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Патент USA US3020293

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United States Patent 0
3,020,283
C6
Patented Feb. 6, 1962
1
2
3,020,283
The quaternary ammonium salts of the present inven
tion may be prepared by conventional means known to
BIS-LEPIDINES
Richard U. Schock, Jr., and Richard B. Hasbrouck, Lake
Forest, 111., and Donald E. Dickson, Kenosha, Wis., as
signors to Abbott Laboratories, Chicago, Ill., a cor
pora?on of Illinois
those skilled in the art, as for example, heating the base
with a quaternizing agent such as an alkylsulfate, lower~
alkyl halide or other suitable agent.
The following examples illustrate the invention, but are
-
not to be construed as a limitation thereof.
No Drawing. Filed Oct. 20, 1958, Ser. No. 768,064
12 Claims. (Cl. 260--.288)
EXAMPLE 1 '
The present invention is concerned with novel bis~ 10 N ,N’-bis-(2-lepidyl ) -] ,6-diamin0hexane dihydrochloride
lepidines represented by the formula:
CH3
CHa
'
(EH;
CH3
15
A mixture of 35 grams (0.197 mole) of 2-chloro
and non-toxic salts thereof.
In this and succeeding I
lepidine, 11.5 grams (0.098 mole) of 72% 1,6-diamino
. hexane and 23.4 grams of phenol was heated slowly to
formulas, Y represents an alkylene group having from 2 20 150° ‘C. at which point the'reaction' became exothermic
to 12 carbon atoms inclusive, phenylene, cyclohexyl, 1,4
and the temperature increased rapidly to- 260° C. The
xylyl or 1,4-phenylenebisethylene and each R1 and R2
reaction mixture was then allowed‘to cool to 60° C. and
represents hydrogen, lower alkyl, lower alkoxy, hydroxy,
. poured into 400 milliliters of-acetone with constant stir
_ ring. Two milliliters of concentrated'hydrochloric acid
alkoxy” refer to the alkyl and alkoxy radicals containing 25 was thereafter added to the ‘acetone mixture which was
chlorine or bromine. The terms “lower alkyl” and “lower
from 1 to 5 carbon atoms, inclusive. These compounds
may be conveniently isolated as dihydrochloridcs which
salts are crystalline solids slightly soluble in waterf If
desired, the bases may be readily obtained by the addi
rated by ?ltration, washed successively with water and
“acetone and recrystallized from boiling water. As a re
herein refers to acid addition salts of the above bases such
'Analysis.—-Calcd. for c26H3oN,.2Hc1.4H2o: '0:
‘cooled with ice. The precipitate which formed was sepa~
~sult of these operations, there was obtained an N,N’-bis
tion of ammonium hydroxide to a warm solution of the 30 (2-lepidyl) -1,6-diaminohexane dihydrochloride as a white,
dihydrochloride. The term “non-toxic salts” as employed
a crystalline solid which melted at 278-282“ C.
as the hydrochlorides, sulfates, stearates, citrates, lactates,
Found: C=56.93%;
aminobenzoates and the like, as well as the quaternary
ammonium salts of said bases wherein quaternization oc 35
The quaternary ammonium methiodide salt of the fore—
curs on a nuclear nitrogen atom in the lepidine nucleus.
’ going compound was prepared by suspending 9.5 grams
Such quaternary ammonium salts include the methosul
of N,N'-bis-(2-lepidyl)~1,6-diaminohexane in 100 ml. of
dry toluene and 50 ml. of nitrobenzene and heating the
ates, p-toluenesulfonates, loweralkyl benzoates" and the
resulting mixture at the boiling temperature and under
like. The bases, and more particularly their non-toxic 40 re?ux. Dimethylsulfate (6.5 ml.) was thereafter added
salts, are useful as anthelmintics for the control of pin
portionwise with stirring over a period of one hour. The
Worms and tapeworms in mice, dogs and higher mammals.
reaction mixture was then cooled and poured into 200
The new compounds may be prepared by the reaction
,ml. of acetone. The crude dimethosulfate salt which
of a diamine represented by the formula H2N—Y—NH2
precipitated was dissolved in 100 ml. of hot water and 15
with a Z-chlorolepidine represented by the formula: .
45 grams of sodium iodide added to the resulting solution.
fates, methiodides, methochlorides, loweralkyl propion
.
The N,N'-bis-(2-lepidyl)-1,6-diaminobenzene dimeth
iodide which precipitated was removed by ?ltration and
CH:
R:
l
recrystallized from water.
,
Analysis. -- Calculated for C28H36N4I2H2O:
—o1v
N/
R2
.
.
C=
-50 48.01%; H=5.47%; N=8.00%. Found: C=48.09%;
.
H=5.60%; N=8.88%.
EXAMPLE II
The reaction, which is sometimes exothermic, takes place
smoothly in the presence of phenol at the temperature
range of from about 125° C. to 175° C. with the forma-. 55
tion of the desired product as the dihydrochloride. The ‘
temperature may be controlled by external heating or
cooling as may be required. Good results are obtained
when at least two molecular proportions of the 2-chloro
lepidine compound is reacted with one molecular propor 60
tion of diamine.
In carrying out the reaction, the reactants are mixed 7
with a quantity of phenol and the resulting mixture heated
at a temperature of from about 125° C. to 175 ° C. with
N,N’-bis-(6-methoxy-2-lepidyl) -1,-6-diamin0hexane
dihydrochloride
CH2
CH3
CHQO
.A mixture of 31.9 grams (0.152 mole) of 2-chloro~6
methoxy-lepidine; 12.3 grams (0.076 mole) of 72% 1,6-di
aminohexane and 40 grams of phenol was heated at a
external cooling if necessary to control the reaction. 65 temperature of 165° C. for a period of 6 hours.- The re
Upon completion of the reaction, the reaction mixture is 7.5. action mixture was then poured into acetone and processed
cooled and poured into a suitable, inert, organic solvent
as described in Example I to obtain the N,N’-bis-(6
such as acetone. The desired bis-lepidine product may
methoxy-2-lepidyl)-1,6-diaminohexane dihydrochloride as
then be isolated by conventional means as the dihydro- .
chloride. The crystalline dihydrochloride which precipi- 70
tates is removed by ?ltration, washed with water and __.
recrystallized from boiling water.
a crystalline solid which melted at 282-286° C.
7
.Analysis. -- calcd. for C28H34N4O2-2HCl‘25H2O:
C=58.20%; H=7.15%; N=9.70%. Found: C=58.20%;
H=6.61%; N=9.76%.
3,020,283
A.
lepidines and diamines. ‘In the table which follows,
speci?c radicals are substituted for Y, R1 and R2 in the
3
7
EXAMPLE n1
following generic formula:
N,N' - bis - (6,8-dimethyl-2-lepidyl)-J,6-diaminohexane
dihydrochloride
CH3
(‘1113
5
B30
CH!
21161
N// NH—(OH2)a—-NH \N
(‘3H8
10
(llHa
Thus, N,N’-bis-(2-lepidyl)-l,2-diam=inoethane wherein Y
is ('CH2)2 and each R1 and R2 are hydrogen may bepre
pared by the reaction of 2-chlorolepidine and ethylenedi
A mixture of 23.0 grams (0.112 mole) of 2-chloro
amine.
6,8-dimethyllepidine, 9.1 grams (0.056 mole) of 72% 1,6
Calculated
Y
R;
(0112):“EH03(OHM
(01125.
R2
Moles
Water 0i
Hydration
H
H
H
H
HHHH
D-PhenyIene. . .
1,4-0y91011eXy1- - -
H
H
H
H
4. 0
3. 5
(OHz)1(01105lA-xylyl
(CH5) 1..
(GHDM
H
H
n
H
H--.
H
H
n
H
H
0. 25
2. 0
3. 25
0. 5
0
—0H2CH2
CHZCHL . -
M.P. °O.
2. 0
3. 0
0.75
1. 75
321-323
249. 5-250. 5
268-269
154-155. 5
Percent
0
Percent
H
Found
Percent
N
Percent
0
58. 68
57.56
63. 23
61.68
Percent
H
Per
cent
N
58. 54
57.25
63.00
61.40
6. 26
6. 68
6. 51
6. 90
12. 41
11.52
12.26
11.48
6. 30
6. 78
6. 77
7.08
12.68
11.65
12. 48
12. 06
34
324-326
58. 31
58. 86
6. 02
6. 65
10. 47
10. 56
270-274
176-178
317
93-95
157-158
66. 18
62. 70
61.14
66. 66
68. 30
7. 09
7. 50
6. 33
7. 52
7. 63
11. 44
10.47
10. 18
10. 72
10. 62
57. 99
59. 05
6. 05
7. 25
10. 83
10. 39
66. 11
62.34
60. 93
67. 07
67. 91
6. 98
7. 56
6. 50
7. 23
7. 54
11.40
10.12
10.47
10.60
10. 31
______ _-
69.13
6. 10 ...... ._
64. 70
64. 50
63. 70
8. 03
8. 18
7. 28
H
H
0
320-325
69. 36
6. 21
(0H2)1(01101»
(OHM
H
H
G-OFH
H
H
Fr
2. 0
2. 25
1. 5
132
210
285-288
64.46
64.47
63. 80
8. 03
8. 20
7. 45
(01195. .
70m
H’
0. 5
346-349
66. 13
7. 34 ______ ._
66. 70
7. 63 ______ __
(05106.
H
801251----
0
298. 5-299 5
68.29
7.65
68.12
7.61
(CH?
60111
62.03
6.41
.
(6111):.--
0
50015.
800134
26
9. 70
9. 40
10. 60
10.62
9. 11
9. 29
9.18
10. 80
10.70
62.05
6.57 ...... _
58. 39
7. 25
1. 25
238. 5-239. 5
58. 67
6. 99
(OHM ..................................... -_ 6"OO5Hl1---.. H ....... -_
(CH1) 6H
7-01
0
0
248. 5-249.5
189-138
67.18
66. 80
8.15
8.70
6. 04 ______ _-
66.93
66.74
8.03
8.87
6. 13 ______ -
8. 89
(0112»
0
279-281
59. 36
5. 94
59. 16
6. 03
2186
5-01
s-cHq
action mixture Was thereafter poured into acetone and
processed as in Example I to obtain the above named di 45
hydrochloride as a white solid melting at 336-338° C.
EXAMPLE IV
examples, other bis-lepidines may be prepared of which
the following are representative:
.N,N’ - bis - (6-bromo-2-lepidyl)-1,6- diaminohexane di
hydrochloride by the reaction of 2-chloro-6-bromolepidine
and 1,6-diaminohexane.
N,N'-bis-(8-ethoxy-2-lepidyl)-l,2-diaminoethane dihy
drochloride by the reaction of 2-chloro-8-ethoxylepidine
50 and ethylenediamine.
N,N' - bis-(7-propoXy-2-lepidyl)-l,4-diaminobutane di
hydrochloride by the reaction of 2-chloro-7-propoxylepi
dine and 1,4-diaminobutane.
N,N' - bis - (8-methyl-2-lepidyl)-1,6-diaminohexane di
hydrochloride
CH3
9. 86
In a similar manner to that described in the foregoing
diaminohexane and 30 'grams of phenol was heated at a
temperature of 165° C. for a period of 6 hours.‘ The re
Analysis.--calcd. for C3oH38N4-2HCl-05H2O: C:
67.10%; H=7.70%; N=10.40%. Found: C=67.10%;
H=7.38%; N=l0.60%.
10. 06
N,N'-bis-(6,8-dibutyl-2-lepidyl)-l,3-diaminopropane di
CH8
55 hydrochloride by the reaction of 2-chloro-6,8-dibutyl
lepidine and 1,3-diaminopropane.
N-,N'-'-bis-'(8-propyl-2-lepidyl) -'1 ,7 -diarninoheptane dihy
drochloride by the ‘reaction of 2-ch10r0-8-propyllepidine
N, NH-(CH2)6—-NH \N
(‘11:13
(‘3116
‘and 1,7-diaminoheptane.
60
N,N'-bis-(5,7-diethyl-2-lepidyl)-1,9-diaminononane di
hydrochlon'de by the reaction of 2-chloro-5,7-diethyl~
This compound was prepared by heating a mixture of
lepidine and 1,9 diaminononane.
19 grams (0.10 mole) of 2-chloro-8-methyllepidine, 8.05
N,N’-bis-(7-butoxy-2-lepidyl)-1,8-diaminooctane dihy
grams (0.05 mole) of 72% 1,6-diaminohexane and 30
drochloride by the reaction of 2-chloro-7-butoxylepidine
grams of phenol at 175° C. for about 6 hours. Upon
completion of the reaction, the reaction mixture was 65 and 1,8-diaminooctane.
processed as previously described to obtain the above
N,~N' - bis-(6,8 - dibromo-2-lepidyl)-1,l2 - diarninodo
named dihydrochloride which melted at 297—300° C.
decane dihydrochloride by the reaction of 2-chloro-6,8-di~
Analysis.-—calcd. for C28H34'N4'2HCl-05H2O: C=
bromolepidine and 1,12-diaminododecane.
66.20%; H=7.32%; N=1l.00%. Found: C=66.70%;
N,N’-bis-(6 - amyl-Z-lepidyl)-1,l0-diaminodecane dihy
70
H=7.54%; N=ll.20%.
drochloride by the reaction of 2-chloro-6-amyllepidine
EXAMPLE V
and 1,10-diaminodecane.
In a manner similar to that described in the foregoing
The 2-chlorolepidines employed as one of the starting
materials as herein described are, in general, known
examples, other bis-lepidines were prepared and char
acterized by the reaction of the appropriate 2-chloro- 75 ‘compounds. Others may be prepared by methods in
3,020,288
themselves known. The general method of preparation
is illustrated by the following series of reactions:
Y
Boiling Point
in ° 0.
(CH2)1...(CH2 __
(011109 ....
(CH3) m
...
220-234/760 mm.
110/10 mm.
124/10 mm.
.
gCHgha
_____
mews/10 mm.
__... 1111-1115/03 mm.
(3112);: ............................................ ..
M.P.=65.
10 —®-.................................... -. 85-87/20 ‘mm.
—o mQ-o HT-......................... -- 141/10 mm.
15
—CHrCH:A®—GH:—CH1-— ........... -- 115/03 mm.
The new bis-lepidine products are effective parasiticides
and are adapted to be employed for the control of pin
20 worms such as Syphacia obvelata and tapeworms such
as Hymenolepis nana, Dipylidium caninum and Taenia
complete controls of Syphacia obvelata and Hymenolepis
mma, Dipylidium caninum and Taem'a pisiformis. In rep~
resentative operations, substantially complete controls of
25 Syphacia obvelata and Hymenolepis nana have been ob
tained by oral administration to mice of from 25 to 300
milligrams per kilogram of body weight of N,N’-bis-(2
lepidyl)-1,7-diaminoheptaue dihydrochloride.
Thus, aniline or one of its ring-substituted derivatives is
We claim:
'
condensed with ethyl acetoacetate by the method of 30
1. A compound selected from the group consisting of
Campbell et al., J. Org. Chem, 11, 805 (1946) to form
bases represented by the formula: 1
the corresponding acetoacetanilide which is cyclized with
Offer
sulfuric acid by the method of Kaslow and Sommer, I.
Am. Chem. Soc. 68, 645 (1946), to form a 2-hydroxy
lepidine. The latter is converted to the 2-chlorolepidine 35
CHa
R1
by treatment with phosphorus oxychloride using the
R1
i NJ—NH-—Y—HN \N
method of Kaslow and Sommer cited above. The melting
R3
R2
points of some of the 2~chlorolepidines employed in the
present invention are tabulated below wherein R1 and
and non-toxic ‘acid-addition and lower alkyl quaternary
R2 are substituted by speci?c radicals and in the positions 40 ammonium salts thereof wherein Y represents a member
designated in the generic formula
of the group consisting of alkylene groups having from
2 to 12 carbon atoms inclusive, phenylene, cyclohexyl,
OH:
1,4-xylyl and 1,4—phenylenebisethylene and each R1 and
B2
N’
R2 represents a member of the group consisting of hydro
45 gen, loweralkyl, loweralkoxy, hydroxy, chloro and bromo.
2. A compound represented by the formula:
—C1
R1
R1
R2
Melting
50
Point, ° C.
H
6-CH3
H
H
6.0133
H
G-OGH:
5-OCH3
?-OCsHn
H
5-01
H
H
7-CH3
S-CHa
58. 5
96
49
60
8-CH3
129
52. 5
143
116
76
98
74
S-CaHs
S-OCHs
H
7-01
S-CHa
wherein n is an integer from 2 to 12, inclusive.
3. A non-toxic acid-addition salt of a compound as
55 claimed in claim 2.
4. A dihydrochloride salt of a compound as claimed
in claim 2.
5. A compound represented by the formula:
60
The diamines, H2N—Y~NH2, also employed as start
ing materials in the present invention wherein Y is
phenylene or (CH2)2 through (CH2)6 are all commer
cially available. The diamines in which Y is (CH2), 65
through (CH2)12,
R1
CH5
CH9
I
R!
NH-Y-HN
R2
R3
wherein each R1 and R2 represent lower alkyl and Y is
phenylene.
6. A compound represented by the formula:
are known compounds and were prepared by known 70
methods by catalytic reduction of the corresponding
dinitriles. For convenience, the boiling points or melt
ing points of these diamines are shown in the table below
wherein Y is substituted by the radicals designated in the
generic formula H2N--Y-—NH2
75
CH3
3,020,283
‘2''
8
wherein each R1 and R2 represent loweralkoxy and Y is
10. N,N’-bisé(2-lepidyl)-1,9v- diaminononane dihydro
cyclohexyl.
chloride.
7. A compound represented by the formula:
C111i
_
7
11. N,N'-bis-(2-lepidy1)-1,1l-diaminoundecane dihydro
CH3
Chloride.
l
‘5
12. N,N’ - bis-(6-methoxy-2-1epidy1)-1,6 - diaminohex
ane dihydrochloride.
References Cited in the ?le of this patent
or
N,
NH—(CHa)n-—HN
\ /
N
-o1
wherein n is an integer from 2 to 12, inclusive.
3, N,N'-bis-(2-1epidy1)-1,6-diamiI10h6XaI1e dihydro-
chloride.
9. N,N' - bis-(2-1epidyI)-1,7 - diaminoheptane dihydro
chloride.
m
-
I
28
UNITED STATES PATENTS
3
2,933,324
’
’
J
D
17
957
$333k______________ " Aisle 25, i959
\
“WWWMm
-
‘
UNITED STATES PATENT OFFICE
CERTIFICATION OF CORRECTION
Patent No. 3 I020 , 283
February 6' 1962
Richard H. Schock, Jr., et a1°
It is hereby certified that error appears in the above numbered pat
ent requiring correction and that the said Letters Patent should read as
corrected below.
Column 6, lines 22 and 23, strike out "complete controls of
Syphacia obvelata and Hymenolepis nana, Dipylidium caninum and
Taenia"; column 6‘ lines 32 to 38, and lines 59 to 64, the for
mula, each occurrence, should appear as shown below instead of as
in the patent:
Signed and sealed this 5th day of June 1962.
( SEAL)
Attest:
ERNEST W. SWIDER
Attesting Officer
DAVID L. LADD
Commissioner of Patents
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