JPH07110858B2 - Method for producing chromoglycic acid derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a novel cromoglycic acid derivative.

[0002]

2. Description of the Related Art Conventionally, general formula (II):

[0003]

[Chemical 3]

The compound represented by the formula [hereinafter, also referred to as cromoglycic acid (II)] has an antiallergic action, and has been generally used as an antiallergic agent in the form of its sodium salt.

[0005]

[Problems to be Solved by the Invention] Cromoglycic acid (II)
Since is not absorbed from the digestive tract, it has been usually sprayed and inhaled into both the nasal cavity and the oral cavity using a dedicated sprayer. However, this administration method is difficult to inhale (especially in children and the elderly) in terms of operation of the sprayer. Therefore, it has been earnestly desired to develop a cromoglycic acid-based compound that can be absorbed even by oral administration and to establish a manufacturing method thereof. The object of the present invention is to provide a process for the preparation of the above compounds.

[0006]

Means for Solving the Problems The present inventors have conducted various studies in order to obtain novel orally administrable cromoglycic acid compounds, and as a result, the following cromoglycic acid derivative (I) has been obtained.
Has excellent absorbability from the digestive tract, and after absorption, each ester moiety is rapidly hydrolyzed by an in vivo enzyme to be converted into cromoglycic acid (II) (hereinafter, also referred to as non-ester form), that is, By orally administering the cromoglycic acid derivative (I), a high blood concentration of the non-ester compound having excellent antiallergic activity is obtained, and the antiallergic activity lasts for a long time. It has been found that the use of an acid addition salt can improve the absorption efficiency and at the same time facilitate the stabilization of the cromoglycic acid derivative (I), the isolation operation, and the formulation of an oral administration preparation. Furthermore, it was found that oral administration of cromoglycic acid derivative (I) in the presence of an organic acid significantly increased the solubility of cromoglycic acid derivative (I) in the digestive tract, and established a method for producing cromoglycic acid derivative (I). By doing so, the present invention has been completed.

That is, the present invention has the general formula (I):

[0008]

[Chemical 4]

[Wherein R ¹ is an α or β- amino acid residue (ester bond), and R ² and R ³ are lower alkyloxy-substituted or unsubstituted lower alkyl groups, 1-alkanoyloxyalkyl groups, 1- Alkoxycarbonyloxyalkyl group, phthalidyl group or 5-methyl-1,3-
A compound represented by a dioxole-2-one-4-ylmethyl group] [that is, a cromoglic acid derivative (I)] and a non-toxic salt thereof are characterized by the general formula (III):

[0010]

[Chemical 5]

(Wherein R ² and R ³ have the same meanings as defined above) and the general formula (IV): R ^{1 ′} OH (IV) (wherein R ^{1 ′} is an amino group. t-butoxycarbonyl group
Α- or β-amino acid residue protected by (ester bond)
Engineering of reacting a compound represented by the illustrated) (IV)
It is about to pass .

R ¹ in the general formula (I) and the general formula
Regard R ^{1 'in} (IV), the amino acid residues are those that form an ester bond with the adjacent oxygen atom, Ru α or β- amino acid residues der. Cal amino acid residues or may, D member may be any of L-form and DL-form, or even those two or more amino acids form a peptide. Examples of such amino acid residues include the followings.

Neutral amino acid residues: Aliphatic amino acid residues [glycyl, alanyl, valyl, leucyl, isoleucyl, etc.], oxyamino acid residues [seryl, threonyl, etc.], sulfur-containing amino acid residues [cysteinyl, cystyl, methionyl, etc.] ], Amide amino acid residues [asparaginyl, glutaminyl, etc.], aromatic amino acid residues [phenylalanyl, tyrosyl, tryptophyll, etc.] acidic amino acid residues: aspartyl, glutamyl, etc. basic amino acid residues: histidyl, lysyl, arginyl, etc. Imino acid residues: Prolyl, oxyprolyl, etc. Amino acid residues other than α-amino acids: β-alanyl, etc. Peptide residues: Glycylglycyl, alanylglycyl, leucylglycyl, etc.

With respect to R ² and R ³ in the general formula (I), lower alkyl is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n. -Butyl, iso-butyl, t-
Butyl, n-pentyl and n-hexyl.

In the 1-alkanoyloxyalkyl group represented by R ² and R ³ , the alkanoyl moiety has 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms, and the alkyl moiety has 1 to 4 carbon atoms, preferably 1 to 4 carbon atoms. It is 2. Examples of such groups include acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl, iso-butyryloxymethyl, pivaloyloxymethyl, n-valeryloxymethyl, 2-methylbutyryloxymethyl, iso-
Valeryloxymethyl, n-hexanoyloxymethyl, 3-methylvaleryloxymethyl, neohexanoyloxymethyl, 2-methylhexanoyloxymethyl, 2,2-dimethylbutyryloxymethyl, diethylacetoxymethyl, dipropyl Acetoxymethyl, 2,
2-dimethylvaleryloxymethyl, neoheptanoyloxymethyl, cyclohexanoyloxymethyl, cyclohexylacetoxymethyl, 1-acetoxyethyl,
1-n-propionyloxyethyl, 1-n-butyryloxyethyl, 1-iso-butyryloxyethyl, 1-
Examples thereof include n-valeryloxyethyl, 1-pivaloyloxyethyl, 1-iso-valeryloxyethyl, 1-n-hexanoyloxyethyl, 1-cyclohexanoyloxyethyl and the like.

In the alkoxycarbonyloxyalkyl group represented by R ² and R ³ , the alkoxy moiety has 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms, and the alkyl moiety has 1 to 3 carbon atoms, preferably 2. Such groups include
For example, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-n-propoxycarbonyloxyethyl, 1-iso-propoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl, 1-tert-butoxycarbonyloxyethyl. 1
-Pentyloxycarbonyloxyethyl, 1-hexyloxycarbonyloxyethyl and the like can be mentioned.

Preferred R ² and R ³ are methyl,
Ethyl, propyl, isopropyl, ethoxyethyl, ethoxymethyl, pivaloyloxymethyl, acetoxymethyl, 1-acetoxyethyl, 1-n-propionyloxyethyl, 1-ethoxycarbonyloxyethyl, 5
-Methyl-1,3-dioxol-2-on-4-ylmethyl may be mentioned.

The cromoglycic acid derivative (I) preferably forms an acid addition salt (non-toxic salt) at its amino acid residue, and the acid for forming such an acid addition salt has amino acid residue There is no particular limitation as long as it is a pharmaceutically acceptable acid that can form a salt with. Examples of such acids include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid and toluenesulfonic acid. The use of such a salt further improves the absorbability from the digestive tract and facilitates formulation.

According to the present invention, the cromoglycic acid derivative (I) is produced as follows. General formula (III):

[0020]

[Chemical 6]

(Wherein R ² and R ³ have the same meanings as defined above) and a compound of formula (IV): R ^{1 ′} OH (IV) (wherein R ^{1 ′} is as defined above) Meaning) and the reaction with the compound (IV) .

The compound (IV) is used in this reaction as a free carboxylic acid or as a reactive derivative thereof. That is, as a free acid or a salt of sodium, potassium, calcium, triethylamine, pyridine, or the like, or an acid halide thereof (acid chloride, acid bromide, etc.), acid anhydride salt, mixed acid anhydride [substituted phosphoric acid (dialkylphosphoric acid, etc.) , Alkyl carbonate (monoethyl carbonate etc.)
Etc.], an active amide (amide with imidazole, etc.), an ester (cyanomethyl ester, 4-nitrophenyl ester, etc.), etc. as a reactive derivative to be subjected to an acylation reaction.

When the compound (IV) is used in the form of a free acid, it is preferable to use a suitable condensing agent, for example, an N, N'-substituted carbodiimide such as N, N'-dicyclohexylcarbodiimide. Kind, N,
A dehydrating agent such as an azolide compound such as N′-carbonylimidazole or N, N′-thionyldiimidazole is used. When these condensing agents are used, the reaction is considered to proceed via the reactive derivative of carboxylic acid. In this reaction, it is preferable to use a base such as 4-dimethylaminopyridine as a catalyst.

This reaction is usually carried out in an inert solvent.
Specific examples of the solvent include water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine and other organic solvents, and mixtures thereof. can give.

In this reaction, amino in compound (IV)
The group is protected with a t-butoxycarbonyl group.

[0026]

[0027]

[0028]

[0029]

By reacting the compound (IV) in which the amino group is protected by a t-butoxycarbonyl group with the compound (III), the compound of the general formula (I ')

[0031]

[Chemical 7]

[0032] (wherein each symbol is the same defined above) the compounds represented by (I ') is produced, the compound by removal of the protecting group from the compound (I) is produced. In addition,
Compound (I ′) may be isolated, but it is usually subjected to a protecting group elimination reaction without isolation.

An example of the elimination reaction of the amino-protecting group is as follows.
For example, formic acid or dioxane solution of hydrogen chloride in formic acid
Is used.

[0034]

[0035]

[0036]

[0037]

[0038]

The reaction temperature in the elimination reaction of the protective group of amino group is not particularly limited, cold reject preferably carried out under mild conditions of room temperature to about slightly warming.

The compound (III) is produced from the known compound cromoglycic acid (II) as follows. That is,
Cromoglycate (lithium, sodium, potassium,
Alkali metal or alkaline earth metal salts such as cesium,
A salt of an organic amine such as trimethylamine, triethylamine, pyridine) and a general formula: R—X (V) (wherein R represents the same meaning as R ² or R ^3, and X represents a group reactive with a carboxyl group). The compound (V) represented is reacted in a polar solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide and hexamethylphosphoramide at room temperature to 100 ° C.

Instead of cromoglycate, cromoglycic acid is replaced by an alkali metal salt of carbonic acid (eg sodium hydrogen carbonate, potassium carbonate), an alkaline earth metal salt (eg cesium carbonate) or a lower alkyl acid (eg acetic acid).
The reaction may be carried out in the presence of the alkali metal salt or alkaline earth metal salt.

The reaction is also carried out in chloroform in the presence of a catalytic amount of a quaternary ammonium chloride (eg a phase transfer catalyst such as benzyltributylammonium chloride).
It can be carried out in a two-layer system of an organic solvent such as methylene chloride and water.

Examples of the group reactive with the carboxyl group for X in the general formula (V) include halogen atoms such as Cl, Br and I, methyl, trisulfonate and the like.
When the obtained cromoglycic acid derivative (I) is a free base, it can be converted into a non-toxic acid addition salt by a means known per se.

The anti-allergic therapeutic agent for oral administration can be produced by diluting the thus produced cromoglycic acid derivative (I) or a non-toxic salt thereof with a pharmaceutical excipient according to a means known per se. The dilution is performed according to a method known per se such as mixing. Specifically as an excipient,
Examples thereof include starch, lactose, sugar, calcium carbonate, calcium phosphate and the like.

By the way, it is preferable to further add an organic acid to the antiallergic therapeutic agent for oral administration. Thus, the solubility of the cromoglycic acid derivative in the gastrointestinal tract is enhanced, and the absorption into blood is facilitated. The organic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include maleic acid, fumaric acid, tartaric acid, citric acid, succinic acid, malic acid, oxalic acid, mandelic acid, malonic acid and benzoic acid. Carboxylic acid etc. are mentioned as a preferable thing. The amount of the organic acid added is usually 0.01 to 2 with respect to 1 mol of the cromoglycic acid derivative (I).
It is 0 mol, preferably 1 to 10 mol.

If desired, the anti-allergic therapeutic agent for oral administration may further contain other additives such as binders (eg, starch, gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, etc.), Lubricants (eg, magnesium stearate, talc, etc.) and disintegrants (eg, carboxymethyl cellulose calcium, talc, etc.) are mentioned as preferred additives. After mixing the various components, the mixture can be formulated into a dosage form suitable for oral administration such as capsules, tablets, fine granules, granules and dry syrup according to a method known per se.

The antiallergic agent of the present invention is an oral antiallergic agent for allergic diseases similar to cromoglycic acid (II), such as bronchial asthma, allergic rhinitis, throat irritation, spring catarrh and chronic allergic conjunctivitis. Used as an allergic agent. In the case of oral administration, it is desirable to administer the daily dose in 1 to several times, and the daily dose may vary depending on the condition, age, weight, etc. Can be administered in 1 to 4 divided doses.

[0048]

[Functions / Effects] The cromoglycic acid derivative (I) and its non-toxic salt of the present invention, when orally administered, are rapidly absorbed from the digestive tract and, after absorption, are hydrolyzed by the in vivo enzyme to respond Converted to non-ester form.
Thus, excellent antiallergic properties of the non-ester form are developed. Therefore, the cromoglycic acid derivative (I) and its non-toxic salt are used as oral antiallergic agents.

According to the production method of the present invention, it is possible to efficiently produce the cromoglycic acid derivative (I) and its non-toxic salt having the above-mentioned properties.

[0050]

[Examples / Experimental Examples] Hereinafter, examples and experimental examples will be described.
The present invention will be described more specifically, but the present invention is not limited thereto.

Abbreviations in the following are as follows. DSCG ... Sodium cromoglycate DMF ... Dimethylformamide DCC ... N, N-dicyclohexylcarbodiimide DMSO ... Dimethylsulfoxide BOC ... t-Butoxycarbonyl

Example 1 Synthesis of L-lysyl cromoglycic acid diethyl ester dihydrochloride 1) Cromoglycic acid diethyl ester 524 mg, di-B
OC-L-lysine 520 mg, dimethylaminopyridine 6
1 mg is added to 10 ml methylene chloride. DCC31 at 0 ℃
0 mg is added, and the mixture is stirred at the same temperature for 30 minutes and at room temperature for 6 hours. The precipitated urea body is filtered off, the filtrate is concentrated and purified by silica gel column chromatography to obtain 580 mg of di-BOC-L-lysyl chromoglycic acid diethyl ester (yield, 68%).

[0053]

[Table 1]

2) 470 mg of the compound obtained in 1) is dissolved in 1.1 ml of formic acid, 2.8 ml of 1.4M hydrogen chloride dioxane solution is added under ice cooling, and the mixture is stirred at room temperature for 30 minutes. The reaction solution was poured into isopropyl ether and the precipitate was collected by filtration to obtain 351 mg (yield, 88%) of L-lysyl chromoglycic acid diethyl ester dihydrochloride.

[0055]

[Table 2]

Example 2 Synthesis of glycyl chromoglycic acid diethyl ester hydrochloride By using BOC-glycine and in the same manner as in Example 1, glycyl cromoglycic acid diethyl ester hydrochloride is obtained.

[0057]

[Table 3]

Example 3 Synthesis of L-alanyl cromoglic acid dimethyl ester hydrochloride L-alanyl cromoglic acid dimethyl ester hydrochloride was obtained in the same manner as in Example 1 using chromoglycic acid dimethyl ester and BOC-L alanine.

[0059]

[Table 4]

Example 4 Synthesis of L-alanylchromoglycic acid diethyl ester hydrochloride Using BOC-L-alanine, L-alanylchromoglycic acid diethyl ester hydrochloride was obtained in the same manner as in Example 1.

[0061]

[Table 5]

Example 5 Synthesis of β-alanyl-chromoglycic acid diethyl ester hydrochloride β-alanyl-chromoglycic acid diethyl ester hydrochloride was obtained by the same method as in Example 1 using BOC-β-alanine.

[0063]

[Table 6]

Example 6 Synthesis of N-glycyl glycyl chromoglycic acid diethyl ester hydrochloride N-glycyl glycyl glycyl chromoic acid diethyl ester hydrochloride was prepared in the same manner as in Example 1 using N- (BOC-glycyl) glycine. obtain.

[0065]

[Table 7]

Example 7 Synthesis of N- (L-alanyl) glycyl cromoglycic acid diethyl ester hydrochloride Example 1 using N- (BOC-L-alanyl) glycine
N- (L-alanyl) glycyl cromoglycic acid diethyl ester hydrochloride is obtained by a method similar to.

[0067]

[Table 8]

Example 8 Synthesis of N- (L-leucyl) glycyl chromoglycic acid diethyl ester hydrochloride Example 1 using N- (BOC-L-leucyl) glycine
N- (L-leucyl) glycyl cromoglycic acid diethyl ester hydrochloride is obtained by a method similar to.

[0069]

[Table 9]

Example 9 Synthesis of L-valyl cromoglycolic acid diethyl ester hydrochloride L-valyl cromoglycic acid diethyl ester hydrochloride was obtained in the same manner as in Example 1 using BOC-L-valine.

[0071]

[Table 10]

Example 10 Synthesis of L-leucyl chromoglycic acid diethyl ester hydrochloride L-Leucyl chromoglycic acid diethyl ester hydrochloride was obtained in the same manner as in Example 1 using BOC-L-leucine.

[0073]

[Table 11]

Example 11 Synthesis of L-lysyl chromoglycic acid di (2-ethoxyethyl) ester dihydrochloride 1) 2-mixed solution of 3 ml of triethylamine and 20 ml of DMF
Add ethoxyethyl bromide 3ml, DSCG 4g 9
Stir at 0 ° C. for 3 hours. 200 ml of water and 50 ml of ethyl acetate are added to the reaction solution, and the organic layer is separated. The extract is washed with an aqueous sodium bicarbonate solution and a saline solution and then dried with sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 2.6 g of cromoglic acid di (2-ethoxyethyl) ester.
(Yield 50%) is obtained.

[0075]

[Table 12]

2) L-lysyl cromoglycic acid di (2-ethoxyethyl) ester dihydrochloride was obtained by the same method as in Example 1 using diBOC-L-lysine.

[0077]

[Table 13]

Example 12 Di (2-ethoxyethyl) L-alanyl cromoglycate
Synthesis of ester hydrochloride L-alanyl cromoglycic acid di (2-ethoxyethyl) ester hydrochloride is obtained by the same method as in Example 11.

[0079]

[Table 14]

Example 13 N- (L-alanyl) glycyl cromoglycic acid di (2-
Synthesis of ethoxyethyl) ester hydrochloride N- (B-L-alanyl) glycine was used to prepare N- (L-alanyl) glycyl chromoglycic acid di (2-ethoxyethyl) by a method similar to that of the compound of Example 11.
The ester hydrochloride is obtained.

[0081]

[Table 15]

Example 14 Synthesis of L-lysyl cromoglycic acid di (pivaloyloxymethyl) ester dihydrochloride 1) 500 mg of cromoglycic acid di (pivaloyloxymethyl) ester was dissolved in 4 ml of methylene chloride, and diBOC-
370 mg of L-lysine and 14 mg of dimethylaminopyridine were added, and 1.8 ml of 1M-DCC methylene chloride solution was added dropwise at 0 ° C. After stirring for 4 hours, the precipitated urea body was filtered off, the residue was purified by silica gel column chromatography, and di-BOC-
710 mg (97% yield) of L-lysyl chromoglycic acid di (pivaloyloxymethyl) ester are obtained.

[0083]

[Table 16]

2) 400 mg of the compound obtained in 1) was dissolved in 0.8 ml of formic acid, and 1.4M hydrogen chloride dioxane solution 2 was added.
Add ml and stir at room temperature for 5 minutes. By adding isopropyl ether, 300 mg (yield 86%) of L-lysyl cromoglycic acid di (pivaloyloxymethyl) ester dihydrochloride was obtained.

[0085]

[Table 17]

Example 15 Synthesis of L-alanyl cromoglic acid di (pivaloyloxymethyl) ester hydrochloride L-alanyl cromoglycic acid di (pivalo) was prepared in the same manner as in Example 14 using BOC-L-alanine. Iloxymethyl) ester hydrochloride is obtained.

[0087]

[Table 18]

Example 16 Synthesis of β-alanyl cromoglycic acid di (acetoxymethyl) ester hydrochloride Example 14 was performed using cromoglic acid di (acetoxymethyl) ester and BOC-β-alanine.
A β-alanyl cromoglycic acid di (acetoxymethyl) ester hydrochloride is obtained in the same manner as in.

[0089]

[Table 19]

Example 17 Synthesis of N- (glycyl) glycyl chromoglycolic acid di (1-acetoxyethyl) ester hydrochloride 1) 6.1 g of DSCG was dissolved in 96 ml of water, and 96 ml of chloroform and benzyltri-n-butylammonium chloride 7 were dissolved. 0.5 g was added, and 1-bromoethyl acetate 4 g
Is added dropwise over 15 minutes. During this time, adjust the pH to 6 with NaHCO _3.
Keep on. Stir for 45 hours. The chloroform layer is separated, dried over sodium sulfate, evaporated to remove the solvent, and purified by silica gel column chromatography to obtain 4.4 g (yield 58%) of cromoglycic acid di (1-acetoxyethyl) ester.

[0091]

[Table 20]

2) 780 mg of the compound obtained in 1) was dissolved in 8 ml of methylene chloride, N- (BOC-glycyl) glycine 396 mg, dimethylaminopyridine 74 mg, DCC
Add 352 mg and stir at 0 ° C. for 17 hours. The precipitated urea body is separated by filtration, washed with an aqueous citric acid solution, and dried with sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography to obtain N- (B
669 mg (64% yield) of OC-glycyl) glycyl chromoglycic acid di (1-acetoxyethyl) ester are obtained.

[0093]

[Table 21]

3) 600 mg of the compound obtained in 2) is dissolved in 1.2 ml of formic acid, 3.6 ml of 1.3M hydrogen chloride dioxane solution is added under ice cooling, and the mixture is stirred at room temperature for 30 minutes. The reaction solution was poured into isopropyl ether, and the precipitate was collected by filtration and dried to obtain 492 mg (yield 89%) of N- (glycyl) glycyl chromoglycic acid di (1-acetoxyethyl) ester hydrochloride.

[0095]

[Table 22]

Example 18 N- (L-alanyl) glycyl cromoglycate di (1-
Synthesis of acetoxyethyl) ester hydrochloride Example 1 using N- (BOC-L-alanyl) glycine
By a method similar to 7, N- (L-alanyl) glycyl cromoglycic acid di (1-acetoxyethyl) ester hydrochloride is obtained.

[0097]

[Table 23]

Example 19 Synthesis of L-alanyl cromoglic acid di (1-acetoxyethyl) ester hydrochloride L-alanyl cromoglic acid di (1-acetoxy) was prepared in the same manner as in Example 17 using BOC-L-alanine. The ethyl) ester hydrochloride is obtained.

[0099]

[Table 24]

Example 20 Synthesis of β-alanyl cromoglic acid di (1-acetoxyethyl) ester hydrochloride β-alanyl cromoglic acid di (1-acetoxy) was prepared in the same manner as in Example 17 using BOC-β-alanine. The ethyl) ester hydrochloride is obtained.

[0101]

[Table 25]

Example 21 Di (1-acetoxyethyl) L-lysyl cromoglycate
Synthesis of ester dihydrochloride N-lysyl cromoglycic acid di (1-acetoxyethyl) ester dihydrochloride is obtained by the same method as in Example 17 using di-BOC-L-lysine.

[0103]

[Table 26]

Example 22 L-α-aspartyl cromoglycic acid di (5-methyl-)
2-oxo-1,3-dioxol-4-ylmethyl)
Synthesis of ester hydrochloride 1) 1 g of DSCG was suspended in 40 ml of DMF, 0.91 g of 4-bromomethyl-5-methyl-1,3-dioxol-2-one was added, and the mixture was stirred at 40 ° C for 2 hours. Water 40
After adding 0 ml, extraction with methylene chloride, washing with water, drying and evaporation of the solvent, 1.0 g of di (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl) chromoglycate (yield 80%) was obtained. To get

[0105]

[Table 27]

2) 1.0 g of the compound obtained in 1) was dissolved in 10 ml of methylene chloride, 531 mg of BOC-L-aspartic acid β-t-butyl ester and 88 mg of dimethylaminopyridine were added, and then 417 mg of DCC was added at 0 ° C. Addition and stirring for 5 hours. The precipitated urea body is filtered off, the solvent is distilled off, ethyl acetate is added, the solution is washed with an aqueous citric acid solution and brine, and then dried with sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain N-BOC-β-t-butyl-L-aspartic acid cromoglycic acid di (5-methyl-2-oxo-1,3-).
625 mg (45% yield) of dioxol-4-ylmethyl) ester are obtained.

[0107]

[Table 28]

3) 377 mg of the compound obtained in 2) is dissolved in 0.8 ml of formic acid, 2 ml of 1.4M hydrogen chloride dioxane solution is added under ice cooling, and the mixture is stirred at room temperature for 20 hours. By pouring the reaction solution into isopropyl ether, L-α-aspartyl cromoglic acid di (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl) ester hydrochloride 379 mg (yield 95%) To get

[0109]

[Table 29]

Example 23 Glycylcromoglycic acid di (5-methyl-2-oxo-)
Synthesis of 1,3-dioxol-4-ylmethyl) ester hydrochloride By the same method as in Example 22 using BOC-glycine, glycylcromoglycic acid di (5-methyl-2-oxo-1,3-dioxole-4) was prepared. -Ylmethyl) ester hydrochloride is obtained.

[0111]

[Table 30]

Example 24 Synthesis of L-alanylchromoglycic acid di (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl) ester hydrochloride The same procedure as in Example 22 was performed using BOC-L-alanine. Depending on the method, L-alanyl cromoglycic acid di (5-methyl-2
-Oxo-1,3-dioxol-4-ylmethyl) ester hydrochloride is obtained.

[0113]

[Table 31]

Example 25 Synthesis of β-alanylchromoglycic acid di (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl) ester hydrochloride Similar to Example 22 using BOC-β-alanine. Depending on the method, β-alanyl cromoglycic acid di (5-methyl-2
-Oxo-1,3-dioxol-4-ylmethyl) ester hydrochloride is obtained.

[0115]

[Table 32]

Example 26 Synthesis of L-prolyl cromoglycic acid di (5-methyl-2-oxo-1,3-dioxol-4-ylmethyl) ester hydrochloride Similar to Example 22 using BOC-L-proline. Depending on the method, L-prolyl cromoglycate di (5-methyl-2)
-Oxo-1,3-dioxol-4-ylmethyl) ester hydrochloride is obtained.

[0117]

[Table 33]

Example 27 Synthesis of β-alanylchromoglycic acid di (1-ethoxycarbonyloxyethyl) ester hydrochloride 1) 0.5 g of DSCG was added to 20 ml of DMF, and 1 under ice cooling.
2 g of iodoethyl carbonate are added dropwise over 2 hours. After stirring for 2 hours, the mixture was poured into 200 ml of water, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and the solvent was distilled off to obtain 256 mg (yield 38%) of cromoglic acid di (1-ethoxycarbonyloxyethyl) ester.

[0119]

[Table 34]

2) The compound obtained in 1) was treated in the same manner as in Example 14 with β-alanylchromoglycic acid di (1).
-Ethoxycarbonyloxyethyl) ester hydrochloride is obtained.

[0121]

[Table 35]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

Acute toxicity test The above-mentioned example was applied to ICR male mice consisting of 3 mice per group.
Cromoglycic acid prepared in 1, 4, 7, 11 and 12
An aqueous solution of the derivative was administered orally. The results are shown in Table 41 below.
Shown in.

[0135]

[Table 41]

Formulation Formulation Example 1 A tablet having the following composition is produced by a usual method. Compound of Example 1 5 mg Polyvinylpyrrolidone 20 mg Starch 75 mg Magnesium stearate 2 mg

Pharmaceutical Formulation Example 2 A tablet having the following composition is produced by a usual method. Compound of Example 1 10 mg Tartaric acid 50 mg Starch 50 mg Magnesium stearate 3 mg

Pharmaceutical Formulation Example 3 A tablet having the following composition is produced by a usual method. Compound of Example 4 20 mg Starch 50 mg Hydroxypropyl cellulose 3 mg Magnesium stearate 5 mg

Pharmaceutical Formulation Example 4 The compound of Example 9 and citric acid are added and mixed to produce a capsule according to a usual capsule filling method. Compound of Example 9 100 mg Citric acid 25 mg Magnesium stearate 1 mg

Formulation Formulation 5 According to the method of Formulation Formulation Example 4, a capsule having the following composition is produced. Compound of Example 1 20 mg Magnesium stearate 2 mg Lactose is added to make a total of 100 mg

Pharmaceutical Formulation Example 6 A dry syrup preparation is produced according to the following composition. Compound of Example 12 50 mg Citric acid 25 mg Sugar 70 mg CMC-Na 20 mg

The results of HPLC measurement of the urinary recovery rate (corresponding amount of cromoglic acid) when the compound of the present invention was orally administered (5 mg / kg) to a rabbit in an aqueous solution or suspension were shown in Table 42 below. Show.

[0143]

[Table 42]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Nobuharu Kakeya, 16 from 3-10 Takadai, Nagaokakyo, Kyoto Prefecture (72) Inventor, Kazuhiko Kitao, 12, Mitsutanagamachi, Matsugasaki, Sakyo-ku, Kyoto City, Kyoto Prefecture (56) References JP 62-42981 (JP, A)

Claims (1)

[Claims] 1. A compound represented by the general formula (III): (Wherein R ² and R ³ have the same meanings as described below) and the general formula (IV): R ^{1 ′} OH (IV) (In the formula, R ^{1 ′} has an amino group of t-butoxy. Carbonyl group
Α- or β-amino acid residue protected by (ester bond)
Characterized <br/> going through the step of reacting a compound (IV) represented by the illustrated) general formula (I): ## STR2 ## [Wherein R ¹ is an α or β- amino acid residue (ester bond)
R ² and R ³ are each a lower alkyloxy-substituted or unsubstituted lower alkyl group, a 1-alkanoyloxyalkyl group, a 1-alkoxycarbonyloxyalkyl group, a phthalidyl group or 5-methyl-1,3-dioxole-2. And a non-toxic salt of the cromoglycic acid derivative.