Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-09
2002-05-07
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S367000, C544S371000, C544S357000, C544S121000, C544S364000, C514S252110, C514S253100
Reexamination Certificate
active
06384030
ABSTRACT:
The present invention is concerned with water soluble azoles as broad-spectum 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 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 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 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-aryloxymethyl-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.
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)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 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 disclose tetrahydrofuran antifungals, which are taught to be soluble and/or suspensible in an aqueous medium suitable for intravenous administration, containing substitution groups readily convertible in vivo into hydroxy groups.
Saksena et al. in Bioorganic & Medicinal Chemistry Letters (1995), 5(2), 127-132, discloses some tetrahydrofuran based azole antifungals such as (3R-cis)-4-[4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[2-(dimethylamino)ethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one. Saksena et al. reported of said azole that, when compared to SCH 51048, it was profoundly less active as antifungal.
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 pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein
L represents a radical of formula
wherein
each Alk independently represents C
1-6
alkanediyl optionally substituted with hydroxy or C
1-4
alkyloxy;
each n independently is 1, 2 or 3;
Y represents O, S or NR
2
;
each R
1
independently represents hydrogen, aryl, Het
1
, or C
1-6
alkyl optionally substituted with one, two or three substituents each independently 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 or Het
2
;
each R
2
independently represents hydrogen or C
1-6
alkyl; or
in case R
1
and R
2
are attached to the same nitrogen atom, they may be taken together to form a heterocyclic radical selected from morpholinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl; said heterocyclic radical may optionally be substituted with C
1-4
alkyl, aryl, Het
2
, arylC
1-4
alkyl, Het
2
C
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; or they may be taken together to form an azido radical;
each R
3
independently represents hydrogen, hydroxy or C
1-4
alkyloxy;
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
1
represents a monocyclic or bicyclic heterocyclic radical; said monocyclic heterocyclic radical being selected from the group pyridinyl, 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-tetra-hydro-quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phtalazinyl
Backx Leo Jacobus Jozef
Heeres Jan
Meerpoel Lieven
Odds Frank Christopher
Van der Veken Louis Jozef Elisabeth
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