Invasive fungal infections are well recognised as diseases of the immunocompromised host. Over the last twenty years there have been significant rises in the number of recorded instances of fungal infection (Groll et al., 1996. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 33, 23-32). In part this is due to increased awareness and improved diagnosis of fungal infection. However, the primary cause of this increased incidence is the vast rise in the number of susceptible individuals. This is due to a number of factors including new and aggressive immunosuppressive therapies, increased survival in intensive care, increased numbers of transplant procedures and the greater use of antibiotics worldwide.
In certain patient groups, fungal infection occurs at high frequency; lung transplant recipients have a frequency of up to 20% colonisation and infection with a fungal organism and fungal infection in allogenic hoemopoetic stem transplant recipients is as high as 15% (Ribaud et al., 1999, Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis. 28:322-30).
Currently only four classes of antifungal drug are available to treat systemic fungal infections. These are the polyenes (e.g., amphotericin B), the azoles (e.g., ketoconazole or itraconazole) the echinocandins (e.g., caspofungin) and flucytosine.
The polyenes are the oldest class of antifungal agent being first introduced in the 1950's. The exact mode of action remains unclear but polyenes are only effective against organisms that contain sterols in their outer membranes. It has been proposed that amphotericin B interacts with membrane sterols to produce pores allowing leakage of cytoplasmic components and subsequent cell death.
Azoles work by inhibition of the 14α-demethylase via a cytochrome P450 dependent mechanism. This leads to a depletion of the membrane sterol ergosterol and the accumulation of sterol precursors resulting in a plasma membrane with altered fluidity and structure.
Echinocandins work by the inhibition of the cell wall synthetic enzyme β-glucan synthase. This leads to abnormal cell wall formation, osmotic sensitivity and cell lysis.
Flucytosine is a pyrimidine analogue interfering with cellular pyrimidine metabolism as well DNA, RNA and protein synthesis. However widespread resistance to flucytosine limits its therapeutic use.
It can be seen that to date the currently available antifungal agents act primarily against only two cellular targets; membrane sterols (polyenes and azoles) and β-glucan synthase (echinocandins).
Resistance to both azoles and polyenes has been widely reported leaving only the recently introduced echinocandins to combat invasive fungal infections. As the use of echinocandins increases resistance by fungi will inevitably occur.
The identification of new classes of antifungal agent is required to give the promise of positive therapeutic outcomes to patients.
WO 2004082606 discloses certain 2-indolizin-3-yl-2-oxo-acetamides as TNFα and/or PDE4 inhibitors, which may be used for the treatment of cancer, inflammatory disorders, and autoimmune diseases. These compounds differ from the present invention as the 2-position of the indolizine (i.e. R2 in this invention) is unsubstituted.
U.S. Pat. No. 6,645,976, WO 9603383 and J. Med. Chem. 1996, 39, (19), 3636 disclose the preparation of (1-benzyl-6-(3-carboxypropyloxy)-2-ethyl-indolizin-3-yl)glyoxylamide and its use as a sPLA2 inhibitor. This compound and its intermediates differ from the present invention as they contain a benzyl group in position 1 of the indolizine (i.e. R7 in this invention).
The following compounds which may be used in the present invention are commercially available and are sold without mention of use:    alpha-Oxo-2-phenyl-N-(4,5,6,7-tetrahydro-2-benzothiazolyl)-3-indolizineacetamide,    N-Cyclohexyl-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(2,4-Dimethyl-5-nitrophenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[3-[(Diethylamino)sulfonyl]phenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[2-[4-(Aminosulfonyl)phenyl]ethyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    2-Chloro-4-fluoro-benzoic acid 3-[[oxo-(2-phenyl-3-indolizinyl)acetyl]amino]propyl ester,    N-[2-(1,1-Dimethylethyl)phenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(3-Bromophenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    3,5-Dimethyl-1-[oxo(2-phenyl-3-indolizinyl)acetyl]-piperidine,    N-(2-Hydroxyethyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[2-[(4-Nitrobenzoyl)oxy]ethyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    2-(4-Chlorophenyl)-alpha-oxo-3-Indolizineacetic acid (2-fluorophenyl)methyl ester,    4-Fluoro-benzoic acid 2-[[[2-(4-chlorophenyl)-3-indolizinyl]oxoacetyl]amino]ethyl ester,    1-[[2-(4-Chlorophenyl)-3-indolizinyl]oxoacetyl]hexahydro-1H-azepine,    2-(4-Chlorophenyl)-alpha-oxo-3-indolizineacetic acid cyclopentyl ester,    2-(4-Chlorophenyl)-N-(2-hydroxyethyl)-alpha-oxo-3-indolizineacetamide,    4-(1,1-Dimethylethyl)-benzoic acid 2-[[[2-(4-chlorophenyl)-3-indolizinyl]oxoacetyl]amino]ethyl ester,    1-[Oxo(2-phenyl-3-indolizinyl)acetyl]-4-phenyl-piperazine,    2,6-Dimethyl-4-[oxo(2-phenyl-3-indolizinyl)acetyl]-morpholine,    N-1,3-Benzodioxol-5-yl-2-(4-chlorophenyl)-alpha-oxo-3-indolizineacetamide,    N-(4-Ethoxyphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(2,4-Dimethylphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(3-Hydroxypropyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-Methyl-N-(1-methyl-4-piperidinyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[3-[(Diethylamino)sulfonyl]-4-methylphenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(6-Methoxy-3-pyridinyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(3-Methoxyphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[4-Methyl-3-(4-morpholinylsulfonyl)phenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-2-phenyl-N-[3-(1-piperidinylsulfonyl)phenyl]-3-indolizineacetamide,    N-(4-Chloro-2-methoxy-5-methylphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(2-Chloro-3-pyridinyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[2-[[(4-Chlorophenyl)amino]carbonyl]phenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[5-[(Diethylamino)sulfonyl]-2-(4-morpholinyl)phenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-N-(3-phenoxyphenyl)-2-phenyl-3-indolizineacetamide,    alpha-Oxo-2-phenyl-N-[4-(trifluoromethyl)phenyl]-3-indolizineacetamide,    alpha-Oxo-2-phenyl-N-[4-(1-piperidinyl)phenyl]-3-indolizineacetamide,    4-Chloro-2-nitro-benzoic acid 3-[[oxo(2-phenyl-3-indolizinyl)acetyl]amino]propyl ester,    3-[(2,6-Dimethyl-4-morpholinyl)sulfonyl]-benzoic acid 3-[[oxo(2-phenyl-3-indolizinyl)acetyl]amino]propyl ester,    N-(2,3-Dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(3,5-Dimethoxyphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(3-Chloro-4-fluorophenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[4-[(Diethylamino)sulfonyl]phenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(3,4-Dimethylphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-N-(2-phenoxyphenyl)-2-phenyl-3-indolizineacetamide,    N-[5-(1,1-Dimethylethyl)-2-methoxyphenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-2-phenyl-N-[4-(1-piperidinylsulfonyl)phenyl]-3-indolizineacetamide,    N-(2,3-Dimethylphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(4-Bromo-2-fluorophenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-2-Naphthalenyl-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[2-Chloro-5-(4-morpholinylsulfonyl)phenyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    2,3-Dichloro-benzoic acid 3-[[oxo(2-phenyl-3-indolizinyl)acetyl]amino]propyl ester,    3,4-Dichloro-benzoic acid 3-[[oxo(2-phenyl-3-indolizinyl)acetyl]amino]propyl ester,    N-(2,4-Dimethoxyphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    2-(4-Chlorophenyl)-alpha-oxo-N-phenyl-3-indolizineacetamide,    4-[[2-(4-Chlorophenyl)-3-indolizinyl]oxoacetyl]-morpholine,    N-Ethyl-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-2-phenyl-N-[3-(trifluoromethyl)phenyl]-3-indolizineacetamide,    4-[[Oxo(2-phenyl-3-indolizinyl)acetyl]amino]-benzoic acid methyl ester,    N,N-Diethyl-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[2-(Dimethylamino)ethyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    2-Methyl-alpha-oxo-3-indolizineacetic acid,    N-(2-Methoxyphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-1-Naphthalenyl-alpha-oxo-2-phenyl-3-indolizineacetamide,    1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[oxo(2-phenyl-3-indolizinyl)acetyl]-isoquinoline,    N-(1-Cyano-1-methylethyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-2-phenyl-N-(2-phenylethyl)-3-indolizineacetamide,    Hexahydro-1-[oxo(2-phenyl-3-indolizinyl)acetyl]-1H-azepine,    alpha-Oxo-2-phenyl-N-4H-1,2,4-triazol-4-yl-3-indolizineacetamide,    1,2,3,4-Tetrahydro-1-[oxo(2-phenyl-3-indolizinyl)acetyl]-quinoline,    N-(6-Methoxy-2-benzothiazolyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-2-phenyl-N-2-thiazolyl-3-indolizineacetamide,    N-[(4-Methoxyphenyl)methyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-[(4-Bromophenyl)methyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-(1,1-Dimethylethyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    N-Butyl-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-N-[(3-phenoxyphenyl)methyl]-2-phenyl-3-indolizineacetamide,    N-Ethyl-alpha-oxo-N,2-diphenyl-3-indolizineacetamide,    alpha-Oxo-N,2-diphenyl-3-indolizineacetamide,    N-[2-(3,4-Dimethoxyphenyl)ethyl]-alpha-oxo-2-phenyl-3-indolizineacetamide,    alpha-Oxo-2-phenyl-N-(phenylmethyl)-3-indolizineacetamide,    4-[Oxo(2-phenyl-3-indolizinyl)acetyl]-morpholine,    N-(4-Methylphenyl)-alpha-oxo-2-phenyl-3-indolizineacetamide,    2-Methyl-alpha-oxo-3-indolizineacetic acid ethyl ester,    N,N-Dimethyl-2-phenyl-3-indolizineglyoxylamide,    2-Oxo-2-(2-phenyl-indolizin-3-yl)-N-(4-trifluoromethyl-phenyl)-acetamide,    N-(2,4-Dichloro-phenyl)-2-oxo-2-(2-phenyl-indolizin-3-yl)-acetamide,    2-Oxo-2-(2-phenyl-indolizin-3-yl)-N-(3-trifluoromethyl-phenyl)-acetamide,    2-Oxo-2-(2-phenyl-indolizin-3-yl)-N-(4-piperidin-1-yl-phenyl)-acetamide,