U.S. patent number 3,794,725 [Application Number 05/319,481] was granted by the patent office on 1974-02-26 for pharmaceutical compositions containing certain 3-nitro-furyl-4-azolidinylidene-azolones-5 and method of use.
This patent grant is currently assigned to Boehringer Ingelheim GmbH. Invention is credited to Roland Maier, Robert Sauter.
United States Patent |
3,794,725 |
Maier , et al. |
February 26, 1974 |
PHARMACEUTICAL COMPOSITIONS CONTAINING CERTAIN
3-NITRO-FURYL-4-AZOLIDINYLIDENE-AZOLONES-5 AND METHOD OF USE
Abstract
Pharmaceutical compositions containing as active ingredients
compounds of the formula ##SPC1## Wherein R.sub.1 is hydrogen,
straight or branched alkyl of 1 to 6 carbon atoms,
monohydroxy-(alkyl of 1 to 6 carbon atoms), or ##SPC2## Where
R.sub.4 and R.sub.5 are each straight or branched alkyl of 1 to 4
carbon atoms, or, together with each other and the nitrogen atom to
which they are attached, morpholino, pyrrolidino, piperidino or
N'-methyl-piperazino, R.sub.2 is hydrogen or alkyl of 1 to 3 carbon
atoms, R.sub.3 is hydrogen, straight or branched alkyl of 1 to 5
carbon atoms, or monohydroxy-(alkyl of 1 to 5 carbon atoms), X is
oxygen, imino(--NH--) or methylimino(--NCH.sub.3 --), Y is oxygen,
sulfur or imino, and n is 0 or 1, Or, to the extent that the
compounds contain one or more basic nitrogen atoms, non-toxic acid
addition salts thereof; and methods of using the compositions as
bactericidal preparations against grampositive and gramnegative
bacteria and against trichomonas.
Inventors: |
Maier; Roland (Biberach/Riss,
DT), Sauter; Robert (Laupheim, DT) |
Assignee: |
Boehringer Ingelheim GmbH
(Ingelheim/Rhine, DT)
|
Family
ID: |
27182862 |
Appl.
No.: |
05/319,481 |
Filed: |
December 29, 1972 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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177435 |
Sep 2, 1971 |
3717629 |
Feb 20, 1973 |
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Foreign Application Priority Data
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Sep 11, 1970 [DT] |
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2045049 |
Jun 4, 1971 [DT] |
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2127735 |
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Current U.S.
Class: |
514/365; 514/183;
514/236.5; 514/326; 514/378; 514/254.04; 514/254.07; 514/252.19;
514/235.8; 514/236.8; 514/374 |
Current CPC
Class: |
C07D
417/14 (20130101); C07D 413/14 (20130101); Y02P
20/55 (20151101) |
Current International
Class: |
C07D
413/14 (20060101); C07D 413/00 (20060101); C07D
417/00 (20060101); C07D 417/14 (20060101); A61k
027/00 () |
Field of
Search: |
;424/246,248,250,267,270,272,273,274 |
References Cited
[Referenced By]
U.S. Patent Documents
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2394068 |
February 1946 |
Kendall et al. |
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Primary Examiner: Goldberg; Jerome D.
Attorney, Agent or Firm: Hammond & Littell
Parent Case Text
This is a division of copending application Ser. No. 177,435, filed
Sept. 2, 1971, now U.S. Pat. No. 3,717,629 issued Feb. 20. 1973.
Claims
We claim:
1. A bactericidal or trichomonacidal pharmaceutical dosage unit
composition consisting essentially of an inert pharmaceutical
carrier and an effective bactericidal or trichomonacidal amount of
a compound of the formula ##SPC18##
wherein R.sub.1 is hydrogen, alkyl of 1 to 6 carbon atoms,
monohydroxy-(alkyl of 1 to 6 carbon atoms), or ##SPC19##
where R.sub.4 and R.sub.5 are each alkyl of 1 to 4 carbon atoms,
or, together with each other and the nitrogen atom to which they
are attached, morpholino, pyrrolidino, piperidino or
N'-methyl-piperazino,
R.sub.2 is hydrogen or alkyl of 1 to 3 carbon atoms,
R.sub.3 is hydrogen, alkyl of 1 to 5 carbon atoms, or
monohydroxy-(alkyl of 1 to 5 carbon atoms),
X is oxygen, imino or methylimino,
Y is oxygen, sulfur or imino, and
n is 0 or 1, or, when R.sub.1 is --CH.sub.2 --NR.sub.4 R.sub.5, as
defined above, a non-toxic, pharmacologically acceptable acid
addition salt thereof.
2. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-(imidazolidinylidene-2")-isoxazolone-5.
3. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-(oxazolidinylidene-2")-isoxazolone-5.
4. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-(3"-methyl-oxazolidinylidene-2")-isoxazolone-5.
5. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-(thiazolidinylidene-2")-isoxazolone-5.
6. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-(5"-methyl-oxazolidinylidene-2")-isoxazolone-5.
7. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-(4"-methyl-oxazolidinylidene-2")-isoxazolone-5.
8. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5.
9. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-(1",3"-tetrahydrooxazinylidene-2")-isoxazolone-5.
10. The composition of claim 1, wherein said compound is
3-(5'-nitro-furyl-2')-4-[5"-(dimethylamino-methyl)-oxazolidinylidene-2"]-i
soxazolone-5 or a non-toxic, pharmacologically acceptable acid
addition salt thereof.
11. The method of inhibiting the growth of grampositive and
gramnegative bacteria or trichomonas in a warm-blooded animal,
which comprises topically or perorally administering to said animal
an effective bactericidal or trichomonacidal amount of a compound
of the formula ##SPC20##
wherein R.sub.1 is hydrogen, alkyl of 1 to 6 carbon atoms,
monohydroxy-(alkyl of 1 to 6 carbon atoms), or ##SPC21##
where R.sub.4 and R.sub.5 are each alkyl of 1 to 4 carbon atoms,
or, together with each other and the nitrogen atom to which they
are attached, morpholino, pyrrolidino, piperidino or
N'-methyl-piperazino,
R.sub.2 is hydrogen or alkyl of 1 to 3 carbon atoms,
R.sub.3 is hydrogen, alkyl of 1 to 5 carbon atoms, or
monohydroxy-(alkyl of 1 to 5 carbon atoms),
X is oxygen, imino or methylimino,
Y is oxygen, sulfur or imino, and
n is 0 or 1, or, when R.sub.1 is --CH.sub.2 --NR.sub.4 R.sub.5, as
defined above, a non-toxic, pharmacologically acceptable acid
addition salt thereof.
Description
This invention relates to novel pharmaceutical compositions
containing as active ingredients certain
3-nitrofuryl-4-azolidinylidene-azolones-5, as well as to methods of
using these compositions as bactericidal preparations.
More particularly, the present invention relates to bactericidal
pharmaceutical compositions containing a compound of the formula
##SPC3##
Wherein R.sub.1 is hydrogen, straight or branched alkyl of 1 to 6
carbon atoms, monohydroxy-(alkyl of 1 to 6 carbon atoms), or
##SPC4##
Where R.sub.4 and R.sub.5 are each straight or branched alkyl of 1
to 4 carbon atoms, or, together with each other and the nitrogen
atom to which they are attached, morpholino, pyrrolidino,
piperidino or N'-methyl-piperazino,
R.sub.2 is hydrogen or alkyl of 1 to 3 carbon atoms,
R.sub.3 is hydrogen, straight or branched alkyl of 1 to 5 carbon
atoms, or monohydroxy-(alkyl of 1 to 5 carbon atoms),
X is oxygen, imino(--NH--) or methylimino(--NCH.sub.3 --),
Y is oxygen, sulfur or imino, and
n is 0 or 1,
Or, to the extent that the compound contains one or more basic
nitrogen atoms, a non-toxic, pharmacologically acceptable acid
addition salt thereof.
The compounds embraced by formula I above may be prepared by a
number of different methods involving well known chemical
principles, among which the following method has proved to be
particularly convenient and efficient:
By reacting a compound of the formula ##SPC5##
Wherein X has the same meanings as in formula I, and
R.sub.5 and R.sub.6 are each alkyl or, together with each other,
alkylene,
With an amine of the formula ##SPC6##
Wherein R.sub.1, R.sub.2, R.sub.3, Y and n have the same meanings
as in formula I.
The reaction is preferably carried out in the presence of an inert
organic solvent or suspension medium at a temperature between
20.degree. and 150.degree. C. Examples of particularly suitable
solvent and suspension media are polar organic liquids, such as
alkanols, dioxane, alkanones, dimethylformamide or
dimethylsulfoxide.
The intermediate compound formed by the reaction, of the formula
##SPC7##
wherein R.sub.1, R.sub.2, R.sub.3, X, Y and n have the same
meanings as in formula I and R.sub.6 has the same meaning as in
formula II, may optionally be isolated and subsequently converted
into the corresponding compound of the formula I, for instance, by
heating to a temperature between 100.degree. and 200.degree. C in
the presence of a polar organic solvent, such as
dimethylsulfoxide.
In those instances where the above-described method yields a
compound of the formula I which comprises one or more basic
nitrogen atoms, the basic compound may, if desired, be converted
into an acid addition salt thereof by conventional procedures.
Examples of non-toxic, pharmacologically acceptable acid addition
salts are those formed with hydrochloric acid, hydrobromic acid,
sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric
acid, fumaric acid, 8-chlorotheophylline or the like.
The starting compounds of the formula II may be prepared by
nitrating a compound of the formula ##SPC8##
wherein X, R.sub.6 and R.sub.7 have the meanings previously
defined.
A compound of the formula V wherein R.sub.6 and R.sub.7 are alkyl,
in turn, may be prepared by reacting a furan derivative of the
formula ##SPC9##
wherein X has the meanings previously defined, with carbon
disulfide in the presence of a strong base, followed by alkylation
of the dithio compound formed thereby.
Finally, those compounds of the formula V wherein R.sub.6 and
R.sub.7 together form an alkylene chain linking the two sulfur
atoms may be prepared by subjecting a compound of the formula VI to
a condensation reaction with a trithiocarboxonium salt of the
formula ##SPC10##
wherein R.sub.8 is alkyl, A is alkylene, and Z is an anion.
The trithiocarboxonium salts of the formula VII, in turn, are
accessible by alkylation of a cyclic trithiocarbonate with a
dialkylsulfate, for example.
The following examples further illustrate the preparation of
compounds of the formula I as well as a few starting compounds of
the formulas II and III.
Preparation of Starting Materials
EXAMPLE A
3-(furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
7.9 gm (0.18 mol) of 55 percent sodium hydride were deoiled by
decantation with petroleum ether and then suspended in 100 cc of
dimethylsulfoxide. While exteriorly cooling the suspension with
ice, a solution of 13.5 gm (0.09 mol) of 3
-(furyl-2')-isoxazolone-5 and 6.9 gm (0.09 mol) of carbon disulfide
in 50 cc of dimethylsulfoxide was slowly added dropwise thereto,
and then the mixture was stirred for 30 minutes. Thereafter, while
thoroughly cooling, 25.6 gm (0.18 mol) of methyl iodide were added
dropwise, and then the resulting mixture was heated for 30 minutes
at 50.degree.-60.degree. C. Subsequently, after cooling, the
reaction mixture was poured over ice, and the aqueous mixture was
extracted with ethyl acetate. The organic phase was dried over
sodium sulfate, and the ethyl acetate was evaporated, leaving a red
oil which crystallized upon addition of a little ether. 12 gm (53
percent of theory) of yellow crystalline
3-(furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5, m.p.
86.degree. C, of the formula ##SPC11##
were obtained.
Using an analogous procedure, the following additional starting
compounds of the formula V were prepared:
a. 3-(Furyl-2')-4-[(bis-methylmercapto)-methylene]-pyrazolone- 5, a
red crystalline substance, m.p. 148.degree. C, of the formula
##SPC12##
from 3-(furyl-2')-pyrazolone-5.
b. 3-(Furyl-2')-4-[(bis-methylmercapto)-methylene]-1
-methyl-pyrazolone-5, a yellow crystalline substance, m.p.
83.degree. C, from 3-(furyl-2')-1-methyl-pyrazolone-5 (m.p.
193.degree. C); the latter, in turn, was prepared from ethyl
furoylacetate and N-methyl-hydrazine.
EXAMPLE B
3-(furyl-2')-4-[1",3"-dithiacyclopentanylidene-2"]-isoxazolone-5
12.1 gm (0.08 mol) of 3-(furyl-2')-isoxazolone-5 and 42 gm (0.16
mol) of 2-methylmercapto-1,3-dithiolaniummethylsulfate (prepared by
heating a mixture of equimolar amounts of ethylene trithiocarbonate
and dimethylsulfate on a water bath) were dissolved in 100 cc of
pyridine, a solution of 16.2 gm (0.16 mol) of triethylamine in 100
cc of pyridine was added, and the mixed solution was heated for 3
hours at 70.degree. C. Thereafter, the pyridine was drawn off in
vacuo, the residue was admixed with water, and the crystalline
substance formed thereby was collected by vacuum filtration and
recrystallized from ethanol. 8.6 gm (42.3 percent of theory) of the
faintly yellow crystalline compound, m.p. 160.degree.-162.degree.
C, of the formula ##SPC13##
were obtained.
Analysis: C.sub.10 H.sub.17 NO.sub.3 S.sub.2 ; mol. wt. 253.3
Calculated: C-47.41%; H-2.78%; N-5.53%; S-25.32%
Found: C-47.40%; H-2.94%; N-5.51%; S-25.05%
a. Using an analogous procedure, 3-(furyl-2')-4-[3"
-methyl-thiazolidinylidene-2"]-isoxazolone-5, m.p. 128.degree. C
(from isopropanol), was prepared from 3-(furyl-2')-isoxazolone-5
and 3-methyl-2-methyl-mercapto-thiazolidinium-methosulfate; the
latter was, in turn, prepared from
2-methylmercapto-.DELTA.2-thiazoline and dimethylsulfate.
EXAMPLE C
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
2.55 gm (0.01 mol) of
3-(furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5 were
dissolved in concentrated sulfuric acid, the resulting solution was
cooled to -20.degree. C, and then 0.85 gm (0.01 mol) of sodium
nitrate was added in small portions. Thereafter, the reaction
mixture was allowed to stand at room temperature overnight and was
then poured over ice. The precipitate formed thereby was collected
and recrystallized from ethyl acetate, yielding 1.2 gm (40 percent
of theory) of the yellowish-orange crystalline compound, m.p.
162.degree. C, of the formula ##SPC14##
Analysis: C.sub.10 H.sub.8 N.sub.2 O.sub.5 S.sub.2 ; mol. wt.
300.32
Calculated: C-40.00%; H-2.69%; N-9.33%; S-21.35%
Found: C-39.80%; H-2.76%; N-9.35%; S-21.45%
Using an analogous procedure, the following additional starting
compounds of the formula II were prepared:
a.
3-(5'-Nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-pyrazolone-5,
reddish-brown crystals, m.p. 164.degree. C, from
3-(furyl-2')-4-[(bis-methylmercapto)-methylene]-pyrazolone-5.
b. 3-(5'-Nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]
-1-methyl-pyrazolone-5, yellow crystals, m.p. 200.degree. C, from
3-(furyl-2')-4-[(bis-methylmercapto)-methylene]-1-methyl-pyrazolone-5.
c. 3-(5'-Nitro-furyl-2')-4-[1",3"
-dithiacylclopentanylidene-2"]-isoxazolone-5, brown crystals, m.p.
188.degree. C (from dimethylformamide/water), from
3-(furyl-2')-4-[1",3"-dithiacyclopentanylidene-2")-isoxazolone-5.
EXAMPLE D
3-morpholino-2-hydroxy-n-propylamine
A mixture consisting of 69.5 gm (0.29 mol) of
3-chloro-2-hydroxy-n-propyl-phthalimide (see Berichte Deutsch.
Chem. Ges. 50, 280), 53.2 gm (0.61 mol) of morpholine and 170 cc of
ethanol was heated at its boiling point for 6 hours. Thereafter,
the ethanol was evaporated, the residue was boiled for three hours
with 600 cc of aqueous 20 percent hydrochloric acid, the mixture
was allowed to cool and was then vacuum-filtered, the filtrate was
concentrated by evaporation to 150 cc, and the concentrate was made
strongly alkaline with solid caustic alkali. The oil precipitated
thereby was taken up in benzene, and the aqueous phase was
extracted twice with benzene. The combined benzene phases were
dried over sodium sulfate and then fractionally distilled in vacuo,
yielding 17.2 gm of the oily compound, b.p. 146.degree.-148.degree.
C at 12 mm Hg, of the formula ##SPC15##
Using an analogous procedure, the following additional starting
compounds of the formula III were prepared:
a. 3-Piperidino-2-hydroxy-n-propylamine, a colorless oil, b.p.
128.degree.-129.degree. C at 12 mm Hg, from
3-chloro-2-hydroxy-n-propyl-phthalimide and piperidine.
b. 3-Pyrrolidino-2-hydroxy-n-propylamine, a colorless oil, b.p.
120.degree.-121.degree. C at 12 mm Hg, from
3-chloro-2-hydroxy-n-propyl-phthalimide and pyrrolidine.
c. 3-(N'-methyl-piperazino)-2-hydroxy-n-propylamine, an oil, b.p.
116.degree.-118.degree. C at 0.2 mm Hg, from
3-chloro-2-hydroxy-n-propyl-phthalimide and
N-methyl-piperazine.
d. 3-(Di-n-butylamino)-2-hydroxy-n-propylamine, a colorless oil,
b.p. 101.degree. C at 0.3 mm Hg, from
3-chloro-2-hydroxy-n-propyl-phthalimide and di-n-butylamine.
e. 3-(Di-isopropylamino)-2-hydroxy-n-propylamine, a colorless oil,
b.p. 95.degree. C at 0.01 mm Hg, from
3-chloro-2-hydroxy-n-propyl-phthalimide and diisopropylamine.
Preparation of End Products
EXAMPLE 1
3-(5'-nitro-furyl-2')-4-[oxazolidinylidene-2"]-isoxazolone-5
A mixture consisting of 2 gm (0.0066 mol) of
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5,
0.41 gm (0.0066 mol) of ethanolamine and 30 cc of acetone was
heated at its boiling point for 1 hour. Thereafter, the reaction
mixture was allowed to cool, and the precipitate formed thereby was
collected by vacuum filtration and washed several times with
acetone. 1.4 gm (80 percent of theory) of the yellowish-crystalline
compound, m.p. 263.degree. C (decomp.), of the formula
##SPC16##
were obtained.
Analysis: C.sub.10 H.sub.7 N.sub.3 O.sub.6 ; mol. wt. 265.19
Calculated: C - 45.25%; H - 2.66%; N - 15.87%
Found: C - 45.40% H - 2.74%; N - 15.70%
EXAMPLE 2
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[imidazolidinylidene-2"]-isoxazolone- 5,
m.p. 280.degree. C (decomp.; recrystallized from dioxane), was
prepared from
3-(5'-nitro-furyl-2')-4-[(bismethylmercapto)-methylene]
-isoxazolone-5 and ethylenediamine.
EXAMPLE 3
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[1"-(.beta.-hydroxy-ethyl)-imidazolidinylidene-2"]
-isoxazolone-5, m.p. 226.degree. C (decomp.), was prepared from
3-(5'-nitro-furyl-2')-4-[bis-methylmercapto)-methylene]
-isoxazolone-5 and N-(.beta.-hydroxy-ethyl)-ethylenediamine.
EXAMPLE 4
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5, m.p. 150.degree. C (recrystallized from methanol),
was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and diethanolamine.
EXAMPLE 5
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[1"-methyl-imidazolidinylidene-
2"]-isoxazolone-5, m.p. 238.degree. C (decomp.), was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and N-methyl-ethylene-diamine.
EXAMPLE 6
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-methyl-oxazolidinylidene-
2"]-isoxazolone-5, m.p. 205.degree. C (recrystallized from
ethylacetate/acetone), was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and N-methyl-ethanolamine.
EXAMPLE 7
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[thiazolidinylidene-2"]-isoxazolone-5, m.p.
210.degree. C, was prepared from 3-(5'-nitrofuryl-2')-4
-[(bis-methylmercapto-methylene]-isoxazolone-5 and cysteamine.
EXAMPLE 8
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[4",5"-dimethyl-oxazolidinylidene-2"]-isoxazolone-
5, m.p. 251.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 2-amino-3-hydroxy-n-butane.
EXAMPLE 9
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[5"-methyl-oxazolidinylidene-
2"]-isoxazolone-5, m.p. 253.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 1-amino-2-hydroxy-n-propane.
EXAMPLE 10
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[4"-methyl-oxazolidinylidene
2"]-isoxazolone-5, m.p. 280.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 2-amino-1-hydroxy-n-propane.
EXAMPLE 11
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[1",3"-tetrahydro-oxazolidinylidene-
2"]-isoxazolone-5, m.p. 273.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]
isoxazolone-5 and 1-amino-3-hydroxy-n-propane.
EXAMPLE 12
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[5"-hydroxymethyl-oxazolidinylidene- 2"
-isoxazolone-5, m.p. 225.degree. C (decomp.), was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto-methylene]
-isoxazolone-5 and 1-amino-2,3-dihydroxy-n-propane.
EXAMPLE 13
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[5"-isopropyl-oxazolidinylidene-
2"]-isoxazolone-5, m.p. 185.degree. C (recrystallized from
ethanol), was prepared from
3-(5'-nitro-furyl-2')-4-[(bismethylmercapto)-methylene
-isoxazolone-5 and 1-amino-2-hydroxy- 3-methyl-n-butane.
EXAMPLE 14
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[4"-methyl-5"-ethyl-oxazolidinylidene-2"]-isoxazol
one-5, m.p. 230.degree. C (recrystallized from dioxane), was
prepared from 3-(5'-nitro-furyl-2'
)-4-[(bis-methylmercapto)-methylene]-isoxazolone-5 and
2-amino-3-hydroxy-n-pentane.
EXAMPLE 15
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[5"-isopropyl-4"-methyloxazolidinylidene-2"]-isoxa
zolone-5, m.p. 204.degree. C (recrystallized from ethanol/acetone),
was prepared from
3-(5'-nitrofuryl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 2-amino-3-hydroxy-4-methyl-n-pentane.
EXAMPLE 16
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[1"-ethyl-imidazolidinylidene-
2"]-isoxazolone-5, m.p. 235.degree. C (decomp.), was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and N-ethyl-ethylene-diamine.
EXAMPLE 17
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-ethyl-oxazolidinylidene-
2"]-isoxazolone-5, m.p. 166.degree. C (recrystallized from
ethanol), was prepared from 3-(5'-nitro-furyl-2')-4-[
(bismethylmercapto)-methylene]-isoxazolone-5 and
N-ethyl-ethanolamine.
EXAMPLE 18
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[hexahydropyrimidinylidene-
2"]-isoxazolone-5, m.p. 243.degree. C (decomp.), was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methyl-mercapto)-methylene]-isoxazolone-5
and 1,3-diamino-n-propane.
EXAMPLE 19
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[5"-n-hexyl-oxazolidinylidene-2"]-isoxazolone-5,
m.p. 135.degree. C (recrystallized from ethanol), was prepared from
3-(5'-nitro-furyl-2')-4-[(bismethylmercapto)-methylene]
-isoxazolone-5 and 1-amino-2-hydroxy-n-octane
EXAMPLE 20
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[5"-n-pentyl-oxazolidinylidene-
2"]-isoxazolone-5, m.p. 165.degree. C, was prepared from 3-(
5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-
5 and 1-amino-2-hydroxy-n-heptane.
EXAMPLE 21
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[4"-ethyl-5"-methyl-oxazolidinylidene-2"]-isoxazol
one-5, m.p. 222.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methyl-mercapto)-methylene]-isoxazolone-5
and 3-amino-2-hydroxy-n-pentane.
EXAMPLE 22
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[4"-ethyl-oxazolidinylidene-
2"]-isoxazolone-5, m.p. 246.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 2-amino-1-hydroxy-n-butane.
EXAMPLE 23
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[1"-methyl-hexahydropyrimidinylidene-2"]-isoxazolo
ne-5, m.p. 225.degree. C (decomp.), was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and N-methyl-1,3-diamino-n-propane.
EXAMPLE 24
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-thiazolidinylidene-2"]-
isoxazolone-5, m.p. 188.degree. C (decomp.), was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and N-(.beta.-hydroxy-ethyl)-cysteamine.
EXAMPLE 25
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-hydroxy-n-propyl)-5"-methyl-oxazolidin
ylidene-2"]-isoxazolone-5, m.p. 130.degree. C (recrystallized from
isopropanol), was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and di-(.beta.-hydroxy-n-propyl)-amine.
EXAMPLE 26
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-n-butyl-oxazolidinylidene-
2"]-isoxazolone-5, m.p. 110.degree. C (recrystallized from
ethanol), was prepared from
3-(5'-nitro-furyl-2')-4-[(bismethylmercapto)-methylene]
-isoxazolone-5 and N-n-butylethanolamine.
EXAMPLE 27
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[1"-n-propyl-imidazolidinylidene-2"]-isoxazolone-5
, m.p. 200.degree. C (recrystallized from dioxane), was prepared
from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and N-n-propyl-ethylene-diamine.
EXAMPLE 28
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-hydroxy-n-propyl)-oxazolidinylidene-2"
]-isoxazolone-5, m.p. 153.degree. C (recrystallized from ethanol),
was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and N-(.beta.-hydroxy-n-propyl)-ethanolamine.
EXAMPLE 29
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-(.gamma.-hydroxy-n-propyl)-oxazolidinylidene-2
"]-isoxazolone-5, m.p. 185.degree. C (recrystallized from ethanol),
was prepared from 3-(5'-nitro-furyl-2')
-4-[(bis-methylmercapto)-methylene]-isoxazolone-5 and
N-(.gamma.-hydroxy-n-propyl)-ethanolamine.
EXAMPLE 30
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-methyl-n-butyl)-oxazolidinylidene-2"]-
isoxazolone-5, m.p. 140.degree. C (recrystallized from ethanol),
was prepared from 3-(5'-nitro-furyl-2')
-4-[(bis-methylmercapto)-methylene]-isoxazolone-5 and
N-(.beta.-methyl-n-butyl)-ethanaolamine.
EXAMPLE 31
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3",5"-dimethyl-oxazolidinylidene-2"]-isoxazolone-
5, m.p. 196.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto-methylene]
-isoxazolone5 and 1-methylamino-2-hydroxy-propane.
EXAMPLE 32
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[3"-isopropyl-oxazolidinylidene-2"]-isoxazolone-5,
m.p. 198.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and N-iospropyl-ethanolamine.
EXAMPLE 33
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[imidazolidinylidene-2"]-isoxazolone-5,
m.p. 275.degree. C (decomp.; recrystallized from dioxane), was
prepared from
3-(5'-nitro-furyl-2')-4-[1",3"-dithiacyclopentanylidene-2"]-isoxazolone-5
and ethylenediamine.
EXAMPLE 34
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[5"-methyl-oxazolidinylidene-2"]-pyrazolone-5,
m.p. 275.degree. C (decomp.; recrystallized from ethanol), was
prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-pyrazolone-5
and 1-amino-2-hydroxy-n-propane.
EXAMPLE 35
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[thiazolidinylidene-2"]-pyrazolone-5, m.p.
287.degree. C (recrystallized from dimethylfomamide), was prepared
from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-pyrazolone-5
and cysteamine.
EXAMPLE 36
Using a procedure analogous to that described in Example 1,
3-(5'-nitro-furyl-2')-4-[5"-methyl-oxazolidinylidene-
2"]-1-methyl-pyrazolone-5, m.p. 274.degree.-275.degree. C
(recrystallized from ethanol), was prepared from
3-(5'-nitro-furyl-2')
-4-[(bis-methylmercapto)-methylene]-1-methyl-pyrazolone-5 and 1
-amino-2-hydroxy-n-propane.
EXAMPLE 37
3-(5'-nitro-furyl-2')-4-[1",3"-tetrahydrooxazinylidene-2"]-isoxazolone-5
a. 2.0 gm (0.0066 mol) of
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
were suspended in 30 cc of ethanol, and 0.52 gm (0.007 mol) of
3-hydroxy-n-propylamine were added to the suspension. Everything
gradually went into solution, accompanied by evolution of
mercaptan. After 10 minutes of standing the solution was
evaporated, and the residue was recrystallized from ethanol,
yielding 1.2 gm of 3-(5'-nitro-furyl-2')-4-[(methylmercapto)
-(.gamma.-hydroxy-n-propylamino)-methylene]-isoxazolone-5, m.p.
168.degree. C.
b. A mixture of 0.3 gm of this compound and 3 cc of
dimethylsulfoxide was heated at its boiling point for five minutes
and then allowed to cool, and the precipitate formed thereby was
collected by vacuum filtration and washed with ether. 150 mgm of
the same compound as in Example 11, m.p. 275.degree.-280.degree. C,
were obtained.
EXAMPLE 38
3-(5'-nitro-furyl-2')-4-[5"-(dimethylamino-methyl)-oxazolidinylidene-2"]-is
oxazolone-5
11.8 gm (0.04 mol) of 3-(5'-nitro-furyl-2')-4-[(bis
-methylmercapto)-methylene]-isoxazolone-5 were suspended in 150 cc
of ethanol, and 4.83 gm (0.04 mol) of 3-dimethylamino
-2-hydroxy-n-propylamine (prepared according to Friedlander 16,
2896) were added to the suspension. The resulting mixture was
heated at its boiling point for one hour, then allowed to cool,
vacuum-filtered, and the filter cake was washed with ethanol and
ether. 10 gm (80 percent of theory) of the compound, m.p.
192.degree. C, of the formula ##SPC17##
were obtained.
Analysis: C.sub.13 H.sub.14 N.sub.4 O.sub.6 ; mol. wt. 322.3
Calculated: C - 48.45%; H - 4.38%; N - 17.37%
Found: C - 48,50%; H - 4,43%; N - 17.40%
Its hydrochloride, obtained by treating the free base with
hydrochloric acid, had a melting point of 251.degree.-253.degree.
C.
It tartrate, obtained by treating the free base with tartaric acid,
had a melting point of 160.degree.-165.degree. C.
EXAMPLE 39
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(diethylamino-methyl)-oxazolidinylidene-2"]-is
oxazolone-5, m.p. 204.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 3-diethylamino-2-hydroxy-n-propylamine.
EXAMPLE 40
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(piperidino-methyl)-oxazolidinylidene-2"]-isox
azolone-5, m.p. 194.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[
(bis-methylmercapto)-methylene]-isoxazolone-5 and
3-piperidino-2-hydroxy-n-propylamine.
EXAMPLE 41
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(pyrrolidino-methyl)
-oxazolidinylidene-2"]-isoxazolone-5, m.p. 205.degree. C, was
prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]
-isoxazolone-5 and 3-pyrrolidino-2-hydroxy-n-propylamine.
EXAMPLE 42
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(N'-methylpiperazino
-methyl)-oxazolidinylidene-2"]-isoxazolone-5, m.p. 146.degree. C,
was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 3-(N'-methylpiperazino)-2-hydroxy-n-propylamine.
EXAMPLE 43
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(morpholino-methyl)-oxazolidinylidene-2"]-isox
azolone-5, m.p. 220.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 3-morpholino-2-hydroxy-n-propylamine.
EXAMPLE 44
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(di-n-butylaminomethyl)-oxazolidinylidene-2"]-
isoxazolone-5, m.p. 142.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 3-(di-n-butylamino)-2-hydroxy-n-propylamine.
EXAMPLE 45
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(di-isopropylaminomethyl)-oxazolidinylidene-2"
]-isoxazolone-5, m.p. 183.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]-isoxazolone-5
and 3-(di-isopropylamino)-2-hydroxy-n-propylamine.
EXAMPLE 46
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(diethylamino-methyl)-
3-methyl-oxazolidinylidene-2"]-isoxazolone-5, m.p. 96.degree. C,
was prepared from
3-(5'-nitro-furyl-2')-4-[(bis-methylmercapto)-methylene]
-isoxazolone-5 and 3-diethylamino-2
-hydroxy-N-methyl-n-propylamine.
EXAMPLE 47
Using a procedure analogous to that described in Example 38,
3-(5'-nitro-furyl-2')-4-[5"-(dimethylamino-methyl)-oxazolidinylidene-2"]-i
soxazolone-5, m.p. 192.degree. C, was prepared from
3-(5'-nitro-furyl-2')-4-[1",3"-dithiacyclopentanylidene)-2"]-isoxazolone-5
and 3-dimethylamino-2-hydroxy-n-propylamine.
The compounds embraced by formula I above and, if they contain a
basic nitrogen atom, their non-toxic acid addition salts, have
useful pharmacodynamic properties. More particularly, they exhibit
anti-bacterial activities and are especially effective against
grampositive and gramnegative bacteria, such as Staphylococcus
aureus and Escherichia coli, as well as against trichomonads,
especially Trichomonas vaginalis.
For instance, the following specific compounds are effective
against Staphylococcus aureus and Escherichia coli within
concentration ranges as low as 0.6 - 20 .gamma./ml and 0.16 - 20
.gamma./ml, respectively:
A. 3-(5'-nitro-furyl-2')-
4-[imidazolidinylidene-2"]-isoxazolone-5,
B.
3-(5'-nitro-furyl-2')-4-[oxazolidinylidene-2"]-isoxazolone-5,
C.
3-(5'-nitro-furyl-2')-4-[3"-methyl-oxazolidinylidene-2"]-isoxazolone-5,
D.
3-(5'-nitro-furyl-2')-4-[thiazolidinylidene-2"]-isoxazolone-5,
E. 3-(5'-nitro-furyl-2')-4-[5"-methyl-oxazolidinylidene-
2"]-isoxazolone-5,
F. 3-(5'-nitro-furyl-2')-4-[4"-methyl-oxazolidinylidene-
2"]-isoxazolone-5,
G.
3-(5'-nitro-furyl-2")-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5,
H.
3-(5'-nitro-furyl-2')-4-[1",3"-tetrahydrooxazinylidene-2"]-isoxazolone-5,
and
I.
3-(5'-nitro-furyl-2')-4-[5"-(dimethylamino-methyl)-oxazolidinylidene-2"]-i
soxazolone-5.
Compounds (B), (D), (E) and (F) are also very effective against
Trichomonas vaginalis at minimum inhibiting concentrations below
0.2 .gamma./ml.
For pharmaceutical purposes the compounds according to the present
invention are administered to warm-blooded animals topically or
perorally as active ingredients in customary pharmaceutical
compositions, that is, compositions consisting essentially of an
inert pharmaceutical carrier and an effective amount of the active
ingredient, such as tablets, coated pills, capsules, wafers,
powders, solutions, suspensions, emulsions, syrups, suppositories,
vaginal tablets and the like. One effective peroral dosage unit of
the compounds according to the present invention is from 0.167 to
2.5 mgm/kg body weight, preferably 0.83 to 1.67 mgm/kg body
weight.
For topical administration, the preferred concentration is about 1
percent by weight, based on the total weight of the
composition.
The following examples illustrate a few pharmaceutical compositions
comprising a compound of the present invention as an active
ingredient and represent the best modes contemplated of putting the
invention into practical use. The parts are parts by weight unless
otherwise specified.
EXAMPLE 48
Tablets
The tablet composition is compounded from the following
ingredients:
Parts
3-(5'-Nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5 100.0 Lactose 63.0 Potato starch 50.0
Polyvinylpyrrolidone 5.0 Magnesium stearate 2.0
______________________________________ Total 220.0
Preparation
The isoxazolone compound, the lactose and the potato starch are
intimately admixed with each other, the mixture is moistened with
an aqueous 10 percent solution of the polyvinylpyrrolidone, the
moist mass is forced through a 1.5 mm-mesh screen, the resulting
granulate is dried at 45.degree. C and again passed through the
screen, the dry granulate is admixed with the magnesium stearate,
and the composition is compressed into 220 mgm-tablets in a
conventional tablet making machine. Each tablet contains 100 mgm of
the isoxazolone compound and is an oral dosage unit composition
with effective anti-bacterial action.
The same result is obtained when an equal amount of
3-(5'-nitro-furyl-2')-4-[5"
-(dimethylamino-methyl)-oxazolidinylidene- 2"]-isoxazolone-5 or a
non-toxic acid addition salt thereof is substituted for
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5.
EXAMPLE 49
Coated pills
The pill core composition is compounded from the following
ingredients:
Parts 3-(5'-Nitro-furyl-2')-4-[
3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2" ]-isoxazolone-5 50.0
Lactose 30.0 Corn starch 30.0 Gelatin 3.0 Cellulose,
microcrystalline 6.0 Magnesium stearate 1.0
______________________________________ Total 120.0
Preparation
The isoxazolone compound, the lactose and the corn starch are
intimately admixed with each other, the mixture is moistened with
an aqueous 12 percent solution of the gelatin, the moist mass is
forced through a 1.5 mm-mesh screen, the resulting granulate is
dried at 45.degree. C and again passed through a 1.0 mm-mesh
screen, the dry granulate is admixed with the cellulose and the
magnesium stearate, and the composition is compressed into 120
mgm-pill cores, which are subsequently coated with a thin shell
consisting essentially of a mixture of sugar and talcum, and
polished with beeswax. Each coated pill contains 50 mgm of the
isoxazolone compound and is an oral dosage unit composition with
effective anti-bacterial action.
EXAMPLE 50
Vaginal tablets
The tablet composition is compounded from the following
ingredients:
Parts 3-(5'-Nitro-furyl-2')-4-[oxazolidinylidene-2"]-isoxazolone-5
100.00 Sorbitol 885.0 Carboxymethyl cellulose, high viscosity 10.0
Magnesium stearate 5.0 ______________________________________ Total
1,000.0
Preparation
The isoxazolone compound, the sorbitol and the carboxymethyl
cellulose are intimately admixed with each other, the mixutre is
moistened with aqueous 50 percent ethanol (150 gm per 1,000
tablets), the moist mass is granulated through a 2 mm-mesh screen,
the granulate is dried at 45.degree. C and again passed through the
screen, the dry granulate is admixed with the magnesium stearate,
and the composition is compressed into 1,000 mgm-tablets. Each
tablet contains 100 mgm of the isoxazolone compound and is an
intra-vaginal dosage unit composition with effective
anti-trichomonal action.
EXAMPLE 51
Tincture
The tincture is compounded from the following ingredients:
Parts
3-(5'-Nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5 1.0 Polyethyleneglycol 400 99.0
______________________________________ Total 100.0
Preparation
The isoxazolone compound is dissolved in the polyethyleneglycol by
heating, and the solution is cooled to room temperature and then
filtered. The resulting tincture contains 1 percent by weight of
the isoxazolone compound and is a topical composition with
effective anti-bacterial action.
The same result is obtained when an equal amount of
3-(5'-nitro-furyl-2')-4-[5"-(dimethylamino-methyl)-oxazolidinylidene-2"]-i
soxazolone-5 or a non-toxic acid addition salt thereof is
substituted for 3-(5'-nitro-furyl-2')-4-[3"-(.beta.
-hydroxy-ethyl)-oxazolidinylidene-2"]-isoxazolone-5.
EXAMPLE 52
Lotion
The suspension is compounded from the following ingredients:
Parts
3-(5'-Nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5 1.0 Sorbitan monopalmitate (Span 40) 1.0 Polyglycol
ether (Cremophor 0) 2.0 Cetyl stearyl alcohol (Lanette 0) 2.0
Spermoceti 1.0 Decyl oleate 5.0 Paraffin oil 1.0 Distilled water
87.0 ______________________________________ Total 100.0
Preparation
The ingredients, except the active substance and the water, are
admixed with each other, and the mixture is melted, brought to
70.degree. C, and then emulsified into the distilled water at the
same temperature. The resulting aqueous emulsion is cooled to
40.degree. C, and the finely milled isoxazolone compound is
suspended therein with the aid of an immersion homogenizer. The
finished composition is then cooled to room temperature. The
resulting lotion, which must be thoroughly shaken before use,
contains 1 percent by weight of the isoxazolone compound and is a
topical composition with effective anti-bacterial action.
The same result is obtained when an equal amount of
3-(5'-nitro-furyl-2')-4-[5"-(dimethylamino-methyl)-oxazolidinylidene-2"]-i
soxazolone-5 or a non-toxic acid addition salt thereof is
substituted for
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5.
An oral dosage unit composition comprising a compound of the
instant invention may, in addition, contain one or more other
active ingredients, such as a muscle-relaxant, as illustrated by
the following example.
EXAMPLE 53
coated pills
The pill core composition is compounded from the following
ingredients:
Parts
3-(5'-Nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5 50.0 Papaverine 25.0 Corn starch 32.0 Gelatin 3.0
Cellulose, microcrystalline 9.0 Magnesium stearate 1.0
______________________________________ Total 120.0
Preparation
The isoxazolone compound, the papaverine and the corn starch are
intimately admixed with each other, the mixture is moistened with
an aqueous 12 percent solution of the gelatin, the moist mass is
forced through a 1.5 mm-mesh screen, the resulting granulate is
dried at 45.degree. C and again passed through a 1.0 mm-mesh
screen, the dry granulate is admixed with the cellulose and the
magnesium stearate, and the composition is compressed into 120
mgm-pill cores, which are subsequently coated with a thin shell
consisting essentially of a mixture of sugar and talcum, and
finally polished with beeswax. Each coated pill contains 50 mgm
isoxazolone compound and 25 mgm of papaverine, and is an oral
dosage unit composition with effective anti-bacterial and
muscle-relaxing actions.
The same result is obtained when an equal amount of
3-(5'-nitro-furyl-2')-4-[5"-dimethylamino-methyl)-oxazolidinylidene-2"]-is
oxazolone-5 or a non-toxic acid addition salt thereof is
substituted for
3-(5'-nitro-furyl-2')-4-[3"-(.beta.-hydroxy-ethyl)-oxazolidinylidene-2"]-i
soxazolone-5.
Analogous results are obtained when any one of the other nitrofuran
derivatives embraced by formula I, or a non-toxic acid addition
salt thereof, is substituted for the particular isoxazolone
compound in Examples 48 to 53. Likewise, the amount of active
ingredient in these illustrative examples may be varied to achieve
the dosage unit range set forth above, and the amounts and nature
of the inert pharmaceutical carrier ingredients may be varied to
meet particular requirements.
While the present invention has been illustrated with the aid of
certain specific embodiments thereof, it will be readily apparent
to others skilled in the art that the invention is not limited to
these particular embodiments, and that various changes and
modifications may be made without departing from the spirit of the
invention or the scope of the appended claims.
* * * * *