Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-10-16
2002-09-10
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S337000, C548S112000, C558S087000
Reexamination Certificate
active
06448401
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to an improved process for preparing certain water-soluble azole compounds useful in the treatment of serious systemic fungal infections. More particularly, the present invention relates to an improved process for preparing the water-soluble prodrugs having the general formula
Wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, R and R
1
are each independently hydrogen or (C
1
-C
6
)alkyl, and pharmaceutically acceptable salts thereof.
DESCRIPTION OF THE PRIOR ART
Triazole antifungal compounds are well known in the prior art. Of the several classes known, one particularly potent class contains a tertiary hydroxyl group. For example, U.S. Pat. No. 5,648,372 discloses that (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1 H-1,2,4-triazol-1-yl)-butan-2-ol has anti-fungal 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 this problem was disclosed in European Patent Application 829478, 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
U.S. Pat. No. 5,707,977 and WO 95/19983 disclose water soluble prodrugs having the general formula
wherein X is OP(O)(OH)
2
or an easily hydrolyzable ester OC(O)RNR
1
R
2
.
WO 95/17407 discloses water-soluble azole prodrugs of the general formula
wherein X is P(O)(OH)
2
, C(O)—(CHR
1
)
n
—OP(O)(OH)
2
or C(O)—(CHR
1
)
n
—(OCHR
1
CHR
1
)
m
OR
2
.
WO 96/38443 discloses water-soluble azole prodrugs of the general formula
U.S. Pat. No. 5,883,097 discloses water-soluble amino acid azole prodrugs such as the glycine ester
The introduction of the phosphonooxymethyl moiety into hydroxyl containing drugs has been disclosed as a method to prepare water-soluble prodrugs of hydroxyl containing drugs.
European Patent No. Application 604910 discloses phosphonooxymethyl taxane derivatives of the general formula
wherein at least one of R
1′
, R
2″
, R
3′
, R
6′
or R
7′
is OCH
2
OP(O)(OH)
2
.
European Patent No. Application 639577 discloses phosphonooxymethyl taxane derivatives of the formula T-[OCH
2
(OCH
2
)
m
OP(O)(OH)
2
]
n
wherein T is a taxane moiety bearing on the C13 carbon atom a substituted 3-amino-2-hydroxypropanoyloxy group; n is 1, 2 or 3; m is 0 or an integer from 1 to 6 inclusive, and pharmaceutically acceptable salts thereof.
WO 99/38873 discloses O-phosphonooxymethyl ether prodrugs of a diaryl 1,3,4-oxadiazolone potassium channel opener.
Golik, J. et al,
Bioorganic & Medicinal Chemistry Letters,
1996, 6:1837-1842 discloses novel water soluble prodrugs of paclitaxel such as
In pending U.S. Provisional Patent No. Application Ser. No. 60/177,169 filed Jan. 20, 2000 by our colleagues, Yasutsugu Ueda, John D. Matiskella, Jerzy Golik and Thomas W. Hudyma, the entire disclosure of which is hereby incorporated by reference, there is described the series of water-soluble prodrugs having general formula I shown below
wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, R and R
1
are each independently hydrogen or (C
1
-C
6
)alkyl, and pharmaceutically acceptable salts thereof.
The compounds of general formula I are prepared in the above application by the following reaction scheme.
In this method, A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary or secondary hydroxyl group, Pr represents conventional hydroxy-protecting groups such as t-butyl, benzyl or allyl, and R and R
1
are each independently hydrogen or (C
1
-C
6
)alkyl. In a preferred embodiment, R and R
1
are both hydrogen.
The antifungal compound of interest, II, is converted into phosphate ester intermediate IV by O-alkylation with chloride intermediate III in the presence of a suitable base such as sodium hydride. Ester intermediate IV is then subjected to a conventional de-protection step to remove the hydroxyl-protecting groups Pr and give end product I which, if desired, may be converted to a desired pharmaceutically acceptable salt.
The present invention greatly improves on the above process by allowing the O-alkylation step to be carried out in substantially increased yield.
SUMMARY OF THE INVENTION
The present invention represents an improved process for preparing the water-soluble antifungal prodrugs of general formula I
above. More particularly, the present invention is directed to a process for the preparation of a water-soluble prodrug of the formula
wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, and R and R
1
are each independently hydrogen or (C
1
-C
6
)alkyl, or a pharmaceutically acceptable salt thereof, which comprises
(a) reacting a compound of the formula A—OH wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group with a compound of the formula
in which R and R
1
are as defined above and Pr represents a hydroxyl-protecting group with a source of iodide ion in an inert organic solvent and in the presence of base at a temperature of from about 25° C. to 50° C. to form an intermediate of the formula
wherein Pr, A, R and R
1
are as defined above, and
(b) removing the protecting groups Pr from intermediate IV by conventional means to produce a compound of the formula
and, if desired, converting said compound I by conventional means to a pharmaceutically acceptable salt thereof.
The compounds of general formula I function as “prodrugs” when administered in vivo, i.e. they are converted to the biologically active parent azole in the presence of alkaline phosphatase.
DETAILED DESCRIPTION
As used herein “(C
1
-C
6
)alkyl” refers to a straight or branched chain saturated aliphatic group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, etc.
The term “pharmaceutically acceptable salt” as used herein is intended to include phosphate salts with such counterions as ammonium, metal salts, salts with amino acids, salts with amines and salts with other bases such as piperidine or morpholine. Both mono- and bis-salts are intended to be encompassed by the term “pharmaceutically acceptable salts”. Specific embodiments include ammonium, sodium, calcium, magnesium, cesium, lithium, potassium, barium, zinc, aluminum, lysine, arginine, histidine, methylamine, ethylamine, t-butylamine, cyclohexylamine, N-methylglucamine, ethylenediamine, glycine, procaine, benzathene, diethanolamine, triethanolamine, piperidine and morpholine. For the most preferred embodiment, (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[(dihydrogen phosphonoxy)methoxy]butane, the t-butylamine and lysine salts are especially preferred as they can be obtained as single polymorph crystalline solids of high purity with good solubility and stability.
The compounds of formula I can be solvated or non-solvated. A preferred solvate is a hydrate.
A most preferred compound prepared by the present invention is (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[(dihydrogen phosphonoxy)methoxy]butane or a pharmaceutically acceptable salt thereof. This prodrug exhibits much improved aqueous solubility (>10 mg/mL at pH 7, 5-6 mg/mL at pH 4.3) compared with the parent compound which enables it to be used for parenteral admin
Chen Chung-Pin
Connolly Timothy Paul
Kolla Laxma Reddy
Matiskella John D.
Mueller Richard H.
Bristol--Myers Squibb Company
McKane Joseph K.
Morse David M.
Shameen Golam M M
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