JPH02111762A - Tricyclic compound - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {R<1> is COOH or protected COOH; R<2> is aryl (lower) alkyl or heterocyclic (lower) alkyl which may have a suitable substituent group; R<3> is H, CN or halogen; A is lower alkylene; X is O or S; Z is N or CH} and salts thereof. EXAMPLE:3-(3,4-Dichlorobenzyl)-2,3-dihydro-2-oxo-1H-pyrido[4,3,2-de]qu inazoline-1- ethyl acetate. USE:An aldose reductase inhibitor useful as a remedy for diabetic complications, such as corneal damage faulty union, cataract, neuropathy, retinopathy or nephropathy. PREPARATION:A compound expressed by formula II or salt thereof is reacted with a compound expressed by formula III (X<1> is leaving group) or salt thereof or a compound expressed by formula IV or salt thereof is reacted with a compound expressed by the formula X<2>-R<2> (X<2> is leaving group) or salt thereof to afford the compound expressed by formula I or salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION 1. Field of Industrial Application The tricyclic compound of the present invention represented by the following general formula (1) and its salt have aldose reductase inhibitory activity,
It is useful as a medicine.

“Conventional technology.

Although many compounds having aldose reductase inhibitory activity are known, the tricyclic compound represented by the following general formula (1) of the present invention is not known.

[Problems to be Solved by the Invention] Compounds that have aldose reductase inhibitory activity and are useful as pharmaceuticals are known, but this invention was made with the intention of developing a pharmaceutical with excellent properties.

1. Constitution of the Invention This invention relates to a novel tricyclic compound. More specifically, the present invention provides novel tricyclic compounds having aldose reductase inhibitory activity and useful as therapeutic agents for diabetic complications such as corneal wound healing defects, cataracts, Neuroba/-5 retinopathy, renal disorders, etc. Regarding salt.

The novel tricyclic compound of this invention can be represented by the following general formula (1).

can do.

Production method 1 or a salt thereof or a salt thereof [wherein R1 is a carboxy group or a protected carboxy group, R2 is an aryl (lower) alkyl group that may have an appropriate substituent, or a salt thereof a heterocyclic (lower) alkyl group which may be present; R3 is hydrogen, cyan group or halogen; A is a lower alkylene group; X is O or Sl; Z is N or CI;

According to this invention, the target compound (I) and its salts are produced by the production method described below (I) or its salt production method 2 (IV) or its salt or its salt (Ia) or its salt. (I) or a salt thereof (Ib) or a salt thereof Production method 4 (IX) or a salt thereof (X) (X3 means a halogen, R1 means a protected carboxy group).

Raw material compounds (I[), (IV) and (IX) are new and can be produced by the following production method.

Production method A (VI) or a salt thereof (■) (I) or a salt thereof (wherein R1, R2, R3 have the same meanings as before, Xl is a leaving group, X2 is a leaving group, X and Z are so (I[) or its salt manufacturing method B 弶】mureidan (■) or its salt (■) (IV) or its salt (IX) or its salt (in the formula, R, R, R , A, X, z oyohi x2ha each has the same meaning as before).

Compound (VI) or a salt thereof can be produced by the methods disclosed in Production Examples 1 to 7 below, or in a manner similar to those methods.

Compound (■) or a salt thereof can be produced by the methods disclosed in Production Examples 1 to 3 and 9 below, or in a similar manner thereto.

Preferred examples of the various definitions in the above and below descriptions of this specification will be explained in detail below.

"Lower" shall mean 1 to 6 subatomic atoms, unless otherwise specified.

Suitable protected carboxy groups include esterified carboxy groups, and specific examples of the ester moiety of the esterified carboxy group include those that may have appropriate substituents, such as Lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, hexyl ester, such as acetoxymethyl ester, propionyloxymethyl ester, butyl ester, etc. Ryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxymethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester lower alkanoyloxy(lower)alkyl esters such as, for example, lower alkanesulfonyl(lower)alkyl esters such as 2-menlethyl ester, e.g. 2-iodoethyl ester, 2.2.2-t')'
Mono (or di or tri) such as 70-mouth ethyl ester
Halo (lower) alkyl esters; lower alkenyl esters such as vinyl esters and allyl esters; lower alkynyl esters such as ethynyl esters and propynyl esters; such as benzyl esters, 4-methoxybenzyl esters, 4-nitrobenzyl esters, phenethyl esters , trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester,
3.4-'; Al(lower) alkyl ester which may have a suitable substituent such as methoxybenzyl ester, 4-hydroxy-3,5-ditertiary butylbenzyl ester; For example, phenyl ester, 4-chlorophenyl ester, tolyl ester, 4-tertiary butylphenyl ester, xylyl ester, mesityl ester, ri7
Examples include allyl esters which may have appropriate substituents such as nyl esters.

Suitable lower alkyl moieties of the "aryl (lower) alkyl group and the heterocyclic (lower) alkyl group" include methyl, ethyl, propyl, isopropyl, butyl,
and straight or branched lower alkyl groups such as isobutyl, tertiary butyl, pentyl, hexyl, etc.
Among them, preferred are C1-C4 alkyl groups.

Suitable 1-anol moieties of "aryl (lower) alkyl groups" include phenyl, naphthyl, etc., and these aryl groups may be substituted with suitable halogens such as chlorine, bromine, iodine or fluorine. It may have 1 to 3 substituents.

"A preferred heterocyclic moiety of a heterocyclic (lower) alkyl group,
means a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom such as an oxygen atom, an atom atom, a nitrogen atom, etc. Particularly preferred heterocyclic groups include, for example, pyrrolyl, pyrrolinyl,
Imidazolyl, pyrazolyl, pyridyl and its N-oxyto, pyrimidyl, pyrazinyl, pyridazinyl, such as 4H-1,2,4-triazolyl, IH-1°2.3
-triazolyl, 2H-triazolyl such as 1,2,3-triazolyl, tetrazolyl such as IH-tetrazonol, 2H-tetrazolyl, e.g. 4,5-dihydro-
1,2,4-triazinyl, 2,5-dihydro-1,2
, 4-triazinyl and other unsaturated 3- to 8-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as dihydrotriazinyl; for example, 1 nitrogen button such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc. to 4 saturated 3- to 8-membered heteromonocyclic groups; for example, indolyl,
Isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazolyl, benzotriazolyl, tetraclopyridyl, such as tetracylo[1
, 5-b] tetraclopyridazinyl such as pyridazinyl,
Unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms such as 2-hydrotriazolobyridazinyl; for example, oxasilyl, inoxasilyl, such as 1,2,4-oxadiazolyl, 1,3,4-oxaneazolyl , 1.2.5-
Oxygen atom 1 in oxadiazolyl, etc.
unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 2 atoms and 1 to 3 nitrogen atoms; for example, rIl such as morpholinyl, 1 to 2 atoms;
a saturated 3- to 8-membered heteromonocyclic group containing 1 to 3 nitrogen atoms; for example, 1 to 2 # atoms and 1 to 3 nitrogen atoms, such as benzoxacylyl, benzoxadiazolyl, etc. unsaturated fused heterocyclic groups containing: e.g. 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, e.g.
, 1 to 2 small atoms such as thiadiazolyl such as , 2.4-thiadiazonol, 1.3.4-thiadiazolyl, 1.2.5-thianoazolyl, 1,2.3-thiadiazolyl, and 1 to 2 nitrogen atoms An unsaturated 3- to 8-membered heteromonocyclic group containing 3 atoms; For example, a saturated 3- to 8-membered heteromonocyclic group containing 1 to 2 atoms and 1 to 3 nitrogen atoms such as thiazolidinyl; unsaturated 3 to 8 negative heteromonocyclic groups containing 1 atom atom such as , thienyl; for example, 1 to 2 atom atoms such as benzothiazolyl, benzothiadiazonol, and 1 to 3 nitrogen atoms;
Examples include halogens such as chlorine, bromine, iodine or fluorine, such as methoxy, ethoxy, propoxy, impropoxy, butoxy, inbutoxy,
Lower alkoxy groups such as tertiary butoxy, pentyloxy, hexyloxy, such as methyl, ethyl, propyl,
Suitable substituents such as lower alkyl groups such as isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, aryl groups such as phenyl, naphthyl, mono (or di or tri) halo (lower) alkyl groups, etc. It may have one to three pieces.

"A suitable lower alkyl moiety in a mono (or di or tri) halo (lower) alkyl group."

Examples include those exemplified above.

Preferred r halogen and mono (or di or tri)
Suitable halogen moieties in the "halo(lower)alkyl group" include chlorine, bromine, iodine and fluorine.

Suitable primary alkylene groups include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene,
Straight chain or branched alkylene groups such as propylene are mentioned, among which particularly preferred examples include C1
-C4 alkylene group is mentioned.

Preferred examples of "leaving groups" include acid residues, and preferred examples of "acid residues" include halogens such as chlorine, bromine, and iodine, such as methanesulfonyloxy, benzenesulfonyloxy, and toluenesulfonyl. Examples include sulfonyloxy groups such as oxy.

Preferred embodiments of the target compound (1) are as follows.

R1 is a carboxy group or a protected carboxy group [
More preferably an esterified carboxy group, most preferably a lower alkoxycarbonyl group, R2 is an aryl (lower) alkyl group optionally having 1 to 3 halogen atoms [more preferably 1 to 2 halogen atoms] a phenyl (lower) alkyl group which may have a phenyl (lower) alkyl group, most preferably a dihalophenyl (lower) alkyl group]; a thiazolyl which may have 1 to 3 substituents selected from the group consisting of a halogen and an aryl group; (lower grade)”
Alkyl group [more preferably thiazolyl (lower) alkyl group optionally having 1 to 2 substituents selected from the group consisting of halogen and phenyl group, most preferably thiazolyl (lower) having halogen and phenyl group Alkyl group]; Benzothiazolyl (lower) alkyl group which may have 1 to 3 substituents selected from the group consisting of halogen, mono (or di or tri) halo (lower) alkyl group, and lower alkyl group, More preferably, substituents 1 to 2 selected from the group consisting of halogen, mono (or di or tri) halo (lower) alkyl group and lower alkyl group
a benzothiazolyl (lower) alkyl group which may have 1 to 3 substituents; a quinolyl (lower) alkyl group; a benzimidazolyl (lower) alkyl group [more preferably a substituent selected from the group consisting of halogen and a lower alkyl group]
or benzoxacylyl (lower) alkyl optionally having 1 to 3 substituents selected from the group consisting of halogen, lower alkyl group, and lower alkokene group; Base [
More preferably, benzoxacylyl (which may have a halogen, a lower alkyl group, or a lower alkoxy group)
lower) alkyl group], R3 is hydrogen, cyan group or halogen, A is a lower alkylene group [more preferably C1C
5 alkylene group, most preferably medelene group, X is O
or S, Z is N or CH.

Suitable salts of the target compound (1) are pharmaceutically acceptable and commonly used non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, and alkali metal salts such as calcium salts and magnesium salts. metal salts such as ammonium salts, such as tonomethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, organic base salts such as N,N'-dibenzylethylenediamine salts, such as formate salts, acetate salts, trifluoroacetate, maleate, tartrate, methanesulfonate,
Organic acid salts such as benzenesulfonate and toluenesulfonate; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate; e.g. alkynine salt, aspartate,
Examples include salts with amino acids such as glutamate.

The method for producing the object compound (I) of the present invention will be explained in detail below.

(1) Production method 1 Compound (I) or a salt thereof can be produced by reacting compound (n) or a salt thereof with compound (III) or a salt thereof.

Suitable salts of compound (I[>) include the same salts as exemplified for compound (1).

Suitable salts of compound (I[[>) include the same base salts as exemplified for compound (1).

This reaction is carried out using alkali metals such as lithium, sodium, and alkaline earth metals such as calcium, alkali metal hydrides such as sodium hydride,
For example, alkali metal hydrides such as calcium hydride,
For example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal acid salts such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate, e.g. sodium methoxy alkali metal alkanoic acid salts such as sodium acetate, trialkylamines such as triethylamine, such as pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc. It can be carried out in the presence of an organic or inorganic base such as a pyridine compound, quinoline, etc.

This reaction is usually carried out in a solvent such as methylene chloride, methanol, ethanol, propatool, tetrahydrofuran, N,N-dimethylformamide, or a mixture thereof, but any solvent that does not adversely affect the reaction may be used. The reaction can be carried out in any other solvent.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

(2) Production method 2 Compound (■), ξ, or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof.

Suitable salts of compounds (11/) and (V) include the same salts exemplified for compound (1).

This reaction is preferably carried out in the presence of an organic or inorganic base as mentioned in the explanation of Production Method 1.

This reaction can be carried out in substantially the same manner as Production Method 1, and therefore the description of Production Method 1 may be referred to for the reaction method and reaction conditions such as solvent and reaction temperature.

(3) Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to an elimination reaction of the carboxy protecting group.

Suitable methods for the elimination reaction include conventional methods such as hydrolysis, reduction, etc.

<1) Hydrolysis Hydrolysis is preferably carried out in the presence of a base or acid.

Suitable bases include, for example, alkali metals such as sodium, potassium, alkaline earth metals such as magnesium, calcium, hydroxides, carbonates or subhydrogen salts of these metals, trialkylamines such as trimethylamine, triethylamine, etc. , bifrin, and organic bases.

Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples include organic acids such as tritaloloacetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide.

Desorption using a Lewis acid such as a trihaloacetic acid such as tritaloloacetic acid or trifluoroacetic acid is preferably carried out in the presence of a cation scavenger such as anisole or phenol.

The reaction is usually carried out in a solvent such as water, an alcohol such as methanol or ethanol, methylene chloride, tetrahydrofuran, or a mixture thereof, but the reaction may be carried out in any other solvent that does not adversely affect the reaction. It can be carried out.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

(i) Reduction Reduction is carried out according to conventional methods including chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts used for catalytic reduction include platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, such as palladium sponges, palladium black, palladium oxide, palladium carbon, colloidal palladium, Palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, etc., reduced iron,
Commonly used iron catalysts such as Unido iron, reduced steel, copper catalysts such as Raney copper, Ullmann copper, etc.

The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide, or mixtures thereof. Furthermore, if the acids used in the chemical reduction are liquids, they can also be used as solvents.

The reaction temperature for this reaction is not particularly limited, but the reaction is usually carried out under cooling or heating.

Production method 4 Compound (I) or a salt thereof can be produced by reacting compound (fX) or a salt thereof with compound (X).

This reaction is usually carried out in a solvent such as tetrahydrofuran or N,N-dimethylformamide, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

The method for producing raw material compounds (II), (IV) and (IX) will be explained below.

Production method A Compound (II>) or a salt thereof is produced by reacting compound (VI) or a salt thereof with compound (■).

This reaction is usually carried out in a solvent such as tetrahydrofuran or N,N-dimethylformamide, but the reaction can be carried out in any other solvent as long as it does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Production method B Compound (IV) or a salt thereof can be produced by reacting compound (■) or a salt thereof with compound (■).

This reaction can be carried out in substantially the same manner as Production Method A, and therefore, the description of Production Method A may be referred to for the reaction method and reaction conditions such as solvent and reaction temperature.

Production method C Compound (IX) or a salt thereof can be produced by reacting compound (■) or a salt thereof with compound (V) or a salt thereof.

This reaction can be carried out in substantially the same manner as Production Method 1, and therefore the description of Production Method 1 may be referred to for the reaction method and reaction conditions such as solvent and reaction temperature.

This novel tricyclic compound (I) and its salts have been found to have aldose reductase inhibitory activity, which can inhibit diabetic complications such as corneal wound healing defects, cataracts, neuropathy, retinopathy, and renal damage. It is particularly valuable as a drug for the therapeutic treatment of cataracts and neuropathies.

The aldose reductase inhibitory activity values of some representative tricyclic compounds (I) are shown below.

(A) In vitro test (1) Enzyme assay method: 0.5M phosphate buffer (pH 6,2) o,
t mQ2.0M lithium sulfate 0
．． 2. Compound of this invention (dissolved in physiological saline) 0.11IQ Enzyme solution (aldose reductase solution, prepared with <2 below)) 0.5mQ60mM
D, L-glyceraldehyde 0.05mQ2,5
mM Niftenamide adenine dinucleotide phosphate (reduced form) (NADPH)
0.05mQ When the above reaction solution was reacted at 35°C for 2 minutes, the degree of decrease in NADPH was measured using LKB Product A, B, (LK
B Producer A, B, ) Automatic Reaction Rate Analyzer LKB-8600 (Automatic Reactio
n RateAnalyzer LKB-8600). The enzyme activity when the change in absorbance was 0001 per minute was determined to be 1 unit.

(2) Adjustment of oxygen solution Take the rabbit's eye and collect the crystalline lens from it.

The lens was homogenized with 3 times the volume of distilled water at 4°C (all the following operations were also performed at 4°C), then 1O1000G
The mixture was centrifuged for 60 minutes to obtain a supernatant. This supernatant was dialyzed against 21 ml of 005M saline. The dialyzed fluid thus obtained was used as an enzyme solution.

(3) Test compound 3-(4-bromo-2-fluorobenzyl)2,3-dihydro-2-oxoIH-pyrido[4,3,2-de
1-quinazoline-1-acetic acid [hereinafter abbreviated as compound A] (4) Test results The results are shown in the table below.

The ICso value (M) refers to the concentration of the compound of the present invention that inhibits aldose reductase activity by 50%.

(B) In vivo test Inhibitory effect of drug on accumulation of sorbitol in sciatic nerve (1) Test method Group 1 5 animals Sprague-D
After fasting male rats (6 weeks old) for 24 hours, streptocytosine was added to 2mM citrate buffer (p
H4,5) and administered intraperitoneally at a dose of 2mfL7kg (streptocytosine 75mg/kg). One week later, blood was collected from the tail vein, blood sugar level was measured, and 300mg
Rats with a blood sugar level of 10% or higher were used in the test as streptocytosine diabetic rats. A predetermined amount of the test drug was suspended in a 0.5% methylcellulose solution and was administered to these diabetic rats for 8 days after administration of streptocytosine.
The mice were orally administered once a day for 5 days from day 1 (these were referred to as the streptocytosine-treated drug administration group). Final drug administration 6
After a period of time, the rats were sacrificed and the content of sorbitol in the sciatic nerve was determined.

The content of sorbitol in the sciatic nerve was also measured from the control group, a streptocytosine-treated drug-free group and a streptocytosine-treated drug-free group, and the results showed that the test drug had an inhibitory effect on sorbitol accumulation in the sciatic nerve. was expressed as the inhibition rate value calculated from the following formula.

Formula: S: Sorbitol content in the sciatic nerve in the streptocytocin-treated, drug-free group SD: Sorbitol content in the sciatic nerve in the streptozotocin-treated, drug-treated group N: Sorbitol content in the sciatic nerve in the streptocytocin-treated, drug-free group ( 2) Test compound: 2.3-dihydro-3-[(5-fluorobenzothiazol-2-yl)methyl]-2-year-old xoperimidine-1
- Acetic acid [hereinafter abbreviated as compound B] (3) Test results Pharmaceutical compositions contain, for example, the active compound of the present invention, that is, compound (I) or a salt thereof, in an organic compound suitable for external, internal or local administration. Alternatively, it may be provided in the form of a solid, semi-solid or liquid preparation containing an inorganic carrier or/and excipient. The active compound, together with non-toxic and pharmacologically acceptable auxiliary ingredients, can be used, for example, in tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, etc.
used to provide suitable dosage forms such as. Such auxiliary ingredients include, for example, water, glucose,
lactose, gelatin, mannitol, starch paste,
Magnesium trisilicate, cornstarch, keratin,
Included are those that can be effectively used in the production of solid, semi-solid or liquid formulations, such as colloidal silica, potato starch, urea, and the like. Additionally, adjuvants such as stabilizers, fillers, colorants and fragrances may also be included.

Pharmaceutical compositions according to the invention may also contain preservatives to preserve the activity of the active compounds. The composition should contain an amount of the active compound sufficient to produce the desired therapeutic effect on the relevant disease process or pathology.

When this pharmaceutical composition is used in humans, it is preferably administered intravenously, intramuscularly or orally. The effective amount of each active compound depends on the age and/or condition of the patient being treated. However, generally the pharmaceutical compositions will contain about 50 mg, 100 mg, 250 mg, 5 mg per unit dosage form.
00 mg or 1000 mg of active compound and for humans or animals from 0.1 to 1 kg body weight.
A daily dose of 100 mg is administered.

The present invention will be explained in detail below with reference to Production Examples and Examples.

Qssenma 10 Nashi j1 Ranjo 1.8-dinitronaphthalene (1,09g), iron powder (2
0 mg) and bromine (0,411111) is heated to 130° C. with stirring. After stirring the mixture for 4 hours, sodium thiosulfate solution is added thereto, the precipitated solid is washed with water and triturated with ethanol to give 3-bromo-1,8-dinitronaphthalene (0.53 g).

mp: 153-156℃ 1 product 1 3-bromo-1,8-dinitronaphthalene (8,98g
), cuprous chloride (4.19 g) in N,N-dimethylformamide (10IIIQ) is stirred under reflux for 3 hours. After cooling, ferric chloride (15 g) and IN hydrochloric acid (3
01119) is added to the mixture and the precipitated solid is washed with water and ethanol to give 3-chloro-1,8-dinitronaphthalene (5.57 g).

mp i 141-144℃ 11 1 (1) 3-bromo-1,8-dinitronaphthalene (0,
5g), iron powder (1.1g), ferrous sulfate heptahydrate (0
, 11g), water (611111) and ethanol (3
, 6-) is stirred under reflux for 2 hours. After filtration and evaporation of the solvent, the residue is extracted with chloroform and chromatographed on silica gel to obtain 3-boulomo-1,8-naphthalenediamine (0.25 g).

NMR (CDCl2.δ): 4.58 (4)1.
br s), 6.61 (1) 1゜dd, J=1.6
．． 7Hz), 6.62 (IH, d, 2Hz),
7.0-7.3 (2M, m), 7.33 (IH,
d, C2Hz) The following compound is obtained in the same manner as in Production Example 3 (1).

(2) 3-chloro-1,8-naphthalenediamine.

NMR (CDC1s, 8) = 4.55 (4H, b
r s), 6.52 (IHld, J=2Hz3.
6.58 (IH, dd, J'2. 7Hz>, 7
．． 05-7.25 (3H,ee) (3) 3-cyano-1,8-naphthalenediamine.

mp: 1J15-187℃ Otori j ■ 1 look (1) reef-chloro-5-nitroquinoline! A mixture of N-oxide (11,7 g) and phenol (117 g) is heated to 110-120° C. for 30 minutes. Add 3,4-dichlorobenzylamine (18.3 g) to this mixture. The mixture is stirred under the same conditions for 4 hours, cooled and diluted with dry ether (IP). Filter off the precipitated material,
The ether solution is saturated with hydrogen chloride and the precipitated material is filtered off. Recrystallization from methanol gives 4-(3,4-dichlorobenzylamino)-5-nitroquinoline-N-oxyto hydrochloride (t3.2 g).

NMR (DMSO-d6.δ): 4.80 (2H
, s), 6.92 (LH.

d, J=8Hz>, 7.45 (IH, dd, J=8
．． 1Hz), 7.68 (18, d, J: 8Hz),
7.76 (LH, d, J=IHz), 8.18 (l
H, dd, J=8.8Hz), 8.45 (IH, d
d, J=8°0.5Hz), 8.55 (LH, dd
, J=8.0.5Hz), 8.85(LH,d,J=
8Hz), 9.00 (IH, br s) Production Example 4 (
The following compound is obtained in the same manner as in 1).

(2) 4-(4-bromo-2-fluorobenzylamino)-5-nitroquinoline-N-oxyto hydrochloride.

NMR (DMSO-d6.δ): 4.78 (2H
, s), 6.98 (LH.

d, J-near Hz), 7.45 (2H, m),
7.65 (LH, dd, J=8゜IHz),
8.18 (IH, d, J=8Hz), 8.4
0 (LH, ddJ=8.8Hz>, 8.56
(IH, d, J: 8Hz), 8.90 (LH
.

d, J = 7Hz) Production Example 5 (1) 4-(3,4-dichlorobenzylamino)5-nitroquinoline N-oxyto hydrochloride (2.0g), reduced iron (2.0g)) JJ and Vinegar # (40ffllll)
The mixture is heated to 100° C. for 1 hour while stirring. After the mixture has been cooled and filtered, the solvent is distilled off. The residue is extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate.

The solvent was distilled off to obtain 5-amino-4-(3,4-dichlorobenzylamino)quinoline (0.76 g) as crystals.

NMR (DMSO-da, S)' 4.42 (2
H1s), 6.20 (IHld.

J=6Hz), 6.80 (LH, d, J=8Hz)
, 7.2-7.7 (6H, m), 8.40 (IH
, d, J=6Hz) The following compound is obtained in the same manner as in Production Example 5(1).

(2) 5-amino-4-(4-bromo-2-fluorobenzylamino)quinoline.

mp: >200°C IR (Skul): 3450. 3400
cm-1 Production Example 6 3-bromo 1,8-naphthalenediamine (2,48g
), 4-bromo-2-fluorobenzyl bromide (2,81
g) and potassium carbonate (1,6 g) in ethanol (5
0mu) Stir the warm mixture at 50°C overnight.

The mixture is filtered and the solvent is evaporated. The residue is chromatographed on silica gel and eluted with a mixed solvent of hexane and benzene (2:1).

From the first fraction 1-amino-3-bromo-8(4-bromo-2-fluorobenzylamino)naphthalene (0,84
g) is obtained.

NMR (CDCl2.δ): 4.36 <28. d
, J=5.4)1z), 4.62(2H,br s)
, 5.86 (IH, br t), 6.49 (I
H, dd.

JJ, 7Hz), 6.75 (LH, d, J=2H
z), 7.0-7.4 (6H section) 8-amino-3-bromo-1(4-bromo-2-fluorobenzylamino)naphthalene (1,03
g) is obtained.

NMR (CDC1a, S)' 4.17 (2H1
br s), 4.37 (2H3s), 6.51 (
LH, d, J=2Hz), 6.68 (IH, dd.

J=2.8.5.8Hz), 7.1-7.4 (6H
, m) 1 production ■U The following compound was obtained in the same manner as in Production Example 6.

1-Amino-8-(4-bromo-2-fluorobenzylamino)-3-chloronaphthalene.

NMR (CDCl2.8): 4.32 (2H,s
), 5.05 (2H.

br s), 6.46 (IH, dd, J=2.7H
z), 6.59<IH,d, J=2Hz), 7.0
-7.4 (6H, m)8-amino-1-(4-bromo-2-fluorobenzylamino)-3-chloronaphthalene.

NMR (CDC13,8)' 4.34 (2H,s
), 6.36 (IH, d.

J: 2Hz), 6.66 (LH, dd, J=3.5
Hz), 7.1-7.4 (6H, se) Production Example B (1) 5-amino-4-(3,4-dichlorobenzylamino)quinoline (0.74 g) in tetrahydrofuran (
151n11) To the solution is added N,N'-carbonyldiimidazole (0.57 g) and the mixture is stirred overnight. After distilling off the solvent, the crude crystals were washed with ethyl acetate to give 3-
(3,4-dichlorobenzyl)-2゜3-dihydro-2
-OxoIH-pyrido[4°3.2-de]quinazoline (0.64 g) is obtained.

NMR (DMSO-da, S)' 5-15 (2
H1s), 6.55 (LHld, J=6Hz), 6
．． 75 (1)1. d, J=8Hz), 7.3-7.
7 (6H, m), 8.45 (LH, d, J=68Z
>The following compound is obtained in the same manner as in Production Example 8 (1).

(2) 3-(4-bromo-2-fluorobenzyl)-2
,3-dihydro-2-oxoIH-pid[4,3,
2-delquinazoline.

mp: >250°C NMR (DMSO-ds, 8)' 5.15 (2
H0s), 6.51 (LHld.

J=6Hz>, 6.78 (IH, d, J=8Hz>
, 7.20 (IH, dd.

J=8.8Hz), 7.35 (2H, d, J=8H
z), 7.6 (28゜m), 8.48 (IH,
d, J=6Hz>(3>5-bromo-1-(4-bromo-2-fluorobenzyl)-2,3-dihydro-2-oxoperimidine.

mp: 316-320°C (4) 8-bromo-1-(4-bromo-2-fluorobenzyl)-2,3-dihydro-2-oxoperimidine.

mp i 307-311”C (5) 1-(4-bromo-2-fluorobenzyl)-5
-chloro-2,3-dihydro-2-oxoperimidine.

mp: 301-303°C (6) 1-(4-bromo-2-fluorobenzyl)-8
-chloro-2,3-dihydro-2-oxoperimidine.

mp: 308-311℃ (7) 1-.(3,4-dichlorobenzyl) -2,3
-dihydro-2-oxoperimidine.

mp: 267-269°C (8) 1-(4-bromo-2-fluorobenzyl)-2
, 3-dihydro-2-oxoperimidine.

mp: 302°C (decomposition) (9) 1-(4-bromo-2-fluorobenzyl)-5
-cyano-2,3-dihydro-2-oxoperimidine.

mp: >340°C (10) 1-(4-bromo-2-fluorobenzyl)-
8-cyano-2,3-dihydro-2-oxoperimidine.

mp: >340°C (11>7-bromo-1-(4-bromo-2-fluorobenzyl')-2,3-dihydro-2-oxoperimidine.

mp: 298℃ 1 production■1 1.8-Naphthalenediamine (25g), tert-butyl bromoacetate (30.9g) and potassium carbonate (24 sections) in dry ethanol (300all) at 50%
Stir at ℃ for 10 hours. After filtration and evaporation of the solvent, the residue was chromatographed using silica gel (700 g), a mixed solvent of hexane and ethyl acetate (5:
1) to obtain N-tertiary butoxycarbonylmethyl-1,8-naphthalenediamine (33.30 g).

NMR (CDC13,l; )' 1,51 (9H
9s), 3.88 (2)1. s).

6.41 (1)1. dd, J=8.1Hz), 5.
5 (21(, br s).

6.70 (1)1. dd, J=8.1Hz), 7.
15-7.30 (5H, m) 1 blood sample (1) N-tertiary butoxycarbonylmethyl-1°8-
To a solution of naphthalene diamine (2,72 g) in tetrahydrofuran (4 oma) is added N,N'-carbonyldiimidazole (1,78 g) and the mixture is refluxed for 2 hours. After distilling off the solvent, the residue was crystallized from ethyl acetate to give 2,3-dihydro-2-year-old xoperimidine-1.
-Tertiary butyl acetate (2.28 g) is obtained.

N gate (DMSO-d6.δ): 1.45 (9H,
s), 4.60 (21°s), 6.48 (IH
, d, 8 Hz), 6.64 (LH, d.

J=811z), ya (5H, m) Production Example 10 (
The following compound is obtained in the same manner as in 1).

(tert-butyl 8-bromo-2,3-dihydro-2-oxyperimidine-1-acetate).

mp: 232°C (decomposed) (3) Tertiary butyl 5-bromo-2,3-dihydro-2-year-old xoperimidine-1-acetate.

mp: 220°C (decomposed) (4) 8-chloro-2,3-dihydro-2-oxoperimidine-1-tertiary butyl acetate.

mp: 225°C (decomposition) (5>5-chloro-2,3-dihydro-2-oxo °
Lamidine-1-tert-butyl acetate.

mp: 212°C (decomposition) Production Example 11 N-tertiary poxylponylmethyl-1,8-naphthalenediamine (0,49 g), 4-bromo-2-fluorobenzyl-bromide (0,48 g) and potassium carbonate (0.25 g) of ethanol (t5mQ) was stirred at 50° C. for 3 hours and then filtered. The filtrate was concentrated and the residue was subjected to column chromatography using silica gel and crystallized from diisopropyl ether-hequinane to give N-tertiary poxycarbonylmethane-N'-(4-
Bromo-2-fluorobenzyl)-1,8-naphthalenediamine (0,L9[) is obtained.

mp; 131-132°C 11-B 1.8-naphthalenediamine (io, og), 3.4-
Dichlorobenzyl-chloro IJ F (8,77ffl1
1) A mixture of 7M potassium (s, 8g) and ethanol (200mQ) was stirred at 50°C for 3 days, filtered, and the solvent was distilled off. The residue was extracted with ether and chromatographed on silica gel to give N-(3
4-dichlorobenzyl)-1,8-naphthalenediamine (11,04 g) is obtained.

NMR (CDC13,15>' 4.27 (2H8
s), 6.32 (LHldd.

J: 6.3Hz>, 6.60 (LH, dd, J near, 1Hz), 7.0-7.5 (7H) The following compound was obtained in the same manner as in Production Example 12.

N-(4-bromo-2-fluorobenzyl)-1,8-
Naphthalenediamine.

NMR (CDCl2.,ri): 4.37 (2H
, s), 6.45 (LH, dd.

J=5.3Hz), 6.67 (IH, dd, J=7
．． 1Hz), 7.1-7.4 (714,m) Production Example 14 3-Bromo-1,8-naphthalenediamine and tertiary butyl bromoacetate are reacted in the same manner as in Production Example 9 to obtain the following compound.

8-Amine-3-bromo 1-tertiary butoxycarponylmethylaminonaphthalene.

mp: 129-131°C 1-amino-3-bromo-8=tertiary-butoxycarbonylmethylaminonaphthalene mp: 144-146°C Butyl is reacted in the same manner as in Production Example 9 to obtain the following compound.

8-Amino-1-tertiary-butoxycarbonylmethylamino-3-chloronaphthalene.

mp: 11B-118°C 1-amino-8-tertiary poxylponylmethelamino-3-chloronaphthalene.

mp: 122 124°C Production Example 16 3-bromo-1.8-dinitronaphthalene (5.1g
), cupric cyanide (2.4 g) and N,N-dimethylformamide (5 mg) are stirred under reflux for 4 hours. I of ferric chloride hexahydrate (iog) was added to this mixture.
Add N hydrochloric acid solution, collect the precipitate by filtration, and recrystallize from chloroform to obtain 3-cyano-1,8-dinitronaphthalene (2
．． 16 g).

mp: 197-'204℃ Production example 17 The following compound is obtained in the same manner as in Production Example 6.

1-Amino-8-(4-bromo-2-fluorobenzylamino)-3-cyanonaphthalene.

mp: 170-172°C 8-amino-1-(4-bromo-2-fluorobenzylamino)-3-cyanonaphthalene.

mp: 165-168°C Production Example 18 1,8-naphthalenediamine (12.0g), 4-bromo-2-fluorobenzylfuromide (19.7g)
, a mixture of potassium Jj2 acid (11.2 g) and ethanol (100 mQ) was stirred at 50 °C overnight,
After filtration, the solvent 10 is distilled off. The residue was chromatographed on silica gel to give N-(4-bromo-2-
fluorobenzyl)-1,8-naphthalenediamine (9
．． 71 g) is obtained.

NMR (CDCl2, f; ) i 4, 37 (
28,s), 6.45 (LH, ddC5, 3Hz
), 6.67 (18, dd, J=7.1Hz),
7.1-7,4 (7H,+n) Production Example 19 (1) N-tertiary butoxyluponylmethyl-1.

8-naphthalenediamine (4.91 g) and tert-butyl carbonate (4.74 g) and tetrahydrofuran (
A mixture of 50 mQ ) was stirred at 50° C. overnight, and tetrahydrofuran was distilled off. The residue was extracted with ether and subjected to column chromatography using silica gel.
Elution with hexane-ethyl acetate (4:1) gives N-tertiary butoxyluponyl N'-tertiary butoxyluponylmethyl-1,8-naphthalenediamine (5,04 g).

mp: 92-94℃ The following compound is obtained in the same manner as in Production Example 19(1).

(2) N-(4-bromo-2-fluorobenzyl)-N
' - Tertiary poxylponyl-1,8-1 phthalenediamine.

NMR (CDCl2-5)' 1.51 (
9H,s), 4.22 (2H,s).

6.87 (if(,dd,J=7.1)1z), 7
．． 2-7.6 (6H, nt).

8.23 (18, dd, J = 7.1 Hz) Production Example 20 (1) N-tertiary poxycarbonyl-N'-tertiary poxycarbonylmethyl-1,8-naphthalenediamine (5,04 g) and 2.4.4.6-Tetrabromo-2,5-cyclohexadien-1-one (5,55g
) and methylene chloride (601+1Q) in a water bath.
Stir for a minute and evaporate the solvent. The residue was subjected to column chromatography using silica gel and eluted with hexane-ethyl acetate (4:1) to give 4-bromo-8-tertiary-butoxylponylamino-1-tertiary-butoxylponylmedel. Aminonaphthalene (1.05 g) is obtained.

rap: 90℃ (decomposition) The following compound is obtained in the same manner as in Production Example 20(1).

(2) 4-bromo 1-(4-bromo 2-fluorobenzylamino)-8-tert-butoxycarbonylaminonaphthalene.

IR (Nujol): 1680 crn-'
Production side 21 4-bromo 1-(4-bromo 2-fluorobenzylamino)-8 = tertiary butoxycarbonylaminonaphthalene (3 g) was dissolved in trifluoroacetic acid (5 needles) and methylene chloride (2fflQ), and the mixture was heated to room temperature. Stir for 30 minutes. a Diameter reduction, IN sodium hydroxide aqueous solution (5i+11
) and extracted with methylene chloride (20 ml x 3). The crude product was purified by column chromatography (silica gel; hexane:methylene chloride-1:1),
8-Amino-4-bromo-1-(4-bromo-2-fluorobenzylamino)naphthalene (2.0 g) is obtained.

NMR (CDC13,S)' 4.37
(2)1. s), 5.1-6.3 <31(.

m>, 6.38 (IH, d, J=8Hz),
6.85 (IH, dd, J: Otsu 1Hz), 7.2-
7.4 (4H, m), 7.52 (LH, d.

J=8Hz), 7.79 (LH, dd, J=8.1
Hz) Example 1 (1) 3-(3,4-dichlorobenzyl)-2,3-dihydro-2-oxo IH-pyrido [4,3°2-de
To a stirred solution of coquinazoline (0.64 g) in dry N,N-dimethylformamide (1011111) 60% sodium hydride (0.09 g) is added under water cooling and the mixture is stirred at room temperature for 1.5 hours. Bromoacetic acid-Ldel (0.37 g) is added to the mixture and the mixture is stirred at room temperature for 3 hours. To this mixture was added IN salt #c, 2 mQ) and water (50 ffll!), the precipitated solid was collected by filtration,
Wash with water, dry, 3-(3,4-dichlorobenzyl)-
2,3-dihydro-2-oxoIH-pyrido[4,3
,2-de]quinazoline-1-ethyl acetate (0.85g
).

NMR (DMSO-da, 6i)' 1.24 (
3H1t-1J=7Hz＞, 4,20(2H,q,J
=7)Lz), 5.03 (2H,s), 5.
42 (2H, s).

7.11 (18, d, J=8Hz>, 7.35
(2H, m), 7.65 (3H, nt),
8.02 (18,dd, J=8.8Hz), 8
．． 33 (IH, d, J=8Hz>) The following compound is obtained in the same manner as in Example 1(l).

(2) 3-(4-bromo-2-fluorobenzyl)-2
,3-dihydro-2=oxo-IH-pyrido[4,3,
2-de]quinazoline-1-acetic acid m ether.

NMR (DMSO-da, δ): 1.21 (3H
, t, J=7Hz), 4.18(2)1. q, J near Hz), 4.90 (2H,s), 5.25 (2
8,s).

6.68 (LH, d, J=6Hz), 6.90 <
LH, d, J = 8Hz).

7.15 (IH, dd, J: 8.8Hz), 7.3
6 (LH, dd.

J=8.1Hz), 7.50 (LH, d, J:8H
z), 7.64 (IH.

dd, J=8.1Hz>, 7.68 (IH, d, J
= 8 Hz>, 8.57 (18, d, J = 6 Hz> .

mp: 184-186°C (4) 8-bromo-3-(4-bromo-2-fluorobenzyl)-2,3-dihydro-2-year-old xoperimidine-
1-Ethyl acetate.

mp: 209-211°C (5) 3-(4-bromo-2-fluorobenzyl)-8
-Chloro-2,3-dihydro-2-year-old xoperimidine-
1-Tertiary butyl acetate.

mp: 163 165°C (6) 3-(4-bromo-2-fluoropencyl)-5
-Chloro-2,3-dihydro-2-year-old xoperimidine-
1-Tertiary butyl acetate.

mp: 221-223°C (7) Ethyl 3-(3,4-dichlorobenzyl)-2,3-dihydro-2-year-old xoperimidine-1-acetate.

mp: 149 151°C (8) 3-(4-bromo-2-fluorobenzyl)-2
, 3-dihydro-2-oxoperimidine-1-ethyl acetate.

mp; 196-199°C (9) 3-(4-bromo-2-fluorobenzyl)-8
-Cyano-2,3-dihydro-2-year-old xoperimidine-
1=tertiary butyl acetate.

mp: 175°C (decomposed) (10) 3-(4-bromo-2-fluorobenzyl)-
5-Cyano-2,3-dihydro-2-year-old xoberimidine-1-tert-butyl acetate.

mp: 210 212°C (11) Ethyl 6-bromo-3-(4-bromo-2-fluorobenzyl)-2,3-dihydro-2-exoperimidine-1-acetate.

K-1 (1) 2,3-dihydro-2-oxoperimidine-1-
To a solution of tertiary-butyl acetate (1.49 g) in dry N,N-dimethylformamide (15 mQ) is added 60% sodium hydride (0.24 g) under water cooling. After stirring the mixture for 1 hour under water cooling, 5-chloro-2-chloromethylbenzothiazole (1.1 g) was dried with N.

Add N-dimethylformamide (1511Q) solution to this. The mixture was stirred at room temperature overnight and was then stirred with IN hydrochloric acid (
2,5111Q) is added to this. Add water (10
Add 0mQ). Filter the precipitated brown solid, wash with water,
Dry and recrystallize from ethyl acetate to give 3-[(5-'7
0Lopenzothiazol-2-yl)metelco2.3-
Tert-butyl dihydro 2-oxoberimidine-1-acetate (1,63 g) is obtained.

mp: 210-212℃ The following compound is obtained in the same manner as in Example 2 (1).

(2) Tertiary butyl 3-(2-quinolylmethyl)-2,3-dihydro-2-year-old xoperimidine-1-acetate.

mp: 150°C (3) 2.3-dihydro-3-[(1-methyl-IH-
benzimidazol-2-yl)metelco 2-oxoperimidine-1-tert-butyl acetate.

NMR (DMSO-ds, δ): 1.45 (9H
,s), 4.01 (3H.

s), 4.76 (2H, s), 5.55
(2H, s), 6.65 (LH, dd, J=8.
LHz), 6.86 (LH, dd, J=8
゜1)1z), 7.1-7.6 (8)1. m)
(4) 3-(2-benzoxasilylmethyl)-2,3
-Dihydro-2-year-old xoperimidine-1-tert-butyl acetate.

mp: 175-179°C (5) 3-[(5,6-dichloro-1-methyl=IH-
benzimidazol-2-yl)methyl-2,3-dihydro-2-oxoperimidine-1-tert-butyl acetate.

NMR (DMSO-ds, S): 3.94 (3H
,s), 4.75 (2H1s), 5.55 (2
H,s), 6.66 (LH,d, J=8Hz).

6.80 (LH, d, J: 8Hz), 7.2-7.
5 (4H, m), 7.80 (LH, s), 7.9
9 (l)I,5)(6)2.3-dihydro-3-((
6-Medoxybenzoxazol-2-yl)methyl]
-2-year-old xoperimidine-1-tert-butyl acetate.

NMR (DMSO-ds.S): 1.43 (9
H,s), 3.80 (3H.

s), 4.75 (2H, s), 5.54 (2H
,s), 6.67 (18°dd, J=7.2Hz)
, 6.86 (IH, dd, J near, 2Hz)6.
95 (1)1. dd, J=8.2Hz), 7.40
(5H, m>.

7.55 (1M, d, at 7 Hz) (7) 3-[(5-chlorobenzoxazol-2-yl)methyl]-2,3-dihydro-2-tert-butyl xoperimidine-1-acetate.

mp: 172-175°C (8) 3-[(5,6-cyclopenzothiazole-2
-yl)methyl-2,3-dihydro-2-oxoperimidine-1-tert-butyl acetate.

mp: 154-156°C (9) 2.3-dihydro-3-[(5-fluorobenzothiazol-2-yl)methylco-2-oxoberimidine-1-tert-butyl acetate.

mp: 212-213°C (10) 3-[(5-bromobenzothiazol-2-yl)methyl]-2,3-dihydro 2-oxoperimidine-1-tert-butyl acetate.

NMR (CDCl2.8)' 1-26 (9H-
s), 4.40 (2H9s) 5.32 (2H,s)
, 6.23 (IH, dd, 8.2Hz).

6.40 (IH, dd, J=8.2Hz>, 7.1
-7.2 (4H, m).

7.23 (1B, dd, J=8. IHz>, 7.
33 (18, d.

J4Hz), 8.09 (IH, d, J=IHz) (
11) 2.3-dihydro-3-[(5-ethylbenzoxazol-2-yl)methyl-2-oxoperimidine-1-tert-butyl acetate.

IR (Sujoor): 1740. 1660
cm-1(12) 2.3-dihydro-3-[(5-
Methylbenzoxazol-2-yl)metelco-2-
Oxoberimidine-1-tert-butyl acetate.

IR (Streak 3-L): 1740. 1660
am-1(13)2.3-dihydro-3-[(6-fluorobenzothiazol-2-yl)methyl] -2-
xoperimidine-1 = tert-butyl acetate.

IR (Streak 3-L): 1740. 1660
am-1(14)2.3-dihydro-3-[(7-fluorobenzothiazol-2-yl)metelco-2-oxoperimidine-1-tert-butyl acetate.

IR (Streak 1-L): 1740. 1660
am-'(15) 2,3-dihydro-3-[(4-
fluorobenzothiazol-2-yl)methyl]-2-
Tertiary butyl xoberimidine-1-acetate.

IR (Stripe 3-L)' 1740. 1660
am-1BMR (DtiSO-ds, S)' 1
．． a3 (9H, s), 4.77 (2H1s),
5.65 (2)1. s>, 6.70 (IH
, m), 6.90 (lH, m), 7.40 (
8H, m), 7.88 (l)1. d, C3Hz>
(16) 2.3-dihydro-3-[(5-methylbenzothiazol-2-yl)medel]-2-year-old xoperimidine-1-tert-butyl acetate.

IR (Streak 9-L): 1740. 1660
cm-1BMR (DMSO-d6.δ): 1.4
5 (9)! , s), 2.40 (3H.

s), 4.75 (2H, s), 5.63 (2H
, s), 6.67 (IH.

m), 6.86 (LH, m), 7.2-7.5
(5H, m), 7.79 (18, bs), 7.90
(IH, d,, C3Hz) (17) 2°3-dihydro-2-year-old xo-3-[(5-trifluoromethylbenzothiazol-2-yl)methylcoperimidine-1-acetic acid tertiary Budel.

IR: 1740. 1660
am-1(18) 8-Chloro-3-[(5-chlorobenzothiazol-2-yl)methyl]-2,3-dihydro-2-oxoperimidine-1-tert-butyl acetate.

mp: 188-191°C (19) 8-bromo3-[(5-chlorobenzodeazol-2-yl)methyl]-2.3-dihydro2-
Oxoperimidine-1-tert-butyl acetate.

mp: 186-188℃ (4,000 f3) 1U 1 (1) 2.3-dihydro-2-oxoperimidine-1-
To a solution of tertiary-butyl acetate (0.39 g) in dry N,N-dimethylformamide (5 mQ) is added 60% sodium hydride (0.06 g) with stirring under water cooling. 7i! After stirring the mixture at room temperature for 1 hour, it was added with dry N,N-
A solution of dimethylformamide (5 ml) is added. The mixture is stirred for 3 hours, acidified with IN hydrochloric acid (0.8 mQ) and diluted with water. The solid that precipitates is collected by filtration, washed with water, dried and resuspended from ethyl acetate. It crystallized to give tert-butyl 3-[(5-bromobenzothiazol-2-yl)methyl]-2,3-dihydro-2-oxoperimidine-1-acetate (
0.38 g) are obtained as crystals.

NMR (CDC13,S): 1.26 (9H1s
>, 4.40 (2H1s).

5.32 (2H, s), 6.23 (IH, dd,
J: 8.2Hz).

6.40 (LH, dd, J: 8.2Hz), 7.1
-7.2 (4H, m).

7.23 (IH, dd, J=8.1Hz), 7.3
3 (IH, d.

J=8Hz), 8.09 (IH, d, J=IHz)
The following compound is obtained in the same manner as in Example 3 (1).

(2) Tertiary butyl 3-(2-pentthiazolylmethyl)23-dihydro-2-year-old xoberimidine-1-acetate.

N1IR (DMSO-da, δ): 1.45 (9
H,s), 4.78 (2H.

s>, 5.66 (2H, s), 6.70 (LH
, m), 6.90 (LH.

m), 7.3-7.6 (6H, m), 8.0 (
2H,m)(3)3-[(5-bromo-4-phenylthiazol-2-yl)methyl]-2,3-dihydro2
-oxoperimidine-1-tert-butyl acetate.

NMR (DMSOds, f; )' 1.42 (9
H,s), 4.75 (2H1s), 5.51
<2H, s), 6.70 (IH, dd, J=8.
2) 1z) 6.48 (IH, dd, J=8.2
Hz), 7.3-3.6 (7H, m).

7.86 (2H, m) (4) 3-[(6-Promobenzothiazol-2-yl)methyl]-2.3-dihydro 2-oxoperimidine-1-tert-butyl acetate.

mp: 151-152°C (5) Tertiary butyl 3-[(6-chlorobenzothiazol-2-yl)methyl]-2,3-dihydro-2-year-old xoperimidine-1-acetate.

NMR (DMSO-ds, 8)'t, 42 (
9H1s>, a, 75 (2H1s), 5.65
(2)1. s), 6.68 <IH, ddj=8゜2
Hz>.

7.00 (IH, dd, J=8.2Hz), 7.3
−7.6 (5H, m>.

8.00 (IH, d, J=8Hz), 8.20 (
IH, d,, CIHz>(6) 3-[(4,6-dipromobenzotheazol-2-yl)methyl]-2,3-dihydro-2-oxoberimidine-1-tert-butyl acetate.

NMR (DMSO-da, S)' 1.43 (9
H1s), 4.77 (2H9s), 5.70 (2
H,s), 6.70 (18,dd, J=8.2Hz
).

6.91 (18, dd, J=8.2Hz>, 7.4
5 (4H, m>.

8.01 (IH, d, J=IHz), 8.35 (
LH, d, J: 1Hz) (7) 8-bromo-3-[(5
-bromobenzothiazol-2-yl)methyl]-2.
3-dihydro-2-oxoperimidine-1-tert-butyl acetate.

mp: 177-180°C (8) 5-bromo-3-[(5-bromobenzothiazol-2-yl)methyl-2,3-dihydro-2-oxoberimidine-1-tert-butyl acetate.

mp: 184 186°C <9) Tertiary butyl 3-[(5-bromobenzothiazol-2-yl)methyl]-8-chloro2,3-dihydro-2-year-old xoperimidine-1-acetate.

mp: 163-166°C (10) 3-[(5-bromobenzothiazol-2-yl)metelco-5-chloro2,3-dihydro-2-oxoperimidine-1-tert-butyl acetate.

mp: 183-186°C λJIM± (1) 3-(3,4-dichlorobenzyl)-2,3-dihydro-2-oxo IH-pyrido [4,3°2-de
] Quinazoline-1-ethyl acetate (0,84&), IN
*A mixture of aqueous sodium oxide solution (4 ml) and methanol (zomQ) is stirred under reflux for 1 hour. After cooling, IN hydrochloric acid (51 nQ) is added to the mixture.

The solution is treated with activated carbon and diluted with water, then the methanol is distilled off. The precipitated crystals are collected by filtration, washed with water, and dried.
3-(3,4-dichlorobenzyl)-2,3-dihydro-2-oxoIH-pid[4,3,2-da]quinazoline-1-acetic acid (0,62 g) is obtained.

mp: >250℃ IR (Stripe 3-L)' 1685 am-1H
MR (DMSO-d6.δ): 4.32 (2H,
s), 5.25 (2H.

s>, 6.71 (l)i, d, J=7)1z)
, 6.42 (1) t, d.

J:8Hz), 7.3-7.7 (5H, m), 8
．． 55 (LH, d.

J=7Hz) The following compound is obtained in the same manner as in Example 4 <1).

(2) 3-(4-bromo-2-fluorobenzyl)-2
,3-dihydro-2-oxoIH-pyrido[4,3,
2-da] quinazoline-1-acetic acid.

mp: 305-310℃ IR (Sujoor): 1690. 1630.
1600 cm-1 HMR (DMSO-ds, l;
)' 4.81 (2H,s), 5.
24 (2H1s), 6.65 (IH, d, J=
6Hz), 6.90 (1)1. d.

J=8Hz), 7.15 (LH, dd, J=8.8
Hz), 7.33 (LH, dd, J=8.1Hz),
7.47 (LH, d, J=8Hz).

7.65 <2)1. m>, 8.55 (IH, d
, J=6)1z>(3) 5-bromo-3-(4-bromo-2-fluorobenzyl)-2,3-dihydro-2-dihydro-xoperimidine-1-acetic acid.

mp: 260-263°C NMR (DMSOda, S)' 4.74 (2H
3s), 5.22 (2H1s), 6.73 (IH
, d, J=IHz>, 6.78 (LH, dd, J=
1°7Hz), 7.14 (L)1. t, J=8Hz
), 7.3-7.5 (38゜m>, 7.6-7.
8 (28,m)(4) 8-Bromo-3-(4-bromo-2-fluorobenzyl)-2,3-dihydro-2-year-old xoperimidine-1-acetic acid.

mp: 265-268°C NMR (DMSO-ds, S): 4.78 (2H
1s), 5,21 (2H2s), 6.64 (IH
, dd, J: 1.7 Hz), 6.89 (LH, d.

J=IHz>, 7.10 (IH, t, J=8Hz)
, 7.3-7.5 (3H.

m), 7.5-7゜7 (2H, m) (5) 3-(3
, 4-dichlorobenzyl)-2,3-hydro-2-dichlorobenzyl-1-acetic acid.

mp: 222-225°C NMR (DMSO~da, 8): 4.77 (2H
,s), 5.24 (2H9s), 6.65 (L
H, dd, J=6.3Hz), 6.72 (11(,
dd.

J=7.2Hz), 7.2-7.45 (5H, m)
, 7.55-7.65 (2H, m>, 13.1 (
LH, bs) (6) 3-(4-bromo-2-fluorobenzyl)-2,3-dihydro-2-oxoperimidine 1
- Acetic acid.

NMR (DMSO-d6.δ); 4.76 (2H,s
), 5.22 (21゜s〉16.5g (IH, d
d, J=6.2Hz), 6.72 (LH, dd.

J=7.2Hz), 7.13 (18,t, J:8H
z>, 7.2-7.5 (5H, m), 7.63 (
IH, dd, J=10.2Hz), 13.1(LH,
bs) (7) 6-bromo-3-(4-bromo-2-fluorobenzyl)-2,3-dihydro-2-dihydro-xoperimidine-1-acetic acid.

mp: 252°C (decomposition) Tue 11''1 (1) 3-[(5-chlorobenzothiazol-2-yl)methyl]-2.3-dihydro-2-oxoberimidine-1-tert-butyl acetate ( A solution of 1,63 g) in trifluoroacetic acid (16 ml) was stirred at room temperature for 1 hour. After diluting the mixture with ethanol (48 mQ), the precipitated crystals were collected by filtration, washed with ethanol, vacuum dried, and 3-[
(5-chlorobenzothiazol-2-yl)methyl]-
2.3-dihydro-2-oxoperimidine-1-acetic acid (
1.28 g) is obtained.

mp: 243 244°C NMR (DMSO-da, f; )' 4.73 (
2H9s), 5-68 (2H9s), 6.74 <
18. dd, J=8.2Hz), 6.88 (LH,
dd.

J:8.2Hz), 7.3-7.6 (4)1. m)
, 8.1 (2H, m) The following compound is obtained in the same manner as in Example 5(1).

(2) 3-(2-benzothiazolylmethyl)-2,3-
Dihydro-2-year-old xoperimidine-1-acetic acid.

mp: 233℃ IR (Stripe Seal) '1670. 1625.
1590 am-1 MMR (DMSO-ds, l;
)' 4.70 <2H9s), s, 65 (2
H1s), 6.70 <LH,m>, 6.90
(IH, m), 7.3-7.6 (6H, m),
8.05 (28, m><3>2.3-dihydro-
2-year-old xo-3-(2-quinolylmethyl)perimidine-
1-acetic acid.

mp: 300℃ IR (streak seal): 1650. 1630.
1580 cm-1 MMR (DMSOds, 8)
' 4.45 (2H1s), 5.47 (2H1s
), 6.60 (2H, m>, 7.2-8.1 (
9)1. m), 8.35 (11, d, J=8H2) (4) 2.3-dihydro-3-[(1-methyl-IH-
benzimidazol-2-yl)methyl]-2-oxoperimidine-1-acetic acid.

mp: 318℃ IR (X dii4): 1660. 1630.
1695 am-1MMR (DMSO-da, S)
' 4.10 (3H1s), 4.80 (2H3s
), 5.81 (2)1. s), 6.80
(2H, m), 7.3-7.7 (8H, m), 7
．． 90 (1M, d, J-8Hz><5>3-[(5-
Bromo-4-phenyltheasol-2-yl)methyl-2,3-dihydro-2-oxoperimidine-1-acetic acid.

mp: 305°C (decomposition) IR (streak 1-4)' 1670. 1620.
1585 cm-1 MMR (DMSOds, l;
)' 4.27 (2H1s>, 5.47 (2H-
s), 6.55 (18, d, J=8Hz),
6.90 (LH, dd, J=8, IHz), 7
．． 2-7.6 (7H, m), 7.90 (2H, m
) (6) 3-[(5-bromobenzothiazol-2yl)methyl]-2,3-dihydro-2-oxoperimidine-1-acetic acid.

mp 7148-152℃ NMR (DMSOda, S)' 4.3
5 (2H,s), 5.28 (2Hs),
6.31 (1)1. dd, J:8. 2Hz),
6.38 (IH, dd.

J-8,2Hz>, 7.13 (4H, m), 7.
24 (LH, dd.

J=8.1Hz), 7.97 (IH, d, J=8H
z>, 8.05 (11,d, J:IHz) (7) 3-[(6-bromobenzothiazol-2-yl)methyl]-2,3-dihydro-2-oxoperimidine-1-acetic acid.

mp: 265 273°C IR: 1660. 1625.
1590 cm-1MMR (DMSO-d6.δ)
: 4.82 (2H,s), 5.66 (21(
.

s), 6.72 (IH, dd, J4.2Hz), 6.
93 (IH.

dd, J=8. 2Hz>, 7.40 (4H,
m), 7.66 (18°dd, 8.1Hz
), 7.97 (IH, d, J=8Hz>, 8
．． 35 (IH, d, J=lH2) (8) 3-[(6-chlorobenzothiazol-2-yl)medel]-2,3-dihydro-2-oxoperimidine-1-acetic acid.

mp: 267-268℃ IR (Stripe Seal)' 1720. 1660.
1625. 1595 cm-'NMR (DMSO
-da,S)' 4.65 <2H1s), 5.5
0 (2H1s), 6.60 (LH, dd, J:8
．． 2Hz), 6.75 (IH, dd.

J=8.2Hz), 7.20 (4H, m>, 7.
33 (IH, dd.

J4. LHz), 7.82 (LH, d, J=8H
z), 8.07 [IH, d, J=IHz> (9) 3-(2-benzoxasilylmethyl)-2,3
-dihydro-2-year-old xoperimidine-1-acetic acid.

mp: 299-304°C IR: 1720. 1680.
1625. 1590 cm-INMR (DMSO
-da,S)' 4.95 (2)1. s)-5,
74 (2) 1°s), 6.85 (IH, dd, =
8. 2Hz), 7.03 (LH.

ddJ=8. 2Hz>, 7.55 (6H, m),
7.85 (2)1. m>(10) 3-(5,6
-dichloro-1-methyl-IH-benzimidazole-
2-yl)methyl]-2,3-dihydro-2-oxoperimidine-1-acetic acid.

mp: 299-315°C IR: 1660. 1625.
1590 am-1 MMR (DMSOda, 8
)' 4-78 (2H,s), 5.55
(2H.

s), 6.71 (IH, dd, J=8.1Hz),
6.81 (IH, dd.

J=8.1Hz), 7.3-7.5 (4H, m),
7.82 (LH,s).

8.01 (LH,5) (11) 2.3-dihydro-3-[(6-medoxybenzoxazol-2-yl)methyl]-2-year-old xoperimidine-1-acetic acid.

mp: 267-273°C IR: 1720. 1680.
1620. 1610°1590 cm-' NMR (DMSO-da, 8)' 3.70 (3
H1s), 4.69 (2H1s), 5.44 (2
H, s), 6.65 (LH, dd, J=7.2Hz
).

6.80 (IH, dd, J=7.2H2),
6.87 (LH, dd, J=8゜IHz), 7.3
2 (5H, m>, 7.50 (IH, d, J=7H
z) (12) 3-[(4,6-dipromobenzothiazol-2-yl)methyl]-2,3-dihydro-2-oxoperimicin-1-acetic acid.

mp: 269-273℃ IR (Stripe 1-L)' 1725. 1665.
1620. 1590 cm-'NMR (DMSO
-9, S): 4.75 (2H, s), 5.6
1 (2H.

s), 6.70 (IH, dd, J=7.1Hz),
6.88 (IH, dd.

J=7.1Hz), 7.38 (4H, m>, 7.
95 (IH, d.

J=IHz), 8.30 (IH, d, J:IHz)
(13) 3-[(5,6-enchloropenzotheazol-2-yl)methyl]-2,3-dihydro-2-oxoperimidine-1-acetic acid.

mp2 273-277℃ NMR (DMSO-ds, l; )' 4.81 <
2H,s), s, 68 (2H1s), 6.76
(IH, dd, J=7.2Hz), 6.87 (IH
, dd.

J=7. 2) 1z), 7.40 (4H, m>
, 8.32 (IH, s).

8.42 (IH,5) (14>2.3-dihydro-3-[(5-fluorobenzothiazol-2-yl)methyl-2-oxoperimidine-1-acetic acid.

mp2 233-238℃ NMR (DMSO-da, S)' 4.79 (2
H1s), 5-67 (2H1s), 6.75 (I
H, dd, J=7.2Hz>, 6.90 (LH, d
d.

J=7.2Hz), 7.40 (5H, m), 7.
40 (IH, dd.

J=12゜2Hz), 8.11 (LH, dd, J=
15.6 Hz) (15) 3-(4-Bromo-2-fluorobenzyl)-8-chloro-2,3-dihydro-2-dihydro-xoperimidine-1-acetic acid.

mp: 253-256°C NMR (DMSO-da, S): 4.77 (
2H,s), 5.22 (2H.

s), 6.63 (IH, dd, J=1.7Hz),
6.80 (LH, d.

J-IHz>, 7.11 (IH, t, J=8H
z), 7.3-7.4 (3H.

m>, 7.50 (lH, d, J = IHz), 7
．． 64 (IH, dd.

J=1.8H2> (16) 3-(4-bromo-2-fluorobenzyl)-
5-Chloro-2,3-dihydro-2-year-old xoperimidine-1-acetic acid.

mp: 246-249°C NMR (DMSO-ds, l;)' a, 73
(2H1s), 5.21 <2H0s), 6.62
(18, d, J=IHz), 6.75 (IH, dd
.

J=1.7Hz), 7.16 (LH,t, J=8H
z), 7.3-7.5 (4H, m), 7.63 (
LH, dd, J: 1.8 Hz) (17) 2.3-dihydro-3-((5-chlorobenzoxazol-2-yl)methyl-2-oxoperimidine-1-acetic acid.

mp: 267-270°C NMR (DMSO-ds, l; )' 4.75 (
2H1s), s, 55 (2H1s), 6.70
(LH, m), 6.90 (IH, m), 7.45
(58,m), 7.80 (2H,m>(1g)2.
3-dihydro-3-[(5-ethylbenzoxazol-2-yl)methyl]-2-oxoperimidine-1-acetic acid.

mp' 219-220℃ NMR (DMSO-ds, S): t, 18 (3
H, t, J=7Hz>, 2.70 (2) 1. q,,c
7Hz>, 4.77 (2H,s), 5.55
(2H, s).

6.70 (l)1. m), 6.85 (IH,
m), 7.3-7.6 (7H, m) (19) 2.3-dihydro-3-[(5-methylbenzoxazol-2-yl)methyl]-2-year-old xoperimidine-1-acetic acid.

mp: 267-272°C NMR (DMSO-ds, S)' 2-38 (3
H,s), 4.75 (2H1s), 5.55 (
2H,s), 6.70 (IH,m>, 6.85(
IH, m), 7.18 (1)1. d, J=8H
z), 7.3-7.5 (5H.

m), 7.57 (2H, d, J=8Hz) (20)
2.3-dihydro-3-[(6-fluorobenzothiazol-2-yl)methyl2-oxoperimidine-1
- Acetic acid.

mp: 267-268°C NMR (DMSO-da, δ)' 4.80 (2H
,s), 5.63 (2H.

s), 6.70 (LH, m), 6.88 (IH
, m), 7.35 (5H, m), 8.00 (2H
, +n) (21) 2.3-dihydro-3-[(7-fluorobenzothiazol-2-yl)methyl]-2-dihydro-quinperimidine-1-acetic acid.

mp: 267-271°C NMR (DMSO-ds, S)' 4.80
(2H0s), 5.70 (2H9s>, 6
．． 75 (IH, m), 6.90 (IH, +n),
7.40 (5H, m>, 7.60 (LH, in)
, 7.90 (LH, d, J=8Hz) (22)2.
3-dihydro-3-[(4-fluorobenzothiazol-2-yl)methyl-2-oxoperimidine-1=acetic acid.

mp: 141-143°C NMR (DMSO-da, S)' a, 82 (
2H1s), 5.72 (2H1s), 6.75 (
IH, m), 6.90 (18, m), 7.40 (
6H, m>, 7.88 (IH, d, C3Hz) (2
3) 2.3-dihydro-3-[(5-methylbenzothiazol-2-yl)methyl]-2-year-old xoperimidine-1-acetic acid.

mp: 148-151°C NMR (DMSO-ds, 8)' 2. to (
3H,s), 4.80 (21(.

s), 5.62 (2H, s), 6.72 (IH
, m), 6.85 (LH, m), 7.25 (IH
, d, J=8Hz), 7.40 (4H, m).

7.80 (IH, s), 7.90 (LH, d, J
=8Hz) (24) 2.3-dihydro-2-year-old xo3
-[(5trifluoromethylbenzothiazol-2-yl)methyl]perimidine-1-acetic acid M.

mp; 262-267°C NMR (DMSO-ds, δ): 4.82 (2H
,s), 5.72 (28s), 6.75 (IH
, m>, 6.90 (IH, m>, 7.90<48
．． m), 7.77 (IH, d, J=8)1z),
8.85 (2H,m)(25) 8-bromo-3-[
(5-bromobenzthiazol-2-yl)methyl]-
2.3-dihydro-2-oxoperimidine-1-acetic acid.

mp: 300°C (decomposition) (26) 5-bromo-3-[(5-bromobenzothiazol-2-yl)methyl:]-]2,3-dihydro-2-oxoperimidine 1-acetic acid.

mp: 287-290°C (27) 3-[(5-bromobenzothiazol-2-yl)methyl]-8-chloro2,3-dihydro-2-year-old xoperimidine-1-acetic acid.

mp 2 289-293°C (zg>3-[(5-bromobenzothiazol-2-yl)methyl]-5-chloro2,3-dihydro-2-year-old xoperimidine-1-acetic acid.

mp: 278 282°C (29) 8-chloro-3-[(5-chlorobenzothiazol-2-yl)methyl]-2.3-dihydro 2-
Oxoperimidine-1-acetic acid.

mp: 2136°C (decomposed) (30) 8-bromo3-[(5-chlorobenzothiazol-2-yl)methyl]-2,3-dihydro-2
-xoperimidine-1-acetic acid.

mp: 280-284°C (31) 3-(4-bromo-2-fluorobenzyl)-
8-Cyano-2,3-dihydro-2-year-old xoperimidine-1-acetic acid.

mp: 272-275°C NMR (DMSO-da, l; )' 4-81 (
2H1s), 5-25 (2H0s), 6.82 (
LH, t, J=4Hz), 7.1-7.2 (2H,
m).

7.33 (LH, dd, J=8.3Hz), 7.4
5-7.55 (2H.

m), 7.62 (LH, dd, J=io, 3Hz
), 8.00 (IH,s)<32) 3-(4-bromo-2-fluorobenzyl)-5-cyano-2,3-dihydro-2-year-old xoperimidine-1-acetic acid.

mp: 262-264°C NMR (DMSO-ds, δ): 4.73 (2)
1. s), 5.23 (2H.

s), 6.94 (IH, s>, 6.97 (LH
, dd, J=8.2Hz>.

7.13 (IH, t, J-8Hz), 7.34 (
IH, dd, J=83Hz>, 7.5 (3H, m)
, 8.00 (LH,5)(33) 7-bromo-3
-(4-bromo-2-fluorohenno-shi)-2,3-
Dihydro-2-year-old xoberimicin-1-acetic acid.

mp: 257°C (decomposition) (34) 3-(4-bromo-2-fluorobenzyl)
-2,3-'; Hydro-2-thioxoperimidine-1
- Acetic acid.

mp: 252°C (decomposition) NMR (DMSo-ct6.8)' 4.8-6.
2 (4H1m>, 6.61 (LH, d, J=7Hz
), 6.84 (LH, dd, J=5.3Hz).

7.08 (LH, t, J: 8Hz>, 7.3-7.
5 (5H, m), 6.64 (IH, dd, J=10
．． 2 Hz) 0-reciprocal N-Second-class poxylponylmethyl-N'(4-bromo-2-fluorobenzyl)-1,8r phthalenediamine (92 mg) in dry tetrahydrofuran (2 mA)
Add ophosgene (0.02 mQ) to the solution and stir at room temperature for 4 hours. The solvent is evaporated and the residue is extracted with ethyl acetate and washed with aqueous sodium bicarbonate solution. Evaporate the solvent and triturate with ethanol to obtain 3-(4-bromo 2-
Tert-butyl 1-acetate (67 mg) was obtained.

mp: 190 193°C Example 7 4-bromo-8-tertiary poxylponylamino-1
- tertiary butoxycarbonylmethylaminonaphthalene (
1,05 g) of dry, N,N-dimethylformamide (6 ml) solution in 60% sodium hydride (122 ml) in a water bath.
mg) and stir for 30 minutes.

A solution of 4-bromo-2-fluorobenzyl-bromide (0.75 g) in dry N,N-dimethylformamide (2 mQ) is added to this mixture and stirred for 1 hour. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is dried over magnesium sulfate and the solvent is distilled off. The residue was subjected to column chromatography using silica gel, eluted with hexane-methylene chloride (1:2), and triturated with hexane and ether to give 7-bromo-3-(4-bromo-2-
Tertiary butyl (fluorobenzyl)-2,3-dihydro-2-oxoperimidine-1-acetate (0.84 g) is obtained.

mp: 163-166@c Patent applicant: Fujisawa Pharmaceutical Co., Ltd.

Claims (1)

[Claims] General formula: ▲ Numerical formulas, chemical formulas, tables, etc. A good aryl (lower) alkyl group or a heterocyclic (lower) alkyl group that may have a suitable substituent, R^3 is hydrogen, cyano group or halogen, A is a lower alkylene group, X is O or S , Z means N or CH] and salts thereof.