Antifungal ethers

Details Antifungal ethers Antifungal ethers

2002-02-04

2003-06-24

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235800, C514S252110, C514S254070, C544S121000, C544S357000, C544S366000, C544S370000, C540S598000

Reexamination Certificate

active

06583136

ABSTRACT:

The present invention is concerned with water soluble azole containing ethers as broad-spectrum antifungals and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
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. 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 immuno-compromised 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 immuno-compromised patients. However, concern is growing about fungal resistance to some of these agents, especially these with a relatively 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 this group of patients.
Also the treatment of onychomycosis, i.e. fungal infection of the nails, may well be served by potent water soluble antifungals. It is long desired to treat onychomycosis via the transungual route. The problem that then arises is to ensure that the antifungal agents will penetrate into and beneath the nail. Mertin and Lippold (J. Pharm.
Pharmacol. (1997), 49, 30-34) stated that in order to screen for drugs for topical application to the nail plate, attention has to be paid mainly to the water solubility of the compound. The maximum flux through the nail is beneficially influenced by increasing the water solubility of the antifungal. Of course, efficacy in treating onychomycosis via the transungual route is also dependent on the potency of the antifungal.
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 or transungually. 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 or transungual 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 available as a broad-spectrum antifungal on a world-wide basis.
EP-A-0, 118,138 and EP-A-0,228,125 disclose 4-[4-[4-[4-[[2-aryl-2-azolyl-1,3dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-alkyloxyalkyl-3H-1,2,4-triazol-3-one derivatives as antifungals. WO 95/17407 discloses tetrahydrofuran antifungals as well as WO 96/38443 and WO 97/00255. The latter two publications disclose tetrahydrofuran antifungals, which are taught to be soluble and/or suspendible in an aqueous medium suitable for intravenous administration, containing substitution groups readily convertible in vivo into hydroxy groups.
Unexpectedly, the compounds of the present invention are potent broad-spectrum antifungals with good water solubility.
The present invention concerns compounds of formula
the N-oxide forms, the salts, the quaternary amines and stereochemically isomeric forms thereof, wherein
D represents a radical of formula
 wherein the dotted line represents the bond attaching D to the remainder of the compound of formula (1);
X is N or CH;
R
3
is hydrogen or halo;
R
4
is halo;
—A—B— represents a bivalent radical of formula
—N═CH—  (i),
—CH═N—  (ii),
—CH═CH—  (iii),
—CH
2
—CH
2
  (iv),
wherein one hydrogen atom in the radicals (i) and (ii) may be replaced by a C
1-4
alkyl radical and one or more hydrogen atoms in radicals (iii) and (iv) may be replaced by a C
1-4
alkyl radical;
Alk represents C
1-6
alkanediyl;
Y represents C
1-6
alkanediyl optionally substituted with one or two substituents selected from halo, hydroxy, mercapto, C
1-4
alkyloxy, C
1-4
alkylthio, aryloxy, arylthio, arylC
1-4
alkyloxy, arylC
1-4
alkylthio, cyano, amino, mono- or di(C
1-4
alkyl)amino, mono- or di(aryl)amino, mono- or di(arylC
1-4
alkyl)amino, C
1-4
alkyloxycarbonylamino, benzyloxycarbonylamino, aminocarbonyl, carboxyl, C
1-4
alkyloxycarbonyl, guanidinyl, aryl and Het;
R
1
represents hydrogen, C
1-4
alkyl or arylC
1-6
alkyl; R
2
represents hydrogen, C
1-4
alkyl or arylC
1-6
alkyl; or R
1
and R
2
may be taken together to form a heterocyclic radical selected from morpholinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl or phthalimid-1-yl; said heterocyclic radical may optionally be substituted with C
1-4
alkyl, aryl, Het, arylC
1-4
alkyl, HetC
1-4
alkyl, hydroxyC
1-4
alkyl, amino, mono- or di(C
1-4
alkyl)amino, aminoC
1-4
alkyl, mono- or di(C
1-4
alkyl)aminoC
1-4
alkyl, carboxyl, aminocarbonyl, C
1-4
alkyloxycarbonyl; C
1-4
alkyloxycarbonylamino or mono- or di(C
1-4
alkyl)aminocarbonyl;
aryl represents phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl, indenyl or indanyl; each of said aryl groups may optionally be substituted with one or more substituents selected from halo, C
1-4
alkyl, hydroxy, C
1-4
alkyloxy, nitro, amino, trifluoromethyl, hydroxyC
1-4
alkyl, C
1-4
alkyloxyC
1-4
alkyl, aminoC
1-4
alkyl, mono- or di(C
1-4
alkyl)aminoC
1-4
alkyl;
Het represents a monocyclic or bicyclic heterocyclic radical; said monocyclic heterocyclic radical being selected from the group piperazinyl, homopiperazinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, pyranyl, tetrahydropyranyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, oxazolidinyl, isoxazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl; said bicyclic heterocyclic radical being selected from the group quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phtalazinyl, cinnolinyl, chromanyl, thiochromanyl, 2H-chromenyl, 1,4-benzodioxanyl, indolyl, isoindolyl, indolinyl, indazolyl, purinyl, pyrrolopyridinyl, furanopyridinyl, thienopyridinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, benzofuranyl, benzothienyl; whereby each of said mono- or bicyclic heterocycle may optionally be substituted with one or where possible more substituents selected from halo, C
1-4
alkyl, hydroxy, C
1-4
alkyloxy, nitro, amino, trifluoromethyl, hydroxyC
1-4
alkyl, C
1-4
alkyloxy-C
1-4
alkyl, aminoC
1-4
alkyl, mono- or di(C
1-4
alkyl)aminoC
1-4
alkyl, aryl or arylC
1-4
alkyl.

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