JPH0694450B2 - Pivalic acid p-substituted phenyl ester derivative, method for producing them and elastase inhibitor containing them as active ingredients - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to pivalic acid p-substituted phenyl ester derivatives represented by the following general formula (I) having an elastase inhibitory activity.

[0002]

[Chemical 18] [In the formula, all symbols have the same meanings as described below. ]

[0003]

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 and the hydrophobic site of protein that directly function to maintain the elasticity of lung tissue [J. Cell. Biol., 40 , 366 (196
9)]. Furthermore, elastase selectively decomposes not only elastin but also the cross-linked region of collagen fibers [J. Bio
chem., 84, 559 (1978)], and also acts on tissue structural proteins such as proteoglycan [J. Clin. Invest. , 57, 615].
(1976)] and plays a central role in connective tissue metabolism.

[0004] In vivo, elastase common inhibitors to serine enzyme, alpha ₁ - by proteinase inhibitor (α ₁ -PI) but is deactivated, an enzyme - when there is a disturbance in the balance of the inhibitor system, Tissue-destructive symptoms appear [Schweiz. Med. Wshr., 114, 895 (198
Four) ]. Elastin turnover in normal tissues is very slow [Endocrinology, 120, 92 (1978)], but emphysema [Am. Rev. Respir. Dis., 110 , 254 (1974)] and atherosclerosis [Lab. Invest., 22 , 228 (1
970)] or rheumatoid arthritis [in Neutral Proteas
es of Human Polymorphonuclear Leukocytes, Urban an
d Schwarzenberg, Baltimore-Munich (1978), p. 390]
Under various pathological conditions such as Escherichia coli, abnormal elastin degradation is observed, and the relationship between elastase and disease has been attracting attention [infection, inflammation, immunity, 13, 13 (1983)].

[0005]

2. Description of the Related Art Under the above background, research and development of elastase inhibitors have recently been actively conducted, and various elastase inhibitors have been proposed and applied for patents. Particularly recently, for example, U.S. Pat.

[0006]

[Chemical 19] [In the formula, X ^a represents a carbonyl group, a methylene group, an oxygen atom,
Azo group, sulfonyl group, -CH (OH)-,

[0007]

[Chemical 20]

Or together with a benzene ring

[Chemical 21] Represents,

R ^a and R ^1a are an alkyl group having 2 to 6 carbon atoms and an acylaminoalkyl group, an alkoxy group having 1 to 6 carbon atoms, an alkenyl group and a carboxyalkyl group,
Cycloalkyl group having 3 to 6 carbon atoms or 1 to 10 carbon atoms
Represents an alkoxycarbonylalkyl group of R ^2a and R ^3a are a hydroxyl group, a halogen atom, a pyranyloxy group,
C1-C4 alkyl group, alkenyl group, hydroxyalkyl group and formylalkyl group or C1-C4
6 represents a carboxylalkyl group. ] The compound shown by these is disclosed.

[0010]

OBJECTS OF THE INVENTION The present inventors have conducted extensive studies to find a compound having an elastase inhibitory action which has a chemical structure completely different from those of the conventional compounds, and as a result, the compound represented by the general formula (I) is obtained. It was found that the compound to be achieved achieves the object, and completed the present invention.

[0011]

[Comparison with Prior Art] US Patent 4 mentioned in the prior art
No. 683241 discloses certain pivalic acid benzoylphenyl esters and benzenesulfonylphenyl esters as elastase inhibitors,
The sulfamoylphenyl ester and carbamoylphenyl ester of the present invention have a structure that cannot be easily analogized from these compounds, and it was unexpected that they also have an elastase inhibitory action.

[0012]

DISCLOSURE OF THE INVENTION That is, the present invention has the general formula (I)

[0013]

[Chemical formula 22]

[Wherein Y is a sulfonyl (-SO _2- ) group or

[Chemical formula 23]

(I) R ¹ and R ² may be the same or different, and (1) a hydrogen atom, (2) an alkyl group having 1 to 16 carbon atoms or (3) a formula

[0016]

[Chemical formula 24] (In the formula, X is a single bond, a sulfonyl (—SO ₂ —) group, an alkylene group having 1 to 4 carbon atoms, a —COOH group, or

[0017]

[Chemical 25] Represents an alkylene group having 1 to 4 carbon atoms which may be substituted with

[0018]

[Chemical formula 26] Represents a carbocycle or a heterocycle,

N represents an integer of 1 to 5, R ^{4 s} may be the same or different, 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. an alkylthio group having 1 to 6 carbon atoms, d. a hydroxyl group, a halogen atom, a nitro group or a trihalomethyl group, e. a formula —NR ⁴¹ R ⁴² (in the formula, R ⁴¹ and R ⁴² may be the same or different) A hydrogen atom or an alkyl group having 1 to 4 carbon atoms), f. A tetrazole group,

G. Sulfonic acid (--SO ₃ H) group or hydroxymethyl (--CH ₂ OH) group, h. Formula --SO ₂ NR ⁴¹ R ⁴² (wherein R ⁴¹ and R ⁴² have the same meanings as described above). Represent)
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, R ⁴³ represents a hydrogen atom, A group represented by a C1-4 alkyl group or a benzyl group), j. Formula —CONR ⁴¹ R ⁴² (wherein R ⁴¹ and R ⁴² have the same meanings as described above).
A group represented by the formula: 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. ) Group,

A group represented by the formula: -COO-Z ⁴² -CONR ⁴¹ R ⁴² (wherein all symbols have the same meanings as described above), m. Formula -OCO-R ⁴⁵ (in the formula, R ⁴⁵ is a group represented by an alkyl group having 1 to 8 carbon atoms or a p-guanidinophenyl group, 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.

[0022]

[Chemical 27]

(Where

[Chemical 28]

Is an amino acid residue, R ⁴⁷ is a single bond or an alkyl group having 1 to 4 carbon atoms, R ⁴⁸ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ⁴⁹ is a hydroxyl group or a carbon atom. An alkoxy group having 1 to 4 carbon atoms, an amino group, an amino group substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms, a carbamoylmethoxy group, or 1 or 2 carbon atoms in the nitrogen atom of carbamoyl; A carbamoylmethoxy group in which the alkyl group of -4 is substituted, or,

[0025]

[Chemical 29]

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 (ii) R ¹ and R ² , together with the nitrogen atom to which they are attached, are a heterocycle containing at least one nitrogen atom substituted with —COOH or an unsubstituted ring. Represents a heterocycle containing at least one nitrogen atom, R ³ is (1)
Hydrogen atom, (2) 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) acyloxy group having 2 to 5 carbon atoms Represents,
m represents an integer of 1 to 4. ] (However, N- [o- (p-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine is excluded.), Or a non-toxic salt or acid addition salt thereof, a method for producing the same, or them. Relates to an elastase inhibitor containing as an active ingredient.

In this specification, including the claims,
When simply expressed as “alkyl group”, “alkylene group”, “alkenylene group”, “alkoxy group” and “acyloxy group”, these are straight chain or branched chain alkyl group, alkylene group, alkenylene group, alkoxy group. Group and acyloxy group. General formula (I)
Of these, the sulfonyl and carbonyl groups represented by Y are both preferable. In the general formula (I), the number of carbon atoms represented by R ³ is 1 to
Examples of the alkyl group of 6 include methyl, ethyl, propyl,
Butyl, pentyl and hexyl groups and their isomers are mentioned, all preferred. In the general formula (I), R
Examples of the halogen atom represented by ³ and R ⁴ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the general formula (I), the number of carbon atoms represented by R ³ is 1 to
Examples of the alkoxy group of 4 include a methoxy group, an ethoxy group, a propoxy group, and a butyloxy group and isomers thereof, and all of them are preferable. Examples of the acyloxy group having 2 to 5 carbon atoms represented by R ³ in the general formula (I) include acetoxy, propyloxy, butyloxy, heptyloxy groups and isomers thereof, and any of them is preferable.

In the general formula (I), the alkyl group having 1 to 16 carbon atoms represented by R ¹ and R ² includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, Dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl groups and isomers thereof are mentioned, all of which are preferred. Examples of the alkylene group having 1 to 4 carbon atoms represented by X and Z ⁴¹ in the general formula (I) include methylene, ethylene, trimethylene and tetramethylene groups and isomers thereof, and all of them are preferable. General formula (I)
During,

[0030]

[Chemical 30]

The carbocyclic ring represented by means a monocyclic or bicyclic aromatic ring having 12 or less carbon atoms which may be partially or entirely saturated. Examples of these rings include benzene, naphthalene, indene, azulene rings and rings in which some or all of them are saturated. In the general formula (I),

[0032]

[Chemical 31]

The heterocycle represented by means a monocyclic or bicyclic carbon which may be partially or wholly saturated and a heterocycle having 12 or less hetero atoms. Among these rings, those having one or two heteroatoms are preferable. Examples of these rings include furan, thiophene, pyrrole,
Oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran, benzothiophene, indolizine, chromene, quinoline, isoquinoline, quinolidine, purine, indazole , Quinazolines, cinnolines, quinoxalines, phthalazines, pteridine rings and rings in which some or all of these are saturated.

In the general formula (I), the number of carbon atoms represented by R ⁴ is 1 to
Examples of the alkyl group of 8 include methyl, ethyl, propyl,
Butyl, pentyl, hexyl, heptyl and octyl groups and their isomers are mentioned, all preferred. Examples of the alkoxy group having 1 to 14 carbon atoms represented by R ⁴ in the general formula (I) include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, Dodecyloxy, tridecyloxy, tetradecyloxy groups and isomers thereof are mentioned, all are preferable, and methoxy, pentyloxy, decyloxy groups and isomers thereof are particularly preferable.

In the general formula (I), the number of carbon atoms represented by R ⁴ is 1 to
Examples of the alkylthio group of 6 include methylthio, ethylthio,
Examples include propylthio, butylthio, pentylthio, hexylthio groups and isomers thereof, all of which are preferred. In formula (I), R ⁴ is also preferably halogen, trihalomethyl, nitro, hydroxy, tetrazole, sulfonic acid or hydroxymethyl. General formula (I)
In the formula, R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁶ have 1 to 4 carbon atoms.
Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group and isomers thereof, and all of them are preferable.

In the general formula (I), the carbon number represented by Z ⁴¹ is 2 to 2.
The alkenylene group of 4 includes vinylene, propenylene and butenylene groups and isomers thereof,
Both are preferable. Examples of the alkyl group having 1 to 8 carbon atoms represented by R ⁴⁵ in the general formula (I) include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl groups and isomers thereof, and all of them are preferable. . In the general formula (I), examples of the alkylene group having 1 to 6 carbon atoms represented by Z ⁴³ include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene groups, and isomers thereof, all of which are preferable. In the general formula (I), the formula

[0037]

[Chemical 32]

The amino acid residue represented by may be the residue of any amino acid, and these residues include those in which the carboxy group is converted into an ester. Preferred are residues of neutral or acidic amino acids. Specifically, residues of glycine, alanine, valine, phenylalanine, lysine, and methionic acid and their esters (preferably alkyl ester having 1 to 4 carbon atoms and carbamoyl substituted with alkyl group having 1 to 4 carbon atoms) Methyl ester).

In the general formula (I), R ¹ and R ² together with the nitrogen atom to which they are bonded represent --CO
A heterocycle which is substituted with an OH group or is unsubstituted and which contains at least one nitrogen atom means a monocyclic or bicyclic carbon which may be partially or wholly saturated and a heterocyclic atom number of 12 Refers to the following heterocycles. Of these rings, those having one or two heteroatoms are preferred.

Examples of these rings include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran, Benzothiophene, indolizine, chromene, quinoline, isoquinoline, quinolidine, purine, indazole, quinazoline, cinnoline, quinoxaline,
Examples include fratadine, pteridine rings and rings in which some or all of them are saturated. The acid addition salt of the compound represented by formula (I) is preferably non-toxic and water-soluble. Suitable acid addition salts include, for example, the hydrochloride salt,
Inorganic acid salts such as hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethane Organic acid salts such as sulfonate, benzene sulfonate, toluene sulfonate, isethionate, glucuronate and gluconate are mentioned.

The compound of the present invention represented by the general formula (I) is
It is converted into a salt by a known method. The salt is preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (sodium, potassium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine). , Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.) and the like.

[0042]

According to the present invention, the compound of the present invention represented by the general formula (I) can be produced by using any of the following steps. In each formula, R ¹¹ and R ²¹ have the same meanings as R ¹ and R ² , respectively, but at least one group represents a group containing a benzyloxycarbonyl group, and R ¹² and R ²² each represent R 1. ¹ and R ² have the same meanings, but at least one of the groups represents a group containing a carboxyl group, and R ¹³
Represents a group represented by R ¹ or R ² excluding a hydrogen atom, R ¹⁴ represents an alkyl group having 1 to 4 carbon atoms, and X represents
Represents a halogen atom, and R ³¹ represents an acyloxy group.

[0043]

[Chemical 33]

[0044]

[Chemical 34]

Step 1 is an esterification reaction, which is carried out in the presence of a tertiary amine in an inert organic solvent (for example, methylene chloride, ethyl acetate, benzene, hexane, diethyl ether) at room temperature and corresponding hypaloyl. It is carried out by reacting with a halide. As such a dehydrohalogenating agent, a tertiary organic amine, and if desired, an inorganic base such as a metal bicarbonate can be used. Aliphatic, aromatic or heterocyclic amines such as triethylamine, tributylamine, dimethylaniline, pyridine and the like are used as the tertiary organic amine. Of these, pyridine is particularly preferable because it also acts as a solvent for the reaction components.

Step 2 is an amidation reaction and is represented by the general formula (II
I) in the presence of an organic or inorganic base (eg, a tertiary amine such as triethylamine) in an inert organic solvent (eg, methylene chloride) or in the absence thereof,
It is carried out by reacting with a corresponding amine at a temperature of -20 ° C to 0 ° C (preferably under ice cooling). Step 3 is a debenzylation reaction, which is performed in a hydrogen gas atmosphere using a catalyst such as palladium-carbon in an inert organic solvent (eg, acetic acid, THF) mixed solution at a temperature of 0 ° C. to 40 ° C. (preferably Room temperature).

Step 4 is an N-alkylation reaction, which is carried out at room temperature with an alkyl halide in the presence of a suitable base (eg sodium hydride) in a suitable inert organic solvent (eg benzene, tetrahydrofuran, dimethylformamide). It is carried out at the reflux temperature. Step 5 is a deacylation reaction, which is carried out at room temperature in the presence of a catalyst (eg triethylamine), for example in methanol. The compounds represented by the general formulas (II) and (III) used in the above step can be produced according to a known combination of reactions, for example, the following reaction step formula A. In the formula, G represents a methoxy group or an acetoxy group, and other symbols have the same meanings as described above.

[0048]

[Chemical 35]

All the reactions in the above reaction scheme are carried out by known methods. In each reaction in the present specification, the reaction product is a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or column chromatography or washing, recrystallization. And the like. Purification may be carried out for each reaction or after completion of several reactions.

[0050]

[Starting material] General formula (IV) used in the production method of the present invention,
The starting materials represented by (V) and (VII) are all known compounds or can be easily prepared by known methods. For example, R ^1, R ² of general formula (IV) is, in the general formula (I) R ^1, the R ² (3)
The compound represented by the general formula (XI) representing the group of -p. Can be synthesized from the compound represented by the general formula (VIII) according to the following reaction scheme B. In the formula, the sum of p and r is 1
Represents an integer of 5 and r does not take 0. R ²⁴ represents a group other than p. Among the groups represented by R ⁴ .

[0051]

[Chemical 36]

[0052]

[Effect] pivalic acid p- represented by the general formula (I) of the present invention
Since the substituted phenyl ester derivative, its non-toxic salt and its acid addition salt have an elastase inhibitory effect, it is possible to prevent the occurrence of diseases caused by elastase degradation, collagen fiber degradation and / or abnormal proteoglycan degradation in mammals, especially humans. Useful for treatment and / or prevention. Such diseases include emphysema, atherosclerosis and rheumatoid arthritis. The elastase inhibitory action of the compound of the present invention was confirmed by the screening system described below.

Inhibitory effect on elastase (1) Experimental method Using human neutrophil elastase, the method of Bieth et al. [Bi
Med., 75, 350 (1974)]. That is, a synthetic substrate [succinyl-alanyl-] having relatively high specificity for neutrophil elastase
Prolyl-alanyl-p-nitroanilide (Suc-Ala-Pr
o-Ala-pNA, manufactured by Peptide Research Laboratories)].

1 mM Suc-Ala-Pro-Ala-pNA (dissolved in 100 mM with N-methylpyridone, 1/100 of the amount was added to the reaction mixture), 0.1 M Tris-HCl buffer (pH 8.
0), 0.2 M aqueous sodium chloride solution, 1 ml of a reaction mixture consisting of various sample solutions and enzyme solutions was incubated at 37 ° C. for 30 minutes. After the reaction was stopped by adding 100 μl of 50% acetic acid to the reaction solution, 405 of released p-nitroanilide was removed.
The absorbance was measured at nm, and the inhibition rate was calculated by the following formula. Inhibition rate (%) = [1- (sample value-blank value) / (control value-blank value)] x 100

(2) Results The results are shown in Table I.

[0056]

[Table 1]

[0057]

[Table 2]

[0058]

[Table 3]

[0059]

[Table 4]

[0060]

[Toxicity] From the experimental results, it was confirmed that the compound of the present invention has an elastase inhibitory action. Furthermore, the toxicity of the compound of the present invention was sufficiently low, and it was confirmed that the compound of the present invention can be used safely as a drug. [Indication] Therefore, it was confirmed that the compound of the present invention is useful for the treatment and / or prevention of the diseases caused by the abnormally enhanced degradation of elastin and other proteins by elastase in mammals, especially humans.

[Dose] In order to use the compound of the present invention represented by the general formula (I) and its acid addition salt for the above purpose, it is usually administered systemically or locally, orally or parenterally. Although the dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., it is usually 50 mg to 500 mg per adult orally once or several times a day, or Or 1 per adult per adult
Parenteral administration (preferably intravenous administration) is carried out once to several times a day in the range of 0 mg to 200 mg. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose range may be sufficient in some cases, or a dose exceeding the range may be necessary in some cases.

Solid compositions for oral administration according to the present invention include tablets, powders, granules and the like. 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. The composition comprises, according to a conventional method, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, 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, suspensions, syrups, elixirs and the like, and generally used inert diluents. For example, it contains purified water and ethanol. This composition may contain, in addition to an inert diluent, auxiliary agents 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 stabilizer such as sodium bisulfite and a buffer to provide isotonicity, for example sodium chloride, sodium citrate or citric acid. The method for producing the spray agent is described in, for example, US Pat.
Details are given in 691 and 3095355.

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 compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers (eg glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injectable solution before use. Other compositions for parenteral administration include external preparations containing one or more active substances and prepared by a method known per se, coating agents such as soft koh, suppositories for rectal administration. And pessaries for vaginal administration and the like.

[0065]

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. In addition, "TL" in Reference Examples and Examples.
“C”, “NMR” and “IR” respectively represent “thin layer chromatography”, “nuclear magnetic resonance spectrum” and “infrared absorption spectrum”. The solvent in the parentheses described at the place of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. IR is measured by the KBr method and NMR is measured in deuterated chloroform (CDCl ₃ ) unless otherwise specified.

Reference Example 1 1- (N-methyl-N-phenyl) sulfamoyl-4
-Methoxybenzene

[Chemical 37]

P-Methoxybenzenesulfonyl chloride (965 mg) was dissolved in a mixed solution of methylaniline (500 mg) triethylamine (2 ml) and methylene chloride (10 ml) under ice cooling and stirred for 30 minutes. The reaction solution was further stirred at room temperature overnight. After the reaction was completed, the mixture was extracted with ether. It was washed successively with 1N-HCl, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound.

Reference Example 2 p- [N-methyl-N- (p-bromophenyl) sulfamoyl] phenol

[Chemical 38]

Boron tribromide (2.2 ml) was added to a solution of the compound obtained in Reference Example 1 in methylene chloride (10 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution is -20 ° C to -30
After cooling to ℃, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over sodium sulfate, and purified by silica gel column chromatography (methylene chloride: ethyl acetate = 10: 1) to give the title compound (900 mg) having the following physical data. . TLC: Rf 0.20 (methylene chloride: ethyl acetate = 3
0: 1).

Reference Example 3 p- [N- (p-tolyl) carbamoyl] phenol

[Chemical Formula 39]

[P-acetoxy-N- (p-tolyl)] benzamide (300 m) obtained in the same manner as in Reference Example 1.
g) in methanol solution (50 ml) with potassium carbonate (50 ml)
0 mg) was added and the mixture was stirred overnight. The obtained reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The extract is 1N-hydrochloric acid,
The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound having the following physical data. TLC: Rf 0.31 (methylene chloride: ethyl acetate = 1
0: 1).

[0072]Example 1  Pivalic acid p- [N- (p-bromophenyl) -N-me
Tylsulfamoyl] phenyl ester

[Chemical 40]

Pivaloyl chloride (0.5 ml) was added to a triethylamine (1.5 ml) -methylene chloride (5 ml) mixed solution of the compound obtained in Reference Example 2 or Reference Example 3 under ice cooling, and the mixture was allowed to stand for 10 minutes. Then, the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ether, water, 1N-HCl,
The extract was washed successively with water, saturated sodium hydrogen carbonate, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Recrystallization from ethyl acetate-hexane gave the title compound (510 mg) having the following physical data. TLC: Rf 0.81 (methylene chloride: ethyl acetate = 3
0: 1); IR: 1750,1590,1460,1400,1350 cm ^-1 . Hereinafter, using the corresponding starting materials, Reference Example 1 → Reference Example 2
(Or reference example 3)-> same operation as in example 1
The target compounds shown in II and III were obtained.

[0074]

[Table 5]

[0075]

[Table 6]

[0076]

[Table 7]

[0077]

[Table 8]

Reference Example 4 Sodium p-pivaloyloxybenzenesulfonate

[Chemical 41]

Pivaloyl chloride (2.4 g) was added to p-
Hydroxybenzenesulfonic acid (1.74g) 4N-Na
It was dissolved in a mixed solution of OH (7.5 ml) and THF (5 ml), stirred for 10 minutes under ice cooling, and further reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the crystals were filtered off. The crystals obtained were washed twice with a small amount of ice water and dried to give the title compound (1.26 g) having the following physical data. TLC: Rf 0.65 (ethyl acetate: acetic acid: water = 6: 2:
1).

Reference Example 5 p-pivaloyloxybenzenesulfonyl chloride

[Chemical 42]

Thionyl chloride (2.1 ml) was added to the compound (2.8 g) obtained in Reference Example 4 in DMF solution (33 ml).
In addition, the mixture was stirred under ice cooling for 30 minutes and further at room temperature for 30 minutes. The reaction solution was extracted with ether-hexane (1: 1) and washed twice with ice water. After drying with magnesium sulfate, the title compound (2.49 g) having the following physical data was obtained. TLC: Rf 0.34 (hexane: ethyl acetate = 10:
1).

Example 2 Pivalic acid p- [N-((trans-p-carboxycyclohexyl) methyl) sulfamoyl] phenyl ester

[Chemical 43]

The same operation as in Reference Example 1 was carried out using the sulfonyl chloride obtained in Reference Example 5 to obtain the title compound (110 mg) having the following physical data. TLC: Rf 0.32 (chloroform: methanol: acetic acid = 100: 5: 1); NMR: 7.9 (2H, d), 7.25 (2H, d), 4.4 (1H, m), 2.8 (2H,
m), 2.4-1.0 (9H, m), 1.35 (9H, s). Hereinafter, using the sulfonyl chloride obtained in Reference Example 5 and the corresponding amine, the same operation as in Example 2 was performed, and the following table was used.
The target compounds shown in IV and V were obtained.

[0084]

[Table 9]

[0085]

[Table 10]

[0086]

[Table 11]

[0087]

[Table 12]

[0088]

[Table 13]

[0089]

[Table 14]

[0090]

[Table 15]

[0091]

[Table 16]

[0092]

[Table 17]

[0093]

[Table 18]

[0094]

[Table 19]

[0095]

[Table 20]

[0096]

[Table 21]

[0097]

[Table 22]

[0098]

[Table 23]

[0099]

[Table 24]

[0100]

[Table 25]

[0101]

[Table 26]

[0102]

[Table 27]

[0103]

[Table 28]

[0104]

[Table 29]

[0105]

[Table 30]

[0106]

[Table 31]

[0107]

[Table 32]

[0108]

[Table 33]

[0109]

[Table 34]

[0110]

[Table 35]

[0111]

[Table 36]

[0112]

[Table 37]

[0113]

[Table 38]

[0114]

[Table 39]

[0115]

[Table 40]

[0116]

[Table 41]

Example 3 Pivalic acid p- [N- (p- (p-guanidinobenzoyloxy) phenyl) sulfamoyl] phenyl ester

[Chemical 44]

The compound of the present invention (5) obtained in Example 2 (7)
A hydrochloride of p-guanidinobenzoyl chloride (800 mg) was added to a pyridine solution (5 ml) of (00 mg) under ice cooling, and the mixture was stirred for 2 hours. After the reaction, ether was added and the supernatant was removed, then saturated sodium hydrogen carbonate was added to obtain an oily carbonate. After further removing sodium hydrogen carbonate, silica gel column chromatography (ethyl acetate: acetic acid: water = 400: 100: 30) was performed to obtain the title compound (532 mg) having the following physical properties. TLC: Rf 0.80 (ethyl acetate: acetic acid: water = 3: 1:
1); IR: ν 3600 to 2300, 1750 to 1700, 1680, 1500, 140
0.

Example 4 Pivalic acid p- [N- (p-benzyloxycarbonylphenyl) sulfamoyl] phenyl ester

[Chemical formula 45]

The procedure of Reference Example 1 → Example 1 was performed using the corresponding sulfonyl chloride as a starting material to obtain the title compound (210 mg: the compound obtained in Example 1 (5)). Thereafter, the corresponding amine and pivaloyl chloride were used to operate in the same manner as in Example 4 to obtain the compounds of the present invention shown in the following Table VI.

[0121]

[Table 42]

[0122]

[Table 43]

Example 5 Pivalic acid p- [N- (p-carboxyphenyl) sulfamoyl] phenyl ester

[Chemical formula 46]

In a hydrogen gas atmosphere, the benzyl compound (190 mg) obtained in Example 4, 10% Pd-C (30 mg), acetic acid (10 ml) and THF (4 ml) were stirred at room temperature for 3 hours. The reaction solution was filtered, azeotropically concentrated with a toluene-THF mixed solution, and recrystallized with an ethyl acetate-hexane mixed solution to obtain the title compound (143 mg) having the following physical properties. TLC: Rf 0.56 (ethyl acetate: hexane = 1: 1
1); IR: ν 2700 to 2400, 1750, 1680, 1600, 1340, 129
0, 1200, 1160, 1110 cm ^-1 . Thereafter, the same operation as in Example 5 was carried out using the corresponding benzyl compound to obtain the compounds of the present invention shown in Table VII below.

[0125]

[Table 44]

[0126]

[Table 45]

[0127]

[Table 46]

[0128]

[Table 47]

[0129]

[Table 48]

Example 6 Pivalic acid p-[(N-methyl-N-phenyl) sulfamoyl] phenyl ester

[Chemical 47]

The compound of the present invention (300) obtained in Example 1 (1)
THF solution (8 ml) of (mg) was added to sodium hydride (37 mg) under ice cooling in an argon atmosphere, and the mixture was stirred for 2 hours. Methyl iodide (66 μl) and hexamethylphosphoramide (HMPA) (1 ml) were added to the reaction solution.
Stir for 0 minutes. After extraction with ether, the extract was washed successively with water and saturated brine. Further, it was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (180 mg) having the following physical properties. TLC: Rf 0.61 (methylene chloride: ethyl acetate = 3
0: 1); IR: ν 1750,1590,1490,1450,1340 cm ^-1 . Thereafter, the corresponding pivalic acid derivative was used and operated in the same manner as in Example 6 to obtain the compounds of the present invention shown in the following Table VIII.

[0132]

[Table 49]

Example 7 Pivalic acid 3-hydroxy-4-[(N-methyl-N-
Phenyl) sulfamoyl] phenyl ester

[Chemical 48]

The compound of the present invention (83) obtained in Example 2 (112)
mg), methanol (5 ml) and triethylamine (
0.3 ml) was stirred at room temperature for 3 hours. Extracted with ether,
It was washed successively with 1N hydrochloric acid, water, and saturated saline. The extract was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (68 mg) having the following physical data. TLC; Rf 0.34 (methylene chloride: ethyl acetate = 3
NMR (CDCl ₃ ); δ 7.0 to 7.4 (6H, m), 6.65 (1H,
d), 6.1 (1H, 2d), 3.5 (3H, s), 1.3 (9H, s).

[0135]

[Formulation Example] After mixing the following components by a conventional method,
100 tablets that are compressed to have 50 mg of active ingredient in each tablet
I got a lock.・ N- [5-methylthio-2- (p-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine ………… 5g ・ Fibrin calcium glycolate (disintegrant) …… 0.2g ・ Magnesium stearate (lubrication Agent) ………… 0.1g ・ Microcrystalline cellulose ………… 4.7g

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/44 7431-4C 31/445 AED C07C 235/46 7106-4H 235/52 7106-4H 311 / 29 7419-4H 311/42 7419-4H 311/48 7419-4H 323/42 7419-4H C07D 207/16 8217-4C 211/60 9165-4C 211/62 9165-4C 213/42 213/76 233 / 56 233/60 104 295/22 319/20

Claims (11)

[Claims] 1. A compound represented by the general formula (I): [Wherein Y is a sulfonyl (—SO ₂ —) group or (i) R ¹ and R ² may be the same or different and (1) a hydrogen atom, (2) a carbon number 1 to 16 which may be substituted with a carboxylic acid.
Or an alkyl group of formula (3) (In the formula, X is a single bond, a sulfonyl (—SO ₂ —) group, an alkylene group having 1 to 4 carbon atoms, a —COOH group, or Represents an alkylene group having 1 to 4 carbon atoms which may be substituted with Represents a carbocycle or a heterocycle, n represents an integer of 1 to 5, R ⁴ may be the same or different, a. A hydrogen atom or an alkyl group having 1 to 8 carbon atoms, b. ~ 14 alkoxy group, c. Alkylthio group having 1 to 6 carbon atoms, d. Hydroxyl group, halogen atom, nitro group or trihalomethyl group, e. Formula -NR ⁴¹ R ⁴² (wherein R ⁴¹ and R ⁴² are the same. Kamata may be different, the group represented by.) represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, f. a tetrazole group, g. sulfonic acid (-SO ₃ H) group or a hydroxymethyl (-CH ₂ OH) 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, R ⁴³ represents a hydrogen atom, A group represented by a C1-4 alkyl group or a benzyl group), j. Formula —CONR ⁴¹ R ⁴² (wherein R ⁴¹ and R ⁴² have the same meanings as described above).
A group represented by the formula: 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: -COO-Z ⁴² -CONR ⁴¹ R ⁴² (wherein all symbols have the same meanings as described above), m. Formula -OCO-R ⁴⁵ (formula: Wherein R ⁴⁵ represents an alkyl group having 1 to 8 carbon atoms or a p-guanidinophenyl group. N. Formula —CO—R ⁴⁶ (In the formula, R ⁴⁶ is an alkyl group having 1 to 4 carbon atoms. Represents a group.)
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. ), A group represented by p. (In the formula, Represents an amino acid residue, R ⁴⁷ represents a single bond or a carbon number of 1.
Represents to 4 alkyl groups, R ⁴⁸ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R ⁴⁹ represents a hydroxyl group, an alkoxy group, an amino group having 1 to 4 carbon atoms, one or two carbon atoms 1 to the nitrogen atom of an amino group, carbamoylmethoxy group or carbamoyl substituted with 1 to 4 alkyl groups
Or two carbamoylmethoxy groups substituted with 1 to 2 alkyl groups having 1 to 4 carbon atoms, or in the formula: 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 (ii) R ¹ and R ² , together with the nitrogen atom to which they are attached, are a heterocycle containing at least one nitrogen atom substituted with —COOH or at least an unsubstituted ring. Represents a heterocycle containing one nitrogen atom,
R ³ is (1) hydrogen atom, (2) 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) carbon Represents an acyloxy group of the number 2 to 5, and m represents an integer of 1 to 4. ] The compound (however, N
Excludes-[o- (p-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine. ), Or their non-toxic or acid addition salts. 2. The compound according to claim 1, wherein Y represents a sulfonyl group (—SO ₂ —). 3. A compound represented by the formula: The compound according to claim 1, wherein is a carbocycle. 4. embedded image The compound according to claim 1, wherein is a phenyl group. 5. The compound according to claim 1, wherein one of R ⁴ represents an amino acid residue. 6. The compound according to claim 1, wherein the amino acid residue represented by R ⁴ is a glycine residue. 7. The compound according to claim 1, wherein the amino acid residue represented by R ⁴ is an alanine residue. 8. The compound is N- [m- (3-methyl-4
-Pivaloyloxybenzene) sulfonylaminobenzoyl] glycine, N- [o- (3-methyl-4-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine, N- [5-chloro-2- (3-methyl) -4-Pivaloyloxybenzene) sulfonylaminobenzoyl] glycine, N- [2- (3-Methyl-4-pivaloyloxybenzene) sulfonylamino-5-pentyloxybenzoyl] glycine, N- [5-decyloxy −
2- (3-methyl-4-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine, N- [2- (3
-Methyl-4-pivaloyloxybenzene) sulfonylamino-5-methylbenzoyl] glycine, N- [2-
(P-pivaloyloxybenzene) sulfonylamino-
5-chlorobenzoyl] glycine, N- [5-methylthio-2- (p-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine, N- [2- (3-methyl-4-pivaloyloxybenzene) sulfonyl Amino-
4-trifluoromethylbenzoyl] glycine, N-
[2- (p-pivaloyloxybenzene) sulfonylamino-4-trifluoromethylbenzoyl] glycine,
N- [5-decyloxy-2- (p-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine, N
-[2- (3-Methyl-4-pivaloyloxybenzene) sulfonylamino-5-methylthiobenzoyl] glycine, N- [2- (p-pivaloyloxybenzene)
Sulfonylamino-5-propylthiobenzoyl] glycine, N- [o- (p-pivaloyloxybenzene) sulfonylaminobenzoyl] -2R-phenylglycine, N- [o- (3-methyl-4-pivaloyl) Oxybenzene) sulfonylaminobenzoyl] -2R-phenylglycine, N- [5-methyl-2- (p-pivaloyloxybenzenesulfonylamino) benzoyl] glycine, N- [o- (p-pivaloyloxybenzene 7. A compound according to claim 6, which is sulfonylamino) benzoylglycine] methyl ester or N- [5-pentyloxy-2- (p-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine. 9. The compound is N- [o- (3-methyl-4
-Pivaloyloxybenzenesulfonylamino) benzoyl] -dl-alanine, N- [o- (3-methyl-4
-Pivaloyloxybenzenesulfonylamino) benzoyl] -β-alanine, N- [o- (3-methyl-4-
Pivaloyloxybenzenesulfonylamino) benzoyl] -1-alanine, N- [5-chloro-2- (3-methyl-4-pivaloyloxybenzene) sulfonylaminobenzoyl] -1-alanine or N- [5 -Chloro-2- (3-methyl-4-pivaloyloxybenzene)
8. The compound according to claim 7, which is sulfonylaminobenzoyl] -β-alanine. 10. A general formula: [In the formula, all symbols have the same meanings as described in claim 1. ] Is subjected to an esterification reaction,
Alternatively, the general formula: [In the formula, all symbols have the same meanings as described above. ] The compound represented by the formula] is subjected to an amidation reaction, or a compound represented by the general formula: [Wherein R ¹¹ and R ²¹ have the same meanings as R ¹ and R ² , respectively, but at least one group represents a group containing a benzyloxycarbonyl group, and other symbols have the same meanings as described above. Represent. ] The compound represented by the formula] is subjected to a debenzylation reaction, or a compound represented by the general formula: [In the formula, R ¹³ represents a group represented by R ¹ or R ² excluding a hydrogen atom, and other symbols have the same meanings as described above. ] The compound represented by the formula is subjected to an N-alkylation reaction, or a compound represented by the general formula: [In the formula, R ³¹ represents an acyloxy group, and other symbols have the same meanings as described above. ] The compound represented by the general formula (I) is characterized in that it is subjected to a deacylation reaction. [In the formula, all symbols have the same meanings as described above. ] The manufacturing method of pivalic acid p-substituted phenyl ester derivative shown by these (however, N- [o- (p-pivaloyloxybenzene) sulfonylamino benzoyl] glycine is excluded.). 11. A compound represented by the general formula (I): [In the formula, all symbols have the same meanings as described in claim 1. ] Pivalic acid p-substituted phenyl ester derivative represented by (provided that N- [o- (p-pivaloyloxybenzene) sulfonylaminobenzoyl] glycine is excluded.), And their non-toxic salts or acid addition salts are effective. An elastase inhibitor contained as a component.