WO1994020126A1

WO1994020126A1 - Use of peptides for the manufacture of a medicament

Info

Publication number: WO1994020126A1
Application number: PCT/JP1994/000285
Authority: WO
Inventors: Kunihiko Soneoka; Hidetoshi Shuto; Takashi Fujii
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1993-03-03
Filing date: 1994-02-23
Publication date: 1994-09-15

Abstract

A use of peptide compounds of formula (I), (II) or (III) and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for preventing or treating chronic obstructive pulmonary diseases, iritis, psoriasis, inflammatory intestinal diseases, hepatitis, tenalgia attended to hyperlipidemia, postoperative neuroma, vulvar vestibulitis, hemodialysis-associated itching, lichen planus, laryngopharyngitis, bronchiectasis, coniosis whooping cough, pulmonary tuberculosis, emesis or mental diseases.

Description

USE OF PEPTIDES FOR THE MANUFACTURE OF A MEDICAMENT.

Technical Field : This invention relates to a new use of peptide compounds. More specifically, this invention relates to a new use of peptide compounds for chronic obstructive pulmonary diseases, iritis, psoriasis, inflammatory intestinal diseases, hepatitis, tenalgia attended to hyperlipidemia, postoperative neuroma, vulvar vestibulitis, hemodialysis-associated itching, lichen planus, laryngopharyngitis, bronchiectasis, conoisis, whooping cough, pulmonary tuberculosis, emesis and mental diseases and the like.

Disclosure of the Invention :

Accordingly, this invention provides a new use of the peptide compounds for preventing or treating the diseases as mentioned above. Further, this invention provides a prophylactic or therapeutic agent for the diseases as mentioned above, which comprises the peptide compounds.

Still further, this invention provides a method for preventing or treating the diseases as mentioned above, which comprises administering said peptide compounds to mammals.

Furthermore, this invention provides a pharmaceutical composition for preventing or treating the diseases as mentioned above, which comprises said peptide compounds, as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.

The compounds used in this invention are known to 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, particularly substance P mediated diseases such as asthma (e.g. European Publication No. 0 443 132 Al). And the compounds used in this invention are expected to be used for treating bronchitis such as chronic bronchitis, acute bronchitis and diffuse panbronchilitis. Further the compounds used in this invention exhibit analgesic action and are expected to be of use for treating various pains or aches such as migraine, headache, toothache, cancerous pain and back pain; and superficial pain on congelation, burn, herpes zoster or diabetic neuropathy.

The inventors of this invention have found that the peptide compounds of this invention are also useful for the treatment of chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema; iritis; psoriasis; inflammatory intestinal diseases, particularly Crohn's diseases; hepatitis; tenalgia attended to hyperlipidemia; postoperative neuroma, particularly of mastectomy; vulvar vestibulitis; hemodialysis-associated itching; lichen planus; laryngopharyngitis; bronchiectasis; conoisis; whooping cough; pulmonary tuberculosis; emesis; or mental diseases, particularly anxiety and depression.

The peptide compounds used in the present invention can be represented by the following general formulae.

wherein R*-- is aryl, or a group of the formula

wherein X¹ is CH or N, and Z¹ is 0 or N-R¹⁷, in which R*^*-⁷ is hydrogen or lower alkyl, R² is hydroxy or lower alkoxy, R-** is hydrogen or lower alkyl which may have suitable substituent(s) , R⁴ is ar(lower)alkyl which may have suitable substituent(s) , A¹ is carbonyl or sulfonyl, and Y-*- is bond or lower alkenylene, and pharmaceutically acceptable salts thereo_f,

wherein R^*-*^* is lower alkyl, aryl, arylamino, pyridyl, pyrrolyl, pyrazolopyridyl, guinolyl, or a group of the formula :

wherein the symbol of a line and dotted line is a single bond or a double bond, X² is CH or N, and Z² is 0, S or NH, each of which may have suitable substituent(s) ; R*-*" is hydrogen or lower alkyl; R⁷ is suitable substituent; R8 is lower alkyl which may have suitable substituent(s) , and R9 is ar(lower)alkyl which may have suitable substituent(s) or pyridyl(lower)alkyl, or R8 and R⁹ are linked together to form benzene- condensed lower alkylene; R¹⁰ is hydrogen or suitable substituent; A² is an amino acid residue, which may have suitable substituent(s) ; and Y² is bond, lower alkylene or lower alkenylene, and pharmaceutically acceptable salts thereof, and

wherein R¹¹ is hydrogen or an acyl group; R*^***² is hydroxy and

R¹³ is carboxy or protected carboxy, or

R¹² and R**-³ are linked together to represent a group of the formula : -o-_C- «

0

R¹⁴ is hydroxy or protected hydroxy; R¹***¹ is hydroxy or protected hydroxy; R*--⁶ is hydroxy, protected hydroxy or lower alkoxy; and

= is a single bond or a double bond, and pharmaceutically acceptable salts thereof.

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, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an a ino 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. The suitable examples and illustrations of the various definitions used in the compounds of the formulae (I), (II) and (III) are explained in detail in the following.

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 "aryl" may include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl, and the like, in which the preferred one is Cg-C^g aryl and the most preferred one is phenyl. Suitable "lower alkenylene" is one having 2 to 6 carbon atom(s) and may include vinylene, propenylene, and the like, in which the preferred one is vinylene.

Suitable "lower alkyl which may have suitable substituent(s)" may include a conventional group, which is used in the field of art such as lower alkyl as exemplified above, carboxy(lower)alkyl (e.g. carboxymethyl, carboxyethyl, etc. ) , protected carboxy(lower)alkyl such as esterified carboxy(lower)alkyl, for example, lower alkoxycarbonyl(lower)alkyl (e.g. methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, etc.), carbamoyl(lower)alkyl which may have suitable substituent(s) such as carbamoyl(lower)alkyl (e.g., carbamoylmethyl, carbamoylethyl, carbamoylpropyl, etc.) and carbamoyl(lower)alkyl having suitable substituent(s) , for example, lower alkylcarbamoyl(lower)alkyl (e.g., methylcarbamoylmethyl , ethylcarbamoylmethyl, etc.), amino(lower)alkylcarbamoyl(lower)alkyl (e.g. , aminomethylcarbamoylmethyl, aminoethylcarbamoylmethyl, etc.), lower alkylamino(lower)alkylcarbamoyl(lower)alkyl (e.g. dimethylaminomethylcarbamoylmethyl, dimethylaminomethylcarbamoyl ethyl, etc. ) , lower alkylamino(lower)alkyl (e.g. dimethylaminomethyl, dimethylaminoethyl, etc. ) , hydroxy(lower)alkyl (e.g.; hydroxy ethyl, hydroxyethyl, etc.), protected hydroxy(lower)alkyl such as acyloxy(lower)alkyl, for example, lower alkanoyloxy(lower)alkyl (e.g. acetyloxyethyl, acetyloxypropyl, acetyloxybutyl, acetyloxypentyl, propionyloxymethyl, butyryloxymethyl, hexanoyloxymethyl, etc. ) , and the like.

Suitable "ar(lower)alkyl which may have suitable substituent(s)" may include a conventional group, which is used in the field of amino acid and peptide chemistry, such as ar(lower)alkyl (e.g. trityl, benzhydryl, benzyl, phenethyl, etc.), substituted ar(lower)alkyl, for example, mono or di or trihalophenyl(lower)alkyl (e.g., o-fluorobenzγl, m-fluorobenzyl, p-fluorobenzyl, o-trifluoromethylbenzyl, etc.), and the like.

Suitable "lower alkoxy" may include straight or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like.

Suitable "lower alkylene" is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, hexamethylene, and the like, in which the preferred one is methylene, ethylene or trimethylene.

Suitable "an amino acid residue" means a bivalent residue derived from an amino acid, and such amino acid may be glycine (Gly), D- or L- alanine (Ala), β-alanine (BAla), D- or L- valine (Val), D- or L- leucine (Leu), D- or L- isoleucine (lie), D- or L- serine (Ser), D- or L- threonine (Thr), D- or L- cysteine (Cys), D- or L- methionine (Met), D- or L- phenylalanine (Phe), D- or L- tryptophan (Trp) , D- or L- tyrosine (Tyr), D- or L- proline (Pro), D- or L- didehydroproline (ΔPΓO) such as

3,4-didehydroproline (Δ(3,4)PΓO), D- or L- hydroxypropine (Pro(OH)) such as 3-hydroxyproline (Pro(30H)) and 4- hydroxyproline (Pro(40H)), D- or L- azetidine-2-carboxylic acid (Azt), D- or L- thioproline (Tpr), D- or L- aminoproline (Pro(NH₂)) such as 3-aminoproline (Pro(3NH2)) and 4-aminoproline (Pro(4 H2)), D- or L- pyroglutamic acid (pGlu), D- or L- 2-aminoisobutyric acid (Aib) , D- or L- glutamic acid (Glu), D- or L- aspartic acid (Asp), D- or L- glutamic (Gin), D- or L- asparagine (Asn), D- or L- lysine (Lys), D- or L- arginine (Arg), D- or L- histidine (His), D- or L- ornithine (Orn), D- or L- hydroxypiperidinecarboxylic acid such as 5-hγdroxypiperidine-2-carboxylic acid, D- or L- mercaptoproline (Pro(SH)) such as 3-mercaptoproline (Pro(3SH)) and 4-mercaptoproline (Pro(4SH)), whose side chains are amino, hydroxy, thiol or carboxy groups, may be substituted by the suitable substituent(s) . Said suitable substituent(s) may include acyl such as carbamoyl, lower alkanoyl (e.g., formyl, acetyl, etc.), trihalo(lower)alkoxycarbonyl (e.g. 2,2,2- trichloroethoxycarbonyl, etc. ) , ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), lower alkylsulfonyl (e.g., mesyl ethylsulfonyl, etc.), lower alkoxalyl (e.g., methoxalyl, ethoxalyl, etc.), arylsulfonyl (e.g., phenylsulfonyl, tolylsulfonyl, etc.), haloar(lower)- alkoxycarbonyl (e.g., o-chlorobenzyloxycarbonyl, etc.), carboxy(lower)alkanoyl (e.g., carboxyacetyl, carboxypropionyl, etc.), glycyl, β-alanγl, N-lower alkoxycarbonylglycyl (e.g., N-t-butoxycarbonylglycyl, etc.) and N-lower alkoxycarbonyl-β-alanyl (e.g., N-t-butoxycarbonyl-β-alanyl, etc. ) , N,N-di(lower)alkylamino(lower)alkanoyl (e.g. , N,N-dimethylaminoacetyl, N,N-diethylaminoacetyl, N, -dimethylaminopropionyl, N,N-diethylaminopropionγl, etc.), carboxyalyl, morpholinocarbonyl, amino(lower)alkanoyl (e.g., aminoacetyl, aminopropionyl, etc. ) , N-ar(lower)alkoxycarbonylamino(lower)alkanoyl (e.g., N-benzyloxycarbonylaminoacetyl, etc.), threonyl, N-lower alkoxycarbonylthreonyl (e.g. N-t-butoxγcarbonylthreonγl, etc.), N-lower alkanoylthreonyl (e.g., N-acetylthreonyl, etc.), N-lower alkoxycarbonyl(lower)alkyl-N-lower alkoxycarbonylamino(lower)alkanoyl (e.g. , N-t-butoxycarbonylmethyl-N-t-butoxycarbonγlaminoacetyl, etc.), α-glutamyl, N-ar(lower)alkoxycarbonyl-O- ar(lower)alkyl-α-glutamyl (e.g., N-benzyloxycarbonyl-O- benzyl-α-glutamyl, etc.), γ-glutamyl, N-ar(lower)alkoxycarbonyl-O-ar(lower)alkyl-γ-glutamyl (e.g., N-benzyloxycarbonyl-O-behzyl-γ-glutamyl, etc.), lower alkyl (e.g., methyl, ethyl, t-butyl, etc.), carboxy(lower)alkyl (e.g. carboxymethyl, etc.), morpholino, glycine amide, threonino amide, N'-glutamino N-lower alkylamide (e.g., N'-glutamino N-t-butylamide, etc.), di(lower)alkylamino (e.g. dimethylamino, etc.), ar(lower)alkyl (e.g., benzyl, phenethyl, etc.), trihalo(lower)alkyl (e.g., 2,2,2-trichloroethyl, etc. ) , lower alkoxycarbonyl(lower)alkyl (e.g. , methoxycarbonylmethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl, etc. ) , or usual protecting group used in the field of art. In case that such amino acid contain a thio, it may be its sulfoxide or sulfone.

Suitable "pyridyl(lower)alyl" may include 2-pyridyl- ethyl, 3-pyridylmethyl, 4-pyridylmethyl, and the like. Suitable group of the formula : _/R8

-N. , in which R⁸ and R⁹ are linked together to

^R form benzene-condensed lower alkylene, may include 1-indolinyl, 2-isoindolinyl, 1,2,3,4-tetrahydro- quinolin-1-yl, l,2,3,4-tetrahydroisoquinolin-2-yl, and the like.

Suitable substituent on R^*-^*1 moiety may include a conventional group, which is used in the field of amino acid and peptide chemistry, such as lower alkyl which may have suitable substituent(s) , amino protective group; each as defined above, hydroxy, halogen (e.g. fluoro, chloro, etc.), lower alkoxy (e.g. methoxy, butoxy, etc.), N,N- di(lower)alkylamino (e.g. dimethyla ino, etc. ) , lower alkoxycarbonyl (e.g. methoxycarbonyl, t-butoxycarbonyl, etc.), and the like.

Suitable substituent for R⁷ and R¹⁰ may include a conventional group, which is used in the field of amino acid and peptide chemistry, such as lower alkyl which may have suitable substituent(s) as mentioned above, carboxy(lower)alkoxy, protected carboxy(lower)alkoxy, each as defined above, halogen (e.g. fluoro, chloro, etc.), hydroxy, lower alkoxy (e.g. methoxy, butoxy, etc.), nitro, amino, protected amino, in which amino protective group is as defined above, and the like. The term "higher" is intended to mean 7 to 20 carbon atoms, unless otherwise indicated.

Suitable "acyl" may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows :-

Aliphatic acyl such as lower or higher alkanoyl (e.g. for yl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2 , 2-di ethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc. ) ; lower or higher alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc. ) ; lower or higher alkanesulfonyl (e.g. methanesulfonyl,. ethanesulfonyl, etc.); lower or higher alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl, etc.); or the like; Aromatic acyl such as aroyl (e.g. benzoyl, toluoyl, naphthoyl, etc.); ar(lower)alkanoyl [e.g. phenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl, phenylhexanoyl, etc. ) , naphthyl(lower)alkanoyl (e.g. naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar(lower)alkenoyl [e.g. phenyl(lower)alkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc. ) , naphthyl(lower)alkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl, naphthylpentenoyl, etc.), etc.]; ar(lower)alkoxycarbonyl [e.g. phenyl(lower)alkoxy¬ carbonyl (e.g. benzyloxycarbonyl, etc. ) , 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, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc.); heterocyclicglyoxyloyl (e.g. thiazolylglyoxyloyl, thienylglyoxyloyl, etc. ) ; or the like; in which suitable heterocyclic moiety in the terms "heterocycliccarbonyl", "heterocyclic(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.

And, especially preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered more preferably 5 or 6- membered heteromonocyclic group containing 1 to 4-nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H- 1,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.), tetrazolyl (e.g. lH-tetrazolyl, 2H-tetrazolyl^", etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, guinolyl, isoquinolyl, indazolyl, benzotriazolyl, 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), for example, 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), for example, morpholinyl, sydnonyl, etc. ; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, 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), for example, 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), for example, thiazolidinyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 to 6- membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc. ; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc. ; unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc. and the like.

The acyl moiety as stated above may have one to ten, same or different, suitable substituent(s) such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butγl, pentyl, hexyl, etc.); lower alkenyl (e.g. vinyl, allyl, 1-propenyl, 1 or 2 or 3- butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5- hexenyl, etc. ) ; lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.); lower alkylthio (e.g. methylthio, ethylthio, etc.); lower alkylamino (e.g. methylamino, etc.); cyclo(lower)alkyl (e.g. cyclopentyl, cyclohexyl, etc.); cyclo(lower)alkenyl (e.g. cyclohexenyl, etc. ) ; halogen; amino; protected amino; hydroxy; protected hydroxy; cyano; nitro; carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo; amino(lower)alkyl (e.g. aminomethyl, aminoethyl, etc. ) ; carbamoyloxy; hydroxy(lower)alkyl (e.g. hydroxymethyl,

1 or 2-hydroxyethyl, 1 or 2 or 3-hydroxypropyl, etc.); cyano(lower)alkenylthio (e.g. cyanovinylthio, etc.); or the like.

Suitable "hydroxy protective group" in the term "protected hydroxy" may include phenyl(lower)alkyl (e.g. benzyl, etc.), acyl as mentioned above, and the like. Suitable "protected carboxy" may include esterified carboxy.

Suitable example of the ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethγl ester, etc.) which may have at least one suitable substituent(s) , for example, lower alkanoyloxγ(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxy ethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)- acetoxyethyl ester, l(or 2 or 3)-acetoxypropyl ester, l(or 2 or 3 or 4)-acetoxybutyl ester, l(or 2)-propionyloxyethyl ester, l(or 2 or 3)-propionyloxypropyl ester, l(or 2 ) ~ butyryloxyethyl ester, l(or 2)-isobutyryloxyethyl ester, l(or 2)-pivaloyloxyethyl ester, l(or 2)-hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, l(or 2)- pentanoyloxyethyl ester, etc.], lower alkanesulfonyl- (lower)alkγl ester (e.g. 2-mesylethyl ester, etc.), mono(or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethγl ester, etc.), lower alkoxycarbonyloxy(lower)alkyl ester (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxγcarbonyloxyethyl ester, 1-ethoxycarbonyl- oxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene(lower)alkyl ester, or

(5-lower alkyl 2-oxo-l,3-dioxol-4-yl) (lower)alkyl ester [e.g. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-l,3-dioxol-4-yl)methyl ester, (5-propyl-2- oxo-l,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc. ) ; ar(lower)alkyl ester which may have at least one suitable substituent(s) such as mono(or di or tri)phenyl(lower)- alkyl ester which may have at least one suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert- butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.

Particularly, the preferred embodiments of R¹, R², R³, R⁴, A¹ and Y¹ are as follows. R¹ is phenyl; benzofuryl; indazolyl; or indolyl (e.g. lH-indol-3-yl, etc.); 1-lower alkyl indolyl (e.g. l-methyl-lH-indol-2-yl, l-methyl-lH-indol-3-yl, l-isopropyl-lH-indol-3-yl, etc. ) , R² is hydroxy; or lower alkoxy (e.g. methoxy, etc.), R³ is hydrogen; lower alkyl (e.g. methyl, etc.); or hydroxy(lower)alkyl (e.g. hydroxymethyl, hydroxyethyl, etc. ) , R⁴ is phenyl(lower)alkyl (e.g. benzyl, phenethyl, etc. ) ; or halophenyl(lower)alkyl (e.g. o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, etc.); A¹ is carbonyl; or sulfonyl, and Y^**- is bond; or lower alkenylene (e.g. vinylene, etc.).

Particularly, the preferred embodiments of R , R^, R⁷, R⁸, R⁹, R¹⁰, A² and Y² are as follows.

R^*-> is aryl such as phenyl and naphthyl, which may have one or more, preferably one to three halogen or lower alkoxy (e.g. phenyl, difluorophenyl, dimethoxyphenyl, etc. ) ; benzofuryl; pyridyl; or a group of the formula :

wherein R¹⁸ is hydrogen; or lower alkyl (e.g. methyl, etc.); R⁶ is hydrogen; or lower alkyl (e.g. methyl, etc.); R⁷ is lower alkyl which may have one or more, preferably one to three halogen (e.g. methyl, trifluoromethyl, etc. ) ; amino; acylamino such as lower alkanesulfonylamino (e.g. methanesulfonylamino, etc.); carboxy(lower)alkoxy (e.g. carboxymethoxy, etc.); esterified carboxy(lower)alkyl such as lower alkoxycarbonyl( lower)alkoxy (e.g. ethoxycarbonylmethoxy, etc.); halogen (e.g. fluoro, chloro, etc.); lower alkoxy (e.g. methoxy, etc.); or nitro; R⁸ is lower alkyl (e.g. methyl, etc.); R⁹ is ar( lower)alkyl such as mono or di or triphenyl(lower)alkyl, preferably phenyl( lower)alkyl

(e.g. benzyl, etc. ) ; R¹⁰ is hydrogen; lower alkyl (e.g. methyl, etc.); or halogen (e.g. chloro, etc.); A² is a bivalent residue derived from an amino acid, which may have suitable substituent(s) such as hydroxyproline (e.g. 4-hydroxyproline, etc. ) ; or didehydroproline (e.g. 3,4-didehydroproline, etc. ) ; and Y² is bond; lower alkylene (e.g. ethylene, etc.); or lower alkenylene (e.g. vinylene, etc.).

Particularly, the preferred embodiments of R¹¹, R¹², R¹³, R1⁴, R15 and R¹⁶ are as follows. R¹¹ is hydrogen, ar(lower)alkoxycarbonyl (more preferably phenyl(lower)alkoxycarbonyl) , lower alkanoyl, higher alkanoyl (more preferably C-j_5~C2o alkanoyl), aroyl (more preferably benzoyl), heterocyclic(lower)alkanoyl (more preferably thienyl(lower)alkanoyl) , ar(lower)alkenoyl substituted with a lower alkenyl group (more preferably phenyl(lower)alkenoyl substituted with a lower alkenyl group), or ar(lower)alkanoyl substituted with a lower alkyl group (more . preferably phenyl(lower)alkanoyl substituted with a lower alkyl group) ;

R^**-² is hydroxy and

R-^*-³ is carboxy or esterified carboxy (more preferably lower alkoxycarbonyl), or

R^*--² and R*--³ are linked together to represent a group of the formula : -o-_C- •

II o R1 is hydroxy, ar(lower)alkoxy (more preferably phenyl(lower)alkoxy) or acyloxy (more preferably lower alkanoyloxy) ; R^**-^*** is hydroxy, ar(lower)alkoxy (more preferably phenyl(lower)alkoxy) or acyloxy (more preferably lower alkanoyloxy) ;

R^**-^**-" is hydroxy, lower alkoxy, ar(lower)alkoxy (more preferably phenyl(lower)alkoxy) or acyloxy (more preferably lower alkanoyloxy) ; and = is a single bond or a double bond.

Further, the most interesting compounds are the compounds A, B and C of the following formulae.

(Compound A)

(Compound B)

35 (Compound C) The compounds of the general formulae (I), (II) and (III), and the specific compounds mentioned above are known compounds, and the methods for preparation thereof are described, for example, in the following publications, or they can be prepared by a conventional method.

European Patent Publication 0 443 132 A2 European Patent Publication 0 482 539 A2 European Patent Publication 0 336 230 A2 International Publication WO 93/21215

The peptide compounds of the present invention may be administered as pure compounds or mixtures of compounds or preferably, in a pharmaceutical vehicle or carrier. The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the peptide compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external including topical, enteral, intravenous, intramuscular, parenteral, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for tablets, pellets, capsules, suppositories, solutions (saline, for example), emulsion, suspension (olive oil, for example), lotions, creams, ointment, dragees, granules, powder, injection, cataplasm, gel, tape, ophthalmic solutions, syrup, aerosol, and other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, 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 object 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 using the method of the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans.

For applying this composition to a human, it is preferable to apply it by oral, parenteral, external (topical), enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.

While the dosage of therapeutically effective amount of the peptide compounds varies from and also depends upon the age and condition of each individual patient to be treated, a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg of the active ingredient is generally given for treating diseases, and an average single dose of about 0.1 mg, 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered.

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

Example 1 Compound A 1 mg

Lactose 39 mg

total 40 mg Example 2

Compound B 1 mg Lactose 39 mg

total 40 mg

Example 3

Compound C 1 rag Lactose 39 mg

total 40 mg

Claims

1. A use of peptide compounds of the formula

wherein R¹ is aryl, or a group of the formula

wherein X¹ is CH or N, and Z¹ is 0 or N-R¹⁷, in which R¹⁷ is hydrogen or lower alkyl, R² is hydroxy or lower alkoxy, R³ is hydrogen or lower alkyl which may have suitable substituent(s) ,

R⁴ is ar(lower)alkyl which may have suitable substituent(s) , A*-- is carbonyl or sulfonyl, and Y-^*** is bond or lower alkenylene, and pharmaceutically acceptable salts thereof, R⁵— Y²—CO—A² (II)

wherein R⁵ is lower alkyl, aryl, arylamino, pyridyl, pyrrolyl, pyrazolopyridyl, quinolyl, or a group of the formula :

x² z²

wherein the symbol of a line and dotted line is a single bond or a double bond,

X² is CH or N, and Z² is O, S or NH, each of which may have suitable substituent(s) ; R⁶ is hydrogen or lower alkyl;

R⁷ is suitable substituent; R⁸ is lower alkyl which may have suitable substituent(s) , and R⁹ is ar(lower)alkyl which may have suitable substituent(s) or pyridyl(lower)alkyl, or R⁸ and R⁹ are linked together to form benzene-condensed lower alkylene; R¹⁰ is hydrogen or suitable substituent; A² is an amino acid residue, which may have suitable substituent(s) ; and Y² is bond, lower alkylene or lower alkenylene, and pharmaceutically acceptable salts thereof, or

wherein R-*-^*-- is hydrogen or an acyl group; R^**-² is hydroxy and

R^*³ is carboxy or protected carboxy, or R¹² and R¹³ are linked together to represent a group of the formula : -o-_C-

R**-⁴ is hydroxy or protected hydroxy;

R¹⁵ is hydroxy or protected hydroxy;

R¹⁶ is hydroxy, protected hydroxy or lower alkoxy; and

== is a single bond or a double bond, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for preventing or treating chronic obstructive pulmonary diseases, iritis, psoriasis, inflammatory intestinal diseases, hepatitis, tenalgia attended to hyperlipidemia, postoperative neuroma, vulvar vestibulitis, hemodialysis-associated itching, lichen planus, laryngopharyngitis, bronchiectasis, conoisis, whooping cough, pulmonary tuberculosis, emesis or mental diseases.

2. A use of claim 1 of the compound (I) defined in claim 1.

3. A method for preventing or treating chronic obstructive pulmonary diseases, iritis, psoriasis, inflammatory intestinal diseases, hepatitis, tenalgia attended to hyperlipidemia, postoperative neuroma, vulvar vestibulitis, hemodialysis-associated itching, lichen planus, laryngopharyngitis, bronchiectasis, conoisis, whooping cough, pulmonary tuberculosis, emesis or mental diseases, which comprises administering the compound (I), (II) or (III) defined in claim 1 to mammals.

4. A method of claim 3 which comprises administering the compound (I) defined in claim 1 to mammals.

5. A pharmaceutical composition for preventing or treating chronic obstructive pulmonary diseases, iritis, psoriasis, inflammatory intestinal diseases, hepatitis, tenalgia attended to hyperlipidemia, postoperative neuroma, vulvar vestibulitis, hemodialysis-associated itching, lichen planus, laryngopharyngitis, bronchiectasis, conoisis, whooping cough, pulmonary tuberculosis, emesis or mental diseases, comprising a compound (I), (II) or (III) defined in claim 1, as an active ingredient, in association with a pharmaceutically acceptable. substantially non-toxic carrier or excipient.

6. A pharmaceutical composition of claim 5 comprising the compound (I) defined in claim 1 as an active ingredient.

7. A use of the compound (I), (II) or (III) defined in claim 1 for preventing or treating chronic obstructive pulmonary diseases, iritis, psoriasis, inflammatory intestinal diseases, hepatitis, tenalgia attended to hyperlipidemia, postoperative neuroma, vulvar vestibulitis, hemodialysis-associated itching, lichen planus, laryngopharyngitis, bronchiectasis, conoisis, whooping cough, pulmonary tuberculosis, emesis or mental diseases.

8. A use of claim 7 of the compound (I) defined in claim 1.