WO2004080389A2

WO2004080389A2 - Hydroxyeicosadienamide compounds

Info

Publication number: WO2004080389A2
Application number: PCT/US2004/005222
Authority: WO
Inventors: John R. Falck; Tohru Tanami; Naoya Ono; Tomomichi Chonan; Hitomi Hirano; Noriyuki Miyata; Yoshihisa Toda; Shigeru Okuyama
Original assignee: Taisho Pharmaceutical Co., Ltd.; Board Of Regents, The University Of Texas System
Priority date: 2003-03-07
Filing date: 2004-03-05
Publication date: 2004-09-23
Also published as: WO2004080389A3

Abstract

The present invention provides a hydroxyeicosadienamide compound an excellent inhibitory effect on elastase release, which is represented by Formula (I): (I), wherein n represents an integer of 0 to 5, and R represents an optionally substituted C1-20 alkyl group, an optionally substituted aryl group, -NRXRY, an optionally substituted unsaturated heterocyclic ring, or -(C1-4 alkylene)-Q or Q, wherein Q is an optionally substituted C4-10 bridged hydrocarbon or an optionally substituted aryl group, or a pharmaceutically acceptable salt or hydrate thereof.

Description

HYDROXYEICOSADIENAMIDE COMPOUNDS This application is based on and claims priority from U.S. Provisional Application No. 60/452,562, filed March 7, 2003 which is incorporated herein by reference in its entirety for all purposes. FIELD OF THE INVENTION The present invention relates to novel hydroxy- eicosadienamide compounds or pharmaceutically acceptable salts or hydrates thereof , as well to as an elastase release inhibitor comprising any one of these compounds or salts or hydrates as an active ingredient .

BACKGROUND OF THE INVENTION

Protease released f om neutrophils , a kind of lymphocyte, primarily mediates the digestion of foreign microorganisms (e.g., bacteria) and damaged cells, and it plays an important role in the defense mechanisms of the body. Neutrophil elastase (hereinafter simply referred to as elastase), which is a kind of serine protease, is released in abundance from granules of neutrophils appearing in response to infection and inflammatory diseases. Elastase is an enzyme capable of digesting interstitial proteins such as elastin, collagen, proteoglycan and fibronectin, which are predominantly found in connective tissues of the body, including the lungs, cartilage, vascular walls, skin and ligaments. It has also become clear that elastase acts on other proteins and cells .

In the body, elastase helps maintain the body's homeostasis while being controlled by endogenous inhibitor proteins such as αl-protease inhibitor, α2-maσroglobulin and secretory leukocyte protease inhibitor. However, when overrelease of elastase and decreased levels of the inhibitors at inflammatory sites result in loss of balance between elastase and endogenous inhibitors , the inhibitors fail to control elastase, resulting in damage to the above connective tissues in the body.

Namely, it appears that neutrophil elastase is associated with a wide range of tissue damage, including digestion of elastic fibers found in abundance particularly in lung tissue and blood vessels, because the substrate specificity of neutrophil elastase may be directed not only to elastic fibers mainly composed of elastin, but also to various extracellular matrices. It has also been suggested that in addition to acute inflammatory tissue damage, neutrophil elastase is associated with certain chronic inflammatory diseases (M. Ogawa, "Neutrophil elastase" Herusu Publishing Co. (1992)). Thus, an elastase release inhibitor is expected to be useful as a preparation for preventing or treating such diseases, and an increasing number of studies have been conducted, with various elastase release inhibitors having been reported. However, none of the inhibitors reported thus far exhibits sufficient therapeutic effect . US Patent No. 6,359,158 discloses 16-hydroxy-eicosatetraenoic acid compounds (16-HETE) as an elastase release inhibitor, and teaches that the modifications made to the terminal carboxyl group of 16-HETE result in a molecule having an equivalent or better stability than 16-HETE. However, no compounds disclosed in US Patent No. 6,359,158 have exhibited satisfactory stability over time. Hence, a clinically useful preparation has not yet been developed. SUMMARY OF THE INVENTION

The object of the present invention is to provide novel hydroxyeicosadienamide compounds or pharmaceutically acceptable salts or hydrates thereof, which are stable and show an excellent inhibitory effect on elastase release. As a result of extensive and intensive efforts to attain the above-mentioned object, the inventors of the present invention have found that, against the above description on eicosatetraenoic acid compounds, in the case of hydroxyeicosadien compounds, the terminal sulfonamide group results in much better stability in comparison with the terminal carboxyl group, and they finally completed the invention based on this finding.

Namely, in one aspect, the present invention provides a hydroxyeicosadienamide compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof (hereinafter referred to as "the compound of the present invention" ) :

wherein n represents an integer of 0 to 5 , and R represents a C₁.₂₀ alkyl group which may be substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a cyan© group and a Cι_₅ alkoxy group, an unsaturated heterocyclic ring which may be substituted with one or more members selected from the group consisting of a Cι_₅ alkyl group, a Cι_₅ alkyl group substituted with halogen atom(s), an oxo group, a halogen atom and a hydroxyl group, -NR^XR^Y wherein R^x and R^γ are independently hydrogen, a Cι_₅ alkyl group, a C₁-15 acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an oxo group, or an aryl group which may be substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a Cι_₅ alkyl group, a C₁-5 alkyl group substituted with halogen atom(s), a nitro group, a cyano group, a thiol group, a C₁-5 alkoxy group, a C₂.₅ alkoxycarbonyl group and a carboxyl group, or -(Ci-₄ alkylene)-Q or Q

Q is a C₄-ιo bridged hydrocarbon which may be substituted with one or more members selected from Group A or an aryl group which may be substituted with one or more members selected from Group B, Group A consists of a hydroxyl group, a C1-5 alkyl group, an oxo group, a halogen atom and a Cι_₅ alkoxy group, and Group B consists of a halogen atom, a hydroxyl group, a Cι_ ₅ alkyl group, a Cι_₅ alkyl group substituted with halogen atom(s), a nitro group, a cyano group, a thiol group, a C_λ. ₅ alkoxy group, a C₂-s alkoxycarbonyl group, a carboxyl grou , a phenyl or phenoxy group which may be substituted with one or more members selected from the group consisting of a halogen atom; a hydroxyl group; a Cι_₅ alkyl group; a Cι_₅ alkyl group substituted with halogen atom(s); a nitro group; a cyano group; a thiol group; a Cχ.₅ alkoxy group; a C2-₅ alkoxycarbonyl group; and a carboxyl group, an unsaturated heterocyclic ring which may be substituted with one or more members selected from the group consisting of a Cι_₅ alkyl group; a Cι_₅ alkyl group substituted with halogen atom(s); an oxo group; a halogen atom; and a hydroxyl group, -NR^XR^Y (wherein R^x and R^γ are independently hydrogen, a Cι_₅ alkyl group, a C₁-15 acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an oxo group, or an aryl group which may be substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a Cι_₅ alkyl group, a C₁-₅ alkyl group substituted with halogen atom(s), a nitro group, a cyano group, a thiol group, a Cι_ ₅ alkoxy group, a C₂.₅ alkoxycarbonyl group and a carboxyl group) , and -NHC0NR_AR_B (wherein R& and R_B are independently a hydrogen atom, a Cι.₅ alkyl group or a phenyl group which may be substituted with one or more members selected from the group consisting of a halogen atom; a hydroxyl group; a C₁-₅ alkyl group; a Cι_₅ alkyl group substituted with halogen atom(s); a nitro group; a cyano group; a thiol group; a C%-₅ alkoxy group; a C₂_₅ alkoxycarbonyl group; and a carboxyl group) .

In another aspect, the present invention provides the hydroxyeicosadienamide compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof, wherein n in Formula ( I ) is 3.

In another aspect, the present invention provides the hydroxyeicosadienamide compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof, wherein R represents a Cι.₂₀ alkyl group, an unsaturated heterocyclic ring which may be substituted with one or more members selected from the group consisting of a Cι-₅ alkyl group; a Cι.₅ alkyl group substituted with halogen atom(s); an oxo group; a halogen atom; and a hydroxyl group, -(Cι-₄ alkylene)-Q or Q wherein Q is an aryl group which may be substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a Cι-₅ alkyl group, a Cι_₅ alkyl group substituted with halogen atom(s), a nitro group, a cyano group, a thiol group, a Cι-₅ alkoxy group, a C₂.₅ alkoxycarbonyl group, a carboxyl group, a phenyl or phenoxy group which may be substituted with one or more members selected from the group consisting of a halogen atom; a hydroxyl group; a Cι-5 alkyl group; a Cι_₅ alkyl group substituted with halogen atom(s); a nitro group; a cyano group; a thiol group; a Cι_₅ alkoxy group; a C₂-s alkoaεycarbonyl group and a carboxyl group, -NRR^Y (wherein R^x and R^γ are independently hydrogen, a Cι-₅ alkyl group or a C₁-₁5 acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an 0220 group) , and -NHCONRARB (wherein R& and R_B are independently a hydrogen atom, a Cι_₅ alkyl group or a phenyl group which may be substituted with one or more members selected from the group consisting of a halogen atom; a hydroxyl group; a Cι_₅ alkyl group; a C3.-5 alkyl group substituted with halogen atom(s); a nitro group; a cyano group; a thiol group; a Cχ.₅ alkoxy group; a C₂.₅ alkoxycarbonyl group; and a carboxyl group) .

In another aspect, the present invention provides the hydroxyeicosadienamide compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof, wherein R represents a C₈-i6 alkyl group or an aryl group which is substituted with -NR^XR^Y (wherein R^x is hydrogen, R^γ is a Ci-15 acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an oxo grou . ) . In another aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient , any one of the above compounds of Formula ( I ) or a pharmaceutically acceptable salt or hydrate thereof. In another aspect, the present invention provides an elastase release inhibitor comprising, as an active ingredient , any one of the above compounds of Formula ( I) or a pharmaceutically acceptable salt or hydrate thereof .

In another aspect, the present invention provides a prophylactic or therapeutic preparation for an elastase- associated disease, which comprises, as an active ingredient , any one of the above compounds of Formula ( I ) or a pharmaceutically acceptable salt or hydrate thereof. In another aspect, the present invention provides a method for preventing or treating an elastase-associated disease, which comprises administering to a mammal a prophylactiσally or therapeutically effective amount of any one of the above compounds of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof .

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof.

As used herein, the term "compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof" is intended to encompass its optical isomers including (S), (R) and racemic configurations. Preferably, it has the

(R) configuration.

The definition of R in the above Formula (I) will be explained below.

The term "Cι_₂o alkyl group" refers to a linear, branched or cyclic Cι_₂o alkyl group, including a methyl grou , an ethyl group, a propyl grou , a butyl group , a tert-butyl group, a pentyl group, an isohexyl group, a hexyl group, a heptyl group, an octyl group, a decyl group, a dodecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an eicosyl group, a σyclopropyl group, a cyσlobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The term ™Cι_₅ alkoxy group" refers to a linear or branched Cι_₅ alkoxy group, including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group and a tert-butoxy group.

The term "aryl group" refers to an aromatic hydrocarbon group, but it includes a phenyl group condensed with a partially saturated C₅_₇ hydrocarbon ring. Examples of the "aryl group" include a phenyl group, an indenyl group and a naphthyl group.

The term "Cι_₅ alkyl group" refers to a linear or branched Cι_₅ alkyl group, including a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group and a pentyl group.

The term "Cι-₅ alkyl group substituted with halogen atom(s)" refers to a linear or branched Cι_₅ alkyl group substituted with halogen atom(s), preferably fluorine atom(s) including a trifluoromethyl group, a 2,2,2- trifluoroethyl group and a tetrafluoroethyl group.

The term "C₂_₅ alkoxycarbonyl group'' refers to a linear or branched alkoxycarbonyl group, including a methoxycarbonyl group, an ethoxycarbonyl group, an n- propoxycarbonyl group, an isopropoxycarbonyl group, an n- butoxycarbonyl group, an isobutoxycarbonyl group, a tert- butoxycarbonyl group and a sec-butoxycarfoonyl group. Examples of the "Cι_ι₅ acyl group" as used here include an acetyl group, a butyryl group, a pivaloyl group, a crotonoyl group, a foenzoyl group, a toluoyl group, a diphenylacetyl group, a naphthoyl group and a fluorenecarbonyl grou . Examples of the "unsaturated heterocyclic ring" include a thienyl group, a quinolyl group, an isoquinolyl group, a benzothienyl group, a furyl group, a benzofuranyl group, a pyridyl group, an imidazolyl group, an isothiazolyl group, an isoxazolyl group, a pyrimidyl group, an indolyl group, a pyrazolyl group and a dihydropyrazolyl group (e.g., a 4 ,5-dihydropyrazolyl group).

The term "Cι_₄ alkylene" refers to a linear or branched Cι_₄ alkyl group, including methylene, ethylene, propylene, isopropylene, butylenes and isobutylene. Examples of the "(Cι_4 alkylene)-(an optionally substituted aryl group)" include a benzyl group, a phenethyl group, a phenylpropyl group (e.g., a 2- phenylpropyl group) , a phenylbutyl group (e.g., a 4- phenylbutyl group), a naphthylmethyl group, a naphthylethyl group (e.g., a 2- (1-naphthyl)ethyl group), a methoxybenzyl group (e.g., a 4-methoxybenzyl group), a chlorobenzyl group (e.g., a 3-chlorobenzyl group), an aminobenzyl group (e.g., a 2-aminobenzyl group), a phenoxybenzyl group, an indenylmethyl group (e.g., a 2- indenylmethyl group) and a biphenylmethyl group (e.g., a 4-biphenylmethyl group) .

Examples of the "bridged hydrocarbon" include a bicyclohydrocarbon, such as a bicycloheptyl group (e.g., a biσyclo[2.2. l]heptyl group), a bicyclobutyl group (e.g., a bicyclot 1 • 1.0]butyl group), a bicyclopentyl group, a bicyclooctyl group (e.g., a bicyclot 3.2. l]octyl group), a bicyclononanyl group (e.g., a bicyclo[5.2.0]nonanyl group) , a camphanyl group, a norbornyl group, a bornyl group, an ada antyl group, a pinanyl group, a thujyl group, a caryl group and a camphanyl group. n represents an integer of 0 to 5, preferably 2, 3 or 4 , and more preferably 3. The term "pharmaceutically acceptable salt" refers to, for example, a salt with an alkali metal such as sodium or potassium; a salt with an alkaline earth metal such as calcium or magnesium; or a salt with ammonia, methylamine, dimethylamine, diethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, triethanolamine, monomethylmonoethanolamine, tromethamine, lysine, ornithine, piperazine, benzathine, 3-aminopyridine, procaine, choline, 2-amino-4-methylpyridine, tris(hydroxymethyl)aminomethane or ethylenediamine; tetraalkylammonium salt.

Typical examples of the compound of Formula (I) according to the present invention will be presented below. Compound n R

1 1 nButyl R

2 1 nNonadecyl R

3 1 Benzyl

4 1 4-Bromo-6-methylphenyl R

5 2 Methyl R

6 2 nButyl S

7 2 Phenyl R

8 2 Methylamino R

9 2 p-Tolyl R

10 2 m-Chlorophenyl S

11 2 2,4,6-Trichlorophenyl R

12 2 Diethylamino S

13 3 Methyl R

14 3 Ethyl S

15 3 nButyl R

16 3 tBirtyl R

17 3 iHexyl S

18 3 nOctyl R

19 3 nDecyl R

20 3 nDodecyl R

21 3 nHexadecyl R

22 3 nEicosyl S

23 3 Phenyl R

24 3 o-Tolyl R

25 3 p-Tolyl R

26 3 Mesityl R

27 3 m-Cumenyl S

28 3 2,4,6-Tri (iPropyl)phenyl R

29 3 o-Chlorophenyl R 30 3 m-Chlorophenyl R

31 3 p-Chlorophenyl R

32 3 p-Bromophenyl R

33 3 p-lodophenyl R

34 3 4-Chloro-2-fluorophenyl S

35 3 2,4,5-Trichlorophenyl R

36 3 2,4,6-Trichlorophenyl S

37 3 4-Chloro-2-trifluoromelhylphenyl R

38 3 4-Bromo-6-methylphenyl S

39 3 4-Chloro-2,6-dimethylphenyl R

40 3 p-Nitrophenyl R

41 3 2,4-Dichloro-5-methoxycarbonylphenyl R

42 3 4-Biphenyl R

43 3 2-Naphthyl R

44 3 5-Dimethylamino-1 -naphthyl R

45 3 8-Quinolyl R

46 3 2-(1 -Naphtyl)ethyl R

47 3 4-Bromo-2,5-dichloro-3-thienyl R

48 3 3-Benzo[b]thienyl R

49 3 Dimethylamino R

50 3 4-(Diphenylacetamino)phenyl R

51 3 4-[(9-Oxo-9H-fluorene-4-carbonyl)amino]phenyl R

52 3 3-(3-Methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)phenyl R

53 3 3-[3-(3,4-Dichlorophenyl)ureido]phenyl R

54 3 4-[3-(3,4-Dichlorophenyl)ureido]phenyl R

UU 3 4-(2,4-Dichlorobenzoylamino)phenyl R

56 3 7,7-Dimethyl-2-oxobicyclo[2.2.1]hept-1-ylmethyl R

57 3 4-Aminophenyl R

58 4 nOctyl S

59 4 nHeptadecyl R 60 4 o-Tolyl R

61 4 p-Chlorophenyl S

62 4 4-Chloro-2-fluorophenyl R

63 4 2_!6-Dichloro-4-methyIphenyl

64 4 2-Biphenyl S

65 4 Dimethylamino R

66 4 4-(Diphenylacetamido)phenyl R

67 5 Ethyl R

68 5 nHeptadecyl R

69 5 2,4,6-Trichlorophenyl S

70 5 4-Bromo-6-methylphenyl R

Configuration of the 16-carbon atom with the hydroxyl group attached

Preferred examples of the compound according to the present invention are as follows: octane-1-sulfoniσ acid [ (R) -(5Z , 14Z) -16-hydroxy-eicosa- 5,14-dienoyl]amide (Compound 18);

Decane-1-sulfonic aicd [ (R) - (5Z, 14Z) -16-hydroxyeicosa- 5,14-dienoyl]amide (Compound 19) dodecane-1-sulfonic acid [ (R) - (5Z, 14Z) -16-hydroxyeicosa- 5, 14-dienoyl]amide (Compound 20); hexadecane-1-sulfonic acid [ (R)-(5Z,14Z) -16-hydroxy- eicosa-5, 14-dienoyl]amide (Compound 21); N- [ (R) - ( 5Z , 14Z) - 16-hydroxyeicosa-5 , 14-dienoyl] -4- methylbensenesulfonamide (Compound 25); 3-chloro-_W- [ (R)- (5Z, 14Z) -16-hydroxyeicosa-5, 14- dienoylJbenzenesulfonamide (Compound 30); 2 , 4 , 5-trichloro-JV- [ (R) - ( 5Z , 14Z ) -16-hydroxyeicosa-5 , 14- dienoyl]benzenesulfonamide (Compound 35); naphthalene-2-sulfonic acid [(R)-(5Z,14Z)-16- hydroxyeicosa-5 , 14-dienoyl]amide (Compound 43 ) ; 2-(naphthalen-l-yl)ethanesulfonic acid [ (R)-(5Z,14Z) -16- hydroxyeicosa-5, 14-dienoyl3amide (Compound 46);

JV-[4-{(R)~16-hydroxyeicosa-5 , 14-dienoylsulfamoyl}phenyl3 - 2,2-diphenylacetamide (Compound 50);

9-oxo-9H-fluorene-4-σarboxylic acid [4-{ (R) - (5Z, 14Z) -16- hydroxyeicosa-5 , 14-dienoylsulfamoyl}phenyl]amide (Compound 51); and

4~amino-N-[ (R) - (5Z, 14Z) -16-hydroxyeicosa-5, 14- dienoyl]benzenesulfonamide (Compound 57).

The compounds of the present invention which are in a solid state at room temperature are preferable in formulating a preparation. Examples of such compounds include the hydroxyeicosadienamide compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof, wherein R represents a C₈-i6 alkyl group or an aryl group which is substituted with -NR^XR^Y (wherein R^x is hydrogen, R^γ is a Cχ-₁₅ acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an oxo group. ) .

The compound of Formula (I) can be prepared from the compound described in US Patent No. 6,359,158, the disclosure of which is hereby incorporated by reference in its entirety, or a compound of Formula (II) prepared according to this patent. For example, the compound of Formula (I) can be prepared as summarized in the following reaction scheme :

(II) (i)

(wherein R and n are as defined above) .

In an appropriate organic solvent (e.g., dichloromethane, tetrahydrofuran, dimethylformamide, hexamethylphosphoric triamide, _N-methylpyrrolidinone) , if necessary, the compound of Formula (II) is mixed with an activating agent (e.g., diisopropylcarbodiimide, dicyclohexylcarbodiimide, 1-ethyl-3- (3- dimethylaminopropyl)carbodiimide, carbonyldiimidazole, benzotriazol-1-yloxy-t is(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy- tris(pyrrolidino)phosphonium hexafluorophosphate, ethyl chloroformate, pentafluorophenyl trifluoroacetate) and reacted at a temperature ranging from 0°C to the reflux point of the solvent, preferably 0°C to room temperature, and if necessary, in the presence of W-hydroxysuccinimide or 1-hydroxybenzotriazole. The reaction mixture is then reacted with a compound of Formula (III) at a temperature ranging from 0°C to the reflux point of the solvent, preferably 0°C to room temperature, and if necessary, in the presence of a base (e.g., pyridine, triethyla ine, diisopropylethylamine, 4- (dimethylamino)pyridine, 1,8- diazabicyclo[5.4.0]undec-7-ene) to give the compound of Formula (I) . The compound of the present invention may be formulated into a pharmaceutical composition in combination with carriers, excipients and other additives commonly used in formulation. The compound of the present invention is administered systemically or topically by oral, parenteral or inhalation (e.g., intrarectal, subcutaneous, intramuscular, intravenous, transdermal) route. For example, it may be administered orally in any commonly available dosage form such as tablets, powders, granules, micronized dusts, capsules, aerosols, solutions, emulsions or suspensions. For an intravenous administration, it may be formulated into an aqueous or non-aqueous solution, an emulsion, a suspension, a reconstitutable solid preparation which is dissolved in an injection medium immediately before use, etc. Alternatively, the compound of the present invention may be formulated by forming an inclusion compound with α- , β- or γ-cyclodextrin or any modified cyclodextrin . Further, such an inclusion compound may be injected in a dosage form of aqueous or non-aqueous solution, emulsion, suspension, etc. Although the dose of the compound will vary depending on, e.g., the age and body weight of a patient, the daily dose for adults is 1 ng/kg to 1000 mg/kg in single or divided doses. The compound of the present invention has an excellent inhibitory effect on elastase release, as shown in the Test Example below.

The compound of the present invention is therefore effective in preventing or treating elastase-associated pathological conditions, including both acute inflammatory tissue damage and certain chronic inflammatory diseases. The compound of the present invention is widely available for prevention or treatment of the following elastase-associated diseases or pathological conditions: pulmonary emphysema, adult respiratory distress syndrome, pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, cystic pulmonary fibrosis), pneumonia (e.g., chronic interstitial pneumonia), bronchitis (e.g., chronic bronchitis, diffuse panbronchiolitis) , (chronic) respiratory infections, bronσhiectasia, asthma, pancreatitis, nephritis, multiple organ failure (e.g., liver failure), arthrosis (e.g., chronic rheumatoid arthritis, arthrosσlerosis , osteoarthritis) , psoriasis, periodontitis , arteriosclerosis (e.g., atherosclerosis), postoperative complications (e.g., graft rejection in organ transplantation), premature rupture of the membrane, hydroa, shock, diseases associated with abnormal coagulofibrinolysis (e.g., sepsis, septic shock, leukemia), systemic lupus erythematosus , disseminated intravascular coagulation, ischemic reperfusion injury (e.g., that observed in brain infarction, heart diseases or kidney diseases, such as myocardial infarction), corneal cicatrization, spondylitis, gastric muσosal lesion (e.g., acute gastric mucosal lesion) , and inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease, intestinal Behσet's disease). EXAMPLES

The present invention will be further described in the following Examples and Test Examples. However, the present invention is not to be interpreted restrictedly because of these descriptions .

Example 1

N- [ (R)-(5Z,14Z)-16-Hydroxyeicosa-5, 14-dienoyl] -2-methyl- benzenesulfonamide (Compound 24)

To a solution of (R) -16-hydroxyeicosa-5, 14-dienoic acid (200 mg, 0.616 mmol) in methylene chloride (10 mL) , carbonyldiimidazole (120 mg, 0.74 mmol) was added at room temperature and further stirred at the same temperature for 30 minutes. To this solution, o-toluenesulfonamide (116 mg, 0.678 mmol) and 1, 8-diazabicyclo[5. .0]undeσ-7- ene (103 mg, 0.678 mmol) were added at room temperature and further stirred at the same temperature for 17 hours. The reaction mixture was neutralized with aqueous hydrochloric acid (3M, 3 L) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate and then concentrated. The resulting crude product was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate (10-33%)) to give the titled compound (172 mg).

300 MHz)ppm: 0.91(t, J=6.8Hz, 3H) , 1.19-1.71(m, 18H), 1.90-2.20(m, 6H) , 2.27(t, J=7.4Hz, 2H) , 2.67(s, 3H), 4.40-4.50(m, 1H) , 5.16-5.28(m, 1H) , 5.32- 5.44(m, 2H), 5.45-5.56(m, 1H) , 7.29-7.43(m, 2H) , 7.48- 7.56(m, 1H), 8.13-8.19(m, 1H) , 8.57(br s, 1H) IR(Neat): 3501, 3246, 3065, 3006, 2928, 2855, 1722, 1456, 1384, 1342, 1280, 1172, 1127, 1064, 845, 759, 708, 691, 592, 543, 495 cm^"1

Example 2 N- [ (R) - ( 5Z , 14Z) -16-Hydroxyeicosa-5 , 14-dienoyl] - -methyl- benzenesulfonamide (Compound 25)

Using p-toluenesulfonamide instead of o-toluene- sulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

^- MRζCDCls, 300 MHz)ppm: 0.90(t, J=6.9Hz, 3H) , 1.19-1.74(m, 18H) , 1.88-2.18(m, 6H) , 2.23(t, J=7.5Hz, 2H) , 2.44(s, 3H), 4.40-4.50(m, 1H) , 5.16-5.27(m, 1H) , 5.32- 5.42(m, 2H), 5.45-5.55(m, 1H) , 7.30-7.37(m, 2H) , 7.91- 7.97(m, 2H) , 8.42(br s, 1H)

IR(Neat): 3502, 3247, 3006, 2927, 2855, 1718, 1598, 1456, 1344, 1308, 1188, 1170, 1089, 1020, 845, 814, 729, 705, 662, 552 cm^"1

Example 3

4-Chloro-jM- [ (R) - ( 5Z , 14Z) -1 -hydroxyeicosa-5 , 14-dienoyl] - bensenesulfonamide (Compound 31)

Using 4-chlorobenzenesulfonamide instead of o- toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz)ppm: 0.91(t, J=7.0Hs, 3H) , 1.19-1.73(m, 18H), 1.87-2.17(m, 6H) , 2.23(t, J=7.5Hz, 2H) ,

4.40-4.50(m, 1H) , 5.17-5.29(m, 1H) , 5.31-5.43(m, 2H) ,

5.45-5.55(m, 1H) , 7.46-7.54(m, 2H) , 7.96-8.03(m, 2H) ,

8.54(br s, 1H)

IR(Neat): 3502, 3247, 3006, 2928, 2855, 2360, 1718, 1586, 1456, 1398, 1349, 1280, 1172, 1134, 1092, 1015, 829,

754, 620, 543, 481 cm^"1

Example 4

2-Chloro-iV-[ (R)-(5Z,14Z )-16-hydroxyeicosa-5, 14-dienoyl]- benzenesulfonamide (Compound 29) Using 2-chlorobenzenesulfonamide instead of o- toluenesulfonamide in Example 1 , substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz)ppm: 0.90(t, J=6.9Hz, 3H) , 1.19-1.73(m, 18H) , 1.86-2.23(m, 6H) , 2.30(t, J=7.5Hz, 2H) ,

4.38-4.50(m, 1H) , 5.17-5.30(m, 1H) , 5.31-5.56(m, 3H) ,

7.44-7.61(m, 3H) , 8.23-8.32(m, 1H) , 8.80(br s, 1H)

IR(Neat): 3006, 2928, 2855, 1723, 1573, 1456, 1350,

1286, 1255, 1177, 1130, 1110, 1044, 849, 760, 667, 582, 546, 504, 471 cm^"1

Example 5

4-Bromo-iV- [ (R) - ( 5Z , 14Z) -16-hydroxyeicosa-5 , 14-dienoyl] - benzenesulfonamide (Compound 32)

Using 4-bromobenzenesulfonamide instead of o- toluene-sulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz)pprti: 0.9l(t, J=6.8Hz, 3H) ,

1.19-1.74(m, 18H) , 1.87-2.18(m, 6H) , 2.23(t, J=7.4Hz, 2H) ,

4.39-4.50(m, 1H) , 5.17-5.28(m, 1H) , 5.32-5.44(m, 2H) ,

5.46-5.56(m, 1H) , 7.62-7.73(m, 2H) , 7.87-7.98(m, 2H) , 8.62(br s, 1H)

IR(Neat): 3248, 3006, 2927, 2855, 1718, 1576, 1467, 1391, 1350, 1278, 1173, 1088, 1069, 1012, 845, 740, 702, 606, 542, 421 cm^"1

Example 6

3-Chloro-_N^r- [ (R) - ( 5Z , 14Z) -16-hydroxyeicosa-5 , 14-dienoyl] - benzenesulfonamide (Compound 30)

Using 3-σhlorobenzenesulfonamide instead of o- toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz)ppm: 0.91(t, J=6.7Hz, 3H) ,

1.18-1.72(m, 18H) , 1.87-2.20(m, 6H) , 2.25(t, J=7.5Hz, 2H) ,

4.38-4.52(m, 1H) , 5.18-5.29(m, 1H) , 5.32-5.44(m, 2H) , 5.46-5.56(m, 1H) , 7.45-7.54(m, 1H) , 7.57-7.65(m, 1H) ,

7.94-8.05(m, 2H), 8.70(br s, 1H)

IR(Neat): 3247, 3007, 2928, 2855, 1720, 1581, 1461, 1351, 1299, 1176, 1108, 1080, 999, 849, 789, 670, 581, 496 cm

Example 7

5-Dimethylaminonaphthalene-l-sulfonic acid [(R)-(5Z,14Z)- 1 -hydroxyeicosa-5 , 1 -dienoyl3amide (Compound 44)

Using 5- imethylamino-1-naphthalenesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound. ^Η-NMRfCDCls, 300 MHz)ppm: 0.90(t, J=6.8Hz, 3H) , 1.16-1.74(m, 18H) , 1.8l-2.27(m, 8H) , 2.89(s, 6H) , 4.40- 4.52(m, 1H), 5.09-5.20(m, 1H) , 5.25-5.56(m, 3H) , 7.15- 7.23(m, 1H), 7.52-7.64(m, 2H) , 8.17-8.25(m, 1H) , 8.46- 8.53(m, 1H) , 8.57-8.64(m, 1H) , 8.71(br s, 1H) IR(Neat): 3247, 2928, 2855, 1723, 1576, 1456, 1408, 1343, 1234, 1203, 1168, 1146, 1061, 947, 846, 790, 625, 570, 483 cm^"1

Example 8 Naphthalene-2-sulfonic acid [ (R) - (5Z, 14Z) -16- hydroxyeicosa-5, 14-dienoyl] amide (Compound 43)

Using 2-naphthalenesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compoun .

^- MRCCDCla, 300 MHz)ppm: 0.90(t, J=6.9Hz, 3H) , 1.14-1.69(m, 18H) , 1.81-2.17(m, 6H) , 2.25(t, J=7.5Hz, 2H) , 4.39-4.50(m, 1H) , 5.13-5.25(m, 1H) , 5.26-5.43(m, 2H) , 5.44-5.55(m, IH), 7.58-7.72(m, 2H) , 7.88-8.05(m, 4H) , 8.55(br s, IH) , 8.64-8.70(m, IH)

IR(Neat): 3246, 3006, 2927, 2855, 1719, 1592, 1456, 1345, 1270, 1170, 1130, 1074, 864, 817, 748, 658, 640, 617, 550, 476 cm^"1

Example 9

N- [ (R) - ( 5Z , 14Z) -16-Hydroxyeicosa-5 , 14-dienoyl] -4-nitro- benzenesulfonamide (Compound 40) Using 4-nitrobenzenesulfonamide instead of o- toluene-sulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz) δppm: 0.91(t, J=6.9Hz, 3H) , 1.21-1.43(m, 10H) , 1.54-1.69(m, 8H) , 1.88-2.20(m, 6H) ,

2.24(t, J=7.5Hz, 2H), 4.40-4.52(m, IH) , 5.16-5.57(m, 4H) , 8.24-8.31(m, 2H) , 8.35-8.41(m, 2H) , 8.83-8.93(m, IH)

IR(Neat): 3524, 3271, 3006, 2928, 2855, 1719, 1608,

1534, 1458, 1350, 1314, 1176, 1122, 1088, 1014, 845, 737, 684, 611, 542, 462 cm^"1

Example 10

4-Amino-iV-[ (R)-(5Z,14Z) -16-hydroxyeicosa-5, 14-dienoyl] - benzenesulfonamide (Compound 57) Using -aminobenzenesulfonamide instead of o- toluene-sulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound. ¹H-NMR(CDC1₃, 300 MHz) δppm: 0.91(t, J=6.8Hz, 3H) ,

1.16-1.72(m, 18H) , 1.88-2. I7(m, 6H) , 2.22(t, J=7.5Hz, 2H) ,

4.38-4.49(m, IH) , 5.17-5.54(m, 4H) , 6.62-6.17(m, 2H) , 7.77-7.85(m, 2H) , 8.21(br s, IH)

IR(Neat): 3479, 3379, 3233, 3006, 2928, 2855, 1707,

1630, 1596, 1505, 1456, 1384, 1323, 1190, 1160, 1088, 832, ', 552 cm^"1

Example 11 2 , 4 , 5-Triσhloro- - [ (R) - ( 5Z , 14Z) -16-hydroxyeicosa-5 , 14- dienoyl]benzenesulfonamide (Compound 35)

Using 2,4,5-trichlorobenzenesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz) δppm: 0.91(t, J=6.9Hz, 3H) , 1.21-1.71(m, 18H), 1.89-2.18(m, 6H) , 2.29(t, J=7.5Hz, 2H) , 4.40-4.50(m, IH) , 5.15-5.57(m, 4H) , 7.62(s, IH) , 8.35(s, IH) , 8.85(br s, IH) IR(Neat): 3006, 2928, 2855, 1722, 1570, 1540, 1440,

1358, 1177, 1111, 1068, 893, 688, 654, 622, 588, 536, 510, 480 cm^"1

Example 12 2 , 4-Dichloro-i- [4-{ (R) - (5Z , 14Z) -16-hydroxyeicosa-5 , 14- dienoylsulfamoyl}phenyl]benzamide (Compound 55)

Using 2 , 4-dichloro-l- ( -sulfamoylphenyl)benzamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz) δppm: 0.90(t, J=6.8Hz, 3H) ,

1.17-1.69(m, 18H), 1.88-2.18(m, 6H) , 2.23(t, J=7.4Hz, 2H) , 4.37-4.47(m, IH) , 5.16-5.5 (m, 4H) , 7.35-7.42(m, IH) ,

7.46-7.51(m, IH) , 7.68-7.74(m, IH) , 7.77-7.87(m, 2H) ,

8.00-8.09(m, 2H) , 8.40(br s, IH) , 8.66(br s, IH)

IR(Neat): 3294, 3011, 2929, 2856, 1696, 1668, 1594, 1537, 1497, 1466, 1403, 1352, 1328, 1281, 1257, 1216, 1167, 1106, 903, 841, 757, 686, 667, 587, 568 cm^"1

Example 13 -[(R)-(5Z,14Z) -16-Hydroxyeicosa-5 , 14-dienoyl] -2 , 4 , 6- triisopropylbenzenesulfonamide (Compound 28) Using 2 , 4 , 6-triisopropylbenzenesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

300 MHz) δppm: 0.90(t, J=6.9Hz, 3H) , 1.17-1.70(m, 36H) , 1.90-2.16(m, 6H) , 2.24(t, J=7.7Hz, 2H) ,

2.82-2.98(m, IH) , 4.10-4.26(m, 2H) , 4.39-4.49(m, IH) , 5.17-5.56(m, 4H) , 7.18(s, 2H) , 8.38(br s, IH)

IR(Neat): 3233, 2958, 2929, 2857, 1722, 1600, 1567,

1462, 1384, 1364, 1331, 1168, 1120, 1060, 1038, 940, 882, 849, 730, 661, 557 cm^"1

Example 14

4-Biphenylsulfonic acid [ (R) - ( 5Z, 14Z) -16-hydroxyeicosa- 5, 14-dienoyl] amide (Compound 42)

Using 4-biphenylsulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compoun .

¹H-NMR(CDC1₃, 300 MHz)ppm: 0.9l(t, J=6.6Hz, 3H) ,

1.19-1.73(m, 18H), 1.88-2.20(m, 6H) , 2.26(t, J=7.4Hz, 2H) ,

4.39-4.51(m, IH) , 5.17-5.30(m, IH) , 5.31-5.43(m, 2H) ,

5.44-5.55(m, IH) , 7.39-7.54(m, 3H) , 7.57-7.66(m, 2H) , 7.70-7.80(m, 2H) , 8.09-8.18(m, 2H) , 8.40-8.60(m, IH)

IR(Neat): 3247, 3006, 2927, 2855, 1719, 1595, 1565, 1465, 1345, 1171, 1092, 1008, 842, 763, 722, 697, 671, 589, 528 cm^"1

Example 15

N~ [ (R) -(5Z,14Z) -16-Hydroxyeicosa- 5, 14-dienoyl] -4-iodo- benzenesulfonamide (Compound 33)

Using 4-iodobenzenesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

^-NMRfCDCls, 300 MHz)ppm: 0.91(t, J=6.8Hz, 3H) , 1.19-1.74(m, 18H) , 1.86-2.18(m, 6H) , 2.23(t, J=7.5Hz, 2H) , 4.39-4.49(m, IH), 5.17-5.28(m, IH) , 5.32-5.44(m, 2H) , 5.45-5.55(m, IH) , 7.72-7.80(m, 2H) , 7.86-7.94(m, 2H)

IR(Neat): 3005, 2927, 2854, 1712, 1570, 1456, 1386, 1348, 1273, 1172, 1086, 1055, 1007, 845, 818, 731, 601,

542 cm^" Example 16

2- (Naphthalen-l-yl)ethanesulfonic acid [ (R) - (5Z, 14Z) -16- hydroxyeicosa-5, 1 -dienoyl] amide (Compound 46) Using 2- (naphthalen-l-yl)ethanesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

^-NMRfCDCls, 300 MHz)ppm: 0.90(t, J=6.8Hz, 3H) , 1.21-1.67(m, 18H) , 1.93-2.17(m, 8H) , 3.57-3.66(m, 2H) , 3.82-3.91(m, 2H) , 4.39-4.49(m, IH) , 5.20-5.30(m, IH) , 5.33-5.34(m, 3H) , 7.36-7.46(m, 2H) , 7.48-7.62(m, 2H) , 7.76-7.82(m, IH) , 7.85-8.02(m, 2H)

IR(Neat): 3247, 3006, 2927, 2855, 1712, 1599, 1511, 1458, 1343, 1267, 1237, 1131, 1003, 850, 780, 642, 603, 542, 508, 490 cm^-1

Example 17

W- [ (R) - (5Z, 14Z) -16-Hydroxyeicosa-5 , 14-dienoyl]methane- sulfonamide (Compound 13)

Using methanesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound. ¹H-NMR(CDC1₃, 300 MHz)δppm: 0. 1 ( t , J=6.8Hz, 3H) , 1.20-1.80(m, 18H), 1.93-2.20(m, 6H) , 2.32(t, J=7.5Hz, 2H) , 3.29(s, 3H), 4.37-4.50(m, IH) , 5.24-5.55(m, 4H) , 8.26(br s, IH) IR(Neat): 3400, 3010, 2929, 2854, 1708, 1654, 1456,

1407, 1384, 1338, 1122, 1022, 974, 857, 751, 520, 418 cm^"1

Example 18 Dodecane-l-sulfonic acid [ (R) - (5Z , 14Z) -16-hydroxyeicosa- 5, 14-dienoyl] amide (Compound 20)

Using 1-dodeσanesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

^-NMRfCDC^, 300 MHz)ppm: 0.88(t, J=6.8Hz, 3H) ,

0.91(t, J=6.8Hz, 3H), 1.17-1.89(m, 38H) , 1.95-2.20(m, 6H) ,

2.31(t, J=7.5Hz, 2H), 3.38-3.47(m, 2H) , 4.39-4.49(m, IH) ,

5.24-5.55(m, 4H) , 8.05-8.35(m, IH) IR(KBr): 3304, 3008, 2921, 2852, 1717, 1694, 1444,

1408, 1380, 1340, 1326, 1226, 1165, 1117, 1038, 887, 769, 719, 647, 562, 515 cm^"1

Example 19 Decane-1-sulfonic aicd [ (R) - (5Z, 14Z) -16-hydroxyeicosa- 5, 14-dienoyl]amide (Compound 19)

Using 1-decanesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

^-NMR CDCla, 300 MHz)ppm: 0.88(t, J=6.9Hz, 3H) , 0.90(t, J=6.9Hz, 3H), 1.19-1.89(m, 34H) , 1.95-2.17 (m, 6H) , 2.32(t, J=7.5Hz, 2H), 3.37-3.48(m, 2H) , 4.38-4.49(m, IH) , 5 . 24- 5 . 55 (m, 4H) , 8 . 28 (br s , IH)

IR(KBr): 3299, 3008, 2954, 2928, 2850, 1718, 1695, 1445, 1407, 1380, 1340, 1326, 1236, 1202, 1165, 1115, 1038, 883, 769, 720, 647, 604, 562, 516 cm^"1

Example 20

Octane- 1-sulfonic acid [ (R) - ( 52, 14Z) -16-hydroxyeicosa-

5, 14-dienoyl] amide (Compound 18)

Using 1-octanesulfonamide instead of o-toluene- sulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz) δppm: 0.88(t, J=6.8Hz, 3H) , 0.90(t, J=6.8Hz, 3H), 1.18-1.87(m, 30H) , 1.95-2.18(m, 6H) , 2.32(t, J=7.5Hz, 2H) , 3.38-3.47(m, 2H) , 4.44(dt, J=8.1, 6.7Hz, IH), 5.24-5.55(m, 4H) , 8.20(br s, IH)

IR(KBr) : 3275, 3007, 2945, 2920, 2873, 2852, 1695, 1458, 1414, 1377, 1339, 1327, 1305, 1288, 1250, 1177, 1134, 1059, 1030, 1015, 958, 866, 772, 723, 604, 532, 482, 420 cm^"1

Example 21

Hexadecane-1-sulfonic acid [ (R) - (5Z, 14Z) -16-hydroxyeicosa- 5, 1 -dienoyl]amide (Compound 21) Using 1-hexadecanesulfonamide instead of o-toluenesulfonamide in Example 1 , substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

300 MHz) δppm: 0.88(t, J=6.8Hz, 3H) , 0.90(t, J=6.8Hz, 3H), 1.00-1.87(m, 46H) , 1.92-2.18(m, 6H) , 2.31(t, J=7.5Hz, 2H), 3.36-3. 6 (m, 2H) , 4.44(dt, J=8.4, 6.7Hz, IH), 5.24-5.55(m, 4H) , 8.18(br S, IH) IR(KBr): 3303, 3009, 2959, 2920, 2875, 2851, 1716, 1472, 1445, 1435, 1409, 1380, 1340, 1327, 1165, 1118, 1039, 884, 769, 718, 647, 562, 513 cm^"1

Example 22 2-Methyl-propane-2-sulfonic acid [ (R) -(5Z,14Z) -16-hydroxyeicosa-5, 14-dienoyl] amide (Compound 16)

Using 2-methyl-2-propanesulfonamide instead of o- toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

^- RfCDCls, 300 MHz)ppm: 0.90(t, J=6.8Hz, 3H) , 1.21-1.79(m, 27H) , 1.95-2.15(m, 6H) , 2.41(t, J=7.5Hz, 2H) , 4.38-4.48(m, IH) , 5.24-5.54(m, 4H) , 7.60(br s, IH)

IR(Neat): 3497, 3247, 3004, 2928, 2855, 1718, 1459, 1372, 1332, 1238, 1202, 1132, 1020, 837, 730, 660, 533, 511 cm^"1

Example 23

Butane-1-sulfonic acid [ (R)-(5Z,14Z) -16-hydroxyeicosa- 5, 1 -dienoyl3amide (Compound 15)

Using 1-butanesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compoun .

¹H-NMR(CDC1₃, 300 MHz) δppm: 0.91(t, J=7.3Hz, 3H) , 0.96(t, J=7.4Hs, 3H), 1.22-1.86(m, 22H) , 1.94-2.18(m, 6H) ,

2.32(t, J=7.5Hz, 2H), 3.39-3.48 (m, 2H) , 4.39-4.49(m, IH) , 5.24-5.56(m, 4H) , 8.21(br s, IH)

IR(Neat): 3498, 3246, 3006, 2929, 2856, 1712, 1457, 1380, 1338, 1241, 1132, 1005, 850, 731, 561, 507 cm^"1

Example 24 N-{ (R) - ( 5Z , 14Z) -16-Hydroxyeicosa-5 , 14-dienoyl}benzene- sulfonamide (Compound 23)

Using benzenesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz)ppm: 0.90(t, J=6.8Hz, 3H) , 1.16-1.78(m, 18H) , 1.86-2.20(m, 6H) , 2.25(t, J=7.4Hz, 2H) , 4.39-4.51(m, IH) , 5.15-5.56(m, 4H) , 7.50-7.69(m, 3H) , 8.03-8.11(m, 2H) , 8.60-9.10(br, IH) IR(Neat): 3502, 3247, 3068, 3006, 2928, 2855, 1722,

1586, 1451, 1348, 1173, 1135, 1089, 1001, 844, 756, 720, 687, 580, 543 cm^"1

Example 25 if- [4-{ (R) -16-Hydroxyeicosa-5, 1 -dienoylsulfamoylj-phenyl] - 2,2-diphenylace mide (Compound 50)

Using 2 , 2-diphenyl-N- ( -sulfa oylphenyl) acetamide instead of o-toluenesul onamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

^^•H-NMRfCDCls, 300 MHs) δppm: 0.90(t, J=6.7Hz, 3H) ,

1.19-1.68(m, 18H), 1.88-2.14(m, 6H) , 2.19(t, J=7.5Hz, 2H) , 4.44(dt, J=9.2, 6.5Hz, IH) , 5.11(s, IH) , 5.16-5.27(m, IH) ,

5.32-5.43(m, 2H), 5.44-5.54 (m, IH) , 7.27-7.42(m, 9H) ,

7.60-7.68(m, 3H) , 7.94-8.00(m, 2H) , 8.40(br s, IH)

IR(KBr) : 3438, 3319, 3282, 3204, 3008, 2925, 2853, 1678, 1609, 1595, 1538, 1496, 1455, 1404, 1354, 1338, 1319, 1276, 1253, 1190, 1167, 1145, 1093, 1032, 1014, 1003, 973, 887, 845, 744, 702, 624, 574, 555 cm^"1

Example 26

2,4-Dichloro-5-[ (R) -( 5Z , 14Z) -16-hydroxyeicosa-5, 14- dienoylsulfamoyl Jbenzoic acid methyl ester (Compound 41)

Using 2, 4-diσhloro-5-sulfamoylbenzoic acid methyl ester instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound. ¹H-NMR(CDC1₃, 300 MHz)ppm: 0.91(t, J=6.8Hz, 3H) , 1.22-1.71(m, 18H) , 1.91-2.20(m, 6H) , 2.29(t, J=7.5Hz, 2H) , 3.96(s, 3H), 4.41-4.51(m, IH) , 5.18-5.30(m, IH) , 5.33- 5.56(m, 3H), 7.65(s, IH) , 8.76(s, IH) , 8.90(br s, IH)

IR(Neat): 3007, 2928, 2855, 1725, 1584, 1542, 1435, 1354, 1290, 1257, 1175, 1117, 1078, 899, 780, 686, 619, 531, 485 cm^"1

Example 27 N- {(R)-(5Z, 14Z)- 16-Hydroxyeicosa-5, 14-dienoyl} -3- ( 3- methyl-5-oxo-4, 5-dihydropyrazol-l-yl)benzenesulfonamide (Compound 52)

Using 3- (3-methyl-5-oxo-4, 5-dihydropyrazol-l-yl) - benzenesulfonamide instead of o-toluenesulfonamide in Example 1 , substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz)ppm: 0.90(t, J=6.8Hz, 3H) ,

1.19-1.74(m, 18H) , 1.86-2.18(m, 6H) , 2.22(s, 3H) , 2.26(t, J=7.5Hz, 2H), 3.44-3.49(m, 2H) , 4.35-4.52(m, IH) , 5.16-

5.55(m, 4H), 7.51-7.60(m, IH) , 7.84-7.91(m, IH) , 8.24-

8.31(m, IH) , 8.39(br s, IH) , 8.50-8.55(m, IH)

IR(Neat): 3436, 3233, 3006, 2929, 2855, 1720, 1596, 1482, 1356, 1174, 1087, 1002, 848, 792, 756, 682, 587, 510 cm^"1

Example 28

4- {3- (3, 4-Dichlorophenyl)ureido}-Jy-{(R)-(5Z,14Z) -16- hydroxyeicosa-5, 14-dienoyl}benzenesulfonamide (Compound 54)

Using 4-{3-(3,4-dichlorophenyl)ureidobenzenesulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound. ¹H-NMR(DMSO-d₆, 300 MHz)ppm: 0.84(t, J=6.7Hs, 3H) , 1.09-1.50(m, 18H) , 1.79-2.04(m, 6H) , 2.17(t, J=7.1Hz, 2H) , 4.11-4.25(m, IH) , 4.46(d, J=4.5Hz, IH) , 5.14-5.36(m, 4H) , 7.31-7.38(m, IH) , 7.51-7.69(m, 3H) , 7.78-7.91(m, 3H) , 9 . 14 ( s , IH) , 9 . 33 ( s , IH ) , 11 . 90 ( br s , IH )

IR(Neat): 3468, 3339, 3008, 2928, 2855, 1686, 1666, 1588, 1536, 1478, 1406, 1384, 1344, 1305, 1265, 1226, 1165, 1090, 837, 734, 679, 657, 574 cm^"1

Example 29

3-{3- (3, 4-Dichlorophenyl)ureido}-I-{(R)-(5Z,14Z) -16- hydroxyeicosa-5 , 14-dienoyl}benzenesulfonamide (Compound 53) Using 3-{3- (3, 4-dichlorophenyl)ureido>benzene- sulfonamide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(DMSO-d₆, 300 MHz)ppm: 0.84(t, J=6.7Hz, 3H) , 1.08-1.58(m, 18H), 1.79-2.06(m, 6H) , 2.20(t, J=7.2Hz, 2H) , 4.11-4.27(m, IH) , 4.46(d, J=4.5Hz, IH) , 5.15-5.36(m, 4H) , 7.32-7.39(m, IH), 7.47-7.56(m, 3H) , 7.60-7.69(m, IH) , 7.89-7.92(m, IH) , 8.19-8.22(m, IH) , 9.05(s, IH) , 9.26(s, IH), 12.04(br s, IH) IR(Neat): 3468, 3367, 3008, 2928, 2855, 1702, 1591, 1542, 1476, 1429, 1380, 1304, 1227, 1171, 1134, 1084, 1029, 996, 841, 787, 755, 682, 580, 514 cm^"1

Example 30 9-Oxo-9H-fluorene-4-carboxylic acid [4-{ (R) - (5Z, 14Z) -16- hydroxyeicosa-5 , 14-dienoylsulfamoylj-phenyl] amide (Compound 51)

Using 9-oxo-9H-fluorene-4-carboxylic acid (4- sulfamoylphenyl)amide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in

Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz) δppm: 0.89(t, J=6.8Hz, 3H), 1.17-1.70(m, 18H) , 1.87-2.15(m, 6H) , 2.26(t, J=7.4Hz, 2H) ,

4.35-4.45(m, IH), 5.18-5.54(m, 4H) , 7.28-7.47(m, 3H) ,

7.58-7.75(m, 4H) , 7.89-7.96(m, 2H) , 8.07-8.14(m, 2H) ,

8.40(br s, IH), 8.57 (br s, IH)

IR(Neat): 3256, 3007, 2928, 2855, 1718, 1592, 1530, 1498, 1453, 1402, 1323, 1249, 1169, 1090, 967, 840, 738, 694, 661, 627, 592, 549 cm^"1

Example 31

Quinoline-8-sulfonic acid [ (R) - (5Z, 14Z) -16-hydroxyeicosa- 5, 14-dienoyl] amide (Compound 45)

Using quinoline-8-sulfonic acid amide instead of o- toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound. ^-NMR CDCls, 300 MHz) δppm: 0.90(t, J=6.7Hz, 3H) , 1.17-1.70(m, 18H), 1.81-2.20(m, 6H) , 2.32(t, J=7.5Hz, 2H) , 4.44(dt, J=8.4, 6.5Hz, IH) , 5.10-5.22(m, IH) , 5.25-5.56(m, 3H), 7.54-7.62(m, IH) , 7.67-7.75(m, IH) , 8.08-8.16(m, IH) , 8.26-8.34(m, IH), 8.57-8.64(m, IH) , 9.02-9.12(m, IH) IR(Neat): 3368, 3010, 2926, 2854, 1715, 1615, 1598, 1567, 1498, 1458, 1410, 1384, 1337, 1246, 1219, 1174, 1154, 1132, 1076, 1024, 994, 877, 832, 792, 769, 671, 632, 595, 579, 553, 529, 508 cm^"1 Example 32

4-Bromo-2,5-dichlorothienyl-3-sulfonic acid [ (R)- (5Z, 14Z) -

16-hydroxyeicosa-5, 1 -dienoyl]amide (Compound 47) Using 4-bromo-2, 5-dichlorothienyl-3-sulfonic acid amide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz) δppm: 0.91(t, J=6.8Hz, 3H) , 1.20-1.78(m, 18H), 1.90-2.20(m, 6H) , 2.33(t, J=7.5Hz, 2H) , 4.39-4.50(m, IH), 5.20-5.57(m, 4H)

IR(Neat): 3233, 3006, 2928, 2855, 1725, 1495, 1456, 1424, 1367, 1274, 1174, 1119, 1068, 898, 843, 730, 668, 581, 531, 500 cm^"1

Example 33

Benzo[b]thienyl-3-sulfonic acid [ (R) -(5Z, 14Z) -16-hydroxyeicosa-5, 14-dienoyl] amide (Compound 48)

Using benzo[b] thienyl-3-sulfonic acid amide instead of o-toluenesulfonamide in Example 1, substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

^Η-NMRfCDCla, 300 MHz) δppm: 0.91(t, J=6.8Hz, 3H) , 1.18-1.70(m, 18H), 1.84-2.l9(m, 6H) , 2.24(t, J=7.5Hz, 2H) , 4.41-4.51(m, IH) , 5.12-5.57(m, 4H) , 7.44-7.56(m, 2H) , 7.89-7.94(m, IH), 8.19-8.26(m, IH) , 8.57(br s, IH) , 8.59(s, IH)

IR(Neat): 3247, 3109, 3005, 2927, 2854, 1708, 1456, 1348, 1166, 1120, 1064, 977, 836, 756, 731, 597, 565, 522, 481 cm^"1

Example 34 Dimethylsulfamic acid [ (R) - (5 , 14Z) -16-hydroxyeicosa-5 , 14- dienoyl] amide (Compound 49 )

Using dimethylsulfamic acid amide instead of o- toluenesulfonamide in Example 1 , substantially the same procedure as shown in Example 1 was repeated to give the titled compound.

¹H-NMR(CDC1₃, 300 MHz) δppm: 0.91(t, J=6.8Hz, 3H) , 1.20-1.79(m, 18H) , 1.95-2.17(m, 6H) , 2.29(t, J=7.5Hz, 2H) , 2.96(s, 6H), 4.38-4,48(m, IH) , 5.24-5.54(m, 4H) , 7.97(br s, IH) IR(Neat): 3271, 3006, 2928, 2855, 1717, 1458, 1411, 1356, 1281, 1164, 1136, 1059, 974, 834, 713, 544, 521, 498 cm^"1

Test Example 1 fMLP (N-formyl-Met-Leu-Phe) -stimulated elastase release test

The compounds prepared in the Examples of the present application were tested for their inhibition (%) of elastase production from neutrophils stimulated by fMLP (N-formyl-Met-Leu-Phe).

Neutrophils were prepared from rats 15 to 18 hours after intraperitoneal administration of 1% casein in physiological saline (120 mL/kg) . After decapitation, each rat was subjected to peritoneal lavage with cold PBS and the lavage solution was collected and centrifuged (1,500 rpm) , followed by resuspension in HBSS (Hank's Balanced Salt Solution) to give a cell density of 1 x 10⁷ neutrophils/mL. To this suspension, cytochalasin B (final concentration: 5 μg/mL) was added in order to prime the

Cβi.J.S •

The above suspension was dispensed into each well of

96-well culture plates in a volume of 190 μL per well. The test plate was incubated in the presence of the compounds from the Examples at defined concentrations ( 1 x 10^~7 M to 3 x 10^"5 M) in 5% C0₂ at 37°C. After 10 minutes, 20 μM fMLP (10 μL) was added and stirred.

The control well was incubated in the absence of the compounds from the Examples in 5% C0₂ at 37°C for 10 minutes. In the case of incubation with fMLP, 20 μM fMLP (10 μL) was then added and stirred. In the case of incubation without fMLP, a 0.4% ethanol solution (10 μL) was added instead of fMLP and stirred. Each plate was incubated for an additional 10 minutes .

Elastase production was stopped on ice and each culture supernatant was collected by centrifugation (1,500 rpm) . Measurement of elastase activity in each culture supernatant

Elastase activity in each culture supernatant was measured as follows, using an elastase-specific substrate (N-succinyl-L-alanyl-L-alanyl-L-proline-valine-MCA) .

A substrate solution was prepared as a 0.12 mM solution of N-succinyl-L-alanyl-L-alanyl-L-proline-valine- CA (Peptide Institute, Inc., Osaka, Japan) in 50 mM Tris solution (pH 8.0).

The substrate solution (50 μL) was added to the culture supernatant (50 μL) and incubated at 37°C for 30 minutes. Elastase activity was evaluated by measuring the fluorescence intensity at excitation and emission wavelengths of 360 nm and 480 nm, respectively. The inhibitory activity against elastase release (% inhibition of elastase production) was calculated according to the following equation:

Inhibition (%) = {1- (A-C)/(B-C) } x 100 where A represents the fluorescence intensity in the presence of fMLP (1 μM) , B represents the fluorescence intensity in the presence of fMLP (1 μM) and a test compound, and C represents the fluorescence intensity in the absence of fMLP and the test compound. A concentration required to produce 50% inhibition

(IC₅₀) was calculated from the concentration-inhibition curve. Table 1 shows the results obtained. Table 1

Test compound IC₅o (μM)

Compound 13 25.5

Compound 18 5.69

Compound 21 6.04

Compound 25 3.08

Compound 30 1.90

Compound 35 2.42

Compound 57 10.28

In the above table. Compounds 13, 18, 21, 25, 30, 35 and 57 correspond to the compound numbers in the typical examples listed above.

These results demonstrate that the compound of the present invention has a potent inhibitory activity against elastase release.

Test Example 2 [Stability test 1]

Compound 13, compound 25 and the compound of Example 7 in US 6359158 were tested for stability upon storage at an elevated temperature (40 °C) for one day. The following procedure was taken to measure the percent intact drug remaining: each of the test drugs was metered in a test tube in an amount of about 1 mg and stored at room temperature or at 40 °C with the test tube stoppered and kept from light (by means of aluminum foil) ; after one day, 10 ml of 50% water/acetonitrile mixture was added into the test tube to dissolve the test drug and quantitation was made by liquid chromatography. HPLC conditions Column: CAPCELL PAK UG120, 5 μm, φ4.6 x 150 mm (SHISEIDO) Column temperature: 40 °C

Detector: UV absorptiometer (detection wavelength: 200 nm) Flow rate: 1.0 l/min Injection loading: 10 μl Mobile phase:

0.1% aqueous phosphoric acid/acetonitrile (47:53)

... Example 7 (US 6,359,158)

0.1% aqueous phosphoric acid/acetonitrile (50:50) ... Compound 13 0.1% aqueous phosphoric acid/acetonitrile (40:60) ... Compound 25 Results

The data for percent intact drug remaining are shown in Table 2 with respect to compound 13, compound 25 and the compound of Example 7 in US 6359158 that were stored for one day at room temperature and at the elevated temperature of 40 °C. The compound of Example 7 in US 6359158 was found unstable since it showed a very low level of percent intact drug remaining. In contrast, compounds 13 and 25 of the present invention were found stable since they showed high levels of percent intact drug remaining. Table 2

Example 7 Compound 13 Compound 25 (US 6359158)

RT, 1 day 0__L2 101.0 102.3

40 °C, 1 day 0 99.4 101.3 Test Example 3 [Stability test 2]

Compound 20, compound 46 and the compound of Example 18 in US 6359158 were tested for stability upon storage at an elevated temperature (40 °C) for three months. The following procedure was taken to measure the percent intact drug remaining: each of the test drugs was metered in a test tube in an amount of about 1 mg and stored at room temperature or at 40 °C with the test tube stoppered and kept from light (by means of aluminum foil); after three months, 10 ml of 50% water/acetonitrile mixture was added into the test tube to dissolve the test drug and quantitation was made by liquid chromatography.

HPLC conditions

Column: CAPCELL PAK UG120, 5 μm, φ4.6 x 150 mm (SHISEIDO) Column temperature: 40 °C

Detector: UV absorptiometer (detection wavelength: 200 nm)

Flow rate: 1.0 ml/min

Injection loading: 10 μl

Mobile phase: 0.1% aqueous phosphoric acid/acetonitrile (40:60) ... Example 18 (US 6,359,158)

0.1% aqueous phosphoric acid/acetonitrile (30:70) ... Compound 46

0.1% aqueous phosphoric acid/acetonitrile (10:90) ... Compound 20

Results

The data for percent intact drug remaining are shown in Table 3 with respect to compound 20, compound 46 and the compound of Example 18 in US 6359158 that were stored for three months at the elevated temperature of 40 °C. The compound of Example 18 in US 6359158 was found unstable since it showed a very low level of percent intact drug remaining. In contrast, compounds 20 and 46 of the present invention were found stable since they showed high levels of percent intact drug remaining. Table 3

Example 18 Compound 46 Compound 20 (US 6359158)

40 °C, 3 months 13.3 89.1 98.2

INDUSTRIAL APPLICABILITY

The present invention provides novel hydroxyeicosadienamide compounds or pharmaceutically acceptable salts or hydrates thereof, which are stable and show an excellent inhibitory effect on elastase release.

Claims

WHAT IS CLAIMED IS:

1. A hydroxyeicosadienamide compound of Formula (I) or a pharmaceutically acceptable salt or hydrate thereof :

(I) wherein n represents an integer of 0 to 5 , and R represents a C₁-₂₀ alkyl group which may be substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group and a Cι_₅ alkoxy group, an unsaturated heterocyclic ring which may be substituted with one or more members selected from the group consisting of a Cι_₅ alkyl group, a Cι_₅ alkyl group substituted with halogen atom(s), an oxo group, a halogen atom and a hydroxyl group, -NR^XR^Y wherein R^x and R^γ are independently hydrogen, a Cι-₅ alkyl group, a Cι_ι₅ acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an oxo group, or an aryl group which may be substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a Cι_₅ alkyl group, a Cι_₅ alkyl group substituted with halogen atom(s), a nitro group, a cyano group, a thiol group, a Cι_₅ alkoxy group, a C₂-5 alkoxycarbonyl group and a carboxyl group, or -(Ci_₄ alkylene) -Q or Q

Q is a C4-10 bridged hydrocarbon which may be substituted with one or more members selected from Group A or an aryl group which may be substituted with one or more members selected from Group B,

Group A consists of a hydroxyl group, a Cι_₅ alkyl group, an oxo group, a halogen atom and a C₁.₅ alkoxy group, and Group B consists of a halogen atom, a hydroxyl group, a Cι_ ₅ alkyl group, a Cι_₅ alkyl group substituted with halogen atom(s), a nitro group, a cyano group, a thiol group, a Cι_ ₅ alkoxy group, a C2-5 alkoxycarbonyl group, a carboxyl group, a phenyl or phenoxy group which may be substituted with one or more members selected from the group consisting of a halogen atom; a hydroxyl group; a C₁.5 alkyl group; a C₁-5 alkyl group substituted with halogen atom(s); a nitro group; a cyano group; a thiol group; a Cι_₅ alkoxy group; a C2-₅ alkoxycarbonyl group; and a carboxyl group, an unsaturated heterocyclic ring which may be substituted with one or more members selected from the group consisting of a Cι_₅ alkyl group; a Cι_₅ alkyl group substituted with halogen atom(s); an oxo group; a halogen atom; and a hydroxyl group, -NR^XR^Y (wherein R^x and R^γ are independently hydrogen, a Cι_₅ alkyl group, a C₁-₁₅ acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an oxo grou , or an aryl group which may be substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a Cι_₅ alkyl group, a Cι_₅ alkyl group substituted with halogen atom(s), a nitro group, a cyano group, a thiol group, a Cj.- s alkoxy group, a C₂-₅ alkoxycarbonyl group and a carboxyl group), and -NHCONR_AR_B (wherein R_a and R_B are independently a hydrogen atom, a C₁-₅ alkyl group or a phenyl group which may be substituted with one or more members selected from the group consisting of a halogen atom; a hydroxyl group; a C₁-5 alkyl group; a Cι_₅ alkyl group substituted with halogen atom(s); a nitro group; a cyano group; a thiol group; a Cι_₅ alkoxy group; a C₂-s alkoxycarbonyl group; and a carboxyl group) .

2. The hydroxyeicosadienamide compound or a pharmaceutically acceptable salt or hydrate thereof according to claim 1 , wherein n in Formula ( I ) is 3.

3. The hydroxyeicosadienamide compound or a pharmaceutically acceptable salt or hydrate thereof according to claim 1 or 2, wherein R represents a Cι-₂₀ alkyl group, an unsaturated heterocyclic ring which may be substituted with one or more members selected from the group consisting of a C₁-5 alkyl group; a Cχ.₅ alkyl group substituted with halogen atom(s); an oxo group; a halogen atom; and a hydroxyl group, -(C₁-₄ alkylene) -Q or Q wherein Q is an aryl group which may be substituted with one or more members selected from the group consisting of a halogen atom, a hydroxyl group, a Cι_₅ alkyl group, a C₁-5 alkyl group substituted with halogen atom(s), a nitro group, a cyano group, a thiol group, a Cι_₅ alkoxy group, a C₂-5 alkoxycarbonyl group, a carboxyl group, a phenyl or phenoxy group which may be substituted with one or more members selected from the group consisting of a halogen atom; a hydroxyl group; a C₁-5 alkyl group; a C₁-5 alkyl group substituted with halogen atom(s); a nitro group; a cyano group; a thiol group; a C1-5 alkoxy group; a C₂_₅ alkoxycarbonyl group; and a carboxyl group, -NR^XR^Y (wherein R^x and R^γ are independently hydrogen, a C₁.5 alkyl group or a Ci-₁₅ acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an oxo group), and -NHCONR_ARB (wherein R_A and R_B are independently a hydrogen atom, a Cχ.₅ alkyl group or a phenyl group which may be substituted with one or more members selected from the group consisting of a halogen atom; a hydroxyl group; a C1-5 alkyl group; a C1-5 alkyl group substituted with halogen atom(s); a nitro group; a cyano group; a thiol group; a Cι_₅ alkoxy group; a C2-5 alkoxycarbonyl group; and a carboxyl group).

4. The hydroxyeicosadienamide compound or a pharmaceutically acceptable salt or hydrate thereof according to claim 1 or 2 , wherein R represents a C₈-i6 alkyl group or an aryl group which is substituted with -

NR^XR^Y (wherein R^x is hydrogen, R^γ is a C₁-₁5 acyl group which may be substituted with one or more members selected from the group consisting of a halogen atom and an oxo group.)

5. A pharmaceutical composition comprising, as an active ingredient, the hydroxyeicosadienamide compound or a pharmaceutically acceptable salt or hydrate thereof according to any one of claims 1 to .

6. An elastase release inhibitor comprising, as an active ingredient, the hydroxyeicosadienamide compound or a pharmaceutically acceptable salt or hydrate thereof according to any one of claims 1 to 4.

7. A preparation for preventing or treating an elastase-associated disease, which comprises, as an active ingredient, the hydroxyeicosadienamide compound or a pharmaceutically acceptable salt or hydrate thereof according to any one of claims 1 to 4.

8. A method for preventing or treating an elastase- associated disease, which comprises administering to a mammal a prophylactically or therapeutically effective amount of the hydroxyeicosadienamide compound or a pharmaceutically acceptable salt or hydrate thereof according to any one of claims 1 to 4.