Amphotericin derivatives

Details Amphotericin derivatives Amphotericin derivatives

1990-12-06

2001-09-04

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S006500

Reexamination Certificate

active

06284736

ABSTRACT:

The present invention relates to novel compounds having pharmacological activity, their preparation, compositions containing them and their use in the treatment of fungal infections in animals, including humans.
The polyene macrolide amphotericin B, produced by
Streptomyces nodosus
, is widely used for the treatment of fungal infections.
Amphotericin B is the only complex polyene macrolide whose molecular structure and absolute configuration has been firmly established by X-ray crystallographic analysis. Amphotericin B has the formula (A):
Derivatives of amphotericin B substituted at the 14-position of the amphotericin B nucleus have now been prepared. These derivatives have been found to have anti-fungal activity and have potential utility as anti-fungal agents.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein R
1
is a carboxylic acid group, a derivative thereof, a ketone residue, an aldehyde function or optionally substituted methyl; R
2
is hydroxy, C
1-8
alkoxy or a fluorine atom; and R
3
is an amino group or a derivative thereof.
As used herein, the term carboxylic acid group derivative includes esters, and amides. Ester groups include alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl and heteroaralkyloxycarbonyl goups. Amides include primary, secondary and tertiary amides. For example the amino moiety may be substituted by one or two alkyl groups. A ketone residue may be an alkyl, aryl or heteroaryl ketone residue. A suitable value for R
1
when optionally substituted methyl is hydroxymethyl.
Unless otherwise specified, each alkyl,alkenyl or alkoxy group is preferably a C
1-6
group, more preferably a C
1-4
group and may be straight chain or branched.
When used herein, the term aryl includes both monocyclic and bicyclic carbocyclic moieties, for example phenyl and naphthyl. An aryl moiety may be mono-, di-, or tri-substituted by groups including carboxy, alkoxycarbonyl, hydroxy, alkyl, alkoxy, halogen, and amino optionally substituted by alkyl, and is preferably mono- or di-substituted.
The term heteroaryl includes 5- or 6-membered monocyclic and 9- or 10-membered bicyclic heteroaryl.
In addition, 5- or 6-membered monocyclic and 9- or 10-membered bicyclic heteroaryl preferably contain one or two heteroatoms selected from nitrogen, oxygen and sulphur which in the case of there being more than one heteroatom may be the same or different. When 9- or 10-membered bicyclic heteroaryl, the two rings are fused, preferably with one 5- or 6-membered ring containing a single heteroatom.
Unless otherwise specified, the term halogen includes fluorine, chlorine, bromine and iodine.
When used herein, the term amino group derivative includes acyl derivatives, in particular acyl derivatives bearing a basic substituent such as N-D-lysyl and N-D-ornithyl derivatives, guanidine derivatives, and N-glycosyl derivatives. The preparation of suitable amino group derivatives is described in European Patent Publication 0 010 297 (Schering), European Patent Publication 0 031 722 (Dumex) and U.S. Pat. No. 4,195,172.
Compounds of formula (I) and salts thereof may also form solvates such as hydrates and the invention also extends to these forms. When referred to herein it is understood that a compound of the invention or a salt thereof includes solvates.
Pharmaceutically acceptable salts of compounds of formula (I) may be formed conventionally, for example by reaction with the appropriate acid or base.
Compounds of formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, oxalic, methanesulphonic, aspartic and ascorbic. The invention also extends to quaternary salts.
Compounds of formula (I) wherein R
1
is hydroxycarbonyl can form basic addition salts with bases, such as conventional pharmaceutically acceptable bases, for example sodium hydrogen carbonate, potassium carbonate, lithium hydroxide, triethylamine, pyridine, lutidine and N-methylglucamine.
The formation of compounds of formula (I) of the present invention creates a further chiral centre at the 14-position of the amphotericin B nucleus. Compounds of formula (I) are therefore capable of existing in different stereoisomeric forms. The invention extends to each of these forms and to mixtures thereof. Compounds of formula (I) having different stereochemistry at the 14-position may be obtained by stereospecific syntheses, as hereinafter described.
Suitable values for R
1
include hydroxycarbonyl, C
1-4
alkoxycarbonyl such as methoxycarbonyl, C
1-4
alkenyloxycarbonyl such as prop-2-enyloxycarbonyl, and hydroxymethyl.
Suitable values for R
2
include hydroxy, C
1-4
alkoxy such as methoxy, and fluoro.
Preferably R
3
is an amino group.
The present invention also provides a process for the preparation of compounds of formula (I) which process comprises the reaction of a compound of formula (II):
wherein R
1
′ is R
1
as defined for formula (I); R
3
′ is a protected amino group; and each R
4
′ is hydrogen or a silyl protecting group; with a peracid, followed by selective substitution at the anomeric 13-position of the intermediate so formed in the presence of a compound R
2
—H where R
2
is as defined for formula (I); and thereafter, optionally or as necessary and in any appropriate order converting R
3
′ to an R
3
amino group, removing R
4
′ when a silyl protecting group, interconverting R
1
, interconverting R
2
, forming an amino group derivative, and forming a pharmaceutically acceptable salt.
A suitable peracid for reaction with a compound of formula (II) is m-chloroperbenzoic acid. When R
4
′ is silyl, the reaction is suitably carried out under anhydrous conditions at reduced temperature in an inert solvent, for example n-hexane, methylene chloride or tetrahydrofuran.
The intermediate formed by reaction with a peracid may be progressed, without isolation, to a compound of formula (I) by carrying out the reaction with peracid in the presence of a compound R
2
—H (where R
2
is hydroxy or C
1-8
alkoxy). For example, where R
2
is hydroxy and R
4
′ is hydrogen, the reaction with peracid is conveniently carried out in aqueous tetrahydroforan. Alternatively, the isolated intermediate may be further reacted with a compound R
2
—H.
Where each R
4
′ in a compound of formula (II) is a silyl protecting group, the intermediate formed by reaction with a peracid has been isolated and shown to be a compound of formula (III):
wherein R
1
′ and R
3
′ are as defined for formula (II); each R
4
′ is a silyl protecting group; and R
2
′ is acyloxy. It will be appreciated that the R
2
′ acyloxy substituent at position-13 will correspond to the chosen peracid. Thus, for example, when the peracid is m-chloroperbenzoic acid, R
2
′ is m-chlorobenzoyloxy.
The 14-hydroxy substituent in compounds of formula (III) has been shown by spectroscopic analysis to have the (S)-configuration. (S)-stereochemistry is retained at the 14-position in compounds of the invention of formula (I) when prepared by this process variant.
Conversely, compounds of formula (I) prepared from an intermediate of formula (II) in which each R
4
′ is hydrogen have been shown to have (R)-stereochemistry at the 14-position.
Where an intermediate compound of formula (III) is isolated, the conditions under which selective substitution at the anomeric 13-position is effected may be varied according to the desired value of R
2
.
Thus where R
2
in a compound of formula (I) is C
1-8
alkoxy, a compound of formula (III) may be dissolved in an inert solvent and stirred at ambient temperature with the corresponding C
1-8
alkyl alcohol. For example, where R
2
in a compound of formula (I) is methoxy, a compound of formula (III) may be stirred for 20 to 24 hours in a mixture of methylene chloride and methanol.
Where R
2
in a c

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