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Патент USA US3075994

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United States Patent 0 ”
1
Patented Jan. 29, 1953
2
and is illustrated by methyl, ethyl, n-propyl, visobutyl, n~
butyl, n-hexyl and the like.
3,675,984
1 = [(LQWER - ARGMATHC) - (LGWER - ALKYL)]=4
The term “lower-alkylene,” as used herein, means alkyl~
{(L?i‘VElii-ARQMATiQ-(LOWER - ALKYDIMINOI
EA-BEHYDRGQUL‘QGLHNES AND Tl-IEER PREPA~
RATHQN
Alexander R. darrey, Albany, NY, assignor to Sterling
Drug lino, New Yorir, NJEL, a corporation of Delaware
No Brewing. Filed May 9, 1953, Ser. No. 734,127
16
(Cl. 266-488)
ene radicals having from one to four carbon atoms in—
cluding
10
This invention relates to compositions of matter of the
class of basic quinoline derivatives, to their acid-addition
salts, and to the preparation of these compounds.
and the like.
The invention here resides in a composition of matter
selected from the group consisting of: (a) l-[(loWer-aro 15 The term “lower-aromatic,” as used herein, means radi~
cals having one or two aromatic rings each having from
matic) - lower ~ alkyl)] - 4 - [?ower-aromatic) - (lower
?ve to six ring-atoms which are carbocyclic or hetero
aikyl)imino]-l,4-dihydroquinolines; and, (b) acid-addi~
tion salts thereof.
cyclic, as illustrated by phenyl, naphthyl, biphenylyl furyl,
The physical embodiments of my invention have been
tested by standard chemotherapeutic evaluation proced- ‘
pyridyl and thienyl radicals. Ar and Ar’ preferably rep
resent monocarbocyclic-aryl radicals having six ring-car
bon atoms, i.e., aryl radicals of the benzene series. These
embodiments, which are preferred primarily because of
their commerical practicability due to availability of inter
ures in mice and found to possess amthelmintic activity.
Among the compounds of my invention are those which
in free base form are represented by the structural For
mula I
25
mediates, include the unsubstituted-phenyl radical and
phenyl radicals substituted by substituents including halo,
nitro, lower-alkoxy, lower-alkyl, lower-alkylmercapto,
loWer-alkylsulfonyl, lower-alkylarnino, di-(lower-alkyl)—
Q fl.
N/
ainino, tri?uoromethyl, lower-acylarnino, and the like.
The substituted-phenyl radicals have preferably from one
30 to three substituents including those given above; and,
furthermore, these substituents can be in any of the avail
able positions of the phenyl nucleus, and where more than
one substituent, they can be the same or different and
they can be in any of the various position combinations
where Q represents hydrogen or from one to two low 35 relative to each other. Thus Ar and Ar’ each compre
molecular weight substituents at positions 3, 5, 6, 7 and 8
hend the unsubstitutedphenyl radical as Well as substi
of the quinoline nucleus selected from the group consist
tuted-phenyl radicals illustrated by: nitrophenyl radicals
ing of halo, lower-alkoxy, lower-alkyhnercapto, lower
alkyl, nitro and tri?uoromethyl radicals; Y and Y’ each
represent lower-alkylene radicals; Ar and Ar’ each repre 40
sent lower-aromatic radicals including phenyl, naphthyl,
biphenylyl, thienyl, furyl, pyridyl and pyrimidyl radicals;
and R represents hydrogen or a lower-alkyl radical.
in the above general Formula l the quinoline nucleus
can be unsubstituted at the positions other than 1 and 4 45
or it can be substituted further at one to two or” the nor
mally aromatic positions of the quinoline ring, namely,
3, 5, 6, 7 or 8, by the substituents named above. When
Q represents two substituents, they can be the same or
different and can be in any of said available aromatic 50
positions relative to each other. The halo substituents
can be chloro, bromo, iodo or ?uoro. The lower-alicoxy,
lower-alkylmercapto and lower-alkyl substituents have
preferably from one to six carbon atoms and includes:
methox‘, ethoXy, n-propoxy, isopropoxy, n-butoxy, iso
butoxy, Z-butoxy, n-pentoxy, n-hexoxy and the like when
lower-alkoxt; methylmercapto, ethylmercapto, n-propyl
mercapto, isobutylmercapto, n-hexylmercapto and the like
when lower-alkylmercapto; and methyl, ethyl, n-propyl,
isopropyl, n-butyl, n-hexyl and the like when lower-alkyl.
including 4-nitrophenyl, S-nitrophenyl, Z-nitrophenyl, 2,4
dinitrophenyl, etc.; (lower-alkoxylated)-phenyl including
3-ethoxyphenyl, Z-methoxyphenyl, 2,4-dimethoxyphenyl,
2,4,6-trimethoxyphenyl, 3,4-diethoxyphenyl, etc; (lower
alkylated)-phenyl including 4~methylphenyl, B-ethyl
phenyl, Z-methylphenyl, 2,4-dimethylphenyl, 3,4,5-tri
methylphenyl, 4-isopropylphenyl, etc; halogenated-phenyl
including 2-chlorophenyl, 4-chlorophenyl, 2,4-dibromo
phenyl, S-iodophenyl, 2,4-dichlorophenyl, 3,4-dichloro
phenyl, 2,4,6~trichlorophenyl, 4-?uorophenyl, etc; and
other substituted-phenyl radicals including 3-tri?uoro—
methylphenyl, 4-methylmercaptophenyl, 4-methylsulfo
nylphenyl, 4-n-butylarninophenyl, 4-hydroxyphenyl, 4-di
ethylaminophenyl, 2-chloro-4-ethoxyphenyl, 4~acetylarni
nophenyl, and the like.
Particularly preferred embodiments of my invention
are compounds of'the above Formula I and their acid
addition salts of Formula II where Q represents a halo
radical, R represents hydrogen, Y’ and Y’ each represent
CH2, and where the aryl radicals designated as Ar and
Ar’ each represent a monocarbocyclic-aryl radical having
60 six ring-carbon atoms, that is, an aryl radical or" the hen
The quinoline nucleus can be further substituted at the
zene series, as de?ned and illustrated hereinabove, these
2-pcsition by a lower-alkyl radical represented above as
particular embodiments being preferred because they pos
R; the term “lower-alkyl,” as used herein, means alkyl
sess in greater degree the applied use characteristics in
radicals having from one to six carbon atoms, inclusive,
dicated in the speci?cation.
>
8,075,98é
3
4»
readily reconverted into their acid-addition salts by treat
Embodiments in the form of their acid-addition salts
can be represented by the general structural Formula 11
ment with an acid, I prefer to represent the acid salt form
by Formula II.
As an illustration, I prefer to represent the hydrochlo
ride salt of 7-chloro-l-(Z-chlorobenzyl)-4-(4-chloroben
zylimino)-l,4-dihydroquinoline by the following struc
tural Formula Ha:
Q m/LR
H01
N
Y-Ar
II
10
where Q, Y’, Ar’, R, Y and Ar have the meanings desig
nated above and An represents an anion.
The anion designated above as An can be any anion 15
and is preferably a chemotherapeutically acceptable anion,
for instance, chloride, bromide, iodide, sulfate, phosphate,
sulfamate, benzenesulionate, para-toluenesulfonate, meth
anesulfonate, ethanesulfonate, citrate, tartrate, and the
like; the anion has no appreciable activity of its own in 20
the high dilutions at which the acid-addition salts as a
whole are effective. In particular, the anion appears to
contribute nothing to the chemotherapeutic properties
which inhere to the cation portion of the substituted -l_,4
dihydroquinolines of the present invention. However,
Ila
Alternatively, this compound can be named 7 -chloro-l-(2
chlorobenzyl ) -4-(4-chlorobenzylamino) quinolinium chlo
ride or 7-chloro-4-(4-chlorobenzylamino)quinoline 2
chlorobenzochloride and can be represented by the struc
tural Formula 11b:
preferred compounds are those in which An represents
halide, in particular, chloride, iodide or bromide, since
these are derived from readily available starting materials.
By a chemotherapeutically acceptable anion, I mean any
anion which is innocuous to the animal organism in chem
otherapeutic doses of the acid-addition salt, so that bene
01—
Ni
01/ \CHs—©
?cial physiological properties inherent in the cation are
not vitiated by any possible side-ettects ascribable to the
anions; in other words, the latter do not substantially aifect
the chemotherapeutic properties inherent in the cations.
I
7
11!)
Thus, it is to be understood that although I prefer to rep
resent the acid-addition salt form of my compounds by
The acid-addition salts are prepared directly as de~
scribed hereinafter or they are prepared from the free base
either by dissolving the free base in an aqueous alkanol
the structural formula designated above as H, i.e., as an
acid-addition salt of a 1-[(lower-aromatic)-(lower-alkyl)]
solution containing the appropriate acid and isolating the
4-[(lower-aromatic)-(lower-alkyl)imino} - 1,4 - dihydro
‘salt by evaporating the solution if necessary, or by react
ing the free base and acid in an organic solvent, e.g., lower
alkanol, in which case the salt separates directly or can
quinoline, this 4-imin0-1,4-dihydroquinoliue structure ac
tually represents only one of the contributing members of
a resonance hybrid; and, further, it is to be understood
that the salt form of my invention comprehends not only
be obtained by concentration of the solution. ' Alterna
tively, the acid-addition salts can be prepared by treating
an acid-addition salt (Formula 11) prepared directly as
noted above withan anion exchange resin saturated with
this 4-imino-l,4-dihydroquinoline structure (as speci?cally
illustrated above as Ila) but also other contributing mem
bers of the resonance hybrid including the l-{(loWer-aro~
the desired anion.
matio) - lower-alkyl)l - 4 - [?ower-aromatic) - (lower
Although chemotherapeutically acceptable», salts. are pre
alkyl) amino] -quinolinium salt structure (as speci?cally il
ferred, all acid-addition salts are within the scope of my
invention. All acid-addition salts are useful as sources of
the free base form even if the particular salt per se is not
desired as the ?nal product, as for example when the salt
is formed only for purposes of puri?cation or identi?ca
tion, or when it is used as an intermediate in preparing a
lustrated above as 1112).
The compounds of Formula II are conveniently pre
pared by reacting the corresponding 4-[(lower-arornatic)
(lower-alkyDamino]-quinoline having the Formula HI
chemotherapeutically acceptable salt by ion exchange pro 55
cedures.
Concerning the structure of the acid-addition salts rep
resented above as Formula II, the following considerations
are presented. From chemical and physical data it ap
pears that structure 11 is actually a resonance hybrid
whose main contributing structures are represented as fol~
lows by A<—-> B:
0
111
where ‘Q, Y’, Ar‘ and R have the meanings designated
above, with a (lower-aromatic)-(lower-alkyl) ester of the
formula Ar-Y-An, where Ar, Y and An have the mean~
ings given above, and, if the compounds of Formula I are
desired, then reacting the resulting acid-addition salt of
the 1-[ (lower-aromatic)-(lower-alkyl)] - 4 - [(lower-aro'-'
matic)-'(lower-alkyl)imino] - 1,4 - dihydroquinoline salt
(Formula II above) with an acid-acceptor to yield the
product in free base form (Formula I). Thus, the reac- -
70 tion of 7-chloro-4-(4-chlorobenzylarnino)quinoline with
benzyl chloride yields the hydrochloride of 1-benZyl-7
chloro-4-(4-chlorobenzylimino) - 1,4 - dihydroquinoline
Since my compounds infree base form (Formula I) ‘are
which when treated with an acid-acceptor yields l-benzyla
readily obtained from their acid-addition salts by reaction
7-chloro-4( 41chlorobenzylimino) ~l ,4-dihydroquinoline...
75
with an acid-acceptor, as show11-be10W,endsiuc_e they are
scrapes
6
The step of reacting the 4-[(lovv'er-aron1atic)-(lower
reaction as for example, ethanol, and the like. if an
alkyl)amino]-quinoline (Formula Ill) with the ester
Ar-Y-An is carried out preferably by heating the re
inert solvent is used, the product usually separates from
solution upon cooling, or can be obtained by concentra
tion of the solution.
actants between about 50° C. and 150° C., a particularly
preferred range being between about 80° C. and 120° C.
The reaction can be run below 50° C., but it takes longer.
The reaction is carried out preferably in an organic sol
vent which is inert under the conditions of the reaction
The following examples will further illustrate the in
vention without, however, limiting it thereto.
as for example, acetonitrile, acetone, ethanol, Z-propa
A. 1-[(L0Wer-Ar0matic)-(Lower-Alkyl)1-4
EXAMPLE 1
1101, and the like. When an inert solvent is used, the 10
product usually separates from solution upon cooling, or
can be obtained by concentration of the solution. The
Hrzlohuz'nolinium Halides
The preparation or" these intermediates is illustrated
by the following preparation of 7-chloro-l-(2-chloro
reaction takes place most readily with (lower-aromatic)
(lower-allryl) esters Ar—Y—An where An represents the
benzyl)-4-iodoquinolinium iodide:
A reaction mixture containing 80 g. of 4,7-dichloro
anion of a strong inorganic acid or an organic sulfonic 15
quinoline, 128 g. of Z-chlorobenzyl chloride, 177 g. of
acid. The chloride, bromide or iodide are preferred be
sodium iodide and 1200 cc. of acetone was re?uxed for
cause of the more ready availability of the requisite
twenty-four hours with stirring. The reaction mixture
(lower-aromatic) - (lower - alkyl) halides. Compounds
Was allowed to cool and the precipitate was collected;
where the anion An represents anions other than halogen
or anions of strong acids can be prepared preferably 20 Washed successively with acetone, water and acetone.
There was thus obtained 130 g. (60% yield) of 7-chloro
by reacting the free base form of my compounds having
l-(2-chlorobenzyl)~4-iodoquinolinitm1 iodide, MP. 208
Formula i with the appropriate acid according to the
procedure described above.
209" C. (uncorr).
Followinc the above procedure using an equivalent
The step of reacting the acid-addition salt of the 1
quantity of 4,5-dichloroquinoline in place of 4,7—dichloro
[(lower - aromatic) - (lower - alkyD] - 4 - [(lower
quiuoline, the product obtained was S-chloro-l-(Z-chloro
aromatic) - (lower - allsyDirnino] - 1,4 - diiydroquino
benzyl)-4-iodoquinohniu1n iodide, MP. 20l-202° C.
line (Formula ll) with an acid-acceptor is carried out at
with decomposition.
Analysis.——~Cslcd. for Cl?HmClglNl-ll: C, 35.45; H,
2.04; I“, 23.42. Found: C,‘ 35.28; H, 2.30; l*, 25.6.
room tern erature or by warming, if necessary. The re
action can be carried out in an aqueous or organic sol
vent; however, it is preferably carried out in an organic
solvent inert under the conditions of the reaction as for
Following the above procedure using an equivalent
quantity of benzyl chloride in place of Z-chlorobenzyl
chloride, the product obtained was l-benzyl-7-chloro-4
iodoquinoliniurn iodide, MP. 220-222° C. with decom
position.
Analysis. ——- Calcd.
for CIGHHCHNHI: I, 50.1.
Found: l, 48.79.
example, anhydrous methanol, ethanol, and the like. The
purpose of the acid-acceptor is to take up the hydrogen
halide (or HAn) which is split out during the course of
the reaction. The acid-acceptor is a basic substance
which preferably forms freely water-soluble lay-products
easily separable from the product of the reaction, includ
ing for example, sodium hydroxide, potassium hydroxide,
sodium carbonate, potassium carbonate, sodium acetate,
sodium allroxides, potassium allcoxides, sodium amide,
Following the above procedure in the absence of so
dium iodide, 4,7-dichloroquinoline and 2-chlorobenzyl
40 chloride react to form l~(2-chlorobenzyl)-4~,7-dichloro
and the like.
The compounds or" Formulas l and H can also be pre-,
quinoliniurn chloride; use of 4,7-dibrornoquinoline and
Z-bromobenzyl bromide in the absence of sodium iodide
pared by reacting the corresponding 4-haloquinoliniurn
yields
1 - (2 - bromobenzyl) - 4,7 - dibromoquinolinium
bromide.
halide having the Formula IV
, Other l-[ (lower-aromatic) - (lower-alhyl) ]-4-haloquino
linium iodides that can be prepared following the above
procedure using the appropriate 4-haloquinoline, (lower~
aromatic)-(lower-alkyl)-halide and sodium iodide in
clude: 3,7-dichloro-4-iodo-l - ( 3-nitrobenzyl) quinolinium
50 iodide, 7-bromo-1-(2,4-dimethoxybenzyl) - 4 - iodoquino
where Q, R, Y and Ar have the meanings designated
above, An represents a halide ion and X represents a
chloro, brorno or iodo radical, with a lower-aromatic)
(lower-alliynamine or" the formula Ar'—-Y'—NH2 and
reacting the resulting HAn acid-addition salt (Formula
II) with an acid-acceptor to yield the product in free base
form (Formula 1). Thus, the reaction of 7-bromo-1
(2 - chloro - 4 - ethcsrybenzyl) - 4 - iodoquinolinium io
zylarnine yields the hydriodide of
7
~
brorno - 4 -
(2
- bromo‘oenzylimino)
-
l
chioro - 4 - etboxybenzyl) - 1,4 - dihydroquinolin '
-
(2—
and,
the corresponding compound in free base form is ob
tained by treating the hydriodide salt with an acid-ac 65
ceptor as described above.
The reaction of the 4-haloquinolinium halide (Formula
IV) with a (lower ~ aromatic) - (lower - alkyl) - amine
Ar'—Y'——Nl-ln is carried out preferably by heating the
reactants at a temperature between about 50° C. and 70
150° (3., preferably between about '75 and 125° C.; the
reaction can be run at room temperature, but it takes
longer. The reaction is preferably carried out in an or
ganic solvent which is inert under the conditions of the 75
linium iodide, 8-chloro-4-iodo-l-(2,4,6-trimethoxybenzyl)
quinolinium iodide, l-(3-ethylbenzyl)-4-iodo-7-tri?uoro~
methylquinolinium iodide, 4-iodo-7-methylmercapto-1
(Z-methylrnercaptobenzyl)quinolinium iodide, 7-chloro~
l - [2 - (4 - chlorophenyl)ethyl]-4-iodo-2-methylquino
linium iodide, l-(4-biphenylylrnethyl)-7-chlor0-4-iod0—
quinolinium iodide, 7-chloro-4-iodo-l-(Z-thienylrnethyl)
quinolinium iodide, 7-chloro-1-(2-furylmethyl)-4~iodo~
quinolinium iodide, 7-chloro-4-iodo-l—(3-pyridylrnethyl)
rnethyl)quinolinium iodide, 7-chloro-l-(4-dirnethylarnino
benzyl)-4-iodoquinolinium iodide, 7-chloro-4-iodo-l-(2
pyridylmethyl)quinolinium iodide, 7-chloro-4-iodo-l~(2
quinolinium iodide, 7 - chloro - 4- - iodo-l-(2~pyrirnidyl
methoxybenzyl)quinolinium iodide, 6,7-dichloro-l- [2-‘
( 2,4-dirnethoxyphenyl) ethyl] -4-iodoquinolinium iodide,
7 - bromo-l-(2-chloro-4-rnethoxybenzyl)~4-iodoquinolin
ium iodide, l-[4-(4-chlorophenyl)butyl]-4-iodo-3-nitro~
quinolinium iodide, 6,8-dimethoxy-4-iodo-l-(2,4,6-tri
chlorobenzyi)quinolinium iodide, 8-n-butoxy-4-iodo-1~(3
tri?uoromethylbenzyl)quinolinium iodide, l-(4-n-butyl
mercaptobenzyl)~6-n-hexyloxy-4-iodoquinolinium iodide,
4 — iodo - 8 - isobutylrnercapto-l-(3-phenylpropyl)quino
linium iodide, 7-chloro-4-iodo-o-methoxy-l-(4-n-propyl
sulfonylbenzyl)quinolinium iodide, l-(4-n-butylamino
benzyl)-4-iodo-7-methylquinolinium iodide, 4,7-diido-1
accesses
aromatic)-'(loWer-alky1) amine include those compounds
(4-iodobenzy1)quinolinium iodide, 7-chloro-4-iodo-1-(2
methylrnercaptobenzyl)-3-nitroquinolinium iodide, 1-(2
1 of Examples 3-31.
EXAMPLE 3
chlorobenzyl)~4-iodoquinoliniurn iodide, 7-chloro-4-iodo
4-benzylirnino - 3,7 - dichloro-l-(3-nitrobenzyl)-1,4-di
l-(2-naphthylrnethyl)quinoliniurn iodide, and the like.
B. 1-[ (Lower-Aromatic) - (Lower-Alley!) 1-4- [ (Lower
hydroquinoline hydriodide is obtained using 3,4-dichloro~
4-iodo-1-(3-nitrobenzyl)quinolinium iodide and benzyl
5)
Aromatic) -(L0wer-Allcyl) Imin0-1,4-Dihydroquinoline
amine; and the hydriodide is then converted into the corre
The preparation of these compounds by ?rst reacting a
sponding free base and hydrochloride.
1-[(lower-aromatic)-(lower-ail<:yl)] - 4 - haloquinolinium
halide with a (lower - aromatic) - (lower - alkyl) - amine
EXAMPLE 4
101
Ar'——Y’—-NH2 is illustrated by the following preparation
7-chloro-1 - (2 - chlorobenzyl) - 4 - (3 - ethoxy‘oenzyl
of l-benzyl - 'i - chloro-4-(3-chlorobenzylimino)-l,4-di
irnino)-l,4-dihydroquinoline hydriodide is obtained using
hydroquinoline hydriodide, free base and hydrochloride:
7~chloro-l-(Z-chlorobenzyl) - 4 - iodoquinoliniurn iodide
and 3-ethoxybenzylamine; and the hydriodide is then con
A mixture containing 7 g. of 1-benZyl-7-chloro-4-iodo
quinolinium iodide, 6 g. of 3-chlorobenzylarnine and 100 15 verted into the corresponding free base and hydrochloride.
cc. of absolute ethanol Was heated; the resulting hot
EXAMPLE 5
solution was treated With decolorizing charcoal and ?l—
S-chloro-1-(2-chlorobenzyl)-4-{2,4,6 - trimethoxybenzyl
tered; and the ?ltrate was cooled to yield a crystalline
precipitate. The precipitate was collected to give '7 g.
(96% yield) of 1-benZyl-7-chloro-4-(3-chlorobenzyl
imino)-l,4-dihydroquinoline hydriodide, melting point
20s
irnino)-1,4-dihydroquinoline hydriodide is obtained using
S-chloro-1-(2-chlorobenzyl)-4-iodoquinolinium iodide and
2,4,G-trimethoxybenzylamine; and the hydriodide is then
converted into the corresponding free base and hydrochlo
228-230° C.
ride.
The above hydriodide salt was converted into its free
base form by suspending the salt in ethanol and treat
EXA EE’LE 6
ing the suspension with 5 cc. of 35% aqueous sodium 25
7-bromo - 1 - (2,4 - dirnethoxybeuzyl) ~ 4 - (2 - fluoro
hydroxide solution. The resulting solid was collected and
benzylirnino)-1,4-dihydroquinoline hydriodide is obtained
recrystallized from isopropyl alcohol to yield 3 g. of 1
using 7-bromo-4-iodo - 1 ~ (2,4 - dirnethoxybenzyDquino
benzyl-7-chloro - 4 - (3 - chlorobenzylirnino)-1,4-dihydro
liniurn iodide and Z-fluorobenzylarnine, and the hydrio
quinoline, melting point 108—109° C.
dide is then converted into the corresponding free base
The hydrochloride salt Was formed by dissolving the 30
and hydrochloride.
1 - benZyl-7-chloro-4-(3-chlorobenzylirnino)-l,4-dihydro
EXAMPLE 7
quinoline base in ethanol and treating the ethanol solu
tion with an excess of solution of hydrogen chloride in
4-(2 - brornobenzylimino) - 8 - chloro _ 1 - (2,4,6-tri
ethanol followed by addition of ether. The crystalline
product that separated was collected to yield 2.7 g. of
methoxybenzyl)-l,4-dihydroquinoline hydriodide is ob
tained using 8-chloro-4~iodo-l-(2,4,?-trirnethoxybenzyl)
1 - benzyl-7-chloro-4-(3-chlorobenzylirnino)-1,4-dihydro
quinoliniurn iodide and Z-brornobenzylarnine; and the
hydriodide is then converted into the corresponding free
base and hydrochloride.
EXAMi’LE 8
quinoline hydrochloride, melting point 231.0-232.4° C.
(corn).
Analysis.—Calcd. for C23H18ClzN2HCl: Cl, 24.75‘; N,
6.50. Found: Cl, 24.60; N, 6.42.
Alternatively, as discussed hereinabove, 1-benzyl-7
.1-(3 - ethylbenzyl) - 4 - (3 - iodobenzylirnino)-7-tri
chloro-4-(3-chlorobenzylimino) - 1,4 - dihydroquinoline
?uorornethyl-1,4-dihydroquinoline hydriodide is obtained
hydrochloride can be called 1-benzyl-7-chloro-4-(3-ch1oro
using 1 - (3 - ethylbenzyl)-4-iodo-7-tri?uoromethylquino
benzylarnino) quinolinium chloride.
Following the above procedure using 1-benzyl-4,'7-di
chloroquinoliniurn chloride in place of l-benzyl-7-chloro
liniurn iodide and 3-iodobenzylarnine; and the hydriodide
45 is then converted into the corresponding ‘free base and
hydrochloride.
4-iodoquinoliniurn iodide, there is obtained directly 1
EXAMPLE 9
benzyl-7-chloro-4-(3-chlorobenzylimino) - 1,4 - dihydro
quinoline hydrochloride; using 1~benzy1-4-brorno-7-chloro
4-(2 - chlorobenzylimino) - 7 - methylrnercapto-l-(Z
methylmercaptobenzyl)-1,4 - dihydroquinoline hydriodide
quinolinium bromide, there is 1-benzyl-7-chloro-4-(3
is obtained using 4-iodo-7-methylmercapto-l~(2-rnethyl~
mercaptobenzyl)quinoliniurn iodide and Z-chlorobenzyl
chlorobenzylirnino) -l,4-dihydroquinoline hydrobrornide.
Substitution of the hydrogen chloride in the above
amine; and the hydriodide is then converted into the cor~
reaction with l-benzyl-7-chloro-4-(3-chlorobenzylirnino)
1,4-dihydroquinoline by hydrogen bromide, phosphoric
responding free base and hydrochloride.
acid, sulfuric acid, tartaric acid, sulfarnic acid or methane 55
sulfonic acid, there can be obtained 1-benzyl-7-chloro
4-(3-chlorobenzylimino) - l,4 - dihydroquinoline hydro
60
EXAMPLE 2
1-benzyi-4-(4-brornobenzylimino) - 7 - chloro - 1,4 - di
hydroquinoline hydriodide is obtained following the pro
cedure described in Example 1(B) using 1-benzyl-7
aromatic)-(loWer-alkyl)irnino]-1,4-dihydroquinolines that
driodide is obtained using 7-chloro-1-[2-(4-chlorophen
yl)ethyl]-4-iodo-2-rnethylquinoliniurn iodide and Z-naph
thylmethylamine; and the hydriodide is then converted
into the corresponding free base and hydrochloride.
EXAMPLE ll
1-(4 - biphenylylrnethyl) - 7 - ehloro - 4 - (4 - methyl
benzylirnino)-1,4-dihydroquinoiine hydriodide is obtained
chloro-4-iodoquinolinium iodide and 4-bromobenzyl
amine; and the hydriodide is then converted into the
corresponding free base and hydrochloride.
Other 1- [ (lower-aromatic) -(lower-alkyl) ] -4-[ (lower
7-chloro - 1 - [2 - (4 ~ chlorophenyl)ethyl] - 2 - methyl
4-(2 - naphthylmethylimino) - 1,4 - dihydroquinoline hy
bromide, phosphate, sulfate, tartrate, sulfamate or meth
anesulfonate, respectively, instead of the hydrochloride.
EXAMPLE 1O
using l-(4-biphenylylniethyl)~7-chloro~4-iodoquinoliniurn
iodide and 4-rnethylbenzylamine; and the hydriodide is
then converted into the corresponding free base and by
70 drochloride.
can be prepared following the above procedure in Ex
ample l(B-) for the preparation of 1-benzyl-7-chloro-4
(3-chlorobenzylimino)-1,4-dihydroquinoline and its hy
drohalide salts using the appropriate 1-[ (lower~aromatic)
(lower-alkyl)]-4-iodoquinolinium iodide and (lower~ 75
EXAMPLE 12
4-(3 -,ethylbenzyli1nino) - 7 - chloro - 1 -(2 - thienyl
methyl)-1,4-dihydroquiuoline hydriodide is obtained
using 7-chloro-4-iodo - 1 - (2 - thienylmethyl) quinolinium
3,075,934.
g,
1E’
iodide and 3-ethyibenzyiarnine; and the hydriodide is then
converted into the corresponding free base and hydro
chloride.
odide is obtained rising 6,8-diineLhoxy-4-iodod-(2,4,6
trichiorobenzyi)quinoiinium iodide and 2~rnethylrnercap~
tobenzylarnine; and the hydriodide is then converted into
the corresponding free base and hydrochloride.
EXAMPLE 23
EXAMPLE 13
7-chioro - 4 - (2,4 - dimethylbenzylirnino) _ 1 - ’ 2-fury1~
methyl) - 1,4 - dihydroquinoiine hydriodide is obtained
using 7-chloro-1-(2 - furyirnethyi) - 4 - iodoquinoliniurn
S-n-butoxy - 4 - (2 - pyrimidyimethylimino) - 1-(3-tri
?uorornethyibenzyl)-l,4-dihydroquinoline hydriodide is
iodide and 2,4-dirnethylbenzyiarnine; and the hydriodide
is then converted into the corresponding free base and by
drochloride.
obtained using 8-n-butoXy-4-iodo-1 - (3 - tri?uoromethyl
benzyDquinoiiniurn iodide and Z-pyrimidylmethylamine;
10
and the hydriodide is then converted into the correspond
EXAMPLE 14
ing free base and hydrochloride.
7-chloro - 1 - (3 _ pyridyhnethyi) ~ 4 ~ (3,4,5-trirnethyl4
benzylirnino)-1,4-dihydroquinoiine hydriodide is obtained
EXAMPLE 24
using 7-chioro-4-iodo-1 - (3 - pyridyhnethyl)quinoiiniurn
4-(4-n-butylaminobenzylimino) - 1 - (4-n-bu-tyln1ercap
iodide and 3,4,S-trimethyibenzylmrine; and the hydriodide 15 tobenzyl)~6-n-hexyloxy-L4
- dihydroquinoline' hydriodide
is then converted into the corresponding free base and
is obtained using 1-(4-n-butylmercaptobenzyl)-6-n-hexy1
oxy-4-iodoquinolinium iodide and 4-n-butylarni-nobenzyl
hydrochloride.
EXAMPLE l5
amine; and the hydriodide is then converted into the cor
responding free base and hydrochloride. ‘
7-ch1oro - 4 _ (2 - ChlOl'O'Uéi’lZYlii‘?iIlO) - l - (2-pyrirni
dyhnethyD-1,4-dihydroquinoiine hydriodide is obtained
EXAMPLE 25
using 7-chioro-4-iodo-l~(" - pyrinridyiniethyl)quinoliniurn
iodide and Z-ehiorobenzyiamine; and the hydriodide is
then converted into the corresponding free base and hy
drochloride.
EXAMPLE i6
I
8 - isobuty1mercapto-1-( 3-phenylpropy1) - 4 - (2,4,6~tri
chlorobenzylimino)-1,4-dihydroquinoline'hydriodide is ob
tained using 4-iodo-8-isobutylmercapto-1-(3-phenylpro~
pyl)-quinolinium iodide and 2,4,6-trich1orobenzy1amine;
and the hydriodide is then converted into the correspond
ing free base and hydrochloride.
7~chioro - l - (4 - dirnethylaminobenzyi) - 4 ~ (4 - iso
propylbenzyiin1ino)-1,4 - dihydroquinoline hydriodide is
EXAMPLE 26
obtained using 7-chioro-l - (4 ~ dimethyiarninobenzyl)-4
iodoquinoiininnr iodide and di-isopropyibenzyiarnine; and
the hydriodide is then converted into the correseonding
free base and hydrochloride.
7-chl0ro - 6 - methoXy-4-(2—nitrobenzylimino)-1 - (4-n
propylsulfonylbenzyl)-1,4-dihydroquinoline hydriode is
obtained using 7-chloro-4-iodo-6-methoxy-l-(4-n-propyl—
EXAMPLE 17
sulfonylbenzyl)quinolinium- iodide and Z-nitrobenzyl
amine; and the hydriodide is then converted into the
corresponding free base ‘and hydrochloride.
T-chloro - 4 - (4 - diethyiaminobenzylimino) - 1 - (2
pyridyirnethyi)-i,4-dihydroquinoiine hydriodide is ob
tained using 7-chioro-4-iodo-i-(Z-PyridyImethyi)quinc
EXAMPLE 27
linium iodide and 4-diethylaminobenzyiamine; and the
hydriodide is then converted into the corresponding free
40
base and hydrochloride.
1-(4-n-butylaminobenzyl) - 4 - (2-iodobenzy1imino)~7
methyl-1,4-dihydroquinoline hydriodide is obtained-using
1-(4-n-butylarnin0benzyl) - 4 - iodo-7-methy1quinolinium
EXAit/iPLE 18
iodide and Z-iodobenzylarnine; and the hydriodide is then
4 - (4 - biphenylniethylimino) - 7 - chloro-l-(Z-rne
converted into the corresponding free base and hydro~
thoxybenzyl}1,4-dihydroquinoline hydriodide is obtained
chloride.
using 7-chloro-4-iodo-1 - (2 - *nethoxybenzyi)qninoiininm 45
EXAMPLE 28
iodide and 4-biphenyiyhneihylamine; and the hydriodide
is then converted into the corresponding free base and
hydrochloride.
4-(2~ch1oro-4-ethoxybenzy1imino) - 7 - iodo-1-(4-iodo
-
benzyl)-1,4-dihydroquinoline hydriodide is obtained us
EXAliiPLE 19
6,7-dichioro~l - [2 — (2,4 - dimethoxyphenyi)ethyl]~4~ 50
(Z-thienyintethylimino)-i,4 - dihydroquinoline hydriodide
is obtained using (SJ-dichloro-l-[2-(2,4-dirnethoxyphen
yDethyl}~4-iodoquinoiiniurn iodide and Z-thienyimethyl
55
furyimethylinrino)-l,4-dihydroqninoline hydrio ' e is ob
EXAMPLE 29
4-(4-acetylaminobenzylimino) - 7 - chloro-I-(Zmethyl
mercaptobenzyl)-3-nitro-1,4-dihydroquinoline hydriodide
the corresponding free base and hydrochloridef
tained using 'I-bromo-i-(Z-chioro - 4 - rnethoxyphenyi}~4~
iodoquinoliniurn iodide and Z-furylmethyiarnine; and the
hydriodide is then converted into the corresponding free
EXAMPLE 30
base and hydroehlori e.
1-(2-chlorobenzyD-4 - (4-rnethylsulfonylbenzylimino) -
65
1,4-dihydroquinoline hydriodide is obtained using 1-(2~
chlorobenzyl)-4-iodoquinolinium iodide and 4-rnethyisul
fonylbenzylamine; and the hydriodide is then converted
into the corresponding free base and hydrochloride.
1 - [4 - (4 - chlorophenyhbutyi] _ 3 - nitro - 4 - (3 - pyri~
dylrnethyiirnino)-1,4-dihvdroquinoline hydriodide is ob
tained using 1-[4~(4-chiorophenyi}bntyi}~4-iodo-3-nitro
qninoiiniuni iodide and E-pyridylmethyiamine; and the
hvdriodide is then converted into the corresponding free 70
base and hydrochloride.
EXAMPLE 31
7-chloro-1-(Z-naphthylrnethyl) - 4 - (3-tri?uorornethyl
benzylimino)-1,4-dihydroquinoline hydriodide is obtained
using 7-chloro-4-iodo - 1 - (Z-naphthyhnethyl)quinoliniurn
EXAMPLE 22
iodide and 3-tri?noromethylbenzylamine; and the hy
driodide is then converted into the corresponding free
6,8-din1ethox' - 4 - (2 - niethyiolercaptobenlylimino)~
1-(2,4,6 - trichiorobenz‘ i) - 1,4 - dihydrc-quinoiine hydri
'
is obtained using 7-chloro-4-iodo-1-(Z-methylmercapto
benzyl)-3-nitroquinolinium iodide and 4-acetylamino
benzylarnine; and the hydriodide is then converted into
EXAIVIPLE 20
7-brorno - i - (2 - chloro - 4 - methoxyphenyD-4-(2
EXAMPLE 21
converted into the corresponding free base and hydro
chloride.
'
amine; and the hydriodide is then converted into the cor
responding free base and hydrochloride.
ing 4,7-diiodo-1-(4-iodobenzyl)quinolininm iodide and 2
chloro-4-ethoxybenzylamine;' and the hydriodide is then
75
base and hydrochloride.
'
'
‘i
aemees
11
12
Analysis.-—Calcd. ‘for CMHZUCIZNZHCI: Cl, 24.00; N,
EXAMPLE 32
6.31. Found: Cl, 23.95; N, 6.30.
EXAMPLE 37
4-benzylimino-7-chloro-1- (Z-chlorobenzyl) -1,4-dihydro
quinoline hydrochloride is obtained following the proce
dure described in Example 1(3), using l-(Z-chloro
5.
benzyl)-4,7-dichloroquinolinium chloride and benzyl
amine.
EXAMPLE 33
7~bromo-1-(Z-bromobenzyl) - 4-(2-phenylethylimino)
1,4-dihydroquinoline hydrobromide is obtained following
the procedure described in Example 1(8) using 1-(2
7-Chl0r0-1-(2-Chl0r0benzyl) -4-(2-Chl0robenzyIimino)
1,4-Dihydr0qainoline and Salts
Following the procedure described in Example 103)
using 5.4 g. of 7-chloro-l-(Z-chlorobenzyl)-4-i0doquino
linium iodide, 7.1 g. of Z-chlorobenzylamine and 100 cc.
10 of ethanol, there was ?rst obtained 6 g. of 7-chloro-l-(2
bromobenzyl)-4,7-dibromoquinolinium bromide and 2
chlorob enzyl ) -4- (2-chlorobenzylimino) -l ,4-dihy droquino
line hydriodide, MP. 253—257° C., with decomposition.
phenylethylarnine.
The hydriodide salt was converted, as in Example 1(B),
to 7~chloro~1-(2-chlorobenzyl)~4-(2-chlorobenzylimino)
EXAMPLE 34
1,4-dihydroquinoline, MP. l33.6—-135.4° C. (com).
Analysis.-—Calcd. for C23H17C13N2Z Cl, 24.90; N, 6.55.
Found: Cl, 24.75; N, 6.60.
1-Benzyl-4~Benzylimino-7-Chlam-1,4-Dihydroquinoline
and Saltsv
Following the procedure described in Example 1(B)
using 13.5 g. of 1-henzyl-7-chlor0-4-iodoquinolinium
Treatment of the above imino base in ethanol solu
tion with a. solution of hydrogen chloride in ethanol
'as in Example 1(B) yielded 3 g. of '7-chloro-1-(2-chloro
benzyl)-4-(2 - chlorobenzylimino)-l,4-dihydroquinoline
hydrochloride, MP. 25l.2-255.2° C. (corr.) when re
iodide, 17.3 g. or" benzylamine and 100 cc. of absolute
ethanol, there was ?rstobtained 12.5 g. (95% yield) of
1-benzyl-4-benzylimino-7-chloro-1,4-dihydroquinoline hy
driodide, M.P. 212—2l5° C.
crystallized from absolute ethanol.
This hydriodide salt in
Analysis.-—Calcd. for CggH?ClaNg'HCli Cl", 7.65; N,
ethanol solution was heated with excess 35% aqueous
sodium hydrioxide solution as inExample 1(B) to yield 25 6.05. Found: Cl“, 7.44; N, 6.30.
10.5 g. (81% yield) of 1-benzy1-4-benzylimino-7-chloro
1,4-dihydroquinoline, M.P.~123—.125° C. This free base
EXAMPLE 38
7 - Chloro - 1
form was then dissolved in ethanol and the resulting solu
tion treated with a‘solution of hydrogen chloride in
-
(2
- Chlorobenzyl)-4-(2,4-Dichl0ro~
benzylimino)-1,4-Dihydr0quirz0line and Salts
Following the procedure described in Example 1(B)
ethanolas in Example 1(B) to yield 8.5 g. of l-benzyl-4
benzylimino-7-chloro-1,4-dihydroquinoline hydrochloride,
using 5.4 g. :of 7-ch-loro-1-(2~chlorobenzyl)-4-iodoquino
M1’. 249.6-255.6° C. (corn) when recrystallized from
linium iodide, 7.0 g. of 2,4-dichlorobenzylamine and 100
isopropyl alcohol-absolute ‘ethanol.
Analysis.—-Calcd. for C23H19ClN2?Cl: Cl“, 8.99; N,
7.09. Found: Cl“, ‘8.80; N, 6.96.
cc. of absolute ethanol, there was ?rst obtained 6.5 g.
‘of 7 - chloro-l-(Z-chlorobenzyl)-4-(2,4-dichlorobenzyl
EXAMPLE 35
dichlorobenzylimino)-l,4-dihydroquinoline, ‘MP. 159.6
1-Benzyl-7-Chl0ro-4-(3,4-Dichl0r0benzylimino)
1,4-Dihydr0quin0lin-e and ‘Salts
'
imino)1,4-dihydroquinoline hydriodide, which was con
verted into 6 g. of 7-chloro-l-(2-chlorobenzyl)-4-(2,4
161.4" C. (corn), when recrystallized from absolute
ethanol.
40
Anaiysis.-—Calcd. for C23H16Cl4N2: NK, 6.07; NAP,
This preparation was carried out following the proce
dure described in Example 1(B) using 10 g. of 1-benzyl-7
chloro-4-iodoquinolinium iodide, 11.6 g. of 3,4-dichloro
3.04. Found: NK, 5.99; NAP, 3.0.1.
Reaction of the above imino base with hydrogen chlo
ride as in Example 1(B) yielded 7-chloro-l-(2-chloro
benzylamine and 100 cc. of absolute ethanol. There was
benzyl) - 4 - (2,4 - dichlorobenzylimino)-l,4-dihydro
?rst obtained 12 g. (98% yield.) of l-benzyl-7-chloro-4
quinoline hydrochloride, MP. 2684-2710” C. (corn)
(3,4-dichlorobenzylimino) -1,4-dihydroquinoline hydriode,
when recrystallized from ethanol.
M.P. 257-259° C. The hydriodide salt dissolved in ethan
Analysis.-—Calcd. for C23H16Cl4N2l-ICl: Cl, 7.12; N,
01 was treated with 5 cc. of 35% aqueous sodium hydrox
ide as in Example 1(3) to give 9 g. of 1-henzyl-7-chloro
5.61. Found: Cl, 7.00; N, 5.58.
4-(3,4-dichlorobenzylimino) - 1,4-dihydroquinoline which 50
EXAMPLE 39
was recrystallized from ethanol to yield 7 g. of the puri
tied base, M.P. 138—139° C.
verted
into
>7 - Chloro-l-(Z-Chlorobenzyl)-4-(4-Chl0robenzylimin0)
The base was then con
1,4-Dihydr0qz4inoline and Salts
Following the procedure described in Example 1(3)
using 5.4 g. of 7-chlor0-1-(2-chlorobenzyl)-4-iodoquino
1 - benzyl - 7 - chloro-4-(3,4-dichlorobenzyl
imino)-1,4-dihydroquinoline hydrochloride, M.P. 223.4
224.6° C. (corr.).
linium iodide, 7 g. of 4-chlorobenzylamine and 100 cc. of
absolute ethanol, there was ?rst obtained 4.8 g. of 7
chloro-1-( 2-chlorobenzyl)-4-(4-chlorobenzylirnino) - 1,4
Analysis.-Calcd. for C23H1-7Cl3N2l-1C1: Cl, 30:59; N,
6.04. Found: Cl, 30.40; N, 5.95.
EXAMPLE 36
1 -Benzyl-.7-Chlor0-4- [2-(4-Chl0r0phenyl) Ethylimino] -
1,4-Dihydr0quin0line and Salts
Following the procedure described in Example 1(B)
using 10 g. of 1-benzyl-7-chloro-4~iodoquinoliniurn iodide,
13. g. of 2-(4-chlorophenyl)ethylarnine hydrochloride,
60
dihydroquinoline hydriodide, which was then converted
into 2.9 g. of 7-chloro-I-(Z-chlorobenzyl)-4-(4-chloro
benzylimino) -l,4-dihydroquinoline, MP. 155.4-l56.8° C.
(corn) when recrystallized from absolute ethanol.
Analysis.--Calcd. for czaHmClgNzz Cl, 24.90; N, 6.56.
Found: Cl, 25.85; N, 6.54.
'
Reaction of the above imino base with hydrogen chlo
3.8 g. of potassium hydroxide (to neutralize the HCl of 65 ride as in Example 1(B) yields 7-chl-oro-l-(2-chlo1‘o
the 2-(4-chlorophenyl)ethylamine hydrochloride) and
100 cc. of ethanol, there was obtained l-benzyl-7-chloro
4-[2-(4-chlorophenyl)ethylimino] - l,4 - dihydroquinoline
hydriodide. The hydriodide when treated as in Example
103) yielded 7.5 g. of 1-benzyl-7-chloro-4-[2~(4-chloro 70
phenyl)ethyliminol-1,4-dihydroquinoline, which was then
converted into l-benzyl-7-chloro-4-[2-(4-chlor0phenyl)
ethylimino] -1,4-dihydroquinoline hydrochloride, M.P.
2880-2922’ C. (corn), when recrystallized from ab
solute ethanol.
benzyl) - 4 - (4-chlorobenzylirnino)-1,4-dihydroquinoline
hydrochloride.
EXAMPLE 40
S-Chloro-J-(Z-ChZOrobenzyl) .- 4 - (2,4-D'ichl0r0benzy1
imino)-1,4-Dihydraqain0line and Salts
Following [the procedure described in Example 103)
using 23 g. of S-chioro-l-(2-chlorobenzyl)-4~iodoquino
linium iodide, 30 g. of 2,4-dichlorobenzylamine and 300
$675,984
13
cc. of absolute ethanol, there was ?rst obtained 27 g. of
benzylamino)-2-methylquinoline, MP. 178.4-182.6° C.
S-chloro-l-(Z-chlorobenzyl)-4-(2,4-dichlorobenzylimino)
(corn) when recrystallized from benzene.
l,4-dihydroquinoline hydriodide, M.P. 232—234° C. with
Analysis.—-Calcd. for C17H15ClN2: Cl, 12.54; N, 9.91.
Found: Cl, 12.69;‘N, 9.99.
Following the above procedure but using 22 g. of
4,7-dichloroquinoline, 60 g. of 2,4-dichlorobenzylamine
decomposition. The hydriodide was converted as in Ex
ample 1(B) to S-chloro-1-(2-chlorobenzyl)-4-(2,4-dichlo
robenzylimino)-l,4-dihydroquinoline, M.P. 155-157° C.
The imino base was then converted into the hydrochloride
and no phenol, there was obtained 5.5 g. of 7-chloro-44
salt, M.P. 238.6—246.8° C. (corr.) when recrystallized
(2,4-dichlorobenzylamino)quinoline, M3. 2102-2131)“
twice from isopropyl alcohol and once from methanol.
v C. (corn) when recrystallized twice from ethanol-di
' Analysis-Called.‘ for C23H16Cl4N2.HCl: Cl-, 7.12; N, 10 methylforamide and once from rdirnethylformarnide-water.
5.61. Found: Cl-, 6.93; N, 5.48.
EXAMPLE 41
Analysis.—Calcd. for Clsl-lnClaNzz C, 56.93; H, 3.23;
N, 4.15. Found: C, 56.98; H, 3.21; N, 4.26.
Following the above procedure used for the prepara
7-Cl1l0ro - 1 - (Z-Chlorobenzyl)-4-[2-(4-Methylphenyl)
Etlzyiimirto]-1,4-Dihydroquinoline and Salts
Following the procedure described in Example 1(B)
using 5.4 g. of 7-chloro-1~(2-chlorobenzyl)-4-iodoquino—
tion of 7-chl'oro-4-(4-chlorobenzylamino)quinoline using
15
4-?uorobenzyla-mine, l-naphthylmethylamine, 4-biphenyl
ylmethylamine, 2 - thienylmethylamine, 2 - furylrnethyl
amine, S-chloro-2-pyridylmethylarnine, Z-pyrimidylmeth
linium iodide, 4.1 g. of 2-(4-methylphenyl)ethylamine and
ylamine or 4-(4-chlorophenyl)-butylamine in place of 4
7.5 cc. of ethanol, there was obtained 4.9 g. of 7-chloro—
chlorobenzylamine, there is obtained, respectively, 7
l - (2-chlorobenzyl)-4-[2-(4-methylphenyl)ethylimino1 20 chloro-4-(‘l-?uorobenzylaniino) quinotline, 7qchl=oro—4-( 1
naphthylmethylamino) quinoline, 4- ( 4-biphenylylmethyl
amino) -7-.chloroquinoline, 7-chloro-4- ( Z-thienylrnethyl
1,4-dihydroquinoline hydriodide, which was converted
into 2.7 g. of the corresponding imino base, 7-chloro-1-_
amino)quinoline, 7-chloro-4-(2-furylmethylamino-quinc
(2-chlorobenzyl) - 4 - [2-(4-methylphenyl)ethyliminol
1,4-dihydroquinoline, M.P.~153.8-155.0° C. (corn).
line, '7-ch1oro-4-(5-chloro-Z-pyridylmethylamino)quinc
Analysis.—-Calcd. for C25H22Cl2N2: Cl, 16.83; N, 6.65. 25 line, 7-chloro-4-(Z-pyrimidylmethylamino)quinoline or
Found Cl, 16.78; N, 6.66.’
7-.chlo1‘o-4- [4- ( 4-chlorophenyl) -butyl amino] quinoline.
The irnino base is converted into its corresponding hy
drochloride salt following the procedure described in
Example 1(3).
‘ Other 4-[(lower-aromatic)-(lower~all<yl)arnino]-quin
solines that can be prepared following the above proce
.
dure for the preparation of 7-chlo-ro-4-(4-chlorobenzyl
EXAMPLE 42
30
amin0)quinoline using the appropriate 4-chloro-, 4-bromo
or 4-iodoquinoline and aromatic-alkylamine include: 4
7~Clzl0r0—1-(2-Clzl0r0benzyl) - 4 - (3,4-Metlzylenedioxy
(4-n-butoxybenzylamino)~6,‘7-dichloroquinoline, 3-nitro
benzylimino)-1,4-Dihydr0quin0line and Salts
Following the procedure described in Example 1(B)
using 5.4 g. of 7>chloro-1-(Z-chlorobenzyl)-4-iodoquino=
chloro-4—n-propoxybenzylarnino)-7 - tri?uo-romethylquin
linium iodide, 4.5 g. of 3,4-nethylenedioxybenzyl~
oline, 4 - (4-n-amylaminobenzylamino)-6,8-dimethoxy
4-(4~n-propylsulfonylbenzylarnino) quinoline, 7-chloro-4
(2-niethylrnercaptohenzylamino)~3-nitroquinoline, 4-(2
quinoline, 7-methylmercapto-4-(3-tri?uoromethylbenzyl
amine and 75 cc. of ethanol, there was obtained 5.3
g. of 7-chloro-l-(Z-chlorobenzyl)~4-(3,4~methylenedioxy
benzylimino)-1,4-dihydroquinoline hydriodide, which was
amino)quinoline, 7 - methyl-4-(4-propionylaminobenzyl~
amino)quinoline, and the like.
then converted into 2.5 g. of 7-chloro-1-(Z-chlorobenzyl) 40
4 - (3,4 - methylenedioxybenzylimino) - 1,4 - dihydro
, B. 1 {Ammatic-(Lower-A lkyl) 1-4- [Aromaz‘z'c- (Lower
AIkJ’D-Imz'no] -1,4-Diltydr0quin0lines
quinoline, MP. 124.8—126.2° C. (corn) when recrystal
lized from ethanol.
The preparation of these compounds by reacting a 4
Analysis.—Calcd. for C24H18C12N20'2: C1,
N,
6.41. Found: Cl, 16.11; N, 6.45.
[aromatic-(lower-alkyl)-imino]~quinoline with an aro
45
7-chloro-l-(2~chlorobenzyl) - 4 - (3,4-methylenedi-oxy
matic-(lower-alkyl) ester or" a strong acid designated
above as Ar-Y-An is illustrated by the following prep
benzylirnino)-1,4-dihydroquinoline hydrochloride is ob
aration of 7-chloro-1~(2,4-dich1orobenzyl)-4-(2,4-dichlo
tained by treating a solution of the above imino base in
isopropyl ‘alcohol with a solution of hydrogen chloride
robenzvlimino)-1,4-dihydroquinoliue hydrochloride:
'
, A mixture containing 10‘ g. of 7-chloro-4-(2,4~dichloro
in isopropyl valcohol as in Example 1(B).
50
benzylamino)quinoline, 30 g. of 2,4-dichlorobeuzyl chlo
ride and 200 cc. of acetonit-rile was refluxed with stirring
for about ?fteen hours. The reaction mixture was al
lowed to cool and the precipitate that separated was col
lected and recrystallized from ethanol to give 11 g. (69%
EXAMPLE 43
A. 4 - [(Lower-Aromatic)-(L0wer-Alkyl)Amin0]
Qza'nolz'nes
The preparation of these intermediate compounds is
illustrated by the following synthesis of 7-chloro-4-(4
chlorobenzylamino) quinoline :
A mixture containing 40 g. of 4,7-dichloroquinol-ine, 51
yield) of 7-cl1lo-ro-1-(2,4-dichloro-benzyl)4-(2,4-dichlo
robenzylimino)-l,4-dihydroquinoline hydrochloride, MP.
244.6-247.4° C. (corn).
Analysis.-~Calcd. for C23H15Cl5N2HCl: Cl, 39.96; N,
5.25. Found: Cl, 39.85; N, 5.17.
g. of 4-chlorobenzylamine ‘and 80 g. of phenol was heated
To a cooled solution containing 9 g. of 7—chloro-1-(2,4
60
with stirring at about 120° C. for about ?fteen hours.
The reaction mixture was cooled, treated with 35%
quinoline hydrochloride in 250 cc. of ethanol and 50 cc.
aqueous sodium hydroxide solution until strongly basic,
of Water- was added 25 cc. of 5% aqueous sodium hy
diluted with an equal volume of water and cooled. The
droxide solution. Another 50cc. of water was added and
resulting precipitate was collected and recrystallized from
ethanol to'yield 49 g. (81% yield) of 7-chloro-4-(4 65 the precipitate was collected and recrystallized twice from
dichlorobenzyl)-4-(2,4-dichlorobenzylimino)-l,4-dihydro~
chlorobenzylarnino)quinoline, MP. 185-187" C.
A
sample recrystallized a second time from methanol and
melting at 136.2—188.4° C. (corn) was submitted for
analysis.
Arzalysis.--Calcd. for ClsHlzclzNgz Cl, 23.40; N, 9.25.‘
Found Cl, 23,28; N, 9.26.
Following the above procedure but using 25 g. of 4
chloro-Z-methylquinoline, 35 g. of 4-chlorobenzylamine
benzene to yield 4 g. of 7—chloro-l-(2,4-dichlorobenzyl)—
4—(2,4-dichlorobenzylamino)-1,4-dihydroquinoline, ML’.
167.4~173.2° C. (corr.).
Analysis.-Calcd. for C23H15Cl5N-2: Cl, 35.74; N, 5.63.
70 Found: Cl, 36.09; N, 5.86.
EXAMPLE 44
7-Ch l0r0~1 ~( 4~Ch lorobenzyl ) ~4- (4 -Ch lorobenzylimirzo ) -
1,4-Dihydroquinoline Hydrochloride
and 60 g. of phenol, there was obtained 4-(4-chloro 75
’ Following the procedure described in Example 43 (B)
3,075,934
15
1&5
Z-methyl-1,4-dihydroquinoline hydrochloride as a mono
using 9 g. or" 7-chloro-4-(4-chlorobenzy1amino)quinoline,
hydrate, MJP. 268.0—27l.4° C. (corn) when recrystal
24 g. of 4-chlorobenzyl chloride and 200 cc. of acetoni
trile, there was obtained 9.3 g. of 7-chloro-l-(4-chl0ro
lized from ethanol.
, Analysis.--Calcd. for CZJ-ImCINQl-ICLHZO: Cl“, 8.28;
benzyl)-4-(4-chlorobenzylimino)-1 , 4 - dihydroquinoline
N, 6.58; E20, 4.22. Found: 01-, 8.20; N, 6.58; H2O,
hydrochloride, MP. 264.2-271.2° C. (corn).
4.24.
Analysis.—~Calcd. fQf'C23H17C13N2-HC1I Cl‘, 7.65; N,
1 - benzyl - 4 - (4 - chlorobenzylimino) - 2 - methyl
6.04. Found: Cl“, 7.46; N, 6.03.
l,4-dihydroquinoline in free base form is obtained from
7-chloro-l-(4~chlorobenzyl-4-(4 - chlorobenzylamino)
the hydrochloride by reaction with aqueous sodium hy
1,4-dihydroquinoline in free base form is obtained from
the hydrochloride by reaction with aqueous sodium hy 10 droxide solution following theprocedure described above
in Example 43 (B).
droxide solution following the procedure described above
EXAMPLE 49
in Example 43 (B) .
1 -Benzyl-7-Ch [01'0-4- (4 -Chlor0benzy limino) -l ,4
EXAMPLE 45
7-ChI0ro-1 -(4-ClilOT0b€?Zyl) -4-(2,4
Dichlorobenzylimino) -1 ,4-Dihydroquinoline
Dihydroquiizoline Hydrochloride
15
Following the procedure described in Example 43(8)
Hydrochloride
using 97g. of 7-chloro-4-(4-chlonobenzylamino)quinoline,
Following the procedure described in Example 43(3)
using 4 g. of 7-chloro-4-(2,4-dichlorobenzylamino)quin
22 g. of benzyl chloride and 225 cc. of acetonitrilc, there'
was obtained 9.4 g. of lébenzyl-7-chloro-4-(4-chloro
quinoline hydrochloride, MZP. 2684-2705“ C. (com)
6.50. Found: Cl-, 8.12; ‘N, 6.45.
oline, 9.7 g. of 4-chlorobenzyl chloride and 100 cc. of 20 -benzylimino)-1,4-dihydroquindline hydrochloride, M.P.
274.S-280.6° C. (corn) when recrystallized from ethanol.
acetonitrile, there was obtained 3.7 .g. of 7-chloro-1-(4
Analysis.-—Calcd. 'for C23H18Cl3N2HCl: Cl", 8.25; N,
chlorobenzyl)-4-(2,4-dichlor0benzylimino)11,4 - dihy-dro
when recrystallized ?rom ethanol.
Aualysis.—Calcd. for C23H16Cl4N2HCl: Cl“, 7.12; N,
l - benzyl - 7 - chloro - 4 - (4 - chlorobenzylimino)
25 1,4-dihydroquinoline in free base form is obtained from
the hydrochloride by reaction with aqueous sodium hy
droxide solution following the procedure described above
in Example 43(B).
EXAMPLE 50
5.62. Found: (31-, 7.12; N, 5.70.
7-chloro-1-(4-chlorobenzyl) - 4 - (2,4 - dichlorobenzyl
imino)-1,4-dihydroquinoline in free base .form is obtained
from the hydrochloride by reaction with aqueous sodium
hydroxide solution following the procedure described
30
Following the procedure described inExample 43(B)
using 4 g. of 7-ehloro-4-(2,4-dichlorobenzylamino)quin
EXAMPLE 46
5 -"h lore-1 -(4-Chl0r0benzyl ) -4-(2,4
Dichlorobenzylim i110) -] ,4-Dilzy droquinoline
Hydrochloride
1-Benzyl47-Chlor0-4-(2,4-Dicltloroberzzylimino)-1,4
Dihydroquinoline Hydrochloride
above in Example 43 (B) .
35 ioline, 7.5 g. of benzyl chloride and 100 cc. of acetonitrile,
Following the procedure described in Example 43 (B)
there was obtained 2.3 g. of l-benzyl-7-chloro-4-(2,4~
dichlorobenzylirnino)-1,4~dihydroquinoline hydrochloride,
M.P. 275.2—278.0° C. (corn) when recrystallized from
using 10 g. of S-chloro-4 - (2,4-dichlorobcnzylamino)
ethanol.
quinoline, 24 g. of 4-chlorobenzyl chloride and 225 cc.
Analysis-Ca’lcd. for C23H17C13N2.HC11 Cl“,
N,
40
of acetonitrile, there was obtained 11.4 g. of S-chloro-l
6.04. Found: 01'', 7.30; N, 5.91.
(4-chlorobenzyl)-4-(2,4-dichlorobenzylimino)--1,4 - dihy
1 - benzyl - 7 - chloro - 4 - (2,4 - dichlorobenzylimino)
droquinoline hydrochloride, M.P. 244.6~247.0° C. (corn)
1,4-di-hydroquin-oline in free base form is obtained from
when recrystallized from ethanol.
Analysis.—Calcd. for C23H16Cl4N2HC1: Cl-, 7.12; N,
5.62. Found: Cl~7 6.90; N, 5.45.
5 -cl1loro- l- ( 4-chlorobenzyl) -4- (2,4 - dichlorobenzylimi
no)—l,4-dihydroquinoline in free base ‘form is obtained
from the hydrochloride by reaction with aqucoussodium
‘hydroxide solution following the procedure described
above in Example 43 (B).
EXAMPLE 47
1 ~Bcnzyl-4-Benzylimino-1 ,4-Dihydroquinoline
Hydrochloride
Following the procedure described in Example 43(B)
using 10 g. of 4-benzylaminoquinoline, 27 g. of benzyl
chloride and 225 cc. of acetonitrilc, there was obtained
the hydrochloride by reaction with aqueous sodium hy
droxide solution following the procedure described above
in Example 43(3).
EXAMPLE 51
I-Bcnzyl-S-Chloro-Il- (2,4-Dichl0robenzylimino) -1,4
Dihydroquinoline Hydrochloride
Following the procedure described in Example 43(B)
using 10 g. of 5-chloro-4-(2,4-dichlorobenzylarnino)quin
oline, 19 g. of benzyl chloride and 225 cc. of acetonitrile,
there was obtained 7.9 g. of 1-benzyl-5-chloro-4-(2,4
dichlorobenzylimino)-1,4-dihydroquinoline hydrochloride,
MP. 2344-2426” C. (corn) when recrystallized from
isopropyl alcohol-ethanol.
Analysis.—Calcd. for CZ3H1qCI3N2l-ICI: Cl", 7.65; N,
6.04. Found: Cl“, 7.54; N, 5.89.
12.3 g. of l-benzyl-4-benzylimino-1,4-dihydroquinoline
hydrochloride, MP. 287 .4-293.4° C. (corn) with decom 60 l - benzyl - 5 - chloro - 4 - (2,4 -vdichlorobenzylimino)
1,4-dihydroquino1ine in free base form is obtained from
position.
the hydrochloride by reaction with aqueous sodium hy
Analysis.—-Calcd. for CzgHzoNzl-lcl: Cl”, 9.84; N,
droxide solution following the procedure described above
7.76. Found: Cl: 9.71; N, 7.60.
in Example 43 (B).
1-benzyl-4-benzylimino-l,4-dihydroquinoline in free
EXAMPLE 52
base form is obtained irorn the hydrochloride by reaction
with aqueous sodium hydroxide solution following the
1 -Benzyl-4~(2,4-Diclzl0r0benzylimino)-6-MetIzoxy-1,4
procedure described above in Example 43(3).
EXAMPLE 48
1-Benzyl-4~(Chlorobenzylimino)-2-Metlzyl<1,4
Dilzydroquinoline Hydrochloride
Following the procedure described in Example 43(B)
using 2 g. of 4-(4-chlorobenzylamino)-2-methylquinoline,
Dihydroquinoline Hydrochloride
Following the procedure described in Example 43 (B)
using 10 g. of 4-(2,4-dichlorobenzylamino)-6-methoxy
quinoline, 19 g. of benzyl chloride and 200 cc. of aceto
nitrile, there was obtained 6.8 g. of l-benzyl-4-(2,4-di
chlorobenzylirnino)~6-methoxy-1,4-dihydroquinoline hy
drochloride, MP. 2650-2684“ C. (corn) with decompo
sition when recrystallized from ethanol.
was obtained 2.4 g. of l-‘oenzyl-ll-(4-ch1orobenaylimino) 75
4 g. of benzyl chloride and 50 cc. of acetonitrile, there
3,075,984
17
. 18
Analysis.—-Calcd. for C24H20Cl2N2OHCl: Cl-, 7.72;
7-chloro-4-(Z-thienylmethylamino)quinoline and Z-bro
mobenzyl bromide.
N, 6.08. Found: Cl-, 7.56; N, 6.07.
1 - benzyl - 4 - (2,4 - dichlorobenzylimino) - 6 - me
EXAMPLE 59
thoxy-1,4-dihydroquinoline in free base form is obtained
from the hydrochloride by reaction with aqueous sodium
7-chloro-1-(3-?uorobenzyl)-4 - (2 - furylmethy1iinino)
1,4-dihydroquinoline hydrochloride is obtained following
the procedure described in Example 43(B) using 7-chloro
hydroxide solution following the procedure described
above in Example 43 (B).
4‘-(2-furylmethylamino)quinoline and 3-?uorobenzyl'chlo
EXAMPLE 53
ride.
7-Chloro-1- (3-Chl0robenzyl) -4- (4-Chlor0benzylimino) -
EXAMPLE 60
10
1,4-Dihydroquinoline Hydrochloride
7-chloro-4-(5—chloro - 2 - pyridylmethylimino) - 1 - (2
Following the procedure described in Example 43(B)
using 9 g. of 7-chloro-4-(4~chlorobenzylamino)quinoline,
phenylethyl)-1,4-dihydroquinoline hydrochloride is ob
tained following the procedure descrbied in Example
benzyl) - 4 - (4 - chlorobenzylimino) - 1,4 - dihydroquin
EXAMPLE 61
24 g. of 3-chlorobenzyl chloride and 200 cc. of acetoni
43(B) using 7-chloro-4-(5-chloro-2—pyridylamino)quinor
trile, there was obtained 8.7 g. of 7-chloro—1-(3-chloro— 15 line and 2-phenylethyl chloride.
oline hydrochloride, M.P. 256.6-261.6° C. (corn) when
recrystallized from ethanol.
7-chloro-1-(Z-methylmercaptobenzyl) - 4 - (2 - pyrimi
dylmethylimino)-1,4-dihydroquinoline hydrochloride is
Analysis.—Caled. for C23H1qCl3N2.HCl: Cl, 30.60; N,
6.04. Found: Cl, 30.64; N, 6.04.
20
7 _ chloro - 1 - (3 - chlorobenzyl) - 4 - (4 - chloro
obtained following the procedure described in Example
43(B) using 7-chloro-4-(Z-pyrimidylmethylamino)quino;
line and Z-methylmercaptobenzyl chloride.
benzylimino)-1,4-dihydroquinoline in free base form is
obtained from the hydrochloride by reaction with aque
‘ EXAMPLE 62
ous sodium hydroxide solution following the procedure
l-(4-n-butoxybenzyl)
- 7 - chloro - 4 - [4
25
described above in Example 43 (B).
- (4 - chloro
phenyl)butylimino]-1,4-dihydroquinoline hydriodide is
EXAMPLE s4
obtained following the'procedure described in Example
43 (B) using 7-chloro-4- [4-(4-chlorophenyl) butylamino}
quinoline and 4-n-butoxybenzyl iodide.
7-Chl0ro-4-(4-Chl0robenzylimino) -1- (4-Nitrobenzyl) -
1,4-Dihydroquinoline Hydrochloride
30
Following the proeedure'described in Example 43(B)
using 9 g. of 7-chloro-4-(4-ohlorobenzylamino)quinoline,
5.2 g. of 4-nitrobenzyl chloride and 175 cc. of ethanol,
there was obtained 4.7 g. of 7-chlorro-4-(4-chlorobenzyl
imino) -1- (4-nitrobenzyl ) -1,4-dihydroquinoline hydrochlo
ride,‘ M.P. 276.8-278.4° C. (corn) with decomposition
EXAMPLE 63
4-(4-n-butoxybenzylimino)-6,7-dichloro - 1 - (2 -'naph'
thylmethyl)-1,4-dihydroquinoline hydrobromide is ob‘
tained following the procedure described in Example
35
when recrystallized from ethanol.
43 (B) using
-(4-n-butoxybenzylamino)-6,7-dichloroa
quinoline and Z-naphthylmethyl bromide.
‘
.
EXAMPLE 64
N,Analysis.-Ca.lcd.
8.85. Found: Cl, for
22.45;
C23H11C12N302.HC1I
N, 9.02.
Cl,
1-(4-biphenylylrnethyl-3-nitro - 4(4 - n-propylsulfonyl
benzylimino)-l,4-dihydroquinoline hydrochloride is ob-_
benzyl)-1,4-dihyd=roquinoline in free base form is obtained 40 tained following the procedure described in Example
from the hydrochloride by ‘reaction with aqueous sodium
43(B) using 3 nitro-4-(4-n-propylsulfonylbenzylamino)
hydroxide solution following the procedure described
quinoline, and 4-biphenylylmethyl chloride.
7 - chloro - 4 - (4 - chlorobenzylimino) - 1 - (4 - nitro~
above in Example 43(B).
Other
‘ _
.
.
1~ [ ( lower-aromatic) -(lower-alkyl) ]_-4- [ (lower
EXAMPLE 65
_
v
aromatic)-(lower-a1ky1)irnino]-1,4-dihydroquinolines that
7-chloro-4-(Z-methylmercaptobenzylimino) - 3 - nitro
can be prepared following the above procedure described
‘ 1-(2-thienylmethyl)-1.4-dihydroquinoline hydrochloride is
in Example 43(B) using the appropriate 4-[(lower-aro
obtained following the procedure described in Example
matic) -(-lower-alkyl) amino] quinoline _ and (lower-aro
matic)-(loWer-alkyl) ester of a strong acid include those
43 (B) using 7-chloro-4-(Z-methylmercaptobenzylamino)
compounds given in Examples 55-69, inclusive.
EXAMPLE 55
3-nitroquinoline and Z-thienylmethyl chloride.
50
EXAMPLE 66
4-(2-chloro-4-n-propoxybenzylimino) - 1 - ( 2
-furyl
methyl)-7-tri?uoromethyl-1,4 - dihydroquinolirie hydro~
chloride is obtained following the procedure described in
1-benzyl-7-chloro-4-(4 - ?uorobenzylimino) - 1,4 - dihy}
droquinoline hydrochloride is obtained following the pro
cedure described in Example 43(B) using 7-chloro-4-(4- _55 Example 43(B) using 4-(2-chloro-4-n-propoxybenzyh
amino)-7-tri?uoromethylquinoline and 2 .- furylmethyl
?uorobenzylamino)quinoline and benzyl chloride. __
chloride.
.
EXAMPLE 56
EXAMPLE 67
7-chloro-4~( l-naphthylmethylimino) - 1 - (2,4,6-triiodo
4-(4-n-amylaminobenzylimino)-6,8 - dimethoxy - 1 - {(31
benzyl)-1,4-dihydroquinoline hydriodide is obtained fol 60 pyridylmethyl)-l,4-dihydroquinoline
hydrochloride is ob-v
lowing the procedure described Example 43(B) using
tained following the procedure described in Example
-chloro-4-(l-naphthylmethylamino)quinoline and 2,4,6
triiodobenzyl iodide.
j
I"
43(B) using 4-(4-n-amylaminobenzylamino)-6v,8~dimeth
f
EXAMPLE 57*‘
4-(4-biphenylylmethylimii1o) - 7 - chloro - l - [4 - (2
chlorophenyl)butyl]-1,4-dihydroquinoline hydrochloride
oxyquinoline
. and 3-pyridylmethyl
. EXAMPLE 68
chloride.
7-methylmercapto-l-(2-pyrimidylmethyl) - 4 - (3 - tri
?uoromethylbenzylimino)-1,4 - dihydroquinoline hydro
chloride is obtained following the' procedure described in
is'obtained following the procedure described in Example
43 (B) using 4-(4-biphenylylmethylamino)-7-chloroquino
line and 4-(2-chlorophenyl)butyl chloride.
._ '1 ' I‘: ~
65
.70
EXAMPLE 58
1-(2-bromobcnzyl) - 7 - chloro - 4 - (2 - thienylmethyl
imino)-l,4-dihydroquinoline hydrobromide is obtained
following the procedure described in Example 43 (B) using 75
Example 43(B) using 7-methylmercapto-4-(3-tri?uoro
methylbenzylamino)quinoline and 2 - pyrimidylmethyl
chloride.
EXAMPLE 69
1-(2,4-dibromobenzyl)-7 - methyl - 4 4 (4 - propionyl
arninobenzylimino)-1,4-dihydroquinoline hydrobromide is
3,075,9'254.
l9
20
.
'
4. 7 - chloro '- 1 ‘- (2 - chloroben'zyl) - 4 - ('4 - chloro -
oh'tained following the procedure described in Example
benzylimino) -1,4-dihydroquinoli_ne.
43 (B) using 7-methyl-4-(4-propionylamiiiobenzylamino) ~
benzylimino)-1,4-dihydroquinoline hydrochloride.
The, compounds of Examples 55-69,. inclusive, can be
converted into their free base form by ‘reaction with an
acid-acceptor according to the procedure given in Exam
ple 1(B) for the conversion of 1-benzy1-7-chloro-4-(3;
b'enZylimino)-l,4-dihydroquinoline hydrochloride.
7. 1 - benzyl - 7 - chloro - 4 - '(3 - chlorobenzylimino) '
l,4-dihydroquinoline hydrochloride.
8. i - benzyl - 7 - chloro - 4 - (4 ~ chlorobenzylimino)
1,4-dihydroquinoline hydrochloride.
chlorobenzylimino)-1,4-dihydroquinoline hydrochloride
droquinoline by reaction with aqueous sodium hydroxide
9.
‘I Chemotherapeutic evaluation of the I-KlOW'er-aromat
_ic)-(lower-alkyl)]-4-[(lower-aromatic) - (lower - alkyl)
imino]-l,4-dihydroquinolines rand acid-addition salts of
imino)-l,4-dihydroquinoline hydrochloride.
the foregoing examples has demonstrated that they are use
ful as anthelmintic agents. When administered orally to
imino)'-1,4-dihydroquinoline hydrochloride.
.M
..
.
.
,.
,
10. l - benzyl - 7 - chloro - 4 - (2,4 - dichlorobenzyl -
11. 1 - benzyl - 7 - chloro - 4 - (3,4 - dichlor'obenzyl -
,
12. A process for the preparation of the acid-addition
Swiss mice infected with the tapeworm Hymenolepis narm,
the compounds completely cured the animals of the infec
tion at dosage levels as low as>25 mg. per kg. of body
weight per day.v Some of the compounds, for instance, 1
vhenzyl-4~benzylirnino-f7-chloro;1,4 - dihydroquinoline hy
salt of the l - [(lower - aromatic) - (lower - alkyl)] ¢ 4 [(lower - aromatic) - (lower - aikyl?mino] - 1,4 - dihy -
droquinoline having the structural formula
drochloride, 1-benzyl-7-chloro-4-(3-chlorobenzylimino)
1,4-dihydroquinoline hydrochloride, l-benzyl-7-chloro-4
HAD.
lFT'—Y’-Ar'
(4.-chlorobenzylimino)-1,14 - dihydr'oqninoline hydrochlo
ride, l-benzyl-7-chloro-4-‘(3,4-dichlorobenzylimi'no)-1,4;
dihydroquinoline hydrochloride, 7-chloro-1-(3-chloroben
Q.
zyl) ‘-4-(4;chlorobenzy1imino) - 1,4 - dihydroquinoline hy
R
drochloride and 7-chloro-1-(4—chlorobenzyl) -4-(4-chloro
N
benzylimino)-1,4-dihydroquinoline hydrochloride, have
EDso values below ‘about 10 mg. per kg. per day, ED50
meaning the effective dose necessary to clear 50% of the
Swiss mice of the tapeworm infection.
-
l - benzyl - 4 - benzylimino - 7 - chloro - 1,4 - di -
hydroquinoline hydrochloride.
7
I
6. 7 -_chloro - 1, - (4 - chlorobenzyl) - 4 - (4 - chloro ~
into 1-benzyl-7-chloro-4-(3-chlorobenzylimino)-1,4-dihy
Solution“
_
>5. 7 - chloro - 1 - (3 - chlorobenzyl) - 4 - (4 - chloro -
quinoline and 2,4-dibromobenzyl bromide.‘
Y-Ar
30
where Q is selected from the group consisting of hydro
_
gen and from one to two substituents at positions 3,. 5,
My iiew 1‘-[(lower-aromatic)-(lower-alkyl)]-4-[(low
6, 7 and 8 of the quinoline nucleus selected from the
er-arom'atic)-(lower;alkyl)imino] -l,4 - dihydroquinolines
and acid-addition salts ‘can be prepared for use by incoré
porating them in syruprtablet', or capsule form for oral
consisting of halo, 'lower-alkoxy, lower-alkylmen
as group
capto, lower-alkyl, nitro and trifluoromethyl, Y and Y’
administration. They can be formulated in the same man
ner as known compounds having anthelmintic properties
such as phenothiazine, piperazine citrate, and the like.
radicals selected from the group consisting of phenyl,
I
claim:
,
_
v
,
are each lower-alkylene, Ar and Ar’ are each aromatic
naphthyl, biphenylyl, thienyl, furyl, pyridyl and pyrimidyl,
40 R is a member selected from the group consisting of
I
hydrogen, and lower-alkyl, and An is an anion of a
1. A compositionrof matter 2selected from the group
strong acid, which comprises reactingthe corresponding
consisting of: (a) the 1 '- [(lower ‘- aromatic) - (lower -
4 - [(lower - aromatic) - (lower - alkyl) amino] - 'quino +
a1ky1)] - 4 - [(lower _-> aromatic) - (lower - a1kyl)irnino] -
line having the formula
l,4_-dihydroquinoline having the structural formula
so
N
4'—-Atr
where Q,VY’, Ar’ and R have the meanings already desig
riated, with an ester having the formula Ar—-Y;-An.
13. A-process for the preparation of the acid-addition
where Q is vis'elr'ected from the ‘group consisting of hydro
genan'd from one to two substituents at positions 3, 5',
6', 7 and 8 of the quinoline nucleus selected from ‘the
salt of ‘the -l "- ar‘ylrnethyl - 4 - arylmethylirnino '- 7 - halo -
group consisting of halo, lowerlalkoxy, lower-al-kylme'r
1,4-dihydroquinoline having ‘the structural formula
capto, lower-alkyl, nitro and tri?uoromethyl, Y and Y’
are each lower-alkylene, Ar ‘and ‘Ar’ are each aromatic
radicals. selected from, the, group consistingof phenyl,
‘jr'rhphthyl, biphenylyl, thienyl,,'furyl, pyridyl and pyrimidyl,
and R is a member selected from the groupv consisting
60
‘gr droge'n and lower-alkyl', and, (b) acid-‘addition salts
thereof.
A.
.
,
.
.
-
~
2. The l - ary “Methyl - '4 - arylmethylimino - 7 - halo -
1,4-dil'1ydroquino1ine5haviing the structural formula
N
éJHiAr
N-CHiAr’
where ‘Q is halo,
and Ar’ are each, mondcarbncyeiie
and having si'x ring-carbon atoms and An is an anion
of a strong acid, which comprises reacting the ‘corre
sponding 4-arylmethyla'mino-7ahaloquinoline with an
hum
whereiQyis halo, and
cyclicaryl having
and Ar’ ‘are each monocarbo
ring-carbon “atoms.
,
_,
i i x
‘ '. The acid'iaddition salt of the'cornpound'of ‘claim 2.
ester having the formula ArCHr-An.
14. A process for me preparation of the hydrohalide
of the 1 - '[ (lower ; aromatic) '_- (‘lower - ‘alky1)] "- 4 "
~[‘(lower - aromatic) '- (lower “- ‘alkyl)imin'0] "- 1,4 ’- ‘dihy "
3,07 5,984
21
22
droquinoline which in free base form has the structural
formula
where Q is halo, An is a halide ion, and Ar and Ar’
are each monocarbocyclic-aryl having six ring-carbon
atoms, which comprises reacting the corresponding 1
arylrnethyl—4,7-dihaloquinolinium halide with an aryl~
methylamine having the formula Ar’—CH2NH2.
16. A process for the preparation of the 1-[(lower
aromatic) - (lower - alkyl)] - 4 - [(lower - aromatic) -
(lower ~ alkyl)imino] - 1,4 - dihydroquinoline having the
structural formula
10
where Q is selected from the group consisting of hydro
gen and from one to two substituents at positions 3, 5,
6, 7 and 8 of the quinoline nucleus selected from the
group consisting of halo, lower-al-koxy, lower-alkylmer
capto, lower-alkyl, nitro and tri?uoromethyl, Y and Y’ 15
are each lower-alkylene, Ar and Ar’ are each aromatic
radicals selected from the group consisting of phenyl,
naphthyl, biphenylyl, thienyl, furyl, pyridyl and pyrimidyl,
and R is a member selected from the group consisting
of hydrogen and lower-alkyl, which comprises reacting
where Q is selected from the group consisting of hydro~
20 gen and from one to two substituents at positions 3, 5,
6, 7 and 8 of the quinoline nucleus selected from the
a 4-haloquinolinium halide having the ‘formula
group consisting of halo, lower-alkoxy, lower-alkylmer
capto, lower-alkyl, nitro and tri?uoromethyl, Y and Y’
Hal
are each lower-alkylene, Ar and Ar’ are each aromatic
25 radicals selected ‘from the group consisting of phenyl,
naphthyl, biphenylyl, thienyl, furyl, pyridyl and pyrimidyl
and R is a member selected from the group consisting
of hydrogen and lower-alkyl, which comprises reacting
\N/ R
Ar-Y
An
the corresponding acid-addition salt with an acid-ac
30 ceptor.
where Q, R, Y and Ar have the meanings already given,
References Cited in the ?le of this patent
UNITED STATES PATENTS
Hal is a member selected from the group consisting of
chloro, bromo and iodo, and An is a halide ion, with
a (lower-aromatic)-(lower-alkyl)-amine having the for 35
mula Ar'— '—-NH2.
15. A process for the preparation of the l-arylmethyl
4-arylmethylimino-1,4-dihydroquinoline hydrohalide hav~
ing the structural formula
HAn
40
2,419,199
2,526,417
2,554,737
2,940,974
B-urckhalter et a1. _____ __ Apr.
Reitsema _____________ __ Oct.
Hae?iger et a1 ________ _.. May
Surrey ______________ __ June
22,
17,
29,
14,
1947
1950
1951
1960
OTHER REFERENCES
Ochiari: Chem. Abstracts, p. 6637, vol. 45 (1951).
QNI
Elder?eld: Heterocyclic Compounds, vol. 4, pages 1675
168, John Wiley and Sons, 1952.
Gopalchari: Chem. Abstracts, vol. 49, p. 3967 (1955).
Schock: Journal Amer. Chem. Soc., pp. 1670-72
(1957), vol. 79.
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent No. 3,075,984
,
January 29, 1963
Alexander R. Surrey
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 1, lines 15 and 16, for “'—aromatic)—lower—" read
—— —aromatic)—(lower— ——; column 2, line 17, after "biphenylyl"
insert a comma; column 4, lines 47 and 48, for "—aromati'c)—
l'0wer—" read —— —aromatic)—(lower— ——; column 6, line 75, for
"4,7—diido—l—" read —— 4,7-diiodo-l- ——; column 10, line 32,
for ‘"hydriode" read —— hydriodide ——; line 54, for "—(2methyl—"
read —— —(2-methyl— ——; column 11, line 25, for "hydrioxide"
read —— hydroxide ——; line 46, for "hydriode" read —— hydriodide
——; column 14, line 10, for "methylforamide" read —— methylfor
mamide ——; line 23, for "—(2-furylmethylamino—quino—" read
-— -(2—furylmethylamino) quino- ——; line 67, for "—(2,4—dichlo—
robenzylamino)—" read —— —(2,4-dichlorohenzylimino)— ——;
column 15, line 8, for "-(4-chlorobenzyl—4—(4—chlorobenzylamino)~"
read —— -(4—chlorobenzyl)—4—(4—chlorobenzylimin0)— ——;
line
69, for "-(Chlorobenzylimino)—", in italics, read -—— ~(4-Chloro
benzy1imino)— —-, in italics; column 21, lines 3 to 9, the
formula should appear as shown below instead of as in the
patent:
N
LAI
Signed and sealed this 19th day of November 1963.
(SEAL)
Attest:
_
_
EDWIN L, REYNOLDS
Acting Commissioner
ERNEST W. SWIDER
Attesting Officer
'
of Patents
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