JP2984403B2 - Isoquinolone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel isoquinolone derivative, a method for producing the same, and an aldose reductase inhibitor containing the isoquinolone derivative as an active ingredient.

[0002]

2. Description of the Related Art Aldose reductase (hereinafter referred to as "A
R ") is an enzyme that reduces aldoses such as glucose and galactose to polyols such as sorbitol and galactitol in the living body. Accumulates in the lens, peripheral nerves, kidneys, etc., resulting in complications of diabetes such as retinopathy, cataract,
It is known that nervous disorders and renal disorders occur. Therefore, the above-mentioned complications of diabetes can be prevented or treated by inhibiting the action of AR.

[0003] The fact that isoquinolone derivatives have an AR inhibitory action is disclosed in, for example, Japanese Patent Application Laid-Open No. 56-92871.

The compound described in this prior art is a compound wherein the 4-position substituent on the isoquinolone ring is carboxymethyl or alkoxycarbonylmethyl, and the 4-position substituent on the isoquinolone ring is carboxymethyloxy or alkoxycarbonyl. Compounds having a structure that is methyloxy, carboxyethyl or alkoxycarbonylethyl, or carboxyethenyl or alkoxycarbonylethenyl are not known before.

[0005]

DISCLOSURE OF THE INVENTION An isoquinolone derivative which has not been described in the above-mentioned prior art documents and which has an AR inhibitory action is found to be more useful than the above-mentioned known substances. From the viewpoint of enrichment of technology by elucidation of unlisted substances and diversification of selectivity in the field of application as a medicine, further elucidation and development are being demanded.

[0006] Under such circumstances, the present invention aims to provide a novel isoquinolone derivative and a medicament containing this derivative as an active ingredient.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, introduced a group which has not been known as a substituent at the 4-position of the isoquinolone ring onto the isoquinolone ring. Thus, the present invention was completed by synthesizing an isoquinolone derivative having a new structure.

That is, the present invention provides the following general formula (1)

Embedded image Wherein R ¹ is unsubstituted or any position on the ring is halogen, C ₁ -C ₅ lower alkyl, C ₂ -C ₅
Represents an aromatic ring group substituted by one or two substituents independently selected from C ₅ lower alkenyl and C ₁ -C ₅ halogenated alkyl, and R ² represents a hydrogen atom or C ₁
It represents a lower alkyl group -C _5, and X is O, CH
Or, in CH ₂ , when X is O or CH ₂ , the dashed line together with the solid line represents a single bond, and when X is CH, the dashed line together with the solid line represents a double bond. The present invention relates to an isoquinolone derivative or a pharmaceutically acceptable non-toxic salt thereof.

Further, the present invention relates to the above-mentioned general formula (1)
And an aldose reductase inhibitor comprising, as an active ingredient, an isoquinolone derivative or a pharmaceutically acceptable non-toxic salt thereof.

Specific examples of the group R ^{1 in} the compound represented by the general formula (1) include phenyl, 1-naphthyl,
2-naphthyl, 2-, 3- or 4-methylphenyl,
2-, 3- or 4-ethylphenyl, 2-, 3- or 4-propylphenyl, 2-, 3- or 4-isopropylphenyl, 2-, 3- or 4-butylphenyl, 2-, 3- or 4-i-butylphenyl, 2-,
3- or 4-t-butylphenyl, 2-, 3- or 4-pentylphenyl, 2-, 3- or 4-chlorophenyl, 2, 3- or 4-bromophenyl, 2-3
-Or 4-fluorophenyl, 2-, 3- or 4-
Trifluoromethylphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 2-fluoro-4-bromophenyl, 3-fluoro-5-bromophenyl, 2
-Fluoro-5-bromophenyl, 2-, 3- or 4
-Methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2,3-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, and the like. Specific examples of R ² include hydrogen. Atoms, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl and the like.

The isoquinolone derivative of the present invention represented by the general formula (1) can be obtained by the following step (1):

Embedded image (Wherein R ¹ has the meaning defined above)
-Formyl-1-isoquinolone compound and the following general formula
(3) (alk-O) ₂ P (O) CH ₃ CO ₂ R ^2a (3) (where alk is a lower alkyl group such as methyl, ethyl, propyl, etc., and R ^2a is a C ₁ -C ₅ lower alkyl. a dialkylphosphono acid alkyl ester represented by the representative of the group) is reacted with Wittig-Horner reaction in the presence of sodium hydride, the following general formula (1 ^I)

Embedded image Wherein R ¹ and R ^2a have the meanings defined above, or

[0012] (Step 2) following general formula Compounds of this general formula (1 ^I) was hydrolyzed under alkaline conditions (1 ^II)

Embedded image Wherein R ¹ has the meaning as defined above, or

(Step 3) Further, the compound of the general formula (1 ^II ) is catalytically hydrogenated to give the following general formula (1 ^III )

Embedded image Wherein R ¹ has the meaning as defined above, or

(Step 4) The following general formula (4)

Embedded image (Wherein R ¹ has the meaning defined above)
- hydroxy-1-isoquinolone compound of the general formula _{(5) X · CH 2 ·} COOR 2a (5) ( wherein, X represents a halogen such as chlorine, bromine or iodine, the meaning of R ^2a is as defined above Is reacted in the presence of a base with a haloacetic acid alkyl ester represented by the following general formula (1 ^IV ):

Embedded image Wherein R ¹ and R ^2a have the meaning as defined above, or

[0015] (Step 5) In formula (1 ^IV) compound by hydrolysis under alkaline conditions the following general formula (1 ^V)

Embedded image (Wherein R ¹ has the meaning as defined above).

The compounds of the general formulas ( ^1I ) to ( ^1V ) are all compounds included in the range of the compound of the general formula (1).

The reaction of the 4-formyl-1-isoquinolone compound with the alkyl dialkylphosphonoacetate in the above step 1 is carried out under the reaction conditions for converting a formyl group into an ethylene group by a well-known Wittig-Horner reaction. That is, 4-formyl 1-isoquinolone compound 1
The formyl group is converted to an alkoxycarbonylethenyl group by reacting the alkyl dialkylphosphonoacetate with 0.5 to 10 moles, preferably 1 to 5 moles, of the alkyl ester in the presence of sodium hydride.
The base is 0.5 based on the alkyl dialkylphosphonoacetate.
２2 mol, preferably equimolar. This reaction is preferably carried out in an inert organic solvent at room temperature to the boiling point of the solvent. Examples of organic solvents that can be used in this reaction include hydrocarbons such as n-hexane, ligroin, benzene, and toluene; lower alcohols such as methanol, ethanol, and i-propanol; ether solvents such as ether, tetrahydrofuran, and dioxane; ethyl,
Esters such as butyl acetate, ethylene dichloride,
Chloroform hydrocarbon solvents such as chloroform, trichloroethylene and carbon tetrachloride, aprotic polar solvents such as dimethylsulfoxide, dimethylformamide, diethylformamide, and dimethylacetamide, and protic polar solvents such as citric acid and acetic acid. These can be used alone or in combination of two or more in some cases. Specific examples of the dialkyl phosphonoacetic acid alkyl ester used in this reaction include diethyl phosphono acetic acid methyl ester, diethyl phosphono acetic acid ethyl ester,
Diethyl phosphonoacetic acid propyl ester and the like can be mentioned.

The separation and purification of the desired product from the reaction mixture thus obtained can be carried out by usual means in this technical field. For example, the solvent is distilled off from the reaction mixture, the residue is dissolved in another solvent, washed with water, dried, the solvent is distilled off, and then purified by chromatography, recrystallization, or other means to obtain the desired product. get.

In the compound thus obtained,
When the target product in which the group R ^2a is hydrogen is desired, R ^2a is hydrolyzed in Step 2 described above, that is, R ^2a is hydrogenated.
It is converted to a compound in which ^2a is hydrogen. This hydrolysis reaction proceeds under reaction conditions unaffected except for the ester group of the isoquinolone compound. For example, in an aqueous alcohol solvent or an alcohol-tetrahydrofuran mixed solvent in the presence of a base such as sodium hydroxide at room temperature. ~ 1
The reaction is carried out at a temperature of 00 ° C. for a reaction time of about several minutes to several hours.

The product thus obtained by the hydrolysis reaction can be purified by the same purification means as described in the above step 1.

If a compound obtained by hydrogenating the carboxyethenyl group at the 4-position in the compound thus obtained and converting it to a carboxyethyl group is desired, the compound obtained in the step 2 by the above-mentioned step 3 is obtained. The compound is catalytically hydrogenated. This catalytic hydrogenation can be performed under known catalytic hydrogenation reaction conditions. That is, the above step 3
Is dissolved in an inert organic solvent, in the presence of a hydrogenation catalyst such as Raney nickel, platinum black, platinum supported on carbon, palladium black, and the like, hydrogen gas under normal pressure to pressure and normal temperature. It is performed by contacting under heating at about 100 ° C. Specific examples of the inert organic solvent used in this case include the organic solvent used in Step 1. The end of the reaction can be monitored by hydrogen consumption. At the end of the reaction, the catalyst is filtered off and the filtrate is separated and purified in the same way as described in step 1.

In the compound of the general formula (1) of the present invention, X
Is produced by step 4 described above. In the reaction of the 4-hydroxy-1-isoquinolone compound with the alkyl haloacetate in Step 4, 0.5 to 5 mol of the latter is used in an inert organic solvent with respect to 1 mol of the former, preferably as an acid binder. The reaction is carried out in the presence of a base, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or an organic base such as pyridine or dimethylaniline at a temperature from room temperature to the boiling point of the solvent. Specific examples of the inert organic solvent used in this case include the organic solvent used in Step 1. After completion of the reaction, the solvent is distilled off, the residue is dissolved in a solvent that is immiscible with water, the solution is washed with water to remove water-soluble products, and the solvent is distilled off from the solvent layer. Purification is performed by purification means, for example, chromatography, recrystallization and the like.

In the compound thus obtained, if the target compound in which the group R ^2a is hydrogen is desired, the compound in which the group R ^2a is lower alkyl is hydrolyzed by the same hydrolysis reaction as in the step 2 described above. Is done. The hydrolysis reaction conditions used here are the same as those described in Step 2.

The isoquinolone derivative represented by the general formula (1) of the present invention has an activity of inhibiting AR that reduces aldose to a corresponding polyol, thereby suppressing an abnormal increase in intracellular sorbitol content in diabetic patients. Therefore, the compound (1) of the present invention and salts thereof are useful for the prevention or treatment of diabetic complications such as retinopathy, cataract, neuropathy and renal disorder.

The AR inhibitory action of the compounds of the present invention can be determined, for example, by using AR obtained from a rat lens in a laboratory experiment.
A modification of the method described in J. Biol. Chem., 240 , 877-882 (1965) (Biochemical Pharmacology, 25 , 2505-2513 (1965)
976)), the AR at 10 ^-5 molar concentration was
Was significantly inhibited.

The present invention further comprises an isoquinolone derivative represented by the general formula (1) or a pharmaceutically acceptable non-toxic salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or shell. A pharmaceutical composition comprising: These pharmaceutical compositions can be prepared into solid, semi-solid or liquid preparations by methods well known to those skilled in the art. Examples of formulations include tablets, capsules, troches, syrups, granules, powders, injections, suspensions,
There are inhalants and the like. In addition, a double-layer tablet or a multilayer tablet can be prepared together with other drugs. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, an enteric-coated tablet, or a film-coated tablet. These formulations are administered orally or as an injection.

[0027] The amount of the active ingredient in these preparations is not more than 0.1% of the preparation.
It is between 1 and 100% by weight, suitably between 1 and 50% by weight for formulations for oral administration and between 0.1 and 10% by weight for formulations for injection.

The administration method and dosage of the pharmaceutical composition of the present invention are not particularly limited, and are appropriately selected depending on various preparation forms, administration route, age of patient, gender, degree of disease and the like. The daily dose is 0.01-1000
mg.

The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto.

[0030]

EXAMPLES Example 1 4- (2-methoxycarbonylethenyl) -2- (3,
1.3 g (6.2 mmol) of methyl 4-dichlorobenzyl) -1-isoquinolone diethylphosphonoacetate
And 0.25 g (6.2 mmol) of 60% sodium hydride
Was reacted in 25 ml of dry tetrahydrofuran at room temperature for 10 minutes, and 2- (3,4-dichlorobenzyl) was added thereto.
1.32 g of 4-formyl-1-isoquinolone (4.0 m
(mol) in 30 ml of dry tetrahydrofuran was added dropwise and reacted at room temperature for 1 hour. The solvent was distilled off from the reaction mixture under reduced pressure, the residue was dissolved in chloroform, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The title compound (1.06 g, yield 69%) was obtained. Properties: crystal ¹ H NMR: (CDCl ₃ ) 3.81 (s, 3H), 5.
19 (s, 2H), 6.28 (d, 2H), 7.18 (d
d, 1H), 7.35-7.45 (m, 3H), 7.58
(Dt, 1H), 7.76 (dt, 1H), 7.84
(D, 1H), 7.97 (d, 1H), 8.49 (dd,
1H).

Example 2 4- (2-carboxyethenyl) -2- (3,4-dichlorobenzyl) -1-isoquinolone 4- (2-methoxycarbonylethenyl) -2 obtained in Example 1 above. -(3,4-dichlorobenzyl) -1-
Isoquinolone (1.06 g, 2.7 mmol) was dissolved in a methanol-tetrahydrofuran mixture, and 2N Na was added thereto.
3 ml of an OH aqueous solution was added and reacted at room temperature for 4 hours. After confirming the disappearance of the ester by thin layer chromatography, water was added, the organic solvent was distilled off under reduced pressure, 1N HCl was added to neutralize the solution, and the precipitated crystals were collected by filtration and washed with water. 0.94 g (yield 92%) of the title compound was obtained.

Example 3 4- (β-carboxyethyl) -2- (3,4-dichlorobenzyl) -1-isoquinolone 4- (2-carboxyethenyl)-obtained in Example 2
0.60 g (1.60 mmol) of 2- (3,4-dichlorobenzyl) -1-isoquinolone was dissolved in 60 ml of ethanol-tetrahydrofuran (1: 1), and palladium-soluble.
Carbon (5% 0.1 g) was added and hydrogenated for 1 hour in the presence of 1 atm of hydrogen. The catalyst was filtered off, the solvent was distilled off, and the white crystals obtained were washed with ether and dried to obtain 0.52 g (yield 86%) of the title compound.

Example 4 2- (3,4-dichlorobenzyl) -4-methoxycarbonylmethoxy-1-isoquinolone 2- (3,4-dichlorobenzyl) -4-hydroxy-
2.4 g (9.5 mmol) of 1-isoquinolone, 1.2 g (7.8 mmol) of bromoacetic acid ethyl ester and 1.1 g (8.0 mmol) of potassium carbonate were added to 15 ml of dimethyl sulfoxide, and reacted at 60 ° C. for 2 hours. . The reaction mixture was returned to room temperature, poured into a saturated aqueous solution of ammonium chloride, and the mixture was extracted with benzene. Benzene was distilled off from the extract, and the obtained crystals were recrystallized from a mixed solution of chloroform and benzene to obtain 2.33 g (yield 79%) of the title compound.

Example 5 4-Carboxymethoxy-2- (3,4-dichlorobenzyl) -1-isoquinolone 2- (3,4-dichlorobenzyl) obtained in Example 4
1.20 g (3.1 mmol) of 4-methoxycarbonylmethoxy-1-isoquinolone was dissolved in a mixture of methanol and tetrahydrofuran, and 2N NaOH aqueous solution 3 was added thereto.
ml was added and reacted at room temperature for 1 hour. The reaction mixture was treated in the same manner as in Example 2 to obtain 1.1 g (yield: 95%) of the title compound.

Examples 6 to 13 The reaction procedures described in Examples 4 and 5 were repeated in the same manner as in Examples 6 to 13 except that the starting materials used were those corresponding to the following desired products. The compound was obtained. The chemical structures and physical properties of these compounds are shown together with those of the compounds of Examples 2 to 5 in Tables 1, 2, 3 and 4 below.

[0036]

[Table 1]

[0037]

[Table 2]

[0038]

[Table 3]

[0039]

[Table 4]

The AR inhibitory activity of the compound of the present invention was evaluated by the following experimental method. Experimental method: Hayman (S. Hayman) and Kinoshita (J.
H. Kinoshita) [J. Biol. Chem., 240 ,
877-882 (1965)], a method modified by SD Varma and Kinoshita [Biochemical Pharmacolog
y, 25 , 2505-2513 (1976)].

Details of Experimental Method: Male SD rats were decapitated and sacrificed, the lens was excised, homogenized in cold water, and centrifuged to prepare a supernatant as a crude aldose reductase solution.

Separately, a 0.1 M sodium phosphate buffer (pH 6.2) containing 0.4 M ammonium sulfate was prepared at 30 ° C., and the compound of the present invention, the above crude aldose reductase solution and nicotine Amidoadenine dinucleotide phosphate reduced form (NADPH) is dissolved and incubated at 30 ° C. for 3 minutes.
The reaction was started by adding L-glyceraldehyde. In this case, the concentration of the compound of the present invention to be dissolved was 10 ⁻⁵ M. Further, the total volume of the solution was adjusted to 1.0 ml and NADPH was adjusted to 0.1.
Solutions were prepared to contain 6 mM, 10 mM DL-glyceraldehyde, and 0.01 to 0.016 units aldose reductase.

The inhibitory effect of the compounds of the present invention on the enzymatic activity was determined for each 1.0 ml reaction mixture containing the compounds of the present invention at the above concentrations.

The measurement was conducted by following the change in absorbance using light having a wavelength of 340 nm as NADPH was oxidized and disappeared over time after the addition of DL-glyceraldehyde as described above.

The AR inhibitory activity of the compound of the present invention (indicated by the number of the example) thus measured was expressed as an inhibition rate (%) as a relative activity to a control value. The results are shown in Table 5 below.

[0046]

[Table 5]

Some specific forms of pharmaceutical preparations containing the compound of the present invention as an active ingredient are shown below.

Formulation Example 1 Tablet (1 tablet) Each component is uniformly mixed to obtain a powder for direct hitting. This is formed into a tablet having a diameter of 6 mm and a weight of 100 mg by a rotary tableting machine.

Formulation Example 3 Granules (1 packet) B. Compound of Example 7 10 mg Lactose 90 mg Corn starch 50 mg Microcrystalline cellulose 50 mg Hydroxypropylcellulose 10 mg Ethanol 90 mg After uniformly mixing the components of A, the solution of B is added and kneaded, sized by an extrusion granulation method, and then dried by a dryer at 50 ° C. The dried granules are sieved to a particle size of 297 μm to 1460 μm to obtain granules. 200mg per package
And

Formulation Example 13 Injection The sodium chloride and the active ingredient are dissolved by adding distilled water to a total volume of 1.0 ml.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ identification code FI A61K 31/00 643 A61K 31/00 643E 31/47 31/47 (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 217/24 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A compound of the general formula (1) Wherein R ¹ is unsubstituted or any position on the ring is halogen, C ₁ -C ₅ lower alkyl, C ₂ -C ₅
Represents an aromatic ring group substituted by one or two substituents independently selected from C ₅ lower alkenyl and C ₁ -C ₅ halogenated alkyl, and R ² represents a hydrogen atom or C ₁
It represents a lower alkyl group -C _5, and X is O, CH
Or, in CH ₂ , when X is O or CH ₂ , the dashed line together with the solid line represents a single bond, and when X is CH, the dashed line together with the solid line represents a double bond. Isoquinolone derivatives. 2. A compound of the general formula (2) (Wherein R ¹ has the meaning defined above)
-Formyl-1-isoquinolone compound and the following general formula
(3) (alk-O) ₂ P (O) CH ₃ CO ₂ R ^2a (3) (where alk is a lower alkyl group such as methyl, ethyl, propyl, etc., and R ^2a is a C ₁ -C ₅ lower alkyl. A dialkylphosphonoacetic acid alkyl ester represented by the general formula (1 ^I ): (Wherein R ¹ and R ^2a have the meanings defined above). 3. A compound of the general formula (1 ^I ) (Wherein R ¹ and R ^2a have the meanings defined above) by hydrolyzing a compound represented by the general formula (1 ^II ) below under alkaline conditions. (Wherein R ¹ has the meaning as defined above). 4. A compound of the general formula (1 ^II ) Wherein R ¹ has the meaning defined above, comprising catalytically hydrogenating a compound of the general formula (1 ^III ): (Wherein R ¹ has the meaning as defined above). 5. A compound of the general formula (4) (Wherein R ¹ has the meaning defined above)
- hydroxy-1-isoquinolone compounds of the general formula _{(5) X · CH 2 ·} COOR 2a (5) ( wherein, X represents a halogen such as chlorine, bromine or iodine, R ^2a has the meaning defined above) Reacting with a haloacetic acid alkyl ester represented by the general formula (1 ^IV ) (Wherein R ¹ and R ^2a have the meanings as defined above). 6. A compound of the general formula (1 ^IV ) (Wherein R ¹ and R ^2a have the meanings as defined above), which is obtained by hydrolyzing a compound represented by the formula (1 ^V ) under alkaline conditions. (Wherein R ¹ has the meaning as defined above). 7. An aldose reductase inhibitor comprising an isoquinolone derivative represented by the general formula (1).