Amino acid ester containing azole antifungals

Details Amino acid ester containing azole antifungals Amino acid ester containing azole antifungals

2002-11-15

2004-03-09

Bernhardt, Emily (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C514S254070

Reexamination Certificate

active

06703506

ABSTRACT:

FIELD OF THE INVENTION
The present invention is concerned with novel broad-spectrum azole antifungals and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
BACKGROUND OF THE INVENTION
Systemic fungal infections in man are relatively rare in temperate countries and many of the fungi that can become pathogenic normally live commensally in the body or are common in the environment. However, the past few decades have witnessed an increasing incidence of numerous life-threatening systemic fungal infections world-wide and these now represent a major threat to many susceptible patients, particularly those already hospitalized. Most of the increase can be attributed to improved survival of immunocompromised patients and the chronic use of antimicrobial agents. Moreover, the flora typical of many common fungal infections is also changing and this is presenting an epidemiological challenge of increasing importance. Patients at greatest risk include those with impaired immune functioning, either directly as a result of immunosuppression from cytotoxic drugs or HIV infection, or secondary to other debilitating diseases such as cancer, acute leukaemia, invasive surgical techniques or prolonged exposure to antimicrobial agents. The most common systemic fungal infections in man are candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis and cryptococcosis.
Antifungals such as ketoconazole, itraconazole and fluconazole are employed for the treatment and prophylaxis of systemic fungal infections in immunocompromised patients. However, concern is growing about fungal resistance to some of these agents, especially these with a more narrow spectrum, e.g. fluconazole. Worse still, it is recognized in the medical world that about 40% of the people suffering from severe systemic fungal infections are hardly, or not at all, able to receive medication via oral administration. This inability is due to the fact that such patients are in coma or suffer from severe gastroparesis. Hence the use of insoluble or sparingly soluble antifungals such as itraconazole, that are difficult to administer intravenously, is heavily impeded in said group of patients.
Consequently, there is a need for new antifungals, preferably broad-spectrum antifungals, against which there is no existing resistance and which can be administered intravenously. Preferably the antifungal should also be available in a pharmaceutical composition suitable for oral administration. This enables the physician to continue treatment with the same drug after the patient has recovered from the condition which required intravenous administration of said drug.
U.S. Pat. No. 4,267,179 discloses heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxy-methyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles useful as antifungal agents. Said patent encompasses itraconazole, which is now available as a broadspectrum antifungal on a world-wide basis.
U.S. Pat. No. 4,916,134 teaches 4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]triazolones having improved antimicrobial properties.
U.S. Pat. No. 4,791,111 discloses derivatives of [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles, structurally related to some of the compounds of the present invention, which are taught to have favourable anti-microbial properties. A particular compound disclosed herein is cis-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]-phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-3H-1,2,4-triazol-3-one, said compound being a stereoisomeric mixture of all possible enantiomers and diastereomers having the cis configuration at the 1,3-dioxolane ring. WO 93/19061 discloses the [2R-[2&agr;,4&agr;,4(R*)]], [2R-[2&agr;,4&agr;,4(S*)]], [2S-[2&agr;,4&agr;,4(S*)]] and [2S-[2&agr;,4&agr;,4(R*)]] stereospecific isomers of itraconazole, which are taught to have greater water solubility than the respective diastereomeric mixtures thereof.
WO 95/19983 discloses derivatives of [[4-[4-(4-phenyl-1-piperazinyl)phenoxy-methyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles, structurally related to some of the compounds of the present invention, which are taught to be water-soluble antimicrobial agents.
WO 95/17407 discloses tetrahydrofuran antifungals as well as WO 96/38443 and WO 97/00255. The latter two publications discloses tetrahydrofuran antifungals, which are taught to be soluble and/or suspendible in an aqueous medium suitable for IV, containing substitution groups readily convertible in vivo into hydroxy groups.
SUMMARY OF THE INVENTION
The present invention concerns novel compounds of formula
the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein —A—B— forms a bivalent radical of formula:
—N═CH—  (a),
—CH═N—  (b),
—CH═CH—  (c),
 wherein one hydrogen atom in the radicals (a) and (b) may be replaced with a C
1-6
alkyl-radical and up to two hydrogen atoms in radical (c) may be replaced by a C
1-6
alkyl-radical;
L represents the acyl moiety of an amino acid, and thus —O—L represents an amino acid ester group;
D is a radical of formula
 wherein
X is N or CH;
R
1
is halo;
R
2
is hydrogen or halo.
DETAILED DESCRIPTION
In the definitions hereinabove and hereinafter the term halo defines fluoro, chloro, bromo and iodo; C
1-6
alkyl is generic to straight and branch chained hydrocarbons having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and the possible branched isomers thereof.
In the definition of L, the term “amino acid” is meant to include, but not limited to,
the 20 &agr;-amino acids commonly found in proteins such as, glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine; and,
amino acids of relatively rare occurrence which have been identified in specialized types of proteins such as, for example, 4-hydroxyproline, hydroxylysine, desmosine and isodesmosine; and,
over 150 other amino acids occuring biologically in free or combined form but never in proteins whether they are &agr;-, &bgr;-, &ggr;- and &dgr;-amino acids or whether they have a L-or D-configuration such as, for example, &bgr;-alanine, homocysteine and homoserine, citrulline, ornithine, &ggr;-aminobutyric acid, D-glutamic acid and D-alanine; and
synthetic amino acid analogues, such as, for example, phenylglycine, p-fluorophenylalanine, thionine, norleucine and the like.
In the definition of L, the term “amino acid” is also meant to include those amino acids in which the amino moiety is mono- or disubstituted; in such instances L may be represented by —L′—NR
x
R
y
. Examples of R
x
and R
y
include hydrogen, C
1-6
alkyl and art-known protective groups for the amino moiety, e.g. tert-butyloxycarbonyl, benzyloxycarbonyl, trifluoromethoxycarbonyl or those protective groups mentioned in Chapter 7 of “Protective Groups in Organic Synthesis” by T. Greene and P. Wuyts (John Wiley & Sons, Inc. 1991). R
x
and R
y
may also form together with the nitrogen atom of the amino moiety of the amino acid a ring such as, for example, a pyrrolidine, piperidine, morpholine, piperazine or substituted piperazine ring, said substituted piperazine being a piperazine ring substituted on the 4-position of the piperazine ring with, for instance, C
1-6
alkyl, hydroxyC
1-6
alkyl, aminoC
1-6
alkyl, mono- or di(C
1-6
alkyl)aminoC
1-6
alkyl.
For instance, in the case L is the acyl

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