Use of macrolactones as anti-allergics

Details Use of macrolactones as anti-allergics Use of macrolactones as anti-allergics

1991-08-19

1993-06-08

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549266, 549271, A61K 31365

Patent

active

052179907

DESCRIPTION:

BRIEF SUMMARY
The invention concerns the use of macrolactones of the general formula ##STR1## wherein R.sub.1 represents a hydrogen atom or a C.sub.1 -C.sub.4 -alkyl radical, R.sub.2 a hydrogen atom, a hydroxyl or an acetoxy radical, R.sub.3, R.sub.4, in each case independently of one another, a hydrogen atom, a hydroxyl or an acetoxy radical or together an oxygen atom and --.cndot.= a cis- or trans-configurated carbon centre, for the treatment of allergic and inflammatory illnesses, especially for the inhibition of the activation of pro-inflammatory-acting leukocytes, such as e.g. the antigen-induced degranulation of peripheral human leukocytes.
All of the compounds encompassed by the general formula I are known and described or can be prepared in analogous manner from known compounds.
Thus, cladospolides A and B were isolated from Cladosporium cladosporioides (A. Hirota et al., Agric. Biol. Chem., 49 ((1985) 731). The absolute stereo-chemistry on the three asymmetric centres was determined by relevant NMR methods and X-ray structural analyses (H. Hirota et al., Bull. Chem. Soc. Jpn., 58 (1985) 2147; H. Hirota et al., Agric. Biol. Chem., 49((1985) 903). The total synthesis of cladospolide A was recently described (K. Mori et al., Liebigs Ann. Chemie, ((1987) 863).
The diacetates of cladospolides A and B are obtained in per se known manner by acetylation in pyridine with acetic anhydride.
Patulolides A, B and C were isolated from Penicillium urticae mutants S 11 (ATCC 48165) or S 11 R 59 (IFO 31725) (D. Rodphaya et al., J. Antibiotics, 39 (1986) 629; J. Sekiguchi et al., Tetrahedron Letters, 26, (1985)) 2341).
The biosynthesis of these compounds was recently elucidated (D. Rodphaya et al., J. Antibiotics, 41 ((1988) 1649).
The total synthesis were also recently described (K. Mori et al., Liebigs Ann. Chem. ((1988) 13).
The previously known biological activity of the macrolactones according to claim 2 is limited to the following spheres:
Cladospolide A acts weakly inhibitingly on the root growth of lettuce seeds (Lactuca sativa), whereas, in the same test system, cladospolide B acts promotingly (A. Hirota et al., Agric. biol. Chem., 49 ((1985) 731). The hydrogenation products of cladospolides A and B were also described. They possess no biological activity in the above sense (A. Hirota et al., Agric. Biol. Chem., 49 ((1985) 731).
Patulolides A, B and C have also been described as weakly fungistatic and anti-bacterial active materials but also as plant growth inhibiting materials (D. Rodphaya et al., J. Antibiotics, 39 (1986) 629; JP-222192, 4.10.1985, Takeda Chemical Ind. K.K.).
Surprisingly, it could now be found in simple in vitro screening systems that the compounds according to the invention inhibit the activation of leukocytes for mediator liberation and, furthermore, also exhibit a spasm-inhibiting, anti-allergic activity. This action was demonstrated in the test process for anti-allergics, the antigen-caused constriction of passive sensitised guinea pig lung parenchyma strips.
Therefore, the subject of the present invention is the use of macrolactones of the general formula I: ##STR2## wherein R.sub.1 represents a hydrogen atom or a C.sub.1 -C.sub.4 -alkyl radical, R.sub.2 a hydrogen atom, a hydroxyl or an acetoxy radical, R.sub.3, R.sub.4, in each case independently of one another, a hydrogen atom, a hydroxyl or an acetoxy radical or together an oxygen atom and --.cndot.= a cis- or trans-configurated carbon centre, for the treatment of allergic diseases.
By C.sub.1 -C.sub.4 -alkyl therein is understood a methyl, ethyl, propyl or butyl radical, preferably methyl.
Quite especially preferred are the compounds in which R.sub.1 =methyl and R.sub.2 =hydrogen and R.sub.3 and R.sub.4 together represent an oxygen atom; the double bond possesses cis- or trans-substitution.
For the detection of the anti-allergic action, there was used the inhibition of the proteinase liberation from peripheral human leukocytes induced by anti-IgE antibodies (Wilhelmset et al. XII Congress Europ. Acad. Allergology Clin. Immunology, Rome, Sep

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