), 6.62 (1H, s),

 7.12 (1H, dd, J = 2.6, 8.9Hz), 7.17 (1H, d, J = 2.3Hz), 7.72 (1H, d, J = 8.6Hz), 7.88 (1H, d, J = 8.9Hz), 8.40 (1H, dd, J = 1.7, 8.6Hz), 8.83 (1H, s) F ABMS (m / z): 437 (M + 1) +

Example 57

 Preparation of methoxymethyl 6- (4-hydroxy-6-methyl-1-pyrimidinyl) -1-2_naphthyloxyacetate (Compound 57)

 Cesium 6- (4-hydroxy-1 6-methyl_2-pyrimigel) 12-naphthyloxyacetate (300 mg) in DMF (2 ml) was mixed with methoxymethane chloride (0.06 ml). In addition, the mixture was stirred at room temperature for 2 hours. The reaction mixture was distributed 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 using a silica gel column (hexane-ethyl acetate). Compound 57 was obtained as a white solid.

 1H-NMR (CDC13 / TS):

 δ = 2.56 (3Η, s), 3.38 (3H, s), 5.08 (2H, s), 5.36 (2H, s), 6.64 (1H, s),

7.12 (1H, dd, J = 2.6, 8.9Hz), 7.16 (1H, d, J = 2.6Hz),

 7.71 (1H, d, J-8.6Hz), 7.88 (1H, d, J = 8.9Hz), 8.40 (1H, dd, J = l.7, 8.6Hz),

8.83 (1H, s)

F ABMS (m / z): 355 (M + 1) + Example 58

 Preparation of 2- [2- (2-Methoxyethoxy) ethoxy] ethyl 6- (4-Hydroxy-1-6-methyl-2-pyrimidinyl) -1-2-naphthyloxyacetate (Compound 58)

 Triethylene glycol monomethyl ether (0.8 ml) was dissolved in pyridine (2 ml), methanesulfonic acid chloride (0.39 ml) was added at 0 ° C, and the mixture was stirred for 2 hours. The reaction solution was distributed with ethyl acetate-dilute hydrochloric acid aqueous solution, and the ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution and purified water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2- [2- ( 2-Methoxyxetoxy) ethoxy] ethyl methanesulfonate was prepared. The obtained 2- [2- (2-methoxyethoxy) ethoxy] ethyl methanesulfonate (12 Omg) was converted to cesium 6- (4-hydroxy-16-methyl-1-2-pyrimidini-2-naphthinoleoxy). Acetate (200 mg) in DMF (2 ml) was added and stirred at room temperature for 2 hours 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. After concentration under reduced pressure, the residue was purified by a silica gel column (chloroform-form-ethanol) to obtain Compound 58 as a colorless oily substance.

 1H-band R (CDCl3 / TMS):

 6 = 1.57 (3H, s), 2.55 (3H, s), 3.52-3.79 (8H, m), 4.34-4.40 (4H, m),

 5.07 (2H, s), 6.62 (1H, s), 7.13 (1H, dd, J = 2.6, 8.6Hz),

 7.17 (1H, d, J = 2.0Hz), 7.72 (1H, d, J = 8.9Hz), 7.89 (1H, d, J = 8.9Hz), 8.40 (1H, dd, J = 1.7, 8.9Hz) ), 8.82 (1H, s)

 F ABMS (m / z): 457 (M + 1) +

 Example 59

 Production of N_ 2 -phthalimidoethyl 6-(4-hydroxy-16 -methyl-2-pyrimidinyl)-1 -naphthyloxyacetate (Compound 59)

Cesium 6- (4-hydroxy-16-methyl-12-pyrimidinyl) -12-naphthyloxyacetate (200mg) in DMF (1ml) solution was mixed with N- (2-chlorinated tyl) phthalimide (105mg) ) Was added and the mixture was stirred at room temperature for 2 hours. Reaction liquid 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 purified by a silica gel column (chloroform-form-ethanol) to obtain compound 59. Was.

 1H-Awake R (CDC13 / TMS):

 δ = 2.53 (3Η, s), 3.99 (2Η, t, J = 5.OHz), 4.47 (2H, t, J = 5.0Hz), 5.02 (2H, s),

6.58 (1H, s), 7.11 (1H, dd, J = 2.3, 8.6Hz), 7.15 (1H, d, J = 2.3Hz),

7.64-7.76 (5H, m), 7.86 (1H, d, J = 8.9Hz), 8.33 (1H, dd, J = l.7, 8.6Hz),

8.74 (1H, s)

 FABMS (m / z): 4 84 (M + 1) +

Example 60

 Preparation of 2-N, N-dimethylaminoethynole 6- (4-hydroxy-16-methyl-12-pyrimidinyl) -1,2-naphthyloxyacetate (Compound 60) Cesium 6- (4-hydroxyloxy) 2-Dimethylaminoethane chloride (54 mg) was added to a solution of 1-6-methyl-12-pyrimidinyl) -12-naphthyloxyacetate (200 mg) in DMF (2 ml), and the mixture was stirred at room temperature for 2 hours. . The reaction solution was distributed with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was extracted with chloroform and the extract was concentrated under reduced pressure, and the solvent was distilled off to obtain Compound 60 as a white solid.

 1H-NMR (CDC13 / TMS):

 δ = 2.28 (6H, s), 2.54 (3H, s), 2.65 (2H, t, J = 5.6Hz), 4.35 (2H, t, J = 5.6Hz),

 5.02 (2H, s), 6.60 (1H, s), 7.04-7.08 (2H, m), 7.61 (1H, d, J = 8.6Hz), 7.80 (1H, d, J2 8.3Hz), 8.31 (1H , Dd, J = l.6, 8.6Hz), 8.74 (1H, s)

 FABMS (m / z): 3 8 2 (M + 1) +

 Example 6 1

 Preparation of 2-morpholinoletyl 6- (4-hydroxy-16-methyl-1-pyrimidyl) _2-naphthyloxyacetate (compound 61)

Cesium 6- (4-hydroxy-6-methyl-12-pyrimidinyl) -12-naphthyloxyacetate (300 mg) in DMF (2 ml) solution (112 mg) was added and the mixture was stirred at room temperature for 2 hours. Reaction solution After partitioning 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 by a silica gel column (chloroform-ethanol) to obtain compound 61. .

 1H-MR (CDC13 / TMS):

 6 = 2.39 (4H, t, J = 4.6Hz), 2.56 (3H, s), 2.62 (2H, t, J = 5.6Hz),

 3.61 (4H, t, J = 4.6Hz), 4.34 (2H, t, J = 5.6Hz), 504 (2H, s), 6.61 (1H, s), 7.10 (1H, dd, J = 2.3, 8.6Hz), 7.12 (1H, d, J = l.3Hz), 7.68 (1H, d, J = 8.9Hz), 7.85 (1H, d, J = 8.6Hz), 8.37 (1H, dd, J = l) .7, 8.6Hz), 8.80 (1H, s)

 F ABMS (m / z): 4 24 (M + 1) +

Example 6 2

 Preparation of 2-pyridylmethyl 6- (4-hydroxy-6-methyl-2-pyrimigel) -1-2-naphthyloxyacetate (compound 62)

 To a solution of cesium 6- (4-hydroxy-6-methyl-2-pyrimidinole) -12-naphthyloxyacetate (150 mg) in DMF (1 ml) was added 2-picolin chloride (47 mg). Stirred at room temperature for 2 hours. The reaction solution 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 (form-form ethanol). Compound 62 was obtained.

 1H-NMR (CDC13 / TMS):

 δ = 2.55 (3Η, s), 5.14 (2H, s), 5.36 (2H, s), 6.63 (1H, s), 7.01-7.15 (3H, m),

7.23-7.39 (2H, m), 7.65 (1H, d, J = 8.6Hz), 7.80 (1H, d, J = 8.6Hz),

 8.35 (1H, dd, J = l.7, 8.6Hz), 8.51 (1H, d, J = 5.0Hz), 8.77 (1H, s)

 F ABMS (m / z): 402 (M + 1) +

 Example 63

 Preparation of 2-piperidinoethynole 6- (4-hydroxy-16-methyl-12-pyrimidinyl) -12-naphthyloxyacetate (compound 63)

Cesium 6- (4-hydroxy-6-methyl-2-pyrimidinyl) _ 2-naphthyloxyacetate (200mg) in DMF (2ml) solution was mixed with 1- (2-chlorinated tyl) piperidine ( 74 mg) and stirred at room temperature for 2 hours. Vinegar After partitioning with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer was washed with purified water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 63 as a colorless oily substance.

 1H-Marauder R (CDCl3 / TMS):

 δ = 1.37-1.41 (2Η, m), 1.50-1.58 (4H, m), 2.37—2.40 (4H, m), 2.54 (3H, s),

2.64 (2H, t, J = 5.9Hz), 4.35 (2H, t, J = 5.9Hz), 4.98 (2H, s), 6.59 (1H, s),

7.06-7.10 (2H, m), 7.64 (1H, d, J = 8.9Hz), 7.83 (1H, d, J = 8.6Hz),

 8.33 (1H, dd, J = l.7, 8.6Hz), 8.76 (1H, d, J = l.0Hz)

 FABMS (m / z): 4 22 (M + 1) +

Example 64

 Production of pivaloyloxymethyl 6- (4-hydroxy-16-methyl-2-pyrimidinyl) -12-naphthyloxyacetate (Compound 64)

 Chloromethyl pivalate (0.07 ml) was added to a solution of cesium 6- (4-hydroxy-16-methyl-2-pyrimidinyl) -12-naphthyloxyacetate (200 mg) in DMF (1 ml). In addition, the mixture was stirred at room temperature for 2 hours. 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 (hexane monoethyl acetate) to give the compound. 64 was obtained as a colorless oil.

 1H-NMR (CDC13 / TMS):

 δ = 1.12 (9Η, s), 2.56 (3H, s), 5.10 (2H, s), 5.85 (2H, s), 6.63 (1H, s),

7.12 (1H, dd, J = 2.6, 8.9Hz), 7.16 (1H, d, J = 2.0Hz),

 7.71 (1H, d, J = 8.6Hz), 7.89 (1H, d, J = 8.9Hz), 8.39 (1H, dd, J = l.7, 8.6Hz),

8.81 (1H, s)

 FABMS (m / z): 4 2 5 (M + 1) +

 Example 6 5

Preparation of N, N-dimethylaminocarbonylmethyl 6 _ (4-hydroxy-6-methyl-1-pyrimidinyl) _ 2-naphthyloxyacetate (Compound 65) Cesium 6- (4-hydroxy 6-methyl- 2-Pirimigel) A solution of 2-naphthyloxyacetate (200 mg) in DMF (1 ml) Dimethylacetamide (0.09 ml) was added, and the mixture was stirred at room temperature for 2 hours. Purified water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with chloroform and hexane to obtain Compound 65.

 1H-Awake R (DMSO-d6 / TMS):

 δ = 2.50 (3Η, s), 2.83 (3H, s), 2.89 (3H, s), 4.93 (2H, s),

 5.21 (2H, s), 6.84 (1H, s), 7.12 (1H, dd, J = 2.3, 8.6Hz),

 7.16 (1H, d, J = 2.3Hz), 7.75 (1H, d, J = 8.9Hz), 7.99 (1H, d, J = 8.6Hz), 8.32 (1H, dd, J = 1.7, 8.9Hz) ), 8.82 (1H, s), 9.97 (1H, s)

 F ABMS (m / z): 396 (M + 1) +

Example 66

 Production of 2-Hydroxitytyl 6- (4-Hydroxy-6-methyl-12-pyrimidinyl) -1-2-naphthyloxyacetate (Compound 66)

 Ethylene glycol monobenzinoreate / le (1.4 ml) was dissolved in pyridine (2 ml), methanesulfonic acid chloride (0.85 ml) was added at 0 ° C, and the mixture was stirred for 2 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 then purified on a silica gel column (hexane monoethyl acetate). Ndiroxityl methanesulfonate was prepared. DMF of cesium 6- (4-hydroxy-16-methynole-2-pyrimidinyl) -2-naphthyloxyacetate (400 mg) obtained from 2-benzyloxyshethyl methanesulfonate (230 mg) was obtained. (2 ml) solution and stirred for 8 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 and concentrated under reduced pressure. To the residue was added 10% palladium activated carbon (200 mg), and the mixture was stirred as a solution of ethanol (8 ml) under a hydrogen stream for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified with a silica gel column (hexane monoethyl acetate) to obtain Compound 66.

 1H-NMR (CDC13 / TMS):

 δ = 2.56 (3Η, s), 3.80-3.84 (2H, m), 4.34 (2H, t, J = 4.6Hz), 5.08 (2H, s),

6.64 (1H, s), 7.10-7.16 (2H, m), 7.73 (1H, d, J = 8.6Hz), 7.90 (1H, d, J = 8.9Hz), 8.41 (1H, dd, J = 1.7, 8.9Hz), 8.83 (1H, s)

 F ABMS (m / z): 355 (M + 1) +

Example 67

 Preparation of (S) 1-(+)-2,3-dihydroxypropyl 6- (4-hydroxy-6-methyl-2-pyrimidinyl) -2-naphthyloxyacetate (Compound 67)

 (S) One (+)-2,2-dimethyl-1,3-dioxolan-14-methanol (1.2 ml) is dissolved in pyridine (2 ml), and methanesulfonic acid chloride (0.85 m l) was added and the mixture was stirred for 2 hours. The reaction solution 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 (hexane-ethyl acetate).

(S)-(+) — 2,2-dimethyl-1,3-dioxolan-14-methyl methanesulfonate was obtained. The obtained (S)-(+) — 2,2-dimethyl-1,3,3-dioxolan-4-methinole methanesulfonate (210 mg) was treated with cesium 6— (4-hydroxy-6-methinolay 2-pyrimidinole) 1-2. A solution of naphthyloxyacetate (400 mg) in DMF (2 ml) was added and stirred for 2 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 and concentrated under reduced pressure. The residue was dissolved in ethanol (8 ml), stirred at 60 ° C for 4 hours, concentrated under reduced pressure, and purified by silica gel column (hexane monoethyl acetate) to give compound 67 as a white solid. Obtained.

 1H-NMR (CD30D / TMS):

 δ = 2.53 (3H, s), 3.51-3.53 (2H, m), 3.86 (1H, m),

 4.20 (1H, dd, J = 6.3, 11.2Hz), 4.29 (1H, dd, J = 4.6, 11.2Hz), 5.10 (2H, s), 6.71 (1H, s), 7.09-7.13 (2H, m) , 7.70 (1H, d, J = 8.9Hz),

 7.86 (1H, d, J = 8.6Hz), 8.31 (1H, dd, J = 1.6, 8.9Hz), 8.74 (1H, s) F ABMS (m / z): 385 (M + 1) +

 Example 68

Preparation of 6- (2-pyrimidinyl) -1-2-naphthyloxyacetic acid (Compound 68) 2-Amidino-6-naphthol'methanesulfonate (282 mg), 1,1,3,3-tetramethoxypropane (2 ml), and acetonitrile (2 ml) in a sealed tube at 140 ° C for 1 hour Heated. The reaction solution was partitioned with a solution of aqueous sodium hydrogencarbonate in saturated sodium bicarbonate, the chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified on a silica gel column (ethyl hexane monoacetate). (2-Pyrimidinyl) 1-2-naphthol was obtained. The obtained 6- (2-pyrimidinyl) -12-naphthol (25 mg) was dissolved in DMF (2 ml), and anhydrous potassium carbonate (46 mg) and methyl bromide acetate (0.1 ml) were added. For 1 hour. After partitioning the reaction solution with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, the ethyl acetate layer is dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue is washed with hexane and ethanol to give methyl 6- (2 —Pirimigel) I obtained 2-naphthyloxyacetate. The obtained methyl 6- (2-pyrimidinyl) _2-naphthyloxyacetate (24 mg) was suspended in ethanol (5 ml), and a 2N aqueous sodium hydroxide solution (0.2 ml) was added. Stirred for minutes. The reaction solution was neutralized with dilute hydrochloric acid and then concentrated under reduced pressure. Compound 68 was obtained by adding purified water to the residue and collecting the precipitated solid by filtration.

 1H-NMR (DMS0-d6 / TMS):

 δ = 4.85 (2Η, s), 7.27 (1H, dd, J = 2.6, 8.9Hz), 7.35 (1H, d, J = 2.6Hz), 7.45 (1H, t, J = 5.0Hz), 7.92 (1H , d, J = 8.6Hz), 8.06 (1H, d, J = 8.9Hz), 8.46 (1H, dd, J = l.7, 8.6Hz), 8.93-8.94 (3H, m), 13.09 (1H, br)

FABMS (m / z): 281 (M + 1) +

Example 69

 Preparation of 6- (4-chloro _ 6-methynole-1-pyrimidinyl) -12-naphthyloxyacetic acid (Compound 69)

6- (4_Chloro-6-methynole-1-pyrimidinole) 1-2-naphthol (79 Omg) and anhydrous potassium carbonate (800 mg) are suspended in DMF (5 ml) and t-butyl bromide acetate (0 ml) is added at room temperature. . 84 ml) was added and stirred. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and purified water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane, There was obtained t-butyl 6- (4-methyl-1-6-methylpyrimidinyl) -12-naphthyloxyacetate (800 mg). The obtained t-butyl 6- (4-chloro-16-methylpyrimidinyl) -12-naphthyloxyacetate (350 mg) was dissolved in trifluoroacetic acid (3 ml) and stirred at room temperature for 2 hours. A mixed solution (300 ml) of ether / hexane (1: 1) was added to the reaction solution, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration to obtain Compound 69 as a white solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.58 (3H, s), 4.84 (2H, s), 7.27 (1H, dd, J = 2.3, 8.9Hz), 7.34 (1H, s), 7.53 (1H, s), 7.92 (1H, d, J = 8.9Hz), 8.08 (1H, d, J = 8.9Hz), 8.39 (1H, d, J = 8.9Hz), 8.87 (1H, s), 13.07 (1H, br)

 FABMS (m / z): 3 2 9 (M + 1) +

Example 70

 Preparation of 2- [6- (4-hydroxy-1-6-methyl-2-pyrimidinyl) -1-naphthyloxy] ethyl acetate (Compound 70)

 2- (6-Hydroxy-1-naphthyl) -1-6-methylpyrimidine_4-thiol (1.1 g) and anhydrous potassium carbonate (890 mg) are suspended in DMF (10 ml), and the mixture is suspended at room temperature in 2-bromoethyl. Acetate (0.48 ml) was added, and the mixture was stirred at 80 ° C for 18 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and purified water. The ethyl acetate layer was washed with purified water and a 5% aqueous solution of citric acid, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified with a silica gel column (Formula methanol). (4-Hydroxy-6-methyl-2-pyrimidinyl) -2-naphthyloxy] ethyl acetate (compound 70) and 2- {2- [6- (2-acetoethoxyethoxy) —2-naphthyl 1-Methyl-4-pyrimigeroxy} ethyl acetate (yellow oil) was obtained.

 1H-NMR (CDC13 / TMS):

 δ = 2.09 (3Η, s), 2.54 (3Η, s), 4.49-4.52 (2H, m), 4.75-4.78 (2H, m),

 6.52 (1H, s), 7.12-7.17 (2H, m), 7.71 (1H, d, J = 8.6Hz),

7.86 (1H, d, J = 8.6Hz), 8.41 (1H, s), 8.50 (1H, d, J = 8.6Hz), 8.85 (1H, s) F ABMS (m / z): 339 (M + 1) +

Example 71

 Preparation of 2- {2- [6- (2-hydroxyethoxy) 1-2-naphthyl] -1-6-methyl-4-pyrimidinyloxy} ethanol (Compound 71)

In Example 70, the yellow oily substance (2- {2- [6- (2-acetoethoxyethoxy) 1-2-naphthyl] -12-naphthyl] -6-methyl-4-pyrimidinyloxy} finally obtained with compound 70. Ethyl acetate) (10 Omg) was dissolved in methanol (1 ml), 4N aqueous sodium hydroxide solution (1.0 Oml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with a 4N hydrochloric acid-dioxane solution, purified water was added and the mixture was stirred, and the precipitated solid was collected by filtration to obtain Compound 71.

 1H-NMR (DMS0-d6 / TMS):

 δ = 2.49 (3H, s), 3.79-3.81 (4H, m), 4.15 (2H, t, J = 5.0Hz),

 4.52 (2H, t, J = 5.0Hz), 4.91-4.93 (2H, m), 6.71 (1H, s),

 7, 22 (1H, dd, J = 2.3, 8.9Hz), 7.38 (1H, d, J = 2.3Hz), 7.89 (1H, d, J = 8.9Hz), 8.01 (1H, d, J = 8.9Hz) ), 8.43 (1H, dd, J = 1.7, 8.9Hz), 8.86 (1H, s)

F ABMS (m / z): 341 (M + 1) +

Example 72

 Production of 2- [6- (4-hydroxy-6-methyl-2-pyrimidinyl) -1-2-naphthyloxy] ethanol (Compound 72)

 Dissolve 2- [6- (4-hydroxy-6-methyl-1-pyrimidyl) -12-naphthyloxy] ethyl acetate (48 Omg) in methanol (3 ml) and add 4N aqueous sodium hydroxide at room temperature. (2.8 ml) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was neutralized with 4N hydrochloric acid-dioxane solution, and the precipitated solid was collected by filtration to obtain Compound 72.

 1H-Marauder R (DMS0-d6 / TMS):

 δ = 2.47 (3H, s), 3.76-3.82 (2H, m), 4.51 (2H, t, J = 5.0Hz),

 4.90 (1H, t, J = 5.6Hz), 6.69 (1H, s), 7.10-7.17 (2H, m),

 7.76 (1H, d, J = 8.6Hz), 7.94 (1H, d, J = 8.6Hz),

8.36 (1H, dd, J = l.3, 8.6Hz), 8.81 (1H, s), 9.96 (1H, br) F ABMS (m / z): 2 9 7 (M + 1) +

Example 73

 Preparation of 6- (4-hydroxy-6-methyl-2-pyrimidinyl) -1-2-naphthoic acid 'hydrochloride (Compound 73)

 Toluene (6000 ml) was added to dimethyl 2,6-naphthalenedicarboxylate (20 lg), and dissolved by heating. A solution of potassium hydroxide (46 g) in methanol (920 ml) was added. 7 5. The mixture was stirred at C for 1 hour. The reaction solution was returned to room temperature, and the precipitated solid was collected by filtration and washed with toluene and purified water. The obtained solid was dissolved by heating in purified water (4000 ml), concentrated hydrochloric acid was added, and the precipitated solid was collected by filtration and washed with acetone to obtain 6-methoxycarbonyl-12-naphthoic acid. Was. The obtained 6-methoxycarbonyl-2-naphthoic acid (136 g) was dissolved in toluene (82 Oml), and thionyl chloride (84.5 g) and DMF (0.1 ml) were added. The mixture was refluxed for 2 hours. After cooling the reaction solution, a 28% aqueous ammonia solution (110 ml) was added, and the mixture was stirred at room temperature for 1 hour. Purified water was added to the reaction solution, and the precipitated solid was collected by filtration and washed with toluene to obtain methyl 6-forcerubamoyl-12-naphthalate as a white solid.

 An aqueous solution (70 ml) of sodium hydroxide (45.4 g) was added to a solution of the obtained methyl 6-forcerubamoyl-2-naphthoate (130 g) in ethanol (1300 ml), and the mixture was heated under reflux for 1 hour. . The reaction solution was concentrated under reduced pressure, and the residue was partitioned between purified water and a mixed solvent of methylene chloride and methanol (4: 1). Concentrated hydrochloric acid was added to the aqueous layer, and the precipitated solid was collected by filtration and washed with acetone to obtain 6-force rubamoyl-2-naphthoic acid as a white solid. DMF (0.2 ml) was added to the obtained solution of 6-force rubamoyl-1-naphthoic acid (40 g) in thionyl chloride (200 ml), and the mixture was heated under reflux for 4.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was washed with hexane and isopropyl ether to give 6-cyano 2-naphthoyl chloride as a white-yellow solid.

A solution of the obtained 6-cyano-2-naphthoyl chloride (40 g) in methanol (600 ml) was stirred at room temperature for 3 days, and the precipitated white solid was collected by filtration to give methyl 6-cyano-2-naphthalate. I got Methyl 6-cyano-2-naphthate obtained (32 g) was dissolved in methanol (1600 ml), hydrogen chloride gas was allowed to pass under water cooling until the solution was saturated, the solution was sealed, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, the residue was washed with ether and acetone, dissolved in methanol (1900 ml) under ice-cooling, and ammonia gas was passed until saturation under ice-cooling. The mixture was stoppered and stirred at room temperature for 6 days. After the reaction solution was concentrated under reduced pressure, purified water (300 ml) and concentrated hydrochloric acid (280 ml) were added to the residue, and the mixture was heated under reflux for 3 hours. After cooling the reaction solution, the precipitated solid was collected by filtration and washed with acetone to obtain 6-amidinol 2-naphthoic acid · hydrochloride.

To a solution of the obtained 6-amidino-2-naphthoic acid ′ hydrochloride (3.2 g) in methanol (15 Om 1) was added sodium methoxide (2.7 g) and ethyl acetate acetoacetate (2.4 g). And stirred at 50 for 6 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in purified water (500 ml), and concentrated hydrochloric acid was added until the solution became acidic. The precipitated solid was collected by filtration, and washed with purified water, methanol, and acetone to obtain Compound 73 as a white solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.45 (3H, s), 6.53 (1H, s), 8.07-8.19 (2H, m), 8.28 (2H, s), 8.69 (1H, s), 8.87 (1H, s)

 F ABMS (m / z): 281 (M + 1) +

Example 74

 Of N— 2— (N,, N, dimethinoleamino) ethyl 6— (4-chloro-16-methyl-2-pyrimidinyl) _2-amidophthamide dihydrochloride (Compound 74)

To a solution of 6- (4-hydroxy-1-6-methyl-2-pyrimidinyl) -1-naphthoic acid-hydrochloride (40 Omg) in thionyl chloride (5 ml), add DMF (0.05 ml) and heat for 3 hours Refused. The reaction solution was concentrated under reduced pressure, ether (3 Oml) was added to the residue, and the precipitated solid was collected by filtration. The obtained solid was added to a solution of N, N-dimethylethylenediamine (190 mg) in pyridine (10 ml) and stirred for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was partitioned between purified chloroform and purified water. The mouth layer is dried over anhydrous magnesium sulfate to reduce After concentration under reduced pressure, purification was carried out using a silica gel column (form-form-methanol). The obtained product was dissolved in acetone (100 ml), concentrated hydrochloric acid (0.5 ml) was added, and the precipitated pale yellow solid was collected by filtration to obtain Compound 74.

 1H- 丽 R (DMSO-d6, D20 / TMS):

 δ = 2.51 (3Η, s), 2.90 (6Η, s), 3.39 (2H, t, J = 5.6Hz), 3.75 (2H, t, J = 5.6Hz),

 6.64 (1H, s), 8.13-8.28 (4H, m), 8.70 (1H, s), 8.93 (1H, s) FABMS (m / z): 36 9 (M + 1) +

Example 75

 Preparation of 2- (6-t-butoxycarbonylmethoxy-2-naphthyl) -1-hydroxy-5-pyrimidinecarboxylic acid (Compound 75)

 Anhydrous carbonate (2.1 g) and DMF (100 ml) of ethyl 4-hydroxy-1- (6-hydroxy-2-naphthynole) -5-pyrimidinecarboxylate (3.1 g) After adding potassium iodide (166 mg) and stirring at room temperature for 1 hour, t-butyl bromoacetate (2 g) was added and the mixture was stirred for 6 hours. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, the residue is partitioned with ethyl acetate-purified water, the ethyl acetate layer is dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then concentrated on a silica gel column. ) To give t-butyl 6- (5-ethoxycarbonyl-4-hydroxy-2-pyrimidinyl) -12-naphthyloxyacetate as a white solid.

 To a solution of the obtained t-butynole 6- (5-ethoxycarbonyl 4-hydroxy-2-pyrimidinyl) -12-naphthyloxyacetate (1.5 g) in ethanol (35 ml) was added 2N water. An aqueous solution of potassium oxide (6 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with a dilute aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration and then purified by a silica gel column (form-form-methanol-acetic acid) to obtain Compound 75 as a white solid.

 lH-NMR (DMS0-d6, D20 / TMS):

 5 = 1.40 (9H, s), 5.07 (2H, s), 7.19-7.24 (2H, m), 7.83 (1H, d, J-8.9Hz),

7.94 (1H, d, J = 8.9Hz), 8.36 (1H, d, J = 8.9Hz), 8.86 (1H, s), 9.08 (1H, s) FABMS (m / z): 397 ( M + 1) + Example 76

 Preparation of 6- (4_Methyl-1-pyrimidinyl) -2-naphthoic acid 'hydrochloride (Compound 76)

 To a solution of 6- (4-hydroxy-1-6-methyl-2-pyrimidinyl) -1-naphthoic acid-hydrochloride (2.9 g) in thionyl chloride (35 ml) was added DMF (0.05 ml) for 6 hours. It was heated to reflux. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (200 ml), 5% palladium on activated carbon (500 mg) was added, and the mixture was stirred for one day and night under a hydrogen stream. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column (form: chloroform). The obtained product was suspended in purified water (30 ml), sodium hydroxide (500 mg) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was filtered, the filtrate was neutralized with acetic acid. After the precipitated solid was collected by filtration, it was dissolved in acetone (30 ml), concentrated hydrochloric acid (1 ml) was added, and the precipitated yellow solid was collected by filtration to obtain Compound 76.

 lH-NMR (DMS0-d6 / TMS):

 6 = 2.61 (3H, s), 7.40 (1H, d, J = 5. OHz), 8.02 (1H, dd, J = l.3, 8.6Hz),

 8.19-8.25 (2H, m), 8.58 (1H, dd, J = 1.3, 8.6Hz), 8.65 (1H, s), 8.82 (1H, d, J = 5.3Hz), 9.04 (1H, s)

 FABMS (m / z): 265 (M + 1) +

Example 77

Ethyl 2- [6_ (2-t-butoxycarbonylaminoethoxy) -1-naphthyl] -14-hydroxy-1-5-pyrimidinecarboxylate (compound 77) ethyl 4-hydroxy-1 2- (6-hydroxy Dissolve 2--1-naphthinole-5-pyrimidinecarboxylate (3.1 g) in DMF (100 ml), add anhydrous potassium carbonate (2.1 g) and potassium iodide (166 mg), and add room temperature. After stirring for 1 hour, N- (t-butoxycarbonyl) -12-chloroethylamine (3.6 g) was added, and the mixture was stirred at 100 ° C for 15 hours. The reaction solution was filtered, purified water (300 ml) was added to the filtrate, and the precipitated solid was collected by filtration and purified by a silica gel column (clonal form) to obtain Compound 77. 1H-Cafe R (DMS0-d6 / TMS):

 δ = 1.34 (3H, t, J = 7.3Hz), 1.38 (9H, s), 3.46 (2H, dd, J = 5.6, 11.6Hz),

 4.31 (2H, dd, J = 7.3, 14.2Hz), 4.64 (2H, t, J = 5.6Hz), 6.99 (1H, br), 7.14-7.20 (2H, m), 7.80 (1H, d, J = 8.9Hz), 8.01 (1H, d, J = 8.9Hz),

 8.32 (1H, s), 8.39 (1H, dd, J = 1.7, 8.9Hz), 8.96 (1H, s), 9.02 (1H, s)

F ABMS (m / z): 454 (M + 1) +

Example 78

 Ethyl 3- [6- (4-Hydroxy-1-6-methyl-12-pyrimidinyl) -12-naphthylcarbonyl] aminopropionate ■ Preparation of hydrochloride (compound 78) 6- (4-Hydroxy-6-methyl- 2-Pyrimidyl) 1-naphthoic acid 'hydrochloride (71 Omg) was dissolved in a mixed solvent (60 ml) of pyridine-purified water (9: 1), and 13-alanineethyl ester' hydrochloride (39 Omg) and DCC (1.1 g) were added, and the mixture was stirred at room temperature for 1 晚. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Acetone (40 ml) and ether (80 ml) were added to the residue, and the precipitated solid was collected by filtration. (Methanol). The obtained product was dissolved in acetone (80 ml), concentrated hydrochloric acid (1 ml) was added, and the precipitated white solid was collected by filtration to obtain Compound 78.

 1H- 丽 R (DMS0-d6, D20 / TMS):

 δ 2 1.14 (3H, t, J = 7.3Hz), 2.41 (3H, s), 2.60 (2H, t, J = 6.9Hz),

 3.53 (2H, t, J = 6.9Hz), 4.04 (2H, dd, J = 7.3, 14.2Hz), 6.52 (1H, s),

 7.99 (1H, dd, J = 1.7, 8.6 Hz), 8.11-8.20 (3H, m), 8.47 (1H, s), 8.72 (1H, s) F ABMS (m / z): 380 (M + 1 ) +

Example 79

 Preparation of 3- [6- (4-hydroxy-6-methyl-1-pyrimidinyl) -12-naphthylcarbonyl] aminopropionic acid (Compound 79)

 Ethyl 3- [6- (4- (hydroxy-16-methyl-12-pyrimigel) -12-naphthylcarbonylamino] propionate 'hydrochloride (408mg) purified water

(15 ml), 2N aqueous sodium hydroxide solution (2.5 ml) was added at room temperature, and the mixture was stirred for 30 minutes. After the reaction solution was neutralized with acetic acid, the precipitated white solid Was collected by filtration to obtain Compound 79.

 lH-NMR (DMS0-d6, D20 / TMS):

 δ = 2.35 (3Η, s), 2.61 (2H, t, J = 6.9Hz), 3.56 (3H, t, J = 6.9Hz), 6.30 (1H, s), 8.00 (1H, d, J = 8.6Hz) ), 8.13-8.26 (3H, m), 8.48 (1H, s), 8.74 (1H, s) F ABMS (m / z): 35 2 (M + 1) +

Example 80

 Production of N-2- (Ν ', N'-dimethylamino) ethyl 6- (4-hydroxy-6-methyl-2-pyrimidinyl) 2-naphthoic acid amide dihydrochloride (Compound 80)

 6- (4-Hydroxy-6-methyl-2-pyrimidinyl) -12-naphthoic acid 'hydrochloride (26 Omg) was dissolved in a mixed solvent (13 ml) of pyridine-purified water (9: 1), and N , N-Dimethylethylenediamine 'dihydrochloride (15 Omg) and DCC (40 Omg) were added, and the mixture was stirred at room temperature for 1 晚. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. Acetone (25 ml) and ether (50 ml) were added to the residue, and the precipitated solid was collected by filtration and purified by a silica gel column (2-butanone monohydrate monoformic acid). The resulting product was dissolved in acetone (100 ml), concentrated hydrochloric acid (1 ml) was added, and the precipitated pale yellow solid was collected by filtration to obtain Compound 80.

 lH-NMR (DMS0-d6, D20 / TMS):

 δ = 2.39 (3Η, s), 2.84 (6H, s), 3.32 (2H, t, J = 5.6Hz), 3.69 (3H, t, J = 5.6Hz),

6.46 (1H, s), 8.15-8.27 (4H, m), 8.61 (1H, d, J = 5.6Hz),

 8.74 (1H, d, J = 5.6Hz)

 F ABMS (m / z): 3 5 1 (M + 1) +

 Example 8 1

 Preparation of ethyl 2- [6- (2-aminoethoxy) 1-2-naphthyl] -14-hydroxy-5-pyrimidinecarboxylate 'dihydrochloride (Compound 81)

Ethyl 2- [6- (2_t-butoxycarbonylaminoethoxy) -12-naphthyl] -14-hydroxy-15-pyrimidinecarboxylate (28 Omg) and 4N hydrochloric acid-dioxane solution (5 ml) were added. The mixture was stirred at room temperature for 3 hours. Precipitated The yellow solid was collected by filtration to obtain Compound 81.

 1H-Circle R (DMS0-d6, D20 / TMS):

 δ = 1.29 (3Η, t, J = 6.9Hz), 3.32 (2H, m), 4.27 (2H, dd, J = 6.9, 14.2Hz),

 4.83 (2H, m), 7.12-7.18 (2H, m), 7.76 (1H, d, J = 8.9Hz),

 7.95 (1H, d, J = 8.9Hz), 8.33 (1H, d, J = 8.9Hz), 8.87 (1H, s), 8.98 (1H, s)

FABMS (m / z): 354 (M + 1) +

Example 82

 Preparation of 2- [6- (2-t-butoxycarbonylaminoethoxy) -1-2-naphthyl] -4-hydroxy-5-pyrimidinecarboxylic acid (Compound 82)

 Ethyl 2- [6- (2-t-butoxycarbonylaminoethoxy) -l-naphthyl] -4-hydroxyl-5-pyrimidinecarboxylate (907mg) in ethanol (20ml) solution of 2N aqueous potassium hydroxide (4 ml) was added and the mixture was stirred at room temperature for 5 hours. The reaction solution was neutralized with acetic acid, activated carbon (lOOmg) was added thereto, and the mixture was stirred uniformly. Then, insolubles were removed by filtration, purified water (250 ml) was added to the filtrate, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and washed with purified water to obtain Compound 82.

 1H-band R (DMS0_d6, D20 / TMS):

 6 = 1.30 (9Η, s), 3.41 (2Η, t, J = 5.6Hz), 4.61 (2H, t, J = 5.6Hz),

 7.13 (1H, d, J = 8.9Hz), 7.17 (1H, s), 7.76 (1H, d, J = 8.9Hz), 7.96 (1H, d, J = 8.9Hz), 8.35 (1H, d, J = 8.9Hz), 8.90 (1H, s), 8.96 (1H, d, J = 2.6Hz)

 FABMS (m / z): 426 (M + 1) +

 Example 83

 Preparation of 2- [6- (2-aminoethoxy) 1-2-naphthyl] -4-hydroxy-5-pyrimidinecarboxylic acid dihydrochloride (Compound 83)

 To 4- [6- (2-t-butoxycarbonylaminoethoxy) -12-naphthyl] -14-hydroxy-15-pyrimidinecarboxylic acid (383 mg) was added 4N hydrochloric acid-dioxane solution (7 ml). Stirred at room temperature for 4 hours. The precipitated solid was collected by filtration and washed with acetone to give Compound 83.

1H-band R (DMS0-d6, D20 / TMS): δ = 3.33 (2H, t, J = 5.0Hz), 4.86 (2H, t, J = 5.0Hz), 7.13-7.19 (2H, m),

7.77 (1H, d, J = 8.9Hz), 796 (1H, d, J = 8.9Hz), 831 (1H, d, J = 8.9Hz),

8.65 (1H, d, J = 2.0Ηζ), 8.9 (1H, s), 9.01 (1H, d, J = l.3Hz) F ABMS (m / z): 326 (M + 1) +

Example 84

 Preparation of methyl 4- (methoxy-2-)-(6-methoxy-2-naphthyl) -1,5-pyrimidinecarboxylate (Compound 84)

 Ethyl 4-hydroxy-2- (6 hydroxy-1-naphthyl) 5-pyrimidinecarboxylate (3.1 g) was dissolved in DMF (100 ml), and anhydrous potassium carbonate (4.2 g) was added. After stirring for 1 hour, methyl iodide (3.1 g) was added and the mixture was stirred for 20 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the residue was partitioned with purified form-form purified water. The chromate form layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then purified by a silica gel column (toluene-chloroform form) to obtain Compound 84 as a white solid.

 1H-Awake R (DMS0-d6 / TMS):

 δ = 1.33 (3H, t, J = 6.9Hz), 3.92 (3H, s), 4.19 (3H, s), 4.31-4.34 (2H, m),

7.24 (1H, d, J = 8.6Hz), 7.41 (1H, s), 7.94 (1H, d, J = 8.6Hz),

8.04 (1H, d, J = 8.6Hz), 8.47 (1H, d, J = 8.6Hz), 8.97 (1H, s), 9.02 (1H, s) F ABMS (m / z): 339 (M + 1) +

Example 85

 Preparation of 4-Methoxy-2- (6-methoxy1-2naphthyl) -15-pyrimidinecarbonic acid (Compound 85)

 To a solution of ethyl 4-methoxy-6- (6-methoxy-2-naphthyl) -5-pyrimidinecarboxylate (248 mg) in ethanol (8 ml) was added 2N aqueous potassium hydroxide (2 ml), and the mixture was added at room temperature. Stir for 18 hours. After the reaction solution was neutralized with a dilute aqueous hydrochloric acid solution, purified water (50 ml) was added, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration and washed with purified water and ethanol to obtain Compound 85.

 lH-NMR (DMS0-d6 / TMS):

δ = 3.93 (3Η, s), 4.18 (3Η, s), 7.24 (1H, dd, J = 2.6, 8.9Hz), 7.40 (1H, d, J = 2.3Hz), 7.94 (1H, d, J = 8.9Hz), 8.04 (1H, d, J = 8.9Hz),

8.47 (1H, dd, J = l.3, 8.6Hz), 8.97 (1H, s), 9.03 (1H, s), 13.24 (1H, br) F ABMS (m / z): 3 1 1 ( M + 1) +

Example 8 6

 Preparation of ethyl 4-amino-2- (6-hydroxy-2-naphthyl) -15 pyrimidincarboxylate (compound 86)

 To a solution of 2-amidino 6 naphthol methanesulfonate (14.1 g) in ethanol (200 ml) was added ethyl ethoxymethylene cyanoacetate (9.7 g) and sodium methoxide (5.9 g). ) Was added and the mixture was stirred at room temperature for 20 hours. The precipitated solid was collected by filtration, washed with ethanol, added with purified water (200 ml) and concentrated hydrochloric acid (1 ml), and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and washed with purified water and methanol to obtain Compound 86 as a white solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 1.34 (3Η, t, J = 7.3Hz), 4.33 (2H, dd, J = 7.3, 14.2Hz), 7.12-7.18 (2H, m), 7.58 (1H, br), 7.77 (1H, d, J = 8.9Hz), 7.92 (1H, d, J = 8.9Hz), 8.02 (1H, br),

8.35 (1H, dd, J = 2.0, 8.9Hz), 8.84 (1H, s), 8.88 (1H, s), 10.02 (1H, s) F ABMS (m / z): 310 (M + 1) +

Example 8 7

 4-Hydroxy-1- (6-hydroxy-2-naphthyl) -1-pyrimidine power Production of liponitrile (compound 87)

To a solution of 2-amidino 6 naphthol methanesulfonate (14.1 g) in ethanol (200 ml) was added ethoxymethylene cyanoacetate (9.7 g) and sodium methoxide (5.9 g). ) Was added and the mixture was stirred at room temperature for 20 hours. The precipitated solid (compound 86) was filtered, and the filtrate was concentrated under reduced pressure. Water (300 ml) and concentrated hydrochloric acid (6 ml) were added to the residue, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, washed with ethanol, dissolved in DMF (100 ml), added with activated carbon (10 g), and stirred uniformly. After the reaction solution was filtered, ether (1500 ml) was added to the filtrate, and the mixture was stirred at room temperature for 3 days. The precipitated solid was collected by filtration, dissolved in methanol (100 ml), and concentrated hydrochloric acid (0.5 ml) was added. Stirred for hours. The precipitated solid was collected by filtration and washed with methanol to obtain Compound 87.

 1H-NMR (DMS0-d6 / TMS):

 δ = 7.18-7.21 (2Η, m), 7.82 (1H, d, J = 8.9Hz), 7.92 (1H, d, J = 8.9 Hz), 8.12 (1H, dd, J = 2.0, 8.9Hz), 8.74 (2H, s), 10.29 (1H, s), 13.58 (1H, br)

FABMS (m / z): 264 (M + 1) +

Example 88

 2- (6-Hydroxy-2-naphthyl) -1-4-Hydroxy-1-5-pyrimidine power Production of lipoxymidine 'hydrochloride (Compound 88)

 2- (6-Hydroxy-1-2-naphthyl) -14-Hydroxy-1-5-pyrimidine power Dissolve loponitrile (790 mg) in methanol (100 ml) and saturate hydrogen chloride gas under ice-cooling. Then, the mixture was sealed and stirred at room temperature for 2 days. After concentrating the reaction solution under reduced pressure, the residue was dissolved in methanol (50 ml), the solution was passed under ice-cooling until ammonia gas was saturated, the solution was sealed, and the mixture was stirred for 3 days. After the reaction solution was concentrated under reduced pressure, a 10% aqueous hydrochloric acid solution was added to the residue, and the precipitated solid was collected by filtration and purified by a silica gel column (form-form-methanol-acetic acid). A 10% aqueous hydrochloric acid solution was added to the obtained product, and the precipitated solid was collected by filtration and washed with acetone to obtain Compound 88 as a yellow solid.

 1H-band R (DMS0-d6 / TMS):

 δ = 7.21-7.24 (2Η, m), 7.85 (1H, d, J = 8.9Hz), 7.95 (1H, d, J = 8.9Hz),

8.17 (1H, dd, J = 2.0, 8.9Hz), 8.82 (1H, s), 9.04 (3H, s), 9.51 (2H, br), 10.41 (1H, br)

 FABMS (m / z): 281 (M + 1) +

 Example 89

 Preparation of 4-Amino-2- (6-hydroxy-1-naphthyl) -15-pyrimidinecarbonic acid (Compound 89)

To a solution of ethyl 4-amino-2- (6-hydroxy-12-naphthyl) -15-pyrimidinecarboxylate (329 mg) in methanol (10 ml) was added a 2N aqueous hydroxide aqueous solution (5 ml), and the mixture was stirred at room temperature. Stirred for 20 hours. The reaction solution is under reduced pressure Then, the residue was neutralized with a dilute aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration and washed with purified water to obtain Compound 89.

 1H-NMR (DMS0-d6 / TMS):

 δ = 7.20-7.23 (2H, m), 7.80 (1H, d, J = 8.9Hz), 7.89 (1H, d, J = 8.9Hz), 8.30 (1H, dd, J = 1.7, 8.9Hz) , 8.77 (1H, s), 8.9 (1H, s)

 FABMS (m / z): 28 2 (M + 1) +

Example 90

 Preparation of 6- (4-amino-1-5-carboxy-12-pyrimidinyl) -12-naphthyloxyacetic acid (Compound 90)

 Ethyl 2- (6-hydroxy-2-naphthyl) -14-amino-5-pyrimidinecarboxylate (1.6 g) was dissolved in DMF (100 ml), and anhydrous carbon dioxide (1.5 g) was added. Then, potassium iodide (83 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Then, methyl bromide acetate (84 1 mg) was added, and the mixture was stirred for 20 hours. The reaction solution was filtered, purified water (500 ml) was added to the filtrate, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration, and purified by a silica gel column (hexane monochloroform) to give methyl 6 — (4-amino-5-ethoxycarbonyl-2-pyrimidyl-2-naphthyloxyacetate was obtained as a white solid. The obtained methyl 6- (4-amino-5-ethoxy) To a solution of carbonyl-12-pyrimidinyl) 1-2-naphthyloxyacetate (381 mg) in methanol (10 ml) was added a 2N aqueous hydroxide solution (4 ml), and the mixture was added at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, the residue was neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration and washed with purified water to obtain Compound 90.

 lH-NMR (DMS0-d6 / TMS):

 δ = 3.44 (2Η, br), 4.87 (2H, s), 7.82 (1H, dd, J = 2.3, 8.9Hz),

 7.35 (1H, d, J = 2.3Hz), 7.86-8.04 (4H, m), 8.43 (1H, dd, J = l.7, 8.9Hz),

8.89 (1H, s), 8.91 (1H, s)

 FABMS (m / z): 340 (M + 1) +

 Example 9 1

Ethyl 5-ethoxycarbonyl 2- (6-ethoxycarbonylmethoxy) Preparation of 2-naphthyl) -4 -Pyrimidinyloxyacetate (Compound 91) Ethyl 2- (6-Hydroxy-1-2-naphthyl) -14-Hydroxy-1-5-pyrimidinecarboxylate (3.1 g) was dissolved in DMF (100 ml), and potassium carbonate anhydride (4.2 g) and potassium iodide (166 mg) were added. After stirring at room temperature for 1 hour, ethyl bromide acetate (3.7 g) was added. ) Was added and stirred for 20 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was partitioned between chloroform and purified water. The black-mouthed form layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane (200 ml) was added to the residue, and the precipitated solid was collected by filtration and washed with methanol to obtain Compound 91.

 lH-NMR (DMS0-d6 / TMS):

 δ = 1.18-1.27 (6H, m), 1.35 (3H, t, J = 6.9Hz), 4.17—4.26 (4H, m),

 4.35 (2H, dd, J = 6.9, 14.2Hz), 4.96 (2H, s), 5.21 (2H, s),

 7.31 (1H, dd, J = 2.3, 8.9Hz), 7.39 (1H, d, J = 2.3Hz),

 7.92 (1H, d, J = 8.9Hz), 8.01 (1H, d, J = 8.9Hz), 8.34 (1H, dd, J = l.3, 8.9Hz), 8.88 (1H, s), 9.10 (1H , S)

 F ABMS (m / z): 483 (M + 1) +

Example 92

 Preparation of 5-hydroxyl-2- (6-carboxymethoxy-2-naphthyl) -14-pyrimidinyloxyacetic acid (Compound 92)

 Ethyl 5-ethoxycarbonyl 2- (6-ethoxycarbonylmethoxy-2-naphthyl) 2-N-hydroxylation power of a solution of 1,4-pyrimidinyloxyacetate (2.4 g) in methanol (140 ml) An aqueous solution of lime (25 ml) was added, followed by stirring at room temperature for 20 hours. Activated carbon (2 g) was added to the reaction solution, and the mixture was stirred uniformly, followed by filtration. After the filtrate was neutralized with concentrated hydrochloric acid and stirred at room temperature for 1 hour, the precipitated solid was collected by filtration and washed with purified water to obtain Compound 92 as a yellow solid.

 1H-Awake (DMS0-d6 / TMS):

 δ = 4.79 (2Η, s), 5.07 (2Η, s), 7.27 (1H, dd, J = 2.6, 8.9Hz),

 7.34 (1H, d, J = 2.6Hz), 7.88 (1H, d, J = 8.9Hz), 7.99 (1H, d, J = 8.9Hz),

8.39 (1H, dd, J = l.7, 8.9Hz), 8.89 (1H, s), 8.99 (1H, s) F ABMS (m / z): 397 (M-1)

Example 93

 Preparation of ethyl 4-hydroxy 2- (6-meth-1-2-naphthyl) -1,5-pyrimidine carboxylate (Compound 93)

 Ethyl 4-hydroxy-2- (6-hydroxy-12-naphthyl) -15-pyrimidinecarboxylate (3.1 g) was dissolved in DMF (100 ml), and anhydrous potassium carbonate (1.7 g) was dissolved. After stirring at room temperature for 1 hour, methyl iodide (1.4 g) was added, and the mixture was stirred for 20 hours. After the reaction solution was filtered, purified water (40 Oml) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. After the precipitated solid was collected by filtration, the solid was purified by a silica gel column (hexane / monochrome form) to obtain Compound 93 as a white solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 1.33 (3Η, t, J = 6.9Hz), 4.17 (3H, s), 4.31 (2H, dd, J = 6.9, 14.2Hz),

 7.15-7.20 (2H, m), 7.8 (1H, d, J = 8.9Hz), 7.98 (1H, d, J = 8.9Hz), 8.39 (1H, dd, J = l.7, 8.9Hz) , 8 · 92 (1H, s), 9.00 (1H, s), 10.13 (1H, s)

F ABMS (m / z): 325 (M + 1) +

Example 94

 Preparation of 4-hydroxy-2- (6-methoxy-2-naphthyl) -1-5-pyrimidinecarbonic acid (compound 94)

 To a solution of ethyl 4-hydroxy-2- (6-methoxy-1-naphthyl) -15-pyrimidinecarboxylate (649 mg) in methanol (20 ml) was added 2N aqueous oxidizing water solution (8 ml). The mixture was stirred at room temperature for 20 hours. After the reaction solution was concentrated under reduced pressure, the residue was neutralized with dilute hydrochloric acid, and the precipitated solid was collected by filtration and washed with purified water to obtain Compound 94 as a yellow solid.

 lH-NMR (DMS0-d6 / TMS):

 δ 2 4.18 (3Η, s), 7.16-7.21 (2Η, m), 7.82 (1H, d, J = 8.9Hz),

 7.99 (1H, d, J = 8.9Hz), 8.42 (1H, dd, J = 1.7, 8.9Hz), 8.94 (1H, s), 9.03 (1H, s)

F ABMS (M / z): 297 (M + 1) + Example 95

 Synthesis of 2- (6-hydroxy-1-naphthyl) -1-6-methylpyrimidin-14-ol (Compound 95)

 1-Carboxy-6-naphthyl acetate (5.1 g) was suspended in ethyl acetate (10 Oml), phosphorus pentachloride (23 g) was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, ether (400 ml) was added to the residue, ammonia gas was passed through under ice-cooling for 5 minutes, and the mixture was sealed and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and washed with purified water and ether to give 1-potassium rubamoyl-6-naphthyl acetate as a white solid. The obtained 1-rubumoyl 6-naphthyl acetate (3 g) was dissolved in methylene chloride (15 ml), and triethyloxodinotetrafluoroborate (2.9 g) was added under a nitrogen stream. The mixture was stirred at room temperature. The precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in anhydrous methanol (30 ml), and after passing ammonia gas under ice-cooling for 20 minutes, the mixture was capped and stirred at room temperature. Two hours later, the reaction solution was cooled again, and after passing ammonia gas for 20 minutes, the mixture was sealed and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ether and dissolved in a small amount of methanol. After adding ether (50 Oml), concentrated hydrochloric acid was added, and the precipitated solid was collected by filtration to obtain 1-amidino-16-naphthol 'hydrochloride as a brown solid. A solution of sodium metal (140 mg) in methanol (70 ml) was prepared, 11-amidino 6-naphthol 'hydrochloride (50 mg) and ethyl acetate acetate (0.35 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was washed with 1N aqueous hydrochloric acid and purified water, and collected by filtration to obtain Compound 95 as a brown solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.12 (3H, s), 5.78 (1H, s), 7.07-7.11 (2H, m), 7.34 (1H, t, J = 7.6Hz),

7.48 (1H, d, J = 6.3Hz), 7.59 (1H, d, J = 7.6Hz), 8.40 (1H, d, J = 9.2Hz) FABMS (m / z): 253 (M + 1) +

Example 96

6— [2 -— (4-hydroxy-6-methyl-2-pyrimidinyl) ethyl] 1 2 Production of mono-naphthyloxyacetic acid (Compound 96)

 6 To a solution of monobromo-2-naphthol (22.3 g) and anhydrous lithium carbonate (17.9 g) in DMF (200 ml) was added methyl bromide acetate (11.4 ml) and stirred for 1 hour. did. After the reaction solution was concentrated under reduced pressure, purified water (1000 ml) was added to the residue, and the precipitated white solid was collected by filtration to obtain methyl 6-bromo-2-naphthyl oxyacetate. The obtained methyl 6-bromo-1-naphthyloxacetate (5.0 g) was dissolved in DMF (17 ml), and acrylonitrile (1.3 ml), palladium acetate (4 mg), and tri-o-tolylphosphine were dissolved. (1 Omg) and sodium acetate (1.7 g) were added, and the mixture was stirred at 130 ° C for 12 hours. The reaction solution was partitioned between ethyl acetate and dilute aqueous hydrochloric acid, 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-methanol) to obtain a white solid. The obtained methyl 6- (2-cyanoethenyl) -12-naphthyloxyacetate (90 mg) was dissolved in ethyl acetate (10 ml), and 10% palladium on activated carbon (90 mg) was added. The mixture was stirred under flowing water for 3 days. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure and purified by a silica gel column (hexane monoethyl acetate) to obtain a white solid. The obtained methyl 6- (2-cyanoethyl) -12-naphthyloxyacetate (650 mg) is dissolved in methanol (10 ml), and the solution is saturated with hydrochloric acid gas at room temperature, and then sealed. And stirred for 2 days. Ether was added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was dissolved in methanol (10 ml), and ammonia gas was passed at room temperature until the gas became saturated. Then, the mixture was sealed and stirred for 4 days. The reaction solution was concentrated under reduced pressure, ether was added to the residue, and the precipitated solid was collected by filtration to obtain a white solid. To a solution of sodium methoxide (87 mg) in methanol (10 ml) was added methyl 6- (2-amidinoethyl) -12-naphthyloxyacetate 'hydrochloride (31 Omg) to ethyl ethyl acetate (31 Omg). 0.16 m 1) and stirred at room temperature for 24 hours. The reaction solution was partitioned with ethyl acetate-1N aqueous hydrochloric acid, and the ethyl acetate layer was washed with purified water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 96.

lH-NMR (DMS0-d6 / TMS): δ = 2.17 (3H, s), 2.86 (2H, dd, J = 6.3, 9.6Hz), 3.09 (2H, dd, J = 6.3, 9.6Hz), 4.54 (2H, s), 6.03 (1H, s) , 7.22-7.28 (2H, m), 7.37 (1H, m), 7.67—

 7.81 (3H, m), 12.32 (lH'br)

 F ABMS (m / z): 3 39 (m + 1) +

Example 9 7

 Preparation of methyl 5- (4-hydroxy-16-methyl-2-pyrimidinyl) -1-naphthyloxyacetate (compound 97)

 2- (6-Hydroxy-1-naphthyl) -16-methylpyrimidin-1-ol (1.5 g) and anhydrous potassium carbonate (1.3 g) are suspended in DMF (10 ml), and the suspension is carried out at room temperature. Then, methyl bromide acetate (0.48 ml) was added thereto, and the mixture was stirred at 40 ° C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified by a silica gel column (chloroform / methanol) to obtain Compound 97 as a pale brown solid.

 lH-NMR (DMS0-d6 / TMS):

 δ = 2.55 (3Η, s), 3.71 (3Η, s), 5.07 (2H, s), 7.06 (1H, s),

 7.11 (1H, dd, J = 2.3, 9.2Hz), 7.22 (1H, d, J = 2.3Hz), 7.51 (1H, t, J = 7.6Hz),

7.75 (1H, d, J = 7.6Hz), 7.86 (1H, d, J = 8.3Hz), 8.33 (1H, d, J = 9.2Hz) F ABMS (m / z): 3 2 5 (m + 1) +

Example 98

 Preparation of 5- (4-hydroxy-16-methyl-12-pyrimigel) -12-naphthyloxyacetic acid (Compound 98)

 Methyl 5- (4-hydroxy-16-methyl-2-pyrimidinyl) -12-naphthyloxyacetate (94 mg) was dissolved in methanol (2 ml), and a 4N aqueous sodium hydroxide solution (3 ml) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, neutralized by adding dilute hydrochloric acid, and the precipitated solid was collected by filtration to obtain Compound 98.

 lH-NMR (DMS0-d6 / TMS):

δ = 2.49 (3Η, s), 4.93 (2Η, s), 6.90 (1H, s), 7.11 (1H, dd, J = 2.3, 9.2Hz), 7.18 (1H, s), 7.46 (1H, t, J = 7.6Hz), 7.75 (1H, d, J = 7.0Hz), 7.80 (1H, d, J = 7.6Hz), 8.51 (1H, d, J = 9.2Hz), 9.77 (1H, s) FABMS (m / z): 3 1 1 (m + 1) +

Example 99

 Preparation of 1-methyl_3-methoxycarbonylmethyl-5- (6-methoxycarbonylmethoxy-2-naphthylmethylene) hydantoin (Compound 99)

 6-Hydroxy-1-naphthaldehyde (1.2 g) and 1-methylhydantoin (800 mg) were dissolved in ethanol (40 ml), and piperidine (1.5 ml) was added, followed by heating under reflux. After cooling the reaction solution, the precipitated solid was collected by filtration to obtain a yellow-orange solid. The obtained solid and anhydrous potassium carbonate (540 mg) were suspended in DMF (20 ml), and methyl bromide acetate (480 mg) was added, followed by stirring at room temperature for 1 hour. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was partitioned between chloroform and purified water. The port-form layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by a silica gel column (clo-form) to obtain Compound 99.

 1H-Round R (CDC13 / TMS):

 δ = 3.30 (3Η, s), 3.78 (3H, s), 3.84 (3H, s), 4.39 (2H, s), 4.77 (2H, s),

6.42 (1H, s), 7.06 (1H, d, J = 2.6Hz), 7.23 (1H, dd, J = 2.6, 9.2Hz),

 7.70 (1H, d, J = 8.6Hz), 7.80 (1H, d, J = 9.2Hz), 8.05 (1H, dd, J = l.7, 8.6Hz),

8.33 (1H, s)

 FABMS (m / z): 41 3 (M + 1) +

Example 100

 1-Methylenol 3-Methoxycarboninolemethynole 5- (6-Methoxycanolebonyl methoxy-2-naphthylmethylene) Production of hydantoin-12-imide (Compound 100)

6-Hydroxy-1-naphthaldehyde (2 g) and creatinine (1.3 g) were dissolved in methanol (6 Om 1), and the mixture was added with piperidine (2.3 mL) and heated under reflux for one hour. After cooling the reaction solution, the precipitated solid was collected by filtration and washed with ethanol. The obtained solid and anhydrous potassium carbonate (lg) were suspended in DMF (35 ml), and methyl bromide acetate (900 mg) was added, followed by stirring at room temperature for 1 hour. The reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. Purification provided compound 100.

 1H-Ran R (CDC13 / TMS):

 δ = 3.25 (3Η, s), 3.78 (3H, s), 3.83 (3H, s), 4.47 (2H, s), 4.76 (2H, s), 6.23 (IH, s), 705 (IH, d, J = 2.3Hz), 7.21 (1H, dd, J = 2.6, 9.2Hz),

 7.68 (IH, d, J = 8.9Hz), 7.78 (1H, d, J = 8.9Hz), 7.98 (1H, dd, J = 1.7, 8.6Hz),

8.24 (lH, s)

 F ABMS (m / z): 4 1 2 (M + 1) +

Table 1 shows the compounds obtained in the above Examples.

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Compound No A B X Y z

 83 0 (CH2) 2NH2 H H COOH OH 2-HCI

84 0CH3 H H COOEt OCH3

85 0CH3 H H COOH OGH3

86 OH H NH2 COOEt H

87 OH H H CN OH

88 OH H H 丫 ^ OH HCI

 NH

 89 OH H NH2 COOH H

90 OCH2COOH H NH2 COOH H

91 OCH2COOEt HH COOEt OCH2COOE1

98

製剤処方例 1 (錠剤） C6Z0 / 66df / 13d StOie / 00 OAV

Formulation example 1 (tablets)

 Compound of the present invention 00 g

 Lactose 90 g

 Hydroxip mouth pinoresenolerose 20 g

 Microcrystalline cellulose 7 7 g

 Magnesium stearate 0 3 g

 Talc 10 g

According to a conventional method, a tablet containing 10 mg of the compound of the present invention is obtained.

Formulation example 2 (injection)

 1 mg of the compound of the present invention

 5% glucose injection 2 m 1

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

Formulation example 3 (suppository)

 Compound of the present invention 0 mg

 Cocoa butter

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

 The compound of the present invention has a fibrinolysis-promoting action and exhibits an excellent thrombolytic action, and is therefore effective for diseases caused by thrombus. Various types of thrombosis such as 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 due to vascular surgery and extravasation and improvement of blood flow obstruction, 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, an antithrombotic agent alone, or as a thrombolytic agent It can be used in combination with a thrombosis therapeutic agent.

The present invention compound has a fibrinolysis promoting action, in order to exhibit excellent thrombolytic action, to be effective in diseases caused in connection with the thrombus, the following experimental examples proven _c (1) plasmin Measurement of formation promoting activity

The present compound, 1 X 1 0 - ² becomes M as dimethyl sulfoxide (DM S Was dissolved in O), diluted 1 to 2 X 10- ³ M in 2 Omm phosphate buffer solution containing the prepared solution 0. 1 5 M sodium chloride _(P H 7. 4), the present invention compound solution Prepare. Glutamate-type human plasminogen (final concentration: 0,1 μ 、), human recombinant t-Ρ (final concentration: 50 M) and the compound of the present invention (final concentration: 300 μM) were each added to a 96-well microtiter plate. Add 50 to each plate and incubate at 37 ° C for 1 hour. Then, add 50 μl of a synthetic substrate solution (S-2251, 2 mM), which is a plasmin substrate, to each well, and measure the absorbance (A 1) at 405 nm immediately after the addition. Then, incubate again at 37 ° C for 15 minutes and measure the absorbance (A2) at 405 nm. The difference between the obtained absorbances (A1 and A2) is determined, 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

 Compound Plasmin formation promoting action

 None (control) 1

 2 1.55

 5 1.42

 6 1.28

 8 1-58

 1 1 1. 3

 1 3 1.21

 14 1.42

 1 5 1.33

 1 7 1. 3

 1 9 1.25

 22 1.43

 23 1. 3 1

 26 1. 4

 31 1.24

 33 1.26

 34 1.83

 36 1.34

 37 1.51

 39 1.65

 40 1.26

41 1.32 Table 2 (continued)

 42 1.49

43 1.25

44 1.43

45 1.58

49 1.48

50 1.29

51 1.3

52 1.46

54 1.9

56 1.34

57 1.36

60 1.54

61 1.46

65 1.82

66 1.56

67 1.74

68 1.47

69 1.77

70 1.3

71 1.63

74 1.8

75 1.58

76 1.4

78 1.3

79 1.49

80 1.51

81 1.36

82 1.64

84 2.04

85 1.39

87 1.25

92 1.3

93 1.5

94 1.3

96 1.58

97 1.39

98 1. 47

99 1.72

100 1. 4 (2) Effect of oral administration on improving lethality in mouse lung thrombosis lethal model

 The experiment was performed using d d Y male mice 6 weeks old. The compound of the present invention was suspended in distilled water so as to be 1 mg / kg (10 ml) and orally administered to a mouse fasted for 4 hours. Distilled water was orally administered to the disease state control group. 6 hours after administration, thrombin

(1 O U / m 1) was administered via the tail vein at a dose of 1 ml to induce thrombosis. Table 3 shows the results.

Table 3

(3) Effect of intravenous administration on the lethality of mouse pulmonary thrombotic lethal model

 The experiment was performed using d d Y male mice 6 weeks old. The compound of the present invention was dissolved in a 5% glucose solution to a concentration of 0.1 mg / kg (10 ml), and administered via the left tail vein of a mouse fasted for 4 hours. A 5% glucose solution was similarly administered to the disease control group. Fifteen minutes after the administration, thrombin (10 UZml) was administered at a dose of 1 ml from the right tail vein to induce thrombus. Table 4 shows the results.

 Table 4

(4) Oral administration of thrombolysis in rat venous thrombotic model This model is a thrombus model in which the jugular vein of a rat is ligated under anesthesia and a thrombus is formed at the ligated site. This model was created by partially modifying the model used to prove the effectiveness of the thrombolytic agents t-PA and UK, which narrows the jugular vein and causes thrombus to form at the site of stenosis. (Reference: Wessler Stanford, eta 1., J. Appl. 1. Physiol, 14 (6); 943—946 (1595)). In the experiment, SD male rats were used. After exposing the jugular vein of the rat under anesthesia (inhalation anesthesia with ether), it was ligated while retaining blood with a suture. 500 units / m 130 μI of thrombin was injected into the blood retention site to generate a thrombin thrombus at the blood retention site. Two minutes after the injection of thrombin, the ligated site was opened and the neck was sutured. After confirming the recovery of the righting reflex 30 minutes after the injection of thrombin, 10 mg / kg of 6- (4-hydroxy-6-methyl-2-pyrimigel) _2-naphthyloxyacetic acid (compound 14 of the present invention) was orally administered. did.

 Three hours after administration of the compound of the present invention, the jugular vein in which a thrombus was formed was removed under ether anesthesia. After the thrombus remaining in the isolated blood vessel was washed with a physiological saline solution, the amount of residual thrombus protein was measured using the Bio-Rad Company, DC-proteinassay method. As a result, administration of the compound of the present invention significantly reduced the amount of residual thrombus protein, proving the thrombolytic effect of the compound of the present invention.

 (5) Efficacy in an arterial thrombotic model using a hamster bag by oral administration The hamster bag was exposed under anesthesia, and the thrombus formation time in microvessels caused by microscopic, electric and ADP stimulation and its This model measures the time until the thrombus disappears. This model is an arterial thrombus model with platelet aggregation, and is used to evaluate the efficacy of antiplatelet agents.

Golden hamsters were used in the experiments. 6_ (4-Hydroxy-6-methyl-12-pyrimidinyl) -12-naphthyloxyacetic acid 1 Omg / kg was orally administered. Ticlovidine 10 Omg / kg was orally administered similarly as a positive control. Tick port neutravidin in antiplatelet agent sold inhibits platelet aggregation by AD P this and force ^s Reported Rereru (Yoshiharu Takiguchi et al., Thrombosis and

 Haemato stasis., 1992, 68 (4), 460-463 (1992)).

Administration 1. Five hours later, the 頰 bag was exposed under anesthesia. Under a microscope, electricity to micro arteries Upon stimulation, ADP was released into the arteries, and the time required for thrombus formation in the microarteries and the time required for the thrombus to disappear was measured.

 As a result, the thrombus formed in the microartery of the animal to which the compound of the present invention was administered disappeared more rapidly than the positive control group, demonstrating the effectiveness of the compound of the present invention.

(6) Enhancement of fibrinolytic activity using ¹²⁵ I-fibrin plate

 6- (4-Hydroxy-6-methyl-2-pyrimidinyl) Dissolve 2-naphthyloxyacetic acid in dimethylsulfoxide (DMSO), then add 0.15 M sodium chloride in 2 OmM phosphate buffer (pH 7. 4) Diluted to ΙμΜ with. Τ. A fibrin clot was prepared according to the method of Inoue et al. (Thrombosis and Haemostasis, 79 (3), 591-596, 1998). That is, add 100 μl of 125 iodinated fibrinogen (1 mg / m 1) to each well of a 96-well microtiter plate, dry, and then add thrombin (0.5 unit Zml) to each well. 100 / zl was added thereto and incubated at 37 ° C for 3 hours to prepare a fibrin clot.

After washing the fibrin clot with 20 mM phosphate buffer, glutamate-type human plasminogen (final concentration 1 / igZml) and natural t-PA (final concentration 1 unit / ml) were added to each well. Was added in 50/1 increments. To this was added 100 μl of the previously prepared ΙμΜ 6- (4-hydroxy-16-methyl-2-pyrimidinyl) -12-naphthyloxyacetic acid solution, and the mixture was incubated at 37 ° C for 1 hour. Thereafter, the radioactivity of each of the solution in the well and the well after solution recovery was measured with a gamma counter. The ratio of the radioactivity of the solution to the sum of the radioactivity of the solution and the well was determined as the fibrinolytic activity. By determining the ratio of the fibrinolytic activity of the compound of the present invention to the control (natural t-PA and glutamic acid type-plasminogen), it is possible to determine the effect of the compound of the present invention on fibrinolytic activity. it can. As a result, the compound of the present invention exhibited an excellent fibrinolytic activity-enhancing effect of 1.4 against Control 1. (7) When 6- (4-hydroxy-6-methyl-1-pyrimidinyl) -12-naphthyloxyacetic acid was repeatedly orally administered to SD rats at doses of 125, 250 and 50 mg / kg for 14 days, No abnormality was observed due to the administration of the compound of the present invention. Powerful.

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)

(Wherein R 1 and R 2 are different, R 1 is a hydrogen atom, a hydroxyl group, a lower alkoxy group which may have a substituent, a lower alkoxycarbonyloxy group, a lower alkyl group having a substituent, a substituent A lower alkenyl group having one COOH or -CONH-R12 (Rl ² is a lower alkyl group having a substituent)  R2 represents a hydrogen atom, a halogen atom or one CH2 CONH—R13 (R13 is a hydrogen atom or a lower alkyl group having a substituent);  R3

(R 10 is an oxygen atom or NH, and R 11 is a lower alkoxycarbonyl lower alkyl group).  R5 and R6 may be the same or different,  R5 represents a hydrogen atom, a hydroxyl group, an amino group or a lower alkyl group, Re represents a hydrogen atom, a hydroxyl group, a halogen atom, OS 03H or a lower alkoxy group having a substituent, R 7 represents a hydroxyl group, a lower alkyl group, an amino group or a lower alkoxy group, R8 represents a hydrogen atom, a lower alkoxycarbonyl group, COOH, a cyano group or an amidino group,  R9 represents a linear or branched alkyl group having 1 to 7 carbon atoms which may have an amino group as a substituent.  (Provided that R 1 is a methoxy group having a phenyl group as a substituent, R 3

 R6 (Except when R 5 is a methyl group and R 6 is a hydroxyl group))) or formula (2)

(In the formula, R4 represents a hydroxyl group or —OCH2COO—R14 (R14 represents a hydrogen atom or a lower alkyl group).) And salts thereof, and solvates thereof.  2. R 2 is a hydrogen atom, R3 is  The compound according to claim 1, a salt thereof, and a solvate thereof (wherein R1 is a methoxy group having a phenyl group as a substituent, and R5 is a methyl group. Except when R 6 is a hydroxyl group). 3. Ethinole 4-Hydroxy 2- (6-Hydroxy-l-Naphthinole) -l5-Pyrimidine carboxylate, 2- [6- (2-N, N-dimethylaminoethoxy) -2-Naphthyl] -l6 —Methylpyrimidine— 4-ol 'hydrochloride, 2-N, N-dimethyl- {2-[6- (2-N, N-dimethylaminoethoxy) -1-naphthyl] -1-6-methylpyrimidinyl-4-oxy} ethylamine 'dihydrochloride, 6-methyl-2- [6-(3 — N-Methylaminopropoxy) -1-2-naphthyl] pyrimidin-4-ol 'hydrochloride, 2- [6- (2-N, N-dibenzylaminoethoxy) -1-2-naphthyl] -1-6- Methylpyrimidine-1-ol 'hydrochloride, methyl 2- (6-methoxycarbonylmethoxy-2-naphthyl) -1-6-methyl_4-pyrimidinyloxyacetate, 6- (4-hydroxy-6- Methyl-2-pyrimidinyl) 1-2-naphthyloxyacetic acid, sodium 6- (4-hydroxy-6-methyl-12-pyrimidinyl) -12-naphthyloxyacetate, 6- (4-hydroxysulfonyl) 6-methyl-2-pyrimidinyl) 2-naphthyloxyacetic acid, 2- [6- (2-N, N-diarylaminoethoxy) 1-2-naphthyl] -6-methylpyrimidin-14-ol 'hydrochloride, 2--(2-N , N-Dimethylaminoethoxy) 16- (4-Hydroxy-6-methyl-12-pyrimigel) 1-11-Naphthylacetoamide, Etyl 1-Rubamoylmethyl 1-6- (4-Hydroxy-16-methyl-) 2-Pyrimidinyl) -1-2-naphthyloxyacetate, ethyl 3- {2- (6- (4-hydroxy-6-methyl-2-pyrimidinyl) —2-naphthyloxy] ethyl} amino-3-amino Propionate, 2- (6-carboxymethoxy-2-naphthyl) 16-methyl-14-pyrimidyloxyacetic acid, ethyl 4- [6- (4-Hydroxy-1-6-methyl-12-pyrimidinyl) 1-2 Naphthyloxy] butyrate, 4— [6— (4— Droxy 6-methyl-12-pyrimidinyl) -12-naphthyloxy] butanoic acid, 4- {2- [6- (3-carboxypropoxy) -12-naphthyl] -6-methyl-4-pyrimidinyloxy} butanoic acid, Methyl 6- (4,6-dihydroxy-1-2-pyrimidinyl) -1-2-naphthyloxyacetate, Methyl 6-hydroxy-12- (6-methoxycarbonylmethoxy-2-naphthyl) 1-4-pyri Midinyloxyacetate, 6- (4-chloro-6-methyl-2-pyrimidinyl) 1,2-naphthol, 6- (4-Methyl-2_pyrimigel) 1,2-naphthol, methyl 6- (4— Methyl-2-pyrimiger) 1-2-naphthyloxyacetate, 6- (4-methyl-12-pyrimidyl) 1-2-naphthyloxyacetic acid, 2- [6- (4-methyl-2-pyridyl) (Midinyl) 1-2-naphthyloxy] ethylamine 'hydrochloride, N-2-aminoethyl [6- (4-hydroxy-16-methyl-2-pyrimidinyl) -12-naphthyloxy] acetamide' hydrochloride, 6- [4- (3-aminopropoxy) -1-6-methyl-2-pyrimidinyl] -12-naphthyloxyacetic acid 'hydrochloride, 6- {4- [N- (2-aminoethyl) aminocarbonylmethoxy]]-6- Methyl-2-pyrimidinyl} — 2-naphthyloxyacetic acid 'hydrochloride, 1- [N- (2-aminoethyl) aminocanoleponinolemethyl] — 6— (4-hydroxy-1-6-methyl-2-pyrimidi) Nil) 1-Naphthyloxyacetic acid 'hydrochloride, 6- (4-Hydroxy-l6-methyl- 2-pyrimidinyl) 1-l-odo-2- 2-naphthyloxyacetic acid, nonanyl 6- (4-hydroxy-6-methyl-2-) Pyrimidinyl 2-Naphthyloxyacetate, methoxymethyl 6- (4-Hydroxy-16-methyl-12-pyrimidinyl) 1-2-Naphthyloxyacetate, 2-N, N-dimethylaminoethyl 6 ― (4-Hydroxy-6-methyl-1-pyrimidinyl) 1-2-naphthyloxyl acetate, 2-morpholinoethyl 6— (4-Hydroxy-6-methyl-12-pyrimidinyl) 1-2-Naphthyloxyl Settate, N, N-Dimethylaminocarbonylmethyl 6- (4-hydroxy-6-methyl-2-pyrimidinole) -1-2-naphthinoleoxyacetate, 2-Hydroxyshetinole 6- (4-hydroxy-1 6 — Methyl-1-pyrimidinyl) 1-2-naphthyloxyacetate, (S) — (+) 1,2,3-dihydroxypropyl 6— (4-hydroxy-6-methyl-12-pyrimidinyl) ) — 2 —Naphthyloxyacetate, 6_ (2-pyrimidyl) —2 —Naphthyloxyacetic acid, 6— (4-Chloro-6-methyl-2-pyrimidinyl) 1-2-Naphthyloxyacetic acid, 2— [6— (4—Hydroxyoxy) 6-methyl-1-pyrimidinyl) -2-naphthyloxy] ethyl acetate, 2- {2- [6- (2-hydroxyethoxy) -12-naphthyl] -16-methyl-4-pyrimidinyloxy} ethanol, N—2— (Ν ', N'-dimethylamino) ethyl 6- (4-chloro-6_methyl-1-pyrimidinyl) -1-naphthoic acid amide dihydrochloride, 2- (6_t-butoxycarbonyl Methoxy 2-naphthyl) 1-4-hydroxy-5-pyrimidinecarboxylic acid, 6- (4-methyl-2-pyrimidinyl) -12-naphthoic acid 'hydrochloride, ethyl 3- チ ル 6- [4- (4-hydroxy) 6-methyl-2-pi Limidinyl) — 2-naphthylcarbonyl] aminopropionate hydrochloride, 3- [6- (4-hydroxy-6-methyl-2-pyrimidinyl) -1-2-naphthylcarbonyl] aminopropionic acid, N—2— ( Ν ', N'-Dimethylamino) ethyl 6- (4-hydroxy-16-methyl-12-pyrimidyl) -12-naphthoic acid amide' dihydrochloride, ethyl 2- [6- (2-aminoethoxy 1) 2-Naphthyl] —4-hydroxyl 5-pyrimidine carboxylate 'dihydrochloride, 2- [6- (2-t-butoxycarbonylaminoethoxy) 1-2-naphthyl] -4-Hydroxy-1 5-Pyrimidinecarboxylic acid, ethyl 4-Methoxy-2— (6-Methoxy-2-naphthyl) -1-5-Pyrimidine carboxylate, 4-Methoxy-2— (6-Methoxy-2-naphthyl) -1 5— Piri mizinka Bonic acid, 4-hydroxy-1-2-1 (6-hydroxy-12-naphthyl) -1-5-pyrimidine carbonitrile, 5-force rubox-1--2- (6-carboxymethoxy-2-naphthyl) 1-4-pyrimidinyl 4-Hydroxy-2- (6-methoxy-2-naphthyl) -1,5-pyrimidinecarboxylate, 4-hydroxy-12- (6-methoxy1-2-naphthyl) -1,5-pyrimidinecarboxylic Acid, 6- [2- (4-hydroxy-6-methyl-2-pyrimidinyl) ethyl] -1-naphthyloxyacetic acid, methyl 5- (4-hydroxy-16-methyl-2-pyrimidinyl) 1-2-naphthyl Oxyacetate, 5- (4-hydroxy-6-methyl-12-pyrimidinyl) -12-naphthyloxyacetic acid, 1-methyl-3-methoxycarbonylmethyl-5- (6-methoxycarbonyl) Bonirume Tokishi 2- naphthylmethylene) hydantoin, 1 one methyl one 3 over main Tokishikarubo two Rumechiru 5- (6-main-butoxycarbonyl main butoxy one 2-Na Fuchirumechiren) hydantoin one 2 f Mi de.  4. 6- (4-Hydroxy-1-6-methinolay 2-pyrimidinole) 1-2-Naphthinoleoxyacetic acid, its salt compounds and solvates thereof.  5.2 2-hydroxy-6- (4-hydroxy-6-methyl-2-pyrimidinyl)-1-naphthylacetamide,  2— (2—t—butoxycarboninoleaminoethoxy) 1 6— (4-hydroxyloxy) 6-methyl-2-pyrimidinyl)-1-naphthyl acetoamide, 2- (6-hydroxy-2-naphthynole) pyrimidine-1,4,6-diol, Ethyl 2- (6-hydroxy-1-naphthyl) -1-4-amino-5-pyrimidine carboxylate, or Ethyl 5-ethoxycarbonyl-2- (6-ethoxycarbonylmethoxy-1-naphthyl) -14-pyrimidinyl oxyacetate.  6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4. 7. Equation (1)

(In the formula, R i and R 2 are different, and R i is a hydrogen atom, a hydroxyl group, a lower alkoxy group which may have a substituent, a lower alkoxycarbonyloxy group, a lower alkyl group having a substituent, a substituent A lower alkenyl group having one COOH or -CONH-R12 (R1 ² is a lower alkyl group having a substituent) represents,  R2 represents a hydrogen atom, a halogen atom or one CH2 CONH—R13 (R13 is a hydrogen atom or a lower alkyl group having a substituent),  R3

(R 10 represents an oxygen atom or NH, and R 11 represents a lower alkoxycarbonyl-lower alkyl group). R5 and R6 may be the same or different, R5 represents a hydrogen atom, a hydroxyl group, an amino group or a lower alkyl group,  R6 represents a hydrogen atom, a hydroxyl group, a halogen atom, OS03H or a lower alkoxy group having a substituent,  R7 represents a hydroxyl group, a lower alkyl group, an amino group or a lower alkoxy group, R8 represents a hydrogen atom, a lower alkoxycarbonyl group, COOH, a cyano group or an amidino group,  R9 represents a linear or branched alkyl group having 1 to 7 carbon atoms which may have an amino group as a substituent. ) Or equation (2)

 (Wherein, R4 represents a hydroxyl group or —OCH 2 COO—R14 (R14 represents a hydrogen atom or a lower alkyl group).) Or a salt thereof or a solvate thereof.  8. The thrombolytic agent according to any one of claims 6 and 7.  9. The fibrinolysis promoter according to claim 6 or 7.  10. The antithrombotic agent according to claim 6 or 7.