Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-08
2002-06-25
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S154000
Reexamination Certificate
active
06410528
ABSTRACT:
This invention relates to novel morpholino ethers having antifungal activity. More particularly it relates to novel sordaricin derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, more particularly in the prevention or treatment of diseases in animals, including humans, caused by fungal infection.
British Patent Specification No. 1,162,027 describes the preparation of an antibiotic, SL2266, by the cultivation of the strain NRRL 3196 of the fungus species
Sordaria araneosa.
SL 2266, later named sordarin, is reported to have fungistatic activity. The same research group also described in Helvetica Chimica Acta (1971), 51, 119-120 the degradation of sordarin to sordaricin. Published Japanese Patent Application No. J6 2040292A describes the preparation of an antibiotic, zofimarin, which is reported to have antifungal activity. Sordarin, sordaricin and zofimarin may be represented by formula (A) below
where
OR as
describes sordarin;
OR as OH describes sordaricin; and
OR as
describes zofimarin.
Although sordarin and zofimarin exhibit antifungal activity, both compounds are only moderately active and have limited spectra of action when tested against a battery of fungal organisms.
WO96/14326 and WO96/14327 describe novel sordarin derivatives which exhibit useful antifungal activity. WO99/09974 and WO99/09975 describe 4-cyano-4-deformyl sordarin and sordaricin derivatives which exhibit antifungal activity.
We have now found a novel group of sordaricin derivatives which exhibit a useful spectrum of antifungal activity and which can be conveniently prepared from readily available starting material.
Thus according to a first aspect of the invention, we provide compounds of formula (I).
and physiologically acceptable salts and or metabolically labile derivatives thereof, wherein R
1
represents C
1-6
straight or branched chain alkyl, C
1-6
straight or branched chain alkoxy, optionally substituted phenoxy, C
3-6
straight or branched chain alkenyloxy (optionally substituted by 1 or 2 halogen atoms) or C
1-4
straight or branched alkoxy substituted by an optionally substituted phenyl group, C
3-8
straight or branched chain alkynyl, C
3-6
straight or branched chain alkenyl (optionally substituted by C
1-4
alkoxy or 1 or 2 halogen atoms), optionally substituted phenyl, optionally substituted C
3-7
cycloalkyl, optionally substituted C
5-7
cycloalkenyl, C
2-4
straight or branched chain alkyl substituted by (C
1-4
alkoxy, C
1-4
alkyl thio or halogen), C
1-4
straight or branched chain alkyl substituted by (C
1-4
alkoxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl, propadienyl, cyano, optionally substituted C
3-7
cycloalkyl, optionally substituted 5 or 6 membered heteroaryl, or 1 or 2 optionally substituted phenyl groups), or methyl substituted by C
1-6
alkanoyl or optionally substituted benzoyl; R
2
represents a group selected from hydrogen, C
1-6
straight or branched chain alkyl, C
3-6
straight or branched chain alkenyl, optionally substituted phenyl or C
1-4
alkyl substituted with a group selected from C
1-4
alkoxy, hydroxy, acyloxy, alkoxycarbonyl or aryloxycarbonyl, and R
3
represents a group selected from formyl or cyano.
According to a second aspect of the present invention we provide compounds of formula (I) and physiologically acceptable salts and or metabolically labile derivatives thereof, wherein R
1
represents C
1-6
straight or branched chain alkyl, C
1-6
straight or branched chain alkoxy, optionally substituted phenoxy, C
3-6
straight or branched chain alkenyloxy or C
1-4
straight or branched alkoxy substituted by an optionally substituted phenyl group, C
3-8
straight or branched chain alkynyl, C
3-6
straight or branched chain alkenyl (optionally substituted by C
1-4
alkoxy or 1 or 2 halogen atoms), optionally substituted phenyl, optionally substituted C
3-7
cycloalkyl, optionally substituted C
5-7
cycloalkenyl, C
2-4
straight or branched chain alkyl substituted by (C
1-4
alkoxy, C
1-4
alkylthio or halogen), C
1-4
straight or branched chain alkyl substituted by (C
1-4
alkoxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl, cyano, optionally substituted C
3-7
cycloalkyl, optionally substituted 5 or 6 membered heteroaryl, or 1 or 2 optionally substituted phenyl groups), or methyl substituted by C
1-6
alkanoyl or optionally substituted benzoyl; R
2
is methyl and R
3
is CHO.
Physiologically acceptable salts of the compounds of formula (I) include salts formed with physiologically acceptable acids or bases as well as internal salts.
Suitable physiologically acceptable salts of the compounds of formula (I) with bases include inorganic base salts such as alkali metal salts (for example sodium and potassium salts) and ammonium salts and organic base salts. Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. dicyclohexylamine), optionally substituted benzylamine (e.g. phenylbenzylamine or p-bromobenzylamine), procaine, ethanolamine, diethanolamine, N-methylglucosamine and tri(hydroxymethyl)methylamine salts and amino acid salts (e.g. lysine and arginine salts).
Suitable physiologically acceptable acid addition salts includes those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid and organic acids such as acetic acid, propionic acid, succinic acid, lactic acid, tartaric acid, citric acid, maleic acid, benzoic acid or salicylic acid.
References hereinafter to a compound of formula (I) includes that compound and physiologically acceptable salts thereof.
Other salts which are not physiologically acceptable may be useful in the preparation of compounds of formula (I) and these form a further aspect of the invention.
Metabolically labile derivatives of compounds of formula (I) are compounds which are converted in the body into compounds of formula (I). Examples of such derivatives include conventional metabolically labile esters formed from the free carboxylic acid in the molecule. It is well known in the field of medicinal chemistry that there is a wide range of structurally distinct esters of carboxylic acid which are readily hydrolysed in the body to yield the parent carboxylic acid or a salt thereof and it is to be understood that the present invention encompasses all such esters.
It is to be understood that the present invention encompasses any individual isomers, including optical isomers, of compounds represented by formula (I) above as well as mixtures thereof, including wholly or partially racemic mixtures thereof.
When R
1
is C
1-6
straight or branched chain alkyl group examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, pentyl, isopentyl, 1-ethylpropyl, hexyl or isohexyl.
When R
1
is C
1-4
straight or branched alkoxy substituted by optionally substituted phenyl examples of such groups include phenylmethoxy, phenylethoxy or phenylpropoxy.
When R
1
is C
1-6
straight or branched alkoxy examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy or hexyloxy.
When R
1
is a C
3-6
alkenyl group examples of such groups include allyl, 2-methylallyl, 3-methylallyl or 3,3-dimethylallyl.
When R
1
is a C
3-6
alkenyl group substituted by C
1-4
alkoxy this is conveniently C
3-6
alkenyl substituted by methoxy e.g. 2-methoxyallyl or 2-methoxymethylallyl.
When R
1
is C
3-6
alkenyl substituted by one or two halogen atoms this is conveniently C
3-6
alkenyl substituted by 1 or 2 halogen atoms selected from fluorine chlorine or bromine e.g. 2-fluoromethylallyl, 2-chloroallyl, 2-bromoallyl, 2-fluoroallyl, 3-fluoroallyl or 3,3-difluoroallyl.
When R
1
is C
3-6
alkenyloxy optionally substituted by 1 or 2 halogen atoms this is conveniently C
3-6
alkenyoxy optionally substituted by bromine or chlorine or fluorine e.g. allyloxy, 2-chloroallyloxy, 2-bromoallyloxy, 2-fluoroallyloxy.
The term aryl as a group or part of a group means optionally substituted phenyl.
Th
Bueno Jose M.
Chicharro Gonzalo Jesus
Coteron Jose-Miguel
Cuevas Juan Carlos
Fiandor Jose M.
Glaxo Wellcome S.A.
Nixon & Vanderhye
Ramsuer Robert W.
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