Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-17
2001-06-05
Oswecki, Jane C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S424000, C514S428000, C548S530000, C548S533000
Reexamination Certificate
active
06242476
ABSTRACT:
This application is a 371 of PCT/JP98/01300 filed Mar. 25, 1998.
TECHNICAL FIELD
The present invention relates to leukotriene A
4
hydrolase inhibitors containing mercaptoacylproline derivatives as active ingredients and particularly provides useful drugs as therapeutic agents for inflammatory diseases such as rheumatic diseases.
BACKGROUND ART
Leukotriene A
4
(hereinafter abbreviated as LTA
4
) hydrolase, which is one of epoxide hydrolases, is a metal-containing enzyme which requires zinc in its active center.
LTA
4
hydrolase plays a catalyst-like role on biochemical conversion from LTA
4
into leukotriene B
4
(hereinafter abbreviated as LTB
4
), which is a strong pro-inflammatory substance.
LTB
4
is an arachidonic acid metabolite which is produced in 5-lipoxygenase pathway, is biosynthesized in various cells including mast cell, neutrophil, monocyte, macrophage, etc., and plays a role as an important mediator in inflammation. LTB
4
induces chemotaxis, aggregation and degranulation of leukocyte and accumulation of polymorphonuclear leukocyte, and accelerates blood-vessel permeability and edema formation. For this reason, it was reported that particularly high level of LTB
4
is detected at lesion sites in inflammatory diseases such as rheumatic diseases (J. Clin. Invest., 66, 1166-1170 (1980)), psoriasis (Br. J. Pharmacol., 83, 313-317 (1984)), inflammatory bowel diseases (Gastroenterology, 86, 453-460 (1984)) and gout (Lancet, 2, 1122-1124 (1982)), and in sputum in cystic fibrosis (Lancet, 342, 465-469 (1993)).
Accordingly, compounds which inhibit LTA
4
hydrolase are expected to prevent production of LTB
4
and exhibit therapeutic effects on inflammatory diseases such as rheumatic diseases.
Mercaptoacylproline derivatives, which are active ingredients in the present invention, are reported in U.S. Pat. No. 4,316,906 and J. Med. Chem., 31, 875-885 (1988) as antihypertensive agents having inhibitory effects on ACE. However, there is no report about LTA
4
hydrolase inhibition effects of compounds having a substituent in 4th-position of proline skeleton of these mercaptoacylproline derivatives. Compounds having a (lower cycloalkylphenyl)alkyl group in 4th-position of proline skeleton are novel compounds which are not described in literature.
As mentioned above, the mercaptoacylproline derivatives are known to have the inhibitory effects on ACE and to be useful as the antihypertensive agents. However, it is a very interesting subject to find new medical use of these compounds.
The present inventors studied in order to find new medical use of the known mercaptoacylproline derivatives and mercaptoacylproline derivatives synthesized newly. As a result, these compounds were found to exhibit excellent inhibitory activities on LTA
4
hydrolase.
DISCLOSURE OF THE INVENTION
The present invention relates to LTA
4
hydrolase inhibitors containing compounds represented by the following general formula [I] or salts thereof (hereinafter referred to as the present compounds) as active ingredients and novel compounds represented by the following general formula [II] or salts thereof.
The groups defined above will be described in more detail. The lower alkyl means straight or branched lower alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, hexyl or isobutyl. The lower alkanoyl means straight or branched alkanoyl having 2 to 6 carbon atoms such as acetyl, propionyl, butyryl, hexanoyl, isobutyryl or pivaloyl. The lower alkoxy means straight or branched lower alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy or hexyloxy. The lower cycloalkyl means cyclic lower cycloalkyl having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The halogens atom means fluorine, chlorine, bromine and iodine. The lower alkylene means straight or branched lower alkylene having 1 to 6 carbon atoms such as methylene, ethylene, propylene or butylene.
Preferred examples of the above-mentioned compounds include the followings.
Compounds of the above general formula [I] wherein R
1
represents a hydrogen atom, a lower alkanoyl group or a benzoyl group, particularly preferably a hydrogen atom, and salts thereof.
Compounds of the above general formula [I] wherein R
2
represents a hydrogen atom or a lower alkyl group, particularly preferably a hydrogen atom, and salts thereof.
Compounds of the above general formula [I] wherein R
3
represents a hydrogen atom or a lower alkyl group, particularly preferably a methyl group, and salts thereof.
Compounds of the above general formula [I] wherein R
4
represents a hydrogen group or a lower alkyl group, particularly preferably a hydroxyl group, and salts thereof.
Compounds of the above general formula [I] wherein R
5
represents a phenyl group or a naphthyl group which can be substituted by a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group or a lower alkylthio group, more preferably a phenyl group which can be substituted by a lower alkyl group or a lower cycloalkyl group, particularly preferably a phenyl group which can be substituted by an isopropyl group, a t-butyl group or a cyclohexyl group, and salt thereof.
Compounds of the above general formula [I] wherein “Z” represents a sulfur atom or an oxygen atom, particularly preferably a sulfur atom, and salt thereof.
Compounds of the above general formula [I] wherein “A” represents a lower alkylene group, particularly preferably a methylene group, and salts thereof.
Compounds of the above general formula [I] wherein “n” represents 0, 1 or 2, particularly preferably 1, and salts thereof.
Specific examples of particularly preferred compounds are (4S)-4-(4-isopropylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, (4S)-4-(4-t-butylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline and (4S)-4-(4-cyclohexylbenzylthio-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, which are represented by the following formulae [III], [IV] and [V], respectively, and salts thereof.
Among the novel compounds represented by the above general formula [II], the following compounds are exemplified as preferred compounds.
Compounds of the above general formula [II] wherein R
6
represents a hydrogen atom, a lower alkanoyl group or a benzoyl group, particularly preferably a hydrogen atom, and salts thereof.
Compounds of the above general formula [II] wherein R
7
represents a hydrogen atom or a lower alkyl group, particularly preferably a hydrogen atom, and salts thereof.
Compounds of the above general formula [II] wherein R
8
represents a hydrogen atom or a lower alkyl group, particularly preferably a methyl group, and salts thereof.
Compounds of the above general formula [II] wherein R
9
represents a hydroxyl group or a lower alkoxy group, particularly preferably a hydroxyl group, and salts thereof.
Compounds of the above general formula [II] wherein R
10
represents a lower cycloalkyl group, particularly preferably a cyclohexyl group, and salts thereof.
Compounds of the above general formula [II] wherein “Z” represents a sulfur atom or an oxygen atom, particularly preferably a sulfur atom, and salts thereof.
Compounds of the above general formula [II] wherein “A” represents a lower alkylene group, particularly preferably a methylene group, and salts thereof.
Compounds of the above general formula [II] wherein “n” represents 0, 1 or 2, particularly preferably 1, and salts thereof.
Specific examples of particularly preferred compounds are (4S)-4-(4-cyclohexylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline, which is represented by the following formula [V], and salts thereof.
The above-mentioned salts can be any pharmaceutically acceptable salts. Examples thereof are hydrochlorides, sulfates, phosphates, lactates, maleates, fumarates, ox
Ban Masakazu
Fujimura Ken-ichi
Horiuchi Masato
Mita Shiro
Suhara Hiroshi
Frishauf, Holtz Goodman, Langer & Chick, P.C.
Oswecki Jane C.
Santen Pharmaceutical Co. Ltd.
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