Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-09-24
2003-11-11
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S148000, C544S153000, C544S154000
Reexamination Certificate
active
06645960
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to novel carboxylic acid esters 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
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 antingal activity.
DETAILED DESCRIPTION OF THE INVENTION
We have now found a novel group of sordaricin derivatives which exhibit a useful spectrum of antifungal activity when administered orally 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 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; R represents phthalidyl, (2-oxo-5methyl-1,3-dioxolen-4-yl)methyl or the group CHR
4
OCO(O)pR
5
wherein R
4
is hydrogen or C
1-4
alkyl, p is zero or 1, R
5
is C
1-6
alkyl, C
5-8
cycloalkyl (optionally substituted by C
1-3
alkyl or carboxyl), C
1-4
alkyl substituted by C
1-3
alkoxy or carboxyl, C
1-6
alkyl substituted by one or more groups selected from amino, (C
1-4
alkylamino di(C
1-4
alkyl)amino or carboxyl, phenyl (optionally substituted by carboxyl or aminoalkyl, C
1-4
alkylaminoalkyl or di(C
1-4
alkyl)aminoalkyl, or R
5
is a 5-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from oxygen or nitrogen.
Physiologically acceptable salts of the compounds of formula (I) include salts formed with physiologically acceptable acids, and where the compound contains a carboxyl group then the invention also includes salts with a physiologically acceptable base.
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.
Suitable physioligically acceptable base addition salts include those formed with alkali and alkaline metal earths e.g. sodium or potassium salts, or with physiologically acceptable organic bases.
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.
It is to be understood that the present invention encompasses any individual isomers, including optical isomers and rotamers, of compounds represented by formula (I) above as well as mixtures thereof, including wholly or partially racemic mixtures thereof.
The term alkyl when used above to refer to a group or part of a group e.g. alkoxy includes straight or branched chain alkyl groups.
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
alkenyloxy 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.
The term optionally substituted phenyl as a group or part of a group e.g. phenoxy or phenylalkyl includes phenyl or phenyl substituted by 1 or 2 groups which may be the same or different and selected from C
1-4
alkyl, halogen (fluorine, chlorine, bromine or iodine), hydroxy, C
1-4
alkoxy, methylenedioxy or trifluoromethyl.
The term optionally substituted C
3-7
cydoalkyl as a group or part of a group is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group which may be substituted by 1 or 2 methyl, methoxy, hydroxy or phenyl groups or may be fused to a phenyl ring to form a bicyclic ring system linked to the rest of the molecule via a carbon atom in with the cyloalkyl ring e.g. indanyl or tetrahydronaphthyl.
When R
1
is a C
2-4
alkyl group substituted by halogen examples of suitable groups include 2-chloroethyl, 2-fluoroethyl, trifluoroethyl.
The term straight or branched C
3-6
alkynyl includes 2-propynyl, 1-methyl-2-propynyl and 3-methyl-2-propynyl or 1,1-dimethyl-2-propynyl.
When R
1
is C
5-7
cycloalkenyl examples of such groups include cyclohexen-3-yl or cyclopenten-3-yl.
When R
1
is C
1-4
alkyl substituted by heteroaryl group, the term heteroaryl refers to a 5 or 6 membered heteroaryl group wherein the 5 membered group contains a single heteroatom selected from oxygen, sulphur or nitrogen an
Fiandor Jose Maria
Huss Sophie
Glaxo Wellcome S.A.
Kinzig Charles M.
McCarthy Mary E.
Ramsuer Robert W.
Sieburth Kathryn L.
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