KR100500400B1 - Chalcone derivatives and drugs containing the same - Google Patents

Abstract

The present invention relates to a carcon derivative represented by the following general formula (1) or a derivative thereof and a medicine containing the same as an active ingredient.

[Wherein A represents a phenyl group, a quinolyl group, etc., W represents a vinyl group, etc., and R ₁ to R ₅ each represent a carboxy group, cyano group, alkyloxycarbonyl group, etc.]

Such compounds have excellent cys-LT receptor antagonism and are useful as antiallergic agents and the like.

Description

CHALCONE DERIVATIVES AND DRUGS CONTAINING THE SAME

The present invention relates to a carcon derivative having excellent cis-roycotriene receptor antagonism and a medicament containing the same.

Peptidolycotriene (LT) is a bioactive substance synthesized in animal tissue from eicosapolyenoic acid such as arachidonic acid, among which LTC ₄ , LTD ₄ , LTE ₄ are in vivo and in vitro. Is also known as an important causative agent of bronchial asthma (Henderson, WR, Jr. Ann. Intern. Med., 121, 684-697, 1994). In addition, the symptoms of these leukotrienes include airway contraction, mucus hypersecretion, pulmonary edema, and as a result, they cause airway disorders characteristic of asthma. The inhalation effect of LTC ₄ and LTD ₄ is 1000 times higher than that of histamine, and LTE ₄ is less active than other types of leukotrienes, but the resulting airway contraction is more persistent than others. (Larsen, JS, Acosta, EP Ann. Pharmacother, 27, 898-903, 1993).

As such, the biosynthetic pathways of leukotrienes and the role in diseases are evident, and thus the development of inhibitors of leukotrienes and antagonists to cis-LT receptors (cys-LT receptors) has become active. Metters, KM, J. Lipid Mediators Cell Signaling, 12, 413-427, 1995). In recent clinical reports, cys-LT receptor antagonists have been found to be extremely effective against various asthma (Taylor, IK, Thorax, 50, 1005-1010, 1995; Pauwels, RA, Joos, GF, Kips). JC Allergy, 30, 615-622, 1995).

However, the reality is that compounds with sufficiently satisfactory cys-LT receptor antagonism have not yet been found.

Accordingly, an object of the present invention is to provide a compound having high cys-LT receptor antagonism and a medicament containing the compound.

In view of the above facts, the present inventors have studied diligently to obtain a compound having a high cys-LT receptor antagonism. As a result, the novel compound represented by the following general formula (1) has a high cys-LT receptor antagonism. The present invention has been completed by discovering that it is also useful as a medicine.

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

[Wherein A is a substituted or unsubstituted phenyl group; Or a substituted or unsubstituted naphthyl group, or a group (Wherein X represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group, B represents -CH = CH-, -N (R ⁶ )-(wherein R ⁶ represents a lower alkyl group or a lower alkoxyalkyl group)) , -O- or -S-}.

W represents -CH = CH- or -CH ₂ O-,

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as or different from each other, and each hydrogen atom, halogen atom, hydroxy group, lower alkyl group, lower alkoxy group, carboxyl group, cyano group, alkyloxycarbonyl group, tetrazolyl group, The group -CONHR ⁷ (where R ⁷ represents a hydrogen atom lower alkyl group) or the group -O (CH ₂ ) nR ⁸ (where R ⁸ represents a carboxyl group, an alkyloxycarbonyl group or a tetrazolyl group, and n represents a number from 1 to 4) Provided that at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represents a carboxyl group, cyano group, alkyloxycarbonyl group, tetrazolyl group, -CONHR ⁷ or -O (CH ₂ ) nR ⁸ It is to provide a carcon derivative, a salt thereof or a solvate thereof.

The present invention also provides a medicament comprising the carcon derivative (1) and salts or solvates thereof as an active ingredient.

Furthermore, this invention provides the cys-LT receptor antagonist which uses a carcon derivative (1) and its salt or solvate as an active ingredient.

The present invention also provides an antiallergic agent comprising the carcon derivative (1) and salts or solvates thereof as an active ingredient.

The present invention also provides a pharmaceutical composition composed of a carcon derivative (1) and salts thereof or solvates thereof and a pharmacologically acceptable carrier.

The present invention also provides a method for treating allergic diseases, characterized by administering an effective amount of the carcon derivative (1) and salts or solvates thereof.

[Embodiment of the Invention]

In the carcon derivative represented by the general formula (1), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Moreover, as a lower alkyl group, a C1-C6 linear or branched alkyl group is preferable, As a specific example, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, n-hexyl group, etc. are mentioned as a preferable example, Among these, a methyl group, an ethyl group, and t-butyl group are especially preferable. The lower alkoxy group is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include methoxy group, ethoxy group, pulverized or branched propoxy group, butoxy group, pentyloxy group and hexyloxy group. Although, among these, a methoxy group, an ethoxy group, a propoxy group, butoxy group, etc. are preferable, and a methoxy group is especially preferable. As the lower alkoxyalkyl group, a C _1-6 alkoxyC _1-6 alkyl group is preferable, and as a specific example, methoxymethyl group, methoxyethyl group, methoxypropyl group methoxybutyl group, ethoxymethyl group, ethoxyethyl group, ethoxypropyl group, Ethoxybutyl group, a propoxymethyl group, a propoxyethyl group, a propoxypropyl group, a propoxybutyl group, etc. are mentioned, Among these, an ethoxyethyl group is especially preferable. Examples of the alkyloxycarbonyl group include C _1-6 alkyloxycarbonyl groups such as methyloxycarbonyl group, ethyloxycarbonyl group, propyloxycarbonyl group, and butyloxycarbonyl group, and ethyloxycarbonyl group is particularly preferable.

As a substituted or unsubstituted phenyl group or substituted or unsubstituted naphthyl group represented by A in General formula (1), the phenyl group which the halogen atom, lower alkyl group, or lower alkoxy group may be substituted; And a naphthyl group which may be substituted by a halogen atom, a lower alkyl group or a lower alkoxy group, but a phenyl group and a naphthyl group are particularly preferable. Examples of X include a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group and a lower alkoxy group, and among these, a hydrogen atom and a halogen atom are particularly preferable.

At least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ represents a carboxy group, cyano group, alkyloxycarbonyl group, tetrazolyl group, group -CONHR ⁷ or group -O (CH ₂ ) nR ⁸ , The remainder being the same or different from each other is a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxyl group, a cyano group, an alkyloxycarbonyl group, a tetrazolyl group, a group -CONHR ⁷ or a group -O (CH ₂ ) nR ⁸ Indicates. Here, in particular, one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is a carboxyl group, cyano group, alkyloxycarbonyl group, tetrazolyl group, group -CONHR ⁷ or -O (CH ₂ ) nR ⁸ , and the rest is The same or different ones are preferably a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group.

In addition, the group -O (CH ₂₎ represents the number of n of nR ⁸ is 1 to 4, and 1 or 2 are preferred, especially 1 is most preferred.

The salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmacologically acceptable salt. Examples thereof include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, manganese salt, iron salt and aluminum salt; Acid addition salts of mines such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; Or acid addition salts of organic acids such as benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartarate and citrate.

In addition, the compound (1) of the present invention may exist in the form of a solvate represented by a hydrate, but the solvate is also included in the present invention.

The compound (1) of the present invention may also exist in the form of tautomers of keto-enol tautomers, but such tautomers are also included in the present invention.

Compound (1) of the present invention can be produced, for example, by a method shown by the following reaction scheme.

(Wherein A, W, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as described above).

That is, the compound of the present invention is reacted by reacting the aldehyde derivative of Compound (2) with the acetophenone derivative of Compound (3) in a polar solvent such as methanol, ethanol, tetrahydrofuran or water in the presence of a base such as sodium hydroxide or potassium hydroxide. 1) can be obtained.

Compound (2) can be obtained by reacting a known hydroxybenzaldehyde with a chloromethylated aromatic compound when W is -CH ₂ O-. In addition, when W is -C = C-, it can obtain by condensing a known dialdehyde derivative of benzene and a methyl aromatic compound in presence of acetic anhydride.

In the compound (3), when R ¹ is a hydroxy group and one of the remaining R ² to R ⁵ is a carboxyl group or a cyano group, it can be obtained by a price potential from the acetyl derivative represented by the compound (4).

(Wherein R ¹ , R ² , R ³ , R ⁴ , or R ⁵ are as defined above).

In the compound (3), when ^one of R ¹ to R ⁵ is an alkyloxycarbonyl group or tetrazolyl group, it can be obtained from a carboxylic acid derivative or a nitrile derivative according to a known method. For example, a carboxylic acid derivative (wherein ^one of R ¹ to R ⁵ in the compound (3) is a carboxyl group) is refluxed with 5% sulfuric acid in alcohol to thereby correspond to an ester (R ¹ to R in the compound (3)). ^{One of 5} is an alkyloxycarbonyl group]. In addition, a nitrile derivative (where ^one of R ¹ to R ⁵ in the compound (3) is a cyano group) is reacted with sodium azide in the presence of ammonium chloride in DMF to thereby correspond to a tetrazole derivative (R ¹ in compound (3)). One of -R ⁵ is a tetrazolyl group].

In the case where ^one of R ¹ to R ⁵ in compound (3) is -OCH ₂ CO ₂ CH ₂ CH ₃ , a suitable hydroxyacetophenone derivative is one in which R ¹ to R ⁵ in compound (3) are hydroxy groups. It can obtain by alkylation by reaction with and chloroethyl acetate. In the compound (3), when ^one of R ¹ to R ⁵ is —OCH ₂ CN ₄ H, wherein CN ₄ H represents a tetrazolyl group, firstly, a suitable hydroxyacetophenone derivative and 2-bromoacetonitrile are used. Reacted with sodium azide in the presence of ammonium chloride in DMF, and wherein ^one of R ¹ to R ⁵ in the compound (3) is an alkoxy group by alkylating the hydroxyacetophenone derivative corresponding thereto. You can get it.

The compound (1) of the present invention can be obtained by the above method, but can be purified using conventional purification means such as recrystallization and column chromatography, if necessary. If necessary, the salt or solvate described above can also be converted by known methods.

Compound (1) of the present invention thus obtained and its salts or solvates thereof have excellent cys-LT receptor antagonism, as shown in Examples described later, and have asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, It is effective as a medicament for treating or preventing urticaria, psoriasis, rheumatism, inflammatory colitis, cerebral ischemia and stroke.

The medicament according to the present invention is composed of the above-described compound (1) and salts or solvates thereof as an active ingredient, and is not particularly limited in the dosage form, but may be appropriately selected depending on the therapeutic purpose. Oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, casts, and the like, and such dosage forms can be prepared according to methods known to those skilled in the art.

When preparing an oral solid preparation, an excipient, a binder, a disintegrating agent, a brightening agent, a coloring agent, a colliding agent, a odorant and the like are mixed with the compound (1) of the present invention, and the resulting mixture is purified by a conventional method. , Dragees, granules, powders, capsules and the like can be prepared. Such additives may be generally used in the art. Examples of excipients include lactose, white sugar, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, and the like. Ethanol, propanol, sweet syrup, glucose, starch, gelatin, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone Examples of disintegrating agents include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearate monoglycerol stearate, lactose, and the like. Borax, polyethyleneglycol, etc. are mentioned, As a copper, sucrose, a tangerine, a citric acid, a tartaric acid, etc. are mentioned. The can.

When preparing an oral liquid preparation, a copulation agent, a buffer, a stabilizer, a odor agent, etc. can be added to the compound (1) of the present invention, and an oral solution, a syrup, an elixir, etc. can be prepared according to a conventional method. In this case, the above-mentioned thing may be mentioned as a mating agent, sodium citrate etc. are mentioned as a buffer, Tragant, gum arabic, gelatin, etc. are mentioned as a stabilizer.

When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an isotonicity agent, a local anesthetic and the like can be added to the compound (1) of the present invention, and it can be prepared as a subcutaneous, intramuscular and intravenous injection according to a conventional method. In this case, sodium citrate, sodium acetate, sodium phosphate, and the like are used as pH adjusting agents and buffers, sodium pyrosulfite, EDTA, thioglycolic acid, thiouic acid and the like as stabilizers, and procaine hydrochloride, lidocaine hydrochloride, and the like as local anesthetics. Examples of the topical agent include sodium chloride and glucose.

When preparing a suppository, the compound (1) of the present invention is formulated with a carrier for a preparation known in the art, for example, polyethylene glycol, lanolin, cacao fat, fatty acid triglyceride, and the like. After adding surfactant, such as), it can manufacture according to a conventional method.

When preparing an ointment, the base, stabilizer, wetting agent, preservative, etc. which are normally used for the compound (1) of this invention are mix | blended as needed, and it mixes and formulates by a conventional method. Examples of the base include liquid paraffin, white petrolatum, mercury, octyldodecyl alcohol, paraffin, and the like, and methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl paraoxybenzoate, and the like as a preservative.

In addition to the above, inhalants, eye drops, and nasal drops can be prepared according to conventional methods.

The dosage of the medicine of the present invention varies depending on age, weight, symptoms, dosage form, frequency of administration, etc., but in general, in adults, it is preferable to administer orally or parenterally administer 1 to 1000 mg once or several times a day. .

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to these examples.

Preparation Example 1

Synthesis of 4- (2-quinolylmethoxy) benzaldehyde

A mixture of 6.42 g (0.03 mol) of 2-chloromethylquinoline hydrochloride, 3.66 g (0.03 mol) of 4-hydroxybenzaldehyde and 9.12 g (0.066 mol) of anhydrous potassium carbonate was dissolved in 50 ml of DMF and heated at 90 ° C. overnight. . The reaction solution was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with 1N NaOH and saturated brine, dried over sodium sulfate, and distilled under reduced pressure to obtain 7.11 g (yield 91%) of the title compound.

Melting Point: 81.0 ~ 82.1 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.41 (2H, s, CH ₂ O), 7.10 (2H, d, J = 8.7 Hz, H3, H5),

       7.47-7.51 (1H, m, H6-quinoline), 7.58 (1H, d, J = 8.5 Hz, H3-quinoline),

       7.67-7.71 (1H, m, H7-quinoline), 7.74-7.79 (1H, m, H5-quinoline),

       7.79 (2H, d, J = 8.7 Hz, H2, H6), 8.07 (1H, d, J = 8.3 Hz, H8-quinoline),

       8.15 (1H, d, J = 8.5 Hz, H4-quinoline), 9.86 (1H, s, ArCHO).

Preparation Example 2

Synthesis of 3- (2-quinolylmethoxy) benzaldehyde

In the same manner as in Production Example 1, the title compound was obtained from 3-hydroxybenzaldehyde.

Melting Point: 55.1∼57.1 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.35 (2H, s, CH ₂ O), 7.20 (1H, m, H 4),

       7.36-7.47 (3H, m, H5-quinoline, H6-quinoline, H5),

       7.64-7.69 (1H, m, H7-quinoline), 7.72-7.76 (1H, m, H6),

       8.01 (1H, d, J = 8.3 Hz, H8-quinoline), 8.11 (1H, d, J = 8.5 Hz, H4-quinoline),

       9.87 (1 H, s, ArCHO).

Preparation Example 3

Synthesis of 2- (2-quinolylmethoxy) benzaldehyde

In the same manner as in Production Example 1, the title compound was obtained from 2-hydroxybenzaldehyde.

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.48 (2H, s, CH ₂ O), 7.06 (1H, d, J = 8.4 Hz, H3),

       7.45-7.58 (2H, m, H5, H6-quinoline), 7.64 (1H, d, J = 8.5 Hz, H3-quinoline),

       7.69-7.88 (4H, m, H5-quinoline, H7-quinoline, H4, H6),

       8.20 (1H, d, J = 8.5 Hz, H4-quinoline), 8.30 (1H, d, J = 8.3 Hz, H8-quinoline),

       10.64 (1H, s, ArCHO).

Preparation Example 4

Synthesis of 4-[(7-chloro-2-quinoline) methoxy] benzaldehyde

The title compound was obtained from 7-chloro-2-chloromethylquinoline in the same manner as in Preparation Example 1.

Melting Point: 130 ~ 133 ℃

Preparation Example 5

Synthesis of 4- [1- (2-benzothiazolyl) methoxy] benzaldehyde

The title compound was obtained from 2-chloromethyl-1-benzothiazole in the same manner as in Preparation Example 1.

Melting Point: 135 ~ 137 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.57 (2H, s, CH ₂ O), 7.16 (1H, d, J = 8.8 Hz, H3, H5),

       7.35-7.57 (2H, m, H5-benzothiazole, H6-benzothiazole),

      7.87 (2H, d, J = 8.8 Hz, H2, H6), 7.91 (1H, d, J = 8.3 Hz, H4-benzothiazole),

       8.06 (1H, doublet, J = 8.8 Hz, H7-benzothiazole), 9.90 (1H, s, CHO).

Preparation Example 6

Synthesis of 4- [1- (1-methyl-2-benzimidazolyl) -methoxy] benzaldehyde

The title compound was obtained from 2-chloromethyl-1-methylbenzidazole in the same manner as in Production Example 1.

Melting Point: 140 ~ 142 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.48 (2H, s, CH ₂ O), 7.14-7.42 (5H, m, Ar-H), 7.71-7.90 (3H, m, Ar-H),

       9.88 (1 H, s, CHO).

Preparation Example 7

Synthesis of 4- [1- (1-ethoxyethyl-2-benzimidazolyl) methoxy] benzaldehyde

The title compound was obtained from 2-chloromethyl-1-ethoxyethylbenzimidazole in the same manner as in Production Example 1.

Melting Point: 96 ~ 97 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

1.10 (3H, t, J = 6.8 Hz, OCH ₂ CH ₃ ), 3.29 (2H, q, J = 6.8 Hz, OCH ₂ CH ₃ ),

3.75 (2H, t, J = 5.4 Hz, NCH ₂ CH ₂ O), 4.49 (2H, t, J = 5.4 Hz, NCH ₂ CH ₂ O),

5.57 (2H, s, CH ₂ O), 7.14-7.47 (5H, m, Ar-H), 7.74-7.89 (3H, m, Ar-H),

       9.89 (1 H, s, CHO).

Preparation Example 8

Synthesis of 3-benzyloxybenzaldehyde:

In the same manner as in Production Example 1, the title compound was obtained from benzyl bromide.

Melting Point: 50.8∼52.2 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.11 (2H, s, CH ₂ O), 7.21-7.47 (10H, m, Ar-H), 9.96 (1H, s, CHO).

Preparation Example 9

Synthesis of 4-benzyloxybenzaldehyde

The title compound was obtained from benzyl bromide in the same manner as in Preparation Example 1.

Melting Point: .70.0 ~ 71.8 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.14 (2H, s, CH ₂ O), 7.05 (2H, d, J = 8.8 Hz, H3, H5),

       7.33-7.45 (5H, m, Ph), 7.83 (2H, d, J = 8.8 Hz, H2, H6),

       9.87 (1 H, s, CHO).

Preparation Example 10

Synthesis of 3- (2-naphthylmethoxy) benzaldehyde

The title compound was obtained from 2-chloromethylnaphthalene in the same manner as in Preparation Example 1.

Melting Point: 107 ~ 110 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.29 (2H, s, CH ₂ O), 7.22-7.32 (1H, m, Ar-H), 7.41-7.59 (6H, m, Ar-H),

       7.80-7.92 (4H, m, Ar-H), 9.98 (1H, s, CHO).

Preparation Example 11

Synthesis of 4- (2-naphthylmethoxy) benzaldehyde

The title compound was obtained from 2-chloromethylnaphthalene in the same manner as in Preparation Example 1.

Melting Point: 106 ~ 108 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.31 (2H, s, CH ₂ O), 7.12 (2H, d, J = 8.8 Hz, H3, H5),

       7.42-7.58 (3H, m, Ar-H), 7.76-7.92 (6H, m, Ar-H), 9.89 (1H, s, CHO).

Preparation Example 12

Synthesis of 4- [2- (2-quinolyl) ethenyl] benzaldehyde

30 g (0.22 mol) of 1,4-benzenedialdehyde, 21 g (0.15 mol) of 2-methylquinoline, and 41.5 ml (0.40 mol) of acetic anhydride were dissolved in 160 ml of xylene and heated to reflux for 7 hours. After cooling the reaction liquid to room temperature, 200 ml of petroleum ether was added, and the precipitate was filtered off. The mother liquor was further concentrated under reduced pressure, and the residue was recrystallized from ether to obtain 13.6 g (yield 35%) of the title compound.

Melting Point: 111.9 ~ 113.0 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

       7.46-7.51 (2H, m, Ar-H), 7.54-7.80 (6H, m, Ar-H, H-olefin),

       7.87-7.91 (2H, m, Ar-H), 8.08 (1H, d, J = 8.4 Hz, Ar-H),

       8.14 (1H, doublet, J = 8.6 Hz, H4-quinoline), 10.00 (1H, s, CHO).

Preparation Example 13

Synthesis of 4- [2- (7-chloro-2-quinolyl) ethenyl] benzaldehyde

The title compound was obtained from 7-chloro-2-methylquinoline in the same manner as in Preparation Example 12.

Melting Point: 178 ~ 180 ℃

Preparation Example 14

Synthesis of 3- [2- (2-quinolyl) ethenyl] benzaldehyde

The title compound was obtained from 2-methylquinoline in the same manner as in Preparation Example 12.

Melting Point: 78.6 ~ 80.8 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

       7.42-7.89 (9H, m, Ar-H, H-olefin), 8.05-8.16 (3H, m, Ar-H),

       10.04 (1H, s, CHO).

Preparation Example 15

Synthesis of 2-hydroxy-5- (5-tetrazolyl) acetophenone

A mixture of 2.0 g (12.4 mmol) of 5-cyano-2-hydroxyacetophenone, 4.1 g (62 mmol) of sodium azide and 3.35 g (62 mmol) of ammonium chloride was dissolved in 35 mL of DMF, and 100 It heated at ° C for 3 days. The reaction solution was poured into water, the pH was adjusted to 5, and extracted with ethyl acetate. After drying the organic layer with Na ₂ SO ₄ , the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 1.42 g (yield 56%) of the title compound.

Melting Point: 181.8 ~ 184.9 ℃

¹ H-NMR (DMSO) δ (ppm):

       7.42-7.89 (9H, m, Ar-H, H-olefin), 8.05-8.16 (3H, m, Ar-H),

       10.04 (1H, s, CHO).

Preparation Example 16

Synthesis of 5-bromo-3-carboxy-2-hydroxyacetophenone

1) To a mixture of 100 g (0.46 mol) of 5-bromosalicylic acid and 105 ml of acetic anhydride, 0.5 ml of concentrated sulfuric acid was added while stirring. After a few minutes, 1000 ml of water was added, and the precipitate was obtained by filtration and washed with water. The white material obtained by filtration was dissolved in 1000 ml of ethyl acetate, washed with saturated brine (2 x 300 ml), dried over sodium sulfate, distilled under reduced pressure and 105 g of 2-acetyloxy-5-bromobenzoic acid as white crystals. (Yield 88%) was obtained.

Melting Point: 199 ~ 203 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

2.26 (3H, s, CH ₃ CO ₂ Ar), 7.20 (1H, d, J = 8.6 Hz, H3),

       7.84 (1H, doublet of doublets, J = 2.6, 8.6 Hz, H4), 8.03 (1H, d, J = 2.6 Hz, H6).

2) A mixture of 100 g (0.39 mol) of 2-acetyloxy-5-bromobenzoic acid and 159 g (1.20 mol) of aluminum chloride was placed in a three neck flask and heated to 160 ° C. while stirring with a stirrer. After 3 hours, the reaction solution was cooled to room temperature and poured into 800 g of ice water containing 200 ml of concentrated hydrochloric acid. The slurry was extracted with ethyl acetate (3 × 350 mL), washed with 1N hydrochloric acid (3 × 200 mL), saturated brine (400 mL), dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was diluted with dichloromethane. The product was washed to remove by-products, and filtered to obtain 36.4 g (yield 36%) of the title compound as a brown powder.

Melting Point: 200.1 ℃

¹ H-NMR (DMSO) δ (ppm):

2.59 (3H, s, CH ₃ CO), 7.92 (1H, d, J = 2.7 Hz, H4),

8.01 (1H, doublet, J = 2.7 Hz, H6), 11.64 (1H, brs, ArOH, ArCO ₂ H).

Preparation Example 17

Synthesis of 3-carboxy-5-chloro-2-hydroxyacetophenone

In the same manner as in Production Example 16, the title compound was obtained.

Melting Point: 173.7 ~ 175.8 ℃

¹ H-NMR (DMSO) δ (ppm):

2.59 (3H, s, CH ₃ CO), 7.92 (1H, d, J = 2.7 Hz, H4),

8.01 (1H, doublet, J = 2.7 Hz, H6), 11.64 (1H, brs, ArOH, ArCO ₂ H).

Preparation Example 18

Synthesis of 3-carboxy-5-fluoro-2-hydroxyacetophenone

In the same manner as in Production Example 16, the title compound was obtained.

Melting Point: 156.8 ~ 159.2 ℃

¹ H-NMR (DMSO) δ (ppm):

2.59 (3H, s, CH ₃ CO), 7.92 (1H, d, J = 2.7 Hz, H4),

8.01 (1H, doublet, J = 2.7 Hz, H6), 11.64 (1H, brs, ArOH, ArCO ₂ H).

Preparation Example 19

Synthesis of 3-carboxy-2-hydroxy-5-methylacetophenone

The title compound was obtained in the same manner as in Production Example 16.

Melting Point ： 122.2-125.8 ° C

¹ H-NMR (DMSO) δ (ppm):

2.32 (3H, s, ArCH ₃ ), 2.67 (3H, s, COCH ₃ ), 7.77 (1H, d, J = 2.3 Hz, H3 / 5),

8.05 (1H, doublet, J = 2.3 Hz, H3 / 5), 9.25 (1H, brs, CO ₂ H),

       13.45 (1H, broad singlet, ArOH).

Preparation Example 20

Synthesis of 3-carboxy-2-hydroxyacetophenone

Dissolve 10.0 g (38.6 mmol) of 5-bromo-3-carboxy-2-hydroxyacetophenone in 75 ml of ethanol, add 1.0 g of 10% Pd / C, and carry out contact reduction at room temperature under hydrogen stream for 2 hours. did. The catalyst was filtered off and the filtrate was neutralized with 2N NaOH. After removing the solvent, the residue white material was dissolved in 1N NaOH, and 3N HCl was added, and the resulting precipitate was filtered to give 6.8 g (yield 98%) of the title compound as a white solid.

Melting Point: 131.8 ~ 133.0 ℃

¹ H-NMR (DMSO) δ (ppm):

2.63 (3H, s, CH ₃ COAr), 7.03 (1H, t, J = 7.8 Hz, H5),

       7.94 (1H, doublet of doublets, J = 1.8, 7.8 Hz, H4), 8.03 (1H, doublet of doublets, J = 1.8, 7.8 Hz, H6).

Preparation Example 21

Synthesis of 5-t-butyl-3-ethoxycarbonyl-2-hydroxyacetophenone

10 g (60 mmol) of ethyl salicylate was dissolved in 50 mL of dichloromethane, and 11.75 g (88 mmol) of anhydrous aluminum chloride was added, followed by dropping 5.6 g (60 mmol) of t-butyl chloride. After stirring at room temperature for 3 hours, 14.8 g (120 mmol) of acetylbromide was slowly added. After stirring overnight, the reaction solution was poured into ice water containing 3M hydrochloric acid. The reaction mixture was extracted with ethyl acetate, distilled under reduced pressure to remove the solvent, and the residue was purified by column chromatography (ethyl acetate / petroleum ether = 1/20) to obtain 7.20 g (yield 45%) of the title compound.

Melting Point: 63.5 ~ 65.3 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

1.24 (9H, s, C (CH ₃ ) ₃ ), 1.36 (3H, t, J = 7.1 Hz, CO ₂ CH ₂ CH ₃ ),

2.62 (3H, s, COCH ₃ ), 4.36 (2H, q, J = 7.1 Hz, CO ₂ CH ₂ CH ₃ ),

       7.93 (1H, d, J = 2.7 Hz, H4), 7.98 (1H, d, J = 2.7 Hz, H6).

Preparation Example 22

Synthesis of 3-cyano-5-chloro-2-hydroxyacetophenone

50 g (0.35 mol) of 2-amino-4-chlorophenol was dissolved in 500 ml of 2.5N HCl, cooled to 0 ° C, and 50 ml of 25.25 g (0.37 mol) of sodium nitrite solution was slowly added. After stirring for 30 minutes, 100 ml of cooled potassium iodide 70 g (0.42 mol) in water solution was slowly added. The reaction solution was raised to room temperature and stirred overnight. The reaction solution was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure to obtain 89.7 g (yield 99%) of 4-chloro-2-yodophenol. Subsequently, 85 g (0.33 mol) of 4-chloro-2-iodophenol and 32.5 g (0.36 mol) of copper cyanide were dissolved in 150 ml of DMF, heated and refluxed for 2 hours, and then the DMF was distilled off under reduced pressure. Extracted with and washed. The insolubles were removed by filtration, and the solvent was distilled off under reduced pressure to obtain 40.4 g of 5-chloro-2-hydroxybenzonitrile (yield 80%) (melting point: 150.3 to 152.6 ° C). Subsequently, 39.25 g (0.25 mol) of 5-chloro-2-hydroxybenzonitrile were dissolved in 40 ml of acetic anhydride, and 0.5 ml of concentrated sulfuric acid was added. The reaction solution was heated to 60 ° C. for 10 minutes, and then water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with 1N NaOH and saturated brine, dried over Na ₂ SO _4, and then the solvent was distilled off under reduced pressure to obtain 45 g (yield 92%) of 2-acetoxy-5-chlorobenzonitrile. Subsequently, a mixture of 44 g (0.23 mol) of 2-acetoxy-5-chlorobenzonitrile and 99 g (0.75 mol) of aluminum chloride was heated at 160 ° C. for 3 hours. The reaction solution was cooled to room temperature, poured into ice water containing 100 ml of concentrated hydrochloric acid, the slurry was extracted with ethyl acetate (3 x 350 ml), 1N hydrochloric acid (3 x 200 ml) and saturated brine (400 ml). After washing and drying over sodium sulfate, the solvent was distilled off under reduced pressure, the residue was washed with dichloromethane to remove by-products, and filtered to obtain 16.5 g (yield 38%) of the title compound as a brown powder.

Melting Point: 137.9 ~ 139.8 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

2.72 (3H, s, COCH ₃ ), 8.21 (1H, d, J = 2.5 Hz, H4 / 6),

       8.32 (1H, doublet, J = 2.5 Hz, H4 / 6), 12.77 (1H, brs, ArOH).

Preparation Example 23

Synthesis of 5-chloro-2-hydroxy-3- (5-tetrazolyl) acetophenone

In the same manner as in Production Example 15, the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm):

2.72 (3H, s, COCH ₃ ), 8.21 (1H, d, J = 2.5 Hz, H4 / 6),

       8.32 (1H, doublet, J = 2.5 Hz, H4 / 6), 12.77 (1H, brs, ArOH).

Preparation Example 24

Synthesis of Methyl 3-acetyl-4-methoxybenzoate

3.60 g (20 mmol) of 3-acetyl-4-hydroxybenzoic acid and 5.68 g (40 mmol) of methyl iodide were dissolved in 60 mL of DMF, and 11.06 g (80 mmol) of potassium carbonate was added thereto to obtain 2 at room temperature. It stirred for hours. DMF was distilled off under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from acetone-hexane to give 1.42 g (yield 34%) of the title compound as a brown powder.

Melting Point: 83 ~ 85 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

2.62 (3H, s, COCH ₃ ), 3.90 (3H, s, CO ₂ CH ₃ ), 3.98 (3H, s, OCH ₃ ),

       7.02 (1H, doublet, J = 8.8 Hz, H5), 8.16 (1H, dd, J = 2.0, 8.8 Hz, H6).

       8.40 (1H, doublet, J = 2.0 Hz, H2).

Preparation Example 25

Synthesis of 3-acetyl-5-chloro-4-hydroxybenzoic acid

10.16 g (56 mmol) of 3-chloro-4-hydroxybenzoic acid hemihydrate was dissolved in 20 ml of acetic anhydride, 0.5 ml of concentrated sulfuric acid was added, the mixture was stirred at 100 ° C for 3 hours, and then allowed to stand at room temperature overnight. The precipitate was obtained by filtration and washed with benzene to obtain 8.95 g (yield 75%) of 4-acetoxy-3-chlorobenzoic acid (melting point: 149-151 占 폚). Subsequently, a mixture of 8.95 g (41.7 mmol) of 4-acetoxy-3-chlorobenzoic acid and 22.23 g (167 mmol) of aluminum chloride was heated at 180 ° C. for 3 hours. After adding ice and 1N hydrochloric acid, the mixture was extracted with ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized with ethyl acetate to give 2.97 g of the title compound as a yellow powder. Yield 33%).

¹ H-NMR (CD ₃ OD) δ (ppm):

2.73 (3H, s, COCH ₃ ), 8.17 (1H, d, J = 2.0 Hz, H2 / 6),

       8.48 (1H, doublet, J = 2.0 Hz, H2 / 6).

Preparation Example 26

Synthesis of 4-acetyl-hydroxybenzoic acid

0.2 ml of concentrated sulfuric acid was added to 10 ml of 10.07 g (72.9 mol) of 3-hydroxybenzoic acid anhydrous acetic anhydride, and the mixture was stirred at 60 ° C for 1 hour, and then left at room temperature overnight. The precipitate was obtained by filtration, washed with benzene and air dried. Recrystallization with acetone-hexane gave 8.92 g (yield 67.9%) of colorless crystals of 3-acetoxybenzoic acid (melting point: 149-151 캜). Next, a mixture of 8.92 g (49.5 mmol) of 3-acetoxybenzoic acid and 26.33 g (198 mmol) of aluminum chloride was heated at 160 ° C. for 3 hours. After adding ice and 1N hydrochloric acid, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 1.61 g of the title compound as pale yellow powder. Yield 18%) was obtained.

Melting Point: 204 ~ 205 ℃

¹ H-NMR (CDCl ₃ -DMSO) δ (ppm):

2.70 (3H, s, COCH ₃ ), 7.52 (1H, dd, J = 2.0, 8.8 Hz, H6),

       7.54 (1H, d, J = 2.0 Hz, H2), 7.87 (1H, d, J = 8.8 Hz, H5),

       12.07 (1 H, s, OH).

Preparation Example 27

Synthesis of n-butyl 3-acetyl-4-butoxybenzoate

The title compound was obtained in the same manner as in Production Example 24.

Melting Point: 39 ~ 40 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

0.97 (3H, t, J = 6.8 Hz, CH ₂ CH ₂ CH ₂ C H ₃ ),

1.01 (3H, t, J = 6.8 Hz, CH ₂ CH ₂ CH ₂ C H ₃ ),

1.35-1.96 (8H, m, OCH ₂ C H ₂ C H ₂ CH ₃ , CO ₂ CH ₂ C H ₂ C H ₂ CH ₃ ),

2.64 (3H, s, COCH ₃ ), 4.13 (2H, t, J = 6.8 Hz, CO ₂ C H ₂ CH ₂ CH ₂ CH ₃ ),

4.30 (2H, t, J = 6.8 Hz, OC H ₂ CH ₂ CH ₂ CH ₃ ), 6.99 (1H, d, J = 8.8 Hz, H5),

       8.13 (1H, doublet of doublets, J = 2.5, 8.8 Hz, H6), 8.39 (1H, d, J = 2.5 Hz, H2).

Preparation Example 28

Synthesis of 3- [1- (1-ethoxyethylbenzimidazol-2-yl) methoxy] benzaldehyde

In the same manner as in Production Example 1, the title compound was obtained.

Melting Point: 98 ~ 100 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

1.10 (3H, t, J = 6.8 Hz, OCH ₂ C H ₃ ), 3.39 (2H, q, J = 6.8 Hz, OC H ₂ CH ₃ ),

3.76 (2H, t, J = 5.4 Hz, NCH ₂ C H ₂ ), 4.49 (2H, t, J = 5.4 Hz, NC H ₂ CH ₂ ),

5.52 (2H, s, CH ₂ O), 7.23-7.53 (6H, m, Ar-H),

       7.58 (1H, d, J = 1.0 Hz, Ar-H), 7.74-7.83 (1H, m, Ar-H),

       9.98 (1 H, s, CHO).

Preparation Example 29

Synthesis of 3-acetyl-4-hydroxy-5-methylbenzoic acid

1) A mixture liquid of 10.89 g (58 mmol) of 4-bromocresol and 50 ml of NMP solution of 10.39 g (116 mmol) of cyanide was stirred at 190 ° C for 2 hours. Subsequently, 43 g of FeCl ₃ · 6H ₂ O, 65 mL of water, and 11 mL of concentrated hydrochloric acid were added to the reaction solution, which was stirred at 80 ° C. for 30 minutes and then cooled. Water and ethyl acetate were added to the reaction mixture, the organic phase was dried over Na ₂ SO ₄ , distilled under reduced pressure, and the residue was purified by column chromatography (chloroform / methanol: 40/1) to give a dark brown oil, 4-cyano. 10.32 g of cresol were obtained.

2) 80 ml of 50% sodium hydroxide was heated to reflux overnight in 100 ml of 10.32 g of ethanol solution of 4-cyanocresol. Concentrated hydrochloric acid was added to acidify the reaction solution, and the precipitated crystals were collected by filtration, washed, and dried to give 5.91 g (yield 66.9%) of 4-hydroxy-3-methylbenzoic acid as a white powder.

Melting Point: 164∼165 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

2.16 (3H, s, CH ₃ ), 6.81 (1H, d, J = 8.3 Hz, H6),

       7.60 (1H, dd, J = 2.0, 8.1 Hz, H5), 7.66 (1H, d, J = 1.2 Hz, H3),

       9.47 (1H, broad singlet, COOH).

3) 16.8 mL (178 mmol) of acetic anhydride was added to 50 mL of a pyridine solution of 5.42 g (35.6 mmol) of 4-hydroxy-3-methylbenzoic acid. The mixture was stirred at room temperature overnight, and the reaction solution was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with 2N hydrochloric acid and saturated brine, dried over Na ₂ SO ₄ , distilled off the solvent under reduced pressure, recrystallized with ethyl acetate-hexane, and 4-acetoxy-3-methyl as white powder. 3.64 g (yield 52.6%) of benzoic acid were obtained.

Melting Point: 153 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

2.25 (3H, s, C5-CH ₃ ), 2.36 (3H, s, CH ₃ COO),

       7.13 (1H, d, J = 8.3 Hz, H3), 7.97 (1H, ddd, J = 0.7, 1.7, 8.3 Hz, H2),

       8.01 (1H, doublet of doublets, J = 0.7, 1.7 Hz, H6).

4) A mixture of 3.01 g (15.5 mmol) of 4-acetoxy-3-methylbenzoic acid and 8.27 g (62 mmol) of aluminum chloride was slowly heated to 160 ° C. After 3 hours, the reaction solution was poured into ice water, and the precipitated crystals were extracted with ethyl acetate. The organic layer was washed, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and recrystallized from ethyl acetate-hexane to give 1.78 g (yield 59.3%) of the title compound as a brown powder.

Melting Point: 215 ~ 218 ℃

¹ H-NMR (DMSO-d ₆ ) δ (ppm):

2.23 (3H, t, J = 0.7 Hz, C5-CH ₃ ), 2.67 (3H, s, CH ₃ CO),

       7.95 (1H, td, J = 0.7, 2.2 Hz, H6), 8.30 (1H, dd, J = 0.7, 2.2 Hz, H2).

Example 1

Synthesis of 5'-carboxy-2'-hydroxy-4-[(2-quinolyl) methoxy] carcon

A mixture of 2.63 g (10 mmol) of 4- (2-quinolylmethoxy) benzaldehyde and 1.80 g (10 mmol) of 5-carboxy-2-hydroxyacetophenone was dissolved in 50 mL of ethanol and 25% KOH aqueous solution 25 ML was added and stirred for 1 week at room temperature. The reaction solution was poured into ice water, acidified by addition of 3N HCl, the precipitate was collected by filtration, washed, and then recrystallized from ethanol-DMF to give 1.28 g (yield 30%) of the title compound as a yellow powder.

Melting Point: 242.7 ~ 246.7 ℃

¹ H-NMR (DMSO) δ (ppm):

5.47 (2H, s, CH ₂ O), 7.10 (1H, d, J = 8.7 Hz, H3 '),

       7.16 (2H, d, J = 8.8 Hz, H3, H5), 7.61-7.65 (1H, m, H6-quinoline),

       7.69 (1H, d, J = 8.5 Hz, H3-quinoline), 7.77 (1H, d, J = 15.6 Hz, Hα),

       7.77-7.82 (1H, m, H7-quinoline), 7.81 (1H, d, J = 15.6 Hz, Hβ),

       7.88 (2H, d, J = 8.8 Hz, H2, H6), 8.00 (1H, d, J = 8.2 Hz, 5H-quinoline),

      8.03-8.05 (2H, m, H4 ', H8-quinoline), 8.43 (1H, d, J = 8.5 Hz, H4-quinoline),

       8.55 (1H, doublet, J = 2.1 Hz, H6 ').

Hereinafter, the compound shown in Table 1 was obtained by the method similar to Example 1.

TABLE 1

Example Compound people Melting Point (℃)  2  5'-carboxy-2'-hydroxy-3-[(2-quinolyl) methoxy] carcon 190.6-192.4  3  5'-carboxy-2'-hydroxy-2-[(2-quinolyl) methoxy] carcon 168.9-169.1  4  4-benzyloxy-5'-carboxy-2'-hydroxycarcon 212.1-215.3  5  3-benzyloxy-5'-carboxy-2'-hydroxycarcon 103.4-104.9  6  2-benzyloxy-5'-carboxy-2'-hydroxycarcon 172.1-175.5  7  3'-carboxy-2'-hydroxy-4-[(2-quinolyl) methoxy] carcon 232.9-235.3  8  3'-carboxy-5'-fluoro-2'-hydroxy-4-[(2-quinolyl) methoxy] carcon 219.5-220.3  9  3'-carboxy-5'-fluoro-2'-hydroxy-4-[(2-quinolyl) methoxy] carcon 222.1-222.5 10  3'-carboxy-5'-chloro-2'-hydroxy-3-[(2-quinolyl) methoxy] carcon 175-177 (d) 11  5'-bromo-3'-carboxy-2'-hydroxy-4-[(2-quinolyl) methoxy] carcon 233.7-234.2 12  4'-carboxy-2'-hydroxy-4-[(2-quinolyl) methoxy] carcon 228-231 (d) 13  4'-carboxy-2'-hydroxy-3-[(2-quinolyl) methoxy] carcon 233-234 (d) 14  4'-carboxy-4- [1- (1-ethoxyethylbenzimidazol-2-yl) methoxy] -2'-hydroxycarcon 222-225 (d) 15  2'-carboxy-4-[(2-quinolyl) methoxy] carcon 238-240 (d) 16  2'-carboxy-3-[(2-quinolyl) methoxy] carcon 131-134

Example 17

Synthesis of 5'-ethoxycarbonyl-2'-hydroxy-4-[(2-quinolyl) methoxy] carcon

A mixture of 0.527 g (2 mmol) of 4- (2-quinolylmethoxy) benzaldehyde and 0.416 g (2 mmol) of 5-ethoxycarbonyl-2-hydroxyacetophenone was added to 25 ml of an ethanol solution of 7% KOH. It dissolved in and stirred at room temperature for 1 week. The reaction solution was poured into iced water, acidified by addition of 3N HCl, the precipitate was obtained by filtration, washed with water, and recrystallized with ethanol-DMF to obtain 0.499 g (yield 55%) of the title compound.

Melting Point: 167.7∼168.1 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

4.41 (2H, q, J = 7.1 Hz, CO ₂ CH ₂ CH ₃ ), 5.46 (2H, s, CH ₂ O),

       7.04 (1H, d, J = 8.7 Hz, H3 '), 7.11 (2H, d, J = 8.7 Hz, H5),

7.41 (3H, t, J = 7.1 Hz, CO ₂ CH ₂ CH ₃ ), 7.56-7.59 (1H, m, H6-quinoline),

       7.60 (1H, d, J = 15.3 Hz, Hα), 7.66-7.68 (1H, m, H7-quinoline),

       7.67 (2H, d, J = 8.7 Hz, H2, H6), 7.74-7.78 (1H, d, m, H5-quinoline),

       7.84 (1H, d, J = 8.1 Hz, H8-quinoline), 7.94 (1H, d, J = 15.3 Hz, Hβ),

      8.10 (1H, d, J = 8.5 Hz, H3-quinoline), 8.15 (1H, dd, J = 2.0, 8.7 Hz, H4 '),

       8.22 (1H, d, J = 8.5 Hz, H4-quinoline), 8.65 (1H, d, J = 2.0 Hz, H6 '),

       13.44 (1H, s, ArOH).

Hereinafter, the compound shown in Table 2 and Table 3 was obtained by the method similar to Example 17.

TABLE 2

Example Compound people Melting Point (℃) 18  5'-cyano-2'-hydroxy-4-[(2-quinolyl) methoxy] carcon 192.6-193.8 19  2'-hydroxy-4-[(2-quinolyl) methoxy] -5 '-(5-tetrazolyl) carcon 232.7-233.3 20  2'-hydroxy-3-[(2-quinolyl) methoxy] -5 '-(5-tetrazolyl) carcon 228.4-229.9 21  5'-carboxy-3'-chloro-2'-hydroxy-4-[(2-quinolyl) methoxy] -carcon 234-245 (d) 22  2'-hydroxy-4- [1- (1-methyl-2-benzimidazolyl) methoxy] -5 '-(5-tetrazolyl) carcon 248-250 23  4- [1- (1-ethoxyethyl group-2-benzimidazolyl) methoxy) -2'-hydroxy-5 '-(5-tetrazolyl) carcon 234-236 (d) 24  4- [1- (2-benzothiazolyl) methoxy] -2'-hydroxy-5 '-(5-tetrazolyl) carcon 244-247 (d) 25  2'-hydroxy-3- (2-naphthylmethoxy) -5 '-(5-tetrazolyl) carcon 217-218 (d) 26  2'-hydroxy-4- (2-naphthylmethoxy) -5 '-(5-tetrazolyl) carcon 256-258 (d) 27  4-[(7-chloro-2-quinolyl) methoxy] -2'-hydroxy-5 '-(5-tetrazolyl) carcon 173-177 (d) 28  4- [2- (7-chloro-2-quinolyl) ethenyl] -2'-hydroxy-5 '-(5-tetrazolyl) carcon 262-265 (d) 29  5'-carboxy-2'-methoxy-4-[(2-quinolyl) methoxy] carcon 224-226 (d)

TABLE 3

Example Compound people Melting Point (℃) 30  5'-carboxy-2'-methoxy-3- (2-quinolylmethoxy) carconHCl 228-231 (d) 31  2'-n-butoxy-5'-carboxy-3- (2-quinolylmethoxy) carcon 170-173 (d) 32  2'-n-butoxy-5'-carboxy-4- (2-quinolylmethoxy) carconHCl 232-235 (d) 33  3-[(1-ethoxyethylbenzimidazol-2-yl) methoxy] -2'-hydroxy-5 '-(tetrazol-5-yl) carconHCl 234-236 (d) 34  3'-carboxy-5'-chloro-3-[(1-ethoxyethylbenzimidazol-2-yl) methoxy] -2'-hydroxycarcon 206-208 (d) 35  3'-cyano-4- (2-quinolylmethoxy) carcon 172-175 36  3'-cyano-3- (2-quinolylmethoxy) carcon 175-177 37  4'-carboxy-3-[(1-ethoxyethylbenzimidazol-2-yl) methoxy] -2'-hydroxycarconHCl 217-220 (d) 38  5'-carboxy-2'-hydroxy-3'-methyl-3- (2-quinolylmethoxy) carcon 195-198 (d) 39  5'-carboxy-2'-hydroxy-3'-methyl-4- (2-quinolylmethoxy) carcon 246-248 (d)

Example 40

Synthesis of 3'-carboxy-2'-hydroxy-3- [2- (2-quinolyl) ethenyl] carcon

A mixture of 1.30 g (5 mmol) of 4- [2- (2-quinolyl) ethenyl] benzaldehyde and 0.90 g (5 mmol) of 3-carboxy-2-hydroxyacetophenone, 50 ml of THF and 50 ml of ethanol 30 mL of 25% KOH aqueous solution was added, and a solvent was added every time a precipitate came out in the middle, stirring at room temperature for 1-2 weeks. The reaction solution was poured into ice water, acidified by addition of 3N HCl, and the precipitate was obtained by filtration, which was purified by column chromatography and recrystallization to obtain 0.70 g (yield 33%) of the title compound.

Melting Point: 237.2 ~ 240.2 ℃

¹ H-NMR (DMSO) δ (ppm):

5.44 (2H, s, CH ₂ O), 7.06 (1H, t, J = 7.7 Hz, H5 '),

       7.15-7.18 (1H, m, H4), 7.37-7.38 (2H, m, H5, H6),

       7.55 (1H, s, H2), 7.60-7.62 (1H, m, H6-quinoline),

       7.64-7.67 (2H, m, Hα, Hβ), 7.72 (1H, d, J = 8.5 Hz, H3-quinoline),

       7.76-7.80 (1H, m, H7-quinoline), 7.92-7.94 (1H, m, H4 '/ H6'),

       7.95-8.02 (3H, m, H 4 '/ H 6', H 5-quinoline, H 8 -quinoline),

       8.43 (1H, doublet, J = 8.5 Hz, H4-quinoline).

Hereinafter, the compound shown in Table 4 was obtained by the method similar to Example 40.

TABLE 4

Example Compound people Melting Point (℃) 41  3'-carboxy-2'-hydroxy-3-[(2-quinolyl) methoxy] carcon 176.9-178.1 42  5'-bromo-3'-carboxy-2'-hydroxy-3-[(2-quinolyl) methoxy] carcon 185.1-186.0 43  3'-carboxy-2'-hydroxy-4- [2- (2-quinolyl) ethenyl] carcon 267.1-269.2 44  5'-carboxy-2'-hydroxy-4- [2- (2-quinolyl) ethenyl] carcon 257.7-260.0 45  5'-cyano-2'-hydroxy-3- [2- (2-quinolyl) ethenyl] carcon 221.6-222.3 46  2'-hydroxy-3- [2- (2-quinolyl) ethenyl] -5 '-(5-tetrazolyl) carcon 226.0-228.2 47  4-benzyloxy-5'-ethoxycarbonyl-2'-hydroxycarcon 133.7-135.9 48  3'-carboxy-5'-fluoro-2'-hydroxy-3- [2- (2-quinolyl) ethenyl] carcon 275.7-277.1 49  3'-carboxy-5'-chloro-2'-hydroxy-3- [2- (2-quinolyl) ethenyl] carcon 278.5-280.9 50  5'-Bromo-3'-carboxy-2'-hydroxy3- [2- (2-quinolyl) ethenyl] carcon 264.1-266.0 51  3'-carboxy-2'-hydroxy-5'-methyl-3- [2- (2-quinolyl) ethyl] carcon 163.2-163.7 52  3'-carboxy-2'-hydroxy-5'-methyl-3- [2- (2-quinolyl) ethyl] carcon 234.6-236.7 53  5'-Chloro-3'-cyano-2'-hydroxy-3- [2- (2-quinolyl) ethenyl] carcon 231.6-233.3 54  5'-chloro-2'-hydroxy-3- [2- (2-quinolyl) ethenyl] -3 '-(5- tetrazolyl) carcon > 300 55  5 '-(carboxymethoxy) -2'-hydroxy-3- [2- (2-quinolyl) ethenyl] carcon 220.0-220.9 56  2'-hydroxy-3- [2- (2-quinolyl) -ethenyl] -5 '-[(5-tetrazolyl) methoxy] carcon > 300 57  4 '-(carboxymethoxy) -2'-hydroxy-3- [2- (2-quinolyl) ethenyl] carcon > 300 58  5'-cyano-2'-hydroxy-3-[(2-quinolyl) methoxy] carcon 210.4-211.9 59  5'-chloro-2'-hydroxy-4- [2- (2-quinolyl) ethenyl] -3 '-(5- tetrazolyl) carcon > 300

Test Example 1

Antiroycotriene D ₄ action (in vitro testing)

The ileum of the guinea pig was removed, cut into a length of about 2 cm, hung in a container filled with Krebs buffer, and the isotonicity and shrinkage reaction of leukotrienes D ₄ was recorded on the recorder. The Krebs buffer was kept warm at 37 ° C and a mixed gas (95% O ₂ -5% CO ₂ ) was injected. First, leukotriene D ₄ was added to the tracheal bath to measure response to each dose. This was washed several times with buffer, and then a constant concentration of test compound (indicated by the example number below) was added to the incubator for 30 minutes, and then the response to the dose of leukotriene D ₄ was measured. The results are shown in Table 5.

TABLE 5

Test compound Anti-LTD ₄ action (IC ₅₀ value) 19 6.7 × 10 ^-8 M 23 4.8 × 10 ^-7 M 29 2.9 × 10 ^-7 M 40 1.2 × 10 ^-7 M

Test Example 2

Leukotrien D ₄ receptor binding inhibition test

0.3 ml of 10 mM piperazine N, N'-bis (2-ethanesulfonate) buffer (pH 7.5) containing 0.2 nM [ ³ H] leukotriene D ₄ , protein of the guinea pig's membrane and test compound The reaction was quenched by adding ice-cooled tris hydrochloric acid / sodium chloride buffer solution (10 mM / 100 mM, pH 7.5) to the incubator for a minute and immediately filtering with a Wattman CF / C filter. The filter was washed twice with 20 ml of ice-cold buffer and the radioactivity of the residue was measured with a scintillation counter which is a liquid. According to the measured value when no test compound was added and the measured value when the test compound of various concentrations were added, the reaction according to the capacity of the inhibitory action of the test compound was measured to obtain a 50% inhibitory concentration (IC ₅₀ ) value from the IC ₅₀ . The dissociation constant (K _D ) was calculated using the Cheng-Prusoff equation. In the saturation experiment, it was found that the maximum binding amount (Bmax) of 2 μM of leukotriene D ₄ was 988 fmol / mg protein. In addition, the dissociation constant (K _D ) of [ ³ H] Roycotriene D ₄ was 2.616 × 10 ⁻¹⁰ M and the slope when interpreted as a Hill plot was 0.99. In figures in Table 6 represents the% inhibition of the dissociation constant K _D (㏖) or high concentration (10μM).

TABLE 6

Test compound LTD Receptor (%) One 4.50 × 10 ^-7 M 2 6.90 × 10 ^-7 M 3 18% 4 23% 5 3.35 × 10 ^-5 M 6 0% 7 3.07 × 10 ^-7 M 8 3.96 × 10 ^-7 M 9 7.32 × 10 ^-7 M 10 ― 11 2.10 × 10 ^-6 M 12 ― 13 ― 14 ― 15 ― 16 ― 17 16% 18 4.31 × 10 ^-6 M 19 1.41 × 10 ^-8 M 20 2.09 × 10 ^-7 M 21 1.70 × 10 ^-6 M 22 3.18 × 10 ^-8 M 23 5.27 × 10 ^-7 M 24 2.33 × 10 ^-7 M 25 1.92 × 10 ^-5 M 26 4%

Table 6 (continued)

Test compound LTD Receptor (%) 27 1.96 × 10 ^-7 M 28 2.39 × 10 ^-7 M 29 1.88 × 10 ^-7 M 30 3.57 × 10 ^-7 M 31 3.00 × 10 ^-7 M 32 41% 33 8.85 × 10 ^-6 M 34 1.05 × 10 ^-5 M 35  8% 36  6% 37 26% 38 2.24 × 10 ^-6 M 39 1.00 × 10 ^-6 M 40 2.62 × 10 ^-8 M 41 4.15 × 10 ^-7 M 42 2.05 × 10 ^-7 M 43 2.00 × 10 ^-7 M 44 5.85 × 10 ^-7 M 45 3.46 × 10 ^-7 M 46 2.10 × 10 ^-8 M 47 ― 48 1.40 × 10 ^-7 M 49 6.64 × 10 ^-9 M 50 2.07 × 10 ^-7 M 51 1.05 × 10 ^-7 M 52 2.08 × 10 ^-7 M

Table 6 (continued)

Test compound LTD Receptor (%) 53 4.49 × 10 ^-7 M 54 8.28 × 10 ^-7 M 55 1.75 × 10 ^-7 M 56 4.46 × 10 ^-8 M 57 2.04 × 10 ^-7 M 58 38% 59 ―

The carcon derivative (1) and salts thereof of the present invention have excellent cys-LT receptor antagonism, have asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, urticaria, psoriasis, rheumatism, inflammatory colitis, It is effective as a medicament for the treatment or prevention of cerebral ischemia and stroke.

Claims (10)

Carcon derivatives of the following general formula (1), salts thereof or solvates thereof [Wherein A is a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group, or (Wherein X represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group, B represents -CH = CH-, -N (R ⁶ )-(wherein R ⁶ represents a lower alkyl group or a lower alkoxyalkyl group)) , -O- or -S-}, W represents -CH = CH- or -CH ₂ O-, and one of the groups represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ Carboxyl group, cyano group, alkyloxycarbonyl group, tetrazolyl group, group -CONHR ⁷ (wherein R ⁷ represents a hydrogen atom or a lower alkyl group) or group -O (CH ₂ ) nR ⁸ where R ⁸ is a carboxyl group, an alkyloxycarbonyl group Or a tetrazolyl group, n represents a number from 1 to 4), and the rest are the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or a lower alkoxy group. However, one of R ¹ , R ² , R ³ , R ^4, and R ⁵ is a carboxy group or cyano group, except that the rest are all hydrogen atoms.]. The compound according to claim 1, wherein in formula (1), R ₁ represents a hydroxy group or an alkoxy group, and one of R ₂ , R ₃ , R ₄ , and R ₅ is a carboxyl group, cyano group, alkyloxycarbonyl group, tetrazolyl group, group A carcon derivative, a salt thereof, or a solvate thereof, which represents -CONHR ⁷ or a group -O (CH ₂ ) nR ⁸ , the remainder being the same or different from each other and representing a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, or a lower alkoxy group. (delete) Treatment of a disease selected from the group consisting of asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, urticaria, psoriasis containing the carcon derivative according to claim 1, a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier Or prophylactic pharmaceutical composition. A pharmaceutical composition for the treatment or prophylaxis of inflammatory colitis comprising the carcon derivative according to claim 1, a salt thereof or a solvate thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for the treatment or prevention of cerebral ischemia or stroke, comprising the carcon derivative according to claim 1, a salt thereof, or a solvate thereof and a pharmaceutically acceptable carrier. (delete) (delete) (delete) The carcon derivative according to claim 1 or 2, wherein the carcon derivative is 5'-carboxy-2'-hydroxy-2-[(2-quinolyl) methoxy] carcon, 4-benzyloxy-5'-carboxy-. 2'-hydroxycarcon, 2-benzyloxy-5'-carboxy-2'-hydroxycarcon, 5'-ethoxycarbonyl-2'-hydroxy-4-[(2-quinolyl) meth Oxy] carcon, 2'-hydroxy-4- (2-naphthylmethoxy) -5 '-(5-tetrazolyl) carcon, 2'-n-butoxy-5'-carboxy-4- (2 -Quinolylmethoxy) carcon, 4'-carboxy-3-[(1-ethoxyethylbenzimidazol-2-yl) methoxy] -2'-hydroxycarcon and 5'-cyano-2 Carcon derivatives, salts or solvates thereof, excluding '-hydroxy-3-[(2-quinolyl) methoxy] carcon.