WO1995000536A1

WO1995000536A1 - Peptide compounds

Info

Publication number: WO1995000536A1
Application number: PCT/JP1994/000985
Authority: WO
Inventors: Masaaki Matsuo; Daijiro Hagiwara; Hiroshi Miyake; Norihiro Igari; Kenji Murano
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1993-06-22
Filing date: 1994-06-20
Publication date: 1995-01-05

Abstract

The object compound of formula (IA), wherein R1 is heterocyclic group or tetrahydronaphthyl, R2 is optionally protected hydroxy, R3 is lower alkyl, R4 is ar(lower)alkyl, and X1 is O or N-R5, in which R5 is hydrogen or lower alkyl, and pharmaceutically acceptable salt thereof which are useful as a medicament.

Description

DESCRIPTION

PEPTIDE COMPOUNDS TECHNICAL FIELD

The present invention relates to new peptide compounds and pharmaceutically acceptable salt thereof .

More particularly, it relates to new peptide compounds and pharmaceutically acceptable salts thereof which have pharmacological activities such as tachykinin antagonism, especially substance P antagonism, neurokinin A antagonism, neurokinin B antagonism, and the like, to processes for preparation thereof , to pharmaceutical composition comprising the same, and to a use of the same as a medicament.

One object of the present invention is to provide new and useful peptide compounds and pharmaceutically acceptable salts thereof which have pharmacological activities such as tachykinin antagonism , especially substance P antagonism , neurokinin A antagonism, neurokinin B antagonism, and the like.

Another object of the present invention is to provide processes for the preparation of said peptide compounds and salts thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said peptide compounds and pharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a use of said peptide compound or a pharmaceutically acceptable salt thereof as tachykinin antagonist , especially substance P antagonist, neurokinin A antagonist or neurokinin B antagonist, useful for treating or preventing tachykinin mediated diseases, for example , respiratory diseases such as asthma , bronchitis , rhinitis, cough, expectoration, and the like ; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like ; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis , and the like ; inflammatory diseases such as rheumatoid arthritits, osteoarthritis, and the like ; pains or aches (e.g., migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals.

DISCLOSURE OF INVENTION

The object compounds of the present invention can be represented by the following general formula (IA)~(IC).

wherein R¹ is heterocyclic group or tetrahydronaphthyl,

R² is optionally protected hydroxy,

R³ is lower alkyl,

R⁴ is ar( lower) alkyl, and

X¹ is O or N-R⁵, in which R⁵ is hydrogen or lower alkyl.

wherein R⁶ is protected hydroxy,

R⁷ is naphthyl or a group of the formula

in which R⁸ and R⁹ are each lower alkyl or halogen,

R³ is lower alkyl,

R⁴ is ar ( lower) alkyl,

X² is O or N- R¹⁰, in which R¹⁰ is lower alkyl,

provided that R⁶ is not mesyloxy when X² is O.

wherein R¹¹ is aryloxy(lower)alkyl, lower alkylindenyl or oxotetrahydrobenzofuryl,

R² is optionally protected hydroxy,

R³, R¹² and R¹³ are each lower alkyl,

R⁴ is ar(lower)alkyl, and

Y is O or NH.

According to the present invention, the new peptide compounds (I A)~(I C) can be prepared by the processes which are illustrated in the following schemes.

Process 1

Process 2

Process 3

Process 4

Process 5

Process 6

Process 7

wherein R¹, R², R³, R⁴, R⁶, R⁷, R¹¹, R¹², R¹³, X¹, and X² are each as defined above,

R_a ¹ is , in which is indoldiyl, and D

is amino protective group, and

R_b ¹ is in which is indoldiyl.

R¹⁴ is -OCOCH₂-, -OCOCH(CH₃)-, -OCOCH₂CH(COOH)- , or -OCO(CH₂)₂CH(COOH)-,

R¹⁵ is hydrogen, or lower alkyl,

R¹⁶ is amino protective group

R¹⁷ is -CH₂CH(R^a)-, in which R^a is protected amino

group,

R¹⁸ is protected carboxy group, and

R¹⁹ is lower alkyl.

As to the starting compounds (IIA)~(IIC), (IIIA)~(IIIC) and (IV) some of them are novel and can be prepared by the procedures described in the preparations and Examples mentioned later or a conventional manner.

Throughout the present specification, the amino acid, peptides, protective groups, condensing agents, etc. are indicated by the abbreviations according to the IUPAC-IUB (Commission on Biological Nomenclature) which are in common use in the field of art.

Moreover, unless otherwise indicated, the amino acids and their residues when shown by such abbreviations are meant to be L-configured compounds and residues.

Suitable pharmaceutically acceptable salts of the starting and object compound are conventional non- toxic salt and include an acid addition salt such as an organic acid salt (e. g. acetate, trifluoroacetate , maleate , tartrate , methanesulfonate , benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e. g.

hydrochloride, hydrobromide, hydriodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), or a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e. g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.) , or the like.

In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6, preferably

1 to 4 carbon atom(s), unless otherwise indicated.

Suitable "lower alkyl" may include a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert

-butyl, pentyl, hexyl, and the like, in which the most preferred one is methyl.

Suitable "halogen" may include fluoro, chloro, bromo and iodo.

Suitable "aryloxy(lower)alkyl" may include phenoxy methyl, phenoxyethyl, naphthyloxymethyl, anthryloxy- methyl, and the like.

Suitable "lower alkylindenyl" may include 1-methylindenyl, 3-methylindenyl, and the like.

Suitable "ar(lower)alkyl" may include a conventional group, which is used in the field of amino acid and peptide chemistry, such as mono- or di- or triphenyl(lower)alkyl (e. g. trityl, benzhydryl, benzyl, phenethyl, etc. ), and the like.

Suitable "optionally protected hydroxy" means that the hydroxy group may be protected by a conventional protective group such as acyl (e.g. acetyl, mesyl, etc.), and the like. Suitable " heterocyclic group" may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur nitrogen atom and the like. Especially preferably heterocyclic group may be

5 or 6-membered aromatic heteromonocyclic group (e. g. pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, etc.), 5- or 6-membered aliphatic heteromonocyclic group (e. g. morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, dithiacyclopentyl, etc.), unsaturated condensed heterocyclic group containing 1 to 3 nitrogen atom(s) (e. g. indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.), unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e. g. benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, etc.), unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) (e. g. benzothienyl, benzodithiinyl, etc.), unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) (e. g. 2, 3-dihydro- 1, 4-benzodioxin-6-yl, etc.), unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e. g. oxazolyl, isoxazolyl, oxadiazolyl (e. g. 1, 2, 4-oxadiazolyl, 1, 3,4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc.) etc.), saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), (e. g. morpholinyl, sydnonyl, etc.), unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e. g. benzoxazolyl, benzoxadiazolyl, etc.), unsaturated 3 to 8-membered ( more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g. thiazolyl, isothiazolyl, thiadiazolyl ( e. g. 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, etc.), dihydrothiazinyl, etc.), saturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g. thiazolidinyl, etc.), unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) (e. g. thienyl, dihydrodithiinyl, dihydrodithionyl, etc.), unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e. g. benzothiazolyl, benzothiadiazolyl, etc.), unsaturated 3 to 8-membered (more preferably 5 to 6-membered) heteromonocyclic group containing an oxygen atom (e. g. furyl, etc.), unsaturated 3 to 8-membered (more preferably

5 to 6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s) (e.g. dihydrooxathiinyl, etc.), unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s) (e.g. benzoxathiinyl, etc.), and the like. Thus defined heterocyclic group may have suitable substituent(s) such as amino, oxo, halogen as chloro, lower alkyl as defined above, acyl as defined below, and the like. Preferable example of such groups are triazolyl having amino and lower alkyl

(e.g. 3-amino-1-methyl-1H-triazol-5-yl, etc.), triazolyl having amino (e.g. 3-amino-1H-triazolyl-5-yl, etc.), benzoisothiazolyl having oxo (e.g. 1, 1-dioxobenzoisothiazolyl, etc.), indolyl having acyl or lower alkyl (e. g. 1-formylindol-3-yl, 1-methylindol-3 -yl, etc.).

Suitable hydroxy protective group in the term " protected hydroxy" may include acyl, ar (lower) alkyl (e. g. benzyl, trityl, etc.), lower alkoxy (lower) alkyl (e. g. methoxymethyl, 1-methyl-1-methoxyethyl, methoxypropyl, etc.), tetrahydropyranyl, aryl

(e.g. phenyl, etc.), lower alkyKe. g. methyl, ethyl, etc.), a group of the formula :

wherein P is -, or carbonyl,

A is -, or alkylene(e. g. methylene, ethylene, trimethylene, propylene, tetramethylene, methytrimethylene, dimethylethylene, hexamethylene, etc.),

B is di(lower)alkylamino (e. g. dimethylamino, diethylamino, etc.), lower or higher alkoxycarbonylamino (e. g. methoxycarbonylamino, ethoxycarbonylamino , t - butoxycarbonylamino , t -pentyloxycarbonylamino, heptyloxycarbonylamino, etc.), 5- or 6- membered aliphatic heteromonocyclic group (e. g. morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, dithiacyclopentyl, etc.), or glycyl, and

Q is hydrogen, lower alkyl (e. g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, hexyl, etc.), carboxy, or ar( lower) alkyl ester which may have one or more substituent(s) such as mono-(or di or tri)phenyl( lower) alkyl ester which may have one or more suitable substituent(s) (e. g. benzyl ester, 4- methoxybenzyl ester, 4-nitrobenzyl ester , phenethyl ester, benzhydryl ester, trityl ester, bis (methoxyphenyl)- methyl ester,

3, 4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.), and the like.

Suitable "optionally protected hydroxy" means that the hydroxy group may be protected by a conventional protective group such as acyl (e.g. acetyl, mesyl, etc.), and the like.

Suitable "protected hydroxy" may include acyloxy wherein " acyl" moiety can be referred to the ones as mentioned below.

Suitable example of acyl may be illustrated as follows:- Aliphatic acyl such as lower or higher alkanoyl (e. g. formyl, acetyl, succinyl, hexanoyl, heptanoyl, stearoyl, etc.), lower or higher alkoxycarbonyl (e. g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.), lower or higher alkanesulfonyl ( e. g. methanesulfonyl, ethanesulfonyl, etc.), or the like;

Aromatic acyl such as aroyl (e. g. benzoyl, toluoyl, naphthoyl, etc.), ar(lower)alkanoyl such as phenyK lower) alkanoyl (e. g. phenylacetyl, phenylpropionyl, etc.), aryloxycarbonyl ( e. g. phenoxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy( lower) alkanoyl ( e. g. phenoxyacetyl, phenoxypropionyl, etc. ), arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.), arenesulfonyl (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.), or the like;

Heterocyclic acyl such as heterocycliccarbonyl (e. g. thenoyl, furoyl, nicotinoyl, etc.), heterocyclic ( lower) alkanoyl (e. g. thienylacetyl, thiazolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc.), heterocyclicthio-(lower)alkanoyl (e. g. thienylthioacetyl, thiazolylthioacetyl, isothiazolylthioacetyl, thiadiazolylthioacetyl, tetrazolylthioacetyl, etc.);

heterocyclicglyoxyloyl (e. g. thiazolylglyoxyloyl, thienyl-glyoxyloyl, etc.), or the like; in which suitable heterocyclic moiety in the term " heterocycliccarbonyl", " heterocyclic(lower) alkanoyl", " heterocyclicthio(lower)-alkanoyl" and "heterocyclicglyoxyloyl " as mentioned above means, in more detail, saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.

The processes for preparing the object compound (I A)~(I C) are explained in detail in the following.

Process 1

The object compound (IA) or a salt thereof can be prepared by reacting the compound (IIA) or its reactive derivative at the amino group or a salt thereof with the compound (IIIA) or its reactive derivative at the carboxy group or a salt thereof.

Suitable reactive derivative at the amino group of the compound (IIA) may include Schiff' s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IIA) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound ( IIA) with a silyl compound such as bis (trimethylsilyl) acetamide, mono(trimethyl- syliy) acetamide, bis (trimethylsilyl) urea or the like; a derivative formed by reaction of the compound (IIA) with phosphorus trichloride or phosgene, and the like.

Suitable salts of the compound (IIA) and its reactive derivative can be referred to the ones as exemplified for the compound (IA).

Suitable reactive derivative at the carboxy group of the compound (IIIA) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride within acid such as substituted phosphoric acid [e. g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiousulfuric acid, sulfuric acid, sulfonic acid [ e. g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e. g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2- ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substitued imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e. g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH₃)₂N⁺=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pantachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N- hydroxy compound [ e. g. N, N-dimethylhydroxylamine, 1- hydroxy- 2-( 1H)- pyridone, N-hydroxysuccinimide, N- hydroxyphthalimide, 1- hydroxy- 1H-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (IIIA) to be used.

Suitable salts of the compound ( IIIA) and its reactive derivative may be a base salt such such as an alkali metal salt [e.g. sodium salt, pottasium salt, etc.], an alkaline earth metal salt [e. g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.], or the like, and an acid addition salt as exemplified for the compound (IA).

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

In this reaction, when the compound (IIIA) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N ' - dicyclohexylcarbodiimide ; N - cyclohexyl - N ' -morpholinoethylcarbodiimide ; N - cyclohexyl - N ' -( 4 - di ethylaminocyclohexl )carbodiimide; N,N'-diethylcarbodi-imide, N, N'-diisopropylcarbodiimide; N-ethyl-N'-(3-di-methylaminopropyl)carbodiimide ; N, N ' - carbonylbis- ( 2- methylimidazole) ; pentamethyleneketene- N- cyclohexylimine ; diphenylketene- N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylen; trialkyl phosphite ; ethyl polyphosphate ; isopropyl polyphosphate ; phosphorus oxychloride ( phosphoryl chloride) ; phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate {e. g. ethyl chloroformate, isopropyl chloroformate, etc.}; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; benzotriazol- 1- yl- oxy- tris- ( dimethylamino ) phosphoniumhexafluorophosphate ; 1 - ( p -chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so- called

Vilsmeier reagent prepared by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di (lower)alkylbenzylamine, or the like.

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

Process 2

The compound (IA-b) or a salt thereof can be prepared by subjecting a compound (IA-a) or a salt thereof to removal reaction of the amino- protective group in R¹ _a.

Suitable salts of the compounds (IA-a) and (IA-b) can be referred to the ones as exemplified for the compound (IA).

This 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 or an acid including Lewis acid.

Suitable base may include an inorganic base and an organic base such as an alkali metal [e. g. sodium, potassium, etc.]. an alkaline earth metal [e. g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, hydrazine, trialkylamine [e.g. 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 [e. g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], an inorganic acid [e. g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride,, etc. ] and an acid addition salt compound [e.g. pyridine hydrochloride, etc.].

The elimination using Lewis acid such as trihaloacetic acid [e. g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferablycarried out in the presence of cation trapping agents [e. g. anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, an alcohol [e. g. methanol, ethanol, etc. ], methylene chloride, chloroform, tetrachloromethane, 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 heating.

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 [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e. g. 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 catalysts [e. g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.]. palladium catalysts [e. g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonte, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt,

Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron etc.], copper catalysts [e. g. reduced copper, Raney copper, Ullman copper, etc.] and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol , ethanol , propanol , N , N - dimethylformamide , or a mixture thereof . Additionally, in case that the above- mentioned acid 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 diethtyl 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 heating.

Process 3

The object compound ( IB) or a salt thereof can be prepared by subjecting the compound ( IIB) or a salt thereof to introduction reaction of the hydroxy protective group.

The introduction reaction of the hydroxy protective group can be carried out by reacting the compound ( IIB) or a salt thereof with , for example, a group of the formula : R²⁰- OH ( IIIB) or the reactive derivative at the carboxy group, or R²⁰Z ( IVB) ( wherein R²⁰ is hydroxy protective group, Z is halogen such as chloro, bromo, fluoro, and iodo).

Suitable salts of the compound (IIB) and its reactive derivative can be referred to the ones as exemplified for the compound (IB). Suitable reactive derivative at the carboxy group of the compound ( IIIB) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride ; an acid azide ; a mixed acid anhydride within acid such as substituted phosphoric acid [ e. g . dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc. ] , dialkylphosphorous acid, sulfurous acid, thiousulfuric acid , sulfuric acid , sulfonic acid [ e . g . methanesulfonic acid, etc. ] , aliphatic carboxylic acid [ e. g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2- ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substitued imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e. g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH₃)₂N⁺=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pantachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N - hydroxy compound [ e. g. N, N-dimethylhydroxylamine, 1- hydroxy- 2-( 1H)- pyridone, N-hydroxysuccinimide, N- hydroxyphthalimide, 1- hydroxy- 1H-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (IIIB) to be used.

Suitable salts of the compound ( IIIB) and its reactive derivative may be a base salt such such as an alkali metal salt [e.g. sodium salt, pottasium salt, etc.], an alkaline earth metal salt [e. g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, etc.], or the like, and an acid addition salt as exemplified for the compound (IB).

In this reaction, when the compound (IIIB) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N ' - dicyclohexylcarbodiimide ; N - cyclohexyl - N ' -morpholinoethylcarbodiimide ; N - cyclohexyl - N ' - ( 4 - di ethylaminocyclohexyl )carbodiimide; N,N'-diethylcarbodi-imide, N, N'-diisopropylcarbodiimide; N-ethyl-N'-(3-di-methylaminopropyl) carbodiimide ; N , N ' - carbonylbis-( 2- methylimidazole ) ; pentamethyleneketene- N- cyclohexylimine ; diphenylketene- N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylen; trialkyl phosphite ; ethyl polyphosphate ; isopropyl polyphosphate ; phosphorus oxychloride ( phosphoryl chloride) ; phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate {e. g. ethyl chloroformate, isopropyl chloroformate, etc.}; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; benzotriazol- 1- yl-oxy- tris-( dimethylamino ) phosphoniumhexafluorophosphate ; 1 - ( p -chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so- called Vilsmeier reagent prepared by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal [e. g. sodium, potassium, etc.]. an alkaline earth metal [e. g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di (lower)alkylbenzylamine, or the like.

Process 4

The compound (IB-b) or a salt thereof can be prepared by subjecting a compound (IB-a) or a salt thereof to removal reaction of the amino protective group in R¹⁶.

Suitable salts of the compounds (IB-a) and (IB-b) can be referred to the ones as exemplified for the compound (IB).

This reaction can be carried out in substantially the same manner as Process 2, and therefore the reaction mode and reaction conditions [e. g. solvent, reation temperature, etc.] referred to those as explained in Process 2 .

Process 5

The compound (IB-d) or a salt thereof can be prepared by subjecting a compound (IB-c) or a salt thereof to removal reaction of the carboxy protective group in R¹⁸.

Suitable salts of the compounds (IB-c) and (IB-d) can be referred to the ones as exemplified for the compound (IB).

Process 6

The object compound (IC-a) or a salt thereof can be prepared by reacting the compound (IIC) or its reactive derivative at the amino group or a salt thereof with the compound (IIIC) or its reactive derivative at the carboxy group or a salt thereof.

Suitable salts of the compounds (IC-a), (IIC) and (IIIC) can be referred to the ones as exemplified for the compound (IC).

This reaction can be carried out in substantially the same manner as Process 1, and therefore the reaction mode and reaction conditions [e. g. solvent, reation temperature, etc.] referred to those as explained in Process 1 .

Process 7

The object compound (IC-b) or a salt thereof can be prepared by reacting the compound (IIC) or its reactive derivative at the amino group or a salt thereof with the compound (IIIC-a).

This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as alcohol [e. g. methanol, ethanol, propanol, 2-methoxyethanol etc.], tetrahydrofuran, dioxane , dimethyl sulfoxide , N , N -dimethylformamide, or a mixture thereof.

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

The compounds obtained by the above processes can be isolated and purified in a conventional manner, for example, pulverization , recrystallization , colum chromtography , reprecipitation, and the like.

It is to be noted that the compound (I A)~(I C) and the other compounds may include one or more stereoisomers due to asymmetric carboun atoms, and all of such isomers and mixture thereof are included within the scope of this invention.

The object compounds (I A)~(I C) and pharmaceutically acceptable salt thereof have pharmacological activities such as tachykinin antagonism, especially substance P antagonism, neurokinin A antagonism or neurokinin B antagonism, and therefore are useful for treating or preventing tachykinin mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like;

ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like;

cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritits, osteoarthritis, and the like;

pains or aches (e. g., migraine, headache, toothache, cancerous pain, back pain, etc.); and the like.

Further, it is expected that the object compounds (I A)~(I C) of the present invention are useful for treating or preventing ophthalmic diseases such as uveitis, glaucoma, and the like; gastrointestinal diseases such ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; inflammatory diseases such as nephritis, and the like; circulatory diseases such as hypertension, angina pectoris, cardiac failure, thrombosis, and the like; epilepsy; spartic paralysis; pollakiuria; dementia; Alzheimer's diseases;

schizophrenia; Huntington's chorea; carcinoid syndrome; and the like, and useful for immunosuppresive agent.

For therapeutic purpose, The compounds (I A)~(I C) and pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external, enteral, intravenous, intramuscular, inhalant, nasal or intraarticular administration. The pharmaceutical preparations may be tablet, granule, dragees, capsule, solution, suspension, emulsion, ointment, or the like.

If desired, there may be included in these preparations auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of the compound (I A)~(I C) will vary depending upon the age and condition of the patient, an average single dose of about 0.1mg, 1mg, 10mg, 50mg, 100mg, 250mg,

500 mg and 100mg of the compound (I A)~(I C) may be effective for treating asthma and the like. In general, amounts between 0.1 mg/body and about 1, 000mg/body may be administered per day.

The following examples are given for purpose of illustrating the present invention in detail.

In these examples, there are employed the following abbreviations in addition to the abbreviations adopted by the IUPAC -IUB.

Ac : acetyl

Boc : t-butoxycarbonyl

Bu^t : t-butyl

Bzl : benzyl

DMF : dimethylformamide

DMSO : dimethylsulfoxide

Et : ethyl

HOBT : N-hydroxybenzotriazole

Me : methyl

Ms : mesyl

HC1/DOX : hydrogen chloride in 1,4-dioxane

TEA : triethylamine

TFA : trifluoroacetic acid

THF : tetrahydrofuran

WSC : 1-ethy-3-(3'-dimethylaminopropyl)-carbo diimide

The Starting Compounds used and the Object Compounds obtained in the following examples are given in the Table as below, in which the formula of the former compounds

are in the upper and the formula of the latter compounds are in the lower, respectively.

Preparation 1

To an ice- cooled solution of Starting Compound (5.00g), N -methylbenzylamine (1.82 g), and HOBT (2.30 g) in methylene chloride (75 ml), was added WSC·HCl (3.17 g). The solution was stirred at the same temperature for an hour and at room temperature overnight. After evaporation, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with sodium hydrogencarbonate solution, water, 0.

5N hydrochloric acid, and sodium chloride solution. Evaporation gave Object Compound (6.52 g) as a syrup.

IR (CHCl₃) : 3330, 2990, 2940, 1710, 1640cm^-1

NMR (DMSO-d₆, δ) : 1.23 and 1.33(9H, s), 2.8-3.2(5H, m),

4.4-4.9(3H, m), 7.0-7.7, 7.9-8.3, 9.25 and 9.65(12H, m)

MASS M⁺ : 435

Preparation 2

To an ice-cooled solution of Starting Compound (6.13 g) in methylene chloride (60 ml) was added 4N-HCl/DOx (60 ml). The solution was stirred at the same temperature for five minutes. Then the cooling bath was removed and the solution was stirred at room temperature for half an hour. After evaporation, the residue was triturated with ether, the precipitates were collected by filtration, and dried over sodium hydroxide in vacuo to give Object Compound (4.97 g).

IR (Nujol) : 1708, 1640cm^-1

NMR (DMSO-d₆, δ) : 2.64(3H, s), 3.2-3.3(2H, m), 4.4 and 4. 6-4.8(3H, m), 6.9-7.5(7H, m), 7.6-7.8(2H, m), 8.2(1H, m) 9.2 and 9.7(1H, m), 8.60(3H, brs)

MASS M⁺ : 548

Preparation 3

To an ice- cooled solution of Starting Compound (1.87 g), Boc-(2S, 4R)-Pro(4OH)-OH (3.00 g) and HOBT (1.09 g) in a mixed solvent of methylene chloride (40 ml) and dimethylformamide (10 ml) was added WSC (1.49 ml). The solution was stirred at the same temperature for an hour and at room temperature overnight. After evaporation, the reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with an aqueous sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, water and an aqueous sodium chloride solution, and was dried over magnesium sulfate. After evaporation, the residue was purified on a silica gel column (80 g) eluting with a mixed solvent of chloroform and methanol to give Object

Compound (2.43 g) as an amorphous solid. (200: 1 to 19 : 1 gradient)

IR (CHCl₃) : 3320, 2990, 2950, 1690, 1640cm^-1

NMR (DMSO-d₆, δ) : 1.23, 1.38(9H, s), 1.45-2.10(2H, m), 2.65 -3.50(7H, m), 4.10-5.25(6H, m), 6.95-8.70(11H, m), 9.23, 9. 65(1H, s)

MASS M⁺ : 548

Preparation 4

To an ice-cooled solution of Starting Compound (2.38 g) and anisole (2.23 ml) in methylene chloride (20 ml) was added 4N -HCl/DOX (20 ml).

The solution was stirred at the same temperature for five minutes and at room temperature for fifty five minutes. After evaporation, the residue was triturated with ether, and the precipitates were collected by filtration and dried to give Object Compound (1.95 g) as an amorphous solid.

IR (Nujol) : 3300, 2680, 1710, 1669, 1625, 1563cm^-1

NMR (DMSO-d₆, δ) : 1.65- 1.95, 2.10-2.45(2H, m), 2.80, 2.84 (3H, s), 2.90-3.60(5H, m), 4.20-4.60(4H, m), 4.95-5.25(1H, m), 7.00-7.85, 7.95-8.35, 8.50-8.80, 9.20-10.30(14H, m)

Preparation 5

The object compound was obtained according to a

similar manner to that of Preparation 1.

IR (CHCl₃) : 3420 (sh), 3300, 1690, 1630 cm^-1

NMR (DMSO-d₆, δ) : 1.29 and 1.36(9H, 2s), 2.71 and 2.78(3H, 2s), 2.9-3.2(2H, m)(β-CH₂), 4.3-4.8(3H, m)(N-Bzl+ α• H), 6. 8-7.6(11H, m), 10.81 and 10.87(1H, 2s)(NH)

Preparation 6

Starting compound (8.15 g), powdered sodium hydroxide (4 g), cetyltrimethylammonium chloride (0.8 g), and methyl iodide (5.68 g) were mixed in methylene chloride (100 ml). The mixture was stirred at room temperature overnight. Methyl iodide (5.68 g) was added and the mixture was stirred additional 24 hours. To the mixture was added 1N hydrochloric acid (40 ml) and the organic layer was separated. After concentration, water and ethyl acetate were added to the residue. The organic layer was washed successively with water, diluted sodium hydrogencabonate solution, 0.5N hydrochloric acid, and brine, and dried over magnesium sulfate. After concentration, the crude material was purified on a silica-gel column (150 g) eluting with a mixed solvent of methylene chloride and acetate (30:1) to give the object compound (5.13 g).

IR (CHCl₃) : 3300, 2980, 1705, 1640, 1480, 1365, 1165 cm^-1 NMR (DMSO-d₆, δ) : 1.2-1.45(9H, m), 2.72 and 2.77(3H, s),

2.9-3.2(2H, m), 3.69 and 3.71(3H, s), 4.35-4.8(3H, m), 6.9 -7.6(11H, m)

MASS : M⁺¹ 422, 421, m/e 304, 184, 144 Preparation 7

The object compound was obtained according to a

similar manner to that of Preparation 2.

IR (CHCl₃) : 3400, 2920, 1645, 1490, 1450, 1375, 1250 cm^-1

NMR (DMSO-d₆, δ) : 2.51 and 2.65(3H, s), 3.1-3.4(2H, m), 3. 6-3.75(3H, m), 3.9-4.05 and 4.3-4.65(3H, m), 6.9-7.7(10H, m), 8.57(2H, br-s)

Preparation 8

The object compound was obtained according to a

similar manner to that of Preparation 3. IR (CHCl₃) : 3420, 2990, 1675, 1630, 1475, 1450, 1405,

1160 cm^-1

NMR (DMSO-d₆, δ) : 1.28 and 1.40C9H, s), 1.3-1.85 (1H, m), 1.85-2.1(1H, m), 2.7 and 2.73(3H, s), 2.9-3.5(4H, m), 3.69

(3H, s), 4.1-4.7(4H, m), 4.9-5.2(2H, m), 6.8-7.6(10H, m), 8. 35-8.5(1H, m)

Preparation 9

The object compound was obtained according to a

similar manner to that of Preparation 4.

IR (Nujol) : 3350, 1675, 1630, 1550, 1325, 1245 cm^-1

NMR (DMSO-d₆₎ δ) : 1.7-1.9(1H, m), 2.2-2.4(1H, m), 2.72 and

2.97(3H, s), 3.15-3.4(4H, m), 3.72(3H, s), 4.25-4.55(4H, m), 4.9-5.15(1H, m), 5.5-5.6(1H, m), 6.9-7.65(11H, m), 9.15-9.

3(1H, m)

Preparation 10

To a solution of sodium ethoxide (7.1 g) in anhydrous ethanol (340 ml) were added successively 2-chloromethyl-5, 6, 7, 8-tetrahydronaphthalene (17.1 g) and 2-acetamide-diethylmalonate

(20.6 g) at room temperature. The solution was gradually heated to the refluxing temperature and heated under reflux for two hours. After heating was stopped, the mixture was immediately filtered and the filtrate was concentrated. Ethanol (20 ml) was added to the crystalline residue and the product was filtered, washed with ethanol, and dried to give the object compound (14.

7 g).

mp : 108- 109ºC

NMR (DMSO-d₆, δ) : 1.17(6H, t, J = 7Hz), 1.7(4H, m), 1.93(3H, s), 2.64(6H, m), 4.14(4H, q, J = 7Hz), 6.6-6.67(2H, m), 6.94 (1H, m), 7.99(1H, s)

Preparation 11

The starting compound (14.4 g) was dissolved in a solution of pottasium hydroxide (4.47 g) in a mixture of water (144 ml) and ethanol (144 ml). The solution was heated under reflux for four and half an hour. Ethanol was evaporated under reduced pressure, and the residual solution was acidified to pH1 with concentrated hydrochloric acid. The precipitated material was extracted with ethyl acetate and the organic layer was washed with water and dried over magnesium sulfate. Evaporation gave the object compound as a crystalline solid (6.40 g)

: mp 147-149°C.

NMR (DMSO-d₆, δ) : 1.70(4H, m), 1.79(3H, s), 2.66(4H, m), 2.

7-3.0(2H, m), 4.3(1H, m), 6.8-6.9(3H, m), 8.14(1H, d, J = 8Hz)

Preparation 12

The starting compound (5.4 g) was dissolved in a solution of sodium hydroxide (0. 84 g) in water ( 129 ml). The temperature was kept at 37°C and the pH was adjusted to 7.5. Then cobaltous chloride hexahydrate (27 mg) and Acylase Amano 15000 (270 mg) were added. The mixture was stirred at this temperature overnight while the pH was maintained at 7.5 with the addition of 1N sodium hydroxide solution. The precipitates were collected by filtration, washed with water, and dried to give the object compound (2.0 g); mp 210 ºC (dec). The optical purity was confirmed by TLC analysis on Chiral Plate (MercK) using a mixed solvent of acetonitrile-methanol-water (4:1:1) as a mobile phase.

NMR (NaOD, δ) : 1.70(4H, m), 2.66(4H, m), 2.7-3.2(2H, m), 3.6(1H, m), 7.0(3H, m) Preparation 13

To a suspended mixture of Starting Compound ( 1.5 g) in a mixed solvent of water (15 ml) and acetone (15 ml) was added triethylamine (2.1 ml) under ice- cooling. To the solution was added a solution of di-tert butyldicarbonate (1.79 g) in acetone (5 ml), and the solution was stirred at the same temperature for two hours and at room temperature for additional two hours.

After removal of the acetone, water (30 ml) was added and the aqueous solution was washed once with with ethyl acetate. The aqueous layer was then acidified to pH 2 with an addition of 6N hydrochloric acid and was extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride solution and was dried over magnesium sulfate. Evaporation, gave Object

Compound (1.94 g) as a syrup.

IR (CHCl₃) : 3460, 1730-1710, 1670, 1500, 1455-1400,

1370 cm^-1

NMR (DMSO-d₆, δ) : 1.33(9H, s), 1.65-1.75(4H, m), 2.6-3.0(6H, m), 3.95-4.1(1H, m), 6.6-7.1(4H, m), 12.54 (1H, br-s)

MASS : M⁺ 319 Preparation 14

The object compound was obtained according to a

similar manner to that of Preparation 1.

IR (CHCl₃) : 3470, 3250, 1710, 1645, 1500, 1460, 1370,

1250 cm^-1

NMR (DMSO-d₆, δ) : 1.2-1.4(9H, m), 1.6-1.8(4H, m), 2.55-2.

95(9H, m), 4.45-4.7(3H, m), 6.65-7.4(9H, m)

MASS : M⁺ 422

Preparation 15

The object compound was obtained according to a

similar manner to that of Preparation 2.

IR (Nujol) : 3420, 3220, 1650, 1610, 1580, 1495, 1450,

1280 cm^-1

NMR (DMSO-d₆, δ) : 1.65-1.85(4H, m), 2.55-2.75(7H, m), 2.85-3.15(2H, m), 4.05-4.65(3H, m), 6.85-7.35(8H, m), 8.42(2H, br-s)

MASS : M⁺ 322

Preparation 16

The object compound was obtained according to a similar manner to that of Preparation 3.

IR (CHCl₃) : 3450-3300, 1690-1670, 1640, 1500, 1450 cm^-1 NMR (DMSO-d₆₎ δ) : 1.2-1.5(9H, m), 1.65-1.8(5H, m), 1.85-2.05(1H, m), 2.55-3.05(9H, m), 3.2-3.5(2H, m), 4.1-5.05(6H, m), 6.65-7.35(8H, m), 8.2-8.4(1H, m)

MASS : M⁺ 535

Preparation 17

The object compound was obtained according to a similar manner to that of Preparation 4.

IR (CHCl₃) : 3450 - 3250, 1680, 1640, 1550, 1500, 1450cm^{- 1} NMR (DMSO-d₆, δ) : 1.65-1.9 (5H,m), 2.25-2.4 (1H,m), 2.55-3.45 (41H.m), 4.2-5.0 (5H,m), 5.45-5.6 (1H,m), 6.7-7.35 (8H,m), 8. 59 (1H,br-s), 9.05-9.2 (1H,m), 10.01 (1H,br - s)

Preparation 18

The object compound was obtained according to a

similar manner to that of Preparation 10.

NMR (DMSO-d₆, δ) : 1.63(6H, t, J = 7Hz), 1.93(3H, s), 3.31 (2H, s), 4.13(4H, q, J = 7Hz), 4.19(4H, s), 6.4(2H, m), 6.74(1H, m),

8.08(1H, s)

Preparation 19

A solution of the starting compound (11.4 g) in a mixture of acetic acid (57 ml) and concentrated hydrochloric acid (57 ml) was heated under reflux for six hours. After cooling, the mixture was concentrated and the crystalline residue was collected by filtration by washing out with ethanol, and dried to give the object compound (6.86 g).

mp : 220ºC (dec)

NMR (DMSO-d₆, D₂ O, δ) : 3.03(2H, d, J=6Hz), 4.08(1H, t, J=6Hz), 4.21(4H, s), 6.7-6.8(3H, m), 8.42(3H, s)

Preparation 20

The starting compound (7.27 g) was dissolved in 1N sodium hydroxide ( 100 ml). To the solution was added acetic anhydride ( 6. 09 ml) dropwise at 15 °C. After the addition was completed, the reaction mixture was stirred at room temperature for two hours. The mixture was acidified with cone hydrochloric acid to pHl and the precipitated material was extracted with ethyl acetate.

THe extract was washed with water and dried over magnesium sulfate. After concentration, the crystalline solid resulted was collected by filtration by washing out with water, and dried to give the object compound ( 5. 88 g).

mp : 157- 159 °C

NMR (DMSO- d₆, δ ) : 1. 78 ( 3H, s), 2. 70 ( 1H, dd, J = 9. 4Hz, 13. 8Hz), 2. 90 ( 1H, dd, J = 4. 9Hz, 13. 8Hz), 4. 19 ( 4H, s), 4. 3 ( 1H, m ), 6. 6-6. 77 ( 3H, m ), 8. 13 ( 1H, d, J = 8Hz), 12. 6 ( 1H, brs) Preparation 21

The starting compound (5.0 g) was dissolved in a solution of sodium hydroxide (0.80 g) in water (100 ml). The temperature was kept at 37 °C and the pH was adjusted to 7.5. Then cobaltous chloride hexahydrate (25 mg) and Acylase Amano 15000 (250 mg) were added. The mixture was stirred at this temperature overnight while the pH was maintained at 7.5 with the addition of 1N sodium hydroxide solution.

Preparation 22

The solution was acidified to pH1 with 1N - hydrochloric acid and was extracted with ethyl acetate twice. The aqueous layer was separated and was neutralized to pH7.0 with the addition of 1N sodium hydroxide solution. To the aqueous layer were added acetone (30 ml) and triethylamine (2.89 ml). To the mixture was added di - tert - buthldicabonate (2.46 g) dissolved in acetone (10 ml) under ice - cooling. The resulting solution was stirred overnight at room temperature. After removal of the acetone, water (30 ml) was added and the solution was washed with ether once. The aqueous layer was separated and then acidified to pH1 with an addition of 1N hydrochloric acid. The extract was washed with an aqueous solution of sodium chloride and was dried over magnesium sulfate. Evaporation gave the object compound as a syrup (3.50 g). mp : 172- 174 C

IR (CHCl₃) : 3350-3100, 1730-1700, 1590, 1510 cm^-1

NMR (DMSO-d₆, δ) : 1.33(9H, m), 2.6-2.95(2H, m), 3.9-4.05

(1H, m), 4.19(4H, s), 6.6-6.8(3H, m), 8.13(1H, d, J = 7.7Hz), 12.48(1H, br-s)

MASS : M⁺ 323 Preparation 23

The object compound was obtained according to a

similar manner to that of Preparation 1.

IR (CHCl₃) : 3450, 3300, 1710, 1640, 1590, 1510, 1450,

1370 cm^-1

NMR (DMSO-d₆, δ) : 1.25- 1.4(9H, m), 2.65-2.9(5H, m), 4.1- 4.7(7H, m), 6.5-6.85 and 7.0-7.4(9H, m)

Preparation 24

The object compound was obtained according to a

similar manner to that of Preparation 2.

IR (CHCl₃) : 3500-3350, 1660-1640, 1595, 1505, 1450, 1370 cm^-1 NMR (DMSO-d₆, δ) : 2.71(3H, s), 2.8-3.0(2H, m), 4.1-4.65(3H, m), 4.20(4H, m), 6.8-7.4(8H, m), 8.36(2H, br-s) Preparation 25

The object compound was obtained according to a

similar manner to that of Preparation 3.

IR (CHCl₃) : 3450-3300, 1690-1670, 1640, 1590, 1510, 1450,

1365 cm^-1

NMR (DMSO-d₆, δ) : 1.2-1.45(9H, m), 1.65-2.05(2H, m), 2.6 -3.0(5H, m), 3.15-3.5(2H, m), 4.1-5.0C10H, m), 6.45-7.35(8H, m), 8.2-8.35(1H, m)

Preparation 26

IR (CHCl₃) : 3400-3150, 1680, 1645-1620, 1590, 1565-1545, 1510,

1450-1430 cm^-1

NMR (DMSO-d₆₎ δ) : 1.75-1.9(1H, m), 2.4-2.55 (1H, m), 2.7-3.2(7H, m), 4.21(4H, s), 4.2-5.0(5H, m), 5.55-5.6(1H, m), 6.

55-7.4(8H, m), 8.61(1H, br-s), 9.10(1H, d, J = 7.5Hz), 9.95(1H, br-s)

Preparation 27

The object compound was obtained according to a

similar manner to that of Preparation 13.

IR (CHCl₃) : 3450, 3350, 1720, 1510, 1440, 1400, 1370 cm^-1

NMR (DMSO-d₆, δ) : 1.31(9H, s), 3.0-3.3(2H, m), 4.15-4.25(1H, m), 7.15-8.05(6H, m), 12.73(1H, br-s)

MASS : M⁺ 321

Preparation 28

The object compound was obtained according to a

similar manner to that of Preparation 2.

IR (CHCl₃) : 3450, 3320, 1710, 1690, 1640, 1550, 1500-1480,

1370cm^-1

NMR (DMSO-d₆, δ) : 1.1-1.45(9H, m), 2.7-2.8(3H, m), 3.05-3.3(2H, m), 4.25-4.9(3H, m), 7.0-8.0(11H, m) Preparation 29

The object compound was obtained according to a

similar manner to that of Preparation 2.

IR (CHCl₃) : 3500-3400, 1665-1640, 1490, 1455, 1430,

1375 cm^-1

NMR (DMSO-d₆, δ) : 2.43(3H, s), 3.25-3.5(2H, m), 3.8-4.7(3H, m), 7.0-8.1(10H, m), 8.61(2H, br-s)

Preparation 30

The object compound was obtained according to a

similar manner to that of Preparation 3. IR (CHCl₃) : 3450-3300, 1600-1675, 1640, 1490, 1410,

1370 cm^-1

NMR (DMSO-d₆, δ) : 1.2-1.5(9H, m), 1.5-2.05(2H, m), 2.7-2. 85(3H, m), 3.05-3.5(4H, m), 4.1-5.3(6H, m), 6.9-8.0 and 8. 45-8.6(11H, m)

Preparation 31

The object compound was obtained according to a

similar manner to that of Preparation 4.

IR (CHCl₃) : 3450-3200, 1680, 1640, 1570-1545, 1495, 1450 cm^-1

NMR (DMSO-d₆, δ) : 1.75-1.9(1H, m), 2.2-2.4(1H, m), 2.65-2.8(3H, m), 3.0-3.5(4H, m), 4.3-5.7(6H, m), 6.95-8.05(10H, m), 8.67(1H, br-s), 9.30(1H, d, J = 7.8Hz), 10.01(1H, br-s) Preparation 32

To an ice-cooled solution of the starting compound (1.07g) and triethylamine (0.46ml) in 20ml of ethyl acetate was added phenacyl bromide (0.66g). The mixture was stirred for two hours at the temperature and four hours at room temperature. Triethylamine (0.46ml) was added and the mixture was stirred overnight at room temperature. Water was added to the mixture and the organic layer was washed successively with sodium hydrogen carbonate solution, water, 1N hydrochloric acid, and brine, and dried over magnesium sulfate. Evaporation gave a crystalline solid which was washed with diisopropyl ether and dried to give the object compound (0.80g).

IR (Nujol) : 3460, 1750, 1705, 1500, 1345, 1170 cm^-1

NMR (DMSO-d₆, δ) : 1.38(9H, s), 2.8-3.05(2H, m), 4.45-4.55 (1H, m), 5.14(2H, s), 5.49(2H, s), 7.3-8.0(11H, m)

Preparation 33

To an ice-cooled solution of the starting compound (1.45g) in methylene chloride (30ml) was added 4N hydrochloric acid in dioxane (13.3ml). The mixture was stirred at the temperature for ten minutes and at room temperature for two hours. The mixture was concentrated under vacuum and the residue was triturated with diisopropyl ether. The precipitates were filtered and dried to give the object compound (1.14g).

IR (Nujol) : 3200, 1750, 1735, 1700, 1600, 1320, 1220 cm^-1 NMR (DMSO-d₆, δ) : 3.15-3.3(2H, m), 4.48(1H, t, J = 5.5Hz), 5.

24(2H, s), 5.52(2H, s), 7.7-8.05(10H, m), 8.81(3H, br-s) MASS : M+1 342

Preparation 34

The starting compound (1.12g), Z-glycine (0.62g), and HOBT

(0.40g) were suspended in 25ml of methylene chloride and the mixture was ice-cooled. Then WSC (0.54ml) was

added and the resulting solution was stirred at the temperature for an hour and at room temperature overnight. The solvent was evaporated and the residue was diluted with water and was extracted with ethyl acetate. The organic layer was washed successively with sodium hydrogencabonate solution, water, 1N hydrochloric acid, and brine, and dried over magnesium sulfate. Evaporation gave the object compound as an oil (1.60g). IR (CHCl₃) : 3350, 1750-1730, 1700, 1600, 1460cm^-1

NMR (DMSO-d₆, δ) : 2.85-3.1(2H, m), 3.69(2H, d, J = 6Hz), 4.79 (1H, d, d, J=6.3, 14Hz), 5.04(2H, s), 5.14 (2H, s), 5.49(2H, s), 7. 3-8.0(16H, m), 8.48(1H, d, J = 8Hz)

MASS : M⁺¹ 533, M⁺¹ 532

Preparation 35

To a solution of the starting compound ( 1. 55g) in dimethylformamide (25ml) under nitrogen atmosphere was heated to 35 °C and pyridine, acetyl acetone was added. Further, zinc was added and under the same condition, it was stirred for 5 hours. An insoluble compound was filtered and washed in dimethylformamide, and evaporated. Water was added and was extracted with ethyl acetate. The organic layer was washed with

1N hydrochloric acid, water, and brine, and dried over magnesium sulfate. Evaporation gave the object compound as an oil (1.20g).

IR (Nujol) : 3370, 3280, 1745, 1655, 1555, 1530, 1435,

1300 cm^-1

NMR (DMSO-d₆, δ) : 2.6-2.85(2H, m), 3.66(1H, t, J = 8Hz), 4.69 (1H, d, d, J=6Hz, 14Hz), 5.03(2H, s), 5.12(2H, s), 7.25-7.55(12H, m), 8.39(1H, d, J = 8Hz), 12.54(1H, br-s)

MASS : M⁺¹ 415

Preparation 36

To an ice- cooled mixture of benzofuran-2-carboxylic acid (0.

15g), the starting compound (0.45 g), and HOBT (0.12g) in 9 ml of methylene chloride was added WSC (0.17 ml).

The resulting solution was stirred at the same temperature for half an hour and overnight at room temperture. N, N-dimethyl-1, 3-propanediamine (0.05 ml) was added thereto and the mixture was stirred for additional two hours. The mixture was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with saturated sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid and brine, and dried over magnesium sulfate. After evaporation, the crude material was subjected to a silica gel ( 20 g) chromatography eluting with a mixed solvent of chloroform and methanol (from 1% to 2.5%, gradient). Concentration of the fractions and pulverization with diisopropyl ether gave the object Compound (0.40 g).

IR (Nujol) : 3300, 1630, 1565 cm^-1

NMR (DMSO-d₆, δ) : 1.85-2.15 (2H, m), 2.15-3.10 (2H, m), 2.76, 2.77 and 2.89 (3H, s), 3.60-5.20 (8H, m), 6.85-7.80 (13H, m), 8.50-8.80 (1H, m)

MASS : M⁺ 594

Preparation 37

To a suspended mixture of benzofuran-2-carboxylic acid

(0.31 g) and HOBT (0.26 g) in methylene chloride (10 ml) was added WSC·HCl (0.37 g) at room temperature. The resulting solution was stirred for thirty minutes. During this period, a solution of the starting Compound (1.0 g) and TEA (0.29 ml) in methylene chloride (10 ml) in an another reaction vessel under ice-cooling. The two reaction mixture were mixed at room temperature and the resulting mixture was stirred at room temperature overnaight. After evaporation, the residue was diluted in water and extracted with ethyl acetate. The organic layer was washed successively with sodium hydrogen carbonate solution, water, IN hydrochloric acid and brine, and dried over magnesium sulfate. After evaporation, the crude product was purified on a silica gel (54 g) column eluting with a mixed solvent of methylene chloride and methanol (50:1 to 20:1, gradient elution).

The purified material was crystallized with a mixed solvent of ethyl acetate and diisopropyl ether to give the object Compound (0.77 g).

mp : 137-139°C

IR (Nujol) : 3400, 3250, 3100, 1630, 1570, 1420 cm^-1

NMR (DMSO-d₆, δ) : 1.7-1.9 (1H, m); four singlet at 2.05, 2. 10, 2.11 and 2.17 (6H); 2.2-2.4 (1H, m); four singlets at 2. 60, 2.64,2.73 and 2.79 (3H); 2.8-3.5 (2H, m); 3.6-4.1 (2H, m); 4.3-5.2 (6H, m), 6.6-7.8 (14H, m); 8.54 and 8.73 (1H, d, J = 8Hz)

MASS : M⁺ 553 Preparation 38

To a solution of phenol (5.0 g) in 80 ml of dimethylformamide were added pottasium carbonate 14.69 g and pottasium iodide

(4.41g). The misture was cooled with ice and the starting compound (4.81 g) dissolved in 20 ml of dimethylformamide wad added dropwise under nitrogen atmosphere. The mixture was sirred for ten minutes at the temperature and for an hour at room temperature. The mixture was filtered, evaporated under reduced pressure, diluted in water and extracted with ethyl acetate. The organic layer was washed successively with saturated sodium hydrogen carbonate solution, water, 0.5Nhydrochloric acid, and brine, and dried over magnesium sulfate. After evaporation, the crude product was purified on a silica-gel column chromatography eluting with chloroform to give the object compound (3.99 g) IR(neat): 3070, 2950, 1597, 1493, 1447 cm^-1

MASS M + : 133

NMR (DMSO-d₆, δ): 5.17(2H, s);7.00-7.15(3H, m):7.30-7.50(2H, m) Preparation 39

The starting compound (3.99 g) was treated with 20 ml of saturated hydrochloric acid solution in ethanol under ice-cooling. The mixture was stirred for additional twenty minutes and the crystalline precipitates were collected by filtration, washed with ether, dried under vacuum to give the object compound (4.52g). m. p.108- 109ºC

IR (Nujol); 1673, 1600, 1589, 1552 cm^-1

Elemental Analysis for C₁₀H₁₃N₁O₂• HCl(%)

Calcd. :C 55.69, H 6.54, N 6.49, Cl 16.44

Found. :C 55.33, H 6.81, N 6.68

Example 1

To an ice-cooled solution of 1-methylindole-3-carboxylic acid (1.20g), Starting Compound (0.433g) and HOBT (0.333 g) in dimethylformamide (25 ml) was added WSC (0.338 g). The solution was stirred at the same temperature for and hour and at room temperature overnight. After evaporation, the reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with an aqueous sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, water, and an aqueous sodium chloride solution, and dried over magnesium sulfate. After evaporation, the residue was purified an a silica-gel column (50 g) eluting with a mixed solvent of chloroform and methanol (100 : 1 to 25 : 1, gradient). The fractions containing the desired compound were collected and evaporated to give Object Compound (1.44 g) as an amorphous solid.

IR (Nujol) : 3300, 1710, 1635, 1605, 1530 cm^{- 1}

NMR (DMSO-d₆, δ) : 1.7 - 2.2 (2H,m), 2.7 - 2.9 (3H,s), 3.0 - 3.3 (2H,m), 3.6-4.0 (5H,m), 4.3-4.8 (4H,m), 5.0-5.2 (2H,m), 7.0-8.3,8.

7,9.2 and 9.6 (17H,m)

Example 2

To a solution of the starting compound (670 mg) in methanol (30 ml) was added 0.1N sodium hydroxide (11.1 ml).

The solution was stirred for twenty minutes at room temperature and methanol was evaporated. The mixture was extracted with ethyl acetate and the organic layer was washed with water, brine, and dried over magnesium sulfate. After evaporation, the residue was triturated with diisopropyl ether, collected by filtration, dried to give the object compound as an amorphous solid (573 mg).

IR (Nujol) : 3300,1630,1600 (sh),1530 cm^-1

NMR (DMSO-d6, δ) : 1.7-2.2 (2H,m), 2.64 and 2.66 (3H,s), 2.9 -3.3 (2H,m), 3.6-4.0 (5H,m), 4.2-4.4 (3H,m), 4.7-4.8 (1H,m), 5.0-5.2 (2H,m), 6.8-7.6 (13H,m), 7.89 (1H,brs), 8.06 (1H,d,J = 7.3Hz), 8.43

(1H.brs), 10.83 and 10. 87 (1H, s)

Example 3

The object compound was obtained according to a similar manner to that of Example 1.

IR (Nujol) : 3400, 3250, 1740, 1630, 1530, 1320, 1245 cm^{- 1}

NMR (DMSO-d₆, δ) : 1.7-2.2 (2H,m), 2.7 (3H,s), 2.9-3.3 (2H,m),

3.55-4.0 (8H,m), 4.25-5.1 (6H,m), 6.85-8.15 (15H,m), 8.45-8.6 (1H, m)

Example 4

IR (Nujol) : 3450, 3300, 3100, 1660, 1630, 1605, 1445, 1320 cm^{- 1} NMR (DMSO-d₆, δ) : 1.6 - 2.1 (6H,m), 2.55 - 3.05 (9H,m), 3.6 - 4. 0 (5H,m), 4.25-5.05 (6H,m), 6.7-8.15 (13H,m), 8.3-8.5 (1H,m) MASS : M^{+ 1} 593, M⁺ 592

Example 5

The object compound was obtained according to a similar manner to that of Example 1.IR (CHCl₃) : 3400-3300, 1660, 1645 - 1620, 1590, 1530, 1510, 1465, 1430, 1370 cm^{- 1}

NMR (DMSO-d₆, δ) : 1.75 - 2.15 (2H,m), 2.6 - 3.0 (5H,m), 3.6 - 4. 0 (2H,m), 3.85 (3H,s), 4.19 (4H,s), 4.2-5.05 (6H,m), 6.5-7.55 and 7. 8-8.1 (13H,m), 8.3-8.4 (1H,m)

Example 6

IR (CHCl₃) : 3450 - 3300, 1660, 1650 - 1595, 1530, 1470, 1420, 1370 cm^{- 1}

NMR (DMSO-d₆, δ) : 1.7 - 2.05 (2H,m), 2.70 (3H,s), 3.0 - 3.5 (2H, m), 3.6-4.05 (2H,m), 3.86 (3H,s), 4.20-5.25 (6H,m), 6.9-8.15 (15H, m), 8.58 (1H,br-s)

Example 7

To an ice-cooled solution of benzofuran-2-carboxylic acid (0.46 g), Starting Compound (1.40 g) and HOBT (0.39 g) in methylene chloride (28 ml) was added WSC (0.52 ml). The solution was stirred at the same temperature for an hour and at room temperature overnight. After evaporation, the reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with an aqueous sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, water, and an aqueous sodium chloride solution, and dried over magnesium sulfate. After evaporation, the residue was purified an a silica-gel column (50 g) eluting with a mixed solvent of chloroform and methanol (from 99 : 1 to 19 : 1, gradient). The fractions containing the desired compound were collected and evaporated to give Object Compound (1.50 g) as an amorphous solid. IR (Nujol) : 3300, 1710, 1630, 1562cm^-1

NMR (DMSO-d₆,δ) : 1.60-2.45 (2H,m), 2.64,2.77,2,83 (3H,s), 2. 90-3.25 (2H,m), 3.60-4.15 (2H,m), 4.20-4.75 (4H,m), 4.85-5.30 (2H, m), 6.75-7.85 (15H,m), 8.15-8.30 (1H.m), 8.75-9.35 (1H,m)

MASS M⁺ : 592

Example 8

To a solution of the starting compound (1.0 g) in methanol

(45 ml) was added 0.1N sodium hydroxide (16.9 ml). The solution was stirred for two hours at room temperature and methanol was evaporated. The mixture was extracted with ethyl acetate and the organic layer was washed with water, brine, and dried over magnesium sulfate. After evaporation, the residue was triturated with diisopropyl ether, collected by filtration, dried to give the object compound as an amorphous solid (750 mg).

IR (Nujol) : 3300, 1630, 1562cm^-1

NMR (DMSO-d₆,δ) : 1.60-2.50 (2H,m), 2.56,2.67,2,69 (3H,s), 2. 90-3.30 (2H,m), 3.60-3.95 (2H,m), 4.20-5.30 (6H,m), 6.65-7.90 (15H, m), 8.60-8.90 (1H,m), 10.78,10.84,10.88 (1H,s)

MASS M⁺ : 564

Example 9

To a sosolution of the starting compound (1.0g), Boc-glycine (0.37g), and 4 - (N,N-dimethylamino) pyrdine (0.13g) in dimethylformamide (20ml) was added WSC-HCl (0.41g) at room temperature. The mixture was stirred overnight at this temperature. WSC-HCl (0.41g) was added and the mixture was stirred for additional four hours. The mixture was concentrated under reduced pressure, diluted in water, and extracted with ethyl acetate. The organic layer was washed successively with sodium hydrogen carbonate solution, water, in hydrochloric acid, water, brine, and dried over magnesium sulfate. Evaporation gave 1.17g of the object compound.

IR (CHCl₃) : 3320, 1755, 1710, 1645-1630, 1470-1415,

1370 cm^-1 NMR (DMSO-d₆, δ) : 1.32 (9H,s), 2.0 - 2.3 (8H,m), 2.65 - 3.0 (5H, m), 3.55-5.4 (10H.m), 3.84 (3H,s), 6.75-7.55 and 7.85-8.1 (13H,m), 8.51 (1H,br-s) Example 10

The object compound was obtained according to a similar manner to that of Example 9.

IR (CHCl₃) : 3300, 1750, 1690, 1645 - 1630, 1470 - 1430,

1250cm^-1

NMR (DMSO-d₆, δ) : 1.17 and 1.31 (9H,s), 2.0-2.3 (8H,m), 2.7 -3.05 (8H,m), 3.8-5.0 (11H,m), 5.15-5.2 (1H,m), 6.8-7.55 and 7. 85-8.1 (13H,m), 8.51 (1H.br - s)

Example 11

IR (CHCl₃) : 3320, 1745, 1710, 1640, 1500, 1470 - 1450, 1370cm^{- 1} NMR (DMSO-d₆, δ) : 1.05 - 1.35 (12H,m), 2.0 - 2.3 (8H,m), 2.65 -3.05 (5H,m), 3.84 (3H,s), 3.8-5.35 (8H,m), 6.75-8.15 (14H,m), 8.51 (1H, br - s)

Example 12

The starting compound (1.0g), N,N-dimethylglycine hydrochloride (0.27g), 4- (N,N-dimethylamino) pyridine (0.13g) were dissolved in 20 ml of dimethylformanide. To this solution was added WSC-HCl (0.68g) and the mixture was stirred overnight at room temperature. The mixture was evaporated, diluted in sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was successively washed with water and sodium chloride solution, and dried over magnesium sulfate. Evaporation gave 0.81g of an amorphous solid. This product was dissolved in 16 ml of methylene chloride. The solution was ice-cooled and 0.31ml of 4N hydrochloric acid in dioxane. Evaporation of the mixture gave the object compound as an amorphous solid (0.81g).

IR (CHCl₃) : 3420, 1755, 1680, 1645-1630, 1470- 1420, 1375 cm^-1

NMR (DMSO-d₆, δ) : 2.05-2.4 (8H,m), 2.65-3.0 (11H,m), 3.85 (3H, s), 3.9-5.45 (9H,m), 6.7-7.55 and 7.9-8.1 (13H,m), 8.48 (1H,br -s), 10.50 (1H,br-s)

Example 13

The object compound was obtained according to a similar manner to that of Example 15.

IR (CHCl₃) : 3450-3250, 1750, 1650-1590, 1525, 1460-1410, 1370cm^{- 1}

NMR (DMSO-d₆, δ) : 1.1 - 1.3 (6H,m), 2.0 - 2.5 (8H,m), 2.65 - 3. 0 (5H,m), 3.1-3.3 (4H,m), 3.85 (3H,s), 3.9-5.05 (8H,m), 5.4-5.5 (1H, m), 6.7-7.35 and 7.85-8.1 (13H,m), 8.49 (1H,br-s), 10.46 (1H.br-s)

Example 14

The object compound was obtained according to a similar manner to that of Example 12.

IR (CHCl₃) : 3420, 3300, 1740, 1680, 1645, 1470 - 1420, 1375cm^{- 1} NMR (DMSO-d₆,δ) : 1.16 (6H,t,J = 7.2Hz), 2.0 - 2.4 (8H,m), 2.7 - 3.3 (13H,m), 3.85 (3H,s), 3.9-5.4 (7H,m), 6.75-7.45 and 7.85-8.1 (13H, m), 8.48 (1H,br -s), 10.43 (1H,br - s)

Example 15

Sodium N,N-diethylglycinate (0.39g) was suspended in

20ml of methylene chloride and 4N hydrochloric acid solution in ethyl acetate (0.64ml) was added there to Dimethylformamide (20ml) and the starting compound (1.0g) was added and the mixture was ice-cooled. Into this mixture were added 4- (N,N-dimethylamino) pyridine (0.12g) and WSC-HCl (0.49g) and the mixture was stirred for ten minutes at this temperature and overnight at room temperature. Sodium N,N-diethylglycinate (0.39g), 4N hydrochloric acid solution in ethyl acetate (0.64ml), 4-(N,N-dimethylamino) pyridine (0.12g), and WSC-HCl (0.49g) were added and the mixture was stirred for additional two hours. The solvent was evaporated, diluted in water, and extracted with ethyl acetate.

The organic layer was washed successively with saturated sodium hydrogen carbonate solution, water, and sodium chloride solution.

After evaporation, the crude product was purified on a preparative high performance liquid chromatography : column, YMC

Pac R&D ODS 15-5, 5μm (50mm ø x 250mm); eluent, acetonitrile

-0.1% aqueous trifluoroacetic acid (1:1); flow rate, 118ml/min.

The fractions containing the target compound were collected and acetonitrile was evaporated under reduced pressure. The residual solution was neutralized to pH 7 with an addition of sodium hydrogen carbonate and was extracted with ethyl acetate twice.

The extracts were combined, washed with water and sodium chloride solution, and dried over magnesium sulfate. After evaporation, the residue was dissolved in 10ml of methylene chloride. To this solution was added 0.29ml of 4N hydrochloric acid solution in ethyl acetate and the mixture was stirred for half an hour at room temperature. Evaporation gave the object compound as an amorphous solid (0.84g).

IR (CHCl₃) : 3450-3250, 1750, 1680, 1640-1625, 1470-1415, 1375cm^-1

NMR (DMSO-d₆, δ) : 1.1-1.25(6H, m), 1.95-2.4(2H, m), 2.7-3.25(9H, m), 3.85(3H, s), 3.85-5.5(9H, m), 6.85-8.15(17H, m),

8.61(1H, br-s), 10.36(1H, br-s)

MASS (FAB) : (M + H)⁺ 702.5

Example 16

IR (CHCl₃) : 3330, 1755, 1710, 1650, 1470, 1370 cm^-1

NMR (DMSO-d₆, δ) : 1.25-1.45(9H, m), 1.9-2.3(2H, m), 2.7- 3.1(5H, m), 3.85(3H, s), 3.5-5.4(9H, m), 6.95-8.15(14H, m), 8.54(1H, br-s)

Example 17

IR (CHCl₃) : 3300, 1740, 1720, 1710, 1645-1630, 1500, 1470-1450, 1365cm^-1

NMR (DMSO-d₆, δ) : 1.31(9H, s), 2.0-2.3(8H, m), 2.6-3.0(7H, m), 3.84(3H, s), 3.8-5.3(11H, m), 6.8-7.55 and 7.8-8.1(18H, m), 8.48(1H, br-s)

Example 18

IR (CHCl₃) : 3320, 1740-1720, 1675, 1645-1630, 1480-1415, 1370cm^-1

NMR (DMSO-d₆, δ) : 2.0-2.3(8H, m), 2.6-3.0(7H, m), 3.6-5. 35(11H, m), 3.82(3H, s), 6.8-7.55 and 7.9-8.1(24H, m), 8.4-8. 6(2H, m)

Example 19

IR (CHCl₃) : 3300, 1755, 1710, 1630, 1575, 1500, 1420,

1370 cm^-1

NMR (DMSO-d₆, δ) : 1.25-1.4(3H, m), 2.0-2.4(8H, m), 2.6-3. 0(5H, m), 3.6-5.4(9H, m), 6.55-7.85(14H, m), 8.6-8.85(1H, m) Example 20

IR (CHCl₃):3320, 2999, 2950, 1756, 1693, 1631, 1570cm^-1

NMR (DMSO-d₆, δ) : 1.17, 1.32, 1.37(9H, s), 2.05, 2.10, 2.12, 2. 17(6H, s), 1.95-2.35(2H, m), 2.60-3.05(8H, m), 3.80-5.45(9H, m), 6.55-7.85(13H, m), 8.55-8.90(1H, m)

Example 21

The object compound was obtained according to a similar manner to that of Example 9. IR (CHCl₃) : 3310, 2990, 1745, 1710, 1632 cm^-1

NMR (DMSO-d₆, δ) : 1.19, 1.23, 1.29, 1.33(9H, s), 1.05-1.40(3H, m), 2.04, 2.10, 2.12, 2.17(6H, s), 1.90-2.40(2H, m), 2.62,2.65,

2.73, 2.79(3H, s), 2.70-3.05(2H, m), 3.80-5.40(8H, m), 6.55-7. 85(14H, m), 8.55-8.85 (1H, m)

Example 22

IR (Nujol) : 3400, 1753, 1640, 1560 cm^-1

NMR (DMSO-d₆, δ) : 2.05, 2.10, 2.12, 2.17(6H, s), 1.05-2.45(2H, m), 2.61, 2.65, 2.73, 2.81, 2.86(9H, s), 2.55-3.05(2H, m), 3.80 -5.05, 5.20-5.55(9H, m), 6.55-7.90(13H, m), 8.55-8.95 (1H, m), 10.62(1H, brs)

Example 23

IR (Nujol) : 3450-3200, 1755, 1640cm^-1

NMR (DMSO-d₆, δ) : 1.05-1.35(6H, m), 2.05, 2.10, 2.12, 2.17

(6H, s), 2.00-2.45(2H, m), 2.61, 2.65, 2.73, 2.80(3H, s), 2.70- 3.10(2H, m), 3.05-3.35(4H, m), 3.80-5.05, 5.20-5.60(9H, m), 6.55-7.85(13H, m), 8.55-8.70, 8.80-8.90 (1H, m), 10.24 (1H, brs)

Example 24

IR (Nujol) : 3450-3250, 2610, 1739, 1640, 1628, 1560cm^-1 NMR (DMSO-d₆, δ) : 1.00- 1.30(6H, m), 2.05,2.10, 2.12, 2.17

(6H, s), 1.95-2.45(2H, m), 2.62, 2.65, 2.73, 2.79(3H, s), 2.70-3.35(10H, m), 3.80-5.00, 5.15-5.40(7H, m), 6.55-7.85(13H, m), 8.55-8.85 (1H, m), 10.42 (1H, brs) Example 25 The object compound was obtained according to a similar manner to that of Example 9.

IR (CHCl₃) : 3310, 1740, 1630, 1500, 1455, 1415 cm^-1

NMR (DMSO-d₆, δ) : 1.2-1.4(9H, m), 1.7-2.3(8H, m), 2.6-3. 05(7H, m), 3.8-5.4(10H, m), 6.55-7.85 (19H, m), 8.55-8.8(1H, m)

Example 26

IR (CHCl₃) : 3300, 1740, 1710, 1690, 1645-1620, 1570, 1500, 1455,

1415cm^-1

NMR (DMSO-d₆, δ) : 1.2-1.4(9H, m), 1.7-2.45(12H, m), 2.6- 3.05(5H, m), 3.8-5.35(10H, m), 6.6-7.85(19H, m), 8.55-8.8(1H, m)

Example 27

IR (CHCl₃) : 3400, 2050, 1750, 1630, 1560 cm^-1

NMR (DMSO-d₆, δ) : 1.00-1.30(6H, m), 1.90-2.45(2H, m), 2.77, 2.90(3H, s), 2.55-3.25(6H, m), 3.80-5.55(9H, m), 6.90-7.90(13H, m), 8.55-8.90(1H, m), 10.20(1H, brs) Example 28

To an ice-cooled solution of the starting compound (1.10g) in 22ml of methylene chloride was added 6.2ml of 4N hydrochloric acid in dioxane. The resulting solution was stirred for five minutes at this temperature and for additional an hour at room temperature. After evaporation of the mixture, the residue was triturated with ether, filtered, and dried under vacuum to give 0.95g of the object compound.

IR (CHCl₃) : 3450-3250, 1755, 1680, 1645-1625, 1470, 1440-1420, 1375cm^-1

NMR (DMSO-de, δ) : 2.05-2.4(8H, m), 2.6-3.0(5H, m), 3.7-4. 0(5H, m), 4.1-5.5(7H, m), 6.7-7.55 and 7.9-8.1(14H, m), 8. 35-8.5(3H, m)

Example 29

The object compound was obtained according to a similar manner to that of Example 28.

IR (CHCl₃) : 3450-3200, 1755, 1680, 1645-1620, 1470-1430, 1375 cm^-1

NMR (DMSO-de, δ) : 1.41(3H, d, J = 7.1Hz), 2.05-2.4(8H, m), 3. 7-3.05(5H, m), 3.85(3H, s), 3.9-5.45(8H, m), 6.8-8.1(14H, m),

8.45-8.65(3H, m)

Example 30

IR (CHCl₃) : 3500-3300, 1755, 1645-1600, 1470-1420, 1360 cm^-1 NMR (DMSO-d₆, δ) : 2.05-2.5(8H, m), 2.52(3H, s), 2.7-3.0(5H, m), 3.8-5.0(11H, m), 4.95-5.1 (1H, m), 6.75-7.55 and 7.9-8. 1(13H, m), 8.49(1H, br-s), 9.25-9.4(2H, m)

Example 31

IR (CHCl₃) : 3450-3200, 1755, 1680, 1645-1630, 1470,

1380 cm^-1

NMR (DMSO-d₆, δ) : 1.95-2.4(2H, m), 2.65-3.1(5H, m), 3.86 (3H, s), 3.7-5.5(9H, m), 6.95-8.15(13H, m), 8.3-8.7(4H, m)

Example 32

IR (Nujol) : 3400, 3250, 1740, 1680, 1645-1605, 1470-1440,

1375 cm^-1

NMR (DMSO-d₆, δ) : 2.0-2.4(8H, m), 2.5-3.0(7H, m), 3.85(3H, s), 3.9-5.4(8H, m), 6.75-7.55 and 7.9-8.15(14H, m), 8.2-8. 4(3H, m)

Example 33

IR (CHCl₃) : 3450-3220, 1755, 1680, 1630, 1570, 1500, 1452, 1420 cm^-1

NMR (DMSO-d₆, δ) : 1.95-2.4(8H, m), 2.5-3.05(5H, m), 3.7- 5.5(9H, m), 6.55-7.85(13H, m), 8.5-8.9(4H, m)

Example 34

IR (Nujol) : 3400, 1756, 1630, 1567 cm^-1

NMR (DMSO-d₆, δ) : 2.05, 2.10, 2.17 (6H, s), 2.00-2.45(2H, m),

2.55-3.10(8H, m), 4.80-5.05, 5.20-5.55(9H, m), 6.55-7.85(13H, m), 8.55-8.90 (1H, m), 9.24 (2H, brs)

Example 35

IR (Nujol) : 3440-3240, 1754, 1630, 1562 cm^-1

NMR (DMSO-d₆, δ) : 1.35-1.55(3H, m), 2.05, 2.10, 2.12, 2.17(6H, s), 1.95-2.45(2H, m), 2.61, 2.64, 2.73, 2.80(3H, s), 2.70-3.10 (2H, m), 3.85-5.05, 5.15-5.50(8H, m), 6.55-7.85 (13H, m), 8.

35-8.85(4H, m)

Example 36

IR (Nujol) : 3420-3200, 1740, 1680, 1645-1620, 1560, 1450, 1260

-1190 cm^-1

NMR (DMSO-d₆, δ) : 2.0-2.4(8H, m), 2.55-3.05(7H, m), 3.8- 5.4(8H, m), 6.55-7.85(14H, m), 8.2-9.0(4H, m) Example 37

IR (Nujol) : 3350-3100, 1740, 1680, 1645-1615, 1565, 1500, 1450, 1420 cm^-1

NMR (DMSO-d₆, δ) : 1.95-2.4(12H, m), 2.6-3.1(5H, m), 3.7-5.4(8H, m), 6.55-7.85U4H, m), 8.3-8.85(4H, m)

Example 38

The starting compound (1.5g) was dissolved in 30ml of methanol. This solution was hydrogenated over 0.3g of palladium on charcoal (10%) under atmospheric pressure for two and half an hour. Filtration and evaporation of the mixture gave 1.25g of the object compound as an amorphous solid (1.25g).

IR (CHCl₃) : 3320, 1740-1710, 1640, 1635-1610, 1500, 1470-1420,

1370 cm^-1

NMR (DMSO-d₆, δ) : 1.31(9H, s), 2.0-2.25(8H, m), 2.6-3.0(7H, m), 3.84(3H, s), 4.05-5.3(8H, m), 6.75-7.55 and 7.85-8.15(15H, m), 8.47 (1H, br-s)

Example 39

The object compound was obtained according to a similar manner to that of Example 38.

IR (Nujol) : 3450-3250, 1740, 1690-1670, 1635-1620, 1530, 1250 cm^-1

NMR (DMSO-d₆, δ) : 2.0-2.4(8H, m), 2.6-3.0(7H, m), 3.85(3H, s), 4.0-5.4(10H, m), 6.7-7.55 and 7.9-8.1 (15H, m), 8.4-8.6

(3H, m), 8.89(1H, d, J = 8Hz) Example 40

IR (CHCl₃) : 3310, 1740-1685, 1645-1620, 1570, 1500, 1455, 1415,

1370 cm^-1

NMR (DMSO-d₆, δ) : 1.2-1.4(9H, m), 1.95-2.4(8H, m), 2.55- 3.0(7H, m), 3.8-5.4(8H, m), 6.5-7.85(15H, m), 8.5-8.8(1H, m)

Example 41

IR (CHCl₃) : 3300, 1690, 1710, 1645-1625, 1570, 1500, 1450, 1420 cm

NMR (DMSO-d₆, δ) : 1.2- 1.4(9H, m), 1.6-2.45 (12H, m), 2.6-3.1(5H, m), 3.7-5.4(8H, m), 6.55-7.85(15H, m), 8.55-8.8(1H, m)

Example 42

The starting compound (1. 0g), 2-(N, N-diethylamino)-ethylchlorid• hydrochloride (0.30g), ethyltrimethylammonium chloride

(56mg) was dissolved in CH₂Cl₂ (20ml). To the mixture was added powdered sodium hydroxide (0.35g) and the mixture was stirred overnight at room temperature. The mixture was filtered through cellulose powder and the filtrate was washed successively with water and sodium chloride solution, and dried over magnesium sulfate. After evaporation, the residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid. The aqueous layer was neutralized to pH 7 with sodium hydrogen carbonate solution and was extracted with ethyl acetate again. The extract was washed with sodium chloride solution and dried over magnesium sulfate. After evaporation, the residue was applied to a column of silica- gel (28g) for medium pressure chromatography eluting with chloroform-methanol (50:1 to 10:1, gradient) to give 0.45g of purified product. This compound was dissolved in 10ml of methylene chloride and 0. 17ml of 4N hydrochloric acid in dioxane was added. Evaporation gave the object compound as an amorphous solid (0.33g).

IR (CHCl₃) : 3500-3250, 1640-1620, 1525, 1460-1415 cm^-1

NMR (DMSO-d₆, δ) : 1.05-1.25(6H, m), 1.8-2.3(8H, m), 2.7-3.3(13H, m), 3.73(3H, s), 3.7-4.0(2H, m), 4.15-5.0(5H, m), 6.7-7.55 and 7.85-8.05(13H, m), 8.40(1H, br-s), 10.27(1H, br -s)

MASS (FAB) : 666.5 (M+1)⁺ Example 43

The object compound was obtained according to a similar manner to that of Example 42.

IR (CHCl₃) : 3450-3200, 1680, 1640, 1470-1420, 1375 cm^-1 NMR (DMSO-d₆, δ) : 1.8-2.4(8H, m), 2.7-3.2(5H, m), 3.2-3. 45(6H, m), 3.65-5.0(17H, m), 6.7-7.55 and 7.85-8.1(13H, m),

8.38(1H, br-s), 10.93(1H, br-s)

MASS : (M+1) 680

Example 44

IR (CHCl₃) : 3420-3200, 1680, 1655, 1640-1620, 1470-1415,

1375 cm^-1

NMR (DMSO-d₆, δ) : 1.1-1.25(6H, m), 1.75-2.35(2H, m), 2.75-3.25(9H, m), 3.65-5.2(14H, m), 6.85-8.15(17H, m), 8.53(1H, br-s), 10.41 (1H, br-s)

MASS : (M+H)⁺ 688

Example 45

IR (CHCl₃) : 3500-3250, 1680, 1645-1620, 1450, 1420-1410 cm^-1 NMR (DMSO-d₆, δ) : 1.1-1.25(6H, m), 1.75-2.4(8H, m), 2.6-3.3(9H, m), 3.65-5.2(11H, m), 6.55-7.85(13H, m), 8.5-8.8(1H, m), 10.44 (1H, br-s)

MASS : M⁺ 653

Example 46

The starting compound (0.70g) was suspended in 14 ml of methylene chloride. Then pyridine (0.43ml) and triethylamine

(0.19ml) were added under ice-cooling. The resulting solution was cooled to -20°C and phenoxyacetyl choloride (0.23 g) was added. The mixture was stirred for two hours during which period the temperature was gradually raised to 0°C. Pyridine (0.86 ml) was added and the mixture was stirred for additional half an hour. The solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with saturated sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, and brine, and dried over magnesium sulfate. After evaporation, the crude product was purified on a column of silca-gel (20g) eluting with chloroform-methanol (from 0.5% to 5%, gradient). Concentration of the main fractions and trituration with diisopropylether gave 0.30g of the object compound.

IR(Nujol): 3300, 1638, 1602 cm^-1

MASS M⁺ : 543

NMR(DMSO-d⁶)δ : 1.55-2.30(8H, m);2.60-3.00(5H, m);3.20-3. 90(3H, m);4.10-5.20(7H, m);6.60-7.40(13H, m);8.30-8.45, 8.

70-8.85 (1H, m)

Example 47

The Object Compound was obtained according to a similar manner to that of Example 46.

IR(Nujol): 3300, 1627 cm^-1

MASS M+ :565

NMR(DMSO-d⁶) δ:1.45-2.30(2H, m);2.11, 2.16, 2.18(9H, s);

2.35-3.05(2H, m);2.57, 2.73, 2.80(3H, s);3.20-3.75(4H, m);3. 95-5.20(6H, m);6.40-7.55(12H, m);8.35-8.65(1H, m)

Example 48

The Object Compound was obtained according to a similar manner to that of Example 46. Example 49

To an ice- cooled solution of the starting compound (0. 70 g) and triethylamine ( 0. 20 ml) in 14 ml of methylene chloride was added the object compound of Preparation 39 ( 0. 27 g ). The mixture was stirred for 3 days at room temperature, during which period the object compound of Preparation 39 ( 0. 26 g ) and triethylamine ( 0. 09 ml) were added.

The mixture was concentrated, diluted in water, and was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution , and was dired over magnesium sulfate. After concentration, the crude product was purified on a column of nautral alumina ( 20 g ) eluted with chloroform -methanol ( from 1 % to 5 % gradient ) to give partially purified product. This product was dissolved in 5 ml of ethyl acetate and 0. 25 ml of 4N- hydrochloric acid in ethyl acetate was added.

The mixture was diluted with ether and washed with water. The aqueous layer was separated and lyophilized to give the object compound ( 1. 22 g).

Claims

1. A compound of the formula :

wherein R¹ is heterocyclic group or tetrahydronaphthyl,

R² is optionally protected hydroxy,

R³ is lower alkyl,

R⁴ is ar ( lower) alkyl, and

X¹ is O or N-R⁵, in which R⁵ is hydrogen or lower alkyl,

and a pharmaceutically acceptable salt thereof .

2. A compound of the formula :

wherein R⁶ is protected hydroxy,

R⁷ is naphthyl or a group of the formula :

in which R⁸ and R⁹ are each lower alkyl or halogen,

R³ is lower alkyl,

R⁴ is ar(lower)alkyl,

X² is O or N-R¹⁰, in which R¹⁰ is lower alkyl, provided that R⁶ is not mesyloxy when X² is O, and a pharmaceutically acceptable salt thereof.

3. A compound of the formula :

R² is optionally protected hydroxy,

R³, R¹² and R¹³ are each lower alkyl,

R⁴ is ar(lower)alkyl, and

Y is O or NH,

and a pharmaceutically acceptable salt thereof.