JPH05194366A - Glycine derivative-monosodium salt-tetrahydrate, its production, medicine containing the same and production of intermediate for the same derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound, having elastase inhibiting action and useful for treating and preventing pulmonary emphysema, atherosclerosis, rheumarthritis, etc. CONSTITUTION:N-[o-(p-Pivaloyloxybenzenesulfonylamino)benzoyl] glycine. monosodium salt.tetrahydrate expressed by formula I. This compound expressed by formula I is obtained by recrystallizing monosodium salt of N-[o-(p- pivaloyloxybenzenesulfonylamino)benzoyl] glycine expressed by formula II from water or a hydrous water-soluble organic solvent and drying the resultant crystal with an air blast.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a glycine derivative. More specifically, 1) Formula (I)

[0002]

[Chemical 9]

N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate represented by: 2) a method for producing the same, 3) containing it as an active ingredient A drug, and 4) its intermediate formula (II)

[0004]

[Chemical 10]

The present invention relates to a process for producing N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine represented by:

[0006]

BACKGROUND OF THE INVENTION The lysosome hydrolase group released from neutrophils plays an important role in the biological defense reaction against tissue damage caused by microorganisms or inflammation. Of the lysosomal enzyme group, elastase and cathepsin G, which belong to neutral serine proteinases localized in azure granules, mainly play a role of connective tissue degradation. In particular, elastase decomposes the elastic connective tissue by cleaving the cross-linking structure of elastin or the hydrophobic part of the protein that directly functions to maintain the elasticity of lung tissue and the like [J. Cell. Biol., 40 , 366 (1969 )]. Furthermore, elastase selectively degrades not only elastin but also the cross-linked region of collagen fibers [J. Biochem., 84 , 559.
(1978)] In addition, it plays a central role in connective tissue metabolism such as [J. Clin. Invest., 57 , 615 (1976)], which also acts on tissue structural proteins such as proteoglycan.

In the living body, elastase is inactivated by an inhibitor common to serine enzymes, α ₁ -proteinase inhibitor (α ₁ -PI), but when the enzyme-inhibitor system balance is disturbed, Tissue-destructive symptoms appear [Schweiz.Med.Wshr. , 114 , 895 (1984)].
Elastin turnover in normal tissues is very slow [E
ndocrinology , 120 , 92 (1978)] is emphysema [Am.Rev.Respi
r.Dis., 110, 254 (1974)], atherosclerosis [Lab.Invest. , 22, 228 (1979)] or rheumatoid arthritis [in Neutral Proteases of Human Polymorphonuclear
Leukocytes, Urban and Schwarzenberg, Baltimore-Mun
ich (1978), page 390] and the like, abnormal elastin degradation was observed under various pathological conditions, and the relationship between elastase and disease has been noted [infection, inflammation, immunity, 13, 13 (198
3)].

[0008]

2. Description of the Related Art Under the above background, research on elastase inhibitors has been extensively conducted recently, and various elastase inhibitors have been proposed and applied for patents. For example, in Japanese Patent Application Laid-Open No. 3-20253, the general formula (A)

[0009]

[Chemical 11]

[Wherein Y represents a sulfonyl group or a carbonyl group, (1) R ¹ and R ² may be the same or different, (1) a hydrogen atom, (2) a carbon number of 1 to 1
6 alkyl group or formula (3)

[0011]

[Chemical 12]

(In the formula, X represents a single bond, a sulfonyl group, an alkylene group having 1 to 4 carbon atoms, or an alkylene group having 1 to 4 carbon atoms which may be substituted with a carboxyl group or a benzyloxycarbonyl group,

[0013]

[Chemical 13]

Represents a carbocycle or a heterocycle, n represents an integer of 1 to 5, R ^{4 s} may be the same or different, and (a) a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, b) an alkoxy group having 1 to 14 carbon atoms, (c) 1 carbon atom
~ 6 alkylthio group, (d) hydroxyl group, halogen atom, nitro group or trihalomethyl group, (e) formula -NR ⁴¹ R
^{A group represented by 42} (in the formula, R ⁴¹ and R ⁴² may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms),

(F) tetrazole group, (g) sulfonic acid group or hydroxymethyl group, (h) formula --SO ² NR ⁴¹ R ⁴² (wherein R ⁴¹ and R ⁴² have the same meanings as described above).
A group represented by: (i) Formula —Z ⁴¹ —COOR ⁴³ (In the formula, Z ⁴¹ represents a single bond, an alkylene group having 1 to 4 carbon atoms or an alkenylene group having 2 to 4 carbon atoms, and R ⁴³ is a hydrogen atom. Represents an alkyl group having 1 to 4 carbon atoms or a benzyl group),

(J) Formula —CONR ⁴¹ R ⁴² (In the formula, R ⁴¹ and R ⁴² have the same meanings as described above.)
A group represented by: (k) Formula —COO—Z ⁴² —COOR ⁴³ (In the formula, Z ⁴² represents an alkylene group having 1 to 4 carbon atoms,
R ⁴³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a benzyl group. ), A group represented by the formula (CO) -COO-Z ⁴² -CONR ⁴¹ R ⁴² (wherein all symbols have the same meanings as described above);

[0017] (m) formula -OCO-R ⁴⁵ (wherein, R ⁴⁵ represents. An alkyl group or a p- guanidinophenyl group having 1 to 8 carbon atoms) groups represented by, (n) formula -CO-R ⁴⁶ (In the formula, R ⁴⁶ represents an alkyl group having 1 to 4 carbon atoms.)
A group represented by: (o) Formula —O—Z ⁴³ —COOR ⁴⁵⁰ (In the formula, Z ⁴³ represents an alkylene group having 1 to 6 carbon atoms,
R ⁴⁵⁰ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or p
Represents a guanidinophenyl group. ) Group,
(p) expression

[0018]

[Chemical 14]

[0019] (wherein,> N-Z ⁴⁴ -CO- represents an amino acid residue, R ⁴⁷ represents a single bond or an alkyl group having 1 to 4 carbon atoms, R ⁴⁸ is 1 to 4 hydrogen atoms or carbon atoms R ⁴⁹ represents a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, an amino group, or 1 or 2 carbon atoms having 1 to 4 carbon atoms.
1 to 2 in the nitrogen atom of the amino group, carbamoylmethoxy group or carbamoyl substituted by the alkyl group of
A carbamoylmethoxy group in which one alkyl group having 1 to 4 carbon atoms is substituted, or in the formula,

[0020]

[Chemical 15]

Represents a heterocycle containing 3 to 6 carbon atoms, and R ⁴⁷ and R ⁴⁹ have the same meanings as described above. ) The group shown by. Or (2) R ¹ and R ² together with the nitrogen atom to which they are attached, are —COOH
Represents a heterocycle containing at least one nitrogen atom substituted with or a non-substituted heterocycle containing at least one nitrogen atom, R ³ is (1) a hydrogen atom, (2) a hydroxy group,

(3) Alkyl group having 1 to 6 carbon atoms, (4) halogen atom, (5) alkoxy group having 1 to 4 carbon atoms or (6)
Represents an acyloxy group having 2 to 5 carbon atoms, m is 1 to 4
Represents the integer. ] Or a non-toxic salt or acid addition salt thereof has an elastase inhibitory effect, and is therefore useful for treating diseases caused by elastase, such as emphysema, atherosclerosis and rheumatoid arthritis. Is listed. In the compound represented by the formula (II), in the general formula (A), Y represents a sulfonyl group, ^one of R ¹ and R ² represents a hydrogen atom, and the other represents the formula.

[0023]

[Chemical 16]

[Wherein X represents a single bond,

[0025]

[Chemical 17]

Is a carbocycle (benzene ring), and n is 1
And R ⁴ is the formula

[0027]

[Chemical 18]

[0028] (wherein,> N-Z ⁴⁴ -CO represents an amino acid residue (glycine), R ⁴⁷ represents a single bond, R ⁴⁸ represents a hydrogen atom, R ⁴⁹ represents a hydroxyl group.) Represented by The base ] The compound of Example 2 (63)
It is specifically disclosed in.

The present inventors have prepared and studied various non-toxic salts for the purpose of improving the solubility of the compound represented by the formula (II), and as a result, found that the sodium salt is most suitable. .. However, the monosodium salt of the compound represented by the formula (II) is hygroscopic, and when left to stand in the air, it hydrates over time to form a mixture of 1, 2 and 3 hydrates. Through the steps, it was finally found to be tetrahydrate. Such hygroscopicity is not desirable in view of the purpose of providing a stable pharmaceutical product having uniform physicochemical properties.

[0030]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies to improve these problems, and as a result, the formula (II)
The monosodium salt of the compound represented by the formula (I)
It was found that when synthesized in the form of the tetrahydrate represented by, the hygroscopicity is avoided and a constant composition is maintained, so that the formulation is excellent. Incidentally, this tetrahydrate is not described at all in Japanese Patent Application Laid-Open No. 3-20253 and there is no description suggesting it. Further, it is not possible to predict from the specification of JP-A No. 3-20253 that the hygroscopic property of the monosodium salt of the compound represented by the formula (II) is avoided by making it a tetrahydrate.

[0031]

DISCLOSURE OF THE INVENTION The present invention includes: 1) Formula (I)

[0032]

[Chemical 19]

N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate represented by: 2) its production method, 3) containing it as an active ingredient Drug and 4) its intermediate (Formula (II))

[0034]

[Chemical 20]

The present invention relates to a method for producing N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine represented by:

[0036]

[Method for producing the compound of the present invention] The compound of the present invention represented by the formula (I) has the formula (II)

[0037]

[Chemical 21]

The compound of formula (1) is reacted with, for example, an equimolar to 1.20 mol of sodium hydroxide, sodium hydrogen carbonate or sodium carbonate in an inert solvent (eg, tetrahydrofuran (THF), dioxane, acetone, etc.) to obtain The obtained crude crystals are recrystallized with water or a water-containing water-soluble organic solvent (for example, water-containing methanol, water-containing ethanol, water-containing propyl alcohol, water-containing acetone, water-containing methyl ethyl ketone, water-containing dioxane, etc.), and the obtained crystals are 2
It is produced by blast drying for 4 hours or more. The present invention also provides a novel method for producing a compound represented by formula (II). That is, the compound represented by the formula (II) corresponds to the compound represented by the formula (II), which is produced according to the following reaction process formula [A] in Japanese Patent Application Laid-Open No. 3-20253 by the applicant. Only the part is extracted.).

[0039]

[Chemical formula 22]

However, in the case of industrially producing the compound represented by the formula (II), the method described in JP-A No. 3-20253 has the following problems. That is, in the amidation reaction in the reaction process formula [A],
The nucleophilicity of the amino group of the compound shown in (VI) is fairly weak. Therefore, in this reaction, the compound represented by the formula (V) not only reacts with the amino moiety of the compound represented by the formula (VI) but also partially reacts with the carboxylic acid moiety. This reaction produces a mixed acid anhydride, and subsequent reactions produce many types of by-products. This makes it very difficult to improve the yield of the compound represented by the formula (II) (the yield of the steps from the formula (V) to the formula (II) is about 30%).

Therefore, the method disclosed in the above specification is
The method for industrially synthesizing the compound represented by the formula (II) is not always satisfactory. Therefore, formula (II)
As a result of studying the method for producing the compound represented by the formula (1), it was found that it can be industrially produced free by using the process represented by the following reaction process formula [B].

[0042]

[Chemical formula 23]

That is, according to the above reaction process formula [B],
In carrying out the sulfonamidation reaction (step [C]), by using the compound represented by the formula (IV) in which the carboxyl group is protected by a benzyl group, the reaction step formula [A]
Among them, the production of by-products is less than in the conventional method using the compound represented by the formula (VI), and the compound represented by the formula (III) produced by the sulfonamidation reaction can be easily purified, Since the reduction reaction to the compound represented by the formula (II) is quantitatively performed, the compound represented by the formula (II) can be obtained in high purity and high yield (from the formula (IV) to the formula (II)). The yield in the steps up to is about 85%.). Next, the reaction of each step in the reaction step formula [B] will be described. Process [a]
Is an amidation reaction, the acid halide in the presence of amines (eg, triethylamine, pyridine, picoline, etc.)

[0044]

[Chemical formula 24]

And an inert solvent [for example,
Halogenated hydrocarbon system (methylene chloride, chloroform,
Carbon tetrachloride, tetrachloroethane, hexachloroethane, etc.), ether type (tetrahydrofuran (THF), tetrahydropyran, dioxane, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, methyl ethyl ether, etc.), benzene type (benzene, toluene, xylene, etc.) )], -20 to 50 ° C
It is carried out by reacting with.

Step [b] is a reduction reaction, in which the nitro compound is treated with an inert solvent [eg ether system (the same as above),
From room temperature in the presence or absence of alcohols (methanol, ethanol, propanol, etc.), water or mixed solvents thereof, with iron, zinc or tin and an acid (eg concentrated hydrochloric acid, concentrated sulfuric acid, acetic acid, etc.) The reaction is carried out at the reflux temperature of the solvent, or in the presence of an alcohol solvent (the same as above), sodium borohydride (NaBH ₄ ) and nickel chloride (NiCl 2
₂ ) in the presence or absence of an inert solvent [eg, alcoholic (same as above), ether (same as above)]. , Sodium sulfide / ammonium chloride / ammonia water system, or an inert solvent [eg,
Alcohol system (same as above), ether system (same as above)] in the presence or absence of sodium hydrosulfite (Na ₂ S ₂ O ₄ ) / ammonia water system, or N , N-dimethylformamide (DMF) or 1,3-dimethyl-2-imidazolinone (DMI) and acetic acid in a mixed solvent in the presence of Raney nickel under a hydrogen gas atmosphere under normal pressure or pressure, 3
It is carried out by reacting at 0 to 100 ° C, preferably 35 to 40 ° C.

Step [c] is a sulfonamidation reaction, which comprises the compound of formula (IV) and amines (the same as above).
In the presence of a sulfonyl chloride represented by the formula (V) with or without an inert solvent [for example, a halogenated hydrocarbon system (the same as the above), an ether system (the same as the above)] or -20 It is carried out by reacting at -50 ° C. Step [d] is a reduction reaction, and the compound represented by the formula (III) is treated with an inert solvent [for example, a halogenated hydrocarbon system (the same as the above), an ether system (the same as the above), an alcohol system (the same as the above). ), DMF, acetic acid, ethyl acetate or a mixed solvent of two or more thereof] in the presence of a hydrogenation catalyst (eg, palladium carbon, palladium black, palladium, platinum dioxide, nickel, Raney nickel, etc.) under normal pressure or pressure. In hydrogen gas at 0 to 200 ° C., preferably at room temperature. The starting material and each reagent in the production method of the present invention are known per se or can be produced by a known method. For example, the compound represented by the formula (VIII) is commercially available, and the compound represented by the formula (V) is described in JP-A-3-20253.

[0048]

The N- [o-of the present invention represented by the formula (I)
Since (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate is a uniform and stable compound having no hygroscopicity and has an elastase inhibitory action, elastase in mammals, especially humans It is useful for the treatment and / or prevention of diseases (emphysema, atherosclerosis, rheumatoid arthritis, etc.) caused by abnormal increase in elastin degradation, collagen fiber degradation and / or proteoglycan degradation due to A.

Further, the method for producing the compound represented by the formula (II) of the present invention is (i) the sulfonamidation reaction of the compound represented by the formula (V) Since the compound is used, the production of by-products is small, the yield is improved, and (ii) the compound represented by the formula (III) can be easily purified, and the reduction reaction in the next step is quantitatively performed. This is an industrially useful production method in which the compound represented by the formula (II) is obtained in high purity. The compound represented by the formula (II) obtained by the method of the present invention is easily recrystallized as a sodium salt from an aqueous solvent to give the monosodium salt tetrahydrate of the present invention represented by the formula (I). be able to.

The hygroscopicity and pharmacological effect of the compound of the present invention have been confirmed by the following tests. 1. Hygroscopic Test (Experimental Method) N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate (the compound of the present invention) and N- [o- (p
-Pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt (comparative compound),
Each was left under the conditions of a temperature of 25 ° C. and a humidity of 75%.
The weight of each of them was measured with time, and the hygroscopicity was obtained by comparing with the initial value, and the results shown in Table 1 were obtained.

[0051]

[Table 1]

(Results) As is clear from Table 1, the comparative compounds absorb moisture and increase in weight over time, but the compounds of the present invention show no change in weight. Therefore, it can be said that the compound of the present invention is a uniform and stable compound having no hygroscopicity. 2. Inhibitory effect on elastase Using human neutrophil elastase, the method of Bieth et al. [Bi
ochem.Med., 75 , 350 (1974)]. That is, a synthetic substrate [succinyl-alanyl-] having relatively high specificity for neutrophil elastase
Prolyl-alanyl-p-nitroanilide (Suc-Ala-Pro
-Ala-pNA, manufactured by Peptide Research Laboratories)]. 1 mM Suc-Ala-Pro-Ala-pNA (dissolved in 100 mM with N-methylpyridone and added 1/100 of the amount to the reaction mixture), 0.1 M Tris-HCl buffer (pH 8.
0), 0.2 M sodium chloride solution, 1 ml of reaction mixture consisting of various concentrations of sample solution and enzyme solution at 37 ° C.
Incubated for minutes. 50μ acetic acid 100μ in the reaction solution
After stopping the reaction by adding l, the released p-nitroanilide was measured by the absorbance at 405 nm to obtain the inhibition rate,
The _C50 value was calculated. As a result, the IC ₅₀ value of the compound of the present invention represented by the formula (I) was 0.046.

[0053]

[Toxicity] The toxicity of the compound of the present invention is extremely low, and it can be judged that it is sufficiently safe for use as a medicine.

[0054]

[Application to Pharmaceuticals] The compound of the present invention represented by the formula (I) is
Since it has an elastase inhibitory effect, elastin degradation by elastase, collagen fiber degradation and /
Alternatively, it is useful for treating and / or preventing diseases (emphysema, atherosclerosis, rheumatoid arthritis, etc.) caused by abnormally increased proteoglycan degradation. Formula (I)
When the compound of the present invention represented by the above is used for the above purpose, it is usually administered systemically or locally, orally or parenterally. The dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually in the range of 50 mg to 500 mg per adult per dose.
Orally administered once to several times a day, or in the range of 10 to 200 mg per adult per dose,
It is parenterally administered once to several times a day (preferably intravenous administration) or continuously administered intravenously in the range of 1 hour to 24 hours a day.

Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient in some cases, and a dose exceeding the range may be required in some cases. When the compound of the present invention is administered, it is used as solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories and the like. Solid compositions for oral administration include tablets, pills,
Capsules, powders, granules and the like are included.

Capsules include hard capsules and soft capsules. In such solid compositions, the one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminometasilicate. Mixed with magnesium acid. According to a conventional method, the composition contains an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, and a solubilizing agent such as glutamic acid or aspartic acid. It may be contained. If necessary, tablets or pills should be sucrose, gelatin,
It may be coated with a film of a gastric or enteric substance such as hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Also included are capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups, elixirs and the like, and generally used inert diluents (eg purified water, Ethanol) may be included. In addition to the inert diluent, this composition may contain an auxiliary agent such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative. Other compositions for oral administration include spray formulations which contain one or more active substances and are formulated in a manner known per se. The composition may contain, in addition to an inert diluent, a stabilizing agent such as sodium bisulfite and a buffering agent to give isotonicity, for example, sodium chloride, sodium citrate or citric acid. The method for producing the spray agent is described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355.

The injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of the non-aqueous solution and suspension include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. Such a composition further includes a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, an isotonicity agent, a buffering agent,
Dissolution aids (eg glutamic acid, aspartic acid)
Such an auxiliary agent may be included. These are sterilized by filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. These can also be used by preparing a sterile solid composition and sterilizing or dissolving in a sterile solvent for injection before use. Other compositions for parenteral administration include one or more active substances, which are prescribed by a conventional method, such as an external solution, a soft ko, a liniment, a suppository for rectal administration and an intravaginal administration. Including pessaries for.

[0059]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in the parentheses described in the place of separation by thin layer chromatography (TLC) indicates the elution solvent or developing solvent used, and the ratio represents the volume ratio. The infrared absorption spectrum (IR) was measured by the KBr tablet method.

Reference Example 1 N- (2-nitrobenzoyl) glycine benzyl ester

[0061]

[Chemical 25]

Glycine benzyl ester p-toluenesulfonate (4.049 g) and methylene chloride (20 m
Triethylamine (4.6 ml) was added to the mixture of l). 2-Nitrobenzoyl chloride (1.322 ml) was added dropwise to the mixed solution under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was acidified by adding 1N hydrochloric acid, the organic layer was washed successively with water, aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound having the following physical data. (3.16 g) was obtained. TLC: Rf 0.7 (chloroform: methanol: acetic acid = 30: 3: 1)

Reference Example 2 N- (2-aminobenzoyl) glycine benzyl ester

[0064]

[Chemical formula 26]

Iron powder (3.02 g) was added little by little to a mixed solution of the nitro compound (2.82 g) obtained in Reference Example 1 in THF (18 ml) and water (9 ml) at room temperature. Then, 2N hydrochloric acid (1.08 ml) was added dropwise, and the mixture was stirred at room temperature overnight. A 2N sodium hydroxide aqueous solution (1.2 ml) was added to the obtained reaction solution, the mixture was filtered through Celite, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.05 g) having the following physical data. TLC: Rf 0.6 (chloroform: methanol: acetic acid = 100: 5: 1)

Reference Example 3 N- (2-aminobenzoyl) glycine benzyl ester (manufactured separately)

[0067]

[Chemical 27]

5N sodium hydroxide aqueous solution (40 m
Raney nickel (8.4 g) was added into 1) in small portions over 30 minutes at 50 ° C. After stirring the mixture at 50 ° C. for 1 hour, the Raney nickel was washed with water. Then, the water is added to 1,3-dimethyl-2-imidazolinone (DMI).
Replaced by. A mixture of Raney nickel (4.2 g), the nitro compound obtained in Reference Example 1 (14 g), acetic acid (1.4 ml) and DMI (70 ml) was placed in an autoclave at 40
The mixture was stirred at 25 ° C for 3 hours at ℃. The reaction solution was filtered through Celite, and the filtrate was poured into water. The resulting precipitate was collected by filtration. The solid was air-dried at room temperature for 1 week to obtain the title compound (11.2 g) having the following physical properties. TLC: Rf 0.6 (chloroform: methanol: acetic acid = 100: 5: 1)

Example 1 N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine benzyl ester

[0070]

[Chemical 28]

A mixture of the amine (2.28 g) obtained in Reference Example 2 and pyridine (36 ml) was added to p-pivaloyloxybenzenesulfonyl chloride (see JP-A-3-20) under ice cooling.
Manufactured by the method described in Reference Example 5 of Japanese Patent No. 253; 2.6
6 g) was added and the mixture was stirred at room temperature overnight. The reaction solution was added into concentrated sulfuric acid / water (52 ml / 100 ml), and the mixture was extracted with ethyl acetate. The extract is water, an aqueous solution of sodium hydrogen carbonate,
The extract was washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was crystallized by adding n-hexane, filtered and dried under reduced pressure to obtain the title compound (3.70 g) having the following physical properties as pale yellow crystals. TLC: Rf 0.64 (ethyl acetate: n-hexane = 1: 1
1); IR (cm ^-1 ): ν 3425,2976,1757,1642,1597,1540,
1495,1457,1406; NMR (CDCl ₃ ) δ (ppm): 7.75 to 7.65 (3H, m),
7.50 ~ 7.30 (6H, m), 7.18 ~ 7.00 (3H, m), 6.41 (1H, brs),
5.21 (2H, s), 4.04 (2H, d), 1.30 (9H, s).

Example 2 N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine

[0073]

[Chemical 29]

The compound obtained in Example 1 (3.70 g), methanol (40 ml) and 10% palladium on carbon (3
90 mg) of the mixture was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 3 hours. The reaction solution was filtered through Celite, concentrated under reduced pressure,
The title compound (2.91 g) having the following physical data was obtained as white crystals. TLC: Rf 0.14 (chloroform: methanol: acetic acid = 100: 5: 1); IR (cm ⁻¹ ): ν 3432,2978,1749,1722,1647,1524,
1493,1453,1407; NMR (CDCl ₃ + CD ₃ OD) δ (ppm): 7.77 (2
H, d, J = 8.5Hz), 7.66 (1H, d, J = 7.5Hz), 7.63 (1H, d, J = 7.5H)
z), 7.46 (1H, t, J = 7.5Hz), 7.15 (2H, d, J = 8.5Hz), 7.13 (1
H, t, J = 7.5Hz), 3.98 (2H, s), 1.35 (9H, s).

Example 3 N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt.4
Hydrate

[0076]

[Chemical 30]

The compound (8.69 g) obtained in Example 2 was added to T
It was dissolved in HF (40 ml) while hot. 5N sodium hydroxide aqueous solution (4.2 ml) was added under cooling, and the solvent was distilled off under reduced pressure. The obtained crude crystals were dissolved in water (30 ml) with heating and left at 5 to 10 ° C. overnight. The precipitated crystals were collected by filtration, washed with ice water, and air-dried at room temperature for 24 hours to give the title compound (8.55 g) having the following physical properties as white crystals. Moisture quantitative value (Karl Fischer method): 13.65% (theoretical value 13.63%); IR (cm ^-1 ): ν 3440,2979,1755,1626,1589,1494,
1401,1344,1273,1217,1155,1126,1094,942,848,754,68
7,600,576; Molecular structure: Figure 1.

[0078]

[Formulation Example] The following components are mixed by a conventional method, the solution is sterilized by a conventional method, 5 ml each is filled in a vial, and freeze-dried by a conventional method. A vial containing 100 mg of active ingredient in 1 vial. I got 100 bottles.・ N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt ・ tetrahydrate ・ ・ ・ 10 g ・ Distilled water ・ ・ ・ 500 ml ・ Sodium chloride ・ ・ ・ 7 g ・ Sodium carbonate (anhydrous) ...... 1.5 g

[Brief description of drawings]

FIG. 1 N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] obtained according to Example 3.
It is a molecular structure based on X-ray diffraction of glycine monosodium salt tetrahydrate.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/22 ABX 8413-4C ACD 8413-4C ADN 8413-4C ADS 8413-4C AED 8413-4C

Claims (4)

[Claims] 1. Formula (I): N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate represented by 2. Formula (II): Wherein N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt is recrystallized with water or a water-containing water-soluble organic solvent, and the obtained crystal is blow-dried. Formula (I) A method for producing N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate represented by: 3. Formula (I): An elastase inhibitor containing N- [o- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine monosodium salt tetrahydrate represented by as an active ingredient. 4. Formula (IV): And a compound of formula (V) The compound represented by the formula (III) was obtained by subjecting it to a sulfonamidation reaction. A compound characterized by subjecting a compound represented by
(II) [Chemical 8] The manufacturing method of the compound shown by these.