JPH0710839A - Indoloylguanidine derivative - Google Patents

Abstract

PURPOSE:To obtain a new indoloylguanidine derivative useful as a therapeutic and preventive agent for hypertension, myocardial ischemia, reperfusion disorder, etc., owing to its inhibiting action on a sodium/proton exchange transport system. CONSTITUTION:This compound is expressed by the formula I [R1 is H, a (substituted)alkyl, alkenyl, alkynyl, cycloalkyl, halogen, NO2, acyl, carboxyl, an aromatic group, OR3, NR6R7, SO2NR6R7, etc.; R2 is H, a (substituted)alkyl, cycloalkyl, OH, alkoxy or CH2R20; R3 is H, a (substituted)alkyl, acyl, CH2R60, etc.; R6 and R7 is H, a (substituted)alkyl, acyl, CH2R60 or R6 and R7 together bind to form 5-7 membered cyclic amino; R20, R30 and R60 are alkenyl or alkynyl]or its acid adduct salt permissible as medicines, e.g. 1-methyl-2- indoloylguanidine. The compound can be obtained by subjecting a reactive derivative of an indolocarboxylic acid of the formula II (X is an eliminable group easily substitutable with a nucleophilic reagent) to react with guanidine in an inactive solvent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel indoloylguanidine derivative. The compound of the present invention has a sodium / proton (Na ⁺ / H ⁺ ) exchange transport system inhibitory action, and is a disease caused by enhancement of the sodium / proton (Na ⁺ / H ⁺ ) exchange transport system, for example, hypertension, arrhythmia, narrowing Cardiac disorders, cardiac hypertrophy, organ damage due to ischemia reperfusion (eg myocardial ischemia reperfusion injury, surgical procedures (eg organ transplantation and PTCA (Percu
taneous Transluminal Coronary Angioplasty)), cerebral ischemic disorder (eg, cerebral infarction, sequel after stroke, cerebral edema, etc.), hyperproliferation of cells (eg, fibroblast proliferation, smooth muscle) Diseases caused by cell proliferation, mesangial cell proliferation, etc. (eg, atherosclerosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, renal glomerulosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications, post-PTCA) Restenosis, etc.), etc., and is useful as a preventive drug.

[0002]

2. Description of the Related Art Certain polycyclic aroylguanidine derivatives, for example, naphthalene, 9,10-dihydroanthracene, benzofuran, 2,3-dihydrobenzofuran, benzothiophene, benzothiazole, methylenedioxybenzene as a polycycle, Pyridothiophene, pyrimidothiophene, quinoline, 1,6-naphthyridine, 1,8-
Naphthyridine, 3,4-dihydrobenzopyran, 3,4
-Dihydroquinazolin-4-one, 1,2,3,4-tetrahydroquinazolin-2-one, quinoxaline, 5,
6,7,8-tetrahydroquinoxaline, benzazepine, benzotriazepine, benzimidazolothiazine,
Polycyclic aroylguanidine derivatives having a benzopyranopyran or benzocarbazole ring are known, and as an aroylguanidine derivative having an indole ring, 1
-Guanidinocarbonyltryptophan (registered in Chemical Abstracts, but has no mention of literature name.
Registration number: 18322-34-4) is known.

On the other hand, certain monocyclic aroylguanidine derivatives such as pyrazinoylguanidine derivatives represented by amiloride are sodium / proton (Na ⁺ /
It is known to have an inhibitory action on the H ⁺ ) exchange transport system and an antiarrhythmic action (for example, J. Membrane Biol., V
ol. 105, 1 (1988); Circulation, Vol. 79, 1257 (19
89)). Further, it was recently reported that a benzoylguanidine derivative has a sodium / proton (Na ⁺ / H ⁺ ) exchange transport system inhibitory action and an antiarrhythmic action (for example, J. Mol. Cell. Cardiol. ., Vol.24, Sup
pl.I, S.92 (1992); J. Mol. Cell. Cardiol., Vol.24,
Suppl.I, S.117 (1992); JP-A-3-106858; JP-A-5-339228).

[0004]

DISCLOSURE OF THE INVENTION The present invention has a sodium / proton (Na ⁺ / H ⁺ ) exchange transport system inhibitory action and is caused by enhancement of the sodium / proton (Na ⁺ / H ⁺ ) exchange transport system. Diseases such as hypertension, arrhythmia, angina, cardiac hypertrophy, ischemia-reperfusion-induced organ damage (eg myocardial ischemia-reperfusion injury, surgical treatment (eg organ transplantation and PTCA).
(Percutaneous Transluminal Coronary Angioplasty))
), Cerebral ischemic dysfunction (eg cerebral infarction related dysfunction, encephalopathy after stroke, cerebral edema, etc.), cell hyperproliferation (eg fibroblast proliferation, smooth muscle cell proliferation, mesangial cell proliferation) Etc.) (eg, atherosclerosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, renal glomerulosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications, restenosis after PTCA, etc.), etc. An object of the present invention is to provide a novel indoloylguanidine derivative which is useful as a therapeutic or preventive agent for.

[0005]

The present invention provides the following general formula (1):

[Chemical 3] (In the formula, R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group,
Halogen atom, nitro group, acyl group, carboxyl group,
Alkoxycarbonyl group, aromatic group, or formula-O
_{R 3, -NR 6 R 7,} -SO 2 NR 6 R 7 or -S
(O) _n represents a group represented by R _40, which may be substituted one by one or the same or different, and R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group,
It represents a hydroxyl group, an alkoxy group, or a group represented by the formula —CH ₂ R ₂₀ . R ₃ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, or a group of formula —CH ₂ R ₃₀ (R ₃₀
Represents an alkenyl group or an alkynyl group), and R ₆ and R ₇ are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group,
An acyl group or a group represented by the formula —CH ₂ R ₆₀ (R ₆₀ represents an alkenyl group or an alkynyl group), or R ₆ and R ₇ are bonded to each other to form another hetero atom in the ring. It represents a saturated 5- to 7-membered cyclic amino group which may be contained, R ₄₀ represents an alkyl group or a substituted alkyl group, n represents 0, 1 or 2, and R ₂₀ represents an alkenyl group or an alkynyl group. However, in the above general formula, the R ₁ group and the guanidinocarbonyl group may be substituted on either the 6-membered ring portion or the 5-membered ring portion of the indole ring. And an pharmaceutically acceptable acid addition salt thereof.

Various groups in the present invention will be described below. As the alkyl group, for example, linear or branched carbon such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, octyl and the like. Examples thereof include alkyl groups having 8 or less atoms.

Examples of the alkenyl group include alkenyl groups having 6 or less carbon atoms such as vinyl, allyl, isopropenyl, 1-propenyl, butenyl, pentenyl and hexenyl.

Examples of the alkynyl group include ethynyl,
Examples thereof include alkynyl groups having 2 to 6 carbon atoms such as propargyl, butynyl and pentynyl.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Examples of the halogen atom include fluorine, chlorine and bromine atoms.

Examples of the acyl group include linear or branched alkanoyl groups having 8 or less carbon atoms such as acetyl, propanoyl and 2-methylpropanoyl, and 10 carbon atoms such as phenylacetyl and phenylpropanoyl. The following arylalkanoyl groups include, for example, benzoyl, 1-naphthoyl, 2-naphthoyl, and other aroyl groups having 11 or less carbon atoms.

Examples of the alkoxycarbonyl group include linear or branched alkoxycarbonyl groups having 6 or less carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and 2-propoxycarbonyl.

The aromatic group includes an aryl group which may have a substituent and a heteroaryl group which may have a substituent. Examples of the aryl group include phenyl and
Aryl groups having 10 or less carbon atoms such as naphthyl,
Examples of the heteroaryl group include 2-, 3-, 4-pyridyl, 2-, 3-furyl, 2-, 3-thienyl, 1
A 5- to 6-membered heteroaryl group containing 1 to 4 nitrogen atoms such as-, 3-, 4-oxazolyl, 3-, 4-, 5-isoxazolyl and 1 to 2 nitrogen atoms and 1 oxygen atom.
A 5- or 6-membered heteroaryl group containing one or one sulfur atom.

Substituents in the substituted aryl group and the substituted heteroaryl group include a hydroxyl group, an alkoxy group, a halogen atom, a nitro group, and a group represented by the formula —NR ₆ R ₇ .

As the alkoxy group, for example, methoxy,
Examples thereof include linear or branched alkoxy groups having 6 or less carbon atoms such as ethoxy, isopropoxy and tert-butoxy.

The saturated 5- to 7-membered cyclic amino group which may have other heteroatoms in the ring and which is formed by R ₆ and R ₇ being bonded to each other is, for example, 1 to 1 nitrogen atom.
5- to 7-membered ring groups containing 3 or 5- to 7-membered ring groups containing 1 nitrogen atom and 1 oxygen atom, and more specifically 1-pyrrolidinyl, piperidino, 1-piperazinyl,
Examples thereof include morpholino and 4-methylmorpholino.

Substituents in the substituted alkyl group include a cycloalkyl group, a halogen atom, a hydroxyl group, an alkoxy group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an acyl group, an aromatic group, and a formula --CONR ₄ R ₅ or --NR. ₆ R ₇ is included, R ₄ and R ₅ independently of each other represent a hydrogen atom or an alkyl group, or
Alternatively, R ₄ and R ₅ are bonded to each other to represent a saturated 5- to 7-membered cyclic amino group which may contain other heteroatoms in the ring. In particular, when R ₁ , R ₂ and R ₃ are substituted alkyl groups, examples of the substituent include a cycloalkyl group, a halogen atom, a hydroxyl group, an alkoxy group, a carboxyl group,
Examples thereof include an alkoxycarbonyl group, an acyl group, an aromatic group, and a group represented by the formula —CONR ₄ R ₅ or —NR ₆ R ₇ , and examples of the substituent when R ₆ and R ₇ are substituted alkyl groups , Cycloalkyl group, hydroxyl group, alkoxy group, carboxyl group, alkoxycarbonyl group,
Examples thereof include an acyl group, an aryl group, and a group represented by the formula —CONR ₄ R ₅ or —NR ₄ R ₅ . Moreover, as the alkyl part of the substituted alkyl group, the same examples as the above-mentioned alkyl group can be given.

Examples of such a substituted alkyl group include an alkyl group having 1 to 5 carbon atoms substituted with a cycloalkyl having 3 to 6 carbon atoms, a polyhaloalkyl group having 1 to 5 carbon atoms, and a carbon atom number. A hydroxyalkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 6 carbon atoms, a cyanoalkyl group having 2 to 6 carbon atoms, a carboxyalkyl group having 2 to 6 carbon atoms, an alkoxycarbonyl having 3 to 8 carbon atoms An alkyl group, an alkanoylalkyl group having 3 to 8 carbon atoms, an aroylalkyl group having 16 or less carbon atoms, an optionally substituted phenyl or naphthyl-C ₁ -C ₅ alkyl group, a nitrogen atom being one one or two C ₁ -C ₃ alkyl substituted carbamoyl -C ₁ optionally -C ₃ alkyl group, one nitrogen atom or two C ₁ -C ₃ Al Le or C ₇ -C ₁₁ aralkyl substituted by amino -C ₁ optionally -C ₅ alkyl group, a saturated 5- to 7-membered cyclic amino -C ₁ -C ₃ alkyl group, and the like.

A typical example of the substituted alkyl group is R ₁
In, trifluoromethyl, trifluoroethyl,
A polyhaloalkyl group having 1 to 3 carbon atoms such as trichloromethyl, hydroxymethyl, hydroxyethyl, 1-
Examples thereof include a hydroxyalkyl group having 1 to 6 carbon atoms such as hydroxyethyl, and an aminoalkyl group having 1 to 5 carbon atoms such as aminomethyl, aminoethyl, 1-aminoethyl, etc., and R ₂ is hydroxyethyl or hydroxy. Propyl, hydroxybutyl, 2-hydroxypropyl, 3,4-dihydroxybutyl etc. have 1 carbon atom
~ 6 hydroxyalkyl group, C1-6 alkoxyalkyl group such as methoxyethyl, ethoxyethyl, methoxypropyl, etc., C2-6 carboxyalkyl group such as carboxyethyl, carboxypropyl, methoxycarbonylmethyl, 3 to 3 carbon atoms such as ethoxycarbonylmethyl and methoxycarbonylethyl
7 alkoxycarbonylalkyl group, benzyl, phenylethyl, phenylpropyl, phenylbutyl, 1-
Alternatively, phenyl or naphthyl-C ₁ -C ₅ alkyl group such as 2-naphthylmethyl (C ₁ -C ₃ alkyl group in phenyl or naphthyl moiety, halogen atom, nitro group, amino group, hydroxyl group, C ₁ -C ₃ alkoxy) Carbamoylmethyl, carbamoylmethyl, carbamoylethyl, dimethylcarbamoylmethyl, etc., in which the nitrogen atom may be substituted with one or two C ₁ -C ₃ alkyl. ₁ -C ₃ alkyl group, aminoethyl, aminopropyl, dimethylaminoethyl, such as diethylaminoethyl, an amino -C be nitrogen atoms optionally substituted by one or two C ₁ -C ₃ alkyl ₁ -C ₅ Examples include alkyl groups,
R ₃ and R ₄₀ have 1 carbon atom such as hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, hydroxybutyl and 2,3-dihydroxypropyl.
~ 6 hydroxyalkyl group, carboxyalkyl group having 2 to 6 carbon atoms such as carboxymethyl, carboxyethyl, phenyl-C ₁ -C ₅ alkyl group such as benzyl, phenylethyl, phenylpropyl, carbamoylmethyl, carbamoylethyl, etc. Carbamoyl-C ₁
To C ₃ alkyl groups, aminoethyl, aminopropyl, dimethylaminoethyl, dimethylaminopropyl, benzylmethylaminoethyl, etc., with one or two nitrogen atoms substituted by C _{1 to} C ₃ alkyl or C _{7 to} C ₁₁ aralkyl. And optionally saturated 5- to 7-membered cyclic amino-C ₁ -C ₃ alkyl group such as amino-C ₁ -C ₅ alkyl group, 1-pyrrolidinylethyl, piperidinoethyl, etc., and R ₆ and R ₇ In, there may be mentioned phenyl-C ₁ -C ₅ alkyl groups such as phenylethyl.

The saturated 5- to 7-membered cyclic amino group which may have other heteroatoms in the ring and which is formed by R ₄ and R ₅ being bonded to each other is the above-mentioned R ₆ and R ₇
The same examples as in the case of the cyclic amino group formed by can be mentioned.

Examples of the group represented by the formula -S (0) _n R ₄₀ include a methylsulfonyl group, an ethylsulfonyl group,
Examples thereof include an alkylsulfonyl group having 8 or less carbon atoms such as a propylsulfonyl group and an isopropylsulfonyl group, and a corresponding alkylsulfinyl group and an alkylthio group.

The compound of the present invention represented by the general formula (1) can be produced, for example, by the following method. (A) The compound (1) of the present invention can be obtained by reacting a reactive derivative of indolecarboxylic acid represented by the general formula (3) with guanidine in an inert solvent.

[Chemical 4] (In the formula, X represents a leaving group which can be easily displaced by a nucleophile, and R ₁ and R ₂ have the same meaning as described above.)

In this reaction, when the indolecarboxylic acid derivative (3) has a group active in the reaction such as a hydroxyl group or an amino group, these groups are protected in advance by a protecting group, and this reaction is carried out. The target indoloylguanidine derivative (1) can be produced by removing the protecting group after carrying out.

Examples of the reactive derivative of carboxylic acid include acid halides, acid anhydrides (including mixed acid anhydrides) and ester derivatives. Specific examples of the acid halides include acid chlorides or acid bromides. As the mixed acid anhydride, ethyloxycarbonyl chloride, an alkyloxy chloride type such as isobutyloxycarbonyl chloride, and a mixed acid anhydride with an α-polyalkyl-substituted carboxylic acid chloride type compound such as diethylacetyl chloride and trimethylacetyl chloride, As the ester derivative, p-
Mention may be made of active esters such as nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and common esters such as methyl ester and ethyl ester. Such a reactive derivative of a carboxylic acid is prepared according to a general method which is usually carried out.
It can be easily obtained from the corresponding carboxylic acid.

When reacting with an acid halide or acid anhydride (including mixed acid anhydride), it can be carried out in the presence of a base or an excess of guanidine in a solvent under cooling to room temperature. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like, and organic bases such as triethylamine and pyridine are used as the base, and aromatic hydrocarbons such as benzene, toluene and xylene are used as the solvent. solvent,
Tetrahydrofuran, ether solvent such as 1,4-dioxane, halogenated hydrocarbon solvent such as dichloromethane, chloroform, 1,2-dichloroethane, amide solvent such as dimethylformamide and dimethylacetamide, basic solvent such as pyridine, or These mixed solvents are mentioned.

The reaction with the ester derivative is carried out in the presence of equimolar or excess guanidine in a solvent while cooling or heating. In the case of an active ester, for example, tetrahydrofuran, 1,2-dimethoxyethane, an ether solvent such as dioxane, an ester solvent such as ethyl acetate, dimethylformamide or a mixed solvent thereof, in the case of another ester, For example,
It is preferable to carry out the reaction in an alcohol solvent such as methanol, ethanol or isopropanol, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane, dimethylformamide or a mixed solvent thereof. In some cases, it is also possible to heat at around 130 ° C. for a short time after distilling off the solvent.

(B) The compound (1) of the present invention is obtained by reacting the indolecarboxylic acid represented by the general formula (4) with guanidine, preferably in the presence of a condensing agent, in an inert solvent at room temperature or under heating. Can be obtained by

[Chemical 5] (In the formula, R ₁ and R ₂ have the same meanings as described above.) In this reaction, when the indolecarboxylic acid (4) has a reactive group such as a carboxyl group, a hydroxyl group or an amino group, Protects these groups with a protecting group in advance, and after carrying out this reaction, the protecting group is removed to give the desired indoloylguanidine derivative (1).
Can be manufactured.

The reaction is carried out, for example, by dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), benzotriazol-1-yl-tris (dimethylamino). ) Phosphonium hexafluorophosphide salt (BOP), diphenylphosphonyl azide (DPPA), N, N-carbonyldiimidazole (Angew.Chem.Int.Ed.Engl., Vol. 1, 35
1 (1962)) in the presence of a condensing agent, such as N-hydroxysuccinimide (HONSu),
1-hydroxybenzotriazole (HOBt), 3-
Hydroxy-4-oxo-3,4-dihydro-1,2,
Addition of additives such as 3-benzotriazine (HOObt), for example, aromatic hydrocarbon solvents such as benzene, toluene, xylene, tetrahydrofuran, 1,4-
In an ether solvent such as dioxane, a halogenated hydrocarbon solvent such as dichloromethane, chloroform and 1,2-dichloroethane, an amide solvent such as dimethylformamide and dimethylacetamide, a basic solvent such as pyridine, or a mixed solvent thereof. It is preferable to carry out.

(C) The compound (1a) of the present invention can be obtained by debenzylating the benzyloxyindoloylguanidine derivative represented by the general formula (5).

[Chemical 6] (In the formula, R ₂ has the same meaning as described above.) The debenzylation reaction is a catalytic reduction reaction using a palladium / carbon catalyst (J. Chem. Soc., 1953, 4058) or hydrochloric acid / acetic acid (J Amer. Chem. Soc., Vol.73, 5765 (1951)).
It can be carried out according to the method described in the literature such as decomposition reaction under acidic conditions such as.

(D) The compound (1b) of the present invention can be obtained by reducing the nitroindoloylguanidine derivative represented by the general formula (6).

[Chemical 7] (In the formula, R ₂ has the same meaning as described above.) As reducing conditions, zinc, iron, tin or tin chloride (I
I) etc. under acidic conditions (Ann., 641, 81 (19
61), J. Amer. Chem. Soc., Vol.66, 1781 (1944), etc.), sodium dithionite (Na ₂ S ₂ O ₄ ) (J. Amer.
Chem. Soc., Vol.72, 1361 (1950), etc., reduction with sulfide, palladium / carbon (Synth. Commun., 1,
47 (1971)), Raney Nickel (Org. Synth., IV, 226 (19
The catalytic reduction reaction using a catalyst such as 63)) can be applied.

As the protective group for protecting the hydroxyl group, amino group, carboxyl group and the like active in the reaction of the above-mentioned production method (a) or (b), a general protective group used in the field of synthetic organic chemistry may be used. The introduction and removal of such protecting groups can be carried out according to conventional methods (eg Pr
otective Groups in Organic Synthesys, JOHN WILLEY
& SONS, 1991). For example, as a hydroxyl-protecting group,
Examples thereof include a methoxymethyl group and a tetrahydropyranyl group, and examples of the amino group-protecting group include a tert-butyloxycarbonyl group. Such a hydroxyl-protecting group can be removed by reacting in a solvent such as hydrous methanol, hydrous ethanol, or hydrous tetrahydrofuran in the presence of an acid such as hydrochloric acid, sulfuric acid, or acetic acid to protect the amino group. The group can be removed by reacting in a solvent such as hydrous tetrahydrofuran, methylene chloride, chloroform or hydrous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid.

In the case of protecting the carboxyl group, examples of the form of protection include tert-butyl ester, orthoester, acid amide and the like. In the case of tert-butyl ester, removal of such a protecting group is carried out, for example, by reacting in a water-containing solvent in the presence of hydrochloric acid,
In the case of orthoester, for example, it is carried out by treating with an acid in a solvent such as water-containing methanol, water-containing tetrahydrofuran, and water-containing 1,2-dimethoxyethane, and subsequently by treating with an alkali such as sodium hydroxide to obtain the acid amide. In the case, for example, in the presence of an acid such as hydrochloric acid or sulfuric acid,
It can be carried out by reacting in a solvent such as water, hydrous methanol, hydrous tetrahydrofuran.

The indolecarboxylic acids used as the raw material compounds in the above-mentioned production methods (a) and (b) are, for example, indole-5-carboxylic acid, 5-chloro-2-indolecarboxylic acid, indole-3-carboxylic acid and indole-carboxylic acid. 2-
Commercially available products such as carboxylic acid, indole-4-carboxylic acid and 5-methoxy-2-indolecarboxylic acid can be obtained or can be synthesized by a known method.

For example, according to Reissert's method (Reissert's indole synthesis method), 4-chloro-2-indolecarboxylic acid (J. Chem. Soc., 1955, 3490), 6-n
-Amyl-2-indolecarboxylic acid (J. Amer. Chem.
Soc., Vol.75, 4921 (1953)), 7-indolecarboxylic acid (J. Amer. Chem. Soc., Vol.77, 5700 (1955)),
5-Cyano-2-indolecarboxylic acid (J. Org. Che
m., Vol. 18, 354 (1953)), 6-cyano-2-indolecarboxylic acid (J. Chem. Soc., 1924, 2285), 6-benzyloxy-2-indolecarboxylic acid (J. Chem. So
c., 1937, 1726) etc. can be synthesized.

According to Fischer's method (Fischer's indole synthesis method), nitro-2-indolecarboxylic acid (J. Amer. Chem. Soc., Vol. 80, 4621 (1958)), 7-
Chloro-2-indolecarboxylic acid (J. Chem. Soc., 19
55, 3499), 4-trifluoromethyl-2-indolecarboxylic acid (J. Amer. Chem. Soc., Vol. 79, 1745 (195
7)) etc. can be synthesized. The 2-indolecarboxylic acids can also be synthesized based on a known method using a benzaldehyde derivative as a raw material (for example, Tetrahedron, Vol. 42, 3259 (1986)).

Furthermore, 4-indolecarboxylic acids, 5
-For indolecarboxylic acids and 6-indolecarboxylic acids, see the literature (J. Chem. Tech. Biotechnol.,
Vol.36, 562 (1986), Tetrahedron Letters, Vol.27, 1
653 (1986)). 1
-Hydroxyindolecarboxylic acids are described in the literature (Chem.
Ber., Vol.56, 1024 (1923)).

General formula (1) produced as described above
Examples of the compound represented by are the following compounds. 1-methyl-2-indoloylguanidine 1-methyl-3-indoloylguanidine 1-methyl-4-indoloylguanidine 1-methyl-5-indoloylguanidine 1-methyl-6-indoloylguanidine

4-chloro-1-methyl-2-indoloylguanidine 5-chloro-1-methyl-2-indoloylguanidine 6-chloro-1-methyl-2-indoloylguanidine 7-chloro-1-methyl- 2-Indoloylguanidine 5-Chloro-2-indoylguanidine 1,4-Dimethyl-2-indoloylguanidine 1,5-Dimethyl-2-indoloylguanidine 1,6-Dimethyl-2-indoloylguanidine 1,7 -Dimethyl-2-indoloylguanidine

4-Methoxy-1-methyl-2-indoloylguanidine 5-methoxy-1-methyl-2-indoloylguanidine 6-methoxy-1-methyl-2-indoloylguanidine 7-methoxy-1-methyl- 2-Indoyl guanidine 1-methyl-4-nitro-2-indoyl guanidine 1-methyl-5-nitro-2-indoyl guanidine 1-methyl-6-nitro-2-indoyl guanidine 1-methyl-7- Nitro-2-indoloylguanidine 4-amino-1-methyl-2-indoloylguanidine 5-amino-1-methyl-2-indoloylguanidine 6-amino-1-methyl-2-indoloylguanidine 7-amino- 1-methyl-2-indoloylguanidine

1-benzyl-2-indoloylguanidine 1-benzyl-3-indoloylguanidine 1-benzyl-5-indoloylguanidine 1-isopropyl-2-indoloylguanidine 1-isopropyl-3-indoloylguanidine 1- Isopropyl-5-indoloylguanidine

2-indoloylguanidine 3-indoloylguanidine 5-indoloylguanidine 4-hydroxy-1-methyl-2-indoloylguanidine 5-hydroxy-1-methyl-2-indoloylguanidine 6-hydroxy-1- Methyl-2-indoloylguanidine 7-hydroxy-1-methyl-2-indoloylguanidine

1- (3-dimethylaminopropyl) -4
-Trifluoromethyl-2-indoloylguanidine 1- (3-diethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine 1- [3- (N-pyrrolidinyl) propyl] -4-trifluoromethyl-2 − Indoylguanidine

6- (3-aminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- (3-dimethylaminopropoxy) -1-methyl-
4-Trifluoromethyl-2-indoloylguanidine 6- (3-diethylaminopropoxy) -1-methyl-
4-Trifluoromethyl-2-indoloylguanidine 6- (2-aminoethoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine 6- (2-dimethylaminoethoxy) -1-methyl-4
-Trifluoromethyl-2-indoloylguanidine 6- (2-diethylaminoethoxy) -1-methyl-4
-Trifluoromethyl-2-indoloylguanidine

1-Methyl-6- [3- (N-pyrrolidinyl) propoxy] -4-trifluoromethyl-2-indoloylguanidine 1-methyl-6- [2- (N-pyrrolidinyl) ethoxy] -4- Trifluoromethyl-2-indoloylguanidine 1- (3-dimethylaminopropyl) -4-methoxy-
2-Indoylguanidine 1- (3-diethylaminopropyl) -4-methoxy-
2-indoloylguanidine 1- (3-aminopropyl) -4-methoxy-2-indoloylguanidine

4-Methoxy-1- [3- (N-pyrrolidinyl) propyl] -2-indoloylguanidine 6- (3-aminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine 6- ( 3-Dimethylaminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine 6- (3-diethylaminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine 6- (2-aminoethoxy) -4-Methoxy-1-methyl-2-indoloylguanidine 6- (2-dimethylaminoethoxy) -4-methoxy-
1-Methyl-2-indoloylguanidine 6- (2-diethylaminoethoxy) -4-methoxy-
1-methyl-2-indoloylguanidine

4-methoxy-1-methyl-6- [3-
(N-Pyrrolidinyl) propoxy] -2-indoloylguanidine 4-methoxy-1-methyl-6- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine 7- (3-aminopropoxy) -4- Methoxy-1-methyl-2-indoloylguanidine 7- (3-dimethylaminopropoxy) -4-methoxy-1-methyl-2-indoloylguanidine 7- (3-diethylaminopropoxy) -4-methoxy-1-methyl -2-Indoyl guanidine

4-methoxy-1-methyl-7- [3-
(N-Pyrrolidinyl) propoxy] -2-indoloylguanidine 1- (3-dimethylaminopropyl) -4-isopropoxy-2-indoloylguanidine 1- (3-diethylaminopropyl) -4-isopropoxy-2-indo Roylguanidine 1- (3-aminopropyl) -4-isopropoxy-2
-Indoloylguanidine 4-isopropoxy-1- [3- (N-pyrrolidinyl)
Propyl] -2-indoloylguanidine

6- (3-Aminopropoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine 6- (3-Dimethylaminopropoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine 6- (3-Diethylaminopropoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine 6- (2-aminoethoxy) -4-isopropoxy-1
-Methyl-2-indoloylguanidine 6- (2-dimethylaminoethoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine 6- (2-diethylaminoethoxy) -4-isopropoxy-1-methyl- 2-indoloylguanidine

4-isopropoxy-1-methyl-6-
[3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 4-isopropoxy-1-methyl-6- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine 7- (3-aminopropoxy ) -4-Isopropoxy-
1-Methyl-2-indoloylguanidine 7- (3-dimethylaminopropoxy) -4-isopropoxy-1-methyl-2-indoloylguanidine 7- (3-diethylaminopropoxy) -4-isopropoxy-1-methyl -2-Indoloylguanidine 4-isopropoxy-1-methyl-7- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine

1- (3-aminopropyl) -4-methyl-2-indoloylguanidine 1- (3-dimethylaminopropyl) -4-methyl-2
-Indoyl guanidine 1- (3-diethylaminopropyl) -4-methyl-2
-Indoloylguanidine 4-methyl-1- [3- (N-pyrrolidinyl) propyl] -2-indoloylguanidine 6- (3-aminopropoxy) -1,4-dimethyl-2
− Indoylguanidine

1,4-Dimethyl-6- (3-dimethylaminopropoxy) -2-indoloylguanidine 6- (3-diethylaminopropoxy) -1,4-dimethyl-2-indoloylguanidine 1,4-dimethyl- 6- (2-Dimethylaminoethoxy) -2-indoloylguanidine 6- (2-diethylaminoethoxy) -1,4-dimethyl-2-indoloylguanidine 6- (2-aminoethoxy) -1,4-dimethyl- 2-
Indoyl guanidine

1,4-Dimethyl-6- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 1,4-dimethyl-6- [2- (N-pyrrolidinyl) ethoxy] -2-indoloyl Guanidine 7- (3-aminopropoxy) -1,4-dimethyl-2
-Indoloylguanidine 1,4-dimethyl-7- (3-dimethylaminopropoxy) -2-indoloylguanidine 7- (3-diethylaminopropoxy) -1,4-dimethyl-2-indoloylguanidine 1,4-dimethyl -7- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine

4-tert-butyl-1-methyl-2-indoloylguanidine 1- (3-aminopropyl) -4-tert-butyl-2-
Indoloylguanidine 4-tert-butyl-1- (3-dimethylaminopropyl) -2-indoloylguanidine 4-tert-butyl-1- (3-diethylaminopropyl) -2-indoloylguanidine 4-tert-butyl- 1- [3- (N-pyrrolidinyl) propyl] -2-indoloylguanidine

6- (3-dimethylaminopropoxy)-
1-Methyl-2-indoloylguanidine 6- (3-diethylaminopropoxy) -1-methyl-
2-indoloylguanidine 6- (2-aminoethoxy) -1-methyl-2-indoloylguanidine 6- (2-dimethylaminoethoxy) -1-methyl-2
-Indoylguanidine 6- (2-diethylaminoethoxy) -1-methyl-2
− Indoylguanidine

1-Methyl-6- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine 1-Methyl-6- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine 7- ( 3-dimethylaminopropoxy) -1-methyl-
2-Indoylguanidine 7- (3-diethylaminopropoxy) -1-methyl-
2-Indoloylguanidine 1-methyl-7- [3- (N-pyrrolidinyl) propoxy] -2-indoloylguanidine

The compound represented by the general formula (1) can be made into an acid addition salt with a pharmaceutically acceptable inorganic acid or organic acid, if necessary. Examples of such acid addition salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, Salts with organic carboxylic acids such as aspartic acid and glutamic acid; methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
Examples thereof include salts with sulfonic acids such as hydroxybenzene sulfonic acid and dihydroxybenzene sulfonic acid.

The compound of the present invention has a sodium / proton (Na ⁺ / H ⁺ ) exchange transport system inhibitory action, and is a disease caused by abnormality of the sodium / proton (Na ⁺ / H ⁺ ) exchange transport system, for example, hypertension. It is useful as a therapeutic or prophylactic drug for myocardial ischemia-reperfusion injury, arrhythmia, cerebral edema, cardiac hypertrophy, vascular lesion, arteriosclerosis.

The compounds of the present invention can be administered orally or parenterally when they are used as medicines. That is, it can be orally administered in a commonly used dosage form such as powder, granules, tablets, capsules, syrups, suspensions, or the like, or, for example, as a solution, emulsion or suspension thereof. The dosage form can be parenterally administered in the form of injection. It may also be administered rectally in the form of suppositories. The above suitable dosage forms can be produced, for example, by incorporating the active compound into an acceptable conventional carrier, excipient, binder, stabilizer and diluent. When used in an injection form, for example, an acceptable buffer,
A solubilizing agent and an isotonicity agent can also be added. The dose and the number of doses vary depending on, for example, the target disease, symptoms, age, body weight, and administration form, but usually 0.1 to 2000 mg / day, preferably 1 to 200 mg / day for adults are divided into one or several divided doses. It can be administered.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Experimental Examples, but the present invention is not limited thereto.

Reference Example 1 Synthesis of 7-chloro-2-indolecarboxylic acid (Fisher's indole synthesis method) a) Synthesis of ethyl 2- (2-chlorophenyl) hydrazonopropionate Ethyl 2-methylacetoacetate (14.4) g, 0.10 mo
50% aqueous potassium hydroxide solution (50 g) was added dropwise to a solution of l) in ethanol (100 ml) at 0 ° C. Add ice (7
0 g) and then o-chloroaniline (12.8 g, 0.10
mol), sodium nitrite (13.6 g, 0.20 mol) and concentrated hydrochloric acid (60 g) were added at once in a diazonium salt solution. The reaction solution was stirred at 0 ° C. for 30 minutes, and the precipitate was collected by filtration and dried under reduced pressure to give the target ethyl 2- (2
-Chlorophenyl) hydrazono propionate (9.10 g,
37.7%).

B) Synthesis of ethyl 7-chloro-2-indolecarboxylate Ethyl 2- (2-chlorophenyl) hydrazonopropionate (8.00 g, 33.2 mmol) obtained above was polyphosphoric acid.
(20 g), and gradually heat to 190 ℃, 1
Hold at 90 ° C. for 5 minutes. The reaction solution was cooled to 60 ° C., water was added, the mixture was extracted with ethyl acetate (three times), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By separating and purifying by silica gel column chromatography, the target ethyl 7
-Chloro-2-indolecarboxylate (3.40 g, 4
5.7%). ¹ H nmr (CDCl ₃ ) δ; 1.40-1.46 (3H, m), 4.43 (2H, dd,
J = 7.3, 14.2Hz), 7.09 (1H, t, J = 7.9Hz), 7.25 (1H, d,
J = 2.3Hz), 7.32 (1H, dd, J = 1.0, 7.6Hz), 7.58-7.61 (1
H, m), 9.02 (1H, br-s).

The reaction was carried out according to the method of Reference Example 1 to synthesize the compounds shown below. (1) Ethyl 5-nitro-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.42-1.47 (3H, m), 4.45 (2H, dd,
J = 7.3, 14.2Hz), 7.38 (1H, dd, J = 0.7, 2.0Hz), 7.5
0 (1H, d, J = 9.3Hz), 8.21-8.25 (1H, m), 8.69 (1H, d, J
= 2.0Hz), 9.3 (1H, br-s). (2) Ethyl 7-nitro-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.42-1.48 (3H, m), 4.43-4.51 (2
H, m), 7.25-7.28 (1H, m), 7.37 (1H, d, J = 2.3Hz), 8.0
4-8.08 (1H, m), 8.31 (1H, dd, J = 1.0, 7.9Hz), 10.4 (1
(H, br-s). (3) Ethyl 4-methoxy-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.38-1.43 (3H, m), 3.96 (3H, s),
4.36-4.44 (2H, m), 6.51 (1H, d, J = 7.9Hz), 7.01 (1H,
d, J = 8.3Hz), 7.22 (1H, d, J = 7.9Hz), 7.34-7.35 (1H,
m), 8.9 (1H, br-s).

(4) Ethyl 6-methoxy-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.38-1.43 (3H, m), 3.85 (3H, s),
4.39 (2H, dd, J = 7.3, 14.2Hz), 6.80-6.84 (2H, m), 7.1
6-7.17 (1H, m), 7.52-7.56 (1H, m), 8.9 (1H, br-s). (5) Ethyl 4-nitro-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.44 -1.49 (3H, m), 4.43-4.51 (2
H, m), 7.41-7.47 (1H, m), 7.77-7.80 (1H, m), 7.92 (1
H, dd, J = 1.0, 2.3Hz), 8.20 (1H, dd, J = 0.7, 7.9H
z), 9.4 (1H, br-s). (6) Ethyl 6-nitro-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.46 (3H, t, J = 7.3Hz), 4.48 (2H,
dd, J = 7.3, 14.2Hz), 7.29-7.30 (1H, m), 7.78 (1H, d,
J = 8.9Hz), 8.05 (1H, dd, J = 2.0, 8.9Hz), 8.42 (1H, t,
J = 1.0Hz), 9.6 (1H, br-s).

(7) Ethyl 4-trifluoromethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.42-1.47 (3H,
m), 4.45 (2H, dd, J = 6.9, 14.2Hz), 7.35
-7.41 (2H, m), 7.46-7.49 (1H, m), 7.62
(1H, d, J = 8.3Hz), 9.32 (1H, br-
s). (8) Ethyl 6-trifluoromethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.47 (3H,
m), 4.41-4.49 (2H, m), 7.26-7.27 (1H,
m), 7.36-7.40 (1H, m), 7.73-7.81 (2H,
m), 9.26 (1H, br-s).

(9) Ethyl 7-phenyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.28-1.43 (3H,
m), 4.41 (2H, dd, J = 6.9, 14.2Hz), 7.20
-7.26 (1H, m), 7.35-7.57 (6H, m), 7.66-
7.70 (2H, m), 9.11 (1H, br-s). (10) Ethyl 4-acetyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.47 (3H,
m), 2.72 (3H, s), 4.40-4.48 (2H, m), 7.
38 (1H, dd, J = 7.3, 8.2Hz), 7.66 (1H,
dd, J = 1.0, 8.3 Hz), 7.78 (1H, dd, J =
1.0, 7.3 Hz), 7.99-8.00 (1 H, m), 9.42 (1
H, br-s).

Reference Example 2 Synthesis of 4-methyl-2-indolecarboxylic acid (Lysert indole synthesis method) a) Synthesis of (6-methyl-2-nitrophenyl) pyruvic acid Potassium tert.-butoxide (11.2 g, 0.10) 2-Methyl-3-nitrotoluene (15.1 g, 0.10 mol) and diethyl oxalate (14.
A solution of 6 g, 0.10 mol) in ethanol (10 ml) was added. The reaction solution was stirred at room temperature for 1.5 hours and then heated under reflux for 1.5 hours. Further, water (60 ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution, ice water was added, and the mixture was washed with ethyl acetate (twice), the aqueous layer was acidified with concentrated hydrochloric acid, extracted with chloroform (three times), and the extract was washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure to obtain the desired 6-methyl-2-nitrophenylpyruvic acid.
(10.4 g, 46.6%) was obtained.

B) Synthesis of 4-methyl-2-indolecarboxylic acid 6-methyl-2-nitrophenylpyruvic acid obtained above
A 5% aqueous solution of ammonia (10.4 g, 46.6 mmol) was suspended in water (324 ml) containing iron (II) sulfate heptahydrate (96.4 g, 0.33 mol) and 28% aqueous ammonia (37 ml). It was added to the suspension and heated under reflux for 10 minutes. After removing the insoluble matter by filtration, the filtrate was acidified with concentrated hydrochloric acid, extracted with ethyl acetate (3 times), the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. , The desired 4-methyl-2-indolecarboxylic acid (4.30 g, 24.5% (2-
Yield from methyl-3-nitrotoluene)) was obtained. ¹ H nmr (DMSO-d ₆ ) δ; 2.49 (3H, s), 6.83 (1H, d, J =
6.3Hz), 7.08-7.14 (2H, m), 7.25 (1H, d, J = 8.3Hz), 11.
7 (1H, br-s), 12.8 (1H, br-s).

The reaction was carried out according to the method of Reference Example 2 to synthesize the compounds shown below. (1) 4-chloro-2-indolecarboxylic acid ¹ H nmr (DMSO-d ₆ ) δ; 7.06 (1H, d, J = 2.0Hz), 7.16
(1H, d, J = 7.6Hz), 7.22-7.28 (1H, m), 7.42 (1H, d, J =
7.9Hz), 12.2 (1H, br-s), 13.2 (1H, br-s). (2) 6-chloro-2-indolecarboxylic acid ¹ H nmr (DMSO-d ₆ ) δ; 7.04-7.10 (2H , m), 7.43 (1H,
d, J = 0.7Hz), 7.65 (1H, d, J = 8.6Hz), 11.9 (1H, br-s),
13.0 (1H, br-s). (3) 5-methyl-2-indolecarboxylic acid ¹ H nmr (DMSO-d ₆ ) δ; 2.36 (3H, s), 6.98 (1H, dd, J =
1.0, 2.0Hz), 7.04-7.08 (1H, m), 7.30-7.33 (1H, m),
7.40 (1H, s), 11.6 (1H, br-s), 12.9 (1H, br-s). (4) 6-Methyl-2-indolecarboxylic acid ¹ H nmr (DMSO-d ₆ ) δ; 2.40 ( 3H, s), 6.87-6.90 (1H,
m), 7.00-7.01 (1H, m), 7.21 (1H, s), 7.50 (1H, d, J = 8.
3Hz), 11.6 (1H, br-s), 12.7 (1H, br-s).

(5) 7-Methyl-2-indolecarboxylic acid ¹ H nmr (DMSO-d ₆ ) δ; 2.52 (3H, s), 6.93-7.02 (2H,
m), 7.09 (1H, d, J = 2.0Hz), 11.5 (1H, br-s), 12.8 (1H,
br-s). (6) 7-benzyloxy-2-indolecarboxylic acid ¹ Hnmr (DMSO-d ₆ ) δ; 5.27 (2H, s),
6.86 (1H, d, J = 7.3Hz), 6.94-7.00 (1H,
m), 7.07 (1H, dd, J = 2.0, 7.3Hz), 7.17
-7.23 (1H, m), 7.31-7.43 (3H, m), 7.65
(2H, d, J = 6.9Hz), 11.82 (1H, br-
s), 12.81 (1H, br-s). (7) 4-benzyloxy-2-indolecarboxylic acid ¹ Hnmr (DMSO-d ₆ ) δ; 5.24 (2H, s),
6.62 (1H, d, J = 6.9Hz), 7.00-7.17 (3
H, m), 7.31-7.44 (3H, m), 7.50-7.53 (2
H, m), 11.78 (1H, br-s), 12.85 (1H,
br-s).

Reference Example 3 Synthesis of methyl 6-indole carboxylate a) Synthesis of methyl 4-chloro-3-nitrobenzoate 4-chloro-3-nitrobenzoic acid (10.0 g, 49.6 mmol)
In methanol (100 ml) at 0 ° C with thionyl chloride
(11.8 g, 99.2 mmol) was added dropwise. The reaction mixture was heated under reflux for 2 hours, the solvent was evaporated under reduced pressure, ice water was added to the obtained residue to make it alkaline with aqueous ammonia, and the mixture was extracted with ethyl acetate (three times), and the extract was washed with water and anhydrous sulfuric acid. After drying over magnesium, the solvent was distilled off under reduced pressure to give methyl 4
-Chloro-3-nitrobenzoate (10.9 g,> 99%)
Got b) Synthesis of methyl 3-nitro-4-trimethylsilylethynylbenzoate Methyl 4-chloro-3-nitrobenzoate (10.7 g, 49.6 mmol) obtained above, trimethylsilylacetylene
A mixture of (8.77 g, 89.3 mmol), dichloro-bis (triphenylphosphine) palladium (0.4 g) and triethylamine (120 ml) was heated with stirring at 75 ° C. for 3 hours. The reaction solution was cooled, the insoluble material was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give methyl 3-nitro-4-trimethylsilylethynylbenzoate ( 8.40 g, 61.0%) was obtained.

C) Synthesis of methyl 4- (2,2-dimethoxyethyl) -3-nitrobenzoate The methyl 3-nitro-4-trimethylsilylethynylbenzoate (3.00 g, 10.8 mmol) obtained above was added to sodium methoxide. (2.92 g, 54.1 mmol) was added to a methanol solution, and the mixture was heated under reflux for 30 minutes. After cooling the reaction solution to 0 ° C,
Acetic acid (5.52 g, 54.1 mmol) was added, and then the solvent was evaporated under reduced pressure. Ice water was added to the obtained residue, which was extracted with dichloromethane (3 times), the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography. By this, methyl 4
-(2,2-Dimethoxyethyl) -3-nitrobenzoate (2.40 g, 82.4%) was obtained. d) Synthesis of methyl 3-amino-4- (2,2-dimethoxyethyl) benzoate Methyl 4- (2,2-dimethoxyethyl) obtained above
5% palladium-carbon (0.50 g) was added to a mixed solvent of 3-nitrobenzoate (4.40 g, 16.3 mmol) in methanol (200 ml) and acetic acid (2 ml), and catalytic reduction was performed at room temperature and atmospheric pressure. , Methyl 3 by post-treatment according to a conventional method
-Amino-4- (2,2-dimethoxyethyl) benzoate (4.16 g) was obtained.

E) Synthesis of methyl 6-indole carboxylate The methyl 3-amino-4- (2,2-dimethoxyethyl) benzoate (4.00 g, 16.7 mmol) obtained above was treated with 1N.
Add to the hydrochloric acid (15 ml) / ethanol (15 ml) solution and add 60
The mixture was heated and stirred at 0 ° C for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Methyl 6-indole carboxylate (3.00 g,>
99%). ¹ H nmr (CDCl ₃ ) δ; 3.95 (3H, s), 7.13-7.45 (4H, m),
7.68-7.72 (1H, m), 8.94 (1H, br-s).

Reference Example 4 Synthesis of methyl 1-methyl-2-indolecarboxylate 2-indolecarboxylic acid (2.00 g, 12.4 mmol) was added to 6
It was added to a suspension of 0% sodium hydride (0.99 g, 24.8 mmol) and dimethylformamide (40 ml) and stirred at room temperature to give a transparent solution, and then methyl iodide (7.05 g, 7.05 g, at room temperature) 49.6 mmol) of dimethylformamide (10 m
l) The solution was added dropwise and stirred at room temperature for 5 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to recrystallize the residue obtained by recrystallization with n-hexane. Thus, methyl 1-methyl-2-indole carboxylate (1.70 g, 72.4%) was obtained. ¹ H nmr (CDCl ₃ ) δ; 3.91 (3H, s), 4.08 (3H, s), 7.12
-7.18 (1H, m), 7.30 (1H, s), 7.32-7.41 (2H, m), 7.66-
7.70 (1H, m).

Reactions were carried out according to the method of Reference Example 4 to synthesize the compounds shown below. (1) Methyl 1-methyl-5-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.82 (3H, s), 3.93 (3H, s), 6.58
(1H, dd, J = 1.0, 3.3Hz), 7.11 (1H, d, J = 3.3Hz), 7.32
(1H, d, J = 8.6Hz), 7.91-7.95 (1H, m), 8.39-8.40 (1H,
m). (2) Methyl 1-methyl-3-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.82 (3H, s), 3.91 (3H, s), 7.24
-7.37 (3H, m), 7.77 (1H, s), 8.14-8.20 (1H, m). (3) Methyl 1-methyl-4-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.84 (3H, s), 3.98 (3H, s), 7.10
-7.11 (1H, m), 7.20 (1H, d, J = 3.0Hz), 7.24-7.29 (1H,
m), 7.53 (1H, d, J = 8.2Hz), 7.91 (1H, dd, J = 1.0, 7.6H
z).

(4) Methyl 4-chloro-1-methyl-
2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.60 (3H, s), 3.75 (3H, s), 6.80
-6.83 (1H, m), 6.89-6.95 (2H, m), 7.05 (1H, d, J = 0.7H
z). (5) Methyl 5-chloro-1-methyl-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.64 (3H, s), 3.78 (3H, s), 6.93
(1H, s), 6.97-7.02 (2H, m), 7.36 (1H, t, J = 1.3Hz). (6) Methyl 6-chloro-1-methyl-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.91 (3H, s), 4.04 (3H, s), 7.09
-7.13 (1H, m), 7.25-7.26 (1H, m), 7.38-7.39 (1H, m),
7.56-7.59 (1H, m).

(7) Methyl 7-chloro-1-methyl-
2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.91 (3H, s), 4.47 (3H, s), 6.99
(1H, m), 7.26-7.30 (2H, m), 7.52-7.56 (1H, m). (8) Methyl 1,4-dimethyl-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 2.56 ( 3H, s), 3.92 (3H, s), 4.07
(3H, s), 6.93-6.96 (1H, m), 7.17-7.29 (2H, m), 7.33
(1H, d, J = 0.7Hz). (9) Methyl 1,5-dimethyl-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 2.44 (3H, s), 3.90 (3H, s), 4.05
(3H, s), 7.16-7.29 (3H, m), 7.42-7.45 (1H, m).

(10) Methyl 1,6-dimethyl-2-
Indole carboxylate ¹ H nmr (CDCl ₃ ) δ; 2.51 (3H, s), 3.90 (3H, s), 4.05
(3H, s), 6.99 (1H, dd, J = 1.0, 8.3Hz), 7.12-7.16 (1H,
m), 7.24-7.26 (1H, m), 7.55 (1H, d, J = 8.2Hz), 7.42-
7.45 (1H, m). (11) Methyl 1,7-dimethyl-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 2.80 (3H, s), 3.89 (3H, s), 4.35
(3H, s), 6.97 (2H, m), 7.25-7.27 (1H, m), 7.26 (1H,
s), 7.48 (1H, d, J = 7.3Hz). (12) Methyl 1-methyl-5-methoxy-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.85 (3H, s), 3.90 ( 3H, s), 4.05
(3H, s), 7.00-7.09 (2H, m), 7.19-7.30 (2H, m).

(13) Benzyl 1-benzyl-5-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 5.33 (2H, s), 5.38 (2H, s), 6.64
(1H, d, J = 3.3Hz), 7.06-7.49 (12H, m), 7.92 (1H, dd,
J = 1.7, 8.9Hz), 8.45-8.46 (1H, m). (14) Isopropyl 1-isopropyl-5-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.38 (6H, d, J = 6.3Hz) , 1.53 (6H,
d, J = 6.6Hz), 4.62-4.75 (1H, m), 5.21-5.35 (1H, m),
6.60 (1H, d, J = 3.3Hz), 7.27 (1H, d, J = 3.3Hz), 7.36 (1
H, d, J = 8.6Hz), 7.90 (1H, dd, J = 1.7, 8.6Hz), 8.38 (1
H, d, J = 1.7Hz).

Reference Example 5 Synthesis of methyl 1-methyl-6-indole carboxylate Methyl 6-indole carboxylate (3.00 g, 1
7.1 mmol), 60% sodium hydride (0.68 g, 17.1 m)
mol), methyl iodide (4.86 g, 34.4 mmol) and dimethylformamide (60 ml) according to the method of Reference Example 4, methyl 1-methyl-6-indolecarboxylate (2.75 g, 86.9%). ) Got. ¹ H nmr (CDCl ₃ ) δ; 3.86 (3H, s), 3.95 (3H, s), 6.51
-6.53 (1H, m), 7.21 (1H, d, J = 3.3Hz), 7.63 (1H, d, J =
8.6Hz), 7.78-7.82 (1H, m), 8.10 (1H, s).

Reactions were carried out according to the method of Reference Example 5 to synthesize the compounds shown below. (1) Ethyl 4-methoxy-1-methyl-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.39 (3H, t, J = 7.3Hz), 3.96 (3H,
s), 4.06 (3H, s), 4.35 (2H, dd, J = 7.3, 14.2Hz), 6.5
0 (1H, d, J = 7.6Hz), 6.98 (1H, d, J = 8.6Hz), 7.24-7.30
(1H, m), 7.42 (1H, d, J = 0.7Hz). (2) Ethyl 6-methoxy-1-methyl-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.37-1.42 (3H, m), 3.89 (3H, s),
4.03 (3H, s), 4.31-4.39 (2H, m), 6.75 (1H, s), 6.80-
6.84 (1H, m), 7.25 (1H, s), 7.53 (1H, d, J = 8.9Hz). (3) Ethyl 1-methyl-4-nitro-2-indolecarboxylate ¹ H nmr (CDCl ₃ ). δ; 1.45 (3H, t, J = 7.3Hz), 4.17 (3H,
s), 4.39-4.47 (2H, m), 7.41-7.48 (1H, m), 7.74-7.77
(1H, m), 7.96 (1H, d, J = 1.0Hz), 8.18-8.21 (1H, m).

(4) Ethyl 1-methyl-6-nitro-
2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.41-1.46 (3H, m), 4.17 (3H, s),
4.38-4.46 (2H, m), 7.34 (1H, d, J = 1.0Hz), 7.75 (1H,
dd, J = 0.7, 8.9Hz), 8.03 (1H, dd, J = 2.0, 8.9Hz), 8.3
9 (1H, d, J = 2.0Hz). (5) Ethyl 1-methyl-5-nitro-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.41-1.46 (3H, m), 4.14 (3H , s),
4.41 (2H, dd, J = 7.3, 14.2Hz), 7.42-7.46 (2H, m), 8.2
2-8.26 (1H, m), 8.66 (1H, d, J = 2.0Hz). (6) Ethyl 1-methyl-7-nitro-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.43 (3H , t, J = 7.3Hz), 4.00 (3H,
s), 4.37-4.45 (2H, m), 7.20 (1H, t, J = 7.9Hz), 7.43
(1H, s), 7.85-7.93 (2H, m).

(7) Methyl 1-benzyl-2-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.86 (3H, s), 5.84 (2H, s), 7.02
-7.06 (2H, m), 7.13-7.44 (7H, m), 7.70-7.73 (1H, m). (8) Methyl 1-benzyl-3-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 3.91 ( 3H, s), 5.34 (2H, s), 7.13
-7.17 (2H, m), 7.20-7.36 (6H, m), 7.85 (1H, s), 8.17-
8.21 (1H, m). (9) Methyl 1-isopropyl-3-indolecarboxylate ¹ H nmr (CDCl ₃ ) δ; 1.56 (6H, d, J = 6.9Hz), 3.92 (3H,
s), 4.64-4.74 (1H, m), 7.24-7.31 (2H, m), 7.39-7.42
(2H, m), 7.96 (1H, s), 8.15-8.20 (1H, m). (10) Ethyl 1,3-dimethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.42-1.47 (3H ，
m), 2.59 (3H, s), 4.01 (3H, s), 4.37-4.
45 (2H, m), 7.10-7.18 (1H, m), 7.31-7.38
(2H, m), 7.64-7.67 (1H, m).

(11) Ethyl 1-methyl-4-methylsulfonyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.46 (3H,
m), 3.14 (3H, s), 4.16 (3H, s), 4.41 (2)
H, dd, J = 7.3, 14.2Hz), 7.48 (1H, dd,
J = 7.3, 8.3 Hz), 7.68-7.71 (2H, m), 7.81
-7.84 (1H, m). (12) Ethyl 1-methyl-6-methylsulfonyl-
2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.41-1.46 (3H,
m), 3.11 (3H, s), 4.16 (3H, s), 4.37-4.
45 (2H, m), 7.34 (1H, d, J = 0.7Hz), 7.
62-7.70 (2H, m), 7.83 (1H, dd, J = 0.7,
8.6 Hz), 8.07 (1H, d, J = 0.7 Hz). (13) Methyl 4-fluoro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.92 (3H, s), 4.09
(3H, s), 6.77-6.83 (1H, m), 7.16 (1H,
d, J = 8.3 Hz), 7.23-7.31 (1H, m), 7.36
(1H, s).

(14) Methyl 4-bromo-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.93 (3H, s), 4.08
(3H, s), 7.16-7.26 (1H, m), 7.31-7.35
(3H, m). (15) Methyl 1- (2-naphthylmethyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.86 (3H, s), 6.00
(2H, s), 7.14-7.32 (3H, m), 7.37-7.43
(5H, m), 7.66-7.78 (4H, m). (16) Methyl 1- (2-phenylethyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.06 (2H, t, J = 7.
9Hz), 3.90 (3H, s), 4.74-4.80 (2H,
m), 7.11-7.33 (9H, m), 7.66-7.69 (1H,
m).

(17) Methyl 1- (4-bromobenzyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.87 (3H, s), 5.79
(2H, s), 6.92 (2H, dd, J = 2.0, 6.6H
z), 7.15-7.23 (1H, m), 7.31-7.38 (5H,
m), 7.70-7.74 (1H, m). (18) Methyl 1- (4-nitrobenzyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.87 (3H, s), 5.93
(2H, s), 7.14-7.41 (5H, m), 7.42 (1H,
d, J = 0.7 Hz), 7.73-7.77 (1H, m), 8.09-
8.14 (2H, m). (19) Methyl 1- (3-phenylpropyl) -2-
Indole carboxylate ¹ Hnmr (CDCl ₃ ) δ; 2.06-2.22 (2H,
m), 2.69 (2H, d, J = 8.0Hz), 3.90 (3H,
s), 4.60 (2H, t, J = 8.0Hz), 7.05-7.40
(9H, m), 7.66 (1H, d, J = 8.0Hz).

(20) Methyl 1- (2-methoxyethyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.28 (3H, s), 3.73
(2H, t, J = 5.9Hz), 3.91 (3H, s), 4.74
(2H, t, J = 5.9Hz), 7.14 (1H, ddd, J
= 1.0, 6.9, 7.4 Hz), 7.31 (1H, d, J = 0.7)
Hz), 7.36 (1H, dd, J = 1.3, 6.9Hz), 7.
48 (1H, dd, J = 0.7, 8.6Hz), 7.66 (1H,
dd, J = 1.1, 8.3 Hz). (21) Methyl 1- (2-diethylaminoethyl)-
2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.03 (6H, t, J = 7.
3Hz), 2.61 (4H, q, J = 7.3Hz), 2.70-2.
82 (2H, m), 3.91 (3H, s), 4.58-4.70 (2
H, m), 7.14 (1H, ddd, J = 1.3, 6.7, 8.6
Hz), 7.27 (1H, d, J = 1.0Hz), 7.34 (1
H, ddd, J = 1.0, 6.7, 7.1 Hz), 7.43 (1
H, dd, J = 1.0, 8.6 Hz), 7.61-7.71 (1H,
m). (22) Ethyl 4-chloro-1- (2-diethylaminoethyl) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.00 (6H, t, J = 7.
3Hz), 1.42 (3H, t, J = 7.3Hz), 2.59 (4
H, q, J = 7.3 Hz), 2.69-2.80 (2H, m), 4.
38 (2H, q, J = 7.3Hz), 4.56-4.68 (2H,
m), 7.14 (1H, dd, J = 1.0, 7.3Hz), 7.18
-7.28 (1H, m), 7.29-7.35 (1H, m), 7.37
(1H, d, J = 0.7Hz).

(23) Synthesis of methyl 1- [2- (2-tetrahydropyranyl) oxyethyl] -2-indolecarboxylate Methyl 2-indolecarboxylate (2.0 g, 1
1.4mmol), 60% sodium hydride (0.55g, 13.7mmol)
, 2- (2-iodoethoxy) tetrahydropyran (prepared from 2-iodoethanol and 3,4-dihydro-2H-pyran; 3.63 g, 13.7 mmol) and dimethylformamide (50 ml) according to the method of Reference Example 5. The reaction was carried out to obtain methyl 1- [2- (2-tetrahydropyranyl) oxyethyl] -2-indolecarboxylate (2.87 g, 83.0%). ¹ Hnmr (CDCl ₃ ) δ; 1.27-1.75 (6H,
m), 3.26-3.54 (2H, m), 3.75 (1H, dt, J
= 4.6, 10.2Hz), 4.03 (1H, dt, J = 4.6, 1)
0.2Hz), 4.47 (1H, t, J = 3.0Hz), 4.80
(2H, t, J = 3.7Hz), 7.13 (1H, t, J = 7.
0Hz), 7.22-7.38 (2H, m), 7.53 (1H, d,
J = 8.0 Hz), 7.65 (1H, d, J = 8.0 Hz).

(24) Methyl 1- [3- (2-tetrahydropyranyl) oxypropyl] -2-indolecarboxylate 2- (2-iodopropoxy) instead of 2- (2-iodoethoxy) tetrahydropyran The reaction was performed according to the method of Reference Example 5 (23) except that tetrahydropyran was used to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 1.42-1.97 (6H,
m), 2.11 (2H, dt, J = 5.9, 11.2Hz), 3.33
(1H, dt, J = 7.9, 8.3Hz), 3.40-3.55 (1
H, m), 3.72-3.88 (2H, m), 3.94 (3H,
s), 4.52 (1H, dd, J = 3.0, 4.3Hz), 4.69
(2H, dt, J = 0.9, 1.7Hz), 7.14 (1H, d
dd, J = 1.0, 7.0, 7.9 Hz), 7.27-7.37 (2
H, m), 7.48 (1H, dd, J = 0.9,8.5Hz),
7.66 (1H, dt, J = 1.0, 7.9Hz).

(25) Synthesis of methyl 1- (3-tert-butoxycarbonylaminopropyl) -2-indolecarboxylate Methyl-2-indolecarboxylate (5.00 g, 2
8.5mmol), 60% sodium hydride (1.26g, 31.4mmo)
l), tert-butyl N- (3-iodopropyl) carbamate (3-iodopropylamine and di-tert dioxide
-Prepared from butyl; 12.3 g, 43.2 mmol) and dimethylformamide (60 ml) were reacted according to the method of Reference Example 5 to give methyl 1- (3-tert-butoxycarbonylaminopropyl) -2-indolecarboxylate. (2.54 g, 27%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.45 (9H, s), 1.90
-2.10 (2H, m), 3.00-3.20 (2H, m), 3.91
(3H, s), 4.62 (2H, t, J = 6.9Hz), 4.98
(1H, br-s), 7.06-7.20 (1H, m), 7.28-
7.44 (3H, m), 7.68 (1H, d, J = 7.3Hz).

(26) Methyl 1- (2-tert-butoxycarbonylaminoethyl) -2-indolecarboxylate tert-butyl N- (3-iodopropyl) carbamate Instead of tert-butyl N- (2-iodopropyl) ) The reaction was performed according to the method of Reference Example 5 (25) except that carbamate was used to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 1.41 (9H, s), 3.53
(2H, t, J = 5.9Hz), 3.90 (3H, s), 4.68
(2H, t, J = 6.3Hz), 4.60-4.80 (1H,
m), 7.15 (1H, ddd, 1H, J = 1.0, 6.9, 7.
4Hz), 7.27-7.38 (2H, m), 7.48 (1H, d,
J = 8.3 Hz), 7.66 (1H, d, J = 7.9 Hz). (27) Ethyl 1-methyl-4- (2-tetrahydropyranyl) oxyethyl-2-indolecarboxylate The title compound was obtained in the same manner as in Reference Example 5. ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 1.53-1.91 (6H, m), 3.50-3.61 (1H,
m), 3.84-4.03 (1H, m), 4.09 (3H, s), 4.
34-4.42 (2H, m), 4.75 (1H, t, J = 3.6H
z), 4.83 (1H, d, J = 12.2Hz), 5.08 (1H,
d, J = 12.2Hz), 7.18 (1H, t, J = 4.0H
z), 7.32-7.33 (2H, m), 7.42 (1H, s).

(28) Ethyl 4-chloro-1- [4-
(2-Tetrahydropyranyl) oxybutyl] -2-indolecarboxylate 2- (2-iodoethoxy) tetrahydropyran and methyl 2-indolecarboxylate instead of 2
The reaction was performed according to the method of Reference Example 5 (23) except that-(4-iodobutoxy) tetrahydropyran and ethyl 4-chloro-2-indolecarboxylate were used to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 1.42 (3H, t, J = 7.
3Hz), 1.41-2.00 (10H, m), 3.32-3.56 (2
H, m), 3.68-3.90 (2H, m), 4.38 (2H, q,
J = 7.3 Hz), 4.55 (1 H, t, J = 4.0 Hz), 4.
60 (2H, t, J = 7.6Hz), 7.13 (1H, dd, J
= 1.0, 7.6Hz), 7.22 (1H, d, J = 8.2H
z), 7.32 (1H, d, J = 8.3Hz), 7.39 (1H,
s). (29) Methyl 1- (3: 4-isopropylidenedioxybutyl) -2-indolecarboxylate In the method of Reference Example 5 except that iodide 3: 4-isopropylidenedioxybutyl was used instead of methyl iodide. The reaction was carried out in the same manner to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 1.34 (3H, s), 1.46
(3H, s), 1.90-2.18 (2H, m), 3.52 (1H,
dd, J = 6.9, 7.9 Hz), 3.91 (3H, s), 3.97
(1H, dd, J = 5.9, 7.9Hz), 4.01-4.17 (1
H, m), 4.58-4.80 (2H, m), 7.15 (1H, dd
d, J = 1.0, 6.9, 7.4 Hz), 7.31 (1H, d, J
= 0.7 Hz), 7.35 (1H, ddd, J = 1.3, 6.9,
7.6 Hz), 7.47-7.55 (1 H, m), 7.63-7.70 (1
H, m).

(30) Methyl 1- [2- [1- (4-
Methyl-2,6,7-trioxabicyclo [2.2.
2] octyl)] ethyl] -2-indolecarboxylate 2- [1- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octyl)] instead of methyl iodide The reaction was performed according to the method of Reference Example 5 except that ethyl was used to obtain the title compound. ¹ Hnmr (CDCl ₃ ) δ; 0.79 (3H, s), 2.17
(2H, ddd, J = 2.6, 5.3, 7.9Hz), 3.89
(6H, s), 3.90 (3H, s), 5.87 (2H, dd
d, J = 2.3, 5.6, 7.9 Hz), 7.12 (1H, dd
d, J = 1.0, 6.9, 7.4 Hz), 7.27 (1H, d, J
= 0.7 Hz), 7.32 (1H, ddd, J = 1.3, 6.9,
7.6Hz), 7.48 (1H, dd, J = 0.7, 8.6H
z), 7.65 (1H, ddd, J = 1.0, 1.5, 8.3H
z). The following compounds were synthesized in the same manner as in Reference Example 5. (31) Methyl 4-benzyloxy-1-methyl-2
- indole carboxymethyl acrylate _{^{1 Hnmr (CDCl 3) δ;}} 3.89 (3H, s), 4.06
(3H, s), 5.22 (2H, s), 6.57 (1H, d, J
= 7.6Hz), 6.99 (1H, d, J = 8.6Hz), 7.22
-7.28 (1H, m), 7.30-7.51 (6H, m).

(32) Methyl 6-benzyloxy-1
-Methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.89 (3H, s), 4.02
(3H, s), 5.15 (2H, s), 6.85 (1H, d, J
= 2.31Hz), 6.91 (1H, dd, J = 2.3, 8.6H
z), 7.24 (1H, d, J = 1.0Hz), 7.34-7.44
(3H, m), 7.47-7.52 (2H, m), 7.53-7.57
(1H, m). (33) Methyl 7-benzyloxy-1-methyl-2
- indole carboxylate _{^{1 Hnmr (CDCl 3) δ;}} 3.89 (3H, s), 4.38
(3H, s), 5.19 (2H, s), 6.78 (1H, d, J
= 8.6 Hz), 6.97-7.03 (1H, m), 7.24-7.27
(2H, m), 7.33-7.51 (5H, m).

Reference Example 6 Synthesis of methyl 2-indolecarboxylate In a solution of 2-indolecarboxylic acid (30.0 g, 186.2 mmol) in methanol (300 ml), thionyl chloride (4
4.3 g, 372.3 mmol) was added dropwise. The reaction solution was heated under reflux for 2 hours, the solvent was distilled off under reduced pressure, and ice water was poured into the obtained residue. The mixture was made alkaline with aqueous ammonia, extracted with ethyl acetate (three times), the extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
Methyl 2-indolecarboxylate (32.34 g, 9
9.2%). ¹ H nmr (CDCl ₃ ) δ; 3.95 (3H, s), 7.13-7.45 (4H, m),
7.69 (1H, dd, J = 1.0,7.9Hz), 8.91 (1H, br-s).

Reactions were carried out according to the method of Reference Example 6 to synthesize the compounds shown below. (1) Methyl 3-indole carboxylate ¹ H nmr (CDCl ₃ ) δ; 3.93 (3H, s), 7.24-7.31 (2H, m),
7.38-7.45 (1H, m), 7.93 (1H, d, J = 3.0Hz), 8.17-8.22
(1H, m), 8.63 (1H, br-s) (2) Methyl 4-fluoro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.96 (3H, s), 6.78
-6.85 (1H, m), 7.18-7.30 (3H, m), 8.99
(1H, br-s). (3) Methyl 4-bromo-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.97 (3H, s), 7.17
(1H, dd, J = 7.6, 8.3Hz), 7.28 (1H, d
d, J = 1.0, 2.3 Hz), 7.32-7.39 (2H, m),
9.05 (1H, br-s).

(4) Methyl 7-benzyloxy-2
- indole carboxylate _{^{1 Hnmr (CDCl 3) δ;}} 3.93 (3H, s), 5.21
(2H, s), 6.80 (1H, d, J = 6.9Hz), 7.01
-7.08 (1H, m), 7.19 (1H, dd, J = 2.3, 4.
3Hz), 7.24-7.31 (1H, m), 7.35-7.51 (5
H, m), 9.07 (1H, br-s). (5) Methyl 4-benzyloxy-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.93 (3H, s), 5.22
(2H, s), 6.58 (1H, d, J = 7.6Hz), 7.03
(1H, d, J = 8.3Hz), 7.19-7.26 (1H,
m), 7.31-7.44 (4H, m), 7.50 (2H, d, J =
7.3 Hz), 8.84 (1H, br-s).

Reference Example 7 Synthesis of methyl 5-indole carboxylate A mixture of 5-indolecarboxylic acid (1.00 g, 6.21 mmol) and 10% hydrogen chloride / methanol (50 ml) was added to 2 parts.
After heating under reflux for an hour, the reaction solution was poured into ice water and neutralized with sodium bicarbonate. Then, the mixture was extracted with ethyl acetate (three times), the extract was washed with sodium bicarbonate water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give methyl 5-indolecarboxylate (0.42 g, 38.6%). Got ¹ H nmr (CDCl ₃ ) δ; 3.93 (3H, s), 6.64-6.66 (1H, m),
7.26-7.29 (1H, m), 7.40 (1H, dd, J = 0.7, 8.6Hz), 7.9
1 (1H, dd, J = 1.7, 8.6Hz), 8.3-8.6 (2H, m).

Reference Example 8 Synthesis of methyl 1-isopropyl-5-indolecarboxylate Isopropyl 1-isopropyl-5-indolecarboxylate (2.20 g, 8.97 mmol), 2N aqueous caustic soda solution (100 ml) and ethanol (100 ml) The mixture was heated under reflux for 1 hr, and the solvent was evaporated under reduced pressure. Then
Water was added to the residue, which was then acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration and dried under reduced pressure to give crude 1-isopropyl-5-indolecarboxylic acid (2.00 g). This crude 1-isopropyl-5-indolecarboxylic acid (2.00 g) and 60% sodium hydride (0.44 g, 1
1.1 mmol), methyl iodide (2.87 g, 20.2 mmol) and dimethylformamide (50 ml) were reacted according to the method of Reference Example 4 to give methyl 1-isopropyl-5-indolecarboxylate (1.64 g, isopropyl). Yield from 1-isopropyl-5-indolecarboxylate: 84.2%) was obtained. ¹ H nmr (CDCl ₃ ) δ; 1.54 (6H, d, J = 6.9Hz), 3.93 (3H,
s), 4.65-4.75 (1H, m), 6.61 (1H, d, J = 3.3Hz), 7.28
(1H, d, J = 3.3Hz), 7.37 (1H, d, J = 8.6Hz), 7.9 (1H, d
d, J = 1.7, 8.6Hz), 8.39 (1H, d, J = 1.7Hz).

Reference Example 9 Synthesis of 7-chloro-2-indolecarboxylic acid Ethyl 7-chloro-2-indolecarboxylate (3.40 g, 15.2 mmol), 2N caustic soda aqueous solution (100 m
The mixture of l) and ethanol (100 ml) was heated under reflux for 1 hour, and then the solvent was distilled off under reduced pressure. Next, ice water was added to the residue, which was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3
The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 7-chloro-2-indolecarboxylic acid (2.85 g, 95.8%). ¹ H nmr (DMSO-d ₆ ) δ; 7.04-7.09 (1H, m), 7.19 (1H,
d, J = 2.0Hz), 7.30 (1H, dd, J = 1.0, 7.6Hz), 7.62 (1H,
d, J = 8.3Hz), 11.9 (1H, br-s), 13.1 (1H, br-s).

Reference Example 10 Synthesis of 1-isopropyl-2-indolecarboxylic acid Methyl 2-indolecarboxylate (6.00 g, 3
4.2 mmol), 60% sodium hydride (1.36 g, 34.2
mmol), isopropyl iodide (6.40 g, 37.7 mmol)
And dimethylformamide (100 ml), Reference Example 4
The reaction is carried out according to the method described in 1., and methyl 1-isopropyl-2-indolecarboxylate and isopropyl
A mixture of 1-isopropyl-2-indolecarboxylate was obtained. This mixture and 2N caustic soda solution (15
0 ml) and ethanol (150 ml) were reacted according to the method of Reference Example 9 to obtain 1-isopropyl-2-indolecarboxylic acid (3.71 g, 53.3%). ¹ H nmr (DMSO-d ₆ ) δ; 1.58 (6H, d, J = 6.9Hz), 5.74-
5.85 (1H, m), 7.05-7.11 (1H, m), 7.19-7.28 (2H, m),
7.64-7.72 (2H, m), 12.9 (1H, br-s).

Reference Example 11 Synthesis of methyl 1-methyl-7-indolecarboxylate a) Ethyl 7-carbomethoxy-1-methyl-2-
Synthesis of Indole Carboxylate Ethyl-7-carbomethoxy-2-indolecarboxylate (5.00 g, 20.2 mmol) obtained by performing the reaction according to the method of Reference Example 1 was treated with 60% sodium hydride (0.81 g, 20.2mmol) and dimethylformamide (8
0 ml) and stirred at room temperature to form a transparent solution, and then methyl iodide (5.74 g, 40.4 mmol) at room temperature.
Was added dropwise, followed by stirring at 50 ° C. for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue, which was separated by silica gel column chromatography. Purification yielded ethyl 7-carbomethoxy-1-methyl-2-indolecarboxylate (5.20 g, 98.5%).

B) Synthesis of 1-methylindole-2,7-dicarboxylic acid Ethyl 7-carbomethoxy-1-methyl-2-indolecarboxylate (5.20 g, 19.9 mmol), 2N aqueous sodium hydroxide solution (90 ml) and Ethanol (150
ml) was heated to reflux for 3 hours. Ice water was added to the residue obtained by concentrating the reaction solution under reduced pressure, and 2N hydrochloric acid was added dropwise to make the reaction solution acidic. The precipitated solid is collected by filtration,
1-methylindole-by drying under reduced pressure
2,7-dicarboxylic acid (4.70 g,> 99%) was obtained.

C) Synthesis of 1-methyl-7-indolecarboxylic acid 1-methylindole-2,7-dicarboxylic acid (4.60
g, 21.0 mmol), copper (II) oxide (0.5 g) and quinoline (50 ml) were heated and stirred at 180 ° C. for 1 hour. After cooling the reaction mixture, it was poured into 2N hydrochloric acid (200 ml),
Extraction with ethyl acetate (3 times), washing with saturated brine, drying over anhydrous magnesium sulfate, evaporation of the solvent under reduced pressure and separation and purification of the residue by silica gel column chromatography gave 1-methyl. -7-Indolecarboxylic acid (1.82 g, 49.0%) was obtained.

D) Synthesis of methyl 1-methyl-7-indolecarboxylate 1-Methyl-7-indolecarboxylic acid (1.82 g, 10.4)
Thionyl chloride (3.09 g, 26.0 mmol) was added dropwise to a methanol solution (70 ml) of (mmol) at 0 ° C. The reaction solution was heated under reflux for 2 hours, the solvent was distilled off under reduced pressure, and ice water was poured into the obtained residue. The mixture was made alkaline with aqueous ammonia, extracted with ethyl acetate (3 times), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography. By doing so, methyl 1-methyl-7-indolecarboxylate (1.16 g, 59.0%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 3.88 (3H, s), 3.96
(3H, s), 6.54 (1H, d, J = 3.3Hz), 7.10
(1H, t, J = 7.6Hz), 7.67 (1H, d, J = 7.
3Hz), 7.75 to 7.78 (1H, m). Reference Example 12 Synthesis of ethyl-7-benzyloxy-4-chloro-2-indolecarboxylate a) Synthesis of 3-benzyloxy-6-chloro-2-nitrotoluene 4-chloro-3-methyl-2-nitrophenol ( 1.50
g, 8.00 mmol), benzyl bromide (1.50 g, 8.80 mmol),
Potassium carbonate (2.43 g, 17.6 mmol) and acetone (70
The mixture was heated to reflux for 2 hours. Then, the insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was separated and purified by silica gel column chromatography to give 3-benzyloxy-6-chloro-2-nitrotoluene (2.22
g,> 99%).

B) Synthesis of ethyl (3-benzyloxy-6-chloro-2-nitrophenyl) pyruvate In a suspension of potassium ethoxide (0.67 g, 7.92 mmol) in diethyl ether (50 ml) at room temperature. Diethyl oxalate (1.20 g, 7.92 mmol) was added dropwise. Then 3-benzyloxy-6-chloro-2-nitrotoluene (2.00
g, 7.20 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with diethyl ether (2
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography to give (3-benzyloxy). Ethyl-6-chloro-2-nitrophenyl) pyruvate (1.60 g, 53.5%) was obtained.

C) Ethyl 7-benzyloxy-4-
Synthesis of chloro-2-indolecarboxylate Ethyl (3-benzyloxy-6-chloro-2-nitrophenyl) pyruvate (1.60 g, 4.24 mmol), 20% titanium trichloride aqueous solution (22.9 g, 29.7 mmol) and acetone The mixture (60 ml) was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (three times), the extract solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue on a silica gel column. By separating and purifying by chromatography, ethyl 7-benzyloxy-4-chloro-2
-Indole carboxylate (0.50 g, 35.8%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.39 to 1.44 (3H,
m), 4.40 (2H, dd, J = 6.9, 14.2Hz), 5.18
(2H, s), 6.69 (1H, d, J = 8.3Hz), 7.01
(1H, d, J = 8.3Hz), 7.26 to 7.27 (1H,
m), 7.35 to 7.48 (5H, m), 9.15 (1H, br-
s).

Reference Example 13 Synthesis of ethyl-6-benzyloxy-4-chloro-2-indolecarboxylate a) Synthesis of ethyl-3- (4-benzyloxy-2-chlorophenyl) -2-azidopropenoate 4 -Benzyloxy-2-chlorobenzaldehyde (5.
40 g, 21.9 mmol) and ethyl azide acetate (11.3
g, 87.6 mmol) in ethanol solution (70 ml)
It was slowly added dropwise at 70 ° C. to an ethanol solution (70 ml) of sodium ethoxide (5.95 g, 87.6 mmol). After further stirring at -10 ° C for 5 hours, the reaction temperature was gradually raised to room temperature. The reaction mixture was poured into saturated ammonium chloride aqueous solution (200 ml) and extracted with ethyl acetate (3 times).
The extract was washed with a saturated aqueous solution of ammonium chloride, followed by washing with a saturated saline solution and dried over anhydrous magnesium sulfate. , Ethyl 3- (4-benzyloxy-2-chlorophenyl) -2-azitopropenoate (4.50 g, 57.5%) was obtained.

B) Ethyl-6-benzyloxy-4-
Synthesis of Chloro-2-indole Carboxylate A solution of ethyl 3- (4-benzyloxy-2-chlorophenyl-2-azidopropenoate (4.50 g, 12.6 mmol) in toluene (100 ml) was heated under reflux for 3 hours. Was concentrated under reduced pressure, and the residue obtained was separated and purified by silica gel column chromatography to give ethyl-
6-Benzyloxy-4-chloro-2-indolecarboxylate (3.73 g, 89.9%) was obtained. ¹ Hnmr (CDCl ₃ ) δ; 1.38-1.43 (3H,
m), 4.35 to 4.43 (2H, m), 5.09 (2H, s), 6.
79 (1H, dd, J = 0.7, 2.0Hz), 6.95 (1H,
d, J = 2.0 Hz), 7.23 to 7.24 (1H, m), 7.31 to
7.45 (5H, m), 8.94 (1H, br-s).

Reference Example 14 Synthesis of methyl 1- (2-carbamoylethyl) -2-indolecarboxylate a) Synthesis of methyl 1- (2-cyanoethyl) -2-indolecarboxylate Methyl 2-indolecarboxylate (10.0 g) ,Five
7.1 mmol) in 1,4-dioxane (150 ml) in acrylonitrile (3.63 g, 68.4 mmol) and N-
Benzyltrimethylammonium hydroxide (40%
Methanol solution (2.2 ml) was added, and the mixture was stirred at 55 ° C for 1 hr. The residue obtained by concentrating the reaction solution under reduced pressure was added to a mixed solution of acetic acid (5 ml) and water (500 ml), the aqueous layer was extracted with methylene chloride (twice), and the extract was washed with water. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give methyl 1- (2-cyanoethyl) -2-indolecarboxylate (13.0
g) was obtained.

B) Synthesis of methyl 1- (2-carbamoylethyl) -2-indolecarboxylate Methyl 1- (2-cyanoethyl) -2-indolecarboxylate (3.12 g, 13.7 mmol), 10% aqueous sodium carbonate solution ( 30 ml), 30% hydrogen peroxide water (30 m
A mixture of l) and acetone (100 ml) was stirred at room temperature for 4 hours. Then, cool the reaction mixture to 0 ° C. and then
Excess peroxide was decomposed by dropping a 0% sodium sulfite aqueous solution. Next, most of the acetone in the reaction solution was distilled off under reduced pressure, and the concentrated solution was extracted with ethyl acetate (3
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography to give methyl 1- (2 -Carbamoylethyl)-
2-Indole carboxylate (2.30 g, 68%) was obtained.

¹ Hnmr (CDCl ₃ ) δ; 2.75 (2
H, ddd, J = 1.7, 5.9, 7.6 Hz), 3.92 (3
H, s), 4.85 (2H, ddd, J = 1.7, 5.9, 7.6)
Hz), 5.37 (1H, br-s), 5.72 (1H, br-
s), 7.16 (1H, ddd, J = 1.0, 6.9, 7.4H
z), 7.32 (1H, d, J = 1.0Hz), 7.37 (1H,
ddd, J = 1.0, 7.3, 7.8 Hz), 7.53 (1H, d
d, J = 0.8, 8.4 Hz), 7.67 (1H, dt, J = 1.
0,7.9 Hz).

The reaction was carried out according to the method of Reference Example 14,
The compounds shown below were synthesized. (1) Ethyl 1- (2-carbamoylethyl) -4
-Chloro-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.43 (3H, t, J = 7.
3Hz), 2.65-2.82 (1H, m), 4.39 (2H, q,
J = 7.3 Hz), 4.84 (2H, ddd, J = 1.0, 6.
3,7.3 Hz), 5.45 (1H, br-s), 5.68 (1
H, br-s), 7.14 (1H, d, J = 7.9 Hz), 7.
26 (1H, dd, J = 7.6, 8.2Hz), 7.41 (1H,
d, J = 1.0Hz), 7.45 (1H, d, J = 8.6H)
z).

Reference Example 15 Methyl 7-carbamoylmethoxy-1-methyl-2-
Synthesis of indole carboxylate a) Synthesis of methyl 7-hydroxy-1-methyl-2-indolecarboxylate Methyl 7-benzyloxy-1-methyl-2-indolecarboxylate (2.31 g, 7.82 mmol) was added to tetrahydrofuran (50 ml). ) And methanol (50 ml) in a mixed solvent, and then 10% palladium / carbon (0.
After the addition of 5 g), the catalytic reduction was usually carried out at normal pressure. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to give methyl 7-hydroxy-1-methyl-.
2-indole carboxylate (1.63g,> 99%)
Got

B) Synthesis of methyl 7-carbamoylmethoxy-1-methyl-2-indolecarboxylate Methyl 7-hydroxy-1-methyl-2-indolecarboxylate (0.50 g, 2.44 mmol) in 60% sodium hydride ( 0.01 g, 2.44 mmol) and dimethylformamide (25 ml) were added to the suspension, and the mixture was stirred at room temperature to become a transparent liquid, and then 2-chloroacetamide (0.25 g, 2.68 mmol) was added at room temperature. In addition, it stirred at 50 degreeC for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 times).
Then, the extract is washed with water and dried over anhydrous magnesium sulfate,
The solvent was evaporated under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to give methyl 7-carbamoylmethoxy-1-methyl-2-indolecarboxylate (0.54 g, 84.4%). ¹ Hnmr (CDCl ₃ ) δ; 3.91 (3H, s), 4.41
(3H, s), 4.67 (2H, s), 5.70 (1H, br-
s), 6.41 (1H, br-s), 6.70-6.73 (1H,
m), 7.03 (1H, t, J = 7.9Hz), 7.62 (1H,
s), 7.31-7.34 (1H, m).

Reactions were carried out according to the method of Reference Example 15 to synthesize the compounds shown below. (1) Methyl 1-methyl-7- (2-phenylethoxy) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 3.17-3.22 (2H,
m), 3.87 (3H, s), 4.24 (3H, s), 4.31-4.
36 (2H, m), 6.68 (1H, d, J = 7.6Hz), 6.
94-7.00 (1H, m), 7.18-7.35 (7H, m). (2) Methyl 1-methyl-7- (3-phenylpropoxy) -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 2.16-2.26 (2H,
m), 2.84-2.90 (2H, m), 3.89 (3H, s), 4.
07-4.12 (2H, m), 4.43 (3H, s), 6.64 (1
H, d, J = 6.9Hz), 6.97 (1H, t, J = 7.9H
z), 7.18-7.23 (5H, m), 7.25-7.33 (2H,
m).

(3) Ethyl 7-carbamoylmethoxy-4-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.33-1.36 (3H,
m), 4.29-4.37 (5H, m), 4.60 (2H, s), 6.
69 (1H, d, J = 8.3Hz), 7.06 (1H, dd, J
= 0.7, 8.2 Hz), 7.15 (1H, d, J = 0.7H
z), 7.38 (1H, br-s), 7.54 (1H, br-
s). (4) Ethyl 4-chloro-7- (2-dimethylaminoethoxy) -1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 2.36 (6H, s), 2.82 (2H, t, J = 5.9H)
z), 4.17 (2H, t, J = 5.9Hz), 4.33-4.40
(5H, m), 6.59 (1H, d, J = 8.3Hz), 6.96
(1H, d, J = 7.9Hz), 7.30 (1H, s).

(5) Ethyl 6-carbamoylmethoxy-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.38-1.43 (3H,
m), 4.03 (3H, s), 4.32-4.40 (2H, m), 4.
60 (2H, s), 5.61 (1H, br-s), 6.59 (1
H, br-s), 6.79 (1H, d, J = 2.3 Hz), 6.
84 (1H, dd, J = 2.3, 8.6Hz), 7.26-7.27
(1H, m), 7.57-7.60 (1H, m). (6) Ethyl-4-chloro-1-methyl-7- [2-
(N-pyrrolidinyl) ethoxy] -2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 1.79-1.84 (4H, m), 2.63-2.68 (4H,
m), 2.97-3.02 (2H, m), 4.20-4.24 (2H,
m), 4.33-4.41 (5H, m), 6.60 (1H, d, J =
8.6Hz), 6.97 (1H, d, J = 8.3Hz), 7.31
(1H, s).

(7) Methyl 7- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.43 (9H, s), 2.09
(2H, t, J = 6.3Hz), 3.35-3.42 (2H,
m), 3.89 (3H, s,), 4.13-4.18 (2H, m),
4.39 (3H, s), 4.73 (1H, br-s), 6.69 (1
H, d, J = 7.9 Hz), 6.96-7.02 (1H, m), 7.
21-7.26 (2H, m). (8) Ethyl 7- (3-tert-butoxycarbonylaminopropoxy) -4-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.38-1.44 (12H,
m), 2.03-2.13 (2H, m), 3.33-3.40 (2H,
m), 4.12 (2H, t, J = 5.9Hz), 4.33-4.41
(5H, m), 4.70 (1H, br-s), 6.58 (1H,
d, J = 8.3Hz), 6.96 (1H, d, J = 8.3H)
z), 7.31 (1H, s).

(9) Ethyl 6- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.37-1.42 (3H,
m), 1.45 (9H, s), 2.02 (2H, dd, J = 6.
3,12.5Hz), 3.33-3.40 (2H, m), 4.02 (3
H, s), 4.10 (2H, t, J = 5.9Hz), 4.35 (2
H, dd, J = 6.9, 14.2Hz), 4.78 (1H, br-
s), 6.76 (1H, s), 6.78-6.83 (1H, m), 7.
24-7.26 (1H, m), 7.53 (1H, d, J = 8.6H
z). (10) Ethyl 7- (2-tert-butoxycarbonylaminoethoxy) -4-chloro-1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 1.45 (9H, s), 3.63 (2H, dd, J = 5.
3,10.6Hz), 4.13 (2H, t, J = 5.3Hz), 4.
30-4.41 (5H, m), 4.63-4.89 (1H, m), 6.58
(1H, d, J = 8.3Hz), 6.97 (1H, d, J = 8.3.
3Hz), 7.31 (1H, s).

(11) Methyl 1-methyl-7- [2-
(2-Tetrahydropyranyl) oxyethoxy] -2-
Indole carboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.52-1.85 (6H,
m), 3.50-3.58 (1H, m), 3.83-3.90 (5H,
m), 4.11-4.19 (1H, m), 4.26-4.30 (2H,
m), 4.42 (3H, s), 4.73-4.75 (1H, m), 6.
70-6.73 (1H, m), 7.01 (1H, t, J = 7.9H
z), 7.22-7.26 (2H, m). (12) Ethyl 4-chloro-1-methyl-7- [2-
(2-Tetrahydropyranyl) oxyethoxy] -2-
Indole carboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.42 (3H, t, J = 7.
3Hz), 1.52-1.85 (6H, m), 3.51-3.56 (1
H, m), 3.81-3.91 (2H, m), 4.10-4.17 (1
H, m), 4.23-4.27 (2H, m), 4.33-4.40 (5
H, m), 4.72-4.73 (1H, m), 6.61 (1H, d,
J = 8.2Hz), 6.96 (1H, d, J = 8.3Hz), 7.
30 (1H, s).

(13) Ethyl 4-chloro-7- (2:
3-isopropylidenedioxypropoxy) -1-methyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.47 (9H,
m), 3.91-3.99 (1H, m), 4.06-4.23 (3H,
m), 4.33-4.41 (5H, m), 4.51-4.63 (1H,
m), 6.60 (1H, d, J = 8.3Hz), 6.97 (1H,
d, J = 8.3 Hz), 7.31 (1 H, s). (14) Ethyl 4-chloro-1-methyl-7- [4-
(2-Tetrahydropyranyl) oxybutoxy] -2-
Indole carboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39-1.44 (3H,
m), 1.52-1.85 (8H, m), 1.87-2.04 (2H,
m), 3.44-3.55 (2H, m), 3.79-3.91 (2H,
m), 4.10 (2H, t, J = 6.3Hz), 4.33-4.41
(5H, m), 4.58-4.61 (1H, m), 6.56 (1H,
d, J = 8.3Hz), 6.96 (1H, d, J = 8.3H)
z), 7.30 (1H, s).

Reference Example 16 Synthesis of ethyl-4-carboxy-1-methyl-2-indolecarboxylate a) Ethyl 4-hydroxymethyl-1-methyl-2
-Synthesis of indolecarboxylate Ethyl 1-methyl-4- (2-tetrahydropyranyl) oxymethyl-2-indolecarboxylate (4.00 g, 12.6 mmol) in a mixed solvent of 2N hydrochloric acid (20 ml) / tetrahydrofuran (60 ml). It was melted and stirred at 50 ° C. for 1 hour. The reaction mixture was poured into ice water, the aqueous layer was extracted with ethyl acetate (three times), the extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl 4 was obtained by separating and purifying the residue by silica gel column chromatography.
-Hydroxymethyl-1-methyl-indole carboxylate (2.90 g, 99%) was obtained.

B) Synthesis of ethyl 4-carboxy-1-methyl-2-indolecarboxylate Ethyl 4-hydroxymethyl-1-methyl-indolecarboxylate (0.70 g, 3.00 mmol) was dissolved in acetone (30 ml) and Jones reagent (chromium (VI) oxide (26.7 g) in concentrated sulfuric acid (23 ml) at room temperature in the solution.
3.3 ml of a reagent prepared by dissolving in water (40 ml) and diluting the whole with 100 ml of water) was added dropwise, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was poured into ice water, the aqueous layer was extracted with chloroform (three times), the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. By separating and purifying by silica gel column chromatography, ethyl 4-carboxy-1-
Methyl-2-indolecarboxylate (0.38g, 5
1.2%) was obtained. ¹ Hnmr (DMSO-d ₆ ) δ; 1.34-1.40 (3H,
m), 4.08 (3H, s), 4.35 (2H, dd, J = 7.
3, 14.2Hz), 7.41-7.47 (1H, m), 7.72 (1
H, s), 7.82-7.89 (2H, m), 12.7 (0.5H, b)
r-s).

Reference Example 17 Synthesis of ethyl 6-benzyloxy-4-methyl-2-indolecarboxylate a) Synthesis of 4-benzyloxy-2-methylbenzoic acid 5-Benzyloxy-2-bromotoluene (5.00 g, 18.
A mixture of 9 mmol), magnesium metal (0.46 g, 18.9 mmol), a catalytic amount of iodine and tetrahydrofuran (20 ml) was heated under reflux for 2 hours. Next, the reaction solution was cooled to −50 ° C., and then carbon dioxide was bubbled for 30 minutes. The reaction temperature was raised to room temperature and further stirred at room temperature for 2 hours. Then, the reaction solution was poured into IN hydrochloric acid water, extracted with ethyl acetate (twice), the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue on silica gel. By separating and purifying by column chromatography, 4-benzyloxy-2-methylbenzoic acid (1.40
g) got. b) Synthesis of methyl 4-benzyloxy-2-methylbenzoate 4-benzyloxy-2-methylbenzoic acid (1.40 g, 5.78
mmol), thionyl chloride (1.37 g, 11.6 mmol) and methanol (50 ml) were used and the reaction was carried out according to Reference Example 6 to give methyl 4-benzyloxy-2-methylbenzoate (0.7).
7g) was obtained. c) Synthesis of 4-benzyloxy-2-methylbenzyl alcohol A suspension of lithium aluminum hydride (0.11g, 2.93mmol) in tetrahydrofuran (20ml) was cooled to 0 ° C and methyl 4-benzyl was added to the suspension. A solution of oxy-2-methylbenzoate (0.75g, 2.93mmol) in THF (20ml) was added dropwise at 0 ° C. The reaction solution was stirred at 0 ° C. for 2 hours and then post-treated by a conventional method to give 4-benzyloxy-2-methylbenzyl alcohol (0.66 g).

D) Synthesis of 4-benzyloxy-2-methylbenzaldehyde 4-benzyloxy-2-methylbenzyl alcohol
(0.70g, 3.07mmol), manganese dioxide (2.67g, 30.7mmo
A mixture of l), methanol (0.5 ml) and chloroform (20 ml) was stirred at room temperature for 11 hours. Next, insoluble matter is filtered off, the obtained filtrate is concentrated under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography to give 4-benzyloxy-2-methylbenzaldehyde.
(0.60g) was obtained. e) Synthesis of ethyl 3- (4-benzyloxy-2-methylphenyl) -2-azidopropenoate 4-benzyloxy-2-methylbenzaldehyde (2.8
0g, 12.4mmol), ethyl azide acetate (6.39g, 49.5
mmol), sodium ethoxide (3.37 g, 49.5 mmol) and ethanol (50 ml) were used and the reaction was carried out according to a) of Reference Example 13 to obtain ethyl 3- (4-benzyloxy-2-methylphenyl) -2. -Azidopropenoate (3.24g) was obtained.

F) Synthesis of ethyl 6-benzyloxy-4-methyl-2-indolecarboxylate Ethyl 3- (4-benzyloxy-2-methylphenyl) -2-azidopropenoate (3.22 g) and toluene
(100 ml) was used and the reaction was carried out according to b) of Reference Example 13 to obtain ethyl 6-benzyloxy-4-methyl-2-indolecarboxylate (2.66 g). ¹ Hnmr (CDCl ₃ ) δ; 1.38 to 1.43 (3H, m), 2.51 (3H, s),
4.38 (2H, dd, J = 6.9,14.2Hz), 5.09 (2H, s), 6.72 (2H, s),
7.19 (1H, d, J = 2.3Hz), 7.29 to 7.46 (5H, m), 8.71 (1H, br-
s). The reaction was performed according to the method of Reference Example 17 to synthesize the compound shown below. (1) Ethyl 6-benzyloxy-4-trifluoromethyl-2-indolecarboxylate ¹ Hnmr (CDCl ₃ ) δ; 1.39 to 1.44 (3H, m), 4.37 to 4.45 (2
H, m), 5.14 (2H, s), 7.05 (1H, s), 7.23 to 7.24 (1H.m), 7.
30 (1H, s), 7.35 to 7.47 (5H, m), 8.92 (1H, br-s).

[0127]

【Example】

Example 1 Synthesis of 1-methyl-2-indoloylguanidine Guanidine hydrochloride (8.58) was added to a solution of sodium methoxide (4.85 g, 89.8 mmol) in methanol (70 ml).
g, 89.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, and then the precipitated salt was filtered off to give a solution of methyl 1-methyl-2-indolecarboxylate (1.70 g, 8.97).
mmol) was added, and then methanol was distilled off under reduced pressure. The obtained residue was heated at 130 ° C for 5 minutes and allowed to stand at room temperature for 1 hour, then water was poured into the reaction solution and extracted with ethyl acetate (3 times). The extract solution was washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to obtain 1-methyl-2-indoloylguanidine of interest. This was dissolved in chloroform and hydrochloric acid was salified with hydrogen chloride / ether to give 1-methyl-2-indoloylguanidine hydrochloride (0.70 g, 30.8%). mp 250 ℃ or more. ¹ H nmr (DMSO-d ₆ ) δ; 4.04 (3H, s),
7.12-7.21 (1H, m), 7.31-7.44 (1H, m), 7.61 (1H, d, J =
8.6Hz), 7.73 (1H, d, J = 7.9Hz), 7,89 (1H, s), 8.5 (2H,
br-s), 8.7 (2H, br-s), 11.9 (1H, br-s).

Example 2 Synthesis of 1-methyl-5-indoloylguanidine Methyl 1-methyl-5-indolecarboxylate (1.00 g, 5.29 mmol), guanidine hydrochloride (5.05 g,
52.9 mmol) and sodium methoxide (2.85 g, 5
(2.9 mmol) in methanol (50 ml) was reacted according to the method of Example 1 to obtain 1-methyl-5-indoloylguanidine hydrochloride (0.92 g, 68.9%). mp 260 ℃ or more. ¹ H nmr (DMSO-d ₆ ) δ; 3.86 (3H,
s), 6.62-6.64 (1H, m), 7.50 (1H, d, J = 3.3Hz), 7.61 (1
H, d, J = 8.9Hz), 7.91-7.95 (1H, m), 8.44 (2H, br-s),
8.47 (1H, d, J = 1.3Hz), 8.7 (2H, br-s), 11.7 (1H, br-
s).

Example 3 Synthesis of 1-methyl-3-indoloylguanidine Methyl 1-methyl-3-indolecarboxylate (1.00 g, 5.29 mmol), guanidine hydrochloride (5.05)
g, 52.9 mmol) and sodium methoxide (2.85 g,
The reaction was performed according to the method of Example 1 from a methanol solution (50 ml) of 52.9 mmol) to obtain 1-methyl-3-indoloylguanidine hydrochloride (0.48 g, 35.9%). mp 252-253 ℃. ¹ H nmr (DMSO-d ₆ ) δ; 3.91 (3H, s),
7.25-7.37 (2H, m), 7.58-7.61 (1H, m), 8.15 (1H, dd,
J = 1.3, 6.6Hz), 8.3 (2H, br-s), 8.6 (2H, br-s), 8.78 (1
H, s), 11.8 (1H, br-s).

Example 4 Synthesis of 1-methyl-4-indoloylguanidine Methyl 1-methyl-4-indolecarboxylate (0.85 g, 4.49 mmol), guanidine hydrochloride (4.29 g,
44.9 mmol) and sodium methoxide (2.43 g, 44.
Example 1 from a methanol solution (50 ml) of 9 mmol).
The reaction was carried out according to the method of 1) to give 1-methyl-4-indoloylguanidine hydrochloride (0.75 g, 66.1%). mp 186-187 ℃. ¹ H nmr (DMSO-d ₆ ) δ; 3.88 (3H, s),
6.97 (1H, d, J = 3.0Hz), 7.92-7.35 (1H, m), 7.56 (1H, d,
J = 3.0Hz), 7.84 (1H, d, J = 7.9Hz), 7.98 (1H, d, J = 7.6
Hz), 8.5 (2H, br-s), 8.7 (2H, br-s), 11.7 (1H, br-s).

Example 5 Synthesis of 4-chloro-1-methyl-2-indoloylguanidine Methyl 4-chloro-1-methyl-2-indolecarboxylate (2.00 g, 8.94 mmol), guanidine hydrochloride (8.54 g) , 89.4 mmol) and sodium methoxide (4.83 g, 89.4 mmol) in methanol (50 ml) were reacted according to the method of Example 1 to give 4-chloro-1-methyl-2-indoloylguanidine. The hydrochloride salt (1.06g, 41.3%) was obtained. mp 288-290 ℃. ¹ H nmr (DMSO-d ₆ ) δ; 4.05 (3H, s),
7.24 (1H, d, J = 7.6Hz), 7.35-7.41 (1H, m), 7.62 (1H, d,
J = 8.6Hz), 7.98 (1H, s), 8.56 (2H, br-s), 8.63 (2H, b
rs), 12.0 (1H, br-s).

The reaction was carried out according to the method of Example 1 to synthesize the compounds of Examples 6 to 81 below. Example 6 5-Chloro-1-methyl-2-indoloylguanidine / hydrochloride Yield: 43.6% .mp 281-282 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 4.03 (3H, s), 7.39 (1H, dd, J = 2.0, 8.9Hz), 7.67
(1H, d, J = 8.9Hz), 7.77 (1H, s), 7.81 (1H, d, J = 1.7H
z), 8.5 (2H, br-s), 8.6 (2H, br-s), 11.9 (1H, br-s). Example 7 6-chloro-1-methyl-2-indoloylguanidine / hydrochloride Rate: 59.6% .mp 290-294 ℃. ¹ H nmr (DMSO-d ₆ ).
δ; 4.02 (3H, s), 7.17 (1H, dd, J = 2.0, 8.6Hz), 7.74
-7.77 (2H, m), 7.84 (1H, s), 8.5 (2H, br-s), 8.6 (2H,
br-s), 11.9 (1H, br-s). Example 8 7-chloro-1-methyl-2-indoloylguanidine-hydrochloride Yield: 56.5% .mp 243-244 ° C. ¹ H nmr (DMSO -d ₆ )
δ; 4.33 (3H, s), 7.11-7.17 (1H, m), 7.41 (1H, d, J =
7.6Hz), 7.71 (1H, d, J = 7.9Hz), 7.81 (1H, s), 8.5 (2H,
br-s), 8.6 (2H, br-s), 12.0 (1H, br-s).

Example 9 1,4-Dimethyl-2-indoloylguanidine-hydrochloride Yield: 32.5% .mp 279-280 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 2.53 (3H, s), 4.02 (3H, s), 6.96 (1H, d, J = 6.9H
z), 7.26-7.32 (1H, m), 7.41 (1H, d, J = 8.3Hz), 7.99 (1
H, s), 8.5 (2H, br-s), 8.7 (2H, br-s), 11.9 (1H, br-
s). Example 10 1,5-Dimethyl-2-indoloylguanidine / hydrochloride Yield: 30.5% .mp 281-282 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 2.41 (3H, s), 4.00 (3H, s), 7.23 (1H, d, J = 8.9H
z), 7.48-7.51 (2H, m), 7.79 (1H, s), 8.5 (2H, br-s),
8.7 (2H, br-s), 11.9 (1H, br-s). Example 11 1,6-Dimethyl-2-indoloylguanidine-hydrochloride Yield: 63.1% .mp 267-269 ° C. ¹ H nmr (DMSO-d ₆ )
δ; 2.47 (3H, s), 3.99 (3H, s), 7.02 (1H, d, J = 8.3H
z), 7.41 (1H, s), 7.61-8.00 (2H, m), 8.4 (2H, br-s),
8.5 (2H, br-s), 11.6 (1H, br-s).

Example 12 1,7-Dimethyl-2-indoloylguanidine / hydrochloride Yield: 27.3% .mp 271-273 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 2.78 (3H, s), 4.25 (3H, s), 6.99-7.11 (2H, m),
7.53 (1H, d, J = 7.6Hz), 7.70 (1H, s), 8.4 (2H, br-s),
8.6 (2H, br-s), 11.8 (1H, br-s). Example 13 5-Methoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 50.1% .mp 235-236 ° C. ¹ H nmr (DMSO-d ₆ )
δ; 3.80 (3H, s), 4.01 (3H, s), 7.03-7.07 (1H, m),
7.16 (1H, d, J = 2.3Hz), 7.52 (1H, d, J = 8.9Hz), 7.75 (1
H, s), 8.4 (2H, br-s), 8.7 (2H, br-s), 11.8 (1H, br-
s).

Example 14 1-Methyl-6-indoloylguanidine / hydrochloride Yield: 62.1% .mp 297-298 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 3.94 (3H, s), 6.55 (1H, dd, J = 0.7, 3.0Hz), 7.61
(1H, d, J = 3.0Hz), 7.67-7.78 (2H, m), 8.4 (2H, br-s),
8.6 (1H, s), 8.9 (2H, br-s), 12.0 (1H, br-s).

Example 15 1-Benzyl-2-indoloylguanidine / hydrochloride Yield: 54.9%. Mp 228-229 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 5.86 (2H, s), 7.03 (2H, d, J = 6.6Hz), 7.17-7.39
(4H, m), 7.57 (1H, d, J = 8.3Hz), 7.78 (1H, d, J = 7.9H
z), 7.98 (1H, s), 8.4 (2H, br-s), 8.6 (2H, br-s), 11.
9 (1H, br-s). Example 16 1-Benzyl-3-indoloylguanidine / hydrochloride Yield: 66.2% .mp 252-253 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 5.53 (2H, s), 7.23-7.37 (7H, m), 7.62-7.66 (1H,
m), 8.15-8.18 (1H, m), 8.3 (2H, br-s), 8.6 (2H, br-
s), 8.95 (1H, s), 11.8 (1H, br-s). Example 17 1-Isopropyl-3-indoloylguanidine-hydrochloride Yield: 49.7% .mp 221-223 ° C. ¹ H nmr ( DMSO-d ₆ )
δ; 1.51 (6H, d, J = 6.6Hz), 4.85-4.90 (1H, m), 7.24-
7.34 (2H, m), 7.67 (1H, d, J = 7.6Hz), 8.14-8.17 (1H,
m), 8.3 (2H, br-s), 8.6 (2H, br-s), 9.12 (1H, s), 11.
9 (1H, br-s).

Example 18 2-Indoylguanidine hydrochloride: Yield: 61.9% .mp 192-194 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 7.09-7.14 (1H, m), 7.28-7.34 (1H, m), 7.49 (1H,
d, J = 8.3Hz), 7.71 (1H, d, J = 8.3Hz), 8.5 (2H, br-s),
8.7 (2H, br-s), 12.06 (1H, br-s), 12.13 (1H, br-s) .. Example 19 3-Indoloylguanidine hydrochloride: Yield: 42.2%. Mp 287 ° C. ¹ H nmr (DMSO-d ₆ ) δ;
7.20-7.29 (2H, m), 7.53 (1H, dd, J = 1.7, 6.6Hz), 8.12
-8.16 (1H, m), 8.3 (2H, br-s), 8.7 (2H, br-s), 8.83 (1
H, d, J = 3.3 Hz), 11.8 (1H, br-s), 12.2 (1H, br-s). Example 20 5-Indoylylguanidine hydrochloride salt yield: 55.9%. Mp 219-222 ° C. ^{. 1 H nmr (DMSO-d} 6)
δ; 6.61-6.63 (1H, m), 7.50-7.56 (2H, m), 7.85-7.89
(1H, m), 8.45 (2H, br-s), 8.49 (1H, d, J = 1.7Hz), 8.75
(2H, br-s), 11.6 (1H, br-s), 11.7 (1H, br-s).

Example 21 1-Isopropyl-5-indoloylguanidine · hydrochloride Yield: 72.5% .mp 219 ° C. ¹ H nmr (DMSO-d ₆ ) δ;
1.48 (6H, d, J = 6.6Hz), 4.81-4.88 (1H, m), 6.67 (1H,
d, J = 3.3Hz), 7.68-7.71 (2H, m), 7.89-7.93 (1H, m),
8.3-8.6 (3H, m), 8.7 (2H, br-s), 11.7 (1H, br-s). Example 22 4-methoxy-1-methyl-2-indoloylguanidine / hydrochloride Yield: 54.5 % .mp 281-282 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 3.93 (3H, s), 4.01 (3H, s), 6.62 (1H, d, J = 7.9H
z), 7.16 (1H, d, J = 8.6Hz), 7.30-7.36 (1H, m), 7.83 (1
H, s), 8.5 (2H, br-s), 8.6 (2H, br-s), 11.7 (1H, br-
s). Example 23 6-Methoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 75.5% .mp 272 ° C. ¹ H nmr (DMSO-d ₆ ) δ;
3.87 (3H, s), 4.00 (3H, s), 6.81 (1H, dd, J = 2.0, 8.9H
z), 7.05 (1H, d, J = 2.0Hz), 7.59 (1H, d, J = 8.9Hz), 7.
84 (1H, s), 8.4 (2H, br-s), 8.7 (2H, br-s), 11.8 (1H,
br-s).

Example 24 1-Methyl-4-nitro-2-indoloylguanidine hydrochloride Yield: 97.7% .mp 292-293 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 4.14 (3H, s), 7.59-7.65 (1H, m), 8.16 (1H, m),
8.20-8.28 (2H, m), 8.5 (4H, br-s), 11.8 (1H, br-s). Example 25 1-Methyl-6-nitro-2-indoloylguanidine / hydrochloride Yield: 68.4 % .mp 279-283 ℃. ¹ H nmr (DMSO-d ₆ ).
δ; 4.15 (3H, s), 7.89 (1H, s), 7.95-8.03 (2H, m),
8.51-8.66 (5H, m), 12.1 (1H, br-s). Example 26 1-Methyl-7-nitro-2-indoloylguanidine / hydrochloride Yield: 66.8%. Mp 268-270 ° C. ¹ H nmr (DMSO-d ₆ )
δ; 3.83 (3H, s), 7.36 (1H, t, J = 7.9Hz), 7.98 (1H,
s), 8.06 (1H, dd, J = 1.0, 7.9Hz), 8.19 (1H, dd, J = 1.
0, 7.9Hz), 8.44-8.74 (4H, m), 12.2 (1H, br-s).

Example 27 1-Methyl-5-nitro-2-indoloylguanidine · hydrochloride Yield: 73.6% .mp 294-295 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 4.09 (3H, s), 7.86-7.91 (2H, m), 8.23 (1H, dd, J
= 2.3, 9.2Hz), 8.49 (4H, br-s), 8.83 (1H, d, J = 2.3H
z), 11.9 (1H, br-s). Example 28 1-Methyl-7-indoloylguanidine / hydrochloride Yield: 37.4% mp203-204 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.78 (3H, s), 6.60 (1H,
d, J = 3.3Hz), 7.16 (1H, t, J = 7.6H
z), 7.44 (1H, d, J = 3.0Hz), 7.53 (1H,
d, J = 7.6 Hz), 7.85 (1H, d, J = 7.9H
z), 8.44 (2H, br-s), 8.52 (2H, br-
s), 11.90 (1H, br-s).

Example 29 1-Methyl-4-trifluoromethyl-2-indoloylguanidine · hydrochloride Yield: 57.8% mp 283-285 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.10 (3H, s), 7.52-7.58 (2
H, m), 7.91 (1H, s), 7.98-8.01 (1H,
m), 8.4-8.8 (4H, m), 11.99 (1H, br-
s). Example 30 5-Fluoro-1-methyl-2-indoloylguanidine-hydrochloride Yield: 60.8% mp278-281 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.03 (3H, s), 7.25-7.33 (1
H, m), 7.54 (1H, dd, J = 2.3, 9.6Hz),
7.69 (1H, dd, J = 4.6, 9.2Hz), 7.82 (1
H, s), 8.51 (2H, br-s), 8.69 (2H, br)
-S), 11.98 (1H, br-s).

Example 31 5-Ethoxy-1-methyl-2-indoloylguanidine · hydrochloride Yield: 30.9% mp 234-236 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.35 (3H, t, J = 6.9Hz),
3.99 (3H, s), 4.05 (2H, dd, J = 6.9, 14.2
Hz), 7.05 (1H, dd, J = 2.3, 9.2Hz), 7.
16 (1H, d, J = 2.3Hz), 7.54 (1H, d, J =
8.9Hz), 7.73 (1H, s), 8.42 (2H, br-
s), 8.65 (2H, br-s), 11.81 (1H, br-
s). Example 32 5-Benzyloxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 45.2% mp 249-251 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.99 (3H, s), 5.14 (2H,
s), 7.12-7.16 (1H, m), 7.28-7.58 (7H,
m), 7.67 (1H, s), 8.28-8.68 (4H, m), 1
1.71 (1H, brs). Example 33 1-Methyl-6-trifluoromethyl-2-indoloylguanidine · hydrochloride Yield: 44.4% mp 255-257 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.11 (3H, s), 7.44 (1H, d
d, J = 1.3, 8.6 Hz), 7.97 (1H, d, J = 8.6
Hz), 8.10 (1H, s), 8.48 (2H, br-s),
8.63 (2H, br-s), 12.03 (1H, br-s).

Example 34 7-Benzyloxy-1-methyl-2-indoloylguanidine · hydrochloride Yield: 53.5% mp221−222 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.27 (3H, s), 5.26 (2H,
s), 6.97-7.08 (2H, m), 7.27-7.56 (5H,
m), 7.72 (1H, s), 8.43 (2H, br-s), 8.
60 (2H, br-s), 11.80 (1H, br-s). Example 35 1- (2-naphthylmethyl) -2-indoloylguanidine-hydrochloride Yield: 56.4% mp 254-255 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 6.02 (2H, s), 7.17-7.27 (2
H, m), 7.32-7.38 (1H, m), 7.43-7.48 (3
H, m), 7.60 (1H, d, J = 7.9 Hz), 7.73-7.
86 (4H, m), 8.07 (1H, s), 8.43 (2H, br
-S), 8.67 (2H, br-s), 12.04 (1H, br)
-S). Example 36 1- (2-phenylethyl) -2-indoloylguanidine-hydrochloride Yield: 55.1% mp262-264 ° C ¹ Hnmr (D
_{MSO-d 6) δ; 2.97-3.03} (2H, m), 4.73-4.
79 (2H, m), 7.13-7.24 (6H, m), 7.32-7.38
(1H, m), 7.59 (1H, d, J = 7.9Hz), 7.73
(1H, d, J = 7.9Hz), 7.84 (1H, s), 8.43
(2H, br-s), 8.62 (2H, br-s), 11.78
(1H, br-s).

Example 37 1- (4-Bromobenzyl) -2-indoloylguanidine · hydrochloride Yield: 53.3% mp 260-263 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 5.82 (2H, s), 6.99 (2H,
d, J = 8.3 Hz), 7.17-7.23 (1H, m), 7.35-
7.40 (1H, m), 7.47 (2H, d, J = 8.3Hz),
7.57 (1H, d, J = 8.3Hz), 7.79 (1H, d, J
= 7.9 Hz), 8.06 (1H, s), 8.47 (2H, br-
s), 8.69 (2H, br-s), 12.07 (1H, br-
s). Example 38 1- (4-Nitrobenzyl) -2-indoloylguanidine-hydrochloride Yield: 42.7% mp245-247 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 5.98 (2H, s), 7.20-7.27 (3
H, m), 7.39 (1H, t, J = 7.3Hz), 7.56 (1
H, d, J = 8.3Hz), 7.82 (1H, d, J = 7.9H)
z), 8.05 (1H, s), 8.16 (2H, d, J = 8.6H
z), 8.41 (2H, br-s), 8.61 (2H, br-
s), 12.02 (1H, br-s). Example 39 1- (4-Methoxybenzyl) -2-indoleguanidine-hydrochloride Yield: 54.8% mp239-240 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.68 (3H, s), 5.78 (2H,
s), 6.82 (2H, d, J = 8.6Hz), 7.18 (1H,
t, J = 7.3 Hz), 7.34-7.40 (1H, m), 7.61
(1H, d, J = 8.6Hz), 7.77 (1H, d, J = 7.6.
9Hz), 7.92 (1H, s), 8.43 (2H, br-
s), 8.60 (2H, br-s), 11.89 (1H, br-
s).

Example 40 1- (3-Phenylpropyl) -2-indoloylguanidine · hydrochloride Yield: 39.0% mp 147-148 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.97-2.13 (2H, m), 5.62 (2
H, t, J = 8.0Hz), 4.59 (2H, t, J = 7.0H
z), 7.11-7.34 (6H, m), 7.40 (1H, dt, J
= 1.0, 8.0 Hz), 7.57 (1H, d, J = 8.0H
z), 7.76 (1H, d, J = 8.0Hz), 7.81 (1H,
s), 8.25-8.70 (4H, m), 11.75 (1H, br-
s). Example 41 1- (4-phenylbutyl) -2-indoloylguanidine-hydrochloride Yield: 51.0% mp154-155 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 1.43-1.65 (2H, m), 1.65-1.
68 (2H, m), 2.57 (2H, t, J = 8.0Hz), 4.
58 (1H, t, J = 7.0Hz), 7.03-7.32 (6H,
m), 7.39 (1H, dt, J = 1.0, 8.0Hz), 7.63
(1H, d, J = 8.0Hz), 7.73 (1H, d, J = 8.
0Hz), 7.92 (1H, s), 8.20-9.00 (4H,
m), 11.95 (1H, br-s).

Example 42 1-Isopropyl-6-indoloylguanidine · hydrochloride Yield: 37.7% mp218-220 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.51 (6H, d, J = 6.6Hz),
4.92-5.02 (1H, m), 6.59 (1H, d, J = 3.0H
z), 7.66-7.81 (3H, m), 8.41 (2H, br-
s), 8.66 (1H, s), 8.86 (2H, br-s), 1
2.04 (1H, br-s). Example 43 1-Benzyl-6-indoloylguanidine-hydrochloride Yield: 44.5% mp227-228 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 5.57 (2H, s), 6.62 (1H,
d, J = 3.0 Hz), 7.24-7.32 (5H, m), 7.69-
7.79 (2H, m), 7.81 (1H, d, J = 3.0Hz),
8.43 (2H, br-s), 8.71 (1H, s), 8.86 (2
H, br-s), 12.06 (1H, br-s). Example 44 1-Isopropyl-4-indoloylguanidine hydrochloride Yield: 49.0% mp 95-97 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 1.48 (6H, d, J = 6.6Hz), 4.87
(1H, m), 7.01 (1H, d, J = 3.0Hz), 7.26
-7.31 (1H, m), 7.72 (1H, d, J = 3.3H
z), 7.91 (1H, d, J = 8.3Hz), 8.02 (1H,
d, J = 7.6 Hz), 8.54 (2H, br-s), 8.83
(2H, br-s), 11.85 (1H, br-s).

Example 45 1-Benzyl-4-indoloylguanidine · hydrochloride Yield: 42.6% mp203−205 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 5.52 (2H, s), 7.03 (1H,
d, J = 3.0 Hz), 7.17-7.32 (6H, m), 7.74
(1H, t, J = 1.7Hz), 7.84 (1H, d, J = 7.
9Hz), 7.98 (1H, d, J = 7.6Hz), 8.48 (2
H, br-s), 8.77 (2H, br-s), 11.79 (1
H, br-s). Example 46 4-Benzyloxy-1-methyl-2-indoloylguanidine / hydrochloride Yield: 57.6% mp 260 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.01 (3H, s), 5.26 (2H, s), 6.75
(1H, d, J = 7.6Hz), 7.20 (1H, d, J = 8.
6Hz), 7.30-7.54 (6H, m), 7.75 (1H,
s), 8.40 (4H, br-s), 11.41 (1H, br-
s). Example 47 1,3-Dimethyl-2-indoloylguanidine / hydrochloride Yield: 55.5% mp 228-229 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.56 (3H, s), 3.84 (3H,
s), 7.12-7.18 (1H, m), 7.34-7.40 (1H,
m), 7.53 (1H, d, J = 8.3Hz), 7.69 (1H,
d, J = 7.9 Hz), 8.61-8.68 (4H, m), 11.67
(1H, br-s).

Example 48 1-Methyl-7-phenyl-2-indoloylguanidine hydrochloride Yield: 58.9% mp265-267 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.07 (3H, s), 7.27 (1H,
d, J = 7.3 Hz), 7.41-7.75 (7H, m), 7.89
(1H, s), 8.50 (4H, br-s), 11.77 (1
H, br-s). Example 49 4-Acetyl-1-methyl-2-indoloylguanidine hydrochloride yield: 45.4% mp 288-289 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.71 (3H, s), 4.07 (3H,
s), 7.50-7.56 (1H, m), 7.91-7.97 (2H,
m), 8.25 (1H, s), 8.53 (4H, br-s), 1
1.71 (1H, br-s). Example 50 6-Benzyloxy-1-methyl-2-indoloylguanidine · hydrochloride Yield: 42.7% mp 269-270 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 3.99 (3H, s), 5.20 (2H,
s), 6.89 (1H, d, J = 10.6Hz), 7.22 (1H,
s), 7.35-7.58 (6H, m), 7.62-7.67 (1H,
m), 8.4 (4H, br-s), 11.35 (1H, br-
s).

Example 51 4-Ethoxy-1-methyl-2-indoloylguanidine hydrochloride: Yield: 69.8% mp262-263 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.42 (3H, t, J = 6.9Hz),
3.99 (3H, s), 4.19 (2H, q, J = 6.9Hz),
6.62 (1H, d, J = 7.6Hz), 7.16 (1H, d, J
= 8.6Hz), 7.28-7.34 (1H, m), 7.77 (1H,
s), 8.51 (4H, br-s), 11.60 (1H, br-
s). Example 52 1- (2-carbamoylethyl) -2-indoloylguanidine · hydrochloride Yield: 30.0% mp 285-286 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.55 (2H, t, J = 7.3Hz),
4.74 (2H, t, J = 7.3Hz), 6.85 (1H, br-
s), 7.17 (1H, t, J = 6.9Hz), 7.33 (1H,
br-s), 7.39 (1H, ddd, J = 1.0, 7.3, 7.
8 Hz), 7.70 (2H, dd, J = 8.4, 17.7Hz),
7.82 (1H, s), 8.46 (2H, br-s), 8.64 (2
H, br-s), 11.85 (1H, br-s). Example 53 1-Propyl-2-indoloylguanidine-hydrochloride Yield: 53.2% mp218-219 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 0.85 (3H, t, J = 7.6Hz),
1.66-1.77 (2H, m), 4.51 (2H, dd, J = 6.
9,7.6Hz), 7.10-7.23 (1H, m), 7.32-7.45
(1H, m), 7.65 (1H, d, J = 8.6Hz), 7.73
(1H, d, J = 7.9Hz), 7.97 (1H, s), 8.52
(2H, br-s), 8.77 (2H, br-s), 12.01
(1H, br-s).

Example 54 1- (2-Methoxyethyl) -2-indoloylguanidine · hydrochloride Yield: 15.0% mp 174-176 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 3.16 (3H, s), 3.63 (2H,
t, J = 5.3Hz), 4.72 (2H, t, J = 5.3H)
z), 7.11-7.22 (1H, m), 7.31-7.44 (1H,
m), 7.66 (1H, d, J = 8.6Hz), 7.72 (1H,
d, J = 7.9 Hz), 7.89 (1H, s), 8.49 (2H,
br-s), 8.70 (2H, br-s), 11.96 (1H,
br-s). Example 55 4-Fluoro-1-methyl-2-indoloylguanidine · hydrochloride Yield: 53.1% mp 281-282 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.04 (3H, s), 6.97 (1H, d
d, J = 7.6, 10.2 Hz), 7.35-7.43 (1H, m),
7.50 (1H, d, J = 8.3Hz), 7.89 (1H, s),
8.48-8.60 (4H, m), 11.92 (1H, br-s). Example 56 4-Bromo-1-methyl-2-indoloylguanidine hydrochloride yield: 58.2% mp 306-307 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.04 (3H, s), 7.30-7.36 (1
H, m), 7.42 (1H, d, J = 7.6Hz), 7.69 (1
H, d, J = 8.6Hz), 7.78 (1H, s), 8.56 (4
H, br-s), 11.91 (1H, br-s).

Example 57 4-isobutyroxy-1-methyl-2-indoloylguanidine hydrochloride Yield: 58.1% mp 245-247 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 1.05 (6H, d, J = 6.9Hz),
2.06-2.16 (1H, m), 3.90 (2H, d, J = 6.3H
z), 3.99 (3H, s), 6.61 (1H, d, J = 7.9H
z), 7.16 (1H, d, J = 8.6Hz), 7.28-7.34
(1H, m), 7.84 (1H, s), 8.51 (4H, br-
s), 11.65 (1H, br-s). Example 58 4-Isopropoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield: 62.3% mp 269-270 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 1.35 (6H, d, J = 5.9Hz),
3.99 (3H, s), 4.75-4.84 (1H, m), 6.65 (1
H, d, J = 7.6Hz), 7.14 (1H, d, J = 8.6H)
z), 7.28-7.34 (1H, m), 7.75 (1H, s), 8.
53 (4H, br-s), 11.59 (1H, br-s).

Example 59 1-Methyl-7- (2-phenylethoxy) -2-indoloylguanidine · hydrochloride Yield: 24.3% mp155-156 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 3.21 (2H, t, J = 6.3Hz),
4.13 (3H, s), 4.43 (2H, t, J = 6.3Hz),
6.95 (1H, d, J = 7.9Hz), 7.08 (1H, t, J
= 7.9 Hz), 7.25-7.44 (6H, m), 7.60 (1H,
s,) 8.44 (4H, br-s), 11.62 (1H, br-
s). Example 60 1-Methyl-7- (3-phenylpropoxy) -2-indoloylguanidine hydrochloride Yield: 46.1% mp165-166 ° C ¹ Hnmr (D
_{MSO-d 6) δ; 2.12-2.17} (2H, m), 2.79-2.
85 (2H, m), 4.09-4.13 (2H, m), 4.31 (3
H, s), 6.83 (1H, m), 7.00-7.05 (1H,
m), 7.19-7.32 (6H, m), 7.69 (1H, s), 8.
56 (4H, br-s), 11.75 (1H, br-s).

Example 61 7-Benzyloxy-4-chloro-1-methyl-2-indoloylguanidine · hydrochloride Yield: 54.4% mp 264 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.27 (3H, s), 5.26 (2H, s), 6.96
(1H, d, J = 8.6Hz), 7.11 (1H, d, J = 8.6Hz)
3Hz), 7.32-7.54 (5H, m), 7.78 (1H,
s), 8.5-8.6 (4H, m), 11.94 (1H, br-
s). Example 62 4-Carboxy-1-methyl-2-indoloylguanidine hydrochloride yield: 40.5% mp 302-303 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.07 (3H, s), 7.48-7.54 (1
H, m), 7.86-7.95 (2H, m), 8.10 (1H,
s), 8.3-8.7 (4H, m), 11.58 (1H, br-
s), 13.0 (0.7H, br-s). Example 63 7-carbamoylmethoxy-1-methyl-2-indoloylguanidine · hydrochloride Yield: 56.7% mp 268-269 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.32 (3H, s), 4.61 (2H,
s), 6.76 (1H, d, J = 7.9Hz), 7.03 (1H,
t, J = 7.9Hz), 7.30 (1H, d, J = 7.6H)
z), 7.40 (1H, br-s), 7.58 (1H, br-
s), 7.68 (1H, s), 8.54 (4H, m), 11.74
(1H, br-s).

Example 64 7-carbamoylmethoxy-4-chloro-1-methyl-
2-Indoloylguanidine / hydrochloride Yield: 29.7% mp270-271 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.33 (3H, s), 4.61 (2H,
s), 6.73 (1H, d, J = 8.3Hz), 7.10 (1H,
d, J = 8.3 Hz), 7.39 (1H, br-s), 7.58
(1H, br-s), 7.74 (1H, s), 8.57 (4H,
br-s), 11.93 (1H, br-s). Example 65 4-Chloro-7- (2-dimethylaminoethoxy) -1
-Methyl-2-indoloylguanidine / hydrochloride Yield: 50.8% mp287-288 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 2.86 (6H, d, J = 5.0Hz),
3.62-3.64 (2H, m), 4.29 (3H, s), 4.51-4.
55 (2H, m), 6.92 (1H, d, J = 8.2Hz), 7.
14 (1H, d, J = 8.3Hz), 7.88 (1H, s), 8.
6-8.9 (4H, m), 11.01 (1H, br-s), 1
2.13 (1H, br-s). Example 66 6-carbamoylmethoxy-1-methyl-2-indoloylguanidine hydrochloride yield: 26.8% mp 275 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 3.98 (3H, s), 4.53 (2H, s), 6.90
-6.95 (1H, m), 7.11 (1H, d, J = 2.0H
z), 7.45 (1H, br-s), 7.58 (1H, br-
s), 7.65 (1H, d, J = 8.9Hz), 7.77 (1H,
s), 8.38-8.58 (4H, m), 11.72 (1H, br-
s).

Example 67 1-Methyl-6- (2-phenylethoxy) -2-indoloylguanidine · hydrochloride Yield: 48.6% mp219-221 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 3.07-3.12 (2H, m), 3.97 (3
H, s), 4.29 (2H, t, J = 6.9Hz), 6.79-6.
83 (1H, m), 7.11 (1H, d, J = 2.0Hz), 7.
23-7.39 (5H, m), 7.60 (1H, d, J = 8.6H
z), 7.74 (1H, s), 8.36-8.56 (4H, m), 1
1.67 (1H, br-s). Example 68 1-Methyl-6- (3-phenylpropoxy) -2-indoloylguanidine hydrochloride Yield: 72.4% mp232-233 ° C ¹ Hnmr (D
_{MSO-d 6) δ; 2.02-2.13} (2H, m), 2.75-2.
81 (2H, m), 3.97 (3H, s), 4.07 (2H, t,
J = 6.3 Hz), 6.82-6.86 (1 H, m), 7.06 (1
H, d, J = 1.7 Hz), 7.16-7.33 (5H, m), 7.
61 (1H, d, J = 8.9Hz), 7.75 (1H, s), 8.
36-8.58 (4H, m), 11.69 (1H, br-s). Example 69 1-Methyl-6-methylsulfonyl-2-indoloylguanidine-hydrochloride Yield: 30.7% mp303-304 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.25 (3H, s), 4.12 (3H,
s), 7.65 (1H, dd, J = 1.3, 8.6Hz), 7.97
-8.00 (2H, m), 8.24 (1H, s), 8.57 (2H,
br-s), 8.74 (2H, br-s), 12.23 (1H, b
r-s).

Example 70 1-Methyl-4-methylsulfonyl-2-indoloylguanidine · hydrochloride Yield: 19.4% mp 313-314 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 3.30 (3H, s), 4.10 (3H,
s), 7.60 (1H, dd, J = 7.6, 8.3Hz), 7.72
-7.75 (1H, m), 8.04-8.07 (2H, m), 8.63
(4H, br-s), 12.29 (1H, br-s). Example 71 4-chloro-1- (2-methoxyethyl) -2-indoloylguanidine-hydrochloride Yield: 27.0% mp 147-150 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.15 (3H, s), 3.63 (2H,
t, J = 5.3Hz), 4.73 (2H, t, J = 5.3H)
z), 7.26 (1H, d, J = 6.9Hz), 7.31-7.44
(1H, m), 7.66 (1H, d, J = 8.6Hz), 7.94
(1H, s), 8.60 (2H, br-s), 8.67 (2H,
br-s), 12.05 (1H, br-s). Example 72 1- (2-carbamoylethyl) -4-chloro-2-indoloylguanidine hydrochloride yield: 11.0% mp 295 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 2.56 (2H, t, J = 6.9Hz), 4.76 (2
H, t, J = 6.9 Hz), 6.84 (1H, br-s), 7.
26 (1H, d, J = 7.7Hz), 7.30-7.46 (2H,
m), 7.68 (1H, d, J = 8.2Hz), 7.89 (1H,
s), 8.56 (2H, br-s), 8.62 (2H, br-
s), 11.95 (1H, br-s).

Example 73 4-Chloro-1-methyl-7- [2- (N-pyrrolidinyl) ethoxy] -2-indoloylguanidine-hydrochloride Yield: 53.8% mp 250 ° C ¹ Hnmr (DMSO-
_{d 6) δ; 1.93-2.03 (4H} , m), 3.0-3.2 (2
H, m), 3.61-3.71 (4H, m), 4.30 (3H,
s), 4.51-4.54 (2H, m), 6.92 (1H, d, J =
8.2Hz), 7.14 (1H, d, J = 8.3Hz), 7.85
(1H, s), 8.6-8.7 (4H, m), 11.20 (1
H, br-s), 12.07 (1H, br-s). Example 74 4-chloro-7- (3-dimethylaminopropoxy)-
1-Methyl-2-indoloylguanidine / hydrochloride Yield: 35.4% mp 250 ° C. ¹ Hnmr (DMSO-
_{d 6) δ; 2.24-2.30 (2H} , m), 2.78 (6H,
s), 3.2-3.3 (2H, m), 4.20 (2H, t, J =
5.9Hz), 4.29 (3H, s), 6.85 (1H, d, J =
8.3Hz), 7.11 (1H, d, J = 8.3Hz), 7.82
(1H, s), 8.5-8.7 (4H, m), 10.74 (1
H, brs), 12.04 (1H, br-s). Example 75 7- [2- (N-benzyl-N-methylamino) ethoxy] -4-chloro-1-methyl-2-indoloylguanidine-hydrochloride Yield: 43.5% mp 230 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 2.80 (3H, s), 3.61 (2H, br-
s), 4.20 (3H, s), 4.40-4.57 (4H, m), 6.
89 (1H, d, J = 8.3Hz), 7.13 (1H, d, J =
8.3 Hz), 7.45-7.47 (3 H, m), 7.6-7.7 (2
H, m), 7.82 (1H, s), 8.5-8.7 (4H,
m), 11.10 (1H, br-s), 12.04 (1H, br
-S).

Example 76 4-Isopropenyl- ¹ -methyl-2-indoloylguanidine-hydrochloride Yield: 41.5% mp 235 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 2.24 (3H, s), 4.03 (3H, s), 5.35
-5.36 (1H, m), 5.48 (1H, d, J = 1.0H
z), 7.15 (1H, dd, J = 0.7, 7.3Hz), 7.38
(1H, dd, J = 7.3, 8.6Hz), 7.56 (1H,
d, J = 8.6 Hz), 8.07 (1H, s), 8.45-8.70
(4H, m), 12.03 (1H, br-s). Example 77 4-Isopropyl-1-methyl-2-indoloylguanidine-hydrochloride Yield: 75.6% mp 255 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 1.35 (6H, d, J = 6.9 Hz), 3.27-3.
37 (1H, m), 4.02 (3H, s), 7.03 (1H, d,
J = 6.9 Hz), 7.31-7.37 (1 H, m), 7.44 (1
H, d, J = 8.6 Hz), 8.08 (1 H, s), 8.42-8.
70 (4H, m), 11.97 (1H, br-s). Example 78 1- (2-Diethylaminoethyl) -2-indoloylguanidine-hydrochloride Yield: 19.3% mp 250 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 1.28 (6H, t, J = 7.3Hz), 3.10-3.
43 (6H, m), 4.88-5.10 (2H, m), 7.23 (1
H, t, J = 7.6 Hz), 7.46 (1H, ddd, J = 1.
0, 8.3, 8.7Hz), 7.76 (1H, d, J = 7.6H)
z), 7.94 (1H, d, J = 8.7Hz), 8.09 (1H,
br-s), 8.61 (2H, br-s), 8.79 (2H, b
r-s), 11.27 (1H, br-s), 12.3 (1H, b
r-s).

Example 79 4-chloro-1- (2-diethylaminoethyl) -2-
Indoyl guanidine / hydrochloride Yield: 36.0% mp 260-261 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 1.28 (6H, t, J = 7.3Hz),
3.10-3.48 (6H, m), 4.90-5.15 (2H, m), 7.
31 (1H, d, J = 7.7Hz), 7.45 (1H, dd, J
= 7.7, 8.3Hz), 7.98 (1H, d, J = 8.3H)
z), 8.14 (1H, br-s), 8.72 (2H, br-
s), 8.75 (2H, br-s), 11.38 (1H, br-
s), 12.33 (1H, br-s). Example 80 1- (2-Dimethylaminoethyl) -2-indoloylguanidine · hydrochloride Yield: 27.0% mp239-242 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.84 (6H, s), 3.23-3.53 (2
H, m), 4.85-5.08 (2H, m), 7.23 (1H, d
d, J = 7.3, 7.9 Hz), 7.41-7.43 (1H, m),
7.77 (1H, d, J = 7.9Hz), 7.88 (1H, d, J
= 8.3 Hz), 8.11 (1H, s), 8.64 (2H, br-
s), 8.81 (2H, br-s), 11.09 (1H, br-
s), 12.26 (1H, br-s).

Example 81 4-Chloro-1- (2-dimethylaminoethyl) -2-
Indoyl guanidine hydrochloride: Yield: 26.0% mp245-248 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 2.84 (6H, s), 3.31-3.52 (2
H, m), 4.88-5.08 (2H, m), 7.32 (1H, d,
J = 7.6Hz), 7.46 (1H, dd, J = 7.6, 8.3H
z), 7.91 (1H, d, J = 8.3Hz), 8.16 (1H,
s), 8.71 (2H, br-s), 8.77 (2H, br-
s), 11.19 (1H, m), 12.32 (1H, br-
s). Example 82 Synthesis of 1-benzyl-5-indoloylguanidine In a methanol solution (50 ml) of sodium methoxide (1.26 g, 23.4 mmol), guanidine hydrochloride (2.24
g, 23.4 mmol) and dissolved, then benzyl 1
-Benzyl-5-indolecarboxylate (0.80
g, 2.34 mmol) was added, and the mixture was heated with stirring at 50 to 60 ° C. for 30 hours. Methanol was distilled off under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to obtain 1-benzyl-5-indoloylguanidine of interest. This was subjected to hydrochloric acid salification with a 2N hydrochloric acid aqueous solution to obtain 1-benzyl-5-indoloylguanidine hydrochloride (0.08 g, 10.4%). mp 216-222 ℃. ¹ H nmr (DMSO-d ₆ ) δ; 5.51 (2H, s),
6.69 (1H, d, J = 2.6Hz), 7.20-7.34 (5H, m), 7.62-7.68 (2
H, m), 7.88 (1H, dd, J = 1.7, 8.9Hz), 8.43-8.48 (3H,
m), 8.72 (2H, br-s), 11.7 (1H, br-s).

Example 83 7-Methoxy-1-methyl-2-indoloylguanidine hydrochloride a) 2-methoxyaniline (24.6 g, 0.20 mmol), sodium nitrite (15.2 g, 0.22 mmol), concentrated hydrochloric acid ( 84 ml),
Ethyl 2-methylacetoacetate (28.8 g, 0.20 mmo
l) and ethanol (20 ml), referential example 1-a)
The reaction was carried out according to the method of 1. to obtain crude ethyl 2- (2-methoxyphenylhydrazono) propionate (23.0 g). b) The crude ethyl 2- (2-methoxyphenylhydrazono) propionate (23.0 g) obtained above was added to 10% hydrogen chloride / ethanol (150 ml), and the mixture was heated under reflux for 30 minutes.
After cooling, the reaction solution was poured into ice water and extracted by ether extraction (three times), the extract solution was washed with water, washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. Was crudely purified by silica gel column chromatography to obtain crude ethyl 7-methoxy-2-indolecarboxylate (8.00 g).

C) Crude ethyl 7-methoxy-obtained above
2-indolecarboxylate (8.00 g, 36.5 mmol
), 60% sodium hydride (1.44 g, 36 mmol),
Reaction was carried out from methyl iodide (7.76 g, 54.7 mmol) and dimethylformamide (50 ml) according to the method of Reference Example 5 to obtain crude ethyl 7-methoxy-1-methyl-2.
-Indole carboxylate (4.4 g) was obtained. d) Crude ethyl 7-methoxy-1-methyl-obtained above
2-indolecarboxylate (4.40 g, 18.9 mmol)
, Guanidine hydrochloride (18.0 g, 189 mmol) and sodium methoxide (10.2 g, 189 mmol) in methanol
(150 ml), the reaction was carried out according to the method of Example 1,
7-Methoxy-1-methyl-2-indoloylguanidine hydrochloride (1.58 g, yield from 2-methoxyaniline: 5.6%) was obtained. mp 252-253 ℃. ¹ H nmr (DMSO-d ₆ ) δ; 3.93 (3H, s),
4.28 (3H, s), 6.86 (1H, d, J = 7.6Hz), 7.05 (1H, t, J = 7.
9Hz), 7.26 (1H, d, J = 7.6Hz), 7.74 (1H, s), 8.5 (2H, b
rs), 8.6 (2H, br-s), 11.8 (1H, br-s).

Example 84 Synthesis of 1-isopropyl-2-indoloylguanidine 1-isopropyl-2-indolecarboxylic acid (2.00
g, 9.84 mmol) and carbonyldiimidazole (2.3
9 g, 14.8 mmol) in tetrahydrofuran (60 ml
Was stirred at room temperature for 2 hours and then at 45-50 ° C. for 1 hour. After returning this to room temperature, guanidine hydrochloride (5.
64 g, 59.0 mmol) and triethylamine (5.97 g,
59.0 mmol) in dimethylformamide (30 ml) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure,
Water was added to the obtained residue and pH = 5-6 with 2N hydrochloric acid aqueous solution.
After adjusting to, extraction with ethyl acetate (three times), drying over anhydrous magnesium sulfate, filtration of the crystals precipitated by acidification with hydrogen chloride / ether and drying, the desired 1-
Isopropyl-2-indoloylguanidine hydrochloride (1.31 g, 47.4%) was obtained. mp 150-151 ℃. ¹ H nmr (DMSO-d ₆ ) δ; 1.61 (6H, d, J
= 7.3Hz), 5.46-5.57 (1H, m), 7.15 (1H, t, J = 7.9Hz), 7.
32-7.38 (1H, m), 7.68-7.78 (3H, m), 8.5 (2H, br-s),
8.7 (2H, br-s), 11.8-11.9 (1H, m).

The reaction is carried out according to the method of Example 84,
The compound of Example 85 below was synthesized. Example 85 1-carbamoylmethyl-2-indoloylguanidine · hydrochloride Yield: 2.1% mp 261-262 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 5.17 (2H, s), 7.10-7.28 (2
H, m), 7.32-7.45 (1H, m), 7.56 (1H, d,
J = 8.6Hz), 7.59 (1H, br-s), 7.75 (1
H, dd, J = 0.7, 7.0 Hz), 7.81 (1H, s),
8.45 (2H, br-s), 8.61 (2H, br-s), 1
1.90 (1H, br-s).

Example 86 Synthesis of 5-chloro-2-indoloylguanidine 5-chloro-2-indolecarboxylic acid (2.00 g, 10.2
mmol), carbonyldiimidazole (1.82 g, 11.3 m
mol), guanidine / hydrochloride (5.86 g, 61.3 mmol),
Triethylamine (6.20 g, 61.3 mmol), tetrahydrofuran (50 ml) and dimethylformamide (50 ml)
), The reaction was carried out according to the method of Example 84, and
-Chloro-2-indoloylguanidine hydrochloride (1.85
g, 66.2%) was obtained. mp 250 ℃ or more. ¹ H nmr (DMSO-d ₆ ) δ; 7.32 (1H, dd,
J = 2.0, 8.9Hz), 7.51 (1H, d, J = 8.9Hz), 7.82 (2H, s),
8.53 (2H, br-s), 8.68 (2H, br-s), 12.2 (1H, br-s), 1
2.3 (1H, br-s).

Example 87 Synthesis of 6-amino-1-methyl-2-indoloylguanidine 1-Methyl-6-nitro-2-indoloylguanidine
(1.10 g, 4.21 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 ml) and methanol (100 ml), and then,
10% palladium / carbon (0.5
After adding 0 g), catalytic reduction was carried out at room temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and hydrogen chloride / methanol was added to the obtained residual liquid to perform hydrochloric acid salification to give 6-amino-1-methyl-2-indoloylguanidine / hydrochloric acid. Obtained salt (0.73 g, 64.7%). mp 282-283 ℃. ¹ H nmr (DMSO-d ₆ ) δ; 4.00 (3H, s),
7.06 (1H, dd, J = 1.7, 8.6Hz), 7.39 (1H, s), 7.76 (1H,
d, J = 8.6Hz), 7.93 (1H, s), 8.5 (2H, br-s), 8.7 (2H, b
rs), 9.0-10.3 (2H, br), 12.0 (1H, br-s).

Reaction was carried out according to the method of Example 87,
The following compounds of Examples 88 to 90 were synthesized. Example 88 4-Amino-1-methyl-2-indoloylguanidine hydrochloride yield:> 99%. Mp 279-283 ° C. ¹ H nmr (DMSO-d ₆ ) δ;
4.00 (3H, s), 6.80 (1H, d, J = 7.6Hz), 7.20-7.31 (2H,
m), 7.84 (1H, s), 8.5 (2H, br-s), 8.6 (2H, br-s), 11.
9 (1H, br-s). Example 89 5-Amino-1-methyl-2-indoloylguanidine / hydrochloride Yield: 89.8% .mp 301-302 ° C. ¹ H nmr (DMSO-d ₆ ).
δ; 4.04 (3H, s), 7.35-7.39 (1H, m), 7.72-7.79 (2H,
m), 7.93 (1H, s), 8.5 (2H, br-s), 8.7 (2H, br-s), 10.1
(2H, br-s), 12.1 (1H, br). Example 90 7-Amino-1-methyl-2-indoloylguanidine / hydrochloride Yield: 66.7% .mp 299-300 ° C. ¹ H nmr ( DMSO-d ₆ )
δ; 4.28 (3H, s), 7.08-7.14 (1H, m), 7.24 (1H, d, J =
7.3Hz), 7.55 (1H, d, J = 7.9Hz), 7.76 (1H, s), 8.5 (2H,
br-s), 8.6 (2H, br-s), 12.0 (1H, br-s).

Example 91 Synthesis of 5-hydroxy-1-methyl-2-indoloylguanidine 5-Benzyloxy-1-methyl-2-indoloylguanidine (0.83 g, 2.58 mmol) obtained in Example 32 Dissolve in methanol (50 ml), then in a nitrogen stream,
10% Palladium / carbon (0.30 g) was added with stirring at room temperature, and then catalytic reduction was performed at room temperature and atmospheric pressure. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to obtain 5-hydroxy-1-methyl-2-indoloylguanidine. Furthermore, this 5-hydroxy-1-methyl-2-indoloylguanidine was treated with hydrogen chloride / methanol to give 5-hydroxy-1-methyl-2-indoloylguanidine hydrochloride (0.37 g, 68.6 g).
%) Was obtained. mp288-289 ° C. ¹ Hnmr (DMSO-d ₆ ).
δ: 3.96 (3H, s), 6.93-6.98 (2H, m), 7.43
-7.47 (1H, m), 7.65 (1H, s), 8.43 (2H,
br-s), 8.65 (2H, br-s), 9.18 (1H,
s), 11.76 (1H, br-s).

The reaction is carried out according to the method of Example 91,
The following compounds of Examples 92-96 were synthesized. Example 92 7-Hydroxy-1-methyl-2-indoloylguanidine · hydrochloride Yield 53.0% mp244-246 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 4.29 (3H, s), 6.71 (1H,
d, J = 7.6 Hz), 6.88-6.94 (1H, m), 7.12
(1H, d, J = 7.9Hz), 7.65 (1H, s), 8.42
-8.56 (4H, m), 10.08 (1H, s), 11.70 (1
H, br-s). Example 93 4-Hydroxy-1-methyl-2-indoloylguanidine-hydrochloride yield 27.4% mp 267-268 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 3.96 (3H, s), 6.50 (1H,
d, J = 7.6Hz), 7.00 (1H, d, J = 8.3H)
z), 7.16-7.22 (1H, m), 7.71 (1H, s), 8.
42 (4H, br-s), 10.14 (1H, br-s), 1
1.51 (1H, br-s).

Example 94 6-Hydroxy-1-methyl-2-indoloylguanidine · hydrochloride Yield 73.4% mp 270-271 ° C. ¹ Hnmr (DM
SO-d ₆ ) δ; 3.90 (3H, s), 6.72-6.76 (1
H, m), 6.81 (1H, s), 7.53-7.61 (2H,
m), 8.4 (4H, br-s), 9.76 (1H, br-
s), 11.39 (1H, br-s). Example 95 4-Chloro-7-hydroxy-1-methyl-2-indoloylguanidine-hydrochloride Yield 23.9% mp 280 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 4.30 (3H, s), 6.70 (1H, d, J = 7.
9Hz), 6.96 (1H, d, J = 8.3Hz), 7.68 (1
H, s), 8.54 (4H, br-s), 10.37 (1H,
s), 11.79 (1H, br-s). Example 96 4-Chloro-6-hydroxy-1-methyl-2-indoloylguanidine hydrochloride Yield 40.1% mp 270 ° C ¹ Hnmr (DMSO-d
₆ ) δ; 3.91 (3H, s), 6.83-6.84 (2H, m),
7.77 (1H, s), 8.3-8.7 (4H, m), 10.14
(1H, s), 11.72 (1H, br-s).

Example 97 Synthesis of 4-acetamido-1-methyl-2-indoloylguanidine a) Synthesis of ethyl 4-amino-1-methyl-2-indolecarboxylate Ethyl 1-methyl-4-nitro-2- Indole carboxylate (1.37 g, 5.52 mmol) was dissolved in a mixed solvent of tetrahydrofuran (50 ml) and methanol (50 ml), then 10% palladium / carbon (0.30 g).
After the addition of, was catalytically reduced at room temperature and atmospheric pressure. After the reaction,
The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography to give ethyl 4-amino-1-methyl-2-indolecarboxylate (1.2 g,> 99). %) Was obtained.

B) Synthesis of ethyl 4-acetamido-1-methyl-2-indolecarboxylate Ethyl 4-amino-1-methyl-2-indolecarboxylate (1.2 g, 5.52 mmol) was added to pyridine (20 m).
It was dissolved in l) and acetic anhydride (10 ml) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 2 hours, poured into ice water, extracted with ethyl acetate (three times), the extract was washed with 1N hydrochloric acid, followed by washing with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. After that, the solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to obtain ethyl 4-acetamide-
1-methyl-2-indolecarboxylate (1.40
g, 97.9%) was obtained.

C) 4-acetamido-1-methyl-2
-Synthesis of indoloylguanidine Ethyl 4-acetamido-1-methyl-2-indolecarboxylate (1.40 g, 5.38 mmol), guanidine hydrochloride (5.14 g, 53.8 mmol) and sodium methoxide (2.91 g, 53.8 mmol) Methanol solution (50 ml)
The reaction was carried out according to the method of Example 1 to give 4-acetamido-1-methyl-2-indoloylguanidine.
The hydrochloride salt (1.15 g, 69.0%) was obtained. mp 277-279 ° C. ¹ Hnmr (DMSO-d ₆ ).
δ: 2.15 (3H, s), 3.99 (3H, s), 7.30-7.35
(2H, m), 7.5-7.6 (1H, m), 7.79 (1H,
s), 8.4-8.7 (4H, m), 10.00 (1H, br-
s), 11.68 (1H, br-s).

The reaction is carried out according to the method of Example 97,
The following compounds of Examples 98-100 were synthesized. Example 98 5-acetamido-1-methyl-2-indoloylguanidine · hydrochloride Yield 49.2% mp 260-261 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.06 (3H, s), 3.99 (3H,
s), 7.46 (1H, dd, J = 2.0, 8.9Hz), 7.56
(1H, d, J = 8.9Hz), 7.83 (1H, s), 8.09
(1H, d, J = 1.7Hz), 8.47 (2H, br-
s), 8.71 (2H, br-s), 9.97 (1H, br-
s), 11.92 (1H, br-s). Example 99 7-acetamido-1-methyl-2-indoloylguanidine hydrochloride yield 17.1% mp 285 ° C. ¹ Hnmr (DMSO-d
₆ ) δ; 2.10 (3H, s), 4.07 (3H, s), 7.07-
7.15 (2H, m), 7.61-7.64 (1H, m), 7.76 (1
H, s), 8.45 (2H, br-s), 8.60 (2H, br)
-S), 9.90 (1H, br-s), 11.86 (1H, br)
-S). Example 100 6-acetamido-1-methyl-2-indoloylguanidine-hydrochloride Yield 63.8% mp 280-281 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 2.09 (3H, s), 3.95 (3H,
s), 7.18 (1H, dd, J = 1.7, 8.6Hz), 7.64
(1H, d, J = 8.9Hz), 7.72 (1H, s), 8.09
(1H, s), 8.2-8.8 (4H, m), 10.17 (1
H, br-s), 11.75 (1H, br-s).

Example 101 Synthesis of 1-hydroxy-2-indoloylguanidine a) Synthesis of methyl 1-hydroxy-2-indolecarboxylate 1-Hydroxy-2-indolecarboxylic acid (3.99 g,
22.5 mmol), thionyl chloride (5.36 g, 45.0 mmol) and methanol (100 ml) were carried out according to the method of Reference Example 6 to give methyl 1-hydroxy-
2-Indole carboxylate (2.56 g, 59.5%) was obtained. b) Synthesis of 1-hydroxy-2-indoloylguanidine Methyl 1-hydroxy-2-indolecarboxylate (1.00 g, 5.23 mmol), guanidine hydrochloride (5.00
g, 52.3 mmol) and sodium methoxide (2.82 g,
Example 1 from a methanol solution (50 ml) of 52.3 mmol)
The reaction was carried out according to the method of 1 to obtain 1-hydroxy-2-indoloylguanidine hydrochloride (0.56 g, 42.0%). mp 217 ° C. ¹ Hnmr (DMSO-d ₆ ) δ;
7.13-7.19 (1H, m), 7.37-7.52 (2H, m), 7.
69-7.73 (1H, m), 8.45 (2H, br-s), 8.70
(2H, br-s), 11.4-11.8 (2H, m).

Example 102 Synthesis of 1-methoxy-2-indoloylguanidine a) Synthesis of methyl 1-methoxy-2-indolecarboxylate Methyl 1-hydroxy-2-indolecarboxylate (0.56 g, 2.93 mmol) was added to nitrogen. At room temperature in the air flow,
60% Sodium hydride (0.12g, 2.93mmol) was added to a suspension of tetrahydrofuran (20ml). After confirming that the reaction solution became transparent, methyl iodide (0.83 g,
5.86 mmol) was added and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate (3
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography to give methyl 1-methoxy-2-. Indole carboxylate (0.46 g, 76.5%) was obtained. b) Synthesis of 1-methoxy-2-indoloylguanidine Methyl 1-methoxy-2-indolecarboxylate (0.46 g, 2.24 mmol), guanidine hydrochloride (2.14)
g, 22.4 mmol) and sodium methoxide (1.21 g,
22.4 mmol) in a methanol solution (15 ml) was used in Example 1.
The reaction was performed according to the method described in (1) to give 1-methoxy-2-indoloylguanidine hydrochloride (0.15 g, 24.9%). mp 214 ° C. ¹ Hnmr (DMSO-d ₆ ) δ;
4.16 (3H, s), 7.21-7.26 (1H, m), 7.44-7.
50 (1H, m), 7.62 (1H, d, J = 8.6Hz), 7.
74-7.79 (2H, m), 8.48 (2H, br-s), 8.66
(2H, br-s), 11.93 (1H, br-s).

Example 103 Synthesis of 5-benzamido-1-methyl-2-indoloylguanidine a) Synthesis of ethyl 5-benzamido-1-methyl-2-indolecarboxylate Ethyl 5-amino-1-methyl-2- Indole carboxylate (0.80 g, 3.67 mmol) was added to pyridine (20 m
l) and benzoyl chloride (0.57
g, 4.03 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hours. The reaction solution was cooled to room temperature, poured into ice water, extracted with ethyl acetate (three times), the extract was washed with 1N hydrochloric acid, followed by washing with a saturated sodium hydrogen carbonate aqueous solution, dried over anhydrous magnesium sulfate, and then the solvent. Was distilled off under reduced pressure, and the residue obtained was separated and purified by silica gel column chromatography to give ethyl 5-benzamide-1-methyl-2.
-Indole carboxylate (0.62 g, 52.5%) was obtained. b) Synthesis of 5-benzamido-1-methyl-2-indoloylguanidine Ethyl 5-benzamido-1-methyl-2-indolecarboxylate (0.62 g, 1.92 mmol), guanidine hydrochloride (3.68 g, 38.4 mmol) And sodium methoxide (2.08g, 38.4mmol) in methanol (50ml)
Then, the reaction was carried out according to the method of Example 1 to give 5-benzamido-1-methyl-2-indoloylguanidine.
The hydrochloride salt (0.38 g, 53.1%) was obtained. mp 185-190 ° C. ¹ Hnmr (DMSO-
_{d 6) δ; 4.03 (3H} , s), 7.50-7.60 (4H,
m), 7.63-7.74 (1H, m), 7.81 (1H, s), 7.
96-8.00 (2H, m), 8.25 (1H, d, J = 1.7H
z), 8.44 (2H, br-s), 8.62 (2H, br-
s), 10.26 (1H, br-s), 11.82 (1H, br)
-S).

The reaction was carried out according to the method of Example 103 to synthesize the compounds of the following Examples 104-106. Example 104 4-benzamido-1-methyl-2-indoloylguanidine-hydrochloride Yield 54.7% mp 302-303 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.04 (3H, s), 7.37-7.64 (6
H, m), 7.87 (1H, s), 8.05-8.09 (2H,
m), 8.52 (4H, br-s), 10.35 (1H, br-
s), 11.70 (1H, br-s). Example 105 7-benzamido-1-methyl-2-indoloylguanidine-hydrochloride Yield 45.7% mp318-319 ° C ¹ Hnmr (D
MSO-d ₆ ) δ; 4.07 (3H, s), 7.16-7.24 (2
H, m), 7.53-7.72 (4H, m), 7.80 (1H,
m), 8.04-8.06 (2H, m), 8.45 (2H, br-
s), 8.61 (2H, br-s), 10.44 (1H, br-
s), 11.88 (1H, br-s).

Example 106 6-benzamido-1-methyl-2-indoloylguanidine · hydrochloride Yield 40.1% mp 309 ° C. ¹ Hnmr (DMSO-
_{d 6) δ; 4.00 (3H} , s), 7.48-7.62 (4H,
m), 7.70-7.75 (2H, m), 7.98-8.01 (2H,
m), 8.27 (1H, s), 8.2-8.8 (4H, m), 1
0.45 (1H, br-s), 11.73 (1H, br-
s). Example 107 Synthesis of 1- (4-aminobenzyl) -2-indoloylguanidine 1- (4-Nitrobenzyl) -2-indoloylguanidine (0.45g, 1.20mmol), 10% palladium / carbon (0.50g) , Tetrahydrofuran (25 ml) and methanol (25 ml) were used and the reaction was carried out according to the method of Example 87 to give 1- (4-aminobenzyl) -2-indoloylguanidine hydrochloride (0.33 g, 79.7%). Obtained. mp 226-228 ° C. ¹ Hnmr (DMSO-d
₆ ) δ; 5.83 (2H, s), 7.00-7.13 (4H, m),
7.17-7.23 (1H, m), 7.34-7.40 (1H, m), 7.
58 (1H, d, J = 8.3Hz), 7.79 (1H, d, J =
7.9Hz), 8.02 (1H, s), 8.50 (2H, br-
s), 8.66 (2H, br-s), 9.0-9.8 (2H,
m), 12.01 (1H, br-s).

Example 108 Synthesis of 1- (2-hydroxyethyl) -2-indoloylguanidine Methyl 1- [2- (2-tetrahydropyranyl) oxyethyl] -2-indolecarboxylate (1.00
g, 3.30mmol), guanidine hydrochloride (3.15g, 33.0mm)
ol) and sodium methoxide (1.78g, 33.0mmol)
Was reacted according to the method of Example 1 to give 1- [2- (2-tetrahydropyranyl) oxyethyl] -2-indoloylguanidine (0.85 g). Subsequently, this compound (0.69 g) was dissolved in hydrochloric acid / methanol and stirred at room temperature for 5.5 hours. The reaction solution was concentrated under reduced pressure, a mixed solvent of methanol / diethyl ether was added to the residue, the precipitate was collected by filtration, and the product on the filter was dried under reduced pressure to give 1- (2-hydroxyethyl). ) -2-Indoloylguanidine hydrochloride (0.49 g,
65%). mp 190-193 ° C ¹ Hnmr (DMSO-
_{d 6) δ; 3.60-3.82 (2H} , m), 4.60 (2H, t,
J = 5.0 Hz), 4.74-4.97 (1H, brs), 7.17
(1H, dt, J = 7.0, 7.8Hz), 7.38 (1H, d
t, J = 7.0, 7.8 Hz), 7.66 (1H, d, J = 8.0)
Hz), 7.72 (1H, d, J = 8.0Hz), 7.84 (1
H, s), 8.20-8.90 (4H, m), 11.87 (1H, b
r-s).

The reaction was carried out according to the method of Example 108 to obtain the following compounds of Examples 109-110. Example 109 1- (3-Hydroxypropyl) -2-indoloylguanidine · hydrochloride Yield 81.0% mp 206-207 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 1.90 (2H, dt, J = 6.9,
7.3Hz), 3.39 (2H, t, J = 6.3Hz), 4.60
(2H, t, J = 6.9Hz), 7.18 (1H, dd, J =
7.0, 7.8Hz), 7.41 (1H, dd, J = 7.1, 8.5
Hz), 7.65 (1H, d, J = 8.2Hz), 7.74 (1
H, d, J = 7.8 Hz), 7.88 (1 H, s), 8.28-8.
85 (4H, m), 11.87 (1H, br-s). Example 110 1- (4-hydroxybutyl) -2-indoloylguanidine / hydrochloride Yield 84.0% mp 226 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 1.30-1.50 (2H, m), 1.62-1.86
(2H, m), 3.38 (2H, t, J = 6.4Hz), 4.43
(1H, br-s), 4.56 (2H, t, J = 7.3H
z), 7.17 (1H, t, J = 7.4Hz), 7.40 (1H,
ddd, J = 1.0, 6.9, 7.4 Hz), 7.65 (1H,
d, J = 8.3Hz), 7.73 (1H, d, J = 7.9H)
z), 7.96 (1H, s), 8.52 (2H, br-s), 8.
76 (2H, br-s), 12.00 (1H, s).

Example 111 Synthesis of 3-methyl-2-indoloylguanidine a) Synthesis of ethyl 2-phenylhydrazonobutyronate Aniline instead of o-chloroaniline and ethyl 2-methylacetoacetate. Ethyl 2
-Ethyl 2-phenylhydrazonobutyronate was obtained according to the method described in Reference Example 1-a), except that ethyl acetoacetate was used. b) Synthesis of ethyl 3-methyl-2-indolecarboxylate Ethyl 2-phenylhydrazonobutyronate (25.0
g) was dissolved in hydrochloric acid / ethanol (80 ml) and heated under reflux for 1 hour. The reaction solution was cooled to room temperature, poured into ice water, extracted with diethyl ether (3 times), the extract solution was washed with water, then with a saturated sodium hydrogen carbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography to obtain ethyl 3-methyl-2-indolecarboxylate (14.0 g, 69.0%).
Got

C) Synthesis of 3-methyl-2-indoloylguanidine Ethyl 3-methyl-2-indolecarboxylate (1.50 g, 7.38 mmol), guanidine hydrochloride (7.05 g,
73.8 mmol) and sodium methoxide (3.99 g, 73.8
(Methanol) (50 ml) in methanol according to the method of Example 1 to give 3-methyl-2-indoloylguanidine hydrochloride (1.61 g, 86.3%). mp285-286 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 2.60 (3H, s), 7.12 (1H, t, J = 7.
9Hz), 7.31-7.44 (2H, m), 7.70 (1H, d,
J = 7.9 Hz), 8.46 (4H, br-s), 11.78 (1
H, br-s), 11.94 (1H, br-s).

Example 112 1-Methyl-7- (3-phenylpropionamide)-
Synthesis of 2-indoloylguanidine a) Synthesis of ethyl 1-methyl-7- (3-phenylpropionamido) -2-indolecarboxylate Ethyl 7-amino-1-methyl-2-indolecarboxylate (0.20 g, 0.92 mmol), 3-phenylpropionic acid (0.14 g, 0.94 mmol), 4-dimethylaminopyridine (0.11 g, 0.94 mmol), and dicyclohexylcarbodiimide (0.19 g, 0.94 mmol) in methylene chloride (5 ml), The mixture was stirred at room temperature for 24 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (three times), the extract solution was washed with 1N hydrochloric acid, 5% aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was separated and purified by silica gel column chromatography to obtain ethyl 1-methyl-7- (3-phenylpropionamido) -2-indolecarboxylate.

B) Synthesis of 1-methyl-7- (3-phenylpropionamido) -2-indoloylguanidine Ethyl 1-methyl-7- (3-phenylpropionamido) -2-indolecarboxylate (0.42 g, 1.
21 mmol), guanidine hydrochloride (2.31 g, 24.2 mmol) and sodium methoxide (1.31 g, 24.2 mmol) in methanol (30 ml) were reacted according to the method of Example 1 to give 1-methyl-7. -(3-phenylpropionamide) -2-indoloylguanidine hydrochloride (0.
16 g, 34.9%) was obtained. mp279-280 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 2.72 (2H, t, J = 7.6Hz), 2.96 (2
H, t, J = 7.6 Hz), 3.34 (3H, s), 7.03-7.
14 (2H, m), 7.20-7.24 (1H, m), 7.29-7.31
(4H, m), 7.62 (1H, d, J = 6.9Hz), 7.69
(1H, s), 8.53 (4H, m), 9.89 (1H, s),
11.76 (1H, br-s).

Reaction was carried out according to the method of Example 112 to synthesize the compound of Example 113 below. Example 113 1-Methyl-6- (3-phenylpropionamide)-
2-Indoylguanidine hydrochloride yield 34.6% mp 245-247 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 2.66-2.71 (2H, m), 2.91
-2.97 (2H, m), 3.95 (3H, s), 7.16-7.30
(6H, m), 7.63-7.71 (2H, m), 8.13 (1H,
s), 8.36-8.52 (4H, m), 10.16 (1H, br-
s), 11.67 (1H, br-s). Example 114 Synthesis of 1- (3-aminopropyl) -2-indoloylguanidine Methyl 1- (3-tert-butoxycarbonylaminopropyl) -2-indolecarboxylate (1.50 g,
4.51mmol), guanidine hydrochloride (4.31g, 45.1mmol)
And a solution of sodium methoxide (2.44 g, 45.1 mmol) in methanol (60 ml) were reacted according to the method of Example 1 to give 1- (3-tert-butoxycarbonylaminopropyl) -2-indoloylguanidine ( 1.57
g) was obtained. This compound (1.55 g) was dissolved in hydrochloric acid / methanol and stirred at 70 ° C. for 3.5 hours. By recrystallizing the residue obtained by concentrating the reaction solution under reduced pressure from water,
1- (3-aminopropyl) -2-indoloylguanidine hydrochloride (0.65 g, 46.0%) was obtained. mp296-297 ° C ¹ Hnmr (DMSO-
d ₆ ) δ; 2.05 (2H, ddd, J = 7.6, 11.4, 14.5)
Hz), 2.63-2.86 (2H, m), 4.65 (2H, t, J
= 7.3Hz), 7.19 (1H, t, J = 7.9Hz), 7.42
(1H, t, J = 7.6Hz), 7.74 (2H, d, J = 8.
6Hz), 7.83-8.16 (4H, m), 8.27-9.03 (4
H, m), 12.00-12.30 (1H, br-s).

The reaction was carried out according to the method of Example 114 to synthesize the compound of the following Example 115. Example 115 1- (2-aminoethyl) -2-indoloylguanidine / hydrochloride Yield 54.0% mp 240 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 3.14-3.30 (2H, m), 4.77 (2H,
t, J = 6.3 Hz), 7.22 (1H, dd, J = 7.3, 7.
6Hz), 7.45 (1H, dd, J = 7.3, 7.6Hz),
7.77 (1H, d, J = 7.6Hz), 7.83 (1H, d, J
= 7.6 Hz), 8.03 (1H, br-s), 8.20 (3H,
br-s), 8.58 (2H, br-s), 8.74 (2H, b
r-s), 12.14 (1H, br-s).

Example 116 Synthesis of 4-aminomethyl-1-methyl-2-indoloylguanidine Ethyl 1-methyl-4-tert-butyloxycarbonylaminomethyl-2-indolecarboxylate (1.
40g, 4.21mmol), guanidine hydrochloride (4.02g, 42.1)
mmol) and sodium methoxide (2.27 g, 42.1 mmol)
The reaction was performed according to the method of Example 1 from the methanol solution (60 ml) to give 1-methyl-4-tert-butyloxycarbonylaminomethyl-2-indoloylguanidine (1.50 g). This compound was dissolved in a mixed solution of trifluoroacetic acid (35 ml) / methylene chloride (70 ml) and stirred at room temperature for 2 hours. Ice water was poured into the residue obtained by concentrating the reaction solution under reduced pressure, the aqueous layer was made alkaline with 28% ammonia water, and then extracted with ethyl acetate (three times).
The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was hydrochloric acid-chlorinated with hydrogen chloride / ether to give 4-aminomethyl-1-. Methyl-2-indoloylguanidine
The hydrochloride salt (0.58 g, 43.2%) was obtained. mp283-284 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.06 (3H, s), 4.28 (2H, d, J = 6.
6Hz), 7.32 (1H, d, J = 6.9Hz), 7.43-7.
49 (1H, m), 7.66 (1H, d, J = 8.3Hz), 8.
28 (1H, s), 8.5-8.7 (5H, m), 8.79 (2
H, br-s), 12.28 (1H, br-s).

The reaction was carried out according to the method of Example 116 to synthesize the compounds of the following Examples 117-122. Example 117 7- (3-aminopropoxy) -1-methyl-2-indoloylguanidine · hydrochloride Yield 51.8% mp 287-288 ° C. ¹ Hnmr (D
MSO-d ₆ ) δ; 2.09-2.17 (2H, m), 3.32 (2
H, br-s), 4.21 (2H, t, J = 5.9Hz), 4.
28 (3H, s), 6.86 (1H, d, J = 6.9Hz), 7.
05 (1H, t, J = 7.9Hz), 7.28 (1H, d, J =
7.9 Hz), 7.76 (1 H, s), 7.98 (3 H, br-
s), 8.47-8.67 (4H, m), 11.92 (1H, br-
s). Example 118 7- (3-aminopropoxy) -4-chloro-1-methyl-2-indoloylguanidine · hydrochloride Yield 41.7% mp299-300 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 2.14-2.19 (2H, m), 3.00
-3.02 (2H, m), 4.21-4.26 (2H, m), 4.28
(3H, s), 6.83 (1H, d, J = 8.3Hz), 7.10
(1H, d, J = 8.3Hz), 7.88 (1H, s), 8.18
(3H, br-s), 8.6-8.7 (4H, m), 12.12
(1H, br-s).

Example 119 6- (3-aminopropoxy) -1-methyl-2-indoloylguanidine.hydrochloride Yield 61.3% mp 280-281 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 2.09-2.16 (2H, m), 3.01
(2H, d, J = 6.3Hz), 4.02 (3H, s), 4.19
-4.24 (2H, m), 6.87 (1H, dd, J = 2.0, 8.
9Hz), 7.15 (1H, s), 7.75 (1H, d, J = 8.
9Hz), 7.95 (1H, s), 8.07 (3H, br-
s), 8.51-8.80 (4H, m), 12.00 (1H, br-
s). Example 120 1- (3-aminopropyl) -4-chloro-2-indoloylguanidine-hydrochloride Yield 46.0% mp 280-282 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 1.95-2.16 (2H, m), 2.65
-2.88 (2H, m), 4.66 (2H, t, J = 6.6H
z), 7.29 (1H, d, J = 7.6Hz), 7.42 (1H,
dd, J = 7.6, 8.3 Hz), 7.79 (1H, d, J = 3.
0Hz), 8.02 (3H, br-s), 8.11 (1H,
s), 8.68 (2H, br-s), 8.78 (2H, br-
s), 12.2 (1H, br-s).

Example 121 7- (2-aminoethoxy) -4-chloro-1-methyl-2-indoloylguanidine hydrochloride Yield 31.9% mp 285 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 3.2-3.4 (2H, m), 4.30 (3H,
s), 4.33-4.37 (2H, m), 6.89 (1H, d, J =
8.3Hz), 7.13 (1H, d, J = 8.3Hz), 7.83
(1H, s), 8.33 (3H, br-s), 8.6-8.7
(4H, m), 12.06 (1H, br-s). Example 122 6- (3-aminopropoxy) -4-chloro-1-methyl-2-indoloylguanidine · hydrochloride Yield 38.7% mp 230 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 2.06-2.11 (2H, m), 2.97-2.99
(2H, m), 4.00 (3H, s), 4.18-4.23 (2H,
m), 6.96 (1H, d, J = 1.7Hz), 7.14 (1H,
s), 7.95 (1H, s), 8.09 (3H, br-s), 8.
5-8.7 (4H, m), 12.03 (1H, br-s).

Example 123 Synthesis of 4-hydroxymethyl-1-methyl-2-indoloylguanidine Ethyl 1-methyl-4- (2-tetrahydropyranyl) oxymethyl-2-indolecarboxylate (1.50 g, 4.73 mmol) ), Guanidine hydrochloride (6.02 g, 6
3.0 mmol) and sodium methoxide (3.40 g, 63.0 m)
mol) solution in methanol (60 ml) according to the method of Example 1 to obtain 1-methyl-4- (2-tetrahydropyranyl) oxymethyl-2-indoloylguanidine. This compound was then added to 2N hydrochloric acid (30 ml)
/ Dissolve in a mixed solvent of tetrahydrofuran (60 ml),
The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, the aqueous layer was made alkaline with 28% ammonia water and then extracted with ethyl acetate (three times), the extract solution was washed with saturated saline solution and dried with anhydrous magnesium sulfate, and then the solvent was added. The residue obtained by evaporation under reduced pressure was separated and purified by silica gel column chromatography to give 4-hydroxymethyl-1.
-Methyl-2-indoloylguanidine was obtained. Next, this compound was subjected to hydrochloric acid salification with hydrogen chloride / methanol to obtain 4-hydroxymethyl-1-methyl-2-indoloylguanidine hydrochloride (0.58 g, 44.2%). mp226-229 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.03 (3H, s), 4.80 (2H, s), 5.26
(1H, brs), 7.17 (1H, d, J = 6.9Hz),
7.34-7.39 (1H, m), 7.48 (1H, d, J = 8.3H
z), 7.93 (1H, s), 8.48-8.60 (4H, m), 1
1.81 (1H, br-s). The reaction was carried out according to the method of Example 123 to synthesize the compounds of the following Examples 124-133.

Example 124 7- (2-Hydroxyethoxy) -1-methyl-2-indoloylguanidine · hydrochloride Yield 62.5% mp 243-244 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 3.82 (2H, br-s), 4.12
-4.15 (2H, m), 4.31 (3H, s), 4.94 (1H,
br-s), 6.86 (1H, d, J = 7.3Hz), 7.03
(1H, t, J = 7.9Hz), 7.26 (1H, d, J = 7.9.
3Hz), 7.73 (1H, s), 8.45-8.63 (4H,
m), 11.82 (1H, br-s). Example 125 4-chloro-7- (2-hydroxyethoxy) -1-methyl-2-indoloylguanidine hydrochloride salt yield 17.7% mp 277-279 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 3.79-3.83 (2H, m), 4.12
-4.15 (2H, m), 4.31 (3H, s), 4.9 (1H,
br-s), 6.85 (1H, d, J = 8.3Hz), 7.10
(1H, d, J = 8.3Hz), 7.75 (1H, s), 8.58
(4H, br-s), 11.88 (1H, br-s).

Example 126 6- (2-Hydroxyethoxy) -1-methyl-2-indoloylguanidine · hydrochloride Yield 59.8% mp265-268 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 3.32-3.77 (2H, m), 3.98
(3H, s), 4.08-4.11 (2H, m), 4.91 (1H,
br-s), 6.81-6.85 (1H, m), 7.08 (1H,
s), 7.61 (1H, d, J = 8.9Hz), 7.81 (1H,
s), 8.39-8.64 (4H, m), 11.77 (1H, br-
s). Example 127 4-chloro-7- (2,3-dihydroxypropoxy)
-1-Methyl-2-indoloylguanidine / hydrochloride Yield 40.2% mp237-238 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 3.50 (2H, d, J = 5.9H
z), 3.88-3.91 (1H, m), 4.03 (1H, dd, J
= 5.6,9.9 Hz), 4.15 (1H, dd, J = 4.0, 9.
9Hz), 4.30 (3H, s), 6.85 (1H, d, J = 8.
3Hz), 7.11 (1H, d, J = 8.3Hz), 7.68 (1
H, s), 8.50 (4H, br-s), 11.76 (1H, b
r-s).

Example 128 4-Chloro-7- (3-hydroxypropoxy) -1-
Methyl-2-indoloylguanidine / hydrochloride yield 53.2% mp210-212 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 1.93-2.02 (2H, m), 3.60
-3.64 (2H, m), 4.15-4.20 (2H, m), 4.28
(3H, s), 6.84 (1H, d, J = 8.6Hz), 7.09
(1H, d, J = 8.3Hz), 7.77 (1H, s), 8.5
-8.6 (4H, m), 11.92 (1H, br-s). Example 129 4-chloro-7- (4-hydroxybutoxy) -1-methyl-2-indoloylguanidine hydrochloride salt yield 69.5% mp 220-222 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 1.59-1.67 (2H, m), 1.84
-1.89 (2H, m), 3.45-3.50 (2H, m), 4.10-
4.15 (2H, m), 4.29 (3H, s), 6.84 (1H,
d, J = 8.3Hz), 7.10 (1H, d, J = 8.3H)
z), 7.71 (1H, s), 8.52 (4H, br-s), 1
1.80 (1H, br-s). Example 130 4-chloro-1- (3-hydroxypropyl) -2-indoloylguanidine-hydrochloride Yield 60.0% mp213-215 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 1.78-1.98 (2H, m), 3.30
-3.45 (2H, m), 4.61 (2H, t, J = 7.3H
z), 4.68 (1H, br-s), 7.27 (1H, d, J =
7.6Hz), 7.39 (1H, dd, J = 7.3, 8.6H
z), 7.66 (1H, d, J = 8.6Hz), 7.93 (1H,
s), 8.55 (2H, br-s), 8.64 (2H, br-)
s), 11.96 (1H, br-s).

Example 131 4-chloro-1- (4-hydroxybutyl) -2-indoloylguanidine hydrochloride Yield 48.0% mp 226-227 ° C. ¹ Hnmr
(DMSO-d ₆ ) δ; 1.28-1.51 (2H, m), 1.60
-1.84 (2H, m), 3.37 (2H, t, J = 6.6H
z), 4.44 (1H, br-s), 4.58 (1H, t, J =
7.3Hz), 7.28 (1H, d, J = 7.6Hz), 7.39
(1H, dd, J = 7.6, 8.6Hz), 7.68 (1H,
d, J = 8.6Hz), 7.92 (1H, s), 8.53 (2H,
br-s), 8.63 (2H, br-s), 11.92 (1H,
br-s). Example 132 4-Chloro-6- (2-hydroxyethoxy) -1-methyl-2-indoloylguanidine-hydrochloride Yield 51.9% mp 250-252 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 3.74-3.77 (2H, m), 3.99
(3H, s), 4.11 (2H, t, J = 5.0Hz), 6.94
(1H, d, J = 2.0Hz), 7.13 (1H, s), 7.80
(1H, s), 8.3-8.7 (4H, m), 11.76 (1
H, br-s). Example 133 1- (3,4-dihydroxybutyl) -2-indoloylguanidine-hydrochloride Yield 73.0% mp219-222 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 1.53-1.73 (1H, m), 1.85
-2.04 (1H, m), 3.12-3.55 (3H, m), 4.37-
4.88 (4H, m), 7.18 (1H, t, J = 7.3Hz),
7.40 (1H, ddd, J = 1.0, 7.3, 7.8Hz), 7.
65 (1H, d, J = 8.3Hz), 7.74 (1H, d, J =
7.9Hz), 7.86 (1H, s), 8.21 (2H, br-
s), 8.67 (2H, br-s), 11.87 (1H, br-
s).

Example 134 Synthesis of 1- (2-carboxyethyl) -2-indoloylguanidine 1- [2- [1- (4-methyl-2,6,7-trioxabicyclo [2.2.2] ] Octyl)] Ethyl] -2-
Indoyl guanidine (0.80g, 2.23mmol) 1,2
-Suspended in dimethoxyethane (80 ml), 1N hydrochloric acid (8 ml) was added thereto, and the mixture was stirred at room temperature for 20 minutes. Subsequently, 1N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at room temperature for 40 minutes. Subsequently, 4N hydrochloric acid (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the resulting residue was washed with water, and then the water was filtered off. The product on the filter was recrystallized from 0.5N hydrochloric acid to obtain 1- (2-carboxyethyl) -2-indoloylguanidine hydrochloride (0.44 g, 64.0%). mp 254 ° C. ¹ Hnmr (DMSO-d ₆ ) δ; 2.
72 (2H, t, J = 7.3Hz), 4.76 (2H, t, J =
7.4Hz), 7.17 (1H, t, J = 7.9Hz), 7.40
(1H, ddd, J = 1.0, 6.9, 7.4Hz), 7.68
(1H, d, J = 8.6Hz), 7.73 (1H, d, J = 7.
9Hz), 7.91 (1H, s), 8.50 (2H, br-
s), 8.72 (2H, br-s), 12.22 (1.5H, br)
-S).

Example 135 7-Carboxymethoxy-4-chloro-1-methyl-2
-Synthesis of indoloylguanidine 7-carbamoylmethoxy-4-obtained in Example 64
A suspension of chloro-1-methyl-2-indoloylguanidine hydrochloride (0.40 g, 1.11 mmol) in 2N hydrochloric acid (100 ml) was heated under reflux for 1 hour. The reaction solution was gradually cooled, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 7
-Carboxymethoxy-4-chloro-1-methyl-2-
Indoylguanidine hydrochloride (0.39 g, 97.2%) was obtained. mp283-284 ° C. ¹ Hnmr (DMSO-
d ₆ ) δ; 4.34 (3H, s), 4.84 (2H, s), 6.82
(1H, d, J = 8.3Hz), 7.09 (1H, d, J = 8.3.
3Hz), 7.69 (1H, s), 8.48 (4H, br-
s), 11.5-13.5 (1.3H, br-s).

The reaction was carried out according to the method of Example 135 to synthesize the compounds of the following Examples 136-137. Example 136 7-Carboxymethoxy-1-methyl-2-indoloylguanidine · hydrochloride Yield 41.5% mp 264 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 4.34 (3H, s), 4.84 (2H, s),
6.83 (1H, d, J = 7.6Hz), 7.03 (1H, t, J
= 7.9 Hz), 7.30 (1H, d, J = 7.9 Hz), 7.74
(1H, s), 8.47-8.63 (4H, m), 11.71 -12.0
7 (1H, m), 12.6-13.3 (1H, m). Example 137 6-carboxymethoxy-1-methyl-2-indoloylguanidine-hydrochloride Yield 53.0% mp 298 ° C. ¹ Hnmr (DMS
O-d ₆ ) δ; 3.97 (3H, s), 4.79 (2H, s),
6.85 (1H, dd, J = 2.0, 8.9Hz), 7.09 (1
H, s), 7.63 (1H, d, J = 8.9Hz), 7.72 (1
H, s), 8.34-8.51 (4H, m), 10-13 (2
H, m).

Example 138 1-Methyl-7- (2-phenylethylamino) -2-
Synthesis of indoylguanidine a) Synthesis of ethyl 1-methyl-7- (2-phenylethylamino) -2-indolecarboxylate Ethyl 7-amino-1-methyl-2-indolecarboxylate (0.10 g, 0.46 mmol) , Phenylacetaldehyde (50% isopropanol solution; 0.12g, 0.50
mmol), sodium cyanoborohydride (0.043 g, 0.
69 mmol) and acetic acid (0.1 ml) in acetonitrile (5 m
l) After stirring the solution at room temperature for 15 minutes, acetic acid (0.2 m
l) was added and left at room temperature for 15 hours. 1 in the reaction mixture
It was obtained by adding N sodium hydroxide aqueous solution and then extracting with diethyl ether (three times), washing the extract with 1N potassium hydroxide aqueous solution, and drying over anhydrous magnesium sulfate, and then distilling off the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography to give ethyl acetate.
1-methyl-7- (2-phenylethylamino) -2-
Indole carboxylate (0.045 g, 30.5%) was obtained.

B) Synthesis of 1-methyl-7- (2-phenylethylamino) -2-indoloylguanidine Ethyl 1-methyl-7- (2-phenylethylamino) -2-indolecarboxylate (0.16 g, 0.51
mmol), guanidine hydrochloride (0.49 g, 5.09 mmol) and sodium methoxide (0.28 g, 5.09 mmol) in methanol (10 ml) to carry out the reaction according to the method of Example 1 to give 1-methyl-7. -(2-Phenylethylamino) -2-indoloylguanidine hydrochloride (0.075
g, 39.5%) was obtained. mp220-223 ° C ¹ Hnmr (DMSO-
_{d 6) δ; 2.96-3.02 (2H} , m), 3.29-3.35 (2
H, m), 4.18 (3H, s), 6.60-6.95 (1H,
m), 6.99 (1H, d, J = 7.3Hz), 7.06 (1H,
d, J = 7.3 Hz), 7.20-7.25 (1H, m), 7.31-
7.33 (4H, m), 7.64 (1H, s), 8.42-8.59 (4
H, m), 11.73 (1H, br-s).

Reaction was carried out according to the method of Example 138 to synthesize the compound of Example 139 below. Example 139 1-Methyl-6- (2-phenylethylamino) -2-
Indoyl guanidine / hydrochloride yield 26.6% mp243-246 ° C ¹ Hnmr
(DMSO-d ₆ ) δ; 2.91-2.97 (2H, m), 3.38
-3.51 (2H, m), 3.92 (3H, s), 6.70 (1H,
s), 6.79 (1H, d, J = 7.9Hz), 7.20-7.29
(1H, m), 7.31 (4H, m), 7.49 (1H, d, J
= 8.6 Hz), 7.76 (1 H, s), 8.35-8.63 (4 H,
m), 11.64 (1H, br-s).

Example 140 Synthesis of 1- (3-aminopropyl) -4-trifluoromethyl-2-indoloylguanidine a) Ethyl-1- (3-tert-butoxycarbonylaminopropyl) -4-trifluoromethyl Synthesis of 2-indolecarboxylate Ethyl 4-trifluoromethyl-2-indolecarboxylate (2.60 g, 10.11 mmol), 60% sodium hydride (0.445 g, 11.12 mmol), tert-butyl N-
(3-Iodopropyl) carbamate (4.32 g, 15.17
mmol) and dimethylformamide (100 ml),
The reaction was performed according to the method of Reference Example 5 (25) to obtain ethyl 1- (3-tert-butoxycarbonylaminopropyl) -4-trifluoromethyl-2-indolecarboxylate (2.81 g, 67.1%). .

B) 1- (3-aminopropyl) -4-
Synthesis of trifluoromethyl-2-indoloylguanidine Ethyl 1- (3-tert-butoxycarbonylaminopropyl) -4-trifluoromethyl-2-indolecarboxylate (2.81 g, 6.78 mmol), guanidine hydrochloride (6.48) g, 67.8 mmol) and sodium methoxide (3.66 g, 67.8 mmol) in methanol (100 ml) were reacted according to the method of Example 1 to give 1- (3-
tert-Butoxycarbonylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine (2.83
g) was obtained. This compound (2.72 g) was reacted according to the method of Example 114 to give 1- (3-aminopropyl) -4-trifluoromethyl-2-indoloylguanidine hydrochloride (1.45 g, 57.0%). ) Got. mp 245 ° C (decomposition) ¹ Hnmr (DMSO-
d ₆ ) δ; 1.99-2.20 (m, 2H), 2.70-2.89 (2
H, m), 4.72 (2H, t, J = 6.9Hz), 7.51-7.
68 (2H, m), 8.06 (3H, br-s), 8.06-8.27
(2H, m), 8.71 (2H, br-s), 8.80 (2H,
br-s), 12.30 (1H, br-s).

Example 141 Synthesis of 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine (1) Ethyl 1- (3-dimethylaminopropyl)-
Synthesis of 4-trifluoromethyl-2-indolecarboxylate Ethyl 4-trifluoromethyl-2-indolecarboxylate (2.07 g, 4.84 mmol), 60% sodium hydride (0.43 g, 10.7 mmol), 3-chloropropyl Ethyl 1- (3-dimethylaminopropyl) -4-trifluoro was obtained by using dimethylamine / hydrochloride (1.15 g, 7.26 mmol) and dimethylformamide (80 ml) according to the method of Reference Example 5. Methyl-2-indolecarboxylate (1.77 g, 74%) was obtained. (2) Synthesis of 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine Ethyl 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indolecarboxylate (1.77 g, 3.45 mmol), guanidine hydrochloride (3.30 g,
34.5 mmol) and sodium methoxide (1.87 g, 34.5
(1 mmol) in a methanol solution (100 ml) according to the method of Example 1, 1- (3-dimethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine hydrochloride (0.42 g, 28 %) Was obtained. mp 252-255 ℃ ¹ Hnmr (DMSO-d ₆ ) δ; 2.07-2.30 (2H, m)
, 2.58-2.60 (6H, m), 3.00-3.19 (2H, m), 4.59-4.81 (2
H, m), 7.49-8.67 (2H, m), 8.04-8.26 (2H, m), 8.71 (2
H, br-s), 8.79 (2H, br-s), 10.69 (1H, br-s), 12.29 (1
H, br-s) By carrying out the reaction according to the method of Example 141,
The following compounds of Examples 142-147 were synthesized.

Example 142 1- (3-Dimethylaminopropyl) -2-indoloylguanidine · hydrochloride Yield 12.3% mp 240 ° C. ¹ Hnmr (DMSO-d ₆ ).
δ; 2.04-2.27 (2H, m), 2.60-2.78 (6H, m), 2.98-3.17
(2H, m), 4.51-4.72 (2H, m), 7.12-7.28 (1H, m), 7.37-
7.49 (1H, m), 7.75 (1H, d, J = 8.3Hz), 8.07 (1H, s), 8.60
(2H, br-s), 8.81 (2H, br-s), 10.50 (1H, br-s), 12.15
(1H, br-s) Example 143 4-chloro-1- (3-dimethylaminopropyl) -2
-Indoylguanidine hydrochloride, yield 47.6% mp 237-240 ℃ ¹ Hnmr (DMSO-d ₆ ).
δ; 2.07-2.27 (2H, m), 2.70 (6H, d, J = 1.3Hz), 3.02-3.14
(2H, m), 4.55-4.72 (2H, m), 7.30 (1H, d, J = 7.3Hz), 7.3
8-7.48 (1H, m), 7.77 (1H, d, J = 8.6Hz), 8.06 (1H, s), 8.6
1 (2H, br-s), 8.68 (2H, br-s), 10.36 (1H, br-s), 12.11
(1H, br-s)

Example 144 1- [2- (N-pyrrolidinyl) ethyl] -2-indoloylguanidine-hydrochloride Yield 23.8% mp 236-239 ° C. ¹ Hnmr (DMSO-d ₆ ).
δ; 1.75-2.11 (4H, m), 2.88-3.13 (2H, m), 3.40-3.68 (4
H, m), 4.85-5.04 (2H, m), 7.16-7.29 (1H, m), 7.40-7.5
4 (1H, m), 7.78 (1H, d, J = 7.9Hz), 7.87 (1H, d, J = 8.3Hz),
8.10 (1H, s), 8.62 (2H, br-s), 8.81 (2H, br-s), 11.17
(1H, br-s), 12.24 (1H, br-s) Example 145 4-chloro-1- [2- (N-pyrrolidinyl) ethyl]
-2-Indoyl guanidine / hydrochloride Yield 6.1% mp 220 ℃ ¹ Hnmr (DMSO-d ₆ ) δ;
1.72-2.10 (4H, m), 2.83-3.13 (2H, m), 3.41-3.69 (4H, m
m), 4.86-5.05 (2H, m), 7.32 (1H, d, J = 7.7Hz), 7.45 (1
H, dd, J = 8.3, 7.7Hz), 7.89 (1H, d, J = 8.3Hz), 8.14 (1H, br
-s), 8.67 (2H, br-s), 8.74 (2H, br-s), 11.35 (1H, br-
s), 12.28 (1H, br-s) Example 146 1- (3-Diethylaminopropyl) -4-trifluoromethyl-2-indoloylguanidine-hydrochloride Yield 30.8% mp 222-225 ° C ¹ Hnmr (DMSO) -d ₆ )
δ; 1.18 (6H, t, J = 6.9Hz), 2.08-2.30 (2H, m), 2.92-3.2
0 (6H, m), 4.57-4.80 (2H, m), 7.50-7.65 (2H, m), 8.07
-8.24 (2H, m), 8.66 (2H, br-s), 8.78 (2H, br-s), 10.5
8 (1H, br-s), 12.30 (1H, br-s)

Example 147 1- [2- (N-morpholinyl) ethyl] -2-indoloylguanidine · hydrochloride Yield 20.5% mp 180 ° C. ¹ Hnmr (DMSO-d ₆ ) δ;
3.00-3.27 (2H, m), 3.27-3.70 (4H, m), 3.70-4.10 (4H, m
m), 4.88-5.14 (2H, m), 7.15-7.30 (1H, m), 7.39-7.52
(1H, m), 7.78 (1H, d, J = 7.9Hz), 7.90 (1H, d, J = 8.9Hz),
8.10 (1H, s), 8.65 (2H, br-s), 8.81 (2H, br-s), 11.85
(1H, br-s), 12.26 (1H, br-s)

Example 148 Synthesis of 6- (3-aminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine a) Ethyl 6-benzyloxy-1-methyl-4-trifluoromethyl- Synthesis of 2-indolecarboxylate Ethyl 6-benzyloxy-4-trifluoromethyl-2-indolecarboxylate (2.20 g, 6.06 mmol),
Using 60% sodium hydride (0.24 g, 6.06 mmol), methyl iodide (1.72 g, 12.1 mmol) and dimethylformamide (50 ml), the reaction was carried out according to the method of Reference Example 5, ethyl 6-benzyloxy. -1-Methyl-4-trifluoromethyl-2-indolecarboxylate (2.25 g) was obtained. b) Synthesis of ethyl 6-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 6-benzyloxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate (2.23
g, 5.91 mmol), 10% palladium / carbon (0.3 g) and tetrahydrofuran (50 ml) were reacted according to the method of Reference example 15, a) to obtain ethyl 6-hydroxy-1-methyl-4-tri Fluoromethyl-2-indole caboxylate (1.70 g) was obtained. c) Synthesis of ethyl 6- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 6-hydroxy-1-methyl-4-trifluoromethyl-2- Indole carboxylate (1.00g, 3.4
8 mmol), 60% sodium hydride (0.14 g, 3.48 mmol), te
rt-Butyl N- (3-iodopropyl) carbamate
(0.99 g, 3.48 mmol) and dimethylformamide (40 ml) were reacted according to the method of Reference Example 5 to obtain ethyl 6
-(3-tert-butoxycarbonylaminopropoxy)
-1-Methyl-4-trifluoromethyl-2-indolecarboxylate (1.28 g) was obtained.

D) 6- (3-aminopropoxy) -1-
Synthesis of methyl-4-trifluoromethyl-2-indoloylguanidine Ethyl 6- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-4-trifluoromethyl-2
-Indole carboxylate (1.28 g, 2.88 mmol), guanidine hydrochloride (5.50 g, 57.6 mmol) and sodium methoxide (3.11 g, 57.6 mmol) in methanol (60 ml) according to the method of Example 1 6- (3-tert-butoxycarbonylaminopropoxy) -1-methyl-4-
Trifluoromethyl-2-indoloylguanidine (0.4
1g) was obtained. This compound (0.41 g) was reacted according to the method of Example 114 to give 6- (3-aminopropoxy) -1-methyl-4-trifluoromethyl-2.
-Indoylguanidine hydrochloride (0.27g, 21.8%) was obtained. mp 272-274 ℃, ¹ Hnmr (DMSO-d ₆ ) δ; 2.08〜2.13 (2
H, m), 2.99 to 3.01 (2H, m), 4.05 (3H, s), 4.24 to 4.28 (2H.
m), 7.21 (1H, s), 7.48 (1H, s), 7.97 (1H, s), 8.07 (3H, br
-s), 8.56 to 8.70 (4H, m), 12.06 (1H, br-s). By carrying out the reaction according to the method of Example 148,
The following compound of Example 149 was synthesized. Example 149 6- (3-aminopropoxy) -1,4-dimethyl-2-
Indoylguanidine hydrochloride mp 265-267 ℃, ¹ Hnmr (DMSO-d ₆ ) δ; 2.04〜2.09 (2
H, m), 2.46 (3H, s), 2.96 to 2.99 (2H, m), 3.98 (3H, s), 4.
13 ~ 4.18 (2H.m), 6.65 (1H, s), 6.91 (1H, s), 8.00 ~ 8.04
(4H, m), 8.44 (2H, br-s), 8.73 (2H, br-s), 11.92 (1H, b
rs).

Example 150 6- (3-Dimethylaminopropoxy) -1-methyl-
Synthesis of 4-trifluoromethyl-2-indoloylguanidine a) Ethyl 6- (3-dimethylaminopropoxy)-
Synthesis of 1-methyl-4-trifluoromethyl-2-indolecarboxylate Ethyl 6-hydroxy-obtained in Example 148 b)
1-Methyl-4-trifluoromethyl-2-indolecarboxylate (1.00 g, 3.48 mmol), 60% sodium hydride (0.35 g, 8.70 mmol), 3-chloropropyldimethylamine hydrochloride (0.82 g, 5.22) mmol) and dimethylformamide (40 ml) according to the method of Reference Example 4 to give ethyl 6- (3-dimethylaminopropoxy) -1-methyl-4-trifluoromethyl-2-.
Indole carboxylate (0.72 g) was obtained. b) Synthesis of 6- (3-dimethylaminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine Ethyl 6- (3-dimethylaminopropoxy) -1-
Methyl-4-trifluoromethyl-2-indole caboxylate (0.72 g, 1.93 mmol), guanidine hydrochloride (3.6
9g, 38.7mmol) and sodium methoxide (2.09g, 38.7mmo
l) in methanol solution (50 ml) was reacted according to the method of Example 1 to give 6- (3-dimethylaminopropoxy) -1-methyl-4-trifluoromethyl-2-indoloylguanidine-hydrochloric acid. A salt (0.31 g, 35.0%) was obtained. mp 264-265 ℃, ¹ Hnmr (DMSO-d ₆ ) δ; 2.17〜2.23 (2
H, m), 2.80 (6H, s), 3.2 to 3.4 (2H, m), 4.06 (3H, s), 4.2
3 to 4.27 (2H.m), 7.20 (1H, s), 7.50 (1H, s), 7.88 (1H, s)
s), 8.5 to 8.7 (4H, m), 10.27 (1H, br-s), 11.90 (1H, br-
s).

The compound of the following Example 151 was synthesized by performing the reaction according to the method of Example 150. Example 151 1,4-Dimethyl-6- (3-dimethylaminopropoxy) -2-indoloylguanidine hydrochloride mp 282-284 ° C., ¹ Hnmr (DMSO-d ₆ ) δ; 2.14 to 2.20 (2
H, m), 2.46 (3H, s), 2.79 ~ 2.80 (6H, m), 3.1 ~ 3.3 (2H.
m), 3.98 (3H, s), 4.13 to 4.17 (2H, m), 6.66 (1H, s), 6.9
3 (1H, s), 7.99 (1H, s), 8.42-8.74 (4H, m), 10.26 (1H, br
-s), 11.85 (1H, br-s).

Test Example 1 Na ⁺ / H ⁺ exchange transport system inhibitory effect (in vitro test) [Test method] Iemori et al. (J. Hypertension, 8, 153)
(1990)). That is, using rat thoracic aortic media-derived smooth muscle cells, the intracellular pH during acid loading was measured.
The change was used as an index to evaluate the inhibitory effect on the Na ⁺ / H ⁺ exchange transport system. [Test Results] The IC ₅₀ value of the inhibitory action on the Na ⁺ / H ⁺ exchange transport system according to the present test method was 0.058 μM for the compound of Example 1 of the present invention and 0.
05 μM, 2.1 μM for the compound of Example 22,
0.02 μM for compound of Example 55, Example 2
0.0009 μM for compound of Example 9, Example 118
Of the control compound was 0.01 μM, dimethyl amiloride of the control compound was 0.60 μM, and 5-hexamethylene amiloride was 0.14 μM.

Test Example 2 Na ⁺ / H ⁺ exchange transport system inhibitory effect (in vitro test) [Test method] Mungre et al. Method (Exp. Cell Res., 193,
236 (1991)). That is, the rat thoracic aortic media-derived smooth muscle cells were used to evaluate the Na ⁺ / H ⁺ exchange transport system inhibitory action using the cytotoxicity upon acid loading as an index. [Test Results] The minimum effective concentration (M) of the inhibitory action on the Na ⁺ / H ⁺ exchange transport system by the present test method for the compounds of each Example
EC) was as shown in Table 1.

[0215]

[Table 1]

[0216]

[Table 2]

[0217]

[Table 3]

[0218]

[Table 4] In Table 1, * indicates that measurement could not be performed due to cytotoxicity.

Test Example 3 Inhibition test of arrhythmia by ischemia reperfusion in rat (in vivo test) [Test method] Method of Crome et al. (J. Cardiovasc. Pharmac
ol., 8, 1249 (1986)). That is, the suppression of arrhythmia induced by recanalization after coronary artery occlusion in rats was evaluated using the suppression of ventricular tachycardia incidence, ventricular fibrillation incidence and mortality as indexes. [Test Results] With respect to the compound of Example 1 of the present invention, the inhibitory effects on the incidence of ventricular tachycardia, the incidence of ventricular fibrillation, and the mortality rate in this test are shown in Table 2.

[0220]

[Table 5] [Table 2] Reperfusion arrhythmia suppression test ─────────────────────────────────── Compound dose Ventricular tachycardia incidence Ventricular fibrillation incidence mortality rate ─────────────────────────────────── Example 1 0.3 mg / kg 50% 0% 0% 0.1 mg / kg 70% 10% 10% EIPA 1 mg / kg 43% 0% 0% 0.3 mg / kg 100% 56% 44% Control group 100% 95% 76% ───────────────────────────────────

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/40 ABX 9454-4C (72) Inventor Kazuhiro Nakano 3-1, Kasuganode, Konohana-ku, Osaka City No. 98 Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Takeshi Noguchi 3-1,98 Kasuga, Konohana-ku, Osaka City In-house Sumitomo Pharmaceutical Co., Ltd. (72) Akira Miyagishi 3 Kasuga, Konohana-ku, Osaka 1st-98th Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Naohito Ohashi 3-1-198 Kasugade, Konohana-ku, Osaka City Sumitomo Pharmaceuticals Co., Ltd.

Claims (13)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group,
Halogen atom, nitro group, acyl group, carboxyl group,
Alkoxycarbonyl group, aromatic group, or formula-O
_{R 3, -NR 6 R 7,} -SO 2 NR 6 R 7 or -S
(O) _n represents a group represented by R _40, which may be substituted one by one or the same or different, and R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group,
It represents a hydroxyl group, an alkoxy group, or a group represented by the formula —CH ₂ R ₂₀ . R ₃ is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, or a group of formula —CH ₂ R ₃₀ (R ₃₀
Represents an alkenyl group or an alkynyl group), and R ₆ and R ₇ are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group,
An acyl group or a group represented by the formula —CH ₂ R ₆₀ (R ₆₀ represents an alkenyl group or an alkynyl group), or R ₆ and R ₇ are bonded to each other to form another hetero atom in the ring. It represents a saturated 5- to 7-membered cyclic amino group which may be contained, R ₄₀ represents an alkyl group or a substituted alkyl group, n represents 0, 1 or 2, and R ₂₀ represents an alkenyl group or an alkynyl group. However, in the above general formula, the R ₁ group and the guanidinocarbonyl group may be substituted on either the 6-membered ring portion or the 5-membered ring portion of the indole ring. ) Indoyl guanidine derivative represented by the following) or a pharmaceutically acceptable acid addition salt thereof. 2. R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a cycloalkyl group, a halogen atom, a nitro group, an alkanoyl group, a carboxyl group, an aryl group, an alkylsulfonyl group, or a formula —OR ₃ or —NR ₆ R ₇ is a group, R ₃ is a hydrogen atom, an alkyl group or a substituted alkyl group, and R ₆ and R ₇ are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkanoyl group. Or an aroyl group or a saturated 5- to 7-membered cyclic amino group in which R ₆ and R ₇ are bonded to each other and may contain another hetero atom in the ring. Derivatives or pharmaceutically acceptable acid addition salts thereof. 3. R ₁ is a hydrogen atom, an alkyl group, a substituted alkyl group (provided that the substituent is a hydroxyl group or a —NR ₆ R ₇ group), a polyhaloalkyl group, an alkenyl group, a cycloalkyl group, a halogen atom, nitro. Group, alkanoyl group,
Carboxyl group, phenyl group, alkylsulfonyl group,
Or the formula —OR ₃₁ (R ₃₁ is a hydrogen atom, an alkyl group or a substituted alkyl group (provided that the substituent is a hydroxyl group, a carboxyl group, a phenyl group, a carbamoyl group, a mono- or di-
An indroylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 1, which is a group represented by an alkylcarbamoyl group or a group represented by the formula: -NR ₆ R ₇ ). 4. R ₁ is an alkyl group, a polyhaloalkyl group, an alkenyl group, a halogen atom, a nitro group, or a group of formula —OR ₃₂ (R ₃₂ is a hydrogen atom, an alkyl group or a substituted alkyl group (wherein the substituent is a hydroxyl group, Carbamoyl group, mono- or di-alkylcarbamoyl group or formula -NR
₆ Indian acryloyloxy guanidine derivative or an acid addition pharmaceutically acceptable salt thereof according to claim 1, wherein the a group represented by R ₇ is a group represented by) represents an). 5. R _{1, which} is a hydrogen atom, an alkyl group, a substituted alkyl group, a hydroxyl group or an alkoxy group,
The indoloylguanidine derivative according to 2, 3 or 4 or a pharmaceutically acceptable acid addition salt thereof. 6. The indoloylguanidine derivative according to claim 1, which is a 2-indoloylguanidine compound, or a pharmaceutically acceptable acid addition salt thereof. 7. A general formula (2): (In the formula, R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are each independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a halogen atom, a nitro group. , An acyl group, a carboxyl group, an alkoxycarbonyl group, an aromatic group, or the formula —OR ₃ , —N
_{R 6 R 7, -SO 2 NR} 6 R 7 or -S (O) _n R
Represents a group represented by ₄₀ , R ₂ is a hydrogen atom, an alkyl group,
It represents a substituted alkyl group, a cycloalkyl group, a hydroxyl group, an alkoxy group, or a group represented by the formula —CH ₂ R ₂₀ . R ₃
Represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, or a group represented by the formula —CH ₂ R ₃₀ (R ₃₀ represents an alkenyl group or an alkynyl group), and R ₆ and R ₇ are independent of each other. A hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, or the formula —CH ₂ R
_A saturated group which may represent a group represented by ₆₀ (R ₆₀ represents an alkenyl group or an alkynyl group), or R ₆ and R ₇ may be bonded to each other to contain another hetero atom in the ring;
To a 7-membered cyclic amino group, R ₄₀ represents an alkyl group or a substituted alkyl group, n represents 0, 1 or 2, and R ₂₀ represents an alkenyl group or an alkynyl group. )
The indoloylguanidine derivative represented by or a pharmaceutically acceptable acid addition salt thereof. 8. The indoloylguanidine derivative according to claim 7, wherein R ₈ is a hydrogen atom, and R ₁₀ is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable acid addition salt thereof. 9. R ₉ is a hydrogen atom, an alkyl group, a polyhaloalkyl group, a cycloalkyl group, an alkenyl group, a halogen atom, a nitro group, an alkylsulfonyl group, or a compound represented by the formula:
The indoloylguanidine derivative or a pharmaceutically acceptable acid addition salt thereof according to claim 7 or 8, which is a group represented by OR ₃₃ (R ₃₃ represents a hydrogen atom, an alkyl group or an aralkyl group). 10. R ₁₁ and R ₁₂ , independently of one another,
Hydrogen atom, an alkyl group, a substituted alkyl group (wherein the substituent is a hydroxyl group or -NR ₆ R ₇ group) polyhaloalkyl group, an alkenyl group, a cycloalkyl group, a halogen atom, a nitro group, or the formula -OR ₃ or, -NR ₆ R ₇
The indoloylguanidine derivative according to claim 7, 8 or 9, which is a group represented by: or a pharmaceutically acceptable acid addition salt thereof. 11. The method according to claim 7, wherein R ₂ is a hydrogen atom, an alkyl group, a substituted alkyl group, a hydroxyl group or an alkoxy group.
The indoloylguanidine derivative according to 8, 9 or 10 or a pharmaceutically acceptable acid addition salt thereof. 12. A sodium / proton exchange transport system inhibitor comprising the indoloylguanidine derivative according to claim 1 or 7, or a pharmaceutically acceptable acid addition salt thereof. 13. A therapeutic or prophylactic agent for hypertension, arrhythmia, angina, cardiac hypertrophy, organ damage due to ischemia-reperfusion, cerebral ischemia, or diseases caused by cell hyperproliferation. The sodium / proton exchange transport system inhibitor described.