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Патент USA US3022311

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3,022,308
i ; lyric‘
‘Patented Feb. 20, 1962
1
2
hygroscopic than those containing the decahydroisoquino
3 022 308
.
linium group.
DECAHYDROBENZOI’WR’IDINE QUATERNARIES
'
.
The compounds of the present invention have been
evaluated by standard pharmacological testing procedures
and demonstrated to produce hypotensive activity in liv~
Chester John Cavallito and Allan Poe Gray, Decatur,
111., assignors to Irwin, Neisler and Co., Decatur, Ill,
a corporation of Illinois
ing animals. This hypotensive activity is not related to the
No Drawing. Filed Dec. 3, 1957, Ser. No. 700,280
7 Claims. (Cl. 260—286)
peripheral ganglionic blocking activity of the compounds
and, as a result, this provides the advantage of eliminat
This invention relates to unsymmetrical bis-(quaternary
ing many of the undesirable side reactions associated withv
the use of hypotensive agents which depend upon such
ammonium)-subs‘tituted alkane salts, . and is more par
ticularly concerned with such compounds wherein the two
ganglionic blockade for their hypotensive eifect. As can
‘quaternary ammonium nitrogens are separated by 2 to 4
be seen from the representative pharmacological data
presented infra the compounds of the present invention
carbon atoms, inclusive, of the alkane portion of the
are of relatively low order toxicity, high potency hypo<
molecule, wherein the smaller quaternary ammonium
group contains up to six carbon atoms and up to one-N-‘ 15 tensive activity with low order ganglionic blocking action
heteromonocyclic group, and wherein the larger quater
as compared with hypotensive activity. The compounds
nary ammonium group is a N-lower-alkyldecahydrobenzo
pyridinium radical. It is the concept of a composition
of the present invention may be administered to- the ani
' mal organism orally, intravenously, intramuscularly, sub
cutaneously, ‘and intracutaneously in solid form as in a
of matter having a molecular structure wherein this par
ticular larger quaternary ammonium group is separated 20 tablet or in liquid form in water or with any of‘the usual
by 2-4 carbons from the smaller quaternary ammonium
group that is the speci?c inventive feature.
The compounds of the present invention can be made
The, N - lower-alkyldecahydrobenzopyridinium radical ‘
by the reaction of a suitable haloalkyl quaternary’ am
‘includes N - lower-alkyldecahydroquinolinium and N
monium halide (that which corresponds to all of the, de
lower-alkyldecahydroisoquinolinium structures wherein 25 sired end molecule save the larger quaternary ammonium
the lower-alkyl substituent contains up to about four car
,moiety) with the appropriate N-lower-alklydecahydro
bons.
'
'
*
j
benzopyridine- The reaction is carried out in- a suitable
The smaller quaternary ammonium radical includes tri
solvent'such as acetonitrile, dimethylformamide, alcohol,
methylammonium, N-methylpiperidinium, N-methylmor
,dioxane-alcohol mixtures, et cetera. Reaction v'is pref
pholinium, N - methylpyrrolidinium, dimethylethylam
erably carried out at re?ux temperatures over prolonged
premium and diethylmethylammonium with trimethylam
time periods (1/2—4 days). Some of the starting omega
haloalkyl quaternary ammonium halides are reported in
monium and N-methylpyrrolidinium as preferred struc
tures.
'
'J.A.(‘3.S. -77, 3648, (1955) and a type process whereby
The two quaternary ammonium nitrogens may be' sep- ' such class of intermediates can be prepared,_for_ their
arated by 2-4 carbon atoms of the alkane, with separa» 35 preparation is described in our copending application
tion by 2, or 3 carbons being preferred. , The alkane
Serial 406,053 ?led January 25, 1954; which issued De
excipients.
chain can be branched chain or straight chain and can
contain up to about six carbon atoms. The quaternary
ammonium nitrogens may be attached at the ends of the
alkane chain or in any portion therein so long as they,
are separated from each other by the proper number of
carbon atoms. Those compounds within the scope of
the present invention which are alpha, omega-bis-(quater
I
'
'
i
cember 24, 1957 as“U.S. Patent 2,817,664.
' '
»
,
The use of a cis— ‘or a trans-decahydrobenzopyridine
40
starting base will yield a bis-quaternary ammonium salt
product with,lrespectively, a cis- or a trans-fused deca
J hydrobenzopyridine nucleus.
N-alkyl-cis-decahydroquin
olines (for example) react more rapidly than do the cor
responding trans-isomers, but if the quaternization of a
cis-trans mixture of isomeric decahydroquinolines is car
nary ammonium)-substituted alkane salts are a preferred
45 ried essentially to completion the product will likewise
class.
The two anions can be any of the pharmaceutically ac
be a mixture of isomers. ‘ If, however, two equivalents
ceptable anions, and may be the same or different.
Thus, the compounds of the present invention may be
described as bis-(quaternary-ammonium)-substituted al
kane salts, wherein the two quaternary nitrogen atoms
are separated by from 2 to 4 carbon atoms, inclusive, of
the alkane portion of the molecule; wherein one quater
nary ammonium group contains up to 6 carbon atoms, -
inclusive, and up to one N-teteromonocyclic group; where
in the other quaternary ammonium group is a N-lower
of a cis-trans mixture of the secondary decahydroquino
line bases are alkylated with one equivalent of an alkyl
halide, there is' obtained one equivalent each of trans
decahydroquinoline hydrohalide and of an N-alkyl-cis
decahydroquinoline. The latter will then yield a bis
quaternary ammonium salt product with a cis-fused deca
hydroquinoline nucleus.
’
V
I
>
Another method of preparingthe compounds of the
55 present invention which sometimes may be used is to bis
alkyldecahydrobenzopyridine radical and, wherein the
quaternize the free diamine base corresponding to the
anions are non-toxic acid residues.
desired end molecule.
The compounds of the present invention are generally
'
solids, which can exist in the cis or trans form or as
The following examples will more particularly illustrate
the compounds of the present invention and the pro
mixtures thereof and any and all forms of the compound
are intended when not otherwise speci?ed. The isom
be construed aslimiting.
erism is in the juncture of the two rings of the decahydro
benzopyridine system. Those compounds ‘which contain
"the decahydroquinolinium structure‘ ‘are generall-ymore =
cedures whereby they may be prepared, but are not to
.
I
Example 1
.
>
.
- An acetonitrile solution of 5.4 grams (0.035 mole) of
8,022,308
3
4
anol-ethyl acetate, yielding 9 grams ('72 percent of theory)
.1-methyldecahydroquinoline (cis-trans mixture) and 9.1
grams (0.035 mole) of 3-bromopropyltrimethylammo
of ethylene - 1 - (1-methyldecahydroquinolinium)-2-(tri- .
methylammonium) dibromide as a hygroscopic solid,
nium bromide was refluxed on the steamhath for 15 hours.
The cooled solution was diluted with ether to yield 12.8
melting at 142 degrees centigrade With decomposition.
Analysis-Calculated: C, 45.00; H, 8.06; Br, 39.93.
Found: C, 44.75; H, 7.78; Br, 39.91.
grams (88 percent of theory) of trimethylene-l-(l-methyl
decahydroquinolinium)-3 - (trimethylammonium) dibro
mide as a ‘hygroscopic solid, melting with gas evolution
Example 6
A
soluble
of
10.0
grams
(0.06 mole) of 2umethyldeca
Analysis.—-Calculated: C, 46.38; H, 8.29; Br, 38.58.
hydroisoquinoline
and
17.0
grams (0.06 mole) of 3
10
Found: C, 46.11; H, 8.10; Br, 38.15.
'
bromopropyltrimethylammonium bromide in 50 milliliters
at 108-110 degrees ccntigrade.
_
Example 2
of acetonitrile was re?uxed on the steam-bath for 7
hours. The precipitate, which formed on cooling, was
A-s'olution of 8:0‘gr'ams (0.05 mole) of Lmethyl-trans
decahydroquinoline and 13.6 grams (0.05 mole) of 3
recrystallized from isopropyl alcohol to give 15.5 grams
brornopropyltrimethyl-ammonium bromide in isopropyl 15 (57 vpercent yield) of trimethylene-1-(2-methyldecahydro
alcohol was re?uxed on the steam-bath for 24 hours.
isoquinolinium) - 3 - (tri-methylammonium)dibromide as
vAddition of ether to ‘the cooled ‘solution precipitated an
colorless crystals, melting vat 228-230 degrees centigrade.
oil which was'diss'olved in ethanol and reprecipitated with
Analysis-Calculated: C, 46.40; H, 8.27; Br, 38.58.
ether. ‘Drying the oil over P205 in ‘vacuo afforded 11.0
Found: C, 45.72; H, 8.58; Br, 38.65.
‘grams (51 percent of the theoretical yield) ‘of trimethyl 20
‘Example 7
ene-1-( l-methyl-tran's - decahydr'oquinolinium)-‘3 - (tri
Following the general procedure described in Example
methylarnmonium) dibrornide as an extremely hygro
scopic solid, melting from 130 to 136 degrees centigrade.
Analysis-,Calculated: C, 46.38; H, 8.29; Br, 38.58.
‘Found: c, 45.56; H, 3.27; Br, 38.33.
_
6, Z-methyldecahydroisoquinoline was reacted with 3
bromopropyl-l-methylpyrrolidinium bromide to a?ord
colorless crystals of trimethylene-l-(Z-methyldecahydro
-
‘Example 3
isoquinolinium) - 3 - (l-methylpyrrolidinium) dibromide,
melting‘ point 218-220 degrees centigrade, after several
Following the procedure of Example 2, l-ethyldecahy
recrystallizations from isopropyl alcohol.
droquinoline (from -a mixture of cis and trans-decahy
7
‘ Analysis---~Calculated: C, 49.09; H, 8.24; Br, 36.30.
droquinoline) was reacted with 3-bromopropyltrimethyl- ~
ammonium bromide to yield 65 percent of the theoretical 30 Found: C, 49.45; H, 8.64; Br, 36.22.
From the isopropyl alcohol mother liquors there was
obtained a smaller amount of crystalline material, which
methylammonium) dibromide, an extremely hygroscopic
melted at 196-499 degrees centigrade ‘after recrystalli
material. It is'probable that the product is almost en—
zation from isopropyl alcohol and was apparently "a
, Analysis.—-Calculated: Br, 37.32. Found: Br, 37.23.
of trimethy_lene-1-( 1-ethyldecahydroquinolinium) ~3-(tri
tirely derivedlfrom cis-decahydroquinoline.
stereoisomeric trimethylene-1-(2-methyldectahydroisoquin
35
olinium) -3-( l-methylpyrrolidinium) dibromide.
Analysis.—Calculated: C, 49.09; H, 8.24; Br, 36.30.
Found: C, 49.32; H,"8.2.9; Br, 36.48.
Example 4
Essentially as described in Example 1, reaction of >1
methyl-trans-decahydroquinoline with 3-bromopropyl-N
Example 8
methylpyrrolidinium bromide a?orded 52 percent of the 40
theoretical ‘yield of trimethylene-'1‘-‘( l-methyl-tr'ans-deca
hydroquinoliniu'm) -3-( lémethylpyrrolidinium) dibromide
Following‘ the procedure of Example 1, l-butyldecahy
vdroquinoline (cis-trans mixture) was reacted with 4
‘chlorobutyltrimethyl-ammonium chloride to produce tet
‘as a hygroscopic ‘solid melting at 87-88 degrees centi
"grade.
"ramethylehe-l-(1-burtyldeoahydroquinolinium) '- 4 ~ (tri
A?alysis.-‘—éCalculated: c, 49.09; H, 3.24; Br, 36.30.
Found: 0, 43.50; a, 8.08; Br, 3572. ,
45
Example 5
methylamrnonium) dichloride as a hygroscopic solid.
Example 9
Following the‘ procedure of Example ‘2,, l-ethyl-trans
A. To 30 grams (0.22'mole) of decahydroquinoline
(c-is-trans mixture) was added, dropwise with stirring,
‘decahydroquinoline was reacted with 3-iodopropyldiethyl
vmethylamrnonium iodide to produce trimethylene-l-(‘l
a solution of_11."6 grams (0.11 mole) of ‘dimethylamino
50 ethyl-trams-decahydroquinolinium) - 3-(diethylmethylam
ethyl chloride in 75 milliliters of benzene. The reaction
mixture was re?uxed on the steam-bath for 80 hours.
moniurn) diiodide as an extremely hygroscopic solid.
Filtering off the precipitate of decahydroquinoline hy
drochloride land distilling the residue yielded 9.0 ‘grams
(40 percent of theory) of 1-(dimethylaminoethyl)-dec
ahyd'roquinoline, boiling'point 104—106 degrees centigrade
Example 10
Following the procedure of Example l,‘1-propyldecahy
55 droquinoline was reacted with 3-bromopropyl-N-methyl
morpholinium bromide to product trimethylene - 1-(1
propyldecahydroquinolinium)43 - (methylmorpholinium)
dibromide ‘as a hygroscopic solid.
‘at 1.5 millimeters, r1925 1.4862. ‘Since the decahydroquin
oline’hyd'rochloride obtained was‘shown to be almost pure
trans '(melting'point of the base), it is probable that
"the product "is essentially derived from cis-decahydroquin—
Example 1 1
60
oline.
Following the'procedure of Example 7, Z-methyldec
chloride, prepared by the addition of etherealihydrogen
ahydroisoquin‘oline was reacted vwith '4-chlo'rohutyltri
'methylammonium chloride ‘to produce tetramethylene-l
chloride to an ether solution of the base and recrystallized
(2-methyldecahydroisoquinolinium) - 4 - (trimethylam
1-(dimethylaminoethyl)-decahydroquinoline dihydro
‘from ethanol, melted ‘at ‘272 degrees centigrade with de 65 moniu'm) dichloride.
composition.
_
.
.
"Example 12
_
Analysis-Calculated: C, 55.10; H, 9.96; Cl, 25.03.
Found: c, 55.24; H, 10.21; or, 24.48.
_ Following the procedure of Example ‘3, 2-‘ethyldecahy
B. ‘Into a methanol solution of 6.5 grams (0.03 mole) 70 droisoquinoline was reacted with 3-bromopropyltrimethyl
ammonium bromide to produce trimethylene-1-(2-ethyl
of l-(dimethylaminoethyl)fdecahydroquinoline was intro
duced ‘8.8 grams (0.09 mole) of methyl bromide. After
being heated in a pressure bottle‘at 75 degrees centigrade
for 24 hours, the cooled'solution was diluted with ethyl
acetate. The precipitated oil was crystallized from eth 75
decahydroisoquinolinium)~3 - (trirnethylarnmonium) di
h'romide.
_
.
V.
Example 13
7
Following the procedure of Example 7, 2-ethyldecahy
3,022,308
E
a
droisoquinoline was reacted with 2-br'omoe‘thylriiethyl
pyrrolidinium bromide to produce ethylene-‘1-2(-ethyl
II. Hypo'tensive ‘activity: Effects on the blood pressure‘
of anesthetized dogs:
decahydroisoquinolinium - 2 - (methylpyrrolidinium) di
bromide.
Compound of Example
Example 14
LV. dose,
mgjkg.
Percent Duration ,
13.1’. fall hours
Following the procedure of Example 7, 2-butyldecahy
1 _________________________________ __
droisoquinoline was reacted with B-bromopropyl-N-meth
ylmorpholinium bromide to produce trimethylene-l
(2 - butyldecahydroisoquinolinium) - 3 - (methylmorphm
linium) dibromide.
.
0.025
2 _________________________________ __
Essentially as described in our paper J. Am. Chem. Soc.,
__________________ __
"
0.1
15
5 _________________________________ __
0.1
6 _________________________________ _-
0.01
20
7 (high-melting material) ......... ..
0.01
0. 025
7 (low melting material) __________ _.
>4
>4
60
>4
20
35
65
0. 25
1.0
>1. 0
0.6
2
>3
__________________ __
5 ........ __
0. 5
0.1
1~(4-bromo-2 - pentyl) - l - methylpyrrolidinium bromide.
50
60
__________________ __
0.05
0.1
In a similar manner to Example 15, N-methylpyrroli
dine was reacted with 2,4-dibromopentane to provide
>2
>2
10
30'
50
0.025
0.05
0.1
methylene-1 - (1 - methyldecahydroquinolinium) - 3 - (tri
>4
__________________ __
0. 25
0. 5
1. 0
hydroquinoline (cis-trans mixture) to yield Z-ethyltri
45
60
50
__________________ __
0.01
0. 05
cedure of Example 1, this was reacted with 1—methyldeca
45
65-70
'
>2
>3
40
>3
55-60
>3
III. Sympathetic ganglionic blockade on anesthetized
cats by superior cervical ganglion-nictitating membrane
preparation-—electrical stimulation:
Then, following the procedure of Example 7, this was
reacted with 2-methyldecahydroisoquinoline to yield
1,3-dimethyltrimethylene-l - (Z-methyldecahydroisoquino
linium)-3-(l-methylpyrrolidinium) dibromide.
Example 17
Compound of
Example
LV. dose,
mgJkg.
Degree of block (0—4~|where 4+ is complete
Duration,
hours
blockade)
In a similar manner to Example 15, trimethylamine
was reacted with 1,4-dibromo~2-methylpehtane to provide
1 ___________________ _.
4-bromo-2-methyl-l-pentyltrimethylammonium 'bromide.
Then, following the procedure of Example 6, this was
reacted with Z-methyldecahydroisoquinoline to yield 1,3
0. 05
__________ _ _
0. 1
0.25
0. 4
1. 0
>1. 0
0. 5
v0. 125
-dimethyltetramethylene - 1 - (Z-methyldecahydroisoquinm
linium)~4-(trimethylammonium) dibromide.
Example 18
Two equivalents of decahydroquinoliue (cis-trans mix
. >1.5
0.005
77, 3648 (1955), trimethylamine was reacted with l-bro
methyl-ammonium) dibromide.
Example 16
>1. 0
55
0. 0250. 05
0.1
0. 5
4 _________________________________ -_
0. 25
30
0.1
0.01
10
‘Example 15
mo-2-bromornethylbutane to provide Z-bromomethylbutyl
trimethylammonium bromide. Then, following the pro
, 10
0. 05
__________ _ _
0.25
0.75
0.05
0.1
0
0.75
0.25
4-0
5 ___________________ ._
1.0
0.5
_________ _.
0.25
_________ __
0. 5
0.75
1.0
ture) was reacted with 1 equivalent of 1,3-dichloro—
butane in benzene solution, in a manner similar to that
>2
IV. Effect on the pupils of unanesthetized male cats:
described in Example 5A, to provide 1-(3-chlorobutyl)
cis-decahydroquinoline. This, reacted with pyrrolidine in
essentially the same manner, yielded l-(3-pyrrolidino»
Compound LP. dose
of Example rug/kg.
Pupil Dilation
Reaction to Light
butyl)-cis-decahydroquinoline, which was then treated
with excess methyl iodide to yield l-methyltrimethylene
4 _________ __
pyrrolidinium) diiodide.
Example 19
0.05
None ______ __
01
3 - ( l - methyl-cis-decahydroquinolinium) - 1 - (l-methyl
0.15
Complete.
Complete _. None (duration about 2 hours).
___..do _____ __
None.
50
V. Effect when the compound of Example 4 was ad
ministered intravenously to an unaesthetized male monkey
‘In a completely analogous manner to Example 18,
in a dosage of 0.75 milligrams per kilogram of body
piperidine was reacted with 2,3-dichlorobutane to provide
weight was: No immediate etfects. The animal became
l-(3-chloro-2-butyl)-pipetridine. Reaction of this with
somewhat quieter and there was possibly some dilation of
decahydroisoquinoline yielded 2-(3-piperidino-2-butyl)
the pupils. The monkey showed no evidence of dry
decahydroisoquinoline, which was then treated with excess
mouth or postural hypotension.
methyl iodide thereby affording 1,2-dimethylethylene~l
Various modi?cations which will be obvious to those
(Z-methyldecahydroisoquinolinium) - 2 - (l-methylpiper
skilled in the art may be made in the present invention
60
idinium) diiodide.
without departing from the spirit or scope thereof, and
The following illustrates typical pharmacological test
it is to be understood that we intend to limit ourselves
results obtained for the compounds of the present inven
only by the scope of the appended claims.
tion:
We claim:
I. Acute toxicity (LD50) by intravenous injection in
mice—-dosage in terms of milligrams per kilogram of body
weight:
wherein one quaternary ammonium group is selected
Compound of Example:
I.V. toxicity
1
__
2
__
4
_
5
1. Bis - (quaternary ammonium) - substituted alkane
salts; wherein the alkane portion is selected from the
group consisting of alkanes having 2-6 carbon atoms;
67.5
73.5
63.0
from the group consisting of trimethylammonium, di
70 methylethylarnmonium,
methylpiperidinium,
diethylmethylammonium,
N-methylmorpholinium and
N
N
methylpyrrolidinium; wherein the other quaternary am
31.5
monium group is N-lower-alkyldecahydrobenzopyridin
7 (high melting) _______________________ __ 60.5
7 (low melting) _______________________ __ 62.0
ium; wherein the two quaternary nitrogen atoms are sep
75 arated by from 2 to 4 carbon atoms, inclusive, of the
3,022,308
7
8
alkane poytion of the, molecule; andrwherein the two
7. Trirnvethylene - 1 - (2 - methyldeeahyroisoquinof
1inium)-3-‘(1-n1ethy1pyrro1ic1inium) dibromide.
anions are each non-toxic acid residues.
2. Trimethylene- 1, - (1 - methyidecahydroquinohni
References Cited in the ?le of this patent
UNITED STATES PATENTS
um)-3-(trimethylammonium) dihromide.
3. Trimethylene - 1 - (1 - methyl - trans - decahydi'o
quinoliniun1)—3 ~ ( trimethy] ammonium) dibromide.
2,834,779
4.. Trimethylene - 1 - (1 - methy1- trans - decahydro
FOREIGN PATENTS
quinoliniurn) -3-( 1-methy1pyn'olidinium) dibromide.
5. Ethylene - 1 (1 - methyldec'ahydroquinolinum) - 2
(trimethylammcnium) dibromidc.
6. Trimethylene - 1 - (2 - methyldecahydroisoquino
linium)-3-(trimethyiamrnoniurn) dibromide.
'
Biel et a1 _____________ __ May 13, 1959
1,108,117
10
France ______________ __ Aug. 24, 1955
OTHER REFERENCES
Rice: J.A_C.S., vol. 75 (page 4911) (1953).
Gray et' 31.: J.A.C.S., v01. 77 (1955) p. 3536.
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