# Patent

## Title
Indole derivatives exhibiting chymase-inhibitory activities and process for preparation thereof

## Abstract

According to this invention, there is provided an indole derivative having the general formula (I) 




wherein A is an oxygen atom or a nitrogen atom which nitrogen atom is optionally substituted with an alkyl group, and (i) R1 and R2 each stand for a hydrogen atom or an alkyl group, independently, or (ii) R1 and R2 as taken together form a cycloalkyl group or an aromatic ring, or (iii) R1 and R2 as taken together form a heterocyclic ring, and R3 is a hydrogen atom, a (C1-C10)alkyl group or others, R4 is a substituted alkyl group and R5 is a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group and so on, as novel compounds by a novel chemical synthetic process. The indole derivative of formula (I) exhibits a useful chymase inhibitory activity.

## Background
TECHNICAL FIELD
This invention relates to a novel indole derivative having a high inhibitory activity to an enzyme, chymase, as well as to a process for the preparation of said indole derivative. This invention further relates to novel synthetic processes for the preparation of SF2809-I, -II, -III, -IV, -V and -VI substances which have earlier been obtained by the inventors of this invention each as a compound having an inhibitory activity to the enzyme chymase.
BACKGROUND ART
The enzyme chymase, which is mentioned simply as chymase sometime hereinafter, is a chymotripsin-like serine protease. Chymase is mainly stored in mast cells and can be secreted in tissues of heart, blood vessel, skin and others. As one of the main actions of chymase, it is known that chymase has such action as to produce angiotensin II from angiotensin I which is a substrate. Angiotensin II is known to exhibit a strong constrictive activity on vascular smooth muscle cells, leading to hypertension and cardiac insufficiency. It has hitherto been thought that the production of angiotensin II is affected mainly by the participation and action of angiotensin-converting enzyme (ACE).
Recently, however, there has been suggested newly that another physiological mechanism exists for the production of angiotensin II in local tissues as induced by serine proteinase, which is different from that by ACE. Reference is made specifically to some reports which reveal that angiotensin II as produced in human heart and blood vessel systems is mainly resulted from the conversion of angiotensin I by a chymase rather than the conversion of angiotensin I by ACE [see “Biochem. Biophys. Res. Coummun.”, 1987, No.149, p.1186; and “Circ. Res.”, 1990, No.66, p.883]. Other literatures have reported that chymase has many functions, including promotion of the degranulation of mast cell, activation of interleukin-1β, conversion of endoserine, and so on.
In view of these facts, it is expected that a compound capable of inhibiting the enzymatic activity of a human chymase, that is, a human chymase inhibitor is useful as new medicines for the therapeutic or prophylactic treatment of diseases in the cardiovascular system, such as hypertension, cardiac insufficiency, and of allergic diseases such as asthma, rheumatism, atopic dermatitis and others.
Until now, there are known several compounds having a chymase inhibitory activity. For example, we, the inventors of this invention, have already found that the cultivation of a microbial strain, SF2809 of a family Micromonosporaceae, which is a new microorganism as isolated by us from a soil sample collected at Hachijo Island, Tokyo, produces six compounds each having a chymase inhibitory activity in the resulting culture. Then, we have succeeded in isolating these six compounds from the culture and determined fully their chemical structures. As a result, we have recognized that all the six compounds are to be novel compounds hitherto unknown, and we have designated them as SF2809-I substance, SF2809-II substance, SF2809-III substance, SF2809-IV substance, SF2809-V substance and SF2809-VI substance, respectively. These SF2809-I, -II, -III, -IV, -V and -VI substances each are compounds which are represented by the following formula (A), formula (B), formula (C), formula (D), formula (E) and formula (F). 







It has been confirmed that each of the substances SF2809-I, -II, -III, -IV, -V and -VI above-mentioned, as novel compounds, has a chymase inhibitory activity (refer to the specification of PCT application No. PCT/JP99/06738 filed on Dec. 1, 1999 and laid open under an international publication WO 00/32587 on Jun. 8, 2000).
On the other hand, there are disclosed peptide-type compounds having an inhibitory activity to human chymase in the specifications of the publications WO95/27053 and WO95/27055, and non-peptide-type chymase inhibitors in the specifications of the publication WO96/04248 and Japanese Patent Application publication Kokai Hei-10-87567. Furthermore, several chymase inhibitory compounds originated from a microorganism metabolite are disclosed in Japanese Patent Application publication Kokai Hei-10-101666. Up to now, however, these known compounds having a chymase inhibitory activity have not yet been utilized clinically in therapeutic and prophylactic treatments of the various diseases as above-mentioned in which a chymase can participate.
Thus, at present, there occurs a keen demand in the art to provide such new compounds which have a high chymase inhibitory activity with low toxicity against mammals.
While, the chemical structures of SF2809-I, -II, -III, -IV, -V and -VI substances of the formulae (A)-(F) given above, respectively, which have been provided by us, differ from those of the already known chymase inhibitors, and it has been expected that SF2809-I to IV substances are useful as chymase inhibitors usable for elucidation of the mechanism of the chymase inhibitory activity and also for studying the physiological activities other than the chymase inhibitory activity. However, SF2809-I to VI substances which are the metabolic products of a microorganism have such disadvantage that the steps of the process required for their isolation and purification are complicated when the SF2809-I to VI substances are to be isolated from their culture broth of the SF-2809-I to VI-producing microorganism. Another disadvantage is in that the amounts of SF2809-I to VI substances so produced by cultivation of said microorganisms are only very small.
Accordingly, so far as there is used the process for the production of SF2809-I to VI substances by a small scale cultivation of the SF2809 strain belonging to Micromonosporaceae as above-mentioned, there necessarily exists such problem that the amount produced of each of SF2809-I to VI substances is much poorer than the amount which will be required to be employed for carrying out further investigations on the progress of chemical syntheses for producing novel derivatives from the SF2809 substances in order to improve their physiological activities and also will be required to be employed for studying the utilizability of the SF2809 substances as a chymase-inhibitor.
It is now strongly demanded to develop and provide such new chemical synthetic processes for producing SF2809-I to VI substances, which can make it possible to produce each of SF2809 substances in ample amount and in an efficient way. However, there was no available chemical process in the prior art which can be utilized directly to develop new chemical synthetic process for producing the SF2809-I to VI substances.
We, the inventors of this invention, have made search in a lot of chemical literature, with our intention of finding out some chemical reactions which are utilizable to create and develop novel processes for chemical synthetic production of the SF2809-I to VI substances. According to this search, we have now found that, in respect of the processes for chemical synthesis of bis-indole derivatives having two indole groups bonded together via a methylene group, there is known a process of synthesizing a symmetric bis-indole derivative of the undermentioned formula (J) in which process two molecules of an indole compound of the undermentioned formula (G) are subjected to a condensation reaction with a benzaldehyde derivative of the undermentioned formula (H) according to the following reaction equation (A):

Reaction Equation (A) 




wherein R stands for phenyl group, hydroxymethyl methyl group, formyl group, cyano group, acetyl group, or dimethylaminomethyl group [see Ulf Pindur, “Arch. Pharma.” (published from Weinheim), Vol.317, pp.502-505 (1984)].

There is also known a chemical synthetic process for producing a bis-quinol derivative having two 4-hydroxy-1-methyl-2-quinoline moieties bonded together via a methylene group, in which process two molecules of 4-hydroxy-1-methyl-2-quinoline of the undermentioned formula (K) are subjected to a condensation reaction with an imilidene compound of the undermentioned formula (L) so as to synthesize the symmetric bis-quinol derivative of the undermentioned formula (M), according to the following reaction equation (B): 




wherein R1 stands for methyl group or phenyl group and R2 stands for hydrogen atom, chlorine atom, methyl group, methoxy group or nitro group [see V Sudhakarrao and Malleshwar Daebarwar, “Indian Journal of Chemistry” Vol.25B, pp.540-541 (1986)].

Furthermore, there is known a chemical synthetic process for producing an indole derivative having an oxolane ring bonded to an indol-3-yl group via a methylene group, in which process an indole compound of the undermentioned formula (G′), paraformaldehyde of the formula (N) and an oxolane derivative of the formula (O) are simultaneously subjected to condensation reaction by a single step reaction of multicomponents so as to synthesize an indole derivative of the undermentioned formula (O), according to the following reaction equation (C): 




wherein R stands for a group selected from hydrogen atom, bromine atom, methyloxy group, cyano group and phthaliminomethyl group and X stands for an integer of 1 or higher [see “Synthesis” p.254 (1999)].

However, it is to be noticed that in this process, the 3-position of the indole compound of formula (G′) is the site of the reaction with the compound of formula (N), and so the 2-position of the indole ring of formula (G′) does not participate in the reaction as concerned, and that the yield of the compound of formula (Q) as produced in said single step reaction of the multicomponents is not so good.
We have once presumed that, with reference to the process of the reaction equation (A), the process of the reaction equation (B) and the process of the reaction equation (C) as subjected to our above examination, it would be difficult to foresee and predict any appropriately devised chemical process which can produce, through a chemical synthetic route, each of the SF2809-I to VI substances having the unique structures of the above-mentioned formulae (A) to (F).
On the other hand, in recent years, there has been developed noticeably “combinatorial chemistry” as a novel technique capable of speeding up the generation of lead compounds and the optimization of these lead compounds and capable of reducing the period of time required for searching prospective compounds usable for new medicines, in the field of the development of medicine [refer to “Molecular Diversity and Combinatorial Chemistry”, written by I. M. Chaikin and K. D. Janda, and published by American Chemical Society in 1996; and “J. Med. Chem.”, Vol.37, p.1233 (1994); and “Chem. Rev.”, Vol.96, p.555 (1996)]. One of the core techniques of “combinatorial chemistry” is a combinatorial synthesis in which a compound library comprising many compounds is prepared rapidly. In the process of combinatorial synthesis, there are included a solid phase synthesis wherein the synthesis of a compound is carried on an insoluble solid polymeric support, called as a solid phase, as well as a liquid phase synthesis wherein the synthesis of an aimed compound is carried out in a solution, which liquid phase synthesis has been used much prominently [see “A Practical Guide to Combinatorial Chemistry”, written by A. W. Czarnik and S. H. DeWitt, and published by American Chemical Society (1997)]. Among the known processes for the combinatorial liquid phase synthesis as mentioned above, a superior process is a multicomponent single step reaction procedure in which a compound is synthesized by reactions of multiple (3 or more) and different reaction component compounds in a single reaction step for rapid preparation of a compound library, resulting in a merit such that the library of compounds can be prepared much more speedily, as compared with such a synthetic method in which the multiple and different reaction component compounds are reacted successively in multi-reaction steps. As examples of the multicomponent single step reaction procedure, there are known Ugi reaction [see “Angew. Chem. Int. Ed. Engl.”, Vol.34, p.2280 (1995)] and Mannich-type reaction [see “Synthesis”, p.1401 (1999)].
DISCLOSURE OF INVENTION
A primary object of this invention is to provide novel compounds having a chymase inhibitory activity higher than those of the already known chymase inhibitors. A second object of this invention is to provide a chemical synthetic process which can synthesize in a facile and efficient way the novel compounds having such chymase inhibitory activity. A third object of this invention is to provide new chemical synthetic processes which can produce the above-mentioned SF2809-I to VI substances, in a facile and efficient way.
We have paid our attention to the combinatorial liquid phase synthetic process comprising the multicomponent single step reaction, and we have first investigated new processes which can synthesize in a facile way the SF2809-I to VI substances of the formulae (A)-(F) having the chymase inhibitory activity (see the PCT Application No. PCT/JP99/06738 application) according to the combinatorial liquid phase process.
First of all, we have carried out our investigations with our intention of chemically synthesizing SF2809-V substance of the formula (E). As a result, we have now found that SF2809-V substance of the following formula (E) 




can be synthesized by effecting a single step reaction of three reaction components consisting of, 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and benzaldehyde of the formula (γ-3) 




and 3-(2-acetaminoethyl)indole of the formula (β-1) 




in a solvent, for example, benzene or toluene in the presence of a substance capable of acting as an acid such as acetic acid or trichloroacetic acid, or in a substance capable of acting both as an acid and as a solvent, for example, acetic acid.

We have further continued our studies, and as a result we have now found that SF2809-I substance of the formula (A) 




can be synthesized by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and formaldehyde

HCHO  (γ-1)

and 3-(2-acetaminoethyl)indole of the formula (β-1) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid; and further that SF2809-II substance of the formula (B) 




can be produced by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and 4-hydroxybenzaldehyde of the formula (γ-2) 




and 3-(2-acetaminoethyl)indole of the formula (β-1) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

We have further found that SF2809-III substance of the formula (C) 




can be produced by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and formaldehyde of the formula (γ-1)

HCHO  (γ-1)

and 3-(2-hydroxyethyl)indole of the formula (β-2) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

We have also found that SF2809-IV substance of the formula (D) 




can be produced by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and 4-hydroxybenzaldehyde of the formula (γ-2) 




and 3-(2-hydroxyethyl)indole of the formula (β-2) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

We have moreover found that SF2809-VI substance of the formula (F) 




can be produced by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and benzaldehyde of the formula (γ-3) 




and 3-(2-acetaminoethyl)indole of the formula (β-1) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

As described above, we have thus succeeded in synthesizing the SF2809-I to VI substances by using the technique of the multicomponent single step reaction.
Yet further, we have proceeded another investigations. As a result, we have now found that in general, a variety of such novel indole derivatives, which are represented collectively by the general formula (I) given hereinafter, can be efficiently synthesized with success, when a compound of the general formula (II) 




wherein A, R1 and R2 have the same meanings as defined in the general formula (I) given hereinafter is used in place of the 2-quinolinone compound of the formula (α) above, and also when an aldehyde compound of the general formula (III)

R3—CHO  (III)

wherein R3 has the same meaning as defined below in the under-mentioned general formula (I) is used, or such a compound which is chemically equivalent to said aldehyde compound (III) and is represented by the general formula (III′)

R3—CH═N—R9  (III′)

wherein R3 has the same meaning as defined below and R9 is an alkyl group or other is used in place of the aldehyde compound of the formula (γ-1), (γ-2) or (γ-3) above, and when concurrently an indole compound of the general formula (IV) 




wherein R4 and R5 have the same meanings as defined in the undermentioned general formula (I) is used in place of the 3-(2-acetaminoethyl or 2-hydroxyethyl)indole of the formula (β-1) or (β-2) above, thus resulting in that the compound of the general formula (II) and the compound of the general formula (III) or (III′) and the compound of the general formula (IV) are simultaneously subjected to a multicomponent single step reaction in solution in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

Furthermore, we have found that each of the indole derivatives having the general formula (I) exhibits a high chymase inhibitory activity. On the basis of our findings as above-mentioned, this invention has been completed.
In a first aspect of this invention, therefore, there is provided an indole derivative which is a compound represented by the general formula (I) 




wherein A is an oxygen atom or a nitrogen atom to which nitrogen atom is bonded a hydrogen atom or such a (C1-C10) alkyl group which is, in turn, optionally substituted by a substituent selected from a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group and an acyl group, particularly an alkanoyl group or an aroyl group;

(i) R1 and R2 each stand for a hydrogen atom or an optionally substituted (C1-C10)alkyl group, independently, or (ii) R1 and R2 as taken together form an optionally substituted (C5-C10)cycloalkyl group or an optionally substituted (C6-C20)aromatic ring, particularly a benzene ring, or (iii) R1 and R2 as taken together form an optionally substituted, saturated or unsaturated heterocycric ring containing one or more nitrogen, oxygen or sulfur atom(s), provided that the possible substituent(s) optionally present on the said optionally substituted alkyl group or cycloalkyl group or aromatic ring or heterocyclic ring may be one or more and is or are selected from a halogen atom, a (C1-C10) alkyl group and a (C1-C10)alkoxy group;
R3 stands for a hydrogen atom, an optionally substituted (C1-C10)alkyl group, an optionally substituted (C5-C10)cycloalkyl group or an optionally substituted (C6-C20)aryl group, particularly a phenyl group, or R3 stands for an optionally substituted, saturated or unsaturated heterocyclic group containing one or more nitrogen, oxygen or sulfur atom(s), provided that the possible substituent(s) optionally present on the said optionally substituted alkyl group or cycloalkyl group or aryl group or heterocyclic group may be one or more and is or are selected from a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group, and that two or more of the said possible substituents as selected may be combined together to form one cyclic group;
R4 stands for an optionally substituted (C1-C10)alkyl group where the possible substituent(s) optionally present on the said alkyl group may be one or more and is or are selected from a hydroxyl group, an acyl group, particularly an alkanoyl group or an aroyl group, a (C1-C10)alkyloxycarbonyl group, a cyano group, an amino group, an acylamino group, particularly an alkanoylamino group or an aroylamino group, an acyloxy group, particularly an alkanoyloxy group, an ureido group and a sulfonylamino group, and where the said possible substituent(s) is or are optionally further substituted by one or more of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a (C6-C20)aryl group, particularly a phenyl group, an acyl group, particularly an alkanoyl group or an aroyl group, an acylamino group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10) alkoxy group;
R5 stands for a hydrogen atom, a halogen atom, a (C1-10)alkyl group or a (C1-C10)alkoxy group;
but with such provisos that, in the general formula (I),

    (i) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is hydrogen atom, R4 is 2-acetaminoethyl group and R5 is hydrogen atom;
    (ii) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is 4-hydroxyphenyl group, R4 is 2-acetaminoethyl group and R5 is hydrogen atom;
    (iii) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is hydrogen atom, R4 is 2-hydroxyethyl group and R5 is hydrogen atom;
    (iv) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is 4-hydroxyphenyl group, R4 is 2-hydroxyethyl group and R5 is hydrogen atom;
    (v) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is phenyl group, R4 is 2-acetaminoethyl group and R5 is hydrogen atom; and
    (vi) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is phenyl group, R4 is 2-hydroxyethyl group and R5 is hydrogen atom;

or a pharmaceutically acceptable salt or a solvate thereof.



Further, according to a first preferred embodiment of the first aspect of this invention, the compound of the general formula (I) above may include an indole derivative which is a compound having the general formula (Ia) 




wherein A has the same meaning as defined above;

B stands for a cyclic group, which cyclic group B either stands for an optionally substituted (C6-C20)aromatic ring, particularly a benzene ring, or the cyclic group B stands for an optionally substituted, saturated or unsaturated heterocyclic ring containing one or more nitrogen, oxygen or sulfur atom(s), provided that the possible substituent(s) optionally present on the said optionally substituted aromatic ring or heterocyclic ring is or are selected from a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group and the said possible substituent(s) may be either single or plural ones;
R3 has the same meaning as defined above;
R6 stands for a hydroxyl group, an optionally substituted acyl group, particularly an alkanoyl group or an aroyl group, an optionally substituted (C1-C10)alkyloxycarbonyl group, a cyano group, an optionally substituted amino group, particularly an acylamino group, particularly an alkanoylamino group or an aroylamino group, an optionally substituted acyloxy group, particularly an alkanoyloxy group, an optionally substituted ureido group or an optionally substituted sulfonylamino group, provided that the possible substituent(s) optionally present on the said optionally substituted groups is or are selected from a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a (C6-C20)aryl group, particularly a phenyl group, an acyl group, particularly an alkanoyl group, an acylamino group, a halogenated (C1-C10)alkyl group, a halogenated (C1-C10)alkoxy group and a halogenated acyl group;
R7 stands for a hydrogen atom, a halogen atom, a (C1-C6)alkyl group or a (C1-C6) alkoxy group;
but with such provisos that, in the general formula (Ia),

    (i) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is hydrogen atom, R6 is acetamino group and R7 is hydrogen atom;
    (ii) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is 4-hydroxyphenyl group, R6 is acetamino group and R7 is hydrogen atom;
    (iii) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is hydrogen atom, R6 is hydroxyl group and R7 is hydrogen atom;
    (iv) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is 4-hydroxylphenyl group, R6 is hydroxyl group and R7 is hydrogen atom;
    (v) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is phenyl group, R6 is acetamino group and R7 is hydrogen atom; and
    (vi) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is phenyl group, R6 is hydroxyl group and R7 is hydrogen atom.


Further, according to a second preferred embodiment of the first aspect of this invention, the compound of the general formula (I) above may include an indole derivative which is a compound having the general formula (Ib) 




wherein B, R3, R6 and R7 have the same meanings as defined above, respectively;

R8 stands for a hydrogen atom or a straight or branched (C1-C10)alkyl group;
but with such provisos that in the general formula (Ib),

    (i) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is hydrogen atom, R6 is acetamino group and R7 is hydrogen atom;
    (ii) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is 4-hydroxyphenyl group, R6 is acetamino group and R7 is hydrogen atom;
    (iii) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is hydrogen atom, R6 is hydroxyl group and R7 is hydrogen atom;
    (iv) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is 4-hydroxyphenyl group, R6 is hydroxyl group and R7 is hydrogen atom;
    (v) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is phenyl group, R6 is acetamido group and R7 is hydrogen atom; and
    (vi) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is phenyl group, R6 is hydroxyl group and R7 is hydrogen atom.


Of course, it is clear that from the indole derivatives of the general formula (I), of the general formula (Ia) and of the general formula (Ib), respectively, there are excluded those substances of SF2809-I to VI which are disclosed in the specification of the aforesaid PCT application No. PCT/JP99/06738 [because of the definitions given in the provisios of (i), (ii), (iii), (iv), (v) and (vi) as shown in the “provisos” requirements prescribed for the general formulae (I), (Ia) and (Ib) given hereinbefore].
So far as the indole derivative of the general formula (I), or the indole derivative of the general formula (Ia) or (Ib) according to the first aspect of this invention is concerned with, a halogen atom given in the general formula (I), (Ia) or (Ib) means a fluorine, chlorine, bromine or iodine atom.
Further, in the general formula (I), (Ia) or (Ib), an alkyl group which R1 to R4 may denote a straight or branched (C1-C10)alkyl group. As such alkyl group, there are exemplified straight chain alkyl groups, e.g. methyl group, ethyl group and n-butyl group, as well as branched chain alkyl groups, e.g. isopropyl group, isobutyl group, t-butyl group or 2,2-dimethylpropyl group.
As a (C5-C10)cycloalkyl group which R1, R2 and R3 may denote, there may be exemplified cyclopentyl group or cyclohexyl group.
As a (C6-C20)aryl group which R3 may denote, or (C6-C20)aryl group which may optionally be born on the alkyl group R4, there may be exemplified phenyl group, naphthyl group or anthracenyl group.
Alkyloxycarbonyl group as above-mentioned may include, for example, methyloxycarbonyl group or benzyloxycarbonyl group.
Acyloxy group as above-mentioned may include an alkanoyloxy group or an aroyloxy group, for example, acetyloxy group, ethylcarbonyloxy group, cyclohexylcarbonyloxy group, benzoyloxy group, benzylcarbonyloxy group or undecanoylcarbonyloxy group and others.
Examples of an alkoxy group above-mentioned are methoxy group or trifluoromethoxy group and others.
Acyl group above-mentioned may be an alkanoyl group or an aroyl group, typical examples of which are acetyl group, propionyl group, benzylcarbonyl group, benzoyl group and others.
As the acylamino group above-mentioned, there may be exemplified an alkanoylamino group or an aroylamino group, typical examples of which are acetylamino group, propionylamino group, cyclohexylcarbonylamino group, benzoylamino group, benzylcarbonylamino group or undecanoylcarbonylamino group and others.
As carbamoyl groups above-mentioned, there may be exemplified methyloxycarbonylamino group, benzyloxycarbonylamino group, t-butyloxycarbonylamino group or allyloxycarbonylamino group and others.
Examples of an ureido group above-mentioned are aminocarbonylamino group, N′-methylaminocarbonylamino group, piperidinocarbonylamino group, morpholinocarbonylamino group, N′-methyl-N′-phenylaminocarbonylamino group and others.
Further, the sulfonylamino group above-mentioned may include butylsulfonylamino group, phenylsulfonylamino group, benzylsulfonylamino group and naphthylsulfonylamino group, and so on.
In the general formula (I), by a cycloalkyl group which may be constituted by R1 and R2 taken together is meant a residue of a saturated cycloalkane such as cyclopentane ring and cyclohexane ring. Also in the general formula (I), examples of an aromatic ring or a heterocyclic ring which can be constituted by R1 and R2 taken together may include an aromatic ring such as benzene ring, naphthalene ring and the like, as well as or saturated heterocyclic ring such as tetrahydrofuran ring, pyrrolidine ring and the like, and an unsaturated heterocyclic ring such as pyrazole ring, thiazole ring and the like.
In the general formula (I), (Ia) or (Ib), by a (C6-C20)aryl group for R3 is meant an aromatic hydrocarbon ring such as phenyl group, naphthyl group and anthracenyl group.
As examples of an optionally substituted heterocyclic ring containing one or more nitrogen atom(s), oxygen atom(s) or sulfur atom(s) which may be formed by R1 and R2 taken together or which is represented by R3, there may be mentioned a residue of a saturated five-membered heterocyclic ring such as tetrahydrofuran, pyrrolidine, imidazoline or oxazoline; a residue of an unsaturated five-membered heterocyclic ring such as pyrrole, oxazole, imidazole or thiazole; a residue of a saturated six-membered heterocyclic ring such as piperidine, piperazine or morpholine ring; a residue of an unsaturated six-membered heterocyclic ring such as pyridine, pyridazine, pyrimidine or pyrazine ring; and a residue of a condensed heterocyclic ring such as indole, benzoxazole, benzothiazole, coumarin, quinoline, purine or xanthine ring. Further, in the general formula (Ia) or (Ib), the heterocyclic ring which the ring B denotes may be any heterocyclic ring as exemplified in the above.
The indole derivative of the general formula (I) according to the first aspect of this invention may either be in the free form or in the form of a pharmaceutically acceptable salt thereof. As such salts, they may be pharmaceutically acceptable non-toxic salts. Preferably, there may be mentioned the salts with a pharmaceutically acceptable inorganic acid such as a hydrohalogenic acid, e.g. hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc., sulfuric acid, nitric acid, phosphoric acid, hydroperoxy acid, carbonic acid and the like; as well as the salts with a pharmaceutically acceptable organic carboxylic acid such as acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, propionic acid, formic acid, malic acid; and the salts with an acidic amino acid such as aspartic acid, glutamic acid; the salts with an alkylsulfonic acids or arylsulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and so on. The compound of the formula (I) may also be in the form of a solvate thereof. Typical solvate is hydrate.
The indole derivative having the general formula (I) according to this invention include all the optical isomers and the racemic mixtures thereof.
Processes for the preparation of the indole derivative of the general formula (I) according to the first aspect of this invention will be explained in detail hereinafter.
For exemplary compounds of the indole derivative of the general formula (I) or the indole derivative of the general formula (Ia) or (Ib) according to the first aspect of this invention, they are listed in Table 1-1 to Table 1-7 where 81 compounds are shown by their compound Nos. 003 to 083 along with their chemical structural formulae, as well as in Table 2-1 to Table 2-44 where 530 compounds are shown by their compound Nos. 084 to 613 along with their chemical structural formulae.







TABLE 1-1







Compound No. 003









Compound No. 004









Compound No. 005









Compound No. 006









Compound No. 007









Compound No. 008









Compound No. 009









Compound No. 010









Compound No. 011









Compound No. 012









Compound No. 013









Compound No. 014























TABLE 1-2







Compound No. 015









Compound No. 016









Compound No. 017









Compound No. 018









Compound No. 019









Compound No. 020









Compound No. 021









Compound No. 022









Compound No. 023









Compound No. 024









Compound No. 025









Compound No. 026























TABLE 1-3







Compound No. 027









Compound No. 028









Compound No. 029









Compound No. 030









Compound No. 031









Compound No. 032









Compound No. 033









Compound No. 034









Compound No. 035









Compound No. 036









Compound No. 037









Compound No. 038























TABLE 1-4







Compound No. 039









Compound No. 040









Compound No. 041









Compound No. 042









Compound No. 043









Compound No. 044









Compound No. 045









Compound No. 046









Compound No. 047









Compound No. 048









Compound No. 049









Compound No. 050























TABLE 1-5







Compound No. 051









Compound No. 052









Compound No. 053









Compound No. 054









Compound No. 055









Compound No. 056









Compound No. 057









Compound No. 058









Compound No. 059









Compound No. 060









Compound No. 061









Compound No. 062























TABLE 1-6







Compound No. 063









Compound No. 064









Compound No. 065









Compound No. 066









Compound No. 067









Compound No. 068









Compound No. 069









Compound No. 070









Compound No. 071









Compound No. 072









Compound No. 073









Compound No. 074























TABLE 1-7







Compound No. 075









Compound No. 076









Compound No. 077









Compound No. 078









Compound No. 079









Compound No. 080









Compound No. 081









Compound No. 082









Compound No. 083























TABLE 2-1







Compound No. 084









Compound No. 085









Compound No. 086









Compound No. 087









Compound No. 088









Compound No. 089









Compound No. 090









Compound No. 091









Compound No. 092









Compound No. 093









Compound No. 094









Compound No. 095









Compound No. 096









Compound No. 097









Compound No. 098























TABLE 2-2







Compound No. 099









Compound No. 100









Compound No. 101









Compound No. 102









Compound No. 103









Compound No. 104









Compound No. 105









Compound No. 106









Compound No. 107









Compound No. 108









Compound No. 109









Compound No. 110























TABLE 2-3







Compound No. 111









Compound No. 112









Compound No. 113









Compound No. 114









Compound No. 115









Compound No. 116









Compound No. 117









Compound No. 118









Compound No. 119









Compound No. 120









Compound No. 121









Compound No. 122























TABLE 2-4







Compound No. 123









Compound No. 124









Compound No. 125









Compound No. 126









Compound No. 127









Compound No. 128









Compound No. 129









Compound No. 130









Compound No. 131









Compound No. 132









Compound No. 133









Compound No. 134























TABLE 2-5







Compound No. 135









Compound No. 136









Compound No. 137









Compound No. 138









Compound No. 139









Compound No. 140









Compound No. 141









Compound No. 142









Compound No. 143









Compound No. 144









Compound No. 145









Compound No. 146























TABLE 2-6







Compound No. 147









Compound No. 148









Compound No. 149









Compound No. 150









Compound No. 151









Compound No. 152









Compound No. 153









Compound No. 154









Compound No. 155









Compound No. 156









Compound No. 157









Compound No. 158























TABLE 2-7







Compound No. 159









Compound No. 160









Compound No. 161









Compound No. 162









Compound No. 163









Compound No. 164









Compound No. 165









Compound No. 166









Compound No. 167









Compound No. 168









Compound No. 169









Compound No. 170























TABLE 2-8







Compound No. 171









Compound No. 172









Compound No. 173









Compound No. 174









Compound No. 175









Compound No. 176









Compound No. 177









Compound No. 178









Compound No. 179









Compound No. 180









Compound No. 181









Compound No. 182























TABLE 2-9







Compound No. 183









Compound No. 184









Compound No. 185









Compound No. 186









Compound No. 187









Compound No. 188









Compound No. 189









Compound No. 190









Compound No. 191









Compound No. 192









Compound No. 193









Compound No. 194























TABLE 2-10







Compound No. 195









Compound No. 196









Compound No. 197









Compound No. 198









Compound No. 199









Compound No. 200









Compound No. 201









Compound No. 202









Compound No. 203









Compound No. 204









Compound No. 205









Compound No. 206























TABLE 2-11







Compound No. 207









Compound No. 208









Compound No. 209









Compound No. 210









Compound No. 211









Compound No. 212









Compound No. 213









Compound No. 214









Compound No. 215









Compound No. 216









Compound No. 217









Compound No. 218























TABLE 2-12







Compound No. 219









Compound No. 220









Compound No. 221









Compound No. 222









Compound No. 223









Compound No. 224









Compound No. 225









Compound No. 226









Compound No. 227









Compound No. 228









Compound No. 229









Compound No. 230























TABLE 2-13







Compound No. 231









Compound No. 232









Compound No. 233









Compound No. 234









Compound No. 235









Compound No. 236









Compound No. 237









Compound No. 238









Compound No. 239









Compound No. 240









Compound No. 241









Compound No. 242























TABLE 2-14







Compound No. 243









Compound No. 244









Compound No. 245









Compound No. 246









Compound No. 247









Compound No. 248









Compound No. 249









Compound No. 250









Compound No. 251









Compound No. 252









Compound No. 253









Compound No. 254























TABLE 2-15







Compound No. 255









Compound No. 256









Compound No. 257









Compound No. 258









Compound No. 259









Compound No. 260









Compound No. 261









Compound No. 262









Compound No. 263









Compound No. 264









Compound No. 265









Compound No. 266























TABLE 2-16







Compound No. 267









Compound No. 268









Compound No. 269









Compound No. 270









Compound No. 271









Compound No. 272









Compound No. 273









Compound No. 274









Compound No. 275









Compound No. 276









Compound No. 277









Compound No. 278























TABLE  2-17







Compound No. 279









Compound No. 280









Compound No. 281









Compound No. 282









Compound No. 283









Compound No. 284









Compound No. 285









Compound No. 286









Compound No. 287









Compound No. 288









Compound No. 289









Compound No. 290























TABLE 2-18







Compound No. 291









Compound No. 292









Compound No. 293









Compound No. 294









Compound No. 295









Compound No. 296









Compound No. 297









Compound No. 298









Compound No. 299









Compound No. 300









Compound No. 301









Compound No. 302























TABLE 2-19







Compound No. 303









Compound No. 304









Compound No. 305









Compound No. 306









Compound No. 307









Compound No. 308









Compound No. 309









Compound No. 310









Compound No. 311









Compound No. 312









Compound No. 313









Compound No. 314























TABLE 2-20







Compound No. 315









Compound No. 316









Compound No. 317









Compound No. 318









Compound No. 319









Compound No. 320









Compound No. 321









Compound No. 322









Compound No. 323









Compound No. 324









Compound No. 325









Compound No. 326























TABLE 2-21







Compound No. 327









Compound No. 328









Compound No. 329









Compound No. 330









Compound No. 331









Compound No. 332









Compound No. 333









Compound No. 334









Compound No. 335









Compound No. 336









Compound No. 337









Compound No. 338























TABLE 2-22







Compound No. 339









Compound No. 340









Compound No. 341









Compound No. 342









Compound No. 343









Compound No. 344









Compound No. 345









Compound No. 346









Compound No. 347









Compound No. 348









Compound No. 349









Compound No. 350























TABLE 2-23







Compound No. 351









Compound No. 352









Compound No. 353









Compound No. 354









Compound No. 355









Compound No. 356









Compound No. 357









Compound No. 358









Compound No. 359









Compound No. 360









Compound No. 361









Compound No. 362























TABLE 2-24







Compound No. 363









Compound No. 364









Compound No. 365









Compound No. 366









Compound No. 367









Compound No. 368









Compound No. 369









Compound No. 370









Compound No. 371









Compound No. 372









Compound No. 373









Compound No. 374























TABLE 2-25







Compound No. 375









Compound No. 376









Compound No. 377









Compound No. 378









Compound No. 379









Compound No. 380









Compound No. 381









Compound No. 382









Compound No. 383









Compound No. 384









Compound No. 385









Compound No. 386




























Compound No. 387









Compound No. 388









Compound No. 389









Compound No. 390









Compound No. 391









Compound No. 392









Compound No. 393









Compound No. 394









Compound No. 395









Compound No. 396









Compound No. 397









Compound No. 398























TABLE 2-27







Compound No. 399









Compound No. 400









Compound No. 401









Compound No. 402









Compound No. 403









Compound No. 404









Compound No. 405









Compound No. 406









Compound No. 407









Compound No. 408









Compound No. 409









Compound No. 410























TABLE 2-28







Compound No. 411









Compound No. 412









Compound No. 413









Compound No. 414









Compound No. 415









Compound No. 416









Compound No. 417









Compound No. 418









Compound No. 419









Compound No. 420









Compound No. 421









Compound No. 422























TABLE 2-29







Compound No. 423









Compound No. 424









Compound No. 425









Compound No. 426









Compound No. 427









Compound No. 428









Compound No. 429









Compound No. 430









Compound No. 431









Compound No. 432









Compound No. 433









Compound No. 434























TABLE 2-30







Compound No. 435









Compound No. 436









Compound No. 437









Compound No. 438









Compound No. 439









Compound No. 440









Compound No. 441









Compound No. 442









Compound No. 443









Compound No. 444









Compound No. 445









Compound No. 446























TABLE 2-31







Compound No. 447









Compound No. 448









Compound No. 449









Compound No. 450









Compound No. 451









Compound No. 452









Compound No. 453









Compound No. 454









Compound No. 455









Compound No. 456









Compound No. 457









Compound No. 458























TABLE 2-32







Compound No. 459









Compound No. 460









Compound No. 461









Compound No. 462









Compound No. 463









Compound No. 464









Compound No. 465









Compound No. 466









Compound No. 467









Compound No. 468









Compound No. 469









Compound No. 470























TABLE 2-33







Compound No. 471









Compound No. 472









Compound No. 473









Compound No. 474









Compound No. 475









Compound No. 476









Compound No. 477









Compound No. 478









Compound No. 479









Compound No. 480









Compound No. 481









Compound No. 482























TABLE 2-34







Compound No. 483









Compound No. 484









Compound No. 485









Compound No. 486









Compound No. 487









Compound No. 488









Compound No. 489









Compound No. 490









Compound No. 491









Compound No. 492









Compound No. 493









Compound No. 494























TABLE 2-35







Compound No. 495









Compound No. 496









Compound No. 497









Compound No. 498









Compound No. 499









Compound No. 500









Compound No. 501









Compound No. 502









Compound No. 503









Compound No. 504









Compound No. 505









Compound No. 506























TABLE 2-36







Compound No. 507









Compound No. 508









Compound No. 509









Compound No. 510









Compound No. 511









Compound No. 512









Compound No. 513









Compound No. 514









Compound No. 515









Compound No. 516









Compound No. 517









Compound No. 518























TABLE 2-37







Compound No. 519









Compound No. 520









Compound No. 521









Compound No. 522









Compound No. 523









Compound No. 524









Compound No. 525









Compound No. 526









Compound No. 527









Compound No. 528









Compound No. 529









Compound No. 530























TABLE 2-38







Compound No. 531









Compound No. 532









Compound No. 533









Compound No. 534









Compound No. 535









Compound No. 536









Compound No. 537









Compound No. 538









Compound No. 539









Compound No. 540









Compound No. 541









Compound No. 542























TABLE 2-39







Compound No. 543









Compound No. 544









Compound No. 545









Compound No. 546









Compound No. 547









Compound No. 548









Compound No. 549









Compound No. 550









Compound No. 551









Compound No. 552









Compound No. 553









Compound No. 554























TABLE 2-40







Compound No. 555









Compound No. 556









Compound No. 557









Compound No. 558









Compound No. 559









Compound No. 560









Compound No. 561









Compound No. 562









Compound No. 563









Compound No. 564









Compound No. 565









Compound No. 566























TABLE 2-41







Compound No. 567









Compound No. 568









Compound No. 569









Compound No. 570









Compound No. 571









Compound No. 572









Compound No. 573









Compound No. 574









Compound No. 575









Compound No. 576









Compound No. 577









Compound No. 578























TABLE 2-42







Compound No. 579









Compound No. 580









Compound No. 581









Compound No. 582









Compound No. 583









Compound No. 584









Compound No. 585









Compound No. 586









Compound No. 587









Compound No. 588









Compound No. 589









Compound No. 590























TABLE 2-43







Compound No. 591









Compound No. 592









Compound No. 593









Compound No. 594









Compound No. 595









Compound No. 596









Compound No. 597









Compound No. 598









Compound No. 599









Compound No. 600









Compound No. 601









Compound No. 602























TABLE 2-44







Compound No. 603









Compound No. 604









Compound No. 605









Compound No. 606









Compound No. 607









Compound No. 608









Compound No. 609









Compound No. 610









Compound No. 611









Compound No. 612









Compound No. 613
















Now, there will be given Test Example which demonstrates the chymase inhibitory activity of some exemplary compounds chosen from the indole derivatives of the general formula (I) according to the first aspect of this invention.


TEST EXAMPLE 1


    (a) The preparation of the enzyme chymase was carried out as follows. That is, a recombinant pro-type human chymase to be used had been prepared in accordance with the method of Urata et al's report [“J. Biol. Chem.”, Vol.266, p.17173 (1991)]. Further, the chymase product as preliminarily purified was activated in accordance with the method of Murakami et al's report [“J. Biol. Chem.”, Vol.270, p.2218 (1991)]. The resulting activated chymase product was purified with heparin Sepharose to afford an active-type human chymase.
    (b) To 50 μl of Buffer A (comprising 0.5-3.0M NaCl and 50 mM tris-HCl, pH 8.0) containing 1-5 ng of the active-type human chymase as obtained by the above-mentioned methods, was added 2 μl of a solution in dimethylsulfide which contained an indole derivative of this invention as the substance to be tested. Then, to the resultant mixture, there was added 50 μl of Buffer A containing 0.5 mM of succinyl-alanyl-histidyl-prolyl-phenylalanyl-p-nitroanilide (a product of Backem Co.) as the substrate. The resulting reaction mixture was incubated at room temperature for 5 minutes. The chymase inhibitory activity was assessed by measuring the changes in the absorbance of a light at 405 nm of the resulting reaction solution with the passage of time. The chymase inhibitory activity of the indole derivatives tested of this invention was evaluated in term of IC50 values (in molar concentration, M).


The indole derivatives of this invention as tested in this Example are the compounds of Compound No. 003, 021, 026, 027, 030, 076 and 078 shown in Table 1 above. The structural formulae of the compounds as tested are shown in the following Table 3.







TABLE 3







Compound No. 003









Compound No. 021









Compound No. 026









Compound No. 027









Compound No. 030









Compound No. 076









Compound No. 078
















The results of the test so obtained are shown in the following Table 4.








TABLE 4





Compound Tested
Chymase inhibitory activity IC50


(Compound No. in Table 1)
(molar concentration)







003
2.64 × 10−9


021
1.40 × 10−9


026
4.39 × 10−10


027
5.11 × 10−9


030
5.87 × 10−10


076
8.93 × 10−10


078
1.86 × 10−9









As demonstrated by the Test Example above, the indole derivatives of the general formula (I) according to the first aspect of this invention have a high chymase inhibitory activity and thus are useful as a chymase inhibitor and utilizable for therapeutic or prophylactic treatments of diseases in which a chymase participates.
According to a second aspect of this invention, therefore, there is provided a pharmaceutical composition comprising as an active ingredient at least one of the indole derivative of the general formula (I) or a pharmaceutically acceptable salt or a solvate thereof, in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition according to the second aspect of this invention may be used for a therapeutic or prophylactic treatment of cardiac infarction, cardiomegaly, cardiac insufficiency, myocardosis, arteriosclerosis, hypertension, hemangioendtyrosis, peripheral cardiovascular disorder, renal insufficiency, inflammation, allergy, atopic dermatitis, rheumatism, asthma, or bronchitis.
Further, according to a third aspect of this invention, there is provided a chymase inhibitor characterized in that said inhibitor comprises as an active ingredient at least one of the indole derivative of the general formula (I) or a pharmaceutically acceptable salt or a solvate thereof.
Still further, according to a fourth aspect of this invention, there is provided a medicament to be used for therapeutic or prophylactic treatment of diseases in which an enzyme chymase participates, characterized in that said medicament comprises as an active ingredient at least one of the indole derivative of the general formula (I) or a pharmaceutically acceptable salt or a solvate thereof.
The indole derivative of the general formula (I) according to the first aspect of this invention and a pharmaceutically acceptable salt or a solvate thereof (particularly hydrate), as well as the indole derivative of the general formula (I) and a pharmaceutically acceptable salt or a solvate thereof usable as the active ingredient which are incorporated in the pharmaceutical composition of the second aspect of this invention, may be administered, orally or parenterally, to a patient having a disease to be cured or prevented. In cases where the indole derivative of this invention is parenterally administered, it can be administered by intravenous or intra-arterial injection or by intraperitoneal or intra-muscular or other intra-tissular injection or by subcutaneous injection or by intramucosal administration or by application to skin.
The pharmaceutical composition according to the fourth aspect of this invention may be formulated, depending upon the route of its administrations, into an appropriate form for oral administration or into an appropriate form for parenteral administration. Concretely speaking, as an orally administrable preparation, there may be formulated tablets, capsules, pills, powder, granules, fine grains, syrup, emulsion, suspension, solution, aqueous solution and the like. As a parenterally administrable preparation, there may be formulated injection preparations such as those for intravenous, intramuscular or subcutaneous injection, ophthalmic solutions, collunarium, rectal suppository, as well as percutaneous absorbable preparations such as ointment, hard ointment or adhesive tapes, or an implant and so on.
A variety of the preparations above-mentioned may be formulated in a usual manner with incorporating therein excipient, disintegrator, binder, lubricant and/or coloring agent which are conventionally used. As a non-toxic excipient usable, there may be exemplified lactose, glucose, corn starch, sorbitol, crystalline cellulose, etc. As examples of a disintegrator, there may be mentioned starch, sodium alginate, gelatin, calcium carbonate, dextrin, etc. As a binder, there may be exemplified dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, hydroxypropyl cellulose, polyvinylpyrrolidone, etc. As typical examples of the lubricant, there may be mentioned talc, magnesium stearate, polyethylene glycol, hydrogenated oil, etc. As a coloring agent, there may be used, for example, Brilliant Blue, erythrosine, Tartrazine, etc.
Liquid preparations such as the solution, suspension, syrup and the like may be prepared in a usual manner with incorporating, in addition to the active ingredient, glycerol esters, alcohols, water, vegetable oils, etc. Capsule preparations may be prepared by filling the granules, powder or solution containing the active ingredient in soft or hard capsules.
In the injection preparations, there may be added, at need, a buffering agent (for example, acetate, citrate, phosphate, etc.), a pH adjuster (for example, sodium hydrogen carbonate, sodium hydroxide, hydrochloric acid, etc.) and may also be added, an antioxidant (for example, ascorbic acid, sodium sulfite, sodium pyrosulfite, etc.) as a stabilizer, or a preservative (for example, benzyl alcohol, chlorobutanol, p-hydroxybenzoic acid methyl ester, phenol, etc.).
In formulating the percutaneous absorbable preparations, the active ingredient may be mixed with oils, fats or petrolatum to form an ointment or may be mixed with an emulsifier to form a cream. In formulating the rectal suppository, the active ingredient may be mixed with a gelatin soft capsule material, followed by shaping the mixture into a suppository.
For the percutaneous preparations, they may be prepared in the form of a preparation made of a liquid or powdery composition containing the active ingredient. In the liquid preparation, there may be used, as the base, for example, water, saline solution, phosphate buffer, acetate buffer etc., and may further be added a surfactant, oxidation inhibitor, stabilizer, preservative, viscosity improver, and the like. In the powdery preparation, there may be used, as the base, for example, a water-absorbent base such as a water-soluble salt of polyacrylic acid, amylose, etc., or a barely water-soluble base such as cellulose, starch, etc. It is preferable to use a water-absorbent base. Further, into the powdery preparation, there may be incorporated, for example, an oxidation inhibitor, preservative, coloring agent, antiseptic agent, and the like. These liquid and powdery preparations for the percutaneous administration may also be applied to the skin, for example, by spray-coating.
For the ophthalmic solution preparations, they may be formulated in the form of an aqueous or non-aqueous eye drop preparation containing the indole derivative as the active ingredient. As a solvent to be used in such aqueous eye drop preparation, there may be used a sterilized purified water, physiological saline, and the like. In case where the sterilized purified water is used as the sole solvent, the eye drop preparation may take the form of an aqueous suspension with addition of a surface active agent, etc., or it may take the form of a solubilized preparations with using a non-ionic surface active agent as a solubilizing agent. In case where the ophthalmic preparation is administered by methods other than by the eye dropping, it may be administered as an eye ointment, coatable liquid preparation, insert preparationor or other.
Into the various preparations as above-mentioned, there may be added, if necessary, a pharmaceutically acceptable carrier, an isotonic agent, preservative, antiseptic agent, buffer, emulsifier, dispersant, stabilizer, or others. Further, in order to attain a sterilized or sterile preparation, it is also possible, during the processes of formulating the various preparations, to add a pharmaceutically acceptable germicide and/or to apply a pharmaceutically acceptable treatment of sterilization (such as filtration, heating, photo-irradiation).
The content of the active compound of this invention to be incorporated in the pharmaceutical composition according to the second aspect of this invention may depend upon the type of the preparations thereof, but it is usually in a range of 0.05-50% by weight, preferably in a range of 0.1-20% by weight, based on the weight of the composition.
The dosage of the indole derivative of this invention may be appropriately decided, depending upon each particular case, by taking into consideration the age, body weight, sex, difference in diseases, extent of symptoms and other parameters. For the oral administrations, the dosage is usually in a range of about 1-1000 mg/day for an adult, preferably 1-100 mg/day for an adult. For the parenteral administrations as made by intravenous, subcutaneous, intramuscular, percutaneous or intraperitoneal injection or in the form of collunarium, eye-drops, inhalants, etc., the dose of the indole derivative is usually 0.1-100 mg/day for an adult, preferably 0.3-50 mg/day for an adult.
Further, in case where the indole derivative, or the salt or solvate thereof (for example, hydrate) according to this invention is used as a prophylactic agent, it may be administered in advance in a usual manner, depending upon the symptoms of a disease to be protected.
As described hereinbefore, the indole derivative of the general formula (I) according to the first aspect of this invention may be synthesized by a multicomponent single step reaction of the three compounds consisting of the compound of the general formula (II), the compound of the general formula (III) and the compound of the general formula (IV) in the presence of a substance capable of acting as an acid.
According to a fifth aspect of this invention, therefore, there is provided a process for the preparation of the indole derivative represented by the following general formula (I) 




wherein A is an oxygen atom or a nitrogen atom to which nitrogen atom is bonded a hydrogen atom or such a (C1-C10)alkyl group which is, in turn, optionally substituted by a substituent selected from a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group and an acyl group, particularly an alkanoyl group or an aroyl group;

(i) R1 and R2 each stand for a hydrogen atom or an optionally substituted (C1-C10)alkyl group, independently, or (ii) R1 and R2 as taken together form an optionally substituted (C5-C10)cycloalkyl group or an optionally substituted (C6-C20)aromatic ring, particularly a benzene ring, or (iii) R1 and R2 as taken together form an optionally substituted, saturated or unsaturated heterocycric ring containing one or more nitrogen, oxygen or sulfur atom(s), provided that the possible substituent(s) optionally present on the said optionally substituted alkyl group or cycloalkyl group or aromatic ring or heterocyclic ring may be one or more and is or are selected from a halogen atom, a (C1-C10)alkyl group and a (C1-C10)alkoxy group;
R3 stands for a hydrogen atom, an optionally substituted (C1-C10)alkyl group, an optionally substituted (C5-C10)cycloalkyl group or an optionally substituted (C6-C20)aryl group, particularly a phenyl group, or R3 stands for an optionally substituted, saturated or unsaturated heterocyclic group containing one or more nitrogen, oxygen or sulfur atom(s), provided that the possible substituent(s) optionally present on the said optionally substituted alkyl group or cycloalkyl group or aryl group or heterocyclic group may be one or more and is or are selected from a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group, and that two or more of the said possible substituents as selected may be combined together to form one cyclic group;
R4 stands for an optionally substituted (C1-C10)alkyl group where the possible substituent(s) optionally present on the said alkyl group may be one or more and is or are selected from a hydroxyl group, an acyl group, particularly an alkanoyl group or an aroyl group, a (C1-C10)alkyloxycarbonyl group, a cyano group, an amino group, an acylamino group, particularly an alkanoylamino group or an aroylamino group, an acyloxy group, particularly an alkanoyloxy group, an ureido group and a sulfonylamino group, and where the said possible substituent(s) is or are optionally further substituted by one or more of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a (C6-C20)aryl group, particularly a phenyl group, an acyl group, particularly an alkanoyl group or an aroyl group, an acylamino group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group;
R5 stands for a hydrogen atom, a halogen atom, a (C1-C10)alkyl group or a (C1-C10)alkoxy group;
but with such provisos that, in the general formula (I),

    (i) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is hydrogen atom, R4 is 2-acetaminoethyl group and R5 is hydrogen atom;
    (ii) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is 4-hydroxyphenyl group, R4 is 2-acetaminoethyl group and R5 is hydrogen atom;
    (iii) a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is hydrogen atom, R4 is 2-hydroxyethyl group and R5 is hydrogen atom;
    (iv) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is 4-hydroxyphenyl group, R4 is 2-hydroxyethyl group and R5 is hydrogen atom;
    (v) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is phenyl group, R4 is 2-acetaminoethyl group and R5 is hydrogen atom; and
    (vi) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which they are bonded, there is excluded the case where R3 is phenyl group, R4 is 2-hydroxyethyl group and R5 is hydrogen atom; which process comprises a single step reaction of three components consisting of a compound of the following general formula (II) 




wherein A, R1 and R2 each have the same meanings as defined for the general formula (I) above, and an aldehyde compound of the general formula (III)

R3—CHO  (III)

wherein R3 has the same meaning as defined for the general formula (I) above or a compound of the general formula (III′)

R3—CH═N—R9  (III′)

wherein R3 has the same meaning as defined above and R9 is an optionally substituted, straight or branched (C1-C10)alkyl group, an optionally substituted, straight or branched (C2-C10)alkenyl group, an optionally substituted, straight or branched (C2-C10)alkynyl group or an optionally substituted C6 aryl or higher aryl group, and wherein the possible substituent(s) optionally present on the said optionally substituted alkyl group, alkenyl group, alkynyl group or aryl group is or are selected from a halogen atom, an amino group, nitro group, cyano group, an acyl group, particularly an alkanoyl group or an aroyl group, an optionally substituted, straight or branched (C1-C10)alkyl group, an optionally substituted (C3-C20)cycloalkyl group, an optionally substituted, straight or branched (C2-C10)alkenyl group, an optionally substituted, straight or branched (C2-C10)alkynyl group, an optionally substituted (C6-C20)aryl group, particularly a phenyl group, an acyloxy group, an optionally substituted, straight or branched (C1-C10)alkoxy group, an acyl group, particularly an alkanoyl group or aroyl group, an acylamino group, a carbamoyl group, an ureido group, a sulfonylamino group, an optionally substituted, straight or branched (C1-C10)alkyloxycarbonyl group, a carbamoyl group and an acyloxy group, as well as an indole compound of the general formula (IV) 




wherein R4 and R5 each have the same meanings as defined for the general formula (I), in an organic solvent or in an aqueous solvent in the presence of a substance capable of acting as an acid, provided that, depending on the natures of the groups R1 to R5 of the compound of the formula (I) to be prepared, there are relevantly chosen a compound of the formula (II) bearing the relevantly corresponding R1 and R2, and a compound of the formula (III) or (III′) bearing the relevantly corresponding R3, as well as a compound of the formula (IV) bearing the relevantly corresponding R4 and R5, upon carrying out the reaction.



The compound of the general formula (II) which is to be used in the process according to the fifth aspect of this invention is preferably such one that is selected from a class of compound which have chemical structures and Compound Codes respectively shown in the following Table 5. The compounds shown in Table 5 are all already known, except the compound of Code A09.










TABLE 5







Compound Code
Chemical Structure









A01








A02








A03








A04








A05








A06








A07








A08








A09















The aldehyde compound of the general formula (III) which is to be used in the process according to the fifth aspect of this invention is preferably such one that is selected from a class of aldehydes which have chemical structures and the Compound Codes shown respectively in the following Table 6. All the compounds shown in Table 6 are already known.










TABLE 6







Compound Code
Chemical Structure









B01








B02








B03








B04








B05








B06








B07








B08








B09








B10








B11








B12








B13








B14








B15








B16















The indole compound of the general formula (IV) which is to be used in the process according to the fifth aspect of this invention is preferably such one that is selected from a class of already known indole derivatives which have chemical structures and Compound Codes respectively shown in the following two tables, Table 7a and Table 7b.








TABLE 7a





Compound



Code
Chemical Structure







C01







C02







C03







C04







C05







C06







C07







C08







C09







C10







C11







C12







C13







C14







C15







C16







C17







C18







C19







C20






















TABLE 7b





Compound



Code
Chemical Structure







C21







C22







C23







C24







C25







C26







C27







C28







C29







C30







C31







C32







C33







C34







C35














The process according to the fifth aspect of this invention does not embrace the process for the preparation of SF2809-I to VI substances having the formulae (A) to (F) which have been excluded from the scope of the indole derivative of the general formula (I).
Therefore, according to the fifth aspect of this invention, when 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




wherein Me denotes methyl group is used as the compound of the general formula (II) and also formaldehyde or 4-hydroxybenzaldehyde or benzaldehyde is used as the aldehyde compound of the general formula (III), it does not occur that 3-(2-acetaminoethyl)indole of the formula (β-1) 




or 3-(2-hydroxyethyl)indole of the formula (β-2) 




is selected as the indole compound of the formula (IV) to be used.

In the process according to the fifth aspect of this invention, the reaction as effected is shown by the following reaction equation (D).

Reaction Equation (D): 




In the reaction equation above, R1 to R5 have the same meanings as defined in the general formula (I).
The process according to the fifth aspect of this invention is to be carried out in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid. The reaction may preferably be carried out in an anhydrous condition, but may also proceed in the presence of an amount of water. The reaction temperature may be in a range of from −78° C. to the boiling point of the solvent used. It is preferred that the reaction to produce the indole derivative of the general formula (I) according to this invention is carried out at a temperature of 60° C. to 100° C. for a reaction time of 1 hour to 48 hours.
Instead of the aldehyde of the general formula (III), there may be used such compound which is represented by the general formula (III′)

R3—CH═N—R9  (III′)

wherein R3 has the same meaning as defined for the general formula (I) and R9 is an optionally substituted, straight or branched (C1-C10)alkyl group, an optionally substituted, straight or branched (C2-C10)alkenyl group, an optionally substituted, straight or branched (C2-C10)alkynyl group or an optionally substituted C6 aryl or higher aryl group, and wherein the possible substituent(s) optionally present on the said optionally substituted alkyl group, alkenyl group, alkynyl group or aryl group is or are selected from a halogen atom, an amino group, nitro group, cyano group, an acyl group, particularly an alkanoyl group or an aroyl group, an optionally substituted, straight or branched (C1-C10)alkyl group, an optionally substituted (C3-C20)cycloalkyl group, an optionally substituted, straight or branched (C2-C10)alkenyl group, an optionally substituted, straight or branched (C2-C10)alkynyl group, an optionally substituted (C6-C20)aryl group, particularly a phenyl group, an acyloxy group, an optionally substituted, straight or branched (C1-C10)alkoxy group, an acyl group, particularly an alkanoyl group or aroyl group, an acylamino group, a carbamoyl group, an ureido group, a sulfonylamino group, an optionally substituted, straight or branched (C1-C10)alkyloxycarbonyl group, a carbamoyl group and an acyloxy group.

In this process, it is usual that the reaction as intended is carried out by dissolving simultaneously the compound of formula (II), the compound of formula (III) or (III′) and the compound (IV) in an organic solvent, and conducting the reaction in the resulting solution. The molar ratio between the compound of formula (II), the compound of formula (III) or (III′) and the compound (IV) to be subjected to the intended reaction may be chosen optionally as desired, but is preferably at a ratio of 2:3:2. As the reaction solvent, there may be used benzene, toluene, xylene, tetrahydrofuran, diethylether, dioxane, acetonitrile, chloroform, methylene chloride, acetic acid, formic acid, N,N-dimethylformamide, dimethylsulfoxide, and the like. Instead of the organic solvent, aqueous solvent such as water may also be used. The substance capable of acting as an acid may be used at an equimolar ratio to the compound of the general formula (III) used.
The substance capable of acting as an acid may be an organic acid, for example, a lower alkanoic acid such as acetic acid; a trihalogenated lower alkanoic acid such as trichloroacetic acid, trifluoroacetic acid, etc., p-toluenesulfonic acid, p-toluenesulfonic acid pyridinum, methanesulfonic acid, etc., or an inorganic acid, such as polyphosphoric acid, hydrochloric acid, sulfuric acid, nitric acid, etc. or Lewis acid, such as aluminium chloride, titanium tetrachloride, etc. There may also be used, as the substance capable of acting as an acid, “Polymer Supported Acid” which is supported on a solid phase such as polymers and can act as an acid upon the reaction intended. The use of acetic acid as the reaction medium is preferred because acetic acid is effective not only as the solvent, but also for the substance capable of acting as an acid.
When it is intended to produce the indole derivatives of the general formula (I) according to this invention by means of the process according to the fifth aspect of this invention, it is feasible that the compound of formula (II), the compound of formula (III) or (III′), and/or the compound of formula (IV)each having occasionally the substituent(s) which are reactive or functional, are protected at such reactive or functional site(s) with suitable protecting substituent(s). If such a protecting group is necessary for the blocking purpose, it is possible to utilize, for example, such protecting groups which are described in a book titled “Protecting Group in Organic Synthesis” written by T. W. Green and published in 1991 by John Wiley and Sons. The protecting group(s) as once introduced may be removed after completion of the reaction intended.
After the completion of the reaction, the compound of formula (I) desired can, in many cases, spontaneously deposit from the resulting reaction solution. The indole derivative as intended may be recovered by filtering the intended substance so deposited out of the reaction solution. If the intended substance is not yielded in such a deposited form, the indole derivative as intended may be recovered by subjecting the reaction solution to a post-treatment conventionally adopted in the usual chemical synthetic reactions, or by applying a usual purification method. For example, the isolation and purification of the intended indole derivative may be effected, for example, by operations for separation of liquids, distillation method, sublimation method, precipitation method, or crystallization method, or by normal phase or reversed phase column chromatography using silica gel or cellulose, preparative TLC method or HPLC method. Otherwise, the intended indole derivative may be recovered by a method of forming a salt thereof which is sparingly soluble in a solvent, followed by filtering off the deposited compound, or by a method of converting the intended indole derivative into its further derivative.
As a method for obtaining an optically active substance of the indole derivative of the general formula (I), there may be utilized a method of chemical synthesis wherein one or more of the starting compounds of formulae (II), (III), (IV) are used in the form of their optically active compounds. Otherwise, there may be utilized a synthesis method with using one or more of the starting compounds having an introduced asymmetric auxiliary group, a synthesis method with using a catalyst capable of introducing asymmetric site, a method of optical resolution comprising a preferential crystallization by utilizing the formation of a sparingly soluble, optically active salt, a method of optical resolution comprising use of a microorganism or enzyme, a method of optical resolution comprising chiral column chromatography, typically by HPLC, or a method of obtaining optically active substance comprising converting the racemic mixture into diastereomers, separating the diasteromers from each other, followed by converting each diastereomer again to an optically active compound as intended. Thus, by selecting appropriate method(s) from these above-mentioned methods or employing some selected methods in combination, the desired optically active substance of the indole derivative of the general formula (I) can be harvested.
The indole derivative which is once prepared by the process according to the fifth aspect of this invention may then be converted into another compound or compounds which can fall within the scope of this invention, by further chemically modifying their substituent(s) (R1 to R5) of said indole derivative.
As described hereinbefore, we have succeeded in producing by chemical synthesis process the SF2809-I to SF2809-VI substances which are described in the specification of PCT Application No. PCT/JP99/06738.
According to a sixth aspect of this invention, therefore, there is provided a process for the preparation of SF2809-I substance represented by the formula (A) 




which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and formaldehyde of the formula (γ-1)

HCHO  (γ-1)

and 3-(2-acetaminoethyl)indole of the formula (β-1) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

According to a seventh aspect of this invention, there is provided a process for the preparation of SF2809-II substance represented by the formula (B) 




which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and 4-hydroxybenzaldehyde of the formula (γ-2) 




and 3-(2-acetaminoethyl)indole of the formula (β-1) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

According to an eighth aspect of this invention, there is provided a process for the preparation of SF2809-III substance represented by the formula (C) 




which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and formaldehyde of the formula (γ-1)

HCHO  (γ-1)

and 3-(2-hydroxyethyl)indole of the formula (β-2) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

According to a ninth aspect of this invention, there is provided a process for the preparation of SF2809-IV substance represented by the formula (D) 




which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and 4-hydroxybenzaldehyde of the formula (γ-2) 




and 3-(2-hydroxyethyl)indole or the Formula (β-2) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

According to a tenth aspect of this invention, there is provided a process for the preparation SF2809-V substance represented by the formula (E) 




which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and benzaldehyde of the formula (γ-3) 




and 3-(2-acetaminoethyl)indole of the formula (β-1) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

Further, according to an eleventh aspect of this invention, there is provided a process for the preparation of SF2809-VI substance represented by the formula (F) 




which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




and benzaldehyde of the formula (γ-3) 




and 3-(2-acetaminoethyl)indole of the formula (β-1) 




in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

Each of the aforesaid processes according to the sixth to the eleventh aspects of this invention may be conducted in the same manner as described fully hereinbefore for the process according to the fifth aspect of this invention.
BEST MODE FOR CARRYING OUT THE INVENTION
The process for the preparation of some typical compounds among the indole derivatives of the general formula (I) according to this invention will now be illustrated with reference to the following Referential Example and Examples. However, this invention is in no way limited to these Examples.
REFERENTIAL EXAMPLE 1
Preparation of 7-hydroxy-4-methyl-4H-thiazolo[5,4-b]-pyridin-5-one of the Formula (IIa) 




(corresponding to the compound shown in the Table 5 as Compound Code A09)

To a solution of methyl 5-methylaminothiazol-4-carboxylate (5.0 g, 29 mmol) in methylene chloride (50 ml), were added bromo-tris(pyridino)phosphonium hexafluorophosphate (15.6 g, 34.8 mmol), diisopropylethylamine (12.7 ml, 72.6 mmol) and mono-t-butyl malonate (5.4 ml, 34.8 mmol) under ice cooling. The resulting reaction mixture was then stirred for 10 minutes and was further stirred at room temperature overnight. To the reaction mixture, were further added bromo-tris(pyridino)phosphonium hexa-fluorophosphate (10.5 g), diisopropylethylamine (9.78 ml) and mono-t-butyl malonate (3.4 ml), and the resulting mixture was stirred at room temperature for 6 hours.
The resulting reaction solution was washed with water and then dried over anhydrous magnesium sulfate, and the dried solution was distilled to remove the solvent therefrom. The residue obtained was purified by a silica gel chromatography (as developed with n-hexane-ethyl acetate=1:1), to afford an oily substance (5.0 g). This oily substance (5.0 g) was dissolved in an ethanol (10 ml) and the ethanolic solution was added to an ethanolic solution of sodium ethoxide which had been prepared from metallic sodium (1.1 g) and anhydrous ethanol (300 ml). The resulting mixture was heated under reflux for 12 hours. After the resulting reaction solution was cooled to room temperature, a volume of concentrated hydrochloric acid (30 ml) was added slowly thereto, and the resulting mixture was heated under reflux for 2 hours. Thus, there was deposited a solid substance from the reaction solution as formed. This deposit was filtered off and the filtrate so obtained was concentrated. The deposit formed in the resulting concentrate was separated by filtration therefrom, and the resulting deposit solid was suspended in water. Then, the aqueous suspension was stirred for 30 minutes. The resulting aqueous suspension was filtered to give a solid substance, and the resultant solid was dried at 50° C. overnight. There was thus obtained the titled compound of the above formula (IIa) (1.3 g, yield 25%) as a novel compound.
1H-NMR (DMSO-d6) δ: 3.50 (3H, s), 5.74 (1H, s), 8.85 (1H, s), 11.44 (1H, s)
Mass spectrum (TSP): m/z 183 (M++1)
The reaction step effected by the above process may be expressed by the following reaction equation. 




In the above equation, -But stands for tertiary butyl group.

EXAMPLE 1
Preparation of the Compound of the Following Formula (I-003) 




(corresponding to the compound given in Table 1-1 as Compound No.003)

To to acetic acid (3 ml) were added 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




[the compound given in Table 5 as Compound Code A01 and belonging to compound of the general formula (II)] (35 mg; 200 μmol), 3-fluorobenzaldehyde of the formula (γ-4) 




[the compound given in Table 6 as Compound Code B02 and belonging to compound of the general formula (III)] (32 μl; 300 μmol) and 3-[2-(3,5-di-trifluoromethylbenzoyl)aminoethyl] indole of the following (β-3) 




[the compound given in Table 7b as Compound Code C22 and belonging to compound of the general formula (IV)] (80 mg; 200 μmol).

Acetic acid used as above could act not only as the organic solvent for the reaction medium, but also for a substance which is capable of acting as an acid. The resulting solution (namely, the reaction mixture) was stirred at 65° C. for 20 hours. After the completion of the reaction, the resulting reaction solution was concentrated. The resulting residue was purified by a silica gel column chromatography (as gradiently developed with chloroform−methanol=1:0 to 60:1). Thus, there was obtained the titled compound of the above formula (I-003) (86 mg; yield 63%).
Examples 2 to 81
Similarly to the process of Example 1 above, there was produced each of the compounds of Compound Nos. 004 to 014 given in Table 1-1 above; compounds of Compound Nos. 015 to 026 given in Table 1-2; compounds of Compound Nos. 027 to 038 given in Table 1-3; compounds of Compound Nos. 039 to 050 given in Table 1-4; compounds of Compound Nos. 051 to 062 given in Table 1-5; compounds of Compound Nos. 063 to 074 given in Table 1-6; and compounds of Compound Nos. 075 to 083 given in Table 1-7.
In Table 8-1 to Table 8-7 given hereinafter, there are summarily shown Compound Nos. (see Table 1-1 to Table 1-7) of the indole derivatives of the formula (I) as produced in the above Example 1 and in the present Examples 2 to 81, their molecular formulae, their theoretical molecular weights and their found values of the mass spectra data (m/z values).
In Table 8-1 to Table 8-7, there are also listed the three starting compounds which were used as the multicomponents for the single step reaction to produce each of the intended compounds of the general formula (I) and which each are indicated by Compound Nos. in the following Tables 8-1 to 8-7. Thus, in the following tables, the three starting compounds as used, that is, the compound of the general formula (II), compound of the general formula (III) and compound of the general formula (IV) as used in each Example are respectively indicated by Compound Code (A01 to A09) as shown in Table 5, by Compound Code (B01 to B16) as shown in Table 6, and by Compound Code (C01 to C35) as shown in Table 7a to Table 7b given hereinbefore.










TABLE 8-1









Compound of formula (I) as produced
Starting compounds as used














Ex-



Mass spectrum
Compound code for
Compound code for
Compound code for


ample
Compound
Molecular
Theoretical
Found values
compound of formula
compound of formula
compound of formula


No.
No.
formula
Molecular weight
(m/z)
(II)
(III)
(IV)

















1
003
C36H26F7N3O3
681
682(M + H+)
A01
B02
C22


2
004
C36H31F3N4O4
640
641(M + H+)
A01
B05
C12


3
005
C36H34N4O4
586
587(M + H+)
A01
B06
C12


4
006
C36H32BrN3O5
666
668(M + H+)
A01
B01
C18


5
007
C36H32FN3O5
605
606(M + H+)
A01
B02
C18


6
008
C36H33N3O5
587
588(M + H+)
A01
B09
C18


7
009
C34H26BrF2N3O5
642
644(M + H+)
A01
B01
C16


8
010
C34H26F3N3O3
581
582(M + H+)
A01
B02
C16


9
011
C40H32BrN3O5
682
644(M + H+)
A01
B01
C21


10
012
C33H33BrN4O5
613
615(M + H+)
A01
B01
C11


11
013
C33H33F2N4O5
552
553(M + H+)
A01
B02
C11


12
014
C33H32F2N4O5
570
570(M + H+)
A01
B03
C11



















TABLE 8-2









Compound of formula (I) as produced
Starting compounds as used














Ex-



Mass spectrum
Compound code for
Compound code for
Compound code for


ample
Compound
Molecular
Theoretical
Found values
compound of formula
compound of formula
compound of formula


No.
No.
formula
Molecular weight
(m/z)
(II)
(III)
(IV)





13
015
C34H33F3N4O3
602
603(M + H+)
A01
B04
C11


14
016
C34H27BrF2N4O3
657
659(M + H+)
A01
B01
C13


15
017
C36H25F7N2O4
682
683(M + H+)
A01
B02
C08


16
018
C38H26F6N2O6
722
723(M + H+)
A01
B08
C08


17
019
C36H26F6N2O4
664
665(M + H+)
A01
B09
C08


18
020
C40H32N2O4
604
605(M + H+)
A01
B09
C07


19
021
C37H31F3N2O6
656
657(M + H+)
A01
B04
C03


20
022
C34H23BrF2N2O4
643
645(M + H+)
A01
B01
C02


21
023
C34H24F4N2O4
600
601(M + H+)
A01
B03
C02


22
024
C29H25FN2O4
484
485(M + H+)
A01
B02
C10


23
025
C35H28F3N3O3
595
596(M + H+)
A01
B04
C19


24
026
C37H30BrN3O4S
692
693(M + H+)
A01
B01
C26



















TABLE 8-3









Compound of formula (I) as produced
Starting compounds as used














Ex-



Mass spectrum
Compound code for
Compound code for
Compound code for


ample
Compound
Molecular
Theoretical
Found values
compound of formula
compound of formula
compound of formula


No.
No.
formula
Molecular weight
(m/z)
(II)
(III)
(IV)





25
027
C38H30F3N3O5S
697
698(M + H+)
A01
B05
C26


26
028
C34H27BrN2O4
607
609(M + H+)
A01
B01
C05


27
029
C35H27F3N2O4
596
597(M + H+)
A01
B04
C05


28
030
C35H27F3N2O5
612
613(M + H+)
A01
B05
C05


29
031
C34H33BrN2O4
613
615(M + H+)
A01
B01
C06


30
032
C35H33F3N2O4
602
603(M + H+)
A01
B04
C06


31
033
C36H29BrN2O4
621
623(M + H+)
A01
B01
C09


32
034
C36H29F3N2O4
610
611(M + H+)
A01
B04
C09


33
035
C36H29F3N2O5
626
627(M + H+)
A01
B05
C09


34
036
C37H12N2O6
600
601(M + H+)
A01
B08
C09


35
037
C33H33BrN2O4
601
603(M + H+)
A01
B01
C20


36
038
C33H28BrN3O4S
642
644(M + H+)
A01
B01
C28



















TABLE 8-4 









Compound of formula (I) as produced
Starting compounds as used














Ex-



Mass spectrum
Compound code for
Compound code for
Compound code for


ample
Compound
Molecular
Theoretical
Found values
compound of formula
compound of formula
compound of formula


No.
No.
formula
Molecular weight
(m/z)
(II)
(III)
(IV)





37
039
C34H30BrO4S
656
658(M + H+)
A01
B01
C29


38
040
C35H31BrN4O5S
699
701(M + H+)
A01
B01
C27


39
041
C33H34N4O4
550
551(M + H+)
A01
B09
C15


40
042
C31H32F3N3O5
655
656(M + H+)
A01
B04
C25


41
043
C37H35N3O6
617
618(M + H+)
A01
B07
C25


42
044
C29H25BrN2O4
545
547(M + H+)
A01
B01
C01


43
045
C27H22BrN3O3
516
518(M + H+)
A01
B01
C31


44
046
C27H20BrN3O2
498
500(M + H+)
A01
B01
C32


45
047
C36H30N2O5
574
547(M + H+)
A05
B09
C17


46
048
C30H27NO5
481
481(M + H+)
A05
B10
C01


47
049
C31H27BrN2O5
587
589(M + H+)
A07
B01
C23


48
050
C26H25N3O3
451
425(M + H+)
A04
B09
C24



















TABLE 8-5









Compound of formula (I) as produced
Starting compounds as used














Ex-



Mass spectrum
Compound code for
Compound code for
Compound code for


ample
Compound
Molecular
Theoretical
Found values
compound of formula
compound of formula
compound of formula


No.
No.
formula
Molecular weight
(m/z)
(II)
(III)
(IV)





49
051
C29H33N3O3
471
472(M + H+)
A01
B11
C24


50
052
C30H29N3O3
479
479(M + H+)
A01
B10
C24


51
053
C30H25F3N3O3
533
534(M + H+)
A01
B15
C24


52
054
C27H25N3O3S
471
472(M + H+)
A01
B14
C24


53
055
C31H33N3O4S
543
544(M + H+)
A01
B09
C30


54
056
C39H46N2O4
606
607(M + H+)
A01
B09
C35


55
057
C36H32N2O6
588
589(M + H+)
A01
B06
C04


56
058
C26H22N2O2
394
395(M + H+)
A01
B09
C33


57
059
C36H31ClN2O6
622
623(M + H+)
A02
B09
C03


58
060
C36H30ClF3N4O4
674
675(M + H+)
A02
B09
C14


59
061
C39H47N3O3
743
606(M + H+)
A01
B09
C34


60
062
C30H25ClF3N3O4
583
584(M + H+)
A02
B05
C24



















TABLE 8-6









Compound of formula (I) as produced
Starting compounds as used














Ex-
Com-


Mass spectrum
Compound code for
Compound code for
Compound code for


ample
pound
Molecular
Theoretical
Found values
compound of formula
compound of formula
compound of formula


No.
No.
formula
Molecular weight
(m/z)
(II)
(III)
(IV)





61
063
C33H33NO7
579
580(M + H+)
A06
B09
C03


62
064
C38H32F3N3O5
631
632(M + H+)
A06
B09
C14


63
065
C28H27BrN2O4
535
535(M + H+)
A06
B01
C24


64
066
C36H31BrN2O5S
683
683(M + H+)
A06
B01
C26


65
067
C33H29N3O6S
595
595(M + H+)
A09
B09
C03


66
068
C33H27BrF3N5O4S
726
728(M + H+)
A09
B01
C14


67
069
C34H27BrN4O4S2
699
701(M + H+)
A09
B01
C26


68
070
C26H33N3O3
459
460(M + H+)
A01
B12
C24


69
071
C41H32F3N3O4
687
688(M + H+)
A01
B05
C21


70
072
C34H29N5O4S
603
604(M + H+)
A08
B09
C26


71
073
C26H23BrN4O4
535
536(M + H+)
A08
B01
C10


72
074
C25H24BrN5O3
534
499(M − 2H2O+)
A08
B01
C24



















TABLE 8-7









Compound of formula (I) as produced
Starting compounds as used














Ex-



Mass spectrum
Compound code for
Compound code for
Compound code for


ample
Compound
Molecular
Theoretical
Found values
compound of formula
compound of formula
compound of formula


No.
No.
formula
Molecular weight
(m/z)
(II)
(III)
(IV)





73
075
C33H30N4O5S
595
596(M + H+)
A09
B09
C18


74
076
C26H22BrN3O4S
552
554(M + H+)
A09
B01
C10


75
077
C26H23N3O4S
474
474(M + H+)
A09
B09
C10


76
078
C31H29N3O5
523
524(M + H+)
A01
B16
C24


77
079
C33H28BrN3O6S
674
676(M + H+)
A09
B01
C24


78
080
C25H26N3O3
415
415(M + H+)
A03
B09
C24


79
081
C27H28N4O3S
472
473(M + H+)
A09
B09
C24


80
082
C30H31N5O3S
541
542(M + H+)
A09
B09
C11


81
083
C31H26N4O3S
534
535(M + H+)
A09
B09
C19









In Examples 2 to 81, the respective compounds of the formulae (II), (III) and (IV) used as the starting compounds were dissolved together simultaneously in a volume of acetic acid and the intended reaction was effected in the resulting solution in acetic acid. The yields of the resulting product compounds of the general formula (I), namely the compounds of Compound Nos. 004 to 083 were 80% to 10%.
In cases where the product compound of the formula (I) contained a bromine atom or bromine atoms, its mass spectrum pattern as measured showed the observed two ion peaks which were near the ion peak value equal to the theoretical molecular weight of the product compound. These two ion peaks were attributable to the isotopes of the bromine atom of the said product. The numerical figures which are given in Table 8 as the found values of the mass spectra data denote the ion peak of a higher intensity among the two ion peaks.
EXAMPLE 82
This Example illustrates an example of the production of SF2809-I substance of the following formula (A) 




by the process according to the sixth aspect of this invention.

To acetic acid (10 ml) were added 4-hydroxy-1-methyl-2-quinolinone of the following formula (α) 




(the compound of Compound Code A01 given in Table 5) (350 mg; 2.0 mmol) and formaldehyde of the formula (γ-1)

HCHO  (γ-1)

(the compound of Compound Code B13 given in Table 6)(75 mg; 30 mmol) and 3-(2-acetaminoethyl)indole of the formula (β-1) 




[compound of Compound Code C24 given in Table 7b](404 mg; 2.0 mmol). The resulting solution in acetic acid was heated on an oil bath at 80° C. for 12 hours under stirring.

After the completion of the reaction, the resulting reaction solution was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (as developed with chloroform-methanol, 1:0 to 60:1, by gradient development). There was obtained the target compound, SF2809-I substance (65 mg; Yield 8.3%). All the physical property data of SF2809-I substance as obtained in this Example were coincident with those of SF2809-I substance which was obtained by the fermentation process as described in the specification of No. PCT Application No. PCT/JP99/06738.
EXAMPLE 83
This Example illustrates an example of the production of SF2809-V substance of the following formula (E) 




by the process according to the tenth aspect of this invention.

To acetic acid (500 ml) were added 4-hydroxy-1-methyl-2-quinolinone of the formula (α) above (the compound of Compound Code A01 given in Table 5)(10.5 g; 60 mmol) and benzaldehyde of the formula (γ-3) 




(the compound of Compound Code B09 given in Table 6)(9.56 g; 90 mmol) and 3-(2-acetaminoethyl)indole of the formula (β-1) above (the compound of Compound Code C24 given in Table 7b)(12.12 g; 60 mmol).

The resulting solution in acetic acid was heated on an oil bath at 70-80° C. for 19 hours under stirring. The resulting reaction solution was allowed to stand to cool down to room temperature. Thereafter, the crystals as deposited from the cooled reaction solution were separated by suction-filtration. Upon washing the so separated crystals twice with methanol, SF2809-V substance was obtained in the form of colorless fine crystalline powder (21.3 g; yield 75%). All the physical property data of SF2809-V substance as obtained in this Example were coincident with those of SF2809-V substance which are shown in the specification of PCT Application No. PCT/JP99/06738.
Industrial Applicability
According to this invention, the indole derivative of the general formula (I) above-mentioned can be obtained by a chemical synthetic process in a facile and efficient way. The indole derivative of the general formula (I) has a high chymase inhibitory activity and hence is useful for a therapeutic or prophylactic treatment for a variety of diseases in which the enzyme chymase participates, for example, diseases of circulatory system such as hypertension and cardiac insufficiency, as well as allergosis such as asthma, rheumatism and atopic dermatitis.

## Claims

1. An indole derivative represented by the following formula (I) 




or a pharmaceutically acceptable salt of or a solvate thereof, wherein:
A is an oxygen atom or a nitrogen atom which is bonded to a hydrogen atom or to a (C1-C10)alkyl group which is, in turn, optionally substituted by a substituent selected from the group consisting of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group and an acyl group; 
(i) R1 and R2 each stand for a hydrogen atom or an optionally substituted (C1-C10)alkyl group, independently, or 
(ii) R1 and R2 as taken together form an optionally substituted (C5-C10)cycloalkyl group or an optionally substituted (C6-C20)aromatic ring, or 
(iii) R1 and R2 as taken together form an optionally substituted, saturated or unsaturated heterocycric ring containing one or more nitrogen, oxygen or sulfur atom(s), 
wherein substituent(s) optionally present on the optionally substituted alkyl group or cycloalkyl group or aromatic ring or heterocyclic ring may be one or more and is or are selected from the group consisting of a halogen atom, a (C1-C10)alkyl group and a (C1-C10)alkoxy group; 
R3 stands for a hydrogen atom, an optionally substituted (C1-C10)alkyl group, an optionally substituted (C5-C10)cycloalkyl group or an optionally substituted (C6-C20)aryl group, or R3 stands for an optionally substituted, saturated or unsaturated heterocyclic group containing one or more nitrogen, oxygen or sulfur atom(s), wherein the substituent(s) optionally present on the optionally substituted alkyl group or cycloalkyl group or aryl group or heterocyclic group may be one or more and is or are selected from the group consisting of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group and wherein two or more of the substituents as selected may be combined together to form one cyclic group; 
R4 stands for an optionally substituted (C1-C10)alkyl group wherein the substituent(s) optionally present on said alkyl group may be one or more and is or are selected from the group consisting of a hydroxyl group, an acyl group, a (C1-C10)alkyloxy-carbonyl group, a cyano group, an amino group, an acylamino group, an acyloxy group, an ureido group and a sulfonylamino group, and wherein the substituent(s) is or are optionally further substituted by one or more of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a (C6-C20)aryl group, an acyl group, an acylamino group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group; 
R5 stands for a hydrogen atom, a halogen atom, a (C1-C10)alkyl group or a (C1-C10)alkoxy group; 
but with such provisos that, in the formula (1): 
(i) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is hydrogen atom, R4 is 2-acetaminoethyl group and R5 is hydrogen atom; 
(ii) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is 4-hydroxyphenyl group, R4 is 2-acetaminoethyl group and R5 is hydrogen atom; 
(iii) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is hydrogen atom, R4 is 2-hydroxyethyl group and R5 is hydrogen atom; 
(iv) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and are bonded, there is excluded the case where R3 is 4-hydroxyphenyl group, R4 is 2-hydroxyethyl group and R5 is hydrogen atom; 
(v) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is phenyl group, R4 is 2-acetaminoethyl group and R5 is hydrogen atom; and 
(vi) when A is a methylated nitrogen atom and also R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is phenyl group, R4 is 2-hydroxyethyl group and R5 is hydrogen atom.

2. The indole derivative or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1 which is a compound represented by the formula (Ia) 




wherein:
A has the same meaning as defined in claim 1; 
B stands for a cyclic group, which cyclic group B either stands for an optionally substituted (C6-C20)aromatic ring, or the cyclic group B stands for an optionally substituted, saturated or unsaturated heterocyclic ring containing one or more nitrogen, oxygen or sulfur atom(s), wherein the substituent(s) optionally present on the optionally substituted aromatic ring or heterocyclic ring is or are selected from the group consisting of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group and the substituent(s) may be either single or plural ones; 
R3 has the same meaning as defined in claim 1; 
R6 stands for a hydroxyl group, an optionally substituted acyl group, an optionally substituted (C1-C10)alkyloxy-carbonyl group, a cyano group, an optionally substituted amino group, an optionally substituted acyloxy group, an optionally substituted ureido group or an optionally substituted sulfonylamino group, wherein the substituent(s) optionally present on the optionally substituted groups is or are selected from the group consisting of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a (C6-C20)aryl group, an acyl group, an acylamino group, a halogenated (C1-C10)alkyl group, a halogenated (C1-C10)alkoxy group and a halogenated acyl group; 
R7 stands for a hydrogen atom, a halogen atom, a (C1-C6)alkyl group or a (C1-C6)alkoxy group; 
but with such provisos that, in the formula (Ia), 
(i) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is hydrogen atom, R6 is acetamino group and R7 is hydrogen atom; 
(ii) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is 4-hydroxyphenyl group, R6 is acetamino group and R7 is hydrogen atom; 
(iii) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is hydrogen atom, R6 is hydroxyl group and R7 is hydrogen atom; 
(iv) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is 4-hydroxyiphenyl group, R6 is hydroxyl group and R7 is hydrogen atom; 
(v) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is phenyl group, R6 is acetamino group and R7 is hydrogen atom; and 
(vi) when A is a methylated nitrogen atom and B is a benzene ring, there is excluded the case where R3 is phenyl group, R6 is hydroxyl group and R7 is hydrogen atom.

3. The indole derivative or a pharmaceutically acceptable salt or a solvate thereof as claimed in claim 1, which is a compound represented by the formula (Ib) 




wherein:
B stands for a cyclic group, which cyclic group B either stands for an optionally substituted (C6-C20)aromatic ring, or the cyclic group B stands for an optionally substituted, saturated or unsaturated heterocyclic ring containing one or more nitrogen, oxygen or sulfur atom(s), wherein the substituent(s) optionally present on the optionally substituted aromatic ring or heterocyclic ring is or are selected from the group consisting of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group and the substituent(s) may be either single or plural ones; 
R3 has the same meaning as defined in claim 1; 
R6 stands for a hydroxyl group, an optionally substituted acyl group, an optionally substituted (C1-C10)alkyloxy-carbonyl group, a cyano group, an optionally substituted amino group, an optionally substituted acyloxy group, an optionally substituted ureido group or an optionally substituted sulfonylamino group, wherein the substituent(s) optionally present on the optionally substituted groups is or are selected from the group consisting of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a (C6-C20)aryl group, an acyl group, an acylamino group, a halogenated (C1-C10)alkyl group, a halogenated (C1-C10)alkoxy group and a halogenated acyl group; 
R7 stands for a hydrogen atom, a halogen atom, a (C1-C6)alkyl group or a (C1-C6)alkoxy group; 
R8 stands for a hydrogen atom or a straight or branched (C1-C10)alkyl group; 
but with such provisos that in the formula (1b): 
(i) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is hydrogen atom, R6 is acetamino group and R7 is hydrogen atom; 
(ii) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is 4-hydroxyphenyl group, R6 is acetamino group and R7 is hydrogen atom; 
(iii) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is hydrogen atom, R6 is hydroxyl group and R7 is hydrogen atom; 
(iv) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is 4-hydroxyphenyl group, R6 is hydroxyl group and R7 is hydrogen atom; 
(v) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is phenyl group, R6 is acetamido group and R7 is hydrogen atom; and 
(vi) when B is a benzene ring and R8 is methyl group, there is excluded the case where R3 is phenyl group, R6 is hydroxyl group and R7 is hydrogen atom.

4. The compound as claimed in claim 1, wherein the compound is one of the following formulas:












Compound No. 005









Compound No. 006









Compound No. 007









Compound No. 008









Compound No. 009









Compound No. 010









Compound No. 011









Compound No. 012









Compound No. 013









Compound No. 014









Compound No. 015









Compound No. 016









Compound No. 017









Compound No. 018









Compound No. 019









Compound No. 020









Compound No. 021









Compound No. 022









Compound No. 023









Compound No. 024









Compound No. 025









Compound No. 026









Compound No. 027









Compound No. 028









Compound No. 029









Compound No. 030









Compound No. 031









Compound No. 032









Compound No. 033









Compound No. 034









Compound No. 035









Compound No. 036









Compound No. 037









Compound No. 038









Compound No. 039









Compound No. 040









Compound No. 041









Compound No. 042









Compound No. 043









Compound No. 044









Compound No. 045









Compound No. 046









Compound No. 047









Compound No. 048









Compound No. 049









Compound No. 050









Compound No. 051









Compound No. 052









Compound No. 053









Compound No. 054









Compound No. 055









Compound No. 056









Compound No. 057









Compound No. 058









Compound No. 059









Compound No. 060









Compound No. 061









Compound No. 062









Compound No. 063









Compound No. 064









Compound No. 065









Compound No. 066









Compound No. 067









Compound No. 068









Compound No. 069









Compound No. 070









Compound No. 071









Compound No. 072









Compound No. 073









Compound No. 074









Compound No. 075









Compound No. 076









Compound No. 077









Compound No. 078









Compound No. 079









Compound No. 080









Compound No. 081









Compound No. 082









Compound No. 083

5. A pharmaceutical composition comprising as an active ingredient at least one of the indole derivative of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or a solvate thereof, in combination with a pharmaceutically acceptable carrier or carriers.

6. A pharmaceutical composition as claimed in claim 5, adapted for use as a therapeutic or prophylactic treatment of cardiac infarction, cardiomegaly, cardiac insufficiency, mycardosis, arteriosclerosis, hypertension, hemangioendotyrosis, periphery cardiovascular disorder, renal insufficiency, inflammation, allergy, atopic dermatitis, rheumatism, asthma, or bronchitis.

7. A composition comprising an indole derivative of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt or a solvate thereof, said composition adapted for use as a chymase inhibitor.

8. A process for the preparation of an indole derivative which is a compound as claimed in claim 1 and represented by the formula (I) 




wherein A is an oxygen atom or a nitrogen atom which is bonded to a hydrogen atom or to a (C1-C10)alkyl group which is, in turn, optionally substituted by a substituent selected from a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group and an acyl group;
(i) R1 and R2 each stand for a hydrogen atom or an optionally substituted (C1-C10)alkyl group, independently, or (ii) R1 and R2 as taken together form an optionally substituted (C5-C10)cycloalkyl group or an optionally substituted (C6-C20)aromatic ring, or (iii) R1 and R2 as taken together form an optionally substituted, saturated or unsaturated heterocycric ring containing one or more nitrogen, oxygen or sulfur atom(s), wherein the substituent(s) optionally present on the optionally substituted alkyl group or cycloalkyl group or aromatic ring or heterocyclic ring may be one or more and is or are selected from the group consisting of a halogen atom, a (C1-C10)alkyl group and a (C1-C10)alkoxy group; 
R3 stands for a hydrogen atom, an optionally substituted (C1-C10)alkyl group, an optionally substituted (C5-C10)cycloalkyl group or an optionally substituted (C6-C20)aryl group, or R3 stands for an optionally substituted, saturated or unsaturated heterocyclic group containing one or more nitrogen, oxygen or sulfur atom(s), wherein the substituent(s) optionally present on the optionally substituted alkyl group or cycloalkyl group or aryl group or heterocyclic group may be one or more and is or are selected from the group consisting of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group, and wherein two or more of the substituents as selected may be combined together to form one cyclic group; 
R4 stands for an optionally substituted (C1-C10)alkyl group wherein the substituent(s) optionally present on the alkyl group may be one or more and is or are selected from the group consisting of a hydroxyl group, an acyl group, a (C1-C10)alkyloxy-carbonyl group, a cyano group, an amino group, an acylamino group, an acyloxy group, an ureido group and a sulfonylamino group, and wherein the substituent(s) is or are optionally further substituted by one or more of a halogen atom, a (C1-C10)alkyl group, a (C1-C10)alkoxy group, a (C6-C20)aryl group, an acyl group, an acylamino group, a halogenated (C1-C10)alkyl group and a halogenated (C1-C10)alkoxy group; 
R5 stands for a hydrogen atom, a halogen atom, a (C1-C10)alkyl group or a (C1-C10)alkoxy group; 
but with such provisos that, in the formula (I): 
(i) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is hydrogen atom, R4 is 2-acetaminoethyl group and R5 is hydrogen atom; 
(ii) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is 4-hydroxyphenyl group, R4 is 2-acetaminoethyl group and R5 is hydrogen atom; 
(iii) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and are bonded, there is excluded the case where R3 is hydrogen atom, R4 is 2-hydroxyethyl group and R5 is hydrogen atom; 
(iv) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and are bonded, there is excluded the case where R3 is 4-hydroxyphenyl group, R4 is 2-hydroxyethyl group and R5 is hydrogen atom; 
(v) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which R1 and R2 are bonded, there is excluded the case where R3 is phenyl group, R4 is 2-acetaminoethyl group and R5 is hydrogen atom; and 
(vi) when A is a methylated nitrogen atom and R1 and R2 as taken together form a benzene ring in association with the ring-forming carbon atoms to which they are bonded, there is excluded the case where R3 is phenyl group, R4 is 2-hydroxyethyl group and R5 is hydrogen atom; 

said process comprising a single step reaction of three components (a)-(c) consisting of:
(a) a compound of the formula (II) 




 wherein A, R1 and R2 each have the same meanings as defined for the formula (I) above; 
(b) an aldehyde compound of the formula (III) or formula (III′) where: 


R3—CHO  (III) 


 wherein R3 has the same meaning as defined for the formula (I) above and where: 


R3—CH═N—R9  (III′) 


wherein R3 has the same meaning as defined above, and 
R9 is an optionally substituted, straight or branched (C1-C10)alkyl group, an optionally substituted, straight or branched (C2-C10)alkenyl group, an optionally substituted, straight or branched (C2-C10)alkynyl group or an optionally substituted C6 aryl or higher aryl group, and wherein the substituent(s) optionally present on the optionally substituted alkyl group, alkenyl group, alkynyl group or aryl group is or are selected from the group consisting of a halogen atom, an amino group, nitro group, a cyano group, an acyl group, an optionally substituted, straight or branched (C1-C10)alkyl group, an optionally substituted (C3-C20)cycloalkyl group, an optionally substituted, straight or branched (C2-C10)alkenyl group, an optionally substituted, straight or branched (C2-C10)alkynyl group, an optionally substituted (C6-C20)aryl group, an acyloxy group, an optionally substituted, straight or branched (C1-C10)alkoxy group, an acyl group, an acylamino group, a carbamoyl group, an ureido group, a sulfonylamino group, an optionally substituted, straight or branched (C1-C10)alkyloxycarbonyl group, a carbamoyl group, an acyloxy group; and 
(c) an indole compound of the formula (IV) 




wherein R4 and R5 each have the same meanings as defined for the formula (I), in an organic solvent or in an aqueous solvent in the presence of a substance capable of acting as an acid, with proviso such that, depending on the natures of the groups R1 to R5 of the compound of the formula (I) to be prepared, there are relevantly chosen a component (a) compound of the formula (II) bearing the relevantly corresponding R1 and R2, and a component (b) compound of the formula (III) or (III′) bearing the relevantly corresponding R3, and a component (c) compound of the formula (IV) bearing the relevantly corresponding R4 and R5, upon carrying out the reaction.

9. The process as claimed in claim 8, wherein the component (a) compound of the formula (II) is one of the following formulas:














Compound Code
Chemical Structure









A01








A02








A03








A04








A05








A06








A07








A08








A09

10. The process as claimed in claim 8, wherein the component (b) aldehyde compound of the formula (III) is a compound selected from the aldehydes which have the following formulas:














Compound Code
Chemical Structure









B01








B02








B03








B04








B05








B06








B07








B08








B09








B10








B11








B12








B13








B14








B15








B16

11. The process as claimed in claim 8, wherein the component (c) indole compound of the formula (IV) is a compound selected from the indoles which have the following formulas:











Compound



Code
Chemical Structure







C01







C02







C03







C04







C05







C06







C07







C08







C09







C10







C11







C12







C13







C14







C15







C16







C17







C18







C19







C20







C21







C22







C23







C24







C25







C26







C27







C28







C29







C30







C31







C32







C33







C34







C35

12. The process as claimed in claim 8, wherein the component (c) indole compound of the formula (IV) is neither
3-(2-acetaminoethyl)indole of the formula (β-1) 




nor 3-(2-hydroxyethyl)indole of the formula (β-2) 




in the case when component (a) is
(i) 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




 where Me stands for methyl group and concurrently 
(ii) component (b) the aldehyde compound is formaldehyde or 4-hydroxybenzaldehyde or benzaldehyde.

13. A process for the preparation of a compound named as SF2809-I substance and having formula (A) 




said process comprising reacting three components (a)-(c) in a single step reaction, the three components consisting of
(a) 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




(b) formaldehyde of the formula (γ-1) 


HCHO  (γ-1) 


 and 
(c) 3-(2-acetaminoethyl)indole of the formula(β-1) 





with the three components (a)-(c) in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

14. A process for the preparation of a compound named as SF2809-II substance and having formula (B) 




said process comprising reacting three components (a)-(c) in a single step, the three components consisting of
(a) 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




(b) 4-hydroxybenzaldehyde of the formula (β-2) 




 and 
(c) 3-(2-acetaminoethyl)indole of the formula (β-1) 





wherein the three components are in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

15. A process for the preparation of a compound named as SF2809-III substance and having formula (C) 




said process comprising reacting three components (a)-(c) in a single step reaction, the three components consisting of
(a) 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




(b) formaldehyde of the formula (γ-1) 


HOHO  (γ-1) 


 and 
(c) 3-(2-hydroxyethyl)indole of the formula (β-2) 




wherein the three components are in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

16. A process for the preparation of a compound named as SF2809-IV substance and having formula (D) 




said process comprising reacting three components (a)-(c), in a single step reaction, the three components consisting of
(a) 4-hydroxy-1-methyl-2-quinolinone of the formula (a) 




(b) 4-hydroxybenzaldehyde of the formula (γ-2) 




 and 
(c) 3-(2-hydroxyethyl)indole of the formula (β-2) 





wherein the three are in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

17. A process for the preparation of a compound named as SF2809-V substance and having formula (E) 




said process comprising reacting three components (a)-(c) in a single step reaction, the three components consisting of
(a) 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




(b) benzaldehyde of the formula (γ-3) 




 and 
(c) 3-(2-acetaminoethyl)indole of the formula (β-1) 





wherein the three components are in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

18. A process for the preparation of a compound named as SF2809-VI substance and having formula (F) 




said process comprising reacting three components (a)-(c) in a single step reaction, the three components consisting of
(a) 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 




(b) benzaldehyde of the formula (γ-3) 




 and 
(c) 3-(2-acetaminoethyl)indole of the formula (β-1) 





wherein the three are in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.