JPH0826011B2 - Aminomethylisochroman derivative and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound useful as a pharmaceutical compound for ameliorating the symptoms caused by thromboxane A ₂ and an aminomethylisochroman derivative comprising a pharmaceutically acceptable salt thereof.

[0002]

The vascular changes in thrombosis and atherosclerosis are caused by the interaction of two substances in the arachidonic acid metabolic pathway, namely thromboxane A ₂ (TXA).
₂ ) and prostaglandin I ₂ (PGI ₂ ) control has been revealed. These two kinds of substances have mutually opposing actions, and TXA ₂ has platelet aggregation, vasoconstriction and bronchoconstriction actions, while PGI ₂ has platelet aggregation inhibition, vasodilation and bronchodilation actions.

[0003] Platelet involvement is considered to be important for the onset and progression of atherosclerosis, and administration of antithrombotic drugs, particularly platelet aggregation inhibitors, is effective for treating atherosclerosis-related diseases. Is being recognized.
Further, in thrombosis and ischemic diseases, excessive aggregation of platelets or increase in platelet consumption is guided in the direction of TXA ₂ biosynthesis, thus disturbing the equilibrium of TXA ₂ and PGI ₂ . Therefore, in treating and preventing thrombosis and ischemic diseases, it is desirable to inhibit the action of TXA ₂ and assist the action of PGI ₂ .

Based on these ideas, we have begun the development of substances that act on PGI ₂ and have paid attention to the fact that TXA ₂ has strong platelet aggregation and vasoconstriction actions.
A ₂ synthase inhibitors and TXA ₂ receptor antagonists have been developed. As a TXA ₂ receptor antagonist, BM-13177 (Refer (Le
fer AM), Drugs of Today
ay) Volume 21, p. 283 (1985)], BM-13505 [West German Patent No. 3000377], SQ-29548 [Ogletr
ee) et al., Journal of Pharmacology and Experimental Teraviewtics (J. Pharma
col.Exp.Ther.) 34, 435 (1985)].

[0005]

[Problems to be Solved by the Invention] In patients with myocardial infarction, arteriosclerosis, thrombosis, diabetes, hyperlipidemia, etc., TXA ₂ production is high and a physiological imbalance between TXA ₂ and PGI ₂ occurs. It is reported that Therefore, to suppress the physiological activities of TXA _2, the development of TXA ₂ synthetase inhibitor or TXA ₂ receptor antagonists have attracted attention. The inhibitor corrects the pathophysiological imbalance of TXA ₂ / PGI ₂ , but its own physiological activity due to the temporary accumulation of prostaglandin H ₂ (PGH ₂ ) (platelet aggregation and vascular smooth muscle contraction) There is a problem that you can not control. On the other hand, TXA ₂ receptor antagonist is TXA ₂ / PGH ₂
Since it directly antagonizes the receptor of the drug, it has been proved that the inhibitory effect is more effective than the inhibitor, and the development of the antagonist is particularly desired.

[0006]

The present inventors have synthesized an aminomethylisochroman derivative represented by the general formula (I), and this novel compound surprisingly has a strong antagonistic action against thromboxane A _2. The present invention has been completed by finding out that The present invention has the general formula (I)

[0007]

[Chemical 6]

(Wherein R ₁ is substituted with one or more of an alkyl group, a halogen, an alkyl group, an alkoxy group, a nitro group, a trifluoromethyl group, a hydroxy group, a carboxy group or an alkoxycarbonyl group. May represent an aryl group, an aralkyl group or a heterocycle, R ₂ represents a hydroxy group, an alkoxy group or a verdyloxy group, or has the formula: —NR ₃ R ₄ (R ₃ and R ₄ are the same or different, Hydrogen, an alkyl group or an aralkyl group), and n represents 1 to 6), and an aminomethylisochroman derivative comprising a pharmaceutically acceptable salt thereof.

In the general formula (I), the alkyl group generally represents a linear or branched hydrocarbon group having 1 to 12 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl,
Hexyl, isohexyl, heptyl, octyl, isooctyl groups and the like can be mentioned. The aryl group generally represents an aromatic group having 6 to 12 carbon atoms, and examples thereof include a phenyl group, a naphthyl group and a biphenyl group.

The aralkyl group generally means an aryl group having 7 to 14 carbon atoms bonded through an alkylene chain. Aralkyl groups having 1 to 6 carbon atoms in the aliphatic part and 6 to 12 carbon atoms in the aromatic part are preferred. Examples thereof include benzyl, naphthylmethyl, phenethyl and phenylpropyl groups.

Examples of the heterocycle include pyridine, isoquinoline, indole and pyrimidine. The alkoxy group generally represents an alkyl bonded via an oxygen atom, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and a tertiary butoxy group.

An aryloxy group generally means an aryl group in which an aromatic group having 6 to 12 carbon atoms is bonded via an oxygen atom. Examples include phenoxy and naphthoxy groups. An aralkoxy group generally means an aralkyl group having 7 to 14 carbon atoms, the alkylene of which is attached via an oxygen atom. Aralkoxy groups in which the aliphatic part has 1 to 6 carbon atoms and the aromatic part has 6 to 12 carbon atoms are preferred. Mention may be made, for example, of the benzyloxy, naphthylmethoxy, phenetoxy and phenylpropoxy groups.

Halogen includes fluorine, chlorine, bromine,
Iodine can be mentioned. A more preferable specific example of the compound of the present invention is a compound represented by the following general formula (Ia) and a pharmaceutically acceptable salt thereof.

[0014]

[Chemical 7]

(In the formula, R ₁ is an alkyl group which may be substituted with halogen, halogen, a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, a nitro group or trifluoro group. A methyl group, a hydroxy group, a carboxy group, an aryl group which may be substituted by one or more with an alkoxycarbonyl group, an aralkyl group, a heterocycle,
n represents 1 to 6).

Further, as typical compounds of this group, [1- (benzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (toluenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1-
(4-Ethylbenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (4-Fluorobenzenesulfonylaminomethyl) isochroman-6-
Yl] oxyacetic acid, [1- (4-methoxybenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (4-nitrobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1-
(3-Nitrobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (2-Nitrobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (Benzylsulfonylaminomethyl) isochroman-6- Yl] oxyacetic acid, 4- [1
-(4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxybutyric acid, 5- [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-
6-yl] oxyvaleric acid, [1- (trifluoromethanesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (ethanesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (n -Octanesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (2,5-dichlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (2,4,5-trichlorobenzene Sulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (2,3,4,5,6-pentafluorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (2,5 -Dimethylbenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (2 4,6-Trimethylbenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (2-Nitro-4-trifluoromethylbenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- ( 3,5-Dichloro-2-hydroxybenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (4-carboxybenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (1- Naphthalenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid,
[1- (2-naphthalenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (2-methoxycarbonylbenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (8-quinolinesulfonyl] Aminomethyl) isochroman-6-yl] oxyacetic acid, [1- (β-styrenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid, [1- (10
-Camphorsulfonylaminomethyl) isochroman-
6-yl] oxyacetic acid and the like, and pharmaceutically acceptable salts thereof can be mentioned.

The novel aminomethylisochroman derivative of the present invention has a pair of diastereomers as an enantiomer, a mixture of a pair of enantiomers, or in the case where the compound has an asymmetric center in the substituent. It can exist as a mixture.

When the compound (I) of the present invention is used as a medicine, it can be used not only in a free form but also in a pharmaceutically acceptable salt form. Examples of the pharmaceutically acceptable salt include, for example, sodium salts, potassium salts, alkali metal salts such as lithium salts, calcium salts, alkaline earth metal salts such as magnesium salts, ammonium salts, ethylimine salts, triethylamine salts,
Diethanolamine salt, triethanolamine salt, dicyclohexylamine salt, dimethylaminoethanol salt,
Examples thereof include amine salts such as arginine salt and ethylenediamine salt, and sodium salt and potassium salt are particularly preferable. These salts can be formed by conventional means, for example in the free acid form, in a solvent or medium in which the salt is insoluble, or in a solvent such as water which can be removed by vacuum drying or lyophilization. It can be formed by reacting a compound with one equivalent or more of a suitable base, or by exchanging an ion of an existing salt with another ion using a suitable ion exchange resin.

According to the invention, the novel aminomethylisochroman derivatives of the general formula (I) have the general formula (II)

[0020]

Embedded image

(Wherein R ₂ and n are the same as in the general formula (I)), the amines represented by the general formula (III): R ₁ SO ₃ H (III) (wherein R ₁ is It is obtained by reacting with an acid represented by the general formula (I) or an active derivative thereof, for example, an acid chloride or an active ester.

If R _{2 of the} resulting compound (I) is not hydroxy, then the salt is prepared by subsequent hydrolysis to the free carboxylic acid and reaction with the corresponding base. The amines represented by the general formula (II) are novel, and the amine is represented by the general formula (IV)

[0023]

[Chemical 9]

(Wherein Prot (eg, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, etc.) represents a protecting group for an amino group) is represented by the general formula (V): X (CH ₂ ) _n COR ₂ (V) (In the formula, R ₂ and n are the same as those in the general formula (I), and X is
A leaving group, which represents, for example, chlorine, bromine, iodine, an alkylsulfonyl group or a toluenesulfonyl group) to give a protected form of the condensation product, which is then removed by a suitable method. Can be manufactured.

The compound of the general formula (I) has the general formula (VI)

[0026]

[Chemical 10]

The phenols represented by the formula (wherein R ₁ has the same meaning as in the general formula (I)) are represented by the general formula (V): X (CH ₂ ) _n COR ₂ (V) (in the formula, R ₂ , n has the same meaning as in formula (I), and X
Is a leaving group and is obtained by condensation with a compound represented by, for example, chlorine, bromine, iodine, alkylsulfonyl group or toluenesulfonyl group. When R _{2 of the} obtained compound (I) is not a hydroxy group, if necessary,
It is then hydrolyzed to the free carboxylic acid and, in the case of salt preparation, reacted with the corresponding base.

The compounds of the general formula (IV) and the general formula (VI) can be produced by the following method.

[0029]

[Chemical 11]

In the formula, R ₁ and Prot are the same as above. General formula (VII) is known and general formula (VIII) is partially known. Hereinafter, the above reaction will be described in detail. The final product (I) comprises an amine of the general formula (II), a sulfonic acid of the general formula (III) or an activated derivative thereof, such as a sulfonyl chloride, a sulfonic anhydride or a sulfonic acid ester, and a condensing agent, such as a hydroxylation. Alkali metal or alkaline earth metal hydroxides such as sodium, potassium hydroxide and barium hydroxide, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, or triethylamine, pyridine, N
-It is obtained by reacting in the presence of an organic base such as ethylmorpholine. Depending on the type of sulfonic acid derivative used,
Inert solvents such as methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, ether, dimethylformamide, acetonitrile and / or protic solvents such as water, methanol and ethanol are used as suitable solvents. The reaction temperature is preferably about -20 ° C to 120 ° C, and is appropriately selected depending on the properties of the raw materials and the produced compound.

In the condensation reaction between the compounds (IV) and (V) and the condensation reaction between the compounds (VI) and (V), the compound (V)
As the leaving group, halides such as chlorine, bromine and iodine, alkylsulfonyl such as methanesulfonyl and trifluoromethylsulfonyl, or toluenesulfonyl can be used. The reaction can be carried out in a suitable solvent in the presence of a condensing agent. As the condensing agent, for example, sodium hydroxide, potassium hydroxide, alkali metal or alkaline earth metal hydroxides such as barium hydroxide, potassium carbonate, sodium carbonate, carbonates such as sodium hydrogen carbonate,
Alternatively, an organic base such as triethylamine, pyridine or diazabicycloundecane can be preferably used,
As the solvent, for example, acetone, butanone, dimethylformamide, dimethylsulfoxide, ethanol, dioxane or toluene, or a halogenated hydrocarbon such as methylene chloride or chloroform can be used. It is often advantageous to add alkali metal halides such as sodium iodide or potassium iodide. The reaction temperature is preferably about -20 ° C to 150 ° C,
It is appropriately selected depending on the properties of raw materials and products.

The compound (VIII) can be obtained by cleaving the aryl ether from the compound (VII). Cleavage of aryl ethers can be achieved by hydrogen bromide, hydrogen iodide (which may coexist with red phosphorus), trifluoroacetic acid, pyridine hydrochloride, concentrated hydrochloric acid, magnesium iodide etherate, aluminum chloride, boron tribromide, and tribromide. It can be obtained by cleavage with an acid such as boron chloride or boron triiodide, or by cleavage with a base such as sodium-liquid ammonia, lithium-biphenyl, lithium-collidine iodide or sodium thiolate. The solvent can be appropriately selected depending on the nature of the raw material and the type of reaction reagent, and acetic anhydride, benzene, methylene chloride, tetrahydrofuran, dimethylformamide (DMF), water or the like is used. The reaction temperature is preferably about -80 ° C to 150 ° C and is appropriately selected depending on the properties of the raw materials and products.

Compound (IV) can be obtained from compound (VIII) by protecting the amino group according to a conventional method. Also,
Compound (VI) can be obtained from compounds (VIII) and (III) in the same manner as the reaction of compounds (II) and (III). The condensate thus obtained is isolated and purified from the reaction mixture by using a usual separation and purification means, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography and the like. can do.
Condensates, if required, hydrochloric acid, trifluoroacetic acid,
Acid treatment with formic acid etc., alkali saponification using aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide etc., catalytic reduction using metal catalyst such as palladium black, palladium-carbon, platinum oxide etc. The desired product can be obtained by deprotection by a known method.

The novel aminomethylisochroman derivatives of the present invention are used as active compounds in medicine. This compound exhibits a platelet aggregation inhibitory action, a vasoconstriction inhibitory action, and a bronchoconstriction inhibitory action. The compound can preferably be used for the treatment of thrombosis, thromboembolism, ischemia, or as anti-asthma and anti-allergic agents. The novel active compounds are prepared in a conventional manner using inert, non-toxic, pharmaceutically suitable excipients or solvents in conventional formulations such as tablets, capsules, dragees, pills, tablets. Granules,
It can be granules, aerosols, syrups, emulsions, suspensions and solutions. The therapeutically effective compound can be present in each case in a concentration of about 0.5 to 90% by weight, based on the total formulation, ie in an amount sufficient to achieve the treatment described above. Formulations are prepared, for example, by extending the active compound with solvents and / or excipients, if appropriate with emulsifiers and / or suspending agents. If water is used as the diluent, it is also possible, if appropriate, to use organic solvents as auxiliary solvents. Auxiliaries such as water, non-toxic organic solvents such as paraffin (eg petroleum fraction), vegetable oils (eg peanut oil, sesame oil) and alcohols (eg ethanol and glycerin),
Excipients such as powdered natural minerals (eg clay, alumina, talc and chalk), powdered synthetic minerals (eg highly dispersible silica and silicates), sugars (eg sucrose, lactose and dextrose), emulsifiers (eg Polyoxyethylene fatty acid ester and polyoxyethylene fatty alcohol ether, alkyl sulfonate,
Aryl sulfonates), suspending agents (eg lignin sulfite waste liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

Administration is carried out in the usual way, preferably orally or parenterally. In that special case, it can also be done translingually or intravenously. Water is used in particular as injectable medium, which contains stabilizers, solubilizers and / or buffers which are customary for injectable solutions. Such additives may be, for example, tartrate buffer, borate buffer, ethanol, dimethylsulfoxide, complexing agents (eg ethylenediaminetetraacetic acid), polymeric polymers for viscosity adjustment (eg liquid polyethylene oxide) or hydrogen. Is a polyethylene derivative of sorbitan chloride. For oral administration, especially in the case of aqueous suspensions, flavoring or coloring agents may be added to the active compound together with the auxiliaries mentioned above.

The dosage depends on the route of administration, the age of the recipient,
It depends on the state of health and weight, the extent of the illness, at the same time, the type of other treatments that may be given, the frequency of treatment and the type of effect desired. Usually, the daily dose is 0.01 to 10 active compounds.
It is 0 mg / kg body weight. To achieve the desired result, it is usually 0.
05 to 50 and 0.1 to 30 mg / kg of the strain are effective after one or several times a day.

[0037]

INDUSTRIAL APPLICABILITY The aminomethylisochroman derivative of the present invention has a strong antagonistic action against thromboxane A _2, and therefore, it is used as an active compound in medicine by utilizing this property. Further, it can be used for treating thrombosis, thromboembolism, ischemia, or as an anti-asthma drug and an anti-allergic drug.

[0038]

[U-46619-induced vasoconstriction inhibition test]

(U-46619: 9,11-dideoxy-9α, 11α-methanoepoxy prostaglandin F2α; thromboxane A
₂ Stable related substances) Each test substance was dissolved in distilled water.
A substance insoluble in distilled water was dissolved in ethanol or DMSO, diluted with distilled water, and then subjected to the test.

Male Wistar-KY rats were sacrificed by exsanguination, thoracotomy was performed, and the thoracic aorta was extracted. The obtained blood vessel sample was suspended in a tissue chamber (10 ml volume) filled with a nutrient solution (Krebs-Henselite solution) heated at 37 ° C. and aerated with 95% O ₂ -5% CO ₂ gas. U-46619 for the sample
(Prepared to be 3 × 10 ^-8 M in the chamber) was applied at 60-minute intervals, and single-dose method (3 × 10 ^-8 M) was applied.
M) was used. The test substance was applied to the tissue chamber 10 minutes before the application of U-46619.

The concentration (IC ₅₀ ) of the test substance that inhibits U-46619-induced vasoconstriction by 50% was measured. The results are shown in the table below.

[0041]

[Table 1] U-46619-induced vasoconstriction inhibitory activity [Production Example] Reference Example 1 (6-Methoxyisochroman-1-yl) methylamine hydrochloride 3-methoxyphenethyl alcohol (36.5 g) and aminoacetaldehyde diethyl acetal (35.1 g) in 1,4-
A solution of dioxane (70 ml) was bubbled with a dry hydrochloric acid gas at 0 ° C. with stirring until it was saturated. The resulting mixture at room temperature
After stirring for 24 hours, water (400 ml) was added, and the mixture was made alkaline with 20% aqueous sodium hydroxide solution. The obtained aqueous solution was extracted with chloroform (300 ml), the chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the residue was dissolved in ether, and a hydrochloric acid-ether solution was added. The formed hydrochloride was filtered and recrystallized from methanol-ether to obtain (6-methoxyxocurman-1-yl) methylamine.hydrochloride (40.8 g, 74%) as pale yellow crystals.

¹ H-NMR (D ₂ O) δ 2.7 to 3.1 (2 H, m, ArC
H ₂ ), 3.3 to 3.6 (2H, m, NCH ₂ ), 3.7 to 4.5 (2H, m, OC
H ₂ ), 3.3 (3H, s, MeO), 4.9 ~ 5.2 (1H, m, CH), 6.8 ~
7.3 (3H, m, Ar) IR (cm ^-1 ); 3351, 2950, 1745, 1692, 1546, 1505, 12
65, 1221, 1211, 1109, 1094.

Reference Example 2 (6-Hydroxyisochroman-1-yl) methylamine hydrobromide The hydrochloride salt (35.0 g) obtained in Reference Example 1 was dissolved in water (700 ml) and sodium carbonate was added. After making it a weak alkali, it was extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (700 ml), and a solution of boron tribromide (34.7 ml) in dichloromethane (700 ml) was added dropwise over 20 minutes at -70 ° C with stirring. The reaction mixture was stirred at the same temperature for 3 hours, returned to room temperature, and concentrated under reduced pressure. Ice-cold methanol (500 ml) was added to the residue, the mixture was concentrated under reduced pressure again, and the residue was crystallized from ethanol to give (6-hydroxyisochroman-1-yl) methylamine hydrobromide (24.2 g, 61%). Obtained as light brown crystals.

¹ H-NMR (D ₂ O) δ 2.7 to 3.0 (2 H, m, ArC
H ₂ ), 3.4 to 3.6 (2H, m, NCH ₂ ), 3.7 to 4.4 (2H, m, OC
H ₂ ), 4.9 to 5.2 (1H, m, CH), 6.7 to 7.2 (3H, m, Ar) IR (cm ^-1 ); 3200, 3025, 2950, 2905, 1617, 1487, 14
46, 1296, 1228, 1082, 817.

Example 1 N-benzyloxycarbonyl- (6-hydroxyisochroman-1-yl) methylamine The hydrobromide salt (38.2 g) obtained in Reference Example 2 was added to water (400 ml).
Sodium hydrogencarbonate (32.1 g) and ethyl acetate (120 ml) were added. A solution of benzyloxycarbonyl chloride (14.5 ml) in ethyl acetate (120 ml) was added to the obtained mixture, and the mixture was stirred at room temperature for 1 hr. Further, benzyloxycarbonyl chloride (14.5 ml) and sodium hydrogen carbonate (32.1 g) were added, and the mixture was stirred for 2 hours. After the reaction was completed, the ethyl acetate layer was separated, and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined, washed with diluted hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) and N-benzyloxycarbonyl- (6-hydroxyisochroman-1-yl) methylamine (28.9 g, 63%)
Was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ 2.5 to 2.9 (2H, m, ArC
H ₂ ), 3.3 to 4.2 (4H, m, NCH ₂ , OCH ₂ ), 4.5 to 4.8 (1H,
m, CH), 5.0 (2H, s, ArCH ₂ O), 5.1 ~ 5.4 (1H, m, NHC
O), 6.4 to 6.9 (3H, m, Ar), 7.1 (5H, s, Ar) IR (cm ^-1 ); 3365, 1692, 1586, 1530, 1510, 1456, 12
60, 1149, 1104 Example 2 [1- (N-benzyloxycarbonylaminomethyl) isochroman-6-yl] ethyl oxyacetate The phenol body (21.6 g) obtained in Example 1 was added to 2-butanone (300 ml). Dissolve and add anhydrous potassium carbonate (20.9g)
The mixture was heated under reflux for 30 minutes. Ethyl bromoacetate (12.6 g) was added dropwise to the resulting mixture, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5N aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give ethyl [(1- (N-benzyloxycarbonyl) aminomethyl) isochroman-6-yl] oxyacetate (2
6.0 g, 94%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ 1.3 (3H, t, J = 7Hz, C
H ₃ CH ₂ O), 2.6 to 3.0 (2H, m, ArCH ₂ ), 3.1 to 4.1 (4H, m,
NCH ₂ , OCH ₂ ), 4.25 (2H, q, J = 7Hz, OCH ₂ CH ₃ ), 4.6 (2H,
s, OCH ₂ CO), 4.7 to 4.9 (1H, m, CH), 5.1 (2H, s, ArCH ₂
O), 6.7 to 7.1 (3H, m, Ar), 7.3 (5H, s, Ar) IR (cm ^-1 ); 3351, 1745, 1691, 1546, 1265, 1211, 110
9, 1094.

Example 3 [6- (Ethoxycarbonylmethoxy) isochroman-1-yl] methylamine hydrochloride The protected compound (30.7 g) obtained in Example 2 was converted into ethyl acetate (450 m
It was dissolved in l) and palladium-black (3.1 g) was added. The resulting mixture was stirred at room temperature under a hydrogen gas stream. After confirming deprotection, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ether and hydrochloric acid-ether was added to obtain a crude hydrochloride salt. This was recrystallized from methanol-ether to obtain [6- (ethoxycarbonylmethoxy) isochroman-1-yl] methylamine.hydrochloride (22.3 g, 96%) as colorless crystals.

¹ H-NMR (D ₂ O) δ 1.3 (3H, t, J = 7Hz, CH ₃
CH ₂ O), 2.7 to 3.0 (2H, m, ArCH ₂ ), 3.3 to 3.5 (2H, m, N
CH ₂ ), 3.6 to 4.2 (2H, m, OCH ₂ ), 4.25 (2H, q, J = 7Hz, O
CH ₂ CH ₃ ), 4.7 (2H, s, OCH ₂ CO), 4.9 ~ 5.1 (1H, m, C
H), 6.7 to 7.2 (3H, m, Ar) IR (cm ^-1 ); 3375, 3035, 2990, 1768, 1735, 1612, 15
03, 1251, 1205.

Example 4 [1- (Benzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The hydrochloride salt (2.0 g) obtained in Example 3 was suspended in acetonitrile (25 ml) and triethylamine (2.3 ml). Was added. The resulting solution was added with benzenesulfonyl chloride (1.2
A solution of g) in acetonitrile (3 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane: ethyl acetate =
3: 1) and purified by ethyl [(1- (benzenesulfonylaminomethyl) isochroman-6-yl] oxyacetate.
(2.0 g, 75%) was obtained as colorless crystals.

The crystals obtained (1.7 g) were added to methanol (17 m
l), add 1N potassium hydroxide aqueous solution (17 ml),
The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was dissolved in the residue, and the solution was made acidic with 6N hydrochloric acid. The resulting mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with water,
It was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained crude crystals were recrystallized from ethyl acetate-hexane to give [(1-
(Phenylsulfonylaminomethyl) isochroman-6
-Yl] oxyacetic acid (1.6 g, 98%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.5 to 2.9 (2H, m, ArCH ₂ ), 3.0 to 3.5 (2H, m, NC
H ₂ ), 3.5 to 4.0 (2H, m, OCH ₂ ), 4.5 (2H, s, OCH ₂ CO), 4.
6 to 4.8 (1H, m, CH), 6.6 to 7.0 (3H, m, Ar), 7.3 to 7.8
(5H, m, Ar) IR (cm ^-1 ); 3235, 2950, 1740, 1504, 1451, 1433, 13
35, 1228, 1169, 1138, 1080.

[0053] Example 5 [1- (toluenesulfonylaminomethyl)
Isochroman-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 4 to give [(1- (toluenesulfonylaminomethyl) isochroman-6-yl].
Oxyacetic acid (1.7 g, 94%) was obtained as colorless crystals (recrystallized from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.4 (3H, s, ArCH ₃ ), 2.5 to 2.9 (2H, m, ArCH ₂ ), 3.
0 ~ 3.5 (2H, m, NCH ₂ ), 3.5 ~ 4.0 (2H, m, OCH ₂ ), 4.5 (2
H, s, OCH ₂ CO), 4.6 ~ 4.9 (1H, m, CH), 6.6 ~ 7.0 (3H,
m, Ar), 7.1 to 7.8 (4H, m, Ar) IR (cm ^-1 ); 3260, 2980, 1780, 1610, 1495, 1410, 13
30, 1255, 1180, 1155, 1130, 1085, 800.

Example 6 [1- (4-Chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The reaction and treatment were carried out in the same manner as in Example 4 to give [(1- (4-chlorobenzenesulfonylaminomethyl) isochroman. −
6-yl] oxyacetic acid (1.9 g, 98%) was obtained as colorless crystals (recrystallized from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.5 to 2.9 (2H, m, ArCH ₂ ), 3.0 to 3.4 (2H, m, NC
H ₂ ), 3.5 to 4.3 (2H, m, OCH ₂ ), 4.5 (2H, s, OCH ₂ CO), 4.
6 to 4.8 (1H, m, CH), 6.5 to 7.0 (3H, m, Ar), 7.3 to 7.9
(4H, m, Ar) IR (cm ^-1 ); 3310, 3090, 2930, 1730, 1610, 1580, 15
00, 1475, 1420,1330, 1275, 1220, 1165, 1090, 1080,
740.

Example 7 [1- (4-Ethylbenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The reaction and treatment were carried out in the same manner as in Example 4 to give [(1- (4-ethylbenzenesulfonylaminomethyl) isochroman]. −
6-yl] oxyacetic acid (2.0 g, 99%) was obtained as colorless crystals (recrystallized from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 1.3 (3H, t, J = 8Hz, C H ₃ CH ₂ ), 2.5 to 3.0 (4H, m, ArCH
₂ , C H ₂ CH ₃ ), 3.1 to 3.5 (2H, m, NCH ₂ ), 3.6 to 4.2 (2H,
m, OCH ₂ ), 4.6 (2H, s, OCH ₂ CO), 4.6 ~ 4.9 (1H, m, C
H), 6.6 to 7.0 (3H, m, Ar), 7.2 to 7.9 (4H, m, Ar) IR (cm ^-1 ); 3560, 3220, 2970, 2920, 2880, 1730, 17
10, 1610, 1500, 1430, 1330, 1230, 1160, 1135, 1080,
1050, 810.

Example 8 [1- (4-Fluorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The reaction and treatment were conducted in the same manner as in Example 4, and [(1- (4-fluorobenzenesulfonylaminomethyl) ) Isochroman-6-yl] oxyacetic acid (2.1 g, 98%) was obtained as colorless crystals (recrystallized from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.5 to 2.9 (2H, m, ArCH ₂ ), 3.1 to 3.4 (2H, m, NC
H ₂ ), 3.5 to 4.2 (2H, m, OCH ₂ ), 4.55 (2H, s, OCH ₂ CO),
4.6 to 4.8 (1H, m, CH), 6.5 to 7.1 (3H, m, Ar), 7.1 to 7.
4 (2H, m, Ar), 7.6 ~ 8.0 (2H, m, Ar) IR (cm ^-1 ); 3300, 2920, 2850, 1740, 1585, 1500, 14
20, 1330, 1230, 1160, 1150, 1080, 835.

Example 9 [1- (4-Methoxybenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The reaction and treatment were carried out in the same manner as in Example 4, and [(1- (4-methoxybenzenesulfonylaminomethyl ) Isochroman-6-yl] oxyacetic acid (1.8 g, 78%) was obtained as colorless crystals (recrystallized from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.5 to 2.9 (2H, m, ArCH ₂ ), 3.0 to 3.4 (2H, m, NC
H ₂ ), 3.5 to 4.3 (2H, m, OCH ₂ ), 3.85 (3H, s, OMe), 4.55
(2H, s, OCH ₂ CO), 4.6 to 4.8 (1H, m, CH), 6.5 to 7.1 (5
H, m, Ar), 7.4 ~ 7.9 (2H, m, Ar) IR (cm ^-1 ); 3240, 2920, 1750, 1720, 1590, 1500, 14
20, 1320, 1260, 1195, 1150, 1130, 1080, 1050.

Example 10 [1- (4-Nitrobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The reaction and treatment were carried out in the same manner as in Example 4 to give [(1- (4-nitrobenzenesulfonylaminomethyl) isochroman. −
6-yl] oxyacetic acid (2.2 g, 98%) was obtained as colorless crystals (recrystallized from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.5 to 2.9 (2H, m, ArCH ₂ ), 3.2 to 3.5 (2H, m, NC
H ₂ ), 3.6 to 4.2 (2H, m, OCH ₂ ), 4.5 (2H, s, OCH ₂ CO), 4.
6 to 4.8 (1H, m, CH), 6.5 to 7.1 (3H, m, Ar), 7.8 to 8.4
(4H, m, Ar) IR (cm ^-1 ); 3300, 3100, 2900, 1730, 1620, 1520, 15
00, 1340, 1330,1300, 1240, 1160, 1140, 1080, 840,7
30.

Example 11 [1- (3-Nitrobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The reaction and treatment were carried out in the same manner as in Example 4 to give [(1- (3-nitrobenzenesulfonylaminomethyl) isochroman. −
6-yl] oxyacetic acid (1.9 g, 98%) was obtained as colorless crystals (recrystallized from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.5 to 2.9 (2H, m, ArCH ₂ ), 3.2 to 4.3 (4H, m, NCH ₂ ,
OCH ₂ ), 4.55 (2H, s, OCH ₂ CO), 4.6 ~ 4.9 (1H, m, CH),
6.5 to 7.1 (3H, m, Ar), 7.8 to 8.6 (4H, m, Ar) IR (cm ^-1 ); 3300, 2900, 1750, 1610, 1530, 1505, 14
30, 1355, 1340, 1305, 1240, 1165, 1095, 760.

Example 12 [1- (2-Nitrobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The reaction and treatment were carried out in the same manner as in Example 4 to give [(1- (2-nitrobenzenesulfonylaminomethyl) isochroman. −
6-yl] oxyacetic acid (1.9 g, 93%) was obtained as colorless crystals (recrystallized from ethyl acetate-hexane).

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.6 to 2.9 (2H, m, ArCH ₂ ), 3.2 to 4.3 (4H, m, NCH ₂ ,
OCH ₂ ), 4.6 (2H, s, OCH ₂ CO), 4.6 ~ 4.9 (1H, m, CH), 6.6
~ 7.1 (3H, m, Ar), 7.7 ~ 8.2 (4H, m, Ar) IR (cm ^-1 ); 3300, 2900, 1735, 1720, 1610, 1530, 15
05, 1425, 1370, 1310, 1230, 1160, 1100, 850, 790.

Example 13 [1- (Benzylsulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The reaction and treatment were carried out in the same manner as in Example 4 to give [(1-benzylsulfonylaminomethyl) isochroman-6-yl]. Oxyacetic acid (1.5g, 94%) was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.6 to 3.0 (2H, m, ArCH ₂ ), 3.1 to 3.5 (2H, m, NC
H ₂ ), 3.6 to 4.1 (2H, m, OCH ₂ ), 4.2 (2H, s, ArCH ₂ SO ₂ ).
, 4.6 (2H, s, OCH ₂ CO), 4.6 ~ 4.9 (1H, m, CH), 6.0
~ 7.0 (3H, m, Ar), 7.35 (5H, s, Ar) IR (cm ^-1 ); 3300, 2950, 1750, 1610, 1505, 1320, 12
10, 1160, 1130.

Example 14 N- (4-chlorobenzene)
Sulfonyl- (6-hydroxyisochroman-1-yl) methylamine To the mixture of the hydrobromide salt (34.6 g) obtained in Reference Example 2, triethylamine (41 ml) and dichloromethane (300 ml), p
A solution of -chlorobenzenesulfonyl chloride (30.9 g) in dichloromethane (100 ml) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and the organic layer was separated. The dichloromethane layer was washed with diluted hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and N- (4
-Chlorobenzene) sulfonyl- (6-hydroxyisochroman-1-yl) methylamine (11.1 g, 33%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.6 to 2.9 (2H, m, ArCH ₂ ), 3.0 to 3.5 (2H, m, NC
H ₂ ), 3.6 to 4.2 (2H, m, OCH ₂ ), 4.6 to 4.9 (1H, m, CH),
6.5 ~ 7.0 (3H, m, Ar), 7.3 ~ 7.9 (4H, m, Ar) IR (cm ^-1 ); 3480, 3300, 1589, 1324, 1160, 1093, 108
5, 754.

Example 15 [1- (4-chlorobenzene) sulfonylaminomethyl) isochroman-6-yl] oxyacetic acid The phenol body (4.0 g) obtained in Example 14 was dissolved in 2-butanone (60 ml), Add anhydrous potassium carbonate (3.4g) 30
The mixture was heated under reflux for a minute. Ethyl bromoacetate in the resulting mixture
(2.0 g) was added dropwise, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5N aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl].
Ethyl oxyacetate (1.9g, 38%) was obtained as a colorless oil.

The oil obtained (1.7 g) was added to methanol (15 ml).
, 1N potassium hydroxide aqueous solution (15 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and the solution was made acidic with 6N hydrochloric acid. The obtained mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained crude crystals were recrystallized from ethyl acetate-hexane to give [1- (4-
Chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid (1.5 g, 92%) was obtained as colorless crystals. In addition, instrumental data of the obtained compound coincided with that of the compound obtained in Example 6.

Example 16 4- [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxybutyric acid As in Example 15, N- (4-chlorobenzene) sulfonyl- (6-hydroxyisochroman- 1-yl) methylamine (5.0 g) and ethyl 4-bromobutyrate (3.0 g) were reacted and treated to give 4- [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl].
Oxybutyric acid (1.4 g, 26%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ + CD ₃ OD + DMSO-d ₆ ) δ 1.8 to 2.9 (6H, m, CH ₂ CH ₂ CO, ArCH ₂ ), 3.0 to 3.3 (2H,
m, NCH ₂ ), 3.5 to 4.2 (4H, m, OCH ₂ X2), 4.5 to 4.9 (1
H, m, CH), 6.5 to 7.0 (3H, m, Ar), 7.3 to 7.9 (4H, m, A)
r) IR (cm ^-1 ); 3130, 2930, 2870, 1710, 1690, 1600, 15
80, 1500, 1460, 1380, 1320, 1230, 1150, 1140, 1080,
1050, 1000, 830.

Example 17 5- [1- (4-Chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyvaleric acid As in Example 15, N- (4-chlorobenzene) sulfonyl- (6-hydroxyisochroman -1-yl) methylamine (5.0 g) and ethyl 5-bromovalerate (3.2 g)
Was reacted and treated to give 5- [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyvaleric acid (1.8 g, 30%) as an amorphous substance.

¹ H-NMR (CDCl ₃ + CD ₃ OD + DMSO-d ₆ ) δ 1.5 to 2.0 (4H, m, C-CH ₂ CH ₂ -C), 2.1 to 3.0 (4H, m, CH
₂ CO, ArCH ₂ ), 3.1 to 3.4 (2H, m, NCH ₂ ), 3.5 to 4.2 (4H,
m, OCH ₂ , X2), 4.5 to 4.8 (1H, m, CH), 6.6 to 7.1 (3H,
m, Ar), 7.4 ~ 8.0 (4H, m, Ar) IR (cm ^-1 ); 3280, 2950, 2840, 1700, 1605, 1500, 14
70, 1430, 1370, 1330, 1300, 1260, 1240, 1200, 1150,
1080, 740.

Example 18 [1- (4-Chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid sodium salt The crystal (400 mg) obtained in Example 6 was dissolved in 2 methanol (5 ml) to give sodium methoxy. (187 mg) was added at 0 ° C. The obtained solution was concentrated under reduced pressure and lyophilized to dryness to obtain [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid sodium salt (430 mg, quantitative yield) as a white powder. It was

¹ H-NMR (DMSO-d ₆ ) δ 2.5 to 2.8 (2 H, m, A
rCH ₂ ), 3.2 to 3.3 (2H, m, NCH ₂ ), 3.4 to 4.1 (2H, m, OC
H ₂ ), 4.25 (2H, s, OCH ₂ CO), 4.5 to 4.7 (1H, m, CH), 6.
5 to 6.9 (3H, m, Ar), 7.3 to 7.9 (4H, m, Ar) IR (cm ^-1 ); 3425, 3150, 1605, 1500, 1430, 1330, 12
50, 1150, 1110, 1090, 1060, 830, 760.

Example 19 [1- (4-Chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid / potassium salt As in Example 18, [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6- [L-Oxyacetic acid (400 mg) and 1N potassium hydroxide (0.97 ml) are reacted and treated to give [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid.
The potassium salt (450 mg, quantitative yield) was obtained as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ 2.5 to 2.9 (2H, m, A
rCH ₂ ), 3.2 to 3.4 (2H, m, NCH ₂ ), 3.5 to 4.2 (2H, m, OC
H ₂ ), 4.3 (2H, s, OCH ₂ CO), 4.5 to 4.8 (1H, m, CH), 6.6
~ 6.9 (3H, m, Ar), 7.4 ~ 7.9 (4H, m, Ar) IR (cm ^-1 ); 3300, 2850, 1610, 1505, 1420, 1330, 12
40, 1150, 1095, 1065, 830, 750.

Example 20 [1- (4-Chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid / ammonium salt As in Example 18, [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl] [1- (4-chlorobenzenesulfonylaminomethyl) isochroman-6-yl] oxyacetic acid ammonium salt (450 mg) , Quantitative yield) was obtained as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ 2.6 to 2.9 (2H, m, ArCH ₂ ), 3.0 to 3.3 (2H, m, NCH ₂ ), 3.3 to 4.0 (2H, m, OCH ₂ ), 4.3 (2H, s, OCH ₂ CO), 4.4 to 4.7 (1H, m, CH), 6.5 to 7.0 (3H, m, Ar), 7.5 to 8.0 (4H, m, Ar) IR (cm ^-1 ); 3200, 2950, 1580, 1500, 1450, 1435, 1330, 1255, 1160, 1110, 1095, 1055, 830, 710. Conducting a reaction and processing in the same manner as in Example 21 [1- (trifluoromethanesulfonyl aminomethyl) Isokuro-6-yl] oxy acetic acid Example 4, [1- (trifluoromethanesulfonyl aminomethyl) isochroman-6-yl] oxy acid (1.1 g, 89%) the ethyl acetate - was recrystallized from hexane to give colorless crystals. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.7 to 3.1 (2H, m, ArCH ₂ ), 2.4 to 4.3 (4H, m, NCH ₂ OCH ₂ ), 4.6 (2H, s, OCH ₂ CO), 4.7 ~ 5.0 (1H, m, CH), 6.7 ~ 7.2 (3H, m, Ar) IR (cm ^-1 ); 3200, 1750, 1700, 1620, 1505, 1435, 1380, 1365, 1260, 1230, 1190, 1180 , 1150, 1140, 1060. Conducting a reaction and processing in the same manner as in Example 22 [1- (2-naphthalenesulfonyl aminomethyl) isochroman-6-yl] oxy acetic acid Example 4, [1- (2-naphthalenesulfonyl amino Nomechiru) isochroman-6-yl Oxyacetic acid (0.93 g, 88%) was recrystallized from ethyl acetate- hexane to give colorless crystals. ¹ H-NMR (CDCl ₃ + CD ₃ OD) δ 2.5 to 2.8 (2H, m, ArCH ₂ ), 3.3 to 3.5 (2H, m, NCH ₂ ), 3.6 to 4.1 (2H, m, OCH ₂ ), 4.5 ( 2H, s, OCH ₂ CO), 4.6 to 4.9 (1H, m, CH), 6.5 to 6.9 (3H, m, Ar), 7.4 to 8.4 (7H, m, Ar) IR (cm ^-1 ); 3300, 1730, 1700, 1610, 1510, 1440, 1330, 1230, 1155, 1100. Conducting a reaction and processing in the same manner as in Example 23 [1- (4-carboxyphenyl benzenesulfonylamino-methyl) isobutyl chroman-6-yl] oxy acetic acid Example 4, [1- (4-carboxyphenyl benzenesulfonylamino-methyl) isochroman 6-yl] oxy acetic acid (0.92 g, 98%) was recrystallized from ethyl acetate to give colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ 2.6 to 2.9 (2H, m, ArCH ₂ ), 3.0 to 3.4 (2H, m, NCH ₂ ), 3.5 to 4.0 (2H, m, OCH ₂ ), 4.6 (2H , s, OCH ₂ CO), 4.5 to 4.8 (1H, m, CH), 6.6 to 7.2 (3H, m, Ar), 7.8 to 8.2 (4H, m, Ar) IR (cm ^-1 ); 3250, 2900 , 1740, 1690, 1500, 1420, 1335, 1290, 1270, 1160. Example 24 [1- (8-quinolinesulfonylaminomethyl) isochroman- 6-yl] oxyacetic acid The reaction and treatment were carried out in the same manner as in Example 4 to give [1- (8-quinolinesulfonylaminomethyl ) isochroman-6-yl. ] Oxyacetic acid (1.1 g, 56%) was recrystallized from methanol to give colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ 2.3 to 2.7 (2H, m, ArCH ₂ ), 2.9 to 3.9 (4H, m, NCH ₂ , OCH ₂ ), 4.6 (2H, s, OCH ₂ CO), 4.5 ~ 4.8 (1H, m, CH), 6.4 ~ 7.0 (3H, m, Ar), 7.5 ~ 7.9 (2H, m, Ar), 8.1 ~ 8.6 (3H, m, Ar), 8.9 ~ 9.1 (1H, m) , Ar) IR (cm ^-1 ); 3300, 2850, 1740, 1610, 1505, 1430, 1400, 1330, 1300, 1240, 1160, 1140, 1110, 1090, 1060, 840, 820.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/47 ACD C07D 405/12 215

Claims (8)

[Claims] 1. A compound of the general formula (I) (In the formula, R ₁ is an alkyl group, or an aryl which may be substituted with one or more of a halogen, an alkyl group, an alkoxy group, a nitro group, a trifluoromethyl group, a hydroxy group, a carboxy group and an alkoxycarbonyl group. Base,
Aralkyl group, pyridyl, isoquinolyl, indolyl,
Represents pyrimidyl , R ₂ represents a hydroxy group, an alkoxy group, a verdyloxy group, or has the formula: —NR ₃ R ₄
(R ₃ and R ₄ are the same or different and each represents hydrogen, an alkyl group or an aralkyl group), and n is 1 to 6
A compound represented by the formula (4) and a pharmaceutically acceptable salt thereof. 2. A compound represented by the general formula (Ia): (In the formula, R ₁ is an alkyl group which may be substituted with halogen, or halogen, a lower alkyl group having 1 to 4 carbon atoms,
A lower alkoxy group having 1 to 3 carbon atoms, a nitro group, a trifluoromethyl group, a hydroxy group, a carboxy group, an aryl group which may be substituted by one or more with an alkoxycarbonyl group, an aralkyl group, pyridyl, isoquinolyl, a
An aminomethylisochroman derivative consisting of a compound represented by the formula (1) and a pharmaceutically acceptable salt thereof. 3. A thromboembolic disorder comprising as an active substance the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and / or diluents . Therapeutic and prophylactic agents. 4. A compound represented by the general formula (II) : (In the formula, R ₂ is a hydroxy group, an alkoxy group,
Or a formula: —NR ₃ R ₄ (R ₃ and
R _{4 s} are the same or different and each represents hydrogen, alkyl group or
Represents an aralkyl group), and n represents 1 to 6)
Consisting of the indicated compound and pharmaceutically acceptable salts thereof
Aminomethylisochroman derivative. 5. The general formula (II) according to claim 4 , wherein R
₂ , n is the same as the above) and a compound represented by the general formula (III): R ₁ SO ₃ H (III) (wherein R ₁ is the same as above), or an activity thereof. 3. Preparation of a derivative according to claim 1 or 2, characterized in that, when R _{2 of the} produced compound (I) is not a hydroxy group, hydrolysis is carried out to a free carboxylic acid, if necessary, by reacting with a derivative. Law. 6. The claimFourOf the general formula (II)CompoundTo
A method for producing a compound of general formula (IV) (In the formula, Prot represents an amino-protecting group.And acetyl,
Benzyloxycarbonyl or tertiary butoxycarboni
Le) Is represented by the general formula (V): X (CH₂)_nCOR₂ (V) (In the formula, R₂, N are the same as above, X is chlorine, odor
Element, iodine, alkyl sulfonyl group or toluene sulfonyl group
A group represented by
A production method characterized by removing a group. 7. A compound represented by the general formula (VI): (Wherein R ₁ is the same as above), a phenol of the general formula (V): X (CH ₂ ) _n COR ₂ (V) (wherein R ₂ and n are the same as above) X represents chlorine, bromine, iodine, an alkylsulfonyl group or a toluenesulfonyl group), and R _{2 of the} produced compound (I) is not a hydroxy group. The method for producing the derivative according to claim 1 or 2, wherein the hydrolysis is carried out. 8. The active substance according to claim 1 or 2.
Or a pharmaceutically acceptable salt thereof as the case may be.
With one or more inert carriers and / or diluents
A preventive agent for arteriosclerosis, which is also contained in