JPS63165357A - P-guanidinobenzoic acid phenyl ester derivative and drug containing said derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [(R<1>)m is 2-methyl, 3-methoxy, 3,5-dicarboxy, 5-ethanesulfonyloxy-3-methoxymethyl, etc.]. EXAMPLE:p-Guanidinobenozic acid 3,5-dichlorophenyl ester methanesulfonate. USE:An elastase inhibitor. Since a trypsin inhibitor and a plasmin inhibitor have also inhibitory action on elastase, the inhibitors are effective for treating and preventing diseases caused by abnormal sthenia of proteolysis of elastin, etc., by elastase. PREPARATION:An acid addition salt of a compound shown by formula II (X is halogen) is reacted with a compound shown by formula III (R<2> is H, 1-4C alkyl, 1-4C alkoxy, etc.; n is 1-5) in the presence of a dehydrohalogenating agent (e.g. pyridine) at 0 deg.C-room temperature to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel p-guanidinobenzoic acid derivatives and pharmaceuticals containing them. More specifically, a novel p-guanidinobenzoic acid phenyl ester derivative represented by the general formula (in the formula, all symbols have the same meanings as below), and a general formula (in the formula, all This invention relates to an elastase inhibitor containing a p-quanidinobenzoic acid phenyl ester derivative as an active ingredient.

[Background of the invention]

Lysosomal hydrolases released from neutrophils play an important role in biological defense responses against tissue damage caused by microorganisms or inflammation. Among the lysosomal # elements, elastase and catebusin G, which belong to neutral serine proteinases localized in azurophilic granules, play a main role in decomposing connective tissue. In particular, elastase decomposes elastic connective tissue by cutting the crosslinked structures of elastin and hydrophobic sites of proteins, which directly function to maintain the elasticity of lung tissue [J, Ce11. Biol,, 40.366 (19
69)]. Furthermore, elastase selectively degrades not only elastin but also the crosslinked regions of collagen fibers [J
.

Biochem, 84, 559 (1978)) et al.
It also acts on tissue structural proteins such as proteoglycans (J
, CI in, Invest.

57.615 (1976)] plays a central role in connective tissue metabolism.

In living organisms, elastase is a common inhibitor of serine enzymes, α1-proteinase inhibitor ((4-P
I), but when the balance of the enzyme-inhibitor system is disturbed, tissue-destructive symptoms appear [Schweiz, Med, Wshr.

114.895 (1984)].

The turnover of elastin in normal tissues is very slow [
Endocrinology 120, 92 (1
978)] is emphysema (Am, Rev, Re5pi)
r, Di*, 110, 254 (1974): 1, atherosclerosis [Lab, Inves.
T.

22.228 (1970)] or rheumatoid arthritis [1nNeutral Proteases of H
uman PolymorphonuclearLeu
kocytem, Urban and Scbwar
Zenberg, Baltimore-Munic
(1978), p. 390], abnormalities in elastin degradation are observed under pathological conditions, and the relationship between elastase and disease is attracting attention [Infection, Inflammation, and Immunology, 13.13 ( 1983)].

[Conventional technology]

Against this background, research and development of elastase inhibitors has recently been actively conducted, and various elastase inhibitors have been proposed and patent applications have been filed. Until now, no elastase inhibitor has been known.

Various esters of p-quanidinobenzoic acid are known.

For example, (1) Japanese Patent Publication No. 54-40534 discloses a compound represented by the formula; (2) Japanese Patent Publication No. 50-4038 discloses a compound represented by the general formula (wherein ♂ is an aromatic (The aromatic group may be substituted with a lower alkyl group, a lower alkoxycarbonyl group, a carboxyl group, a carboxy lower alkyl group, a carboethoxy lower alkyl group, a lower alkoxy group, an acylamido group, or a carbamoyl group) Compounds shown in excerpts are disclosed only in relevant parts.
In the formula, Za represents a carbon-carbon covalent bond, a group selected from the group consisting of a methylene group, an ethylene group, and a nylene group. ) is disclosed, and (4) etc. is disclosed in Patent Application Publication No. 55-55154 of 1983, the compound represented by the general formula (
In the formula, zb represents a methylene group, ethylene group or vinylene group, and Rb represents a lower alkyl group. (5) West German Publication No. 3005580 discloses a compound represented by the general formula (wherein zC represents a sulfonyl group or a group represented by 1100, and zd represents a single bond, methylene , ethylene or vinylene, and Rc and/or Rd represent hydrogen or alkyl.
General formula (wherein Re and/or Rf represent hydrogen, alkyl, aryl, nitro, amino, alkylamino, dialkylamine, alkoxy, carboxy, carbalkoxy or norogen, and t represents zero or 1.

) A compound represented by is disclosed.

(7) USP-4,423,069 describes the general formula [wherein Rg is halogen, trihalomethyl, nitrile group, formyl group, OR', C0R1, C0OR'
, C0NH, or CoNRjRkC, where R',
R5 or Rk represents an alkyl group having 1 to 8 carbon atoms.

), and R represents hydrogen or a group represented by the symbol Hg. ] A method for inhibiting fertility is disclosed, in which a compound represented by the following formula or a salt thereof is administered. (wherein Ro represents hydrogen, an ether group, an ester group, or a carbamoyl group, excluding the case where R and R simultaneously take hydrogen.) An acrosin inhibitor containing a compound or a salt thereof is disclosed.

However, in the specifications of (1) to (6) above, all of these compounds have the effect of inhibiting trypsin and plasmin, so they are useful for the treatment of acute pancreatitis and for bleeding disorders as anti-plasmin agents. Similarly, all the compounds in the specifications (7) and (8) above have the effect of inhibiting acrosin, etc., which are important enzymes during fertilization. It is only described that it is useful as an inhibition method or as a fertilization inhibitor.

There is no mention of the elastase inhibitory effect of these compounds, and no reports have been made to date confirming the presence or absence of the effect.

Elastase belongs to the same class of serine proteinases as trypsin and plasmin (hereinafter, trypsin and plasmin will be referred to as "other serine proteinases" to distinguish them from elastase), but these are different from each other due to their enzyme-protein properties and substrate specificity. Therefore, it is best to consider elastase to be an essentially completely different group of enzymes from other serine proteinases, and a completely different perspective should be taken when developing inhibitors of these enzymes. You should think about it from That is, elastase, particularly human neutrophil elastase, has a molecular weight of about 30,000 [Biochem
, J., 155.255 (1976) E, isoelectric point within the range of -8,77 to 9.15 1: Anal, B
iochem, 90, 481 (1978)).
ion in Health and Disease
”, edited by D. Evered and J. Whelan, p. 51, Excelpta Media, At
osterdam (1980)] and has different enzymatic protein properties from other serine proteinases. Furthermore, in terms of substrate specificity, elastase is an endopeptidase that mainly cleaves at the C-terminal side of alanine residues, and this point also differs from other serine proteinases.

Since the two are fundamentally different in this way, it is completely impossible to extrapolate elastase inhibitors from other serine proteinase inhibitors.

[Purpose of the invention]

Based on these considerations, the present inventors have conducted intensive research to find an elastase inhibitor with a chemical structure completely different from conventional elastase inhibitors, and as a result, the present inventors have discovered the following:
It was unexpectedly discovered that a certain p-guanidinoaminoic acid phenyl ester derivative known as a serine protease inhibitor has an elastase inhibitory effect, thereby constituting the present invention.

This experiment was the first to confirm that other serine proteinase inhibitors also have an elastase inhibitory effect, which was completely unexpected until then.

[Structure of the invention]

Therefore, the present invention provides the general formula [wherein (R'')m is 2-methyl, 3-methyl, 2,3-dimethyl, 3.5-
Dimethyl, 3-ethyl 2-methoxy, 3-methoxy, 4-methoxy, 3.5-
Dimethoxy, 5-ethanesulfonyloxy-3-methoxymethyl, 3
-Hydroxy-5-methoxymethyl, 5-(4-guanidinobenzoyloxy)-3-methoxymethyl, 3.5-dicarboxy, 3-carboxy-2-chloro,
2-carboquine-5-chloro, 2-chloro-3-methoxycarbonyl, 2-chloro-4-methoxycarbonyl,
3-chloro-4-methoxycarbonyl, 5-chloro-2
-methoxycarbonyl, 3-chloro-5-methoxycarbonyl, 3,5-bis(impropoxycarbonyl),
5-chloro-2-impropoxycarbonyl, 2-chloro-3-isopropoxycarbonyl, 3-sec-butoxycarbonyl-2-chloro, 3-methoxycarbonylmethyl, 2-chloro-3-methoxycarbonylmethyl, 2-90 Rho-4-methoxycarbonylmethyl, 3-chloro-4-methoxycarbonylmethyl, 4-(2-methoxycarbonylvinyl), 2-fluoro, 3-fluoro, 4-fluoro, 2,6-difluoro,
2.3-difluoro, 2.3,4,5.6-pentafluoro, 2-chloro, 3-chloro, 4-chloro, 2,5-
Dichloro, 2.6-dichloro, 3.5-dichloro, 3-
Chloro-5-methoxy, 4-chloro-3-methoxy, 2
-chloro-5-methoxy, 2-bromo, 3-bromo, 4
-Iodo, 2-trifluoromethyl, 3-trifluoromethyl, 3.5-bistrifluoromethyl, 3-acetyl, 2-acetyl-5-methoxy, 2-acetyl-5-
Propoxy, 2-acetyl-5-chloro, 5-chloro-
2-7'ropionyl, 5-chloro-2-isobutyryl,
3-benzoyl, 4-benzoyl, 4-benzoyl-2
-chloro, 4-benzoyl-2,3-dichloro, 5-chloro-2-cyclopentylacetyl, 3-acetoxy, 4-acetoxy, 5-acetoxy-3
-Chloro, 3-10-5-propionyloxy, 3-
Benzoyloxy, 3-(4-guanidinobenzoyloxy), 3.5-bis(4-guanidinobenzoyloxy), 3-acetyl-3-(4-guanidinobenzoyloxy), 5-(4-guanidinobenzoyloxy)-
3-methoxycarbonyl, 3-chloro-3-(4-guanidinobenzoyloxy), 5-(4-guanidinobenzoyloxy)-3-methoxy, 5-(4-guanidinobenzoyloxy)-3-methyl, 5-acetoxy Methyl-3-chloro, 4-mesyl, 5-mesyloxy-3-methoxy, 3-chloro-5-mesyloxy, 3-chloro-5-ethanesulfonyloxy, 3-chloro-5-isopropanesulfonyloxy, 5
-benzenesulfonyloxy-3-chloro, 5-ethanesulfonyloxy-3-methyl, 5-carbamoyl-3-chloro, 3-(N,N-dimethylcarbamoyl-methylcarbamoyl), 3-(4-guanidinobenzoyloxy) -5-(N-methylcarbamoyl), 3.
5-bis(N-ethylcarbamoyl), 3,5-his(N-7′-bicarbamoyl, 5-(N-benzylcarbamoyl)-3-(4-guanidinobenzoyloxy), 3-chloro-5-( N-(3-pyridyl)carbamoyl), 3-chloro-5-(N,N-dimethylcarbamoyloxy), 3-chloro-5-(N-ethylcarbamoyloxy), 3-sulfamoyl, 3-chloro-4- (N,N
-dimethylsulfamoyl), 2-(N,N-diethylsulfamoyl), 3-(N,N-diethylsulfamoyl), 4-(N,N-diethylsulfamoyl),
3-chloro-4-(N,N-diethylsulfamoyl), 3-chloro-5-(N,N-diethylsulfamoyl), 4-(N,N-diethylsulfamoyl)-2-fluoro , 4-(N,N-dipropylsulfamoyl), 4-(1-pyrrolicinylsulfonyl, 3-piperidinosulfonyl, 3-morpholinosulfonyl, 4-morpholinosulfonyl, 3-chloro-5-(N- (4-sulfamoylphenyl)carbamoyl), 3-10 rho5-[N-(
4-(N,N-dimethylsulfamoyl)phenyl)carbamoyl], 3-chloro-5-(N-(
4-(N,N-diethylsulfamoyl)phenyl)carbamoyl], 2-chloro-5-(N-mesylamino), 3-chloro-
5-(N-ethanesulfonylamino), 3-nitro, 4
-nitro, 3-hydroxy-5-methyl, 5-hydroxy-3-methoxy, 5-hydroxy-3-methoxycarbonyl, 3
-chloro-5-hydroxy7,3-(4-guanidinobenzoyloxy)-5-hydroxy,5-hydroxy-3
-(N-methylcarbamoyl), a-(N-benzylcarbamoyl) 3-guanidino, 4-guanidino, 2-chloro-5-guanidino, 5-benzyloxy-3-chloro, 3-chloro-5-(4- guanidinophenylthiomethyl), 3-chloro-5-(4-morpholinosulfonyl)phenoxymethyl, 3-methoxy-5-(4-morpholinosulfonyl)phenoxymethyl, 3-chloro-5-(3-pyridyl)oxymethyl, 3-Methoxy-5-(1.1-dioxothiazol-3-yl)carbonyl-3-chloro-5-(1.
Represents a group selected from 1-dioxothiazol-3-yl) carbonyl and 3-yl groups. ] The present invention relates to a p-guanidinobenzoic acid phenyl ester derivative represented by the following, and a novel compound that is an acid addition salt thereof.

In the group of compounds represented by the general formula (IA), there are some compounds that can be found in the various inventions described in the above-mentioned [Prior Art] as a general concept. The description is complete, therefore, all compounds of general formula (IA) are considered to be entirely new.

Furthermore, the present invention provides a method for the general formula (wherein R2 is: (1) a hydrogen atom, (11) an alkyl group having 1 to 4 carbon atoms, (11) an alkoxy group having 1 to 4 carbon atoms, (IV)
Alkoxymethyl group having 2 to 5 carbon atoms, (V) 2CO
OR'' (in the formula, R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms); (vl) a group represented by the formula CH2COOR' (in the formula, R1 represents the same meaning as above); group, (wit) formula CH = CH - CO.OR"
In formula C, R3 represents the same meaning as above. ), (veil) halogen atom, (iX) trifluoromethyl group, (X) COR' (wherein R4 is an alkyl group having 1 to 4 carbon atoms, phenyl group, quanidinophenyl group, cyclopentylmethyl group or cyclohexylmethyl group; A group represented by the formula CH,0COR' (in the formula, R4 represents the same meaning as above), (Xii+) a group represented by the formula So, R' (in the formula, R4 represents the same meaning as above), (xiv) A group represented by the formula 050.R' (in the formula, R4 represents the same meaning as above), (×■) 2C0NR'R' (in the formula, R5 and R6 are each independently a hydrogen atom , represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group, a pyridyl group, or R,, R' and the nitrogen atom to which they are bonded together represent a pyrrolidinyl group, a piperidino group, or a morpholino group. represents a group), (XVi) a group represented by the formula 0CONR'R' (in the formula, R5 and R
6 represents the same meaning as above. ], (xvil) a group represented by the formula So, NR'R' (wherein R3 and R6 have the same meanings as above), a group represented by R
6 represents the same meaning as above. ), (XI
X) Formula NH30,R' (wherein, R1 has 1 to 1 carbon atoms
4 represents an alkyl group or a phenyl group. ), (xx) nitro group, (XXI) hydroxyl group, (XXi) hydroxymethyl group, (xxl liganidino group, (xxlv) benzyloxy group, (XXV) guanidinophenylthiomethyl group, (xxv)
l) morpholinosulfonylphenoxymethyl group, (xxll) pyridyloxymethyl group or (11D
(1,1-dioquinthiazol-3-yl)carbonyl group, n represents an integer of 1 to 5, and when n represents an integer of 2 or more, each R2 may be the same or or may be different. ) denoted by p-
The present invention also relates to a novel use of guanidinobenzoic acid phenyl ester derivatives and their acid addition salts as esterase inhibitors as active ingredients.

In this specification, including the claims, when the term "alkyl group" is used, it means a straight-chain or branched alkyl group.

an alkyl group represented by R2 in general formula (IB),
The alkyl moiety in the alkoxy group represented by R2 and the alkyl group represented by R3, R4, R5, R6 and R7 include methyl, ethyl, propyl, butyl groups and isomers thereof, and any group is also preferable.

In general formula (IB), examples of the halogen atom represented by R2 include fluorine, chlorine, bromine and iodine atoms, and any group is preferable.

In general formula (IB), any group represented by (1) to (xxvm) is preferable as the group represented by R2.

The acid addition salts of the compounds represented by formulas (IA) and (IB) are preferably non-toxic and water-soluble.

Suitable acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoic acid. Examples include organic acid salts such as citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate.

All compounds of the present invention represented by general formula (IB) (including compounds represented by general formula (IA)) can be produced by known methods.

For example, an acid addition salt of a compound represented by the general formula (wherein, Manufactured by reaction.

Since the above reaction is a condensation reaction that produces hydrogen halide as a by-product, it is advantageous to have a dehydrogenating/hydrogenating agent present in order to accelerate the reaction. As such a deno-hydrogenating agent, a tertiary organic amine and, if desired, an inorganic base such as gold scrap bicarbonate can be used. As tertiary organic amines, aliphatic or aromatic or heterocyclic amines such as triethylamine, tributylamine, dimethylaniline, pyridine and the like are used. Among these, pyridine is particularly preferred since it also acts as a solvent for the reaction components.

Further, as the inorganic base, for example, bicarbonate sorter soda, caustic soda, etc. are used.

As the solvent, for example, benzene, toluene, tetrahydrofuran, pyridine, etc. can be used, and as mentioned above, pyridine is particularly preferred since it also acts as a dehydrogenating agent.

Since the reaction proceeds relatively quickly, it may be carried out at room temperature, or with slight cooling if desired, and is generally preferably carried out at 0°C to room temperature. The reaction time varies depending on the reaction temperature used, but generally 30 minutes to 4 hours, preferably 30 minutes to 2.5 hours is sufficient.

In carrying out the reaction, it is preferable to dissolve the above-mentioned starting compound (1) in a solvent, preferably pyridine, and add starting compound (II) to this solution. When pyridine is used as a solvent, the raw material compound (n) does not decompose, and therefore the reaction becomes a heterogeneous system. is formed.If a solvent other than pyridine is used, a homogeneous system is not necessarily obtained, but the reaction can be carried out even in a heterogeneous system.

The desired product is formed in the form of a salt with hydrogen halide. In decomposing the desired product, depending on the solvent used, sulfur bicarbonate is added with or without concentrating to convert the product into a carbonate, which precipitates as crystals. Particularly when pyridine is used as a solvent, crystals are precipitated by directly converting it into a carbonate without evaporating and concentrating it. Of course, the desired product can also be obtained by evaporating the solvent to dryness, but this is preferable since a highly purified product can be obtained by crystallization as described above.

The compound (IB) of the present invention thus obtained can be further converted into the above-mentioned appropriate acid addition salt by a known method, if desired.

In addition, if it does not precipitate as crystals during the process of converting it into the above-mentioned salt, it can be purified by column chromatography using silica gel or the like.

The starting compound (If) used in the above reaction can be produced by a conventional method of reacting p-guanidinobenzoic acid with thionyl chloride. In this case, the raw material compound (II
) is a hydrogen halide salt, especially a hydrochloride.

The starting compound (II) is obtained as a salt of hydrogen chloride, which is produced as a by-product when acid ride (II) is produced from guanidinobenzoic acid, and it is advantageous to use it as it is.

Is the compound represented by general formula (1) a known compound?
Alternatively, it can be easily manufactured by a known method.

Furthermore, among the compounds of the present invention represented by the general formula (IB), R
A compound in which at least one of 1 represents a carboxyl group, that is, a compound of the general formula (wherein R2a represents a group represented by R2 excluding the carboxyl group, and p is an integer within the range of 1 to 5). , q represents 0 or an integer within the range of 1 to 4,
and I)+Q represents an integer within the range of 1 to 5. ) can be obtained by subjecting a compound represented by the general formula (wherein the symbol φ represents a phenyl group, and the other symbols have the same meanings as above) to a debenzylation reaction. Such debenzylation reaction is carried out in an inert gas atmosphere (eg, argon, nitrogen, etc.) using, for example, an anhydrous hydrogen bromide-acetic acid solution. The temperature is generally 0 to 50°C, preferably room temperature.

Compound (IV) can be obtained by subjecting an acid addition salt of the compound represented by the general formula (II) to an esterification reaction with a compound represented by the general formula (in the formula, all symbols have the same meanings as above). obtained by. This reaction is carried out analogously to the previous description.

Compound (V) can also be obtained by subjecting a compound represented by the general formula (in which all symbols have the same meanings as above) to benzylation reaction. The benzylation reaction is carried out by a known method.

The compound represented by the general formula (VI) is a known compound or can be easily produced by a known method.

A compound of the present invention represented by the general formula (■) in which at least one of R2 represents a hydroxymethyl group, that is, a compound represented by the general formula (wherein, 1t2b represents a group other than the hydroxymethyl group among the groups represented by R2). where r represents an integer within the range of 1 to 5, 3 represents O or an integer within the range of 1 to 4, r + s represents an integer within the range of 1 to 5,
Other symbols have the same meanings as above. ) can be obtained by subjecting a compound represented by the general formula (wherein THP represents a 2-tetrahydropyranyl group, and other symbols have the same meanings as above) to a THP removal reaction. It will be done. Such THP removal reaction is preferably carried out in an aqueous solution of an organic acid (preferably acetic acid) such as acetic acid, 7'lobionic acid, oxalic acid, p-toluenesulfonic acid, or an aqueous solution of an inorganic acid such as hydrochloric acid or sulfuric acid. The reaction is preferably carried out in the presence of a water-miscible solvent such as methanol or an ether such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran at a temperature from room temperature to 75°C (preferably at a temperature of 37°C or higher).

Further, the acid addition salt of the compound represented by the general formula (II) and the compound represented by the general formula (in the formula, all symbols have the same meanings as above) are subjected to an esterification reaction. This reaction is carried out in the same manner as described above.

The compound represented by the formula ON) can be debenzylated by subjecting the compound represented by the general formula (in which all symbols have the same meanings as above) to a debenzylation reaction. Such a debenzylation reaction can be carried out in a general manner using, for example, ethyl acetate, ethanol, benzene, etc. under a hydrogen gas atmosphere using palladium-carbon as a catalyst.
This is carried out at a temperature of 0 to 40°C (preferably at room temperature).

The compound represented by formula (■) is a known compound or can be obtained by a known method.

Furthermore, among the compounds of the present invention represented by the general formula (IB), R2 (in the formula) is (1) a hydrogen atom, (1) an alkyl group having 1 to 4 carbon atoms, (iii) a carbon number 1 ~40 alco+'7 groups, (1■
) alkoxymethyl group having 2 to 5 carbon atoms, (v) 2C00
A group represented by R3 (wherein R3 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), (vl) 2CH, G
In the OOR3C formula, R3 has the same meaning as above. The group shown in .

(V:+) Halogen atom, (v:1i) Trifluoromethyl group, (IX) 2C
A group represented by OR' (in the formula, R4 represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a guanidinophenyl group, a cyclopentylmethyl group, or a cyclohexylmethyl group), (x) 200OR' (formula (wherein, R4 represents the same meaning as above), (x1) a group represented by the formula CH20COR' (wherein R4 represents the same meaning as above), (x1) a group represented by the formula So, R' (In the formula, R4 represents the same meaning as above. A group represented by (xiii) Formula 050.R' C, where R4 represents the same meaning as above. )2〇〇NR'R' (In the formula, R5 and R6
each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group, a pyridyl group, or R5, Ra and the base atom to which they are bonded together represent a pyrrolidinyl group, Represents a piperidino group or a morpholino group. ), a group represented by (×■) formula 0CONR'R' (wherein R5 and R6
has the same meaning as above. ), (xVl) a group of the formula SO, NR'R' (wherein R5 and R
6 represents the same meaning as above. ), R6 has the same meaning as above. ), (Formula 110 NH30, R7 (in the formula, R? represents an alkyl group having 1 to 4 carbon atoms or a phenyl group), (XI) hydroxyl group, (xx) hydroxy Methyl group (XXi) Guanidino group (xii) Benzyloxy group, (xxtii) Guanidinophenylthiomethyl group, (x
Xlv) morpholinosulfonylphenoxymethyl group, (XXV) pyridyloxymethyl group or (XXVi)
represents a (1,1-dioxothiazol-3-yl)carbonyl group, n' represents an integer of 1 to 5, and when n' represents an integer of 2 or more, each R2 (is the same as each other and The compound represented by the general formula (in which RE and n' have the same meanings as above) and the compound represented by the formula It can also be produced by reacting the cyanamides shown.

In the above reaction, starting compound (X) is added to water or an inert organic solvent such as methanol, ethanol, or tetrahydrofuran, or a mixed solvent of water and alcohol, and an equimolar amount or an excess of mineral acid to compound (X) is added. For example, the reaction can be carried out by adding an excess of the compound of formula (XI) in the presence of hydrochloric acid or sulfuric acid and allowing the reaction to proceed from room temperature to the reflux temperature of the reaction mixture for 15 minutes to 2 hours.

The generated target compound is converted into a single uj+ in the same manner as in the previous method.
i, purified and optionally converted into an acid addition salt.

The raw material compound (X) used in the above reaction is the corresponding p-
The nitrobenzoic acid phenyl ester compound is easily dissolved in a lower alkanol such as ethanol and catalytically reduced in the presence of a hydrogenation catalyst such as palladium on carbon, palladium black, platinum dioxide, or nickel at room temperature and pressure or under heat and pressure. can be manufactured. Cyanamide (XI), which is the raw material for Mu-man, is a known compound.

〔effect〕

The p-quanici-7benzoic acid phenyl ester derivatives represented by formulas (IA) and (IB) of the present invention, and their addition salts, have an elastase inhibitory effect, and therefore elastin decomposition by elastase in mammals, especially humans. , is useful for the treatment and/or prevention of diseases caused by abnormal acceleration of collagen fiber degradation and/or proteocrycan degradation. Such diseases include emphysema, atherosclerosis and rheumatoid arthritis.

The elastase inhibitory effect of the compounds 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. [Biochem, Med, 75, 350 (
This was done using a slightly modified method based on [1970]. That is, a synthetic substrate [succinyl-alanyl-prolyl-alanyl-p-nitroanilide (5ue-Ala-Pro-Al
a-pNA, manufactured by Peptide Institute)].

1mM 5uc-Ala-Pro-Ala-pNA
(Dissolved in N-methylpyridone to 100mM, 10
(added 1/0 volume to the reaction mixture), 0.1 M toIJ
A reaction mixture of 1 me consisting of a hydrochloric acid buffer (pH 8,0), a 0.2 M sodium chloride bath solution, a sample solution and an enzyme solution at different concentrations was incubated at 37° C. for 30 minutes.

After terminating the reaction by adding 100 μt of 50-line acetic acid to the reaction mixture, free p-nitroanilide was measured by absorbance at 405 nm, and the inhibition rate was determined using the following formula.

(2) Results The results are shown in Table 1.

Remarks 1) The compound of the present invention is the compound described in Example 4 of JP-A-50-4038.

The inhibition ratio is shown when the concentration of the two compounds is 50 μt/−.

The experimental results confirmed that the compound of the present invention has an elastase inhibitory effect. 4 of the compound of the present invention
It was confirmed that the toxicity was sufficiently low and that it could be used safely as a medicine.

For example, in an intravenous acute toxicity test using mice, (R2)n in general formula (IB) is 2.5.
-') chloro, hydrogen M, 3-chloro-5-hydroxy, 3-chloro-5-ethanesulfonyloxy and 3
LD of a compound representing -chloro-4-(N,N-diethylsulfamoyl). Both territories are 50~150η/!
It was within the range of i4. Therefore, the compounds of the present invention are useful for the treatment and/or treatment of diseases caused by abnormal degradation of proteins such as elastin by elastase in mammals, especially humans.
or confirmed to be useful for prevention.

The compounds of the present invention represented by general formulas (IA) and (IB) and their acid addition salts are used for the above purposes (usually administered systemically or locally, orally or parenterally).

The dosage varies depending on age, body weight, symptoms, therapeutic effects, administration method, treatment time, etc., but it is usually administered orally once to several times a day in the range of 5oINi, ~500mg per adult. Alternatively, it is administered parenterally (preferably intravenously) once to several times a day in the range of 10 mq to 200 mq per adult. Of course, as mentioned above, the dosage varies depending on various conditions, so there are cases in which t smaller than the above-mentioned dosage range is sufficient, and there are cases in which it is necessary to exceed the range.

Solid compositions for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances are present in at least one inert diluent, such as milk, mannitol, grape mulch, hydroxypropylcellulose, diluent, etc.
Mixed with M-crystalline cellulose, starch, polyvinylpyrrolidone, and magnesium aluminate metasilicate. The composition is prepared in a conventional manner, with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as fibrin calcium gluconate, stabilizers such as lactose, It may also contain stimulants such as glutamic acid or aspartic acid. The formulation or pill may be coated with a film of a water-soluble or enteric substance such as white sugar, gelatin, hydroxypropyl cellulose, or hydroquinopropyl methyl cellulose phthalate, or may be coated with two or more layers, if necessary. . Capsules of absorbable substances such as gelatin are also hypothesized.

Liquid compositions for oral administration refer to pharmaceutically formulated emulsions, solutions, suspensions, syrups, elixirs, etc., and include commonly used inert diluents, e.g. M-made water and ethanol. In addition to inert diluents, this composition may contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents,
It may contain aromatics and preservatives.

Other compositions for oral administration include sprays containing one or more active substances and formulated according to methods known per se. In addition to inert diluents, the composition may also contain stabilizers such as sodium bisulfite and isotonic buffers, such as sodium chloride, sodium citrate, or citric acid. . The manufacturing method of the spray agent is, for example,
It is described in detail in the specifications of No. 2868691 and No. 3095355.

The injection for parenteral administration according to the present invention is hypothetically a sterile aqueous or non-aqueous solution, suspension, or emulsion. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.

Such compositions may further contain preservatives, wetting agents, emulsifying agents,
Adjuvants such as dispersants, stabilizers (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid) may also be mentioned. These may be sterilized, for example by filtration through bacteria-retaining filters, by incorporation of fungicides or by irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

Other compositions for non-oral administration refer to one or more active substances and are prepared in a manner known per se (
These include external liquid preparations, liniments such as soft creams, suppositories for intrarectal administration, and pessaries for intravaginal administration.

〔Example〕

EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited to these Examples.

Note that rlRJ in the examples represents "infrared absorption spectrum", and unless otherwise specified, measurements were made by the KBr method. Moreover, "mesylate" in the table means "methane sulfonate".

Example 1 p-guanidinobenzoic acid 3,5-dichlorophenyl ester methanesulfonate L p-guanidinobenzoyl chloride hydrochloride (West German Patent No. 3005580 and US Pat. No. 428341)
It was manufactured by the method described in each Example 1 of the specification of No. 8. ) 700 ■, 3,5-zik o.

A mixture of phenol 4901Ni and pyridine 10m was stirred for 30 minutes under water cooling. Diethyl ether was added to the reaction mixture and the mixture was decanted, and a saturated sodium bicarbonate aqueous solution was added to the resulting supernatant to obtain the desired carbonate. The obtained crystals were sequentially washed with water and acetone and dried in vacuum. The crystals were suspended in ethanol, 0.124-methanesulfonic acid was added, and the precipitated crystals were vacuum-dried to obtain a standard crude compound (white crystals) 5 having the following physical properties.
06η was obtained.

Melting point = 232-234°C; IR value 3340, 3150, 1730, 16
80, 1620.1600°1570.1550,1
410, 1260, 1200, 1170°1090,
1060, 1040G.

Hereinafter, in the same manner as in Example 1, the compounds of the present invention shown in Table 2 were obtained using p-guanidinobenzoyl chloride hydrochloride and a corresponding phenol compound.

Example 124 p-guanidinobenzoic acid 3-carboxy-2-chlorophenyl ester hydrobromide After adding 1N sodium hydroxide 4- to 3-carboxy-2-chlorophenol 700Tli, it was concentrated under reduced pressure to obtain the corresponding sodium Got salt. The sodium salt was dissolved in 20 rntf of hexamethylphosphoramide, 0.58 ml of benzyl bromide was added, and the mixture was stirred overnight.

The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, washed with anhydrous sodium sulfate, and concentrated under reduced pressure.

Residue and p-quanidinobenzoyl chloride hydrochloride (
JP-A-55-115865 and U.S. Patent No. 4
283418, according to the method described in each Example 1. ) IP in pyridine in an ice-water bath.
Stir for 5 minutes.

Diethyl ether was added to the reaction mixture and the mixture was decanted, saturated aqueous sodium bicarbonate solution was added to the insoluble residue, and the crystals were filtered, washed successively with water and acetone, and dried in vacuo.

The obtained crystal 200 Mi was heated to 30 Mi in an argon atmosphere.
Approximately 54 kg of hydrogen thiobromide-acetic acid was added and stirred at room temperature for 3 hours.

Diethyl ether was added to the reaction mixture, and the precipitated crystals were further washed with diethyl ether and dried under vacuum to obtain the title compound (yellow powder) 192■ having the same physical properties.

Melting point: 220-227°C.

Hereinafter, Example 125 and Example 1260 compounds of the present invention having the physical property values shown in Table 3 were obtained in the same manner as Example 124.

Example 127 p-guanidinobenzoic acid 3-chloro-5-hydroxymethylphenyl ester acetate 3-chloro-5- and droxybenzoic acid 1.97Of are dissolved in dimethylformamide 30- and hydrogenated I-IJ
601η of aluminum was added thereto, and the mixture was stirred for 10 minutes at room temperature.

4.288 f of benzyl bromide was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. After adding 30 mg of ethyl acetate to the reaction mixture, the mixture was washed with water several times, dried over anhydrous magnesium sulfate, and condensed under reduced pressure Ia. The obtained residue was subjected to silica gel column chromatography (elution solvent, hexane:ethyl acetate = 1
0:1) TyrI111! ! 3-chloro-5-benzyloxybenzoic benzyl ester 3.61f having the following physical properties was obtained.

TLC (hexipane: ethyl acetate = 10:1):
Rfo, 26° benzyl body 3.614 with tetrahydro7ran 50 tn
Lithium aluminum hydride 579 dissolved in t
(2) was added, and the mixture was allowed to react at room temperature for 2 hours.

Ethyl acetate was added to the reaction mixture to decompose excess reagent, and the mixture was poured into a 1N aqueous sodium hydride solution.

After the reaction mixture was extracted with diethyl ether, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (elution solvent: dichloromethane) to obtain 3- Chloro-5-benzyloxybenzyl alcohol 1.502f
I was.

TLC (chloroform:methanol=10:1):Rf
1.502r of O,69° alcohol was dissolved in 20-dichloromethane, dihydropyran 65519 and a catalytic amount of p-toluenesulfonic acid were added, and the mixture was reacted at room temperature for 1 hour.

Add a small amount of pyridine to the reaction mixture, wash with water, and add #
Shrunk. The obtained residue was subjected to silica gel column chromatography (elution solvent, hexane:ethyl acetate = 10:l).
) and the following physical properties were determined as Wt63-chloro-5-benzyloxybenzyl alcohol-Q-(2-tetrahydrohyranyl)ether 1.83? I got it.

TLC (hexane:ethyl acetate = 1O:1):
The benzylic compound 996η obtained with RfO 120° was dissolved in 7-ethyl acetate and debenzylated using 10% palladium on carbon as a catalyst at room temperature and pressure under a hydrogen atmosphere. The reaction was completed after 3 hours, and the obtained crude product was subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5: 1).
) to produce 3-chloro-3-(
2-Tetrahydrobilanyloxinemethylphenol 2
Obtained Cape 74.

TLC (hexane: ethyl acetate = 5:3): RfO12
4゜phenol 274 wi is dissolved in pyridine 3-,
396η of p-quanidinobenzoyl chloride hydrochloride was added and reacted at room temperature for 2 hours.

20rnt of diethyl ether was added to the reaction mixture, and the precipitate was counted. The precipitate was further washed with diethyl ether. An aqueous solution of sodium bicarbonate was added to the insoluble residue, and the resulting carbonate was collected from door to door.

The crude carbonate was dissolved in 60 qb acetic acid and heated at 37°C for 2 hours.
Allowed time to react.

After distilling off the acetic acid under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform:methanol:vinegar [= 1O:2:1) to obtain the title compound 100■ having the following physical properties. Ta.

TLC (chloroform: methanol: acetic acid = 10:2:
1): Rf O, 26: NMR (CD30D)
: δ8.2 (2H, d, J=8k), 7.
42 (2H, d, J=8Hz), 7.30 (LH, bs
), 7.16 (2H, bs).

4.64 (2H, s).

Example 128 p-Quanidinobenzoic acid 3-chloro-3-(4-morpholinosulfonyl)phenoxymethylphenyl ester acetate 3-chloro-5-hydroxybenzoic acid 4.041!9 was dissolved in dichloromethane 10-, and dihydro Pyran 25619 was added. A catalytic amount of p-1-luenesulfonic acid was added and the reaction was allowed to proceed at room temperature for 1 hour.

A small amount of pyridine was added to the reaction mixture, which was further washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the corresponding (
2-tetrahydropyranyl) ether was obtained.

The obtained crude product was used in the next reaction without being purified.

That is, the crude product was dissolved in 10 volumes of tetrahydro7ran, cooled in an ice water bath, and lithium aluminum hydride 1331! q was added and stirred. After raising the reaction temperature to room temperature and reacting for 1 hour, ethyl acetate was added to the reaction mixture to decompose excess reagent.

The reaction mixture was poured into 20 d of 1N sodium hydroxide, the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate = 5:2). ) to obtain 541 Wq of 3-chloro-3-(2-tetrahydropyranyloxy)benzyl alcohol having the physical properties shown in the figure.

TLC (hexane: ethyl acetate = 5:3): RfO, 5
゜The obtained alcohol body 484■ is dichloromethane 10
Dissolved in ml.

Add 242 µm of triethylamine to this mixture, cool it in an ice water bath, and then add 273 µm of methanesulfonyl chloride.
q was added dropwise. After raising the reaction temperature to room temperature, it was washed with water, dried over anhydrous WLf1m magnesium, and concentrated under reduced pressure to obtain the corresponding mesylate.

The obtained crude product was used in the next reaction without purification.

460 ~ of p-morpholinosulfonylphenol was added to 7 ml of tetrahydrofuran and 1 ml of hequipmethylphosphoramide.
- was dissolved in a mixed solvent with. 57.6 μ of sodium hydride was added to this mixture and stirred for 10 minutes.

Next, the mesylate obtained above was added to this reaction solution and reacted at room temperature for 1 hour.

Water was added to the reaction mixture layer and extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained crude product was dissolved in a mixed solvent of 5 parts of methanol and 5 parts of tetrahydrofuran, and further 50 η of p-toluenesulfonic acid was added, and the mixture was allowed to react at room temperature for 2 hours, and the solvent was distilled off.
The residue was purified by silica gel column chromatography (hexane=ethyl acetate=5:3) to obtain 228 η of 3-chloro-,5-(4-morpholinosulfonyl)phenoxymethylphenol having the following physical properties.

TLC (hexane: ethyl acetate = 5:3): RfO01
Esterification was carried out in the same manner as in Example 1 using 8° phenol compound 228 Misaki, p-guanidinobenzoyl chloride hydrochloride 2071q, and pyridine 3-.

The product was purified by silica gel column chromatography (elution solvent, ethyl acetate:acetic acid:water=400:100:3).
0) to obtain the title compound 150Y having the following physical properties:
I got n9.

TLC (chloroform: methanol: acetic acid = 10:2:
l) 2 Rf O,7:IR:J/360
0~2500, 1720, 1680, 1560°140
0.1330α-1° Example 129 p-7 Nidinobenzoic acid 3-methoxy-3-(4-morpholinosulfonyl roughhenoxymethylphenyl ester acetate) By the same method as described in Example 128, the following physical properties were obtained. The title compound (white powder) was obtained.

TLC (ethyl acetate: acetic acid: water = 400: 100
: 30):RfO, 72; IR:l/ 3600-2500, 1720, 168
0,1590゜1400.1340 Sub-10 Formulation Example 1 p-guanidinobenzoic rit3-chloro0-5-t: troxyphenyl ester methanesulfo yts salt <prepared in Example 1) LOP, cellulose gluconic acid calcium(
Disintegrant) 400Wq, Magnesium Stearate (Lubricant) 200119 and Microcrystalline Cellulose 94? were mixed and tableted in a conventional manner to obtain 100 tablets containing 1009 active ingredients in each tablet.

Formulation Example 2 p-Guanidinobenzoic acid 3-chloro-5-hydroxyphenyl ester methanesulfonate (prepared in Example 1) IP was dissolved in ethanol 10-, sterilized through a bacteria retention filter, and 5+ag 50 per ampoule by adding 0.5 - per ampoule.
The ampoule was sealed. The contents of the ampoule contain an appropriate volume of diluent, e.g.
It is diluted to 2.5 with 8.6 Tris-HCl buffer and used as an injection.

Formulation Example 3 p-f7:-') Nobenzoic acid 3-chloro-5-ethanesulfonyloxyphenyl ester methanesulfonate (
(produced in Example 1) 10 f, cellulose calcium gluconate (disintegrant) 400 η, magnesium stearate (lubricant) 20 (1 mg and microcrystalline cellulose 9
．． 42 were mixed in a conventional manner and compressed into tablets to form 100
100 tablets containing the active ingredient (2) were obtained.

Formulation Example 4 p-Quanidinobenzoic acid 3-chloro-5-ethanesulfonyloquine phenyl ester methanesulfonate (prepared in Example 1) 11 was dissolved in ethanol 10 and sterilized through a bacteria retention filter; The ampoule was sealed by adding 50 Flv of drug per ampoule by adding 0.5-ml of 5rR per ampoule. The contents of the ampoule are diluted to 2.5 with an appropriate volume of diluent, such as Tris-HCl buffer of pH 6.8, and used as an injection.

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I A) [In the formula, (R^1)_m is 2-methyl, 3-methyl, 2,3-dimethyl, 3 ,5-
Dimethyl, 3-ethyl, 2-methoxy, 3-methoxy, 4-methoxy, 3,5-
Dimethoxy, 5-ethanesulfonyloxy-3-methoxymethyl, 3
-Hydroxy-5-methoxymethyl, 5-(4-guanidinobenzoyloxy)-3-methoxymethyl, 3,5-dicarboxy, 3-carboxy-2-chloro,
2-carboxy-5-chloro, 2-chloro-3-methoxycarbonyl, 2-chloro-4-methoxycarbonyl,
3-chloro-4-methoxycarbonyl, 5-chloro-2
-methoxycarbonyl, 3-chloro-5-methoxycarbonyl, 3,5-bis(isopropoxycarbonyl),
5-chloro-2-isopropoxycarbonyl, 2-chloro-3-isopropoxycarbonyl, 3-sec-butoxycarbonyl-2-chloro, 3-methoxycarbonylmethyl, 2-chloro-3-methoxycarbonylmethyl, 2-chloro -4-methoxycarbonylmethyl, 3-chloro-4-methoxycarbonylmethyl, 4-(2-methoxycarbonylvinyl), 2-fluoro, 3-fluoro, 4-fluoro, 2,6-
Difluoro, 2,3-difluoro, 2,3,4,5,6
-pentafluoro, 2-chloro, 3-chloro, 4-chloro, 2,5-dichloro, 2,6-dichloro, 3,5-dichloro, 3-chloro-5-methoxy, 4-chloro-3-
Methoxy, 2-chloro-5-methoxy, 2-bromo, 3
-bromo, 4-iodo, 2-trifluoromethyl, 3-
Trifluoromethyl, 3,5-bistrifluoromethyl, 3-acetyl, 2-acetyl-5-methoxy, 2-acetyl-5-propoxy, 2-acetyl-5-chloro, 5
-chloro-2-propionyl, 5-chloro-2-isobutyryl, 3-benzoyl, 4-benzoyl, 4-benzoyl-2-chloro, 4-benzoyl-2,3-dichloro, 5-chloro-2-cyclopentylacetyl, 3-acetoxy, 4-acetoxy, 5-acetoxy-3-chloro, 3-chloro-5-propionyloxy, 3-benzoyloxy, 3-(4-guanidinobenzoyloxy),
3,5-bis(4-guanidinobenzoyloxy), 3
-acetyl-5-(4-guanidinobenzoyloxy)
, 5-(4-guanidinobenzoyloxy)-3-methoxycarbonyl, 3-chloro-5-(4-guanidinobenzoyloxy), 5-(4-guanidinobenzoyloxy)-3-methoxy, 5-(4-guanidino benzoyloxy)-3-methyl, 5-acetoxymethyl-3-chloro, 4-mesyl, 5-methyloxy-3-methoxy, 3-chloro-5-mesyloxy, 3-chloro-5-ethanesulfonyloxy, 3- Chloro-5-isopropanesulfonyloxy, 5
-benzenesulfonyloxy-3-chloro, 5-ethanesulfonyloxy-3-methyl, 5-carbamoyl-3-chloro, 3-(N,N-dimethylcarbamoyl), 2-chloro-3-(N-methylcarbamoyl) , 3-(4-guanidinobenzoyloxy)
-5-(N-methylcarbamoyl), 3,5-bis(N
-ethylcarbamoyl), 3,5-bis(N-propylcarbamoyl), 5-(N-benzylcarbamoyl)-
3-(4-guanidinobenzoyloxy), 3-chloro-5-{N-(3-pyridyl)carbamoyl}, 3-chloro-5-(N,N-dimethylcarbamoyloxy), 3-chloro-5-( N-ethylcarbamoyloxy), 3-sulfamoyl, 3-chloro-4-(N,N-dimethylsulfamoyl), 2-(N,N-diethylsulfamoyl), 3-(N,N-diethylsulfamoyl) famoile)
, 4-(N,N-diethylsulfamoyl), 3-chloro-4-(N,N-diethylsulfamoyl), 3-chloro-5-(N,N-diethylsulfamoyl), 4-
(N,N-diethylsulfamoyl)-2-fluoro,
4-(N,N-dipropylsulfamoyl), 4-(1
-pyrrolidinylsulfonyl), 3-piperidinosulfonyl, 3-morpholinosulfonyl, 4-morpholinosulfonyl, 3-chloro-5-{N-(4-sulfamoylphenyl)carbamoyl}, 3-chloro-5- [N-{4-(N
, N-dimethylsulfamoyl)phenyl}carbamoyl], 3-chloro-5-[N-{4-(N,N-diethylsulfamoyl)phenyl}carbamoyl], 2-chloro-5-(N-mesylamino ), 3-chloro-
5-(N-ethanesulfonylamino), 3-nitro, 4
-nitro, 3-hydroxy-5-methyl, 5-hydroxy-3-methoxy, 5-hydroxy-3-methoxycarbonyl, 3
-chloro-5-hydroxy, 3-(4-guanidinobenzoyloxy)-5-hydroxy, 5-hydroxy-3
-(N-methylcarbamoyl), 3-(N-benzylcarbamoyl)-5-hydroxy, 3-chloro-5-hydroxymethyl, 3-guanidino, 4-guanidino, 2-chloro-5-guanidino, 5-benzyloxy -3-chloro, 3-chloro-5-(4-guanidinophenylthiomethyl), 3-chloro-5-(4-morpholinosulfonyl)phenoxymethyl, 3-methoxy-5-(4-morpholinosulfonyl)phenoxymethyl, 3-chloro-5-(3-pyridyl)oxymethyl, 3-methoxy-5-(1,1-dioxothiasol-3-
yl)carbonyl and 3-chloro-5-(1,1-dioxothiazol-3-yl)carbonyl. ] A p-guanidinobenzoic acid phenyl ester derivative or an acid addition salt thereof. 2) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I B) (In the formula, R^2 is (i) a hydrogen atom, (ii) an alkyl group having 1 to 4 carbon atoms, (iii) a carbon number 1 -4 alkoxy group, (iv) alkoxymethyl group having 2 to 5 carbon atoms, (v) formula COOR^3 (wherein R^3 is a hydrogen atom or a carbon number 1
~4 alkyl group. ), (vi)
A group represented by the formula CH_2COOR^3 (in the formula, R^3 represents the same meaning as above), (vii) a group represented by the formula CH=CH-COOR^3 (in the formula, R^3
has the same meaning as above. ), (viii) halogen atom, (ix) trifluoromethyl group, (x) formula COR^4 (wherein R^4 is an alkyl group having 1 to 4 carbon atoms, phenyl group, guanidinophenyl group) , cyclopentylmethyl group or cyclohexylmethyl group), (xi) a group represented by the formula OCOR^4 (wherein R^4 represents the same meaning as above). (xii) a group represented by the formula CH_2OCOR^4 (in the formula, R^4 represents the same meaning as above); (xiii) a group represented by the formula SO_2R^4 (in the formula, R^4 represents the same meaning as above); ), (xiv) a group represented by the formula OSO_2R^4 (in the formula, R^4 represents the same meaning as above), (xv) a group represented by the formula CONR^5R^6 (in the formula, R^5 and R
Each ^6 independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group, a pyridyl group, or R^5, R^6 and the nitrogen atom to which they are bonded are Together they represent a pyrrolidinyl group, a piperidino group, or a morpholino group. ), (xvi) a group represented by the formula OCONR^5R^6 (in the formula, R^5 and R^6 represent the same meanings as above), (xvii) a group represented by the formula SO_2NR^5R^6 ( In the formula, R^5
and R^6 have the same meanings as above. ), (xviii) formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
In the formula, R^5 and R^6 have the same meanings as above. ), (xix) a group represented by the formula NHSO_2R^7 (in the formula, R^7 represents an alkyl group having 1 to 4 carbon atoms or a phenyl group), (xx) a nitro group, (xxi) hydroxyl group, (xxii) hydroxymethyl group, (xxiii) guanidino group, (xxiv) benzyloxy group, (xxv) guanidinophenylthiomethyl group, (xxv
i) Morpholinosulfonylphenoxymethyl group, (xx
vii) pyridyloxymethyl group or (xxviii
)(1,1-dioxothiazol-3-yl)carbonyl group, n represents an integer of 1 to 5, and when n represents an integer of 2 or more, each R^2 may be the same as each other. may be different. ) An esterase inhibitor containing a p-guanidinobenzoic acid phenyl ester derivative or an acid addition salt thereof as an active ingredient.