JPH0764801B2 - p-guanidinobenzoic acid phenyl ester derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel p-guanidinobenzoic acid derivative. More specifically, the new general formula (IA) (In the formula, all symbols have the same meanings as described below.) A p-guanidinobenzoic acid phenyl ester derivative or an acid addition salt thereof.

BACKGROUND OF THE INVENTION The lysosomal hydrolase group released from neutrophils plays an important role in the biological defense reaction against tissue damage caused by microorganisms or inflammation. Of the lysosomal enzyme group, elastase and cathepsin G, which belong to neutral serine proteinases localized in azure granules, mainly play a role of connective tissue degradation. In particular, elastase decomposes the elastic connective tissue by cleaving the cross-linking structure of elastin or the hydrophobic site of the protein that directly functions to maintain the elasticity of lung tissue [J. Cell. Biol., 40 , 366 (1969 )]. Furthermore, elastase selectively decomposes not only elastin but also the cross-linked region of collagen fibers [J. Biochem., 84 , 559 (197
8)] In addition, it plays a central role in connective tissue metabolism such as [J. Clin. Invest., 57 , 615 (1976)] which also acts on tissue structural proteins such as proteoglycan.

In the living body, elastase is an inhibitor common to serine enzymes, α ₁ -proteinase inhibitor (α ₁ -P
Although it is inactivated by I), tissue destructive symptoms appear when the enzyme-inhibitor system balance is disturbed [Schweiz. Med. Wshr., 114 , 895 (1984)].

Elastin turnover in normal tissues is very slow [Endocrinology, 120 , 92 (1978)], but emphysema [Am.
v.Respir.Dis., 110 , 254 (1974)], atherosclerosis [Lab.Invest., 22 , 228 (1970)] or rheumatoid arthritis [in Neutral Proteases of Human Po
lymorphonuclear Leukocytes, Urban and Schwarzenber
g, Baltimore-Munich (1978), p. 390] and the like, abnormal elastin degradation was observed under various pathological conditions, and the relationship between elastase and disease has attracted attention [infection, inflammation, immunity, 13 , 13 (1983)].

[Conventional technology]

Against the background described above, research and development of elastase inhibitors have recently been vigorously carried out, various elastase inhibitors have been proposed, and patents have been filed.However, guanidinobenzoic acid derivatives such as the present invention have been proposed. No elastase inhibitor consisting of is known until now.

On the other hand, various esters of p-guanidinobenzoic acid have been conventionally known.

For example, (1) Japanese Patent Publication No. (2) JP-A-50-4038 discloses a compound represented by the general formula: (In the formula, R ^a represents an aromatic group, and the aromatic group is 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. The compound represented by the formula (3) is disclosed in Japanese Patent Publication No. 57-35870. (Wherein Z ^a represents a group selected from the group consisting of ^a carbon-carbon covalent bond, a methylene group, an ethylene group and a vinylene group.) Is disclosed, and (4) JP-A-55-55154. In the specification, the general formula (Wherein, Z ^b represents a methylene group, an ethylene group or a vinylene group, and R ^b represents a lower alkyl group), and (5) West German Laid-Open Patent No. 3005580 discloses , General formula (Wherein, Z ^c represents a group represented by sulfonyl groups or Z ^d -CO, Z ^d is a single bond, represents methylene, ethylene or vinylene, R ^c and / or R ^d represents hydrogen or alkyl.) The compound represented by (6) West German Laid-Open Patent No. 1905813 has the general formula (In the formulae, R ^e and / or R ^f represents hydrogen, alkyl, aryl, nitro, amino, alkylamino, dialkylamino, alkoxy, carboxy, carboalkoxy or halogen, and 1 represents zero or 1.) Disclosed compounds are disclosed.

(7) USP No. 4,423,069 describes the general formula [In the formula, R ^g is halogen, trihalomethyl, a nitrile group,
Formyl group, OR ⁱ , COR ⁱ , COOR ⁱ , CONH ₂ or CONR ^j R
^k (wherein R ⁱ , R ^j, or R ^k represents an alkyl group having 1 to 8 carbon atoms), and R ^h represents hydrogen or a group represented by the symbol R ^g . ] A method for inhibiting conception by administering a compound represented by the formula or a salt thereof is disclosed. (8) JP-A-61-43151 (In the formula, R ¹ represents hydrogen, a nitrile group or an ether group, R ^m represents a hydrogen, an ether group, an ester group or a carbamoyl group, and R ¹ and R ^m exclude hydrogen at the same time.) Acrosin inhibitors containing the indicated compounds or salts thereof are disclosed.

However, in the above specifications (1) to (6), since all of these compounds have an action of inhibiting trypsin and plasmin, they are useful for treating acute pancreatitis and as an antiplasmin agent for hemorrhagic diseases. Since all of the compounds in the above specifications (7) and (8) also have the action of suppressing acrosin, which is an important enzyme during fertilization, It is only described to be useful as an inhibition method or a fertilization inhibitor.

The elastase inhibitory action of these compounds has not been mentioned at all, and no report has been made to confirm the presence or absence of the action until now.

Elastase belongs to the same serine proteinase as trypsin and plasmin (hereinafter, trypsin and plasmin are referred to as "other serine proteinases" to distinguish them from elastase.) It is very different in terms of sex, therefore, it is preferable to think that elastase is a group of enzymes that are essentially completely different from other serine proteinases, and when developing inhibitors for them, a completely different viewpoint You should think about it.

That is, elastase, particularly human neutrophil elastase, has a molecular weight of about 30,000 [Biochem.J., 155 , 255 (1976)],
Isoelectric point within pH 8.77-9.15 [Anal.Biochem., 90 , 481
(1978)] basic glycoprotein [“Protein Degradatio
n in Health and Disease ", edited by D. Evered and J. Whelan,
51, Excerpta Medica, Amsterdam (1980)], which differs from other serine proteinases in enzymatic protein properties. Further, in terms of substrate specificity, elastase is an endopeptidase that cleaves mainly at the C-terminal side of alanine residues, and this point also differs from other serine proteinases. Thus, since the two are fundamentally different, it is completely impossible to infer an inhibitor of elastase from other serine proteinase inhibitors.

[Object of the Invention]

Based on these findings, the present inventors conducted research to find an elastase inhibitor having a chemical structure completely different from that of conventional elastase inhibitors, and as a result, surprisingly known as other serine proteinase inhibitors. It was found that some of the p-guanidinobenzoic acid phenyl ester derivatives described above had an elastase inhibitory action.

The fact that other serine proteinase inhibitors also have an elastase inhibitory effect was first confirmed by this experiment, and it was completely unexpected until then.

Therefore, the present inventors have conducted extensive studies to find out a novel p-guanidinobenzoic acid phenyl ester derivative having an elastase inhibitory effect, and as a result, completed the present invention.

[Structure of Invention]

Therefore, the present invention has the general formula (IA) [In the formula, (R ¹ ) _m is 2-methyl, 3-methyl, 2,3-dimethyl, 3-ethyl, 2-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-ishipropoxycarbonyl, 3-sec-butoxycarbonyl-2-chloro, 3-methoxycarbonylmethyl, 2-chloro-3-methoxycarbonylmethyl, 2-chloro-4-methoxycarbonylmethyl, 3-chloro-4-methoxy Carbonylmethyl, 2-fluoro, 3-fluoro, 4-fluoro, 2,6-difluoro, 2,3-difluoro, 2,3,4,5,6-pentafluoro, 2-chloro, 3-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-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-guanidinobenzoyloxy)-
3-methyl, 5-acetoxymethyl-3-chloro, 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), 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), 3-
Chloro-4- (N, N-diethylsulfamoyl), 3-
Chloro-5- (N, N-diethylsulfamoyl), 4-
(N, N-diethylsulfamoyl) -2-fluoro, 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, 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, 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 And 3-chloro-5- (1,1-dioxothiazol-3-yl) carbonyl group. ] The p- guanidino benzoic acid phenyl ester derivative shown by these, and the novel compound which is its acid addition salt.

In the group of compounds represented by the general formula (IA), as a superordinate concept, there are some that are included in each of the inventions described in the above [Prior Art], but specific description of individual compounds Therefore, all the compounds represented by the general formula (IA) are considered to be completely novel.

The acid addition salt of the compound represented by formula (IA) is preferably non-toxic and water-soluble. Suitable acid addition salts include, for example, hydrochloride, hydrobromide, hydroiodide,
Inorganic acid salts such as sulfates, phosphates, nitrates, or acetates, lactates, tartrates, benzoates, citrates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates Organic salts such as salts, isethionates, glucuronates and gluconates can be mentioned.

The compound represented by the general formula (IA) can be produced by a known method. For example, the general formula (II) (In the formula, X represents a halogen atom.) And an acid addition salt of the compound represented by the general formula (III) (In the formula, (R ¹ ) _m has the same meaning as above.) It is produced by reacting.

Since the above reaction is a condensation reaction which produces hydrogen halide as a by-product, it is advantageous to allow the presence of a dehydrohalogenating agent in order to accelerate the reaction. 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. Further, as the inorganic base, for example, sodium bicarbonate, sodium carbonate, caustic soda, etc. are used.

As the solvent, for example, benzene, toluene, tetrahydrofuran, pyridine and the like can be used. As described above, pyridine is particularly preferable because it also acts as a dehydrohalogenating agent.

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

In carrying out the reaction, the above-mentioned starting compound (III)
Is dissolved in a solvent, preferably pyridine, and the starting compound (II) is added to this solution. The starting compound (II) does not dissolve when pyridine is used as a solvent, and thus the reaction becomes a heterogeneous system, but since the target product dissolves in pyridine as the reaction progresses, it eventually forms a homogeneous solution. .
When a solvent other than pyridine is used, a homogeneous system is not always 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 this target product, depending on the solvent used, it may be concentrated, or sodium bicarbonate may be added without concentration to convert the product into a carbonate, which precipitates as crystals. In particular, when pyridine is used as a solvent, crystals are precipitated by directly converting to carbonate without evaporative concentration. Of course, the desired product can be obtained by evaporating the solvent to dryness, but it is preferable to precipitate the crystals as described above because a purified product having a high purity can be obtained.

The compound (IA) of the present invention thus obtained can be further converted, if desired, into a suitable acid addition salt described above by a known method.

Further, when it does not precipitate as crystals in the process of converting to the above salt, it can be purified by column chromatography using silica gel or the like.

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

The raw material compound (II) is obtained as a salt of hydrogen halide produced as a by-product when the acid halide (II) is produced from p-guanidinobenzoic acid, and it is advantageous to use this salt as it is.

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

Further, among the compounds of the present invention represented by the general formula (IA), compounds in which at least one of R ¹ represents a carboxyl group, that is, the general formula (IA-a) (In the formula, R ^1a represents a chloro group among the groups represented by R ¹ , p represents 1 or 2, q represents 0 or 1, and p + q represents 2.)
General formula (IV) (In the formula, the symbol φ represents a phenyl group and the other symbols have the same meanings as described above.) The compound can be obtained by subjecting the compound to a debenzylation reaction. Such debenzylation reaction is carried out in an atmosphere of an inert gas (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.

Further, the compound (IV) is a compound of the general formula (V) and an acid addition salt of the compound represented by the general formula (II). (In the formula, all symbols have the same meanings as described above.) The compound can be obtained by subjecting the compound to an esterification reaction. This reaction is carried out as described above.

The compound (V) has the general formula (VI) (In the formula, all symbols have the same meanings as described above.) The compound can be obtained by subjecting it to a benzylation reaction. The benzylation reaction is performed by a known method.

Is the compound represented by the general formula (VI) a known compound,
Alternatively, it can be easily produced by a known method.

Among the compounds of the present invention represented by the general formula (IA), a compound in which ^one of R ¹ represents a hydroxymethyl group, that is, the formula (IA-b) The compound represented by the formula (VII) (In the formula, THP represents a 2-tetrahydropyranyl group.) The compound can be obtained by subjecting it to a de-THP reaction. Such de-THP reaction is, for example, acetic acid
In an aqueous solution of an organic acid such as propionic acid, oxalic acid or p-toluenesulfonic acid (preferably acetic acid) or an aqueous solution of an inorganic acid such as hydrochloric acid or sulfuric acid, an organic solvent, which is preferably miscible with water, such as methanol or 1, Ethanol such as 2-dimethoxyethane, dioxane or tetrahydrofuran
It may be carried out at a temperature of room temperature to 75 ° C (preferably a temperature of 37 ° C or higher) in the presence of tellurium.

In addition, the compound (VII) is a compound of the formula (VIII) It can be obtained by subjecting a compound represented by: to an esterification reaction. Such a reaction is carried out as described above.

The compound represented by the formula (VIII) has the formula (IX) It can be obtained by subjecting a compound represented by to a debenzylation reaction. Such debenzylation reaction is generally carried out in a hydrogen gas atmosphere using palladium-carbon as a catalyst and ethyl acetate, ethanol, benzene or the like at a temperature of generally 0 to 40 ° C. (preferably at room temperature). Be done.

The compound represented by the formula (IX) 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 (IA),
General formula (IA-c) [In the formula, (R ^1c ) _m is 2-methyl, 3-methyl, 2,3-dimethyl, 3-ethyl, 2-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-ishipropoxycarbonyl, 3-sec-butoxycarbonyl-2-chloro, 3-methoxycarbonylmethyl, 2-chloro-3-methoxycarbonylmethyl, 2-chloro-4-methoxycarbonylmethyl, 3-chloro-4-methoxy Carbonylmethyl, 2-fluoro, 3-fluoro, 4-fluoro, 2,6-difluoro, 2,3-difluoro, 2,3,4,5,6-pentafluoro, 2-chloro, 3-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-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-guanidinobenzoyloxy)-
3-methyl, 5-acetoxymethyl-3-chloro, 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), 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), 3-
Chloro-4- (N, N-diethylsulfamoyl), 3-
Chloro-5- (N, N-diethylsulfamoyl), 4-
(N, N-diethylsulfamoyl) -2-fluoro, 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-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, 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 And 3-chloro-5- (1,1-dioxothiazol-3-yl) carbonyl group. ] The compound represented by the general formula (X) (In the formula, (R ^1c ) _m has the same meaning as described above.) It can also be produced by reacting a cyanamide represented by the formula (XI) NH ² —CN (XI). .

In the above reaction, the 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 an alcohol, and an equimolar amount or excess mineral acid with the compound (X), For example hydrochloric acid,
It is carried out by adding an excess of the compound of the formula (XI) in the presence of sulfuric acid and reacting at room temperature to the reflux temperature of the reaction mixture for 15 minutes to 2 hours.

The produced target compound is isolated and purified in the same manner as in the above method, and if desired, converted to an acid addition salt.

The starting compound (X) used in the above reaction is the corresponding p-
Easily by dissolving a nitrobenzoic acid phenyl ester compound in a lower alkanol such as ethanol and catalytically reducing it in the presence of a hydrogenation catalyst such as palladium carbon, palladium black, platinum dioxide, nickel under normal temperature or normal pressure or under heating and pressure. It can be manufactured. The other raw material, cyanamide (XI), is a known compound.

[Effect] Since the p-guanidinobenzoic acid phenyl ester derivative represented by the general formula (IA) and the acid addition salt thereof of the present invention have an elastase inhibitory action, elastin degradation by elastase and collagen fiber in mammals, particularly humans It is useful for the treatment and / or prevention of diseases caused by abnormally high level of the degradation of proteoglycan and / or abnormal proteoglycan degradation. 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 (i) Experimental method Using human neutrophil elastase, the method of Bieth et al. [Bio
chem.Med., 75 , 350 (1974)]. That is, a synthetic substrate [succinyl-alanyl-prolyl-alanyl-p-nitroanilide (Suc-Ala-Rro-
Ala-pNA, manufactured by Peptide Research Laboratories)].

1 mM Suc-Ala-Rro-Ala-pNA (100 mM with N-methylpyridone
Was added to the reaction mixture. ) 0.1
Reaction mixture consisting of M Tris-HCl buffer (pH 8.0), 0.2 M sodium chloride solution, various concentrations of sample solution and enzyme solution
1 ml was incubated for 30 minutes at 37 ° C. 50% in the reaction solution
After the reaction was stopped by adding 100 μl of acetic acid, the released p-
Nitroanilide was measured by the absorbance at 405 nm, and the inhibition rate was calculated by the following formula.

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

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. For example, in an acute toxicity test by intravenous administration using mice, (R ¹ ) _m in the general formula (IA) is 2,5-dichloro, 3-chloro-5-hydroxy, 3-chloro-5-ethanesulfonyloxy. And 3
The LD50 values of the compound representing -chloro-4- (N, N-diethylsulfamoyl) were both in the range of _{50 to} 150 mg / Kg. Therefore, it was confirmed that the compound of the present invention is useful for the treatment and / or prevention of diseases caused by abnormally enhanced degradation of elastin and other proteins by elastase in mammals, especially humans.

To use the compound of the present invention represented by the general formula (IA) and an acid addition salt thereof for the above purpose, they are usually administered systemically or locally, orally or parenterally. Although the dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., it is usually orally administered once per adult in the range of 50 mg to 500 mg once a day, or Per adult, 1 to 10 mg to 200 mg per day per day
It is administered parenterally (preferably intravenously) from once to several times. 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 such as purified water. , Including ethanol. In addition to an inert diluent, this composition contains a wetting agent, an auxiliary agent such as a suspending agent, a sweetening agent, a flavoring agent,
It may contain a fragrance 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 such as sodium chloride, sodium citrate or citric acid to provide isotonicity. A method for producing a spray agent is described in, for example, US Pat. No. 2868.
691 and 3095355.

The injections for parenteral administration according to the present invention include aseptic 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 non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. Such a composition may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose) and 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 solvent for injection before use.

Other compositions for parenteral administration include external preparations containing one or more active substances and formulated by a method known per se, coating agents such as ointments, suppositories for rectal administration. And pessaries for vaginal administration and the like.

〔Example〕

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

In the examples, "IR" represents "infrared absorption spectrum", and unless otherwise specified, it was measured by the KBr method. Moreover, "mesylate" in the table means "methanesulfonate".

Example 1 p-guanidinobenzoic acid 3,5-dichlorophenyl ester methanesulfonate p-Guanidinobenzoyl chloride hydrochloride (prepared by the method described in Example 1 of West German Patent No. 3005580 and US Patent No. 4283418, respectively) 70
0 mg, 3,5-dichlorophenol 490 mg and pyridine 10 m
The mixture of 1 was stirred for 30 minutes under ice cooling. Diethyl ether was added to the reaction mixture and decantation was performed, and a saturated aqueous solution of sodium hydrogencarbonate was added to the obtained supernatant to obtain the desired carbonate. The obtained crystals were washed successively with water and acetone and dried under vacuum. The crystals were suspended in ethanol, 0.124 mg of methanesulfonic acid was added, and the precipitated crystals were vacuum dried to obtain 506 mg of the title compound (white crystals) having the following physical data.

Melting point: 232-234 ℃; IR value; ν3340,3150,1730,1680,1620,1600,1570,1550,14
10,1260,1200,1170,1090,1060,1040cm ^-1 .

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 the corresponding phenol compound.

Example 113 p-Guanidinobenzoic acid 3-carboxy-2-chlorophenyl ester hydrobromide After adding 4 ml of 1N sodium hydroxide to 700 mg of 3-carboxy-2-chlorophenol, the mixture was concentrated under reduced pressure to obtain the corresponding sodium salt. Dissolve the sodium salt in 20 ml of hexamethylphosphoramide, and add 0.58 ml of benzyl bromide.
Was added and stirred overnight. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

1 g of the residue and p-guanidinobenzoyl chloride hydrochloride (prepared by the method described in Example 1 of JP-A-55-115865 and US Pat. No. 4,283,418) in an ice water bath in pyridine. And stirred for 15 minutes. Diethyl ether was added to the reaction mixture, the mixture was decanted, saturated aqueous sodium hydrogencarbonate solution was added to the insoluble residue, and the crystals were filtered, washed with water and acetone in that order, and dried under vacuum.

200 mg of the obtained crystals were added with about 5 ml of 30% hydrogen bromide-acetic acid in an argon atmosphere, and the mixture was stirred at room temperature for 3 hours. Diethyl ether was added to the reaction mixture, and the precipitated crystals were washed with diethyl ether and vacuum dried to obtain 192 mg of the title compound (yellow powder) having the following physical data.

Melting point: 220-227 ° C.

Then, the compounds of the present invention of Examples 114 and 115 having the physical properties shown in Table 3 were obtained in the same manner as in Example 113.

Example 116 p-guanidinobenzoic acid 3-chloro-5-hydroxymethylphenyl acetic acid salt 1.970 g of 3-chloro-5-hydroxybenzoic acid was dissolved in 30 ml of dimethylformamide, 60 ml of sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes. Benzyl bromide in the reaction solution
4.288 g was added, and the mixture was stirred at room temperature for 2 hours. After adding 30 ml of ethyl acetate to the reaction mixture, the mixture was washed several times with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent, hexane: ethyl acetate = 10: 1) to obtain 3.61 g of 3-chloro-5-benzyloxybenzoic acid benzyl ester having the following physical properties. It was

TLC (hexane: ethyl acetate = 10: 1): Rf 0.26.

Dissolve 3.61 g of benzyl compound in 50 ml of tetrahydrofuran, add 579 mg of lithium aluminum hydride,
The reaction was carried out at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture to decompose excess reagents, and the mixture was poured into a 1N aqueous sodium hydroxide solution. After the reaction mixture was extracted with diethyl ether, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent, dichloromethane) to give the following physical properties 3 1.502 g of -chloro-5-benzyloxybenzyl alcohol was obtained.

TLC (chloroform: methanol = 10: 1): Rf0.69.

Dissolve 1.502 g of alcohol in 20 ml of dichloromethane,
Dihydropyran (655 mg) and a catalytic amount of p-toluenesulfonic acid were added, and the mixture was reacted at room temperature for 1 hour. In the reaction mixture,
A small amount of pyridine was added, washed with water, and further concentrated. The obtained residue was purified by silica gel column chromatography (elution solvent, hexane: ethyl acetate = 10: 1) to give 3-chloro-5-benzyloxybenzyl alcohol-O- (2- 1.83 g of tetrahydropyranyl) ether was obtained.

TLC (hexane: ethyl acetate = 10: 1): Rf 0.20.

Dissolve the obtained benzyl derivative (996 mg) in ethyl acetate (7 ml) to obtain 10
% Palladium carbon as a catalyst, and debenzylation was carried out at room temperature, atmospheric pressure and hydrogen atmosphere. The reaction was completed after 3 hours, and the obtained crude product was purified by silica gel column chromatography (elution solvent, hexane: ethyl acetate = 5: 1) to give 3-chloro-5- (2 having the following physical properties. 274 mg of tetrahydropyranyloxymethyl) phenol were obtained.

TLC (hexane: ethyl acetate = 5: 3): Rf 0.24.

274 mg of the phenol compound was dissolved in 3 ml of pyridine, 396 mg of p-guanidinobenzoyl chloride hydrochloride was added, and the mixture was reacted at room temperature for 2 hours. Diethyl ether 20 was added to the reaction mixture.
ml was added and the precipitate was collected by filtration. The precipitate was washed with diethyl ether. A carbonate produced by adding an aqueous sodium hydrogen carbonate solution to the insoluble residue was filtered off. The crude carbonate was dissolved in 3 ml of 60% acetic acid and reacted at 37 ° C. for 2 hours. After distilling off acetic acid under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent, chloroform: methanol: acetic acid = 10: 2: 1) to obtain 100 mg of the title compound having the following physical properties.

TLC (chloroform: methanol: acetic acid = 10: 2: 1): Rf0.
26; NMR (CD ₃ OD): δ8.2 (2H, d, J = 8Hz), 7.42 (2H, d, J = 8H)
z), 7.30 (1H, bs), 7.16 (2H, bs), 4.64 (2H, s).

Example 117 p-guanidinobenzoic acid 3-chloro-5- (4-morpholinosulfonyl) phenoxymethylphenyl ester
Acetate 404 mg of 3-chloro-5-hydroxybenzoic acid was dissolved in 10 ml of dichloromethane, and 256 mg of dihydropyran was further added. Adding a catalytic amount of p-toluenesulfonate,
The reaction was carried out 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.

The obtained crude product was used for the next reaction without purification. That is, the crude product was dissolved in 10 ml of tetrahydrofuran and cooled in an ice water bath, 133 mg of lithium aluminum hydride was added to this mixed solution, and the mixture was 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 ml of 1N sodium hydroxide, the mixture was extracted with ethyl acetate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent, hexane: ethyl acetate = 5: 2). Purification was carried out to obtain 541 mg of 3-chloro-5- (tetrahydropyranyloxy) benzyl alcohol having the following physical data.

TLC (hexane: ethyl acetate = 5: 3): Rf 0.5.

The obtained alcohol compound (484 mg) was dissolved in dichloromethane (10 ml). To this mixed solution, 242 mg of triethylamine was added, cooled in an ice-water bath, and 273 mg of methanesulfonyl chloride was added dropwise. After the reaction temperature was raised to room temperature, it was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the corresponding mesylate.

The obtained crude product was used for the next reaction without purification.
460 mg of p-morpholinosulfonylphenol was dissolved in a mixed solution of 7 ml of tetrahydrofuran and 1 ml of hexamethylphosphoramide. Sodium hydride 5
7.6 mg was added and stirred for 10 minutes. Then, 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, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The crude product obtained was added with 5 ml of methanol and 5 ml of tetrahydrofuran.
Dissolve it in a mixed solvent of ml and add p-toluenesulfonic acid.
50 mg was added and reacted at room temperature for 2 hours, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 5: 3) and has the following physical data 3-
228 mg of chloro-5- (4-morpholinosulfonyl) phenoxymethylphenol was obtained.

TLC (hexane: ethyl acetate = 5: 3): Rf 0.18.

Esterification was carried out in the same manner as in Example 1 using 228 mg of the phenol derivative, 207 mg of p-guanidinobenzoyl chloride hydrochloride and 3 ml of pyridine. The product was subjected to silica gel column chromatography (elution solvent, ethyl acetate: acetic acid: water = 40).
The title compound 15 having the following physical data after being purified at 0: 100: 30)
0 mg was obtained.

TLC (chloroform: methanol: acetic acid = 10: 2: 1): Rf0.
7; IR: ν3600 to 2500,1720,1680,1560,1400,1330 cm ^-1 .

Example 118 p-Guanidinobenzoic acid 3-methoxy-5- (4-morpholinosulfonyl) phenoxymethylphenyl ester acetic acid salt The title compound (white powder) having the following physical data was obtained by the same production method as described in Example 117.

TLC (ethyl acetate: acetic acid: water = 400: 100: 30): Rf0.72; IR: ν3600 to 2500,1720,1680,1590,1400,1340 cm ⁻¹ .

Formulation Example 1 p-guanidinobenzoic acid 3-chloro-5-hydroxyphenyl ester methanesulfonate (prepared in Example 1) 10 g, calcium fibrin glycolate (disintegrant) 4
00 mg, magnesium stearate (lubricant) 200 mg and microcrystalline cellulose 9.4 g were mixed by a conventional method and compressed to give 100 tablets each containing 100 mg of active ingredient.

Formulation Example 2 1 g of p-guanidinobenzoic acid 3-chloro-5-hydroxyphenyl ester methanesulfonate (prepared in Example 1) was dissolved in 10 ml of ethanol, sterilized through a bacteria-retaining filter, and per 5 ml ampoule. 0.5 ml
Each ampoule contained 50 mg of drug and the ampoule was sealed. The content of the ampoule is diluted with an appropriate volume of a diluting solution, for example, Tris-HCl buffer having a pH of 8.6 to 2.5 ml and used as an injection.

Formulation Example 3 p-guanidinobenzoic acid 3-chloro-5-ethanesulfonyloxyphenyl ester methanesulfonate (produced in Example 1) 10 g, calcium fibrin glycolate (disintegrant) 400 mg, magnesium stearate (lubrication Agent) 200 mg and microcrystalline cellulose 9.4 g were mixed by an ordinary method and compressed to obtain 100 tablets each containing 100 mg of active ingredient.

Formulation Example 4 1 g of p-guanidinobenzoic acid 3-chloro-5-ethanesulfonyloxyphenyl ester methanesulfonate (prepared in Example 1) was dissolved in 10 ml of ethanol and sterilized through a bacteria-retaining filter to give 5 ml. By inserting 0.5 ml per ampoule, 5 per ampoule
The ampoule was sealed with 0 mg of drug included.
The content of the ampoule should be a suitable volume of diluent, for example pH 6.8.
It is used as an injection by diluting to 2.5 ml with Tris-HCl buffer.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 277/20 295/22 Z // A61K 31/425 ABG ABX ACD AED C12N 9/99

Claims (1)

[Claims] 1. A general formula [In the formula, (R ¹ ) _m is 2-methyl, 3-methyl, 2,3-dimethyl, 3-ethyl, 2-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-ishipropoxycarbonyl, 3-sec-butoxycarbonyl-2-chloro, 3-methoxycarbonylmethyl, 2-chloro-3-methoxycarbonylmethyl, 2-chloro-4-methoxycarbonylmethyl, 3-chloro-4-methoxy Carbonylmethyl, 2-fluoro, 3-fluoro, 4-fluoro, 2,6-difluoro, 2,3-difluoro, 2,3,4,5,6-pentafluoro, 2-chloro, 3-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-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-guanidinobenzoyloxy)-
3-methyl, 5-acetoxymethyl-3-chloro, 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), 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), 3-
Chloro-4- (N, N-diethylsulfamoyl), 3-
Chloro-5- (N, N-diethylsulfamoyl), 4-
(N, N-diethylsulfamoyl) -2-fluoro, 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, 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, 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 And 3-chloro-5- (1,1-dioxothiazol-3-yl) carbonyl group. ] The p- guanidino benzoic acid phenyl ester derivative shown by these, or its acid addition salt.