Novel 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) 1

Description

TECHNICAL FIELD

[0001] 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

[0002] 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).

[0003] 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.

[0004] 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.

[0005] 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). 23

[0006] 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).

[0007] 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.

[0008] 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.

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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):

[0013] Reaction Equation (A) 4

[0014] 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)].

[0015] 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): 5

[0016] 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)].

[0017] 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): 6

[0018] 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)].

[0019] 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 (O) as produced in said single step reaction of the multicomponents is not so good.

[0020] 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).

[0021] 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

[0022] 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.

[0023] 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.

[0024] 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) 7

[0025] 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) 8

[0026] and benzaldehyde of the formula (γ-3) 9

[0027] and 3-(2-acetaminoethyl)indole of the formula (β-1) 10

[0028] 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.

[0029] We have further continued our studies, and as a result we have now found that SF2809-I substance of the formula (A) 11

[0030] can be synthesized by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 12

[0031] and formaldehyde

HCHO  (γ-1)

[0032] and 3-(2-acetaminoethyl)indole of the formula (β-1) 13

[0033] 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) 14

[0034] can be produced by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 15

[0035] and 4-hydroxybenzaldehyde of the formula (γ-2) 16

[0036] and 3-(2-acetaminoethyl)indole of the formula (β-1) 17

[0037] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0038] We have further found that SF2809-III substance of the formula (C) 18

[0039] can be produced by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 19

[0040] and formaldehyde of the formula (γ-1)

HCHO  (γ-1)

[0041] and 3-(2-hydroxyethyl)indole of the formula (β-2) 20

[0042] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0043] We have also found that SF2809-IV substance of the formula (D) 21

[0044] can be produced by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 22

[0045] and 4-hydroxybenzaldehyde of the formula (γ-2) 23

[0046] and 3-(2-hydroxyethyl)indole of the formula (β-2) 24

[0047] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0048] We have moreover found that SF2809-VI substance of the formula (F) 25

[0049] can be produced by effecting a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 26

[0050] and benzaldehyde of the formula (γ-3) 27

[0051] and 3-(2-acetaminoethyl)indole of the formula (β-1) 28

[0052] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0053] 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.

[0054] 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) 29

[0055] 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)

[0056] 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′)

[0057] 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) 30

[0058] 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.

[0059] 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.

[0060] In a first aspect of this invention, therefore, there is provided an indole derivative which is a compound represented by the general formula (I) 31

[0061] 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;

[0062] (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;

[0063] 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;

[0064] 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;

[0065] R5 stands for a hydrogen atom, a halogen atom, a (C1-10)alkyl group or a (C1-C10)alkoxy group;

[0066] but with such provisos that, in the general formula (I),

[0067] (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;

[0068] (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;

[0069] (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;

[0070] (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;

[0071] (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

[0072] (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;

[0073] or a pharmaceutically acceptable salt or a solvate thereof.

[0074] 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) 32

[0075] wherein A has the same meaning as defined above;

[0076] 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;

[0077] R3 has the same meaning as defined above;

[0078] 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;

[0079] R7 stands for a hydrogen atom, a halogen atom, a (C1-C6)alkyl group or a (C1-C6) alkoxy group;

[0080] but with such provisos that, in the general formula (Ia),

[0081] (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;

[0082] (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;

[0083] (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;

[0084] (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;

[0085] (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

[0086] (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.

[0087] 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) 33

[0088] wherein B, R3, R6 and R7 have the same meanings as defined above, respectively;

[0089] R8 stands for a hydrogen atom or a straight or branched (C1-C10)alkyl group;

[0090] but with such provisos that in the general formula (Ib),

[0091] (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;

[0092] (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;

[0093] (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;

[0094] (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;

[0095] (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

[0096] (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.

[0097] 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].

[0098] 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.

[0099] 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.

[0100] As a (C5-C10)cycloalkyl group which R1, R2 and R3 may denote, there may be exemplified cyclopentyl group or cyclohexyl group.

[0101] 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.

[0102] Alkyloxycarbonyl group as above-mentioned may include, for example, methyloxycarbonyl group or benzyloxycarbonyl group.

[0103] 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.

[0104] Examples of an alkoxy group above-mentioned are methoxy group or trifluoromethoxy group and others.

[0105] 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.

[0106] 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.

[0107] As carbamoyl groups above-mentioned, there may be exemplified methyloxycarbonylamino group, benzyloxycarbonylamino group, t-butyloxycarbonylamino group or allyloxycarbonylamino group and others.

[0108] Examples of an ureido group above-mentioned are aminocarbonylamino group, N′-methylaminocarbonylamino group, piperidinocarbonylamino group, morpholinocarbonylamino group, N′-methyl-N′-phenylaminocarbonylamino group and others.

[0109] Further, the sulfonylamino group above-mentioned may include butylsulfonylamino group, phenylsulfonylamino group, benzylsulfonylamino group and naphthylsulfonylamino group, and so on.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] The indole derivative having the general formula (I) according to this invention include all the optical isomers and the racemic mixtures thereof.

[0115] 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.

[0116] 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
34
Compound No. 004
35
Compound No. 005
36
Compound No. 006
37
Compound No. 007
38
Compound No. 008
39
Compound No. 009
40
Compound No. 010
41
Compound No. 011
42
Compound No. 012
43
Compound No. 013
44
Compound No. 014
45

[0117]

TABLE 1-2
Compound No. 015
46
Compound No. 016
47
Compound No. 017
48
Compound No. 018
49
Compound No. 019
50
Compound No. 020
51
Compound No. 021
52
Compound No. 022
53
Compound No. 023
54
Compound No. 024
55
Compound No. 025
56
Compound No. 026
57

[0118]

TABLE 1-3
Compound No. 027
58
Compound No. 028
59
Compound No. 029
60
Compound No. 030
61
Compound No. 031
62
Compound No. 032
63
Compound No. 033
64
Compound No. 034
65
Compound No. 035
66
Compound No. 036
67
Compound No. 037
68
Compound No. 038
69

[0119]

TABLE 1-4
Compound No. 039
70
Compound No. 040
71
Compound No. 041
72
Compound No. 042
73
Compound No. 043
74
Compound No. 044
75
Compound No. 045
76
Compound No. 046
77
Compound No. 047
78
Compound No. 048
79
Compound No. 049
80
Compound No. 050
81

[0120]

TABLE 1-5
Compound No. 051
82
Compound No. 052
83
Compound No. 053
84
Compound No. 054
85
Compound No. 055
86
Compound No. 056
87
Compound No. 057
88
Compound No. 058
89
Compound No. 059
90
Compound No. 060
91
Compound No. 061
92
Compound No. 062
93

[0121]

TABLE 1-6
Compound No. 063
94
Compound No. 064
95
Compound No. 065
96
Compound No. 066
97
Compound No. 067
98
Compound No. 068
99
Compound No. 069
100
Compound No. 070
101
Compound No. 071
102
Compound No. 072
103
Compound No. 073
104
Compound No. 074
105

[0122]

TABLE 1-7
Compound No. 075
106
Compound No. 076
107
Compound No. 077
108
Compound No. 078
109
Compound No. 079
110
Compound No. 080
111
Compound No. 081
112
Compound No. 082
113
Compound No. 083
114

[0123]

TABLE 2-1
Compound No. 084
115
Compound No. 085
116
Compound No. 086
117
Compound No. 087
118
Compound No. 088
119
Compound No. 089
120
Compound No. 090
121
Compound No. 091
122
Compound No. 092
123
Compound No. 093
124
Compound No. 094
125
Compound No. 095
126
Compound No. 096
127
Compound No. 097
128
Compound No. 098
129

[0124]

TABLE 2-2
Compound No. 099
130
Compound No. 100
131
Compound No. 101
132
Compound No. 102
133
Compound No. 103
134
Compound No. 104
135
Compound No. 105
136
Compound No. 106
137
Compound No. 107
138
Compound No. 108
139
Compound No. 109
140
Compound No. 110
141

[0125]

TABLE 2-3
Compound No. 111
142
Compound No. 112
143
Compound No. 113
144
Compound No. 114
145
Compound No. 115
146
Compound No. 116
147
Compound No. 117
148
Compound No. 118
149
Compound No. 119
150
Compound No. 120
151
Compound No. 121
152
Compound No. 122
153

[0126]

TABLE 2-4
Compound No. 123
154
Compound No. 124
155
Compound No. 125
156
Compound No. 126
157
Compound No. 127
158
Compound No. 128
159
Compound No. 129
160
Compound No. 130
161
Compound No. 131
162
Compound No. 132
163
Compound No. 133
164
Compound No. 134
165

[0127]

TABLE 2-5
Compound No. 135
166
Compound No. 136
167
Compound No. 137
168
Compound No. 138
169
Compound No. 139
170
Compound No. 140
171
Compound No. 141
172
Compound No. 142
173
Compound No. 143
174
Compound No. 144
175
Compound No. 145
176
Compound No. 146
177

[0128]

TABLE 2-6
Compound No. 147
178
Compound No. 148
179
Compound No. 149
180
Compound No. 150
181
Compound No. 151
182
Compound No. 152
183
Compound No. 153
184
Compound No. 154
185
Compound No. 155
186
Compound No. 156
187
Compound No. 157
188
Compound No. 158
189

[0129]

TABLE 2-7
Compound No. 159
190
Compound No. 160
191
Compound No. 161
192
Compound No. 162
193
Compound No. 163
194
Compound No. 164
195
Compound No. 165
196
Compound No. 166
197
Compound No. 167
198
Compound No. 168
199
Compound No. 169
200
Compound No. 170
201

[0130]

TABLE 2-8
Compound No. 171
202
Compound No. 172
203
Compound No. 173
204
Compound No. 174
205
Compound No. 175
206
Compound No. 176
207
Compound No. 177
208
Compound No. 178
209
Compound No. 179
210
Compound No. 180
211
Compound No. 181
212
Compound No. 182
213

[0131]

TABLE 2-9
Compound No. 183
214
Compound No. 184
215
Compound No. 185
216
Compound No. 186
217
Compound No. 187
218
Compound No. 188
219
Compound No. 189
220
Compound No. 190
221
Compound No. 191
222
Compound No. 192
223
Compound No. 193
224
Compound No. 194
225

[0132]

TABLE 2-10
Compound No. 195
226
Compound No. 196
227
Compound No. 197
228
Compound No. 198
229
Compound No. 199
230
Compound No. 200
231
Compound No. 201
232
Compound No. 202
233
Compound No. 203
234
Compound No. 204
235
Compound No. 205
236
Compound No. 206
237

[0133]

TABLE 2-11
Compound No. 207
238
Compound No. 208
239
Compound No. 209
240
Compound No. 210
241
Compound No. 211
242
Compound No. 212
243
Compound No. 213
244
Compound No. 214
245
Compound No. 215
246
Compound No. 216
247
Compound No. 217
248
Compound No. 218
249

[0134]

TABLE 2-12
Compound No. 219
250
Compound No. 220
251
Compound No. 221
252
Compound No. 222
253
Compound No. 223
254
Compound No. 224
255
Compound No. 225
256
Compound No. 226
257
Compound No. 227
258
Compound No. 228
259
Compound No. 229
260
Compound No. 230
261

[0135]

TABLE 2-13
Compound No. 231
262
Compound No. 232
263
Compound No. 233
264
Compound No. 234
265
Compound No. 235
266
Compound No. 236
267
Compound No. 237
268
Compound No. 238
269
Compound No. 239
270
Compound No. 240
271
Compound No. 241
272
Compound No. 242
273

[0136]

TABLE 2-14
Compound No. 243
274
Compound No. 244
275
Compound No. 245
276
Compound No. 246
277
Compound No. 247
278
Compound No. 248
279
Compound No. 249
280
Compound No. 250
281
Compound No. 251
282
Compound No. 252
283
Compound No. 253
284
Compound No. 254
285

[0137]

TABLE 2-15
Compound No. 255
286
Compound No. 256
287
Compound No. 257
288
Compound No. 258
289
Compound No. 259
290
Compound No. 260
291
Compound No. 261
292
Compound No. 262
293
Compound No. 263
294
Compound No. 264
295
Compound No. 265
296
Compound No. 266
297

[0138]

TABLE 2-16
Compound No. 267
298
Compound No. 268
299
Compound No. 269
300
Compound No. 270
301
Compound No. 271
302
Compound No. 272
303
Compound No. 273
304
Compound No. 274
305
Compound No. 275
306
Compound No. 276
307
Compound No. 277
308
Compound No. 278
309

[0139]

TABLE 2-17
Compound No. 279
310
Compound No. 280
311
Compound No. 281
312
Compound No. 282
313
Compound No. 283
314
Compound No. 284
315
Compound No. 285
316
Compound No. 286
317
Compound No. 287
318
Compound No. 288
319
Compound No. 289
320

[0140]

TABLE 2-18
Compound No. 291
321
Compound No. 292
322
Compound No. 293
323
Compound No. 294
324
Compound No. 295
325
Compound No. 296
326
Compound No. 297
327
Compound No. 298
328
Compound No. 299
329
Compound No. 300
330
Compound No. 301
331
Compound No. 302
332

[0141]

TABLE 2-19
Compound No. 303
333
Compound No. 304
334
Compound No. 305
335
Compound No. 306
336
Compound No. 307
337
Compound No. 308
338
Compound No. 309
339
Compound No. 310
340
Compound No. 311
341
Compound No. 312
342
Compound No. 313
343
Compound No. 314
344

[0142]

TABLE 2-20
Compound No. 315
345
Compound No. 316
346
Compound No. 317
347
Compound No. 318
348
Compound No. 319
349
Compound No. 320
350
Compound No. 321
351
Compound No. 322
352
Compound No. 323
353
Compound No. 324
354
Compound No. 325
355
Compound No. 326
356

[0143]

TABLE 2-21
Compound No. 327
357
Compound No. 328
358
Compound No. 329
359
Compound No. 330
360
Compound No. 331
361
Compound No. 332
362
Compound No. 333
363
Compound No. 334
364
Compound No. 335
365
Compound No. 338
366
Compound No. 337
367
Compound No. 338
368

[0144]

TABLE 2-22
Compound No. 339
369
Compound No. 340
370
Compound No. 341
371
Compound No. 342
372
Compound No. 343
373
Compound No. 344
374
Compound No. 345
375
Compound No. 346
376
Compound No. 347
377
Compound No. 348
378
Compound No. 349
379
Compound No. 350
380

[0145]

TABLE 2-23
Compound No. 351
381
Compound No. 352
382
Compound No. 353
383
Compound No. 354
384
Compound No. 355
385
Compound No. 356
386
Compound No. 357
387
Compound No. 358
388
Compound No. 359
389
Compound No. 360
390
Compound No. 361
391
Compound No. 362
392

[0146]

TABLE 2-24
Compound No. 363
393
Compound No. 364
394
Compound No. 365
395
Compound No. 366
396
Compound No. 367
397
Compound No. 368
398
Compound No. 369
399
Compound No. 370
400
Compound No. 371
401
Compound No. 372
402
Compound No. 373
403
Compound No. 374
404

[0147]

TABLE 2-25
Compound No. 375
405
Compound No. 376
406
Compound No. 377
407
Compound No. 378
408
Compound No. 379
409
Compound No. 380
410
Gompound No. 381
411
Compound No. 382
412
Compound No. 383
413
Compound No. 384
414
Compound No. 385
415
Compound No. 386
416

[0148]

Compound No. 387
417
Compound No. 388
418
Compound No. 389
419
Compound No. 390
420
Compound No. 391
421
Compound No. 392
422
Compound No. 393
423
Compound No. 394
424
Compound No. 395
425
Compound No. 396
426
Compound No. 397
427
Compound No. 398
428

[0149]

TABLE 2-27
Compound No. 399
429
Compound No. 400
430
Compound No. 401
431
Compound No. 402
432
Compound No. 403
433
Compound No. 404
434
Compound No. 405
435
Compound No. 406
436
Compound No. 407
437
Compound No. 408
438
Compound No. 409
439
Compound No. 410
440

[0150]

Compound No. 411
441
Compound No. 412
442
Compound No. 413
443
Compound No. 414
444
Compound No. 415
445
Compound No. 416
446
Compound No. 417
447
Compound No. 418
448
Compound No. 419
449
Compound No. 420
450
Compound No. 421
451
Compound No. 422
452

[0151]

TABLE 2-29
Compound No. 423
453
Compound No. 424
454
Compound No. 425
455
Compound No. 426
456
Compound No. 427
457
Compound No. 428
458
Compound No. 429
459
Compound No. 430
460
Compound No. 431
461
Compound No. 432
462
Compound No. 433
463
Compound No. 434
464

[0152]

TABLE 2-30
Compound No. 435
465
Compound No. 436
466
Compound No. 437
467
Compound No. 438
468
Compound No. 439
469
Compound No. 440
470
Compound No. 441
471
Compound No. 442
472
Compound No. 443
473
Compound No. 444
474
Compound No. 445
475
Compound No. 446
476

[0153]

TABLE 2-31
Compound No. 447
477
Compound No. 448
478
Compound No. 449
479
Compound No. 450
480
Compound No. 451
481
Compound No. 452
482
Compound No. 453
483
Compound No. 454
484
Compound No. 455
485
Compound No. 456
486
Compound No. 457
487
Compound No. 458
488

[0154]

TABLE 2-32
Compound No. 459
489
Compound No. 460
490
Compound No. 461
491
Compound No. 462
492
Compound No. 463
493
Compound No. 464
494
Compound No. 465
495
Compound No. 466
496
Compound No. 467
497
Compound No. 468
498
Compound No. 469
499
Compound No. 470
500

[0155]

TABLE 2-33
Compound No. 471
501
Compound No. 472
502
Compound No. 473
503
Compound No. 474
504
Compound No. 475
505
Compound No. 476
506
Compound No. 477
507
Compound No. 478
508
Compound No. 479
509
Compound No. 480
510
Compound No. 481
511
Compound No. 482
512

[0156]

TABLE 2-34
Compound No. 483
513
Compound No. 484
514
Compound No. 485
515
Compound No. 486
516
Compound No. 487
517
Compound No. 488
518
Compound No. 489
519
Compound No. 490
520
Compound No. 491
521
Compound No. 492
522
Compound No. 493
523
Compound No. 494
524

[0157]

TABLE 2-35
Compound No. 495
525
Compound No. 496
526
Compound No. 497
527
Compound No. 498
528
Compound No. 499
529
Compound No. 500
530
Compound No. 501
531
Compound No. 502
532
Compound No. 503
533
Compound No. 504
534
Compound No. 505
535
Compound No. 506
536

[0158]

TABLE 2-36
Compound No. 507
537
Compound No. 508
538
Compound No. 509
539
Compound No. 510
540
Compound No. 511
541
Compound No. 512
542
Compound No. 513
543
Compound No. 514
544
Compound No. 515
545
Compound No. 516
546
Compound No. 517
547
Compound No. 518
548

[0159]

TABLE 2-37
Compound No. 519
549
Compound No. 520
550
Compound No. 521
551
Compound No. 522
552
Compound No. 523
553
Compound No. 524
554
Compound No. 525
555
Compound No. 526
556
Compound No. 527
557
Compound No. 528
558
Compound No. 529
559
Compound No. 530
560

[0160]

TABLE 2-38
Compound No. 531
561
Compound No. 532
562
Compound No. 533
563
Compound No. 534
564
Compound No. 535
565
Compound No. 536
566
Compound No. 537
567
Compound No. 538
568
Compound No. 539
569
Compound No. 540
570
Compound No. 541
571
Compound No. 542
572

[0161]

TABLE 2-39
Compound No. 543
573
Compound No. 544
574
Compound No. 545
575
Compound No. 546
576
Compound No. 547
577
Compound No. 548
578
Compound No. 549
579
Compound No. 550
580
Compound No. 551
581
Compound No. 552
582
Compound No. 553
583
Compound No. 554
584

[0162]

TABLE 2-40
Compound No. 555
585
Compound No. 556
586
Compound No. 557
587
Compound No. 558
588
Compound No. 559
589
Compound No. 560
590
Compound No. 561
591
Compound No. 562
592
Compound No. 563
593
Compound No. 564
594
Compound No. 565
595
Compound No. 566
596

[0163]

TABLE 2-41
Compound No. 567
597
Compound No. 568
598
Compound No. 569
599
Compound No. 570
600
Compound No. 571
601
Compound No. 572
602
Compound No. 573
603
Compound No. 574
604
Compound No. 575
605
Compound No. 576
606
Compound No. 577
607
Compound No. 578
608

[0164]

TABLE 2-42
Compound No. 579
609
Compound No. 580
610
Compound No. 581
611
Compound No. 582
612
Compound No. 583
613
Compound No. 584
614
Compound No. 585
615
Compound No. 586
616
Compound No. 587
617
Compound No. 588
618
Compound No. 589
619
Compound No. 590
620

[0165]

TABLE 2-43
Compound No. 591
621
Compound No. 592
622
Compound No. 593
623
Compound No. 594
624
Compound No. 595
625
Compound No. 596
626
Compound No. 597
627
Compound No. 598
628
Compound No. 599
629
Compound No. 600
630
Compound No. 601
631
Compound No. 602
632

[0166]

TABLE 2-44
Compound No. 603
633
Compound No. 604
634
Compound No. 605
635
Compound No. 606
636
Compound No. 607
637
Compound No. 608
638
Compound No. 609
639
Compound No. 610
640
Compound No. 611
641
Compound No. 612
642
Compound No. 613
643

[0167] 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

[0168] (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.

[0169] (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).

[0170] 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
644
Compound No. 021
645
Compound No. 026
646
Compound No. 027
647
Compound No. 030
648
Compound No. 076
649
Compound No. 078
650

[0171] 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

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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.).

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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).

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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) 651

[0190] 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;

[0191] (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;

[0192] 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;

[0193] 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;

[0194] R5 stands for a hydrogen atom, a halogen atom, a (C1-C10)alkyl group or a (C1-C10)alkoxy group;

[0195] but with such provisos that, in the general formula (I),

[0196] (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;

[0197] (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;

[0198] (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;

[0199] (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;

[0200] (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

[0201] (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) 652

[0202] 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)

[0203] 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′)

[0204] 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) 653

[0205] 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.

[0206] 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           654
A02           655
A03           656
A04           657
A05           658
A06           659
A07           660
A08           661
A09           662

[0207] 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           663
B02           664
B03           665
B04           666
B05           667
B06           668
B07           669
B08           670
B09           671
B10           672
B11           673
B12           674
B13           675
B14           676
B15           677
B16           678

[0208] 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  679
C02  680
C03  681
C04  682
C05  683
C06  684
C07  685
C08  686
C09  687
C10  688
C11  689
C12  690
C13  691
C14  692
C15  693
C16  694
C17  695
C18  696
C19  697
C20  698

[0209]

TABLE 7b
Compound
Code Chemical Structure
C21  699
C22  700
C23  701
C24  702
C25  703
C26  704
C27  705
C28  706
C29  707
C30  708
C31  709
C32  710
C33  711
C34  712
C35  713

[0210] 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).

[0211] Therefore, according to the fifth aspect of this invention, when 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 714

[0212] 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) 715

[0213] or 3-(2-hydroxyethyl)indole of the formula (β-2) 716

[0214] is selected as the indole compound of the formula (IV) to be used.

[0215] In the process according to the fifth aspect of this invention, the reaction as effected is shown by the following reaction equation (D).

[0216] Reaction Equation (D): 717

[0217] In the reaction equation above, R1 to R5 have the same meanings as defined in the general formula (I).

[0218] 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.

[0219] 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′)

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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) 718

[0229] which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 719

[0230] and formaldehyde of the formula (γ-1)

HCHO  (γ-1)

[0231] and 3-(2-acetaminoethyl)indole of the formula (β-1) 720

[0232] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0233] 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) 721

[0234] which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 722

[0235] and 4-hydroxybenzaldehyde of the formula (γ-2) 723

[0236] and 3-(2-acetaminoethyl)indole of the formula (β-1) 724

[0237] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0238] 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) 725

[0239] which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 726

[0240] and formaldehyde of the formula (γ-1)

HCHO  (γ-1)

[0241] and 3-(2-hydroxyethyl)indole of the formula (β-2) 727

[0242] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0243] 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) 728

[0244] which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 729

[0245] and 4-hydroxybenzaldehyde of the formula (γ-2) 730

[0246] and 3-(2-hydroxyethyl)indole or the Formula (β-2) 731

[0247] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0248] According to a tenth aspect of this invention, there is provided a process for the preparation SF2809-V substance represented by the formula (E) 732

[0249] which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 733

[0250] and benzaldehyde of the formula (γ-3) 734

[0251] and 3-(2-acetaminoethyl)indole of the formula (β-1) 735

[0252] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0253] 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) 736

[0254] which comprises a single step reaction of three components consisting of 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 737

[0255] and benzaldehyde of the formula (γ-3) 738

[0256] and 3-(2-acetaminoethyl)indole of the formula (β-1) 739

[0257] in an organic solvent or an aqueous solvent in the presence of a substance capable of acting as an acid.

[0258] 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

[0259] 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

[0260] Preparation of 7-hydroxy-4-methyl-4H-thiazolo[5,4-b]-pyridin-5-one of the Formula (IIa) 740

[0261] (corresponding to the compound shown in the Table 5 as Compound Code A09)

[0262] 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.

[0263] 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.

[0264] 1 H-NMR (DMSO-d6) δ: 3.50 (3H, s), 5.74 (1H, s), 8.85 (1H, s), 11.44 (1H, s)

[0265] Mass spectrum (TSP): m/z 183 (M++1)

[0266] The reaction step effected by the above process may be expressed by the following reaction equation. 741

[0267] In the above equation, —But stands for tertiary butyl group.

EXAMPLE 1

[0268] Preparation of the Compound of the Following Formula (I-003) 742

[0269] (corresponding to the compound given in Table 1-1 as Compound No.003)

[0270] To to acetic acid (3 ml) were added 4-hydroxy-1-methyl-2-quinolinone of the formula (α) 743

[0271] [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) 744

[0272] [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) 745

[0273] [the compound given in Table 7b as Compound Code C22 and belonging to compound of the general formula (IV)] (80 mg; 200 μmol).

[0274] 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 (1-003) (86 mg; yield 63%).

EXAMPLES 2 TO 81

[0275] 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.

[0276] 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).

[0277] 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

[0278]

	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

[0279]

	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

[0280]

	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

[0281]

	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

[0282]

	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

[0283]

	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

[0284] 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%.

[0285] 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

[0286] This Example illustrates an example of the production of SF2809-I substance of the following formula (A) 746

[0287] by the process according to the sixth aspect of this invention.

[0288] To acetic acid (10 ml) were added 4-hydroxy-1-methyl-2-quinolinone of the following formula (α) 747

[0289] (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)

[0290] (the compound of Compound Code B13 given in Table 6)(75 mg; 30 mmol) and 3-(2-acetaminoethyl)indole of the formula (β-1) 748

[0291] [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.

[0292] 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

[0293] This Example illustrates an example of the production of SF2809-V substance of the following formula (E) 749

[0294] by the process according to the tenth aspect of this invention.

[0295] 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) 750

[0296] (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).

[0297] 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

[0298] 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 general formula (I)

2. An indole derivative or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, wherein the compound of the general formula (I) according to claim 1 is a compound having the following general formula (Ia)

3. An indole derivative or a pharmaceutically acceptable salt or a solvate thereof as claimed in claim 1, wherein the compound of the general formula (I) shown in claim 1 is a compound having the following general formula (Ib)

4. A compound as claimed in claim 1, wherein the compound of the general formula (I) shown in claim 1 is one of totally 81 compounds, which have such compound numbers of Compound No.003 through Compound No.083 and have such structural formulae as given in the following Tables:—

5. A pharmaceutical composition comprising as an active ingredient at least one of the indole derivative of the general formula (I) as claimed in claim 1, or the indole derivative of the general formula (Ia) as claimed in claim 2 or the indole derivative of the general formula (Ib) as claimed in claim 3, or at least one of the indole derivative as claimed and shown in the Tables given in claim 4, 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, which is to be used for 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 chymase inhibitor, characterized in that the inhibitor comprises as an active ingredient at least one of the indole derivative of the general formula (I) as claimed in claim 1, or the indole derivatives of the general formula (Ia) as claimed in claim 2, or the indole derivative of the general formula (Ib) as claimed in claim 3, or at least one of the indole derivative as claimed and shown in Tables given in claim 4, or a pharmaceutically acceptable salt or a solvate thereof.

8. A medicament to be used for a therapeutic or prophylactic treatment of a disease 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) as claimed in claim 1, or the indole derivative of the general formula (Ia) as claimed in claim 2, or the indole derivative of the general formula (Ib) as claimed in claim 3, or at least one or of the indole derivative as claimed and shown in Tables given in claim 4, or a pharmaceutically acceptable salt or a solvate thereof.

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

10. A process as claimed in claim 9, wherein the compound of the general formula (II) given in claim 9 is one selected from the compounds which have respectively the chemical structures and the compound codes respectively shown in the following Table:

11. A process as claimed in claim 9, wherein the aldehyde compound of the general formula (III) given in claim 9 is a compound selected from the aldehydes which have the chemical structures and the compound codes respectively shown in the following Table:

12. A process as claimed in claim 9, wherein the indole compound of the general formula (IV) given in claim 9 is a compound selected from the indoles which have the chemical structures and the compound codes respectively shown in the following two Tables:

13. A process as claimed in claim 9, wherein the indole compound of the general formula (IV) used is neither 3-(2-acetaminoethyl)indole of the formula (β-1)

14. A process for the preparation of SF2809-I substance represented by the formula (A)

15. A process for the preparation of SF2809-II substance represented by the formula (B)

16. A process for the preparation of SF2809-III substance represented by the formula (C)

17. A process for the preparation of SF2809-IV substance represented by the formula (D)

18. A process for the preparation of SF2809-V substance represented by the formula (E)

19. A process for the preparation of SF2809-VI substance represented by the formula (F)