21-(2-oxo-tetrahydrofuran)-thio pregnane derivatives, a process

Details 21-(2-oxo-tetrahydrofuran)-thio pregnane derivatives, a process 21-(2-oxo-tetrahydrofuran)-thio pregnane derivatives, a process

1998-06-24

2000-01-11

McKane, Joseph K.

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

514473, 514887, 514465, 549314, 549435, 424434, A61K 3134, A61L 904, C07D30718

Patent

active

060132442

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel anti-inflammatory and anti-allergic compounds of the pregnane series and to processes for their preparation. The present invention also relates to pharmaceutical formulations containing the compounds and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.
Glucocorticosteroids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. However, such glucocorticosteroids may suffer from the disadvantage of causing unwanted systemic effects following administration. WO94/13690, WO94/14834, WO92/13873 and WO92/13872 all disclose glucocorticosteriods which are alleged to possess anti-inflammatory activity coupled with reduced systemic potency.
The present invention provides a novel group of compounds which possess useful anti-inflammatory activity whilst having little or no systemic activity. Thus, the compounds of the present invention represent a safer alternative to those known glucocorticoids which have poor side-effect profiles.
Thus, according to one aspect of the invention, there is provided a compound of formula (I) ##STR2## and soivates thereof, in which R.sub.1 individually represents --OC(.dbd.O)C.sub.1-6 alkyl; .alpha. or .beta. configuration) or methylene; ##STR3## wherein R.sub.5 and R.sub.6 are the same or different and each represents hydrogen or C.sub.1-6 alkyl; or halogen; and
In the above definitions, the term "alkyl" as a group or part of a group means a straight chain, or, where available, a branched chain alkyl moiety. For example, it may represent a C.sub.1-4 alkyl function as represented by methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
The solvates may, for example, be hydrates.
References hereinafter to a compound according to the invention includes both compounds of formula (I) and their solvates, particularly pharmaceutically acceptable solvates.
It will be appreciated that the invention includes within its scope all stereoisomers of the compounds of formula (I) and mixtures thereof.
In particular the compounds of formula (I) contain an asymmetric centre at the point of attachment of the lactone moiety. Thus, the invention includes within its scope both of the diasteroisomers at this asymmetric centre and mixtures thereof.
Diastereoisomers and mixtures thereof at the asymmetric centre formed when R.sub.1 and R.sub.2 together represents ##STR4## and R.sub.5 and R.sub.6 are different are also included within the scope of the present invention.
The sulphur linkage to the lactone moiety can be to either the alpha, beta or gamma carbon atoms of the lactone, ##STR5##
A preferred group of compounds of the invention are compounds of formula (I) in which R.sub.1 individually represents OC(.dbd.O)C.sub.1-6 alkyl, more preferably OC(.dbd.O)C.sub.1-3 alkyl, especially OC(.dbd.O)ethyl. Compounds within this group in which R.sub.2 is methyl are generally preferred.
Another preferred group of compounds are compounds of formula (I) in which R.sub.1 and R.sub.2 together represent ##STR6## wherein R.sub.5 and R.sub.6 are the same or different and each represents hydrogen or C.sub.1-6 alkyl, particularly hydrogen or C.sub.1-3 alkyl, especially hydrogen, methyl or n-propyl.
Compounds of formula (I) in which R.sub.3 and R.sub.4, which can be the same or different, each represents hydrogen, fluorine or chlorine, particularly hydrogen or fluorine, are preferred. Especially preferred are compounds in which both R.sub.3 and R.sub.4 are fluorine.
A particularly preferred group of compounds of the present invention are compounds of formula (I) in which R.sub.1 is OC(.dbd.O)C.sub.1-6 alkyl, particularly OC(.dbd.O)C.sub.1-3 alkyl, especially OC(.dbd.O)ethyl; R.sub.2 is methyl; R.sub.3 and R.sub.4, which can be the same or different, each represents hydrogen or fluorine, especially fluorine; and represents a single or a double bond.
A further particularly preferred group of compounds of the invention are compounds of formula

REFERENCES:
Chemical & Pharmaceutical Bulletin, 37(12), Dec. 1989, Japan pp. 3286-3293 XP002026042 Mitsukuchi et al.
Chemical & Pharmaceutical Bulletin, 37 (7), Jul. 1989, Japan pp. 1795-1801 XP002026043 Mitsukuchi et al.

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