AU713460B2 - Indole derivatives as cGMP-PDE inhibitors - Google Patents

Description

WO 96/32379 PCT/JP96/00892 1

DESCRIPTION

INDOLE DERIVATIVES AS cGMP-PDE INHIBITORS This invention relates to novel compounds having pharmacological activity, to a process for their production and to a pharmaceutical composition containing the same.

More particularly, it relates to novel indole compounds, which have pharmaceutical activity such as inhibiting activity of cyclic guanosine phosphodiesterase (hereinafter described as cGMP-PDE), to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.

Accordingly, one object of this invention is to provide the novel indole compounds, which have an inhibiting activity of cGMP-PDE.

Another object of this invention is to provide a process for production of the indole compounds.

A further object of this invention is to provide a pharmaceutical composition containing, as active ingredients, the indole compounds.

Still further object of this invention is to provide a use of the indole compounds for treating or preventing various diseases.

Further, this invention also relates to a new use of inhibitors of cyclic nucleotide phosphodiesterases.

(hereinafter described as cyclic nucleotide-PDEs) In more detail, this invention relates to a new use of cyclic nucleotide-PDEs inhibitors for preventing or treating glomerular diseases, tubulo-interstitial diseases or renal failure, or diabetic complications.

Accordingly, this invention provides a new use of cyclic nucleotide-PDE inhibitors for preventing or treating glomerular diseases, tubulo-interstitial diseases or renal 2 failure, or diabetic complications.

Further, this invention provides an agent and a pharmaceutical composition for preventing or treating glomerular diseases, tubulo-interstitial diseases or renal failure, or diabetic complications, which comprises cyclic nucleotide-PDE inhibitors.

Still further, this invention provides a method for preventing or treating glomerular diseases, tubulointerstitial diseases or renal failure, or diabetic complications, which comprises administering cyclic nucleotide-PDE inhibitors.

represented by the following general formula *0 S4(I) acyl, cyano, hydroxyimino (lower) alkyl, lower alkenyl :optionally substituted with oxo, lower alkyl optionally ""substituted with protected carboxy, carboxy or hydroxy, or aryl;

R

2 is hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy or hydroxy; is lower alkenyl or lower alkyl, both of which are optionally substituted with one or more substituent(s) selected from the group consisting of o wherein

R

1 is hydrogen, halogen, nitro, carboxy, protected carboxy, acyl, cyano, hydroxyimino (lower) alkyl, lower alkenyl optionally substituted with oxo, lower alkyl optionally 'substituted with protected carboxy, carboxy or hydroxy, or aryl;

R

2 is hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy or hydroxy; 3is lower alkenyl or lower alkyl, both of which are optionally substituted with one or more substituent(s) selected from the group consisting of oxo, WO 96/32379 PCTIJP96/00892 3 aryl optionally substituted with one or more substituent(s) selected from the group consisting of halogen, aryl, lower alkoxy, lower alkylenedioxy, cyano, nitro, carboxy, protected carboxy, acyl, and amino optionally substituted with acyl or protected carboxy, and a heterocyclic group optionally substituted with halogen; and

R

4 is carboxy, protected carboxy, acyl, cyano, halogen, a heterocyclic group, amino optionally substituted with acyl or protected carboxy, or lower alkyl optionally substituted with protected carboxy, carboxy or acyl; in addition to their significances above,

R

1 and R 2 together with the carbon atoms to which they are attached, represent a 4- to 7-membered carbocyclic ring optionally substituted with oxo, or its pharmaceutically acceptable salt.

The compounds of formula may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. Furthermore certain compounds of formula which contain alkenyl groups may exist as cis- or transisomers. In each instance, the invention includes both mixtures and separate individual isomers.

The compounds of formula may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.

The compound of the formula and its salt can be in the form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.

Also included in the scope of invention are radiolabelled derivatives of compounds of formula which are suitable for biological studies.

WO 96/32379 PCT/JP96/00892 4 A preferred group of compounds of formula is that wherein

R

1 is cyano, acyl, or lower alkyl optionally substituted with hydroxy;

R

2 is hydrogen, acyl, lower alkenyl, or lower alkyl optionally substituted with lower alkoxy or hydroxy;

R

3 is methyl substituted with aryl or a heterocyclic group, wherein aryl is optionally substituted with one or more substituent(s) selected from the group consisting of halogen, lower alkylenedioxy, protected carboxy and carboxy; and

R

4 is acyl, cyano, or a heterocyclic group; in addition to their significances above,

R

1 and R 2 together with the carbon atoms to which they are attached, represent a 4- to 7-membered carbocyclic ring optionally substituted with oxo.

A more preferred group of compounds of formula is that wherein

R

1 is lower alkyl, or lower alkanoyl optionally substituted with hydroxy, lower alkoxy or aryl; R2 is hydrogen, lower alkenyl, or lower alkyl optionally substituted with lower alkoxy;

R

3 is benzyl optionally substituted with one Or more substituent(s) selected from the group consisting of halogen and lower alkylenedioxy; and

R

4 is acyl, cyano, or a heterocyclic group.

A particularly preferred group of compounds of formula is that wherein R1 is lower alkyl, or lower alkanoyl optionally substituted with hydroxy, lower alkoxy or aryl;

R

2 is hydrogen, lower alkenyl, or lower alkyl optionally substituted with lower alkoxy;

R

3 is benzyl optionally substituted with one or more WO 96/32379 PCT/JP96/00892 5 substituent(s) selected from the group consisting of halogen and lower alkylenedioxy;

R

4 is

I

R

R s

-CON<

\R

6

R

5 is hydrogen or lower alkyl, and

R

6 is hydrogen, hydroxy, lower alkoxy, arylsulfonyl, a heterocyclic group, or lower alkyl optionally substituted with lower cycloalkyl or a heterocyclic group; in addition to their significances above,

R

5 and R 6 together with the nitrogen atom to which they are attached, may represent a heterocyclic group.

An especially preferred group of compounds of formula is that wherein

R

1 is lower alkanoyl optionally substituted with alkoxy,

R

2 is lower alkyl,

R

3 is benzyl optionally substituted with one or more substituent(s) selected from the group consisting of halogen and lower alkylenedioxy, and R4 is carbamoyl.

According to this invention, the object compounds or its salt can be prepared by the following processes.

WO 96/32379 PTJ9109 PCT/JP96/00892 -6 Process 1

-R

4

R

3 xi(III) or its salt R2 N

(I)

or its salt (I I) or its salt Rl 4 Deesterification

R

Ra I I R N R N 3 3 (I-1) or its salt (1-2) or its salt Process 3 Ri ~H-Ny. 5 JT R4 11R6 I b or its reactive- R derivative at 3 the amino group, or its salt or its reactive derivative at the carboxy group, or its salt R N I 3 (1-3) or its salt WO 96/32379 PCT/JP96/00892 -7 4 Deesterification

R

or its salt (1-4) or its salt Process Rl R4 _H N: o r R N de: or or its reactive derivative at the carboxy group, or its salt R 6 it reactive rivative at the rboxy group, its salt (1-6) or its salt Process 6 a p4 R2 ZR (1-7) or its salt Reduction 1 RbR RN~a (1-8) or its salt WO 96/32379 WO 9632379PCT/JP96/00892 8- I R4 R2" N 3

(V)

R~

I

R 4 R N 43 (1-9) or its salt or its salt Process 8 Dehydration (I-11) or its salt (1-12) or its salt Process 9

CN

R

2 rN (1-12) or its salt (1-13) or its salt WO 96/32379 WO 9632379PCT/JP96/00892 9- Process 4 Deesterification (1-14) or its salt I I

R

Rb N (1-15) or its salt Process 11 J1N Intramolecular acylation (1-15) or its reactive derivative at the carboxy group, or its salt Process 12 (1-16) or its salt H-Nw11R 11R 6 or its sa (IV)-R or its salt (1-17) or its salt WO 96/32379 WO 9632379PCT/JP96/00892 10 Process 13

R"N

Fo rmyl at ion.

(1-9) or its salt 3s 14 H- Oxidation I 3 (1-19) or its salt 0 (1-19) or its salt 0 (1-20) or its salt R2' N C OOH (1-21) or its salt

R

2 (1-22) or its salt

I

WO 96/32379 PCT/J1P96/00892 11 Process 16 R I1 I NH2 13

R

(1-23) or its reactive derivative at the amino group, or its salt

R

8

-X

3

(VI)

or its salt, or R 9

-N=C=O

(VII)

or its salt RlN I I

NHR

8 R N 1 3 (1-24) or its salt Process 17 (1-25) or its salt Reduction RiR RL N (1-26) or its salt Process 18 (T-27) or its salt Dealkylation

R

2 Z Rj (1-28) or its salt WO 96/32379 WO 9632379PCT/JP96/00892 12 Rc)N (1-29) or its salt oxidation I jR N -3 (1-30) or its salt I 3 (1-9) or its salt Halogenation 3hi 4 hII (1-31) or its salt Process 21 (1-9) or its salt Nitration 0 2 N N

RN

(1-32) or its salt WO 96/32379 WO 9632379PCT1JP96/00892 13 Process 22 I 1R4 (1-7) or its salt Reduction Ri I IjR (1-33) or its salt Process 23 J 4

R'

R2 N (1-34) or its salt k

R

(1-35) or its salt Process 24 I

R

R N 13 RKf (1-36) or its reactive derivative at the amino group, or its salt

R

8

-X

3

(VI)

or its salt or R 9 -N=C0O (VI I) or its salt N 1 (1-37) or its salt WO 96/32379 PCT/JP96/00892 14 wherein R1 to R 6 are each as defined above,

R

1 is lower alkanoyl optionally substituted with protected a carboxy or carboxy, R1 is lower alkyl optionally substituted with protected carboxy or carboxy, R1 is lower alkenoyl, aroyl, or lower alkanoyl optionally c substituted with protected carboxy, carboxy or aryl, Rd is chloroacetyl, 1 i R Re is

-COCH

2 N 6 Ri is lower alkanoyl substituted with lower alkoxy,

R

1 is lower alkanoyl substituted with hydroxy, g Rh is halogen, R! is lower alkyl optionally substituted with protected carboxy or carboxy, R1 is lower alkanoyl, Rk is hydroxyimino(lower)alkyl, R2 is lower alkyl substituted with protected carboxy, R2 is lower alkyl substituted with carboxy, R2 is 1-hydroxy(lower)alkyl, Rd is lower alkanoyl, R3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with protected carboxy,

R

3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with carboxy, R is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with WO 96/32379 PCT/JP96/00892 15 -CON 1- R 6 Rd is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with nitro, R3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with amino, R3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with amino,

R

3 is lower alkenyl or lower alkyl, both of which are g optionally substituted with oxo and both of which are substituted with aryl which is substituted with amino substituted with acyl, R is protected carboxy or lower alkyl substituted with protected carboxy, Rb is carboxy or lower alkyl substituted with carboxy,

R

4 is rC or lower alkyl substituted with -coN

R

7 is hydrogen, protected carboxy, or -CON

RR

R

8 is acyl,

R

9 is lower alkyl, X1 is leaving group, X2 and X3 are each as the same as X 1 and n is 1, 2, 3 or 4.

In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.

WO 96/32379 PCT/JP96/00892 16 The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.

Suitable "lower alkyl" and lower alkyl moiety in the terms "lower alkoxy" and "hydroxyimino(lower)alkyl", may be a straight or branched C 1

-C

6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in which preferable one is C1-C 4 lower alkyl such as methyl, ethyl, propyl, butyl, isobutyl or tert-butyl.

Suitable "lower alkenyl" may be a straight or branched

C

2

-C

6 alkenyl such as ethenyl, propenyl allyl or 1-propenyl), butenyl, isobutenyl, or the like.

Suitable "lower cycloalkyl" may include one having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or the like.

Suitable "aryl" and aryl moiety in the term of "arylsulfonyl", "aroyl" and "ar(lower)alkanoyl" may include phenyl, naphthyl, tolyl, mesityl, xylyl, or the like.

Suitable "halogen" may be fluoro, chloro, bromo or iodo.

Suitable "lower alkylenedioxy" may include methylenedioxy, ethylenedioxy, or the like.

Suitable "protected carboxy" may be a pharmaceutically acceptable and a common protected carboxy, such as an esterified carboxy, or the like, and concrete examples of the ester moiety in said esterified carboxy may be lower alkyl optionally substituted with aryl methyl, ethyl, propyl, tert-butyl, benzyl, and so on).

Suitable "heterocyclic group" may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group such as unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g.

4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,

I

WO 96/32379 PCT/JP96/00892 17 etc.], tetrazolyl lH-tetrazolyl, 2H-tetrazolyl, etc.], etc.; saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g.

pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.

tetrazolo[1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated, 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, etc.; unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], etc.; saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms morpholinyl, etc.];.

unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.

saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms thiazolidinyl, etc.];

III

WO 96/32379 PCT/JP96/00892 18 (11) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms benzothiazolyl, benzothiadiazolyl, etc.]; (12) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms or 1 to 2 oxygen atoms benzothiophen, benzofuran, etc.]; or the like.

"Heterocyclic group" defined above may be substituted with suitable substituent(s) such as lower alkyl, hydroxy, halogen, a heterocyclic group, or the like 3hydroxypyrrolidine, 4-methylpiperadine, 4-hydroxypiperidine, 1-methylimidazole, 4-(pyrimidin-2-yl)piperazin, and so on) Suitable "acyl" may be aliphatic acyl, aromatic acyl or aliphatic acyl optionally substituted aryl, which are derived from carboxylic acid or carbamic acid.

The aliphatic acyl may include lower alkanoyl optionally substituted with one or more suitable substituent(s) such as hydroxy, lower alkoxy, carboxy, protected carboxy, halogen, lower alkylthio, heterocyclicthio, oxo, cyclo(lower)alkyl or a heterocyclic group formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, 3,3-dimethylbutanoyl, 3-hydroxy-3methylbutanoyl, 3-oxo-butanoyl, 3-methoxycarbonylpropanoyl, 3-carboxypropanoyl, 4-methoxycarbonylbutanoyl, 4-carboxybutanoyl, methylthioacetyl, (1-methylimidazol-2yl)thioacetyl, hydroxyacetyl, methoxyacetyl, ethoxyacetyl, 3-methoxybutanoyl, chloroacetyl, morpholinoacetyl, piperidinylacetyl, 4-methylpiperidin-1-ylacetyl, 4-hydroxypiperidinyl, pyrolidinylacetyl, 4-(pyrimidin-2yl)piperidinylacetyl, 3-hydroxypyrrolidinylacetyl, oxolan-4-ylacetyl, and so on); cyclo(lower)alkanecarbonyl cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and so on); lower alkenoyl acryloyl, methacryloyl, crotonoyl, WO 96/32379 PCT/JP96/00892 19 3-methylbutanoyl, and so on); /R5 (wherein R 5 is hydrogen or lower alkyl, and R 6

\R

6 is hydrogen, hydroxy, lower alkoxy, arylsulfonyl, a heterocyclic group, lower alkyl optionally substituted with lower cycloalkyl or a heterocyclic group, or the like, in addition to their significances above, R 5 and R 6 together with the nitrogen atom to which they are attached, may represent a heterocyclic group), such as carbamoyl, Nmethylcarbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl, N,N-diethylcarbamoyl, N-propylcarbamoyl, N-phenylsulfonylcarbamoyl, N-methoxycarbamoyl, yl)carbamoyl, 1-pyrolidinylcarbonyl, piperidinocarbonyl, 4-methyl-l-piperazinylcarbonyl, 4-cyclohexyl-lpiperazinylcarbonyl, morpholinocarbonyl, 4-thiomorpholinylcarbonyl, or the like.

The aromatic acyl may include aroyl optionally substituted with one or more suitable substituent(s) such as nitro benzoyl, naphthoyl, nitrobenzoyl, and so on), or the like.

The aliphatic acyl substituted with aryl,may include ar(lower)alkanoyl which may have one or more suitable substituent(s) such as lower alkoxy phenylacetyl, 4-methoxyphenylacetyl, and so on) or the like.

Suitable "arylsulfonyl" may include phenylsulfonyl, tosyl, methoxyphenylsulfonyl, or the like.

Suitable "leaving group" may include hydroxy, halogen, acyloxy, in which the halogen and the acyl moiety may be those as exemplified above, or the like.

The starting compound (II) is prepared in similar manners to those of the below-mentioned Preparations.

WO 96/32379 PCT/JP96/00892 20 Suitable salts of the compounds to (1-36) and (II) to (VII) may include pharmaceutically acceptable salts such as basic salts, for example, alkali metal salt (e.g.

sodium salt, potassium salt, etc.), alkaline earth metal salt calcium salt, magnesium salt, etc.), ammonium salt, amine salt triethylamine salt, N-benzyl-N-methylamine salt, etc.) and other conventional organic salts, or acid addition salts, for example, hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or the like.

The processes for preparing the object compound are explained in detail in the following.

Process 1 The compound or its salt can be prepared by reacting the compound (II) or its salt with the compound (III) or its salt.

This reaction is usually carried out in the presence of an inorganic or an organic base.

Suitable inorganic base may include an alkali metal sodium, potassium, etc.], an alkali metal hydroxide sodium hydroxide, potassium hydroxide, etc.], alkali metal hydrogen carbonate sodium hydrogen carbonate, potassium hydrogen carbonate, etc.], alkali metal carbonate sodium carbonate, etc.], alkali earth metal carbonate [calcium carbonate, etc.], or the like.

Suitable organic base may include tri(lower)alkylamine triethylamine, N,N-diisopropylethylamine, etc.], alkyl lithium methyl lithium, butyl lithium, etc.], lithium diisopropylamide, lithium hexamethyldisirazido, alkali metal hydride sodium hydride, potassium hydride, etc.] or the like.

~I___illlL--IUIII__ I-IIIli---~-.I WO 96/32379 PCT/JP96/00892 21 The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process 2 The object compound or its salt can be prepared by subjecting a compound to deesterification.

The reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base, an acid, or the combination of Lewis acids and Lewis bases.

Suitable base may include an inorganic base and an organic base.

Suitable inorganic base may be the same as those exemplified in Process 1.

Suitable organic base may include tri(lower)alkylamine trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.

Suitable acid may include an organic acid formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e.g.

hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, etc.].

The hydrolysis is also carried out in the presence of the combination of Lewis acids and Lewis bases.

Suitable Lewis acid may include metal halide I WO 96/32379 PCT/JP96/00892 22 aluminum chloride, aluminum bromide, titanium(IV) chloride, tin(IV) chloride, etc.], metal alkoxide titanium(IV) isopropoxide, etc.] or the like.

Suitable Lewis base may include lower alkyl thiol ethanethiol, ethanedithiol, etc.], di(lower)alkyl sulfide [dimethylsulfide, etc.], or the like.

The reaction is usually carried out in a solvent such as water, an alcohol methanol, ethanol, etc.], xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

The reduction can be applied preferably for elimination of the ester moiety such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, or the like. The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are a combination of metal tin, zinc, iron, etc.] or metallic compound chromium chloride, chromium acetate, etc.] and an organic or inorganic acid exemplified above.

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst platinum on carbon, platinum oxide, etc.], palladium catalyst [e.g.

palladium black, palladium oxide, palladium on carbon, etc.] or any other catalyst ordinary employed in the field of organic synthetic chemistry. The catalytic reduction may be carried out in the presence of hydrogen or hydrogen doner such as formic acid, ammonium formate, cyclohexene, or the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such

I

WO 96/32379 PCT/JP96/00892 23 as water, an alcohol methanol, ethanol, propanol, etc.], N,N-dimethylformamide, or a mixture thereof.

Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.

Process 3 The compound or its-salt can be prepared by reacting the compound or its reactive derivative at the carboxy group, or its salt, with the compound (IV) or its reactive derivative at the amino group, or its salt, according to any well known procedure.

Suitable reactive derivative at the amino group of the compound (IV) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IV) with a carbonyl compound such as aldehyde, ketone or the like;-a silyl derivative formed by the reaction of the compound (IV) with a silylating reagent such as trimethylsilyl chloride, N,O-bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide, or the like.

Suitable reactive derivative of the compound may include an acid chloride, acid azide, an acid anhydride, an activated amide, an activated ester, or the like.

The suitable acid anhydride may include a mixed acid anhydride with an acid such as substituted phosphoric acid dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfuric acid, thiosulfuric acid, alkanesulfonic acid

IX~

WO 96/32379 PCT/JP96/00892 24 methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkanoic acid pivalic acid, pentanoic acid, isopentanoic acid, etc.), aromatic carboxylic acid benzoic acid, chlorobenzoic acid, fluorobenzoic acid, nitrobenzoic acid, etc.),or the like.

Suitable activated amide may be imidazoylamide, 4-substituted imidazoylamide, dimethylpyrazolylamide, triazolylamide tetrazolylamide, or the like.

Suitable activated ester may be dimethyliminomethyl

[(CH

3 2 N=CH-] ester, vinyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl thioester, p-nitrophenyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 8-quinolyl thioester, an ester with a N-hydroxy compound N,N-dimethylhydroxylamine, l-hydroxy-2Hpyridone, N-hydroxysuccinimido, N-hydroxybenzotriazole, N-hydroxyphthalimide, etc.), or the like.

These reactive derivatives can optionally be selected from them according to the kind of compound to be used.

When the compound is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of condensing agent.

Suitable condensing agent may include a carbodiimide N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-(3dimethylaminopropyl)carbodiimide or its hydrochloride, etc.) diphenylphosphinic azido, diphenylphosphinic chloride, diethylphosphoryl cyanide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, N,N'-carbonyldiimidazole, 2-ethoxy-lethoxycarbonyl-l,2-dihydroquinoline, cyanuric.chloride, or the like.

The reaction may be also carried out in the presence of organic or inorganic base such as alkali metal carbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, or WO 96/32379 PCT/JP96/00892 25 the like.

The reaction is usually carried out in a conventional solvent such as water, acetone, alcohol methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process 4 The compound or its salt can be prepared by subjecting the compound or its salt to deesterification.

This deesterification can be carried out in a similar manner to that of the Process 2, and therefore the reagents to be used and the reaction conditions solvent, reaction temperature, etc.) can be referred to those of the Process 2.

Process The compound or its salt can be prepared by reacting the compound or its reactive derivative at the carboxy group, or its salt, with the compound'(IV) or its reactive derivative at the amino group, or its salt.

This reaction can be carried out in a similar manner to that of the Process 3, and therefore the reagents to be used and the reaction conditions solvent, reaction temperature, etc.) can be referred to those of the Process 3.

Process 6 The compound or its salt can be prepared by reacting a compound or its salt with a reducing agent.

Suitable reducing agent may be diborane, sodium borohydride, lithium aluminum hydride or the like.

WO 96/32379 PCT/JP96/00892 26 The reaction is usually carried out in a conventional solvent such as diethyl ether, tetrahydrofuran or any other organic solvent which dose not adversely influence the reaction.

The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.

Process 7 The compound (1-10) or its salt can be prepared by reacting the compound or its salt with an acylati.g agent Suitable acylating agent may be a conventional one used in the Friedel-Crafts acylation reaction such as an acid halide acid chloride, acid bromide, etc.], an acid anhydride or the like.

This reaction is preferably carried out in the presence of a Lewis acid such as aluminum halide aluminum chloride, aluminum bromide, etc.], titanium halide [e.g.

titanium tetrachloride, etc.], zinc halide zinc chloride), boron trifluoride or the like.

The reaction is usually carried out in a conventional solvent such as carbon disulfide, dichloroethane, tetrachloromethane, benzene or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 8 The compound (1-12) or its salt can be prepared by subjecting the compound (I-11) or its salt to dehydration at the carbamoyl group.

Dehydration is carried out in the conventional manner, which is capable dehydrating a carbamoyl group to cyano group, and suitable dehydrating agent may be phosphorus compound phosphorous pentoxide, phosphorus WO 96/32379 PCT/JP96/00892 27 pentachloride, phosphorous oxychloride, pyrocatechyl phosphorus trichloride, and so on); thionyl chloride; or a combination of triaryl phosphine triphenyl phosphine, and so on) and chloroform or carbon tetrachloride.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, carbon tetrachloride,

N,N-

dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process 9 The object compound (1-13) or its salt can be prepared by reacting a compound (1-12) or its salt with an azide compound.

Suitable azide compound may be alkali metal azide [e.g.

sodium azide, potassium azide, etc.], alkaline earth metal azide calcium azide, etc.], aluminum azide, hydrogen azide, trimethyltin azide, or the like.

The reaction is preferably carried out in the presence of ammonium halide ammonium chloride, ammonium bromide, etc.], lower alkylammonium halide trimethylammonium chloride, triethylammonium chloride, etc.] or the like.

The reaction is usually carried out in a conventional solvent such as tetrahydrofuran, dioxane, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction can be carried out under warming to heating.

Process The compound (1-15) or its salt can be prepared by subjecting the compound (1-14) or its salt to WO 96/32379 PCT/JP96/00892 28 deesterification.

This deesterification can be carried out in a similar manner to that of the Process 2, and therefore the reagents to be used and the reaction conditions solvent, reaction temperature, etc.) can be referred to those of the Process 2.

Process 11 The compound (1-16) or its salt can be prepared by subjecting the acid chloride or acid anhydride derived from the compound (1-15) or its salt to intramolecular acylation reaction.

This intramolecular acylation reaction can be carried out in a similar manner to that of the Process 7, and therefore the reagents to be used and the reaction conditions solvent, reaction temperature, etc.) can be referred to those of the Process 7.

Process 12 The compound (1-18) or its salt can be prepared by reacting the compound (1-17) or its salt with compound (IV).

This reaction is preferably carried out in the presence of organic or inorganic base exemplified in Process 1, and/or alkali metal iodide sodium iodide, potassium iodide, etc.).

The reaction is usually carried out in a solvent such as water, tetrahydrofuran, dioxane, N,N-dimethylformamide or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature of under warming to heating.

Process 13 The compound (1-19) or its salt can be prepared by WO 96/32379 PCT/JP96/00892 29 reacting a compound or its salt with a formylating agent.

Suitable formylating agent may be N,N-dimethylformamide;

(CH

3 2 N+=CHC1lCl 2 PO2 (so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with phosphorus oxychloride, phosgene, etc.); or the like.

When a formylating agent is N,N-dimethylformamide, the reaction is preferably carried out in the presence of a base such as lower alkyl alkali metal n-butyl lithium, ethyl magnesium bromide, etc.], or the like.

The reaction is usually carried out in a solvent such as dioxane, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, chloroform, or any other organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 14 The compound (1-20) or its salt can be prepared by subjecting the compound (1-19) or its salt to oxidation reaction.

Oxidation is carried out in a conventional manner, which is capable of oxidizing formyl group to carboxy group, and suitable oxidizing reagent may be oxygen acid such as periodate sodium periodate, potassium periodate, etc.), peroxy acid such as peroxybenzoic acid peroxybenzoic acid, m-chloroperoxybenzoic acid, etc.), potassium permanganate, cromic acid, sodium hypochlorite, or the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, dichloromethane, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction.

Among these solvents, hydrophilic solvents may be used WO 96/32379 PCT/JP96/00892 30 in a mixture with water.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

Process The compound (1-22) or its salt can be prepared by subjecting the compound (1-21) or its salt to a rearrangement reaction.

The rearrangement reaction, which is capable of converting the carboxy group into amino group optionally substituted with protected carboxy or acyl carbamyl substituted with lower alkyl, etc.), may be the condition such as Curtius Rearrangement, Hoffmann reaction, Schmidt reaction, or the modification thereof.

For example, the Curtius rearrangement consists of the formation of acid azide, the decomposition of acid azide to isocyanate and nitrogen, and the reaction of isocyanate with water, alcohol or amine to afford amine, urethane or urea, respectively.

Acid azide can be prepared by treating corresponding acid hydrazide with nitrous acid, treating corresponding acid chloride with alkali metal azide, treating carboxylic acid with diphenylphosphoryl azide, or the like.

Acid azide can be rearranged in inert solvent toluene, dichloromethane, etc.), from which the isocyanate can be isolated, or in the presence of reagents like alcohol or amine which will react with the intermediate isocyanate to form urethan or urea. Amine or its salt can be obtained by hydrolysis of isocyanate, urethan, or urea.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process 16 The compound (1-24) or its salt can be prepared by reacting the compound (1-23) or its reactive derivative at WO 96/32379 PCT/JP96/00892 31 the amino group, or its salt, with the compound (VI) or its salt, or the compound (VII) or its salt.

When free acid is used as the compound the reaction is preferably carried out in the presence of condensing agent exemplified in Process 3.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, isopropyl alcohol, etc.], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process 17 The compound (I-26) or its salt can be prepared by subjecting a compound (1-25) or its salt to reduction.

The present reduction is carried out by chemical reduction, catalytic reduction, or the like.

Suitable reducing agents to be used in chemical reduction are a combination of metal tin, zinc, iron, etc.] or metallic compound chromium chloride, chromium acetate, etc.] and an organic or inorganic.acid formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst platinum, platinum black, platinum oxide, etc.], palladium catalyst palladium black, palladium oxide, palladium on carbon, etc.], nickel catalyst reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalyst reduced cobalt, Raney cobalt, etc.], iron catalyst reduced iron, Raney iron, etc.], copper catalyst reduced copper, Raney copper, Ullman copper, etc.] or the like.

WO 96/32379 PCT/JP96/00892 32 The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol methanol, ethanol, propanol, etc.], N,N-dimethylformamide, or a mixture thereof.

Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent and other conventional solvent such as diethyl ether, methylene chloride, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.

Process 18 The compound (I-28) or its salt can be prepared by subjecting a compound (1-27) or its salt to cleavage of ether bond.

The cleavage of ether bond is carried out .in the presence of an acid including Lewis acid hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, boron trichloride, etc.], tri(lower)alkylsilyliodide trimethylsilyliodide, etc.], or any other method ordinary employed in the field of organic synthesis.

The reaction is usually carried out in a solvent such as water, acetic acid, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

Process 19 The compound (1-30) or its salt can be prepared by subjecting the compound (1-29) or its salt to oxidation.

WO 96/32379 PCT/JP96/00892 33 This oxidation can be performed according to the general procedures ordinarily employed in the field of organic chemistry, which is capable of oxidizing a secondary alcohol to ketone, and suitable oxidizing agent is, for example, derivatives of hexavalent chromium(CrVI) chromium trioxide, sodium dichromate, chromium trioxide-dipyridine complex, etc.) or heptavalent manganese(MnVII) (e.g.

potassium permanganate, manganese dioxide, etc.).

The reaction is usually carried out in a conventional solvent such as water, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethyl.formamide, acetone, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process The compound (1-31) or its salt can be prepared by subjecting the compound or its salt to halogenation.

This halogenation is usually carried out by using a conventional halogenating agent such as halogen chlorine, bromine, etc,), phosphorus trihalide phosphorus tribromide, phosphorus tichloride, etc.), phosphorus pentahalide phosphorus pentachloride, phosphorus pentabromide, etc.), phosphorus oxychlroide phosphoryl trichloride, phosphoryl monochloride, etc.), thionyl halide thionyl chloride, thionyl bromide, etc.), oxalyl halide oxalyl chloride, oxalyl bromide, etc.), sulfuryl halide sulfuryl chloride, etc.), pyridinium hydrobromide perbromide, or the like.

This reaction is usually carried out in a solvent such as water, alcohol methanol, ethanol, isopropyl alcohol, etc.), benzene, dioxane, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene dichloride, chloroform, diethyl ether or any other solvent which dose not WO 96/32379 PCT/JP96/00892 34 adversely affect the reaction.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process 21 The compound (1-32) or its salt can be prepared by reacting a compound or its salt with a nitrating agent.

Suitable nitrating agent may be nitric acid, fuming nitric acid, potassium nitrate, nitronium tetrafluoroborate or the like.

The reaction is usually carried out in.an acid or an acid anhydride such as sulfuric acid, acetic acid, acetic anhydride or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 22 The compound (I-33) or its salt. can be prepared by subjecting the compound or'its salt to reduction.

This reduction can be performed according:.to the general procedures ordinarily employed in the field of organic chemistry, which is capable of reducing a ketone to a secondary alcohol, and suitable reducing agent is, for example, metal hydride such as aluminum hydrides (e.g.

lithium aluminum hydride, lithium di(lower)alkylaluminum hydride, Red-Al etc.), boron hydrides sodium borohydride, sodium borocyanohydride, etc.), or the like.

The reaction is usually carried out in a conventional solvent such as water, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide, acetone, or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

WO 96/32379 PCT/JP96/00892 35 Process 23 The compound (1-35) or its salt can be prepared by reacting a compound (1-34) or its salt with hydroxylamine or its salt.

The reaction is usually carried out in a conventional solvent such as water, an alcohol methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, dioxane or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

The reaction is preferably carried out in the presence of an inorganic or organic base exemplified in Process 1.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 24 The compound (1-37) or its salt can be prepared by reacting the compound (1-36) or its reactive derivative at the amino group, or its salt with the compound (VI) or compound (VII).

This reaction can be carried out in a similar manner to that of Process 16 and therefore the regents to be used and the reaction conditions reaction temperature, etc.) can be referred to those of the Process 16.

The compounds and pharmaceutically acceptable salts thereof of the present invention possess inhibitory activity of cGMP-PDE (especially PDE-V), relaxant activity of smooth muscle, bronchodilator activity, vasodilative activity, inhibitory activity of smooth muscle cells proliferation, inhibitory activity of allergy, and so on.

The compounds and pharmaceutically acceptable salts thereof, therefore, have utility in the treatment and WO 96/32379 PCT/JP96/00892 36 prevention of various diseases, such as angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases diabetic glomerulosclerosis, etc.), renal tubulo-intestinal diseases nephropathy induced by FK506, cyclosporins, or the like), renal failure, atherosclerosis, conditions of reduced blood vessel patency post-percutaneous transluminal coronary angioplasty), peripheral vascular disease, stroke, chronic reversible obstructive lung diseases (e.g.

bronchitis, asthma (chronic asthma, allergic asthma)), allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility irritable bowel syndrome), impotence organic impotence, psychic impotence, etc.), or diabetic complications diabetic gangrene, diabetic arthropathy, diabetic glomerulosclerosis, diabetic dermopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc.).

Besides the compounds of the formula many compounds, disclosed in various prior publicatibns, are known to have a cyclic nucleotide-PDE inhibitory activity.

Particularly, a compound having the following formula

O

HN

N(VIII)

"~COONa and its analogous compound, and a compound having the following formula WO 96/32379 PCT/JP96/00892 37 002

HN

N J S N r

(IX)

N v OEt and its analogous compounds, which have an inhibiting activity of cyclic nucleotide-PDE (especially cGMP-PDE), were known and disclosed in International Patent Publication No.

WO 93/07124 and European Patent Publication No. EP 0 526 004.

And, various cyclic nucleotide-PDE inhibitors (e.g.

papaverine, dipyridamole, etc.) were known and disclosed in Biochemical Pharmacology, vol 46 No. 5, P 833-839.

And further, until now cGMP-PDE inhibitors as exemplified above have been also known to be useful for treating or preventing of various diseases, for example, according to the International Publication No. W093/07124, angina pectoris, cardiac infarction, ischemic heart disease, for example, chronic and acute cardiac failure, lung hypertension which may be complicated with cor pulmonale, hypertension caused by various factors, peripheral circulatory failure, brain dysfunction, bronchitic asthma and allergic disorder, for example, atopic dermatitis, allergic rhinitis, or the like.

The inventors of this invention have surprisingly found that the cyclic nucleotide-PDE inhibitors are useful for treating or preventing glomerular diseases, renal tubulointerstitial diseases and chronic renal failure.

According to "International Statistical Classification WO 96/32379 PCT/JP96/00892 38 of Diseases and Related Health Problems (tenth revision)" H. 1992), diseases of genitourinary system are divided into several groups, such as glomerular diseases, renal tubulo-interstitial diseases, renal failure and so on.

Glomerular Diseases are divided into several subgroups, such as rapidly progressive nephritis syndrome, recurrent and persistent haematuria, chronic nephritic syndrome, nephrotic syndrome, glomerular disorders in other diseases, and so on.

The diseases, to which glomerular disorder is ascribed, are for example infectious and parasitic diseases; neoplastic diseases; blood diseases and disorders involving the immune mechanism; diabetes mellitus; other endocrine, nutritional and metabolic diseases; systemic connective tissue disorders Goodpasture's syndrome, systemic lupus erythematosus, Wegener's granulomatosis, etc.); and so on.

Renal tubulo-interstitial diseases are also divided into several subgroups, one of which is drug- and heavy-metalinduced tubulo-interstitial and tubular conditions, and another one of which is renal tubulo-interstitial disorders in other diseases. The former subgroup includes analgesic nephropathy; nephropathy induced by drugs FK506, cyclosporins, and so on), medicaments and biological substances; nephropathy induced by unspecified drug, medicament and biological substance; nephropathy induced by heavy metals; and toxic nephropathy. In the latter subgroup, the diseases, to which renal tubulo-interstitial disorder is ascribed, are for example infectious and parasitic diseases, neoplastic diseases, blood diseases and disorders involving the immune mechanism, metabolic diseases, systematic connective tissue disorders sicca syndrome, systematic lupus erythematosus), transplant rejection, and so on.

Renal failure is divided into three subgroups, one of which is chronic renal failure.

The cyclic nucleotide-PDE inhibitors are useful for WO 96/32379 PCT/JP96/00892 39 treating or preventing glomerular diseases, particularly glomerular disorders in other diseases, more particularly glomerular disorders in diabetes mellitus and glomerular disorders in systemic lupus erythematosus; renal tubulointerstitial diseases, particularly drug- and heavy-metalinduced tubulo-interstitial and tubular conditions, and renal tubulo-interstitial disorders in other disease, more particularly nephropathy induced by drugs FK506, cyclospolins, and so on), medicaments and biological substances, and renal tubulo-interstitial disorders in systemic connective tissue disorder; and chronic renal failure.

The cyclic nucleotide-PDEs include cyclic adenosine 3',5'-monophosphate phosphodiesterase (hereinafter described as cAMP-PDE) and cGMP-PDE. cAMP-PDE and cGMP-PDE play a major role in the regulation of intracellular concentrations of cAMP and cGMP, respectively. The cyclic nucleotide-PDEs are classified into five isozyme families, based largely on primary protein and cDNA sequence information, as follows Ca++-calmodulin(CaM)-dependent family (Type cGMPstimulated family (Type II); cGMP-inhibited by a large number of positive inotropic agents such as milrinone (Type III); cAMP-specific family, selectively inhibited by rolipram (Type IV); cGMP-specific family, selectively inhibited by zaprinast (Type V).

The term "immunophilin" is intended to mean a macromolecular protein or glycoprotein, which is capable of recognizing and selectively binding with immunosuppressive agent such as FK506, cyclosporins, rapamycins and so on, and have a peptidyl-propyl cis-trans isomerase activity; for example, FK506 binding protein (hereinafter indicated as FKBP) and intracellular receptor to the cyclosporins, preferably, FKBP-12 and cyclophilin produced by mammal, for WO 96/32379 PCT/JP96/00892 40 example, cattle or man.

Immunophilin is known and is obtained by substantially the same method of J. Am. Chem. Soc., 113, 1409-1411 (1991), Proc. Natl. Acad. Sci. 88, 6229-6233 (1991), Nature 346, 671-674 (1991) and 337, 473-475, 476-478 (1989), International Patent Application Nos. 91/17493, 92/01052, Japanese Patent Application No. 2-209897 and so on.

The compound designated as FK506 (or FR-900506) and its analogous compounds are well known to have a potent immunosuppressive activity and are produced by fermentation of the genus streptomyces, especially Streptomyces tukubaensis No. 9993 (FERM BP-927) or Streptomyces hygroscopicus subsp. yakusimaensis No. 7238 (FERM BP-928) (European Patent No. 0184162-B1).

The cyclosporins, for example, cyclosporin A, B, C, D, E, F and G, and its derivatives, are disclosed in United State Patent Nos. 4,117,118, 4,215,199, 4,288,431, 4,388,307, Helv. Chem. Acta 60, 1568 (1977) and 65, 1655 (1982), Transplant. Proc., 17, 1362 (1985) and so on,' and are well known to have an immunosuppressive activity.

However, FK506 and cyclosporins are also known to induce a renal tubulo-interstitial disease.

The cyclic nucleotide-PDE inhibitors can be administered in a pure or impure form and in a single compound or a mixture thereof, preferably, in a pharmaceutical vehicle or carrier.

The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the cyclic nucleotide PDE inhibitors, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, intravenous, WO 96/32379 PCT/JP96/00892 41 intramuscular, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solutions (saline, for example), emulsion, suspensions (olive oil, for example), and any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.

Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc..' and humans, preferably humans.

For applying this composition to a human, it is preferable to apply-it by external (topical), oral, parenteral, enteral, intravenous, or intramuscular administration.

While the dosage of therapeutically effective amount of the macrolide compounds varies from and also depends upon the age and condition of each individual patient to be treated, in case of the systemic administration/ a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 100 mg of the active ingredient is generally.given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic administration in humans will be in the range of about 0.3 WO 96/32379 PCT/JP96/00892 42 mg/kg/day.

And further, it is considered that the compounds, which have a cyclic nucleotide-PDE inhibitory activity, described in the European Patent Publication Nos. 579,496, 534,443, 526,004, 636,626; United State Patent Nos. 3,819,631, 5,294,612, 5,488,055; International Patent Application Nos.

93/07,124, 94/19,351; Japan Patent Publication No.

07-330,777; and so on, are useful for treating or preventing glomerular diseases, tubulo-interstitial diseases and renal failure.

In order to exhibit the usefulness of the present invention, the activity of compound and the activity of the compound of (VIII) or papaverine, or dipyridamole, the representative compound of the cyclic nucleotide-PDE inhibitors, is shown in the following.

Test 1.

cGMP-Phosphodiesterase (PDE) assay cGMP-PDE was separated from other isozymes in human platelets by a modification of the method of Thompson et. al.

(Cyclic Nucleotide Phosphodiesterase (PDE), in Methods of Enzymatic analysis, Vol 4, p127-234, 1984). In enzyme inhibition assays, the test compounds were dissolved in DMSO and then diluted with assay buffer (50 mM Tris-HCl, pH 0.1 mM dithiothreitol, 2 mM EGTA and 10 u/ml snake venom), at final concentrations ranging from 10-1 0 to 10-6M.

Assays were performed at 0.1 M substrate 3 H]-cGMP) concentration, at 30°C for 10 minutes using enzyme dilutions which gave 10-20% hydrolysis of substrate. Each assay was initiated by addition of substrate and terminated by addition of anion exchange resin (Dowex 1-X8, 25 4g/mg) followed by centrifugation for 10 minutes (3000 rpm, at 4°C).

WO 96/32379 PCT/JP96/00892 43 Radioactivity of supernatant 3 H-GMP) was assayed by liquid scintillation counting.

The compounds prepared in the present Examples 3, 4, 6, 9, 12, 15, 18, 21, 22-(2) to 23, 24-(1), 26, 37-(6), 37-(11), 37-(12), 37-(14), 37-(17), 38-(2), 39, 42, 43, 58, 60, 63, 69, 70, 72, 73-(33), 73-(36), 73-(40), 75-(10), 75-(15), 75-(21), 75-(23), 75-(27), 75-(29), 75-(30), 75-(35), 75-(38) and 75-(39), which were selected as the representative compounds of the present invention, had IC50 values below 100 nM.

Test 2.

Smooth muscle relaxant The aorta were carefully removed from male Wistar rats, cleaned of fat and extraneous tissue. Spirally cut strips of the aorta were placed in a 25 ml organ bath containing Tyrode solution of the following composition NaCl, 137; KC1, 2.7; CaC1 2 1.8; NaH 2

PO

4 0.4; NaHCO 3 12.0; MgSO 4 1.1; glucose, 5.6. The bath was maintained at 37°C and bubbled with 95% 02 and 5% CO2. The spirally cut strip was stretched to a resting force of 1.0 g, and the isometric contraction was recorded via a force development transducer on an ink writing recorder. Tissues were equilibrated for 60 minutes before contraction was induced by noradrenaline (NA, 1 M).

The test compounds were cumulatively added to organ bath in increasing concentrations ranging from 10 8 to 10 5 M, after maximum stable constriction to NA had been achieved.

For example, the compounds prepared in the present Examples 6, 12, 37-(12), 43, 72, 73-(33), 73-(36) and which were selected as the representative compounds of the present invention, had WO 96/32379 PCT/JP96/00892 44 values below 100 nM.

Test 3.

vSMC proliferation Vascular smooth muscle cells (vSMCs) were prepared from explants of the thoracic aorta of 10 week old male Wistar rats by a modification of the method of Ross Cell Biol., 172, 1971). They were cultured in DMEM containing fetal calf serum, 1% penicillin G and 1% streptomycin at 37°C in a 95% air, 5% CO2 humidified atmosphere. vSMCs were seeded in 24 well plates and cultured in the presence of fetal calf serum for 3 days. Cell growth then was arrested by transfer to serum free DMEA. After 24 hours, each test compound or vehicle was added to medium for 1 hour, and then cells were stimulated by PDGF (10 ng/ml). After 24 hours of additional incubation, 3 H]-thymidine (1 4Ci/ml) was added during the final 4 hours of incubation time, and trichloracetic acid insoluble radioactivity was assayed by liquid scintillation counting.

For example, the compounds prepared in the present Examples 3, 9, 15, 23, 27-(8), 37-(14), 60, 75-(29) and 75-(30), which were selected as representative compounds of the present invention, had IC50 below 100 nM.

Test 4.

Vasopressin induced-vasospasm model Male Donryu rats, weighing 160-200 g, were anesthetized intraperitoneally with sodium pentobarbital (60 mg/kg) minutes before intravenous administration of vasopressin, and the femoral vein was cannulated with polyethylene tubing (diameter 0.8 mm). Coronary vasospasm was induced with WO 96/32379 PCT/JP96/00892 45 vasopressin (0.2 iu/kg) dissolved in saline through the cannula in the femoral vein. The each test compound mg/kg) was administered orally 30 minutes before the administration of vasopressin. The standard limb lead II of the electrocardiogram was recorded with an electrocardiograph. The depression of ST segment was measured as the difference in the amplitudes of the ST segment after and just before the administration of vasopressin. The amplitudes of ST segment were measured at intervals of 0.5 minutes for 5 minutes after administration of vasopressin.

For example, the compounds prepared in the present Examples 3, 6, 12, 37-(12), 42 and 43 of the present invention, showed more than 50% inhibiting activity, respectively.

Test Cyclosporin nephritis model Spontaneously hypertensive rats weighing 250-300 g were used. Cyclosporin dissolved in olive-oil containing ethanol was given orally to the animals in a daily dose mg/kg for 2 weeks. After the last dosing of cyclosporin, 24-hours urine was collected for urinalysis. Blood was withdrawn from the abdominal aorta under ether anesthesia 24 hours after the last dosing of cyclosporin, and plasma was separated by centrifugation for biochemical analysis. The animal were bled to death and kidneys were removed for histopathological examination.

The each test compound (3.2 mg/kg) was dissolved in PEG 400 and given orally by the volume of 1 ml/kg twice a day for two weeks.

Biochemistry and urinalysis Urine volume, plasma creatinine, urine creatinine, blood urea nitrogen, plasma WO 96/32379 PCT/JP96/00892 46 sodium, urine sodium, plasma potassium and urine potassium, were measured with an autoanalyzer (TBA-20R Toshiba, OM-6020 Daiichi Kagaku).

Histopathology The kidneys were fixed in phosphatebuffered 10% formalin and its paraffin specimens were prepared and these sections were stained with hematoxylin.

The compound (VIII), the compound and the compounds prepared in the present Examples 3 and 6, which were selected as representative compounds of the present invention, showed more than 50% recovery in a measure cf blood urea nitrogen, and more than 40% recovery in a measure of creatinine clearance (ml/kg/min), respectively.

Test 6.

FK506 nephritis model Spontaneously hypertensive rats weighing 250-300 g were used. FK506 dissolved in olive-oil containing 5% ethanol was given orally to the animals in a daily dose 18 mg/kg for 1 week. After the last dosing of FK506, 24-hours urine was collected for urinalysis. Blood was withdrawn from the abdominal aorta under ether anesthesia 24 hours after the last dosing of FK506, and plasma was separated by centrifugation for biochemical analysis.

The each test compound was dissolved in PEG 400 and given orally by the volume of 1 ml/kg twice a day for two weeks.

Biochemistry and urinalysis Urine volume, plasma creatinine, urine creatinine, blood urea nitrogen, plasma sodium, urine sodium, plasma potassium and urine potassium, were measured with an autoanalyzer (TBA-20R Toshiba, OM-6020 Daiichi Kagaku).

The compound (VIII) and the compound prepared in Example 6, which was selected as representative compounds of this invention, showed more than 50% recovery in urinary sodium WO 96/32379 PCT/JP96/00892 47 excretion, and more than 45% recovery in a measure of creatinine clearance (ml/kg/min), respectively.

Prevention of experimental FK506-induced nephritis by cyclic nucleotide regulating drugs FK506 was administered orally to male Sprague-Dawley rats (body weights; 292-329 g) fed with low sodium diet (0.05% Sodium) in a daily dose of 10 mg/kg/day for 14 days.

FK506 was provided in a solid dispersion formulation and dissolved in distilled water to a final concentration of 2 mg/ml. Papaverine was dissolved in saline to 5 mg/ml.

Dipyridamole formulation; 5 mg/ml) was purchased from Dainippon Pharmaceutical Co., Ltd. Papaverine (20 mg/kg) or dipyridamole (20 mg/kg) was administered intramuscularly minutes before FK506 dosing. After the final dosing of FK506, 24-hours urine was collected for urinalysis. Blood was withdrawn from the abdominal aorta under ether anesthesia 24 hours after final dosing of FK506, and plasma was separated for biochemical analysis and plasma renin activity measurements. The kidney was removed from each animal and was fixed with in 10% formalin solution for histological analysis.

Papaverine and dipyridamole significantly improved renofunction of FK506 dosed rats. Both compounds showed more than 50% recovery in a measure of blood urea nitrogen, and more than 50% recovery in a serum creatinine.

Test 7.

Diabetic glomerulosclerosis model 6 weeks old Male SD rats were treated with streptozotocin (60 mg/kg to induce diabetes mellitus.

One week after streptozotocin treatment, test compound, 3.2, WO 96/32379 PCT/JP96/00892 48 mg/kg was started to be orally administered twice a day for 16 weeks.

The compound prepared in Example 6, which was selected as representative compound of this invention, retarded the onset of diabetic cataract and improved the parameters reflecting the abnormalities of peripheral circulation (improved the decreased blood flow in ears and raised the decreased skin temperature on foot pad).

Said compound, 10 mg/kg, perfectly recovered the reduced valiance of RR intervals in cardioelectrography, reduced on average by 37% the elimination of protein in urine, and perfectly inhibited the increased 4-hydroxyproline contents in renal cortex.

Test 8.

Impotence model Effect of test compound on nitroprusside or Ach-induced relaxation in isolated rat corpora cavernosa Male SD rats were anesthetized with sodium pentobarbital mg/kg intraperitoneally, and the corpora cavernosa was excised. The tunica albuginea was dissected according to the methods described by Italiano et al. (Pharmacological Research, 30, No.4, 1994) and used for in vitro pharmacological study. The erectile tissue strip was placed in a 25 ml organ bath containing Krebs-Ringer solution. The bath was maintained at 37°C and bubbled with 95% 02 and CO2. The strip was stretched with a resting force of 0.25 g, and isometric contraction were recorded via force development transducer on a recorder.

The strip was equilibrated in the Krebs-Ringer solution for about 60 minutes, and preconstructed by 0.1 mM norepinephrine to ascertain the responsibility of each preparation. The strip was washed several times, and then WO 96/32379 PCT/JP96/00892 49 constricted by 0.1 mM norepinephrine. After getting stable constrictile response to norepinephrine, the first doseresponse curve for sodium nitroprusside or Ach was obtained.

After washing a few times for 60 minutes, the strip was constricted by norepinephrine again, and the second doseresponse curve'for sodium nitroprusside or Ach was obtained.

The test compound was added 30 minutes before adding norepinephrine. The compound prepared in Example 6, which was selected as representative compound of this invention, at 10 -7 M potentiated nitroprusside-induced relaxation of corpora cavernosa, and ED 50 value of dose-response curve to nitroprusside was about 50 fM.

Said compound at 10 -7 M also potentiated Ach-induced relaxation of corpora cavernosa. 100 pM Ach-induced relaxant response to the contractile response induced by 10 -4 M norepinephrine-was only 11.0% in control preparation, but this relaxant response to Ach increased to 18.7% in the presence of 10 -7 M said compound.

Effect of test compound on the relaxation elicited by electrical field stimulation in rat corpora cavernosa.

The rat erectile tissue strip prepared according to the method described by Italiano et al. (Pharmacological Research, 30, No4, 1994) was placed 25 ml organ bath containing Krebs-Ringer solution. The bath was maintained at 37 0 C and bubbled with 95% 02 and 5% C02. The solution also contained atropine (1 pM) and guanethidine (50 pM). The erectile tissue strip was stretched with a resting force of 0.25 g, and isometric contraction were recorded via force development transducer on a recorder. The bipolar platinum electrode connected to the electric stimulator was placed around the strip.

The strip was equilibrated in the Krebs-Ringer solution WO 96/32379 PCT/JP96/00892 50 for about 60 minutes and preconstructed by 0.1 mM norepinephrine to ascertain the responsibility of each preparation. The strip was washed several times, and then constricted by 0.1 mM norepinephrine. After getting stable contractile response to norepinephrine, the first electrical field stimulation (1 to 45Hz, 20V, 0.5 msec duration, 90 sec interval) was delivered, 30 minutes after adding the tested compound, the second electrical field stimulation was delivered.

The compound prepared in Example 6, which was selected as representative compound of this invention, at 10 -7 M potentiated relaxation of corpora cavernosa elicited by electrical field stimulation in rat corpora cavernosa.

Relaxant response elicited by 30Hz was only 14.3% in control preparation, but this relaxant response increased to 17.1% in the presence of 10 -7 M said compound.

Male beagle weighing 8.0 12.0 kg were anesthetized with pentobarbital sodium (35 mg/kg, After tracheotomy, the animal was artificially ventilated using a volume-cycled ventilator. The femoral artery was cannulated for continuous blood pressure and heart rate monitoring. The femoral vein was cannulated for maintenance of anesthesia and administration of tested compound. Two laser-dopper probes were placed in the corpus spongiosum penis and corpus cavernosum penis for recording blood flow. After a period of stabilization of all parameters, tested compound was injected intravenously at a various concentration. The administration of the compound prepared in Example 6,-which was selected as representative compound of this invention, increased in the blood flow of both corpus spongiosum penis and corpus cavernosum penis without hemodynamic change. The increase in blood flow reached a peak value of 55% of baseline and continued for longer than 15 minutes after the administration of said compound 1.0 mg/kg.

WO 96/32379 PCTIJP96/00892 51 Effect of tested compound on genital grooming and penile erection in male mice.

Eight weeks old male ICR mice were housed under standard conditions of temperature, lighting and water supply before the experiment.

The test compound was dissolved in PEG400. After oral administration of the test compound, each mouse was transferred to an individual cage.

The genital grooming and penile erection were observed for one hour.

The compound prepared in Example which were selected as representative compound of this invention markedly increased the frequencies of genital grooming by average of 266-% and lengthened the duration of penile erection by average of 171% Test 9.

Toxities of Compound (I) Test on the toxicity by repetitive oral administration of the compounds prepared in Example 6 and which were selected as representative compound of this invention, in SD rat was conducted and the dead at dose of 32mg/kg once a day for 14 consecutive days could not be observed.

The following preparations and examples are given for the purpose of illustrating the present invention.

(to be continued on the next page) WO 96/32379 PCT/JP96/00892 52 Preparation 1 To a solution of 2-amino-4-methoxycarbonylphenyl trifluoromethanesulfonate (2.6 g) in a mixture of pyridine (5.6 ml) and dichloromethane (20 ml) was added benzyl chloroformate (2.08 ml) at 0°C, and the mixture was stirred at 20°C for 4.5 hours. The mixture was diluted with dichloromethane and washed successively with diluted hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane to give 2-benzyloxycarbonylamino-4methoxycarbonylphenyl trifluoromethanesulfonate (2.61 g) as colorless crystals.

NMR (CDC1 3 5) 3.92 (3H, 5.23 (2H, 6.89 (1H, br 7.3-7.45 (6H, 7.83 (1H, dd, J=l, 8Hz), 8.81 (1H, s) A mixture of 2-benzyloxycarbonylamino-4methoxycarbonylphenyl trifluoromethanesulfonate (1.01 g), 1-pentynyl(tributyl)stannane (1.02 lithium chloride (0.29 g) and tetrakis(triphenylphosphine)palladium (80 mg) in dioxane (24 ml) was heated at 100"C for 2 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate to give methyl 3-benzyloxycarbonylamino-4-(1pentynyl)benzoate (536 mg) as colorless crystals.

NMR' (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.67 (2H, m), 2.44 (2H, t, J=7Hz), 3.87 (3H, 5.23 (2H, s), 7.25-7.7 (7H, 8.78 (1H, s) To a solution of methyl 3-benzyloxycarbonylamino-4-(1pentynyl)benzoate (949 mg) in tetrahydrofuran (24 ml) was added gold(III)sodium chloride (24 mg) under argon atmosphere, and the mixture was heated under reflux for 100 minutes. The solvent was evaporated in vacuo and the residue WO 96/32379 PCT/JP96/00892 53 was chromatographed on silica gel eluting with a mixture of hexane, dichloromethane, and ethyl acetate to give methyl l-benzyloxycarbonyl-2-propylindole-6-carboxylate (852 mg) as colorless crystals.

NMR (CDC1 3 6) 0.98 (3H, t, J=7Hz), 1.71 (2H, m), 2.97 (2H, t, J=7Hz), 3.90 (3H, 5.49 (2H, s), 6.39 (1H, 7.3-7.6 (6H, 7.91 (1H, dd, J=l, 8Hz), 8.80 (1H, s) To a solution of methyl l-benzyloxycarbonyl-2propylindole-6-carboxylate (200 mg) in a mixture of methanol and ethyl acetate 8 ml) was added 10% palladium on carbon (30 mg), and the mixture was stirred under hydrogen atmosphere for 20 minutes. The catalyst was removed by filtration through celite and washed with methanol. The filtrate was evaporated in vacuo to give methyl 2propylindole-6-carboxylate (112 mg) as colorless crystals.

NMR (CDC1 3 6) 1.02 (3H, t, J=7Hz), 1.78 (2H, m), 2.76 (2H, t, J=7Hz), 3.93 (3H, 6.29 (1H, s), 7.51 (1H, d, J=8Hz), 7.77 (1H, d, J=8Hz), 8.04 (1H, 8.15 (1H, br s) To a stirring suspension of aluminum chloride (294 mg) and acetyl chloride (0.08 ml) in dichloromethane (10 ml) was added methyl 2-propylindole-6-carboxylate (200 mg), and the mixture was stirred at 20°C for 1 hour. The resulting mixture was poured onto ice and extracted with ethyl acetate.

The combined organic phase was washed with aqueous sodium bicarbonate and brine, then dried over sodium sulfate and evaporated in vacuo. The residue was triturated with isopropyl ether to give methyl 3-acetyl-2-propylindole-6carboxylate (78 mg) as colorless crystals.

NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.81 (2H, m), 2.69 (3H, 3.18 (2H, t, J=7Hz), 3.96 (3H, s), 7.93 (1H, dd, J=i, 8Hz), 8.01 (1H, d, J=8Hz), 8.12 WO 96/32379 WO 9632379PCT/JP96/00892 54 (1H, di, J1lHz), 8.88 (1H, br s) Prepration 2 Methyl 3-isobutyryl-2-propylifldole-6-carboxYlate (474 mg) was prepared from methyl 2-propylindole-6-carboxylate (700 mg) and isobutyryl chloride (1.01 ml) in a similar manner to that of Preparation 1 NI'R (ODC1 3 5) :1.04 (3H1, t, J=8Hz), 1.28 (6H, d, J=8Hz), 1.83 (2H, sextet, J=8Hz), 3.18 (2H1, t, J=8Hz), 3.52 (2H, septet, J=8Hz), 3.96 (3H, s), 7.92 (2H, 8.16 (1H, 9.13 (1H, br s) Pre~paration 3 Methyl 3-propionyl-2-propylindole6-carboxylate (298 mg) was prepared from methyl 2-propylindole-6-carboxylate (500 mg) and propionyl chloride (0.40 ml) in a similar manner to that of Preparation 1 NMR (CDC1 3 5) :1.04 (3H, t, J=8Hz), 1.29 (3H, t, J=81-z), 1.83 (2H, sextet, J=8Hz), 3.06 q, J=BHz), 3.20 (211, t, J==8Hz), 3.96 (31, 7.93 (1H, dci, J=1, 8Hz), 8.00 (1H, d, J=8Hz), 8.15 (111, ci, J=lHz), 9.22 (1H, s), Prenaration 4 Methyl 3-benzyloxycarbonylamino-4-(4-methyl-ipentynyl)benzoate (2.25 g) was prepared from 2benzyloxycarbonyl amino- 4-methoxycarbonylphenyl trifluoromethanesulfonate (3.0 g) and (4-methyl-ipentynyl) (tributyl)stannane (2.7 g) in a similar manner to that of Preparation 1 NMR (CDC1 3 5) :1.05 (6H, di, J=8Hz), 1.88-2.02 (111, in), 2.40 (2H, di, J=8Hz), 3.90 (3H, 5.25 (2H-, 7.32-7.45 (6H, in), 7.52 (1H, 7.66 (1H, di, J=8Hz), 8.78 (1H, s) WO 96/32379 WO 9632379PCT/JP96I00892 Methyl 1-benzyloxycarbofyl2isobutylindole- 6 carboxylate (1.67 g) was prepared from methyl 3benzyloxycarboflylamiflo- 4 (4-methyl-1-pefltynyl)beflzoate (2.15 g) in a similar manner to that of Preparation 1 NMR (CDCl 3 1 5) :0.90 d, J=8Hz), 1.90-2.04 (1H, in), 2.86 (2H, d, J=8Kz), 3.90 (3H, 5.48 (2H, 6.38 (1H, 7.40-7.56 (6H, in), 7.91 (1H, d, J=8Hz) 8.82 (1H, s) Methyl 2-isobutylindole-6-carboxylate (752 mng) was prepared from methyl 1-benzyloxycarbonyl2isobutylindole- 6 carboxylate (1.5 g) in a similar manner to that of Preparation 1 MR (CDCl 3 5) :0.98 (6H, d, J=8Hz), 1.95-2.08 (1H, mn), 2.66 (2H, d, J=8Hz), 3.92 (3H, 6.28 (1H, 7.53 (1H, d, J=8Hz), 7.76 (1H, d, J=8Hz), 8.08 (1K, s) 8.23 (1H, br s) Methyl 2 -isobutyl-3-isobutyrylindoie-6carboxylate (246 mng) was prepared from methyl 2-jsobutylindole6-carboxylate (300 mg) and isobutyryl chloride (0.41 ml) in a similar manner to that of Preparation 1 NMP. (CDCl 3 5) :0.98 (6H, d, J=8Hz), 1.27 (1H, d, J=8Hz), 2.10-2.23 (1H, in), 3.06 (2H, d, J=8Kz), 3.52 (2K, septet, J=8Kz), 3.96 (3K, 7.92 (2K, 8.16 (1K, 9.02 (1H, s) Prenaration Methyl 3-benzyloxycarbonylamino- 4 (l-butynyl)benzoate (646 mg) was prepared from 2-benzyloxycarbonylamfino- 4 methoxycarbonyiphenyl trifluoromethanesulfonate (1.82 g) and 1-butynyl(tributyl)stannane (1.51 g) in a similar manner to that of Preparation 1 MR (ODC1 3 5) :1.26 (3H, t, J=7Kz), 2.50 (2H, q, J=7Hz), 3.91 (3H, 5.24 (2H, 7.3-7.5 (7K, WO 96/32379 WO 9632379PCT/J1P96/00892 56 in7.65 (1H, dd, J=1, 8Hz), 8.79 (1H, br s) Methyl 1-benzyloxycarbonyl-2-ethylifldole-6-carboxylate (551 mg) was prepared from methyl 3-benzyloxycarbonylamino-4- (1-butynyl)benzoate (640 mg) in a similar manner to that of Preparation 1 NMR (ODC1 3 5) :1.30 (3H, t, J=7Hz), 3.05 (2H, q, J=7Hz), 3.88 (3H, 4.98 (2H, 6.92 (1H, s), 7.35-7.60 (6H, in), 7.89 (1H, dd, J=1, 8Hz), 8.79 (1H, s) Methyl 2-ethylindole-6-carboxylate (306 mg) was prepared from methyl 1-benzyloxycarbonyl-2-ethylindole-6-carboxylate (546 mg) in a similar manner to that of Preparation 1 NI'R (CDC1 3 5) :1.38 (3H, t, J=7Hz), 2.82 (2H, q, J=7Hz), 3.91 (3H, 6.30 (1H, 7.50 (1H, d, J=8Hz), 7.75 (1H, d, J=8Hz), 8.03 (1H, 8.14 (1H, br s) Methyl 2-ethyl-3-propionylindole-6-carboxylate (435 mg) was prepared from methyl 2-ethylindole-6-carboxylate (660 mg) and propionyl chloride (0.62 ml) in a similar manner to that of Preparation 1 NMR (CDC1 3 :1.29 (3H, t, J=7Hz), J1.39 (3H, t, J=7Hz), 3.06 (2H, t, J=7Hz), 3.26 (2H, t, J=7Hz), 3.94 (3H, 7.24 (1H, 7.92 (1H, d, J=8Hz), 7.98 (1H, d, J=8Hz), 8.14 (1H, 8.92 (1H, br s) Preloaration 6 Methyl 3-isobutyrylindole-6-carboxylate (618 mg) was prepared from methyl indole-6-carboxylate (500 mg) and isobutyryl chloride (0.84 ml) in a similar manner to that of Preparation 1 NMP. (ODC1 3 5) :1.28 (6H, d, J=7Hz), 3.35 (1H, in), 3.96 (3H, 7.93-8.06 (2H, in), 8.19 (1H, 8.46 WO 96/32379 PCT/JP96/00892 57 (1H, d, J=8Hz), 8.96 (1H, br s) To a solution of methyl 3-isobutyrylindole-6-carboxylate (146 mg) in tetrahydrofuran (5 ml) was added 1M solution of brane-tetrahydrofuran complex in tetrahydrofuran (1.8 ml), and the mixture was stirred at 50"C for 1 hour. The resulting mixture was evaporated in vacuo, and the residue was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, and dried over sodium sulfate. After evaporation of solvent, the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate to give methyl 3isobutylindole-6-carboxylate (105 mg) as colorless crystals.

NMR (CDC1 3 5) 0.94 (6H, d, J=7Hz), 1.98 (1H, m), 2.62 (2H, d, J=7Hz), 3.93 (3H, 7.12 (1H, s), 7.61 (1H, d, J=8Hz), 7.78 (1H, d, J=8Hz), 8.08 (1H, 8.16 (1H, br s) Methyl 2-acetyl-3-isobutylindole-6-carboxylate (43 mg) was prepared from methyl 3-isobutylindole-6-carboxylate (99 mg) and acetyl chloride (0.073 ml) in a similar manner to that of Preparation 1 NMR (CDC1 3 5) 1.01 (6H, d, J=7Hz), 2.02 (1H, m), 2.69 (3H, 2.98 (2H, d, J=7Hz),.3.96 (3H, s), 7.73 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz), 8.11 (1H, 9.09 (1H, br s) Preparation 7 Methyl 3-acetylindole-6-carboxylate (470 mg) was prepared from methyl indole-6-carboxylate (655 mg) and acetyl chloride (0.27 ml) in a similar manner to that of Preparation 1 NMR (DMSO-d 6 5) 2.46 (3H, 3.88 (3H, 7.79 (1H, d, J=8Hz), 8.10 (1H, 8.24 (1H, d, J=8Hz), 8.52 (1H, s) WO 96/32379 WO 9632379PCT/JP96100892 58 Methyl 3-ethylindole-6-carboxylate (327 mg) was prepared from methyl 3 -acetylindole-6-carboxylate (470 mg) in a similar manner to that of Preparation 6 I4R (ODC1 3 5) :1.33 (3H, t, J=7Hz), 2.78 (2H, q, J=7Hz), 3.93 (3H, 7.15 (1H, 7.63 (lH, d, j=8Hz), 7.79 (1H, d, J=8Hz), 8.12 (1H, 8.14 (1H, br s) Methyl 3 -ethyl-2-propionvlindole-6-carboxylate (65.7 mg) was prepared from methyl 3-ethvlindole-6-carboxylate (184 mg) and propionyl chloride (0.17 in a similar manner to that of Preparation 1 MR (ODCd 3 5) :1.29 (3H, t, j=7Hz), 1.34 (3H, t, J=7Hz), 3.03 (2H, q, J=7Hz), 3.14 (2H, q, J=7Kz), 3.94 (3K, 7.73 (1H, d, 7.79 (1H, d, J=8Hz), 8.13 (1K, 9.10 (1H, br s) Prenaration 8 3-isobutvryl-2-propylindole-6-carboxylic acid (853 mg) was prepared from methyl 3-isobutvryl-2-propylindole-6carboxylate (935 mg) in a similar manner to that of Example 2.

NYhR (DM.SO-d 6 5) 0.95 (3H, t, M=Hz), 1.14 (6H, d, j=BHz), 1.72 (2H, sxe, J=8Kz), .3.08 (2H, t, M=Hz), 3.46 (KH, septet, J=8Hz), 7.76 (1H, d, M=Hz), 7.92 KH, dd, J=1, MK), 8.00 (1H, d, J=!Hz) 3-Isobutyryl-2-propylindole-6-carboxamide (853 mg) was prepared from 3-isobutyryl-2-propylindole-6-carboxylic acid (935 mg) in a similar manner to that of Example 6.

MR (DMSO-d 6 5) 0.95 (3H, t, M=Hz), 1.15 (6H, d, M=Hz), 1.70 (2H, sextet, M=8z), 3.07 (2H, t, M=Hz), 3.46 (1H, septet, J=8Hz), 7.26 (1H, br s), 7.72 KH, d, M=9z), 7.87 (1H, dd, J~1, 9Hz), WO 96132379 WO 9632379PCT/JP96/00892 59- 7. 94 (1H, d, J=lHz) Preiparation 9 Met-hylI 3 -benzoyli- 2 -propylindole-6-carboxylate (289 mg) was porepared from methinyl 2 -propylindole-6-carboxylate (500 mg) and benzoyl chloride (970 mg) in. a similar manner to that of Prenaratt on 1 NMIR (ODCd 3 :0.82 (3H, r, J=8Hz), 1.66 (2H, sextet, J=8Hz), 2.78 (2H, z, J=8Hz), 3.85 (3H, s), 29 (1H, d, J=8Hz) 7.49-7. 54 (2H, in), 7. 60-7. 64 (4H, mn), 8.02 (iH, s) Prencaration To a stirred solution of m-ethyl' 2--propy'Lindole-6carboxylate (911 mng) in ac-etonitr--ile (15 ml) was added chlorosul-fonylisocyanate (0.6 gr) in acetonitrile (1.5 ml) at 000. The mixture was stirred at 000 for 30 minutes, then N,N-diinethylformamide (0.35 g) in. acetonit--rile (15 ml) was added at 000. The resultant mixture was stirred at 2000 for 40 minutes, and then poured into water. The mixture was exracted wit" methylene chloride thr-ee times, and the combined orga-ni c pohase was cred over sodium sul fate and evaporated in vacuo. The residue was chromatographed on silica gelI eluting with a mixture of ethyl acetate and hexane to give the crystals which were recrystallized from a mixture of ethyl acetate and hexane to give methyl 3-cyano-2-9 proocylindole-o'-carboxylate (535 mng) as colorless crystals.

mp :148.5-150'C !R :3251, 2218, 1710, 1284, 1218 cin 1 NTMR (,\ODC 3 1.07 (3H, t, J=7Hz), 1.89 (2H, sextet, J=7Hz), 3.00 (2H, U=H) 3.9(H 7.70 (1H, d, J=7.5Kz)\, 7.95 (1H, d, J=7.5Hz), 8.19 (1H, s) 9 05 (1KH, br s) MASS :243 (M 76 (br)) WO 96/32379 WO 9632379PCT/JP96/00892 60 Prenaration 11 Methyl 3-acetyl-2-ethylindole-6-carboxylate (106 mg) was prepared from methyl 2-ethylindole-6-carboxylate (237 mg) and acetyl chloride (0.19 ml) in a similar manner to that of Preparation 1 NMIR (CDCl 3 5) 1.42 (3H, t, J=7Hz), 2.69 (3H, s), 3.27 (2H, q, J=7Hz), 3.96 (3H, 7.93 (1H, d, J=8Hz), 8.01 (KH, d, J=8Hz), 8.12 (KH, 8.93 (lH, br s) Preparation 12 Methyl 2-ethyl-3-isobutyrylindole-6-carboxylate (200 mg) was prepared from methyl 2-ethylindole-6-carboxylate (317 mg) and isobutyryl chloride (0.36 ml) in a similar manner to that of Preparation 1 NMIR (CDCl 3 5) :1.28 (6H, d, J=7Hz), 1.38 (3H, t, J=7Hz), 3.25 (2H, q, J=7Hz), 3.51 (1H, in), 3.94 (3H, 7.92 8.13 (1H, 8.92 (1K, br

S)

Preoaration 13 Methyl 3-benzyloxycarbonylamino-4- (1-propynyl) benzoate (1.34 g) was prepared from 2-benzyloxycarbonylamino-4methoxycarbonylphenyl trifluoromethanesulfonate (2.1 g) and tributyl(1-propynyl)stannane (2.49 g) in a similar manner to that of Preparation 1 NMIR (CDCl 3 5) :2.14 (3M, 3.91 (3H, 5.24 (2H, 7.35-7.50 (6H, in), 7.65 (1H, d, J=8Hz), 8.82 (1H, s) Methy! 1-benzyloxycarbonyl-2-methylindole-6-carboxylate g) was prepared from methyl 3-benzyloxycarbonylanino-4- (l-propynyl)benzoate (1.32 g) in a similar manner to that of Preparation 1 NM?. (CDC1 3 5) 2.63 (3H, 3.89 (3H, 5.50 (2K, WO 96/32379 PCT1JP96/00892 61 6.38 (1H, 7.35-7.56 (6H, 7.91 (1H, d, J=8Hz), 8.81 (1H, s) Methyl 2-methylindole-6-carboxylate (562 mg) was prepared from methyl 1-benzvloxycarbonyl-2-methylindole-6carboxylate (1.18 g) in a similar manner to that of Preoaration 1 (4) NMIR (CDCl 3 5) 2.49 (3H, 3.92 (3H, 6.28 (1K, 7.51 (1H, d, J=8Hz), 7.77 (1H, d, J=8Hz), 8.03 (1H, 8.12 (11, br s) Mehyl 3-isobutyryl-2-methylindole--carboxylate (142 mg) was prepared from methyl 2-methvlindole-6-carboxylate (305 mg) and isobutyryl chloride (0.47 ml) in a stmilar manner Eo that of Preparation 1 NMR (CDC1 3 5) 1.26 (6H, d, J=7Hz), 2.81 (3H, s), 3.47 (1H, 3.93 (3H, 7.92 (1H, d, J=8Hz), 8.09 (1H, 8.85 (1H, br s) Preiaration 14 Methyl 3-benzyloxycarbonylamino-4- (3-methox-1propynyl)benzoare (4.23 g) was prepared from 2benzyloxycarbonylamino-4-methoxycarbonylphenyl Trifluorome thanesuifonate (7.73 g) and (3-methoxy-lpropynyl)tributylstannane (6.67 g) in a similar manner to that of Preparazion 1 (2) \T-R (CDC 5) 3.44 3.91 (3H, 4.38 (2H, 5.23 (2H, 7.3-7.5 (7H, 7.69 (1H, d, j=8Hz), 8.82 (1H, s) Methyl 1-benzyloxycarbonyl-2-methoxvmethylindole-6carboxylate (2.14 g) was prepared from methyl 3benzvloxycarbonVialflIno-4-(3-methoxy-l-propynyl)benzoate (4.23 g) in a similar manner to thatz of Preparation 1 (3) NMNR (CDCl-, 5) 3.44 (3K, 3.88 (3H, 4.80 (2H, WO 96/32379 PTJ9109 PCT/JP96/00892 62 49 (2H, s) 6 .70 7.38-7.58 (6H, mn), 7. 92 (1HK, d, J=8Hz) 8. 80 (i1K, s) Methyl 2-methoxymTethylindoi-e-6-carboxylate (0.42 g) was urenared from methyl i1-benzy'Loxycarbonyl -2methoxvmrethylindole-6-carboxyiat-e (2.12 g) in a similar manner to that of Preparation 1 NNR (ODC1 3 6) :3.41 (3H, 3.94 (3H, 4.64 (2H, 6.47 (1H, 7.59 (1H, d, J=8Kz), 7.80 (11H, d, J=8Hz), 8.11 (1H, 8.59 (1HK, br s) Methyl 3 -isobutyryl-2-meth.noxymethviindole-6-carboxylate (146 mg) was prepared from methyl 2-methoxymethyiindole-6carboxylate (396 mg) and isobu-.yryl chloride (0.53 ml) in a similar manner to that of Preparation 1 NMR (CDC1 3 65) :1.26 (6K, d, j=7Kz), 3.48 (1K, in), 3.58 (3K, 3.94 (3K, 5.03 (2K, 7.88 (1K, d 7J=8Kz), 7.96 (1H, d, J=8Kz), 8.18 (1H, 9.45 (1K, br s) Preparation To a solution of methyl 2-propylindole-6-carboxylate (300 mg) in dichloromethane (10 mln_) was added a ILM solution of tin(IV) chloride in dichloromethane (2.76.ml) at The mixture was stirr-ed at 200C- for 30 minutes, then methoxyacetyl c~lloride (0.25 ml1) was added. After stirred at 0 C -for 30 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl1 acetate and hexane (1:10-1:1) to give methyl 3-methoxyacetyl-2-propylindole-6-carboxylate (135 mg) as pale yellow crystals.

mn 127-129 0

C

NMR ('CDCI- 6) 1.05 (3K, J8Kz), 1.83 (2K, WO 96/32379 WO 9632379PCT/JP96/00892 63 sextet, J=8Hz), 3.02 (2H, t, J=8Hz), 3.57 (3H, s), 3.97 (3H, 4.72 (2H, 7.83 (1H, di, J=8Hz), 7.95 (1H, di, J=8Hz), 8.18 (1H, 9.38 br s) 3-Methnoxyacetyl-2-p~ropyli':ndo'le-6'-carboxylic acid (108 mg) was prepared from methyl 3-.methoxyacetyl-2-prop~ylindole- 6-carboxvlate (120 mg) in a similar manner to that of Example 2.

M I'C >2500C NMTR (DMSO-d 6 5) 0.97 (3H, J=8Hz), 1.74 (2H, sextet, J=8Hz), 3.09 (2H, t, j=8Hz), 3.38 (3H, s), C.61 (2H, 7.75 (1H, di, J=8Hz), 7.91 (1H, di, 8Hz), 8.00 (1K, s) 1,3) 3-Me:h-oxyacetvl-2-D~ropylindole-6-carboxamride (89 mg) was prepared from 3-methoxyacetyl--2-propylindole-6-carboxylic acid (95 mg.) in a similar manner to that of Exampole 6.

mp 165-167*C NR(DMSO-d 6 0.95 (31-H, t, j=8Hz), 1.74 (2H, sextet, J=8Kz), 3.06 (2H, t, J=8Kz), 3.38 (3H, s), (2H, s) 7.25 1, br 70 (1H, di, J=8Hz) Pre~oaration 16 To a So-lution of methyl 2-armino-3-hydroxybenzoate (882 mg) in pyridine (2 ml) was added acetic anhydride (1.2 ml) and the mixt-ure was stirred at 2000 for 18 hours. The reaction m-4xture was diluted with diuisoporonyl ether, and the resulting solid was collected and washed with duisopropyl ether. The solid was triturated with duJisopropyl ether to give methyl 2-acetamido-3-acetoxybenzoate (1.25 g) as solid.

NNMR (CODd 3 5 2.18 (3K, 2.26 (3K, 3.90 (3H, §,7.27 (1H, t, J=8Hz), 7.39 (1H, di, J=8Hz),, 7.83 di, J=8Hz), 9.09 (1H, br s) WO 96/32379 WO 9632379PCT/JP96/00892 -64 Prep)aration 17 The following compounds described in to were preoared in a similar manner to that of Preparation 16.

Methyl 3 -acetamido-4-acetLoxybenzoate NMR (CDCl 3 5) :2.21 (3H, 2.37 (3H, 3.93 (3H, 7.22 (1H, d, j=8Hz), 7.83 (iH, d, J=8Hz), 8.22 (11H, s) Methyl 4 -acetamido-3-acetoxybenzoate NM(DMSO-d 6 5) :2.12 2.33 (3H, 3.84 (3H, 7.73 (1H, d, J=2Hz), 7.82 (1N, dd, J=2, 8Hz), 8.22 (1H, d, J=8Hz), 9.64 (1H, s) (31) Methyl 3 -acetamido-2-acetoxybenzoate NMI. (CDC' 3 5 2.20 (3M, 2.43 (3M, 3.91 (3M, 7.29 (1H, r, J=8Hz), 7.74 (1H, d, J=8Hz), 8.51 (11H, d, J=8Hz) Methyl 3 -acetamido-4-trif-luor -omethanesulfonyloxyphenylacetate mp :68.5-70'C :3341, 1727, 1699, 1437, 1425 cm 1 i NMR (CDC1 3 :2.24 (3M, 3.68 (3M, 3.73 (3M, 7.11 (1K, dd, j=8, 1Hz), 7.24-7.30 (2H, in), 8.19 (iN, s) MASS 354 149 (bpc) Precaration 18 To a solution of methyl 2 -acetamido-3-acetoxybenzoate kI.72 g) in methanol (9 ml) was added powdered potassium carbonate (1.4 and the mixture was stirred for minutes. The resulting solid was removed by filtration and washed with methanol. The filtrate was evaporated in vacuo, andJ the resi-due was acidified with 1N hydrochloric acid and WO 96/32379 PCT/JP96/00892 65 extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with a mixture of isopropyl ether and hexane to give methyl 2-acetamido-3hydroxybenzoate (1.21 g) as solid.

NMR (CDC1 3 5) 2.33 (3H, 3.93 (3H, 7.14 (1H, t, J=8Hz), 7.23 (1H, d, J=8Hz), 7.61 (1H, d, J=8Hz), 9.88 (1H, s) PreDaration 19 The following compounds described in to were prepared in a similar manner to that of Preparation 18.

Methyl 3-acetamido-4-hydroxybenzoate NMR (DMSO-d 6 5) 2.11 (3H, 3.80 (3H, 6.93 (1H, d, J=8Hz), 7.56 (1H, d, J=2Hz), 8.47 (1H, s), 9.20 (1H, s) Methyl 4-acetamido-3-hydroxybenzoate NMR (DMSO-d 6 6) 2.14 (3H, 3.78 (3H, 7.37 (1H, dd, J=2, 8Hz), 7.45 (1H, d, J=2Hz), 8.08 (1H, d, J=8Hz), 9.32 (1H, s) Methyl 3-acetamido-2-hydroxybenzoate NMR (CDC1 3 5) 2.33 (3H, 4.97 (3H, 6.90 (1H, t, J=8Hz), 7.56 (1H, d, J=8Hz), 7.81 (1H, br s), 8.57 (1H, d, J=8Hz) Preparation To a solution of methyl 2-acetamido-3-hydroxybenzoate (1.2 g) in a mixture of pyridine (1.4 ml) and dichloromethane (2 ml) was added slowly trifluoromethanesulfonic anhydride (1.1 ml) at 0°C. When addition was completed, the mixture was stirred at 20°C for 20 minutes. The resulting mixture was poured into ice and extracted with ethyl acetate. The WO 96/32379 WO 9632379PCTIJIP96/00892 66 organic phase was washed with 1N hydrochloric acid, aqueous sodium bi4carbonate and brine, dried over sodium sulfate and evapcorated in vacuo. The residue was triturated with a mixture of dichloromethane and hexane to give methyl 2acetamido-3-tri-Fluoromethanesulfonyloxybenzoa'te (1.78 g) as solid.

NMR (ODCI' 3 ,5 2. 24 (3 S) 3. 93 (31K, s) 7. 34 (11H, tJ=BKz), 7.49 (1H, d, J=8Kz), 7.99 (lH, d, J=8Hz), 8.90 (1H, br s) Pre-oaration 21 The follocwing com-oounds described ir to were prepared in a similar manner to that of Preparation Methyl 3-acetamido-4-trifluoromethanesulfonyloxybenzoate NMR (ODCd 3 :2.25 (3H, 3.93 (3H, 7.37 (1H, d, J=gHz), 7.92 mn), 8.86 (1H, br s) Methyl 4-acetaindo-3-trifluoromethanesulfonyloxybenzoate NYR (CDCd 3 2.27 (3H, 3.94 (3H, 7.51 (1H, ICr 7.94 (1H, d, J=2Hz), 8.05 (1H, dd, J=2, 8Hz), 8.47 (1H, d, J=8Hz) Methyl 3 -ace tami do- 2 t _J fuo romTe thane sul fonyloxybenz oat e NMR (CDC 3 5 2.23 (3H, 3.93 (3H, 7.40 (1K, br 7.43 (1H, t, j=8Hz), 7.70' (1K, d, J=8Kz), 8.39 1KH, d, J=8Hz) Methyl 3-nitro-4-trifluorornethanesulfonyloxyphenylacetate rnp 44-45C IR (KBr) 1736, 1544, 1434, 1340 c- NIVR (CDC1, 3.75 (2H, 3.76 (3K, 7.41 (1H, 7.68 (1H, dd, J=8, 8.10 (1H, d, jl; WO 96/32379 WO 9632379PCT/JP96/00892 67 MASS 343 135 (bp) Prenaratiofl 22 The following com-pounds described in to were prepared from a similar manner to that of Preparation 1 MethylI 2-acetamido-3- (l-pentynyl)benzoate NM(CDC1 3 1.06 (3H, t, J=7Hz), 1.64 (2H, in), 2.20 (3H, 2.43 (2H, t, J=7Hz), 3.88 (3H, s), 71.16 (1H, t, J=8Hz), 7.57 (1H, d, J=8Hz), 7.76 A4J=8Hiz) 8. 42 (1H, br s) Methyl 4-acetamido-3- (1-pentvynyl)benzoate NM-R (ODCd 3 5) :1.11 (3H, t, J-=8Hz), 1.68 (2H, sextet, J=8Hz), 2.24 (3H, 2.52 (2H, t, J=8Hz), 3.89 (3H, s)l, .7.94 (1H, dd, 8Hz), 8.07 (1H, d, 8.12 (1H, br 8.48 (1H, d, J=8Hz)l Methyl 3-acetamnido-2- (1-pentvnyl)benzoate NM?. (CDC1 3 :1.12 (3H, t, J=7Hz), 1.73 (2H, mn), 2.22 (3H, 2.59 J=7Hz), 3.91 (3H, s), .32 (1H, t, J=8Hz), 7.63 (1H, d, J=8Hz), 8.29 (1K, sr 8.62 (1H, d, J=8Hz) Pre-oaration 23 A mixture of methyl 3-acetami, do-4-tri-"fluoromethanesulfonyloxybenzoate (1.43 methyl 5-hexynoate (582 mg), p~allad-iu-TP.1 chloride (14.9 mg), triphenylphos-ohine (43.8 mg) and copper(T) chloride (32 mng) in diethylamine (18 mrl) was stirred at 2000 for 14 hours. The sol-vent was evaporated in vacuo and the residue was chromatogralphed on silica gelI eluting wit-h a mixture of hexane and ethyl acetate to give methyl 3-acetamid--o-4- (5-methoxvcarbon,.yl-1-pentynyl) benzoate (1.15 g) as colorless crystals.

NNIR (C:)C01 5) 2.02 (2H, ra), 2.27 (3H, 2.53 (2H, WO 96/32379 PCT/JP96/00892 68 t, J=7Hz), 2.63 (2H, t, J=7Hz), 3.68 (3H, 3.90 (3H, 7.41 (1H, d, J=8Hz), 7.70 (1H, d, J=8Hz), 8.00 (1H, br 8.98 (1H, br s) Preparation 24 The following compounds described in to were prepared in a similar manner to that of Preparation 23.

Methyl 3-acetamido-4-(1-pentynyl)benzoate NMR (CDCl 3 5) 1.12 (3H, t, J=7Hz), 1.65 (2H, m), 2.23 (3H, 2.54 (2H, t, J=7Hz), 3.90 (3H, s), 7.43 (1H, dd, J=1, 8Hz), 7.70 (1H, 7.95 (1H, br 8.98 (1H, br s) Methyl 3-acetamido-4-(4-methoxycarbonyl-lbutynyl)benzoate NMR (CDC13, 5) 2.32 (3H, 2.68 (2H, 2.80 (2H, 3.73 (3H, 3.89 (3H, 7.38 (1H, d, J=8Hz), 7.67 (1H, 8.28 (1H, br 9.04 (1H, br s) Methyl 3-acetamido-4-(1-pentynyl)phenylacetate mp 77-78°C IR (KBr) 3293, 1739, 1699, 1665, 1428 cm-1 NMR (CDC1 3 5) 1.09 (3H, t, J=7Hz), 1.69 (2H, sextet, J=7Hz), 2.22 (3H, 2.49 (2H, t, J=7Hz), 3.64 (2H, 3.70 (3H, 6.94 (1H, d, 7.31 (1H, d, J=7.5Hz), 7.93 (1H, br 8.33 (1H, s) MASS :274 bp) Precaration The following compounds described in to were prepared in a similar manner to that of PreDaration 1 WO 96/32379 PCT/JP96/00892 69 Methyl 1-acetyl-2-( 3 -methoxycarbonylpropyl)indole-6carboxylate NMR (CDCl 3 5) 2.08 (2H, 2.43 (2K, t, J=7Hz), 2.86 (3H, 3.12 (2H, t, J=7Hz), 3.67 (3H, s), 3.94 6.49 (lH, 7.52 (1H, d, J8Hz), 7.93 (1K, d, JM8Hz), 8.47 (1H, s) Methyl l-acetyl- 2 -propylindole-7-carboxylate NMR (OCd 3 5) 1.04 (3H, z, J=7Hz), 1.78 (2H, i), 2.39 (3H, 2.79 (2H, i, 3.91 (3H, 6.38 (1H, 7.23 (1H, t, J=8Hz), 7.68 (1H, d, J=8Kz), 7.79 (1K, d, J=8Hz) Methyl l-acetyl- 2 -propylindile-6-carboxylate NMR (CDC1 3 5) 1.06 (3H, t, J=7Hz), 1.77 (2K, i), 2.82 3.03 (2H, J=8z), 3.94 (3H, s), 6.47 (1K, 7.49 (1K, d, J=8Hz), 7.94 (1H, d, j8z), 8.53 (1K, s) Methyl l-acetyl- 2 NMR (CDC1 3 5) 1.05 (3K, z, J=8Kz), 1.75 (2H, sextet, J=8Hz), 2.76 (3H, 2.98 (2H, t, J=8Kz), 3.94 (3K, 6.48 (1K, d, J=lHz), 7.87 (1H, d, =8z 7.95 (1K, d, J=8Hz), 8.18 s) Methyl i-acetyl- 2 -propylindole-4-carboxylate NMR (CDC 3 5) 1.07 (3H, t, J=7Kz), 1.80 (2H, i), 2.76 (3H, 3.01 (2H, t, J=7Hz), 3.97 (3H, s), 7.18 (1H, 7.28 (1K, t, j=8Kz), 8.06 (1H, d, J=8Hz), 8.15 (1K, c, j=8HO Methyl 1-acetyl-2- (2-methoxycarbonylethyl) indole-6carboxylate NMR (CDC1 3 5) 2.78 (2H, t, J=7Kz), 2.87 (3H, s), 3.39 (2H, t, J=7Mz), 3.68 (3H, 3.94 (3H, s), WO 96/32379 PCT/JP96/00892 70 6.49 (1H, 7.52 (1H, d, J=8Hz), 7.93 (1H, d, J=8Hz), 8.46 (1H, s) Methyl l-acetyl-2-propylindol-6-ylacetate mp 85-87°C IR (KBr) 1736, 1700, 1376, 1320, 1303 cm 1 NMR (CDC1 3 5) 1.04 (3H, t, J=7Hz), 1.74 (2H, sextet, J=7Hz), 2.75 (3H, 2.96 (2H, t, J=7Hz), 3.70 (2H, 3.75 (3H, 6.40 (1H, 7.14 (1H, d, J=8Hz), 7.43 (1H, d, J=8Hz), 7.81 (1H, s) MASS :274 74 (bp) Preparation 26 To a solution of methyl l-acetyl-2-(3methoxycarbonylpropyl)indole-6-carboxylate (2.34 g) in methanol (20 ml) was added powdered potassium carbonate (1.04 and the mixture was stirred under reflux for 10 minutes.

The resulting mixture was evaporated in vacuo and the residue was acidified with 1N hydrochloric acid and extracted with chloroform. The organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and then evaporated in vacuo. The residue was triturated with ether to give methyl 2-(3-methoxycarbonylpropyl)indole-6carboxylate (1.23 g) as solid.

NMR (CDC13, 5) 2.07 (2H, 2.42 (2H, t, J=7Hz), 2.84 (2H, t, J=7Hz), 3.68 (3H, 3.92 (3H, s), 6.31 (1H, 7.52 (1H, d, J=8Hz), 7.78 (1H, d, J=8Hz), 8.07 (1H, 8.39 (1H, br s) Preparation 27 The following compounds described in to were prepared in a similar manner to that of Preparation 26.

Methyl 2-propylindole-7-carboxylate NMR (CDC13, 5) 1.02 (3H, t, J=7Hz), 1.78 (2H, m), WO 96/32379 PCT/JP96/00892 71 2.78 (2H, t, J=7Hz), 3.98 (3H, 6.28 (11, M), 7.09 (1H, t, J=8Hz), 7.72 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz), 9.58 (1M, br s) 3 Methyl 2-propylindole-6-carboxylate Methyl NYR (CDC1 3 5) 1.02 (3M, z, J=8Hz), 1.76 (2H, sextet, J=8Hz), 2.74 (2H, t, J=8Hz), 3.92 (3H, s), 6.33 (1H, d, J=lz), 7.28 (1H, d, J=8Hz), 7.73 (1H, d, J=8Hz), 8.10 (11, br 8.28 (1H, s) Methyl 2-propylindole-4-carboxvlate NMR (DC1 3 5) 1.03 (3H, t, J=7Hz), 1.80 (2H, m), 2.78 (2H, 3.98 (3H, 6.89 (1H, 7.14 (1M, t, J=8Hz), 7.48 (1H, d, J=8Hz), 7.84 (1H, d, J=8Hz), 8.08 (1H, br s) Methyl 2-(2-methoxycarbonlethyl) indole-6-carboxylate NIWR (CDC1 3 5) 2.78 (2H, 3.10 (2H, 3.73 (3, 3.93 (3H, 6.30 IlH, 7.53 (1H, d, J-8Mz), 7.76 (iH, d, Je=-8Mz), 8.08 (1H, 8.88 (IN, br s) Preopration 28 The fllowing compounds described in to (19) were prepared in a similar manner to that of Preparation 1 Methyl 3-isobutyryl-2-propylindcle-7-carboxylate NMR (DC1 3 5) 1.04 (3H, t, J=7Hz), 1.27 (6H, d, 7=7Hz), 1.82 (2H, 3.26 (2H, 3.47 (1H, in), 3.99 (3H, 7.28 (1H, z, J=8Hz), 7.85 (1H, d, J=8Hz), 8.18 (1H, s) Met.,l 3-isobutyryl-2-propylindole-5-carboxylate WO 96/32379 WO 9632379PCT/JP96/00892 72 NMR (CDC1 3 6) 1.04 (3H, t, J=8Hz), 1.28 (6H, d, J=8Hz), 1.78 (2H, sextet, J=8Hz), 3.15 t, J=8Hz), 3.56 (1H, septet, J=8Hz), 3.96 (3H, s), 7.37 (1H, d, 7.93 (1H, dci, J=l, 8Hz), 8.66 (1H, d, J=8Hz), 8.75 (1H, br s) Methyl 3- (3-methoxycarbolylprolaloyl) indole-6carboxylate NMR (DMSO-d 6 5) 2.65 (2H, t, J=7Hz), 3.22 t, J=7Hz), 3.59 (3H, 3.87 7.80 (1H, d, J=8Hz), 8.10 (1H, 8.23 (1H, d, J=8Hz), 8.59 (1H, s) Methyl 3-acetyl-2-inethylindole-6-carboxYlate NMR (CDCl 3 5) :2.54 (3H, 2.73 (3H, 3.86 (3H, 7.76 (1H, d, J=8Hz), 7.97 (1H, 8.12 (1H, d, J=8Hz) Methyl 2-iethyl-3-propionylindole-6-Carboxylate NMR (ODC1 3 5) :1.12 (3H, t, J=7Hz), 2.72 (3H, s), 2.92 (2H, q, J=7Hz), 3.86 (3H, 7.75 (1H, d, J=8Kz), 7.96 (1K, 8.11 (1H, d, J=8Hz) Methyl 3- 3-diinethylbutanoyl) indole-6 7 carboxylate NMR (ODC1 3 5) :1.11 (9H, mn), 2.33 (2K, 3.94 (3K, 7.92-8.0 (2K, mn), 8.19 (1H, 8.52 (1H, di, J=8Kz), 8.90 (1H, br s) Ethyl 3-isobutyry1-2-propylifdol6ylacetate IR (Neat) :3300, 1740, 1625cm1 NMR (ODC1 3 5) :1.04 (3H, t, J=7Kz), 1.25 (6H, di, J=7Kz), 1.26 (3K, t, J=7Kz), 1.77 (2K, sextet, J=7Kz), 3.12 (2H, t, J=7Hz), 3.41-3.55 (1H, in), 3.72 (2H, 4.16 (2H, q, J=7Kz), 7.17 (1H, di, J=7.5Hz), 7.30 (1H, 7.82 (1H, d, J=7.5Hz), 8.40 WO 96132379 PCT/JP96/0092 73 (1K, br s) MASS z) 316 74 (bp) Methyl 3-isobutyryl-2-propyli-dol-6-ylacetate IR (Neat) 3290,-1730, 1625 cm 1 NMR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.26 (6H, d, JT=7Hz), 1.76 (2H, sextet, J=7Hz), 3.12 (2H, t, J=7Hz), 3.41-3.54 (1H, 3.71 (2H, 3.75 (3H, 7.16 (1H, d, J=7.5Hz), 7.30 (11, 7.83 (1H, d, J=7.5Hz), 8.40 (1H, br s) MASS 302 bc) Methyl 2-acetyl-3-methvlindole-6-carboxylate NMR (ODC1 3 5) 2.66 (3H, 2.67 (3H, 3.94 (3H, 7.72 (1H, d, J=8Hz), 7.81 (1K, c, J=8Hz), 8.11 (1K, 9.09 (1H, br s) Methyl 3-propionylindole-6-carboxylate NMR (CDCl 3 5) 1.12 (3H, t, J=7Hz), 2.89 (2H, q, J=7Hz), 3.87 (3H, 7.79 (1K, d, J=8Hz), 8.11 (1K, 8.28 (1H, d, J=8Hz), 8.53 (1H, s) (11) Methyl 2-proDionyl-3-propylindole-6-carboxylate -N-MR (CDCl 3 5) 1.06 (3H, t, J=7Hz), .1.29 (3H, t, J=7Hz), 1.74 (2H, 2.95-3.13 (4H, 3.94 (3H, 7.72 (1K, d, J=8Hz), 7.79 (1H, d, J=8Hz), 8.12 (1K, 9.11 (1H, br s) (12) Methyl 2-isobutyryl-3-propylindole-6-carboxylate NMR (CDC1 3 5) 1.04 (3H, t, J=7Kz), 1.29 (6H, t, J=7Hz), 1.76 (2K, 3.09 (2H, 3.44 (1H, m), 3.94 (3H, 7.71 (1H, d, J=8Hz), 7.79 (1H, d, J=8Kz), 8.12 (1H, 9.12 (1H, br s) (13) Methyl 3-cyclopropanecarbonyl-2-propylindole-6- WO 96/32379 PCT/JP96/00892 74 carboxylate mp 152.5-154*C IR (KBr) 3371, 1687, 1623, 1458 cm- 1 NM (CDC1 3 5) 1.00-1.09 (2H, 1.02 (3H, t, J=7Hz), 1.28-1.32 (2H, 1.82 (2H, sextet, J=7Hz), 2.56-2.65 (1K, 3.15 (2H, t, J=7Hz), 3.96 (3H, 8.00 (2H, ASB, J=8, 8Hz), 8.15 (1H, 8.89 (1H, br s) MASS 286 bp) (14) Methyl 3-cyclobutanecarbonyl-2-propylindole-6carboxvlate mm -59-1600C IR 1692, 1645, 1623 cm- 1 NMR (CDCl 3 5) 1.06 (3H, t, J=7Hz), 1.83 (2H, sextet, J=7Hz), 1.93-2.13 (2H, 2.30-2.51 (4H, 3.20 (2H, t, J=7Hz), 3.95 (3H, 3.99 (1H, quintet, J=7Hz), 7.93 (2H, 8.15 (1H, 9.08 (1H, br s) MASS 300 (M 74 (bp) Methyl 3 -cyclopentanecarbonyl-2-propylindole-6carboxylate 137-139 0

C

IR (KBr) 1692, 1647, 1624 cm- 1 .N-MR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.64-1.82 (6H, 1.94-2.05 (4H, 3.17 (2H, J=7Hz), 3.72 quintet, J=7Hz), 3.95 (3H, 7.93 (2H, ABX, J=8, 8, 1Hz), 8.15 (1H, d, J=lHz), 9.19 (1H, s) MASS 314 bp) (16) Methyl 3-cyclohexanecarbony1-2-propylindole-6carboxylate mrn :136-1370C IR (KBr) 1691, 1651, 1487, 1435 cm-1 WO 96/32379 WO 9632379PCT/JP96/00892 75 NMR (CDC1 3 65) 1.03 (3H, t, 3=7Hz),. 1.25-2.04 (12H, mn), 3.14-3.25 (1H, in), 3.18 (2H, t, J=7Hz), 3.97 (3H, 7.90 (2H, q, J=7.5Hz), 8.17 (1H, 9.16 (1H, br s) MASS (rn/z) :328 74 (bp) (17) Methyl 3- (3-methyl-2-butenoyl) 2 -propylindole-6c-arboxylate IflD 46-1470C IK :1715, 1464, 1433, 1220 cmn 1 NM'R (CDCi 3 6) :1.05 (3H, t, 3=7Hz), 1.82 (2H, sextet, J)=7Hz), 2.05 (3H, 2.20 (3H, 3.18 (2H, J=7Hz), 3.94 (3H, 6.63 (1H, 7.95 (2H, AB, J=7.5, 7.5Hz), 8.11 (1H, 8.88 (1H, br s) MASS (rn/z) 300 (M 74 (bp) (18) Methyl1 3 -crotonoyl-2-propylindole-6-carboxylate mp :153-154*C 1K :1715, 1650, 1583, 1567, 1459, 1432 cm- 1 NMR (CD1 3 6) :1.05 (3H, t, 3=7Hz), 1.83 (2H, sextez, J=7Hz), 2.04 (3H, dd, J=7, 1Hz), 3.15 (2H, t 3=7Hz), 3.96 (3H, 6.89 (1H, dcl, 3=15, 1Hz), 7.04 (1H, dd, J=15, 7Hz), 7.94 (2H, dq, J=7, 1Hz), 8.12 (1H, 8.99 (1H, br s) MAkSS 286 (19) 3-Ace:vl-6-chloroindole NMKI 'CDC-!3, 6) :2.44 (3H, 7.19 (1K, d, 3=8Hz), 7.51 (1H, 8.14 (1H, d, 3=8Kz), 8.35 (1H, s) Prenaration 29 The following compounds described in to were prepared in a similar manner to that of Prepration 6 WO 96/32379 WO 9632379PCT/JP96/00892 76 Methyl 3- (3-methoxycarbonyipropyl) indole-6-carboxylate NM'R (CDC1 3 5) :2.04 (211, in), 2.37 (2H, t, J=7Hz), 2.81 (2H, t, J=7Hz), 3.64 (311, 3.93 (311, s), 7.16 (1H1, 7.61 (11H, di, J=811z), 7.79 (1H1, di, J=8Hz), 8.10 (1H, 8.22 (1H, br s) Methyl 3-methylindole-6-carboxylate NMR (ODCd 3 5) :2.33 (3H, 3.93 (311, 7.12 (1H, 7.59 (1H1, d, J=811z), 7.80 (111, d, J=811z), 8.09 (1H, 8.10 (1H, br s) Methyl 3--propylindole-6-carboxylate NMR (ODCd 3 5) :1.00 (3H1, t, J=7Hz), 1.74 (211, mn), 2.73 (2H1, t, J=711z), 3.93 (311, 7.14 (1H, d, J=111z), 7.60 (111, d, J=8Hz), 7.79 (1H1, d, J=8Hz), 8.10 (111, 8.18 (111, br s) Prenaration To a solution of methyl 3-(3-iethoxycarbonylpropyl)indole-6--carboxylate (656 mg) in methanol (24 ml) was added 1N aqrueous sodium hydroxide (2.46 ml), and the mixture was StiLrred at 20'0 for 2 days. The resulting mixture was evapcorated in vacuo, and the residue was acidified with 1N hydrochloric acid (2.6 ml) and extracted with ethyl acetate.

The organic phase was washed with brine, dried over sodium sulfate and evapcorated in vacuo. The residue was triturated Witzh ether to give methyl 3-(3-ca=rboxvpropyl)indole-6carboxylate (486 mg) as solid.

NMR (ODC1 3 5) :2.03 (2H1, in), 2.37 (211, in), 2.80 (2H, in), 3.93 (3H, 7.17 (111, 7.59 (111, d, J=8Hz), 7.74 (111, d, J=811z), 8.09 (111, s) Prenaration 31 A mixture of methyl 3-(3-carboxypropyl)indole-6carboxy'late (173 ing), triphenylphosphine (191 mng) and carbon WO 96/32379 PCT/JP96/00892 77 tetrachloride (1.0 ml) in 1,2-dichloroethane (10 ml) was heated at 80"C for 2 hours. The resulting mixture was diluted with chloroform and washed with water, aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel thin layer chromatography with a mixture of hexane and ethyl acetate and recrystallized from a mixture of hexane and ethyl acetate to give methyl 8oxo-5,6,7,8-tetrahydrocarbazole-2-carboxylate (72.2 mg) as colorless crystals.

NMR (CDC13, 6) 2.29 (2H, 2.69 (2H, t, J=7Hz), 3.03 (2H, t, J=7Hz), 3.94 (3H, 7.69 (1H, d, J=8Hz), 7.82 (1H, d, J=8Hz), 8.16 (1H, 8.95 (1H, br s) Preparation 32 To a stirred mixture of methyl (dimethylamino)vinyl]-3-nitrobenzoate (500 mg), which was prepared by the method of Brown et al. described in Journal of Medicinal Chemistry, vol. 35, page 2419 (1992), and pyridine (0.16 ml) in tetrahydrofuran (3 ml) was added butyryl chloride (0.21 ml) at 200C. The reaction mixture was stirred at 40 0 C for 24 hours and 50 0 C for 4 hours. After cooled to 20°C, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane to give methyl 4-(l-dimethylaminomethylene-2oxopentyl)-3-nitrobenzoate (426 mg) as colorless amorphous.

NMR (CDC1 3 5) 0.89 (3H, t, J=7Hz), 1.52-1.65 (2H, 2.30 (2H, t, J=7Hz), 2.78 (6H, 3.99 (3H, 7.34 (1H, d, J=7.5Hz), 7.56 (1H, 8.18 (1H, dd, J=7.5, 1Hz), 8.51 (1H, d, J=1Hz) MASS 321 WO 96/32379 PCT/JP96/00892 78 Preparation 33 A solution of methyl 4 -(l-dimethylaminomethylene-2oxopentyl)-3-nitrobenzoate (172 mg) in dioxane (9 ml) was refluxed for 4 days. The resulting mixture was evaporated in vacuo, and the residue was purified by thin layer chromatography with a mixture of hexane and ethyl acetate to give methyl 3 -nitro-4-(2-oxopentyl)benzoate (127 mg).

NMR (CDC13, 5) 0.97 (3H, t, J=7Hz), 1.69 (2H, m), 2.60 (2H, t, J=7Hz), 3.95 (3H, 4.16 (2H, s), 7.36 (1H, d, J=8Hz), 8.22 (1H, d, J=8Hz), 8.73 (1H, s) Preparation 34 To a solution of methyl 3 -nitro-4-(2-oxopentyl)benzoate (114 mg) in a mixture of tetrahydrofuran (1.5 ml), ethanol ml) and water (2.1 ml) was added sodium hydrosulfite and the mixture was stirred under reflux for minutes. The resulting mixture was evaporated in vacuo, and the residue was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by thin layer chromatography with a mixture of hexane and ethyl acetate to give methyl 2-propylindole-6-carboxylate (54.6 mg).

Preparation To a stirred solution of 3-isobutyryl-2-propylindole-6carboxylic acid (331 mg) in tetrahydrofuran (5 ml) were added benzylalcohol (1.25 ml), dicyclohexylcarbodiimide (303 mg) and 4-dimethylaminopyridine (20 mg) at 20°C. The reaction mixture was stirred at 20 0 C for 8 hours. The precipitated urea was filtered off and the filtrate was evaporated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water two times and brine. The WO 96/32379 WO 9632379PCT/JP96/00892 79 organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chroinatographed on silica gel eluting with a mixture of ethyl acetate and hexane to give the crystals which were recrystallized from a mixture of ethyl acetate and hexane t-o give benzyl 3 -isobutyryl-2propvlindole-6-carboxylate (215 mng) as colorless crystals.

mr) 102-104 0

C

!R (KBr) :1700, 1655 cin-- NM?. (ODC1 3 6) 1.05 (3H, t, J=7Hz), 1.28 (6H, t, J=7Hz), 1.73-1.87 in), 3.17 (2H, tL, J=7Hz), 3.45-3.53 (1H, mn), 5.40 (2H, 7.32-7.50 (5H, mn), 7.95 (2K11, A-B, J=9, 8Hz), 8.14 (1H, 8.59 (1H, br s) MA.SS (in/z) :364 76 (bp) Prenaration 36 The following compound was prepared in a similar manner to that of Exam-ole 3-2.

Methyl 3-oml-ndl---abxlt NMTR (CDC1 3 5) :3.88 (3H, 7.83 (1H, dd, J=1, 8Hz), 8.12 (1K, 8.16 (1H, d, J=8Hz), 8.49 (1H, s) 12. 45 (1K, br s) Prenaration 37 To a solution o-f methyl 3-i-scbut-yryl-2-propoylindole-6 carboxylate (201 mng) in carbon :etrachloride (7 mlI) was added N-broinosuccinimide (1867 mng) and 2, 21 -azobis 4 -inethoxy-2, 4dirnethylvaleronitrile)' (20 mg) and refluxed for 30 minutes.

The resulting mixture was filtered and the filtrate was evaporated In vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting wiLth a m~ixture of hexane and ethyl acetate to give methyl 2- (1-broinopropyl) 3isbtrlnol--abxlt (179 mng).

WO 96/32379 PCT/JP96/00892 80 This compound was used immediately without purification.

Preparation 38 To a solution of methyl 2-(1-bromopropyl)-3isobutyrylindole-6-carboxylate (179 mg) in 1,2-dichloroethane (8 ml) was added N,N-diisopropylethylamine (0.24 ml) and refluxed for 40 minutes. The resulting mixture was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with diluted hydrochloric acid, water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. Trituration with diethyl ether gave methyl 3-isobutyryl-2-(1-propenyl)indole-6-carboxylate (55.2 mg).

NMR (CDC1 3 5) 1.27 (6H, d, J=7Hz), 2.01 (3H, d, J=7Hz), 3.47 (1H, 3.93 (3H, 6.44 (1H, m), 7.32 (1H, d, J=16Hz), 7.89 (1H, d, J=8Hz), 7.94 (1H, d, J=8Hz), 8.11 (1H, 8.94 (1H, br s) Preparation 39 To a solution of methyl 2-(1-bromopropyl)-3isobutyrylindole-6-carboxylate (323 mg) in acetic acid (3 ml) was added potassium acetate (345 mg) and the mixture was stirred at 6C°C for 2 hours. The resulting mixture was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with water, aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate to give methyl 2- (1-acetoxypropyl)-3-isobutyrylindole-6-carboxylate (207 mg).

NMR (CDC1 3 5) 0.99 (3H, t, J=7Hz), 1.23 (3H, d, J=7Hz), 1.29 (3H, d, J=7Hz), 1.94 (1H, 2.08 (1H, 2.18 (3H, 3.52 (1H, 3.94 (3H, s), 6.6- (1H, 7.88 (1H, d, J=8Hz), 7.94 (1H, d, J=8Hz), 8.18 (1H, 9.09 (1H, br s) WO 96/32379 PCT/JP96/00892 81 Preparation To a mixture of methyl 2 -propylindole-6-carboxylate methoxyacetic acid (4.6 ml) and carbontetrachloride (13.4 ml) in 1,2-dichloroethane (45 ml) was added slowly triphenylphosphine (16.7 g) in 1,2-dichloroethane (30 ml) over 1 hour under reflux, and the resulting mixture was heated under reflux for additional 8 hours. After evaporation of solvent, the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate and triturated with diethyl ether to give methyl 3-methoxyacetyl-2-propylindole-6-carboxylate (8.11 g).

Preparation 41 The following compound was prepared in a similar manner to that of Preparation 15 Methyl 3 -ethoxyacetyl-2-propylindole-6-carboxylate NMR (CDC1 3 5) 1.05 (3H, t, J=7Hz), 1.32 (3H, t, J=7Hz), 1.84 (2H, sextet, J=8Hz), 3.22 (2H, t, J=7Hz), 3.74 (3H, q, J=7Hz), 3.97 (3H, 4.75 (2H, 7.83 (1H, d, J=8Hz), 7.94 (1H, d, J=8Hz), 8.15 (1H, 9.27 (1H, br s) Preparation 42 To a stirred mixture of methyl 4-hydroxyphenylacetate (10.0 g) in acetic acid (55 ml) was added nitric acid (22.1 ml) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After warmed to 20°C, the reaction mixture was diluted with water (200 ml) and precipitated crystals were collected. The crystals were dissolved in chloroform, and the solution was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of chloroform and hexane to give methyl 4-hydroxy-3-nitrophenylacetate (9.3 g) as yellow crystals.

WO 96/32379 WO 9632379PCT/JP96/00892 82 mp 64-69*C IP. 1734, 1540, 1534, 1263, 1170 cm- NIVR (CDd 3 5) 3.64 (2H1, 3.73 (3H, 7.14 (1H, d, J=8Hz), 7.52 (1H, dd, j=8, 1Hz), 8.02 (1H, d, J=lHz) MASS 210 AM+- 1) Premaration 43 iron powder (2.5 g) was added to a stirred mixture of methyl 3 -nitro-4-trifluoromethanesul fonyloxyphenylacetate (2.97 g) and conc. hydrochloric acid (7.3 ml) in methanol (22 at 000 in some small portion. The reaction mixture was strred at 2000 for 2 hours, then poured into a mixture of ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane to give methyl 3 -amino- 4 -trifluoromethanesulfonyloxyphenylacetate (2.34 g) as colorless crystals.

mp 66-690C N14R (CDCl 3 5) 3.57 (2H, 3.71 (3H, 3.94 (2H, 6.67 (1H, dd, J=7.5, 1Hz), 6.79 (1H, d, Jl!Hz), 7.11 (1H, d, Prenaration 44 The following compounds were prepared from methyl acetyl 2 -propylindol-6-ylacetate in a similar manner to that of Prenaration 26.

Methyl 2 -propylindol-6-ylacetate IR (Neat) 3400, 1740 cm- 1 NIM'R (OD1 3 5) 1.00 (3H, t. J=7Hz), 1.75 (2H, sextet, J=7Hz, 2.72 (2H, t, J=7Hz), 3.70 (3H, s), 3.72 (2H, 6.22 (1K, 6.99 (1H, d, WO 96/32379 WO 9632379PCT/J1P96/00892 83 7.22 (1H, 7.47 (1H, di, J=7.5HZ), 7.83 (1H, b2 s) MIAS S 232 (M

T

74 (bp) Ethyl 2 -propylindol-6-viacetate IR (Neat) :3400, 1735 cm-1 NMR (ODC1 3 5) :1.00 (3H, t, J=7Hz), 1.05 (3H, t, j=7Hz), 1.74 (2H, sextet, J=7Kz), 2.72 t, J=7Hz), 3.69 (3H, 4.13 (2H, a, J=7Hz), 6.20 (1H, 6.99 (1H, di, J=7.5Hz), 7.23 (1H, 7.46 (1H, di, J=7.5Kz), 7.83 (1H, br s) MASS :346 (M 74 (bp) 2 -Propylindol-6-ylacetic acid mp 85-87*C 1K (KBr) :3381, 1701, 1691 cm- 1 NMR (ODCd 3 5) :1.00 (3H, J=7Kz), 1.73 (2H, sextet, J=7Hz), 2.72 (2H, t, J=7Hz), 3.73 (2H, s), 6.21 (1H, 6.98 (1K, di, J=7.5Hz), 7.21 (1H, s), 7.48 (1H, di, J=7.5Hz), 7.83 (1H, br s) MALS S 216 bp), Preparation To a stirred solution of methyl 3-ethylindole-6carboxylate (138 mg) in dichloromethane (5 ml) was added sulfuryl chloride (0.066 ml), and the mixture was stirred at 2001C -For 1 hour. The resulting mixture was poured into ice and extracted with ethyl acetate. The combined organic phase was washed with aqrueous sodium bicarbonate and brine, then dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixzure of 'nexane and etk.hyl acetate to give methyl 2 -chloro-3-ethylindole-6'-carboxylte (58.2 mg) as a solid.

NMR (ODC1 3 5) :1.26 (3H, t, J=7Hz), 2.76 (2H, q, J=7Hz), 3.92 (3H, 7.54 (1K, di, j=8Hz), 7.82 WO 96/32379 PCT/JP96/00892 84 (1H, d, J=8Hz) 8.02 (1H, 8.19 (1H, br s) Preparation 46 To a stirred solution of methyl 3 -formylindole-6carboxylate (368 mg) in 1,4-dioxane (10 ml) was added acetylmethylene triphenylphosphorane (1.15 and the mixture was stirred under reflux for 12 hours. The resulting mixture was evaporated in vacuo, redissolved with ethyl acetate and washed with IN hydrochloric acid and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and ethyl acetate to give methyl 3-(3-oxo-l-butenyl)indole-6-carboxylate (75 mg) as a solid.

NMR (CDC1 3 5) 2.39 (3H, 3.95 (3H, 6.79 (1H, d, J=15Hz), 7.71 (1H, 7.80 (1H, d, J=8Hz), 7.87-7.96 (2H, 8.14 (1H, s) Preparation 47 The following compound was prepared from in a similar manner to that of Preparation 46.

Methyl 3-( 2 -methoxycarbonylethenyl)indole-6-carboxylate NMR (DMSO-d 6 5) 3.72 (3H, 4.87 (3H, 6.44 (13, d, J=15Hz), 7.76 (1H, d, J=8Hz), 7.89 (1H, d, 7.98 (1H, d, J=8Hz), 8.10 (1H, 8.20 (1H, s) PreDaration 48 To a solution of methyl 3 2 -methoxycarbonylethenyl)indole-6-carboxylate (213 mg) in a mixture of 1,4-dioxane (2 ml) and methanol (3 ml) was added 10% palladium on carbon mg) and the mixture was stirred under hydrogen at 200C for hours. The resulting mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was WO 96/32379 WO 9632379PCT/JP96/00892 85 triturated with diisopropyl ether to give methyl 3-(2methoxycarbonylethyl) indole-6-carboxylate (177 mg).

NMR (ODC1 3 5) 2.72 (2H, t, J=7Hz), 3.12 (2H, t, J=7Hz), 3.68 (3H, 3.94 (3H, 7.20 (1H, d, j=2Hz), 7.62 (KH, d, J=8Hz), 7.82 (1H, d, J=8Hz), 8.12 8.21 (1H, br s) Prenaration 49 Th following compound was prepared from a similar manner :0 that of Preparation 3- (6-Methoxycarbonylindol-3-yl) propionic acid NI'R (CDCl 3 5) :2.72 (2H, t, J=7Hz), 3.10 (2H, t, J=7Hz), 3.94 (3H, 7.19 (1H, 7.60 (1H, d, j=8Hz), 7.77 (1H, d, J=8Hz), 8.10 (1H, s) Preparazion The following compound was prepared in a similar manner to that of Preparation 31.

Methyl 3 -oxo-l, 2 3 ,4-tetrahydrocyclopent[blindole-6 carboxylate AMYR (ODCd 3 5) 3.05 (2H, in), 3.14 (2H, in), 3.97 (3H, 7.76 (1H, d, J=8Hz), 7.85 (1H, d, J8Kz), 8.21 (1H, s) Prenaration 51 The following compounds described in to were prepared inl a similar manner to that of Preparation 8 3->yclopropanecarbonyl-2-propylindole-6-carboxylic acid mp :250.5-251.5'C (dec.) IR (KBr) :1685, 1600, 1463, 1424, 1300 ciiG 1 NM?. (CDCl 3

-CD

3 OD, 5) :1.00-1.09 (2H, in), 1.02 (3H, t, J=7Hz), 1.25-1.29 (2H, in), 1.81 (2H, sextet, WO 96/32379 PCT/JP96/00892 86 J=7Hz), 2.59-2.69 (1H, rn) 1 3.12 (2H, t, J=7Hz), 7.99 (2H, A, 7.5Hz), 8.09 s) MASS 270 (M-l) 3-Cyclobutanecarbonyl-2-propyiindole-6-carb acid Mrn 244-2450C IR 1688, 1419, 1292 cmJ 1 NM?. (CDO1 3

-CD

3 0D, 5) 1.05 (3H, t, J=7Hz), 1.80 (2H, sextet, J=7Hz), 1.92-2.15 (2H, in), 2.29-2.49 (2H, 4.01 (1K, quintet, J=7Hz), 7.90 (2H, 8.08 (1H, s) MSS (rn/z) 286 74 (bp) 3-Ccloentanecaronyl-2-pro indole-6-carboxylic acid M-p 233-235 0

C

-1 I (KBr) 1673, 1611, 1463, 1453 cm TI'4R (CD01 3

-CD

3 oD, 0.99 (3H, t, J=7Hz), 1.51-1.79 (6H, 1.89-1.97 (4H, 3.10 (2H, t, J=7Hz), 3.70 (1H, quintet, J=7Hz), 7.85-7.94 (2H, 8.05 (1H, s) MASS 298 bp) 3 -Cyclohexanecarbony- 2 -roylindole-6-carboxvlic acid T~np 217-218*C TR (KBr) 1675, 1614, 1457 cirJ- N-M? (CDC1 3

-CD

3 0D, 5) 0.99 (3H, t, J=7Hz), 1.19-1.56 (6H, 1.74 (2H, sextet, J=7Hz), 1.80-1.95 (4H, 3.08 (2H, t, J=7Kz), 3.09-3.20 (1K, 7.80 (1K, d, J=8Hz), 7.88 (1K, dd, J=8, 1Hz), 8.03 (1H, d, j=1Hz) M AS S 312 bp) 3 -(3-Methyl-2-butenoyl) 2 -prooylndolee66carboxylic acid 246-248oC (dec.) IR 1669, 1465, 1423 cmJ 1 WO 96/32379 PCT/JP96/00892 87 NM (DMSO-d 6 l) 0.96 (3H, t, J=7Hz), 1.75 (2H, sextet, J=7Hz), 2.00 (3H, 2.09 (3H, 3.08 (2H, t, J=7Hz), 6.60 (1H, 7.73 (11, d, 7.95 (1H, d, J=7.5Hz), 7.99 (1H, s) MASS 284 (M

T

bp), 82 (bp) Preparation 52 The following compounds described in zo were prepared in the similar manner to that of Example 6.

3 -Ccloproanecarbonyl-2-ro pylindol 6 emr 120-122 0 c IR 1670, 1623, 1599, 1394 cin 1 NIR (DMSO-d, 6) 0.94 (3H, t, J=7Hz), 0.99-1.04 (4H, in), 1.73 (2H, sextet, J=7Hz), 2.55-2.62 (1H, m), 3.07 (2H, t, J=7Hz), 7.22 (1H, br 7.69 (1K, dd, 1Kz), 7.93 (1K, d, J=lHz), 7.96 (1K, br s), 8.00 (1H, c, MASS (in/z) 269 98 (bp) 3 -Cyclobutanecarbonlvi 2 -proov-ncidole-6-carboxamide 253-255'C IR (Kar) 1675, 1624, 1605, 1456, 1397 cin 1 -N-MR (DMSO-d 6 6) 0.97 (3H, t, J=7Hz), 1.66-1.89 (3H, 1.97-2.09 (1K, 2.23-2.30 (4H, 3.09 (2H, J=7z), 3.99 cuintet, J=7Kz), 7.24 (1H, br 7.69 d, J=7.5Hz), 7.86 (1H, c, 7.90 7.97 (1K, br s) MASS 285 85 (bp) 3 OYCylopentanecarbonyl-2-propylindole-6- carboxd 213-2.15"C IR 1666, 1628, 1623, 1604 cm 1 NMR (CDO1 3

-CD

3 D, 5) 1.01 (3H, t, J=7Kz), 1.61-1.83 (EK, 1.90-1.98 (4K, 3.13 (2H, t, J=7Hz), WO 96/32379 PCT/JP96/00892 88 3.69 (1H, quintet, JL77z), 7.52 (1H, dci, J=8, 1Hz)", 7.91 (1H, d, J'lHz), 7.96 (1H, di, J=8Hz) MASS (in/z) 299 74 (bp) 3 -Cyclohexanecarbony-2-propyinioe6carboxaice mp :245-247*C IR (KBr) :1663, 1627, 1595, 1459, 1402 cm- 1 NMR (DMSO-c1 6 0.95 t, J=7Hz), 1.16-1.30 (1H, mn), 1.35-1.46 (4H, mn), 1.70 (2H, sextet, J=7Hz), 1.75-1.88 (5H, mn), 3.05 (2H, t, J=7Hz), 3.10-3.17 (1H, mn), 7.25 (1H, br 7.70 (1H, dd, 1Hz), 7.81 (1H, d, J=7.5Hz), 7.93 (1H, di, J=l~z), 7.95 (1H, br s) MASS 313 (M 85 (bp) 3- (3-Methyl-2-butenoyl) 2 -propylindoe-6-carboxaie mp :179-181*C IR (KBr) :1669, 1648, 1591, 1458, 1394 cmn 1 NMR (DMSO-d 6 5) 0.95 (3H, t, J=7Hz), 1.72 (2H, sextet, J=7Hz), 1.99 (3H, 2.05 (3H, 3.05 (2H, t, J=7Hz), 6.59 (1H, 7.22 (1H, br 7.67 (1H, d, J=7.5Hz), 7.88 (1H, di, J=7.5Hz), 7.90 (1H, 7.92 (1H, br s) MASS (in/z) 285 85 (bp) 3- (3-Methoxybutanoyl) 2 -propylinie-6-carboxamiie mp :140-144*C IR (KBr) :1644, 1623, 1604, 1460, 1394 citf 1 NMR (CDC1 3 6) :1.02 (3H, t, J=7Hz), 1.30 (3K, ci, J=7Hz), 1.80 (2K, sextet, J=7Kz), 2.98 (1H, dci, 7Hz), 3.17 (2H, t, J=7Kz), 3.39 (1H, dci, 7Hz), 3.40 (3H, 7.10 (1K, sextet, J=7Hz), 7.55 (1K, dci, J=8, 1Hz), 8.02 (1K, ci, J=8Hz), 8.10 (1H, ci, 9.60 (1H, br s) MASS (in/z) :303 74 (bp) WO 96/32379 WO 9632379PCT/JP96/00892 89 Prelparation 53 The following compound was prepared from methyl 3crotonyl- 2 -propylindole-6-carboxylate in a similar manner to that of Preparation 8 3- (3-Methoxybutanoyl) -2-propyiindole-6--carboxylic acid mp :286-288*C (dec.) IR (KBr) :3288, 1685, 1645, 1620 c- NNR (DMSO-d 6 :0.96 (3H, t, J=7Hz), 1.19 d, J=7Hz), 1.73 (2H, sextet, J=7Hz), 2.90 (1H, dd, 7Hz), 3.08 (2H, t, J=7Hz), 3.13 (3H, 3.15 (1H, dd, J=15, 7Hz), 3.91 (1H, sextet, J=7Hz), 7.26 (1H, d, J=BHz), 7.99 (1H, 8.00 (1H, d, J=8Hz) MASS 302 98 (bp) WO 96/32379 PTJ9109 PCT/JP96/00892 90 ExamDle 1 To a solution of methyl 3 -acetyl-2-propylindole-6carboxylate (74 mg) in dimethylformamide (1.4 ml) was added sodium hydride 15.4 mg) The mixture was stirred at 20'C for 30 minutes, then 2-chlorobenzyl bromide (0.045 ml) was added. After stirred for 1 hour, the mixture was diluted wi:n ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo to give methyl 3-acetyl-l- (2-chlorobenzyl) -2propylindole-6-carboxylate (125 mg) as solid.

NM'R (ODC1 3 5) :1.01 (3H, t, J=7Hz), 1.63 (2H, in), 2.74 (3H, 3.05 (2H, in), 3.89 (3H, 5.49 (2H, 6.22 (1H, d, J=BHz), 7.03 (1H, t, J=8Hz), 7.20 (1H, t, J=8Hz), 7.46 (IH, d, MBHz), 7.93 s), 7.97 (1H, d, J=BHz), 8.04 (1H, d, J8BHz) Examtnle 2 To a solution of methyl 3 -acetyl-1-(2-chlorobenzyl)-2propylindole-6-carboxylate (125 mg) in ethanol (6 ml) was added 1N aqueous sodium hydroxide (0.7 ml), and the mixture was stirred under reflux for 1 hour. The resulting mixture was evaporated in vacuo, and the residue was acidified with 1N hydrochloric acid (0.75 ml) and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with isopropyl ether to give 3-acetyl-1- (2chlorobenzyl) 2 -propylindole-6-carboxylic acid (78 mg) as s0lid.

NYR (ODC1 3 5) 1.02 (3H, t, J=7Hz), 1.61 (2H, in), 2.76 (3H, 3.08 (2H, in), 5.52 6.24 (1H, d, M=Hz), 7.04 t, J=8Hz), 7.22 (1H, t, J=8Hz), 7.46 (lH, d, M=Hz), 7.99 (11, 8.03 (1H, di, M=Hz), 8.08 (1H, J=8Hz) ExaInle 3 WO 96/32379 PTJ9/09 PCT/JP96/00892 91. To a solution of 3 -acetyl-1-(2-chlorobenzy1)-2propylindole-6-carboxylic acid (74 mg) in dimethylformamide (2 ml) were added l-hydroxybenzotriazole (38 mg), 1-(3dimvethylaminopropyl) 3 -ethylcarbodi-imide hydrochloride (98 mg) and 3N methanol solution off ammoniJa (0.5 ml) After stirred at 20'C for 14 hours, the resulting mixture was diluted with ethyl acetate. The organic Phase was washed successively with 1N hydrochlori-c acid, water, aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with isopropyl ether to give 3- a-cetyl- l-(9-chlorobenzyl)-2pronylindole-6-carboxamide (67 mrg) as colorless crystals.

mp 208-211'C N-1 (CDCl 3 5) 1.01 t, J=7Hz), 1.61 (2H, mn), 2.73 (3H, 3.06 in), 5.49 (2H, 6.22 (1H, dd, J=1, 8Hz), 7.02 (1H, dt, J=1, 8Hz), 7.21 (1H, dt, J=1, 8Hz), 7.45 (1K, dd, J=1, 8Hz), 7.63 (1H, dd, J=l, 8Hz), 7.84 (1H, d, J=8Hz), 8.07 (1H, d, j=8Hz) Example4 Met-hyl 1-(2-ch-lorobenzyl) 3 'Isobutyryl-2-orooyli ndole-o'carboxylate (533 mg) was prepared from methyl 3 -isobutyryl-2propylindole- 6-carboxylate (440 mg) and 2-chlcrobenzyl bro-mide (346 mag) in a similar manner to that of Example 1.

NMR (ODCd 3 5) :1.01 J=8Hz), 1.30 (6H, d, J=8Hz), 1.55-1L.66 (2H, mn), 3.02-3.07 12H, in), 3.58 (2H, septet, J=8Hz), 3.90 (3H, 5.50 (2H, s), 6.24 (1H, dd, J=1, 8Hz), 7.05 (1H, dt, J=l, 8Hz), 7.24 (1H, dt, J=l, 8Hz), 7.46 (1K, dd, 8Hz), 7.95 (1H, 7.97 (21H, S) Examvnle 1- (2-Ch--,lorobenzyl) 3 -isobutyrvl-2-propylindole-6carboxylic acid (450 mg) was prepared from methyl 1-(2- WO 96/32379 WO 9632379PCT/JP96/00892 -92 chlorobenzyl)-3-isobutyryl-2-propylindole Ecab ixlt (510 mg) in a similar manner to that of Example 2.

NN-R (DMSO-d 6 a) :0.92 (3H, t, J=8Hz), 1.18 (6H, d, M8Kz), 1.38-1.52 (2H, mn), 3.02-3.08 (2H, in), 3.55 (2H, septet, J=8Hz) 5.68 (2H, 6.28 (1K, dd, J=1, 8Hz), 7.18 (1K, at, J=l, 8Hz), 7.32 (1H, at, J=1, 8Hz), 7.52 (1H, aa, J=1, 8Hz), 7.84 (1H, dda, 8Hz), 7.97 (1H, d, J=lHz), 8.00 (1K, d, J=8Hz) Example 6 To a solution of l-( 2 -chlorobenzy1)-3-isobutvryl.2propylindole-6-carboxylic acid (150 mg) in dimethylformamiae (3 were aaded l-hydroxybenzotriazole (102 mng), 1-(3dimethylaminopropyl) 3 -ethylcarboaiimiae hydrochloride (109 mg) After stirrea at 20'C over night, the resulting mixture was poured into 28% aqueous ammonia (5 ml) The mixture was partitionea between ethyl acetate ana water, ana the organic phase was washed with 1N hydrochloric acia ana brine, ariea over sodium sulfate ana evaporated in vacuo. The crystalline resiaue was recrystallizea from a mixture of ethyl acetate ana hexane to give l-( 2 -chlorobenzyl)-3-isobutyryi-2.

propylindole-6-carboxamide (123 mng) as colorless crystals.

mp 185-186'C NMR (ODC1 3 5) 1.01 (3H, t, J=8Hz), 1.30 (6H, d, j=8Hz), 1.55-1.66 (2H, mn), 3.00-3.06 (2H, in), 3.56 (2H, septet, M8Kz), 5.49 (2H, 6.24 (1H, aa, j=1, 8Hz), 7.04 (1H, at, J=1, 8Hz), 7.23 (KH, dt, 8Hz), 7.46 KH, aa, J=1, 8Hz), 7.63 (1K, aa, 8Hz), 7.85 (1K, d, J1!Hz), 7.97 (1K, a, J=8Hz) Exampole 7 Methyl 1- 2 -chlorobenzyl)3propionyl2propylinaoleG6 carboxylate (436 mng) was preparea from methyl 3 -propionyl-2propylindole-6-carboxylate (260 mng) and 2 -chlorobenzyl bromide (21S mc in a similar mnnrer to that of Example 1.

_I_

WO 96/32379 PCT/JP96/00892 93 ~nX (ODd 3 1.02 t, J=8Hz), 1.30 (3H, t, J=8Hz), 1.55-1.68 (2H, 3.00-3.16 (4H, 3.90 (3H, 5.49 (2H, 6.22 (1H, ad, J=1, 8Hz), 7.05 (1H, at, J=1, 8Hz), 7.23 (1H, dt, J=1, 8Hz), 7.46 (1K, ad, J=1, 8Hz), 7.93 (1H, d, J=8Hz), 7.96 (1K, ad, J=1, 8Hz), 3.03 (1K, d, J=8Kz) Exainrle 8 1-(2-Chlorobenzyl)-3-propionyl-2-propylindole-6 carboxylic acid (308 -ig) was prepared from methyl 1-(2chlorobenzyl)-3-propionv -2-propylindole (425 mg) in a similar manner to that of Exainle 2.

NNIR (DMSO-d 6 0.94 (3H, t, J=8Hz), 1.14 (3H, t, J=8z), 1.49 (2H, sextet, J=8Hz), 3.00-3.10 (4H, 5.67 (2K, 6.27 (1H, dd, J=1, 8Hz), 7.18 (1H, dt, J=1, 8Hz), 7.32 (1K, at, J=1, 8Hz), 7.56 (1K, da, J=1, 8Hz), 7.83 (1H, dd, J=1, 8Hz), 7.96 (1K, d, J=1Hz), 8.09 (1H, d, J=8Hz) Examnle 9 1-(2-Chiorobenzyl)-3-proionyl-2-proylindole6 carboxamide (81 mg) was prepared from i-( 2 -chlorobenzyl)-3propionyl-2-propylindole-6-carboxylic acid (100 mg) in a similar manner to that off Example 6.

mP l511520C NMR (CDC1 3 5) 1.02 (3H, t, J=8Hz), 1.30 (3H, t, J=8Hz), 1.62 (2K, sextet, J=8Hz), 3.04-3.14 (4H, 5.50 (2H, 6.22 dd, J=1, 8Hz), 7.03 (1H, at, J=1, 8Hz), 7.22 (11, at, J=1, 8Hz), 7.45 (1K, da, J=1, 8Hz), 7.64 (1H, dd, J=1, 8Hz), 7.84 (1H, d, J=1Hz), 8.06 (1H, d, J=8Hz) Example Methyl 1-( 2 -chlorobenzyl) 2 -isobutv-3-isobutyryiindole 6-carboxylate (258 mg) was prepared from methyl 2 -isobutyl-3- WO 96/32379 PCT/JP96/00892 94 isobutyrylindole-6-carboxylate (210 mg) and 2-chlorobenzyl bromide (157 mg) in a similar manner to that of Example 1.

NMR (CDC13, 5) 0.97 (6H, d, J=7Hz), 1.31 (6H, d, J=7Hz), 1.96-2.10 (1K, 3.04 (2H, d, J=7Hz), 3.60 (1H, septet, J=7Hz), 3.90 (3H, 5.53 (2H, 6.18 (1H, d, J=8Hz), 7.04 (1H, t, J=8Hz), 7.23 (1H, t, J=SHz), 7.46 (1H, t, J=8Hz), 7.94 (1H, s), 7.96 i2H, s) Example 11 1-(2-Chlorobenzyl)-2-isobutyl-3-isobutyrylindole6carboxylic acid (184 mg) was prepared from methyl 1-(2chlorobenzyl)-2-isobutyl-3-isobutyrylindole6carboxylate (213 mg) in a similar manner to that of Example 2.

(DMSO-d 6 6) 0.88 (6H, d, J=8Hz), 1.17 (6H, d, J=7Hz), 1.82-1.95 (IH, 3.07 (2H, d, J=8Hz), 3.57 (1H, septet, J=7Hz), 5.68 (2H, 6.25 (1H, d, JM8Kz), 7.18 (1H, t, J8Hz), 7.33 (1H, t, J=8Hz), 7.57 (1H, d, J=8Hz), 7.85 (1K, d, J=8Hz), 7.95 (1H, 8.00 (1H, d, J=8Hz) Example 12 1-(2-Chlorobenzyl)-2-isobutyl-3-isobutyrylindole6 carboxamide (143 mg) was prepared from l( 2 -chlorobenzyl)-2isobutyl-3-isobutyrylindole-6-carboxylic acid (160 mg) in a similar manner to that of Example 6.

NM (DMSO-d 6 5) 0.86 (6H, d, J=8Hz), 1.17 (6H, d, J=7Hz), 1.80-1.94 (1H, 3.02 (2H, d, J=8Kz), 3.57 (1H, septet, J=7Hz), 5.62 (2H, 6.16 (1H, d, J=8Hz), 7.18 (1H, t, J=8z), 7.30-7.35 (2H, i), 7.57 (iN, d, J=8Hz), 7.82 (1K, d, J=8Hz), 7.94 (1H, 7.96 (1H, d, J=8Hz), 8.00 (1K, s) Examle 13 Methyl 1-(2-chlorobenzyl)- 2 -ethyl-3-propionylindole-6 WO 96/32379 WO 9632379PCTIJP96/00892 95 carboxylate (278 mg) was prepared from methyl 2-ethvl-3propionylindole-6-carboxylate (215 mg) and 2 -chlorobenzyl bromide (0.24 ml) in a similar manner to that of Example i.

NM?. (ODC1 3 :1.22 t, J=7Hz), 1.30 (3H, t, J=7Hz), 3.05-3.20 (4H, in), 3.90 (3H, 5.50 (2H, 6.22 (1H, d, J=8Hz), 7.02 (1K, r, j=8Hz), 7.20 (1H, t, J=8Hz), 7.46 (1H, d, J=8Hz), 7.92 s), 7.95 (lH, d, J=8Hz), 8.04 (iH, d, J=8Hz) Examnle 14 1- (2-Chlorobenzyi) 2 -ethyl-3-propionylindole-6carboxylic acid (417 mg) was prepared from methyl 1-(2chlorobenzyl) 2 -ethyl-3-propionylindole6-carboxylate (453 mg) in a similar manner to that of Example 2.

NM~R (DMSO-d 6 6) :1.09 (3H, t, J=7Hz), 1.17 (3H, t, J=7Hz), 3.08 (2H, t, J=7H-z), 3.11 (2H, t, J=7Hz), 5.68 (2H, 6.24 (1K, d, M=8z), 7.18 (1H, t, M=Hz), 7.31 (lH, t, J=8Hz), 7.57 (1H, d, M=8z), 7.83 (lH, d, J=8Hz), 7.95 (1K, 8.13 (1H, d, J=8Hz) Example 1- (2-Ohlorobenzyl) 2 -ethyl-3-propionylindole.6carboxamide (242 mg) was prepared from 1-(2-chlorobenzyl)-2ethyl- 3 -propionylindole-6-carboxylic acid (252 mg) in a similar manner to that of Example 3.

NM?. (CDCl 3 6) :1.23 (3H, t, J=7Hz), 1.29 (3H, t, J=7Hz), 3.08-3.18 (4H, in), 5.49 (2H, 6.19 (1K, d, J=8Hz), 7.02 (1H, t, J=8Hz), 7.21 (1H, t, J=8Hz), 7.46 (1H, d, j=8Hz), 7.62 (1H, d, J=8Kz), 7.83 (1H, 8.09 (1H, d, J=8Hz) Exmle16 Methyl 2- acetvl-1- (2-chlorobenzyl) 3 -isobutylindole-6carboxylate (71.4 mg) was prepared from methyl 2 -acetyl-3- WO 96/32379 PCTIJP96/00892 96 isobutylindole-6-carboxylate (58 mg) and 2-chlorobenzyl bromide (0.04 ml) in a similar manner to that of Example 1.

NYIR (CDC1 3 5) 1.02 (6H, d, J=7Hz), 2.02 (114, i), 2.59 (3H, 3.01 (2H, d, J=7Hz), 3.90 (3H, s), 5.84 (2H, 6.19 d, J=8Hz), 6.99 t, J=8Hz), 7.15 (UH, t, J=8Hz), 7.40 (lH, d, J=8Kz), 7.75 (1H, d, J=8Hz), 7.83 (1H, d, J=8Hz), 7.98 (1, Example 17 2-Acetyl-1- (2-chlorobenzyl)- 3 -isobutylindole-6carboxylic acid (45.3 mg) was prepared from methyl 2-acetyl- 1-( 2 -chlorobenzl)-3-isobutindole-6carboxylate (67 mg) in a s.mlar manner to that of Examole 2.

NM?. (CDC 3 5) 1.02 (6H, d, J=7Hz), 2.03 (1K, i), 2.62 (3H, 3.03 (2H, d, J=7Hz),.5.76 (2H, s), 6.19 (1H, d, J=8Hz), 7.00 (1H, t, J=8Hz), 7.14 (1H, t, J=8Hz), 7.41 (1H, d, J=8Hz), 7.77 (1H, d, J=8Hz), 7.86 (1H, d, J=8Hz), 8.02 (1H, s) Examole 18 2-Acetyl-1- (2-chlorobenzyl)-3-isobutylindole-6carboxamide (33.4 ng) was prepared from 2-acetyl-1-(2chicrobenzyl)-3-isobutylindole-6-carboxylic acid (41.7 mg) in a similar manner to that of Example 3.

NIR (CDC- 3 1.01 d, J=7Kz), 2.02 (1K, i), 2.62 (3H, 3.03 (2H, d, J=7Hz), 5.54 (2H, s), 6.22 (1H, d, J8Hz), 6.99 (1H, t, J=8Hz), 7.16 (1H, t, J=8Hz), 7.41 k, d, J=8Hz), 7.54 (1H, d, J=8Bz) 7.78 (1H, d, J8Hz), 7.70 (1H, s) Examole 19 Methyl (2-chlorobenzyl.)- 3 -ethyl-2-propionylindole-6carboxylate (66 mg) was prepared from methyl 3-ethyl-2procionvlindce-6-carboxylate (88 ng) and 2-chlorobenzyl WO 96/32379 WO 9632379PCT/JP96/00892 97 bromide (0.051 ml) in a similar manner to that of Example 1.

NMR (ODC1 3 6) :1.16 (3H, t, J=711z), 1.38 (3H, t, J=711z), 2.95 (2H1, q, J=7Hz), 3.14 (21H, q, J=7Hz), 3.90 (3H1, 5.72 (2H1, 6.23 (1H1, di, J=811z), 6.98 (1H, t, J=811z), 7.14 (1H1, t, J=811z), 7.39 (1H, d, J=811z), 7.77 (1H1, di, J=8Hz), 7.85 (1H1, d, J=8Hz), 7.97 (1H1, s) Example 1- (2-Chlorobenzyl) -3-ethyl-2-propionylindole-6carboxylic acid (48.7 mg) was prepared from methyl l-(2chlorobenzyl) 3 -ethyl-2-propionylindole-6-carboxylate (59.4 mg) in a similar manner to that of Example 2.

NI'R (ODC1 3 6) :1.16 (3H, t, J=711z), 1.37 (311, t, J=7Hz), 2.94 (211, q, J=7Hz), 3.15 (2H, q, J=7Hz), 5.72 (2H, 6.25 (1H, di, J=811z), 6.99 (1H1, t, J=8Hz), 7.15 (1H1, t, J=8Hz), 7.40 (111, di, J=8Hz), 7.78 (1H, di, J=8Hz), 7.87 (1H di, J=8Hz), 8.01 (111,

S)

Exam-ple 21 1- (2-Chlorobenzyl) -3-ethyl-2-propionylindole-6carboxamide (40.4 mg) was prepared from l-(2-chlorobenzyl)-3ethyl-2-propionylindole-6-carboxylic acid (46 mg) in a similar manner to that of Example 3.

NMR (ODC1 3 6) :1.16 (311, t, J=711z), 1.38 (311, t, J=711z), 2.96 (2H, q, J=7Hz), 3.14 (2H1, q, J=7Hz), 5.72 (211, 6.25 (111, di, J=8Hz), 7.00 (1H, t, J=811z), 7.14 (1H1, t, J=8Hz), 7.39 (1Hi, di, J=8Hz), 7.56 (111, d, J=811z), 7.79 (1H, 7.80 (111, di, J=811z) Example 22 The following compounds described in 1) to 6) were prepared by reacting the compound obtained in Example 2

M

WO 96/32379 WO 9632379PCT/JP96/00892 98 or Example 34-19), and a suitable amine (IV) in a similar manner to that of Exmpe3 3-Acetyl-l (2-chlorobenzyl) N-diinethyl-2-propylinciole- 6-carboxamide mp 150-153*C NMR (CDCl 3 5) :1.03 (3H, t, J=7Hz), 1.63 (2H, in), 2.72 (3H, 2.98 (6H, br 3.09 (2H, mn), 5.44 (2H, 6.26 (1H, dd, J=1, 8Hz), 7.03 (1H, dt, J=1, 8Hz), 7.20 (1H, dt, J=l, 8Hz), 7.29 (1H, s), 7.35 (1H, d, J=8Hz), 7.43 (1H, dci, J1l, 8Hz), 8.03 (1H, d, J=8Hz) 3-Acetyl-1- (2-chlorobenzyl) -N-cyclopropylinethyl-2propylindole-6-carboxanide mp 158-162'C NMR (ODC1 3 5) 0.28 (2H, mn), 0.55 (2H, in), 1.03 (3H, t, J=7Hz), 1.05 (1H, mn), 1.60 (2H, mn), 2.72 (3H, 3.04 (2H, in), 3.31 (2H, mn), 5.49 (2H, 6.22 (1H, d, J=8Hz), 6.28 (1H, in), 7.03 (1H, t, J=8Hz), 7.22 (1H, t, J=BHz), 7.45 (1H, d, J=8Hz), 7.61 (1H, dci, J=1, 8Hz), 7.82 (1H, d, J=lHz), 8.05 (1H, d, J=8Hz) 3-Acetyl-1- (2-chlorobenzyl) (2-pyridylinethyl)-2propylindole- 6-carboxainide mp 172-175*C NNR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.63 (2H, in), 2.73 (3H, 3.07 (2H, mn), 4.75 (2H, d, 5.51 (2H, 6.22 (1H, d, J=8Hz), 7.02 (1H, t, J=8Hz), 7.15-7.27 (2H, mn), 7.33 (1H, di, J=8Hz), 7.44 (1H, di, J=8Hz), 7.58-7.76(3H, 7.88 (1H, 8.07 (1H, di, J=8Hz), 8.56 (1H, mn) 3-Acetyl-1- (2-chlorobenzyl)-6- (iorpholinocarbonyl)-2- WO 96/32379 WO 9632379PCT/JP96/00892 99 propylindole NMR (CDC13 5) 1.03 t, J=7Hz), 1.63 (2H, mn), 2.73 (3H, 3.09 (2H, mn), 3.63 (8H, br 5.44 (2H, 6.23 (1H, d, J=81-z), 7.06 (1H, t, J=8Hz), 7.2-7.4 (3H, in), 7.46 (1H, d, J=8Hz), 8.06 (1H, di, J=8Kz) 3-Acetyl-l- (2-chlorobenzyl) -N-phenylsulfonyl-2propylindole- 6-carboxainide inp 206-208'C NMR (CDC1 3 5) 0.99 (3H, t, J=7Hz), 1.54 (2H, mn), 2.72 (3H, 3.02 (2H, mn), 5.43 (2H, 6.13 (1H, d, J=8Hz), 7.00 (1H, t, J=8Hz), 7.21 (1H, t, J=8Hz), 7.43 (1H, di, J=8Hz), 7.5-7.7 (4H, mn), 7.77 (1H, 8.08 (1H, di, J=8Hz), 8.13-8.18 (2H, in), 8.81 (1H, br s) 1- (2-Chlorobenzyl) -3-formyl-N-phenylsulfonyl-2propylindole- 6-carboxainide inp 242-245*C NMR (CDC1 3 5) 0.87 (3H, t, J=7Hz), 1.49 (2H, mn), 3.07 (2H, t, J=7Hz), 5.66 (2H, 6.32 (1H, d, J=8Hz), 7.18 (1H, t, J=8Hz), 7.33 (1H, t, J=8Hz), 7.55-7.75 (4H, mn), 7.88 (1H, in), 7.96 (1H, 7.98 (1H, d, J=8Hz), 8.09 (1H, 8.23 (1H, di, J=8Hz) 1- (2-Chlorobenzyl) -3-forinyl-2-propyl-N- yl) indole-6-carboxanide mp 275'C (dec.) NMR (DMSO-d 6 5) :0.90 (3H, t, J=7Hz), 1.54 (2H, in), 3.13 (2H, t, J=7Hz), 5.69 (2H, 6.38 (1H, d, J=8Hz), 7.19 (1H, t, J=8Hz), 7.33 (1H, t, J=8HZ), 7.60 (1H, d, J=8Kz), 8.03 (1H, d, J8BHz), 8.31 (1H, 8.32 (1H, di, J=8Hz), >10 (1H, s) WO 96/32379 PCT/JP96/00892 100 Example 23 1-Hydroxybenzotriazole (68 mg) and 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg) were added to a solution of l-(2-chlorobenzyl)-3isobutyryl-2-propylindole-6-carboxylic acid (100 mg) in dimethylformamide (3 ml), and the mixture was stirred at overnight, then hydroxylamine hydrochloride (35 mg) and diisopropylethylamine (0.088 ml) were added. After stirred at 20 0 C for 2 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with 1N hydrochloric acid and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by preparative thin layer chromatography with 10% methanol in chloroform and recrystallization from ethyl acetate to give 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6carbohydroxamic acid (67 mg) as pale red crystals.

mp 185-186°C NMR (CDC1 3 5) 1.00 (3H, t, J=8Hz), 1.28 (6H, d, J=8Hz), 1.60 (2H, sextet, J=8Hz), 3.02-3.06 (2H, 3.53 (2H, septet, J=8Hz), 5.47 (2H, 6.20 (1H, dd, J=l, 8Hz), 7.03 (1H, t, J=8Hz), 7.20 (1H, t, J=8Hz), 7.46 (1H, d, J=8Hz), 7.57 (1H, d, J=8Hz), 7.77 (1H, 7.97 (1H, d, J=8Hz) Example 24 The following compounds described in 1) to 2) were prepared by reacting the compound obtained in Example and a suitable amine (IV) in a similar manner to that of Example 23.

1-(2-Chlorobenzyl)-3-isobutyryl-O-methyl-2-propylindole- 6-carbohydroxamic acid NMR (CDC1 3 5) 1.00 (3H, t, J=8Hz), 1.30 (6H, d, J=8Hz), 1.54-1.66 (2H, 3.00-3.06 (2H, 3.53 (1H, septet, J=8Hz), 3.86 (3H, 5.49 (2H, s), WO 96/32379 WO 9632379PCT/JP96/00892 101 6.22 (1H, dd, J=1, 8Hz), 7.03 (1H, dt, J=1, 8Hz),' 7.23 (1H, dt, J=1, 8Hz), 7.46 (1H, dd, 8Hz), 7.56 (1H, cid, J=1, 8Hz), 7.75 (1H, d, J=lHz), 7.96 (1H, d, J=8Hz), 8.82 (1H, s) 1- (2-Chlorobenzyl)-3-isobutyl-2-propyl-N- (2pyridylinethyl) indole-6-carboxanide NMR (CDC1 3 :1.00 (3H, t, J=8Hz), 1.30 (6H, di, J=8Hz), 1.62 (2H, sextet, J=8Hz), 3.03-3.07 (2H, mn), 3.57 (1H, septet, J=8Hz), 4.66 (2H, di, J=6Hz), 5.50 (2H, 6.24 (1H, dci, 8Hz), 7.02 (1H, dt, J=1, 8Hz), 7.18-7.24 (2H, in), 7.33 (1H, di, J=8Hz), 7.45 (1H, di, J=8Hz), 7.62-7.68 (21, mn), 7.72 (1H, dd, J=l, 8Hz), 7.88 (1H, d, J=lHz), 7.98 (1H, di, J=BHz), 8.56 (1H, di, J=6Hz) Examiple The following compounis describei in 1) to 2) were prepared by reacting the compound (II) obtained in Preparation 8 and a suitable halide (III) in a similar manner to that of Examp~le 1.

1- (4-Chloro-2-fluorobenzyl)--3-isobutyryl-2-propylindole- 6-carboxamide mp :200-202*C IR :3380, 3195, 1650, 1620 crrJ 1 NMR (CDCl 3 5) :1.03 (3H, t, J=7Hz), 1.30 (6H, di, J=7Hz), 1.52-1.65 (2H, in), 3.06-3.10 (2H, in), 3.49- 3.59 (1H, in), 5.47 (2H, 6.34 (1H, cicd, J=8, 8, 1Hz), 6.94 (1K, dci, J=8, 1Hz), 7.19 (1K, ci, J=8Hz), 7.60 (1H, ci, J=8Hz), 7.89 (1H, 7.97 (1H, ci, J=8Hz) MASS 415 76 (bp) 3-Isobutyryl- (2-methoxycarbonylbenzyl) -2-propylindole-6- WO 96/32379 WO 9632379PCT/J1P96/00892 102 carboxamide mp :170-172*C :3420, 1720, 1650 cm'i NM?. (ODC1 3 5) :1.00 (3K, t, J=7Hz), 1.33 d, J=7Hz), 1.56-1.69 (2H, Qn, 3.00-3.06 (2H, Qn, 3.54- 3.63 (KH, in), 4.02 (3K, 5.91 (2H, 6.69 (1H, d, J=7.SHz), 7.24-7.36 mn), 7.63 (1H, dd, J=8, 1Hz), 7.80 (1H, 7.99 (1H, d, J=8Hz), 8.12-8.16 m) MASS 421 Example 26 A mixture of 3 -isobutyryl-2-propylindole- 6-carboxamide (100 mg), 4-chlorobenzyl bromide (113 mng) and potassium carbonate (152 mg) in dimethylformanide (2 ml) was heated at for 2 hours, and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was crystallized from a mixture of ethyl acetate and hexane. The crude crystals were recrystallized fromn a mixture of ethyl acetate and hexane to give 1-(4chlorobenzyl) 3 -isobutyryi-2-propylindole-6-carboxamide (97 mng) as colorless crystals.

mp 183-184*C NM?. (ODCd 3 5) 1.01 (3H1, t, J=7Hz), 1.29 (6H, d, j=7Kz), 1.50-1.64 (2H, in), 3.06-3.12 (2H, in), 3.55 (2H, septet, j=7Hz), 5.42 (2H, 6.87 (2H, d, J=8Hz), 7.25 (2H, d, J=8Hz), 7.60 (1H, dd, J=l, 8H), 7.87 (1K, d, J=lHz), 7.95 (1H, d, j=8Hz) Exancle 27 The following compounds described in 1) to 8) were prepared by reacting the compound obtained in Preparation 8 or Preparation 15 and a suitable halide (III) in a similar manner to that of Exainle 26.

WO 96/32379 PCTIJP96/00892 103 1-Benzvl-3-isobutvryl-2-propylindole-6-c mp 164-166 0

C

NMR (CDC1 3 1.00 (3H, t, J=7Hz), 1.29 (6H, d, J=7Hz), 1.60 (2K, sextet, J=7Hz), 3.09-3.13 (2H, 3.55 (2K, septet, J=7Hz), 5.46 (2H, s), 6.96-6.98 (2H, 7.24-7.32 (2H, 7.61 (1H, d, J=8Hz), 7.91 (1H, 7.95 (1H, d, Ju8Hz) 1-(3-Chlorobenzyl)-3-isobutyry-2-propy1dole6 carboxamide rnp 164-166 0

C

NMR (CDC1 3 5) 1.00 (3H, t, J=7Hz), 1.30 (6H, d, J=7Kz), 1.50-1.65 (2H, 3.06-3.12 (2K, 3.55 (2H, septet, J=7Hz), 5.42 (2H, 6.78 (1H, dd, J=1, 8Hz), 6.96 (1K, d, J=IHz), 7.18-7.27 (2K, m), 7.60 (1H, d, J=8Kz), 7.88 (1H, 7.95 (1H, d, J=8Hz) 3 -Isobutyry-2-propyl-1 2 -tr'i-fuoroiethylbenzyl)incoe 6-carboxamide mp 86-87'C NMR (CDC1 3 5) 0.99 (3H, t, J=7Kz), 1.30 (6H, d, J=7Hz), 1.52-1.65 (2H, 2.98-3.04 (2K, in), 3.56 (2H, septet, J=7Kz), 5.62 (2K, 6.33 (1K, d, J=8Kz), 7.30 (1K, T, J=1Kz), 7.38 (1H, t, J=1Kz), 7.64 (1H, d, J=8z), 7.75 (1H, d, J=8Kz), 7.84 (1H, 7.98 (1H, d, J=8Kz) 3-Isobutvryl-l-( 2 -phenyibenzvl)-2-propylinoie-6carboxaide mp 162-1640C NMR (CDC1 3 5) 0.89 (3H, t, J=7Kz), 1.27 (6K, d, J=71Kz), 1.36-1.50 (2H, 2.90-2.96 (2H, 3.53 (2K, septet, J=7Kz), 5.32 (2K, 6.48 (1H, d, J=8Hz), 7.10-7.16 (1H, rn), 7.30-7.34 (2H, 7.42- WO 96/32379 PCT1JP96100892 104 7.84 (3H, in), 7.52-7.55 (2H, in), 7.60 (1H, d, J=8Hz), 7.84 (1H, 7.93 (1H, d, J=8Kz) 1-[(5-Chlorothien-2-yl)iethyll-3-isobutyryl-2propylindole-6-carboxamide mp 178-180*C NMR (CDC1 3 6) 1.07 (3H, t, J=7Hz), 1.27 (6H, d, J=7Hz), 1.65 (2H, sextet, J=7Hz), 3.15-3.20 (2H, 3.54 (2H, septet, J=7Hz), 5.46 (2H, 6.59 (1H, d, J=2Hz), 6.72 (2H, d, J=2Hz), 7.60 d, J=8Hz), 7.92 (1H, d, J=8Hz), 8.04 (1H, s) 3 -Isobutyryl-l-phenethyl-2-propylindole-6-carboxamide mp 180-181*C NMR (CDC13, 6) 1.02 (3H, t, J=7Hz), 1.26 (6H, d, J=7Hz), 1.61 (21, septet, J=7Hz), 2.88-2.92 (2H, 3.10 (2H, t, J=7Hz), 3.52 (2H, septet, J=7Hz), 4.42 (2H, t, J=7Hz), 7.05-7.09 (21, 7.22-7.32 (3H, 7.52 (1H, d, J=8Hz), 7.92 (1H, d, J=8Hz), 7.96 (1H, s) 1-(2-Chlorobenzyl)-3-iethoxyacetyl-2-propylindole-6carboxaide mp 165-167C NMR (DMSO-d 6 6) 0.92 (3H, t, J=8Hz), 1.46 (2H, sextet, J=8Hz), 3.01-3.05 (2H, 3.42 (3H, s), 4.68 (2H, 5.62 (2H, 6.22 (1H, d, J=8Hz), 7.16 (1H, t, J=8Hz), 7.28 (1H, br 7.32 (1H, t, J=8Hz), 7.56 (1H, d, J=8Hz), 7.92 (1H, d, J=8Kz), 7.93 (1H, br 8.01 (1H, s) 1-(6-Chloro-3,4-iethyleredioxybenzyl)-3-methoxyacetyl-2propylindole-6-carboxaiide mp 204-206'C NMR (DMSO-d 6 6) 0.95 (3H, t, J=8Kz), 1.50 (2H, WO 96/32379 WO 9632379PCT/JP96/00892 105 sextet, J=8Hz), 3.02-3.06 (2H, Wn, 3.40 (3H, s), 4.70 (2H, 5.51 (1H, 5.98 (2K, 7.23 (1H, 7.32 (1H, br 7.80 (1H, d, J=8Hz), 7.93 (1K, d, J=8Hz), 7.96 (1H, br 8.02 (1H, s) Exampole 28 The following compounds described in 1) to 16) were prepared by reacting the compound (II) obtained in Preparation 2, Preparation 6 Preparation 9, Preparation 10, Preparation 12, Preparation 13 or Preparation 14 and a suitable halide (III) in a similar manner to that of Exampole Methyl 1- (2-fluorobenzyl) 3 -isobutyryl-2-propylindole-6carboxylate mp :120-121.5'C TR :1710, 1700, 1660 cm- 1 NMR (ODC 3 5) :1.02 (3H, r, J=7Hz), 1.29 (6H, d, j=7Hz), 1.55-1.64 O2H, mn), 3.06-3.12 (2K, in), 3.51- 3.61 (1H, mn), 3.92 (3K, 5.50 (2H, 6.43 (1H, 6.95 (1H, t, j=7Hz), 7.10-7.17 (1H, in), 7.22-7.28 (1H, in), 7.95 (2H, 8.02 (1H, s) MASS :396 (M4-f1), 76 (bp) Merhy! 1- 2 -broinobenzy)-3-isobutyryl-2-propylindole.6carboxylate mp :90-92'C :1705, 1650 cmi 1 NMR (ODCd 3 5) :1.02 (3H, t, J=7Kz), 1.30 (6H, d, J=7Kz), 1.56-1.67 (2H, mn), 3.04 (2H, t, J=7Kz), 3.52-3.61 KH, in), 3.93 (3H, 5.47 (2H, 6.20 (1H, t, J=7.5Hz), 7.06-7.18 (2K, in), 7.65 (1H, t, 7.95 (1K, 7.97 (2K, s) MASS (in/z) :458 (M 458 (M 41), 76 (bp) WO 96/32379 PCT/JP96/00892 106 Methyl 1- 2 -iodobenzy1)-3-isobutyryl-2-propylindole6 carboxylate IR (KBr) 1710, 1650, 1430 cm-1 NMR (CDC1 3 6) 1.03 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.53-1.67 (2H, 2.98-3.05 (2H, 3.53- 3.62 (1H, ro), 3.93 (3H, 5.37 (2H, 6.16 (1H, t, J=7.5Kz), 6.99 t, J=7.SHz), 7.12 (1H, t, 7.90-7.97 (4H, m) MASS 504 1) Methyl 3-isobutyryl- -(2-iethvlbenzyl)-2-propylindole-6carboxvlate MIp 99-1020C !R (KBr) 1705, 1650, 1285 cm-i 1 NNR (CD01 3 6) 1.00 (3H, t, j=7Hz), 1.30 (6H, d, J=7Kz), 1.54-1.69 (2K, 2.50 (3H, 3.00-3.06 (2H, 3.51-3.65 (1H, 3.89 (3H, 5.39 (2H, 6.17 (1K, t, J=7.Hz), 6.98 (1H, t, 7.18 (1H, t, J=7.5Hz), 7.25 (1H, d, J=7.5Hz), 7.92 (1K, 7.96 (2H, s) MvA S S 392 (M+l) Methyl 3-isobutvryl-l-(2-methoxybenzyi)-2-propylindole- 6-carboxylate 'up 103-105'C IR 1710, 1650 c' 1 hT'R (CDC1 3 6) 1.01 (3H, J=7Hz), 1.30 (6H, d, J=7Hz), 1.56-1.68 (2K, ir), 3.05-3.10 (2K, 3.53- 3.62 (iN, 3.90 (3H, 3.98 (3H, 5.44 (2H, 6.27 (1H, d, J=7.5Hz), 6.74 (1H, t, 6.94 (1H, d, J=7.5Hz), 7.25 (1H, t, J=7.5Kz), 7.95 (2H, 8.00 (1H, d, MASS r/z) 408 (Mi+l) 76 (bp) Methyl 1-( 2 -cyanoberzyl)-3-isobutyryl-2-propylindole-6- WO 96/32379 PCT/JP96/00892 107 carboxylate rp 159-1610C IR 2220, 1730, 1660 cm-i NMR (CDC1 3 5) 1.04 (31, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.52-1.65 (2H, 3.03-3.08 (2H, in), 3.53- 3.60 (1H, 3.92 (3H, 5.66 (2H, 6.44-6.49 (11, 7.38-7.43 (2H, 7.76-7.80 (1H, 7.95 (1H, 7.98 (2H, s) MFASS 403 76 lbp) Methyl 3-isobutyryl-1-( 2 -nitrobenzyl)-2-ropylindole-6 carboxylate ID 165.5-166.5 C IR (KBr) 1705, 1650, 1530, 1520 cm- 1 NMR (ODC1 3 5) 1.00 (31, t, J=7Hz), 1.31 (6H, d, J=7Hz), 1.56-1.65 (2H1, 3.03 (2H, t, J=7Hz), 3.54-3.65 (1H, 3.90 (31, 5.89 (21, 6.27 (11, d, J=7.5Hz), 7.40-7.51 (2H, 7.89 (11, s), 9.00 (2H, 8.30 (11, d, MASS 423 1) 76 (bp) Methyl 6-dichlorobenzvl)-3-±sobutyryl--2 propylindole-E-carboxylate mI !29.5-1320C IR 1710, 1660, 1430- cm- 1 NMR (CDC1 3 5) 0.96 (311, t, J=7Hz), 1.27 (6H, d, J=7Hz), 1.39-1.50 (21, 3.15-3.20 (2H, 3.47- 3.60 (11, 3.92 (3H, 5.70 (2H, 7.17-7.39 (3H, 7.88 (2H, 8.03 (1H1, s) MA.SS 446 (M+1) Methyl 1-( 2 -chloro-4-florobenzyl)-3-isobuyryl12 propylndole-6-carboxylate mp 140-141CC TR (KBr) 1705, 1649, 1488, 1279 c-nT WO 96/32379 WO 9632379PCT/J1P96/00892 108 NMR (CDCl 3 5 1.03 (3H, t, J=7Hz), 1.40 (6H, d, J=7Hz), 1.52-1.66 (2H, in), 3.01-3.06 (2H, mn), 3.52- 3.60 (1H, mn), 3.93 (3H, 5.48 (2H, 6.20-6.25 mn), 6.79 (1H, ddd, J=7.5, 7.5, 1Hz), 7.21-7.25 (1K, mn), 7.94 (1H, 7.97 (2H, s) MASS (in/z) :430 76 (bp) Methyl 1- (4-broio-2-fluorobenzyl) -3-isobutyryl-2propvlindole- 6-carboxylate TR :1705, 1649, 1488, 1279 cnf 1 NMR (CDCI 3 5 1.03 (3H, t, J=7Hz), 1.29 (6H, di, J7H) 1.316m2,i), 3.05-3.10 (2H, mn), 3.51- 3.60 (1K, in), 3.94 (3H, 5.44 (2H, 6.28 (1K, J=7.SHz), 7.10 (1H, dci, J=7.5, 1Hz), 7.35 (1H, a, J=7.5Hz), 7.96 (1H, s) MllAS S (in/z) :4 76 4 74 7 6 (bp) (11) Methyl1 3-benzoyl-1- (2-chlorobenzyl) -2-propylindole-6carboxylate NM?. (CDCl 3 5) 0.94 (3H, t, j=8Hz), 1.56-1.70 (2K, 2.93-2.98 (2K, in), 3.87 (3H, 5.55 (2H, s), 6.33 (1H, ddd, J~1, 8Kz), 7.08 (1H, cit, J=l, 8Kz), 7.(1H, d, J=8Kz), 7.22-7.28 (1H, in), 7.46-7.52 (31, in), 7.57-7.63 (1K, in), 7.72-7.82 (3K, mn), 7.93 (1141, d, J=lKz) (12) Methyl 1- 2 -chlorobenzy1)-3-cyano-2-propyli-nioe-6carboxylate xnD '32-1330C (KBr) :2215, 1709, 1284 cm-1

(CDCI

3 5) :1.01 (3H, t, J=7Kz), 1.70 (2K, sextet, J=7Hz), 2.89 (2H, t, J=7.5Kz), 3.92 (3H, 5.49 (2H, 16.24 (1K, di, J=7.SHz), 7.08 (1H, J=7.5Hz), 7.22-7.28 (1H, mn), 7.47 (1H, di, WO 96/32379 PCT1JP96/00892 109 7.77 (11, d, J=7.5Hz), 7.95-8.o (2H, m) MLALSS (mn/z) 367 76 (bp) (13) Methyl 1-( 2 -chlorobenzyi)- 2 ethyl-3-isobutvrylindole 6 carboxylate NTR (CDC1 3 5) 1.22 (3H, r, J=7Hz), 1.31 (6H, d, J7=7Hz), 3.08 (2H, a, J=7Hz), 3.56 (1H, 3.91 (3H, 5.50 (2H, 6.23 (1K, d, J=8Hz), 7.04 (1H, t, J=8Hz), 7.22 (1K, c, J=8Hz), 7.46 (1H, d, J=8Hz), 7.93-7.98 (3H, m) (14) Methyl 1-( 2 -chlorobenzyl)-3-isobutry1-2-methylindole...

carboxvlate NNR (CDCI 3 6) 1.32 (6H, d, J=7Hz), 2.71 (3H, s), 3.56 (1H, 3.92 (3H, 5.52 (2H, 6.24 (1H, d, J=8Hz), 7.05 (1H, t, J=8z), 7.23 (1H, t, J=8Kz), 7.46 d, J=8Hz), 7.92-8.05 (3H, in) Methyl 1-(2-chlorobenzyl)- 3 -isobutyrvl-2methoxvmethylindole-6-carboxlate NYR (ODC1 3 6) 1.29 (6H, d, J=7Hz), 3.31 (3H, s), 3.55 (1K, mn), 3.89 (3H, 4.91 (2H, 5.63 (2H, 6.23 (1H, 6, J=8Hz), 7.02 (1H, J=8Hz), 7.19 (1H, t, J=8Hz), 7.44 (1K, d, J=8Hz), 7.95-8.02 (3H, n) (16) Methyl 1-(2-chLorobenzyl) 3 -isobutyrylindole-6carboxvate NMR (CD-13, 6) 1.26 (6H, d, J=7Hz), 3.28 (1H, in), 3.93 (3H, 5.52 (2H, 6.77 (1H, d, J=8Kz), 7.18 t, J=8Hz), 7.29 (1K, t, J=8Hz), 7.48 (1H, d, J=8Hz), 7.89 (1K, 8.02 (1H, d, J=8Hz), 8.10 (1K, 8.49 (1K, d, J=8Hz) Examinle 29

I

WO 96/32379 PCT/JP96/00892 110 The following compounds described in 1) to 2) were prepared from the compound (II) obtained in Preparation 1 and Preparation 2 in a similar manner to that of Example 26.

Methyl 3 -isobutyryl-2-propy-1-(2-pyridylmethyl)indole- O6carboxylate NMR (CDCl 3 6) 1.01 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 2.60 (2H, sextet, J=7Hz), 3.12-3.16 (2H, 3.56 (2H, septet, J=7Hz), 3.90 (3H, 5.58 (2H, 6.58 (1H, d, J=8Hz), 7.22 (1H, dd, 8Hz), 7.55 (1H, dt, J=1, 8Hz), 7.94 (2H, 8.02 (1H, 8.63 (1H, dd, J=1, Methyl 3 -acetyi-l-r6 chloro-3, 4-methylenedioxybenzyl)-2- Propylindole G6carboxylate p 210-2120C NMR (CDC13 6) 1.04 (31H, t, J=7Hz), 1.63 (2H, sextet, J=7Hz), 2.37 (3H, 3.04-308 (2H, m), 3.92 (3H1, 5.40 (2H, 5.70 5.90 (2H, 6.92 (1H, 7.95 (1H, s5), 7.97 (1H, d, J=8Hz), 8.04 (1H, d, J=8Hz) Examole To a solution of methyl 3 -acetyI-(2chlorobenzyl)-2ethylindole-6-carboxylate (110 g) in tetrahylrofuran (5 m) was added 1M solution of boran in tetrahydrofuran (0.6 mi) in one portion at 0"C. The oran in tetrahydofuran (0.6 ml) in one portion at 00c The mixture was stirred at 200C for 1 hour, then quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnes sulfate and evaporated in vacuo. The residue was chromaographed on silica gel eluting with a mixture of hexane and ethyl acetate to give methyl 1-(2chlorobenzyl)-2,3-diethylindole-6-carboxylate (42 mg) as colorless crystals.

mp 86-880C

I

WO 96/32379 WO 9632379PCT/JP96/00892 ill i R (KB r) 1710, 1240 cm-1 MR (CDCd 3 5) :1.13 (3H, t, J=7Hz), 1.30 (3H, t, J=7Kz), 2.69 (2H, t, J=7Hz), 2.79 (2H, q, J=7Kz), 3.90 (3H, 5.44 (2H, 6.17 (1K, J=8Hz), 7.00 (1H, t, J=8Hz), 7.19 (1H, t, J=8Hz), 7.42 (1H, d, J=7.5Kz), 7.60 (1K, d, J=8Hz), 7.80 (1H, d., j=8Hz), 7.88 (1K, s) MASS 356 AM 4l) ExarnDle 31.

Methyl 1- (2-chlorobenzyl) 2 -propylindole-6-carboxylate (400 mg) was prepared from methyl 2 -propylindole-6carboxylate (350 mg) and 2-chlorobenzyl bromide (364 mg) irn a similar manner to that of Example 1.

MR (CDC1 3 5) :0.99 (3H, t, J=8Hz), 1.74 (2H, sextet, J=8Hz), 2.60 (2H, t, J=8Hz), 3.87 (3H, s), 5.43 (2H, 6.16 d, J=8Hz), 6.43 (1H, 7.00 (1H, t, J=SKz), 7.18 (1H, t, J=8Kz), 7.43 (1H, d, J=8Kz), 7.60 (1H, d, J=8Hz), 7.80 (1K, d, J=8Hz), 7.90 (1H, s) Examnle 32 To a stirred solution of dimethylformamide (3 ml) and phosphorus oxychloride (0.056 ml1) was added methyl 2propylindole-6-carboxylate (187 mg), and the mixture was stirred at 000 for 20 minutes. The resulting mixture was poured into ammonia water (3 and extracted with ethyl acetate. The combined organic phase was washed with brine, then dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel to give methyl 1- (2-chlorobenzyl) 3fry--rplndl--abxlt (153 mg) as colorless oil.

MR (CDC1 3 5) :1.00 (3K, t, J=7Kz), 1.66 (2H, i) 3.01 (2H, t. J=7Hz), 3.90 (3K, 5.48 (2K, s), 6.29 (1K, d, J=8Kz), 7.06 (1H, t, j=BKz), 7.24 (1H, WO 96/32379 WO 9632379PCT/JP96/00892 112 t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.91 (1H, 8.01 (1H, d, J=8Hz) 8.37 (1H, d, J=8Hz) >10 (1Hi, s) Exam-ple 33 Methyl 1- (2-chlorobenzyl) -3-phenylacetyl-2-propylindole- 6-carboxylate (230 mg) was prepared from methyl 1-(2chlorobenzyl)-2-propylindole-6-carboxylate (380 mg) and phenylacetyl chloride (189 mg) in a similar manner to that of Preparation 1 NMR (CDCl 3 5) :0.97 (3H, t, J=8Hz), 1.55-1.67 (2H, in), 3.02-3.07 (2H, mn), 3.91 (3H, 4.42 (2H. s), 5.52 (2H, 6.24 (1H, d, J=8Hz), 7.05 (1H, t, J=8Hz), 7.20-7.40 (6H1, mn), 7.46 (1H1, d, J=8Hz), 7.97 (iH, 7.99 (1H, d, J=8Hz), 8.11 (1H, d, J=8Hz) Examip1e 34 The following compounds described in 1) to 21) were prepared from the compound obtained in Example 28, Example 29, Example 30, Example 32 or Example 33 in a similar manner to that of Examnple 2.

1- (2-Fluorobenzyl) -3-isobutyryl-2-propylindole-6carboxylic acid mp :212-213*C IR (KBr) :1685, 1650 cm- 1 NMR (ODC1 3 5) :1.03 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.55-1.68 (2H, in), 3.09-3.14 (2H, in), 3.52- 3.62 (1H, in), 5.50 (2H, 6.47 (1H, t, 6.97 (1H, t, J=7.5Hz), 7.15 (1H, t, J=7.5Hz), 7.24- 7.30 (1H, in), 7.95-8.04 (2H, in), 8.08 (1H, s) MASS 380 1- (2-Bromobenzyl) -3-isobutyryl-2-propylindole-6carboxylic acid WO 96/32379 PCT/JP96/00892 113 m P 193-19400 IR (Kar) 1690, 1670 cm- NMR (CD01 3 5) 1.03 (3H, t, J=7Hz), 1.31 (6H, d, J=7Hz), 1.57-1.65 (2i, 3.01-3.07 (2H, 3.52- 3.61 (1H, 5.49 (2H, 6.22 (1H, t, 7.07-7.18 (2H, 7.66 (1K, t, J=7.5Hz), 7.97-8.01 (3K, in) MASS (in/z) 442 440 1-( 2 -Iodobenzyl)-3-isobutyryl-2-propylinole6carboxylic acid Mp 21000 IR (KEr) 1710, 1640, 1435, 1200 cm- 1 NMR (CDC1 3 5) 1.04 (3H, t, J=7Hz), 1.31 (6H, d, J=7Kz), 1.55-1.68 (2H, 3.00-3.06 (2K, 3.53- 3.62 (1K, 5.38 (2K, 6.18 (1K, d, 6.99 (1H, t, J=7.5Hz), 7.14 (1K, t, J=7.5Kz), 7.94 (1H, d, J=7.5Kz), 7.97-8.03 (3H, m) AS S 488 61 (bp) 3-Isobuyryl-l-(2-iethylberzyl)- 2 -propylindole-6carboxvlic acid p :186-188oC IR (KBr) 1690 cm- N~IR (CDC1 3 1.01 (3H, t, J=7Hz), 1.31 (6K, d, J=7Hz), 1.56-1.69 (2K, 2.50 (3H, 3.02-3.09 (2K, 3.52-3.67 (1H, 5.39 (2K, 6.17 (1H, d, J=7.5Kz), 6.98 (1H, t, J=7.5Kz), 7.17 (1H, r, 7.25 (1H, d, .5Hz), 7.97 (1H, 8.00 (2H, s) MASS (ri/ z) 378 76 (bp) 3-Isobutyryl-1-(2-iethoxvbenzyl)- 2 -ropylindole-6crboxviic acid i 190-1910C WO 96/32379 PCT/JP96100892 114 IR (Kr) 1685, 1650, 1250 cin' NMR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.30 d, J=7Hz), 1.58-1.68 (2H, 3.07-3.13 (2H, 3.54- 3.63 (1H, 3.98 (3H, 5.45 (2H, 6.30 (1H, d, J=7.5Hz), 6.75 (IH, t, J=7.5Hz), 6.94 (1H, d, 7.24 (1H, t, J=7.5Kz), 7.94-8.02 (2H, m), 8.05 (1H, s) MASS 394 76 (bp) 1-( 2 -Oyanobenzyi)-3-isobutyryl-2-propylindole.6carboxylic acid np 213.5-215C IR (KBr) 2220, 1717 cmn 1 NNR (CDC13, 5) 1.04 (3H, t, J=7Hz), 1.31 (6K, d, J=7z), 1.53-1.67 (2H, 3.04-3.09 (2H, 3.52- 3.62 (1H, 5.69 (2H, 6.47-6.50 (1H, i), 7.39-7.44 (2H, 7.77-7.80 (1K, 7.99-8.04 (3H, m) MASS 389 76 (bp) 3 -Isobutyryl-l-( 2 -nitrobenzyl)- 2 -propylindole-6carboxylic acid mp 214-215'C IR (KBr) 1695, 1655, 1545 cin 1 NMR (CDC1 3 5) 1.02 (3H, t, J=7Kz), 1.32 (6H, d, J=7Kz), 1.57-1.65 (2K, 3.03 (2H, t, J=7Hz), 3.54-3.63 (1H, 5.89 (2H, 6.28 (1H, d, 7.39-7.51 (2H, 7.92 (1H, 8.02 (2H, 8.30 d, MAkSS 409 (MS+1) 1- (2,6-Dichlorobenzvl) 3 -isobutyryl-2-Dropyiindole6 carboxylic acid inp 241.5-243'C (dec.) IR (KBr) 1675, 1650 cm WO 96/32379 PCT/JP96/00892 115 NNTR (CDC1J, 0.99 (3H, t, J=7Hz), 1.28 (6H, d, J=7Hz), 1.39-1.52 (2H, 3.17-3.22 (2H, in), 3.50- 3.59 (1H, 5.71 (2H, 7.24-7.28 (1H, i), 7.37-7.40 (2H, 7.94 (2H, q, J=7.5Hz), 8.10 (1K, s) MASS 432 76 (bp) 1- 2 -Chloro-4-Fluorobenzyb)-3-isobutyryl-2-propylindoie- 6'carboxylic acid mp 243-244'C IR (KBr) 1676, 1648, 1491 cin 1 NYR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.30 (6H, d, j=7Hz), 1.60 (2H, sextet, J=7Hz), 3.01-3.07 (2H, in), 3.53-3.62 (1H, 5.49 (2H, 6.20-6.26 (1H, in), 6.79 (1H, ddd, J=7.5, 7.5, lz), 7.23 (1H, dd, lz), 7.96 (1H, 7.99 (1H, d, MASS 414 1-( 4 -Broio-2-fluoroberzyl) -3-isobutyryl-2-propylindole- 6-carboxylic acid rnp 210-211cc I? 1677, 1646, 1486 cin 1 NY?. (CD01 3 5) 1.04 (3H, t, J=7Hz), 1.30 d, J=7Hz), 1.55-1.67 (2K, 3.07-3.12 (2H, 3.52- 3.60 (1K, 5.46 (2H, 6.32 (1K, t, 7.11 (1H, d, J=7.5Kz), 7.35 (1H, d, J=7.5Hz), 7.96- 8.03 (3H, m).

MASS (rn/z) 460 458 (11) 3-Benzoyi h-(2-chlorobenzva-2-propylindole-6-carboxylic acid NMR (DMSO-d 6 5) 0.95 (3K, t, J=8Kz), 1.66 (2H, sextet, J=8Hz), 2.98 (2H, t, j=8Kz), 5.55 (2H, s), 6.35 (1K, dd, J1, 8Hz), 7.09 (1K, dt, J=l, 8Hz), 7.20-7.27 (2K, 7.48 (1H, t, J=8Hz), 7.57-7.62 WO 96/32379 PCTIJP96/00892 116 i, 7.72-7.82 (3H, 7.98 (1H, s) (12) 1-( 2 -Chlorobenzyl)-3-cyano-2-propylindole-6-carboxylic acid rnp 239.5-2410C IR (Kr) 2224, 1671, 1287, 1264 cn 1 NMR (DC1 3 6) 1.00 (3H, t, J=7Hz), 1.70 (2H, sextez, J=7Hz), 2.89 (2H, t, J=7Hz), 5.50 (2H, s), 6.25 (1H, d, J=7.5Hz), 7.18 (1H, ddt, J=7.5, 1Hz), 7.25 (iN, ddd, J=7.5, 7.5, 1Hz), 7.47 (1H, d, 7.SHz), 7.78 (1H, dd, J=7.5, 1Hz), 7.99 d, 8.01 (1H, d, MASS (rn/z) 351 (13) 1-( 2 -Chlorobenzyl) -2-ethyl-3-isobutyryindole.6carboxypic acid NMR (CD1 3 6) 1.22 (3H, t, J=7Hz), 1.31 (6H, d, J=7Hz), 3.12 (2H, q, J=7Hz), 3.57 (1H, 5.51 (2H, 6.23 (1H, d, J=8Hz), 7.04 (1H, t, J=8Hz), 7.22 (iN, t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.95-8.05 (3H, m) (14) 1-( 2 -Chiorobenzyl)-3-isobutyryl-2-nethyliole 6 carboxylic acid NMR (CDC1 3 6) 1.31 (6H, d, J=7Hz), 2.72 (3H, s), 3.56 (1N, 5.51 (2H, 6.25 (1H, c, J=8Hz), 7.05 (1H, t, J=8Hz), 7.23 (iN, J=8Hz), 7.46 (1H, d, J=8Hz), 8.05 (3H, s) (15) 1- 2 -COhlcorobenzyl) -3-isobutyr-2-me. e:oxvm ethylindiG-6carboxviic acid -NMP (CDC1 3 6) 1.32 (6HE, d, J=7Hz), 3.35 (3H, s), 3.58 (1H, 4.94 (2H, 5.68 (2H, 6.28 (1H, c, J=8Hz), 7.03 (1H, r, J=8Hz), 7.20 (1H, t, Jr=8Hz), 7.45 (1H, c, J=8Hz), 8.0-8.05 (3H, m) WO 96/32379 PCTIJP96/00892 117 (16) 1-(2-Chlorobenzyl)-3-isbutyryincole-6-carboxylic acid NMR (CDO1 3 5) 1.25 (6H, d, J=7Hz), 3.30 (1H, i), 5.52 (2H, 6.79 (1H, d, J=8Hz), 7.18 (1H, t, J=8Hz), 7.28 (1K, t, J=8Hz), 7.47 (1K, d, J=8Hz), 7.91 (1H, 8.03 (1K, d, J=8Hz), 8.12 (1H, s), 8.48 (1H, d, J=8Hz) (17) 3 -Isobutyryl-2-propyl-l-(2-pyridylmethyl)indole-6carboxvlic acid NM?. (DMSO-d 6 5) 0.92 (3H, r, J=7Kz), 1.16 (6H, d, J=7Hz), 1.46 (2H, sextet, J=7Hz), 3.12-3.17 (2H, in), 3.52 (2H, septet, J=7Hz), 5.72 (2H, 7.16 (1H, d, j=8Hz), 7.29 (1H, dc, J=5, 8Hz), 7.76 (1H, t, J=8Hz), 7.81 (1K, d, J=8Hz), 7.96 (1H, t, J=8Kz), 8.06 (1H, 8.48 (1H, d, (18) 1-(2-Chlorobenzyl)-2,3-diethyidole-6-carboxyic acid MID :258-259oC (dec.) IR (KBr) 1675, 1290 cm- 1 NMR (CDC1 3 5) 1.14 (3H, t, J=7Hz), 1.30 (3H, t, J=7Hz), 2.71 (2H, q, J=7Hz), 2.80 (2H, q, J=7Hz), 5.45 (2H, 6.18 (1H, d, J=7.5Kz), 7.00 (1H, t, 7.19 (1K, t, J=7.5Hz), 7.42 (1K, d, 7.62 (1K, c, JU7.5Hz), 7.84 (1H, d, J=7.5Kz), 7.91 (1K, s) MASS (rn/z) 340 (19) (2-Chlorobenzyl)-3- ormyl-2- ro y-d 6c x acid NY. (Od 3 5) 1.01 (3H, t, J=7Hz), 1.67 (2K, m), 3.03 (2H, t, J=7Hz), 5.50 (2K, 6.40 (1H, d, J=8Kz), 7.08 (1K, t, J3Hz), 7.24 (1H, t, J=8Kz), 7.48 (1H, d, J=8Kz), 7.98 (1H, 8.07 (1K, d, J=8Hz), 18.40 (1K, d, J=8Hz) WO 96/32379 PCT/JP96/00892 118- 2 -Chlorobenzyl) -3-phenylacetyl-2-propylindoleS6carboxylic acid NMR (DMSO-d 6 5) 0.90 (3H, t, J=8Hz), 1.45 (2H, sextet, J=8Hz), 3.04-3.08 (2H, 4.43 (2H, s), 5.68 (2H, 6.27 (1H, d, J=8Hz), 7.18 (lI, t, J=8Hz), 7.23-7.35 (6H, 7.58 (1H, d, J=8Hz), 7.85 (1K, d, J=8Hz), 7.98 (1H, 8.19 (1H, d, j=8Hz) (21) 3-Acetyl-l-(6-chloro-3, 4 -methylenedioxybenzyi)-2propylindole-6-carboxyiic acid mp 238-239*C NMR (CDC1 3 -CD30D 1:1, 6) 1.06 (3H, t, J=8Hz), 1.65 (2H, sextet, J=8Hz), 2.76 (31, 3.08-3.14 (2H, 5.48 (2H, 5.74 (1H, 5.92 (2H, 6.96 (1H, 7.99 (1K, d, J=8Hz), 8.02 (1H, 8.08 (1H, d, J=8Hz) Examule Methyl 3-acetyl-l-( 2 -chlorobenzyl)- 2 -ethylindole-6carboxylate (170 mg) was prepared from methyl 3 -acetyl-2ethvlindole-6-carboxylate (100 mg) and 2 -chlorobenzyl bromide (0.06 in a similar manner to that of Example 1.

This product was used immediately without purification in the below-mentioned Examr~1e 36.

ExamnDle 36 3-Acetyl- 1- (2-chlorobenzyl) 2 -ethlindole-6-carboxvLic acid (137 ng) was prepared from methyl 3-acetyl-l-(2chlorobenzvl)-2-ethylindole-o'carboxylate (170 mg) in a similar manner to that of ExainDle 2.

NMIR (DMSO-d 6 1.11 (3H, t, J=7Hz), 2.67 (3H, s), 3.11 (2H, a, J=7Kz), 5.68 (2H, 6.26 (1H, d, j=8Hz), 7.19 (1H, t, J=8Kz), 7.32 (1H, t, J=8Hz), WO 96/32379 WO 9632379PCT/JP96/00892 119 7.58 (1H, d, J=8Hz), 7.83 (1H, d, J=BHz), 7.94 (1H, s) 8.13 (1H, d, J=8Hz) Example 37 The following compounds described in 1) to 19) were prepared from the compound obtained in Example 34 and Example 36 in a similar manner to that of Examnple 3.

1- (2-Fluorobenzyl) 3 -isobutyryl-2-propylindole-6carboxyamide mp :198 0

C

(KBr) :3200, 1650, 1610 cm- 1 NNR (CDCl 3 5) :1.03 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.55-1.64 (2H, mn), 3.06-3.12 (2H, in), 3.50- 3.60 (1H, in), 5.50 (2H, 6.42 (1H, t, 6.95 (2H, t, J=7.5Hz), 7.09-7.17 (1H, mn), 7.22-7.28 (1H, in), 7.61 (1H, t, J=7.5Hz), 7.90 7.96 (1H, t, MASS 381 (M+1) 1- 2 -Bromobenzyl)-3-isobutyryl-2-propylindole6carboxamide mp :173-174'C IR :3400, 1660, 1630 cm- 1 NMR (ODC1 3 6) :1.03 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.57-1.68 (2H, in), 3.00-3.06 (2K, mn), 3.51- 3.61 (1H, mn), 5.46 (2H, 6.20 (1H, t, 7.05-7.18 (2H, in), 7.60-7.66 (1H, in), 7.83 (1H, s), 7.99 (1H, t, MASS (in/z) :443 441 76 (bp) 1- (2-Iodobenzyl) -3-isobutyryl--2-propylindole-6carboxainide mp :186-187*C :3400, 1665, 1640 cm- 1 WO 96/32379 PCTJP96/00892 120 NMR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.54-1.67 (2H, 2.99-3.05 (2H, 3.51- 3.60 (1K, in), 5.39 (2H, 6.15 (1K, d, J=7.SHz), 6.99 (lH, J=7.5HZ', 7.11 U1H, t, J=7.5Hz), 7.64 (1K, d, J=7.5Hz), 7.82 (1H, 7.92 (1K, c, J=7Hz), 7.99 (1K, d, J=7Kz) MSS (in/z) 489 76 (bp) 3 -Isczutyryl-1-( 2 -iethylbenzyl)- 2 -propylindole6carboxamide mp 190-191C IR 3395, 1650, 1625, 1410 cmn 1 NMR (ODC1 3 5) 1.00 (3H, t, J=7Hz), 1.31 (6H, d, 7Hz), 1.54-1.68 (2H, 2.49 3.00-3.07 3.52-3.61 (1k, 5.38 (2H, 6.14 (1H, 6.98 (1H, t, J=7.5Kz), 7.17 (1H, t, 7.24 (1H, d, J=7.5Hz), 7.60 (1K, d, 7.82 (1K, 7.99 (1H, d, MASS :377 76 (bp) 3 -Iscb-tyryl-1-( 2 -mehoxybenzy1))-2..propylindoleG carboxamide ip 174-175*C IR (Kzr) 3370, 1655, 1650, 1625 cin 1 'NR (ODCd 3 5) 1.01 (3H, t, J=7Kz), 1.30 (6K, d, J7Hz), 1.57-1.69 (2H, 3.05-3.10 (2H, 3.52- 3.61 (1K, 3.97 (3H, 5.43 (2H, 6.24 (1H, a, J=7.5Hz), 6.74 (2H, t, J=7.Sz), 6.93 (1H, d, 7.24 (1K, t, J=7.5Kz), 7.59 (1H, d, 7.88 (1K, 7.97 (1H, d, MASS S 393 76 (bp) l-( 2 -Caanobenzy) 3 3 isobutyry1-2-pro ylinoie-.

carboxa ide rnp I43-1440c i WO 96/32379 PCT/JP96/00892 121 IR (KBr) 3377, 3190, 2227, 1645 cm- NMR (ODC13, 5) 1.04 (3H, t, J=7Hz), 1.30 (6H, c, J=7Hz), 1.52-1.65 (2H, 3.02-3.08 (2H, 3.50- 3.59 (1K, 5.68 (2H, 6.45-6.49 m), 7.38-7.43 (21, 7.65 (1H, d, J=7.5Hz), 7.74-7.78 (1H, 7.87 (1K, 7.99 (1H, d, MASS 388 (M 62 (bp) 3-Isobutyryl-l-( 2 -nitrobenzyl)- 2 -propylindoie-6carboxamide inp :181-1820C IR 3190, 1670, 1610, 1535, 1400 cmn 1 NY. [(CDC1 3 5) 1.00 (3H, r, J=7Hz), 1.32 (6H, d, J=7Hz), 1.58-1.67 (2H, 3.02 (2H, t, J=7Hz), 3.52-3.61 (1H, 5.89 (2H, 6.27 (1H, d, 7.39-7.50 (2H, 7.63 (11, d, 7.80 (1H, 7.99 (1K, d, J=7.5Hz), 8.28 (1H, d, MASS 408 (M 71), 76 (br) 6 -Dichlorobenzy)- 3 isobutyrv-2propylindole6 carboxamide rnp :207.5-209*C IT (KEr) 3395, 1650, 1615 cmr 1 (CDO1 3 5) 0.98 (3H, t, J=7Kz), 1.28 (6H, d, j=7Hz), 1.39-1.50 (2H, 3.16-3.21 (2H, m), 3.49-3.58 (1K, in), 5.70 7.22-7.25 (1K, i), 7.35-7.39 (2H, 7.60 (1K, d, 7.86-7.90 (2K, i, 7.99 (1K, d, MASS (mi/z) 431 76 (bo) 1- 2 -Chloro-4-fluorobezyi)-3-isobutyry1-2-propyindole- 6-carboxamide mp :192-193'C 7 KB r 3336, 3180, 1650, 1494, 1411 cin-' WO 96/32379 PCT/JP96/00892 122 NMR (CDC1 3 6) 1.03 (3M, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.53-1.65 (2H, 3.01-3.07 (2H, 3.50- 3.60 (1H, mn), 5.47 (2H, 6.20 (1H, d, J=8, 6.78 (1H, ddd, J=7.5, 7.5, 1Hz), 7.23 (1HI, d, J=8, 1Hz), 7.63 (1H, d, J7.5Hz), 7.85 (1H, s), 7.99 (1H, d, J=8Hz) MASS 415 76 (bp) 1-( 4 -Bromo-2-fiuorobelzyl)-3 i sobutyry-2-propylindole- 6 -carboxamide rap :197-198.5'c IR 3377, 3189, 1652, 1617, 1487, 1408 crn 1 NMR (CDC 3 5) 1.04 (3M, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.53-1.64 (2H, 3.05-3.11 (2H, 3.48- 3.60 (iM, 5.44 (2H, 6.29 (iM, t, 7.09 (1H, d, J=7.5Hz), 7.33 (1H, dc, J=7.5, 1Hz), 7.62 d, J=7.5Hz), 7.90 (1H, c, J=lHz), 7.97 (1M, d, MASS 461 459 (M

T

76 (bp) (11) 1-( 2 -Chlorobenzyl)-3-cyano-2-propylindole.6-carboxaci mp 222-223.5"O IR (KBr) 3443, 3183, 2215, 1679, 1394 cmC 1 NMR (CDC1 3 5) 1.02 (3M, t, j=7Mz), 1.70 (2H, sextet, J=7Hz), 2.89 (2M, t, J=7.5Mz), 5.50 (2H, 6.21 (iM, d, J=7.5Hz), 7.08 (1H, t, 7.24 (1H, ddd, J=7.5, 7.5, lz), 7.47 (i1, d, 7.61 (iM, c, J=7.5Hz), 7.77 (1H, d, 7.89 (1H, d, J=lHz) MASS 352 76 (bp) (12' 2 -Chlorobenzyl)-2-ethyi-3-sobutyrylinie- 6 carboxaide mp 178-180.50C NMR (CDC1 3 5) 1.22 (3H, t, J=7Hz), 1.30 (6H, d,

I

WO 96/32379 WO 9632379PCTIJP96OOS8fl 123 J=7Hz), 3.09 (2H, q, J=7Hz), 3.56 (lH, in), 5.51 (2H, 6.22 (1H, d, J=8HZ), 7.04 (1H, t, J=8Hz), 7.22 (1K, t, JS8HZ), 7.44 (1H, d, J=8Hz), 7.63 (1K, d, J=8Hz), 7.82 (1K, 7.98 (2Kj d, J=8Hz) (13) 1- 2 -Chlorobenzyl)- 3 -isobutyryl-2-inethy1±ndole-6 carboxamide inp 212-2150C NMR (CDC1 3 6) 1.30 (6H, d, J=7Hz), 2.69 (3H, s), 3.53 (1H, mn), 5.48 (2H, 6.21 (1H, d, J=8Hz), 7.04 (1H, t, J=8Hz), 7.23 (1H, t, J=8Hz), 7.45 (1H, d, J=8Kz), 7.62 (1K, d, J=8Hz), 7.87 (1H, 8.03 (1H, d, J=8Hz) (14) 1- 2 -Chlorobenzyl)-3>.-sobutyry1l2-methoxmehyinoe6 carboxamide mp 204-206*C NNR (DCd 3 1.32 (6H, d, J=7Hz), 3.34 (3H, s), 3.57 (1K, mn), 4.92 (2H, 5.65 (2H, 6.24 (1K, d, J=8Hz), 7.03 (1K, t, J=8Kz), 7.21 (1H, t, j=8Kz), 7.44 (1H, d, J=8Hz), 7.67 (1K, d, J=8Hz), 7.83 (1K, 8.02 (1K, d, J=HSz) 1- 2 -Chorobenz Y)3-isobutyyryidol 6 aboxm in: 235-2370C NR(DMSO-d 6 65) 1.16 (6H, d, J=7Hz), 3.40 (1H, in), 5.67 (2K, 6.70 (1K, d, J=8Kz), 7.2-7.4 (3K, mn), 7.56 (1H, d, J=8Hz), 7.80 (1H, d, J=8Hz), 7.96 (1K, br 8.04 (1K, 8.27 (1K, d, J8KBz), 8.64 (1K,

S

(16) 3 -'isobutvrY1-2-propy..1. 2 -pyridylimethyl) inrdole-6carboxainide (DMSO-d 6 6) 0.90 (3H, t, J=7Kz), 1.17 (6H, d, 77z), 1.46 (2H, sextez, J=7Hz), 3.08-3.15 (2K, WO 96/32379 PCT/JP96/00892 124 in3.52 (2H, septet, 5.66 (2H, 7.08 (lIH, d, J=8H-z), 7.28-7.32 (2H, in), 7.78 (lIH, d, j=BIiz), 7.92 dl, J=8Hz), 8.09 (li, 8.50 d, (17) 1- 2 Chlorobenzyij J-diethiin oe6:,boxm mp:- 8 5-187.50c Th (KBr) :3400, 1650, 1610 cm- 1 NIVR (OD1 3 6) :1.15 (3H, t, J=7Hz), 1.29 (3H, t, J=7-Hz), 2.69 (2H, q, J=7Hz), 2.80 (2H, q, J=7H-z, 5.44 (2H, 6.17 (IH, d, J=7.11-z), 7.00 (IN, t, J=7.SHz), 7.18 (1H, t,

J=

7 .5Hz), 7.41 (1K, cd, 7.47 (1K, d, J=7.5Eiz), 7.62 (1K, d, 7.76 (iN, s) MASS (rn/z) :341 76 (bp) (18) 3 -Acety- 2 -ch].orobeflzy1) 2 -ethyl~i-nole-.6-carboxm rnp 217-220-C NMR (CDC! 1.2)3H 1.2 (3K t, J=7Eiz), 2.73 (3H, s), 3.12 (2.111, a, J=7Hz), 5.49 (2H, 6.20 (1K, di, J-8i-iz), 7.02 (1K, t, j=8Hiz), 7.22 t, J=8Iiz), 7.43 (1H, d, J=8Hz), 7.63 (1K, di, J=8Hz), 7.83 (iN, (19) 1- 2 -Chlorob en zy for i l 2 p oy 1 nd l a b x m 2450C (diec.)e 3.11 (2H, t, J=7Hz), 5.64 (2H, 6.32 (1H, di, J=3'8HzT), 7.21 (1H, t, J=8Hz), 7.25-7.35 (2H, mn), 7.60 (1K, d, J=B8iz), 7.83 (1H, di, J=Bz), 7.95 (1H, d, j=8Hz), 7.97 (1K, 8.21 (1K, di, J=8Hz), (1K, s,) The follow~ng com-.pouncis diescribedi in 1) to 3) were WO 96/32379 PCT/JP96/00892 125 prepared from the compound obtained in Example 34-11), Example 34-20) or Example 34-21) in a similar manner to that of Eam-ole 3-Benzoyl-l- 2 -chlorobenzyl)-2-propylindole6.

carboxamide NMR (DMSO-d 6 5) 0.78 (3H, t, J=8Hz), 1.46 (2H, sextet, J=8Hz), 2.88 (2H, t, J=8Hz), 5.66 (2H, s), 6.33 (1H, dd, J=1, 8Hz), 7.08 (1K, dt, J=l, 8Hz), 7.20-7.38 (3H, in), 7.52-7.72 (7H, in), 7.88 (1H, br 7.99 (1H, s) 1- (2-Chlorobenzyl) 3 -phenylacetyl-2-propylindole.6c arbox ami de NNR (DMSO-d 6 5 0.88 (3H, t, J=8Kz), 1.47 (2H, sextet, J=8Hz), 2.98-3.03 (2H, in), 4.42 (2H, s), 5.63 (2H, 6.20 (1H, d, J=8Kz), 7.17 (1H, t, J=8Hz), 7.24-7.35 (6H, in), 7.57 (1HK, d, J=8Hz), 7.82 (1HK, d, J=8Kz), 7.95 (1H, br 8.02 (1K, s), 8.14 (1LH, d, J=8Kz) 3-Acetyl-1- (6-chloro-3, 4 -methylenedioxybenzyl) -2propylindole- 6 -carboxamide mp 220-223 0

C

NNR (DMSO-d 6 0.94 (3H, t, J=8Kz), 1.50 (2K, sextet, J=8Kz), 2.65 (3K, 3.02-3.06 (2K, in), 5.52 (2H, 5.66 (1H, 5.99 (2K, 7.23 (1K, 7.86 (1H, d, J=8Hz), 8.01 (1K, 8.05 (1HK, d, J= 8Hz) Examiple 39 To a solution of 3 -isobutyryl-2-propyl--(2pyridylmethyl)indole-6-carboxamide (80 mng) in chloroform (2 ml) was added 1MK solution of hydrogen chloride in methanol (1 ml) at 25'C, and the mixture was stirred for 15 minutes.

WO 96/32379 PCT/JP96/00892 126 After evaporation of solvent, the residue was crystallized from a mixture of ethanol and ethyl acetate to give 3isobutyryl-2-propyl-l- 2 -pyridylmethyl) indl-~abxm hydrochloride (80 rg) as colorless crystals.

mp 230-235*C NM. (DMSO-d 6 5) 0.92 (3H, t, J=7Hz), 1.17 (6H, d, J=7Hz), 1.45 (2H, sextet, J=7Hz), 3.08-3.14 (2H, 3.52 (2H, septet, J=7Hz), 5.74 (2H, 7.09 (1K, d, J=8Hz), 7.46 (1H, dd, J=5, 8Hz), 7.79 (1H, d, 3=8Hz), 7.90 (1K, d, J=8Hz) 7.92 (1H, t, J=8Kz), 8.12 (1K, 8.62 (1H, d, Examole -arboxybenzyl)-3-isobutyryl---propy'Lnoe6 carboxaiide (242 mg) was prepared from 3 -isobutyryl-l-(2methoxvcarbonylbezyl)-2-propyi ndole-- (265 rg) in a similar manner to that of Example 2.

mp 268-269'C (dec.) IR (KBr) 1740, 1690, 1625, 1620 cm 1 NYIR (DM-SO-d 6 5) 0.90 (3H, t, J=7Hz), 1.19 (6H, d, J7Hz, 1.42-1.51 (21, 2.94-3.06 (2H, 3.50- 3.60 (1K, 5.96 6.06-6.10 (1K, i), 7.37-7.40 (2H, 7.79-7.82 (1K, 7.91-7.95 (IH, 7.99 (1H, 8.03-8.06 (iH, m) MASS (in/z) 407 86 (bp) Examnle 41 1-( 2 -Carbamoylbenzyl)-3-soutyrv-2- ro carboxamide (102 mg) was prepared from l-( 2 -carboxybenzyL)-3isobutyryl-2-propylindole-6-carboxamide (164 mg) in a similar manner to that of Example 3.

rip :273-274*c IR (KBr) 1690 cm-i NMR (DMSO-d 6 5) 0.91 (3H, t, J=7Kz), 1.19 (6H, d, J=7Kz), 1.41-1.51 (2H, 2.94-2.99 (2H, 3.48- WO 96/32379 PCT/JP96/00892 127 3.57 (1K, in), 5.79 (2H, 6.17 (KH, d, 7.22-7.35 (3H, Mn), 7.61-7.68 (2H, in), 7.80 d, 7.92-7.97 (2H, mn), 8.04 (1K, 8.13 (1H, s) MAS S (in/Z) 406 87 (bp) Examp~le 42 To a solution of phosphorus oxychloride (0.031 ml) in dimethylformamide (1.2 ml) was added l-(2-chlorobenzyl)-2ethyl- 3 -propionylindole6carboxamide (112 mng) at 0 0 C, and the mixture was stirred for 15 minutes. The resulting mixture was poured into ammonia water and ice, and then extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with a mixture of hexane and isopropyl ether to give l-( 2 -chlorobenzyl)-2ethl3 propionylindole-6carbonitrile (93 mng) as a solid.

mp il5-118*C NI4R (ODC1 3 6) 1.25 (3H, t, J=7Kz), 1.30 (3H, t, J=7Hz), 3.09 (2H, q, J=7Kz), 3.17 (2H, q, J=7Hz), 5.47 (2K, 6.21 (1K, d, J=8Kz), 7.07 (1K, t, M=8z), 7.25 (1H, t, JBSz), 7.45-7.55 (3H, in), 8.09 (1K, d, j=7Kz) Examiel 43 1- (2-Chlorobenzyl) 2 -ethyl-3-isobutyrylindole-6 carbonitrile (239 mg) was prepared from l-(2-chlorobenzyl)-2ethyl-3-isobutyrylindoe6carboxamide (280 mng) in a similar manner to that of Example 42.

mp l32-134*O MR (CDCl 3 6) 1.23 (3K, t, J=7Kz), 1.31 (6H, d, J=7Hz),. 3.13 (2H, q, J=7Kz), 3.50 (1K, in), 5.48 (2H, 6.22 (1K, d, M=8z), 7.07 (lH, t, J=8Kz), 7.27 (1H, t, J=8Hz), 7.27 (1K, d, j=MK), 7.44-7.53 (2H, in), 8.02 (1K, d, J=8Hz) WO 96/32379 WO 9632379PCT/JP96/00892 128 Examiple 44 To a solution of 1-( 2 -chlorobenzy)-2ethyl.3propionyidoe-6-carbonitrile (107 mg) in xylene (5 ml) was added trimethyltin azide (190 mg), and the mixture was stirred at 12000 for 14 hours. The resulting mixture was poured into 1N HCl and extracted with ethyl acetate. The organic phase was washed with-). brine, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica ge 1 I eluting with 20% methanol'I in chloroform to give 1- 2 -chlorobenzyl) 2 -ethyl-3-prooionyl-6- (77 mg) as a solid.

rnp 178-181*C NMvR ("DCd 3 5) 1.18 (3H, t, J=7Hz), 1.34 (3H, t, J*=7Hz), 3.0-3.15 in), 5.42.(2H, 6.21 (1H, cJ=8H-z), 6.94 (1H, t J=8Hz), 7.13 (1H, t, J=BMz), 7.33 (1K, d, J=8Hz), 8.03 (1H, d, J=8Hz), 8.05 (1H, 8.25 (1H, d, J=8Hz) Examnle (2-Ch -lorobenzyl)-2-ethyi--3- iosbutyryl-6- (1K-t.etrazol- (109 mng) was prepared from. l-( 2 -chlcrobenzyl)-2et-hyl- 3 -iscbu-..-yrylincole6carbonitrii-le (130 mng) in a similar manner to ca of Examnle 44.

mp 160-163'C NR(CD013 5 1.18 (3H, t, J=7Hz), 1.31 (6H, d, 3.04 a, j=7H-z), 3.52 in), 5.37 6.20 (1H, d, J=8Hz), 6.94 (1H, t, J=8Hz), 7.11I (1H, t, rJ8Hz), 7.33 (1K, d, J=8Hz), 8.00 (1H, di, J=BHz), 8.02 (1K, 8.13 (1H, d, J=8Hz) Exainole 46 The fcfo-owing compounds described in to were prepared in a similar manner to that of Preparation Methvyl 3 -carboxypropyl)-1- 2 -chlorobenzyl) indole-6- WO 96/32379 PCT/JP96/00892 129 carboxylate NMR (CDC1 3 6) 2.04 (2H, 2.45 (2H, t, J=7Hz), 2.73 (2H, t, J=7Hz), 3.89 (3H, 5.44 (2H, s), 6.14 (1H, d, J=8Hz), 6.47 (1H, s),'7.01 (1H, t, J=8Hz), 7.18 (1H, t, J=8Hz), 7.44 (1H, d, J=8Nz), 7.62 (1H, d, J=8Hz), 7.83 (1H, d, J=8Hz), 7.93 (1H,

S)

2- (2-Carboxyethyl)-l-(2-chlorobenzyl)indole-6carboxylate NMR (CDC1 3 5) 2.76 (2H, t, J=7Hz), 2.96 (2H, t, J=7Hz), 3.88 (3H, 5.46 (2H, 6.16 (1H, d, J=8Hz), 6.46 (1H, 7.01 (1H, t, J=8Hz), 7.20 (1H, t, J=8Hz), 7.43 (1H, d, J=8Hz), 7.62 (1H, d, J=8Hz), 7.82 (1H, d, J=8Hz), 7.93 (1H, s) Prenaration 47 The following compounds described in to were prepared in a similar manner to that of Prenaration 31.

Methyl 9-(2-chorobenzyl)-5-oxo-5,6,7,8tezrahvdrocarbazole-2-carboxylate N-R (CDC1 3 5) 2.24 (2H, 2.62 (2H, t, J=7Hz), 2.86 (2H, t, J=7iz), 3.90 (3H, 5.47 (2H, s), 6.34 (1H, d, J=8Nz), 7.09 (1H, t, J=8Hz), 7.25 (1H, t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.97 (1K, 7.99 (i1, d, J=8Hz), 8.33 (1H, d, J=8Hz) Methyl 4-(2-chlorobenzyl)-1-oxo-l,2,3,4tetrahydrocyclopent[bindole-6-carboxylate NIM? (CDC1 3 5) 2.9-3.15 (4H, 3.91 (3H, 5.46 (2H, 6.66 (1H, d, j=8Hz), 7.17 (1K, t, J=8Hz), 7.29 (1H, t, J=8Hz), 7.48 d, J=8Hz), 7.94-8.06 (3H, m) WO 96132379 WO 9632379PCT/JP96/00892 130 Example 48 The following compounds described in to were Prepared in a similar manner to that of Preparation 1 Methyl 3-chloroacetyl-i- 2 -chlorobenzylj-2-propylindole.

6-carboxvlate MI 14 3-14 500 TR 1722, 1666 cm- NMR (CDCd 3 5) :1.03 (3H, t, J=7Hz), 1.5,5-1.66 (2H, mn), 3.05-3.10 (2H, mn), 3.91 (3H, 4.82 (2H, s), 5.53 (2H, 6.25 d, J=7.5Hz), 7.05 (1H, t, J=7. 5Hz) 7.20-7.25 (liH, in) 7.49 (1H, d, J=7.5Hz) 7.88 (1H, d, J=8Hz), 7.98 (1H, 8.00 (1H, d, J= 8HKz) MLAS S z) 418 76 (bp) 1- (2-Chlorobenzyl) 3 -crotonoyl-2-p-ropylindole-6c-arboxarnide mp :185.5-186.5'C IR (KBr) :1648, 1614, 1443, 1414, 1388cm INI4R (ODCd 3 5) :1.00 (3H, t, J=7Hz), 1.64 (2H, sextet, J=7Hz), 2.04 (31H, d, Jr=7Hz), 3.00 (2H, t, j=7Hz), 5.51 (2H, 6.24 (1H, d, j=8Hz), 6.92 (1H, d, J=15Hz), 7.00-7.06 (2H, mn), 7.23 (1H, t, j=8Hz), 7.46 (1H, d, J=7.5Hz), 7.60 (1H, d, 7.83 (1H, 7.99 (1H, d, J=8Hz) MASS 395 (M 74 (bp) Examn1e 49 A mixture of methyl 3 -chloroacetyl-1-(2-chlorobenzyl)-2pro-cylinrdole-6-carboxylate (123 mng) and morpholine (1 ml) was stirred at 50'C for 2.5 hours. After cooled to 2000, the reaction mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid and water, dried over magnesium sulfate and evaporated in vacuo. The WO 96/32379 WO 9632379PCT/JP96/00892 131residue was chromatogra~hed on s-iica gel eluting with a mixture of ethyl acetate and hexane to give methyl 1- (2-chlorobenzyl) 3 -morpholinoacetyl-2-propylinddie-6 carboxylate (94 mg) as colorless amorphous.

IR (KB r) :1712, 1657 cm 1 i NMR (CDCl 3 5 1.02. \13H, r, J=7Hz), 2.60-1.65 (2H, in,2.70-2.75 (4H, in), 2.06' (2H, tL, J=7Hz), 3.84 (4H, t, J=7Hz), 3.90 (2H, 3.92 (3H, 5.52 (2H, 6.24 (1H, d, J=7.5Hz), 7.06 (1Hi, t, j=7.5Hz), 7.242 (1H, r, J=7.5Hz), 7.48 (1H, d, 7.94-7.98 (3H, m) MASS :469 Examp~le To a mixture of methyl 2 -c-hiorobenzyl)-3-formyl.>pr-opylindole-6-carboxylate (263 mg), 2 -methyl-2-butene (220 mng) and sodium dihydrogenphos-phate (2.28 mng) in a mixture of tert-butanol (7 ml) and water (1.3 ml) was added sodium chlorite (219 mng) at 20 0 C. The reaction mixture was stirred at 40 0 C for 2 hours. The reaction mixture was acidified with 1N hydrochloric acid at 000 and extracted with chloroform three times. The organic phase was dried over sodium sulfate and evap~orated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane to give l-( 2 -chlorobenzy)-6-methoxycarbonyl>2 propylindole-3-carboxylic acid (94 mg) as pale yellow crystals.

mnp 229-232.

0 C (dec.) !R 1715, 1658, 1.441, 1275, 1227 cmn 1 NMIR (CDC1 3 5) 1.05 (3H, t, J=7Hz), 1.60-1.70 (2H, in), 3.10-3.18 (2H, mn), 3.93 (3H, 5.54 (2H, s), 6.78 (11H, d, J=7.5Hz), 7.06 (1K, t, j=7.5Kz), 7.21- 7.25 (1H, in,7.49 (11H, d, J=7.5Hz), 7.95 (1H, s), 7.99 (1H, d, J=8Hz), 8.33 (1H, d, J8Kz) MASS :384 77 (bp)) WO 96/32379 WO 9632379PCT/JP96/00892 132 Examiole 51 To a stirred suspension of 60% sodium hydride (470 mg) in N,N-dimethylformamide (6 ml) was added a solution of methyl 2 -ethylindole-6-carboxylate (1.99 g) in N,Ndimethvlformamide (12 ml) at 20*C. The mixture was stirred at 20 0 C for 30 minutes. To this mixture was added 2chlorobenzvlbromide (2.21 g) at 2000 and the mixture was stirred at 20*C for 5.5 hours. N,N-Dimethylformamide was evaporated off,, and the residue was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodiLum sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane to give crystals which were washed with hexane to give methyl 1-(2chlorobenzyi) 1- 2 -ethylindole-E':-carboxylate (2.71 g) as colorless crystals.

mp 67-89C 1K (KBr) 1709, 1278, 1236 crnJ 1 NMR (ODCd 3 5) 1.35 (3H, t, J=7Hz), 2.67 (2H, q, J=7Hz), 3.91 (3H, 5.45 (2H, 6.17 (l1H, d, J7=7Hz), 6.46 (1H, 7.02 (1H, dd, J=7, 7Hz), 7.19 (1I.H, dd, J=7, 7Hz), 7.44 (1H, d, J=7Hz), 7.62 (1H, d, j=7Hz), 7.72 (1H, d, J=7Hz), 7.93 (1H, s) MASS :328 76 (bp:) Exam-ole 52 The following compound was prepared in a similar manner to that of Exam-ole 32.

Methyl (2-chlorobenzyl) -2-ethyl-3-formylindole-6carboxylate mp, 168-169'C IR (KBr) 1715, 1650 cmrJ- -NMR (CXCI 3 1.27 (3H, t, J=7Hz), 3.06 (2H, q, J=77Nz), 3.90 (3H, 5.50 (2H, 6.18 (IH, d, WO 96/32379 PCT/JP96/00892 133 J=7Hz), 7.05 (1H, t, J=7Hz), 7.21-7.24 (1H, m), 7.48 (1H, d, J=7.5Hz), 7.95 (1H, 8.01 (1H, d, J=7Hz), 8.28 (1H, d, J=7Hz), 10.25 (1H, s) MASS 356 76 (bp) Example 53 A mixture of 1-(2-chlorobenzyl)-3-isobutyryl-2propylindole-6-carboxylic acid (100 mg), diphenylphosphoryl azide (97 mg) and triethylamine (53 mg) in tert-butanol (4 ml) was refluxed for 2 hours, and then partitioned between ethyl acetate and diluted with hydrochloric acid. The organic layer was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo.

The residue was purified by silica gel thin layer chromatography with a mixture of hexane and ethyl acetate to give 6-tert-butoxycarbonylamino-l-( 2 -chlorobenzyl)- 3-isobutyryl-2-propylindole (125 mg) as a pale yellow oil.

NMR (CDC1 3 5) 0.98 (3H, t, J=7Hz), 1.28 (6H, d, J=7Hz), 1.48 (9H, 1.52-1.64 (2H, 2.96-3.02 (2H, 3.54 (1H, septer, J=7Hz), 5.42 (2H, s), 6.30 (1H, d, J=8Hz), 6.52 (1H, 7.05 (1H, t, J=8Hz), 7.09 (1H, d, J=8Hz), 7.20 (1H, t, J=8Hz), 7.36-7.45 (2H, 7.82 (1H, d, J=8Hz) Example 54 To a solution of 6 -tert-butoxycarbonylamino-l-(2chlorobenzyl)-3-isobutyryl-2-propylindoe (110 mg) in ethyl acetate (1 m1) was added 4N hydrogen chloride in ethyl acetate at 20°C, and the mixture was stirred at the same temperature for 4 hours. The precipitates were collected by filtration and washed with ethyl acetate to give 6-amino-l- 2 -chlorobenzyl)-3-isobutyryl-2-propylindole hydrochloride mg) as powder.

NMR (DMSO-d 6 5) 0.92 (3H, t, J=7Hz), 1.18 (6H, d, J=7Hz), 1.49 (2H, sextet, J=7Hz), 3.02-3.08 (2H, I 1--1 WO 96/32379 PCT/JP96/00892 134 3.52 (1H, septet, J=7Hz), 5.58 (2H, 6.24 (1H, d, J=8Hz), 7.17-7.35 (4H, 7.57 (1H, d, J=8Hz), 8.02 (1H, d, J=8Hz) Example To a stirred solution of 6-tert-butoxycarbonylamino-l- 2 -chlorobenzyl)-3-isobutyryl-2-propylindole (581 mg) in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at 20°C. The reaction mixture was stirred at 20°C for 6.5 hours, then diluted with IN aqueous sodium hydroxide and extracted. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:6 to 1:4) to give 6-amino-l-(2chlorobenzyl)-3-isobutyryl-2-propylindole (361 mg) as yellow oil.

NMR (CDC1 3 5) 1.00 (3H, t, J=7Hz), 1.29 (6H, d, J=7Hz), 1.51-1.64 (2H, 2.98-3.03 (2H, 3.49- 3.57 (1H, 5.34 (2H, 6.36 (1H, d, 6.46 1 H 6.71 (1H, d, J=7.5Hz), 7.08 (1H, t, 7.21 (1H, t, J=7.5Hz), 7.45 (1H, d, 7.85 (1H, d, MASS 369 Example 56 To a stirred solution of 6 -amino-l-(2-chlorobenzyl)-3isobutyryl-2-propylindole (79 mg) and triethylamine (0.065 mi) in dichloromethane (2 ml) was added acetyl chloride (0.02 ml) at 0°C. The reaction mixture was stirred at 20°C for 2 hours, then diluted with dichloromethane. The organic phase was washed with 1N hydrochloric acid, water, aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane to give crystals which were recrystallized from a WO 96/32379 PCT/JP96/00892 135 mixture of ethyl acetate and hexane to give 6-acetamide-1- (2chlorobenzyl) 3 -isobutyryl-2-propylindole (48 ing) as colorless crystals.

mp :147-1480C IR (KBr) :1664, 1648, 1507, 1412 cm- 1 NM~R (CDC1 3 5) :1.00 (3H, t, J=7Hz), 1.29 (6H, di, J=7Hz), 1.51-1.65 (2H, mn), 2.17 (3H, 2.99-3.05 (2H, mn), 3.49-3.58 (1H, mn), 5.43 (2H, 6.30 (1H, d, J==7.5Hz), 7.04 (1H, t, J=7.5Hz), 7.13-7.23 (3H, mn), 7.44 (1H, d, J=7.5Hz), 7.72 (1H, 7.85 (1H, d, MASS (in/z) 411 (M+1) Exainle 57 To a stirred solution of 6 -amino-1-(2-chlorobenzyl)-3isobutyryl-2-propylindole (100 ing) in chloroform (2 ml) was added iethylisocyanate (0.5 ml) at 000. The reaction mixture was stirred at 2000 for 1 hour, then evaporated. The residue was chroinatographei on silica gel eluting with a mixture of ethyl acetate and hexane to give crystals which were recrystallized from a mixture of ethyl acetate and hexane to give 1- 2 -chlorobenzyl)-3-isobutyryl-6- (3-iethylureido) -2propylindole (75 ing) as colorless crystals.

mp :106-108.5*C IR (KBr) :1635, 1550, 1506 cmJ 1 NMR (CD1 3 5 1.01 (3H, t, J=7Hz), 1.30 (6H, di, J=7Hz), 1.53-1.65 (2H, mn), 2.78 (3H, di, J=7HZ), 3.00-3.06 (2H, mn), 3.49-3.57 (1H, in), 4.61 (1H, di, J=7Hz), 5.42 (2H, 6.29-6.32 (2H, in), 7.02-7.07 (2H, mn), 7.22 (1H, ddd, J=7.5, 7.5, 1Hz), 7.46 (1H, di, J=7.5Hz), 7.88 (1H, d, MASS (in/z) 426 (M 76 (bp) Example 58 To a stirred solution of 6 -amino-1-(2-chlorobenzyl)-3- WO 96/32379 PCT/JP96/00892 136 isobutyryl-2-propylindole (147 mg) in dichloromethane (2 ml) was added acetic formic anhydride (0.5 ml) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, then diluted with dichloromethane. The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane to give crystals which were recrystallized from a mixture of ethyl acetate and hexane to give 1-(2chlorobenzyl)-6-formamido-3-isobutyryl-2-propylindole mg) as colorless crystals.

mp 113-115"C IR (KBr) 1666, 1647, 1508 cm- 1 NMR (CDC1 3 5) 1.00, 1.03 (3H, t and t, J=7Hz), 1.28, 1.30 (6H, d and d, J=7Hz), 1.54-1.65 (2H, m), 2.99-3.09 (2H, 3.47-3.57 (1H, 5.43 (2H, d, J=4Hz), 6.31 (1H, d, J=7.5Hz), 6.82-7.10 (2H, m), 7.17-7.25 (2H, 7.43-7.77 (2H, 7.90 (1H, dd, 7.5Hz), 8.37-8.58 (1H, m) MASS 397 Examole 59 A solution of 3 -isobutyryl-l-(2-nitrobenzyl)-2propylindole-6-carboxamide (316 mg) in methanol (10 ml) was hydrogenated over 10% palladium on carbon at 20°C for 6 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of methanol and chloroform (1:30) to give an oil which was dissolved in a mixture of chloroform (10 ml) and methanol (20 ml). To this solution was added 10% hydrogen chloride in methanol (0.9 ml), and the mixture was stirred at 20°C for 1 hour and evaporated in vacuo. The residue was recrystallized from a mixture of methanol and diisopropyl ether to give 1-( 2 -aminobenzyl)-3isobutyryl-2-propylindole-6-carboxamide hydrochloride (415 1 WO 96/32379 PCTIJP96/00892 137 ing) as colorless crystals.

mp :255-257 0

C

1R 1650, 1550, 1455 cm- 1 NMR (DMSO-d 6 6) 0.95 (3H, t, J=7Hz), 1.20 (3H, t, j=7Hz), 1.46-1.59 (2H, Qn, 2.96-3.01 (2H, mn), 5.67 (2H, 5.89 (1H, di, j=7.5Hz), 6.87 (1H, br t, j=7Hz), 7.19-7.34 (3H, mn), 7.80 (1H, d, 7.92-7.98 (2H, mn), 8.03 (1H, s) MASS 378 86 (bp) Exainzle 6 To a solution of l-( 2 -chlorobenzy2)-3-methoxyacetyl-2 propylindole-6-carboxamcide (168 ing) in a mixture of dichloromethane (10 ml) and methanol (0.5 ml) was added iM solution of boron tribroinide in dichloromethane (2.5 ml) at 530C. The reaction mixture was warmed gradually to -12'C during 3 hours. Then 1M solution of boron tribromide in dichloromethane (2.5 ml) was added, and the mixture was stirred for 20 minutes at -120C. The reaction mixture was diluted with water and extracted with 10i methanol in chloroform. The organic phase was washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate and washed with hexane to give 1-(2chlorobenzyl) 3hdoyctl--rplnoe--abxmd (120 mng) as colorless crystals.

mp 231-233.5 0

C

IR (KBr) :3405, 3159, 1673, 1647, 1616, 1395 cm- 1 NMR (DMSO-d 6 5) 0.94 (3H, t, J=7Hz), 1.40-1.52 (2K, mn), 3.05 (3K, t, J=7Kz), 4.75 (2K, t. J=6Hz), 4.90 (1K, t, J=6Kz), 5.65 (2H, 6.22 (1K, di, j=7.SHz), 7.18 KH, t, J=7.5Hz), 7.27-7.35 (2H, in), 7.58 (1K, d, J=7.5Hz), 7.81 d, J=7.5Hz), 7.92 (2H, di, J=7.5Hz), 8.01 (iH, s) MASS :385 (M 86 ObN

I

WO 96/32379 PCT/JP96/00892 138 Example 61 To a stirred mixture of benzyl 3-isobutyryl-2propylindole-6-carboxylate (207 mg) and diisopropylethylamine (295 mg) in dichloromethane (6 ml) were added 2 -chlorobenzoyl chloride (299 mg) and 4 -dimethylaminopyridine (12 mg) at 0°C.

The reaction mixture was refluxed for 15 hours. The reaction mixture was cooled to 20°C and washed with IN hydrochloric acid, water, saturated sodium bicarbonate, water and brine.

The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:10) to give benzyl 1-( 2 -chlorobenzoyl)-3-isobutyryl-2propylindole-6-carboxylate (330 mg) as yellow crystals.

mp 67.5-70°C IR (KBr) 1780, 1710, 1700, 1300 cm- 1 NMR (CDC1 3 5) 0.99 (3H, t, J=7Hz), 1.27 (6H, t, J=7Hz), 1.74 (2H, sextet, J=7Hz), 3.12 (2H, t, J=7Hz), 3.39-3.48 (1H, 5.25 (2H, 7.33-7.45 (8H, 7.53-7.58 (2H, 7.80 (1H, d, 7.98-8.05 (1H, m) MASS 502 Example 62 A solution of benzyl 1-( 2 -chlorobenzoyl)-3-isobutyryl-2propylindole-6-carboxylare (304 mg) in methanol (6 ml) was hydrogenated over 10% palladium on carbon at 20°C for 9 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of methanol and.chloroform (1:30) to give crystals which were recrystallized from a mixture of ethyl acetate and hexane to give 1-(2chlorobenzoyl)-3-isobutyryl-2-propylindole-6-carboxylic acid (189 mg) as colorless crystals.

IR (KBr) 1710, 1695, 1980, 1315 cm- 1 NMR (CDC1 3 6) 0.95 (3H, t, J=7Hz), 1.27 (6H, t, WO 96/32379 PCT/JP96/00892 139 J=7Hz), 1.64-1.75 (2H, 3.03-3.09 (1H, 3.40- 3.49 (1H, 7.48-7.52 (2H, 7.58-7.67 (3H, m), 7.92 (2H, AB, J=8, Example 63 To a stirred solution of 1-(2-chlorobenzyl)-3formylindole-6-carboxamide (47 mg) in dimethylformamide (1.6 ml) was added chromic anhydride (125 mg) and sulfuric acid (0.05 ml), and the mixture was stirred at 20"C for hours. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol to give 6-carbamoyl- 1-( 2 -chlorobenzyl)indole-3-carboxylic acid (8.3 mg) as a solid.

mp 240"C (dec.) NMR (DMSO-d 6 5) :5.64 (2H, 6.71 (1H, d, J=8Hz), 7.26 (1H, t, J=8Hz), 7.28 (1H, br 7.36 (1H, t, J=8Hz), 7.56 (1H, d, J=8Hz), 7.78 (1H, d, J=8Hz), 7.92 (1H, br 8.06 (1H, 8.07 (1H, d, J=8Hz), 8.20 (1H, s) Example 64 To a solution of l-(2-chlorobenzyl)-2-(1-hydroxypropyl)- 3 -isobutyrylindole-6-carboxamide (19 mg) in acetone (3 ml) was added Jone's reagent until the red color existed continuously. The reaction was quenched by 2-propanol, then the mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 1-(2chlorobenzyl)- 3 -isobutyryl-2-propionylindole-6-carboxamide (9.3 mg).

mp 145-147°C NMR (CDC1 3 5) 1.15 (3H, t, J=7Hz), 1.33 (6H, d, J=7Hz), 2.60 (2H, q, J=7Hz), 3.47 (1H, 5.46 WO 96/32379 WO 9632379PCTIJP96/00892 140 (2H, 6.50 (1H, d, J=8Hz), 7.09 (1H, t, J=8Kz), 7.21 (1H, t, J=8Kz), 7.42 (1H, d, J=8Hz), 7.70 (1H, d, J=8Hz), 7.88 (1H, 7.98 (1K, S) Example The following compound was prepared in a similar manner to that of Preparation 3-Chloro-1- (2-chlorobenzyl) 2 -propylindole-6-carboxamide mp 163-166*C NMR (CDCl 3 5) :0.95 (3H, t, J=7Hz), 1.58 in), 2.73 (2H, t, J=7Hz), 5.43 (211, 6.19 (1H, d, J=8Hz), 7.01 (1H, t, J=8Hz), 7.18 (1H, t, J=8Hz), 7.43 (1K, d, J=8Hz), 7.54 (1H, d, J=8Hz), 7.67 (111, d, J=8Kz), 7.82 (1K, s) Example 66 To a stirred solution of methyl 1-(2-bromobenzyl)-2propylindole-6-carboxamide (52 mg) in a mixture of dichloromethane (3 ml) and pyridine (1 ml) was added pyridinium bromide perbromide (50 mg), and the mixture was stirred at 0OC for 1.5 hours. The resulting mixture was diluted with ethyl acetate and washed with diluted hydrochloric acid, aqueous sodium bicarbonate and brine, then dried over sodium sulfate and evaporated in vacuo. The residue was triturated with a mixture of hexane and diisopropyl ether to give 3-bromo-1-(2-bromobenzyl)-2propylindole-6-carboxamide (33 mg) as a solid.

mp 122-125 0

C

NMR (ODC1 3 5) 0.98 (3H, t, J=711z), 1.57 (2H, in), 2.73 (2H, t, J=7Hz), 5.42 (2H, s) 6.15 (1H, d, J=8Hz), 7.0-7.16 (2H, in), 7.5-7.65 (3H, in), 7.79 (1K, s) Exaile 67 WO 96/32379 WO 9632379PCTIJP96I00892 141 The following compounds described in to were prepared in a similar manner to that of Example 4.

1- (2-Chlorobenzyl) 3 -isobutyryl-2-propylindole6carbonitrile mp 130-131*C NMR (CDCl 3 1.03 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.56-1.68 (2H, in), 3.06-3.12 (2H, mn), 3.51 (1H, septet, J=7Hz), 5.46 (2H, 6.23 (1H, d, J=8Hz), 7.08 (1H, t, J=8Hz), 7.27 (1H, t, J=BHz), 7.46-7.52 (3H, in), 8.01 (1H, d, J=8Hz) 9- (2-Chlorobenzyl)-8-oxo-5, 6,7, B-tetrahydrocarbazole-2carbonitrile mp 173-176*C NMR (ODC1 3 5) 2.29 (2H, mn), 2.69 (2H, t, J=7Hz), 3.08 (2H, t, J=7Hz), 5.94 (2H, 6.30 (1H, d, J=8Hz), 7.02 (1H, t, J=8Hz), 7.19 (1H, t, J=8Hz), 7.8(1H, d, J=8Hz), 7.42 d, J=8Hz), 7.54 (1H, 7.78 (1H, d, J=8Hz) Examrle 68 To a solution of l-( 2 -chlorobenzyl)-3-isobutyryl-2propylindole-6-carbonitrile (70 mng) in a mixture of methanol (2 ml) and tetrahydrofuran (2 ml) was added sodium borohydride (21 mg) at 2500. After stirred at 25'C for 2 hours, the reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give 1- (2-chlorobenzyl) (1-hydroxy-2mehlrpl--rplnoe6croirl (28 mg) as pale yellow crystals.

mp 126-127*C NMR (ODC1 3 5) 0.76 (3H, d, J=7Hz), 0.98 (3H, t, WO 96/32379 WO 9632379PCT/JP96/00892 142 J=7Hz), 1.22 (3H, d, J=7Hz),, 1.50-1.64 (2H, i) 1.87 (1H, d, J=2Hz), 2.32-2.44 (2H, in), 2.63-2.80 (2H, in), 4.58 (1Hi, dd, J=2, 8Hz), 5.38 (2H, s), 6.15 (1H, d, J=8Hz), 7.05 (1H, t, J=8HZ), 7.22 (1H, t, J=8Hz), 7.32 (1H, d, J=8Hz), 7.38 (iN, 7.46 d, J=8Hz), 7.91 (1H, d, J=8Hz) Examiple 69 The following compound was prepared in a similar manner to that of Exaile 68.

1- (2-Chlorobenzyl) -2-ethyl-3- (1-hydroxy-2-inethylpropyl) indole- 6-carboxamide mp 169-172*C NMR (CDCl 3 0.78 (3H, d, J=7Hz), 1.17 (3H, t, J=7Nz), 1.23 (3H, d, J=7Hz), 2.41 (1H, mn), 2.74 (2H, in), 4.60 (1H, in), 5.43 (2H, 6.14 (iH, d, J=8Hz), 6.98 (1H, t, J=8Nz), 7.17 (1H, t, J=8Hz), 7.4-7.5 (2H, in), 7.76 (1H, 7.85 (1H, d, J=8Hz) Examp~le To a suspension of 3 -acetyl-1-(2-chlorobenzyl)-2propylindole-6-carboxamide (36.5 mg) in ethanol (5 ml) was added hydroxylainine hydrochloride (70 mng) and sodium acetate (200 mg), and the mixture was heated in a sealed tube at 100 0 C. The reaction was evaporated in vacuo, then the residue was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 1-(2-chlorobenzyl)-3-(ihydroxyiminoethyl) 2 -propylindole-6-carboxanide (32.7 ing).

mp 212-216*C NNR (ODC1 3 5) :0.94 (3H, t, J=7Hz), 1.56 (2H, in), 2.39 (3H, 2.80 (2H, mn), 5.45 (2H, 6.21 (1H, d, J=8Hz), 6.99 (1H, t, J=8Hz), 7.20 (iH, t, WO 96/32379 PCT/JP96/00892 143 J=8Hz), 7.42 (1H, d, J=8Hz), 7.50 (1H, 7.70- 7.78 (2H, m) Example 71 1-(2-Aminobenzyl)-3-isobutyryl-2-propylindole-6carboxamide hydrochloride (111 mg) was dissolved in chloroform, and the solution was washed with 1N aqueous sodium hydroxide, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in chloroform (3 ml), and then methyl isocyanate (1.5 ml) was added at 0°C. After stirred at 20°C for 2 hours, the mixture was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and tetrahydrofuran, and the solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of 1,4-dioxane and hexane to give 3-isobutyryl-l-[2- 3 -methylureido)benzyl]-2-propylindole-6-carboxamide (74 mg) as colorless crystals.

mp 222-223°C IR (KBr) 1648, 1617, 1557 cm-1 NMR (DMSO-d 6 5) 0.91 (3H, t, J=7Hz), 1.18 (6H, d, J=7Hz), 1.42-1.50 (2H, 2.71 (3H, d, 2.92-3.00 (2H, 3.50-3.56 (1H, 5.48 (2H, s), 5.99 (1H, d, J=8Hz), 6.34-6.39 (1H, 6.86 (1H, t, J=7.5Hz), 7.18 (1H, t, J=7.5Hz), 7.28 (1H, s), 7.55 (1H, t, J=7.5Hz), 7.78 (1H, d, J=7.5Hz), 7.92- 7.97 (3H, 8.21 (1H, s) MASS :435 86 (bp) Example 72 To a solution of methyl 1-(2-chlorobenzyl)-2propylindole-6-carboxylate (200 mg) in trifluoroacetic acid (2 ml) was added concentrated nitric acid (0.3 ml) at 0"C.

After stirred at 0°C for 30 minutes, the reaction mixture was partitioned between ethyl acetate and water. The organic WO 96/32379 PCT/JP96/00892 144 layer was washed with aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, and evaporated in vacuo.

The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of ethyl acetate and hexane to give methyl 1-(2-chlorobenzyl)-3nitro- 2 -propylindole-6-carboxylate (73 mg) as pale yellow crystals.

NM'R (CDCl 3 6) :1.04 (3H, t, J=7Hz), 1.68 (2H, sextet, J=7Hz), 3.14-3.18 (2H, in), 3.91 (3H, s), 5.13 (2H, 6.32 (1H, d, J=8Hz), 7.08 (1H, t, J=8Hz), 7.27 (1H, t, J=8Hz), 7.48 (1H, d, J=8Hz), 7.98 (1H, 8.08 (1H, d, J=8Hz), 8.43 (1H, d, J=8Hz) ExamTle 73 The following compounds described in to (44) were prepared in a similar manner to that of Example 1.

Methyl 1- (2-chlorobenzyl)-2- (3-methoxycarbonyipropyl) indole-6-carboxylate MR (CDC1 3 I 6) :2.04 (2H, mn), 2.88 (2H, t, CP=7Hz), 2.69 (2H, t, J=7Hz), 3.62 (3H, 3.89 (3H, s), 5.43 (2H, 6.14 (1H, d, J=8Hz), 6.46 (1H, s), 7.01 (1H, t, J=8Hz), 7.18 (1H, t, J=8Hz), 7.42 (1H, d, J=8Hz), 7.59 (1H, d, J=8Kz), 7.80 (1H, d, J=8Hz), 7.90 (1H, s) Methyl 1- (2-chlorobenzyl) 2 -methoxycarbonylethyl) indole-6-carboxylate MR (CDCl 3 5) :2.77 (2H, in), 2.98 (2H, mn), 3.69 (3H, 3.88 (3K, 5.45 (2H, 6.16 (1H, d, J=8Kz), 6.41 (1K, 7.02 (1H, t, J=8Kz), 7.19 (1H, t, J=8Kz), 7.42 (1H, d, J=8Kz), 7.60 (1H, d, J=8Kz), 7.81 (1H, d, J=8Hz), 7.91 (1K, s) WO 96/32379 PCT/JP96/00892 145 Methyl 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-7carboxylate NMR (CDC1 3 6) 1.02 (3H, t, J=7Hz), 1.79 (6H, d, J=7Hz), 1.63 (2H, 3.01 (2H, 3.52 (1H, m), 3.56 (3H, 5.61 (2H, 6.08 (1H, d, J=8Hz), 6.98 (1H, t, J=8Hz), 7.17 (1H, t, J=8Hz), 7.2-7.45 (3H, 8.12 (1H, d, J=8Hz) Methyl 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-5carboxylate NMR (CDC1 3 6) 1.03 (3H, t, J=8Kz), 1.34 (6H, d, J=8Hz), 1.62 (2H, sextet, J=8Hz), 3.06-3.10 (2H, 3.64 (1H, septet, J=8Kz), 3.96 (3H, 5.47 (2K, 6.26 (1H, d, J=8Kz), 7.06 (1H, t, J=8Hz), 7.20 (1H, t, J=8Hz), 7.25 (1H, d, J=8Hz), 7.47 (1H, dd, J=1, 8Hz), 7.92 (1H, d, J=8Hz), 8.68 (1H, d, J=lHz) Methyl 1-(6-chloro-3,4-methylenedioxybenzyl)-3- NMR (CDC1 3 6) 1.05 (3H, t, J=8Hz), 1.32 (6H, d, J=8Hz), 1.62 (2K, sextet, J=8Hz), 3.06 (2H, t, J=8Kz), 3.63 (1H, septet, J=8Hz), 3.96 (3K, s), 5.36 (2H, 5.74 (1K, 5.88 (2K, 6.92 (1H, 7.20 (1H, d, J=lOHz), 7.82 (1H, d, J=lOHz), 8.76 (1K, s) Methyl 1-(2-chlorobenzyl)-2-propylindole-4-carboxylate NMR (CDC1 3 6) 1.01 (3H, t, J=7Hz), 1.78 (2K, m), 2.67 (2H, t, J=7Kz), 3.99 (3H, 5.42 (2H, s), 6.18 (1H, d, J=8Kz), 7.01 (1H, t, J=8Hz), 7.03 (1H, 7.11 (1H, t, J=8Kz), 7.18 (1H, t, J=8Hz), 7.30 (1H, d, J=8Kz), 7.43 (1K, d, J=8Kz), 7.89 (1K, d, J=8Kz) WO 96/32379 WO 9632379PCT/JP96I00892 146 Methyl 9- (2-chlorobenzyl) -8-oxo-5, 6,7,8tetrahydrocarbazole-2-carboxylate NMR (CDCl 3 6) :2.27 mn), 2.67 (2H, t, J=7Hz), 3.11 (2H, t, J=7Hz), 3.90 (3H, 5.95 (2H, s), 6.25 (1H, d, J=8)Hz), 6.98 (1H, t, J=8Hz), 7.15 (1H, t, J=8Kz), 7.40 (1H, d, J=8Hz), 7.74 (1H, d, J=8Hz), 7.84 (1H, d, J=8Hz), 7.99 (1H, s) Methyl 9- (6-chloro-3, 4-iethylenedioxybenzyl)-8-oxo- 5, 6,7, B-tetrahydrocarbazole-2-carboxylate NI'R (CDCl 3 :2.18 (2H, in), 2.63 (2H, t, J=7Hz), 3.07 (2H, t, J=7Hz), 3.84 (3H, 5.68 (1H, s), 5.83 (2H, 5.96 (2H, 7.18 (1H, 7.84 (1H, d, J=8Kz), 7.92 (1H, d, J=8Hz), 8.03 (1H, s) Methyl 1- (4-bromo-2-chlorobenzyl) -3-isobutyryl-2propylindole- 6-carboxylate mp :65-67*C IR (KBr) :1715, 1705, 1656, 1456, 1433 cin 1 NMR (CDC1 3 6) :1.03 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.52-1.64 (2H, mn), 2.99-3.05 (2H, mn), 3.51- 3.60 (1H, mn), 3.92 (3H, 5.45 (2H, 6.09 (1H, d, J=7.5Hz), 7.18 (1H, d, J=7.5Hz), 7.66 (1H, s), 7.90 (1H, 7.99 (2H, s) MASS (in/z) :492 1- (2-Acetaiidobenzyl)-3-isobutyryl-2-propylindole-6carboxainide mp :235-236*C IR :1693, 1656, 1457 cmn 1 lNR (CDC1 3 6) :0.91 (3H, t, J=7Hz), 1.18 (6H, cd, J=7Kz), 1.39-1.50 (2K, mn), 2.17 (3H, 2.92-2.99 (2K, mn), 3.50-3.59 (1H, mn), 5.49 (2K, 6.07 (1H, di, J=7.SHz), 7.00 (1H, t, J=7.5Kz), 7.21-7.29 (2H, in), 7.39 (1H, di, J=7.5Kz), 7.79 (1H, d, WO 96/32379 PCT/JP9600892 147 7.92-7.96 (3H, 9.85 (1H, s) MASS 420 86 (bp) (11) Methyl 1-(2-chlorobenzyl)-3-formylindole-6-carboxylate NMR (CDCl 3 6) 3.93 (3H, 5.52 (2H, 6.88 (1H, dd, J=l, 8Hz), 7.21 (1H, dt, J=l, 8Hz), 7.32 (1H, dt, J=1, 8Hz), 7.49 (1H, d, J=1, 8Hz), 7.82 (1H, 8.02 (1H, d, J=l, 8Hz), 8.13 (1H, d, J=lHz), 8.36 (1H, d, J=8Hz), 10.0 (1H, s) (12) Methyl 3-acetyl-l-(2-chlorobenzyl)-2-rethyindoie-6carboxylate This compound was use immediately without purification.

(13) Methyl 1-(2-chlorobenzyl)-2-methyi-3-propionylindole-6carboxylate NMR (CDC1 3 6) 1.31 (3N, t, J=7Nz), 2.70 (3N, s), 3.09 (2H, q, J=7Nz), 3.90 (3H, 5.50 (2H, s), 6.22 (1H, c, J=8Hz), 7.04 (1H, t, J=8Nz), 7.24 (1H, t, J=8Nz), 7.46 (1H, d, J=8Hz), 7.92-7.98 (2H, m), 8.08 (1H, d, J=8Hz) (14) Methyl 1-(2-chlorobenzo[b]thiophen-3-ylmethyl)-3isobutyryl-2-methylinole-6-carboxylate NMR (DMSO-d 6 65) 1.14 (6H, c, J=7Hz), 2.72 (3H, s), 3.48 (1H, 3.81 (3H, 5.91 (2H, 7.3-7.5 (3H, 7.80 (1H, c, J=8Hz), 7.98 (1H, c, J=8Hz), 8.06 (1H, c, J=8Hz), 8.19 (1H, s) Methyl 1-(benzothiazol-2-ylethyl)-2-ethyi-3isobutyrylindole-6-carboxylate NMR (CDC1 3 6) 1.28 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 3.24 (2H, q, J=7Hz), 3.53 (1H, 3.91 (3H, 5.82 (2H, 7.25-7.53 (2H, 7.72 (1H, WO 96/32379 PCT/JP96/00892 148 7.8-8.1 (3H, 8.18 (1H, s) (16) Methyl 1- (benzo[b thiophen-5-ylmethyl) -3-isobutyryl-2propylindole-6-carboxylate NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.32 (6H, d, J=7Hz), 1.62 (2H, 3.13 (2H, 3.57 (1H, m), 3.87 (3H, 5.57 (2H, 7.03 (1H, d, J=8Hz), 7.18 (1H, d, J=6Hz), 7.29 (1H, 7.44 (1H, d, J=6Hz), 7.79 (1H, d, J=8Hz), 7.94 (2H, 8.02 (1H, s) (17) Methyl 1-allyl-3-isobutyryl-2-propylindole-6-carboxylate NMR (CDCl 3 5) 1.07 (3H, t, J=7Hz), 1.28 (6H, d, J=7Hz), 1.69 (2H, 3.12 (2H, 3.54 (1H, m), 3.94 (3H, 4.84 (2H, 4.87 (1H, 5.22 (1H, 5.98 (1H, 7.89 (1H, d, J=8Hz), 7.94 (1H, d, J=8Hz), 8.04 (1H, s) (18) Methyl 1-(2-chlorobenzyl)-3-isobutyryl-2-(1propenyl)indole-6-carboxylate NMR (CDC1 3 5) 1.23 (6H, d, J=7Hz), 1.93 (3H, d, J=7Hz), 3.51 (1H, 3.89 (3H, 5.50 (2H, s), 6.41 (1H, 6.42 (1H, d, J=8Hz), 6.73 (1H, d, J=l6Hz), 7.07 (1H, t, J=8Hz), 7.23 (1H, t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.89 (1H, 7.95 (1H, d, J=8Hz), 8.18 (1H, d, J=8Hz) (19) Methyl 2-(l-acetoxypropyl)-l-(2-chlorobenzyl)-3isobutyrylindole-6-carboxylate NMR (CDC1 3 5) 1.04 (3H, t, J=7Hz), 1.2-1.35 (9H, 1.9-2.1 (2H, 3.59 (1H, 3.89 (3H, s), 5.61 (1H, d, J=l7Hz), 5.79 (1H, d, J=17Hz), 6.04 (1H, d, J=8Hz), 6.71 (1H, 7.01 (1H, t, J=8Hz), 7.21 (1H, t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.87 (1H, 7.92 (1H, d, J=8Hz), 7.97 (1H, d, J=8Hz) WO 96/32379 PCT/JP96/00892 149 Methyl 3-(3,3-dimethylbutaoyl)-1-(2chlorobenzyl)indole-6-carboxylate NMR (CDCl 3 5) 1.09 (9H, 2.69 (2H, 3.93 (3H, 5.50 (2H, 6.73 (1H, d, J=Bz), 7.17 (1H, t, J=8Hz), 7.28 (1H, t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.82 (1H, 8.00 (1H, d, J=8Hz), 8.08 (1H, s), 8.53 (1H, d, J=8Hz) (21) Ethyl 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindol-6ylacetate IR (Neat) 1730, 1655 cm- 1 NMR (CDC1 3 5) 1.00 (3H, t, J=7Hz), 1.20 (3H, t, J=7iz), 1.29 (6H, d, J=7Hz), 1.55-1.65 (2H, m), 3.01-3.08 (2H, 3.54-3.60 (1H, 3.69 (2H, s), 4.11 (2H, q, J=7Kz), 5.44 (2H, 6.30 (1H, d, 7.03-7.10 (2H, 7.21 (2H, d, 7.46 (1H, d, J=7.5Hz), 7.89 (1H, d, MASS 440 74 (bp) (22) Methyl 1-(6-chloro-3,4-iethylenecioxybenzyl)-3isobutyryl-2-propylindol-6-ylacetate mp 119-120.5*C IR (KBr) 1744, 1735, 1732, 1644, 1508 cmn 1 NMR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.29 (6H, d, J=7Hz), 1.55-1.65 (2H, 3.00-3.07 (2H, 3.53- 3.61 (1H, 3.70 (3H, 3.72 (2H, 5.33 (2H, 5.80 (2H, 5.91 (2H, s),6.93 (1H, 7.01 (1H, 7.21 (1H, d, J=7.5Hz), 7.89 (1H, d, MASS 470 74 (bp) (23) Methyl 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate NMR (CDC1 3 1.02 (3H, t, J=7Hz), 1.75 (2H, m), 2.62 (2H, t, J=7Hz), 3.87 (3H, 5.42 (2H, s), 6.16 (1H, d, J=8Hz), 6.42 (1H, 7.01 (1H, t, WO 96/32379 PCT/JP96/00892 150 J=8Hz), 7.19 (1H, t, J=8Hz) 7.42 (1H, t, J=8Hz), 7.58 (1H, t, J=8Hz), 7.79 (1K, d, J=8Hz), 8.92 (1H,

S)

(24) Methyl 1-( 2 -bromobenzyl)-2-propylindole-6-carboxylate NMR (CDC1 3 6) 0.99 (3H, t, J=7Hz), 1.74 (2H, m), 2.59 (2H, t, J=7Hz), 3.88 (3H, 5.37 (2H, S), 6.12 (1H, d, J=8Hz), 6.42 (1H, 7.0-7.15 (2H, 7.52-7.65 (2H, 7.79 (1H, d, J=8Hz), 7.89 (1H, s) Methyl 2-acetyl-l-(2-chlorobenzyl)-3-iethylincole-6carboxylate NMR (CDCl 3 6) 2.61 (3H, 2.71 3.90 (3H, 5.82 (2H, 6.19 (1H, d, J=8Hz), 6.97 (1H, t, J=8Hz), 7.14 (1H, t, J=8Hz), 7.41 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz), 7.86 (1H, d, J=8Hz), 7.99 (1H,

S)

(26) Methyl 2-chloro-l-(2-chlorobenzyl)-3-ethylindole-6carboxylate NMR (CDC1 3 6) 1.29 (3H, t, J=7Hz), 2.83 (2H, q, J=7Hz), 3.90 5.50 (2H, 6.29 (1H, d, J=8Kz), 7.04 (1H, t, J=8Hz), 7.19 (1H, t, J=8Hz), 7.42 (1H, d, J=8Hz), 7.61 (1H, d, J=8Hz), 7.83 (1H, d, J=8Hz), 7.90 (1H, s) (27) Methyl 1-(2-chlorobenzyl)-2-propionyl-3-propyliole-6carboxylate NNR (CDC1 3 6) 1.07 (3H, t, J=7Hz), 1.17 t, J=7Hz), 1.78 (2H, 2.94 (2H, q, J=7Hz), 3.09 (2H, 3.89 (3H, 5.72 (2H, 6.23 (1H, d, J=8Hz), 6.98 (1H, t, J=8Hz), 7.15 (1H, t, J=8Hz), 7.39 (1H, d, J=8Hz), 7.76 (1H, d, J=8Hz), 7.83 (1H, d, J=8Hz), 7.96 (1H, s) WO 96/32379 WO 9632379PCT/JP96/00892 151 (28) Methyl 1- 2 -chlorobenzyl)-2-sobutyryl..propylnole6carboxylate NM. (CDC1 3 5 1.03 (3K, t, J=7Hz), 1.11 (6H, d, J=7Hz), 1.75 (2H, mn), 3.02 (2H, in), 3.35 (1H, in), 3.89 (3H, 5.64 (2H, 6.28 (1H, di, J=8Hz), 6.99 (1H, t, J=8Kz), 7.16 (1H, t, J=8Hz), 7.38 (1H, d, J=8Hz), 7.73 (1H, d, J=8Hz), 7.84 (1H, cd, J=8Hz), 7.96 (1H, s) (29) Methyl 1- (2-chlorobenzyl)-3- (3-oxo-1-butenyl) indole-6carboxylate NMR (CDCl 3 5 2.38 (3H, 3.93 (3H, 5.48 (2H, 6.7-6.8 (2H, mn), 7.17 (1H, t, J=8Kz), 7.28 (1H, t, J=8Hz), 7.47 (1K, di, J=8Hz), 7.54 (1K, 7.74 (1H, d, J=15Hz), 7.96 (1K, 8.11 (1K, s) Methyl 4-(2-chlorobenzyl)-3-oxo-1,2,3,4tetrahydrocyclopent fbIindole-6-carboxylate NM?. (OD1 3 5 3.06 (2H, mn), 3.17 (2H, mn), 3.92 (3K, 5.72 (2K, 6.59 (1K, di, J=8Kz), 7.06 (1H, t, J=8Hz), 7.19 (1H, t, J=8Hz), 7.42 (1K, di, J=8Kz), 7.78 (1H, d, J=8Kz), 7.87 (1H, di, J=8Kz), 8.04 (1H,

S)

(31) Methyl 4- (6-chloro-3, 4-methylenedioxybenzyl) -3-oxo- 1,2,3, 4-tetrahydrocyclopent fbIincole-6-carboxylate NMR (CDC1 3 5) :3.06 (3H, in), 3.14 (2H, in), 3.94 (3H, 5.60 (2H, 5.88 (2K, 6.11 (1H, 6.88 (1H, 7.76 (1H, di, J=8Hz), 7.86 (1H, di, J8Kz), 8.09 (1H, s) (32) 1- (2-Chlorobenzyl) -3--cyclopropariecarbonyl-2propylindole- 6-carboxainide mp 162-163.5*C (KBr) 1675, 1612, 1444, 1383 cmJ 1 WO 96/32379 PCT/JP96/00892 152 NMR (DMSO-d 6 6) 0.90 (3H, t, J=7Hz), 1.08 (4H, d, J=7Hz), 1.48 (2H, sextet, J=7Hz), 2.65-2.72 (1H, 3.00 (2H, t, J=7Hz), 5.62 (2H, 6.21 (1H, d, J=8Hz), 7.18 (1H, t, J=8Kz), 7.32 (1H, t, J=8Hz), 7.58 (1H, d, J=8Hz), 7.80 (1H, d, J=8Hz), 7.93 (1H, 8.01 (1H, 8.10 (1H, d, J=7Hz) MASS 395 74 (bp) (33) 1-(6-Chloro-3,4-iethylenedioxybenzyl)-3cyclopropanecarbonyl-2-propylindole-6-carboxaide mp 162-163.5'C IR (KBr) 1675, 1612, 1444, 1383 cm- 1 NMR (DMSO-d 6 5) 0.90 (3H, t, J=7Hz), 1.08 (4H, d, J=7Hz), 1.48 (2H, sextet, J=7Hz), 2.65-2.72 (1H, 3.00 (2H, t, J=7Hz), 5.62 (2H, 6.21 (1H, d, J=8Hz), 7.18 (1H, t, J=8Hz), 7.32 (1H, t, J=8Hz), 7.58 (1H, d, J=8Hz), 7.80 (1K, d, J=8Hz), 7.93 (1H, 8.01 (1H, 8.10 (1K, d, J=7z) MASS 395 74 (bp) (34) 1-(2-Chlorobenzyl)- 3 -cyclobutanecarbonyl-2-propylindole- 6-carboxamide mp 162-165*C IR (KBr) 1660, 1654, 1445, 1437 cm 1 NMR (CDC1 3 6) 1.02 (3H, t, J=7Hz), 1.62 (2H, sextet, J=7Kz), 1.95-2.14 (2K, 2.35-2.52 (4H, 3.05-3.10 (2H, 4.05 (1H, quintet, J=7Kz), 5.50 (2H, 6.22 (1K, d, J=7.5Hz), 7.04 (1H, t, 7.21 (1H, t, J=7.5Kz), 7.47 (1H, d, J=7.5z), 7.63 (1K, d, J=7.5Kz), 7.82 (1K, 7.97 (1H, d, MASS 409 74 (bp) 1-(6-Chloro-3,4-iethylenedioxybenzyl)-3cyclobutanecarbonyl-2-propylindole-6-carboxaide WO 96/32379 PCTIJP96/00892 153 mp 240-2410C IR 1658, 1636, 1503, 1482, 1451 cm- 1 NMR (DMSO-d 6 5) 0.94 (3H, t, J=7Hz), 1.49 (2H, sextet, J=7Hz), 1.79-1.90 (1H, 1.96-2.07 (1H, 2.24-2.33 (4H, 3.03 (2H, t, J=7Hz), 4.07 (1H, quintet, J=7Hz), 5.51 (2H, 5.65 (1H, s), 6.00 (2H, 7.24 (1H, 7.31 (1H, br 7.79 (1K, d, J=7.5Hz), 7.94 (1H, br 7.95 (1H, d, 8.00 (1H, s) MASS 453 85 (bp) (36) 1-(2-Chlorobenzyl)-3-cyclopentanecarbonyl-2propylindole-6-carboxamide mp 201.5-202.5oC IR (KBr) 1654, 1607, 1447, 1437, 1387 cm- 1 NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.59-1.82 (6H, 1.99-2.07 (4H, 3.02-3.09 (2H, 3.79 (1H, quintet, J=7Kz), 5.52 (2H, 6.23 (1H, d, 7.05 (1H, t, J=7.5Hz), 7.22 (1H, t, J=7.5Hz), 7.47 (1H, d, J=7.5Kz), 7.63 (1H, d, 7.86 (1H, 8.04 (1H, d, MASS 423 74 (bp) (37) 1-(6-Chloro-3,4-methylenedioxybenzyl)-3cyclopentanecarbonyl-2-propylindole-6-carboxaide mp 236-237*C IR (KBr) 1662, 1506, 1477 cm- 1 NMR (DMSO-d 6 5) 0.93 (3H, t, J=7Kz), 1.40-1.50 (2H, 1.61-1.68 (4H, 1.81-1.95 (4H, 3.00 (2H, t, J=7Hz), 3.73-3.82 (1H, 5.50 (2H, 5.64 (1H, 6.00 (2H, 7.24 (1H, 7.30 (1H, br 7.80 (1K, d, J=7.5Hz), 7.95 (1H, br 8.00 (1H, d, J=7.5Kz), 8.01 (1H, s) MASS 467 85 (bp) WO 96/32379 PCT/JP96/0092 154 (38) 1-(2-Chlorobenzyl)- 3 -cyclohexanecarbonyl-2-propylindole- 6-carboxamide mp 208-210'C IR (KBr) 1686, 1625, 1609, 1444, 1410 cin 1 NMR (DMSO-d 6 6) 0.90 (3H, t, J=7Hz), 1.19-1.30 (1H, 1.39-1.49 (6H, 1.67-1.93 (5H, 2.99 (2H, t, J=7Hz), 3.18-3.27 (1H, 5.61 (2H, 6.19 (iN, d, J=7.5Hz), 7.18 (1H, t, J=7.5Hz), 7.29 (1H, 7.32 (1H, t, J=7.5Hz), 7.58 (1H, d, 7.80 (1H, d, J=7.5Hz), 7.90 (2H, d, J=7.5Hz), 93.00 (1H, s) MASS 437 85 (bp) (39) 1-(6-Chloro-3,4-iethylenedioxybenzyl)-3cyclohexanecarbonyl-2-propylindole-6-carboxaide mp 209-211*C IR (KBr) 1623, 1611, 1506, 1391 cm- 1 NMR (DMSO-d 6 5) 0.93 (3H, t, J=7Hz), 1.20-1.28 (1H, 1.39-1.51 (6H, 1.68-1.92 (5H, 2.96-3.01 (2H, 3.19-3.27 (1H, 5.52 (2H, 5.64 (1H, 6.00 (2H, 7.24 (1H, 7.31 (1H, br s), 7.85 (2H, AB, J=7.5, 7.5Hz), 7.96 (1H, br 8.01 (1H, s) MASS 481 85 (bp) 1-(2-Chlorobenzyl)-3-(3-iethyl-2-butenoyl)-2propylindole-6-carboxaiide mp 187-188'C IR 1680, 1648, 1614, 1598, 1446, 1384 cm- 1 NM (DMSO-d 6 5) 0.90 (3K, t, J=7Hz), 1.49 (2H, sextet, J=7Hz), 2.01 (3H, 2.10 (3H, 2.99 (2H, t, J=7Hz), 5.61 (2H, 6.19 (1H, d, 6.66 (1H, 7.19 (1K, t, J=7.5Hz), 7.29 (1H, br 7.32 (1H, t, J=7.5Hz), 7.58 (1H, d, J=7.5Hz), 7.78 (1H, d, J=7.5Kz), 7.90 (1H, br s), WO 96132379 PCT1JP96/00892 155 7.97 (2H, d, J=7 SHz) MASS 409 (M 85 (bp) (41) 1-(6-Chloro-3,4-methylenedioxybenzyl)-3-(3-methyl-2butenoyl)-2-propylindole-6-carboxamide mp 227-229*C IR (KBr) 1654, 1606, 1505, 1482, 1449, 1388 cm-- NMR (DMSO-d 6 5) 0.94 (3H, t, J=7Hz), 1.50 (2H, sextet, J=7Hz), 2.01 (3H, 2.09 (3H, 3.00 (2H, t, J=7Hz), 5.50 (2H, 5.67 (1H, 6.00 (2H, 6.66 (1H, 7.25 (1H, 7.30 (1H, br 7.77 (1H, d, J=7.5Hz), 7.91-7.99 (3H, m) MASS 453 85 (bp) (42) 1-(2-Chlorobenzyl)-3-(3-methoxybutanoyl)-2-propylindole- 6-carboxamide mp 155-157*C IR (KBr) 1656, 1610, 1447, 1437, 1389 cm-1 NMR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.34 (3H, d, J=7Hz), 1.63 (2H, sextet, J=7Hz), 3.01-3.09 (3H, 3.41 (3H, 3.47 (1H, d, J=16, 7Hz), 4.14 (1H, sextet, J=7Hz), 5.51 (2H, 6.22 (1H, dd, 1Hz), 7.05 (1H, ddd, J=7.5, 7.5, 1Hz), 7.23 (1H, ddd, J=7.5, 7.5, 1Hz), 7.46 (1H, dd, 1Hz), 7.62 (1H, dd, J=7.5, 1Hz), 7.76 (1H, d, J=lHz), 8.09 (1H, d, MASS 427 74 (bp) (43) 1-(6-Chloro-3,4-methylenedioxybenzyl)-3-(3iethoxybutanoyl)-2-propylindole-6-carboxamide mp 190-192.5*C IR 1654, 1652, 1608, 1505, 1482 cr'1 NMR (CDC1 3 5) 1.04 (3H, t, J=7Kz), 1.33 (3H, d, J=7Hz), 1.62 (2K, sextet, J=7Kz), 3.00-3.09 (3H, 3.40 (3H, 3.45 (1H, dd, J=16, 7Hz), 4.12 WO 96/32379 WO 9632379PCT/JP96/00892 156 (1H, sextet, J=7Hz), 5.40 (2H, 5.70 (1H, s), 5.90 (2H, 6.91 (1H, 7.61 (1H, d, 7.88 (1H, 8.08 (1H, d, MASS 471 74 (bp) (44) 3-Acetyl-6-chloro-1- (2-chlorobenzyl) indole NMR (CDCl 3 5) :2.49 (3H, 5.41 (2H, 6.75 d, J=8Hz), 7.18 (1H, t, J=8Hz), 7.19 (1H, t, J=8Hz), 7.2-7.33 (3H, in), 7.48 (1H, d, J=8Hz), 7.72 (1H, 8.33 (1H, d, J=8Hz) Examople 74 The following compounds described in to (43) were prepared in a similar manner to that of Exmle2 9- (2-Chlorobenzyl)-5-oxo-5, 6,7, 8-tetrahydrocarbazole-2carboxylic acid NM'R (CDCl 3 5) 2.24 (2H, in), 2.63 (2H, t, J=7Hz), 2.88 (2H, t, J=7Kz), 5.47 (2H, 6.36 (1H, d, J=8Hz), 7.09 (1H, t, J=8Hz), 7.26 (1H, t, J=8Hz), 7.47 (1H, d, J=8Hz), 8.02 (1H, 8.04 (1H, d, J=8Hz), 8.37 (1H, d, J=8Hz) 4- (2-Ohlorobenzyl) -l-oxo-1,2, 3, 4-tetrahydrocyclopent- [bjindole-6-carboxylic acid NM. (DMSO-d 6 5 2.87 (2H, mn), 3.03 (2H, in), 5.64 (2K, 6.93 (1H, d, J=8Kz), 7.29 (1H, t, J=8Kz), 7.37 (1H, t, J=8Hz), 7.58 (1H, d, J=8Kz), 7.78 (1H, d, J=8Hz), 7.83 (1H, d, J=8Hz), 8.05 (1K, ,s) 1- 2 -Chlorobenzyl)-3-isobutyryl-2-propylindole-7carboxylic acid NI4R (CDCl 3 5) 1.03 (3K, t, J=7Kz), 1.29 (6H, d, J=7Kz), 1.64 (2H, in), 3.03 (2H, in), 3.56 (1H, in), 5.75 (2H, 6.04 (1H, d, J=8Kz), 6.96' (1H, t, WO 96/32379 PCT/JP96/00892 157 J=8Hz), 7.12 (1H, t, J=8Hz), 7.29 (1H, t, J=8Hz), 7.33 (1H, d, J=8Hz), 7.67 (1H, d, J=8Hz) 8.19 (1H, d, J=8Hz) 1-( 2 -Chlorobenzyl)-3-isobutyryl-2-propylindoe.S carboxylic acid NMR (DMSO-d 6 5) 0.90 (3H, t, J=8Hz), 1.19 (6H, d, J=8Hz), 1.62 (2H, sextet, J=8Hz), 3.02 (2H, t, J=8Hz), 3.51 (1H, septet, J=8Hz), 5.64 (2H, s), 6.28 (1H, d, J=8Hz), 7.18 (1K, t, J=8Hz), 7.32 (1H, t, J=8Hz), 7.50 (1H, d, J=8Hz), 7.56 (1H, d, J=8Hz), 7.78 (1H, d, J=8Hz), 8.58 (1K, s) 1-(6-Chloro-3, 4 -methylenedioxybenzyl)-3-isobutyryl-2propylindole-5-carboxyiic acid NMR (CDC1 3 5) 1.04 (3H, t, J=7Hz), 1.32 (6H, d, J=7Hz), 1.62 (2H, sextet, J=7Hz), 3.06-3.12 (2H, 3.66 (1H, septet, J=7Hz), 5.36 (2H, 5.74 (1H, 5.90 (2H, 6.93 (1H, 7.23 (1H, d, J=8Hz), 7.96 (1H, d, J=1, 8Hz), 8.76 (1K, d, J=lz) 1-( 2 -Chlorobenzyl)-2-propylinole-4-carboxylic acid NMR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.80 (2H, m), 2.67 (2H, t, J=7Hz), 5.43 (2K, 6.19 (1K, d, J=8Kz), 7.03 (1H, t, J=8Kz), 7.1-7.25 (3H, 7.34 (1K, c, J=8Hz), 7.41 (1H, d, J=8KZ), 7.99 (1H, d, J=8Hz) 9-(2-Chlorobenzyl)-8-oxo-5,6,7, 8 -tetrahydrocarbazole-2carboxylic acid NMR (CDC1 3 5) 2.28 (2H, 2.68 (2H, t, J=7Hz), 3.13 (2H, t, J=7Kz), 5.95 (2K, 6.27 (1K, d, J=8Hz), 6.99 (1H, t, J=8Hz), 7.16 (1K, t, J=8Kz), 7.42 (1H, c, J=8Hz), 7.77 (1K, c, J=8Hz), 7.87 (1H, WO 96/32379 PCTJP96/00892 158 d, J=8Hz), 8.03 (1H, s) 9-(6-Chloro- 3 ,4-methylenedioxybenzyl)-8-oxo-5,6,7,8tetrahydrocarbazole-2-carboxylic acid NMR (DMSO-d 6 2.19 (2H, 2.63 (2H, t, J=7Hz), 3.06 (2H, t, J=7Hz), 5.70 (1H, 5.82 (21, s), 5.96 (2H, 7.16 (1H, 7.73 (1H, d, J=8Hz), 7.88 (1H, d, J=8Wz), 7.98 (1H, s) 1-(4-Bromo-2-chlorobenzyl)-3-isobutyryl-2-propylind~le- 6-carboxylic acid mp 234-235*C IR (KBr) 1677, 1648, 1418 cm- 1 NMR (CDC1 3 1.04 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.54-1.64 (2H, 3.02-3.08 (2H, 3.50- 3.61 (1H, 5.44 (2H, 6.10 (1H, t, J=8Hz), 7.18 (1H, dd, J=8, 1Hz), 7.65 (1H, d, J=lHz), 7.94- 8.05 (3H, m) MASS 476 1-( 2 -Chlorobenzyl)-3-orpholinoacetyl-2-propylindoe6 carboxylic acid IR 1652, 1441, 1115 cm- 1 NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.60 (2H, sextet, J=7Wz), 2.74 (4H, t, J=6.5Hz), 3.03-3.09 (2H, 3.86 (4H, t, J=6.5Hz), 3.93 (2H, 5.52 (2H, 6.25 (1H, d, J=7.5Hz), 7.05 (1H, t, 7.22 (1H, t, J=7.5Hz), 7.47 (1H, d, 7.90-8.01 (3H, m) MASS 455 (11) 1-(2-Ohlorobenzyl)-3-(N,N-diiethylcarbamoyl)-2propylindole-6-carboxylic acid IR (KEr) 1704, 1596, 1219 cm 1 NMR (CD 3 5) 0.93 (3H, t, J=7Hz), 1.52-1.63 (2H, WO 96/32379 WO 9632379PCT/JP96/00892 159 mn), 2.80-2.90 (2H, in), 3.13 (6H, 5.48 (2H, s), 6.30 (1H, d, J=7.5Hz), 7.04 (1H, t, J=7.5Hz), 7.20 (1H, t, J=7.SHz), 7.44 (1H, d, J=7.5Hz), 7.50 (1H, d, J=7.5Hz), 7.91 (1H, d, J=7.5Hz), 7.96 (1H, s) MASS :399 (12) 1- (2-Chlorobenzyl) 3 -morpholinocarbonyl-2-propylindole- 6-carboxylic acid IR (KBr) :3410, 1615, 1540, 1444, 1400 cm- 1 NMR (DMSO-d 6 6) :0.84 (3H, t, J=7Hz), 1.39-1.49 (2H, in), 2.76-2.84 (2H, in), 3.56 (6H, br 3.68 (2H, br 5.52 (2H, 6.24 (1H, d, J=7.5Hz), 7.16 (1H, t, J=7.5Hz), 7.29 (1H, t, J=7.5Hz), 7.40 (1H, d, J=7.5Hz), 7.54 (1H, d, J=7.5Hz), 7.79 (1H, s), 7.81 (1H, s) MASS (in/z) :439 99 (bp) (13) 1- (2-Chlorobenzyl) -2-propylindole-3, 6-dicarboxylic acid mp :241-243*C (dec.) IR :1669, 1525, 1443, 1385 cmf 1 NMR (DMSO-d 6 6) :0.90 (3H, t, J=7Hz), 1.44-1.55 (2H, mn), 3.12 (2H, t, J=7Hz), 5.56 (2H, 6.22 (1H, d, 7.17 (1H, t, J=7.5Hz), 7.30 (1H, t, 7.57 (1H, d, J=7.5Hz), 7.79 (1K, 8.06 (1H, d, MASS :370 99 (bp) (14) 1- (2-Chlorobenzyl) 2 -ethyl-3-fornylindole-6-carboxylic acid mp :241-242*C (dec.) IR (KBr) :1675, 1650, 1295 cmf 1 NMR (CDC1 3 65) :1.29 (3H, t, J=7Hz), 3.09 (2H, q, J=7Hz), 5.52 (2H, 6.30 (1H, d, J=7.SHz), 7.08 (1H, t, J=7.5Hz), 7.25 (1H, t, J=7.5Hz), 7.49 (1K, d, J=7.5Hz), 7.97 (1H, 8.03 (1H, d, WO 96/32379 PCT1JP96/00892 160 8.35 (1W, d, J=7.5Hz), 10.25 (1H, s) MASS 340 1-( 2 -Chlorobenzyl)-3-foriylindole-6-carboxylic acid NMR (DMSQ-d 6 5) 5.73 (2H, 6.96 (1H, d, J=8Hz), 7.23-7.4 (2H, 7.56 (1H, d, J=8Hz), 7.89 (1H, d, J=8Hz), 8.15 (1H, 8.21 (1H, 8.54 (iN, s), 10.0 (1H, s) (16) 3-Acetyl-l-( 2 -chlorobenzy)-2-methylindole-6-carboxylic acid NMR (CDC1 3 5) 2.71 (3H, 2.76 (3H, 5.50 (2H, 6.22 (1W, d, J=8Wz), 7.05 (1W, t, J=8Hz), 7.22 (1H, t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.95-8.15 (3H, 8.08 (1H, d, J=8Hz) (17) 1-(2-Chlorobenzyl)- 2 -iethy1-3-propionylindole-6carboxylic acid NMR (DMSO-d 6 5) 1.14 (3H, t, J=7Hz), 2.69 (3H, s), 3.04 (2H, q, J=7Hz), 5.67 (2H, 6.24 (1H, d, J=8Hz), 7.18 (1H, d, J=8Hz), 7.22 (1H, t, J=8Wz), 7.58 (iN, d, J=8Hz), 7.83 (1H, d, J=8Hz), 7.99 (1H, 8.16 (1H, d, J=8Hz) (18) 1-( 2 -Chlorobenzo[blthiophen-3-ylmethyl)-3-isobutyryl-2iethylirdole-6-carboxylic acid NMR (CDC1 3 5) 1.25 (6H, d, J=7Hz), 2.71 (3H, s), 3.50 (1W, 5.61 (2W, 6.99 d, J=8Wz), 7.12 (1W, t, J=8Hz), 7.28 (1H, t, J=8Hz), 7.68 (1H, d, J=8Hz),7.95-8.02 (2W, 8.23 (1H, s) (19) 1-(Benzothiazol-2-ylmethyl)- 2 -ethyl-3-isobutyrylindole- 6-carboxylic acid NMR (CDC1 3 5) 1.28 (3H, t, J=7Wz), 1.30 (6H, d, J=7Hz), 3.24 (2H, q, J=7Wz), 3.58 (1H, in), 5.86 WO 96/32379 PCT/JP96/00892 161 (2H, 7.39 (1H, t, J=8Hz), 7.52 (1H, t, J=8Hz) 7.87 (1H, d, J=8Hz), 7.9-8.06 (3H, 8.20 (1H, s) 1-(Benzo[blthiophen-5-yliethyl)-3-isobutyryl-2propylindole-6-carboxylic acid NMR (CDC1 3 6) 1.02 (3H, t, J=7Hz), 1.32 (6H, d, J=7Hz), 1.63 (2H, 3.14 (2H, 3.57 (1H, m), 5.58 (2H, 7.04 (1H, d, J=8Hz), 7.19 (1H, d, J=6Hz), 7.31 (1H, 7.43 (1H, d, J=6Hz), 7.81 (1H, d, J=8Hz), 7.9-8.02 (2H, 8.08 (1H, s) (21) 1-( 2 ,4-Dichlorobenzyl)-3-isobutyryl-2-propylindole-6carboxylic acid NMR (DMSO-d 6 6) 0.92 (3H, t, J=7Kz), 1.18 (6H, d, J=7Hz), 1.46 (2H, sextet, J=7Hz), 3.02-3.07 (2H, 3.54 (2H, septet, J=7Hz), 5.68 (2H, 6.27 (1H, d, J=8Hz), 7.28 (1H, dd, J=2, 8Hz), 7.76 (1H, d, J=2Hz), 7.84 (1H, d, J=8Hz), 7.96 (1H, 8.01 (1H, d, J=8Hz) (22) 3-Isobutyryl-2-propyl-l-(3-pyridylnethyl)indole-6carboxylic acid NMR (CDC13, 6) 1.04 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.63 (2H, sextet, J=7Hz), 3.15 (2H, t, J=7Hz), 3.57 (2H, septet, J=7Hz), 5.51 (2H, s), 7.19-7.28 (2H, 7.95-8.01 (2H, 8.04 (1H, s), 8.52-8.56 (2H, m) (23) 3-Isobutyryl-2-propyl-l-(l-naphthyliethyl)indole-6carboxylic acid NMR (DMSO-d 6 6) 0.86 (3H, t, J=7Hz), 1.22 (6H, d, J=7Hz), 1.52 (2H, sextet, J=7Hz), 3.05-3.10 (2H, in), 3.60 (1K, septet, J=7Kz), 6.15 (1H, d, J=8Hz), 6.17 (2H, 7.28 (1H, t, J=8Hz), 7.64 (1H, t, J=8Kz), 7.72 (1H, t, J=8Hz), 7.84 (2H, d, J=8Hz), WO 96/32379 PCT/JP96/00892 162 7.92 (1H, 8.12 (1H, d, J=8Hz), 8.15 (1H, d, J=8Hz), 8.36 (1H, d, J=8Hz) (24) 3-Isobutyryl-2-propyl-l-(2-naphthylmethyl)irdole-6carboxylic acid NMR (DMSO-d 6 6) 0.92 (3H, t, J=7Hz), 1.19 (6H, d, J=7Hz), 1.48 (2H, sextet, J=7Hz), 3.14-3.18 (2H, 3.57 (1H, septet, J=7Hz), 5.81 (2H, 7.20 (1K, d, J=8Kz), 7.45-7.52 (3K, 7.76-7.90 (4H, 8.02 (1K, d, J=8Kz), 8.08 (1H, s) l-Allyl- 3 -isobutyryl-2-propylindole-6-carboxylic acid NM (CDC1 3 6) 1.08 (3H, t, J=7Hz), 1.28 (6K, d, J=7Hz), 1.69 (2H, 3.13 (2K, 3.56 (1H, i), 4.88 (2K, 4.90 (1H, 5.23 (1H, 5.98 (1H, 7.94 (1H, d, J=8Kz), 8.02 (1H, d, J=8Hz), 8.13 (1K, s) (26) 1-(2-Chlorobenzyl)-3-isobutyryl-2-(l-propenyl)indole-6carboxylic acid NMR (CDC1 3 5) 1.26 (6H, d, J=7Hz), 1.93 (3H, d, J=7Kz), 3.51 (1H, 5.50 (2K, 5.92 m), 6.44 (1K, d, J=8Kz), 6.74 (1H, d, J=l6Hz), 7.09 (1H, t, J=8Hz), 7.23 (1H, t, J=8Kz), 7.48 (1K, d, J=8Kz), 7.92 (1K, 8.02 (1K, d, J=8Kz), 8.21 (1K, d, J=8Kz) (27) 1-(2-Chloroberzyl)-2-(l-hydroxypropyl)-3isobutyrylindole-6-carboxylic acid NM (CDC1 3 5) 0.92 (3H, t, J=7Hz), 1.29 (3K, d, J=7Hz), 1.36 (3K, d, J=7Kz), 1.52 (1H, 1.88 (1H, 3.70 (1K, 4.73 (1H, 5.51 (1K, d, J=17Hz), 5.69 (1K, d, J=l7Hz), 6.44 (1H, d, J=8Hz), 7.09 (1H, t, J=8Kz), 7.23 (1H, t, J=8Kz), 7.45 (1H, ci, J=8Kz), 7.9-8.1 (3H, m) WO 96/32379 WO 9632379PCT/JP96/00892 163 (28) 1- (2-Chlorobenzyl) 3-dimethylbutanoyl) irdole-6carboxylic acid NM~R (CDC1 3 5) 1.08 (9H, 2.70 (2H, 5.52 (2H, 6.77 (1H, d, J=8Hz), 7.17 (1H, t, J=8Hz), 7.28 (1H, t, J=8Hz), 7.47 (1H, d, J=8Kz), 7.86 (1H, s), 8.03 (1H, d, J=8Kz), 8.12 (1K, 8.53 (1H, d, J=8Hz) (29) 1- (6-Chloro-3, 4-methylerxedioxybenzyl) -3-methoxyacetyl-2propylindole-6-carboxylic acid NMR (CDC1 3 :0.96 (3H, t, J=7Hz), 1.45-1.58 (2H, mn), 3.10 (2H, t, J=7Hz), 3.40 (3H, 4.69 (2H, 5.55 (2H, 5.76 (1H, 5.98 (2K, 7.23 (1H, 7.82 (1H, d, J=8Kz), 7.94 (1H, 7.96 (1K, d, J=8Kz) 1- (2-Chlorobenzyl) -3-ethoxyacetyl-2-propylindole-6carboxylic acid NMR (DMSO-d 6 5) :0.94 (3H, t, J=7Kz), 1.17 (3H, t, J=7Hz), 1.48 (2K, sextet, J=7Kz), 3.08 (3H, t, J=7Kz), 3.62 (2H, q, J=7Kz), 4.74 (2H, 5.68 (2K, 6.28 (1H, d, J=8Kz), 7.18 (1H, t, J=8Kz), 7.32 (1K, t, J=8Kz), 7.56 (1H, d, J=8Kz), 7.82 (1H, d, J=8Kz), 7.96 (1K, 7.98 (1H, d, J=8Kz) (31) 1- (2-Chlorobenzyl) -3-isobutyryl-2-propyjlindol-6-ylacetic acid IR (KBr) :1715, 1650 crrJ 1 NMR (CDC1 3 5 1.00 (3H, t, J=7Kz), 1.30 (6H, d, J=7Kz), 1.54-1.66 (2H, in), 3.00-3.08 (2H, mn), 3.50- 3.62 (1H, in), 3.71 (2H, 5.47 (2H, 6.30 (1K, d, J=7.5Kz), 7.01-7.08 (2H, in), 7.19-7.25 (2H, in), 7.45 (1K, d, J=7.5Kz), 7.89 (1K, d, MASS (in/z) :412 74 (bp) WO 96/32379 PCT/JP96/00892 164 (32) 1-(6-Chloro-3,4-methylenedioxybenzyl)-3-isobutyry2.

propylindole-6-ylacetic acid mp 81-83 0

C

IR (KBr) 1715, 1650 cm- 1 NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.29 (6H, d, J=7Hz), 1.54-1.67 (21, 3.01-3.07 (2H, 3.51- 3.60 (1H, 3.75 (2H, 5.33 (2H, 5.79 (1H, 5.89 6.91 (1H, 7.12 (11, 7.21 (1H, d, J=7.5Hz), 7.89 (1H, d, MASS 456 (M 74 (bp) (33) 1-(2-Chlorobenzyl)- 2 -propylindole-6-carboxylic acid NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.74 (2H, m), 2.61 (2H, t, J=7Hz), 5.42 (2H, 6.19 (1H, d, J=8Hz), 6.46 (1H, 7.02 (1H, t, J=8Hz), 7.18 (1H, t, J=8Kz), 7.43 (1H, d, J=8Hz), 7.61 (1H, d, J=8Hz), 7.85 (1H, d, J=BHz), 7.95 (1H, s) (34) 1-(2-Broiobenzyl)- 2 -propylindole-6-carboxylic acid NMR (CDC1 3 5) 1.00 (3H, t, J=7Hz), 1.73 (2H, i), 2.61 (2H, t, J=7Hz), 5.37 (2H, 6.12 (1H, d, J=8Hz), 6.46 (1H, 7.0-7.18 (2H, 7.61 (1H, d, J=8Hz), 7.85 (1H, d, J=8z), 7.96 (1H, s) (35) 2-Acetyl-l-(2-chlorobenzyl)-3-methylindole-6-carboxylic acid NMR (DMSO-d 6 5) 2.62 (3K, 2.69 (3K, 5.82 (2H, 6.10 (1H, d, J=8Hz), 7.09 (1H, t, J=8Kz), 7.24 (1H, t, J=8Hz), 7.51 (1H, d, J=8Hz), 7.72 (1H, d, J=8Kz), 7.93 (1K, d, J=8Hz), 7.96 (1H, s) (36) 2-Chloro-l-(2-chlorobenzyl)-3-ethylindole-6-carboxylic acid NMR (CDC1 3 5) 1.30 (3H, t, J=7Hz), 2.84 (2H, q, J=7Hz), 5.50 (2H, 6.29 (1H, d, J=8Hz), 7.06 WO 96/32379 PCTIJP96/00892 165 (1H, t, J=8Hz), 7.19 (1H, t, J=8Hz), 7.43 (1H, d, J=8Hz), 7.63 (1H, d, J=8Hz), 7.88 (1H, d, J=8Hz), 7.93 (1H, s) (37) 1-( 2 -Chlorobenzyl)-2-propionyl-3-propyliole6caboxylic acid NMR (CDC1 3 5) 1.06 (3H, t, J=7Hz), 1.14 (3H, t, J=7Hz), 1.76 (2H, in), 2.94 (2H, q, J=7Hz), 3.09 (2H, 5.72 (2H, 6.27 (1H, d, J=8Hz), 6.99 (1H, t, J=8Hz), 7.14 (1H, t, J=8Hz), 7.39 (1H, d, J=8Hz), 7.78 (1H, d, J=8Hz), 7.87 (1H, d, J=8Kz), 8.02 (1H, s) (38) 1-(2-Chlorobenzyl)- 2 -isobutyryl-3-propylindole-6carboxylic acid NMR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.11 (6H, d, J=7Hz), 1.76 (2H, 3.03 (2H, 3.34 (1H, m), 5.64 (2H, 6.30 (1H, d, J=8Hz), 7.01 (1H, t, J=8Hz), 7.14 (1H, t, J=8Hz), 7.39 (1H, d, J=8Hz), 7.78 (1H, d, J=8Hz), 7.88 (1H, d, J=8Hz), 8.02 (1H,

S)

(39) 1-(2-Chlorobenzyi)-3-(3-oxo-1-butenyl)indole-6carboxylic acid NMR (DMSO-d 6 5) 2.32 (3H, 5.67 (2H, 6.76 (1H, d, J=15Hz), 6.86 (1H, d, J=8Hz), 7.28 (1H, t, J=8Hz), 7.37 (1H, t, J=8Hz), 7.54 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz), 7.83 (1H, d, J=15Hz), 8.08 (1H, d, J=8Hz), 8.11 (1H, 8.21 (1H, s) 4-(2-Chlorobenzyl)-3-oxo-1,2,3, 4-tetrahydrocyciopent[blindole-6-carboxylic acid NMR (CDC1 3 5) 3.07 (2H, 3.17 (2H, 5.72 (2H, 6.58 (1K, d, J=8Hz), 7.06 (1H, t, J=8Hz), 7.18 (1H, t, J=8Hz), 7.40 (1H, d, J=8Hz), 7.78 (1H, d, WO 96/32379 WO 9632379PCT/JP96/00892 166 J=8Hz) 7. 89 (1H, d, J=8Hz) 8. 09 (1H, s) (41) 4-(6-Chloro-3,4-methylenedioxybenzyl)-3-oxo-1,2,3,4tetrahydrocyclopent indole-6-carboxylic acid NMR (CDC1 3 5) :3.07 (2H, in), 3.16 (2H, mn), 5.61 (2H, 5.88 (2H, 6.10 (1H, 6.88 (1W, 7.78 (1H, d, J=8Hz), 7.88 (1H, d, J=8Hz), 8.12 (1H, s) (42) 1- (2-Chlorobenzyl)-3-nitro-2-propylindole-6-carboxylic acid lNR (DMSO-d 6 5 0.95 (3H, t, J=7Wz), 1.55 (2H, sextet, J=7Hz), 3.18-3.22 (2H, mn), 5.78 (2H, s), 6.52 (1H, d, J=8Hz), 7.22 (1H, t, J=8Hz), 7.33 (1H, t, J=8Wz), 7.58 (1H, d, J=8Wz), 7.97 (1H, d, J=8Wz), 8.08 (1H, s) 8.27 (1H, d, J=BHz) (43) 1- (2-Chloro-4-carboxybenzyl)-3-isobutyryl-2propylindole- 6-carboxamide NMR (DMSO-d 6 5) :0.90 (3H, t, J=7Wz), 1.18 (6H, d, J=7Wz), 1.46 (2W, sextet, J=7Wz), 3.00-3.05 (2W, in), 3.55 (1H, septet, J=7Hz), 5.68 (2H, 6.33 (1H, d, J=8Wz), 7.30 (1W, 7.72 (1H, dd, J=2, 8Wz), 7.92 (1W, 7.95-7.99 (2W, mn), 8.03 (1H, d, J=8Wz) Example The following compounds described in to (41) were prepared in a similar manner to that of Exm~e3 9- (2-Chlorobenzyl) -5-oxo-5, 6,7, 8-tetrahydrocarbazole-2carboxamide mp 295*C (dec.) lNR (DMSO-d 6 5) 2.13 (2H, mn), 2.48 (2H, t, J=7Wz), 2.92 (2H, t, J=7Wz), 5.62 (2W, 6.41 (1H, d, J=8Hz), 7.21 (1H, t, J=8Hz), 7.27 (1H, br 7.33 WO 96/32379 WO 9632379PCT/JP96/00892 167 (1H, t, J=BHz), 7.57 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz) 7. 92 (1H, br s) 8. 02 (1H, s) 8. 08 (1H, d, J=8Nz) 4- (2-Chlorobenzyl)-1-oxo-1,2,3, 4 -tetrahydrocyciopent[bjindole- 6-carboxainide mp >300*C NM'R (DMSO-1 6 2.88 (2H, mn), 2.97 (2H, mn), 5.61 (2H, 6.81 (1H, di, J=8Hz), 7.27 (1H, t, J=8Hz), 7.36 (1H, br 7.38 (1H, t, J=8Hz), 7.57 (1H, d, J=8Hz), 7.76 (1H, d, J=8Hz), 7.79 (1H, cd, J=8Hz), 7.96 (iH, br 8.05 (1H, s) 1- (2-Chlorobenzyl) 3 -isobutyryl-2-propyliniole-7carboxainide inp 181-183'C NI4R (ODC1 3 5) 1.03 (3H, t, J=7Hz), 1.27 (6H, d, J=7Hz), 1.61 (2H, in), 3.02 (2H, mn), 3.53 (1H, mn), 5.34 (1H, br 5.46 (1H, br 5.69 (2H, s), 5.99 (1H, d, J=8Hz), 6.96 (1H, t, J=8Hz), 7.14 (1H, t, J=8Nz), 7.15-7.25 (2H, mn), 7.37 (1H, di, J=8Hz), 8.07 (1H, mn) 1- (2-Chlorobenzyi) 3 carboxainide NMR (CD1 3 5 1.03 (3H, t, J=8Hz), 1.32 (6K, di, J=BHz), 1.64 (2H, sextet, J=8Hz), 3.06 (2H, t, J=8Hz), 3.62 (1H, septet, J=8Hz), 5.46 (2H, s), 6.26 (1H, di, J=8Hz), 7.05 (1H, t, J=8Hz), 7.20 (1K, t, J=8Hz), 7.2 (1H, di, J=8Kz), 7.47 (1H, di, J=BHz), 7.65 (1H, di, J=8Hz), 8.55 (1H, s) 1- (6-Chioro-3, 4 -iethylenedioxybenzyi)-3-isobutyryl-2- NYP. (ODC1 3 5) :1.05 (3H, t, J=7Hz), 1.32 (6H, di, WO 96/32379 PCTI/P96/00892 168 J=7Hz), 1.60-1.72 (2H, 3.04-3.10 (2H, 3.59 (1H, septet, J=7Hz), 5.38 (2H, 5.74 (1H, s), 5.92 (2H, 6.92 (1H, 7.22 (1H, d, J=8Hz), 7.66 (1H, cd, J=1, 8Hz), 8.50 (1H, d, J=lz) 1-(2-Chlorobenzyl) 2 -propylindole-4-carboxaide mp 198-200*C NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.76 (2H, i), 2.66 (2H, t, J=7Hz), 5.41 (2H, 6.18 (1H, d, J=8Nz), 6.85 (1H, 7.1-7.3 (3H, 7.43 (1H, d, J=8Hz), 7.52 (1H, d, J=8Nz) 9-(2-Chiorobenzyl)-8-oxo-5,6, 7 ,8-tetrahydrocarbazole-2carboxaide mp 25500 (dec.) NMR (DMSO-d 6 5) 2.18 (2H, 2.56 (2H, t, J=7Nz), 3.07 (2H, t, J=7Hz), 5.88 (2H, 6.08 (1H, d, J=8Nz), 7.11 (1H, t, J=8Hz), 7.25 (1H, t, J=8Hz), 7.36 (1H, br 7.52 (1H, d, J=8Hz), 7.72 (1H, d, J=8Hz), 7.85 (1H, d, J=8Hz), 8.02 (2H, m) 9-(6-Chloro-3, 4 -methylenedioxybenzyl)-8-oxo-5,6,7,8tetrahydrocarbazole-2-carboxamide mp 27000 (dec.) NMR (DMSO-d 6 5) 2.17 (2H, 2.58 (2H, t, J=7Hz), 3.08 (2H, t, J=7Hz), 5.52 (1H, 5.78 (2H, s), 5.96 (2H, 7.17 (1H, 7.40 (1H, br 7.71 (1H, d, J=8Hz), 7.86 (1H, d, J=8Hz), 7.96 (1H, s), 8.01 (1H, br s) 1-( 4 -Bromo-2-chlorobenzyl)- 3 -isobutyry-2-propylinole- 6 -carboxaiide mp 199-201'C IR (KBr) 3382, 1654, 1619, 1488, 1404 cm 1 NMR (CDC1 3 5) 1.04 (3H, t, J=7Hz), 1.30 (6H, d, WO 96/32379 PCT/JP96/00892 169 J=7Hz), 1.54-1.66 (2H, 3.00-3.05 (2H, in), 3.50- 3.60 (1H, 5.45 (2H, 6.09 (1H, t, 7.17 (1H, cd, J=7.5, 2Hz), 7.62 (1H, cd, 2Hz), 7.65 (1H, d, J=2Hz), 7.83 (1H, 7.99 (1H, d, J=7.SHz) MASS 477 1-(2-Chlorobenzyl)-3-morpholinoacetyl-2-propyinole.

6 carboxamide IR (KBr) 1654, 1616, 1452 cin 1 NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.58-1.68 (2H, 2.73 (4H, t, J=6.5Hz), 3.05-3.10 (2H, 3.84 (4H, t, J=6.5Hz), 3.89 (2H, 5.51 (2H, 6.23 (1H, d, J=7.5Hz), 7.05 (1H, t, J=7.SHz), 7.22 (1H, t, J=7.5Hz), 7.46 (1H, d, J=7.5Nz), 7.64 (1H, d, 7.84 (1H, 7.98 (1H, d, MASS 454 (M+1) (11) Methyl 1-(2-chlorobenzyl)-3-(N,N-dimethylcarbamoyl)-2propylindole-6-carboxylate IR (KBr) 1703, 1610 cm 1 NMR (CDC1 3 5) 0.94 (3H, t, J=7Hz), 1.56-1.63 (2H, 2.76-2.87 (2H, 3.11 (6H, br 3.90 (3H, 5.49 (2H, 6.29 (1H, d, J=7.5Hz), 7.04 (1H, t, J=7.5Hz), 7.21 (1H, t, J=7.5Hz), 7.45 (1H, d, 7.49 (1H, d, J=7.5Hz), 7.86 (1H, d, 7.90 (iN, s) MASS 413 (Mf+1) (12) Methyl 1-(2-chlorobenzyl)-3-(morpholinocarbonyl)-2propylinole- 6 -carboxylate IR (KBr) 1715, 1617, 1277, 1227 cmJ 1 NMR (CDC1 3 5) 0.85 (3H, t, J=7Hz), 1.56-1.63 (2H, 2.82-2.90 (2H, 3.69 (6H, br 3.77 (2H, br 3.90 (3H, 5.48 (2H, 6.29 (1H, d,

I

WO 96/32379 PCT/JP96/00892 170 7.04 (1H, t, J=7.5Hz), 7.21 (1H, ddd, 7.5, 2Hz), 7.45 (1H, d, J=7.5Hz), 7.54 (1H, d, J=7.5Hz), 7.88 (1H, 7.91 (1H, d, J=2Hz) MASS 455 76 (bp) (13) 6-Carbamoyl-l-( 2 -chlorobenzyl)-N,N-dimethyl2.

propylindole-3-carboxamide mp 213-2140C IR (KBr) 1676, 1601 cin 1 NMR (CDC1 3 5) 0.93 (3H, t, J=7Hz), 1.52-1.62 (2H, 2.76-2.86 (2H, 3.12 (6H, br 5.47 (2H, 6.27 (1H, d, J=7.5Hz), 7.03 (1H, t, 7.20 (1H, t, J=7.5Hz), 7.44 (1H, d, J=7.5Hz), 7.49- 7.54 (2H, 7.78 (1H, s) MASS 398 76 (bp) (14) 1-(2-Chlorobenzyl)-3-(morpholinocarbonyl)-2propylindole-6-carboxamide mp 229-2300C IR (KBr) 3448, 3359, 3326, 1675, 1606 cmi 1 NMR (CDC1 3 5) 0.95 (3H, t, J=7Hz), 1.57-1.62 (2H, 2.82-2.89 (2H, 3.69 (6H, br 3.78 (2H, br 5.49 (2H, 6.28 (1H, d, J=7.5Hz), 7.04 (1H, t, J=7.5Hz), 7.21 (1H, t, J=7.5Hz), 7.45 (1H, t, J=7.5Hz), 7.55 (2H, 7.80 (1H, s) MASS 440 76 (bp) 1-( 2 -Chlorobenzyl)-2-propylindole-3, 6 -dicarboxaide mp 29600 (dec.) IR (KBr) 3376, 3188, 1644, 1613 cmJ 1 NMR (DMSO-d 6 5) 0.88 (3H, t, J=7Hz), 1.40-1.51 (2H, 2.98 (2H, t, J=7Hz), 5.57 (2H, 6.17 (1H, d, 7.14-7.35 (6H, 7.58 (1H, d, 7.73 (1H, d, J=7.5Hz), 7.83-7.89 (1H, 7.95 (1H,

S)

WO 96132379 PCT/JP96/00892 171 MASS 370 86 (bp) (16) 1-( 2 -Chlorobenzyl)-2-ethyl-3-formylindole...carboxamide mp 260-261*C IR (KBr) 3400, 1685, 1635, 1615, 1390 cm 1 NMR (CDC1 3 5) 1.29 t, J=7Hz), 3.08 (2H, q, J=7Hz), 5.52 (2H, 6.29 (1H, d, J=7.5Hz), 7.07 (1H, t, J=7.5Hz), 7.24 (1H, t, J=7.5Hz.), 7.49 (1H, d, J=7.5Hz), 7.69 (1H, d, J=7.5Hz), 7.86 (1H, s), 8.35 (1H, d, J=7.5Hz), 10.24 (1H, s) MASS 341 (M+1) (17) 1-( 2 -Chlorobenzoyl)-3-isobutyryl-2-propylinole.6carboxamide mp 125-126.5'C IR (KBr) 1700, 1650 cm 1 NMR (CDC1 3 5) 0.90 t, J=7Hz), 1.28 (6H, d, J=7Kz), 1.61-1.74 (2H, 2.98-3.05 (2K, 3.40- 3.49 (1H, 7.48-7.53 (3H, 7.59-7.65 (2H, i), 7.79 (2H, AB, J=8, MASS 411 76 (bp) (18) 1-( 2 -Chlorobenzyl)-3-formylindole-6-carboxaide mp 237-240*C NMR (DMSO-d 6 5) 5.68 (2H, 6.86 (1H, d, J=8Hz), 6.25-6.4 7.58 (1H, d, J=8Kz), 7.84 (1H, d, J=8Hz), 7.98 (1H, br 8.14 (1H, 8.17 (1H, d, J=8Kz), 8.46 (1H, 9.98 (1H, s) (19) 3-Acetyl-1- 2 -chlorobenzyl)-2-methyl indole-6-carboxami de mp 272-276*C NMR (DMSO-d 6 5) 2.63 (3K, 2.65 (3H, 5.61 (2H, 6.17 (1H, d, J=8Kz), 7.18 (1H, t, J=8Hz), 7.27 (1H, br s)i 7.32 (1H, t, J=8Hz), 7.57 (1H, d, J=8Kz), 7.80 (1H, d, J=8Hz), 7.94 (1H, br 8.03 WO 96/32379 PCT/JP96/00892 172 (1H, s) 8. 11 (1H, s) 1-( 2 -Chlorobenzy)-2-methyl-3-propionylidole..G carboxamide mp 215-217'C NMR (DMSO-d 6 5) 1.14 (3H, t, J=7Hz), 2.64 (3H, s), 3.04 (2H, q, J=7Hz), 5.62 (2H, 6.18 (1H, d, J=8Hz), 7.18 (1H, t, J=8Hz), 7.29 (1H, br 7.32 (1H, t, J=8Hz), 7.57 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz), 8.02 (1H, 8.10 (1H, d, J=8Hz) (21) 1-( 2 -Chlorobenzo[blthiophen-3-ylmethyl)-3-sobutyryl 2 methylindole-6-carboxamide mp 25500 (dec.) NMR (DMSO-d 6 5) 1.13 (6H, d, J=7Hz), 2.63 (3H, s), 3.47 (1H, 5.84 (2H, 7.2-7.42 (4H, 7.48 (1H, d, J=8Hz), 7.89 (1H, br 7.95-8.0 (2H, i), 8.23 (1H, s) (22) 1-(Benzothiazol-2-ylmethyl)-2-ethyl-3-isobutyrylindole.

6-carboxaiide mp 188-190.5'C (dec.) NMR (CDC1 3 5) 1.28 (3H, t, J=7Kz), 1.29 (6H, d, J=7Hz), 3.27 (2H, q, J=7Hz), 3.53 (1H, 5.82 (2H, 7.36 (1H, t, J=8Hz), 7.49 (1H, t, J=8Hz), 7.66 (1K, d, J=8Hz), 7.74 (1H, d, J=8Hz), 7.97 (1H, d, J=8Hz), 8.02 (1H, d, J=8Hz), 8.07 (1H, s) (23) 1-(Benzo[b]thiophen-5-ylmethyl)-3-isobutyryl.2propylindole-6-carboxamide mp 189-192*C (dec.) NMR (CDC1 3 5) 1.02 (3H, t, J=7Hz), 1.31 (6H, d, J=7Hz), 1.62 (2H, 3.14 (2H, 3.57 (1H, m), 5.58 (2H, 7.02 (1H, d, J=8Kz), 7.18 (1K, i, J=6Kz), 7.29 (1H, 7.43 (1H, d, J=6Kz), 7.60 m m WO 96/32379 PCT/JP96/00892 173 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz), 7.92 (1H, s), 7.97 (1H, d, J=8z) (24) 1-( 2 ,4-Dichlorobenzyl)- 3 -isobutyry-2-prpylincole. 6.

carboxaide mp l91-192*C NMR (DMSO-d 6 6) 0.92 (3H, t, J=7Hz), 1.18 (6H, d, J=7Hz), 1.45 (2H, sextet, J=7Hz), 3.00-3.05 (2H, 3.55 (21, septet, J=7Hz), 5.60 (2H, 6.18 (1H, d, J=8Kz), 7.28 (1H, d, J=2, 8Hz), 7.31 (1H, 7.76 (1H, d, J=2Hz), 7.82 (1H, c, J=8Hz), 7.92 (1K, br 7.94 (1H, 7.98 (1H, d, J=8Hz) 3 -Isobutyryl-2-propyl-l-(3-pyridyliethyl)incole-6carboxaide mp 230-235*C NMR (CDC1 3 6) 1.02 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.60 (2H, sextet, J=7Kz), 3.08-3.16 (2H, 3.56 (2H, septet, J=7Hz), 5.48 (2H, 7.19- 7.24 (2H, 7.61 (1H, d, J=8Hz), 7.92 (1H, s), 7.96 (1H, d, J=8Hz), 8.38 (1H, d, J=2Hz), 8.52 (1H, cd, J=2, (26) 3 -Isobutyryl-2-propyl-l-(1-naphthyliethyl)indole-6carboxaide ip 202-203*C NMR (CDC1 3 5) 0.96 (3H, t, J=7Hz), 1.34 (6K, d, J=7Hz), 1.61-1.68 (2K, 3.08 (2H, dd, J=7, 8Hz), 3.61 (1H, septet, J=7Kz), 5.90 (2K, 6.28 (1H, c, J=8Hz), 7.21 (1H, t, J=8Hz), 7.58-7.69 (3K, m), 7.76 (1H, c, J=8Kz), 7.78 (1H, 7.94 (1H, d, J=8Hz), 8.00 (1K, d, J=8Kz), 8.08 (1H, c, J=8Kz) (27) 3 -Isobutyryl-2-propyl-l-(2-naphthylmethyl)incole-6carboxamide WO 96/32379 PCT/JP96/00892 174 mp 189-190 0

C

NMR (CDCl 3 5) 0.98 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.55-1.68 (2H, 3.14-3.18 (2H, 3.58 (1H, septet, J=7Hz), 5.58 (2H, 7.15 (1H, dd, J=l, 8Hz), 7.28 (1K, 7.42-7.48 (2H, 7.60- 7.66 (2H, 7.78 (2H, d, J=8Hz), 7.93 (1H, d, J=1Hz), 7.98 (1K, d, J=8Hz) (28) l-Allyl-3-isobutyryl-2-propylindole-6-cao id mp 155-158*C NMR (CDC1 3 5) 1.06 (3H, t, J=7Hz), 1.27 (6H, d, J=7Hz), 1.71 (2H, 3.11 (2H, 3.51 (1H, i), 4.83 (2H, 4.86 (1H, 5.19 (1K, 5.96 (1H, 7.58 (1H, d, J=8Kz), 7.89 (1H, d, J=8Hz), 7.96 (1H, s) (29) 1- (2-Chlorobenzyl) -3-isobutyryl-2- (l-propenyl) indole-6carboxaide mp 190-1930C NMR (CDC1 3 5) 1.23 (6H, d, J=7Hz), 1.93 (3H, d, J=7Hz), 3.51 (1K, 5.48 (2H, 5.91 (1H, dq, 7Hz), 6.41 (1H, d, J=8Hz), 6.71 (1H, d, 7.07 (1H, t, J=8Kz), 7.23 (1H, t, J=8Hz), 7.46 (1K, d, J=8Kz), 7.62 (1H, d, J=8Hz), 7.80 (1H, 8.24 (1H, d, J=8Kz) 1-( 2 -Chlorobenzyl)-2-(1-hydroxypropyl)-3isobutyrylindole-G-carboxaiide mp 220-223*C NMR (CDC1 3 5) 0.94 (3H, t, J=7Hz), 1.32 (3H, d, J=7Hz), 1.39 (3K, d, J=7Hz), 1.52 (1K, 1.93 (1H, 3.69 (1H, 4.68 (1H, 5.48 (1H, d, J=17Hz), 5.66 (1K, d, J=17z), 6.33 (1H, d, J=lOHz), 6.43 (1H, d, J=8Hz), 7.07 (1H, t, J=8Kz), 7.21 (1K, t, J=8z), 7.44 (1H, d, J=8Kz), 7.68 (1H,

I

WO 96/32379 WO 9632379PCT/JP96/00892 175 d, J=8HZ) 7.92 (1H, s) 7.96 (1H, d, J=8HZ) (31) 1- (2-Chlorobenzyi)-3- 3-dimethylbutanoyl) indole-6carboxamide mp :202-205*C NMR (CDCi 3 5) 1.08 (9H, 2.69 (2H, 5.50 (2H, 6.73 (1H, d, J=8Kz), 7.14 (1H, t, J=8Hz), 7.28 (1H, t, J=8Hz), 7.45 (1H, di, J=8Hz), 7.62 (1K, di, J=8Hz), 7.80 (1H, 7.99 (1H, 8.53 (1H, di, J=8Hz) (32) 1- (2-Chlorobenzyl) 2 -propyiinciole-6-carboxamiie mp :174-1770C NMR (CDC1 3 5) 1.00 (3H, t, J=7Hz), 1.74 (2H, mn), 2.61 (2H, t, J=7Hz), 5.43 (2H, 6.15 (1H, d, J=8Hz), 6.44 (1H, 7.00 (1H, t, J=8Hz), 7.18 (1H, t, J=8Hz), 7.4-7.5 (2H, mn), 7.61 (1H, ci, J==8Hz), 7.79 (1H, s) (33) 1- (2-Broinobenzyl) 2 -propyiindole-6-carboxaie mp :166-168*C NNR (ODC1 3 5) 1.00 (3H, t, J=7Hz), 1.73 (2H, mn), 2.59 (2H, mn), 5.36 (2H, 6.10 (1H, ci, J=8Hz), 6.42 (1H, 7.0-7.15 (2H, mn), 7.46 (1H, dcl, J=1, 8Hz), 7.61 (1K, dci, J=1, 8Hz), 7.76 (1H, s) (34) 2-Acetyl-1- 2 -chiorobenzyl)-3-methyliniole-6-carboxaie mp 234-236*C NMR (DMSO-c1 6 5) 2.58 (3H, 2.71 (3H, 5.79 (2H, 6.03 (1K, ci, J=8Hz), 7.09 (1H, t, J=8Hz), 7.24 (1H, t, J=8Hz), 7.35 (1H, br 7.50 (1H, di, J=8Hz), 7.70 (1H, d, J=8Kz), 7.92 (1H, d, J=8Hz), 7.98 (1K, 7.99 (1H, br s) (35) 2-Chloro-1- (2-chlorobenzyl) 3 -ethyiindole-6-carboxamide WO 96/32379 PCT/JP96/00892 176 mp 195-198 0

C

NMR (CDCJ 3 6) 1.27 (3H, t, J=7Hz), 2.83 (2H, q, J=7Hz), 5.49 (2H, 6.29 (1H, d, J=8Hz), 7.03 (1H, t, J=8Hz), 7.18 (1W, t, J=8Hz), 7.42 (1H, d, J=8Hz), 7.50 (1H, d, J=8Hz), 7.63 (1H, d, J=8Hz), 7.77 (1W, s) (36) 1-(2-Chlorobenzyl)- 2 -propionyl-3-propylindole-6carboxamide mp 165-167C NMR (CDC1 3 6) 1.05 (3H, t, J=7Hz), 1.13 (3H, t, J=7Hz), 1.76 (2H, 2.93 (2H, q, J=7Hz), 3.08 (2H, 5.70 (2H, 6.23 (1H, d, J=8Hz), 6.97 (1H, t, J=8Hz), 7.12 (1H, t, J=8Hz), 7.47 (1H, d, J=8Hz), 7.53 (1H, d, J=8Wz), 7.74 (1H, 7.76 (1H, d, J=8Hz) (37) 1-(2-Chlorobenzyl)- 2 -isobutyry-3-propylindole-6carboxaiide mp 159-160.50C NMR (CDC1 3 6) 1.03 (3H, t, J=7Wz), 1.12 (6H, d, J=7Wz), 1.76 (2H, 3.04 (2H, 3.36 (1H, m), 5.66 (2W, 6.29 (1H, d, J=8Hz), 6.99 (1H, t, J=8Wz), 7.14 (1H, t, J=8Wz), 7.38 (1H, d, J=8Wz), 7.56 (1W, d, J=8Wz), 7.76 (1W, d, J=8Hz), 7.77 (1H,

S)

(38) 1-( 2 -Chlorobenzy1)-3-(3-oxo-l-butenyl)indole6 carboxaide mp 248-250*C NMR (DMSO-d 6 6) 2.30 (3H, 5.61 (2H, 6.74 (1W, d, J=8Wz), 6.75 (1W, d, J=l5Hz), 7.2-7.4 (3H, 7.54 (1W, d, J=8Wz), 7.77 (1H, d, J=8Hz), 7.80 (1H, d, J=15Hz), 7.98 (1H, br 8.04 (1H, d, J=8Hz), 8.11 (1W, 8.14 (1W, s) WO 96/32379 PCT/JP96/00892 177 (39) 4-( 2 -Chlorobenzyl)-3-oxo-1,2,3,4tetrahydrocyclopent[b]indole-6-carboxamide mp 28900 (dec.) NMR (DMSO-d 6 6) 2.95 (2H, 3.10 (2H, 5.67 (2H, 6.37 (1H, d, J=8Hz), 7.16 (1H, t, J=8Hz), 7.28 (1H, t, J=8Hz), 7.40 (1H, br 7.53 (1H, d, J=8Hz), 7.74 (1H, d, J=8Hz), 7.88 (1H, d, J=BHz), 8.01 (1H, br 8.07 (1H, s) (40) 4-( 6 -Chloro- 3 ,4-methylenedioxybenzyl)3 oxo123 4 tetrahydrocyclopent b]indole-6-carboxamide mp 28200 (dec.) NMR (DMSO-d 6 6) 2.98 (2H, 3.09 (2H, 5.54 (2K, 5.97 (2H, 5.98 7.17 (1H, s), 7.43 (1H, br 7.71 (1H, d, J=8Kz), 7.86 (1H, d, J=8Hz), 8.03 (1H, br 8.05 (1H, s) (41) 1-[2-Chloro-4-(N-phenylsulfonylcarbaoyl)benzyl]3isobutyryl-2-propylindole-6-carboxamide mp 147-150C NMR (DMSO-d 6 6) 0.88 (3H, t, J=7Kz), 1.18 (6H, d, J=7Hz), 1.45 (2K, sextet, J=7Kz), 2.98-3.03 (2H, 3.55 (1H, septet, J=7Kz), 5.68 (2H, 6.27 (1H, d, J=8Hz), 7.28 (1H, 7.60-7.64 (3H, i), 7.69 (1H, dd, J=2, 8Kz), 7.80 (1H, d, J=8Kz), 7.92- 7.96 (4K, 8.06 (1H, s) Example 76 The following compound described in to were prepared by a similar manner to that of Example 6.

1-(6-Chloro-3, 4 -methylenedioxybenzyl)-3-methoxyacetyl-2propylindole-6-carboxamide 1-(2-Chlorobenzyl)- 3 -ethoxyacetyl-2-propylindole-6- WO 96/32379 PCT/JP96/00892 178 carboxaide NMR (DMSO-d 6 5) 0.93 (3H, t, J=7Hz), 1.18 (3H, t, J=7Hz), 1.46 (2H, sextet, J=7Hz), 3.03 (3H, t, J=7Hz), 3.62 (2H, q, J=7Hz), 4.74 (2H, 5.63 (2H, 6.22 (1H, d, J=8Hz), 7.17 (1H, t, J=8Hz), 7.30 (1H, 7.33 (1H, t, J=8Hz), 7.58 (1H, d, J=8Hz), 7.80 (1H, d, J=8Hz), 7.92 (1H, d, J=8Hz), 7.94 (1H, 8.00 (1H, s) 1-(2-Chlorobenzyl)-3-isobutyryl-2-propylndol. 6ylacetamide mp 146-148 0

C

IR (KBr) 1715, 1650 cm-l NMR (CDC1 3 5) 1.01 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.57-1.67 (2H, 3.02-3.08 (2H, 3.51- 3.60 (1H, 3.66 (2H, 5.45 (2H, 6.29 (1H, d, J=7.5Hz), 7.04-7.09 (2H, 7.21 (2H, t, 7.47 (1H, d, J=7.5Hz), 7.93 (1H, d, MASS 411(M 74 (bp) 1-(6-Chloro-3, 4 -methylenedioxybenzyl)-3-isobutyryl-2propylindole-6-ylacetaiide mp 136-138*C IR (KBr) 1655, 1505 cm- 1 NMR (CDC1 3 5) 1.04 (3H, t, J=7Hz), 1.29 (6H, d, J=7Hz), 1.55-1.67 (2H, 3.01-3.07 (2H, 3.50- 3.58 (1H, 3.69 (2H, 5.33 (2H, 5.75 (1H, 5.90 (2H, 6.92 (1H, 7.09 (1H, 7.19 (1H, d, J=7.5Hz), 7.91 (1H, d, MASS 455 74 (bp) 1-( 2 -Chlorobenzyl)-3-nitro-2-propylindole-6-carboxain e NMR (DMSO-d 6 5) 0.95 (3H, t, J=7Hz), 1.54 (2H, sextet, J=7Hz), 3.13-3.17 (2H, 5.72 (2H, s), WO 96/32379 WO 9632379PCT/JP96/00892 179 6. 44 (1H, di, J=BKz) 7. 20 (1H, t, J=8Hz) 7. 36 (1H, t, J=BHz), 7.42 (iH, 7.60 (1H, d, J=8Hz), 7.96 d, J=8Hz), 8.03 (1H, 8.10 (1H, 8.22 (1H, di, J=8Hz) Examiple 77 The following compounds described in to (13) were prepared in a similar manner to that of Example 26.

1- (4-Chloro-2-fluorobenzyl) -3-methoxyacetyl-2propylindole- 6-carboxamide mp l92-193*C NM?. (DMSO-d 6 6) 0.94 (3H, t, J=7Hz), 1.44 (2H, sextet, J=7Hz), 3.09 (2H, t, J=7Hz), 3.41 (3H, s), 4.69 (2H, 5.64 (2H, 6.50 (1H, t, J=8Hz), 7.18 (1H, dci, J=2, 8Hz), 7.33 (1H, 7.55 (1H, dd, J=2, 8Hz), 7.79 (1H, ci, J=8Hz), 7.89 (1H, di, J=8Hz), 7.92 (1H, 8.06 (iH, s) 1- 4-Dichlorobenzyl)-3-methoxyacetyl-2-propyliniole-6carboxamide mp 203-205*C NM?. (DMSO-d 6 ,1 6) :0.94 (3H, t, J=7Hz), 1.98 (2H, sextet, J=7Hz), 3.04 (2H, t, J=7Hz), 3.42 (3K, s), 4.71 (2H, 5.60 (2H, 6.20 (1H, d, J=8Hz), 7.27 (1H, dci, 8Hz), 7.32 (1H, 7.77 (1H, di, J=2Hz), 7.82 (1H, ci, J=8Hz), 7.92 (1K, ci, J=8Hz), 7.94 (1H, 7.98 (1K, s) 1- (4-Bromo-2-chlorobenzyl) -3-methoxyacetyl-2propylindole- 6-carboxamide mp 178-180*C NM?. (DMSO-d 6 6) 0.94 (3H, t, J=7Kz), 1.48 (2K, sextet, J=7Kz), 3.04 (2H, t, J=7Kz), 3.42 (3K, s), 4.68 (2H, 5.57 (2H, 6.13 (1H, ci, J=8Kz), WO 96/32379 WO 9632379PCTIJI'96/00892 180 7.30 (1H, 7.38 (1H, dd, J=2, 8Hz), 7.80 (1H, d, J=8Hz), 7.86 (1H, d, J=2Hz), 7.90 (1H, d, J=8Hz), 7.93 (1H, 7.97 (1H, S) 1- (4-Bromo-2-fluorobenzyl) -3-methoxyacetyl-2propylindole- 6-carboxamide mp 197-199*C NM?. (DMSO-d 6 5) 0.94 (3H, t, J=7Hz), 1.48 (2H, sextet, J=7Hz), 3.09 (2H, t, J=7Hz), 3.40 (3H, s), 4.67 (2H, 5.62 6.43 (1H, d, J=8Hz), 7.28 (1H, dd, J=2, 8Hz), 7.65 (1H, dci, J=2, 8Hz), 7.78 (1H, di, J=8Hz), 7.90 (1H, d, J=8Hz), 7.92 (1H, 8.05 (1H, s) 1- (2-Chloro-4-fluorobenzyl)-3-methoxyacetyi-2propylindole- 6-carboxamide mp 174-176*C NM?. (DMSO-d 6 5) :0.93 (3H, t, J=7Wz), 1.48 (2H, sextet, J=7Hz), 3.04 (2H, t, J=7Hz), 3.42 (3H, s), 4.70 (2H, 5.58 (2H, 6.25 (1H, ci, J=8Hz), 7.06 (1H, cit, J=2, 8Hz), 7.32 (1H, 7.50 (1H, dci, J=2, 8Hz), 7.80 (1H, di, J=8Hz), 7.92 (1H, di, J=8Hz), 7.94 (1H, 8.00 (1H, s) 1- (Benzo[blthiophen-5-ylmethyl)-3-methoxyacetyl-2propylindole- 6-carboxamide mp 197-199*C (dec.) NM?. (DMSO-d 6 5) :0.92 (3H, t, J=7Hz), 1.48 (2H, sextet, J=7Hz), 3.14 (2H, t, J=7Hz), 3.42 (3H, s), 4.72 (2H, 5.74 (2W, 7.10 (1H, di, J=8Wz), 7.28 (1H, 7.38 (1H, di, J=5Hz), 7.44 (1H, s), 7.75 (1H, di, J=5Wz), 7.78 (1W, di, J=8Wz), 7.88 (1H, di, J=8Hz), 7.92 (1W, 7.96 (1H, ci, J=8Hz), 8.12 (1H, s) WO 96/32379 PCT/JP96/00892 181 Methyl 1-(2, 4 -dichlorobenzyl)-3-isobutyryl-2 propylindole- 6 -carboxylate NMR (CDC1 3 6) 1.02 (3H, t, J=7Hz), 1.31 (6H, d, J=7Hz), 1.60 (2H, sextet, J=7Kz), 3.06 (2H, t, J=7Hz), 3.58 (2H, septet, J=7Hz), 3.93 (3H, s), 5.46 (2H, 6.16 (1H, d, J=8Hz), 7.04 (1H, d, J=8Hz), 7.50 (1H, 7.90 (1H, 7.96 (2H, s) Methyl 3 -isobutyryl-2-propyl-l-(3-pyridyliethyl)indole- 6-carboxylate NMR (CDC1 3 6) 1.02 (3H, t, J=7Hz), 1.30 (6H, d, J=7Hz), 1.60 (2H, sextet, J=7Hz), 3.12 (2H, t, J=7Hz), 3.56 (2H, septet, J=7Hz), 3.92 (3H, s), 5.48 (2H, 7.14-7.23 (2H, 7.92-7.95 (2H, i), 7.98 (1H, 8.42 (1H, d, J=2Hz), 8.54 d, Methyl 3 -isobutyryl-2-propyl-l-(l-naphthyliethyl)indole- 6-carboxylate NMR (CDC 3 6) 0.97 (3H, t, J=7Hz), 1.34 (6H, d, J=7Hz), 1.64 (2K, sextet, J=7Hz), 3.04-3.10 (2H, 3.63 (1K, septet, J=7Hz), 3.84 (3H, 5.92 (2K, 6.28 d, J=8Kz), 7.22 (1H, t, J=8Hz), 7.62 (1H, t, J=8Hz), 7.69 (1H, t, J=8Hz), 7.77 (1H, d, J=8Kz), 7.77 (2K, 7.92 (1K, s) Methyl 3 -isobutyry1-2-propyl-l-(2-raphthylmethyl)indole- 6-carboxylate NMR (CDCi, 6) 1.00 (3K, t, J=7Hz), 1.32 (6K, d, J=7Hz), 1.55-1.68 (2K, 3.13-3.18 (2K, 3.60 (1K, septet, J=7Kz), 3.88 (3K, 5.62 (2H, s), 7.17 (1K, d, J=8Kz), 7.29 (2K, 7.42-7.48 (2H, 7.64-7.68 (1K, 7.80 (2K, d, J=2Kz), 7.96 (2K, 8.04 (1H, s) 182 (11) Methyl l-(6-chloro-3, 4 -methylenedioxybenzyl)-3methoxyacetyl-2-propylindole- 6 -carboxylate NMR (CDC1 3 5) 1.04 (3H, t, J=7Hz), 1.56-1.72 (2H, 3.06-3.13 (2H, 3.58 (3H, 3.93 (3H, s), 4.73 (2H, 5.40 (2H, 5.70 (1H, 5.88 (2H, 6.92 (1H, 7.83 (1H, d, J=8Hz), 7.96 (1H, 7.98 (1H, d, J=8Hz) (12) Methyl 1-( 2 -chlorobenzyl)- 3 -ethoxyacetyl-2-propylindole- 6-carboxylate NMR (CDC1 3 5) 1.03 (3H, t, J=7Hz), 1.34 (3H, t, J=7Hz), 1.56-1.70 (2H, 3.10 (3H, t, J=7Hz), 3.77 (2H, q, J=7Hz), 3.92 (3H, 4.79 (2H, s), 5.52 (2H, 6.24 (1H, d, J=8Hz), 7.03 (1H, t, o:15 J=8Hz), 7.22 (1H, t, J=8Hz), 7.46 (1H, d, J=8Hz), 7.85 1H d, J=8Hz), 7.92 (1H, 7.98 (1H, d, SJ=8Hz) (13) 1-( 2 -Chloro-4-methoxycarbonylbenzyl)-3-isobutyryl-2propylindole-6-carboxamide o* NMR (CDC1 3 5) 1.01 (3H, t, J=7Hz), 1.32 (6H, d, J=7Hz), 1.60 (2H, sextet,- J=7Hz), 3.02-3.06 (2H, n 3.56 (1H, septet, J=7Hz), 3.90 (3H, 5.53 (2H, 6.28 (1H, d, J=8Hz), 7.63 (1H, d, J=8Hz), 7.69 (1H, d, J=8Hz), 7.82 (1H, 7.98 (1H, d, J=8Hz), 8.14 (1H, s) Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims (1)

183- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A compound of the formula: R R2 R 4 R N (I 1 3 R wherein R 1 is hydrogen, halogen, nitro, carboxy, protected carboxy, acyl, cyano, hydroxyimino (lower) alkyl, lower alkenyl optionally substituted with oxo, lower alkyl optionally substituted with protected carboxy, carboxy or hydroxy, or aryl; R 2 is hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy or hydroxy; R 3 is lower alkenyl or lower alkyl, both of which are optionally substituted with one or more substituent(s) selected from the group consisting of 25 /Ki) oxo, aryl optionally substituted with one or more substituent(s) selected from the group consisting of halogen, aryl, lower alkoxy, lower alkylenedioxy, cyano, nitro, carboxy, protected carboxy, acyl, and amino optionally substituted with acyl or protected carboxy, and a heterocyclic group optionally substituted WO 96/32379 PCT/JP96/00892 184 with halogen; and R 4 is carboxy, protected carboxy, acyl, cyano, halogen, a heterocyclic group, amino optionally substituted with acyl or protected carboxy, or lower alkyl optionally substituted with protected carboxy, carboxy or acyl; in addition to their significances above, R 1 and R 2 together with the carbon atoms to which they are attached, represent a 4- to 7- membered carbocyclic ring optionally substituted with oxo, or its pharmaceutically acceptable salt. 2. A compound of claim 1, wherein R 1 is cyano, acyl, or lower alkyl optionally substituted with hydroxy, R 2 is hydrogen, acyl, lower alkenyl, or lower alkyl optionally substituted with lower alkoxy or hydroxy, R 3 is methyl substituted with aryl or a heterocyclic group, wherein aryl is optionally substituted with one or more substituent(s) selected from the group consisting of halogen, lower alkylenedioxy, protected carboxy and carboxy, and R 4 is acyl, cyano, or a heterocyclic group, in addition to their significances above, R 1 and R 2 together with the carbon atoms to which they are attached, represent a 4- to 7- membered carbocyclic ring optionally substituted with oxo. 3. A compound of claim 2, wherein R 1 is lower alkyl, or lower alkanoyl optionally substituted with hydroxy, lower alkoxy or aryl, R 2 is hydrogen, lower alkenyl, or lower alkyl optionally WO 96/32379 PCT/JP96/00892 185 substituted with lower alkoxy, and R 3 is benzyl optionally substituted with one or more substituent(s) selected from the group consisting of halogen and lower alkylenedioxy. 4. A compound of claim 3, wherein R4 is R R -CON \R 6 R 5 is hydrogen, or lower alkyl, and R 6 is hydrogen, hydroxy, lower alkoxy, arylsulfonyl, a heterocyclic group, or lower alkyl optionally substituted with lower cycloalkyl or a heterocyclic group, in addition to their significances above, R 5 and R 6 together with the nitrogen atom to which they are attached, may represent a heterocyclic group. A compound of claim 4, wherein R1 is lower alkanoyl optionally substituted with alkoxy, R2 is lower alkyl, and R 4 is carbamoyl. 6. A process for preparing a compound of the formula R 1 R2 IR 4 (I) R 2 N R3 wherein R is hydrogen, halogen, nitro, carboxy, protected WO 96/32379 PCT/JP96/00892 186 carboxy, acyl, cyano, hydroxyimino(lower)alkyl, lower alkenyl optionally substituted with oxo, or lower alkyl optionally substituted with protected carboxy, carboxy or hydroxy; R 2 is hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy or hydroxy; R 3 is lower alkenyl or lower alkyl, both of which are optionally substituted with one or more substituent(s) selected from the group consisting of oxo, aryl optionally substituted with one or more substituent(s) selected from the group consisting of halogen, aryl, lower alkoxy, lower alkylenedioxy, cyano, nitro, carboxy, protected carboxy, acyl, and amino optionally substituted with acyl or protected carboxy, and a heterocyclic group optionally substituted with halogen; and R 4 is carboxy, protected carboxy, acyl, cyano, halogen, a heterocyclic group, amino optionally substituted with acyl or protected carboxy, or lower alkyl optionally substituted with protected carboxy, carboxy or acyl; in addition to their significances above, R 1 and R 2 together with the carbon atoms to which they are attached, represent a 4- to 7- membered carbocyclic ring optionally substituted with oxo, or its pharmaceutically acceptable salt, which comprises, a) reacting a compound of the formula I~I~~ WO 96/32379 PCT/JP96/00892 187 (II) wherein R 1 R 2 and R 4 are each as defined above, or its salt, with a compound of the formula R 3 x 1 (III) wherein R 3 is the one as defined above, and X1 is a leaving group, to give a compound of the formula R 1 I1 t/ R 4 (I) wherein R 1 R 2 R 3 and R 4 are each as defined above, or its salt ii) subjecting a compound of the formula R 1 S---R 4 (I-1) wherein R 1 R 2 and R 3 are each as defined above, and WO 96/32379 PCT/JP96/00892 188 R4 is protected carboxy or lower alkyl substituted with protected carboxy, or its salt, to deesterification to give a compound of the formula R 1 SR (1-2) 2 R N 3 wherein R 1 R 2 and R 3 are each as defined above, and Rb is carboxy or lower alkyl substituted with carboxy, or its salt, iii) reacting a compound of the formula defined above, or its reactive derivative at the carboxy group, or its salt, with a compound of the formula H-N 5 (IV) R 6 wherein R 5 is hydrogen or lower alkyl, and R 6 is hydrogen, hydroxy, lower alkoxy, arylsulfonyl, a heterocyclic group, or lower alkyl optionally substituted with lower cycloalkyl or a heterocyclic group, in addition to their significances above, R 5 and R 6 together with the nitrogen atom to which they are attached, may represent a heterocyclic group, or its reactive derivative at the amino group, or its salt, to give a compound of the formula WO 96/32379 PCT/JP96/00892 189 Ri R4 2x2 R N I 3 (1-3) wherein R 1 R 2 R 3 R 5 and R 6 are each as defined above, and 4 is -R5 c -CON, R or lower alkyl substituted with -CON NRE or its salt; iv) subjecting a compound of the formula (1-4) wherein R 1 R 2 and R 4 are each as defined above, and Ra is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with protected WO 96/32379 PCT/JP96/00892 190 carboxy, or its salt, to deesterification to give a compound of the formula R 1 R2R 4 R N R3 wherein R 1 R 2 and R 4 are each as defined above, and Rb is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with carboxy, or its salt; v) reacting a compound of the formula defined above, or it reactive derivative at the carboxy group, or its salt, with the compound of the formula (IV) defined above, or its reactive derivative at the amino group, or its salt, to give a compound of the formula R 1 I R 4 (I-6) R2 N 3 C WO 96/32379 PCT/JP96/00892 191 wherein R 1 R 2 R 3 R 5 and R 6 are each as defined above, and R3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with -coNR 6 or its salt; vi) reducing a compound of the formula R 1 RR RR 4 (1-7) wherein R 2 R 3 and R 4 are each as defined above, and Ra is lower alkanoyl optionally substituted with protected carboxy or carboxy, or its salt, to give a compound of the formula (1-8) 192 wherein R 2 R 3 and R 4 are each as defined above, and Rb is lower alkyl optionally substituted with protected carboxy or carboxy, or its salt; vii) reacting a compound of the formula R2 R 4 (1-9) R2, 13 SgoR C wherein R 2 R 3 and R 4 are each as defined above, or its salt, with a compound of the formula R 1 X 2 (V) C wherein Ri is lower alkenoyl, aroyl, or lower alkanoyl optionally substituted with protected carboxy, carboxy, or aryl, X 2 is a leaving group, or its salt, to give a compound of the formula *e R 1 R -R4 wherein Rc, R 2 R 3 and R 4 are each as defined above, WO 96/32379 PCT/JP96/00892 193 or its salt; viii) dehydrating a compound of the formula 1 R2 CONH 2 R2 Nm 3 (I-11) wherein R 1 R 2 and R 3 are each as defined above, or its salt, to give a compound of the formula R 1 R2 CN (1-12) R 2 N R3 wherein R 1 R 2 and R 3 are each as defined above, or its salt; ix) reacting a compound of the formula (1-12) defined above, or its salt, with azide compound, to give a compound of the formula (1-13) WO 96/32379 PCT/JP96/00892 194 wherein R1, R 2 and R 3 are each as defined above, or its salt; x) subjecting a compound of the formula (1-14) wherein R 3 and R 4 are each as defined above, and R2 is lower alkyl substituted with protected carboxy, or its salt, to deesterification to give a compound of the formula I R 4 (1-15) R3 wherein R 3 and R 4 are each as defined above, and R2 is lower alkyl substituted with carboxy, or its salt; xi) subjecting a compound of the formula (1-15) defined above, or its salt, to intramolecular acylation to give a compound of the formula WO 96/32379 PCT/JP96/00892 195 (1-16) wherein R 3 and R 4 are each as defined above, and n is 1, 2, 3 or 4, or its salt; xii) reacting a compound of the formula R 1 R 4 (1-17) R2 N R3 wherein R 2 R 3 and R 4 are each as defined above, and Rd is chloroacetyl, or its salt, with a compound of the formula (IV) defined above, or its salt, to give a compound of the formula -R 4 (1-18) WO 96/32379 PCT/JP96/00892 196 wherein R 2 R 3 and R 4 are defined above, and R e is -COCH 2 N R 6 or its salt; xiii) formylating a compound of the formula defined above, or its salt, to give a compound of the formula (1-19) wherein R 2 R 3 and R 4 are each as defined above, or its salt; xiv) oxidizing a compound of the formula (1-19) defined above, or its salt, to give a compound of the formula O HO- R2R4 (1-20) wherein R 2 R 3 and R 4 are each as defined above, WO 96/32379 PCT/JP96/00892 197 or its salt; xv) subjecting a compound of the formula R 1 I I COOH (1-21) R N A3 wherein R 1 R 2 and R 3 are each as defined above, or its salt, to rearrangement reaction to give a compound of the formula R 1 Rl I I NHR (1-22) R2 N R3 wherein R 1 R 2 R 3 R 5 and R 6 are each as defined above, and R 7 is hydrogen, protected carboxy, or -or its saCONlt; or its salt; xvi) reacting a compound of the formula WO 96/32379 PCT/JP96/00892 198 R 1 R2 NH 2 (1-23) R2/ N 3 wherein R 1 R 2 and R 3 are each as defined above, or its reactive derivative at the amino group, or its salt, with a compound of the formula R 8 X 3 (VI) wherein R 8 is acyl, and X3 is leaving group, or its salt, or a compound of the formula R -N=C=O (VII) wherein R 9 is lower alkyl, to give a compound of the formula (1-24) WO 96/32379 PCT/JP96/00892 199 wherein R 1 R 2 R 3 and R 8 are same as defined above, or its salt, xvii) reducing a compound of the formula 1 RR2 R4 RZ2S R (1-25) wherein R 1 R 2 and R 4 are each as defined above, and Rd is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with nitro, or its salt, to give a compound of the formula (1-26) wherein R 1 R 2 and R4 are each as defined above, and R 3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo WO 96/32379 PCT/JP96/00892 200 and both of which are substituted with aryl which is substituted with amino, or its salt; xviii) subjecting a compound of the formula R 1 RR 4 (I-27) wherein R 2 R and R 4 are each as defined above, and R1 is lower alkanoyl substituted with lower alkoxy, or its salt, to dealkylation to give a compound of the formula R 1 RR 4 (1-28) R 2 A3 wherein R 2 R 3 and R 4 are each as defined above, and R1 is lower alkanoyl substituted with hydroxy, or its salt; or its salt; xix) oxidizing a compound of the formula WO 96/32379 PCT/JP96/00892 201 (I-29) wherein R 1 R 3 and R 4 are each as defined above, and R2 is 1-hydroxy(lower)alkyl, or its salt, to give a compound of the formula R 1 R I (1-30) R3 wherein R 1 R 3 and R 4 are each as defined above, and R2 is lower alkanoyl, or its salt; xx) halogenating a compound of the formula defined above, or its salt, to give a compound of the formula (1-31) WO 96/32379 PCT/JP96/00892 202 wherein R 2 R 3 and R 4 are each as defined above, and Rh is halogen, or its salt; xxi) subjecting a compound of the formula defined above, or its salt, to nitration to give a compound of the formula 0 2 N. (1-32) wherein R 2 R 3 and R 4 are each as defined above, or its salt; xxii) reducing a compound of the formula defined above, or its salt, to give a compound of the formula R 4 (1-33) 3 wherein R 2 R 3 and R 4 are each as defined above, and RT is lower alkyl optionally substituted with protected carboxy or carboxy, or its salt; WO 96/32379 PCT/JP96/00892 203 xxiii) reacting a compound of the formula 1 I R 4 (I-34) wherein R 2 R 3 and R 4 are each as defined above, and R is lower alkanoyl, or its salt, with hydroxylamine or its salt, to give a compound of the formula (1-35) wherein R 2 R 3 and R 4 are each as defined above, and Rk is hydroxyimino(lower)alkyl, or its salt; or xxiv) reacting a compound of the formula WO 96/32379 PCT/JP96/00892 204 (1-36) wherein R 1 R 2 and R 4 are each as defined above, R3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with amino, or its reactive derivative at the amino group, or its salt, with a compound of the formula (VI) defined above or its salt, or a compound of the formula (VII) defined above, to give a compound of the formula R 1 R I R 4 (I-37) R2 -1 9 wherein R 1 R 2 and R 4 are each as defined above, and Rg is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with amino substituted with acyl, 205 or its salt. 7. A pharmaceutical composition comprising the compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient. 8. A compound of claim 1 when used as a medicament. 9. A use of the compound of claim 1 for the manufacture of a medicament for inhibiting cGMP-PDE. 10. A use of the compound of claim 1 for the manufacture of a medicament for treating or preventing angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tuburo-intestinal S• diseases, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, urticaria, impotence, diabetic complication, glaucoma or diseases characterized by disorders of gut motility. 11. A method for treating or preventing angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases, renal tuburo-intestinal diseases, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, urticaria, impotence, diabetic complication, glaucoma or diseases ^AL/4 characterized by disorders of gut motility, by uL administering the compound of claim 1. 12. The use of a cyclic nucleotide-PDE inhibitors, or its 206 pharmaceutical acceptable salt, for preventing or treating glomerular diseases, renal tubulo-interstitial diseases, chronic renal failure or diabetic complications. 13. The use of a cyclic nucleotide-PDE inhibitors, or its pharmaceutical acceptable salt, for manufacturing a medicament for preventing or treating glomerular diseases, renal tubulo-interstitial diseases, chronic renal failure or diabetic complications. 14. A compound according to claim 1 substantially as hereinbefore described with reference to the Examples. DATED this 28TH day of SEPTEMBER, 1999 Fujisawa Pharmaceutical Co., Ltd. by DAVIES COLLISON CAVE Patent Attorneys for the applicant(s)