JPH02152966A - 4-hydroxycarbostyril derivative - Google Patents

Abstract

NEW MATERIAL:A 4-hydroxycarbostyril derivative expressed by formula I (R<1> is H, lower alkyl, phenyl or phenyl-lower alkyl; R<2> is H or lower alkyl; R<3> is alkyl optionally having lower alkoxy or heterocyclic ring as a substituent group or phenyl-lower alkyl or naphthyl-lower alkyl optionally having alkyl, halogen, alkoxy or sulfamoyl on the phenyl ring; R<2> and R<3>, together with the adjacent N, may form heterocyclic ring). EXAMPLE:N-o-Chlorobenzyl 4-hydroxy-1-methylcarbostyril-3-carboxamide. USE:A treating and preventive agent for diseases, such as inflammation, allergy or asthma. PREPARATION:Carbostyril-3-carboxylic acid esters expressed by formula II and amines expressed by formula III are subjected to dealcoholizing condensation reaction to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 4-hydroxycarbostyryl derivatives.

Conventional technology The derivative of the present invention is a new compound that has not been described in any literature.

DISCLOSURE OF THE INVENTION As will be described later, the present invention aims to provide a compound useful as a pharmaceutical.

Steps for Solving Problems The above object is achieved by a 4-hydroxycarbostyryl derivative represented by the following general formula (I>).

R1 (In the formula, R1 represents a hydrogen atom, a lower alkyl group, a phenyl group, or a phenyl lower alkyl group. R2 represents a hydrogen atom or a lower alkyl group. R3 has a lower alkoxy group or a heterocyclic group as a substituent. Indicates a certain alkyl group, a phenyl lower alkyl group or a naphthyl lower alkyl group which may have a lower alkyl group, halogen atom, lower alkoxy group or sulfamoyl group on the phenyl ring. R2 and R3 together with the nitrogen atom to which they are bonded A heterocyclic group may be formed.] In the above general formula CI>, the lower alkyl group is
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, 5ec-butyl, tert-butyl, pentyl, and hexyl groups.

Examples of the phenyl lower alkyl group include benzyl, 2
-Phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-phenylpropyl, 3-benzylpentyl, 1
Straight chain alkyl groups having 1 to 6 carbon atoms having a phenyl group such as -methyl-2-phenylbutyl group as a substituent can also be exemplified by branched alkyl groups.

Examples of the alkyl group that may have a lower alkoxy group or a heterocyclic group as a substituent include methoxymethyl, 2-ethoxyethyl, 3-propoxypropyl,
4-butoxybutyl, 5-pentyloxypentyl, 6
-hexyloxyhexyl, 2-isopropoxyethyl, 2-ethyl-1-methoxybutyl, (1-pyrrolidinyl)methyl, (2-pyrrolidinyl)butyl, (3-pyrrolidinyl)hexyl, piperidinoethyl, (2-piperidyl)propyl , morpholinopentyl, (3-tetrahydrofuryl)ethyl, furfuryl, (3-furyl)hexyl, (2-pyranyl)ethyl, (1-pyrrolyl)methyl, (2-pyridyl)methyl, (3-pyridyl)ethyl, ( C1-6 alkoxy groups such as 4-pyridyl)hexyl groups, 5-6 membered saturated or unsaturated heterocyclic groups having a nitrogen atom or oxygen atom as a heteroatom, or an indolyl group; Examples include straight chain or branched alkyl groups.

Examples of phenyl lower alkyl groups that may have a lower alkyl group, halogen atom, lower alkoxy group or sulfamoyl group on the phenyl ring include 2-methylbenzyl, 4-isopropyl, in addition to the unsubstituted phenyl lower alkyl groups listed above. Benzyl, 4-(3-hexylphenyl)hexyl, 2.3.4-trimethylbenzyl,
2-fluorobenzyl, 3-chlorobenzyl, 4-bromobenzyl, 6-(2-iodophenyl)hexyl, 2
゜4-dichlorobenzyl, 2,4.6-trichlorobenzyl, 2-methoxybenzyl, 4-(3-isopropoxyphenyl)butyl, 6-(4-hexyloxyphenyl)hexyl, 2- (3,4= dimethoxyphenyl)
Ethyl, 3-(2,3,4-trimethoxyphenyl)
1 to 1 of substituents consisting of a straight chain or branched alkyl group having 1 to 6 carbon atoms such as a propyl group, a halogen atom, a straight chain or branched alkoxy group having 1 to 6 carbon atoms, and a sulfur moyl group. Examples include straight-chain or branched alkyl groups having 1 to 6 carbon atoms to which 3 phenyl groups are bonded.

Naphthyl lower alkyl groups include, for example, 1-naphthylmethyl, 1-(1-naphthyl)ethyl, 3-(2-naphthyl)propyl, 2-methyl-3-(1-naphthyl)butyl, 5-(1-naphthyl) ) C1-6 having a naphthyl group such as pentyl or 6-(1-naphthyl)hexyl group
Examples include straight chain or branched alkyl groups.

In addition, examples of the heterocyclic group formed by R2 and R3 together with the nitrogen atom to which they are bonded include nitrogen atoms, oxygen atoms, etc. Examples include 5- to 6-membered saturated heterocyclic groups that may have atoms as petero atoms.

The derivative of the present invention represented by the above general formula (I) is a novel compound, and the leukotriene C4 (
It has an antagonistic effect on LTC4>, leukotriene D, (LTDa'), etc., and also has the effect of suppressing the production of leukotrienes by inhibiting the activity of arachidonic acid 5-lipoxygenase. It has a therapeutic effect on diseases such as inflammation, allergies, and asthma, and is useful in the pharmaceutical field as a therapeutic and preventive agent for such diseases.

The derivative of the present invention represented by the above general formula (I>) is, for example, carbostyryl-3 as shown in the following reaction formula (1).
-Can be produced by dealcoholization condensation reaction between carboxylic acid esters and amines.

R' (n) (III) R1 (I> (In the formula, R1, R2 and R3 are the same as above. R' represents a hydrogen atom, a lower alkyl group, an aralkyl group or an aromatic group.) The above dealcoholization condensation reaction proceeds easily in the absence of a solvent or in a suitable organic solvent at room temperature to the boiling point temperature of the solvent,
In this way, the derivative of the present invention can be obtained in good yield. In the above, as the organic solvent, aromatic hydrocarbons such as benzene, toluene, and xylene, aprotic solvents such as dimethylformamide, alcohols such as ethanol, isopropanol, butanol, etc. can be advantageously used.

Further, the ratio of each starting material used in the above reaction is not particularly limited, but usually compound (I[I) is used in at least an equimolar amount, preferably 1.
It is appropriate to use about 5 to 5 times the molar amount, more preferably about 2 to 3 times the molar amount, and the reaction is usually completed in about 1 to 5 hours.

Since the derivative of the present invention has a phenolic hydroxyl group,
This can be reacted with a suitable basic substance, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc., in a conventional manner to form a pharmacologically acceptable salt, and such a salt is also a free form of the derivative of the present invention. It has the same pharmacological activity as, and is included in the present invention.

The carbostyryl-3-carboxylic acid ester (If') used as a starting material in the above dealcoholization condensation reaction can be prepared by various commonly known methods, for example, as shown in reaction formulas (2) and (3) below. It can be synthesized by the following methods.

Reaction formula (2) 20(IV) (I) Reaction formula (3): That is, the above raw material compound (I) is, for example, the reaction formula (2)
As shown in
pola et al., J. Heterocycle
icChem, 16, 1605 (1979))
.

Furthermore, as shown in the reaction formula (3) above, dehydrochlorination of 4-hydroxycarbostyryl-3-carboxylic acid ester (l) having no substituent at the 1-position of carbostyril and alkyl halide (VI) Starting compound (II) can also be obtained by a condensation reaction.

The derivatives of the present invention obtained by each of the above reactions can be separated and purified from within the reaction system by a conventional method after completion of the reaction. Examples of the separation and purification means include precipitation methods, extraction methods, recrystallization methods, column chromatography, and preparative thin layer chromatography.

The compounds of the present invention are usually used in the form of several pharmaceutical preparations. The preparation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquid , suspending agents, etc.), soft blue agents, etc. When forming into a tablet, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propatool, simple syrup, etc. , glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene Sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin, cocoa butter,
Disintegration inhibitor for hydrogenated oil etc., quaternary ammonium base,
Absorption enhancers such as sodium lauryl sulfate, glycerin,
Moisturizing agents such as starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, tablets may be coated with conventional coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets,
It may be a film coated tablet or a double tablet or multilayer tablet.

When forming into an emulsion, carriers such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, powdered tragacanth,
Binders such as gelatin and ethanol, and disintegrants such as laminaran and agar can be used. When forming into a suppository, carriers such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols,
Gelatin, semi-synthetic glyceride, etc. can be used. Capsules are usually prepared by mixing the compound of the present invention with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules, etc. according to conventional methods. Injectable solutions, emulsions, suspensions, etc. are sterilized and preferably made isotonic with blood. When molding into such a form, for example, water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used as a diluent. In this case, sufficient amounts of salt, glucose,
Glycerin and the like may be included in the pharmaceutical preparation, and conventional solubilizing agents, buffering agents, soothing agents, etc. may also be added. Furthermore, the pharmaceutical preparation may contain coloring agents, preservatives, fragrances, flavoring agents, sweeteners, etc. and other pharmaceuticals as required.

When forming into a paste, cream or gel form, white vaseline, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as diluents.

The amount of the compound of the present invention to be contained in the above pharmaceutical preparation is not particularly limited and may be appropriately selected from a wide range, but it is usually 1 to 70% by weight in the preparation.

The method of administering the above pharmaceutical preparation is not particularly limited and is determined depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, emulsions, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, and are administered intramuscularly, intradermally, or intravenously as needed.
Administered subcutaneously or intraperitoneally. Suppositories are administered rectally.

The dosage of the above pharmaceutical preparation is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but usually the amount of the compound of the present invention, which is an active ingredient, is 1 kU of body weight per day.
The dosage is preferably about 0.5 to 20 mQ per day, and the preparation can be administered in 1 to 4 divided doses a day.

EXAMPLES Examples will be given below to explain the present invention in more detail.

Example 1 2.5 g of 4-hydroxy-1-methylcarbostyryl-3-carboxylic acid ethyl ester, 1.5 g of O-chlorobenzylamine, and 50 IIli2 xylene were heated under reflux for 3 hours and concentrated to dryness. The precipitate was recrystallized from ethyl acetate to give N-0-chlorobenzyl 4-hydroxy-1-
Methyl carbostyryl-3-carboxamide 2.8
g) to give birth.

Melting point: 180-182°C Example 2 1.65 g of 1-pencyl-4-hydroxycarbostyryl-3-carboxylic acid ethyl ester, 0.7-2-pyridylmethylamine, and 50 mQ of xylene are heated under reflux for 3 hours. The reaction solution was concentrated to dryness, and the precipitate was dissolved in ethyl acetate.
Recrystallized from n-hexane to give N-2-pyridylmethyl 1-benzyl-4-hydroxycarbostyryl-3-
1.8 g of carboxamide are obtained.

Melting point: 197-199°C Examples 3-36 In the same manner as in Examples 1 and 2, each of the derivatives of the present invention shown in Table 1 below was obtained using appropriate raw materials.

In Table 1, the melting points of each compound and the compounds obtained in Examples 1 and 2 are also listed.

Table I> Next, leukotriene antagonism tests conducted on the compounds of the present invention and their results are listed.

A guinea pig weighing 250 to 550 q is stunned with a blow to the head and exsanguinated to death. The ileum is removed into Tyrode's solution, and a 2-3 cm ileal section is taken and suspended in a 20TIli2 Magnus tube filled with Tyrode's solution at 37°C. Intestinal motility is recorded using an isotonic transducer (manufactured by Nihon Kohden, TD-1123) under a load of 0.5 CI.
After fixing the response to ˜10 −6 M, the contraction of leukotriene D4 to 2riMmf2 is measured repeatedly at 15 minute intervals.

Leukotriene D when pretreated with test compound for 1Q minutes
The % inhibition is calculated by comparing the shrinkage caused by No. 4 with the shrinkage when the above pretreatment was not performed.

Repeat the same test by increasing the added concentration of the test compound stepwise, and create a dose-response curve from the obtained values.
The ID501 value of the test compound is determined from the curve.

The results of the above tests conducted using the following compounds as test compounds are shown in Table 2 below.

<Test compound> 1...N-0-chlorobenzyl 4-hydroxy-1
-Methylcarbostyryl- suamide 2...N-benzyl 1-benzyl-4-hydroxycarbostyryl- 3...N-2- (2-pyridyl)ethyl 4-hydroxy-1-methylcarbostyryl- ruboxamide 4 ...N-2-piperidinoethyl 4-hydroxy-
1-Methylcarbostyryl-3-carboxamide Table 2 From Table 2 above, it can be seen that the compounds of the present invention have excellent leukotriene antagonistic activity.

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Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 represents a hydrogen atom, a lower alkyl group, a phenyl group, or a phenyl lower alkyl group. R^2 represents a hydrogen atom or a lower alkyl group. R^3 is an alkyl group that may have a lower alkoxy group or a heterocyclic group as a substituent, a phenyl lower alkyl group that may have a lower alkyl group, a halogen atom, a lower alkoxy group, or a sulfamoyl group on the phenyl ring, or naphthyl. Indicates a lower alkyl group. Also R^2
and R^3 may form a heterocyclic group together with the nitrogen atom to which they are bonded. ] A 4-hydroxycarbostyryl derivative represented by: