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Description  |
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FIELD OF THE INVENTION
The present invention relates to methods useful in combating Pneumocystis
carinii pneumonia and prodrug compounds useful therefor.
BACKGROUND OF THE INVENTION
Pentamidine is used for the treatment of Pneumocystis carinii pneumonia, or
"PCP". The importance of pentamidine has dramatically escalated recently
due to the marked increase of patients suffering from PCP. The increase in
the afflicted patient population is an unfortunate consequence of the
increasing presence of the Acquired Immunodeficiency Syndrome ("AIDS"). It
is now estimated that approximately 70 percent of AIDS patients contract
PCP. Because of the high incidence of PCP in AIDS patients, pentamidine
has found utility not only in the treatment of PCP, but also as
prophylaxis, in preventing or delaying the initial onset or recurrence of
PCP, especially in AIDS patients. Currently, pentamidlne is most commonly
administered as a therapeutic agent by intravenous infusion and as a
prophylactic agent by aerosol dosage.
However, an unfortunate side effect of pentamidine is its toxicity. Some
fatalities have been attributed to severe hypotension, dysglycemia, and
cardiac arrhythmias in patients treated with pentamidine. Contrawise,
insufficient dosage may result in dissemination of disease beyond the
lung, an occurrence which is associated with a poor prognosis. Therapeutic
drug monitoring is not used because of the cost and complexity of the
currently available assay techniques which require the extraction of
plasma and High Performance Liquid Chromatography (HPLC) analysis. As a
result, the toxicity of pentamidine is a significant concern, which is
driving the market toward the development of pentamidine substitutes
capable of avoiding or minimizing the undesirable side effects associated
with the use of pentamidine. See, e.g., J. Spychala et al., Eur. J. Med.
Chem. 29, 363-367 (1994); I. O. Donkor et al., J. Med. Chem. 37, 4554-4557
(1994); R. R. Tidwell et al., J. Protozool. 6, 148S-150S (1991).
Accordingly, it is an object of the present invention to provide new
compounds useful in the treatment of P. carinii pneumonia.
SUMMARY OF THE INVENTION
A method of treating Pneumocystis carinii pneumonia in a subject in need of
such treatment is disclosed. The method comprises orally administering to
the subject a bis-benzamidoxime, derivative thereof, or a pharmaceutically
acceptable salt thereof (hereinafter referred to as the "active
compound"), that is reduced in the subject to produce a benzamidine having
anti-P. carinii activity. The method of the present invention may
alternatively comprise intravenously administering to the subject an
active compound as disclosed herein.
A second aspect of the present invention is a pharmaceutical formulation
comprising, in combination with a pharmaceutically acceptable carrier, a
bis-benzamidoxime, or a pharmaceutically acceptable salt thereof, that is
reduced in a mammalian subject after administration thereto to produce a
benzamidine having anti-Pneumocystis carinii activity, subject to the
proviso that said bis-benzamidoxime is not
1,5-bis(4'-(N-hydroxyamidino)phenoxy)pentane.
A third aspect of the present invention are active compounds useful in
carrying out a therapeutic method of the present invention.
A fourth aspect of the present invention is the use of an active compound
as disclosed herein for the manufacture of a medicament useful in carrying
out a therapeutic method of treatment as given above.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a spectral illustration of the metabolism of bis-benzamidoximes
of the present invention by rat liver homogenate 9000.times.g supernatant
fraction. In the metabolism studies illustrated in FIGS. 1A, 1B, 1C, and
1D, homgenates containing 167 .mu.M test compound as substrate plus a
cofactor solution were incubated at 37.degree. C. for 10 minutes, then
assayed by HPLC as described below in Example 7. In all Figures, "IS"
means internal standard. FIG. 1A illustrates the metabolism of compound 1
into its amidine analog pentamidine (indicated in the Figure by the
numeral 2) and its monoamidine-monoamidoxime derivative (indicated in the
Figure by the numeral 9). FIG. 1B illustrates the metabolism of compound 3
into its amidine analog (indicated in the Figure by the numeral 4). FIG.
1C illustrates the metabolism of compound 5 into its amidine analog
(indicated in the Figure by the numeral 6). FIG. 1D illustrates the
metabolism of compound 7 into its amidine analog (indicated in the Figure
by the numeral 8).
FIG. 2 is a graphical illustration of the time course of reduction of
bis-benzamidoxime compound 1 to its monoamidine-monoamidoxime product
expressed by the measure of nmol of product/mg of protein (y-axis value)
as a function of time in minutes (x-axis value). The open circles
represent data points for the reduction of compound 1 in the rat liver
post-mitochondrial supernatant fraction described below in Example 7. The
closed circles represent data points for the reduction of compound 1 in
the rat liver microsomal fractions, also described in Example 7.
FIG. 3 is a spectral illustration of the metabolism of bis-benzamidoxime
compound 1 into its amidine analog pentamidine (indicated in the Figure by
the numeral 2) and its monoamidine-monoamidoxime derivative (indicated in
the Figure by the numeral 9) by the 9000.times.g supernatants of
homogenates of rat liver (FIG. 3A); rat kidney (FIG. 3B); rat lung (FIG.
3C) and rat heart (FIG. 3D).
FIG. 4 is a spectral illustration of the metabolism of bis-benzamidoximes
of the present invention in intact BRL 3A hepatocytes in vitro. In the
metabolism studies illustrated in FIGS. 4A, 4B, 4C, and 4D, cells cultured
in Ham's F-12 medium containing 5% fetal bovine serum and 10 .mu.M
diamidoxime substrate were incubated for 24 hours at 37.degree. C. under
5% CO.sub.2. The extracellular medium was extracted and then assayed by
HPLC as described below in Example 7. In all Figures, "IS" means internal
standard. FIG. 4A illustrates the metabolism of compound 1 into its
amidine analog pentamidine (indicated in the Figure by the numeral 2) and
its monoamidine-monoamidoxime derivative (indicated in the Figure by the
numeral 9). FIG. 4B illustrates the metabolism of compound 3 into its
amidine analog (indicated in the Figure by the numeral 4). FIG. 4C
illustrates the metabolism of compound 5 into its amidine analog
(indicated in the Figure by the numeral 6). FIG. 4D illustrates the
metabolism of compound 7 into its amidine analog (indicated in the Figure
by the numeral 8).
DETAILED DESCRIPTION OF THE INVENTION
Active compounds of the present invention are, in general, the
bis-benzamidoxime derivatives of benzamidines that have anti-Pneumocystis
carinii activity. The benzamidines having anti-P. carinii activity may be
mono-benzamidines, wherein one amidoxime group of the bis-benzamidoxime
derivative is reduced; alternatively, they may be bis-benzamidines wherein
both amidoxime groups of the bis-benzamidoxime derivative are reduced.
Thus, bis-benzamidoxime derivatives of benzamidines having anti-P. carinii
activity are an aspect of the present invention. Examples of such
benzamidines are disclosed in, e.g., U.S. Pat. No. 2,277,861 to Ewins et
al.; U.S. Pat. No. 2,410,796 to Newberry et al.; U.S. Pat. No. 4,933,347
to Tidwell et al.; and PCT Application No. US93/09477 (applicant
specifically intends the disclosure of these and all other patent
references cited herein to be incorporated herein by reference).
As used herein, the term "cycloalkyl" as used herein refers to C3 to C6
cyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl. Cyclohexyl and cyclopentyl are currently preferred. The term
"aryl" as used herein refers to C3 to C10 cyclic aromatic groups such as
phenyl, naphthyl, and the like, and includes substituted aryl groups such
as tolyl. The term "hydroxyalkyl" as used herein refers to C1 to C4 linear
or branched hydroxy-substituted alkyl, i.e., --CH.sub.2 OH,
--(CH.sub.2).sub.2 OH, etc. The term "aminoalkyl" as used herein refers to
C1 to C4 linear or branched amino-substituted alkyl, wherein the term
"amino" refers to the group NR'R", wherein R' and R" are independently
selected from H or lower alkyl as defined above, i.e., --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, etc. The term "oxyalkyl" as used herein
refers to C1 to C4 oxygen-substituted alkyl, i.e., --OCH.sub.3, and the
term "oxyaryl" as used herein refers to C3 to C10 oxygen-substituted
cyclic aromatic groups.
One preferred group of compounds useful in the practice of the present
invention are bis-benzamidoximes of the formula I:
##STR1##
wherein:
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl,
hydroxyalkyl, aminoalkyl or alkylaminoalkyl;
R.sub.3 is H, loweralkyl, oxyalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl,
aryl, aminoalkyl, alkylaminoalkyl or halogen;
n is from 2 to 6;
X is O or S; and
Y is H or loweralkyl;
or pharmaceutically acceptable salts thereof.
A second preferred group of compounds useful in the practice of the present
invention are bis-benzamidoximes of the formula II:
##STR2##
wherein:
R.sub.1 and R.sub.2 are each independently selected from the group
consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl,
hydroxyalkyl, aminoalkyl or alkylaminoalkyl;
R.sub.3 is H, loweralkyl, oxyalkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl,
aryl, aminoalkyl, alkylaminoalkyl or halogen;
R.sub.4 is --OY, or R.sub.1 and R.sub.4 together represent
##STR3##
wherein R.sub.5 is
##STR4##
Y is H or loweralkyl;
n is an integer from 0 to 2; and
A is a heterocyclic aromatic group selected from the group consisting of:
##STR5##
wherein R.sub.6 and R.sub.7 are each independently selected from the group
consisting of H, loweralkyl, halogen, oxyalkyl, oxyaryl, or oxyarylalkyl;
or pharmaceutically acceptable salts thereof.
As noted above, the methods of the present invention are useful for
treating P. carinii pneumonia. The methods of the present invention are
useful for treating these conditions in that they inhibit the onset,
growth, or spread of the condition, cause regression of the condition,
cure the condition, or otherwise improve the general well-being of a
subject inflicted with, or at risk of contracting the condition.
Subjects to be treated by the methods of the present invention are
typically human subjects, although the methods of the present invention
may be useful with any suitable subject known to those skilled in the art.
As noted above, the present invention provides pharmaceutical formulations
comprising the aforementioned active compounds, or pharmaceutically
acceptable salts thereof, in pharmaceutically acceptable carriers for
oral, intravenous, or aerosol administration as discussed in greater
detail below.
The therapeutically effective dosage of any specific compound, the use of
which is in the scope of present invention, will vary somewhat from
compound to compound, patient to patient, and will depend upon the
condition of the patient and the route of delivery. As a general
proposition, a dosage from about 0.1 to about 100 mg/kg will have
therapeutic efficacy, with all weights being calculated based upon the
weight of the active base, including the cases where a salt is employed. A
dosage from about 10 mg/kg to about 50 mg/kg may be employed for oral
administration. The duration of the treatment is usually once per day for
a period of two to three weeks or until the P. carinii pneumonia is
essentially controlled. Lower doses given less frequently can be used to
prevent or reduce the incidence of recurrence of the infection.
In accordance with the present method, an active compound as described
herein, or a pharmaceutically acceptable salt thereof, may be administered
orally as a solid or as a liquid, or may be administered intravenously.
Alternatively, the active compound or salt may also be administered by
inhalation. When administered through inhalation the active compound or
salt should be in the form of a plurality of solid particles or droplets
having a particle size from about 0.5 to about 5 microns, preferably from
about 1 to about 2 microns.
Besides providing a method for treating P. carinii pneumonia, the active
compounds of the present invention also provide a method for prophylaxis
against P. carinii pneumonia in an immunocompromised patient, such as one
suffering from AIDS, who has had at least one episode of P. carinii
pneumonia, but who at the time of treatment is not exhibiting signs of
pneumonia. As P. carinii pneumonia is an especially potentially
devastating disease for immunocompromised patients it is preferable to
avoid the onset of P. carinii pneumonia, as compared to treating the
disease after it has become symptomatic. Accordingly, the present
invention provides a method for the prophylaxis against P. carinii
pneumonia comprising administering to the patient a prophylactically
effective amount of the active compound or a pharmaceutically acceptable
salt thereof. The forms for administration of the compound or salt in
accordance with this method may be the same as utilized for the purpose of
actually treating a patient suffering from P. carinii pneumonia.
An additional useful aspect of the present invention is a method for
prophylaxis against even an initial episode of P. carinii pneumonia in an
immunocompromised patient who has never experienced an episode of P.
carinii pneumonia. In this respect, a patient who has been diagnosed as
being immunocompromised, such as one suffering from AIDS or ARC (AIDS
related complex), even before the onset of an initial episode of P.
carinii pneumonia, may avoid or delay suffering from the infection by
having administered a prophylactically effective amount of an active
compound of the present invention or a pharmaceutically acceptable salt
thereof. The compound or salt may be administered in the same fashion as
in the treatment of patients suffering from P. carinii pneumonia.
In the manufacture of a medicament according to the invention (a
"formulation"), active agents or the pharmaceutically acceptable salts
thereof (the "active compound") are typically admixed with, inter alia, an
acceptable carrier. The carrier must, of course, be acceptable in the
sense of being compatible with any other ingredients in the formulation
and must not be deleterious to the subject. The carrier may be solid or
liquid, or both, and is preferably formulated with the compound as a
unit-dose formulation, for example, a tablet, which may contain from 0.05%
to 99% by weight of the active compound. One or more active compounds may
be incorporated in the formulations of the invention (e.g. the formulation
may contain one or more additional anti-P. carinii agents as noted above),
which formulations may be prepared by any of the well-known techniques if
pharmacy consisting essentially of admixing the components, including one
or more accessory therapeutic ingredients.
Formulations suitable for oral administration may be presented in discrete
units, such as capsules, cachets, lozenges, or tablets, each containing a
predetermined amount of the active compound; as a powder or granules; as a
solution or a suspension in an aqueous or non-aqueous liquid; or as an
oil-in-water or water-in-oil emulsion. Such formulations may be prepared
by any suitable method of pharmacy which includes the step of bringing
into association the active compound and a suitable carrier (which may
contain one or more accessory ingredients as noted above). In general, the
formulations of the invention are prepared by uniformly and intimately
admixing the active compound with a liquid or finely divided solid
carrier, or both, and then, if necessary, shaping the resulting mixture.
For example, a tablet may be prepared by compressing or molding a powder
or granules containing the active compound, optionally with one or more
accessory ingredients. Compressed tablets may be prepared by compressing,
in a suitable machine, the compound in a free-flowing form, such as a
powder or granules optionally mixed with a binder, lubricant, inert
diluent, and/or surface active/dispersing agent(s). Molded tablets may be
made by molding, in a suitable machine, the powdered compound moistened
with an inert liquid binder. Formulations for oral administration may
optionally include enteric coatings known in the art to prevent
degradation of the formulation in the stomach and provide release of the
drug in the small intestine.
In addition to the active compounds or their salts, the pharmaceutical
compositions may contain other additives, such as pH adjusting additives.
In particular, useful pH adjusting agents include acids, such as
hydrochloric acid, bases or buffers, such as sodium lactate, sodium
acetate, sodium phosphate, sodium citrate, sodium borate, or sodium
gluconate. Further, the compositions may contain microbial preservatives.
Useful microbial preservatives include methylparaben, propylparaben, and
benzyl alcohol. The microbial preservative is typically employed when the
formulation is placed in a vial designed for multidose use. Of course, as
indicated, the pharmaceutical compositions of the present invention may be
lyophilized using techniques well known in the art.
Other pharmaceutical compositions may be prepared from the water-insoluble
active compounds, or salts thereof, such as aqueous base emulsions. In
such an instance, the composition will contain a sufficient amount of
pharmaceutically acceptable emulsifying agent to emulsify the desired
amount of the active compound or salt thereof. Particularly useful
emulsifying agents include phosphatidyl cholines, and lecithin.
Further, the present invention provides liposomal formulations of the
active compounds and salts thereof. The technology for forming liposomal
suspensions is well known in the art. When the active compound or salt
thereof is an aqueous-soluble salt, using conventional liposome
technology, the same may be incorporated into lipid vesicles. In such an
instance, due to the water solubility of the compound or salt, the
compound or salt will be substantially entrained within the hydrophilic
center or core of the liposomes. The lipid layer employed may be of any
conventional composition and may either contain cholesterol or may be
cholesterol-free. When the compound or salt of interest is
water-insoluble, again employing conventional liposome formation
technology, the salt may be substantially entrained within the hydrophobic
lipid bilayer which forms the structure of the liposome. In either
instance, the liposomes which are produced may be reduced in size, as
through the use of standard sonication and homogenization techniques.
Of course, the liposomal formulations containing the active compounds or
salts thereof, may be lyophilized to produce a lyophilizate which may be
reconstituted with a pharmaceutically acceptable carrier, such as water,
to regenerate a liposomal suspension.
Pharmaceutical formulations are also provided which are suitable for
administration as an aerosol, by inhalation. These formulations comprise a
solution or suspension of the desired active compound or a salt thereof or
a plurality of solid particles of the compound or salt. The desired
formulation may be placed in a small chamber and nebulized. Nebulization
may be accomplished by compressed air or by ultrasonic energy to form a
plurality of liquid droplets or solid particles comprising the compounds
or salts. The liquid droplets or solid particles should have a particle
size in the range of about 0.5 to about 5 microns. The solid particles can
be obtained by processing the solid active compound, or a salt thereof, in
any appropriate manner known in the art, such as by micronization. Most
preferably, the size of the solid particles or droplets will be from about
1 to about 2 microns. In this respect, commercial nebulizers are available
to achieve this purpose.
Preferably, when the pharmaceutical formulation suitable for administration
as an aerosol is in the form of a liquid, the formulation will comprise a
water-soluble active compound of the present invention or a salt thereof,
in a carrier which comprises water. A surfactant may be present which
lowers the surface tension of the formulation sufficiently to result in
the formation of droplets within the desired size range when subjected to
nebulization.
Formulations of the present invention suitable for intravenous
administration comprise sterile aqueous and non-aqueous injection
preparations of the active compound, which preparations are preferably
isotonic with the blood of the intended recipient. These preparations may
include anti-oxidants, buffers, bacteriostats, and solutes that render the
formulation isotonic with the blood of the intended recipient. Aqueous and
non-aqueous sterile suspensions may include suspending agents and
thickening agents. The formulations may be presented in unit/dose or
multi-dose containers, for example sealed ampules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example, saline or
water-for-injection immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders, granules
and tablets of the kind previously described.
As indicated, the present invention provides both water-soluble and
water-insoluble compounds and salts. As used in the present specification,
the term "water-soluble" is meant to define any composition which is
soluble in water in an amount of about 50 mg/mL, or greater. Also, as used
in the present specification, the term "water-insoluble" is meant to
define any composition which has solubility in water of less than about 20
mg/mL. For certain applications, water soluble compounds or salts may be
desirable whereas for other applications water-insoluble compounds or
salts likewise may be desirable.
Examples of active compounds of the present invention include, but are not
limited to:
1,3-bis(4'-(N-hydroxyamidino)phenoxy)propane
1,3-bis(2'-methoxy-4'-(N-hydroxyamidino)phenoxy)propane
1,4-bis(4'-(N-hydroxyamidino)phenoxy)butane
1,3-bis(4'-(4-hydroxyamidino)phenoxy)propane di-hemimaleinate
1,3-bis(2'-methoxy-4'-(N-hydroxyamidino)phenoxy)propane di-hemimaleinate
1-(4'-(N-hydroxyamidino)phenoxy)butane bis-maleinate
2,5-bis-[4-amidinophenyl]furan bis-amidoxime
2,5-bis-[4-amidinophenyl]furan bis-O-methylamidoxime
2,5-bis-[4-amidinophenyl]furan bis-O-ethylamidoxime
Compounds employed in carrying out the present invention may be prepared in
accordance with techniques known to those skilled in the art, particularly
in light of the disclosure and examples set forth below.
As indicated, the compounds used in the present invention may be present as
pharmaceutically acceptable salts. Such salts include the maleinate,
gluconate, lactate, acetate, tartarate, citrate, phosphate, borate,
nitrate, sulfate, and hydrochloride salts.
The salts of the present invention may be prepared, in general, by reacting
two equivalents of the pyrimidine base compound with the desired acid, in
solution. After the reaction is complete, the salts are crystallized from
solution by the addition of an appropriate amount of solvent in which the
salt is insoluble.
As noted above, the active compounds of the present invention according to
Formula I may be prepared according to methods known in the art. For
example, the active compounds above may be prepared by first synthesizing
known bis-nitriles using Allen's procedure for alkylation of phenols. See
J. N. Ashley et al., J. Chem. Soc. 103-116 (1942); C. F. H. Allen et al.
Org. Synth. Coll. III, 141-41 (1955). The active compounds can then be
obtained by using variations of the known technique of Clement and Raether
and by using appropriate reagents. See B. Clement and W. Raether, i
Arzneim. Forsch. 35, 1009-1014 (1985).
Active compounds of the present invention according to Formula II may also
be produced by methods known in the art. For example, a two-step process
using Pinner methodology may be used to convert a nitrile into an imidate
ester, followed by reaction of the imidate ester with hydroxylamine. A.
Pinner, Ber. 17, 184 (1884). Alternatively, amidoximes according to
Formula II may be prepared by the direct conversion of a nitrile into the
amidoxime by the reaction with hydroxylamine in the presence of base. I.
Lamb et al., J. Chem. Soc. 1253 (1939).
Subjects with other microbial infections, in addition to P. carinii
pneumonia, may also be treated by the methods of the present invention in
the same manner as described above. These infections may be caused by a
variety of microbes, including fungi, algae, protozoa, bacteria, and
viruses. Exemplary microbial infections that may be treated by the method
of the present invention include, but are not limited to, infections
caused by Giardia lamblia, Cryptosporidium parvum, Cryptococcus
neoformans, Candida albicans, Candida tropicalis, Salmonella typhimurium,
Plasmodium falciparum, and Leishmania mexicana amazonensis.
The following examples are provided to illustrate the present invention,
and should not be construed as limiting thereon. In these examples, mM
means millimolar, mL means milliliters, mm means millimeters, cm means
centimeters, .degree.C. means degrees Celsius, g means grams, kg means
kilograms, m.p. means ng point, MHz means megahertz, M means molar, h
hours, NMR means nuclear magnetic resonance, FAB fast atom bombardment,
DMF means dimethylformamide, EtOH means ethyl alcohol, DMSO means
dimethylsulfoxide, HPLC means high-pressure liquid chromatography, TLC
means thin-layer chromatography, dec means decomposition point.
In the following Examples, the following compound designations are used
throughout.
Compound # Name
a 1,5-bis(4'-(N-hydroxyamidino)phenoxy)pentane
b 1,3-bis(4'-(N-hydroxyamidino)phenoxy)propane
c 1,3-bis(2'-methoxy-4'-(N-hydroxyamidino)phenoxy)propane
d 1,4-bis(4'-(N-hydroxyamidino)phenoxy)butane
1 1,5-bis(4'-(N-hydroxyamidino)phenoxy)pentane
di-hemimaleinate
2 1,5-bis(4'-amidinophenoxy)pentane; pentamidine
3 1,4-bis(4'-(N-hydroxyamidino)phenoxy)butane di-maleinate
4 1,4-bis(4'-amidinophenoxy)butane
5 1,3-bis(4'-(4-hydroxyamidino)phenoxy)propane
di-hemimaleinate
6 1,3-bis(4'-amidinophenoxy)propane
7 1,3-bis(2'-methoxy-4'-(N-hydroxyamidino)phenoxy)propane
di-hemimaleinate
8 1,3-bis(2'-methoxy-4'-amidinophenoxy)propane
9 2,5-bis-[4-amidinophenyl]furan
10 2,5-bis-[4-amidinophenyl]furan bis-amidoxime
11 2,5-bis-[4-amidinophenyl]furan bis-O-methylamidoxime
12 2,5-bis-[4-amidinophenyl]furan bis-O-ethylamidoxime
EXAMPLE 1
Synthesis of Formula I Compounds: Preparation of bis-benzonitriles
42 mmol of 1,5-dibromopentane (for preparing pentamidine derivatives) or
1,3-dibromopentane (for preparing propamidine derivatives) is added to a
suspension of 84 mmol of the appropriate 4-hydroxybenzonitrile and 126
mmol of K.sub.2 CO.sub.3 in 200 mL DMF. The mixture is warmed to
65-70.degree. C. and allowed to stir overnight. The mixture is diluted in
400 mL of H.sub.2 O, the precipitated product is collected and washed with
H.sub.2 O. The crude bis-benzonitriles are recrystallized from ethanol.
EXAMPLE 2
Synthesis of Formula I Compounds: Preparation bis-benzamidoximes
32 mL of a 21% sodium ethoxide (in ethanol) solution is added to a hot
solution of 98 mmol of NH.sub.2 OH.HCl in 100 mL ethanol. The NaCl is
removed by filtration and the filtrate is entered directly into a flask
containing 10 mmol of the appropriate bis-benzonitrile from Example 1. The
mixture is warmed to reflux and allowed to stir for 5 hrs, cooled to room
temperature and permitted to stand overnight. The precipitated product is
collected, washed with ethanol and dried in a vacuum desiccator. The
following spectral and analytic data were collected:
Compound (a): m.p.>164-65.degree. C.; (literature value: 163.degree. C.;
see R. R. Tidwell et al., J. Med Chem. 26, 294-98 (1983)); 3.6 g, 60%.
Novel Compound (b): m.p. 162.degree. C., (1.6 g, 47%); .sup.1 H-NMR (300
MHz, DMSO) .delta.2.18 (m, 2 H), 4.16 (t, J=5.9 Hz, 4 H), 5.72 (s, 4 H),
6.95 (d, 4 H, J=8.6 Hz), 7.59 (d, 4 H, J=8.6 Hz), 9.45 (s, 2 H) ppm; FABMS
m/z 345 (M+H); Exact mass calculated for C.sub.17 H.sub.21 N.sub.14
O.sub.4 : 345.1563; found: 345.1557; Anal. (C.sub.17 H.sub.21 N.sub.14
O.sub.4) C, H, N.
Novel Compound (c): m.p.117.degree. C. (2.9 g, 73%); .sup.1 H-NMR (300 MHz,
DMSO) .delta.2.17 (m, 2 H), 4.14 (t, 4 H, J=5.9 Hz), 5.74 (s, 4 H), 6.98
(d, 2 H, J=8.4 Hz), 9.46 (s, 2 H) ppm; FABMS m/z 405 (M+H); Exact mass
calculated for C.sub.19 H.sub.25 N.sub.4 O.sub.6 : 405.1774; found:
405.1795; Anal. (C.sub.19 H.sub.25 N.sub.4 O.sub.6.(H.sub.2 O).sub.1.3 :
C, H, N.
Novel Compound (d): m.p.200.degree. C. (dec) (1.0 g, 33%); .sup.1 H-NMR
(300 MHz, DMSO) .delta.1.87 (s, 2 H), 4.05 (s, 2 H), 5.72 (s, 4 H), 6.95
(d, 4 H, J=8.7 Hz), 7.60 (d, 2 H, J=8.7 Hz), 9.45 (s, 2 H) ppm; FABMS m/z
359 (M+H); Anal. (C.sub.18 H.sub.22 N.sub.4 O.sub.4): C, H, N.
Further elemental analysis data is shown in Table 1.
TABLE 1
Elemental Analyses of Novel Amidoximes
Compound Molecular Formula Calculated Found
b C.sub.17 H.sub.20 N.sub.4 O.sub.4 C: 59.30; H: 5.81; C:
59.12; H: 5.86;
N: 16.28 N: 16.00
c C.sub.19 H.sub.24 N.sub.4 O.sub.6.(H.sub.2 O).sub.1.3 C:
53.34; H: 6.27; C: 53.64; H: 6.01;
N: 13.10 N: 12.71
d C.sub. | | |
