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Патент USA US3075985

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United States Patent 0
3,075,975
Patented Jan. 29, 1963
1
2
in dogs, few clinicians would even consider it for use
3 075,975
against human pinworms.
ANTHELMINTI'C BISIILBAZQLES AND METHOD
Arthur P. Phillips, Tuckahoe, and Robert B. Burrows,
Ardsley, N.Y., assignors to Burroughs Wellcome & C0.
(U.S.A.) Ina, Tuclrahoe, N.Y., a corporation of New
York
No Drawing. Filed June 7, 1961, Ser. No. 115,996
7 Claims. (Cl. 260-2409)
This application relates to a novel group of distilbazole
derivatives having anthelmintic activity, especially against
We have found that certain closely related compounds,
shown in Formula II, retain this high activity against pin
worrns while possessed of very low oral toxicities. This
effect is presumably due to failure of the compounds II to
be absorbed by the digestive system of the host. In this
formula, 11 is an integer having the values 2 and 3, R’ is
an alkyl group selected from the class consisting of the
methyl, ethyl and n-propyl groups, and X— is the anion
of a non-toxic acid.
CH2
CH2
(CH2) n
N
1/
CH9
X_
II
human pin-worms. This is a continuation-in-part of our
This anion does not contribute to the anthelmintic action
and its identity is not important as long as it is pharma
ccpending application Serial No. 104,798, ?led April 24,
1961.
ceutically acceptable. Iodide, bromide, chloride, toluene
This parasite (Erzterobius vermicularz's) is the most 25 sulfonate, and ethyl sulfate, for example, are convenient
anions and essentially equivalent values for X—.
Accordingly, the invention comprises a novel group of
distilbazole compounds of the preceding formula and the
administration of these compounds in the treatment of
common nematode parasite of the human inhabitants of
North America and Europe. It is particularly common
among young children and frequently spreads through a
family. Since it dwells in the lower intestine, it is diffi
cult to eradicate. At the same time, while it is a nuisance
and shocking to the sensibilities of many people, it is not 30
nematode infestations, particulary human pin-worms.
In Table I are shown the result of tests with illustrative
usually dangerous and serious effects upon the host have
compounds of this invention and of three close relatives,
not been clearly demonstrated.
?rst in regard to toxicity (LDso) in mice and secondly
Because of the relatively innocuous nature of this para—
in eliminating the pin-worm of mice, Syphacia obvelata.
site, clinicians rightly insist that any remedy should it_ 35 (This parasite has been found in past experience to be of
self be non-toxic and otherwise harmless (whereas with
particular value as vectors which indicate drugs useful
more serious infections certain hazards in treatment may
against the human pin-worm.) It will be seen that the
be and often have been accepted). One drug in common
?rst three compounds of the table, having dimethylamino
use against pinworms, piperazine, is both effective and
or diethylamino groups on the benzene rings have LD50
safe. It has, however, the disadvantage that treatment 40 values of 25—35 mg./kg. while high efficiency against pin
must be continuous over a substantial period of time, for
worms requires 1/3 to 1/2 of that amount.
The six following compounds are active at about the
example at least one to two weeks.
In our companion application Serial No. 104,798, ?led
April 24, 1961, we have disclosed that various distilbazoles
same level, but have an entirely different order of toxicity
(LD5O being over 1000 mg./kg. in four of the six cases).
such as that shown in Formula I (where X“ is an anion) 45 All of these compounds were administered as iodides
wherefore differences in molecular weights were negligible
as regards relative toxicity. When the alkyl group R’ is
lengthened to the butyl stage, the consistent pattern of
high e?iciency and low toxicity breaks down, i.e. one of
50 these homologues is relatively ineffective and the other
considerably more toxic (LD50=300 mg./kg.).
These compounds are conveniently prepared by con
densation of two mols of p-pyrrolidino or p-piperidino
CH3
I
benzaldehyde with a quaternary salt of 2,6-lutidine (in
55 the diagram 11, R’ and X— have the same values as above).
are highly effective in eliminating a variety of nematode
parasites, including pinworms. This particular compound,
unfortunately, is relatively toxic in mice and the thera 60
peutic index is correspondingly low. While its toxicity is
not constant from host to host and it may have thera
peutic use in certain disorders, e.g. hookworm, especially
——>
CH2
II
nao?N, om
R’
X
Since the compounds II are very sparingly soluble in most
3,075,975
3
potassium carbonate.
solvents the usual metathetical conversions of anions (e.g.
4,
After removing potassium car
bonate and ether the excess aniline was distilled in vacuo
that of an iodide to a chloride by treatment with silver
and saved, and the product was collected. N-phenyl
pyrrolidine boiled at 133-134” C. at 19 mm.; the yield
salt that anion which is desired in the product. Again, (Fl was 130 g. (88-90%).
conveniently, the anion may be that introduced by the
EXAMPLE 3
alkyiating agent. Thus if one desires that in H R’ should
chloride) are rather unsatisfactory. It is consequently
convenient to have as the anion of the lutidine quaternary
be ethyl and X— iodide, 2,6-lutidine is allrylated with ethyl
p-Pyrrolidinobenzaldehyde.—To 32 cc. of dimethyl
iodide. If X- should be the ethylsulfate anion, alkyla
for-rnamide chilled in an ice bath was added 9 cc. (=16
tion would be with diethyl sulfate. Similarly, alkylation 10 g.) of phosphorus oxychloride over 10 minutes with stir
of 2,6-lutidine with propyl p-toluenesulfonate a?fords 2,6
ring. To the chilled and stirred mixture 15 g. of N~
dimethyl-l-propylpyridiniurn tosylate which is then con
phenylpyrrolidine was added dropwise during 15-30 min
densed with p-pyrrolidinobenzaldehyde or p-piperidino
utes. The reaction mixture was heated for 2-21/z hours
benzaldehyde to give 2,6-bis-p-pyrrolidino or piperidino
at 100° C., then was cooled and poured onto 100 g. of
styrylpyridine n-propyl tosylate.
ice. The aqueous solution was basi?ed to pH 11 by the
.addition of about 25 1g. of sodium hydroxide (as 40-50%
aqueous solution). After standing for 1/2-1 hour the
product was extracted with several portions of ether
Alternatively, metathetical interconversions are read
ily accomplished at this stage so that to make a Com
pound II where X— is chloride, it is easy to convert 2,6
lutidine methiodide to the metho-chloride by warming
20 and the ether extracts were dried over potassium carbo—
with methanolic hydrogen chloride.
nate. After removing potassium carbonate the dried
The compounds '11 are dark-colored crystals whose
ether solution was concentrated. Upon cooling the prod
surface color ranges from dark red to almost black.
uct crystallized. The product can be puri?ed by recrystal
They melt with probable decomposition well above 200°
lization from ether in which it is moderately soluble,
and are sparingly soluble in virtually all solvents, the
from hexane in which it is very sparingly soluble, or
solutions being pinkish or reddish if suf?ciently concen 25 from mixtures of the two. The yield of pure product
trated. In water so little material dissolves that the sol
vent is not visibly colored. The color is due to an intense
was 16 g. (90%); M.P. 85—86° C.
By ‘the same procedure N-phenylpiperidine was con
but broad absorption band, approximately identical as
between the individual compounds.
verted to p-piperidinobenz-aldehyde, M.P., 63-64° C.
The A max. is at
about 495 mu (Em=55,000-60,000) but intense absorp
tion (Em 40,000 or over) is manifest from about 460
30
EXAMPLE 4
2,6-bis-(p-pyrrolidinostyryl) -1-ethylpyridinium iodide
530 mi».
The melting points being attended by decomposition
A mixture containing 2.6 g. of 2,6-lutidine ethiodide,
are somewhat dependent on the rate of heating. Further,
100 cc. of methanol, 4.2 g. of p-pyrrolidinobenzaldehyde
the dark color of the compounds renders precise observa 35 and 1 cc. of piperidine was re?uxed on a steam ‘bath.
Insoluble solid precipitated and heavy bumping started
tion of the melting points extremely di?icult. The data
in less than on hour. After 2 hours this product was col
on melting points of the compounds II must, therefore,
lected (2 g.) and the ?ltrates were re?uxed for 20 hours
be regarded as only approximate. They are of little
value for identification and of no value as criteria of 40 longer. A second crop of 2.5 g. was obtained and on
standing another day or so the ?ltrates gave a third crop
purity.
of one g. The total yield was 5.5 g. (90-95%) in three
EXAMPLE 1
crops, MP. 282-283” C. The product was nearly insolu
ble in hot methanol and was puri?ed by washing several
times with ether and then digesting one or two times with
10-20 times its weigh-t of hot methanol. Because it is
Preparations
2,6-lutidine ethiodide.-A mixture of 107 g. of 2,6
di?icult to recrystallize it is desirable that nearly all in
soluble impurities (dust, boiling stones, etc.) be removed
from the easily puri?ed reactants before the ?nal con—
lutidine and 312 g. of ethyl iodide was re?uxed for 24
hours on a steam bath. The product was collected by
?ltration (1st crop 170 g), the ?ltrates were re?uxed 24
densation step and be kept out as much as possible there
hours longer (2nd crop 40 g), and the ?ltrates again 50 after.
On a larger scale bumping can become a major prob
re?uxed for 24 hours (3rd crop 15 g.). The total yield
was 225 g. (85%).
lem. In such cases a powerful stirrer should be used or
the reaction-mixture should be held at 60-65" C. or
After two recrystallizations from
ethanol 185-195 g. (70-75%) of pure product resulted;
M. P.2l2-214° C.
To prepare the etho-chloride, 10 g. of the ethiodide was
.dissolved in 200 cc. of methanol and hydrogen chloride
below the boiling point of methanol.
When the p-pyrrolidinobenzaldehyde is condensed by
the same procedure with 2,6-lutidine ethochloride, the
gas was run in until 20 g. had been absorbed. The solu
tion was then warmed on the steam bath, most of the
chloride which decomposes above 270° and on gross ex
product is 2,6-bis-(p-pyrrolidinostyryl) pyridine etho
solvent being gradually distilled out. One hundred cc. 60 amination cannot be distinguished from the ethiodide.
Di?erent values are obtained on analysis.
of 10% methanolic hydrogen chloride was then added
By the same procedures p-pyrrolidinobenzaldehyde
and the process repeated. Finally the ?ask was evacu
was
condensed with -2,6-lutidine methiodide and 2,6-luti
rated on the steam bath. The rather hydroscopic residue
was the etho-chloride of 2,6-lutidine and was suitable for
synthetic purposes without further manipulation.
dine-n-propiodide to give 2,6 - bis - (p-pyrrolidinostyryl)
65
pyridine methiodide and propiodide. These compounds
melted with decomposition at 295-7 ° and 265-7" re
EXAMPLE 2
spectively. Condensation of the aldehyde with 2,6-luti
dinepropyl tosylate ‘afforded 2,6-bis-(pyrrolidinostyryl)
N-phenylpyrr'oIidine.-—A mixture of 216 g. of 1,4-di 70 pyridine propyl tosylate which decomposes around 260".
Similarly p-piperidinobenzaldehyde was condensed with
bromobutane, 500 cc. of methanol and 465 g. of aniline
was re?uxed for 5 hours at 100° C. Methanol was evapo
rated and 120 g. of sodium hydroxide (as 40-50% aque
ous solution) was added to the residue. The organic
‘layer was taken up in ether and dried over anhydrous
2,6-lutidine methiodide, ethiodide and propiodide giving
2,6-bis-(piperidinostyryl) pyridine methiodide, ethiodide
and propiodide which melt with decomposition at 222-5",
242-4“ and 228-9° respectively.
3,075,975
5
6
TABLE I.—ACTIVITIES AND TOXICITIES OF COMPOUNDS OF THE
FORMULA
E?ectiveness against Syphacia
WRL No.
RRN
abuelata in mice
LDgo,
mg. 'g.
R’
(mice)
Single
Percent
Mice
dose
worms
cleared]
mgjkg. removed
48-236 ..... _-
61-2 _______ __
60-434 _____ __
(CHmN ____ -.
(CHmN .... _-
(C1H3)2N-____
61-31 """""" N\
0H1 __________ __
25
ch15 .......... -.
35
5
2.5
92
51
2/13
0/6
25
10
7.5
5
2.5
20
97
92
86
69
99
5/9
1/6
2/6
1/6
4/5
CH3
>1 ' 000
10
5
20
10
99
67
96
92
4/5
1/12
3/6
2/6
5
so 2/6
Cm:
1,350
2g
13g
6 2/3
22
188 25g
CH3 .......... _-
.
CHZCHZCHS“. >1,000
N
61-144 ..... __ N
5/5
5/5
7/13
3/3
__
61-143 ..... __ N
100
100
97
100
/
61-75 ...... __ N
61-26 ______ -.
20
1.5
10
20
/_
61-32...... _- N a
Mice
dosed
CH6 .......... --
>
>
01H, .......... __
01120112033“-
>1,o00
s00
450
10
84
3/6
20
100
3/3
13
10
5
99
98
88
6/9
3/9
0/9
20
100
6/6
10
5
100
83
6/6
2/4
20
100
6/6
10
5
96
90
4/6
2/6
What we claim is:
1. A compound of the formula
/CH’
?g’
(CE;),;N—©—CH=CH \N, OH=CH—®-N\ )CHz),
0m
/ +
R
011,
X
wherein n has the values of 2 and 3, R is selected from
the class consisting of the methyl, ethyl and n-propyl
groups, and X- is an anion derived from a pharmaceuti
cally acceptable acid.
didZ-e. 2,6-bis-(pyrrolidinostyryl)-1-methyl pyridinium io-
2,534,237
2,890,982
Cusic _______________ __ Dec. 19, 1950
Natt ________________ __ June 16, 1959
656,515
GreatBritain _________ __ Aug, 22, 1951
55
FOREIGN PATENTS
3. 2,6-bis-(pyrrolidinostyryl)-1-ethylpyridinium iodide.
dig‘ 'z’é'bls'(pyrrohdmostyryl) ' 1 ‘Propylpyndlmum 10‘
OTHER REFERENCES
Welch et al.: Science, volume 105, pages 486-8, May
5e..2,6-bis-(piperidinostyryl)-1-methylpyridinium iodide. 60 9’érgg‘gger et a1, Science volume 105 a e 496 Ma 9
6. 2,6-bis-(piperidinostyryl)-l-ethylpyridinium iodide.
1947
‘ "
’
’P g
’
y
’
7' 2’6'b1S'(p1pendmostyryl)'l'p mpylp yndmmm lodlde'
Venkatararnan: The Chemistry of Synthetic Dyes,
References Cited in the ?le of this patent
65 volume II, pages 1172-33 and 1185, Academic Press Inc.,
UNITED STATES PATENTS
New Yak’ 1952'
1,994,170
Dabclow et a1. ________ __ Mar. 12, 1935
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