Derivatives of p-guanidinobenzoic acid

Abstract

Compounds presented by the general formula: ##STR1## [wherein when Y is oxygen, R.sup.2 is H, alkyl, alkoxy, alkoxymethyl, --COOR.sup.3, --CH.sub.2 COOR.sup.3, --CH=CH--COOR.sup.3, halogen, --CF.sub.3, --COR.sup.4, --OCOR.sup.4, --CH.sub.2 OCOR.sup.4, --SO.sub.2 R.sup.4, --OSO.sub.2 R.sup.4, --CONR.sup.5 R.sup.6, --OCONR.sup.5 R.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --CONH--SO.sub.2 NR.sup.5 R.sup.6, --NHSO.sub.2 R.sup.7, --NO.sub.2, --OH, --CH.sub.2 OH, guanidino, benzyloxy, guanidinophenylthiomethyl, morpholinosulfonylphenoxymethyl, pyridyloxymethyl, or (1,1-dioxothiazol-3-yl)carbonyl, or when Y is sulfur, R.sup.2 is H, alkyl, alkoxy, halogen, --COOR.sup.3, --CH.sub.2 COOR.sup.3, --NO.sub.2, or --SO.sub.2 NR.sup.5 R.sup.6, and n represents an integer of one to five, and when n represents more than two, each of R.sup.2 may be the same group or the different group.] and acid addition salts thereof have inhibitory effect on elastase, and, therefore, are useful for the treatment and/or prevention of diseases induced by abnormal enhancing of degradation of proteins such as elastin and the like, by the action of elastase in mammals, especially in human beings.

Description

FIELD OF THE INVENTION

The present invention relates to derivatives of p-guanidinobenzoic acid and the pharmaceutical agents containing them as active ingredients.

More particularly, it relates to new derivatives of p-guanidinobenzoic acid of the general formula: ##STR2## (wherein all symbols are the same meaning as described hereinafter.), and relates to elastase inhibitors containing, as active ingredient, derivatives of p-guanidinobenzoic acid of the general formula: ##STR3## (wherein all symbols are the same meaning as described hereinafter.).

BACKGROUND OF THE INVENTION

Lysosomal hydrolases of neutrophils have an important role for an organism defense reaction against tissue damage caused by microbe or inflammation etc.

Elastase and cathepsin G, which belong to neutral serine proteinase locally existed in azurophil granule mainly play a part in decomposition of a connective tissue.

Especially, elastase degrades elastic connective tissue by cleaving the cross-linking of elastin which directly maintains the elasticity of lung tissue etc., and by cleaving hydrophobic part of protein [J. Cell. Biol., 40, 366 (1969)] and degrades the cross-linking area of collagen selectively [J. Biochem., 84, 559 (1978)], and it acts on such as proteoglycans etc. [J. Clin. Invest., 57, 615 (1976)].

Elastase is inactivated by .alpha..sub.1 -proteinase inhibitor (.alpha..sub.1 -PI) that is natural occurring inhibitor for serine, proteinase in vivo and the unbalance of enzyme and inhibitor system causes the destruction of the tissue [Schweiz. Med. Wshr., 114, 895 (1984)].

The turnover of elastin in normal tissue is very slow [Endocrinology, 120, 92 (1978)], but the pathological acceleration in degradation of elastin is found under various unsound state such as pulmonary emphysema [Am. Rev. Respir. Dis., 110, 254 (1974)], atherosclerosis [Lab. Invest., 22, 228 (1970) and rheumatoid arthritis [in Neutral Proteases of Human Polymorphonuclear Leukocytes, Urban and Schwarzenberg, Baltimore--Munich (1978), page 390], suggesting the relationship of elastase and diseases [Infection.Inflammation.Immunity, 13, 13 (1983)].

PRIOR ARTS

Under the background as mentioned above, recently the studies and development on elastase inhibitors have been conducted heartily, various substances inhibiting elastase have been proposed and many patent applications have been filed. However, elastase inhibitors consisting of derivatives of guanidinobenzoic acid, as shown in the present invention, have not been known at all till now.

On the other hand, heretofore the various esters of p-guanidinobenzoic acid have been known. For example, when Y is an oxygen atom in the general formulae (IA) and (IB)

(1) in the specification of Japanese Patent Kokoku No. 54-40534, the compounds of the general formula: ##STR4## has been disclosed, (2) in the specification of Japanese Patent Kokai No. 50-4038, the compounds of the general formula: ##STR5## (wherein R.sup.a represents an aromatic group, and an said aromatic group may be substituted by 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) (abstracted related points) have been disclosed, (3) in the specification of Japanese Patent Kokoku No. 57-35870, the compounds of the general formula: ##STR6## (wherein Z.sup.a represents the grcup selected from the group consist of a carbon- carbon covalent bond, a methylene group, an ethylene grcup and a vinylene group) have been disclosed, (4) in the specification of Japanese Patent Kokai No. 55-55154, the compounds of the general formula: ##STR7## (wherein Z.sup.b represents a methylene group, an ethylene group or a vinylene group, and R.sup.b represents a lower alkyl group.) have been disclosed, (5) in the specification of Germany Patent Publication No. 3005580, the compounds represented by the general formula: ##STR8## (wherein Z.sup.c represents a sulfonyl group or the group represented by Z.sup.d -CO, Z.sup.d represents a bond, methylene, ethylene or vinylene, R.sub.c and/or R.sup.d represent a hydrogen atom or a alkyl group.) have been disclosed, (6) in the specification of Germany Patent Publication No. 1905813, the compounds of the general formula: ##STR9## (wherein R.sup.e and/or R.sup.f represent a hydrogen atom; an alkyl group, an aryl group, a nitro group, an amino group, an alkylamino group, a dialkylamino group, an alkoxy group, a carboxy group, a carboalkoxy group or a halogen atom, 1 represents an integer of zero or one.) have been disclosed. (7) in the specification of U.S. Pat. No. 4,423,069, the method to inhibit conception by giving the compounds represented by the general formula: ##STR10## [wherein R.sup.g represents a halogen, a trihalomethyl, a nitryl group, a formyl group, OR.sup.i, COR.sup.i, COOR.sup.i, CONH.sup.2 or CONRjR.sup.k (wherein R.sup.i, R.sup.j or R.sup.k represent an alkyl group of one to eight carbon atoms), R.sup.h represents a hydrogen atom or the group represented by the symbol R.sup.g.] and a salt thereof have been disclosed, (8) In the specification of Japanese Patent Kokai No. 61-43151, the compounds represented by the general formula: ##STR11## (wherein R.sup.l represents a hydrogen, a nitrile group or an ether group, R.sup.m represents a hydrogen, an ether group, an ester group or a carbamoyl group, except that R.sup.l and R.sup.m represent a hydrogen at the same time.) and agents of depressing acrocine have been disclosed, On the other hand, when Y is a sulfur atom, (9) In the specification of Japanese Patent Kokoku No. 55-42076, the compounds described by the general formula: ##STR12## (wherein R.sup.n represents a hydrogen atom or an ethoxycarbonyl group and symbol m' represents an integer of four to six) have been disclosed, (10) in the specification of Japanese Patent Kokoku No. 56-3345, the compounds described by the general formula: ##STR13## (wherein A represents a straight- or branched-chain alkylene group of one to ten carbon atoms, B represents p-phenylene group or divalent alicyclic group, symbol a represents zero or one, symbol b represents zero or one, the total number of a and b represent one or two, R.sup.o represents the group selected from the group of an ethoxycarbonylalkyl group of one to ten carbon atoms, the alicyclic group, a phenyl group, a naphtyl group and a phenylalkyl group and the alicyclic group and the aromatic group described above, may be replaced by a lower alkyl group, an ethoxycarbonyl group, an ethoxycarbonyl-lower alkyl group, a carboxyalkyl group, a halogen atom, an alkoxy group, an acylamino group, an alkylsulfonyl group, a carboxy group, a thiocarboxy group, a mercaptocarbonyl group, a nitro group or a carbamoyl group.) have been disclosed.

In the specifications (1) to (6), (9) and (10) mentioned above, it is described that all these compounds have inhibitory effects on trypsin and plasmin, and therefore, are useful for the treatment of acute pancreatitis and bleeding diseases as anti-plasmin agents. And there is no description about an inhibitory effect of these compounds on elastase in the above specifications, nor report concerning about the examination of the effect so far.

Likewise, in the specifications (7) and (8) mentioned above, it is described that all compounds have inhibitory effects on acrocine etc. which are important enzymes in fertilization, and accordingly it is useful as the method for inhibition of conception and as an agent for inhibition of fertilization.

Elastase belongs to serine proteinase like trypsin and plasmin (hereinafter described "trypsin and plasmin" as "other serine proteinase" in order to distinguish from elastase), but is much different from them in point of enzymatic property and substrate specificity. Accordingly, it is reasonable to consider that elastase is a quite different enzyme group from other serine proteinase essentially, and therefore, the development of elastase inhibitors should be considered from a quite different point of view.

That is, elastase, especially human neutrophil elastase is a basic glycoprotein ["Protein Degradation in Health and Disease", edited by D. Evered and J. Whelan, page 51, Excerpta Medica, Amsterdam (1980)] having the molecular weight of about 30,000 [Biochem. J., 155, 255 (1976)], its isoelectric point being between pH 8.77 and 9.15 Anal. Biochem., 90, 481 (1978)], and therefore, it is different from other serine proteinases in proteinic property.

Furthermore, in substrate specificity, elastase is classified as endopeptidases which mainly cleave a protein at the carboxy terminal of alanine residue. Even in this point, elastase is different from other serine proteinase. As said above, there is the fundamental differences between both enzyme, and therefore it is entirely impossible to analogize elastase inhibitors from other serine proteinase inhibitors.

PURPOSE OF THE INVENTION

As the result of energestic investigations in order to find new elastase inhibitory agents that have quite different chemical structure from conventional one, based on these findings, the present inventors have now found the fact that a kind of derivatives of p-guanidinobenzoic acid phenyl ester, known as inhibitory agents of other serine proteinase, unexpectedly has an inhibitory effect on elastase, then completed this invention.

The fact that inhibitory agents of other serine proteinase have an inhibitory effect on elastase, has been confirmed experimentaly for the first time, and was never anticipated until now.

CONSTITUTION OF THE INVENTION

Accordingly, the present invention relates to the novel compounds, i.e. derivatives of p-guanidinobenzoic acid of the general formula: ##STR14## [wherein Y represents an oxygen atom or a sulfur atom and i) when Y is an oxygen atom, (R.sup.1)m represents the group selected from 2-methyl, 3-methyl, 2,3-dimethyl, 3,5-dimethyl, 3-ethyl, 2-methoxy, 3-methoxy, 4-methoxy, 3,5-dimethoxy, 5-etanesulfonyloxy-3-methoxymethyl, 3-hydroxy-5-methoxymethyl, 5-(4-guanidinobenzoyloxy)-3-methoxymethyl, 3-carboxy-2-chloro, 3,5-dicarboxy, 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-guanidinobenzoyloxy)-3-methyl, 5-acetoxymethyl-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-etanesulfonyloxy-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)carbamcyl)}, 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-pyrrolidinylsulfonyl), 3-piperidinosulfonyl, 3-morpholinosulfonyl, 4-morpholinosulfonyl, 3-chloro-5-{N-(4-sulfamoylphenyl)carbamoyl}, 3-chloro-5-[N-{4-(N,N-diethylsulfamoyl)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-dioxothiazol-3-yl)carbonyl and 3-chloro-5-(1,1-dioxothiazol-3-yl)carbonyl group.

ii) When Y is a sulfur atom, (R.sup.1)m represents the group selected from 2-methyl, 3-methyl, 4-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 4-fluoro, 2-chloro, 3-chloro, 4-chloro, 2,5-dichloro, 2,6-dichloro, 3,4-dichloro, 2-bromo, 2-methoxycarbonyl, 4-carboxy, 4-carboxymethyl, 4-ethoxycarbonylmethyl, 4-nitro and 4-(N,N-diethylaminosulfonyl)group.] or an acid addition salt thereof.

In the group of compounds described in the general formula (IA), there are some compounds contained in each invention described in the above item [Prior art] as the broad scope, but there is no specific description about individual compound. Accordingly, all compounds represented by the general formula (IA) are considered to be quite novel.

Further, the present invention relates to the novel use as elastase inhibitors containing derivatives of p-guanidinobenzoic acid, as active ingredient, represented by the general formula: ##STR15## [wherein Y represents an oxygen atom or a sulfur atom and i) when Y is an oxygen atom, R.sup.2 represents

(i) a hydrogen atom, (ii) an alkyl group of one to four carbon atoms, (iii) an alkoxy group of one to four carbon atoms, (iv) an alkoxymethyl group of two to five carbon atoms, (v) a group represented by the formula: COOR.sup.3 (wherein R.sup.3 represents a hydrogen atom or an alkyl group of one to four carbon atoms.), (vi) a group represented by the formula: CH.sub.2 COOR.sup.3 (wherein R.sup.3 is the same meaning as described hereinbefore.), a group represented by the general formula: CH.dbd.CH--COOR.sup.3 (wherein R.sup.3 is the same meaning as described hereinoefore.), (viii) a halogen atom, (ix) a trifluoromethyl group, (x) a group represented by the formula: COR.sup.4 (wherein R.sup.4 represents an alkyl group of one to four carbon atoms, a phenyl group, guanidinophenyl group, cyclopentylmethyl group or cyclohexylmethyl group.), (xi) a group represented by the formula: OCOR.sup.4 (wherein R.sup.4 is the same meaning as described hereinbefore.), (xii) a group represented by the general formula: CH.sub.2 OCOR.sup.4 (wherein R.sup.4 is the same meaning as described hereinbefore.), (xiii) a group represented by the general formula: SO.sub.2 R.sup.4 (wherein R.sup.4 is the same meaning as described hereinbefore.), (xiv) a group represented by the general formula: OSO.sub.2 R.sup.4 (wherein R.sup.4 is the same meaning as described hereinbefore.), (xv) a group represented by the general formula: CONR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6 represent a hydrogen atom, an alkyl group of from one to four carbon atoms, a phenyl group, a benzyl group, a pyridyl group independently, or R.sup.5, R.sup.6 and a nitrogen atom, to which R.sup.5 and R.sup.6 are linked, together represent a pyrrolidinyl group, a piperidino group or morpholino group.), (xvi) a group represented by the general formula: OCONR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6 are the same meaning as described hereinbefore.), (xvii) a group represented by the general formula: SO.sub.2 NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6 are the same meaning as described hereinbefore.), (xviii) a group represented by the general formula: ##STR16## (wherein R.sup.5 and R.sup.6 are the same meaning as described hereinbefore.), (xix) a group represented by the general formula: NHSO.sub.2 R.sup.7 (wherein R.sup.7 represents an alkyl group of from one to four carbon atoms or a phenyl group.), (xx) a nitro group, (xxi) a hydroxy group, (xxii) a hydroxymethyl group, (xxiii) a guanidino group, (xxiv) a benzyloxy group, (xxv) a guanidinophenylthiomethyl group, (xxvi) a morpholinosulfonylphenoxymethyl, (xxvii) a pyridyloxymethyl or (xxviii) (1,1-dioxothiazol-3-yl)carbonyl group. ii) when Y is a sulfur atom, R.sup.2 represents (i) a hydrogen atom, (ii) an alkyl group of one to four carbon atoms, (iii) an alkoxy group of one to four carbon atoms, (iv) a halogen atom, (v) a group represented by the formula: COOR.sup.3 (wherein R.sup.3 is the same meaning as described hereinbefore.), (vi) a group represented by the formula: CH.sub.2 COOR.sup.3 (wherein R.sup.3 is the same meaning as described hereinbefore.), (vii) a nitro group or (viii) a group represented by the fcrmula: SO.sub.2 NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6 are the same meanirg as described hereinbefore.) and symbol n represents an integer of one to five, and when symbol n represents more than two, each of R.sup.2 may be the same group or the different group.] or an acid addition salt thereof.

In this specification containing claims, the term "an alkyl group" means the straight- or branched-chained alkyl group.

In the general formula (IB), as the alkyl group represented by R.sup.2, as the alkyl moiety in the alkoxy group represented by R.sup.2 and as the alkyl group represented by R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7, a methyl, an ethyl, a propyl, a butyl group and the isomer thereof are cited, and all of them are preferred.

In the general formula (IB), as the halogen atom represented by R.sup.2, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom are cited, and all of them are preferred.

In the general formula (IB), as the group represented by R.sup.2, and all group represented by (i) to (xxvii) is preferred.

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

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

All compounds of the present invention, represented by the general formula (IB) [including the compounds represented by the general formula (IA)] may be prepared by well-known methods.

For example, it may be prepared by reacting an acid addition salt of a compounds represented by the general formula: ##STR17## (wherein X represents an halogen atom) with a compounds represented by the general formula: ##STR18## (wherein Y, R.sup.2 and n are the same meaning as described hereinbefore).

As the above reaction is the condensation accompanied by the formation of hydrogen halide, it is advantageous to use a dehydrohalogenation agent to promote the reaction.

As for the dehydrohalcgenation agent, there can be used a tertiary organic amire, or if desired, there can be used a inorganic base such as a metal bicarbonate, etc.

As a tertiary organic amine, there can be used aliphatic, aromatic or heterocyclic amine, for example, triethylamine, tributylamine, dimethylaniline, pyridine and the like.

Particularly, pyridine is preferable because it is useful also as a solvent of reaction ingredient.

Further, as an inorganic base, there can be used, for example, sodium bicarbonate, sodium carbonate, sodium hydroxide and the like.

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

Since the reaction proceeds comparatively fast, it may be carried out at the room temperature, or if desired, with a little cooling, generally the reaction may be carried out at a temperature from 0.degree. C. to the room temperature.

The reacticn time varies depending upcn the reaction temperature to be used, and it is generally 30 minutes to 4 hours, preferably 30 minutes to 2.5 hours.

In carrying out the reaction, the starting material (III) described above is dissolved in a solvent, preferably in pyridine, the starting materials (II) is added into above solution.

When pyridine is used as a solvent, the compound (II) is not dissolved therein and therefore the reaction is hetetogeneous system. However the desired product is soluble in pyridine, and therefore the reaction mixture becomes homogeneous with the progress of the reaction. In the case where any other solvent than pyridine is used, the reaction mixture is not always homogeneous but the reaction can be carried out in a heterogeneous system.

The desired product is obtained as a salt with hydrogen halide. The product may be separated and purified by the following post-treatment. That is to say, the reaction mixture is concentrated or not concentrated depending upon the used solvent. If not concentrated, the product is crystallized as the carbonate salt by adding sodium bicarbonate to the reaction mixture. Particularly when pyridine is used as a solvent, the carbonate salt of the product is obtained as crystals by treating the reaction product mixture with sodium bicarbonate, without evaporation and concentration. Of course, it is possible to obtain the product by the evaporation of the solvent, but it is preferable that the product is crystallized as a salt as mentioned above, because in the latter case the product is higher in purity than in the former treatment.

The compounds (IB) of the present invention thus obtained can be converted further, if desired, to a suitable acid addition salt described above by known methods.

Besides, in the case that the product is crystallized as no salt in the route of conversion to a salt mentioned above, the product can be purified by column chromatography using silica-gel, etc.

The starting materials (II), used in the above-mentioned reaction, can be prepared by the conventional method that p-guanidinobenzoic acid may be reacted with thionylchloride.

In this case, the starting materials (II) can be prepared as the salt with hydrogen halide, especially hydrochloride.

The starting materials (II) may be obtained as the salt with a hydrogen halide which is by-produced in the formation of acid halide (II) from guanidinobenzoic acid, and it is advantageous that the obtained salt may be used without any operation.

The compounds represented by the general formula (III) are known compounds, or can be preparated easily by the known methods.

Further, of the compound of the present invention represented by the general formula (IB), the compound wherein at least one group of R.sup.2 represent a carboxyl group, that is, the ccmpounds represented by the general formula: ##STR19## (wherein R.sup.2a represents the groups hereinbefore described for R.sup.2 except for a carboxy group, and p represents an integer of between one to five and q represents zero and an integer of between one to four, and the total number of p and q represented an integer of between one to five.) can be obtained by subjecting the compounds represented by the general formula: ##STR20## (wherein symbol .PHI. represents a phenyl group and the other symbols are the same meaning as described hereinbefore) to the reaction for eliminating benzyl group. The said reaction for eliminating benzyl group may be carried out, for example, using anhydrous solution of hydrogen bromide-acetic acid in an atmosphere of an inert gas (e.g. argon, nitrogen etc.).

It is suitable that the reacticn temperature is generally at 0.degree. to 50.degree. C., preferably at the room temperature.

And the compound (IV) can be obtained by subjecting the acid addition salt of the compounds represented by the general formula (II) and the compounos represented by the general formula: ##STR21## (wherein all symbols are the same meaning as described hereinbefore.) to esterification reaction.

This reaction may be carried out by the same conditions as mentioned hereinbefore.

And the compound (V) can be obtained by subjecting the compounds represented by the general formula: ##STR22## (wherein all symbols are the same meaning as described hereinbefore.) to benzylation reaction.

The benzylation reaction may be carried out by the known methods.

The ccmpound represented by the general formula (VI) is the known compound or can be easily prepared by the known methods.

In the compound of present invention represented by the general formula (IB), the compound wherein at least one group of R.sup.2 represents a hydroxymethyl group, i.e., the compound represented by the general formula: ##STR23## (wherein R.sup.2b represents the groups hereinbefore described for R.sup.2 except for a hydroxymethyl group, and r represents an integer of between one to five and s represents zero and an integer of between one to four, and the total number of r and s represented an integer of between one to five, the other symbols are the same meaning as described hereinbefore.) can be obtained by subjecting the compounds represented by the general formula: ##STR24## (wherein THP represents 2-tetrahydropyranyl group and the other symbols are the same meaning as described hereinbefore.) to reaction for eliminating a THP group.

The said reacticn for eliminating a THP group may be carried in an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid (preferably, acetic acid), or in an aqueous solution of an inorganic acid such as hydrochloric acid and sulfuric acid. Suitably, it may be carried out in the presence of a water-miscible organic solvent, for example, methanol, or an ether such as 1,2dimethoxyethane, dioxane or tetrahydrofuran, at a temperature of ambient to 75.degree. C. (preferably more than 37.degree. C.).

And the compound (VII) may be obtained by subjecting an acid addition salt of the compound represented by the general formula (II) and the compounds represented by the general formula: ##STR25## (wherein all symbols are the same meaning as described hereinbefore.) to esterification reaction.

The said reaction may be carried out by the same conditions as mentioned above.

The compound represented by the formula (VIII) can be cbtained by subjecting the compounds represented by the general formula: ##STR26## (wherein all symbols are the same meaning as described hereinbefore.) to the reaction for eliminating a benzyl group.

The said reaction for eliminating benzyl group may be carried out, for example, in an atmosphere of hydrogen gas, using palladium-carbon as catalyst in ethyl acetate, ethanol or benzene etc., at a temperature of 0.degree. C. to 40.degree. C., preferably ambient.

The compounds represented the formula (IX) are known compounds or can be obtained by the known methods.

Further, of the compounds of the present invention represented by the general formula (IB), those represented by the general formula: ##STR27## [wherein R.sup.2c represents (i) a hydrogen atom,

(ii) an alkyl group of one to four carbon atcms, (iii) an alkoxy group of one to four carbon atoms, (iv) an alkoxymethyl group of two to five carbon atoms, (v) a group represented by the formula: COOR.sup.3 (wherein R.sup.3 represents a hydrogen atom or an alkyl group of one to four carbon atoms.), (vi) a group represented by the formula: CH.sub.2 COOR.sup.3 (wherein R.sup.3 is the same meaning as described hereinbefore.), (vii) a halogen atom, (viii) a trifluoromethyl group, (ix) a group represented by the general formula: COR.sup.4 (wherein R.sup.4 represents an alkyl group of from one to four carbon atoms, a phenyl group, guanidinophenyl group, cyclopentylmethyl group or cyclohexylmethyl group.), (x) a group represented by the formula: OCOR.sup.4 (wherein R.sup.4 is the same meaning as described hereinbefore.), (xi) a group represented by the general formula: CH.sub.2 OCOR.sup.4 (wherein R.sup.4 is the same meaning as described hereinbefore.), (xii) a group represented by the general formula: SO.sub.2 R.sup.4 (wherein R.sup.4 is the same meaning as described hereinbefore.), (xiii) a group represented by the general formula: OSO.sub.2 R.sup.4 (wherein R.sup.4 is the same meaning as described hereinbefore.), (xiv) a grcup represented by the general formula: CONR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6 represent a hydrogen atom an alkyl group of from one to four carbon atoms, a phenyl group, a benzyl group, a pyridyl group independently, or R.sup.5, R.sup.6 and a nitrogen atom, to which R.sup.5 and R.sup.6 are linked, together represent a pyrrolidinyl group, a piperidino group or morpholino group.), (xv) a group represented by the general formula: OCONR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6 are the same meaning as described hereinbefore.), (xvi) a group represented by the general formula: SO.sub.2 NR.sup.5 R.sup.6 (wherein R.sup.5 and R.sup.6 are the same meaning as described hereinbefore.), (xvii) a group represented by the general formula: ##STR28## (wherein R.sup.5 and R.sup.6 are the same meaning as described hereinbefore.), (xviii) a group represented by the general formula: NHSO.sub.2 R.sup.7 (wherein R.sup.7 represents an alkyl group of from one to four carbon atoms or a phenyl group.), (xix) a hydroxy group, (xx) a guanidino group, (xxi) a benzyloxy group, (xxii) a guanidinophenylthiomethyl group, (xxiii) a morpholinosulfonylphenoxymethyl or (xxiv) a pyridyloxymethyl grcuo and symbol n' represenzs an integer of one to five, and when symbol n' represents more than two, each of R.sup.2c represents the same group or the different group.] may be prepared by reacting the compounds described by the general formula: ##STR29## (wherein R.sup.2c and n' are the same meaning as described hereinbefore.) with a cyanamide described by the formula: --H.sub.2 N--CN (XI)

The above-mentioned reaction may be carried out by adding the starting material (X) into water or an inert organic solvent such as methanol, ethanol, tetrahydrofuran, or into the mixed solvent of water and alcohol, adding thereto an excess amount of a compound of the formula (XI) under the existence of equimolecular or excess amount to the compound (X), of a mineral acid such as hydrochloric acid, sulfuric acid, and then reacting for 15 minutes to two hours at a temperature from ambient to the reflux temperature of the reaction mixture.

The desired compound prepared may be isolated and purified by the same method as hereinbefore described, and if required, converted into an acid addition salt thereof.

The starting material (X), used in above-mentioned reaction, may be easily prepared by dissolving the corresponding p-nitrobenzoic acid phenyl ester compound in a lower alkanol such as ethanol, and then subjecting to catalytic reduction in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium black, platinum dioxide or nickel at atmospheric temperature and pressure or by heating and adding pressure.

The cyanamide (XI), another starting material, is a known compound.

EFFECT

Delivatives of p-guanidinobenzoic acid phenyl ester described by the general formula (IA) and (IB), and acid addition salts thereof, of the present invention, have an inhibitory effect on elastase. Accordingly, it is useful for treatment and/or prevention of diseases induced by the abnormal enhancing of the degradation of elastin, collagen fiber and/or proteoglican, by the action of elastase, in mammals, especially in human beings.

Examples of such diseases are pulmonary emphysema, atherosclerosis and rheumatoid arthritis and the like.

An inhibitory effects of compounds on elastase were ccnfirmed by the screening system mentioned below.

INHIBITORY EFFECT ON ELASTASE

(1) Method of Experiment

The test was carried out by the slight modification of the method of Bieth et al [see Biochem. Med., 75, 350 (1974)] using elastase from human neutrophil.

Namely, it is a spectrophotometric method using the synthesized substrate [succinyl-alanyl-prolyl-alanyl-p-nitroanilide (Suc-Ala-Pro-Ala-pNA, produced by peptide laboratory) which has comparatively high specificity on neutrophil elastase.

The reaction mixture consisted of 1 mM Suc-Ala-Pro-Ala-pNA (dissolving in N-methylpyrrolidone to the concentration of 100 mM, and then adding 1/100 amount of the solution to the reaction mixture.), 0.1 M buffer solution of tris-hydrochloric acid (pH 8.0), 0.2 M sodium chloride aqueous solution, the sample solution of various concentrations and enzyme solution in a final volume of 1.0 ml was incubated at 37.degree. C. for 30 minutes.

The reaction was stopped by the addition of 100 .mu.l of 50% acetic acid into the reaction mixture, and then p-nitro anilide released was measured on absorbance of 405 nm.

Inhibition percentage of the test compounds was caliculated by the following equation: ##EQU1##

(2) Results

The results are shown in Table 1.

TABLE 1__________________________________________________________________________Inhibitory Effect on Elastase ##STR30## (IB-c)(1) when Y represents an oxygen atom in the general formula (IB-c): Inhibitory Effect on ElastaseExample Structural Formula of Sample Inhibition IC50No. (R.sup.2)n Salt % at 100 .mu.M (.mu.M)__________________________________________________________________________ hydrogen.sup.1) phosphate 54.6.sup.2)2 2-methyl mesylate 20.23 3-methyl mesylate 45.6 4-methyl.sup.1) mesylate 28.44 2,3-dimethyl mesylate 5.95 3,5-dimethyl mesylate 46.26 3-ethyl mesylate 39.67 2-methoxy mesylate 23.18 3-methoxy mesylate 50.9 1009 4-methoxy mesylate 44.410 3,5-dimethoxy acetate 40.011 5-etanesulfonyloxy-3- acetate 66.0 60.0 methoxymethyl12 3-hydroxy-5-methoxymethyl acetate 14.0 >20013 5-(4-guanidinobenzoyloxy)- 2 acetate 89.0 9.1 3-methoxymethyl148 3-carboxy-2-chloro hydrobromide 20.0147 3,5-dicarboxy hydrobromide 25.0149 2-carboxy-5-chloro hydrobromide 60.014 2-chloro-3-methoxycarbonyl mesylate 90.7 4.015 2-chloro-4-methoxycarbonyl mesylate 55.6 98.016 3-chloro-4-methoxycarbonyl mesylate 42.017 5-chloro-2-methoxycarbonyl mesylate 92.2 5.818 3-chloro-5-methoxycarbonyl acetate 1.819 3,5-bis(isopropoxycarbonyl) mesylate 5.220 5-chloro-2- mesylate 14.0 isopropoxycarbonyl21 2-chloro-3- mesylate 2.0 isopropoxycarbonyl22 3-sec-butoxycarbonyl-2- mesylate 2.6 chloro23 3-methoxycarbonylmethyl acetate 15.624 2-chloro-3- mesylate 50.0 methoxycarbonylmethyl25 2-chloro-4- mesylate 40.0 methoxycarbonylmethyl26 3-chloro-4- mesylate 13.3 methoxycarbonylmethyl27 4-(2-methoxycarbonylvinyl) mesylate 31.028 2-fluoro mesylate 76.3 40.029 3-fluoro mesylate 81.1 21.030 4-fluoro mesylate 10.731 2,6-difluoro mesylate 3.732 2,3-difluoro acetate 3.733 2,3,4,5,6-pentafluoro mesylate 92.1 5.834 2-chloro mesylate 76.8 27.035 3-chloro mesylate 87.6 8.036 4-chloro mesylate 14.9.sup.2)37 2,5-dichloro mesylate 85.8 1.138 2,6-dichloro mesylate 89.9 2.01 3,5-dichloro mesylate 97.0 0.439 3-chloro-5-methoxy mesylate 91.1 2.440 4-chloro-3-methoxy mesylate 39.041 2-chloro-5-methoxy acetate 13.042 2-bromo mesylate 82.1 16.043 3-bromo mesylate 91.7 6.044 4-iodo mesylate 11.245 2-trifluoromethyl mesylate 72.4 23.046 3-trifluoromethyl mesylate 71.4 13.047 3,5-bistrifluoromethyl mesylate 3.248 3-acetyl mesylate 4.149 2-acetyl-5-methoxy acetate 40.050 2-acetyl-5-propoxy mesylate 54.051 2-acetyl-5-chloro acetate 1.852 5-chloro-2-propionyl mesylate 1.653 5-chloro-2-isobutylyl acetate 6.554 3-benzoyl mesylate 92.055 4-benzoyl mesylate 33.356 4-benzoyl-2-chloro mesylate 57.1 48.057 4-benzoyl-2,3-dichloro mesylate 50.558 5-chloro-2- acetate 1.9 cyclopentylacetyl59 3-acetoxy acetate 25.760 4-acetoxy mesylate 27.861 5-acetoxy-3-chloro acetate 0.4862 3-chloro-5-propionyloxy acetate 0.3863 3-benzyloxy mesylate 78.3 11.064 3-(4-guanidinobenzoyloxy) acetate 15.065 3,5-bis(4- 3 mesylate 38.0 guanidinobenzoyloxy)66 3-acetyl-5-(4- 2 acetate 72.0 guanidinobenzoyloxy)67 5-(4-guanidinobenzoyloxy)- 2 acetate 70.0 3-methoxycarbonyl68 3-chloro-5-(4- acetate 0.6 guanidinobenzoyloxy)69 5-(4-guanidinobenzoyloxy)- 2 acetate 1.6 3-methoxy70 5-(4-guanidinobenzoyloxy)- acetate 6.4 3-methyl71 5-acetoxyemthyl-3-chloro acetate 3.072 4-mesyl mesylate >100.073 5-mesyloxy-3-methoxy acetate 4.774 3-chloro-5-mesyloxy acetate 1.075 3-chloro-5- acetate 1.1 ethanesulfonyloxy76 3-chloro-5- acetate 1.1 isopropanesulfonyloxy77 5-benzenesulfonyloxy-3- acetate 0.8 chloro78 5-etanesulfonyloxy-3-methyl acetate 27.079 5-carbamoyl-3-chloro acetate 5.280 3-(N,N-dimethylcarbamoyl) mesylate 30.081 2-chloro-3-(N- mesylate 6.0 methylcarbamoyl)82 3-(4-guanidinobenzoyloxy)- 2 acetate 38.0 5-(N-methylcarbamoyl)83 3,5-bis(N-ethylcarbamoyl) mesylate 28.084 3,5-bis(N-propylcarbamoyl) mesylate 36.085 5-(N-benzylcarbamoyl)-3-(4- 2 acetate 27.0 guanidinobenzoyloxy)86 3-chloro-5-{N-(3- 2 acetate 0.93 pyridyl)carbamoyl}87 3-chloro-5-(N,N- acetate 0.76 dimethylcarbamoyloxy)88 3-chloro-5-(N-ethyl- mesylate 1.1 carbamoyloxy)89 3-sulfamoyl acetate 65.090 3-chloro-4-(N,N- acetate 140.0 dimethylsulfamoyl91 2-(N,N-diethylsulfamoyl) mesylate 180.092 3-(N,N-diethylsulfamoyl) mesylate 35.093 4-(N,N-diethyulsulfamoyl) mesylate 58.094 3-chloro-4-(N,N- acetate 22.0 diethylsulfamoyl)95 3-chloro-5-(N,N- acetate 4.8 diethylsulfamoyl)96 4-(N,N-diethylsulfamoyl)-2- acetate 61.0 fluoro97 4-(N,N-dipropylsulfamoyl) mesylate 58.098 4-(1-pirolidinylsulfonyl) acetate 77.99 3-piperidinosulfonyl acetate 41.0100 3-morpholinosulfonyl acetate 44.2101 4-morpholinosulfonyl acetate 34.9102 3-chloro-5-{N-(4- acetate 1.3 sulfamoylphenyl)carbomoyl}103 3-chloro-5-[N-{4-(N,N- acetate 0.95 dimethylsulfamoyl)phenyl} acetate 0.95 carbamoyl104 3-chloro-5-[N-{4-(N,N- acetate 1.1 diethylsulfamoyl)phenyl} carbamoyl105 2-chloro-5-(N-mesylamino) acetate 8.5106 3-chloro-5-(N- acetate 15.0 ethanesulfonylamino107 3-nitro mesylate 87.0 11.0108 4-nitro mesylate 60.1 120.0109 3-hydroxy-5-methyl acetate 160.0110 5-hydroxy-3-methoxy acetate 20.0111 5-hydroxy-3-methoxycarbonyl acetate 45.0112 3-chloro-5-hydroxy mesylate 8.3113 3-(4-guanidinobenzoyloxy)- 2 mesylate 42.0114 5-hydroxy-3-(N- acetate 22.0 methylcarbamoyl)115 3-(N-benzylcarbamoyl)-5- acetate 88.0 hydroxy150 3-chloro-5-hydroxymethyl acetate 4.5116 3-guanidino 2 acetate 20.0117 4-guanidino 2 mesylate >100.0118 2-chloro-5-guanidino 2 acetate 47.0119 5-benzyloxy-3-chloro acetate 4.7120 3-chloro-5-(4- 2 acetate 6.0 guanidinophenylthiomethyl)151 3-chloro-5- acetate 1.4 morpholinosulfonyl- phenoxymethyl152 3-methoxy-5-(4- acetate 7.0 morpholinosulfonyl) phenoxymethyl121 3-chloro-5-(3-pyridyl) 2 acetate 1.1 oxymethyl122 3-methoxy-5-(3'- acetate 12.0 sulfonylpyrrolidine) carboxamido123 3-chloro-5-(3'- acetate 3.1 sulfonylpyrrolidine) carboxamido__________________________________________________________________________(ii) when Y represents a sulfur atom in the general formula (IB-c): Elastase Inhibitory EffectExample Structural Formula of Sample Inhibition % IC.sub.50No. (R.sup.2)n Salt at 50 .mu.g/ml (.mu.M)__________________________________________________________________________124 hydrogen Phosphate 94.0 2.1125 2-methyl mesylate 76.3 20126 3-methyl mesylate 89.7 5.0127 4-methyl tosylate 29.3128 2-methoxy mesylate 79.8 21.0129 3-methoxy sulfonate 89.2 6.4130 4-methoxy mesylate 48.2131 4-fluoro mesylate 83.0 21.0132 2-chloro mesylate 93.0 1.8133 3-chloro mesylate 81.2 0.3134 4-chloro mesylate 69.5135 2,5-dichloro mesylate 92.1 0.1136 2,6-dichloro mesylate 64.5 45137 3,4-dichloro mesylate 35.5138 2-bromo mesylate 83.1 1.6139 4-carboxyl mesylate 23.2140 4-carboxymethyl sulfonate 47.8141 2-methoxycarbonyl mesylate 96.3 2.6142 2-ethoxycarbonyl mesylate 69.1144 4-ethoxycarboxymethyl mesylate 75.5145 4-nitro mesylate 64.2 18.0146 4-(N,N- acetate 73.1 11.0 acethylaminosulfonyl__________________________________________________________________________ Remarks: .sup.1) shows that this compound is described in Example 4 in the specification of Japanese Patent Kokai No. 504038. .sup.2) shows inhibition percentage when the concentration of drug is 50 .mu.g/ml.

The result of the experiment showed that the compounds of the present invention have an inhibitory effect on elastase.

Further, it was confirmed that the toxicity of the compounds of the present invention is enough low and they can be useful enough safely for medical supplies.

For example, in the acute toxicity test in mice by intravenous administration, the LD.sub.50 values of compounds wherein Y represents an oxygen atom in the general formula (IB) and (R.sup.2)n represents 2,5-dichloro, a hydrogen atom, 3-chloro-5-hydroxy, 3-chloro-5-ethanesulfonyloxy and 3-chloro-4-(N,N-diethylsulfamoyl), were between 50 and 150 mg/kg, respectively.

The other the LD.sub.50 values of compounds wherein Y represents a sulfur atom in the general formula (IB) and (R.sup.2)n represents 2,5-dichloro group, a hydrogen atom, 3-chloro-5-hydroxy, 3-chloro-5-ethanesulfonyloxy and 3-chloro-4-(N,N-diethylsulfamoyl), were between 50 and 150 mg/kg, respectively.

Accordingly, it was confirmed that the compounds of the present invention can be useful for the treatment and/or prevention of diseases induced by abnormal enhancing of degradation of proteins such as elastin and the like, by the action of elastase in mammals, especially in human beings.

For the purpose mentioned above, the compounds of the present invention, described in the general formula (IA) and (IB) or an acid addition salts thereof may normally be administered systemically or partially, usually by oral or parenteral administration.

The dose to be administrated is determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person for one time are generally between 50 mg and 500 mg, by oral administration up to several times per day, and between 10 mg and 200 mg, by parenteral administration (preferably by intravenous administration) up to several times per day.

As mentioned above, the doses to be used depend on various conditions. Therefore, there are cases in which doses lower than the ranges specified above and doses greater than the ranges specified above, may be used.

Solid compositions according to the present invention for oral administration include compressed tablets, dispersible powders and granules. In such solid compositions, one or more of the active compound(s) is, or are, admixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate aluminate. The compositions may also comprise, as is normal practice, additional substances other than inert diluents e.g. lubricating agents such as magnesium stearate, and, disintegrating agents such as cellulose calcium gluconate, stabilizing agents such as lactose and solubilizers such as glutamic acid and asparaginic acid. The tablets or pills may, if desired, be made into gastric film-coated or enteric film-coated coated tablets or pills, such as sugar-coated, gelatin-coated, hydroxypropylcellulcse-coated or hydroxypropylmethylcellulose phthalate-coated tablets or pills; two or more layers may be used. The compositions for oral administration also include capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as distilled water or ethanol. Besides inert diluents such compositions may also comprise adjuvants such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.

Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s). Besides inert diluents such compositions may also comprise stabilizers such as sodium bisulfite and buffer for isotonicity, for example sodium chloride, sodium citrate or citric acid.

The manufacturing methods of spray compositions have been described in detail, for example, specifications of the U.S. Pat. No. 2,868,691 and No. 3,095,355.

Preparations for injection according to the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Example of aqueous solvents or suspending media are distilled water for injection and physiological salt solution. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (registered Trade Mark). These compositions may also include adjuvants such as preserving, wetting, emulsifying and dispersing agents stabilizing agents (e.g. lactose) and solubilizers (e.g. glutamic acid and asparaginic acid). They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.

Other compositions for parenteral administration include liquids for external use, and endermic liniments such as ointments, suppositories for rectal administration and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by known methods.

EXAMPLE

The following Reference Examples and Examples illustrate the preparation of compounds of the present invention, however, the present invention is rot restricted to them. In the Examples, "IR" represents "Infrared absorption spectrum". Except when specified otherwise, infrared absorption spectra were recorded by KBr tablet. In the table, "Mesylate" represents "methansulfonyl group".

EXAMPLE 1

p-guanidinobenzoic acid 3,5-dichlorophenyl ester methanesulfonate ##STR31##

The mixture of 700 mg of p-guanidinobenzoyl chloride hydrochloride (prepared by the methods described in Example 1 of each of the specification of Japanese Patent Kokai No. 55-115865 and U.S. Pat. No. 4,283,418), 490 mg of 3,5-dichlorophenol and 10 ml of pyridine was stirred for thirty minutes. Diethyl ether was added into the reaction mixture, and the mixture was decanted.

A saturated aqueous solution of sodium bicarbonate was added into the obtained layer of ether to obtain the desired carbonate.

The obtained crystal was washed with water and acetone, successive, was dried in vacuum.

Dried crystal was suspended in ethanol, 0.124 ml of methanesulfonic acid was added thereto, and precipitated crystal was dried in vacuum to give 506 mg of the title compound (white crystal) having the following physical data: melting point: 232.degree..about.234.degree. C.;

IR value: .nu.3340, 3150, 1730, 1680, 1620, 1600, 1570, 1550, 1410, 1260, 1200, 1170, 1090, 1060, 1040 cm.sup.-1.

Hereinafter, by the same procedure as described in Example 1, p-guanidinobenzoyl chloride hydrochloride and desired phenol compound or thiophenol compounds were used to obtain compounds of the present invention described in following table 2 [compound (IB) wherein Y is an oxygen atom) and table 3 [compounds (IB) wherein Y is a sulfur atom]. ##STR32##

TABLE 2__________________________________________________________________________Example The Structure of Products The AppearanceNo. (R.sup.2)n HX (Salt) of Products m.p. and IR Value of__________________________________________________________________________ Products hydrogen phosphate white crystal 205.about.208.degree. C.2 2-methyl mesylate yellow crystal 199.about.200.degree. C.3 3-methyl mesylate white powder 143.about.144.degree. C.4 2,3-dimethyl mesylate yellow crystal 202.about.205.degree. C.5 3,5-dimethyl mesylate pale yellow crystal 184.about.185.degree. C.6 3-ethyl mesylate white crystal 142.about.143.degree. C.7 2-methoxy mesylate white crystal 196.about.197.degree. C.8 3-methoxy mesylate white crystal 162.about.164.degree. C.9 4-methoxy mesylate pink crystal 173.about.174.degree. C.10 3,5-dimethoxy acetate yellow wax .nu. 2900.about.3400, 1730, 1570.about.1610, 1470 1420, 1260, 1130, 1070, 1040 cm.sup.-1 (neat)11 5-etanesulfonyloxy-3- acetate pale brown bubbly .nu. 2500.about.3500, 1730, 1680, 1570, methoxymethyl powder 1400, 1360, 1255, 1170, 1110, 1070 cm.sup.-112 3-hydroxy-5-methoxymethyl acetate creamy colored .nu. 3700.about.3300, 3300.about.2300, 1720, 1685, bubbly powder 1600, 1570, 1450, 1410, 1265, 1135, 1080 cm.sup.-113 5-(4-guanidinobenzoyloxy)-3- 2 acetate brown bubbly powder .nu. 3700.about.2250, 1740, 1690, 1560, methoxymethyl 1400, 1260, 1180, 1125, 1070 cm.sup.-114 2-chloro-3-methoxycarbonyl mesylate white powder 188.about.190.degree. C.15 2-chloro-4-methoxycarbonyl mesylate white powder 206.about.207.degree. C.16 3-chloro-4-methoxycarbonyl mesylate pink powder 206.about.210.degree. C.17 5-chloro-2-methoxycarbonyl mesylate white powder 170.about.175.degree. C.18 3-chloro-5-methoxycarbonyl acetate white bubbly powder .nu. 3480, 3000, 1730, 1600, 1640, 1580, 1420, 1260, 1170, 1100, 1060 cm.sup.-119 3,5-bis(isopropoxycarbonyl) mesylate white crystal 155.about.157.degree. C.20 5-chloro-2-isopropoxycarbonyl mesylate white crystal 202.about.203.degree. C.21 2-chloro-3-isopropoxycarbonyl mesylate white bubbly powder .nu. 3300, 3150, 1720, 1680, 1600, 1570, 1240, 1040 cm.sup.-122 3-sec-butoxycarbonyl-2-chloro mesylate white crystal 177.about.180.degree. C.23 3-methoxycarbonylmethyl acetate colorless oil .nu. 3500.about.3300, 1700.about.1500, 1400 cm.sup.-1 (neat)24 2-chloro-3-methoxycarbonylmethyl mesylate white crystal 194.about.196.degree. C.25 2-chloro-4-methoxycarbonylmethyl mesylate white powder 170.about.171.degree. C.26 3-chloro-4-methoxycarbonylmethyl mesylate white powder 181.about.182.degree. C.27 4-(2-methoxycarbonylvinyl) mesylate pink crystal 225.about.230.degree. C.28 2-fluoro mesylate pink crystal 168.about.170.degree. C.29 3-fluoro mesylate white crystal 97.about.101.degree. C.30 4-fluoro mesylate white crystal 163.about.164.degree. C.31 2,6-difluoro mesylate white powder 219.about.221.degree. C.32 2,3-difluoro acetate white crystal >300.degree. C.33 2,3,4,5,6-pentafluoro mesylate white crystal 181.about.183.degree. C.34 2-chloro mesylate pale orange crystal 198.about.200.degree. C.35 3-chloro mesylate white crystal 200.about.202.degree. C.36 4-chloro mesylate white crystal 185.about.188.degree. C.37 2,5-dichloro mesylate white crystal 221.about.223.degree. C.38 2,6-dichloro mesylate pink crystal 234.about.237.degree. C.39 3-chloro-5-methoxy mesylate white powder 205.about.207.degree. C.40 4-chloro-3-methoxy mesylate white powder 125.about.128.degree. C.41 2-chloro-5-methoxy acetate white bubbly powder .nu. 3360, 3000, 1745, 1680, 1600, 1570, 1500, 1410, 1260, 1160, 1080, 1020 cm.sup.-142 2-bromo mesylate pale pink crystal 194.about.197.degree. C.43 3-bromo mesylate white crystal 212.about.214.degree. C.44 4-iodo mesylate white crystal 174.about.176.degree. C.45 2-trifluoromethyl mesylate white crystal 191.about.193.degree. C.46 3-trifluoromethyl mesylate white crystal 195.about.198.degree. C.47 3,5-bistrifluoromethyl mesylate yellow powder 194.about.198.degree. C.48 3-acetyl mesylate white crystal 180.about.182.degree. C.49 2-acetyl-5-methoxy acetate brown wax .nu. 2900.about.3500, 1730, 1680, 1480, 1260, 1140 cm.sup.-1 (neat)50 2-acetyl-5-propoxy mesylate brown oil .nu. 3300, 3150, 1740, 1670, 1600, 1560, 1060, 1040 cm.sup.-1 (neat)51 2-acetyl-5-chloro acetate brown bubbly powder .nu. 3400, 3000, 1740, 1690, 1600, 1570, 1400, 1260, 1180, 1060 cm.sup.-152 5-chloro-2-propionyl mesylate white bubbly powder .nu. 3400, 3000, 1740, 1690, 1590, 1440, 1410, 1370, 1250, 1180,53 5-chloro-2-isobutyryl acetate yellow bubbly .nu. 3350, 3000, 1735, 1680, 1580, powder 1400, 1260, 1200, 1170, 1080, 1060, 1010 cm.sup.-154 3-benzoyl mesylate white powder 172.about.175.degree. C.55 4-benzoyl mesylate brown powder 218.about.220.degree. C.56 4-benzoyl-2-chloro mesylate white powder 190.about.192.degree. C.57 4-benzoyl-2,3-dichloro mesylate white powder 169.about.173.degree. C.58 5-chloro-2-cyclopentylacetyl acetate white bubbly powder .nu. 3350, 2950, 1540, 1690, 1600, 1570, 1400, 1260, 1200, 1180, 1060 cm.sup.-159 3-acetoxy acetate brown wax .nu. 3350, 3150, 1720, 1680, 1610, 1580, 1410, 1270, 1140, 1080, 1050 cm.sup.-1 (neat)60 4-acetoxy mesylate pale brown wax .nu. 3650.about.2500, 1760, 1740, 1700, 1680, 1630, 1610, 1570, 1510, 1470, 1410, 1375, 1280 cm.sup.-161 5-acetoxy-3-chloro acetate white bubbly powder .nu. 3400, 3100, 1740, 1685, 1600, 1400, 1320, 1260, 1140, 1070, 1010 cm.sup.-162 3-chloro-5-propionyloxy acetate pale brown .nu. 2500.about.3500, 1720, 1680, 1580, amorphous 1400 cm.sup.-163 3-benzoyloxy mesylate pale brown wax .nu. 3200, 1730, 1680, 1600, 1570, 1480, 1450, 1410, 1250, 1130 cm.sup.-1 (neat)64 3-(4-guanidinobenzoyloxy) acetate white bubbly powder .nu. 3350, 3150, 1730, 1680, 1600, 1570, 1250, 1170, 1130, 1060, 1040, 1020 cm.sup.- 165 3,5-bis(4-guanidinobenzoyloxy) 3 mesylate pale yellow bubbly .nu. 3350, 3150, 1730, 1680, 1600, powder 1560, 1450, 1250, 1170, 1120, 1060, 1040 cm.sup.-166 3-acetyl-5-(4- 2 acetate while solid .nu. 3650.about.2200, 1740, 1690, 1570, guanidinobenzoyloxy) 1410, 1260, 1180, 1135, 1070 cm.sup.-167 5-(4-guanidinobenzoyloxy)-3- 2 acetate pale brown solid .nu. 3650.about.2300, 1730, 1690, 1570, methoxycarbonyl 1400, 1260 cm.sup.-168 3-chloro-5-(4- acetate yellow bubbly .nu. 3150, 1740, 1680, 1600, 1560, guanidinobenzoyloxy) powder 1440, 1270, 1180, 1130, 1060, 1040 cm.sup.-169 5-(4-guanidinobenzoyloxy)-3- 2 acetate colorless solid .nu. 3650.about.2200, 1740, 1690, 1610, methoxy 1570, 1410, 1260, 1180, 1150, 1130, 1070, 1020 cm.sup.-170 5-(4-guanidinobenzoyloxy)-3- 2 acetate pale brown bubbly .nu. 2500.about.3600, 1720, 1680, 1560, methyl powder 1400, 1260, 1175, 1120, 1070 cm.sup.-171 5-acetoxymethyl-3-chloro acetate colorless oil .nu. 3400, 1730, 1680, 1560, 1400, 1240, 1170, 1140, 1060, 1010, 860, 740, 640 cm.sup.-172 4-mesyl mesylate white powder 200.about.215.degree. C.73 5-mesyloxy-3-methoxy acetate white bubbly powder .nu. 3400, 1730, 1680, 1600, 1400, 1360, 1260, 1180, 1140, 1110, 1060 cm.sup.-174 3-chloro-5-mesyloxy acetate white bubbly powder .nu. 3400, 3000, 1740, 1690, 1600, 1440, 1410, 1370, 1250, 1180, 1120, 1070 cm.sup.-175 3-chloro-5-ethanesulfonyloxy acetate white bubbly powder .nu. 3350, 3000, 1740, 1680, 1590, 1560, 1400, 1260, 1200, 1180, 1060, 1020 cm.sup.-176 3-chloro-5-isopropanesulfonyloxy acetate white bubbly powder .nu. 3400, 2900, 1740, 1640, 1600, 1430, 1400, 1240, 1180, 1110, 1060 cm.sup.-177 5-benzenesulfonyloxy-3-chloro acetate white bubbly powder 190.about.195.degree. C.78 5-etanesulfonyloxy-3-methyl acetate pale brown bubbly .nu. 2500.about.3600, 1730, 1680, 1560, powder 1400, 1260, 1170, 1110 cm.sup.-179 5-carbamoyl-3-chloro acetate white amorphous .nu. 3400, 1680, 1570, 1400, 1300, 1270, 1230, 1180, 1100, 1080, 1010, 880, 850, 760, 650 cm.sup.-180 3-(N,N-dimethyl)carbamoyl mesylate white solid .nu. 3650.about.3200, 3150, 1735, 1680, (hygroscopicity) 1600, 1570, 1510, 1480, 1450, 1400, 1310, 1280, 1200, 1060 cm.sup.-181 2-chloro-3-(N-methylcarbamoyl) mesylate white crystal 201.about.205.degree. C.82 3-(4-guanidinobenzoyloxy)-5-(N- 2 acetate colorless solid .nu. 3650.about.2300, 1740, 1690, 1560, methylcarbamoyl) 1510, 1400, 1250, 1180, 1125, 1065 cm.sup.-183 3,5-bis(N-ethylcarbamoyl) mesylate brown wax .nu. 3200, 1735, 1680, 1640, 1560, 1260, 1200, 1050 cm.sup.-184 3,5-bis(N-propylcarbamoyl) mesylate yellow bubbly .nu. 3300, 3150, 1730, 1640, 1560, powder 1260, 1200, 1040 cm.sup.-185 5-(N-benzylcarbamoyl)-3-(4- 2 acetate colorless solid .nu. 3650.about.2300, 1740, 1700, 1640, guanidinobenzoyloxy) 1600, 1570, 1420, 1260, 1190, 1140, 1080 cm.sup.-186 3-chloro-5-{N-(3- 2 acetate pale brown bubbly .nu. 3400, 3100, 1740, 1680, 1580, pyridyl)carbamoyl} powder 1480, 1420, 1420, 1260, 1080 cm.sup.-187 3-chloro-5-(N,N- acetate white bubbly powder .nu. 3400, 3000, 1730, 1700, 1580, dimethylcarbamoyloxy) 1440, 1390, 1260, 1160, 1130, 1070 cm.sup.-188 3-chloro-5-(N-ethylcarbamoyloxy) mesylate white bubbly powder .nu. 3400, 3150, 1730, 1680, 1600, 1570, 1440, 1260, 1200, 1140, 1060 cm.sup.-189 3-sulfamoyl acetate white crystal .nu. 3430, 1735, 1690, 1570, 1410, 1270, 1210, 1180, 1160, 1075, 1010, 765 cm.sup.-190 3-chloro-4-(N,N- acetate yellow bubbly .nu. 3400, 3000, 1740, 1690, 1570, dimethylsulfamoyl) powder 1410, 1340, 1250, 1200, 1160, 1060 cm.sup.-191 2-(N,N-diethylsulfamoyl) mesylate white powder .nu. 3350, 3130, 2980, 1740, 1675, 1600, 1565, 1470, 1330, 1260, 1200, 1055, 1015, 940, 785, 760, 715 cm.sup.-192 3-(N,N-diethylsulfamoyl) mesylate white powder .nu. 3350, 3150, 2980, 1735, 1680, 1600, 1565, 1465, 1330, 1260, 1200, 1065, 1040, 1015, 935, 780, 760, 715 cm.sup.-193 4-(N,N-diethylsulfamoyl) mesylate white crystal .nu. 3400, 3130, 1735, 1695, 1565, 1325, 1270, 1205, 1175, 1150, 1075, 1040, 1015, 945, 720 cm.sup.-194 3-chloro-4-(N,N- acetate pale brown bubbly .nu. 3400, 2500, 1740, 1680, 1560, diethylsulfamoyl) powder 1400, 1250, 1200, 1140, 1060, 1010 cm.sup.-195 3-chloro-5-(N,N- acetate pale brown wax .nu. 3650.about.2100, 1050, 1010, 935, 805, diethylsulfamoyl) 755 cm.sup.-1 (neat)96 4-(N,N-diethylsulfamoyl)-2- acetate yellow wax .nu. 3400, 3000, 1740, 1680, 1560, fluoro 1500, 1410, 1260, 1140, 1070, 1050, 1010 cm.sup.-197 4-(N,N-dipropyl)sulfamoyl mesylate white crystal .nu. 3400, 2980, 1735, 1675, 1600, 1575, 1350, 1265, 1205, 1160, 1050 cm.sup.-198 4-(1-pyrrolidinylsulfonyl) acetate pale brown solid .nu. 3700.about.2200, 1740, 1690, 1590, 1510, 1405, 1340, 1265, 1205, 1160, 1100, 1065, 1015 cm.sup.-199 3-piperidinosulfonyl acetate white solid .nu. 3650.about.3000, 2940, 2850, 1740, 1680, 1570, 1405, 1340, 1265, 1205, 1170, 1070 cm.sup.-1100 3-morpholinosulfonyl acetate white solid .nu. 3650.about.3000, 2960, 2850, 1740, 1680, 1570, 1405, 1355, 1270, 1210, 1170, 1115, 1070 cm.sup.-1101 4-morpholinosulfonyl acetate pale yellow solid .nu. 3700.about.2300, 1740, 1710, 1690, 1570, 1400, 1350, 1270, 1210, 1160, 1120, 1100, 1060, 1020 cm.sup.-1102 3-chloro-5-{N-(4- acetate pale brown .nu. 2500.about.3500, 1720(S), 1660, 1560, sulfamoylphenyl)carbamoyl} amorphous 1520, 1400 cm.sup.-1103 3-chloro-5-[N-{4-(N,N- acetate white bubbly powder .nu. 3400, 1730, 1670, 1570, 1510, dimethylsulfamoyl)phenyl} 1400, 1320, 1250, 1170, 1150, carbamoyl] 1060, 1010, 950, 880, 840, 760, 720, 710 cm.sup.-1104 3-chloro-5-[N-{4-(N,N- acetate while bubbly powder .nu. 3400, 1735, 1680, 1580, 1400, diethylsulfamoyl)phenyl} 1320, 1260, 1150, 1070, carbamoyl] 1020 cm.sup.-1105 2-chloro-5-(N-mesylamino) acetate white crystal .nu. 3450, 3100, 2860.about.2200, 1750, 1695, 1570, 1480, 1405, 1335, 1245, 1175, 1145, 1065, 1050 cm.sup.- 1 (neat)106 3-chloro-5-(N- acetate pale yellow bubbly .nu. 3400, 3150, 1770, 1740, 1680, ethanesulfonylamino) powder 1590, 1400, 1260, 1200, 1130, 1070 cm.sup.-1107 3-nitro mesylate white crystal 162.about.166.degree. C.108 4-nitro mesylate pale brown crystal 228.about.231.degree. C.109 3-hydroxy-5-methyl acetate yellow bubbly .nu. 2500.about.3500, 1720, 1680, 1400, powder 1320, 1260, 1170, 1120 cm.sup.-1110 5-hydroxy-3-methoxy acetate colorless solid .nu. 3650.about.2200, 1730, 1690, 1600, 1570, 1410, 1270, 1160, 1130 cm.sup.-1111 5-hydroxy-3-methoxycarbonyl acetate pale yellow solid .nu. 3650.about.2300, 1720, 1695, 1600, 1570, 1440, 1410, 1330, 1260, 1145 cm.sup.-1112 3-chloro-5-hydroxy mesylate pale brown powder 170.about.173.degree. C.113 3-(4-guanidinobenzoyloxy)-5- 2 mesylate brown bubbly powder .nu. 3350, 3150, 1730, 1680, 1600, hydroxy 1570, 1460, 1400, 1260, 1180, 1120, 1040 cm.sup.-1114 5-hydroxy-3-(N-methylcarbamoyl) acetate pale yellow solid .nu. 3650.about.2300, 1720, 1610, 1570, 1410, 1270, 1150 cm.sup.-1115 (3-(N-benzylcarbamoyl)-5-hydroxy acetate colorless solid .nu. 3650.about.2300, 1740, 1700, 1650, 1600, 1520, 1410, 1340, 1260, 1150, 1080 cm.sup.-1116 3-guanidino 2 acetate pale brown bubbly .nu. 3000.about.3500, 1720, 1680, 1560, powder 1390, 1250, 1160, 1060, 1010 cm.sup.-1117 4-guanidino 2 mesylate brown bubbly powder .nu. 3400, 3150, 1730, 1670, 1620, 1600, 1570, 1510, 1260, 1200, 1040 cm.sup.-1118 2-chloro-5-guanidino 2 acetate white solid .nu. 3700.about.2300, 1740, 1690, 1560, 1400, 1260, 1180, 1070, 1015 cm.sup.-1119 5-benzyloxy-3-chloro acetate pale brown .nu. 3400, 1580, 1415, 1265, amorphous 1140 cm.sup.-1120 3-chloro-5-(4- 2 acetate pale brown .nu. 3350, 1725, 1670, 1560, 1400, guanidinophenylthiomethyl) amorphous 1250, 1180, 1140, 1070, 1010 cm.sup.-1121 3-chloro-5-(3-pyridyl)oxymethyl 2 acetate white bubbly powder .nu. 3400, 1740, 1710, 1580, 1410, 1270, 1260, 1180 cm.sup.-1122 3-methoxy-5-(1,1-dioxothiazol-3- acetate pale gray bubbly .nu. 3600.about.2500, 1720, 1660, 1640, yl)carbonyl powder 1560, 1400, 1310, 1250 cm.sup.-1123 3-chloro-5-(1,1-dioxothiazol-3- acetate white bubbly powder .nu. 3600.about.2700, 1730, 1640, 1570, yl)carbonyl 1400, 1320, 1260, 1240__________________________________________________________________________ cm.sup.-1 ##STR33## TABLE 3__________________________________________________________________________Example The Structure of Products The AppearanceNo. (R.sup.2)n HX (salt) of Products m.p. and IR Value of__________________________________________________________________________ Products124 hydrogen phosphate white crystal 207.about.210.degree. C.125 2-methyl mesylate pale yellow powder 197.about.198.degree. C.126 3-methyl mesylate white powder 203.about.205.degree. C.127 4-methyl p-tosylate white crystal 238.about.240.degree. C.128 2-methoxy mesylate white crystal 184.about.186.degree. C.129 3-methoxy mesylate white powder 188.about.190.degree. C.130 4-methoxy mesylate pale yellow powder 164.about.165.degree. C.131 4-fluoro mesylate pale yellow crystal 238.about.241.degree. C.132 2-chloro mesylate white powder 183.about.184.degree. C.133 3-chloro mesylate white crystal 185.about.190.degree. C.134 4-chloro mesylate white crystal 213.8.about.216.degree. C.135 2,5-dichloro mesylate white powder 209.about.210.degree. C.136 2,6-dichloro mesylate white powder 190.about.195.degree. C.137 3,4-dichloro mesylate white powder 217.about.219.degree. C.138 2-bromo mesylate white powder 190.about.193.degree. C.139 4-carboxy mesylate white crystal 232.about.233.degree. C.140 4-carboxymethyl sulfonate white crystal 228.about.232.degree. C.141 2-methoxycarbonyl mesylate white powder 167.about.169.degree. C.142 4-ethoxycarbonyl phosphate white crystal 188.about.190.degree. C.143 4-ethoxycarbonyl mesylate white crystal 205.about.206.degree. C.144 4-ethoxycarbonylmethyl mesylate white crystal 60.about.65.degree. C.145 4-nitro mesylate pale yellow powder 212.about.215.degree. C.146 4-(N,N-diethylaminosulfonyl) mesylate gray bubbly powder .nu. 3400, 3000, 1675, 1560, 1400, 1330, 1260, 1200, 1170, 1150, 1010 cm.sup.-1__________________________________________________________________________

EXAMPLE 147

P-guanidinobenzoic acid 3-carboxy-2-chlorophenylester hydrobromide ##STR34##

4 ml of 1N sodium hydroxide was added into 700 mg of 3-carboxy-2-chlorophenol, and the mixture was concentrated under reduced pressure to obtain corresponded sodium salt. The sodium salt was dissolved in 20 ml of hexamethylphospholamide, and 0.58 ml of benzylbromide was added into the mixture. The mixture was stirred for one night.

The reaction mixture was diluted with diethylether, and was washed with water and a saturated aqueous solution of sodium chloride. And the mixture was dried over absolute sodium sulfate, and was concentrated under reduced pressure.

The residue and one g of p-guanidinobenzoyl chloride hydrochloride (prepared by the methods described in Example 1 of each of the specification of Japanese Patent Kokai No. 55-115865 and U.S. Pat. No. 4,283,418) was stirred for fifteen minutes in pyridine in ice-water bath.

Diethylether was added into the reaction mixture, the reaction mixture was decantated, a saturated aqueous solution of sodium bicarbonate was added into insoluble residue and the crystal was filtered off. Further, the crystal was washed with successive, water and acetone, and dried in vacuum.

About 5 ml of 30% hydrogen bromide-acetic acid was added into 200 mg of the obtained crystal in an atmosphere of argon, and the mixture was stirred for three hours at ambient temperature. Diethylether was added into the reaction mixture, the precipitated crystal was washed with diethylether, dried in vacuum to give 192 mg of the title compound (yellow powder) having the following physical data: melting point: 220.degree..about.227.degree. C.

Hereinafter, by the same procedure as described in Example 147, the compounds of the present invention, Example 148 and Example 149, having the following physical data described in Table 4 were obtained.

TABLE 4______________________________________The Structure of Products The Appear- m.p. and IRExample HX ance of Value ofNo. (R.sup.2)n (Salt) Products Products______________________________________148 3,5-dicarboxy hydro- yellow 210.about.214.degree. C. bromide powder149 2-carboxy-5- hydro- yellow bubbly at chloro bromide crystal more than 150.degree. C. (gradually decomposed)______________________________________

EXAMPLE 150

P-guanidinobenzoic acid 3-chloro-5-hydroxymethylphenylester acetate ##STR35##

1.970 g of 3-chloro-5-hydroxydbenzoic acid was dissolved in 30 ml of dimethylformamide. 601 mg of sodium hydride was added to the mixture and stirred for ten minutes at ambient temperature.

4.288 g of benzyl bromide was added into the reaction mixture, stirred for two hours at ambient temperature. 30 ml of ethyl acetate was added into the reaction mixture, further the reaction mixture was washed with water at several times. The mixture was dried with absolute magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica-gel (elusion solvent, hexane: ethyl acetate=10:1) to give 3.61 g of 3-chloro-5-benzyloxybenzoic acid benzylester having the following physical data; TLC (hexane: ethyl acetate=10:1): Rf 0.26.

3.61 g of the benzyl compound was dissolved in 50 ml of tetrahydrofuran. 579 mg of lithiumaluminiumhydride was added into the mixture, reacted for two hours at ambient temperature.

Ethyl acetate was added into the reaction mixture to analyse the excess reagent. The mixture was poured into 1N sodium hydroxide. The reaction mixture was extracted with diethylether, and the extract was dried over absolute magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (elusion solvent, dichloromethane) to give 1.502 g of 3-chloro-5-benzyloxybenzylalcohol having the following physical data; TLC (chloroform: methanol=10:1): Rf 0.69.

1.502 g of the alcohol compound was dissolved in 20 ml of dichloromethane. 655 mg of 2,3-dihydropyran and catalytic amount of p-toluenesulfonic acid were added thereto, and the mixture was reacted for one hour at ambient temperature.

A little amount of pyridine was added into the reaction mixture, and the mixture was washed with water, and concentrated under reduced pressure.

The obtained residue was purified by column chromatography on silica-gel (elusion solvent, hexane: ethyl acetate=10:1) to give 1.83 g of 3-chloro-5-benzyloxybenzylalcohol-0-(2-tetrahydropyranyl)ether having the following physical data; TLC (hexane: ethyl acetate=10:1): Rf 0.20.

996 mg of obtained the benzyl compound was dissolved in 7 ml of ethyl acetate, this solution was reacted for eliminating benzyl group using 10% palladium carbon as catalyst at the atmospheric temperature and pressure and under an atmosphere of hydrogen. After three hours, the reaction was stopped, the obtained crude product was purified by column chromatography on silica-gel (elusion solvent, hexane: ethyl acetate=5:1) to give 274 mg of 3-chloro-5-(2-tetrahydropyranyloxymethyl)phenol having the following physical data; 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 into the mixture and reacted for two hours at ambient temperature.

20 ml of diethylether was added into the reaction mixture, the precipitate was filtered off. And further, the precipitate was washed with diethylether. An aqueous solution of sodium bicarbonate was added into the insoluble residue, and the produced carbonate was filtered off.

The crude carbonate was dissolved in 3 ml of 60% acetic acid, reacted for two hours at 37.degree. C.

Acetic acid was distilled off under reduced pressure, the residue was purified by column chromatography on silica-gel (elusion solvent, chloroform: methanol: acetic acid=10:2:1) to give 100 mg of the title compound having the following physical data; TLC (chloroform: methanol: acetic acid=10:2:1): Rf 0.26 NMR (CD.sub.3 OD): .delta.8.2 (2 H, d, J=8 Hz), 7.42 (2 H, d, J=8 Hz), 7.30 (1 H, bs), 7.16 (2 H, bs), 4.64 (2 H, s).

EXAMPLE 151

P-guanidinobenzoic acid 3-chloro-5-(4-morpholinosulfonyl)phenoxymethylphenylester acetate ##STR36##

4.04 mg of 3-chloro-5-hydroxybenzoic acid was dissolved in 10 ml of dichloromethane, and 256 mg of 2,3-dihydropyran was added into the mixture. The catalytic amount of p-toluenesulfonic acid was added thereto, and the mixture was reacted for one hour at ambient temperature.

A little amount of pyridine was added into the reaction mixture, and the obtained mixture was washed with water, dried over absolute magnesium sulfate, and concentrated under reduced pressure to give the corresponded (2-tetrahydropyranyl) ether.

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

That is, the crude product was dissolved in 10 ml of tetrahydrofuran, and cooled in the ice-water bath. 133 mg of lithiumalminiumhydride was added thereto, and the mixture was stirred. The reaction temperature was rised to ambient temperature, and the mixture was further reacted for one hour. Ethyl acetate was added into the reaction mixture to analyse the excess reagent.

The reaction mixture was poured into 20 ml of 1N sodium hydroxide. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by column chromatography or silica-gel (elusion solvent, hexane: ethyl acetate=5:2) to give 541 mg of 3-chloro-5-(2tetrahydropyranyloxy)benzylalcohol having the following physical data; TLC (hexane: ethyl acetate=5:3): Rf 0.5.

484 mg of the alcohol thus obtained was dissolved in 10 ml of dichloromethane. 242 mg of triethylamine was added thereto and the mixture was cooled in ice-water bath. Further 273 mg of methanesulfonylchloride was added dropwise to the mixture. After the reaction temperature was rised to ambient temperature, the mixture was washed with water, dried over absolute magnesium sulfate, and concentrated under reduced pressure to give the corresponded mesylate.

The obtained crude product was used to the next reaction without purifying.

460 mg of p-morpholinosulfonylphenol was dissolved into the mixture of 7 ml of tetrahydrofuran and 1 ml of hexamethylphosphoramide. 57.6 mg of sodium hydride was added thereto, and the mixture was stirred for ten minutes.

Secondly, mesylate obtained above was added into this reaction solution, reacted for one hour at ambient temperature.

Water was added into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over absolute magnesium sulfate, and concentrated under reduced pressure.

The obtained crude product was dissolved in the mixture solvent of 5 ml of methanol and 5 ml of tetrahydrofuran. Further, 50 mg of p-toluenesulfonic acid was added into the mixture, reacted for two hours at ambient temperature to distill off the solvent. The residue was purified by column chromatography on silica-gel (hexane: ethyl acetate=5:3) to give 228 mg of 3-chloro-5-(4-morpholinosulfonyl)phenoxymethylphenol having the following physical data; TLC (hexane: ethyl acetate=5:3): Rf 0.18.

By using 228 mg of the phenol compound thus obtained, 207 mg of p-guanidinobenzoyl chloride hydrochloride and 3 ml of pyridine, the esterification was carried out by the same procedure as described in Example 1.

The product was purified by column chromatography on silica-gel (elusion solvent, ether acetate: acetic acid: water=400:100:30) to give 150 mg of title compound having the following physical data; TLC (chloroform: methanol: acetic acid=10:2:1): Rf 0.7; IR: .nu.3600.about.2500, 1720, 1680, 1560, 1400, 1330 cm.sup.-1.

EXAMPLE 152

p-guanidinobenzoic acid 3-methoxy-5-(4-morpholinosulfonyl)phenoxymethylphenylester acetate ##STR37##

By the same procedure as described in Example 151, the title compound (white powder) having the following physical data was obtained.

TLC (ethyl acetate: acetic acid: water=400:100:30): Rf 0.72;

IR: .nu.2500.about.3600, 1720, 1680, 1590, 1400, 1340 cm.sup.-1.

PREPARATIVE EXAMPLE 1

10 g of p-guanidinobenzoic acid 3-chloro-5-hydroxyphenyl ester methanesulfonate (prepared in Example 112), 400 mg of cellulose calcium gluconate (disintegrator), 200 mg of magnesium stearate (lubricator) and 9.4 g of microcrystalline cellulose were admixed and punched out in conventional manner to give 100 tablets each containing 100 mg of the active ingredient.

PREPARATIVE EXAMPLE 2

One g of p-guanidinobenzoic acid 3-chloro-5-hydroxyphenyl ester methanesulfonate (prepared in Example 112) was dissolved in 10 ml of ethanol and the solution was sterilized by filtration through a bacteria-retaining filter, and placed 0.5 ml portions into 5 ml ampoules to obtain ampoules each containing 50 mg of the active ingredient, and the ampoules were then sealed. The contents of ampoules are used for injection by diluting with a tris-hydrochloric acid buffer solution (pH 8.6) to 2.5 ml.

PREPARATIVE EXAMPLE 3

10 g of p-guanidinobenzoic acid 3-chloro-5-ethanesulfonyloxyphenyl ester acetate (prepared in Example 75), 400 mg of cellulose calcium gluconate (disintegrator), 200 mg of magnesium stearate (lubricator) and 9.4 g of microcrystalline cellulose were admixed and punched out in conventional manner to give 100 tablets each containing 100 mg of the active ingredient.

PREPARATIVE EXAMPLE 4

One g of p-guanidinobenzoic acid 3-chloro-5-ethanesulfonyloxyphenyl ester acetate (prepared in Example 75), was dissolved in 10 ml of ethanol and the solution was sterilized by filtration through a bacteria-retaining filter, and placed 0.5 ml portions into 5 ml ampoules to obtain ampoules each containing 50 mg of the active ingredient, and the ampoules were then sealed. The contents of ampoules are used for injection by diluting with a tris-hydrochloric acid buffer solution (pH 8.6) to 2.5 ml.

PREPARATIVE EXAMPLE 5

10 g of p-guanidinobenzoic acid 2,5-dichlorothiophenyl ester methanesulfonate (prepared in Example 135), 400 mg of cellulose calcium gluconate (disintegrator), 200 mg of magnesium stearate (lubricator) and 9.4 g of microcrystalline cellulose were admixed and punched out in conventional manner to give 100 tablets each containing 100 mg of the active ingredient.

PREPARATIVE EXAMPLE 6

One g of p-guanidinobenzoic acid 2,5-dichlorothiophenyl ester methanesulfonate (prepared in Example 135) was dissolved in 10 ml of ethanol and the solution was sterilized by filtration through a bacteria-retaining filter, and placed 0.5 ml portions into 5 ml ampoules to obtain ampoules each containing 50 mg of the active ingredient, and the ampoules were then sealed. The contents of ampoules are used for injection by diluting with a suitable quantity of dilution, for example, by diluting with a tris-hydrochloric acid buffer solution (pH 8.6) to 2.5 ml.

Claims

1. A derivative of p-guanidinobenzoic acid of the formula (IA): ##STR38## wherein Y represents an oxygen atom and (R.sup.1)m represents the group selected from 3-chloro-4-(N,N-dimethylsulfamoyl), 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, 2-chloro-5-(N-mesylamino), 3-chloro-5-(N-ethanesulfonylamino), and 2-chloro-5-guanidino group, or an acid addition salt of the derivative.

2. The derivative of para-guanidinobenzoic acid of claim 1, wherein the derivative is p-guanidinobenzoic acid 3-chloro-5-(N,N-diethylsulfamoyl)phenyl ester.