JPH04308586A - Benzopyrane derivative - Google Patents

Abstract

PURPOSE:To provide a novel compound havng a Maylard reaction-inhibiting action and an antioxidative action, haivng excellent solubility and oral absorbability and useful as a medicine, etc. CONSTITUTION:A compound of formula I [R<1> is COR<11>, CO(CH2)mR<12> (R<11> is 1-4C alkyl; R<12> is NH2, etc.; (m) is 1-5), R2 is H, 1-4C alkyl]. For example, N-methyl-N-[2-(6-acetoxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2- b]pyran-2-y1]ethyl]-4-guanidinocinnamic amid hydrochloride. The comound of formula I is obtained by reacting a component of formula II with an acid anhydride.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to benzopyran derivatives useful as pharmaceuticals. More specifically, the invention provides i)
General formula (I)

[Formula 2] (In the formula, all symbols have the same meanings as below.) The shown benzopyran derivatives and acid addition salts thereof, ii)
iii) Maillard reaction inhibitors containing them as active ingredients; and iv) antioxidants containing them as active ingredients.

0002

Background of the Invention and Prior Art European Patent Publication No. 387771 discloses compounds of the general formula (A) shown below, which have Maillard reaction inhibiting and antioxidant effects, Diseases caused by various diabetic complications and aging, such as coronary heart disease, peripheral circulation disorders, cerebrovascular disorders, diabetic neuropathy,
For the treatment and/or prevention of nephropathy, arteriosclerosis, arthrsclerosis, cataract, retinopathy, and cancer, or diseases caused by the production of various lipid peroxides, such as arteriosclerosis, diabetes, myocardial infarction, and peripheral circulation disorders. have been described as being useful in the treatment and/or prevention of cerebrovascular disorders, cancer, inflammation, gastrointestinal diseases, and aging.

General formula (A)

[Formula 3] (wherein, R1a is a hydrogen atom, an alkyl having 1 to 4 carbon atoms,
Alkoxy having 1 to 4 carbon atoms, or together with carbon atoms at the 7th and 8th positions, represents a carbon ring having 6 carbon atoms, R2a is a hydrogen atom, an alkyl having 1 to 4 carbon atoms, or a carbon ring having 1 to 4 carbon atoms
represents alkoxy, R3a is a hydrogen atom, and has 2 to 2 carbon atoms.
4 acyl or benzoyl, na represents an integer of 1 to 3, Ya represents alkylene having 1 to 7 carbon atoms, alkenylene having 2 to 7 carbon atoms, or alkynylene having 2 to 7 carbon atoms, Ma is i) Represents a single bond or ii) a group represented by -Da-Ba-, and D
a represents i) -O- or ii) -S-, Ba represents i) an alkylene group having 1 to 4 carbon atoms, or i)
i) represents a group represented by the following formula,

[C4] Za is i) single bond, or ii) Represents the bond shown by the following formula,

embedded image Wa represents a group represented by -W1a-Aa-W2a-, Aa represents i) a single bond or ii) a group represented by the following formula,

[C6] Ea is i) single bond, ii) -O- or iii) represents -S-, formula

The symbol represented by [Image Omitted] is a carbon ring or heterocycle having 4 to 10 carbon atoms, or an alkyl ring having 1 to 3 carbon atoms,
Alkoxy having 1 to 4 carbon atoms, halogen, -COOR7a
represents a carbon ring or heterocycle having 4 to 10 carbon atoms substituted with a group represented by a trihalomethyl or acetamido group, W1a and W2a may be the same or different, i) a single bond, ii) a carbon number alkylene having 1 to 4 carbon atoms, iii) alkenylene having 2 to 4 carbon atoms, or iv)
represents alkynylene having 2 to 4 carbon atoms; R4a represents a hydrogen atom or alkyl having 1 to 4 carbon atoms; R5a represents a hydrogen atom, alkyl having 1 to 4 carbon atoms, or an amino group; R6a represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; represents an alkyl having 1 to 4 carbon atoms, an alkoxy having 1 to 4 carbon atoms, a halogen, a group represented by -COOR8a, a trihalomethyl or acetamido group, R7a represents a hydrogen atom or an alkyl having 1 to 4 carbon atoms, and R8a represents a hydrogen atom or represents an alkyl group having 1 to 4 carbon atoms, and R9a represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a benzyl group. However, i) Da is bonded to Ya and Ba is Z
ii) Ea is bonded to W1a and the formula

The ring represented by [Image Omitted] is bonded to W2a, iii) the double bond or triple bond in the alkenylene or alkynylene is not directly bonded to the oxygen atom, and iv)
Aa is the formula

[Chemical Formula 9], W1a does not represent a single bond, and v) R1a substituted at the carbon atom at the 5th position represents a hydrogen atom or an alkyl having 1 to 4 carbon atoms, and W1a is substituted at the carbon atom at the 7th position. R1a represents a hydrogen atom, alkyl having 1 to 4 carbon atoms, or alkoxy having 1 to 4 carbon atoms, and R1a substituted at the carbon atom at position 8 represents a hydrogen atom or alkyl having 1 to 4 carbon atoms. , R2a represents methyl, R3a represents a hydrogen atom, R4a represents a hydrogen atom, R5a
represents a hydrogen atom, -Ya -Ma -Za -Wa
Excludes compounds in which - represents a linear alkylene group having 1 to 3 carbon atoms. ) or its acid addition salt.

Among the compounds represented by the general formula (A), R
Compounds in which 3a represents a hydrogen atom are described as examples and have actually been synthesized. However, compounds in which R3a represents a hydrogen atom cannot be said to have sufficient solubility and absorbability.

[0005] Therefore, the present inventors conducted intensive studies to find benzopyran derivatives that are easier to form into liquid formulations and/or have effective Maillard reaction inhibition and antioxidant effects when administered orally. As a result, the inventors
General formula (A) in which the hydrogen atom in the portion corresponding to R3a is replaced with an acyl group or an acyl group derivative
The present invention was completed based on the discovery that the solubility and/or absorbability of the compound of the present invention (I) is significantly improved.

[0006]

DISCLOSURE OF THE INVENTION Therefore, the present invention provides: i) General formula

[C10
] (In the formula, R1 is i) -COR11, ii) -CO
(CH2)m R12, iii) -COOR13 or iv) -COO(CH2)n OR14, R
2 represents a hydrogen atom or a C1-4 alkyl group,
R11 represents a C1-4 alkyl group, and R12 is i
) -COOR15, ii) -NH2 or iii) -OR16, R13 represents a C1-4 alkyl group, and R14 represents a C1-4 alkyl group;
-4 alkyl group, R15 represents a C1-4 alkyl group, R16 represents a C1-4 alkyl group, m represents an integer of 1-5, and n represents an integer of 1-5. ) or an acid addition salt thereof, ii) a method for producing them, iii) a Maillard reaction inhibitor containing them as an active ingredient, and iv) an antioxidant containing them as an active ingredient.

In general formula (I), R2, R11, R13
, R14, R15 and R16 are methyl, ethyl, propyl, butyl groups and isomers thereof. Particularly preferred groups are methyl and ethyl.

In the present invention, all isomers are included unless otherwise specified. For example, alkyl groups include straight chain and branched chains, and also include isomers resulting from the presence of asymmetric carbon atoms.

[0009]

[Acid addition salt] The compound of the present invention represented by general formula (I) is
It is converted into the corresponding acid addition salt by known methods. Preferably, the salt is non-toxic and water-soluble. Non-toxic acid addition salts of the compound of formula (I) include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate. , oxalate, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate Examples include organic acid salts such as acid salts. Preferably it is a hydrochloride.

0010

[Comparison with the prior art] The compound of the present invention represented by the general formula (I) has better solubility and/or oral absorption than expected from the prior art compounds.

[0011]

[Process for producing the compound of the present invention] The compound of the present invention represented by the general formula (I) is: i) the general formula (II)

A compound represented by the following formula (wherein R2 represents the same meaning as above), or an acid addition salt thereof, (1) acid anhydride, (2) general formula R11COCl (III) (wherein R11 is the same as above); ) Compounds represented by the general formula R15OCO(CH2)m COCl(
IV) (in the formula, R15 represents the same meaning as above), ■General formula R13OCOCl (V) (in the formula, R1
3 represents the same meaning as above. ), ■General formula R14O(CH2)n OCOCl
(VI) (In the formula, R14 represents the same meaning as above.)
A compound represented by, or ■ General formula R16O(CH2)m COCl (
IX) (wherein R16 represents the same meaning as above) is reacted in the presence of a base (pyridine, triethylamine, etc.) and optionally salt exchanged, or
ii) General formula (VII)

From the compound represented by the formula (wherein Boc represents a tert-butoxycarbonyl group and R2 represents the same meaning as above) or an acid addition salt thereof, an acid (hydrochloric acid, methanesulfonic acid, toluenesulfonic acid etc.) to remove the Boc group.

0012

[Method for producing intermediate] The compound represented by the general formula (II) can be produced by the method described in European Patent Publication No. 387,771. General formula (VII)
The compound represented by is a compound represented by general formula (II) and general formula (VIII)

The compound represented by the formula (in which all symbols have the same meanings as above) is converted into dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl).
It can be produced by reacting in the presence of a condensing agent such as carbodiimide. General formula (III), (IV
), (V), (VI), (VIII) and (IX) are known reagents or can be easily produced from known compounds by known methods.

[0013]

[Starting material] The starting material and each reagent in the present invention are:
They are known per se or can be produced by known methods.

[0014]

[Activity of the compound of the present invention] The compound of the present invention represented by the general formula (I) has a Maillard reaction inhibiting effect and an antioxidant effect. Therefore, the compounds of the present invention are useful for the treatment and/or prevention of various diabetic complications and diseases caused by lipid peroxide production as described above. The compound of the present invention is also a compound with good solubility and oral absorption, and these facts were confirmed by the data shown in Tables 1 and 2 below.

[0015]

[Table 1]

[0016]

[Table 2]

Tables 1 and 2 show that the compounds of the present invention have better solubility and/or oral absorption than would be expected from the prior art compounds.

[0018]

[Toxicity] The toxicity of the compound of the present invention is sufficiently low.
It was confirmed that the compound can be used safely as a pharmaceutical and is particularly useful for treating and/or preventing diseases caused by Maillard reactions in humans.

[0019]

[Application to Pharmaceuticals] The compounds of the present invention represented by the general formula (I) and their acid addition salts are usually administered systemically or locally, orally or parenterally, for the above purposes. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually administered orally once to several times a day in the range of 1 mg to 1000 mg per adult. Alternatively, it is administered parenterally (preferably intravenously) once to several times a day in the range of 0.1 mg to 100 mg per adult. Of course, as mentioned above, the dosage varies depending on various conditions, so there may be cases where a smaller amount than the above dosage range is sufficient,
There are also cases where it is necessary beyond the scope.

When administering the compound of the present invention, solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories and the like are used. Solid compositions for oral administration include tablets, pills,
Includes capsules, powders, granules, etc. Capsules include hard capsules and soft capsules.

In such solid compositions, one or more active substances are present in at least one inert diluent, such as hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid. Mixed with magnesium aluminate. The composition may be prepared in accordance with conventional methods with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as fibrillar calcium glycolate, and solubility aids such as glutamic acid or aspartic acid. It may contain an agent. Tablets or pills may contain white sugar, gelatin,
It may be coated with a film of a gastric or enteric substance such as hydroxypropyl cellulose or hydroxypropyl methylcellulose phthalate, or it may be coated with two or more layers. Also included are capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents ( For example, purified water, ethanol) may be included. In addition to inert diluents, the compositions may also contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, aromatic agents, and preservatives.

Other compositions for oral administration include sprays containing one or more active substances and formulated in a manner known per se. In addition to inert diluents, the compositions may also contain stabilizers such as sodium bisulfite and isotonic buffers, such as sodium chloride, sodium citrate, or citric acid. Methods for producing spray agents are described, for example, in U.S. Pat. No. 2,868,691 and U.S. Pat.
It is described in detail in the specification of the issue.

Injections for parenteral administration according to the present invention include sterile aqueous or nonaqueous solutions, suspensions, and emulsions. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol.
Examples include alcohol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, and solubilizing agents (eg, glutamic acid, aspartic acid). These are, for example, bacteria retention filters.
Sterilization is achieved by filtration through filtration, incorporation of disinfectants, or irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

Other compositions for parenteral administration include external solutions containing one or more active substances and formulated in a conventional manner, liniments such as lozenges, and suppositories for rectal administration. and pessaries for intravaginal administration.

[0026]

[Reference Examples and Examples] The present invention will be explained in detail below with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in parentheses listed in the section for separation by chromatography indicates the developing solvent used, and the proportions indicate volume ratios. Further, IR was measured using the KBr tablet method, and NMR was measured using a heavy methanol solution.

Reference Example 1 N-Methyl-N-[2-[6-(2-tert-butoxycarbonylaminoacetoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[ 1,2
-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide hydrochloride

embedded image N-methyl-N-[2-(6-hydroxy-2,5,7
,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide hydrochloride (1.0
g), N-tert-butoxycarbonylglycine (
395 mg) and 4-dimethylaminopyridine (15
6 mg) was dissolved in dimethylformamide (5.0 ml). Methylene chloride (10.0 ml) was added to this solution, and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (472 mg) was added under ice cooling. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride (100ml). The mixture was washed with water and then with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:acetic acid:water=1
5:2:1) to obtain the title compound (427 mg) having the following physical properties. TLC (ethyl acetate:acetic acid:water=6:1:1):Rf=
0.35; NMR: δ 7.73-7.05 (m, 6H), 4
．． 10 and 4.07 (s, 2H, respectively), 3.77 (
m, 2H), 3.17 and 3.03 (s, 3H respectively)
), 2.68 (t, 2H), 2.10 (s, 3H)
, 2.01 (s, 6H), 1.46 (s, 9H),
1.32 (s, 3H).

Example 1 N-methyl-N-[2-(6-acetoxy-2,5,7
,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide hydrochloride

[Chem.15
] N-methyl-N-[2-(6-hydroxy-2,5,7
,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide hydrochloride (1.0
g) was dissolved in dimethylformamide (20ml). Pyridine (5.0 ml) and then acetyl chloride (0.40 ml) were added dropwise to the solution under ice cooling. 1 of the mixture
Stir for hours. Methanol was added to the reaction mixture under ice cooling, and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:methanol = 19:1 →
9:1) to obtain the title compound of the present invention (360 mg) having the following physical properties. TLC (ethyl acetate:acetic acid:water=6:1:1):Rf=
0.24; IR (cm-1): ν 3323, 2932, 17
52, 1678, 1648, 1600, 151
5, 1459, 1408, 1371, 1213,
1080, 828, 615.

Examples 1(a) to 1(o) Using appropriate benzo[1,2-b]pyran derivatives/hydrochlorides corresponding to appropriate acid chlorides, the procedure was repeated in the same manner as in Example 1. (In the case of salts other than hydrochloride, salt exchange was further performed) to obtain the compounds of the present invention shown in Table 3 below.

[0030]

[Table 3]

[0031]

[Table 4]

[0032]

[Table 5]

[0033]

[Table 6]

[0034]

[Table 7]

[0035]

[Table 8]

Example 2 N-methyl-N-[2-[6-(2-aminoacetoxy)-2,5,7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2- b]Pyran-2-yl]ethyl]-4-guanidinocinnamamide dihydrochloride

embedded image Benzopyran derivative produced in Reference Example 1 (760 mg)
was dissolved in ethanol (10 ml). Add a solution of hydrochloric acid in ethanol (2 ml) to the solution and bring the solution to 60
Warmed to ℃. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1→10:1) to obtain the title compound of the present invention (665 mg) having the following physical properties. TLC (chloroform: methanol: acetic acid = 6:1:1
): Rf=0.10; IR (cm-1): ν 3391, 2932, 17
65, 1677, 1647, 1599, 151
5, 1459, 1401, 1207, 1109,
911, 828, 612.

Example 2 (a) N-[2-[6-(2-aminoacetoxy)-2,5,
7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide dihydrochloride

embedded image N-methyl-N-[2-(6-hydroxy-2,5,7
,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide instead of hydrochloride, benzo[1,2- b] Using a pyran derivative, the compound was produced in the same manner as in Reference Example 1, and in the same manner as in Example 2, the title compound of the present invention having the following physical properties was obtained. TLC (ethyl acetate:acetic acid:water=6:1:1):Rf=
0.13; IR (cm-1): ν 3401, 1762, 16
57, 1626, 1600, 1570, 151
5, 1459, 1401, 1219, 1109,
1077, 823.

Example 2(b) N-methyl-N-[2-[6-(6-aminohexanoyl)oxy-2,5,7,8-tetramethyl-3,4-
Dihydro-2H-benzo[1,2-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide dihydrochloride

[Chemical formula 18] The procedure was carried out in the same manner as in Example 2 using a benzopyran derivative produced in the same manner as in Reference Example 1, using 6-tert-butoxycarbonylaminohexanoic acid in place of N-tert-butoxycarbonylglycine. As a result, the title compound of the present invention having the following physical properties was obtained. TLC (ethyl acetate:acetic acid:water=5:2:1):Rf=
0.25; IR (cm-1): ν 3361, 2940, 17
48, 1675, 1646, 1599, 151
5, 1456, 1412, 1379, 1253,
1162, 1120, 873, 829,
615.

Example 2(c) N-[2-[6-(6-aminohexanoyl)oxy-
2,5,7,8-tetramethyl-3,4-dihydro-2
H-benzo[1,2-b]pyran-2-yl]ethyl]
-4-Guanidinocinnamamide dihydrochloride

embedded image N-methyl-N-[2-(6-hydroxy-2,5,7
,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide instead of hydrochloride, benzo[1,2- b] Pyran, N-ter
6-ter instead of t-butoxycarbonylglycine
Using a benzopyran derivative produced using t-butoxycarbonylaminohexanoic acid in the same manner as in Reference Example 1, the title compound of the present invention having the following physical properties was prepared in the same manner as in Example 2. Obtained. TLC (ethyl acetate:acetic acid:water=3:1:1):Rf=
0.27; IR (cm-1): ν 3620 to 2500, 3
392, 2937, 1742, 1671, 16
26, 1599, 1569, 1515, 1458
, 1246, 1162, 1107.

Formulation Example The following ingredients were mixed in a conventional manner and then tableted to obtain 100 tablets each containing 50 mg of the active ingredient.・N-methyl-N-[2-(6-acetoxy-2,5,
7,8-tetramethyl-3,4-dihydro-2H-benzo[1,2-b]pyran-2-yl]ethyl]-4-guanidinocinnamamide hydrochloride...5
g. Cellulose calcium glycolate (disintegrant)
...0.2 g ・Magnesium stearate (lubricant)
...0.1 g ・Microcrystalline cellulose
...4.7 g

Claims (1)

[Claims] [Claim 1] General formula (I) [Formula 1] (wherein, R1 is i) -COR11, ii) -CO
(CH2)m R12, iii) -COOR13 or iv) -COO(CH2)n OR14, R
2 represents a hydrogen atom or a C1-4 alkyl group,
R11 represents a C1-4 alkyl group, and R12 is i
) -COOR15, ii) -NH2 or iii) -OR16, R13 represents a C1-4 alkyl group, and R14 represents a C1-4 alkyl group;
-4 alkyl group, R15 represents a C1-4 alkyl group, R16 represents a C1-4 alkyl group, m represents an integer of 1-5, and n represents an integer of 1-5. ) or its acid addition salt.