Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-02-11
2001-05-22
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C548S112000
Reexamination Certificate
active
06235728
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel water-soluble azole compounds useful for the treatment of serious systemic fungal infections and suitable for both oral and, particularly, parenteral administration. More particularly, the invention relates to novel water-soluble prodrugs having the general formula
wherein R and R
1
are each independently hydrogen or (C
1
-C
6
)alkyl, Z is nitrogen or CH, Q is the residue of an azole compound of the formula
possessing antifungal activity, X
⊖
is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.
2. Description of the Prior Art
Azole antifungal compounds are well-known in the prior art. U.S. Pat. No. 5,648,372 discloses that (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H,1,2,4-triazol-1-yl)-butan-2-ol has potent antifungal activity.
The utility of this class of compounds is limited by their low water-solubility. For example, the solubility of the above triazole compound in water at pH 6.8 is 0.0006 mg/mL. This greatly impedes developing suitable parenteral dosage forms.
One method of addressing the solubility problem is disclosed in European Published Application 829,478 where the water-solubility of an azole antifungal agent was increased by attaching a linked amino-acid to the azole portion of the molecule.
Alternatively, WO 97/28169 discloses that a phosphate moiety can be attached directly to the tertiary hydroxyl portion of the anti-fungal compound, e.g. the compound having the formula
Published European Patent Application 829,478 discloses water-soluble azole compounds of the general formula
wherein
Q is the remainder of an azole compound of the formula
possessing antifungal activity;
Z is nitrogen or methine;
R
1
and R
2
are each independently hydrogen or —OY in which Y is an easily hydrolyzable ester;
R
3
and R
4
are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower-alkylcarbonyl)thiomethyl, carboxy or methoxycarbonyl; and X
⊖
is a pharmaceutically acceptable anion.
Published PCT Application WO 98/43970 discloses quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compounds where one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo and the substituent can be eliminated in vivo to be converted into an azole antifungal compound. Specifically disclosed are prodrugs wherein the nitrogen atom of the azole ring is quaternized by a group of the formula
wherein R
1
is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; R
2
is a hydrogen atom or a lower alkyl group; X is a nitrogen atom or a methine group; and n is 0 or 1.
SUMMARY OF THE INVENTION
The present invention provides water-soluble azole antifungal agents of the formula
wherein R and R
1
are each independently hydrogen or (C
1
-C
6
)alkyl, Z is nitrogen or CH, Q is the residue of an azole compound of the formula
possessing antifungal activity, X
⊖
is a pharmaceutically acceptable anion and Y is a pharmaceutically acceptable cation.
The compounds of general formula IA, IB and IC function as “prodrugs” when administered in vivo, being converted to the biologically active parent azole in the presence of alkaline phosphatase.
Preferred among the compounds of formula I are those wherein R and R
1
are both hydrogen.
DETAILED DESCRIPTION OF THE INVENTION
As used herein “(C
1
-C
6
)alkyl” refers to a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, etc.
An anion represented by X
⊖
is derived from a pharmaceutically acceptable organic or inorganic acid, e.g. inorganic acids such as hydrochloric, sulfuric, phosphoric, hydrofluoric, hydrobromic, hydroiodic, etc. or aliphatic, aromatic or araliphatic organic acids such as acetic, propionic, methanesulfonic, benzenesulfonic, maleic, citric, succinic, fumaric, mandelic, ascorbic, lactic, gluconic, toluenesulfonic, trifluoromethanesulfonic, trifluoroacetic, etc. Such compounds are also referred to as “pharmaceutically acceptable salts.”
The “Y” substituent shown in structure IC above is a pharmaceutically acceptable cation such as ammonium, an alkali metal (e.g. Na, K, Li, etc.), an alkaline earth metal (e.g. Ca, Mg) or salts with suitable organic bases such as (lower) alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted (lower) alkylamines, e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)-aminomethane), or with bases such as piperidine or morphiline.
The compounds of the present invention can be solvated or non-solvated. A preferred solvate is a hydrate.
Substituent “Z” in the azole ring may be nitrogen, e.g.
or CH, e.g.
The azole of formula II can be a wide variety of azole antifungal agents, including known azole antifungal agents such as miconazole, ketoconazole, fluconazole, itraconazole, saperconazole, clotrimazole, econazole, isoconazole, sulconazole, butoconazole, tioconazole, fenticonazole, omoconazole, flutrimazole, eberconazole, lanoconazole, neticonazole, sertaconazole, genaconazole, Sch-56592, Sch-51048, VR-9746, MFB-1041, VR-9751, T-8581, VR-9825, SSY-726, D-0870, KP-103, ER-30346, etc. The azole compounds, however, are not limited to known antifungal agents and any azole compound of formula II possessing clinically useful antifungal activity is suitable for use in the present invention. The azoles having optical centers may be employed in the form of racemic mixtures or individual separated enantiomers.
A preferred group of compounds I are those wherein Z is nitrogen and Q is
Another preferred group of azole antifungal agents II for use in preparing compounds I are those wherein Z is CH and Q represents
Compounds where R and R
1
are both hydrogen are most preferred in the above-mentioned two groups.
A preferred azole antifungal agent II is itraconazole.
An especially preferred azole antifungal agent II is (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H,1,2,4-triazol-1-yl)-butan-2-ol described in U.S. Pat. No. 5,648,372 and having the structural formula
Compounds I prepared from this azole, especially the compounds where R and R
1
are both hydrogen, exhibit much improved aqueous solubility (>1 mg/ml) over the parent triazole which enables them to be useful for parenteral administration as well as oral administration. Also, these compounds are stable in solution, can be isolated in crystalline form and are readily converted to parent drug in vivo.
The compounds of the present invention can be prepared according to the procedures illustrated below. In general, the triazole antifungal agent of the formula
wherein Z is nitrogen or CH and Q is the residue of an azole compound having antifungal activity is quaternized with a reagent of the formula
in which R and R
1
are as defined above and Pr represents a hydroxyl protecting group such as t-butyl, benzyl or allyl in the presence or absence of an organic solvent such as tetrahydrofuran, acetonitrile or acetone at a temperature above about 75° C. to form
in which Q, Z, X
⊖
, R, R
1
and Pr are as defined above, followed by removal of the hydroxyl protecting groups to give compound IA.
The quaternization may be achieved in the absence or in the presence of other aprotic solvents such as dimethylformaldehyde, dimethylacetaldehyde and N-methylpyrrolidinone at an elevated temperature of above about 75° C. When a separate solvent is employed the solvent may be slowly evaporated with a stream of anhydrous nitrogen to form IV.
The most preferred hydroxy protecting group is the t-butyl group, in which case, the t-butyl group is removed during the quaternization process.
The preferred organic solvent is tetrahydrofuran and the preferred bath temperature range is from about 75° C. to 85° C.
The so-obta
Golik Jerzy
Matiskella John D.
Ueda Yasutsugu
Bristol--Myers Squibb Company
Lambkin Deborah C.
Morse David M.
Wright Sonya N.
LandOfFree
Water-soluble prodrugs of azole compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Water-soluble prodrugs of azole compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Water-soluble prodrugs of azole compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2551850