close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3099673

код для вставки
United States Patent 0 ” ice
"
3,099,663
Patented July so, 1963
1
2
3,099,663
signi?cant number of day-old chicks are arti?cially in
fected with the organism by the oral route. One group
S-NlTRU-FUIJKFURAL AZINES
James D. Johnston, New London, Conn, assignor to
Chas. P?zer & (10., Inc., Brooklyn, N.Y., a corporation
serves as a control and receives no treatment.
This group
is fed a nutritionally adequate diet containing sufficient
protein, carbohydrate, fat, vitamins and minerals to pro
mote growth in healthy chicks. The other group receives
of Delaware
[No Drawing. Filed Apr. 1, 1959, Bar. No. 863,376
6 Claims. (Cl. 260—-347.5)
this same basic diet except that the compound under test
is admixed with the feed in sufficient quantity to provide
a level of 10.1% by weight of active ingredient. The sur
This invention is concerned with antimicrobial agents
and more particularly with a series of novel azine com 10 vival time of all chicks is recorded and from this data is
calculated the ST5Q> that is the 50% survival time in days
pounds which exhibits valuable activity against a variety
at the 95% con?dence limit. The experiment is con
of microorganisms.
tinued for seven days, at which time the surviving birds
I have made the discovery that compounds having the
are sacri?ed and the heart, spleen and liver recovered for
general formula
15 quantitilve determination of viable Salmonella organisms.
‘Compounds which are found to be particularly eifec
tive in this test include, for example, 1~(5-nitro-2-fur
O
are remarkably effective antimicrobial agents showing
activity against a variety of microorganisms, among them 20
organisms which cause disease in animals, including man,
and fungi of industrial signi?cance.
A may advantageously be selected from keto-substituted
alkanoic and alkanedioic acids, less the keto oxygen, or
frural) - 2 - (dimethyl - ,6 - keto - g1utarate)tazine,
nitro - 2 - furfural) ~ 2 - (ethyl 3 - ketobutyrate)
1 - ethyl pyr'uvate - 2 - (5 - nitro - 2 - furfural)
and
1 - (5 - nitro - 2 - furfural) - 2 - (dimethyl
2 - methyl - glutarate) azine.
1 - (5
azine,
azine,
3 - keto
Especially valuable are
1 - (5 - nitro - 2 - fur?ural) - 2 - (diethyl I3 - ketoglu
tarate) azine, and l - (.5 - nitro - 2 - furfural) - 2 - (di
from formyl-substituted alkanoic acids, less the carboxal 25 methyl 2,4-dimethyl-3-ketoglutarate) azine.
These new compounds are conveniently prepared by the
dehyde oxygen. Such substituents will preferably con
condensation
of S-nitro?urfural hydrazone with a carbonyl
tain a total of up to 12 carbon atoms and will include, for
compound, in a solvent such as ethanol or acetonitrile at
example,
re?uxing temperature, according to the following general
30
reaction
'
and
35
Rz-(iH-COOH
where R1 is hydrogen or .alkyl, R2 is alkyl, and x and y are
zero or integers.
where R1 and R2 are selected to conform to the structures
In addition, the salts, such as the alkali 40 hereinabove described. Alternatively, they may be pre
metal and amine salts, and esters, wherein the esterifying
group is alkyl containing up to about 18 carbon atoms,
may be employed in place of the corresponding acids.
The novel compounds of this invention exhibit in vitro
pared by condensing the hydrazone derived from the car
bonyl compound with S-nitrofurfural, or its diacetate.
The carbonyl compounds are in general readily available
or may be synthesized by methods well known to those
activity against a wide variety of microorganisms, includ 45 skilled in the art.
ing gram positive and gram negative bacteria. Effective
For anti-infective application, these new compounds
ness is found, for example, against such organisms as
may be blended with excipients or dispersed in diluents
Micrococcus pyogenes var. aureus, including antibiotic-re
sistant strains, Streptococcus pyogenes, Erysipelothrix
rhusiopalhiae, Corynebacterium diphtheriae, Bacillus sub
tilis, Clostridium perfringens, Escherichia coli, Vibrio
including Water, isotonic saline, oils such as sesame oil,
50 and the like.
Many modes of administration are pos
sible, including oral, subcutaneous, intramuscular, intra
vaneous and topical application, the choice being dictated
by the type and severity of the infection. For adminis
tration to poultry in the treatment of Salmonella infec
ited against a variety of other microorganisms, for exam
tions, the compounds will ordinarily be administered
55
ple, protozoa such as Endomeba histolytica and Tricho
orally, and may be admixed with feed to provide a con
monas vaginalz's, and fungi such as Alternarz'a solani,
centration of at least about 0.001%, and preferably
Cladosporium cladosporoides, Trichophyton rubrum,
0.01% or more by weight of active ingredient.
Pythium debarynum, Aspergillus niger, and Penicillium
The following examples are given solely for the pur
comma, Pasteurella multocida, Mycobacterium 607, and
Mycobacterium berolinense. Effectiveness also is exhib
funiculosum.
pose of illustration and are not to be construed as limi
The compounds of this invention also exhibit activity 60 tations of this invention, many variations of which are
against various species of Salmonella. Among these, a
vpossible without departing from the spirit or scope thereof.
number of compounds are particularly effective in the
treatment of Salmonella infections in poultry. Each year
EXAMPLE I
a signi?cant number of mortalities occur among poultry
A
mixture
of
0.1
mole
S-nitrofurfural hydrazone and
?ocks, especially chickens, as a result of these infections, 65
0.1
mole
of
‘dimethyl-2,4-dimethyl-3-keto-glutarate
in 500
with a large economic loss resulting. The most impor
ml. acetonitrile is heated at re?uxing temperatures for
about four hours. The resulting solution is ?ltered and
the ?ltrate treated with activated carbon and evaporated
phoid, and S. pullorum, which produces white diarrhea in
in vacuum. The clear gum is treated with 250 ml'. meth
70
chicks.
anol and refrigerated. Filtration of the resulting crys
Compounds are evaluated for activity against these or—
talline slurry and recrystallization from methanol yields
ganisms in the following manner. An experimentally
tant diseases of this nature in poultry result from infec~
tions by Salmonella gallinaru‘m, which causes fowl ty
3,099,663
ll
I-(S-nitro-Z-furfural)-2~(idimethy1-2,4-dirnethyl - 3 - keto
monella according to the same procedures, with the fol
glutarate) azine in the form of a. crystalline solid melting
lowing results:
Minimum Inhibitory Concentration‘
at about 155° C.
EXAMPLE II
Meg/ml.
Following the procedure of Example I, diethyl acetone
S. typhosa _________________________________ __ 100
S. pullorum ________________________________ __ 25
S. gallinarum _______________________________ __ 50
dicarboxylate is caused to react with 5-nitrofurfural
hydrazone, yielding 14.6 g. of 1-(5-nitro-2-furfural)-2
('diethyl-?-ketoglutanate) azine in the ‘form of orange
plates melting at about 126° C. and-having the follow
ing elemental analysis: carbon, 49.42%; hydrogen,
5.04%; nitrogen, 12.4%. Ultraviolet absorption maxi
EXAMPLE VII
10
composition:
ma are observed at 3100 A. (e=15,100) and 4060 A.
Percent
(s=29,250 in methaol). An infrared absorption maxi
mum is observed at 5.755 microns.
A typical poultry feed is prepared having the following
Ground yellow corn ______________________ __
51.28
15 Soybean oil meal (51%) ___________________ __
38.15
Corn oil _________________________________ __
Calcium carbonate ________________________ __
6.10
1.20
EXAMPLE ‘ III
Following the procedure of Example I, the following
series of compounds is prepared:
Dicalcium phosphate ______________________ .._
1.35
Salt ____________________________________ __
0.61
20 Delmix (commercially available mineral mix con
taining CaCOs and small amounts of iron, zinc,
manganese and other salts—Limestone Products
Corporation of America, New Jersey) .
Vitamin A (5305 IU/lb.) __________________ __
0.1
25 Vitamin D3 (681 ICU/lb.) _________________ __
0.05
Klotogen F (commercially available form of vita
min K-Abbott Laboratories) ____________ __ 0.0003
Pyridoxine hydrochloride __________________ __ 0.0006
30
D,L—methion-ine __________________________ __
0.140
Niacin USP ______________________________ __ 0.0025
Choline chloride (25%) ___________________ __
Ribo?avin
___..
_____
Calcium pantothenate (45%) ______________ __
0.2
0.06
0.002
Myvamix (commercially available form of vita
35
min E) _______________________________ __
0.05
The products. of Examples I and II are added to dif
ferent samples of this feed to provide compositions con
taining 0.1% by weight of active ingredient. These com
The product of Example I is subjected to standard in
positions are successfully employed in the treatment of
vitro plate tests against a variety of microorganisms. 40 chicks infected with S. gallinarum, no toxic eifects of the
The medium employed is prepared by adding 37 grams
azine being observed. At the conclusion of the experi
of dehydrated Bacto brain-heart infusion B37 (purchased
ment the birds are sacri?ced and the heart, spleen and
from Difco Laboratories of Detroit) to a liter of distilled
liver found to be free of viable Salmonella.
water and sterilizing the resulting solution in an auto~~
When 5-nitrofurfura1 hydnazone is employed in the
clave. The compound under test is added to the brain 45 same test, it is found to be toxic, causing Weight loss and
heart broth in various concentrations; up to 200 mcg.
early death. At levels below 0.1%, it is inactive.
per ml., and the solutions are applied to agar plates
seeded with one of the organisms. In this manner the
EXAMPLE VIII
minimum concentration of active ingredient necessary
1
(5
nitro
Z-furfural)-2<(dimethyl-B-keto-glutarate)
to inhibit organism growth for 24 hours at 37° C. is de 50
azine is tested in vivo against S. gallinarnm and S. pullo
termined. Results are as follows:
rum according to the procedure described in Example
Minimum Inhibitory Concentration
VIII at levels of 0.1, 0.05 and 0.01%. Signi?cant activity
against both infections is noted at all levels with no toxic
Mcg./ml.
effects.
Bacillus subtilis _____________________________ __ 25 55
What is claimed is:
Clostridium perfringens ______________________ __ 25
l. 1~(5-nitro-2-furfural)-2-(ethyl 3-ketobutyrate) azine of
Bacterium ammoniagenes _____________________ .._ 200
the formula
Aerobacter aerogenes ________________________ __ 200
Proteus vulgaris ____________________________ _._ 100
Pseudomonas aeruginosa _____________________ __ 100
Erwinizz amylovora __________________________ __ 100
60
Dcsulfovibrio desulfuricans; __________________ -._ 200
Vibrio comma ______________________________ __ 100
2. 1-(5-nitro-2-furfural)-2-(dimethyl - ,6 - keto - gluta
When S-nitrofurfur-al hydrazone is subjected to the 65 rate) azine of the formula
same series of tests, it does not inhibit organism growth.
EXAMPLE V
The products of Examples II and III are subjected to
3. 1-(5-nitro-2-furfural) - 2 - (diethyl ,B-ketoglutarate)
similar screening tests and are found to be active against 70
azine of the formula
a wide variety of Gram-positive and Gram-negative or
ganisms.
EXAMPLE VI
The product of Example I is screened‘again'st Sal 75
3,099,663
'~
5
6
atoms, alkali-metal salts of said acids and esters of said
4. 1-(5-nitro-2-furfural) - 2 - idimethyl 2,4 dimethy1-3
acids wherein the esterifying group is alkyl containing up
ketoglutarate) azine of the formula
to 18 carbon atoms.
References Cited in the ?le of this patent
FOREIGN PATENTS
CH3
3,225
5. 1-(S-nitro-2-furfural)-2-(dimethy1 3 - keto-2-methy1
180,357
glutarate) azine of the formula
Japan ________________ __ May 14, 1955
Japan _______________ __ Sept. 12, 1949
OTHER REFERENCES
Dann st ‘211.: Chemische Berichte, volume 82, pages 84
to 88 (1949).
Dreizen et al.: Journal of Dental Research, volume 28,
pages 288 to 298 (1949).
15
Chemical Abstracts, volume 45, page 10302 (1951).
Dodd et -al.: J. Am. Pharm. Assoc., volume 39', pages
10
313-315 (1950).
Chemical Abstracts, volume 47, page 6885 (1953).
Dunlop et al.: “The Furans” (ACS Monograph No.
wherein A is a substituted methylidene moiety derived
from a carbonyl compound selected from the group con
sisting of keto-alkanoic acid, keto-alkanedioic acid and
formylalkanoic acid, each acid ‘containing up to 12 carbon
20 119), pages 164 to 165 and 362 to 36-3, Reinhold Publish
ing Corp. (1953).
Derwent French Patents Abstracts, volume 1, No. 11,
Group 3, page 1 (Sept. 29, 1961).
Документ
Категория
Без категории
Просмотров
0
Размер файла
325 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа