DESCRIPTION PHARMACEUTICAL COMPOSITION CONTAINING AN ESTER OR AMIDE PLA2 INHIBITOR TECHNICAL FIELD The present invention relates to a new pharmaceutical composition, which is highly stable and has an improved cutaneous penetration, absorption profile and a low irritation potential. The pharmaceutical composition of the present invention is useful for the therapy and prophylaxis of various diseases of the skin.

BACKGROUND ART The compound or a salt thereof for use in the present invention is known to have high phospholipase A2-inhibiting activity and be, therefore, useful for the prevention and/or therapy of pancreatitis, hepatitis, chronic renal failure, shock (e. g. endotoxin shock, Gram-negative septic shock, etc.), arthritis (e. g. rheumatoid arthritis, osteoarthritis, etc.), respiratory diseases (e. g. bronchial asthma, bronchitis, respiratory distress syndrome of the adult, etc.), diseases of the heart (e. g. myocardial ischemia etc.), allergic diseases, thrombosis, arteriosclerosis, pain, autoimmune diseases, diseases of the skin (e. g. atopic dermatitis, psoriasis, contact dermatitis, etc.), inflammatory enteric diseases (e. g. Crohn's disease, ulcerative colitis, etc.), diseases of the eye (e. g. allergic and inflammatory diseases of the eye, etc.), nasal diseases (e. g. allergic diseases of the nose etc.), gout, traumatic inflammation (e. g. spinal injury etc.) and diseases of the liver (e. g. cirrhosis etc.), or the like. (WO 97/03951).

DISCLOSURE OF THE INVENTION The inventors of the present invention explored in earnest for a useful pharmaceutical composition comprising above-mentioned compound and discovered a composition having satisfactory stability, a good cutaneous absorption profile and/or a low dermal irritation potential.

More particularly, the object of the present invention is to provide a gel composition for external application comprising the above-mentioned compound or a salt thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned compound or a salt thereof, an absorption enhancer, a pharmaceutical base, a thickener and optionally a compatibilizing agent.

The compound (I) for use in the present invention can be represented by the following general formula: wherein Rl is acyl group, R2 is acyl (lower) alkyl, R3 is hydrogen, aryl (lower) alkyl which may have one or more suitable substituent (s), aryl (higher)- alkyl which may have one or more suitable substituent (s), heterocyclic (lower) alkyl which may have one or more suitable substituent (s), higher alkoxy (lower) alkyl, lower alkyl, or higher alkyl, R4 is acyl (lower) alkyl, and X is-O-,-NH-or [wherein R5 is lower alkyl, cyclo (lower) alkyl (lower) alkyl, aryl (lower) alkyl, or heterocyclic (lower) alkyl.

The compound (I) represented by the above-disclosed formula or a salt thereof can be provided by the preparation method described in the laid-open patent application (W097/03951) referred to above, the disclosure of which is incorporated herein by reference.

The preferred salt of the compound (I) is a pharmaceutical acceptable and conventional nontoxic salt and may include salt with an inorganic base, for example, salt with alkali metals (e. g. sodium salt, potassium salt, etc.) and salt with alkaline earth metals (e. g. calcium salt, magnesium salt, etc.); ammonium salt; salt with an organic base such as an organic amine salt (e. g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'- dibenzylethylenediamine salt, etc.); inorganic acid addition salt (e. g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); organic carboxylic or sulfonic acid addition salt (e. g. formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and salt with basic or acidic amino acids (e. g. arginine salt, aspartate, glutamate, etc.).

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

The term"lower"is intended to mean 1 to 6 carbon atom (s) unless otherwise indicated.

The term"higher"is intended to mean 7 to 20 carbon atoms unless otherwise indicated.

Suitable example of"lower alkyl"and"lower alkyl" moiety in the terms used in the present specification may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, or the like.

Suitable"lower alkenyl"and"lower alkenyl"moiety in the terms used in the present specification may include vinyl, 1- (or 2-) 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, methylvinyl, ethylvinyl, 1- (or 2-or 3-) methyl-l- (or 2-)- propenyl, 1- (or 2-or 3-) ethyl-l- (or 2-) propenyl, 1- (or 2- or 3-or 4-) methyl-l- (or 2-or 3-) butenyl, or the like, in which the preferred one may be (C2-C4) alkenyl.

Suitable"higher alkyl"and"higher alkyl"moiety in the terms used in the present specification may include straight or branched one such as heptyl, 2-methylheptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, 11- methyldodecyl, 12-methyltridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, or the like, in which the preferred one may be (C7-C16) alkyl, and the more preferred one may be heptyl, octyl, nonyl, decyl, or tridecyl.

Suitable"lower alkoxy"and"lower alkoxy"moiety in the terms used in the present specification may include straight or branched one such as methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, or the like.

Suitable"higher alkoxy"and"higher alkoxy"moiety in the terms used in the present specification may include straight or branched one such as heptyloxy, 2-methyl- heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, 11-methyldodecyloxy, 12- methyltridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy, or the like.

Suitable"lower alkanoyl"and"lower alkanoyl"moiety in the terms used in the present specification may include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, pivaloyl, or the like.

Suitable"cyclo (lower) alkyl"in the terms used in the present specification may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like.

Suitable"halogen"in the terms used in the present specification may include fluorine, chlorine, bromine, iodine, in which more preferable one may be chlorine.

Suitable"aryl"and"aryl"moiety in the terms used in the present specification may include phenyl, naphthyl, or the like.

Suitable"acyl group"and"acyl"moiety in the terms used in the present specification may be aliphatic acyl, aromatic acyl, heterocyclic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, or the like.

Suitable example of the"acyl group"thus explained may be : (1) lower alkanoyl [e. g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, pivaloyl, etc.] which may have one or more (preferably 1 to 3) suitable substituent (s) such as halogen (e. g. fluoro, chloro, bromo, iodo); hydroxy; lower alkoxy (e. g. methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc.); amino; protected amino, preferably, acylamino such as lower alkoxycarbonylamino (e. g. methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, t- butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino, etc.); or the like; di (lower) alkylamino (e. g. dimethylamino, N- methylethylamino, diethylamino, N-propylbutylamino, dipentylamino, dihexylamino, etc.); lower alkoxyimino (e. g. methoxyimino, ethoxyimino, propoxyimino, butoxyimino, t-butoxyimino, pentyloxyimino, hexyloxyimino, etc.); ar (lower) alkoxyimino such as phenyl (lower) alkoxyimino (e. g. benzyloxyimino, phenethyloxyimino, benzhydryloxyimino, etc.); or the like; (2) higher alkanoyl [e. g. heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, 14- methylpentadecanoyl, 15-methylhexadecanoyl, 10,12- dimethyltetradecanoyl, heptadecanoyl, stearoyl, nonadecanoyl, icosanoyl, etc.] which may have one or more (preferably 1 to 3) suitable substituent (s) as exemplified for those of"lower alkanoyl" ; (3) lower alkenoyl [e. g. acryloyl, crotonoyl, isocrotonoyl, methacryloyl, 3-pentenoyl, 2,4- pentadienoyl, 5-hexenoyl, 2,4-hexadienoyl, etc.] which may have one or more (preferably 1 to 3) suitable substituent (s) as exemplified for those of"lower alkanoyl" ; (4) higher alkenoyl [e. g. 4-heptenoyl, 3-octenoyl, 3,6-decadienoyl, 10- dodecatrienoyl, 4,10-heptadecadienoyl, etc.] which may have one or more (preferably 1 to 3) suitable substituent (s) as exemplified for those of"lower alkanoyl" ; (5) protected carboxy, in which the preferred one may be esterified carboxy such as lower alkoxycarbonyl [e. g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.], halo (lower) alkoxycarbonyl [e. g. chloromethoxycarbonyl, (2,2,2-trichloroethoxy)- carbonyl, (2,2,2-trifluoroethoxy) carbonyl, (2- chloropropoxy) carbonyl, (l-fluoro-4- bromobutoxy) carbonyl, (4-chloropentyloxy)- carbonyl, (6-chlorohexyloxy) carbonyl, etc.], higher alkoxycarbonyl [e. g. heptyloxycarbonyl, octyloxycarbonyl, 2-ethylhexyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, 3,7- dimethyloctyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, 3- methyl-10-ethyldodecyloxycarbonyl, hexadecyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl, icosyloxycarbonyl, etc.], aryloxycarbonyl [e. g. phenoxycarbonyl, naphthyloxycarbonyl, etc.], aryl (lower) alkoxycarbonyl which may have one or more (preferably 1 to 3) suitable substituent (s) such as phenyl (lower) alkoxycarbonyl which may have nitro or lower alkoxy [e. g. benzyloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- methoxybenzyloxycarbonyl, etc.], or the like; (6) carboxy; (7) lower alkylsulfonyl [e. g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, pentylsulfonyl, butylsulfonyl, etc.]; (8) arylsulfonyl [e. g. phenylsulfonyl, 1- (or 2-)-naphthylsulfonyl, etc.] which may have one or more (preferably 1 to 3) suitable substituent (s) such as lower alkyl, di (lower) alkylamino, lower alkylamino (e. g. methylamino, ethylamino, propylamino, butylamino, t-butylamino, pentylamino, hexylamino, etc.), or the like; (9) aryl (lower) alkylsulfonyl such as phenyl (lower) alkylsulfonyl [e. g. benzylsulfonyl, phenethylsulfonyl, benzhydrylsulfonyl, etc.], or the like; (10) aryl (lower) alkanoyl such as phenyl (lower) alkanoyl or naphthyl (lower) alkanoyl [e. g. benzoyl, naphthoyl (e. g. 1-naphthoyl, 2- naphthoyl, etc.), 2-phenylacetyl, 2-phenylpropionyl, 4- (l-naphthyl) butyryl, 3-phenylvaleryl, 2,5- diphenylhexanoyl, etc.], each of which may have one or more (preferably 1 to 3) suitable substituent (s) such as lower alkoxy, aryl (e. g. phenyl, naphthyl, anthryl, etc.), carboxy (lower) alkyl (e. g. carboxymethyl, 2-carboxyethyl, 1-carboxypropyl, 4- carboxybutyl, 3-carboxypentyl, 6-carboxyhexyl, etc.), protected carboxy (lower) alkyl (e. g. methoxycarbonylmethyl, 2-methoxycarbonylethyl, 2- (t-butoxycarbonyl) ethyl, etc.) which may be substituted by aryl (e. g. phenyl, naphthyl, etc.), protected carboxy (lower) alkenyl (e. g. 2- methoxycarbonylvinyl, etc), amidated carboxy (lower) alkyl (e. g. 2-carbamoylethyl, etc.), aryl (lower) alkyl (e. g. benzyl, phenethyl, etc.) which may have one or more suitable substituent (s), or the like; (11) aryl (lower) alkenoyl (e. g. 3-phenylacryloyl, 2-phenylacryloyl, 2-naphthylacryloyl, 3- phenylcrotonoyl, 4-phenylisocrotonoyl, 2- benzylacryloyl, 5-phenyl-3-pentenoyl, 3-naphthyl- 2,4-pentadienoyl, 2-phenyl-5-hexenoyl, 6-phenyl- 2,4-hexadienoyl, etc.); (12) heterocyclic (lower) alkanoyl which may have one or more (preferably 1 to 3) suitable substituent (s) such as lower alkyl, aryl (lower) alkyl which may have one or more suitable substituent (s) (e. g. benzyl, 1-naphthylmethyl, 4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, etc.), heterocyclic (lower) alkyl (e. g. 2-pyridylmethyl, etc.) which may have one or more suitable substituent (s), or the like; (13) heterocyclicsulfonyl; (14) amidated carboxy such as carbamoyl, N-heterocyclic-carbamoyl which may have one or more (preferably 1 to 3) suitable substituent (s) such as lower alkyl, halogen, or the like, N-lower alkyl-N- heterocyclic-carbamoyl, N-lower alkylcarbamoyl (e. g.

N-methylcarbamoyl, N-ethylcarbamoyl, N- propylcarbamoyl, N-butylcarbamoyl, N-t- butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, etc.) which may have one or more (preferably 1 to 3) suitable substituent (s) such as heterocyclic group, hydroxy, or the like, N-aryl (lower) alkylcarbamoyl such as N- (mono-or di-or tri-) phenyl (lower) alkylcarbamoyl (e. g. N- benzylcarbamoyl, N-phenethylcarbamoyl, N- benzhydrylcarbamoyl, N-tritylcarbamoyl, etc.), or the like; or the like.

Suitable"heterocyclic"moiety in the terms used in the present specification may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 to 7-membered) heteromonocyclic group containing 1 to 4 nitrogen atom (s), for example, azepinyl (e. g. 1H-azepinyl, etc), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e. g. 4H-1,2,4-triazolyl, 1H- 1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc), tetrazolyl (e. g.

1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 to 7- membered) heteromonocyclic group containing 1 to 4 nitrogen atom (s), for example, perhydroazepinyl (e. g. perhydro- 1H-azepinyl, etc), pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom (s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl [e. g. imidazo [4,5-c] pyridyl, etc.], tetrahydroimidazopyridyl e. g. 4,5,6,7-tetrahydro [4,5- c pyridyl, etc.], etc.; saturated condensed heterocyclic group containing 1 to 4 nitrogen atom (s), for example, 7-azabicyclo [2.2.1]- heptyl, 3-azabicyclo 3.2.2 nonanyl, 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 condensed heterocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), for example, benzothiazolyl, benzothiadiazolyl, etc.; saturated condensed heterocyclic group containing 1 to 4 nitrogen atom (s), and saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom (s) and 1 to 3 nitrogen atom (s), unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 oxygen atom (s), for example, furyl, etc; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom (s), for example, benzofuranyl (e. g. benzo [b] furanyl, etc.), 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.; or the like.

Suitable"aryl (lower) alkyl" may include mono- (or di- or tri-) phenyl (lower) alkyl (e. g. benzyl, phenethyl, 2-phenylpropyl, 2,4-diphenylbutyl, 1,3,5-triphenylpentyl, 6-phenylhexyl, etc), mono- (or di-or tri-) naphthyl (lower)- alkyl (e. g. 2-naphthylmethyl, 2- (l-naphthyl) ethyl, 2- (2- naphthyl) ethyl, etc.), or the like.

This"aryl (lower) alkyl" may have one or more (preferably 1 to 3) suitable substituent (s) selected from the group consisting of lower alkyl (e. g. methyl, ethyl, butyl, etc.), higher alkyl (e. g. pentyl, etc.), lower alkoxy (e. g. methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc.), aryl (e. g. phenyl, naphthyl, etc), halogen (e. g. fluoro, chloro, bromo, iodo), or the like.

Suitable"aryl (higher) alkyl"may include mono- (or di- or tri-) phenyl (higher) alkyl (e. g. 7-phenylheptyl, 6-phenylheptyl, 4,6-diphenylheptyl, 3,5,7-triphenylheptyl, 8-phenyloctyl, etc.), mono- (or di-or tri-)- naphthyl (higher) alkyl (e. g. 7- (2-naphthyl) heptyl, 8- (1- naphthyl) octyl, etc.), or the like.

Each of the"aryl (higher) alkyl" and "heterocyclic (lower) alkyl"may have one or more (preferably 1 to 3) suitable substituent (s) as exemplified for those of "aryl (lower) alkyl" above.

Suitable"higher alkoxy"moiety in the terms used in the present specification may include straight or branched one such as heptyloxy, 2-methylheptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, 11-methyldodecyloxy, 12-methyltridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy, or the like, in which the preferred one may be (C7-C16) alkoxy, and the more preferred one may be nonyloxy or decyloxy.

Suitable"cyclo (lower) alkyl"moiety in the terms used in the present specification may include the ones having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In aforesaid"acyl group", the preferred one may be (1) lower alkoxycarbonyl, in which the more preferred one may be (Cl-C4) alkoxycarbonyl, and the most preferred one may be t-butoxycarbonyl; (2) aryl (lower) alkanoyl which may have one or more suitable substituent (s), in which the more preferred one may be phenyl (lower) alkanoyl or naphthyl (lower) alkanoyl, each of which may have 1 to 3 suitable substituent (s) selected from the group consisting of carboxy (lower) alkyl (e. g. carboxymethyl, 2-carboxyethyl, 1-carboxypropyl, 4-carboxybutyl, 3- carboxypentyl, 6-carboxyhexyl, etc.); protected carboxy (lower) alkyl (e. g. methoxycarbonylmethyl, 2- methoxycarbonylethyl, 2- (t-butoxycarbonyl) ethyl, etc.) which may be substituted by aryl (e. g. phenyl, naphthyl, etc.) ; protected carboxy (lower) alkenyl (e. g.

2-methoxycarbonylvinyl, etc.); amidated carboxy (lower) alkyl (e. g. 2-carbamoylethyl, etc.) and aryl (lower) alkyl (e. g. benzyl, phenethyl, etc.), the much more preferred one may be phenyl (Cl-C 4) alkanoyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of carboxymethyl; 2-carboxyethyl; methoxycarbonylmethyl;, benzyloxycarbonylmethyl; 2-methoxycarbonylethyl; 2- (t-butoxycarbonyl) ethyl; 2-methoxycarbonylvinyl; 2- carbamoylethyl; benzyl and phenethyl, or naphthyl (Ci -C4) alkanoyl which may have benzyl, the most preferred one may be benzoyl, 2- (carboxymethyl) benzoyl, 2- (2-carboxyethyl) benzoyl, 2- (methoxycarbonylmethyl) benzoyl, 2- (benzyloxycarbonylmethyl) benzoyl, 2- (2-methoxycarbonylethyl) benzoyl, 2- 2- (t-butoxycarbonyl) ethyl] benzoyl, 2- (2-methoxycarbonylvinyl) benzoyl, 2- (2-carbamoylethyl) benzoyl, 2-benzylbenzoyl, 3- benzylbenzoyl, 2-phenethylbenzoyl, 2-naphthoyl or 3-benzylnaphthalen-2-ylcarbonyl; or (3) heterocyclic (lower) alkanoyl which may have one or more suitable substituent (s), in which the more preferred one may be heterocyclic (lower) alkanoyl wherein heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom (s), which may have 1 to 3 lower alkylaryl (lower) alkyl, haloaryl (lower) alkyl or heterocyclic (lower) alkyl, wherein heterocyclic moiety is unsaturated 3 to 8- membered heteromonocyclic group containing 1 to 4 nitrogen atom (s), the more preferred one may be quinolyl (Cl-C4) alkanoyl, isoquinolyl (Cl-C4) alkanoyl, or indolyl (Cl-C4) alkanoyl which may have (Cl-C 4) alkylphenyl (Cl-C4) alkyl, halophenyl (Cl-C4) alkyl, or pyridyl (Cl-C4) alkyl, the much more preferred one may be quinolylcarbonyl, isoquinolylcarbonyl or indolylcarbonyl which may have benzyl, 1- naphthylmethyl, 4-methylbenzyl, 2-chlorobenzyl, 3- chlorobenzyl, 4-chlorobenzyl or 2-pyridylmethyl, the most preferred one may be 2- (or 3-) quinolylcarbonyl, 1- (or 3-) isoquinolylcarbonyl, 1-benzylindol-2- (or 3-) ylcarbonyl, 1- (1-naphthylmethyl) indol-3- ylcarbonyl, 1- (4-methylbenzyl) indol-2- (or 3-) ylcarbonyl, 1- 2- (or 3-or 4-) chlorobenzyl] indol-3-ylcarbonyl or 1- (2-pyridylmethyl) indol-3-ylcarbonyl.

The preferred"acyl"moiety in the term "acyl (lower) alkyl" may be carboxy; protected carboxy, in which the more preferred one may be lower alkoxycarbonyl or aryl (lower) alkoxycarbonyl, the much more preferred one may be (Cl-C4) alkoxycarbonyl or phenyl (Cl-C4) alkoxycarbonyl, and the most preferred one may be methoxycarbonyl or benzyloxycarbonyl; or amidated carboxy, in which the more preferred one may be carbamoyl.

The preferred"substituent"in the terms "aryl (lower) alkyl which may have one or more suitable substituent (s)","aryl (higher) alkyl which may have one or more suitable substituent (s)"and"heterocyclic (lower) alkyl which may have one or more suitable substituent (s)" may include lower alkyl as exemplified above, preferably, (Cl -C4) alkyl, more preferably methyl, ethyl or butyl; higheralkylasexemplifiedabove, preferably (C7-C16) alkyl, more preferably heptyl; aryl as exemplified above, preferably phenyl; or the like.

In the following, some of the preferred embodiments of the compound (I) of the present invention are shown.

(1) the compound (I), wherein Rl is protected carboxy; aryl (lower) alkanoyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkoxy, aryl, carboxy (lower) alkyl, protected carboxy (lower) alkyl which may be substituted by aryl, protected carboxy (lower) alkenyl, amidated carboxy (lower) alkyl and aryl (lower) alkyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; heterocyclic (lower) alkanoyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of loweralkyl, aryl (lower) alkyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen, or heterocyclic (lower) alkyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; R2 is carboxy (lower) alkyl or protected- carboxy (lower) alkyl, R3 is hydrogen; aryl (lower) alkyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; aryl (higher) alkyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; heterocyclic (lower) alkyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; higher alkoxy (lower) alkyl; lower alkyl; or higher alkyl, R4 is carbamoyl (lower) alkyl, and X is-O-,-NH-or [wherein R5 is lower alkyl, cyclo (lower) alkyl (lower) alkyl, aryl (lower) alkyl or heterocyclic (lower) alkyl.

(2) the compound (I), wherein Rl is esterified carboxy (preferably lower alkoxycarbonyl); phenyl (lower) alkanoyl or naphthyl (lower) alkanoyl, each of which may have 1 to 3 suitable substituent (s) selected from the group consisting of carboxy (lower) alkyl, esterified carboxy (lower) alkyl (preferably lower alkoxycarbonyl (lower) alkyl) which may be substituted by phenyl, esterified carboxy (lower) alkenyl (preferably lower alkoxycarbonyl (lower) alkenyl), carbamoyl (lower) alkyland phenyl (lower) alkyl; or heterocyclic (lower) alkanoyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of pyridyl (lower) alkyl, naphthyl (lower) alkyl and phenyl (lower) alkyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl and halogen, in which the heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom (s), R2 is carboxy (lower) alkyl or esterified carboxy (lower) alkyl (preferably methoxycarbonyl (lower) alkyl or benzyloxycarbonyl (lower) alkyl), R3 is hydrogen; phenyl (lower) alkyl which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, higher alkyl and phenyl; naphthyl (lower) alkyl which may be substituted by lower alkyl; phenyl (higher) alkyl; heterocyclic (lower) alkyl, in which the heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom (s); higher alkoxy (lower) alkyl; lower alkyl; or higher alkyl, R4 is carbamoyl (lower) alkyl, and X is-0-,-NH-or [wherein R5 is lower alkyl, phenyl (lower) alkyl or pyridyl (lower) alkyl.

(3) the compound (I), wherein R is indolyl (lower) alkanoyl which may have a suitable substituent selected from the group consisting of pyridyl (lower) alkyl, naphthyl (lower) alkyl, phenyl (lower) alkyl, lower alkylphenyl (lower) alkyl or halophenyl (lower) alkyl, R2 is carboxy (lower) alkyl, R3 is lower alkyl or higher alkyl, R4 is carbamoyl (lower) alkyl and [wherein R5 is lower alkyl.

(4) (3S)-3- N- (n-Propyl)- (2S)-2- l- (2-chlorobenzyl)- indol-3-ylcarbonyl] amino-5-carboxypentanoyl amino- dodecanamide.

It is to be noted that each of the compound (I) may include one or more stereoisomer (s) such as optical isomer (s) and geometrical isomer (s) due to asymmetric carbon atom (s) and double bond (s), and all such isomer (s) and the mixture thereof are included within the scope of the present invention.

The compound (I) or a salt thereof includes solvated compound [e. g., enclosure compound (e. g., hydrate, etc.)].

The compound (I) or a salt thereof includes both its crystal form and non-crystal form.

It should be understood that the compound (I) in the present invention may include the prodrug form.

The pharmaceutical composition of the present invention is applicable to the compounds disclosed in the laid-open patent applications (W095/19959, W096/22966 and W096/15148), the disclosures of which are incorporated herein by references.

The pharmaceutical composition of the present invention can be processed into desired dosage forms by procedures known to those skilled in the art. An exemplary procedure comprises dissolving the compound (I) or a salt thereof in a mixture of the pharmaceutical base and absorption enhancer, optionally adding the compatibilizing agent, and blending the resulting solution with the thickener.

In this procedure, one or more other additive (s) and an additional amount of other absorption enhancer may be simultaneously added to the pharmaceutical base.

As the preferable form of the pharmaceutical composition of the present invention, ointments and gels can be exemplified.

The absorption enhancer for use in the present invention is not particularly restricted, provided that it dissolves the compound (I) or a salt thereof and/or contributes to the cutaneous absorption thereof. The preferred one may be monohydric alcohol fatty acid esters, dibasic acid diesters, lower alkylene carbonates and propylene glycol mono (higher) alkyl esters such as the following.

Monohvdric alcohol fatty acid esters isopropyl myristate, ethyl myristate, butyl myristate, isocetyl myristate, octyldodecyl myristate, isopropylpalmitate, isostearylpalmitate, isopropyl isostearate, isocetyl isostearate, butyl stearate, isocetyl stearate, cetyl isooctanoate, ethyl linoleate, isopropyl linoleate, hexyl laurate, ethyl oleate, decyl oleate, oleyl oleate, octyldodecyl myristate, hexyldecyl, dimethyloctanoate, octyldodecyl neodecanoate, etc.

Dibasic acid diesters diisopropyl adipate, dimethyl adipate, diethyl adipate, diisobutyl adipate, diethyl sebacate, diisopropyl sebacate, dipropyl sebacate, diethyl phthalate, diethyl pimelate, etc.

Lower alkylene carbonates propylene carbonate, ethylene carbonate, etc.

Propylene glycol mono (higher) alkyl esters propylene glycol monocaprylate, etc.

In the present invention, the absorption enhancers above-mentioned can be used each alone or as a mixture of two or more substances.

Particularly, the preferred ones are absorption enhancers which enhance the penetration of the active ingredient through the epidermis. In this sense, dibasic acid diesters and propylene glycol mono (higher) alkyl esters are particularly preferred, and diethyl sebacate and propylene glycol monocaprylate are the most preferred. The formulating amount of the absorption enhancer is not particularly restricted, provided that it is sufficient to dissolve the compound (I) or a salt thereof and/or enhance the cutaneous absorption thereof. Thus, based on the total weight of the composition, the absorption enhancer is used in a proportion of preferably 1-50 % (w/w), more preferably 2-30% (w/w), and most preferably 4-20% (w/w).

The pharmaceutical base for use in the present invention is not particularly restricted, provided that it is compatible with the other ingredients and capable of dissolving the thickener as well. When the pharmaceutical composition of the present invention is a gel composition, it is preferable to use a hydrophilic base capable of dissolving the compound (I) or a salt thereof and the thickener. Particularly, the preferred ones are hydrophilic glycols such as lower alkanediols (e. g. ethylene glycol, propylene glycol, butylene glycol, etc.), diethylene glycols (e. g. diethylene glycol monoethylether, etc.). The formulating amount of the pharmaceutical base in the pharmaceutical composition of the present invention can be judiciously selected.

The thickener for use in the present invention is not particularly restricted only if it is pharmaceutically acceptable and capable of imparting viscosity to the pharmaceutical base and, for example, includes but is not limited to the following organic and inorganic water-soluble macromolecular substances.

(1) Organic substances Native polymers gum Arabic, gum guar, carrageenan, tragacanth, pectin, starch, gum xanthane, gelatin, casein, dextrin, cellulose, etc.

Semisynthetic polymers Cellulose polymers (methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, etc.), carboxymethylstarch, sodium alginate, propylene glycol alginate, etc.

Synthetic polymers carboxyvinyl polymer (Carbopol), polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyvinyl methyl ether, polysodium acrylate, etc.

(2) Inorganic substances bentonite, synthetic magnesium silicate, magnesium aluminosilicate, silicon oxide, etc.

The more preferred ones are cellulose polymers and carboxyvinyl polymer, and the most preferred one is hydroxypropylcellulose.

The formulating amount of the thickener can be judiciously selected according to the desired viscosity of the pharmaceutical composition of the present invention.

Thus, based on the total weight of composition, the thickener is used in a proportion of 0.1-10% (w/w) and more preferably 0.5-5% (w/w).

The compatibilizing agent which is optionally used in the present invention is a substance capable of contributing to the compatibility between the absorption enhancer and the pharmaceutical base and includes but is not limited to the following.

Alcohols isopropyl alcohol, ethanol, oleyl alcohol, cetanol, stearyl alcohol, 2-octyldodecanol, etc.

Aromatic substances crotamiton, etc.

The more preferred one is aromatic substances, and the most preferred one is crotamiton. The formulating amount of said compatibilizing agent is not particularly restricted, provided that it contributes to the binding between the absorption enhancer and the pharmaceutical base. Thus, based on the total weight of the composition, the compatibilizing agent is used in a proportion of 1-30% (w/w), preferably 2-20% (w/w) and more preferably 2.5-10% (w/w).

If necessary, in addition to the above-mentioned ingredients, the pharmaceutical composition may contain the conventional excipient (e. g. lactose, sucrose, starch, mannitol, etc.), stabilizer [antioxidant (e. g. ascorbyl palmitate, tocopherol, etc.)], coloring agent, flavoring agent, diluent, preservative, and other additives as well as other drugs effective in diseases of the skin.

The preferred form of the pharmaceutical composition of the present invention is a gel composition in which the absorption enhancer is a dibasic acid diester, the pharmaceutical base is a hydrophilic glycol, and the thickener is a cellulose polymer, and preferably in which the absorption enhancer is diethyl sebacate, the pharmaceutical base is propylene glycol, and the thickener is hydroxypropylcellulose.

The pharmaceutical composition of the present invention can be put to use by applying it once to 4 times daily to the lesion, particularly the affected area of the skin.

The formulating amount of the compound (I) or a salt thereof in the pharmaceutical composition of the present invention depends on the age of the individual to be treated, the type of disease, its severity and other factors. Thus, based on the total weight of the composition, the recommended formulating amount may be, for example, preferably 0. 001-20% (w/w), more preferably 0.01-10% (w/w), and the most preferably 0.03-3% (w/w). In addition, the composition may contain other drugs effective in diseases of the skin.

Some examples of the pharmaceutical composition of the present invention can be manufactured in the same manner as the following examples.

The following examples are intended to illustrate the present invention in further details and should by no means be construed as defining the scope of the invention.

Test Compound (3S)-3- N- (n-Propyl)- (2S)-2- l- (2-chlorobenzyl) indol- 3-ylcarbonyl] amino-5-carboxypentanoyl] amino] dodecanamide Example 1 In a mixture of propylene glycol and diethyl sebacate was dissolved Test Compound. Then, hydroxypropylcellulose was mixed and stirred to prepare a colorless, clear gel composition for external application.

(Composition 1) Test Compound 0.1 g Diethyl sebacate 10 g Propylene glycol q. s.

Hydroxypropylcellulose 3 g Total 100 g Example 2 The following compositions [Compositions 2 to 7] were prepared according to a similar manner to that of Example 1.

(Composition 2) Test Compound 0.3 g Diethyl sebacate 10 g Propylene glycol q. s.

Hydroxypropylcellulose 3 g Total 100 g (Composition 3) Test Compound 1 g Diethyl sebacate 10 g Propylene glycol q. s.

Hydroxypropylcellulose 3 g Total 100 g (composition 4) Test Compound 3 g Diethyl sebacate 10 g Propylene glycol q. s.

Hydroxypropylcellulose 3 g Total 100 g (Composition 5) Test Compound 1 g Diethyl sebacate 10 g Propylene glycol q. s.

Hydroxypropylcellulose 2 g Total 100 g (Composition 6) Test Compound 1 g Diethyl sebacate 10 g Propylene glycol q. s.

Hydroxypropylcellulose 4 g Total 100 g (Composition 7) Test Compound 1.0 g Diethyl sebacate 10 g Propylene glycol q. s.

Hydroxypropylcellulose 2.5 g Total 100 g Example 3 In a mixture of propylene glycol and diethyl sebacate was dissolved propylene glycol monocaprylate. Then, Test Compound and hydroxypropylcellulose were dissolved therein, and the mixture was stirred to prepare a colorless, clear gel composition for external application.

(Composition 8) Test Compound 1 g Diethyl sebacate 20 g Propylene glycol monocaprylate 10 g Propylene glycol q. s.

Hydroxypropylcellulose 3 g Total 100 g Example 4 In a mixture of propylene glycol and diethyl sebacate was dissolved crotamiton. Then, Test Compound and hydroxypropylcellulose were dispersed therein, and the mixture was stirred to prepare a colorless, clear gel composition for external application.

(Composition 9) Test Compound 1 g Diethyl sebacate 20 g Crotamiton 10 g Propylene glycol q. s.

Hydroxypropylcellulose 3 g Total 100 g Example 5 The transdermal absorption and dermal retention experiment were performed with the pharmaceutical composition of the present invention as described below.

Using the compositions according to Compositions 3, 8 and 9 as prepared in Examples 2-4 and a solution of Test Compound in propylene glycol, a transdermal absorption test and a dermal retention test were carried out in vivo.

Three 7-week-old male SD rats were used as an experimental animal. Each animal was immobilized in supine position on a stereotaxic apparatus, and the hair coat was clipped off with an electric clipper. Then, a depilatory cream (Eva Cream, Tokyo Tanabe Pharmaceutical) was applied.

After 10 minutes, the application area was washed with water, and then, the hairs were removed. The rat was returned to the cage and allowed to stay there for 24 hours. The rat was then immobilized again in supine position on the stereotaxic apparaturs, and the unhaired abdominal skin of the rat was marked off at four corners of a 2.5 cm x 4 cm area. Then, 50 mg of the test composition was applied over the above marked-off skin area. At 24 hours after medication, the treated site was washed with methanol, and the skin in the marked-off area was excised. A 1% (w/w) skin homogenate was prepared, and the amount of Test Compound in this homogenate was determined by high-performance liquid chromatography (HPLC).

The transdermal absorption parameters determined for each drug sample are shown in Table 1.

[Table 1 Cutaneous absorption parameters Test sample Cutaneous drug content after 24hr (% of dose) Test Compound in 1.5 propylene glycol Composition 3 8.1 Composition 8 16.0 Composition 9 17.8 In accordance with the present invention, there could be provided a pharmaceutical composition comprising the compound (I) or a salt thereof which is very satisfactory in stability, handling, feeling of use, irritation threshold and/or cutaneous penetration characteristics.

Particularly, it is by now possible to provide a gel composition for external application which is superior in penetrability through the epidermis, which is a barrier to absorption, as well as in the cutaneous retention (particularly in the corium) of the compound (I) or a salt thereof.

Based on the pharmacologic actions of the active ingredient compound (I) or a salt thereof, the pharmaceutical composition according to the present invention is useful for the therapy and prophylaxis of various diseases of the skin, for example, for the therapy and prophylaxis of psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, vascular edema, angitis (vasculitis), cutaneous erythema, cutaneous eosinophilia, lupus erythematosus, and acne. The gel composition, in particular, of the present invention is useful for the therapy and prophylaxis of psoriasis.