U.S. patent application number 09/729404 was filed with the patent office on 2001-08-23 for water-soluble prodrugs of azole compounds.
Invention is credited to Golik, Jerzy, Matiskella, John D., Ueda, Yasutsugu.
Application Number | 20010016662 09/729404 |
Document ID | / |
Family ID | 27382544 |
Filed Date | 2001-08-23 |
United States Patent
Application |
20010016662 |
Kind Code |
A1 |
Golik, Jerzy ; et
al. |
August 23, 2001 |
Water-soluble prodrugs of azole compounds
Abstract
Water soluble prodrugs of azole antifungal agents are provided
by quaternizing a nitrogen atom of the azole ring with a
phosphonooxymethyl group.
Inventors: |
Golik, Jerzy; (Southington,
CT) ; Matiskella, John D.; (Wallingford, CT) ;
Ueda, Yasutsugu; (Clinton, CT) |
Correspondence
Address: |
MARLA J MATHIAS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
27382544 |
Appl. No.: |
09/729404 |
Filed: |
December 4, 2000 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09729404 |
Dec 4, 2000 |
|
|
|
09503616 |
Feb 11, 2000 |
|
|
|
6235728 |
|
|
|
|
60120954 |
Feb 19, 1999 |
|
|
|
60124397 |
Mar 15, 1999 |
|
|
|
Current U.S.
Class: |
548/112 ;
548/118 |
Current CPC
Class: |
C07F 9/65583 20130101;
C07F 9/6506 20130101; C07F 9/6518 20130101 |
Class at
Publication: |
548/112 ;
548/118 |
International
Class: |
C07F 009/6506; C07F
009/6518 |
Claims
What is claimed is:
1. A compound of the formula 21wherein R and R.sup.1 are each
independently hydrogen or (C.sub.1-C.sub.6)alkyl, Z is nitrogen or
CH, Q is the residue of an azole compound of the formula
22possessing antifungal activity, X.sup..crclbar. is a
pharmaceutically acceptable anion and Y is a pharmaceutically
acceptable cation.
2. A compound of claim 1 wherein R and R.sup.1 are both
hydrogen.
3. A compound of the formula 23wherein Z is N, R and R.sup.1 are
each independently hydrogen or (C.sub.1-C.sub.6)alkyl, Q is
24X.sup..crclbar. is a pharmaceutically acceptable anion and Y is a
pharmaceutically acceptable cation.
4. A compound of the formula 25wherein Z is CH, R and R.sup.1 are
each independently hydrogen or (C.sub.1-C.sub.6)alkyl, Q is
26X.sup..crclbar. is a pharmaceutically acceptable anion and Y is a
pharmaceutically acceptable cation.
5. A compound of claim 3 or claim 4 wherein R and R.sup.1 are both
hydrogen.
6. A compound of the formula 27and its racemate wherein R and
R.sup.1 are each independently hydrogen or (C.sub.1-C.sub.6)alkyl
and X.sup..crclbar. is a pharmaceutically acceptable anion.
7. A compound of claim 6 wherein R and R.sup.1 are both
hydrogen.
8. A compound of the formula 28wherein R and R.sup.1 are each
independently hydrogen or (C.sub.1-C.sub.6)alkyl, X.sup..crclbar.
is a pharmaceutically acceptable anion and Y is a pharmaceutically
acceptable cation.
9. The compound,
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluoro-
phenyl)-1-(1H, 4-phosphonooxymethyl-1,2,4-triazol-1-yl)butan-2-ol,
or a pharmaceutically acceptable salt thereof.
10. A method for the treatment of fungal infections, which
comprises administering an effective antifungal amount of a
compound of claim 1 to a mammalian host in need thereof.
11. A pharmaceutical composition comprising a compound of claim 1
in admixture with a pharmaceutically acceptable adjuvant, diluent
or carrier.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] 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 1
[0003] wherein R and R.sup.1 are each independently hydrogen or
(C.sub.1-C.sub.6)alkyl, Z is nitrogen or CH, Q is the residue of an
azole compound of the formula 2
[0004] possessing antifungal activity, X.sup..crclbar. is a
pharmaceutically acceptable anion and Y is a pharmaceutically
acceptable cation.
[0005] 2. Description of the Prior Art
[0006] 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-y-
l]-2-(2,4-difluorophenyl)-1-(1H,1,2,4-triazol-1-yl)-butan-2-ol has
potent antifungal activity. 3
[0007] 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.
[0008] 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.
4
[0009] 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 5
[0010] Published European Patent Application 829,478 discloses
water-soluble azole compounds of the general formula 6
[0011] wherein
[0012] Q is the remainder of an azole compound of the formula 7
[0013] possessing antifungal activity;
[0014] Z is nitrogen or methine;
[0015] R.sup.1 and R.sup.2 are each independently hydrogen or --OY
in which Y is an easily hydrolyzable ester;
[0016] R.sup.3 and R.sup.4 are each independently a hydrogen or
halogen atom, lower alkyl, lower alkoxy, lower alkylthio,
(lower-alkylcarbonyl)th- iomethyl, carboxy or methoxycarbonyl; and
X.sup..crclbar. is a pharmaceutically acceptable anion.
[0017] 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 8
[0018] wherein R.sup.1 is an optionally substituted hydrocarbon
group or an optionally substituted heterocyclic group; R.sup.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
[0019] The present invention provides water-soluble azole
antifungal agents of the formula 9
[0020] wherein R and R.sup.1 are each independently hydrogen or
(C.sub.1-C.sub.6)alkyl, Z is nitrogen or CH, Q is the residue of an
azole compound of the formula 10
[0021] possessing antifungal activity, X.sup..crclbar. is a
pharmaceutically acceptable anion and Y is a pharmaceutically
acceptable cation.
[0022] 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.
[0023] Preferred among the compounds of formula I are those wherein
R and R.sup.1 are both hydrogen.
DETAILED DESCRIPTION OF THE INVENTION
[0024] As used herein "(C.sub.1-C.sub.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.
[0025] An anion represented by X.sup..crclbar. 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."
[0026] 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.
[0027] The compounds of the present invention can be solvated or
non-solvated. A preferred solvate is a hydrate.
[0028] Substituent "Z" in the azole ring may be nitrogen, e.g.
11
[0029] or CH, e.g. 12
[0030] 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.
[0031] A preferred group of compounds I are those wherein Z is
nitrogen and Q is 13
[0032] Another preferred group of azole antifungal agents II for
use in preparing compounds I are those wherein Z is CH and Q
represents 14
[0033] Compounds where R and R.sup.1 are both hydrogen are most
preferred in the above-mentioned two groups.
[0034] A preferred azole antifungal agent II is itraconazole.
[0035] 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 15
[0036] Compounds I prepared from this azole, especially the
compounds where R and R.sup.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.
[0037] The compounds of the present invention can be prepared
according to the procedures illustrated below. In general, the
triazole antifungal agent of the formula 16
[0038] 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 17
[0039] in which R and R.sup.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.degree. C. to form 18
[0040] in which Q, Z, X.sup..crclbar., R, R.sup.1 and Pr are as
defined above, followed by removal of the hydroxyl protecting
groups to give compound IA.
[0041] 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.degree. C. When a separate solvent is
employed the solvent may be slowly evaporated with a stream of
anhydrous nitrogen to form IV.
[0042] The most preferred hydroxy protecting group is the t-butyl
group, in which case, the t-butyl group is removed during the
quaternization process.
[0043] The preferred organic solvent is tetrahydrofuran and the
preferred bath temperature range is from about 75.degree. C. to
85.degree. C.
[0044] The so-obtained compound may be thereafter converted to a
compound having a different anion X.sup..crclbar., e.g. by anion
exchange, or converted to a desirable pharmaceutically acceptable
solvate, e.g. hydrate.
[0045] Zwitterionic form IB may be prepared from salt form IA by
use of column chromatography e.g. using reverse phase C.sub.18
silica gel, eluting with acetonitrile-water, followed by
crystallization from water.
[0046] The compound in form IC may be prepared from the salt form
IA by basification followed by column chromatography, e.g. using
reverse phase C.sub.18 silica gel, eluting with
acetonitrile-water.
[0047] The compounds of the present invention may be used alone or
formulated as pharmaceutical compositions comprising, in addition
to the active triazole ingredient, a pharmaceutically acceptable
carrier, adjuvant or diluent. The compounds may be administered by
a variety of means, for example, parenterally (intravenous or
intramuscular injection), orally or topically. The pharmaceutical
compositions may be in solid form such as capsules, tablets,
powders, etc. or in liquid form such as solutions, suspensions or
emulsions. Compositions for injection may be prepared in unit dose
form in ampules or in multidose containers and may contain
additives such as suspending, stabilizing and dispersing agents.
The compositions may be in ready-to-use form or in powder form for
reconstitution at the time of delivery with a suitable vehicle such
as sterile water.
[0048] Alternatively, the compounds of the present invention can be
administered in the form of a suppository or pessary, or they may
be applied topically in the form of a lotion, solution, or cream.
Additionally, they may be incorporated (at a concentration up to
10%) into an ointment consisting of a white wax or soft, white
paraffin base together with the required stabilizers and/or
preservatives.
[0049] The compounds of the invention are useful because they
possess pharmacological activities in animals, including
particularly mammals and most particularly, humans. Specifically,
the compounds of the present invention are useful for the treatment
of systemic fungal infections caused, for example, by species of
Candida such as Candida albicans, Cryptococcus neoformans,
Aspergillus flavus, Aspergillus fumigatus, Coccidioides,
Paracoccidiodes, Histoplasma, or Blastomyces, for the treatment of
mucosal infections caused by Candida albicans, and for the
treatment or prevention of topical fungal infections, including
those caused by species of Candida, Trichophyton, Microsporum, or
Epidermophyton.
[0050] Thus, according to another aspect of the invention, there is
provided a method of treating a fungal infection which comprises
administering a therapeutically effective amount of a compound of
the present invention to a host, particularly a mammalian host and
most particularly a human patient. The use of the compounds of the
present invention as pharmaceuticals and the use of the compounds
of the invention in the manufacture of a medicament for the
treatment of fungal infections are also provided.
[0051] The dosage to be administered depends, to a large extent, on
the particular compound being used, the particular composition
formulated, the route of administration, the nature and condition
of the host and the particular situs and organism being treated.
Selection of the particular preferred dosage and route of
application, then, is left to the discretion of the physician or
veterinarian. In general, however, the compounds may be
administered parenterally or orally to mammalian hosts in an amount
of from about 5 mg/day to about 1.0 g/day. These doses are
exemplary of the average case, and there can be individual
instances where higher or lower dosages are merited, and such
dosages are within the scope of this invention. Furthermore,
administration of the compounds of the present inventions can be
conducted in either single or divided doses.
[0052] The in vitro evaluation of the antifungal activities of the
compounds of the invention can be performed by determining the
minimum inhibitory concentration (MIC). The MIC is the
concentration of test compound which inhibits the growth of the
test microorganism. In practice, a series of agar plates, each
having the test compound incorporated at a specific concentration,
is inoculated with a fungal strain and each plate is then incubated
for 48 h at 37.degree. C. The plates are examined for the presence
or absence of fungal growth, and the relevant concentration is
noted. Microorganisms which can be used in the test include Candida
albicans, Asperigillus fumigatus, Trichophyton spp., Microsporum
spp., Epidermophyton floccosum, Coccidioides immitis, and
Torulopsos galbrata. It should be recognized that, as prodrugs,
some compounds of the invention may not be active in the in vitro
test.
[0053] The in vivo evaluation of compounds of the present invention
can be carried out at a series of dose levels by intraperitoneal,
subcutaneous or intravenous injection or by oral administration to
mice which have been inoculated with a strain of fungus (e.g.
Candida albicans). Activity is determined by comparing the survival
of the treated group of mice at different dosage levels after the
death of an untreated group of mice. The dose level at which the
test compound provides 50% protection against the lethal effect of
the infection is noted.
[0054] The compounds of the present invention substantially
increase the solubility of the parent triazole antifungal compound
and also release the bioactive parent compound (i.e. function as a
prodrug) in both rat and human liver homogenates (S 9
preparations).
ILLUSTRATIVE EXAMPLE
[0055] The following examples illustrate the invention, but are not
intended as a limitation thereof.
[0056] In the examples, all temperatures are given in degrees
Centigrade. Melting points were determined on an electrothermal
apparatus and are not corrected. Proton nuclear magnetic resonance
(.sup.1H NMR) spectra were recorded on a Bruker DPX-300, AM-300,
DRX-500, AM-500 or a Varian Gemini 300 spectrometer. Fluorine
nuclear magnetic resonance (.sup.19F NMR) spectra were recorded on
a Bruker DPX-300 spectrometer using trifluoroacetic acid as an
external reference (.delta.-76.0 ppm). All spectra were determined
in CDCl.sub.3, DMSO-d.sub.6, CD.sub.3OD, or D.sub.2O unless
otherwise indicated. Chemical shifts are reported in 8 units
relative to tetramethylsilane (TMS) or a reference solvent peak and
interproton coupling constants are reported in Hertz (Hz).
Splitting patterns are designated as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd,
doublet of doublets; dt, doublet of triplets; and app d, apparent
doublet, etc. Mass spectra were recorded on a Kratos MS-50 or a
Finnegan 4500 instrument utilizing direct chemical ionization (DCI,
isobutene), fast atom bombardment (FAB), or electron spray
ionization (ESI).
EXAMPLE 1
[0057]
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1--
(1H, 4-phosphonooxymethyl-1,2,4-triazol-1-yl)butan-2-ol 19
[0058] To a suspension of
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-
-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, 1 (2.17 g, 5
mmol) in THF (5 mL) was added di-tert-butyl chloromethyl phosphate
2 (2.58 g, 10 mmol). The mixture was heated at 75.degree. C. in an
oil bath with stirring under stream of anhydrous nitrogen. The THF
was slowly evaporated during 5-6 hrs period. After 18 hrs, the
viscous reaction mixture was heated at 85.degree. C. for another 20
hrs. After cooling, this crude thick oil was dissolved in a minimum
amount of 25% acetonitrile-water containing 10 mmol of
trifluoroacetic acid (TFA) and chromatographed on reverse phase
C.sub.18 silica using 25% acetonitrile-water containing 0.1% TFA as
an eluent. The concentration of acetonitrile was raised up to 35%
as the chromatography progressed. Pure fractions were concentrated,
frozen and lyophilized to give the title compound 3 (1.4 g, 2.12
mmol, 42% yield) as a white fluffy powder: .sup.1H NMR (DMSO-d6):
.delta. 10.12 (s, 1H), 9.02 (s, 1H), 8.45 (s, 1H), 8.20 (d, 2H,
J=9), 7.93 (d, 2H, J=9), 7.36-7.25 (m, 2H), 7.01-6.94 (m, 1H),
5.93-5.72 (m, 2H), 5.04 (d, 1H, J=14), 4.77 (d, 1H, J=14), 4.01 (q,
1H, J=7), 1.16 (d, 3H, J=7); MS (MH.sup.+=548); .sup.19F NMR
(DMSO-d6): d -74.55 (s, 4F), -107.5 (s, 1F), -111.1 (s, 1F); Anal.
Calcd for
C.sub.23H.sub.20F.sub.2N.sub.5O.sub.5SP/1.5CF.sub.3CO.sub.2H/0.5H.sub.2O:
C 42.92, H 3.12, N 9.63, F 16.97, H.sub.2O 1.30. Found: C 43.38,
H3.13, N 9.60, F 17.21, H.sub.2O 1.12 (Karl Fischer Method).
[0059] The zwitterionic form of the title compound was prepared as
white crystals from the trifluoroacetate salt by column
chromatography on reverse phase C.sub.18 silica gel, eluting with
30% acetonitrile-water as an eluent, followed by crystallization
from water: mp 145-155.degree. C.; .sup.1H NMR (DMSO-d6): .delta.
10.21 (s, 1H), 8.98 (s, 1H), 8.39 (s, 1H), 8.17 (d, 2H, J=9), 7.90
(d, 2H, J=9), 7.38-7.25 (m, 2H), 6.97-6.91 (m, 1H), 5.76-5.60 (m,
2H), 5.00 (d, 1H, J=14), 4.75 (d, 1H, J=14), 4.04 (q, 1H, J=7),
1.16 (d, 3H, J=7); MS (MH.sup.+=548); .sup.19F NMR (DMSO-d6):
.delta.-73.87 (s, 0.1F), -107.5 (s, 1F), -111.3 (s, 1F); Anal.
Calcd for
C.sub.23H.sub.20F.sub.2N.sub.5O.sub.5SP/0.05CF.sub.3CO.sub.2H/0.4H.sub.2O-
: C 49.51, H 3.75, N 12.50, F 7.29, H.sub.2O 1.29. Found: C 49.39,
H3.71, N 12.42, F 7.98, H.sub.2O 1.21 (Karl Fischer Method).
[0060] The sodium salt of the title compound was prepared as
amorphous powder from the trifluoroacetate salt by basification
with sodium hydroxide followed by column chromatography on reverse
phase C.sub.18 silica gel, eluting with acetonitrile-water.
Preparation of di-tert-butyl chloromethyl phosphate, 2:
[0061] Silver di-t-butyl phosphate (6.34 g, 20 mmol), which was
prepared by mixing di-t-butyl phosphate (obtained from di-t-butyl
phosphite by the method of Zwierzak and Kluba, Tetrahedron, 1971,
27, 3163) with one equivalent of silver carbonate in 50% aqueous
acetonitrile and by lyophilizing to dryness, was placed together
with chloroiodomethane (35 g, 200 mmol) in benzene and stirred at
room temperature for 18 hrs. The reaction mixture was filtered and
the filtrate concentrated under reduced pressure. The residue was
chromatographed on silica and eluted with 2:1 hexanes-ethyl
acetate. Appropriate fractions were concentrated to dryness to
obtain the subtitle compound 2 (3.7 g, 71% yield): .sup.1H NMR
(CDCl.sub.3) .delta. 5.63 (d, 2H, J=17), 1.51 (s, 18H); MS
(MH.sup.+= 259).
EXAMPLE 2
Preparation of N-phosphonooxymethyl itraconazole
[0062] 20
[0063] N-Phosphonooxymethyl itraconazole was prepared as
trifluoroacetate salt in 32% yield by the method described for the
preparation of 3 above from itraconazole (0.5 mmol) and
di-tert-butyl chloromethyl phosphate 2 (2 mmol): .sup.1H NMR
(DMSO-d6): .delta. 10.44 (s, 2/3H), 10.40 (s, 1/3H), 9.33 (s,
2/3H), 9.31 (s, 1/3H), 8.33 (s, 1H), 6.8-7.7 (m, 11H), 5.91 (d,
4/3H, J=14), 5.79 (d, 2/3H, J=14), 5.08-5.18 (m, 2H), 4.37 (m, 1H),
4.10 (m, 1H), 3.93 (m, 2H), 3.76 (m, 2H), 3.34 (br.s, 4H), 3.22 (m,
4H), 1.64-1.71 (m, 2H), 1.27 (d, 3H, J=7), 0.78 (t, 3H, J=7); MS
(MH.sup.+=815); Anal. Calcd for
C.sub.36H.sub.41Cl.sub.2N.sub.8O.sub.8P/1- .6CF.sub.3CO.sub.2H/H2O:
C 46.34, H 4.42, N 11.03, H.sub.2O 1.79. Found: C 46.03, H 4.46, N
11.08, H.sub.2O 1.64 (Karl Fischer Method).
* * * * *